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TW201000446A - New compounds useful in pain therapy - Google Patents

New compounds useful in pain therapy Download PDF

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Publication number
TW201000446A
TW201000446A TW098117487A TW98117487A TW201000446A TW 201000446 A TW201000446 A TW 201000446A TW 098117487 A TW098117487 A TW 098117487A TW 98117487 A TW98117487 A TW 98117487A TW 201000446 A TW201000446 A TW 201000446A
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compound
group
trifluoromethoxy
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alkyl
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TW098117487A
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Chinese (zh)
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Yevgeni Besidski
Alf Claesson
Istvan Macsari
Gabor Csjernyik
Linda I Nilsson
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Astrazeneca Ab
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • 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
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C07D209/46—Iso-indoles; Hydrogenated iso-indoles with an oxygen atom in position 1
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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  • Animal Behavior & Ethology (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • Heart & Thoracic Surgery (AREA)
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  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Indole Compounds (AREA)

Abstract

Compounds of formula I are claimed, wherein R1 is hydrogen, C1-3alkl, C1-3alkoxy, cyano, hydroxy or halo; and wherein said C1-3alkyl is optionally substituted by one or more substituents independently selected from hydroxy, C1-3alkoxy and fluoro; and said C1-3alkoxy is optionally substituted by one or more fluoro; m is 1 or 2; R2 and R3 is each and independently selected from hydrogen, C1-4haloalkyl, C1-4halolkoxy, halo, C1-4alkoxy, C1-4a1ky1 and C3-7cycloalkyloxy; wherein said C3-7cycloalkyloxy is optionally substituted by one or more fluoro; and R2 and R3 may not both be hydrogen; D is C3-7cycloalkyl or C3-7heterocycloalkyl; and wherein said C3-7cycloalkyl or C3-7heterocycloalkyl may optionally be substituted by one or more X4; X4 is halo, C1-3alkyl, C1-3alkylOC1-3alkoxyl, C1-3alkoxy, benzyl, C1-4alkylsulfonyl, oxo, R4O(C=O), R5(C=O), or C5-6 heteroaryl; wherein said C1-3alkyl, C1-3alkylOC1-3alkyl, C1-3alkoxy and C1-4alkylsulfonyl is optionally substituted by one or more fluoro; R4 is C1-4alkyl, C1-4alkylOC1-4alkyl, C5-6cycloalkyl, or aryl; R5 is C1-4alkyl, C1-4fluoroalkyl or C5-6 heteroaryl; L1 is C1-4alkylene or a bond; L2 is C1-3alkylene; with the exception of the compound 2-(cyclohexylmethyl)-3-oxo-N-[2-(trifluoromethyl)benzyl]isoindoline-1-carboxamide; as well as a pharmaceutically acceptable salt, or isomer thereof, or a salt of said isomer. The compounds of the invention are useful in therapy such as pain therapy.

Description

201000446 六、發明說明： 【發明所屬之技術領域】 本發明係關於新IP化人你 ' σ έ有該等化合物之醫藥組合201000446 VI. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a new IP-based person who has a pharmaceutical combination of such compounds

物及該等化合物在治療中夕田、A ^ ” 之用硬。本發明亦係關於製備該 等化合物之方法。 【先前技術】 疼痛病狀之當前治療方牵未丨 ·、 架和用採用極有限的藥理學機制 範圍之化合物。一翻/f卜人‘ *：£： 、口物病鴉片（opioid)刺激内源内啡 肽系統；該類別之一實例為 貝1 J馮馬啡鹼（morphine)。類鴉片類 化合物具有若干限制盆传用夕μ ^ 八更用之缺陷’例如嘔吐及便秘作用 及對呼吸能力之負面影響。第_ 呆—大類止痛藥C〇X_丨或c〇x_ 2型非類固酵消炎止痛華亦且女 屌樂亦具有以下缺點，諸如在劇痛病 狀下功效不足，及在長期传用 用COX- 1抑制劑時致使黏膜潰 瘍。其他目前所用華物夕，.由A m 物之止痛作用的機制尚未得到充分表 徵，且/或具有有限的治療潛力。 已知阻斷神經中大多數鈉通道類型之局部麻醉劑適用於 緩解人體小面積之疼痛且適用於阻斷神經自末梢神經系統 傳導至中柩神經系統。其亦可用於藉由在脊髓處滴注局部 麻醉劑溶液來阻斷感覺信號轉導之最後提及之方法。缺 而，由於其高毒性（尤其心臟毒性），其不能料通常有用 之止痛藥用於全身性投與。因此，仍需要更多參與疼痛信 號轉導之選擇性鈉通道調節劑。 迄今為止’已選殖且在功能上表現九種鈉通道亞型 (Wood JN, Baker M. Cijrri>v,t η, ·The compounds and the compounds are used in the treatment of Xitian, A^". The present invention is also directed to a method for preparing the compounds. [Prior Art] The current treatment of pain conditions is unresolved, framed and used Compounds of a limited range of pharmacological mechanisms. One: /::: opioid stimulates the endogenous endorphin system; one example of this class is phenone 1 von martine (morphine) ). Opioids have a number of limitations that limit the use of pelvic irradiance, such as vomiting and constipation, and negative effects on respiratory capacity. _ _ _ _ big painkillers C 〇 X 丨 or c 〇 x _ Type 2 non-steroidal anti-inflammatory and anti-inflammatory pains also have the following disadvantages, such as insufficient efficacy in severe pain conditions, and mucosal ulceration caused by long-term use of COX-1 inhibitors. Other current Chinese products The mechanism of analgesic action by A m has not been well characterized and/or has limited therapeutic potential. Local anesthetics known to block most of the sodium channel types in the nerve are suitable for relieving pain in small areas of the body and are suitable for use. to The nerve is transmitted from the peripheral nervous system to the medial nervous system. It can also be used to block the last mentioned method of sensory signal transduction by instilling a local anesthetic solution at the spinal cord. Inadequate due to its high toxicity (especially the heart) Toxicity), which cannot be used for systemic administration of painkillers that are usually useful. Therefore, there is still a need for more selective sodium channel modulators involved in pain signaling. So far, 'there have been selected and functionally nine Sodium channel subtype (Wood JN, Baker M. Cijrri>v, t η, ·

Lurrent Option in Pharmacology 140374.doc 201000446 2001，1，17-21)。其在整個肌肉及神經組織中差異性表現 且展示不同生物物理學特性。所有電壓閘控鈉通道（NaV:s) 之特徵在於與其他離子相比對鈉之高度選擇性，及其電壓 依賴性閑控。藉由應用遺傳分析已展示，編碼鈉通道 NaV1.7之基因的突變（該突變使該蛋白喪失功能）可使人類 變得對疼痛幾乎不敏感（c〇x π等人，2〇〇6, 894-898) ° 5Lurrent Option in Pharmacology 140374.doc 201000446 2001, 1, 17-21). It exhibits differential performance throughout the muscle and nerve tissue and exhibits different biophysical properties. All voltage-gated sodium channels (NaV:s) are characterized by a high selectivity to sodium compared to other ions and their voltage-dependent idle control. It has been shown by the application of genetic analysis that a mutation in the gene encoding the sodium channel NaV1.7, which causes the protein to lose its function, makes humans almost insensitive to pain (c〇x π et al., 2〇〇6, 894-898) ° 5

已熟知，神經中電壓閘控之鈉通道在神經痛中起關鍵作 用（Baker MD及Wood JN. 7>e油k户办卿卿⑽㈣㈤嫩 2001，22, 27-31)。末梢神經系統損傷通常在初始損傷消退之 後引起持續很久之神經痛。神經痛之實例包括（但不限於） 疱疹後神經痛、三又神經痛、糖尿病性神經病、慢性下背 痛、擬肢痛、由癌症及化學療法所致之疼痛、慢性骨盆疼 痛、複雜區域疼痛症候群及相關神經痛◎人類患者以及神 經痛之動物模型中已展示，初級傳入感覺神經元之損傷可 引起神經瘤形成及自發活動以及回應通常無害刺激之誘發 活動。NaVl.7表現於人類神經瘤巾，其為通常存在於慢性 疼痛狀悲下之腫脹及過敏神經及神經末梢 Neurochirurgica 2002, 144, 803-810) 〇 在末梢神經損傷之大鼠模型中，損傷神經中之異位活動 對應於疼痛之行為病徵。在該等㈣巾，靜脈内施用納通 道阻斷劑及局部麻醉劑利多卡因（lid〇caine)可以不影響一 般行為及運動功能之濃度抑止異位活動且逆轉觸覺異常疼 痛（Mao J及 Chen LL，2000，87 7-17)。 140374.doc 201000446 除神經痛以外，納通道阻斷劑在癲癇症及心律不整之治 療中亦具有臨床用it。新近來自動物模型之證據表明，納 通道阻斷劑亦可用於由中風或神經外傷造成之缺血情況下 的神經保護及用於患有多發性硬化症（M s)之患者。 【發明内容】 根據本發明，提供一種式I化合物： R°It is well known that the voltage-controlled sodium channel in the nerve plays a key role in neuralgia (Baker MD and Wood JN. 7> e oil k household office Qing Qing (10) (four) (f) tender 2001, 22, 27-31). Peripheral nervous system damage usually causes long-lasting neuralgia after the initial damage has subsided. Examples of neuralgia include, but are not limited to, post-herpetic neuralgia, tri- and neuralgia, diabetic neuropathy, chronic lower back pain, limb pain, pain caused by cancer and chemotherapy, chronic pelvic pain, complex regional pain Syndrome and related neuralgia ◎ Human patients and animal models of neuralgia have been shown that damage to primary afferent sensory neurons can cause neuroma formation and spontaneous activity as well as evoked activity in response to normally innocuous stimuli. NaVl.7 is expressed in human neuroma dentis, which is a swelling and allergic nerve and nerve endings commonly found in chronic painful conditions. Neurochoirurgica 2002, 144, 803-810) In a rat model of peripheral nerve injury, in the injured nerve The ectopic activity corresponds to the behavioral symptoms of pain. In these (four) towels, intravenous administration of the nanochannel blocker and the local anesthetic lidocaine can inhibit ectopic activity and reverse tactile allodynia without affecting the general behavioral and motor function concentrations (Mao J and Chen LL) , 2000, 87 7-17). 140374.doc 201000446 In addition to neuralgia, nanochannel blockers have clinical use in the treatment of epilepsy and arrhythmia. Recent evidence from animal models suggests that nanochannel blockers can also be used for neuroprotection in ischemic conditions caused by stroke or neurological trauma and for patients with multiple sclerosis (M s). SUMMARY OF THE INVENTION According to the present invention, there is provided a compound of formula I: R°

R2 0 其中 R為虱、Cw烷基、Cl_3烷氧基、氰基、羥基或_基； 且其中》亥C〗_3烷基視情況經一或多個獨立地選自羥基、c w 烧氧基及I基之取代基取代；且該Cu炫氧基視情況經一 或多個氟基取代； m為1或2 ; R及R係各自且獨立地選自氫、C丨_4鹵烷基、C卜4鹵烷 氧基、鹵基、Cw烷氧基、ci 4烷基及c3 7環烷氧基；其中 該（：3.7環烧氧基視情況經—或多個i基取代； 且R2及R3不可同時為氫； D為C3·7環烧基或C3·7雜環烷基；且其中該C3_7環烷基或 140374.doc 201000446 該(：3_7雜環烷基可視情況經一或多個X4取代； X為_基、Ci-3烧基、Ci-3烧基OCi-3院基、Ci-3烧氧基、 苯曱基、Cm烷基磺醯基、側氧基、R40(C = 0)、R5(C = 0) 或CS-6雜芳基；其中該Cw烷基、該Cw烷基OCu烷基、該 c 1 -3烧氧基及該C i · 4烧基績隨基視情況經一或多個氟基取 代；R2 0 wherein R is hydrazine, Cw alkyl, Cl_3 alkoxy, cyano, hydroxy or hydrazinyl; and wherein "H" _3 alkyl is optionally independently selected from hydroxy, cw alkoxy Substituting a substituent of the I group; and the Cu decyloxy group is optionally substituted by one or more fluoro groups; m is 1 or 2; R and R are each independently and independently selected from hydrogen, C丨_4 haloalkyl , C 4 4 haloalkoxy, halo, C alkoxy, ci 4 alkyl and c 3 7 cycloalkoxy; wherein (: 3.7 ring alkoxy is optionally substituted by a plurality of i groups; R2 and R3 may not be hydrogen at the same time; D is C3·7 cycloalkyl or C3·7 heterocycloalkyl; and wherein the C3_7 cycloalkyl or 140374.doc 201000446 The (:3-7 heterocycloalkyl group may be subjected to one or Multiple X4 substitutions; X is _ group, Ci-3 alkyl, Ci-3 alkyl OCI-3, Ci-3 alkoxy, phenyl fluorenyl, Cm alkylsulfonyl, pendant oxy, R40 (C = 0), R5 (C = 0) or CS-6 heteroaryl; wherein the Cw alkyl group, the Cw alkyl OCu alkyl group, the c 1 -3 alkoxy group, and the C i · 4 alkyl group Performance is replaced by one or more fluorine groups with the base state;

R為<^_4烧基、Ci-4烧基0(^-4烧基、C5.6環烧基或芳基； ^為匕―4烷基、Ci-4氟烷基或c5_6雜芳基；R is <^_4 alkyl, Ci-4 alkyl 0 (^-4 alkyl, C5.6 cycloalkyl or aryl; ^ is 匕-4 alkyl, Ci-4 fluoroalkyl or c5_6 heteroaryl base;

Li為Cw伸烷基或一鍵； L2為ci-3伸烷基； 其中以下化合物除外： 2-(環己基甲基）-3-側氧基-N_[2_(三氟甲基）苯甲基]異吲 哚啉-1-甲醯胺； 以及其醫藥學上可接受之鹽或異構物或該異構物之鹽。 本發明之—實施例係關於式I化合物，其中： R為氫、Cw烷基、Cl_3烷氧基、鹵基或羥基； m為1 ;Li is Cw alkyl or a bond; L2 is ci-3 alkyl; except for the following compounds: 2-(cyclohexylmethyl)-3-oxo-N_[2_(trifluoromethyl)benzene And pharmaceutically acceptable salts or isomers or salts of such isomers. An embodiment of the invention relates to a compound of formula I, wherein: R is hydrogen, Cw alkyl, Cl-3-alkoxy, halo or hydroxy; m is 1;

Cl-4烷氧基 R係選自氫、cv4烷基、Ci 4i 及ci-4iS烷氧基； R3為氫、湞烷氧基 且R及R3不可同時為氫； D為C4 其中C 代； '6環烷基或C4-6雜環烷基； 4 6衣烷基或C4·6雜環烷基視情況經 一或多個X4取 140374.doc 201000446 χ為齒基、側氧基、r4〇(C=0)、R5(C = 0)或c5-6雜芳 基； R為C · 4烧基； R5ac5.6雜芳基；Cl-4 alkoxy R is selected from the group consisting of hydrogen, cv4 alkyl, Ci 4i and ci-4iS alkoxy; R 3 is hydrogen, decyloxy and R and R 3 are not simultaneously hydrogen; D is C 4 wherein C is; '6 cycloalkyl or C4-6 heterocycloalkyl; 4 6 alkyl or C 4 · 6 heterocycloalkyl as appropriate by one or more X 4 taken 140374.doc 201000446 χ is a dentate, pendant oxy, r 4 〇(C=0), R5(C=0) or c5-6heteroaryl; R is C·4 alkyl; R5ac5.6 heteroaryl;

