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TW201245116A - Tetracycline analogs - Google Patents

Tetracycline analogs Download PDF

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Publication number
TW201245116A
TW201245116A TW100128656A TW100128656A TW201245116A TW 201245116 A TW201245116 A TW 201245116A TW 100128656 A TW100128656 A TW 100128656A TW 100128656 A TW100128656 A TW 100128656A TW 201245116 A TW201245116 A TW 201245116A
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TW
Taiwan
Prior art keywords
infection
group
alkyl
pharmaceutical composition
etoac
Prior art date
Application number
TW100128656A
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Chinese (zh)
Inventor
Chi-Li Chen
Roger B Clark
yong-hong Deng
Louis Plamondon
cui-xiang Sun
Xiao-Yi Xiao
Original Assignee
Tetraphase Pharmaceuticals Inc
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Publication date
Application filed by Tetraphase Pharmaceuticals Inc filed Critical Tetraphase Pharmaceuticals Inc
Publication of TW201245116A publication Critical patent/TW201245116A/en

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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
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    • A—HUMAN NECESSITIES
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
    • A01N43/60—1,4-Diazines; Hydrogenated 1,4-diazines
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/80—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms five-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,2
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/72—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
    • A01N43/84—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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    • A61P31/06—Antibacterial agents for tuberculosis
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    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/12—Oxygen or sulfur atoms
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    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/20—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
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    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
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    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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Abstract

The present invention is directed to a compound represented by Structural Formula (I): or a pharmaceutically acceptable salt thereof. The variables for Structural Formula I are defined herein. Also described is a pharmaceutical composition comprising the compound of Structural Formula I and its therapeutic use.

Description

201245116 六、發明說明： 【發明所屬之技術領域】201245116 VI. Description of the invention: [Technical field to which the invention pertains]

(I)， 或其醫藥學上可接受之鹽，包含結構式〗之化合物之醫 藥組成物及其治療用途。 【先前技術】 四環素為廣泛用於人類及獸醫學之廣譜抗微生物劑。 藉由醱酵或半合成生產之四環素總產量每年達數千㈣。 為達成治療目的而廣泛使用四環素已導致對此等抗生 素產生抗性’甚至在高敏感性細菌種 對其他四環素反應性疾 因此而要針 丙飞届症具有改良之抗細菌活性及 功效的新穎四環素類似物。 發明内容】 式ϊ化合物為針對Iμ m(I), or a pharmaceutically acceptable salt thereof, comprising the pharmaceutical composition of the compound of the formula and its therapeutic use. [Prior Art] Tetracycline is a broad-spectrum antimicrobial agent widely used in humans and veterinary medicine. The total production of tetracycline produced by fermentation or semi-synthesis is several thousand per year (four). The widespread use of tetracycline for therapeutic purposes has led to the development of resistance to these antibiotics', even in highly sensitive bacterial species against other tetracycline-responsive diseases, which have improved antibacterial activity and efficacy in the development of tetracycline. analog. SUMMARY OF THE INVENTION A ruthenium compound is for Iμm

本發明亦包括式I化合物 提供式I中變數之含義： 改良之^細菌活性及功效、：广素f應性疾病或病症具有 一 的新賴四環素類似物： 之醫藥學上可接受之鹽。下文 ‘〇_ci-c6 烷基、 X係選自氣、漠、氣、氣、C1_C6烧基、 201245116 C3-C1Q碳環基、-〇-C3-Ciq碳環基、4-13員雜環基、-Q-m 員雜環基、-S(0)m-R2、-CN、-N(R2)(R3)、_s(〇)m_N(R2)(R3)、 -C(0)-〇_R2、-C(0)_n(R2)(R3)及-NH-C(〇HCl-C6 伸燒 基）-n(r2)(r3)，其中 由X表示之基團中之各烷基或伸烷基視情況經一或多 個氟取代；且 由X表示之基團中之各碳環基或雜環基視情況經一或 多個獨立地選自以下之取代基取代··氟、氯、=〇、_〇H、 C1-C4氟烧基、C1-C4烧基、-0-C1-C4烧基、- 0- C1-C4氟燒基' -NH2、烧基）或院基）2、C3-C1()碳環基或 (4-13員）雜環基； 環E係選自C3-C1G碳環基及（4-1 3員）雜環基； W 係選自 C(R6)、C(R6)2、N 及 N(R7); Q、係選自 C(R6)、C(R6)2、N、N(R7)、〇 及 S ; Y 係選自氫、氟、溴、-CN、-[C(Rla)(Rlb)]n_N(R2)(R3)、 -^R^KRVNOy-NH-CCOHCVC^ 伸烷基 烷基、-NH-qCO-CVCe 烷基、-NH-S(0)m-Cl-C6 烷基、 -NH-S(0)m-C3-Ci。碳環基、_NH-S(0)m-4-13 員雜環基； 各Rla及Rlb係獨立地選自氫、C丨-C4烷基及c3-C10碳 環基； R2係選自氫、CrCu烷基、-C〇-C6伸烷基_c3-Ch)碳環 基及-CG-C6伸烷基-4-13員雜環基； R3係選自氫、C^Cs烷基、-CQ-C6伸烷基_c3-C1G碳環 基、-CG-C6 伸烷基-4-13 員雜環基、-qCO-Ci-C^ 烷基、-CQ-C6- 201245116 伸烷基-C(0)N(R4)(R5)、—c(0)_Cl_c6 伸烷基 _n(r4)(r5)、 -C2-C6 伸炫基-N(R4)(R5)、_s(0)m_c 丨 _c6 烷基、_s(〇)m_c3_Ci0 碳環基及-S(0)m-(4_13員）雜環基，其中： 由R2或R3表示之基團中之各烷基、碳環基、伸烷基或 雜％基視情況且獨立地經一或多個獨立地選自.以下之取代 基取代：氟、氣、-OH、-〇-Cl-C4烷基、Cl_C4烷基、經氟 取代之CVC4烷基、_n(R4)(R5)、CrC丨〇碳環基或4·13昌 環基；或 雜 R2及R3與其所結合之氮原子一起形成4 7 或6-1 3員雙環、螺環或橋連雜環，其中： 、 4-7員單環雜環或6_13員雙環、螺環或橋連雜環才. 况包含1至4個獨立地選自N、s及〇之其他雜原子.思11 4-7員單環雜環或6_13員雙環、螺環或橋連雜戸’ 4伸埝基 况經一或多個獨立地選自以下之取代基取代：长硯情 基、4-13員雜環基、氟、氣、_〇H、_c丨_C4氟烷基、、。灭嶮 烷基、-0-C3-C1G碳環基、-0-4-13員雜環基、_C()_C ^丨、C4 >0、 *埝基 =0、 氟燒基、 '0~cvc4烷基、伸烷基_〇_c丨_C4氟烷基、 烷基、_c(〇)N(R4)(R5)、_n(r4) c(〇) c】、c 及 'C()-C4 伸烷基 _N(R4)(R5)，且 4 各碳環基或雜環基取代基視情況經氟、氯、The invention also includes a compound of formula I which provides the meaning of the variables of formula I: improved bacterial activity and efficacy, a broad-spectrum disease or condition having a novel lycopene analog: a pharmaceutically acceptable salt. The following '〇_ci-c6 alkyl, X is selected from the group consisting of gas, desert, gas, gas, C1_C6 alkyl, 201245116 C3-C1Q carbocyclyl, -〇-C3-Ciq carbocyclyl, 4-13 member heterocyclic ring Base, -Qm member heterocyclic group, -S(0)m-R2, -CN, -N(R2)(R3), _s(〇)m_N(R2)(R3), -C(0)-〇_ R2, -C(0)_n(R2)(R3) and -NH-C(〇HCl-C6 alkyl)-n(r2)(r3), wherein each alkyl group in the group represented by X or The alkylene group is optionally substituted by one or more fluorines; and each carbocyclic group or heterocyclic group in the group represented by X is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, Chlorine, =〇, _〇H, C1-C4 fluoroalkyl, C1-C4 alkyl, -0-C1-C4 alkyl, -0-C1-C4 fluoroalkyl '-NH2, alkyl) or hospital base 2) a C3-C1() carbocyclic group or a (4-13 membered) heterocyclic group; the ring E is selected from the group consisting of a C3-C1G carbocyclic group and a (4-1 3 membered) heterocyclic group; (R6), C(R6)2, N and N(R7); Q, selected from C(R6), C(R6)2, N, N(R7), 〇 and S; Y is selected from hydrogen, Fluorine, bromine, -CN, -[C(Rla)(Rlb)]n_N(R2)(R3), -^R^KRVNOy-NH-CCOHCVC^alkylalkyl, -NH-qCO-CVCe alkyl, -NH-S(0)m-Cl-C6 alkyl, -NH-S(0)m- C3-Ci. Carbocyclyl, _NH-S(0)m-4-13 membered heterocyclic group; each Rla and Rlb are independently selected from the group consisting of hydrogen, C丨-C4 alkyl and c3-C10 carbocyclic; R2 is selected from hydrogen , CrCu alkyl, -C〇-C6 alkylene_c3-Ch) carbocyclyl and -CG-C6 alkylene-4-13 member heterocyclic; R3 is selected from hydrogen, C^Cs alkyl, -CQ-C6 alkylene group _c3-C1G carbocyclic group, -CG-C6 alkylene-4-13 member heterocyclic group, -qCO-Ci-C^ alkyl group, -CQ-C6-201245116 alkylene group -C(0)N(R4)(R5), -c(0)_Cl_c6 alkylene_n(r4)(r5), -C2-C6 exudyl-N(R4)(R5), _s(0 M_c 丨_c6 alkyl, _s(〇)m_c3_Ci0 carbocyclyl and -S(0)m-(4_13 member) heterocyclic group, wherein: each alkyl group or carbocyclic ring in the group represented by R2 or R3 The base, alkylene or heteropoly group is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, gas, -OH, -〇-Cl-C4 alkyl, Cl_C4 alkyl, Fluorine-substituted CVC4 alkyl, _n(R4)(R5), CrC丨〇 carbocyclyl or 4·13 cyclylene; or heterocycles R2 and R3 together with the nitrogen atom to which they are bonded form 4 7 or 6-1 3 Bicyclic, spiro or bridged heterocyclic ring, wherein: 4-7 membered monocyclic heterocyclic ring or 6_13 membered bicyclic ring, spiro ring or bridge Heterocyclic. Contains 1 to 4 other heteroatoms independently selected from N, s and oxime. Si 11 4-7 member monocyclic heterocyclic ring or 6_13 member bicyclic ring, spiro ring or bridged hydrazine '4 埝The base conditions are substituted with one or more substituents independently selected from the group consisting of: long fluorenyl, 4-13 membered heterocyclyl, fluoro, hydrazine, hydrazine, hydrazine, fluoroalkyl, fluoroalkyl. Terpene alkyl, -0-C3-C1G carbocyclic group, -0-4-13 membered heterocyclic group, _C()_C^丨, C4 > 0, *埝 group=0, fluoroalkyl group, '0 ~cvc4 alkyl, alkylene_〇_c丨_C4 fluoroalkyl, alkyl, _c(〇)N(R4)(R5), _n(r4) c(〇) c], c and 'C( )-C4 alkylene_N(R4)(R5), and 4 each carbocyclic or heterocyclic substituent may optionally be fluorine, chlorine,

Cl-C4 氟烷基、Ci-c4 烷基、-0-C丨-c4 烷基、-〇-Cl_c 屮Η2、-NH(Cl-C4烷基）或-N(Ci-C4烷基）2取代； 個 R4及R5各獨立地選自氫及Cl_C4烷基；或 R及R與其所結合之氮原子一起形成視情況包含 201245116 * 選自N、S及〇之其他雜原子的4_7員雜環，其中該4_7員 雜環視情況經氣、氣、_0H、=〇、經氤取代之Ci_C4烷基、 -(VC4烷基或_Cl_C4伸烷基屮彳丨-山烷基取代，且視情況稠 合至苯基； 各R係獨立地選自氫、c3_Ciq碳環基、4_13員雜環基、 氟、氯、-OH、CVQ說烧基、Ci_C4烧基、_〇_C3_Ci。碳環 基、-0-4-13員雜環基、_c〇_C4烷基_〇_c「C4烷基、_C『C4 烧基-O-Crh 說烧基、_c(〇)_Ci_C4 烷基、_c(〇)N(R4)(R5)、 -n(r4)-c(o)-Ci-c4 烷基及 _C(rC4 伸烷基 _N(R4)(R5);或 C(R6)2 為 C = 〇 ; R係獨立地選自氫、-C()-C4伸烷基-C3-C1()碳環基、 -C〇-C4伸烷基_4_13員雜環基、_Ci，c6氟烷基、_CiC6烷基、 ，Cl_C6 羥烷基、-〇-C3_C1q 碳環基、-0-4-13 員雜環基、-C(rC4 伸烷基-〇-(Vc4烷基、_Cq_C4伸烷基_〇_CrC4氣烷基、 烷基 ' _c 丨 _c4 伸烷基 _c(〇)Ci_C4 烷基、 伸烷基-C(0)-〇H、-C(〇)N(R4)(R5)、-烷 基、-c(0)-(c丨-(：4伸院基）_NR4R5及心心伸烧基_n(r4)(r5); 及R之各碳ί衣基或雜環基部分視情況經氟、氯、 -0Η、-0、CVC4 氟烷基、c丨_c4 烷基、_〇_Ci_C4 烷基、_〇 c丨_c4 氟烷基、-NH2、-NH(Cl-C4烷基）或-N(Cl_c4烷基）2取代； 各R係獨立地選自氫、C3_Cid碳環基、4_13員雜環基、 氣、氣、-OH、CVC4氟烧基、Cl_C4烧基、_〇_C3_Ci〇碳環 基、-0-4-13員雜環基、_Cq_C4烷基Q Ci-q烷基、_C『C4 烷基-0-CVC4 氟烷基、=〇、_c(〇)_Ci_C4 烷基、 201245116 -c(o)n(r4)(r5)、-N(R4)_c(〇)_Cl-C4 燒基、 及-S⑼2C1-C4烧基； 4伸兀基 當一個=表示雙鍵時，R9不存在；或 當各=表示單鍵時，R9係選自氩、（：341〇碳環基、413 員雜環基、氟、氯、-〇H、Cl-C4氟烷基吒广^烷基、·〇_C3_Ci〇 碳環基、-0-4-13員雜環基、-C(rc4烷基烷基、_CqC4 烷基-O-CVCU 氟烷基、=〇、-C(〇)_Ci C4 烷基、 -c(〇)n(r4)(r5)、_n(r4)_c⑼_Ci-C4 μ 及 _c〇_c:伸土烧基 -N(R4)(R5); 各ni獨立地為〇、1或2; n為1或2 ; Ρ钓υ或介於 各=表示單鍵或雙鍵，其中至少-個4示單鍵，其阳 制條件為切Ε為視情況經取代之芳族環或視情況經取柯 之雜芳族環時，Χ不為氫。 本發明之另一具體實例係關於一種醫藥組成物，宜 含 Μ ^ L —Τ' ΙΑ, 。晋樂:上可接受之載劑或稀釋劑及本文所揭示之化合物 或其醫藥學上可接受之鹽。該醫藥組成物用於療法中，諸 如治療個體感染。 = 本發明之另一具體實例係關於一種治療個 :，其包含向該個體投予有效量之本文所揭示之：：= 其醫藥學上可接受之鹽。 成 —本發明之另一具體實例為本文所揭示之化合物或其 梵之鹽的用途，其用於製造供治療個體感染的 201245116 • 藥物。 本發明之另一具體實例為本文所揭示之化合物或其醫 藥學上可接受之鹽的用途，其用於療法中，諸如治療個體 感染。 根據本發明之例示性具體實例之以下更特定描述，上 述將顯而易知。 【實施方式】 變數之含義及替代含義 本發明係關於一種由結構式（I)表示之化合物或其醫 藥學上可接受之鹽。以下段落中提供結構式I中之變數及本 文所述之各具體實例之含義及替代含義。應瞭解，本發明 涵蓋本文定義之取代基變數（亦即R丨、R2、R3等）之所有 t- 組合。 X係選自氫、溴、氟、氣' Ci-C6烷基、-0-CVC6烷基、 C3-C丨〇碳環基、-〇_c3-Ci〇碳環基、4-13員雜環基、-0-4-13 員雜環基、-SCOU-R2、-CN、-N(R2)(R3)、-呂⑼^州的化3)、 C(0)-〇_r2、及 _nh_c(〇Hc「C6 伸烷 基）-N(R2)(R3)，其中由X表示之基團中之各烷基或伸烷基 視情況經一或多個氟取代；且由X表示之基團中之各碳環 基或雜環基視情況經一或多個獨立地選自以下之取代基取 代：氟、氯、=0、-OH、CVC4 氟烷基、Ci_c4 烷基、_0_Ci_c4 烷基、-0-Ci-C4 氟烷基、-匪2、烷基）或-N(Ci-C4 烧基）2、C3-C1()碳環基或（4-13員）雜環基。 201245116 在一更特定態樣中，χ係選自氫、氣、氟、_〇CH3、 -OCF3 ' -〇CH2F ' -N(CH2)3 A CF3 0 Y 係選自氫、氟、溴、-CN、-[C(Rla)(Rlb)]n-N(R2)(R3)、 -N(R4)(R5)^n〇2> -NH-C(0)-(C,-C4 ^ &)-N(R4)(R5)' C,-C6 烧基、-NH-C(〇)-C丨-C6 烷基、-NH-S(0)m-C丨-C6 烷基、 -NH-S(0)m-C3-C1G 碳環基、_NH_S(0)m_(4_13 員）雜環基，其 中R a及Rlb係獨立地選自氫、c「C4烷基及C3_Ci〇破環基β 特定言之，Υ為氫。 環Ε為CrC 1()碳環基或4-13員雜環基《特定言之，環 E包含環氮原子。此外，環E為非芳族環。或者，環E為 4-7員雜環基。更特定言之，環E係選自以下結構之 -R® — R6 (B8)〇-2'Cl-C4 fluoroalkyl, Ci-c4 alkyl, -0-C丨-c4 alkyl, -〇-Cl_c 屮Η2, -NH(Cl-C4 alkyl) or -N(Ci-C4 alkyl)2 Substituted; R4 and R5 are each independently selected from hydrogen and Cl_C4 alkyl; or R and R together with the nitrogen atom to which they are bonded form a 4-7 heterocyclic ring optionally containing 201245116* other heteroatoms selected from N, S and fluorene. Wherein the 4-7 member heterocyclic ring is optionally substituted by gas, gas, _0H, = hydrazine, Ci_C4 alkyl substituted by hydrazine, - (VC4 alkyl or _Cl_C4 alkyl hydrazine-alkyli, and optionally thickened) And R is independently selected from the group consisting of hydrogen, c3_Ciq carbocyclyl, 4-13 membered heterocyclic group, fluorine, chlorine, -OH, CVQ, alkyl, Ci_C4 alkyl, _〇_C3_Ci, carbocyclyl, -0-4-13 member heterocyclic group, _c〇_C4 alkyl_〇_c "C4 alkyl group, _C"C4 alkyl group-O-Crh, alkyl group, _c(〇)_Ci_C4 alkyl group, _c(〇 N(R4)(R5), -n(r4)-c(o)-Ci-c4 alkyl and _C(rC4alkylene_N(R4)(R5); or C(R6)2 is C = 〇; R is independently selected from the group consisting of hydrogen, -C()-C4 alkylene-C3-C1() carbocyclic group, -C〇-C4 alkylene group _4_13 member heterocyclic group, _Ci, c6 fluorocarbon Base, _CiC6 alkyl, , Cl_C6 hydroxyalkyl, -〇-C3_C1q carbon ,-0-4-13 membered heterocyclic group, -C(rC4alkyl-indole-(Vc4 alkyl, _Cq_C4 alkylene_〇_CrC4 gas alkyl, alkyl' _c 丨_c4 alkyl) _c(〇)Ci_C4 alkyl, alkyl-C(0)-〇H, -C(〇)N(R4)(R5), -alkyl, -c(0)-(c丨-(: 4 extension of the base) _NR4R5 and core extension base _n (r4) (r5); and R of each carbon ε or heterocyclic moiety as appropriate by fluorine, chlorine, -0 Η, -0, CVC4 fluoroalkyl , c丨_c4 alkyl, _〇_Ci_C4 alkyl, _〇c丨_c4 fluoroalkyl, -NH2, -NH(Cl-C4 alkyl) or -N(Cl_c4 alkyl) 2 substituted; each R Is independently selected from the group consisting of hydrogen, C3_Cid carbocyclyl, 4-13 membered heterocyclic group, gas, gas, -OH, CVC4 fluoroalkyl, Cl_C4 alkyl, _〇_C3_Ci〇 carbocyclyl,-0-4-13 Heterocyclyl, _Cq_C4 alkyl Q Ci-q alkyl, _C "C4 alkyl-0-CVC4 fluoroalkyl, = 〇, _c(〇)_Ci_C4 alkyl, 201245116 -c(o)n(r4)(r5 ), -N(R4)_c(〇)_Cl-C4 alkyl group, and -S(9)2C1-C4 alkyl group; 4 stretching thiol group when a double bond, R9 does not exist; or when each = represents a single bond, R9 is selected from the group consisting of argon, (: 341 〇 carbocyclic group, 413 membered heterocyclic group, fluorine, chlorine, -〇H, Cl-C4 fluoroalkyl fluorene ^Alkyl, 〇_C3_Ci〇 carbocyclyl, -0-4-13 membered heterocyclic group, -C(rc4 alkylalkyl, _CqC4 alkyl-O-CVCU fluoroalkyl, =〇, -C( 〇)_Ci C4 alkyl, -c(〇)n(r4)(r5), _n(r4)_c(9)_Ci-C4 μ and _c〇_c: exudate-N(R4)(R5); each ni Independently 〇, 1 or 2; n is 1 or 2; Ρ fishing rod or between each = represents a single bond or double bond, at least - 4 of which shows a single bond, and its cation condition is cut as When the substituted aromatic ring or the heterocyclic ring of Ke is taken as the case may be, the hydrazine is not hydrogen. Another embodiment of the present invention relates to a pharmaceutical composition preferably comprising Μ ^ L - Τ' ΙΑ. Jinle: An acceptable carrier or diluent and a compound disclosed herein or a pharmaceutically acceptable salt thereof. The pharmaceutical composition is used in therapy, such as treating an individual's infection. Another specific example of the invention relates to a therapeutic comprising: administering to the individual an effective amount of the disclosure disclosed herein:: = a pharmaceutically acceptable salt thereof. Another embodiment of the invention is the use of a compound disclosed herein, or a salt thereof, for the manufacture of a medicament for treating an individual with an infection of 201245116. Another embodiment of the invention is the use of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, for use in therapy, such as treating an individual infection. The above will be apparent from the following more particular description of exemplary embodiments of the invention. [Embodiment] Meaning of the variables and alternative meanings The present invention relates to a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof. The meanings of the variables in Structural Formula I and the specific examples described herein and the alternate meanings are provided in the following paragraphs. It will be understood that the invention encompasses all t-combinations of the substituent variables (i.e., R丨, R2, R3, etc.) as defined herein. X is selected from the group consisting of hydrogen, bromine, fluorine, gas 'Ci-C6 alkyl, -0-CVC6 alkyl, C3-C丨〇 carbocyclyl, -〇_c3-Ci〇 carbocyclyl, 4-13 member Ring group, -0-4-13 member heterocyclic group, -SCOU-R2, -CN, -N(R2)(R3), -Lu(9)^ State 3), C(0)-〇_r2 And _nh_c(〇Hc "C6 alkylene"-N(R2)(R3), wherein each alkyl or alkylene group in the group represented by X is optionally substituted with one or more fluorines; and by X Each carbocyclic or heterocyclic group in the group represented is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, =0, -OH, CVC4 fluoroalkyl, Ci_c4 alkyl, _0_Ci_c4 alkyl, -0-Ci-C4 fluoroalkyl, -匪2, alkyl) or -N(Ci-C4 alkyl) 2, C3-C1() carbocyclyl or (4-13 membered) heterocyclic ring 201245116 In a more specific aspect, the lanthanide is selected from the group consisting of hydrogen, gas, fluorine, _〇CH3, -OCF3 ' -〇CH2F ' -N(CH2)3 A CF3 0 Y is selected from hydrogen, fluorine, bromine , -CN, -[C(Rla)(Rlb)]nN(R2)(R3), -N(R4)(R5)^n〇2> -NH-C(0)-(C,-C4 ^ &amp ;)-N(R4)(R5)' C,-C6 alkyl, -NH-C(〇)-C丨-C6 alkyl, -NH-S(0)mC丨-C6 alkyl, -NH- S(0)m-C3-C1G carbocyclic group, _NH_S(0)m — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — Or a 4-13 membered heterocyclic group. Specifically, the ring E contains a ring nitrogen atom. Further, the ring E is a non-aromatic ring. Alternatively, the ring E is a 4-7 membered heterocyclic group. More specifically, the ring E is selected from the following structures - R® - R6 (B8) 〇 - 2'

<R8W N* ,Re (R8)〇.2—L 、Re JM \ R7<R8W N* , Re (R8)〇.2—L , Re JM \ R7

(R8)〇-： d、 R8 一(R8)〇-: d, R8 one

R7 NT Re (R8)〇-2 R6R7 NT Re (R8) 〇-2 R6

Re R6 7r-n R6Re R6 7r-n R6

R6 R6 (-Ο：R6 R6 (-Ο:

if <"、 叫或^ ^特定言之，環E為^ 或者乂環 E 為 cV\ 環 E 為 J 、HfV、 5^、H3c2l、If <", or ^ ^ specifically, ring E is ^ or ring E is cV\ ring E is J, HfV, 5^, H3c2l,

CH^/、CH^/,

,ch3 〇Λ CH3^? 或θ 。特定言之，環ε為Μ』。 “當環Ε為視情況經取代之芳族環或視情況經取代之* 方埃環時，X不為氫。 10 201245116 W 為 C(R6)、C(R6)2、N 或 N(R7)。特定言之，w 為 n 或N(R7)。 … Q 為 C(R6)、C(R6)2、N、n(r7)、〇戒§。特定言之， 為 C(R6)2 〇 在一態樣中，當環Ε為視情況經取代之芳族環或視情 況經取代之雜芳族環時，X不為氫。 R為氫、（^(：12烷基、_C(rC6伸烷基_C3_Ci❹碳環基或 -匸0-〇6伸烧基- (4-13員）雜環基。 R3為氫、烷基、_c〇_C6伸烷基_C3_Ci()碳環基、 <0-(：6伸烷基-(4-13員）雜環基、_(：(〇)_(：;「(：6烷基、_。匸 伸貌基-C(〇)N(r4)(r5)、_c(〇)_Ci_C6 伸烧基 _n(r4)(二）「 -C2-C6 伸烧基-n(r4)(R5)、_s⑼m_Ci_C6 炫基、_s⑼m 碳環基或-S(〇)m-(4- i 3員）雜環基’其中由r2 4 R3表干3之某0 團中之各烧基、碳環基、伸烧基或雜環基視情況且獨幻1 經—或多個獨立地選自以下之取代基取m、_0H、 -〇-cvc4烧基、Cl-C4烧基、經氟取代之CA炫基、 -n(r4)(r5)、C3-Cl0碳環基或（4_13 員）雜環基。 土 R2及R3與其所結合之氮原子_ 或⑷員雙環、螺環或橋連雜環，雜環, ch3 〇Λ CH3^? or θ. In particular, the ring ε is Μ 』. "When ring Ε is an optionally substituted aromatic ring or, as the case may be, substituted * ang ring, X is not hydrogen. 10 201245116 W is C(R6), C(R6)2, N or N(R7 In particular, w is n or N(R7). ... Q is C(R6), C(R6)2, N, n(r7), 〇 § §. Specifically, C(R6)2 In one aspect, when the cyclic oxime is an optionally substituted aromatic ring or an optionally substituted heteroaromatic ring, X is not hydrogen. R is hydrogen, (^(: 12 alkyl, _C() rC6 alkylene_C3_Ci❹ carbocyclyl or -匸0-〇6 extended alkyl-(4-13 membered) heterocyclic group. R3 is hydrogen, alkyl, _c〇_C6 alkylene group _C3_Ci() carbocyclic ring Base, <0-(:6-alkyl-(4-13 member) heterocyclic group, _(:(〇)_(:;"(:6 alkyl, _. 匸 貌 基 -C (〇 N(r4)(r5), _c(〇)_Ci_C6 Stretching base_n(r4)(2) "-C2-C6 Stretching base-n(r4)(R5), _s(9)m_Ci_C6 炫, _s(9)m carbocyclic group Or -S(〇)m-(4-i 3 member)heterocyclyl' wherein each of the alkyl groups, carbocyclic groups, alkylene groups or heterocyclic groups in the 0 group of the surface of the r2 4 R3 is as appropriate And one or more of the substituents independently selected from the group consisting of m,_0H, -〇-cvc4, and Cl-C4 a fluorine-substituted CA thiol group, a -n(r4)(r5), a C3-Cl0 carbocyclic group or a (4-13 membered) heterocyclic group. The earth R2 and R3 are bonded to a nitrogen atom _ or (4) a bicyclic ring, Spiro or bridged heterocycle, heterocycle

Att, 6-13 I ^ ^ Jf iJ Μ- ^ 員單環雜環 貞以_或橋連雜環視情況 立地選自N、S及0之其他雜原子。該4_7員單環雜個獨 6]3員雙環、螺環或橋連雜環視情況經单展雜壤或該 自以下之取代基取代：c3_C|()碳产 /多個獨立地選 t r r - p> 衣土、4-13員雜環基、氣、 氣、燒基、_Ci_C4 :氟 …c3-c1Q碳環基、 201245116 -0-4-13員雜壤基、-C〇-C4伸烧基- 〇- Ci-C4烧基、-C〇-C4伸 烷基-O-CVCU 氟烷基、=〇、-(^(CO-CVC* 烷基、 -c(o)n(r4)(r5)、-N(R4)-c(o)-c,-c4 烷基及-C〇-C4 伸烷基 -n(r4)(r5) ’且各碳環基或雜環基取代基視情況經氟、氣、 -0H、=0、Ci-C# 氟烷基、（：丨-(：4 烷基、-0-(:,-(:4 烷基、-OG-q 氟烷基、-NH2、-NHCCi-C^烷基）或-Νγγα烷基）2取代。 R4及R5各獨立地為氫或烷基；或 R4及R5與其所結合之氮原子一起形成視情況包含一個 選自N、S及〇之其他雜原子的4_7員雜環，其中該4_7員 雜環視情況經氟、氣、-0H、=〇、經氟取代之Ci_C4烷基、 -cvc：4烷基或_Cl_C4伸烷基_0_Ci_C4烷基取代，且視情況裯 合至苯基。 R6獨立地為氫、C3_C 10碳環基、4-13員雜環基、氟、 氯、-0H、氟烷基、Cl-C4 烷基、-〇-C3-C1()碳環基、 -0-4-13員雜環基、_c〇_C4烷基_〇-C丨_C4烷基、_c〇_c4烷基 -O-CVCU 氟烷基、_c(〇) Ci_C4 烷基、_c(〇)n(r4mr5)、 -n(r4)-c(〇)_Ci_c4 烷基或 _c〇_C4 伸烷基 _n(r、r5广或 C(R6)2 為 C = 〇 〇 或^者，R6獨立地為氫或曱基。特定言之，R6為氫。 R係獨立地選自氫、-C(rc4伸烷基·C3_CiQ碳環基 -C0-C4伸烷基_4_13員雜環基、_Ci_C6氟烷基、_Ci_C6烷基 -CVC6羥烷基、_〇_C3_CiQ碳環基、-〇 4_13員雜環基、_c〇_c 伸烷基-0-Cl_C4烧基、_c〇_c“申烷基_〇Ci_c4氟烷基、 -c(o)-c丨-c4 烷基、_Ci_c4 伸烷基_C(0)_C1_C4 烷基、c 12 201245116 伸烷基-C(0)-0H、-C(0)N(R4)(R5)、烷 基、-C(0)-(C !-C4 伸烷基）-NR4R5 及-c〇-c4 伸烷基-n(r4)(r5); 或者，R7獨立地為氫、-CG-C4伸烷基-c3-c丨〇碳環基、 -(^-(^伸烷基-彳-^員雜環基…匕-匕氟烷基^匕-匕烷基、 -O-Ca-C,。碳環基、-0-(4-13員）雜環基、-C〇-C4伸烷基 -O-Crh 烷基、-C〇-C4 伸烷基-O-Ci-CU 氟烷基、-C(0)-Ci-C4 烧基、-C(0)N(R4)(r5)、-NCRYc^CO-Ci-C^ 烷基或-C〇-C4 伸 烷基-N(R4)(R5)。 或者’ R為H、-Ci-C6氟烧基或- Ct-C^烧基。此外， R7為-CVC6氟烷基或-C^Cs烷基。此外，R7為-d-Ce烷基。 R係選自曱基、乙基、2-氟-乙基、丙基、異丙基、丁基及 戊基。丁基包括第二丁基、第三丁基及異丁基。戊基包括 異戊基及新戊基。 在另一替代情況下’ R7為-C〇_C4伸烷基_C3_Ci〇碳環 基。此外’ R7為-C〇_C4伸烷基-C3_C10環丙基。此外，"為 -Ci伸烧基-環丙基或環丙基。 R及R之各碳環基或雜環基部分視情況經氟 '氣、 -0H、=0、Ci-C4 氟烷基'CVC4 烷基、-0-C丨-C4 烷基、-ο-e丨-C4 敗烧基、-腿2、-nha-C4烷基）或-na-c*烷基）2取代。 各R8係獨立地選自氫、(^-(:⑺碳環基、4_13員雜環基、 氟、氯、-OH、CVCU氟烧基、CVC4烷基、-〇-C3-Ci〇竣環 基、-0-4-13員雜環基、·C(rC4烷基_〇_Ci_C4烷基…Cg_C4 烷基-0-C丨-c4氟烷基、=0、_C(0)_C1_C4烷基、 -C(0)N(R4)(R5)、-NeYqoXi h 烷基、C『C4 伸烷基 13 201245116 -N(R4)(R5)及 4(0)2(:,-(:4 烷基。 或者，各R8獨立地為氫、C3-C1Q碳環基、4-13員雜環 基、氟、氣、 〇 Η、C 1 - C 4 氟烧基、C 1 - C 4 烧基、-〇 - C 3 - C 1 〇 石炭极基、- 0- 4-13貝雜ί哀基、- C〇-C4烧基_〇_Ci-C4烧基、_C〇-C4 烷基-0-CVC4 氟烷基、=0、-(:(0)-(^-(:4 烷基、 -C(0)N(R4)(R5)、-N(R4)-C(0)-CrC4 烷基或-C〇-C4 伸烷基 -N(R4)(R5)。此外，R8獨立地為氫或曱基。特定言之，R8 為曱基。 若R9存在，則其為氫、C3-C1G碳環基、4-13員雜環基、 氟、氯、-OH、CVC4氟烷基、CVC4烷基、-0-C3-C1()碳環 基、-0-4-13 員雜環基、-CG-C4 烷基-0-CVC4 烷基、-CG-C4 烷基-0-CVC4 氟烷基、=0、烷基、 -C(0)N(R4)(R5)、-NCRq-C^CO-Ci-C^ 烷基或-C〇-C4 伸烷基 -N(R4)(R5)。此外，R9為氫或OH。特定言之，R9為氫。或 者，R9為OH。 各m獨立地為0、1或2。特定言之，m為0。 η為1或2。 ρ為0或介於1與4之間的整數。特定言之，ρ為1。 或者，ρ為0。 各=表示單鍵或雙鍵，其中至少一個=表示單鍵。特定 言之表不兩個早鍵。 在結構式（I )化合物之其他具體實例中，當環Ε為視 情況經取代之芳族環或視情況經取代之雜芳族環時，X不為 氫。 14 201245116Att, 6-13 I ^ ^ Jf iJ Μ- ^ member monocyclic heterocyclic ring 贞 or _ bridged heterocyclic ring as the case is selected from other heteroatoms of N, S and 0. The 4_7 member single-ring heterocyclic 6]3 member double-ring, spiro or bridged heterocyclic ring is replaced by a single or mixed substituent: c3_C|() carbon product/multiplely selected trr- p> soil, 4-13 member heterocyclic group, gas, gas, burnt group, _Ci_C4: fluorine...c3-c1Q carbocyclic group, 201245116 -0-4-13 member mixed soil base, -C〇-C4 stretched Base - 〇-Ci-C4 alkyl, -C〇-C4 alkyl-O-CVCU fluoroalkyl, =〇, -(^(CO-CVC* alkyl, -c(o)n(r4)( R5), -N(R4)-c(o)-c, -c4 alkyl and -C〇-C4 alkyl-n(r4)(r5)' and each carbocyclic or heterocyclic substituent The condition is fluorine, gas, -0H, =0, Ci-C# fluoroalkyl, (: 丨-(: 4 alkyl, -0-(:, -(:4 alkyl, -OG-q fluoroalkyl, -NH2, -NHCCi-C^alkyl) or -Νγγαalkyl)2 is substituted. R4 and R5 are each independently hydrogen or alkyl; or R4 and R5 together with the nitrogen atom to which they are bonded are optionally included a 4-7 membered heterocyclic ring of N, S and other heteroatoms of the oxime, wherein the 4-7 membered heterocyclic ring is optionally subjected to fluorine, gas, -OH, = oxime, fluorine-substituted Ci_C4 alkyl, -cvc:4 alkyl or _Cl_C4 Alkyl-0_Ci_C4 alkyl substituted, and as the case may be To a phenyl group. R6 is independently hydrogen, C3_C10 carbocyclyl, 4-13 membered heterocyclyl, fluoro, chloro, -0H, fluoroalkyl, Cl-C4 alkyl, -〇-C3-C1() Carbocyclyl, -0-4-13 membered heterocyclic group, _c〇_C4 alkyl_〇-C丨_C4 alkyl, _c〇_c4 alkyl-O-CVCU fluoroalkyl, _c(〇) Ci_C4 Alkyl, _c(〇)n(r4mr5), -n(r4)-c(〇)_Ci_c4 alkyl or _c〇_C4 alkyl _n (r, r5 wide or C(R6)2 is C = 〇〇 or ^, R6 is independently hydrogen or fluorenyl. In particular, R6 is hydrogen. R is independently selected from hydrogen, -C(rc4alkyl-C3_CiQ carbocyclyl-C0-C4 alkylene) _4_13 member heterocyclic group, _Ci_C6 fluoroalkyl group, _Ci_C6 alkyl-CVC6 hydroxyalkyl group, _〇_C3_CiQ carbocyclic group, -〇4_13 member heterocyclic group, _c〇_c alkyl group-0-Cl_C4 alkyl group , _c〇_c "Alkyl_〇Ci_c4 fluoroalkyl, -c(o)-c丨-c4 alkyl, _Ci_c4 alkyl _C(0)_C1_C4 alkyl, c 12 201245116 alkyl-C (0)-0H, -C(0)N(R4)(R5), alkyl, -C(0)-(C!-C4alkylene)-NR4R5 and -c〇-c4 alkylene-n (r4) (r5); or, R7 is independently hydrogen, -CG-C4 alkyl-c3-c丨〇carbocyclyl, -(^-(^alkyl-彳-^membered heterocyclyl...匕-匕 fluorine Dagger-yl ^ - dagger alkyl, -O-Ca-C ,. Carbocyclyl, -0-(4-13 membered)heterocyclyl, -C〇-C4 alkylene-O-Crh alkyl, -C〇-C4 alkylene-O-Ci-CU fluoroalkyl, -C(0)-Ci-C4 alkyl, -C(0)N(R4)(r5), -NCRYc^CO-Ci-C^ alkyl or -C〇-C4 alkyl-N(R4) (R5). Or 'R is H, -Ci-C6 fluoroalkyl or -Ct-C^alkyl. Further, R7 is -CVC6 fluoroalkyl or -C^Csalkyl. Further, R7 is a -d-Ce alkyl group. R is selected from the group consisting of decyl, ethyl, 2-fluoro-ethyl, propyl, isopropyl, butyl and pentyl. The butyl group includes a second butyl group, a third butyl group, and an isobutyl group. The pentyl group includes an isopentyl group and a neopentyl group. In another alternative, 'R7 is -C〇_C4 alkyl-C3_Ci〇 carbocyclyl. Further, 'R7 is -C〇_C4 alkyl-C3_C10 cyclopropyl. Further, " is -Ci stretch-based-cyclopropyl or cyclopropyl. The carbocyclic or heterocyclic moiety of R and R, as the case may be, by fluorine 'gas, -0H, =0, Ci-C4 fluoroalkyl 'CVC4 alkyl, -0-C丨-C4 alkyl, -ο- e丨-C4 calcined, -leg 2, -nha-C4 alkyl) or -na-c*alkyl)2 substituted. Each R8 is independently selected from the group consisting of hydrogen, (^-(:(7) carbocyclyl, 4-13 membered heterocyclyl, fluoro, chloro, -OH, CVCU fluoroalkyl, CVC4 alkyl, -〇-C3-Ci〇竣 ring ,-0-4-13 membered heterocyclic group, ·C(rC4alkyl_〇_Ci_C4 alkyl...Cg_C4 alkyl-0-C丨-c4 fluoroalkyl, =0, _C(0)_C1_C4 alkyl , -C(0)N(R4)(R5), -NeYqoXi h alkyl, C"C4 alkylene" 201245116 -N(R4)(R5) and 4(0)2(:,-(:4 alkane Alternatively, each R8 is independently hydrogen, a C3-C1Q carbocyclic group, a 4-13 membered heterocyclic group, a fluorine, a gas, a hydrazine, a C 1 -C 4 fluoroalkyl group, a C 1 -C 4 alkyl group, -〇-C 3 - C 1 〇石炭基基, - 0- 4-13贝杂ί, - C〇-C4 alkyl _〇_Ci-C4 alkyl, _C〇-C4 alkyl-0- CVC4 fluoroalkyl, =0, -(:(0)-(^-(:4 alkyl, -C(0)N(R4)(R5), -N(R4)-C(0)-CrC4 alkane Or -C〇-C4 alkyl-N(R4)(R5). Further, R8 is independently hydrogen or fluorenyl. In particular, R8 is a fluorenyl group. If R9 is present, it is hydrogen, C3- C1G carbocyclyl, 4-13 membered heterocyclic group, fluorine, chlorine, -OH, CVC4 fluoroalkyl, CVC4 alkyl, -0-C3-C1()carbocyclyl,-0-4-13 heterocyclic Base, -CG-C4 alkyl-0-CVC4 alkyl, -CG-C4 alkyl -0-CVC4 fluoroalkyl, =0, alkyl, -C(0)N(R4)(R5), -NCRq-C^CO-Ci-C^ alkyl or -C〇-C4 alkylene- Further, R9 is hydrogen or OH. In particular, R9 is hydrogen. Alternatively, R9 is OH. Each m is independently 0, 1, or 2. Specifically, m is 0. Is 1 or 2. ρ is 0 or an integer between 1 and 4. In particular, ρ is 1. Alternatively, ρ is 0. Each = represents a single bond or a double bond, wherein at least a single bond. In particular, there are no two early bonds. In other specific examples of the compound of formula (I), when the cyclic oxime is an optionally substituted aromatic ring or an optionally substituted heteroaromatic ring, X is not Hydrogen. 14 201245116

基）-n(r2)(r3)，其中 由X表示之基圑中之各烷基或伸烧基視情況經一或多 個氟取代；且 本發明之第一具體實例係關於一種由結構式（Γ)表示 之化合物，或其醫藥學上可接受之鹽，其中： 由X表示之基團中之各碳環基或雜環基視情況經一或a group of -n(r2)(r3), wherein each alkyl group or alkylene group in the group represented by X is optionally substituted with one or more fluorines; and the first specific example of the invention relates to a structure A compound represented by the formula (Γ), or a pharmaceutically acceptable salt thereof, wherein: each carbocyclic group or heterocyclic group in the group represented by X is optionally obtained by one or

(4-13員）雜環基； 環E係選自C3-C1Q碳環基及（4-13員）雜環基； C3-C1()碳環基或 W 係選自 C(R6)、C(R6)2、n 及 n(R7); Q 係選自 C(R6)、C(R6)2、n、n(R7)、Ο 及 S ; Y 係選自氫、氟、溴、_CN、_[C(Rla)(Rlb)]n-N(R2)(R3)、 -N(R4)(R5)>n〇2' -NH-C(〇)-(C1-C4 ^.l-)-N(R4)(R5).Cl.Ci 烧基、-NH-C(0)-C丨-C6 烷基、烷基、 -NH-S(0)m-C3-Cl()碳環基、_NH_s(〇)m_4_13 員雜環基； 各Rla& Rlb係獨立地選自氫、Ci_C4烷基及C3_Ci〇碳 環基； R係遥自風、C^-Cu烧基、-C〇-C6伸院基- C3-Cl1()碳環 15 201245116 基及- C〇-C6伸烧基- 4-13員雜環基； R3係選自氫、C|-C8烷基、。。心伸烷基_C3_Ci。碳環 基、-C0-C6伸烧基-4，13員雜環基、_c(〇) Ci C6烧基、_c〇_c6· 伸烧基伸貌基_n(r4)(r5)、 -cvc6 伸烧基-N(R4)(R5)、_s(0)m.Ci_C6^基、·/Π。 碳環基及-S(0)m-(4-i3員）雜環基，其中： 由R2或R3表*之基时之各院基、碳環基、伸烧基或 雜環基視情況且獨立地經-❹個獨立地選自以下之取代 基取代：敦、氣、-OH、_〇-Cl_C4燒基、（Vc^基、 取代之（VM基、_n(r4)(r5)、C3_Ciq碳環基或4_ 環基；或 雜 與其所結合之氮原子—起形成‘7員單環_ 或6- Π員雙環、螺環或橋連雜環，其中： 文 該4-7員單環雜環或該6_13員雙環、螺環或橋連雜广 硯情況包含1至4個獨立地選自N、u 〇之其他雜原子衣 該4-7員單環雜環或該6_13員雙環、螺環或橋連雜王: 視情況經一或多個獨立地選自以下之取代基取代：^、％ 碳環基、4-13員雜環基 '氟、氣、_〇H、_Ci_C4氟烷基、 烷基、-0-C3-C1()碳環基、-〇_4_13員雜環基、_c『c4伸烷C4 -o-q-G烷基、_C〇-C4伸烷基-〇-Cl_C4氟烷基、基 -C(〇)_CrC4 烷基、-C(〇)N(R4)(R5)、^ ^ 、 及-C0-C4伸烷基-N(R4)(r5)，且 4燒基 各碳環基或雜環基取代基視情況經氟、氣、_〇H、、 、 1-C4 氟炫基、C!-C4 烧基、-O-C1-C4 院基、- 〇-Ci-C4 I 户我 201245116 丽2 H(Cl~C4烷基）或-N(C丨-C4烷基）2取代； \及R5各獨立地選自氫及Ci-C4烷基；或 與其所結合之氮原子一起形成視情況包含一個 达自N S及〇之其他雜原子的4_7員雜環，其中該4 7員 雜環視情況經U、惫、nw „ , ^ 乂軋、虱…OH、=〇、經氟取代之κ4烷基、 1 4烧基或-Ci-CU伸烧基-O-C^-C4烧基取代，且視情況稠 合至苯基； 各R係獨立地選自氫、CyC丨〇碳環基、4_13員雜環基、 亂氯-〇Ii、CVC4氟烷基、CVC4烷基、-0-C3-C1Q碳環 基、-0-4-13員雜環基、_C(rC4烷基…心心烷基、_Cg_c4 烷基-o-Ci-c4 氟烷基、_c(0)_Ci_C4 烷基、_c(0)n(r4)(r5)、 -N(R4)-C(0)-Cl_C4 烷基及 _c〇_c4 伸烷基 _n(r4)(r5);或 C(R6)4C = 〇; 各R7係獨立地選自氫、-CG_C4伸烷基_c3_Cl()碳環基、 -(^-(^伸烷基-‘^員雜環基^匕-匕氟烷基^匕-匕烷基、 -〇-C3-C丨〇碳環基、-04-13員雜環基、-C〇-C4伸烷基-0-CVC4 烧基、-C〇-C4伸烷基-O-Ct-G氟烷基、-CCCO-CVCU烷基、 -C(0)N(R4)(R5)、_N(rYc(0)_Ci_C4 烷基及_C(rC4 伸烷基 -N(R4)(R5); 且R6及R7之各碳環基或雜環基部分視情況經氟、氯、 -0H、=〇、C〗-C4 氟烷基、CVC4 烷基、-0-CVC4 烷基、-0-CVC4 敗烧基、-ΝΉ2、-NH(Ci-C4烧基）或-N(Ci-C4烧基）2取代； 各R8係獨立地選自氫、C3-C丨〇碳環基、4-13員雜環基、 氟、氯、-OH、C1-C4氟烧基、C1-C4烧基、-〇_C3-Ci。碳環 17 201245116 基、-〇-4]3負雜環基、_c〇_C4院基_〇_Ci_C4燒基、々A 烷基-〇-Ci-C4 氟烷基、=〇、_c(〇) Ci C4 烷某、 -c ⑼ N(R4)(r5)、娜烧基及土 -N(R4)(R5) ; Q q 伸烷基 R9在存在時獨立地選自氫、G-Cm碳環基、4_i3員雜 環基、氟、氣、-0H、Cl_C4說燒基、Ci_c4烧基、〇c “ 碳環基、_〇·4-13員雜環基、心心烷基-04-ca基、 烷基-0-CVC4氟烷基、=〇、_c(〇)俨 -C⑼聰、^基及 _c 二 土 -N(R4)(R5); 。匕4 伸烷基 各〇1獨立地為0、1或2; η為1或2 ; Ρ為〇或介於丨與4之間的整數，·且 各=表示單鍵或雙鍵’其中至少一個=表示單鍵， ’、限制條件為當環Ε為視情況經取代之芳 況經取代之雜㈣環時，XMl U視滑 在第—具體實例之第-態樣中，環Ε包 中其餘變數之含義俏如笛 aJJA〜 丁 丹 3義係如第一具體實例中或上 含義中所定t。 甘代^義之 在第-具體實例之第_態樣之另一態樣中， N(R7)及N，其中其餘變數 糸^自 .,^ ^ μ 、 a義係如第一具體實例中或上 述替代含義之含義中所定義。(4-13 member) heterocyclic group; ring E is selected from C3-C1Q carbocyclic group and (4-13 membered) heterocyclic group; C3-C1() carbocyclic group or W system is selected from C(R6), C(R6)2, n and n(R7); Q is selected from the group consisting of C(R6), C(R6)2, n, n(R7), Ο and S; Y is selected from hydrogen, fluorine, bromine, _CN , _[C(Rla)(Rlb)]nN(R2)(R3), -N(R4)(R5)>n〇2' -NH-C(〇)-(C1-C4 ^.l-) -N(R4)(R5).Cl.Ci alkyl, -NH-C(0)-C丨-C6 alkyl, alkyl, -NH-S(0)m-C3-Cl() carbocyclyl , _NH_s(〇)m_4_13 member heterocyclic group; each Rla& Rlb is independently selected from hydrogen, Ci_C4 alkyl and C3_Ci〇 carbocyclyl; R is far from wind, C^-Cu alkyl, -C〇-C6 Restricted base - C3-Cl1 () carbocycle 15 201245116 base and - C〇-C6 extended alkyl - 4-13 membered heterocyclic group; R3 is selected from hydrogen, C|-C8 alkyl. . Heart alkyl _C3_Ci. Carbocyclyl, -C0-C6 alkylene-4, 13-membered heterocyclic group, _c(〇) Ci C6 alkyl, _c〇_c6· stretching base _n(r4)(r5), -cvc6 Stretching base -N (R4) (R5), _s (0) m. Ci_C6 ^ base, · / Π. a carbocyclyl group and a -S(0)m-(4-i3 member) heterocyclic group, wherein: each of the substituents, carbocyclic groups, alkylene groups or heterocyclic groups when represented by R2 or R3 are as appropriate And independently substituted by - substituents independently selected from the group consisting of: dimethyl, -OH, _〇-Cl_C4 alkyl, (Vc^, substituted (VM, _n(r4)(r5), a C3_Ciq carbocyclyl or a 4_ ring group; or a hetero atom to form a '7 membered monocyclic _ or a 6-membered bicyclic, spiro or bridged heterocyclic ring, wherein: A ring heterocyclic ring or the 6-13 membered bicyclic, spiro or bridged heteropoly is contained in 1 to 4 other heteroatoms independently selected from N, u 该, the 4-7 membered monocyclic heterocyclic ring or the 6-13 membered bicyclic ring , spiro or bridged: or optionally substituted with one or more substituents selected from the group consisting of: ^, % carbocyclyl, 4-13 membered heterocyclyl 'fluorine, gas, _〇H, _Ci_C4 Fluoroalkyl, alkyl,-0-C3-C1() carbocyclyl, -〇_4_13 member heterocyclic, _c"c4-alkylene C4-oqG alkyl, _C〇-C4 alkyl-hydrazine-Cl_C4 Fluoroalkyl, yl-C(〇)_CrC4 alkyl, -C(〇)N(R4)(R5), ^^, and -C0-C4 alkyl-N(R4)(r5), and 4 calcined Kigui The ring or heterocyclic substituent may optionally be fluorine, gas, 〇H, , 1-C4 fluoroheptyl, C!-C4 alkyl, -O-C1-C4, --Ci-C4 I I 201245116 Li 2 H (Cl~C4 alkyl) or -N(C丨-C4 alkyl) 2 substituted; \ and R5 are each independently selected from hydrogen and Ci-C4 alkyl; or nitrogen bound thereto The atoms together form a 4-7 membered heterocyclic ring containing, as the case may be, other heteroatoms from NS and hydrazine, wherein the 47 heterocyclic ring is optionally subjected to U, 惫, nw „ , ^ 乂 rolling, 虱...OH, =〇, Fluorine substituted κ4 alkyl, 14 alkyl or -Ci-CU extended alkyl-OC^-C4 alkyl, and optionally fused to phenyl; each R is independently selected from hydrogen, CyC丨〇 carbon Cyclic group, 4-13 membered heterocyclic group, chloro-indenyl Ii, CVC4 fluoroalkyl group, CVC4 alkyl group, -0-C3-C1Q carbocyclic group, -0-4-13 membered heterocyclic group, _C(rC4 alkyl group ... heart alkyl, _Cg_c4 alkyl-o-Ci-c4 fluoroalkyl, _c(0)_Ci_C4 alkyl, _c(0)n(r4)(r5), -N(R4)-C(0)-Cl_C4 Alkyl and _c〇_c4 alkylene_n(r4)(r5); or C(R6)4C=〇; each R7 is independently selected from hydrogen, -CG_C4 alkylene_c3_Cl() carbocyclic group , -(^-(^alkyl-'^^-heterocyclyl-匕-fluorene Alkyl 匕-匕 alkyl, -〇-C3-C丨〇 carbocyclyl,-04-13 membered heterocyclic group, -C〇-C4 alkylene-0-CVC4 alkyl, -C〇-C4 Alkyl-O-Ct-G fluoroalkyl, -CCCO-CVCU alkyl, -C(0)N(R4)(R5), _N(rYc(0)_Ci_C4 alkyl and _C(rC4 alkyl) -N(R4)(R5); and each carbocyclic or heterocyclic moiety of R6 and R7, optionally, by fluorine, chlorine, -0H, =〇, C---C4 fluoroalkyl, CVC4 alkyl, -0 -CVC4 alkyl, -0-CVC4 sulphur, - oxime 2, -NH (Ci-C4 alkyl) or -N (Ci-C4 alkyl) 2 substituted; each R8 is independently selected from hydrogen, C3-C Anthracene carbocyclyl, 4-13 membered heterocyclic group, fluorine, chlorine, -OH, C1-C4 fluoroalkyl, C1-C4 alkyl, -〇_C3-Ci. Carbocycle 17 201245116 base, -〇-4]3 negative heterocyclic group, _c〇_C4 院基_〇_Ci_C4 alkyl, 々A alkyl-〇-Ci-C4 fluoroalkyl, =〇, _c(〇 Ci C4 alkane, -c (9) N(R4)(r5), naphthyl and soil-N(R4)(R5); Q q alkylene R9 is independently selected from hydrogen, G-Cm carbon in the presence of Cyclic group, 4_i3 membered heterocyclic group, fluorine, gas, -OH, Cl_C4, alkyl, Ci_c4, 〇c "carbocyclyl, _〇·4-13 membered heterocyclic, cardinyl-04-ca Base, alkyl-0-CVC4 fluoroalkyl, = 〇, _c(〇)俨-C(9) Cong, ^ base and _c 二土-N(R4)(R5); 匕4 alkylene group 〇1 independent The ground is 0, 1 or 2; η is 1 or 2; Ρ is 〇 or an integer between 丨 and 4, and each = represents a single bond or a double bond 'at least one of which represents a single bond, ', limits The condition is that when the ring Ε is a heterocyclic (four) ring which is replaced by a condition which is replaced by the case, the XMl U is slipped in the first aspect of the specific example, and the meanings of the remaining variables in the ring bag are as a flute aJJA~ The Ding Dan 3 meaning system is as defined in the first specific example or in the above meaning. In another aspect of the first aspect of the first specific example, N(R7) and N, wherein Variable from I Mi ^., ^ ^ Μ, a sense line or as in the first specific example of the above meaning alternate meaning defined.

= —具體實例之第—態樣之另—態樣I環£為W 員雜壤基’ Q為c(r6)2，且产p 士 ()2且％ Ε令之所有其他環原子為碳， 18 201245116 其中其餘變數之含義係如第一具體 之含義中所定義。 甲或上述替代含義 在第—具體實例之第二態樣中，产 環E為非芳族環，其中其餘變數之：包含氤原子，且 中或上述替代含義之含義中所定義。h第—具體實例 在第—具體實例之第二態樣之 其中其餘變數之含義係;第= 述替代含義之含義中所定義。 _ I體實例中或上 在第-具體實例之第二態樣之 員雜環基；Q為C(r6)2，且環E中之古心甘’ ，％ E為4_7 其中其餘變數之含義係m -他環原子為碳， 之含義中所定義。 貧例中或上述替代含義= - The other aspect of the specific example - the I-ring is a member of the W-mixed soil base 'Q is c(r6)2, and the production of p-(2) and % Ε order all other ring atoms are carbon , 18 201245116 The meaning of the remaining variables is as defined in the first specific meaning. A or the above alternative meaning In the second aspect of the first embodiment, the ring E is a non-aromatic ring, wherein the remaining variables are: containing a halogen atom, and are defined in the meaning of the above alternative meaning. h - specific example The meaning of the remaining variables in the second aspect of the first embodiment is defined in the meaning of the alternative meaning. _ I in the instance or in the second embodiment of the second embodiment of the heterocyclic group; Q is C (r6) 2, and the ancient heart in the ring E ', % E is 4_7, the meaning of the remaining variables m - the ring atom is carbon, as defined in the meaning. In the case of poverty or the above alternative meaning

第—態樣中’環E包含環氮原子且 力6 - R6 ,。8、 (R8)〇-2 係選自 (RVIn the first aspect, 'ring E contains a ring nitrogen atom and the force 6 - R6 . 8, (R8) 〇-2 is selected from (RV

(8R)〇-2v 7r- I 在第—具體實例之第=離揭 ,Re R6 R9及 ’其中其餘變數之冬羞及 、十·接A人Μ 数之3義係如第一具體實例中或上 逃替代含義之含義中所定義。(8R)〇-2v 7r- I In the first specific example of the first instance, Re R6 R9 and 'the rest of the variables are winter shame and ten. Or as defined in the meaning of the meaning of the escape alternative.

(RV 在一特定態樣中，環Ε係選自 七-、 r / R 及 19 201245116 (Re)〇.2(RV In a particular aspect, the enthalpy is selected from seven-, r/R and 19 201245116 (Re) 〇.2

(R8)〇,(R8) Hey,

R6R6

Re 特定言之，環E為 R7 .甘山 如第-具體實例中或上述替代A義之其二其餘變數之含義係 朁代3義之含義中所定義。 在第〜具體實例之任— -A ^ :先刖心樣之另一態樣_，R7传 選自虱、-Cl_C6烷基、 糸 1-C6氟烧基及_匸〇_匚4伸、户苴 -C3-C10碳環基，或更 4伸坑基 、疋5之，R為氫、_C1_C6烧 -C0-C1 伸掠其 Γ1Λ 山 、 4基_C3'C1G &環基，其中其餘變數之含義係 第一具體實例中或上述替代 … η含義之含義中所定義。 在第一具體實例之任_ 无刖心樣之另一嘘樣中，X係選 自氮 氣、亂、-OCH3、-OC^F ΓΛΓ^ττ 、 3 〇CF3、-〇CH2F、-N(CH2)3 及 CF3， 或更特疋言之’X係選自氫、氣、氣、_〇cH3、_〇cF3及 -N(ch2)3，其中其餘變數之含義係如卜具體㈣Μ 替代含義之含義中所定義。 在第一具體實例之任一先前態樣之另-態樣令，γ為 氫，其中其餘變數之含義係如第—具體實例中或上述替代 含義之含義中所定義。 在本發明之另-具體實例中，化合物由圖式中描述之 任一化合物或其醫藥學上可接受之鹽表示。 下文展不由結構式（I )表示之例示性化合物。 20 201245116Re Specifically, the ring E is R7. The meaning of the remaining variables in the first-specific example or the above-mentioned alternative A meaning is defined in the meaning of the meaning of the third meaning. In the first-specific example - -A ^ : another aspect of the heart-shaped _, R7 is selected from 虱, -Cl_C6 alkyl, 糸1-C6 fluoroalkyl and _匸〇_匚4 extension,苴-C3-C10 carbocyclic group, or 4 keel base, 疋5, R is hydrogen, _C1_C6 burn-C0-C1 stretches its Γ1Λ mountain, 4 base _C3'C1G & ring base, the rest The meaning of the variables is defined in the first concrete example or in the above-mentioned alternative... meaning of the meaning of η. In another example of the first specific example, X is selected from the group consisting of nitrogen, chaos, -OCH3, -OC^F ΓΛΓ^ττ, 3 〇CF3, -〇CH2F, -N(CH2) ) 3 and CF3, or more specifically, the 'X series is selected from the group consisting of hydrogen, gas, gas, _〇cH3, _〇cF3, and -N(ch2)3, and the meanings of the remaining variables are as follows: (4) 替代As defined in the meaning. In a further aspect of any of the preceding aspects of the first embodiment, γ is hydrogen, and the meaning of the remaining variables is as defined in the first embodiment or in the meaning of the above alternative meanings. In another embodiment of the invention, the compound is represented by any of the compounds described in the formula or a pharmaceutically acceptable salt thereof. Exemplary compounds not represented by Structural Formula (I) are shown below. 20 201245116

h3c ch3 « OHH3c ch3 « OH

H3C^CH3 OH O OH'D S8-7-3 nh2H3C^CH3 OH O OH'D S8-7-3 nh2

_2_2

非對映異構體A S13*5-2-1-A 非對映異碱體B S13>5-2-1-BDiastereomer A S13*5-2-1-A diastereoisomer B S13>5-2-1-B

H3C、xh3 4 OHH3C, xh3 4 OH

OH Ο ΟΗ〇Η〇 Ο S2-7-7OH Ο ΟΗ〇Η〇 Ο S2-7-7

Cl h3c. Η H T^Y 1 II OH 0 OH0' S13-5-3-1Cl h3c. Η H T^Y 1 II OH 0 OH0' S13-5-3-1

〇ch3 ..H3C；nXH3〇ch3 ..H3C;nXH3

OH 0 OhPH0 0 S2-7-4OH 0 OhPH0 0 S2-7-4

ΟΗ Ο 〇Η〇Η〇 Ο S12-5-1ΟΗ Ο 〇Η〇Η〇 Ο S12-5-1

-« H H CH-« H H CH

OH Ο OH Ο O S2-7-1OH Ο OH Ο O S2-7-1

9CH, u H$VCH39CH, u H$VCH3

21 20124511621 201245116

S8-7-4S8-7-4

22 20124511622 201245116

Η3αΜΧΗ3 « ^ ΟΗΗ3αΜΧΗ3 « ^ ΟΗ

ο οηΡηο ο S11-8-4ο οηΡηο ο S11-8-4

非對映異構體A S3-7-3-A 非對映異_體巳 S3-7-3-BDiastereomer A S3-7-3-A diastereomeric 巳 巳 S3-7-3-B

23 201245116 9CH3 « H3hT°：h23 201245116 9CH3 « H3hT°:h

o ohoho o 非對映異構體A S3-7-4-A 非對映異_體日 S3-7-4-Bo ohoho o diastereomer A S3-7-4-A diastereomeric _ body day S3-7-4-B

異構體 A S14-6-1-A 異才屢體B S14-6-1-B C、ChIsomer A S14-6-1-A heterogeneous B S14-6-1-B C, Ch

h3c" xh3 OH O 0hPH〇 OH3c" xh3 OH O 0hPH〇 O

非對映異構體A S13-5-3-1-A 非對映異祕體B S13-5-3-1-B 非對映異磁體C S13-5-3-1-C 非對映異構體D S13-5-3-1-DDiastereomer A S13-5-3-1-A Diastereomeric B S13-5-3-1-B Diastereomers C S13-5-3-1-C Diastereomeric Isomer D S13-5-3-1-D

非對映異構體A S3-7-5-A 非對映異構體B S3-7-5-BDiastereomer A S3-7-5-A diastereomer B S3-7-5-B

H2H2

非對映異構體A 非對映異構體B S4-8-1-A S4-8-1-B OHOCH3 H CH3Diastereomer A Diastereomer B S4-8-1-A S4-8-1-B OHOCH3 H CH3

OH O OHOH O OH

非對映異構體A S9-12-1-A 非對映異椒體B S9-12-1-BDiastereomer A S9-12-1-A diastereoisomer B S9-12-1-B

非對映異構體A S5-4-1-ADiastereomer A S5-4-1-A

非對映異巍體B S5-4-1-BDiastereomeric steroid B S5-4-1-B

〇ch3 H H3^rCH3 B .OH〇ch3 H H3^rCH3 B .OH

0 o^Ho o0 o^Ho o

S9-12^3S9-12^3

非對映異構體A S2-7-5-A 非癖映異_體8 S2-7-5-B 24 201245116Diastereomer A S2-7-5-A Non-paraffin _body 8 S2-7-5-B 24 201245116

H3C Q 〇ch3 V % ch3 OH 0 h3c' .ch3 y Ηϊ ,ΟΗH3C Q 〇ch3 V % ch3 OH 0 h3c' .ch3 y Ηϊ ,ΟΗ

非對映異構體A S9-12-3-A 非對映異Μ體Β S9-12-3-BDiastereomer A S9-12-3-A diastereomeric oxime Β S9-12-3-B

非對映異構體A 非對映異構體B ο οηοηο οDiastereomer A Diastereomer B ο οηοηο ο

S4-8-6-A S4-8-6-BS4-8-6-A S4-8-6-B

S12-5-2S12-5-2

_2_2

非對映異構體A S4-8-5-ADiastereomer A S4-8-5-A

非对映異構體B S4-8-5-BDiastereomer B S4-8-5-B

非對映異構體A S3-7-1-ADiastereomer A S3-7-1-A

非讲映異緣體B S3-7-1-BNon-interpretative body B S3-7-1-B

S2-7-6-BS2-7-6-B

非對映異構體A S4-8-2-A 非封映異择體B S4-8-2-BDiastereomer A S4-8-2-A Non-enclosed heteroselector B S4-8-2-B

S9-12-5S9-12-5

S3-7-2S3-7-2

ch h3c、^JCh h3c, ^J

OH O 〇H"D S4-8-3OH O 〇H"D S4-8-3

h3c、nxh3 Η H f OHH3c, nxh3 Η H f OH

OH 0 OH〇H0 O S8-7-4OH 0 OH〇H0 O S8-7-4

S2-7-6-AS2-7-6-A

非對映異構體ADiastereomer A

S2-4-9-A 25 201245116S2-4-9-A 25 201245116

J~\ CF3 h3c. .ch3 Η Η ^ Λ h3c 八 Η V vVVvNH2 Τη Ιι 1 Om 0 HO ^ 0J~\ CF3 h3c. .ch3 Η Η ^ Λ h3c 八 Η V vVVvNH2 Τη Ιι 1 Om 0 HO ^ 0

非對映異構體A S14-6-2-A 非對映異構體B S14-6-2-B 非對映異構體B S14-6-2-C 非對映異構體B S14-6-2-DDiastereomer A S14-6-2-A Diastereomer B S14-6-2-B Diastereomer B S14-6-2-C Diastereomer B S14 -6-2-D

非對映異構體A S14-6-3-A 非對映異構體B S14-6-3-B 非對映異構體C S14-6-3-C 非對映異構體D S14-6-3-DDiastereomer A S14-6-3-A Diastereomer B S14-6-3-B Diastereomer C S14-6-3-C Diastereomer D S14 -6-3-D

非對映異構體A S14-6-4-A 非對映異構體B S14-6-4-B 非對映異構體C S14-6-4-C 非對映異構體D S14-6-4-D 非對映異構體A S14-6-5-A 非對映異構體B S14-6-5-B 非對映異構體C S14-6-5-C 非對映異構體D S14-6-5-D 26 201245116Diastereomer A S14-6-4-A Diastereomer B S14-6-4-B Diastereomer C S14-6-4-C Diastereomer D S14 -6-4-D diastereomer A S14-6-5-A diastereomer B S14-6-5-B diastereomer C S14-6-5-C non-pair Isomer D S14-6-5-D 26 201245116

H3C.n.CH3H3C.n.CH3

非對映異構體A S15-12-3-A 非對映異構體B S15-12-3-BDiastereomer A S15-12-3-A Diastereomer B S15-12-3-B

h3c ch3 y y T OHH3c ch3 y y T OH

OH O HO Ο O 非對映異構體A S15-12-6-AOH O HO Ο O diastereomer A S15-12-6-A

OH O OH〇H〇 OOH O OH〇H〇 O

非對映異構體a S16-8-1-A 非對映異構體B S16-8-1-BDiastereomer a S16-8-1-A diastereomer B S16-8-1-B

H3C、 /CH3 Η Η T ΛH3C, /CH3 Η Η T Λ

h3c、 ,ch3 -H 7 OHH3c, ,ch3 -H 7 OH

OH O OH Ο O 非對映異構體A S16-8-4-A 非對映異構體B S16-8-4-BOH O OH Ο O diastereomer A S16-8-4-A diastereomer B S16-8-4-B

OH OOH O

非對映異構體A S16-8-5-A 非對映異構體B S16-8-5-B 27 201245116Diastereomer A S16-8-5-A Diastereomer B S16-8-5-B 27 201245116

非對映異構體A S17-10-A 非對映異構體A S18-4-1A 非對映異構體B S17-10-B 非對映異構體B S18-4-1BDiastereomer A S17-10-A Diastereomer A S18-4-1A Diastereomer B S17-10-B Diastereomer B S18-4-1B

非對映異構體A S18-4-2A 非對映異構體B S18-4-2BDiastereomer A S18-4-2A Diastereomer B S18-4-2B

非對映異構體A S18-4-3A 非對映異構體A S18-4-3BDiastereomer A S18-4-3A Diastereomer A S18-4-3B

非對映異構體A S18-4-4A 非對映異構體B S18-4-4BDiastereomer A S18-4-4A Diastereomer B S18-4-4B

非對映異構體A S19-10-2-A 非對映異構體A S19-10-3-ADiastereomer A S19-10-2-A Diastereomer A S19-10-3-A

非對映異構體B S19-10-2-B 非對映異構體B S19-10-3-BDiastereomer B S19-10-2-B Diastereomer B S19-10-3-B

非對映異構體A S19-10-4-A 非對映異構體A S19-10-5-ADiastereomer A S19-10-4-A Diastereomer A S19-10-5-A

非對映異構體B S19-10-4-B 非對映異構體B S19-10-5-B 28 201245116Diastereomer B S19-10-4-B Diastereomer B S19-10-5-B 28 201245116

S19-10-6 ΗS19-10-6 Η

S20-9-2S20-9-2

Η 非對映異構體AS20-93-A 非對映異構體Β S20-9-3-BΗ diastereomer AS20-93-A diastereomer Β S20-9-3-B

Η 非對映異構體A S20-94-A 非對映異構體B S20-9~4-B ΗΗ diastereomer A S20-94-A diastereomer B S20-9~4-B Η

非對映異構體A S20-9-5-A 非對映異磁體B S20-9-5-B H3C CH3 μ Ν Η ： ΟΗDiastereomer A S20-9-5-A Diastereomers B S20-9-5-B H3C CH3 μ Ν ΟΗ : ΟΗ

非對映異構體A S20-94-A 非對映異構體B S2〇-9>6>B ΟΗ Ο ΗΟ # Ο Ο 非對映異構體A S20-9-74 非對映異構體Β S2〇-9-7>BDiastereomer A S20-94-A diastereomer B S2〇-9>6>B ΟΗ Ο ΗΟ# Ο Ο diastereomer A S20-9-74 diastereoisomer Body S2〇-9-7>B

H3C CH3 « ^ OHH3C CH3 « ^ OH

非對映異構體A 520·9·β·Α 非對映異裱體B S2〇-9~8»BDiastereomer A 520·9·β·Α diastereomeric steroid B S2〇-9~8»B

非對映異構體A S20-9*9-A 非對映異碡體BS：20-9>9»B 29 201245116Diastereomer A S20-9*9-A Diastereomers BS: 20-9>9»B 29 201245116

,ch3 h3c ch3 H OH,ch3 h3c ch3 H OH

OH O HO ti Ο O 非對映異構體A S20』-10-A 非對映異構體B S2〇-9-1〇-BOH O HO ti Ο O diastereomer A S20』-10-A diastereomer B S2〇-9-1〇-B

H3c、/CH3 y OHH3c, /CH3 y OH

OH O HO ^ Ο O 非對映異構體A S20-9-11-A 非對映異構體B S2〇-9_11-BOH O HO ^ Ο O diastereomer A S20-9-11-A diastereomer B S2〇-9_11-B

〇 丫 CH3 h3c ch3 « OH〇 丫 CH3 h3c ch3 « OH

S20<9-12S20<9-12

〇lCH3〇lCH3

非對映異構體A S20>9-14-A 非對映異構體B S2〇*8-14>B 〇=VCH3Diastereomer A S20>9-14-A Diastereomer B S2〇*8-14>B 〇=VCH3

非對映異構體B S20-9*1$BDiastereomer B S20-9*1$B

非對映異構體B S21-16-6-B 非對映異構體A S21-16-6-A 非對映異構體A S21-16-1-A 非對映異構體B S21-16-1-BDiastereomer B S21-16-6-B Diastereomer A S21-16-6-A Diastereomer A S21-16-1-A Diastereomer B S21 -16-1-B

非對映異構體A S21-16-3-A 非對映異構體B S21-16-3-B 30 201245116Diastereomer A S21-16-3-A Diastereomer B S21-16-3-B 30 201245116

非對映異構體A S21-16-4-A 非對映異構體B S21-16-4-B 非對映異構體A S21-16-5-A 非對映異構體B S21-16-5-B ho2cDiastereomer A S21-16-4-A Diastereomer B S21-16-4-B Diastereomer A S21-16-5-A Diastereomer B S21 -16-5-B ho2c

非對映異構體A S21-16-7-A OCF3 H3C. xh3 y H? OH ㈣ η，rCH3Diastereomer A S21-16-7-A OCF3 H3C. xh3 y H? OH (IV) η,rCH3

h2n OH O HO Η O C 非對映異構體B S21-17-1-BH2n OH O HO Η O C diastereomer B S21-17-1-B

OH O HO H 〇 〇 非對映異構體A S22-8-1-A 非對映異構體B S22-8-1-BOH O HO H 〇 〇 diastereomer A S22-8-1-A diastereomer B S22-8-1-B

h3c、.xh3 9cf3 L, m n 3 H H ： .OHH3c, .xh3 9cf3 L, m n 3 H H : .OH

.OH O HO H 〇 非對映異構體A S22-8-2-A 非對映異構體B S22-8-2-B 〇cf3 h3c、χη3 HV0H a ocf3 Η ΗΪΤ h3〇 Vv Τ ¥ OH 0 Xis I 了 T OH 0 ch3 oh.OH O HO H 〇 diastereomer A S22-8-2-A diastereomer B S22-8-2-B 〇cf3 h3c, χη3 HV0H a ocf3 Η ΗΪΤ h3〇Vv Τ ¥ OH 0 Xis I has T OH 0 ch3 oh

非對映異構體A S22-8-3-A 非對映異構體B S22-8-3-B 非對映異構體A S22-8-4-A 非對映異構體B S22-8-4-BDiastereomer A S22-8-3-A Diastereomer B S22-8-3-B Diastereomer A S22-8-4-A Diastereomer B S22 -8-4-B

0H 0 HO η 〇 〇 非對映異構體A S22-8-5-A0H 0 HO η 〇 〇 diastereomer A S22-8-5-A

非對映異構體A S22-8-6-A 非對映異構體B S22-8-6-B 31 201245116Diastereomer A S22-8-6-A Diastereomer B S22-8-6-B 31 201245116

非對映異構體B S22-8-7-BDiastereomer B S22-8-7-B

非對映異構體A S22-8-8-A 非對映異構體B S22-8-8-BDiastereomer A S22-8-8-A diastereomer B S22-8-8-B

非對映異構體A S24-5-2-ADiastereomer A S24-5-2-A

非對映異構體A S24-6-1-ADiastereomer A S24-6-1-A

非對映異構體A S24-6-2-A 32 201245116Diastereomer A S24-6-2-A 32 201245116

非對映異構體A S25-3-ADiastereomer A S25-3-A

非對映異構體A S26-4-ADiastereomer A S26-4-A

非對映異構體A S28-7-A 非對映異構體B S28-7-BDiastereomer A S28-7-A diastereomer B S28-7-B

非對映異構體A S29-15-2-A 非對映異構體B S29-15-2-BDiastereomer A S29-15-2-A diastereomer B S29-15-2-B

非對映異構體A S29-15-1-A 非對映異構體B S29-15-1-BDiastereomer A S29-15-1-A diastereomer B S29-15-1-B

非對映異構體A S29-15-3-A 非對映異構體B S29-15-3-BDiastereomer A S29-15-3-A diastereomer B S29-15-3-B

非對映異構體A S29-15-4-A 非對映異構體B S29-15-4-B 〜CH, 33 201245116 「烧基（alkyl )」意謂具有指定碳原子數目的視情況經 取代之飽和脂族分支鏈或直鏈單價烴基。因此，「（Ci_C6)烧 基」意謂具有呈直鏈或分支鏈排列之1至6個碳原子之基 團。「（Ci-C6)燒基」包括甲基、乙基、丙基、丁基、戊基及 己基。 「伸烷基（alkylene)」意謂具有指定碳原子數目的視情 況經取代之儉和脂族分支鏈或直鏈二價烴基。因此，「（ C 1 _ ^ ) 伸炫;基」意謂具有呈直鏈排列之1至6個碳原子之二價飽 和脂族基，例如-[(CHA]-，其中η為1至6之整數，「（Ci_C6：) 伸烧基」包括亞甲基、伸乙基、伸丙基、伸丁基、伸戊美 及伸己基。或者，「（Cl-C6)伸烷基」意謂具有呈分支鏈排列 之1至6個碳原子之二價飽和基團，例如： -[(CH2CH2CH2CH2CH(CH3)]- 、 -[(CH2CH2CH2CH2C(CH3)2]-、-[(CH2C(CH3)2CH(CH3))1-及其Diastereomer A S29-15-4-A Diastereomer B S29-15-4-B ~CH, 33 201245116 "Alkyl" means the case with the specified number of carbon atoms. Substituted saturated aliphatic branched or linear monovalent hydrocarbon. Thus, "(Ci_C6)alkyl" means a group having from 1 to 6 carbon atoms arranged in a straight or branched chain. The "(Ci-C6) alkyl group" includes a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group and a hexyl group. "Alkylene" means an optionally substituted anthracene and an aliphatic branched or straight-chain divalent hydrocarbon radical having the specified number of carbon atoms. Therefore, "(C 1 _ ^ ) is swelled; base" means a divalent saturated aliphatic group having 1 to 6 carbon atoms arranged in a straight chain, for example, -[(CHA]-, wherein η is 1 to 6 The integer, "(Ci_C6:) stretching base" includes methylene, ethyl, propyl, butyl, butyl, and hexyl. Alternatively, "(Cl-C6) alkyl" means a divalent saturated group having 1 to 6 carbon atoms arranged in a branched chain, for example: -[(CH2CH2CH2CH2CH(CH3)]-, -[(CH2CH2CH2CH2C(CH3)2]-, -[(CH2C(CH3)2CH) (CH3))1- and

類似基團。特定分支鏈C3伸烷4Similar group. Specific branch chain C3 alkane 4

烷基為 結構式I中之各烷基或伸烷基視情況且獨立地經一或 多個獨立地選自以下之取代基取代：鹵基、_〇H、=〇、 -0-(C丨-c4)烷基、經氟取代之（(：丨-(：4)烷基、-SCOUCVC^) 烷基及-N(R5)(R5)。 「芳基（aryl)」或「芳族（aromatic)」意謂芳族單環或 多環（例如雙環或三環）碳環系統。在一具體實例中，「芳 34 201245116 至:2員單環或雙環系統。芳基系統包括（但不 、石二、秦基、苐基、節基、奠基及蒽基。 圓。「石(earbGeyeIyi)」意謂僅具有環碳原子之環狀基 m ^ ^ ^ 3- -4- 貝至12貝飽和、部分飽和或不飽和 、衣Al辰或6員至12員关其搭' 稠人雔璟^ ^ 員方基環。碳環基部分可為單環、 一橋連雙環、螺雙環或多環部分。 皁環碳環基為具有指定碳原子數 族環煙環或芳❹環。單環碳 鮮或不餘和脂 環块基及苯基。 ^土匕括環烧基、環烯基、 稠合雙環碳環基具有兩 環。第-個環為單環碳環基，且y相鄰環原子的 單環雜環基。 第—個核為單環碳環基或 橋連雙環碳環基具有兩個共 鄰環原子的環。第一個環為單環碳=二個或三個以上相 環碳環基或單環雜環基。 》土，且第二個環為單 螺雙環碳環基具有㈣僅_ m 第-個環為單環碳環基，且=®裱原子之環。 雜環基。 —個環為單環碳環基或單環 多環碳環其§ 厌哀基具有兩個以上之 ，糸統），且相鄰環共同具有至少—個产:，三個環形成三 早環碳環基，且其餘環結構 ^原子。第―個環為 多環系統包括_人 \ %基或單環雜if # 例公、橋連及螺璟备 #免基。 至少兩個共同具有兩個相鄰環原^的二稠合多環系統具有 至少兩個僅共同具有一個環原 ¥。螺多環系統具有 '。橋連多環系统具有 35 201245116 至少兩個共同具有三個或 一阴从上相 邮％原子之環。 「環烷基（cycloalkyl)」意謂飽和脂旌 Γ ^ %々彻葆裱烴環。因此， C3-C7環烧基」意謂（3員至7員）飽和炉 )靶和知族環烴環之烴基。 C3_C7環烷基包括（但不限於）環丙基、 卢3 “ 衣丁基、％戊基' %己基及環庚基。 「 環烯（cycloalkene )」意謂在環巾且女 甲^有—或多個雙鍵之 脂族環烴環。 「環炔（cycloalkyne)」意謂在環中呈古 、有—或多個參鍵之 月曰族環烴環。 「雜（hetero )」係指環系統中之至少__ 5 ^個碳原子成員置 換為至^一個選自N、S及0之雜原子。「 . 雜」亦柏置換非 咏糸統中之至少一個碳肩子忐g 原子成貝雜％系統或雜非環系統 之1、2、3或4個碳原子成員可置換為雜原子。 「雜環基（heterocyclyl)」意謂含有丨、2 獨立地選自N、〇或，之雜原子的環狀4員至 二5個 不飽和脂族或芳族環。當一個雜原子為：或 經單氣化式雔条儿，·B I可視情況 早軋化或雙氧化（亦即_S(〇)U(〇) 璜、辆人她》 )雜^基可為單 <稠0又裱、橋連雙環、螺雙環或多環基團。 「飽和雜環基（saturated heter〇cycly 飽和度（亦即，盔雙鍵或史彳 ，明…、任何不 ，…又建次參鍵）之脂族雜環基。 環 '稠合雙環、橋連雙環、螺雙環或多環基團。、’”、早 單環飽和雜環基之實例包括（但不限 吡咯啶、喻a ^ 礼雜環丁烷、 啶、哌口井、氮雜環庚烷、六氫嘧啶 四氫哌喃、嗎嗌、访你d£ a w虱呋喃、 馬啉π代馬琳、硫代嗎淋！山二氣化物、四氫 36 201245116 -2H-U2-嘆畊、四氫嗔卩井【山二 異噻。坐喷U·二氧化物。 -氡化"噻唑咬、 稠合雙環雜環基具有兩個共 環。第-個環為單環雜環基，且第：：：目鄰％原子的 如環烧基或苯基）戍單^環^個環為單環碳環（諸 (。…環貌Λ，i: 舉例而言，第二個環為 J衣况基，诸如環丙基、環丁 或者，第二個产成—甘 衣戊基及環己基。 不限於）：jrr.稠合雙環雜環基之實例包括（但 23 q 戍二婦并⑷t各基、 2,3-二氫]Η-苯并[d]咪異引木琳、 ^ « r . 紙本井[d]噁唑、2 3 -鸟 开⑷噻唑、八氫苯并⑷噁唑、八氫]Η 1]… 氫苯并⑷。塞唾、八氫環戊 &本并⑷咪嗤、八 L衣戍一席并[。卜比0各、3-氣《& ™ 己烷及3-氮雜雙環[3 2〇]庚烷。 ”裱[3.1.0] 螺雙環雜環基具有兩個僅共同具有— .第一個環為單環雜環基，且第二個^^環。 烷基或苯基）戋單璜雜pi i 早衣奴％ (諸如環 援Μ 環基。舉例而言，第二個環Γ、 裒烷基。或者，第二個環為苯 3 6) 括（但不限於）氮雜碟心 累雙銥雜環基之實例包 •5]二氮 氮雜螺二=:4·， L j卞烷及3,9-二氮雜螺[5.5]十—俨 橋連雙環雜環基具有兩個共同具有三; 鄰環原子的環。第-個環為單環雜環基：且另或三個以上相 ^碳環(諸如環烧基或苯基)或單環雜環基== 銥基之實例包括（但不限於）氮雜雙環[33 ^雜 雙環[3.3·1]壬烧、氮雜雙環似椒、3_氮雜雙疋環^] 37 201245116 辛烧、6-氣雜雙環辛烧及氮雜雙即 雜雙環[2.2.2]辛烷。 』申烷、2-氮 夕J衣雜環基具有兩個以上之環，盆中一 如，三個環形忠二户备祕、 一者為雜環基（例 原子。各pj具有至少一個環 、 夕长糸統包括稠合、橋連及螺環系站 統具有至少兩個共同具有兩個相鄰環原::環稠 :::::兩個僅共同具有-個環原子之環。橋 環:、有至^兩個共同具有三個或三個以上相鄰環原子之 (heteroaryl), 4 r # ^ ^ ( g)J思謂5員至12員單價雜芳族單環 基合右！。 平衣或雙環基團。雜芳 、2、3或4個獨立地選自n、〇b c Ν 〇及S之雜原子。雜 一 7括（但不限於）吱喃令坐、嗟吩、丨， ，，—畊、咪唑、異噻唑、異噁唑、吡4 ^ 吡啶Μ铥 比唑、嗒D井、吡啶' 芳…物、❹井m各、四。坐及售唾。雙環雜 柄二Γ 但不限於）雙環[4.4·0]稍環系統及雙環[4丄〇] :系統’諸如，朵畊、十朵、異十朵、十坐、苯并㈣、 开噻唑、嘌呤、喹啉、異喹啉、 〒唧、呔α井、喹唑啉、 右琳、1，8-α奈啶及喋啶。 雜個特定具體實例中，環Ε之取代基⑭碳環基或 基^部分視情況且獨立地經取代。例示性取代基包括函 土 -(^4)燒基、_0H〜0、_0_((Vc4)烧基、_(Ci C4)伸 38 201245116 貌基-ckg-C4)烧基、經鹵基取代之（Cl_C4)烷基、經^基取 代之o-CC^-Cd烷基及-ccoHCrC^)烷基。 本文所用之「鹵素（halogen)」係指氟、氯、溴或碘。 「烷氧基（alkoxy)」意謂經由氧連接原子連接之烷基。 「（CVCe)烷氧基（（CrCJ-alkoxy)」包括甲氧基、乙氧基、 丙氧基、丁氧基、戊氧基及己氧基。 鹵烷基及_環烷基包括單鹵烷基、多_烷基及全鹵烷 基’其中各鹵素係獨立地選自氟、氯及漠。 「鹵素」與「鹵基（halo)」在本文中可互換使用且各指 氟、氯、漠或峨。 「氟（fluoro )」意謂-F 〇 如本文所用，經氟取代之（Cl_C4)烷基意謂經一或多個 -F基團取代之（CKC4)烷基。經氟取代之（Ci_C4)烷基之實例 & ^ ^ m ^ ) -CF3 ^ -CH2CF3 ' -CH2CF2H ' -ch2ch2f 及-CH2CH2CF3 0 「天然存在之胺基酸側鏈部分（naturally 〇ccurHng amino acid side chain moiety )」係指天然胺基酸中存在之任 何胺基酸側鏈部分。 本發明之另一具體實例為—種醫藥組成物，其包含一 或多種醫藥學上可接受之載劑及/或稀釋劑以及本文所揭示 之化合物或其醫藥學上可接受之鹽。 「醫藥學上可接受之載劑（pharmaceuticaUy acceptabu carder)」及「醫藥學上可接受之稀釋劑 acceptable diluent)」意謂具有足夠純度及品質以用於調配 39 201245116 在向動物或人類適當投予時’典型地不會產生不良反應的 本發明組成物且可用作藥物物質（亦即本發明化合物）之 媒劑的非治療性組分。 亦包括本發明化合物之醫藥學上可接受之鹽。舉例而 S ’含有胺或其他驗性基團之本發明化合物的酸鹽可藉由 使该化合物與合適的有機酸或無機酸反應從而產生醫藥學 上可接爻之陰離子鹽形式來獲得。陰離子鹽之實例包括乙 酸鹽、苯磺酸鹽、苯曱酸鹽、碳酸氫鹽、酒石酸氫鹽、溴 化物、乙二胺四乙酸鈣、樟腦磺酸鹽、碳酸鹽、氣化物、 衿檬酸鹽、二鹽酸鹽、乙二胺四乙酸鹽、乙二磺酸鹽、依 託酸鹽（estolate)、乙磺酸鹽、反丁烯二酸鹽、甘油酸鹽、 葡糖酸鹽、麩胺酸鹽、乙内醯胺苯胂酸鹽 (glycollylarsanilate )、己基間苯二酚酸鹽、氫溴酸鹽、鹽酸 鹽、羥基萘甲酸鹽、碘化物、羥乙基磺酸鹽、乳酸鹽、乳 糖k鹽、韻果酸鹽、順丁稀二酸鹽、杏仁酸鹽、甲續酸鹽、 甲基4 SiL鹽、黏液酸鹽、秦績酸鹽、硝酸鹽、雙經萘酸鹽、 泛酸鹽、磷酸鹽/二磷酸鹽、聚半乳糖醛酸鹽、水楊酸鹽、. 硬脂酸鹽、次乙酸鹽、丁二酸鹽、硫酸鹽、丹寧酸鹽、酒 石酸鹽、茶氣酸鹽（teoclate)、甲苯磺酸鹽及三乙基碘化物 (triethiodide )鹽。 含有羧酸或其他酸性官能基之本發明化合物的鹽可藉 由與合適的鹼反應來製備。該種醫藥學上可接受之鹽可用 提供醫藥學上可接受之陽離子的鹼製成，纟包括鹼金屬鹽 (尤其為鈉鹽及鉀鹽）、鹼土金屬鹽（尤其為鈣鹽及鎂鹽）、 40 201245116 銘鹽及鍵蹿，丨、/ β上1 兮等有：二 學上可接受之有機驗製成之鹽， :專有機驗“三甲胺、三乙胺、嗎琳W、曱 =定、二環已胺、Ν，Ν,·二苯甲基乙二胺、2-經基乙胺、 經乙基）胺、三_(2_經乙基）胺、普魯卡因（⑹）、 -本甲基哌啶、去氫松香胺、Ν，Ν|雙去氫松香胺、葡糖胺、 Ν_甲基U糖胺、三甲基_、奎寧、喹琳及驗性胺基酸（諸 如離胺酸及精胺酸）。 本發明亦包括各種異構體及其混合物。某些本發明化 合物可以各種立體異構形式存在。立體異構體為僅在空間 Ο列上有所不同之化合物。對映異構體為一對立體異構 體，其鏡像最通常因其含有—個充當手性中心的經不對稱 取代之碳原子而不可重疊。「對映異構體―」意 謂彼此互為鏡像且不可重疊之_對分子中之—者。非對映 異構體為最通常因含有兩個或兩個以上經不對稱取代之碳 原子而不呈鏡像關係的立體異構體。「m」表示圍繞 -或多個手性碳原子之取代基的構型。t手性中心未確定 為R或S時，存在純對映異構體或兩種構型之混合物。 「外消旋物（racemate)」或「外消旋混合物（⑽― mixture)」意謂具有等莫耳量之兩種對映異構體的化合物， 其中該等混合物不展現光學活性；亦即其不能旋轉偏振光 平面。 本發明化合物可以個別異構體形式藉由異構體特異性 合成而製得或自異構體混合物解析得之。習知解析技術包 括使用光學活性酸形成成對異構體中之各異構體之自由鹼 41 201245116 使用光學活性胺形成 鹽（繼而分步結晶及 的鹽（繼而分步結晶及再生自由驗）； 成對異構體中之各異構體之酸形式的 再生自由學純㈣、胺或醇形成&對異構體中 之各異構體的酯或醯胺（繼而層析分離及移除手性助劑” 或使用各種熟知之層析法解析起始物質或最終產物之異構 體混合物。 ~ 當根據結構命名或描繪所揭示之化合物的立體化學 時，所命名或描繪之立體異構體相對於其他立 至少60重量。重量％、80重量％、9〇重量= %或99.9重量％純。當根據結構命名或描繪單—對映異構體 時，所描繪或命名之對映異構體為至少6〇重量％、7〇重量 %、80重量％、90重量％、99重量％或99 9重量％光學純。 重量百分比光學純度為所存在之對映異構體的重量除以所 存在之對映異構體與其光學異構體的組合重量所得之比 值。 本电明亦提供一種治療或預防個體感染或定殖 (colonization)的方法，其包含投予該個體有效量之本發明 化合物或其醫藥學上可接受之鹽。 本發明亦提供一種治療或預防患有四環素反應性疾病 或病症之個體的方法，其包含投予該個體有效量之本發明 化合物或其醫藥學上可接受之鹽。 四環素反應性疾病或病症（tetracyCline resp〇nsive disease or disorder )」係指可藉由投予本發明之四環素化合 物來治療、預防或者改善的疾病或病症。四環素反應性疾 42 201245116 病或病症包括感染、癌症、發炎病症、自體免疫疾病、動 脈魏、角膜潰癌作用、氣腫、關節炎、骨質疏鬆症1 關節炎、多發性硬化症、骨肉瘤、骨髓炎、支氣管擴張症、 慢性肺阻塞性疾病、皮膚及眼部疾病、牙周炎、骨質疏鬆 症、類風濕性關節炎、潰瘍性結腸炎、前列腺炎、腫瘤生 :及侵襲、轉移、糖尿病、糖尿病性蛋白尿、泛細支氣管 炎、主動脈或血管動脈瘤、皮膚組織創口、乾眼症、骨骼 及軟骨退化（bone，cartilage degradati〇n)、廬疾、衰老、糖 尿病、血管t風、神經退化性病症、心臟病、幼年糖尿病、 急性及慢性支氣管炎、竇炎及呼吸道感染（包括普通感 冒）、韋格納肉牙腫病（Wegener，s granul〇mat〇sis);嗜令性 皮膚病及其他發炎性疾病’諸如癌療樣皮炎、白血球破裂 性血管炎（ieuk〇cytoclastic vasculitis)、大皰性紅斑狼瘡、 膿皰性牛皮癬、持久性隆起性紅斑；白斑病、盤狀紅斑狼 瘡；壞疽性膿皮病、膿皰性牛皮癬、目叙炎或瞼腺炎、阿兹 海默氏病（Alzheimer^ disease)、退化性黃斑病；急性及慢 性月腸炎及結腸炎；急性及慢性膀胱炎及尿道炎；急性及 慢性皮炎；急性及慢性結膜炎、急性及慢性漿膜炎、尿毒 性心包炎；急性及慢性膽囊炎（ch〇lecystis )、囊腫性纖維 化、急性及慢性陰道炎、急性及慢性葡萄膜炎、藥物反應、 昆蟲咬傷、燒傷及曬傷、骨質量異常（b〇ne mass）、 急性肺損傷、慢性肺部病症、局部缺血、中風或缺血性中 風、皮膚創口、主動脈或血管動脈瘤、糖尿病性視網膜病、 出血性中風、血管新生，及已發現四環素化合物可具有活 43 201245116 性之其他病況（參見例如美國專利第5,789,395號；第 5,834,450 號；第 6,277,061 號；及第 5,532,227 號，其各自 明確地以引用方式併入本文中）。 另外，涵蓋一種治療可受益於調節氧化氮、金屬蛋白 酶、促炎性介體及細胞激素、活性氧物質、免疫反應（包 括趨化性、淋巴細胞轉型、延遲性過敏反應、抗體產生、 吞嗟作用及吞噬細胞氧化代謝）之組分的表現及/或功能之 任何疾病或疾病病況的方法。涵蓋一種治療可受益於調節c 活性蛋白之表現及/或功能、信號傳導路徑（例如FAK信號 傳導路徑）及/或增強COX-2表現及PGE2產生之任何疾病 或疾病病況的方法。涵蓋一種治療可受益於抑制新血管生 成之任何疾病或疾病病況的方法。 本發明化合物可用於預防或治療重要之哺乳動物及獸 醫學疾病，諸如腹瀉、尿路感染、皮膚及皮膚結構（包括 創口）感染、蜂窩組織炎及膿腫、耳鼻喉感染、乳房炎及 其類似疾病。另外，亦包括使用本發明之四環素化合物治 療贅瘤之方法（vail der Bozert 等人，Cancer Res·，48. 6686-6690 (1988))〇 可使用本發明化合物或其醫藥學上可接受之鹽治療的 感染包括（但不限於）皮膚感染、GI感染、尿路感染、生 殖尿路感染、呼吸道感染、竇感染、中耳感染、全身感染、 腹内感染、腎盂腎炎、肺炎、細菌性陰道炎 '鏈球菌性喉 °龍痛、慢性細菌性前列腺炎、婦科及骨盆腔感染、性傳播 細菌性疾病、眼部及耳部感染、霍亂、流行性感冒、支氣 44 201245116 • 管炎、痤瘡、牛皮癬、紅斑痤瘡、膿皰病、瘧疾、性傳播 疾病（包括梅毒及淋病）、退伍軍人病（Legi〇nnaires, disease)、萊姆病（Lyme disease)、落磯山斑點熱（R〇cky M〇Untainspottedfever)、q 熱（Qfever)、斑疹傷寒、腺鼠 疫（bubomc Plague )、氣性壞疽、醫院獲得性感染、鉤端螺 旋體病（leptospkosis)、百日咳、炭疽以及由造成性病淋巴 肉芽腫、包涵體結膜炎或鸚武|病（pSittac〇sis )之病原體所 致之感染。感染可為細菌性、真菌性、寄生蟲性及病毒性 感染（包括對其他四環素化合物有抗性之感染）。特定言 之，感染為腎盂腎炎或尿路感染。 在另一具體實例中，本發明化合物可用於尿路感染 (UTI )、慢性尿路感染（cUTI )或腎盂腎炎療法。 在另一具體實例中，本發明化合物可用於治療選自尿 路感染、呼吸道感染、腹内感染、急性或慢性皮膚及皮膚 結構感染及肺炎之感染。在一特定具體實例中，尿路感染、 呼吸道感染、腹内感染、急性或慢性皮膚及皮膚結構感染 或肺炎為醫院獲得性。在另一特定具體實例中，可為醫院 獲得之尿路感染、呼吸道感染、腹内感染、急性或慢性皮 膚及皮膚結構感染或肺炎係由革蘭氏陰性生物體（gram negative organism )引起。在一特定具體實例中，革蘭氏陰 性生物體為綠膿桿菌（户.)及克留氏肺炎桿菌（尺 )。在另一特定具體實例中，革蘭氏陰性生物體為 腸内菌科（Enterobacteriaceae )。在一甚至更特定具體實例 中，感染為尿路感染（例如，醫院獲得性尿路感染或亦可 45 201245116 一甚至更特定具體實例The alkyl group is each alkyl or alkylene group of formula I optionally substituted with one or more substituents independently selected from the group consisting of halo, 〇H, =〇, -0-(C丨-c4) alkyl, substituted by fluorine ((: 丨-(:4) alkyl, -SCOUCVC^) alkyl and -N(R5)(R5). "aryl" or "aromatic" (aromatic) means an aromatic monocyclic or polycyclic (eg bicyclic or tricyclic) carbocyclic ring system. In a specific example, "fang 34 201245116 to: 2 member single or double ring systems. aryl systems include (but No, stone two, Qinji, sulfhydryl, base, foundation and base. Round (earbGeyeIyi) means a cyclic group with only ring carbon atoms m ^ ^ ^ 3- -4- to 12 Shell saturated, partially saturated or unsaturated, clothing Alchen or 6 to 12 members off the 'thickening 雔璟 ^ ^ member base ring. Carbocyclic group can be single ring, one bridge double ring, screw double ring or more Ring moiety. A saponin carbocyclyl group is a ring or fluorene ring having a specified number of carbon atoms. A single ring of carbon is fresh or not, and an alicyclic block group and a phenyl group. a fused bicyclic carbocyclic group having two rings. a monocyclic heterocyclic group having a monocyclic carbocyclic group and y adjacent to the ring atom. The first nucleus is a monocyclic carbocyclic group or a bridged bicyclic carbocyclic group having two rings adjacent to the ring atom. The ring is a monocyclic carbon = two or more phase-ring carbocyclic groups or a monocyclic heterocyclic group. "Soil, and the second ring is a mono-spirobicyclic carbocyclic group having (iv) only _ m first-ring is a single a cyclic carbocyclic group, and a ring of =® fluorene atoms. Heterocyclic group. — A ring is a monocyclic carbocyclic group or a monocyclic polycyclic carbon ring. § Arsotropic groups have more than two, 糸, and The adjacent rings have at least one product: three rings form a three-earth ring carbocyclic group, and the remaining ring structures are ^ atoms. The first ring is a polycyclic system including _human \ % base or single ring hetero if # , bridging and snail preparation #免基. At least two two fused multi-ring systems having two adjacent rings have at least two having only one ring original. The snail multi-ring system has a 'bridge. A multi-ring system has 35 201245116 at least two rings having a total of three or one atomic from the upper atomic %. "Cycloalkyl" means saturated lipid 旌Γ ^ %々 Bao mounted hydrocarbon ring. Thus, C3-C7 cycloalkyl group burning "means (3-7) with saturated furnace) target and known aromatic hydrocarbon cyclic hydrocarbon rings. The C3_C7 cycloalkyl group includes, but is not limited to, cyclopropyl, lutene 3, butyl ketone, % pentyl '% hexyl, and cycloheptyl. "Cycloalkene" means in the ring towel and the female armor has - Or a plurality of double bond aliphatic cyclic hydrocarbon rings. "Cycloalkyne" means a cyclic hydrocarbon ring in the ring that is ancient, has - or has a plurality of bonds. "Hetero" means that at least __ 5 ^ carbon atom members in the ring system are replaced by a hetero atom selected from N, S and 0. " . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . "Heterocyclyl" means a cyclic 4 to 2 unsaturated aliphatic or aromatic ring containing fluorene, 2 independently selected from N, hydrazine or a hetero atom. When a hetero atom is: or a single gasification type of rafter, BI can be early rolled or double oxidized (that is, _S(〇)U(〇) 璜, car her). Single < thick 0 裱, bridged bicyclic, spiro bicyclic or polycyclic group. "A saturated heterocyclic group (saturated heter 〇 y 饱和 〇 ( 脂 脂 脂 s s s s s s s s s s s s s s s s s s s s 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和 饱和Examples of bicyclic, spiro bicyclic or polycyclic groups, '', early monocyclic saturated heterocyclic groups include (but are not limited to pyrrolidine, a. a. heterocyclobutane, pyridine, piperazine, nitrogen heterocycle) Heptane, hexahydropyrimidine tetrahydropyran, 嗌, visit you d£ aw虱 furan, porphyrin π代马琳, thiophene leaching! Mountain two vapors, tetrahydrogen 36 201245116 -2H-U2- stalking, Tetrahydro sulphate [Mountain diisothia. Sodium U. dioxide. - 氡化" Thiazole bite, fused bicyclic heterocyclic group has two co-rings. The first ring is a monocyclic heterocyclic group. And the:::: neighboring % atom such as cycloalkyl or phenyl) 戍 ^ ^ ring ^ ring is a monocyclic carbocyclic ring (the ... ring shape Λ, i: For example, the second ring is J clothing base, such as cyclopropyl, cyclobutyl or the second production - mannose pentyl and cyclohexyl. Not limited to: jrr. Examples of fused bicyclic heterocyclic groups include (but 23 q 戍 two women And (4) t each base, 2,3-Dihydro]indole-benzo[d]miso-inducing lin, ^ « r . paper well [d]oxazole, 23-bird (4) thiazole, octahydrobenzo(4) oxazole, VIII Hydrogen] Η 1]... Hydrogen benzo (4). Saskatchewan, octahydrocyclopentane & (4) imipenone, eight liters of 戍 并 and [. 卜比0, 3- gas "& TM hexane and 3 - azabicyclo[3 2〇]heptane. "裱[3.1.0] spiro bicyclic heterocyclyl has two only ones together - the first ring is a monocyclic heterocyclic group, and the second ^^ ring Alkyl or phenyl) 戋 璜 pi pi i Early clothing slave % (such as a ring Μ ring group. For example, the second ring Γ, 裒 alkyl. Or, the second ring is benzene 3 6) Examples include, but are not limited to, examples of aza-disc diterpene heterocyclic heterocycles. 5]diazepinespira==4·, L j-decane and 3,9-diazaspiro[5.5] - an indole bridged bicyclic heterocyclic group having two rings having three atoms in common; the first ring is a monocyclic heterocyclic group: and the other or more than three carbon rings (such as a cycloalkyl group or a phenyl group) Or a monocyclic heterocyclic group == Examples of fluorenyl groups include, but are not limited to, azabicyclo[33^heterobicyclo[3.3.1] oxime, azabicyclopoxide, 3_aza double疋环^] 37 201245116 辛,6-qihebicyclooctane and aza-bi-bicyclobicyclo[2.2.2]octane. 』Shen, 2-nitrogen J-heterocyclyl has more than two rings In the basin, the three rings are loyal to the two households, one is a heterocyclic group (such as an atom. Each pj has at least one ring, and the scorpion system includes a fused, bridged, and spiro system. Two have two adjacent ring atoms in common:: ring thick::::: two rings having only one ring atom in common. Bridge ring: there are two or three or more adjacent to each other Heteroaryl, 4 r # ^ ^ ( g)J thinks that 5 to 12 members of the monovalent heteroaromatic monocyclic group are right! . Flat or bicyclic groups. Heteroaryl, 2, 3 or 4 heteroatoms independently selected from the group consisting of n, 〇b c Ν 〇 and S. Miscellaneous 7 (but not limited to) sputum, sputum, sputum, ,, - tillage, imidazole, isothiazole, isoxazole, pyridinium 4 ^ pyridinium azole, 嗒D well, pyridine 'fang... Things, ❹ well m, four. Sit and sell saliva. Double-ringed stalks, but not limited to) bicyclo[4.4·0]slight ring system and bicyclo[4丄〇]: system 'such as, ploughing, ten, ten, ten, benzo (tetra), thiazole,嘌呤, quinoline, isoquinoline, hydrazine, 呔α well, quinazoline, dextran, 1,8-α-nidine and acridine. In a particular embodiment, the substituent 14 carbocyclyl or moiety of the cyclic oxime is optionally substituted independently. Exemplary substituents include functional earth-(^4) alkyl, _0H~0, _0_((Vc4) alkyl, _(Ci C4) extension 38 201245116 morphine-ckg-C4), substituted by halogen (Cl_C4) alkyl, o-CC^-Cd alkyl and -ccoHCrC^alkyl substituted by a group. As used herein, "halogen" means fluoro, chloro, bromo or iodo. "Alkoxy" means an alkyl group attached through an oxygen linking atom. "(CVCe) alkoxy ((CrCJ-alkoxy)" includes methoxy, ethoxy, propoxy, butoxy, pentyloxy and hexyloxy. Haloalkyl and _cycloalkyl include monohalogen Alkyl, poly-alkyl and perhaloalkyl" wherein each halogen is independently selected from the group consisting of fluorine, chlorine and desert. "Halogen" and "halo" are used interchangeably herein and each refers to fluorine or chlorine. "Fluorine" means "F" as used herein, and a fluorine-substituted (Cl_C4)alkyl group means a (CKC4) alkyl group substituted with one or more -F groups. Example of Substituted (Ci_C4)alkyl group & ^ ^ m ^ ) -CF3 ^ -CH2CF3 ' -CH2CF2H ' -ch2ch2f and -CH2CH2CF3 0 "naturally occurring amino acid side chain moiety (naturally 〇ccurHng amino acid side chain moiety ") means any amino acid side chain moiety present in the native amino acid. Another embodiment of the invention is a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and/or diluents and a compound disclosed herein or a pharmaceutically acceptable salt thereof. "Pharmaceutica Uy acceptabu carder" and "pharmaceutically acceptable diluent" means sufficient purity and quality for blending 39 201245116 Appropriate administration to animals or humans The non-therapeutic component of the vehicle of the present invention which typically does not produce an adverse reaction and which can be used as a vehicle for a drug substance (i.e., a compound of the present invention). Also included are pharmaceutically acceptable salts of the compounds of the invention. For example, an acid salt of a compound of the invention containing an amine or other anionic group can be obtained by reacting the compound with a suitable organic or inorganic acid to produce a pharmaceutically acceptable anionic salt form. Examples of the anionic salt include acetate, besylate, benzoate, hydrogencarbonate, hydrogen tartrate, bromide, calcium ethylenediaminetetraacetate, camphorsulfonate, carbonate, vapor, citric acid Salt, dihydrochloride, ethylenediaminetetraacetate, ethanedisulfonate, estolate, ethanesulfonate, fumarate, glycerate, gluconate, glutamine Acid salt, glycolylarsanilate, hexylisophthalate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate , lactose k salt, apalatate, cis-succinate, mandelate, methylate, methyl 4 SiL salt, mucate, chamoenate, nitrate, di-naphthate, Pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, acetal, succinate, sulfate, tannin, tartrate, tea Teoclate, tosylate and triethiodide salts. Salts of the compounds of the invention containing a carboxylic acid or other acidic functional group can be prepared by reaction with a suitable base. The pharmaceutically acceptable salt can be prepared from a base which provides a pharmaceutically acceptable cation, including alkali metal salts (especially sodium and potassium salts), alkaline earth metal salts (especially calcium and magnesium salts). , 40 201245116 Ming salt and key 蹿, 丨, / β上1 兮, etc. There are: two scientifically acceptable organically prepared salts, : specific organic test "trimethylamine, triethylamine, morphine W, 曱 = Ding, bicyclohexylamine, hydrazine, hydrazine, dibenzoylethylenediamine, 2-ethylideneamine, ethylamine, tris-(2-ethyl)amine, procaine ((6) ), - methyl piperidine, dehydroabietylamine, hydrazine, hydrazine | bis-dehydroabietylamine, glucosamine, Ν-methyl U-glycosamine, trimethyl _, quinine, quinoline and test amine Base acids (such as lysine and arginine). The invention also includes various isomers and mixtures thereof. Certain compounds of the invention may exist in various stereoisomeric forms. The stereoisomers are only present on the space array. The different compounds. Enantiomers are a pair of stereoisomers whose mirroring is most often due to the fact that they contain an asymmetrically substituted carbon atom that acts as a chiral center. Overlapping. "Enantiomers" means those that are mirror images of each other and that are not overlapped. Diastereomers are stereoisomers which are most often not mirror imaged by the inclusion of two or more asymmetrically substituted carbon atoms. "m" denotes a configuration of a substituent surrounding - or a plurality of chiral carbon atoms. When the t chiral center is not determined to be R or S, there is a pure enantiomer or a mixture of the two configurations. "racemate" or "racemic mixture ((10)-mixture"" means a compound having two molar equivalents of an enantiomer, wherein the mixtures do not exhibit optical activity; It cannot rotate the plane of polarized light. The compounds of the invention may be prepared as an individual isomer form by isomer specific synthesis or from a mixture of isomers. Conventional analytical techniques include the use of optically active acids to form free bases of the isomers in the isomers. 201245116 Formation of salts using optically active amines (those stepwise crystallization and subsequent precipitation (and then stepwise crystallization and regeneration free) Regeneration of the acid form of each isomer in a pair of isomers (4), amine or alcohol formation & ester or guanamine of each isomer in the isomer (and then chromatographic separation and shift) Derivatization of the starting material or mixture of isomers using a variety of well-known chromatographic methods. ~ When naming or depicting the stereochemistry of the disclosed compounds according to the structure, the stereotypes are named or depicted The construct is at least 60% by weight, 80% by weight, 9% by weight, or 99.9% by weight pure relative to the other. When the single-enantiomer is named or depicted according to the structure, the depicted or named pair The isomer is at least 6% by weight, 7% by weight, 80% by weight, 90% by weight, 99% by weight or 999% by weight optically pure. Weight percent optical purity is the weight of the enantiomer present Opposite The ratio of the combined weight of the construct to its optical isomer. The present invention also provides a method of treating or preventing infection or colonization in an individual comprising administering to the individual an effective amount of a compound of the invention or a pharmaceutical thereof An acceptable salt. The invention also provides a method of treating or preventing an individual having a tetracycline-responsive disease or condition comprising administering to the individual an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. A disease or disorder which can be treated, prevented or ameliorated by administering a tetracycline compound of the present invention. Tetracycline-responsive disease 42 201245116 A disease or condition includes an infection, Cancer, inflammatory disease, autoimmune disease, arterial Wei, corneal ulceration, emphysema, arthritis, osteoporosis 1 arthritis, multiple sclerosis, osteosarcoma, osteomyelitis, bronchiectasis, chronic lung obstructive Disease, skin and eye diseases, periodontitis, osteoporosis, rheumatoid arthritis, ulcerative knot Inflammation, prostatitis, cancer: and invasion, metastasis, diabetes, diabetic proteinuria, bronchiolitis, aortic or vascular aneurysms, skin tissue wounds, dry eye, bone and cartilage degradation (bone, cartilage degradati〇 n), dysentery, aging, diabetes, vascular t wind, neurodegenerative disorders, heart disease, juvenile diabetes, acute and chronic bronchitis, sinusitis and respiratory infections (including the common cold), Wegener meat tooth disease (Wegener , s granul〇mat〇sis); idiopathic skin diseases and other inflammatory diseases such as cancer dermatitis, leukocytic vasculitis, bullous lupus erythematosus, pustular psoriasis, lasting Swelling erythema; leukoplakia, discoid lupus erythematosus; gangrenous pyoderma, pustular psoriasis, ocular inflammation or mumps, Alzheimer's disease, degenerative maculopathy; acute And chronic colitis and colitis; acute and chronic cystitis and urethritis; acute and chronic dermatitis; acute and chronic conjunctivitis, acute and chronic serositis Urinary pericarditis; acute and chronic cholecystitis (ch〇lecystis), cystic fibrosis, acute and chronic vaginitis, acute and chronic uveitis, drug reactions, insect bites, burns and sunburn, abnormal bone quality (b 〇ne mass), acute lung injury, chronic lung disease, ischemia, stroke or ischemic stroke, skin wounds, aortic or vascular aneurysms, diabetic retinopathy, hemorrhagic stroke, angiogenesis, and have been found The tetracycline compound can have other conditions of activity 43 201245116 (see, for example, U.S. Patent Nos. 5,789,395; 5,834,450; 6, 277, 061; and 5, 532, 227 each expressly incorporated herein by reference). In addition, covering a treatment can benefit from the regulation of nitric oxide, metalloproteinases, pro-inflammatory mediators and cytokines, reactive oxygen species, immune responses (including chemotaxis, lymphocyte transformation, delayed allergic reactions, antibody production, swallowing) A method of any disease or disease condition that manifests and/or functions as a component of phagocytic oxidative metabolism. A method of treating any disease or condition that can benefit from modulation of the performance and/or function of a c-active protein, a signaling pathway (e.g., a FAK signaling pathway), and/or enhancement of COX-2 expression and PGE2 production is contemplated. Covers a method of treating any disease or condition that can benefit from the inhibition of new blood vessel production. The compounds of the invention are useful for the prevention or treatment of important mammalian and veterinary diseases such as diarrhea, urinary tract infections, skin and skin structures (including wounds), cellulitis and abscesses, ENT infections, mastitis and the like. . Further, a method of treating a neoplasm using the tetracycline compound of the present invention (vail der Bozert et al., Cancer Res., 48.6686-6690 (1988)) may be used, and a compound of the present invention or a pharmaceutically acceptable salt thereof may be used. Treated infections include, but are not limited to, skin infections, GI infections, urinary tract infections, genital tract infections, respiratory infections, sinus infections, middle ear infections, systemic infections, intra-abdominal infections, pyelonephritis, pneumonia, bacterial vaginitis 'Streptococcus throat laryngeal pain, chronic bacterial prostatitis, gynecological and pelvic infections, sexually transmitted bacterial diseases, eye and ear infections, cholera, influenza, bronchitis 44 201245116 • Tube inflammation, hemorrhoids, Psoriasis, rosacea, impetigo, malaria, sexually transmitted diseases (including syphilis and gonorrhea), Legionnaires, disease, Lyme disease, Rocky Mountain spot heat (R〇cky M〇) Untainspottedfever), q fever, typhus, bubomc Plague, gas gangrene, hospital acquired infection, leptospkosis, hundred Cough, caused by the anthrax and lymphogranuloma venereum, inclusion conjunctivitis or parrot Wu | Infectious Diseases (pSittac〇sis) of the pathogen caused. Infections can be bacterial, fungal, parasitic, and viral infections (including infections that are resistant to other tetracycline compounds). Specifically, the infection is pyelonephritis or urinary tract infection. In another embodiment, the compounds of the invention are useful in urinary tract infection (UTI), chronic urinary tract infection (cUTI) or pyelonephritis therapy. In another embodiment, the compounds of the invention are useful for treating infections selected from the group consisting of urinary tract infections, respiratory infections, intra-abdominal infections, acute or chronic skin and skin structure infections, and pneumonia. In a specific embodiment, urinary tract infections, respiratory infections, intra-abdominal infections, acute or chronic skin and skin structure infections or pneumonia are hospital-acquired. In another specific embodiment, a urinary tract infection, a respiratory infection, an intra-abdominal infection, an acute or chronic skin and a skin structure infection, or a pneumonia, which may be obtained by a hospital, is caused by a gram negative organism. In a specific embodiment, the Gram negative organisms are Pseudomonas aeruginosa (household) and Klebsiella pneumoniae (foot). In another specific embodiment, the Gram-negative organism is Enterobacteriaceae. In an even more specific example, the infection is a urinary tract infection (eg, a hospital-acquired urinary tract infection or may be 45 201245116 an even more specific example

特定態樣t 為醫院獲得之複雜尿路感染）。在另 中，感染為腹内感染，諸如亦可為 染。在另一甚至更特定具體實例中 醫療照護相關性肺炎、呼吸器獲得 在另一具體實例中，本發明化合物可用於治療選自尿 路感染、呼吸道感染、腹内感染、急性或慢性皮膚及皮膚 結構感染及肺炎之感染，其由革蘭氏陰性生物體（例如綠 膿桿菌或克留氏肺炎桿菌）及至少一種選自不動菌屬 (Acinetobacter sPP.)、伯免霍爾德氏菌屣（Burkh〇Ueria spp.)、抗ESPL及碳青黴烯類（carbapenum )之腸内菌科、 MRSA及厭氧菌（anaerobes )之其他生物體引起。在一離 樣中，腸内菌科為大腸桿菌（五.co/z·)。 在一具體實例中，感染可能由細菌（例如厭氧或需氧 細菌）引起。 在另一具體實例中’感染係由革蘭氏陽性細菌 (Gram-positive bacterium )弓丨起。在此具體實例之一特定雜 樣中，感染係由選自以下之革蘭氏陽性細菌引起：桿菌、綱 (Bacilli)’包括（但不限於）葡萄球菌屬 46 201245116 spp.)、鏈球菌屬（SeepiococcMS spp.)、腸球菌屬 (Ewiwiiccws spp.)、桿菌屬（BacH/ws spp.)、李氏菌屬 (IhieWa spp.);放線菌門（Actinobacteria )，包括（但不限 於）丙酸桿菌屬（P⑺spp.)、棒狀桿菌屬 (Cor_y«e6acieriww spp.)、奴卡菌屬（7Voe<2r<^a spp.)、放線 菌屬（spp.);及梭菌綱（Clostridia )，包括 (但不限於）梭菌屬（spp. ) 〇 在另一具體實例中，感染係由革蘭氏陰性細菌 (Gram-negative bacterium)引起。在此具體實例之一態樣 中，感染係由以下細菌引起：變形菌門（Proteobacteria)(例 如 β-變形菌綱 （Betaproteobacteria )及 γ-變形菌綱 (Gammaproteobacteria )) > 包括大腸桿菌（心c/zeric/z/a c〇/〇、沙門氏菌屬（心/_邮//^〇、志贺桿菌屬（、 其他腸内菌科、假單胞菌屬（）、莫拉菌屬 (Moraxe//a )、螺旋桿菌屬（)、窄食單胞菌屬 ()、虫至狐菌屬（βΑ//ονζ·Ζ^ζ·σ )、乙酸菌 (acetic acid bacteria)、退伍軍人桿菌屬（Ζ^ζ·〇«β//β)或 α_ Ά Φ菌綱（诸如沃巴赫氏菌屬（))。在另一態樣 中’感染係由選自以下之革蘭氏陰性細菌引起：藍細菌 (cyanobacteria )、螺旋體菌（Spirochaetes )、綠色琉細菌或 綠色非硫細菌。在此具體實例之一特定態樣中，感染係由 選自以下之革蘭氏陰性細菌引起：腸内菌科（例如大腸桿 菌克留氏肺炎桿菌（尺VehifeZ/a pwewmoWae )，包括含有超 廣譜β-内醯胺酶及/或碳青黴烯酶者）、擬桿菌門 201245116 ()(例如脆弱.擬桿菌（Bacieroz’i/ei· ))、 狐菌科（FAr/c^aceae)(霍亂弧菌（FdWo c/zo/erae))、巴 斯德桿菌科（尸<3iiewre//aceae )(例如流行性感冒嗜血桿菌 (Haemophilus influenzae )) 假單胞菌科 (Psewdomowai/aceae )(例如綠膿桿菌(Pseudomonas aerwgZ‘《0lSa ))、奈瑟氏菌科（WebieWaceae )(例如腦膜炎奈 瑟氏菌{Neisseria wew/wg/Wi/z’i ))、立克次體屬 ()、莫拉菌科（Morajce/Zaceae )(例如卡他莫拉 菌（Moraxe/Zacaiarr/m/k))、變形菌族（/v〇ieeae)之任何 種類、不動菌屬、螺旋桿菌屬及曲桿菌屬（Cam/?少/o6czcier spp.)。在一個特定具體實例中，感染係由選自由以下組成 之群的革蘭氏陰性細菌引起：腸内菌科（例如大腸桿菌、 克留氏肺炎桿菌）、假單胞菌屬及不動菌屬。在另一具體實 例中，感染係由選自由以下組成之群的生物體引起：克留 氏肺炎桿菌、沙門氏菌、希拉腸球菌（£_ )、鮑曼不動 桿菌（i ⑽mam·/)、卡他莫拉菌、流行性感冒嗜血桿菌、 綠膿桿菌、屎腸球菌（/aecz_Mm )、大腸桿菌、金黃色葡萄 球菌（<S. aMrew )及糞腸球菌（五yaeca/& )。 在另一具體貫例中，感染係由一或多種多重抗藥性 (multi-drug resistant ; MDR )革蘭氏陰性細菌引起。 在另-具體實例中，感染係由對ESBL或碳#黴婦類具 有抗性之細菌引起。 在一具體實例中，感染係由作為感染過程之一部分在 細胞内生長的生物體引起。 48 201245116 在另一具體實例中，感染係由選自由以下組成之群的 生物體引起：立克次體目（Rickettsiales );衣原體門 (Chlamydiae);衣原體目（Chlamydiales);退伍軍人桿菌屬； 柔膜菌綱（Mollicutes )，包括（但不限於）黴漿菌屬 (Mycoplasma spp.)(例如肺炎黴漿菌(^Mycoplasma pnewmoniae ));分枝桿菌屬（M_yco6acieri'wm spp.)(例如結 核分枝桿菌（));及螺旋體門 (Spriochaetales )(例如疏螺旋體屬（jBorre/i’a spp.)及密螺 旋體屬（spp.))。 在另一具體實例中’感染係由如 http://www.bt.cdc.gov/agent/agentlist-category.asp (其全部 教示係以引用方式併入本文中）上所述之A類生物防衛生 物體（Category A Biodefense organism )引起。A 類生物體 之貫例包.括（但不限於）炭疽桿菌（)(炭 殖）、耶氏桿菌（yem'm’a )(痕疫）、肉毒桿菌 (CVoiirWkm )(肉毒中毒）或土拉文氏桿菌 (Frawcbe/Za )(兔熱病）。在另一具體實例中，感 知為炭疽杯卤感染。「厌疽桿菌感染（ infection)」包括由暴露於或據稱暴露於炭疽桿菌或蠟狀桿 菌（忍以⑴⑽cerews )菌群之另一成員所致或引起的任何病 況、疾病或病症。 可使用本發明化合物或其醫藥學上可接受之鹽治療的 其他感染包括（但不限於）炭疽、肉毒中毒、腺鼠疫及兔 熱病。 49 201245116 在另一具體實例中，感染係由如 http://www.bt.cdc.gov/agent/agentlist-category.asp (其全部 教示係以引用方式併入本文中）上所述之B類生物防衛生 物體引起。B類生物體之實例包括（但不限於）布氏桿菌屬 (5rwce//a spp_ )、產氣莢膜梭菌（C/wirz’i/z’wm per/Wwgew·?)、 沙門氏菌屬、大腸桿菌01 57:H7、志贺桿菌屬、鼻疽伯克霍 爾德氏菌（wa//ez_)、假性鼻疽伯克霍爾德氏菌 (Burkholderia pseudomallei)、鸚鵡农恿馥{ Chlamydia 、伯納特柯克斯氏體（CoxzW/a 、葡萄球 菌腸毒素B ( 少/ococca/ ewieroiox/n 5)、普氏立克次體 (Rickettsia prowazekii ) >霍亂弧菌及小隱孢子球菌 (Cryptosporidium parvum)。 可使用本發明化合物或其醫藥學上可接受之鹽治療之 其他感染包括（但不限於）布氏桿菌病（Bru ceu 0 sis )、產 氣莢膜梭菌' 食物源性疾病、鼻疽（Glanders )、類鼻疽 (Melioidosis )、鸚鵡病、Q熱及水源性疾病。 在另一具體貫例中’感染可能由一種或一種以上上述 生物體引起。該等感染之實例包括（但不限於）腹内感染 (常為革蘭氏陰性菌種（如大腸桿菌）與厭氧菌（如脆弱擬 才干菌）之混合物）、糖尿病足（鏈球菌屬、沙雷氏菌屬 (&⑽…）、葡萄球菌屬及腸球菌屬之各種組合、厭氧菌（se Dowd等人，PloS one 2008;3:e3326，其全部教示係以引用方 式併入本文中））及呼吸道疾病（尤其具有如囊腫性纖維化 之慢性感染之患者的呼吸道疾病，例如金黃色葡萄球菌加 50 201245116 上綠膿桿菌或流行性感冒嗜血桿菌、非典型病原體）、創口 及腺腫（各種革蘭氏陰性及革蘭氏陽性細菌，尤其為 MSSA/MRSA、凝固酶陰性葡萄球菌、腸球菌（enter〇c〇cci)、 不動菌屬、綠膿桿菌、大腸桿菌、脆弱擬桿菌），及血流感 染（13°/。為多種微生物感染（H wispUngh〇ff等人，ciin Infect. Dis. 2004;39:311-317，其全部教示係以引用方式併 入本文中））。 在一具體實例中，感染係由對一或多種抗生素具有抗 性之生物體引起。 在另一具體實例中，感染係由對四環素或第一代及第 二代四環素抗生素之任何成員（例如多西環素 (d〇Xycycline)或二甲胺四環素（min〇cycHne))具有抗性 之生物體引起。 在另具體貫例中，感染係由對二甲氧苯青黴素 (methicillin)或β_内醯胺類別中之任何抗生素具有抗性之 生物體引起。更特定言之，感染係由對二甲氧苯青徽素具 有抗性之生物體引起。 在另-具體實例令，感染係由對萬古徽素（ν_〇ιη_η ) 具有抗性之生物體引起。 在另-具體實例中，感染係由對㈣_ 或乾啥諾綱（fiuoroquinol〇ne)具有抗性之生物體引起。 在另一具體實例t，感染係由對泰格環徽素 “We)或任何其他四環素衍生物具有抗性之生物體 引起。在一個特定具體實例中， 感木係由對泰格環黴素具 51 201245116 有抗性之生物體引起。 在另一具體實例申，感染係由對β_内醯胺或頭孢菌素 (cephalosporin )抗生素具有抗性之生物體或對青黴烯類 (penems )或碳青黴稀類（carbapenems )具有抗性之生物體 引起。 在另一具體實例中，感染係由對抗微生物肽或生物相 似性治療性處理具有抗性之生物體引起。抗微生物肽（亦 稱為宿主防禦肽）為先天免疫反應之進化保守性組分且可 見於所有類別之生物中。在此狀況下，抗微生物肽係指作 為陰離子肽 '線性陽離子α_螺旋肽、富含特定胺基酸（亦 即，S含脯胺酸、精胺酸、苯丙胺酸、甘胺酸、色胺酸） 之陽離子肽及含有半胱胺酸且形成二硫鍵之陰離子及陽離 子肽之類似物的任何天然存在之分子或任何半/合成分子。 在另一具體實例中，感染係由對巨環内酯 (macrolide )、林可酿胺（Hncosamide )、鏈黴殺陽素 (Strept〇gramin )抗生素、噁唑啶酮及截短側耳素 (pleuromutilin )具有抗性之生物體引起。 在另一具體實例中，感染係由對PTK〇796( 7-二甲胺基， 9-(2,2-二曱基-丙基）_胺基曱基環素）具有抗性之生物體引 起。 在另一具體實例中，感染係由多重抗藥性病原體（對 任何兩種或兩種以上抗生素具有中度或完全抗性）引起。 在另一具體實例中，感染係由對ESBL及碳青黴烯類具 有抗性之大腸桿菌及克留氏肺炎桿菌；腸球菌屬及金黃色 52 201245116 葡萄球菌引起。 在另一具體實例中’感染係由大腸桿菌EC200或克留 氏肺炎桿菌KP453引起。 在另一具體實例中’本發明化合物可用於針對多重而十 藥性革蘭氏陰性細菌之靜脈内/ 口服單一療法中。 在另一具體實例中’四環素反應性疾病或病症並非為 細菌感染。在另一具體實例中，本發明之四環素化合物基 本上為非抗細菌劑。舉例而言，本發明之非抗細菌化合物 可具有大於約4 pg/ml之MIC值（如由此項技術中已知之 檢定及/或實施例151中所提供之檢定所量測）。在另一具體 實例中，本發明之四環素化合物具有抗細菌作用及非：細 菌作用。 ---，、狀人卿往邳關病況 (IPAS)有關之疾病或病症。術語「發炎過程相關病況 lnnaminat〇ry pr。⑽ associated state)」包括炎症或炎性因 :(例如基質金屬蛋白酶（MMP)、氧化氮（n〇)、tnf、 :白素血蛋白、細胞防紫系統、細胞激素、脂質代謝 右蛋白酶、毒性自由基、黏著分子等）以異常量（例如， 改變，例如有益於個體之量）涉及或存在於一定 原… 災仏為活組織對損傷的反應。炎症之 癌症或其他病原體。二炎微生物、㈣ 然而，若其持續較久，則可广1較短，僅持續… 了私為k性炎症》 ㈣包括發炎病症。發炎病症一般特徵在於發熱、發 53 201245116 紅、腫脹、疼痛及功能喪失。發炎病症之原因的實例包括 (但不限於）微生物感染（例如，細菌及真菌感染）、物理 因素（例如’燒傷、輻射及創傷）、化學劑（例如毒素及腐 钮性物質）、組織壞死及各種類型之免疫反應。 可使用本發明化合物或其醫藥學上可接受之鹽治療之 發炎病症的實例包括（但不限於）骨關節炎、類風濕性關 節炎、急性及慢性感染（細菌及真菌感染，包括白喉及百 曰咳）；急性及慢性支氣管炎、竇炎及上哗吸道感染（包括 普通感冒）；急性及慢性胃腸炎及結腸炎；發炎性腸病；急 性及慢性膀胱炎及尿道炎；血管炎；敗血症；腎炎；胰臟 炎；肝炎；狼瘡；發炎性皮膚病症，包括例如濕療、皮炎、 牛皮癬、壞疽性膿皮病、紅斑痤瘡及急性及慢性皮炎；急 性及慢性結膜炎；急性及慢性漿膜炎（心包炎、腹膜炎、 滑膜炎、胸膜炎及腱炎）；尿毒性心包炎；急性及慢性膽囊 炎；急性及慢性陰道炎；急性及慢性葡萄膜炎；藥物反應； 昆蟲咬傷；燒傷（熱、化學及電燒傷）；及曬傷。 IPAS亦包括基質金屬蛋白酶相關病況（MMPAS )。 MMPAS包括特徵在於MMP之量或MMP活性異常的病況。 可使用本發明化合物或其醫藥學上可接受之鹽治療的 基質金屬蛋白酶相關病況（「MMPAS」）之實例包括（但不 限於）動脈硬化、角膜潰瘍、氣腫、骨關節炎、多發性硬 化症（Liedtke 等人，Ann. Neurol. 1998, 44: 35-46 ; Chandler 等人，J. Neuroimmunol. 1997，72: 155-71 )、骨肉瘤、骨髓 炎、支氣管擴張症、慢性肺阻塞性疾病、皮膚及眼部疾病、 54 201245116 * 牙周炎、骨質疏鬆症、類風濕性關節炎、潰瘍性結腸炎、 發炎病症 '腫瘤生長及侵襲（Stetler-Stevenson等人，Annu.The specific pattern t is a complex urinary tract infection obtained by the hospital). In the other case, the infection is an intra-abdominal infection, such as may also be dyed. In another even more specific embodiment, medical care-associated pneumonia, respirator acquisition In another embodiment, the compounds of the invention are useful for treating a urinary tract infection, a respiratory infection, an intra-abdominal infection, acute or chronic skin and skin Structural infections and infections of pneumonia, which are caused by Gram-negative organisms (such as Pseudomonas aeruginosa or Klebsiella pneumoniae) and at least one selected from the group consisting of Acinetobacter sPP. Burkh〇Ueria spp.), anti-ESPL and carbapenem (intestinal fungi, MRSA and other organisms of anaerobes). In an isolated sample, the Enterobacteriaceae is Escherichia coli (five. co/z·). In one embodiment, the infection may be caused by bacteria such as anaerobic or aerobic bacteria. In another embodiment, the infectious line is picked up by a Gram-positive bacterium. In a particular sample of this particular example, the infection is caused by a Gram-positive bacterium selected from the group consisting of: Bacilli, including but not limited to, Staphylococcus 46 201245116 spp., Streptococcus (SeepiococcMS spp.), Ewiwiiccws spp., BacH/ws spp., IhieWa spp.; Actinobacteria, including but not limited to propionic acid Bacillus (P(7)spp.), Corynebacterium (Cor_y«e6acieriww spp.), Nocardia (7Voe<2r<^a spp.), Actinomycetes (spp.); and Clostridia, This includes, but is not limited to, Clostridium (spp.). In another embodiment, the infection is caused by a Gram-negative bacterium. In one aspect of this specific example, the infection is caused by the following bacteria: Proteobacteria (e.g., Betaproteobacteria and Gammaproteobacteria) > c/zeric/z/ac〇/〇, Salmonella (heart/_mail//^〇, Shigella (, other enterobacteriaceae, Pseudomonas (), Moraxella (Moraxe/ /a), Helicobacter (), Stenotrophomonas (), Phytophthora (βΑ//ονζ·Ζ^ζ·σ), acetic acid bacteria, Legionella ( Ζ^ζ·〇«β//β) or α_ Ά Φ fungi (such as the genus Worbachia ()). In another aspect, the 'infection line is caused by Gram-negative bacteria selected from the following: blue A bacterium (cyanobacteria), a spirulina (Spirochaetes), a green sputum bacterium or a green non-sulfur bacterium. In one particular aspect of this specific example, the infection is caused by a Gram-negative bacterium selected from the group consisting of: Enterobacteriaceae ( For example, Escherichia coli Klebsiella pneumoniae (VehifeZ/a pwewmoWae), including extended-spectrum β-endoprostanase And/or carbapenemase), Bacteroides 201245116 () (eg Bacieroz'i/ei·), F. cholerae (FrWo c/) Zo/erae)), Pasteuraceae (corporate <3iiewre//aceae) (eg, Haemophilus influenzae) Psewdomowai/aceae (eg Pseudomonas) aerwgZ' "0lSa"), Neisseriae (WebieWaceae) (eg Neisseria wew/wg/Wi/z'i), Rickettsia (), Moraxaceae ( Morajce/Zaceae) (eg Moraxe/Zacaiarr/m/k), any species of the Proteobacteria (/v〇ieeae), Acinetobacter, Helicobacter and Aspergillus (Cam/? Less /o6czcier spp.). In a specific embodiment, the infection is caused by a Gram-negative bacterium selected from the group consisting of: Enterobacteriaceae (eg, Escherichia coli, Klebsiella kluyii), pseudomonas Genus and Acinetobacter. In another embodiment, the infection is caused by an organism selected from the group consisting of: Klebsiella pneumoniae, Salmonella Bacillus, Enterococcus faecium (£_), Acinetobacter baumannii (i (10)mam·/), Moraxella catarrhalis, Haemophilus influenzae, Pseudomonas aeruginosa, Enterococcus faecium (/aecz_Mm), E. coli, gold Staphylococcus aureus (<S. aMrew) and Enterococcus faecalis (five yaeca/&). In another specific example, the infection is caused by one or more multi-drug resistant (MDR) Gram-negative bacteria. In another embodiment, the infection is caused by a bacteria that is resistant to ESBL or carbonaceous women. In one embodiment, the infection is caused by an organism that grows within the cell as part of the infection process. 48 201245116 In another embodiment, the infection is caused by an organism selected from the group consisting of: Rickettsiales; Chlamydiae; Chlamydiales; Legionella; Mollicutes, including but not limited to Mycoplasma spp. (eg Mycoplasma pnewmoniae); Mycobacterium (M_yco6acieri'wm spp.) (eg tuberculosis) Mycobacterium ()); and Spriochaetales (eg, Borrelia genus (jBorre/i'a spp.) and Treponema genus (spp.)). In another embodiment, the 'infection' is a class A organism as described on http://www.bt.cdc.gov/agent/agentlist-category.asp (the entire teachings of which are incorporated herein by reference) Caused by the Category A Biodefense organism. Examples of Class A organisms including (but not limited to) Bacillus anthracis () (carbon), Yy'm'a (mark), Botox (CVoiirWkm) (botulism) Or Trawococcus (Frawcbe/Za) (rabbit fever). In another embodiment, it is known to be an anthrax cup halogen infection. "Infection" includes any condition, disease or condition caused or caused by exposure to or alleged exposure to another member of the Bacillus anthracis or the bacterium of the genus Bacillus (1) (10) cerews. Other infections which may be treated using the compounds of the invention or their pharmaceutically acceptable salts include, but are not limited to, anthrax, botulism, bubonic plague, and rabbit fever. 49 201245116 In another embodiment, the infection is as described in http://www.bt.cdc.gov/agent/agentlist-category.asp (all of which is incorporated herein by reference) Organoids are caused by anti-health objects. Examples of class B organisms include, but are not limited to, Brucella (5rwce//a spp_), Clostridium perfringens (C/wirz'i/z'wm per/Wwgew·?), Salmonella, Escherichia coli 01 57:H7, Shigella, Burkholderia sinensis (wa//ez_), Burkholderia pseudomallei, parrot farmer { Chlamydia , Bernard Kirk's body (CoxzW/a, staphylococcal enterotoxin B (leo/ococca/ ewieroiox/n 5), Rickettsia prowazekii > Vibrio cholerae and Cryptosporidium parvum (Cryptosporidium parvum). Other infections which may be treated with a compound of the invention or a pharmaceutically acceptable salt thereof include, but are not limited to, Bruceu 0 sis, Clostridium perfringens' food origin Disease, Glanders, Melioidosis, Parrot Disease, Q Heat, and Waterborne Diseases. In another specific example, 'infection may be caused by one or more of the above organisms. Examples of such infections include ( But not limited to) intra-abdominal infections (often Gram-negative species (such as Escherichia coli) Mixed with anaerobic bacteria (such as fragile pseudobacteria), diabetic foot (Streptococcus, Serratia (& (10)...), Staphylococcus and Enterococcus, anaerobic bacteria (se Dowd et al, PloS one 2008; 3: e3326, all of which are incorporated herein by reference)) and respiratory diseases (especially respiratory diseases such as Staphylococcus aureus in patients with chronic infections such as cystic fibrosis) Plus 50 201245116 Pseudomonas aeruginosa or Haemophilus influenzae, atypical pathogens, wounds and glands (various Gram-negative and Gram-positive bacteria, especially MSSA/MRSA, coagulase-negative staphylococcus, enterococci (enter〇c〇cci), Acinetobacter, Pseudomonas aeruginosa, Escherichia coli, Bacteroides fragilis, and bloodstream infections (13°/. for multiple microbial infections (H wispUngh〇ff et al., ciin Infect. Dis. 2004; 39:311-317, the entire teachings of which are incorporated herein by reference)). In one particular example, the infection is caused by an organism that is resistant to one or more antibiotics. Infection is caused by an organism that is resistant to tetracycline or any member of the first and second generation tetracycline antibiotics, such as d〇Xycycline or min〇cycHne. In another specific example, the infection is caused by an organism that is resistant to any of the antibiotics in the class of methicillin or beta-inlactam. More specifically, the infection is caused by an organism that is resistant to dimethoprim. In another specific example, the infection is caused by an organism that is resistant to the ancient vulgaris (ν_〇ιη_η). In another embodiment, the infection is caused by an organism that is resistant to (iv) _ or fiuoroquinol〇ne. In another embodiment t, the infection is caused by an organism that is resistant to Tiger's Ringe "We" or any other tetracycline derivative. In a particular embodiment, the Phytophthora Having 51 201245116 resistant organisms. In another specific example, the infection is caused by an organism that is resistant to β-nadecylamine or cephalosporin antibiotics or to penems or Carbaenes are caused by resistant organisms. In another embodiment, the infection is caused by an organism that is resistant to antimicrobial peptides or therapeutic treatment of biological similarity. Antimicrobial peptides (also known as The host defense peptide) is an evolutionarily conserved component of the innate immune response and can be found in all classes of organisms. In this case, the antimicrobial peptide is referred to as an anionic peptide 'linear cation alpha-helical peptide, rich in specific amino acids. (ie, a cationic peptide containing lysine, arginine, phenylalanine, glycine, tryptophan) and an anion and a cationic peptide containing cysteine and forming a disulfide bond Any naturally occurring molecule or any semi-synthetic molecule. In another embodiment, the infection is caused by antibiotics such as macrolide, Hncosamide, and Strept〇gramin. , oxazolidinone and pleuromutilin are resistant organisms. In another embodiment, the infection is caused by PTK〇796 (7-dimethylamino, 9-(2,2- Dimercapto-propyl)-aminomercaptocycline is caused by a resistant organism. In another embodiment, the infection is caused by a multi-drug resistant pathogen (moderate for any two or more antibiotics) Or completely resistant. In another embodiment, the infection is caused by Escherichia coli and Klebsiella pneumoniae resistant to ESBL and carbapenem; Enterococcus and Golden 52 201245116 Staphylococci. In another embodiment, the 'infection line is caused by E. coli EC200 or K. pneumoniae KP453. In another specific example, 'the compound of the invention can be used for intravenous/oral monotherapy against multiple and ten-medicine Gram-negative bacteria Medium. In another embodiment, the 'tetracycline-reactive disease or condition is not a bacterial infection. In another embodiment, the tetracycline compound of the invention is substantially a non-antibacterial agent. For example, the non-antibacterial compound of the invention may have A MIC value greater than about 4 pg/ml (as determined by assays known in the art and/or assays provided in Example 151). In another embodiment, the tetracycline compound of the invention has antibacterial properties Role and non-bacterial effect ---,, the disease or illness related to the condition of the disease (IPAS). The term "inflammation process related conditions lnnaminat〇ry pr. (10) associated state)" includes inflammation or inflammatory causes: (eg matrix metalloproteinase (MMP), nitric oxide (n〇), tnf,: albumin, cell anti-purple system, cytokines, lipid metabolism, right protease, toxicity Free radicals, adhesion molecules, etc.) are involved in or present in an abnormal amount (for example, a change, such as an amount beneficial to an individual). Disasters are the response of living tissue to damage. Inflammation of cancer or other pathogens. Two inflammatory microbes, (4) However, if it lasts for a long time, it can be wider and shorter, only lasting... privately, it is a inflammatory disease. (4) It includes an inflammatory disease. Inflammatory conditions are generally characterized by fever, hair 53 201245116 red, swelling, pain and loss of function. Examples of causes of inflammatory conditions include, but are not limited to, microbial infections (eg, bacterial and fungal infections), physical factors (eg, 'burns, radiation, and wounds'), chemical agents (eg, toxins and decaying substances), tissue necrosis, and Various types of immune responses. Examples of inflammatory conditions which may be treated using a compound of the invention or a pharmaceutically acceptable salt thereof include, but are not limited to, osteoarthritis, rheumatoid arthritis, acute and chronic infections (bacterial and fungal infections, including diphtheria and hundred Cough); acute and chronic bronchitis, sinusitis and upper eyelid suction infection (including common cold); acute and chronic gastroenteritis and colitis; inflammatory bowel disease; acute and chronic cystitis and urethritis; vasculitis; Sepsis; nephritis; pancreatitis; hepatitis; lupus; inflammatory skin disorders including, for example, moist therapy, dermatitis, psoriasis, gangrenous pyoderma, rosacea and acute and chronic dermatitis; acute and chronic conjunctivitis; acute and chronic serositis (pericarditis, peritonitis, synovitis, pleurisy and tendinitis); urinary pericarditis; acute and chronic cholecystitis; acute and chronic vaginitis; acute and chronic uveitis; drug reactions; insect bites; burns (heat, Chemical and electrical burns); and sunburn. IPAS also includes matrix metalloproteinase-associated conditions (MMPAS). MMPAS includes conditions characterized by an abnormal amount of MMP or abnormal MMP activity. Examples of matrix metalloproteinase-associated conditions ("MMPAS") that can be treated with a compound of the invention or a pharmaceutically acceptable salt thereof include, but are not limited to, arteriosclerosis, corneal ulceration, emphysema, osteoarthritis, multiple sclerosis Symptoms (Liedtke et al., Ann. Neurol. 1998, 44: 35-46; Chandler et al., J. Neuroimmunol. 1997, 72: 155-71), osteosarcoma, osteomyelitis, bronchiectasis, chronic obstructive pulmonary disease , skin and eye diseases, 54 201245116 * periodontitis, osteoporosis, rheumatoid arthritis, ulcerative colitis, inflammatory disease 'tumor growth and invasion (Stetler-Stevenson et al., Annu.