Ligc!·2伸烷基或一鍵；且 1^2為Ci-2伸烧基。 本發明之一實施例係關於式I化合物’其中R1為氫。 本發明之一實施例為式I化合物，其中m為1。 本發明之一實施例為式I化合物，其中R1為氫。 本發明之另一實施例為式I化合物’其中R1為甲基。 本發明之另一實施例為式I化合物，其中R1為曱氧基。 本發明之另一實施例為式I化合物’其中R1為氟基。 本發明之另一實施例為式I化合物’其中R1為羥基。 本發明之一實施例為式I化合物，其中R2為-〇-CF3。 本發明之另一實施例為式I化合物，其中R2為氣基或溴 基。 本發明之另一實施例為式I化合物’其中R2為曱氧基。 本發明之另—實施例為式Ϊ化合物’其中R2為CF 3或 CH2-CF3。 本發明之另一實施例為式I化合物’其中R2為甲基。 本發明之另一實施例為式I化合物，其中R2為異丙基。 本發明之一實施例為式I化合物，其中R3為氫。 本發明之另一實施例為式I化合物’其中R3為曱基。 本發明之另一實施例為式I化合物，其中R3為氯基。 140374.doc -10· 201000446 本發明之另一實施例為式i化合物’其中R3為-ocf3。 本發明之一貫施例為式I化合物’其中L1為一鍵。 本發明之另一實施例為式I化合物’其中L〗為亞甲基。 本發明之另一實施例為式Ϊ化合物，其中h為伸乙基。 本發明之一實施例為式I化合物，其中L2為亞甲基。 本發明之另一實施例為式〗化合物，其中L2為-CH(CH3)-。 本發明之另一實施例為式I化合物，其中Li為伸環丙 基。Ligc!·2 is an alkyl group or a bond; and 1^2 is a Ci-2 extension group. One embodiment of the invention pertains to compounds of formula I wherein R1 is hydrogen. An embodiment of the invention is a compound of formula I, wherein m is 1. An embodiment of the invention is a compound of formula I, wherein R1 is hydrogen. Another embodiment of the invention is a compound of formula I wherein R1 is methyl. Another embodiment of the invention is a compound of formula I, wherein R1 is a decyloxy group. Another embodiment of the invention is a compound of formula I wherein R1 is fluoro. Another embodiment of the invention is a compound of formula I wherein R1 is hydroxy. An embodiment of the invention is a compound of formula I, wherein R2 is -〇-CF3. Another embodiment of the invention is a compound of formula I, wherein R2 is a gas or bromo group. Another embodiment of the invention is a compound of formula I wherein R2 is a decyloxy group. Another embodiment of the invention is a hydrazine compound wherein R2 is CF3 or CH2-CF3. Another embodiment of the invention is a compound of formula I wherein R2 is methyl. Another embodiment of the invention is a compound of formula I, wherein R2 is isopropyl. An embodiment of the invention is a compound of formula I, wherein R3 is hydrogen. Another embodiment of the invention is a compound of formula I wherein R3 is fluorenyl. Another embodiment of the invention is a compound of formula I, wherein R3 is chloro. 140374.doc -10· 201000446 Another embodiment of the invention is a compound of formula i wherein R3 is -ocf3. A consistent embodiment of the invention is a compound of formula I wherein L1 is a bond. Another embodiment of the invention is a compound of formula I wherein L is methylene. Another embodiment of the invention is a hydrazone compound wherein h is an exoethyl group. An embodiment of the invention is a compound of formula I wherein L2 is methylene. Another embodiment of the invention is a compound of formula wherein L2 is -CH(CH3)-. Another embodiment of the invention is a compound of formula I, wherein Li is a cyclopropyl group.

本發明之一實施例為式Ϊ化合物，其中D係選自以下任一 者：吖丁啶基、四氫哌喃基、四氫呋喃基、呪咯啶某、吡 ρ各。定基-2-酮、旅咬基及嗎D林基。 本發明之另一實施例為式〗化合物，其中 τ u為i哀丁基或 己基。 衣 本發明之一實施例為式I化合物，其中X4為氣美 本發明之另一實施例為式I化合物，龙办 c(CH3)3。 、中 X4為-C(0)-〇· C(〇)-〇. 本發明之另一實施例為式I化合物，其中 ch(ch3)2。 為 本發明之另一實施例為式〗化合物，其中X4 CH,。 ^ 'C(0)-CH2- C(0)-CH2- 本發明之另一實施例為式J化合物，其中X4為 -SO?- 本發明之另一實施例為式I化合物，其中X4為 140374.doc • 11 - 201000446An embodiment of the present invention is a hydrazine compound wherein D is selected from the group consisting of azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, purridolidine, and pyrrazine. Dingyl-2-ketone, brigade bite and D-based. Another embodiment of the invention is a compound of the formula wherein τ u is i butyl or hexyl. An embodiment of the invention is a compound of formula I wherein X4 is a gas. Another embodiment of the invention is a compound of formula I, L. c(CH3)3. And X4 is -C(0)-〇·C(〇)-〇. Another embodiment of the invention is a compound of formula I, wherein ch(ch3)2. Another embodiment of the invention is a compound of the formula wherein X4 CH,. ^ 'C(0)-CH2-C(0)-CH2- Another embodiment of the invention is a compound of formula J wherein X4 is -SO?- Another embodiment of the invention is a compound of formula I wherein X4 is 140374.doc • 11 - 201000446

本發明之另一實施例為式1化合物，其中x4為嘧啶美 本發明之另一實施例為式I化合物，其中X4為 本發明之另一實施例為式J化合物，其中X4為笨曱美。 本發明之一實施例為式！化合物，其中D係經X4二取代。 本發明之一實施例為選自以下任—者之化合物： 2-(噁烷-4-基）-3-側氧基_N_[[4_(三氟甲氧基）笨基]曱基]_ 1H-異,n朵-1 _甲醯胺； 2- (4,4-二氟環己基）_3_側氧基_N_[4_(三氟甲氧基）笨曱 基]異吲哚琳-1 -甲醯胺； 3- 側氧基-2-[[(2S)-氧雜環戊_2_基]曱基三氟曱 氧基）苯基]甲基]-1Η-異吲嗓-1 _甲酿胺； N-[l-(4-氣苯基）乙基]_3_側氧基_2_[[(28)_氧雜環戊_2·基] 甲基]-1Η-異吲嗓-1 -甲醯胺；Another embodiment of the invention is a compound of formula 1, wherein x4 is pyrimidine. Another embodiment of the invention is a compound of formula I, wherein X4 is another compound of formula J, wherein X4 is awkward . An embodiment of the invention is of the formula! a compound wherein D is disubstituted by X4. An embodiment of the present invention is a compound selected from the group consisting of: 2-(oxoalkyl-4-yl)-3-oxooxy_N_[[4_(trifluoromethoxy)phenyl] fluorenyl] _ 1H-iso, n-to-1 _carbamamine; 2-(4,4-difluorocyclohexyl)_3_sideoxy_N_[4_(trifluoromethoxy) alum] -1 -carbamidine; 3-oxo-2-[[(2S)-oxo-2-yl]decyltrifluoromethoxy)phenyl]methyl]-1Η-isoindole -1 _ 甲甲胺; N-[l-(4-Phenylphenyl)ethyl]_3_sideoxy_2_[[(28)_ oxol-2-yl]methyl]-1Η- Isoindole-1 -carbamamine;

哚-1 -曱醯胺；哚-1 - guanamine;

140374.doc •12- 201000446 側氧基-2-(1-嘴啶_2-基吖丁啶_3_基）善[4_(三氟曱氧 基）苯甲基]異吲哚啉-1 -甲醯胺； (4’4-—氟環己基）-N-(4-甲氧基笨曱基）_3_側氧基異吲 哚啉_1 -甲醯胺； Ν Π-Ο-氯苯基）乙基]_2_(4,4_二氟環己基）_3_側氧基異吲 哚啉-1 _甲醯胺； Ν Π_(3-氣笨基）乙基]_3_側氧基_2_(四氫_2H-哌喃_4_基） 異吲哚啉-1 -甲醯胺； 2 ((3’3_二氟環丁基）甲基）-3-側氧基三氟曱氧基） 苯甲基）異吲哚啉_丨_甲醯胺； 2 (3’3_二氟環丁基）-3-側氧基-N-(4-(三氟曱氧基）苯曱 基）異°引哚啉-1 -曱醯胺； 244’4·二氟環己基）-7-甲氧基-3-側氧基-N-(4-(三氟甲氧 基）苯甲基）異吲哚啉_丨-甲醯胺； 2_(4,4-二氟環己基）-7-曱基-3-側氧基-N-(4-(三氟曱氧基） 苯甲基）異吲哚啉-1 -曱醯胺； 3_(4·甲基-1_側氧基-3-(4-(三氟曱氧基）苯曱基胺曱醯基） 異吲哚啉-2-基）〇丫丁啶-1-曱酸第三丁酯； 側氧基- 2-(四氫-2Η-略喊-4-基）-N-(l-(4-(三氟曱氧基） 苯基）乙基）異吲哚啉_丨-甲醯胺，異構物4; 3-(1-側氧基_3_(卜（4_(三氟甲氧基）苯基）乙基胺曱醯基） 兴。引π木琳-2 -基）b丫丁 σ定-1 -甲酸第二丁醋，異構物3及4 ; 2_(2-嗎啉基乙基）-3-側氧基-Ν-(4_(三氟曱氧基）苯曱基） 異吲哚啉-1 -曱醯胺； 140374.doc -13· 201000446 3- 侧氧基-2-((四氫呋喃-3-基）曱基）-N-(4-(三氟曱氧基）苯 曱基）異吲哚啉-1-曱醯胺； 2- (1-苯曱基哌啶-4-基）-3-側氧基-N-(4-(三氟曱氧基）苯 甲基）異吲哚啉-1 -曱醯胺； 7-氟-3-側氧基-2-(四氫-2H-哌喃-4-基）-N-(4-(三氟曱氧 基）苯甲基）異吲哚啉-1-曱醯胺； 4- ^-3-側氧基-2-(四氮-2H-0底喃-4-基）-N-(4-(二氟曱氧 基）苯曱基）異吲哚啉-1-甲醯胺； 3- 側氧基-N-(4-(三氟曱氧基）苯甲基）-2-( 1-(3,3,3-三氟丙 醯基）吖丁啶-3-基）異吲哚啉-1-曱醯胺； 2- (1-(甲基磺醯基）吖丁啶-3-基）-3-侧氧基-N-(4-(三氟曱 氧基）苯曱基）異吲哚啉-1-曱醯胺； 3- (卜側氧基-3-(4-(三氟甲氧基）苯甲基胺甲醯基）異吲哚 啉-2-基）吖丁啶-1-曱酸異丙酯； 4- (1-側氧基-3-(4-(三氟曱氧基）苯曱基胺曱醯基）異吲哚 啉-2-基）哌啶-1-曱酸第三丁酯； 3-側氧基-2-(1-丙醯基哌啶-4-基）-N-(4-(三氟甲氧基）苯 曱基）異吲哚啉-1-曱醯胺； 3-側氧基-2-(2-(四氫-2H-哌喃-4-基）乙基）-N-(4-(三氟曱 氧基）苯甲基）異吲哚啉-1-甲醯胺； 3-(1-側氧基-3-(3-(三氟曱氧基）苯曱基胺曱醯基）異吲哚 啉-2-基）吖丁啶-1-曱酸第三丁酯； 3-(1-(2-曱基-4-(三氟甲氧基）苯曱基胺曱醯基）-3-側氧基 異吲哚啉-2-基）吖丁啶-1-曱酸第三丁酯； 140374.doc -14- 201000446 2_(4,4_二氟環己基）-3-側氧基-N-(4-(2,2,2-三氟乙基）笨 曱基）異吲哚啉_；μ甲醯胺； Ν_(3,4-二甲基笨曱基）-3-側氧基-2-(四氫-2Η-哌喃-4-基） 異°引"朵啉-1-甲醯胺； 3- 側氧基-2-(四氫-2H-哌喃_4_基）-N-(l-(4-(三氟甲基）笨 基）環丙基）異吲哚啉-1 -甲醯胺； 4- 羥基-3-側氧基_2-(四氫-2H-哌喃-4-基）-N-(4-(三氟甲氧 基）苯甲基）異吲哚啉-1 -甲醯胺； 4-羥基-Ν-(4-異丙基苯甲基）_3_側氧基_2_(四氫_2Η_哌喃_ 4-基）異吲哚啉“-甲醯胺； 2_(4,4-二氟環己基）_4_羥基_3_側氧基_Ν_(4_(三氟甲基）苯 曱基）異吲哚啉-1-曱醯胺； Ν-(4-溴苯甲基）_3_侧氧基_2_(四氫_2Η_哌喃_4_基）異吲哚 琳-1-甲酿胺；及 Ν_(4_溴苯甲基）_3_侧氧基-2-(四氫-2Η-哌喃-4-基）異吲哚 ^ 啉-1-甲醯胺，異構物2。 為避免疑義，應瞭解在本說明書中，「Ci6」意謂具有 1、2、3、4、5或6個碳原子之含碳基團。 除非另作說明，否則在本說明書中，術語「烷基」包括 直鏈與支鏈烷基，且可為（但不限於）甲基、乙基、正丙 基、異丙基、正丁基、異丁基、第二丁基、第三丁基正 戍基、異戊基、新戊基、正己基或異己基。 如本文所用之術語Cw烷基係定義為具有i至4個碳原子 之直鏈、支鏈或環狀（其中存在至少三個碳原子之環）烷基 140374.doc •15- 201000446 鍵’且：為(但不限於)甲基、乙基、正丙基、異丙基、環 —土衣丁基或第二丁基。如本文所用之術語Cu烷基係 疋義為”有1至3個碳原子之直鏈、支鏈或環狀烧基鍵（存 在三個碳原子之環）’亦即··甲基、乙基、正丙基、異丙 基或環丙基。 支鏈或環狀 伸正丙基、 伸第三丁基 支鏈或環狀 伸正丙基、 如本文用於h之術語Cl_4伸烷基可為直鏈 伸烷基，且包括（但不限於）亞甲基、伸乙基 伸異丙基、伸環丙基、伸正丁基、伸異丁基 及伸環丁基烴鏈。 如本文用於L2之術語C]·3伸烷基可為直鏈 伸烷基，且包括（但不限於）亞甲基、伸乙基 伸異丙基及伸環丙基烴鏈。 除非另作說明，否則術語「烷氧基」係指通式之基 團，其中R係選自烴基。術語r Cw烷氧基」可包括（但不 限於）甲氧基、乙氧基、丙氧基、異丙氧基、丁氧基、第 三丁氧基、異丁氧基、環丙基甲氧基、稀丙基氧基錢丙 基氧基。 於如本文所用之術「Ci3烧氧基」可包括（但不限於）甲 氧基、乙氧基或丙氧基。如本文所用之術纽「 ^ D° 垸氧 暴」可包括（但不限於）曱氧基、乙氧基、丙4 π軋基、異丙氧 基、丁氧基、第三丁氧基、異丁氧基。 在本發明之一實施例中，「Cw烷氧基」可經—或多個氟 原子取代’由此烷氧基中之一或多個氫原子經— 、、' 或多個氟 原子置換’諸如-〇-ch2-cf3、-o-ch2-ch2-cf3、、〇 CH f。 140374.doc -16-140374.doc •12- 201000446 oxo-2-(1-n-pyridin-2-ylazetidine_3_yl) good [4_(trifluoromethoxy)benzyl]isoindoline-1 -carbamamine; (4'4-fluorocyclohexyl)-N-(4-methoxy adenyl)_3_ pendant oxyisoindoline-1-carbamidine; Ν Π-Ο-chloride Phenyl)ethyl]_2_(4,4-difluorocyclohexyl)_3_ pendant oxyisoindoline-1 _formamidine; Ν Π ((3-cyclophenyl)ethyl]_3_sideoxy _2_(tetrahydro-2H-pyran-4-yl)isoindoline-1 -carboxamide; 2 ((3'3-difluorocyclobutyl)methyl)-3-oxo-trifluoride曱oxy)benzyl)isoporphyrin_丨_carbamamine; 2 (3'3-difluorocyclobutyl)-3-oxo-N-(4-(trifluorodecyloxy) Phenylhydrazinyl)pyroline-1 -decylamine; 244'4·difluorocyclohexyl)-7-methoxy-3-oxirane-N-(4-(trifluoromethoxy) Benzyl)isoporphyrin_丨-formamide; 2_(4,4-difluorocyclohexyl)-7-mercapto-3-yloxy-N-(4-(trifluorodecyloxy) Benzyl)isoindoline-1 -decylamine; 3_(4·methyl-1_teroxy-3-(4-(trifluoromethoxy)benzoinyl) hydrazino Porphyrin-2-yl)azetidine-1-decanoic acid third Ester; 2-oxo-(tetrahydro-2-indole-single-4-yl)-N-(l-(4-(trifluoromethoxy)phenyl)ethyl)isoindoline 丨- Methionine, isomer 4; 3-(1-trioxy_3_(b(4-(trifluoromethoxy)phenyl)ethyl)indolyl) b丫丁σ定-1 - formic acid second butyl vinegar, isomers 3 and 4; 2_(2-morpholinoethyl)-3-oxo-oxime-(4_(trifluoromethoxy) Benzoyl)isoindoline-1 -decylamine; 140374.doc -13· 201000446 3-Sideoxy-2-((tetrahydrofuran-3-yl)indolyl)-N-(4-(trifluoro)曱oxy)phenylphenyl)isoindoline-1-decylamine; 2-(1-phenylhydrazinopiperidin-4-yl)-3-oxo-N-(4-(trifluoroanthracene) Oxy)phenylmethyl)isoindoline-1 -decylamine; 7-fluoro-3-oxooxy-2-(tetrahydro-2H-piperidin-4-yl)-N-(4-( Trifluoromethoxy)benzyl)isoindoline-1-decylamine; 4-^-3-o-oxy-2-(tetrazol-2H-0-decan-4-yl)-N- (4-(Difluorodecyloxy)phenylhydrazinyl)isoindoline-1-carboxamide; 3-tertiaryoxy-N-(4-(trifluorodecyloxy)benzyl)-2- (1-(3,3,3-trifluoropropenyl)azetidin-3-yl)isoindoline-1-decylamine; 2 - (1-(Methylsulfonyl)azetidin-3-yl)-3-oxo-N-(4-(trifluoromethoxy)phenylindenyl)isoindoline-1-pyrene Indoleamine; 3-(b-oxy-3-(4-(trifluoromethoxy)benzylamine-carbamoyl)isoindolin-2-yl)pyridinium-1-decanoate Ester; 4-(1-oxooxy-3-(4-(trifluorodecyloxy)phenylhydrazinyl indenyl)isoindolin-2-yl)piperidine-1-decanoic acid tertidine Ester; 3-oxo-2-(1-propenylpiperidin-4-yl)-N-(4-(trifluoromethoxy)phenylhydrazinyl)isoindoline-1-decylamine 3-Phenoxy-2-(2-(tetrahydro-2H-piperidin-4-yl)ethyl)-N-(4-(trifluorodecyloxy)benzyl)isoindoline- 1-methanamine; 3-(1-oxo-3-(3-(trifluorodecyloxy)phenylhydrazinyl)indoline-2-yl)azetidine-1- Tert-butyl citrate; 3-(1-(2-mercapto-4-(trifluoromethoxy)benzoguanamine fluorenyl)-3-oxoisoindoline-2-yl) Tert-butyl butyrate-1-decanoate; 140374.doc -14- 201000446 2_(4,4-difluorocyclohexyl)-3-oxo-N-(4-(2,2,2- Trifluoroethyl) alkaloid)isocarboline _;μ-carbamamine; Ν_(3,4-dimethyl adenyl)-3-side oxygen Benzyl-2-(tetrahydro-2-indole-pyran-4-yl)iso-quote"Porphyrin-1-carboxamide; 3-Sideoxy-2-(tetrahydro-2H-pyranyl-4) -N-(l-(4-(trifluoromethyl)phenyl)cyclopropyl)isoindoline-1 -carboxamide; 4-hydroxy-3-oxooxy-2-(tetrahydrogen) -2H-piperidin-4-yl)-N-(4-(trifluoromethoxy)benzyl)isoindoline-1 -carboxamide; 4-hydroxy-indole-(4-isopropyl Benzyl)_3_sideoxy-2_(tetrahydro-2-indole-pyran-4-yl)isoindoline "-carbamamine; 2_(4,4-difluorocyclohexyl)_4_hydroxy_3 _Sideoxy_Ν_(4_(trifluoromethyl)phenylhydrazolyl)isoindoline-1-decylamine; Ν-(4-bromobenzyl)_3_sideoxy_2_(tetrahydro- 2Η_pyranyl-4-yl)isoindolin-1-cartoamine; and Ν_(4-bromobenzyl)_3_sideoxy-2-(tetrahydro-2-indole-pyran-4-yl) Isopyrazine-1-mercaptoamine, isomer 2. For the avoidance of doubt, it should be understood that in the present specification, "Ci6" means a carbon-containing group having 1, 2, 3, 4, 5 or 6 carbon atoms. Unless otherwise stated, in the present specification, the term "alkyl" includes straight-chain and branched alkyl groups, and may be, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl. , isobutyl, t-butyl, tert-butyl-n-decyl, isopentyl, neopentyl, n-hexyl or isohexyl. The term Cw alkyl as used herein is defined as a straight, branched or cyclic (having a ring of at least three carbon atoms) alkyl having from 1 to 4 carbon atoms. 140374.doc •15-201000446 bond' and : is (but not limited to) methyl, ethyl, n-propyl, isopropyl, cyclo- butyl or butyl. The term "alkylalkyl" as used herein, is defined as "a straight chain, branched or cyclic alkyl bond having from 1 to 3 carbon atoms (a ring having three carbon atoms)", ie, methyl, Base, n-propyl, isopropyl or cyclopropyl. Branched or cyclic extended propyl, extended butyl branch or cyclic propyl, as used herein for the term Cl_4 alkyl a linear alkyl group, and includes, but is not limited to, a methylene group, an exoethyl isopropyl group, a cyclopropyl group, a n-butyl group, an isobutyl group, and a cyclobutyl chain. As used herein for L2 The term C]·3 alkylene may be a linear alkylene group and includes, but is not limited to, methylene, ethyl isopropyl and cyclopropyl hydrocarbon chains. Unless otherwise stated, the term " "Alkoxy" means a group of the formula wherein R is selected from a hydrocarbon group. The term r Cw alkoxy" may include, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, isobutoxy, cyclopropyl Oxy, propyloxy propyl propyloxy. "Ci3 alkoxy" as used herein may include, but is not limited to, methoxy, ethoxy or propoxy. As used herein, "^ D ° 垸 oxygen storm" may include, but is not limited to, decyloxy, ethoxy, propyl 4 π rolling, isopropoxy, butoxy, tert-butoxy, Isobutoxy. In one embodiment of the present invention, "Cw alkoxy" may be substituted with - or a plurality of fluorine atoms - and one or more hydrogen atoms of the alkoxy group are replaced by -, ' or a plurality of fluorine atoms' Such as -〇-ch2-cf3, -o-ch2-ch2-cf3, 〇CH f. 140374.doc -16-

在本說明書中，除非另作說 丑則術語I _烷氧基 201000446 除非另作說明，否則術語「Cw烷基-Ο-e!·3烷基」係指 具有通式R-O-R之醚基，其中R係選自煙基。術語「CK3^ 基OC!—3烷基」可包括（但不限於）二甲醚、甲基乙基醚、甲 基丙基_、乙醚、二丙醚或子基異丙基醚。 在本說明書中’除非另作說明，否則術語「鹵烷基」意 謂如上文所定義之烷基，其係經如上文所定義之_基取 代。術語「C ! _4鹵烧基」可包括（但不限於）氟甲基、二氣 甲基、三氟曱基、氯甲基、二氯f基、三氣甲基或氟氯子 基。 意謂如上文所定義之烷氧基，其係經如上文所定義之齒基 取代術5吾「Cw鹵烷氧基」可包括(但不限於)氟甲氧 基、二氟甲氧基、三氟甲氧基、I乙氧基或二氟乙氧基。 在本說明書中’除非另作說明，否則術語「環炫基」係 =況經取代、部分或完全飽和之單環、雙環或橋接烴 :其術§吾「C3-7環烧基」可為（但不限於m丙基、環 ::或:::或環已基。術語「―係定義為環 二二環，。係指經由氡基…'子連接至分子 …、。P刀的¥烷基。如本文所用之Gw環烷 (但不限於環己基、_0_環丙基、 土之貫例為 基。 礆丁基及-0-環戊 則術語「 之單環、 雜環烷基」 雙環或橋接 在本說明書中， 係指視情況經取代 除非另作說明，否 、部分或完全飽和 140374.doc -17- 201000446 煙環系統’且其另外包含一或多個選自Ο、N或S之雜原 子。術δ吾「C3_7雜環院基」可為（但不限於）四氫旅喃基、 四氫°夫喃基、嗎啉基、吡咯啶基、吡咯啶基-2-酮、吖丁啶 基、°辰啶基。 單獨使用或作為字尾或字首使用之術語「芳基」係指具 有一或多個具有芳族特徵（例如4n+2個非定域電子）且包含 5至多達約14個碳原子之多元不飽和碳環的烴基，其中該 基團係位於芳環之碳上。術語「C6-iq芳基」可為（但不限 於）苯基、萘基及其類似基團。 除非另外規定，否則芳基可經一或多個包括_〇H、鹵 基、氰基、硝基、Cl_6烷基、Ci 0烷氧基或胺磺醯基之取代 基取代田經取代時，芳基較佳經一個與三個之間的取代 基取代。 除非另作說明，否則術語「R5(㈣）」係指具有通式r_ c=o之釀基。 除非另作說明’否則術語「r40(c，」係指具有通式 R-O-(OO)之烷氧羰基。 單獨使用或作為字尾或字首使用 語「雜芳基」係指 方裱，其中％中之至少一個原子為 丁苟非妷兀素，諸如N、s及 〇。各雜芳基可經由該雜芳基之碳 ," 心反原子或經由該雜芳基之 一個氮原子鍵結至分子之其餘部分。 如本文所用之術語「C5-6雜芳其 屯 土」為具有5至6個環原子 且該5至6個環原子中之至少—者 ’、 ..r , 者為绝自>^、8及〇之雜原子 的方ί哀。该「C5.6雜芳基」之實例 例為°比啶基、噻吩基、咪 U0374.doc •18- 201000446 唑基、吡唑基。 在本說明書中，除非另作說明，否則術語 「名主 π, 國基」及 函素」可為氟、碘、氯或溴。 除非另作說明，否則術語「烧基輕基」係指通式媽_r 之基團’其巾R係選自烴基。術語「Ci 4燒基•基」2可 包括（但不限於）甲基伽基、乙基料基、正内基碍酿In the present specification, the term "I-alkoxy 201000446" unless otherwise stated, the term "Cw alkyl-Ο-e!.3 alkyl" means an ether group having the formula ROR, wherein R is selected from the group consisting of nicotine. The term "CK3^-based OC!-3 alkyl" may include, but is not limited to, dimethyl ether, methyl ethyl ether, methyl propyl, diethyl ether, dipropyl ether or isopropyl isopropyl ether. In the present specification 'unless otherwise stated, the term "haloalkyl" means an alkyl group as defined above which is substituted with a radical as defined above. The term "C! _4 haloalkyl" may include, but is not limited to, fluoromethyl, dimethylmethyl, trifluoromethyl, chloromethyl, dichlorof, trimethyl or fluorochloro. An alkoxy group, as defined above, which is a dentate substitution as defined above. 5 "Cw haloalkoxy" may include, but is not limited to, fluoromethoxy, difluoromethoxy, Trifluoromethoxy, I ethoxy or difluoroethoxy. In this specification 'unless otherwise stated, the term "cyclosyl" is a substituted, partially or fully saturated monocyclic, bicyclic or bridged hydrocarbon: its "C3-7 cycloalkyl" may be (But it is not limited to m propyl, ring:: or ::: or cyclohexyl. The term "- is defined as a ring of two rings, which means that it is connected to a molecule via a thiol group...". Alkyl. As used herein, Gw cycloalkane (but not limited to cyclohexyl, 0-cyclopropyl, teretrial). Indole butyl and -0-cyclopentane, the term "monocyclic, heterocycloalkyl" "Double-ring or bridged in this specification means, unless otherwise stated, no, partially or fully saturated 140374.doc -17- 201000446 smoke ring system' and additionally containing one or more selected from Ο, N Or a hetero atom of S. δ 吾 "C3_7 Heterocyclic" can be, but is not limited to, tetrahydronuryl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, pyrrolidinyl-2- Ketone, azetidinyl, acetonyl. The term "aryl" used alone or as a suffix or prefix means having one or more aromatic features (eg 4 a hydrocarbyl group containing from 5 to up to about 14 carbon atoms of a polyunsaturated carbocyclic ring, wherein the group is on the carbon of the aromatic ring. The term "C6-iq aryl" may be (but not limited to) phenyl, naphthyl and the like. Unless otherwise specified, the aryl group may include one or more of _〇H, halo, cyano, nitro, Cl-6 alkyl, Ci 0 alkane When the substituent of the oxy or sulfonyl group is substituted for the field, the aryl group is preferably substituted with a substituent between three and three. Unless otherwise specified, the term "R5((4))") means having the formula R_c=o of the base. Unless otherwise stated, the term "r40(c," refers to an alkoxycarbonyl group having the formula RO-(OO). Used alone or as a suffix or prefix." """""""""""""""" A nitrogen atom of a heteroaryl group is bonded to the rest of the molecule. The term "C5-6 heteroaromatic bauxite" as used herein has 5 to 6 ring atoms. And at least one of the 5 to 6 ring atoms, '..r, is a radical of the hetero atom of the ^^, 8 and 。. Examples of the "C5.6 heteroaryl" Is a pyridyl group, a thienyl group, a mer. U0374.doc • 18- 201000446 oxazolyl, pyrazolyl. In this specification, unless otherwise stated, the terms "name π, national base" and pheromone may be Fluorine, iodine, chlorine or bromine. Unless otherwise stated, the term "alkyl group" refers to the group of the formula _r', and the towel R is selected from the group consisting of hydrocarbons. The term "Ci 4 alkyl group" is used. May include, but is not limited to, methyl gamma, ethyl base, and internal base

基、異丙基磺醯基、正丁基磺醯基、異丁基磺醯基或第三 丁基磺醯基。 應瞭解，在整篇本說明書中，本發明之化合物中環上之 取代基的編號及性質應經選擇以避免空間上之不當組合。 為避免疑義，應瞭解，若在本說明書中基團經「上文所 定義」修飾，則該基團涵蓋最先存在且最廣泛之定義以及 對於該基團之每一特定定義及所有特定定義。 本發明係關於如上文所定義之式〗化合物以及其醫藥學 上可接受之鹽。用於藥物調配物之鹽應為醫藥學上可接受 之鹽。 本發明化合物之適用的醫藥學上可接受之鹽之實例為 (例如）酸加成鹽，諸如與無機或有機酸形成之鹽。適用鹽 之另一實例為驗金屬鹽，諸如驗土金屬鹽；或與有機鹼形 成之鹽。本發明之適用鹽之實例為乙酸鹽、反丁烯二酸 鹽、順丁烯二酸鹽'酒石酸鹽、檸檬酸鹽、鹽酸鹽、氫溴 酸鹽、硫酸鹽及磷酸鹽。 根據本發明適用之其他醫藥學上可接受之鹽及製備該等 鹽之方法可見於（例如）Remington's Pharmaceutical 140374.doc •19- 201000446Base, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl or tert-butylsulfonyl. It will be appreciated that throughout the specification, the numbering and nature of the substituents on the ring in the compounds of the invention should be selected to avoid spatially inappropriate combinations. For the avoidance of doubt, it should be understood that if a group is modified as defined above in this specification, the group covers the first and most broad definition and each specific definition and all specific definitions for that group. . The present invention relates to a compound of the formula as defined above and a pharmaceutically acceptable salt thereof. The salt used in the pharmaceutical formulation should be a pharmaceutically acceptable salt. Examples of suitable pharmaceutically acceptable salts of the compounds of the invention are, for example, acid addition salts, such as those formed with inorganic or organic acids. Another example of a suitable salt is a metal salt, such as a soil metal salt; or a salt formed with an organic base. Examples of suitable salts of the invention are acetates, fumarates, maleate 'tartrates, citrates, hydrochlorides, hydrobromides, sulfates and phosphates. Other pharmaceutically acceptable salts suitable for use in accordance with the present invention and methods of preparing such salts can be found, for example, in Remington's Pharmaceutical 140374.doc • 19-201000446