Rev. Cell Biol· 1993, 9: 541-73 ; Tryggvason 等人，Biochim. Biophys. Acta 1987, 907: 191-217 ; Li 等人，Mol. Carcillog. 1998，22: 84-89)、轉移、急性肺損傷、中風、局部缺血、 糖尿病、主動脈或血_管動脈瘤、皮膚組織創口、乾眼症、 骨路及軟骨退化（Greenwald 等人，Bone 1998，22: 33-38 ; Ryan 等人，Curr. Op. Rheumatol. 1996，8: 238-247)。其他 MMPAS包括美國專利第5,459，135號、第5,321，〇17號、第 5,308,839 號、第 5,258,37 1 號、第 4,935,412 號、第 4,704,383 號、第4,666,897號及第RE 34,656號（其係以全文引用之 方式併入本文中）中所述之MMPAS。 在另一具體實例中，IPAS包括美國專利第5,929,〇55 號及第5,532，227號（其係以全文引用之方式併入本文中） 中所述之病症。 四壞素反應性疾病或病症亦包括與N〇相關病況有關 之疾病或病症。術語「NO相關病況（N〇ass〇ciatedstate)」 包括涉及氧化氮（NO)或誘導性氧化氮合成酶（iN〇s)或 與其有關之病況。NO相關病況包括特徵在於N〇及/或ίΝ〇§ 之量異常的病況。NO相關病況較佳可藉由投予本發明四環 素化合物來治療。作為N〇 4目關病況，亦包括美國專利第 6,231，894 號、第 6，G15,8G4 號、第 5,919,774 號及第 5,789,395 號中所述之病症、疾病及病況”匕等專利各自的全部内容 係以引用方式併入本文中。 55 201245116 可使用本發明化合物或其醫藥學上可接受之鹽治療的 與NO相關病況有關之疾病或病症之實例包括（但不限於） 瘧疾、衰老、糖尿病、血管中風、神經退化性病症（阿茲 海默氏病及亨丁頓氏病（Huntingtois disease ))、心臟病（梗 塞後再/瞿注相關損傷）、幼年糖屎病、發炎病症、骨關節炎、 類風濕性關節炎； '急性、復發性及慢性感染（細菌、病毒 及真菌感染），急性及慢性支氣管炎、竇炎及呼吸道感染（包 括普通感自），急性及慢性胃腸炎及結腸炎；急性及慢性膀 胱炎及尿道炎；急性及慢性皮炎；急性及慢性結膜炎；急 性及慢性漿膜炎（心包炎、腹膜炎、滑膜炎、胸膜炎及腱 炎）；尿毒性心包炎；急性及慢性膽囊炎；囊腫性纖維化、 急性及慢性陰道炎；急性及慢性葡萄膜炎；藥物反應；昆 蟲咬傷；燒傷（熱、化學及電燒傷）；及曬傷。 在另一具體實例中，四環素反應性疾病或病症為癌 症。可使用本發明化合物或其醫藥學上可接受之鹽治療之 癌症的實例包括所有實體腫瘤，亦即癌瘤，例如腺癌及肉 瘤。腺癌為源自腺組織或腫瘤細胞形成可識別之腺狀結構 的癌瘤。肉瘤廣泛包括細胞嵌入如胚性結締組織之織維狀 或均質物質中的腫瘤。可使用本發明方法治療之癌瘤的實 例包括（但不限於）前列腺癌、乳癌、卵巢癌、睾丸痒、 肺癌、結腸癌及乳癌。本發明方法不限於治療此等腫瘤類 型’而可擴展至源自任何器官系統之任何實體腫瘤。可治 療之癌症的實例包括（但不限於）結腸癌、膀胱癌、乳癌、 黑素瘤、卵巢癌、前列腺癌、肺癌以及多種其他癌症。本 56 201245116 發明方法亦可抑制腺癌（諸如前列腺癌、乳癌、腎癌、印 巢癌、睾丸癌及結腸癌）之癌瘤生長。在一具體實例中， 用本發明方法治療之癌症包括美國專利第6,100,248號、第 5,843’925號、第5,837,696號或第5,668，122號（其係以全 文引用之方式併入本文中）中所述之癌症。 或者’四環素化合物可用於預防或降低癌症復發之可 能性’例如可用於在手術切除或放射線療法後治療殘留癌 症。根據本發明可用之四環素化合物因其相較於其他癌症 治療而言實質上無毒而為尤其有利的。 在另一具體實例中’本發明化合物與標準癌症療法（諸 如（但不限於）化學療法）組合投予。 可使用本發明化合物或其醫藥學上可接受之鹽治療的 四環素反應性病況之實例亦包括神經病症，其包括神經精 神病症及神經退化性病症’但不限於諸如阿茲海默氏病、 與阿狄海默氏病相關之癡呆（諸如皮克氏病（pick，s disease))、帕金森氏病（Parkins〇n,s disease)及其他泛發 性路易體疾病（Lewy diffuse body disease )、老年性癡呆、 亨丁頓氏病、妥瑞症候群（Gilles de la Tourette,s syndrome)、多發性硬化症、肌萎縮性侧索硬化（ALs)、進 行性核上麻療、癲癇症及庫賈氏病（Creutzfeldt Jak〇b disease )，自主神經功能障礙（諸如高企壓及睡眠障礙）， 及神經精神病症，諸如抑鬱症、精神分裂症、分裂情感性 精神障礙、科爾薩科夫氏精神病’（K〇rsak〇ff，s psych〇sis )、 狂知、焦慮症或恐怖症，學習或記憶障礙（例如健忘症或 57 201245116 年齡相關之記憶喪失）、注意力缺乏症、精神抑鬱症、重度 抑鬱症'狂躁、強迫症、精神活性物質使用障礙、焦慮症、 恐懼症、恐慌症，以及雙極性情感障㉟（例如嚴重雙極性 情感（情緒）F章礙（BIM))、雙極性情感神經病症（例如 偏頭痛及肥胖症）。 其他神經病/症包括你Ud纟國精神病學協$ (〜士扣Rev. Cell Biol· 1993, 9: 541-73; Tryggvason et al, Biochim. Biophys. Acta 1987, 907: 191-217; Li et al, Mol. Carcillog. 1998, 22: 84-89), metastasis, acute Lung injury, stroke, ischemia, diabetes, aortic or blood-tube aneurysms, skin tissue wounds, dry eye, bone path and cartilage degradation (Greenwald et al., Bone 1998, 22: 33-38; Ryan et al. , Curr. Op. Rheumatol. 1996, 8: 238-247). Other MMPAS include U.S. Patent Nos. 5,459,135, 5,321, 〇17, 5,308,839, 5,258,37, 4,935,412, 4,704,383, 4,666,897, and RE 34,656 The MMPAS described in this document is incorporated by reference. In another embodiment, the IPAS includes the conditions described in U.S. Patent Nos. 5,929, the disclosure of which are incorporated herein by reference. The four-reactive disease or condition also includes a disease or condition associated with a condition associated with N. The term "N〇ass〇ciatedstate" includes conditions involving or associated with nitric oxide (NO) or inducible nitric oxide synthase (iN〇s). The NO-related condition includes a condition characterized by an abnormal amount of N〇 and/or 。. The NO-related condition is preferably treated by administering the tetracycline compound of the present invention. As a condition of N〇4, the entire contents of the patents such as the diseases, diseases, and conditions described in U.S. Patent Nos. 6,231,894, 6, G15, 8G4, 5,919,774, and 5,789,395 are also included. Is incorporated herein by reference. 55 201245116 Examples of diseases or conditions associated with NO-related conditions that may be treated with a compound of the invention or a pharmaceutically acceptable salt thereof include, but are not limited to, malaria, aging, diabetes, Vascular stroke, neurodegenerative disorders (Alzheimer's disease and Huntingtois disease), heart disease (post-infarction/report related injuries), juvenile glycocalyx, inflammatory conditions, osteoarthritis , rheumatoid arthritis; 'acute, recurrent and chronic infections (bacterial, viral and fungal infections), acute and chronic bronchitis, sinusitis and respiratory infections (including common sense), acute and chronic gastroenteritis and colitis Acute and chronic cystitis and urethritis; acute and chronic dermatitis; acute and chronic conjunctivitis; acute and chronic serositis (pericarditis, peritonitis, synovium) , pleurisy and gingivitis); urinary pericarditis; acute and chronic cholecystitis; cystic fibrosis, acute and chronic vaginitis; acute and chronic uveitis; drug reactions; insect bites; burns (heat, chemical and electrical burns) And sunburn. In another embodiment, the tetracycline-reactive disease or condition is cancer. Examples of cancers treatable using a compound of the invention or a pharmaceutically acceptable salt thereof include all solid tumors, ie, carcinomas For example, adenocarcinoma and sarcoma. Adenocarcinoma is a cancer that is derived from glandular tissue or tumor cells to form a recognizable glandular structure. The sarcoma broadly includes cells embedded in a reticular or homogeneous material such as embryonic connective tissue. Examples of cancers treated using the methods of the invention include, but are not limited to, prostate cancer, breast cancer, ovarian cancer, testicular itching, lung cancer, colon cancer, and breast cancer. The methods of the invention are not limited to treating such tumor types and can be extended to the source Any solid tumor from any organ system. Examples of treatable cancers include, but are not limited to, colon cancer, bladder cancer, breast cancer, melanin Tumor, ovarian cancer, prostate cancer, lung cancer, and various other cancers. The method of the invention can also inhibit the growth of cancer of adenocarcinomas such as prostate cancer, breast cancer, kidney cancer, Indian cancer, testicular cancer, and colon cancer. In a specific example, the cancer treated by the method of the present invention includes those described in U.S. Patent Nos. 6,100,248, 5,843,925, 5,837,696, or 5,668,122, the disclosures of each of Cancer. Or 'tetracycline compound can be used to prevent or reduce the possibility of cancer recurrence', for example, can be used to treat residual cancer after surgical resection or radiotherapy. The tetracycline compound usable according to the present invention is substantially more effective than other cancer treatments. It is especially beneficial if it is non-toxic. In another embodiment, the compounds of the invention are administered in combination with standard cancer therapies such as, but not limited to, chemotherapy. Examples of tetracycline-reactive conditions that may be treated using a compound of the invention or a pharmaceutically acceptable salt thereof also include neurological disorders, including neuropsychiatric disorders and neurodegenerative disorders, but are not limited to, for example, Alzheimer's disease, and Alzheimer's disease-related dementia (such as pick, s disease), Parkinsin's disease, and other generalized Lewy diffuse body disease, Alzheimer's disease, Huntington's disease, Gilles de la Tourette (s syndrome), multiple sclerosis, amyotrophic lateral sclerosis (ALs), progressive nuclear anesthesia, epilepsy and CJJ Creutzfeldt Jak〇b disease, autonomic dysfunction (such as high stress and sleep disorders), and neuropsychiatric disorders such as depression, schizophrenia, schizoaffective psychosis, Korsakoff's psychosis' K〇rsak〇ff, s psych〇sis ), madness, anxiety or phobia, learning or memory impairment (eg amnesia or 57 201245116 age-related memory loss), lack of attention Symptoms, depression, severe depression, arrogance, obsessive-compulsive disorder, psychoactive substance use disorder, anxiety disorder, phobia, panic disorder, and bipolar disorder 35 (eg severe bipolar emotion (emotion) F chapter (BIM) )), bipolar emotional neurological disorders (such as migraine and obesity). Other neuropathies/symptoms include your Ud纟Psychiatric Association $ (~ 扣扣

Psychiatric Assodation )之精神障礙診斷及統計手冊 (Diagnostic and Statistical manual of Mental Disorders · DSM)中所列之神經病症，其最新版本係以全文引用之方 式併入本文中。 在另-具體實例中，四環素反應性疾病或病症為糖尿 病。可使用本發明化合物或其醫藥學上可接受之鹽治療的 糖尿病包括（但不限於）幼年糖尿病、糖尿病、第！型糖尿 病或第II型糖尿病。在另-具體實例中，蛋白質糖基化不 受投予本發明四環素化合物影響。在另一具體實例中，本 發明四環素化合物與標準糖尿病療法（諸如（但不限於） 胰島素療法）組合投予。 在另-具體實例中，四環素反應性疾病或病症為骨質 量異常。可使用本發明化合物或其醫藥學上可接受之鹽治 療之骨質量異常包括個體骨質處於將獲益於骨質形成 '修 復,或重塑之病症及病況的病症。舉例而言，骨質量異常包 括骨質疏鬆症（例如，骨強度及密度降低）、骨折、與外科 程序相關之骨質形成（例如，面部重建）、成骨不全（脆骨 症）、低磷酸酶症、柏哲德氏症（Paget，s disease)、纖維性 58 201245116 發育不良、骨硬化病、骨髓瘤骨病及骨鈣流失（諸如與原 發性甲狀旁腺功能充進相關者）。骨質量異常包括個體將獲 益於骨質形成、修復或重塑的所有病況，以及可用本發明 四環素化合物治療的與個體之骨質或骨骼系統相關之所有 其他病症。在另-具體實例中，量異常包括美國專利 第 5,459435 號、第 5,231，017 號、第 5,998,39〇 號、第 5,770,588 號、第 RE 34,656 號、第 5,3〇M39 號第 4,925,833 號、第3,304,227號及第4,666,897號中所述之病症，該等 專利各自係以全文引用之方式併入本文中。 在另-具體實例中，四環素反應性疾病或病症為急性 肺損傷。可使用本發明化合％或其醫藥學上可接受之鹽治 療的急性肺損傷包括成人呼吸窘迫症候群（ards ) '泵後 症侯群（PPS )及創傷。創傷包括任何由外在因素或事 起之對活組織的損傷。創傷之實例包括（但不限於）擠壓 損傷、硬表面觸傷，或割傷，或其他對肺之損傷。 本發明之四環素反應性疾病或病症亦包括慢性肺病。 可使用本發明化合物或其醫藥學上可接受之鹽治療的慢性 肺病之實例包但不限於）哮喘、囊腫性纖維 阻塞性肺病（c_)及氣腫。在另—具體實例中，可使用 本發明化合物或其醫藥學上可接受之鹽治療的急性及 性肺病包括美國專㈣5,977，_號、第M43,231號 :，523,297號及第5,773,㈣號中所述之病症，該等專利各: 係以全文引用之方式併入本文中。 W各自 在另一具體實例中，四環素反應性疾病或病症為局部 59 201245116 缺血、中風或缺血性中風。 另一體實例巾，本發明 < 四環素化合物或其醫藥 學上可接受之鹽可用於治療如上文及美國專利第6,23【，綱 ，第，773,430 號、第 5,919,775 號及第 5,789,395 號（其 係以引用方式併入本文十·）中所述之病症。 在另一具體實例中，本發明之四環素化合物或其醫藥 學^可接受之鹽可用於治療疼痛，例如發炎性疼痛、傷害 感受性疼痛或神經痛。疼痛可為急性或慢性疼痛。 在另-具體實例巾，四環素反應性疾㈤或病症為皮膚 創口。本發明亦提供一種改善上皮化組織（例如皮膚、黏 膜）針對急性創傷性損傷（例如，切傷、燒傷、擦傷等） 之癒合反應的方法。該方法包括使用本發明之四環素化合 物或其醫藥學上可接受之鹽來改善上皮化組織癒合急性創 口的能力。該方法可加快癒合組織之膠原蛋白積聚速率。 該方法亦可藉由降低MMP之膠原蛋白分解（c〇Uagen〇lytic ) 及/或明膠分解（gellatin〇lytic )活性來降低上皮化組織之蛋 白水解活性。在另一具體實例中，本發明之四環素化合物 或其醫藥學上可接受之鹽係投予皮膚表面（例如局部投 予）。在另一具體實例中，本發明之四環素化合物或其醫藥 學上可接受之鹽係用於治療皮膚創口，以及如例如美國專 利第 5,827,840 號、第 4,704,383 號、第 4,935,412 號、第 5,258,371 號、第 5,308,839 號、第 5,459，135 號、第 5,532 227 號及第6,015，804號中所述之其他該等病症；該等專利各自 係以全文引用之方式併入本文中。 60 201245116 在另-具體實例中，四環素反應性疾病或病症為個體 (例如，患有主動脈或血管動脈瘤或有患有該病之風險的個 體等）之血管組織中之主動脈或血管動脈瘤。四環素化合 物或其醫藥學上可接受之鹽可有效減小血管動脈瘤之尺 寸，或其可在血管動脈瘤發病之前投予個體，以便預防動 脈瘤。在一具體實例中，血管組織為動脈，例如主動脈， 例如腹主動脈。在另一具體實例中，本發明四環素化合物 係用於治療美國專利第6,043,225號及第5,834,449號中所 述之病症，該等專利係以全文引用之方式併入本文中。 本發明化合物或其醫藥學上可接受之鹽可單獨或與一 或多種治療劑相組合用於本文所揭示之本發明方法中。 用語「與」另一治療劑或治療「組合（in c〇mbinati〇n with )」包括以單一組合劑型或以多個各別劑型共同投予四 ，環素化合物與另一治療劑或治療；首先投予四環素化合 物，繼而投予另一治療劑或治療；及首先投予另—治療劑 或治療，繼而投予四環素化合物。 作為一特定具體實例，本發明化合物或其醫藥學上可 接梵之鹽可用作由一或多種多重抗藥性（MDR)革蘭氏陰 性細菌引起之感染的單.一療法（靜脈内或口服）。 作為一特定具體實例，本發明化合物或其醫藥學上可 接文之鹽可用作治療尿路感染（UTI )、慢性尿路感染（cUTI ) 或腎盂腎炎的單一療法（靜脈内或口服 另一治療劑可為此項技術中已知用於治療、預防或減 輕四環素反應性疾病或病症之症狀的任何藥劑。其他治療 61 201245116 劑係基於所治療之特定四環素反應性疾病或病症來選擇。 該選擇處於治療醫師之知識範圍内。此外，另一治療劑可 為當與投予四環素化合物組合投予時有益於患者的任何藥 劑。 本發明化合物或其醫藥學上可接受之鹽可單獨或與— 或多種抗生素及/或免疫調節劑（例如去氧膽酸、麥可金 (Macrokine )、阿巴西普（Abatacept )、貝拉西普 (Belatacept )、英利昔單抗（Inmximab )、阿達木單抗 (Adalimumab )、塞妥珠單抗（Cert〇Hzumab peg〇]l )、阿非莫 單抗（Afelimomab)、戈利木單抗（G〇limumab)及 FKBp/ 親環素（Cyclophilin ) /鈣調神經磷酸酶：他克莫司 (Tacrolimus )、環孢素（cicl〇sp〇rin )、吡美莫司 (Pimecrolimus))組合使用。 如本文所用之術語「個體（subject )」意謂需要治療或 預防之哺乳動物’例如伴侶動物（例如狗、貓及其類似動 物）、農畜（例如牛、豬、馬、綿羊、山羊及其類似動物） 及實驗室動物（例如大鼠、小鼠、天竺鼠及其類似動物）。 個體典型地為需要指定治療之人類。 士本文所用之術浯「治療（treating/treatment )」係指 獲=所需的藥理學及/或生理學效應。該效應可包括部分地 或實質上達成或夕種以下結果：部分地或完全地減輕疾 病、·病症或症候群之程H善或改良與病症相關之臨床 症狀或跡象；延遲、拍3朵丨丨、片 制疾病、病症或症候群進展或減小 疾病、病症或症候群進展之可能性。 62 201245116 如本文所用之「預防（preventing/prevention)」係指降 低疾病、病症或症候群發病或產生之可能性。 有效里（effective amount)」意謂活性化合物藥劑引 起個體所品生物反應的量。在-具體實例中，本發明化合 物之有效量為每天約0.01 mg/kg至每天約1000 mg/kg、每 天約0.1 mg/kg至每天約1〇〇 mg/kg ,或每天約〇.5 mg/kg 至每天約50 mg/kg。 本發明包括一種醫藥組成物，其包含醫藥學上可接受 之載劑或稀釋劑以及任何一種本發明化合物。 本發明進一步包括製備組成物之方法，其包含將一或 多種本發明化合物與視情況選用之醫藥學上可接受之載劑 混合；且包括由該種方法產生之組成物，該方法包括習知 醫藥技術。 本發明組成物包括經眼、經口、經鼻、經皮、局部（在 有阻塞或無阻塞下）、靜脈内（團注（bolus )及輸注）、可 吸入及注射（腹膜内、皮下、肌肉内、腫瘤内或非經腸） 調配物。組成物可呈劑量單位形式，諸如錠劑、藥丸、膠 囊、散劑、顆粒、脂質體、離子交換樹脂、無菌眼部溶液 或眼部傳遞裝置（諸如有助於立即釋放、定時釋放或持續 釋放之隱形眼鏡及其類似物）、非經腸溶液或懸浮液、計量 氣霧劑或液體喷霧劑、滴劑、安瓿、自動注射裝置或栓劑； 以用於經眼、經口、鼻内、舌下、非經腸或經直腸或藉由 吸入或吹入投予。 適用於經口投予之本發明組成物包括固體形式，諸如 63 201245116 藥丸、錠劑、囊片、膠囊（各包括立即釋放、定時釋放及 持績釋放調配物）、顆粒及散劑；及液體形式，諸如溶液、 糖漿'酏劑、乳液及懸浮液。可用於眼部投藥之形式包括 無菌溶液或眼部傳遞裝置。可用於非經腸投予之形式包括 無菌溶液、乳液及懸浮液。 本發明組成物可以適用於每週一次或每月一次投藥之 形式投予。舉例而言，活性化合物之不溶性鹽可適合於提 供用於肌肉内注射之儲槽式製劑（例如癸酸鹽），或提供用 於眼睛投藥之溶液》 含有本發明組成物之劑型含有為提供治療效果所需之 有效量的活性成分。組成物可含有約5 θθθ mg至約〇 5 (較佳為約l，000 mg至約〇.5mg)之本發明化合物或其鹽形 式，且可構成任何適用於所選投藥模式的形式。組成物可 每天投予約1次至約5次。可利用#日投藥或一段時間後 給藥（post-periodic dosing)。 對於口服投予，組成物較佳呈含有例如5〇〇毫克至〇 5 毫克活性化合物之錠劑或膠囊形式。劑量應視與所治療之 特定患者有關之因素（例如年齡、體重、飲食及投藥時間）、 所治療病狀之嚴重程度、所用化合物、投藥模式及製劑濃 度而改變。 口服組成物較佳調配成均質組成物，其中活性成分均 勻分散於整個混合物中，其可易於再分成含有等量本發明 化合物之劑量單位。組成物較佳係藉由混合本發明化合物 (或其醫藥學上可接受之鹽）與—或多種視情況存在之醫藥 64 201245116 載劑（諸如澱粉、糖、稀釋劑、成粒劑、潤滑劑、滑動劑、 黏合劑及崩解劑）、一或多視情況存在之惰性醫藥賦形劑 (諸如水、二醇、油、醇、調味劑、防腐劑、著色劑及糖裝）、 一^種視情況存在之習知製錠成分（諸如玉米澱粉、乳 糖、薦糖、山梨糖醇、滑石、硬脂酸、硬脂酸鎖、填酸二 約及多種膠中之任一者及；^ m i 有；及視滑况選用之稀釋劑（諸如水： 來製備。 黏合劑包括殿粉、明#、天然糖（例如葡萄糖及p乳 才）玉米甜未劑以及天然及合成膠（例如阿拉伯膠及黃蓍 膠）。崩解劑包括澱粉、甲基纖維素、瓊脂及膨潤土。、 錠劑及膠囊代表有利之口服單位劑型。鍵劑可使用標 準技術包覆糖衣或包覆膜衣。鍵劑亦可包覆包衣或以其他 方式加以混配以提供延長之控制釋放之治療效果。劑型可 包含内:配藥組分及外配藥組分，纟中外組分呈處於内組分 上之包套形式。兩種組分可進一步由防止在胃中崩解（諸 如腸溶層）且允許内組分完整通過而進入十二指腸之層或 延遲或持續釋放之層隔開。可使用多種腸溶及非腸溶層或 包覆物質（諸如聚合酸、蟲膠、乙醯醇及醋酸纖維素或其 組合）。 本發明化合物亦可經由緩慢釋放組成物投予；其令該 組成物包括本發明化合物及生物可降解的緩慢釋放载劑 (例如聚合載劑）或醫藥學上可接受之非生物可降解的緩慢 釋放載劑（例如離子交換載劑 生物可降解及非生物可降解之緩慢釋放载劑在此項技 65 201245116 術中為熟知的。使用生物可降解之載劑來形成保留活性劑 且在合適％境（例々。，水性、酸性、鹼性環境及其類似環 境）中緩慢降解/溶解以釋放活性劑的粒子或基質。該等粒 子在體液中降解/溶解以於其中釋放活性化合物。該等粒子 較佳為奈米粒子或奈米乳液（例如，其直徑處於約^ _至 5 00 nm之範圍内，直徑較佳為約5〇 nm至2〇〇 ，且直徑 最佳為約100 nm)。在製備緩慢釋放組成物之方法中，首先 將緩慢釋纟冑劑及纟#明化合物轉或分散於有機溶劑 中。將所得混合物添加至含有視情$兄選用之表面活性劑的 水溶液中以得到乳液。接著自乳液中蒸發有機溶劑，以提 供含有緩慢釋放載劑及本發明化合物之粒子的膠狀懸浮 液。 本文所揭示之化合物可經併入以經口或藉由注射以液 體形式（諸如水溶液、經適當調味之糖漿、水性或油懸浮 液、含食用油（諸如棉籽油、芝麻油、椰子油或花生油） 的經調味之乳液及其類似物）或用酏劑或類似醫藥媒劑投 予。適用於水性懸浮液之分散劑或懸浮劑包括合成及天然 膠（諸如黃蓍膠、阿拉伯膠）、褐藻酸鹽、聚葡萄糖、羧甲 基纖、·隹素鈉、甲基纖維素、聚乙烯-吡咯啶酮及明膠。於經 適當調味之懸浮劑或分散劑中的液體形式亦可包括合成膠 及天然膠。對於非經腸投予，需要無菌懸浮液及溶液。當 扁要靜脈内技藥時，使用一般含有合適之防腐劑的等張製 劑。 可經由注射非經腸投予化合物。非經腸調配物可由活 66 201245116 性成分溶解於適當惰性液體載劑中或與其混合而組成。可 接受之液體載劑通常包含水性溶劑及其他視情況選用之有 助於溶解或防腐的成分。該等水性溶劑包括無菌水、林格 氏溶液（Ringer’s s〇Uti〇n)或等張鹽水溶液。其他視情況 選用之成分包括植物油（諸如花生油、棉籽油及芝麻油） 及有機溶劑（諸如丙酮縮甘油（s〇lkeUl )、甘油及甲醯）。 無菌的不揮發油可用作溶劑或懸浮劑。非經腸調配物係藉 由將活性成分溶解或懸浮於液體載劑中以使最終劑量單位 含有0.005重量％至1〇重量％之活性成分來製備。其他添加 劑包括防腐劑、等張劑、增溶劑、穩定劑及疼痛緩解劑。 亦可製備可注射懸浮液，在該狀況下，可使用適當液體載 劑、懸浮劑及其類似物。 可使用合適之鼻内媒劑經鼻内投予本發明化合物。 在另一具體實例t，本發明化合物可藉由吸入直接投 予肺中。 本發明化合物亦可藉由使用合適之局部經皮媒劑或經 皮貼片局部投予或增強。 對於眼部投藥，組成物較佳呈眼用組成物形式。眼用 組成物較佳調配成滴眼劑調配物且填充於適當容器中以有 助於向眼部投藥，例如配備有合適之吸液管的滴管。該等 2成物較佳為無菌且使用純水之水基組成物。除本發明化 口物之外’眼用組成物亦可含有以下一或多者：a)界面活 ί'生切諸如聚氧乙烯脂肪酸酯；b )增稠劑，諸如纖維素、 纖、隹素衍生物、羧乙烯聚合物、$乙烯聚合物及聚乙烯吡 67 201245116 咯啶酮，其濃度典型地處於約〇 〇5%至約5㈣（之 範圍内’ c X #為在含有1氣且視情況包括自纟氧吸收劑（諸 如Fe )之容器中儲存組成物的另一選擇或除此之外亦含有） 抗氧化劑，諸如丁基化經基苯甲醚、抗壞血酸、硫代硫酸 鈉或丁基化羥基甲苯，其濃度為約〇 〇〇〇〇5%至約〇 (wt/vol )，d)乙醇’其濃度為約 〇 〇1%至 〇 5% ( wt/v〇1 ); 及e )其他賦形劑，諸如等張劑、緩衝劑、防腐劑及/或 值控制劑。眼用組成物之pH值需要處於4至8之範圍内。 一在某些具體實例中，本發明組成物包括一或多種其他 藥劑。其他治療劑可為能夠治療、預防或緩解四環素反應 卷疾病或病症之症狀的任何藥劑。或者，其他治療劑可為 田與本發明四環素化合物組合投予時有益於患者的任何藥 劑。 、 雖然已參考本發明之例示性具體實例詳盡地展示及描 述本發明’但熟習此項技術者應瞭解可在形式及細節方面 對其# ψ & & 、 出各種改變而不悖離由隨附申請專利範圍涵蓋之束 發明範疇 實施例 縮寫 乙醯基 水性 芳基 苯甲基The latest edition of the neurological disorder listed in the Diagnostic and Statistical Manual of Mental Disorders (DSM) is incorporated herein by reference in its entirety. In another embodiment, the tetracycline reactive disease or condition is diabetes. Diabetes that can be treated with a compound of the invention or a pharmaceutically acceptable salt thereof includes, but is not limited to, juvenile diabetes, diabetes, first! Type of diabetes or type II diabetes. In another embodiment, protein glycosylation is not affected by administration of the tetracycline compounds of the invention. In another embodiment, the tetracycline compounds of the invention are administered in combination with standard diabetes therapies such as, but not limited to, insulin therapy. In another embodiment, the tetracycline-responsive disease or condition is abnormal bone mass. Abnormal bone quality that can be treated using a compound of the invention or a pharmaceutically acceptable salt thereof includes a condition in which the individual's bone is in a condition and condition that will benefit from 'repair, or remodeling, bone formation. For example, bone quality abnormalities include osteoporosis (eg, decreased bone strength and density), fractures, bone formation associated with surgical procedures (eg, facial reconstruction), osteogenesis imperfecta (brittle bone), hypophosphatase, Paget, s disease, fibrosis 58 201245116 dysplasia, osteopetrosis, myeloma bone disease and loss of bone calcium (such as those associated with primary parathyroid function filling). Abnormal bone mass includes all conditions in which an individual will benefit from bone formation, repair or remodeling, as well as all other conditions associated with the bone or skeletal system of the individual that can be treated with the tetracycline compounds of the invention. In another embodiment, the amount of anomalies includes U.S. Patent Nos. 5,459,435, 5,231,017, 5,998,39, 5,770,588, RE 34,656, 5, 3, M39, 4,925,833. The conditions described in U.S. Patent Nos. 3,304,227 and 4,666,897, each of which are incorporated herein by reference in their entirety. In another embodiment, the tetracycline reactive disease or condition is acute lung injury. Acute lung injury that can be treated with % of the compound of the invention or a pharmaceutically acceptable salt thereof includes adult respiratory distress syndrome (ards) 'Post-Pump Disease Group (PPS) and wounds. Trauma includes any damage to living tissue caused by external factors or events. Examples of wounds include, but are not limited to, crush injuries, hard surface touches, or cuts, or other damage to the lungs. The tetracycline-reactive diseases or conditions of the invention also include chronic lung diseases. Examples of chronic lung diseases which can be treated with a compound of the present invention or a pharmaceutically acceptable salt thereof include, but are not limited to, asthma, cystic fibrous obstructive pulmonary disease (c_), and emphysema. In another embodiment, acute and pulmonary diseases treatable with a compound of the present invention or a pharmaceutically acceptable salt thereof include U.S. Patent No. 5,977, No., No. M 43,231, No. 523,297, and No. 5,773. The conditions described in (4), each of which is incorporated herein by reference in its entirety. In each of the specific examples, the tetracycline-reactive disease or condition is a local 59 201245116 ischemia, stroke or ischemic stroke. Another embodiment of the present invention, the present invention <tetracycline compound or a pharmaceutically acceptable salt thereof, can be used in the treatment of the above, and U.S. Patent Nos. 6,23 [, ed., 773, 430, 5, 919, 775 and 5, 789, 395 (which The condition described in § 10) is incorporated by reference. In another embodiment, the tetracycline compound of the present invention or a pharmaceutically acceptable salt thereof can be used for the treatment of pain, such as inflammatory pain, nociceptive pain or neuralgia. The pain can be acute or chronic pain. In another specific embodiment, the tetracycline reactive disease (V) or condition is a skin wound. The present invention also provides a method of improving the healing response of epithelialized tissue (e.g., skin, mucosa) against acute traumatic injuries (e.g., cuts, burns, abrasions, etc.). The method comprises using the tetracycline compound of the present invention or a pharmaceutically acceptable salt thereof to improve the ability of the epithelial tissue to heal an acute wound. This method accelerates the rate of collagen accumulation in the healing tissue. The method can also reduce the proteolytic activity of the epithelial tissue by reducing the collagen breakdown (c〇Uagen〇lytic) and/or gelatinin lytic activity of MMP. In another embodiment, the tetracycline compound of the present invention or a pharmaceutically acceptable salt thereof is administered to the skin surface (e.g., topically administered). In another embodiment, the tetracycline compound of the present invention or a pharmaceutically acceptable salt thereof is used for the treatment of a skin wound, and as described in, for example, U.S. Patent Nos. 5,827,840, 4,704,383, 4,935,412, 5,258,371, Other such conditions as described in U.S. Patent Nos. 5,308, 839, 5,459, 135, 5, 532, 227, and 6, 015, 804 are incorporated herein by reference in their entirety. 60 201245116 In another embodiment, the tetracycline-reactive disease or condition is an aorta or vascular artery in an vascular tissue of an individual (eg, an aortic or vascular aneurysm or an individual at risk of having the disease, etc.) tumor. The tetracycline compound or a pharmaceutically acceptable salt thereof is effective for reducing the size of a vascular aneurysm, or it can be administered to an individual prior to the onset of a vascular aneurysm in order to prevent arteriomas. In a specific example, the vascular tissue is an artery, such as an aorta, such as the abdominal aorta. In another embodiment, the tetracycline compounds of the present invention are used in the treatment of the conditions described in U.S. Patent Nos. 6,043,225 and 5,834,449 each incorporated herein by reference. The compounds of the invention, or pharmaceutically acceptable salts thereof, may be used in the methods of the invention disclosed herein, alone or in combination with one or more therapeutic agents. The phrase "in combination with" another therapeutic agent or treatment "in combination with (in c〇mbinati〇n with)" includes co-administering a cyclin compound with another therapeutic agent or treatment in a single combined dosage form or in multiple separate dosage forms; The tetracycline compound is administered first, followed by another therapeutic agent or treatment; and the other therapeutic agent or treatment is administered first, followed by administration of the tetracycline compound. As a specific specific example, the compound of the present invention or a pharmaceutically acceptable salt thereof can be used as a single therapy (intravenous or oral) for infection caused by one or more multidrug resistance (MDR) Gram-negative bacteria. ). As a specific specific example, the compound of the present invention or a pharmaceutically acceptable salt thereof can be used as a monotherapy for treating urinary tract infection (UTI), chronic urinary tract infection (cUTI) or pyelonephritis (intravenous or oral another The therapeutic agent can be any agent known in the art for treating, preventing or ameliorating the symptoms of a tetracycline-responsive disease or condition.Other Treatments 61 201245116 The agent is selected based on the particular tetracycline-responsive disease or condition being treated. The choice is within the knowledge of the treating physician. Further, the other therapeutic agent may be any agent that is beneficial to the patient when administered in combination with administration of the tetracycline compound. The compound of the present invention or a pharmaceutically acceptable salt thereof may be used alone or in combination with - or multiple antibiotics and / or immunomodulators (such as deoxycholic acid, Macrokine, Abatacept, Belatacept, Inmximab, adamudan Anti-Adalimumab, Cert〇Hzumab peg〇l, Afelimomab, G〇limumab, and FKBp/Ph. (Cyclophilin) / calcineurin: Tacrolimus, cicl〇sp〇rin, Pimecrolimus, in combination. The term "subject" as used herein. Means mammals that need treatment or prevention, such as companion animals (such as dogs, cats, and the like), farm animals (such as cattle, pigs, horses, sheep, goats, and the like) and laboratory animals (such as large Rats, mice, guinea pigs, and the like. Individuals are typically humans that require treatment. The term "treating/treatment" as used herein refers to the required pharmacology and/or physiology. The effect may include partial or substantial achievement or the following results: partially or completely alleviating the course of the disease, condition or syndrome H or improving the clinical symptoms or signs associated with the condition; delaying, taking 3 The progression of a disease, condition, or syndrome, or the likelihood of a disease, disorder, or syndrome progression. 62 201245116 "Preventing/prevention" as used herein Reducing the likelihood of the onset or production of a disease, condition or syndrome. Effective amount means the amount of biological response of an individual to the active compound agent. In a particular embodiment, the effective amount of the compound of the invention is about 0.01 per day. From mg/kg to about 1000 mg/kg per day, from about 0.1 mg/kg per day to about 1 mg/kg per day, or from about 0.5 mg/kg per day to about 50 mg/kg per day. The invention includes a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and any of the compounds of the invention. The invention further comprises a method of preparing a composition comprising admixing one or more compounds of the invention with a pharmaceutically acceptable carrier optionally selected; and comprising a composition produced by such a method, the method comprising the prior art Medical technology. Compositions of the invention include transocular, oral, nasal, transdermal, topical (with or without obstruction), intravenous (bolus and infusion), inhalable and injectable (intraperitoneal, subcutaneous, Intramuscular, intratumor or parenteral formulations. The composition may be in the form of a dosage unit such as a troche, a pill, a capsule, a powder, a granule, a liposome, an ion exchange resin, a sterile ophthalmic solution or an ocular delivery device (such as for immediate release, timed release or sustained release). Contact lenses and the like), parenteral solutions or suspensions, metered aerosols or liquid sprays, drops, ampoules, automatic injection devices or suppositories; for use in the eye, oral, intranasal, lingual Sublingual, parenteral or rectal or by inhalation or insufflation. Compositions of the invention suitable for oral administration include solid forms such as 63 201245116 pills, lozenges, caplets, capsules (each comprising immediate release, timed release and performance release formulations), granules and powders; and liquid forms Such as solutions, syrups, elixirs, emulsions and suspensions. Forms that can be used for ocular administration include sterile solutions or ocular delivery devices. Forms which can be used for parenteral administration include sterile solutions, emulsions and suspensions. The composition of the present invention can be administered in the form of administration once a week or once a month. For example, an insoluble salt of the active compound may be suitable for providing a sump-type preparation for intramuscular injection (for example, citrate) or a solution for ocular administration. A dosage form containing the composition of the present invention contains a treatment for providing An effective amount of active ingredient required for the effect. The composition may contain from about 5 θ θ θ mg to about ( 5 (preferably from about 10,000 mg to about 0.5 mg) of the compound of the present invention or a salt thereof, and may constitute any form suitable for the selected mode of administration. The composition can be administered from about 1 time to about 5 times a day. It can be administered on a daily basis or post-periodic dosing. For oral administration, the composition is preferably in the form of a lozenge or capsule containing, for example, 5 mg to 5 mg of the active compound. The dosage will vary depending on factors (e.g., age, weight, diet, and time of administration) of the particular patient being treated, the severity of the condition being treated, the compound employed, the mode of administration, and the concentration of the formulation. The oral compositions are preferably formulated as a homogeneous composition in which the active ingredient is uniformly dispersed throughout the mixture, which can be readily subdivided into dosage units containing equal amounts of the compound of the invention. Preferably, the composition is prepared by mixing a compound of the invention (or a pharmaceutically acceptable salt thereof) with - or a plurality of optionally present agents 64 201245116 carrier (such as starch, sugar, diluent, granulating agent, lubricant) , slip agents, binders and disintegrants), inert pharmaceutical excipients (such as water, glycols, oils, alcohols, flavoring agents, preservatives, colorants and sugars) present in one or more cases, Any of the conventional ingot ingredients (such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, stearic acid lock, acid-filled di-coal and various gums) as the case may exist; Mi has; and depends on the slippery choice of thinner (such as water: to prepare. Adhesives include temple powder, Ming #, natural sugar (such as glucose and p milk) corn sweetener and natural and synthetic rubber (such as gum arabic And tragacanth). Disintegrators include starch, methylcellulose, agar and bentonite. Tablets and capsules represent advantageous oral unit dosage forms. The bonding agent can be coated with sugar coating or coated film using standard techniques. Can also be coated or otherwise It is compounded to provide an extended controlled release therapeutic effect. The dosage form may comprise: a pharmaceutical component and an external drug component, and the middle and outer components are in the form of a sheath on the inner component. The two components may be further prevented. Disintegrating in the stomach (such as the enteric layer) and allowing the inner component to pass intact into the layer of the duodenum or the layer of delayed or sustained release. A variety of enteric and non-enteric layers or coating materials (such as polymerization) can be used. Acid, shellac, acetol and cellulose acetate or a combination thereof. The compounds of the invention may also be administered via a slow release composition; the composition comprising the compound of the invention and a biodegradable slow release carrier (eg A polymeric carrier) or a pharmaceutically acceptable non-biodegradable slow release carrier (e.g., an ion exchange carrier biodegradable and non-biodegradable slow release carrier is well known in the art of 2012 201245116). The biodegradable carrier is used to form the retention active agent and slowly degrade/dissolve in a suitable environment (eg, aqueous, acidic, alkaline environment, and the like) to release A particle or matrix of an active agent that degrades/dissolves in a body fluid to release the active compound therein. The particles are preferably nanoparticle or nanoemulsion (eg, having a diameter of between about _ and 50,000 nm). In the range, the diameter is preferably about 5 〇 nm to 2 〇〇, and the diameter is preferably about 100 nm. In the method of preparing the slow release composition, the slow release agent and the 明#明 compound are first transferred or Disperse in an organic solvent. Add the resulting mixture to an aqueous solution containing a surfactant selected as the parent, to obtain an emulsion. The organic solvent is then evaporated from the emulsion to provide a particle containing the slow release carrier and the compound of the present invention. Colloidal suspensions. The compounds disclosed herein may be incorporated by injection or by injection in liquid form (such as aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, containing edible oils (such as cottonseed oil, sesame oil, Flavored emulsion of coconut oil or peanut oil and its analogs) or administered with an expectorant or similar pharmaceutical vehicle. Dispersing or suspending agents suitable for aqueous suspensions include synthetic and natural gums (such as tragacanth, acacia), alginate, polydextrose, carboxymethylcellulose, sodium strontium, methylcellulose, polyethylene - Pyrrolidone and gelatin. Liquid forms in suitably seasoned suspensions or dispersing agents may also include synthetic gums and natural gums. For parenteral administration, sterile suspensions and solutions are required. When the intravenous drug is to be administered intravenously, an isotonic agent generally containing a suitable preservative is used. The compound can be administered parenterally via injection. The parenteral formulation can be prepared by dissolving or mixing the active ingredient in a suitable inert liquid carrier. Acceptable liquid carriers typically contain aqueous solvents and other ingredients which may optionally be dissolved or preserved. Such aqueous solvents include sterile water, Ringer's s Uti〇n or isotonic saline solution. Other ingredients selected include vegetable oils (such as peanut oil, cottonseed oil and sesame oil) and organic solvents (such as acetone glycerol (s〇lkeUl), glycerin and formazan). Sterile, fixed oils can be employed as a solvent or suspension. Parenteral formulations are prepared by dissolving or suspending the active ingredient in liquid vehicle such that the final dosage unit contains from 0.005% to 1% by weight of active ingredient. Other additives include preservatives, isotonic agents, solubilizers, stabilizers, and pain relieving agents. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspensions and the like may be employed. The compounds of the invention may be administered intranasally using a suitable intranasal vehicle. In another embodiment t, the compounds of the invention can be administered directly into the lung by inhalation. The compounds of the invention may also be administered or enhanced topically by the use of a suitable topical transdermal vehicle or transdermal patch. For ocular administration, the composition is preferably in the form of an ophthalmic composition. The ophthalmic composition is preferably formulated as an eye drop formulation and filled in a suitable container to aid in administration to the eye, such as a dropper equipped with a suitable pipette. These 20% are preferably sterile and water based compositions using pure water. In addition to the vat of the present invention, the ophthalmic composition may also contain one or more of the following: a) an interface such as a polyoxyethylene fatty acid ester; b) a thickener such as cellulose, fiber, Alizarin derivatives, carboxyvinyl polymers, ethylene polymers and polyvinylpyrene 67 201245116 rancidone, the concentration of which is typically in the range of from about 5% to about 5 (four) (in the range of 'c X # is 1 gas) And optionally including, in addition to or in addition to the storage of the composition from the oxygen absorbing agent (such as Fe), an antioxidant such as butylated benzoyl ether, ascorbic acid, sodium thiosulfate. Or butylated hydroxytoluene at a concentration of from about 5% to about 〇 (wt/vol), d) ethanol having a concentration of from about %1% to about 5% (wt/v〇1) And e) other excipients such as isotonic agents, buffers, preservatives and/or value control agents. The pH of the ophthalmic composition needs to be in the range of 4 to 8. In some embodiments, the compositions of the present invention comprise one or more other pharmaceutical agents. Other therapeutic agents can be any agent that is capable of treating, preventing or ameliorating the symptoms of a tetracycline-reactive disease or condition. Alternatively, the other therapeutic agent may be any agent which is beneficial to the patient when administered in combination with the tetracycline compound of the present invention. The present invention has been shown and described in detail with reference to the exemplary embodiments of the present invention, but those skilled in the art should understand that in the form and the details thereof, various changes may be made without departing from the invention. Included in the scope of the patent application, the invention is abbreviated as the ethyl aryl benzyl group.

Ac aq Ar Bn 68 201245116Ac aq Ar Bn 68 201245116

Boc 第三丁氧羰基 Bu 丁基 DCE 1,2- 一氣乙烧 DIBAL-H 氫化二異丁基鋁 DMAP 4-(二曱胺基）吡啶 DMF 二曱基曱醯胺 ESI 電喷霧電離 Et 乙基 eq 當量 h 小時 HPLC 高效液相層析 i 異 LDA 二異丙基胺基鋰 LHMDS 雙（三甲基矽烷基）胺基鋰 MHz 兆赫茲 MS 質譜 ml z 質量/電荷比 MW 分子量 NBS iV-溴代丁二醯亞胺 NCS #-氯代丁二醯亞胺 NMR 核磁共振光譜 Ph 苯基 Pr 丙基 s 第二 69 201245116 t 第三 TMEDA WWW，-四曱基乙二胺 TBS 第三丁基二曱基矽烷基 TEA 三乙胺 TFA 三氟乙酸 THF 四氫α夫喃 TLC 薄層層析Boc tert-butoxycarbonyl Bu butyl DCE 1,2- one gas e-boiled DIBAL-H hydrogenated diisobutyl aluminum DMAP 4-(diguanyl)pyridine DMF dimercaptodecylamine ESI electrospray ionization Et B Base eq equivalent h hour HPLC high performance liquid chromatography i iso-LDA diisopropylamino lithium LHMDS bis(trimethyldecyl)amine lithium MHz megahertz MS mass spectrometry ml z mass/charge ratio MW molecular weight NBS iV-bromine Deuterated diamine imine NCS #-chlorobutanediamine imine NMR nuclear magnetic resonance spectrum Ph phenyl Pr propyl s second 69 201245116 t third TMEDA WWW,-tetradecylethylenediamine TBS tert-butyl Mercaptoalkyl-terminated TEA triethylamine TFA trifluoroacetic acid THF tetrahydro-alpha-Fan TLC thin layer chromatography

Tr 三苯甲基Tr trityl

TsOH 對甲苯磺酸 實施例1.製備適用於製備本發明化合物之中間物。 根據以下流程1製備適用於製備式I化合物之中間物。 流程 ch3 nh2TsOH p-toluenesulfonic acid Example 1. An intermediate suitable for the preparation of the compounds of the invention is prepared. An intermediate suitable for the preparation of the compound of formula I is prepared according to Scheme 1 below. Process ch3 nh2

〇ch3 S1-1〇ch3 S1-1

•CHO B「2•CHO B"2

CH3a)NaN〇2 Br, b)CuCN/NaCN nCH3a)NaN〇2 Br, b)CuCN/NaCN n

NH2 了、CN och3 och3 S1-2 S1-3 OCH3NH2, CN och3 och3 S1-2 S1-3 OCH3

0CH30CH3

1) NaCI02 2) (COCI)2 隨後PhOH1) NaCI02 2) (COCI)2 Subsequent PhOH

Boc2〇 DMAP ch3 Boc20 DMAP C02Ph a) Ph((〇Ac)2 CH3〇H 3 b)Zn/HOAc *CO〇PhBoc2〇 DMAP ch3 Boc20 DMAP C02Ph a) Ph((〇Ac)2 CH3〇H 3 b)Zn/HOAc *CO〇Ph

Tr-CI/Et3N OCH3 •CH3Tr-CI/Et3N OCH3 •CH3

70 20124511670 201245116

〇ch3 S1-2 合成SI -2 2_甲氧基-6-甲基苯胺 叫）於 CH3〇H ( 79 mL) 添加溴（9.41 mL，183.10 經由加料漏斗向冰冷卻之 (S1-1 > 25.12 g - 183.10 mmol > 及HO Ac ( 25 mL )中之溶液中逐滴 mmo卜 1 eq)於 H〇Ac ( 79 ) ^ A ）中之溶液。添加完成後使 反應混口物升溫至室溫且㈣2小時…添加EtOAc(150 ⑷，且藉由㈣收集固體並再用_Ae洗條，得到37 2〇 g呈灰白色固體狀之化合物S1_2 ( 鹽）。〇ch3 S1-2 synthesizes SI-2 2 methoxy-6-methylaniline) in CH3〇H (79 mL) bromine (9.41 mL, 183.10 cooled to ice via an addition funnel (S1-1 > A solution of 25.12 g - 183.10 mmol > and HO Ac (25 mL) in a solution of 1 M eq) of H 〇Ac ( 79 ) ^ A ). After the completion of the addition, the reaction mixture was allowed to warm to room temperature and (4) 2 hrs. EtOAc (150 (4) was obtained, and the solid was collected by (4) and then washed with _Ae to give 37. ).

ON 將4-漬-2-甲氧基_6_曱基苯胺（Sl_2, HBr鹽，2〇⑼g， 92.70 mmol’ 1 eq)懸浮於在冰浴中冷卻的濃鹽酸水溶液（η mL)及碎冰（76 g)中。逐滴添加細〇2( 6.52 g，94 6〇 _。卜ON 4-Sodium-2-methoxy-6-nonylaniline (Sl_2, HBr salt, 2 〇 (9) g, 92.70 mmol '1 eq) was suspended in concentrated aqueous hydrochloric acid (η mL) cooled in an ice bath and broken Ice (76 g). Add fine 〇 2 ( 6.52 g, 94 6 〇 _.

1.02 eq)於H2〇 (22 mL)令之溶液。在0〇c下授拌所得混 合物30分鐘且用他2〇〇3水溶液中和。將CuCN ( 1〇 4〇 g， 115.90 mmol ’ i.WeqM H2〇(44mL)中之懸浮液與 NaCN (14.40 g ’ 294.80 mmo卜 3.18 eq)於 22 mL H2〇 中之溶液 混合且於冰浴中冷卻。接著在劇烈攪拌下將初始重氮鹽混 合物添加至CuCN與NaCN之混合物中，同時維持溫度在〇 。(：（在添加期間亦以數份添加曱苯（丨8〇 mL ))。反應混 合物在0°C下攪拌1小時，在室溫下攪拌2小時且再在5〇 °C下攪拌1小時。冷卻至室溫後，分離各層。用甲苯萃取 水層。經合併之有機層用鹽水洗滌，經硫酸鎂脫水且濃縮。 71 201245116 使殘餘物穿過”塞，用甲苯洗務且濃縮，得到Μ 5〇 g呈 淺黃色固體狀之化合物S1-3 »1.02 eq) solution in H2 (22 mL). The resulting mixture was mixed at 0 °c for 30 minutes and neutralized with a 2 oz aqueous solution. Mix a suspension of CuCN (1〇4〇g, 115.90 mmol 'i.WeqM H2〇 (44 mL) with NaCN (14.40 g '294.80 mmob 3.18 eq) in 22 mL H2〇 in an ice bath Cooling. The initial diazonium salt mixture is then added to the mixture of CuCN and NaCN with vigorous stirring while maintaining the temperature at 〇. (: (In the course of the addition, benzene (丨8〇mL) is also added in several portions). The mixture was stirred at 0 ° C for 1 hour, at room temperature for 2 hours and then at 5 ° C for 1 hour. After cooling to room temperature, the layers were separated. The aqueous layer was extracted with toluene. Washed with brine, dried over MgSO4, EtOAc EtOAc EtOAc.

BrYYCH3 y^cH〇 , och3 合成 S1 -4 〇 si4 在-78t：下向 Sl_3(11.34g，5G 2()mmQi , μ)於 U00 mL)中之溶液中緩慢添加i 5 M dibal h之甲苯 ζ 40.10 mL y 60.20 mmnl > ι ο 〜 mmo卜1.2 eq)溶液。使反應物逐漸升 溫至室溫且搜拌隔夜。再冷卻至代後，肖Μ·水溶液 小心地：止反應。所得混合物在室溫下搜# 1小時且用BrYYCH3 y^cH〇, och3 Synthesis S1 -4 〇si4 Slowly add i 5 M dibal h toluene in solution of -78t: to Sl_3 (11.34g, 5G 2()mmQi, μ) in U00 mL) 40.10 mL y 60.20 mmnl > ι ο ~ mmo 1.2 eq) solution. The reaction was gradually warmed to room temperature and mixed overnight. After cooling to the next generation, Xiao Xiao·aqueous solution carefully: stop the reaction. The resulting mixture was searched for #1 hour at room temperature and used

EtOAc萃取三次。經合併之Et〇Ac層用h2〇、腿叫飽和 水溶液及鹽水洗滌，經硫酸鎂脫水且濃縮，得到呈黃色固 體狀之化合物si二4，ί直接用於下一步驟中。 ^V^co2Ph 合成 S1 - 5。 S1-53 經由加料漏斗向S1_4 (50.2〇刪卜i eq)於t_Bu0H ( 200 mL)中之懸浮液中添力口 NaC1〇2(u34 g，酬3〇 mm〇l>2eq) ANaH2P〇4(34.6g，250.80 mm〇l，5eq)^ H2〇(100 mL) _之溶液。添加完成後，添加2_甲基_2_丁 稀（42.4〇mL，〇.4〇m(U，8eq)。所得均質溶液在室溫下 槐拌30分鐘’且移除揮發物。將殘餘物懸浮於WmLH2〇 中。用ma水溶液將溶液酸化至ρΗ = ι且用第三丁基 ㈣萃取H經合併之有機溶液用INNaOH水溶液萃取 三次。經合併之水溶液用6NHC1水溶液酸化，且用Et〇Ac 萃取三次。經合併之Et0Ac萃取物用鹽水洗滌，經硫酸鎮 72 201245116 脫水且濃縮，得丨9 J 8 · 64 g呈灰白色固體狀之苯甲酸中間物， 其直接用於下一步驟中。 °述苯甲酸（8.64g，35.20 mmo卜1 eq)於二氯甲 烧(70 mL )中夕丄 T之，合液中添加乙二醯氯（3.76 mL，42.30 mmol，1.2 ea )，拉切、工 4 接者添加幾滴DMF (警告：氣體逸出）。 在^攪拌混合物3〇分鐘且減壓蒸發揮發物。將殘餘物 在门真工下進步乾燥’得到粗苯甲醯氯。將粗苯甲醯氣 再次溶解於二氯甲烷（7〇mL)中。添加三乙胺。2 3社， 88.1〇_〇1’2.5eq)、苯齡（ 3 98 g，42 3〇_〇i i 2eq) 及 DMAP ( 〇·43 e，飞 s〇 . A 、 S 3·52 mmol，0·1 eq )。在室溫下攪拌混 &物1小時。蒸發容劑。將殘餘物懸浮於扮〇Ac巾，且滤 出沈澱物。有機溶液接著用1NHC1水溶液（三次）、H2〇、 蘭⑶3飽和水溶液和鹽水絲，經硫酸鈉脫水，過濾且濃 縮。藉由急驟層析純化殘餘物，得到呈灰白色固體狀之化 合物 Sl_5(10.05g，89%) :iHNMR(4〇〇MHz CDci3)占 7.41-7.45 (m, 2 Η), 7.22-7.27 (m, 3 Η), 7.04 (d, J = 0.9 Hz, 1 H), 6.97 (d, J = 0.9 Hz, 1 H), 3.87 (s, 3 H), 2.42 (s, 3 H)； MS (ESI) m/z 319.0 (M-H)。 &YYCH3Extract with EtOAc three times. The combined Et 〇Ac layer was washed with aq. EtOAc, EtOAc (EtOAc) EtOAc. ^V^co2Ph Synthesis S1 - 5. S1-53 Adds NaC1〇2 (u34 g, 3〇mm〇l> 2eq) to the suspension in S__4 (50.2〇除i eq) in t_Bu0H (200 mL) via the addition funnel ANaH2P〇4 ( 34.6 g, 250.80 mm 〇l, 5 eq) ^ H2 〇 (100 mL) _ solution. After the addition was completed, 2_methyl_2_butan (42.4 〇mL, 〇.4 〇m (U, 8 eq) was added. The resulting homogeneous solution was stirred at room temperature for 30 minutes' and the volatiles were removed. The solution was suspended in WmLH2 。. The solution was acidified to pH Η = ι and extracted with a third butyl (tetra). The combined organic solution was extracted three times with aqueous NaOH solution. The combined aqueous solution was acidified with aqueous 6NHC1 and Et. The extract was extracted three times. The combined Et0Ac extract was washed with brine and dried over EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc Benzyl benzoic acid (8.64g, 35.20 mmo, 1 eq) in dichloromethane (70 mL), 丄 丄 T, add diethyl hydrazine chloride (3.76 mL, 42.30 mmol, 1.2 ea) to the mixture. Add a few drops of DMF (warning: gas escape). Stir the mixture for 3 minutes and evaporate the volatiles under reduced pressure. The residue is dried under the conditions of the door to obtain crude benzamidine chloride. The crude benzamidine gas was redissolved in dichloromethane (7 mL). Triethylamine was added. 88.1〇_〇1'2.5eq), benzene age (3 98 g, 42 3〇_〇ii 2eq) and DMAP (〇·43 e, fly s〇. A, S 3·52 mmol, 0·1 eq ) . The mixture was stirred at room temperature for 1 hour. Evaporate the container. The residue was suspended in an Ac towel and the precipitate was filtered off. The organic solution was then dehydrated with sodium sulfate, filtered, and concentrated with a 1N aqueous solution of NH.sub.1 (br.), H.sub.2, s. The residue was purified by EtOAc (EtOAc) elut elut elut elut elut elut 3 Η), 7.04 (d, J = 0.9 Hz, 1 H), 6.97 (d, J = 0.9 Hz, 1 H), 3.87 (s, 3 H), 2.42 (s, 3 H); MS (ESI) m/z 319.0 (MH). &YYCH3

OH 合成 S1 -6。 S1.6 在-78 C 下將 BBr3 之 CH2C12 溶液（！ 〇 m，27.96 mL， 27.96 mmol，1 eq)添加至苯醋 S1_5 ( 8 98 g，27 % 咖〇1， 1 eq)於CH2C12 ( 100 mL)中之溶液中。反應混合物在j °C下攪拌20分鐘且在01下攪拌丨5分鐘^緩慢添加NaH(：〇3 73 201245116 飽和水溶液（1 20 mL )。混合物在室溫下攪拌20分鐘且減 壓濃縮。用乙酸乙酯（250 mL)萃取殘餘物。分離有機層 且經無水MgS〇4脫水。過濾經脫水溶液，且濃縮濾液，得 到灰白色固體。藉由自EtOAc/己烧中再結晶來純化殘餘 物，得到呈白色固體狀之所需產物S1-6 ( 6.76 g)。濃縮母 液且藉由急驟管柱層析（2 -1 0 %乙酸乙g旨-己烧）純化殘餘 物’得到額外產物（973 mg ) ( 90%總產率）：NMR (400 MHz, CDC13) δ 11.13 (s, 1 Η), 7.43-7.47 (m, 2 Η), 7.29-7.33 (m, 1 Η), 7.16-7.19 (m, 2 Η), 7.08 (d, J = 1.8 Hz, 1 H), 6.96 (d, J = 1.8 Hz, 1 H), 2.66 (s, 3 H) ； MS (ESI) m/z 305.05, 307.05 (M-H)。 och3 V：co2PhOH synthesis S1 -6. S1.6 Add BBr3 in CH2C12 solution (! 〇m, 27.96 mL, 27.96 mmol, 1 eq) to Benzene vinegar S1_5 (8 98 g, 27 % curry 1, 1 eq) at CH2C12 (100) In the solution in mL). The reaction mixture was stirred at 00 °C for 20 min and stirred for rt for 5 min. </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; The residue was extracted with EtOAc (EtOAc)EtOAc. The desired product S1-6 ( 6.76 g) was obtained as a white solid. The residue was concentrated and purified by flash column chromatography (2 - 10% ethyl acetate) Mg ) ( 90% total yield): NMR (400 MHz, CDC13) δ 11.13 (s, 1 Η), 7.43-7.47 (m, 2 Η), 7.29-7.33 (m, 1 Η), 7.16-7.19 ( m, 2 Η), 7.08 (d, J = 1.8 Hz, 1 H), 6.96 (d, J = 1.8 Hz, 1 H), 2.66 (s, 3 H) ; MS (ESI) m/z 305.05, 307.05 (MH). och3 V:co2Ph

A OH 合成 Sl-7。 S1-7 在 〇°C 下將 PhI(OAc)2 (3_77 g，11·72 mmol，21 eq) 於CH3〇H( 20 mL)中之溶液緩慢添加至S1_6( i 71 g，5 58 leq)於 CH3〇H(30mL)與 M•二嗯烧（1〇mL) 之混合物中的溶液中。接著在室溫下攪拌反應混合物17小 時。添加 HOAc( 6 mL)及 Zn 粉（1_〇9 g，16 74 mm〇卜 3 eq) (輕微放熱）。反應混合物在室溫下攪拌2〇分鐘且經由矽 藻土（Celite)墊過濾。用EtOAc(1〇〇mL)洗滌矽藻土濾 餅。濃縮經合併之濾液。使殘餘物分配於Et0Ac ( 12〇mL：) 與飽和NaHCOV鹽水溶液（將水層調節至pH = 7 )之間。 分離有機層，脫水（MgSCU )且濃縮。藉由急驟管柱層析 (0-4%乙酸乙酯-己烷）純化殘餘物，得到所需產物si-7 74 201245116 ( 763 mg，41%) ： 'H NMR (400 MHz, CDC13) &lt;5 10.70 (s, 1 H), 7.43-7.47 (m, 2 H), 7.30-7.33 (m, 1 H), 7.17-7.20 (m, 2 H), 7.16 (s, 1 H), 3.75 (s, 3 H), 2.67 (s, 3 H) ； MS (ESI) m/z 335.1 1, 337.14 (M-H) °A OH synthesizes Sl-7. S1-7 Slowly add a solution of PhI(OAc)2 (3_77 g, 11.72 mmol, 21 eq) in CH3〇H (20 mL) to S1_6 (i 71 g, 5 58 leq) at 〇 °C In a solution of a mixture of CH3〇H (30 mL) and M•二嗯(1〇mL). The reaction mixture was then stirred at room temperature for 17 hours. Add HOAc (6 mL) and Zn powder (1_〇9 g, 16 74 mm〇 3 eq) (slightly exothermic). The reaction mixture was stirred at room temperature for 2 min and filtered through a pad of Celite. The diatomaceous earth cake was washed with EtOAc (1 mL). The combined filtrate was concentrated. The residue was partitioned between Et0Ac (12 mL:) and saturated aqueous NaHC.s. The organic layer was separated, dehydrated (MgSCU) and concentrated. The residue was purified by EtOAc EtOAc (EtOAc) ;5 10.70 (s, 1 H), 7.43-7.47 (m, 2 H), 7.30-7.33 (m, 1 H), 7.17-7.20 (m, 2 H), 7.16 (s, 1 H), 3.75 ( s, 3 H), 2.67 (s, 3 H) ; MS (ESI) m/z 335.1 1, 337.14 (MH) °

合成Sl-8 將二碳酸二第三丁酯（543 mg，2.49 mmo卜1.1 eq)及 N，N-二曱胺基0比咬（28 mg，0.226 mmol，0_1 eq)添加至盼 Sl-7 (763 mg，2.26mmol，leq)於二氯甲烧（20 mL)中 之溶液中。在室溫下攪拌混合物20分鐘且濃縮。藉由急驟 管柱層析（0-5%乙酸乙酯-己烷）純化殘餘物，得到呈白色 固體狀之化合物 S1-8 ( 783 mg，79% )。4 NMR (400 MHz， CDCI3) δ 7.45-7.41 (m，2 Η)，7.38 (s, 1 Η), 7.26-7.30 (m， 1 Η), 7.22-7.24 (m, 2 Η), 3.81 (s, 3 Η), 2.47 (s, 3 Η), 1.43 (s, 9 Η) ; MS (ESI) m/z 435.14, 437.15 (M-H)。Synthesis of Sl-8 Addition of di-tert-butyl dicarbonate (543 mg, 2.49 mmo, 1.1 eq) and N,N-diaminoamine 0 to bite (28 mg, 0.226 mmol, 0_1 eq) to the desired Sl-7 (763 mg, 2.26 mmol, leq) in dichloromethane (20 mL). The mixture was stirred at room temperature for 20 minutes and concentrated. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut 4 NMR (400 MHz, CDCI3) δ 7.45-7.41 (m, 2 Η), 7.38 (s, 1 Η), 7.26-7.30 (m, 1 Η), 7.22-7.24 (m, 2 Η), 3.81 (s , 3 Η), 2.47 (s, 3 Η), 1.43 (s, 9 Η); MS (ESI) m/z 435.14, 437.15 (MH).

在 〇°C 下將 i-PrMgCl-LiCl 於 THF 中之溶液（1.2 M， 4.9 5 mL，5.94 mmol ’ 1.5 eq)逐滴添加至化合物 Sl-8 ( 1.73 g，3.96 mmol，1 eq)於 THF ( 20 mL)中之溶液中。隨後 在〇°C下攪拌所得黃色反應混合物2小時。將反應物冷卻至 -78°C 且添加 N-Boc 吡略·咬酮（1.35 mL，7.92 mmo卜 2 eq )。 將反應物升溫至室溫且分配於NH4C1飽和水溶液（1 5 0 mL ) 與EtOAc ( 200 mL )之間。分離有機層，經MgS04脫水且 75 201245116 減壓濃縮，得到化合物； 其直接用於下一步驟中。 S1-9，在無進一 步純化的情況下將 \ CH3 C〇2Ph 合成S1-10。A solution of i-PrMgCl-LiCl in THF (1.2 M, 4.9 5 mL, 5.94 mmol < 1.5 eq) was added dropwise to THF (1.73 g, 3.96 mmol, 1 eq) in THF In a solution (20 mL). The resulting yellow reaction mixture was then stirred at 〇 ° C for 2 hr. The reaction was cooled to -78 &lt;0&gt;C and N-Boc &lt;RTI ID=0.0&gt;&gt; The reaction was warmed to rt EtOAc (EtOAc)EtOAc The organic layer was separated, dried with EtOAc EtOAc (EtOAc) S1-9, \CH3 C〇2Ph was synthesized into S1-10 without further purification.

將化合物S1-9溶解於CH/L ( 4 mL)中。在室溫下緩 慢添加TFA(4mL)(氣體逸出）。所得淺棕色溶液在室 溫下攪拌20分鐘，減壓濃縮且添加NaHC〇3飽和水溶液。 用CHAl2 ( 100 mLxl ' 20 mLx2)萃取混合物。經合併之有 機萃取物經MgS〇4脫水且濃縮至約3〇 mL之體積，得到中 間物S1-10之CH2C12溶液。Compound S1-9 was dissolved in CH/L (4 mL). TFA (4 mL) was slowly added at room temperature (gas evolution). The obtained light brown solution was stirred at room temperature for 20 minutes, concentrated under reduced pressure and a saturated aqueous NaH? The mixture was extracted with CHAl2 (100 mL×l '20 mL×2). The combined organic extracts were dehydrated by MgS〇4 and concentrated to a volume of about 3 mL to give a solution of intermediate S1-10 in CH2C12.

合成 Sl-11。 S1-H 向上述溶液中添加二碳酸二第三丁酯（950 mg，4.36 mm〇l ’ 1.1 eq)及 n，N-二甲胺基吡啶（48 mg，0.396 mmol， 〇· 1 eq )。在室溫下攪拌反應混合物1 5分鐘且濃縮。藉由 急驟管柱層析（5-50%乙酸乙酯-己烷）純化殘餘物，得到 呈白色固體狀之所需產物S1-11 ( 1.18 g，70%，經3個步 驟）：NMR (400 MHz，CDC13) 5 7.52 (s，1 H)，7·42·7.45 (m，2 H)，7.24-7.30 (m，3 H)，4_04 (t，J = 6.7 Hz，2 H)，3.71 (s， 3 H)，3.02 (t，J = 7.6 Hz，2 H)，2.45 (s，3 H)，2.05 (p，J =7.9 Hz，2 H)，1.43 (s，9 H) ; MS (ESI) m/z 426.68 (M+H)。Synthesis of Sl-11. S1-H To the above solution was added di-tert-butyl dicarbonate (950 mg, 4.36 mm 〇l '1.1 eq) and n,N-dimethylaminopyridine (48 mg, 0.396 mmol, 〇·1 eq). The reaction mixture was stirred at room temperature for 15 min and concentrated. The residue was purified by EtOAc EtOAc (EtOAc) 400 MHz, CDC13) 5 7.52 (s, 1 H), 7·42·7.45 (m, 2 H), 7.24-7.30 (m, 3 H), 4_04 (t, J = 6.7 Hz, 2 H), 3.71 (s, 3 H), 3.02 (t, J = 7.6 Hz, 2 H), 2.45 (s, 3 H), 2.05 (p, J = 7.9 Hz, 2 H), 1.43 (s, 9 H) ; MS (ESI) m/z 426.68 (M+H).

OBoc S1-12 合成Sl-12。 76 201245116 在 〇 C 下將 NaBH4 ( 104 mg，2.75 mmo卜 5 eq)整份添 加至Sl-11(由300 mg S1_8獲得之粗產物，〇μ mm〇1，i eq) 於CHsOH ( 3 mL )中之溶液中。觀察到氣體逸出。移除冷 浴，且攪拌反應混合物1 〇分鐘。緩慢添加丨N HC丨水溶液 (2 mL )。用NaHC03飽和水溶液（2 mL· )鹼化所得白色 懸浮液至1^ = 8-9且用（：1120：12(15 1111^、1〇1111^2)萃取。 經合併之有機萃取物經NhSO4脫水且濃縮。藉由急驟管柱 層析（50-1〇〇%乙酸乙酯-己烷）純化殘餘物，得到呈無色 油狀之所需產物S1-12 ( 107 mg，46%，經3個步驟）（注 意：此物質在靜置於工作台頂部上時不穩定。若干天後， 其部分分解）：4 NMR (400 MHz，CDC13) 5 7.39-7.42 (m， 2 Η), 7.31 (S, 1 Η), 7.22-7.27 (m, 3 Η), 4.48 (t, J = 7.6 Hz, 1 H)，3.75 (s，3 H)，3.17-3.22 (m，1 H)，3.03-3.10 (m，i H)， 2.41 (s，3 H)，2.23-2.31 (m，1 H)，2.12 (br s，1 H)，1.82-1.96 (m3 2 H), 1.57-1.67 (ms 1 H), 1.41 (s, 9 H) ； MS (ESI) m/z 428.68 (M + H) ° 或者，在室溫下將 HOAc ( 12 pL，0.21 mm〇1，3 eq) 及 Na(〇Ac)3BH ( 45 mg，0.21 mmol，3 eq)添加至化合物OBoc S1-12 synthesizes Sl-12. 76 201245116 Add NaBH4 (104 mg, 2.75 mmo, 5 eq) in aliquots to Sl-1 (crude from 300 mg of S1_8, 〇μ mm 〇1, i eq) to CHsOH (3 mL) In the solution. Gas evolution was observed. The cold bath was removed and the reaction mixture was stirred for 1 min. A solution of 丨N HC丨 (2 mL) was added slowly. The resulting white suspension was basified with a saturated aqueous solution of NaHCO.sub.2 (2 mL.) to &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&&&&&& Dehydrated and concentrated. The residue was purified by flash chromatography eluting elut elut elut elut elut elut elut Step) (Note: This material is unstable when placed on top of the bench. After a few days, it partially decomposes): 4 NMR (400 MHz, CDC13) 5 7.39-7.42 (m, 2 Η), 7.31 ( S, 1 Η), 7.22-7.27 (m, 3 Η), 4.48 (t, J = 7.6 Hz, 1 H), 3.75 (s, 3 H), 3.17-3.22 (m, 1 H), 3.03-3.10 (m,i H), 2.41 (s,3 H),2.23-2.31 (m,1 H), 2.12 (br s,1 H),1.82-1.96 (m3 2 H), 1.57-1.67 (ms 1 H ), 1.41 (s, 9 H) ; MS (ESI) m/z 428.68 (M + H) ° Alternatively, HOAc (12 pL, 0.21 mm〇1,3 eq) and Na(〇Ac) at room temperature 3BH (45 mg, 0.21 mmol, 3 eq) added to the compound

Sl-11 ( 3〇 mg，0.070 mmol，1 eq)於 DCE ( 1 mL)中之溶 液中。在室溫下攪拌反應混合物30分鐘。添加NaHC03飽 和水溶液。用CH2C12 ( 20 mL，10 mL)萃取混合物。經合 併之有機萃取物經脫水（NajO4 )且濃縮’得到所需產物 S1-12 。 77 201245116 门 〇ch3 llYCH3Sl-11 (3 〇 mg, 0.070 mmol, 1 eq) in DCE (1 mL). The reaction mixture was stirred at room temperature for 30 minutes. A saturated aqueous solution of NaHC03 was added. The mixture was extracted with CH2C12 (20 mL, 10 mL). The combined organic extracts are dehydrated (NajO4) and concentrated to give the desired product S1-12. 77 201245116 门 〇ch3 llYCH3

Tr y^C02Ph OBoc S1-13 合成Sl-13 〇 在室溫下將 TrCl( 5.75 g，20.64 mmo 卜 1.2 eq )及 TEA (3.12 mL，22.36 mmo卜 1.3 eq)添加至 Sl-12( 17.2 mmol ,Tr y^C02Ph OBoc S1-13 Synthesis of Sl-13 〇 TrCl ( 5.75 g, 20.64 mmo 1.2 eq) and TEA (3.12 mL, 22.36 mmo 1.2 eq) were added to Sl-12 ( 17.2 mmol, at room temperature).

粗物質，1 eq)於CH2C12 ( 100 mL )中之溶液中。在室溫 下搜:拌反應混合物2小時且濃縮。使殘餘物分配於EtOAc (300 mL )蜱水（100 mL )之間。有機相用水（5〇 mLX2 ) 及鹽水（50 mL )洗滌，經MgSCU脫水，且減壓濃縮，得到 所需產物 Sl-13 : MS (ESI) m/z 670.55 (M+H)。此粗產物 II 由自曱苯中共沸若干次而進一步乾燥且不經進一步純化即 用於後續反應中。 OCH-,Crude material, 1 eq) in CH2C12 (100 mL). Search at room temperature: The reaction mixture was stirred for 2 hours and concentrated. The residue was partitioned between EtOAc (300 mL) EtOAc. The organic phase was washed with water (5 mL EtOAc) (EtOAc m. This crude product II was further dried by azeotropy several times from toluene and used in the subsequent reaction without further purification. OCH-,

合成S1-14 將 BnBr( 66 pL’ 0.56 mmol，1.2 eq)及 K2C03( 77 m , 0.5 6 mmo卜 1.2eq)添加至 Sl-10(0.46 mmol，粗物質，丄叫） 於丙酮（6 mL)中之懸浮液中。添加DMF ( 0.5 mL)。反 應混合物在50°C下攪拌2小時，冷卻至室溫，且減壓濃縮。 使殘餘物分配於水與EtO Ac ( 5 0 mL )之間。有機相用水（3〇 mLx3 )及鹽水（20 mL)洗滌，經Na2S04脫水，且遭縮。 藉由急驟管柱層析（1 〇-1 〇〇%乙酸乙酯-己烷）純化殘餘物 得到所需產物Sl-14( 129 mg，67%，經2個步驟）：4 (400 MHz, CDCI3) δ 7.44-7.42 (m, 2 Η), 7.37-7.29 (m Η), 7.24-7.20 (m, 1 Η), 7.08-7.06 (m, 2 Η), 5.14 (s 9 ⑴ H)， 4.01 (tt5 J = 1.8, 7.6 Hz, 2 H), 3.66 (s, 3 H), 3.01 (tt, J ^ 1 0 78 201245116 7.9 Hz, 2 Η), 2.40 (s, 3 Η), 2.03 (p, J =7.9 Hz, 2 H) ； MS (ESI) m/z 416.42 (M+H)。 實施例2.合成其中環E為1-取代之吡咯啶-2-基之式I 化合物。 根據下文流程2合成式I化合物，其中X為-OCH3，Y 為-Η ;且環E為1-取代之吡咯啶-2-基。 流程2Synthesis of S1-14 Add BnBr (66 pL' 0.56 mmol, 1.2 eq) and K2C03 (77 m, 0.5 6 mmo, 1.2 eq) to Sl-10 (0.46 mmol, crude material, squeak) in acetone (6 mL) In the suspension. Add DMF (0.5 mL). The reaction mixture was stirred at 50 ° C for 2 hours, cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between water and EtO Ac (50 mL). The organic phase was washed with water (3 〇 mL x 3 ) and brine (20 mL), dried over Na 2 SO 4 and taken to shrink. The residue was purified by flash column chromatography eluting elut elut elut elut elut elut elut elut CDCI3) δ 7.44-7.42 (m, 2 Η), 7.37-7.29 (m Η), 7.24-7.20 (m, 1 Η), 7.08-7.06 (m, 2 Η), 5.14 (s 9 (1) H), 4.01 (tt5 J = 1.8, 7.6 Hz, 2 H), 3.66 (s, 3 H), 3.01 (tt, J ^ 1 0 78 201245116 7.9 Hz, 2 Η), 2.40 (s, 3 Η), 2.03 (p, J = 7.9 Hz, 2 H) ; MS (ESI) m/z 416.42 (M+H). Example 2. Synthesis of a compound of formula I wherein ring E is a 1-substituted pyrrolidin-2-yl group. The compound of formula I is synthesized according to Scheme 2 below, wherein X is -OCH3, Y is -Η; and Ring E is 1-substituted pyrrolidin-2-yl. Process 2

79 20124511679 201245116

自 S1-12 合成 S2-3。 在-78°C 下將 n-BuLi( 0.22 mL’ 2.5 Μ/己烷，0.55 mmol， 2.2 eq)逐滴添加至二異丙胺（81 pL，0.58 mmol，2.3 eq ) 於THF ( 3 mL )中之溶液中。在〇°c下攪拌反應溶液5分鐘 且冷卻至-78C。添加 TMEDA( 86 mL，0.58 mmo 卜 2.3 eq )。 在-78°C下撥拌反應溶液1 0分鐘。經由套管逐滴添加酯 S1-12 ( 107 mg ’ 0.25 mmol ’ 1 eq)於 thf ( 1 mL)中之溶 液。在-78 C下檀拌所得橙紅色溶液30分鐘且使用EtOH/ 液氮浴冷卻至-100°C。逐滴添加烯酮S2-1 ( 133 mg，0.28 mmo卜1.1 eq)於THF ( 1 mL)中之溶液。反應物經9〇分 在里逐漸升溫至0 C且用碗酸钟緩衝水溶液（ρ η 7 · 0 )中止。 用EtOAc萃取反應混合物。有機萃取物經Na2S〇4脫水且濃 縮。藉由急驟管柱層析（100%乙酸乙酯，隨後1〇% CHsOH/CHzCl2)純化殘餘物，得到產物混合物，藉由製備 型逆相HPLC在Waters自動純化系統上使用sunfire prepS2-3 was synthesized from S1-12. n-BuLi (0.22 mL '2.5 Μ/hexane, 0.55 mmol, 2.2 eq) was added dropwise to diisopropylamine (81 pL, 0.58 mmol, 2.3 eq) in THF (3 mL) In the solution. The reaction solution was stirred at 〇 °c for 5 minutes and cooled to -78C. Add TMEDA (86 mL, 0.58 mmo b 2.3 eq). The reaction solution was stirred at -78 ° C for 10 minutes. The solution of the ester S1-12 (107 mg '0.25 mmol' 1 eq) in thf (1 mL) was added dropwise via a cannula. The resulting orange-red solution was mixed at -78 C for 30 minutes and cooled to -100 °C using an EtOH / liquid nitrogen bath. A solution of the enone S2-1 (133 mg, 0.28 mmol, 1.1 eq) in THF (1 mL) was added dropwise. The reaction was gradually warmed to 0 C in 9 minutes and stopped with a bowl of acid clock buffer (ρ η 7 · 0). The reaction mixture was extracted with EtOAc. The organic extract was dehydrated and concentrated by Na2S〇4. The residue was purified by flash column chromatography (100% ethyl acetate then 1% CHsOH / CHzCl2) to yield product mixture, using the reversed phase HPLC on the Waters automated purification system using sunfire prep

C18 OBD 管柱[5 /z m ’ 19x5 0 mm ;流速：20 mL/min ;溶 劑 A : H2〇，含 0.1% HC02H ;溶劑 B : Ch3CN，含 01〇/〇 HC02H ;注入體積：4.0 mL ( CH3CN);梯度：20-&gt; 100% B 之A溶液，經i 〇分鐘；質量導向型洗提份收集]再次純化。 收集在5.2-5.9分鐘洗提之具有所需分子量的洗提份且在室 溫下於旋轉蒸發器（R0taVap )上濃縮以移除大部分乙腈。 所仵主要水溶液以飽和NaHC〇3溶液中和且以EtOAc萃 80 201245116 取。有機萃取物經NazSO4脫水且濃縮，得到所需產物S2_3 (6.3 mg，3%，兩種非對映異構體之混合物）：NMR (400 MHz, CDC13) δ 7.38-7.41 (m， 2 Η)， 7.21-7.30 (m， 4 Η)， 5.27, 5.26 (s, 2 Η), 4.37-4.42 (m, 1 Η), 3.91, 3.89 (d, J = 10.4 Hz, 1 H), 3.64, 3.62 (s, 3 H), 3.57-3.58 (m, 1 H), 2.85-3.23 (m, 3 H), 2.33-2.46 (m, 9 H), 2.12-2.28 (m, 2 H), 2.05 (d, J = 14.0 Hz, 1 H), 1.79-1.87 (m, 2 H), 1.44 (s, 9 H), 0.74 (Sj 9 H)j 0-18 (s, 3 H), 0.037, 0.029 (s, 3 H) ； MS (ESI) m/z 816.79 (M + H)。 冷合成！S2-3。或者，亦根據以下程序自si-13 經由S2-2製備化合物S2-3。C18 OBD column [5 /zm ' 19x5 0 mm; flow rate: 20 mL/min; solvent A: H2〇, containing 0.1% HC02H; solvent B: Ch3CN, containing 01〇/〇HC02H; injection volume: 4.0 mL (CH3CN ); Gradient: 20-&gt; 100% B solution of A, after i 〇 minutes; mass-directed elution fraction collection] was purified again. The eluted fraction having the desired molecular weight eluted at 5.2-5.9 minutes was collected and concentrated on a rotary evaporator (R0taVap) at room temperature to remove most of the acetonitrile. The main aqueous solution was neutralized with a saturated NaHC(R) solution and taken up in EtOAc EtOAc. The organic extract was dehydrated and concentrated with NazSO4 to give the desired product S2_3 (6.3 mg, 3%, mixture of two diastereomers): NMR (400 MHz, CDC13) δ 7.38-7.41 (m, 2 Η) , 7.21-7.30 (m, 4 Η), 5.27, 5.26 (s, 2 Η), 4.37-4.42 (m, 1 Η), 3.91, 3.89 (d, J = 10.4 Hz, 1 H), 3.64, 3.62 ( s, 3 H), 3.57-3.58 (m, 1 H), 2.85-3.23 (m, 3 H), 2.33-2.46 (m, 9 H), 2.12-2.28 (m, 2 H), 2.05 (d, J = 14.0 Hz, 1 H), 1.79-1.87 (m, 2 H), 1.44 (s, 9 H), 0.74 (Sj 9 H)j 0-18 (s, 3 H), 0.037, 0.029 (s, 3 H) ; MS (ESI) m/z 816.79 (M + H). Cold synthesis! S2-3. Alternatively, compound S2-3 was also prepared from si-13 via S2-2 according to the following procedure.

在- 72C 下將 w-BuLi (1〇.〇 mL’ 2.4 M/己院，24 08 mmo卜1.4 eq)逐滴添加至二異丙胺（3 4 mL，24.08 mmol， U eq)於THF ( 150 mL)中之溶液中。將反應混合物升溫 至 〇°C 且再冷卻至_74。(：。添加 TMEDA ( 3_61 mL，24.08w-BuLi (1〇.〇mL' 2.4 M/ 院, 24 08 mmo, 1.4 eq) was added dropwise to diisopropylamine (3 4 mL, 24.08 mmol, U eq) in THF (150). In the solution in mL). The reaction mixture was warmed to 〇 ° C and cooled to _74. (: Add TMEDA ( 3_61 mL, 24.08

mmol ’ 14 eq)。在_78〇c下攪拌反應溶液1〇分鐘。在_73 —-74C之間經25分鐘經由套管逐滴添加粗物質si-13於 THF ( 50 mL )中之溶液。在_74〇c下攪拌所得紅橙色溶液 45分鐘’且使用m〇H/液氮浴冷卻至_98t&gt;c。在j?— 下經由套管將預冷卻（_78t )之烯鲖S2-1 (8.30 g，17.2 _01’ leq)於THF(50mL)中之溶液添加至反應混合物 中。使反應混合物經1小時逐漸升溫至_83。〇 ^添加lHMDS 81 201245116 (17.20 mL，1.0 M/THF，17_20 mmol，1 eq )。使反應混 合物經105分鐘逐漸升溫至-15t：。將HC1水溶液（1 N，85 mL)、磷酸鹽緩衝液（pH = 7，200 mL)及NH4C1飽和水 溶液（200 mL)添加至反應物中。用EtOAc ( 200 mL)萃 取反應混合物。有機萃取物用鹽水（100 mL)洗滌，經Na2S04 脫水，且減壓濃縮。藉由製備型逆相HPLC在Waters自動 純化系統上使甩Sunfire Prep C18 OBD管柱[5 e m，19x50 mm ,流速：20 mL/min ;溶劑 A : H20，含 〇_i% HC02H ;Mm ' 14 eq). The reaction solution was stirred at _78 ° C for 1 Torr. A solution of the crude material si-13 in THF (50 mL) was added dropwise via a cannula between _73--74C over 25 min. The resulting red-orange solution was stirred at _74 °c for 45 minutes' and cooled to _98t &gt;c using a m〇H/liquid nitrogen bath. A pre-cooled (_78t) solution of the olefin S2-1 (8.30 g, 17.2 _01' leq) in THF (50 mL) was added via cannula to the reaction mixture. The reaction mixture was gradually warmed to _83 over 1 hour. 〇 ^Add lHMDS 81 201245116 (17.20 mL, 1.0 M/THF, 17_20 mmol, 1 eq). The reaction mixture was gradually warmed to -15 t over 105 minutes. An aqueous solution of HCl (1 N, 85 mL), a phosphate buffer (pH = 7,200 mL), and a saturated aqueous NH4Cl solution (200 mL) were added to the mixture. The reaction mixture was extracted with EtOAc (200 mL). The organic extract was washed with brine (100 mL) dried over Na. The Sunfire Prep C18 OBD column was prepared by preparative reverse phase HPLC on a Waters automated purification system [5 em, 19 x 50 mm, flow rate: 20 mL/min; solvent A: H20, containing 〇_i% HC02H;

/谷劑 B · CH3CN ’ 含 0.1% HC02H ;注入體積：4 〇 mL (CH3CN);梯度：954 100% Β之Α溶液，經7分鐘；UV (350 nm)導向型洗提份收集]純化粗產物。收集第一 350 nm uv峰且濃縮，得到呈橙色固體狀之非對映異構體A S2_2_A (7·81 g’ 43%，經3個步驟），且收集第二35〇nmU^^ 且濃縮’得到呈橙色固體狀之非對映異構體B S2-2_B。 亦藉由急驟管柱層析（5-10〇/。乙酸乙酯-己烷）純化粗 樣本，得到呈兩種非對映異構體之1:1混合物形式的所需產 物 S2_2 (淺黃色固體）：4 NMR (4〇〇 MHz，CDci3)占 15·7δ4&gt; 15.776 (s, 1 Η), 7.66 (s5 0.5 Η), 7.60 (s, 〇.5 Η) .-.57 («1，8 Η)，7.30-7.38 (m，3 Η)，7.09-7.21 (m，9 Η)， 5·31-5·39 (m, 2 Η), 4.68-4.72 (m, 1 Η), 4.05 (d, J = ι〇.4 Ηζ! 〇·5 Η), 3.94 (d3 /= 10.4 Hz, 0.5 Η), 3.42-3.50 (m, ! Η), 3.28 (S} 1·5 Η), 3.20 (dd, 7 = 4.9, 15.3 Hz, 〇.5 Η), 2.90-3.07 (m, 4 Η)» 2-3δ-2.52 (m, 9 Η), 2.10 (d, J = U.〇 Hz, 1 H), 1.81-1.91 1 H), 1.75-1.67 (m, 1 H), 1.60 (s, 4.5 H)s 1.59 (s, 4.5 H), 82 201245116 • 1.43-1.54 (m, 2 Η), 0.87 (s, 4.5 Η), 0.83 (s, 4.5 Η), 0.28 (s&gt; 1.5 H)，0.27 (s，1.5 Η), 0.17 (s, 1.5 H)，0.13 (s, 1.5 Η) ; Ms (ESI) w/z 1058.84 (M+H)。 將化合物S2·2 ( 72 mg，非對映異構體之i: i混合物， 0.068 mmol，1 eq)溶解於〇·5 M HC1於THF中之預混合溶 液（83pL6NHCl溶解於917pLTHF)中。在室溫下授掉 反應溶液45分鐘。逐滴添加NaHC〇3飽和水溶液直至停止 鼓泡。添加磷酸鹽緩衝溶液（pH = 7 )。用EtOAc ( 40 mL ) 萃取所得混合物。有機萃取物經Na2S〇4脫水且濃縮，得到 呈黃色固體狀之所需產物S2_3 ( MS (ESI) m/z 816.72 (M+H))。粗產物不經進一步純化即使用。 合成化合物S2-H。 °H sU H °。 在 23°c 下將 HCH〇( 37%於水中，1.7 卟，0.023 mmo卜 3 eq)、乙酸（1·3 μί ’ 0.023 mmol，3 eq)及三乙醯氧基 硼氫化鈉（3.3 mg，〇·〇15 mmol，2 eq)依序添加至化合物 S2_3 ( 5.4 mg，7.7 // mol，丄 eq)於 氯乙烷（i 社） 中之溶液中。攪拌45分鐘後，反應混合物用磷酸鉀緩衝水 溶液（pH = 7.0)中止且用二氯甲烷（15社，1〇虹）萃取。 經合併之有機萃取物經無水硫酸鈉脫水且濃縮。粗產物（Μ $ (ESI) m/z 830.77 (M+H))不經進一步純化即使用。 在23°C下將HF水溶液（48_5〇%，〇 3 mL)添加至聚 丙稀反應容器中上述中間物於THF(().6mL)中之溶液中。 在23 C下劇烈授拌混合物隔夜且傾入κ2Ηρ〇4水溶液（3 6呂 83 201245116 溶解於30 mL水）中。用Et〇Ac ( 30 mL，15 mL)萃取混 合物。經合併之有機相經無水硫酸鈉脫水且濃縮。在無進 一步純化的情況下將殘餘物直接用於下一步驟。（MS (ESI) m/z 616.56 (M+H) ) 〇 在23 C下將Pd-C ( l〇 wt%，3 mg )整份添加至上述粗 產物於 HC1/CH30H( 〇·5 N，31 pL，2 eq)與 CH30H ( 1 mL) 之混合物中的溶液中。將反應容器密封且藉由短暫地柚空 燒瓶接著用氩氣（1 atm)吹拂而用氩氣淨化。在23〇c下在 氫氣氛圍（1 atm )下攪拌反應混合物丨小時。經由小型矽 篇土塾過;慮反應混合物。濃縮遽液。藉由製備型逆相Hplc 在Waters自動純化系統上使用phen〇menex p〇lymerx 1〇 &quot; rp- r ιοοΑ 管柱[10 以 m，150x21 2〇 mm ;流速：2〇 mL/min ;溶劑 A : 〇·〇5 N HC1/水；溶劑 B : CH3Cn ;注入 體積：3.0mL (〇.〇5NHCi/水）；梯度：1〇—5〇%B，經 l5 分鐘；質量導向型洗提份收集]純化殘餘物。收集在65_9〇 分鐘洗提之含有所需產物之洗提份且冷凍乾燥，得到化合 物 S2-7-1 ( 2.7 mg，鹽酸鹽，57% ( 3 個步驟））：咕 nmr (400 MHz，CD3〇D，鹽酸鹽，非對映異構體之混合物）夂 7.07 (s, 0.6 H), 7.02 (s, 0.4 Η), 4.80-4.84 (m, 〇.6 H), 4.71 (dd, J = 7.3, 10.5 Hz, 0.4 H), 4.10 (s, 1 H), 3.79-3.89 (m, 1 H), 3.76 (s, 1.2 H), 3.69 (s, 1.8 H), 3.32-3.36 (m, 1 H), 3.16-3.26 (m, 1 H), 2.97-3.04 (m, 8 H), 2.83, 2.80 (s, 3 H), 2.57-2.63 (m, 1 H), 2.37-2.44 (m, 1 H), 2.14-2.35 (m, 4 H), 1.61-1.71 (m, 1 H) ； MS (ESI) m/z 528.5 1 (M+H) 〇 84 201245116 藉由與S2_7-l所用類似之程序自S2-3及各種醛製備以 下化合物。/Valent B · CH3CN ' Contains 0.1% HC02H; Injection volume: 4 〇mL (CH3CN); Gradient: 954 100% Β Β solution, after 7 minutes; UV (350 nm) guided extract collection] Purified crude product. The first 350 nm uv peak was collected and concentrated to give the diastereomer A S2_2_A (7·81 g' 43% in three steps) as an orange solid, and the second 35 〇nmU^^ was collected and concentrated. 'A diastereomer B S2-2_B was obtained as an orange solid. The crude sample was also purified by flash column chromatography (5-10 EtOAc / hexanes) to afford the desired product S2 2 as a mixture of two diastereomers (light yellow) Solid): 4 NMR (4 〇〇 MHz, CDci3) occupies 15.7 δ4 &gt; 15.776 (s, 1 Η), 7.66 (s5 0.5 Η), 7.60 (s, 〇.5 Η) .-.57 («1, 8 Η), 7.30-7.38 (m, 3 Η), 7.09-7.21 (m, 9 Η), 5·31-5·39 (m, 2 Η), 4.68-4.72 (m, 1 Η), 4.05 ( d, J = ι〇.4 Ηζ! 〇·5 Η), 3.94 (d3 /= 10.4 Hz, 0.5 Η), 3.42-3.50 (m, ! Η), 3.28 (S} 1·5 Η), 3.20 ( Dd, 7 = 4.9, 15.3 Hz, 〇.5 Η), 2.90-3.07 (m, 4 Η)» 2-3δ-2.52 (m, 9 Η), 2.10 (d, J = U.〇Hz, 1 H ), 1.81-1.91 1 H), 1.75-1.67 (m, 1 H), 1.60 (s, 4.5 H)s 1.59 (s, 4.5 H), 82 201245116 • 1.43-1.54 (m, 2 Η), 0.87 ( s, 4.5 Η), 0.83 (s, 4.5 Η), 0.28 (s&gt; 1.5 H), 0.27 (s, 1.5 Η), 0.17 (s, 1.5 H), 0.13 (s, 1.5 Η); Ms (ESI) w/z 1058.84 (M+H). Compound S2·2 (72 mg, a mixture of diastereomers i: i, 0.068 mmol, 1 eq) was dissolved in a premixed solution of 〇·5 M HCl in THF (83 pL 6 N HCl dissolved in 917 pL THF). The reaction solution was allowed to stand at room temperature for 45 minutes. A saturated aqueous solution of NaHC〇3 was added dropwise until bubbling ceased. Add phosphate buffer solution (pH = 7). The resulting mixture was extracted with EtOAc (40 mL). The organic extract was dried over EtOAc (EtOAc m.) The crude product was used without further purification. The compound S2-H was synthesized. °H sU H °. HCH〇 (37% in water, 1.7 卟, 0.023 mmo 3 eq), acetic acid (1·3 μί ' 0.023 mmol, 3 eq) and sodium triethoxy borohydride (3.3 mg, at 23 ° C, 〇·〇15 mmol, 2 eq) was added sequentially to the solution of compound S2_3 (5.4 mg, 7.7 // mol, 丄eq) in ethyl chloride (i). After stirring for 45 minutes, the reaction mixture was quenched with a potassium carbonate aqueous solution (pH = 7.0) and extracted with methylene chloride (15 EtOAc). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated. The crude product (Μ$ (ESI) m/z 830.77 (M+H)) was used without further purification. An aqueous HF solution (48 5%, 〇 3 mL) was added to a solution of the above intermediate in THF ((). 6 mL) in a polypropylene reaction vessel at 23 °C. The mixture was vigorously mixed at 23 C overnight and poured into an aqueous solution of κ 2 Ηρ〇 4 (3 6 LV 83 201245116 dissolved in 30 mL of water). The mixture was extracted with Et 〇Ac (30 mL, 15 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was used directly in the next step without further purification. (MS (ESI) m/z 616.56 (M+H)) 〇 P P 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 23 HC HC HC HC HC HC HC HC HC HC HC HC HC HC HC HC HC HC HC HC HC HC 31 pL, 2 eq) in a solution in a mixture with CH30H (1 mL). The reaction vessel was sealed and purged with argon by briefly boiling the pomelo flask followed by argon (1 atm). The reaction mixture was stirred under a hydrogen atmosphere (1 atm) at 23 ° C for a few hours. Pass through a small piece of soil; consider the reaction mixture. Concentrated mash. Phen〇menex p〇lymerx 1〇&quot; rp-r ιοοΑ column was used on the Waters automated purification system by preparative reverse phase Hplc [10 in m, 150x21 2〇mm; flow rate: 2〇mL/min; solvent A : 〇·〇5 N HC1/water; solvent B: CH3Cn; injection volume: 3.0 mL (〇.〇5NHCi/water); gradient: 1〇—5〇%B, after 15 minutes; mass-oriented elution collection ] Purify the residue. The extract containing the desired product was eluted at 65_9 min and lyophilized to give compound S2-7-1 (2.7 mg, hydrochloride, 57% (3 steps)): 咕nmr (400 MHz, CD3〇D, hydrochloride, a mixture of diastereomers) 夂7.07 (s, 0.6 H), 7.02 (s, 0.4 Η), 4.80-4.84 (m, 〇.6 H), 4.71 (dd, J = 7.3, 10.5 Hz, 0.4 H), 4.10 (s, 1 H), 3.79-3.89 (m, 1 H), 3.76 (s, 1.2 H), 3.69 (s, 1.8 H), 3.32-3.36 (m , 1 H), 3.16-3.26 (m, 1 H), 2.97-3.04 (m, 8 H), 2.83, 2.80 (s, 3 H), 2.57-2.63 (m, 1 H), 2.37-2.44 (m , 1 H), 2.14-2.35 (m, 4 H), 1.61-1.71 (m, 1 H) ; MS (ESI) m/z 528.5 1 (M+H) 〇84 201245116 by similar to S2_7-l Procedure The following compounds were prepared from S2-3 and various aldehydes.

SZ-TliHNMROOOMH^CDaOD，鹽酸鹽）占 71' (s，0.67 H)，7.07 (s，0.33 H)，4.75-4.80 (m，0.33 H)，4.12 (s，^ Η), 3.82-3.93 (m, 1.67 Η), 3.77 (s, 2 Η), 3.69 (Sj 1 H) 3.34-3.38 (m, 1 H), 2.97-3.27 (m, 11 H), 2.55-2.63 (m, 1 H) 2.12-2.48 (m, 5 H), 1.62-1.74 (m, 3 H), 0.87-0.93 (m, 3 H); MS (ESI) m/z 556.55 (M+H)。SZ-TliHNMROOOMH^CDaOD, hydrochloride) accounted for 71' (s, 0.67 H), 7.07 (s, 0.33 H), 4.75-4.80 (m, 0.33 H), 4.12 (s, ^ Η), 3.82-3.93 ( m, 1.67 Η), 3.77 (s, 2 Η), 3.69 (Sj 1 H) 3.34-3.38 (m, 1 H), 2.97-3.27 (m, 11 H), 2.55-2.63 (m, 1 H) 2.12 - 2.48 (m, 5 H), 1.62-1.74 (m, 3 H), 0.87-0.93 (m, 3 H); MS (ESI) m/z 556.55 (M+H).

S2-7-3: lH NMR (400 MHz, CD3OD,鹽酸鹽）5 7 17 (s5 0.5 H), 7.10 (s, 0.5 H), 4.78-4.82 (m, 1 H), 4.12 (s, 1 H) 3.89-4.00 (m, 1 H), 3.78 (s, 1.5 H), 3.69 (s, 1.5 H), 3.34.3 41 (m，1 H)，3.15-3.26 (m，1 H)，2.84-3.09 (m，9 H)，2.55_2 60 (m，1 H)，2.40 (t，J = 14.6 Hz，1 H)，2.12-2.34 (m，4 Ή) 1.94-2.02 (m，1 H)，1.61-1.70 (m，1 H)，0.88-0,98 (m, 6 H). MS (ESI) m/z 570.58 (M+H)。S2-7-3: lH NMR (400 MHz, CD3OD, hydrochloride) 5 7 17 (s5 0.5 H), 7.10 (s, 0.5 H), 4.78-4.82 (m, 1 H), 4.12 (s, 1 H) 3.89-4.00 (m, 1 H), 3.78 (s, 1.5 H), 3.69 (s, 1.5 H), 3.34.3 41 (m, 1 H), 3.15-3.26 (m, 1 H), 2.84 -3.09 (m,9 H),2.55_2 60 (m,1 H), 2.40 (t,J = 14.6 Hz,1 H),2.12-2.34 (m,4 Ή) 1.94-2.02 (m,1 H) , 1.61-1.70 (m, 1 H), 0.88-0, 98 (m, 6 H). MS (ESI) m/z 570.58 (M+H).

S2-7-4: 4 NMR (400 MHz，CD3OD，鹽酸鹽）δ s，1 Η)， (s, 0.5 Η), 7.06 (s, 0.5 Η), 4.76-4.83 (m, 1 Η), 4.11 ( 85 201245116 3.91-4.02 (m, 1 Η), 3.75 (s, 1.5 Η), 3.68 (s, 1.5 Η), 3.40-3.46 (m&gt; 1 Η), 3.14-3.27 (m, 1 Η), 2.92-3.12 (m, 9 Η), 2.57-2.61 (m&gt; 1 Η), 2.12-2.43 (m, 5 Η), 1.60-1.70 (m, 1 Η), 0.98-1.03 (m&gt; 1 Η), 0.60-0.66 (m, 2 Η), 0.33-0.40 (m, 1 Η), 0.20-0.27 (m，1 Η) ; MS (ESI) m/z 568.58 (M+H)。 合成化合物2-Ί-5-ΑS2-7-4: 4 NMR (400 MHz, CD3OD, hydrochloride) δ s, 1 Η), (s, 0.5 Η), 7.06 (s, 0.5 Η), 4.76-4.83 (m, 1 Η), 4.11 ( 85 201245116 3.91-4.02 (m, 1 Η), 3.75 (s, 1.5 Η), 3.68 (s, 1.5 Η), 3.40-3.46 (m&gt; 1 Η), 3.14-3.27 (m, 1 Η), 2.92-3.12 (m, 9 Η), 2.57-2.61 (m&gt; 1 Η), 2.12-2.43 (m, 5 Η), 1.60-1.70 (m, 1 Η), 0.98-1.03 (m> 1 Η), 0.60-0.66 (m, 2 Η), 0.33-0.40 (m, 1 Η), 0.20-0.27 (m, 1 Η); MS (ESI) m/z 568.58 (M+H). 5-Α

根據與非對映異構體混合物S2-2之保護基脫除反應所 用類似之程序用稀鹽酸處理化合物S2-2-A ( 7.8 1 g，7.38 mm〇1 ’ 1 eq)以移除三苯甲基。將所得自由胺S2-3-A溶解 於DCE( 120 mL)中且冷卻至〇。〇。依序添加乙酸（〇 85 mL， 14.76 mmol ’ 2 eq)及三乙醯氧基石朋氫化鈉（313 g，14 % mmol ’ 2 eq)。經由針筒（用乾冰預冷卻）添加乙醛（〇 83 mL ’ 14·76 mmol ’ 2 eq)。在〇°C下攪拌反應混合物25分 鐘。添加NaHC〇3飽和水溶液（3〇〇 mL)。攪拌反應混合 物20分鐘且用二氣曱烷（4〇〇 mL )萃取。有機萃取物經無 水硫酸鈉脫水且濃縮。藉由急驟管柱層析（8·66%乙酸乙酿 _己烷）純化殘餘物，得到呈淺黃色固體狀之化合物S2-4-5-A (3.45 g ’ 55%，經 2 個步驟）：NMR (4〇〇 MHz，CDCl3) δ 15.73 (s, 1 H)s 7.47-7.49 (m, 2 H), 7.30-7.38 (m, 4 H), 5-34 (s, 2 H), 3.97 (d, J = i〇.4 Hz, 1 H), 3.68 (s, 3 H), 3.63·3·74 (m，1 H)，3.30-3.43 (m，i H)，3.25 (dd，j = 4 9’ 15.9 Hz, H), 2.94-3.02 (m, H)，2.37-2.56 (m，10 H)， 86 201245116 2.10-2.20 (m, 3 H), 1.80-1.92 (m, 2 H), 1.48-1.62 (m, 2 H), 1.52 (s, 9 H), 0.98-1.02 (m, 3 H), 0.82 (s, 9 H), 0.26 (s, 3 H), 0.12 (s, 3 H) ; MS (ESI) m/z 844.75 (M+H)。 根據與製備S2-7-1所用類似之程序脫除化合物 S2-4-5-A 之保護基。利用 si_Cyano 管柱（35 g，以 〇.〇5 N HC1 水溶液洗提）純化，得到呈黃色固體狀之所需化合物 S2-7-5-A( 1.33 g，鹽酸鹽，67%( 2 個步驟））：NMR (400 MHz, CD3OD，鹽酸鹽）5 7·10 (s，1 h)，4.10 (s，1 H)， 3.81-3.91 (m, 1 H), 3.68 (s, 3 H), 3.32-3.37 (m, 1 H), 3.25 (dd, 4.6, 15.6 Hz, 1 H), 2.96-3.21 (m, 11 H), 2.55-2.62 (m, 1 H), 2.40 (t, J= 14.6 Hz, 1 H), 2.23-2.3 4 (m, 4 H), 1.61-1.70 (m, 1 H), 1.25 (t, J = 7.3 Hz, 3 H) ； MS (ESI) m/z 542.35 (M + H)The compound S2-2-A (7.8 1 g, 7.38 mm 〇 1 '1 eq) was treated with dilute hydrochloric acid to remove triphenylbenzene according to a procedure similar to the deprotection of the diastereomer mixture S2-2. methyl. The resulting free amine S2-3-A was dissolved in DCE (120 mL) and cooled to hydr. Hey. Acetic acid (〇 85 mL, 14.76 mmol ' 2 eq) and sodium triethoxy sulfonate (313 g, 14% mmol ' 2 eq) were added sequentially. Acetaldehyde (〇 83 mL '14·76 mmol ' 2 eq) was added via a syringe (precooled with dry ice). The reaction mixture was stirred at 〇 ° C for 25 min. A saturated aqueous solution of NaHC〇3 (3 〇〇 mL) was added. The reaction mixture was stirred for 20 min and extracted with dioxane (4 mL). The organic extract was dehydrated and concentrated with anhydrous sodium sulfate. Purification of the residue by flash column chromatography (EtOAc: EtOAc) : NMR (4〇〇MHz, CDCl3) δ 15.73 (s, 1 H)s 7.47-7.49 (m, 2 H), 7.30-7.38 (m, 4 H), 5-34 (s, 2 H), 3.97 (d, J = i〇.4 Hz, 1 H), 3.68 (s, 3 H), 3.63·3·74 (m, 1 H), 3.30-3.43 (m, i H), 3.25 (dd, j = 4 9' 15.9 Hz, H), 2.94-3.02 (m, H), 2.37-2.56 (m, 10 H), 86 201245116 2.10-2.20 (m, 3 H), 1.80-1.92 (m, 2 H) , 1.48-1.62 (m, 2 H), 1.52 (s, 9 H), 0.98-1.02 (m, 3 H), 0.82 (s, 9 H), 0.26 (s, 3 H), 0.12 (s, 3 H) ; MS (ESI) m/z 844.75 (M+H). The protecting group of compound S2-4-5-A was removed according to a procedure similar to that used for the preparation of S2-7-1. Purification using a si_Cyano column (35 g, eluting with EtOAc EtOAc EtOAc EtOAc) Step)): NMR (400 MHz, CD3OD, hydrochloride) 5 7·10 (s, 1 h), 4.10 (s, 1 H), 3.81-3.91 (m, 1 H), 3.68 (s, 3 H ), 3.32-3.37 (m, 1 H), 3.25 (dd, 4.6, 15.6 Hz, 1 H), 2.96-3.21 (m, 11 H), 2.55-2.62 (m, 1 H), 2.40 (t, J = 14.6 Hz, 1 H), 2.23-2.3 4 (m, 4 H), 1.61-1.70 (m, 1 H), 1.25 (t, J = 7.3 Hz, 3 H) ; MS (ESI) m/z 542.35 (M + H)

S2-7-6-B 根據與S2-7-5-A所用類似之程序自S2-2-B製備化合物 SZ-T-S-B^HNMRHOOMHzJDsOD，鹽酸鹽）6 7.20(s, 1 Η), 4.79 (m, 1 Η), 4.18 (s, 1 Η), 3.92 (m, 1 Η), 3.77 (s, 3 Η), 3.34-3.37 (m, 1 Η), 2.99-3.23 (m, 11 Η), 2.58 (m, 1 Η), 2.30-2.40 (m, 4 Η), 2.13-2.15 (m, 1 Η), 1.64-1.66 (m, 1 Η), 1.30 (br t，J = 7.3 Ηζ，3 Η) ; MS (ESI) m/z 542.48 (Μ+Η)。 87 201245116S2-7-6-B Preparation of the compound SZ-TSB^HNMRHOOMHzJDsOD, hydrochloride)6 7.20(s, 1 Η), 4.79 (m) from S2-2-B according to procedures similar to those used for S2-7-5-A , 1 Η), 4.18 (s, 1 Η), 3.92 (m, 1 Η), 3.77 (s, 3 Η), 3.34-3.37 (m, 1 Η), 2.99-3.23 (m, 11 Η), 2.58 (m, 1 Η), 2.30-2.40 (m, 4 Η), 2.13-2.15 (m, 1 Η), 1.64-1.66 (m, 1 Η), 1.30 (br t, J = 7.3 Ηζ, 3 Η) ; MS (ESI) m/z 542.48 (Μ+Η). 87 201245116

S2-7-6-A 合成化合物S2-7-6-A。 根據與S2-7-1所用類似之程序藉由脫除S2-2-A ( 44 mg，0.042 mmol)之保護基來製備化合物S2-7-6-A ( 16.1 mg，65% ( 3 個步驟））：4 NMR (400 MHz，CD3OD,鹽 酸鹽）5 6.95 (s, 1 Η), 4.89-4.82 (m, 1 Η), 4.10 (s, 1 Η), 3.74 (s, 3 Η), 3.49-3.43 (m, 1 Η), 3.38-3.32 (m, 1 Η), 3.24 (dd, J= 4.1, 15.1 Hz, 1 H), 3.04-2.97 (m, 8 H), 2.52-2.47 (m, 1 H), 2.41 (t, J= 14.4 Hz, 1 H), 2.29-2.16 (m, 4 H), 1.71-1.61 (m，1 H) ; MS (ESI) m/z 514.29 (M+H)。S2-7-6-A Synthetic compound S2-7-6-A. Compound S2-7-6-A ( 16.1 mg, 65% (3 steps) was prepared by removing the protecting group of S2-2-A (44 mg, 0.042 mmol) according to a procedure similar to that used for S2-7-1 )): 4 NMR (400 MHz, CD3OD, hydrochloride) 5 6.95 (s, 1 Η), 4.89-4.82 (m, 1 Η), 4.10 (s, 1 Η), 3.74 (s, 3 Η), 3.49-3.43 (m, 1 Η), 3.38-3.32 (m, 1 Η), 3.24 (dd, J= 4.1, 15.1 Hz, 1 H), 3.04-2.97 (m, 8 H), 2.52-2.47 (m , 1 H), 2.41 (t, J = 14.4 Hz, 1 H), 2.29-2.16 (m, 4 H), 1.71-1.61 (m, 1 H) ; MS (ESI) m/z 514.29 (M+H ).

$2·7·6·θ$2·7·6·θ

合成化合物S2-7-6-B 根據與S2-7-l所用類似之程序藉由脫除s2-2-B(28 mg，0.027 mmol)之保護基來製備化合物s2-7-6-B( 2.3 mg， 16%(2個步驟））：11^1\411(400]^1^，€〇3〇〇，鹽酸鹽）5 6.96 (s, 1 Η), 4.86-4.92 (m, 1 Η), 4.10 (s, 1 Η), 3.78 (s, 3 Η), 3.44-3.47 (m, 2 Η), 3.17-3.21 (m, 1 Η), 2.96-3.08 (m, 8 Η), 2.47-2.54 (m, 1 Η), 2.37 (t, J= 15.1 Hz, 1 H), 2.09-2.29 (m, 4 H)，1.61-1.70 (m，1 H) ; MS (ESI) m/z 514.44 (M + H) » 合成化合物-Ί。 88 201245116Synthesis of Compound S2-7-6-B The compound s2-7-6-B was prepared by removing the protecting group of s2-2-B (28 mg, 0.027 mmol) according to a procedure similar to that used for S2-7-1. 2.3 mg, 16% (2 steps)): 11^1\411(400]^1^, €〇3〇〇, hydrochloride)5 6.96 (s, 1 Η), 4.86-4.92 (m, 1 Η), 4.10 (s, 1 Η), 3.78 (s, 3 Η), 3.44-3.47 (m, 2 Η), 3.17-3.21 (m, 1 Η), 2.96-3.08 (m, 8 Η), 2.47 -2.54 (m, 1 Η), 2.37 (t, J = 15.1 Hz, 1 H), 2.09-2.29 (m, 4 H), 1.61-1.70 (m, 1 H) ; MS (ESI) m/z 514.44 (M + H) » Synthetic compound - hydrazine. 88 201245116

在-78 C 下將 n-BuLi( 0.21 mL’ 1，6 Μ/ 己燒，〇 34 mmol，n-BuLi (0.21 mL' 1,6 Μ/ hexane, 〇 34 mmol, at -78 C

1.1 eq)逐滴添加至二異丙胺（48 μί，〇·34 mm〇i，i J 及 TMEDA ( 51 pL，0.34 mmol，1.1 eq)於 thf ( 5 mL) 中之溶液中。在-78°C下攪拌反應混合物30分鐘。經由套管 添加酯 S1-14 ( 129 mg，0.31 mmol ’ 1 eq)於 thf ( j mL) 中之溶液。所得暗紅色溶液在-78°C下攪拌1小時且使用 EtOH/液氮浴冷卻至-100°C。經由套管將稀綱sty 165 ， 0.34 mmo卜1.1 eq)於THF ( 1 mL)中之溶液添加至反應 混合物中。使反應混合物逐漸升溫至_78°c。添加LHMDS (0.34 mL’ 1.0 M/THF，0.34 mmol，l.l eq)。反應混合物 經90分鐘逐漸升溫至〇。(：，用磷酸鉀緩衝水溶液（pH 7 〇 ) 及ΝΗκι飽和水溶液中止，且用EtOAc(50mL)萃取。有 機萃取物經NajO4脫水且濃縮。藉由製備型逆相hplc在1.1 eq) was added dropwise to a solution of diisopropylamine (48 μί, 〇·34 mm〇i, i J and TMEDA (51 pL, 0.34 mmol, 1.1 eq) in thf (5 mL) at -78° The reaction mixture was stirred for 30 min at C. A solution of the ester S1-14 (129 mg, 0.31 mmol &lt;1&gt; eq) in thf (jmL) was added via the cannula. The obtained dark red solution was stirred at -78 °C for 1 hour. It was cooled to -100 ° C using an EtOH / liquid nitrogen bath. A solution of the crude sty 165, 0.34 mmol, 1.1 eq) in THF (1 mL) was added to the reaction mixture via a cannula. The reaction mixture was gradually warmed to -78 °C. LHMDS (0.34 mL' 1.0 M/THF, 0.34 mmol, l.l eq) was added. The reaction mixture was gradually warmed to hydrazine over 90 minutes. (:, quenched with aqueous potassium phosphate buffer (pH 7 〇) and EtOAc (aq.) and extracted with EtOAc (50 mL). The organic extracts were dried over NajO4 and concentrated.

Waters自動純化系統上使用Sunfire Prep C1 8 OBD管柱[5 # m，19x5 0 mm ;流速：20 mL/min ;溶劑 A : Η20 ,含 0· 1¾ HC02H ’ 溶劑 B : CH3CN，含 0.1 % HC02H ;注入體積：4.0 mL ( CH3CN );梯度：2〇-&gt; 1〇〇% B 之 a 溶液，經 1〇 分鐘； 質量導向型洗提份收集]純化殘餘物。收集具有所需分子量 之洗提份且濃縮’得到所需產物S2-5 ( 1 〇 1 mg ) : 4 NMR (400 MHz, CDC13) δ 16.13 (s, 1 Η), 7.50-7.52 (m, 4 Η ), 7.33-7.41 (m，6 Η), 5.38 (s，2 Η), 5.26, 5.18 (ABq，J = 12.2 89 201245116Sunfire Prep C1 8 OBD column was used on the Waters automated purification system [5 # m, 19x5 0 mm; flow rate: 20 mL/min; solvent A: Η20, containing 0·13⁄4 HC02H 'solvent B: CH3CN, containing 0.1% HC02H; Injection volume: 4.0 mL (CH3CN); Gradient: 2〇-&gt; 1〇〇% B of a solution, 1 minute; mass-oriented elution fraction collection] Purify the residue. The extract having the desired molecular weight is collected and concentrated to give the desired product S2-5 (1 〇 1 mg): 4 NMR (400 MHz, CDC13) δ 16.13 (s, 1 Η), 7.50-7.52 (m, 4 Η ), 7.33-7.41 (m,6 Η), 5.38 (s,2 Η), 5.26, 5.18 (ABq,J = 12.2 89 201245116

Hz，2 H)，4.02-4.06 (m，3 Η), 3.65 (s，3 H)，3.33 (dd，J = 4.9, 15.9 Hz, 1 H), 2.94-3.00 (m, 3 H), 2.37-2.58 (m, 9 H), 2.15 (d, J = 14.6 Hz, 1 H), 2.03-2.11 (m, 2 H), 0.84 (s, 9 H), 0.28 (Sj 3 H)，0.16 (s，3 H) ; MS (ESI) m/z 804.77 (M+H)。Hz, 2 H), 4.02-4.06 (m, 3 Η), 3.65 (s, 3 H), 3.33 (dd, J = 4.9, 15.9 Hz, 1 H), 2.94-3.00 (m, 3 H), 2.37 -2.58 (m, 9 H), 2.15 (d, J = 14.6 Hz, 1 H), 2.03-2.11 (m, 2 H), 0.84 (s, 9 H), 0.28 (Sj 3 H), 0.16 (s , 3 H) ; MS (ESI) m/z 804.77 (M+H).

在 23 °C 下將乙酸（5.0 μί，0.090 mmol，2 eq )及三乙 醯氧基硼氫化鈉（19 mg，0.090 mmol，2 eq )依序添加至 化合物 S2-5 (36 mg’ 0.045 mmol，1 eq)於 l，2-二氯乙烧 (1 mL)中之溶液中。攪拌25分鐘後，添加CH3CHO( 12.7 μΐ^ ’ 0·23 mmol ’ 5 eq)。在室溫下攪拌反應混合物1小時， 用磷酸鉀緩衝水溶液（pH = 7.0 )中止，且用二氣曱烷（3〇 mL，10 mL)萃取。經合併之有機萃取物經無水硫酸鈉脫水 且濃縮，得到S2-6-7，在無進一步純化的情況下將其用於 下一步驟：MS (ESI) m/z 834.80 (M+H)。 在23°C下將HF水溶液（48-5 0%，0.3 mL)添加至聚 丙稀反應谷器中S2-6-7於THF (0.6 mL)令之溶液中。在 2 3°C下劇烈攪拌混合物隔夜且傾入κ2ΗΡ04水溶液（3.6 g 溶解於30 mL水）中。用EtOAc ( 50 mL)萃取混合物。有 機相經無水硫酸鈉脫水且濃縮。在無進一步純化的情況下 將殘餘物直接用於下一步驟：MS (ESI) m/z 72〇 67 (M+H)。 在23°C下將Pd-C ( 1〇 wt%，12 mg)整份添加至上述 粗產物於 hci/ch3oh(〇.5n，180卟，2eq)與 CH3〇H(1 mL )之混合物中的溶液中。將反應容器密封且藉由短暫地 90 201245116 抽空燒瓶接著用氫氣（1 atm )吹拂而用氫氣淨化。在23^ 下在氫氣氛圍（1 atm )下攪拌所得混合物5〇分鐘。經由小 型矽藻土墊過濾反應混合物。濃縮濾液。藉由製備型逆相 HPLC在Waters自動純化系統上使用Phenomenex 10 Μ RP-T 100A 管柱 Π〇 # m，150x21.20 mm ;流速： 20 mL/min ;溶劑 A : 0.05 N HC1/水；溶劑 B : CH3CN ;注 入體積：3.0mL (0.05NHC1/水）：梯度：10-&gt; 50% B，經 1 5分鐘；質量導向型洗提份收集]純化殘餘物。收集在 7.2-9.2分鐘洗提之含有所需產物之洗提份且冷凍乾燥，得 到化合物S2-7-7 ( 11 mg，鹽酸鹽，40% ( 3個步驟））：ιΗ NMR(400 MHz，CD3OD,鹽酸鹽，非對映異構體之混合物） 5 7.13 (s，0.55 H)，7.09 (s，0.45 H)，4.77 (dd，J = 7.8, 10.5Acetic acid (5.0 μί, 0.090 mmol, 2 eq) and sodium triethoxysulfonate (19 mg, 0.090 mmol, 2 eq) were added sequentially to compound S2-5 (36 mg' 0.045 mmol) at 23 °C , 1 eq) in a solution of l,2-dichloroethane (1 mL). After stirring for 25 minutes, CH3CHO (12.7 μΐ^ '0·23 mmol ' 5 eq) was added. The reaction mixture was stirred at room temperature for 1 hour, quenched with aqueous potassium hydrogen carbonate (pH = 7.0), and extracted with dioxane (3 mL, 10 mL). The combined organic extracts were dried with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH An aqueous HF solution (48-5 0%, 0.3 mL) was added to a solution of S2-6-7 in THF (0.6 mL) in a polypropylene reaction vessel at 23 °C. The mixture was stirred vigorously at 23 ° C overnight and poured into a κ 2 ΗΡ04 aqueous solution (3.6 g dissolved in 30 mL water). The mixture was extracted with EtOAc (50 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was used directly in the next step without further purification: MS (ESI) m/z 72 s 67 (M+H). Pd-C (1% wt%, 12 mg) was added in portions to the above crude product in a mixture of hci/ch3oh (〇.5n, 180卟, 2 eq) and CH3〇H (1 mL) at 23 °C. In the solution. The reaction vessel was sealed and purged with hydrogen by briefly evacuating the flask at 90 201245116 followed by blowing with hydrogen (1 atm). The resulting mixture was stirred under a hydrogen atmosphere (1 atm) at 23 ° for 5 Torr. The reaction mixture was filtered through a pad of Celite. The filtrate was concentrated. Phenomenex 10 Μ RP-T 100A tube column # m, 150 x 21.20 mm; flow rate: 20 mL/min; solvent A: 0.05 N HC1/water; solvent by preparative reverse phase HPLC on a Waters automated purification system B: CH3CN; Injection volume: 3.0 mL (0.05 NHC1/water): Gradient: 10-&gt; 50% B over 15 minutes; mass-directed elution fraction collection] Purification residue. The fractions containing the desired product eluted in 7.2-9.2 minutes were collected and lyophilized to give compound S2-7-7 (11 mg, hydrochloride, 40% (3 steps)): ι NMR (400 MHz) , CD3OD, hydrochloride, a mixture of diastereomers) 5 7.13 (s, 0.55 H), 7.09 (s, 0.45 H), 4.77 (dd, J = 7.8, 10.5

Hz, 0.55 Η), 4.12 (s, 1 Η), 3.81-3.91 (m, 1.45 Η), 3.76 (s, 1.35 Η), 3.69 (s, 1.65 Η), 3.30-3.37 (m} 1 Η), 2.96-3.27 (m,Hz, 0.55 Η), 4.12 (s, 1 Η), 3.81-3.91 (m, 1.45 Η), 3.76 (s, 1.35 Η), 3.69 (s, 1.65 Η), 3.30-3.37 (m} 1 Η), 2.96-3.27 (m,

11 H)，2.57-2.62 (m，1 H)，2.43-2.10 (m，5 H)，1.61-1.70 (m， 1 H)，1.20-1.30 (m，3 H) ; MS (ESI) m/z 542.57 (M+H)。 合成化合物S2-7 -名。 S2-7-8 藉由與S2-7-7所用類似之程序自s2_5及丙酮製備化合 物S2-7-8:lHNMR(400 Ml·lz，CD3OD，鹽酸鹽，非對映異 構體之混合物）5 7_13 (s，0.55 Η)，7·08 (s, 0.45 H)，4.07 (s, 1 Η), 3.75 (s, 1.35 Η), 3.64 (s, 1.65 Η), 3.58-3.64 (m, 1 Η), 3.38-3.46 (m, 2 Η), 2.93-3.20 (m, 10 Η), 2.54-2.55 (m, 1 Η), 2.04-2.39 (m, 5 Η), 1.58-1.68 (m, 1 Η), 1.22-1.30 (m, 6 Η) ! 91 201245116 MS (ESI) m/z 556.59 (M + H) 〇11 H), 2.57-2.62 (m, 1 H), 2.43-2.10 (m, 5 H), 1.61-1.70 (m, 1 H), 1.20-1.30 (m, 3 H) ; MS (ESI) m/ z 542.57 (M+H). Synthesis of compound S2-7 - name. S2-7-8 Compound S2-7-8 was prepared from s2_5 and acetone by a procedure similar to that used for S2-7-7: lHNMR (400 Ml·lz, CD3OD, hydrochloride, mixture of diastereomers) ) 5 7_13 (s, 0.55 Η), 7·08 (s, 0.45 H), 4.07 (s, 1 Η), 3.75 (s, 1.35 Η), 3.64 (s, 1.65 Η), 3.58-3.64 (m, 1 Η), 3.38-3.46 (m, 2 Η), 2.93-3.20 (m, 10 Η), 2.54-2.55 (m, 1 Η), 2.04-2.39 (m, 5 Η), 1.58-1.68 (m, 1 Η), 1.22-1.30 (m, 6 Η) ! 91 201245116 MS (ESI) m/z 556.59 (M + H) 〇

S2-4-9-A 合成化合物S2-4-9-A。 在室溫下將 K2C03 ( 7 mg，0.050 mmol，1.2 eq) 、Nal (1.3 mg，0.008 mmol，0.2 eq)及溴乙醇（3.3 μί，0.046 mmo卜 1.1 eq)添加至 S2-3-A ( 0.042 mmo卜 1·0 當量）於 THF ( 1 mL )中之溶液中。在5〇°c下加熱反應混合物2小 時。接著添加〉臭乙醇（5.0 μΐ^，0.070 mmol，1.7 eq)且在 60 C下加熱所得反應混合物2天。將反應混合物冷卻至室 溫’用EtOAc ( 30 mL)稀釋且依次用磷酸鹽緩衝液（pH = 7 ’ 20 mL)及鹽水（20 mL)洗滌。所得有機相經Na2S04 脫水’過濾且減壓濃縮《藉由製備型逆相HPLC在Waters 自動純化系統上使用Sunfire Prep c 1 8 OBD管柱[5 // m，S2-4-9-A Synthesis of compound S2-4-9-A. K2C03 (7 mg, 0.050 mmol, 1.2 eq), Nal (1.3 mg, 0.008 mmol, 0.2 eq) and bromoethanol (3.3 μί, 0.046 mmo, 1.1 eq) were added to S2-3-A (0.042) at room temperature Mmob 1·0 eq.) in THF (1 mL). The reaction mixture was heated at 5 ° C for 2 hours. Then, odor ethanol (5.0 μM, 0.070 mmol, 1.7 eq) was added and the resulting reaction mixture was heated at 60 C for 2 days. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL). The resulting organic phase was <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0>

19x5 0 mm;流速：20 mL/min;溶劑 a: H20,含 0.1% HC02H ; 溶劑 B : CH3CN ’ 含 0.1% HC02H ;注入體積：2.0 mL (CH3CN);梯度：i〇— ι〇0% B之a溶液，經15分鐘； 質量導向型洗提份收集]純化粗產物。收集在86_95分鐘洗 提之具有所需分子量之洗提份且在室溫下於旋轉蒸發器上 濃縮以移除大部分乙腈。所得主要水溶液以飽和NaHC〇3 ♦液中和且以Et〇Ac萃取。有機萃取物經Na2S〇4脫水且濃 縮，得到所需產物 S2-4-9-A ( 9.3 mg，26。/〇 ) : NMR (400 92 201245116 MHz, CDC13) 5 16.20 (br s, 1 H), 7.50-7.46 (m, 4 H ), 7.39-7.25 (m, 7 H), 5.35 (s, 2 H), 5.19 (ABq, J = 12.8, 16.5 Hz, 2 H), 4.01 (d, J= 10.4 Hz, 1 H), 3.88-3.82 (m, 1 H), 3.64 (s, 3 H), 3.67-3.61 (m, 2 H), 3.49-3.41 (m, 2 H), 3.24 (dd, J = 4.3, 15.9 Hz, 1 H), 2.96-2.90 (m, 1 H), 2.78-2.72 (m, 1 H), 2.5 4-2.42 (m, 8H), 2.35-2.17 (m, 3 H), 2.1 1 (d, /= 14.0 Hz, 1 H), 1.79-1.87 (m, 2 H), 1.62-1.49 (m, 1 H), 1.40-1.39 (m, 1 H), 0.84 (s, 9 H), 0.27 (s, 3 H), 0.14 (s, 3 H) ； MS (ESI) m/z 850.53 (M+H)。19x5 0 mm; flow rate: 20 mL/min; solvent a: H20, containing 0.1% HC02H; solvent B: CH3CN' containing 0.1% HC02H; injection volume: 2.0 mL (CH3CN); gradient: i〇— ι〇0% B The solution of a was passed for 15 minutes; the mass-oriented extract was collected] and the crude product was purified. The fractions of the desired molecular weight eluted at 86-95 minutes were collected and concentrated on a rotary evaporator at room temperature to remove most of the acetonitrile. The resulting main aqueous solution was neutralized with saturated NaHC 3 ♦ liquid and extracted with Et EtOAc. The organic extract was dried over Na 2 S 〇 4 and concentrated to give the desired product S s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s , 7.50-7.46 (m, 4 H ), 7.39-7.25 (m, 7 H), 5.35 (s, 2 H), 5.19 (ABq, J = 12.8, 16.5 Hz, 2 H), 4.01 (d, J= 10.4 Hz, 1 H), 3.88-3.82 (m, 1 H), 3.64 (s, 3 H), 3.67-3.61 (m, 2 H), 3.49-3.41 (m, 2 H), 3.24 (dd, J = 4.3, 15.9 Hz, 1 H), 2.96-2.90 (m, 1 H), 2.78-2.72 (m, 1 H), 2.5 4-2.42 (m, 8H), 2.35-2.17 (m, 3 H), 2.1 1 (d, /= 14.0 Hz, 1 H), 1.79-1.87 (m, 2 H), 1.62-1.49 (m, 1 H), 1.40-1.39 (m, 1 H), 0.84 (s, 9 H ), 0.27 (s, 3 H), 0.14 (s, 3 H); MS (ESI) m/z 850.53 (M+H).

非對映異構體A HO OH O HO H 〇 〇Diastereomer A HO OH O HO H 〇 〇

S2-7-9-A 合成化合物S2-1-9-A。 根據與 S2-7-1所用類似之程序藉由脫除化合物 S2-4-9-A之保護基來獲得化合物S2-7-9-A: 4 NMR (400 MHz, CD3OD,鹽酸鹽）&lt;5 7.14 (s, 1 H), 4.94-4.87 (m, 1 Η), 4.10 (s, 1 Η), 3.98-3.92 (m, 1 Η), 3.80-3.66 (m, 2 Η), 3.69 (s, 3 Η), 3.44-3.37 (m, 1 Η), 3.25 (dd, J = 4.6, 15.6 Hz, 1 H), 3.20-3.17 (m, 2 H), 3.07-2.97 (m, 8 H), 2.61-2.54 (m, 1 H), 2.41 (t,J= 14.4 Hz, 1 H), 2.35-2.21 (m, 4 H), 1.71-1.61 (m, 1 H) ; MS (ESI) m/z 558.27 (M+H)。S2-7-9-A Synthesis of compound S2-1-9-A. The compound S2-7-9-A was obtained by removing the protecting group of the compound S2-4-9-A according to a procedure similar to that used for S2-7-1: 4 NMR (400 MHz, CD3OD, hydrochloride) &lt;;5 7.14 (s, 1 H), 4.94-4.87 (m, 1 Η), 4.10 (s, 1 Η), 3.98-3.92 (m, 1 Η), 3.80-3.66 (m, 2 Η), 3.69 ( s, 3 Η), 3.44-3.37 (m, 1 Η), 3.25 (dd, J = 4.6, 15.6 Hz, 1 H), 3.20-3.17 (m, 2 H), 3.07-2.97 (m, 8 H) , 2.61-2.54 (m, 1 H), 2.41 (t, J = 14.4 Hz, 1 H), 2.35-2.21 (m, 4 H), 1.71-1.61 (m, 1 H) ; MS (ESI) m/ z 558.27 (M+H).

非對映異構體A 93 201245116Diastereomer A 93 201245116

S2-7-10-A 合成化合物S2-7-IQ-A。 根據與S2-7-9-A所用類似之程序自S2-3-A及溴丙醇製 備化合物 S2-7-10-A : 4 NMR ( 400 MHz，CD3OD，鹽酸鹽） δ 7.09 (s, 1 Η), 4.92-4.88 (m, 1 Η), 4.10 (s, 1 Η), 3.92-3.86 (m, 1 Η), 3.70 (s, 3 Η), 3.63-3.50 (m, 2 Η), 3.38-3.32 (m, 1 Η), 3.25-3.17 (m, 3 Η), 3.04-2.97 (m, 8 Η), 2.62-2.57 (m, 1 Η), 2.41 (t, J= 14.4 Hz, 1 H), 2.36-2.22 (m, 4 H), 1.85-1.82 (m，2 H)，1.71-1.62 (m, 1 H) ; MS (ESI) m/z 572.30 (M+H)。 實施例3.合成其中環E為1-取代之哌啶-2-基之式I化 合物。 根據以下流程3合成式I化合物，其中X為-OCH3，Y 為-Η ;且環E為1-取代之哌啶-2-基。 流程3S2-7-10-A Synthesis of compound S2-7-IQ-A. Preparation of compound S2-7-10-A from S2-3-A and bromopropanol according to procedures similar to those used for S2-7-9-A: 4 NMR (400 MHz, CD3OD, hydrochloride) δ 7.09 (s, 1 Η), 4.92-4.88 (m, 1 Η), 4.10 (s, 1 Η), 3.92-3.86 (m, 1 Η), 3.70 (s, 3 Η), 3.63-3.50 (m, 2 Η), 3.38-3.32 (m, 1 Η), 3.25-3.17 (m, 3 Η), 3.04-2.97 (m, 8 Η), 2.62-2.57 (m, 1 Η), 2.41 (t, J= 14.4 Hz, 1 H), 2.36-2.22 (m, 4 H), 1.85-1.82 (m, 2 H), 1.71-1.62 (m, 1 H); MS (ESI) m/z 572.30 (M+H). Example 3. Synthesis of a compound of formula I wherein ring E is a 1-substituted piperidin-2-yl group. The compound of formula I is synthesized according to Scheme 3 below, wherein X is -OCH3, Y is -Η; and Ring E is 1-substituted piperidin-2-yl. Process 3

^ys&quot;co2Ph^ys&quot;co2Ph

Ο ΗΟ ΐ Ο 0Bn OTBS O HO Ξ O OBnb)烯酮 S2-1 0TBS OBoc S3-3 BocO S3*4 OH S3-5Ο ΗΟ ΐ Ο 0Bn OTBS O HO Ξ O OBnb) ketene S2-1 0TBS OBoc S3-3 BocO S3*4 OH S3-5

94 20124511694 201245116

〇ch3 BocHN〇ch3 BocHN

C02Ph S3-1 OBoc 合成sh 在 0°C 下向 Sl-8 (436mg’ lmmol，leq)於無水 THF (15 mL )中之溶液中添加z_-PrMgCl-LiCl之THF溶液（1 2 Μ ’ 1.25 mL ’1.5eq)。在〇C下授样混合物30分鐘且冷 卻至-7 8 °C。在N2下逐滴添加2 -側氧基-略咬_ 1 -曱酸第二丁 酯（398 mg，2 mmol ’ 2 eq )於無水 THF ( 5 mL )中之溶 液。反應物經1小時緩慢升溫至-5°C。添加NKUCl飽和水 溶液（10 mL)。用EtOAc ( 15 mLx3 )萃取混合物。經合 併之EtO Ac萃取物用鹽水洗滌，經硫酸鈉脫水且濃縮，得 到化合物S3-1 ( 500 mg，89% )，在無純化的情況下將其直 接用於下一步驟：MS (ESI) m/z 580.0 (M+Na) 〇 r^l 〇ch3 SVyCH3 y^co2Ph * , OBoc 合成 -2。 s3·2 在室溫下向 S3-1 ( 500 mg，0·89 mmo卜 1 eq )於 CH2C12 (10 mL)中之溶液中添加TFA ( 1() mL)。在室溫下授摔 混合物3 0分鐘。濃縮反應混合物。添加NaHC〇3飽和水溶 液（20 mL )。用CH2C12 ( 15 mLx3 )萃取混合物。經合併 之CHzCl2萃取物用鹽水洗滌，經硫酸鈉脫水且濃縮，得到 粗中間物（ 302 mg，1〇〇%)，在無進一步純化的情況下將 其直接用於下一步驟：MS (ESI) m/z 439.9 (M+H)。 向上述粗產物（302 mg，0.88 mmol，1 eq)於 CH2C1 (15 mL)中之溶液中添加（b〇c)2〇 ( 287呵，132軸〇1，2 L5 eq)及 DMAP ( 10.7 mg，（M3 mmo卜 u eq)。在室溫 95 201245116 下攪拌反應混合物30分鐘且濃縮。添加NaHCCh飽和水溶 液（20 mL)。用EtOAc ( 15 mLx3)萃取混合物。經合併 之EtOAc萃取物用鹽水洗滌，經硫酸鈉脫水且濃縮，得到 粗中間物’在無進一步純化的情況下將其直接用於下一步 驟。 在0°C下向上述粗產物於CH3〇H ( 15 mL)中之溶液中 添加 NaBH4 ( 100 mg，2.64 mmol，3 eq )。混合物在 3〇 分 鐘内升溫至室溫。將HC1水溶液（1 N，10 mL )逐滴添加 至反應混合物中，接著用NaHC〇3水溶液中和。用Et〇Ac (15 mLx3 )萃取混合物。經合併之EtOAc萃取物用鹽水洗 務’經硫酸鈉脫水且濃縮，得到產物S3-2 ( 310 mg，粗物 質，79% )，在無缽化的情況下將其直接用於下一步驟：lH NMR (400 MHz, CDC13) δ 7.43-7.47 (m, 2 Η), 7.28-7.32 (m, 1 Η), 7.21-7.25 (m, 2 Η), 4.00-4.04 (m, 1 Η), 3.79 (s, 3C02Ph S3-1 OBoc Synthesis sh Add z_-PrMgCl-LiCl in THF solution (1 2 Μ ' 1.25 mL) to a solution of Sl-8 (436 mg 'lmmol, leq) in anhydrous THF (15 mL) at 0 °C. '1.5eq). The mixture was incubated for 30 minutes at 〇C and cooled to -7 8 °C. A solution of 2-oxooxy-slightly octa- 1 -decanoic acid dibutyl ester (398 mg, 2 mmol '2 eq) in dry THF (5 mL) was added dropwise. The reaction was slowly warmed to -5 °C over 1 hour. A saturated aqueous solution of NKUCl (10 mL) was added. The mixture was extracted with EtOAc (15 mL×3). The combined EtO Ac extract was washed with brine, dried over sodium sulfate and concentrated to afford compound S </RTI> (500 mg, 89%). m/z 580.0 (M+Na) 〇r^l 〇ch3 SVyCH3 y^co2Ph * , OBoc synthesis-2. S3·2 To a solution of S3-1 (500 mg, 0·89 mmo 1 eq) in CH2C12 (10 mL) was added TFA (1 () mL). The mixture was dropped for 30 minutes at room temperature. The reaction mixture was concentrated. A saturated solution of NaHC〇3 (20 mL) was added. The mixture was extracted with CH2C12 (15 mL×3). The combined CHzCl2 extracts were washed with EtOAc EtOAc EtOAc (EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH ) m/z 439.9 (M+H). Add (b〇c) 2〇 (287 °, 132-axis 〇 1, 2 L5 eq) and DMAP ( 10.7 mg) to the above crude product (302 mg, 0.88 mmol, 1 eq) in CH2C1 (15 mL) The reaction mixture was stirred for 30 min at rt EtOAc (EtOAc) EtOAc (EtOAc) Dehydrated over sodium sulphate and concentrated to give a crude intermediate < </ RTI> <RTI ID=0.0>################################################################### NaBH4 (100 mg, 2.64 mmol, 3 eq) was added. The mixture was warmed to room temperature over 3 min. An aqueous solution of HCl (1 N, 10 mL) was added dropwise to the reaction mixture, followed by neutralization with aqueous NaHC 3 The mixture was extracted with EtOAc (15 mL×3). EtOAc EtOAc EtOAc (EtOAc) In the case of the next step: lH NMR (400 MHz, CDC13) δ 7.43-7.47 (m, 2 Η), 7.28-7.32 (m, 1 Η), 7.21-7.25 (m, 2 Η), 4.00-4.04 (m, 1 Η), 3.79 (s, 3

Η)，3.13-3.16 (m，1 Η)，2.77-2.83 (m，1 Η)，2.42 (s，3 Η)， 1.87-1.94 (m，2 Η)，1.55-1.69 (m，4 Η)，1.42 (m，9 Η) ; MS (ESI) w/z 441.9 (Μ+Η)。Η), 3.13-3.16 (m,1 Η), 2.77-2.83 (m,1 Η), 2.42 (s,3 Η), 1.87-1.94 (m,2 Η), 1.55-1.69 (m,4 Η) , 1.42 (m, 9 Η); MS (ESI) w/z 441.9 (Μ+Η).

向 S3-2 ( 310 mg，0.7 mmo卜 1 eq)於 CH2C12 ( 15 mL) 中之溶液中添加（Boc)2〇 ( 228 mg，1_05 mmol，1.5 eq)及 DMAP. ( 8_5 mg，0·07 mmol ’ 0.1 eq)。在室溫下攪拌反應 混合物30分鐘且濃縮至乾燥。添加NaHC03飽和水溶液（20 mL )。用EtOAc ( 15 mLx3 )萃取混合物。經合併之EtOAc 96 201245116 萃取物用鹽水洗滌，經硫酸鈉脫水且濃縮。藉由矽膠急驟 層析純化殘餘物’得到呈淺黃色固體狀之化合物S3_3 ( 250 mg，60%) ： !HNMR (400 MHz, CDC13) δ 7.44-7.47 (m, 2 H)，7.27-7.33 (m，1 h)，7.23-7.26 (m，2 H)，6.85-6.83 (s，1 H)， 3.81 (s, 3 H), 3.13-3.19 (m, 2 H), 2.42 (s, 3 H), 2.07-2.13 (m, 2 H), 1.55-1.76 (m, 4 H), 1.37-1.42 (m, 18 H) ； MS (ESI) m/z 564.1 (M+Na)。Add (Boc) 2〇 (228 mg, 1_05 mmol, 1.5 eq) and DMAP. (8_5 mg, 0·07) to a solution of S3-2 (310 mg, 0.7 mmo 1 eq) in CH2C12 (15 mL) Mmmol ' 0.1 eq). The reaction mixture was stirred at room temperature for 30 minutes and concentrated to dryness. A saturated aqueous solution of NaHCO (20 mL) was added. The mixture was extracted with EtOAc (15 mL×3). The combined EtOAc 96 201245116 extract was washed with brine, dried over sodium sulfate and evaporated. Purification of the residue by flash chromatography on silica gel to afford compound <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; m,1 h),7.23-7.26 (m,2 H), 6.85-6.83 (s,1 H), 3.81 (s, 3 H), 3.13-3.19 (m, 2 H), 2.42 (s, 3 H ), 2.07-2.13 (m, 2 H), 1.55-1.76 (m, 4 H), 1.37-1.42 (m, 18 H); MS (ESI) m/z 564.1 (M+Na).

BocO Ο HO = 〇 OTBS 合成S3-4。 在-78°C下在氛圍下將n_BuLi於己烷中之溶液（〇 48 mL ’ 2·5 Μ ’ 1.2 mmo卜 3.3 eq)逐滴添加至 i_pr2NH ( 〇 17 mL’ 1·2 mmo卜3.3當量）於無水THF( 7 mL)中之溶液中。 &gt;谷液在-78 C下攪拌20分鐘且在〇°c下攪拌3〇分鐘，接著 再冷卻至-78°C。 添加 TMEDA( 0,1 mL，0.48 mmol，1.3 eq)，BocO Ο HO = 〇 OTBS Synthetic S3-4. A solution of n_BuLi in hexane (〇48 mL '2·5 Μ '1.2 mmob 3.3 eq) was added dropwise to the i_pr2NH (〇17 mL'1·2 mmob 3.3 equivalents at -78 °C in an atmosphere). ) in a solution of anhydrous THF (7 mL). &gt; The trough was stirred at -78 C for 20 minutes and at 〇c for 3 hrs, then cooled to -78 °C. Add TMEDA (0,1 mL, 0.48 mmol, 1.3 eq),

97 201245116 黃色泡沫狀之化合物S3-4 ( 〇_ 1 7 g，47% ) : MS (ESI) m/z 930.4 (M+H)。97 201245116 Yellow foamy compound S3-4 ( 〇 _ 1 7 g, 47%): MS (ESI) m/z 930.4 (M+H).

合戒S3-5 在 〇°C 下向化合物 S3-4 ( 150 mg，1.82 mmol , 1 eq) 於THF( 15 mL)中之溶液中添加HC丨水溶液（3 N，3 mL)。 在至溫下稅拌反應混合物4小時，用EtOAc稀釋，用NaHC〇3 飽和水溶液及鹽水洗滌，經硫酸鈉脫水且濃縮。在無進一 步純化的情況下將粗產物S3_5 ( 98 mg，粗物質，100%)直 接用於下一步驟。 合成化合物 S3-7-1A 及 S-3-7-1B 〇To a solution of compound S3-4 (150 mg, 1.82 mmol, 1 eq) in THF (15 mL), EtOAc (3 N, 3 mL). The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The crude product S3_5 (98 mg, crude material, 100%) was used directly in the next step without further purification. Synthetic compounds S3-7-1A and S-3-7-1B 〇

將化合物S3_5 ( 29 mg，〇.〇4 mmo卜1 eq )溶解於12_ 一氣乙烧（1 mL)中。添加甲醛水溶液（9 ，36 5%，〇 12 mmol，3 eq)。在室溫下攪拌i小時後，添加三乙醯氧基 氣化納（17 mg ’ 0.078 mmol，2 eq)。繼續授拌隔夜。 將反應混合物傾入NaHC〇3飽和水溶液中且用二氣甲烷萃 取三次。經合併之有機萃取物用鹽水洗滌，經硫酸鈉脫水 濃縮得到粗中間物认“，在無進一步純化的情況下 將其直接用於下一步驟中。 在聚丙烯小瓶中， 添加HF水溶液（48〇/〇 將S3-6-1溶解於THF ( 1 mL)中。 0.25 mL)。在室溫下攪拌μ小時 98 201245116Compound S3_5 (29 mg, 〇.〇4 mmob 1 eq) was dissolved in 12_1 hexane (1 mL). Aqueous formaldehyde solution (9, 36 5%, 〇 12 mmol, 3 eq) was added. After stirring at room temperature for 1 hour, triethylenesulfoxylate gasified sodium (17 mg '0.078 mmol, 2 eq) was added. Continue to mix and mix overnight. The reaction mixture was poured into a saturated aqueous solution of NaHC.sub.3 and extracted with dichloromethane. The combined organic extracts were washed with brine and dried w~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ 〇/〇 Dissolve S3-6-1 in THF (1 mL). 0.25 mL). Stir at room temperature for μ hours 98 201245116

4 後，將反應混合物傾入〖2肝04水溶液（1·75 g於12.5 mL 水中）且用二氯甲院萃取三次。經合併之有機萃取物用鹽 水洗滌，脫水且濃縮，得到粗中間物。After 4, the reaction mixture was poured into 2 aqueous solution of liver 04 (1·75 g in 12.5 mL of water) and extracted three times with dichloromethane. The combined organic extracts were washed with brine, dried and concentrated to give a crude intermediate.

將上述粗中間物溶解於CH3OH ( 2 mL)中。添加Pd-C (10 wt%，8 mg，3 0% w/w)及 0.5 N HC1/CH30H( 0.5 mL)。 短暫地抽空反應燒瓶且再填充氫氣。在室溫下攪拌反應混 合物且藉由LC-MS監測。反應完成後，經由小型矽藻土墊 過濾混合物。濃縮濾液，得到粗產物，藉由HPLC在Waters 自動純化系統上使用Phenomenex Polymerx 1 〇 β rp_ γThe above crude intermediate was dissolved in CH3OH (2 mL). Pd-C (10 wt%, 8 mg, 30% w/w) and 0.5 N HC1/CH30H (0.5 mL) were added. The reaction flask was briefly evacuated and refilled with hydrogen. The reaction mixture was stirred at room temperature and monitored by LC-MS. After the reaction was completed, the mixture was filtered through a small diatomaceous earth pad. The filtrate was concentrated to give a crude product using Phenomenex Polymerx 1 〇 β rp γ on a Waters automated purification system by HPLC.

100 R 管柱[30x21.20 mm，10 微米；流速：20 mL/min ;溶 劑 A : 0.05 N HC1/水；溶劑 B : CH3OH ;注入體積：4.0 mL (0.05 N HC1/水）；梯度：20— 1 〇〇% B，經 1 〇 分鐘；質量 導向型洗提份收集]將其純化》收集含有所需產物之洗提份 且冷凍乾燥。S3-7-1-A，黃色固體（鹽酸鹽）：1¾ NMR (400 MHz, CD3OD) δ 7.01 (s，1 Η)，4.42-4.51 (m，1 Η)，4.13 (s， 1 Η), 3.80 (s, 3 Η), 3.67 (br d, J = 11.6 Hz, 1 H), 3.20 (dd, J =4.4, 15.6 Hz, 1 H), 2.97-3.12 (m5 8 H), 2.69 (s, 3 H), 2- 41-2.50 (ms 1 H), 2.25-2.35 (m,'1 H), 1.90-2.20 (m, 6 H), 1.60-1.90 (m，2 H) ; MS (ESI) w/z 542.2 (M+H)。S3-7-1-B， 黃色固體（鹽酸鹽）^HNMROOOMHz’CDbOD) δ 7.08 (s, 1 Η), 4.55-4.60 (m, 1 Η), 4.13 (s, 1 Η), 3.70 (s5 3 Η), 3- 61-3.70 (m, 2 Η), 2.97-3.30 (m, 9 Η), 2.61 (s, 3 Η), 2-25-2.55 (m, 2 Η), 1.95-2.15 (m, 6 Η), 1.75-1.90 (m, 1 Η), 1-60-1.75 (m, 1 Η) ； MS (ESI) m/z 542.2 (M+H) 〇 99 201245116 合成化合物83-Ί-100 R column [30x21.20 mm, 10 μm; flow rate: 20 mL/min; solvent A: 0.05 N HC1/water; solvent B: CH3OH; injection volume: 4.0 mL (0.05 N HC1/water); gradient: 20 — 1 〇〇% B, after 1 〇 minutes; mass-oriented extract fraction collection] Purify it, collect the fractions containing the desired product and freeze-dry. S3-7-1-A, yellow solid (hydrochloride): 13⁄4 NMR (400 MHz, CD3OD) δ 7.01 (s, 1 Η), 4.42-4.51 (m, 1 Η), 4.13 (s, 1 Η) , 3.80 (s, 3 Η), 3.67 (br d, J = 11.6 Hz, 1 H), 3.20 (dd, J = 4.4, 15.6 Hz, 1 H), 2.97-3.12 (m5 8 H), 2.69 (s , 3 H), 2- 41-2.50 (ms 1 H), 2.25-2.35 (m, '1 H), 1.90-2.20 (m, 6 H), 1.60-1.90 (m, 2 H) ; MS (ESI ) w/z 542.2 (M+H). S3-7-1-B, yellow solid (hydrochloride)^HNMROOOMHz'CDbOD) δ 7.08 (s, 1 Η), 4.55-4.60 (m, 1 Η), 4.13 (s, 1 Η), 3.70 (s5 3 Η), 3- 61-3.70 (m, 2 Η), 2.97-3.30 (m, 9 Η), 2.61 (s, 3 Η), 2-25-2.55 (m, 2 Η), 1.95-2.15 ( m, 6 Η), 1.75-1.90 (m, 1 Η), 1-60-1.75 (m, 1 Η); MS (ESI) m/z 542.2 (M+H) 〇99 201245116 Synthetic compound 83-Ί-

根據S3-7-1所用之程序藉由HF處理及氫化自83_4製 備 S3-7-2 :巾 NMR (400 MHz，CD3OD) (5 6.99 (Sj l H) 4.51-4.54 (m, 1 H), 4.12 (s, 1 H), 3.75 (s, 3 H), 3.46-3.49 (m, 1 H), 2.98-3.27 (m, 10 H), 2.36-2.44 (m, 1H), 2.25-2.28 (m, 1H), 1.80-2.50 (m, 6H), 1.62-1.71 (m, 1H) ； MS (ESI) m/z 528.1 (M+H)。 根據S3-7-1-A及S3-7-1-B所用之程序自S3-5及各種 醛或酮製備以下化合物。S3-7-2 was prepared by HF treatment and hydrogenation from 83_4 according to the procedure used in S3-7-1: NMR (400 MHz, CD3OD) (5 6.99 (Sj l H) 4.51-4.54 (m, 1 H), 4.12 (s, 1 H), 3.75 (s, 3 H), 3.46-3.49 (m, 1 H), 2.98-3.27 (m, 10 H), 2.36-2.44 (m, 1H), 2.25-2.28 (m , 1H), 1.80-2.50 (m, 6H), 1.62-1.71 (m, 1H) ; MS (ESI) m/z 528.1 (M+H). According to S3-7-1-A and S3-7-1 Procedure for -B The following compounds were prepared from S3-5 and various aldehydes or ketones.

S3-7-3-A： *H NMR (400 MHz, CD3OD) δ 7.04 (s, 1 Η), 4.53-4.54 (m, 1 Η), 4.12 (s, 1 Η), 3.79 (s, 3 Η), 2.98-3.19 (m, 13 Η), 2.38-2.45 (m, 1 Η), 2.25-2.29 (m, 1 Η), 1.98-2.01 (s, 5 Η), 1.77-1.80 (m, 1Η), 1.65-1.72 (m, 1 H), 1.26 (t, J = 7.2 Hz, 3 H) ; MS (ESI) m/z 556_1 (M+H)。S3-7-3-A: *H NMR (400 MHz, CD3OD) δ 7.04 (s, 1 Η), 4.53-4.54 (m, 1 Η), 4.12 (s, 1 Η), 3.79 (s, 3 Η ), 2.98-3.19 (m, 13 Η), 2.38-2.45 (m, 1 Η), 2.25-2.29 (m, 1 Η), 1.98-2.01 (s, 5 Η), 1.77-1.80 (m, 1 Η) , 1.65-1.72 (m, 1 H), 1.26 (t, J = 7.2 Hz, 3 H); MS (ESI) m/z 556_1 (M+H).

S3-7-3-B： *H NMR (400 MHz, CD3OD) § 7.11 (s, 1 H), 4.61-4.65 (m, 1 H), 4.12 (s, 1 H), 3.69 (s, 3 H), 2.88-3.25 (m, 13 H), 2.37-2.44 (m, 1 H), 2.25-2.28 (m, 1 H), 2.00-2.11 (s, 5 100 201245116 Η), 1.80-1.83 (m, 1Η), 1.62-1.71 (m, 1 H), 1.22 (t, J =7.2 Hz, 3 H) ; MS (ESI) m/z 556.1 (M+H)。S3-7-3-B: *H NMR (400 MHz, CD3OD) § 7.11 (s, 1 H), 4.61-4.65 (m, 1 H), 4.12 (s, 1 H), 3.69 (s, 3 H ), 2.88-3.25 (m, 13 H), 2.37-2.44 (m, 1 H), 2.25-2.28 (m, 1 H), 2.00-2.11 (s, 5 100 201245116 Η), 1.80-1.83 (m, 1Η), 1.62-1.71 (m, 1 H), 1.22 (t, J = 7.2 Hz, 3 H); MS (ESI) m/z 556.1 (M+H).

S3-7-4-A S3-7-4-A： *H NMR (400 MHz, CD3OD) δ 7.05 (s, 1 H), 4.56-4.57 (m, 1 H), 4.12 (s, 1 H), 3.99-4.01 (m5 1 H), 3.78 (s, 3 H), 2.80-3.19 (m, 12 H)s 237-2.44 (m, 1 H), 2.25-2.29 (m, 1 H), 1.85-2.07 (s, 5 H), 1.80-1.82 (m, 1 H), 1.62-1.71 (m, 1 H), 1.06-1.08 (m, 1 H), 0.71-0.73 (m, 2 H), 0.30-0.31 (m, 2 H)； MS (ESI) m/z 582.2 (M+H)。S3-7-4-A S3-7-4-A: *H NMR (400 MHz, CD3OD) δ 7.05 (s, 1 H), 4.56-4.57 (m, 1 H), 4.12 (s, 1 H) , 3.99-4.01 (m5 1 H), 3.78 (s, 3 H), 2.80-3.19 (m, 12 H)s 237-2.44 (m, 1 H), 2.25-2.29 (m, 1 H), 1.85- 2.07 (s, 5 H), 1.80-1.82 (m, 1 H), 1.62-1.71 (m, 1 H), 1.06-1.08 (m, 1 H), 0.71-0.73 (m, 2 H), 0.30- MS (ESI) m/z 582.2 (M+H).

S3-7-4-B ： 'H NMR (400 MHz, CD3OD) δ 7.12 (s, 1 H), 4.64-4.68 (m, 1 H), 4.12 (s, 1 H), 3.94-3.97 (m, 1 H), 3.69 (s, 3 H), 2.37-3.24 (m, 12 H), 2.37-2.44 (m, 1 H), 2.25-2.28 (m} 1 H), 2.01-2.12 (m, 5 H), 1.81-1.84 (m, 1 H), 1.65-1.68 (m, 1 H), 1.02-1.04 (m, 1 H), 0.69-0.71 (m, 2 H), 0.28-0.29 (m, 2 H) ; MS (ESI) m/z 582.2 (M+H)。S3-7-4-B : 'H NMR (400 MHz, CD3OD) δ 7.12 (s, 1 H), 4.64-4.68 (m, 1 H), 4.12 (s, 1 H), 3.94-3.97 (m, 1 H), 3.69 (s, 3 H), 2.37-3.24 (m, 12 H), 2.37-2.44 (m, 1 H), 2.25-2.28 (m} 1 H), 2.01-2.12 (m, 5 H ), 1.81-1.84 (m, 1 H), 1.65-1.68 (m, 1 H), 1.02-1.04 (m, 1 H), 0.69-0.71 (m, 2 H), 0.28-0.29 (m, 2 H MS (ESI) m/z 582.2 (M+H).

OH O HO H O 〇 非對映異構體A S3-7-5-A i nh2 S3-7-5-A： 'H NMR (400 MHz, CD3OD) δ 7.09 (s, 1 H), 101 201245116 4.62-4.71 (m, 1 Η), 4.12 (s, 1 Η), 3.69 (s, 3 Η), 3.59-3.63 (m, 1 Η), 2.98-3.19 (m, 11 Η), 2.38-2.41 (m, 1 Η), 2.26-2.29 (m, 1 Η), 1.98-2.01 (m, 5 Η), 1.81-1.83 (m5 1 Η), 1.65-1.68 (m, 1 Η), 1.34 (d, J = 6.4 Hz, 3 H), 1.22 (d, J = 6Hz, 3 H)； MS (ESI) m/z 570.2 (M+H) »OH O HO HO 〇 diastereomer A S3-7-5-A i nh2 S3-7-5-A: 'H NMR (400 MHz, CD3OD) δ 7.09 (s, 1 H), 101 201245116 4.62 -4.71 (m, 1 Η), 4.12 (s, 1 Η), 3.69 (s, 3 Η), 3.59-3.63 (m, 1 Η), 2.98-3.19 (m, 11 Η), 2.38-2.41 (m , 1 Η), 2.26-2.29 (m, 1 Η), 1.98-2.01 (m, 5 Η), 1.81-1.83 (m5 1 Η), 1.65-1.68 (m, 1 Η), 1.34 (d, J = 6.4 Hz, 3 H), 1.22 (d, J = 6Hz, 3 H); MS (ESI) m/z 570.2 (M+H) »

OH O HO Η Ο OOH O HO Η Ο O

非對映異構體B S3-7-5-B S3-7-5-B ： *H NMR (400 MHz, CD3OD) δ 7.14 (s, 1 H), 4.76-4.78 (m, 1 H), 4.11 (s, 1 H), 3.69 (s, 3 H), 3.59-3.63 (m, 1 H), 2.99-3.25 (m, 11 H), 2.39-2.46 (m, 1 H), 2.24-2.27 (m, 1 H), 2.00-2.15 (m, 5 H), 1.83-1.88 (m, 1 H), 1.63-1.72 (m, 1 H), 1.31 (d, J = 6.8 Hz, 3 H), 1.22 (d, J = 6 Hz, 3 H) ； MS (ESI) m/z 570.1(M+H)。Diastereomer B S3-7-5-B S3-7-5-B : *H NMR (400 MHz, CD3OD) δ 7.14 (s, 1 H), 4.76-4.78 (m, 1 H), 4.11 (s, 1 H), 3.69 (s, 3 H), 3.59-3.63 (m, 1 H), 2.99-3.25 (m, 11 H), 2.39-2.46 (m, 1 H), 2.24-2.27 ( m, 1 H), 2.00-2.15 (m, 5 H), 1.83-1.88 (m, 1 H), 1.63-1.72 (m, 1 H), 1.31 (d, J = 6.8 Hz, 3 H), 1.22 (d, J = 6 Hz, 3 H); MS (ESI) m/z 570.1 (M+H).

S3-7-6-A： *H NMR (400 MHz, CD3OD) δ 7.09 (s, 1 H), 4.53-4.57 (m, 1 H), 4.13 (s, 1 H), 3.68 (s, 3 H), 2.84-3.20 (m, 13 H), 2.38-2.45 (m, 1 H), 2.27-2.30 (m, 1 H), 2.01-2.06 (m, 5 H), 1.80-1.82 (m, 2 H), 1.62-1.68 (m, 2 H), 0.84 (t, J = 7.2 Hz, 3 H) ; MS (ESI) m/z 570.2 (M+H)。 102 201245116S3-7-6-A: *H NMR (400 MHz, CD3OD) δ 7.09 (s, 1 H), 4.53-4.57 (m, 1 H), 4.13 (s, 1 H), 3.68 (s, 3 H ), 2.84-3.20 (m, 13 H), 2.38-2.45 (m, 1 H), 2.27-2.30 (m, 1 H), 2.01-2.06 (m, 5 H), 1.80-1.82 (m, 2 H ), 1.62-1.68 (m, 2 H), 0.84 (t, J = 7.2 Hz, 3 H); MS (ESI) m/z 570.2 (M+H). 102 201245116

非對映異構體B S3-7-6-B ： 'H NMR (400 MHz, CD3OD) δ 7.13 (s, 1 H), 4.63-4.66 (m, 1 H), 4.13 (s, 1 H), 3.70 (s, 3 H), 2.80-3.26 (m, 13 H), 2.38-2.45 (m, 1 H), 2.26-2.29 (m, 1 H), 2.00-2.11 (m, 5 H), 1.80-1.81 (m, 2 H), 1.56-1.69 (m, 2 H), 0.81 (t, J = 7.2 Hz，3 H) ; MS (ESI) m/z 570.2 (M+H)。Diastereomer B S3-7-6-B : 'H NMR (400 MHz, CD3OD) δ 7.13 (s, 1 H), 4.63-4.66 (m, 1 H), 4.13 (s, 1 H) , 3.70 (s, 3 H), 2.80-3.26 (m, 13 H), 2.38-2.45 (m, 1 H), 2.26-2.29 (m, 1 H), 2.00-2.11 (m, 5 H), 1.80 -1.81 (m, 2 H), 1.56-1.69 (m, 2 H), 0.81 (t, J = 7.2 Hz, 3 H); MS (ESI) m/z 570.2 (M+H).

S3-7-7 ： *H NMR (400 MHz, CD3〇D) δ 7.19 (s, 1 H), 4.55-4.65 (m, 1 H), 4.14 (s, 1 H), 3.69-3.88 (m, 5 H), 2.91-2.97 (m, 9 H), 2.82-2.88 (m, 1 H), 2.59-2.71 (m, 1 H), 2.3 7-2.44 (m，1 H)，2.26-2.29 (m，1 H)，1.99-2.09 (m，6 H)， 1.79-1.82 (m, 1 H), 1.66-1.68 (m, 1 H), 0.93-0.96 (m, 6 H)； MS (ESI) m/z 584.1(M+H)。 實施例4.合成其十環E為4-取代之嗎啉_5_基之式1化 合物。 根據以下流程4合成式I化合物，其中x為-〇CH3 ’ Y 為-H;且環E為4-取代之嗎淋-5 -基。 流程4 103 201245116 αS3-7-7 : *H NMR (400 MHz, CD3〇D) δ 7.19 (s, 1 H), 4.55-4.65 (m, 1 H), 4.14 (s, 1 H), 3.69-3.88 (m, 5 H), 2.91-2.97 (m, 9 H), 2.82-2.88 (m, 1 H), 2.59-2.71 (m, 1 H), 2.3 7-2.44 (m,1 H), 2.26-2.29 (m , 1 H), 1.99-2.09 (m, 6 H), 1.79-1.82 (m, 1 H), 1.66-1.68 (m, 1 H), 0.93-0.96 (m, 6 H); MS (ESI) m /z 584.1 (M+H). Example 4. Synthesis of a compound of the formula 1 wherein the decacyclic ring E is a 4-substituted morpholine _5- group. The compound of formula I is synthesized according to Scheme 4 below, wherein x is -〇CH3'Y is -H; and ring E is 4-substituted. Flow 4 103 201245116 α

H2/Fd-CH2/Fd-C

OBn S4-1 合成S4-1 〇 向經授拌的SI-7 ( 6.0 g，1 7.8 mmol，1 eq )於無水丙 酮（100 mL)中之溶液中添加 k2C03 ( 4.90 g，35·5 mm〇1， 2 eq )及 BnBr ( 3_7 g，21.6 mmol，1 ·2 eq)。在回流下加 熱反應混合物2小時，冷卻至室溫，且經由小型石夕藤土塾 過滤。濃縮濾液’且藉由矽膠急驟層析（石油醚/Et〇Ac， 400/1至200/1 )純化殘餘物，得到呈白色固體狀之所需產 物 S4-1 (5.5 g，72%) : iH NMR (400 MHz，CDC13)占 7.40-7.43 (m, 2 Η), 7.33-7.38 (m, 5 Η), 7.21-7.25 (m, 1 Η), 7.05-7.08 (m, 3 Η), 5.09 (S} 2 H), 3.78 (s, 3 H), 2.41 (s, 3 H) 〇 104 201245116 o och3 BocHN^^0·OBn S4-1 Synthesis of S4-1 〇 Add k2C03 ( 4.90 g, 35·5 mm〇) to a solution of the mixed SI-7 (6.0 g, 1 7.8 mmol, 1 eq) in dry acetone (100 mL). 1, 2 eq ) and BnBr (3_7 g, 21.6 mmol, 1 · 2 eq). The reaction mixture was heated under reflux for 2 hours, cooled to room temperature, and filtered thru a small stone. The filtrate was concentrated and the residue was purified EtOAc EtOAcjjjjjjjj iH NMR (400 MHz, CDC13) accounted for 7.40-7.43 (m, 2 Η), 7.33-7.38 (m, 5 Η), 7.21-7.25 (m, 1 Η), 7.05-7.08 (m, 3 Η), 5.09 (S} 2 H), 3.78 (s, 3 H), 2.41 (s, 3 H) 〇104 201245116 o och3 BocHN^^0·

OBn 合成S'4-2 在-100C 下向 S4-1 (500 mg，1.17 mmol，1 eq)於無 水THF( 5 mL)中之溶液中緩慢添加„_BuLi之己烷溶液（2.5 Μ ’ 0.52 mL ’ 1.3 0 mmol，1.1 eq )。在-100°C 下攪拌反應 混合物15分鐘。在-i〇〇〇c下添加#·Β〇(ί嗎啉-3-酮（470 mg， 2.3 4 mmol，2 eq)於無水THF ( 5 mL)中之溶液。將反應 混合物升溫至-78°C且攪拌3小時。在-78t：下添加NH4C1 飽和水溶液（50 mL )。將混合物升溫至〇°c且用EtOAc ( 50 mL)萃取。分離有機相，經Na2S04脫水且濃縮。藉由矽膠 急驟層析（石油醚/EtOAc，10/1至6/1 )純化殘餘物，得到 呈黃色油狀之所需產物S4-2 ( 368 mg，57%) : 4 NMR (400 MHz, CDC13) (5 7.41-7.44 (m, 2 Η), 7.33-7.39 (m, 5 Η), 7.23-7.28 (m, 1 Η), 7.18 (s, 1 Η), 7.07-7.10 (m, 2 Η), 5.27 (br s, 1 H), 5.16 (s, 2 H), 4.71 (s, 2 H), 3.75 (s, 3 H), 3.65 (dd, J =5.2, 5.2 Hz, 2 H), 3.38 (dd, J- 5.2, 5.2 Hz, 2 H), 2.41 (Sj 3 H)，1.46 (s，9 H)。OBn Synthesis S'4-2 Slowly add „_BuLi hexane solution (2.5 Μ '0.52 mL) to a solution of S4-1 (500 mg, 1.17 mmol, 1 eq) in anhydrous THF (5 mL) at -100C. '1.3 0 mmol, 1.1 eq. The reaction mixture was stirred at -100 ° C for 15 minutes. Add #·Β〇(ίmorpholin-3-one (470 mg, 2.3 4 mmol,) under -i〇〇〇c 2 eq) a solution in anhydrous THF (5 mL). The mixture was warmed to -78 ° C and stirred for 3 hours. A saturated aqueous solution of NH4C1 (50 mL) was added at -78t: Extracted with EtOAc (50 mL) EtOAc (EtOAcEtOAcEtOAc. Product S4-2 (368 mg, 57%): 4 NMR (400 MHz, CDC13) (5 7.41-7.44 (m, 2 Η), 7.33-7.39 (m, 5 Η), 7.23-7.28 (m, 1 Η ), 7.18 (s, 1 Η), 7.07-7.10 (m, 2 Η), 5.27 (br s, 1 H), 5.16 (s, 2 H), 4.71 (s, 2 H), 3.75 (s, 3 H), 3.65 (dd, J = 5.2, 5.2 Hz, 2 H), 3.38 (dd, J- 5.2, 5.2 Hz, 2 H), 2.41 (Sj 3 H), 1.46 (s, 9 H).

向 S4-2 ( 730 mg ’ 1.33 mmo卜 1 eq)中添加 Hci/Et〇Ac (4 N ’ 10 mL )。在室溫下攪拌反應混合物3小時且濃縮， 得到產物S4-3，在無進一步純化的情況下將其直接用於下 —步驟。 105 201245116HCI/Et〇Ac (4 N ' 10 mL ) was added to S4-2 (730 mg ' 1.33 mmo 1 eq). The reaction mixture was stirred at room temperature for 3 hr and concentrated to give product S4-3, which was used in the next step without further purification. 105 201245116

向粗物質 S4_3 ( 1.33 mmol，1 eq)於 CH3OH ( 20 mL) 中之溶液中添加Pd_C ( 1〇 wt〇/〇，2〇〇 mg)。將反應容器密 封且用氫氣（1 atm )淨化2小時。經由小型矽藻土墊過濾 反應混5物。/農細遽液’得到S4-4 ’在無進一步純化的情 況下將其直接用於下一步驟：iH nmR (400 MHz, CDC13) 5 10.44 (br s} 1 H), 10.06 (br s, 1 H), 7.53 (s, 1 H), 7.42-7.52 (m, 2 H), 7.29-7.40 (ms i H), 7.18 (d, J = 7.6 Hz, 2 H), 4.65-4.69 (m, 1 H), 4.15-4.22 (m, 1 H), 3.99-4.05 (m, 2 H), 3.77-3.83 (m，4 h)，3.51-3.54 (m, 1 H)，3.23-3.36 (m，1 H), 2.55 (s, 3 H) 〇 ’To the solution of the crude material S4_3 (1.33 mmol, 1 eq) in CH3OH (20 mL) was added Pd_C (1 〇 wt〇/〇, 2 〇〇 mg). The reaction vessel was sealed and purged with hydrogen (1 atm) for 2 hours. The reaction mixture was filtered through a small diatomaceous earth pad. /Agricultural fine mash 'Get S4-4' and use it directly in the next step without further purification: iH nmR (400 MHz, CDC13) 5 10.44 (br s} 1 H), 10.06 (br s, 1 H), 7.53 (s, 1 H), 7.42-7.52 (m, 2 H), 7.29-7.40 (ms i H), 7.18 (d, J = 7.6 Hz, 2 H), 4.65-4.69 (m, 1 H), 4.15-4.22 (m, 1 H), 3.99-4.05 (m, 2 H), 3.77-3.83 (m, 4 h), 3.51-3.54 (m, 1 H), 3.23-3.36 (m, 1 H), 2.55 (s, 3 H) 〇'

向化合物S4-4 (上述粗產物之四分之一，〇 33 mm〇i， 1 eq)於1，2-二氣乙烷（5 mL)中之溶液中添加甲醛水溶液 (0.2ml)、TEA(95^’0.37_〇1，2eq)、乙酸（6〇 此， 1_00 mmo卜3 eq)。在室溫下攪拌2小時後，添加三乙醯 氧基侧氫化鈉（142 mg，0.67 mmo丨，2 eq)。在室溫下授 拌反應:¾合物2小時。添加NaH⑶3飽和水溶液及鹽^ U:i，5〇mL)。用EtOAc(5〇mL)萃取混合物。分離有 機相，經NkSO4脫水且濃縮，得到粗產物，在無進一步純 化的情況下將其直接用於下一步驟。 ’ 106 201245116 向上述粗產物於無水CH2C12 ( l〇 mL)中之溶液中添加 一碳酸一第二丁自旨（145 mg’ 0.67 mmol’ 2 eq)及 _ 曱胺基0比咬（4 mg，〇·〇33 mmol，〇. 1 eq )。在室溫下搜摔 混合物1小時且濃縮。藉由prep_TLC純化殘餘物，得到呈 白色固體狀之所需產物S4-5-l( 92 mg，61%，經4個步鄉）To a solution of the compound S4-4 (a quarter of the above crude product, 〇33 mm〇i, 1 eq) in 1,2-diethane (5 mL) was added aqueous formaldehyde (0.2 ml), TEA (95^'0.37_〇1, 2 eq), acetic acid (6 〇, 1_00 mmo b 3 eq). After stirring at room temperature for 2 hours, sodium triethylhydroxide-side sodium hydride (142 mg, 0.67 mmo, 2 eq) was added. The reaction was allowed to proceed at room temperature: 3⁄4 compound for 2 hours. A saturated aqueous solution of NaH(3)3 and a salt of U:i, 5 〇mL) were added. The mixture was extracted with EtOAc (5 mL). The organic phase was separated, dried over NkSO4 and concentrated to give crude material which was taken directly to the next step without further purification. ' 106 201245116 To add a solution of the above crude product in anhydrous CH 2 C 12 ( l 〇 mL) to a second carbonic acid (145 mg '0.67 mmol' 2 eq) and _ amidino group 0 to bite (4 mg, 〇·〇33 mmol, 〇. 1 eq ). The mixture was searched for 1 hour at room temperature and concentrated. Purify the residue by prep_TLC to give the desired product as a white solid, S4-5-1 (92 mg, 61%, by 4 steps)

在-78°C下將《-BuLi於己烷中之溶液（2.5M，〇.4〇mL, 1.00 mmol，5 eq)逐滴添加至二異丙胺（〇.14 m]L，i 〇〇 mmol，5 eq)及 TMEDA ( 0·15 mL，1.00 mmol，5 eq)於 THF ( 2 mL)中之溶液中。在_78。〇下攪拌反應混合物％分 鐘。添力σ S4-5-1 ( 92 mg，0.20 mmol，1 eq)於 THF ( 2 mL) 中之溶液。在-7 8 °C下搜拌所得紅色溶液3 〇分鐘且使用 EtOH/液氮浴冷卻至-10(TC。添加烯酮S2-1 ( 86 mg，〇 18 mmol，0.9 eq)於THF ( 1 mL)中之溶液。反應混合物經 30分鐘逐漸升溫至-i〇°C，用NH^Cl ( 50 mL)飽和水溶液 中止，且用EtOAc ( 50 mL)萃取。分離有機相，經知28〇4 脫水且濃縮’得到S4-6-1，在無進一步純化的情況下將其 直接用於下一步驟中。 合成允合# 心及以在室溫下在聚丙缔 反應容器中向粗物質S4-6-1於THF ( 4 mL)中之溶液中逐 滴添加HF水溶液（48%，8 mL )。在室溫下劇烈授拌混合 物隔夜且傾入Κ2ΗΡ04飽和水溶液（1 50 mL )中。用£tQAe 107 201245116 (20 mLx2)萃取混合物。經合併之有機相經Na2S〇4脫水 且》農縮’得到S 4 · 7 -1，在無進一步純化的情況下將其直接 用於下一步驟中。 在室溫下將Pd-C ( 10 wt〇/〇，50 mg)整份添加至上述粗 產物於 HCl/CH3OH ( 4 N，1 mL)與 CH3〇H ( 5 mL )之現 合物中之溶液中。將反應容器密封且用氫氣（1 atm )淨化 1小時。經由小型石夕藻土塾過濾反應混合物，且漢縮遽液^。 藉由製備型逆相HPLC純化殘餘物，得到呈黃色固體狀之化 合物 S4-8-1-A 及 S4-8-l-B( 5.05 mg + 7.94 mg’ 4.6% + 7 3y (3個步驟），鹽酸鹽）。The solution of -BuLi in hexane (2.5M, 〇.4〇mL, 1.00 mmol, 5 eq) was added dropwise to diisopropylamine (〇.14 m)L, i 〇〇 at -78 °C. Methyl, 5 eq) and TMEDA (0.15 mL, 1.00 mmol, 5 eq) in THF (2 mL). At _78. The reaction mixture was stirred under stirring for % of an hour. A solution of σ S4-5-1 (92 mg, 0.20 mmol, 1 eq) in THF (2 mL). The resulting red solution was mixed at -7 8 °C for 3 且 and cooled to -10 (TC) using EtOH / liquid nitrogen bath. ketene S2-1 (86 mg, 〇 18 mmol, 0.9 eq) in THF (1 The solution was stirred in EtOAc (50 mL) EtOAc (EtOAc)EtOAc. Dehydrated and concentrated to give S4-6-1, which was used directly in the next step without further purification. 6-1 Aqueous HF (48%, 8 mL) was added dropwise in THF (4 mL). The mixture was vigorously stirred at room temperature overnight and poured into a saturated aqueous solution (1 50 mL). The mixture was extracted with tQAe 107 201245116 (20 mL×2). The combined organic phases were dried over Na 2 EtOAc EtOAc EtOAc EtOAc Pd-C (10 wt〇/〇, 50 mg) was added in portions to the above crude product in HCl/CH3OH (4 N, 1 mL) and CH3 〇H (5 mL) The reaction vessel was sealed and purged with hydrogen (1 atm) for 1 hour. The reaction mixture was filtered through a small earthworm, and the residue was purified by preparative reverse phase HPLC. Compounds S4-8-1-A and S4-8-lB (5.05 mg + 7.94 mg ' 4.6% + 7 3y (3 steps), hydrochloride) as a yellow solid.

OH O HO Η 〇 Ο 非對映異構體A S4-8-1-A S4-8-1-A： !H NMR (400 MHz, CD3〇D) δ 7.12 (s，1 4.69-4.71 (m, 1 H), 4.13-4.20 (m, 2 H), 4.00-4.06 (m, 2 H) 3.79-3.85 (m, 4 H), 3.54-3.64 (m, 2 H), 2.97-3.22 (m, 9 H) 2.79 (s, 3 H), 2.42 (dd, J = 14.8, 14.0 Hz, 1 H), 2.25-2.28 (nij 1 H)，1.61-1.71 (m，1 H) ; MS (ESI) m/z 544.1 (M + H)。OH O HO Η 〇Ο diastereomer A S4-8-1-A S4-8-1-A: !H NMR (400 MHz, CD3〇D) δ 7.12 (s,1 4.69-4.71 (m , 1 H), 4.13-4.20 (m, 2 H), 4.00-4.06 (m, 2 H) 3.79-3.85 (m, 4 H), 3.54-3.64 (m, 2 H), 2.97-3.22 (m, 9 H) 2.79 (s, 3 H), 2.42 (dd, J = 14.8, 14.0 Hz, 1 H), 2.25-2.28 (nij 1 H), 1.61-1.71 (m, 1 H) ; MS (ESI) m /z 544.1 (M + H).

S4H.B S4-8-1-B： *H NMR (400 MHz, CD3OD) δ 7.15 (s5 1 4.75-4.77 (m, 1 H), 3.94-4.20 (m, 5 H)} 3.73 (s, 3 H) 3.54-3.63 (m, 2 H), 2.98-3.27 (m, 9 H), 2.71 (s, 3 H), 2.4〇 108 201245116 (dds J= 14.4, 14.4 Hz, 1 H), 2.27-2.30 (m, 1 H), 1.60-1.70 (m, 1 H) ; MS (ESI) m/z 544.1 (M+H)。S4H.B S4-8-1-B: *H NMR (400 MHz, CD3OD) δ 7.15 (s5 1 4.75-4.77 (m, 1 H), 3.94-4.20 (m, 5 H)} 3.73 (s, 3 H) 3.54-3.63 (m, 2 H), 2.98-3.27 (m, 9 H), 2.71 (s, 3 H), 2.4〇108 201245116 (dds J= 14.4, 14.4 Hz, 1 H), 2.27-2.30 (m, 1 H), 1.60-1.70 (m, 1 H); MS (ESI) m/z 544.1 (M+H).

非對映異構體ADiastereomer A

合成化合物S4-8-2-A。 S4^2'A 根據S4-8-1-A及S4-8-1-B所用之程序自S4-4及稀酮 S2-1 製備：4 NMR (400 MHz, CD3OD) &lt;5 6.96 (s, 1 Η), 4.70-4.73 (m, 1 Η), 4.09-4.13 (m, 3 Η) » 3.82-3.87 (m, 1 Η), 3.76 (s, 3 Η), 3.66-3.72 (m, 1 Η), 3.45-3.52 (m, 2 Η), 2.95-3.19 (m, 9 Η), 2.34-2.45 (m, 1 Η), 2.18-2.25 (m, 1 Η), 1.60-1.70 (m, 1 Η) ; MS (ESI) m/z 529.9 (Μ+Η)。The compound S4-8-2-A was synthesized. S4^2'A was prepared from S4-4 and dilute ketone S2-1 according to the procedure used for S4-8-1-A and S4-8-1-B: 4 NMR (400 MHz, CD3OD) &lt;5 6.96 (s , 1 Η), 4.70-4.73 (m, 1 Η), 4.09-4.13 (m, 3 Η) » 3.82-3.87 (m, 1 Η), 3.76 (s, 3 Η), 3.66-3.72 (m, 1 Η), 3.45-3.52 (m, 2 Η), 2.95-3.19 (m, 9 Η), 2.34-2.45 (m, 1 Η), 2.18-2.25 (m, 1 Η), 1.60-1.70 (m, 1 Η) ; MS (ESI) m/z 529.9 (Μ+Η).