Sciences(弟 18版，Mack Publishing Co.)中。 本發明之化合物可展現互變異構現象。所有互變異構形 式及其混合物均包括於本發明之範疇内。詞語「互變異構 現象」係指酮型與烯醇型之間的化學平衡，其中烯醇型與 _型彼此為互變異構物。 本發明之化合物亦可含有一或多個不對稱碳原 可展現光车異構現象，諸如一或多種對映異構物及/或非 :映異構物。非對映異構物可使用習知技術(例如層析或 分步結晶）進行分離。各種立體異構物可藉由使用習知技 術（例如分步結晶或H p L c技術）分離該等化合物之外消旋或 其他混合物而分離。或者’可藉由使適當光學活性起始材 料在不會引起外消旋或差向異構化之條件下反應或藉由 (例如)用均勾對掌性酸進行衍生，繼而藉由習知方法(例如 ^PLC、二氧切層析）分離非對映異構自旨來製備所需光學 異構物。所有立體異構物均包括於本發明之範嘴内。 醫藥組合物 、、^古p 1她例’提供一種醫藥組合物，其包含 . 為 成伤的本發明化合物或其醫筚學上 可接受之鹽以及一或多種 -”干上 劑及/或惰性載#卜 ^上可一之稀釋劑、賦形 醫藥組合物可呈適於經 劑、糖聚、散劑、顆粒或膜囊=，例如鍵劑、丸 脈内、皮T、肌肉内、血〜非經腸注射(包括靜 血s内或輸注）之形式 ,. 液、懸浮液或乳液；適於 ’如無溶 卩技樂之形式，例如軟膏劑、 M0374.doc -20. 201000446 貼片或乳膏劑；或適於經直腸投藥之形式，例如栓劑。 一般而言，以上組合物可依習知方式使用一或多種習知 賦形劑、醫藥學上可接受之稀釋劑及/或惰性载劑來製 備。 在治療哺乳動物（包括人類）時，本發明化合物之合適曰 :量在經口投藥時為約5至100 mg/kg體重且在非經腸投藥 時為約0.01至250 mg/kg體重。Sciences (18th edition, Mack Publishing Co.). The compounds of the invention may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. The phrase "tautomerism" refers to the chemical equilibrium between a keto form and an enol form, wherein the enol form and the _ form are tautomers of each other. The compounds of the present invention may also contain one or more asymmetric carbons which exhibit halo isomerism, such as one or more enantiomers and/or non-images. Diastereomers can be separated using conventional techniques such as chromatography or fractional crystallization. The various stereoisomers can be separated by isolating the racemic or other mixture of the compounds using conventional techniques (e.g., fractional crystallization or HpLc techniques). Or by: derivatizing the appropriate optically active starting material under conditions which do not cause racemic or epimerization or by, for example, deriving the palmitic acid with a homogenate, and then by conventional means Methods (e.g., ^PLC, dioxochromatography) separate the diastereomers to prepare the desired optical isomers. All stereoisomers are included in the mouth of the present invention. A pharmaceutical composition comprising: a pharmaceutical composition comprising: a compound of the invention or a pharmaceutically acceptable salt thereof, and one or more - "drying agents and/or The inert drug can be used as a diluent, a sugar, a powder, a granule or a capsule. For example, a key, a vein, a skin T, an intramuscular, a blood ~ Non-enteral injection (including in the form of intravenous s or infusion), liquid, suspension or emulsion; suitable for 'in the form of no dissolved sputum, such as ointment, M0374.doc -20. 201000446 patch Or a cream; or a form suitable for rectal administration, such as a suppository. In general, the above compositions may be used in a conventional manner using one or more conventional excipients, pharmaceutically acceptable diluents and/or inert carriers. In the treatment of mammals, including humans, suitable sputum levels of the compounds of the invention are from about 5 to 100 mg/kg body weight when administered orally and from about 0.01 to 250 mg/kg when administered parenterally. body weight.

活性成份之典型日劑量在寬範圍内變化且應取決於各種 因素，諸如相關適應症、所治療疾病之嚴重性、投藥途 徑、患者年齡、體重及性別及所用之特定化合物，且可由 醫師確定。 醫藥用途 發明之化合物預期適用於治療。與其他必需納通道相 2，如本文中所述且主張之式丨化合物或其醫藥學上可接 文之鹽以及其相應活性代謝物在鈉通道N a v丄· 7處展現高卢 效能且亦展現對該通道之高度選擇性。因&，本發明之： 合物預期適用於治療糾氣7及〇纖維中所存在之其他納 通道的向上調節相關之病狀。 本發明之化合物可用於對哺乳動物(包括人類)之納通道 產生抑制作用。 本發明之-實施例係關於如上文所定義之式[化合物用 於製造治療NaV1·7介導的病症之藥物之用途。 本發明之式1化合物預期適用於治療疼痛病症，諸如. 急性疼痛；慢性疼痛；神經痛，諸如糖尿賴神經病；與 140374.doc 201000446 關即人及類風濕性疾病相關之發炎疼痛；τ背痛；術後疼 痛’與包括癌症、絞痛、腎絞痛或膽絞痛、月、經、肌肉纖 、’、、痛下月痛、術後疼痛、癌症疼痛、内臟疼痛（諸如 k I·生月盆疼痛、膀胱炎、IB s、胰腺炎）、局部缺血性疼痛 或痛風的多種病狀相關之疼痛。 本發明之另一態樣為式j化合物用於治療血管性頭痛（諸 如偏頭痛）之用途。 本I月之另態樣為式I化合物用於治療與紅斑性肢 痛、牛皮癬、嘔吐、尿失禁及膀胱過度活動（hyperactive bladder)相關之疼痛病狀之用途。 本發明之另一實施例為式I化合物用於治療癲癇症之用 途。 本發明之一實施例係關於如上文所定義之式I化合物用 於治療與關節炎、肌肉纖維疼痛、下背痛、術後疼痛、癌 症疼痛、内臟疼痛（諸如慢性骨盆疼痛、膀胱炎、IBS、胰 腺炎）或局部缺血性疼痛相關的疼痛病狀之用途。 本發明之一實施例係關於如上文所定義之式合物在 治療中之用途。 本發明之另一實施例係關於如上文所定義之式〗化合物 用於製造治療以下疼痛病症的藥物之用途：諸如急性疼 痛；慢性疼痛；神經痛，諸如糖尿病性神經病；與關節炎 及類風濕性疾病相關之發炎疼痛；下背痛；術後疼痛；與 包括癌症、絞痛'腎絞痛或膽絞痛、月經、肌肉纖維疼 痛、下背痛、術後疼痛、癌症疼痛 '内臟疼痛（諸如慢性 140374.doc -22- 201000446 月盆疼痛、膀胱炎、IBS、胰腺炎）、局部缺血性疼痛或痛 風的多種病狀相關之疼痛。 本發明之另一態樣為式I化合物用於製造用於治療血管 性頭痛（諸如偏頭痛）之藥物之用途。 本發明之另一態樣為式I化合物用於製造用於治療與紅 斑性肢痛、牛皮癣、嘔吐、尿失禁及膀胱過度活動相關的 疼痛病狀之藥物之用途。 本發明之另一實施例為式J化合物用於製造用於治療癲 癇症之藥物之用途。 本發明之另一實施例係關於一種治療以下任一疼痛病症 之方法：諸如急性疼痛；慢性疼痛；神經痛，諸如糖尿病 ) 生神k病’與關節炎及類風濕性疾病相關之發炎疼痛；下 背痛；術後疼痛；與包括癌症、絞痛、腎絞痛或膽絞痛、 月經、肌肉纖維疼痛、下背痛、術後疼痛、癌症疼痛、内 臟疼痛（諸如慢性骨盆疼痛、膀胱炎、IBS、胰腺炎）、局 邰缺血性疼痛或痛風的多種病狀相關之疼痛；由此對需要 該治療之個體投與如上文所定義之式〗化合物。 本發明之另一態樣為一種治療血管性頭痛（諸如偏頭痛） 之方法，由此對需要該治療之個體投與如上文所定義之式 Η匕合物。 本發明之另一態樣為一種治療與紅斑性肢痛、牛皮癣、 嘔吐、尿失禁及膀胱過度活動相關的疼痛病狀之方法，由 此對需要該治療之個體投與如上文所定義之式丨化合物。 本發明之另一實施例為一種治療癲癇症之方法，由此對 140374.doc -23- 201000446 需要該治療之個體投與如上文所定義之式i化合物。 本發明之另一實施例為如上文所定義之用於治療以下疼 痛病症之式I化合物：諸如急性疼痛；慢性疼痛·，神㉟ 痛’諸如糖尿病性神經病；與關節炎及類風濕性疾病相關 之發炎疼痛；下背痛；術後疼痛；與包括癌症、絞痛、腎 絞痛或膽絞痛、月經、肌肉纖維疼痛、下背痛、術後疼 痛、癌症疼痛、内臟疼痛（諸如慢性骨盆疼痛、膀胱炎、 IBs、胰腺炎）、局部缺血性疼痛或痛風的多種病狀相關之 疼痛。 本發明之另一態樣為如上文所定義之用於治療血管性頭 痛（諸如偏頭痛）之式I化合物。 本發明之另一態樣為如上文所定義之用於治療與紅斑性 肢痛、牛皮癖…區吐、尿失禁及膀胱過度活動相關的疼痛 病狀之式Π匕合物。 本發明之另-實施例為如上文所定義之用於治療痛痛症 之式I化合物。 組合 如本文所^義之疼痛料可作為唯—治療來應用，或除 本發明化合物以外亦可包括投與其他止痛藥或佐劑治療。 該治療可(例如)包括與本發明化合物組合之以下類別之緩 解疼痛成份中的一或多者： 片止痛#，例如嗎啡驗、飢耗米明⑽〇bemid〇ne)或 务太尼（fentanyl); b)NSAID或cox_1/2類止鋪，例如布洛芬仲零。㈣、 140374.doc -24- 201000446 萘普生（naproxene)、塞來昔布（celecoxib)或阿司匹林 (acetylsalicylic acid)，及其含有一氧化氮供給基團之 類似物； c) 痛佐劑，諸如阿米替林（amitriptyline)、丙味σ秦 (imipramine)、度洛西 丁（duloxetine)或美西律（mexiletine); d) NMDA拮抗劑，例如氣胺酮（ketamine)或德米托番 (dextrometorfan)； e) 通道阻斷劑，例如利多卡因； f) 驚厥藥，例如痛痙寧（carbamazepine)、托°比自旨（topiramate) 或拉莫三嗪（lamotrigine); g) 驚厥/止痛胺基酸，諸如加巴噴丁（gabapentin)或普瑞 巴林（pregabalin); h) 麻驗（cannabinoid) ° 該組合之各活性化合物可同時、分別或依次投與。 實例 製備方法 本發明之一態樣提供一種製備式I化合物或其鹽之方 法。 在整個該等方法之以下說明中，應瞭解，適當時將以熟 習有機合成技術者易於暸解之方式向各反應物及中間物添 加合適保護基且後期自各反應物及中間物移除該等保護 基。使用該等保護基之習知程序以及合適保護基之實例 (例如）描述於「Green's Protective Groups in Organic Synthesis」 P.G.M. Wuts，T.W. Green, Wiley, New York, 2007 中。其他合適反 140374.doc -25- 201000446 應之參考文獻及說明描述於有機化學之教科書（例如 「Advanced Organic Chemistry」，March，第 4版，McGraw Hill (1992)或「Organic Synthesis」，Smith，McGraw Hill, (1994))中。雜環化學之代表性實例參看（例如） 「Heterocyclic Chemistry」，J. A. Joule, K. Mills, G. F· Smith，第 3 版，Chapman and Hall (1995)，第 189-224頁及「Heterocyclic Chemistry」，T. L_ Gilchrist，第 2版，Longman Scientific and Technical (1992)，第 248-282 頁。 除非另外規定，否則術語「室溫」及「環境溫度」應意 謂16°C與25°C之間的溫度。 縮寫： DMF N，N-二曱基曱醯胺 NaOH 氫氧化鈉 HC1 鹽酸 Μ 莫耳濃度 PG 保護基 本發明之一實施例係關於根據方法A及B製備式〗化合物 之方法’其中除非另外規定，否則R1、R2、R3、D、Li、 L2、X4及m係如式I中所定義。Typical daily dosages of the active ingredients vary widely and should depend on various factors such as the relevant indication, the severity of the condition being treated, the route of administration, the age, weight and sex of the patient, and the particular compound employed, and can be determined by the physician. Medical Use The compounds of the invention are expected to be suitable for use in therapy. In combination with other essential nanochannels, the guanidine compound or its pharmaceutically acceptable salt as described herein and its corresponding active metabolite exhibits high efficiency at the sodium channel N av丄·7 and Shows a high degree of selectivity for this channel. Because of &, the composition of the present invention is intended to be useful in the treatment of the upregulation of the correction channel 7 and other nanochannels present in the sputum fiber. The compounds of the invention are useful for inhibiting the passage of mammalian (including human) cells. The present invention is directed to the use of a compound of the formula [as defined above for the manufacture of a medicament for the treatment of a NaV1.7 mediated disorder. The compounds of formula 1 of the present invention are contemplated for use in the treatment of pain conditions, such as: acute pain; chronic pain; neuralgia, such as diabetic urinary neuropathy; and inflammatory pain associated with human and rheumatoid diseases, 140374.doc 201000446; Postoperative pain 'including cancer, colic, renal colic or biliary colic, month, menstrual, muscle fiber, ', painful pain, postoperative pain, cancer pain, visceral pain (such as k I· Pain associated with multiple conditions of gynecological pain, cystitis, IB s, pancreatitis, ischemic pain or gout. Another aspect of the invention is the use of a compound of formula j for the treatment of vascular headaches, such as migraine. Another aspect of this month is the use of a compound of formula I for the treatment of pain conditions associated with erythematous limb pain, psoriasis, vomiting, urinary incontinence and hyperactive bladder. Another embodiment of the invention is the use of a compound of formula I for the treatment of epilepsy. An embodiment of the invention relates to a compound of formula I as defined above for use in the treatment of arthritis, muscle fiber pain, lower back pain, post-operative pain, cancer pain, visceral pain (such as chronic pelvic pain, cystitis, Use of IBS, pancreatitis) or pain conditions associated with ischemic pain. An embodiment of the invention relates to the use of a formula as defined above in therapy. Another embodiment of the invention relates to the use of a compound as defined above for the manufacture of a medicament for the treatment of pain disorders such as acute pain; chronic pain; neuralgia, such as diabetic neuropathy; and arthritis and rheumatoid Inflammatory pain associated with sexually transmitted diseases; lower back pain; postoperative pain; and visceral pain including cancer, colic 'renal colic or biliary colic, menstruation, muscle fiber pain, lower back pain, postoperative pain, cancer pain' (such as chronic 140374.doc -22- 201000446 lumbar pain, cystitis, IBS, pancreatitis), pain associated with multiple conditions of ischemic pain or gout. Another aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment of vascular headaches, such as migraine. Another aspect of the invention is the use of a compound of formula I for the manufacture of a medicament for the treatment of a pain condition associated with erythematous limb pain, psoriasis, vomiting, urinary incontinence and overactive bladder. Another embodiment of the invention is the use of a compound of formula J for the manufacture of a medicament for the treatment of epilepsy. Another embodiment of the present invention relates to a method of treating any of the following pain conditions: such as acute pain; chronic pain; neuralgia, such as diabetes, and inflammatory pain associated with arthritis and rheumatoid diseases; Lower back pain; postoperative pain; and includes cancer, colic, renal colic or biliary colic, menstruation, muscle fiber pain, lower back pain, postoperative pain, cancer pain, visceral pain (such as chronic pelvic pain, bladder Pain associated with multiple conditions of ischemic pain or gout; or a compound of the formula as defined above. Another aspect of the invention is a method of treating a vascular headache, such as a migraine, whereby a subject in need of such treatment is administered a composition of the formula as defined above. Another aspect of the invention is a method of treating a pain condition associated with erythematous limb pain, psoriasis, vomiting, urinary incontinence, and overactive bladder, whereby an individual in need of such treatment is administered a formula as defined above丨 compound. Another embodiment of the invention is a method of treating epilepsy whereby a subject in need of such treatment is administered a compound of formula i as defined above to 140374.doc -23-201000446. Another embodiment of the invention is a compound of formula I as defined above for use in the treatment of a pain condition such as acute pain; chronic pain, "God 35 pain" such as diabetic neuropathy; associated with arthritis and rheumatoid diseases Inflamed pain; lower back pain; postoperative pain; and includes cancer, colic, renal colic or biliary colic, menstruation, muscle fiber pain, lower back pain, postoperative pain, cancer pain, visceral pain (such as chronic Pain associated with multiple conditions of pelvic pain, cystitis, IBs, pancreatitis, ischemic pain, or gout. Another aspect of the invention is a compound of formula I as defined above for use in the treatment of vascular headache (such as migraine). Another aspect of the invention is a formula for the treatment of a pain condition associated with erythematous limb pain, psoriasis, urinary incontinence and overactive bladder as defined above. Another embodiment of the invention is a compound of formula I as defined above for use in the treatment of pain. Combinations The pain material as described herein may be applied as a sole treatment or may include administration of other analgesics or adjuvants in addition to the compounds of the invention. The treatment may, for example, comprise one or more of the following classes of pain-relieving ingredients in combination with a compound of the invention: a tablet analgesic #, such as morphine, hunger (10) 〇bemid〇ne) or fentanyl b) NSAID or cox_1/2 type stop, such as ibuprofen zero. (d), 140374.doc -24- 201000446 naproxene, celecoxib or acetylsalicylic acid, and analogues thereof containing a nitric oxide donor group; c) pain adjuvants, such as Amitriptyline, imipramine, duloxetine or mexiletine; d) NMDA antagonists, such as ketamine or Demetopa ( Dextrometorfan); e) channel blockers, such as lidocaine; f) convulsants, such as carbamazepine, topiramate or lamotrigine; g) convulsions/analgesics Amino acids, such as gabapentin or pregabalin; h) cannabinoid ° The active compounds of the combination can be administered simultaneously, separately or sequentially. EXAMPLES Preparation Methods One aspect of the present invention provides a process for the preparation of a compound of formula I or a salt thereof. Throughout the description of the methods, it will be appreciated that appropriate protection groups will be added to the reactants and intermediates as appropriate, and such protections will be removed from the respective reactants and intermediates, as appropriate to those skilled in the art of organic synthesis. base. Examples of conventional procedures for the use of such protecting groups and suitable protecting groups are described, for example, in "Green's Protective Groups in Organic Synthesis" P.G.M. Wuts, T.W. Green, Wiley, New York, 2007. Other suitable anti-140374.doc -25- 201000446 The references and descriptions should be described in textbooks on organic chemistry (eg "Advanced Organic Chemistry", March, 4th edition, McGraw Hill (1992) or "Organic Synthesis", Smith, McGraw Hill, (1994)). Representative examples of heterocyclic chemistry are described, for example, in "Heterocyclic Chemistry", JA Joule, K. Mills, G. F. Smith, 3rd edition, Chapman and Hall (1995), pp. 189-224 and "Heterocyclic Chemistry". , T. L_Gilchrist, 2nd ed., Longman Scientific and Technical (1992), pp. 248-282. Unless otherwise specified, the terms "room temperature" and "ambient temperature" shall mean temperatures between 16 ° C and 25 ° C. Abbreviations: DMF N,N-dimercaptoguanamine NaOH Sodium hydroxide HC1 Hydrochloric acid hydrazine Molar concentration PG Protection One of the basic embodiments of the invention relates to a method for preparing a compound according to methods A and B 'wherein, unless otherwise specified, Otherwise R1, R2, R3, D, Li, L2, X4 and m are as defined in formula I.

方法A 可藉由 3 組份 Ugi 反應（Journal of Organic Chemistry (1999)，64(3)，1〇74·1〇76)使用經適當取代之2-甲醯基苯甲 酸、胺及異腈在環境溫度下在質子性溶劑（例如甲醇）中反 應來製備式I化合物。 140374.doc -26- 201000446Method A can be carried out by using a 3-component Ugi reaction (Journal of Organic Chemistry (1999), 64(3), 1〇74·1〇76) using appropriately substituted 2-methylmercaptobenzoic acid, an amine and an isonitrile. The compound of formula I is prepared by reaction in a protic solvent such as methanol at ambient temperature. 140374.doc -26- 201000446

方法B 可藉由醯胺偶合反應使用經適當取代之吲哚酮羧酸II及 胺III及合適活化劑（例如，但不限於六氟磷酸氟-Ν,Ν,ϊνΓ,Ν1-四甲基曱脒鏽、六氟磷酸〇_苯并三唑小基-Ν，Ν，Ν、Ν'-四甲基錁或六氟磷酸〇-(7-氮雜苯并三唑-1-基）-Ν，Ν，Ν’，Ν’-四甲基錁）在〇_45°c下在有機鹼（諸如三乙胺、 N，N-二異丙胺或4_(二甲基胺基）吡啶）存在下在非質子性溶Method B can be carried out by a guanamine coupling reaction using an appropriately substituted fluorenone carboxylic acid II and an amine III and a suitable activator (for example, but not limited to, fluoro-plutonium hexafluorophosphate, hydrazine, ϊνΓ, Ν1-tetramethylguanidine) Rust, bismuth hexafluorophosphate _benzotriazole small group - hydrazine, hydrazine, hydrazine, hydrazine - tetramethyl hydrazine or bismuth hexafluorophosphate - (7-azabenzotriazol-1-yl)-hydrazine , Ν, Ν ', Ν'-tetramethyl hydrazine) in the presence of an organic base such as triethylamine, N,N-diisopropylamine or 4-(dimethylamino)pyridine at 〇45 °C Aprotic dissolution

劑（諸如DMF、乙腈、四氫呋喃或二噁烷）中反應來製備式I 化合物。The compound of formula I is prepared by reaction in a solvent such as DMF, acetonitrile, tetrahydrofuran or dioxane.

叛酸II可經由文獻（例如Othman, M·及Decroix, B., Synthetic communications 1996, 26 (15), 2803-2809 ;及Oreic acid II can be found in the literature (eg Othman, M. and Decroix, B., Synthetic communications 1996, 26 (15), 2803-2809; and

Othman, Μ.等人，Tetrahedron 1998，54 (30)，8737-8744)中 所述之程序獲得，其中如下所示在四氯化碳中由（例如）N_ 〉臭丁 — &&亞胺（NBS)使南鄰本一甲酸酿演化，且隨後在〇· 140374.doc -27- 201000446 25°C下在有機鹼（諸如三乙胺、Ν,Ν-二異丙胺或4-(二甲基 胺基V比啶）存在下在溶劑（諸如乙腈）中用胺使環閉合。Obtained by the procedure described in Othman, Μ. et al., Tetrahedron 1998, 54 (30), 8737-8744), which is represented, for example, in carbon tetrachloride by, for example, N_ 〉 臭丁- && The amine (NBS) causes the evolution of the south to the original formic acid, and then in the organic base (such as triethylamine, hydrazine, hydrazine-diisopropylamine or 4-(II) at 〇140374.doc -27- 201000446 25 °C. The ring is closed with an amine in a solvent such as acetonitrile in the presence of methylamino group V in the presence of a pyridine.

通用方法 在以下儀器中之一者上記錄質譜： A) Waters Alliance 2795 HPLC、Waters PDA 2996二極 體陣列偵測器、Sedex 85 ELS偵測器及ZQ單一四極質譜儀 組成之LC-MS系統。該質譜儀配備有以陽離子或陰離子模 式運作之電喷霧離子源（ES)。分別將毛細管電壓設為3.2 kV 且將錐孔電壓設為30 V。在m/z 100-700之間以0.3 s之掃描 時間進行質譜儀掃描。自200-400 nm進行二極體陣列偵測 器掃描。將ELS偵測器之溫度調整為40°C且將壓力設為1.9 巴。在於1 ml/min之流動速率下運行之X-Terra MS C8 3.0 mm><50 mm，3.5 pm(Waters))上執行分離。使用線性梯 度，始於1 00% A(A :於5%乙腈中之1 0 mM乙酸銨，或於 5%乙腈中之8 mM甲酸），終止於100% B(B :乙腈）。將管 柱烘箱溫度設為40°C。 B) Waters樣品管理器 2777C、Waters 1525 μ二元泵、 Waters 1 500管柱烘箱、Waters ZQ單一四極質譜儀、 Waters PDA 2996二極體陣列偵測器及Sedex 85 ELS偵測器 140374.doc -28- 201000446 組成之LC-MS系統。利用大氣壓化學電離（APCI)離子源對 該質譜儀進行組態，該質譜儀另外配備有大氣壓光致電離 (APPI)裝置。質譜儀以陽離子模式進行掃描，其中在APCI 與APPI模式之間轉換。將質量範圍設為w/z 120-800，使用 0.3 s之掃描時間。分別將APPI反射極及APCI電暈設為0.86 kV 及0.80 μΑ。此外，對於APCI與APPI模式，去溶劑化溫度 (300°C)、去溶劑化氣體（400 L/Hr)及錐孔氣體（5 L/Hr)為恆 定的。使用 Gemini管柱C18(3.0 mm><50 mm ’ 3 pm(Phenomenex)) 且以1 ml/min之流動速率運行，從而執行分離。使用線性梯 度，始於100% A(A :於5%甲醇中之10 mM乙酸銨）且終止 於100% B(曱醇）。將管柱烘箱溫度設為40°C。 C) Waters Alliance 2795 HPLC 及在 120°C 下運作之 Waters Micromass ZQ偵測器組成之LC-MS系統。該質譜儀 配備有以陽離子或陰離子模式運作之電喷霧離子源（ES)。 在w/z 100-1000之間以0.3 s之掃描時間進行質譜儀掃描。 所用LC系統為75%乙腈及25%於水中之0.1%曱酸溶液。 在以下儀器中之一者上執行製備型層析： A)具有與自動取樣器組合之自動溶離份收集器（Waters 2767)、梯度泵（Waters 2525)、管柱轉換閥（Column Switch)(Waters CFO)及 PDA(Waters 2996)之 Waters FractionLynx 系統。管柱：XTerra® Prep MS C8 10 μηι OBD™ 19x300 mm或 XTerra® Prep MS C8 10 μιη OBD™ 30x150 mm，二者均具有前導管枉XTerra® Prep MS C8 10 μιη 19x 10 mm柱。將 100% A(於 MilliQ水及 5% 乙腈中之 95% 140374.doc -29- 201000446 0_1 Μ乙酸銨）至100% B(100%乙腈）之梯度用於20 ml/min流 動速率下之LC分離。自210-3 50 nm進行PDA掃描。UV觸 發決定溶離份收集。 B)具有與自動取樣器組合之自動溶離份收集器（Waters 2767)、梯度泵（Waters 2525)、再生泵（Waters 600)、補給 泵（Waters 515)、Waters Active Splitter、管柱轉換閥 (Waters CFO)、PDA(Waters 2996)及 Waters ZQ質譜儀之General Method Mass spectra were recorded on one of the following instruments: A) LC-MS system consisting of Waters Alliance 2795 HPLC, Waters PDA 2996 diode array detector, Sedex 85 ELS detector and ZQ single quadrupole mass spectrometer. The mass spectrometer is equipped with an electrospray ion source (ES) operating in a cationic or anionic mode. Set the capillary voltage to 3.2 kV and the cone voltage to 30 V. The mass spectrometer was scanned between m/z 100-700 with a scan time of 0.3 s. A diode array detector scan is performed from 200-400 nm. The temperature of the ELS detector was adjusted to 40 ° C and the pressure was set to 1.9 bar. Separation was performed on X-Terra MS C8 3.0 mm><50 mm, 3.5 pm (Waters) running at a flow rate of 1 ml/min. A linear gradient starting at 100% A (A: 10 mM ammonium acetate in 5% acetonitrile or 8 mM formic acid in 5% acetonitrile) was terminated at 100% B (B: acetonitrile). The column oven temperature was set to 40 °C. B) Waters Sample Manager 2777C, Waters 1525 μ Binary Pump, Waters 1 500 Column Oven, Waters ZQ Single Quadrupole Mass Spectrometer, Waters PDA 2996 Diode Array Detector and Sedex 85 ELS Detector 140374.doc - 28- 201000446 The LC-MS system consists of. The mass spectrometer was configured using an atmospheric pressure chemical ionization (APCI) ion source, which was additionally equipped with an atmospheric pressure photoionization (APPI) device. The mass spectrometer scans in a cationic mode with a transition between APCI and APPI mode. Set the mass range to w/z 120-800 and use a scan time of 0.3 s. The APPI reflector and APCI corona were set to 0.86 kV and 0.80 μΑ, respectively. In addition, for the APCI and APPI modes, the desolvation temperature (300 ° C), the desolvation gas (400 L/Hr), and the cone gas (5 L/Hr) were constant. Separation was performed using a Gemini column C18 (3.0 mm >< 50 mm' 3 pm (Phenomenex)) and running at a flow rate of 1 ml/min. A linear gradient was used starting at 100% A (A: 10 mM ammonium acetate in 5% methanol) and terminating at 100% B (sterol). The column oven temperature was set to 40 °C. C) LC-MS system consisting of Waters Alliance 2795 HPLC and a Waters Micromass ZQ detector operating at 120 °C. The mass spectrometer is equipped with an electrospray ion source (ES) operating in either cationic or anionic mode. The mass spectrometer scan was performed between w/z 100-1000 with a scan time of 0.3 s. The LC system used was 75% acetonitrile and 25% 0.1% citric acid solution in water. Preparative chromatography was performed on one of the following instruments: A) Automated Dissolve Collector (Waters 2767), Gradient Pump (Waters 2525), Column Switch (Waters Switch) in combination with an autosampler CFO) and PDA (Waters 2996) Waters FractionLynx system. Columns: XTerra® Prep MS C8 10 μηι OBDTM 19x300 mm or XTerra® Prep MS C8 10 μιη OBDTM 30x150 mm, both with a front catheter 枉XTerra® Prep MS C8 10 μιη 19x 10 mm column. A gradient of 100% A (95% 140374.doc -29- 201000446 0_1 ammonium acetate in MilliQ water and 5% acetonitrile) to 100% B (100% acetonitrile) for LC at 20 ml/min flow rate Separation. A PDA scan was performed from 210-3 50 nm. UV triggering determines the fraction collection. B) Automated Dissolve Collector (Waters 2767), Gradient Pump (Waters 2525), Regeneration Pump (Waters 600), Replenishment Pump (Waters 515), Waters Active Splitter, Column Switching Valve (Waters) in combination with an autosampler CFO), PDA (Waters 2996) and Waters ZQ mass spectrometer