非對映異構體B 合成化合物 S4-8-2-B。 s4·8·2·5 根據S4-8-1-A及S4-8-1-B所用之程序自S4-4及稀嗣 S2-1 製備：'H NMR (400 MHz，CD3OD) δ 7.02 (s，1 Η)， 4.72-4.80 (m，1 Η), 4.10-4.17 (m，3 Η) ’ 3.87-3.93 (m，2 H)， 3.75, 3.78 (s，s，3 H 全部），3.35-3.50 (m，2 H)，2.96-3.19 (m， 9 H)，2.35-2.42 (m，1 H)，2.23-2.25 (m，1 H)，1.61-1.70 (m，1 H) ; MS (ESI) m/z 529.9 (M+H)。 根據與S4-8-l-A及S4-8-1-B所用類似之程序自S4_4 及各種醛製備以下化合物。The diastereomer B synthesizes the compound S4-8-2-B. S4·8·2·5 Prepared from S4-4 and dilute S2-1 according to the procedure used for S4-8-1-A and S4-8-1-B: 'H NMR (400 MHz, CD3OD) δ 7.02 (s ,1 Η), 4.72-4.80 (m,1 Η), 4.10-4.17 (m,3 Η) ' 3.87-3.93 (m,2 H), 3.75, 3.78 (s,s,3 H all), 3.35- 3.50 (m, 2 H), 2.96-3.19 (m, 9 H), 2.35-2.42 (m, 1 H), 2.23-2.25 (m, 1 H), 1.61-1.70 (m, 1 H); MS ( ESI) m/z 529.9 (M+H). The following compounds were prepared from S4_4 and various aldehydes according to procedures similar to those used for S4-8-l-A and S4-8-1-B.

109 201245116 S4-8-3 ： *H NMR (400 MHz, CD3OD) δ 7.25, 7.27 (s, s, 1 H 全部），4.75-4.78 (m, 1 H)，4.11-4.18 (m, 3 H)，3.86-4.07 (m, 2 H), 3.68-3.79 (m, 4 H), 3.45-3.49 (m, 1 H), 2.92-3.25 (m, 11 H), 2.37-2.43 (m, 1 H), 2.27-2.31 (m, 1 H), 1.80-1.84 (m，1 H)，1.64-1.71 (m，2 H)，0.84-0.90 (m，3 H) ; MS (ESI) m/z 572.1 (M + H)。109 201245116 S4-8-3 : *H NMR (400 MHz, CD3OD) δ 7.25, 7.27 (s, s, 1 H all), 4.75-4.78 (m, 1 H), 4.11-4.18 (m, 3 H) , 3.86-4.07 (m, 2 H), 3.68-3.79 (m, 4 H), 3.45-3.49 (m, 1 H), 2.92-3.25 (m, 11 H), 2.37-2.43 (m, 1 H) , (2), 2. M + H).

S4-8-4 ： !H NMR (400 MHz, CD3OD) δ 7.33 (s, 1 H), 4.75-4.77 (m, 1 H), 4.16-4.23 (m, 3 H), 4.06 (d, J= 7.2 Hz, 1 H)，3.87-3.97 (m，2 H)，3.70, 3.77 (s，s，3 H 全部），3.54-3.59 (m, 1 H), 2.90-3.24 (m, 11 H), 2.29-2.40 (m, 2 H), 1.64 (ddd, J= 12.8, 12.8, 12.8 Hz, 1 H), 1.11-1.16 (m, 1 H), 0.68-0.71 (m，2 H)，0.22-0.48 (m，2 H) ; MS (ESI) m/z 584.1 (M+H)。S4-8-4 : !H NMR (400 MHz, CD3OD) δ 7.33 (s, 1 H), 4.75-4.77 (m, 1 H), 4.16-4.23 (m, 3 H), 4.06 (d, J= 7.2 Hz, 1 H), 3.87-3.97 (m, 2 H), 3.70, 3.77 (s, s, 3 H all), 3.54-3.59 (m, 1 H), 2.90-3.24 (m, 11 H), 2.29-2.40 (m, 2 H), 1.64 (ddd, J= 12.8, 12.8, 12.8 Hz, 1 H), 1.11-1.16 (m, 1 H), 0.68-0.71 (m, 2 H), 0.22-0.48 (m, 2 H); MS (ESI) m/z 584.1 (M+H).

非對映異構體A S4-8-5-A： 'H NMR (400 MHz, CD3OD) δ 7.17 (s, 1 H), 4.74-4.75 (m, 1 H), 4.19-4.22 (m, 1 H), 4.00-4.12 (m, 3 H), 3.78-3.89 (m, 4 H), 3.72 (d, J= 12.8 Hz, 1 H), 3.40-3.48 (m, 1 H), 2.98-3.26 (m, 11 H), 2.41 (dd, /= 14.4, 14.4 Hz, 1 H), 2.25-2.29 (m, 1 H), 1.61-1.70 (m, 1 H), 1.30 (t, J= 7.2 Hz, 3 H) ; MS (ESI) m/z 558.2 (M+H)。 no 201245116Diastereomer A S4-8-5-A: 'H NMR (400 MHz, CD3OD) δ 7.17 (s, 1 H), 4.74-4.75 (m, 1 H), 4.19-4.22 (m, 1 H), 4.00-4.12 (m, 3 H), 3.78-3.89 (m, 4 H), 3.72 (d, J = 12.8 Hz, 1 H), 3.40-3.48 (m, 1 H), 2.98-3.26 ( m, 11 H), 2.41 (dd, /= 14.4, 14.4 Hz, 1 H), 2.25-2.29 (m, 1 H), 1.61-1.70 (m, 1 H), 1.30 (t, J = 7.2 Hz, 3 H) ; MS (ESI) m/z 558.2 (M+H). No 201245116

S4-8-5-B S4-8-5-B ： 'H NMR (400 MHz, CD3OD) &lt;5 7.20, 7.21 (s, s，1 H 全部），4.78-4.79 (m，1 H)，4.19-4.123 (m，1 H)， 4.11-4.14 (m, 2 H), 4.07-4.08 (m, 1 H), 3.97-4.03 (m, 1 H), 3.71，3·72 (s，s，3 H 全部），3.64-3.68 (m，1 H)，3.41-3.49 (m， 1 H), 2.99-3.27 (m, 11 H), 2.40 (dd, J = 14.4, 14.4 Hz, 1 H), 2.26-2.3 0 (m, 1 H), 1.61-1.70 (m5 1 H), 1.27 (t, J = 7.2 Hz, 3 H) ; MS (ESI) m/z 558.3 (M+H)。S4-8-5-B S4-8-5-B : 'H NMR (400 MHz, CD3OD) &lt;5 7.20, 7.21 (s, s, 1 H all), 4.78-4.79 (m, 1 H), 4.19-4.123 (m,1 H), 4.11-4.14 (m, 2 H), 4.07-4.08 (m, 1 H), 3.97-4.03 (m, 1 H), 3.71,3·72 (s,s, 3 H all), 3.64-3.68 (m, 1 H), 3.41-3.49 (m, 1 H), 2.99-3.27 (m, 11 H), 2.40 (dd, J = 14.4, 14.4 Hz, 1 H), 2.26-2.3 0 (m, 1 H), 1.61-1.70 (m5 1 H), 1.27 (t, J = 7.2 Hz, 3 H); MS (ESI) m/z 558.3 (M+H).

S4-e-6-A S4-8-6-A： *H NMR (400 MHz, CD3OD) δ 7.24 (s, 1 H), 4.80-4.82 (m, 2 H), 4.16-4.18 (m, 2 H), 4.08-4.12 (m, 3 H), 3.77 (d, /=13.2 Hz, 1 H), 3.72 (s, 3 H), 3.45-3.52 (m, 1 H), 2.97-3.28 (m, 9 H), 2.71-2.76 (m, 1 H), 2.42 (dd, J = 14.4, 14.4 Hz, 1 H), 2.25-2.28 (m, 1 H), 2.07-2.09 (m, 1 H), 1.67 (ddd, 13.2, 13.2, 13.2 Hz, 1 H), 0.94 (dd, 6.4, 2.8 Hz, 6 H) ; MS (ESI) m/z 586.1 (M+H)。S4-e-6-A S4-8-6-A: *H NMR (400 MHz, CD3OD) δ 7.24 (s, 1 H), 4.80-4.82 (m, 2 H), 4.16-4.18 (m, 2 H), 4.08-4.12 (m, 3 H), 3.77 (d, /=13.2 Hz, 1 H), 3.72 (s, 3 H), 3.45-3.52 (m, 1 H), 2.97-3.28 (m, 9 H), 2.71-2.76 (m, 1 H), 2.42 (dd, J = 14.4, 14.4 Hz, 1 H), 2.25-2.28 (m, 1 H), 2.07-2.09 (m, 1 H), 1.67 (ddd, 13.2, 13.2, 13.2 Hz, 1 H), 0.94 (dd, 6.4, 2.8 Hz, 6 H); MS (ESI) m/z 586.1 (M+H).

S4-8-6-B ： !H NMR (400 MHz, CD3OD) δ 7.23 (s, 1 H), 111 201245116 4.76-4.79 (m, 2 Η), 4.15-4.21 (m, 3 Η), 3.94-4.03 (m, 2 Η), 3.75-3.86 (m, 4 Η), 3.45-3.51 (m, 1 Η), 2.99-3.22 (m, 9 Η), 2.81-2.87 (m, 1 Η), 2.44 (dd, J = 14.8, 14.4 Hz, 1 H), 2.27-2.31 (m, 1 H), 2.15-2.19 (m, 1 H), 1.68 (ddd, /= 13.2, 13.2, 13.2 Hz, 1 H), 1.02 (d, J= 6.4 Hz, 3 H), 0.9 7 (d, J = 6.8S4-8-6-B : !H NMR (400 MHz, CD3OD) δ 7.23 (s, 1 H), 111 201245116 4.76-4.79 (m, 2 Η), 4.15-4.21 (m, 3 Η), 3.94- 4.03 (m, 2 Η), 3.75-3.86 (m, 4 Η), 3.45-3.51 (m, 1 Η), 2.99-3.22 (m, 9 Η), 2.81-2.87 (m, 1 Η), 2.44 ( Dd, J = 14.8, 14.4 Hz, 1 H), 2.27-2.31 (m, 1 H), 2.15-2.19 (m, 1 H), 1.68 (ddd, /= 13.2, 13.2, 13.2 Hz, 1 H), 1.02 (d, J= 6.4 Hz, 3 H), 0.9 7 (d, J = 6.8

Hz, 3 H) ; MS (ESI) m/z 586.1 (M+H)。 實施例5.合成其中環E為1·取代之3-羥基-吡咯啶-3-基之式I化合物。 根據以下流程5製備式I化合物，其中環e為1 -取代 之3-羥基-吡咯啶-3-基；X為-〇CH3 ;且Y為-H。 流程5Hz, 3 H) ; MS (ESI) m/z 586.1 (M+H). Example 5. Synthesis of a compound of formula I wherein ring E is a substituted 1-hydroxy-pyrrolidin-3-yl group. A compound of formula I is prepared according to Scheme 5 below, wherein ring e is 1-substituted 3-hydroxy-pyrrolidin-3-yl; X is -〇CH3; and Y is -H. Process 5

在-100°C 下在 N2 下向 Sl-8( 436 mg，l.oo mmo 卜 1 eq) 於無水THF ( 15 mL )中之溶液中添加w-BuLi之己烷溶液 (2.5 M，0.60 mL，1,5 eq)。在_l〇〇C下搜掉反應混合物 15分鐘。在-1 oo°c下在n2下逐滴添加3-側氧基_吡咯啶-1 _ 112 201245116 曱酸第二 丁醋（0.37 g，2.00 mmol’ 2 eq)於無水 THF( 5 mL ) 中之溶液。反應物經30分鐘緩慢升溫至_5t。添加NH4C1 飽和水溶液（5 mL ) »用EtOAc萃取混合物三次。經合併 之E t O A c卒取物用鹽水洗條’經硫酸納脫水且濃縮。藉由 急驟層析純化殘餘物，得到呈淺黃色固體狀之化合物 (260 mg « 48% ) ： *H NMR (400 MHz, CDC13) &lt;5 7.44.7.46 (m, 2 H), 7.27-7.31 (m, 1 H),7.20-7.22 (m, 1 H), 3.91-3.97 (m, 2 H), 3.85 (s, 3 H), 3.55-3.58 (m, 2 H), 3.15-3.19 (m, 2 H), 2.43 (s, 3 H), 1.41-1.44 (m, 18 H) ； MS (ESI) m/z 566.1 (M+Na) 0Add hexane solution of w-BuLi (2.5 M, 0.60 mL) to a solution of Sl-8 (436 mg, l.oo mmo 1 eq) in anhydrous THF (15 mL) at -100 °C. , 1,5 eq). The reaction mixture was searched for 15 minutes at _l〇〇C. Add 3-oxo-pyrrolidine-1 _ 112 201245116 decanoic acid second vinegar (0.37 g, 2.00 mmol' 2 eq) in anhydrous THF (5 mL) at -1 oo °c under n2 Solution. The reaction was slowly warmed to _5t over 30 minutes. A saturated aqueous solution of NH.sub.4Cl (5 mL) was added. The combined E t O A c strokes were washed with brine and dehydrated and concentrated. The residue was purified by flash chromatography to give crystals (yield: 260 mg): (H) NMR (400 MHz, CDC13) &lt;5 7.44.7.46 (m, 2 H), 7.27-7.31 (m, 1 H), 7.20-7.22 (m, 1 H), 3.91-3.97 (m, 2 H), 3.85 (s, 3 H), 3.55-3.58 (m, 2 H), 3.15-3.19 (m , 2 H), 2.43 (s, 3 H), 1.41-1.44 (m, 18 H) ; MS (ESI) m/z 566.1 (M+Na) 0

在78 C下在N2氛圍下將”_BuU於己烧中之溶液（^ .5 M 1’20 mmo卜 3.3 eq)逐滴添加至 ζ._ρΓ2ΝΗ ( 〇 17 社，^20·01’3.3%)於無水THF(7mL)中之溶液中。 反應溶液在_78。口攪拌20分鐘且在(TC下攪拌30分鐘， 再冷部至-78 C。添加 TMeda ( 〇 1〇 —，〇 48 eq )，接著經由套管遂法 k 滴添加 S5-1 ( 0.20 g，0.37 mmo卜 1 Μ)於無水THF ( 1虹、士 中之溶液。添加完成後，在-78t 下搜拌所得暗紅色混入 、n D物1小時且冷卻至-100°c。經由套管 、滴添加烯酮S2-l( 〇丨8 · g’ 0.37 mmol，1 eq)於 THF( 1 mL) 肀之洛液。將所得红多、θ LHMnQ , 、'色化合物緩慢升溫至-78 t。添加 LHMDS ( 0.44 mL，I n • M/THF ’ 〇·44 mmol，1.2 eq)且反 113 201245116 應物緩慢升溫至-5。(：。添加NH4C1飽和水溶液。用EtOAc 萃取混合物三次。經合併之EtOAc萃取物用鹽水洗滌，經 硫酸納脫水且濃縮。藉由急驟層析純化殘餘物，得到呈淺 黃色泡沫狀之化合物S5-2 ( 0.1 9 g，55% )，在無進一步純 化的情況下將其用於下一步驟。 合成化合物S5-4-1-A及S5-4-1-B。 向 S5-2 ( 0.13 g，〇·ΐ4 mm〇l，1 eq)於 THF ( 5 mL) 中之溶液中添加HC1水溶液（3 6.5%，0.25 mL)。在室溫 下撥拌16小時後，用EtOAc萃取反應混合物三次。經合併 之EtOAc萃取物用1^说(：〇3飽和水溶液及鹽水洗滌，經硫 酸納脫水且濃縮，得到呈淺黃色固體狀之粗產物，在無純 化的情況下將其直接用於下一步驟。 將上述粗中間物溶解於丨，2_二氣乙烷（3 mL)中。添 加甲搭水溶液（50 μι，過量）及乙酸（25此，〇 42 mm〇1， 3 eq )。在室溫下攪拌i小時後，添加三乙醯氧基硼氫化鈉 (59 mg ’ 0.28 mmo卜2 eq)。繼續攪拌隔夜。將反應混合 物傾入NaHCCh飽和水溶液中且用Et〇Ac萃取三次。經合 併之有機萃取物用鹽水洗滌，經硫酸鈉脫水且濃縮，得到 化合物S5-3-1，在無進一步純化的情況下將其直接用於下 一步驟中。 將S5-3-1溶解於聚丙烯小瓶中之ΤΗρ (2 mL)中。 加HF水溶液（48%，5社）。在室溫下擾拌16小時後 將反應混合物傾入K2Hp〇4水溶液（10g，於250 mL水中） 且用EtOAc萃取三次。經合併之有機相用鹽水洗滌，脫水 114 201245116 且濃縮，得到粗中間物。 將上述粗中間物溶解於CH3OH/l，4-二噁烷（4 mL，1:1 v/v)中。添加 pd_c ( 1〇 wt%，20 mg ’ 30% w/w)及 〇·5 N HCl/CEbOHC 〇·5 mL)。短暫地抽空反應燒瓶且再填充氫氣。 在室溫下攪拌反應混合物且藉由LC-MS監測。反應完成 後，經由小型矽藻土墊過濾懸浮液。濃縮濾液，得到粗產 物’藉由HPLC在Waters自動純化系統上使用Phen〇menex Polymerx 1〇 β RP- γ 1 〇〇 R 管柱[3〇χ21.20 mm，10 微 米；流速：20 mL/min ;溶劑 A : 0.05 N HCl/水；溶劑 Β : CH3OH ;注入體積：4·〇 mL ( 0.05 N HC1/水）；梯度：20 —100°/。β ’經1 〇分鐘；質量導向型洗提份收集]將其純化。 收集含有所需產物之洗提份且冷凍乾燥，得到呈黃色固體 狀之所需產物S5-4-1-Α及S5-4-1-Β (鹽酸鹽）。Add the solution of _BuU in hexane (^.5 M 1'20 mmob 3.3 eq) to ζ._ρΓ2ΝΗ at 78 C under N2 atmosphere ( 〇17 社, ^20·01'3.3%) In a solution of anhydrous THF (7 mL). The reaction solution was stirred at _78 for 20 minutes and stirred at (TC for 30 minutes, then cooled to -78 C. Add TMeda (〇1〇-, 〇48 eq) Then, S5-1 (0.20 g, 0.37 mmob 1 Μ) was added dropwise to the anhydrous THF (1 rainbow, Shishi solution) via a cannula method. After the addition was completed, the dark red mixture was mixed at -78t. n D for 1 hour and cooled to -100 ° C. Add ketene S2-l ( 〇丨8 · g' 0.37 mmol, 1 eq) in THF (1 mL) via a cannula. Red, θ LHMnQ , and 'color compounds slowly warmed to -78 t. Add LHMDS (0.44 mL, I n • M/THF '〇·44 mmol, 1.2 eq) and counter 113 201245116 The temperature was slowly raised to -5. (3. A saturated aqueous solution of EtOAc was added. The compound S5-2 (0.19 g, 55%) was obtained in the next step without further purification. Compounds S5-4-1-A and S5-4-1-B were synthesized. An aqueous solution of HCl (3.5%, 0.25 mL) was added to a solution of EtOAc (5 mL). The reaction mixture was extracted with EtOAc EtOAc EtOAc EtOAc. It was used directly in the next step. The above crude intermediate was dissolved in hydrazine, 2 - di-hexane (3 mL), aqueous solution of acetonitrile (50 μιη, excess) and acetic acid (25 〇 42 mm 〇 1) , 3 eq ). After stirring for 1 hour at room temperature, sodium triethoxysulfonate hydride (59 mg '0.28 mmo 2 eq) was added. Stirring was continued overnight. The reaction mixture was poured into a saturated aqueous solution of NaHCCh and Et. 〇Ac was extracted three times. The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated to give compound S5-3-1. Purification of the case which was used directly in the next step. S5-3-1 was dissolved in 聚丙烯ρ (2 mL) in a polypropylene vial. Add HF aqueous solution (48%, 5 companies). After stirring for 16 hours at room temperature, the reaction mixture was poured into aq. K2H. The combined organic phases were washed with brine, dried (EtOAc EtOAc) The above crude intermediate was dissolved in CH3OH /1,4-dioxane (4 mL, 1:1 v/v). Add pd_c (1〇 wt%, 20 mg ' 30% w/w) and 〇·5 N HCl/CEbOHC 〇·5 mL). The reaction flask was briefly evacuated and refilled with hydrogen. The reaction mixture was stirred at room temperature and monitored by LC-MS. After the reaction was completed, the suspension was filtered through a small diatomaceous earth pad. The filtrate was concentrated to give a crude product. &lt;&quot;&quot;&quot;&quot;&quot;&quot;&quot;&quot&&&&&&&&&&&&&&&&&&&&& Solvent A: 0.05 N HCl/water; solvent Β: CH3OH; injection volume: 4·〇mL (0.05 N HC1/water); gradient: 20-100°/. β ′ is purified by a 1 minute minute; mass-oriented extract fraction collection]. The extract containing the desired product was collected and lyophilized to give the desired product S5-4-1-indole and S5-4-1-indole (hydrochloride) as a yellow solid.

S5-4-1-A S5-4-1-A： ]H NMR (400 MHz, CD3〇D) δ 6.94,6.97 (s, s，全部 1 Η)，4.13 (s，1 Η)，3.88-3.95 (m，2 Η)，3_77 (s，3 Η), 2-73-3.11 (m, Μ Η), 2.73-2.78 (m, ! Η), 2.53-2.55 (m, 1 Η), 2.43-2.46 (m, ι H)j 2.24-2.27 (m,l H), 1.63-1.72 (m5 1 H)； MS (ESI) m/z 544.1 (m + H)。S5-4-1-A S5-4-1-A: ]H NMR (400 MHz, CD3〇D) δ 6.94, 6.97 (s, s, all 1 Η), 4.13 (s, 1 Η), 3.88- 3.95 (m, 2 Η), 3_77 (s, 3 Η), 2-73-3.11 (m, Μ Η), 2.73-2.78 (m, ! Η), 2.53-2.55 (m, 1 Η), 2.43- 2.46 (m, ι H)j 2.24-2.27 (m, l H), 1.63-1.72 (m5 1 H); MS (ESI) m/z 544.1 (m + H).

S5-4-1-B 115 201245116 S5-4-1-B： !H NMR (400 MHz, CD3OD) δ 6.96,6.99 (s5 s，全部 1 H)，4.13 (s，1 h)，3.89-3.96 (m，2 H)，3.80 (s，3 H)， 2.99-3.12 (m，14 H)，2.60-2.68 (m，2 H)，2.36-2.43 (m，1 H), 2.26-2.28 (m, 1 H), 1.63-1.72 (m, 1 H) ； MS (ESI) m/z 544.1 (M + H)。 實施例6.合成其中環e為視情況經取代之芳基的式i 化合物。 根據以下流程6製備式I化合物，其中環e為視情況經 取代之芳基；X為-〇ch3 ;且Y為_Ηβ 流程6S5-4-1-B 115 201245116 S5-4-1-B: !H NMR (400 MHz, CD3OD) δ 6.96, 6.99 (s5 s, all 1 H), 4.13 (s, 1 h), 3.89-3.96 (m, 2 H), 3.80 (s, 3 H), 2.99-3.12 (m, 14 H), 2.60-2.68 (m, 2 H), 2.36-2.43 (m, 1 H), 2.26-2.28 (m , 1 H), 1.63-1.72 (m, 1 H); MS (ESI) m/z 544.1 (M + H). Example 6. Synthesis of a compound of formula i wherein ring e is an optionally substituted aryl group. A compound of formula I is prepared according to Scheme 6 below, wherein ring e is an optionally substituted aryl group; X is -〇ch3; and Y is _Ηβ.

C02Ph S4-1 9CH3 (Het)ArB(OH)2 CH3 Pd催化劑(Het&gt;Ar， och3C02Ph S4-1 9CH3 (Het) ArB(OH)2 CH3 Pd catalyst (Het&gt;Ar, och3

COjPh H^Pd-C ^Het)ArCOjPh H^Pd-C ^Het)Ar

Bo〇2〇 DMAP (Het)Ar 〇CH3 亡CH3 SspsC02Ph OBoc S6-3Bo〇2〇 DMAP (Het)Ar 〇CH3 死CH3 SspsC02Ph OBoc S6-3

a) LDA/TMEDA b) 烯輞S2·1a) LDA/TMEDA b) olefins S2·1

合成 S6-1-1。 在至/皿下在Ν2氛圍下向S41 ( 1〇〇 mg，〇 23 ，1 〇q)於甲苯（5 mL)中之溶液中依序添加57 mg， 〇'47 mm〇1 * 2 6q) ' Pd(PPh3)4 ( 8 mg，0.007 mmol - 0.03 eq) 及K2c〇3(65mg’ 0.47職〇卜_)。在攪拌下在航下 加熱反應混合物隔夜’冷卻至室溫且過渡。濃縮渡液，得 116 201245116 到粗產物’藉由製備型TLC (石油醚：EtOAc，1 〇: 1 )純化， 知到所品化合物 S6-1] ( 9〇 mg，91〇/〇 ) : ιΉ NMR (4〇〇 MHz， CDC13) (5 7.59-7.61 (mj 2 Η), 7.37-7.49 (m, 10 Η), 7.22 7.28 (m，1 Η)，7.15-7.18 (m，1 Η)，6·91 (s，i η)，5.16 (s， 2 H)，3.37 (s，3 H)，三.49 (s，3 H)。Synthesis of S6-1-1. Add 57 mg, 〇'47 mm〇1 * 2 6q) to the solution of S41 (1〇〇mg, 〇23,1 〇q) in toluene (5 mL) under Ν2 atmosphere under ～2. 'Pd(PPh3)4 (8 mg, 0.007 mmol - 0.03 eq) and K2c〇3 (65 mg' 0.47). The reaction mixture was heated under agitation under agitation overnight and cooled to room temperature and transitioned. Concentrate the liquid, and obtain 116 201245116 to the crude product 'purified by preparative TLC (petroleum ether: EtOAc, 1 〇: 1), and know the compound S6-1] (9〇mg, 91〇/〇) : ιΉ NMR (4〇〇MHz, CDC13) (5 7.59-7.61 (mj 2 Η), 7.37-7.49 (m, 10 Η), 7.22 7.28 (m,1 Η), 7.15-7.18 (m,1 Η),6 · 91 (s, i η), 5.16 (s, 2 H), 3.37 (s, 3 H), 3.49 (s, 3 H).

办 9ch3 ^ch3 ,lC02Ph 合成 S6-3-J 0 在室溫下將Pd-c ( I00mg，30%)添加至S6-11 (28〇 mg，0.66 mmol)於甲醇（2〇社）中之溶液中。用氫氣淨 化反應混合物，在H2 (氣球）下攪拌1小時，經由小型矽 藻土塞過濾。濃縮濾》，得到所需產4勿S6H，在無進_ 步純化的情況下將其用於下一步驟。 、 向 S6-2_l 之 CH2Cl2(20ml)溶液中添加 B〇c2〇(〇 i5 g，0.69 mmo卜1.05 eq)及DMAp (催化量）。在室溫下攪 拌反應溶液1.5小時且丨農縮。藉由製備型ΤΙχ純化殘餘, 5H)，7m8(m，1H)，7.25_7.27(m 3H) 33i(s ’ Ο Αλ ^ HV 1 1 Λ Ο9ch3 ^ch3 , lC02Ph Synthesis of S6-3-J 0 Pd-c ( I00mg, 30%) was added to a solution of S6-11 (28〇mg, 0.66 mmol) in methanol (2〇社) at room temperature. in. The reaction mixture was purified with H.sub.2 (EtOAc). Concentration Filtration gave the desired product 4 S6H, which was used in the next step without further purification. To the solution of S6-2_1 CH2Cl2 (20 ml), B〇c2〇 (〇 i5 g, 0.69 mmo Bu 1.05 eq) and DMAp (catalytic amount) were added. The reaction solution was stirred at room temperature for 1.5 hours and quenched. Purification residue by preparative hydrazine, 5H), 7m8 (m, 1H), 7.25_7.27 (m 3H) 33i (s ’ Ο Α λ ^ HV 1 1 Λ Ο

得到呈固體狀之S6-3-1( 220 mg，77%，兩個步驟）：〗H職 (400 MHz，DMS〇-d6) 5 7.52_7.58 (m，2 H)，7 41 7 52 &amp; 在-78°C下向-78°C下之二異丙胺Γ ^ ^ C 0.10 ml » 0.75 mmol , q )之THF ( 2 ml )溶液中逐滴禾士 Ώ T w 同添加( 2.5 Μ , 〇·30 117 201245116 ml ' 0.75 mmol &gt; 5 eq)。反應溶液升溫至-2(TC，搜拌〇 5 小時’且再冷卻至_78°C。添加TMEDA ( 〇·23 mL，ι,50 mmol ’ 10 eq)。在^^匚下攪拌反應混合物Η分鐘。經由 套管逐滴添加 S6-3-l(66mg，0.15 mmol，1 eq)於 thf ( 1 ml)中之溶液。下&amp;拌所得深紅色溶液〇 5小時且 冷卻至- l〇0°C。在- l〇〇°C下經由套管添加稀酮S2-1 ( 108 mg，〇_15 _〇卜1 5 eq)於THF ( 1 ml)中之溶液。使反 應混合物經丨小時升溫至室溫且分配於氯化銨飽和水溶液 (50 ml)與EtOAc ( 10 ml)之間。分離各相且用Et〇Ac 進一步萃取水相3次。將有機萃取物合併，經無水Na2S〇4 脫水且濃縮《藉由製備型TLC純化殘餘物，得到〖1〇 mg呈 黃色固體狀之粗物質S6_4-；L，在無進一步純化的情況下將 其直接用於下一步驟中。Obtained as a solid S6-3-1 (220 mg, 77%, two steps): H (400 MHz, DMS 〇-d6) 5 7.52_7.58 (m, 2 H), 7 41 7 52 &amp; Add - dropwise to the THF (2 ml) solution of diisopropylamine Γ ^ ^ C 0.10 ml » 0.75 mmol , q ) at -78 ° C (2.5 Μ) , 〇·30 117 201245116 ml '0.75 mmol &gt; 5 eq). The reaction solution was warmed to -2 (TC, 〇5 ') and cooled to _78 ° C. TMEDA ( 〇 · 23 mL, ι, 50 mmol ' 10 eq) was added. The reaction mixture was stirred under 匚The solution of S6-3-l (66 mg, 0.15 mmol, 1 eq) in thf (1 ml) was added dropwise via a cannula. The resulting dark red solution was mixed and dried for 5 hours and cooled to - l〇0. °C. Add a solution of the dilute ketone S2-1 (108 mg, 〇_15 _ 1 1 5 eq) in THF (1 ml) via a cannula at -1 ° C. The mixture was warmed to rt and partitioned between EtOAc EtOAc (EtOAc)EtOAc. 4 Dehydration and concentration <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt;

在室溫下將淡HF水溶液（48%，3 ml)添加至聚丙稀 反應容器中粗物質S6-4-1於THF ( 3 ml)中之溶液中。在 室溫下劇烈攪拌反應混合物隔夜且傾入磷酸氫二鉀飽和水 溶液中。用EtOAc ( 30 mLx3 )萃取混合物。經合併之有機 萃取物經無水NaaSO4脫水’過濾且濃縮，得到呈黃色固體 狀之粗中間物，在無進一步純化的情況下將其直接用於下 一步驟中》 將CHWH ( 10 mL )添加至上述中間物中。整份添加A light HF aqueous solution (48%, 3 ml) was added to a solution of the crude material S6-4-1 in THF (3 ml) in a polypropylene solvent. The reaction mixture was vigorously stirred at room temperature overnight and poured into a saturated aqueous solution of dibasic hydrogen phosphate. The mixture was extracted with EtOAc (30 mL×3). The combined organic extracts were <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0> The above intermediates. Whole addition

Pd-C ( 10 wt%，30 mg)及 1 N HC1/CH30H ( 1 ml)。在室 118 201245116 溫下在Η2 (氣球）下攪拌反應混合物丨小時且經由小型石夕 藻土墊過濾。濃縮濾液且藉由HPLC純化，得到呈黃色固體 狀之所需產物S6-5-1 ( 19 mg，鹽酸鹽，8%，三個步驟）. *H NMR (400 MHz, CD3OD) δ 7.61-7.63 (mj 2 Η) 7·44·7·50 (m，3 Η)，6.83 (s，1 Η)，4.16 (s，1 Η)，3.30 (s，3 Η) 3.01-3.12 (m, 9 Η), 2.28-2.38 (m，2 Η), 1.68-1.70 (m，ι η). MS (ESI) m/z 521·〇 (μ+Η)。 實施例7.合成其中環£為^取代之咪唑_2•基之式j化 合物。 根據以下流程7製備式丨化合物，其中環E為丨_取代 之p米嗤-2-基；X為-F;且丫為_^。 流程7 119 201245116Pd-C (10 wt%, 30 mg) and 1 N HC1/CH30H (1 ml). The reaction mixture was stirred under Η 2 (balloon) at room temperature for 12 hours at room temperature and filtered through a small stone bed. The filtrate was concentrated and purified by EtOAc EtOAc (EtOAc) 7.63 (mj 2 Η) 7·44·7·50 (m,3 Η), 6.83 (s,1 Η), 4.16 (s,1 Η), 3.30 (s,3 Η) 3.01-3.12 (m, 9 Η), 2.28-2.38 (m, 2 Η), 1.68-1.70 (m, ι η). MS (ESI) m/z 521·〇 (μ+Η). Example 7. Synthesis of a compound of formula j wherein the ring is a substituted imidazole _2. A hydrazone compound is prepared according to the following Scheme 7, wherein ring E is 丨_substituted pm嗤-2-yl; X is -F; and 丫 is _^. Process 7 119 201245116

co2h a) sBuLi^MEDA b) CH3lCo2h a) sBuLi^MEDA b) CH3l

C02H H3C〇' a) (COCI)2 b) PhOH rHo〇 p CH3OH CHs? f TsOH |Λ^〇Η3 CH(OCH3)3OHC Br'^y^COaPh Br OBn S7-8C02H H3C〇' a) (COCI)2 b) PhOH rHo〇 p CH3OH CHs? f TsOH |Λ^〇Η3 CH(OCH3)3OHC Br'^y^COaPh Br OBn S7-8

OHCOHC

1) iPrMgCI-LiCI 2) HCl水溶液 CO,Ph OBn S7-9 a)乙二胺 i2/k2co3 CH3 b) Phl(OAc)21) iPrMgCI-LiCI 2) HCl aqueous solution CO, Ph OBn S7-9 a) ethylenediamine i2/k2co3 CH3 b) Phl(OAc)2

a) NaH b) R7-la) NaH b) R7-l

a) LDA/TMEDA b) 烯酮S2-1 LHMDS H3C CH3 &quot;Loha) LDA/TMEDA b) ketene S2-1 LHMDS H3C CH3 &quot;Loh

OH 〇 HO H 〇 〇 S7-13OH 〇 HO H 〇 〇 S7-13

1&gt;HF水溶液 b) H2/Pd-C1&gt;HF aqueous solution b) H2/Pd-C

0Γ0Γ

y^co2H och3 合成 -2 〇 S7_2 向在-78°C下冷卻之5-氟-2-曱氧基苯曱酸（S7-1，0.50 g，2.94 mmol，1 eq)之 THF(6 mL)溶液中添加 s-BuLi 溶液（4.60 mL’ 1_40 M/環己烧，6.44 mmol，2.2 eq)及 TMEDA (0.97 mL，6_47 mmol，2.2 eq)。在-7 8°C 下攪拌反應物 2 小時。向反應混合物中逐滴添加蛾曱烧（1.1 0 mL，1 7.64 mmol，6 eq)。使反應物經1小時升溫至25 °C且在25 °C下 攪拌1小時。添加NaOH水溶液（6 N，20 mL)。用第三 丁基曱醚（20 mLx2 )萃取混合物。用鹽酸（6 N)酸化水 120 201245116 •層至pH 1且用EtOAc ( 20 mLx4 )萃取。經合併之EtOAc 萃取物經硫酸鈉脫水且濃縮，得到0.5 i g粗物質S7_2 : ιΗ NMR (400 MHz, CDC13) δ 7.06 (dd, J = 9.8, 8.5 Hz, 1 H), 6.7 5 (dd, 7= 9.8, 3.7 Hz, 1 H), 3.8 6 (s, 3 H), 2.34 (d, /= 2.4 Hz, 3 H) ; MS (ESI) m/2 185.12 (M + H)。 0cCH3 y^cOzPh , och3 合成 SI-l。 S7&gt;3 將乙一酿氯（0.95 mL，11·10 mmol，5.5 eq)添加至 S7_2 ( 0.5 1 g ’ 2.00 mmo卜 1 eq )之二氯甲烷溶液（15 mL， 無水）中。添加DMF ( 〇_l mL)。在25°C下攪拌反應溶液 1小時且濃縮。將所得固體再次溶解於1 5 mL無水二氯甲烷 中。添加苯驗（〇.52g，5_50mmol，2.8eq) ' DMAP ( 0.67 g，5.60 mmol，2.8 eq)及三乙胺（1.90 mL，13.90 mmol， 7 eq)。在25°C下攪拌犮應混合物12小時且濃縮。將EtOAc 及HzO添加至殘餘物中。有機層用NaOH水溶液（i N )、 HA及鹽水洗滌，經硫酸鈉脫水且濃縮。矽膠急驟層析（4〇:i 己烷/EtOAc)，得到〇_4〇 g化合物S7-3( 52%，2個步驟）： 'H NMR (400 MHz, CDC13) &lt;5 7.41-7.47 (m, 2 Η) 7.24-7.31 (m，3 Η)，7.08 (dd，《/= 9.2, 9.2 Ηζ，1 Η)，6.77 (dd， / = 9.2, 3_7 Ηζ，1 Η)，3·88 (s，3 Η)，2_36 (d，J = 2.3 Ηζ，3 Η) ; MS (ESI) w/z 261.12 (Μ+Η)。 έτ y^co2Ph 合成 。'Μ 在-78°C 下將 BBr3 ( 1.85 mL，1 Μ/二氯甲烧，j 85 121 201245116 mmo卜 1.2 eq)添加至 S7-3 ( 0.40 g，1.54 mmol，i eq)之 二氯曱烷溶液（8 mL )中。將反應物自-78°C攪拌至25&lt;&gt;c持 續1.5小時，藉由NaHCCh飽和水溶液中止且濃縮。將Et〇Ac 及HaO添加至反應混合物中。用EtOAc萃取水層。經合併 之EtOAc萃取物經硫酸鈉脫水且減壓濃縮，得到〇 36 g粗 物質 S7-4 : *H NMR (400 MHz, CDC13) δ 10.66 (s, 1 Η) 7.44-7.50 (m, 2 Η), 7.31-7.36 (m,l Η), 7.18-7.26 (m, 3 Η) 6.86 (dd, J = 9.3, 4.9 Hz, 1 H), 2.60 (d, J = 2.4 Hz, 3 H)； MS (ESI) m/z 245.1 1 (M-H)。y^co2H och3 Synthesis-2 〇S7_2 To 5-fluoro-2-nonyloxybenzoic acid (S7-1, 0.50 g, 2.94 mmol, 1 eq) in THF (6 mL) cooled at -78 °C s-BuLi solution (4.60 mL '1_40 M/cyclohexane, 6.44 mmol, 2.2 eq) and TMEDA (0.97 mL, 6-47 mmol, 2.2 eq) were added to the solution. The reaction was stirred at -7 8 °C for 2 hours. Moth sputum (1.10 mL, 1. 7.64 mmol, 6 eq) was added dropwise to the reaction mixture. The reaction was allowed to warm to 25 ° C over 1 hour and stirred at 25 ° C for 1 hour. Aqueous NaOH (6 N, 20 mL) was added. The mixture was extracted with tert-butyl oxime ether (20 mL x 2 ). Acidification of water with hydrochloric acid (6 N) 120 201245116 • layer to pH 1 and extracted with EtOAc (20 mL×4). The combined EtOAc extracts were dried over sodium sulfate and evaporated tolulujjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj = 9.8, 3.7 Hz, 1 H), 3.8 6 (s, 3 H), 2.34 (d, /= 2.4 Hz, 3 H) ; MS (ESI) m/2 185.12 (M + H). 0cCH3 y^cOzPh , och3 Synthesis SI-l. S7&gt;3 B-brewed chlorine (0.95 mL, 11·10 mmol, 5.5 eq) was added to a solution of S.sub.2 (0.51 g, 2.00 mmo, 1 eq) in dichloromethane (15 mL, anhydrous). Add DMF (〇_l mL). The reaction solution was stirred at 25 ° C for 1 hour and concentrated. The resulting solid was redissolved in 15 mL of dry dichloromethane. Add benzene (〇.52g, 5_50mmol, 2.8eq) 'DMAP (0.67 g, 5.60 mmol, 2.8 eq) and triethylamine (1.90 mL, 13.90 mmol, 7 eq). The hydrazine mixture was stirred at 25 ° C for 12 hours and concentrated. EtOAc and HzO were added to the residue. The organic layer was washed with aqueous NaOH (1N), EtOAc and brine. Flash chromatography (4 〇: i hexanes / EtOAc) afforded 〇 4 〇g Compound S7-3 (52%, 2 steps): 'H NMR (400 MHz, CDC13) &lt;5 7.41-7.47 ( m, 2 Η) 7.24-7.31 (m, 3 Η), 7.08 (dd, "/= 9.2, 9.2 Ηζ, 1 Η), 6.77 (dd, / = 9.2, 3_7 Ηζ, 1 Η), 3·88 ( s, 3 Η), 2_36 (d, J = 2.3 Ηζ, 3 Η); MS (ESI) w/z 261.12 (Μ+Η). Έτ y^co2Ph Synthesis. 'Μ Add BBr3 ( 1.85 mL, 1 Μ / dichloromethane, j 85 121 201245116 mmo 1.2 eq) to S7-3 (0.40 g, 1.54 mmol, i eq) of dichloropurine at -78 °C. In an alkane solution (8 mL). The reaction was stirred from -78 °C to 25 &lt;&gt;&gt;c for 1.5 h, quenched with NaHC. Et〇Ac and HaO were added to the reaction mixture. The aqueous layer was extracted with EtOAc. The combined EtOAc extracts were dried over sodium sulfate and evaporatedEtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ), 7.31-7.36 (m,l Η), 7.18-7.26 (m, 3 Η) 6.86 (dd, J = 9.3, 4.9 Hz, 1 H), 2.60 (d, J = 2.4 Hz, 3 H); MS (ESI) m/z 245.1 1 (MH).

Ach3Ach3

Br^y^COgPhBr^y^COgPh

OH 合成 SI-5。 S7·5 將化合物 S7-4 (4.92 g&gt; 20.00 mmol’ 1 eq)溶解於乙 酸（50 mL)中。在室溫下經由針筒添加溴（1·54 mL，30.00 mmol，1.5 eq)。在室溫下攪拌2小時後，反應混合物用 EtO Ac ( 100 mL )稀釋，用水（3x100 mL)及鹽水洗滌，經 硫酸鈉脫水且減壓濃縮，得到7.06 g呈淺黃色固體狀之化 合物 S7-5 : 4 NMR (400 MHz, CDC13) δ 11.14 (s, 1 Η), 7.52 (d, J= 9.2 Hz, 1 H), 7.43-7.49 (m, 2 H), 7.30-7.36 (m, 1 H)，7.16-7.21 (m，2 H)，2.55 (d，·/= 2.3 Hz，3 H)。 j6cCH3OH synthesis SI-5. S7·5 Compound S7-4 (4.92 g&gt; 20.00 mmol' 1 eq) was dissolved in acetic acid (50 mL). Bromine (1·54 mL, 30.00 mmol, 1.5 eq) was added via a syringe at room temperature. After stirring at room temperature for 2 hours, the mixture was diluted with EtOAc EtOAc (EtOAc) 5 : 4 NMR (400 MHz, CDC13) δ 11.14 (s, 1 Η), 7.52 (d, J = 9.2 Hz, 1 H), 7.43-7.49 (m, 2 H), 7.30-7.36 (m, 1 H ), 7.16-7.21 (m, 2 H), 2.55 (d, ·/= 2.3 Hz, 3 H). j6cCH3

Br 入f^C02Ph OBn 合成。 咖 將化合物 S7-5 (粗物質，1.06 g ’ 2.97 mmol，1 eq)溶 解於丙酮（20 mL)中，添加碳酸鉀（0.82 g，5.94 mmol， 2 eq )，且於冰浴中冷卻至0〇C。逐滴添加溴甲苯（0.54 mL ’ 122 201245116 ‘ 4.45 mmol，1.5 eq)。反應混合物在室溫下攪拌2小時且在 5〇°C下攪拌1小時。反應混合物以EtOAc ( 1〇〇 mL )稀釋， 以水及鹽水洗滌，經硫酸鈉脫水且減壓濃縮，得到22 g粗 物質S7-6,藉由管柱層析（Biotage 10 g管柱，2%至5% EtOAc 之己烧溶液梯度）純化，得到1. 〇 3 g ( 8 4 %，兩個步驟）呈 無色油狀之化合物 S7-6 : 4 NMR (400 MHz，CDC13) (5 7.47-7.50 (m, 2 Η), 7.33-7.40 (m, 6 Η), 7.25 (t, J= 7.3 Hz, 1 H), 7.04 (d, J = 8.6 Hz, 2 H), 5.09 (s, 2 H), 2.32 (d, J= 1.8 Hz，3 H)。 0HCyVCH3 ·Br is incorporated into f^C02Ph OBn synthesis. The compound S7-5 (crude, 1.06 g, 2.97 mmol, 1 eq) was dissolved in EtOAc (EtOAc) (EtOAc) 〇C. Bromo-toluene (0.54 mL '122 201245116 ' 4.45 mmol, 1.5 eq) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and at 5 ° C for 1 hour. The reaction mixture was diluted with EtOAc (1 mL)EtOAc.EtOAc. Purification of 5% to 5% EtOAc in EtOAc (EtOAc: EtOAc: EtOAc (EtOAc) 7.50 (m, 2 Η), 7.33-7.40 (m, 6 Η), 7.25 (t, J= 7.3 Hz, 1 H), 7.04 (d, J = 8.6 Hz, 2 H), 5.09 (s, 2 H ), 2.32 (d, J= 1.8 Hz, 3 H). 0HCyVCH3 ·

Br^Y^cOzPh Λ · OBn 合成 SH。 S7-7 藉由在- 78°C 下將《-BuLi (1.6M/己烷，5.10mL，8.16 mmol’ 1.5eq)添加至於THF(15 mL )中之二異丙胺（1.15 mL，8.16 mmol ’ 1.5 eq)中來製備 LDA/THF 溶液。在-20Br^Y^cOzPh Λ · OBn Synthetic SH. S7-7 was added to diisopropylamine (1.15 mL, 8.16 mmol' in THF (15 mL) by -BuLi (1.6 M/hexane, 5.10 mL, 8.16 mmol, 1.5 eq) at -78 °C. The LDA/THF solution was prepared in 1.5 eq). At -20

°C下授拌反應溶液1 5分鐘且冷卻至_78 。逐滴添加於THF (5 mL)中之化合物 S7-6 (2_26 g，5·44 mmol，1 eq)。 形成橙紅色溶液。10分鐘後，逐滴添加DMF( 1.26 mL，16.30 mmol，3 eq)。使反應溶液在1小時内升溫至_2〇。〇，藉由 NH4C1飽和水溶液中止，以EtOAc ( 100 mL)稀釋，用水 及鹽水洗滌’經硫酸鈉脫水且減壓濃縮，得到2 42 g粗物 質S7-7,藉由管柱層析（Bi〇tage 24g管柱，5%至10%EtOAc 之己烧溶液梯度）純化，得到2.23 g ( 92% )呈淺黃色固體 狀之化合物 S7-7 : 4 NMR (400 MHz，CDC13) δ 10.37 (s, 1 Η), 7.47-7.51 (m, 2 Η), 7.33-7.40 (m, 5 Η), 7.27 (t, J = 7.3 123 201245116The reaction solution was stirred at ° C for 15 minutes and cooled to _78. Compound S7-6 (2_26 g, 5.44 mmol, 1 eq) was added dropwise in THF (5 mL). An orange-red solution is formed. After 10 minutes, DMF ( 1.26 mL, 16.30 mmol, 3 eq) was added dropwise. The reaction solution was allowed to warm to _2 Torr in 1 hour. 〇 中 NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH NH Purification of the tage of 24 g, 5% to 10% EtOAc in EtOAc (EtOAc: EtOAc: EtOAc: 1 Η), 7.47-7.51 (m, 2 Η), 7.33-7.40 (m, 5 Η), 7.27 (t, J = 7.3 123 201245116

Hz, 1 Η), 7.02-7.06 (m, 2 Η), 5.12 (s, 2 Η), 2.37 (d, J = 2.3 Hz, 3 H)。 ch3o f H3C〇A(VH3Hz, 1 Η), 7.02-7.06 (m, 2 Η), 5.12 (s, 2 Η), 2.37 (d, J = 2.3 Hz, 3 H). Ch3o f H3C〇A (VH3

Br^y^COjPh A I 〇BnBr^y^COjPh A I 〇Bn

合成 。 SM 在室溫下向化合物S7-7 (10g，22.60 mmol&gt; ieq)於 CH3OH中之溶液中添加原曱酸三曱酯（；4_8 g，45 2〇 mm〇1， 2.eq)及 TSOH-H2O ( 0.13 g ’ 0.68 mmol，0.03 eq )。將反 應混合物加熱至回流隔夜且減壓濃縮。用HA稀釋殘餘物 且用EtOAc萃取。有機層經硫酸鈉脫水且蒸發至乾燥。藉 由石夕膠管柱層析（石油醚：EtOAc，1 00:1至30:1 )純化粗產 物’得到呈淺黃色固體狀之化合物S'8 ( 10 g，91 % ) : ιΗ NMR (400 MHz, CDC13) δ 7.41-7.45 (m, 2 H), 7.25-7.35 (m, 5 H), 7.16-7.21 (m, 1 H), 6.98 (d, J= 8.0 Hz, 2 H), 5.71 (s, 1 H), 5.04 (s, 2 H), 3.46 (s, 6 H), 2.29 (d, J = 2.4 Hz, 3 H) 〇Synthesis. To a solution of the compound S7-7 (10 g, 22.60 mmol &gt; ieq) in CH3OH at room temperature, tridecyl orthoformate (4_8 g, 45 2 〇mm〇1, 2. eq) and TSOH- were added. H2O (0.13 g '0.68 mmol, 0.03 eq). The reaction mixture was heated to reflux overnight and concentrated under reduced pressure. The residue was diluted with HA and extracted with EtOAc. The organic layer was dried over sodium sulfate and evaporated to dryness. The crude product was purified by EtOAc (EtOAc:EtOAc:EtOAc:EtOAc:EtOAc MHz, CDC13) δ 7.41-7.45 (m, 2 H), 7.25-7.35 (m, 5 H), 7.16-7.21 (m, 1 H), 6.98 (d, J = 8.0 Hz, 2 H), 5.71 ( s, 1 H), 5.04 (s, 2 H), 3.46 (s, 6 H), 2.29 (d, J = 2.4 Hz, 3 H) 〇

F 〇HCnA^CH3 合成 S7-9 〇 s〇7B9n 在- 50c 下向 S7-8( 773 mg，1_58 mmol)於 THF( 16 mL ) 中之溶液中添加 LPrMgd-Lid ( 6.6 mL，7 9 mm〇1 )。使 反應溶液經1小時升溫至〇°C。添加氣化銨飽和水溶液（i 〇 mL )。用EtOAc ( 1 〇〇 mL )萃取混合物。EtOAc萃取物用 鹽水（20 mLx2)洗滌，經NaJO4脫水，且濃縮至乾燥。 將殘餘物再次溶解於THF ( 10 mL )中。添加鹽酸（6 n，2 mL )。在至溫下搜拌混合物1 6小時’用EtO Ac ( 150 mL ) 124 201245116 稀釋，用鹽水（50 mLx3 )洗滌，經Na2S04脫水，且濃縮 至乾燥。藉由石夕膠急驟層析（以己烧/EtO Ac ( 1:0至7:1 ) 洗提）純化殘餘物，得到醛S7-9 ( 4 1 7 mg，72% ) : 4 NMR (400 MHz, CDC13) δ 10.37 (s, 1 Η), Ί .22-1 AS (m, 9 Η), 7.05- 7.09 (d, / = 8.Hz, 2 Η), 5.17 (s, 2 Η), 2.41 (s, 3 Η) ° 9VVCH3 X^C02Ph , t OBn 合成 S7-10。 sr-io 向盤 S7-9 ( 417 mg，1.14 爪㈣。於卜bu〇h ( 11.4 mL) 及EtOAc ( 10 mL )中之溶液中添加乙二胺（84 # l，1.26 mmol )。在室溫下攪拌混合物6〇分鐘。添加k2C03( 473 mg， 3.42 mmol)及 I2 ( 376 mg，1.48 mmol)。反應混合物在 70 C下攪拌12小時’冷卻至室溫，以Na2S03飽和水溶液 (5 mL)中止’且用EtOAc ( 1〇〇 mL)萃取。EtOAc萃取 物以鹽水（15 mLx3 )洗滌，經Na2s〇4脫水，且濃縮至乾 燥。將殘餘物溶解於DMSO ( 11 mL)中。添加K2C03 ( 211 mg’ 1_60 mm〇1)及（二乙醯氧基碘）苯（514 mg，ι·6〇 mm〇1)。 在室溫下攪拌反應混合物4小時。再添加K2C03 ( 47 mg， 0.34 mmol)及（二乙醯氧基碘）苯（11〇nig，0.34 mm〇l)。 授拌反應混合物3小時且用EtOAc ( 200 mL )萃取。EtOAc 萃取物以鹽水（40 mLx4)洗滌，經Na2S04脫水且濃縮。 藉由石夕备急驟層析（以己烧/EtOAc ( 1:0至1:1 )洗提）純 化殘餘物’得到 u米唾 S7-10 ( 250 mg，54% ):丨1^ NMR (400 MHz, CDCI3) δ 9.95 (br, 1 Η), 7.83 (d, J= 6.1 Hz, 1 H), 7.05- 7.47 (m, 12 H), 5.21 (s, 2 H), 2.42 (s, 3 H) ； MS (ESI) 125 201245116 m/z 403.36 (M+H)F 〇HCnA^CH3 Synthesis S7-9 〇s〇7B9n Add LPrMgd-Lid (6.6 mL, 7 9 mm〇) to a solution of S7-8 (773 mg, 1_58 mmol) in THF (16 mL) at -50c 1 ). The reaction solution was allowed to warm to 〇 ° C over 1 hour. A saturated aqueous solution of ammonium sulfate (i 〇 mL ) was added. The mixture was extracted with EtOAc (1 mL). The EtOAc extract was washed with brine (20 mL×2), dried over NaCI 4 and evaporated. The residue was redissolved in THF (10 mL). Hydrochloric acid (6 n, 2 mL) was added. The mixture was sifted for 1 hr at rt and diluted with EtO Ac (150 mL) 124 201245116, washed with brine (50 mL×3), dried over Na 2 EtOAc and concentrated to dry. The residue was purified by flash chromatography eluting with EtOAc/EtOAc (EtOAc: EtOAc (EtOAc: EtOAc) MHz, CDC13) δ 10.37 (s, 1 Η), Ί .22-1 AS (m, 9 Η), 7.05- 7.09 (d, / = 8.Hz, 2 Η), 5.17 (s, 2 Η), 2.41 (s, 3 Η) ° 9VVCH3 X^C02Ph , t OBn Synthesize S7-10. Sr-io Add Ethylenediamine (84 #1, 1.26 mmol) to a solution of S7-9 (417 mg, 1.14 Claw (4). in Bubuh ( 11.4 mL) and EtOAc (10 mL). The mixture was stirred at ambient temperature for 6 min. k2C03 (473 mg, 3.42 mmol) and I2 (376 mg, 1.48 mmol) were added. The reaction mixture was stirred at 70 C for 12 hrs, cooled to room temperature, sat. Na2SO3 saturated aqueous solution (5 mL) The mixture was taken up in EtOAc (1 mL). 211 mg' 1_60 mm〇1) and (diethoxyoxyiodo)benzene (514 mg, ι·6〇mm〇1). Stir the reaction mixture for 4 hours at room temperature. Add K2C03 (47 mg, 0.34 mmol) And (diethoxy iodine) benzene (11 〇 nig, 0.34 mm 〇l). The reaction mixture was stirred for 3 h and extracted with EtOAc (200 mL). EtOAc EtOAc. Dehydrated and concentrated. Purification of the residue by flash chromatography ( eluting with hexanes / EtOAc (1:0 to 1:1) to give u-salt S7-10 (250 mg, 54%):丨1^ NMR (400 MHz, CDCI3) δ 9.95 (br, 1 Η), 7.83 (d, J = 6.1 Hz, 1 H), 7.05- 7.47 (m, 12 H), 5.21 (s, 2 H), 2.42 (s, 3 H) ; MS (ESI) 125 201245116 m/z 403.36 (M+H)

合成 在 _78°C 下向 LDA(0.33mmol，3eq)於 THF(1.5mL) 中之溶液中添加 TMEDA ( 49 &quot; L，0.33 mmol ’ 3 eq )。在 -78°C下攪拌5分鐘後，逐滴添加咪唑S7-10 ( 50 mg，〇·12 mmol，1.09 eq)於 tHf ( 〇·5 mL)中之溶液。在-78°C 下攪 拌反應混合物20分鐘。逐滴添加烯酮S2-1 ( 55 mg ’〇· 1 1 mmol，1 eq)於THF ( 0.5 mL)中之溶液。反應混合物經 45分鐘緩慢升溫至_2〇。(：，添加飽和氯化銨溶液（1 mL )及 鹽水（5 mL )，且以EtOAc ( 1 0 mLx3 )萃取。經合併之有 機萃取物經Na2S04脫水且濃縮。在Waters自動純化系統上 使用 Sunfire Prep C18 OBD 管柱[5 # m，19x50 mm ;流速： 20 mL/min;溶劑 A: H20,含 0.1% HC02H;溶劑 B : CH3〇H， 含 0.1% HC02H ;注入體積：3.0 mL ( CH3OH);梯度：6〇 —100% B，經15分鐘；質量導向型洗提份收集]進行製備 型逆相HPLC純化。收集在15.3_18.5分鐘洗提之具有所需 分子量之洗提份且冷凍乾燥，得到28 mg咪唑S7-1 &gt; * A 2 1 (31%) ： 'H NMR (400 MHz, CDC13) δ 16.17 (Sj 1 Η) 〇 〇 (br s，1 H)，7.87 (d，J = 6.7 Hz，1 H)，7.20-7.56 (m，12 H) 5.36 (s，2 H)，5.33 (d，J = 12.1 Hz，1 H)，5.25 (d，J = 12 i H 1 H)，3.97 (d，J = 10.4 Hz, 1 H)，3.30 (dd，J = 14.6, 3.6 hz 又 H), 2.97-3.10 (m, 1 H), 2.45-2.58 (m, 9 H), 2.14 (d, J = i4 〇 126 201245116Synthesis TMEDA (49 &quot; L, 0.33 mmol '3 eq ) was added to a solution of LDA (0.33 mmol, 3 eq) in THF (1.5 mL). After stirring at -78 °C for 5 minutes, a solution of the imidazole S7-10 (50 mg, 〇· 12 mmol, 1.09 eq) in tHf ( 〇·5 mL) was added dropwise. The reaction mixture was stirred at -78 °C for 20 minutes. A solution of the enone S2-1 (55 mg 〇·1 1 mmol, 1 eq) in THF (0.5 mL) was added dropwise. The reaction mixture was slowly warmed to _2 Torr over 45 minutes. (:, a saturated aqueous solution of ammonium chloride (1 mL) and brine (5 mL), EtOAc (EtOAc) (EtOAc) Prep C18 OBD column [5 # m, 19x50 mm; flow rate: 20 mL/min; solvent A: H20, containing 0.1% HC02H; solvent B: CH3〇H, containing 0.1% HC02H; injection volume: 3.0 mL (CH3OH) Gradient: 6〇—100% B, 15 minutes; mass-directed elution fraction collection] preparative reverse phase HPLC purification. The elution fraction with the desired molecular weight eluted at 15.3_18.5 minutes was collected and frozen. Dry to give 28 mg of imidazole S7-1 &gt; * A 2 1 (31%): 'H NMR (400 MHz, CDC13) δ 16.17 (Sj 1 Η) 〇〇 (br s, 1 H), 7.87 (d, J = 6.7 Hz, 1 H), 7.20-7.56 (m, 12 H) 5.36 (s, 2 H), 5.33 (d, J = 12.1 Hz, 1 H), 5.25 (d, J = 12 i H 1 H ), 3.97 (d, J = 10.4 Hz, 1 H), 3.30 (dd, J = 14.6, 3.6 hz and H), 2.97-3.10 (m, 1 H), 2.45-2.58 (m, 9 H), 2.14 (d, J = i4 〇126 201245116

Hz，1 H)，0.83 (s，9 H)，0.27 (s，3 Η), 0·14 (s，3 Η) ; MS (ESI) m/z 791.41 (M+H) 〇Hz, 1 H), 0.83 (s, 9 H), 0.27 (s, 3 Η), 0·14 (s, 3 Η); MS (ESI) m/z 791.41 (M+H) 〇

合成化合物。 S7-13-1 向米°坐87-12-1(28 111§，〇.04〇111111〇1)於1,4-二°惡烧（3 mL )中之溶液中添加HF水溶液（0.3 mL，48% )。反應混 合物在室溫下攪拌6小時，傾入K2HP〇4水溶液（2 g，於5 mL水中）中’且用EtOAc( 10 mLx3 )萃取。經合併之EtOAc 萃取物經NaiS04脫水且濃縮。 將殘餘物再次溶解於CH3OH/l，4-二噁烷溶液（3:1，4 mI〇 中。添加 Pd-C ( 13 mg，10 wt%)及 HC1/CH30H ( 0.5 N ’ 0· 1 mL )。在25°c下使(氣球）鼓泡通過反應混合 物90分鐘《經由小型矽藻土塞過濾混合物。以CH3〇h洗 蘇石夕藻土塞。濃縮濾液得到粗產物。在Waters自動純化系 統上使用 Phenomenex Polymerx 1 〇 &quot; Rp· 100A 管柱 [10 150x21.20mm;流速：20 mL/min ;溶劑 A : 0.05 N HC1/水，溶劑 b : CH3〇H ;注入體積：3.2mL(0.05NHCl/ 水）；梯度：20— 100% B ’經15分鐘；質量導向型洗提份 收集]進行製備型逆相HPLC純化。收集在5_8_8 2分鐘洗提 之具有所需分子量之洗提份且冷凍乾燥，得到所需產物 S7 13-1( 11 mg ’ 鹽酸鹽，53%，經 2 個步驟）：NMR (400 MHz, CD3OD) c5 7.77 (s, 2 Η), 7.36 (d5 /= 5.5 Hz, 1 H), 4.12 (s，1 H)，3.45-3.72 (m, 1 H)，3.05 (s，3 H)，2.97 (s，3 H), 2-95-3.21 (m, 2 H), 2.39-2.49 (m, 1 H), 2.24-2.31 (m, 1 H), 127 201245116Synthetic compounds. S7-13-1 Add HF aqueous solution (0.3 mL) to a solution of 87-12-1 (28 111 §, 〇.04〇111111〇1) in 1,4-two-degree smoldering (3 mL) , 48%). The reaction mixture was stirred at room temperature for 6 hr then poured over EtOAc EtOAc (EtOAc &lt The combined EtOAc extracts were dried over NaiS04 and concentrated. The residue was redissolved in CH3OH/1,4-dioxane solution (3:1, 4 mI). Add Pd-C (13 mg, 10 wt%) and HC1/CH30H (0.5 N '0·1 mL) The balloon was bubbled through the reaction mixture at 25 ° C for 90 minutes. The mixture was filtered through a small diatomaceous earth plug. The sulphate was washed with CH 3 〇h. The filtrate was concentrated to give a crude product. The system uses Phenomenex Polymerx 1 〇&quot; Rp· 100A column [10 150x21.20mm; flow rate: 20 mL/min; solvent A: 0.05 N HC1/water, solvent b: CH3〇H; injection volume: 3.2 mL (0.05 NHCl/water); Gradient: 20-100% B' over 15 minutes; mass-directed elution fraction collection] Preparative reverse phase HPLC purification. The elution fraction with the desired molecular weight eluted at 5-8_8 for 2 minutes was collected and Freeze-drying to give the desired product S7 13-1 (11 mg &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&&& Hz, 1 H), 4.12 (s, 1 H), 3.45-3.72 (m, 1 H), 3.05 (s, 3 H), 2.97 (s, 3 H), 2-95-3.21 (m, 2 H ), 2.39-2.49 (m, 1 H), 2.24-2.31 (m, 1 H), 127 2012451 16

1.63-1.874 (m，！ η) ; MS (ESI)所/z 499.17 (M+H)。 合成 U。 S7-11-2 向咪唑 S7-10 ( ίο mg，0.030 mmol)於 DMF ( 〇_5 mL) 中之溶液中添加NaH( 6 mg，0.1 5 mmol )及異丁基蛾（13 # L’ 0·10 mmol)。反應混合物在室溫下攪拌4小時，以Et〇Ac (20 mL)稀釋，用鹽水（5 mLx4)洗滌，經Na2S04脫水 且濃縮。藉由矽膠急驟層析（以己烷/Et0Ac ( 1:〇至1:1 ) 洗提）純化殘餘物，得到咪唑S7-11-2 : 4 NMR (400 MHz， CD3〇D) (5 6.92-7.5 1 (m, 13 Η), 5.23 (s, 2 Η), 3.68 (d, J = 7.4 Hz, 2 H), 2.39 (d, J= 2.0 Hz, 3 H), 1.95-2.05 (m, 1 H), 0.71 (s，3 H)，0_69 (s，3 H) ; MS (ESI) m/z 459.44 (M + H)。 合成化合物Sl-U-21.63-1.874 (m,! η) ; MS (ESI)/z 499.17 (M+H). Synthesize U. S7-11-2 Add NaH (6 mg, 0.1 5 mmol) and isobutyl moth (13 # L' 0) to a solution of imidazole S7-10 ( ίο mg, 0.030 mmol) in DMF (〇_5 mL). · 10 mmol). The reaction mixture was stirred at room temperature for 4 hr then diluted with EtOAc EtOAc (EtOAc) Purification of the residue by flash chromatography eluting with EtOAc/EtOAc (EtOAc: EtOAc: EtOAc: EtOAc: EtOAc 7.5 1 (m, 13 Η), 5.23 (s, 2 Η), 3.68 (d, J = 7.4 Hz, 2 H), 2.39 (d, J = 2.0 Hz, 3 H), 1.95-2.05 (m, 1 H), 0.71 (s, 3 H), 0_69 (s, 3 H); MS (ESI) m/z 459.44 (M + H).

根據S7-13-1所用之程序自S7-11-2及烯酮S2-1製備 S7-13-2 ： 'H NMR (400 MHz, CD3OD) &lt;5 7.90 (d, J = 1.8 Hz, 1 Η), 7.82 (d, J = 1.8 Hz, 1 H), 7.22 (d, J = 5.5 Hz, 1 H), 4.12 (s, 1 H), 4.03 (d, J = 8.0 Hz, 2 H), 3.05 (s, 3 H), 2.98 (s, 3 H), 2.95-3.24 (m, 3 H), 2.49-2.39 (m, 1 H), 2.24-2.31 (m, 1 H), 2.06-2.17 (m, 1 H), 1.62-1.74 (m, 1 H), 0.85 (d, J = 6.7 Hz, 6 H) ; MS (ESI) m/z 555.49 (M+H)。Preparation of S7-13-2 from S7-11-2 and ketene S2-1 according to the procedure used in S7-13-1: 'H NMR (400 MHz, CD3OD) &lt;5 7.90 (d, J = 1.8 Hz, 1 Η), 7.82 (d, J = 1.8 Hz, 1 H), 7.22 (d, J = 5.5 Hz, 1 H), 4.12 (s, 1 H), 4.03 (d, J = 8.0 Hz, 2 H), 3.05 (s, 3 H), 2.98 (s, 3 H), 2.95-3.24 (m, 3 H), 2.49-2.39 (m, 1 H), 2.24-2.31 (m, 1 H), 2.06-2.17 ( m, 1 H), 1.62-1.74 (m, 1 H), 0.85 (d, J = 6.7 Hz, 6 H); MS (ESI) m/z 555.49 (M+H).

合成化合物。 128 201245116 根據S7-13-2所用之程序自 S7-10及碘曱烷製備 S7-13-3 ： *H NMR (400 MHz, CD3OD) δ 7.80 (s, 1 Η), 7.78 (s, 1 Η), 7.21 (d, J= 5.2 Hz, 1 H), 4.12 (s, 1 H), 3.91 (s, 3 H), 3.58-3.74 (m , 1 H), 3.06 (s, 3 H), 2.98 (s, 3 H), 2.98-3.24 (m, 2 H), 2.39-2.50 (m, 1 H), 2.24-2.31 (m, 1 H), 1.63-1.75 (m, 1 H) ; MS (ESI) m/z 513.22 (M+H)。 實施例8.合成其中X為F且環E為1-取代之吡咯啶-2-基的式I化合物。 根據流程8製備式I化合物，其中環E為1 -取代之吡 咯啶-2-基；X為-F ;且Y為-Η。Synthetic compounds. 128 201245116 Preparation of S7-13-3 from S7-10 and iodonane according to the procedure used in S7-13-2: *H NMR (400 MHz, CD3OD) δ 7.80 (s, 1 Η), 7.78 (s, 1 Η ), 7.21 (d, J = 5.2 Hz, 1 H), 4.12 (s, 1 H), 3.91 (s, 3 H), 3.58-3.74 (m , 1 H), 3.06 (s, 3 H), 2.98 (s, 3 H), 2.98-3.24 (m, 2 H), 2.39-2.50 (m, 1 H), 2.24-2.31 (m, 1 H), 1.63-1.75 (m, 1 H) ; MS (ESI ) m/z 513.22 (M+H). Example 8. Synthesis of a compound of formula I wherein X is F and ring E is a 1-substituted pyrrolidin-2-yl group. A compound of formula I is prepared according to Scheme 8, wherein ring E is a 1-substituted pyrrolidin-2-yl group; X is -F; and Y is -oxime.

流程8 F a) LDA 0 F a) TFA b) 60 °C Γ-λ F rVCH3 _ V [^NB〇C irS^CH3 Br^Y^CC^Ph OBn S7*« NHBocBrA^c〇2ph OBn S8-1 Br*^y^C02Ph OBn S8-2 在-78°C 下向 ζ·-Ργ2ΝΗ ( 0_56 mL，3.97 mmol，1.5 eq) 129 201245116 於THF ( 25 mL )中之溶液中逐滴添加w BuLi ( 2 34心， 1.7 Μ/己烷，3.97 mmol，i.5 eq)。使反應物升溫至且 接著冷卻至-78°C。在-78。(：下添加酯S7-6 ( 1_10 g，2.65 mmol，1 eq)於THF ( 3 mL)中之溶液，且攪拌混合物25 分鐘。在-7 8 C下添加B〇c-2- °比η各α定酮（1 · 2 3 g，6.6 3 mmoL· 2.5 eq)於THF ( 3 mL)中之溶液。反應混合物在_78 °C下攪拌25分鐘，緩慢升溫至-3CTC，且在-30°C下攪拌20 分鐘。以鱗酸鹽緩衝水溶液（5 mL，pH = 7 )中止反應物。 用EtOAc ( 3x1 5 mL )萃取混合物。將有機萃取物合併，經 Na2S〇4脫水且漢縮。藉由石夕膠急驟層析（以己烧/Et〇Ac( 1:0 至7.1 )洗k )純化殘餘物，得到s 8 -1 ( 8 0 0 m g，5 0 % ): 'H NMR (400 MHz, CDC13) 5 7.24-7.50 (m, 8 H), 7.01-7.06 (m, 2 H), 5.09 (s, 2 H), 4.61-4.70 (br, 1 H), 3.20-3.27 (m, 2 H), 2.88 (t, J= 7.0 Hz, 2 H), 2.34 (d, J = 1.8 Hz, 3 H), 1.94 (dq, J= 6.7, 6.7 Hz, 2 H), 1.43 (s, 9 H) ； MS (ESI) m/z 624.44 (M+Na)。Process 8 F a) LDA 0 F a) TFA b) 60 °C Γ-λ F rVCH3 _ V [^NB〇C irS^CH3 Br^Y^CC^Ph OBn S7*« NHBocBrA^c〇2ph OBn S8- 1 Br*^y^C02Ph OBn S8-2 Add w BuLi to the solution of ζ·-Ργ2ΝΗ (0_56 mL, 3.97 mmol, 1.5 eq) 129 201245116 in THF (25 mL) at -78 °C. 2 34 hearts, 1.7 Μ/hexane, 3.97 mmol, i.5 eq). The reaction was allowed to warm up and then cooled to -78 °C. At -78. (: Add a solution of the ester S7-6 (1_10 g, 2.65 mmol, 1 eq) in THF (3 mL) and stir the mixture for 25 min. Add B〇c-2-° ratio η at -7 8 C A solution of each of the α-butanone (1 · 2 3 g, 6.6 3 mmoL · 2.5 eq) in THF (3 mL). The reaction mixture was stirred at -78 °C for 25 min, slowly warmed to -3 CTC, and at -30 The reaction was quenched with EtOAc (3 mL, pH = 7). The mixture was extracted with EtOAc (3×1 5 mL). The organic extracts were combined and dried over Na 2 〇 4 and condensed. The residue was purified by flash chromatography (washing with EtOAc/EtOAc (1:0 to 7.1) to give s 8 -1 (800 mg, 50%): 'H NMR ( 400 MHz, CDC13) 5 7.24-7.50 (m, 8 H), 7.01-7.06 (m, 2 H), 5.09 (s, 2 H), 4.61-4.70 (br, 1 H), 3.20-3.27 (m, 2 H), 2.88 (t, J = 7.0 Hz, 2 H), 2.34 (d, J = 1.8 Hz, 3 H), 1.94 (dq, J= 6.7, 6.7 Hz, 2 H), 1.43 (s, 9 H) ; MS (ESI) m/z 624.44 (M+Na).

Br 人〆^COfh ^ S8-2 ° S8-2 向酉同 S8-1 ( 800 mg，1_33 mmol)於 CH2C12 ( 8 mL)中 之溶液中添加TFA ( 2 mL )。在室溫下攪拌反應混合物1 小時且濃縮。添加K2C03 ( 5.0 g)於水（10 mL)中之溶液， 且用Et〇Ac ( 3x10 mL)萃取混合物。將有機層合併，經 Na2S〇4脫水且濃縮。將殘餘物再次溶解於曱苯/EtOAc (1:1 ’ 25 mL )中，在6(TC下攪拌20小時，且濃縮。藉由 130 201245116 •矽膠急驟層析（以己烷/EtOAc ( 1:0至3 :1 )洗提）純化殘 餘物，得到 S8-2( 600 mg，93% ) : 4 NMR (400 MHz，CDC13) δ 7.24-7.50 (m, 8 Η), 7.02-7.07 (m, 2 Η), 5.10 (s, 2 Η), 4.12-4.17 (m, 2 Η), 2.82-2.89 (m, 2 Η), 2.34 (d, J= 2.4 Hz, 3 H)，2.06-2.15 (m，2 H) ; MS (ESI) m/z 480.3 1 (M-H)。Br 〆^COfh ^ S8-2 ° S8-2 To a solution of S8-1 (800 mg, 1_33 mmol) in CH2C12 (8 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 1 hour and concentrated. A solution of K2C03 (5.0 g) in water (10 mL) was added and the mixture was extracted with Et EtOAc (3×10 mL). The organic layers were combined, dried over Na 2 EtOAc and concentrated. The residue was redissolved in toluene / EtOAc (1:1 '25 mL), EtOAc (EtOAc EtOAc) 0 to 3:1) elution of the residue to give S8-2 (600 mg, 93%): 4 NMR (400 MHz, CDC13) δ 7.24-7.50 (m, 8 Η), 7.02-7.07 (m, 2 Η), 5.10 (s, 2 Η), 4.12-4.17 (m, 2 Η), 2.82-2.89 (m, 2 Η), 2.34 (d, J= 2.4 Hz, 3 H), 2.06-2.15 (m , 2 H) ; MS (ESI) m/z 480.3 1 (MH).

在- 50C 下向 S8-2 ( 500 mg，1.04mmol，1 eq)於 THF (20 mL)中之溶液中添加 z.-PrMgBr-LiCl ( 3.50 tnL，1.2 M/THF，4· 1 6 mmol，4 eq )。反應混合物經1小時緩慢升 溫至0 °C且在0 °C下搜拌2小時。向反應混合物中添加碟酸 鹽緩衝水溶液（10 mL，pH = 7)且用EtOAc ( 1〇〇 mL)萃 取。有機萃取物以鹽水（3x20 mL )洗滌，經Na2S04脫水 且濃縮至乾燥，得到中間物S8-3。 將S8-3再次溶解於CH3〇H ( 20 mL)中且添加NaBH4 (100 mg，2.64 mmol，2.5 eq)。在室溫下攪拌溶液4〇分 鐘。添加HC1/1，4-二噁烷（4 mL，4 N)。在室溫下攪拌混 合物ίο分鐘且濃縮。添加Na0H水溶液（10 mL，】N)。 以EtOAc (3X15 mL)萃取水層。將有機萃取物合併，經 NaJCU脫水，且濃縮。藉由矽膠急驟層析（以己烷/Et〇Ac (1:〇至0:1)洗提）純化殘餘物，得到S8_4( 33〇 mg，79%， 經 2 個步驟）·· iH NMR (4〇〇 MHz，CDCl3)占 7.05-7 45 (m 11 Η), 5.13 (S, 2 Η), 4.41 (t, 7.6 Hz, 1 H)s 3.01-3.18 (m, 2 H), 2.34 (d，1.8 Hz，3 H)，2.20-2.32 (m，1 h)，1 52-1 80 131 201245116 (複合峰，3 Η) ; MS (ESI) w/z 484.13Add z.-PrMgBr-LiCl ( 3.50 tnL, 1.2 M/THF, 4·16 mmol, to a solution of S8-2 (500 mg, 1.04 mmol, 1 eq) in THF (20 mL) 4 eq ). The reaction mixture was slowly warmed to 0 ° C over 1 hour and mixed at 0 ° C for 2 hours. To the reaction mixture was added aq. EtOAc (10 mL, pH = 7). The organic extract was washed with brine (3×20 mL), dried over Na 2 EtOAc and concentrated to dryness S8-3 was redissolved in CH.sub.3 H (20 mL) and Na.sub.2H.sub.4 (100 mg, 2.64 mmol, 2.5 eq). The solution was stirred at room temperature for 4 minutes. Add HC1/1,4-dioxane (4 mL, 4 N). The mixture was stirred at room temperature for 00 minutes and concentrated. Aqueous Na0H (10 mL, EtOAc) was added. The aqueous layer was extracted with EtOAc (3×15 mL). The organic extracts were combined, dried over NaJCU and concentrated. The residue was purified by EtOAc (EtOAc/EtOAc (EtOAc) 4〇〇MHz, CDCl3) accounted for 7.05-7 45 (m 11 Η), 5.13 (S, 2 Η), 4.41 (t, 7.6 Hz, 1 H)s 3.01-3.18 (m, 2 H), 2.34 (d , 1.8 Hz, 3 H), 2.20-2.32 (m, 1 h), 1 52-1 80 131 201245116 (composite peak, 3 Η); MS (ESI) w/z 484.13

(M+H)。 在-78°C 下向 z.-Pr2NH ( 〇·26 mL，i 85 _〇1，2 5 )於 THF(8mL)中之溶液中逐滴添加〜BuU溶液（i 16以， 1.60 1^/己炫’1.85111111〇卜2.5叫）。使反應物升溫至〇。(：且 冷卻至-78°C。添加 TMEDA(0.28mL，i 85mm〇l 2 5eq)， 且在-78 C下攪拌混合物5分鐘。經3分鐘逐滴添加S8_&lt; 330 mg，〇_81 mmo卜hl eq)於丁HF (复社）中之溶液。在_7〇 C下攪拌反應混合物20分鐘且冷卻至—78 °C。經3分鐘逐滴 添加烯酮 S2-1 ( 357 mg，0.74 mmol，1 eq)於 THF ( 1 mL) 中之溶液。混合物經50分鐘緩慢升溫至_丨〇°c且添加磷酸鹽 緩衝水溶液（10 mL，pH = 7)。用 EtOAc ( 3x15 mL)萃 取水層。將有機層合併’經Na2S04脫水且濃縮，得到S8-5， 在無進一步純化的情況下將其用於下一步驟中。 向於 CH2C12 ( 3 mL)中之化合物 S8-5 ( 113 mg，0.14 mmol)中添加 Na(OAc)3BH ( 91 mg，0.43 mmol，3 eq)及 HCHO ( 116 mg，1.43 mmol，10 eq )。在室溫下撥拌混合 物1 6小時且以EtOAc ( 25 mL )稀釋。有機層以磷酸鹽緩 衝水溶液（3x10 mL，pH = 7)洗滌，經Na2S04脫水，且濃 縮。藉由矽膠急驟層析（以己烷/EtOAc ( 1:0至1:1 )洗提） 純化殘餘物，得到S8-6-1 ( 40 mg，35%，經2個步驟）： ^ NMR (4〇〇 mHz, CDC13) δ 16.19 (s, 1 Η), 7.05-7.50 (m, 132 201245116 Π Η), 5.3 5 (s，2 H)，5.11.5 21 (m，3 H)，3 97 (d，10.4 Hz, 1 H), 3.38-3.46 (m, 1 H), 3.18-3.25 (m, 2 H), 2.93-3.03 (m, 1 H), 2.20-2.52 (m, 13 H), 1.47-1.95 (m, 4 H), 0.83 (s, 9 H), 〇'27 (S，3 H), 014 (s&gt; 3 H) ； MS (ESI) m/z 808.76 (M+H) 〇 合成化合物S8(M+H). To a solution of z.-Pr2NH (〇·26 mL, i 85 〇 ,1, 2 5 ) in THF (8 mL) was added dropwise to a solution of &lt;RTI ID=0.0&gt; Has been dazzling '1.85111111 〇 bu 2.5 call). The reaction was allowed to warm to hydrazine. (: and cooled to -78 ° C. TMEDA (0.28 mL, i 85 mm 〇l 2 5 eq) was added, and the mixture was stirred at -78 C for 5 minutes. S8_&lt;330 mg, 〇_81 mmo was added dropwise over 3 minutes. Bu hl eq) solution in Ding HF (Fu Shi). The reaction mixture was stirred at _7 ° C for 20 min and cooled to -78 °C. A solution of the enone S2-1 (357 mg, 0.74 mmol, 1 eq) in THF (1 mL) was added dropwise over 3 min. The mixture was slowly warmed to _ 丨〇 ° C over 50 minutes and a phosphate buffered aqueous solution (10 mL, pH = 7) was added. The aqueous layer was extracted with EtOAc (3×15 mL). The organic layers were combined <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> to <RTI ID=0.0> To a solution of compound S8-5 (113 mg, 0.14 mmol) in CH2C12 (3 mL), Na(OAc)3BH (91 mg, 0.43 mmol, 3 eq) and HCHO (116 mg, 1.43 mmol, 10 eq). The mixture was stirred at room temperature for 16 h and diluted with EtOAc (25 mL). The organic layer was washed with a phosphate buffered aqueous solution (3 x 10 mL, pH = 7), dried over Na 2 SO 4 and concentrated. The residue was purified by flash chromatography eluting with EtOAc / EtOAc (EtOAc (EtOAc:EtOAc) 4〇〇mHz, CDC13) δ 16.19 (s, 1 Η), 7.05-7.50 (m, 132 201245116 Π Η), 5.3 5 (s, 2 H), 5.11.5 21 (m, 3 H), 3 97 (d, 10.4 Hz, 1 H), 3.38-3.46 (m, 1 H), 3.18-3.25 (m, 2 H), 2.93-3.03 (m, 1 H), 2.20-2.52 (m, 13 H), 1.47-1.95 (m, 4 H), 0.83 (s, 9 H), 〇 '27 (S, 3 H), 014 (s&gt; 3 H) ; MS (ESI) m/z 808.76 (M+H) 〇 Synthetic compound S8

向化合物 S8_6-1 ( 40 mg，0.050 mmol)於 1,4-二噁烷 (3社）中之溶液中添加HF水溶液（0.3 mL，48%)»混 合物在室溫下；^4 , + 卜權科· 4小時且傾入κ2Ηρ〇4水溶液（2 g於1〇 mLjJc中）中。用Et〇Ac ( i〇 mLx3 )萃取混合物。將有機 ^ «併，經Na2S〇4脫水，且濃縮。將殘餘物再次溶解於乙 酸乙酿（5 mL)中。添加HC1/曱醇（1 mL，〇·5 N)。濃縮 混合物，得到呈鹽酸鹽形式之中間物。 將上述中間物溶解於CH3〇H/l,4-二噁烷（2:1，3 mL) 中。添加Pd-C (8 mg，5 wt%)。在Η〗（氣球）下攪拌反 應混合物2小時。經由小型矽藻土塞過濾混合物。用甲醇 洗滌矽藻土塞。濃縮濾液得到粗產物。在Waters自動純化 系統上使用 PhenomenexPolymerxl〇 以 Rp_y 1〇〇A 管柱 Π〇 V m ’ 150x21.20 mm ;流速：20 mL/min ;溶劑 A : 0.05 N HC1/水；溶劑 B : CH3〇H ;注入體積：3 〇 ‘（ 〇 〇5 n hci/ 水）；梯度：0— 100% B，經25分鐘；質量導向型洗提份 收集]進行製備型逆相HPLC純化。收集在12 5_14 2分鐘洗 提之具有所需分子量之洗提份且冷凍乾燥，得到所需，產物 S8-7-1 ( 10 mg ’ 鹽酸鹽，34%，經 2 個步驟）：iH NMR (4〇〇 133 201245116 MHz, CD3OD) δ 7.08 (d, J= 5.5 Hz, 1 H), 4.68-4.78 (m, 1 H), 4.09 (s, 1 H), 3.81-3.89 (m, 1 H), 3.04 (s, 3 H), 2.96 (s, 3 H), 2.92-3.28 (m, 4 H), 2.87 (s, 3 H), 2.50-2.62 (m, 1 H), 2.20-2.42 (m, 5 H), 1.58-1.70 (m, 1 H) ； MS (ESI) m/z 516.25 (M + H)。 根據S8-7-1所用之程序自S8-5及各種醛或酮製備以下 化合物。Add HF aqueous solution (0.3 mL, 48%) to a solution of compound S8_6-1 (40 mg, 0.050 mmol) in 1,4-dioxane (3). mixture at room temperature; ^4, + Quan Ke · 4 hours and poured into κ 2 Η 〇 〇 4 aqueous solution (2 g in 1 〇 mLjJc). The mixture was extracted with Et 〇Ac (i 〇 mL x 3 ). The organic ^ « and dehydrated by Na 2 S 〇 4 and concentrated. The residue was redissolved in acetic acid (5 mL). Add HC1/sterol (1 mL, 〇·5 N). The mixture was concentrated to give an intermediate in the form of the hydrochloride. The above intermediate was dissolved in CH 3 〇H/l,4-dioxane (2:1, 3 mL). Pd-C (8 mg, 5 wt%) was added. The reaction mixture was stirred under Η (balloon) for 2 hours. The mixture was filtered through a small diatomaceous earth plug. The diatomaceous earth plug was washed with methanol. The filtrate was concentrated to give a crude material. Phoenomenex Polymerxl® was used on a Waters automated purification system with Rp_y 1〇〇A column Π〇V m '150x21.20 mm; flow rate: 20 mL/min; solvent A: 0.05 N HC1/water; solvent B: CH3〇H; Injection volume: 3 〇 '( 〇〇 5 n hci / water); gradient: 0 - 100% B, after 25 minutes; mass-directed elution fraction collection] preparative reverse phase HPLC purification. The extracts of the desired molecular weight eluted at 12 5_14 for 2 minutes were collected and lyophilized to give the desired product S8-7-1 (10 mg 'hydrochloride, 34% over 2 steps): iH NMR (4〇〇133 201245116 MHz, CD3OD) δ 7.08 (d, J= 5.5 Hz, 1 H), 4.68-4.78 (m, 1 H), 4.09 (s, 1 H), 3.81-3.89 (m, 1 H ), 3.04 (s, 3 H), 2.96 (s, 3 H), 2.92-3.28 (m, 4 H), 2.87 (s, 3 H), 2.50-2.62 (m, 1 H), 2.20-2.42 ( m, 5 H), 1.58-1.70 (m, 1 H); MS (ESI) m/z 516.25 (M + H). The following compounds were prepared from S8-5 and various aldehydes or ketones according to the procedure used in S8-7-1.

OH O HO Η Ο O S8-7-2 S8-7-2： 'H NMR (400 MHz, CD3OD) δ 7.13 (d J= 6 χ Hz, 1 Η), 4.75-4.82 (m, 1 Η), 4.11 (s, 1 Η), 3.83-3.91 (m χ Η), 3.05 (s, 3 Η), 2.97 (s, 3 Η), 2.95-3.24 (m, 6 Η), 2.48-2 62 (m, 1 Η), 2.20-2.42 (複合峰，5 Η), 1.58-1.71 (m，n η)，i 3〇OH O HO Η Ο O S8-7-2 S8-7-2: 'H NMR (400 MHz, CD3OD) δ 7.13 (d J= 6 χ Hz, 1 Η), 4.75-4.82 (m, 1 Η), 4.11 (s, 1 Η), 3.83-3.91 (m χ Η), 3.05 (s, 3 Η), 2.97 (s, 3 Η), 2.95-3.24 (m, 6 Η), 2.48-2 62 (m, 1 Η), 2.20-2.42 (composite peak, 5 Η), 1.58-1.71 (m, n η), i 3〇

(dt，《/= 7.3，1.8 Ηζ，3 Η) ; MS (ESI) m/z 530.29 (Μ+Η)。 S8-7-3： NMR (400 MHz, CD3OD) 5 7.16 (d, J= 6 χ(dt, "/= 7.3, 1.8 Ηζ, 3 Η); MS (ESI) m/z 530.29 (Μ+Η). S8-7-3: NMR (400 MHz, CD3OD) 5 7.16 (d, J= 6 χ

Hz，1 H)，4.83-4.89 (m，1 H)，4.10 (s，1 H)，3.43-3.72 (m 3 H)，3.05 (s，3 H)，2.97 (s，3 H)，2.96-3.25 (m，3 H)，2.5〇·2 62 (m，1 H)，2.20-2.42 (m，5 H)，1.57-1.71 (m，1 H)，i.3(M 38 (m，6 H) ; MS (ESI) m/z 544.30 (M + H)。Hz, 1 H), 4.83-4.89 (m, 1 H), 4.10 (s, 1 H), 3.43-3.72 (m 3 H), 3.05 (s, 3 H), 2.97 (s, 3 H), 2.96 -3.25 (m,3 H), 2.5〇·2 62 (m,1 H), 2.20-2.42 (m,5 H),1.57-1.71 (m,1 H),i.3 (M 38 (m, 6 H) ; MS (ESI) m/z 544.30 (M + H).

134 201245116 S8-7-4 ： 'H NMR (400 MHz, CD3OD) δ *H NMR (400 MHz, CD3OD) δ 7.14 (d, J= 5.5 Hz, 1 H), 4.81-4.87 (m, 1 H), 4.11 (s, 1 H), 3.91-3.99 (m} 1 H), 3.36-3.44 (m, 1 H), 3.05 (s, 3 H), 2.97 (s, 3 H), 2.95-3.22 (m, 5 H), 2.21-2.62 (m, 6 H), 1.98-2.10 (m, 1 H), 1.61-1.72 (m, 1 H), 0.99 (d, J= 6.7 Hz, 3 H), 0.94 (d, J = 6.7 Hz, 3 H) ； MS (ESI) m/z 558.3 1 (M+H)。134 201245116 S8-7-4 : 'H NMR (400 MHz, CD3OD) δ *H NMR (400 MHz, CD3OD) δ 7.14 (d, J = 5.5 Hz, 1 H), 4.81-4.87 (m, 1 H) , 4.11 (s, 1 H), 3.91-3.99 (m} 1 H), 3.36-3.44 (m, 1 H), 3.05 (s, 3 H), 2.97 (s, 3 H), 2.95-3.22 (m , 5 H), 2.21-2.62 (m, 6 H), 1.98-2.10 (m, 1 H), 1.61-1.72 (m, 1 H), 0.99 (d, J = 6.7 Hz, 3 H), 0.94 ( d, J = 6.7 Hz, 3 H) ; MS (ESI) m/z 558.3 1 (M+H).

S8-7-5： *H NMR (400 MHz, CD3OD) δ 7.09 (d, J= 5.5 Hz, 1 H), 4.78-4.83 (m, 1 H), 4.09 (s, 1 H), 3.93-4.02 (m, 1 H), 3.38-3.48 (m, 1 H), 3.04 (s, 3 H), 2.96 (s, 3 H), 2.96-3.18 (m, 5 H), 2.53-2.64 (ms 1 H), 2.20-2.42 (m5 5 H), 1.59-1.71 (m，1 Η), 0.98-1.09 (m，1 H)，0.63-0.71 (m，2 H)，0.26-0.44 (m，2 H) ; MS (ESI) m/z 556.29 (M + H)。 實施例9.合成其中X為-N(CH3)2且環£為j取代之〇比 洛唆-2-基的式I化合物》 根據以下流程9製備式Ϊ化合物，其中環^為丨_取代 之吡咯啶-2-基；X為-N(CH3)2 ;且Y為_H。 流程9 135 201245116S8-7-5: *H NMR (400 MHz, CD3OD) δ 7.09 (d, J = 5.5 Hz, 1 H), 4.78-4.83 (m, 1 H), 4.09 (s, 1 H), 3.93-4.02 (m, 1 H), 3.38-3.48 (m, 1 H), 3.04 (s, 3 H), 2.96 (s, 3 H), 2.96-3.18 (m, 5 H), 2.53-2.64 (ms 1 H ), 2.20-2.42 (m5 5 H), 1.59-1.71 (m,1 Η), 0.98-1.09 (m,1 H),0.63-0.71 (m,2 H),0.26-0.44 (m,2 H) MS (ESI) m/z 556.29 (M + H). Example 9. Synthesis of a compound of formula I wherein X is -N(CH3)2 and the ring is substituted with j. The indole compound is prepared according to Scheme 9 below, wherein the ring is a hydrazine Pyrrolidin-2-yl; X is -N(CH3)2; and Y is _H. Process 9 135 201245116

Vco2hVco2h

a)IPrMgBr LiCI 1) Zn/HOAc H3C、m/CH32)HCHO/HOAc Na(OAc)3BH I、CH3 Β「γ^ΟΗ3 och3 S1-4-a h3c、nxh3 口h4 、H3C、n/CH3a) IPrMgBr LiCI 1) Zn/HOAc H3C, m/CH32) HCHO/HOAc Na(OAc)3BH I, CH3 Β "γ^ΟΗ3 och3 S1-4-a h3c, nxh3 port h4, H3C, n/CH3

CO〇PhCO〇Ph

ch3 b)cjLCh3 b)cjL

Boc {I S9-8 Ν… 1)H2/Pd-C&lt; ΓΓ Γ 二； V ^Uhl3 2)Bo〇2〇 τ 、C02Ph y^c〇2Ph OBn OBoc Β S9-9 a) LDA/TMEDA 烯酮S2-1 LHMDS C02Ph ks^Ji?^C〇2Ph OBn OBn S9-5 S94Boc {I S9-8 Ν... 1)H2/Pd-C&lt; ΓΓ Γ 2; V ^Uhl3 2)Bo〇2〇τ , C02Ph y^c〇2Ph OBn OBoc Β S9-9 a) LDA/TMEDA ketene S2-1 LHMDS C02Ph ks^Ji?^C〇2Ph OBn OBn S9-5 S94

H3C CH3 ^ y? OHH3C CH3 ^ y? OH

O HO H 〇 S9-12O HO H 〇 S9-12

1&gt;HF水溶液 b) H2/Pd-C 1)TFA 2&gt;烷基化1&gt; aqueous solution of HF b) H2/Pd-C 1) TFA 2 &gt; alkylation

合成S9-1 在 0°C下將硝酸（〇·56 mL，68%-70%水溶液，8.57 mmol，1.05 eq )於濃H2S04 ( 2 mL )中之溶液逐滴添加至 化合物 Sl-4-a ( 2.00 g，8·16 mmol，1 eq )於濃 H2S04 ( 20 mL )中之溶液中。反應混合物在0°C下攪拌10分鐘且傾於 冰（200 mL)上。用EtOAc ( 150 mL)萃取混合物。分離 有機相，用鹽水（2x50 mL )洗滌，經硫酸鎂脫水且濃縮， 得到呈橙色固體狀之S9-1 : 1H NMR (400 MHz，CDC13) 5 11.5 (br s, 1 Η), 7.06 (s, 1 Η), 3.90 (s, 3 Η), 2.32 (s, 3 Η)； 136 201245116 NO,Synthesis of S9-1 A solution of nitric acid (〇·56 mL, 68%-70% aqueous solution, 8.57 mmol, 1.05 eq) in concentrated H.sub.2SO (2 mL) was added dropwise to compound Sl-4-a at 0 °C. ( 2.00 g, 8.16 mmol, 1 eq) in a solution of concentrated H2SO4 (20 mL). The reaction mixture was stirred at 0 &lt;0&gt;C for 10 min and poured onto ice (200 mL). The mixture was extracted with EtOAc (150 mL). The organic phase was separated, washed with EtOAc EtOAc EtOAc (mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj , 1 Η), 3.90 (s, 3 Η), 2.32 (s, 3 Η); 136 201245116 NO,

och3 S9-2 MS (ESI) m/z 288.01，289.99 (M-H) 〇 S9-2 〇 將化合物S9-1溶解於二氣甲烷（16 mL)中。添加乙 二醯氣（0.85 mL，Och3 S9-2 MS (ESI) m/z 288.01, 289.99 (M-H) 〇 S9-2 化合物 Compound S9-1 was dissolved in di-methane (16 mL). Add ethylene gas (0.85 mL,

9·79 mmol ’ 1.2 eq)，接著添加數滴 DMF 反應混合物在室溫下攪拌3〇分鐘，濃縮，且在高真空下進 一步乾燥。將殘餘物再次溶解於二氣曱烷（16m]L)中。添 加苯齡（0.92 g’ 9.79 mm〇1，以叫）、三乙胺（ 2 84 mL， 20.40 mmol. 2.5 eq)A DMAP( 100 mg» 0.82 mmoL· 〇.l eq) o 反應混合物在室溫下攪拌丨小時且減壓濃縮。將殘餘物、容 解於EtOAc( 150 mL)中，依次以！ N HCi水溶液（5〇机）、 鹽水（50 mL)、1 N NaOH 水溶液（50 mL)及鹽水（5〇 mL) 洗滌，經無水硫酸鎂脫水且濃縮，得到呈淺黃色固體狀之 所需產物 S9-2:巾 NMR (400 MHz, CDC13) 5 7.41-7.45 2 Η), 7.26-7.30 (m, 1 Η), 7.16-7.21 (m, 2 Η), 7.09 (s 1 、5 1 H)， 3.94 (s, 3 H), 2.38 (s, 3 H) ； MS (ESI) m/z 364.05, 366 〇6 (M-H) 〇9·79 mmol '1.2 eq), followed by the addition of a few drops of DMF. The reaction mixture was stirred at room temperature for 3 hrs, concentrated and dried under high vacuum. The residue was redissolved in dioxane (16 m) L). Add benzene age (0.92 g' 9.79 mm 〇1, called), triethylamine (2 84 mL, 20.40 mmol. 2.5 eq) A DMAP (100 mg» 0.82 mmoL· 〇.l eq) o reaction mixture at room temperature Stir for a few hours and concentrate under reduced pressure. The residue was taken up in EtOAc (150 mL). Washed with aq. EtOAc (5 mL), brine (50 mL), EtOAc (EtOAc) S9-2: towel NMR (400 MHz, CDC13) 5 7.41-7.45 2 Η), 7.26-7.30 (m, 1 Η), 7.16-7.21 (m, 2 Η), 7.09 (s 1 , 5 1 H), 3.94 (s, 3 H), 2.38 (s, 3 H) ; MS (ESI) m/z 364.05, 366 〇6 (MH) 〇

合政 SP-3。 S9-3 在-78°C下將BBr3於二氣甲烷中之溶液（8.16mL，lQ Μ ’ 8.16 mmol ’ 1 eq)緩慢添加至化合物S9-2於二氯甲燒 (32 mL )中之溶液中。在_78〇C下攪拌反應混合物1 $分鐘 且使其於50分鐘内升溫至〇°c。在〇。(：下攪拌1 〇分鐘後， 137 201245116 將反應混合物傾入NaHC03飽和水溶液（50 mL )中且在室 溫下攪拌10分鐘。蒸發揮發物。用EtOAc ( 100 mL，隨後 30 mL )萃取水性混合物。將有機萃取物合併，經無水 &gt;疏酸 鎮脫水且濃縮，得到 S9-3( 2.20 g ):丨11 NMR (400 MHz, CDC13) 6 112 (br s, 1 H), 7.44-7.48 (m, 2 H), 7.32-7.36 (m, 1 H), 7-25 (s, 1 H), 7.16-7.18 (m, 2 H), 2.63 (s, 3 H) ； MS (ESI) m/z 350.0 1, 352.03 (M-H) 〇 N〇2Governance SP-3. S9-3 A solution of BBr3 in di-methane (8.16 mL, lQ Μ ' 8.16 mmol '1 eq) was slowly added to the solution of compound S9-2 in dichloromethane (32 mL) at -78 °C. in. The reaction mixture was stirred at _78 ° C for 1 min and allowed to warm to 〇 °c over 50 min. Here. (After stirring for 1 min, 137 201245116. The reaction mixture was poured into a saturated aqueous NaHCO3 (50 mL) and stirred at room temperature for 10 min. Evaporate evaporated. EtOAc (100 mL The organic extracts were combined, dried over anhydrous &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& m, 2 H), 7.32-7.36 (m, 1 H), 7-25 (s, 1 H), 7.16-7.18 (m, 2 H), 2.63 (s, 3 H) ; MS (ESI) m/ z 350.0 1, 352.03 (MH) 〇N〇2

BrNrVCH3 ^y^co2Ph Λ OBn 口成 S 9 - 4。 S9-4 將 &gt;臭甲本（〇·78 mL，6.56 mmol，1.05 eq)及 K2C03 粉末（1_73 g ’ 12.5 0 mmo卜 2 eq)添加至化合物 S9-3 ( 2.20 g ’ 6.25 mmol，1 eq)於丙酮（mL)中之溶液中。在室 '凰下攪拌混合物隔夜。濾出固體且以Et〇Ac ( 3 0 mL )洗滌。 濃縮據液。藉由急驟管柱層析（2_2〇0/〇 Et〇Ac/己烷）純化殘 餘物’得到呈白色固體狀之所需產物S9-4 ( 1.68 g，47%， 經 4 個步驟）：4 NMR (400 MHz, CDC13) δ 7.32-7.40 (m， 8 Η), 7.15 (s, 1 Η), 7.01-7.03 (m, 2 Η), 5.18 (s, 2 Η), 2.39 (s, 3 Η) ; MS (ESI) m/z 440.09, 442.06 (M-H) 〇 h3c、n,ch3 7 OBn 政 iS P - J。 S9-5 將Zn粉（2.33 g，35.70 mmo卜i〇 eq)逐份添加至化 α 物 S9-4 ( 1.58 g，3.57 mmol，1 eq)於 THF ( 5 mL)與 H〇Ac ( 1 mL )之混合物中的溶液中。（警告：放熱丨）。反 138 201245116 應混合物在室溫下攪拌3.5小時，以EtOAc稀釋，且經由 矽藻土墊過濾。用EtOAc充分洗滌矽藻土墊。用NaHC03 飽和水溶液（60 mL )洗滌濾液。用EtOAc ( 40 mL )萃取 水層。經合併之有機萃取物經硫酸鈉脫水且濃縮，得到粗 苯胺中間物S9-4-a，在無進一步純化的情況下將其直接用 於下一步驟中。 將 HCHO ( 1.59 mL，37%水溶液，21.42 mmo卜 6 eq)、 HOAc ( 0.62 mL，10.71 mmo卜 3 eq)及 Na(OAc)3BH ( 2.27 g，10.71 mmo卜3 eq)添加至中間物S9-4-a於乙腈（30 mL) 中之溶液中。在室温下攪拌反應混合物2小時。再添加 Na(OAc)3BH ( 0.38 g * 1.78 mmol » 0.5 eq)。在室溫下授;掉 反應混合物隔夜。緩慢添加NaHC03飽和水溶液（70 mL ) (鼓泡）。混合物在室溫下攪拌5分鐘且用EtOAc( 100 mL， 隨後50 mL )萃取。經合併之有機萃取物經硫酸鈉脫水且濃 縮。藉由急驟管柱層析（2-5% EtOAc/己烷）純化殘餘物， 得到呈白色固體狀之所需產物S9_5 ( 1.43 g，91 %，經2個 步驟）：NMR (400 MHz，CDC13) δ 7.35-7.44 (m, 7 Η), 7.22-7.26 (m, 1 Η), 7.07-7.09 (m, 3 Η), 5.10 (s, 2 Η), 2.83 (s, 6 Η)，2.42 (s，3 Η) ; MS (ESI) m/z 440.12, 442.13 (Μ + Η) ο b〇chn^xh3c.n.ch3 O^Nj^N-^CH3 OBn 合成 。 在-60°C 下向化合物 S9-5 ( 1.0 g，2.27 mmol，1 eq)於 THF ( 22 mL)中之溶液中逐滴添加（8 5〇 mL， 1_2 M/THF ’ 10.20 mmo卜4.5 eq)。使反應物升溫至ot：且 139 201245116 在0 C下攪拌6小時。添加n-Boc-2-吡咯啶酮（1·89 g，10.20 mm〇1 ’ 4‘5叫）之溶液。混合物在0°C下攪拌2小時且接著 在室溫下搅拌14小時。向混合物中添加磷酸鹽緩衝水溶液 (30 mL ’ PH = 7)且用EtOAc ( 200 mL)萃取。有機萃取 物用鹽水（3X40 mL)洗滌，經Na2s〇4脫水，且濃縮。藉 由石夕膠急驟層析（以己烷/EtOAc ( 1:0至2:1 )洗提）純化 殘餘物’得到 S9-6 (1.12 g，90%):巾 NMR (400 MHz，CDC13) 5 7.04-7.42 (m，10 H)，6.73 (s，1 H)，5.10 (s，2 Η), 4.58-4.65 (br, 1 H), 3.16-3.22 (m, 2 H), 2.77-2.84 (m, 2 H), 2-76 (s, 6 H), 2.37 (s, 3 H), 1.81-1.90 (m, 2 H), 1.42 (s, 9 H) ； MS (ESI) m/z 547.16 (M + H) °BrNrVCH3 ^y^co2Ph Λ OBn is S 9 - 4. S9-4 Add &gt; stinking book (〇·78 mL, 6.56 mmol, 1.05 eq) and K2C03 powder (1_73 g '12.5 0 mmo 2 eq) to compound S9-3 ( 2.20 g ' 6.25 mmol, 1 eq ) in a solution in acetone (mL). Stir the mixture overnight in the room under the phoenix. The solid was filtered off and washed with EtOAc (30 mL). Concentrate the liquid. Purification of the residue by flash column chromatography (2 EtOAc / EtOAc (EtOAc) NMR (400 MHz, CDC13) δ 7.32-7.40 (m, 8 Η), 7.15 (s, 1 Η), 7.01-7.03 (m, 2 Η), 5.18 (s, 2 Η), 2.39 (s, 3 Η) MS (ESI) m/z 440.09, 442.06 (MH) 〇h3c, n, ch3 7 OBn 政 iS P - J. S9-5 Zn powder (2.33 g, 35.70 mmo, i〇eq) was added portionwise to the compound S9-4 ( 1.58 g, 3.57 mmol, 1 eq) in THF (5 mL) and H 〇Ac (1 mL) ) in a solution in a mixture. (Warning: exothermic 丨). Reaction 138 201245116 The mixture was stirred at room temperature for 3.5 hours, diluted with EtOAc and filtered over EtOAc. The diatomaceous earth pad was thoroughly washed with EtOAc. The filtrate was washed with a saturated aqueous solution of NaHC03 (60 mL). The aqueous layer was extracted with EtOAc (40 mL). The combined organic extracts were dried over sodium sulfate and concentrated to give EtOAc EtOAc. Add HCHO ( 1.59 mL, 37% aqueous solution, 21.42 mmo b 6 eq), HOAc (0.62 mL, 10.71 mmo b 3 eq) and Na(OAc) 3BH ( 2.27 g, 10.71 mmo b 3 eq) to the intermediate S9- 4-a in a solution of acetonitrile (30 mL). The reaction mixture was stirred at room temperature for 2 hours. Additional Na(OAc)3BH (0.38 g* 1.78 mmol » 0.5 eq) was added. The reaction mixture was allowed to stand overnight at room temperature. A saturated aqueous solution of NaHCO (70 mL) was added slowly (bubbling). The mixture was stirred at room temperature for 5 min and extracted with EtOAc (EtOAc EtOAc > The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) δ 7.35-7.44 (m, 7 Η), 7.22-7.26 (m, 1 Η), 7.07-7.09 (m, 3 Η), 5.10 (s, 2 Η), 2.83 (s, 6 Η), 2.42 ( s,3 Η) ; MS (ESI) m/z 440.12, 442.13 (Μ + Η) ο b〇chn^xh3c.n.ch3 O^Nj^N-^CH3 OBn synthesis. To a solution of the compound S9-5 (1.0 g, 2.27 mmol, 1 eq) in THF (22 mL), EtOAc (EtOAc) ). The reaction was allowed to warm to ot: and 139 201245116 was stirred at 0 C for 6 hours. A solution of n-Boc-2-pyrrolidone (1·89 g, 10.20 mm〇1 '4'5) was added. The mixture was stirred at 0 °C for 2 hours and then at room temperature for 14 hours. Aqueous phosphate buffered water (30 mL 'pH = 7) was added to mixture and extracted with EtOAc (200 mL). The organic extract was washed with brine (3.times.40 mL), dried over Na.sub. Purification of the residue by flash chromatography ( eluting with hexane / EtOAc (1:0 to 2:1)) afforded S9-6 (1.12 g, 90%): NMR (400 MHz, CDC13) 5 7.04-7.42 (m,10 H), 6.73 (s,1 H),5.10 (s,2 Η), 4.58-4.65 (br, 1 H), 3.16-3.22 (m, 2 H), 2.77-2.84 (m, 2 H), 2-76 (s, 6 H), 2.37 (s, 3 H), 1.81-1.90 (m, 2 H), 1.42 (s, 9 H) ; MS (ESI) m/z 547.16 (M + H) °

在至溫下向酮 S9-6(1.12g’ 2.06 mmol )於 CH2CI2 ( 8 mL· )中之溶液中添加TF a ( 1 mL )。在室溫下攪拌混合物 隔夜。再添加TFA ( 1.5 mL )。將混合物攪拌2小時，減壓 濃縮’且添加K2C03水溶液（5 g於1〇 mL水中）。用Et〇Ac (3x30 mL)萃取混合物《將有機萃取物合併，經Na2S〇4 脫水且濃縮，得到粗中間物。 向存於CH3〇H ( 1 5 mL )中之上述中間物中添加NaBH4 ( 200 mg，5_29 mmol’ 2.5 eq)。在室溫下攪拌反應混合物 1小時，得到S9-7之溶液，在無處理的情況下將其用於以 下步驟中：11^“尺（400 1^2,〇〇(：13)(57.05_7 45 (111，11 H), 5.13 (s, 2 H), 4.49-4.54 (m, 1 Η), 3.02-3.23 (m, 2 Η), 140 201245116 ，2.18-2.27 (m，1 H)， MS (ESI) m/z 431.02 2.80 (s, 3 Η), 2.79 (s, 3 Η), 2.35 (s, 3 Η), 2. 1-78-1.97 (m, 1 Η), 1.22-1.62 (m, 2 Η) ; MS (M+H)。To a solution of ketone S9-6 (1.12 g' 2.06 mmol) in CH2CI2 (8 mL·) was added TF a (1 mL). The mixture was stirred at room temperature overnight. Add TFA (1.5 mL). The mixture was stirred for 2 hours, concentrated under reduced pressure and aqueous K.sub.2CO.sub.3 (5 g. The mixture was extracted with EtOAc (3×30 mL). NaBH4 (200 mg, 5-29 mmol' 2.5 eq) was added to the above intermediate in CH3 〇H (15 mL). The reaction mixture was stirred at room temperature for 1 hour to give a solution of S9-7, which was used in the next step without treatment: 11^"(400 1^2, 〇〇(:13)(57.05_7) 45 (111,11 H), 5.13 (s, 2 H), 4.49-4.54 (m, 1 Η), 3.02-3.23 (m, 2 Η), 140 201245116 , 2.18-2.27 (m,1 H), MS (ESI) m/z 431.02 2.80 (s, 3 Η), 2.79 (s, 3 Η), 2.35 (s, 3 Η), 2. 1-78-1.97 (m, 1 Η), 1.22-1.62 (m) , 2 Η) ; MS (M+H).

OBn S9-8 向上述S9-7於CHbOH中之溶液中添加B〇c2〇( i 2〇g，OBn S9-8 adds B〇c2〇(i 2〇g, to the above solution of S9-7 in CHbOH,

5.50 mmo卜 2*.7 eq)及 Et3N ( 2.0 mL， 在室溫下撥拌反應混合物1小時且濃縮。殘餘物以Et〇Ac (80 mL)稀釋，用鹽水（30 mL)、水（3〇 mL)及鹽水（3〇 inL )洗滌，經Na2S〇4脫水’且濃縮。藉由石夕膠急驟層析（以 己烷/EtOAc ( 4:1 )洗提）純化殘餘物，得到i 26 g S9_8 (定 量）：4 NMR (400 MHz, CDC13) ^ 7.08-7.43 (m5 10 Η), 6.49-6.55 (m5 1 Η), 5.15-5.25 (m, 1 Η), 5.08 (d, J = 11.6 Hz, 1 H), 5.02 (d, J = 11.6 Hz, 1 H), 3.42-3.60 (m, 2 H), 2.77-2.87 (m, 6 H), 2.25-2.36 (m, 4 H), 1.55-1.80 (m, 3 H), 1.45 (s, 2 H), 1.26 (s, 7^H) ； MS (ESI) m/z 531.16 (M+H) °5.50 mmo 2*.7 eq) and Et3N (2.0 mL, stir the reaction mixture for 1 hour at room temperature and concentrate. The residue was diluted with Et EtOAc (80 mL), brine (30 mL), water (3) 〇mL) and brine (3〇inL) were washed, dehydrated with Na2S〇4 and concentrated. The residue was purified by flash chromatography eluting with hexane/EtOAc (4:1) to give i 26 g S9_8 (quantitative): 4 NMR (400 MHz, CDC13) ^ 7.08-7.43 (m5 10 Η), 6.49-6.55 (m5 1 Η), 5.15-5.25 (m, 1 Η), 5.08 (d, J = 11.6 Hz, 1 H), 5.02 (d, J = 11.6 Hz, 1 H), 3.42-3.60 (m, 2 H), 2.77-2.87 (m, 6 H), 2.25-2.36 (m, 4 H), 1.55 -1.80 (m, 3 H), 1.45 (s, 2 H), 1.26 (s, 7^H) ; MS (ESI) m/z 531.16 (M+H) °

OBoc S9-9 合成*SP-P。 向存於 CH3OH/EtOAc ( i:1，2〇 mL)中之化合物 S9-8 (1.26 g’ 2.33 mmol’ 1 eq)中添加 pd_c( 218 mg，1〇wt%)。 在25 C下在H2 (氣球）下攪拌反應混合物丄小時且經由小 型矽藻土塞過濾。用EtOAc洗滌矽藻土塞且濃縮濾液，得 到酚中間物。 141 201245116 向存於CH2C12( 50 mL )中之上述酚中間物中添加B〇c2〇 (900 mg，4.12 mmol，1.8 eq)及 DMAP( 1〇 mg，〇 〇8 麗〇1， 0.03 eq)。反應混合物在室溫下攪拌隔夜且濃縮。殘餘物 以 EtOAc(150mL)稀釋，用水（4〇mLx2)及鹽水（4〇mL) 洗滌’經NaaSCU脫水’且濃縮。藉由矽膠急驟層析（以己 烧/EtOAc ( 5:1)洗提）純化殘餘物，得到906 mg化合物 S9-9 ( 72%，，經 2 個步驟）：4 NMR (400 MH.z，CDC13) (5 7.12-7.44 (m，5 H)，6.77-6.82 (m，1 H)，5.10-5.30 (m, 1 H)， 3.49-3.70 (m, 2 H), 2.77-2.91 (m, 6 H)s 2.30-2.42 (m, 4 H), 1.63-1.90 (m, 3 H), 1.41 (s, 10 H), 1.25 (s, 8 H) ； MS (ESI) w/2 541.76 (M+H)。OBoc S9-9 Synthesis *SP-P. To the compound S9-8 (1.26 g' 2.33 mmol' 1 eq) in CH3OH / EtOAc (i:1, 2 mL) was added pd_c (218 mg, 1% wt%). The reaction mixture was stirred under H2 (balloon) at 25 C for a few hours and filtered through a pad of Celite. The diatomaceous earth plug was washed with EtOAc and the filtrate was concentrated to give a phenol intermediate. 141 201245116 To the above phenol intermediate in CH2C12 (50 mL) was added B〇c2〇 (900 mg, 4.12 mmol, 1.8 eq) and DMAP (1 〇 mg, 〇8 〇8, 0.03 eq). The reaction mixture was stirred at room temperature overnight and concentrated. The residue was diluted with EtOAc (150 mL)EtOAc. The residue was purified by EtOAc (EtOAc) elut elut elut elut elut elut elut elut CDC13) (5 7.12-7.44 (m,5 H), 6.77-6.82 (m,1 H), 5.10-5.30 (m, 1 H), 3.49-3.70 (m, 2 H), 2.77-2.91 (m, 6 H)s 2.30-2.42 (m, 4 H), 1.63-1.90 (m, 3 H), 1.41 (s, 10 H), 1.25 (s, 8 H) ; MS (ESI) w/2 541.76 (M +H).

在- 70C 下向 ’-ΡΓ2ΝΗ (0.52 mL ’ 3.69 mmol，2.2 eq) 於THF ( 20 mL )中之溶液中逐滴添加溶液（2.3 1 mL，1_60 M/己烧’ 3.69 mmoh 2.2 eq)。使反應物升溫至 〇°C 且冷卻至-70°C。添加 TMEDA ( 0.54 mL，3·69 mmol， 2.5 eq )。在-78°C下撥拌反應混合物5分鐘。經5分鐘逐滴 添加 S9-9 ( 906 mg ’ 1.68 mmol，1 eq)於 ThF ( 4 mL)中 之溶液。在-7 0下攪拌反應混合物2 5分鐘。經5分鐘逐滴 添加稀酮 S2-l(810mg’ 1.68mmol，leq)於 THF ( 4 mL ) 中之溶液。反應混合物經3 0分鐘緩慢升溫至_丨〇&lt;»c，添加磷 酸鹽緩衝水溶液（20 mL ’ pH = 7 )，且以乙酸乙酯（1 5〇 mL ) 142 201245116 萃取。有機萃取物以鹽水（3x40 mL)洗滌，經Na2S04脫 水，且濃縮。藉由矽膠急驟層析（以己烷/EtOAc( 1:0至3:1 ) 洗提）純化殘餘物，得到呈兩種非對映異構體之混合物形 式的 S9-10 ( 980 mg，63%) : 4 NMR (400 MHz, CDC13) 5 15.77 (s, 0.5 Η), 15.67 (s, 0.5 Η), 7.24-7.50 (m, 5 Η), 6.74-6.85 (m, 1 Η), 5.34 (s, 2 Η), 5.27-5.02 (m, 1 Η), 3.97-4.03 (m, 1 Η), 3.48-3.70 (m, 2 Η), 2.72-3.15 (m, 8 Η), 2.30-2.63 (m, 9 Η), 2.08-2.15 (m, 1 Η), 1.60-1.95 (m, 3 Η), 1.14-1.56 (m, 19 Η), 0.83 (s, 9 Η), 0.26 (s, 3 Η), 0.12 (s, 3 Η) ; MS (ESI) m/z 929.50 (Μ+Η)。To a solution of ‘-ΡΓ2ΝΗ (0.52 mL, 3.69 mmol, 2.2 eq) in THF (20 mL) was added dropwise (2.3 1 mL, 1 - 60 M / hexanes &gt; The reaction was allowed to warm to 〇 ° C and cooled to -70 °C. TMEDA (0.54 mL, 3.69 mmol, 2.5 eq) was added. The reaction mixture was stirred at -78 °C for 5 minutes. A solution of S9-9 (906 mg ' 1.68 mmol, 1 eq) in ThF (4 mL) was added dropwise over 5 min. The reaction mixture was stirred at -7 0 for 5 minutes. A solution of the dilute ketone S2-l (810 mg ' 1.68 mmol, leq) in THF (4 mL) was added dropwise over 5 min. The reaction mixture was slowly warmed to _ 丨〇 &lt;»c over 30 min, then aqueous sodium phosphate buffer (20 mL &lt;0&gt;&gt; The organic extract was washed with brine (3x 40 mL). The residue was purified by flash chromatography eluting with EtOAc EtOAc (EtOAc:EtOAc:EtOAc %) : 4 NMR (400 MHz, CDC13) 5 15.77 (s, 0.5 Η), 15.67 (s, 0.5 Η), 7.24-7.50 (m, 5 Η), 6.74-6.85 (m, 1 Η), 5.34 ( s, 2 Η), 5.27-5.02 (m, 1 Η), 3.97-4.03 (m, 1 Η), 3.48-3.70 (m, 2 Η), 2.72-3.15 (m, 8 Η), 2.30-2.63 ( m, 9 Η), 2.08-2.15 (m, 1 Η), 1.60-1.95 (m, 3 Η), 1.14-1.56 (m, 19 Η), 0.83 (s, 9 Η), 0.26 (s, 3 Η) ), 0.12 (s, 3 Η); MS (ESI) m/z 929.50 (Μ+Η).

使用製備型逆相HPLC在Waters自動純化系統上利用 Sunfire Prep Ci8 0BD 管柱[5 a m，ι9χ5〇 匪；流速：2〇 mL/min ;溶劑 A : H20，含 〇_1% HC〇2H ;溶劑 B : CH3CN， 含 0.1% hco2h ;注入體積：0.8 mL ( CH3Cn.);梯度：9〇 100% B之A溶液，經丨〇分鐘；質量導向型洗提份收集] 分離兩種非對映異構體。收集在6 2_7 〇分鐘洗提之具有所 需分子量之洗提份且濃縮，得到非對映異構體A S9_1〇_a。 且收集在7.1-7.9分鐘洗提之洗提份且濃縮，得到非對映異 構體 B S9-10-B : S9-10-A 之NMR (4〇〇 MHz，CDCl3)占 15.67 (s, 1 Η), 7.47-7.50 (m, 2 Η), 7.30-7.39 (m, 3 Η), 6.73-6.82 (m，1 Η)，5.34 (s，2 Η)，5.02-5.24 (m，1 Η)，3.98 (d， 143 201245116 J= 10.4 Hz, 1 H), 3.47-3.65 (m, 2 H), 2.23-3.05 (m, 17 H), 2.11 (d, J = 14.6 Hz, 1 H), 1.54-1.89 (m, 3 H), 1.15-1.54 (m, 19 Η), 0·83 (s，9 H)，0.26 (s，3 H)，012 (s，3 H) ; S9_10_A 之 MS (ESI) m/z 929.5 1 (M+H) ; S9-10-B 之1H NMR (400 MHz， CDC13) 5 15.73 (Sj 1 H), 7.45-7.50 (m, 2 H), 7.28-7.40 (m, 3 H), 6.83 (s, 1 H), 5.34 (s, 2 H), 5.15-5.22 (m, 1 H), 4.03 (d, 10.4 Hz, 1 H), 3.56-3.70 (m, 2 H), 2.35-3.15 (m, 17 H), 2.12 (d, J= 14.0 Hz, 1 H), 1.71-1.97 (m, 3 H), 1.15-1.60 (m, 19 H)’ 0.83 (s，9 H)，0.26 (s，3 H)，o.n (s，3 H) ; S9_1〇_B 之 MS (ESI) m/z 929.50 (M+H)。Sunfire Prep Ci8 0BD column [5 am, ι 9 χ 5 〇匪; flow rate: 2 〇 mL/min; solvent A: H20, containing 〇_1% HC 〇 2H; solvent using preparative reverse phase HPLC on a Waters automated purification system B: CH3CN, containing 0.1% hco2h; injection volume: 0.8 mL (CH3Cn.); Gradient: 9〇100% B solution A, 丨〇 minute; mass-oriented elution fraction collection] Separation of two diastereomeric Structure. The eluted fraction having the desired molecular weight eluted at 6 2-7 minutes was collected and concentrated to give the diastereomer A S9_1〇_a. The extracts eluted in 7.1-7.9 minutes were collected and concentrated to give the NMR (4 〇〇 MHz, CDCl3) of the diastereomer B S9-10-B: S9-10-A, 15.67 (s, 1 Η), 7.47-7.50 (m, 2 Η), 7.30-7.39 (m, 3 Η), 6.73-6.82 (m,1 Η), 5.34 (s,2 Η), 5.02-5.24 (m,1 Η) ), 3.98 (d, 143 201245116 J = 10.4 Hz, 1 H), 3.47-3.65 (m, 2 H), 2.23-3.05 (m, 17 H), 2.11 (d, J = 14.6 Hz, 1 H), 1.54-1.89 (m, 3 H), 1.15-1.54 (m, 19 Η), 0·83 (s, 9 H), 0.26 (s, 3 H), 012 (s, 3 H) ; MS of S9_10_A ( ESI) m/z 929.5 1 (M+H); 1H NMR of S9-10-B (400 MHz, CDC13) 5 15.73 (Sj 1 H), 7.45-7.50 (m, 2 H), 7.28-7.40 (m , 3 H), 6.83 (s, 1 H), 5.34 (s, 2 H), 5.15-5.22 (m, 1 H), 4.03 (d, 10.4 Hz, 1 H), 3.56-3.70 (m, 2 H ), 2.35-3.15 (m, 17 H), 2.12 (d, J = 14.0 Hz, 1 H), 1.71-1.97 (m, 3 H), 1.15-1.60 (m, 19 H)' 0.83 (s, 9 H), 0.26 (s, 3 H), on (s, 3 H); MS (ESI) m/z 929.50 (M+H) of S9_1〇_B.

在室溫下向化合物S9_1〇( 22〇 mg,〇 24 mm〇l)於CH2C12 (4 mL )中之溶液中添加tFa ( 1 mL )。攪拌混合物3小 時且減壓濃縮。殘餘物以乙酸乙酯（25 mL )稀釋，用磷酸 鹽緩衝水溶液（10 mLx2，PH = 7 )及鹽水（1 〇 mL )洗滌， 經Na2S〇4脫水，且濃縮至乾燥。 將殘餘物再次溶解於CH2C12 ( 4 mL)中。添加乙醛（40 /z L，0.7 1 mmol，3 eq )及 Na(OAc)3BH( 1 5 1 mg，0.7 1 mmol， 3 eq)。在室溫下攪拌反應混合物1小時，以EtOAc( 25 mL) 稀釋，用磷酸鹽缓衝水溶液（5 mLx2 ’ pH = 7)洗滌，經 Na2S04脫水，且濃縮。藉由矽膠急驟層析（以己烷/EtOAc (1:0至1:1 )洗提）純化殘餘物’得到78 mg化合物S9-11 -1 144 201245116 • ( 43%，經 2 個步驟）：】ΗΝΜΙΙ(400 MHz，CDC13) &lt;5 U.〇8 (s, 1 H), 11.66 (s, 0.5 H), 11.63 (s, 0.5 H), 7.26-7.49 (m, 5 7.14 (s, 1 H), 5.35 (s, 2 H), 5.28 (s, 1 H), 3.95 (d, J = 9.8 Hz, 1 H), 3.62 (d, 7 = 8.0 Hz, 0.5 H), 3.55 (d, J= 8.6 Hz, 0.5 H) 3.28-3.37 (m, 1 H)，3.11-3.27 (m，1 H)，2.91-3.02 (m，1 H)， 2.84 (s, 1.5 H), 2.80 (s, 1.5 H), 2.73 (s, 1.5 H), 2.71 (s, 1.5 H)，2.47 (s，6 H)，2.42-2.64 (m，5 H)，2.04-2.25 (m, 3 H) 1.72-1.94 (m, 2 H), 0.97-1.06 (m, 3 H), 0.84 (s, 9 H), 0.28 (s 3 H), 0.13 (s, 3 H) ；. MS (ESI) m/z 757.35 (M+H) 〇To a solution of the compound S9_1 〇 (22 〇 mg, 〇 24 mm 〇l) in CH2C12 (4 mL) was added tFa (1 mL). The mixture was stirred for 3 hours and concentrated under reduced pressure. The residue was diluted with ethyl acetate (25 mL), washed with EtOAc EtOAc (EtOAc) The residue was redissolved in CH2C12 (4 mL). Acetaldehyde (40 /z L, 0.7 1 mmol, 3 eq) and Na(OAc)3BH (1 5 1 mg, 0.7 1 mmol, 3 eq) were added. The reaction mixture was stirred at room temperature for 1 hr then diluted with EtOAc EtOAc EtOAc. Purification of the residue by flash chromatography (eluent eluting with hexane/EtOAc (1:0 to 1:1) to give 78 mg of compound S9-11 -1 144 201245116 • (43%, in 2 steps): ΗΝΜΙΙ(400 MHz, CDC13) &lt;5 U.〇8 (s, 1 H), 11.66 (s, 0.5 H), 11.63 (s, 0.5 H), 7.26-7.49 (m, 5 7.14 (s, 1 H), 5.35 (s, 2 H), 5.28 (s, 1 H), 3.95 (d, J = 9.8 Hz, 1 H), 3.62 (d, 7 = 8.0 Hz, 0.5 H), 3.55 (d, J = 8.6 Hz, 0.5 H) 3.28-3.37 (m, 1 H), 3.11-3.27 (m, 1 H), 2.91-3.02 (m, 1 H), 2.84 (s, 1.5 H), 2.80 (s, 1.5 H), 2.73 (s, 1.5 H), 2.71 (s, 1.5 H), 2.47 (s, 6 H), 2.42-2.64 (m, 5 H), 2.04-2.25 (m, 3 H) 1.72-1.94 ( m, 2 H), 0.97-1.06 (m, 3 H), 0.84 (s, 9 H), 0.28 (s 3 H), 0.13 (s, 3 H) ;. MS (ESI) m/z 757.35 (M +H) 〇

向化合物 S9-11-1 ( 78 mg，0.10 mmol)於 1，4-二嚼燒 (3 mL )中之溶液中添加pjF水溶液（〇·3 mL，48% )。反 應混合物在室溫下攪拌隔夜且傾入K2HP〇4水溶液（2 g於 5 mL水中）中。以Et0Ac ( 1〇 mLx3 )萃取混合物。將有機 萃取物合併，經NadCU脫水，且濃縮。將殘餘物溶解於 CH2C12 (5mL)中。添加 HC1/甲醇（2mL，0.5N)。減壓 濃縮溶液，得到鹽酸鹽。 向存於CH^OH/l，4-一 °惡烧（3:1 ’ 4 mL )中之上述中間 物中添加Pd-C ( 12 mg，5wt% )。在室溫下在％ (氣球） 下攪拌反應混合物1小時。經由小型矽藻土塞過濾混合物。 用甲醇洗條石夕藻土塞。濃縮濾液得到粗產物。在Waters自 動純化系統上使用 Phenomenex Polymerx 1〇 β Rp. γ 100A 管柱[l〇 〆 m，150x21.20 mm ;流速：2〇 mL/min ;溶 145 201245116 劑 A : 0.05 N HC1/水；An aqueous solution of pjF (〇·3 mL, 48%) was added to a solution of compound S9-11-1 (78 mg, 0.10 mmol. The reaction mixture was stirred overnight at room temperature and poured into aqueous K.sub.2 solution (2 g in 5 mL water). The mixture was extracted with Et0Ac (1 〇 mL x 3 ). The organic extracts were combined, dried over NadCU and concentrated. The residue was dissolved in CH2C12 (5 mL). Add HC1/methanol (2 mL, 0.5 N). The solution was concentrated under reduced pressure to give the hydrochloride. Pd-C (12 mg, 5 wt%) was added to the above intermediate in CH^OH/l, 4- deg. (3:1 '4 mL). The reaction mixture was stirred at % (balloon) for 1 hour at room temperature. The mixture was filtered through a small diatomaceous earth plug. Wash the stone with the methanol. The filtrate was concentrated to give a crude material. Phenomenex Polymerx 1〇 β Rp. γ 100A column [1〇 〆 m, 150x21.20 mm; flow rate: 2 〇 mL/min; solution 145 201245116 A: 0.05 N HC1/water;

溶劑B : CH3OH ;注入體積：2.4 mL (0.05 N HC1/水）；梯度：〇— 1〇〇% b，經25分鐘；質量 導向型洗提份收集]進行製備型逆相HPLC純化。收集在 13.8-15.5分鐘洗提之具有所需分子量之洗提份且冷凍乾 燥，得到30 mg S9-12-1 ( 54%，經2個步驟，鹽酸鹽）：ιΗ NMR (400 MHz, CD3OD) δ 7.08 (s, 0.5 Η), 7.01 (s, 0.5 Η), 4.95-5.10 (m，1 Η), 4.12 (s，1 η), 3.85-4.00 (m，1 η)， 3.31-3.38 (m, 1 Η), 2.77-3.27 (m, 17 Η), 2.52-2.65 (m, 1 Η), 2.38-2.51 (m3 1 Η), 2.17-2.38 (m, 3 Η),. 1.97-2.17 (m, 1 Η), 1.59-1.72 (m, 1 Η)，1.32 (t，J = 7.3 Ηζ，1.5 Η)，1·28 (t，J = 7.3Solvent B: CH3OH; injection volume: 2.4 mL (0.05 N HC1/water); gradient: 〇-1〇〇% b over 25 minutes; mass-oriented elution fraction collection] preparative reverse phase HPLC purification. The extract having the desired molecular weight eluted at 13.8-15.5 minutes was collected and lyophilized to give 30 mg S9-12-1 (54% over 2 steps, hydrochloride): ι NMR (400 MHz, CD3OD) ) δ 7.08 (s, 0.5 Η), 7.01 (s, 0.5 Η), 4.95-5.10 (m,1 Η), 4.12 (s,1 η), 3.85-4.00 (m,1 η), 3.31-3.38 ( m, 1 Η), 2.77-3.27 (m, 17 Η), 2.52-2.65 (m, 1 Η), 2.38-2.51 (m3 1 Η), 2.17-2.38 (m, 3 Η),. 1.97-2.17 ( m, 1 Η), 1.59-1.72 (m, 1 Η), 1.32 (t, J = 7.3 Ηζ, 1.5 Η), 1·28 (t, J = 7.3

Hz, 1.5 Η) ； MS (ESI) m/z 555.28 (M+H) 〇 根據與S9-12-1所用類似之程序自S9-10、S9-10-A或 S9-10-B及各種醛或酮製備以下化合物。Hz, 1.5 Η) ; MS (ESI) m/z 555.28 (M+H) 〇 from S9-10, S9-10-A or S9-10-B and various aldehydes according to procedures similar to those used for S9-12-1 Or a ketone to prepare the following compounds.

S9-12-1-A ： lH NMR (400 MHz, CD3OD) δ 6.98 (s, 1 Η), 4.90-5.10 (m, 1 Η), 4.11 (s, 1 Η), 3.91-3.99 (m, 1 Η), 3.32-3.39 (m, 1 Η), 2.76-3.27 (m, 17 Η), 2.54-2.65 (m, 1 Η), 2.40-2.51 (m, 1 Η), 2.17-2.36 (m5 3 Η), 1.97-2.09 (m, 1 Η), 1-60-1.73 (m, 1 Η), 1.32 (t, /= 7.3 Hz, 3 Η) ； MS (ESI) m/z 555.28 (M+H)。 146 201245116 H3C.n，CH3 H3C、nzCH3S9-12-1-A : lH NMR (400 MHz, CD3OD) δ 6.98 (s, 1 Η), 4.90-5.10 (m, 1 Η), 4.11 (s, 1 Η), 3.91-3.99 (m, 1 Η), 3.32-3.39 (m, 1 Η), 2.76-3.27 (m, 17 Η), 2.54-2.65 (m, 1 Η), 2.40-2.51 (m, 1 Η), 2.17-2.36 (m5 3 Η ), 1.97-2.09 (m, 1 Η), 1-60-1.73 (m, 1 Η), 1.32 (t, /= 7.3 Hz, 3 Η) ; MS (ESI) m/z 555.28 (M+H) . 146 201245116 H3C.n, CH3 H3C, nzCH3

非對映異構體B S9-12-1-B : 'h NMR (400 MHz, CD3〇D) δ 7.03 (s, 1 H), 5.02-5.10 (m, 1 H), 4.09 (s, 1 H)s 3.82-3.90 (m5 1 H), 3.31-3.38 (m, 1 H), 2.78-3.20 (m, 17 H), 2.52-2.62 (m, 1 H), 2.40-2.52 (m, 1 H), 2.20-2.37 (m, 3 H), 2.03-2.15 (m, 1 H), 1.60-1.72 (m, 1 H), 1.27 (t, /= 7.0 Hz, 3 H) ； MS (ESI) m/z 555.27 (M+H)。Diastereomer B S9-12-1-B : 'h NMR (400 MHz, CD3〇D) δ 7.03 (s, 1 H), 5.02-5.10 (m, 1 H), 4.09 (s, 1 H)s 3.82-3.90 (m5 1 H), 3.31-3.38 (m, 1 H), 2.78-3.20 (m, 17 H), 2.52-2.62 (m, 1 H), 2.40-2.52 (m, 1 H ), 2.20-2.37 (m, 3 H), 2.03-2.15 (m, 1 H), 1.60-1.72 (m, 1 H), 1.27 (t, /= 7.0 Hz, 3 H) ; MS (ESI) m /z 555.27 (M+H).

S9-12-2 ： lH NMR (400 MHz, CD3OD) δ 7.04 (s, 1 H), 4.97-5.05 (m, 1 H), 4.12 (s, 1 H), 3.83-3.92 (m, 1 H), 3.33-3.41 (m, 1 H), 2.77-3.22 (m, 18 H), 2.53-2.64 (m, 1 H), 2.40-2.53 (m, 1 H), 2.08-2.40 (m} 4 H), 1.60-1.72 (m, 1 H)； MS (ESI) m/z 541.29 (M + H) 〇S9-12-2 : lH NMR (400 MHz, CD3OD) δ 7.04 (s, 1 H), 4.97-5.05 (m, 1 H), 4.12 (s, 1 H), 3.83-3.92 (m, 1 H) , 3.33-3.41 (m, 1 H), 2.77-3.22 (m, 18 H), 2.53-2.64 (m, 1 H), 2.40-2.53 (m, 1 H), 2.08-2.40 (m} 4 H) , 1.60-1.72 (m, 1 H); MS (ESI) m/z 541.29 (M + H) 〇

S9-12-3 '· !H NMR (400 MHz, CD3〇D) δ 7.08 (s, 0.5 H), 6.98 (s, 0.5 H), 5.23-5.30 (m, 0.5 H), 5.00-5.07 (m, 0.5 H)，4·10 (s，1 H)，3.36-3.76 (m，3 H), 2.77-3.16 (複合峰，15 H), 2.51-2.64 (m, 1 H), 2.41-2.51 (m, 1 H), 2.18-2.32 (m, 3 H), 1.96-2.12 (m, 1 H), 1.59-1.72 (m, 1 H), 1.28-1.37 (m, 6 147 201245116 Η) ; MS (ESI) m/z 569.27 (M+H)。S9-12-3 '· !H NMR (400 MHz, CD3〇D) δ 7.08 (s, 0.5 H), 6.98 (s, 0.5 H), 5.23-5.30 (m, 0.5 H), 5.00-5.07 (m , 0.5 H), 4·10 (s, 1 H), 3.36-3.76 (m, 3 H), 2.77-3.16 (complex peak, 15 H), 2.51-2.64 (m, 1 H), 2.41-2.51 ( m, 1 H), 2.18-2.32 (m, 3 H), 1.96-2.12 (m, 1 H), 1.59-1.72 (m, 1 H), 1.28-1.37 (m, 6 147 201245116 Η) ; MS ( ESI) m/z 569.27 (M+H).

S9-12-3-A S9-12-3-A ： 'H NMR (400 MHz, CD3OD) &lt;5 6.97 (s, 1 H), 4.99-5.08 (m, 1 H), 4.09 (s, 1 H), 3.67-3.75 (m, 1 H), 3.49-3.58 (m, 1 H), 3.40-3.49 (m, 1 H), 2.76-3.14 (m, 15 H), 2.53-2.63 (m, 1 H), 2.24-2.52 (m, 1 H), 2.17-2.29 (m, 3 H), 1.94-2.06(m, 1 H), 1.59-1.72 (m, 1 H), 1.33 (t, J= 6.1 Hz, 3 H) ; MS (ESI) m/z 569.29 (M+H)。S9-12-3-A S9-12-3-A : 'H NMR (400 MHz, CD3OD) &lt;5 6.97 (s, 1 H), 4.99-5.08 (m, 1 H), 4.09 (s, 1 H), 3.67-3.75 (m, 1 H), 3.49-3.58 (m, 1 H), 3.40-3.49 (m, 1 H), 2.76-3.14 (m, 15 H), 2.53-2.63 (m, 1 H), 2.24-2.52 (m, 1 H), 2.17-2.29 (m, 3 H), 1.94-2.06 (m, 1 H), 1.59-1.72 (m, 1 H), 1.33 (t, J = 6.1 Hz, 3 H) ; MS (ESI) m/z 569.29 (M+H).

S9-12-3-B S9-12-3-B ： !H NMR (400 MHz, CD3OD) δ 7.06 (s, 1 H), 5.22-5.28 (m, 1 H), 4.08 (s, 1 H), 3.60-3.68 (m, 1 H), 3.39-3.50 (m, 2 H), 2.80-3.14 (m, 15 H), 2.50-2.60 (m, 1 H), 2.43-2.50 (m, 1 H), 2.20-2.30 (m, 3 H), 1.97-2.11 (m, 1 H), 1.60-1.72 (m, 1 H), 1.30 (t, J= 6.7 Hz, 3 H) ； MS (ESI) m/z 569.21 (M+H) 〇S9-12-3-B S9-12-3-B : !H NMR (400 MHz, CD3OD) δ 7.06 (s, 1 H), 5.22-5.28 (m, 1 H), 4.08 (s, 1 H) , 3.60-3.68 (m, 1 H), 3.39-3.50 (m, 2 H), 2.80-3.14 (m, 15 H), 2.50-2.60 (m, 1 H), 2.43-2.50 (m, 1 H) , 2.20-2.30 (m, 3 H), 1.97-2.11 (m, 1 H), 1.60-1.72 (m, 1 H), 1.30 (t, J = 6.7 Hz, 3 H) ; MS (ESI) m/ z 569.21 (M+H) 〇

S9-12-4 ： 'H NMR (400 MHz, CD3OD) δ 7.06 (s, 0.5 H), 6.99 (s, 0.5 H), 5.05-5.11 (m, 0.5 H), 4.90-4.98 (m, 0.5 H), 4.10 (s, 1 H), 3.96-4.10 (m, 1 H), 3.37-3.48 (m, 1 H), 148 201245116 2.74-3.13 (m, 17 Η), 2.52-2.64 (m, 1 Η), 2.20-2.51 (m, 4 Η), 1.94-2.15 (m, 1 Η), 1.58-1.71 (m, 1 Η), 0.98-1.10 (m, 1 Η), 0.65-0.73 (m, 2 Η), 0.36-0.43 (m, 1 Η), 0.20-0.34 (m, 1 Η)； MS (ESI) m/z 581.30 (M+H)。S9-12-4 : 'H NMR (400 MHz, CD3OD) δ 7.06 (s, 0.5 H), 6.99 (s, 0.5 H), 5.05-5.11 (m, 0.5 H), 4.90-4.98 (m, 0.5 H ), 4.10 (s, 1 H), 3.96-4.10 (m, 1 H), 3.37-3.48 (m, 1 H), 148 201245116 2.74-3.13 (m, 17 Η), 2.52-2.64 (m, 1 Η ), 2.20-2.51 (m, 4 Η), 1.94-2.15 (m, 1 Η), 1.58-1.71 (m, 1 Η), 0.98-1.10 (m, 1 Η), 0.65-0.73 (m, 2 Η) ), 0.36-0.43 (m, 1 Η), 0.20-0.34 (m, 1 Η); MS (ESI) m/z 581.30 (M+H).

S9-12-5 ： ]H NMR (400 MHz, CD3〇D) δ 7.14 (s, 0.5 H), 7.06 (s, 0.5 H), 5.12-5.17 (m, 0.5 H), 4.96-5.00 (m, 0.5 H), 4.12 (s, 1 H), 3.91-4.03 (m, 1 H), 3.35-3.43 (m, 1 H), 2.75-3.14 (m, 17 H), 2.23-2.62 (m, 5 H), 1.94-2.18 (m, 2 H), 1.60-1.73 (m, 1 H), 0.91-1.05 (m, 6 H) ； MS (ESI) m/z 583.30 (M+H) 〇S9-12-5 : ]H NMR (400 MHz, CD3〇D) δ 7.14 (s, 0.5 H), 7.06 (s, 0.5 H), 5.12-5.17 (m, 0.5 H), 4.96-5.00 (m, 0.5 H), 4.12 (s, 1 H), 3.91-4.03 (m, 1 H), 3.35-3.43 (m, 1 H), 2.75-3.14 (m, 17 H), 2.23-2.62 (m, 5 H ), 1.94-2.18 (m, 2 H), 1.60-1.73 (m, 1 H), 0.91-1.05 (m, 6 H) ; MS (ESI) m/z 583.30 (M+H) 〇

藉由直接脫除s9_io之保護基製備：iH NMR (4〇〇 MHz， CD3OD) δ 6.91-6.97 (m, 1 H), 4.86 (m, 1 H), 4.11 (s, 1 H), 2-75-3.72 (m, 17 H), 2.00-2.56 (m, 6 H), 1.72-1.61 (m, 1 H) ; MS (ESI) m/z 527.40 (M+H)。 實施例10.合成其中x為c丨且環E為視情況經取代之 芳基或雜芳基（「（Ht)Ar」）的式ϊ化合物β 根據以下流程1 〇製備式j化合物，其中環Ε為視情況 涇取代之芳基或雜芳基；χ為_C1 ;且Υ為。 流程10 149 201245116Prepared by direct removal of the protecting group of s9_io: iH NMR (4〇〇MHz, CD3OD) δ 6.91-6.97 (m, 1 H), 4.86 (m, 1 H), 4.11 (s, 1 H), 2- 75-3.72 (m, 17 H), 2.00-2.56 (m, 6 H), 1.72-1.61 (m, 1 H); MS (ESI) m/z 527.40 (M+H). Example 10. Synthesis of a compound of the formula 其中 wherein β is c丨 and ring E is an optionally substituted aryl or heteroaryl group ("(Ht)Ar") According to the following Scheme 1, a compound of the formula j is prepared, wherein the ring Ε is an aryl or heteroaryl group which is optionally substituted; χ is _C1; and Υ is. Process 10 149 201245116

〇ch3 S1-5 (H〇Ar〇ch3 S1-5 (H〇Ar

OBn O HO = O 0TBS S10-6 H3C .CH3 H H N (Ht)ArB(OH)2 _▲:-〇、 Pd催化劑 J &quot;--OBn O HO = O 0TBS S10-6 H3C .CH3 H H N (Ht)ArB(OH)2 _▲:-〇, Pd catalyst J &quot;--

OBnOBn

合成S10-1 向化合物 Sl-5(2.52g，7.87mmol，leq)於乙腈（16 mL)中之溶液中整份添加NCS (1_10 g，8·27 mmol，1.05 e q )。用6 0 °C油浴加熱反應混合物4 5小時。蒸發溶劑。將 殘餘物再次溶解於Et20 ( 400 mL )中，以1 N NaOH水溶 液、H20及鹽水洗滌，經硫酸鈉脫水且濃縮，得到2.76 g 呈白色固體狀之化合物S10-1 ( 99%)。在無進一步純化的 情況下將此物質直接用於下一步驟中：4 NMR (400 MHz, CDCI3) δ 7.44 (dd, J = 7.8, 7.8 Hz, 2 H), 7.22-7.28 (m, 3 H), 7.13 (s, 1 H), 3.87 (s, 3 H), 2.51 (s, 3 H) ； MS (ESI) m/z 353.0 (M-H)。Synthesis of S10-1 To a solution of compound Sl-5 (2.52 g, 7.87 mmol, leq) in acetonitrile (16 mL) was added NCS (1_10 g, 8.27 mmol, 1.05 e q ). The reaction mixture was heated with a 60 ° C oil bath for 45 hours. Evaporate the solvent. The residue was redissolved in Et20 (400 mL), EtOAc (EtOAc m. This material was used directly in the next step without further purification: 4 NMR (400 MHz, CDCI3) δ 7.44 (dd, J = 7.8, 7.8 Hz, 2 H), 7.22-7.28 (m, 3 H ), 7.13 (s, 1 H), 3.87 (s, 3 H), 2.51 (s, 3 H); MS (ESI) m/z 353.0 (MH).

OBn S10-3 合成S10-3 〇 150 201245116 • 將化合物 S10-1 ( 2.76 g，7.76 mmol，i eq)溶解於無 水二氣甲卜 一、T^(78mL)中且冷卻至-78°C。在-78°C下逐滴添 加一 /臭化蝴溶液（1〇 Μ於二氯甲烷中，7 76 mL，7.76 mm〇1 1 eq)。所得黃色溶液在-78°C下攪拌15分鐘，且在 〇 C下搜掉3 0分鐘。添加NaHC03飽和水溶液。混合物在室 伽下擾摔10分鐘且用EtO Ac萃取三次。經合併之有機層用 鹽水洗膝’經硫酸鈉脫水且濃縮，得到2,6.9 g呈灰白色固 體狀之酶中間物sl〇_2。在無進一步純化的情況下將此物質 直接用於下一步驟中：iHNMR(400 MHz, CDC13) 5 7.46 (dd, J = 7.8, 7.8 Hz, 2 H), 7.32 (dd, J = 7.8, 7.8 Hz, 1 H), 7.27 (s, 1 H)，7.19 (d, /= 7.8 Hz, 2 H)，2.83 (s, 3 H); MS (ESI) m/z 339.0 (M-H) 〇 將上述酚中間物（7.76 mmol，1 eq)溶解於丙酮（40 mL) t ’ 且在室溫下添加 k2c〇3 (2.14 g，15.50 mmol，2 eq) 及、/臭曱苯（0.97 mL，8.15 mmol，1.05 eq)。在室溫下攪拌 隔夜後’經由矽藻土床過濾反應混合物。用三份EtOAc進 一步洗滌矽藻土濾餅。濃縮經合併之濾液。藉由急驟層析 純化殘餘物，得到2.97 g ( 89%，經3個步驟）呈白色固體 狀之化合物 S10-3: iHNMR (400 MHz，CDC13) J 7.33-7.43 (m, 7 Η), 7.19-7.26 (m, 2 Η), 7.05 (d, J= 7.8 Hz, 2 H), 5.11 (s，2 H)，2.51 (s，3 H) ; MS (ESI) m/z 429.0 (M-H)。OBn S10-3 Synthesis S10-3 〇 150 201245116 • Compound S10-1 ( 2.76 g, 7.76 mmol, i eq) was dissolved in water-free two-gas, I(T) (78 mL) and cooled to -78 °C. A solution of scented butterfly (1 〇 in dichloromethane, 7 76 mL, 7.76 mm 〇 1 1 eq) was added dropwise at -78 °C. The resulting yellow solution was stirred at -78 °C for 15 minutes and was taken for 30 minutes at 〇C. A saturated aqueous solution of NaHCO3 was added. The mixture was spoiled for 10 minutes at room temperature and extracted three times with EtOAc. The combined organic layers were washed with brine and dried over sodium sulfate and concentrated to yield 2, 6.9 g of s. This material was used directly in the next step without further purification: iHNMR (400 MHz, CDC 13) 5 7.46 (dd, J = 7.8, 7.8 Hz, 2 H), 7.32 (dd, J = 7.8, 7.8 Hz, 1 H), 7.27 (s, 1 H), 7.19 (d, /= 7.8 Hz, 2 H), 2.83 (s, 3 H); MS (ESI) m/z 339.0 (MH) The intermediate (7.76 mmol, 1 eq) was dissolved in EtOAc (40 mL) &lt;&quot;&&&&&&&&&&&&&&&&&&&&&&&&&&&&& 1.05 eq). After stirring overnight at room temperature, the reaction mixture was filtered through a bed of diatomaceous earth. The diatomaceous earth filter cake was further washed with three portions of EtOAc. The combined filtrate was concentrated. The residue was purified by EtOAc (EtOAc):jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj -7.26 (m, 2 Η), 7.05 (d, J = 7.8 Hz, 2 H), 5.11 (s, 2 H), 2.51 (s, 3 H) ; MS (ESI) m/z 429.0 (MH).

151 201245116 在-78°C下在A氛圍下將《-BuLi於己烷中之溶液（0.29 mL，2.5 Μ，0.72 mmol，1.2 eq)逐滴添加至 i-Pr2NH ( 〇·ι 丄 mL，0.75 mmol，1.25 eq )於 THF ( 4 mL )中之溶液中。反 應溶液在-78°C下攪拌20分鐘，在〇°C下攪拌5分鐘，且再 冷卻至-78 °C。添加 TMEDA( 0.12 mL，0.78 mmol，1.3 eq)， 接著經由套管添加S10-3 ( 285 mg，0.66 mmol，1.1 eq)於 THF ( 4 mL )中之溶液。所得暗紅色混合物在-781下授拌 1小時且冷卻至- l〇〇°C。經由套管逐滴添加烯酮S2-1 ( 289 mg，0.60 mmol，1 eq )於 THF ( 4 mL )中之溶液》使所得 紅色混合物逐漸升溫至-78°C。添加LHMDS ( 0.60 mL，1,〇 M/THF，0.60 mmol，1 eq)。使反應物逐漸升溫至-5°C。添 加NH4C1飽和水溶液。用CHzCh萃取混合物三次。經合併 之CH2Cl2萃取物用鹽水洗滌，經Na2S04脫水，且濃縮。藉 由Biotage急驟層析純化殘餘物，得到呈淺黃色泡泳狀之化 合物 S10-4 ( 3 59 mg ’ 73% ) : NMR (400 MHz, CDC13) 5 15.9 (s, 1 Η), 7.22-7.52 (m, 10 Η), 6.81 (d, J= 8.6 Hz, 1 H ), 5.3 5 (s, 2 H), 5.20 (d, 11.4 Hz, 1 H), 5.15 (ds /= 11.4 Hz, 1 H), 3.93 (d, / = 10.4 Hz, 1 H), 3.42 (dd, J = 4.9, 15.9 Hz, 1 H), 2.96-3.04 (m, 1 H)s 2.45-2.58 (m, 9 H), 2.12 (d, J = 14.6 Hz，1 H)，0.84 (s，9 H)，0.26 (s，3 H)，0.14 (s, 3 H) ; MS (電 噴霧）m/z 819.4 (M + H)。151 201245116 Add a solution of -BuLi in hexane (0.29 mL, 2.5 Μ, 0.72 mmol, 1.2 eq) to i-Pr2NH (〇·ι 丄mL, 0.75) at -78 °C under A atmosphere. Methyl, 1.25 eq) in THF (4 mL). The reaction solution was stirred at -78 ° C for 20 minutes, at ° ° C for 5 minutes, and cooled again to -78 °C. A solution of S10-3 (285 mg, 0.66 mmol, 1.1 eq) in THF (4 mL). The resulting dark red mixture was stirred at -781 for 1 hour and cooled to -10 °C. The resulting red mixture was gradually warmed to -78 °C by dropwise addition of a solution of the ketene S2-1 (289 mg, 0.60 mmol, 1 eq) in THF (4 mL). LHMDS (0.60 mL, 1, 〇M/THF, 0.60 mmol, 1 eq) was added. The reaction was gradually warmed to -5 °C. A saturated aqueous solution of NH4C1 was added. The mixture was extracted three times with CHzCh. The combined CH.sub.2Cl.sub.2 extracts were washed with brine, dried over Na.sub. The residue was purified by flash chromatography eluting with EtOAc (EtOAc): EtOAc (EtOAc: EtOAc: (m, 10 Η), 6.81 (d, J= 8.6 Hz, 1 H ), 5.3 5 (s, 2 H), 5.20 (d, 11.4 Hz, 1 H), 5.15 (ds /= 11.4 Hz, 1 H ), 3.93 (d, / = 10.4 Hz, 1 H), 3.42 (dd, J = 4.9, 15.9 Hz, 1 H), 2.96-3.04 (m, 1 H)s 2.45-2.58 (m, 9 H), 2.12 (d, J = 14.6 Hz, 1 H), 0.84 (s, 9 H), 0.26 (s, 3 H), 0.14 (s, 3 H) ; MS (electrospray) m/z 819.4 (M + H ).

152 201245116 向壓力小瓶中裝入化合物Sl〇_4( 20 mg，0.024 mmol)、 1H-吡唑-5-侧酸（26 mg，0.12 mm〇卜 5 eq)、二氯 雙（二苯基膦基）二茂鐵]鈀（II)二氣曱烷加合物（！ 〇 mg， 0.0012 mmol，〇,〇5 eq)及碳酸鈉（13 mg，〇 12 mm〇1，5 eq) 0 將小瓶短暫地抽空且填充N2。添加甲苯（1 mL ) 、1，4-二 °惡烧（1 mL)及H20 ( 0.2 mL)。反應混合物用80。〇油浴 加熱2小時，冷卻至室溫，以Et〇Ac稀釋，用磷酸鹽緩衝 水溶液（pH = 7 )及鹽水洗滌’經Na2S04脫水，且濃縮。 藉由Biotage急驟層析純化殘餘物，得到呈淺黃色固體狀之 化合物 S10-5-1 ( 7.40 g，31%) : NMR (400 MHz，CDC13) δ 7·62 (s, 1 Η), 7.25-7.52 (m, 11 Η), 6.78 (d, /= 1.8 Hz, 1 Η ), 5.3 6 (s, 2 Η), 5.21 (d, 11.4 Hz, 1 Η), 5.16 (d, J = 11.4152 201245116 The pressure vial was charged with the compound S1〇_4 (20 mg, 0.024 mmol), 1H-pyrazole-5-side acid (26 mg, 0.12 mm 〇 5 eq), dichlorobis(diphenylphosphine) (ferrocene) palladium (II) dioxane adduct (! 〇mg, 0.0012 mmol, 〇, 〇 5 eq) and sodium carbonate (13 mg, 〇 12 mm 〇 1,5 eq) 0 vial Evacuate briefly and fill N2. Toluene (1 mL), 1,4-dioxin (1 mL) and H20 (0.2 mL) were added. The reaction mixture was used for 80. The oil bath was heated for 2 hours, cooled to room temperature, diluted with Et EtOAc, washed with aq. EtOAc (pH = 7) and brine. The residue was purified by EtOAc EtOAc (EtOAc): -7.52 (m, 11 Η), 6.78 (d, /= 1.8 Hz, 1 Η ), 5.3 6 (s, 2 Η), 5.21 (d, 11.4 Hz, 1 Η), 5.16 (d, J = 11.4

Hz, 1 H), 3.99 (d, J = 10.4 Hz, 1 H), 3.51 (dd, J = 4.9, 15.9 Hz, 1 H), 2.98-3.06 (m, 1 H), 2.45-2.58 (m, 9 H), 2.15 (d, J = 14.6 Hz，1 H), 0.84 (s, 9 H)，0.28 (s，3 H)，0.15 (s，3 H) ; MS (電喷霧）m/z 807.4 (M+H) »Hz, 1 H), 3.99 (d, J = 10.4 Hz, 1 H), 3.51 (dd, J = 4.9, 15.9 Hz, 1 H), 2.98-3.06 (m, 1 H), 2.45-2.58 (m, 9 H), 2.15 (d, J = 14.6 Hz, 1 H), 0.84 (s, 9 H), 0.28 (s, 3 H), 0.15 (s, 3 H) ; MS (electrospray) m/z 807.4 (M+H) »

根據與SI0-5-1所用類似之程序製備化合物si0-5-2(黃 色固體）：NMR (400 MHz，CDC13) 5 16.0 (s，1 H)，8.63 (dd, J= 1.8, 4.9 Hz, 1 H), 8.5 6 (d, J= 1.8 Hz, 1 H), 7.69 (ddd, /= 1.8, 1.8, 7.9 Hz, 1 H), 7.26-7.52 (m, 11 H), 6.88 (s, 1 H ), 5.3 6 (s, 2 H), 5.24 (d, 11.4 Hz, 1 H), 5.1 8 (d, J = 11.4 Hz, 153 201245116 1 H)，3.97 (d，J = 10.4 Hz，1 Η), 3·4 8 (dd，/= 4.9, 15·9 Hz，\ H), 3.01-3.10 (m, 1 H), 2.45-2.60 (m, 9 H), 2.15 (d, j = l4 6 Hz, 1 H)，0.84 (s，9 H)，0_29 (s，3 H)，0.15 (s，3 H) ; Ms (電 喷霧）m/z 818.4 (M+H)。Compound si0-5-2 (yellow solid) was prepared according to a procedure similar to that used for SI0-5-1: NMR (400 MHz, CDC13) 5 16.0 (s, 1 H), 8.63 (dd, J = 1.8, 4.9 Hz, 1 H), 8.5 6 (d, J = 1.8 Hz, 1 H), 7.69 (ddd, /= 1.8, 1.8, 7.9 Hz, 1 H), 7.26-7.52 (m, 11 H), 6.88 (s, 1 H ), 5.3 6 (s, 2 H), 5.24 (d, 11.4 Hz, 1 H), 5.1 8 (d, J = 11.4 Hz, 153 201245116 1 H), 3.97 (d, J = 10.4 Hz, 1 Η ), 3·4 8 (dd, /= 4.9, 15·9 Hz, \ H), 3.01-3.10 (m, 1 H), 2.45-2.60 (m, 9 H), 2.15 (d, j = l4 6 Hz, 1 H), 0.84 (s, 9 H), 0_29 (s, 3 H), 0.15 (s, 3 H); Ms (electrospray) m/z 818.4 (M+H).

OBn O HO = O 0TBS 合成 S10-5-3。 s1〇-5-3 根據與S10-5-l所用類似之程序製備化合物Sl〇_5_3(黃 色固體）：NMR (400 MHz，CDC13)占 1 6.〇 (s，1 H)，8 68 (d, J = 6.1 Hz, 2 H), 7.26-7.52 (m, 12 H), 6.85 (s5 1 H ), 5 36 (s, 2 H), 5.23 (d, / = 1 1.4 Hz, 1 H), 5.1 8 (d, / = H.4 Hz, 1 H) 3.97 (d，= l〇_4 Hz，1 H)，3_48 (dd，J = 4.9, 15.9 Hz，l 3.01-3.10 (m，1 H)，2.45-2.60 (m, 9 H)，2.16 (d，7= 14 6 出 1 H)’ 0.84 (s，9 H)，0.28 (s，3 H)，0.16 (s，3 H) ; MS (電噴霧; w/z 8 1 8.5 (M+H)。OBn O HO = O 0TBS Synthesis S10-5-3. S1〇-5-3 The compound S1〇_5_3 (yellow solid) was prepared according to a procedure similar to that used for S10-5-1: NMR (400 MHz, CDC13) occupies 1. 6. 〇 (s, 1 H), 8 68 ( d, J = 6.1 Hz, 2 H), 7.26-7.52 (m, 12 H), 6.85 (s5 1 H ), 5 36 (s, 2 H), 5.23 (d, / = 1 1.4 Hz, 1 H) , 5.1 8 (d, / = H.4 Hz, 1 H) 3.97 (d, = l〇_4 Hz, 1 H), 3_48 (dd, J = 4.9, 15.9 Hz, l 3.01-3.10 (m, 1 H), 2.45-2.60 (m, 9 H), 2.16 (d, 7 = 14 6 out 1 H)' 0.84 (s, 9 H), 0.28 (s, 3 H), 0.16 (s, 3 H); MS (electrospray; w/z 8 1 8.5 (M+H).

在聚丙烯小瓶中，將化合物 mmol)溶解於 ch3CN( 1.25 mL) ^ 0.25 mL)。在室溫下攪拌i6小 k2hpo4水溶液（1.75§於丨 S10-5-1 ( 22 mg，0.027In a polypropylene vial, the compound mmol) was dissolved in ch3CN (1.25 mL) ^ 0.25 mL). Stir i6 small k2hpo4 aqueous solution at room temperature (1.75 § 丨 S10-5-1 (22 mg, 0.027)

mL )中。添加HF水溶液（48%， 16小時·德，將反應盈会&gt; X 水，且減壓濃縮。 .皿r償件16小時後，將反應混合物傾入 1.75 g於12 j mL水中）中。用CH2C12萃In mL). An aqueous solution of HF (48%, 16 hrs, </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Extracted with CH2C12

以鹽水洗滌，經硫酸鈉脫 將上述殘餘物溶解於Washed with brine and dehydrated with sodium sulfate to dissolve the above residue

Et〇 Ac ( 3 mL )中。添力σ Pd-C( 10 154 201245116 .wt%，丨〇 mg)。短暫地抽空反應燒瓶且再填充氫氣。在室 溫下在1 atm氫氣下攪拌反應混合物直至如藉由LC MS分 析監/則到反應完成。移除氫源。添加甲醇（5 mL )及HC1/ 甲醇（0.5 mL，0.5 N)。攪拌混合物3〇分鐘且經由小型矽 藻土墊過濾。濃縮濾液，得到粗產物，藉由HPLC在Waters 自動純化系統上使用Phenomenex Polymerx 1〇 &quot; rp_ γ 100 R 管柱[3 0x21.20 mm，10 微米；流速：20 mL/min ;溶 劑 A : 〇·〇5 N HC1/水；溶劑 B : CH3OH ;注入體積：4.0 mL (0.05 N HC1/水）；梯度：1 〇-» 1 〇〇% b，經 20 分鐘；質量 導向型洗提份收集]將其純化。收集在19 2〇_2〇 2〇分鐘洗提 之具有所需分子量之洗提份且冷洗乾燥，得到呈黃色固體 狀之 S10-6-1 ( 0.62 mg ’ 鹽酸鹽，總共 5% ) : ^ NMR (400 MHz, CD3OD) δ 7.80 (d, J = 2.3 Hz, 1H), 7.17 (s, 1H), 6.82 (d, J = 2.3 Hz, 1H), 4.10 (s, 1H), 3.45 (m, 1H), 2.92-3.15 (m，8H)，2.41 (dd，= 15_〇，15 〇 Hz, 1H)， 2.22-2.25 (m，1H)，1.60-1.70 (m，1 h) ; MS (電喷霧）w/zEt〇 Ac (3 mL). Add force σ Pd-C (10 154 201245116 .wt%, 丨〇 mg). The reaction flask was briefly evacuated and refilled with hydrogen. The reaction mixture was stirred at room temperature under 1 atm of hydrogen until the reaction was completed by LC MS analysis. Remove the hydrogen source. Methanol (5 mL) and HC1/methanol (0.5 mL, 0.5 N) were added. The mixture was stirred for 3 minutes and filtered through a small diatomaceous earth pad. The filtrate was concentrated to give a crude material using &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&&&&&& ·〇5 N HC1/water; solvent B: CH3OH; injection volume: 4.0 mL (0.05 N HC1/water); gradient: 1 〇-» 1 〇〇% b over 20 minutes; mass-oriented elution fraction collection] It was purified. The extract having the desired molecular weight was eluted at 19 2 〇 2 〇 2 且 minutes and dried by cold washing to give S10-6-1 (0.62 mg 'hydrochloride, 5% total) as a yellow solid. : ^ NMR (400 MHz, CD3OD) δ 7.80 (d, J = 2.3 Hz, 1H), 7.17 (s, 1H), 6.82 (d, J = 2.3 Hz, 1H), 4.10 (s, 1H), 3.45 ( m, 1H), 2.92-3.15 (m,8H), 2.41 (dd,= 15_〇,15 〇Hz, 1H), 2.22-2.25 (m,1H),1.60-1.70 (m,1 h) ; MS (electrospray) w/z

根據與S10-6-1所用類似之程序自sl〇_5_2製備化合物 S10-6-2： ΉνΜΚ(400 ΜΗζ,〇0300) ^ 9.08 (s, 1H), 8.86Compound S10-6-2 was prepared from sl〇_5_2 according to a procedure similar to that used in S10-6-1: ΉνΜΚ(400 ΜΗζ, 〇0300) ^ 9.08 (s, 1H), 8.86

Hz, 1H), 7.11 (s, 1H), 4.12 (s, 1H), 3.45 (m, 1H), 2.92-3.15 (m，8H)，2.47 (dd，J = 15.0，15·〇 Hz，1H)，2.25-2.28 (m，1H)， 155 201245116 1.60-1.70 (m，1H)，MS (電噴霧.）m/z 526.3 (M + H)。Hz, 1H), 7.11 (s, 1H), 4.12 (s, 1H), 3.45 (m, 1H), 2.92-3.15 (m, 8H), 2.47 (dd, J = 15.0, 15·〇Hz, 1H) , 2.25-2.28 (m, 1H), 155 201245116 1.60-1.70 (m, 1H), MS (electrospray.) m/z 526.3 (M + H).

根據與S10-6-1所用類似之程序自si〇_5_3製備化合物 S10-6-3 ： *H NMR (400 MHz, CD3OD) δ 8.97 (d, J = 6.4 Hz, 2H), 8.22 (d, J = 6.4 Hz, 2H), 7.09 (s, 1H), 4.12 (s, 1H), 3.45 (dd, J = 4.6, 16.0 Hz, 1H), 2.97-3.21 (m, 8H), 2.47 (dd, J = 15.0, 15.0 Hz, 1H), 2.24-2.30 (m, 1H), 1.63-1.73 (m, 1H)； MS (電喷霧）m/z 526.3 (M+H)。 實施例11.合成其中X為C丨且環E為l-取代之吡咯啶 -2-基的式I化合物。 根據流程11製備式I化合物，其中環E為1 -取代之吡 洛b定-2 -基，X為-C1，且Y為-H。 流程11Compound S10-6-3 was prepared from si〇_5_3 according to a procedure similar to that used for S10-6-1: *H NMR (400 MHz, CD3OD) δ 8.97 (d, J = 6.4 Hz, 2H), 8.22 (d, J = 6.4 Hz, 2H), 7.09 (s, 1H), 4.12 (s, 1H), 3.45 (dd, J = 4.6, 16.0 Hz, 1H), 2.97-3.21 (m, 8H), 2.47 (dd, J = 15.0, 15.0 Hz, 1H), 2.24-2.30 (m, 1H), 1.63-1.73 (m, 1H); MS (electrospray) m/z 526.3 (M+H). Example 11. Synthesis of a compound of formula I wherein X is C丨 and ring E is 1-substituted pyrrolidin-2-yl. A compound of formula I is prepared according to Scheme 11, wherein ring E is a 1-substituted pyridene b-yl group, X is -C1, and Y is -H. Process 11

156 201245116 ^C02Ph156 201245116 ^C02Ph

OH 合成 SI 1- 1。 S11-1 在-78°C 下向 Sl-5 (3.06 g’ 9·53 mmol，1 eq)於二氯 曱烧（19 mL)中之溶液中逐滴添加BBr3 ( 9.53 mL，1 ·〇 M/CH2C12，9.5 3 mmol，1 eq)。反應混合物在 _78。〇下攪拌 1 5分鐘且在〇°C下攪拌30分鐘。添加NaHC03飽和水溶液。 混合物在室溫下攪拌1 0分鐘且以Et〇Ac萃取（2次）。將 有機萃取物合併’用鹽水洗滌，經硫酸鈉脫水，且減壓濃 縮’得到呈白色固體狀之所需產物S1 id，在無進一步純化 的情況下將其用於下一反應中：4 NMR (400 MHz，CDC13) δ H.13 (s, 1 H), 7.42-7.48 (m, 2 H), 7.29-7.33 (m, 1 H), 7.15-7.20 (m, 2 H), 7.08 (s, 1 H), 6.97 (s, 1 H), 2.66 (s, 3H) ; MS (電喷霧）m/z 305.0 (M-H)。 ^0〇2Ph a · 〇Bn 合成SIi-2。 如.2 向 SI 1-1 ( 9.53 mmol ’ 1 eq)於丙酮（19 mL)中之溶 液中添加 K2C03( 2.63 g，15.00 mmo卜 1.5 eq)及 BnBr( 1 19 mL，10.00 mmol，eq)。混合物在室溫下攪拌隔夜且 經由矽藻土墊過濾。用EtOAc洗滌矽藻土墊。減壓濃縮經 合併之濾液。利用0%-5% EtOAc/己烷進行矽膠急驟層析， 得到呈白色固體狀之所需產物S11-2 ( 3.61 g，96%，經2 個步驟）：NMR (400 MHz，CDC13) δ 7.20-7.45 (m, 8 Η) 7.03-7.09 (m，4 Η)，5.13 (s，2 Η)，2.43 (s，3 Η) ·’ MS (電喷霧） m/z 419.1 (M + Na)。 157 201245116OH synthesis SI 1- 1. S11-1 Add BBr3 ( 9.53 mL, 1 · 〇M) to a solution of Sl-5 (3.06 g' 9·53 mmol, 1 eq) in dichlorohydrazine (19 mL) at -78 °C. /CH2C12, 9.5 3 mmol, 1 eq). The reaction mixture was at _78. Stir under the agglutination for 15 minutes and stir at 〇 ° C for 30 minutes. A saturated aqueous solution of NaHCO3 was added. The mixture was stirred at room temperature for 10 min and extracted with EtOAc (2×). The organic extracts were combined with EtOAc (EtOAc) (EtOAc m. (400 MHz, CDC13) δ H.13 (s, 1 H), 7.42-7.48 (m, 2 H), 7.29-7.33 (m, 1 H), 7.15-7.20 (m, 2 H), 7.08 (s , 1 H), 6.97 (s, 1 H), 2.66 (s, 3H); MS (electrospray) m/z 305.0 (MH). ^0〇2Ph a · 〇Bn Synthesize SIi-2. To a solution of SI 1-1 (9.53 mmol' 1 eq) in acetone (19 mL) was added K2C03 ( 2.63 g, 15.00 mmol, 1.5 eq) and BnBr (1 19 mL, 10.00 mmol, eq). The mixture was stirred overnight at room temperature and filtered through a pad of Celite. The diatomaceous earth pad was washed with EtOAc. The combined filtrate was concentrated under reduced pressure. Flash chromatography on silica gel eluting with EtOAc / EtOAc (EtOAc:EtOAc) -7.45 (m, 8 Η) 7.03-7.09 (m,4 Η), 5.13 (s,2 Η), 2.43 (s,3 Η) ·' MS (electrospray) m/z 419.1 (M + Na) . 157 201245116

合成 S11 -3 〇 S11-3 向壓力小航中裝入化合物Sll-2( 852 mg，2.14 mmol， 1 eq)、N-Boc-2-吡咯硼酸（543 mg，2.57 mmol，1.2 eq)、 二氯Π，1'-雙（二笨基膦基）二茂鐵]鈀（II)二氯曱烷加合物（88 mg ’ 0.11 mm〇卜 〇.〇5 eq)及碳酸鈉（1.14 g，10.7 mmo卜 5 eq )。短暫地抽空小瓶且填充&amp;。添加甲苯（5 mL )、 1，4-二噁烷（5 mL)及H20 ( 1 mL)。反應混合物用9(TC 油浴加熱2小時，冷卻至室溫，以EtOAc稀釋，用磷酸鹽 緩衝水溶液（pH = 7 )及鹽水洗滌，經Na2S04脫水，且濃 縮°藉由Biotage急驟層析純化殘餘物，得到呈無色油狀之 化合物 S11-3 ( 62 1 mg，60% ) ： lH NMR (400 MHz, CDC13) δ 7·22-7.48 (m, 9 H), 7.12 (d, J = 7.8 Hz, 2 H ), 6.89 (d, J = 7.8 Hz, 2 H ), 6.20-6.26 (m, 2 H), 5.15 (s, 2 H), 2.48 (s, 3 H), 1·41 (s，9 H) ; MS (電喷霧）m/z 484.4 (M+H)。Synthesis of S11 -3 〇S11-3 The compound Sll-2 (852 mg, 2.14 mmol, 1 eq), N-Boc-2-pyrroleboronic acid (543 mg, 2.57 mmol, 1.2 eq), Chloroquinone, 1'-bis(diphenylphosphino)ferrocene]palladium(II) dichlorodecane adduct (88 mg '0.11 mm 〇 〇. 〇 5 eq) and sodium carbonate (1.14 g, 10.7 mmo b 5 eq ). Evacuate the vial briefly and fill &amp; Add toluene (5 mL), 1,4-dioxane (5 mL) and H20 (1 mL). The reaction mixture was heated with EtOAc (EtOAc EtOAc (EtOAc)EtOAc. The compound S11-3 (62 1 mg, 60%) was obtained as a colorless oil: lH NMR (400 MHz, CDC13) δ 7·22-7.48 (m, 9 H), 7.12 (d, J = 7.8 Hz , 2 H ), 6.89 (d, J = 7.8 Hz, 2 H ), 6.20-6.26 (m, 2 H), 5.15 (s, 2 H), 2.48 (s, 3 H), 1·41 (s, 9 H) ; MS (electrospray) m/z 484.4 (M+H).

合成SI 1-4 〇 S11-4 將化合物SI 1-3 ( 621 mg，1.28 mmol » 1 eq ) 溶解於曱 醇中。添加Pd-C ( 10% w/w，186 mg)。短暫地抽空反應 燒瓶且再填充氫氣。在室溫下在1 atm H2下攪拌反應混合 物2小時且經由矽藻土墊過濾。用曱醇洗滌矽藻土墊。濃 、缩據液’得到呈白色泡沫狀之中間物。 將上述中間物溶解於丙酮（12 mL)中。添加K2C03( 350 mg ’ 2.54 mmol，2 eq)及 BnBr ( 0.16 mL，1.33 mmo卜 1.04 158 201245116 eq )。在室溫下攪拌隔夜後，經由矽藻土塾過濾反應混合物。 用二份EtOAc洗滌矽藻土墊。濃縮經合併之濾液。藉由 Biotage急驟層析純化殘餘物，得到呈無色油狀之化合物 S11-4 ( 504 mg，81%) : 1h NMR (400 MHz，CDC13，旋轉 異構體）d 7.22-7.48 (m, δ Η), 7.05-7.15 (m, 2 Η), 6.63-6.70 (m，2 Η )，5.13 (s，2 Η)，4.90 及 4.76 (br s，1 Η)， 3.50-3.65 (m, 2 Η), 2.43 (s, 3 Η), 2.25-2.28 (m, 1 Η), 1.72-1.90 (m，3 Η)，1.48 (s，3 Η), 1.26 (s，6 Η) ; MS (電喷霧） m/z 488.4 (Μ+Η)。Synthesis of SI 1-4 〇 S11-4 Compound SI 1-3 (621 mg, 1.28 mmol » 1 eq ) was dissolved in decyl alcohol. Add Pd-C (10% w/w, 186 mg). The reaction flask was briefly evacuated and refilled with hydrogen. The reaction mixture was stirred at 1 atm H2 for 2 h at room temperature and filtered thru a pad. The diatomaceous earth pad was washed with decyl alcohol. The thick, reduced liquid was obtained as an intermediate in the form of a white foam. The above intermediate was dissolved in acetone (12 mL). K2C03 (350 mg '2.54 mmol, 2 eq) and BnBr (0.16 mL, 1.33 mmobu 1.04 158 201245116 eq) were added. After stirring overnight at room temperature, the reaction mixture was filtered through EtOAc. The diatomaceous earth pad was washed with two portions of EtOAc. The combined filtrate was concentrated. Purification of the residue by EtOAc (EtOAc) EtOAc (EtOAc) ), 7.05-7.15 (m, 2 Η), 6.63-6.70 (m, 2 Η ), 5.13 (s, 2 Η), 4.90 and 4.76 (br s, 1 Η), 3.50-3.65 (m, 2 Η) , 2.43 (s, 3 Η), 2.25-2.28 (m, 1 Η), 1.72-1.90 (m, 3 Η), 1.48 (s, 3 Η), 1.26 (s, 6 Η); MS (electrospray ) m/z 488.4 (Μ+Η).

OBn S11+a 合成 Sll-4-a 向化合物 Sll-4 (556 mg，1·14 mmol，1 eq)於 5 mL CH3CN中之溶液中整份添加NCS( 160 mg，1.20 mmo卜1.05 eq )。反應混合物用60°C油浴加熱1 8小時，冷卻至室溫， 且蒸發至乾燥。將殘餘物懸浮於200 mL CH2C12中，用NaOH 水溶液（1 N )、H20及鹽水洗滌，經Na2S04脫水，且濃縮。 藉由Biotage急驟層析純化殘餘物，得到呈白色固體狀之化 合物 Sll-4-a ( 447 mg，75%) : 士 NMR (400 MHz，CDC13, 旋轉異構體之混合物）5 7.22-7.48 (m, 8 Η), 7.05-7.15 (m, 2 Η), 6.63-6.70 (m, 1 Η ), 5.06-5.26 (m, 3 Η), 3.47-3.58 (m, 2 Η), 2.46 (s, 3 Η), 2.25-2.28 (m, 1 Η), 1.55- 1.88 (m, 3 Η), 1.48 (s，3 Η)，1.26 (s，6 Η) ; MS (電喷霧）m/z 522.4 (Μ+Η)。OBn S11+a Synthesis Sll-4-a To a solution of compound Sll-4 (556 mg, 1.14 mmol, 1 eq) in 5 mL CH3CN was added NCS (160 mg, 1.20 mmo, 1.05 eq). The reaction mixture was heated with a 60 ° C oil bath for 18 h, cooled to room temperature and evaporated to dry. The residue was suspended in 200 mL of CH.sub.2 C.sub.2. The residue was purified by EtOAc EtOAc (EtOAc) m, 8 Η), 7.05-7.15 (m, 2 Η), 6.63-6.70 (m, 1 Η ), 5.06-5.26 (m, 3 Η), 3.47-3.58 (m, 2 Η), 2.46 (s, 3 Η), 2.25-2.28 (m, 1 Η), 1.55- 1.88 (m, 3 Η), 1.48 (s, 3 Η), 1.26 (s, 6 Η); MS (electrospray) m/z 522.4 (Μ+Η).

OBn S11^ 合成S11-5。 159 201245116 將化合物 Sll-4-a( 447 mg，0·86 mmol )懸浮於 HC1/1，4-二噁烷（4.0 Μ，9 mL )中。在室溫下擾拌1小時後，蒸發 揮發物。將殘餘物懸浮於EtOAc中，用NaHC03飽和水溶 液及鹽水洗滌，經NaJO4脫水，且濃縮。藉由Biotage.急 驟層析純化殘餘物，得到呈灰白色固體狀之化合物s 11 -5 (338 mg &gt; 93%) ： NMR (400 MHz, CDC13) δ 7.48 (dd, J = 1.8, 7.8 Hz, 2 H), 7.34-7.42 (m, 6 H), 7.26 (t, J = 7.8 Hz, 1 H), 7.14 (d, J = 7.8 Hz, 2 H ), 5.20 (s, 2 H), 4.57 (t, J = 7.4 Hz, 1 H)} 3.04-3.18 (m, 2 H), 2.52 (s, 3 H), 2.34-2.45 (m, 1 H), 2.06 (br s, 1 H), 1.78- 1.85 (m, 2 H), 1.44-1.54 (m, 1 H)； MS (電喷霧）m/z 422.4 (M+H)。OBn S11^ Synthesizes S11-5. 159 201245116 Compound Sll-4-a (447 mg, 0·86 mmol) was suspended in EtOAc / EtOAc (EtOAc) After stirring for 1 hour at room temperature, the volatiles were evaporated. The residue was suspended in EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 2 H), 7.34-7.42 (m, 6 H), 7.26 (t, J = 7.8 Hz, 1 H), 7.14 (d, J = 7.8 Hz, 2 H ), 5.20 (s, 2 H), 4.57 ( t, J = 7.4 Hz, 1 H)} 3.04-3.18 (m, 2 H), 2.52 (s, 3 H), 2.34-2.45 (m, 1 H), 2.06 (br s, 1 H), 1.78- 1.85 (m, 2 H), 1.44-1.54 (m, 1 H); MS (electrospray) m/z 422.4 (M+H).

在-78°C下在N2氛圍下將n_BuLi於己烷中之溶液（2.5 Μ，0·53 mL，0·63 mmo卜 2_3 eq)逐滴添加至 i_Pr2NH ( 〇 2〇 mL ’ 1.38 mmo卜 2·4 eq)於 THF ( 4 mL)中之溶液中。反 應溶液在-78°C下擾拌20分鐘且在下攪拌5分鐘，且再 冷卻至-78t：。添加 TMEDA(〇.22mL，l，50mm〇l，2.6eq)， 接著經由套管添加Sll-S( 267 mg，0_63mm〇1，hleq)於 THF ( 4 mL )中之溶液。所得暗橙色混合物在_78。〇下攪拌 1小時且冷卻至-1〇〇。(^經由套管逐滴添加烯酮sn ( 277 mg，0.58 mmol，1 eq)於 THF (4mL)中之溶液。使所得 混合物逐漸升溫至_78°C。添加LHMDS ( 0.60 mL，1〇 160 201245116 M/THF &gt; 0.60 mmol * 1.05 eq )。使反應混合物逐漸升溫至 -5°C。添加NH4C1飽和水溶液。用EtOAc萃取混合物三次。 經合併之EtOAc萃取物用鹽水洗滌，經Na2S04脫水，且濃 縮。藉由Biotage急驟層析純化殘餘物，得到呈淺黃色泡沫 狀之化合物 Sll-6( 214 mg，46%):丨H NMR (400 MHz, CDC13) 5 7.26-7.5 0 (m, 1 1 H), 5.3 5 (s, 2 H), 5.25 (d, J = 11.4 Hz, 1 H), 5.23 (ds J = 11.4 Hz, 1 H), 4.51 (t, J = 6.9 Hz, 1 H), 3.97 (d, J = 10.4 Hz, 1 H), 3.43 (dd, J = 4.9, 15.9 Hz, 1 H), 2.91-3.09 (m, 3 H), 2.28-2.56 (m, 10 H), 2.12 (d, J = 14.6 Hz, 1 H), 1.54-1.80 (m, 3 H), 1.34-1.48 (m, 2 H), 0.83 (s, 9 H), 0.26 (s，3 H)，0.14 (s，3 H) ; MS (電喷霧）m/z 810.4 (M+H)。A solution of n_BuLi in hexane (2.5 Μ, 0·53 mL, 0·63 mmo b 2_3 eq) was added dropwise to the i_Pr2NH (〇2〇mL ' 1.38 mmob 2 at -78 ° C under N 2 atmosphere. • 4 eq) in THF (4 mL). The reaction solution was scrambled at -78 °C for 20 minutes and stirred for 5 minutes, and cooled again to -78t:. TMEDA (〇.22 mL, 1 , 50 mm ,1, 2.6 eq) was added, followed by a solution of Sll-S ( 267 mg, 0-63 mm 〇1, hleq) in THF (4 mL). The resulting dark orange mixture was at -78. Stir under the arm for 1 hour and cool to -1 Torr. (^ A solution of the ketene sn (277 mg, 0.58 mmol, 1 eq) in THF (4 mL) was added dropwise via a cannula. The mixture was gradually warmed to -78 ° C. LHMDS (0.60 mL, 1 〇 160) </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; Concentration. Purification of the residue by EtOAc EtOAc EtOAc (EtOAc) H), 5.3 5 (s, 2 H), 5.25 (d, J = 11.4 Hz, 1 H), 5.23 (ds J = 11.4 Hz, 1 H), 4.51 (t, J = 6.9 Hz, 1 H), 3.97 (d, J = 10.4 Hz, 1 H), 3.43 (dd, J = 4.9, 15.9 Hz, 1 H), 2.91-3.09 (m, 3 H), 2.28-2.56 (m, 10 H), 2.12 ( d, J = 14.6 Hz, 1 H), 1.54-1.80 (m, 3 H), 1.34-1.48 (m, 2 H), 0.83 (s, 9 H), 0.26 (s, 3 H), 0.14 (s , 3 H) ; MS (electrospray) m/z 810.4 (M+H).

合成化合物S11-8-1。 將化合物 Sll-6 (34 mg，0.042 mmol，1 eq)溶解於 1，2-二氯乙烷（丨mL)中。添加環丙烷羧醛（9.5 #[,0.13 mmol ’ 3 eq )及乙酸（7.2 // L » 0.13 mmol * 3 eq )。在室 溫下撥拌4小時後，添加三乙醯氧基硼氫化鈉（18 mg，0.084 mm()1 ’ 2叫）。繼續攪拌隔夜。將反應混合物傾入NaHC03 飽和水溶液中。用CH2C12萃取混合物三次。經合併之有機 萃取物用鹽水洗滌，經Na2S〇4脫水且濃縮，得到粗物質 S11-7-1，在無進一步純化的情況下將其直接用於下一步驟。 g 在聚丙稀小瓶中’將粗物質S11-7-1溶解於CH3CN( 1.25 mL)中。添加hf水溶液（48%，0·25 mL)。在室溫下授 拌16小時後，將反應混合物傾入K2HP〇4水溶液（175 161 201245116 於12.5 mL水中）中。用cH/丨2萃取混合物三次。經合併 之有機相用鹽水洗滌，經硫酸鈉脫水，且濃縮至乾燥。 將上述殘餘物溶解於Et〇Ac( 4 )中且添加pd_c( 10 14 mg)。短暫地抽空反應燒瓶且再填充氣氣。在丄咖 氫氣下攪拌反應混合物直至如藉由LC_MS分析監測到反應 兀成。移除氫源。添加甲醇（5 mL)及HC1/甲醇（〇 5 ‘， 〇.5 N)。混合物在室溫下攪拌3〇分鐘且經由小型矽藻土墊 過渡。濃縮遽液’得到粗產物，藉由HpLC在偏…自動 .、·屯化系統上使用 Phenomenex P〇lymerx 1 〇 &quot; Rp_ γ ι〇〇 R 管柱[30x21.20 _，10 微米；流速：2〇 mL/min ;溶劑 Α : 0.05 N HC1/水；溶劑 B : CH3〇H ;注入體積：4 〇 ‘（ 〇 〇5 N HC1/水），梯度：〇— 1〇〇% B，經2〇分鐘；質量導向型 洗提份收集]將其純化。收集在1 3 33_15 1〇分鐘洗提之具有 所需分子量之洗提份且冷凍乾燥，得到呈黃色固體狀之化 合物Sll-8-l( 8.8 mg’鹽酸鹽，33%，經3個步驟）：1hnmr (400 MHz, CD3OD) δ 7.28 (s, 1 Η), 5.06-5.10 (m, 1 Η), 4.12 (s, 1 Η), 3.99-4.05 (m, 1 Η)? 3.38-3.50 (m, 2 Η), 2.96-3.13 (m, 10 Η), 2.64-2.71 (ms 1 H), 2.23-2.44 (m, 4 H), 2.06-2.11 (m 1 H)，1.60-1.69 (m，i H), 101·108 (m，i H)， 0.64-0.66 (m，2 H)，0.27-0.39 (m，2 H); MS (電喷霧）滅 572.5 (M+H)。 根據與SI 1-8-1所用類似之程序自S11_6及各種醛製備 以下化合物。 162 201245116Compound S11-8-1 was synthesized. Compound Sll-6 (34 mg, 0.042 mmol, 1 eq) was dissolved in 1,2-dichloroethane (丨mL). Cyclopropanecarboxaldehyde (9.5 #[, 0.13 mmol' 3 eq) and acetic acid (7.2 // L » 0.13 mmol * 3 eq) were added. After stirring for 4 hours at room temperature, sodium triethoxysulfonate (18 mg, 0.084 mm (1 Å) was added). Continue to stir overnight. The reaction mixture was poured into a saturated aqueous solution of NaHCO. The mixture was extracted three times with CH2C12. The combined organic extracts were washed with EtOAc EtOAc m. g The crude material S11-7-1 was dissolved in CH3CN (1.25 mL) in a polypropylene vial. An aqueous solution of hf (48%, 0. 25 mL) was added. After 16 hours of incubation at room temperature, the reaction mixture was poured into an aqueous K2HP 4 solution (175 161 201245116 in 12.5 mL water). The mixture was extracted three times with cH/丨2. The combined organic phases were washed with brine, dried over sodium sulfate dried The above residue was dissolved in Et EtOAc (4) and pd_c (10 14 mg) was added. The reaction flask was briefly evacuated and refilled with air. The reaction mixture was stirred under a hydrogen atmosphere until the reaction was monitored by LC-MS analysis. Remove the hydrogen source. Methanol (5 mL) and HC1/methanol (〇 5 ‘, 〇.5 N) were added. The mixture was stirred at room temperature for 3 minutes and transitioned through a small diatomaceous earth pad. Concentrated sputum 'to obtain a crude product, using Phenomenex P〇lymerx 1 〇&quot; Rp_ γ ι〇〇R column by HpLC on the automatic ..., 屯 system [30x21.20 _, 10 microns; flow rate: 2〇mL/min; solvent Α: 0.05 N HC1/water; solvent B: CH3〇H; injection volume: 4 〇'(〇〇5 N HC1/water), gradient: 〇-1〇〇% B, by 2 〇min; mass-oriented extract fraction collection] was purified. The extract having the desired molecular weight was eluted at 1 3 33_15 for 1 minute and lyophilized to give the compound Sll-8-1 (8.8 mg' hydrochloride, 33% in 3 steps. ): 1hnmr (400 MHz, CD3OD) δ 7.28 (s, 1 Η), 5.06-5.10 (m, 1 Η), 4.12 (s, 1 Η), 3.99-4.05 (m, 1 Η)? 3.38-3.50 ( m, 2 Η), 2.96-3.13 (m, 10 Η), 2.64-2.71 (ms 1 H), 2.23-2.44 (m, 4 H), 2.06-2.11 (m 1 H), 1.60-1.69 (m, i H), 101·108 (m, i H), 0.64-0.66 (m, 2 H), 0.27-0.39 (m, 2 H); MS (electrospray), 572.5 (M+H). The following compounds were prepared from S11_6 and various aldehydes according to procedures similar to those used for SI 1-8-1. 162 201245116

Sll-8_2(黃色固體）^HNMRHOOMI^CDsOD) (5 7.28 (s, 1 Η), 5.01-5.07 (m, 1 Η), 4.14 (s, 1 Η), 3.97-4.04 (m, 1 Η), 3.38-3.46 (m, 2 Η), 2.91-3.13 (m, 11 Η), 2.62-2.68 (m, 1 Η), 2.10-2.47 (m, 5 H)，1.61-1.71 (m, 1 Η) ; MS (電喷霧） m/z 532.4 (M+H)。Sll-8_2 (yellow solid)^HNMRHOOMI^CDsOD) (5 7.28 (s, 1 Η), 5.01-5.07 (m, 1 Η), 4.14 (s, 1 Η), 3.97-4.04 (m, 1 Η), 3.38-3.46 (m, 2 Η), 2.91-3.13 (m, 11 Η), 2.62-2.68 (m, 1 Η), 2.10-2.47 (m, 5 H), 1.61-1.71 (m, 1 Η); MS (electrospray) m/z 532.4 (M+H).

Sll-8-3 (黃色固體）：NMR (400 MHz，CD3OD) 5 7.33 (s，1 H)，5.06-5.11 (m，1 H)，4.13 (s，1 H)，3.97-4.04 (m， 1 H), 3.38-3.46 (m, 2 H), 2.91-3.13 (m, 10 H), 2.62-2.68 (m, 1 H), 2.00-2.47 (m, 6 H), 1.61-1.71 (m, 1 H), 1.02 (d, J= 6.4Sll-8-3 (yellow solid): NMR (400 MHz, CD3OD) 5 7.33 (s, 1 H), 5.06-5.11 (m, 1 H), 4.13 (s, 1 H), 3.97-4.04 (m, 1 H), 3.38-3.46 (m, 2 H), 2.91-3.13 (m, 10 H), 2.62-2.68 (m, 1 H), 2.00-2.47 (m, 6 H), 1.61-1.71 (m, 1 H), 1.02 (d, J= 6.4

Hz, 3 H)，0.94 (d’= 6.4 Hz，3 H) ; MS (電喷霧）m/z 574.5 (M+H) 〇Hz, 3 H), 0.94 (d' = 6.4 Hz, 3 H) ; MS (electrospray) m/z 574.5 (M+H) 〇

S11-8·4 (黃色固體）：lH NMR (400 MHz，CD3OD) 5 7.30 (s，1 H)，5.06-5.10 (m，丄 H)，4 13 (s，！ H)，3 9〇_3 94 (m， 1 H), 3.35-3.46 (m, 2 H), 2.97-3.21 (m, 10 H), 2.64-2.69 (m, 1 H), 2.11-2.46 (m, 5 H), 1.56-1.70 (m, 4 H), 0.90 (d, J= 6.4 Hz，3 H)’ 0.88 (d，j = 6 4 Hz，3 H) ; MS (電喷霧）w/z 588 5 (M+H)。 163 201245116S11-8·4 (yellow solid): lH NMR (400 MHz, CD3OD) 5 7.30 (s, 1 H), 5.06-5.10 (m, 丄H), 4 13 (s,! H), 3 9〇_ 3 94 (m, 1 H), 3.35-3.46 (m, 2 H), 2.97-3.21 (m, 10 H), 2.64-2.69 (m, 1 H), 2.11-2.46 (m, 5 H), 1.56 -1.70 (m, 4 H), 0.90 (d, J = 6.4 Hz, 3 H)' 0.88 (d,j = 6 4 Hz, 3 H) ; MS (electrospray) w/z 588 5 (M+ H). 163 201245116

Sll-8-5 (黃色固體）：4 NMR (400 MHz, CD3OD) (5 7.46 (s, 1 H), 5.11-5.17 (m, 1 H), 4.16-4.22 (m, 1 H), 4.14 (s, 1 H), 3.40-3.54 (m, 2 H), 2.91-3.23 (m, 10 H), 2.13-2.61 (m, 6 H)，1.61-1.70 (m，1 H)，1.03 (s，9 H) ; MS (電喷霧）m/z 588.5 (M + H)。 實施例12.合成其中X為C丨且環E為1-取代之吡咯啶 -2-基的其他式I化合物。 根據流程12製備其他式I化合物，其中環E為1-取代 之吡咯啶-2-基；X為-C1 ;且Y為-H。 流程12Sll-8-5 (yellow solid): 4 NMR (400 MHz, CD3OD) (5 7.46 (s, 1 H), 5.11-5.17 (m, 1 H), 4.16-4.22 (m, 1 H), 4.14 ( s, 1 H), 3.40-3.54 (m, 2 H), 2.91-3.23 (m, 10 H), 2.13-2.61 (m, 6 H), 1.61-1.70 (m, 1 H), 1.03 (s, 9 H) ; MS (electrospray) m/z 588.5 (M + H). Example 12. Synthesis of a further compound of formula I wherein X is C oxime and ring E is 1-substituted pyrrolidin-2-yl. Further compounds of formula I are prepared according to Scheme 12 wherein ring E is 1-substituted pyrrolidin-2-yl; X is -C1; and Y is -H.

C02PhC02Ph

2) TFA2) TFA

a) LDA/TMEDA b) 烯酮S2·1 烷基化a) LDA/TMEDA b) alkenone S2·1 alkylation

164 201245116164 201245116

在 100C 下在 n2 下向 S10-3( 1.01 g，2.33 mmol，1 eq ) 於™F ( 6 mL )中之溶液中逐滴添加n-BuLi ( 0.98 , 2 5 M/己烷，2.45 mmo丨，1.05當量）。在此_1〇(rc下攪拌所得 橙色溶液20分鐘。添加1-(第三丁氧羰基）2_吡咯啶 mg’ 2.45mmol’ U5當量）於THF(6mL)中之溶液。再 攪拌反應混合物2小時，維持溫度低於_78,且藉由添加 HC1水溶液（1 n )中止。將反應混合物升溫至室溫且用 EtOAc萃敢三次。經合併之有機層以鹽水洗滌，經Na2S〇4 脫水’濃縮至乾燥。將殘餘物溶解於Ch2C12 ( 10 mL)中， 用冰浴冷卻’且用TFA ( 10 mL)於CH2C12 ( 10 mL)中之 /谷液處理。在室溫下攪拌反應混合物1小時且濃縮。將殘 餘物溶解於CH/l2中，用NaHC03飽和水溶液及鹽水洗滌， 經NazSO4脫水，且濃縮。藉由Biotage急驟層析純化殘餘 物’得到呈灰白色固體狀之化合物S12-1 ( 0.79 g，81%%): ^ NMR (400 MHz, CDC13) δ 7.33-7.44 (m, 7 Η), 7.26 (t, J =7.8 Hz, 1 H), 7.14 (s, 1 H), 7.05 (d, J = 7.8 Hz, 2 H), 5.16 (s, 2 H), 4.05-4.08 (m, 2 H), 3.02-3.06 (m, 2 H), 2.49 (s, 3 H), 2.05-2.13 (m，2 H) ; MS (電喷霧）m/z 420.4 (M+H)。 H ^?co2Ph 替代合成SI 1-5。 S1〇1B5 除流程11中所述之方法之外，亦根據以下程序自S12-1 165 201245116 製備化合物S11-5»在0°c下向化合物sl2_1(79〇mg，丨88 mmol，leq)於甲醇（20mL)中之溶液中添加^卵4(356 mg’9.40mmol，5eq)。在室溫下攪拌反應混合物3〇分鐘。 添加HC1水溶液（10 mL ’ 1 N)。再繼續攪拌5分鐘。利 用旋轉蒸發器移除溶劑。將殘餘物懸浮於Et0Ac中，用 NaHC〇3飽和水溶液及鹽水洗滌，經Na2S〇4脫水，且濃縮。 藉由Biotage急驟層析純化殘餘物，得到呈灰白色固體狀之 S11-5 ( 634 mg，80% )。Add n-BuLi (0.98, 2 5 M/hexane, 2.45 mmo丨) to a solution of S10-3 (1.01 g, 2.33 mmol, 1 eq) in TMF (6 mL) at rt. , 1.05 equivalent). The resulting orange solution was stirred for 20 min at rt (1 mL). EtOAc (EtOAc &lt;+&gt; The reaction mixture was further stirred for 2 hours maintaining the temperature below -78 and quenched by the addition of aqueous HCl (1 n). The reaction mixture was warmed to room rt and extracted thrice with EtOAc. The combined organic layers were washed with brine and dried over Na 2 EtOAc EtOAc. The residue was dissolved in CH2C12 (10 mL) eluting with EtOAc (EtOAc) The reaction mixture was stirred at room temperature for 1 hour and concentrated. The residue was dissolved in CH.sub.2, washed with brine NaH. Purification of the residue by EtOAc (EtOAc) EtOAc (EtOAc: EtOAc (EtOAc) t, J = 7.8 Hz, 1 H), 7.14 (s, 1 H), 7.05 (d, J = 7.8 Hz, 2 H), 5.16 (s, 2 H), 4.05-4.08 (m, 2 H), 3.02-3.06 (m, 2 H), 2.49 (s, 3 H), 2.05-2.13 (m, 2 H); MS (electrospray) m/z 420.4 (M+H). H ^?co2Ph replaces synthetic SI 1-5. S1〇1B5 In addition to the method described in Scheme 11, the compound S11-5» was prepared from S12-1 165 201245116 according to the following procedure to the compound sl12 (79 mg, 丨88 mmol, leq) at 0 °c. Egg 4 (356 mg '9.40 mmol, 5 eq) was added to the solution in methanol (20 mL). The reaction mixture was stirred at room temperature for 3 minutes. An aqueous solution of HCl (10 mL '1 N) was added. Stirring was continued for another 5 minutes. The solvent was removed using a rotary evaporator. The residue was suspended in EtOAc (EtOAc) EtOAc (EtOAc)EtOAc. The residue was purified by EtOAc EtOAc (EtOAc)

向化合物 S11-5 (60 mg’ 〇_14 mmol，1 eq)於 i，2 -二 氣乙烧（2 mL)中之溶液中添加丙酮（33 #l，0.44 mmol， 3eq)及乙酸（25.5 &quot;L’0.44 mmol，3eq)。在室溫下搜 拌2小時後’添加二乙醯氧基删氫化納（63 mg.ojSmmol， 2 eq ) »繼續攪拌隔夜。將反應混合物傾入NaH(：〇3飽和水 溶液中且用CHzCl2萃取三次。經合併之有機萃取物用鹽水 洗務’經NajCU脫水，且濃縮。藉由Biotage急驟層析純 化殘餘物’得到呈白色固體狀之化合物S12-3-1.( 64 mg， 98%) : *H NMR (400 MHz, CDC13) δ 7.28-7.46 (m, 8 Η), 7.26 (t, J = 7.8 Hz, 1 H), 7.12 (d, J = 7.8 Hz, 2 H ), 5.18 (s, 2 H), 4.14 (dd, J = 5.6, 9.2 Hz, 1 H), 3.14-3.16 (m, 1 H), 2.67-2.74 (m, 1 H), 2.55-2.62 (m, 1 H), 2.47 (s, 3 H), 2.23-2.31 (m, 1 H)，1.67-1.7,4 (m，2 H), 1.43-1.51 (m, 1 H)， 0.95 (d，J = 6.4 Hz，3 H)，0_90 (d，J = 6.4 Hz，3 H) ; MS (電 166 201245116To a solution of compound S11-5 (60 mg 〇 14 mmol, 1 eq) in i. &quot;L'0.44 mmol, 3 eq). After mixing for 2 hours at room temperature, 'diethoxydecyl-dehydrogenation (63 mg.ojSmmol, 2 eq) was added and stirring was continued overnight. The reaction mixture was poured into aq. EtOAc (aq. EtOAc (EtOAc m. Compound S12-3-1. (64 mg, 98%): *H NMR (400 MHz, CDC13) δ 7.28-7.46 (m, 8 Η), 7.26 (t, J = 7.8 Hz, 1 H) , 7.12 (d, J = 7.8 Hz, 2 H ), 5.18 (s, 2 H), 4.14 (dd, J = 5.6, 9.2 Hz, 1 H), 3.14-3.16 (m, 1 H), 2.67-2.74 (m, 1 H), 2.55-2.62 (m, 1 H), 2.47 (s, 3 H), 2.23-2.31 (m, 1 H), 1.67-1.7, 4 (m, 2 H), 1.43-1.51 (m, 1 H), 0.95 (d, J = 6.4 Hz, 3 H), 0_90 (d, J = 6.4 Hz, 3 H) ; MS (Electric 166 201245116

OBn ‘喷霧）m/z 464.3 (M+H) ° 合成 S12-3-2。 S12_3-2 向化合物 Sll-5(50mg，〇，12mmol&gt; 1 eq)於 j)MF ( 1 mL)中之溶液中添加 K2C〇3 ( 25 mg，0.18 mmol，i 5 叫） 及 1-漠-2-氣乙烧（13 #L’ 0.18 mmol ’ 1.5 eq)。用 5〇 °C油浴加熱反應混合物，直至如藉由LC-MS分析監測到反 應完成。將反應混合物冷卻至室溫。添加乙酸乙離。有機 物用ΗζΟ ( 3次）及鹽水洗滌，經NazSO4脫水，且濃縮。 藉由Biotage急驟層析純化殘餘物，得到呈無色油狀之化合 物 S12-3-2 ( 25 mg，45% ) ： 'H NMR (400 MHz, CDC13) δ 7.29-7.45 (m, 8 H), 7.23 (t, J = 7.8 Hz, 1 H), 7.10 (d, J = 7.8 Hz, 2 H ), 5.17 (s, 2 H), 4.29-4.34 (m, 2 H), 3.88 (t, J = 7.8 Hz, 1 H), 3.43-3.48 (m, 1 H), 2.80-2.93 (m, 1 H), 2.34-2.55 (m，6 H)，1.82-1.90 (m，2 H)，1.43-1.52 (m，1 H) ; MS (電喷 霧）m/z 468.3 (M+H)。 n 人ιΓ^Γ°Η3 y^co2Ph Λ OBn 合成 SI2-3-3 〇 S12-3-3 用 55°c 油浴加熱化合物 si 1-5 ( 59 mg ’0_ 14 mmol，1 eq) ' 4 A 分子篩（45 mg)、乙酸（24 &quot; L，0.42 mmo卜 3eq)、[(1-乙氧基環丙基）氧基]三甲基矽烷（84 ^[,0.42 mmol，3 eq)及 NaCNBH3 ( 18 mg，〇 28 麵〇卜 2 當量） 於無水CHsOH ( 2 mL )中之混合物3小時，冷卻至室溫後， 167 201245116 經由矽藻土墊過濾反應混合物。用一小份CH3OH洗滌矽藻 土墊。將經合併之濾液濃縮至乾燥。將殘餘物溶解於CH2C12 中，用NaHC03飽和水溶液及鹽水洗滌，經Na2S04脫水， 且濃縮。藉由Biotage急驟層析純化殘餘物，得到呈無色油 狀之化合物 S12-3-3 ( 57 mg ’ 88%) : b NMR (400 MHz， CDC13) δ 7.29-7.44 (m, 7 Η), 7.23 (t, J = 7.8 Hz, 1 H), 7.18 (s, 1 H), 7.11 (d, J= 7.8 Hz, 2 H ), 5.15 (d, J = 11.5 Hz, 1 H), 5.11 (d, J - 11.5 Hz, 1 H), 4.19 (dd, J = 5.5, 9.2 Hz, 1 H), 3.24 (t, J= 7.8 Hz, 1 H), 2.62-2.69 (m, 1 H), 2.47 (s, 3 H), 2.31-2.40 (m, 1 H), 1.47-1.85 (m, 4 H), 0.27-0.38 (m, 2 H), 0.02-0.16 (m，2 H) ; MS (電喷霧）w/z 462.4 (M+H) 〇OBn ‘spray】m/z 464.3 (M+H) ° Synthesis S12-3-2. S12_3-2 To a solution of compound Sll-5 (50 mg, hydrazine, 12 mmol &gt; 1 eq) in j) MF (1 mL), K2C 〇3 (25 mg, 0.18 mmol, i 5 ) and 1-di- 2-gas b-firing (13 #L' 0.18 mmol ' 1.5 eq). The reaction mixture was heated with a 5 ° C oil bath until the reaction was completed as observed by LC-MS analysis. The reaction mixture was cooled to room temperature. Add acetic acid to leave. The organics were washed with hydrazine (3 times) and brine, dried over NazSO4 and concentrated. The residue was purified by EtOAc (EtOAc) (EtOAc) 7.23 (t, J = 7.8 Hz, 1 H), 7.10 (d, J = 7.8 Hz, 2 H ), 5.17 (s, 2 H), 4.29-4.34 (m, 2 H), 3.88 (t, J = 7.8 Hz, 1 H), 3.43-3.48 (m, 1 H), 2.80-2.93 (m, 1 H), 2.34-2.55 (m, 6 H), 1.82-1.90 (m, 2 H), 1.43-1.52 (m, 1 H); MS (electrospray) m/z 468.3 (M+H). n ιΓ^Γ°Η3 y^co2Ph Λ OBn Synthesis SI2-3-3 〇S12-3-3 Heat compound si 1-5 ( 59 mg '0_ 14 mmol, 1 eq) ' 4 A with 55 ° c oil bath Molecular sieves (45 mg), acetic acid (24 &quot; L, 0.42 mmo 3eq), [(1-ethoxycyclopropyl)oxy]trimethylnonane (84^[, 0.42 mmol, 3 eq) and NaCNBH3 (18 mg, 〇28 〇 2 2 eq.) A mixture of anhydrous CHsOH (2 mL) for 3 hrs, cooled to room temperature, 167 201245116 The reaction mixture was filtered through a pad of Celite. The algae pad was washed with a small portion of CH3OH. The combined filtrate was concentrated to dryness. The residue was dissolved in CH.sub.2Cl.sub.sub.sub.sub. Purification of the residue by EtOAc (EtOAc) EtOAc (EtOAc: EtOAc) (t, J = 7.8 Hz, 1 H), 7.18 (s, 1 H), 7.11 (d, J = 7.8 Hz, 2 H ), 5.15 (d, J = 11.5 Hz, 1 H), 5.11 (d, J - 11.5 Hz, 1 H), 4.19 (dd, J = 5.5, 9.2 Hz, 1 H), 3.24 (t, J = 7.8 Hz, 1 H), 2.62-2.69 (m, 1 H), 2.47 (s , 3 H), 2.31-2.40 (m, 1 H), 1.47-1.85 (m, 4 H), 0.27-0.38 (m, 2 H), 0.02-0.16 (m, 2 H) ; MS (electrospray )w/z 462.4 (M+H) 〇

根據與流程11中所用類似之程序，自S12-3-1及烯酮 s2-i經由邁克爾-狄克曼成環（MichaelDieckmann annulation)、接著脫甲矽基及氫化，製備化合物S12_51 : 4 NMR (400 MHz, CD3OD) 5 7.43 (s，1 h)，5.10-5.16 (m，Compound S12_51 was prepared from S12-3-1 and ketene s2-i via Michael Dieckmann annulation, followed by demethylation and hydrogenation according to procedures similar to those used in Scheme 11: 4 NMR ( 400 MHz, CD3OD) 5 7.43 (s, 1 h), 5.10-5.16 (m,

噴霧）w/z 560·4 (M+H)。 168 201245116Spray) w/z 560·4 (M+H). 168 201245116

根據與流程Η中所用類似之程序，自812_3_2及烯_ S2-1經由邁克爾-狄克曼成環、接著脫曱石夕基及氫化，製備 化合物 S12-5-2. HNMR(4〇〇MHz CD3〇D)占 7 33 (s i H)，5.15-5.21 (m，1 H)，4.78 (d，J = 47.6 Hz，2 Η), 4.14 (s，i H)，3.99-4.10 (m，1 H)，3,40-3.61 (m，4 η), 2.92-3.14 (m，8 H), 2.65-2.71 (m, 1 H), 2.26-2.45 (m, 4 H), 2.08 -2.19 (m, i H)，1.60-1.69 (m，1 H) ; MS (電喷霧）m/z 564 4 (M+H)。According to a procedure similar to that used in the scheme, compound S12-5-2 was prepared from 812_3_2 and alkene_S2-1 via Michael-Dickman ring formation, followed by deuteration and hydrogenation. HNMR (4 〇〇 MHz) CD3〇D) occupies 7 33 (si H), 5.15-5.21 (m, 1 H), 4.78 (d, J = 47.6 Hz, 2 Η), 4.14 (s, i H), 3.99-4.10 (m, 1 H),3,40-3.61 (m,4 η), 2.92-3.14 (m,8 H), 2.65-2.71 (m, 1 H), 2.26-2.45 (m, 4 H), 2.08 -2.19 (m , i H), 1.60-1.69 (m, 1 H); MS (electrospray) m/z 564 4 (M+H).

〇 HO I S12-5-3 合成化合物S12-5-3。 根據與流程11中所用類似之程序，自S12-3-3及烯酮 S2-1經由邁克爾-狄克曼成環、接著脫甲石夕基及氫化，製備 化合物 S12-5-3 : NMR (400 MHz，CD3OD) 5 7.3 1 (s，1 fi), 5.34-5.39 (m, 1 H), 4.13 (s, 1 H), 3.84-4.00 (m, 1 H), 3.40-3.62 (m, 2 H), 2.92-3.14 (m, 10 H), 2.65-2.71 (m, 1 H), 2.26-2.45 (m, 5 H)，1.60-1.69 (m，1 H)，0.84-1.00 (m，2 H)， 0.42-0.48 (m，1 H) ; MS (電喷霧）m/z 558.4 (m + H)。 實施例13.合成其中X為C丨且環e為視情況具有其他 取代基之1-取代之吡咯啶-2-基、哌啶-2-基或氮環庚烷-2-恭的式I化合物。〇 HO I S12-5-3 Synthesis of compound S12-5-3. Compound S12-5-3 was prepared from S12-3-3 and ketene S2-1 via Michael-Dickman ring formation followed by demethylation and hydrogenation according to procedures similar to those used in Scheme 11: NMR ( 400 MHz, CD3OD) 5 7.3 1 (s,1 fi), 5.34-5.39 (m, 1 H), 4.13 (s, 1 H), 3.84-4.00 (m, 1 H), 3.40-3.62 (m, 2 H), 2.92-3.14 (m, 10 H), 2.65-2.71 (m, 1 H), 2.26-2.45 (m, 5 H), 1.60-1.69 (m, 1 H), 0.84-1.00 (m, 2 H), 0.42-0.48 (m, 1 H); MS (electrospray) m/z 558.4 (m + H). Example 13. Synthesis of a 1-substituted pyrrolidin-2-yl, piperidin-2-yl or azacycloheptane-2-conazole wherein X is C丨 and ring e is optionally substituted with other substituents Compound.

根據流程13製備式I化合物’其中環E為多重取代之 ,比咯啶-2-基、哌啶-2-基或氮環庚烷-2-基；X為-C1 ;且Y 169 201245116 為-Η。 流程13The compound of formula I is prepared according to Scheme 13 wherein ring E is a multiple substituent, a pyrrolidin-2-yl, piperidin-2-yl or a nitrogen cycloheptan-2-yl; X is -C1; and Y 169 201245116 is - Hey. Process 13

根據與S12-1所用類似之程序自S10-3及l-N-Boc-2-0辰啶酮製備化合物 S13-1-1 : 4 NMR (400 MHz，CDC13) δ 7.31-7.43 (m, 7 Η), 7.22 (t, J = 7.8 Hz, 1 H), 7.04 (d, J = 7.8 Hz, 2 H ), 6.82 (s, 1 H), 5.13 (s, 2 H), 3.61-3.82 (m, 2 H), 2.46-2.49 (m, 5 H), 1.80-1.88 (m, 2 H), 1.71-1.76 (m, 2 H)； MS (電喷霧）m/z 434.4 (M+H)。Preparation of compound S13-1-1 from S10-3 and lN-Boc-2-0 hexanone according to procedures similar to those used for S12-1: 4 NMR (400 MHz, CDC13) δ 7.31-7.43 (m, 7 Η) , 7.22 (t, J = 7.8 Hz, 1 H), 7.04 (d, J = 7.8 Hz, 2 H ), 6.82 (s, 1 H), 5.13 (s, 2 H), 3.61-3.82 (m, 2 H), 2.46-2.49 (m, 5 H), 1.80-1.88 (m, 2 H), 1.71-1.76 (m, 2 H); MS (electrospray) m/z 434.4 (M+H).

根據與將S12-1還原為sil-5所用類似之程序自 170 201245116 S13-1-1 製備化合物 S13_2_1: lH NMR (4〇〇 MHz, 占 7.30-7.45 (m，7 H)，7 29 (s，i h)，7.22 (t，卜 7 8 Hz，i H)， 7.05 (d’ J = 7.8 Hz，2 h )，5.15 (s，2 H)，4 〇9 (dd，】=2' Hz’ 1 H)，3.20-3.23 (m，1 H)，2.83-2.90 (m，1 H)，2.46 (s， 3 H), 1.86-1.92 (m, 2 H), 1.47-1.70 (ms 4 H), 1.24-1.34 (m, 1 H) ’ MS (電噴霧）m/z 436.4 (M+H)。 合成化合物S13-5-1-1Compound S13_2_1 was prepared from 170 201245116 S13-1-1 according to procedures similar to those used for the reduction of S12-1 to sil-5: lH NMR (4 〇〇 MHz, 7.30-7.45 (m, 7 H), 7 29 (s ,ih), 7.22 (t, Bu 7 8 Hz, i H), 7.05 (d' J = 7.8 Hz, 2 h ), 5.15 (s, 2 H), 4 〇 9 (dd,] = 2' Hz' 1 H), 3.20-3.23 (m, 1 H), 2.83-2.90 (m, 1 H), 2.46 (s, 3 H), 1.86-1.92 (m, 2 H), 1.47-1.70 (ms 4 H) , 1.24-1.34 (m, 1 H) ' MS (electrospray) m/z 436.4 (M+H). Compound S13-5-1-1

根據與製備S11-8-l (鹽酸鹽）中所用類似之程序，自 s 13 2-1經由邁克爾-狄克曼成環、還原性烷基化、脫甲矽基 及氫化來製備化合物S13-5-H : iH NMR (4〇〇 MHz，cD3〇D) ^ 7.30 (s, 1 Η), 4.14 (s, 1 Η), 3.66-3.69 (m, 1 Η), 2.93-3.44 (m, 11 Η), 2.69 (s, 3 Η), 2.36-2.46 (m, 1 Η), 2.26-2.29 (m, 1 Η), 1.93-2.11 (m，5 Η)，1.61-1.81 (m，2 Η) ; MS (電喷霧）m/z 546.4 (M+H)。 根據與S13_5_l-1所用類似之程序自S13-2-1及各種路 來製備以下化合物》Compound S13 was prepared from s 13 2-1 via Michael-Dickman ring formation, reductive alkylation, demethylation and hydrogenation according to procedures similar to those used in the preparation of S11-8-1 (hydrochloride). -5-H : iH NMR (4〇〇MHz, cD3〇D) ^ 7.30 (s, 1 Η), 4.14 (s, 1 Η), 3.66-3.69 (m, 1 Η), 2.93-3.44 (m, 11 Η), 2.69 (s, 3 Η), 2.36-2.46 (m, 1 Η), 2.26-2.29 (m, 1 Η), 1.93-2.11 (m, 5 Η), 1.61-1.81 (m, 2 Η MS (electrospray) m/z 546.4 (M+H). Prepare the following compounds from S13-2-1 and various routes according to procedures similar to those used in S13_5_l-1

S13-5-1-2 ： !H NMR (400 MHz, CD3OD) δ 7.41 (s, 1 Η), 4.15 (s5 1 Η), 3.88-3.92 (m, ! Η), 2.93-3.45 (m, 12 Η), 2·68-2.74 (m，1 Η)，1.98-2.47 (m，8 Η)，161_181 (m，2 Η)， 〇·97 (d，J = 6·4 Ηζ，3 Η)，0.92 (d，J = 6.4 Hz, 3 H) ; MS (電 171 201245116 喷霧）m/z 588.4 (M + H)。S13-5-1-2 : !H NMR (400 MHz, CD3OD) δ 7.41 (s, 1 Η), 4.15 (s5 1 Η), 3.88-3.92 (m, ! Η), 2.93-3.45 (m, 12 Η), 2·68-2.74 (m, 1 Η), 1.98-2.47 (m, 8 Η), 161_181 (m, 2 Η), 〇·97 (d, J = 6·4 Ηζ, 3 Η), 0.92 (d, J = 6.4 Hz, 3 H); MS (Electrical 171 201245116 spray) m/z 588.4 (M + H).

S13-5-1-3 ： *H NMR (400 MHz, CD3〇D) 5 7.38 (s, 1 H), 4.14 (s, 1 H), 3.74-3.80 (m, 1 H), 3.30-3.45 (m, 2 H), 2.93-3.25 (m, 11 H), 2.35-2.48 (m, 1 H), 2.20-2.32 (m, 1 H), 1.85-2.15 (m, 5 H), 1.40-1.84 (m, 5 H), 0.75-0.85 (m, 6 H)； MS (電噴霧）m/z 602.4 (M+H)。S13-5-1-3 : *H NMR (400 MHz, CD3〇D) 5 7.38 (s, 1 H), 4.14 (s, 1 H), 3.74-3.80 (m, 1 H), 3.30-3.45 ( m, 2 H), 2.93-3.25 (m, 11 H), 2.35-2.48 (m, 1 H), 2.20-2.32 (m, 1 H), 1.85-2.15 (m, 5 H), 1.40-1.84 ( m, 5 H), 0.75-0.85 (m, 6 H); MS (electrospray) m/z 602.4 (M+H).

S13-5-1-4 ： *H NMR (400 MHz, CD3OD) &lt;5 7.34 (s, 1 H), 4.13 (s, 1 H), 3.75-3.85 (m, 1 H), 3.38-3.46 (m, 1 H), 2.85- 3.20 (m, 11 H), 2.35-2.40 (m, 1 H), 2.22-2.30 (m, 1 H), 1.85- 2.15 (m, 6 H), 1.55-1.82 (m, 4 H), 0.85 (t, J = 7.4 Hz, 3 H) ; MS (電喷霧）m/z 574.3 (M+H)。S13-5-1-4 : *H NMR (400 MHz, CD3OD) &lt;5 7.34 (s, 1 H), 4.13 (s, 1 H), 3.75-3.85 (m, 1 H), 3.38-3.46 ( m, 1 H), 2.85- 3.20 (m, 11 H), 2.35-2.40 (m, 1 H), 2.22-2.30 (m, 1 H), 1.85- 2.15 (m, 6 H), 1.55-1.82 ( m, 4 H), 0.85 (t, J = 7.4 Hz, 3 H); MS (electrospray) m/z 574.3 (M+H).

S13-5-1-5 ： 'H NMR (400 MHz, CD3OD) δ 7.33 (s, 1 H), 4.13 (s, 1 H), 3.73-3.82 (m, 1 H), 3.37-3.45 (m, 1 H), 2.95-3.20 (m, 11 H), 2.35-2.47 (m 1 H), 2.24-2.32 (m, 1 H), 1.85-2.15 (m, 6 H), 1.57-1.85 (m, 2 H), 1.26 (t, J = 7.3 Hz, 3 H) ; MS (電喷霧）m/z 5 60_4 (M+H)。 172 201245116S13-5-1-5 : 'H NMR (400 MHz, CD3OD) δ 7.33 (s, 1 H), 4.13 (s, 1 H), 3.73-3.82 (m, 1 H), 3.37-3.45 (m, 1 H), 2.95-3.20 (m, 11 H), 2.35-2.47 (m 1 H), 2.24-2.32 (m, 1 H), 1.85-2.15 (m, 6 H), 1.57-1.85 (m, 2 H), 1.26 (t, J = 7.3 Hz, 3 H); MS (electrospray) m/z 5 60_4 (M+H). 172 201245116

S13-5-1-6 :NMR (400 MHz，CD3〇D) 5 7.34 (s，1 H), 4.13 (s, 1 H), 3.95-4.05 (m, 1 H), 3.35-3.45 (m, 2 H), 2.85-3.20 (m，l〇 H)，2.34-2.46 (m，1 H)，2.22-2.30 (m, 1 H)， 1.88-2.15 (m, 5 H), 1.58-1.85 (m, 2 H), 1.02-1.12 (m, 1 H), 0.68-0.77 (m，2 H)，0.20-0.31 (m，2 H) ; MS (電喷霧）m/z 586.4 (M+H)。S13-5-1-6 : NMR (400 MHz, CD3〇D) 5 7.34 (s, 1 H), 4.13 (s, 1 H), 3.95-4.05 (m, 1 H), 3.35-3.45 (m, 2 H), 2.85-3.20 (m, l〇H), 2.34 - 2.46 (m, 1 H), 2.22-2.30 (m, 1 H), 1.88-2.15 (m, 5 H), 1.58-1.85 (m , 2 H), 1.02-1.12 (m, 1 H), 0.68-0.77 (m, 2 H), 0.20-0.31 (m, 2 H) ; MS (electrospray) m/z 586.4 (M+H) .

自S13-2-1與烯酮S2-1之成環產物藉由脫甲矽基、接 著氫化（氣經還原），來製備化合物S13-5-1-7 : 4 NMR (400 MHz5CD3OD) 5 6.93 (s, 1 Η), 6.88 (s, 1 Η), 4.18-4.24 (m, 1 Η), 4.09 (s, 1 Η), 3.45-3.50 (m, 1 Η), 2.90-3.20 (m, 11 Η), 2.55-2.65 (m, 1 Η), 2.17-2.25 (m, 1 Η), 1.50-2.10 (m, 5 Η)； MS (電喷霧）m/z 498.4 (M+H)。The compound S13-5-1-7 was prepared from the ring-forming product of S13-2-1 and the ketene S2-1 by demethylation, followed by hydrogenation (gas reduction): 4 NMR (400 MHz 5CD3OD) 5 6.93 (s, 1 Η), 6.88 (s, 1 Η), 4.18-4.24 (m, 1 Η), 4.09 (s, 1 Η), 3.45-3.50 (m, 1 Η), 2.90-3.20 (m, 11 Η), 2.55-2.65 (m, 1 Η), 2.17-2.25 (m, 1 Η), 1.50-2.10 (m, 5 Η); MS (electrospray) m/z 498.4 (M+H).

合成N-Boc- £ -己内醯胺。己汽龜锻 在 78C 下向 ε-己内酿細（1 ,〇 1 g , 8.88 mmol，1 eq ) 於THF ( 10 mL)中之溶液十逐滴添加n BuLi (3.73机， 2.5^1/己烷，9.32111〇1〇1，1.05叫）。在_78。(：下攪拌反應物Synthesis of N-Boc-£-caprolactam. Adding n BuLi (3.73 machine, 2.5^1/) to the solution of ε-hexane (1, 〇1 g, 8.88 mmol, 1 eq) in THF (10 mL) at 78C Hexane, 9.32111〇1〇1, 1.05). At _78. (: stirring the reactants

°C下擾拌2小時且升溫至室溫。 mL)中之溶液。反應物在-78 。添加NH4C1飽和水溶液（10 173 201245116 mL)及水（5 mL)。用EtOAc ( 3次）萃取混合物。經合 併之有機萃取物經硫酸鈉脫水且減壓濃縮。使用〇%_2〇0/。 EtOAc-己烷進行矽膠急驟層析，得到呈無色油狀之所需產 物（1.50 g，79%):巾 NMR (400 MHz，CDC13) δ 3,72-3.76 (m, 2 Η), 2.60-2.68 (m, 2 Η), 1.68-1.80 (m, 6 Η), 1.24 (s, 9 Η) ; MS (電喷霧）m/z 23 6.6 (M+Na)。The mixture was stirred for 2 hours at ° C and warmed to room temperature. Solution in mL). The reactants are at -78. A saturated aqueous solution of NH4C1 (10 173 201245116 mL) and water (5 mL) were added. The mixture was extracted with EtOAc (3×). The combined organic extracts were dried over sodium sulfate and concentrated. Use 〇%_2〇0/. Flash-chromatography of EtOAc-hexanes EtOAc (EtOAc) 2.68 (m, 2 Η), 1.68-1.80 (m, 6 Η), 1.24 (s, 9 Η); MS (electrospray) m/z 23 6.6 (M+Na).

根據與製備S13 -1 -1中所用類似之程序，使化合物 S10-3 ( 1.02 g，2.35 mmol，1 eq)與 n-BuLi 及 N-B〇c_ ε · 己内醯胺（0.53g，2.47 mmol，l.〇5eq)反應，接著用TFA 脫除B o c保護基’付到非？哀狀胺基嗣。將此胺基嗣中間物 溶解於 THF ( 10 mL)中。添加 Ti(CMPr)4 ( 2.06 mL，7.05 mmol，3 eq )。反應混合物在室溫下攪拌隔夜，以Et〇Ae 稀釋’且傾入水中。經由矽藻土墊過濾混合物。收集有機 層，以鹽水洗滌’經硫酸鈉脫水，且減壓濃縮。使用〇0/。 EtOAc-己烷進行矽膠急驟層析，得到呈灰白色固體狀之環 狀亞胺（291 mg’ 28%’經3個步驟）：MS (電喷霧）m/z 448.0 (M+H) »用NaBH4處理亞胺，得到呈蠟狀固體狀之所需產 物 S13-2-2( 292 mg’ 100%) : NMR (400 MHz, CDC13) 5 7.41-7.48 (m, 2 H), 7.31-7.40 (m, 5 H), 7.21-7.28 (m, 2 H), 7.05-7.11 (m，2 H)，5.14-5.21 (m，2 H)，4.29 (dd，J = 3.6, 9.2Compound S10-3 (1.02 g, 2.35 mmol, 1 eq) was combined with n-BuLi and NB 〇c_ ε · caprolactam (0.53 g, 2.47 mmol, according to procedures similar to those used for the preparation of S13 -1 -1). l. 〇 5 eq) reaction, followed by TFA removal of B oc protecting group 'paid to non? Mild amine hydrazine. This aminoguanidine intermediate was dissolved in THF (10 mL). Ti(CMPr)4 (2.06 mL, 7.05 mmol, 3 eq) was added. The reaction mixture was stirred overnight at room temperature, diluted with Et EtOAc and poured into water. The mixture was filtered through a pad of diatomaceous earth. The organic layer was collected, washed with brine, dried over sodium sulfate and evaporated. Use 〇0/. Flash-chromatography of EtOAc-hexanes eluted EtOAc (EtOAc) Treatment of the imine with NaBH4 afforded the desired product S13-2-2 (292 mg &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&& m, 5 H), 7.21-7.28 (m, 2 H), 7.05-7.11 (m, 2 H), 5.14 - 5.21 (m, 2 H), 4.29 (dd, J = 3.6, 9.2

Hz, 1 H), 3.10-3.17 (m, 1 H), 2.88-2.96 (m, 1 H), 2.48 (s, 3 H)，1.97-2.05 (m，1 H), 1.50-1.90 (m，8 H) ; MS (電噴霧）m/z 174 201245116 450.0 (M+H)。 根據與製備S13-5-1-1所用類似之程序自S13-2-2製備 以下化合物。Hz, 1 H), 3.10-3.17 (m, 1 H), 2.88-2.96 (m, 1 H), 2.48 (s, 3 H), 1.97-2.05 (m, 1 H), 1.50-1.90 (m, 8 H) ; MS (electrospray) m/z 174 201245116 450.0 (M+H). The following compounds were prepared from S13-2-2 according to procedures similar to those used for the preparation of S13-5-1-1.

S13-5-2-1-A S13-5-2-1-A： ]H NMR (400 MHz, CD3OD) &lt;5 7.23 (s, 1 Η), 4.12 (s, 1 Η), 3.65-3.75 (m, 1 Η), 3.50-3.60 (m, 1 Η), 3.38-3.45 (m, 1 Η), 2.95-3.20 (m, 9 Η), 2.78 (s, 3 Η), 2.22-2.45 (m，3H)，1.58-2.28 (m，8 Η) ; MS (電喷霧）m/z 560.4 (M+H)。S13-5-2-1-A S13-5-2-1-A: ]H NMR (400 MHz, CD3OD) &lt;5 7.23 (s, 1 Η), 4.12 (s, 1 Η), 3.65-3.75 (m, 1 Η), 3.50-3.60 (m, 1 Η), 3.38-3.45 (m, 1 Η), 2.95-3.20 (m, 9 Η), 2.78 (s, 3 Η), 2.22-2.45 (m , 3H), 1.58-2.28 (m, 8 Η); MS (electrospray) m/z 560.4 (M+H).

S13~5-2-1-B S13-5-2-1-B： !H NMR (400 MHz, CD3OD) δ 7.24 (s, 1 H), 4.13 (s, 1 H), 3.65-3.75 (m, 1 H), 3.50-3.60 (m, 1 H), 3.38- 3.46 (m, 1 H), 2.95-3.20 (m, 9 H), 2.79 (s, 3 H), 2.38- 2.50 (m，1 H)，2.25-2.32 (m，1 H)，2.10-2.18 (m，2 H)， 1.60-2.05 (m，7 H) ; MS (電喷霧）m/z 5 60.5 (M+H)。 合成f羞-2-呦咯啶銬。N-Boc_5·曱基_2-处咯啶醐 根據與N-Boc- ε -己内醢胺所用類似之程序自5_甲基 -2-吡咯啶酮製備：NMR (400 MHz，CDC13) 5 2.54-2 65 (m, 1 Η), 2.36-2.45 (m, 1 Η), 2.33 (s, 1 Η), 2.09-2.21 (m, γ 175 201245116 H)，1.58-1.67 (m，1 η), l_3〇 (d，J = 6.4 Hz，3 Η)。 根據與製備SI3-5-1-1所用類似之程序自SI0-3及 N-Boc-5-甲基-2-。比π各σ定酮製備以下化合物。S13~5-2-1-B S13-5-2-1-B: !H NMR (400 MHz, CD3OD) δ 7.24 (s, 1 H), 4.13 (s, 1 H), 3.65-3.75 (m , 1 H), 3.50-3.60 (m, 1 H), 3.38- 3.46 (m, 1 H), 2.95-3.20 (m, 9 H), 2.79 (s, 3 H), 2.38- 2.50 (m,1 H), 2.25-2.32 (m, 1 H), 2.10-2.18 (m, 2 H), 1.60-2.05 (m, 7 H); MS (electrospray) m/z 5 60.5 (M+H). Synthesis of shy-2-pyrrolidine. Preparation of N-Boc_5·decyl-2-bryridine from 5-methyl-2-pyrrolidone according to procedures similar to those for N-Boc-ε-caprolactam: NMR (400 MHz, CDC13) 5 2.54-2 65 (m, 1 Η), 2.36-2.45 (m, 1 Η), 2.33 (s, 1 Η), 2.09-2.21 (m, γ 175 201245116 H), 1.58-1.67 (m,1 η) , l_3〇(d, J = 6.4 Hz, 3 Η). The procedures were similar to those used for the preparation of SI3-5-1-1 from SI0-3 and N-Boc-5-methyl-2-. The following compounds were prepared in comparison to π each sigma ketone.

S13-5-3-1 : NMR (400 MHz, CD3OD) δ 7.20-7.35 (m, 1 Η), 5.00-5.15 (m, 1 Η), 4.13 (s, 1 Η), 3.35-3.80 (m, 2 H)，2.00-3.20 (m，18 H)，1.40-1.70 (m，3 Η) ; MS (電喷霧） m/z 546.4 (M+H)。S13-5-3-1 : NMR (400 MHz, CD3OD) δ 7.20-7.35 (m, 1 Η), 5.00-5.15 (m, 1 Η), 4.13 (s, 1 Η), 3.35-3.80 (m, 2 H), 2.00-3.20 (m, 18 H), 1.40-1.70 (m, 3 Η); MS (electrospray) m/z 546.4 (M+H).

S13-5-3-1 -A S13-5-3-1-A： 'H NMR (400 MHz, CD3OD) &lt;5 7.25 (s，3 H), 5.06 (t, J = 8.1 Hz, 1 H), 4.12 (s, 1 H), 3.40-3.48 (m, 1 H), 2.95-3.20 (m, 7 H), 2.79 (s, 3 H), 1.90-2..70 (m, 7 H), 1.60-1.72 (m, 1 H), 1.54 (d, J = 6.4 Hz, 1 H), 1.45 (d, J = 6.4 Hz，3 H) ; MS (電喷霧）m/z 546.4 (M+H)。S13-5-3-1 -A S13-5-3-1-A: 'H NMR (400 MHz, CD3OD) &lt;5 7.25 (s,3 H), 5.06 (t, J = 8.1 Hz, 1 H ), 4.12 (s, 1 H), 3.40-3.48 (m, 1 H), 2.95-3.20 (m, 7 H), 2.79 (s, 3 H), 1.90-2..70 (m, 7 H) , 1.60-1.72 (m, 1 H), 1.54 (d, J = 6.4 Hz, 1 H), 1.45 (d, J = 6.4 Hz, 3 H) ; MS (electrospray) m/z 546.4 (M+ H).

513-5^3-1 -B S13-5-3-1-B:】H NMR (400 MHz，CD3OD) &lt;5 7.27 (s, 1 H), 5.08 (t, J = 8.2 Hz, 1 H), 4.13 (s, 1 H), 3.38-3.46 (m, 1 H), 2.95-3.20 (m, 7 H), 2.80 (s, 3 H), 1.85-2.70 (m, 7 H), 1.70-1.82 (m, 1 H), 1.54 (d, J = 6.4 Hz, 1 H), 1.45 (d, J = 6.9 176 201245116513-5^3-1 -B S13-5-3-1-B:]H NMR (400 MHz, CD3OD) &lt;5 7.27 (s, 1 H), 5.08 (t, J = 8.2 Hz, 1 H ), 4.13 (s, 1 H), 3.38-3.46 (m, 1 H), 2.95-3.20 (m, 7 H), 2.80 (s, 3 H), 1.85-2.70 (m, 7 H), 1.70- 1.82 (m, 1 H), 1.54 (d, J = 6.4 Hz, 1 H), 1.45 (d, J = 6.9 176 201245116

Hz, 3 Η) ; MS (電喷霧）m/z 546.4 (M+H)。Hz, 3 Η) ; MS (electrospray) m/z 546.4 (M+H).

S13-5-3-1-C： 'H NMR (400 MHz, CD3OD) δ 7.29 (s, 1 H), 5.11 (t, J = 9.2 Hz, 1 H), 4.12 (s, 1 H), 3.65-3.75 (m, 1 H), 3.42 (dd, J = 5.7, 16.4 Hz, 1 H), 2.95-3.20 (m, 8 H), 2.83 (s, 3 H), 1.95-2.70 (m, 6 H), 1.59-1.71 (m, 1 H), 1.56 (d, J = 6.4 Hz, 3 H) ; MS (電喷霧）m/z 546.4 (M+H)。S13-5-3-1-C: 'H NMR (400 MHz, CD3OD) δ 7.29 (s, 1 H), 5.11 (t, J = 9.2 Hz, 1 H), 4.12 (s, 1 H), 3.65 -3.75 (m, 1 H), 3.42 (dd, J = 5.7, 16.4 Hz, 1 H), 2.95-3.20 (m, 8 H), 2.83 (s, 3 H), 1.95-2.70 (m, 6 H ), 1.59-1.71 (m, 1 H), 1.56 (d, J = 6.4 Hz, 3 H); MS (electrospray) m/z 546.4 (M+H).

S13-5-3-1-0 S13-5-3-1-D： NMR (400 MHz, CD3OD) δ 7.30 (s, 1 H), 5.09 (t, J = 8.5 Hz, 1 H), 4.12 (s, 1 H), 3.66-3.75 (m, 1 H), 4.43 (dd, J = 4.6, 15.9 Hz, 1 H), 2.95-3.20 (m, 8 H), 2.83 (s, 3 H), 1.95-2.70 (m, 6 H), 1.60-1.71 (m, 1 H), 1.55 (d, J = 6.4 Hz，3 H) ; MS (電喷霧）m/z 546.4 (M+H)。S13-5-3-1-0 S13-5-3-1-D: NMR (400 MHz, CD3OD) δ 7.30 (s, 1 H), 5.09 (t, J = 8.5 Hz, 1 H), 4.12 ( s, 1 H), 3.66-3.75 (m, 1 H), 4.43 (dd, J = 4.6, 15.9 Hz, 1 H), 2.95-3.20 (m, 8 H), 2.83 (s, 3 H), 1.95 -2.70 (m, 6 H), 1.60-1.71 (m, 1 H), 1.55 (d, J = 6.4 Hz, 3 H); MS (electrospray) m/z 546.4 (M+H).

S13-5-3-2 ： JH NMR (400 MHz, CD3OD) δ 7.20-7.36 (m, 1 H), 5.08-5.25 (m, 1 H), 4.20-4.30 (m, 1 H), 4.14 (s, 1 H), 3.38-3.46 (m, 1 H), 2.95-3.20 (m, 10 H), 2.00-2.75 (m, 7 H)，1.60-1.75 (m，1 H)，1.58 (d，J = 6.4 Hz，1 H)，1.46 (d, J = 6.9 Hz，3 H)，0.93 (br t，J = 7.3 Hz，3 H) ; MS (電噴霧）m/z 177 201245116 574.4 (M + H) °S13-5-3-2 : JH NMR (400 MHz, CD3OD) δ 7.20-7.36 (m, 1 H), 5.08-5.25 (m, 1 H), 4.20-4.30 (m, 1 H), 4.14 (s , 1 H), 3.38-3.46 (m, 1 H), 2.95-3.20 (m, 10 H), 2.00-2.75 (m, 7 H), 1.60-1.75 (m, 1 H), 1.58 (d, J = 6.4 Hz, 1 H), 1.46 (d, J = 6.9 Hz, 3 H), 0.93 (br t, J = 7.3 Hz, 3 H) ; MS (electrospray) m/z 177 201245116 574.4 (M + H ) °

S13-5-3-3 ： 'H NMR (400 MHz, CD3OD) δ 7.20-7.42 (m, 1 H), 5.13-5.32 (m, 1 H), 4.28-4.37 (m, 1 H), 4.14 (s, 1 H), 3.37-3.45 (m, 1 H), 2.00-3.30 (m, 15 H), 1.45-1.70 (m, 5S13-5-3-3 : 'H NMR (400 MHz, CD3OD) δ 7.20-7.42 (m, 1 H), 5.13-5.32 (m, 1 H), 4.28-4.37 (m, 1 H), 4.14 ( s, 1 H), 3.37-3.45 (m, 1 H), 2.00-3.30 (m, 15 H), 1.45-1.70 (m, 5

S13-S-3-4 H)’ 0.20-1.05 (m，5 H) ; MS (電喷霧）m/z 5 86.4 (M + H)。 S13-5-3-4 ： 'H NMR (400 MHz, CD3OD) &lt;5 7.22-7.5 1 (m，1 H)，5.08-5.28 (m，1 H)，4.25-4.35 (m，1 H)，4.14 (s，1 H)，3.35-3.45 (m，1 H)，1.95-3.25 (m，15 H)，1.45-1.85 (m，5 H)，〇,7〇_1〇7 (m，7 h) ; MS (電噴霧）m/z 5 8 8.4 (M + H)。S13-S-3-4 H)' 0.20-1.05 (m, 5 H); MS (electrospray) m/z 5 86.4 (M + H). S13-5-3-4 : 'H NMR (400 MHz, CD3OD) &lt;5 7.22-7.5 1 (m,1 H), 5.08-5.28 (m,1 H), 4.25-4.35 (m,1 H) , 4.14 (s, 1 H), 3.35-3.45 (m, 1 H), 1.95-3.25 (m, 15 H), 1.45-1.85 (m, 5 H), 〇, 7〇_1〇7 (m, 7 h) ; MS (electrospray) m/z 5 8 8.4 (M + H).

合竑f差-2-呦咯啶鍔。N-Boc-3·甲基·2·。比咯啶綢 在-78 C 下向 N-Boc-2-n比洛咬 S同（l.〇3g，5.58mmol，1 ecl)於THF( 17 mL)中之溶液中逐滴添加LHMDS( 5.90 mL， M/THF，5·90 mmo卜 1.05 eq)。在-78°C 下攪拌反應溶 1 1小時。添加碘代曱烷（0.70 mL，1 1.15 mmol，於5 mL TilF中，2 eq)。將反應混合物逐漸升溫至-30°C，以EtOAc W ’用NH4C1飽和水溶液及鹽水洗滌，經硫酸鈉脫水， ^'滅壓濃縮。使用0%-30% EtOAc-己烷進行矽膠急驟層析， 到所需產物（622 mg，56%) : 4 NMR (400 MHz，CDC13) 178 201245116 (5 3.70-3.77 (m，1 H)，3.50-3.81 (m，1 Η), 2.48-2.59 (m，1 H)，2.13-2.22 O，1 H)，2.02 (s，1 H)，1.52-1.68 (m，1 H)， 1_20 (d，J = 6.9 Hz，3 H)。 根據與製備Sl3_S-l-i所用類似之程序自si〇-3及 N-Boc-3-甲基-2-0比咯啶酮製備以下化合物。竑 竑 f difference -2- 呦 锷 锷 锷. N-Boc-3·methyl·2·. Adding LHMDS ( 5.90) to a solution of N-Boc-2-n piroxime S (l. 〇3g, 5.58mmol, 1 ecl) in THF (17 mL) at -78 C mL, M/THF, 5·90 mmo, 1.05 eq). The reaction was stirred at -78 ° C for 1 hour. Iododecane (0.70 mL, 1 1.15 mmol in 5 mL TilF, 2 eq) was added. The reaction mixture was gradually warmed to -30 ° C, washed with EtOAc EtOAc. Flash chromatography on silica gel with 0% to 30% EtOAc-hexanes eluted eluted elute 3.50-3.81 (m,1 Η), 2.48-2.59 (m,1 H),2.13-2.22 O,1 H),2.02 (s,1 H),1.52-1.68 (m,1 H), 1_20 (d , J = 6.9 Hz, 3 H). The following compounds were prepared from si〇-3 and N-Boc-3-methyl-2-0-pyrrolidone according to procedures analogous to those used for the preparation of Sl3_S-l-i.

S13-5-4-1 : lH nMR (400 MHz, CD3OD) δ 7.11-7.30 (m，1 H)，4.70-5.10 (m，1 Η), 4.12 (s，1 Η), 3.85-3.95 (m，1 H), 3.38-3.50 (m, 1 H), 2.81-3.25 (m, 13 H), 1.75-2.85 (m, 6 H)，1.58-1.72 (m，1 H)，0.73-1.25 (m，3 H) ; MS (電喷霧）m/z 546.4 (M+H)。S13-5-4-1 : lH nMR (400 MHz, CD3OD) δ 7.11-7.30 (m,1 H), 4.70-5.10 (m,1 Η), 4.12 (s,1 Η), 3.85-3.95 (m , 1 H), 3.38-3.50 (m, 1 H), 2.81-3.25 (m, 13 H), 1.75-2.85 (m, 6 H), 1.58-1.72 (m, 1 H), 0.73-1.25 (m , 3 H) ; MS (electrospray) m/z 546.4 (M+H).

S13-5-4-2 ：，H nMR (400 MHz, CD3OD) (5 7.10-7.33 (m, 1 H), 4.74-5.17 (m, 1 H), 4.12 (s, 1 H), 3.85-4.00 (m, 1 H), 3.35-3.52 (m, 1 H), 2.95-3.25 (m, 11 H), 1.55-2.70 (m, 8 H)，0.7 5-1.08 (m, 6 H) ; MS (電喷霧）m/z 5 74.4 (M+H)。S13-5-4-2 :, H nMR (400 MHz, CD3OD) (5 7.10-7.33 (m, 1 H), 4.74-5.17 (m, 1 H), 4.12 (s, 1 H), 3.85-4.00 (m, 1 H), 3.35-3.52 (m, 1 H), 2.95-3.25 (m, 11 H), 1.55-2.70 (m, 8 H), 0.7 5-1.08 (m, 6 H) ; MS ( Electrospray) m/z 5 74.4 (M+H).

OH 0 H〇H〇 S13-5-4-3 S13-5-4-3 : NMR (400 MHz，CD3OD) 5 7.12-7.35 (m, 1 H), 4.75-5-22 (m, 1 H), 4.11 (s, 1 H), 3.95-4.05 (m, 1 H), 3.35-3.60 (m, 2 H), 2.95-3.25 (m, 10 H), 1.58-2.65 (m, 6 179 201245116OH 0 H〇H〇S13-5-4-3 S13-5-4-3 : NMR (400 MHz, CD3OD) 5 7.12-7.35 (m, 1 H), 4.75-5-22 (m, 1 H) , 4.11 (s, 1 H), 3.95-4.05 (m, 1 H), 3.35-3.60 (m, 2 H), 2.95-3.25 (m, 10 H), 1.58-2.65 (m, 6 179 201245116

H)，0.20-1.20 (m，8 Η) ; MS (電喷霧）m/z 586.4 (M+H)。H), 0.20-1.20 (m, 8 Η); MS (electrospray) m/z 586.4 (M+H).

(m, 1 H)s 4.78-5.23 (m, 1 H), 4.13 (s, 1 H), 3.95-4.10 (m, 1 H), 3.35-3.55 (m, 2 H), 1.60-3.25 (m, 16 H), 0.75-1.10 (m, 10 H) ; MS (電喷霧）m/z 588.4 (M + H)。 實施例14.合成其中X為CF3且環E為1-取代之吡咯 啶-2-基的式I化合物。 根據流程14製備式I化合物，其中環E為1-取代之吡 洛。定-2-基；X為-CF3，且Y為-H。 流程14(m, 1 H)s 4.78-5.23 (m, 1 H), 4.13 (s, 1 H), 3.95-4.10 (m, 1 H), 3.35-3.55 (m, 2 H), 1.60-3.25 (m , 16 H), 0.75-1.10 (m, 10 H); MS (electrospray) m/z 588.4 (M + H). Example 14. Synthesis of a compound of formula I wherein X is CF3 and ring E is a 1-substituted pyrrolidin-2-yl group. A compound of formula I is prepared according to Scheme 14 wherein ring E is 1-substituted pyrrol. D-2-yl; X is -CF3 and Y is -H. Process 14

180 201245116 向存於氯仿（13 mL)中之化合物si 1-4 ( 1.30 g，2.67 mmol ’ ieq)中添加三氟乙酸銀（Mg mg，2.93 mmol，1 · 1 eq)及碘（744 mg，2.93 mmo卜i.i eq)。反應混合物在室 溫下攪拌2.5小時且經由矽藻土墊過濾。用二氯曱烷洗滌矽 藻土墊。經合併之濾液用Na2S203飽和水溶液、NaHC03飽 和水溶液及鹽水洗滌’經硫酸鈉脫水，且減壓濃縮。使用 0%-20% EtO Ac/己烷進行矽膠急驟層析，得到呈白色固體狀 之所需產物 S14-l( 1.55 g，95%):丨H NMR (400 MHz，CDC13) δ 7.20-7.42 (m, 8 Η), 7.11 (d, J = 7.8 Hz, 2 H), 6.50-6.62 (m, 1 H), 5.05-5.17 (m, 3 H), 3.40-3.65 (m, 2 H), 2.56 (s, 3 H), 2.25-2.40 (m, 1 H), 1.50-1.85 (m, 3 H), 1.24, 1.47 (s, s, 9 H)。180 201245116 Add silver trifluoroacetate (Mg mg, 2.93 mmol, 1 · 1 eq) and iodine (744 mg, to compound si 1-4 ( 1.30 g, 2.67 mmol ' ieq) in chloroform (13 mL). 2.93 mmo ii eq). The reaction mixture was stirred at room temperature for 2.5 hours and filtered through a pad of Celite. The diatomaceous earth pad was washed with methylene chloride. The combined filtrate was washed with aq. aq. The desired product S14-l (1.55 g, 95%) was obtained as a white solid: 丨H NMR (400 MHz, CDC13) δ 7.20-7.42. (m, 8 Η), 7.11 (d, J = 7.8 Hz, 2 H), 6.50-6.62 (m, 1 H), 5.05-5.17 (m, 3 H), 3.40-3.65 (m, 2 H), 2.56 (s, 3 H), 2.25-2.40 (m, 1 H), 1.50-1.85 (m, 3 H), 1.24, 1.47 (s, s, 9 H).

將密封管中化合物 S14-1 ( 1.57 g，2.56 mmol，1 eq)、 CH3O2CCF2SO2F ( 3.26 mL ’ 25.6 mmol，10 eq)及 Cul ( 2.44 g ’ 12.8 mmol ’ 5 eq)於 DMF (lOmL)中之溶液在 80°C 下 加熱 24 小時。再添加 CH302CCF2S02F ( 1.63 mL，12.8 mmol，5 eq)及 Cul ( 1.22 g，6·4 mmol，2.5 eq)。反應物 在80°C下加熱20小時，冷卻至室溫，經由矽藻土墊過濾。 用EtOAc洗滌矽藻土墊。經合併之濾液以水及鹽水洗滌， 經硫酸鈉脫水，且減壓濃縮。使用0%-20% EtOAc/己烷進 行矽膠急驟層析’得到呈淺黃色油狀之所需產物SI4-2( 1.39 g，經S14-1污染），在無進一步純化的情況下將其用於下 181 201245116 一步驟。A solution of compound S14-1 ( 1.57 g, 2.56 mmol, 1 eq), CH 3 O 2 CCF 2 SO 2 F ( 3.26 mL ' 25.6 mmol, 10 eq) and Cul ( 2.44 g ' 12.8 mmol ' 5 eq) in DMF (10 mL) Heat at 80 ° C for 24 hours. Additional CH302CCF2S02F ( 1.63 mL, 12.8 mmol, 5 eq) and Cul ( 1.22 g, 4.6 mmol, 2.5 eq). The reaction was heated at 80 ° C for 20 hours, cooled to room temperature and filtered through a pad of Celite. The diatomaceous earth pad was washed with EtOAc. The combined filtrate was washed with water and brine, dried over sodium sulfate The desired product SI4-2 ( 1.39 g, contaminated with S14-1) was obtained as a pale yellow oil, eluting with EtOAc/EtOAc (EtOAc) Next step 181 201245116 a step.

ch3 C02Ph 合成 S14-3 〇 S14.3 將化合物S14-2 ( 1.39 g)與4 M HC1/1，4-二噁烷之混 合物在室溫下攪拌30分鐘且減壓濃縮。將殘餘物溶解於二 氣曱烷（200 mL)中，用NaHC03飽和水溶液及鹽水洗滌， 經硫酸鈉脫水，且減壓濃縮。矽膠急驟層析得到呈油狀之 所需產物 S14-3( 376 mg，32%，經 2 個步驟）：NMR (400 MHz, CDC13) δ 7.68 (s, 1 Η), 7.20-7.45 (m, 8 Η), 7.08 (d, J = 7.3 Hz, 2 H), 5.23 (ABq, J = 11.4, 18.4 Hz, 2 H), 4.65-4.71 (m, 1 H), 3.02-3.15 (m, 2 H), 2.54 (q, J = 3.2 Hz, 3 H), 2.20-2.30 (m, 1 H), 1.92 (br s, 1 H), 1.72-1.82 (m, 2 H), 1.44-1.5 3 (m，1 H) ; MS (電喷霧）m/z 45 6.0 (M+H)。Ch3 C02Ph Synthesis S14-3 〇 S14.3 A mixture of compound S14-2 (1. 39 g) and 4 M EtOAc / EtOAc. The residue was dissolved in EtOAc (EtOAc)EtOAc. The desired product S14-3 (376 mg, 32% over 2 steps): NMR (400 MHz, CDC13) δ 7.68 (s, 1 Η), 7.20-7.45 (m, 8 Η), 7.08 (d, J = 7.3 Hz, 2 H), 5.23 (ABq, J = 11.4, 18.4 Hz, 2 H), 4.65-4.71 (m, 1 H), 3.02-3.15 (m, 2 H ), 2.54 (q, J = 3.2 Hz, 3 H), 2.20-2.30 (m, 1 H), 1.92 (br s, 1 H), 1.72-1.82 (m, 2 H), 1.44-1.5 3 (m , 1 H) ; MS (electrospray) m/z 45 6.0 (M+H).

合成 SI 4-4-1。 si4-m 將化合物 S14-3 ( 376 mg，0.83 mmol，1 eq)溶解於 DCE ( 4 mL )中。添加甲酿水溶液（〇. 1 8 mL，37%水溶液， 2.48 mmo卜 3 eq)及乙酸（0.19 mL，3.30 mmo卜 4 eq)。 在室溫下攪拌反應物20分鐘。添加Na(OAc)3BH( 525 mg， 2.48 mmol，3 eq)。反應混合物在室溫下攪拌隔夜，以二 氣甲烷稀釋，且用NaHC03飽和水溶液（60 mL )洗滌。以 二氣曱烷（2次）萃取水層。經合併之有機溶液以鹽水洗滌， 經硫酸鈉脫水，且減壓濃縮。矽膠急驟層析得到呈無色油 182 201245116 • 狀之所需產物 S14-4-1 ( 318 mg，82% ) : 4 NMR (400 MHz， CDC13) 5 7.64 (S, 1 H), 7.22-7.46 (m, 8 H), 7.08 (d, J = 7.3Synthesis SI 4-4-1. Si4-m Compound S14-3 (376 mg, 0.83 mmol, 1 eq) was dissolved in DCE (4 mL). Agitated aqueous solution (〇.18 mL, 37% aqueous solution, 2.48 mmob 3 eq) and acetic acid (0.19 mL, 3.30 mmob 4 eq) were added. The reaction was stirred at room temperature for 20 minutes. Na(OAc)3BH (525 mg, 2.48 mmol, 3 eq) was added. The reaction mixture was stirred at room temperature overnight, diluted with EtOAc EtOAc m. The aqueous layer was extracted with dioxane (2 times). The combined organic solution was washed with brine, dried over sodium sulfate Flash chromatography of phthalocyanine to give a colorless oil 182 201245116 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; m, 8 H), 7.08 (d, J = 7.3

Hz，2 H)，5.21 (ABq，j = n.3, 14·〇 Hz, 2 H)，3.50-3.58 (m，1 H)，3.18-3.24 (m，1 H)，2.53 (q，J = 3.7 Hz，3 H)，2.20-2.37 (m3 2 H), 2.10 (s, 3 H), 1.84-1.92 (m, 2 H), 1.48-1.62 (m, 1 H) ; MS (電噴霧）m/z 492 2 (M+Na)。Hz, 2 H), 5.21 (ABq, j = n.3, 14·〇Hz, 2 H), 3.50-3.58 (m, 1 H), 3.18-3.24 (m, 1 H), 2.53 (q, J = 3.7 Hz, 3 H), 2.20-2.37 (m3 2 H), 2.10 (s, 3 H), 1.84-1.92 (m, 2 H), 1.48-1.62 (m, 1 H) ; MS (electrospray) m/z 492 2 (M+Na).

在-78°C下向新鮮製備之ldA ( 1.14 mmol，於10 mL THF 中 ’ 1.2 eq)中添加 TMEDA ( 185 μί，1.23 mmol，1·3 eq )。攪拌5分鐘後，逐滴添加化合物si4-4-1 ( 445 mg， 0.95 mmol，1 eq)於 THF ( 5 mL)中之溶液。在-78°C 下攪 拌所得紅色溶液30分鐘。添加烯酮S2-1 ( 456 mg，0.95 mmo卜於5 ml THF中，1 eq )。反應物逐漸升溫至-50t：。 添加 LHMDS ( 1.00 mL，1.0 M/THF，1.00 mmo卜 1.05 eq)。 反應物逐漸升溫至-5 °C。添加NH4C1飽和水溶液。用EtOAc (3次）萃取混合物。經合併之有機萃取物以鹽水洗滌，經 硫酸鈉脫水’且減壓濃縮。使用〇%_2〇% EtOAc/己烷進行 矽膠急驟層析，得到呈淺黃色固體狀之所需產物S14-5-1 (685 mg « 84%) : MS (電喷霧）m/2： 857.9 (M + H)。 根據與S2-7-1所用類似之程序，使化合物S14-5-1進 行脫甲石夕基及氫化，得到以下化合物。 183 201245116To freshly prepared ldA (1.14 mmol in 1 mL of THF < 1.2 eq) was added TMEDA (185 μί, 1.23 mmol, 1·3 eq) at -78 °C. After stirring for 5 minutes, a solution of compound si4-4-1 ( 445 mg, 0.95 mmol, 1 eq) in THF (5 mL). The resulting red solution was stirred at -78 °C for 30 minutes. Enone S2-1 (456 mg, 0.95 mmo in 5 ml THF, 1 eq) was added. The reaction was gradually warmed to -50t:. Add LHMDS (1.00 mL, 1.0 M/THF, 1.00 mmo Bu 1.05 eq). The reaction was gradually warmed to -5 °C. A saturated aqueous solution of NH4C1 was added. The mixture was extracted with EtOAc (3×). The combined organic extracts were washed with brine w... The desired product S14-5-1 (685 mg « 84%): MS (electrospray) m/2: 857.9 was obtained as a pale yellow solid. (M + H). The compound S14-5-1 was subjected to demethylation and hydrogenation according to a procedure similar to that used in S2-7-1 to give the following compound. 183 201245116

S14-6-1-AS14-6-1-A

S14-6-1-A ： Ή NMR (400 MHz, CD3OD) δ 7.37 (s, 1 H)，4.85-4.98 (m，1 H)，4.13 (s，1 H), 3.88-3.96 (m，1 H)， 3.30-3.48 (m5 2 H), 2.92-3.10 (m, 8 H), 2.89 (s, 3 H), 2.56-2.67 (m5 2 H), 2.20-2.35 (m, 3 H), 2.02-2.12 (m, 1 H), 1.5 8-1.70 (m，1 H) ; MS (電喷霧）m/z 566.4 (M+H)。S14-6-1-A : Ή NMR (400 MHz, CD3OD) δ 7.37 (s, 1 H), 4.85-4.98 (m, 1 H), 4.13 (s, 1 H), 3.88-3.96 (m, 1 H), 3.30-3.48 (m5 2 H), 2.92-3.10 (m, 8 H), 2.89 (s, 3 H), 2.56-2.67 (m5 2 H), 2.20-2.35 (m, 3 H), 2.02 -2.12 (m, 1 H), 1.5 8-1.70 (m, 1 H); MS (electrospray) m/z 566.4 (M+H).

S14-6-1-B S14-6-1-B : NMR (400 MHz, CD3OD) (5 7 42 (s 夏 H)，4.72-4.78 (m，1 H)，4.14 (s，1 H)，3.86-3.95 (m，i H) 3.20-3.44 (m，2 H)，2.95-3.10 (m，8 H)，2.76 (s 3 2.60-2.75 (m，2 H)，2.20-2.45 (m，4 H)，1.58-1.72 (m 丨’ MS (電喷霧）m/z 566.4 (M + H)。 ’ 根據與製備S14-6-1-A所用類似之程序自 N-Boc-5 -曱基-2-吡咯鳴酮製備以下化合物。 SU-： 及S14-6-1-B S14-6-1-B : NMR (400 MHz, CD3OD) (5 7 42 (s summer H), 4.72-4.78 (m, 1 H), 4.14 (s, 1 H), 3.86-3.95 (m,i H) 3.20-3.44 (m,2 H), 2.95-3.10 (m,8 H), 2.76 (s 3 2.60-2.75 (m,2 H), 2.20-2.45 (m,4 H), 1.58-1.72 (m 丨' MS (electrospray) m/z 566.4 (M + H). 'According to the procedure used for the preparation of S14-6-1-A from N-Boc-5 - mercapto -2-pyrrolidone prepared the following compounds: SU-: and

S14-6-2-A ： 'H NMR (400 MHz, CD3OD) Η), 5.14 (t, J = 7.8 Hz, 1 H), 4.12 (s, 1 H), 3.92 3.20-3.28 (m, 1H), 2.90-3.06 (m, 8 H), 2.64 (t, 5 7.27(s，4.〇2(m， H)， 15.S14-6-2-A : 'H NMR (400 MHz, CD3OD) Η), 5.14 (t, J = 7.8 Hz, 1 H), 4.12 (s, 1 H), 3.92 3.20-3.28 (m, 1H) , 2.90-3.06 (m, 8 H), 2.64 (t, 5 7.27(s,4.〇2(m, H), 15.

Hz. 184 201245116 '· Η), 2.40-2.56 (m, 2 Η), 2.20-2.33 (m, 2 Η), 1.80-1.87 (m, 1 Η)，1.59-1.68 (m, 1 Η)，1.47 (d, J = 6·4 Hz, 3 Η) ; MS (電喷 霧）m/z 566.2 (M + H)。Hz. 184 201245116 '· Η), 2.40-2.56 (m, 2 Η), 2.20-2.33 (m, 2 Η), 1.80-1.87 (m, 1 Η), 1.59-1.68 (m, 1 Η), 1.47 (d, J = 6·4 Hz, 3 Η); MS (electrospray) m/z 566.2 (M + H).

S14-6-2-B S14-6-2-B ： !H NMR (400 MHz, CD3OD) δ 7.20 (ss 1 H), 5.04 (t, J = 7.8 Hz, 1 H), 4.12 (s, 1 H), 4.06-4.11 (m, 1 H), 3.20-3.28 (m, 1 H), 2.94-3.05 (m, 8 H), 2.59-2.67 (m, 2 H), 2.41-2.48 (m, 1 H), 2.20-2.27 (m, 2 H), 1.80-1.87 (m, 1 H), 1.59-1.68 (m，1 H)，1.48 (d，J = 6.4 Hz, 3 H) ; MS (電喷霧） m/z 566.2 (M+H)。S14-6-2-B S14-6-2-B : !H NMR (400 MHz, CD3OD) δ 7.20 (ss 1 H), 5.04 (t, J = 7.8 Hz, 1 H), 4.12 (s, 1 H), 4.06-4.11 (m, 1 H), 3.20-3.28 (m, 1 H), 2.94-3.05 (m, 8 H), 2.59-2.67 (m, 2 H), 2.41-2.48 (m, 1 H), 2.20-2.27 (m, 2 H), 1.80-1.87 (m, 1 H), 1.59-1.68 (m, 1 H), 1.48 (d, J = 6.4 Hz, 3 H) ; MS (electrospray) Fog) m/z 566.2 (M+H).

S14-6-2-C ： *H NMR (400 MHz, CD3OD) δ 7.23 (s, 1 H), 5.09 (t, J = 7.8 Hz, 1 H), 4.12 (s, 1 H), 3.85-3.90 (m, 1 H), 3.20-3.28 (m, 1H), 2.94-3.03 (m, 8 H), 2.52-2.67 (m, 2 H), 2.36-2.45 (m, 1 H), 2.17-2.25 (m, 2 H), 1.92-2.00 (m, 1 H), 1.5 8-1.68 (m，1 H)，1.5 1 (d, J = 6.4 Hz，3 H) ; MS (電喷霧） m/z 566.2 (M+H) 〇S14-6-2-C : *H NMR (400 MHz, CD3OD) δ 7.23 (s, 1 H), 5.09 (t, J = 7.8 Hz, 1 H), 4.12 (s, 1 H), 3.85-3.90 (m, 1 H), 3.20-3.28 (m, 1H), 2.94-3.03 (m, 8 H), 2.52-2.67 (m, 2 H), 2.36-2.45 (m, 1 H), 2.17-2.25 ( m, 2 H), 1.92-2.00 (m, 1 H), 1.5 8-1.68 (m, 1 H), 1.5 1 (d, J = 6.4 Hz, 3 H) ; MS (electrospray) m/z 566.2 (M+H) 〇

185 201245116 S14-6-2-D ： *H NMR (400 MHz, CD3OD) ¢5 7.34 (s, 1 H), 5.00 (t, J = 7.8 Hz, 1 H), 4.13 (s, 1 H), 3.86-3.91 (m, 1 H), 3.20-3.28 (m, 1 H), 2.95-3.04 (m, 8 H), 2.57-2.66 (m, 2 H), 2.35-2.46 (m, 1 H)，2.17-2.27 (m, 2 H)，1.92-2.00 (m，1 H)， 1.59-1.68 (m，1 H)，1.53 (d，J = 6.4 Hz，3 H) ; MS (電喷霧） m/z 566·2 (M+H) 〇185 201245116 S14-6-2-D : *H NMR (400 MHz, CD3OD) ¢5 7.34 (s, 1 H), 5.00 (t, J = 7.8 Hz, 1 H), 4.13 (s, 1 H), 3.86-3.91 (m, 1 H), 3.20-3.28 (m, 1 H), 2.95-3.04 (m, 8 H), 2.57-2.66 (m, 2 H), 2.35-2.46 (m, 1 H), 2.17-2.27 (m, 2 H), 1.92-2.00 (m, 1 H), 1.59-1.68 (m, 1 H), 1.53 (d, J = 6.4 Hz, 3 H) ; MS (electrospray) m /z 566·2 (M+H) 〇

S14-6~3W S14-6-3-A : 4 NMR (400 MHz，CD3OD) 5 7.32 (s，1 H), 4.95 (t, J = 7.8 Hz, 1 H), 4.19-4.22 (m, 1 H), 4.12 (s, 1 H), 2.95-3.04 (m, 9 H), 2.45-2.79 (m, 6 H), 2.02-2.24 (m, 3 H), 1.59-1.68 (m，1 H)，1.45 (d，J = 6.4 Hz，3 H) ; MS (電喷霧） m/z 580.2 (M+H)。S14-6~3W S14-6-3-A : 4 NMR (400 MHz, CD3OD) 5 7.32 (s,1 H), 4.95 (t, J = 7.8 Hz, 1 H), 4.19-4.22 (m, 1 H), 4.12 (s, 1 H), 2.95-3.04 (m, 9 H), 2.45-2.79 (m, 6 H), 2.02-2.24 (m, 3 H), 1.59-1.68 (m, 1 H) , 1.45 (d, J = 6.4 Hz, 3 H); MS (electrospray) m/z 580.2 (M+H).

非對映異構體B S14-6-3-B S14-6-3-B ： 'H NMR (400 MHz, CD3OD) δ Ί.36 (s, 1 H), 4.71 (t, J = 7.8 Hz, 1 H), 4.19-4.22 (m, 1 H), 4.12 (s, 1 H), 2.96-3.05 (m, 9 H), 2.63-2.74 (m, 5 H), 2.50-2.60 (m, 1 H), 2.21-2.26 (m, 2 H), 2.02-2.11 (m, 1 H), 1.60-1.69 (m, 1 H), 1.44 (d，J = 6.4 Hz，3 H) ; MS (電喷霧）m/z 580.2 (M+H)。 186 201245116Diastereomer B S14-6-3-B S14-6-3-B : 'H NMR (400 MHz, CD3OD) δ 36.36 (s, 1 H), 4.71 (t, J = 7.8 Hz , 1 H), 4.19-4.22 (m, 1 H), 4.12 (s, 1 H), 2.96-3.05 (m, 9 H), 2.63-2.74 (m, 5 H), 2.50-2.60 (m, 1 H), 2.21-2.26 (m, 2 H), 2.02-2.11 (m, 1 H), 1.60-1.69 (m, 1 H), 1.44 (d, J = 6.4 Hz, 3 H) ; MS (electrospray) Fog) m/z 580.2 (M+H). 186 201245116

S14-6-3-C ： *H NMR (400 MHz, CD3OD) δ 7.38 (s, 1 H), 4.99 (t5 J = 7.8 Hz, 1 H), 4.12 (s, 1 H), 3.70-3.76 (m, 1 H), 2.84-3.06 (m, 12 H), 2.48-2.65 (m, 3 H), 2.18-2.26 (m, 1 H), 1.94-2.08 (m, 2 H), 1.60-1.69 (m, 1 H), 1.57 (d, J = 6.4 Hz, 3 H) ; MS (電喷霧）m/z 580.2 (M+H)。S14-6-3-C : *H NMR (400 MHz, CD3OD) δ 7.38 (s, 1 H), 4.99 (t5 J = 7.8 Hz, 1 H), 4.12 (s, 1 H), 3.70-3.76 ( m, 1 H), 2.84-3.06 (m, 12 H), 2.48-2.65 (m, 3 H), 2.18-2.26 (m, 1 H), 1.94-2.08 (m, 2 H), 1.60-1.69 ( m, 1 H), 1.57 (d, J = 6.4 Hz, 3 H); MS (electrospray) m/z 580.2 (M+H).

S14-6-3-D ： *H NMR (400 MHz, CD3OD) δ 7.43 (s, 1 H), 4.80 (t, J = 7.8 Hz, 1 H), 4.12 (s, 1 H), 3.68-3.74 (m, 1 H), 2.96-3.06 (m, 9 H), 2.63-2.71 (m, 5 H), 2.47-2.55 (m, 1 H), 2.21-2.26 (m, 2 H), 2.02-2.11 (m, 1 H), 1.60-1.69 (m, 1 H), 1.5 5 (d，J = 6.4 Hz, 3 H) ; MS (電喷霧）m/z 58 0.2 (M+H)。 根據與製備S14-6-1-A所用類似之程序自Sll-2及 N - B 〇 c - 3 -甲基-2 - °比洛°定酮製備以下化合物。S14-6-3-D : *H NMR (400 MHz, CD3OD) δ 7.43 (s, 1 H), 4.80 (t, J = 7.8 Hz, 1 H), 4.12 (s, 1 H), 3.68-3.74 (m, 1 H), 2.96-3.06 (m, 9 H), 2.63-2.71 (m, 5 H), 2.47-2.55 (m, 1 H), 2.21-2.26 (m, 2 H), 2.02-2.11 (m, 1 H), 1.60-1.69 (m, 1 H), 1.5 5 (d, J = 6.4 Hz, 3 H); MS (electrospray) m/z 58 0.2 (M+H). The following compounds were prepared from Sll-2 and N - B 〇 c - 3 -methyl-2 - ° piroxol according to procedures similar to those used for the preparation of S14-6-1-A.

S14-6-4-A ： 'H NMR (400 MHz, CD3〇D) δ 6.97 (s, 1 Η), 5.25 (d, J = 7.3 Hz, 1 H), 4.13 (s, 1 H), 3.62-3.68 (m, 1 H), 3.41-3.48 (m, 1H), 3.24-3.28 (m, 1 H), 2.85-3.09 (m, 9 H), 187 201245116 2.62 (t, J = 15.1 Hz, 1 H), 2.44-2.54 (m, 1 H), 2.20-2.27 (m, 1 H), 1.84-1.93 (m, 1 H), 1.60-1.69 (m, 1 H), 0.71 (d, J = 6.8 Hz, 3 H) ; MS (電喷霧）m/z 566.2 (M+H)。S14-6-4-A : 'H NMR (400 MHz, CD3〇D) δ 6.97 (s, 1 Η), 5.25 (d, J = 7.3 Hz, 1 H), 4.13 (s, 1 H), 3.62 -3.68 (m, 1 H), 3.41-3.48 (m, 1H), 3.24-3.28 (m, 1 H), 2.85-3.09 (m, 9 H), 187 201245116 2.62 (t, J = 15.1 Hz, 1 H), 2.44-2.54 (m, 1 H), 2.20-2.27 (m, 1 H), 1.84-1.93 (m, 1 H), 1.60-1.69 (m, 1 H), 0.71 (d, J = 6.8 Hz, 3 H) ; MS (electrospray) m/z 566.2 (M+H).

S14-6-4-B ： *H NMR (400 MHz, CD3OD) δ 7.07 (s, 1 H), 5.10 (d, J = 7.3 Hz, 1 H), 4.11 (s, 1 H), 3.61-3.68 (m, 1 H), 3.37-3.46 (m, 1 H), 3.24-3.28 (m, 1 H), 2.86-3.08 (m, 9 H), 2.65 (t, J = 15.1 Hz, 1 H), 2.44-2.54 (m, 1 H), 2.20-2.27 (m, 1 H), 1.84-1.93 (m, 1 H), 1.60-1.69 (m, 1 H), 0.86 (d, J = 6.8 Hz，3 H) ; MS (電喷霧）m/z 566.2 (M+H)。S14-6-4-B : *H NMR (400 MHz, CD3OD) δ 7.07 (s, 1 H), 5.10 (d, J = 7.3 Hz, 1 H), 4.11 (s, 1 H), 3.61-3.68 (m, 1 H), 3.37-3.46 (m, 1 H), 3.24-3.28 (m, 1 H), 2.86-3.08 (m, 9 H), 2.65 (t, J = 15.1 Hz, 1 H), 2.44-2.54 (m, 1 H), 2.20-2.27 (m, 1 H), 1.84-1.93 (m, 1 H), 1.60-1.69 (m, 1 H), 0.86 (d, J = 6.8 Hz, 3 H) ; MS (electrospray) m/z 566.2 (M+H).

S14-6-4-C ： !H NMR (400 MHz, CD3OD) δ Ί .3,1 (s, 1 H), 4.44 (d, J = 10.5 Hz, 1 H), 4.13 (s, 1 H)} 3.53-3.58 (m, 2 H), 3.24-3.28 (m, 1 H), 2.95-3.04 (m, 8 H), 2.62-2.69 (m, 2 H), 2.37-2.45 (m, 1 H), 2.20-2.27 (m, 1 H), 1.81-1.90 (m, 1 H)，1.60-1.69 (m，1 H)，1.01 (d, J = 6.8 Hz，3 H) ; MS (電喷 霧）m/z 566.2 (M+H)。S14-6-4-C : !H NMR (400 MHz, CD3OD) δ Ί .3,1 (s, 1 H), 4.44 (d, J = 10.5 Hz, 1 H), 4.13 (s, 1 H) } 3.53-3.58 (m, 2 H), 3.24-3.28 (m, 1 H), 2.95-3.04 (m, 8 H), 2.62-2.69 (m, 2 H), 2.37-2.45 (m, 1 H) , 2.20-2.27 (m, 1 H), 1.81-1.90 (m, 1 H), 1.60-1.69 (m, 1 H), 1.01 (d, J = 6.8 Hz, 3 H) ; MS (electrospray) m/z 566.2 (M+H).

S14-64-0 188 201245116 S14-6-4-D ： 'H NMR (400 MHz, CD3〇D) δ 7.28 (s, 1 H), 4.60 (d, J = 7.3 Hz, 1 H), 4.12 (s, 1 H), 349-3.56 (m, 2 H), 3.30-3.36 (m, 1 H), 2.95-3.04 (m, 8 H), 2.59-2.70 (m, 2 H), 2.40-2.44 (m, 1 H), 2.20-2.27 (m, 1 H), 1.84-1.90 (m3 1 H), 1.59-1.68 (m，1 H)，1.10 (d，J = 6.8 Hz, 3 H) ; MS (電喷霧） m/z 566.2 (M+H)。S14-64-0 188 201245116 S14-6-4-D : 'H NMR (400 MHz, CD3〇D) δ 7.28 (s, 1 H), 4.60 (d, J = 7.3 Hz, 1 H), 4.12 ( s, 1 H), 349-3.56 (m, 2 H), 3.30-3.36 (m, 1 H), 2.95-3.04 (m, 8 H), 2.59-2.70 (m, 2 H), 2.40-2.44 ( m, 1 H), 2.20-2.27 (m, 1 H), 1.84-1.90 (m3 1 H), 1.59-1.68 (m, 1 H), 1.10 (d, J = 6.8 Hz, 3 H) ; MS ( Electrospray) m/z 566.2 (M+H).

S14-6-5-A S14-6-5-A ： lH NMR (400 MHz, CD3OD) δ 7.15 (s, 1 H), 5.11 (d, J = 7.3 Hz, 1 H), 4.12 (s, 1 H), 3.88-3.92 (m, 1 H)，3.34-3.43 (m，2 H)，2.91-3.10 (m，12 H)，2.55-2.64 (m，2 H), 2.20-2.27 (m, 1 H), 1.78-1.88 (m, 1 H), 1.59-1.69 (m, 1 H)，0.73 (d，J = 6.8 Hz，3 H); MS (電喷霧）m/z 580.2 (M+H)。S14-6-5-A S14-6-5-A : lH NMR (400 MHz, CD3OD) δ 7.15 (s, 1 H), 5.11 (d, J = 7.3 Hz, 1 H), 4.12 (s, 1 H), 3.88-3.92 (m, 1 H), 3.34-3.43 (m, 2 H), 2.91-3.10 (m, 12 H), 2.55-2.64 (m, 2 H), 2.20-2.27 (m, 1 H), 1.78-1.88 (m, 1 H), 1.59-1.69 (m, 1 H), 0.73 (d, J = 6.8 Hz, 3 H); MS (electrospray) m/z 580.2 (M+H ).

S14-6-6-B S14-6-5-B : NMR (400 MHz，CD3OD) 5 7.22 (s，1 H), 5.11 (d, J = 7.3 Hz, 1 H), 4.12 (s, 1 H), 3.83-3.87 (m, 1 H), 3.22-3.40 (m, 2 H), 2.81-3.07 (m, 12 H), 2.55-2.71 (m, 2 H), 2.20-2.27 (m, 1 H), 1.80-1.89 (m, 1 H), 1.60-1.69 (m, 1 H)，0·89 (d，J = 6.8 Hz，3 H); MS (電喷霧）m/z 580.2 (M+H)。 189 201245116S14-6-6-B S14-6-5-B : NMR (400 MHz, CD3OD) 5 7.22 (s, 1 H), 5.11 (d, J = 7.3 Hz, 1 H), 4.12 (s, 1 H ), 3.83-3.87 (m, 1 H), 3.22-3.40 (m, 2 H), 2.81-3.07 (m, 12 H), 2.55-2.71 (m, 2 H), 2.20-2.27 (m, 1 H ), 1.80-1.89 (m, 1 H), 1.60-1.69 (m, 1 H), 0·89 (d, J = 6.8 Hz, 3 H); MS (electrospray) m/z 580.2 (M+ H). 189 201245116

S14-6-5-C ： !H NMR (400 MHz, CD3OD) δ 7.32 (s, 1 H), 4.48 (d, J = 7.3 Hz, 1 H), 4.09 (s, 1 H), 3.88-3.92 (m, 1 H), 3.34-3.43 (m, 2 H), 2.91-3.10 (m, 12 H), 2.38-2.70 (m, 2 H), 2.20-2.27 (m, 1 H), 1.78-1.88 (m, 1 H), 1.59-1.69 (m, 1 H)，0.99 (d，J = 6.8 Hz, 3 H); MS (電喷霧）m/z 580.2 (M+H)。S14-6-5-C : !H NMR (400 MHz, CD3OD) δ 7.32 (s, 1 H), 4.48 (d, J = 7.3 Hz, 1 H), 4.09 (s, 1 H), 3.88-3.92 (m, 1 H), 3.34-3.43 (m, 2 H), 2.91-3.10 (m, 12 H), 2.38-2.70 (m, 2 H), 2.20-2.27 (m, 1 H), 1.78-1.88 (m, 1 H), 1.59-1.69 (m, 1 H), 0.99 (d, J = 6.8 Hz, 3 H); MS (electrospray) m/z 580.2 (M+H).

S14-6-5-D S14-6-5-D ： !H NMR (400 MHz, CD3OD) δ 7.38 (s, 1 H), 4.49 (d, J = 7.3 Hz, 1 H), 4.10 (s, 1 H), 3.82-3.88 (m, 1 H), 3.34-3.43 (m, 2 H), 2.91-3.10 (m, 12 H), 2.55-2.64 (m, 2 H)，2.20-2.27 (m，1 H)，1.78-1.88 (m，1 H), 1.59-1.69 (m，1 霧）m/z 580.2 (Μ + Η)。S14-6-5-D S14-6-5-D : !H NMR (400 MHz, CD3OD) δ 7.38 (s, 1 H), 4.49 (d, J = 7.3 Hz, 1 H), 4.10 (s, 1 H), 3.82-3.88 (m, 1 H), 3.34-3.43 (m, 2 H), 2.91-3.10 (m, 12 H), 2.55-2.64 (m, 2 H), 2.20-2.27 (m, 1 H), 1.78-1.88 (m, 1 H), 1.59-1.69 (m, 1 fog) m/z 580.2 (Μ + Η).

H)，1.12 (d，J = 6.8 Hz，3 H); MS (電喷 F\ N-Boc-(S)-5-(氟乙基)·2·β比咯啶酮 N-B〇c-(S)_5_(氟乙基）_2_。比咯啶酮：在〇下向 (S)-5-(經甲基）-2_。比洛。定酮（！ 58 g，13 7 _〇1)及三苯基 膦（3.97 g，15」mmol，la當量）於無水乙腈（2〇… 中之懸浮液中逐滴添加力8 mL無水乙猜中之四漠化碳 (5_02g，15.lmm。卜hl當量）。所得透明溶液在室溫下 授拌隔夜。藉由旋轉蒸發移除溶劑且藉由.邮急驟層析 190 201245116 •純化殘餘物，得到呈白色固體狀之（s)_5_(溴f基）_2_吡咯啶 酮（2.32§，95〇/0):4匪11(4〇〇]^2，^3〇]；))5618(1^ s, 1 H), 3.94-3.97 (m, ! H), 3.28-3.44 (m, 2 Η), 2.27-2.49 (m, 3 Η)，1.82-1.91 (m，1 Η) ο 將（S)-5-(邊甲基）_2_吼口各淀酮（j 3〇 g，7 32顏〇1)於 20 mL無水乙腈中之溶液逐滴添加至用鋁箔避光保存之H), 1.12 (d, J = 6.8 Hz, 3 H); MS (electrospray F\N-Boc-(S)-5-(fluoroethyl)·2·β-pyridinone NB〇c-( S) _5_(fluoroethyl)_2_.bipiridone: in the underarm (S)-5-(methyl)-2 _. piroxime (! 58 g, 13 7 _〇1) and Triphenylphosphine (3.97 g, 15" mmol, la equivalent) was added dropwise to the suspension of anhydrous acetonitrile (2 〇...) 8 mL of anhydrous B. The carbonized carbon (5_02 g, 15.1 mm. Hl eq.) The resulting clear solution was stirred overnight at room temperature. The solvent was removed by rotary evaporation and purified by flash chromatography 190 201245116. The residue was purified to afford (s) _5_ (br. Base)_2_pyrrolidone (2.32§, 95〇/0): 4匪11(4〇〇]^2,^3〇];))5618(1^ s, 1 H), 3.94-3.97 (m , ! H), 3.28-3.44 (m, 2 Η), 2.27-2.49 (m, 3 Η), 1.82-1.91 (m,1 Η) ο will (S)-5-(edge methyl)_2_吼A solution of each of the ketones (j 3〇g, 7 32 〇 1) in 20 mL of anhydrous acetonitrile was added dropwise to the aluminum foil to protect it from light.

AgF ( 2·32 g ’ 18·30 mmo卜2.5當量）於9 mL乙腈中之懸 浮液中。反應混合物在室溫下攪拌4〇小時且接著經由矽藻 土墊過濾。減壓濃縮濾液，得到棕色油狀物，用Et〇Ac濕 磨；藉由過濾移除所形成之固體。濃縮淺黃色濾液，得到 呈淺黃色油狀之（S)-5_(氟〒基）_2_吡咯啶酮（〇 555 g， 650/0 ):^^11(400 ^2/0300)5 6.74(^ ^4 30 (d, J = 46 Hz, 2 H), 3.86-3.97 (m, 1 H), 2.14-2.42 (m, 3 H), 1 _74-l .83 (m，1 H) 〇 在室溫下向（S)-5_(氟甲基l·2-吡咯啶酮（144 mg，1.23 mmol ’ i當量）於乙腈（5 mL )中之溶液中添加（b〇c)2〇( 295 mg，1_35 mm〇1，u 當量）及 DMAp ( 15 叫，〇 12 腿心， 〇.1當量）。在室溫下攪拌混合物4小時後，藉由旋轉蒸發 移除溶劑。藉由Biotage急驟層析純化殘餘物，得到呈無色 油狀之 n-b〇c-(s)_5_(氟乙基）_2_吡咯啶_(2i2mg，79%): *H NMR (400 MHz, CD3OD) 5 4.57 (d, J = 46 Hz, 1 H), 4.29 (d, J = 27 Hz, 1 H), 2.62-2.72 (m, 1 H), 2.38-2.46 (m, 1 H)，2.13-2.24 (m，1 H)，2.02-2.07 (m，1 H)。 根據與製備S14-6-1-A所用類似之程序自S11_2及 191 201245116 N-Boc-(S)-5-(氟乙基）-2-°比略。定酮製備以下化合物。AgF (2·32 g '18·30 mmo, 2.5 equivalents) was suspended in 9 mL of acetonitrile. The reaction mixture was stirred at room temperature for 4 hours and then filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a brown oil, which was then evaporated. Et. The pale yellow filtrate was concentrated to give (S)-5-(fluoroindolyl)-2-pyrrolidone (〇555 g, 650/0):^^11 (400^2/0300)5 6.74 ^ ^4 30 (d, J = 46 Hz, 2 H), 3.86-3.97 (m, 1 H), 2.14-2.42 (m, 3 H), 1 _74-l .83 (m,1 H) 〇 Add (b〇c) 2〇(295) to a solution of (S)-5_(fluoromethyl l.2-pyrrolidone (144 mg, 1.23 mmol 'i equivalent) in acetonitrile (5 mL) at rt. Mg, 1_35 mm〇1, u equivalent) and DMAp (15 〇, 〇12 leg core, 〇.1 equivalent). After stirring the mixture for 4 hours at room temperature, the solvent was removed by rotary evaporation. The residue was purified to give nb?c-(s)_5_(fluoroethyl)-2-pyrrolidinium (2i2mg, 79%) as a colorless oil: *H NMR (400 MHz, CD3OD) 5 4.57 (d, J = 46 Hz, 1 H), 4.29 (d, J = 27 Hz, 1 H), 2.62-2.72 (m, 1 H), 2.38-2.46 (m, 1 H), 2.13-2.24 (m, 1 H ), 2.02-2.07 (m, 1 H). Procedure similar to that used for the preparation of S14-6-1-A from S11_2 and 191 201245116 N-Boc-(S)-5-(fluoroethyl)-2-° The following compounds were prepared.

S14-6-6 ： NMR (400 MHz, CD3OD) δ 7.26 (s, 1 Η), 5.17 (t5 J = 7.8 Hz, 1 H), 4.70-4.95 (m, 1 H), 4.12-4.25 (m, 1 H), 4.12 (s, 1 H), 3.20-3.28 (m, 1 H), 2.90-3.06 (m, 9 H), 2.64 (t, J = 15.1 Hz, 1 H), 2.50-2.60 (m, 1 H), 2.34-2.46 (m, 1 H)，2.10-2.2 8 (m，3 H)，1.5 9-1.69 (m，1 H) ; MS (電喷霧）m/z 584.2 (M+H) ° 實施例15.合成其中環E為吡咯啶-2-基之式I化合物 根據以下流程15合成式I化合物，其中X為-CF3，Y 為-Η且壤E為°比洛唆-2 -基。 流程15 192 201245116S14-6-6 : NMR (400 MHz, CD3OD) δ 7.26 (s, 1 Η), 5.17 (t5 J = 7.8 Hz, 1 H), 4.70-4.95 (m, 1 H), 4.12-4.25 (m, 1 H), 4.12 (s, 1 H), 3.20-3.28 (m, 1 H), 2.90-3.06 (m, 9 H), 2.64 (t, J = 15.1 Hz, 1 H), 2.50-2.60 (m , 1 H), 2.34-2.46 (m, 1 H), 2.10-2.2 8 (m, 3 H), 1.5 9-1.69 (m, 1 H) ; MS (electrospray) m/z 584.2 (M+ H) ° Example 15. Synthesis of a compound of formula I wherein ring E is pyrrolidin-2-yl. According to the following Scheme 15, a compound of formula I is synthesized, wherein X is -CF3, Y is -Η and the soil E is ° 唆 唆 - 2-base. Flow 15 192 201245116

BrBr

CH, ΧΗ &gt;.0i^ 〇hc^^ch3 ohc、CH, ΧΗ &gt;.0i^ 〇hc^^ch3 ohc,

j JL 『。' ^ΤΎ ^ ΤΎ Br2/HOAc‘ II 、j^C〇2Ph Pd(PPh3)4 y^C02Ph ^^C02Ph 、C02Ph OCH3 K2C03 OCH3 OCH3 OCH3 S1-5 S15-1 S15-2 cf3 OHC ^CH3j JL 『. ' ^ΤΎ ^ ΤΎ Br2/HOAc' II , j^C〇2Ph Pd(PPh3)4 y^C02Ph ^^C02Ph , C02Ph OCH3 K2C03 OCH3 OCH3 OCH3 S1-5 S15-1 S15-2 cf3 OHC ^CH3

C02Ph C H p2CC F2S02F OBn S15-6C02Ph C H p2CC F2S02F OBn S15-6

CulCul

Br OHC.Br OHC.

ch3 C02Ph OBn S15-5Ch3 C02Ph OBn S15-5

BnBr驗 S15-3BnBr test S15-3

〇 晒i tBuv，SxNH2 n晒 sun t tuv, SxNH2 n

Ti(〇Et)4Ti(〇Et)4

MgBf . S15-4MgBf . S15-4

1. TFA-H2O 2. NaBH(OAc)31. TFA-H2O 2. NaBH(OAc)3

a. LDA/TMEDAa. LDA/TMEDA

醛aldehyde

AcOHAcOH

NaBH(OAc)3NaBH(OAc)3

1. HF水溶液 2. Hz/Pd-C1. HF aqueous solution 2. Hz/Pd-C

根據流程1 5製備以下化合物。The following compounds were prepared according to Scheme 15.

och3 S15-1 合成S15-1Och3 S15-1 Synthesis S15-1

將化合物 S1-5 ( 20 g，62·5 mmol，1.0 當量）、2,4,6-三乙烯基環三硼氧烷-°比啶複合物（7.8 g，31.25 mmol，0.50 當量）、Pd(PPh3)4( 2·2 g，1.88 mmo卜 0.030 當量）及 K2C03 (17.25 g，125 mmol，2.0當量）添加至容器中之1.4 mL 193 201245116 二噁烧：H2〇 ( 3 :1，V: V )中。用n2在混合物中鼓泡以移除 〇2 6次。加熱混合物至回流持續19小時。濃縮混合物。使 殘餘物分配於EtOAc與水之間。有機層經Na2S04脫水且蒸 發至乾燥。藉由矽膠管柱層析（以（石油醚：Et〇Ac = 200:1 至100:1至50:1梯度）洗提）純化粗化合物。此舉得到14 8 g ( 88.3%)呈淺黃色固體狀之化合物S15-1 : 4 NMR (400 MHz, CDC13) δ 7.38-7.34 (m, 2 Η), 7.27-7.16 (m, 3 Η), 6.83-6.76 (m, 2 Η), 6.65-6.60 (m, 1 Η), 5.72 (d, / = 17.6 Hz, 1 Η), 5.25 (d, 7=11.2 Hz, 1 H), 3.83 (s, 3 H), 2.38 (s, 3 H)；: MS (ESI) w/z 269.1 (M+H)。 ohc^^ch3 ^co2Ph 0CH3 S15-2 * M S15-2 使富含臭氧之氧蒸汽鼓泡通過化合物si5-1( 21 g，78.3 nunol ’ 1.0當量）於無水ch2C12中之冷（-78°C )溶液，直 至其變為淺藍色。利用TLC追蹤反應。在-78。(：下用氬氣淨 化溶液10分鐘以移除過量〇3。將CH3SCH3 ( 50 mL)添加 至反應混合物中且自-78°C至25°C攪拌5小時。濃縮反應 物。藉由矽膠管柱層析（以（石油醚：Et〇Ac = 1〇〇:1至50:1 至3 0:1梯度）洗提）純化粗化合物，得到13 g ( 6丨6% )呈 淺黃色固體狀之化合物S15-2 : 4 NMR (400 MHz, CDC13) δ 9.97 (s, 1 Η), 7.46-7.41 (m, 2 Η), 7.36-7.22 (m, 5 Η), 3.92 (s，3 Η)，2.51 (s，3 Η) ; MS (ESI) m/z 271.1 (Μ + Η)。 194 201245116Compound S1-5 (20 g, 62·5 mmol, 1.0 eq.), 2,4,6-trivinylcyclotriborane-pyridinium complex (7.8 g, 31.25 mmol, 0.50 equivalent), Pd (PPh3) 4 (2·2 g, 1.88 mmo, 0.030 equivalent) and K2C03 (17.25 g, 125 mmol, 2.0 equivalents) were added to the vessel in a 1.4 mL 193 201245116 dioxane: H2〇 (3:1, V: V). The mixture was bubbled with n2 to remove 〇26 times. The mixture was heated to reflux for 19 hours. The mixture was concentrated. The residue was partitioned between EtOAc and water. The organic layer was dried over Na 2 SO 4 and evaporated to dryness. The crude compound was purified by hydrazine column chromatography eluting with (petroleum ether: Et sAc = 200:1 to 100:1 to 50:1 gradient). This gave 14 8 g (88.3%) of the compound S15-1 as a light yellow solid: 4 NMR (400 MHz, CDC13) δ 7.38-7.34 (m, 2 Η), 7.27-7.16 (m, 3 Η), 6.83-6.76 (m, 2 Η), 6.65-6.60 (m, 1 Η), 5.72 (d, / = 17.6 Hz, 1 Η), 5.25 (d, 7=11.2 Hz, 1 H), 3.83 (s, 3 H), 2.38 (s, 3 H);: MS (ESI) w/z 269.1 (M+H). Ohc^^ch3 ^co2Ph 0CH3 S15-2 * M S15-2 Ozone-rich oxygen vapour was bubbled through compound si5-1 (21 g, 78.3 nunol '1.0 equivalent) in anhydrous ch2C12 (-78 ° C ) The solution until it turns light blue. The reaction was followed by TLC. At -78. (: The solution was purged with argon for 10 minutes to remove excess hydrazine 3. CH3SCH3 (50 mL) was added to the reaction mixture and stirred from -78 ° C to 25 ° C for 5 hours. The reaction was concentrated. Column chromatography (extraction with (petroleum ether: Et 〇Ac = 1 〇〇: 1 to 50:1 to 3 0:1 gradient)) to afford the crude compound to afford 13 g (6 6%) as a pale yellow solid Compound S15-2 : 4 NMR (400 MHz, CDC13) δ 9.97 (s, 1 Η), 7.46-7.41 (m, 2 Η), 7.36-7.22 (m, 5 Η), 3.92 (s, 3 Η) , 2.51 (s, 3 Η) ; MS (ESI) m/z 271.1 (Μ + Η). 194 201245116

OCH； S15-3 合成Si5-3 g，6.62 mmol，1當量）溶解於 將化合物S15-2 ( 1.8 HOAc中將/臭（i.6mL，26.5 mmol，4當量）逐滴添加至 浴液中。在室溫下攪拌反應混合物丨小時。濃縮混合物。 將殘餘物溶解於EtOAc乍且用飽和NaHC〇3、鹽水及水洗 滌。有機物經NhSCU脫水且濃縮至乾燥，得到19 g呈淺 黃色固體狀之化合物S15-3。OCH; S15-3 Synthetic Si5-3 g, 6.62 mmol, 1 eq.) was dissolved in compound S15-2 (1. 6 mL, 26.5 mmol, 4 eq.) was added dropwise to the bath. The reaction mixture was stirred at room temperature for EtOAc (EtOAc) EtOAc (EtOAcjjjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Compound S15-3.

BrBr

OH S154OH S154

OHC 合成S15-4 在- 78°C 下將 BBr3 (4.9g，1.9 mL，19.5 mmol，1.5 當 量）添加至 S15-3(3.5g，13.0 mmol，1.0 當量）之 CH2CI2 溶液（30 mL)中。攪拌反應物自-78°C至25QC持續1.5小 時，用飽和NaHCOs中止且以EtOAc萃取。經合併之Et〇Ac 萃取物經脫水（NazSO4)且濃縮，得到3·3 g粗物質s15_4。OHC Synthesis S15-4 BBr3 (4.9 g, 1.9 mL, 19.5 mmol, 1.5 eq.) was added to a solution of &lt;RTI ID=0.0&gt;&gt; The reaction was stirred from -78.degree. C. to EtOAc (EtOAc). The combined Et〇Ac extract was dehydrated (NazSO4) and concentrated to give 3·3 g of crude material s15_4.

BrBr

OBn S15-5OBn S15-5

OHC 合成S15 - 5 將 K2CO3 ( 3_6 g，26.0 mmo卜 2_0 當量）及填甲苯（4.2 195 201245116 g，26.0 mmol，2.0 當量）添加至化合物 SI 5-4(3.3g，13.0 mmol，1.0當量）於DMF ( 1 5 mL )中之溶液中。在室溫下 攪拌反應混合物2小時。過濾反應混合物（EtOAc洗滌）》 添加水（150 mL )，且用EtOAc萃取混合物。有機層經Na2S04 脫水且濃縮。藉由矽膠管柱層析（以（石油醚：EtOAc = 1 00:1 至5 0:1梯度）洗提）純化粗化合物。此舉得到3 5 g ( 6丨7〇/〇， 3個步驟）呈淺黃色固體狀之化合物S15-5 : 4 NMR (400 MHz, CDC13) δ 10.43 (s, 1 Η), 7.46-7.30 (m, 9 Η), 7.08-7.05 (m, 2 Η), 5.17 (s, 2 Η), 2.52 (s, 3 Η) ； MS (ESI) m/z 425.1 (M+H) ° cf3 0HC^L/CH3 ψοο,, OBn S15-6 合成S15-6 向化合物S15-5 (5 g，11.8 mmol，1.0當量）於無水 DMF 中之溶液中添加 CH302CCF2S02F ( 11.3 g，59 mmol， 5.0 當量）及 Cul ( 4.5 g，23.6 mmol，2.0 當量）。將反應 物加熱至1 00°C持續20小時。過濾混合物且用EtOAc洗滌。 濃縮溶液且用EtOAc及水萃取。有機層經Na2S04脫水且濃 縮’得到7 g呈棕色油狀之粗化合物S15-6 : 4 NMR (400 MHz, CDCI3) δ 10.35-10.32 (m, 1 Η), 7.40-7.28 (m, 9 Η), 7.02-6.83 (m，2 Η)，5.17 (s，2 Η)，2.55-2.51 (m，3 Η) ; MS (ESI) m/z 415.1 (Μ + Η) 0 196 201245116OHC synthesis S15 - 5 K2CO3 (3_6 g, 26.0 mmo 2_0 equivalent) and toluene (4.2 195 201245116 g, 26.0 mmol, 2.0 eq.) were added to compound SI 5-4 (3.3 g, 13.0 mmol, 1.0 eq) In a solution in DMF (1 5 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered (EtOAc EtOAc)EtOAc. The organic layer was dried over Na 2 SO 4 and concentrated. The crude compound was purified by hydrazine column chromatography eluting with (EtOAc (EtOAc: EtOAc: EtOAc:EtOAc) This gave 35 g (6丨7〇/〇, 3 steps) of compound S15-5 as a pale yellow solid: 4 NMR (400 MHz, CDC13) δ 10.43 (s, 1 Η), 7.46-7.30 ( m, 9 Η), 7.08-7.05 (m, 2 Η), 5.17 (s, 2 Η), 2.52 (s, 3 Η) ; MS (ESI) m/z 425.1 (M+H) ° cf3 0HC^L /CH3 ψοο,, OBn S15-6 Synthesis of S15-6 To a solution of compound S15-5 (5 g, 11.8 mmol, 1.0 eq.) in anhydrous DMF, CH302 CCF2S02F ( 11.3 g, 59 mmol, 5.0 eq.) and C. 4.5 g, 23.6 mmol, 2.0 eq.). The reaction was heated to 100 ° C for 20 hours. The mixture was filtered and washed with EtOAc. The solution was concentrated and extracted with EtOAc and water. The organic layer was dried over Na 2 SO 4 and concentrated to give 7 g of crude compound: s. , 7.02-6.83 (m, 2 Η), 5.17 (s, 2 Η), 2.55-2.51 (m, 3 Η) ; MS (ESI) m/z 415.1 (Μ + Η) 0 196 201245116

合成S15-7 在n2氛圍下向S15_5 ( 4 〇 &amp; 9·7〇 mmol )於 THF ( 39 mL)中之〉谷液令添加τ ) 液（工業級，約20% Ti ; 20.1 mL，19.4 mmo卜 2.0 當量），垃- 田里）’接者添加(^)_第三丁烷 續醯胺（1.76g，14.6匪。卜15告 丄弟丁坑亞 D田里）〇在室溫下攪掉 得黃色溶液且利用LC_MS追 得化元成後’在快速搜掉 的同時將反應混合物傾入8〇 mL鹽水中，且再繼續攪拌30 分鐘。經㈣藻土塞過滤所得懸浮液，且用⑽Ac洗條濟 餅。㈣液轉移至分液漏斗中，纟中有機層心水洗務「 經硫酸納脫水，且減懸遣娘。r ^ . 减M，農細藉由Biotage急驟層析純化殘 餘物，得到呈灰白色泡床狀之化合物S15_7( 4 〇7 g，81% ): *H NMR (400 MHz, CDC13) 5 8.96 (br. s5 1 H), 7.23-7.45 (m, 9 H), 7.08 (d, /= 7.3 Hz, 2 H), 5.25 (s, 2 H), 2.58 (q, J = 3-2 Hz, 3 H), 1.24 (s, 9 H) ； MS (f ^ w/z 518&gt;5 (M+H) 〇Synthesis of S15-7 To a solution of S15_5 (4 〇 &amp; 9·7 mmol) in THF (39 mL) in a n2 atmosphere, add τ) solution (industrial grade, about 20% Ti; 20.1 mL, 19.4) Mmob 2.0 equivalent), La-Tian) 'Receiver added (^) _ third butane continued decylamine (1.76g, 14.6 匪. Bu 15 丄 丄 丁 坑 亚 亚 D D Tianli) 〇 at room temperature After the yellow solution was stirred off and the chemical was taken up by LC_MS, the reaction mixture was poured into 8 mL of brine while rapidly searching, and stirring was continued for another 30 minutes. The resulting suspension was filtered through a (iv) algae plug and the cake was washed with (10)Ac. (4) The liquid is transferred to the separatory funnel, and the organic layer of the sputum is washed with water. The sodium sulphate is dehydrated and the suspension is suspended. r ^ . minus M, the residue is purified by Biotage flash chromatography to obtain a grayish white bubble. Bed-like compound S15_7 (4 〇7 g, 81%): *H NMR (400 MHz, CDC13) 5 8.96 (br. s5 1 H), 7.23-7.45 (m, 9 H), 7.08 (d, /= 7.3 Hz, 2 H), 5.25 (s, 2 H), 2.58 (q, J = 3-2 Hz, 3 H), 1.24 (s, 9 H) ; MS (f ^ w/z 518&gt;5 (M +H) 〇

S15-8-AS15-8-A

合成 S15-8-A 向經火焰烘乾之燒瓶中裝入鎖屑（1 〇 ·94 g，45〇 1 ) 及催化量之I2( 761.4 mg，3 mmol)，在N2下用加熱槍（heat gun)加熱2分鐘。一旦其冷卻至室溫，即添加THF ( i 5〇 197 201245116 mL)。添加一小份2♦溴乙基）_1&gt;3二噁烷（2〇 3社，ΐ5〇 mmol)於THF (50 mL)中之溶液。反應開始後，經由套管 添加其餘2-(2-溴乙基二噁烷溶液。於室溫水浴中週期 性冷卻反應混合物以防止回流。添加2_(2溴乙基二噁 貌溶液完成後’授拌反應混合物2小時。隨後將溶液轉移 至確定密封之瓶中以移除剩餘Mg且儲存於冰箱中供未來 使用》 在-78C下在10分鐘内向化合物§15-7(2.32 g,4.49 nnnol)於THF( 18mL)中之溶液中添加上文製備之格林納 溶液（Grignard solution) (ll_2mL)。在此溫度下攪拌混 合物1小時30分鐘後，移除冷浴。當内部溫度達到_48t時， 添加NH4CI飽和水/谷液（30 mL)。分離各層。用Et〇Ac (X2)萃取水層。經合併之有機層以鹽水洗滌，經硫酸鈉 脫水，且減壓濃縮’得到呈白色固體狀之粗產物，使其懸 ’羊於2 5 mL庚烧中。在至溫下搜摔混合物1小時3 〇分鐘， 藉由過滤收集固體且用小份庚烧洗務。在高真空下進一步 乾燥，得到呈白色固體狀之化合物S15-8-A( 2.70 g，95%): H NMR (400 MHz, CDCI3) § (d，《/ = 7 3 Hz 2 H) 7.31-7.37 (m, 5 H), 7.22 (t, J = 7.3 Hz, 1 H), 7.15 (s, 1 H), 7-05 (d, J= 7.3 Hz, 2 H), 5.20 (s, 2 H), 4.88 (dd, /= 7.8, 11.2 Hz, 1 H), 4.47 (t, J - 4.6 Hz, 1 H), 4.04-4.09 (m, 2 H), ^-71-3.75 (m, 3 H), 2.52 (q, J= 3.2 Hz, 3 H), 1.98-2.09 (m, 1 H), 1.81-1.90 (ni, 2 H), 1.62-1.71 (m, 1 H), 1.47-1.57 (m 1Synthesis of S15-8-A To a flame-dried flask, load locks (1 〇·94 g, 45〇1) and catalytic amount of I2 (761.4 mg, 3 mmol) were used. Heat gun was used under N2. Gun) heated for 2 minutes. Once it was cooled to room temperature, THF (i 5 〇 197 201245116 mL) was added. A small portion of a solution of 2♦ bromoethyl) _1 &gt; 3 dioxane (2 〇 3, ΐ 5 〇 mmol) in THF (50 mL) was added. After the reaction started, the remaining 2-(2-bromoethyldioxane solution was added via cannula. The reaction mixture was periodically cooled in a room temperature water bath to prevent reflux. Adding 2_(2 bromoethyl dioxin solution after completion) The reaction mixture was allowed to mix for 2 hours. The solution was then transferred to a defined bottle to remove the remaining Mg and stored in the refrigerator for future use. Under the -78 C in 10 minutes to the compound §15-7 (2.32 g, 4.49 nnnol) The Grignard solution (11 - 2 mL) prepared above was added to a solution in THF (18 mL). After stirring the mixture at this temperature for 1 hour and 30 minutes, the cold bath was removed. When the internal temperature reached _48 t The NH4CI saturated water/salt (30 mL) was added. The layers were separated and evaporated, evaporated, evaporated, evaporated, evaporated. The crude product was allowed to be suspended in 2 5 mL of heptane. The mixture was poured down to the temperature for 1 hour and 3 minutes, and the solid was collected by filtration and washed with a small portion of heptane. Further under high vacuum. Drying to give the compound S15-8-A as a white solid ( 2.70 g, 95%): H NMR (400 MHz, CDCI3) § (d, "/ = 7 3 Hz 2 H) 7.31-7.37 (m, 5 H), 7.22 (t, J = 7.3 Hz, 1 H) , 7.15 (s, 1 H), 7-05 (d, J = 7.3 Hz, 2 H), 5.20 (s, 2 H), 4.88 (dd, /= 7.8, 11.2 Hz, 1 H), 4.47 (t , J - 4.6 Hz, 1 H), 4.04-4.09 (m, 2 H), ^-71-3.75 (m, 3 H), 2.52 (q, J = 3.2 Hz, 3 H), 1.98-2.09 (m , 1 H), 1.81-1.90 (ni, 2 H), 1.62-1.71 (m, 1 H), 1.47-1.57 (m 1

H)，1.3 0 (d，·/= 11.9 Hz, 1 H)，1.17 (s，9 H); MS (電喷霧）m/Z 198 201245116H), 1.3 0 (d,··= 11.9 Hz, 1 H), 1.17 (s, 9 H); MS (electrospray) m/Z 198 201245116

63 4.6 (M+H)。63 4.6 (M+H).

OBn Ο 對映異構體A S15-9-AOBn Ο enantiomer A S15-9-A

合成 SI 5-9-A 將化合物S15-8-A(2.70g’ 4_26mmol)添加至於冰浴 中冷卻之TFA - H2〇 ( 21 mL - 21 mL )的混合物中。接著在 6°C下攪拌所得混合物且利用LC-MS追蹤轉化。完成後，將 反應混合物冷卻至-20°C，且添加NaBH(〇Ac)3。隨後使溫度 升溫至室溫。在室溫下搜拌混合物1小時後，使其再冷卻 至0°C。用45% KOH水溶液調節溶液之pH值至約8。用 MTBE ( x3 )萃取水溶液。經合併之有機層以鹽水洗滌，經 硫酸納脫水’且減壓濃縮。藉由Biotage急驟層析純化殘餘 物，得到呈淺黃色油狀之化合物SI5-9-A ( 1.29 g，66°/。）： Ή NMR (400 MHz, CDC13) δ 7.67 (s，1 H)，7.22-7.46 (m 8 H), 7.08 (d, J = 7.3 Hz, 2 H), 5.22 (ABq, J= 11.4, 18.4 Hz 2 H), 4.64-4.69 (m, 1 H), 3.02-3.16 (m, 2 H), 2.53 (q, J = 3 2 Hz，3 H)，2.21-2.30 (m，1 H)，1.85 (br s，1 H)，1.73-1.80 (m，2 H)，1.44-1.52 (m, 1 H) ; MS (電喷霧）m/z 456.5 (M+H)。Synthesis of SI 5-9-A Compound S15-8-A (2.70 g' 4 - 26 mmol) was added to a mixture of TFA-H2 (21 mL - 21 mL) cooled in ice bath. The resulting mixture was then stirred at 6 ° C and the transformation was followed by LC-MS. After completion, the reaction mixture was cooled to -20 ° C, and NaBH (〇Ac) 3 was added. The temperature was then allowed to warm to room temperature. After mixing the mixture for 1 hour at room temperature, it was again cooled to 0 °C. The pH of the solution was adjusted to about 8 with a 45% aqueous KOH solution. The aqueous solution was extracted with MTBE (x3). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated. Purification of the residue by EtOAc (EtOAc) EtOAc (EtOAc: EtOAc: 7.22-7.46 (m 8 H), 7.08 (d, J = 7.3 Hz, 2 H), 5.22 (ABq, J= 11.4, 18.4 Hz 2 H), 4.64-4.69 (m, 1 H), 3.02-3.16 ( m, 2 H), 2.53 (q, J = 3 2 Hz, 3 H), 2.21-2.30 (m, 1 H), 1.85 (br s, 1 H), 1.73-1.80 (m, 2 H), 1.44 -1.52 (m, 1 H); MS (electrospray) m/z 456.5 (M+H).

非對映異構體A S15-10-ADiastereomer A S15-10-A

合成 S15-10-A 在-78°C下在N2氛圍下將π-BuLi於己烷中之溶液（2 199 201245116 Μ’ 0.21 mL’ 0.53 mm〇i，2.4 當量）逐滴添加至％贿（^ β L，0.55 mmo卜2.5當量）於THF ( 2 mL·)令之溶液中 反應溶液在-781下攪拌20分鐘且在〇°c下攪拌5分鐘， 再冷卻至-78°C。添加 TMEDA ( 86 &quot; L，0_57 _〇1，2 6 當量）’接著經由套管添加S15-9-A ( 110 mg，〇 24 m &amp; mmol , 1.1當量）於THF ( 2 mL )中之溶液。所得暗橙色混合物在 -78°C下攪拌35分鐘且冷卻至_10(rc。經由套管逐滴添加烯 酮 S2-1 ( 1〇6 mg，0.22 mmol ’ 1.0 當量）於 THF ( 2 mL) 中之溶液。使所得混合物逐漸升溫至_78°C。添加LHmds (1.0M/THF，220 &quot;L’OWmmo卜 1.0 當量）。使反應 混合物逐漸升溫至-5°C。添加ΝΗβΙ飽和水溶液。用Et〇Ac 萃取混合物三次。經合併之Et0Ac萃取物以鹽水洗條，經 Na2S〇4脫水，且濃縮。藉由Biotage急驟層析純化殘餘物， 得到呈淺黃色泡沫狀之化合物S15-10-A ( 61 mg，33%): 'H NMR (400 MHz, CDCI3) δ 7.66 (s, 1 Η), 7.27-7.50 (m, 10 Η), 5.35 (s, 2 Η), 5.29 (s, 1 Η), 4.54 (t, J= 6.9 Hz, 1 H), 3.97 (d, J = 10.4 Hz, 1 H), 3.21 (dd, J - 4.9, 15.9 jjz, 1 H), 2.99-3.13 (m, 2 H), 2.67-2.88 (m, 2H), 2.17-2.56 (m, 8 H), 2.12 (d, J= 14.6 Hz, 1 H), 1.54-1.80 (m, 3 H), 1.34-1.48 (m, 2 H)，0.83 (s，9 H), 0.26 (s，3 H)，0.14 (s，3 H) ; MS (電喷霧） m/z 844.8 (M + H)。Synthesis of S15-10-A A solution of π-BuLi in hexane (2 199 201245116 Μ '0.21 mL '0.53 mm〇i, 2.4 eq) was added dropwise to a bribe at -78 ° C under N2 atmosphere. ^β L, 0.55 mmo, 2.5 equivalents) The solution was stirred in THF (2 mL·) in EtOAc. Add TMEDA (86 &quot; L, 0_57 _〇1, 2 6 eq.)' then add S15-9-A (110 mg, 〇24 m &amp; mmol, 1.1 eq.) in THF (2 mL) via cannula Solution. The resulting dark orange mixture was stirred at -78 °C for 35 min and cooled to _10 (rc. EtOAc (1 EtOAc, EtOAc) The solution was gradually warmed to -78 ° C. LHmds (1.0M / THF, 220 &quot; L'OWmmob 1.0 eq.) was added. The reaction mixture was gradually warmed to -5 ° C. A saturated aqueous solution of ΝΗβΙ was added. The mixture was extracted three times with Et.sub.Ac. The combined Et0Ac extracts were washed with brine, dried over Na 2 EtOAc, and concentrated. A (61 mg, 33%): 'H NMR (400 MHz, CDCI3) δ 7.66 (s, 1 Η), 7.27-7.50 (m, 10 Η), 5.35 (s, 2 Η), 5.29 (s, 1 Η), 4.54 (t, J= 6.9 Hz, 1 H), 3.97 (d, J = 10.4 Hz, 1 H), 3.21 (dd, J - 4.9, 15.9 jjz, 1 H), 2.99-3.13 (m, 2 H), 2.67-2.88 (m, 2H), 2.17-2.56 (m, 8 H), 2.12 (d, J= 14.6 Hz, 1 H), 1.54-1.80 (m, 3 H), 1.34-1.48 ( m, 2 H), 0.83 (s, 9 H), 0.26 (s, 3 H), 0.14 (s, 3 H); MS (electrospray) m/z 844.8 (M + H).

200 201245116200 201245116

合成 S15-12-1-A 將化合物 S15-10-A ( 30 mg，〇 〇36 mm〇1，i 當量）溶 解於1，2-二氯乙烷（1 mL)中。添加環丙烷羧醛（8 〇 v L， 〇.Umm〇l，3當量）及乙酸（8」八，〇 14_〇丨，4當量）。 在室溫下攪拌30分鐘後，添加三乙醯氧基硼氫化鈉（22.6 mg，〇_11 mmo丨，3當量）。繼續攪拌隔夜。將反應混合物 傾入NaHC〇3飽和水溶液中。用CH2Ci2萃取混合物三次。 經合併之有機萃取物以鹽水洗滌，經Na2S〇4脫水且濃縮， 得到粗物質S15-11-1-A，在無進一步純化的情況下將其直 接用於下一步骅。Synthesis of S15-12-1-A Compound S15-10-A (30 mg, 〇 〇 36 mm 〇 1, i equivalent) was dissolved in 1,2-dichloroethane (1 mL). Cyclopropanecarboxaldehyde (8 〇 v L, U.Umm〇l, 3 equivalents) and acetic acid (8 VIII, 〇 14 〇丨, 4 equivalents) were added. After stirring at room temperature for 30 minutes, sodium triethoxysulfonate borohydride (22.6 mg, 〇_11 mmol, 3 equivalents) was added. Continue to stir overnight. The reaction mixture was poured into a saturated aqueous solution of NaHC.sub.3. The mixture was extracted three times with CH2Ci2. The combined organic extracts were washed with EtOAc EtOAc EtOAc m.

在聚丙烯小瓶中，將粗物質S15-U-1-A溶解於CH3CN (1.0 mL)中。添加jjF水溶液（48%，0.25 mL)。在室溫 下攪拌16小時後，將反應混合物傾入K2HP〇4水溶液（丨.75 g於12.5 mL水中）中。用CH2Ch萃取混合物三次。經合 併之有機相以鹽水洗條，經硫酸納脫水，且濃縮至乾燥。 將上述粗物質溶解於〇.5NHCl之曱醇（2〇〇 #L)溶 液中尤务過5·揮發物。將預先形成之鹽酸鹽再次溶解於 曱醇（2.0 mL)中且向所得溶液中添加鈀/碳（i〇 wt%，η g)短暫地抽空反應燒瓶且再填充氫氣。在室溫下攪拌 反應混合物且利用LC_MS監測反應。起始物質消耗完後， ，由小型♦藻土塾過濾、混合物。濃㈣液，得到粗物質， 错由HPLC在Waters自動純化系、統上使用Phenomenex Polymerx 10 &quot; Rp_y 1〇〇 r 管柱_，1〇 微 米，流速.20 mL/min ;溶劑 A : 0.05 N HC1/水；溶劑 Β : 201 201245116 CH3CN ;注入體積：4 〇 mL ( 0.05 N HC1/水）；梯度：l〇 〜40% B，經1〇分鐘；質量導向型洗提份收集]將其純化。 收集在8.25-8.90分鐘洗提之具有所需分子量之洗提份且冷 4乾燥’得到呈黃色固體狀之化合物Si5-12-1-A ( 8.5 mg， 鹽酸鹽 ’ 39%，經 3 俩步驟）：NMR (400 MHz, CD3〇D) δ 7.47 (s，1 Η)，4.78-4.85 (m，1 Η)，4.13 (s，1 Η)，4.02-4.08 (m，1 Η)，3.41-3.48 (m，1 Η)，3.23-3.28 (m，1 Η)，2.95-3.05 (m，10 Η), 2.62-2.74 (m，2 Η)，2.17-2.37 (m，4 Η), 1.60-1.69 (m，1 Η)，0.91-0.97 (m，1 Η)，0.58-0.64 (m，2 Η), 0.32-0.35 (m，1 Η)，0.21-0.25 (m，1 H); MS (電喷霧）m/z 606.6 (Μ+Η)。 根據與S15-12-1-A所用類似之程序自S15-10-A及各種 輕或酮製備以下化合物（除S15-12-3_A之外）。The crude material S15-U-1-A was dissolved in CH3CN (1.0 mL) in a polypropylene vial. An aqueous solution of jjF (48%, 0.25 mL) was added. After stirring at room temperature for 16 hours, the reaction mixture was poured into aq. K.sub.2.sub.4 solution ((.75 g in 12.5 mL water). The mixture was extracted three times with CH2Ch. The combined organic phases are washed with brine, dehydrated with sodium sulfate, and concentrated to dryness. The above crude material was dissolved in a solution of 〇.5NHCl in decyl alcohol (2 〇〇 #L), and 5 volatiles were obtained. The preformed hydrochloride was redissolved in decyl alcohol (2.0 mL) and palladium on carbon (i 〇 wt%, η g) was added to the resulting solution to briefly evacuate the reaction flask and refill with hydrogen. The reaction mixture was stirred at room temperature and the reaction was monitored by LC_MS. After the starting material is consumed, it is filtered and mixed by a small ♦ algae. Concentrated (tetra) liquid, crude material was obtained, and the Phenomenex Polymerx 10 &quot; Rp_y 1〇〇r column _, 1 〇 micron, flow rate .20 mL/min; solvent A: 0.05 N was used by HPLC in the Waters automatic purification system. HC1/water; solvent Β : 201 201245116 CH3CN ; injection volume: 4 〇mL (0.05 N HC1/water); gradient: l〇~40% B, after 1 ; minutes; mass-oriented elution fraction collection] . Collect the eluted fraction of the desired molecular weight eluted at 8.25-8.90 minutes and dry 4 to give a compound Si5-12-1-A (8.5 mg, hydrochloride '39%, 3) in a yellow solid. Step): NMR (400 MHz, CD3〇D) δ 7.47 (s, 1 Η), 4.78-4.85 (m, 1 Η), 4.13 (s, 1 Η), 4.02-4.08 (m, 1 Η), 3.41 -3.48 (m,1 Η), 3.23-3.28 (m,1 Η), 2.95-3.05 (m,10 Η), 2.62-2.74 (m,2 Η), 2.17-2.37 (m,4 Η), 1.60 -1.69 (m,1 Η), 0.91-0.97 (m,1 Η), 0.58-0.64 (m,2 Η), 0.32-0.35 (m,1 Η), 0.21-0.25 (m,1 H); MS (electrospray) m/z 606.6 (Μ+Η). The following compounds (except S15-12-3_A) were prepared from S15-10-A and various light or ketones according to procedures similar to those used for S15-12-1-A.

S15-12-2-A ： *H NMR (400 MHz, CD3OD) δ 7.52 (s, 1 Η), 4.82-4.89 (m, 1 Η), 4.14 (s, 1 Η), 3.75-3.80 (m, 1 Η), 3·43-3.50 (m, 2 Η), 3.20-3.28 (m, 1 Η), 2.96-3.05 (m, 8 Η), 2·63~2.75 (m, 2 Η), 2.17-2.34 (m, 4 Η), 1.60-1.69 (m, 1 Η), h26 (d，·/ = 6.9 Ηζ，3 Η)，1.23 (d，= 6‘9 Ηζ，3 Η) ; MS (電 噴霧）w/z 594.5 (Μ+Η) οS15-12-2-A : *H NMR (400 MHz, CD3OD) δ 7.52 (s, 1 Η), 4.82-4.89 (m, 1 Η), 4.14 (s, 1 Η), 3.75-3.80 (m, 1 Η), 3·43-3.50 (m, 2 Η), 3.20-3.28 (m, 1 Η), 2.96-3.05 (m, 8 Η), 2·63~2.75 (m, 2 Η), 2.17- 2.34 (m, 4 Η), 1.60-1.69 (m, 1 Η), h26 (d,·/ = 6.9 Ηζ, 3 Η), 1.23 (d, = 6'9 Ηζ, 3 Η); MS (electrospray )w/z 594.5 (Μ+Η) ο

202 201245116 S15-12-3-A °202 201245116 S15-12-3-A °

根據與S15-12-1-A所用類似之脫除保護基程序自 S15-10-A藉由脫甲矽基及氩化製備815-12-3^:4 NMR (400 MHz, CD3〇D) δ 7.22 (s，1 Η), 4.90-4.99 (m，1 Η)， 4.12 (s, 1 Η), 3.57-3.61 (m, 1 Η), 3.43-3.52 (m, 1 Η), 3.20-3.28 (m, 1 Η), 2.95-3.04 (m, 8 Η), 2.56-2.68 (m, 2 Η), 2.12-2.33 (m，4 Η)，1.60-1.69 (m，1 Η) ; MS (電喷霧）w/z 552.5 (M+H)。Prepare 815-12-3^:4 NMR (400 MHz, CD3〇D) from S15-10-A by demethylation and argonation according to a similar deprotection procedure as used for S15-12-1-A δ 7.22 (s,1 Η), 4.90-4.99 (m,1 Η), 4.12 (s, 1 Η), 3.57-3.61 (m, 1 Η), 3.43-3.52 (m, 1 Η), 3.20-3.28 (m, 1 Η), 2.95-3.04 (m, 8 Η), 2.56-2.68 (m, 2 Η), 2.12-2.33 (m, 4 Η), 1.60-1.69 (m, 1 Η); MS (electricity) Spray) w/z 552.5 (M+H).

S15-12-4-A： 'H NMR (400 MHz, CD3OD) &lt;5 7.42 (s, 1 H), 4.75-4.80 (m, 1 H), 4.13 (s, 1 H), 3.91-3.95 (m, 1 H), 3.33-3.40 (m, 1 H), 3.20-3.28 (m, 1 H), 2.96-3.12 (m, 10 H), 2.63-2.72 (m, 2 H), 2.21-2.34 (m, 4 H), 1.60-1.69 (m, 1 H), 1.24 (t J = 7.3 Hz, 3 H) ; MS (電喷霧）m/z 580.5 (M+H) 〇S15-12-4-A: 'H NMR (400 MHz, CD3OD) &lt;5 7.42 (s, 1 H), 4.75-4.80 (m, 1 H), 4.13 (s, 1 H), 3.91-3.95 ( m, 1 H), 3.33-3.40 (m, 1 H), 3.20-3.28 (m, 1 H), 2.96-3.12 (m, 10 H), 2.63-2.72 (m, 2 H), 2.21-2.34 ( m, 4 H), 1.60-1.69 (m, 1 H), 1.24 (t J = 7.3 Hz, 3 H) ; MS (electrospray) m/z 580.5 (M+H) 〇

S15-12-5-A ： 'H NMR (400 MHz, CD3OD) δ 7.46 (s, 1 H), 4.78-4.80 (m, 1 H), 4.14 (s, 1 H), 3.93-3.99 (m, 1 H), 3.33-3.42 (m, 1 H), 3.20-3.28 (m, 1 H), 2.94-3.08 (m, 10 H), 2.63-2.72 (m, 2 H), 2.18-2.33 (m, 4 H), 1.58-1.70 (m, 3 H), 0.89 (t /= 7.3 Hz，3 H) ; MS (電喷霧）m/z 580.5 (M+H)。 203 201245116S15-12-5-A : 'H NMR (400 MHz, CD3OD) δ 7.46 (s, 1 H), 4.78-4.80 (m, 1 H), 4.14 (s, 1 H), 3.93-3.99 (m, 1 H), 3.33-3.42 (m, 1 H), 3.20-3.28 (m, 1 H), 2.94-3.08 (m, 10 H), 2.63-2.72 (m, 2 H), 2.18-2.33 (m, 4 H), 1.58-1.70 (m, 3 H), 0.89 (t / = 7.3 Hz, 3 H); MS (electrospray) m/z 580.5 (M+H). 203 201245116

S15-12-6-A ： 'H NMR (400 MHz, CD3OD) δ 7.50 (s，1 H), 4.80-4.85 (m, 1 H), 4.14 (s, 1 H), 3.99-4.05 (m, 1 H), 3.33-3.42 (m, 1 H), 3.20-3.28 (m, 1 H), 2.96-3.04 (m, 9 H), 2.63-2.79 (m, 3 H), 2.18-2.33 (m, 4 H), 1.89-1.97 (m, 1 H), 1.60-1.70 (m, 1 H), 0.96 (d, J= 6.9 Hz, 3 H), 0.88 (d, J= 6.9S15-12-6-A : 'H NMR (400 MHz, CD3OD) δ 7.50 (s, 1 H), 4.80-4.85 (m, 1 H), 4.14 (s, 1 H), 3.99-4.05 (m, 1 H), 3.33-3.42 (m, 1 H), 3.20-3.28 (m, 1 H), 2.96-3.04 (m, 9 H), 2.63-2.79 (m, 3 H), 2.18-2.33 (m, 4 H), 1.89-1.97 (m, 1 H), 1.60-1.70 (m, 1 H), 0.96 (d, J = 6.9 Hz, 3 H), 0.88 (d, J = 6.9

Hz，3 H) ; MS (電喷霧）w/z 580.5 (M+H)。Hz, 3 H) ; MS (electrospray) w/z 580.5 (M+H).

S15-12-3-BS15-12-3-B

合成 SI 5-12-3-B 根據與S15-12-3-A所用相同之程序自S15_6及第三 丁烷亞磺醞胺製備化合物815_12_3·β : ,H NMR (4〇〇 MHz， CD3OD) δ 7.26 (Sj 1 Η), 5.05 (t, 7.8 Hz, 1 H), 4.13 (s, 1 H), 3.45-3.59 (m} 2 H), 3.20-3.28 (m, 1 H), 2.95-3.04 (m, 8 H), 2.62 (t, J ~ 15.J HZj j 2.46-2.52 (m, 1 H), 2.14-2.33 (m5 4 H), 1.5 9-1.69 (m} 1 H) ； MS (f ^ ) m/z 552.5 (M+H) ° 實施例16 ·合成其中環E為氮雜環丁烧-2-基之式I化 合物 栢據乂下/;IL程16合成式1化合物，其中X為-CF3，Y 為-Η且環E為氮雜環丁烷_2_基。 流程16 204 201245116Synthesis of SI 5-12-3-B Compound 815_12_3·β : , H NMR (4〇〇MHz, CD3OD) was prepared from S15_6 and third butane sulfinamide according to the same procedure as used for S15-12-3-A. δ 7.26 (Sj 1 Η), 5.05 (t, 7.8 Hz, 1 H), 4.13 (s, 1 H), 3.45-3.59 (m} 2 H), 3.20-3.28 (m, 1 H), 2.95-3.04 (m, 8 H), 2.62 (t, J ~ 15.J HZj j 2.46-2.52 (m, 1 H), 2.14-2.33 (m5 4 H), 1.5 9-1.69 (m} 1 H) ; MS ( f ^ ) m/z 552.5 (M+H) ° Example 16 · Synthesis of a compound of formula I wherein ring E is azetidin-2-yl, in which the compound of formula 1 is synthesized, X is -CF3, Y is -Η and ring E is azetidine-2-yl. Scheme 16 204 201245116

圯 u、*S、N圯 u, *S, N

OBn S15-7OBn S15-7

氯化烯 ? CH3 丙基錄/Βί^'&amp;ΝΗ CO〇Ph DCMChlorinated olefins ? CH3 propyl groups / Β ί ^ ' &amp; ΝΗ CO 〇 Ph DCM

-78 °C-78 °C

OBn S16-1-A, S16-1-B 約1:1非對映異構體OBn S16-1-A, S16-1-B about 1:1 diastereomer

CF3 1)HCI/MeOH CH3 - | 2) 4-N02PhS〇2〇l C02Ph /Pr^Et, DCM J JCF3 1)HCI/MeOH CH3 - | 2) 4-N02PhS〇2〇l C02Ph /Pr^Et, DCM J J

OBn S16-2 1)0s04l NMO THF, H2〇 2) Na丨 04 THF, H2〇OBn S16-2 1)0s04l NMO THF, H2〇 2) Na丨 04 THF, H2〇

K2C〇3, PhSH N ，-NsK2C〇3, PhSH N ,-Ns

1. NaBH4 CH3 2. PPh3l DIAD THF Ns、4 C02Ph^ cf31. NaBH4 CH3 2. PPh3l DIAD THF Ns, 4 C02Ph^ cf3

還原性胺化 或烷基化Reductive amination or alkylation

a) LDA/TMEDA b) 烯酮 LHMDSa) LDA/TMEDA b) ketene LHMDS

1) HF 2) Pd/C, H2 H3C、m/CH31) HF 2) Pd/C, H2 H3C, m/CH3

根據流程16製備以下化合物。The following compounds were prepared according to Scheme 16.