Waters FractionLynx系統。管柱：XBridge™ Prep C8 5 μιη OBDTM 19x100 mm，具有前導管柱：XTerra® prep MS C8 10 μιη 19x10 mm柱。將100% A(於MilliQ水及5%乙腈中之 95% 0.1 Μ乙酸銨）至100% b(100%乙腈）之梯度用於25 ml/min流動速率下之LC分離。自210-350 rnn進行pDA掃 描。以陽離子模式之ESI運行ZQ質譜儀。毛細管電壓為3 kV且錐孔電壓為30 v。混合觸發（11乂及]^8信號）決定溶離 份收集。 在以下儀器中之一者上執行純度分析： A)由G1379A微真空除氣器、G1312A二元泵、Gl367孔 板自動取樣器、G13!6A恆溫管柱室及G1315C二極體陣列 偵測器組成之Agilent HP1100系統。所用管柱為在1〇 ml/min之流動速率下運行之Gemini ci8(3〇X5〇，3 (Phen〇menex))。純度方法由三部分組成：首先進行3分鐘 管柱洗滌，其次執行空白運行且最後分析樣品。對於空白 與樣品均使用線性梯度，始於〗〇〇% A(A :於5%乙腈中之 10 mM乙酸銨）且在3 5分鐘之後終止於1〇〇% b(b :乙腈）。 1403 74.doc -30- 201000446 自波長220 nm、254 nm及290 nm下之樣品運行中減去空白 運行。 B) 具有 PDA(Waters 2996)及 Waters ZQ 質譜儀之 Water Acquity 系統。管柱：Acquity UPLCTM BEH C8 1.7 μηι 2.1x50 mm。將管柱溫度設為65°C。將100°/。Α(Α :於 MilliQ水及5%乙腈中之95% 0.01 Μ乙酸銨）至1〇〇% Β(於 MilliQ水及95%乙腈中之5% 0.01 Μ乙酸銨）之線性2分15秒 梯度用於1.0 ml/min流動速率下之LC分離。自210-350 nm 進行PDA掃描且於254 nm下進行提取以用於純度測定。以 pos/neg轉換模式之ESI運行ZQ質譜儀。毛細管電壓為3 kV 且錐孔電壓為30V。 C) 具有Waters 717 Plus自動取樣器及Waters 2996光電 二極體陣列偵測器之Waters 600控制系統。所用管柱為 ACE C18，5 μηι，6〇x 150 mm。使用線性梯度，始於 95% A(A :於水中之0.1% H3P〇4)且在20 min運行中終止於55% B(B :乙腈）。管柱係在環境溫度下，其中流動速率為1 .〇 mL/min。自200-400 nm進行二極體陣列伯測器掃描。 在於400 MHz下運作且配備有Varian 400 ATB PFG探頭 之Varian Mercury Plus 400 NMR光譜儀上記錄NMR光譜； 或在於400 MHz(質子）及100 MHz(碳13)下運作且配備有 5 mm Z梯度BB0探頭之Varian Unity+400 NMR光譜儀上記 錄NMR光譜；或在於400 MHz(質子）及100 MHz(碳13)下運 作且配備有3 mm Z梯度流動注射SEI iH/D-^C探頭，使用 BEST 215液體處理器進行樣品注射之Bruker av400 NMR光 140374.doc -31 - 201000446 譜儀上記錄NMR光譜；或在於400 MHz(質子）及100 MHz(碳13)下運行且配備有z梯度4-核探頭之Bruker DPX400 NMR光譜儀上記錄NMR光譜。使用以下參考信 號：（除非另外指示’否則）TMS δ 0.00，或DMSO-A之殘 餘溶劑信號δ 2.49 ’ CD3〇D δ 3.31或CDC13 δ 7.25。分別將 單峰、雙重峰、三重峰、四重峰、多重峰及寬峰之共振多 重性表不為s、d、t、q' m及br。 視光譜說明之簡易性而定，光譜中可能表示或可能不表 示出非對映異構物。除非另有說明，否則以溶劑作為内標 以ppm形式給出化學位移。 使用 Merck 矽膠 60(0.040-0.063 mm)，或使用 Combi Flash® Companion™系統使用RediSepTM正相急驟管柱執行 管柱層析。 已使用來自 Advanced Chemistry Development Inc_(ACD/Labs), Toronto ON, Canada, www.acdlabs.com, 2004之ACD/Name，8.0 或 9.0 版軟體及來自 Cambridgesoft, www.cambridgesoft.com, 2008之ELN 2.1版軟體對化合物命名。 【實施方式】 中間物之製備 現將由以下非限制性實例來說明本發明。 實例1-1 2-[1-(第三丁氧基羰基）吖丁啶-3·基】-3-側氧基異吲哚啉-1-曱酸乙酯 140374.doc -32· 201000446Waters FractionLynx system. Column: XBridgeTM Prep C8 5 μιη OBDTM 19x100 mm with front conduit column: XTerra® prep MS C8 10 μιη 19x10 mm column. A gradient of 100% A (95% 0.1 Μ ammonium acetate in MilliQ water and 5% acetonitrile) to 100% b (100% acetonitrile) was used for LC separation at a flow rate of 25 ml/min. The pDA scan was performed from 210-350 rnn. The ZQ mass spectrometer was run in cation mode ESI. The capillary voltage is 3 kV and the cone voltage is 30 v. The mixing trigger (11乂 and ]^8 signals) determines the dissolution collection. Purity analysis was performed on one of the following instruments: A) G1379A micro vacuum deaerator, G1312A binary pump, Gl367 orifice autosampler, G13!6A thermostat column chamber and G1315C diode array detector The Agilent HP1100 system. The column used was a Gemini ci8 (3〇X5〇, 3 (Phen〇menex)) operating at a flow rate of 1 〇 ml/min. The purity method consists of three parts: first a 3 minute column wash, followed by a blank run and finally a sample analysis. A linear gradient was used for both blank and sample, starting with 〇〇% A (A: 10 mM ammonium acetate in 5% acetonitrile) and ending at 1% b (b: acetonitrile) after 35 minutes. 1403 74.doc -30- 201000446 Subtract blank operation from sample runs at wavelengths of 220 nm, 254 nm, and 290 nm. B) Water Acquity system with PDA (Waters 2996) and Waters ZQ mass spectrometer. Column: Acquity UPLCTM BEH C8 1.7 μηι 2.1x50 mm. The column temperature was set to 65 °C. Will be 100 ° /.线性(Α : 95% 0.01 Μ ammonium acetate in MilliQ water and 5% acetonitrile) to 1〇〇% Β (5% of 0.01 Μ ammonium acetate in MilliQ water and 95% acetonitrile) linear 2 minutes 15 seconds gradient For LC separation at a flow rate of 1.0 ml/min. A PDA scan was performed from 210-350 nm and extraction was performed at 254 nm for purity determination. The ZQ mass spectrometer was run with ESI in pos/neg conversion mode. The capillary voltage is 3 kV and the cone voltage is 30V. C) Waters 600 control system with Waters 717 Plus autosampler and Waters 2996 photodiode array detector. The column used was ACE C18, 5 μηι, 6〇x 150 mm. A linear gradient was used starting at 95% A (A: 0.1% H3P〇4 in water) and ending at 55% B (B: acetonitrile) in 20 min run. The column is at ambient temperature with a flow rate of 1 〇 mL/min. The diode array detector is scanned from 200-400 nm. NMR spectra were recorded on a Varian Mercury Plus 400 NMR spectrometer operating at 400 MHz with a Varian 400 ATB PFG probe; or operated at 400 MHz (protons) and 100 MHz (carbon 13) with a 5 mm Z gradient BB0 probe NMR spectra were recorded on a Varian Unity+400 NMR spectrometer; or at 400 MHz (protons) and 100 MHz (carbon 13) equipped with a 3 mm Z gradient flow injection SEI iH/D-^C probe using BEST 215 liquid Bruker av400 NMR light for sample injection by the processor 140374.doc -31 - 201000446 NMR spectra were recorded on the spectrometer; or operated at 400 MHz (protons) and 100 MHz (carbon 13) equipped with a z-gradient 4-core probe NMR spectra were recorded on a Bruker DPX400 NMR spectrometer. The following reference signals were used: (unless otherwise indicated 'otherwise) TMS δ 0.00, or DMSO-A residual solvent signal δ 2.49 ' CD3 〇 D δ 3.31 or CDC13 δ 7.25. The resonance polymorphisms of single peak, double peak, triplet, quartet, multiplet and broad peak are not s, d, t, q' m and br, respectively. Depending on the simplicity of the spectroscopic description, diastereoisomers may or may not be indicated in the spectrum. Unless otherwise stated, the chemical shift is given in ppm using the solvent as an internal standard. Column chromatography is performed using a Merck Silicone 60 (0.040-0.063 mm) or a Combi Flash® CompanionTM system using a RediSepTM normal phase column. ACD/Name, version 8.0 or 9.0 software from Advanced Chemistry Development Inc_ (ACD/Labs), Toronto ON, Canada, www.acdlabs.com, 2004 and ELN version 2.1 from Cambridgesoft, www.cambridgesoft.com, 2008 have been used The software names the compound. [Embodiment] Preparation of Intermediates The present invention will now be illustrated by the following non-limiting examples. Example 1-1 2-[1-(Tertibutoxycarbonyl)azetidin-3yl]-3-oxooxyisoindoline-1-decanoate 140374.doc -32· 201000446

中間物1Intermediate 1

用冰浴將2-(1-溴_2-乙氧基-2-側氧基乙基）苯曱酸乙酯 (2.5 g，7.9 mol)(根據 〇thman等人，Synth. comm. 1996, 26, 2803製備）於乙腈（25 mL)中之溶液冷卻至〇χ：，且將溶 液上方之氣氛交換為氮氣。依次引入三乙胺（2 5 mL，i 8 mmol)及3-胺基-吖丁啶_i-曱酸第三丁酯（2 〇 g，u 6爪〇1), 且將反應混合物溫至環境溫度，同時攪拌隔夜。將粗產物 用乙酸乙酯（100 ml)稀釋且用水、飽和碳酸氫鈉萃取且最 後用鹽水萃取。將有機層經硫酸鎂乾燥，在真空中濃縮。 藉由管柱層析使用於庚烧中之乙酸乙6旨之梯度⑼身/。）來 純化粗產物。彙集含標題化合物之溶離份，且在真空中濃 以產生1.8 g(63%)標題化合物。Ethyl 2-(1-bromo-2-ethoxy-2-oxoethyl)benzoate (2.5 g, 7.9 mol) was used in an ice bath (according to 〇thman et al., Synth. comm. 1996, 26, 2803 Preparation) A solution in acetonitrile (25 mL) was cooled to 〇χ: and the atmosphere above the solution was exchanged to nitrogen. Triethylamine (25 mL, i 8 mmol) and 3-amino-azetidine-i-decanoic acid tert-butyl ester (2 〇g, u 6-claw 1) were introduced in turn, and the reaction mixture was warmed to Ambient temperature while stirring overnight. The crude product was diluted with EtOAc (EtOAc) (EtOAc)EtOAc. The organic layer was dried with MgSO4 and evaporatedEtOAc. The column was subjected to column chromatography for the gradient of acetic acid B in the helium burn (9). ) to purify the crude product. The fractions containing the title compound were combined and concentrated in vacuo to give &lt

!NMR (400 MHz, CDC13) δ 7.79 (d, Η), 7.49 (d, 1 Η), 5.28 (s, 1 Η), 4.70 1 Η), 7.51-7.63 (m, 2 (m, 1H), 4.29-4.38 (m, 1 H)，4.22-4.29 (m，3 H)，4.12-4.21 (m，2 H)，141 (s, 9 H) 1.25 (t, 3 H) ; MS (ESI) w/z 359 [M-H]。 實例1-2 2-丨1-(第三丁氧基幾基）基】_3侧氧基異巧丨嗓啉-1 甲酸!NMR (400 MHz, CDC13) δ 7.79 (d, Η), 7.49 (d, 1 Η), 5.28 (s, 1 Η), 4.70 1 Η), 7.51-7.63 (m, 2 (m, 1H), 4.29-4.38 (m, 1 H), 4.22-4.29 (m, 3 H), 4.12-4.21 (m, 2 H), 141 (s, 9 H) 1.25 (t, 3 H) ; MS (ESI) w /z 359 [MH]. Example 1-2 2-丨1-(Tertidinoxy)yl]_3 oxo-iso-carboline-1carboxylic acid

中間物2 140374.doc •33· 201000446 向2-(1-(第二丁氧基魏基丫丁啶_3_基）_3_側氧基異吲哚 琳-1-甲酸乙醋（1·08 g ’ 3.00 mmol)於曱醇（2〇 mL)中之溶液 中添加Na〇H(l Μ，7.5 mL，7·5 mmol)溶液，且將反應物在 環境溫度下攪拌30 min。用HC1(1 M)中和反應混合物且在真 空中濃縮至乾。將所獲得之固體再溶解於丙酮（25 mL)中且 濾出所形成之固體。用丙酮（10 mL)洗滌濾液，且蒸發溶劑 以生成呈黃色固體狀之標題化合物，〇 975 g (98%)。 JH NMR (400 MHz, OMSO-d6) δ ppm 7.61-7.66 (m, 1 Η), 7.53-7.57 (m, 1 Η), 7.49 (td, 1 Η), 7.34-7.40 (m, 1 Η), 4.98 (s, 1 Η), 4.54-4.68 (m, 1 Η), 4.40 (t, 1 Η), 4.12 (br. s., 1 H), 3.86-4.07 (m，2 H)，1.39 (s, 9 H) ; MS (ESI)m々 333 [M+H]。 實例1-3 2-(4,4-二氟環己基）_3_側氧基異e弓丨味琳甲酸乙醋Intermediate 2 140374.doc •33· 201000446 To 2-(1-(2nd-butoxy-weigi-butyrydin-3-yl)_3_sideoxyisoindolin-1-carboxylic acid ethyl acetate (1· Add a solution of Na〇H (1 Μ, 7.5 mL, 7.5 mmol) in decyl alcohol (2 〇 mL) and stir the reaction at ambient temperature for 30 min. (1 M) The reaction mixture was neutralized and concentrated to dryness in vacuo. The obtained solid was redissolved in acetone (25 mL) and the solid formed was filtered out. The filtrate was washed with acetone (10 mL) and solvent was evaporated. The title compound is obtained as a yellow solid, 〇 975 g (98%). JH NMR (400 MHz, OMSO-d6) δ ppm 7.61-7.66 (m, 1 Η), 7.53-7.57 (m, 1 Η), 7.49 (td, 1 Η), 7.34-7.40 (m, 1 Η), 4.98 (s, 1 Η), 4.54-4.68 (m, 1 Η), 4.40 (t, 1 Η), 4.12 (br. s., 1 H), 3.86-4.07 (m, 2 H), 1.39 (s, 9 H); MS (ESI) m 333 [M+H]. Example 1-3 2-(4,4-difluorocyclohexyl )_3_Sideoxyiso-e-bow-flavored formic acid ethyl vinegar

° 中間物3 根據關於中間物1所述之程序自乙腈（30 mL)中之2-(1-臭-2-乙氧基-2-側氧基乙基）苯曱酸乙醋（2.0 g，6.3 mmol)、三乙胺（1.3 mL，9.3 mmol)及4,4-二氟-環己胺（1.0 g， 7_4 mol)合成標題化合物以生成0.71 g(36%)。 !H NMR (400 MHz, CDC13) δ ppm 7.85 (d, 1 H), 7.45-7.63 (m, 3 H), 5.16 (s, 1 H), 4.11-4.37(m, 3 H), 2.16-2.33 (m, 2 H), 2.05-2.16 (m, 1 H)，1.77-2.04 (m, 5 H), 1_30 (t，3 H) ; MS (ESI) m/z 324 [M+H]。 140374.doc •34- 201000446 實例1-4 2-(4,4-二氟環己基）_3_側氧基異吲哚啉“甲酸° Intermediate 3 2-(1-odor-2-ethoxy-2-oxoethyl)benzoic acid ethyl acetate (2.0 g in acetonitrile (30 mL) according to the procedure described for Intermediate 1 The title compound was synthesized to give the title compound (yield: 6.3 mmol), triethylamine (1.3 mL, 9.3 mmol) and 4,4-difluoro-cyclohexylamine (1.0 g, 7 to 4 mol). !H NMR (400 MHz, CDC13) δ ppm 7.85 (d, 1 H), 7.45-7.63 (m, 3 H), 5.16 (s, 1 H), 4.11-4.37 (m, 3 H), 2.16-2.33 (m, 2 H), 2.05-2.16 (m, 1 H), 1.77-2.04 (m, 5 H), 1_30 (t, 3 H); MS (ESI) m/z 324 [M+H]. 140374.doc •34- 201000446 Example 1-4 2-(4,4-Difluorocyclohexyl)_3_sideoxyisoindoline "formic acid

向2-(4,4-二氟環己基）_3_側氧基異吲哚啉·甲酸乙酯 (〇·7〇 mg ’ 2_2 mmol)於甲醇（2〇叫中之溶液中添= ⑽H(1 Μ，5.4 mL，5.4 mmGl)，同時授拌。將反應物在 環境溫度下攪拌30 min，且隨後用]^^。M)中和。在真空 中蒸發甲醇。將水相用Ηα(1 M)酸化至pH 2且用乙酸乙酯 萃取。將有機層經硫酸鎂乾燥且濃縮以生成呈黃色固體狀 之標題化合物，0.62g(97%)。 H NMR (400 MHz, DMSO-<i6) δ ppm 13.59 (br. s 1 H) 7.68-7.72 (m, 1 H), 7.51-7.67 (m, 3 H), 5.45 (s, 1 H), 4.U (br. s., 1 H), 3.89-4.01 (m, 1 H), 1.87-2.15 (m, 7 H) ; MS (ESI) m/z 296[M+H]。To 2-(4,4-difluorocyclohexyl)_3_sideoxyisoindoline·ethyl formate (〇·7〇mg ' 2_2 mmol) in methanol (2 溶液 之 solution) = (10)H ( 1 Μ, 5.4 mL, 5.4 mm Gl), while mixing. The reaction was stirred at ambient temperature for 30 min and then neutralized with ^^.M). The methanol was evaporated in vacuo. The aqueous phase was acidified to pH 2 with EtOAc (1 M) and extracted with ethyl acetate. The organic layer was dried with EtOAc EtOAc EtOAc. H NMR (400 MHz, DMSO-<i6) δ ppm 13.59 (br. s 1 H) 7.68-7.72 (m, 1 H), 7.51-7.67 (m, 3 H), 5.45 (s, 1 H), 4.U (br. s., 1 H), 3.89-4.01 (m, 1 H), 1.87-2.15 (m, 7 H); MS (ESI) m/z 296 [M+H].