在低於-71°C 下向亞胺 S15-7( 1.04g，2.01 mmol，1 eq) 於無水二氯曱烷（12 mL)中之溶液中添加氯化烯丙基鎂於 THF 中之溶液（1.51 mL，3.01 mmol，1_5 eq)。接著在-78 °C下攪拌所得反應溶液2小時，且添加NH4C1飽和水溶液。 205 201245116 使所得混合物升溫至室溫且用二氯甲烷（50 mL，隨後25 mL )萃取。經合併之有機相經硫酸鎂脫水，過濾，且減壓 濃縮。使用25%4 48% EtOAc/己烷進行矽膠急驟層析，得 到呈白色固體狀之所需產物S16-1-A (極性較大之非對映異 構體’ 504 mg，45%)及呈白色固體狀之S16-1-B (極性較 小之非對映異構體，526 mg，47% ) » S16-l-A(非對映異構體 a) : lH NMR (400 MHz，CDC13) &lt;5 7.41-7.31 (m, 7 Η), 7.26-7.22 (m, 1 Η), 7.16 (s, 1 Η), 7.08- 7.06 (m, 2 Η), 5.75-5.64 (m, 1 Η), 5.20-5.12 (m, 4 Η), 5.06-5.04 (m, 1 Η), 3.68 (d, J= 2.4 Hz, 1 H), 2.62-2.55 (m, 1 H), 2.55 (q, J = 3.7 Hz, 3 H), 2.30-2.22 (m, 1 H), 1.18 (s, 9 H) ; MS (ESI) w/z 560.27 (M+H)。 S16-l-B(非對映異構體 b ) : 'H NMR (400 MHz，CDC13) 5 7-43-7.31 (m, 7 H), 7.25-7.22 (m, 1 H), 7.20 (s, 1 H), 7.08- 7.06 (m, 2 H), 5.61-5.50 (m, 1 H), 5.26, 5.21 (ABq, J = 11.6 Hz, 2 H), 5.09-4.95 (m, 3 H), 3.69 (d, J= 5.5 Hz, 1 H), 2.54 (q} J= 3.0 Hz, 3 H), 2.54-2.50 (m, 1 H), 2.47-2.38 (m, 1Add a solution of allyl magnesium chloride in THF to a solution of the imine S15-7 (1.04 g, 2.01 mmol, 1 eq) in anhydrous dichloromethane (12 mL) (1.51 mL, 3.01 mmol, 1_5 eq). The resulting reaction solution was then stirred at -78 °C for 2 hours, and a saturated aqueous solution of NH4Cl was added. 205 201245116 The resulting mixture was allowed to warm to room rt and extracted with dichloromethane (50 mL then 25 mL). The combined organic phases were dried over MgSO4, filtered and evaporated. The desired product S16-1-A (the more polar diastereomer '504 mg, 45%) was obtained as a white solid as a white solid. S16-1-B as a white solid (small polar diastereomer, 526 mg, 47%) » S16-lA (diastereomer a) : lH NMR (400 MHz, CDC13) &lt;;5 7.41-7.31 (m, 7 Η), 7.26-7.22 (m, 1 Η), 7.16 (s, 1 Η), 7.08- 7.06 (m, 2 Η), 5.75-5.64 (m, 1 Η), 5.20-5.12 (m, 4 Η), 5.06-5.04 (m, 1 Η), 3.68 (d, J= 2.4 Hz, 1 H), 2.62-2.55 (m, 1 H), 2.55 (q, J = 3.7 Hz, 3 H), 2.30-2.22 (m, 1 H), 1.18 (s, 9 H); MS (ESI) w/z 560.27 (M+H). S16-lB (diastereomer b): 'H NMR (400 MHz, CDC13) 5 7-43-7.31 (m, 7 H), 7.25-7.22 (m, 1 H), 7.20 (s, 1 H), 7.08- 7.06 (m, 2 H), 5.61-5.50 (m, 1 H), 5.26, 5.21 (ABq, J = 11.6 Hz, 2 H), 5.09-4.95 (m, 3 H), 3.69 ( d, J= 5.5 Hz, 1 H), 2.54 (q} J= 3.0 Hz, 3 H), 2.54-2.50 (m, 1 H), 2.47-2.38 (m, 1

對映異構體A H)，1_17 (s，9 H) ; MS (ESI) m/z 560.27 (M+H)。 向化合物 S16-1-A( 504 mg，0.90mmol，leq)於甲醇 (5 mL)中之溶液中添加HC1之二噁烷溶液（4 M，1.25 mL· )。在室溫下攪拌所得反應溶液1小時分鐘。逐滴添 206 201245116 •加NaHC〇3飽和水溶液（10 mL)直至鼓泡停止。所得混合 物以鹽水稀釋，用Et0Ac萃取。分離有機相，用鹽水洗滌’ 經MgS〇4脫水，過濾且濃縮，得到所需產物（ms(esi)w々 456.22 (M+H))。在無進一步純化的情況下將粗產物直接用 於下一反應。 在室溫下將二異丙基乙胺（ 234 gL，1.35 mmo卜1.5 eq：) 及4-硝基苯績醯氣（2〇9 mg，0.945 mm〇h eq)添加 至上述產物於CHKh ( 5 mL )中之溶液中。所得黃色反應 溶液在室溫下攪拌2小時且以CHaCU稀釋。所得溶液以鹽 水洗滌，經MgSCU脫水，過濾且減壓濃縮。使用5%— 3〇% EtOAc/己烷進行矽膠急驟層析，得到呈淺黃色泡洙固體狀 之所需產物S16-2-A( 524 mg，91% ’經2個步驟）：iH NMR (400 MHz, CDC13) 5 8·13-8·1〇 (m, 2 Η), 7.75-7.72 (m, 2 Η), 7.36-7.30 (m, 7 Η), 7.26-7.22 (m, 1 Η), 7.〇2.7.〇〇 (m&gt; 2 H), 6.83 (s, 1 H), 6.07 (br s, 1 H), 5.61-5.51 (ιη, ! H)s 5-14-5.10 (m, 2 H)} 5.00-4.99 (m, 1 H), 4.96 (s, 2 H), 2.54-2.47 (m, 1 H), 2.43 (q, 3.7 Hz, 3 H), 2.39-2.31 (m, i H) ; MS (ESI) m/z 663.20 (M+Na)。Enantiomers A H), 1_17 (s, 9 H); MS (ESI) m/z 560.27 (M+H). To a solution of the compound S16-1-A (504 mg, 0.90 mmol, EtOAc) in MeOH (5 mL), EtOAc (4 M, 1.25 mL). The resulting reaction solution was stirred at room temperature for 1 hour. Add dropwise 206 201245116 • Add NaHC〇3 saturated aqueous solution (10 mL) until bubbling stops. The resulting mixture was diluted with brine and extracted with EtOAc. The organic phase was separated, washed with brine &lt;RTI ID=0.0&gt;&gt;&gt;&gt;&gt; The crude product was used directly in the next reaction without further purification. Diisopropylethylamine (234 gL, 1.35 mmo 1.5 eq:) and 4-nitrobenzene oxime (2 〇 9 mg, 0.945 mm 〇h eq) were added to the above product at CHKh (at room temperature) In a solution of 5 mL). The resulting yellow reaction solution was stirred at room temperature for 2 hr and diluted with CH. The resulting solution was washed with brine, dried over MgSO.sub. Flash chromatography on silica gel using 5% - 3 % EtOAc / hexanes to give the desired product S16-2-A ( 524 mg, <RTI ID=0.0> 400 MHz, CDC13) 5 8·13-8·1〇(m, 2 Η), 7.75-7.72 (m, 2 Η), 7.36-7.30 (m, 7 Η), 7.26-7.22 (m, 1 Η) , 7.〇2.7.〇〇(m&gt; 2 H), 6.83 (s, 1 H), 6.07 (br s, 1 H), 5.61-5.51 (ιη, ! H)s 5-14-5.10 (m, 2 H)} 5.00-4.99 (m, 1 H), 4.96 (s, 2 H), 2.54-2.47 (m, 1 H), 2.43 (q, 3.7 Hz, 3 H), 2.39-2.31 (m, i H) ; MS (ESI) m/z 663.20 (M+Na).

對映異構體A S16-3nA 向化合物 S16-2-A ( 464 mg，724 mmol，】、认 Tux? A eq j 於 1 Hr (3 mL)與水（0.6 mL)之混合物中的溶液中添加NM〇( 339 mg ’ 2.90 mmol ’ 4.0 eq)，接著添加 〇s〇4之水溶液（〇 〇4 207 201245116 wt%，184叫’ 0.029 mmo卜0.04eq)。在室溫下攪拌反應 混合物隔夜。添加NhSsO3水溶液，且用二氯甲烷（3χ25 mL) 萃取所得混合物。經合併之有機溶液經硫酸鈉脫水，過濾 且減壓濃縮，得到粗二醇產物：Ms (ESI)所&quot;697 〇7 (M+Na)。 將上述粗產物溶解於THF (5 mL)與水（5 mL)之混 合物中。將所得溶液冷卻至0。(：。接著整份添加NaI〇4(465 mg ’ 2.17mmo卜3.0eq)。在（TC下攪拌所得反應混合物3 小時。添加NhSe3水溶液，且用二氯甲烷（5〇 ，隨後 2x2 5 mL )萃取所得混合物。經合併之有機溶液經硫酸鈉脫 水，過濾且減壓濃縮，得到呈灰白色固體狀之所需醛產物 S16-3-A^： MS (ESI) m/z 641.15 (M-H) ° N，s Y^C〇2Ph OBnEnantiomeric A S16-3nA to a solution of compound S16-2-A (464 mg, 724 mmol,), utilised Tux? A eq j in a mixture of 1 Hr (3 mL) and water (0.6 mL) NM(R) (339 mg ' 2.90 mmol ' 4.0 eq) was added followed by an aqueous solution of 〇s 〇 4 (〇〇4 207 201245116 wt%, 184 s. &quot; 0.029 mmo, 0.04 eq). The reaction mixture was stirred at room temperature overnight. An aqueous solution of NhSsO3 was added, and the mixture was extracted with dichloromethane (3 mL 25 mL). The combined organic solution was dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude diol product: Ms (ESI) &quot;697 〇7 ( M+Na). The above crude product was dissolved in a mixture of THF (5 mL) and water (5 mL). The obtained solution was cooled to 0. (:. Then added NaI〇4 (465 mg ' 2.17mmo) 3.0 eq). The resulting reaction mixture was stirred for 3 hours under TC. EtOAc (aq. Concentration by pressure gave the desired aldehyde product S16-3-A^: MS (ESI) m/z 641. ) ° N,s Y^C〇2Ph OBn

對映異構體A S164-A 在〇°C下向上述醛S16_3_A於曱醇（5mL)與二氣曱烷 (1〇 mL)之混合物中的溶液中整份添加NaBH4 ( 82 mg， 17 mmol ’ 3.0 eq ) »在〇°c下攪拌所得反應混合物2〇分 鐘。添加1 M HC丨水溶液直至鼓泡停止。且用二氣曱烷（5〇 mL隧後2x25 mL· )萃取所得混合物。經合併之有機溶液 經硫酸鎂脫水，過濾且減壓濃縮，得到呈白色固體狀之粗 醇產物· MS (ESI) w/z 667.1 8 (M+Na)。 向上述醇於THF ( 40 mL)中之溶液中添加PPh3 ( 285 mg ’ 1·〇9 mmol，1.5 eq) ’ 接著添加 DIAD ( 214 μι，1.09 mmol，1 ·5 eci)。在室溫下攪拌所得反應混合物2小時，且 208 201245116Enantiomer A S164-A Add NaBH4 (82 mg, 17 mmol) to a solution of the above aldehyde S16_3_A in a mixture of decyl alcohol (5 mL) and dioxane (1 mL) at 〇 °C. '3.0 eq) » The resulting reaction mixture was stirred at 〇 °c for 2 Torr. Add 1 M HC丨 aqueous solution until bubbling stops. The resulting mixture was extracted with dioxane (5 〇 mL 2x25 mL after tunneling). The combined organic solution was dried with EtOAc EtOAc EtOAc EtOAc EtOAc PPh3 (285 mg '1·〇9 mmol, 1.5 eq) was added to a solution of the above alcohol in THF (40 mL), followed by DIAD (214 μιη, 1.09 mmol, 1 ·5 eci). The resulting reaction mixture was stirred at room temperature for 2 hours, and 208 201245116

• 減壓蒸發/谷劑。藉由石夕膠急驟層析（使用10%-&gt; 30。/。EtOAc/ 己烧）純化殘餘物，得到呈白色固體狀之所需產物S16_4_A (366 mg，81%，經 4 個步驟）：咕 NMR (400 MHz，CDC13) ά 8.47-8.44 (m, 2 Η), 8.02-7.99 (m, 2 Η), 7.75 (s, 1 Η), 7.49-7.46 (m, 2 Η), 7.42-7.34 (m, 5 Η), 7.28-7.24 (m, 1 Η), 7.09-7.06 (m, 2 Η), 5.28-5.22 (m, 3 Η), 3.92-3.87 (m, 1 Η), 3.73 (q, 8.5 Hz, 1 H), 2.54 (q, /= 3.0 Hz, 3 H), 2.48-2.43 (m, 1 H)，2.14-2.04 (m，i h) ; MS (ESI) m/z 649.20 (M+Na)。 y^cOzPh OBn• Evaporation under reduced pressure / granules. The residue was purified by flash chromatography eluting EtOAc EtOAc EtOAc : NMR (400 MHz, CDC13) ά 8.47-8.44 (m, 2 Η), 8.02-7.99 (m, 2 Η), 7.75 (s, 1 Η), 7.49-7.46 (m, 2 Η), 7.42- 7.34 (m, 5 Η), 7.28-7.24 (m, 1 Η), 7.09-7.06 (m, 2 Η), 5.28-5.22 (m, 3 Η), 3.92-3.87 (m, 1 Η), 3.73 ( q, 8.5 Hz, 1 H), 2.54 (q, /= 3.0 Hz, 3 H), 2.48-2.43 (m, 1 H), 2.14-2.04 (m, ih) ; MS (ESI) m/z 649.20 ( M+Na). y^cOzPh OBn

對映異構體A S16,5*A 向化合物 S16-4-A( 366 mg，0.584 mmo 卜 1 eq)於 MeCN (5 mL)中之溶液中添加 kc〇3 ( 242 mg，1_75 mmo卜 3.0 叫），接著添加 PhSH ( 72 pL，0.70 mmo卜 1.2 eq)。在室 溫下擾拌所得反應混合物2小時。且再添加phSH ( 2〇 ， 〇·3 eq)。所得反應混合物在室溫下攪拌隔夜， 用水稀釋。且用Et0Ac ( 4〇 mL，隨後15 mL )萃取所得混 合物。經合併之有機溶液經硫酸鈉脫水，過濾且減壓濃縮。 藉由石夕膠急驟層析（使用20%— 80% EtOAc/己烷）純化殘 餘物’得到呈濃稠黃色油狀之所需產物S16_5_A ( 224 mg， 87〇/〇) ： *H NMR (400 MHz, CDC13) (5 7.92 (s, 1 H), 7.48-7.46 (m, 2 H)，7.40-7.33 (m，5 H)，7.26-7.22 (m, 1 H), 7-〇8-7.〇6 (m, 2 H), 5.34-5.23 (m, 3 H), 3.78 (q, /= 7.3 Hz, 1 H), 3.30-3.25 (m, 1 H), 2.67 (br q, J = 8.5 Hz, 1 H), 2.53 (q,Enantiomer A S16,5*A To a solution of compound S16-4-A (366 mg, 0.584 mmo 1 eq) in MeCN (5 mL) was added kc〇3 (242 mg, 1_75 mmob 3.0 Call), then add PhSH (72 pL, 0.70 mmo 1.2 eq). The resulting reaction mixture was scrambled at room temperature for 2 hours. And add phSH ( 2〇 , 〇·3 eq). The resulting reaction mixture was stirred at room temperature overnight and diluted with water. The resulting mixture was extracted with Et0Ac (4 mL, then 15 mL). The combined organic solution was dried over sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography (20% - 80% EtOAc / hexanes) to give the desired product S16_5_A ( 224 mg, 87 〇 / 〇) as a thick yellow oil: *H NMR ( 400 MHz, CDC13) (5 7.92 (s, 1 H), 7.48-7.46 (m, 2 H), 7.40-7.33 (m, 5 H), 7.26-7.22 (m, 1 H), 7-〇8- 7.〇6 (m, 2 H), 5.34-5.23 (m, 3 H), 3.78 (q, /= 7.3 Hz, 1 H), 3.30-3.25 (m, 1 H), 2.67 (br q, J = 8.5 Hz, 1 H), 2.53 (q,

2.4 Hz，3 H)，2.25-2.16 (m，1 H)，2.04 (br s，1 H) ; MS 209 201245116 (ESI) m/z 442.23 (M+H) °2.4 Hz, 3 H), 2.25-2.16 (m, 1 H), 2.04 (br s, 1 H) ; MS 209 201245116 (ESI) m/z 442.23 (M+H) °

OBn 對映異構體A S16-6-14 在 23°C 下將 HCHO ( 37%於水中，145 μί，1.95 mmol ’ 1〇6(})及三乙醯氧基硼氫化鈉（45〇^’〇.214 111111〇卜1_169) 依序添加至化合物S16-5-A(86mg，0.195 mmol，1 eq )於 二氣甲烷（2 mL )中之溶液中。攪拌1小時後，用碳酸氫 鈉飽和水溶液中止反應混合物且用二氣曱烷（20 mL、10 mL )萃取。經合併之有機萃取物經無水硫酸鈉脫水，過濾 且減壓濃縮。藉由矽膠急驟層析（使用1%—25% EtO Ac/己 烷）純化殘餘物，得到呈濃稠油狀之所需產物S16-6-l-A( 65 mg，73%) ： *H NMR (400 MHz, CDC13) δ 7.76 (s, 1 H), 7.48-7.46 (m，2 H)，7.39-7.33 (m，5 H)，7.26-7.24 (m，1 H)， 7.11-7.09 (m, 2 H), 5.31, 5.26 (ABq, J = 11.6 Hz, 2 H), 4.24-4.19 (m, 1 H), 3.43-3.40 (m, 1 H), 2.95-2.89 (m, 1 H), 2.54 (q, J= 3.0 Hz, 3 H), 2.42 (br q, J = 8.5 Hz, 1 H), 2.24 (s, 3 H), 1.99-1.90 (m, 1 H) , MS (ESI) m/z 456.1 1 (M+H) ° 續： OBn 對纖齡 將 K2C03 ( 76 mg，0‘548 _〇卜 i 5 eq)及 EtI ( 32 ， 0.401 mmo卜 1.1 eq)依序添加至化合物 s16_5_a( i6i mg， 0.365 mmo卜ieq)於MeCN(〇 5mL)中之溶液中。所得 反應混合物在50°C下加熱隔夜，且冷卻至室溫。隨後使反 210 201245116 應物分配於EtOAc與水之間。分離有機相，用鹽水洗蘇， 經無水硫酸納脫水，過濾、且減屋濃縮。藉由石夕膠急驟層析 (使用1 20% EtOAc/己烧）純化殘餘物，得到呈濃稠油 狀之所需產物 S16-6-2-A( 65 mg’ 38%):丨!·! NMR (400 MHz, CDC13) δ 7.86 (s, 1 Η), 7.49-7.46 (m, 2 Η), 7.40-7.34 (m, 5 Η), 7.28-7.24 (m, 1 Η), 7.13-7.10 (m, 2 Η), 5.33, 5.27 (ABq, J= 11.6 Hz, 2 H), 4.31-4.26 (m, 1 H), 3.45-3.41 (m, 1 H), 2.88-2.82 (m, 1 H), 2.54 (q, J = 2.4 Hz, 3 H), 2.47-2.34 (m, 3 H), 1.96-1.87 (m, 1 H), 0.91 (t, J — 7.3 Hz, 3 H) ； MS (ESI) w/z 470.1 1 (M+H) 0OBn enantiomer A S16-6-14 HCHO (37% in water, 145 μί, 1.95 mmol '1〇6(}) and sodium triethoxy borohydride (45 〇^) at 23 °C '〇.214 111111〇1_169) was added to a solution of the compound S16-5-A (86 mg, 0.195 mmol, 1 eq) in di-methane (2 mL). After stirring for 1 hour, with sodium bicarbonate The reaction mixture was quenched with aq. EtOAc EtOAc (EtOAc m. The residue was purified by EtOAc (EtOAc): EtOAc (EtOAc) ), 7.48-7.46 (m, 2 H), 7.39-7.33 (m, 5 H), 7.26-7.24 (m, 1 H), 7.11-7.09 (m, 2 H), 5.31, 5.26 (ABq, J = 11.6 Hz, 2 H), 4.24-4.19 (m, 1 H), 3.43-3.40 (m, 1 H), 2.95-2.89 (m, 1 H), 2.54 (q, J = 3.0 Hz, 3 H), 2.42 (br q, J = 8.5 Hz, 1 H), 2.24 (s, 3 H), 1.99-1.90 (m, 1 H) , MS (ESI) m/z 456.1 1 (M+H) ° Continued: OBn For the age of the fiber will be K2C03 (76 mg, 0' 548 _ 〇 i i 5 eq) and EtI (32, 0.401 mmo bl 1.1 eq) were added sequentially to a solution of the compound s16_5_a (i6i mg, 0.365 mmobieq) in MeCN (〇5 mL). The resulting reaction mixture was 50 The mixture was heated overnight at ° C, and cooled to room temperature. Then, the mixture was partitioned between EtOAc and water. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with EtOAc EtOAc (EtOAc) NMR (400 MHz, CDC13) δ 7.86 (s, 1 Η), 7.49-7.46 (m, 2 Η), 7.40-7.34 (m, 5 Η), 7.28-7.24 (m, 1 Η), 7.13-7.10 ( m, 2 Η), 5.33, 5.27 (ABq, J= 11.6 Hz, 2 H), 4.31-4.26 (m, 1 H), 3.45-3.41 (m, 1 H), 2.88-2.82 (m, 1 H) , 2.54 (q, J = 2.4 Hz, 3 H), 2.47-2.34 (m, 3 H), 1.96-1.87 (m, 1 H), 0.91 (t, J — 7.3 Hz, 3 H) ; MS (ESI ) w/z 470.1 1 (M+H) 0

將 K2C03( 98 mg ’ 0.706 mmo卜 2.0 eq)及烯丙基漠（46 pL , 0.530 mmol，1.5 eq)依序添加至化合物 S16_S_A ( 156 mg ’ 0.3 53 mmol，1 eq)於 NMP ( 0.5 mL)中之溶液中。 所得反應混合物在5 0 °C下加熱1小時，且冷卻至室溫。隨 後使反應物分配於EtOAc與水之間。分離有機相，用鹽水 洗滌’經無水硫酸鈉脫水’過濾且減壓濃縮。藉由碎膠争、 驟層析（使用1%— 1 5% EtOAc/己烷）純化殘餘物，得到呈K2C03 (98 mg '0.706 mmob 2.0 eq) and allylic acid (46 pL, 0.530 mmol, 1.5 eq) were added sequentially to compound S16_S_A (156 mg '0.3 53 mmol, 1 eq) in NMP (0.5 mL) In the solution. The resulting reaction mixture was heated at 50 ° C for 1 hour and cooled to room temperature. The reaction was then partitioned between EtOAc and water. The organic phase was separated, washed with brine &lt The residue was purified by flash chromatography (1% - 15% EtOAc / hexane)

濃稠油狀之所需產物S16-6-3-A ( 113 mg，66% ) : 1 jj NMR (400 MHz, CDCI3) (5 7.85 (s, 1 Η), 7.48-7.46 (m, 2 Η), 7.40-7.33 (m，5 H)，7.27-7.23 (m，1 H)，7.13-7.10 (m，2 H)’ 5.76-5.66 (m5 1 H)，5.31，5‘25 (ABq，J = 11.6 Hz，2 H) 5.23-5.17 (m，1 H)，5.07-5.05 (m，1 H)，4.40-4.35 (m 丄 H) 211 201245116 3.43-3.39 (m, 1 Η), 3.10-3.05 (m, 1 Η), 2.98-2.88 (m, 2 Η), 2.5 3 (q, J= 3.0 Hz, 3 H), 2.46 (br q, /= 9.2 Hz, 1 H), 1.94 (p, = 9.7 Hz，1 H) ; MS (ESI) m/z 482.14 (M + H)。The desired product S16-6-3-A (113 mg, 66%): 1 jj NMR (400 MHz, CDCI3) (5 7.85 (s, 1 Η), 7.48-7.46 (m, 2 Η) ), 7.40-7.33 (m,5 H), 7.27-7.23 (m,1 H),7.13-7.10 (m,2 H)' 5.76-5.66 (m5 1 H),5.31,5'25 (ABq,J = 11.6 Hz, 2 H) 5.23-5.17 (m, 1 H), 5.07-5.05 (m, 1 H), 4.40-4.35 (m 丄H) 211 201245116 3.43-3.39 (m, 1 Η), 3.10-3.05 (m, 1 Η), 2.98-2.88 (m, 2 Η), 2.5 3 (q, J= 3.0 Hz, 3 H), 2.46 (br q, /= 9.2 Hz, 1 H), 1.94 (p, = 9.7 Hz, 1 H) ; MS (ESI) m/z 482.14 (M + H).

ΟΒα 對映異構體A S16-64-A 根據與化合物S16-6-1-A與丙酮所用類似之程序自化 合物 S16-5-A 製備化合物 S16-6-4-A : 4 NMR (400 MHz, CDC13) δ 8.01 (s, 1 Η), 7.50-7.45 (m, 2 Η), 7.40-7.33 (m, 5 Η), 7.28-7.24 (m, 1 Η), 7.14-7.11 (m, 2 Η), 5.34, 5.26 (ABq, J = 12.2 Hz, 2 H), 4.41-4.36 (m, 1 H), 3.44-3.39 (m, 1 H), 2.89-2.83 (m, 1 H), 2.54 (q, J= 3.0 Hz, 3 H), 2.44-2.34 (m, 2 H), 1.80 (p, J= 9.8 Hz, 1 H), 0.95 (d, J = 6.7 Hz, 3 H), 0.53 (d，/= 6_7 Hz，3 H) ; MS (ESI) m/z 484_14 (M+H)。ΟΒα Enantiomer A S16-64-A Compound S16-6-4-A was prepared from compound S16-5-A according to a procedure similar to that used for compound S16-6-1-A with acetone: 4 NMR (400 MHz , CDC13) δ 8.01 (s, 1 Η), 7.50-7.45 (m, 2 Η), 7.40-7.33 (m, 5 Η), 7.28-7.24 (m, 1 Η), 7.14-7.11 (m, 2 Η ), 5.34, 5.26 (ABq, J = 12.2 Hz, 2 H), 4.41-4.36 (m, 1 H), 3.44-3.39 (m, 1 H), 2.89-2.83 (m, 1 H), 2.54 (q , J= 3.0 Hz, 3 H), 2.44-2.34 (m, 2 H), 1.80 (p, J= 9.8 Hz, 1 H), 0.95 (d, J = 6.7 Hz, 3 H), 0.53 (d, /= 6_7 Hz, 3 H) ; MS (ESI) m/z 484_14 (M+H).

在-72(3下將《-8111^(116 01^，1.6]^/己烧，〇.185 111111〇1， 1.3 eq)逐滴添加至二異丙胺（28 |iL，0.199 mmol，1.4 eq) 於THF ( 1 mL )中之溶液中。使反應混合物升溫至_2〇°c且 再冷卻至- 74C。添加 TMEDA( 30 pL，0.199 mmo 卜 1.4 eq)。 在-7 8 °C下授拌反應溶液5分鐘。在低於-7 3下經由套管逐 滴添加化合物 Sl6-6-l-A(65 mg，0.142 mmol，1 eq)於 THF ( 0.5 mL)中之溶液。所得紅橙色溶液在_78^下攪拌 30分鐘，且使用EtOH/液氮浴冷卻至-l〇〇°c。將烯酮 212 201245116 (68 mg，0.142 mmol，1 eq)於 THF ( 0.5 mL)中之溶液 添加至反應混合物中。使反應混合物逐漸升溫至_80°C且隨 後添加 LHMDS ( 142 pL，1.0 M/THF，0.142 mmo卜 1 eq)。 使反應混合物逐漸升溫至-1 〇°C。向反應物中添加ΝΗβΙ飽 和水溶液（20 mL )。用EtOAc ( 30 mL )萃取反應混合物。 有機相以鹽水（100 mL)洗滌，經NasSO4脫水，且減壓濃 縮。藉由製備型逆相HPLC在Waters自動純化系統上使用Add to -72% (28111i(116 01^,1.6]^/hexane, 〇.185 111111〇1, 1.3 eq) to diisopropylamine (28 | iL, 0.199 mmol, 1.4 eq) at -72 (3) In a solution of THF (1 mL), the reaction mixture was warmed to 207 ° C and then cooled to -74 C. TMEDA (30 pL, 0.199 mmo, 1.4 eq) was added. The reaction solution was stirred for 5 minutes. A solution of compound Sl6-6-lA (65 mg, 0.142 mmol, 1 eq) in THF (0.5 mL) Stir for 30 minutes at _78^ and cool to -10 °C using EtOH / liquid nitrogen bath. Add a solution of ketene 212 201245116 (68 mg, 0.142 mmol, 1 eq) in THF (0.5 mL) The reaction mixture was gradually warmed to _80 ° C and then LHMDS (142 pL, 1.0 M/THF, 0.142 mmo 1 eq) was added. The reaction mixture was gradually warmed to -1 〇 ° C. Add ΝΗβΙ saturated aqueous solution (20 mL). EtOAc (30 mL)EtOAc.EtOAc. Used on the aters automatic purification system

Sunfire Prep C18 OBD 管柱[5 μ m，19x5 0 mm ;流速：20 mL/min ;溶劑 A : H20，含 0.1% HC02H ;溶劑 B : CH3CN， 含 0.1% HC02H ;注入體積：3 0 mL ( CH3CN):梯度：20 —1 00% B之A溶液，經丨〇分鐘；質量導向型洗提份收集] 純化粗產物。收集含有所需產物之洗提份且濃縮，得到呈Sunfire Prep C18 OBD column [5 μm, 19x5 0 mm; flow rate: 20 mL/min; solvent A: H20, containing 0.1% HC02H; solvent B: CH3CN, containing 0.1% HC02H; injection volume: 30 mL (CH3CN ): Gradient: 20 - 1 00% B solution A, enthalpy minute; mass-oriented elution fraction collection] Purify the crude product. Collecting the extract containing the desired product and concentrating it to obtain

844.29 (M+H) °844.29 (M+H) °

非對映異構體A 213 201245116 根據與化合物S16-7-1-A所用類似之程序自化合物 S16-6-2-A 製備化合物 S16-7-2-A: 4 NMR (400 MHz，CDC13) δ 15.82 (s, 1 Η), 7.64 (s, 1 Η), 7.51-7.47 (m, 4 Η), 7.39-7.30 (m, 5 Η), 7.28-7.24 (m, 1 Η), 5.40, 5.36 (ABq, / = 12.8 Hz, 2 H), 5.36 (s, 2 H), 4.38-4.35 (m, 1 H), 3.97 (d, J = 10.4 Hz, 1 H), 3.49-3.46 (m, 1 H), 3.24-3.20 (m, 1 H), 2.92-2.S6 (m, 2 H), 2.68 (t, J= 15.9 Hz, 1 H), 2.55-2.31 (m, 11 H), 2.11 (d, J= 14.0 Hz, 1 H), 2.02-1.93 (m, 1 H), 0.93 (t, J= 7.3 Hz, 3 H), 0.84 (s, 9 H), 0.27 (s, 3 H), 0.15 (s, 3 H)； MS (ESI) w/z 858.33 (M+H)。Diastereomer A 213 201245116 Compound S16-7-2-A was prepared from compound S16-6-2-A according to procedures analogous to compound S16-7-1-A: 4 NMR (400 MHz, CDC13) δ 15.82 (s, 1 Η), 7.64 (s, 1 Η), 7.51-7.47 (m, 4 Η), 7.39-7.30 (m, 5 Η), 7.28-7.24 (m, 1 Η), 5.40, 5.36 (ABq, / = 12.8 Hz, 2 H), 5.36 (s, 2 H), 4.38-4.35 (m, 1 H), 3.97 (d, J = 10.4 Hz, 1 H), 3.49-3.46 (m, 1 H), 3.24-3.20 (m, 1 H), 2.92-2.S6 (m, 2 H), 2.68 (t, J= 15.9 Hz, 1 H), 2.55-2.31 (m, 11 H), 2.11 ( d, J = 14.0 Hz, 1 H), 2.02-1.93 (m, 1 H), 0.93 (t, J = 7.3 Hz, 3 H), 0.84 (s, 9 H), 0.27 (s, 3 H), MS (ESI) w/z 858.33 (M+H).

非對映異構體A S16-7-3-A 根據與化合物S16-7-1-A所用類似之程序自化合物 S16-6-3-A 製備化合物 S16_7_3_a: iH NMR (400 MHz, CDC13) 6 15·83 (s&gt; 1 H), 7.66 (s, 1 H), 7.51-7.47 (m, 4 H), 7.40- 7.31 (m, 5 H), 7.28-7.24 (m, 1 H), 5.75-5.66 (m, 1 H), 5.40- 5.32 (m, 4 H), 5.22-5.18 (m, 1 H), 5.09-5.08 (m, 1 H), 4.45-4.41 (m, 1 H)} 3.98 (d, J= 10.4 Hz, 1 H), 3.44-3.40 (m, 1 H)，3.25-3.21 (m，【H)，3 〇5 (dd，y = 5 5，14 〇 Hz，i H)， 2.96-2.87 (m, 3 H), 2.68 (t, J = 15.9 Hz, 1 H), 2.56-2.44 (m, 9 H), 2.12 (d, J = 14.0 Hz, 1 H), 2.01-1.92 (m, 1 H), 0.84 (s, 9 H)，0.2 8 (s，3 H)，〇.i6 (s，3 h) ; ms (ESI) w/z 870.28 (M+H)。 214 201245116Diastereomer A S16-7-3-A Compound S16_7_3_a was prepared from compound S16-6-3-A according to procedures similar to those used for compound S16-7-1-A: iH NMR (400 MHz, CDC13) 6 15·83 (s&gt; 1 H), 7.66 (s, 1 H), 7.51-7.47 (m, 4 H), 7.40- 7.31 (m, 5 H), 7.28-7.24 (m, 1 H), 5.75- 5.66 (m, 1 H), 5.40- 5.32 (m, 4 H), 5.22-5.18 (m, 1 H), 5.09-5.08 (m, 1 H), 4.45-4.41 (m, 1 H)} 3.98 ( d, J = 10.4 Hz, 1 H), 3.44-3.40 (m, 1 H), 3.25-3.21 (m, [H), 3 〇 5 (dd, y = 5 5,14 〇Hz, i H), 2.96-2.87 (m, 3 H), 2.68 (t, J = 15.9 Hz, 1 H), 2.56-2.44 (m, 9 H), 2.12 (d, J = 14.0 Hz, 1 H), 2.01-1.92 ( m, 1 H), 0.84 (s, 9 H), 0.2 8 (s, 3 H), 〇.i6 (s, 3 h) ; ms (ESI) w/z 870.28 (M+H). 214 201245116

S16-74-A 根據與化合物SI6-7-1-A所用類似之程序自化合物 S16-6-4-A 製備化合物 S16-7-4-A:丨H NMR (400 MHz，CDC13) δ 15.77 (s, 1 Η), 7.88 (s, 1 Η), 7.51-7.48 (m, 4 Η), 7.40-7.32 (m, 5 Η), 7.28-7.24 (m, 1 Η), 5.38 (s, 2 Η), 5.36 (s, 2 Η), 4.74-4.70 (m, 1 Η), 3.96 (d, J = 10.4 Hz, L H), 3_71-3_66 (m，1 H)，3.27-3.22 (m，1 H)，3.06 (q，·/= 9.2 Hz，1 H), 2.94-2.87 (m, 1 H), 2.72-2.58 (m, 2 H), 2.56-2.42 (m, 9 H), 2.11 (d, J = 14.6 Hz, 1 H), 2.09-1.99 (m, 1 H), 1.02 (d, J =6.7 Hz, 3 H), 0.83 (s, 9 H), 0.64 (d, J = 6.7 Hz, 3 H), 0.27 (s，3 H)，0.15 (s，3 H) ; MS (ESI) w/z 872.3 1 (M+H)。 根據與S16-7-1-A所用類似之程序自S16-1-B製備以下 化合物。S16-74-A Compound S16-7-4-A was prepared from compound S16-6-4-A according to procedures similar to those used for compound SI6-7-1-A: 丨H NMR (400 MHz, CDC13) δ 15.77 ( s, 1 Η), 7.88 (s, 1 Η), 7.51-7.48 (m, 4 Η), 7.40-7.32 (m, 5 Η), 7.28-7.24 (m, 1 Η), 5.38 (s, 2 Η ), 5.36 (s, 2 Η), 4.74-4.70 (m, 1 Η), 3.96 (d, J = 10.4 Hz, LH), 3_71-3_66 (m, 1 H), 3.27-3.22 (m, 1 H ), 3.06 (q, ·/= 9.2 Hz, 1 H), 2.94-2.87 (m, 1 H), 2.72-2.58 (m, 2 H), 2.56-2.42 (m, 9 H), 2.11 (d, J = 14.6 Hz, 1 H), 2.09-1.99 (m, 1 H), 1.02 (d, J = 6.7 Hz, 3 H), 0.83 (s, 9 H), 0.64 (d, J = 6.7 Hz, 3 H), 0.27 (s, 3 H), 0.15 (s, 3 H); MS (ESI) w/z 872.3 1 (M+H). The following compounds were prepared from S16-1-B according to procedures similar to those used for S16-7-1-A.

S16-7-1-B S16-7-1-B ： ]H NMR (400 MHz, CDC13) δ 15.73 (s, 1 Η), 7.74 (s, 1 Η), 7.50-7.47 (m, 4 Η), 7.40-7.31 (m, 5 Η), 7.28-7.24 (m, 1 Η), 5.43, 5.34 (ABq, 12.8 Hz, 2 H), 5.36 (s, 2 H), 4.49-4.46 (m, 1 H), 3.96 (d, J = 11.0 Hz, 1 H), 3.74-3.71 (m, 1 H), 3.21-3.09 (m, 2 H), 2.89-2.82 (m, 1 H), 2.70 (t, J = 15.3 Hz, 1 H), 2.56-2.42 (m, 9 H), 2.35 (s, 3 H), 215 201245116 2.25-2.16 (m, 1 Η), 2.11 (d, J = 14.6 Hz, 1 H), 0.83 (s, 9 H), 0.27 (s，3 H)，0.15 (s, 3 H) ; MS (ESI) m/z 844_19 (M + H)。S16-7-1-B S16-7-1-B : ]H NMR (400 MHz, CDC13) δ 15.73 (s, 1 Η), 7.74 (s, 1 Η), 7.50-7.47 (m, 4 Η) , 7.40-7.31 (m, 5 Η), 7.28-7.24 (m, 1 Η), 5.43, 5.34 (ABq, 12.8 Hz, 2 H), 5.36 (s, 2 H), 4.49-4.46 (m, 1 H ), 3.96 (d, J = 11.0 Hz, 1 H), 3.74-3.71 (m, 1 H), 3.21-3.09 (m, 2 H), 2.89-2.82 (m, 1 H), 2.70 (t, J = 15.3 Hz, 1 H), 2.56-2.42 (m, 9 H), 2.35 (s, 3 H), 215 201245116 2.25-2.16 (m, 1 Η), 2.11 (d, J = 14.6 Hz, 1 H) , 0.83 (s, 9 H), 0.27 (s, 3 H), 0.15 (s, 3 H); MS (ESI) m/z 844_19 (M + H).

非對映異構體B S16-7-2-B ： 'H NMR (400 MHz, CDC13) δ 15.76 (s, 1 H), 7.91 (s, 1 H), 7.50-7.46 (m, 4 H), 7.39-7.31 (m, 5 H), 7.28-7.24 (m, 1 H), 5.42, 5.34 (ABq, J = 12.8 Hz, 2 H), 5.36 (s, 2 H), 4.28 (br s, 1 H), 3.97 (d, J = 10.4 Hz, 1 H), 3.52 (br s, 1 H), 3.20-3.16 (m, 1 H), 2.93-2.82 (m, 2 H), 2.70 (t, J = 15.9 Hz, 1 H), 2.55-2.38 (m, 11 H), 2.11 (d, 7 = 14.6 Hz, 1 H), 2.03-1.95 (m, 1 H), 0.88 (t, J = 7.3 Hz, 3 H), 0.83 (s, 9 H), 0.27 (s，3 H)，0.15 (s，3 H) ; MS (ESI) m/z 8 5 8.33 (M + H)。Diastereomer B S16-7-2-B : 'H NMR (400 MHz, CDC13) δ 15.76 (s, 1 H), 7.91 (s, 1 H), 7.50-7.46 (m, 4 H) , 7.39-7.31 (m, 5 H), 7.28-7.24 (m, 1 H), 5.42, 5.34 (ABq, J = 12.8 Hz, 2 H), 5.36 (s, 2 H), 4.28 (br s, 1 H), 3.97 (d, J = 10.4 Hz, 1 H), 3.52 (br s, 1 H), 3.20-3.16 (m, 1 H), 2.93-2.82 (m, 2 H), 2.70 (t, J = 15.9 Hz, 1 H), 2.55-2.38 (m, 11 H), 2.11 (d, 7 = 14.6 Hz, 1 H), 2.03-1.95 (m, 1 H), 0.88 (t, J = 7.3 Hz, 3 H), 0.83 (s, 9 H), 0.27 (s, 3 H), 0.15 (s, 3 H); MS (ESI) m/z 8 5 8.33 (M + H).

非對映異構體B S16-7-3-B ： !H NMR (400 MHz, CDC13) δ 15.76 (s, 1 H), 7.88 (s, 1 H), 7.51-7.45 (m, 4 H), 7.40-7.31 (m, 5 H), 7.28-7.24 (m, 1 H), 5.70-5.60 (m, 1 H), 5.40, 5.33 (ABq, J = 12.8 Hz, 2 H), 5.36 (s, 2 H), 5.22-5.17 (m, 1 H), 5.09-5.06 (m, 1 H), 4.38-4.34 (m, 1 H), 3.97 (d, J = 10.4 Hz, 1 H), 3.50-3.46 (m, 1 H), 3.20-3.16 (m, 1 H), 3.08-2.93 (m, 3 H), 2.88-2.82 (m, 1 H), 2.70 (t, J= 15.3 Hz, 1 H), 2.56-2.42 (m, 9 H), 2.11 (d, J = 14.6 Hz, 1 H), 2.03-1.94 (m, 1 H), 0.83 (s, 9 216 201245116 Η), 0.27 (s, 3 Η), 0.15 (s, 3 Η) ； MS (ESI) m/z 870.22 (M+H) 〇Diastereomer B S16-7-3-B : !H NMR (400 MHz, CDC13) δ 15.76 (s, 1 H), 7.88 (s, 1 H), 7.51-7.45 (m, 4 H) , 7.40-7.31 (m, 5 H), 7.28-7.24 (m, 1 H), 5.70-5.60 (m, 1 H), 5.40, 5.33 (ABq, J = 12.8 Hz, 2 H), 5.36 (s, 2 H), 5.22-5.17 (m, 1 H), 5.09-5.06 (m, 1 H), 4.38-4.34 (m, 1 H), 3.97 (d, J = 10.4 Hz, 1 H), 3.50-3.46 (m, 1 H), 3.20-3.16 (m, 1 H), 3.08-2.93 (m, 3 H), 2.88-2.82 (m, 1 H), 2.70 (t, J = 15.3 Hz, 1 H), 2.56-2.42 (m, 9 H), 2.11 (d, J = 14.6 Hz, 1 H), 2.03-1.94 (m, 1 H), 0.83 (s, 9 216 201245116 Η), 0.27 (s, 3 Η) , 0.15 (s, 3 Η) ; MS (ESI) m/z 870.22 (M+H) 〇

S16-7-4-B ： NMR (400 MHz, CDC13) δ 15.76 (s, 1 H), 8.03 (s, 1 H), 7.51-7.46 (m, 4 H), 7.40-7.30 (m, 5 H), 7.28-7.24 (m, 1 H), 5.41, 5.33 (ABq, J = 12.8 Hz, 2 H), 5.36 (s, 2 H), 4.38-4.34 (m, 1 H), 3.98 (d, J = 10.4 Hz, 1 H), 3.52-3.49 (m, 1 H), 3.20-3.16 (m, 1 H), 2.95-2.83 (m, 2 H), 2.73 (t, /- 15.3 Hz, 1 H), 2.55-2.42 (m, 9 H), 2.39-2.32 (m, 1 H), 2.12 (d, 14.6 Hz, 1 H), 1.89-1.80 (m, 1 H), 0.95 (d, J =6.1 Hz, 3 H), 0.84 (s, 9 H), 0.50 (d, /= 6.1 Hz, 3 H), 0.27 (s，3 H)，0.16 (s，3 H) ; MS (ESI) m/z 872.32 (M+H)。S16-7-4-B : NMR (400 MHz, CDC13) δ 15.76 (s, 1 H), 8.03 (s, 1 H), 7.51-7.46 (m, 4 H), 7.40-7.30 (m, 5 H ), 7.28-7.24 (m, 1 H), 5.41, 5.33 (ABq, J = 12.8 Hz, 2 H), 5.36 (s, 2 H), 4.38-4.34 (m, 1 H), 3.98 (d, J = 10.4 Hz, 1 H), 3.52-3.49 (m, 1 H), 3.20-3.16 (m, 1 H), 2.95-2.83 (m, 2 H), 2.73 (t, /- 15.3 Hz, 1 H) , 2.55-2.42 (m, 9 H), 2.39-2.32 (m, 1 H), 2.12 (d, 14.6 Hz, 1 H), 1.89-1.80 (m, 1 H), 0.95 (d, J = 6.1 Hz , 3 H), 0.84 (s, 9 H), 0.50 (d, / = 6.1 Hz, 3 H), 0.27 (s, 3 H), 0.16 (s, 3 H) ; MS (ESI) m/z 872.32 (M+H).

S16-7-6-A 在-72°C 下將《-BuLi( 92 pL，1.6 M/己烷，0.147 mmo卜 2.3 eq)逐滴添加至二異丙胺（22 μί，0.154 mmol，2.4 eq) 於THF ( 1 mL )中之溶液中。反應混合物升溫至-20°C且再 冷卻至- 74°C。添加 TMEDA ( 23 pL，0.154 mmol’ 2.4 eq)。 在-78°C下攪拌反應溶液5分鐘。在低於-70°C下經由套管逐 滴添加化合物 S16-5-A(28mg，0.064 mmol，leq)於 Tjjj? (0.5 mL)中之溶液。所得紅橙色溶液在-78°C下攪拌3〇分 鐘，且使用EtOH/液氮浴冷卻至_i〇(Tc。向反應混合物中添 217 201245116S16-7-6-A -BuLi (92 pL, 1.6 M/hexane, 0.147 mmo, 2.3 eq) was added dropwise to diisopropylamine (22 μί, 0.154 mmol, 2.4 eq) at -72 °C. In a solution of THF (1 mL). The reaction mixture was warmed to -20 ° C and cooled to -74 ° C. TMEDA (23 pL, 0.154 mmol' 2.4 eq) was added. The reaction solution was stirred at -78 ° C for 5 minutes. A solution of compound S16-5-A (28 mg, 0.064 mmol, leq) in Tjjj? (0.5 mL) was added dropwise via a cannula at below -70 °C. The resulting red-orange solution was stirred at -78 °C for 3 〇 minutes and cooled to _i 〇 (Tc) using an EtOH / liquid nitrogen bath. 217 201245116 was added to the reaction mixture.

加烯酮 S2-1 ( 3 1 mg，0_064 mmol，1 eq )於 THF ( 0.5 mL ) 中之溶液。使反應混合物逐漸升溫至_10°c。向反應物中添 加NH4C1飽和水溶液（20 mL )。用EtOAc ( 30 mL )萃取 反應混合物。有機相以鹽水（1 〇〇 mL )洗滌，經Na2S04脫 水’且減壓濃縮。藉由製備型逆相HPLC在Waters自動純 化系統上使用 Sunfire Prep C18 OBD 管柱[5 //m，19x50 mm ;流速：20 mL/min ;溶劑 A : H20，含 0.1% HC02H ; 溶劑 B : CH3CN，含 0_1% HC02H ;注入體積：3.0 mL (C H3 CN)，梯度：20—·100% B之A溶液，經1〇分鐘； 質量導向型洗提份收集]純化粗產物。收集含有所需產物之 洗提份’用飽和NaHC〇3中和，且用EtO Ac萃取。有機相 經Na2S〇4脫水且濃縮，得到呈黃色固體狀之所需產物 S16-7-5-A ( 13 mg &gt; 24% ) ： 'H NMR (400 MHz, CDC13) &lt;5 15.75 (s, 1 Η), 7.50-7.48 (m, 4 Η), 7.37-7.22 (m, 7 Η) 5.38-5.30 (m, 4 Η), 3.97-3.86 (m, 2 H)； 3.40-3.38 (m, 1 H), 3.19-3.15 (m, 2 H), 2.86-2.80 (m, 1 H), 2.72-2.64 (m, 2 H) 2.54-2.35 (m, 9 H), 2.12-2.08 (m, 1 H), 0.82 (s, 9 H), 0.26 (Sj 3 H)，0.14 (s，3 H) ; MS (ESI) m/z 830.28 (M + H)。A solution of ketene S2-1 (3 1 mg, 0_064 mmol, 1 eq) in THF (0.5 mL). The reaction mixture was gradually warmed to _10 ° C. A saturated aqueous solution of NH4Cl (20 mL) was added to the mixture. The reaction mixture was extracted with EtOAc (30 mL). The organic phase was washed with brine (1 mL EtOAc) and evaporatedEtOAc. Sunfire Prep C18 OBD column was used on a Waters automated purification system by preparative reverse phase HPLC [5 //m, 19 x 50 mm; flow rate: 20 mL/min; solvent A: H20, containing 0.1% HC02H; solvent B: CH3CN , containing 0_1% HC02H; injection volume: 3.0 mL (C H3 CN), gradient: 20-·100% B solution A, after 1 ; minutes; mass-oriented elution fraction collection] purified crude product. The fractions containing the desired product were collected and neutralized with saturated NaHC(R) 3 and extracted with EtOAc. The organic phase was dried over Na 2 EtOAc (EtOAc m.) , 1 Η), 7.50-7.48 (m, 4 Η), 7.37-7.22 (m, 7 Η) 5.38-5.30 (m, 4 Η), 3.97-3.86 (m, 2 H); 3.40-3.38 (m, 1 H), 3.19-3.15 (m, 2 H), 2.86-2.80 (m, 1 H), 2.72-2.64 (m, 2 H) 2.54-2.35 (m, 9 H), 2.12-2.08 (m, 1 H), 0.82 (s, 9 H), 0.26 (Sj 3 H), 0.14 (s, 3 H); MS (ESI) m/z 830.28 (M + H).

S16-7-6-B 在氮氣下向化合物 S16-7_3_B ( 229 mg，0.263 nunol，j eq) 、1，3-二曱基巴比妥酸（411 mg，2·63 mmo卜 10 eq) 及 Pd(PPh3)4 ( 1 5 mg，0.0 1 3 mmol，0.05 eq )之混合物令添 218 201245116 .加一氯甲烧（3 mL )。所得反應溶液在室溫下攪拌3小時 下攪拌2天。反應混合物以碳酸氫鈉飽和水溶液 中止（鼓泡）且用二氣甲烷（30 mL，隨後1〇 mL)萃取。 、”至s併之有機萃取物經無水硫酸鈉脫水，過濾且減壓濃 縮。藉由製備型逆相HPLC在Waters自動純化系統上使用S16-7-6-B under nitrogen to compound S16-7_3_B (229 mg, 0.263 nunol, j eq), 1,3-dimercaptobarbituric acid (411 mg, 2.63 mmo b 10 eq) and A mixture of Pd(PPh3)4 (1 5 mg, 0.013 mmol, 0.05 eq) was added to 218 201245116. Monochloromethane (3 mL) was added. The resulting reaction solution was stirred at room temperature for 3 hours and stirred for 2 days. The reaction mixture was quenched (bubble) with saturated aqueous sodium bicarbonate and extracted with di-methane (30 mL, then 1 EtOAc). The organic extracts were combined with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Prepared by preparative reverse phase HPLC on Waters automated purification system.

Sunfire Prep C18 OBD 管柱[5 以 m，19x50 mm ;流速：20 mL/min ;溶劑 A : H2〇，含 0.1% HC02H ;溶劑 B : CH3CN， 含 〇.1% HC〇2H ;注入體積：3_0 mL ( CH3CN);梯度：20 —100% B之A溶液，經1〇分鐘；質量導向型洗提份收集] 純化殘餘物。收集含有所需產物之洗提份且冷凍乾燥，得 到呈黃色固體狀之所需產物S16_7_5_B ( 19 mg，9%) : 1h NMR (400 MHz, CDC13) 5 15.70 (s, 1 Η), 7.81 (s} 1 H), 7.58-7.56 (m, 1 H), 7.50-7.25 (m, 9 H), 5.62, 5.53 (ABq, j = 12.2 Hz, 2 H), 5.35 (s, 2 H), 4.04-3.92 (m, 2 H), 3.75-3.66 (m, 1 H)，3.34-3.11 (m, 3 H), 2.88-2.69 (m, 4 H), 2.56-2.30 (m，7 H)，2,11-1.98 (m，1 H)，0.81 (s，9 H)，0.25 (s，3 H)，0.12 (s，3Sunfire Prep C18 OBD column [5 in m, 19x50 mm; flow rate: 20 mL/min; solvent A: H2 〇, containing 0.1% HC02H; solvent B: CH3CN, containing 1.1% HC〇2H; injection volume: 3_0 mL (CH3CN); Gradient: 20 - 100% B solution of A, after 1 min; mass-oriented elution fraction collection] Purify the residue. The extract containing the desired product was collected and lyophilized to give the desired product S16_7_5_B (19 mg, 9%) as a yellow solid: 1h NMR (400 MHz, CDC13) 5 15.70 (s, 1 Η), 7.81 ( s} 1 H), 7.58-7.56 (m, 1 H), 7.50-7.25 (m, 9 H), 5.62, 5.53 (ABq, j = 12.2 Hz, 2 H), 5.35 (s, 2 H), 4.04 -3.92 (m, 2 H), 3.75-3.66 (m, 1 H), 3.34 - 3.11 (m, 3 H), 2.88-2.69 (m, 4 H), 2.56-2.30 (m, 7 H), 2 ,11-1.98 (m,1 H),0.81 (s,9 H),0.25 (s,3 H),0.12 (s,3

非對映異構體A S16-8-1-A H) ; MS (ESI) w/z 830.25 (M+H)。 S16-8-1-A :在 23°C 下將 HF 水溶液（48-50%，0.2 mL) 添加至聚丙烯反應容器中化合物於THF( 〇8 ) 中之溶液中。在23°C下劇烈攪拌混合物K5小時且傾入 Κ2ΗΡ04水溶液（2‘5 g溶解於2〇 mL水中）中。用Et0Ac 219 201245116 (40 mL )萃取混合物。有機相以鹽水洗滌，經無水硫酸鈉 脫水且減壓浪縮。在無進—步純化的情況下將殘餘物直接 用於下一步驟。（MS(ESI)W/Z 730.15 (M+H))。 在23°C下將Pd-C ( 1〇 wt%，8 mg)整份添加至上述粗 產物於二噁烷（1 mL)與Ch3〇h ( i mL)之混合物中的溶 液中。將反應容器狁封且藉由短暫地抽空燒瓶、接著用氫 氣（1 atm)吹拂而用氫氣淨化。在23t：下在氫氣氛圍（i atm) 下攪拌反應混合物1小時30分鐘。再添加pd_c ( 10 wt〇/〇， 8 mg )。所付反應/¾合物再在氫氣（1 atm )下揽拌3 〇分鐘， 且經由小型矽藻土墊過濾。濃縮濾液。藉由製備型逆相 HPLC在Waters自動純化系統上使用phen〇menex pobmeu 10 β RP-r 100A 管柱[l〇 β m，1 50x21.20 mm ;流速： 20 mL/min ;溶劑 A : 0.5% TFA/水；溶劑 B : 0,5% TFA/CH3CN ;注入體積：3·0 mL ( 0.5% TFA/水）；梯度· 5—45% B，經25分鐘；質量導向型洗提份收集]純化殘餘 物。收集在14.7-15.6分鐘洗提之含有所需產物之洗提份且 冷珠乾燥’得到化合物S16-8-l-A(7.02mg，三氟乙酸鹽， 32% ( 2 個步驟））：NMR (400 MHz, CD3〇D，三敗乙酸 鹽）δ 7.04 (s，1 H)，5.94 (t，*/= 8.7 Hz，1 H)，4.18-4.07 (m 2 Η), 4.09 (s5 1 Η), 3.22-3.18 (m, 1 H), 3.11 (s, 3 H) 3.05-2.89 (m, 9 H), 2.70-2.59 (m, 2 H), 2.23-2.19 (m, 1 H) 1.69-1.59 (m, 1 H) ; MS (ESI) m/z 552.1 1 (M+H)。 ’ 根據與S16-8-1-A所用類似之程序藉由相應前驅體之 脫曱矽基及氫化來製備以下化合物。 220 201245116Diastereomer A S16-8-1-A H); MS (ESI) w/z 830.25 (M+H). S16-8-1-A: An aqueous HF solution (48-50%, 0.2 mL) was added to a solution of the compound in THF (?8) in a polypropylene reaction vessel at 23 °C. The mixture K was vigorously stirred at 23 ° C for 5 hours and poured into a 2Κ04 aqueous solution (2 '5 g dissolved in 2 mL of water). The mixture was extracted with Et0Ac 219 201245116 (40 mL). The organic phase was washed with brine, dried over anhydrous sodium sulfate and reduced with reduced pressure. The residue was used directly in the next step without further purification. (MS (ESI) W/Z 730.15 (M+H)). Pd-C (1 〇 wt%, 8 mg) was added in one portion to a solution of the above crude product in a mixture of dioxane (1 mL) and Ch3 〇h (i mL) at 23 °C. The reaction vessel was sealed and purged with hydrogen by briefly evacuating the flask followed by blowing with hydrogen (1 atm). The reaction mixture was stirred under a hydrogen atmosphere (i atm) at 23t: for 1 hour and 30 minutes. Add pd_c (10 wt〇/〇, 8 mg). The reaction/3⁄4 compound was stirred for a further 3 minutes under hydrogen (1 atm) and filtered through a small diatomaceous earth pad. The filtrate was concentrated. The phen〇menex pobmeu 10 β RP-r 100A column was used on a Waters automated purification system by preparative reverse phase HPLC [l〇β m, 1 50×21.20 mm; flow rate: 20 mL/min; solvent A: 0.5% TFA/water; solvent B: 0,5% TFA/CH3CN; injection volume: 3·0 mL (0.5% TFA/water); gradient · 5-45% B, after 25 minutes; mass-oriented elution fraction collection] The residue was purified. The eluted fractions containing the desired product were eluted at 14.7-15.6 minutes and dried by cold beads to give compound S16-8-lA (7.02 mg, trifluoroacetate, 32% (2 steps)): NMR (400) MHz, CD3〇D, triple-salted acetate) δ 7.04 (s,1 H), 5.94 (t,*/= 8.7 Hz, 1 H), 4.18-4.07 (m 2 Η), 4.09 (s5 1 Η), 3.22-3.18 (m, 1 H), 3.11 (s, 3 H) 3.05-2.89 (m, 9 H), 2.70-2.59 (m, 2 H), 2.23-2.19 (m, 1 H) 1.69-1.59 ( m, 1 H) ; MS (ESI) m/z 5521. (M+H). The following compounds were prepared according to procedures similar to those used in S16-8-1-A by deamination and hydrogenation of the corresponding precursors. 220 201245116

S16-8-2^ S16-8-2-A : 4 NMR (400 MHz，CD3OD，三氟乙酸鹽） 6 7·08 (s, 1 H), 5.95 (t, J= 9.2 Hz, 1 H), 4.13-4.09 (m, 3 H), 3-62-3.54 (m, 1 H), 3.43-3.34 (m, 1 H), 3.23-3.19 (m, 1 H), 3-〇7-2.89 (m, 9 H), 2.71-2.59 (m, 2 H), 2.24-2.18 (m, 1 H), ^69-1.59 (m, 1 H), 1.30 (t, J = 7.3 Hz, 3 H) ； MS (ESI) m/z 566.18 (M+H)。S16-8-2^ S16-8-2-A : 4 NMR (400 MHz, CD3OD, trifluoroacetate) 6 7·08 (s, 1 H), 5.95 (t, J = 9.2 Hz, 1 H) , 4.13-4.09 (m, 3 H), 3-62-3.54 (m, 1 H), 3.43-3.34 (m, 1 H), 3.23-3.19 (m, 1 H), 3-〇7-2.89 ( m, 9 H), 2.71-2.59 (m, 2 H), 2.24-2.18 (m, 1 H), ^69-1.59 (m, 1 H), 1.30 (t, J = 7.3 Hz, 3 H); MS (ESI) m/z 566.18 (M+H).

非對映異構體A S16-8-3-A S16-8-3-A : 4 NMR (400 MHz，CD3OD，三氟乙酸鹽） δ 7·°6 (s5 1 Η), 5.96 (t, J= 9.2 Hz, 1 H), 4.15-4.10 (m5 3 H), 3.49-3.44 (m, 1 H), 3.33-3.26 (m, 1 H), 3.23-3.19 (m, 1 H), 3.08-2.87 (m，9 H)，2.71-2.58 (m，2 H)，2.24-2.19 (m，1 H)， 1*73-1.59 (m, 3 H), 1.03 (t, J = 7.7 Hz, 3 H) ； MS (ESI) m/z 580.16 (M + H)。Diastereomer A S16-8-3-A S16-8-3-A : 4 NMR (400 MHz, CD3OD, trifluoroacetate) δ 7·°6 (s5 1 Η), 5.96 (t, J= 9.2 Hz, 1 H), 4.15-4.10 (m5 3 H), 3.49-3.44 (m, 1 H), 3.33-3.26 (m, 1 H), 3.23-3.19 (m, 1 H), 3.08- 2.87 (m,9 H),2.71-2.58 (m,2 H), 2.24-2.19 (m,1 H), 1*73-1.59 (m, 3 H), 1.03 (t, J = 7.7 Hz, 3 H) ; MS (ESI) m/z 580.16 (M + H).

S16-84-A S16-8-4-A : NMR (400 MHz，CD3OD，三氟乙酸鹽） δ 7.24 (s, 1 Η), 5.99 (t, J= 9.6 Hz, 1 H), 4.19-4.07 (m, 3 H), 3.76-3.69 (m, 1 H), 3.28-3.23 (m, 1 H), 3.08-2.95 (m, 8 H), 2.89-2.81 (m，1 H)，2.64-2.51 (m，2 H)，2.24-2.18 (m，1 H)， 221 201245116 1.69-1.59 (m, 1 Η), 1.35 (d, J = 6.4 Hz, 3 H), 1.24 (d, J = 6.4 Hz，3 H) ; MS (ESI) m/z 580.14 (M + H)。S16-84-A S16-8-4-A : NMR (400 MHz, CD3OD, trifluoroacetate) δ 7.24 (s, 1 Η), 5.99 (t, J = 9.6 Hz, 1 H), 4.19-4.07 (m, 3 H), 3.76-3.69 (m, 1 H), 3.28-3.23 (m, 1 H), 3.08-2.95 (m, 8 H), 2.89-2.81 (m, 1 H), 2.64-2.51 (m, 2 H), 2.24 - 2.18 (m, 1 H), 221 201245116 1.69-1.59 (m, 1 Η), 1.35 (d, J = 6.4 Hz, 3 H), 1.24 (d, J = 6.4 Hz , 3 H) ; MS (ESI) m/z 580.14 (M + H).

非對映異構體A S16-8-5-A S16-8-5-A : 4 NMR (400 MHz, CD3OD,三氟乙酸鹽） δ 7.18 (s, 1 Η), 5.98 (t, J = 8.7 Hz, 1 H), 4.19 (q, J = 10.1 Hz, 1 H), 4.09 (s, 1 H), 3.87 (dt, J = 5.0, 9.6 Hz, 1 H), 3.23-3.19 (m, 1 H), 3.06-2.87 (m, 10 H), 2.63 (t, J = 15.1 Hz, 1 H), 2.24-2.18 (m, 1 H), 1.69-1.59 (m, 1 H) ； MS (ESI) m/z 538.23 (M + H)。Diastereomer A S16-8-5-A S16-8-5-A : 4 NMR (400 MHz, CD3OD, trifluoroacetate) δ 7.18 (s, 1 Η), 5.98 (t, J = 8.7 Hz, 1 H), 4.19 (q, J = 10.1 Hz, 1 H), 4.09 (s, 1 H), 3.87 (dt, J = 5.0, 9.6 Hz, 1 H), 3.23-3.19 (m, 1 H), 3.06-2.87 (m, 10 H), 2.63 (t, J = 15.1 Hz, 1 H), 2.24-2.18 (m, 1 H), 1.69-1.59 (m, 1 H) ; MS (ESI) m/z 538.23 (M + H).

S16-8-1-B S16-8-1-B : ’H NMR (400 MHz, CD3OD,三敗乙酸鹽） δ 7.30 (s, 1 H), 5.80 (t, J= 9.2 Hz, 1 H), 4.22-4.18 (m, 1 H), 4.14-4.06 (m, 2 H), 3.29-3.25 (m, 1 H), 3.06-2.95 (m, 11 H), 2.91-2.74 (m, 2 H), 2.64-2.57 (m, 1 H), 2.24-2.18 (m, 1 H), 1.69-1.60 (m，1 H) ; MS (ESI) w/z 552.1 5 (M + H)。S16-8-1-B S16-8-1-B : 'H NMR (400 MHz, CD3OD, tri-acetate acetate) δ 7.30 (s, 1 H), 5.80 (t, J = 9.2 Hz, 1 H) , 2-4.18 (m, 1 H), 4. , 2.64-2.57 (m, 1 H), 2.24-2.18 (m, 1 H), 1.69-1.60 (m, 1 H); MS (ESI) w/z 552.1 5 (M + H).

S16-8-2-B : 4 NMR (400 MHz，CD3OD，三氟乙酸鹽） δ 7.38 (s, 1 Η), 5.79 (t, J = 9.2 Hz, 1 H), 4.17 (dt, J = 3.7, 9.6 Hz, 1 H), 4.09 (s, 1 H), 4.08 (q, J = 9.6 Hz, 1 H), 222 201245116 3.42-3.33 (m, 2 Η), 3.28-3.23 (m, 1 Η), 3.05-2.84 (m, 9 Η), 2.79-2.72 (m, 1 Η), 2.62 (t, J= 15.1 Hz, 1 H), 2.23-2.18 (m, 1 H), 1.69-1.60 (m, 1 H), 1.14 (t, J= 7.3 Hz, 3 H) ； MS (ESI) w/z 566.13 (M+H) 0S16-8-2-B : 4 NMR (400 MHz, CD3OD, trifluoroacetate) δ 7.38 (s, 1 Η), 5.79 (t, J = 9.2 Hz, 1 H), 4.17 (dt, J = 3.7 , 9.6 Hz, 1 H), 4.09 (s, 1 H), 4.08 (q, J = 9.6 Hz, 1 H), 222 201245116 3.42-3.33 (m, 2 Η), 3.28-3.23 (m, 1 Η) , 3.05-2.84 (m, 9 Η), 2.79-2.72 (m, 1 Η), 2.62 (t, J= 15.1 Hz, 1 H), 2.23-2.18 (m, 1 H), 1.69-1.60 (m, 1 H), 1.14 (t, J= 7.3 Hz, 3 H) ; MS (ESI) w/z 566.13 (M+H) 0

S16-8-3-B S16-8-3-B : 4 NMR (400 MHz，CD3〇D，三氟乙酸鹽） 5 7.39 (s，1 H)，5.80 (t，/ = 9.2 Hz，1 H)，4.18 (dt，= 3.2, 9.2 Hz, 1 H), 4.11 (q, J = 9.2 Hz, 1 H), 4.10 (s, 1 H), 3.28-3.19 (m，3 H)，3.05-2.94 (m，8 H)，2.90-2.84 (m，1 H)， 2.81-2.73 (m, 1 H), 2.61 (t, J = 15.1 Hz, 1 H), 2.24-2.18 (m, 1 H), 1.69-1.59 (m, 1 H), 1.53-1.46 (m, 2 H), 0.93 (t, 7.6S16-8-3-B S16-8-3-B : 4 NMR (400 MHz, CD3 〇D, trifluoroacetate) 5 7.39 (s, 1 H), 5.80 (t, / = 9.2 Hz, 1 H ), 4.18 (dt, = 3.2, 9.2 Hz, 1 H), 4.11 (q, J = 9.2 Hz, 1 H), 4.10 (s, 1 H), 3.28-3.19 (m, 3 H), 3.05-2.94 (m,8 H), 2.90-2.84 (m,1 H), 2.81-2.73 (m, 1 H), 2.61 (t, J = 15.1 Hz, 1 H), 2.24-2.18 (m, 1 H), 1.69-1.59 (m, 1 H), 1.53-1.46 (m, 2 H), 0.93 (t, 7.6

Hz，3 H) ; MS (ESI) m/z 580.17 (M+H)。Hz, 3 H) ; MS (ESI) m/z 580.17 (M+H).

S16-8-4-B : 4 NMR (400 MHz，CD3OD，三氟乙酸鹽） δ 7·55 (s&gt; 1 H), 5.76 (t? j= 9i6 Hz, 1 H), 4.19-4.13 (m, 2 H), 4.10 (t, J = 1.4 Hz, 1 H), 3.69-3.63 (m, 1 H), 3.27-3.22 (m, 1 H)，3.05-2.94 (m，8 H)，2.87-2.79 (m，1 H)，2.77-2.59 (m，2 H), 2.24-2.19 (m, l H), 1.70-1.60 (m, 1 H), 1.28 (d, 6.4S16-8-4-B : 4 NMR (400 MHz, CD3OD, trifluoroacetate) δ 7·55 (s&gt; 1 H), 5.76 (t? j = 9i6 Hz, 1 H), 4.19-4.13 (m , 2 H), 4.10 (t, J = 1.4 Hz, 1 H), 3.69-3.63 (m, 1 H), 3.27-3.22 (m, 1 H), 3.05-2.94 (m, 8 H), 2.87- 2.79 (m,1 H), 2.77-2.59 (m,2 H), 2.24-2.19 (m, l H), 1.70-1.60 (m, 1 H), 1.28 (d, 6.4

Hz, 3 H), 0.99 (d, j = 6.4 Hz, 3 H) ； MS (ESI) m/z 580.14 (M+H)。 223 201245116Hz, 3 H), 0.99 (d, j = 6.4 Hz, 3 H); MS (ESI) m/z 580.14 (M+H). 223 201245116

S16-8-5-B S16-8-5-B : NMR (400 MHz，CD3OD，三氟乙酸鹽） δ 7.16 (s, 1 Η), 6.03 (t, J= 7.8 Hz, 1 H), 4.20 (q, J= 9.2 Hz, 1 H), 4.0 8 (d, J = 1.3 Hz, 1 H), 3.8 5 (dt, J = 4.1, 10.1 Hz, 1 H), 3.26-3.20 (m, 1 H), 3.06-2.85 (m, 10 H), 2.63 (t, J = 15.1 Hz, 1 H), 2.24-2.18 (m, 1 H), 1.70-1.60 (m, 1 H) ； MS (ESI) m/z 538.23 (M + H)。 實施例17.合成其中環E為哌啶-2-基之式I化合物 根據以下流程17合成式I化合物，其中X為-CF3，Y 為-Η且環E為哌啶-2-基。 流程17S16-8-5-B S16-8-5-B : NMR (400 MHz, CD3OD, trifluoroacetate) δ 7.16 (s, 1 Η), 6.03 (t, J = 7.8 Hz, 1 H), 4.20 (q, J= 9.2 Hz, 1 H), 4.0 8 (d, J = 1.3 Hz, 1 H), 3.8 5 (dt, J = 4.1, 10.1 Hz, 1 H), 3.26-3.20 (m, 1 H ), 3.06-2.85 (m, 10 H), 2.63 (t, J = 15.1 Hz, 1 H), 2.24-2.18 (m, 1 H), 1.70-1.60 (m, 1 H) ; MS (ESI) m /z 538.23 (M + H). Example 17. Synthesis of a compound of formula I wherein ring E is piperidin-2-yl. A compound of formula I is synthesized according to Scheme 17 below, wherein X is -CF3, Y is -oxime and ring E is piperidin-2-yl. Process 17

.CH, nBuLi.THF; Ν·Β〇〇·2-〇辰咬炉 CC^Ph ..CH, nBuLi.THF; Ν·Β〇〇·2-〇辰咬炉 CC^Ph .

BnBr CF, a)LD 删 EDA χ ,CHlb)烯酮S2-1 llT LHMDS (BnBr CF, a) LD deleted EDA χ , CHlb) ketene S2-1 llT LHMDS (

S17-10 根據流程1 7製備以下化合物 S17-8S17-10 The following compounds were prepared according to Scheme 1 7 S17-8

ch3 C02Ph S17-1 224 201245116 . 合成S17-1 將n-BuLi於己烷中之溶液（1 6 M，8 26 i322 mmol，1·05 eq)緩慢添加至化合物 su_2 ( 5 〇 g，i2 59 mmoh leq)於THF(5〇mL)中之溶液中，維持溫度低於 -96〇C。隨後在-10(TC下攪拌所得橙色反應溶液5分鐘。添 加 N-Boc 哌啶 _ ( 2.76 g，13.85 職〇1，i」eq)於 τΗρ ( 1〇 mL)中之溶液，維持溫度低於·92χ：。使所得黃色反應溶液 升溫至鐵且在該溫度下攪拌i小時。隨後使反應混合物 升溫至（rc。添加NH4C1飽和水溶液，且用Et〇Ac( 2χi 〇〇 mL) 萃取所得混合物。經合併之有機層以鹽水洗滌，經MgS〇4 脫水，過濾且減壓濃縮，得到化合物，在無進一步純 化的情況下將其直接用於下—步驟中：Ms (ESI) m/z 518⑴ (m+h)。 ^ΝΪ|ί^Τ&quot;〇Η3 y^C〇2Ph OBn S17-2 合成sn-i 將化合物S17-1溶解於CH2Cl2(20mL)中。在室溫下 緩慢添加TFA(lOmL)(氣體逸出）。所得暗色溶液在室 皿下攪拌1.5小時，減壓濃縮，且添加至NaHC〇3飽和水溶 液中。用EtOAc ( 120 mL，隨後2x5 0 mL)萃取混合物。經 合併之有機萃取物經MgS〇4脫水且濃縮，得到呈灰白色固 體狀之亞胺S17-2。該物質直接用於下一步驟中：MS (ESI) m/z 400.24 (M + H)。 225 201245116Ch3 C02Ph S17-1 224 201245116 . Synthesis of S17-1 A solution of n-BuLi in hexane (1 6 M, 8 26 i322 mmol, 1.05 eq) was slowly added to the compound su_2 (5 〇g, i2 59 mmoh Leq) in a solution in THF (5 mL) maintained at a temperature below -96 °C. The resulting orange reaction solution was then stirred at -10 (TC) for 5 minutes. Add a solution of N-Boc piperidine _ ( 2.76 g, 13.85 s. 1, i eq) in τ Η (1 〇 mL), maintaining the temperature below 92 χ: The resulting yellow reaction solution was warmed to iron and stirred at this temperature for 1 hour. The reaction mixture was then warmed to (rc). A saturated aqueous solution of NH.sub.4.sub.1 was added and the mixture was extracted with Et.sub.2 (2 χi 〇〇mL). The combined organic layers were washed with EtOAc (EtOAc) m. m+h). ^ΝΪ|ί^Τ&quot;〇Η3 y^C〇2Ph OBn S17-2 Synthetic sn-i Compound S17-1 was dissolved in CH2Cl2 (20 mL). TFA (10 mL) was slowly added at room temperature. (Gas evolution). The resulting dark solution was stirred under a EtOAc EtOAc EtOAc (EtOAc) (EtOAc). The product was dehydrated with MgS 4 and concentrated to give the imamine S17-2 as an off-white solid. It was used directly in the next step:. MS (ESI) m / z 400.24 (M + H) 225 201245116

合成S17-3 在 〇°C 下將 NaBH4 ( 1·43 g，37.8 mmol，3 eq)整份添 加至S17-2於CH3OH ( 10 mL)及二氯曱烷（30 mL)中之 溶液中。觀測到劇烈氣體逸出β 5分鐘後移除冷浴，且在室 溫下攪拌反應混合物1小時。在〇°C下緩慢添加1 N HC1水 溶液（50mL)。用NaHC〇3飽和水溶液（2mL)將所得白 色懸浮液鹼化至pH = 8-9且用CH2C12 ( 150 mL，隨後2χ5〇 mL )萃取。經合併之有機萃取物經MgS〇4脫水且濃縮，得Synthesis of S17-3 NaBH4 (1.43 g, 37.8 mmol, 3 eq) was added in EtOAc to EtOAc (EtOAc) (EtOAc) The vigorous bath was observed to escape β for 5 minutes, the cold bath was removed, and the reaction mixture was stirred at room temperature for 1 hour. A 1 N HCl solution (50 mL) was slowly added at 〇 °C. The resulting white suspension was basified to pH = 8-9 and extracted with CH.sub.2Cl.sub.2 (150 mL then. The combined organic extracts are dehydrated and concentrated by MgS〇4

合成S17-4 08n S17-4 到呈黃色油狀之化合物S17_3: MS (ESI) m/z 402.20 (M + H)。 向上述產物SI 7-3於二氣曱烷（30 mL)中之溶液中添 加二碳酸二第三丁酯（3.02 g，13.85 mmo卜 1.1 eq)及 N，N-二甲胺基°比啶（154 mg，ι·26 mmol，0.1 eq)。在室溫下授 拌反應混合物隔夜且濃縮。藉由急驟管柱層析（5_2〇%乙酸 乙醋-己烧）純化殘餘物，得到呈白色泡沫固體狀之所需產 物 S17-4 ( 3_51 g，56% ’ 經 4 個步驟）：iH NMR (400 MHz， CDC13) δ 7.43-7.40 (mj 2 Η), 7.38-7.29 (m, 5 Η), 7.24-7.20 (m，1 H)，7.11-7.09 (m，2 H)，6·69 (d，J = 11.6 Hz， 2 H)，5.34 (br s，1 H)，5.11 (s，2 h)，4.00 (d，J = 13.4 Hz, 1 H)， 2.67-2.60 (m，1 H)，2.43 (s，3 H)，2.24-2.20 (m，1 H)， 226 201245116Synthesis of S17-4 08n S17-4 to compound S17_3: MS (ESI) m/z 402.20 (M + H). To the solution of the above product SI 7-3 in dioxane (30 mL) was added ditributyl dicarbonate (3.02 g, 13.85 mmo, 1.1 eq) and N,N-dimethylaminopyridinium. (154 mg, ι·26 mmol, 0.1 eq). The reaction mixture was stirred overnight at room temperature and concentrated. The residue was purified by flash column chromatography eluting elut elut elut elut elut elut elut elut elut (400 MHz, CDC13) δ 7.43-7.40 (mj 2 Η), 7.38-7.29 (m, 5 Η), 7.24-7.20 (m,1 H), 7.11-7.09 (m,2 H),6·69 ( d, J = 11.6 Hz, 2 H), 5.34 (br s, 1 H), 5.11 (s, 2 h), 4.00 (d, J = 13.4 Hz, 1 H), 2.67-2.60 (m, 1 H) , 2.43 (s, 3 H), 2.24-2.20 (m, 1 H), 226 201245116

合成S17-5 1.90-1.80 (m, 1 Η), 1.59-1.42 (m, 3 Η), 1.46 (s, 9 Η), 1.35-1.24 (m，1 Η) ; MS (ESI) m/z 524.31 (M+Na) »Synthesis S17-5 1.90-1.80 (m, 1 Η), 1.59-1.42 (m, 3 Η), 1.46 (s, 9 Η), 1.35-1.24 (m,1 Η); MS (ESI) m/z 524.31 (M+Na) »

向化合物 S17-4(3.51 g，6.99mmol，1 eq)於氯仿（36 mL )中之浴液中添加三氟乙酸銀（i.7〇g，7.69 mmol，1.1 eq)及峨（1.95g’ 7.69mmol，1_1 eq)。在室溫下禮拌反 應混合物隔夜且經由矽藻土墊過濾。用二氣曱烷洗滌矽藻 土墊。經合併之濾液以Na2S203飽和水溶液、NaHC03飽和 水溶液及鹽水洗滌。所得有機相經硫酸鎂脫水，過濾且減 壓濃縮。使用5°/。-12% EtOAc/己烷進行矽膠急驟層析，得 到呈白色固體狀之所需產物S17-5 ( 3.87 g，88%) : NMR (400 MHz, CDC13) δ 7.42-7.31 (m, 4 Η), 7.28-7.24 (m, 1 Η), 7.19-7.16 (m, 3 Η), 7.14-7.12 (m, 2 Η), 6.69 (s, 1 Η), 5.23 (dd, J = 4.9, 6.7 Hz, 1 H), 5.17, 5.11 (ABq, J = 12.2 Hz, 2 H), 4.11-4.05 (m, 1 H), 3.25-3.17 (m, 1 H), 2.58 (s, 3 H)s 1.96-1.88 (m} 1 H), 1.74-1.60 (m, 3 H), 1.54-1.48 (m, 1 H), 1.28 (s, 9 H), 1.30-1.23 (m, 1 H) ； MS (ESI) m/z 650.20 (M+Na)。Add silver trifluoroacetate (i.7〇g, 7.69 mmol, 1.1 eq) and hydrazine (1.95 g' to the bath of compound S17-4 (3.51 g, 6.99 mmol, 1 eq) in chloroform (36 mL) 7.69 mmol, 1_1 eq). The reaction mixture was stirred overnight at room temperature and filtered through a pad of Celite. The diatomaceous earth pad was washed with dioxane. The combined filtrate was washed with a saturated aqueous solution of Na.sub.2SO.sub.3, sat. The resulting organic phase was dried over magnesium sulfate, filtered and evaporated. Use 5°/. Flash-chromatography of EtOAc (EtOAc/EtOAc) elute elute elute elute , 7.28-7.24 (m, 1 Η), 7.19-7.16 (m, 3 Η), 7.14-7.12 (m, 2 Η), 6.69 (s, 1 Η), 5.23 (dd, J = 4.9, 6.7 Hz, 1 H), 5.17, 5.11 (ABq, J = 12.2 Hz, 2 H), 4.11-4.05 (m, 1 H), 3.25-3.17 (m, 1 H), 2.58 (s, 3 H)s 1.96-1.88 (m} 1 H), 1.74-1.60 (m, 3 H), 1.54-1.48 (m, 1 H), 1.28 (s, 9 H), 1.30-1.23 (m, 1 H) ; MS (ESI) m /z 650.20 (M+Na).

合成名ΙΊ-6。 OBn S17*6 化合物 S17-5 ( 3.87 g，6· 17 mmol，1 eq )、 227 201245116 CH3〇2CCF2S〇2F( 7.85 mL’ 61.7 mmol，10 eq)及 Cul( 5.87 g，30.8 mmol，5 eq)於DMF ( 20 mL)中之溶液在密封燒 瓶中在80°C下加熱3天。所得反應混合物經冷卻至室溫， 經由矽藻土墊過濾。用EtO Ac洗滌矽藻土墊。經合併之濾 液以水、飽和NH4C1溶液與NH4OH之混合物及鹽水洗滌。 所得有機相經硫酸鎂脫水，過濾且減壓濃縮。使用5%-1 5% EtOAc/己烷進行矽膠急驟層析，得到呈白色泡沫固體狀之 所需產物 S17-6 ( 3.33 g，95% ) : 4 NMR (400 MHz, CDC13) δ V.41-7.31 (m, 7 Η), 7.27-7.23 (m, 1 Η), 7.12-7.09 (m, 2 Η), 6.74 (s, 1 Η), 5.50 (t, J = 6.1 Hz, 1 H), 5.19, 5.13 (ABq, J =12.2 Hz, 2 H), 4.09-4.03 (m, 1 H), 3.07-3.00 (m, 1 H), 2.54 (q, J = 2.4 Hz, 3 H), 1.98-1.89 (m, 1 H), 1.64-1.55 (m, 3 H), 151-1.41 (m，1 H)，1.27 (s, 9 H)，1.25-1.22 (m, 1 H) ; MS (ESI) m/z 592.23 (M+Na) »Synthetic name -6. OBn S17*6 Compound S17-5 ( 3.87 g, 6.17 mmol, 1 eq), 227 201245116 CH3〇2CCF2S〇2F ( 7.85 mL ' 61.7 mmol, 10 eq) and Cul ( 5.87 g, 30.8 mmol, 5 eq) The solution in DMF (20 mL) was heated in a sealed flask at 80 °C for 3 days. The resulting reaction mixture was cooled to room temperature and filtered thru a pad. The diatomaceous earth pad was washed with EtO Ac. The combined filtrate was washed with water, a mixture of saturated NH4Cl solution and NH4OH and brine. The resulting organic phase was dried over magnesium sulfate, filtered and evaporated. The desired product S17-6 ( 3.33 g, 95%) was obtained as a white foam solid: 4 NMR (400 MHz, CDC13) δ V.41. -7.31 (m, 7 Η), 7.27-7.23 (m, 1 Η), 7.12-7.09 (m, 2 Η), 6.74 (s, 1 Η), 5.50 (t, J = 6.1 Hz, 1 H), 5.19, 5.13 (ABq, J = 12.2 Hz, 2 H), 4.09-4.03 (m, 1 H), 3.07-3.00 (m, 1 H), 2.54 (q, J = 2.4 Hz, 3 H), 1.98- 1.89 (m, 1 H), 1.64-1.55 (m, 3 H), 151-1.41 (m, 1 H), 1.27 (s, 9 H), 1.25-1.22 (m, 1 H) ; MS (ESI) m/z 592.23 (M+Na) »

OBn S17-7 S17-7 向化合物 S17-6 (57.1 mg，0_10 mmol，1 eq)於 1，4-二°惡烷（0.5 mL)中之溶液中添加4 M HC1/1，4-二噁烷（0.5 mL )。所得反應溶液在室溫下攪拌隔夜，且以NaHC03飽 和水溶液（4 mL )緩慢中止。用EtOAc萃取所得混合物。 有機相以鹽水洗滌，經硫酸鈉脫水，過濾且減壓滚縮，得 到呈淡黃色固體狀之產物S17-7:丨H NMR (400 MHz，CDC13) 8 7·56 (s，1 H)，7.46-7.43 (m，2 H)，7.40-7.32 (m，5 Η), 228 201245116 7.27-7.22 (m, 1 Η), 7.06-7.04 (m, 2 Η), 5.24, 5.20 (ABq, J = 11.6 Hz，2 H)，4.08-4.05 (m，1 H)，3.21-3.19 (m，i H)，2 83 (dt，J = 2.4，11.6 Hz，1 H)，2.54 (q，J = 3.6 hz 3 h) 1.88-1.66 (m，4 H)，1.63-1.46 (m，2 H)，1.43-1.37 (m，L H);OBn S17-7 S17-7 Add 4 M HC1/1,4-dioxin to a solution of compound S17-6 (57.1 mg, 0-10 mmol, 1 eq) in 1,4-dioxane (0.5 mL) Alkane (0.5 mL). The resulting reaction solution was stirred overnight at room temperature and slowly quenched with NaHCO3 sat. aqueous (4 mL). The resulting mixture was extracted with EtOAc. The organic phase was washed with EtOAc (EtOAc m. 7.46-7.43 (m, 2 H), 7.40-7.32 (m, 5 Η), 228 201245116 7.27-7.22 (m, 1 Η), 7.06-7.04 (m, 2 Η), 5.24, 5.20 (ABq, J = 11.6 Hz, 2 H), 4.08-4.05 (m, 1 H), 3.21-3.19 (m, i H), 2 83 (dt, J = 2.4, 11.6 Hz, 1 H), 2.54 (q, J = 3.6 Hz 3 h) 1.88-1.66 (m, 4 H), 1.63-1.46 (m, 2 H), 1.43-1.37 (m, LH);

合成S17-8 MS (ESI) m/z 470.25 (M + H)。粗產物直接用於下一反應。 將上述化合物S17-7溶解於丙酮（1 mL)中。在室溫 下添加碳酸鉀（21 mg，0.15 mmol，1.5 eq )及漠曱苯（13 μί， 〇· 11 mmol，1.1 eq ) ^反應混合物在室溫下攪拌3小時且在 5〇 C下授:拌隔夜。反應混合物經冷卻至室溫，以Et〇Ac ( 30 mL )稀釋。所得混合物以水及鹽水洗滌，經硫酸鈉脫水， 過/慮且減壓濃縮。藉由急驟管柱層析（丨—丨5 % Et〇Ac/己烷 梯度）純化殘餘物’得到呈無色油狀之化合物s17_8 ( 47 mg 84/〇 兩個步驟）：1hnMR(4〇〇MHz，cdc13)占 7 77 (s, 1 Η), 7.47-7 λδ / /&gt;44 (m, 2 Η), 7.41-7.32 (m, 5 Η), 7.28-7.19 (m, 6 Η), 7.06-7.〇s 2 Η), 5.24, 5.14 (ABq, J = 11.6 Hz, 2 H), 3 · 7 3 - 3.7 0 (m 1 、 5 Η)? 3.65 (d, J = 14.0 Hz, 1 H), 3.04-3.01 (m, 1 H), 2.89 (d, j ^ j 2.06-1.99 (m，丨 H)， 1.44-1.38 (m，2 H); J ^ 14.0 Hz, 1 H), 2.56 (q, J = 3.7 Hz, 3 H), 1 H), 1.88-1.79 (m, 2 H), 1.66-1.57 (m, 2 H), 2 H) ; MS (ESI) m/z 560.30 (M+H)。 229 201245116Synthesis of S17-8 MS (ESI) m/z 470.25 (M + H). The crude product was used directly in the next reaction. The above compound S17-7 was dissolved in acetone (1 mL). Potassium carbonate (21 mg, 0.15 mmol, 1.5 eq) and hydrazine benzene (13 μί, 〇·11 mmol, 1.1 eq) were added at room temperature. The reaction mixture was stirred at room temperature for 3 hours and was given at 5 〇C. : Mix overnight. The reaction mixture was cooled to room temperature and diluted with EtOAc (30 mL). The mixture was washed with water and brine, dried over sodium sulfate Purification of the residue by flash column chromatography ( 丨 丨 丨 % 〇 〇 / hexane / hexane gradient) gave the compound s17_8 ( 47 mg 84 / 〇 two steps) as a colorless oil: 1 hnMR (4 〇〇 MHz) , cdc13) occupies 7 77 (s, 1 Η), 7.47-7 λδ / /&gt;44 (m, 2 Η), 7.41-7.32 (m, 5 Η), 7.28-7.19 (m, 6 Η), 7.06 -7.〇s 2 Η), 5.24, 5.14 (ABq, J = 11.6 Hz, 2 H), 3 · 7 3 - 3.7 0 (m 1 , 5 Η)? 3.65 (d, J = 14.0 Hz, 1 H ), 3.04-3.01 (m, 1 H), 2.89 (d, j ^ j 2.06-1.99 (m, 丨H), 1.44-1.38 (m, 2 H); J ^ 14.0 Hz, 1 H), 2.56 ( q, J = 3.7 Hz, 3 H), 1 H), 1.88-1.79 (m, 2 H), 1.66-1.57 (m, 2 H), 2 H) ; MS (ESI) m/z 560.30 (M+ H). 229 201245116

合成S17-9 在-70°C 下將 n-BuLi ( 68 μί，1.6 Μ/己烷，0.109 mmol， 1.3 eq)逐滴添加至二異丙胺（17 μί，0.118 mmol，1.4 eq) 於THF ( 1 mL )中之溶液中。使反應混合物升溫至-20°C且 再冷卻至- 78°C。添加 TMEDA( 1 8 pL，0.1 1 8 mmol，1.4 eq )。 在-78°C下攪拌反應溶液5分鐘。在低於-70°C下經由套管逐 滴添加化合物 S17,8(47 mg，0.084 mmol，1 eq)於 THF (0.5 mL)中之溶液。在_78°(：下攪拌所得紅橙色溶液40分 鐘，且使用EtOH/液氮浴冷卻至-100°C。將烯酮S2-1 (40 mg，0.084 mmol，1 eq )於 THF ( 0.5 mL )中之溶液添加至 反應混合物中。使反應混合物逐漸升溫至-90。(：且隨後添加 LHMDS ( 84 ，1.0 M/THF，0.084 mmo卜 1 eq)。反應混 合物逐漸升溫至_ 1 (TC。向反應物中添加NH4C1飽和水溶液 (20 mL)。用EtOAc ( 30 mL)萃取反應混合物。有機相 以鹽水（100 mL )洗滌，經Na2S04脫水，且減壓濃縮。藉 由製備型逆相HPLC在Waters自動純化系統上使用SunfireSynthesis of S17-9 n-BuLi (68 μί, 1.6 Μ/hexane, 0.109 mmol, 1.3 eq) was added dropwise to diisopropylamine (17 μί, 0.118 mmol, 1.4 eq) in THF at -70 °C. In a solution of 1 mL). The reaction mixture was allowed to warm to -20 °C and then cooled to -78 °C. TMEDA (1 8 pL, 0.1 1 8 mmol, 1.4 eq) was added. The reaction solution was stirred at -78 ° C for 5 minutes. A solution of the compound S17,8 (47 mg, 0.084 mmol, 1 eq) in THF (0.5 mL) was added dropwise over EtOAc. The resulting red-orange solution was stirred at _78 ° (: 40 min and cooled to -100 ° C using EtOH / liquid nitrogen bath. enone S2-1 (40 mg, 0.084 mmol, 1 eq) in THF (0.5 mL The solution was added to the reaction mixture. The reaction mixture was gradually warmed to -90. (: and then LHMDS (84, 1.0 M/THF, 0.084 mmo, 1 eq) was added. The reaction mixture was gradually warmed to _ 1 (TC. A saturated aqueous solution of NH.sub.4Cl.sub.2 (20 mL) was evaporated. Sunfire on Waters Automated Purification System

Prep C180BD 管柱[5 &quot;m，19x5 0mm ;流速：20 mL/min ; 溶劑 A : H2〇，含 HC02H ;溶劑 B : CH3CN，含 〇_1% HC〇2H ;注入體積：3.0 mL ( CH3CN);梯度：800-&gt; 100% B之A溶液，經10分鐘；質量導向型洗提份收集]純化粗產 物。收集含有所需產物之洗提份且濃縮，得到呈黃色固體 230 201245116 狀之所需產物S17-9(非對映異構體之約1:1混合物，62 mg &gt; 78% ) ： !H NMR (400 MHz, CDC13) δ 15.69 (s, 0.5 H), 15.64 (s, 0.5 H), 7.86 (s, 0.5 H), 7.82 (s, 0.5 H), 7.50-7.48 (m, 4 H), 7.40-7.32 (m, 5 H), 7.31-7.25 (m, 4 H), 7.19-7.14 (m, 2 H), 5.38-5.27 (m, 4 H), 4.03-3.97 (m, 1.5 H), 3.88-3.83 (m, 1 H), 3.76 (d, J = 14.0 Hz, 0.5 H), 3.34-3.19 (m, 3 H), 2.93-2.71 (m, 2 H), 2.58-2.45 (m, 8 H), 2.32-2.22 (m, 1 H), 2.13 (d, J = 14.0 Hz, 1 H), 1.94-1.58 (m, 5 H), 1.44-1.38 (m 1 H), 0.84 (s, 4.5 H), 0.83 (s, 4.5 H), 0.274 (s, 1.5 H), 0.268 (s, 1.5 H), 0.16 (s, 1.5 H), 0.15 (s, 1.5 H) ； MS (ESI) m/z 948.41 (M+H)。Prep C180BD column [5 &quot;m, 19x5 0mm; flow rate: 20 mL/min; solvent A: H2〇, containing HC02H; solvent B: CH3CN, containing 〇_1% HC〇2H; injection volume: 3.0 mL (CH3CN Gradient: 800-&gt; 100% B A solution, 10 minutes; mass-oriented extract fraction collection] Purified crude product. The extract containing the desired product was collected and concentrated to give the desired product S17-9 (yield: 1:1 mixture of diastereomers, 62 mg &gt; 78%) as a yellow solid 230 201245116 : !H NMR (400 MHz, CDC13) δ 15.69 (s, 0.5 H), 15.64 (s, 0.5 H), 7.86 (s, 0.5 H), 7.82 (s, 0.5 H), 7.50-7.48 (m, 4 H), 7.40-7.32 (m, 5 H), 7.31-7.25 (m, 4 H), 7.19-7.14 (m, 2 H), 5.38-5.27 (m, 4 H), 4.03-3.97 (m, 1.5 H), 3.88-3.83 (m, 1 H), 3.76 (d, J = 14.0 Hz, 0.5 H), 3.34-3.19 (m, 3 H), 2.93-2.71 (m, 2 H), 2.58-2.45 (m, 8 H), 2.32-2.22 (m, 1 H), 2.13 (d, J = 14.0 Hz, 1 H), 1.94-1.58 (m, 5 H), 1.44-1.38 (m 1 H), 0.84 (s, 4.5 H), 0.83 (s, 4.5 H), 0.274 (s, 1.5 H), 0.268 (s, 1.5 H), 0.16 (s, 1.5 H), 0.15 (s, 1.5 H) ; MS (ESI) m/z 948.41 (M+H).

合成 S17-10。 根據標準脫除保護基程序（脫甲矽基及氫化）自化合 物S2-10獲得化合物S17-9。藉由製備型逆相HPLC在Waters 自動純化系統上使用Phenomenex Polymerx 1 〇 # RPi 100A 管柱[10 &quot; m ’ 150x21.20 mm ;流速：20 mL/min ;溶 劑 A : 0·05 N HC1/水；溶劑 b : CH3CN ;注入體積：3.0 mL (0.05 N HC1/水）；梯度：〇— 40% B，經20分鐘；質量導 向型洗提份收集]分離兩種非對映異構體。收集含有所需產 物之洗提份且冷凍乾燥。 S17-10-A(在12.6-13.7分鐘洗提，非對映異構體A): 231 201245116 'H NMR (400 MHz, CD3OD,鹽酸鹽）5 7.24 (s, 1 Η), 4.64 (dd, J= 1.8, 9.6 Hz, 1 H), 4.14 (s, 1 H), 3.57-3.53 (m, 1 H), 3.29-3.23 (m, 2 H), 3.08-2.95 (m, 8 H), 2.59 (t, J = 15.1 Hz, 1 H), 2.26-2.22 (m, 1 H), 2.04-1.98 (m, 3 H), 1.94-1.76 (m, 3 H)，1.68- 1.58 (m, 1 H) ; MS (ESI) m/z 566.30 (M + H)。 S17-10-B(在14.7-15.6分鐘洗提，非對映異構體B): 'Η NMR (400 MHz, CD3OD,鹽酸鹽）5 7.29 (s, 1 Η), 4.52 (dd, J= 1.8, 9.6 Hz, 1 H), 4.1 4 (d, J = 0.9 Hz, 1 H), 3.5 4-3.5 1 (m, 1 H), 3.27-3.23 (m, 2 H), 3.05-2.96 (m, 8 H), 2.63 (t, J = 15.1 Hz, 1 H), 2.26-2.18 (m, 2 H), 2.05-1.86 (m, 4 H), 1.81-1.75 (m, 1 H), 1.69-1.59 (m, 1 H) ； MS (ESI) m/z 566.30 (M+H)。 實施例18.合成其中環E為哌啶-2-基之式I化合物 根據流程18合成式I化合物，其中X為-CF3，Y為-Η 且環Ε為哌啶-2-基。 流程18 1.還原性 胺化Synthesis of S17-10. Compound S17-9 was obtained according to the standard removal of the protecting group procedure (demethylhydrazine and hydrogenation) from compound S2-10. Phenomenex Polymerx 1 〇# RPi 100A column [10 &quot; m ' 150x21.20 mm ; flow rate: 20 mL/min; solvent A: 0·05 N HC1/ by preparative reverse phase HPLC on a Waters automated purification system Water; solvent b: CH3CN; injection volume: 3.0 mL (0.05 N HC1/water); gradient: 〇- 40% B over 20 minutes; mass-oriented elution fraction collection] Separation of the two diastereomers. The fractions containing the desired product are collected and lyophilized. S17-10-A (extracted in 12.6-13.7 minutes, diastereomer A): 231 201245116 'H NMR (400 MHz, CD3OD, hydrochloride) 5 7.24 (s, 1 Η), 4.64 (dd , J= 1.8, 9.6 Hz, 1 H), 4.14 (s, 1 H), 3.57-3.53 (m, 1 H), 3.29-3.23 (m, 2 H), 3.08-2.95 (m, 8 H), 2.59 (t, J = 15.1 Hz, 1 H), 2.26-2.22 (m, 1 H), 2.04-1.98 (m, 3 H), 1.94-1.76 (m, 3 H), 1.68- 1.58 (m, 1 H) ; MS (ESI) m/z 566.30 (M + H). S17-10-B (extracted in 14.7-15.6 minutes, diastereomer B): 'Η NMR (400 MHz, CD3OD, hydrochloride) 5 7.29 (s, 1 Η), 4.52 (dd, J = 1.8, 9.6 Hz, 1 H), 4.1 4 (d, J = 0.9 Hz, 1 H), 3.5 4-3.5 1 (m, 1 H), 3.27-3.23 (m, 2 H), 3.05-2.96 ( m, 8 H), 2.63 (t, J = 15.1 Hz, 1 H), 2.26-2.18 (m, 2 H), 2.05-1.86 (m, 4 H), 1.81-1.75 (m, 1 H), 1.69 -1.59 (m, 1 H); MS (ESI) m/z 566.30 (M+H). Example 18. Synthesis of a compound of formula I wherein ring E is piperidin-2-yl. A compound of formula I is synthesized according to Scheme 18 wherein X is -CF3, Y is -Η and cyclopeptone is piperidin-2-yl. Scheme 18 1. Reductive Amination

烯丙基溴.ΝΜΡ K2C〇3, NalAllyl bromide. ΝΜΡ K2C〇3, Nal

R? = Pr 或k他烷基R? = Pr or k-alkyl

Pd{PPh3)4 NDMBA OCMPd{PPh3)4 NDMBA OCM

根據流程1 8製備以下化合物。 232 201245116The following compounds were prepared according to Scheme 18. 232 201245116

合成化合物S18-1-A及S18-1-B 在-72°C 下將《-BuLi( 363 μί&gt;1·6Μ/己烷，0.581 mmo 卜 2.4 eq)逐滴添加至二異丙胺（86 μί，0.605 mmol，2.5 eq) 於THF ( 2 mL )中之溶液中。使反應混合物升溫至_2〇〇c且Synthesis of Compounds S18-1-A and S18-1-B -BuLi ( 363 μί &gt; 1.6 Μ / hexane, 0.581 mmo 卜 2.4 eq) was added dropwise to diisopropylamine (86 μί) at -72 °C. , 0.605 mmol, 2.5 eq) in THF (2 mL). The reaction mixture is allowed to warm to _2 〇〇 c and

再冷卻至-74C。添加 TMEDA( 91 pL，0.605 mmol，2.5 eq)。 在-78°C下攪拌反應溶液5分鐘》在低於-70°C下經由套管逐 滴添加化合物 S17-7 ( 114 mg，0.242 mmol，1 eq)於 THF (1 mL)中之溶液。在_78〇c下攪拌所得紅橙色溶液3〇分 鐘’且使用EtOH/液氮浴冷卻至_100。匚。將浠酮su ( U7 mg ’ 0.242 mmol，1 eq)於 THF ( 0.5 mL)中之溶液添加至 反應混合物中。使反應混合物逐漸升溫至_丨01。向反應物 中添加nh4ci飽和水溶液（20 mL)。用Et0Ac (3〇 mL) 萃取反應混合物。有機相以鹽水（1〇〇 mL)洗滌，經Na2S〇4 脫水，且減壓濃縮。藉由製備型逆相HpLC在Waters自動 純化系統上使用SunfirePrepC180BD管柱[5 &quot;m，19x50 mm ;流速：20 mL/min ;溶劑 A : h2〇，含 〇 i% 溶劑 B : Ch3CN，含 〇_1% HC〇2H ;注入體積：3 〇 mL (CH3CN)，梯度：20— 1〇〇% B之A溶液，經分鐘； 2里導向型洗提份收集]純化粗產物。收集在7 $分鐘洗 提之3有所需產物之洗提份，以飽和NaHc〇3中和，且用 Et〇Ac萃取。有機相經叫抓脫水且濃縮，得到呈黃色固 233 201245116 體狀之所需.產物 S18_l-A( 27.5 mg，14%):丨11 NMR (400 MHz， CDC13) δ 7.60 (s, 1 Η), 7.52-7.46 (m, 4 Η), 7.39-7.25 (m, 6 Η), 5.35 (s, 2 Η), 5.27 (s, 2 Η), 3.98-3.95 (m, 2 Η), 3.21-3.15 (m, 2 Η), 2.83-2.69 (m, 3 Η), 2.53-2.43 (m, 8 Η), 2.10 (d, J= 14.6 Hz, 1 H), 1.86-1.81 (m, 1 H), 1.66-1.22 (m, 6 H), 0.81 (s, 9 H), 0.26 (s, 3 H), 0.13 (s, 3 H) ； MS (ESI) m/z 858.3 3 (M+H)。收集在8.6-9.5分鐘洗提之含有所需產物之 洗提份，以飽和NaHC〇3中和，且用EtOAc萃取。有機相 經Na2S〇4脫水且濃縮’得到呈黃色固體狀之所需產物 S18-1-B ( 23.6 mg » 12%) : &gt;H NMR (400 MHz, CDC13) δ 7.56 (s, 1 Η), 7.50-7.46 (m, 4 Η), 7.39-7.26 (m, 6 Η), 5.36 (s, 2 Η), 5.34, 5.27 (ABq, /= 12.2 Hz, 2 H), 4.05-4.01 (m, 1 H) 3.97 (d, J= 14.0 Hz, 1 H), 3.23-3.19 (m, 2 H), 2.87-2.67 (ms 3 H), 2.54-2.41 (m, 8 H), 2.11 (d, J = 14.6 Hz, 1 H) 1.87-1.85 (m, 2 H), 1.69-1.37 (m, 5 H), 0.82 (s, 9 H), 0.26 (sCool to -74C. TMEDA (91 pL, 0.605 mmol, 2.5 eq) was added. The reaction solution was stirred at -78 °C for 5 minutes, and a solution of the compound S17-7 (114 mg, 0.242 mmol, 1 eq) in THF (1 mL) was added dropwise. The resulting red-orange solution was stirred at _78 〇c for 3 Torr and cooled to _100 using an EtOH/liquid nitrogen bath. Hey. A solution of the fluorenone su (U7 mg '0.242 mmol, 1 eq) in THF (0.5 mL) was added to the reaction mixture. The reaction mixture was gradually warmed to _丨01. A saturated aqueous solution of nh4ci (20 mL) was added to the mixture. The reaction mixture was extracted with Et0Ac (3 mL). The organic phase was washed with brine (1 mL), dried over Naz. SunfirePrepC180BD column was used on the Waters automated purification system by preparative reverse phase HpLC [5 &quot;m, 19x50 mm; flow rate: 20 mL/min; solvent A: h2 〇, containing 〇i% solvent B: Ch3CN, containing hydrazine _1% HC〇2H; injection volume: 3 〇mL (CH3CN), gradient: 20-1% B solution of A, after minute; 2-lead-type elution fraction collection] Purify the crude product. The extracts of the desired product were collected at 7 </ RTI> for 7 min, neutralized with sat. NaHc.sub.3 and extracted with Et.sub.Ac. The organic phase is dehydrated and concentrated to give the desired product as a yellow solid 233 201245116. Product S18_l-A (27.5 mg, 14%): 丨11 NMR (400 MHz, CDC13) δ 7.60 (s, 1 Η) , 7.52-7.46 (m, 4 Η), 7.39-7.25 (m, 6 Η), 5.35 (s, 2 Η), 5.27 (s, 2 Η), 3.98-3.95 (m, 2 Η), 3.21-3.15 (m, 2 Η), 2.83-2.69 (m, 3 Η), 2.53-2.43 (m, 8 Η), 2.10 (d, J= 14.6 Hz, 1 H), 1.86-1.81 (m, 1 H), 1.66-1.22 (m, 6 H), 0.81 (s, 9 H), 0.26 (s, 3 H), 0.13 (s, 3 H); MS (ESI) m/z 858.3 3 (M+H). The fractions containing the desired product eluted in 8.6-9.5 minutes were collected, neutralized with saturated NaHC.sub.3 and extracted with EtOAc. The organic phase was dried over Na.sub.2.sub.4 and concentrated to give the desired product S18-1-B (23.6 mg &lt;RTI ID=0.0&gt;&gt; , 7.50-7.46 (m, 4 Η), 7.39-7.26 (m, 6 Η), 5.36 (s, 2 Η), 5.34, 5.27 (ABq, /= 12.2 Hz, 2 H), 4.05-4.01 (m, 1 H) 3.97 (d, J = 14.0 Hz, 1 H), 3.23-3.19 (m, 2 H), 2.87-2.67 (ms 3 H), 2.54-2.41 (m, 8 H), 2.11 (d, J = 14.6 Hz, 1 H) 1.87-1.85 (m, 2 H), 1.69-1.37 (m, 5 H), 0.82 (s, 9 H), 0.26 (s

3 H)，0.14 (s, 3 H) ; MS (ESI) m/z 858.33 (M+H)。 合成化合物18-2。 將 K2C03 (1.50 g’ 10.82 mmo卜 2.0 eq)及稀丙基填 (702 μί ’ 8·12 mmol，1.5 eq)依序添加至粗化合物Sl7j (2.54 g，5_41 mmo卜 1 eq)於 NMP ( 4 mL )中之溶液中。 所得反應混合物在7 〇 C下加熱1 · 5小時，且冷卻至室 隨後使反應物分配於EtOAc與水之間。分離有機相，用鹽 234 201245116 _ 水洗務，經無水硫酸納脫水，過滤且減麼濃縮。藉由^夕膠 急驟層析（使用1 %-&gt; 14% EtOAc/己烷）純化殘餘物，得到 呈白色固體狀之所需產物S18-2 ( 1·78 g，68%，經兩個步 驟）：4 NMR (400 MHz，CDC13) (5 7.59 (s，1 H)，7.47-7.44 (m，2 Η), 7.40-7.32 (m，5 H)，7.27-7.22 (m，1 H)，7.09-7.07 (m, 2 H), 5.68-5.58 (m, 1 H), 5.20 (s, 2 H), 5.13-5.09 (m, 1 H), 5.05-5.03 (m, 1 H), 3.40-3.57 (m, 1 H), 3.19-3.16 (m, 13 H), 0.14 (s, 3 H); MS (ESI) m/z 858.33 (M+H). Compound 18-2 was synthesized. K2C03 (1.50 g' 10.82 mmo 2.0 eq) and a propyl (702 μί '8·12 mmol, 1.5 eq) were added sequentially to the crude compound Sl7j (2.54 g, 5_41 mmo, 1 eq) in NMP (4) In the solution in mL). The resulting reaction mixture was heated at 7 ° C for 1-5 h and cooled to room then partitioned between EtOAc and water. The organic phase was separated, washed with water 234 201245116 _ water, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by EtOAc EtOAc (EtOAc) Step): 4 NMR (400 MHz, CDC13) (5 7.59 (s, 1 H), 7.47-7.44 (m, 2 Η), 7.40-7.32 (m, 5 H), 7.27-7.22 (m, 1 H) , 7.09-7.07 (m, 2 H), 5.68-5.58 (m, 1 H), 5.20 (s, 2 H), 5.13-5.09 (m, 1 H), 5.05-5.03 (m, 1 H), 3.40 -3.57 (m, 1 H), 3.19-3.16 (m, 1

H), 3.03-2.98 (m, 1 H), 2.55 (q, J= 3.7 Hz, 3 H), 2.42 (dd, J =7.9, 14.0 Hz, 1 H), 2.02 (dt, J = 3.0, 12.2 Hz, 1 H), 1.82-1.60 (m, 4 H), 1.38- 1.33 (m, 2 H) ； MS (ESI) m/z 510.21 (M+H)。H), 3.03-2.98 (m, 1 H), 2.55 (q, J = 3.7 Hz, 3 H), 2.42 (dd, J = 7.9, 14.0 Hz, 1 H), 2.02 (dt, J = 3.0, 12.2 Hz, 1 H), 1.82-1.60 (m, 4 H), 1.38- 1.33 (m, 2 H); MS (ESI) m/z 510.21. (M+H).

ΟΒη Ο S18-3 OHi Ο 〇Bn OTBS 合成化合物SI 8-3。 根據與SI8-1所用類似之程序自S18_2 ( 1.77 g)及烯 鋼S2_1製備。藉由矽膠急驟層析（使用1%~&gt;15% EtOAc/ΟΒη Ο S18-3 OHi Ο 〇Bn OTBS Synthetic compound SI 8-3. Prepared from S18_2 ( 1.77 g) and olefin steel S2_1 according to procedures similar to those used in SI8-1. Flash chromatography by gelatin (using 1%~&gt; 15% EtOAc/

H), 3.00-2.98 (m, 0.5 H), 2.84 44 (m, 0.5 Η), 3.27-3.11 (m, 2 -2.73 (m, 2.5 H), 2.55-2.30 (m, 235 201245116 9 Η), 2.12 (d, J = 14.0 Hz, 1 H), 2.01-1.95 (m, 1 H), 1.80-1.54 (m, 4 H), 1.41-1.12 (m, 2 H), 0.83 (s, 9 H), 0.27 (s, 3 H)，0.15 (s, 3 H) ; MS (ESI) m/z 898.32 (M+H)。H), 3.00-2.98 (m, 0.5 H), 2.84 44 (m, 0.5 Η), 3.27-3.11 (m, 2 -2.73 (m, 2.5 H), 2.55-2.30 (m, 235 201245116 9 Η), 2.12 (d, J = 14.0 Hz, 1 H), 2.01-1.95 (m, 1 H), 1.80-1.54 (m, 4 H), 1.41-1.12 (m, 2 H), 0.83 (s, 9 H) , 0.27 (s, 3 H), 0.15 (s, 3 H); MS (ESI) m/z 898.32 (M+H).

OBn Ο OH= O OTBS S18-1 pF3 h，CH3 合成S18-1 在氮氣下向化合物 S18-3( 300 mg，0.334 mmol，1 eq)、 1，3-二甲基巴比妥酸（522 mg，3.34 mmol，10 eq )及 Pd(PPh3)4 (19.3 mg，0.017 mmol，0.05 eq)之混合物中添加二氯甲 烷（4 mL )。在3 5 C下攪拌所得反應溶液3小時。反應混 合物以碳酸氫納飽和水溶液中止（.鼓泡）且用二氣甲烧（3〇 mL，隨後1 〇 mL )萃取。經合併之古搶 1汗心有機卒取物經無水硫酸 鈉脫水’過爐、且減壓濃縮。藉由石夕勝各驟思/ /修总驟層析（使用10% 100% EtOAc/己烷）純化殘餘物，犋丨 件到呈頁色固體狀之所 需產物S18-1 (非對映異構體之約1:1混合物，261叫， 91%) : *H NMR (400 MHz，CDci3)占 7 6i (s，i h)， 7.52-7.47 (m, 4 H), 7.39-7.26 (m, 6 H), 5.36 (Sj 2 H), 5.32, 5.24 (ABq, 7= 12.2 Hz, 1 H), 5.28 (s ] λ λ. 。U，1 H)，4.07-4.04 (m，0.5 H)，3.99-3.95 (m，1.5 H)，3.28-3.16 (m 2 FT、i or» 2 H)，2.89-2.67 (m,3OBn Ο OH= O OTBS S18-1 pF3 h,CH3 Synthesis of S18-1 Under nitrogen to compound S18-3 (300 mg, 0.334 mmol, 1 eq), 1,3-dimethylbarbituric acid (522 mg Methanol (4 mL) was added to a mixture of 3.34 mmol, 10 eq) and Pd (PPh3) 4 (19.3 mg, 0.017 mmol, 0.05 eq). The resulting reaction solution was stirred at 3 5 C for 3 hours. The reaction mixture was quenched with a saturated aqueous solution of sodium bicarbonate (bubble) and extracted with hexane (3 〇 mL, then 1 〇 mL). The combined ancient smashed 1 sweat organic extract was dehydrated by anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by a flash chromatography (10% 100% EtOAc / hexanes) elute to the desired product S18-1 (non-aligned) Approximately 1:1 mixture of isomers, 261, 91%): *H NMR (400 MHz, CDci3) for 7 6i (s, ih), 7.52-7.47 (m, 4 H), 7.39-7.26 (m , 6 H), 5.36 (Sj 2 H), 5.32, 5.24 (ABq, 7= 12.2 Hz, 1 H), 5.28 (s ] λ λ. U,1 H), 4.07-4.04 (m, 0.5 H) , 3.99-3.95 (m, 1.5 H), 3.28-3.16 (m 2 FT, i or» 2 H), 2.89-2.67 (m, 3

H), 2.55-2.40 (m, 8 H), 2.11 (d, J = i 4 , T 14·6 Hz, 1 H)s 1.87-1.80 (m, 1.5 H), 1.67-1.27 (m, 5.5 H), 〇.83 (s 4 c U, 4.5 H), 0.82 (s, 4.5 H), 0.27 (s, 1.5 H), 0.26 (s, 1.5 H) 〇 is 飞 c 八 υ·15 (s，1.5 H)，0.14 (s’ 1.5 H) ; MS (ESI) m/z 858.39 (M+H)。 236 201245116 . 如關於化合物S1S-2-1-A所述，藉由用適當醛或酮進行 還原性胺化、接著脫曱矽基及氫化’自S18-1製備以下化合 物。H), 2.55-2.40 (m, 8 H), 2.11 (d, J = i 4 , T 14·6 Hz, 1 H)s 1.87-1.80 (m, 1.5 H), 1.67-1.27 (m, 5.5 H ), 〇.83 (s 4 c U, 4.5 H), 0.82 (s, 4.5 H), 0.27 (s, 1.5 H), 0.26 (s, 1.5 H) 〇is fly c gossip · 15 (s, 1.5 H), 0.14 (s' 1.5 H); MS (ESI) m/z 858.39 (M+H). 236 201245116. The following compounds were prepared as described for the compound S1S-2-1-A by reductive amination with an appropriate aldehyde or ketone followed by dehydration and hydrogenation from S18-1.

合成 S18-4-1。Synthesis of S18-4-1.

自HCHO開始，接著進行兩個脫除保護基步驟來製備 S18-4-1。藉由製備型逆相HPLC在Waters自動純化系統上 使用 Phenomenex Polymerx 10 β RP-r l〇〇A 管柱[l〇 M m，150x21.20 mm ;流速：20 mL/min ;溶劑 A : 〇 〇5 N HC1/ 水，溶劑B . CH3CN，注入體積：3.〇 mL ( ο·。】n HC1/水）. 梯度：0—40% B，經20分鐘；質量導向型洗提份收集]分 離兩種非對映異構體。收集含有所需產物之洗提份且冷凍 乾燥。 S18-4-1-A(在15.0-15.6分鐘洗提，非對映異構體A): ^nmrmoomhlcdwd，鹽酸鹽）δ 74〇(s1h)448 (dd, 2.3, 11.4 Hz, 1 H), 4.13 (Sj ! H)j 3.67-3.64 (m, l H)s 3.40-3.33 (m，1 H)，3.29-3.25 (m，！ H)，3 〇9·2 97 (m，8 H)， 2.66 (t, 7 = 14.6 Hz, 1 H), 2.56 (Sj 3 H)j 2.25-2.22 (m, 2 H), 2.06-2.00 (m, 4 H), 1.74-1.59 (m} 2 H) ； MS (ESI) m/z 580.25 (M+H)。 S18_4_1_B(在13.4·14·2分鐘洗提，非對映異構體B): hNMRHOOMHz’CDWD，鹽酸鹽）5 741(s1h)462 (dd, 2.8, 11.4 Hz, 1 H), 4.13 (s&gt; χ H)&gt; 3.72-3.68 (m, 1 H), 237 201245116 3.42-3.22 (m, 2 Η), 3.08-2.96 (m, 8 Η), 2.72 (s, 3 Η), 2.62 (t, J = 14.6 Hz, 1 H), 2.23 (ddd, J = 2.8, 5.0, 13.7 Hz, 1 H), 2.07-1.89 (m, 5 H), 1.78-1.70 (m, 1 H), 1.68-1.58 (m5 1 H)； MS (ESI) m/z 580.23 (M+H)。Starting with HCHO, two deprotection steps were followed to prepare S18-4-1. Phenomenex Polymerx 10 β RP-r l〇〇A column was used on a Waters automated purification system by preparative reverse phase HPLC [l〇M m, 150 x 21.20 mm; flow rate: 20 mL/min; solvent A: 〇〇 5 N HC1/water, solvent B. CH3CN, injection volume: 3. 〇mL ( ο·.) n HC1/water). Gradient: 0-40% B, after 20 minutes; mass-oriented elution fraction collection] separation Two diastereomers. The extract containing the desired product was collected and lyophilized. S18-4-1-A (extracted at 15.0-15.6 min, diastereomer A): ^nmrmoomhlcdwd, hydrochloride) δ 74 〇 (s1h) 448 (dd, 2.3, 11.4 Hz, 1 H) , 4.13 (Sj ! H)j 3.67-3.64 (m, l H)s 3.40-3.33 (m,1 H), 3.29-3.25 (m,! H),3 〇9·2 97 (m,8 H) , 2.66 (t, 7 = 14.6 Hz, 1 H), 2.56 (Sj 3 H)j 2.25-2.22 (m, 2 H), 2.06-2.00 (m, 4 H), 1.74-1.59 (m} 2 H) MS (ESI) m/z 580.25 (M+H). S18_4_1_B (extracted at 13.4·14·2 minutes, diastereomer B): hNMRHOOMHz 'CDWD, hydrochloride) 5 741 (s1h) 462 (dd, 2.8, 11.4 Hz, 1 H), 4.13 (s&gt;; χ H)&gt; 3.72-3.68 (m, 1 H), 237 201245116 3.42-3.22 (m, 2 Η), 3.08-2.96 (m, 8 Η), 2.72 (s, 3 Η), 2.62 (t, J = 14.6 Hz, 1 H), 2.23 (ddd, J = 2.8, 5.0, 13.7 Hz, 1 H), 2.07-1.89 (m, 5 H), 1.78-1.70 (m, 1 H), 1.68-1.58 ( MS (ESI) m/z 580.21. (M+H).

合成 S18-4-2。 自CHsCHO開始，接著進行兩個脫除保護基步驟來製 備S18-4-2。藉由製備型逆相HPLC在Waters自動純化系統 上使用 Phenomenex Polymerx 10 认 Rp_ γ 100Α 管柱[10 &quot;m ’ 1 50x2 1.20 mm ;流速：20 mL/min ;溶劑 A : 0.05 N HC1/ 水’溶劑 B : CH3CN ;注入體積：3.〇mL( 0.05 NHC1/水）； 梯度：0— 40% B，經20分鐘；質量導向型洗提份收集]分 離兩種非對映異構體。收集含有所需產物之洗提份且冷凍 乾燥》 S18-4-2-A(在12.9-13.8分鐘洗提，非對映異構體A): H NMR (400 MHz，CD3OD，鹽酸鹽）占 7.47 (s, 1 Η), 4.67 (dd, J = 2.3, 11.4 Hz, 1 H), 4.13 (d, J = 〇&gt;9 Hz, 1 H), 3-90-3.87 (m, 1 H), 3.38-3.12 (ms x H), 3.26-3.15 (m, 2 H), 3-09-2.92 (m, 9 H), 2.60 (t, J = 15.! Hz, 1 H), 2.23 (ddd, J = 2-3, 4.6, 13.3 Hz, 1 H), 2.06-2.03 (m, 3 H), 1.99-1.91 (m, 2 H), 1.78-1.72 (m, 1 H), 1.68-1.58 (m, 1 H), 1.30 (t, J= 7.3Synthesis of S18-4-2. Starting with CHsCHO, two deprotection steps were followed to prepare S18-4-2. Phenomenex Polymerx 10 was used for Rp_ γ 100Α column by preparative reverse phase HPLC on a Waters automated purification system [10 &quot;m ' 1 50x2 1.20 mm ; flow rate: 20 mL/min; solvent A : 0.05 N HC1/water' Solvent B: CH3CN; injection volume: 3. 〇mL (0.05 NHC1/water); Gradient: 0-40% B over 20 minutes; mass-oriented elution fraction collection] Separation of the two diastereomers. The extract containing the desired product was collected and lyophilized. S18-4-2-A (extracted at 12.9-13.8 minutes, diastereomer A): H NMR (400 MHz, CD3OD, hydrochloride) Accounting for 7.47 (s, 1 Η), 4.67 (dd, J = 2.3, 11.4 Hz, 1 H), 4.13 (d, J = 〇&gt;9 Hz, 1 H), 3-90-3.87 (m, 1 H ), 3.38-3.12 (ms x H), 3.26-3.15 (m, 2 H), 3-09-2.92 (m, 9 H), 2.60 (t, J = 15.! Hz, 1 H), 2.23 ( Ddd, J = 2-3, 4.6, 13.3 Hz, 1 H), 2.06-2.03 (m, 3 H), 1.99-1.91 (m, 2 H), 1.78-1.72 (m, 1 H), 1.68-1.58 (m, 1 H), 1.30 (t, J= 7.3

Hz，3 H) ; MS (ESI) m/z 594.21 (m + H)。 238 201245116 參 . S18-4_2_B(在14.7-15.6分鐘洗提，非對映異構體B): iNMRGOOMHz’CD^D，鹽酸鹽）（5 7.46 (s 1 Η) 4 53 (dd，《/— 2.3，11.4 Ηζ，1 Η), 4·13 (s，1 Η)，3.80-3.77 (m 1 Η) 3.28-3.22 (m，2 Η)，3.08-2.84 (m, 10 Η)，2.65 (t，151 Ηζ 1 Η), 2.26-2.22 (m, 2 Η), 2.11-2.04 (m, 3 Η), 2.02-1.98 (m 1 Η), 1.78-1.72 (m, 1 Η), 1.68-1.59 (m, 1 Η), l&gt;22 (t J = 7 3 Ηζ，3 Η)，· MS (ESI) m/z 594.21 (Μ+Η) 0Hz, 3 H) ; MS (ESI) m/z 594.21. (m + H). 238 201245116 参. S18-4_2_B (extracted in 14.7-15.6 minutes, diastereomer B): iNMRGOOMHz 'CD^D, hydrochloride) (5 7.46 (s 1 Η) 4 53 (dd, "/ — 2.3,11.4 Ηζ,1 Η), 4·13 (s,1 Η), 3.80-3.77 (m 1 Η) 3.28-3.22 (m,2 Η), 3.08-2.84 (m, 10 Η), 2.65 ( t, 151 Ηζ 1 Η), 2.26-2.22 (m, 2 Η), 2.11-2.04 (m, 3 Η), 2.02-1.98 (m 1 Η), 1.78-1.72 (m, 1 Η), 1.68-1.59 (m, 1 Η), l&gt;22 (t J = 7 3 Ηζ, 3 Η), · MS (ESI) m/z 594.21 (Μ+Η) 0

S18-4-3 S18-4-3。自丙酮製備。在還原性胺化步驟後分離兩種 非對映異構體，且分別進行保護基脫除步驟。 S18-4-3-A(在13.4-14.1分鐘洗提，非對映異構體八）： *H NMR (400 MHz, CD3OD,鹽酸鹽）δ 7.44 (S) 1 Η), 4.68 (dd, J= 2.3, 11.4 Hz, 1 H), 4.12 (s, 1 H), 3.66-3.63 (m, 1 H), 3.27-3.20 (m, 2 H), 3.07-2.96 (m, 9 H), 2.68 (t, j= 14.6 Hz 1 H), 2.29-2.20 (m, 2 H), 2.09-1.96 (m, 4 H), 1.82-1.60 (m, 2 H), 1.32 (d, J = 6.4 Hz, 3 H), 1.17 (d, J = 6.4 Hz, 3 H) ； MS (ESI) m/z 608.14 (M+H卜 S18-4-3-B(在12.7-13.6分鐘洗提，非對映異構體B ): 4 NMR (400 MHz，CD3OD，鹽酸鹽）δ 7.44 (s, 1 Η), 4.87-4.85 (m, 1 Η), 4.12 (d, 〇.9 Hz, 1 H), 3.68-3.65 (m, 1 H), 3.60-3.54 (m, 1 H), 3.38-3.30 (m, 2 H), 3.10-2.95 (m, 8 H), 2.5 8 (t, J = 15.1 Hz, 1 H), 2.22 (ddd, ^ = 2.8, 4.6, 13.3 Hz, 239 201245116 1 Η), 2.13-2.03 (m, 3 Η), 1.98-1.90 (m, 2 Η), 1.78-1.74 (m, 1 Η), 1.6 8-1.5 8 (m, 1 Η), 1.3 8 (t, J = 6.9 Hz, 3 H), 1.21 (t, / = 6.9 Hz，3 H) ; MS (ESI) w/z 608.18 (M+H)。S18-4-3 S18-4-3. Prepared from acetone. The two diastereomers are separated after the reductive amination step and the protecting group removal step is carried out separately. S18-4-3-A (extracted in 13.4-14.1 minutes, diastereomer 8): *H NMR (400 MHz, CD3OD, hydrochloride) δ 7.44 (S) 1 Η), 4.68 (dd , J= 2.3, 11.4 Hz, 1 H), 4.12 (s, 1 H), 3.66-3.63 (m, 1 H), 3.27-3.20 (m, 2 H), 3.07-2.96 (m, 9 H), 2.68 (t, j = 14.6 Hz 1 H), 2.29-2.20 (m, 2 H), 2.09-1.96 (m, 4 H), 1.82-1.60 (m, 2 H), 1.32 (d, J = 6.4 Hz , 3 H), 1.17 (d, J = 6.4 Hz, 3 H) ; MS (ESI) m/z 608.14 (M+Hb S18-4-3-B (extracted at 12.7-13.6 min, non-computing Isomer B): 4 NMR (400 MHz, CD3OD, hydrochloride) δ 7.44 (s, 1 Η), 4.87-4.85 (m, 1 Η), 4.12 (d, 〇.9 Hz, 1 H), 3.68-3.65 (m, 1 H), 3.60-3.54 (m, 1 H), 3.38-3.30 (m, 2 H), 3.10-2.95 (m, 8 H), 2.5 8 (t, J = 15.1 Hz, 1 H), 2.22 (ddd, ^ = 2.8, 4.6, 13.3 Hz, 239 201245116 1 Η), 2.13-2.03 (m, 3 Η), 1.98-1.90 (m, 2 Η), 1.78-1.74 (m, 1 Η), 1.6 8-1.5 8 (m, 1 Η), 1.3 8 (t, J = 6.9 Hz, 3 H), 1.21 (t, / = 6.9 Hz, 3 H) ; MS (ESI) w/z 608.18 (M+H).

SI8-4-4。根據標準脫甲矽基及氫化程序，自化合物 S18-3獲得。藉由製備型逆相HPLC在Waters自動純化系統 上使用 Phenomenex Polymerx 10 β RP- r l〇〇A 管柱[10 &quot;m，150x21.20 mm ;流速：20 mL/min ;溶劑 A : 0.05 N HC1/ 水；溶劑 B : CH3CN ;注入體積：3.0 mL( 0.05 N HC1/水）； 梯度：0— 40% B，經20分鐘；質量導向型洗提份收集]分 離兩種非對映異構體。收集含有所需產物之洗提份且冷凍 乾燥。 S18-4-4-A(在12.5-13.2分鐘洗提，非對映異構體a): H NMR (400 MHz，CD3OD,鹽酸鹽）占 7.44 (s, 1 Η), 4.68 (dd, J= 2.3, 11.4 Hz, 1 H), 4.12 (s, 1 H), 3.91-3.88 (m, 1 H), 3.37-3.31 (m, 1 H), 3.28-3.23 (m, 1 H), 3.08-2.86 (m, 10 H), 2.62 (t, J = 15.1 Hz, 1 H), 2.22 (ddd, J= 2.8, 4.6, 13.7 Hz, 1 H), 2.08-2.02 (m, 3 H), 1.98-1.90 (m, 2 H), 1.87- 1.58 (m, 4 H), 0.87 (t, J - 7.3 Hz, 3 H) , MS (ESI) m/z 608.23 (M + H) ° S18-4-4-B(在13.4-13.9分鐘洗提，非對映異構體B): bNMR (400 MHz，CD3〇D，鹽酸鹽）占 7.43 (s, 1 Η), 4.56 (dd, J = 2.3, 11. 4 Hz, 1 H), 4.12 (s, 1 H), 3.82-3.80 (m, 1 H), 240 201245116 3.28-3.25 (m, 1 Η), 3.04-2.96 (m, 9 Η), 2.83-2.63 (m, 3 Η), 2.26-2.22 (m, 2 Η), 2.10-1.98 (m, 4 Η), 1.78-1.59 (m, 4 Η), 0·82 (t，7.3 Hz，3 Η) ; MS (ESI) m/z 608.23 (M+H)。 實施例19.其中環E為嗎啉-3-基之式I化合物 根據以下流程19合成式I化合物，其中X為-CF3，Y 為-Η且環Ε為嗎啉-3-基。 流程19SI8-4-4. Obtained from compound S18-3 according to standard demethylation and hydrogenation procedures. Phenomenex Polymerx 10 β RP- rl〇〇A column was used on a Waters automated purification system by preparative reverse phase HPLC [10 &quot;m, 150 x 21.20 mm; flow rate: 20 mL/min; solvent A: 0.05 N HC1 / water; solvent B: CH3CN; injection volume: 3.0 mL (0.05 N HC1/water); gradient: 0-40% B over 20 minutes; mass-oriented elution fraction collection] separation of two diastereomers . The extract containing the desired product was collected and lyophilized. S18-4-4-A (extracted in 12.5-13.2 minutes, diastereomer a): H NMR (400 MHz, CD3OD, hydrochloride), 7.44 (s, 1 Η), 4.68 (dd, J= 2.3, 11.4 Hz, 1 H), 4.12 (s, 1 H), 3.91-3.88 (m, 1 H), 3.37-3.31 (m, 1 H), 3.28-3.23 (m, 1 H), 3.08 -2.86 (m, 10 H), 2.62 (t, J = 15.1 Hz, 1 H), 2.22 (ddd, J= 2.8, 4.6, 13.7 Hz, 1 H), 2.08-2.02 (m, 3 H), 1.98 -1.90 (m, 2 H), 1.87- 1.58 (m, 4 H), 0.87 (t, J - 7.3 Hz, 3 H) , MS (ESI) m/z 608.23 (M + H) ° S18-4- 4-B (extracted at 13.4-13.9 minutes, diastereomer B): b NMR (400 MHz, CD3 〇D, hydrochloride) as 7.43 (s, 1 Η), 4.56 (dd, J = 2.3) , 11. 4 Hz, 1 H), 4.12 (s, 1 H), 3.82-3.80 (m, 1 H), 240 201245116 3.28-3.25 (m, 1 Η), 3.04-2.96 (m, 9 Η), 2.83-2.63 (m, 3 Η), 2.26-2.22 (m, 2 Η), 2.10-1.98 (m, 4 Η), 1.78-1.59 (m, 4 Η), 0·82 (t, 7.3 Hz, 3 Η); MS (ESI) m/z 608.23 (M+H). Example 19. Compound of Formula I wherein Ring E is Morpholin-3-yl The compound of Formula I is synthesized according to Scheme 19 below, wherein X is -CF3, Y is - indole and the oxime is morpholin-3-yl. Process 19

S11-2S11-2

BocHNBocHN

NaBH(OAc)3NaBH(OAc)3

CH3〇2CCF2S〇2F Cul.DMFCH3〇2CCF2S〇2F Cul.DMF

燒基化Fibrillation

a) LDA/TMEDA b) 婦酮S2·1a) LDA/TMEDA b) ketone S2·1

根據流程19製備以下化合物。 241The following compounds were prepared according to Scheme 19. 241

xh3 &quot;C02Ph OBn S19-1 合成化合物S19-1。 ^-l〇〇°CT^ S19-5 ( 2.0 g„ 5.03 mm〇1 , 1&gt;〇eq) 水THF (20 mL)中之溶液中緩慢添加㈣似之己烧溶液 (2.5 Μ，2.4 mL，6,04 mm〇1，1 2 eq)。在.。〇下賴 所得混合物i 5分鐘。在_ 1〇〇。〇下向混合物中添加詞〇c·嗎 啉-3-酮（1.22 g，6.06 mmol，1 2 eq)於盔卜 丁 γ g，61.1〇/〇) : MS (ESI) υ eq)於無水 THF ( 6 mL) 中之溶液。添加後，在·抓下㈣混合物i小時且以^ N HC1溶液中止。用Et〇Ac(5〇mLx2)萃取混合物。分離經 合併之有機相’經Na2S〇4脫水’過濾幻農縮。藉由急驟層 析（ 200〜300目，石油_t〇Ac = 8:i至6:1梯度）純化殘 餘物’得到呈黃色油狀之Si9_i w/z 542.0 (M+Na)。Xh3 &quot;C02Ph OBn S19-1 Synthetic compound S19-1. ^-l〇〇°CT^ S19-5 ( 2.0 g „ 5.03 mm〇1 , 1&gt;〇eq) Slowly add (iv) a solution of hexane (20 mL) in water (2.5 mL, 2.4 mL, 6,04 mm 〇1,1 2 eq). The mixture was obtained for 5 minutes at .. In _ 1 〇〇, the 〇c·morpholin-3-one (1.22 g, 6.06 mmol, 1 2 eq) in Helmets γ g, 61.1 〇 / 〇): MS (ESI) υ eq) in anhydrous THF (6 mL). After addition, the mixture was grasped (4) for 1 hour and The solution was quenched with ^ N HCl solution. The mixture was extracted with Et 〇Ac (5 〇 mL x 2 ). The combined organic phases were separated by 'Na 2 S 〇 4 dehydration' filtration by flash chromatography (200~300 mesh, petroleum _ 〇Ac = 8:i to 6:1 gradient) EtOAc EtOAc (EtOAc)

合成化合物。 1·0 eq)於無水二氣甲燒 向 S19-1 ( 1.6 g，3 〇8 匪〇1 (1a5 mL)中之溶液中添加TFA(10mL)。在2rc下攪拌 所得混“勿1小時。蒸發溶劑，得到呈暗黃色油狀之粗物 質S19 2其直接用於下一步驟：MS (ESI) m/z 420.0 (m+h2o)。 242 201245116Synthetic compounds. 1·0 eq) TFA (10 mL) was added to a solution of S19-1 (1.6 g, 3 〇8 匪〇1 (1a5 mL) in anhydrous methane. The mixture was stirred at 2 rc for 1 hour. Evaporation of the solvent gave EtOAc (EtOAc) m.

OBn S19-3 合成化合物S19-3。 向粗物質S19-2於1，2-二氯乙烷（30 mL)中之溶液中 添加二乙酿乳基石朋氮化納（1.96 g，9.24 mmol ’ 3.0 eq)。 在室溫下攪拌所得混合物1小時。濃縮反應混合物，且以OBn S19-3 synthesizes compound S19-3. To a solution of the crude material S19-2 in 1,2-dichloroethane (30 mL), EtOAc (1. The resulting mixture was stirred at room temperature for 1 hour. Concentrate the reaction mixture and

EtOAc ( 1〇〇 mL)稀釋殘餘物，傾入飽和NaHC03 ( 50 mL) 中。有機層以鹽水洗滌’經Na2S04脫水，過濾且濃縮，得 到呈淺黃色油狀之粗物質S19_3，其直接用於下一步驟：Ms (ESI) m/z 403.9 (M+H)。The residue was diluted with EtOAc (1 mL EtOAc)EtOAc. The organic layer was washed with EtOAc EtOAc (EtOAc)EtOAc.

合成化合物S19-4。 OBn S194 向粗物質 S19-3 ( 3.08 mmol)於無水 MeCN ( 30 mL)Compound S19-4 was synthesized. OBn S194 to crude material S19-3 (3.08 mmol) in anhydrous MeCN (30 mL)

中之溶液中添加二碳酸二第三丁酯（840 mg，3.85 mmol， 1·25 eq)及 DMAP ( 38 mg ’ 0.31 mmol，o.i eq)。在 25°C 下搜拌所得混合物隔夜。濃縮反應物，且，藉由石夕膠管柱層 析（石油醚/EtOAc = 10/1 )純化殘餘物，得到呈戈々色、由 狀之產物 S19-4 ( 880 mg，56.8%，經 3 個步驟）.iH NMR (400 MHz, CDC13) 5 7.48-7.30 (m, 7 Η), 7.28-7.20 (m, 1 Η), 7.11-7.09 (m, 2 Η), 7.02-6.99 (m, 2 H), 5.13 (s 2H) 5.03-5.00 (m, 1 H), 4.30 (d, 7 = 16.0 Hz, 1 H)s 3.87-3.^1 (m^ 243 201245116 2 Η), 3.96-3.72 (m, ι H), 3.61-3.52 (m5 1 H), 3.03-2.93 (m, 1 H)’ 2〇44 (S，3H)，U7 (s, 9 H)。MS (ESI) m/z 526.1 (M+Na)。 〔扣 ^[^COjPh OBn S19-5 合成化合物。 向化5物819-4(880〇1层，1.75 111111〇1)於氣仿（25 1111〇 中之'合液中添加三氟乙酸銀（501 mg，2.27 mmo卜1.3 eq)， 接著添加碟（576 mg，2.27 mmol，1.3 eq)。形成黃色沈澱 物。在至溫下攪拌所得混合物5小時。經由小型矽藻土墊 過濾冷液’且用三份洗滌濾餅。有機溶液接著依序 以10% Na2S2〇3、飽和NaHC〇3及鹽水洗滌，經Na2S〇4脫 水’過渡且濃縮《藉由矽膠管柱層析（石油醚/Et〇= ι 〇/ i ) 純化殘餘物，得到呈白色固體狀之化合物Sl9_5 (丨〇 g， 90.9%) ： JHNMR (400 MHz, CDC13) 5 7.43-7.39 (m, 2 H), 7.37-7.33 (m, 5 H), 7.27-7.23 (m, 1 H), 7.12-7.10 (m, 2 H), 6.86 (s, 1H), 5.21-5.20 (m, 1 H), 5.14 (s, 2H), 3.94-3.80 (m, 4 H), 3.69-3.63 (m, 1 H), 3.47-3.39 (m, 1 H), 2.58 (s, 3 H), 1.32 (s，9 H)。MS (ESI) w/z 651.8 (M+Na)。Di-tert-butyl dicarbonate (840 mg, 3.85 mmol, 1.25 eq) and DMAP (38 mg '0.31 mmol, o.i eq) were added to the solution. The resulting mixture was sifted overnight at 25 °C. The reaction was concentrated, and the residue was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Steps).iH NMR (400 MHz, CDC13) 5 7.48-7.30 (m, 7 Η), 7.28-7.20 (m, 1 Η), 7.11-7.09 (m, 2 Η), 7.02-6.99 (m, 2 H), 5.13 (s 2H) 5.03-5.00 (m, 1 H), 4.30 (d, 7 = 16.0 Hz, 1 H)s 3.87-3.^1 (m^ 243 201245116 2 Η), 3.96-3.72 ( m, ι H), 3.61-3.52 (m5 1 H), 3.03-2.93 (m, 1 H)' 2〇44 (S, 3H), U7 (s, 9 H). MS (ESI) m/z 526.1 (M+Na). [ buckle ^ [^COjPh OBn S19-5 synthetic compound. Add 5 819-4 (880 〇 1 layer, 1.75 111111 〇 1) to a gas imitation (25 1111 〇 ', add silver trifluoroacetate (501 mg, 2.27 mmo, 1.3 eq), then add the dish (576 mg, 2.27 mmol, 1.3 eq). A yellow precipitate formed. The mixture was stirred at room temperature for 5 hr. The cold liquid was filtered through a small diatomaceous earth pad and the filter cake was washed with three portions. 10% Na2S2〇3, saturated NaHC〇3 and brine were washed, dehydrated by Na2S〇4, “transition and concentration”. The residue was purified by column chromatography (petroleum ether/Et〇= ι 〇 / i ) to give white Solid compound Sl9_5 (丨〇g, 90.9%) : JHNMR (400 MHz, CDC13) 5 7.43-7.39 (m, 2 H), 7.37-7.33 (m, 5 H), 7.27-7.23 (m, 1 H ), 7.12-7.10 (m, 2 H), 6.86 (s, 1H), 5.21-5.20 (m, 1 H), 5.14 (s, 2H), 3.94-3.80 (m, 4 H), 3.69-3.63 ( m, 1 H), 3.47-3.39 (m, 1 H), 2.58 (s, 3 H), 1.32 (s, 9 H). MS (ESI) w/z 651.8 (M+Na).

合成化合物S19-6。 在 N2 下向化合物 SI 9-5 ( 1.0 g，1.59 mmol，1.0 eq) 244 201245116 於無水DMF ( 20 mL ) 中之溶液中添加Cul ( 908 mg，4.77 mmol，3,0 eq)及二氟_氟磺醯基-乙酸甲酯（i 53呂，7 % mmol，5·0 eq)。將反應物密封且在6〇t下加熱24小時。 冷卻至室溫時，過濾反應混合物且用Et〇Ac稀釋。混合物 以NH4〇H:NH4Cl之1:4溶液及鹽水洗滌，經Na2S〇4脫水， 過濾且濃縮。藉由矽膠管柱層析（石油醚/Et〇Ac =丨〇/1 ) 純化殘餘物，得到呈白色固體狀之產物Sl9_6 ( 〇 8 g， 88.1%) : &gt;HNMR (400 MHz, CDC13) 5 7.44-7.33 (m, 7 Η), 7.29-7.25 (m, 1 Η), 7.13-7.11 (m, 2 Η), 6.85 (s, 1 Η), 5-41-5.39 (m, 1 Η), 5.19 (dd, J = i2.〇, 12.〇 Hz, 2 H), 3.93-3.79 (m, 4 H), 3.66-3.60 (m, 1 H), 3.31-3.24 (m, 1 H),Compound S19-6 was synthesized. To a solution of compound SI 9-5 (1.0 g, 1.59 mmol, 1.0 eq) 244 201245116 in anhydrous DMF (20 mL), C.sub.2 ( 908 mg, 4.77 mmol, 3,0 eq) and difluoro Fluroxysulfonyl-methyl acetate (i 53 ly, 7 % mmol, 5.0 eq). The reaction was sealed and heated at 6 Torr for 24 hours. Upon cooling to room temperature, the reaction mixture was filtered and diluted with EtOAc. The mixture was washed with a 1:4 solution of NH.sub.4H:H.sub.4Cl.sub.4 and brine. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) 5 7.44-7.33 (m, 7 Η), 7.29-7.25 (m, 1 Η), 7.13-7.11 (m, 2 Η), 6.85 (s, 1 Η), 5-41-5.39 (m, 1 Η) , 5.19 (dd, J = i2.〇, 12.〇Hz, 2 H), 3.93-3.79 (m, 4 H), 3.66-3.60 (m, 1 H), 3.31-3.24 (m, 1 H),

合成化合物S19-1。 OBn S19-7 2.56 (q, /= 2.8 Hz，3 H), 1.33 (s，9 H) 〇 向 SI9-6( 200 mg ’ 0.3 5 mmol)於無水二氣甲烧（6 mL) 中之溶液中添加TFA ( 2 mL )。在25°C下攪拌所得混合物 1小時。濃縮反應混合物，且殘餘物直接用於下—步驟中： MS (ESI) m/z 471.9 (M+H)。Compound S19-1 was synthesized. OBn S19-7 2.56 (q, /= 2.8 Hz, 3 H), 1.33 (s, 9 H) SI to SI9-6 (200 mg '0.3 5 mmol) in anhydrous two gas (6 mL) Add TFA (2 mL). The resulting mixture was stirred at 25 ° C for 1 hour. The reaction mixture was concentrated, and EtOAc m m m m m m

c&quot;3 OBn S19-8-1 合成化合物S19-8-1。 向粗物質 S19-7 ( 0.175 mmol)於 1，2-二氯乙烧（5 mL) 245 201245116 中之溶液中添加丙醛（3 1 mg )。在室溫下授拌1小時後， 添加三乙醯氧基硼氫化鈉（112mg，0.53 mmol，3.0 eq )。 在25°C下攪拌所得混合物1小時且藉由LC_MS監測。以 EtOAc( 3 0 mL )稀釋反應混合物且傾入飽和NaHC〇3( 2〇 mL )c&quot;3 OBn S19-8-1 Synthetic compound S19-8-1. To the solution of the crude material S19-7 (0.175 mmol) in 1,2-dichloroethane (5 mL) 245 201245116 was added propionaldehyde (3 1 mg). After stirring for 1 hour at room temperature, sodium triethoxysulfonate hydride (112 mg, 0.53 mmol, 3.0 eq) was added. The resulting mixture was stirred at 25 ° C for 1 hour and monitored by LC_MS. The reaction mixture was diluted with EtOAc (30 mL) and poured sat. NaHC.

合成化合物S19-9-1。 中。分離各層且用EtOAc再卒取水層兩次。經合併之有機 層以鹽水洗蘇’經Na2S〇4脫水’過濾且濃縮。藉由prep_TLC 純化殘餘物，得到呈白色固體狀之產物S19-8 ( 70 mg )。 在-7 8°C下將n-BuLi於己烷中之溶液（25m，〇.21 mL， 0.544 mmo卜4.0 eq)逐滴添加至二異丙胺（π # L，0.544 mmo卜 4·0 eq)及 TMEDA ( 79 mg，〇.68 mmol , 5.0 eq)於 THF ( l mL )中之溶液中。在_78°c下攪拌所得混合物3〇分 在里。添加 S19-8-l(70mg’ 0.136mmol，l.〇eq)於 THF ( 1 ·0 mL)中之溶液。隨後在_78它下攪拌所得深紅色溶液3〇分 鐘。將烯0)5| S2-1 (52mg，O.llmmol，〇.8eq)於 THF ( 1.0 mL )中之溶液添加至反應混合物中。所得混合物經3 〇分鐘 升溫至-HTC。反應物以飽和NHUCl ( 50 mL)中止，且用 EtOAc ( 50 mL )萃取。分離有機相，經Na2s〇4脫水，過濾 且濃縮。殘餘物直接用於下一步驟。Compound S19-9-1 was synthesized. in. The layers were separated and the aqueous layer was taken twice with EtOAc. The combined organic layers were washed with brine and dried over Na.sub.2. The residue was purified by EtOAc (EtOAc): A solution of n-BuLi in hexane (25 m, 〇.21 mL, 0.544 mmo, 4.0 eq) was added dropwise to diisopropylamine (π # L, 0.544 mmo, 4·0 eq) at -7 8 °C. And TMEDA (79 mg, 〇.68 mmol, 5.0 eq) in THF (1 mL). The resulting mixture was stirred at _78 ° C for 3 minutes. A solution of S19-8-1 (70 mg &lt;RTI ID=0.0&gt;0&gt; The resulting dark red solution was then stirred under _78 for 3 Torr. A solution of the olefin 0)5|S2-1 (52 mg, EtOAc, EtOAc. The resulting mixture was warmed to -HTC over 3 min. The reaction was quenched with EtOAc (50 mL)EtOAc. The organic phase was separated, dried over Na.sub.2, filtered and concentrated. The residue was used directly in the next step.

S19-10-1 246 201245116 合成化合物S19-1Q-1。 在室溫下向聚丙烯反應容器中粗物質sMdd於THF (4 mL )中之溶液中逐滴添加HF水溶液（4〇%，8 mL )。 在25 C下劇烈攪拌混合物2小時且傾入K2hP〇4飽和水溶液 (150 mL)中。用EtOAc ( 2x20 mL)萃取混合物。經合併 之有機相經Na2S〇4脫水，過據且濃縮。在室溫下將pd_c( 1 〇 wt%，50 mg )整份添加至上述粗產物於甲醇（4 μ，丄 mL)與甲醇（5 mL)之混合物中的黃色溶液中。將反應容 器密封且用氫氣（1 atm )淨化丨小時。隨後經由小型石夕藻 土塾過丨慮反應混合物’且濃縮遽液。藉由製備型逆相Hplc 純化殘餘物，得到呈黃色固體狀之S19-10_l ( 36.0 mg): 'H NMR (400 MHz, CD3OD) δ 7.82, 7.78 (s, i Η 全部）， 4.78-4.76 (m, 1 Η), 4.32-4.26 (m, 1 Η), 4.22-4.05 (m, 3 Η) 3.96-3.78 (m, 2 H)，3.58-3.53 (m，1 H)，3.40-3.35 (m，1 η)， 3.20-2.92 (m，9 H)，2.86-2.83 (m，1 H)，2.71-2.60 (m，i H)， 2.32-2.28 (m, 1 H), 1.90-1.70 (m, 3 H), 0.96, 0.87 (tj 7 2 Hz，3 H 全部）；MS (ESI) m/z 610.1 (M + H)。 根據與關於S19-10-1所述類似之方法製備以下化合 物。S19-10-1 246 201245116 Synthesis of compound S19-1Q-1. An aqueous HF solution (4%, 8 mL) was added dropwise to a solution of the crude material sMdd in THF (4 mL). The mixture was vigorously stirred at 25 C for 2 hours and poured into a saturated aqueous solution of K?h?? The mixture was extracted with EtOAc (2×20 mL). The combined organic phases were dried over Na 2 SO 4 and concentrated. Pd_c (1 〇 wt%, 50 mg) was added in portions to a yellow solution of the above crude product in a mixture of methanol (4 μ, 丄 mL) and methanol (5 mL). The reaction vessel was sealed and purged with hydrogen (1 atm) for a few hours. The reaction mixture was then passed through a small earthworm, and the mash was concentrated. The residue was purified by preparative reverse-phase H.sub.sub.sub.sub.sub.sub.sub.sssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss m, 1 Η), 4.32-4.26 (m, 1 Η), 4.22-4.05 (m, 3 Η) 3.96-3.78 (m, 2 H), 3.58-3.53 (m, 1 H), 3.40-3.35 (m ,1 η), 3.20-2.92 (m,9 H),2.86-2.83 (m,1 H),2.71-2.60 (m,i H), 2.32-2.28 (m, 1 H), 1.90-1.70 (m , 3 H), 0.96, 0.87 (tj 7 2 Hz, 3 H all); MS (ESI) m/z 610.1 (M + H). The following compounds were prepared according to a method similar to that described in S19-10-1.

S19-10-2-A S19-10-2-A： NMR (400 MHz, CD3〇D) δ 7.55 (s, H)，4.86-4.83 (m，1 H)，4.23-4.00 (m，4 H)，3,86-3.80 (m， 247 201245116 Η), 3.72-3.60 (m, 2 Η), 3.41-3.33 (m, 1 Η), 3.07-2.98 (m, 8 Η), 2.85 (s, 3 Η), 2.65-2.62 (m, 1 Η), 2.26 (m, 1 Η), 1.66 (m, 1 Η) ; MS (ESI) m/z 582.0 (Μ+Η)。S19-10-2-A S19-10-2-A: NMR (400 MHz, CD3〇D) δ 7.55 (s, H), 4.86-4.83 (m, 1 H), 4.23-4.00 (m, 4 H ),3,86-3.80 (m, 247 201245116 Η), 3.72-3.60 (m, 2 Η), 3.41-3.33 (m, 1 Η), 3.07-2.98 (m, 8 Η), 2.85 (s, 3 Η), 2.65-2.62 (m, 1 Η), 2.26 (m, 1 Η), 1.66 (m, 1 Η); MS (ESI) m/z 582.0 (Μ+Η).

S19-10.2-B S19-10-2-B ： 'H NMR (400 MHz, CD3OD) &lt;5 7.54 (s, 1 H), 4.76-4.73 (m, 1 H), 4.24-4.11 (m, 4 H), 4.02-3.96 (m, 1 H), 3.68-3.59 (m, 2 H), 3.29-2.99 (m, 9 H), 2.72-2.69 (m, 4 H), 2.29-2.26 (m, 1 H), 1.66 (m5 1 H) ； MS (ESI) m/z 582.0 (M+H)。S19-10.2-B S19-10-2-B : 'H NMR (400 MHz, CD3OD) &lt;5 7.54 (s, 1 H), 4.76-4.73 (m, 1 H), 4.24-4.11 (m, 4 H), 4.02-3.96 (m, 1 H), 3.68-3.59 (m, 2 H), 3.29-2.99 (m, 9 H), 2.72-2.69 (m, 4 H), 2.29-2.26 (m, 1 H), 1.66 (m5 1 H); MS (ESI) m/z 582.0 (M+H).

S19*10-3«A S19-10-3-A ： 'H NMR (400 MHz, CD3OD) δ 7.36 (s, 1 H), 4.17-4.15 (m, 1 H), 4.10-3.95 (m, 2 H), 3.92-3.86 (m, 1 H), 3.59-3.54 (m, 2 H), 3.23-2.99 (m, 9 H), 2.69-2.60 (m, 1 H), 2.28-2.25 (m, 1 H), 1.67 (m, 1 H) ； MS (ESI) m/z 568.1 (M+H) oS19*10-3«A S19-10-3-A : 'H NMR (400 MHz, CD3OD) δ 7.36 (s, 1 H), 4.17-4.15 (m, 1 H), 4.10-3.95 (m, 2 H), 3.92-3.86 (m, 1 H), 3.59-3.54 (m, 2 H), 3.23-2.99 (m, 9 H), 2.69-2.60 (m, 1 H), 2.28-2.25 (m, 1 H), 1.67 (m, 1 H) ; MS (ESI) m/z 568.1 (M+H) o

S19-10-3-B ： 'H NMR (400 MHz, CD3OD) 5 7.45 (s, 1 H), 4.82-4.79 (m, 1 H), 4.22-4.09 (m, 3 H), 4.08-4.02 (m, 1 248 201245116 Η), 3.95-3.90 (m, 1 Η), 3.60-3.49 (m, 2 Η), 3.27-2.99 (m, 9 Η), 2.70-2.61 (m, 1 Η), 2.30-2.27 (m, 1 Η), 1.68 (m, 1 Η)； MS (ESI) 568.1 (Μ + Η)。S19-10-3-B : 'H NMR (400 MHz, CD3OD) 5 7.45 (s, 1 H), 4.82-4.79 (m, 1 H), 4.22-4.09 (m, 3 H), 4.08-4.02 ( m, 1 248 201245116 Η), 3.95-3.90 (m, 1 Η), 3.60-3.49 (m, 2 Η), 3.27-2.99 (m, 9 Η), 2.70-2.61 (m, 1 Η), 2.30- 2.27 (m, 1 Η), 1.68 (m, 1 Η); MS (ESI) 568.1 (Μ + Η).

S19-10-4-A ： Ή NMR (400 MHz, CD3OD) δ 7.60 (s, 1 H), 4.23-3.79 (m, 6 H), 3.51-3.38 (m, 2 H), 3.29-3.26 (m, 1 H), 3.13-2.86 (m, 9 H), 2.69-2.57 (m, 1 H), 2.25-2.20 (m, 1 H), 1.63 (m 1 H), 1.34 (J = 9.6 Hz, 3 H) ； MS (ESI) m/z 596.1 (M+H)。S19-10-4-A : NMR (400 MHz, CD3OD) δ 7.60 (s, 1 H), 4.23-3.79 (m, 6 H), 3.51-3.38 (m, 2 H), 3.29-3.26 (m , 1 H), 3.13-2.86 (m, 9 H), 2.69-2.57 (m, 1 H), 2.25-2.20 (m, 1 H), 1.63 (m 1 H), 1.34 (J = 9.6 Hz, 3 H) ; MS (ESI) m/z 596.1 (M+H).

S19-10-4-B ： lH NMR (400 MHz, CD3OD) 6 7.63 (s, 1 H), 4.75-4.73 (m, 1 H), 4.21-3.96 (m, 5 H), 3.78-3.74 (m, 1 H), 3.53-3.44 (m, 1 H), 3.24-3.20 (m, 1 H), 3.06-2.97 (m, 9 H), 2.69-2.60 (m, 1 H), 2.28-2.23 (m, 1 H), 1.65 (m, 1 H), 1.27 (J= 9.2 Hz，3 H) ; MS (ESI) m/z 596.1 (M+H)。S19-10-4-B : lH NMR (400 MHz, CD3OD) 6 7.63 (s, 1 H), 4.75-4.73 (m, 1 H), 4.21-3.96 (m, 5 H), 3.78-3.74 (m , 1 H), 3.53-3.44 (m, 1 H), 3.24-3.20 (m, 1 H), 3.06-2.97 (m, 9 H), 2.69-2.60 (m, 1 H), 2.28-2.23 (m , 1 H), 1.65 (m, 1 H), 1.27 (J = 9.2 Hz, 3 H); MS (ESI) m/z 596.1 (M+H).

S19-10-5-A ： 'H NMR (400 MHz, CD3OD) δ 7.77-7.72 (m，1 H)，4.80-4.78 (m，1 H)，4.40-4.34 (m, 1 H)，4.18-4.13 249 201245116 (m, 4 Η), 3.89 (d, J = 12.8 Hz, 1 H) 3.62-3.55 (m, 1 H), 3.27-2.99 (m, 10 H), 2.72-2.59 (m, 2 H), 2.30-2.27 (m, 1 H), 2.16-2.12 (m, 1 H), 1.69 (m, 1 H), 1.00 (d, J= 6.8 Hz, 3 H), 0_95 (d，/ = 6.8 Hz，3 H) ; MS (ESI) m/z 624.1 (M+H)。S19-10-5-A : 'H NMR (400 MHz, CD3OD) δ 7.77-7.72 (m, 1 H), 4.80-4.78 (m, 1 H), 4.40-4.34 (m, 1 H), 4.18- 4.13 249 201245116 (m, 4 Η), 3.89 (d, J = 12.8 Hz, 1 H) 3.62-3.55 (m, 1 H), 3.27-2.99 (m, 10 H), 2.72-2.59 (m, 2 H ), 2.30-2.27 (m, 1 H), 2.16-2.12 (m, 1 H), 1.69 (m, 1 H), 1.00 (d, J = 6.8 Hz, 3 H), 0_95 (d, / = 6.8 Hz, 3 H) ; MS (ESI) m/z 624.1 (M+H).

S19-10-5-B ： *H NMR (400 MHz, CD3OD) δ 7.58 (s, 1 H), 4.32 (t, J= 12.0 Hz, 1 H), 4.20-4.16 (m, 2 H), 3.98-3.92 (m, 3 H), 3.63-3.56 (m, 1 H), 3.40-3.46 (m, 1 H), 3.08-2.99 (m5 9 H), 2.94-2.88 (m, 1 H), 2.70-2.62 (m, 1 H), 2.28-2.17 (m, 1 H), 1.66 (ms 1 H), 1.07 (d, J= 6.8 Hz, 3 H), 0.97 (d, J = 6.8 Hz，3 H) ; MS (ESI) m/z 624.1 (M+H)。 〔n^V^ch3 H3C 人 CHSf^C〇2ph OBn S19-8-6S19-10-5-B : *H NMR (400 MHz, CD3OD) δ 7.58 (s, 1 H), 4.32 (t, J = 12.0 Hz, 1 H), 4.20-4.16 (m, 2 H), 3.98 -3.92 (m, 3 H), 3.63-3.56 (m, 1 H), 3.40-3.46 (m, 1 H), 3.08-2.99 (m5 9 H), 2.94-2.88 (m, 1 H), 2.70- 2.62 (m, 1 H), 2.28-2.17 (m, 1 H), 1.66 (ms 1 H), 1.07 (d, J = 6.8 Hz, 3 H), 0.97 (d, J = 6.8 Hz, 3 H) MS (ESI) m/z 624.1 (M+H). [n^V^ch3 H3C person CHSf^C〇2ph OBn S19-8-6

向粗物質S19-7 ( 0.4 mmol )於MeCN ( 10 mL )中之溶 液中添加 2-碘丙烷（1 mL)及 K2C03 ( 166 mg，1.2 mmol， 3·〇 eq)。在80°C至9(TC下加熱24小時後，濃縮混合物。 藉由Prep-TLC純化殘餘物’得到呈白色固體狀之S19-8-6 (140 mg * 68.3%) ： *H NMR (400 MHz, CDC13) δ 7.58 (s， 1H), 7.45 (d, J= 6.8 Hz, 2 H), 7.41-7.35 (m, 5 H), 7.28-7.25 (m, 1 H), 7.10 (d} J = 7.6 Hz, 2 H), 5.21 (dd, J = 12.0, 12.0 Hz, 2 H), 4.17-4.14 (m, 1 H), 3.98 - 3.95 (m, 1 H), 3.79 (dd, J 250 201245116 = 11.2, 3.2 Hz, 1 Η), 3.70-3.64 (m, 1 Η), 3.16 (t, J=10.8 Hz, 1 H), 2.76-2.73 (m, 1 H), 2.67-2.60 (m, 2 H), 2.56-2.54 (m, 3 H), 0.92 (d, J = 6.8 Hz, 3 H), 0.85 (d, J= 6.8 Hz, 3 H) ； MS (ESI) m/z 514.0 (M+H)。2-Iodopropane (1 mL) and K2C03 (166 mg, 1.2 mmol, 3·〇 eq) were added to a solution of crude material S19-7 (0.4 mmol) in MeCN (10 mL). After heating at 80 ° C to 9 (24 hours after TC, the mixture was concentrated. Purified residue by Prep-TLC) gave S19-8-6 (140 mg * 68.3%) as a white solid: *H NMR (400 MHz, CDC13) δ 7.58 (s, 1H), 7.45 (d, J = 6.8 Hz, 2 H), 7.41-7.35 (m, 5 H), 7.28-7.25 (m, 1 H), 7.10 (d} J = 7.6 Hz, 2 H), 5.21 (dd, J = 12.0, 12.0 Hz, 2 H), 4.17-4.14 (m, 1 H), 3.98 - 3.95 (m, 1 H), 3.79 (dd, J 250 201245116 = 11.2, 3.2 Hz, 1 Η), 3.70-3.64 (m, 1 Η), 3.16 (t, J=10.8 Hz, 1 H), 2.76-2.73 (m, 1 H), 2.67-2.60 (m, 2 H), 2.56-2.54 (m, 3 H), 0.92 (d, J = 6.8 Hz, 3 H), 0.85 (d, J = 6.8 Hz, 3 H) ; MS (ESI) m/z 514.0 (M+ H).