實例I-S 2-[l-(2-糠酿基）旅咬-4-基l·3-側氡基異《弓丨鳴嚇^1_甲酸乙醋Example I-S 2-[l-(2-糠)) Bite-4-yl l·3-Side 氡 异 《 丨 丨 丨 丨 吓 吓 吓 1 1 1

根據關於中間物1所述之程序自乙腈（30 mL)中之2-(1- •35- 140374.doc 201000446 漠--2-乙氧基-2-側氧基乙基）苯甲酸乙醋（2.5 g，7.9 mmol)、三乙胺（2.2 mL，15.8 mm〇i)及 ι_(2_糠醯基）哌啶_ 4-胺（1.8 g，9.3 mmol)合成標題化合物以生成ι·2 g(4〇%)。 'Η NMR (400 MHz, CDC13) δ ppm 7.85 (d, 1 H), 7.45-7.62 (m, 4 H), 7.01 (d, 1 H), 6.43-6.54 (m, 1 H), 5.18 (s, 1 H), 4.70 (br s, 2 H), 4.32-4.45 (m, 1 H), 4.17-4.31 (m, 2 H), 3.01 (br s, 2 H), 2.04-2.19 (m, 2 H), 1.76-2.04 (m, 2 H)，1.22-1.35 (m，3 H) ; MS (ESI) m/z [M+H]。 實例1-6 2-[1-(2-糠醯基）哌啶_4-基]-3-側氧基異吲哚啉-1-甲酸2-(1- •35-140374.doc 201000446 ---2-ethoxy-2-oxoethyl)benzoic acid acetate from acetonitrile (30 mL) according to the procedure described for Intermediate 1 (2.5 g, 7.9 mmol), triethylamine (2.2 mL, 15.8 mm 〇i), and ι_(2-fluorenyl)piperidine-4-amine (1.8 g, 9.3 mmol). g (4〇%). 'Η NMR (400 MHz, CDC13) δ ppm 7.85 (d, 1 H), 7.45-7.62 (m, 4 H), 7.01 (d, 1 H), 6.43-6.54 (m, 1 H), 5.18 (s , 1 H), 4.70 (br s, 2 H), 4.32-4.45 (m, 1 H), 4.17-4.31 (m, 2 H), 3.01 (br s, 2 H), 2.04-2.19 (m, 2 H), 1.76-2.04 (m, 2 H), 1.22-1.35 (m, 3 H); MS (ESI) m/z [M+H]. Example 1-6 2-[1-(2-indolyl)piperidin-4-yl]-3-oxooxyisoindoline-1-carboxylic acid

根據關於中間物2所述之程序由2-[1 糠酸基）°底啶-4_ 基]-3-側氧基異吲哚啉小曱酸（0.382 g，i·00 mmo1)與 NaOH(l Μ，1.5 mL，l·5 mmo1)在曱醇（10 mL)中之反應合 成標題化合物以生成黄色固體，o.338 g(95%)。MS (ESI) m/z 3 55 [M+H]。 實例Ι·7 3-側氧基-2-(1-嘧啶_2-基吖丁啶_3_基）異吲哚啉_1_曱酸乙酯According to the procedure described for Intermediate 2, 2-[1 decanoic acid] oxaridin-4-yl]-3-oxooxyisoindoline citrate (0.382 g, i·00 mmo1) and NaOH ( l Μ, 1.5 mL, EtOAc (m.) MS (ESI) m / z 3 55 [M+H]. Example Ι·7 3-Phenoxy-2-(1-pyrimidin-2-ylazetidine_3_yl)isoindoline_1_decanoate

中間物7 140374.doc -36- 201000446 步驟1 : 向2-[1-(第三丁氧基羰基）吖丁啶_3_基]_3_側氧基異吲哚 啉-1-甲酸乙酯（1.0 g，27 mm〇1)於無水二氯曱烷（i〇 mL) 中之溶液中添加三氟乙酸（2·〇 mL)，且將反應混合物在環 境溫度下攪拌2 h。在真空中濃縮反應混合物且將殘餘物 溶解於水（10 mL)中，用碳酸氫鈉溶液使其鹼化且用乙酸 乙酯（3x3 0 ml)萃取。將經組合之有機層用鹽水洗滌，經硫 酸鈉乾燥且在真空中濃縮以生成〇 72 g(1〇〇%)。 步驟2 : 將2-/臭嘴咬（5〇〇 mg，3· 1 5 mmol)、步驟1之去保護胺 (722 mg，2.17 mmol)、Pd2(dba)3(200 mg，0.22 mmol)、 2,2’-雙（二苯基膦基聯萘（2〇〇 mg，〇 μ mmol)及碳酸 铯（1.1 g ’ 3.3 mmol)於曱苯〇15 mL)中之混合物脫氣，同 時用氮氣沖洗，且隨後加熱至80。(3歷時丨9 h。將反應混合 物用乙酸乙醋稀釋，用水及鹽水洗滌，經硫酸鈉乾燥且在 真空中濃縮。藉由管柱層析使用於己烷中之乙酸乙酯之梯 度（5 0-80%)來純化殘餘物以生成590 mg(63%)所需化合 物。 ]H NMR (400 MHz, CDC13) δ ppm 8.35 (d, 2 Η), 7.85 (d, 1 Η), 7.48-7.67 (m, 3 Η), 6.60 (t, 1H), 5.38 (s, 1H), 4.91-5.07 (m，1 H)，4.51-4.61 (m，2 H)，4.40-4.51 (m，2 H), 4.11-4.34 (m，2 H)，1.27 (t, 3 H) ; MS (ESI) 339 [M+H]。 實例1-8 3-側氧基-2-(1-嘧啶-2-基吖丁啶_3_基）異吲哚啉-1-曱酸 140374.doc •37- 201000446Intermediate 7 140374.doc -36- 201000446 Step 1: To 2-[1-(t-butoxycarbonyl)azetidine_3_yl]_3_oxetoxyisoindoline-1-carboxylate (1.0 g, 27 mm 〇 1) Trifluoroacetic acid (2·〇mL) was added to a solution of anhydrous dichloromethane (1 mL), and the mixture was stirred at ambient temperature for 2 h. The reaction mixture was concentrated in vacuo and EtOAc EtOAc m. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. Step 2: 2 - / odor bite (5 〇〇 mg, 315 mmol), step 1 of the deprotected amine (722 mg, 2.17 mmol), Pd2 (dba) 3 (200 mg, 0.22 mmol), a mixture of 2,2'-bis(diphenylphosphinobiphthalene (2 〇〇 mg, 〇μ mmol) and cesium carbonate (1.1 g '3.3 mmol) in indolephthalic acid 15 mL) was degassed with nitrogen Rinse and then heat to 80. (3). The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. 0-80%) to purify the residue to give 590 mg (63%) of desired compound.]H NMR (400 MHz, CDC13) δ ppm 8.35 (d, 2 Η), 7.85 (d, 1 Η), 7.48- 7.67 (m, 3 Η), 6.60 (t, 1H), 5.38 (s, 1H), 4.91-5.07 (m, 1 H), 4.51-4.61 (m, 2 H), 4.40-4.51 (m, 2 H ), 4.11-4.34 (m, 2 H), 1.27 (t, 3 H); MS (ESI) 339 [M+H]. Azetidine _3_yl)isoindoline-1-decanoic acid 140374.doc •37- 201000446

中間物s 根據關於中間物2所述之程序由3-側氧基-2-(1-嘧啶-2-基 吖丁啶-3-基）異吲哚啉-1-甲酸乙酯（0.338 g，1.00 mmol)與 NaOH(l Μ，2.5 mL，2.5 mmol)在曱醇（5 mL)與四氫0夫喃 (5 mL)之混合物中的反應合成標題化合物以生成黃色固 體，0.301 g(97%)。 丨11丽11(400 河沿，01^0-£/6)3卩口1118.34(4 2印，7.60-7.66 (m, 1 Η), 7.53-7.57 (m, 1 Η), 7.49 (td, 1 Η), 7.38 (t5 1 Η), 6.67 (t, 1 Η), 5.02 (s, 1 Η), 4.80-4.90 (m, 1 Η), 4.51-4.58 (m, 1 Η), 4.23-4.34 (m, 2 Η), 4.18 (t, 1 Η) ； MS (ESI) m/z 3 11 [M+H]。 實例1-9 (3,3-二氟環丁基）甲胺Intermediate s Ethyl 3-oxo-2-(1-pyrimidin-2-ylazetidin-3-yl)isoindoline-1-carboxylate according to the procedure described for Intermediate 2 (0.338 g The title compound was synthesized as a yellow solid (0.31 g, EtOAc, EtOAc, EtOAc (EtOAc) %).丨11丽11(400 riverside, 01^0-£/6)3卩口1118.34(4 2印, 7.60-7.66 (m, 1 Η), 7.53-7.57 (m, 1 Η), 7.49 (td, 1 Η), 7.38 (t5 1 Η), 6.67 (t, 1 Η), 5.02 (s, 1 Η), 4.80-4.90 (m, 1 Η), 4.51-4.58 (m, 1 Η), 4.23-4.34 ( m, 2 Η), 4.18 (t, 1 Η); MS (ESI) m/z 3 11 [M+H]. Example 1-9 (3,3-difluorocyclobutyl)methylamine

將3,3-二氟環丁腈（113 mg，0·97 mmol)溶解於曱醇（20 mL)中，且在25°C下以1.0毫升/分鐘流動速率在全H2模式 下在連續流動氫化裝置（H_Cube)中使用Pd/C(l〇%標準柱） 進行氫化。使溶液流經該系統兩次。在減壓下移除溶劑以 生成呈油狀之標題化合物（6 5 · 0 mg，5 5.6%，60%純度）。 140374.doc -38- 201000446 該化合物無需進一步純化即使用。 ]H NMR (500 MHz, CDC13) δ (ppm) 2.73 (d, 2 Η) 2.61-2.70 (m，3 Η) 2.17-2.27 (m, 2 H)。 實例1-10 N-(l-(4-(三氟曱氧基）苯基）乙基）甲醯胺3,3-Difluorocyclobutyronitrile (113 mg, 0.97 mmol) was dissolved in decyl alcohol (20 mL) and continuously flowed at a flow rate of 1.0 ml/min in full H2 mode at 25 °C. Hydrogenation was carried out using a Pd/C (10% standard column) in a hydrogenation unit (H_Cube). The solution was passed through the system twice. The solvent was removed under reduced pressure to give the title compound (6 5 · 0 mg, 5 5.6%, 60% purity). 140374.doc -38- 201000446 This compound was used without further purification. ]H NMR (500 MHz, CDC13) δ (ppm) 2.73 (d, 2 Η) 2.61-2.70 (m, 3 Η) 2.17-2.27 (m, 2 H). Example 1-10 N-(l-(4-(Trifluoromethoxy)phenyl)ethyl)carboxamide

將卜（4-(三氟甲氧基）苯基）乙胺（0.352 g，1.72 mmol)溶 解於二氣甲烷（4 mL)中’置於n2氣氛下，且冷卻至〇。〇。 逐滴添加甲酸苯酯（0.1 87 mL，1.72 mmol)且將混合物在室 溫下攪拌1 6小時。在真空中移除溶劑且在二氧化矽管柱上 使用庚烷：乙酸乙酯=100:0至0:100作為梯度來純化殘餘 物。無色油狀物，284 mg(71%)。 *H NMR (500 MHz, CDC13) δ (ppm) 8.20 (s, 1 H) 7.36 (d, 2 H) 7.17-7.22 (m, 2 H) 5.77 (br. s., 1 H) 5.24 (t, 1 H) 1.53 (d，3 H)。MS (ESI) m/z 234 [M+H]。 實例1-11 1-(1·異氰基乙基）-4-(三氟甲氧基）苯Di(4-(trifluoromethoxy)phenyl)ethylamine (0.352 g, 1.72 mmol) was dissolved in di-methane (4 mL). Hey. Phenyl formate (0.187 mL, 1.72 mmol) was added dropwise and the mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified using a heptane: ethyl acetate = <RTI ID=0.0>> Colorless oil, 284 mg (71%). *H NMR (500 MHz, CDC13) δ (ppm) 8.20 (s, 1 H) 7.36 (d, 2 H) 7.17-7.22 (m, 2 H) 5.77 (br. s., 1 H) 5.24 (t, 1 H) 1.53 (d, 3 H). MS (ESI) m/z 234 [M+H]. Example 1-11 1-(1·Isocyanoethyl)-4-(trifluoromethoxy)benzene

中間物11 140374.doc •39- 201000446 將N-(l-(4-(三氟甲 土）本基）乙基）甲酿胺（0.275 g， 1.18 mmol)溶解於二 。 —虱甲烷（4 mL)中且在N2氣氛下冷卻 至-15 C。添加ν,Ν-二里不A， —，、丙基乙胺（0.780 mL，4.72 mmol)，繼而添加氧氯 軋化 ％(0.132 mL，1.42 mmol)，且使 所仔混合物緩k達到室溫（3小時）。隨後添加甲醇（1.5 mL) =中止反應。冑混合物用二氯曱烧稀釋且用飽和祕叫 溶液洗條兩次。將柄鈿A ^ 士 uu # & 、‘'二、” 5之有機举取物用鹽水洗務，經無 水硫酸鈉乾燥，過濾且蒸發以生成呈棕色油狀之產物， 284 mg(112%) ’其無需進一步純化即使用。 H NMR (500 MHz, CDC13) δ (ppm) 7.41 (d, 2 Η) 7.24-7.29 (m, 2 Η) 4.85 (q，1 Η) 1.70 (d，2 H)。MS (ESI) Μ 216 [M+H]。 實例1-12 心(3-(三氟甲氧基）苯甲基）甲醯胺Intermediate 11 140374.doc • 39- 201000446 N-(l-(4-(trifluoromethane)benyl)ethyl)caraamine (0.275 g, 1.18 mmol) was dissolved in two. - 虱 methane (4 mL) and cooled to -15 C under N2 atmosphere. Add ν, Ν-二里不 A, —, propylethylamine (0.780 mL, 4.72 mmol), then add oxychloride rolling % (0.132 mL, 1.42 mmol), and allow the mixture to slow to room temperature (3 hours). Methanol (1.5 mL) was then added = the reaction was stopped. The mash mixture was diluted with dichlorohydrazine and washed twice with a saturated solution. The organic extracts of the sputum A ^ 士 uu # &, ''2,' 5 were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to give a brown oil, 284 mg (112%) ) 'It is used without further purification. H NMR (500 MHz, CDC13) δ (ppm) 7.41 (d, 2 Η) 7.24-7.29 (m, 2 Η) 4.85 (q,1 Η) 1.70 (d,2 H MS (ESI) 216 216 [M+H]. Example 1-12 Heart (3-(trifluoromethoxy)benzyl)carbamide

NH H 0 中間物12 根據關於實例10所述之方法使用（3-(三氟曱氧基）苯基） 甲胺（0.2 g，1.05 mmol)及曱酸苯醋（0.117 mL，1.05 mmol) 製備標題化合物。無色油狀物，120 mg(52%)。 !H NMR (500 MHz, CDC13) δ (ppm) 8.31 (s, 1 H) 7.35-7.40 (m，1 H) 7.22-7.26 (m, 1 H) 7.15 (br· s·，2 H) 5.92 (br. s.，1 H) 4.53 (d, 2 H) ° MS (ESI) m/z 220 [M+H] ° 140374.doc -40- 201000446 實例1-13 異氰基甲基）-3-(三氟甲氧基）苯NH H 0 Intermediate 12 was prepared according to the procedure described for Example 10 using (3-(trifluoromethoxy)phenyl)methylamine (0.2 g, 1.05 mmol) and phenyl phthalic acid (0.117 mL, 1.05 mmol). Title compound. Colorless oil, 120 mg (52%). !H NMR (500 MHz, CDC13) δ (ppm) 8.31 (s, 1 H) 7.35-7.40 (m,1 H) 7.22-7.26 (m, 1 H) 7.15 (br· s·, 2 H) 5.92 ( Br. s.,1 H) 4.53 (d, 2 H) ° MS (ESI) m/z 220 [M+H] ° 140374.doc -40- 201000446 Example 1-13 Isocyanomethyl)-3- (trifluoromethoxy)benzene

根據關於實例U所述之方法使用N-(3-(三氟甲氧基）苯甲 基）甲醯胺（120 mg，〇55 mm 土 } —異丙基乙胺（0.362 題化合物。 ^ W知N-(3-(Trifluoromethoxy)benzyl)carbamamine (120 mg, 〇55 mm soil}-isopropylethylamine (0.362 compound. ^ W) was used according to the method described in Example U. know

棕色油狀物，1 1 〇 用。 ]Η NMR (500 MHz, (d, 1 Η) 7.21-7.25 202 [Μ+Η]。實例1-14 mg(100〇/〇)， 其無需進一步純化即使 CDC13) δ (ppm) 7.43-7.49 (m, 1 H) 7.31 (m, 2 H) 4.69 (s，2 H)。MS (ESI) m/z N-(2-甲基-4-(三I甲氧基）苯曱基）曱酿胺Brown oil, 1 1 〇. Η NMR (500 MHz, (d, 1 Η) 7.21-7.25 202 [Μ+Η]. Example 1-14 mg (100 〇/〇), which requires no further purification even if CDC13) δ (ppm) 7.43-7.49 ( m, 1 H) 7.31 (m, 2 H) 4.69 (s, 2 H). MS (ESI) m/z N-(2-methyl-4-(tri-methoxy)phenyl)