S19-10-6： *H NMR (400 MHz, CD3OD) δ 7.81, Ί.19 (s, 1 H 全部），5.09-5.06 (m, 1 H), 4.35 (dd，*/= 11.6，11.6 Hz, 1 H), 4.24-4.19 (m, 3 H), 4.14-3.92 (m, 1 H), 3.70-3.50 (m, 2 H), 3.42-3.34 (m, 1 H), 3.28-3.00 (m, 9 H), 2.72-2.57 (m, 1 H), 2.30-2.27 (m, 1 H), 1.68 (m, 1 H), 1.50, 1.43 (d, J= 6.4S19-10-6: *H NMR (400 MHz, CD3OD) δ 7.81, Ί.19 (s, 1 H all), 5.09-5.06 (m, 1 H), 4.35 (dd, */= 11.6, 11.6 Hz , 1 H), 4.24-4.19 (m, 3 H), 4.14-3.92 (m, 1 H), 3.70-3.50 (m, 2 H), 3.42-3.34 (m, 1 H), 3.28-3.00 (m , 9 H), 2.72-2.57 (m, 1 H), 2.30-2.27 (m, 1 H), 1.68 (m, 1 H), 1.50, 1.43 (d, J= 6.4

Hz，3 H 全部），1.28, 1.24 (d，《/= 6.4 Hz, 3 H 全部）；MS (ESI) w/z 610.1 (M + H)。 實施例20.其中環E為哌畊-2-基之式I化合物 根據以下流程20合成式I化合物，其中X為-CF3，Y 為-Η且環Ε為哌畊-2-基。 流程20 251 201245116Hz, 3 H all), 1.28, 1.24 (d, "/= 6.4 Hz, 3 H all); MS (ESI) w/z 610.1 (M + H). Example 20. Compound of Formula I wherein Ring E is Piperidin-2-yl. A compound of Formula I is synthesized according to Scheme 20 below, wherein X is -CF3, Y is -Η and the oxime is piperidin-2-yl. Process 20 251 201245116

Br CH3Br CH3

ΎΎ NIS.TFA OBn S11-2 C02PhNIS NIS.TFA OBn S11-2 C02Ph

C02PhC02Ph

C02Ph 1) LDA.TMEDA 2) 烯酮S2·1 烷基化C02Ph 1) LDA.TMEDA 2) Enone S2·1 alkylation

1)TFA/DCM 2) NaBH(OAc)3 C02Ph1) TFA/DCM 2) NaBH(OAc)3 C02Ph

CH302CCF2S02F Cul BocHNCH302CCF2S02F Cul BocHN

S20-3 烯丙基S20-3 allyl

DMBA/Pd(PPh3)4DMBA/Pd(PPh3)4

烧基化、醯化 或磺醯化 r9Acrylation, deuteration or sulfonation

J)HF 2) Pd/CJ) HF 2) Pd/C

RgRg

根據流程20製備以下化合物。The following compounds were prepared according to Scheme 20.

S20-1 合成S20-1。 向 Sll-2(1.0g，2.52mmol)於乙腈（10mL)中之溶 液中添加，碘代丁二醯亞胺（1.13 g，5.03 mmol，2.0當量）， 接著添加三It乙酸（〇·19 mL ’，2.52 mmol，1 ·0當量）。在 252 201245116 loot油浴中加熱所得淺紅色溶液2小時。冷卻至室溫時， 反應混合物以EtOAc.稀釋且依序用10〇/〇 Na2S203、飽和 NaHC〇3及鹽水洗滌，經仏28〇4脫水，過渡且濃縮。藉由 急驟層析純化殘餘物，得到呈白色固體狀之S20_1( 121 g， 92.4%) : MS (ESI) m/z 545.3 (M+Na) » OF^S20-1 synthesizes S20-1. To a solution of Sll-2 (1.0 g, 2.52 mmol) in acetonitrile (10 mL), iododiimimide (1.13 g, 5.03 mmol, 2.0 eq.), followed by tri-acetic acid (〇·19 mL) ', 2.52 mmol, 1 · 0 equivalents). The resulting light red solution was heated in a 252 201245116 loot oil bath for 2 hours. Upon cooling to room temperature, the reaction mixture was diluted with EtOAc. EtOAc EtOAc EtOAc. The residue was purified by EtOAc EtOAc (EtOAc)

TjC j co2Ph OBn S20-2 將 S20-1 ( ι·2 g，2.29 mmo卜 1 當量）、Cul ( 2.64 g，TjC j co2Ph OBn S20-2 will be S20-1 ( ι·2 g, 2.29 mmo 1 equivalent), Cul ( 2.64 g,

13·76 mmo卜6當量）及二氟-氟磺醯基乙酸甲酯（2 64 g， 13.76 mmol，6 eq)於DMF中之混合物加熱至6〇&lt;t持續12 小時。混合物以存於NH4C1水溶液中之25% nh4〇h水溶液 稀釋且用存於石油醚（5x2〇 mL)中之1〇% Et〇Ac萃取。濃 縮有機層且利用石夕膠（以1 〇% EtOAc之石油喊溶液洗提） 純化’得到呈白色固體狀之S2〇_2( 1〇〇 g，91〇/。）： MS (ESO m/z 496.7 (M+Na)。A mixture of 13·76 mmo (6 equivalents) and methyl difluoro-fluorosulfonylacetate (2 64 g, 13.76 mmol, 6 eq) in DMF was heated to 6 〇 &lt; t for 12 hours. The mixture was diluted with a 25% aqueous solution of nh 4 hr in NH.sub.2Cl.sub.1 and extracted with &lt;RTIgt; The organic layer was concentrated and purified using EtOAc (EtOAc) eluting with EtOAc EtOAc EtOAc (EtOAc) z 496.7 (M+Na).

CH3 C02Ph OBn S20.3CH3 C02Ph OBn S20.3

稀丙基O CFq BocHN^s^，S 合成S20-3 〇 在-1.00 c 下在 N2 下向 S20-2 ( 800 mg，1.72 _〇l )於 無水THF ( 12 mL)中之溶液中緩慢添加n_BuLi ( i 〇4 mL， 2.6mmol，i.5當量）。在·1〇(rc下攪拌所得紅色溶液別分 在里。將2 -側氧基- 4- (丙-2 -浠-1-基）η底口井_ι_甲酸第三丁醋 253 201245116 ( 500 mg，2.08 mmol，1.2 當量）於無水 THF (2 mL)中 之溶液添加至反應混合物中。再在_丨〇〇〇c下攪拌溶液5分鐘 且隨後在-78 C下搜拌1小時。反應物之顏色緩慢變成黃 色。將溶液添加至NH4C1水溶液中。用CH2C12 ( 4x120 mL) 萃取’濃縮且藉由製備型TLC ( CH2C12:曱醇=60:1)純化，Dilyl propyl O CFq BocHN^s^, S Synthetic S20-3 〇 Slowly added to a solution of S20-2 (800 mg, 1.72 _〇l) in anhydrous THF (12 mL) under N2 at -1.00 c n_BuLi (i 〇 4 mL, 2.6 mmol, i. 5 eq.). The red solution obtained by stirring at 1 〇 is divided into two. The 2-oxo-oxy-4-(propan-2-indole-1-yl) η bottom well _ι_carboxylic acid third vinegar 253 201245116 A solution of (500 mg, 2.08 mmol, 1.2 eq.) in dry THF (2 mL) was added to the reaction mixture. The solution was stirred for 5 min at _ 丨〇〇〇c and then 1 hour at -78 C. The color of the reaction was slowly changed to yellow. The solution was added to aq. NH4C1, extracted with CH2C12 (4×120 mL), concentrated and purified by preparative TLC (CH2C12: methanol: 60:1).

得到 S20-3 ( 800 mg，52%) : MS (ESI) m/z 627.1 (M+H)。 合 4。 ，Obtained S20-3 (800 mg, 52%): MS (ESI) m. 4. ,

向 S20-3 ( 500 mg，0.8 mmol)於 CH2C12 ( 5 mL)中之 溶液中添加TFA ( 2 mL )與CH2C12 ( 2 mL )之混合物。在 2〇°C下攪拌所得淺黃色溶液2小時。濃縮反應混合物，得 到粗亞胺。MS (ESI) m/z 509.0 (M+H)。向粗物質（410 mg， 0.8 mmol )於l，2-二氯乙烷（1〇mL)中之溶液中添加三乙 酿氧基硼氫化鈉（510 mg，2.4 mmol，3當量）。在20 °C下 攪拌所得棕色溶液2小時。混合物以NaHC03中止且用 CH2C12 ( 20 mLx4 )萃取。濃縮經合併之萃取物，得到粗物 質S20-4，在無純化的情況下將其直接用於下一步驟中：MSA mixture of TFA (2 mL) and CH2C12 (2 mL) was added to a solution of S20-3 (500 mg, 0.8 mmol) in CH2C12 (5 mL). The resulting pale yellow solution was stirred at 2 ° C for 2 hours. The reaction mixture was concentrated to give crude imine. MS (ESI) m/z 509.0 (M+H). To a solution of the crude material (410 mg, <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; The resulting brown solution was stirred at 20 ° C for 2 hours. The mixture was quenched with NaHC03 and extracted with CH2C12 (20 mL×4). The combined extracts were concentrated to give crude material S20-4 which was used directly in the next step without purification: MS

OBn S20-5-1 (ESI) m/z 5 11.2 (M + H)。 合成 S20-5-1。 254 201245116 向820-4( 324 1^’0.64 111111〇1)於1，2-二氯乙烷（2〇1111^) 中之溶液中添加1 mL甲醛水溶液。攪拌所得黃色混合物隔 夜。添加三乙醯氧基硼氫化鈉（407 mg，19.2 mmol，3者 量），且攪拌混合物2小時。反應混合物以NaHC〇3中止且 用CHiClz ( 20 mLx4 )萃取。濃縮經合併之萃取物且藉由製 備型TLC純化，得到S20-5-1 ( 150 mg，46%，經3個步驟）. MS (ESI) m/z 525.1 (M+H)。OBn S20-5-1 (ESI) m/z 5 11.2 (M + H). Synthesis S20-5-1. 254 201245116 To a solution of 820-4 (324 1^'0.64 111111〇1) in 1,2-dichloroethane (2〇1111^) was added 1 mL of aqueous formaldehyde solution. The resulting yellow mixture was stirred overnight. Sodium triethoxysulfonate (407 mg, 19.2 mmol, 3 parts) was added, and the mixture was stirred for 2 hr. The reaction mixture was quenched with NaHC.sub.3 and extracted with CH.sub.z. The combined extracts were concentrated and purified by EtOAc EtOAc (EtOAc)

OBn S20-6-2 合成。 向 S20-4 ( 200 mg ’ 0.39 mmol，1 當量）於 CH2C1CH2C1 (10 mL )中之溶液中添加〇 2 mL笨曱醛。攪拌所得黃色 混合物隔夜。將三乙醯氧基硼氫化鈉（248 mg，0.94 mmol， 3當量）添加至溶液中。再攪拌混合物4小時。混合物以 NaHC〇3中止且用CH2C12 ( 20 mLx4 )萃取。濃縮有機層且 藉由製備型TLC純化’得到S20-5-2 ( 120 mg，62%) : MS (ESI) m/z 601.1 (M+H)。OBn S20-6-2 synthesis. To a solution of S20-4 (200 mg '0.39 mmol, 1 eq.) in CH2C1CH2C1 (10 mL) was added EtOAc (2 mL). The resulting yellow mixture was stirred overnight. Sodium triethoxy borohydride (248 mg, 0.94 mmol, 3 eq.) was added to the solution. The mixture was stirred for another 4 hours. The mixture was quenched with NaHC(R)3 and extracted with CH2C12 (20 mL x4). The organic layer was concentrated and purified by preparative EtOAc EtOAc (EtOAc)

HOi 0 OTBS 合成 S20-6-1 〇 在- 78C 下向二異丙胺（i7〇mL，12 mmol)於 THF ( 5 mL )中之溶液中逐滴添加nBuLi ( 4.8 mL，12 mmo卜2.50 Μ 255 201245116HOi 0 OTBS Synthesis S20-6-1 〇 Add nBuLi (4.8 mL, 12 mmo Bu 2.50 Μ 255) to a solution of diisopropylamine (i7 〇 mL, 12 mmol) in THF (5 mL) at -78C. 201245116

己烷溶液）。在-78°C下攪拌反應物30分鐘。添加TMEDA (3.5 mL，24 mmo卜 2 當量）。在-78°C 下向 S2〇-5-l( 50 mg， 0.095 mmol ’ 1，〇當量）於Thf ( 1.0 mL)中之溶液中逐滴 添加上述LDA溶液（〇.4 mL)，得到深紅色溶液。在_78»c 下攪拌混合物1 0分鐘。在_78。(：下逐滴添加烯酮S24 ( 46 mg，0.095 mmol , 1_〇 當量）於 THF ( 1〇 mL)中之溶液。 反應物之顏色變成棕色。在攪拌下該棕色溶液經1小時之 時期自_78°C開始逐漸升溫至，得到黃色混合物。反應 物以氣化銨飽和水溶液（2〇 mL )中止且用CH2C12 ( 20 mL x4 )萃取。濃縮經合併之萃取物且藉由製備型tlc純化， 得到 S20-6-1 ( 50 mg) : MS (ESI) m/z 913.3 (M + H)。Hexane solution). The reaction was stirred at -78 °C for 30 min. Add TMEDA (3.5 mL, 24 mmo b 2 equivalents). The above LDA solution (〇.4 mL) was added dropwise to a solution of S2〇-5-l (50 mg, 0.095 mmol '1, 〇 equivalent) in Thf (1.0 mL) at -78 ° C to give a deep Red solution. The mixture was stirred at _78»c for 10 minutes. At _78. (: A solution of enone S24 (46 mg, 0.095 mmol, 1 〇 equivalent) in THF (1 mL) was added dropwise. The color of the reaction turned brown. The brown solution was stirred for 1 hour. The temperature was gradually increased from _78 ° C to give a yellow mixture. The reaction was quenched with a saturated aqueous solution of ammonium sulfate (2 mL) and extracted with CH2C12 (20 mL×4). The combined extracts were concentrated and prepared by tlc Purification gave S20-6-1 (50 mg): MS (ESI) m.

合成 S2Q-1-1。 向 S20-6-1 ( 20 mg ’ 〇·02 mm〇1)及 13_二甲基巴比妥 心（9 mg ’ 0·06 mmo卜 3 當量）於 ch2CI2 ( 3 mL)中之溶 液中添加 Pd(PPh3)4 ( 14 mg，〇 〇1 _〇1，〇 6 當量）。在 N2下在35。。油浴中加熱所得淺黃色溶液2小時。濃縮反應 混合物’得到粗物質咖心，其在無進一步純化的情況下 使用：MS (ESI) m/z 873.4 (M+H)。 256 201245116 CH I N、Synthesis of S2Q-1-1. Add to S20-6-1 (20 mg ' 〇·02 mm〇1) and 13_Dimethyl Barbitol (9 mg '0·06 mmob 3 equivalents) in ch2CI2 (3 mL) Pd(PPh3)4 (14 mg, 〇〇1 _〇1, 〇6 equivalent). Under N2 is at 35. . The resulting pale yellow solution was heated in an oil bath for 2 hours. The reaction mixture was concentrated to give a crude material (EtOAc) m. 256 201245116 CH I N,

OBn O HO§ 〇 OBn OTBS S20*8-1 合成 S20-8-1。 向S20-7-1 ( 35 mg)於12-二氯乙烷（5 mL)中之溶 液中添加0.2 mL甲醛水溶液及三乙醯氧基硼氫化鈉（26 mg) °在室溫下攪拌混合物2小時。反應物以NaHC:〇3水 /谷液中止且用CHzCl2 ( 20 mLx4 )萃取。濃縮經合併之萃取 物且粗物質（S20-8-1 )直接用於下一步驟中：MS (ESI) m/z 887.4 (M+H)。OBn O HO§ 〇 OBn OTBS S20*8-1 Synthesis S20-8-1. Add 0.2 mL of formaldehyde solution and sodium triethoxysulfonate (26 mg) to a solution of S20-7-1 (35 mg) in 12-dichloroethane (5 mL). Stir the mixture at room temperature. 2 hours. The reaction was quenched with NaHC: 〇3 water / EtOAc and extracted with CHzCl2 (20 mL×4). The combined extracts were concentrated and EtOAc (EtOAc) m.

ΟΒη Ο HCH 〇 OBn OTBS S20-8-2 向 S20-7-1 ( 0.055 mol)於 CH2C12 ( 5 mL)中之溶液ΟΒη Ο HCH 〇 OBn OTBS S20-8-2 to S20-7-1 (0.055 mol) in CH2C12 (5 mL)

添加至所得黃色混合物中。再在室溫下攪拌混合物2小時 LCMS -濃縮，得到粗產物 :MS (ESI) m/z 915.1 LCMS顯示反應完成。過濾混合物且濃縮 (S20-8-2)，其直接用於下一步驟中：Ms (M+H)。 0¾爲 ΜAdd to the resulting yellow mixture. The mixture was stirred at room temperature for further EtOAc (EtOAc) m. The mixture was filtered and concentrated (S20-8-2), which was used directly in the next step: Ms (M+H). 03⁄4 is Μ

OBn Ο η〇ξ Ο 〇Βη 0TBS S20-8-3 257 201245116 合成 S20-8-3 〇 向 S20-7-1 ( 0.11 mol)於 Ch2C12 ( 5 mL)中之溶液中 添加 K2C03 ( 22 mg，2.0 當量）。在 〇〇c 下將 MsCl ( 0.2 mL ) 添加至混合物中。在室溫下攪拌所得黃色混合物3小時。 過濾混合物且濃縮，得到粗產物（S20-8-3 )’其直接用於 下一步驟中：MS (ESI) m/z 951.3 (M+H) ° ch3OBn Ο η〇ξ Ο 0η 0TBS S20-8-3 257 201245116 Synthesis S20-8-3 K Add K2C03 ( 22 mg, 2.0) to a solution of S20-7-1 (0.11 mol) in Ch2C12 (5 mL) equivalent). MsCl (0.2 mL) was added to the mixture under 〇〇c. The resulting yellow mixture was stirred at room temperature for 3 hours. The mixture was filtered and concentrated to give a crude material (S20-8-3), which was used directly in the next step: MS (ESI) m/z 951.3 (M+H) ° ch3

S20-9-1-A.B 合成 S20-8-1-A、S20-8-1-B。 向S20-8-1 ( 35 mg)於THF ( 3 mL)中之溶液甲添加 48% HF水溶液〇 mL)。在室溫下㈣所得淺黃色溶液2 小時。藉由添加K2HP〇4水溶液將pH值調節至約8且用 ch2ci2萃取。濃縮萃取物且再次溶解於f醇（5社）及甲 醇/HC1 (0.5 mL)中。添加 pd_c ( 1〇 wt〇/〇，5 叫），且在 H2f在室溫下攪拌混合物2小時。過濾反應混合物，濃縮 且藉由製備型逆相肌⑽化，得到之兩種非對映 異構體。 ' S20-9-1-A (非對映異構體A) : 1h nmr (彻他， CD3OD) 5 7.66(s, 1 Η), 4-46-4.49 (m,l Η), 4.13 (s,l Η)! 3-62-3.83 (m, 6 Η), 3.29-3.30 (m, 1 H), 2.99-3.13 (m, l〇 H)j 2.61-2.70 (m，2 H)，2 39 (s, 3 h)，2 22_2 25 (m，i h): 1-61-1.70 (m, 1 H) ； MS (ESI) m/z 594.8 (M+H) 〇 ， 258 201245116 S20-9-1-B (非對映異構體 B ) : 4 NMR (400 MHz， CD3OD) δ 7.59 (s, 1 Η), 4.25-4.43 (m, 1 Η), 4.12 (s, 1 Η), 3.37-3.77 (m, 5 Η), 2.92-3.10 (m, 12 Η), 2.57-2.70 (m, 1 Η), 2.33-2.50 (m, 3 Η), 2.18-2.27 (m, 1 Η), 1.59-1.69 (m, 1 Η)； MS (ESI) m/z 594.8 (M+H) ° 藉由與S20-9-1所用類似之方法自S20_4 (關於其中R8 =烷基之類似物）或S20-5-2 (關於其中R8 = Η之類似物） 製備以下化合物。S20-9-1-A.B Synthesis S20-8-1-A, S20-8-1-B. To a solution of S20-8-1 (35 mg) in THF (3 mL) was added 48% HF aqueous solution 〇 mL). The pale yellow solution obtained at room temperature (iv) was allowed to stand for 2 hours. The pH was adjusted to about 8 by addition of K 2 HP 4 aqueous solution and extracted with ch 2 ci 2 . The extract was concentrated and redissolved in f-ol (5) and methanol/HC1 (0.5 mL). Pd_c (1 〇 wt 〇 / 〇, 5 Å) was added, and the mixture was stirred at room temperature for 2 hours at room temperature. The reaction mixture was filtered, concentrated and subjected to preparative reverse phase muscle (10) to give the two diastereomers. 'S20-9-1-A (diastereomer A): 1h nmr (Through, CD3OD) 5 7.66(s, 1 Η), 4-46-4.49 (m,l Η), 4.13 (s , l Η)! 3-62-3.83 (m, 6 Η), 3.29-3.30 (m, 1 H), 2.99-3.13 (m, l〇H)j 2.61-2.70 (m, 2 H), 2 39 (s, 3 h), 2 22_2 25 (m, ih): 1-61-1.70 (m, 1 H) ; MS (ESI) m/z 594.8 (M+H) 〇, 258 201245116 S20-9-1 -B (diastereomer B) : 4 NMR (400 MHz, CD3OD) δ 7.59 (s, 1 Η), 4.25-4.43 (m, 1 Η), 4.12 (s, 1 Η), 3.37-3.77 (m, 5 Η), 2.92-3.10 (m, 12 Η), 2.57-2.70 (m, 1 Η), 2.33-2.50 (m, 3 Η), 2.18-2.27 (m, 1 Η), 1.59-1.69 (m, 1 Η); MS (ESI) m/z 594.8 (M+H) ° from S20_4 (About R8 = alkyl analog) or S20-5 by a method similar to that used for S20-9-1 -2 (About R8 = analog of hydrazine) The following compounds were prepared.

S20-9-2 ΗS20-9-2 Η

cN κ S20-9-2 ： !H NMR (400 MHz, CD3OD) δ 7.59, 7.72 (2s, 1 H 全部），5.13-5.30 (m, 1 H)，4· 18 (s，1 Η), 3.80-3.92 (m, 6 Η), 3.24-3.33 (m, 1 Η), 2.99-3.08 (m, 8 Η), 2.69-2.72 (tn, 1 Η), 2.26-2.29 (m, 1 Η), 1.67-1.70 (m, 1 Η) ； MS (ESI) m/z 567.0 (M+H)。cN κ S20-9-2 : !H NMR (400 MHz, CD3OD) δ 7.59, 7.72 (2s, 1 H all), 5.13-5.30 (m, 1 H), 4· 18 (s,1 Η), 3.80 -3.92 (m, 6 Η), 3.24-3.33 (m, 1 Η), 2.99-3.08 (m, 8 Η), 2.69-2.72 (tn, 1 Η), 2.26-2.29 (m, 1 Η), 1.67 -1.70 (m, 1 Η); MS (ESI) m/z 567.0 (M+H).

S20-9&lt;3^\ S20-9-3-A ： *H NMR (400 MHz, CD3OD) δ 7.54,7.68 (2s，1 H 全部），5.27-5.30 (m，1 H)，4.15 (s，1 H)，3.69-3.88 (m, 6 H), 3.24-3.28 (m, 1 H), 2.94-3.11 (m, 11 H), 2.61-2.72 (m, 1 H), 2.25-2.28 (m, 1 H), 1.63-1.72 (m, 1 H) ； MS (ESI) 259 201245116 m/z 58 1 ·0 (M+H)。 CH3S20-9&lt;3^\ S20-9-3-A : *H NMR (400 MHz, CD3OD) δ 7.54, 7.68 (2s, 1 H total), 5.27-5.30 (m, 1 H), 4.15 (s, 1 H), 3.69-3.88 (m, 6 H), 3.24-3.28 (m, 1 H), 2.94-3.11 (m, 11 H), 2.61-2.72 (m, 1 H), 2.25-2.28 (m, 1 H), 1.63-1.72 (m, 1 H); MS (ESI) 259 201245116 m/z 58 1 ·0 (M+H). CH3

S20-9-3-B ： *H NMR (400 MHz, CD3OD) δ Ί.66 (s, 1 H), 5.11-5.14 (m, 1 H), 4.16 (s, 1 H), 3.74-4.02 (m, 7 H), 3.23-3.37 (m, 1 H), 2.98-3.15 (m, 11 H), 2.63-2.72 (m, 1 H), 2.25-2.35 (m, 1 H), 1.61-1.82 (m, 1 H) ； MS (ESI) m/z 580.9 (M + H)。S20-9-3-B : *H NMR (400 MHz, CD3OD) δ Ί.66 (s, 1 H), 5.11-5.14 (m, 1 H), 4.16 (s, 1 H), 3.74-4.02 ( m, 7 H), 3.23-3.37 (m, 1 H), 2.98-3.15 (m, 11 H), 2.63-2.72 (m, 1 H), 2.25-2.35 (m, 1 H), 1.61-1.82 ( m, 1 H); MS (ESI) m/z 580.9 (M + H).

S20-94-A S20-9-4-A ： lH NMR (400 MHz, CD3OD) &lt;5 7.57 (s, 1 H), 5.34-5.36 (m, 1 H), 4.16 (s, 1 H), 3.65-4.98 (m, 7 H), 3.40-3.43 (m, 2 H), 3.23-3.28 (m, 1 H), 2.90-3.31 (m, 7 H), 2.62-2.66 (m, 1 H), 2.24-2.28 (m, 1 H), 1.62-1.69 (m, 1 H), 1.48 (t，3 H) ; MS (ESI) m/z 595.1 (M+H) 〇S20-94-A S20-9-4-A : lH NMR (400 MHz, CD3OD) &lt;5 7.57 (s, 1 H), 5.34-5.36 (m, 1 H), 4.16 (s, 1 H), 3.65-4.98 (m, 7 H), 3.40-3.43 (m, 2 H), 3.23-3.28 (m, 1 H), 2.90-3.31 (m, 7 H), 2.62-2.66 (m, 1 H), 2.24-2.28 (m, 1 H), 1.62-1.69 (m, 1 H), 1.48 (t,3 H) ; MS (ESI) m/z 595.1 (M+H) 〇

OH O HO h 〇 〇 非對映異構趙B S20&lt;3-4-B NHa S20-9-4-B ： !H NMR (400 MHz, CD3OD) &lt;5 7.67 (s, 1 H), 5.10-5.19 (m, 1 H), 4.15 (s, 1 H), 3.75-4.00 (m, 7 H), 3.42-3.44 (m, 2 H), 3.23-3.26 (m, 1 H), 3.01 -3.07 (m, 7 H), 260 201245116 . 2.62-2.64 (m, 1 Η), 2.25-2.28 (m, 1 Η), 1.66-1.67 (m, 1 Η), 1.44-1.47 (m，3 Η) ; MS (ESI) m/z 595.1 (M+H)。OH O HO h 〇〇 diastereomeric Zhao B S20&lt;3-4-B NHa S20-9-4-B : !H NMR (400 MHz, CD3OD) &lt;5 7.67 (s, 1 H), 5.10 -5.19 (m, 1 H), 4.15 (s, 1 H), 3.75-4.00 (m, 7 H), 3.42-3.44 (m, 2 H), 3.23-3.26 (m, 1 H), 3.01 -3.07 (m, 7 H), 260 201245116 . 2.62-2.64 (m, 1 Η), 2.25-2.28 (m, 1 Η), 1.66-1.67 (m, 1 Η), 1.44-1.47 (m, 3 Η); MS (ESI) m/z 595.1 (M+H).

S20-9-5-A ： !H NMR (400 MHz, CD3OD) δ 7.58 (s, 1 H), 4.13 (s, 1 H), 4.00-4.08 (m, 1 H), 3.33-3.42 (m, 2 H), 3.50-3.61 (m, 4 H), 3.35-3.43 (m, 1 H), 2.90-3.28 (m, 8 H), 2.68-2.72 (m, 1 H), 2.00-2.38 (m, 4 H), 1.61-1.71 (m, 1 H)； MS (ESI) m/z 581.0 (M+H)。S20-9-5-A : !H NMR (400 MHz, CD3OD) δ 7.58 (s, 1 H), 4.13 (s, 1 H), 4.00-4.08 (m, 1 H), 3.33-3.42 (m, 2 H), 3.50-3.61 (m, 4 H), 3.35-3.43 (m, 1 H), 2.90-3.28 (m, 8 H), 2.68-2.72 (m, 1 H), 2.00-2.38 (m, 4 H), 1.61-1.71 (m, 1 H); MS (ESI) m.

S20-9-5-B ： 'H NMR (400 MHz, CD3OD) δ Ί.63 (s, 1 H), 4.30-4.35 (m, 1 H), 4.13 (s, 1 H), 3.41-3.72 (m, 6 H), 2.92-3.30 (m, 9 H), 2.58-3.69 (m, 1 H), 2.30-2.54 (m5 3 H), 2.18-2.27 (m, 1 H), 1.61-1.72 (m, 1 H) ； MS (ESI) m/z 581.0 (M+H)。S20-9-5-B : 'H NMR (400 MHz, CD3OD) δ Ί.63 (s, 1 H), 4.30-4.35 (m, 1 H), 4.13 (s, 1 H), 3.41-3.72 ( m, 6 H), 2.92-3.30 (m, 9 H), 2.58-3.69 (m, 1 H), 2.30-2.54 (m5 3 H), 2.18-2.27 (m, 1 H), 1.61-1.72 (m , 1 H) ; MS (ESI) m/z 581.0 (M+H).

非對映異構體A S20-9-6-A ： *H NMR (400 MHz, CD3OD) δ 7.63 (s, 1 H), 4.86-4.87 (m, 1 H), 4.14-4.32 (m5 1 H), 3.76-3.82 (m, 2 H), 3.46-3.56 (m, 3 H), 3.34-3.36 (m, 1 H), 3.22-3.28 (m, 3 261 201245116 Η), 2.99-3.14 (m, 8 Η), 2.62-2.68 (m, 2 Η), 2.24-2.29 (m, 4 Η), 1.64-1.69 (m, 1 Η), 1.40 (t, J = 6.8 Hz, 3 H), MS (ESI) m/z 609.1 (M + H)。Diastereomer A S20-9-6-A : *H NMR (400 MHz, CD3OD) δ 7.63 (s, 1 H), 4.86-4.87 (m, 1 H), 4.14-4.32 (m5 1 H ), 3.76-3.82 (m, 2 H), 3.46-3.56 (m, 3 H), 3.34-3.36 (m, 1 H), 3.22-3.28 (m, 3 261 201245116 Η), 2.99-3.14 (m, 8 Η), 2.62-2.68 (m, 2 Η), 2.24-2.29 (m, 4 Η), 1.64-1.69 (m, 1 Η), 1.40 (t, J = 6.8 Hz, 3 H), MS (ESI ) m/z 609.1 (M + H).

S20-9-6-B ： 'H NMR (400 MHz, CD3OD) δ 7.60-7.69 (2s，1 H 全部），4.6 卜 4.71 (m，1 H)，4.15-4.48 (m，1 H)， 3.45-3.96 (m, 4 H), 3.34-3.36 (m, 2 H), 3.23-3.32 (m, 2 H), 2.89-3.12 (m, 8 H), 2.00-2.78 (m, 6 H)} 1.55- 1.68 (m, 1 H) 1.38 (t，J = 7.2 Hz, 3 H) ; MS (ESI) m/z 609.1 (M+H)。S20-9-6-B : 'H NMR (400 MHz, CD3OD) δ 7.60-7.69 (2s, 1 H all), 4.6 b 4.71 (m, 1 H), 4.15-4.48 (m, 1 H), 3.45 -3.96 (m, 4 H), 3.34-3.36 (m, 2 H), 3.23-3.32 (m, 2 H), 2.89-3.12 (m, 8 H), 2.00-2.78 (m, 6 H)} 1.55 - 1.68 (m, 1 H) 1.38 (t, J = 7.2 Hz, 3 H); MS (ESI) m/z 609.1 (M+H).

S20-9-7-A ： !H NMR (400 MHz, CD3OD) &lt;5 7.76 (s, 1 H), 4.51-4.66 (m, 1 H), 4.04 (s, 1 H), 3.32-3.91 (m, 6 H), 3.26-3.29 (m, 1 H), 3.12-3.16 (m, 1 H)} 2.87-2.96 (m, 9 H), 2.50-2.61 (m, 1 H), 2.12-2.16 (m, 1 H), 1.49-1.59 (m, 1 H), 1.17 (t，J = 7.2 Hz, 3 H) ; MS (ESI) m/z 595.2 (M+H)。S20-9-7-A : !H NMR (400 MHz, CD3OD) &lt;5 7.76 (s, 1 H), 4.51-4.66 (m, 1 H), 4.04 (s, 1 H), 3.32-3.91 ( m, 6 H), 3.26-3.29 (m, 1 H), 3.12-3.16 (m, 1 H)} 2.87-2.96 (m, 9 H), 2.50-2.61 (m, 1 H), 2.12-2.16 ( m, 1 H), 1.49-1.59 (m, 1 H), 1.17 (t,J = 7.2 Hz, 3 H); MS (ESI) m/z 595.2 (M+H).

S20-9-7-B ： !H NMR (400 MHz, CD3OD) δ 7.84 (s, 1 H)，4.69-4.71 (m，1 H)，4.16 (s，1 H)，3.63-3.90 (m，6 H)， 262 201245116 • 3.20-3.29 (m, 1 Η), 2.64-2.99 (m, 11 Η), 2.25-2.28 (m, 1 Η), 1.63-1.72 (m, 1 Η), 1.21 (t, J = 6.8 Hz,3 H) ； MS (ESI) m/z 595.2 (M+H)。S20-9-7-B : !H NMR (400 MHz, CD3OD) δ 7.84 (s, 1 H), 4.69-4.71 (m, 1 H), 4.16 (s, 1 H), 3.63-3.90 (m, 6 H), 262 201245116 • 3.20-3.29 (m, 1 Η), 2.64-2.99 (m, 11 Η), 2.25-2.28 (m, 1 Η), 1.63-1.72 (m, 1 Η), 1.21 (t , J = 6.8 Hz, 3 H) ; MS (ESI) m/z 595.2 (M+H).

S20-9-8-A ： NMR (400 MHz, CD3〇D) δ 7.62-7.70 (s，1 H 全部），4.1〇_4 56 (m，2 H)，3.40-3.78 (m，6 H), 2.91-3.10 (m，11 H)，2.24-2.87 (m，3 H)，2.19-2.48 (m，2 H)， 1.58-1.72 (m，1 H)，1.14 (m, 3 H) ; MS (ESI) m/z 609.0 (M+H)。S20-9-8-A : NMR (400 MHz, CD3〇D) δ 7.62-7.70 (s, 1 H all), 4.1〇_4 56 (m, 2 H), 3.40-3.78 (m, 6 H) , 2.91-3.10 (m,11 H),2.24-2.87 (m,3 H), 2.19-2.48 (m,2 H), 1.58-1.72 (m,1 H), 1.14 (m, 3 H) ; MS (ESI) m/z 609.0 (M+H).

S20-9-8-B ： *H NMR (400 MHz, CD3OD) &lt;5 7.64 (s, 1 H), 4.10-4.34 (m, 2 H), 3.51-3.68 (m, 6 H), 2.90-3.08 (m, 13 H), 2.52-2.72 (m, 2 H), 2.24-2.29 (m, 2 H), 1.61-1.70 (m, 1 H)，1.04-1.10 (m，3 h) ; MS (ESI) m/z 609.0 (M+H)。 ^ch3S20-9-8-B: *H NMR (400 MHz, CD3OD) &lt;5 7.64 (s, 1 H), 4.10-4.34 (m, 2 H), 3.51-3.68 (m, 6 H), 2.90- 3.08 (m, 13 H), 2.52-2.72 (m, 2 H), 2.24-2.29 (m, 2 H), 1.61-1.70 (m, 1 H), 1.04-1.10 (m, 3 h); MS ( ESI) m/z 609.0 (M+H). ^ch3

S20-9-9-A ： 'H NMR (400 MHz, CD3OD) &lt;5 7.69 (s, 1 H), 4.42-4.63 (m, 1 H), 4.14 (s, 1 H), 3.72-3.88 (m, 4 H), 3.40-3.69 (m, 2 H), 3.32-3.40 (m, 2 H), 3.01-3.09 (m, 4 H), 263 201245116 2.97-3.00 (m, 3 Η), 2.85-2.97 (m, 2 Η), 2.58 -2.69 (m, 1 Η), 2.19-2.30 (m, 1 Η), 1.57-1.72 (m, 1 Η), 1.42 (t, J = 7.2 Hz, 3 H)，1_16 (t，J = 6.8 Hz，3 H) ; MS (ESI) m/z 623.0 (M+H)。S20-9-9-A : 'H NMR (400 MHz, CD3OD) &lt;5 7.69 (s, 1 H), 4.42-4.63 (m, 1 H), 4.14 (s, 1 H), 3.72-3.88 ( m, 4 H), 3.40-3.69 (m, 2 H), 3.32-3.40 (m, 2 H), 3.01-3.09 (m, 4 H), 263 201245116 2.97-3.00 (m, 3 Η), 2.85- 2.97 (m, 2 Η), 2.58 -2.69 (m, 1 Η), 2.19-2.30 (m, 1 Η), 1.57-1.72 (m, 1 Η), 1.42 (t, J = 7.2 Hz, 3 H) , 1_16 (t, J = 6.8 Hz, 3 H); MS (ESI) m/z 623.0 (M+H).

S20-9-9-B ： 'H NMR (400 MHz, CD3OD) δ 7.76 (s, 1 H), 4.52-4.61 (m, 1 H), 4.14 (s, 1 H), 3.50-3.91 (m, 6 H), 3.40-3.43 (m, 2 H), 2.97-3.11 (m, 7 H), 2.61-2.80 (m, 2 H), 2.45 -2.60 (m, 1 H), 2.24 -2.27 (m, 1 H), 1.66 -1.72 (m, 1 H), 1.40 -1.44 (t, J = 7.2 Hz, 3 H), 1.15 (t, J = 6.8 Hz, 3 H) ； MS (ESI) m/z $23.1 (M+H)。S20-9-9-B : 'H NMR (400 MHz, CD3OD) δ 7.76 (s, 1 H), 4.52-4.61 (m, 1 H), 4.14 (s, 1 H), 3.50-3.91 (m, 6 H), 3.40-3.43 (m, 2 H), 2.97-3.11 (m, 7 H), 2.61-2.80 (m, 2 H), 2.45 - 2.60 (m, 1 H), 2.24 -2.27 (m, 1 H), 1.66 -1.72 (m, 1 H), 1.40 -1.44 (t, J = 7.2 Hz, 3 H), 1.15 (t, J = 6.8 Hz, 3 H) ; MS (ESI) m/z $23.1 (M+H).

S2〇-9-10-A。藉由S2〇-8_2之標準保護基脫除反應製 備：'H NMR (400 MHz，CD3OD) δ 7.50-7.59 (d, 1 Η), 4.49-4.67 (m, 2 Η), 4.16-4.45 (m, 2 Η), 3.43-3.91 (m, 6 Η), 2.90-3.19 (m, 8 Η), 2.61-2.77 (m, 2 Η), 2.11-2.30 (m, 4 Η),S2〇-9-10-A. Prepared by standard protection group removal of S2〇-8_2: 'H NMR (400 MHz, CD3OD) δ 7.50-7.59 (d, 1 Η), 4.49-4.67 (m, 2 Η), 4.16-4.45 (m , 2 Η), 3.43-3.91 (m, 6 Η), 2.90-3.19 (m, 8 Η), 2.61-2.77 (m, 2 Η), 2.11-2.30 (m, 4 Η),

264 201245116 S20-9-10-B。藉由S20-8-2之標準保護基脫除反應製 備：4 NMR (400 MHz，CD3OD) δ 7.54-7.57 (2s，1 Η 全部）， 4.58-4.75 (m, 2 Η), 4.29-4.44 (m, 2Η), 4.15 (s, 1H), 3.45-3.89 (m, 5 H), 3.21-3.27 (m, 1 H), 2.81-3.19 (m, 9 H), 2.71-2.79 (m, 1 H), 2.15-2.28 (m, 4 H), 1.61-1.74 (m, 1 H)； MS (ESI) m/z 623.2 (M+H)。 藉由與S20-9-10-A及S20-9-10-B所用類似之方法自 S20-4 (關於其中R8 =烷基之類似物）或S20-5-2 (關於其 中R8 = Η之類似物）製備以下化合物。264 201245116 S20-9-10-B. Prepared by standard protection group removal reaction of S20-8-2: 4 NMR (400 MHz, CD3OD) δ 7.54-7.57 (2s, 1 Η all), 4.58-4.75 (m, 2 Η), 4.29-4.44 ( m, 2Η), 4.15 (s, 1H), 3.45-3.89 (m, 5 H), 3.21-3.27 (m, 1 H), 2.81-3.19 (m, 9 H), 2.71-2.79 (m, 1 H ), 2.15-2.28 (m, 4 H), 1.61-1.74 (m, 1 H); MS (ESI) m/z 623.2 (M+H). By a method similar to that used for S20-9-10-A and S20-9-10-B from S20-4 (for an analog in which R8 = alkyl) or S20-5-2 (in which R8 = Η Analogs) The following compounds were prepared.

非對映異構體A S20-9-11-A ： 'H NMR (400 MHz, CD3OD) δ 7.32 (s, 1 Η), 4.68-4.72 (m, 1 Η), 4.14-4.19 (m, 1 Η), 3.51-3.67 (m, 2 Η), 3.25-3.27 (m, 6 Η), 2.90-3.11 (m, 8 Η), 2.58-2.67 (m, 1 Η), 2.12-2.28 (m, 3 Η), 1.55-1.72 (m, 1 Η) ； MS (ESI) m/z 609.1 (M+H)。Diastereomer A S20-9-11-A : 'H NMR (400 MHz, CD3OD) δ 7.32 (s, 1 Η), 4.68-4.72 (m, 1 Η), 4.14-4.19 (m, 1 Η), 3.51-3.67 (m, 2 Η), 3.25-3.27 (m, 6 Η), 2.90-3.11 (m, 8 Η), 2.58-2.67 (m, 1 Η), 2.12-2.28 (m, 3 Η), 1.55-1.72 (m, 1 Η); MS (ESI) m/z 609.1 (M+H).

OH O HO g Ο O 非對映異構體B S20-9-11-B S20-9-11-B ： *H NMR (400 MHz, CD3OD) δ 7.38-7.40 (m, 1 H), 4.60-4.68 (m, 1 H), 4.21-4.41 (m, 1 H), 3.93-4.18 (m, 1 H), 3.50-3.75 (m, 4 H), 2.93-3.25 (m, 10 H), 2.65-2.74 (m, 1 H), 2.12-2.25 (m, 3 H), 1.61-1.72 (m, 1 H) ； MS (ESI) 265 201245116 m/z 609.1 (M+H) 〇 0^/CH3OH O HO g Ο O diastereomer B S20-9-11-B S20-9-11-B : *H NMR (400 MHz, CD3OD) δ 7.38-7.40 (m, 1 H), 4.60- 4.68 (m, 1 H), 4.21-4.41 (m, 1 H), 3.93-4.18 (m, 1 H), 3.50-3.75 (m, 4 H), 2.93-3.25 (m, 10 H), 2.65- 2.74 (m, 1 H), 2.12-2.25 (m, 3 H), 1.61-1.72 (m, 1 H) ; MS (ESI) 265 201245116 m/z 609.1 (M+H) 〇0^/CH3

s S20-9-12 ： *H NMR (400 MHz, CD3OD) δ 7.64, 7.68 (s, 1 H 全部），4.62-4.75 (m，1 H)，4.30-4.43 (m, 1 H),呼.15 (s, 1 H), 3.69-3.95 (m, 2 H), 3.33-3.69 (m, 1 H), 3.27-3.33 (m, 1 H), 2.99-3.07 (m, 12 H), 2.66-2.76 (m, 1 H), 2.13-2.23 (m, 4 H), 1.66-1.68 (m, 1 H), 1.38 (t, J = 7.2 Hz, 3 H) ； MS (ESI) m/z 637.0 (M + H)。s S20-9-12 : *H NMR (400 MHz, CD3OD) δ 7.64, 7.68 (s, 1 H all), 4.62-4.75 (m, 1 H), 4.30-4.43 (m, 1 H), call. 15 (s, 1 H), 3.69-3.95 (m, 2 H), 3.33-3.69 (m, 1 H), 3.27-3.33 (m, 1 H), 2.99-3.07 (m, 12 H), 2.66- 2.76 (m, 1 H), 2.13-2.23 (m, 4 H), 1.66-1.68 (m, 1 H), 1.38 (t, J = 7.2 Hz, 3 H) ; MS (ESI) m/z 637.0 ( M + H).

ΟΗ Ο ΗΟ 2 〇 〇 S20-9-13 S20-9-13。藉由S20-8-3之標準保護基脫除反應製備： !Η NMR (400 MHz, CD3〇D) δ 7.62 (2s，1 H 全部）， 4.80-4.82 (m, 1 Η), 3.34-4.14 (m, 8 Η), 3.15-3.27 (m, 1 Η), 2.98-3.05 (m, 11 Η), 2.68 (s, 3 Η), 2.23-2.26 (m, 1 Η), 1.59-1.71 (m，1 Η) ; MS (ESI) m/z 659.0 (Μ+Η)。 藉由與S20-9-13所用類似之方法自S20-4 (關於其中 R8 =烷基之類似物）或S20-5-2 (關於其中R8 = Η之類似 物）製備以下化合物。 266 201245116ΟΗ Ο ΗΟ 2 〇 〇 S20-9-13 S20-9-13. Prepared by the standard protecting group removal reaction of S20-8-3: !Η NMR (400 MHz, CD3〇D) δ 7.62 (2s, 1 H all), 4.80-4.82 (m, 1 Η), 3.34-4.14 (m, 8 Η), 3.15-3.27 (m, 1 Η), 2.98-3.05 (m, 11 Η), 2.68 (s, 3 Η), 2.23-2.26 (m, 1 Η), 1.59-1.71 (m , 1 Η) ; MS (ESI) m/z 659.0 (Μ+Η). The following compounds were prepared by a method analogous to that used in S20-9-13 from S20-4 (for analogs wherein R8 = alkyl) or S20-5-2 (for analogs wherein R8 = oxime). 266 201245116

非對映異構體A S20-9-14-A ： !H NMR (400 MHz, CD3OD) δ 7.32 (s, 1 H), 4.72-4.78 (m, 1 H), 4.11 (s, 1 H), 3.96-4.02 (m, 2 H), 3.32-3.68 (m, 6 H), 3.15-3.23 (ms 1 H), 2.95-3.03 (m, 9 H), 2.50-2.61 (m3 1 H), 2.20-2.25 (m, 1 H), 1.58- 1.65 (m, 1 H)； MS (ESI) m/z 645.2 (M + H)。Diastereomer A S20-9-14-A : !H NMR (400 MHz, CD3OD) δ 7.32 (s, 1 H), 4.72-4.78 (m, 1 H), 4.11 (s, 1 H) , 3.96-4.02 (m, 2 H), 3.32-3.68 (m, 6 H), 3.15-3.23 (ms 1 H), 2.95-3.03 (m, 9 H), 2.50-2.61 (m3 1 H), 2.20 - 2.25 (m, 1 H), 1.58- 1.65 (m, 1 H); MS (ESI) m/z 645.2 (M + H).

非對映共稱瓶ϋ UH O HO Μ Ο Ο S20-9-15-B ： *H NMR (400 MHz, CD3OD) δ 7.63 (s, 1 H), 4.74-4.75(m, 1 H), 3.87-4.10 (m, 6 H), 3.49-3.55 (m, 4 H), 2.95-3.02 (m, 11 H), 2.58-2.62 (m, 1 H), 2.20-2.23 (m, 1 H), 1.62-1.64 (m, 1 H), 1.33 (t, J = 7.2 Hz, 3 H) ； MS (ESI) m/z 672.9 (M+H)。 實施例21.其中環E為吡咯啶-2-基之式I化合物 根據以下流程21合成式I化合物，其中X為-〇CF3，Y 為-Η或-NH2且環E為吡咯啶-2-基。 流程21 267 201245116 ?CF3 hno3 h2so4 〇cf3非 共 20 20 S20-9-15-B : *H NMR (400 MHz, CD3OD) δ 7.63 (s, 1 H), 4.74-4.75 (m, 1 H), 3.87 -4.10 (m, 6 H), 3.49-3.55 (m, 4 H), 2.95-3.02 (m, 11 H), 2.58-2.62 (m, 1 H), 2.20-2.23 (m, 1 H), 1.62 -1.64 (m, 1 H), 1.33 (t, J = 7.2 Hz, 3 H); MS (ESI) m/z 672.9 (M+H). Example 21. A compound of formula I wherein ring E is pyrrolidin-2-yl is synthesized according to Scheme 21 below, wherein X is -〇CF3, Y is -Η or -NH2 and ring E is pyrrolidine-2- base. Process 21 267 201245116 ?CF3 hno3 h2so4 〇cf3

och3 21-2 och3 21-1 ocf3Och3 21-2 och3 21-1 ocf3

1) BBr3 2) BnBr CH3 K2C03 Br •C02Ph OCF31) BBr3 2) BnBr CH3 K2C03 Br • C02Ph OCF3

CH3 b) CH3I ‘C02Ph OCH3 21-8 〇CF3 〇CF3 a) NaN〇2 OCF, Ν32^2〇4CH3 b) CH3I ‘C02Ph OCH3 21-8 〇CF3 〇CF3 a) NaN〇2 OCF, Ν32^2〇4

OCH3 21-3 a) sBuN2Li TMEDAOCH3 21-3 a) sBuN2Li TMEDA

'C02Ph'C02Ph

b) PhOHb) PhOH

BocHN、BocHN,

a) /PrMgCI-UCI b) A/-Boc °比略啶酮 21-10a) /PrMgCI-UCI b) A/-Boc °bibridone 21-10

〇cf3 ^ch3 1) TFA 2) NaBH4 c l 〇cf3 YYCH3 烯丙基溴 K2C03 〇CF3 rVCH3 sp&quot;C02Ph OBn y^co2Ph OBn \ y^co2Ph OBn 21-11 21-12 a) LDA/TMEDA b) 婦酮/LHMDS〇cf3 ^ch3 1) TFA 2) NaBH4 cl 〇cf3 YYCH3 Allyl bromide K2C03 〇CF3 rVCH3 sp&quot;C02Ph OBn y^co2Ph OBn \ y^co2Ph OBn 21-11 21-12 a) LDA/TMEDA b) /LHMDS

Pd(PPh3)4 二曱基巴比妥酸Pd(PPh3)4 dimercaptobarbituric acid

烷基化Alkylation

21-1721-17

och3 根據流程2 1製備以下化合物 ocf3 S21-2 合成化合物S21-2。 268 201245116 在15分鐘内在0°C下向對三氟甲氧基苯曱醚（i9.2〇g， O.lOmol，1當量）於二氯曱烧（200mL)中之溶液中逐滴 添加硝酸（14.29 mL，69%，0.22 mol，2.2 當量）於硫酸（17.86 mL )中之預冷卻（〇°C )溶液。攪拌反應物自〇至室溫隔 夜。移除水層。有機層以碳酸氫鈉（1 〇〇 mLx2 )飽和水溶 液及鹽水（1 〇〇 mLx 1 )洗滌’經硫酸鈉脫水，且濃縮至乾 燥，得到呈灰白液體狀之所需化合物S21-2 ( 24.20 g，定 量）：Rf = 0.45( 20% EtOAc/己烷）；NMR (400 MHz, CDC13) 8 7.75 (d, J= 2.4 Hz, 1 H), 7.42 (dd, J= 3.0, 9.2 Hz, 1 H), 7.10 (d，/= 9_2 Hz，1 H)，3.97 (s，3 H)。 〇cf3 och3 S21-3 合成化合物S21-3。 在0°C下向化合物S21-2(0.10 mol，1當量）於THF (600 mL)中之溶液中添加 Na2S204 ( 102.4 g，85%，0_5 0 mol ’ 5當量）於水（400 mL )中之溶液。在室溫下授拌反 應物16小時。收集有機層。用EtOAc ( 1〇〇 mLx3 )萃取水 層。經合併之有機層經硫酸納脫水且濃縮。將EtOAc ( 200 mL )添加至殘餘物中。過濾不溶性物質。收集濾液。將HC1 水溶液（150 mL，2 N)及甲醇（150 mL)添加至固體中。 在至溫下搜拌混合物2小時，以NaOH水溶液（6 N )中和， 且用EtOAc( 1〇〇 mLx3)萃取。將萃取物與先前保存之扮〇心 濾液合併，經硫酸鈉脫水，且濃縮至乾燥，得到呈深黃色 269 201245116 液體狀之所需產物 S21-3 ( 16.69 g，81%) : Rf = 0.50 ( 20% EtOAc/己烷）^ΗΝΜΪ^ΟΟΟΜΗζ,ΟϋαΟ 5 6.70(d，/ = 9.2 Hz, 1 Η), 6.59 (s, 1 Η), 6.57 (d, J= 9.2 Hz, 1 H), 3.83 (s, 3 H) ; MS (ESI) m/z 208.0 (M+H)。 〇cf3 水2 och3 S21-4 合成化合物S21-4。 在 0°C 下向化合物 S21-3(16.69g，0.081mol，1 當量） 於二氣甲烷（250 mL )中之溶液中以小份添加吡啶-HBr3 (31·09 g ’ 0.097 mo卜1.2當量）。反應混合物在〇°c下攪 拌1小時’用Na2S203水溶液（1 M，100 mLx3)及鹽水（100 mLx 1 )洗滌’經硫酸鈉脫水且濃縮。利用〇〇/0至2〇〇/0 EtOAc/ 己烷進行矽膠急驟管柱層析，得到呈灰白液體狀之所需產 物821-4(21.3〇8’92%):1^=〇.30 ( 200/〇£1〇八〇/己烷）； NMR (400 MHz, CDC13) δ 6.90 (s, 1 Η), 6.66 (d, 7 = 1.2 Hz, 1 Η), 4.01 (br s, 2 H), 3.83 (s, 3 H) ； MS (ESI) m/z 286.0 (M+H)。Och3 The following compound was prepared according to Scheme 2 1 ocf3 S21-2 Compound S21-2. 268 201245116 Addition of nitric acid to a solution of p-trifluoromethoxyphenyl hydrazine (i9.2 〇g, 0.1 mol, 1 eq.) in dichlorohydrazine (200 mL) at 0 ° C over 15 min. (14.29 mL, 69%, 0.22 mol, 2.2 eq.) Pre-cooled (〇 ° C) solution in sulfuric acid (17.86 mL). The reaction was stirred from room temperature to room temperature overnight. Remove the water layer. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate (1 mL mL) and brine (1 〇〇mL×1), dried over sodium sulfate, and concentrated to dryness to give the desired compound S21-2 ( 24.20 g , quantitative): Rf = 0.45 (20% EtOAc / hexane); NMR (400 MHz, CDC13) 8 7.75 (d, J = 2.4 Hz, 1 H), 7.42 (dd, J = 3.0, 9.2 Hz, 1 H ), 7.10 (d, /= 9_2 Hz, 1 H), 3.97 (s, 3 H). 〇cf3 och3 S21-3 Synthetic compound S21-3. Add Na2S204 (102.4 g, 85%, 0_50 mol '5 equivalents) to water (400 mL) in a solution of compound S21-2 (0.10 mol, 1 eq.) in THF (600 mL). Solution. The reaction was allowed to stir for 16 hours at room temperature. Collect organic layers. The aqueous layer was extracted with EtOAc (1 mL mL). The combined organic layers were dried over sodium sulfate and concentrated. EtOAc (200 mL) was added to the residue. Filter insoluble materials. The filtrate was collected. An aqueous solution of HCl (150 mL, 2 N) and methanol (150 mL) were added to a solid. The mixture was stirred at rt for 2 h, neutralized with EtOAc (EtOAc) (EtOAc) The extract was combined with the previously preserved core filtrate, dehydrated with sodium sulfate and concentrated to dryness to give the desired product S21-3 ( 16.69 g, 81%) as a dark yellow 269 201245116 liquid: Rf = 0.50 ( 20% EtOAc/hexane)^ΗΝΜΪ^ΟΟΟΜΗζ,ΟϋαΟ 5 6.70(d, / = 9.2 Hz, 1 Η), 6.59 (s, 1 Η), 6.57 (d, J= 9.2 Hz, 1 H), 3.83 ( s, 3 H) ; MS (ESI) m/z 208.0 (M+H). 〇 cf3 water 2 och3 S21-4 Synthetic compound S21-4. Pyridine-HBr3 (31.09 g '0.097 mob 1.2 equivalents) was added in small portions to a solution of the compound S21-3 (16.69 g, 0.081 mol, 1 eq.) in di-methane (250 mL). ). The reaction mixture was stirred at 0&lt;0&gt;C for 1 hr.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The desired product 821-4 (21.3 〇 8'92%) in the form of a pale white liquid was obtained by flash chromatography on EtOAc / EtOAc / hexanes: EtOAc. (200/〇£1〇8〇/hexane); NMR (400 MHz, CDC13) δ 6.90 (s, 1 Η), 6.66 (d, 7 = 1.2 Hz, 1 Η), 4.01 (br s, 2 H ), 3.83 (s, 3 H); MS (ESI) m/z 286.0 (M+H).

och3 S21-5 合成化合物S21-5。 在〇°C下向存於二噁烷（70 mL)及HC1水溶液（70 mL， 8.5 N)中之化合物 S21.-4 ( 19.84 g，69.58 mmol，1 當量） 中緩慢添加NaN02 ( 5.26 g，76.23 mmol，1.1當量）於水 270 201245116 -(28 mL )中之溶液。在室溫下攪拌反應混合物30分鐘且 在0C下緩慢添加至經攪拌之KI ( 115.50 g，0.70 mo卜10 當里）於水（140 mL )中的溶液中（氣體逸出〇 。反應混 合物在室溫下授拌72小時且用Et〇Ac ( 200 mLxl、50 mLx 2 )萃取。合併萃取物且濃縮。將殘餘物再次溶解於Et〇Ac (100 mL )中。溶液以 Na2s〇3 水溶液（2 ]Vi，100 mLx2 )、 碳酸氫鈉飽和水溶液（丨〇〇 mLx丨）及鹽水（丨〇〇 mLx丨）洗 蘇’經硫酸鈉脫水且濃縮。利用〇%至5% EtOAc/己烷進行 石夕膠急驟管柱層析’得到呈無色液體狀之所需化合物S21_5 (19.80§，72%):1^=〇.66(1〇。/()阶〇7^/己烷）；1]9[胸11 (400 MHz, CDC13) δ 7.67 (s, 1 Η), 6.99 (s, 1 Η), 3.87 (s, 3 Η)。 ocf3Och3 S21-5 Synthetic compound S21-5. Slowly add NaN02 (5.26 g,) to compound S21.-4 ( 19.84 g, 69.58 mmol, 1 eq.) in dioxane (70 mL) and EtOAc (EtOAc (EtOAc) 76.23 mmol, 1.1 eq.) in water 270 201245116 - (28 mL). The reaction mixture was stirred at room temperature for 30 minutes and slowly added at 0 ° to a stirred solution of KI (115.50 g, 0.70 s of 10 s) in water (140 mL). The mixture was stirred at room temperature for 72 hours and extracted with Et 〇Ac (200 mL×1, 50 mL×2). The extracts were combined and concentrated. The residue was redissolved in Et EtOAc (100 mL). 2 ]Vi, 100 mL×2 ), a saturated aqueous solution of sodium bicarbonate (丨〇〇 mL×丨) and brine (丨〇〇 mL×丨), washed with sodium sulfate, dehydrated and concentrated with 〇% to 5% EtOAc/hexane. The desired compound S21_5 (19.80 §, 72%) in the form of a colorless liquid was obtained by flash column chromatography. (1.= 〇.66 (1 〇./() order 〇7^/hexane); ]9[chest 11 (400 MHz, CDC13) δ 7.67 (s, 1 Η), 6.99 (s, 1 Η), 3.87 (s, 3 Η). ocf3

• BrA• BrA

y^COaH OCH3 S21-6 合成化合物S21-6。 將化合物 S21-5(18.80g’47.36 mmol，1 當量）於 thf (100 mL)中之溶液冷卻至-78°C且在30分鐘内逐滴添加 /•PrMgCl-LiCl ( 43.72 mL ’ 1.3 Μ 於 THF 中，56.84 mmol， 1·2當量）。在-78°C下攪拌反應物30分鐘。在_78°C下使無 水二氧化碳鼓泡通過反應混合物持續3 0分鐘。撥拌反應混 合物自-7 8°C至室溫持續2小時，添加HC1水溶液（1 N，1〇〇 mL) ’且濃縮。用EtOAc ( 5〇 mLx4)萃取水性混合物。經 合併之萃取物經硫酸鈉脫水且濃縮至乾燥，得到呈灰白固 271 201245116 體狀之所需產物 S21-6( 15_37g，定量）：MS(ESI) m/z 3 12.9 (M-H) 〇 ocf3 y^co2Ph och3 S21-7 合成化合物S21-7。 在0°C下向存於二氯曱烷（100 mL)中之化合物S21-6 (粗物質，47.36 mmo卜1當量）中逐滴添加DMF( 0.10 mL， 1.3 0 mmol，〇_〇27 當量）及乙二醯氣（19.64 mL，122.00 mmol ’ 2.5當量）（氣體逸出）。在室溫下攪拌反應物ι 5 小時且濃縮至乾燥。將殘餘物再次溶解於二氣曱烷（1 〇〇Y^COaH OCH3 S21-6 The compound S21-6 was synthesized. The solution of compound S21-5 (18.80 g '47.36 mmol, 1 eq.) in thf (100 mL) was cooled to -78 ° C and /PrMgCl-LiCl (43.72 mL ' 1.3 Μ 56.84 mmol, 1.2 eq. in THF. The reaction was stirred at -78 °C for 30 min. Water-free carbon dioxide was bubbled through the reaction mixture at -78 °C for 30 minutes. The mixture was stirred from -7 ° C to room temperature for 2 hours, and an aqueous solution of HCl (1 N, 1 〇〇 mL) was added and concentrated. The aqueous mixture was extracted with EtOAc (5 mL mL). The combined extracts are dehydrated with sodium sulfate and concentrated to dryness to give the desired product S21-6 (15-37 g, quantitative): MS (ESI) m/z 3 12.9 (MH) 〇ocf3 y ^co2Ph och3 S21-7 Synthesis of compound S21-7. DMF (0.10 mL, 1.3 0 mmol, 〇_〇27 equivalents) was added dropwise to the compound S21-6 (crude, 47.36 mmo, 1 equivalent) in dichloromethane (100 mL). And ethylene bismuth (19.64 mL, 122.00 mmol '2.5 equivalents) (gas evolution). The reaction was stirred at room temperature for 5 hours and concentrated to dryness. Re-dissolve the residue in dioxane (1 〇〇

mL )中。添加苯齡（5.51 g，58.55 mmol，1.2 當量）、DIE A (12.67 mL，72.74 mmo卜 1.5 當量）及 DMAP ( 0.60 g，4.91 mmol ’ 0.10當量）。反應溶液在室溫下攪拌隔夜且濃縮。 將殘餘物再次溶解於EtOAc中。溶液以碳酸氫鈉飽和水溶 液（50 mLx2 )及鹽水（50 mLxl )洗滌，經硫酸納脫水， 且濃縮至乾燥。利用〇%至20% EtO Ac/己烧進行石夕膠急驟管 柱層析’得到呈無色油狀之所需產物S21_7( n 〇〇 g，9〇%): Rf - 0.3 3( 10% EtO Ac/ 2, ) ； 'H NMR (400 MHz, CDC13) &lt;5 7.95 (d, / = 1.2 Hz, 1 H), 7.45-7.3 7 (m, 2 H), 7.29-7.16 (m, 4 H)，3_8ό (s，3 H) ; MS (ESI) m/z 391.0 (M + H)。 OCF^ ΒγΎ^〇η3 T^c°2Ph 〇ch3 S21-8 合成化合物。 272 201245116 • 將·^Βιΐ2ΝΗ( 14·64 mL，84.85 mmo卜 2 當量）及 Et3N-HCl (146 mg，1.06 mmol，0.025 當量）溶解於無水 THF ( 15〇 mL)中且冷卻至-78°C。逐滴添加„BuLi ( 34.00 mL，2.5 Μ 於己烷中，85.00 mmol，2當量）。在代下攪拌溶液1〇 分鐘且再冷卻至-78°C。添加TMEDA ( 12.75 mL，85.00 mmol，2當量），接著經30分鐘逐滴添加存於THF( 1〇〇 mL) 中之化合物 S21-7(16.61g’ 42.47mmol，1 當量）。在·78 °C下攪拌反應物1小時。經一分鐘快速添加峨代曱烧（丨8.5 〇 mL，0.30 mol，7當量）。攪拌反應物自_78〇c至室溫持續2 小時，添加氣化銨飽和水溶液（200 mL )，且濃縮《用EtOAc (100 mLx3 )萃取水溶液。經合併之萃取物經硫酸納脫水 且濃縮。利用〇%至10°/。EtOAc/己烧進行矽膠急驟管柱層 析，得到呈灰白油狀之所需產物S21-8 ( 11.76 g，69%)：In mL). Benzene age (5.51 g, 58.55 mmol, 1.2 equivalents), DIE A (12.67 mL, 72.74 mmo, 1.5 equivalents) and DMAP (0.60 g, 4.91 mmol '0.10 equivalents) were added. The reaction solution was stirred overnight at room temperature and concentrated. The residue was redissolved in EtOAc. The solution was washed with a saturated aqueous solution of sodium hydrogencarbonate (50 mL×2) and brine (50 mL×l), dried over sodium sulfate and concentrated to dry. The desired product S21_7 (n 〇〇g, 9〇%) is obtained as a colorless oil using 〇% to 20% EtO Ac/hexane to give the desired product as a colorless oil: Rf - 0.3 3 (10% EtO) Ac/ 2, ) ; 'H NMR (400 MHz, CDC13) &lt;5 7.95 (d, / = 1.2 Hz, 1 H), 7.45-7.3 7 (m, 2 H), 7.29-7.16 (m, 4 H ), 3_8 ό (s, 3 H) ; MS (ESI) m/z 391.0 (M + H). OCF^ ΒγΎ^〇η3 T^c°2Ph 〇ch3 S21-8 Synthetic compound. 272 201245116 • Dissolve ·^Βιΐ2ΝΗ (14.64 mL, 84.85 mmo 2 equivalents) and Et3N-HCl (146 mg, 1.06 mmol, 0.025 eq.) in dry THF (15 mL) and cooled to -78 °C . „BuLi (34.00 mL, 2.5 Μ in hexane, 85.00 mmol, 2 eq.) was added dropwise. The solution was stirred for 1 〇 and then cooled to -78 ° C. TMEDA ( 12.75 mL, 85.00 mmol, 2 Equivalent), then compound S21-7 (16.61 g '42.47 mmol, 1 eq.) in THF (1 mL) was added dropwise over 30 min. The reaction was stirred at 780 ° C for one hour. Quickly add deuterated simmer (丨8.5 〇mL, 0.30 mol, 7 eq.) in minutes. Stir the reaction from _78 〇c to room temperature for 2 hours, add a saturated aqueous solution of ammonium sulphate (200 mL), and concentrate. The aqueous solution was extracted with EtOAc (100 mL EtOAc). -8 ( 11.76 g, 69%):

Rf = 0.60( 20〇/〇 EtOAc/己烷）；4 NMR (400 MHz，CDC13) (5 7.48-7.41 (m, 2 Η), 7.32-7.25 (m5 1 Η), 7.23 (d, J = 7.3 Hz, 2 H), 7.10 (s, 1 H), 3.91 (s, 3 H), 2.44 (s, 3 H) ； MS (ESI) m/z 402.9 (M-H) ° 〇CF3Rf = 0.60 (20 〇 / 〇 EtOAc / hexane); 4 NMR (400 MHz, CDC13) (5 7.48-7.41 (m, 2 Η), 7.32-7.25 (m5 1 Η), 7.23 (d, J = 7.3 Hz, 2 H), 7.10 (s, 1 H), 3.91 (s, 3 H), 2.44 (s, 3 H) ; MS (ESI) m/z 402.9 (MH) ° 〇CF3

BrVT^CH3 C02PhBrVT^CH3 C02Ph

OH 合成化合物紛。 在-78°C下向存於二氯曱烷（60mL)中之化合物S21-8 (12.26 g’ 30.26 mmol，1 當量）中逐滴添加 BBr3( 33_3〇 mL， 1.0 Μ於二氣甲烧中，33.30 mmol，1.1當量）。搜摔反與 物自-78 C至〇 C持續1小時。添加碳酸氩納飽和水溶液（2〇〇 273 201245116 mL )。處合物在室溫下撥拌1 5分鐘且用二氣甲烧（$ 〇 mL X4 )萃取。經合併之萃取物經硫酸鈉脫水且濃縮，得到呈 灰白油狀之粗紛（12.00g，定量）：Rf=〇7〇(2〇0/〇 Et〇Ac/ 己烷）；NMR (400 MHz，CDC13) &lt;5 10.97 (s，1 H)， 7.50-7.44 (m，2 H)，7.38-7.30 (m，1 H)，7.25-7.15 (m，3 H)， 2.68 (s, 3 H) ； MS (ESI) m/z 388.9 (M-H) 〇 OBn S21-9 合成化合物S21-9。 將上述粗盼（30.26 111111〇卜1當量）溶解於〇1^(3〇1111〇 中。添加碳酸钟（8.35 g，60.50 mmol，2當量）及漠曱苯 (4·3 1 mL，36.28 mmol ’ 1.2當、量）。反應混合物在室溫下 棍摔1小時，以EtOAc(300mL)稀釋，用水（600mLxl、 100 mLx 1 )及鹽水（100 mLx 1 )洗滌，經硫酸鈉脫水且濃 縮。利用0%至10% EtOAc/己烷進行矽膠急驟管柱層析，得 到呈白色固體狀之所需產物S21-9 ( 13.20 g，91%，經兩個 步驟）：Rf = 0.70 ( 20% EtOAc/己烷）；4 NMR (400 MHz， CDC13) δ 7.43-7.20 (m, 8 Η), 7.16 (s, 1 Η), 7.03 (d, J= 9.1 Hz, 2 H), 5.12 (s, 2 H), 2.43 (s, 3 H) ； MS (ESI) m/z 479.0 (M-H)。OH synthetic compounds. To a compound S21-8 (12.26 g '30.26 mmol, 1 eq.) in dichloromethane (60 mL) was added dropwise BBr3 (33_3 〇mL, 1.0 Μ in dioxane) at -78 °C. , 33.30 mmol, 1.1 eq.). The search for counter-offs from -78 C to 〇 C lasted for 1 hour. A saturated aqueous solution of argon carbonate (2 〇〇 273 201245116 mL) was added. The mixture was stirred at room temperature for 15 minutes and extracted with two gas ($ 〇 mL X4). The combined extracts are dried over sodium sulfate and concentrated to give a crude white oil (12.00 g, quantitative): Rf=〇7〇(2〇0/〇Et〇Ac/hexane); NMR (400 MHz , CDC13) &lt;5 10.97 (s,1 H), 7.50-7.44 (m,2 H), 7.38-7.30 (m,1 H), 7.25-7.15 (m,3 H), 2.68 (s, 3 H MS (ESI) m/z 388.9 (MH) 〇 OBn S21-9 Compound S21-9. The above crude expectation (30.26 111111 1 1 equivalent) was dissolved in 〇1^(3〇1111〇. Carbonate clock (8.35 g, 60.50 mmol, 2 eq.) and benzene (4·3 1 mL, 36.28 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour, diluted with EtOAc (300 mL), washed with water (600 mL×l, 100 mL×1) and brine (100 mL×1), dried over sodium sulfate and concentrated. The desired product S21-9 ( 13.20 g, 91% in two steps) was obtained as a white solid: Rf = 0.70 (20% EtOAc / EtOAc / EtOAc Hexane); 4 NMR (400 MHz, CDC13) δ 7.43-7.20 (m, 8 Η), 7.16 (s, 1 Η), 7.03 (d, J = 9.1 Hz, 2 H), 5.12 (s, 2 H ), 2.43 (s, 3 H); MS (ESI) m/z 479.0 (MH).

OBn S21-10 合成化合物S21-10。 274 201245116 經10分鐘在0°C下向存於THF中之化合物S21-9( 4.81 g ’ 10.00 mmol，1 當量）中逐滴添加 iPrMgC1_LiCl ( n.54 mL ’ 1.3 Μ 於 THF 中，15.00 mmol，1.5 當量）。反應物在 〇 C下搜拌2小時且冷卻至_ 7 8 °C。添加b 〇 c °比咯咬酮（3.41 mL·’ 20.00mm〇l，2當量）。在攪拌下反應物經1小時自_78 C升溫至室溫。添加氣化銨飽和水溶液（2〇〇 mL )。用EtOAc (100 mLxl、50 mLx2 )萃取混合物。經合併之EtOAc萃取 物經硫酸鋼脫水且減壓濃縮。利用〇_丨5% Et〇Ac/己烷進行 矽膠急驟官柱層析，得到呈白色固體狀之所需產物S21_1〇 (3.20 g ’ 56% ) : Rf 〇·4〇 ( 20% EtOAc/己烷）；4 NMR (400 MHz, CDC13) d 7.47.45-7.30 (m5 6 H), 7.28-7.20 (m, 1 H), 7.08-7.02 (m, 3 H), 6.87 (s, 1 H), 5.14 (s, 2 H), 4.00 (br t, 7 = 8.9 Hz，2 H)，2.63 (dt，J = 2.5, 9.2 Hz，2H)，2.40 (s，3 H)， 1.30-1.10 (m，2 H) ; MS (ESI) m/z 588.2，（M-H、。 ocf3 5 v A/ hN\VCH3 y^co2Ph OBn S21-11 合成化合物S21-11。 在〇°c下向存於二氯甲烧mL)令之化合物s2i_iq (3.25 g，5.53 mmol，1當量）中添加TFA_二氯甲燒（机， 1:1，v/v)。反應溶液在室溫下攪拌3〇分鐘且減壓濃縮至乾 燥。將碳酸氫鈉飽和水溶液（丨〇〇 mL )添加至殘餘物中。 用二亂甲烧（50 mLx4 )萃取混合物。經合併- —氣甲烧萃 取物經硫酸納脫水且減壓濃縮，得到呈灰白油狀 衣亞胺 275 201245116 中間物（2.73 g) : 4 NMR (400 MHz，CDC13) 5 7.45-7.20 (m, 9 H), 7.06 (d, 10.3 Hz, 2 H), 5.17 (s, 2 H), 4,03 (t, / = 7.4 Hz, 2 H), 2.92 (t, J = 8.0 Hz, 2 H), 2.44 (s, 3 H), 2.11-2.00 (m，2 H) ; MS (ESI) m/z 470.0 (M+H)。OBn S21-10 Synthetic compound S21-10. 274 201245116 iPrMgC1_LiCl (n.54 mL '1.3 Μ in THF, 15.00 mmol, was added dropwise to the compound S21-9 ( 4.81 g '10.00 mmol, 1 eq.) in THF over 10 min. 1.5 equivalents). The reaction was stirred at 〇 C for 2 hours and cooled to _ 7 8 °C. b 〇 c ° is added to the ketamine (3.41 mL·' 20.00 mm 〇l, 2 equivalents). The reaction was warmed from _78 C to room temperature over 1 hour with stirring. A saturated aqueous solution of ammonium sulfate (2 〇〇 mL) was added. The mixture was extracted with EtOAc (100 mL×l, 50 mL×2). The combined EtOAc extracts were dried over EtOAc EtOAc. The desired product S21_1 〇 (3.20 g ' 56% ) was obtained as a white solid: mp 〇 〇 〇 〇 〇 20 20 20 20 〇 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 20 4 NMR (400 MHz, CDC13) d 7.47.45-7.30 (m5 6 H), 7.28-7.20 (m, 1 H), 7.08-7.02 (m, 3 H), 6.87 (s, 1 H) , 5.14 (s, 2 H), 4.00 (br t, 7 = 8.9 Hz, 2 H), 2.63 (dt, J = 2.5, 9.2 Hz, 2H), 2.40 (s, 3 H), 1.30-1.10 (m , 2 H) ; MS (ESI) m/z 588.2, (MH, ocf3 5 v A/ hN\VCH3 y^co2Ph OBn S21-11 Synthetic compound S21-11. Stored in chloroform at 〇°c To a solution of the compound s2i_iq (3.25 g, 5.53 mmol, 1 eq.) was added TFA-dichloromethane (machine, 1:1, v/v). The reaction solution was stirred at room temperature for 3 minutes and concentrated under reduced pressure to dryness. A saturated aqueous solution of sodium hydrogencarbonate (? mL) was added to the residue. The mixture was extracted with two chaotically burned (50 mL x 4 ). The combined gas-burning extract was dehydrated with sodium sulfate and concentrated under reduced pressure to give a white oily ylide 275 201245116 intermediate (2.73 g): 4 NMR (400 MHz, CDC13) 5 7.45-7.20 (m, 9 H), 7.06 (d, 10.3 Hz, 2 H), 5.17 (s, 2 H), 4,03 (t, / = 7.4 Hz, 2 H), 2.92 (t, J = 8.0 Hz, 2 H) , 2.44 (s, 3 H), 2.11-2.00 (m, 2 H); MS (ESI) m/z 470.0 (M+H).

將上述中間物再次溶解於甲醇（4〇 mL )中且冷卻至〇 C °添加硼氫化鈉（i.05 g，2776 mmol，5當量）。在室 溫下攪拌反應物30分鐘。再添加硼氩化鈉（1.〇〇 gx2 )。 在室溫下攪拌反應物30分鐘《添加HC1水溶液（2 N)直 至pH = 2-3。添加碳酸氫鈉飽和水溶液（丨〇〇 mL )。用二 氣曱烧（50 mLx4 )萃取混合物。經合併之二氣甲烷萃取物 經硫酸鈉脫水且濃縮’得到呈灰白油狀之S21-11 ( 2.71 g， 粗物質）：MS (ESI) w/z 472.1 (M+H)。 S21-12 合成化合物S21-12。 在室溫下向存於乙腈（20mL)中之化合物S21-ll(粗The above intermediate was redissolved in methanol (4 mL) and cooled to EtOAc &lt;RTI ID=0.0&gt;&gt; The reaction was stirred at room temperature for 30 minutes. Additional sodium borohydride (1. 〇〇 gx2 ) was added. The reaction was stirred at room temperature for 30 minutes "Add HCl aqueous solution (2 N) until pH = 2-3. A saturated aqueous solution of sodium bicarbonate (丨〇〇 mL) was added. The mixture was extracted with a gas purge (50 mL x 4 ). The combined dimethyl methane extracts were dried <RTI ID=0.0>: </RTI> EtOAc (EtOAc) S21-12 Synthesis of compound S21-12. Compound S21-ll (thick) in acetonitrile (20 mL) at room temperature

物質’ 5_53 mmol’ 1當量）中添加碳酸卸（ι·ΐ2 g，8.12 mmol， 1.5當直）及稀丙基演（〇_53mL，6.13mmol，1.1當量）。 在室溫下攪拌反應物14小時。添加水（1 〇〇 mL )。用二氯 曱烷（100 mLxl、50 mLx3)萃取混合物。經合併之二氯曱 烷萃取物經硫酸鈉脫水且減壓濃縮。利用〇_20% EtOAc/己 烷進行矽膠急驟管柱層析，得到呈白色固體狀之所需產物 S21-12( 2_26 g，80%) : Rf 〇.60( 20% EtOAc/己烷）；NMR 276 201245116To the material '5_53 mmol' 1 equivalent), carbonic acid was removed (1·2 g, 8.12 mmol, 1.5 as straight) and the propyl group (〇_53 mL, 6.13 mmol, 1.1 eq.). The reaction was stirred at room temperature for 14 hours. Add water (1 〇〇 mL). The mixture was extracted with dichloromethane (100 mL x 1 , 50 mL x 3). The combined dichloromethane extract was dried over sodium sulfate and concentrated under reduced pressure. The desired product S21-12 (2_26 g, 80%) was obtained as a white solid: EtOAc: EtOAc: EtOAc NMR 276 201245116

(400 MHz, DC1, CD3OD, CDCI3) δ 8.30 (s, 1 H), 7.52 (d, J =6.7 Hz，2 H)，7.35-7.20 (m, 7 H), 7.03 (d，8.6 Hz，2 H), 6.04-5.90 (m, 1 H), 5.55-5.35 (m, 4 H), 4.38 (dd, J = 7.3, 11.0 Hz, 1 H), 4.05-3.95 (m, 1 H), 3.63 (dd, J= 6.1, 13.4 Hz, 1 H), 2.23 (dd, J= 8.0, 12.3 Hz, 1 H), 2.98 (dd, / = 10.4, 18.9 Hz, 1 H), 2.58-30 (m, 3 H), 2.18-2.08 (m, 1 H) ； MS (ESI) m/z 510.1 (M-H) »(400 MHz, DC1, CD3OD, CDCI3) δ 8.30 (s, 1 H), 7.52 (d, J = 6.7 Hz, 2 H), 7.35-7.20 (m, 7 H), 7.03 (d, 8.6 Hz, 2 H), 6.04-5.90 (m, 1 H), 5.55-5.35 (m, 4 H), 4.38 (dd, J = 7.3, 11.0 Hz, 1 H), 4.05-3.95 (m, 1 H), 3.63 ( Dd, J= 6.1, 13.4 Hz, 1 H), 2.23 (dd, J= 8.0, 12.3 Hz, 1 H), 2.98 (dd, / = 10.4, 18.9 Hz, 1 H), 2.58-30 (m, 3 H), 2.18-2.08 (m, 1 H) ; MS (ESI) m/z 510.1 (MH) »

S21-13 合成化合物S21-13。 在- 78°C下向存於無水THF( 10 mL)中之二異丙胺（0.56 mL，4.00 mmol，1.2 當量）中逐滴添加《BuLi ( 1·60 mL， 2.5 Μ於己烧中，4.00 mmol，1.2當量）。反應物在〇C下 攪拌10分鐘且冷卻至_78。〇。添加TMEDA ( 0.62 mL，4.00 mmol ’ 1.2當量），接著經1〇分鐘逐滴添加化合物S21-12 (1.70 g，3.32 mmol，於 1〇 mL THF 中，1 當量）。在-78 C下授拌深紅色反應溶液1〇分鐘。逐滴添加LHMDS ( 4.00 ’ 1 Μ於THF中，4.00 mmol，1_2當量），接著經5分 鐘逐滴添加烯酮 S2-1 ( 1.60 g，3.32 mmol，於 1〇 mL THF 中’ 1當量）。在攪拌下使反應物經i小時自-78°c升溫至〇 c。添加氯化銨飽和水溶液（10〇 mL)。用二氯甲烷（2〇〇 mLx 1、5〇 mLx2 )萃取混合物。經合併之二氯曱烷萃取物經 硫酸鈉脫水且濃縮。利用0-20% EtOAc/己烷進行矽膠急驟 277 201245116 二柱層析’彳于到所需·產物S21_13(非對映異構體A: 1.13 g， K色固體’ 38% ;非對映異構體B，1.10 g，黃色固體，37% ; A與B之混合物：0_41 g，黃色固體，16。/。）。非對映異構 體 S21-13-A: Rf 〇.5〇( 2〇% EtOAc/己烷）；NMR (400 MHz， DC1，CD3〇D，CDC13) 5 7.99 (s，1 H)，7_43 (d，&lt;/= 7.3 Hz，2 H), 7.32-7.27 (m, 2 H), 7.25-7.10 (m, 2 H), 7.10-7.03 (m, 1 H), 7.02-6.96 (m, 1 H), 6.68-6.60 (m, 2 H), 5.85-5.65 (m, 1 H), 5.46 (d, J = 12.8 Hz, 1 H), 5.29 (d, J = 12.8 Hz, 1 H), 5.28-5.15 (m, 4 H), 4.62 (d, J= 3.0 Hz, 1 H), 4.30-4.22 (m, 1 H), 3.85-3.77 (m&gt; 1 H), 3.44 (dd, /= 5.5, 12.0 Hz, 1 H), 3.15-3.10 (m, 1 H), 3.08-3.02 (m, 1 H), 3.00-2.85 (m, 8 H), 2.82-2.72 (m, 1 H), 2.45-1.90 (m, 6 H), 1.71-1.60 (m, 1 H), 0.57 (s, 9 H), 0.00 (s, 3 H), -0.28 (s, 3 H) ； MS (ESI) m/z 900.2 (M+H)。非對映異構體 S21-13-B : Rf = 0.45 ( 20% EtOAc/己烷）；4 NMR (400 MHz, DC1，CD3OD，CDC13) δ 8.01 (s, 1 H), 7.52 (d, J = m7.3 Hz, 2 H), 7.40-7.35 (m, 2 H), 7.31-7.21 (m, 5 H), 7.20-7.13 (m, 1 H), 5.88-5.75 (m, 1 H), 5.55- 25 (m, 6 H), 4.71 (d, J = 3.0 Hz, 1 H), 4.40-4.34 (m, 1 H), 3.90-3.80 (m, 1 H), 3.52 (dd, J = 6.1, 12.0 Hz, 1 H), 3.33-3.25 (m, 1 H), 3.20-2.90 (m, 9 H), 2.90-2.80 (m, 1 H), 2.55- 2.45 (m, 1 H), 2.42-2.25 (m, 2 H), 2.24-2.05 (m, 3 H), 1.75- 1.65 (m, 1 H), 0.66 (s, 9 H), 0.09 (s5 3 H), -0.21 (s, 3 H) ; MS (ESI) m/z 900.2 (M + H)。 278 201245116S21-13 Synthesis of compound S21-13. To a solution of diisopropylamine (0.56 mL, 4.00 mmol, 1.2 eq.) in anhydrous THF (10 mL), EtOAc (1········· M, 1.2 equivalents). The reaction was stirred at 〇C for 10 minutes and cooled to _78. Hey. TMEDA (0.62 mL, 4.00 mmol </ RTI> 1.2 eq.) was added, followed by the dropwise addition of compound S21-12 (1.70 g, 3.32 mmol in 1 〇 THF, 1 eq) over 1 hr. The dark red reaction solution was mixed at -78 C for 1 minute. LHMDS (4.00' 1 Μ in THF, 4.00 mmol, 1 - 2 eq.) was added dropwise, followed by the addition of the enone S2-1 ( 1.60 g, 3.32 mmol, 1 eq. The reaction was allowed to warm from -78 ° C to 〇 c over 1 hour with stirring. A saturated aqueous solution of ammonium chloride (10 〇 mL) was added. The mixture was extracted with dichloromethane (2 〇〇 mL x 1, 5 〇 mL x 2 ). The combined dichloromethane extract was dried over sodium sulfate and concentrated.矽 急 277 201245116 Two-column chromatography with 0-20% EtOAc/hexanes to give the desired product S21_13 (diastereomer A: 1.13 g, K color solids) 38%; diastereomer Construct B, 1.10 g, yellow solid, 37%; mixture of A and B: 0-41 g, yellow solid, 16%. Diastereomer S21-13-A: Rf 〇.5 〇 (2〇% EtOAc/hexanes); NMR (400 MHz, DC1, CD3 〇D, CDC13) 5 7.99 (s, 1 H), 7_43 (d, &lt;/= 7.3 Hz, 2 H), 7.32-7.27 (m, 2 H), 7.25-7.10 (m, 2 H), 7.10-7.03 (m, 1 H), 7.02-6.96 (m, 1 H), 6.68-6.60 (m, 2 H), 5.85-5.65 (m, 1 H), 5.46 (d, J = 12.8 Hz, 1 H), 5.29 (d, J = 12.8 Hz, 1 H), 5.28-5.15 (m, 4 H), 4.62 (d, J = 3.0 Hz, 1 H), 4.30-4.22 (m, 1 H), 3.85-3.77 (m&gt; 1 H), 3.44 (dd, /= 5.5 , 12.0 Hz, 1 H), 3.15-3.10 (m, 1 H), 3.08-3.02 (m, 1 H), 3.00-2.85 (m, 8 H), 2.82-2.72 (m, 1 H), 2.45- 1.90 (m, 6 H), 1.71-1.60 (m, 1 H), 0.57 (s, 9 H), 0.00 (s, 3 H), -0.28 (s, 3 H) ; MS (ESI) m/z 900.2 (M+H). Diastereomer S21-13-B: Rf = 0.45 (20% EtOAc/hexanes); 4 NMR (400 MHz, DC1, CD3OD, CDC13) δ 8.01 (s, 1 H), 7.52 (d, J = m7.3 Hz, 2 H), 7.40-7.35 (m, 2 H), 7.31-7.21 (m, 5 H), 7.20-7.13 (m, 1 H), 5.88-5.75 (m, 1 H), 5.55- 25 (m, 6 H), 4.71 (d, J = 3.0 Hz, 1 H), 4.40-4.34 (m, 1 H), 3.90-3.80 (m, 1 H), 3.52 (dd, J = 6.1 , 12.0 Hz, 1 H), 3.33-3.25 (m, 1 H), 3.20-2.90 (m, 9 H), 2.90-2.80 (m, 1 H), 2.55- 2.45 (m, 1 H), 2.42- 2.25 (m, 2 H), 2.24-2.05 (m, 3 H), 1.75- 1.65 (m, 1 H), 0.66 (s, 9 H), 0.09 (s5 3 H), -0.21 (s, 3 H MS (ESI) m/z 900.2 (M + H). 278 201245116

S21-14-B 合成化合物S21-14-B。 向存於一氯曱烷（10mL)中之化合物S21_13_B ( 〇 5〇 g，0.56 mmol，1當量）中添加况沁二曱基巴比妥酸（〇·87 g，5.57 mmol，10 當量）及 Pd(PPh3)4 ( 〇 13 g，〇 12 _〇1， 〇,2當量鮮黃色溶液藉由使氮氣鼓泡通過而脫氣5分鐘， 在氮氣下在45 C下加熱1小時，冷卻至室溫，以Et〇Ac( 1〇〇 mL)稀釋，用10%碳酸鈉水溶液（5〇 mLx2)及鹽水（5〇 mL X 1 )洗務’經硫酸納脫水’且減壓濃縮。利用8〇_丨〇〇% Et〇Ac/ 己烷進行矽膠急驟管柱層析’得到呈黃色固體狀之所需產 物 S21-14-B ( 0.48 g ’ 定量）：Rf 〇 45 ( Et〇Ac) ; MS (腺) w/z 860.4 (M+H)。S21-14-B Synthesis of compound S21-14-B. To the compound S21_13_B (〇5〇g, 0.56 mmol, 1 equivalent) in the presence of monochloromethane (10 mL) was added bismuthyl barbituric acid (〇·87 g, 5.57 mmol, 10 eq.) and Pd(PPh3)4 (〇13 g, 〇12 _〇1, 〇, 2 equivalents of fresh yellow solution was degassed by bubbling nitrogen through for 5 minutes, heated at 45 C for 1 hour under nitrogen, and cooled to room The mixture was diluted with Et 〇Ac (1 〇〇 mL), washed with 10% aqueous sodium carbonate (5 〇 mL×2) and brine (5 〇 mL X 1 ), dried under sodium sulfate, and concentrated under reduced pressure. _丨〇〇% Et〇Ac/hexane was subjected to flash column chromatography to give the desired product S21-14-B (0.48 g ' quantitative) as a yellow solid: Rf 〇45 ( Et〇Ac); MS (gland) w/z 860.4 (M+H).

S21-14-A 合成化合物S21-14-A。 類似地對非對映異構體S21-13-A ( 200 mg)脫除保護 基，得到非對映異構體S21-14-A( 117 mg，黃色固體，62% ): Rf 0.45 ( EtOAc) ； (ESI) m/z 860.4 (M+H) 〇S21-14-A Synthesis of compound S21-14-A. Deprotection of the diastereomer S21-13-A (200 mg) eluted to give the diastereomers S21-14-A ( 117 mg, yellow solid, 62%): Rf 0.45 (EtOAc ) (ESI) m/z 860.4 (M+H) 〇

279 201245116279 201245116

S21-15-6-B 合成化合物S21-15-6-B。S21-15-6-B Synthesis of compound S21-15-6-B.

向存於二氣乙烷（1 mL)中之化合物S21-14 ·Β (37 mg， 0.043 mmol ’ 1 當量）中添加丙酮（63 μί，0·86 mmo卜 20 當量）、HOAc( 52 μί，0.86 mmo卜 20 當量）及 Na(OAc)3BH (91 mg，0.43 mmol，1〇當量）。反應溶液在室溫下攪拌ι 小時，添加碳酸氫鈉飽和水溶液（20 mL )，且用二氣曱烧 (20 mLx3 )萃取。經合併之二氣甲烷萃取物經硫酸鈉脫水 且濃縮至乾燥，得到呈黃色泡沫狀之所需化合物（40 mg， 粗物質）：MS (ESI) w/z 902.2 (M+H)。Add acetone (63 μί, 0·86 mmo, 20 equivalents), HOAc (52 μί, to the compound S21-14 · Β (37 mg, 0.043 mmol ' 1 eq) in dioxane (1 mL). 0.86 mmo (20 equivalents) and Na(OAc)3BH (91 mg, 0.43 mmol, 1 〇 equivalent). The reaction solution was stirred at room temperature for 1 hour, a saturated aqueous solution of sodium hydrogencarbonate (20 mL) was then evaporated and evaporated. The combined dimethyl methane extracts were dried over sodium sulfate and concentrated to dryness tolulululululululululululululululu

S21-16-6-B 合成化合物S21-15-6-B。 向存於 THF ( 1.5 mL)中之化合物 S21-15-6-B ( 0.043 mmol ’粗物質）中添加48% HF水溶液（〇.75 mL)。在室 溫下攪拌溶液隔夜且添加至25% K：2HP〇4水溶液（30 mL) 中。用二氣曱烧（20 mLx3 )萃取混合物。經合併之二氣曱 烷萃取物經硫酸鈉脫水且濃縮至乾燥，得到呈黃色泡泳狀 之脫甲石夕基之中間物（30 mg，粗物質）：ms (ESI) m/z 788.1 (m+h) » 將上述粗中間物溶解於0.1 N He 1於甲醇•二。惡烧（5 mL，4:卜 v/v)中之溶液中。添加 10%pd_c( Umg 8 5 μπι〇1, 0.2 g 1)。用氫氣吹拂反應谷器且在室溫下在氫氣 280 201245116 下㈣！小時。用小型石夕蒸土塞濾'出催化劑。用甲醇（Μ X3)洗滌矽藻土塞。減壓濃縮經合併之據液。在p〇iymerx 管柱（以〇%至·乙腈-0.05 N HC1水溶液洗提，經乃 分幻上進行製備型HPLC純化，得到呈黃色固體狀之所需 產物S21-l6-6-B(18mg，雙鹽酸鹽，69%，經三個步驟）： 心腿㈣請也⑶刪5 7.34(s iH) 4 95 4 8〇(m， 1 Η), 4.10 (s, 1 Η), 3.74-3.65 (m5l Η), 3.50-3.35 (m, 2 Η), 3.20 (dd, J = 6.5, 16.9 Hz, 1 H), 3.10-2.95 (m, 2 H), 3.03 (s, 3 H), 2.95 (s, 3 H), 2.62-2.53 (m, 1 H), 2.42 (t, 14.3 Hz, 1 H), 2.33-2.18 (m, 4 H), 1.65 (dd, J = 13&gt;〇&gt; 24 ! Ηζ&gt; t H)&gt; 1.27 (d, J= 3.7 Hz, 3 H), 1.25 (d, J= 3.7 Hz, 3 H) ； MS (ESI) w/z 6 1 0.1 (M+H)。S21-16-6-B Synthesis of compound S21-15-6-B. To a solution of the compound S21-15-6-B (0.043 mmol of crude material) in THF (1.5 mL), a 48% aqueous HF solution (.75 mL) was added. The solution was stirred overnight at room temperature and added to a 25% K: 2 HP 4 aqueous solution (30 mL). The mixture was extracted with a gas purge (20 mL x 3 ). The combined dioxane extract was dehydrated over sodium sulfate and concentrated to dryness to give crystals eluted eluted eluted eluted with m+h) » Dissolve the above crude intermediate in 0.1 N He 1 in methanol • two. In a solution of smoldering (5 mL, 4: Bu v/v). Add 10% pd_c (Umg 8 5 μπι〇1, 0.2 g 1). Blow the reaction vessel with hydrogen and at room temperature under hydrogen 280 201245116 (four)! hour. The catalyst was filtered out using a small stone kiln plug. The diatomaceous earth plug was washed with methanol (Μ X3). The combined liquids were concentrated under reduced pressure. Purification on a p〇iymerx column (purified from 〇% to acetonitrile-0.05 N HCl) and purified by preparative HPLC to give the desired product S21-l6-6-B (18 mg) as a yellow solid. , bis-hydrochloride, 69%, after three steps): heart leg (four) please also (3) delete 5 7.34 (s iH) 4 95 4 8 〇 (m, 1 Η), 4.10 (s, 1 Η), 3.74- 3.65 (m5l Η), 3.50-3.35 (m, 2 Η), 3.20 (dd, J = 6.5, 16.9 Hz, 1 H), 3.10-2.95 (m, 2 H), 3.03 (s, 3 H), 2.95 (s, 3 H), 2.62-2.53 (m, 1 H), 2.42 (t, 14.3 Hz, 1 H), 2.33-2.18 (m, 4 H), 1.65 (dd, J = 13&gt;〇&gt; 24 Ηζ&gt; t H)&gt; 1.27 (d, J = 3.7 Hz, 3 H), 1.25 (d, J = 3.7 Hz, 3 H); MS (ESI) w/z 6 1 0.1 (M+H).

使用類似程序自中間物S21-13-A、S21-13-B、S21-14-A 或S21-14-B製備以下化合物。The following compounds were prepared from the intermediates S21-13-A, S21-13-B, S21-14-A or S21-14-B using a similar procedure.

非對映異構體a oh ΰ Ηά 8 OCF3 .. H3CvN^CH3Diastereomer a oh ΰ Ηά 8 OCF3 .. H3CvN^CH3

S21-16-6-A 自 S21-14-A 及丙酮製備：iH nMR (400 MHz, CD3OD) δ 1 .Π (s, 1 Η), 4.95-4.75 (m} i H), 4.09 (s, 1 H), 3.73-3.65 (m, 1 H), 3.52-3.45 (m, 2 H), 3.30-2.90 (m, 3 H), 3.04 (s, 3 H), 2.95 (s，3 H), 2.65-2.55 (m，1 h)，2.43 (t, J= 14.1 Hz, 1 H), 2.32-2.08 (m, 4 H), 1.65 (dd, J = 13.7, 25.3 Hz, 1 H), 1.2 8 (d, J= 7.0 Hz, 3 H), 1.27 (d, J = 6.4 Hz, 3 H) ； MS (ESI) m/z 610.1 (M + H)。 281 201245116S21-16-6-A Prepared from S21-14-A and acetone: iH nMR (400 MHz, CD3OD) δ 1 .Π (s, 1 Η), 4.95-4.75 (m} i H), 4.09 (s, 1 H), 3.73-3.65 (m, 1 H), 3.52-3.45 (m, 2 H), 3.30-2.90 (m, 3 H), 3.04 (s, 3 H), 2.95 (s, 3 H), 2.65-2.55 (m, 1 h), 2.43 (t, J = 14.1 Hz, 1 H), 2.32-2.08 (m, 4 H), 1.65 (dd, J = 13.7, 25.3 Hz, 1 H), 1.2 8 (d, J = 7.0 Hz, 3 H), 1.27 (d, J = 6.4 Hz, 3 H); MS (ESI) m/z 610.1 (M + H). 281 201245116

S21-16-1-A 藉由S21-14-A之完全保護基脫除反應製備：lH NMR (400 MHz, CD3〇D) δ 7.16 (s, 1 Η), 4.95-4.80 (m, 1 Η), 4.10 (s，1 Η), 3.60-3.55 (m，2 Η), 3.35-2.90 (m, 2 Η), 3.17 (dd, &lt;/ = 4.5，15.5 Hz, 1 Η), 3.04 (s，3 Η), 2.95 (s，3 Η), 2.62-2.52 (m，1 H)，2_40 (t，J= 14.6 Hz，1 H)，2.35_2.05 (m，4 H), 1.64 (dd, J = 14.0, 25.7 Hz, 1 H) ； MS (ESI) m/z 568.1 (M+H)。S21-16-1-A was prepared by the complete protection group removal reaction of S21-14-A: lH NMR (400 MHz, CD3〇D) δ 7.16 (s, 1 Η), 4.95-4.80 (m, 1 Η ), 4.10 (s,1 Η), 3.60-3.55 (m,2 Η), 3.35-2.90 (m, 2 Η), 3.17 (dd, &lt;/ = 4.5, 15.5 Hz, 1 Η), 3.04 (s ,3 Η), 2.95 (s,3 Η), 2.62-2.52 (m,1 H),2_40 (t,J= 14.6 Hz,1 H), 2.35_2.05 (m,4 H), 1.64 (dd , J = 14.0, 25.7 Hz, 1 H) ; MS (ESI) m/z 568.1 (M+H).

S21-16-1-B 藉由S21-14-B之完全保護基脫除反應製備：lH NMR (400 MHz, CD3OD) δ 7.20 (s, 1 Η), 4.95-4.85 (m, 1 Η),S21-16-1-B was prepared by the complete protecting group removal reaction of S21-14-B: lH NMR (400 MHz, CD3OD) δ 7.20 (s, 1 Η), 4.95-4.85 (m, 1 Η),

4.11 (s, 1 Η), 3.54-3.45 (πι} 2 Η), 3.20 (dd, J — 5.2, 15.5 Hz, 1 H), 3.10-2.95 (m, 2 H), 3.05 (s, 3 H), 2.96 (s, 3 H), 2.55-2.15 (m，6 H), 1.65 (dd，= 13.4, 24.5 Hz，1 H) ; MS (ESI) w/z 568.1 (M+H) 04.11 (s, 1 Η), 3.54-3.45 (πι} 2 Η), 3.20 (dd, J — 5.2, 15.5 Hz, 1 H), 3.10-2.95 (m, 2 H), 3.05 (s, 3 H) , 2.96 (s, 3 H), 2.55-2.15 (m,6 H), 1.65 (dd,= 13.4, 24.5 Hz, 1 H) ; MS (ESI) w/z 568.1 (M+H) 0

v. OH 〇 HO R Ο Ov. OH 〇 HO R Ο O

S21-16-2-B 在製備S21-16-1-B中以副產物形式獲得化合物 S21 胃 16-2-B (由於 THF 中之雜質）：^ NMR (400 MHz, 282 201245116 CD3OD) δ 7.28 (s, 1 Η), 4.95-4.75 (m, 1 Η), 4.11 (s, 1 Η), 3.94-3.85 (m, 1 Η), 3.55-3-45 (m, 2 Η), 3.42-2.95 (m5 5 Η), 3.04 (s, 3 Η), 2.96 (s, 3 Η), 2.63-2.55 (m, 1 Η), 2.47-2.20 (m, 6 H), 1.80-1.60 (m, 3 H)&gt; 640.1 (M+H)。S21-16-2-B Compound S21 was obtained as a by-product in the preparation of S21-16-1-B. Stomach 16-2-B (due to impurities in THF): ^ NMR (400 MHz, 282 201245116 CD3OD) δ 7.28 (s, 1 Η), 4.95-4.75 (m, 1 Η), 4.11 (s, 1 Η), 3.94-3.85 (m, 1 Η), 3.55-3-45 (m, 2 Η), 3.42-2.95 (m5 5 Η), 3.04 (s, 3 Η), 2.96 (s, 3 Η), 2.63-2.55 (m, 1 Η), 2.47-2.20 (m, 6 H), 1.80-1.60 (m, 3 H )&gt; 640.1 (M+H).

!.53-1.43 (m, 2 H) ； MS (ESI) m/z!.53-1.43 (m, 2 H) ; MS (ESI) m/z

S21-16-3-A 自 S21-14-A 及甲搭製備：NMR (400 MHz, CD3OD) δ 7.24 (s, 1 H), 4.75 (dd, 7= 6.4, 8.4 Hz, 1 H), 4.09 (d, J = 1.2 Hz, 1 H), 3.92-3.84 (m, 1 H), 3.48-3.35 (m, 1 H), 3.25-2.90 (m，3 H)，3.04 (s。 3 H)，2.95 (s，3 H)，2.83 (s，3 H)， 2.65-2.55 (m, 1 H), 2.48-2.08 (m, 5 H), 1.65 (dd, J = 13.4, 24.8 Hz，1 H) ; MS (ESI) m/z 582·1 (M+H)。Preparation of S21-16-3-A from S21-14-A and preparation: NMR (400 MHz, CD3OD) δ 7.24 (s, 1 H), 4.75 (dd, 7= 6.4, 8.4 Hz, 1 H), 4.09 (d, J = 1.2 Hz, 1 H), 3.92-3.84 (m, 1 H), 3.48-3.35 (m, 1 H), 3.25-2.90 (m, 3 H), 3.04 (s. 3 H), 2.95 (s,3 H), 2.83 (s,3 H), 2.65-2.55 (m, 1 H), 2.48-2.08 (m, 5 H), 1.65 (dd, J = 13.4, 24.8 Hz, 1 H) MS (ESI) m/z 582·1 (M+H).

非對映共稱fSBOH O HO q 〇 o S21-16-3-B - 自 S21-14-B 及甲醛製備：'H NMR (400 MHz，CD3OD) δ 7.27 (s, 1 H), 4.80-4.73 (m, 1 H), 4.10 (s, 1 H), 3.88-3.80 (m, 1 H), 3.45-3.35 (m, 1 H), 3.28-2.95 (m, 3 H), 3.04 (s, 3 H)，2.96 (s，3 H)，2.77 (s，3 H)，2.62-2.53 (m，1 H)，2.48-2.20 (m, 5 H), 1.65 (dd, J = 14.0, 25.9 Hz, 1H) ； MS (ESI) m/z 582.1 (M+H)。 283 201245116Non-enantiomerically co-named fSBOH O HO q 〇o S21-16-3-B - Prepared from S21-14-B and formaldehyde: 'H NMR (400 MHz, CD3OD) δ 7.27 (s, 1 H), 4.80-4.73 (m, 1 H), 4.10 (s, 1 H), 3.88-3.80 (m, 1 H), 3.45-3.35 (m, 1 H), 3.28-2.95 (m, 3 H), 3.04 (s, 3 H), 2.96 (s, 3 H), 2.77 (s, 3 H), 2.62-2.53 (m, 1 H), 2.48-2.20 (m, 5 H), 1.65 (dd, J = 14.0, 25.9 Hz, 1H) ; MS (ESI) m/z 5821. (M+H). 283 201245116

h3c 非對映矣僻姐/\ w nw π wH3c non-enantiomeric sister / \ w nw π w

S21-16-4-A 自 S21-14-A 及乙醛製備：】H NMR (400 MHz，CD3〇D) δ 7.27 (s, 1 H), 4.76 (dd, J = 6.5, 8.4 Hz, 1 H), 4.10 (s, 1 H), 3.95-3.85 (m, 1H), 3.40-3.32 (m, 1 H), 3.35-2.90 (m, 5 H), 3.04 (s, 3 H), 2.95 (s, 3 H), 2.64-2.54 (m, 1 H), 2.43 (t, J = 14.6 Hz, 1 H), 2.37-2.05 (m, 4 H), 1.65 (dd, 7= 13.4, 25.0 Hz, 1 H), 1_28 (t’ /= 7.3 Hz, 3 H) ; MS (ESI) m/z 596.2 (M + H)。S21-16-4-A from S21-14-A and acetaldehyde preparation: H NMR (400 MHz, CD3〇D) δ 7.27 (s, 1 H), 4.76 (dd, J = 6.5, 8.4 Hz, 1 H), 4.10 (s, 1 H), 3.95-3.85 (m, 1H), 3.40-3.32 (m, 1 H), 3.35-2.90 (m, 5 H), 3.04 (s, 3 H), 2.95 ( s, 3 H), 2.64-2.54 (m, 1 H), 2.43 (t, J = 14.6 Hz, 1 H), 2.37-2.05 (m, 4 H), 1.65 (dd, 7= 13.4, 25.0 Hz, 1 H), 1_28 (t' /= 7.3 Hz, 3 H); MS (ESI) m/z 596.2 (M + H).

非對映呉構殺BOH O HO Fl Ο υNon-enantiomeric structure kills BOH O HO Fl Ο υ

S21-16-4-B 自 S21-14-B 及乙醛製備：4 NMR (400 MHz, CD3〇D) δ 7.28 (s, 1 H), 4.85-4.75 (m, 1 H), 4.10 (s, 1 H), 3.90-3.82 (m, 1 H), 3.40-2.90 (m, 6 H), 3.04 (s, 3 H), 2.96 (s, 3 H), 2.60-2.53 (m, 1 H), 2.42 (t, J = 14.2 Hz, 1 H), 2.35-2.10 (m, 4 H), 1.66 (dd, J= 14.0, 25.0 Hz, 1 H), 1.23 (t, J = 7.3 Hz, 3 H) ) ; MS (ESI) w/z 596.1 (M+H)。S21-16-4-B Preparation from S21-14-B and acetaldehyde: 4 NMR (400 MHz, CD3〇D) δ 7.28 (s, 1 H), 4.85-4.75 (m, 1 H), 4.10 (s , 1 H), 3.90-3.82 (m, 1 H), 3.40-2.90 (m, 6 H), 3.04 (s, 3 H), 2.96 (s, 3 H), 2.60-2.53 (m, 1 H) , 2.42 (t, J = 14.2 Hz, 1 H), 2.35-2.10 (m, 4 H), 1.66 (dd, J = 14.0, 25.0 Hz, 1 H), 1.23 (t, J = 7.3 Hz, 3 H )); MS (ESI) w/z 596.1 (M+H).

S21-16-5-A 自S21-13-A藉由脫甲矽基及氫化反應製備：4 NMR (400 MHz, CD3OD) δ 7.28 (s, 1 Η), 4.80-4.70 (m, 1 Η), 4.09 (s, 1 Η), 3.96-3.87 (m, 1 Η), 3.40-3.32 (m, 1 Η), 284 201245116 • 3.25-2.90 (m, 11 Η), 2.63-2.53 (m, 1 Η), 2,44 (t, J = 14.7 Hz 1 H), 2.35-2.05 (m, 4 H)，1.77-1.55 (m，3 H), 0.92 (t «/= 7 'S21-16-5-A Prepared from S21-13-A by demethylation and hydrogenation: 4 NMR (400 MHz, CD3OD) δ 7.28 (s, 1 Η), 4.80-4.70 (m, 1 Η) , 4.09 (s, 1 Η), 3.96-3.87 (m, 1 Η), 3.40-3.32 (m, 1 Η), 284 201245116 • 3.25-2.90 (m, 11 Η), 2.63-2.53 (m, 1 Η ), 2,44 (t, J = 14.7 Hz 1 H), 2.35-2.05 (m, 4 H), 1.77-1.55 (m, 3 H), 0.92 (t «/= 7 '

Hz，3 H) ; MS (ESI) w/z 610.1 (M+H)。Hz, 3 H) ; MS (ESI) w/z 610.1 (M+H).

非對哄共稱篮BOH O HO fl Ο ONon-confrontation basket BOH O HO fl Ο O

S21-16-5-B 自S21-13-B藉由脫甲石夕基及虱化反應製備：nMR (400 MHz, CD3OD) δ 7.41 (s, 1 Η), 4.85-4.75 (m, 1 Η), 4.14 (s, 1 Η), 3.95-3.87 (m, 1 Η), 3.42-3.33 (m, 1 Η), 3.22 (dd, J = 3.9, 15.6 Hz, 1 H), 3.15-2.90 (m, 10 H), 2.61-2.50 (m, 1 H), 2.40 (t, /= 14.9 Hz, 1 H), 2.38-2.22 (m, 4 H), 1.72-1.56 (m, 3 H), 0.90 (t, J = 7.6 Hz, 3 H) ； MS (ESI) m/z 610.1 (M+H) 〇S21-16-5-B Prepared from S21-13-B by de-plating and deuteration: nMR (400 MHz, CD3OD) δ 7.41 (s, 1 Η), 4.85-4.75 (m, 1 Η ), 4.14 (s, 1 Η), 3.95-3.87 (m, 1 Η), 3.42-3.33 (m, 1 Η), 3.22 (dd, J = 3.9, 15.6 Hz, 1 H), 3.15-2.90 (m , 10 H), 2.61-2.50 (m, 1 H), 2.40 (t, /= 14.9 Hz, 1 H), 2.38-2.22 (m, 4 H), 1.72-1.56 (m, 3 H), 0.90 ( t, J = 7.6 Hz, 3 H) ; MS (ESI) m/z 610.1 (M+H) 〇

非對呎共稱瓶A 〇 HO H ◦ ^Non-confrontation bottle A 〇 HO H ◦ ^

S21-16-7-A 自S21-14-A及溴乙酸第三丁酯開始，接著脫甲矽基及 氫化反應來製備：4 NMR (400 MHz，CD3OD) 5 7.28 (s，1 Η), 4.78-4.95 (m, 1 Η), 4.09 (br s, 3 H), 3.55-3.45 (m, 1 H), 3.30-2.98 (m, 5 H), 3.04 (s, 3 H), 2.95 (s, 3 H), 2.93-2.53 (m, 1 H), 2.47-2.13 (m, 4 H), 1.70-1.58 (m, 1 H) ； MS (ESI) m/z 626.3 (M+H)。S21-16-7-A is prepared starting from S21-14-A and tributyl bromoacetate, followed by demethylation and hydrogenation: 4 NMR (400 MHz, CD3OD) 5 7.28 (s, 1 Η), 4.78-4.95 (m, 1 Η), 4.09 (br s, 3 H), 3.55-3.45 (m, 1 H), 3.30-2.98 (m, 5 H), 3.04 (s, 3 H), 2.95 (s , (3, H), 2.

285 201245116285 201245116

S21-17-1-B 在〇°C下向存於硫酸（1 mL)中之化合物S21-16-1-B (76 mg，0.1 3 mmol，1當量）中添加石肖酸納（1 3 mg，〇. 1 5 mmol ’ 1.2當量）。在0°C下攪拌反應溶液30分鐘且逐滴 添加至經攪拌之乙醚（100 mL )中。將沈澱物收集於小型 石夕藻土墊上’再用乙醚（1〇 mLX3 )洗滌，且用甲醇（20 mL) 洗提。將f醇洗提液濃縮至乾燥，得到呈黃色固體狀之石肖 基中間物：MS (ESI) w/z 613.1 (M+H) 〇 將上述硝基中間物溶解於〇· i N HC1之甲醇（5 mL )溶 液中。添加10% Pd-C (52 mg，0.2當量）。反應容器用氫 氣吹拂且在室溫下在氫氣（i atm)下攪拌丨小時。用小型 石夕藻土塾濾出催化劑且用甲醇（2 mLx3 )洗滌。將甲醇渡 液濃縮至乾燥。進行製備型逆相HPLC純化，得到呈黃色固 體狀之所需產物S21.17-1-B (42 mg ’三鹽酸鹽，59%，經 ^ ^ ) ： 5.05-4.90 (m, 1 H), 4.12 (s, 1 H), 3.52-3.45 (m, 1 H)&gt; 3.13 (dd, /= 4.3, 15.5 Hz, 1 H), 3.l〇.2.9〇 (nij 2 H)? ^ (s, 3 H)j 2.96 (s, 3 H), 2.50-2.15 (m, 6 H)} 1&gt;63 (dd&gt; y j •，25·〇 Hz，1 H) ; MS (ESI) m/z 583.1 (M + H)。. 實施例22·合成其中環E為哌啶_2•基之式i化合物 .根據以下流程22合成式Ϊ化合物，其中Xt〇cF3, Y 马-Η且環e為哌啶_2_基。 流程22 286 201245116S21-17-1-B Adds succinate (1 3 ) to compound S21-16-1-B (76 mg, 0.1 3 mmol, 1 eq.) in sulfuric acid (1 mL) at 〇 °C Mg, 〇. 1 5 mmol '1.2 equivalents). The reaction solution was stirred at 0 ° C for 30 minutes and added dropwise to a stirred diethyl ether (100 mL). The precipitate was collected on a small pad of celite and washed again with diethyl ether (1 mL mL) and eluted with methanol (20 mL). The f alcohol eluate was concentrated to dryness to give a succinyl intermediate as a yellow solid: MS (ESI) w/z 613.1 (M+H) 〇 The above nitro intermediate was dissolved in methanol of 〇· i N HC1 ( 5 mL) in solution. 10% Pd-C (52 mg, 0.2 eq.) was added. The reaction vessel was purged with hydrogen and stirred at room temperature under hydrogen (i atm) for a few hours. The catalyst was filtered off with a small celite and washed with methanol (2 mL×3). The methanol mixture was concentrated to dryness. Purification by preparative reverse phase HPLC gave the desired product S21.17-1-B (42 mg &lt;RTI ID=0.0&gt;&gt; , 4.12 (s, 1 H), 3.52-3.45 (m, 1 H)&gt; 3.13 (dd, /= 4.3, 15.5 Hz, 1 H), 3.l〇.2.9〇(nij 2 H)? ^ ( s, 3 H)j 2.96 (s, 3 H), 2.50-2.15 (m, 6 H)} 1&gt;63 (dd&gt; yj •,25·〇Hz,1 H) ; MS (ESI) m/z 583.1 (M + H). Example 22. Synthesis of a compound of formula i wherein ring E is piperidine_2. The compound of formula , is synthesized according to the following Scheme 22, wherein Xt〇cF3, Y is Η-Η and ring e is piperidinyl-2-yl. Flow 22 286 201245116

OBn S21-9OBn S21-9

a) n-BuLi b) |^NBoca) n-BuLi b) |^NBoc

DM BA Pd(PPh3)4DM BA Pd(PPh3)4

根據流程22製備以下化合物。The following compounds were prepared according to Scheme 22.

OBn 0 OCF^ CH3 C02Ph S22-1 合成化合物S22-1。 在-100°C 下在 N2 下向 S21-9 ( 1 g，2.10 mmol )於無水 THF ( 1 0 mL )中之溶液中緩慢添加BuLi ( 1 mL，2.5 mmol， 1.2當量）。在-100 °C下檟:拌所得洋紅（carmine)溶液20 分鐘。在此溫度下將存於無水THF ( 3 mL )中之2-側氧基 派0定-1-甲酸第三丁酯（460 mg，2.30 mmol，1.1當量）添 287 201245116 加至溶液中。 C下攪拌1小時。反應物之 添加至NhCl水溶液中。用 縮且利用矽膠（以10〇/〇 Et0 付到 S 2 2 -1 ( 1 σ，β . 。溶液再在-loot下攪拌5分鐘，且接著在_78 小時。反應物之顏色緩慢地變成黃色。將溶液 •^水溶液中。用CH2C12 ( 4x10 mL )萃取，濃 隊（以10% ptOAc之石油醚溶液洗提）純化， ' (1 g ’ 80〇/〇) ： *HNMR (400 MHz, CDC13) δ 7.24-7.41 (m，8H)，7 〇l 7 〇7 (% 3H)，5 i6 (s，2h)，4 (s， 1H)，2.87-2.91 (m，2H)，2.43 (s，3H)，2.30-2.32 (m, 2H)，OBn 0 OCF^ CH3 C02Ph S22-1 Synthesis of compound S22-1. BuLi (1 mL, 2.5 mmol, 1.2 eq.) was slowly added to a solution of S21-9 (1 g, 2.10 mmol) in anhydrous THF (10 mL). - at -100 °C: Mix the resulting carmine solution for 20 minutes. To the solution was added 287 201245116 of 2-tert-oxy-t-butyl-1-carboxylic acid tert-butyl ester (460 mg, 2.30 mmol, 1.1 eq.) in anhydrous THF (3 mL). Stir for 1 hour at C. The reactant was added to an aqueous solution of NhCl. Use shrinking and use silicone (apply to 10 2 / 〇 Et0 to S 2 2 -1 ( 1 σ, β .. the solution is stirred at -loot for 5 minutes, and then at _78 hours. The color of the reaction slowly becomes Yellow. Add the solution to the aqueous solution. Purify with CH2C12 (4x10 mL), concentrate (extract with 10% ptOAc in petroleum ether), '(1 g '80〇/〇): *HNMR (400 MHz, CDC13) δ 7.24-7.41 (m,8H),7 〇l 7 〇7 (% 3H),5 i6 (s,2h),4 (s, 1H),2.87-2.91 (m,2H),2.43 (s , 3H), 2.30-2.32 (m, 2H),

1.52-1.55 (mj 411),1.42 (s, 9H)； MS (ESI) m/z 502.2 (M-Boc)〇 S22-2 合成化合物3Ί2-2。 向 S22-l ( 1.5 g，2.5 mmol)於 CH2C12 ( 20 mL)中之 溶液中添加TFA ( 10 mL)與CH2C12 ( l〇 mL)之混合物。 在20 C下攪拌所得淺黃色溶液2小時。濃縮反應混合物， 得到粗物質S22-2，在無純化的情況下將其直接用於下一步1.52-1.55 (mj 411), 1.42 (s, 9H); MS (ESI) m/z 502.2 (M-Boc) 〇 S22-2 Synthesis of compound 3Ί2-2. A mixture of TFA (10 mL) and CH2C12 (1 mL) was added to a solution of S22-l (1.5 g, 2.5 mmol) in CH2C12 (20 mL). The resulting pale yellow solution was stirred at 20 C for 2 hours. The reaction mixture was concentrated to give the crude material S22-2, which was used directly in the next

驟中.MS (ESI) m/z 484.2 (M+H)。 S22-3 合成化合物S22-3。 向S22-2 (2g，粗物質）於ι，2-二氯乙烧（20 mL· )中 之溶液中添加NaBH4 ( 400 mg )。在20。(：下攪拌所得棕色 201245116 溶液2小時。藉由添加NaHC〇3水溶液（1 mL )中止反應 混合物且用CH2C12 ( 20 mLx4 )萃取。濃縮萃取物，得到粗 物質S22-3 ’在無純化的情沉下將其直接用於下一步驟中： MS (ESI) w/z 486.2 (M+H)。MS (ESI) m/z 484.2 (M+H). S22-3 Synthesis of compound S22-3. To a solution of S22-2 (2 g, crude material) in EtOAc, EtOAc (EtOAc) At 20. (: The obtained brown 201245116 solution was stirred for 2 hours. The reaction mixture was quenched by the addition of aqueous NaHC 3 (1 mL) and extracted with CH2C12 (20 mL×4). The extract was concentrated to give crude material S22-3. Sink it and use it directly in the next step: MS (ESI) w/z 486.2 (M+H).

S22-4 合成化合物S22-4。 向S22-3( 2 g粗物質）及3-溴丙稀（400 mg)於CH3CN (10mL)中之溶液中添加K2CO3 ( 500 mg)。在3〇t下撥 拌混合物2小時《過濾混合物，濃縮且純化，得到呈淺黃 色油狀之 S22-4( 700 mg，54%，經 3 個步驟）：MS (ESI) m/z 526.2 (M + H)。S22-4 Synthesis of compound S22-4. K2CO3 (500 mg) was added to a solution of S22-3 (2 g of crude material) and 3-bromopropyl (400 mg) in CH3CN (10 mL). The mixture was stirred at 3 Torr for 2 hours. The mixture was filtered, concentrated and purified to give EtOAc (EtOAc, m. M + H).

ΟΒη Ο HO = Ο 0Bn OTBS S22-5 合成化合物S22-5。 在-78°C 下向二異丙胺（1.70 mL，12 mmol)於 THF ( 5 mL )中之溶液中逐滴添加nBuLi ( 4.8 mL，12 mmol，2.5 Μ 己烷溶液）。在-78°C下攪拌反應物30分鐘。向溶液中添加 TMEDA ( 3_5 mL，24 mmol，2 當量）。在-78 °C 下將上述 LDA 溶液（2.5 mL)逐滴添加至 S22-4( 550 mg，1·05 mmol， 1 ·〇當量）於THF ( 2.0 mL )令之混合物中，得到深紅色溶 289 201245116 液。在-78t：下攪拌混合物l〇分鐘。在-78°(：下向溶液中逐 滴添加存於THF ( 2.0 mL )中之烯酮S2-1 (507 mg，1.05 mmol，1.0當量）。反應物之顏色變成黃色。在授拌下黃色 溶液經1小時之時期自-78°C逐漸升溫至0°C。反應物以氣 化銨飽和水溶液（20 mL )中止且用CH2C12 ( 4x20 mL )萃 取。濃縮萃取物且藉由製備型TLC純化，得到S22-5 ( 600 mg，63%) : MS (ESI) m/z 457.8 (M/2+H)。ΟΒη Ο HO = Ο 0Bn OTBS S22-5 Synthesis of compound S22-5. To a solution of diisopropylamine (1.70 mL, 12 mmol) in THF (5 mL), EtOAc (EtOAc, EtOAc. The reaction was stirred at -78 °C for 30 min. To the solution was added TMEDA (3_5 mL, 24 mmol, 2 eq.). The above LDA solution (2.5 mL) was added dropwise to a mixture of S22-4 (550 mg, 1.05 mmol, 1 · 〇 equivalent) in THF (2.0 mL) at -78 °C to give a deep red solution. 289 201245116 Liquid. The mixture was stirred at -78 t: for 1 minute. The enone S2-1 (507 mg, 1.05 mmol, 1.0 eq.) in THF (2.0 mL) was added dropwise at -78[deg.] (the lower portion of the solution. The color of the reaction turned yellow. The solution was gradually warmed from -78 ° C to 0 ° C over a period of 1 h. The reaction was quenched with a saturated aqueous solution of ammonium sulfate (20 mL) and extracted with CH2C12 (4×20 mL). The extract was concentrated and purified by preparative TLC , S22-5 (600 mg, 63%): MS (ESI) m.

S22-6 合成化合物S22-6。 向 S22-5 ( 700 mg ’ 0.77 mmol)及 DMBA ( 359 mg， 2.30 mmo丨，3當量）於CH2Cl2(1〇 mL)中之溶液中添加S22-6 Synthesis of compound S22-6. Add to S22-5 (700 mg '0.77 mmol) and DMBA (359 mg, 2.30 mmo丨, 3 equivalents) in CH2Cl2 (1 mL)

Pd(PPh3)4 ( 178 mg，1.15 mmol，0.2 當量）。在 n2 下在 35 °C油浴中加熱所得淺黃色溶液24小時。濃縮反應混合物， 得到粗物質S22-6,其直接用於下一步驟中：ms(esi)w/z 437.8 (M/2 + H) °Pd(PPh3)4 (178 mg, 1.15 mmol, 0.2 eq.). The resulting pale yellow solution was heated in a 35 ° C oil bath for 24 hours under n2. The reaction mixture was concentrated to give the crude material S22-6, which was used directly in the next step: ms (esi) w/z 437.8 (M/2 + H) °

合成 S22-1-1 〇 向S22-6 ( 50 mg)於1&gt;2-二氣乙烷（5 ^中之溶液 290 201245116 • 中添加0·2 mL甲醛水溶液。添加NaBH(OAc)3 ( 50 mg)， 且攪拌反應混合物2小時。藉由添加NaHC〇3水溶液將溶液 調節至鹼性pH值且用CHAl2 (20mLx4)萃取。濃縮萃取 物，得到粗物質S22-7，其直接用於下一步驟中：MS (ESI) w/z 444.7 (M/2 + H)。Synthesis of S22-1-1 〇 to S22-6 (50 mg) in 1&gt;2-di-ethane (5^ solution 290 201245116 • Add 0. 2 mL of formaldehyde solution. Add NaBH(OAc)3 ( 50 (mg), and the reaction mixture was stirred for 2 hours. The solution was adjusted to basic pH with aqueous NaH.sub.3 solution and extracted with CH.sub.2.sub.2 (20 mL.sup.4). In the step: MS (ESI) w/z 444.7 (M/2 + H).

OH O HO Η 〇 Ο S22-8-1 合成化合物sus-ι。 向S22-7-1 ( 50 mg粗物質）於THF ( 3 mL)中之溶液 中添加HF(3mL)。在室溫下攪拌所得淺黃色溶液2小時。 濃鈿反應混合物。將該物質再次溶解於甲醇（5 )及甲 醇/HC1 (〇.5mL)中，且添加pd/c (5mg)。在％下在室 概下攪拌混合物2小時。過濾反應混合物，濃縮且藉由製 備型逆相HPLC純化，得到sm]之非對映異構體（6 6 mg + 8.3 mg)。 S22-8-1-A (非對映異構體 a ):丨η NMR (400 MHz， CD3OD) (5 7.31 (s, l Η), 4.48-4.50 (m, 1 Η), 4.14 (s, 1 Η), 3.72 (m, 1 Η), 3.36-3.42 (m, 1 Η), 3.04-3.28 (m5 9 Η), 2-73 (s, 3 Η), 2.46-2.49 (m, 1 H), 2.21-2.30 (m, 1 H), 1.94 2.10 (m} 6 H), 1.62-1.66 (rrij χ H) ； MS (ESI) m/z 596.3 (M + H)。 S22-8_l-B (非對映異構體 B ) : 1h nMR (4〇〇 MHz， CD3OD) δ 7.32 (s, 1 4.49.4 53 (m, 1 H), 4.15 (s, 1 H), 291 201245116 3.65-3.74 (m，1 h)，3.40-3.42 (m，1 Η), 3.00-3.27 (m，9 Η), 2.60 (s，3 H)，2.43-2.47 (m，1 H)，2.25-2.29 (m，1 H)，2_07 -2.27 (m, 6 H), 1.70-1.75 C01» 1 H) : MS (ESI) m/z 596.2 (M+H)。 根據與關於S 2 2 - 8 -1所述類似之方法製備以下化合物。OH O HO Η 〇 Ο S22-8-1 Synthetic compound sus-ι. HF (3 mL) was added to a solution of EtOAc (3 mL). The resulting pale yellow solution was stirred at room temperature for 2 hours. Concentrate the reaction mixture. This material was redissolved in methanol (5) and methanol/HC1 (〇. 5 mL), and pd/c (5 mg) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, concentrated and purified by preparative reverse phase HPLC to afford sm. S22-8-1-A (diastereomer a): 丨η NMR (400 MHz, CD3OD) (5 7.31 (s, l Η), 4.48-4.50 (m, 1 Η), 4.14 (s, 1 Η), 3.72 (m, 1 Η), 3.36-3.42 (m, 1 Η), 3.04-3.28 (m5 9 Η), 2-73 (s, 3 Η), 2.46-2.49 (m, 1 H) , 2.21-2.30 (m, 1 H), 1.94 2.10 (m} 6 H), 1.62-1.66 (rrij χ H) ; MS (ESI) m/z 596.3 (M + H). S22-8_l-B (Non Enantiomer B) : 1h nMR (4〇〇MHz, CD3OD) δ 7.32 (s, 1 4.49.4 53 (m, 1 H), 4.15 (s, 1 H), 291 201245116 3.65-3.74 (m , 1 h), 3.40-3.42 (m,1 Η), 3.00-3.27 (m,9 Η), 2.60 (s,3 H),2.43-2.47 (m,1 H), 2.25-2.29 (m,1 H), 2_07 - 2.27 (m, 6 H), 1.70-1.75 C01» 1 H) : MS (ESI) m/z 596.2 (M+H), according to the same as described for S 2 2 - 8 -1 Methods The following compounds were prepared.

S22-8-2-A S22-8-2-A。自S22-6開始，遵循脫曱矽基及氩化反應 來製備：NMR (400 MHz，CD3OD) δ 7.20 (s, 1 Η), 4.46-4.48 (爪，1 Η)，4.15 (s，1 Η)，3.55-3.59 (m，1 Η)， 2.98-3.32 (仿，l〇 Η)，2.42-2.46 (m，1 Η)，2.24-2.28 (m，1 Η)， 1.65-2.12 (如，7 Η) ; MS (ESI) m/z 582.1 (Μ+Η)。S22-8-2-A S22-8-2-A. Prepared from S22-6 following deamination and argonization: NMR (400 MHz, CD3OD) δ 7.20 (s, 1 Η), 4.46-4.48 (claw, 1 Η), 4.15 (s, 1 Η) ), 3.55-3.59 (m,1 Η), 2.98-3.32 (imitation, l〇Η), 2.42-2.46 (m,1 Η), 2.24-2.28 (m,1 Η), 1.65-2.12 (eg, 7 Η) ; MS (ESI) m/z 582.1 (Μ+Η).

非對映ίNon-optical ί

S22-8-2-B S22-8-2-B。自S22-6開始，遵循脫甲矽基及氫化反應 來製備：4 NMR (400 MHz, CD3OD) δ 7.25 (s, 1H), 4.50-4.52 (m, 1H), 4.15 (s, 1H), 3.50-3.53 (m, 1H), 2.99-3.32 (m, 10H), 2.42-2.47 (m, 1H), 2.25-2.30 (m, 1H), 1.65-2.09 (m, 7H) ; MS (ESI) m/z 582.1 (M+H)。S22-8-2-B S22-8-2-B. Prepared from S22-6 following demethylation and hydrogenation: 4 NMR (400 MHz, CD3OD) δ 7.25 (s, 1H), 4.50-4.52 (m, 1H), 4.15 (s, 1H), 3.50 -3.53 (m, 1H), 2.99-3.32 (m, 10H), 2.42-2.47 (m, 1H), 2.25-2.30 (m, 1H), 1.65-2.09 (m, 7H) ; MS (ESI) m/ z 582.1 (M+H).

S22-8-3-A 292 201245116 S22-8_3_a。自S22-6及乙醛開始，接著脫甲矽基及氫 化反應來製備：NMR (4 00 MHz，CD3OD) 5 7.36 (s, 1H), 4.53-4.57 (m，ih)，4_15 (s，1H)，3.74-3.77 (m，1H)，2.87-3.26 (m, 12H), 2.41-2.47 (m, 1H), 2.25 -2.29 (m, 1H), 2.03-2.15 (m, 5H), 1.66-1.72 (m, 2 H), 1.22-1.26 (t, 7.2 Hz, 3H)； MS (ESI) m/.z 610.1 (M+H)=S22-8-3-A 292 201245116 S22-8_3_a. Prepared from S22-6 and acetaldehyde, followed by demethylation and hydrogenation: NMR (4 00 MHz, CD3OD) 5 7.36 (s, 1H), 4.53-4.57 (m, ih), 4_15 (s, 1H ), 3.74-3.77 (m, 1H), 2.87-3.26 (m, 12H), 2.41-2.47 (m, 1H), 2.25 -2.29 (m, 1H), 2.03-2.15 (m, 5H), 1.66-1.72 (m, 2 H), 1.22-1.26 (t, 7.2 Hz, 3H); MS (ESI) m/.z 610.1 (M+H)=

非對电、穴傅瓶ϋ OH Ο HO Η 〇 ^Non-electricity, hole Fu bottle ϋ OH Ο HO Η 〇 ^

S22-8-3-B S22-8-3-B。自S22-6及乙醛開始，接著脫曱矽基及氫 化反應來製備：NMR (400 MHz, CD3OD) δ 7.36 (s，1 Η), 4.53-4.57 (m, 1 Η), 4.15 (s, 1 Η), 3.82-3.85 (m, 1 Η), 2.88-3.29 (m，12 Η)，2.43-2.50 (m，1 Η)，2.25 -2.28 (m，1 Η)’ 2.01-2.07 (m&gt; 5 Η), 1.72-1.78 (m, 2 Η), 1.20-1.32 (t, /= 7.2 Ηζ，3 Η) ; MS (ESI) m/2 610.1 (Μ+Η)。S22-8-3-B S22-8-3-B. Prepared from S22-6 and acetaldehyde, followed by dehydration and hydrogenation: NMR (400 MHz, CD3OD) δ 7.36 (s, 1 Η), 4.53-4.57 (m, 1 Η), 4.15 (s, 1 Η), 3.82-3.85 (m, 1 Η), 2.88-3.29 (m,12 Η), 2.43-2.50 (m,1 Η), 2.25 -2.28 (m,1 Η)' 2.01-2.07 (m&gt; 5 Η), 1.72-1.78 (m, 2 Η), 1.20-1.32 (t, /= 7.2 Ηζ, 3 Η); MS (ESI) m/2 610.1 (Μ+Η).

非東π两偁猫A OH O HO Ο ΟNon-east π two 偁 cat A OH O HO Ο Ο

S22-8-4-A S22-8_4_a。自S22-6及丙醛開始，接著脫甲矽基及氫 化反應來製備：NMR (400 MHz, CD3OD) 5 7.35 (s，1 Η), 4.53-4.55 (m, 1 Η), 4.14 (s, 1 Η), 3.83-3.86 (m, 1 Η), 2.70-3.29 (m，12 Η)，2.05-2.50 (m，7 Η)，1.61-1.90 (m，4 Η)， 0.86-0.93 (m，3 Η) ; MS (ESI) m/z 624.1 (Μ + Η)。 293 201245116 HP、S22-8-4-A S22-8_4_a. Prepared from S22-6 and propionaldehyde, followed by demethylation and hydrogenation: NMR (400 MHz, CD3OD) 5 7.35 (s, 1 Η), 4.53-4.55 (m, 1 Η), 4.14 (s, 1 Η), 3.83-3.86 (m, 1 Η), 2.70-3.29 (m, 12 Η), 2.05-2.50 (m, 7 Η), 1.61-1.90 (m, 4 Η), 0.86-0.93 (m, 3 Η) ; MS (ESI) m/z 624.1 (Μ + Η). 293 201245116 HP,

非對映異構艘B OH O HO Η 〇 〇Diastereomeric vessel B OH O HO Η 〇 〇

S22-8-4-B S22-8-4-B。自S22-6及丙醛開始，接著脫甲矽基及氫 化反應來製備：4 NMR (400 MHz，CD3OD) &lt;5 7.38 (s，1 Η), 4.55-4.58 (m, 1 Η), 4.15 (s, 1 Η), 3.76-3.80 (m, 1 Η), 2.81-3.29 (m, 12 Η), 2.00-2.50 (m, 7 Η), 1.62-1.89 (m, 4 Η), 0.86-0.93 (t，3 Η) ; MS (ESI) w/z 624.1 (M+H)。S22-8-4-B S22-8-4-B. Prepared starting with S22-6 and propionaldehyde, followed by demethylation and hydrogenation: 4 NMR (400 MHz, CD3OD) &lt;5 7.38 (s, 1 Η), 4.55-4.58 (m, 1 Η), 4.15 (s, 1 Η), 3.76-3.80 (m, 1 Η), 2.81-3.29 (m, 12 Η), 2.00-2.50 (m, 7 Η), 1.62-1.89 (m, 4 Η), 0.86-0.93 (t, 3 Η); MS (ESI) w/z 624.1 (M+H).

S22-8-5-A S22-8-5-A。自S22-6及丙酮開始，接著脫曱矽基及氫 化反應來製備：NMR (400 MHz，CD3OD)占 7.35 (s，1 Η), 4.61-4.59 (m, 1 Η), 4.10 (s, 1 Η), 3.64-3.61 (m, 1 Η), 3.25-2.97 (m, 11 Η), 2.42 (m, 1 Η), 2.29-1.98 (m, 7 Η), 1.80-1.71 (m, 1 Η), 1.32-1.30 (d, J = 6.4 Hz, 3 H), 1.21-1.20 (d，·/= 6.4 Hz，3 H) ; MS (ESI) m/z 624_1 (M+H)。S22-8-5-A S22-8-5-A. Prepared from S22-6 and acetone, followed by dehydration and hydrogenation: NMR (400 MHz, CD3OD) 7.35 (s, 1 Η), 4.61-4.59 (m, 1 Η), 4.10 (s, 1 Η), 3.64-3.61 (m, 1 Η), 3.25-2.97 (m, 11 Η), 2.42 (m, 1 Η), 2.29-1.98 (m, 7 Η), 1.80-1.71 (m, 1 Η) , 1.32-1.30 (d, J = 6.4 Hz, 3 H), 1.21-1.20 (d, ·== 6.4 Hz, 3 H) ; MS (ESI) m/z 624_1 (M+H).

S22-7-6 ΟΒη Ο HO £ 〇 0Bn OTBS 合成化合物。 向S22-6 ( 50 mg)於CH2C12 ( 10 mL)中之溶液中添 加PyBOP ( 30 mg )、DIEA (0.2mL)及第三丁氧羰基胺基 294 201245116S22-7-6 ΟΒη Ο HO £ 〇 0Bn OTBS Synthetic compound. To a solution of S22-6 (50 mg) in CH2C12 (10 mL) was added PyBOP (30 mg), DIEA (0.2 mL) and &lt;RTI ID=0.0&gt;

(M-Boc)/2+H)。(M-Boc)/2+H).

S22-8-6-A S22_8_6-A。自S22-7-6開始，遵循脫甲矽基及氫化反 應來製備.NMR (400 MHz，CD3OD) 5 7.37 (s，1 H)， 6.42 (s，1 H)，4.74-4.80 (m，3 H)，4.40-4.43 (m，1 Η), 4.12-4.16 (m，1 H)，3.61-3.95 (m, 9 H)，2.59-2.99 (m，4 H)， 2-23-2.45 (m, 4 H), 1.95-2.10 (mj χ H) ； MS (ESI) m/z 639.0 (M+H)。S22-8-6-A S22_8_6-A. Prepared from S22-7-6, following demethylation and hydrogenation. NMR (400 MHz, CD3OD) 5 7.37 (s, 1 H), 6.42 (s, 1 H), 4.74-4.80 (m, 3) H), 4.40-4.43 (m, 1 Η), 4.12-4.16 (m, 1 H), 3.61-3.95 (m, 9 H), 2.59-2.99 (m, 4 H), 2-23-2.45 (m , 4 H), 1.95-2.10 (mj χ H); MS (ESI) m/z 639.0 (M+H).

S22-8-6-B S22-8-6-B。自S22-7-6開始，遵循脫甲矽基及氫化反 應來製備：4 NMR (400 MHz，CD3OD) δ 6.87 (s, 1 Η), 5·62 (s, 1 H), 4.01-4.09 (m, 3 H), 3.51-3.67 (m, 2 H), 2.97-3.21 (m，9 h)，1.65-2.39 (m，9 H) ; MS (ESI) m/z 639.2 (M+H)。 利用與S22-8-6-A所用類似之程序自S22-6及各別胺基 酸來製備以下化合物。S22-8-6-B S22-8-6-B. Prepared from S22-7-6 following demethylation and hydrogenation: 4 NMR (400 MHz, CD3OD) δ 6.87 (s, 1 Η), 5·62 (s, 1 H), 4.01-4.09 ( m, 3 H), 3.51-3.67 (m, 2 H), 2.97-3.21 (m, 9 h), 1.65-2.39 (m, 9 H); MS (ESI) m/z 639.2 (M+H). The following compounds were prepared from S22-6 and the respective amino acids using a procedure similar to that used for S22-8-6-A.

295 201245116295 201245116

S22-8-7-B S22-8-7-B ： 'H NMR (400 MHz, CD3OD) δ 6.88 (s, 1 H)» 5 84 (s, 1 H), 4.10-4.17 (m, 2 H), 3.63-3.70 (m, 1 H), 3.44-3.52 (m} 2 H), 3.12-3.16 (m, 2 H), 2.99-3.11 (m, 7 H), 2.7 5 (s,3 H), 1.5 9-2.3 8 (m, 9 H)； MS (ESI) m/z 65 3.3 (M + H) °S22-8-7-B S22-8-7-B : 'H NMR (400 MHz, CD3OD) δ 6.88 (s, 1 H)» 5 84 (s, 1 H), 4.10-4.17 (m, 2 H ), 3.63-3.70 (m, 1 H), 3.44-3.52 (m} 2 H), 3.12-3.16 (m, 2 H), 2.99-3.11 (m, 7 H), 2.7 5 (s, 3 H) , 1.5 9-2.3 8 (m, 9 H); MS (ESI) m/z 65 3.3 (M + H) °

S22-8-8-A S22-8-8-A ： 'H NMR (400 MHz, CD3OD) δ 6.75 (s, 1 H), 5.75 (m5 i H), 4.55-4.56 (m, 2 H), 4.12 (s, 1 H), 3.51-3.80 (m) 4 h), 2.92-3.25 (m, 11 H), 2.01-2.35 (m, 7 H), 1.3 1-1.89 (m，6 H) ; MS (ESI) m/z 693.1 (M + H)。S22-8-8-A S22-8-8-A : 'H NMR (400 MHz, CD3OD) δ 6.75 (s, 1 H), 5.75 (m5 i H), 4.55-4.56 (m, 2 H), 4.12 (s, 1 H), 3.51-3.80 (m) 4 h), 2.92-3.25 (m, 11 H), 2.01-2.35 (m, 7 H), 1.3 1-1.89 (m, 6 H) ; MS (ESI) m/z 693.1 (M + H).

S22-8-8-B S22-8-8-B ： *H NMR (400 MHz, CD3OD) δ 6.92 (s, 1 H)，5.67(m，1 H)，4.47-4.48 (m，2 H)，4.13 (s，1 H)，3.62-3.78 (m, 4 H), 2.99-3.23 (m, 11 H), 2.09-2.44 (m, 7 H), 1.61-1.92 (m，6 H) ; MS (ESI) m/z 693.3 (M+H)。S22-8-8-B S22-8-8-B : *H NMR (400 MHz, CD3OD) δ 6.92 (s, 1 H), 5.67 (m, 1 H), 4.47-4.48 (m, 2 H) , 4.13 (s, 1 H), 3.62-3.78 (m, 4 H), 2.99-3.23 (m, 11 H), 2.09-2.44 (m, 7 H), 1.61-1.92 (m, 6 H) ; MS (ESI) m/z 693.3 (M+H).

非重i·映..--Non-weight i·映..--

S22-8-9-B S22-8-9-B ： 'H NMR (400 MHz, CD3OD) δ 6.92 (s, 1 Η), 5.70 (m, 1 Η), 4.36 (s, 2 Η), 4.10 (s, 1 Η), 3.39-3.70 (m, 3 296 201245116 Η), 2.90-3.22 (m, 14 Η), 1.99-2.40 (m, 4 Η), 1.63-1.88 (m, 5 Η) ; MS (ESI) w/z 667.3 (Μ+Η)。 實施例23.合成其中環E為吡咯啶-2-基之式I化合物 根據流程23合成式I化合物，其中X為-F，Y為-H且 環E為吡咯啶-2-基。 流程23S22-8-9-B S22-8-9-B : 'H NMR (400 MHz, CD3OD) δ 6.92 (s, 1 Η), 5.70 (m, 1 Η), 4.36 (s, 2 Η), 4.10 (s, 1 Η), 3.39-3.70 (m, 3 296 201245116 Η), 2.90-3.22 (m, 14 Η), 1.99-2.40 (m, 4 Η), 1.63-1.88 (m, 5 Η); MS (ESI) w/z 667.3 (Μ+Η). Example 23. Synthesis of a compound of formula I wherein ring E is pyrrolidin-2-yl. A compound of formula I is synthesized according to Scheme 23 wherein X is -F, Y is -H and ring E is pyrrolidin-2-yl. Process 23

炫基化Hyun

OPhOPh

1) TFA/水 2) NaBH(OAc)3 /-PrMgCI1) TFA/water 2) NaBH(OAc)3 /-PrMgCI

tBu FtBu F

根據流程23製備以下化合物。The following compounds were prepared according to Scheme 23.

ΟΒη Ο S23-1 合成化合物S2S-1。 搭S7-7 ( 1.0 g，2.25 mmol) 、（ί) -第三丁基亞石黃醯胺 (328 mg，2.71 mmol)及 CuS〇4 ( 897 mg，5.62 mmol)於 甲苯（7 mL )中之溶液在60°C下攪拌隔夜。用矽藻土過濾 297 201245116 混合物且濃縮。藉由矽膠急驟層析（以己烷/EtOAc ( 1 :〇至 3:1 )洗提）純化殘餘物，得到S23-1 ( 9 1 0 mg，74% ) : 4 NMR (400 MHz, CDC13) δ 8.84 (s，1 Η)，7.52-7.47 (m，2 H)，7.41-7.23 (複合峰，6 H)，7.07-7.03 (m，2 H)，5.12 (s，2 Η), 2.38 (d, J = 2.4 Hz, 3 H), 1.30 (s, 9 H) ； MS (ESI) m/z 546.16 (M + H)。ΟΒη Ο S23-1 The compound S2S-1 was synthesized. Take S7-7 (1.0 g, 2.25 mmol), (ί)-T-butyl sulphate (328 mg, 2.71 mmol) and CuS〇4 (897 mg, 5.62 mmol) in toluene (7 mL) The solution was stirred overnight at 60 °C. Filter with diatomaceous earth 297 201245116 Mixture and concentrate. The residue was purified by EtOAc (EtOAc/EtOAc (EtOAc) δ 8.84 (s,1 Η), 7.52-7.47 (m,2 H), 7.41-7.23 (complex peak, 6 H), 7.07-7.03 (m, 2 H), 5.12 (s, 2 Η), 2.38 ( d, J = 2.4 Hz, 3 H), 1.30 (s, 9 H) ; MS (ESI) m/z 546.16 (M + H).

S23-2-A 合成化合物S23-2-A。 在-78°C 下向亞胺 S23-l ( 0.87 g，1.60 mmol)於 THF (8 mL )中之溶液中添加溴化烷基鎂（0.6 M THF溶液，8 mL，4_79 mmo1 )。攪拌混合物1小時。添加飽和氯化銨溶 液（8 mL ) ’且使混合物升溫至室溫。混合物以EtOAc ( 300 mL )稀釋，用飽和氣化銨溶液（2x50 mL )洗滌，且濃縮。 藉由石夕膠急驟層析（以己烷/EtOAc ( 1:0至7:3)洗提）純 化殘餘物’得到S23-2-A (約1 g)。S23-2-A Synthesis of compound S23-2-A. To a solution of the imine S23-l (0.87 g, 1.60 mmol) in THF (8 mL) was added &lt;RTI ID=0.0&gt;&gt;&gt; The mixture was stirred for 1 hour. A saturated ammonium chloride solution (8 mL) was added and the mixture was allowed to warm to room temperature. The mixture was diluted with EtOAc (300 mL)EtOAc. S23-2-A (about 1 g) was obtained by flash chromatography (purified by hexane/EtOAc (1:0 to 7:3)).

S23-3-A 合成化合物S23-3-A。 在 〇 C 下向 S23-2-A( 500 mg，0.76 mmol)於 THF ( 0.5 mL)中之溶液中添加TFA ( 4.5 mL)及水（3 mL)。混合 298 201245116 物在0°C下攪拌4小時且接著在5°C下儲存隔夜，添加 NaBH(OAc)3 ( 620 mg » 2.93 mmol)。在 〇°C 下擾拌溶液 ι 小時。將混合物冷卻至-20°C ’以NaOH( 50。/。水溶液，5 8 mL ) 中止，用MTBE ( 3x15 mL )萃取，脫水（Na2S04)，且濃 縮。藉由矽膠急驟層析（以己烷/EtOAc ( 1:〇至0:1 )至甲 醇/二氯曱烧（1:9)洗提）純化殘餘物，得到S23-3-A(297 mg» 82%) ： lH NMR (400 MHz, CDC13) δ 7.51-7.47 (m, 2 H)，7.40-7.23 (複合峰，6 H)，7.04 (d，J = 8·6 Hz，2 H)，5.08 (s, 2 H), 4.78-4.71 (m, 1 H), 3.30-3.22 (m, 1 H), 3.03-2.97 (m, 1 H), 2.32 (d, J= 2.4 Hz, 3 H), 2.21-1.82 (m, 4 H) ； MS (ESI) w/z 484.15 (M+H)。S23-3-A The compound S23-3-A was synthesized. To a solution of S23-2-A (500 mg, 0.76 mmol) in THF (0.5 mL), EtOAc (EtOAc) Mix 298 201245116 Stir at 0 °C for 4 hours and then store at 5 °C overnight, add NaBH(OAc)3 ( 620 mg. Spoil the solution for ι hours at 〇 °C. The mixture was cooled to -20 ° C. NaOH (50% aqueous solution, 5 8 mL). The residue was purified by flash chromatography eluting with EtOAc/EtOAc (EtOAc:EtOAc:EtOAc:EtOAc 82%) : lH NMR (400 MHz, CDC13) δ 7.51-7.47 (m, 2 H), 7.40-7.23 (complex peak, 6 H), 7.04 (d, J = 8·6 Hz, 2 H), 5.08 (s, 2 H), 4.78-4.71 (m, 1 H), 3.30-3.22 (m, 1 H), 3.03-2.97 (m, 1 H), 2.32 (d, J = 2.4 Hz, 3 H), 2.21-1.82 (m, 4 H) ; MS (ESI) w/z 484.15 (M+H).

對映異傅瓶《· OBn OOpposite Fu bottle "· OBn O

S23-4-AS23-4-A

合成化合物S23-4-A 在-60°C 下向溴化物 S23-3-A ( 291 mg，0.60 mmol )於 THF ( 10 mL)中之溶液中添加 z_PrMgCl-LiCl ( 2.3 mL 之 1.3 M THF溶液，3 .〇 mm〇i )。使混合物緩慢升溫至〇。〇且 在0°C下攪拌1.5小時。混合物以磷酸鹽緩衝液（pH = 7， 10 mL)中止且用MTBE ( 3x15 mL)萃取。將有機層合併， 脫水（Na2S04)且濃縮，得到 S23_4_a ( 235 mg，96%)： 4 NMR (400 MHz，CDCI3) 5 7.45-7.05 (複合峰，11 H)， 5.13 (s, 2 H), 4.41 (t, J = 7.3 Hz, 1 H), 3.18-3.01 (m, 2 H), 2.34 (d，·/= 2.4 Hz，3 H)，2.32-2.20 (m，1 H)，1.80-1.52 (複 299 201245116 合峰，3 Η) ; MS (ESI) m/z 405.97 (M+H)。Synthesis of Compound S23-4-A To a solution of the bromide S23-3-A (291 mg, 0.60 mmol) in THF (10 mL), EtOAc (3 mL) , 3 .〇mm〇i ). The mixture was allowed to warm slowly to hydrazine. The mixture was stirred at 0 ° C for 1.5 hours. The mixture was quenched with phosphate buffer (pH = 7, 10 mL) and extracted with MTBE (3×15 mL). The organic layers were combined, dried (Na2SO4) and concentrated to give EtOAc (EtOAc: EtOAc: EtOAc: 4.41 (t, J = 7.3 Hz, 1 H), 3.18-3.01 (m, 2 H), 2.34 (d,·/= 2.4 Hz, 3 H), 2.32-2.20 (m,1 H),1.80-1.52 (Review 299 201245116 Hefeng, 3 Η); MS (ESI) m/z 405.97 (M+H).

S23-5-A 合成化合物。 在-7〇°C 下向卜Pr2NH((M9 mL，h33 mm〇1)於 THf (3 mL )中之溶液中逐滴添加rt_BuLi溶液（〇 53 mL之2 5 M己烷溶液，1.33 mmol )。藉由移除冷卻浴使反應物升溫 至0C ’且隨後冷卻至-75C。添加TMEDA ( 0.20 mL，1.3 3 mmol )，且攪拌混合物5分鐘《向LDA溶液中逐滴添加胺 S23-4-A ( 235 mg ’ 0.58 mmol)於 THF ( 1 mL)中之溶液。 添加完成後，在-72°C下攪拌反應混合物20分鐘。使溫度冷 卻至·8 0°(：。逐滴添加烯酮S2-1 ( 280 mg，0.58 mmol)於 THF ( 1 mL)中之溶液。混合物經50分鐘緩慢升溫至-i〇 °C。混合物以飽和氣化銨溶液（3 mL )中止且用MTB E ( 2 5 mL )稀釋。混合物以飽和氯化銨溶液（3x10 mL )洗滌，脫 水（Na2S04 )且濃縮。藉由矽膠急驟層析（以己烷/EtOAc (1:0至0:1)至二氣甲烷/曱醇（1:9)洗提）純化殘餘物， 得到 S23-5-A( 231 mg’ 50%產率）：4 NMR (400 MHz，CDC13) δ 16.20 (s，1 Η)，7.50-7.05 (複合峰，11 Η)，5.35 (s，2 Η)， 5.22 (d, J= 12.2 Hz, 1 H), 5.17 (d, J= 12.2 Hz, 1 H), 4.39 (t, J= 7.6 Hz, 1 H), 3.96 (d, J= 10.4 Hz, 1 H), 3.22 (dd, J= 15.9, 4.9 Hz, 1 H), 3.10-3.00 (m, 1 H), 3.00-2.91 (m, 1 H), 2.5 5-2.05 (複合峰，11 H)，1.95-1.47 (複合峰，4 H)，0.82 (s，9 300 201245116S23-5-A Synthetic compound. Add rt_BuLi solution (〇53 mL of 2 5 M hexane solution, 1.33 mmol) to a solution of Pr2NH ((M9 mL, h33 mm〇1) in THf (3 mL) at -7 °C The reaction was warmed to 0 C ' by removing the cooling bath and then cooled to -75 C. TMEDA (0.20 mL, 1.3 3 mmol) was added and the mixture was stirred for 5 min. "Amine S23-4- was added dropwise to the LDA solution. A solution of A ( 235 mg '0.58 mmol) in THF (1 mL). After the addition was completed, the reaction mixture was stirred at -72 ° C for 20 minutes. The temperature was cooled to 80 ° (: dropwise addition of ketene a solution of S2-1 (280 mg, 0.58 mmol) in THF (1 mL). The mixture was slowly warmed to -1 ° C over 50 min. The mixture was quenched with saturated aqueous ammonium sulfate (3 mL) and used with MTB E ( 2 5 mL) diluted. The mixture was washed with saturated ammonium chloride solution (3×10 mL), dehydrated (Na 2 SO 4 ) and concentrated. EtOAc (1:0 to 0:1) to hexane The methane/furfuryl alcohol (1:9) was eluted to purify the residue to give S23-5-A ( 231 mg 50% yield): 4 NMR (400 MHz, CDC13) δ 16.20 (s, 1 Η), 7.50 -7.05 (composite peak, 11 Η), 5.35 ( s,2 Η), 5.22 (d, J= 12.2 Hz, 1 H), 5.17 (d, J= 12.2 Hz, 1 H), 4.39 (t, J= 7.6 Hz, 1 H), 3.96 (d, J = 10.4 Hz, 1 H), 3.22 (dd, J= 15.9, 4.9 Hz, 1 H), 3.10-3.00 (m, 1 H), 3.00-2.91 (m, 1 H), 2.5 5-2.05 (composite peak , 11 H), 1.95-1.47 (composite peak, 4 H), 0.82 (s, 9 300 201245116

Η), 0.26 (s, 3 Η), 0.13 (s, 3 Η) ； MS (ESI) m/z 794.49 (M+H) 〇Η), 0.26 (s, 3 Η), 0.13 (s, 3 Η); MS (ESI) m/z 794.49 (M+H) 〇

S23-6-1-A 合成化合物S2Z-6-1-A。 向存於二氯甲烷（1 mL)中之S23-5-A ( 50 mg)中添 加 NaBH(OAc)3 ( loo mg)及曱醛（37%水溶液，〇Λ mL)。 混合物在室溫下攪拌！小時且隨後以ΜΤΒΕ( 2〇 mL )稀釋。 有機層以W酸鹽緩衝液（pH = 7，2x7 mL )洗務，脫水 (Na2S〇4)且濃縮。藉由矽膠急驟層析（以己烷/EtOAc( 1:〇 至1.1 )洗提）純化殘餘物，得到S23_6-l-A : MS (ESI) m/z 808.45 (M+H)。S23-6-1-A Synthesis of compound S2Z-6-1-A. NaBH(OAc)3 (loo mg) and furfural (37% aqueous solution, 〇Λ mL) were added to S23-5-A (50 mg) in dichloromethane (1 mL). The mixture is stirred at room temperature! Hour and then dilute with ΜΤΒΕ (2〇 mL). The organic layer was washed with W-acid buffer (pH = 7, 2 x 7 mL), dehydrated (Na.sub.2) and concentrated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

S23-7-1-A 合成化合物。 向化合物S23-5-A ( 25 mg )於1，4-二噁烷（丨5 mL ) 中之溶液中添加HF溶液（〇·5 mL之48%水溶液）。撥拌混 合物3小時且隨後以磷酸氫二鉀溶液（自5 g K2HP〇4及5 mL 水製備）中止。用Et0Ac ( 2χ10 )萃取混合物。將所有有機 層合併，脫水（NkSO4)且濃縮。向殘餘物之甲醇/二噁烷 溶液（2:1，3 mL)中添加鈀/碳（2〇 mg，5 wt%)。在h2 (氣球）下授拌反應物1小時。經由小型石夕藻土塞過滅混 合物且用甲醇沖洗。濃縮濾液，得到粗產物。在Waters自 301 201245116 動純化系，統上使用 Phenomenex Polymerx 1〇 &quot; rp_ γ 100Α 管柱[10 以 m ’ 150x21.2〇 mm ;流速：2〇 mL/min ;溶 劑A: 0.05 N HC1/水；溶劑B:甲醇；注入體積：！ 8 mL( 〇 〇5 N HC1/水）；梯度：〇— 100% b，經25分鐘；質量導向型 洗提份收集]進行製備型逆相HPLC純化。收集在u 112 4 分鐘洗提之具有所需分子量之洗提份且冷凍乾燥，得到5 Η mg S23-7-1-A ： 'h NMR (400 MHz, CD3〇D) § 6.98 (d / = 6.1 Hz，1 H)，4.87-4.79 (m，1 H)，4.09 (s，1 H), 3.49-3.42 (m 2 H)，3.24-2.94 (複合峰，9 H)，2.55-2.12 (複合峰，6 &quot;0-1.58 (m，1 H) ; MS (ESI) m/z 502.23 (M+H)。S23-7-1-A Synthetic compound. An HF solution (〇·5 mL of a 48% aqueous solution) was added to a solution of the compound S23-5-A (25 mg) in 1,4-dioxane (5 mL). The mixture was mixed for 3 hours and then quenched with dipotassium hydrogen phosphate solution (prepared from 5 g K2HP 〇 4 and 5 mL water). The mixture was extracted with Et0Ac (2χ10). All organic layers were combined, dehydrated (NkSO4) and concentrated. Palladium on carbon (2 mg, 5 wt%) was added to the residue in methanol / dioxane (2:1, 3 mL). The reaction was stirred for 1 hour under h2 (balloon). The mixture was passed through a small celite and washed with methanol. The filtrate was concentrated to give a crude material. In Waters from 301 201245116, the system was purified using Phenomenex Polymerx 1〇&quot; rp_ γ 100Α column [10 in m ' 150x21.2〇mm; flow rate: 2〇mL/min; solvent A: 0.05 N HC1/water Solvent B: methanol; injection volume:! 8 mL (〇 〇 5 N HC1/water); Gradient: 〇 - 100% b, 25 minutes; mass-directed elution fraction collection] Preparative reverse phase HPLC purification. The eluted fractions of the desired molecular weight eluted in u 112 for 4 minutes were collected and lyophilized to give 5 Η mg S23-7-1-A: 'h NMR (400 MHz, CD3〇D) § 6.98 (d / = 6.1 Hz, 1 H), 4.87-4.79 (m, 1 H), 4.09 (s, 1 H), 3.49-3.42 (m 2 H), 3.24-2.94 (complex peak, 9 H), 2.55-2.12 (composite Peak, 6 &quot;0-1.58 (m, 1 H); MS (ESI) m/z 502.23 (M+H).

S23-7-2-A 非對映：S23-7-2-A diastereoisomer:

S23-7-2-A:根據製備 S23-7-1-A 之程序自 s23-6_i_A 製備：1!! NMR (400 MHz, CD3OD) (5 7.09 ((1,7=5.5¾ 1 H)，4.75-4.67 (m，1 H)，4.10 (s，1 Η), 3.89-3.82 (m, i H) 3.〇4 (s，3 H)，2.96 (s，3 H)，3.26-2.94 (複合峰，4 H)，2 87 (s 3 H)，2.62-2.53 (m，1 H)，2.40-2.21 (複合峰，5 H)，1.70] 58 (m，1 H) ; MS (ESI) w/z 516.24 (M+H)。 實施例24·合成其中環e為吡咯啶-2-基之式i化合物 流程24 302 201245116S23-7-2-A: Prepared from s23-6_i_A according to the procedure for preparation of S23-7-1-A: 1!! NMR (400 MHz, CD3OD) (5 7.09 ((1,7=5.53⁄4 1 H), 4.75-4.67 (m,1 H), 4.10 (s,1 Η), 3.89-3.82 (m, i H) 3.〇4 (s,3 H), 2.96 (s,3 H), 3.26-2.94 ( Compound peak, 4 H), 2 87 (s 3 H), 2.62-2.53 (m, 1 H), 2.40-2.21 (complex peak, 5 H), 1.70] 58 (m, 1 H) ; MS (ESI) w/z 516.24 (M+H). Example 24·Synthesis of a compound of formula i wherein ring e is pyrrrolidine-2-yl. Scheme 24 302 201245116

1) PhLitTHF;nBuU 2) CH3l1) PhLitTHF; nBuU 2) CH3l

链或醐,NEt3 lnCI3, NaBH(OAc)3Chain or 醐, NEt3 lnCI3, NaBH(OAc)3

根據流程24製備以下化合物。 ohc、^^ch3 OBn 合成2-(苯f氧基h4_甲醯基_6_f基苯甲酸苯酯。 在-l〇〇°C下向 Sll_2 (5.00 g，12.6 mm〇i，i 當量）於 THF(4〇mL) t之溶液中逐滴添加正丁基鐘於己烧中之溶 液（2·5 Μ ’ 5‘29 mL，13.2 mm。卜 1.05 當量），維持内部 溫度低於_97。(：。在-100。(：下攪拌所得橙色溶液1〇分鐘，此 時經8分鐘逐滴添加所製得之dmF( 1.45 mL，18.9mmo卜 1.5當量）於THF ( 5 mL)中之溶液。使溶液升溫至-^^， 接著添加氯化銨飽和水溶液（2〇mL)。將所得混合物傾入 氣化銨飽和水溶液（20 mL)及水（20 mL)中且用EtOAc (2x5 0 mL )萃取。經合併之有機層經硫酸鋼脫水，過渡且 減壓濃縮。藉由矽膠急驟管柱層析（用3_4〇% Et〇Ac:己烷 303 201245116 作為洗提劑）純化所得油狀物，得到呈白色固體狀之標題 化合物（3.19 g，75% ) : 4 NMR (400 MHz, CDC13) δ 9.96 (s, 1 Η), 7.46-7.42 (2 Η), 7.39-7.30 (m, 7 Η), 7.27-7.22 (m, 1 Η), 7.09-7.05 (m, 2 Η), 5.21 (s, 2 Η), 2.51 (s, 3 Η) ； MS (ESI) m/z 345.14 (M-H)。The following compounds were prepared according to Scheme 24. Ohc, ^^ch3 OBn Synthesis of 2-(phenylf-oxyl h4_carbamimidyl-6-f-benzoic acid phenyl ester. To Sll_2 (5.00 g, 12.6 mm〇i, i equivalent) at -10 °C A solution of n-butyl oxime in hexane (2·5 Μ '5'29 mL, 13.2 mm. 1.05 eq.) was added dropwise to a solution of THF (4 〇 mL) t, maintaining the internal temperature below _97. (:. At -100. (: The resulting orange solution was stirred for 1 Torr, at which time a solution of the obtained dmF (1.45 mL, 18.9 mmo, 1.5 equivalents) in THF (5 mL) was added dropwise over 8 minutes. The solution was warmed to -^^, then a saturated aqueous solution of ammonium chloride (2 mL) was added. The mixture was poured into a saturated aqueous solution of ammonium sulfate (20 mL) and water (20 mL) with EtOAc (2×50 mL The combined organic layer is dehydrated by sulfuric acid steel, and the mixture is concentrated and concentrated under reduced pressure. The oil is purified by silica gel column chromatography (3_4〇% Et〇Ac: hexane 303 201245116 as eluent). The title compound (3.19 g, 75%) was obtained as a white solid: 4 NMR (400 MHz, CDC13) δ 9.96 (s, 1 Η), 7.46-7.42 (2 Η), 7.39-7.30 (m, 7 Η ), 7.27-7.22 (m, 1 Η), 7.0 9-7.05 (m, 2 Η), 5.21 (s, 2 Η), 2.51 (s, 3 Η); MS (ESI) m/z 345.14 (M-H).

S24-1-A 合成化合物mi-A。 根據與關於S23-3 (成環）及SI5·5 ( Boc保護及碘化） 所述類似之方法自2-(苯甲氧基）_4_曱醯基-6-曱基苯曱酸苯 S旨製備：iH NMR (400 MHz，CDC13，旋轉異構體）5 7.42-7.20 (m，8 H)，7.11 (d，7.8 Hz，2 H)，6.62-6.20 (m，1S24-1-A Synthesis of compound mi-A. According to a method similar to that described for S23-3 (ringing) and SI5·5 (Boc protection and iodination) from 2-(benzyloxy)_4_indolyl-6-mercaptobenzoic acid benzene S Preparation: iH NMR (400 MHz, CDC13, rotamer) 5 7.42-7.20 (m, 8 H), 7.11 (d, 7.8 Hz, 2 H), 6.62-6.20 (m, 1

H), 5.17-5.05 (m, 3 H), 3.65-3.40 (m, 2 H), 2.56 (s, 3 H), 2.40-2.25 (m, 1 H), 1.85- 1.50 (m, 3 H), 1.47, 1.24 (s, s, 9 H) , MS (ESI) m/z 612.17 (M-H) 〇H), 5.17-5.05 (m, 3 H), 3.65-3.40 (m, 2 H), 2.56 (s, 3 H), 2.40-2.25 (m, 1 H), 1.85- 1.50 (m, 3 H) , 1.47, 1.24 (s, s, 9 H) , MS (ESI) m/z 612.17 (MH) 〇

S24-2-AS24-2-A

合成化合物S24H 向存於一·»惡烧（35 mL )中之化合物S24-1-A ( 605 mg， 〇·987 mmo卜1 eq)中添加HC1之二噁烷溶液（4 Μ，3 mL)。 析出白色固體。授拌8 〇分鐘後，將反應物小心地添加至碳 酸氣納溶液（飽和水溶液，70 mL )中，隨後用EtOAc ( 2χ 304 201245116 .50 mL)卒取。經合併之有機層經硫酸鈉脫水，過濾且減壓 農縮&amp;存於丙_ (15 mL )中之此粗中間物中添加碳酸钟 (211 mg ’ 1·5 3 mm〇1 ’ i 5 eq)，接著添加溴甲苯（152 ， 1·2 8 mmol ’ 1’3 eq)。將反應物加熱至5〇&lt;&gt;c持續3小時且 ^後在—氣甲烧洗》條下經由石夕_ 土過滤。減壓濃縮滤液且 ，由矽膠急驟管杈層析（洗提齊&quot;-30% EtOAc/己烷）純化， 得到呈無色油狀之S24_2 a ( 389叫，Μ%) : ^麗^ (柳 MHz, CDC13) δ 7.49 (s, 1 Η), 743-7.39 (m, 1 Η), 7.36-7.19 (m, 12 Η), 7.09-7.04 (m, 2 Η), 5.18 (d, J = 11.6 Hz, 1 H), 5.12(dJt/=：ii &lt; χτ b Hz, 1 H), 3.86 (t, J= 8.5 Hz, 1H), 3.81 (d, J —13.4 Hz 1 WA Ο λ 5 3.20 (dj /= 13.4 Hz, 1 H), 3.17-3.12 (m, 1 H), 2,57 (s 1 ^ ^ J H), 2.49-2.38 (m, 1 H), 2.31 (q, J= 8.5 Hz, 1 H), 1.84-1 74 Λ • 2H), 1.46-1.34 (m, 1 H) ； MS (ESI) m/z 602.13 (M-H) 〇Synthesis of Compound S24H To a solution of compound S24-1-A (605 mg, 〇·987 mmob 1 eq) in a ························· . A white solid precipitated. After 8 minutes of mixing, the reaction was carefully added to a solution of sodium carbonate (salt aqueous solution, 70 mL), and then was taken from EtOAc (2 χ 304 201245116 .50 mL). The combined organic layer was dehydrated with sodium sulfate, filtered and evaporated under reduced pressure &amp;&lt;RTIID=0.0&gt;&gt; Eq) followed by the addition of bromotoluene (152, 1·28 mmol '1'3 eq). The reaction was heated to 5 Torr &lt;&gt;c for 3 hours and then filtered under a strip of slag. The filtrate was concentrated under reduced pressure and purified by EtOAc EtOAc EtOAc (EtOAc) MHz, CDC13) δ 7.49 (s, 1 Η), 743-7.39 (m, 1 Η), 7.36-7.19 (m, 12 Η), 7.09-7.04 (m, 2 Η), 5.18 (d, J = 11.6 Hz, 1 H), 5.12 (dJt/=:ii &lt; χτ b Hz, 1 H), 3.86 (t, J= 8.5 Hz, 1H), 3.81 (d, J — 13.4 Hz 1 WA Ο λ 5 3.20 ( Dj /= 13.4 Hz, 1 H), 3.17-3.12 (m, 1 H), 2,57 (s 1 ^ ^ JH), 2.49-2.38 (m, 1 H), 2.31 (q, J= 8.5 Hz, 1 H), 1.84-1 74 Λ • 2H), 1.46-1.34 (m, 1 H) ; MS (ESI) m/z 602.13 (MH) 〇

合成化合物Z A。Synthesis of compound Z A.

在- 78。。it &amp; A L下向新鮮製備之LDA ( 1.28 mm〇l，於10 mL THF 中，2 4 p、 .ecl〕中添加 TMEDA( 240 μί，1 ·6〇 mmol，3 eq )。 攪拌5分鍺你 里便’逐滴添加化合物S24-2-A ( 387 mg，0.64 mmol &gt; 1 ο p, \ q )於THF ( 4 mL )中之溶液，之後以THF ( 1 mL )沖洗，他# 0 艰待内部溫度低於-7 0 C。所得紅色溶液在_ 7 8 °C下攪拌八 。At - 78. . It &amp; AL was added to freshly prepared LDA ( 1.28 mm 〇l, in 4 mL of THF, 2 4 p, .ecl) to add TMEDA (240 μί, 1 ·6 〇 mmol, 3 eq). Stir for 5 min. In your case, add the solution of the compound S24-2-A (387 mg, 0.64 mmol &gt; 1 ο p, \ q ) in THF (4 mL), then rinse with THF (1 mL). The internal temperature was less than -7 0 C. The resulting red solution was stirred at _78 °C.

刀鐘，隨後冷卻至-89 C。逐滴添加存於thF 305 201245116 (4mL)中之稀酬 S2-l(256 mg，0.53mmol，leq)，内 部溫度升至-7 8 °C。使反應物經1 〇 5分鐘逐漸升溫至-1 〇 °C。 添加NH4C1飽和水溶液（4 mL )。將混合物傾入NH4C1飽 和水溶液（20 mL)中且用EtOAc ( 2x50 mL)萃取。經合 併之有機層以1 N NaOH ( 2x25 mL ) 、NH4C1飽和水溶液 (30 mL )及鹽水（20 mL )洗滌，隨後經硫酸鈉脫水，過 濾且減壓濃縮。.使用2-25% EtOAc/己烷作為洗提劑進行矽 膠急驟層析，得到呈固體狀之所需產物S24_3_A ( 387 mg， 73%) ： 'H NMR (400 MHz, CDC13) &lt;5 16.00 (s, 1 H), 7.56 (s, 1 H), 7.51-7.46 (m, 2 H), 7.45-7.40 (m, 2 H), 7.39-7.24 (m, l〇 H), 5.3 5 (s, 2 H), 5.2 5 (d, J = 12.8 Hz, 1 H), 5.19 (d, / = 12.8 Hz, 1 H), 3.97 (d, J = 10.4 Hz, 1 H), 3.80 (t, 7= 7.9 Hz, 1 H), 3.77 (d, J = 13.4 Hz, 1 H), 3.3 6 (dd, J = 16.5, 4.9 Hz, 1 H), 3.25 (d, J= 4.0 Hz, 1 H), 3.21-3.13 (m, 1 H), 3.02-2.92 (m, 1 H), 2.61-2.27 (m, 10 H), 2.15 (d, J= 14.6 Hz, 1 H), 1.79 1.68 (m，2 H), 1.39-1.21 (m，2 H)，0.83 (s, 9 H)，0.27 (s，The knife clock is then cooled to -89 C. The dilute S2-l (256 mg, 0.53 mmol, leq) stored in thF 305 201245116 (4 mL) was added dropwise, and the internal temperature was raised to -7 8 °C. The reaction was gradually warmed to -1 〇 °C over 1 〇 5 minutes. A saturated aqueous solution of NH4C1 (4 mL) was added. The mixture was poured into aq. EtOAc (20 mL)EtOAc The combined organic layers were washed with 1N EtOAc (EtOAc) (EtOAc) The desired product S24_3_A (387 mg, 73%) was obtained as a solid: <H NMR (400 MHz, CDC13) &lt;5 16.00 (s, 1 H), 7.56 (s, 1 H), 7.51-7.46 (m, 2 H), 7.45-7.40 (m, 2 H), 7.39-7.24 (m, l〇H), 5.3 5 (s , 2 H), 5.2 5 (d, J = 12.8 Hz, 1 H), 5.19 (d, / = 12.8 Hz, 1 H), 3.97 (d, J = 10.4 Hz, 1 H), 3.80 (t, 7 = 7.9 Hz, 1 H), 3.77 (d, J = 13.4 Hz, 1 H), 3.3 6 (dd, J = 16.5, 4.9 Hz, 1 H), 3.25 (d, J = 4.0 Hz, 1 H), 3.21-3.13 (m, 1 H), 3.02-2.92 (m, 1 H), 2.61-2.27 (m, 10 H), 2.15 (d, J = 14.6 Hz, 1 H), 1.79 1.68 (m, 2 H ), 1.39-1.21 (m, 2 H), 0.83 (s, 9 H), 0.27 (s,

S24-4-1-A ( R = H ) S24-4-2-A ( R = CH3 ) 合成化合物324-444及S24 4 2 a。 在95 C下向S24_3_A ( 1〇7叫，〇 匪〇卜】⑷於 (mL)中之〉谷液中逐滴添加苯基鋰溶液（ism於乙 306 201245116 •鍵中，132叫，0.237 mmoi，2·2 eq)，維持溫度低於％ °C。在-95°C下揽拌所得暗黃色溶液10分鐘。添加正丁基鐘 之己烷溶液（1.6 Μ ’ 88 μί，0.14 mmo卜 1.3 叫）。在 _95 °c下攪拌所得橙色溶液ίο分鐘。添加碘代甲烧（34 gL，〇 54 mmol ’ 5 eq)，且使反應混合物經40分鐘緩慢升溫至_78 °C。添加NHUCl飽和水溶液（3 mL )，將反應物升溫至環 境溫度，且隨後傾入NHUC1飽和水溶液（1 〇 mL)中並用 EtOAc ( 2x3 5 mL )萃取。經合併之有機層經硫酸鈉脫水， 過濾，且減壓濃縮。經由矽膠急驟管柱層析（使用2-25% 丑1〇八〇/己烷作為洗提劑）純化，得到化合物824-4_2-人（17 mg，18% )以及化合物 S24-4-1-A ( 63 mg，68% )。化合物 S24-4-1-A: MS (ESI) mA 866.29 (M+H)。化合物 S24-4-2-A : 'Η NMR (400 MHz, CDC13) δ 16.24 (s, 1 H), 7.54-7.49 (m, 3 H)，7.48-7.44 (m，2 H), 7.42-7.27 (m，l〇 H)，7.26-7.21 (m， 1 H), 5.37 (s, 2 H), 5.27 (d, J = 12.2 Hz, 1 H), 5.19 (d, J = 12.2 Hz, 1 H), 4.07 (t, J= 6.7 Hz, 1 H), 4.04 (d, /= 10.4 Hz, 1 H), 3.82 (d, J = 13.4 Hz, 1 H), 3.65 (t, J = 7.9 Hz, 1 H), 3.19-3.04 (m，3 H)，3.01-2.91 (m，1 H)，2.60-2.43 (m，9 H)， 2.30-2.18 (m, 4 H), 2.12 (d, J = 14.0 Hz, 1 H), 1.87-1.67 (m, 2 H), 1.49-1.42 (m, 1 H), 0.84 (s, 9 H), 0.29 (s, 3 H), 0.16 (s, 3 H) ; MS (ESI) w/z 880.29 (M+H)。S24-4-1-A (R = H) S24-4-2-A (R = CH3) Compounds 324-444 and S24 4 2 a were synthesized. At 95 C, add phenyl lithium solution to S24_3_A (1〇7, 〇匪〇卜) (4) in the solution of (mL) in the solution. (ism in B 306 201245116 • Key, 132 call, 0.237 mmoi , 2·2 eq), maintain the temperature below % ° C. Mix the dark yellow solution for 10 minutes at -95 ° C. Add n-butyl hexane solution (1.6 Μ ' 88 μί, 0.14 mmo Bu 1.3 The resulting orange solution was stirred at _95 °c for ί. minutes, iodo methane (34 gL, 〇54 mmol '5 eq) was added, and the reaction mixture was slowly warmed to _78 ° C over 40 min. NHUCl was added. Aqueous saturated aqueous solution (3 mL), EtOAc EtOAc (EtOAc m. Concentration under reduced pressure. Purification via silica gel column chromatography (using 2-25% ugly hexanes/hexanes as eluent) afforded compound 824-4_2- human (17 mg, 18%) and compound S24- 4-1-A (63 mg, 68%). Compound S24-4-1-A: MS (ESI) mA 866.29 (M+H). Compound S24-4-2-A: 'Η NMR (400 MHz, CDC13 δ 16.24 (s, 1 H), 7.54-7.49 (m, 3 H), 7.48-7.44 (m, 2 H), 7.42-7.27 (m, l〇H), 7.26-7.21 (m, 1 H) , 5.37 (s, 2 H), 5.27 (d, J = 12.2 Hz, 1 H), 5.19 (d, J = 12.2 Hz, 1 H), 4.07 (t, J = 6.7 Hz, 1 H), 4.04 ( d, /= 10.4 Hz, 1 H), 3.82 (d, J = 13.4 Hz, 1 H), 3.65 (t, J = 7.9 Hz, 1 H), 3.19-3.04 (m, 3 H), 3.01-2.91 (m,1 H), 2.60-2.43 (m,9 H), 2.30-2.18 (m, 4 H), 2.12 (d, J = 14.0 Hz, 1 H), 1.87-1.67 (m, 2 H), 1.49-1.42 (m, 1 H), 0.84 (s, 9 H), 0.29 (s, 3 H), 0.16 (s, 3 H); MS (ESI) w/z 880.29 (M+H).

S24-5-1-A 307 201245116 S24-5-1-A。遵循如關於S23-7-1-A所述之脫曱矽基及 氫化反應，自 S24-4-1-A 製備：ΑΝΜΙΙΟΟΟΜΗζ,ΟΟβΟ) δ 6.94 (s, 1 Η), 6.91 (s, 1 Η), 4.64-4.55 (m, 1 Η), 4.12 (s, 1 Η), 3.55-3.40 (m, 2 Η), 3.16-2.83 (m, 9 Η), 2.57 (t, J = 14.0 Hz, 1 H), 2.55-2.45 (m, 1 H), 2.32-2.08 (m, 4 H), 1.66-1.52 (m，1 H) ; MS (ESI) m/z 484.14 (M+H)。S24-5-1-A 307 201245116 S24-5-1-A. Follow the deamination and hydrogenation reactions as described in S23-7-1-A, prepared from S24-4-1-A: ΑΝΜΙΙΟΟΟΜΗζ, ΟΟβΟ) δ 6.94 (s, 1 Η), 6.91 (s, 1 Η ), 4.64-4.55 (m, 1 Η), 4.12 (s, 1 Η), 3.55-3.40 (m, 2 Η), 3.16-2.83 (m, 9 Η), 2.57 (t, J = 14.0 Hz, 1 H), 2.55-2.45 (m, 1 H), 2.32-2.08 (m, 4 H), 1.66-1.52 (m, 1 H); MS (ESI) m/z 484.14 (M+H).

非對映異稱瓶A HO O HO ^ 〇 0Non-diametric bottle A HO O HO ^ 〇 0

S24-5-2-A S24-5_2_A。遵循如關於S23-7_l-A所述之脫甲矽基及 氫化反應’自 S24-4-2-A 製備：^ΝΜΙΙΟΟΟΜΗζ,ΟΟβΟ) δ 6.97 (s, 1 Η), 4.99-4.81 (m, 1 Η), 4.10 (s, 1 Η), 3.56-3.40 (m, 2 Η), 3.17 (dd, J = 15.9, 4.9 Hz, 1 H), 3.08-2.85 (m, 9 H), 2.56-2.46 (m, 1 H), 2.39-2.04 (m, 7 H), 1.70-1.57 (m, 1 H)； MS (ESI) m/z 498_14 (M+H) »S24-5-2-A S24-5_2_A. Follow the demethylation group and hydrogenation reaction as described in S23-7_l-A 'Prepared from S24-4-2-A: ^ΝΜΙΙΟΟΟΜΗζ,ΟΟβΟ) δ 6.97 (s, 1 Η), 4.99-4.81 (m, 1 Η), 4.10 (s, 1 Η), 3.56-3.40 (m, 2 Η), 3.17 (dd, J = 15.9, 4.9 Hz, 1 H), 3.08-2.85 (m, 9 H), 2.56-2.46 ( m, 1 H), 2.39-2.04 (m, 7 H), 1.70-1.57 (m, 1 H); MS (ESI) m/z 498_14 (M+H) »

非對映異柄瓶Λπυ 〇 ho y 〇 ο Η非 异 柄 ho ho ho y 〇 ο Η

S24-6-1-A 合成化合物S24-6-1-A。 向 S24-5-l-A(18mg’0.032 mmol ’ 1 eq )於 DMF ( 900 μΙ〇中之溶液中添加乙路（8.9 pL，〇·16 mmol，5 eq)及 三乙胺（45 μι，0.32 mm〇l，i〇 eq)，接著添加三氣化銦 (&lt;1 mg，0.004 mmo卜&lt;〇·1 eq)及三乙醯氧基硼氫化鈉（32 mg，0.15 mmol，4.7 eq) 。18小時後，添加HC1之甲醇溶 308 201245116 • 液㈠.251^’400 ^)，接著添加乙醚（i〇mL)。在用乙 醚洗滌的情況下經由矽藻土過濾橙色沈澱物，接著用3:丨曱 醇：1.25 N HC1之曱醇溶液（1 〇 mL )自矽藻土沖洗所需化合 物。減壓濃縮曱醇洗滌液且藉由HPLC在Waters自動純化 系統上使用 Phenomenex Polymerx 10 μ RP-γ 100 R 管S24-6-1-A Synthesis of compound S24-6-1-A. Add S-B (8.9 pL, 〇·16 mmol, 5 eq) and triethylamine (45 μιη, 0.32 mm) to a solution of S24-5-lA (18 mg '0.032 mmol ' 1 eq ) in DMF (900 μM) 〇l, i〇eq), followed by the addition of indium trioxide (&lt;1 mg, 0.004 mmo &lt; 〇·1 eq) and sodium triethoxy borohydride (32 mg, 0.15 mmol, 4.7 eq). After 18 hours, HCl solution 308 201245116 • solution (1).251^'400 ^) of HCl was added, followed by diethyl ether (i 〇 mL). The orange precipitate was filtered through diatomaceous earth while washing with diethyl ether, and then the desired compound was washed from celite with 3: methanol: 1.25 N HCl in methanol (1 〇 mL). Concentrate the decyl alcohol wash under reduced pressure and use Phenomenex Polymerx 10 μ RP-γ 100 R tube on a Waters automated purification system by HPLC.

柱[3 0x2 1.20 mm ’ 1 0 微米；流速：20 mL/min ;溶劑 A : 0.05 N HC1/水；溶劑 B : CH3CN ;注入體積：1.8 mL ( 0.05 N HC1/ 水）；梯度：0— 30% B，經25分鐘；質量導向型洗提份收 集]純化。收集在10.2-11.0分鐘洗提之具有所需分子量之洗 提份且冷凍乾燥，得到呈黃色固體狀之化合物S24-6-1-A (1.21 mg，鹽酸鹽，6%) ·· 4 NMR (400 MHz, CD3OD) δ 7.00 (s, 1 Η), 6.96 (s, 1 Η), 4.43-4.34 (m, 1 Η), 4.08 (s, 1 Η), 3.90-3.81 (m, 1 Η), 3.22-3.88 (m, 12 Η, 2.66-2.47 (m, 2 Η), 2.34-2.15 (m, 4 Η), 1.67-1.54 (m, 1 Η), 1.27 (t J = 7.3 Hz, 3 H) ; MS (ESI) 512.15 (M+H)。Column [3 0x2 1.20 mm ' 1 0 μm; flow rate: 20 mL/min; solvent A: 0.05 N HC1/water; solvent B: CH3CN; injection volume: 1.8 mL (0.05 N HC1/water); gradient: 0-30 % B, after 25 minutes; mass-oriented extract fraction collection] purified. The extract having the desired molecular weight eluted at 10.2-11.0 min was collected and lyophilized to give the compound S24-6-1-A (1.21 mg, hydrochloride, 6%) as a yellow solid. (400 MHz, CD3OD) δ 7.00 (s, 1 Η), 6.96 (s, 1 Η), 4.43-4.34 (m, 1 Η), 4.08 (s, 1 Η), 3.90-3.81 (m, 1 Η) , 3.22-3.88 (m, 12 Η, 2.66-2.47 (m, 2 Η), 2.34-2.15 (m, 4 Η), 1.67-1.54 (m, 1 Η), 1.27 (t J = 7.3 Hz, 3 H MS (ESI) 512.15 (M+H).

S24-6-2-A 合成化合物S24-6-2-A。 向 S24-5-1-A ( 18 mg，0.032 mmo卜 1 eq)於 DMF ( 900 μ!〇中之溶液中添加丙酮（11.8 μίν，0.16 mmo卜5 eq)及 三乙胺（45 μί，0.32 mmol，10 eq)，接著添加三氯化銦 (&lt;1 mg，0.004 mmo卜&lt;〇.l eq)及三乙醯氧基硼氫化納（30 mg，0.14 mmol，4_5 eq) 。1 8小時後’添加HC1之曱醇溶 309 201245116 液（1.25Ν，400 μΙ〇 ’接著添加乙醚（1〇mL)。在用乙 謎洗條的情況下經由矽藻土過濾橙色沈澱物，接著用3 :丨甲 醇：1.25 N HC1之曱醇溶液（10 mL)自矽藻土沖洗所需化合 物°減壓濃縮曱醇洗滌液且藉由HPLC在Waters自動純化 系統上使用 Phenomenex Polymerx 10 &quot; rP_ r 1〇〇 尺管 柱[3 0x2 1.20 mm ’ 10 微米；流速：2〇 mL/min ;溶劑 a : 0.05 HC1/水’ ’谷劑 B . CH3CN ;注入體積：1 ·8 mL ( 〇.〇5 N HCI/ 水），梯度：0-&gt; 3 0% B，經25分鐘；質量導向型洗提份收 集]純化。收集在u 8_13 5分鐘洗提之具有所需分子量之洗S24-6-2-A Synthesis of compound S24-6-2-A. Add acetone (11.8 μίν, 0.16 mmo 5 eq) and triethylamine (45 μί, 0.32) to the solution of S24-5-1-A (18 mg, 0.032 mmo 1 eq) in DMF (900 μ! 〇) M, 10 eq), followed by the addition of indium trichloride (&lt;1 mg, 0.004 mmo&lt;1 eq) and triethyloxyborohydride (30 mg, 0.14 mmol, 4_5 eq). After the hour, 'Add HCl 1 曱 alcohol soluble 309 201245116 solution (1.25 Ν, 400 μ Ι〇 ' followed by the addition of diethyl ether (1 〇 mL). Filter the orange precipitate with diatomaceous earth with a sacred strip, followed by 3 : 丨methanol: 1.25 N HCl solution in decyl alcohol (10 mL). The desired compound was rinsed from diatomaceous earth. The decyl alcohol washing solution was concentrated under reduced pressure and Phenomenex Polymerx 10 &quot; rP_r 1 was used on the Waters automatic purification system by HPLC. 〇〇尺柱柱[3 0x2 1.20 mm ' 10 microns; Flow rate: 2〇mL/min; Solvent a: 0.05 HC1/Water' 'Valent B. CH3CN; Injection volume: 1 · 8 mL ( 〇.〇5 N HCI/water), gradient: 0-&gt; 30% B, after 25 minutes; mass-directed elution fraction collection] Purification. Washed at u 8_13 for 5 minutes eluted with the desired molecular weight

提伤且冷康乾燥’得到呈黃色固體狀之化合物S24-6-2-A (4.05 mg ’鹽酸鹽，21%) : 4 NMR (400 MHz，CD3OD) δ 7.04 (s’ 1 Η)，7.03 (s，1 η)，4.60-4.51 (m，1 Η)，4.09 (s，1 Η)， 3 70 3.59 (m，1 H)，3.54-3.37 (m，2 H)，3.16-2.87 (m，9 H)， 2 67 2·45 (m，2 H)，2.30-2.14 (m，4 H)，1.69-1.53 (m，1 H)， 1 34 1 on ( 6 H) ； MS (ESI) m/z 524.08 (M-H) 〇 實施例25.合成其中環e為吡咯啶-2-基之式i化合物 根據以下流程25合成式I化合物，其中χ為烷基，γ 為Η且％ ε為吡咯啶_ 2基。 流程25 310 201245116Lifting and cold drying to give the compound S24-6-2-A (4.05 mg 'hydrochloride, 21%) as a yellow solid: 4 NMR (400 MHz, CD3OD) δ 7.04 (s' 1 Η), 7.03 (s,1 η), 4.60-4.51 (m,1 Η), 4.09 (s,1 Η), 3 70 3.59 (m,1 H),3.54-3.37 (m,2 H),3.16-2.87 ( m,9 H), 2 67 2·45 (m,2 H), 2.30-2.14 (m,4 H), 1.69-1.53 (m,1 H), 1 34 1 on ( 6 H) ; MS (ESI m/z 524.08 (MH) 〇 Example 25. Synthesis of a compound of formula i wherein ring e is pyrrrolidine-2-yl. The compound of formula I is synthesized according to the following Scheme 25, wherein hydrazine is alkyl, γ is hydrazine and % ε is Pyrrolidine _ 2 group. Process 25 310 201245116

-ch3 COjPh 1HDA/TMEDA 2) S2-1-ch3 COjPh 1HDA/TMEDA 2) S2-1

OBn S24-1-AOBn S24-1-A

1) HF 2) H2. Pd/C1) HF 2) H2. Pd/C

根據流程25製備以下化合物。The following compounds were prepared according to Scheme 25.

合成化合物S25-1-A。 在-78°C下向新鮮製備之LDA ( 1.30 mm〇l，於1〇 mL THF 中 ’ 2.4 eq)中添加 TMEDA( 244 卟，i 〇 随仏 3 。 攪拌5分鐘後，逐滴添加化合物824·1-Α (4〇〇 mg，〇 64 mmol，1_2 eq)於THF (4 mL)中之溶液，之後以thf㈠ mL)沖洗，維持内部溫度低於_7〇t ◊在_78它下攪拌所得 红色溶液25分鐘。逐滴添加存於THF(4mL)中之烯酮幻巧 (264 mg ’ 0·5 5 mmol ’ 1 eq)，維持内部溫度低於_7(Γ(：。 使反應物經i小時逐漸升溫至—⑺^。添加NH4C1飽和水溶 液（4mL)。將混合物傾入和水溶液（i〇mL)中 且用EtOAc ( 2x3 5 mL)萃取。經合併之# $ &amp; # 水，過濾，且減壓濃縮。矽膠急驟層析得到呈黃色固體狀 之所需產物 S25-1-A ( 365 mg，67%) : lHNMR(4〇〇MHz， 311 201245116 CDC13，旋轉異.構體）5 15.94，15.89 (s，1 H)，7.52-7.25 (m, 15 H), 6.68, 6.60 (s, 1 H), 5.35 (s, 2 H), 5.31-5.21 (m, 1 H)，5.16-4.97 (m, 2 H)，3.99-3.91 (m, 1 H)，3.61-3.49 (m，1 H), 3.44-3.28 (m, 2 H), 3.01-2.91 (m, 1 H), 2.61-2.39 (m, 9 H), 2.37-2.21 (m, 1 H), 2.19-2.09 (m, 1 H), 1.47 (s, 6 H), 1.27-1.18 (m, 6 H) 0.84 (s, 9 H), 0.27 (s, 3 H), 0.15, 0.13 (s, 3 H) ; MS (ESI) w/z 1002.16 (M + H)。The compound S25-1-A was synthesized. Add TMEDA (244 卟, i 〇 with 仏3) to freshly prepared LDA (1.30 mm 〇l, 1 〇mL in THF) at -78 ° C. After stirring for 5 minutes, add compound 824 dropwise. · 1-Α (4〇〇mg, 〇64 mmol, 1_2 eq) in THF (4 mL), then rinsed with thf (1 mL), maintaining the internal temperature below _7 〇t ◊ stirring at _78 The resulting red solution was allowed to stand for 25 minutes. The enone illusion (264 mg '0.55 mmol '1 eq) in THF (4 mL) was added dropwise, maintaining the internal temperature below _7 (Γ::. To aq. The desired product S25-1-A (365 mg, 67%) was obtained as a yellow solid: mp NMR (4 〇〇 MHz, 311 201245116 CDC13, rot.). 15.94, 15.89 (s , 1 H), 7.52-7.25 (m, 15 H), 6.68, 6.60 (s, 1 H), 5.35 (s, 2 H), 5.31-5.21 (m, 1 H), 5.16-4.97 (m, 2 H), 3.99-3.91 (m, 1 H), 3.61-3.49 (m, 1 H), 3.44-3.28 (m, 2 H), 3.01-2.91 (m, 1 H), 2.61-2.39 (m, 9 H), 2.37-2.21 (m, 1 H), 2.19-2.09 (m, 1 H), 1.47 (s, 6 H), 1.27-1.18 (m, 6 H) 0.84 (s, 9 H), 0.27 ( s, 3 H), 0.15, 0.13 (s, 3 H); MS (ESI) w/z 1002.16 (M + H).

S25-2-A 合成化合物S25-2-A。 向 S25-1-A ( 18.6 mg，0.018 mmol，1 eq)於 THF:H2〇 (9:1，lmL)中之溶液中添加乙烯基三氟硼酸鉀（3.7 mg， 0_027 mmo卜 1.5 eq)、Pd(dppf)Cl2-CH2Cl2 ( 1.3 mg，0.002 mmol，0.15 eq)及構酸鉀（12.2 mg，0.057 mmol，3 eq )。 將反應物密封且加熱至80°C。2 1小時後，再添加鈀催化劑 (0.5 mg，0.04 eq)且再對反應物加熱。對 12.8 mg S25-1-A (0.013 mmol)進行類似反應，且合併粗反應混合物，隨後 經由矽藻土過濾，減壓濃縮，且經由矽膠急驟管柱層析（用S25-2-A Synthesis of compound S25-2-A. Add potassium vinyl trifluoroborate (3.7 mg, 0_027 mmo, 1.5 eq) to a solution of S25-1-A ( 18.6 mg, 0.018 mmol, 1 eq) in THF:H.sub.2 (9:1, 1 mL). Pd(dppf)Cl2-CH2Cl2 (1.3 mg, 0.002 mmol, 0.15 eq) and potassium silicate (12.2 mg, 0.057 mmol, 3 eq). The reaction was sealed and heated to 80 °C. After 1 hour, additional palladium catalyst (0.5 mg, 0.04 eq) was added and the reaction was heated. A similar reaction was carried out on 12.8 mg of S25-1-A (0.013 mmol), and the crude reaction mixture was combined, then filtered over Celite, concentrated under reduced pressure and purified by silica gel column chromatography

3-40% EtOAc/己烷作為洗提劑）純化，得到S25-1-A:S25_2-A 之4:1混合物（1 1.7 mg)。 對19 mg S25-l-a ( 0.019 mmol)重複上述反應條件， 且將經過濾反應物與上述S25-1-A:S25-2_A混合物合並且 使用製備型逆相HPLC在Waters自動純化系統上利用 312 201245116Purification with 3-40% EtOAc/hexanes as eluent gave a 4:1 mixture (1 1.7 mg) of S25-1-A:S25_2-A. The above reaction conditions were repeated for 19 mg of S25-l-a (0.019 mmol), and the filtered reaction mixture was combined with the above-mentioned S25-1-A:S25-2_A and used on a Waters automated purification system using preparative reverse phase HPLC 312 201245116

Sunfire Prep C18 OBD 管柱[5 &quot; m，19X5 0 mm ;流速：20 mL/min ;溶劑 A : H20，含 0.1% HC02H ;溶劑 B : CH3CN， 含 0.1% HC02H ;注入體積：2.5 mL ( CH3CN):梯度：50 — 100%B之A溶液，經20分鐘；質量導向型洗提份收集] 純化。收集在15.4-15.9分鐘洗提之具有所需分子量之洗提 份且冷束乾燥，得到呈黃色膜狀之S25_2_A( 4 6 mg，10% ): 4 NMR (400 MHz，CDC13，旋轉異構體）5 16.13，16.05 (s, 1 H), 7.52-7.24 (m, 15 Η), 6.74-6.56 (m, 2 Η), 5.64-5.57 (m, 1 Η), 5.35 (s, 2 Η), 5.28-4.89 (m, 4 Η), 3.97 (d, J= 10.4 Hz, 1 H), 3.61-3.29 (m, 2 H), 3.14 (dd, J = 16.5, 4.3 Hz, 1 H), 2.93-2.81 (m, i H), 2.55-2.35 (m, 9 H), 2.20-1.98 (m, 2 H), i-77-1.49 (m, 4 H), 1.46, 1.18 (s, 9 H), 0.83 (s, 9 H), 0.26 (s, 3 H)，0.14, 〇 13 (s，3 h) ; MS (ESI) w/z 902.32 (M+H)。Sunfire Prep C18 OBD column [5 &quot; m, 19X5 0 mm; flow rate: 20 mL/min; solvent A: H20, containing 0.1% HC02H; solvent B: CH3CN, containing 0.1% HC02H; injection volume: 2.5 mL (CH3CN ): Gradient: 50 - 100% B solution A, after 20 minutes; mass-directed elution fraction collection] Purification. The extract having the desired molecular weight eluted at 15.4-15.9 minutes and cold-dried to obtain S25_2_A (46 mg, 10%) in the form of a yellow film: 4 NMR (400 MHz, CDC13, rotamer ) 5 16.13,16.05 (s, 1 H), 7.52-7.24 (m, 15 Η), 6.74-6.56 (m, 2 Η), 5.64-5.57 (m, 1 Η), 5.35 (s, 2 Η), 5.28-4.89 (m, 4 Η), 3.97 (d, J= 10.4 Hz, 1 H), 3.61-3.29 (m, 2 H), 3.14 (dd, J = 16.5, 4.3 Hz, 1 H), 2.93- 2.81 (m, i H), 2.55-2.35 (m, 9 H), 2.20-1.98 (m, 2 H), i-77-1.49 (m, 4 H), 1.46, 1.18 (s, 9 H), 0.83 (s, 9 H), 0.26 (s, 3 H), 0.14, 〇 13 (s, 3 h); MS (ESI) w/z 902.32 (M+H).

S2S-3-A :遵循如關於S23-7-l-A所述之脫曱矽基及氫 化反應’自 S25-2-A 製備：】H NMR (400 MHz, CD3〇D) 5 6·99 (s, 1 Η), 4.10 (S, 1 Η), 3.60-3.43 (m, 2 Η), 3.20-2.84 (m, 10 Η)，2.80-2.67 (m，2 Η), 2.58-2.48 (m，1 Η), 2.46-2.35 (m， 1 Η), 2.34-2.15 (m, 3 Η), 2.14-2.02 (m, 1 Η), 1.71-1.57 (m, 1 Η)，1·39 (t，&gt;/= 7.3 Ηζ，3 Η) ; MS (ESI)w/z 512.21 (Μ+Η)。 實施例26.合成其中環ε為吡咯啶-2-基之式I化合物 根據以下流程26合成式I化合物，其中X為-Η，Y為 313 201245116 -Η且環E為吡咯啶-2-基 流程26S2S-3-A: followed by deamination and hydrogenation as described in S23-7-lA 'Prepared from S25-2-A: H NMR (400 MHz, CD3〇D) 5 6·99 (s , 1 Η), 4.10 (S, 1 Η), 3.60-3.43 (m, 2 Η), 3.20-2.84 (m, 10 Η), 2.80-2.67 (m, 2 Η), 2.58-2.48 (m,1 Η), 2.46-2.35 (m, 1 Η), 2.34-2.15 (m, 3 Η), 2.14-2.02 (m, 1 Η), 1.71-1.57 (m, 1 Η),1·39 (t,&gt) ;/= 7.3 Ηζ, 3 Η) ; MS (ESI) w/z 512.21 (Μ+Η). Example 26. Synthesis of a compound of formula I wherein ring ε is pyrrolidin-2-yl. A compound of formula I is synthesized according to Scheme 26 below, wherein X is -Η, Y is 313 201245116 -Η and ring E is pyrrolidin-2-yl Process 26

1) HF 2) H2l Pd/C HCHO, HOAc NaBH(OAc)31) HF 2) H2l Pd/C HCHO, HOAc NaBH(OAc)3

h3c、n,ch3 根據流程26製備以下化合物H3c, n, ch3 The following compounds were prepared according to Scheme 26

非對映異構體A ΟΒη Ο HODiastereomer A ΟΒη Ο HO

S26-1-A 合成化合物S26-1-A。 向 S25-l-A( 363 mg，0.362 mmol，1 eq)於一 mL )中之溶液中添加HC1之二噁烷溶液（4 N ’ 授拌2 3小時後，逐滴添加氫氧化納水溶液（1 N 噁烷（ 1 mL) .5 a。用 Et〇Ac 且將溶液傾入碳酸氫鈉飽和水溶液（20 mL )中 、 液（l〇mL) (35 mL )萃取此溶液且再用碳酸氫鈉飽和水 洗丨條有機層。用S26-1-A Synthesis of compound S26-1-A. Add a solution of HCl in dioxane to a solution of S25-lA (363 mg, 0.362 mmol, 1 eq in 1 mL) (4 N ' after mixing for 23 hours, add sodium hydroxide solution (1 N dropwise) Oxane (1 mL) .5 a. Ethyl AcAc was used and the solution was poured into a saturated aqueous solution of sodium bicarbonate (20 mL), and the solution was extracted (3 mL) (35 mL) and then saturated with sodium bicarbonate Wash the organic layer of the strip.

EtOAc(30mL)萃取經合併之水層 ，立隨 314 201245116 後經合併之有機層用鹽水洗滌（20 mL )，經硫酸鈉脫水， 過濾且減壓濃縮。經由矽膠急驟管柱層析（用2- 1 6%曱醇之 CH2C12溶液作為洗提劑）純化，得到呈固體狀之S26-1-A (208 mg &gt; 64%) : !H NMR (400 MHz, CDC13) δ 7.53-7.45 (m, 5 Η), 7.43-7.40 (m, 1 Η), 7.39-7.29 (m, 5 Η), 5.35 (s, 2 Η), 5.25 (s, 2 Η), 4.40 (dd, /= 7.9, 6.7 Hz, 1 Η), 3.96 (d, J = 10.4 Hz, 1 H), 3.36 (dd, J= 15.9, 4.9 Hz, 1 H), 3.18-3.02 (m, 2 H), 2.99-2.89 (m, 1 H), 2.60-2.30 (m, 10 H), 2.14 (d, J = 14.0 Hz, 1 H), 1.80-1.60 (m, 2 H), 1.35- 1.25 (m, 1 H), 0.82 (s, 9 H), 0.27 (s, 3 H), 0.13 (s, 3 H) ； MS (ESI) m/z 900.10 (M-H) 〇The combined aqueous layers were extracted with EtOAc EtOAc EtOAc. Purification by silica gel flash column chromatography (2: 6% decyl alcohol in CH2C12 as eluting solvent) afforded S26-1-A (208 mg &gt; 64%) as solid: :H NMR (400 MHz, CDC13) δ 7.53-7.45 (m, 5 Η), 7.43-7.40 (m, 1 Η), 7.39-7.29 (m, 5 Η), 5.35 (s, 2 Η), 5.25 (s, 2 Η) , 4.40 (dd, /= 7.9, 6.7 Hz, 1 Η), 3.96 (d, J = 10.4 Hz, 1 H), 3.36 (dd, J= 15.9, 4.9 Hz, 1 H), 3.18-3.02 (m, 2 H), 2.99-2.89 (m, 1 H), 2.60-2.30 (m, 10 H), 2.14 (d, J = 14.0 Hz, 1 H), 1.80-1.60 (m, 2 H), 1.35- 1.25 (m, 1 H), 0.82 (s, 9 H), 0.27 (s, 3 H), 0.13 (s, 3 H) ; MS (ESI) m/z 900.10 (MH) 〇

S26-2-A 合成化合物S26-2-A。 向 S26-1-A ( 208 mg，0.231 mmo卜 1 eq)於 CH2C12 ( 4 mL)中之溶液中添加曱醛水溶液（37〇/〇溶液，52 0，0.69 mmo卜 3 eq)及乙酸（40 μι，0.69 mmo卜 3 eq)。10 分鐘 後添加二乙酿氧基棚氫化納（147 mg，0.69 mmol，3 eq ) 且在環境溫度下攪拌反應物。3小時後，將溶液傾入飽和碳 酸氫納水溶液（25 mL)中且用EtOAc ( 2x20 mL)萃取。 經合併之有機層經硫酸鈉脫水，過濾且減壓濃縮。藉由矽 膠急驟管柱層析（用5-40% EtOAc/己烷作為洗提劑）純化 所得油狀物’得到呈黃色固體狀之S26_2_A( ία mg，68%): 315 201245116 lH NMR (400 MHz, CDC13) ^ ic Qo , -98 (s, 1 H), 7.52-7.44 (m 4 H)，7.40-7.28 (m，6 H)，7.28-7 (m，1 H)，5.35 (s，2 H) 5.28 (d, 7=12.8 Hz, 1H)S 5.2 (d, j = , 9 s „ 12.8 Hz, 1 H), 3.97 (d J= 10.4 Hz, 1 H), 3.42 (t, J = 8 5 u , S.5Hz，lH)3.34(dd，/=165 4-9 Hz, 1 H), 3.27-3.19 (m j m ’ 1 H), 3.01-2.91 (m, j H) 2.60-2.31 (m，10 H)，2.18-2.08 (m 4 m ' 4 H), 1.85-1.72 (m, 2 H) 1.35-1.18 (m, 2 H), 0.83 (s, 9 H) 〇 〇7 , H3C、m,CH3S26-2-A Synthesis of compound S26-2-A. To a solution of S26-1-A (208 mg, 0.231 mmo 1 eq) in CH2C12 (4 mL) was added aqueous furfural (37 〇 / 〇 solution, 52 0, 0.69 mmo, 3 eq) and acetic acid (40) Μι, 0.69 mmo Bu 3 eq). After 10 minutes, diethyl oxy hydride was added (147 mg, 0.69 mmol, 3 eq) and the reaction was stirred at ambient temperature. After 3 hours, the solution was poured into EtOAc EtOAc EtOAc. The combined organic layers were dried over sodium sulfate, filtered and evaporated. Purification of the obtained oil by EtOAc (EtOAc: EtOAc/hexanes) elute MHz, CDC13) ^ ic Qo , -98 (s, 1 H), 7.52-7.44 (m 4 H), 7.40-7.28 (m,6 H), 7.28-7 (m,1 H), 5.35 (s, 2 H) 5.28 (d, 7 = 12.8 Hz, 1H) S 5.2 (d, j = , 9 s „ 12.8 Hz, 1 H), 3.97 (d J= 10.4 Hz, 1 H), 3.42 (t, J = 8 5 u , S.5Hz, lH) 3.34 (dd, /=165 4-9 Hz, 1 H), 3.27-3.19 (mjm ' 1 H), 3.01-2.91 (m, j H) 2.60-2.31 (m , 10 H), 2.18-2.08 (m 4 m ' 4 H), 1.85-1.72 (m, 2 H) 1.35-1.18 (m, 2 H), 0.83 (s, 9 H) 〇〇7 , H3C, m , CH3

非對映異構體A〇Bn Ο h0 ί ά 〇Bn OTBS }, °·27 (s, 3 H), 0.14 (s l H) ； MS (ESI) m/z 914.09 (M-H) 〇 1 * 3Diastereomer A〇Bn Ο h0 ί ά 〇Bn OTBS }, °·27 (s, 3 H), 0.14 (s l H) ; MS (ESI) m/z 914.09 (M-H) 〇 1 * 3

S26-3-A 合成化合物S26-3-A。 在-95°C 下向 S26-2-A ( 61·4 m Λ 8 * 0.067 mmol «lea) 於THF ( 4 mL )中之溶液中逐滴添务 同添加苯基鋰溶液（1.8 M於 。乙謎中，心卜。·147^。卜2·2⑷，維持溫度低於_90 C。在-90°C下攪拌所得暗黃色溶液1〇分鐘。添加正丁基鋰 之己烷溶液（2.5M，35叫，0.087 mm〇1，i 3eq)。在 ％ °C下攪拌所得橙色溶液1〇分鐘。添加碘代曱烷（21 gL〇 33 mmol ’ 5 eq)，且使反應混合物經15分鐘緩慢升溫至_65 C。添加ΝΗβΙ飽和水溶液（1 mL )，使反應物升溫至環 境溫度’且隨後傾入NH4C1飽和水溶液（10 mL)中且用S26-3-A Synthesis of compound S26-3-A. To a solution of S26-2-A (61.4 m Λ 8 * 0.067 mmol «lea) in THF (4 mL) was added dropwise a solution of phenyl lithium (1.8 M) at -95 °C. In the mystery of the mystery, the heart is 147. 2. 2 (2), maintain the temperature below _90 C. Stir the resulting dark yellow solution at -90 ° C for 1 。. Add n-butyl lithium hexane solution (2.5 M, 35 is called, 0.087 mm 〇 1, i 3 eq. The resulting orange solution was stirred at % ° C for 1 Torr. Iododecane (21 g L 〇 33 mmol ' 5 eq) was added and the reaction mixture was allowed to pass for 15 minutes. Slowly warm to _65 C. Add a saturated aqueous solution of ΝΗβΙ (1 mL), warm the reaction to ambient temperature' and then pour into a saturated aqueous solution of NH4C1 (10 mL) and use

EtOAc ( 2x20 mL )萃取。經合併之有機層經硫酸鈉脫水， 過濾且減壓濃縮。使用製備型逆相HPLC在Waters自動純 化系統上用31111衍^?“？（：18〇3〇管柱[5&quot;111’19父50 111111; 316 201245116 . 流速：20 mL/min ;溶劑 A : H20，含 〇_l% HC02H ;溶劑 B : CH3CN，含 〇.i〇/0 HC02H ;注入體積：1.3 mL ( CH3CN)； 梯度：30— 100% b之a溶液，經20分鐘；質量導向型洗 提份收集]純化所得油狀物。收集在0.6-2.6分鐘洗提之具有 所需分子量之洗提份且冷凍乾燥，得到C7-H化合物 S26-3-A ( 26.6 mg - 50%) ： MS (ESI) m/z 788.19 (M-H) °Extract with EtOAc (2 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and evaporated. Preparative reverse phase HPLC was used on the Waters automated purification system with 31111 derivative "? (: 18 〇 3 〇 column [5 &quot; 111 '19 parent 50 111111; 316 201245116. Flow rate: 20 mL / min; solvent A: H20, containing 〇l% HC02H; solvent B: CH3CN, containing 〇.i〇/0 HC02H; injection volume: 1.3 mL (CH3CN); gradient: 30-100% b a solution, 20 minutes; mass-oriented The extract obtained was purified. The obtained oil was purified. The eluted fraction of the desired molecular weight eluted in 0.6-2.6 minutes was collected and lyophilized to give C7-H compound S26-3-A (26.6 mg - 50%): MS (ESI) m/z 788.19 (MH) °

S26-4-A :遵循如關於S23_7-1_A所述之脫甲矽基及氫 化反應’自 S26-3-A 製備。4 NMR (400 MHz，CD3OD) 5 7.01 (s, 1 Η), 7.00 (Sj 1 Η), 4.40-4.29 (m, 1 Η), 4.10 (s, 1 Η), 3.92-3.81 (m，1 H)，3.18-2.86 (m，10 H)，2.80 (s，3 h)， 2.67-2.46 (m, 2 H), 2.38-2.16 9m, 4 H), 1.67-1.53 (m, 1 H)； MS (ESI) aw/z 498.16 (M+h) 〇 實施例27.合成其中環E為旅咬-2·基之式I化合物 根據以下抓程27合成式z化合物，其中χ為，γ 為-Η且環Ε為派咬·2_基。 流程27 317 201245116S26-4-A: Prepared according to the demethylation group and hydrogenation reaction as described in relation to S23_7-1_A from S26-3-A. 4 NMR (400 MHz, CD3OD) 5 7.01 (s, 1 Η), 7.00 (Sj 1 Η), 4.40-4.29 (m, 1 Η), 4.10 (s, 1 Η), 3.92-3.81 (m, 1 H ), 3.18-2.86 (m, 10 H), 2.80 (s, 3 h), 2.67-2.46 (m, 2 H), 2.38-2.16 9m, 4 H), 1.67-1.53 (m, 1 H); MS (ESI) aw/z 498.16 (M+h) 〇. Example 27. Synthesis of a compound of formula I wherein ring E is a brigone-2 group. According to the following Scheme 27, a compound of formula z is synthesized, wherein χ is, γ is -Η And the ring is a bite · 2_ base. Process 27 317 201245116

根據流程27製備以下化合物 、N Boc tbso、..r^〇 甲基秒烷基）氧基甲 合成N-Boc-(S)-5-丨（第三丁基二 基】- 2-°比嗜·咬酮。 向經攪拌之（&lt;S)-5-(羥甲基β ^f 土 J 2-。比咯啶酮（1 〇3 g，9 〇2 mm〇1)於DMF(18mL)中之溶液中依序添加㈣（737叫，The following compound, N Boc tbso, ..r^〇methyl sec-alkyl)oxymethyl was synthesized according to Scheme 27 to synthesize N-Boc-(S)-5-indole (t-butyldiyl)-2-one ratio To the bitter ketone. To the stirred (&lt;S)-5-(hydroxymethylβ^f soil J2-.pyrrolidone (1 〇3 g,9 〇2 mm〇1) in DMF (18 mL) In the solution in the order (4) (737 called,

當量）及第三丁基二甲基石夕烧基氯化物（i63 g，10.8 mmol，1.2當量）。在室溫下攪拌24小時後，將反 應混合物傾入NH4CI飽和水溶液（75 mL)中。用EtOAc 萃取溶液三次。經合併之有機層以H2〇、鹽水洗；：條，經硫酸 鈉脫水，且減壓濃縮。藉由Biotage急驟層析純化殘餘物， 得到呈無色油狀之化合物（&lt;S)-5-[(第三丁基二曱基矽烧基） 氧基曱基]-2-吡咯啶酮（1.96 g ’ 95%) : 士 NMR (400 MHz， CDCI3) δ 5.70 (br. s, 1 Η), 3.66-3.73 (m, 1 Η), 3.57 (dd, J =3.7, 10.1 Hz, 1 H), 3.38 (dd, J = 7.8, 10.1 Hz, 1 H), 318 201245116 2.27-2.32 (m, 2 Η), 2.07-2.16 (m, 1 Η), 1.62-1.72 (m, 1 Η), 0.83 (s，9 H)，0.00 (s，6 H)。 在室溫下向（S)-5-[(第三丁基二甲基矽烷基）氧基甲 基]-2-吡咯啶酮（1.96 g，8.55 mm〇〖，1當量）於乙腈（17mL) 中之溶液中添加（Boc)2〇( 2.05 g，9.41 mmol，1.1當量）及 DMAP ( 104 mg，0.86 mmol，0.1當量）。在室溫下搜拌混 合物4小時後，藉由旋轉蒸發移除溶劑。藉由Bi〇Uge急驟 層析純化殘餘物，得到呈淺黃色油狀之#_b〇c_(iS)_5_[(第三 丁基—甲基石夕烧基）氧基甲基]_2_ n比略咬綱（2.72 g，97%). Ή NMR (400 MHz, CD3OD) 5 4.12-4.16 (m, 1 H), 3.66-3.73 (m，1 H)，3.88 (dd，3.7, 1()1 Hz，t H)，3 65 «Equivalent) and tert-butyl dimethyl sulphur chloride (i63 g, 10.8 mmol, 1.2 eq.). After stirring at room temperature for 24 hours, the reaction mixture was poured into a saturated aqueous solution of NH4CI (75 mL). The solution was extracted three times with EtOAc. The combined organic layers were washed with H.sub.2 and brine. The residue was purified by EtOAc (EtOAc) (EtOAc) 1.96 g ' 95%) : NMR (400 MHz, CDCI3) δ 5.70 (br. s, 1 Η), 3.66-3.73 (m, 1 Η), 3.57 (dd, J = 3.7, 10.1 Hz, 1 H) , 3.38 (dd, J = 7.8, 10.1 Hz, 1 H), 318 201245116 2.27-2.32 (m, 2 Η), 2.07-2.16 (m, 1 Η), 1.62-1.72 (m, 1 Η), 0.83 ( s, 9 H), 0.00 (s, 6 H). To (S)-5-[(t-butyldimethylmethylalkyl)oxymethyl]-2-pyrrolidone (1.96 g, 8.55 mm 〇, 1 eq.) in acetonitrile (17 mL) at room temperature (Boc) 2 〇 (2.05 g, 9.41 mmol, 1.1 eq.) and DMAP (104 mg, 0.86 mmol, 0.1 eq.) were added to the solution. After mixing the mixture for 4 hours at room temperature, the solvent was removed by rotary evaporation. The residue was purified by flash chromatography eluting with EtOAc EtOAc (EtOAc): Bite (2.72 g, 97%). NMR NMR (400 MHz, CD3OD) 5 4.12-4.16 (m, 1 H), 3.66-3.73 (m, 1 H), 3.88 (dd, 3.7, 1()1 Hz ,t H),3 65 «

C02Ph OBnC02Ph OBn

J - 7.8, 10.1 Hz, 1 H), 2.62-2.72 (m, 1 H), 2.30-2.37 (m, 1 H), 1.95-2.〇nm5 2^), 1.50 (s, 9 H), 〇.84 (s, 9 H), 0.00 (Sj 6 H) 〇 J ,7 kJ - 7.8, 10.1 Hz, 1 H), 2.62-2.72 (m, 1 H), 2.30-2.37 (m, 1 H), 1.95-2.〇nm5 2^), 1.50 (s, 9 H), 〇 .84 (s, 9 H), 0.00 (Sj 6 H) 〇J , 7 k

HO E S27-2 S27-2 :根據與S12-3所用類似之程序自及 A^〇C-W-5-[(第三丁基二甲基石夕貌基）氧基甲基]_2_料咬 ^t^：*HNMR(400 MHz5CD3〇D) , 7.47 (d, 7 = 7.8 Hz 2 H)，7.08_7.40 (m，14H)，5.15(ABq，j=u4，i84Hz2^ 4-69 (s, 1 H), 4.16-4.20 (m, 1 H), 3.73 (d, J = 13.3 Hz, 1 H)/ 3.68 (s，3 H)，3.41 (d，J = 13.3 Hz，i H)，3 27 …，2 叫 2.98-3.00 (m，i H)，2.38 (s，3H)，ι82·22〇 (m，3 抝 1.52-1.61(111，111);_(電噴霧卜/2 538 〇(1^扣。 ， 319 201245116HO E S27-2 S27-2 : According to a procedure similar to that used in S12-3, and from A^〇CW-5-[(t-butyldimethyl sulphate)oxymethyl]_2_ bite ^t^: *HNMR(400 MHz5CD3〇D), 7.47 (d, 7 = 7.8 Hz 2 H), 7.08_7.40 (m, 14H), 5.15 (ABq, j=u4, i84Hz2^ 4-69 (s , 1 H), 4.16-4.20 (m, 1 H), 3.73 (d, J = 13.3 Hz, 1 H)/ 3.68 (s,3 H), 3.41 (d, J = 13.3 Hz, i H), 3 27 ...,2 is 2.98-3.00 (m,i H), 2.38 (s,3H), ι82·22〇(m,3 拗1.52-1.61(111,111);_(electrospray Bu/2 538 〇( 1^ buckle. , 319 201245116

合成 及 52Ί-4。 在 0°C 下向化合物 S27-2 ( 111 mg，〇·2ΐ mrn〇l)於二氣 甲烧（2.0 mL )中之溶液申添加DAST ( 4 1 ml，0·3 1 mmol， 1.5當量）。所得混合物在室溫下攪拌2小時且隨後用 NaHC03飽和水溶液小心地中止。用EtOAc萃取溶液三次。 經合併之有機層用鹽水洗滌’經硫酸鈉脫水，且減壓濃縮。 藉由Biotage急驟層析純化殘餘物，得到呈無色油狀之化合 物S27-3( 67 mg，59%)及呈白色固體狀之化合物S27-4( 22 mg，19%)。S27-3 : 'H NMR (400 MHz, CD3OD) ά 7.48 (d， J= 7.8 Hz, 2 H), 7.12-7.40 (m, 14 H), 5.17 (ABq, n.4, 18.4 Hz, 2 H), 4.20 (dd, /= 6.4, 8.6 Hz, 1 H), 4.02-4.09 (m, 1 H), 3.90-3.98 (m, 1 H), 3.79 (d, J = 13.3 Hz, 1 H), 3.67 (s, 3 H), 3.50 (d, J= 13.3 Hz, 1 H), 3.13-3.23 (m, 1 H), 2.38 (s, 3 H), 2.10-2.17 (m, 1 H), 1.96-2.05 (m, 1 H), 1.79-1.85 (m, i H)，1.5 1 -1.61 (m，1 H) ; MS (電喷霧）w/z 540.0 (M+H)。 S27-4 ： NMR (400 MHz, CD3OD) δ 7.42 (d, J = 7.8 Hz, 2 H), 7.18-7.37 (m, 12 H), 7.42 (d, J= 7.8 Hz, 2 H), 5.13 (dj 7= 11.4 Hz, 1 H), 5.02 (d, J= 11.4 Hz, 1 H), 4.79 (br d, J = 47 Hz, 1 H), 3.87 (d, 13.3 Hz, 1 H), 3.75 (s, 3 H), 3.73 (d, J= 13.3 Hz, 1 H), 3.28-3.37 (m, 1 H), 2.89 (d, J= 14.2 Hz, 1 H)，2.39 (s，3 H)，1.94-2.26 (m，3 H)，1.60-1.80 (m，2 H); 320 201245116 MS (電喷霧）m/z 540.0 (M+H)。Synthesis and 52Ί-4. Add DAST (4 1 ml, 0·3 1 mmol, 1.5 eq.) to a solution of compound S27-2 (111 mg, 〇·2ΐ mrn〇l) in dioxin (2.0 mL) at 0 °C. . The resulting mixture was stirred at room temperature for 2 hours and then carefully quenched with a saturated aqueous solution of NaHC. The solution was extracted three times with EtOAc. The combined organic layers were washed with brine <~~~ The residue was purified by EtOAc EtOAc EtOAc (EtOAc) S27-3: 'H NMR (400 MHz, CD3OD) ά 7.48 (d, J = 7.8 Hz, 2 H), 7.12-7.40 (m, 14 H), 5.17 (ABq, n.4, 18.4 Hz, 2 H ), 4.20 (dd, /= 6.4, 8.6 Hz, 1 H), 4.02-4.09 (m, 1 H), 3.90-3.98 (m, 1 H), 3.79 (d, J = 13.3 Hz, 1 H), 3.67 (s, 3 H), 3.50 (d, J = 13.3 Hz, 1 H), 3.13-3.23 (m, 1 H), 2.38 (s, 3 H), 2.10-2.17 (m, 1 H), 1.96 -2.05 (m, 1 H), 1.79-1.85 (m, i H), 1.5 1 -1.61 (m, 1 H); MS (electrospray) w/z 540.0 (M+H). S27-4 : NMR (400 MHz, CD3OD) δ 7.42 (d, J = 7.8 Hz, 2 H), 7.18-7.37 (m, 12 H), 7.42 (d, J = 7.8 Hz, 2 H), 5.13 ( Dj 7= 11.4 Hz, 1 H), 5.02 (d, J= 11.4 Hz, 1 H), 4.79 (br d, J = 47 Hz, 1 H), 3.87 (d, 13.3 Hz, 1 H), 3.75 ( s, 3 H), 3.73 (d, J = 13.3 Hz, 1 H), 3.28-3.37 (m, 1 H), 2.89 (d, J = 14.2 Hz, 1 H), 2.39 (s, 3 H), 1.94-2.26 (m, 3 H), 1.60-1.80 (m, 2 H); 320 201245116 MS (electrospray) m/z 540.0 (M+H).

S27-5 合成化合物S21-5。 根據與關於S23-7-1所述類似之程序，自S27-3及烯酮 S2-1經由邁克爾-狄克曼成環、接著脫曱矽基及氫化反應’ 製備化合物 827-5:41^1^11(400 MHz，CD3OD) &lt;5 7.00 (s， 1 Η), 4.63-4.99 (m, 2 Η), 4.10-4.24 (m, 1 Η), 4.10 (s, 1 Η), 3.80 (s, 3 Η), 2.96-3.22 (m, 10 Η), 2.51-2.60 (m, 1 Η), 2.04-2.43 (m，5 H)，1.60-1.70 (m，1 Η) ; MS (電喷霧） 546.1 (M+H)。S27-5 Synthesis of compound S21-5. Compound 827-5:41^ was prepared from S27-3 and ketene S2-1 via Michael-Dickman ring formation followed by dehydration and hydrogenation according to procedures similar to those described for S23-7-1. 1^11 (400 MHz, CD3OD) &lt;5 7.00 (s, 1 Η), 4.63-4.99 (m, 2 Η), 4.10-4.24 (m, 1 Η), 4.10 (s, 1 Η), 3.80 ( s, 3 Η), 2.96-3.22 (m, 10 Η), 2.51-2.60 (m, 1 Η), 2.04-2.43 (m, 5 H), 1.60-1.70 (m, 1 Η); MS (electrospray) Fog) 546.1 (M+H).

S27-6 合成S27-6。 根據與關於S23-7-1所述類似之程序，自S27-4及烯酮 S2-1經由邁克爾-狄克曼成環、接著脫曱矽基及氫化反應， 製備化合物S27-6 : H NMR (400 MHz, CD3OD) δ 6.99 (s,S27-6 Synthesis of S27-6. Compound S27-6 was prepared from S27-4 and ketene S2-1 via Michael-Dickman ring formation followed by dehydration and hydrogenation according to procedures similar to those described for S23-7-1: H NMR (400 MHz, CD3OD) δ 6.99 (s,

MS (電喷霧）w/z 546.1 (Μ+Η)。 實施例28.合成其中環ε為雙環之式j I化合物 321 201245116 根據以下流程28合成式I化合物，其中X為OCH3，Υ 為-Η且環Ε為雙環。 流程28MS (electrospray) w/z 546.1 (Μ+Η). Example 28. Synthesis of a compound of formula j I wherein ring ε is bicyclic 321 201245116 A compound of formula I is synthesized according to Scheme 28 below, wherein X is OCH3, Υ is -Η and Ε is bicyclic. Process 28

OBn S4-1OBn S4-1

R11CI3 Nal04R11CI3 Nal04

BrBr

la) LDA/TMEDA lb) 烯酮 S2·1 1) TFA 2) Na2C03La) LDA/TMEDA lb) ketene S2·1 1) TFA 2) Na2C03

2) HF水溶液 3) Hz/Pd-C 9CH3 H %广2) HF aqueous solution 3) Hz/Pd-C 9CH3 H % wide

OH O HO S28-7 根據流程2 8製備以下化合物。OH O HO S28-7 The following compound was prepared according to Scheme 28.

Ο 合成N-Boc-3 -稀丙基-2-°比0各°定酮。 根據與關於#-Boc-3-甲基-2-吡咯啶酮所述類似之程 序，自 #-Boc-2-吡咯啶酮及烯丙基溴製備：NMR (400 MHz, CDCI3) δ 5.70-5.81 (m, 1 Η), 5.04-5.10 (m, 2 Η), 3.70-3.76 (m, 1 Η), 3.52-3.59 (m, 1 Η), 2.53-2.63 (m, 2 Η), 2.06-2.21 (m, 2 H)，1.62-1.72 (m，1 Η), 1.51 (s，9 H)。 322 201245116Ο Synthesis of N-Boc-3 - propyl -2- to ketone. Prepared from #-Boc-2-pyrrolidone and allyl bromide according to procedures similar to those described for #-Boc-3-methyl-2-pyrrolidone: NMR (400 MHz, CDCI3) δ 5.70- 5.81 (m, 1 Η), 5.04-5.10 (m, 2 Η), 3.70-3.76 (m, 1 Η), 3.52-3.59 (m, 1 Η), 2.53-2.63 (m, 2 Η), 2.06- 2.21 (m, 2 H), 1.62-1.72 (m, 1 Η), 1.51 (s, 9 H). 322 201245116

I C〇2ph 〇Bn S28-2 之程序，自S4-1及AT-Boc-3-稀 合成化合物S28_2。 根據與Sll-4所用類似 丙基2比&quot;各。定酮製備化合物S28-2 : 4 NMR (400 MHz, CD3OD, 5 7.21-7.41 (m, 8 Η), 旋轉異構體之混合物）The procedure for I C 〇 2 ph 〇 Bn S28-2 was synthesized from S4-1 and AT-Boc-3- dilute compound S28_2. According to the use of Sll-4 similar to the propyl 2 ratio &quot; each. Preparation of the compound S28-2 : 4 NMR (400 MHz, CD3OD, 5 7.21-7.41 (m, 8 Η), a mixture of rotamers)

f C02Ph OBn 7·12 (d，7.8 Hz，2 Η)，6.41 及 6.52 (s，1 H)，5.56-5.83 (m, 1 Η), 4.84-5.12 (m3 6 H)j 3.30-3.84 (m, 5 Η), 1.22-2.36 (m, 16 H) ’ MS (電喷霧）w/z 558.4 (M+H)。 S28-3 合成化合物。 向經授拌之化合物S28-2 ( 302 mg，0.54 mmol)於乙 猜（6 mL)中之溶液中添加RuC13 ( 5.6 mg，0.027 mmo卜 〇·〇5當量）於HW ( 1〇 mL)中之溶液。隨後整份添加過碘 酸納（231 mg ’ 1.〇8 mm〇卜2當量）。在室溫下攪拌所得 混合物3小時’接著用1〇0/〇 Na2S2〇3水溶液中止。用Et〇Ac 萃取溶液三次。經合併之有機層用鹽水洗滌，經硫酸鈉脫 水’且減壓濃縮。藉由Bi〇tage急驟層析純化殘餘物，得到 呈無色油狀之化合物S28-3 ( 134 mg，44%) : NMR (400 323 201245116 MHz, CDC13) δ 9.60 (s, 1 Η), 7.20-7.40 (m, 8 Η), 7.12 (d, J= 7.8 Hz, 2 H), 6.39 (s, 1 H), 5.03-5.22 (m, 3 H), 3.40-3.74 (m, 4 H), 2.85- 3.02 (m, 1 H), 2.35-2.45 (m, 1 H), 2.36 (s, 3 H)，1.70-2.00 (m，2 H), 1.44 及 1.2 5 (s，9 H) ; MS (電喷霧） m/z 560.2 (M+H) 〇f C02Ph OBn 7·12 (d, 7.8 Hz, 2 Η), 6.41 and 6.52 (s, 1 H), 5.56-5.83 (m, 1 Η), 4.84-5.12 (m3 6 H)j 3.30-3.84 (m , 5 Η), 1.22-2.36 (m, 16 H) ' MS (electrospray) w/z 558.4 (M+H). S28-3 Synthetic compound. To a solution of the compound S28-2 (302 mg, 0.54 mmol) in B. (6 mL) was added RuC13 (5.6 mg, 0.027 mmo 〇·〇5 eq) in HW (1 〇mL) Solution. Subsequent sodium iodate (231 mg ' 1. 〇 8 mm 2 2 equivalents) was added in portions. The resulting mixture was stirred at room temperature for 3 hours' and then quenched with a 1 〇0/〇 Na2S2〇3 aqueous solution. The solution was extracted three times with Et〇Ac. The combined organic layers were washed with brine w~~~~~ The residue was purified by EtOAc EtOAc (EtOAc): 7.40 (m, 8 Η), 7.12 (d, J= 7.8 Hz, 2 H), 6.39 (s, 1 H), 5.03-5.22 (m, 3 H), 3.40-3.74 (m, 4 H), 2.85 - 3.02 (m, 1 H), 2.35-2.45 (m, 1 H), 2.36 (s, 3 H), 1.70-2.00 (m, 2 H), 1.44 and 1.2 5 (s, 9 H) ; MS ( Electrospray) m/z 560.2 (M+H) 〇

S28-4 合成化合物S28-4。 在0°C下向化合物S28-3 ( 250 mg，0.45 mmo卜1當量） 於甲醇（4.5 mL )中之溶液中添加NaBH4 ( 34 mg，0.89 m m ο 1 ’ 2當直）。在室溫下授拌反應混合物3 〇分鐘。添加 HC1水溶液（1 Ν，5 mL )。再繼續攪拌5分鐘。用旋轉蒸 發器移除溶劑。用EtOAc萃取溶液三次。經合併之有機層 用NaHC03飽和水溶液及鹽水洗滌，經Na2S04脫水，且濃 縮。藉由Biotage急驟層析純化殘餘物，得到呈無色油狀之 S28-4 ( 242 mg &gt; 96%) ： ]H NMR (400 MHz, CDC13) δ 7.20-7.40 (m, 8 Η), 7.12 (d, J = 7.8 Hz, 2 H), 6.40 (s, 1 H), 5.03-5.25 (m, 3 H), 3.30-3.81 (m, 7 H), 2.45-2.58 (m, 1 H), 2.37 (s，3 H)，1.80-1.95 (m，1 H)，1.50-1.60 (m，3 H)，1·42 及 1.2 5 (s，9 Η) ; MS (電喷霧）5 62.2 (M+H)。 324 201245116S28-4 Synthesis of compound S28-4. To a solution of the compound S28-3 (250 mg, 0.45 mmo, 1 eq.) in methanol (4.5 mL) was added NaBH4 (34 mg, 0.89 m m ο 1 s 2 s straight) at 0 °C. The reaction mixture was stirred at room temperature for 3 minutes. Add an aqueous solution of HC1 (1 Ν, 5 mL). Stirring was continued for another 5 minutes. Remove the solvent with a rotary evaporator. The solution was extracted three times with EtOAc. The combined organic layers were washed with a saturated aqueous solution of NaH.sub.3 and brine, dried over Na? The residue was purified by EtOAc (EtOAc) elut elut elut elut elut elut elut elut d, J = 7.8 Hz, 2 H), 6.40 (s, 1 H), 5.03-5.25 (m, 3 H), 3.30-3.81 (m, 7 H), 2.45-2.58 (m, 1 H), 2.37 (s,3 H),1.80-1.95 (m,1 H),1.50-1.60 (m,3 H),1·42 and 1.2 5 (s,9 Η) ; MS (electrospray) 5 62.2 (M +H). 324 201245116

合成化合物S28-5。 S28-5 在〇°C下向化合物S28-4 ( 47 mg，0.084 mmo卜1當量） 及 PPh3 ( 26.3 mg，0.1〇 mm〇1，i 2 當量）於乙腈（】〇 mL) 中之溶液中添加NBS ( 17,9 mg，0.10 mm〇i，1.2當量）。 在此溫度下攪拌反應混合物1小時，接著用Et〇 Ac稀釋。 溶液以出〇及鹽水洗滌兩次，經Na2S〇4脫水，濃縮。藉由 Biotage急驟層析純化殘餘物，得到呈無色油狀之s28-5( 38 mg &gt;72%) : *H NMR (400 MHz, CDC13) δ 7.20-7.40 (m, 8 Η), 7.12 (d, J= 7.8 Hz, 2 H), 6.38 (s, 1 H), 5.03-5.25 (m, 3 H), 3.20-3.80 (m, 7 H), 2.54-2.68 (m, 1 H), 2.37 (s, 3 H)}Compound S28-5 was synthesized. S28-5 To a solution of compound S28-4 (47 mg, 0.084 mmo 1 equivalent) and PPh3 ( 26.3 mg, 0.1〇mm〇1, i 2 equivalent) in acetonitrile (] 〇mL) at 〇 °C NBS (17,9 mg, 0.10 mm 〇i, 1.2 eq.) was added. The reaction mixture was stirred at this temperature for 1 hour, followed by dilution with Et. The solution was washed twice with hydrazine and brine, dried over Na 2 EtOAc and concentrated. The residue was purified by EtOAc (EtOAc) elut elut elut elut elut elut elut d, J = 7.8 Hz, 2 H), 6.38 (s, 1 H), 5.03-5.25 (m, 3 H), 3.20-3.80 (m, 7 H), 2.54-2.68 (m, 1 H), 2.37 (s, 3 H)}

1.85-1.95 (m，1 H)，1.50-1.70 (m，3 H)，L42 及 1.25 (s，9 H) ; MS (電喷霧）m/z 624.2 及 626.2 (M+H)。 S28-6 合成化合物me。 在0 C下向化合物S28-5 ( 149 mg，0.24 mmol )於二氯 甲烷（1.2 mL)中之溶液中添加tfa ( 1.2 mL)於二氯曱烧 (1.2 mL )中之溶液。在室溫下攪拌混合物3〇分鐘後，用 325 201245116 旋轉蒸發器移除揮發物。將殘餘物溶解於遍…溶液 乂免矛NaHC03、鹽水洗務，經叫瓜脫水，且濃縮。將 殘餘物★解於氣仿（3 3 mL)中。添加碳酸納（126 4叫， 1.19 mmo卜5當量）及h2〇 ( 〇 4机）。在6代油浴中加 熱混合物2小時。在其冷卻至室溫後，添加二氣甲烷（4〇 L ) ’谷液以只2〇、鹽水洗務，經Na2S04脫水，且濃縮。 藉由Biotage急驟層析純化殘餘物，得到呈無色油狀之 S28-6(68mg’64〇/0,兩個步驟）：iHNMR(4〇〇MHz，CDCl3) 7.45 (d, 7 = 7.8 Hz, 2 Η), 7.22-7.39 (m, 7 Η), 7.10 (d, J = 7.8 Hz，2 H)，5.19 (s, 2 H)，4.00 (s，1 h)，3.69 (s, 3 H), 3.32 J ~ 3.7 Hz, 1 H), 3.14-3.24 (m, 1 H), 2.92-2.98 (m, 1 H), 2-75-2.83 (m, 1 H), 2.50-2.56 (m, 1 H), 2.37 (s, 3 H), 192-2.03 (m，1 H)，1.34-1.47 (m，2 H)，1.21-1.25 (m，1 H); MS (電噴霧）m/z 624.2 及 626.2 (M+H)。 製備 S28-7-A 及 S28-7-B。 根據與關於S23-7-1-A所述類似之程序，自S28-6及烯 嗣S2-1經由邁克爾-狄克曼成環、接著脫曱矽基及氫化反 應’製備兩種非對映異構體S28_7_A及S28-7-B。1.85-1.95 (m, 1 H), 1.50-1.70 (m, 3 H), L42 and 1.25 (s, 9 H); MS (electrospray) m/z 624.2 and 626.2 (M+H). S28-6 Synthesis of compound me. A solution of tfa (1.2 mL) in dichlorohydrazine (1.2 mL) was added to a solution of compound S28-5 (149 mg, 0.24 mmol) in m. After stirring the mixture for 3 minutes at room temperature, the volatiles were removed using a 325 201245116 rotary evaporator. Dissolve the residue in a solution... The solution is washed with NaHC03, brine, dehydrated by melon, and concentrated. The residue was dissolved in a gas (3 3 mL). Add sodium carbonate (126 4, 1.19 mmo, 5 equivalents) and h2〇 (〇 4). The mixture was heated in a 6-generation oil bath for 2 hours. After it was cooled to room temperature, di-methane (4 〇 L ) gluten solution was added to wash with only 2 Torr, brine, dehydrated with Na 2 SO 4 , and concentrated. The residue was purified by EtOAc EtOAc (EtOAc): 2 Η), 7.22-7.39 (m, 7 Η), 7.10 (d, J = 7.8 Hz, 2 H), 5.19 (s, 2 H), 4.00 (s, 1 h), 3.69 (s, 3 H) , 3.32 J ~ 3.7 Hz, 1 H), 3.14-3.24 (m, 1 H), 2.92-2.98 (m, 1 H), 2-75-2.83 (m, 1 H), 2.50-2.56 (m, 1 H), 2.37 (s, 3 H), 192-2.03 (m, 1 H), 1.34-1.47 (m, 2 H), 1.21-1.25 (m, 1 H); MS (electrospray) m/z 624.2 And 626.2 (M+H). Prepare S28-7-A and S28-7-B. Preparation of two diastereoisomers from S28-6 and olefinic S2-1 via Michael-Dickman ring formation followed by dehydration and hydrogenation according to procedures similar to those described for S23-7-1-A Isomers S28_7_A and S28-7-B.

S28-7-A S28-7-A ： 'H NMR (400 MHz, CD3OD) δ 6.93 (s, 1 Η), 4·96 (s, 1 H), 4.12 (s, 1 H), 3.80 (s, 3 H), 3.71-3.76 (m, 1 H), 3-5〇 (t, 3.6 Hz, 1 H), 3.40-3.46 (m, 1 H), 2.97-3.20 (m, 11 326 201245116 Η), 2.24-2.36 (m，3 H)，2.04-2.13 (m，1 Η)，1.79-1.92 (m，2 H)，1.59-1.69 (m，1 H) ; MS (電喷霧）W//z 540.2 (M+H)。S28-7-A S28-7-A : 'H NMR (400 MHz, CD3OD) δ 6.93 (s, 1 Η), 4·96 (s, 1 H), 4.12 (s, 1 H), 3.80 (s , 3 H), 3.71-3.76 (m, 1 H), 3-5 〇 (t, 3.6 Hz, 1 H), 3.40-3.46 (m, 1 H), 2.97-3.20 (m, 11 326 201245116 Η) , 2.24-2.36 (m,3 H), 2.04-2.13 (m,1 Η), 1.79-1.92 (m,2 H), 1.59-1.69 (m,1 H) ; MS (electrospray) W// z 540.2 (M+H).

S28-7-B S28-7-B ： !H NMR (400 MHz, CD3〇D) δ 6.95 (s5 1 H), 4.94 (s，1 H)，4.11 (s，1 H)，3.75-3.81 (m，1 H)，3.7 5 (s，3 H)， 3.39-3.47 (m，2 H)，2.97-3.20 (m，11 H)，2.15-2.46 (m，4 H)， 1.80-1.92 (m，2 H)，1.59-1.69 (m，1 H) ; MS (電喷霧）m/z 540.2 (M+H) 〇 實施例29.合成其中環e為雙環之式i化合物 根據以下流程29合成式i化合物，其中χ為_〇ch3，γ 為-Η且環Ε為雙環。 流程29 327 201245116S28-7-B S28-7-B : !H NMR (400 MHz, CD3〇D) δ 6.95 (s5 1 H), 4.94 (s, 1 H), 4.11 (s, 1 H), 3.75-3.81 ( m,1 H),3.7 5 (s,3 H), 3.39-3.47 (m,2 H),2.97-3.20 (m,11 H),2.15-2.46 (m,4 H), 1.80-1.92 (m , 2 H), 1.59-1.69 (m, 1 H); MS (electrospray) m/z 540.2 (M+H) 〇 Example 29. Synthesis of a compound of formula i wherein ring e is bicyclic is synthesized according to Scheme 29 below A compound of formula i, wherein χ is _〇ch3, γ is -Η and Ε is bicyclic. Process 29 327 201245116

NaOH HO'NaOH HO'

,OCH3 MsCl Q OMs 0CH3 S29-3, OCH3 MsCl Q OMs 0CH3 S29-3

OCH3 och3 S29-1 BocHNOCH3 och3 S29-1 BocHN

Na, NH3 S29*4 BnNH2Na, NH3 S29*4 BnNH2

N I Bn S29-5 ΟN I Bn S29-5 Ο

NaBH4 ch3NaBH4 ch3

還原性 烷基化 OBn O S29-10Reductive alkylation OBn O S29-10

OBn Ο S29-11OBn Ο S29-11

1) HF 2) H2) Pd/C1) HF 2) H2) Pd/C

B〇C2〇B〇C2〇

H2l Pd/CH2l Pd/C

,ch3 „,ch3,ch3 „,ch3

OH O OH H 〇 S29-15 根據流程29製備以下化合物 ,〇ch3OH O OH H 〇 S29-15 The following compounds were prepared according to Scheme 29, 〇ch3

丨W S29-2 合成化合物以9-1。 將 NaOH (1.0 g，25.2 mmol，1·0 eq)添加至化合物 S29-1 ( 4.0 g，25.2 mmol，1 ·0 eq )於甲醇（96 mL )與 H20 (8 mL )之混合物中的溶液中。在室溫下攪拌反應混合物 隔夜。用EtOAc萃取反應混合物三次。水層以濃鹽酸酸化 至pH 2且隨後用 EtOAc萃取三次。經合併之萃取物經 328 201245116丨W S29-2 The compound was synthesized as 9-1. Add NaOH (1.0 g, 25.2 mmol, 1.0 eq) to a solution of compound S29-1 (4.0 g, 25.2 mmol, 1 ·0 eq) in a mixture of methanol (96 mL) and H20 (8 mL) . The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted three times with EtOAc. The aqueous layer was acidified to pH 2 with concentrated hydrochloric acid and then extracted thrice with EtOAc. The combined extracts were passed 328 201245116

NajO4脫水，過濾且濃縮， (3.4 g，產率 93% )，其 | 得到呈無色油狀之粗物質Dehydration of NajO4, filtration and concentration (3.4 g, yield 93%), which gave crude material as colorless oil

1.68-1.63 (m, 1 Η), 1.32-1.68-1.63 (m, 1 Η), 1.32-

S29-2 •接用於下一步驟：NMR (400 (S&gt; 3 Η), 2.12-2.03 (m, 2 Η), 1.26 (m，1 H) o S29-3 合成化合物S2H。 將 BH3.THF 之 THF 溶液（1μ，31 1.3 eq)逐滴添加至化合物，广，μS29-2 • Used in the next step: NMR (400 (S&gt; 3 Η), 2.12-2.03 (m, 2 Η), 1.26 (m,1 H) o S29-3 Synthesis of compound S2H. BH3.THF The THF solution (1μ, 31 1.3 eq) was added dropwise to the compound, broad, μ

添加後，使混合 ，31.4 mL，31.4 mmol， 24.2 mmol » 1.0 3小時。反應混合物以After addition, mix, 31.4 mL, 31.4 mmol, 24.2 mmol » 1.0 3 hours. Reaction mixture

NaHC〇3飽和水溶液中止且用Et〇Ac萃取三次。萃取物經無 水NazSO4脫水，過濾且濃縮，得到呈無色油狀之粗物質 S29-3，其直接用於下一步輙：iH NMR (400 MHz，CDC13) 5 4.11 - 4.06 (m, 1 Η), 3.93 - 3.89 (m, 1 Η), 3.67 (s, 3 Η), 2.23 (m，lH)，1.78-1.71(m，iH)，1.61-1.56(m，lH)，1.13- 1·〇8 (m，2 H)。The NaHC 3 saturated aqueous solution was quenched and extracted three times with Et EtOAc. The extract was dehydrated with anhydrous NazSO4, filtered and concentrated to give a crude material, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, 3.93 - 3.89 (m, 1 Η), 3.67 (s, 3 Η), 2.23 (m, lH), 1.78-1.71 (m, iH), 1.61-1.56 (m, lH), 1.13 - 1·〇8 ( m, 2 H).

S29-4 合成化合物-4。 在〇°C下向化合物S29-3 (粗物質，24.2 mmol )於二氣 曱烷（80 mL)中之溶液中添加〇ΙΕΑ( 9·36 g，72.6 mmol)， 接者添加MsCl(3.76mL，48.4mniol)。在〇C下槐摔反應 混合物3小時。移除溶劑後，用EtOAc萃取殘餘物三次。 329 201245116S29-4 Synthesis of Compound-4. Add hydrazine (9·36 g, 72.6 mmol) to a solution of compound S29-3 (crude material, 24.2 mmol) in dioxane (80 mL) at 〇 ° C, then add MsCl (3.76 mL) , 48.4mniol). The reaction mixture was smashed under 〇C for 3 hours. After the solvent was removed, the residue was extracted three times with EtOAc. 329 201245116

萃取物經無水Na2S04脫水，過濾且隨後濃縮。粗物質S29-4 在無進一步純化的情況下即直接用於下一步驟：NMR (400 MHz, CDC13) δ 4.61-4.57 (m，1 Η)，4.36-4.30 (m，1 H)，3_69 (s，3 H)，2.96 (s，3 h)，1.93-1.87 (m，1 H)，1.77-1.73 (m，1 H)，1.22 (s，1 H)，1.16-1.12 (m，1 H)。 S29-5 合成化合物S29-5。The extract was dried over anhydrous Na 2 SO 4 , filtered and then concentrated. The crude material S29-4 was used directly in the next step without further purification: NMR (400 MHz, CDC13) δ 4.61-4.57 (m, 1 Η), 4.36-4.30 (m, 1 H), 3_69 ( s,3 H),2.96 (s,3 h),1.93-1.87 (m,1 H),1.77-1.73 (m,1 H),1.22 (s,1 H),1.16-1.12 (m,1 H ). S29-5 Synthesis of compound S29-5.

將三乙胺（3.44 g，34 mmol)及苯甲胺（2.43 g，22.7 mmol)添加至化合物S29-4 (粗物質，22.7 mmol)於THF (80 mL )中之溶液中。在80°C下加熱反應溶液3小時。反 應物以水中止且用EtOAc萃取三次。萃取物經Na2S04脫 水’過濾且隨後濃縮。藉由HPLC純化殘餘物，得到呈無色 油狀之 S29-5 ( 1·4 g，30%，四個步驟）：NMR (400 MHz, CDCI3) δ 7.31-7.14 (m, 5 Η), 4.36-4.26 (m, 2 Η), 3.40-3.62 (m, 1 Η), 3.16-3.13 (m, 1 Η), 1.99-1.96 (m, 1 Η), 1.81-1.78 (m，1 H)，1.11-1.06 (m, 1 H)，0.58-0.55 (m，1 H)。 S29-6 合成化合物S29-6。 在- 78°C 下將化合物 S29-5(1.4g，7.49mm〇l)於 THF (5 _5 mL )中之溶液添加至26.5 ml液氨中，接著依序逐份 添加EtOH ( 3 50 mg)及Na ( 700 mg)。攪拌所得暗藍色混 330 201245116 合物15分鐘且隨後用固體NH4C1巾止M吏液氨在室溫下蒸 、將殘餘物，合解於Et〇Ac中且用水洗滌。有機層經 ^過;慮且/辰縮，得到呈無色油狀之粗物質S29-6，在無 進一f純化的情況下將其直接用於下一步驟中。 … 9-0Triethylamine (3.44 g, 34 mmol) and benzylamine (2.43 g, 22.7 mmol) were added to a solution of compound S29-4 (cr. The reaction solution was heated at 80 ° C for 3 hours. The reaction was quenched with water and extracted three times with EtOAc. The extract was filtered off with Na2SO4 and then concentrated. The residue was purified by EtOAc (EtOAc EtOAc): 4.26 (m, 2 Η), 3.40-3.62 (m, 1 Η), 3.16-3.13 (m, 1 Η), 1.99-1.96 (m, 1 Η), 1.81-1.78 (m, 1 H), 1.11 1.06 (m, 1 H), 0.58-0.55 (m, 1 H). S29-6 Synthesis of compound S29-6. A solution of the compound S29-5 (1.4 g, 7.49 mm 〇l) in THF (5 _5 mL) was added to 26.5 ml of liquid ammonia at -78 ° C, followed by sequential addition of EtOH (3 50 mg). And Na (700 mg). The resulting dark blue blend 330 201245116 was stirred for 15 minutes and then evaporated with a solid NH4C1. The organic layer was taken up in vacuo to afford crude material S29-6 as colorless oil, which was used directly in the next step without further purification. ... 9-0

Boc S29-7 合成化合物829-Ί。 將 Boc20 ( 3.24 g，14.88 mmol)及 DMAP ( 200 mg) 、、小加至化合物S29-6 (粗物質，7.49 mmo 1)於二氣曱烧（25 mL )中之溶液中。在室溫下攪拌反應混合物3小時。隨後 邋縮反應混合物且藉由TLC純化殘餘物，得到呈白色固體 狀之 S29-7 ( 500 mg，3 4%，兩個步驟）：丨H NMR (400 MHz,Boc S29-7 Synthetic compound 829-Ί. Boc20 (3.24 g, 14.88 mmol) and DMAP (200 mg) were added to a solution of compound S29-6 (crude, 7.49 mmol) in dioxane (25 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was then condensed and the residue was purified by EtOAc (EtOAc:EtOAc:

CdC13) δ 3.78-3.74 (m, 1 Η), 3.66 (d, J= 12, 1 Η), ^97-1.94 (t, 1 Η), 1.87-1.82 (m, 1 Η), 1.46 (s, 9 Η),CdC13) δ 3.78-3.74 (m, 1 Η), 3.66 (d, J= 12, 1 Η), ^97-1.94 (t, 1 Η), 1.87-1.82 (m, 1 Η), 1.46 (s, 9 Η),

^18-1.12 (m, 1 Η), 0 BocHN^18-1.12 (m, 1 Η), 0 BocHN

C02Ph OBn .76-0.73 (m，1 H)。 S29-8 合成化合物名。 在-100°(：下將11-6111^之己烷溶液（2.5 1^，1.51111^，3.8 ^iniol).逐滴添加至化合物 S4-1 ( 1·4 g，3.3 mmol)於 THF (7 mL )中之溶液中。在該溫度下攪拌反應混合物30分鐘。 向此混合物中逐滴添加化合物S29-7 ( 500 mg，2.54 mmol ) 於THF ( 3 mL )中之溶液。添加後，使混合物逐漸升溫至 331 201245116 室溫。反應混合物以NH4C1飽和水溶液中止且用EtOAc萃 取二次。萃取物經Na2S〇4脫水’過渡且濃縮。藉由tlc純 化殘餘物’得到呈白色固體狀之S29-8( 900 mg，產率81%): *H NMR (400 MHz, CDC13) (5 7.44-7.42 (m, 2 Η), 7.38-7.34 (m, 6 Η), 7.26-7.25 (m, 1 Η), 7.10-7.05 (m, 3 Η), 5.14 (s, 2 Η), 3.79 (s, 2 Η), 3.57-3.52 (m, i H), 3.25-3.22 (m5 1 H), 2.86-2.81 (m, i H), 2.00-1.90 (m, ! H), 2.41 (s, 9 H)，1.25 (s，2 H)。C02Ph OBn .76-0.73 (m, 1 H). S29-8 Synthetic compound name. Add 1-1-6111 hexane solution (2.5 1 ^, 1.51111^, 3.8 ^iniol) at -100 ° (: dropwise) to compound S4-1 (1.4 g, 3.3 mmol) in THF (7) The solution was stirred at this temperature for 30 minutes. To this mixture was added dropwise a solution of compound S29-7 (500 mg, 2.54 mmol) in THF (3 mL). The temperature was gradually increased to 331 201245116. The reaction mixture was quenched with aq. EtOAc EtOAc EtOAc. (900 mg, yield 81%): *H NMR (400 MHz, CDC13) (5 7.44-7.42 (m, 2 Η), 7.38-7.34 (m, 6 Η), 7.26-7.25 (m, 1 Η) , 7.10-7.05 (m, 3 Η), 5.14 (s, 2 Η), 3.79 (s, 2 Η), 3.57-3.52 (m, i H), 3.25-3.22 (m5 1 H), 2.86-2.81 ( m, i H), 2.00-1.90 (m, ! H), 2.41 (s, 9 H), 1.25 (s, 2 H).

S29-9 合成化合物S29-9。 向化合物S29-8 ( 900 mg，1.65 mmol )於二氣甲烷（9 中之溶液中添加TFA ( 4.5 mL) 。在室溫下攪拌反應 混合物1小時。移除溶劑後，將殘餘物溶解於Et〇Ac中且 用NaHC〇3飽和水溶液洗滌β分離有機層，且用Et〇Ac萃 取水層兩次。經合併之萃取物經Na2S04脫水，過濾且濃縮。 粗產物直接用於下一步驟中。S29-9 Synthesis of compound S29-9. To the solution of the compound S29-8 (900 mg, 1.65 mmol) in di-methane (yield of TFA (4.5 mL). The mixture was stirred at room temperature for 1 hour. After the solvent was removed, the residue was dissolved in Et. The organic layer was separated and washed with aq. NaH.sub.3 saturated aqueous solution, and the aqueous layer was extracted twice with Et.sub.Ac. The combined extracts were dried over Na2S04, filtered and concentrated. The crude product was used directly in the next step.

S29-10 合成化合物S29_1()。 向化合物S29-9 (粗物質S29-10 Synthesis of compound S29_1(). To compound S29-9 (crude substance

中之溶液中添加NaBH •物質，1.65 mmol)於甲醇（9 mL) (169 mg，4.46 mmol)。在室溫下 332 201245116 . 攪拌反應混合物5分鐘’此時TLC顯示起始物質消耗完。 反應浪合物以NH；4C1飽和水溶液中止且用EtOAc萃取。萃 取物經NazSCU脫水，過濾且濃縮。藉由tlc純化殘餘物， 得到呈白色固體狀之所需產物（6〇〇 mg，兩個步驟之產率 為 84.6%)。 使用以下一般程序來製備化合物S29-15。 A 〇/CH3 'V^co2Ph OBn S29-11 合成化合物S29-11。 在室溫下攪拌化合物S29-1 〇 ( 200 mg，0.465 mmol )、 R’CiC^R&quot; ( 100 e L ’ r,r&quot;ch = R)及 cH3C〇〇h ( 50 叫） 於DCE(5mL)中之混合物}小時。添加NaBH(〇Ac)3(25〇 mg ’ 1 ·1 8 mm〇l )。再攪拌1小時後，反應混合物以NaHC03 飽和水合液中止且用Et〇Ac萃取三次。有機相經Na2S〇4脫 水，，渡且濃縮。粗產物直接用於下一步驟。 /A 〇XHa R^iiccH3 T^C〇2PhAdd NaBH•substrate, 1.65 mmol) to methanol (9 mL) (169 mg, 4.46 mmol). At room temperature 332 201245116 . Stir the reaction mixture for 5 minutes' At this point TLC showed the starting material was consumed. The reaction mixture was quenched with aq. aq. The extract was dehydrated by NazSCU, filtered and concentrated. The residue was purified by EtOAc (EtOAc:EtOAc) Compound S29-15 was prepared using the following general procedure. A 〇/CH3 'V^co2Ph OBn S29-11 Synthetic compound S29-11. Stir compound S29-1 〇 (200 mg, 0.465 mmol), R'CiC^R&quot; (100 e L 'r, r&quot;ch = R) and cH3C〇〇h (50 ng) at DCE (5 mL) at room temperature The mixture in the mixture} hours. NaBH(〇Ac)3 (25〇 mg '1 ·1 8 mm〇l) was added. After stirring for an additional 1 hour, the reaction mixture was quenched with NaHC03 sat. EtOAc. The organic phase was dehydrated with Na 2 S 〇 4 and then concentrated. The crude product was used directly in the next step. /A 〇XHa R^iiccH3 T^C〇2Ph

OH S29-12 合成化合物S29-12。 向化σ物S29-11 (粗物質，0.437 mmol)於甲醇（5 mL) 中之溶液中添加Pd/C ( 200 mg)。將懸浮液抽空且回填H2 j在室溫下攪拌2小時U催化劑且濃㈣液。在無進 一步純化的情況下將殘餘物直接用於下—步驟。 333 201245116OH S29-12 Synthesis of compound S29-12. To a solution of the sigma S29-11 (crude material, 0.437 mmol) in methanol (5 mL) was added Pd / C (200 mg). The suspension was evacuated and backfilled with H2j at room temperature for 2 hours with U catalyst and concentrated (d). The residue was used directly in the next step without further purification. 333 201245116

S29-13 合成化合物S29-13。 向化合物S29-12 (粗物質，〇_465 mm〇1 )於二氣曱烷 (5 mL)令之溶液中添加BoC2〇 (22〇 mg)及DMap (6〇S29-13 Synthesis of compound S29-13. Add BoC2〇 (22〇 mg) and DMap (6〇) to the compound S29-12 (crude substance, 〇_465 mm〇1) in dioxane (5 mL)

mg) ^反應混合物在室溫下攪拌2小時且隨後濃縮至乾燥。 藉由TLC純化殘餘物，得到呈白色固體狀之所需產物。 S29-14 合成化合物S29-14。 在-78°C 下將 n-BuLi 之己烷溶液（2.5 Μ，0.24 ml，0.6 mmol)逐滴添加至二異丙胺（0.09 mL，0.6 mmol)及TMEDA (90 μι，0.6 mmol)於無水THF ( 3 mL·)中之溶液中。添 加後，混合物在-78°C下攪拌1 〇分鐘，在〇它下攪拌3〇分 鐘，且再冷卻至-78°C。向其中添加化合物S29-13 ( 63 mg， 0.12 mmol)於無水THF ( 1 mL)中之溶液。在-78°C下授拌 所得深紅色溶液30分鐘且隨後冷卻至_10(rc。添加烯酮 S2-1 ( 58 mg，0.12 mmol)於無水 THF ( 1 mL)中之溶液。 添加後’使溶液逐漸升溫至室溫。反應混合物以NH4C1飽 和水溶液中止且用EtOAc萃取三次。萃取物經Na2S04脫 水，過濾且濃縮。粗產物直接用於下一步驟中。 334 201245116 rGHa h3c、mxh3The reaction mixture was stirred at room temperature for 2 hours and then concentrated to dryness. The residue was purified by EtOAc (EtOAc) S29-14 Synthesis of compound S29-14. A solution of n-BuLi in hexane (2.5 Μ, 0.24 mL, 0.6 mmol) was added dropwise at -78 °C to diisopropylamine (0.09 mL, 0.6 mmol) and TMEDA (90 μιη, 0.6 mmol) in anhydrous THF In a solution (3 mL·). After the addition, the mixture was stirred at -78 ° C for 1 Torr, stirred under stirring for 3 Torr, and cooled to -78 ° C again. A solution of the compound S29-13 (63 mg, 0.12 mmol) in anhydrous THF (1 mL) The resulting dark red solution was stirred at -78 °C for 30 min and then cooled to _10 ( rc. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The solution was gradually warmed to room temperature. The mixture was quenched with EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc.

S29-15 合成化合物S29-15。 將HF水溶液（40%’ 5 緩慢添加化合物S29_14(粗 物質，0.12 mm〇l)於THF (5 mi)令之攪拌溶液中。在室 溫下劇烈攪拌混合物3小時，此時將混合物傾入K2hP〇4飽 和水溶液（150 mL)中。用EtOAc萃取混合物三次。萃取 物經NkSO4脫水，過濾且濃縮。將該物質再次溶解於甲醇 (SmL)中，且添加Pd/C(9〇mg)，接著添加則甲醇 (4N’ 〇.5mL’ 2.0mmol)。將懸浮液抽空且回填H2且隨 後在室溫下㈣2小時。渡出催化劑且濃縮渡液、。藉由製 備型HPLC純化殘餘物，得到呈龙名田躺」 呈黃色固體狀之所需產物。 根據關於上文S29-1S之一和 */A. o^H3 H3C.k„CH3 力又転序製備以下化合物。S29-15 Synthesis of compound S29-15. The aqueous solution of HF (40% '5 was slowly added to compound S29_14 (crude material, 0.12 mm 〇l) in THF (5 mi) to stir the solution. The mixture was stirred vigorously at room temperature for 3 hours, at which time the mixture was poured into K2hP The mixture was extracted with EtOAc (3 mL) EtOAc (EtOAc)EtOAc.EtOAc.sssssssssssssssssssssssssss Add methanol (4N' 〇.5mL '2.0mmol). The suspension was evacuated and backfilled with H2 and then at room temperature (d) for 2 hours. The catalyst was withdrawn and the liquid was concentrated. The residue was purified by preparative HPLC to give Long Mingtian lays down the desired product as a yellow solid. The following compounds were prepared according to one of the above S29-1S and */A. o^H3 H3C.k.

非對映異構體A &amp; ^ 〇TDiastereomer A &amp; ^ 〇T

S29-1S-1-A S29-15-1-A :自 S29-10 直技制供 ιτ 旦接製備。1H NMR (400 MHZ CD3OD) &lt;5 7.16 (s，1 H)，5.19 卜 ’ H J- 3.2 Hz，1 H)，4.09 (s 1 H), 3.73 (S) 3 H), 3.65-3.61 rm , ^ ， W，1 H)，3.42-3.40 (m，1 m 3.23- 3.18 (m，1 H)，3.02-2.95 s ， im} 8 H), 2.45-2.38 (m, 1 H) 2.24- 2.21 (m，l H)，2.14-2.12 (m 1TJ、，η ’ 、m，1 H)，1.98-1.95 (m，1 H) 1.69-1.60 (m, 1 H), 1.14-1.09 rm , ΛS29-1S-1-A S29-15-1-A : Prepared from S29-10 for direct processing. 1H NMR (400 MHZ CD3OD) &lt;5 7.16 (s, 1 H), 5.19 卜 'H J- 3.2 Hz, 1 H), 4.09 (s 1 H), 3.73 (S) 3 H), 3.65-3.61 rm , ^ , W, 1 H), 3.42-3.40 (m, 1 m 3.23- 3.18 (m, 1 H), 3.02-2.95 s , im} 8 H), 2.45-2.38 (m, 1 H) 2.24- 2.21 (m, l H), 2.14 - 2.12 (m 1TJ,, η ' , m, 1 H), 1.98-1.95 (m, 1 H) 1.69-1.60 (m, 1 H), 1.14-1.09 rm , Λ

1 H), 0.55 (m, 1 H) ； MS (ESI) m/z 526.1 (M+H)。 335 2012451161 H), 0.55 (m, 1 H); MS (ESI) m/z 526.1 (M+H). 335 201245116

非對映異構艘B OH O OH合Ο Ο πDiastereomeric B OH O OH combined Ο π

S29-15-1-B S29-15-1-B :自 S29-10 直接製備。1Η NMR (400 ΜΗζ， CD3OD) δ 7.15 (s, 1 Η), 5.19 (d, J= 3.6 Hz, 1 H), 4.11 (s, 1 H), 3.81 (s, 3 H), 3.67-3.63 (m, 1 H), 3.46-3.43 (m, 1 H), 3.17-2.95 (m, 9 H), 2.33-2.26 (m, 2 H), 2.15-2.11 (m, 1 H), 1.97-1.94 (m, 1 H), 1.67-1.57 (m, 1 H), 1.30-1.29 (m, 1 H), 1.09-1.07 (m，1 H) ; MS (ESI) m/z 526.1 (M + H)。S29-15-1-B S29-15-1-B: Prepared directly from S29-10. 1Η NMR (400 ΜΗζ, CD3OD) δ 7.15 (s, 1 Η), 5.19 (d, J= 3.6 Hz, 1 H), 4.11 (s, 1 H), 3.81 (s, 3 H), 3.67-3.63 ( m, 1 H), 3.46-3.43 (m, 1 H), 3.17-2.95 (m, 9 H), 2.33-2.26 (m, 2 H), 2.15-2.11 (m, 1 H), 1.97-1.94 ( m, 1 H), 1.67-1.57 (m, 1 H), 1.30-1.29 (m, 1 H), 1.09-1.07 (m, 1 H); MS (ESI) m/z 526.1 (M + H).

非對映；Depolarization

S29-15-2-A S29-15-2-A:自S29-10及甲醛水溶液製備。4 NMR (400 MHz, CD3OD) δ 7.14 (s, 1 Η), 5.15 (d, J = 3.6 Hz,l H), 4.12 (s, 1 H), 3.87 (d, /= 2.8 Hz ,1 H), 3.79-3.66 (m, 1 H), 3.22-3.31 (m, 1 H), 3.10-2.78 (m, 7 H), 2.65 (s, 3 H), 2.42-2.35 (m, 1 H), 2.29-2.26 (m, 1 H), 2.16-2.12 (m, 1 H), 1.96-1.92 (m, 1H), 1.67-1.64 (m, 1 H), 1.12-1.09 (m, 1 H),S29-15-2-A S29-15-2-A: Prepared from S29-10 and aqueous formaldehyde solution. 4 NMR (400 MHz, CD3OD) δ 7.14 (s, 1 Η), 5.15 (d, J = 3.6 Hz, l H), 4.12 (s, 1 H), 3.87 (d, /= 2.8 Hz , 1 H) , 3.79-3.66 (m, 1 H), 3.22-3.31 (m, 1 H), 3.10-2.78 (m, 7 H), 2.65 (s, 3 H), 2.42-2.35 (m, 1 H), 2.29 -2.26 (m, 1 H), 2.16-2.12 (m, 1 H), 1.96-1.92 (m, 1H), 1.67-1.64 (m, 1 H), 1.12-1.09 (m, 1 H),

非對映六州〇H O OH 〇 〇 Η 0.98-0.94 (m，1 H) ; MS (ESI) 540.3 (M+H)。Diastereomeric six-state 〇H O OH 〇 Η Η 0.98-0.94 (m,1 H) ; MS (ESI) 540.3 (M+H).

S29-15-2-B S29-15-2-B:自S29-10及曱醛水溶液製備。lHNMR(4〇〇 336 201245116 MHz, CD3〇D) δ 7.25 (s, 1 Η), 5.17 (d, J = 3.6 Ηζ,Ι H), 3.87 (s, 1 H), 3.84-3.71 (m, 1 H), 3.62-3.30 (m, 1 H), 3.25-3.21 (m, 1 H), 3.05-2.98 (m, 7 H), 2.78 (s, 3 H), 2.17-2.11 (m, 1 H), 1.96-1.92 (m, 1 H), 1.71-1.62 (m, 1 H), 1.48-1.44 (m,l H), 1.39-1.35 (m, 1 H), 1.25-1.24 (m, 1 H), 1.11-1.05 (m, 1 H) ; MS (ESI) w/z 540.3 (M+H)。S29-15-2-B S29-15-2-B: Prepared from S29-10 and aqueous furfural. lHNMR(4〇〇336 201245116 MHz, CD3〇D) δ 7.25 (s, 1 Η), 5.17 (d, J = 3.6 Ηζ, Ι H), 3.87 (s, 1 H), 3.84-3.71 (m, 1 H), 3.62-3.30 (m, 1 H), 3.25-3.21 (m, 1 H), 3.05-2.98 (m, 7 H), 2.78 (s, 3 H), 2.17-2.11 (m, 1 H) , 1.96-1.92 (m, 1 H), 1.71-1.62 (m, 1 H), 1.48-1.44 (m, l H), 1.39-1.35 (m, 1 H), 1.25-1.24 (m, 1 H) , 1.11-1.05 (m, 1 H); MS (ESI) w/z 540.3 (M+H).

mm

S29-15-3-A S29-15-3-A:自 S29-10 及丙醛製備。4 NMR (400 MHz, CD3OD) δ 7.12 (s, 1 H), 5.19 (s, 1 H), 3.89 (s, 1 H), 3.86-3.79 (m, 1 H), 3.78 (s, 3 H), 3.65-3.51 (m, 2 H), 3.30- 2.96 (m, 11 H), 2.43-2.35 (m, 1 H), 2.29-2.22 (m, 1 H), 2.17-2.10 (m, 1 H), 1.97-1.93 (m, 1 H), 1.72-1.50 (m, 3 H), 1.31- 1.28 (m, 1 H), 1.15-1.10 (m, 1 H), 0.90 (t, 7.2 Hz, 3 H) ; MS (ESI) w/z 568.1 (M+H)。S29-15-3-A S29-15-3-A: Prepared from S29-10 and propionaldehyde. 4 NMR (400 MHz, CD3OD) δ 7.12 (s, 1 H), 5.19 (s, 1 H), 3.89 (s, 1 H), 3.86-3.79 (m, 1 H), 3.78 (s, 3 H) , 3.65-3.51 (m, 2 H), 3.30- 2.96 (m, 11 H), 2.43-2.35 (m, 1 H), 2.29-2.22 (m, 1 H), 2.17-2.10 (m, 1 H) , 1.97-1.93 (m, 1 H), 1.72-1.50 (m, 3 H), 1.31- 1.28 (m, 1 H), 1.15-1.10 (m, 1 H), 0.90 (t, 7.2 Hz, 3 H MS (ESI) w/z 568.1 (M+H).

非两傅姐〇 oh o oh y o o πNon-two Fu sisters oh o oh y o o π

S29-15-3-B S29-15-3-B:自 S29-10 及丙醛製備。4 NMR (400 MHz, CD3OD) δ 7.23 (s, 1 H), 4.97 (s, 1 H), 3.95 (s, 1 H), 3.85-3.82 (m,l H), 3.77-3.48 (m, 3 H), 3.08-2.97 (m, 11 H), 2.48-2.39 (m, 1 H), 2.28-2.22 (m, 1 H), 2.15-2.13 (m, 1 H), 1.97-1.93 (m, 2 H), 1.69-1.66 (m, 1 H), 1.26-1.24 (m, 2 H), 337 201245116 1.07-0.93 (m, 1 Η), 0.91- 0.87 (m, 3 Η) ； MS (ESI) m/z 568.1 (M+H)。S29-15-3-B S29-15-3-B: Prepared from S29-10 and propionaldehyde. 4 NMR (400 MHz, CD3OD) δ 7.23 (s, 1 H), 4.97 (s, 1 H), 3.95 (s, 1 H), 3.85-3.82 (m, l H), 3.77-3.48 (m, 3 H), 3.08-2.97 (m, 11 H), 2.48-2.39 (m, 1 H), 2.28-2.22 (m, 1 H), 2.15-2.13 (m, 1 H), 1.97-1.93 (m, 2 H), 1.69-1.66 (m, 1 H), 1.26-1.24 (m, 2 H), 337 201245116 1.07-0.93 (m, 1 Η), 0.91-0.87 (m, 3 Η) ; MS (ESI) m /z 568.1 (M+H).

S29-15-4-A S29-15-4-A:自 S29-10 及丙酮製備。4 NMR (400 MHz， CD3OD) δ 7.23 (d, J= 5.6 Hz, 1 H), 5.30 (d, J = 4.0 Hz, 1 H), 4.14 (s, 1 H), 3.81 (s, 3 H), 3.78-3.69 (m, 2 H), 3.55-3.52 (m, 1 H), 3.21-2.98 (m, 9 H), 2.40-2.27 (m, 2 H), 2.16-2.11 (m, 1 H), 1.97-1.93 (m, 1 H), 1.69-1.60 (m, 1 H), 1.35 (d, J = 6.8 Hz, 3 H), 1.26-1.20 (m, 4 H), 0.92-0.83 (m, 1 H)； MS (ESI) m/z 567.9 (M+H)。S29-15-4-A S29-15-4-A: Prepared from S29-10 and acetone. 4 NMR (400 MHz, CD3OD) δ 7.23 (d, J = 5.6 Hz, 1 H), 5.30 (d, J = 4.0 Hz, 1 H), 4.14 (s, 1 H), 3.81 (s, 3 H) , 3.78-3.69 (m, 2 H), 3.55-3.52 (m, 1 H), 3.21-2.98 (m, 9 H), 2.40-2.27 (m, 2 H), 2.16-2.11 (m, 1 H) , 1.97-1.93 (m, 1 H), 1.69-1.60 (m, 1 H), 1.35 (d, J = 6.8 Hz, 3 H), 1.26-1.20 (m, 4 H), 0.92-0.83 (m, MS (ESI) m/z 567.9 (M+H).

非對映異構體B〇H O OH go 〇Diastereomer B〇H O OH go 〇

S29-15-4-B S29-15-4-B:自 S29-10 及丙酮製備。*ΗΝΜΙΙ (400 MHz， CD3OD) δ 7.34 (s, 1 Η), 5.33 (d, J= 3.6 Hz, 1 H), 4.15 (s, 1 H), 3.74 (s, 3 H), 3.73-3.7 (m, 3 H), 3.49-3.99 (m, 1 H), 3.29-2.99 (m, 9 H), 2.44-2.37 (m, 1 H), 2.32-2.27 (m, 1 H), 2.17-2.11 (m, 1 H), 1.97-1.92 (m, 1 H), 1.70-1.60(m, 1 H), 1.46-1.42 (m, 1 Η), 1.32 (d, J = 6.4 Hz, 3 H), 1.23 (d, 6.8S29-15-4-B S29-15-4-B: Prepared from S29-10 and acetone. *ΗΝΜΙΙ (400 MHz, CD3OD) δ 7.34 (s, 1 Η), 5.33 (d, J = 3.6 Hz, 1 H), 4.15 (s, 1 H), 3.74 (s, 3 H), 3.73-3.7 ( m, 3 H), 3.49-3.99 (m, 1 H), 3.29-2.99 (m, 9 H), 2.44-2.37 (m, 1 H), 2.32-2.27 (m, 1 H), 2.17-2.11 ( m, 1 H), 1.97-1.92 (m, 1 H), 1.70-1.60 (m, 1 H), 1.46-1.42 (m, 1 Η), 1.32 (d, J = 6.4 Hz, 3 H), 1.23 (d, 6.8

Hz，1 H)，1.0-0.95 (m, 1 H) ; MS (ESI) m/z 567.9 (M+H)。 實施例30.合成其中環E為吡啶-3-基之式I化合物Hz, 1 H), 1.0-0.95 (m, 1 H); MS (ESI) m/z 567.9 (M+H). Example 30. Synthesis of a compound of formula I wherein ring E is pyridin-3-yl

根據以下流程30合成式I化合物，其中X為-OCH3，Y 338 201245116 為-Η且環E為》比咬_ 3 _基。 流程30The compound of formula I is synthesized according to the following Scheme 30, wherein X is -OCH3, Y 338 201245116 is -Η and ring E is "biter". Process 30

OBoc S1-8OBoc S1-8

根據流程3 0製備以下化合物。The following compounds were prepared according to Scheme 30.

S30-1 合成化合物S3 n。 在-78。(3下向存於_78。匚下之THF中的二異丙胺（0.16 mL，1 · 1 5 mmol，5 .〇 當量）中逐滴添加 nBuLi ( 0.46 mL， 2.50 Μ/己烷，mm〇1，5 〇 當量）及 TMEDA ( 0.17 mL， l15 mmo1 ’ 5.〇當量）。在-78t：下攪拌反應物30分鐘。在 _78°C 下將存於 thf 中之化合物 Sl-8( 100 mg，0.23 mmol， 1 ·〇當量）逐滴添加至反應混合物中。在-78°C下攪拌所得深 紅色溶液1 5分鐘。將所得混合物冷卻至-1 〇〇。(：且添加存於 稀酮 S2-1 ( 1〇〇 mg ’ 0.23 mmol，1_0 當量）。深 紅色'合液在攪拌下經30分鐘之時期自-l〇〇°C逐漸升溫至〇 339 201245116 °C，且以氯化銨飽和水溶液（2〇 mL )中止。用Et〇Ac萃取 黃綠色混合物兩次。經合併之EtOAc萃取物經脫水 (NaJO4 )且濃縮，得到粗產物。藉由石夕膠管柱（2〇〇〜3 〇〇 目’以PE:EA = 200:1— 100:1—50:1洗提）純化粗化合物， 得到50 mg呈黃色固體狀之化合物S30-1:丨H NMR (400 MHz， CDC13) δ 13.9 (s, 1 Η), 7.37-7.34 (m, 2 Η), 7.29-7.19 (m, 4 H)，5.23 (s，2 Η), 3.75 (d，10.0 Hz，1 H)，3·63 (s，3 H)， 3.25-3.18 (m, 1 H), 2.90-2.80 (m, 1 H), 2.45-2.28 (m, 9 H), 2.05-1.98 (m, 1 H), 1.46 (s, 9 H), 0.73 (s, 9 H), 0.15 (s, 3 H), 0.02 (s，3 H) ; MS (ESI) w/z 827.1 (M+H)。S30-1 synthesizes the compound S3 n. At -78. (3) Add nBuLi (0.46 mL, 2.50 Μ/hexane, mm〇) to diisopropylamine (0.16 mL, 1 · 15 mmol, 5 〇 )) in THF under 匚. 1,5 〇 equivalent) and TMEDA (0.17 mL, l15 mmo1 ' 5. 〇 equivalent). The reaction was stirred at -78 t: for 30 minutes. The compound Sl-8 (100) was stored in TF at _78 °C. Mg, 0.23 mmol, 1 · 〇 equivalent) was added dropwise to the reaction mixture. The resulting dark red solution was stirred at -78 ° C for 15 minutes. The resulting mixture was cooled to -1 〇〇. Ketone S2-1 (1〇〇mg '0.23 mmol, 1_0 equivalent). The deep red 'liquid mixture gradually warmed from -10 °C to 〇339 201245116 °C under stirring for 30 minutes, and chlorinated The ammonium saturated aqueous solution (2 mL) was quenched. The yellow-green mixture was extracted twice with Et.sub.Ac. The combined EtOAc extracts were dried (NaJO4) and concentrated to give a crude product. The crude compound was purified by the procedure of PE: EA = 200:1 - 100:1 - 50:1 to give 50 mg of compound S30-1 as a yellow solid: 丨H NMR (400 M Hz, CDC13) δ 13.9 (s, 1 Η), 7.37-7.34 (m, 2 Η), 7.29-7.19 (m, 4 H), 5.23 (s, 2 Η), 3.75 (d, 10.0 Hz, 1 H ),3·63 (s,3 H), 3.25-3.18 (m, 1 H), 2.90-2.80 (m, 1 H), 2.45-2.28 (m, 9 H), 2.05-1.98 (m, 1 H ), 1.46 (s, 9 H), 0.73 (s, 9 H), 0.15 (s, 3 H), 0.02 (s, 3 H); MS (ESI) w/z 827.1 (M+H).

S30-2 合成化合物S3Q-2。 將化合物 S30-1 ( 50 mg，0.061 mmol )、2-胺基。比咬- 3-硼酸（25 mg，0.182 mmol) ' K2C03 ( 25 mg &gt; 0.182 mmol) 及 Pd(PPh3)4 ( 10 mg)於二噁烷（3 mL)及 h2〇 ( 1 mL) 中之混合物在80-90°C下加熱2小時》反應混合物以h2〇稀 釋且用EtOAc萃取。將萃取物脫水且濃縮。粗物質S30_2 直接用於下一步驟中。S30-2 Synthetic compound S3Q-2. Compound S30-1 (50 mg, 0.061 mmol), 2-amino group. BIT- 3-boronic acid (25 mg, 0.182 mmol) 'K2C03 (25 mg &gt; 0.182 mmol) and Pd(PPh3)4 (10 mg) in dioxane (3 mL) and h2 (1 mL) The mixture was heated at 80-90 °C for 2 h. The extract was dehydrated and concentrated. The crude material S30_2 was used directly in the next step.

S30-3 340 201245116 將HF水溶液（4〇% ’ 5 ml)緩慢添加至化合物S30-2 (粗物質，0.12 mmol)於THF ( 5 ml)中之攪拌溶液中。 在至下劇烈檀掉混合物3小時，此時將混合物傾入 K2HP〇4飽和水溶液（5〇 mL)中。用EtOAc萃取混合物： 次。萃取物經NhSCU脫水，過濾且濃縮。將該物質再次容 解於曱醇（5mL)中，且添加Pd/C( 9 mg)，接著添加 甲醇（4 N ’ 0.5 mL，2.0 mmol )。抽空懸浮液且回填只 且隨後在室溫下攪拌2小時。濾出催化劑，且濃縮渡液 藉由製備型HPLC純化殘餘物，得到呈黃色固體狀 S30-3 ： *H NMR (400 MHz, CD3OD) § 7.97-7.95 (m χ 7.06-7.03 (m，1 H)，6.82 (2s，1 H 全部），4.12 (s，1 Η) 3 j H)’ ， ’ _45 (s， 3 H)，3.31-2.99 (m, 9 H)，2.38-2.22 (m，2 H)，1.69-1 v , T (m, i H) ; MS (ESI) m/z 537.0 (M+H)。 實施例3 1.合成其中環E為°比洛咬_ 2 -基之式i化八物 流程31S30-3 340 201245116 An aqueous solution of HF (4% 5%) was slowly added to a stirred solution of compound S30-2 (crude, 0.12 mmol) in THF (5 ml). The mixture was vigorously shaken off for 3 hours at the bottom, at which time the mixture was poured into a saturated aqueous solution of K2HP 〇 4 (5 〇 mL). The mixture was extracted with EtOAc: times. The extract was dehydrated by NhSCU, filtered and concentrated. This material was again taken up in decyl alcohol (5 mL), and Pd/C (9 mg) was added, followed by methanol (4 N ' 0.5 mL, 2.0 mmol). The suspension was evacuated and backfilled only and then stirred at room temperature for 2 hours. The catalyst was filtered off, and the residue was purified by preparative EtOAc (EtOAc) EtOAc (EtOAc) ), 6.82 (2s, 1 H all), 4.12 (s, 1 Η) 3 j H)' , ' _45 (s, 3 H), 3.31-2.99 (m, 9 H), 2.38-2.22 (m, 2 H), 1.69-1 v, T (m, i H); MS (ESI) m/z 537.0 (M+H). Example 3 1. Synthesis of a compound in which the ring E is in the range of 比 2 -

.CH3 1) Br^NaOAc 2) TFA C02Ph.CH3 1) Br^NaOAc 2) TFA C02Ph

a) PhLi, nBuU b) C02 1) LDA 2) S2-1a) PhLi, nBuU b) C02 1) LDA 2) S2-1

r7r7'nh HOBt, EDCIR7r7'nh HOBt, EDCI

1) HF 2) H2, Pd/C1) HF 2) H2, Pd/C

341 201245116 根據流程31製備以下化合物。341 201245116 The following compounds were prepared according to Scheme 31.

S31-1 合成化合物。 在室溫下向存於HOAc ( 20 mL)中之S11-4 ( 2.03 g， 4.16 mmo卜 1 當量）中添加 NaOAc ( 0.69 g，8.39 mmol，2 當$)及漠（0.23 mL ’ 4.3 7 mmol ’ 1.05當量）。在室溫下 攪拌反應溶液2小時《再添加溴（〇 〇5 mL )。攪拌反應物 30分鐘且減壓濃縮。利用5% EtOAc/己烧進行矽膠急驟管 柱層析’得到呈白色固體狀之所需產物S31-1 ( 1.40 g， 60%) : 'H NMR (400 MHz, CD3OD) δ 7.45-7.16 (m, 8 Η), 7·1〇 (d5 /= 8.8 Hz, 2 Η), 6.63, 6.57 (s, s, 1 H), 5.23-5.10 (m, 1 H), 5.08 (t, J= 12.2 Hz, 2 H), 3.58 (br tr, 7.0 Hz, 1 H), 3-52-3.42 (m, 1 H), 2.50, 2.47 (s, s, 3 H), 2.38-2.25 (m, 1 H), 1-85-1.50 (m, 3 H), 1.47, 1.25 (s, s, 9 H) H VCco2Ph OBn S31-2 合成化合物SU-2。 向 S3 1-1 ( 920 mg，1.62 mmol)於二氯曱烷（i〇 mL) 中之溶液中添加TFA ( 5 mL )，且在室溫下攪拌反應混合 勿1】、時。濃縮反應混合物且直接用於下一步驟中。 342 201245116S31-1 Synthetic compound. Add NaOAc (0.69 g, 8.39 mmol, 2 when $) and desert (0.23 mL '4.3 7 mmol) to S11-4 (2.03 g, 4.16 mmo 1 equivalent) in HOAc (20 mL) at room temperature. '1.05 equivalents). The reaction solution was stirred at room temperature for 2 hours "addition of bromine (〇 5 mL). The reaction was stirred for 30 min and concentrated under reduced pressure. The desired product S31-1 ( 1.40 g, 60%) was obtained as a white solid: <H NMR (400 MHz, CD3OD) δ 7.45-7.16 (m) , 8 Η), 7·1〇 (d5 /= 8.8 Hz, 2 Η), 6.63, 6.57 (s, s, 1 H), 5.23-5.10 (m, 1 H), 5.08 (t, J= 12.2 Hz , 2 H), 3.58 (br tr, 7.0 Hz, 1 H), 3-52-3.42 (m, 1 H), 2.50, 2.47 (s, s, 3 H), 2.38-2.25 (m, 1 H) , 1-85-1.50 (m, 3 H), 1.47, 1.25 (s, s, 9 H) H VCco2Ph OBn S31-2 Synthesis of compound SU-2. To a solution of S3 1-1 (920 mg, 1.62 mmol) in dichloromethane (1 mL) was added TFA (5 mL), and the mixture was stirred at room temperature. The reaction mixture was concentrated and used directly in the next step. 342 201245116

S31-3 合成化合物S31-3。 在室溫下授拌S31-2 (823 mg，1.76 mmol)、、;臭甲笨 (3 62 mg，2.12 mmol)及碳酸鉀（487 mg，3.53 mmol)於S31-3 Synthesis of compound S31-3. S31-2 (823 mg, 1.76 mmol), stinky (3 62 mg, 2.12 mmol) and potassium carbonate (487 mg, 3.53 mmol) were added at room temperature.

MeCN ( 10 mL )中之混合物1小時。濃縮混合物，且使殘 餘物分配於EtOAc與H20之間。用EtOAc ( 20 mLX3 )萃 取水相。將經合併之萃取物脫水，濃縮且藉由管柱層析（〇 至5% EtOAc之石油醚溶液梯度）純化。用石油醚濕磨所得 油狀物且濃縮，得到呈白色固體狀之S31-3 ( 900 mg，92%， 經兩個步驟）。The mixture in MeCN (10 mL) was 1 hour. The mixture was concentrated and the residue was partitioned betweenEtOAc andEtOAc. The aqueous phase was extracted with EtOAc (20 mL EtOAc). The combined extracts were dried, concentrated and purified with EtOAc EtOAc EtOAc The resulting oil was triturated with EtOAc (EtOAc)EtOAc.

Ο &gt; S31-4 合成化合物S31-4。 ΟΒη Ο HO Ξ Ο 0Bn OTBSΟ &gt; S31-4 Synthesis of compound S31-4. ΟΒη Ο HO Ξ Ο 0Bn OTBS

在-78°C下向THF溶液（2 mL)中添加新鮮製備之ldA (0.77 mmo卜 1.08 mmol )且隨後添加 S31-3 ( 200 mg，0.3 6 mmol)於THF ( 1 mL)中之溶液。其持續5分鐘。隨後在 -78°C 下逐滴添加烯酮（140 mg，0.29 mmol )於 THF( 0.5 mL ) 中之溶液。將反應混合物傾入飽和NH4CI中且用EtOAc( 20 mLx2 )萃取。乾燥且濃縮，藉由製備型TLC(石油醚：EtOAc = 8:1 )純化’得到呈黃色泡泳狀之所需產物（90 mg，33% ): 343 201245116 lH NMR (400 MHz, CD3OD) δ 16.06 (s, 1H), 7.62 (s, 1H), 7.54-7.49 (m, 4H), 7.41-7.28 (m, ΠΗ), 5.39 (s, 2H), 5.27-5.25 (q, 2H), 4.03-3.99 (m, 2H), 3.80-3.76 (m3 1H), 3.51 (m, 1H), 3.24-3.20 (m, 2H), 3.05-2.95 (m, 1H), 2.53-2.34 (m, 10H), 2.33 (m, 1H), 2.20-2.16 (m, 1H), 1.95-1.71 (m, 2H), 1.58 (m, 1H), 0.31 (s, 3H), 0.19 (s, 3H), 〇.〇9 (s, 9H) ； MS (ESI) m/z 473·4 (M/2 + H)。Freshly prepared lDA (0.77 mmo, 1.08 mmol) was added to a solution of THF (2 mL) and then a solution of S31-3 (200 mg, 0.36 mmol) in THF (1 mL). It lasts for 5 minutes. A solution of the enone (140 mg, 0.29 mmol) in THF (0.5 mL) was then added dropwise at -78 °C. The reaction mixture was poured into EtOAc (20 mLEtOAc) Drying and concentrating, EtOAc (EtOAc: EtOAc = EtOAc) 16.06 (s, 1H), 7.62 (s, 1H), 7.54-7.49 (m, 4H), 7.41-7.28 (m, ΠΗ), 5.39 (s, 2H), 5.27-5.25 (q, 2H), 4.03- 3.99 (m, 2H), 3.80-3.76 (m3 1H), 3.51 (m, 1H), 3.24-3.20 (m, 2H), 3.05-2.95 (m, 1H), 2.53-2.34 (m, 10H), 2.33 (m, 1H), 2.20-2.16 (m, 1H), 1.95-1.71 (m, 2H), 1.58 (m, 1H), 0.31 (s, 3H), 0.19 (s, 3H), 〇.〇9 ( s, 9H) ; MS (ESI) m/z 473·4 (M/2 + H).

ΟΒη Ο HO Ξ Ο 0Βη 0TBS S31-5 合成化合物SU-5。 在-78°C下將苯基鋰之二正丁醚溶液（2 Μ，79 &quot;L， 0.158 mmol)逐滴添加至 S31-4 ( 50 mg，0.053 mmol)於 THF ( 1 mL )中之溶液中，形成橙色溶液。2分鐘後，在-78 °C下逐滴添加正丁基鋰之己烷溶液（2.5 Μ .，42 y L，0.106 mmol) ’形成黃色溶液β 2分鐘後，使C02 (穿過濃H2S04 兩次）在反應混合物中鼓泡2分鐘，且使溶液經1小時逐 漸升溫至室溫。反應物以飽和NH4C1中止，乾燥且濃縮。 該物質直接用於下一步驟中。MS (ESI) m/z 910.3 (M + H)。ΟΒη Ο HO Ξ Ο 0Βη 0TBS S31-5 Synthesis of compound SU-5. A solution of phenyllithium di-n-butyl ether (2 Μ, 79 &quot; L, 0.158 mmol) was added dropwise to s31-4 (50 mg, 0.053 mmol) in THF (1 mL). In the solution, an orange solution was formed. After 2 minutes, a solution of n-butyllithium in hexane (2.5 Μ., 42 y L, 0.106 mmol) was added dropwise at -78 °C. 'Yellow solution β was formed for 2 minutes, then C02 (through concentrated H2S04 two) The reaction mixture was bubbled for 2 minutes, and the solution was gradually warmed to room temperature over 1 hour. The reaction was quenched with saturated NH4C1, dried and concentrated. This material was used directly in the next step. MS (ESI) m/z 910.3 (M + H).

ΟΒη Ο ΗΟ Ξ Ο OTBS 344 201245116 S31-6-1 合成化合物S31-6-1。 向 S31-5 ( 50 mg，0.05 5 mmol )及丙 _卜胺（2〇 yL， 0.237 mmol)於 DMF( 1 mL)中之溶液中添加 H〇Bt( 7 mg， 0.055 mmol)及 EDCI ( 21 mg ’ 0·011 mmol)。在室溫下授 拌反應混合物隔夜。濃縮反應混合物且藉由製備型TLC (石 油醚：EtOAc = 5:1 )純化，得到 S31-6-1 ( 30 mg，60%，經 兩個步驟）：MS (ESI) m/z 476.3 (M/2+H)。ΟΒη Ο ΗΟ Ξ Ο OTBS 344 201245116 S31-6-1 Synthetic compound S31-6-1. Add H〇Bt (7 mg, 0.055 mmol) and EDCI (21) to a solution of S31-5 (50 mg, 0.05 5 mmol) and propylamine (2 〇yL, 0.237 mmol) in DMF (1 mL) Mg '0·011 mmol). The reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was concentrated and purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc /2+H).

H2 合成化合物。 將HF水溶液（40%溶液，1 mL )添加至化合物S31-6-1 (30mg’32 ymol)於THF ( 2 mL )中之溶液中。2小時 後’將反應混合物傾入飽和K2HP〇4溶液（1 〇 mL )中且用 EtOAc ( 3xl〇 mL)萃取。經合併之萃取物經Na2S〇4脫水’ 過濾且濃縮。將該物質溶解於曱醇（1 mL )中，且添加4 Μ HC1 之甲醇溶液（0.10 mL)及 1〇〇/0 Pd/C ( Aldrich，2 mg)。 引入氫氣氛圍。1小時後，LCMS指示單苯甲基及二苯曱基 中間物。過濾反應混合物，且再添加2 mg 10% Pd/C。在室 溫下攪拌混合物1小時。過濾反應混合物，濃縮濾液且藉 由製備型HPLC純化物質，得到S31-7-1 ( 4.7 mg，23%， 經兩個步驟）：NMR (400 MHz，CD3OD) &lt;5 7.41 (m，5H)， 345 201245116 7.06 (s, 1H), 4.56 (m, 1H), 4.30 (m, 1H), 4.13 (s, 1H), 3.62 (m, 1H), 3.44-3.43 (m, 2H), 3.07-3.00 (m, 9H), 2.93-2.88 (m, 1H), 2.68-2.62 (m, 2H), 2.31-2.21 (m, 4H), 1.71-1.62 (m, 3H), 1.03 (m, 3H) ; MS (ESI) w/z 659.1 (M+H) 〇 實施例32.抗細菌活性 根據以下方案研究本發明化合物之抗細菌活性。 最小抑制濃度（Minimum Inhibitory Concentration; MIC)檢定 根據臨床及貫驗室標準協會（Clinical and Laboratory Standards Institute，CLSI )指導（例如，CLSI. Performance standards for antimicrobial susceptibility testing;第 19 次資 訊補充.CLSI 文件 M100-S19, CLSI, 940 West Valley Road， Suite 1400, Wayne, Pennsylvania 19087-1898, USA, 2009 ) 測定MIC。簡言之，融化冷凍之細菌菌株且於穆勒-辛頓培 養液（Mueller Hinton Broth ; MHB )或其他適當培養基（鏈 球菌屬需要jk液且嗜血桿菌屬（)需要氣化血 紅素（hemin )及NAD )上繼代培養。在培育隔夜後，在穆 勒-辛頓ϊ复脂（Mueller Hinton Agar)上繼代培養菌株且再 培育隔夜。針對適當之菌落形態及缺乏污染觀察菌落。選 擇分離之菌落以製備相當於0.5麥氏標準（McFarland standard)的起始接種物。使用MHB將起始接種物1:125 稀釋（此為工作接種物）供進一步使用。藉由在無菌水中 稀釋至5 · 128 mg/mL之最終濃度來製備測試化合物。將抗生 素（冷;東儲存、融化且在融化3小時内使用）及化合物進 346 201245116 . 一步稀釋至所需之工作濃度。 如下進行檢定。將5O0MHB添加至96孔板之孔212 中。將100 μί適當稀釋之抗生素添加至孔t中。自孔！移 出50 μΧ抗生素且添加至孔2中，且藉由上下抽吸5次混合 孔2之内含物。移出孔2中之50 混合物且添加至孔^ 中，且如上混合。以相同方式繼續連續稀釋直至孔12為止。 自孔12移出50 gL以使所有孔皆含有5〇此。接著將5〇此 工作接種物添加至所有測試孔中。藉由將5〇 工作接種物 及50 pL MHB添加至空孔中來製備生長對照孔。接著根據 CLSI準則在35。(：下培育各板隔夜，自培育箱中移出且使用 板讀取鏡對來自各孔之細菌生長進行讀取。記錄測試化合 物預防細菌生長之最小抑制濃度（MIC )。 實施例： 1 2 3 4 5 6 7 8 9 10 11 [Abt] 32 16 8 4 2 1 0.5 0.25 , _ + 0.125 0.06 0.03 Υ£β 0.015 生長 - - - - - + + + + + + - ^-1--1___ I 卞 丨十丨 + + [abt]=孔t之抗生素濃度（μ§/ηι1)生長=細菌生長（混濁 說明：MIC = 2 jig/mL 測定接種物濃度之方案（活菌計數） 將5〇μ1接種物抽吸至孔i中。將9〇μ1無菌〇.9%NaCi 抽吸至96孔微量滴定板之孔2_6中。自孔i移出ι〇 4[且 #其添加至孔2中’繼而混合。自孔2移巾1〇叫且與孔3 之内含物混合，且依此類推形成連續稀釋液直至孔6。自各 347 201245116 孔移出1 0 μί且點於適當瓊脂板上。將板置於3 5。(：培育箱 中隔夜。若1 0 pL斑點中存在不同菌落，則對其進行計數。 藉由將菌落數乘以稀釋因數計算活菌計數。 孔之斑點 1 2 3 4 5 6 稀釋因數 102 1Ό3 104 105 106 107〜 細菌菌株 在最小抑制濃度（MIC )檢定中研究下文列出之細菌菌 株。使用主要來自美國且於2007-2010年分離之臨床菌株來 測定MIC50/MIC90值（分別抑制50%或90%之物種集合的 最低濃度）。 生物體 菌株名稱 關鍵特性 金黃色葡萄球菌 SA100 ATCC 13709，MSSA，史密斯菌株（Smith strain) 金黃色葡萄球菌 SA101 ATCC29213，CLSI 品質控制菌株，MSSA 金黃色葡萄球菌 SA191 HA-MRSA，四環素抗性，肺感染模型分離抶 金黃色葡萄球菌 SA161 HA-MRSA，四環素抗性，如(M) 金黃色葡萄球菌 SA158 四環素抗性，如(K) 表皮葡萄球菌 (Staphylococcus epidermidis ) SE164 ATCC 12228，CLSI品質控制菌株，四環素抗性 糞腸球菌 EF103 ATCC29212，tet-1/R，對照菌株 糞腸球菌 EF159 四環素抗性，如(M) 糞腸球菌 EF327 創口分離株（US)，如〇1) 屎腸球菌 EF404 血液分離株（US)，如(M) 肺炎鏈球菌 [Streptococcus pneumoniae ) SP106 ATCC 49619 ’ CLSI品質控制菌株 肺炎鏈球菌 SP160 四環素抗性，/e/(M) 化膿鏈球菌 {Streptococcus pyogenes ) SP312 2009臨床分離株，如(Μ) 化膿鏈球菌 SP193 用於功效模型之化膿鏈球菌；tetS ; 對續醯胺敏感 流行性感冒嗜血桿菌 HI262 四環素抗性，安比西林（ampicillin)抗性 348 201245116 卡他莫拉菌 MC205 ATCC 8176’CLSI品質控制菌株 大腸桿菌 EC107 ATCC 25922，CLSI品質控制菌株 大腸桿菌 EC155 四環素抗性，如(A) P腸桿菌 EC878 MG1655 tolC::kan 大腸桿菌 EC880 ΙρχΑ 大腸桿菌 EC882 impA 大腸桿菌 EC200 MDR尿路致病性；血清型〇i7:K52:Hl8 ; UMN 026 ； trimeth/sulfa-R ； BAA-1161 陰溝腸桿菌 C Enterobacter cloacae ) EC108 ATCC 13047 &gt; wt 陰溝腸桿菌 EC603 尿液分離株（西班牙） 克留氏肺炎桿菌 KP109 ATCC 13883 &gt; wt 克留氏肺炎桿菌 KP153 四環素抗性，如(A)，MDR，ESBL+ 克留氏肺炎桿菌 KP194 ATCC 700603，1994 ESBL+尿液分離株 〔來自維吉尼亞（Virginia))，MDR 克留氏肺炎桿菌 KP457 2009 ESBL+，CTX-M，OXA 奇異變形桿菌 C Proteus mirabilis ) PM112 ATCC 35659 奇異變形桿菌 PM385 尿液ESBL+分離株 綠膿桿菌 PA111 ATCC 27853，wt，對照菌株 綠膿桿菌 PA169 Wt，PA170-173 之親本 綠膿桿菌 PA170 流出泵MexAB-OprM過度產生劑 綠膿桿菌 PA173 ΡΑΠΟΔ/ηβχΖ; MexXY-(缺少功能性流出泵） 綠膿桿菌 PA555 ATCC BAA-47，野生型菌株PAOl 綠膿桿菌 PA556 多重-Mex流出泵剔除菌株 綠膿桿菌 PA689 血液分離株（US) 綠膿桿菌 PA884 ATCC 35351 ;不明確之外膜突變； 對疏水性抗生素過度敏感 奇異變形桿菌 PM385 2008尿液分離株 〔來自美國中部東北地區之女性），具ES(3L產生性 綠膿桿菌 PA1145 鼠類肺炎模型中所用之菌株 綠膿桿菌 PA673 2009尿液分離株 〔來自美國中部東北地區之男性的導尿管） 綠膿桿菌 PA693 2009分離株 〔來自美國太平洋地區之女性的角膜刮片） 綠膿桿菌 PA694 2009尿液分離株（來自南大西洋之女性） 綠膿桿菌 PA695 2009尿液分離株（來自中部東南地區之女性） 349 201245116H2 Synthetic compound. An aqueous HF solution (40% solution, 1 mL) was added to a solution of compound S31-6-1 (30 mg &apos; The reaction mixture was poured into a saturated K.sub.2 solution (1 mL) and extracted with EtOAc (3.times. The combined extracts were dehydrated through Na 2 S 〇 4 filtered and concentrated. This material was dissolved in decyl alcohol (1 mL), and 4 Μ HCl solution of methanol (0.10 mL) and 1 〇〇/0 Pd/C (Aldrich, 2 mg) were added. A hydrogen atmosphere is introduced. After 1 hour, LCMS indicated the monobenzyl and diphenylguanidino intermediates. The reaction mixture was filtered, and an additional 2 mg of 10% Pd/C was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj , 345 201245116 7.06 (s, 1H), 4.56 (m, 1H), 4.30 (m, 1H), 4.13 (s, 1H), 3.62 (m, 1H), 3.44-3.43 (m, 2H), 3.07-3.00 (m, 9H), 2.93-2.88 (m, 1H), 2.68-2.62 (m, 2H), 2.31-2.21 (m, 4H), 1.71-1.62 (m, 3H), 1.03 (m, 3H) ; MS (ESI) w/z 659.1 (M+H) 〇 Example 32. Antibacterial activity The antibacterial activity of the compound of the present invention was investigated according to the following protocol. The Minimum Inhibitory Concentration (MIC) assay is based on the Clinical and Laboratory Standards Institute (CLSI) guidelines (eg, CLSI. Performance standards for antimicrobial susceptibility testing; 19th Information Supplement. CLSI Document M100) -S19, CLSI, 940 West Valley Road, Suite 1400, Wayne, Pennsylvania 19087-1898, USA, 2009) Determination of MIC. Briefly, the frozen bacterial strain is thawed and the Mueller Hinton Broth (MHB) or other suitable medium (Streptococcus requires jk solution and Haemophilus () requires gasification of heme (hemin) And NAD) subculture. After overnight incubation, the strains were subcultured on Mueller Hinton Agar and incubated overnight. Colonies were observed for appropriate colony morphology and lack of contamination. The isolated colonies were selected to prepare a starting inoculum equivalent to 0.5 McFarland standard. The starting inoculum was diluted 1:125 (this is the working inoculum) for further use using MHB. Test compounds were prepared by dilution in sterile water to a final concentration of 5 · 128 mg/mL. Antibiotics (cold; stored in the East, thawed and used within 3 hours of melting) and compounds in 346 201245116 . Dilute in one step to the desired working concentration. The verification is performed as follows. 5O0HB was added to well 212 of a 96-well plate. Add 100 μL of the appropriately diluted antibiotic to the well t. Since the hole! 50 μL of antibiotic was removed and added to well 2, and the contents of well 2 were mixed by pumping up and down 5 times. The 50 mixture in well 2 was removed and added to the wells and mixed as above. Continuous dilution was continued in the same manner up to the well 12. 50 gL was removed from the well 12 so that all wells contained 5 Å. Five ounces of this inoculum were then added to all test wells. Growth control wells were prepared by adding 5 〇 working inoculum and 50 pL MHB to the wells. Then according to the CLSI guidelines at 35. (: Each plate was incubated overnight, removed from the incubator and the growth of bacteria from each well was read using a plate reading mirror. The minimum inhibitory concentration (MIC) of the test compound to prevent bacterial growth was recorded. Example: 1 2 3 4 5 6 7 8 9 10 11 [Abt] 32 16 8 4 2 1 0.5 0.25 , _ + 0.125 0.06 0.03 Υ£β 0.015 Growth - - - - - + + + + + + - ^-1--1___ I 卞丨 十丨 + + [abt] = antibiotic concentration of hole t (μ§ / ηι1) growth = bacterial growth (turbidity: MIC = 2 jig / mL method for determining inoculum concentration (live count) 5 〇 μ1 inoculation The substance was aspirated into the well i. 9 μl of sterile 〇.9% NaCi was aspirated into the well 2_6 of the 96-well microtiter plate. The ι〇4 was removed from the well i [and # it was added to the well 2' and then mixed Transfer from the hole 2 to the squeak 1 and mix with the contents of the hole 3, and so on to form a serial dilution until the hole 6. Remove 10 μί from each 347 201245116 hole and place on the appropriate agar plate. At 35. (: overnight in the incubator. If there are different colonies in the 10 pL spot, count them. Calculate the live bacteria by multiplying the number of colonies by the dilution factor The spot of the hole 1 2 3 4 5 6 Dilution factor 102 1Ό3 104 105 106 107~ Bacterial strains The bacterial strains listed below were studied in the minimum inhibitory concentration (MIC) assay. The use was mainly from the United States and was isolated in 2007-2010. Clinical strains to determine MIC50/MIC90 values (respectively inhibit the lowest concentration of 50% or 90% of the species collection). Biological strain name key characteristics Staphylococcus aureus SA100 ATCC 13709, MSSA, Smith strain Golden yellow grapes Cocci SA101 ATCC29213, CLSI quality control strain, MSSA Staphylococcus aureus SA191 HA-MRSA, tetracycline resistance, lung infection model isolation, Staphylococcus aureus SA161 HA-MRSA, tetracycline resistance, such as (M) Staphylococcus aureus SA158 Tetracycline resistance, such as (K) Staphylococcus epidermidis SE164 ATCC 12228, CLSI quality control strain, tetracycline resistant Enterococcus faecalis EF103 ATCC29212, tet-1/R, control strain Enterococcus faecalis EF159 tetracycline resistance, such as (M) Enterococcus faecalis EF327 wound isolate (US), such as 〇1) Enterococcus faecalis EF404 blood isolate US), such as (M) Streptococcus pneumoniae SP106 ATCC 49619 'CLSI quality control strain S. pneumoniae SP160 tetracycline resistance, /e/(M) Streptococcus pyogenes SP312 2009 clinical isolate, such as (Μ) Streptococcus pyogenes SP193 Streptococcus pyogenes for efficacy model; tetS; Sustained by guanidine-sensitive Haemophilus influenzae HI262 Tetracycline resistance, ampicillin resistance 348 201245116 Moraxella catarrhalis MC205 ATCC 8176'CLSI quality control strain Escherichia coli EC107 ATCC 25922, CLSI quality control strain Escherichia coli EC155 Tetracycline resistance, such as (A) Enterobacteria EC878 MG1655 tolC::kan Escherichia coli EC880 ΙρχΑ E. coli EC882 impA E. coli EC200 MDR urinary tract Pathogenicity; serotype 〇i7: K52: Hl8; UMN 026; trimeth/sulfa-R; BAA-1161 Enterobacter cloacae C. EC108 ATCC 13047 &gt; wt Enterobacter cloacae EC603 urine isolate (Spain) g K. pneumoniae KP109 ATCC 13883 &gt; wt Klebsiella pneumoniae KP153 tetracycline resistance, such as (A), MD R, ESBL+ K. pneumoniae KP194 ATCC 700603, 1994 ESBL+ urine isolate (from Virginia), MDR Klebsiella pneumoniae KP457 2009 ESBL+, CTX-M, OXA Proteus mirabilis PM112 ATCC 35659 Proteus mirabilis PM385 urine ESBL+ isolate Pseudomonas aeruginosa PA111 ATCC 27853, wt, control strain Pseudomonas aeruginosa PA169 Wt, PA170-173 parent Pseudomonas aeruginosa PA170 efflux pump MexAB-OprM overproduction agent green pus Bacillus PA173 ΡΑΠΟΔ/ηβχΖ; MexXY- (lack of functional efflux pump) Pseudomonas aeruginosa PA555 ATCC BAA-47, wild-type strain PAOl Pseudomonas aeruginosa PA556 Multiple-Mex outflow pump rejection strain Pseudomonas aeruginosa PA689 Blood isolate (US) Green Pseudomonas PA884 ATCC 35351; Unclear outer membrane mutation; Over-sensitive to hydrophobic antibiotics Proteus mirabilis PM385 2008 Urine isolate (from women in the northeastern United States) with ES (3L-producing Pseudomonas aeruginosa PA1145 rodent The strain used in the pneumonia model, Pseudomonas aeruginosa PA673 2009 urine isolate (from the northeastern United States) Catheter) Pseudomonas aeruginosa PA693 2009 isolate (corneal scraping from women in the Pacific) Pseudomonas aeruginosa PA694 2009 urine isolate (female from the South Atlantic) Pseudomonas aeruginosa PA695 2009 urine isolate ( Women from the southeastern part of the country) 349 201245116

鲍曼不動桿菌 (Acinetobacter baumannii) AB110 ATCC 19606 &gt; wt 鮑曼不動桿菌 AB250 囊腫性纖維化分離株，MDR 嗜麥芽窄食單胞菌 ^ Stenotrophomonas maltophilia) SM256 囊腫性纖維化分離株，MDR 洋蔥伯克霍爾德氏菌 {Burkholderia cenocepacia) BC240 囊腫性纖維化分離株，MDR *MDR :多重抗藥性；MRSA :二甲氧苯青黴素抗性金 黃色葡萄球菌；MSS A :二甲氧苯青黴素敏感性金黃色葡萄 球菌；HA-MRSA :醫院相關之MRSA ; iei(K):主要革蘭氏 陽性四環素流出機構；iei(M):主要革蘭氏陽性四環素核糖 體保護機構；ESBL+ :超廣譜卢-内醯胺酶 結果 本發明化合物之最小抑制濃度（MIC )值提供於表1至 表7中。表中名稱A、B及C定義如下：「A」=等於或低 於三個對照組中的任一者關於該菌株所示的最低MIC ;「C」 =等於或高於三個對照組中的任一者關於該菌株所示的最 高MIC ; 「B」=所有其他情形（例如，低於三個對照組中 的任一者所示的最高MIC，但高於三個對照組中的任一者 所示的最低ΜIC )。 350 201245116 BC240 U u U CJ u u pq CJ U o CQ CQ u CQ u u 〇 u u u SM256 u u 〇 &lt; u o C o u o U (J u &lt; &lt; (J u u u u AB250 o &lt; U &lt; u u &lt; &lt; c &lt; U &lt; u &lt; &lt; u &lt; u &lt; u PA173 &lt; CQ U H 之 CQ u &lt; &lt; &lt; &lt; U &lt; &lt; &lt; PQ u &lt; &lt; &lt; u PA169 u U U U U u u u u u U u u CQ CQ u u CJ u o PM112 35659 CQ U u CQ U u CQ CQ CQ CQ 〇 &lt; CQ &lt; &lt; u CQ CQ CQ u KP194 700603 H U u CQ U u CQ CQ &lt; PQ 卜 CQ U &lt; &lt; o CQ CQ &lt; u KP153 tetA U CQ u &lt; CQ u &lt; CQ &lt; &lt; u &lt; u &lt; &lt; o 0Q &lt; &lt; CQ EC 155 tetA 〇 CQ u CQ CQ u CQ CQ &lt; CQ CJ CQ o CQ &lt; u CQ CQ &lt; 0Q EC 107 25922 0Q CQ U PQ CQ u CQ CQ PQ CQ CQ CQ CQ &lt; CQ u CQ CQ &lt; CQ MC205 8176 CQ 〇 U &lt; 0Q u &lt; CQ &lt; &lt; DQ &lt; U &lt; &lt; u &lt; CQ &lt; U HI262 33929 &lt; 〇 〇 &lt; 〇 u &lt; &lt; &lt; &lt; 卜 &lt; &lt; &lt; &lt; o &lt; &lt; &lt; a SP193 8668 CQ OQ U &lt; CQ u &lt; CQ CQ CQ CQ &lt; CQ &lt; &lt; u CQ CQ &lt; CQ SP160 tetM ffl CQ CQ CQ CQ CQ CQ CQ U CQ CQ CQ CQ CQ CQ CQ 0Q CQ SP106 49619 CQ CQ u &lt;C &lt; u c CQ &lt; &lt; H &lt; (Ώ &lt; &lt; u &lt; &lt; &lt; CQ EF159 tetM U CQ CQ CQ CQ CQ CQ CQ CQ CQ CQ CQ U CQ CQ CQ CQ U 03 CQ SE164 12228 U &lt; CQ &lt; &lt; CQ &lt; &lt; &lt; &lt; m &lt;d ffl &lt; &lt; CQ &lt; &lt; &lt; m SA158 tetK H CQ CQ &lt; CQ CQ &lt; CQ CQ &lt; CQ &lt; CQ &lt; &lt; U CQ CQ &lt; CQ SA161, 〇 CQ CO CQ CQ CQ CQ CQ CQ CQ PQ CQ U CQ U U CQ U U CQ SA100 13709' CQ CQ U &lt; CQ U &lt; CQ oa CQ &lt; &lt; U &lt; CQ U CQ CQ CQ U SA101 29213 U 〇 U CQ U U CO U CQ U ω CQ U CQ CQ U U 〇 U U 化合物 S7-13-1 S13-5-2-1-B Sll-8-4 S12-5-1 S13-5-1-4 S13-5-4-4 S13-5-2-1-A S12-5-3 S2-7-8 S8-7-5 S10-6-2 S13-5-1-1 S9-12-6 Sll-8-2 S8-7-2 Sll-8-5 S13-5-4-1 S9-12-2 S2-7-4 S13-5-4-3 201245116 BC240 u 〇 o u u u u u CQ u u u 〇 u CQ CQ u a a u u u SM256 &lt; u u u u u u u U H 〇 u u u &lt; &lt; u u u u u u AB250 &lt; &lt; u u u &lt; &lt; &lt; &lt; 〇 &lt; &lt; u u &lt; &lt; u u u &lt; &lt; u PA173 &lt; &lt; H 之 u NT NT &lt; &lt; U u H X &lt; o u &lt; NT u H 之 u &lt; &lt; CQ PA169 u u u u u u u u U u U CQ CJ o CQ u u U u u 03 U PM112 35659 CQ m u u u u m CQ U u u &lt; u u &lt; &lt; u &lt; u CQ &lt; U KP194 700603 &lt; u u CJ u u CQ U 卜 o u &lt; u u &lt; &lt; u &lt; a &lt; &lt; U KP153 tetA c CQ CQ u u CQ &lt; PQ u u CQ &lt; u u &lt; &lt; u &lt; CQ &lt; &lt; ffl EC155 tetA &lt; CQ OQ u u PQ &lt; OQ u u OQ &lt; o CJ &lt; CQ u CQ CQ &lt; CQ CQ EC 107 25922 CQ CQ CQ u CQ 0Q &lt; CQ CQ CQ 03 &lt; u CQ &lt; CQ CQ CQ CQ &lt; CQ CQ MC205 8176 &lt; &lt; CQ CJ U U &lt; &lt; CQ U U C u u &lt; &lt; o U u &lt; &lt; U HI262 33929 C &lt; U u u U &lt; &lt; U U U &lt; u u &lt; &lt; u &lt; u &lt; &lt; U SP193 8668 &lt; OQ CQ o u CQ &lt; &lt; OQ CQ CQ CQ CD u &lt; &lt; CQ CQ CQ CQ CQ CQ SP160 tetM CQ CQ CQ u CQ CQ CQ CQ OQ U OQ CQ CQ CQ CQ CQ CQ CQ CQ CQ CQ CQ SP106 49619 &lt; &lt; &lt; u u OQ &lt; &lt; OQ CQ CQ &lt; U U &lt; &lt; U CQ u &lt; &lt; OQ EF159 tetM CQ CQ CQ CQ CQ CQ CQ CQ PQ U m CQ CQ CQ CQ CQ CQ U CQ CQ OQ CQ SE164 12228 &lt; &lt; &lt; u CQ &lt; &lt; &lt; PQ U &lt; &lt; CQ m &lt; &lt; CQ aa CQ &lt; &lt; CQ SA158 tetK OQ &lt; CQ CQ CQ OQ &lt; CQ OQ U PQ CQ CQ CQ &lt; &lt; CQ CQ 0Q 0Q CQ OQ SA161 tetM U CQ CQ u m CQ CQ CQ CO U PQ CQ CQ m PQ CQ CQ u PQ U U CQ SA100 13709 CQ CQ CQ u u CQ CQ CQ &lt; OQ CQ CQ U CJ CQ &lt; a CQ U CQ CQ U ISA101 29213 U CQ U u u U U CQ CQ U U 03 U u CQ CQ u u U U CQ U 化合物 S8-7-3 Sll-8-1 S13-5-1-6 S7-13-2 S13-5-3-4 S13-5-3-3 S2-7-3 S13-5-1-5 S10-6-3 S7-13-3 S13-5-3-2 S2-7-7 S13-5-1-2 Sll-8-3 S8-7-1 S13-5-3-1 S13-5-1-3 S13-5-1-7 S8-7-4 S2-7-2 S2-7-1 S13-5-4-2 201245116 BC240 U 寸 00 SM256 u — — AB250 u 00 00 PA173 u &gt;32 o PA169 o (N CO (N γ&lt;·&gt; PM112 35659 u 寸 OO KP194 700603 u &lt;N m cs ro OO KP153 tetA o (N m CO — I EC 155 tetA u cn 00 »〇 o EC 107 25922 CQ 00 O 0.0313 MC205 8176 o 0.125 &lt;0.0156 &lt;0.0156 HI262 33929 u 一 — SP193 8668 CQ 0.0156 0.0156 SP160 tetM u oo &lt;N 0.0156 SP106 49619 CQ 0.25 &lt;0.0156 0.0156 EF159 tetM 0Q 00 v〇 0.0625 SE164 12228 CQ 寸 0.125 0.125 SA158 tetK CQ 0.0313 0.0625 SA161 tetM CQ (N 00 0.125 SA100 13709 QQ — 0.0625 0.0625 SA101 29213 U »n 0.0625 0.0625 化合物 S12-5-2 山環素 (Sancycline) 二甲胺四環素 泰格環黴素 201245116Acinetobacter baumannii AB110 ATCC 19606 &gt; wt Acinetobacter baumannii AB250 Cystic fibrosis isolate, MDR Stenotrophomonas maltophilia SM256 Cystic fibrosis isolate, MDR Onion Burkholderia cenocepacia BC240 Cystic fibrosis isolate, MDR *MDR: multidrug resistance; MRSA: methicillin-resistant Staphylococcus aureus; MSS A: methicillin sensitivity Staphylococcus aureus; HA-MRSA: hospital-related MRSA; iei (K): major Gram-positive tetracycline efflux mechanism; iei (M): major Gram-positive tetracycline ribosome protection mechanism; ESBL+: ultra- broad spectrum - Endactase Results The minimum inhibitory concentration (MIC) values of the compounds of the invention are provided in Tables 1 to 7. The names A, B and C in the table are defined as follows: "A" = equal to or lower than the lowest MIC shown by the strain control for any of the three control groups; "C" = equal to or higher than the three control groups Either of the highest MICs shown for this strain; "B" = all other cases (eg, below the highest MIC shown by any of the three control groups, but higher than any of the three control groups) The lowest Μ IC shown in one). 350 201245116 BC240 U u U CJ uu pq CJ U o CQ CQ u CQ uu 〇uuu SM256 uu 〇&lt; uo C ouo U (J u &lt;&lt; (J uuuu AB250 o &lt; U &lt; uu &lt;&lt; c &lt; U &lt; u &lt;&lt; u &lt; u &lt; u PA173 &lt; CQ UH CQ u &lt;&lt;&lt;&lt; U &lt;&lt;&lt; PQ u &lt;&lt;&lt; PA169 u UUUU uuuuu U uu CQ CQ uu CJ uo PM112 35659 CQ U u CQ U u CQ CQ CQ CQ 〇&lt; CQ &lt;&lt; u CQ CQ CQ u KP194 700603 HU u CQ U u CQ CQ &lt; PQ Bu CQ U &lt;&lt; o CQ CQ &lt; u KP153 tetA U CQ u &lt; CQ u &lt; CQ &lt;&lt; u &lt; u &lt;&lt; o 0Q &lt;&lt; CQ EC 155 tetA 〇CQ u CQ CQ u CQ CQ &lt; CQ CJ CQ o CQ &lt; u CQ CQ &lt; 0Q EC 107 25922 0Q CQ U PQ CQ u CQ CQ PQ CQ CQ CQ CQ &lt; CQ u CQ CQ &lt; CQ MC205 8176 CQ 〇U &lt; 0Q u &lt; CQ &lt;&lt; DQ &lt; U &lt;&lt; u &lt; CQ &lt; U HI262 33929 &lt;〇〇&lt; 〇u &lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt; o &lt;&lt;&lt; a SP193 8668 CQ OQ U &lt; CQ u &lt; CQ CQ CQ CQ &lt; CQ &lt;&lt; u CQ CQ &lt; CQ S P160 tetM ffl CQ CQ CQ CQ CQ CQ CQ U CQ CQ CQ CQ CQ CQ CQ 0Q CQ SP106 49619 CQ CQ u &lt;C &lt; uc CQ &lt;&lt; H &lt; (Ώ &lt;&lt; u &lt;&lt;&lt; CQ EF159 tetM U CQ CQ CQ CQ CQ CQ CQ CQ CQ CQ CQ U CQ CQ CQ CQ U 03 CQ SE164 12228 U &lt; CQ &lt;&lt; CQ &lt;&lt;&lt;&lt; m &lt;d ffl &lt CRT &lt CQ CQ PQ CQ U CQ UU CQ UU CQ SA100 13709' CQ CQ U &lt; CQ U &lt; CQ oa CQ &lt;&lt; U &lt; CQ U CQ CQ CQ U SA101 29213 U 〇U CQ UU CO U CQ U ω CQ U CQ CQ UU 〇UU Compound S7-13-1 S13-5-2-1-B Sll-8-4 S12-5-1 S13-5-1-4 S13-5-4-4 S13-5- 2-1-A S12-5-3 S2-7-8 S8-7-5 S10-6-2 S13-5-1-1 S9-12-6 Sll-8-2 S8-7-2 Sll-8 -5 S13-5-4-1 S9-12-2 S2-7-4 S13-5-4-3 201245116 BC240 u 〇ouuuuu CQ uuu 〇u CQ CQ uaauuu SM256 &lt; uuuuuuu UH 〇uuu &lt;&lt; uuuuuu AB250 &lt;&lt; uuu &lt;&lt;&lt;&lt;&lt;&lt;&lt; uu &lt; & Uuu &lt;&lt; u PA173 &lt;&lt; H u NT NT &lt;&lt; U u HX &lt; ou &lt; NT u H u &lt;&lt; CQ PA169 uuuuuuuu U u U CQ CJ o CQ uu U uu 03 U PM112 35659 CQ muuuum CQ U uu &lt; uu &lt;&lt; u &lt; u CQ &lt; U KP194 700603 &lt; uu CJ uu CQ U ou &lt; uu &lt;&lt; u &lt; a &lt;&lt; U KP153 tetA c CQ CQ uu CQ &lt; PQ uu CQ &lt; uu &lt;&lt; u &lt; CQ &lt;&lt; ffl EC155 tetA &lt; CQ OQ uu PQ &lt; OQ uu OQ &lt; o CJ &lt; CQ CQ CQ &lt; CQ CQ EC 107 25922 CQ CQ CQ u CQ 0Q &lt; CQ CQ CQ 03 &lt; u CQ &lt; CQ CQ CQ CQ &lt; CQ CQ MC205 8176 &lt;&lt; CQ CJ UU &lt;&lt; CQ UUC uu &lt; o U u &lt;&lt; U HI262 33929 C &lt; U uu U &lt;&lt; UUU &lt; uu &lt;&lt; u &lt; u &lt;&lt; U SP193 8668 &lt; OQ CQ Ou CQ &lt;&lt; OQ CQ CQ CQ CD u &lt;&lt; CQ CQ CQ CQ CQ CQ SP160 tetM CQ CQ CQ u CQ CQ CQ CQ OQ U OQ CQ CQ CQ CQ CQ CQ CQ CQ CQ CQ CQ SP106 49619 &lt;&lt;&lt; uu OQ &lt;&lt; OQ CQ CQ &lt; UU &lt;&lt; U CQ u &lt;&lt; OQ EF159 tetM CQ CQ CQ CQ CQ CQ CQ CQ PQ U m CQ CQ CQ CQ CQ CQ U CQ CQ OQ CQ SE164 12228 &lt;&lt;&lt; u CQ &lt;&lt;&lt; PQ U &lt;&lt; CQ m &lt;&lt; CQ aa CQ &lt;&lt; CQ SA158 tetK OQ &lt; CQ CQ CQ OQ &lt; CQ OQ U PQ CQ CQ CQ &lt; CQ CQ 0Q 0Q CQ OQ SA161 tetM U CQ CQ um CQ CQ CQ CO U PQ CQ CQ m PQ CQ CQ u PQ UU CQ SA100 13709 CQ CQ CQ uu CQ CQ CQ &lt; OQ CQ CQ U CJ CQ &lt; a CQ U CQ CQ U ISA101 29213 U CQ U uu UU CQ CQ UU 03 U u CQ CQ Uu UU CQ U Compound S8-7-3 Sll-8-1 S13-5-1-6 S7-13-2 S13-5-3-4 S13-5-3-3 S2-7-3 S13-5- 1-5 S10-6-3 S7-13-3 S13-5-3-2 S2-7-7 S13-5-1-2 Sll-8-3 S8-7-1 S13-5-3-1 S13 -5-1-3 S13-5-1-7 S8-7-4 S2-7-2 S2-7-1 S13-5-4-2 201245116 BC240 U inch 00 SM256 u — — AB250 u 00 00 PA173 u &gt;32 o PA169 o (N CO (N γ&lt;·&gt; PM112 35659 u inch OO KP194 700603 u &lt;N m cs ro OO KP153 tetA o (N m CO — I EC 155 tetA u cn 00 »〇o EC 107 25922 CQ 00 O 0.0313 MC205 8176 o 0.125 &lt;0.0156 &lt;0.0156 HI262 33929 u one - SP 193 8668 CQ 0.0156 0.0156 SP160 tetM u oo &lt;N 0.0156 SP106 49619 CQ 0.25 &lt;0.0156 0.0156 EF159 tetM 0Q 00 v〇0.0625 SE164 12228 CQ inch 0.125 0.125 SA158 tetK CQ 0.0313 0.0625 SA161 tetM CQ (N 00 0.125 SA100 13709 QQ — 0.0625 0.0625 SA101 29213 U »n 0.0625 0.0625 Compound S12-5-2 Sancycline dimethylamine tetracycline tetagcycline 201245116

201245116 BC240 υ o u u 寸 00 Ό SM256 D u u 〇 — — AB250 &lt; &lt; &lt; &lt; Ό 00 OO EC603 tetA CQ CQ &lt; CQ m &gt;32 fS PA689 U CQ CQ 〇 00 — PA884 35151 CQ CQ ω PQ 寸 — 0.0625 PA556 U 〇 CQ 〇 — 0.125 0.25 PA555 BAA-47 〇 o o 〇 &lt;N v〇 v〇 PM385 υ υ &lt; U OO KP457 CTX-M-15 u CQ &lt; U oo oo — 1 EC882 旨 CQ QQ &lt; 0Q 0.25 VO o ?l v〇 ll EC880 U a CQ CQ &lt; CQ ! i 0.25 &lt;0.0156 VO v*&gt; 〇 EC878 tolC CQ CQ CQ ra — 0.25 0.0313 (EC155 tetA DQ C &lt; 〇 (N m 00 o EC 107 25922 CQ CQ CQ CQ oo o 0.0313 SP312 tetM m ca CQ υ 寸 Ό &lt;0.0156 SP160 tetM CQ 0Q m &lt; oc (N v〇 ll EF404 tetM CQ o CQ CQ OO 0.0313 EF327 tetM CQ CQ m CQ 々 &lt;N CO 0.0625 SA158 tetK CQ CQ CQ CQ 0.0313 0.0625 | SA161 tetM U CJ m U cs 00 0.125 SA101 29213 u u o U V) 0.0625 0.0625 化合物 S4-8-5-B S3-7-6-A S3-7-3-B S4-8-1-B 山環素 二甲胺四環素 泰格環擻素 201245116 BC240 (J u u CQ u 'CQ u u CJ &lt; CQ CJ u o u u 〇 u 寸 OO Ό SM256 o u o &lt; υ &lt; o u u &lt; &lt; u u u u u o u — — AB250 &lt; &lt; &lt; &lt; &lt; &lt; u &lt; &lt; &lt; &lt; &lt; &lt; &lt; CJ u &lt; &lt; v〇 OO OO PA556 CQ u u 00 CQ &lt; CQ u CQ u CQ PQ CQ PQ u u CQ — 0.125 J 0.25 PA555 U υ υ &lt; 〇 &lt; CJ u u &lt; u L&gt; U U υ u &lt; 〇 fS PO v〇 PM112 35659 CQ PQ &lt; CQ &lt; &lt; &lt; u &lt; CQ OQ CQ OQ &lt; υ &lt; CQ OO 一 KP194 700603 s &lt; &lt; &lt; H 2 &lt; H 2： s &lt; &lt; &lt; &lt; &lt; H 2 H 2 &lt; &lt; (S &lt;N OO KP153 tetA &lt; CQ ω &lt; &lt; &lt; CQ &lt; &lt; &lt; &lt; &lt; &lt; &lt; 〇 CQ &lt; &lt; &lt;s ΓΛ OO EC155 tetA &lt; CQ CQ &lt; &lt; &lt; m &lt; CQ &lt; CQ &lt; CQ CQ 〇 DQ CQ &lt; &lt;N cn OO •Λ d EC 107 25922 CQ m oa &lt; 00 &lt; CQ CQ 03 &lt; DO CQ OQ CQ CQ m CQ 0Q 00 w-&gt; o 0.0313 MC205 8176 CQ υ &lt; CQ &lt; &lt; CQ QQ m &lt; &lt; CQ U CQ 〇 0Q CQ CQ 0.125 NO yn o &lt;0.0156 HI262 33929 &lt; u &lt; &lt; &lt; &lt; &lt; &lt; &lt; &lt; &lt; &lt; &lt; &lt; &lt; 〇 &lt; &lt; — 一 SP312 CQ 0Q CQ CQ CO CQ ω U 0Q CQ CQ 〇 m CQ 〇 〇 CQ U Ό &lt;0.0156 SP160 tetM CQ 03 CQ PQ CQ CQ CQ oa &lt; CQ CQ CQ CQ U pa CQ 0Q 00 (N 0.0156 SP106 49619 &lt; CQ &lt; &lt; &lt; &lt; CQ &lt; &lt; &lt; &lt; &lt; m OQ (J &lt; &lt; CQ 0.25 Ό ll 0.0156 1 EF159 tetM D CQ CQ CQ u PQ 0Q U u CQ CQ U u U U CQ CQ U OO v〇 0.0625 1 SE164 12228 &lt; CQ &lt; &lt; &lt; &lt; 0Q &lt; &lt; &lt; &lt; &lt; &lt; &lt; CQ &lt; &lt; &lt; 寸 0.125 0.125 1 SA158 tetK DQ CQ CQ &lt; CQ &lt; 0Q 0Q CQ &lt; &lt; CQ CQ ca CQ CQ DQ CQ 寸 0.0313 0.0625 SA161 tetM U CQ CQ 03 U CQ U U CJ CQ CQ U CJ u a υ CQ CJ (N OO 0.125 1 SA191 U &lt; CQ CQ U &lt; υ U U QQ CQ U U u u CJ CQ 〇 OO OO O SA101 29213 m υ U CQ &lt; u U U 03 CQ CQ U u a u 〇 u »n 0.0625 0.0625 化合物 S9-12-3 S13-5-3-1-C S14-6-1-A S13-5-3-1-A S9-12-1 S2-7-5-A S3-7-2 S2-7-5-B S9-12-4 S14-6-1-B S13-5-3-1-D S9-12-1-A S9-12-3-B S9-12-1-B S2-7-6-B S9-12-5 S13-5-3-1-B S9-12-3-A 山環素 二甲胺四環素 泰格環黴素1 201245116 KP153 tetA U (N m 00 KP109 13883 u oo 0.125 EC108 13047 u 00 (N 0.25 PA111 27853 u ΓΛ 00 AB110 19606 o 0.25 0.063 0.25 EC155 tetA o (N m oo EC 107 25922 CQ 00 Ό d 0.031 SP160 tetM CQ 00 (N 0.016 SP106 49619 0Q 1 ! 0.25 Ό »n o ?l 0.0156 EF159 tetM CQ 00 v〇 0.063 EF103 29212 CQ 00 0.031 SA158 tetK 寸 0.031 0.063 SA161 MRSA, tetM PQ &lt;N 00 0.125 SA100 13709 OQ 0.063 0.063 SA101 29213 〇 in o 0.063 0.063 化合物 S10-6-1 山環素 二甲胺四環素 泰格環黴素 201245116201245116 BC240 υ ouu inch 00 Ό SM256 D uu 〇 — — AB250 &lt;&lt;&lt;&lt;&lt; Ό 00 OO EC603 tetA CQ CQ &lt; CQ m &gt;32 fS PA689 U CQ CQ 〇00 — PA884 35151 CQ CQ ω PQ Inch — 0.0625 PA556 U 〇CQ 〇— 0.125 0.25 PA555 BAA-47 〇oo 〇&lt;N v〇v〇PM385 υ υ &lt; U OO KP457 CTX-M-15 u CQ &lt; U oo oo — 1 EC882 CQ QQ &lt; 0Q 0.25 VO o ?lv〇ll EC880 U a CQ CQ &lt; CQ ! i 0.25 &lt;0.0156 VO v*&gt; 〇EC878 tolC CQ CQ CQ ra — 0.25 0.0313 (EC155 tetA DQ C &lt; 〇(N m 00 o EC 107 25922 CQ CQ CQ CQ oo o 0.0313 SP312 tetM m ca CQ υ inch Ό &lt;0.0156 SP160 tetM CQ 0Q m &lt; oc (N v〇ll EF404 tetM CQ o CQ CQ OO 0.0313 EF327 tetM CQ CQ m CQ 々&lt;N CO 0.0625 SA158 tetK CQ CQ CQ CQ 0.0313 0.0625 | SA161 tetM U CJ m U cs 00 0.125 SA101 29213 uuo UV) 0.0625 0.0625 Compound S4-8-5-B S3-7-6-A S3-7 -3-B S4-8-1-B cyclin dimethylamine tetracycline taegin 201245116 BC240 (J uu CQ u 'CQ uu CJ &lt; CQ CJ uouu 〇u inch OO Ό SM256 ouo &lt; υ &lt; ouu &lt;&lt; uuuuuou — — AB250 &lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&gt;; v〇OO OO PA556 CQ uu 00 CQ &lt; CQ u CQ u CQ PQ CQ PQ uu CQ — 0.125 J 0.25 PA555 U υ υ &lt;〇&lt; CJ uu &lt; u L&gt; UU υ u &lt; 〇fS PO v〇PM112 35659 CQ PQ &lt; CQ &lt;&lt;&lt; u &lt; CQ OQ CQ OQ &lt; υ &lt; CQ OO - KP194 700603 s &lt;&lt;&lt;&lt;&lt; H 2 &lt; H 2: s &lt;&lt;&lt;&lt;&lt;&lt; H 2 H 2 &lt;&lt; (S &lt;N OO KP153 tetA &lt; CQ ω &lt;&lt;&lt; CQ &lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;s ΓΛ OO EC155 tetA &lt; CQ CQ &lt;&lt;&lt; m &lt; CQ &lt; CQ &lt; CQ CQ 〇 DQ CQ &lt; N cn OO • Λ d EC 107 25922 CQ m Oa &lt; 00 &lt; 00 &lt; CQ CQ 03 &lt; DO CQ OQ CQ CQ m CQ 0Q 00 w-&gt; o 0.0313 MC205 8176 CQ υ &lt; CQ &lt;&lt; CQ QQ m &lt;&lt; CQ U CQ 〇0Q CQ CQ 0.125 NO yn o &lt;0.0156 HI262 33929 &lt; u &lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt; &Lt;〇&lt;&lt; — A SP312 CQ 0Q CQ CQ CO CQ ω U 0Q CQ CQ 〇m CQ 〇〇CQ U Ό &lt;0.0156 SP160 tetM CQ 03 CQ PQ CQ CQ CQ oa &lt; CQ CQ CQ CQ U pa CQ 0Q 00 (N 0.0156 SP106 49619 &lt; CQ &lt;&lt;&lt;&lt; CQ &lt;&lt;&lt;&lt;&lt;&lt; m OQ (J &lt;&lt; CQ 0.25 Ό ll 0.0156 1 EF159 tetM D CQ CQ CQ u PQ 0Q U u CQ CQ U u UU CQ CQ U OO v〇0.0625 1 SE164 12228 &lt; CQ &lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt; CQ &lt;&lt;;&lt; inch 0.125 0.125 1 SA158 tetK DQ CQ CQ &lt; CQ &lt; 0Q 0Q CQ &lt;&lt; CQ CQ ca CQ CQ DQ CQ inch 0.0313 0.0625 SA161 tetM U CQ CQ 03 U CQ UU CJ CQ CQ U CJ ua υ CQ CJ (N OO 0.125 1 SA191 U &lt; CQ CQ U &lt; υ UU QQ CQ UU uu CJ CQ 〇OO OO O SA101 29213 m υ U CQ &lt; u UU 03 CQ CQ U uau 〇u »n 0.0625 0.0625 Compound S9-12-3 S13-5-3-1-C S14-6-1-A S13-5-3-1-A S9-12-1 S2-7-5-A S3-7-2 S2-7 -5-B S9-12-4 S14-6-1-B S13-5-3-1-D S9-12-1-A S9-12-3-B S9-12-1-B S2-7- 6-B S9-12-5 S13-5-3-1-B S9-12-3-A Cyclic dimethylamine tetracyclic Susiecycline 1 201245116 KP153 tetA U (N m 00 KP109 13883 u oo 0.125 EC108 13047 u 00 (N 0.25 PA111 27853 u ΓΛ 00 AB110 19606 o 0.25 0.063 0.25 EC155 tetA o (N m oo EC 107 25922 CQ 00 Ό d 0.031 SP160 tetM CQ 00 (N 0.016 SP106 49619 0Q 1 ! 0.25 Ό »no ?l 0.0156 EF159 tetM CQ 00 v〇0.063 EF103 29212 CQ 00 0.031 SA158 tetK inch 0.031 0.063 SA161 MRSA, tetM PQ &lt;N 00 0.125 SA100 13709 OQ 0.063 0.063 SA101 29213 〇in o 0.063 0.063 Compound S10-6-1 Cyclosodium dimethylamine tetracycline texathine 201245116

BC240 U 〇 CQ CQ &lt; ω CQ aa CQ u u u CQ o CJ o o CQ &lt; SM256 u o U U &lt; &lt; U u a o u u υ 〇 u o o u U υ tN u o &lt; U &lt; &lt; &lt; &lt; &lt; &lt; &lt; &lt; &lt; &lt; &lt; u &lt; &lt; &lt; &lt; EC603 tetA CQ CQ CQ U m CQ m CQ o u CQ CQ CQ CQ CQ u CQ a m CQ PA689 &lt; &lt; &lt; &lt; CQ CQ CQ CQ o o U U &lt; m 〇 u U OQ OQ &lt; PA884 35151 CQ OQ &lt; CQ CQ CQ O o u U CJ &lt; PQ U o U CO m CQ PA556 &lt; &lt; &lt; &lt; CQ O u 〇 u o U U &lt; u U u U u &lt; &lt; PA555 BAA-47 &lt; &lt; &lt; &lt; &lt; &lt; u U o u U υ &lt; u U o U u &lt; &lt; PM385 &lt; &lt; &lt; &lt; &lt; &lt; CQ m o U ca &lt; &lt; CQ u OQ &lt; &lt; &lt; KP457 CTX-M-15 &lt; &lt; &lt; &lt; PQ CQ u o o u U o &lt; OQ U o u o CQ &lt; EC882 imp CQ CQ &lt; &lt; &lt; &lt; &lt; &lt; CQ DQ U &lt; &lt; &lt; &lt; o &lt; &lt; &lt; &lt; EC880 -Ipxc CQ OQ &lt; &lt; &lt; &lt; &lt; &lt; υ &lt; U &lt; &lt; &lt; &lt; CJ &lt; &lt; m &lt; EC878 tolC CQ ca &lt; CQ &lt; &lt; u u o U o u &lt; &lt; o o u CQ CQ &lt; EC 155 tetA CQ CQ CQ m CQ CQ DQ CQ CQ CQ CQ QQ &lt; CQ u a CQ CQ EC107 25922 OQ m &lt; CQ &lt; &lt; CQ CQ CQ OQ OQ CQ &lt; &lt; CQ CQ CQ CQ CQ &lt; SP312 tetM OQ CD CQ CQ PQ CQ OQ CQ CQ CQ OQ CQ CQ CQ CQ CQ CO .CQ CQ CQ SP160 tetM QQ CD OQ CQ OQ CQ OQ CQ CQ CQ CQ QQ &lt; &lt; &lt; OQ CQ &lt; aa &lt; EF404 .tetM CQ OQ CQ m OQ CQ 03 CQ OQ CQ CQ CQ CO CQ CQ CQ CQ CQ u DQ EF327 tetM U OQ CQ m CQ CQ OQ CQ CQ CQ OQ CQ CQ m CQ CQ CQ CQ CQ CQ SA158 tetK PQ CQ ω &lt; &lt; DQ CQ PQ CQ CQ CQ &lt; &lt; CQ DQ CQ OQ &lt; &lt; SA161 tetM U U u CQ CQ CQ CD CQ QQ CQ m OQ OQ CQ CO CQ m CJ OQ SA101 29213 U (J u CQ CD CJ a 〇 U U o &lt; &lt; OQ U U CQ ffl CD 化合物 S24-5-2-A S25-3-A S16-8-5-A S16-8-5-B S16-8-1-A S16-8-1-B S16-8-2-A S16-8-2-B S16-8-3-A S16-8-3-B S16-8-4-A i S16-8-4-B S15-12-3-A S15-12-4-A S15-12-5-A S15-12-6-A S15-12-1-A S15-12-2-A S17-10-A S17-10-B 201245116BC240 U 〇CQ CQ &lt; ω CQ aa CQ uuu CQ o CJ oo CQ &lt; SM256 uo UU &lt;&lt; U uaouu 〇 〇uoou U υ tN uo &lt; U &lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&gt;&lt;&lt;&lt;&gt;&lt;&lt;&lt;&gt;&lt;&lt;&lt;&gt; CQ CQ oo UU &lt; m 〇u U OQ OQ &lt; PA884 35151 CQ OQ &lt; CQ CQ CQ O ou U CJ &lt; PQ U o U CO m CQ PA556 &lt;&lt;&lt;&lt;&lt; CQ O u 〇uo UU &lt; u U u U u &lt;&lt; PA555 BAA-47 &lt;&lt;&lt;&lt;&lt;&lt; u U ou U υ &lt; u U o U u &lt;&lt; PM385 &lt;&lt; &lt &lt;&lt;&lt; CQ mo U ca &lt;&lt; CQ u OQ &lt;&lt;&lt; KP457 CTX-M-15 &lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&gt; EC882 imp CQ CQ &lt;&lt;&lt;&lt;&lt;&lt;& CQ DQ U &lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt; U &lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&gt;&lt;&lt;&gt;&lt;&lt;&gt;&lt;&lt;&gt;&lt;&lt;&gt;&lt;&lt;&gt;&lt;&lt;&gt;&gt; EC 155 tetA CQ CQ CQ m CQ CQ DQ CQ CQ CQ CQ QQ &lt; CQ ua CQ CQ EC107 25922 OQ m &lt; CQ &lt;&lt; CQ CQ CQ OQ OQ CQ &lt;&lt; CQ CQ CQ CQ CQ &lt; SP312 tetM OQ CD CQ CQ PQ CQ OQ CQ CQ CQ OQ CQ CQ CQ CQ CQ CO .CQ CQ CQ SP160 tetM QQ CD OQ CQ OQ CQ OQ CQ CQ CQ CQ QQ &lt;&lt;&lt; OQ CQ &lt; aa &lt; EF404 .tetM CQ OQ CQ m OQ CQ 03 CQ OQ CQ CQ CQ CO CQ CQ CQ CQ CQ u DQ EF327 tetM U OQ CQ m CQ CQ OQ CQ CQ CQ OQ CQ CQ m CQ CQ CQ CQ CQ CQ SA158 tetK PQ CQ ω &lt &lt; DQ CQ PQ CQ CQ CQ &lt;&lt; CQ DQ CQ OQ &lt;&lt; SA161 tetM UU u CQ CQ CQ CD CQ QQ CQ m OQ OQ CQ CO CQ m CJ OQ SA101 29213 U (J u CQ CD CJ a 〇UU o &lt;&lt; OQ UU CQ ffl CD Compound S24-5-2-A S25-3-A S16-8-5-A S16-8-5-B S16-8-1-A S16-8 -1-B S16-8-2-A S16-8-2-B S16-8-3-A S16-8-3-B S16-8-4-A i S16-8-4-B S15-12 -3-A S15-12-4-A S15-12-5-A S15-12-6-A S15-12-1-A S15-12-2-A S17-10-A S17-10-B 201245116

BC240 &lt; 〇 CJ 0Q υ Ο ο ο CQ u CD o 〇 υ CQ u υ u u υ o SM256 &lt; o o &lt; ο ο ο U ο &lt; u o o u u &lt; CJ CJ o CJ o u ο in (Ν 5 &lt; &lt; o C u &lt; &lt; U ο &lt; &lt; &lt; &lt; &lt; &lt; o &lt; a υ CJ u 1 EC603 丨 1 tetA CQ ω DQ CQ ο CQ CQ CQ CQ &lt; CQ &lt; CQ &lt; m &lt; u CQ u u m CQ PA689 OQ u 〇 CQ ο 0Q CQ CJ &lt; &lt; &lt; &lt; OQ &lt; o CQ o o υ &lt; CQ DQ 1 PA884 35151 1 CQ o 〇 CQ u 03 CQ υ &lt; ca DQ m CQ CQ u CQ u υ CQ m CQ CQ PA556 CQ o U U ο U U ο &lt; &lt; &lt; &lt; CQ CQ u &lt; o 〇 CQ CQ OQ CQ PA555 BAA-47 &lt; o U &lt; ο α Ο CJ &lt; &lt; &lt; &lt; 〇 〇 o &lt; a u u 〇 &lt; U 1 PM385 &lt; (j U &lt; U 0Q CQ ο &lt; &lt; &lt; &lt; &lt; &lt; CJ &lt; o υ u &lt; CQ CQ 1 KP457 CTX-M-15! CQ u 〇 ω U U CQ CJ &lt; &lt; &lt; &lt; CQ ω u &lt; u o u CQ CQ CQ i EC882 imp &lt; 0Q OQ &lt; υ &lt; &lt; CQ CQ CQ U cn CQ u OQ &lt; a &lt; u U CQ CQ EC880 IpxC &lt; CQ U &lt; υ &lt; &lt; &lt; m OQ CQ m OQ OQ CQ PQ a &lt; CJ 〇 U υ EC87S tolC &lt; u 〇 &lt; ο ο 0Q Ο CQ CQ CQ CQ OQ CQ CQ &lt; u CQ CQ U CQ CQ EC 155 tetA &lt; CQ CQ &lt; ο CQ CQ CQ CQ CQ CQ m CQ CQ CO &lt; CQ CO o U ffl CQ 1 EC107 25922 &lt; CQ PQ &lt; CQ CQ &lt; CQ CD CQ CQ CQ CQ CQ CQ &lt; CQ CQ CQ CQ CQ CQ 1 SP312 | 1 tetM &lt; ω ω &lt; CQ &lt; &lt; CQ CQ m CQ CQ CQ m ca o CQ u CQ CQ m 1 SP160 tetM &lt; CQ CQ &lt; CQ &lt; &lt; CQ CQ CQ U CQ CQ CQ &lt; o &lt; u CQ CQ CQ EF404 tetM &lt; CQ CQ &lt; CQ &lt; &lt; CQ CQ cn 〇 〇 U CQ U CQ o m o U CQ CQ EF327 tetM CQ CQ &lt; CQ &lt; &lt; CQ υ OQ U DQ U CQ CQ m CQ CQ u υ CQ m SA158 tetK &lt; m &lt; 03 &lt; &lt; 0Q 〇Q &lt; m ca CQ CQ CQ &lt; QQ DQ OQ CD m CQ SA161 tetM CQ CD CD CQ CQ CQ ω CQ 〇 u u u U υ 〇 o 〇 CQ u υ υ CJ 1 SA101 29213 pa υ CJ ω υ DQ U 〇 CQ υ u U υ u &lt; U U u u u υ 化合物 S18-4-1-A S18-4-1-B S18-4-2-A S18-4-2-B S18-4-4-A 1 S18-4-4-B S18-4-3-A ； S18-4-3-B S23-7-1-A S23-7-2-A S24-5-1-A S26-4-A S24-6-1-A S24-6-2-A S29-15-2-A S29-15-2-B S29-15-3-A S29-15-3-B S30-3 S2-7-6-A S2-7-9-A S2-7-10-A 201245116 BC240 U u u u u u 寸 〇〇 ^ SM256 U u u &lt; u r ·&gt; 的 (J — ^ — ο to &lt;Ν u u &lt; &lt; u CJ 三 〇〇 〇〇 HC603 tetA &lt; u CD &lt; CQ B 32 &gt;32 2 PA689 &lt; &lt; U CQ &lt; CQ ^ - PA884 35151 CQ CO ω CQ CQ B 4 1 0.0625 PA556 &lt; &lt; u CQ CQ B 1 0.125 0.25 PA555 BAA-47 &lt; &lt; CJ &lt; υ υ S ^ ^ PM385 &lt; &lt; u &lt; &lt; CQ 〇〇 竺寸 KP457 CTX-M-15 CQ 0Q u CO CQ CJ oo oo — HC882 」m_P—- m 0Q &lt; &lt; 〇 c 0.25 &lt;0.0156 &lt;0.0156 EC880 IpxC CQ L) &lt; &lt; U C 0.25 &lt;0.0156 &lt;0.0156 EC878 tolC CQ CQ u &lt; CQ C 1 0.25 0.0312 EC155 tetA CQ o ffl &lt; CQ CQ P! «= 5 EC 107 25922 CQ CQ CQ &lt; m B 8 0.5 0.0312 SP312 tetM CQ υ m CQ CQ CQ 〇 ?. SP160 tetM CQ υ m &lt; m Ό CQ 〇〇 &lt;N 〇 EF404 tetM CQ u u £Q υ c 4 8 0.0312 EF327 tetM CO o CQ CQ υ C 4 32 0.0625 SA158 tetK CQ QQ CQ &lt; m B 4 0.0312 0.0625 SA161 tetM U 〇 CQ oa o C 2 8 0.125 1 SA101 29213 U U U CQ o C 0.5 0.0625 0.0625 化合物 S29-15-1-A S29-15-1-B S29-15-4-A S29-15-4-B S28-7-A Μ Λ. j? ^ s ^ ^Ϊ § s弓Ϊ诠 $ 4 201245116 BC240 OQ &lt; u 寸 OO 竺 SM256 U o u U - 2 - AB250 &lt; &lt; &lt; &lt; 〇〇 〇〇 EC603 tetA CQ CQ B 32 &gt;32 2 PA1145 Vivisource U u &lt;J &lt;N CJ 寸一g d PA556 &lt; &lt; U C 1 0.125 0.25 PA555 BAA-47 &lt; &lt; U ^ Ό 、 PM385 &lt; &lt; m &lt;：〇0 三寸 KP457 CTX-M-15 &lt; &lt; u CQ 00 〇〇 *— EC882 D. CQ &lt; CQ A 0.25 &lt;0.0156 &lt;0.0156 EC880 U a &lt; &lt; &lt; A 0.25 &lt;0.0156 &lt;0.0156 EC878 tolC CQ &lt; U A 1 0.25 0.0312 EC155 tetA CQ CQ CQ &lt; P! =〇 S EC 107 25922 &lt; &lt; CQ A 8 0.5 0.0312 SP160 tetM CQ &lt; CQ A 8 2 &lt;0.0156 1 EF404 tetM U CQ CQ B 4 8 0.0312 EF327 tetM CQ CQ CQ B 4 32 0.0625 SA158 tetK &lt; &lt; CQ A 4 0.0312 0.0625 SA161 tetM U CQ CQ B 2 S 0.125 SA101 29213 CQ CQ U B 0.5 0.0625 0.0625 S14-6-2-A S14-6-2-B SI 4-6-3-A 2 -3 Γ ^ &quot;Λ ^ 201245116BC240 &lt; 〇CJ 0Q υ Ο ο ο CQ u CD o 〇υ CQ u υ uu υ o SM256 &lt; oo &lt; ο ο ο U ο &lt; uoouu &lt; CJ CJ o CJ ou ο in (Ν 5 &lt;&lt; o C u &lt;&lt; U ο &lt;&lt;&lt;&lt;&lt;&lt;&lt; a &lt; a υ CJ u 1 EC603 丨1 tetA CQ ω DQ CQ ο CQ CQ CQ CQ &lt; CQ &lt; CQ &lt; m &lt; m &lt; u CQ uum CQ PA689 OQ u 〇CQ ο 0Q CQ CJ &lt;&lt;&lt;&lt; OQ &lt; o CQ oo υ &lt; CQ DQ 1 PA884 35151 1 CQ o 〇CQ u 03 CQ υ &lt ; ca DQ m CQ CQ u CQ u υ CQ m CQ CQ PA556 CQ o UU ο UU ο &lt;&lt;&lt;&lt;&lt; CQ CQ u &lt; o 〇CQ CQ OQ CQ PA555 BAA-47 &lt; o U &lt; ο α Ο CJ &lt;&lt;&lt;&lt; 〇〇o &lt; auu 〇 &lt; U 1 PM385 &lt; (j U &lt; U 0Q CQ ο &lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&gt; o υ u &lt; CQ CQ 1 KP457 CTX-M-15! CQ u 〇ω UU CQ CJ &lt;&lt;&lt;&lt;&lt; CQ ω u &lt; uou CQ CQ CQ i EC882 imp &lt; 0Q OQ &lt; υ &lt ; &lt; CQ CQ CQ U cn CQ u OQ &lt; a &lt; u U CQ CQ EC880 IpxC &lt; CQ U &lt; υ &lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt; EC87S tolC &lt; u 〇&lt; ο ο 0Q Ο CQ CQ CQ CQ OQ CQ CQ &lt; u CQ CQ U CQ CQ EC 155 tetA &lt; CQ CQ &lt; ο CQ CQ CQ CQ CQ CQ m CQ CQ CO &lt; CQ CO o U ffl CQ 1 EC107 25922 &lt; CQ PQ &lt; CQ CQ &lt; CQ CD CQ CQ CQ CQ CQ CQ &lt; CQ CQ CQ CQ CQ CQ 1 SP312 | 1 tetM &lt; ω ω &lt; CQ &lt;&lt; CQ CQ m CQ CQ CQ m ca o CQ u CQ CQ m 1 SP160 tetM &lt; CQ CQ &lt; CQ &lt;&lt; CQ CQ CQ U CQ CQ CQ &lt; o &lt; u CQ CQ CQ EF404 tetM &lt; CQ CQ &lt; CQ &lt;&lt; CQ CQ cn 〇〇 U CQ U CQ omo U CQ CQ EF327 tetM CQ CQ &lt; CQ &lt;&lt; CQ υ OQ U DQ U CQ CQ m CQ CQ u υ CQ m SA158 tetK &lt; m &lt; 03 &lt;&lt; 0Q 〇Q &lt; m ca CQ CQ CQ &lt; QQ DQ OQ CD m CQ SA161 tetM CQ CD CD CQ CQ CQ ω CQ 〇uuu U υ 〇o 〇CQ u υ υ CJ 1 SA101 29213 pa υ CJ ω υ DQ U 〇CQ υ u U υ u &lt; UU uuu υ Compound S18-4-1-A S18-4-1-B S18-4-2-A S18-4-2-B S18 -4-4-A 1 S18-4-4-B S18-4-3-A ; S18-4-3-B S23-7-1-A S23-7-2-A S24-5-1-A S26-4-A S24-6-1-A S24-6-2-A S29-15-2-A S29-15-2-BS 29-15-3-A S29-15-3-B S30-3 S2-7-6-A S2-7-9-A S2-7-10-A 201245116 BC240 U uuuuu inch〇〇^ SM256 U uu &lt ; ur ·&gt; (J — ^ — ο to &lt;Ν uu &lt;&lt; u CJ 三〇〇〇〇HC603 tetA &lt; u CD &lt; CQ B 32 &gt;32 2 PA689 &lt;&lt; U CQ &lt; CQ ^ - PA884 35151 CQ CO ω CQ CQ B 4 1 0.0625 PA556 &lt;&lt; u CQ CQ B 1 0.125 0.25 PA555 BAA-47 &lt;&lt; CJ &lt; υ υ S ^ ^ PM385 &lt;&lt; u &lt;&lt; CQ K inch KP457 CTX-M-15 CQ 0Q u CO CQ CJ oo oo — HC882 ”m_P—- m 0Q &lt;&lt; 〇c 0.25 &lt;0.0156 &lt;0.0156 EC880 IpxC CQ L) &lt;;&lt; UC 0.25 &lt;0.0156 &lt;0.0156 EC878 tolC CQ CQ u &lt; CQ C 1 0.25 0.0312 EC155 tetA CQ o ffl &lt; CQ CQ P! «= 5 EC 107 25922 CQ CQ CQ &lt; m B 8 0.5 0.0312 SP312 tetM CQ υ m CQ CQ CQ 〇?. SP160 tetM CQ υ m &lt; m Ό CQ 〇〇&lt;N 〇EF404 tetM CQ uu £Q υ c 4 8 0.0312 EF327 tetM CO o CQ CQ υ C 4 32 0.0625 SA158 tetK CQ QQ CQ &lt; m B 4 0.0312 0.0625 SA161 tetM U 〇CQ oa o C 2 8 0.125 1 SA101 29 213 UUU CQ o C 0.5 0.0625 0.0625 Compound S29-15-1-A S29-15-1-B S29-15-4-A S29-15-4-B S28-7-A Μ Λ. j? ^ s ^ ^Ϊ § s bow Ϊ $ 4 201245116 BC240 OQ &lt; u 寸 OO 竺 SM256 U ou U - 2 - AB250 &lt;&lt;&lt;&lt; 〇〇〇〇 EC603 tetA CQ CQ B 32 &gt;32 2 PA1145 Vivisource U u &lt;J &lt;N CJ inch-gd PA556 &lt;&lt; UC 1 0.125 0.25 PA555 BAA-47 &lt;&lt; U ^ Ό , PM385 &lt;&lt; m &lt;: 〇 0 three-inch KP457 CTX-M -15 &lt;&lt; u CQ 00 〇〇*— EC882 D. CQ &lt; CQ A 0.25 &lt;0.0156 &lt;0.0156 EC880 U a &lt;&lt;&lt; A 0.25 &lt;0.0156 &lt;0.0156 EC878 tolC CQ &lt; UA 1 0.25 0.0312 EC155 tetA CQ CQ CQ &lt; P! =〇S EC 107 25922 &lt;&lt; CQ A 8 0.5 0.0312 SP160 tetM CQ &lt; CQ A 8 2 &lt;0.0156 1 EF404 tetM U CQ CQ B 4 8 0.0312 EF327 tetM CQ CQ CQ B 4 32 0.0625 SA158 tetK &lt;&lt; CQ A 4 0.0312 0.0625 SA161 tetM U CQ CQ B 2 S 0.125 SA101 29213 CQ CQ UB 0.5 0.0625 0.0625 S14-6-2-A S14-6-2- B SI 4-6-3-A 2 -3 Γ ^ &quot;Λ ^ 201245116

201245116201245116

BC240 〇 u u u o u U u o 〇 υ ο a u υ o o o υ o o υ SM256 o u CJ CJ u u U CJ o 〇 u U o 〇 u CJ u u CJ o CJ υ AB250 u o O &lt; o o υ u υ U ο U u &lt; u o u &lt; u &lt; 〇 u EC603 tetA o o (J CJ u u CQ CQ CQ CQ υ DQ υ CQ CO υ u CQ CQ CQ υ υ PA693 o u u u u u o u 〇 υ u U u U u υ a U U υ u u PA673 o u u o o o u o u o υ υ o υ o ο o 〇 (J υ υ O PA669 o a u u o o 〇 a o ο υ o u u u u 〇 U a CJ u PA1145 Vivisource o u o a υ u o (J u u υ υ tj o u u o U U CJ u u PA556 o υ υ u o a 0Q CD CQ u υ CQ o 0Q u o υ υ U o u o PA555 !BAA-47 o u u u υ u u (J u o υ &lt; CJ o u u o υ u o o u PM385 o o o u u o ffl 〇 CQ o U &lt; υ CQ υ υ u υ u υ o o KP457 CTX-M-15 υ υ u u u CQ CQ CQ CQ CQ υ CQ u 03 CJ CJ u υ CJ u u CJ EC878 tolC o u u u o oa ΙΏ CQ CQ CQ U m u &lt; u u o CQ o u u CJ EC155 tetA u o o a o CQ CQ CQ CQ m CQ &lt; u CQ CQ o u &lt; CQ CQ o u EC 107 25922 υ o υ 03 m m CQ CQ PQ CQ 03 CQ QQ CQ CQ u CQ CQ QQ CQ u u SP160 tetM CO ω u CQ o o CQ PQ CQ CQ Ο CQ u CQ CQ u CQ CD CQ CQ QQ u EF404 tetM CO m m CQ υ CJ CQ U CQ CQ υ CQ u CQ u u u CQ U 0Q υ u EF327 tetM CO CQ CQ CQ u υ CQ CQ QQ CQ ο CQ u CQ o υ υ CQ CQ m CQ (J SA158 tetK CQ m m m CQ CQ CQ CQ QQ CQ CQ &lt; CQ &lt; CQ u CQ &lt; CQ CQ QQ 0Q SA161 tetM CO m CQ CQ a u U U 〇 υ ο CQ o CQ 〇 u u υ 〇 u CJ u SA101 29213 o o o υ u o U 〇 a υ U CQ o CQ u u u u 〇 u o υ 化合物 S19-10-1 S19-10-5-A S19-10-5-B S19-10-6 S20-9-2 i S20-9-3-A S20-9-3-B S20-9-4-A ; j S20-9-4-B S20-9-5-A S20-9-5-B S20-9-7-A S20-9-7-B S20-9-1-A S20-9-1-B S20-9-8-A S20-9-8-B S20-9-6-A S20-9-6-B S20-9-9-A S20-9-9-B S20-9-11-A 201245116BC240 〇uuuou U uo 〇υ ο au υ ooo υ oo υ SM256 ou CJ CJ uu U CJ o 〇u U o 〇u CJ uu CJ o CJ υ AB250 uo O &lt; oo υ u υ U ο U u &lt; uou &lt; u &lt; 〇u EC603 tetA oo (J CJ uu CQ CQ CQ CQ υ DQ υ CQ CO υ u CQ CQ CQ υ υ PA693 ouuuuuou 〇υ u U u U u υ a UU υ uu PA673 ouuooououo υ υ o υ o ο o 〇 (J υ υ O PA669 oauuoo 〇ao ο υ ouuuu 〇U a CJ u PA1145 Vivisource ouoa υ uo (J uu υ υ tj ouuo UU CJ uu PA556 o υ uo uoa 0Q CD CQ u υ CQ o 0Q uo υ υ U ouo PA555 !BAA-47 ouuu υ uu (J uo υ &lt; CJ ouuo υ uoou PM385 ooouuo ffl 〇CQ o U &lt; υ CQ υ υ u υ u υ oo KP457 CTX-M-15 υ υ uuu CQ CQ CQ CQ CQ υ CQ u 03 CJ CJ u υ CJ uu CJ EC878 tolC ouuuo oa ΙΏ CQ CQ CQ U mu &lt; uuo CQ ouu CJ EC155 tetA uooao CQ CQ CQ CQ m CQ &lt; u CQ CQ ou &lt; CQ CQ Ou EC 107 25922 υ o υ 03 mm CQ CQ PQ CQ 03 CQ QQ CQ CQ u CQ CQ QQ CQ uu SP160 tetM CO ω u CQ oo CQ PQ CQ CQ Ο CQ u CQ CQ u CQ CD CQ CQ QQ u EF404 tetM CO mm CQ υ CJ CQ U CQ CQ υ CQ u CQ uuu CQ U 0Q υ u EF327 tetM CO CQ CQ CQ u υ CQ CQ QQ CQ ο CQ u CQ o υ υ CQ CQ m CQ (J SA158 tetK CQ mmm CQ CQ CQ CQ QQ CQ CQ &lt; CQ &lt; CQ u CQ &lt; CQ CQ QQ 0Q SA161 tetM CO m CQ CQ au UU 〇 ο ο CQ o CQ 〇uu υ 〇u CJ u SA101 29213 ooo υ uo U 〇a υ U CQ o CQ uuuu 〇uo υ Compound S19-10-1 S19-10-5-A S19-10-5-B S19 -10-6 S20-9-2 i S20-9-3-A S20-9-3-B S20-9-4-A ; j S20-9-4-B S20-9-5-A S20-9 -5-B S20-9-7-A S20-9-7-B S20-9-1-A S20-9-1-B S20-9-8-A S20-9-8-B S20-9- 6-A S20-9-6-B S20-9-9-A S20-9-9-B S20-9-11-A 201245116

BC240 a u u o u (j u CQ CQ u &lt; u CQ u CJ u o u u u L) &lt; SM256： 1 1 o u u u u u u U u (j &lt; u u o o &lt; CJ o u U o AB250 o u u (J υ u u &lt; &lt; &lt; &lt; &lt; &lt; CJ &lt; &lt; &lt; &lt; &lt; u &lt; &lt; EC603 tetA u υ u u υ u u CQ CQ CQ &lt; CO CQ u CQ CQ CQ CQ u CD &lt; PA693 a u u (J u u (J &lt; &lt; 〇 &lt; u U o a (J o U U υ U &lt; PA673 u u u υ u υ u &lt; &lt; U &lt; υ &lt; o a 〇 &lt; o u CJ U &lt; PA669 u u o u u u u &lt; &lt; U &lt; υ &lt; o o U &lt; u a o U &lt; PA1145 Vivisource u u u u υ υ u a U U CJ o a o a U u u CJ u U υ PA556 CJ u u u o 〇 υ &lt; &lt; 〇 CQ u tj u o 〇 o o o o CQ &lt; PA555 BAA-47 u u o o u u u &lt; &lt; υ &lt; u &lt; u u U &lt; o υ u U &lt; PM385 u u u o tj u u &lt; &lt; o &lt; u &lt; u CQ U &lt; CQ u u CQ &lt; KP457 CTX-M-15 u o u o u o u &lt; &lt; o &lt; u CQ u U □3 CQ Q u CQ &lt; EC878 tolC CQ 〇 u u ο u o CQ &lt; m &lt; o &lt; o o u CQ CQ a u CQ &lt; EC155 tetA u u 0Q CQ u 0Q υ OQ PQ CQ &lt; 00 &lt; CQ CQ CQ &lt; CQ CQ o CQ &lt; EC 107 25922 OQ u m υ υ 〇 u &lt; &lt; CQ &lt; 0Q &lt; CQ CQ PQ &lt; CQ m CQ 0Q &lt; SP160 telM QQ CQ CQ CQ u qq CQ CQ &lt; 03 &lt; QQ &lt; U CQ CQ &lt; &lt; m υ QQ &lt; EF404 tetM U U u U u u 〇 CJ CQ o CQ 0Q CQ CQ CQ CQ CQ CQ ω u U CQ EF327 tetM U u CQ CQ u CQ CO u CQ CQ 0Q CQ CQ CQ CQ CQ CQ CQ m u U CQ SA158 tetK CQ CO CQ m CQ CQ CQ &lt; &lt; CQ &lt; CQ &lt; CQ CQ CQ &lt; CQ m CQ m &lt; SA161 tetM U u o o o U U CJ CQ m CQ CQ CQ CQ CQ CQ CQ 〇 CQ CJ u CQ SA101 29213 U u u u u U U CQ CQ u CQ U U U U &lt; 〇 a u CQ CQ 化合物 S20-9-11-B S20-9-10-A S20-9-10-B S20-9-12 S20-9-14-A S20-9-13 S20-9-15-B S21-16-1-A S21-16-1-B S21-16-3-A S21-16-3-B S21-16-4-A S21-16-4-B S21-16-5-A S21-16-5-B S21-16-6-A S21-16-6-B S21-16-2-B S21-17-1-B S21-16-7-A S22-8-2-A S22-8-2-B 201245116 BC240 U pa o u o u o 〇 ο ο U ο υ υ U υ 寸 〇〇 竺 SM256, o &lt; u u o u CJ u ο ο ο U CJ ο ο 〇 — 2 — AB250 &lt; &lt; &lt; u u &lt; &lt; o U υ υ υ ο υ U u 〇〇 EC603 tetA CQ CQ CQ &lt;J u CQ CQ υ ο U υ υ υ ω CQ 〜 &lt;N U S PA693 u 〇 〇 υ o U a u υ ο ο U υ υ U c &gt;32 | &gt;32 &gt;32 PA673 u U U u u U o υ ο ο ο ο υ ο ο 1 c ；&gt;32 &gt;32 32 PA669 o 〇 〇 o u 〇 a υ ο υ ο υ υ ο υ 1 ;c &gt;32 &gt;32 32 .PA1145 Vivisource u (J U υ u o u υ ο ο U U U U υ C 4 1 0.0625 PA556 i u υ υ u o u a υ ο ο υ ο υ &lt; CQ C 1 0.125 0.25 PA555 BAA-47 &lt;J &lt; &lt; u o o u ο a U U υ ο υ υ υ p! ' ^ S PM385 u &lt; υ u u CQ υ ο υ υ υ ο 00 &lt; (J 00 2 寸 KP457 CTX-M-15 u u o u o o o ο U ο υ υ ο C0 CQ CJ oo 〇〇 — EC878 tolC o CQ QQ o o u CQ υ ο U CQ ο CQ CQ CQ ! c 1 1 0.25 0.0312 EC155 tetA 0Q &lt; &lt; ω υ ω 00 U CJ υ QQ CQ PQ υ m υ P! « 5 EC 107 25922 CQ &lt; CQ 0Q o CQ CQ CJ CJ υ CQ CQ CQ CQ CQ c 8 0.5 0.0312 SP160 tetM DQ &lt; &lt; υ o &lt; &lt; υ ο υ 0Q CQ CQ 0Q CQ Ό U 〇〇 rs 〇 ?l EF404 tetM U QQ u 03 &lt; ο υ ο U υ ο υ Ο c 4 8 0.0312 EF327 tetM PQ 0Q m CQ m CQ &lt; ο ο U U ο υ ο υ B 4 32 0.0625 SA158 , tetK 丨 CD &lt; CQ CQ u m &lt; PQ υ DD CQ CQ CQ CQ ffl 1 1 B 4 0.0312 0.0625 SA161 tetM CQ CQ CQ u o CQ cd υ ο Ο Ο U U υ u C 2 S 0.125 SA101 29213 〇 U U o u u CD υ υ υ Ο υ υ υ (J C 0.5 0.0625 0.0625 化合物 S22-8-1-A S22-8-1-B S22-8-3-A 1 S22-8-3-B S22-8-4-A i S22-8-4-B S22-8-5-A S22-8-6-A S22-8-6-B S22-8-7-B S22-8-9-B S22-8-8-A S22-8-8-B S27-5 S27-6 *鉍 ^ ^ f « Σ2 -3 ^ ^ Λ ^ 201245116 實施例33·活體内模型及細胞檢定 小鼠全身感染方案 針對小鼠全身感染（敗血症）模型之活體内抗細菌活 性篩選化合物。在模型中，用金黃色葡萄球菌史密斯接種 物腹膜内注射CD」雌性小鼠（18_22公克），該接種物在 24至48小時内使知·存活率為〇%。達成此作用所需之細菌 劑量係先前經由毒性研究確定。在感染後f i小時，小鼠 靜脈内接受3 mg/nU或經口接$ 3〇 mg/mi。典型地，每個 劑量組處理6隻小鼠。評估及記錄動物存活率，持續48小 時。針料化合物記錄第48小時存活率百分比。存活率百 分比值提供於表8令。 表8BC240 auuou (ju CQ CQ u &lt; u CQ u CJ uouuu L) &lt; SM256: 1 1 ouuuuuu U u (j &lt; uuoo &lt; CJ ou U o AB250 ouu (J υ uu &lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&lt;&gt;&lt;&lt;&lt;&gt;&lt;&lt;&gt;&lt;&lt;&gt;&gt;&lt;&lt;&gt;&gt;&gt;&lt;&lt;&gt;&gt;&lt;&lt;〇&lt; u U oa (J o UU υ U &lt; PA673 uuu υ u υ u &lt;&lt; U &lt; υ &lt; oa 〇&lt; ou CJ U &lt; PA669 uuouuuu &lt;&lt; U &lt; υ &lt; oo U &lt; uao U &lt; PA1145 Vivisource uuuu υ υ UU CJ oaoa U uu CJ u U υ PA556 CJ uuuo 〇υ &lt;&lt; 〇CQ u tj uo 〇oooo CQ &lt; PA555 BAA- 47 uuoouuu &lt;&lt; υ &lt; u &lt; uu U &lt; o υ u U &lt; PM385 uuuo tj uu &lt; o &lt; u &lt; u CQ U &lt; CQ uu CQ &lt; KP457 CTX-M -15 uououou &lt;&lt; o &lt; u CQ u U □3 CQ Q u CQ &lt; EC878 tolC CQ 〇uu ο uo CQ &lt; m &lt; o &lt; oou CQ CQ au CQ &lt; EC155 tetA uu 0Q CQ u 0Q υ OQ PQ CQ &lt; 00 &lt CQ CQ CQ &lt; CQ CQ o CQ &lt; EC 107 25922 OQ um υ υ 〇u &lt;&lt; CQ &lt; 0Q &lt; CQ CQ PQ &lt; CQ m CQ 0Q &lt; SP160 telM QQ CQ CQ CQ u qq CQ CQ &lt; 03 &lt; QQ &lt; U CQ CQ &lt;&lt; m υ QQ &lt; EF404 tetM UU u U uu 〇CJ CQ o CQ 0Q CQ CQ CQ CQ CQ CQ ω u U CQ EF327 tetM U u CQ CQ u CQ CO u CQ CQ 0Q CQ CQ CQ CQ CQ CQ CQ mu U CQ SA158 tetK CQ CO CQ m CQ CQ CQ &lt;&lt; CQ &lt; CQ &lt; CQ CQ CQ &lt; CQ m CQ m &lt; SA161 tetM U Uooo UU CJ CQ m CQ CQ CQ CQ CQ CQ CQ 〇CQ CJ u CQ SA101 29213 U uuuu UU CQ CQ u CQ UUUU &lt; 〇au CQ CQ Compound S20-9-11-B S20-9-10-A S20- 9-10-B S20-9-12 S20-9-14-A S20-9-13 S20-9-15-B S21-16-1-A S21-16-1-B S21-16-3-A S21-16-3-B S21-16-4-A S21-16-4-B S21-16-5-A S21-16-5-B S21-16-6-A S21-16-6-B S21 -16-2-B S21-17-1-B S21-16-7-A S22-8-2-A S22-8-2-B 201245116 BC240 U pa ououo 〇ο ο U ο υ υ U υ inch inch 〇竺SM256, o &lt; uuou CJ u ο ο ο U CJ ο ο 〇 — 2 — AB250 &lt;&lt;&lt; uu &lt;&lt; o U υ υ ο υ U u 〇〇EC603 tetA CQ CQ CQ &lt;J u CQ CQ υ ο U υ υ υ ω CQ ~ &lt;NUS PA693 u 〇〇υ o U au υ ο ο U υ υ U c &gt;32 | &gt ;32 &gt;32 PA673 u UU uu U o υ ο ο ο ο υ ο ο 1 c ;&gt;32 &gt;32 32 PA669 o 〇〇ou 〇a υ ο υ ο υ υ ο υ 1 ;c &gt;32 &gt;32 32 .PA1145 Vivisource u (JU υ uou υ ο ο UUUU υ C 4 1 0.0625 PA556 iu υ uo uoua υ ο ο υ ο υ &lt; CQ C 1 0.125 0.25 PA555 BAA-47 &lt;J &lt;&lt; Uo ο a U U υ ο υ υ υ p! ' ^ S PM385 u &lt; υ uu CQ υ ο υ υ υ ο 00 &lt; (J 00 2 inch KP457 CTX-M-15 uuouooo ο U ο υ υ ο C0 CQ CJ oo 〇〇— EC878 tolC o CQ QQ oou CQ υ ο U CQ ο CQ CQ CQ ! c 1 1 0.25 0.0312 EC155 tetA 0Q &lt;&lt; ω υ ω 00 U CJ υ QQ CQ PQ υ m υ P! « 5 EC 107 25922 CQ &lt; CQ 0Q o CQ CQ CJ CJ υ CQ CQ CQ CQ CQ c 8 0.5 0.0312 SP160 tetM DQ &lt;&lt; υ o &lt;&lt; υ ο υ 0Q CQ CQ 0Q CQ Ό U 〇〇rs 〇 ?l EF404 tetM U QQ u 03 &lt; ο υ ο U υ ο υ Ο c 4 8 0.0312 EF327 tetM PQ 0Q m CQ m CQ &lt; ο ο UU ο υ ο υ B 4 32 0.0625 SA158 , tetK 丨CD &lt; CQ CQ um &lt; PQ υ DD CQ CQ CQ CQ ffl 1 1 B 4 0.0312 0.0625 SA161 tetM CQ CQ CQ uo CQ cd υ ο Ο Ο UU υ u C 2 S 0.125 SA101 29213 〇UU ouu CD υ υ υ Ο υ υ υ (JC 0.5 0.0625 0.0625 Compound S22-8-1-A S22-8-1 -B S22-8-3-A 1 S22-8-3-B S22-8-4-A i S22-8-4-B S22-8-5-A S22-8-6-A S22-8- 6-B S22-8-7-B S22-8-9-B S22-8-8-A S22-8-8-B S27-5 S27-6 *铋^ ^ f « Σ2 -3 ^ ^ Λ ^ 201245116 Example 33. In vivo model and cell assay Mouse systemic infection protocol Compounds were screened for in vivo antibacterial activity against a mouse systemic infection (sepsis) model. In the model, CDs of female mice (18-22 g) were intraperitoneally injected with S. aureus Smiths inoculum, and the inoculum was found to have a survival rate of 〇% within 24 to 48 hours. The bacterial dose required to achieve this effect was previously determined by toxicity studies. At f i hours after infection, the mice received 3 mg/nU intravenously or $3 〇 mg/mi orally. Typically, 6 mice were treated per dose group. Animal survival was assessed and recorded for 48 hours. The needle compound recorded the percentage of survival at 48 hours. The percentage of survival rate is given in Table 8. Table 8

化合物# S8-7-1 58- 7-2 511- 8-2 512- 5-1 S13-5-3-1 SI 3-5-2-1-A S13-5-3-1-A S12-5-3 S13-5-1-4 S13-5-1-6 S11-8-1 59- 12-3 S9-12-1 S2-7-7 S2-7-8 366 201245116 化合物# 存活£ Ψ (%) 靜脈内 經口 3 mg/kg 30 mR/kg S2-7-3 100% 100% S-2-7-4 100% 100% S2-7-2 100% 100% 除表8中之化合物之外，化合物S14-6-1-B在全身感染 方案中顯示100%保護作用。 嗜中性白血球減少性呼吸道肺炎鏈球菌感染模型 在經四環素抗性tet(M)肺炎鏈球菌菌株SP160攻毒之 嗜中性白金球減少性BALB/c鼠類肺感染模型中測試化合 物。藉由用環磷醯胺預處理使小鼠嗜中性白血球減少且經 由鼻内投予使其感染SP160。在感染後第2小時及第12小 時用30 mg/kg化合物對小鼠經口給藥或用1〇 mg/kg化合物 靜脈内給藥。在開始處理後第24小時，使小鼠安樂死且藉 由接種肺勻漿來定量肺中之細菌減少。數據記為相對於未 經處理之對照組的肺菌落形成單位之1〇gi(&gt;降低。測試結果 展示於表9中。 嗜中性白血球減少性呼吸道感染模型 在以經由鼻内投予感染之四環素抗性tet(M) MRS A菌 株SA191攻毒之嗜中性白血球減少性balB/c鼠類肺感染 模型中測試化合物。在第2小時及第12小時，以50 mg/kg 化合物對小鼠進行經口給藥或經由靜脈内投藥以10 mg/kg 對小鼠進行給藥。在開始處理後第24小時，使小鼠安樂死 且藉由接種肺勻漿來定量肺中之細菌減少。數據記為相對 於未經處理之對照組的肺菌落形成單位之1〇gi&lt;)降低。測試 367 201245116 結果展示於表9中。 D.尿路致病性大腸桿菌EC200及克留氏肺炎桿菌 ESBL分離株KP4S3之腎臟感染模型 在經由靜脈内注射以四環素抗性大腸桿菌菌株尿路致 病性EC200攻毒之BALB/c鼠類腎臟感染模型中測試化合 物。在感染後第12小時及第24小時，用2 mg/kg測試化合 物經口處理小鼠。對於靜脈内投藥，測試化合物劑量為5 mg/kg。在開始處理後第36小時，使小鼠安樂死且藉由接 種腎勻漿來定量腎臟中之細菌減少。結果在表6中報導為 相對於未經處理之對照組（未接受測試化合物）的腎臟中 菌洛形成單位（CFU )之1、降低。以與測試化合物相同 之方式投予劑量為2 mg/kg/經口給藥及靜脈内給藥的比較 化合物左氧氟沙星（levof丨〇xacin )。以與測試化合物相同之 方式投予劑量為20 mg/kg/靜脈内給藥的比較化合物美羅培 南（meropenem 結果展示於表9中且論述於下文。 亦在經由靜脈内注射（含2%卡拉膠（carageenenD以 左氧氟沙星抗性ESBL+菌株KP453攻毒之BALB/c鼠類腎 臟感染模型中測試化合物。在感染後第12小時及第24 I ，，用50 mg/kg測試化合物經口處理小鼠。對於靜脈内投 藥，測试化合物劑量為20 mg/kg *在開始處理後第36小時， 使小鼠安樂死且藉由接種勻漿來定量腎臟中之細菌減少、。 結果在表6中報導為相對於未經處理之對照組（未接a貝， 試化合物）的腎臟中菌落形成單位（Cfu)之丨〇g|〇又貝 比較化合物。 1〇 低 368 201245116 表9 化合物# 細菌接種量之loglO降低 SP160 tei(M)肺 SA191 MRSA 肺 EC200 UTI KP453 ESBL UTI 靜脈内 經口 靜脈内 經口 靜脈内 經口 靜脈内 經口 10 mg/kg 30 mg/kg 10 mg/kg 50 mg/kg 5 mg/kg 2 mg/kg 20 mg/kg 50 mg/kg S2-7-5-A &gt; -5.97 -2.50 -3.11 -2.47 -4.05 -3.07 -3.78 -1.49 S11-8-2 -0.06, 0.03 -1.78 -2.18 S12-5-1 -1.26 比較化合物： 化合物 劑量/途徑 模型 細菌接種量之LoglO降低 左氧氟沙星 2 mg/kg/經口給藥 EC200 UTI -3.8 左氧氟沙星 2-5 mg/kg/靜脈内給藥 EC200 UTI -4.88 美羅培南 20 mg/kg/靜脈内給藥 EC200 UTI -3.1 美羅培南 30 mg/kg/靜脈内給藥 KP ESBL UTI -1.44 E.大鼠中之藥物動力學研究 ' 在禁食（給藥前1 8個小時未進食）之雄性史泊格-多利 大鼠（Sprague-Dawley rat)(每組3隻動物）中，藉由向頸 靜脈中經靜脈内投藥1 mg/kg及經口管飼10 mg/kg來評估 測試化合物S2-7-5-A。在長達24小時内對各給藥途徑取10 個血漿樣本進入塗佈肝素之Vacutainer管中。使用内標藉由 LC/MS/MS定量測試化合物之血漿濃度。使用WinNONLIN 來測定PK參數土標準差（AUC、Cmax、CL、Vss及口服生 物利用率％ ( %F ))且列於表1 0中。 369 201245116 表ίο 化合物# 口服’大鼠（10 mg/kg) 靜脈内，大鼠（1 mg/kg) S2-7-5-A Cmax (ng/mL) 91.3 551 VA (h) 7.7 AUC (ng*h/mL) 963 1046 Cl 972 Vdss 7.71 %F 8.62% MIC9q檢定 使用表11中所列之細菌菌株之新近臨床分離株來測定 測試化合物及臨床比較物之最小抑制濃度（MIC)，關於 90%分離株為MIC9。，.且關於50%分離株為MIC5Q。根據如 上所述之臨床實驗室標準協會（CLSI )準則，藉由以96孔 格式進行微量滴定培養液稀釋來進行MIC。 藉由10倍連續稀釋測定活菌計數。在無菌〇 9〇/〇 NaC1 中製備稀釋液。將微升接種物及5種稀釋液中之每一種 接種於血液或穆勒·辛頓瓊脂板上，在37。(：及5% (：02下培 育隔夜且計數。結果展示於表11中。 370 201245116 饀a合 &quot;Sjd ^ 螺4茳 S y ® s § « m Sa _ g S 3 § 省ί £ I w f2 16/&gt;128 0.5 -&gt;128 16/&gt;128 0.5 -&gt;128 &gt;128/&gt;128 &gt;128-&gt;128 2/32 &lt;0.5 - &gt;64 8/32 0.5 - &gt;32 4/&gt;64 &lt;0.5-&gt;128 8/&gt;64 &lt;0.5 -&gt;128 0.25/1 &lt;0.063 - 2 VI ?ι 建它黴素 (gentamicin ) —._ i 8/&gt;32 &lt;0.25 - &gt;64 &gt;8 /&gt;32 &lt;0.25 - &gt;32 8/&gt;32 2-&gt;32 0.5/&gt;32 &lt;0.25 - &gt;32 &gt;32/&gt;32 &lt;0.5- &gt;32 2/&gt;32 &lt;0.25 - &gt;32 8/&gt;32 &lt;0.25 - &gt;32 2/32 0.5 - &gt;64 00 -jq 第3代 頭孢菌素 &gt;32/&gt;64 0.03 - &gt;64 &gt;32 /&gt;64 2-&gt;64 &gt;32/&gt;32 32 - &gt;32 &lt;0.5/&gt;32 &lt;0.5 - &gt;32 &gt;32/&gt;32 4-&gt;32 32/&gt;64 0.063 - &gt;64 &gt;32/&gt;64 0.5 - &gt;64 0.063/0.5 &lt;0.03 - &gt;64 &lt;0.5/32 &lt;0.03- &gt;64 i 氟喹諾酮 _i 4/&gt;32 &lt;0.016-&gt;64 8/&gt;32 0.03- &gt;64 &gt;32/&gt;32 8-&gt;32 &lt;0.25/&gt;4 0.03 - &gt;32 0.5/&gt;4 0.03 - &gt;32 0.5/&gt;32 &lt;0.016-&gt;32 &gt;4/32 0.03 - &gt;32 0.063/8 &lt;0.03-&gt;64 (N — d . 乂丨心 (N (N 〇 ο VI VI 碳青黴烯 0.063/16 0.03 - &gt;32 0.063/32 0.03 - &gt;32 32/&gt;32 4-&gt;32 t—H r-^ VI . CO —Ο VI Ο 0.063/0.25 0.03-1 0.031/0.5 &lt;0.016-&gt;32 0.031/0.13 &lt;0.016-&gt;32 4/16 0.063 - &gt;32 &lt;1/4 &lt;0.5 -4 泰格環黴素 0.5/2 0.13-16 1/4 0.25-16 C! · — 〇 0.5/2 0.063 -4 0.25/0.5 0.063 -1 0.25/1 0.031 - &gt;8 0.25/2 0.063 - &gt;8 00 — ^ 1 (N oo 5 , CN ^ o 化合物 S2-7-5-A 1 1 0.25/0.5 0.063 -8 0.25/1 0.063 -8 0.5/1 0.25 - 8 0.25/0.5 &lt;0.016 - 1 0.125/0.25 &lt;0.016-0.5 0.12/0.25 &lt;0.016-0.5 0.12/0.25 &lt;0.016-0.5 2/2 0.25 - 8 0.5/1 0.13-2 164 rH 生物體 1 克留氏肺炎桿菌 克留氏肺炎桿菌 ESpL 克留氏肺炎桿菌 KPC m s' t 5 軸亏 他1 2 產酸克雷伯氏桿菌 (ESPL) 大腸桿菌 大腸桿菌(ESpL) 奇異變形桿菌 m I5 晚| 掛1 201245116Compound # S8-7-1 58- 7-2 511- 8-2 512- 5-1 S13-5-3-1 SI 3-5-2-1-A S13-5-3-1-A S12- 5-3 S13-5-1-4 S13-5-1-6 S11-8-1 59- 12-3 S9-12-1 S2-7-7 S2-7-8 366 201245116 Compound # survival £ Ψ ( %) Intravenous oral 3 mg/kg 30 mR/kg S2-7-3 100% 100% S-2-7-4 100% 100% S2-7-2 100% 100% Except for the compounds in Table 8 In addition, compound S14-6-1-B showed 100% protection in a systemic infection regimen. Neutrophilic leukopenic pneumococcal infection model The compounds were tested in a neutrophil-reduced BALB/c murine lung infection model challenged with tetracycline-resistant tet(M) pneumococcal strain SP160. Mouse neutrophils were reduced by pretreatment with cyclophosphamide and infected with SP160 by intranasal administration. Mice were orally administered with 30 mg/kg of compound or intravenously with 1 mg/kg of compound at 2 hours and 12 hours after infection. At 24 hours after the start of treatment, the mice were euthanized and the reduction in bacteria in the lungs was quantified by inoculation of lung homogenates. Data are reported as 1 〇gi (&gt; reduction relative to the lung colony forming unit of the untreated control group. The test results are shown in Table 9. The neutrophilic reduced respiratory infection model is administered by intranasal infection. Tetracycline-resistant tet(M) MRS A strain SA191 challenged neutrophil-reducing balB/c mouse lung infection model test compound. At 2 hours and 12 hours, 50 mg/kg compound versus small Mice were orally administered or administered intravenously at 10 mg/kg. At 24 hours after the start of treatment, the mice were euthanized and the reduction in bacteria in the lungs was quantified by inoculating lung homogenates. Data are reported as 1 〇gi&lt;) reduction in lung colony forming units relative to untreated controls. Test 367 201245116 The results are shown in Table 9. D. Renal infection model of urinary pathogenic Escherichia coli EC200 and Klebsiella pneumoniae ESBL isolate KP4S3 in BALB/c rodent via intravenous injection of tetracycline-resistant Escherichia coli strain urinary pathogenic EC200 Test compounds in a kidney infection model. Mice were orally treated with a 2 mg/kg test compound at 12 hours and 24 hours after infection. For intravenous administration, the test compound dose was 5 mg/kg. At 36 hours after the start of treatment, the mice were euthanized and the reduction in bacteria in the kidney was quantified by inoculation of kidney homogenate. The results are reported in Table 6 as a decrease in the number of mycorrhizal forming units (CFU) in the kidney relative to the untreated control group (test compound not receiving). The comparative compound levofloxacin (levof丨〇xacin) was administered at a dose of 2 mg/kg/oral and intravenously in the same manner as the test compound. The comparative compound meropenem was administered at a dose of 20 mg/kg/intravenously in the same manner as the test compound (meropenem results are shown in Table 9 and discussed below. Also via intravenous injection (containing 2% carrageenan) (Carageenen D was tested in a BALB/c murine kidney infection model challenged with levofloxacin resistant ESBL+ strain KP453. At 12 hours and 24 I post infection, mice were orally treated with 50 mg/kg test compound. Intravenous administration, the test compound dose was 20 mg/kg * At 36 hours after the start of treatment, the mice were euthanized and the bacterial reduction in the kidney was quantified by inoculating the homogenate. The results are reported in Table 6 as relative to The untreated control group (not abalone, test compound) in the kidneys of the colony forming unit (Cfu) 丨〇g|〇贝贝 comparison compound. 1〇low 368 201245116 Table 9 Compound # bacterial inoculum loglO reduction SP160 tei (M) Lung SA191 MRSA Lung EC200 UTI KP453 ESBL UTI Intravenous Oral Oral Oral Oral Oral Oral 10 mg/kg 30 mg/kg 10 mg/kg 50 mg/kg 5 mg/kg 2 mg/kg 20 Mg/kg 50 mg/kg S2-7-5-A &gt; -5.97 -2.50 -3.11 -2.47 -4.05 -3.07 -3.78 -1.49 S11-8-2 -0.06, 0.03 -1.78 -2.18 S12-5-1 -1.26 Comparative Compounds: Compound Dose/Pathway Models LoglO Reduced Levofloxacin 2 mg/kg/oral Administration EC200 UTI -3.8 Levofloxacin 2-5 mg/kg/Intravenous EC200 UTI -4.88 Meropenem 20 mg /kg/ Intravenous EC200 UTI -3.1 Meropenem 30 mg/kg/Intravenous KP ESBL UTI -1.44 E. Pharmacokinetic Study in Rats' Fasting (18 hours before dosing) Intravenous Sprague-Dawley rats (3 animals per group) were administered intravenously to the jugular vein at 1 mg/kg and by oral gavage at 10 mg/kg. Evaluation of test compound S2-7-5-A. Ten plasma samples were taken from each route of administration into Vacutainer tubes coated with heparin for up to 24 hours. The compounds were quantified by LC/MS/MS using internal standards. Plasma concentration. The soil standard deviation (AUC, Cmax, CL, Vss and oral bioavailability % (%F)) of the PK parameters were determined using WinNONLIN and are listed in Table 10. 369 201245116 表ίο 化合物# Oral 'rat (10 mg/kg) intravenously, rat (1 mg/kg) S2-7-5-A Cmax (ng/mL) 91.3 551 VA (h) 7.7 AUC (ng *h/mL) 963 1046 Cl 972 Vdss 7.71 %F 8.62% MIC9q assay uses the recent clinical isolates of the bacterial strains listed in Table 11 to determine the minimum inhibitory concentration (MIC) of test compounds and clinical comparators, for 90% The isolate was MIC9. And about 50% of the isolates are MIC5Q. The MIC was performed by microtiter culture dilution in a 96-well format according to the Clinical Laboratory Standards Association (CLSI) guidelines as described above. Viable counts were determined by 10-fold serial dilution. Dilutions were prepared in sterile 〇 9〇/〇 NaC1. Each of the microliter inoculum and the 5 dilutions was inoculated onto blood or Muller Hinton agar plates at 37. (: and 5% (: 02 cultivating overnight and counting. The results are shown in Table 11. 370 201245116 饀a 合&quot;Sjd ^ snail 4茳S y ® s § « m Sa _ g S 3 § Province ί £ I w f2 16/&gt;128 0.5 -&gt;128 16/&gt;128 0.5 -&gt;128 &gt;128/&gt;128 &gt;128-&gt;128 2/32 &lt;0.5 - &gt;64 8/32 0.5 - &gt;32 4/&gt;64 &lt;0.5-&gt;128 8/&gt;64 &lt;0.5 -&gt;128 0.25/1 &lt;0.063 - 2 VI ?ι statamicin —._ i 8/&gt;32 &lt;0.25 - &gt;64 &gt;8 /&gt;32 &lt;0.25 - &gt;32 8/&gt;32 2-&gt;32 0.5/&gt;32 &lt;0.25 - &gt;32 &gt;32/&gt;32&lt;0.5-&gt;322/&gt;32&lt;0.25 - &gt;32 8/&gt;32 &lt;0.25 - &gt;32 2/32 0.5 - &gt;64 00 -jq 3rd generation Cephalosporin &gt;32/&gt;64 0.03 -&gt;64 &gt;32 /&gt;64 2-&gt;64 &gt;32/&gt;32 32 - &gt;32 &lt;0.5/&gt;32 &lt;0.5 - &gt;32 &gt;32/&gt;32 4-&gt;32 32/&gt;64 0.063 - &gt;64 &gt;32/&gt;64 0.5 - &gt;64 0.063/0.5 &lt;0.03 - &gt;64 &lt;0.5 /32 &lt;0.03-&gt;64 i fluoroquinolone_i 4/&gt;32 &lt;0.016-&gt;64 8/&gt;32 0.03-&gt;64 &gt;32/&gt;32 8-&gt;32 &lt;0.25/&gt;4 0.03 - &gt;32 0.5/&gt; 4 0.03 - &gt;32 0.5/&gt;32 &lt;0.016-&gt;32 &gt;4/32 0.03 - &gt;32 0.063/8 &lt;0.03-&gt;64 (N - d . 乂丨心(N (N 〇ο VI VI carbapenem 0.063/16 0.03 - &gt;32 0.063/32 0.03 - &gt;32 32/&gt;32 4-&gt;32 t-H r-^ VI . CO —Ο VI Ο 0.063/0.25 0.03 -1 0.031/0.5 &lt;0.016-&gt;32 0.031/0.13 &lt;0.016-&gt;32 4/16 0.063 - &gt;32 &lt;1/4 &lt;0.5 -4 Tagamycin 0.5/2 0.13- 16 1/4 0.25-16 C! · — 〇0.5/2 0.063 -4 0.25/0.5 0.063 -1 0.25/1 0.031 - &gt;8 0.25/2 0.063 - &gt;8 00 — ^ 1 (N oo 5 , CN ^ o Compound S2-7-5-A 1 1 0.25/0.5 0.063 -8 0.25/1 0.063 -8 0.5/1 0.25 - 8 0.25/0.5 &lt;0.016 - 1 0.125/0.25 &lt;0.016-0.5 0.12/0.25 &lt ;0.016-0.5 0.12/0.25 &lt;0.016-0.5 2/2 0.25 - 8 0.5/1 0.13-2 164 rH organism 1 Klebsiella pneumoniae ESpL Klebsiella pneumoniae KPC ms' t 5 Axis loss he 1 2 acid-producing Klebsiella (ESPL) Escherichia coli (ESpL) Proteus mirabilis m I5 night | hanging 1 201245116

&gt;64/&gt;64 1 -&gt;128 2/16 &lt;0.5-&gt;64 s 5 寸 01 O VI 4/&gt;64 &lt;0.5 - &gt;64 1—1 CN ίη 〜二 1/&gt;128 128- &gt;128 $ € 叼《Λ VI ?| 128 /&gt;128 8-&gt;128 16/&gt;128 0.5-&gt;128 1/16 &lt;0.25 - &gt;32 Ο 1 ?ι VI 0.5/1 &lt;0.25 - &gt;8 0.5/16 &lt;0.25 - &gt;32 OO ;二 ^ CN 0.5/8 &lt;0.25 - &gt;8 00 U 00 00公 A s N d VI 4/&gt;32 0.5 - &gt;32 00 CN in ο V丨？丨 16/&gt;32 &lt;0.25 - &gt;32 (N CN m co A今 CN CN m cn Λ Λ &gt;32/&gt;64 0.13 - &gt;64 以 VI ?, in in ?l ?l P! S Λ Λ ιΛ ο ο VI VI d - ?l Vl l/&gt;64 &lt;0.5 - &gt;64 Ό VI ?, &lt;0.03-4 &lt;0.03-32 9K-ZV0 9K/9K 1/16 &lt;0.5 - &gt;64 16/32 2-&gt;32 0.25/16 &lt;0.016-&gt;32 CN m (N ^ d ?l Vl S A VI ' Ό 芝7 CN ο ^ νι ?ι d 1 S3 VI VI &lt;0.25/&gt;4 &lt;0.25 - &gt;4 芝Λ νι ?, Λ ^ 寸 d VI 4/32 0.063-&gt;32 yn S ^ § ^ ?| 1/8 0.13-32 4/8 0.5 - &gt;32 &lt;1/4 0.031 - &gt;32 VI ^ VI V! ί—H __ VI °? VI VI &lt;Ν 寸 CO V, 3 X1 VI VI VI ?| VI ?| 1/2 &lt;0.5-2 4/&gt;32 0.13 - &gt;32 00 Vl V, Z€&lt;-8 ZZ&lt;/Z£&lt; CN &lt;N m m A ^ (N ' CO 寸 1/4 0.25-8 0.5/0.5 0.25 - 4 0.25/0.5 0.12-1 CN (Ν » ο 0.25/0.5 0.12-1 0.5/1 0.12-2 2/4 0.25-8 2/8 0.25-16 0.5/4 &lt;0.016 - 8 0.12/0.5 0.06-0.5 0.5/2 0.031-8 8/32 0.25 - &gt;32 0.25/2 0.063 -4 0.12/0.25 0.06-1 0.12/0.12 0.06 - 0.25 0.25/0.5 0.12-0.5 0.12/0.25 0.03 - 0.25 0.25/0.5 0.06 - 0.5 0.5/1 0.25-2 1/2 0.12-8 0.13/1 &lt;0.016-4 0.06/0.12 &lt;0.016-0.12 0.25/1 &lt;0.016-8 8/16 0.13 - &gt;32 in % QO a\ tn σ\ σ\ o m 铖 產氣腸桿菌 (Enterobacte r aerogenes) m ΒΓ-» QL. 黏質沙雷氏菌 (Serratia marcescens) m 蚱. 弗氏檸檬酸桿菌 (Citrobacter freundii) 摩氏摩根氏菌 (Morganella morganii) 斯氏普羅威登斯菌 (Providencia stuartii) m 蛛 ilS? K- 窥 洛菲不動桿菌 (Acinetobacter lwoffii) 嗜麥芽寡食單胞菌 (Stenotrophomonas maltophila) m 弊 m H 201245116 Q § ND 0.25/2 &lt;0.03-&gt;4 ND Q 0.12/0.12 &lt;0.06 -0.25 ND ND 4/&gt;32 1 -&gt;32 &lt;0.5/&lt;0.5b &lt;0.5 - 2 &lt;0.016/&lt;0.03 &lt;0.016-0.063 0.004/0.03 &lt;0.002-&gt;1 ND 2/32 0.25 - &gt;32 0.06/0.06 &lt;0.03 - 0.06 0.03/0.03 &lt;0.016-0.13 0.008/&gt;2 &lt;0.0005-&gt;2 ND 1/32 0.5 - 32 &lt;0.25/&lt;0.25b &lt;0.25- &lt;0.25 l/2a 0.06-4 ND § 16/32 1 -&gt;32 0.06/0.06 &lt;0.016-0.12 0.12/0.25 &lt;0.016 - 0.5 0.06/0.25 &lt;0.004-0.5 ND 16/32 0.5 - &gt;32 0.03/0.03 &lt;0.015-0.03 0.06/0.12 &lt;0.016-0.12 0.015/0.06 0.008-0.12 0.12/0.5 &lt;0.004-1 3 〇 o 綠膿桿菌 卡他莫拉菌 流行性感冒嗜血桿菌 〇 Λ U ®謹 ^ W) 賊1 ΐ 煤·ι # έ m f 轮日 &lt; S ft»»i C3 野a ^»»1 G p .2 201245116 化合物S2-7-5-A針對革蘭氏陰性病原體之效能為泰格 環黴素之2倍至4倍且強烈地靶向MDR革蘭氏陰性細菌。 S2-7-5-A針對MDR革蘭氏陽性病原體亦具有良好的抗微生 物效能，其中關於MRSA ( n=l〇5 ) 、MSSA ( n=50 )、糞 腸球菌（n = 59)、屎腸球菌（n=15)及肺炎鏈球菌（n=m ) 之代表性 MIC90 值為 〇.5mcg/mL、0.12 mcg/mL、2 mcg/mL、 2 mcg/mL 及 0.12 mcg/mL。 抗生素後效應（post-antibiotic effect ; PAE )檢定 根據 Craig, W.A·, S. Gudmundsson. Post antibiotic effect. In Antibiotics in Laboratory Medicine,第 4 版 (Lorian，V·編）第 269-329 頁，1991. Williams and Wilkins，&gt;64/&gt;64 1 -&gt;128 2/16 &lt;0.5-&gt;64 s 5 inch 01 O VI 4/&gt;64 &lt;0.5 - &gt;64 1 -1 CN ίη 〜二1/&gt ;128 128- &gt;128 $ € 叼"Λ VI ?| 128 /&gt;128 8-&gt;128 16/&gt;128 0.5-&gt;128 1/16 &lt;0.25 - &gt;32 Ο 1 ?ι VI 0.5/1 &lt;0.25 - &gt;8 0.5/16 &lt;0.25 - &gt;32 OO ; 二^ CN 0.5/8 &lt;0.25 - &gt;8 00 U 00 00 A s N d VI 4/&gt;32 0.5 - &gt;32 00 CN in ο V丨?丨16/&gt;32 &lt;0.25 - &gt;32 (N CN m co Anow CN CN m cn Λ Λ &gt;32/&gt;64 0.13 - &gt;64 to VI ?, in in ?l ?l P! S Λ Λ ιΛ ο ο VI VI d - ?l Vl l/&gt;64 &lt;0.5 - &gt;64 Ό VI ?, &lt;0.03-4 &lt;0.03-32 9K-ZV0 9K/9K 1/16 &lt; 0.5 - &gt;64 16/32 2-&gt;32 0.25/16 &lt;0.016-&gt;32 CN m (N ^ d ?l Vl SA VI ' Ό 7 7 CN ο ^ νι ?ι d 1 S3 VI VI &lt;;0.25/&gt;4&lt;0.25 - &gt;4 芝Λ νι ?, Λ ^ inch d VI 4/32 0.063-&gt;32 yn S ^ § ^ ?| 1/8 0.13-32 4/8 0.5 - &gt ;32 &lt;1/4 0.031 - &gt;32 VI ^ VI V! ί—H __ VI °? VI VI &lt;Ν inch CO V, 3 X1 VI VI VI ?| VI ?| 1/2 &lt;0.5- 2 4/&gt;32 0.13 - &gt;32 00 Vl V, Z€&lt;-8 ZZ&lt;/Z£&lt; CN &lt;N mm A ^ (N 'CO inch 1/4 0.25-8 0.5/0.5 0.25 - 4 0.25/0.5 0.12-1 CN (Ν » ο 0.25/0.5 0.12-1 0.5/1 0.12-2 2/4 0.25-8 2/8 0.25-16 0.5/4 &lt;0.016 - 8 0.12/0.5 0.06- 0.5 0.5/2 0.031-8 8/32 0.25 - &gt;32 0.25/2 0.063 -4 0.12/0.25 0.06-1 0.12/0.12 0.06 - 0.25 0.25/0.5 0.12-0.5 0.12/0.25 0.03 - 0.25 0.25/0.5 0.06 - 0.5 0.5/1 0.25-2 1/2 0.12-8 0.13 /1 &lt;0.016-4 0.06/0.12 &lt;0.016-0.12 0.25/1 &lt;0.016-8 8/16 0.13 - &gt;32 in % QO a\ tn σ\ σ\ om 肠Enterobacter aerogenes (Enterobacte r Aerogenes) m ΒΓ-» QL. Serratia marcescens m 蚱. Citrobacter freundii Morganella morganii Providencia stuartii m spider ilS? K- Acinetobacter lwoffii Stenotrophomonas maltophila m disadvantage m H 201245116 Q § ND 0.25/2 &lt;0.03-&gt;4 ND Q 0.12/0.12 &lt;0.06 - 0.25 ND ND 4/&gt; 32 1 -&gt;32 &lt;0.5/&lt;0.5b &lt;0.5 - 2 &lt;0.016/&lt;0.03 &lt;0.016-0.063 0.004/0.03 &lt;0.002-&gt ;1 ND 2/32 0.25 - &gt;32 0.06/0.06 &lt;0.03 - 0.06 0.03/0.03 &lt;0.016-0.13 0.008/&gt;2 &lt;0.0005-&gt;2 ND 1/32 0.5 - 32 &lt;0.25/ &lt;0.25b &lt;0.25- &lt;0.25 l/2a 0.06-4 ND § 16/32 1 -&gt;32 0.06/0.06 &lt;0.016-0.12 0.12/0.25 &lt;0.016 - 0.5 0.06/0.25 &lt;0.004 0.5 ND 16/32 0.5 - &gt;32 0.03/0.03 &lt;0.015-0.03 0.06/0.12 &lt;0 .016-0.12 0.015/0.06 0.008-0.12 0.12/0.5 &lt;0.004-1 3 〇o Pseudomonas aeruginosa, Haemophilus influenzae, Haemophilus influenzae ® U ®谨^ W) Thief 1 ΐ Coal·ι # έ mf round day &lt; S ft»»i C3 wild a ^»»1 G p .2 201245116 The efficacy of compound S2-7-5-A against Gram-negative pathogens is 2 to 4 of geigerin MDR Gram-negative bacteria are targeted and strongly targeted. S2-7-5-A also has good antimicrobial efficacy against MDR Gram-positive pathogens, among which MRSA (n=l〇5), MSSA (n=50), Enterococcus faecalis (n = 59), 屎Representative MIC90 values for Enterococcus (n=15) and Streptococcus pneumoniae (n=m) are 〇.5mcg/mL, 0.12 mcg/mL, 2 mcg/mL, 2 mcg/mL, and 0.12 mcg/mL. The post-antibiotic effect (PAE) assay is based on Craig, WA., S. Gudmundsson. Post antibiotic effect. In Antibiotics in Laboratory Medicine, 4th edition (Lorian, V. ed.) pp. 269-329, 1991. Williams and Wilkins,

Baltimore中所述之程序進行pA]E檢定。 將5毫升培養液自在瓊脂培養基上生長隔夜之新鮮菌 落接種至約lxlO5 - lxl〇6菌落形成單位（CFU) /ml之最終 起始在度。起子培養物（starter culture )在5〇 ml聚丙烯錐 形管中在35 C下在強烈通風（300 rpm)下生長兩小時，隨 後暴露於藥物。在抗生素暴露開始時，將起子培養物（0.5 ml)轉移至50 ml錐形管中含有最終濃度為〇χ、〇 〇〇8χ、2 X、4χ及8x MIC S2-7-5-A的4.5 ml預加溫培養基中。在35 °c下在強烈通風下藥物暴露i小時後，將培養物以ι:ι〇〇或 ι:ιοοο稀釋於預加溫之不含S2_7_5 A的培養基中以監測抗 生素後效應。「〇x」對照組經精確處理為經抗生素處理之培 養物，其中例外為在抗生素暴露期間不存在抗生素。「〇〇〇8 X」對照組在抗生素暴露期間及在轉移至不含S2-7-5-A之培 374 201245116 養基之後含有Μ 〇·_χ聰S2_7_5_a ;此對照組證實在 最高測試漠度（8x MIC)下之化合物殘留（咖pound carry，er)對生長無顯著影響。在多個時間點㈤，暴露 開始時；E!，！小時暴露結束時；SG，稀釋後立即，以及於 不含Sm.A之料基t稀釋後每—何）料養物進行 取樣。將樣本連續稀釋於無菌鹽水中，接種於胰酶大豆壤 脂上，且纟饥下生長隔夜以進行活力計數。每個培養物 之伯測下限為100 CFU/mbPAE結果展示於圖W中以及 正下方之表12中。 S2-7-5-A在暴露於2&gt;&lt;、4&gt;&lt;及8&gt;&lt;罐時分別在❹至以 小時、〇至&gt;3.7小時及i .5至&gt;3.8小時產生pAE。Μ 一般 隨著化合物暴露量愈高而愈長。注意到：在—些情形下， 培養物活力計數（CFU)由於S2_7_5_A針對大腸桿菌克 留氏肺炎桿菌及鮑曼不動桿菌之殺細菌性而降至低於偵測 下限（100 CFU)，且因此在此等情況下不可敎精確pAE (無法說明，UI )。 表12The procedure described in Baltimore performs a pA]E assay. 5 ml of the culture broth was inoculated from fresh colonies grown overnight on agar medium to about 1 x lO5 - lxl 菌 6 colony forming units (CFU) / ml of the final starting degree. The starter culture was grown in a 5 inch ml polypropylene conical tube at 35 C under vigorous aeration (300 rpm) for two hours and then exposed to the drug. At the beginning of antibiotic exposure, the starter culture (0.5 ml) was transferred to a 50 ml conical tube containing final concentrations of 〇χ, 〇〇〇8χ, 2 X, 4χ and 8x MIC S2-7-5-A 4.5 Ml pre-warmed in the medium. After exposure to the drug for 1 hour under intense aeration at 35 °c, the culture was diluted in pre-warmed medium without S2_7_5 A at ι:ι〇〇 or ι:ιοοο to monitor the post-antibiotic effect. The "〇x" control group was accurately treated as an antibiotic-treated culture with the exception of the absence of antibiotics during antibiotic exposure. The “〇〇〇8 X” control group contained Μ 〇·_χ聪 S2_7_5_a during antibiotic exposure and after transfer to S2-7-5-A-free culture 374 201245116; this control group confirmed the highest test indifference The compound carry (er) under (8x MIC) had no significant effect on growth. At multiple points in time (five), exposure begins; E!,! At the end of the hourly exposure; SG, immediately after dilution, and each of the feedstocks after dilution with no Sm.A. The samples were serially diluted in sterile saline, inoculated on tryptic soy loach, and grown overnight overnight for viability counting. The lower limit of the test for each culture was 100 CFU/mbPAE and the results are shown in Figure W and in Table 12 directly below. S2-7-5-A produces pAE at exposure to 2&gt;&lt;, 4&gt;&lt; and 8&gt;&lt;&lt;&gt;&gt;, respectively, to 3.7 hours and i.5 to &gt; 3.8 hours. . Μ Generally, the higher the exposure of the compound, the longer it will be. Note that in some cases, the culture viability count (CFU) falls below the detection limit (100 CFU) due to the bactericidal activity of S2_7_5_A against E. coli K. pneumoniae and Acinetobacter baumannii, and therefore In these cases, it is not possible to accurately pAE (unable to explain, UI). Table 12

375 201245116 PAE=T_C，其中τ=經抗生素處理之培養物之活力計數 在稀釋後立即得到之計數上增加1 l〇gl〇所需的時間； UI .因為由於S2-7-5-A之殺細菌性使得稀釋後之cfu 低於偵測下限（1 〇〇 CFU )而無法說明之結果。 時間殺菌檢定（time-kill assay )375 201245116 PAE=T_C, where τ=the time required for the activity count of the antibiotic-treated culture to increase by 1 l〇gl〇 immediately after dilution; UI. Because of the killing due to S2-7-5-A Bacteriality caused the diluted cfu to be below the lower detection limit (1 〇〇 CFU) and could not be explained. Time-kill assay

在進行時間殺菌檢定之前，按照CLSI標準化方法測定 抗生素儲備液之最小抑制濃度（MIC )值。基本上如CLSI 準則（CLSI· Methods for determining bactericidal activity of antimicrobial agents, approved guideline. CLSI 文件 M26-A，第 19 卷，CLSI，940 West VaUey R0ad，Suite 14〇〇, Wayne PA，USA，1999 )所述進行時間殺菌檢定，其中具有 以下修改.將以約1X1 〇5 _ 1 χ 1 〇6菌落形成單位（) 之最終起始密度接種的5毫升培養物在35 °C下於50 mi聚 丙烯錐形管中劇烈震盪（300 rpm )。在多個時間點對培養物 取樣’以無菌鹽水連續稀釋，且接種於胰酶大豆瓊脂上。 母個培養物之彳貞測下限為1〇〇 CFU/ml。結果展示於圖6-9 中。 S2-7-5-A針對某些革蘭氏陰性病原體及革蘭氏陽性病 原體之殺細菌活性的概述闡述於正下方之表1 3及表14中。 376 201245116 表1 3The minimum inhibitory concentration (MIC) value of the antibiotic stock solution was determined according to the CLSI standardization method before the time sterilization test. Basically, as CLSI (Methods for determining bactericidal activity of antimicrobial agents, approved guideline. CLSI document M26-A, Vol. 19, CLSI, 940 West VaUey R0ad, Suite 14〇〇, Wayne PA, USA, 1999) Perform a time sterilization test with the following modifications. A 5 ml culture inoculated at a final starting density of about 1X1 〇5 _ 1 χ 1 〇6 colony forming units () at 50 °C at 50 ° polypropylene cone Vibrate in the tube (300 rpm). Cultures were sampled at various time points in serial dilutions with sterile saline and plated on tryptic soy agar. The lower limit of detection for the parental culture is 1 〇〇 CFU/ml. The results are shown in Figure 6-9. A summary of the bactericidal activity of S2-7-5-A against certain Gram-negative pathogens and Gram-positive pathogens is set forth in Tables 13 and 14 below. 376 201245116 Table 1 3

表14Table 14

377 201245116 control ; QC )樣本（低、中、高；最少6個標準物具有LLOQ &lt; 3 ng/mL )及標準曲線（雙重複）包括於生物分析操作中。 使用WinNonLin來測定個別及平均PK參數士標準差（口服 生物利用率％( 0/〇F)、Cmax、Tmax、T%、CL、Vss、AUC(O-t)、 AUC(0-〇〇 )及 MRT)。S2-7-5-A 之口服生物利用率為 30.4%。 結果展示於下文表1 5 (靜脈内給藥）及表1 6 ( 口服給藥） 中〇 表15 靜脈内給藥，1 mg/kg 參數 平均值 SD C〇 (ng/ml) 1343 200 T'A (h) 16.57 1.07 Vdss (L/kg) 4 0.4 Cl (ml/hr/kg) 183 16.2 AUC an ( ng · h/ml) 3570 457 AUC〇.~ (ng*h/ml) 5490 486 表16 口服給藥，10 mg/kg 參數 平均值 SD Cmax (ng/ml) 751 155 Tmax (h) 4 0 VA (h) 13.49 4.21 AUC m (ng-h/ml) 10900 2179 AUCo.oo (ng*h/ml) 16333 5346 口服生物利用率％ 30.4% 3.53 在尿濃度方面，在14天毒理學研究中在每個劑量組5 隻雄性（獼猴）及5隻雌性（獼猴）中在所示濃度下測試 378 201245116 • S2-7-5-A。每個採集期及劑量之平均尿含量（微克/毫升） 展不於表17中。第2天，0-8小時尿含量範圍為4 2 241 pg/mL，且在每天投予3_30mg/kg持續13天後穩態含量 (第13天，〇-8小時）顯著較高，範圍為2〇 5至62 5 pg/mLe 此等值與使用S2-7-5-A處理MDR尿路病原體相一致。 表17 採集尿之曰期與時間 尿含量（/za/mL、 3 mg/kg 10 me/ke 30 mp/kfr 第2天，0-8小時 4.2 18.9 24 1 第2天，8-24小時 3.2 6.2 20 5 弟13天，0-8小時 _20.5 1 81.6 62 5 第13天，8-24小時 3.9 11.3 -—-- 32.5 MIC5。及 MIC9❶值： :化合物 S14-6-1-B、sai-U-i-B 及 S15_12_3A 針對多種 、-'田S之MIC5〇及MIC9。值（分別抑制50¾及90%之物種集合 的最低濃度）展示於圖10中。如上所述測定各值。 化合物在大腸桿菌及綠膿桿菌試管内轉錄/轉譯系統 (TNT)中之活性 對於大腸桿菌，在大腸桿菌試管内偶合轉錄/轉譯檢定 (TnT)中，利用自 pBEST-/wc( Promega, Madison, WI)表 現之螢火蟲螢光素酶讀出數據評估抗轉譯活性（IC5Q值）。 對於綠膿桿菌，在Tetraphase開發出針對綠膿桿菌之試管 内TNT檢定。使用來自Uu等人（2〇〇5 Biotechnol. Prog. 21:46〇)及 Kim 等人（2006. J. Biotech· 126:554)之方法的修 379 201245116 改方法，自菌株PA555製備S30萃取物且自PBEST-/«C (Promega，Madison，WI )表現螢火蟲螢光素酶。在兩種TNT 系統中，在37°C下在Costar 96孔黑色檢定板（Costar #3915 ) 中以20-22 μΐ體積操作反應一小時。藉由置於冰上5分鐘， 接著添加每孔25 μΐ螢光素酶受質（pr〇mega, Madison，WI.) 終止反應。利用 LUMIStar Optima 光度計（BMG Labtech )， 在增益設定為3600，0_2秒讀取，各孔之間〇秒下讀取板。 相對於未經處理之對照組，繪製發光百分比相對於抑制5〇0/〇 之抑制劑濃度曲線，標記為值。結果報導為至少兩次 獨立實驗之平均值。 結果圖示於圖Π中且展示與四環素之IC5〇值187377 201245116 control ; QC ) samples (low, medium, high; at least 6 standards with LLOQ &lt; 3 ng / mL) and standard curve (double replicate) included in the bioanalytical operation. Use WinNonLin to determine individual and average PK parameter standard deviation (oral bioavailability % (0/〇F), Cmax, Tmax, T%, CL, Vss, AUC(Ot), AUC(0-〇〇) and MRT ). The oral bioavailability of S2-7-5-A was 30.4%. The results are shown in Table 15 (intravenous administration) and Table 16 (oral administration) below. Table 15 Intravenous administration, 1 mg/kg Parameter mean SD C〇 (ng/ml) 1343 200 T' A (h) 16.57 1.07 Vdss (L/kg) 4 0.4 Cl (ml/hr/kg) 183 16.2 AUC an ( ng · h/ml) 3570 457 AUC〇.~ (ng*h/ml) 5490 486 Table 16 Oral administration, 10 mg/kg Parameter mean SD Cmax (ng/ml) 751 155 Tmax (h) 4 0 VA (h) 13.49 4.21 AUC m (ng-h/ml) 10900 2179 AUCo.oo (ng*h /ml) 16333 5346 Oral bioavailability % 30.4% 3.53 In terms of urine concentration, in the 14-day toxicology study, 5 males (Macaca mulatta) and 5 females (Macaca mulatta) in each dose group at the indicated concentrations Test 378 201245116 • S2-7-5-A. The average urine content (μg/ml) for each collection period and dose is shown in Table 17. On day 2, the 0-8 hour urine content ranged from 4 2 241 pg/mL, and the steady-state content (day 13 , 〇-8 hours) was significantly higher after 13 days of daily administration of 3-30 mg/kg for 13 days. 2〇5 to 62 5 pg/mLe These values are consistent with the use of S2-7-5-A to treat MDR urinary tract pathogens. Table 17 Urine and time urine content of urine collection (/za/mL, 3 mg/kg 10 me/ke 30 mp/kfr Day 2, 0-8 hours 4.2 18.9 24 1 Day 2, 8-24 hours 3.2 6.2 20 5 brother 13 days, 0-8 hours_20.5 1 81.6 62 5 Day 13, 8-24 hours 3.9 11.3 ---- 32.5 MIC5. and MIC9 ❶ value: : Compound S14-6-1-B, sai- UiB and S15_12_3A are shown in Figure 10 for a variety of values, MIC5〇 and MIC9 values of the S (Suppressing 503⁄4 and 90% of the species collection, respectively). The values are determined as described above. Compounds in E. coli and green Activity in the In vitro Intracellular Transcription/Translation System (TNT) of Pseudomonas for E. coli, in E. coli in vitro coupling transcription/translation assay (TnT), using firefly firefly expressed from pBEST-/wc (Promega, Madison, WI) Photorezyme readout data to evaluate anti-translational activity (IC5Q value) For Pseudomonas aeruginosa, an in vitro TNT assay for Pseudomonas aeruginosa was developed in Tetraphase using Uu et al. (2〇〇5 Biotechnol. Prog. 21: 46〇) and Kim et al. (2006. J. Biotech 126:554) method of repair 379 201245116 modified method, from strain PA555 S30 extract was prepared and firefly luciferase was expressed from PBEST-/«C (Promega, Madison, WI). In two TNT systems, at 37 ° C in Costar 96-well black assay plate (Costar #3915) The reaction was run for one hour in a volume of 20-22 μΐ. The reaction was stopped by placing on ice for 5 minutes followed by addition of 25 μM luciferase per well (pr〇mega, Madison, WI.) using LUMIStar Optima photometer (BMG Labtech), read the gain at 3600, 0_2 seconds, read the plate between the wells and leap seconds. Relative to the untreated control, plot the percentage of luminescence relative to the inhibitor that inhibits 5〇0/〇 Concentration curves, labeled as values. Results are reported as the average of at least two independent experiments. The results are shown in Figure 且 and show IC5 depreciation with tetracycline 187

Mg/ml相比，S15-12-3A與S21-16-1-B兩者之平均大腸桿菌 TNT ic50值為〇·25 pg/ml。對於綠膿桿菌，與四環素之1(：5〇 值 1.22 pg/ml 相比，S15-12-3A 與 S21-16-1-B 之平均 TNT 50值刀別為0.1 pg/ml與0.15 pg/mi。因此，在來源於大 腸才干菌及綠膿桿菌之試管内轉錄/轉譯系統中，s1512_3a 及S2M6-1-B比四環素顯著更有效。 一在TNT檢定中亦測試另一種化合物S14_6_1B且其顯 不針對大腸桿菌之IC5〇值為〇 27 gg/mi且針對綠膿桿菌之 1匸5。值為 〇_2i gg/mi。 細胞毒性測試 在72小時細胞毒性檢定中使用HepG2人類肝細胞肝癌 細月^測試S15-12-3-A及S21_16小B。將細胞接種 於微1滴定板中至.亞匯合且用化合物之連續兩倍稀釋液處 380 201245116 理，以64 Mg/ml起始作為最高測試濃度。使用小紅莓 (doxorubicin )作為陽性細胞毒性對照組且如預期進行。在 化合物處理72小時結束時，將細胞洗滌，溶解且藉由用匸川 Titer Glo 試劑（Promega, Madison，WI)量測 ATp 含量來測 定活力。S15-12-3-A 及 821-16·^ 展現 IC5〇 值 &gt;M 如'， 符合非細胞毒性效應。 關於綠膿桿菌PA1145之免疫勝任肺感染模型 經由在輕微麻醉下鼻内投藥〇 〇5ml使重為18至⑼公 克之雌性BALB/c小鼠每隻小鼠感染19x1〇7cfu之綠膿俨 菌。在感染後2小時（T=Rx)及12小時’用化合物處理: 鼠。經靜脈内投f S15-12_3_A、泰格環徽素及阿米卡星 (am—)，且經鼻内給予妥布黴素（_麵_η)。用 各藥物濃度處理6隻小鼠。處理開始後24小時，藉由⑶2 吸入使小鼠安樂死。無菌移出小鼠肺，稱重.，勻襞化，連2 續稀釋，且接種於MacC〇nkey培養基上。在抓下於5% C〇2中將板培育隔夜。藉由計數所接種之菌落，隨後關於連The average E. coli TNT ic50 value of both S15-12-3A and S21-16-1-B was 〇·25 pg/ml compared to Mg/ml. For Pseudomonas aeruginosa, the average TNT 50 values for S15-12-3A and S21-16-1-B were 0.1 pg/ml and 0.15 pg/ compared to tetracycline 1 (:5〇1.22 pg/ml). Therefore, s1512_3a and S2M6-1-B are significantly more effective than tetracycline in the in vitro transcription/translation system derived from large intestines and Pseudomonas aeruginosa. One other compound S14_6_1B was also tested in the TNT assay. The IC5 value for E. coli is not 〇27 gg/mi and 1匸5 for Pseudomonas aeruginosa. The value is 〇_2i gg/mi. Cytotoxicity test using HepG2 human hepatocellular carcinoma in 72-hour cytotoxicity assay Monthly test S15-12-3-A and S21_16 small B. Inoculate the cells in a microtiter plate until subconfluent and use a serial dilution of the compound at 380 201245116 to start with 64 Mg/ml. Maximum test concentration. Use cranberry (doxorubicin) as a positive cytotoxic control group and proceed as expected. At the end of compound treatment for 72 hours, the cells were washed, dissolved and used with Takigawa Titer Glo reagent (Promega, Madison, WI). Measurement of ATp content to determine viability. S15-12-3-A and 821-16·^ Demonstrates IC5 & value &gt;M such as ', consistent with non-cytotoxic effects. About the immunosuppressive lung infection model of Pseudomonas aeruginosa PA1145 The female BALB/c weighs 18 to (9) grams by intranasal administration of 5 ml under mild anesthesia Each mouse was infected with 19x1〇7cfu of Pseudomonas aeruginosa. It was treated with compound 2 hours after infection (T=Rx) and 12 hours. Intravenous administration of f S15-12_3_A, Tiger Ring And amikacin (am-), and intranasally administered tobramycin (_面_η). Six mice were treated with each drug concentration. 24 hours after the start of treatment, mice were euthanized by (3) 2 inhalation The lungs of the mice were aseptically removed, weighed, homogenized, serially diluted, and inoculated on MacC〇nkey medium. The plates were incubated overnight in 5% C〇2, and inoculated by counting. Colonies, followed by

續稀釋液及肺重量進行調举也4I 丁门整來计算每公克肺之菌落形成單 &lt; (CFU) 〇S15-12-3-A、泰格環黴素、阿米卡星及妥布徽 素針對 PAU45 之 MIC 分別為 4μ8/ιηΐ、8μδ/πιΐ、8μβΜΐ 及w結果顯示’相對於未經處理之2“、時對照組， S15-12-3-A產生劑量依賴性CFU降低。結果展示於表 中且圖示描繪於圖12中。 381 201245116 表18 化合物 劑量 (mg/Kg) 途徑 每公克肺之平均 log ίο CFU SD 與26小時對照組相 比之logCFU變化 T=Rx - - 7.09 0.29 •1.47 T=26小時 - • 8.56 0.63 S15-12-3-A 40 靜脈内. 4.91 0.61 -3.65 15 靜脈内 6.40 1.23 -2.16 5 靜脈内 6.90 0.53 -1.66 泰格環黴素 40 靜脈内 8.41 0.3 -0.81 阿米卡暴 40 靜脈内 5.01 0.82 -3.55 妥布黴素 40 鼻内 4.33 0.25 -4.89 關於綠膿桿菌PA694之免疫勝任大腿感染模型 將5隻重為22±2 g之雌性CD-1小鼠之群組於右大腿内 經肌肉内接種（〇·1毫升/大腿）每隻小鼠3_5xi〇6 CFU之 PA694 »在感染後2小時及12小時向小鼠靜脈内投予化合 物S15-12-3-A。「T=RX」對照組不接受藥物處理且在感染 後2小時採集其大腿。其餘小鼠經投予媒劑或s15_12_3_a。 在感染後24小時採集各動物右大腿之肌肉。利用p〇iyu〇n 組織勻漿製造器使所採集之大腿組織在2 mi pBs ( pH 7.4 )Continued dilution and lung weight for the adjustment also 4I Dingmen to calculate the colony formation per gram of lungs &lt; (CFU) 〇S15-12-3-A, geigerin, amikacin and rouble The MICs of auxin against PAU45 were 4μ8/ιηΐ, 8μδ/πιΐ, 8μβΜΐ and w, respectively, and the results showed that 'relative to untreated 2', the control group, S15-12-3-A produced a dose-dependent CFU reduction. Shown in the table and graphically depicted in Figure 12. 381 201245116 Table 18 Compound dose (mg/Kg) Pathway average log per gram of lung ίο CFU SD LogCFU change compared to 26 hour control group T=Rx - - 7.09 0.29 • 1.47 T=26 hours - • 8.56 0.63 S15-12-3-A 40 Intravenous. 4.91 0.61 -3.65 15 Intravenous 6.40 1.23 -2.16 5 Intravenous 6.90 0.53 -1.66 Tagatcycline 40 Intravenous 8.41 0.3 -0.81 Amika Storm 40 Intravenous 5.01 0.82 -3.55 Tobramycin 40 Intranas 4.33 0.25 -4.89 Immunization against Pseudomonas aeruginosa PA694 Competent Thigh Infection Model Five female CD-1 weighing 22 ± 2 g The group of rats was intramuscularly inoculated in the right thigh (〇·1 ml/thigh) 3_5xi〇 per mouse 6 CFU of PA694 » The compound S15-12-3-A was administered intravenously to mice 2 hours and 12 hours after infection. The "T=RX" control group received no drug treatment and collected thighs 2 hours after infection. The remaining mice were administered vehicle or s15_12_3_a. The muscles of the right thigh of each animal were collected 24 hours after infection. Using the p〇iyu〇n tissue homogenizer to make the collected thigh tissue at 2 mi pBs (pH 7.4)

中勻漿化。.隨後將組織勻漿連續稀釋且接種於腦心浸液 (Brain Heart Infusion)瓊脂+ 〇.5%木炭（w/v)上進行 CFU 測定。對於各劑量組測定在感染後24小時相較於對照組計 數之右大腿之總CFU降低^ S15-12-3-A及美羅培南針對綠 膿桿菌PA694之MIC分別為4 pg/ml及〇· 13 pg/mi。結果 展示於表19中且圖示描繪於圖13中。結果顯示，相對於 未經處理之26小時對照組，S15_12_3_A產生劑量依賴性 CFU降低。 382 201245116 表19 化合物 劑量 平均 Logw CPU/ SD 與26小時對照組相 (mg/Kg) 大腿 th之丨〇g CFU變化 40 6.49 0.90 -2.20 S15-12-3-A 15 7.59 0.62 -1.10 5 8.30 1.07 -0.39 40 3.78 0.20 -4.91 美羅培南 15 4.48 0.36 -4.21 5 5.84 0.81 -2.85 感染對照組 T=26 8.69 0.50 一 T=Rx 6.66 0.25 -2.03 關於綠膿桿菌之時間殺菌檢定 在如CLSI準則所述進行之標準時間殺菌檢定中在4x MIC及8x MIC下評估35°C下S15-12-3-A之試管内殺細菌 活性’其中培養物每毫升接種有約1 χ丨〇5 - 1 χ丨〇6菌落形成 單位（CFU )且每個培養物之偵測下限為1〇〇 CFU/mi( CLSI， Methods for determining bactericidal activity of antimicrobial agents; approved guideline,第 19 卷’第 18 期· CLSI 文件 M26-A, 1999, 940 West Valley Road, Suite W⑽，fTa少Pe⑽)。測試四種不同的綠膿桿菌菌 株（PA555 (實驗室菌株PA01) 、PA694 (大腿感染模型 中所用之新近UTI分離株）、PA695 (新近UTI分離株）及 PA1145 (肺感染模型中所用之囊腫性纖維化分離株））。 使用黏菌素（cohstin )作為殺細菌對照抗生素。殺細菌反 應定義為在既定培養物中相對於起始計數（CFU/ml )之24 小時内3 log!。降低（CFU/ml )。對於所測試之所有綠膿桿 菌菌株，S15-12-3-A產生快速之殺細菌反應，在7小時暴 383 201245116 路内產生、..勺3-log降低。與之相&amp;，黏菌素對於三種測試菌 株所產生之生長抑制回彈。 小鼠腎臟感染模型 、，工由靜脈内注射混合有〇2%卡拉膠（抑咖Aldrich ) 之〇·2社克留氏肺炎桿菌κρ453，使重為以至公克之 雌&amp; balb/e小鼠感染。利用化合物si4_6小β、左氧ι沙星、 美羅^南.西司他丁（cilastatin)每日兩次（BID)處理小鼠。 用各藥物濃度處理6隻小鼠。處理開始後36小時，藉由C〇2 吸入使小鼠安樂死。無菌移出小鼠之腎臟，稱重，勻漿化， 連續稀釋’且接種於似培養基上。在抓下於5% c〇2 中將板。月隔夜。II由計數所接種之菌落，隨後關於連續 稀釋液及腎臟重4進行調整來計算每公克腎臟t CFU。表 20概述結果。 表20 化合物 媒劑 給藥途徑 給藥頻率 濃度 (mg/kg) 與36小時對照組 相比之LoglO #化 標準差 S14-〇-1 -ΰ 左氧氟沙星 水 水 經口 每曰兩次 50 -1.76 1.47 經口 每日兩次 25 -0 Ύ) 1 9Π 美羅培南： 西司他丁 鹽水 靜脈内 每日兩次 30 \j -3.28 1 ,Ζλ) 0.82 本文斤引用之所有專利、公開申請案及參考文獻的教 示係以全文引用之方式併入本文中。 雖然已參考本發明之例示性具體實例詳盡地展示及描 述本4月但熟習此項技術者應瞭解可在形式及細節方面 384 201245116 . 對其進行各種改變而不悖離由隨附申請專利範圍涵蓋之本 發明範疇。 明 說 單 簡 式 圖 圖1為展示化合物S 2 - 7 - 5 - A針對所示細菌之抗生素後 效應之曲線圖。 圖2為展示化合物S2-7-5-A針對所示細菌之抗生素後 效應之曲線圖。 圖3為展示化合物S 2 - 7 - 5 - A針對所示細菌之抗生素後 效應之曲線圖。 圖4為展示化合物S 2 - 7 - 5 - A針對所示細菌之抗生素後 效應之曲線圖。 圖5為展示化合物S2-7-5-A針對所示細菌之抗生素後 效應之曲線圖。 圖6為展示使用化合物S2-7-5-A針對所示細菌之時間 殺菌檢定之結果的曲線圖。 圖7為展示使用化合物S2-7-5-A針對所示細菌之時間 殺菌檢定之結果的曲線圖。 圖8為展示使用化合物S 2 - 7 - 5 - A針對所示細菌之時間 殺菌檢定之結果的曲線圖。 圖9為展示使用化合物S2-7-5-A針對所示細菌之時間 殺菌檢定之結果的曲線圖。 圖10展示本發明化合物針對多種細菌之MIC5〇及 MIC9〇 值。 385 201245116 圖11展示使用所提及化合物之TNT檢定的結果。 圖12展示在鼠類肺感染模型中使用所提及化合物之結 果。 圖1 3展示在免疫勝任鼠類大腿感染模型中使用所提及 化合物之結果。 圖14為展示使用所提及化合物針對所示細菌之時間殺 菌檢定之結果的曲線圖。 【主要元件符號說明】 無 386Homogenize in medium. The tissue homogenate was then serially diluted and plated on Brain Heart Infusion agar + 〇. 5% charcoal (w/v) for CFU determination. For each dose group, the total CFU of the right thigh was compared with the control group at 24 hours after infection. S15-12-3-A and the MIC of meropenem against Pseudomonas aeruginosa PA694 were 4 pg/ml and 〇· 13 pg/mi. The results are shown in Table 19 and the illustration is depicted in Figure 13. The results showed that S15_12_3_A produced a dose-dependent decrease in CFU relative to the untreated 26-hour control group. 382 201245116 Table 19 Compound dose mean Logw CPU/SD vs. 26 hours control phase (mg/Kg) Thigh th 丨〇 g CFU change 40 6.49 0.90 -2.20 S15-12-3-A 15 7.59 0.62 -1.10 5 8.30 1.07 -0.39 40 3.78 0.20 -4.91 meropenem 15 4.48 0.36 -4.21 5 5.84 0.81 -2.85 Infected control group T=26 8.69 0.50 A T=Rx 6.66 0.25 -2.03 Time for bactericidal assay of Pseudomonas aeruginosa as described in CLSI guidelines The in vitro bactericidal activity of S15-12-3-A at 35 °C was evaluated in a standard time bactericidal assay at 4x MIC and 8x MIC. The culture was inoculated with about 1 χ丨〇 5 - 1 每 per ml. 6 colony forming units (CFU) and the detection limit of each culture is 1〇〇CFU/mi (CLSI, Methods for determining bactericidal activity of antimicrobial agents; approved guideline, Vol. 19, No. 18 · CLSI document M26- A, 1999, 940 West Valley Road, Suite W (10), fTa less Pe (10)). Four different Pseudomonas aeruginosa strains (PA555 (laboratory strain PA01), PA694 (new UTI isolate used in the thigh infection model), PA695 (new UTI isolate), and PA1145 (cysts used in lung infection models) were tested. Fibrosis isolate)). Cohstin was used as a bactericidal control antibiotic. The bactericidal reaction is defined as 3 log! within 24 hours of the initial count (CFU/ml) in a given culture. Reduced (CFU/ml). For all P. aeruginosa strains tested, S15-12-3-A produced a rapid bactericidal reaction, which was produced within 7 hours of storm 383 201245116. In contrast, colistin inhibited the growth of the growth of the three test strains. The mouse kidney infection model was prepared by intravenous injection of 〇2% carrageenan (IsAl's Aldrich), 2 gram, K. pneumoniae κρ453, and the weight of the female &amp; balb/e mice infection. Mice were treated twice daily (BID) with compound si4_6 small beta, levofloxacin, merlotantan and cilastatin. Six mice were treated with each drug concentration. Mice were euthanized by inhalation of C〇2 36 hours after the start of treatment. The kidneys of the mice were aseptically removed, weighed, homogenized, serially diluted&apos; and inoculated onto a medium. Grab the plate in the 5% c〇2. Overnight. II was counted from the inoculated colonies, and then adjusted for serial dilutions and kidney weight 4 to calculate t CFU per gram of kidney. Table 20 summarizes the results. Table 20 Compound vehicle administration route frequency of administration (mg/kg) Compared with the 36-hour control group, LoglO # standard deviation S14-〇-1 -ΰ Levofloxacin water per mouth twice per 50-1.76 1.47 Oral twice daily 25 -0 Ύ) 1 9 Π Meropenem: cilastatin saline intravenously twice daily 30 \j -3.28 1 , Ζ λ) 0.82 All patents, published applications and references cited in this article The teachings are incorporated herein by reference in their entirety. Although the present invention has been fully shown and described with reference to the exemplary embodiments of the present invention, it should be understood by those skilled in the art in the form of the details and details. 384 201245116. Various changes are made without departing from the scope of the attached patent application. The scope of the invention is covered. Brief Description Single Figure Figure 1 is a graph showing the antibiotic effect of the compound S 2 - 7 - 5 - A against the indicated bacteria. Figure 2 is a graph showing the antibiotic effect of Compound S2-7-5-A against the indicated bacteria. Figure 3 is a graph showing the antibiotic effect of the compound S 2 - 7 - 5 - A against the indicated bacteria. Figure 4 is a graph showing the antibiotic effect of the compound S 2 - 7 - 5 - A against the indicated bacteria. Figure 5 is a graph showing the antibiotic effect of Compound S2-7-5-A against the indicated bacteria. Figure 6 is a graph showing the results of a time sterilization assay using Compound S2-7-5-A for the indicated bacteria. Figure 7 is a graph showing the results of time sterilization assays using the compound S2-7-5-A for the indicated bacteria. Figure 8 is a graph showing the results of a time sterilization assay using the compound S 2 - 7 - 5 - A for the indicated bacteria. Figure 9 is a graph showing the results of a time sterilization assay using the compound S2-7-5-A for the indicated bacteria. Figure 10 shows the MIC5〇 and MIC9〇 values of the compounds of the invention against various bacteria. 385 201245116 Figure 11 shows the results of a TNT assay using the compounds mentioned. Figure 12 shows the results of using the compounds mentioned in the murine lung infection model. Figure 13 shows the results of using the compounds mentioned in the immunization competent murine thigh infection model. Figure 14 is a graph showing the results of a time-killing assay using the compounds mentioned for the indicated bacteria. [Main component symbol description] None 386

Claims (1)

201245116 . 七、申請專利範圍：201245116 . VII. Patent application scope: 1. 一種式I化合物或其醫藥學上可接受之鹽， 其中： X係選自氫、溴、氟、氯、Ci-Ce烷基、_〇_Cl_c6烷基、c3_Cl〇 碳環基、-〇-C3-C1G碳環基、4-13員雜環基、_〇_4·13員雜環 基、-S(0)m-R2、-CN、 -N(r2)(r3)、-S(0)m-N(R2)(R3)、 -C(0)-0-R2、_C(0)-N(R2)(R3)及-NH-CCOHCVCe 伸烷 基）-N(R2)(R3)，其中由X表示之基圑中之各烷基或伸烷基 視情況經一或多個氟取代；且 由X表示之基團中之各碳環基或雜環基視情況經一或多個 氯、=0、-OH、Ci-CU 獨立地選自以下之取代基取代：氟、 氟烧基、C|-C4 烧基、- 〇-Ci_C4 烧基、-O-C1-C4 H 烧基、-NH2、 -NI^CVC^ 烷基）或-i^Ci-CU 烷基）2、C3-C1()碳環基或（4-13 員）雜環基； 環E係選自C3-C丨〇碳環基及（4-13員）雜環基； W 係選自 C(R6)、C(R6)2、N 及 N(R7); Q 係選自 C(R6)、C(R6)2、N、N(R7)、Ο 及 S ; Y 係選自氫、氟、溴、-CN、-[C(Rla)(Rlb)]n-N(R2)(R3)、 -N(R4)(R5)、N02、-NH-C(0)-(CrC4 伸烷基 烷基、-NH-C^CO-CVC^ 烷基、-NH-SCOVCVCe 烷基、 -NH-S(0)m-C3-C丨〇 碳環基、-NH-S(0)m-4-13 員雜環基； 各Rla及R]b係獨立地選自氫、CVC4烷基及C3-ClQ碳環基； 387 201245116 R2係選自氫、Cl-C12烧基、-C(rC6伸烷基_C3_Ciq碳環基及 -C〇-C6伸烧基- 4-13員雜環基； R係選自氫、C丨-C8烷基、_Cg_C6伸烷基_C3_Cm碳環基、 -(^-匕伸烷基-彳-^員雜環基〜^⑴^厂^烷基、％^-伸烷基-c(o)n(r4)(r5)、-C(0)_Ci_C6 伸烷基 _n(r4)(r5)、 •C2-C6 伸烷基烷基、_s(〇)mC3_c⑺ 碳環基及-S(0)m-(4-13員）雜環基，其中： ⑺ 由R2或R3表示之基團中之各烷基 '碳環基、伸烷基或雜環 基視情況且獨立地經一或多個獨立地選自以下之取代基取 代：氣 '氣、-OH、-O-CVq烧基、Ci_C4烧基、經氣取代 之Cl-c4烷基、-N(r4)(r5)、c3_Ci〇碳環基或4_13員雜環美； 或 R及R3與其所結合之敗原子一起形&amp;心7員單環雜環或 6-13員雙環 '螺環或橋連雜環，其中： 該4-7員單環雜環或該6_13員雙環、螺環或橋連雜環視情 況包含…個獨立地選自N、SA〇之其他雜原子/ 該4-7員單環雜環或該⑷M雙環、料或橋連雜環視情 況經-或多個獨立地選自以下之取代基取代：c”C丨。碳‘ 基、4-13員雜環基、氟、氣、_〇H、戈心說燒基、 烧基、-O-C3-Cl0碳環基、〇_4_13員雜環基、_c〇_C4伸貌基 -o-c丨-C4烧基、-eve4伸院基_〇_Ci_C4氣院基、土 C⑼_Cl.c:4 烧基、wwam c 及-C°-C4伸絲谭4)(R5)，且各碳環基或雜環基取代ϋ 情況經氟、氣、-0H、=0、Cl-C4氣燒基、Ci_c4燒基、土 388 201245116 -烷基、-0-Cl_C4 氟烷基、-NH2、-NHCCVC4 烷基）或-N(C「C4 烷基）2取代； R4及R5各獨立地選自氫及C丨-c4烷基；或 R及R5與其所結合之氮原子一起形成視情況包含一個選自 N、S及〇之其他雜原子的4_7員雜環，其中該4_7員雜環 視情況經氟、氯、-OH、=〇、經氟取代之Ci_C4烷基、_C|_C4 烧基或-C1-C4伸烷基烷基取代，且視情況稠合至苯 基； 各R6係獨立地選自氫、C3_Ciq碳環基、4_13員雜環基、氟、 氯、-OH、氟烷基、烷基、-〇_c3-C1()碳環基、 -0-4-13員雜環基、_Cq_C4烷基_〇-Ci_C4烷基、_Cq_C4烷基 -〇-Ci-C4 氟烷基、，c(〇)_Ci_C4 烷基、_c(〇)n(r4)(r5)、 _N(R )_C(0)_Cl'C4 烷基及-C〇-C4 伸烷基 _n(R4)(R5);或 C(R6)2 為 c=0 ; 各R係獨立地選自氫、_Cq_C4伸烷基_C3-C1G碳環基、_Cg_C4 伸烷基-4-13員雜環基、_〇1_(：6氟烷基、_(：1_(：6烷基、_(：1_(：6 羥烷基、-〇-C3-C1()碳環基、-〇_4·13員雜環基、_C『C4伸烷 基_〇-(ν(：4烷基、_C(rC4伸烷基_〇_C|_C4氟烷基、 -qco-cvc^ 烷基、_Cl_c4 伸烷基_c(〇) Ci_C4 烷基、_Ci_C4 伸烷基-C(0)-0H、_C(0)n(r4)(r5)、-烷 基-C(〇)-(Cl-C4 伸烷基）-NR4R5 及-C〇-C4 伸烷基-N(R4)(R5); 且R及R之各碳環基或雜環基部分視情況經氟、氣、_ OH、 0 ci'c4 氟烧基、Ci_C4 烧基、_〇_Ci_C4 虎基、_〇-Ci_C4 氣烧基、-贿2、_NH(Ci-C4烷基）或-N(Cl-C4烷基）2取代； 389 201245116 係獨立地選自氫、C3_Ciq碳環基、4]3員雜環基、說、 氣、-〇H、Cl-c4氟燒基、Cl_c4燒基、办C3_Ci〇碳環基、 办4·13 1雜環基、-CA院基-0-CVC4烧基、-CG-C4烧基 -〇-c:-c4 氟烧基、=。、_c(〇)_Ci C4 燒基、c⑼寧、r”、 -N(R )-C⑼-Cl_c4 烧基、_c。'伸烧基 n(r4)(r5)及 -δ(〇)2(ν(：4 烧基； R9不存在或獨立地選自氫、C3_Ci。碳環基、4_13員雜環基、 :、氣、.、Cl_C4烧基、C|_C4貌基、_〇々Ci。碳環 基、…員雜環基、_cvc4烧基_〇々C4烧基、_c〇_c4 烧基-〇，c4氟院基、=0、_c(〇) Ci_c4院基、 C(〇4)N(R5 )(R5)、-N(R4)-C(0)-C^ 貌基及-cvc4 伸烧基 -N(R4)(R5); 各m獨立地為o、！*〗； η為1或2 ; Ρ為〇或介於1與4之間的整數；且 各=表示單鍵或雙鍵，其中至少一個&amp;表示 =制=為當環㈠視情況經取代之芳族環或視情況經 取代之雜方族環時，X不為氫。 2.如申請專利範圍帛1項之化合物，其中. …獨立地選自氣^伸烧…:碳環^^ 伸烷基-4-U貝雜環基、⑽氣貌基 ' ⑼炫基、 ΜΑ碳環基、射13M雜環HC4伸燒基ΜΑ 烧基、-Co-C“申院基_〇，c〖_C4氣炫基、_c⑼·LG烧基、 -C ⑼ N(R4)(RV -N(RYC⑼_Cl_C4 境基及 _c〇c4 伸烷基 390 201245116 -n(r4)(r1);且R2及R3之各碳環基或雜環基部分視情況經 氟、氯、-OH、=〇、c,-c4 敦燒基、Ci_c4 烧基、_〇 Ci_C4 烷基、-O-CVC4 氟烷基、-NH2、_NH((VC4 烷基）*_n(Ci_C4 烷基）2取代； 各R4係獨立地選自氫、6-(：1()碳環基、4_13員雜環基、氟、 氯、-OH ' CVC4氟烷基、烷基、_〇_C3_C|〇碳環基、 -0-4-13員雜環基、-CG-C4烷基_〇_Ci_C4烷基、_C『C4烷基 -0-CVC4 氟烷基、=〇、-c(o)-Cl_c4 烷基、_c(〇)n(r4)(r5)、 -N(R4)-C(0)-C 丨-C4 烷基及-C〇-C4 伸烷基 _N(R4)(r5)。 3.如申請專利範圍第i項或第2項中任一項之化合物， 其中環E包含環氮原子。 ” 4·如申請專利範圍第3項之化合物，其為非芳族 (R4)〇_r 環E中之所有其他環原子皆為碳。 7.如申請專利範圍第3項之化合物，其中環e係選 (R8)〇-2 . _。 (R4)〇.2 ' ·A compound of the formula I or a pharmaceutically acceptable salt thereof, wherein: X is selected from the group consisting of hydrogen, bromine, fluorine, chlorine, Ci-Ce alkyl, 〇〇_Cl_c6 alkyl, c3_Cl〇 carbocyclyl, 〇-C3-C1G carbocyclic group, 4-13 membered heterocyclic group, _〇_4·13 membered heterocyclic group, -S(0)m-R2, -CN, -N(r2)(r3), - S(0)mN(R2)(R3), -C(0)-0-R2, _C(0)-N(R2)(R3) and -NH-CCOHCVCe alkylene)-N(R2)(R3 Wherein each alkyl or alkylene group in the oxime represented by X is optionally substituted with one or more fluorines; and each of the carbocyclic or heterocyclic groups in the group represented by X is optionally subjected to one or A plurality of chlorine, =0, -OH, and Ci-CU are independently selected from the group consisting of: fluorine, fluoroalkyl, C|-C4 alkyl, - 〇-Ci_C4 alkyl, -O-C1-C4 H An alkyl group, -NH2, -NI^CVC^alkyl) or -i^Ci-CU alkyl) 2, a C3-C1() carbocyclyl or a (4-13 membered) heterocyclic group; a C3-C丨〇 carbocyclyl group and a (4-13 membered) heterocyclic group; W is selected from the group consisting of C(R6), C(R6)2, N and N(R7); and Q is selected from C(R6), C(R6)2, N, N(R7), Ο and S; Y is selected from the group consisting of hydrogen, fluorine, bromine, -CN, -[C(Rla)(Rlb)]nN(R2)(R3), -N (R4) (R5), N0 2, -NH-C(0)-(CrC4 alkylene alkyl, -NH-C^CO-CVC^ alkyl, -NH-SCOVCVCe alkyl, -NH-S(0)m-C3-C丨Anthracene carbocyclyl, -NH-S(0)m-4-13 membered heterocyclic group; each Rla and R]b are independently selected from the group consisting of hydrogen, CVC4 alkyl and C3-ClQ carbocyclyl; 387 201245116 R2 It is selected from the group consisting of hydrogen, Cl-C12 alkyl, -C (rC6 alkylene_C3_Ciq carbocyclic group and -C〇-C6 alkylene group - 4-13 membered heterocyclic group; R system is selected from hydrogen, C丨-C8 Alkyl, _Cg_C6 alkylene group _C3_Cm carbocyclic group, -(^-匕alkyl-indole-heterocyclic heterocyclic group~^(1)^厂^alkyl, %^-alkyl-c(o)n (r4)(r5), -C(0)_Ci_C6 alkylene_n(r4)(r5), •C2-C6 alkylene alkyl, _s(〇)mC3_c(7) carbocyclic group and -S(0)m a (4-13 membered) heterocyclic group, wherein: (7) each alkyl group in the group represented by R2 or R3, a carbocyclic group, an alkylene group or a heterocyclic group, optionally and independently, is one or more independent Substituted from the following substituents: gas 'gas, -OH, -O-CVq alkyl, Ci_C4 alkyl, gas-substituted Cl-c4 alkyl, -N(r4)(r5), c3_Ci〇 carbon ring a group or a 4-13 member heterocyclic ring; or R and R3 together with the atomic atom to which they are combined form a heart 7 member single ring heterocyclic ring or 6-13 member a ring-spiro or bridged heterocyclic ring wherein: the 4-7 membered monocyclic heterocyclic ring or the 6-13 membered bicyclic, spiro or bridged heterocyclic ring optionally comprises: ... a heteroatom independently selected from N, SA〇 / The 4-7 membered monocyclic heterocycle or the (4)M bicyclic, bridge or bridged heterocycle is optionally substituted with one or more substituents independently selected from: c"C丨. Carbon' group, 4-13 membered heterocyclic group, fluorine, gas, _〇H, genomically charged group, alkyl group, -O-C3-Cl0 carbocyclic group, 〇_4_13 member heterocyclic group, _c〇_ C4 extension base-oc丨-C4 burnt base, -eve4 extension yard base_〇_Ci_C4 gas yard base, soil C(9)_Cl.c:4 burnt base, wwam c and -C°-C4 stretch silk tan 4) (R5) And each carbocyclic group or heterocyclic group is substituted with fluorene, fluorine, gas, -OH, =0, Cl-C4 gas group, Ci_c4 alkyl group, soil 388 201245116 - alkyl group, -0-Cl_C4 fluoroalkyl group, -NH2, -NHCCVC4 alkyl) or -N(C"C4 alkyl"2; R4 and R5 are each independently selected from hydrogen and C丨-c4 alkyl; or R and R5 are taken together with the nitrogen atom to which they are bonded Optionally, a 4-7 membered heterocyclic ring selected from N, S and other heteroatoms of hydrazine, wherein the 4-7 membered heterocyclic ring is optionally substituted by fluorine, chlorine, -OH, = fluorene, fluorine substituted Ci_C4 alkyl, _C|_C4 Substituted or -C1-C4 alkylalkyl substituted, and optionally fused to phenyl; each R6 is independently selected from the group consisting of hydrogen, C3_Ciq carbocyclyl, 4-13 membered heterocyclyl, fluoro, chloro, -OH, Fluoroalkyl, alkyl, -〇_c3-C1() carbocyclyl, -0-4-13 membered heterocyclic group, _Cq_C4 alkyl_〇-Ci_C4 alkyl, _Cq_C 4-alkyl-〇-Ci-C4 fluoroalkyl, c(〇)_Ci_C4 alkyl, _c(〇)n(r4)(r5), _N(R)_C(0)_Cl'C4 alkyl and -C 〇-C4 alkylene_n(R4)(R5); or C(R6)2 is c=0; each R is independently selected from hydrogen, _Cq_C4 alkylene group _C3-C1G carbocyclic group, _Cg_C4 alkylene Keto-4-13 member heterocyclic group, _〇1_(:6 fluoroalkyl, _(:1_(:6 alkyl, _(:1_(:6 hydroxyalkyl, -〇-C3-C1() carbon Cyclic group, -〇_4·13 membered heterocyclic group, _C "C4 alkyl"_〇-(ν(:4 alkyl, _C(rC4alkyl)_〇_C|_C4 fluoroalkyl, -qco- Cvc^ alkyl, _Cl_c4 alkyl _c(〇) Ci_C4 alkyl, _Ci_C4 alkyl-C(0)-0H, _C(0)n(r4)(r5), -alkyl-C(〇) -(Cl-C4 alkylene)-NR4R5 and -C〇-C4 alkylene-N(R4)(R5); and each carbocyclic or heterocyclic group of R and R is optionally subjected to fluorine, gas, _ OH, 0 ci'c4 fluoroalkyl, Ci_C4 alkyl, _〇_Ci_C4, ketone, _〇-Ci_C4 gas-burning group, bribe 2, _NH (Ci-C4 alkyl) or -N (Cl-C4 alkane Substituted by singly; 298 201245116 is independently selected from the group consisting of hydrogen, C3_Ciq carbocyclyl, 4]3 membered heterocyclic group, said, gas, -〇H, Cl-c4 fluoroalkyl, Cl_c4 alkyl, C3_Ci〇 carbon Ring base, do 4·13 1 Heterocyclic group, -CA-based group -0-CVC4 alkyl group, -CG-C4 alkyl group -〇-c:-c4 fluoroalkyl group, =. , _c(〇)_Ci C4 alkyl, c(9)-N, r", -N(R)-C(9)-Cl_c4, _c. 'Extension base n(r4)(r5) and -δ(〇)2(ν (:4 alkyl group; R9 is absent or independently selected from hydrogen, C3_Ci. Carbocyclyl, 4-13 membered heterocyclic group, :, gas, ., Cl_C4 alkyl group, C|_C4 appearance group, _〇々Ci. Carbon Cyclic group, heterocyclic group, _cvc4 alkyl group 〇々C4 alkyl group, _c〇_c4 alkyl group-〇, c4 fluorine hospital group, =0, _c(〇) Ci_c4 hospital base, C(〇4)N (R5)(R5), -N(R4)-C(0)-C^, and -cvc4 alkylene-N(R4)(R5); each m is independently o, !*〗; η is 1 or 2; Ρ is 〇 or an integer between 1 and 4; and each = represents a single bond or a double bond, wherein at least one &amp; represents = system = is the ring (a) optionally substituted aromatic ring or X is not hydrogen, as the case is substituted with a heterocyclic ring. 2. A compound according to the scope of claim 1, wherein ... is independently selected from the group consisting of: gas ring extension; -U benheterocyclyl, (10) phenotypic group ' (9) leukoxyl, fluorene carbocyclyl, fluorene 13M heterocyclic ring HC4 stretching base 烧 burning base, -Co-C "申院基_〇, c〗 〖C4 , _c(9)·LG base, -C (9) N(R4)(RV -N(RYC _Cl_C4 and _c〇c4 alkyl 390 201245116 -n(r4)(r1); and each carbocyclic or heterocyclic moiety of R2 and R3 is optionally fluorinated, chloro, -OH, =〇, c , -c4 benzoic acid, Ci_c4 alkyl, _〇Ci_C4 alkyl, -O-CVC4 fluoroalkyl, -NH2, _NH((VC4 alkyl)*_n(Ci_C4 alkyl) 2 substituted; each R4 is independently Selected from hydrogen, 6-(:1() carbocyclyl, 4-13 membered heterocyclic, fluorine, chlorine, -OH 'CVC4 fluoroalkyl, alkyl, _〇_C3_C|〇 carbocyclyl, -0-4 -13 membered heterocyclic group, -CG-C4 alkyl_〇_Ci_C4 alkyl, _C "C4 alkyl-0-CVC4 fluoroalkyl, =〇, -c(o)-Cl_c4 alkyl, _c(〇) n(r4)(r5), -N(R4)-C(0)-C 丨-C4 alkyl and -C〇-C4 alkylene_N(R4)(r5). The compound according to any one of item 2, wherein the ring E comprises a ring nitrogen atom. "4. The compound of claim 3, which is a non-aromatic (R4) 〇 _r ring E The other ring atoms are all carbon. 7. The compound of claim 3, wherein the ring e is selected from (R8) 〇-2. _. (R4) 〇.2 ' (R8)〇-1 (R8)〇-2-(R8)〇-1 (R8)〇-2- R6 （R8)〇- , \ F N i R7 ,R0 .丫 v、 、 R3 ' R2 &gt; R6v人： C YRe^)〇,j / N / 'N R 、 R3 R9 及 tR6 (R8)〇- , \ F N i R7 , R0 .丫 v, , R3 ' R2 &gt; R6v person: C YRe^)〇, j / N / 'N R , R3 R9 and t 391 1 如申請專利範圍第3項或第4項之化合物，其 係選自N(R3)及]sf。 2 如申請專利範圍第5項之化合物，其中： 3 ϊ哀E為4-7員雜環基； 4 Q 為 C(R2)2 ;且 201245116 8.如申請專利範圍第5項至第7項中任一項之化合物， 其中R7係選自氫、-CVC6烷基、-C/C6氟烷基及-C〇-C4伸 烧基- C3-C10礙環基。 9_如申請專利範圍第1項至第8項中任一項之化合物， 其中 X 係選自氫、氣、氟、-och3、-ocf3、-och2f、-n(ch2)3 及 cf3。 10.如申請專利範圍第1項至第9項中任一項之化合 5111 為 Y 中 其 物391 1 The compound of claim 3 or 4, which is selected from the group consisting of N(R3) and]sf. 2 For example, the compound of claim 5, wherein: 3 ϊ E E is a 4-7 member heterocyclic group; 4 Q is C(R2) 2 ; and 201245116 8. If the scope of application patents 5 to 7 A compound according to any one of the preceding claims, wherein R7 is selected from the group consisting of hydrogen, -CVC6 alkyl, -C/C6 fluoroalkyl and -C〇-C4 alkylene-C3-C10. The compound according to any one of claims 1 to 8, wherein X is selected from the group consisting of hydrogen, gas, fluorine, -och3, -ocf3, -och2f, -n(ch2)3 and cf3. 10. If the combination of any of the first to the ninth items of the patent application range 5111 is Y, it is 任 下 2 _2 構 結Any 2 _2 construction H2H2 392 201245116392 201245116 393 201245116393 201245116 394 201245116394 201245116 或其醫藥學上可接受之鹽。 12. —種醫藥組成物，其包含醫藥學上可接受之載劑或 稀釋劑以及如申請專利範圍第1項至第丨丨項中任一項之化 合物。 13·如申請專利範圍第12項之醫藥組成物，其用於治療 或預防個體感染或定殖（c〇l〇nizati〇n)。 14.如申請專利範圍第13項之醫藥組成物，其中該感染 係由作為感染過程之一部分在細胞内生長之生物體引 395 201245116 1·5.如申請專利範圍第13項之醫藥組成物，其中該感染 係由革蘭氏陽性生物體（Gram-positive organism )引起。 16. 如申請專利範圍第15項之醫藥組成物，其中該革蘭 氏陽性生物體係選自桿菌綱（Bacilli );放線菌門 (Actinobacteria);及梭菌綱（Clostridia)。 17. 如申請專利範圍第16項之醫藥組成物，其中該桿菌 綱生物體係選自葡萄球菌屬（Siap/z^y/ococcw·? spp.)、鍵球菌 屬（Arepiococcw·? spp·)、腸球菌屬（五《/erococcw·? spp.)、 桿菌屬（5ac&quot;/Mlsspp.)及李氏菌屬（LbieWflspp·)。 18. 如申請專利範圍第16項之醫藥組成物，其中放線菌 門生物體係選自丙酸桿菌屬（’ Spp.)、棒 狀桿菌屬（spp·)、奴卡菌屬（iVocc^i/z.a spp.) 及放緣菌屣（Actinobacteria spp.)。 19. 如申請專利範圍第16項之醫藥組成物，其中梭菌綱 生物體係選自梭菌屬（C/osir/cZ/M/w spp.) 〇 2〇_如申請專利範圍第13項之醫藥組成物，其中該感染 係由革蘭氏陰性生物體（Gram-negative organism )引起。 21.如申請專利範圍第2〇項之醫藥組成物，其中該革蘭 氏陰性生物體係選自由以下組成之群：腸内菌科 、擬桿菌門、弧菌 科（mWowaeae)、巴斯德桿菌科（尸似ieMre//aceae )、 假單胞菌科（Psewc/omcmai/aceM )、奈瑟氏菌科 (Neisseriaceae)、立克次體屬（z_ae )、莫拉菌科 (Moraxe//如eae )、變形菌族（別）之任何種類、不 396 201245116 , 動菌屬（dckeiohcier spp.)、螺旋桿菌屬(Helicobacter spp.)及曲桿菌屬（Cam/?少/〇 iacier spp ·.)。 22·如申請專利範圍第13項之醫藥組成物，其中該感染 係由選自立克次體目（Rickettsiales )及衣原體目 (Chlamydiales)之生物體引起。 23. 如申請專利範圍第π項之醫藥組成物，其中該感染 係由選自衣原體門（Chlamydiae )及螺旋體門 (Spriochaetales )之生物體引起。 24. 如申請專利範圍第23項之醫藥組成物，其中該螺旋 體門生物體係選自疏螺旋體屬spp.)及密螺旋體 屬(Treponema spp.)。 25. 如申請專利範圍第13項之醫藥組成物，其中該感染 係由選.自柔膜菌綱（Moiiicutes )之生物體引起。 26. 如申請專利範圍第25項之醫藥組成物，其中該柔膜 函綱生物體係選自徽毅菌屬（β Spp· ) 〇 27. 如申請專利範圍第26項之醫藥組成物，其中黴漿菌 屬為肺炎徽聚菌（則.以）。 28. 如申請專利範圍第13項之醫藥組成物，其中該感染 係由選自退伍軍人桿菌屬（Spp·)及分枝桿菌屬 (spp )之生物體引起。 29. 如申請專利範圍第28項之醫藥組成物，其中該分枝 才干菌屬為結核分枝桿菌（)。 30·如申請專利範圍第13項之醫藥組成物，其中該感染 係由一種以上生物體引起。 397 201245116 3 1 ·如申請專利範圍第13項之醫藥組成物，其中該感染 係由對一或多種抗生素具有抗性之生物體引起。 . 3 2.如申睛專利範圍第13項之醫藥組成物，其中該感染 係由對四環素或第一代及第二代四環素抗生素之任何成員 具有抗性之生物體引起。 33. 如申請專利範圍第13項之醫藥組成物，其中該感染 係由對二甲氧苯青黴素（methicilUn )或卢内醯胺類別中之 任何抗生素具有抗性之生物體引起。 34. 如申請專利範圍第33項之醫藥組成物，其中該感染 係由對二曱氧苯青黴素具有抗性之生物體引起。 3 5 .如申請專利範圍第33項之醫藥組成物，其中該召_ 内醜胺類別係選自第二代、第三代及第四代頭孢菌素 (cephalosporin) 〇 36. 如申請專利範圍第13項之醫藥組成物，其中該感染 係由對啥諾嗣（qUjn〇l〇ne )或敗啥諾酮（flu〇r〇quin〇l〇ne ) 具有抗性之生物體引起。 37. 如申請專利範圍第13項之醫藥組成物，其中該感染 係由對泰格環黴素（tigecycline )具有抗性之生物體引起。 38·如申請專利範圍第13項之醫藥組成物，其中該感染 係由對四環素具有抗性之生物體引起。 3 9.如申請專利範圍第π項之醫藥組成物，其中該感染 係由對萬古黴素（vancomycin )具有抗性之生物體引起。 40.如申請專利範圍第13項之醫藥組成物，其中該感染 係由對抗微生物肽或生物相似性治療性處理具有抗性之生 398 201245116 &lt;k , 物體引起。 41·如申請專利範圍第13項之醫藥組成物，其中該感染 係由四環素反應性疾病或病症引起。 42.如申請專利範圍第13項之醫藥組成物，其中該感染 係由對ESBL及碳青黴烯類（carbapenum )具有抗性之大腸 桿菌（凡yc/zerzc/π’α co&quot;)及克留氏肺炎桿菌（尺 pneumoniae )引起。 43·如申請專利範圍第13項之醫藥組成物，其中該感染 係由大腸桿菌EC200或克留氏肺炎桿菌KP453引起。 44_如申請專利範圍第13項之醫藥組成物，其中該感染 係選自尿路感染、呼吸道感染、腹内感染、急性或慢性皮 膚及皮膚結構感染以及肺炎。 45 ·如申請專利範圍第44項之醫藥組成物，其中該感染 為醫院獲得性感染。 46·如申請專利範圍第44項至第45項中任一項之醫藥 組成物，其中該感染係由革蘭氏陰性生物體引起。 47. 如申請專利範圍第46項之醫藥組成物，其中該革蘭 氏陰性生物體係選自綠腺桿菌（/». )及克留氏肺 炎桿菌（尼 pwewmow/ae) 〇 48. 如申請專利範圍第46項之醫藥組成物，其中該革蘭 氏陰性生物體係選自腸内菌科（Enterobacteriaceae)。 49. 如申請專利範圍第47項之醫藥組成物，其中該感染 亦由一或多種以下生物體引起：不動菌屬、伯克霍爾德氏 镜饜（Burkholderia spp.)、對ES /3 L及碳青黴烯類具有抗 399 201245116 性之腸内菌科、MRSA及厭氧菌（anaerobes ) » 50. 如申請專利範圍第49項之醫藥組成物，其中該對 ES冷L及碳青黴烯類具有抗性之腸内菌科為大腸桿菌。 51. 如申請專利範圍第44項至第50項中任一項之醫藥 組成物，其中該感染為尿路感染。 5 2 _如申請專利範圍第5 1項之醫藥組成物，其中該尿路 感染為複雜尿路感染。 5 3 .如申請專利範圍第44項至第50項令任一項之醫藥 組成物’其中該感染為腹内感染。 54.如申請專利範圍第53項之醫藥組成物，其令該感染 為複雜腹内感染。 5 5 .如申請專利範圍第44項至第5 0項中任一項之醫藥 組成物，其中該感染為肺炎。 56.如申請專利範圍第55項之醫藥組成物，其中該肺炎 為呼吸器獲得性肺炎。 5 7 ·如申請專利範圍第5 5項之醫藥組成物，其中該肺炎 為醫療照護相關性肺炎。 58_如申請專利範圍第55項之醫藥組成物，其中該肺炎 為中度至重度社區相關性肺炎。 59. 如申請專利範圍第44項至第50項中任一項之醫藥 組成物’其中該感染為急性或慢性細菌性皮膚及皮膚結構 感染。 60. 如申請專利範圍第59項之醫藥組成物，其中該感染 為急性細菌性皮膚及皮膚結構感染。 400 201245116 , 6 1.如申請專利範圍第59項之醫藥組成物，其中該感染 為慢性細菌性皮膚及皮膚結構感染。 62.如申睛專利範圍第6 1項之醫藥組成物，其中該感染 係選自：糖尿病足感染；需要治療丨〇_ 14天以上之皮膚感 染，及需要間歇性抗微生物療法之皮膚感染。 63 ·如申請專利範圍第59項之醫藥組成物，其中該感染 為單一微生物性或多種微生物性。 64· —種如申請專利範圍第1項至第丨丨項中任一項之化 合物或其醫藥學上可接受之鹽的用途，其係用於製造供治 療或預防個體感染或定殖的藥物。 65. 如申請專利範圍第64項之用途，其中該感染係由作 為感染過程之一部分在細胞内生長之生物體引起。 66. 如申請專利範圍第64項之用途，其中該感染係由革 蘭氏陽性生物體引起。 67. 如申請專利範圍第66項之用途，其中該革蘭氏陽性 生物體係選自桿菌綱；放線菌門；及梭菌綱。 68. 如申請專利範圍第67項之用途，其中該桿菌綱生物 體係選自葡萄球菌屬、鏈球菌屬、腸球菌屬、桿菌屬及李 氏菌屬。 69. 如申凊專利範圍第67項之用途，其中放線菌門生物 體係選自丙酸桿® &gt;|、棒狀桿g屬、奴卡g屬及放線菌屬。 70. 如申明專利範圍第67項之用途，其中梭菌綱生物體 係選自梭菌屬。 7 1 ·如申清專利範圍第“項之用途，其中該感染係由革 401 201245116 蘭氏陰性生物體引起β 72. 如申請專利範圍第71項之用途，其中該革蘭氏陰性 生物體係選自由以下組成之群：腸内菌科、擬桿菌門、弧 菌科、巴斯德桿菌科、假單胞菌科、奈瑟氏菌科、立克次 體屬、莫拉菌科、變形菌族之任何種類、不動菌屬、螺旋 桿菌屬及曲桿菌屬。 73. 如申請專利範圍第64項之用途，其中該感染係由選 自立克次體目及衣原體目之生物體引起。 74. 如申清專利範圍第64項之用途，其中該感染係由選 自衣原體門及螺旋體門之生物體引起。 75. 如申請專利範圍第74項之用途，其中該螺旋體門生 物體係選自疏螺旋體屬及密螺旋體屬。 76·如申請專利範圍第64項之用途，其中該感染係由選 自柔膜菌綱之生物體引起。 77. 如申請專利範圍第76項之用途’其中該柔膜菌綱生 物體係選自黴漿菌屬。 78. 如申請專利範圍第77項之用途’其中黴毁菌屬為肺 炎黴漿菌。 7 9.如申請專利範圍第6 4項之用途’其中該感染係由選 自退伍軍人桿菌屬及分枝桿菌屬之生物體引起。 80. 如申請專利範圍第79項之用途’其中該分枝桿菌屬 為結核分枝桿菌。 81. 如申請專利範圍第64項之用途，其中該感染係由一 種以上生物體引起。 402 201245116 ， 82·如申喷專利範圍第64項之用途其中該感染係由對 -或多種抗生素具有抗性之生物體引起。 士申咕專利範圍第64項之用途，其中該感染係由對 四％素或第-代及第二代四環素抗生素之任何成員具有抗 性之生物體引起。 84^2請專利範圍第以項之用途，其中該感染係由對 -甲氧苯青黴素或^ ·内醯胺類別中之任何抗生素具有抗性 之生物體引起。 85_如申請專利範圍第84項之用途，其中該感染係由對 一甲氧本月#素具有抗性之生物體引起。 86. 如申請專利範圍第84項之用途’其中該内醯胺 類別係選自第二代、第三代及第四代頭抱菌素。 87. 如申請專利範圍第64項之用途，其中該感染係由對 喹諾酮或氟喹諾酮具有抗性之生物體引起。 88. 如申請專利範圍第64項之用途，其中該感染係由對 泰格環Μ素具有抗性之生物體引起。 89. 如申請專利範圍第64項之用途，其中該感染係由對 四環素具有抗性之生物體引起。 90. 如申請專利範圍第64項之用途，其中該感染係由對 萬古黴素具有抗性之生物體引起。 9 1.如申§奢專利範圍第64項之用途，其中該感染係由對 抗微生物肽或生物相似性治療性處理具有抗性之生物體引 起。 92.如申請專利範圍第64項之用途，其中該感染係由四 403 201245116 %素反應性疾病或病症引起。 93.如申請專利範圍第64項之用途’其中該感染係由對 ESBL及碳青黴烯類具有抗性之大腸桿菌及克留氏肺炎桿菌 引起。 94.如申請專利範圍第64項之用途，其中該感染係由大 腸桿菌EC200或克留氏肺炎桿菌KP453引起。 95·如申請專利範圍第64項之用途，其中該感染係選自 尿路感染、呼吸道感染、腹内感染、急性或慢性皮膚及皮 膚結構感染以及肺炎。 9 6 ·如申請專利範圍第9 5項之用途，其中該感染為醫院 獲得性感染。 97. 如申請專利範圍第95項至第96項中任一項之用 途，其中該感染係由革蘭氏陰性生物體引起。 98. 如申請專利範圍第97項之用途，其中該革蘭氏陰性 生物體係選自綠膿桿菌及克留氏肺炎桿菌。 99·如申請專利範圍帛97項之用途，其中該革蘭氏陰性 生物體係選自腸内菌科。 1〇0·如申請專利範圍第98項之用it，其中該感染亦由 -或多種以下生物體引起：不動菌屬、伯克霍爾德氏菌屬、 對聯L及碳青黴婦類具有抗性之腸内菌科、mrsa及厭 氧菌。 100項之用途，其中該對Es /5 L 101.如申請專利範圍第 及碳青徽婦類具有抗性之腸内菌科為大腸桿菌 1 0 1項中任一項之用 102.如申請專利範圍第95項至第 404 201245116 • 途，其中該感染為尿路感染。 103 •如申請專利範圍第102項之用途，其中該尿路感染 為複雜尿路感染。 104. 如申請專利範圍第95項至第ι〇1項中任一項之用 途’其中5亥感染為腹内感染。 105. 如申請專利範圍第1〇4項之用途，其中該感染為複 雜腹内感染* 106. 如申請專利範圍第95項至第1〇1項中任一項之用 途，其中該感染為肺炎。 107. 如申請專利範圍第ι〇6項之用途’其中該肺炎為呼 吸器獲得性肺炎。 108. 如申請專利範圍第1〇6項之用途，其中該肺炎為醫 療照護相關性肺炎。 109. 如申請專利範圍第ι〇6項之用途，其中該肺炎為中 度至重度社區相關性肺炎。 11 0.如申請專利範圍第9 5項至第1 01項中任一項之用 途，其中該感染為急性或慢性細菌性皮膚及皮膚結構感染。 11 1 ·如申請專利範圍第u〇項之用途，其中該感染為急 性細菌性皮膚及皮膚結構感染。 11 2.如申請專利範圍第110項之用途’其中該感染為慢 性細菌性皮膚及皮膚結構感染。 1 1 3 ·如申請專利範圍第1 1 2項之用途，其中該感染係選 自：糖尿病足感染；需要治療1〇_14天以上之皮膚感染；及 需要間歇性抗微生物療法之皮膚感染。 405 201245116 之用途，其中該感染為單 1 14.如申請專利範圍第1 10 一微生物性或多種微生物性。 八、圖式： (如次頁） 406Or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound according to any one of claims 1 to 3. 13. The pharmaceutical composition of claim 12, for use in the treatment or prevention of infection or colonization in an individual (c〇l〇nizati〇n). 14. The pharmaceutical composition according to claim 13 wherein the infection is caused by a living organism which is part of the infection process as part of the infection process 395 201245116 1·5. Wherein the infection is caused by a Gram-positive organism. 16. The pharmaceutical composition of claim 15 wherein the Gram-positive biological system is selected from the group consisting of Bacilli; Actinobacteria; and Clostridia. 17. The pharmaceutical composition of claim 16, wherein the Bacillus system is selected from the group consisting of Staphylococcus (Siap/z^y/ococcw·? spp.), Staphylococcus (Arepiococcw·? spp.), Enterococcus (five "/erococcw·? spp.", Bacillus (5ac&quot;/Mlsspp.) and Listeria (LbieWflspp.). 18. The pharmaceutical composition of claim 16 wherein the actinomycete biological system is selected from the group consisting of Propionibacterium ('Spp.), Corynebacterium (spp.), and Nocardia (iVocc^i/) Za spp.) and Actinobacteria spp. 19. The pharmaceutical composition of claim 16, wherein the Clostridium biological system is selected from the group consisting of Clostridium (C/osir/cZ/M/w spp.) 〇 2〇_ as claimed in claim 13 A pharmaceutical composition wherein the infection is caused by a Gram-negative organism. 21. The pharmaceutical composition of claim 2, wherein the Gram-negative biological system is selected from the group consisting of Enterobacteriaceae, Bacteroides, Vibrio, and Pasteurella Branch (body like ieMre//aceae), Pseudomonas family (Psewc/omcmai/aceM), Neisseriaceae, Rickettsia (z_ae), Moraxe// Eae), any species of the mutant family (other), not 396 201245116, dckeiohcier spp., Helicobacter spp. and genus (Cam/? less / 〇iacier spp ·.) . 22. The pharmaceutical composition of claim 13, wherein the infection is caused by an organism selected from the group consisting of Rickettssias and Chlamydiales. 23. The pharmaceutical composition of claim π, wherein the infection is caused by an organism selected from the group consisting of Chlamydiae and Spriochaetales. 24. The pharmaceutical composition of claim 23, wherein the helical organism is selected from the group consisting of Borrelia spp.) and Treponema spp. 25. The pharmaceutical composition of claim 13 wherein the infection is caused by an organism selected from the group of Moiiicutes. 26. The pharmaceutical composition of claim 25, wherein the flexible membrane biological system is selected from the group consisting of Huishen (β Spp· ) 〇 27. The pharmaceutical composition of claim 26, wherein the mold is The genus Mycoplasma is a pneumonia bacterium (J.). 28. The pharmaceutical composition of claim 13, wherein the infection is caused by an organism selected from the group consisting of Legionella (Spp.) and Mycobacterium (spp). 29. The pharmaceutical composition of claim 28, wherein the genus of the genus is Mycobacterium tuberculosis (). 30. The pharmaceutical composition of claim 13, wherein the infection is caused by more than one organism. 397 201245116 3 1 A pharmaceutical composition according to claim 13 wherein the infection is caused by an organism resistant to one or more antibiotics. 3. 2. The pharmaceutical composition of claim 13 wherein the infection is caused by an organism resistant to tetracycline or any member of the first and second generation tetracycline antibiotics. 33. The pharmaceutical composition of claim 13, wherein the infection is caused by an organism that is resistant to any of the antibiotics in the class of methicillin or lenethide. 34. The pharmaceutical composition of claim 33, wherein the infection is caused by an organism resistant to dicephedin. 3 5. The pharmaceutical composition of claim 33, wherein the serotonin class is selected from the second, third and fourth generation cephalosporin 〇36. The pharmaceutical composition according to item 13, wherein the infection is caused by an organism resistant to U诺嗣 (qUjn〇l〇ne) or flu〇r〇quin〇l〇ne. 37. The pharmaceutical composition of claim 13, wherein the infection is caused by an organism resistant to tegcycline. 38. The pharmaceutical composition of claim 13, wherein the infection is caused by an organism resistant to tetracycline. 3 9. The pharmaceutical composition of claim π, wherein the infection is caused by an organism resistant to vancomycin. 40. The pharmaceutical composition of claim 13, wherein the infection is caused by an anti-microbial peptide or biosimilar therapeutic treatment 398 201245116 &lt;k, an object. 41. The pharmaceutical composition of claim 13, wherein the infection is caused by a tetracycline reactive disease or condition. 42. The pharmaceutical composition of claim 13, wherein the infection is caused by Escherichia coli (yy yc/zerzc/π'α co&quot;) and Keliu, which are resistant to ESBL and carbapennum. Caused by Klebsiella pneumoniae (feet pneumoniae). 43. The pharmaceutical composition of claim 13, wherein the infection is caused by Escherichia coli EC200 or K. gramii KP453. 44. The pharmaceutical composition of claim 13, wherein the infection is selected from the group consisting of a urinary tract infection, a respiratory infection, an intra-abdominal infection, an acute or chronic skin and a skin structure infection, and pneumonia. 45. The pharmaceutical composition of claim 44, wherein the infection is a hospital-acquired infection. The pharmaceutical composition according to any one of claims 44 to 45, wherein the infection is caused by a Gram-negative organism. 47. The pharmaceutical composition of claim 46, wherein the Gram-negative biological system is selected from the group consisting of A. aeruginosa (/».) and Klebsiella pneumoniae (Nice pwewmow/ae) 〇 48. The pharmaceutical composition of the 46th item, wherein the Gram-negative biological system is selected from the group consisting of Enterobacteriaceae. 49. The pharmaceutical composition of claim 47, wherein the infection is also caused by one or more organisms: Acinetobacter, Burkholderia spp., ES/3 L And carbapenems having anti-399 201245116 enterobacteria, MRSA and anaerobes » 50. The pharmaceutical composition of claim 49, wherein the pair of ES cold L and carbapenems The resistant enterobacteriaceae is Escherichia coli. 51. The pharmaceutical composition of any one of claims 44 to 50, wherein the infection is a urinary tract infection. 5 2 _ The pharmaceutical composition of claim 51, wherein the urinary tract infection is a complicated urinary tract infection. 5 3. A pharmaceutical composition as claimed in any one of claims 44 to 50 wherein the infection is an intra-abdominal infection. 54. The pharmaceutical composition of claim 53 wherein the infection is a complex intra-abdominal infection. 5 5. The pharmaceutical composition according to any one of claims 44 to 50, wherein the infection is pneumonia. 56. The pharmaceutical composition of claim 55, wherein the pneumonia is a respiratoric acquired pneumonia. 5 7 · The pharmaceutical composition of claim 55, wherein the pneumonia is a medical care-associated pneumonia. 58. The pharmaceutical composition of claim 55, wherein the pneumonia is moderate to severe community-associated pneumonia. 59. The pharmaceutical composition of any one of claims 44 to 50 wherein the infection is an acute or chronic bacterial skin and skin structure infection. 60. The pharmaceutical composition of claim 59, wherein the infection is an acute bacterial skin and a skin structure infection. 400 201245116 , 6 1. The pharmaceutical composition of claim 59, wherein the infection is chronic bacterial skin and skin structure infection. 62. The pharmaceutical composition of claim 61, wherein the infection is selected from the group consisting of: a diabetic foot infection; a skin infection requiring treatment of 丨〇 _ 14 days or more, and a skin infection requiring intermittent antimicrobial therapy. 63. The pharmaceutical composition of claim 59, wherein the infection is monogenic or multi-microbial. The use of a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or preventing infection or colonization in an individual . 65. The use of claim 64, wherein the infection is caused by an organism that grows in the cell as part of the infection process. 66. The use of claim 64, wherein the infection is caused by a Gram-positive organism. 67. The use of claim 66, wherein the Gram-positive biological system is selected from the group consisting of Bacillus; Actinobacteria; and Clostridium. 68. The use of claim 67, wherein the Bacillus system is selected from the group consisting of Staphylococcus, Streptococcus, Enterococcus, Bacillus, and Listeria. 69. For the purposes of claim 67, the actinomycete biological system is selected from the group consisting of propionic acid rods &gt;|, rods, genus, and actinomycetes. 70. The use of claim 67, wherein the Clostridium organism is selected from the group consisting of Clostridium. 7 1 ·If the application of the patent scope is “the application of the item, the infection is caused by the leather 401 201245116 gram negative organism β 72. For the use of the scope of the patent, the selection of the Gram-negative biological system Free group consisting of: Enterobacteriaceae, Bacteroides, Vibrio, Pasteuraceae, Pseudomonas, Neisseria, Rickettsia, Moraxaceae, Proteobacteria Any species of the family, Acinetobacter, Helicobacter, and Aspergillus. 73. The use of claim 64, wherein the infection is caused by an organism selected from the group consisting of Rickettsia and Chlamydia. For example, the use of the patent scope of claim 64, wherein the infection is caused by an organism selected from the group consisting of a Chlamydia and a spirochete. 75. The use of the spiro-door biosystem from Borrelia, as claimed in claim 74. 76. The use of the genus and the genus Treponema. 76. The use of claim 64, wherein the infection is caused by an organism selected from the group consisting of the genus of the genus of the genus. 77. Strains The system is selected from the group consisting of the genus Mycoplasma. 78. The use of the invention in the scope of claim 77, wherein the genus is a bacterium of the genus Pneumocystis. 7 9. The use of the invention in the scope of claim 46, wherein the infection is caused by It is caused by an organism selected from the genus Legionella and the genus Mycobacterium. 80. For the use of the patent application, item 79, wherein the Mycobacterium is Mycobacterium tuberculosis. 81. Use, wherein the infection is caused by more than one organism. 402 201245116, 82. The use of the patent application of claim 64, wherein the infection is caused by an organism that is resistant to - or a plurality of antibiotics. The use of the scope of item 64, wherein the infection is caused by an organism resistant to any member of the four-dimensional or first-generation and second-generation tetracycline antibiotics. 84^2 The infection is caused by an organism which is resistant to any of the antibiotics in the class of methicillin or meglumine. 85. The use of the invention is in the application of claim 84, wherein the infection is by methoxy This month is caused by a resistant organism. 86. For the use of Article 84 of the patent application 'where the intrinsic amine class is selected from the second, third and fourth generations of cephalosporin. The use of the scope of claim 64, wherein the infection is caused by an organism resistant to quinolone or a fluoroquinolone. 88. The use of the invention in claim 64, wherein the infection is caused by a 89. The use of a ferritin-resistant organism. 89. The use of the invention of claim 64, wherein the infection is caused by an organism resistant to tetracycline. 90. This infection is caused by an organism that is resistant to vancomycin. 9 1. The use of claim 64 of the scope of the invention, wherein the infection is caused by an organism resistant to antimicrobial peptides or therapeutic treatment of biological similarity. 92. The use of claim 64, wherein the infection is caused by a 403 201245116% responsive disease or condition. 93. The use of claim 64, wherein the infection is caused by Escherichia coli and Klebsiella pneumoniae resistant to ESBL and carbapenems. 94. The use of claim 64, wherein the infection is caused by E. coli EC200 or Klebsiella pneumoniae KP453. 95. The use of claim 64, wherein the infection is selected from the group consisting of a urinary tract infection, a respiratory infection, an intra-abdominal infection, an acute or chronic skin and skin structure infection, and pneumonia. 9 6 · If the application of patent application No. 95 is used, the infection is a hospital-acquired infection. 97. The use of any one of clauses 95 to 96, wherein the infection is caused by a Gram-negative organism. 98. The use of claim 97, wherein the Gram-negative biological system is selected from the group consisting of Pseudomonas aeruginosa and Klebsiella pneumoniae. 99. If the scope of the patent application is 97, wherein the Gram-negative biological system is selected from the group consisting of enterobacteriaceae. 1〇0·If you apply for it in the 98th section of the patent application, the infection is also caused by - or more than one of the following organisms: Acinetobacter, Burkholderia, couple L and carbapenem women Intestinal fungi, mrsa and anaerobic bacteria. The use of 100 items, wherein the pair of Es /5 L 101. If the patent application scope and the carbon green emblem are resistant to enteric fungi, it is used in any of the Escherichia coli 101. Patent range 95 to 404 201245116 • The infection is a urinary tract infection. 103 • The use of the urinary tract infection is a complex urinary tract infection as claimed in claim 102. 104. The use of any of items 95 to ι 〇1 of the patent application wherein 5 McAfee infection is an intra-abdominal infection. 105. If the application of the scope of the patent application is referred to in item 1, item 4, wherein the infection is a complex intra-abdominal infection* 106. For the use of any one of the scope of claim 95 to claim 1, wherein the infection is pneumonia . 107. For the purpose of applying for the scope of the patent, item 〇6, where the pneumonia is respiratory acquired pneumonia. 108. For the purposes of claim 1, paragraph 6, the pneumonia is a medical care-associated pneumonia. 109. For the purpose of applying for the scope of patent § 〇6, the pneumonia is moderate to severe community-associated pneumonia. 11 0. The use of any one of claims 159 to 01 wherein the infection is an acute or chronic bacterial skin and skin structure infection. 11 1 · The use of the scope of the patent application, wherein the infection is acute bacterial skin and skin structure infection. 11 2. The use of claim 110, wherein the infection is chronic bacterial skin and skin structure infection. 1 1 3 · For the use of the scope of patent application No. 112, the infection is selected from: diabetic foot infection; skin infection requiring treatment for 1〇_14 days; and skin infection requiring intermittent antimicrobial therapy. 405 The use of 201245116, wherein the infection is a single 1 14. A microbial or a plurality of microbial properties as claimed in claim 1 . Eight, the pattern: (such as the next page) 406
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