中間物14 根據關於實例1 〇所述之方法使用（2_甲基_4_(三氟曱氧基） 苯基）曱胺（0.35 g，1.71 mmol)及甲酸苯酯（0.191 mL，1.71 140374.doc -41 - 201000446 mmol)製備標題化合物。在二氧化矽管柱上使用二氯甲 烧··（二氯f烷/甲醇/氨90:10··1)=100··0至30:70作為梯度來 純化粗產物。白色固體，252 mg(63%)。 Ή NMR (500 MHz, CDC13) δ (ppm) 8.28 (s, 1 Η) 7.27 (t, 1 Η) 7.06 (br. s., 2 H) 5.68 (br. s„ 1 H) 4.49 (d, 2 H) 2.36 (s, 3 H)。MS (ESI) m/z 232 [M-H]。 實例1-15 1-(異氰基曱基）-2-甲基-4-(三氟甲氧基）笨Intermediate 14 (2-methyl-4-[(trifluoromethoxy)phenyl)decylamine (0.35 g, 1.71 mmol) and phenyl formate (0.191 mL, 1.71 140374.). Doc -41 - 201000446 mmol) Preparation of the title compound. The crude product was purified on a ruthenium dioxide column using methylene chloride (dichlorof-hexane/methanol/ammonia 90:10··1) = 100··0 to 30:70 as a gradient. White solid, 252 mg (63%). NMR NMR (500 MHz, CDC13) δ (ppm) 8.28 (s, 1 Η) 7.27 (t, 1 Η) 7.06 (br. s., 2 H) 5.68 (br. s„ 1 H) 4.49 (d, 2 H) 2.36 (s, 3 H). MS (ESI) m/z 232 [MH]. Example 1-15 1-(isocyanoindolyl)-2-methyl-4-(trifluoromethoxy) stupid

中間物15 根據關於貫例11所述之方.法枯田·/ 乃决使用Ν·(2-甲基_4-(三氟曱氧 基）笨甲基）甲醯胺（0.250 g, ] η7 8 i·07 mm〇l)、ν,Ν-二異丙基乙 胺（0.742 mL ’ 4.29 备儿 久乳虱化磷（0.120 mL，1.29 mmol)製備標題化合物。棕 作巴油狀物，3〇〇 mg(130%)，其 無需進一步純化即使用。 MS (ESI) m/z 216[M+H] ° 實例1-16 4-(2,2,2-三氟乙基）苯甲腈 N=Intermediate 15 According to the method described in Example 11, ruthenium was used as a ruthenium (2-methyl-4-(4-trifluoromethoxy)methyl)carbamamine (0.250 g, ] Η7 8 i·07 mm〇l), ν, Ν-diisopropylethylamine (0.742 mL ' 4.29 Prepared for the preparation of the title compound as a crude oil (0.120 mL, 1.29 mmol). 3 〇〇 mg (130%), which was used without further purification. MS (ESI) m/z 216 [M+H] ° Example 1-16 4-(2,2,2-trifluoroethyl)benzene Nitrile N=

中間物16 向 1-溴-4-(2,2,2- I乙基）笨（2.15 9.00 mmol)之 140374.doc -42· 201000446 DMF(25 mL)溶液中添加氰化鋅（2·11 g，i8.〇 mmol)，隨後 添加 Pd(PPh3)4(〇.828 g，0.720 mmol)。將混合物在 i〇〇°c 下加熱18小時，隨後冷卻至室溫，用乙酸乙酯（5〇 mL)稀 釋且經由短矽藻土床過濾。在減壓下濃縮濾液。藉由矽膠 管柱層析使用己烧：乙酸乙酯=9〇: 1 〇作為溶離劑來純化粗 殘餘物以生成呈白色固體狀之標題化合物，8〇〇 mg (480/〇) ° !H NMR (400 MHz, CDC13) δ (ppm) 7.67 (d, 2 Η) 7.43 (d, 2 Η) 3·44 (q，2 H)。19F NMR (400 MHz, CDC13) δ (ppm) -65.85、-65.88及-65.91。MS (ESI) m/z 186 [M+H]。 實例1-17 (4-(2,2,2-三氟乙基）苯基）甲胺Intermediate 16 Add zinc cyanide to a solution of 1-bromo-4-(2,2,2-Iethyl) stupid (2.15 9.00 mmol) 140374.doc -42· 201000446 DMF (25 mL) (2·11 g, i8. 〇mmol), followed by the addition of Pd(PPh3)4 (〇.828 g, 0.720 mmol). The mixture was heated at i.degree. C. for 18 h then cooled to rt, diluted with ethyl acetate (5 EtOAc) and filtered over EtOAc. The filtrate was concentrated under reduced pressure. The title compound was obtained as a white solid, mp EtOAc (EtOAc/EtOAc) NMR (400 MHz, CDC13) δ (ppm) 7.67 (d, 2 Η) 7.43 (d, 2 Η) 3·44 (q, 2 H). 19F NMR (400 MHz, CDC13) δ (ppm) -65.85, -65.88 and -65.91. MS (ESI) m/z 186 [M+H]. Example 1-17 (4-(2,2,2-trifluoroethyl)phenyl)methanamine

將於四氫呋喃（9.40 mL ’ 9.40 mmol)中之1 μ硼烷添加至 4-(2,2,2-二氟乙基）苯甲腈（0.580 g，3_13 mmol)之四氫口夫 喃（15 mL)溶液中。將混合物在6〇t下加熱18小時，冷卻 至室溫且在減壓下濃縮。將殘餘物再溶解於甲醇（丨5 mL) 中，回流2小時且在減壓下濃縮。將粗殘餘物溶解於二氯 甲烷（50 mL)中，用 2 M NaOH 溶液（20 mL)、鹽水（20 mL) 洗滌，經無水硫酸鈉乾燥且過濾。在減壓下濃縮濾液以生 成呈淺黃色油狀之標題化合物，600 mg(； 100%；)。 H NMR (400 MHz, CDC13) δ (ppm) 7.27-7.34 (m, 4 H) 3.88 140374.doc -43- 201000446 (S，2 Η) 3.36 (q, 2H) (NH2 未展示）。19F NMR (400 MHz， CDC13) δ (ppm) -66.42、-66.45及-66.48。MS (ESI) m/z 190 [M+H] 〇 實例1-18 N-(4-(2,2,2-三氟乙基）苯甲基）甲醯胺Add 1 μ borane in tetrahydrofuran (9.40 mL ' 9.40 mmol) to 4-(2,2,2-difluoroethyl)benzonitrile (0.580 g, 3-13 mmol) of tetrahydrofuran (15) mL) in solution. The mixture was heated at 6 Torr for 18 hours, cooled to rt and concentrated under reduced pressure. The residue was redissolved in MeOH (5 mL) and evaporated. The crude residue was dissolved in EtOAc (EtOAc)EtOAc. The filtrate was concentrated under reduced pressure to give the title compound, m. H NMR (400 MHz, CDC13) δ (ppm) 7.27-7.34 (m, 4 H) 3.88 140374.doc -43- 201000446 (S, 2 Η) 3.36 (q, 2H) (NH2 not shown). 19F NMR (400 MHz, CDC13) δ (ppm) - 66.42, -66.45 and -66.48. MS (ESI) m/z 190 [M+H] 实例 Example 1-18 N-(4-(2,2,2-trifluoroethyl)benzyl)carbamide

中間物18 使（4-(2,2,2-三氟乙基）苯基）曱胺（0.650 g，3.40 mmol)於 甲酸乙酯（5 mL)中之溶液回流1 8小時。在減壓下濃縮反應 混合物且藉由矽膠管柱層析使用己烷：乙酸乙酯=1〇〇:〇至 50:50作為溶離劑來純化粗殘餘物以提供呈白色固體狀之 所需化合物，620 mg(84%)。 'H NMR (400 MHz, CDC13) δ (ppm) 8.30 (s, 1 H) 7.29 (s, 4 H) 5.77 (m，1 H) 4.51 (d，2 H) 3.36 (q，2 H)。19F NMR (400 MHz, CDC13) δ (ppm) -66.36、-66.39及-66.41。MS (ESI) m/z 2/S [M+H]。 實例1-19 1-異氰基曱基-4-(2,2,2-三氟乙基）苯Intermediate 18 A solution of (4-(2,2,2-trifluoroethyl)phenyl)decylamine (0.650 g, 3.40 mmol) in ethyl acetate (5 mL) The reaction mixture was concentrated under reduced pressure and purified EtOAc EtOAc EtOAc EtOAc , 620 mg (84%). 'H NMR (400 MHz, CDC13) δ (ppm) 8.30 (s, 1 H) 7.29 (s, 4 H) 5.77 (m, 1 H) 4.51 (d, 2 H) 3.36 (q, 2 H). 19F NMR (400 MHz, CDC13) δ (ppm) - 66.36, -66.39 and -66.4. MS (ESI) m/z 2/S [M+H]. Example 1-19 1-Isocyanodecyl-4-(2,2,2-trifluoroethyl)benzene

中間物19 在-20 C下將氧氯化磷（〇 32〇 mL，3 43 逐滴添加 至N-(4-(2,2,2-二氟乙基）苯曱基）曱醯胺（〇62〇吕，286 140374.doc -44 - 201000446 mmol)及 N，N-二異丙基乙胺（1.97 mL，11.4 mm〇1)於二氯甲 烧（20 mL)中之溶液中。將混合物缓慢溫至室溫且擾掉i6 小時。其後濃縮反應混合物，將殘餘物溶解於甲醇（3 mL) 中且添加三乙胺（2.5 mL)。將反應混合物攪拌5分鐘且在減 壓下濃縮。藉由矽膠管柱層析使用己烷：乙酸乙酯=1〇〇:〇 至8 0:2 0作為溶離劑來純化粗化合物，從而產生呈白色固 體狀之標題化合物，442 mg(78%)。 H NMR (400 MHz, CDC13) δ (ppm) 7.36 (s, 4 Η) 4.66 (s, 2 Η) 3.39 (q，2 H)。19F NMR (400 MHz, CDC13) δ (ppm) -66.31、-66.34及-66.37。MS (ESI) w/z 200 [M+H]。 實例1-20 3-側氧基-2-(四氫-211-哌味-4-基）異《弓丨嗓啉小甲酸乙酯 ο ΓIntermediate 19 Phosphorus oxychloride (〇32〇mL, 3 43 was added dropwise to N-(4-(2,2,2-difluoroethyl)phenyl) decylamine at -20 C ( 〇62〇吕, 286 140374.doc -44 - 201000446 mmol) and N,N-diisopropylethylamine (1.97 mL, 11.4 mm 〇1) in dichloromethane (20 mL). The mixture was slowly warmed to room temperature and was taken up for EtOAc. EtOAc (EtOAc) (EtOAc) Concentration. Purification of the crude compound by EtOAc EtOAc (EtOAc:EtOAc: %) H NMR (400 MHz, CDC13) δ (ppm) 7.36 (s, 4 Η) 4.66 (s, 2 Η) 3.39 (q, 2 H). 19F NMR (400 MHz, CDC13) δ (ppm) - 66.31, -66.34 and -66.37. MS (ESI) w/z 200 [M+H]. Example 1-20 3-Phenoxy-2-(tetrahydro-211-piped-4-yl) Porphyrin small ethyl formate ο Γ

根據關於中間物1所述之程序自乙腈（25 mL)中之2-(1-漠-2-乙氧基-2-側氧基乙基）苯曱酸乙酯（315 g，1〇〇 mmol)、三乙胺（2.23 mL，16·0 mm〇1)及4_胺基四氫哌喃 (1·52 mL ’ 15.0 mmol)製備標題化合物以生成白色固體， 2.35 g(81%)。 H NMR (400 MHz, CD3〇D) δ (ppm) 7.76-7.81 (m, 1 H) 7.61-7.68 (m, 2 H) 7.54-7.60 (m? j H) 5.51 (s, 1 H) 4.22- 4.33 (m，2 H) 4.13-4.22 (m, i h) 3.98.4.06 (m，2 H) 3.47- 140374.doc -45· 201000446 3.57 (m, 2 Η) 1.96-2.18 (m, 2 Η) 1.86-1.94 (m, 2 Η) i 3〇 (t 3 H)。MS (ESI) m/z 290 [M+H]。 實例1-21 3-側氧基-2-(四氫-2H-哌喃-4-基）異吲哚啉曱酸Ethyl 2-(1-indol-2-ethoxy-2-oxoethyl)benzoate (acetonitrile) ( 315 g, 1 〇〇) from acetonitrile (25 mL) The title compound was prepared as a white solid, m., m, m,j,j,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj H NMR (400 MHz, CD3〇D) δ (ppm) 7.76-7.81 (m, 1 H) 7.61-7.68 (m, 2 H) 7.54-7.60 (m? j H) 5.51 (s, 1 H) 4.22- 4.33 (m,2 H) 4.13-4.22 (m, ih) 3.98.4.06 (m,2 H) 3.47- 140374.doc -45· 201000446 3.57 (m, 2 Η) 1.96-2.18 (m, 2 Η) 1.86 -1.94 (m, 2 Η) i 3〇(t 3 H). MS (ESI) m/z 290 [M+H]. Example 1-121 3-Phenoxy-2-(tetrahydro-2H-piperidin-4-yl)isoindoline citric acid

根據關於中間物2所述之程序由3_側氧基_2_(四氫_2仏哌 喃-4-基）異吲哚啉-1·曱酸乙酯（1 45 g，5 〇〇 〇1111〇1)與2 μ NaOH(5-0 mL· ’ 10,0 mmol)在甲醇（15 mL)中之反應合成榡 題化合物以生成白色固體，0.97 g(75%)。 ]H NMR (400 MHz, DMSO-^6) δ (ppm) 13.59 (br. s., 1 H) 7.68-7.72 (m，1 H) 7.58-7.67 (m, 2 H) 7.51-7.57 (m，1 H) 5.44 (s, 1 H) 4.00-4.10 (m) i h) 3.87-3.95 (m, 2 H) 3.35-According to the procedure described for Intermediate 2, 3-ethyloxy-2-(tetrahydro-2-indole-4-yl)isoindoline-1·ethyl decanoate (1 45 g, 5 〇〇〇) 1111 〇 1) The title compound was synthesized by reaction with 2 μl of NaOH (5-0 mL· '10,0 mmol) in MeOH (15 mL) to yield white solid (0.97 g (75%). ]H NMR (400 MHz, DMSO-^6) δ (ppm) 13.59 (br. s., 1 H) 7.68-7.72 (m,1 H) 7.58-7.67 (m, 2 H) 7.51-7.57 (m, 1 H) 5.44 (s, 1 H) 4.00-4.10 (m) ih) 3.87-3.95 (m, 2 H) 3.35-

3.43 (m，2 Η) 1.85-2.04 (m，2 H) 1.76-1.85 (m, 2 H)。MS (ESI) w/z 262 [M+H]。 實例1-22 2-(2-乙氧基-2-側氧基乙基）_6•(甲氧基甲氧基）苯甲酸乙酯3.43 (m, 2 Η) 1.85-2.04 (m, 2 H) 1.76-1.85 (m, 2 H). MS (ESI) w/z 262 [M+H]. Example 1-22 2-(2-Ethoxy-2-oxoethyl)-6•(methoxymethoxy)benzoic acid ethyl ester

^ 〇 0 /。 中間物22 H0374.doc -46- 201000446 在室溫下’將氯（曱氧基）甲烷（3.47 g，43.21 mmol)添力口 至2-(2-乙氧基-2-側氧基乙基）_6-羥基苯甲酸乙酯（7.8 g， 30.86 mmol ’ 根據 如/ 〇f the Chemical Society,^ 〇 0 /. Intermediate 22 H0374.doc -46- 201000446 Add chlorine (methoxy)methane (3.47 g, 43.21 mmol) to 2-(2-ethoxy-2-oxoethyl) at room temperature ) _6-hydroxybenzoic acid ethyl ester (7.8 g, 30.86 mmol' according to / 〇f the Chemical Society,

Chemical Communications 1977，77, 5 名2 繁備）反Ν,Ν-二異 丙基乙胺（8_0 mL，45.94 mmol)於無水二氯甲烷（50 mL)中 之攪拌溶液中。將反應混合物攪拌3小時，用二氣曱烷（5〇 ' mL)稀釋且隨後用水（20 mL)中止反應。分離各相，將有機 厂、 層用鹽水洗滌，經無水硫酸鈉乾燥，過濾且在真空中濃 縮。藉由矽膠管柱層析使用己烷：乙酸乙酯=9〇:〗〇作為溶 離劑來純化粗產物以生成所需產物，7.29 g(79.7%)。 !H NMR (400 MHz, CDC13) δ (ppm) 7.30 (t, 1 Η) 7.09 (d, 1 Η) 6.95 (d, 1 Η) 5.18 (s, 2 Η) 4.38 (q, 2 Η) 4.14 (q, 2 Η)Chemical Communications 1977, 77, 5 (2) ruthenium, a solution of hydrazine-diisopropylethylamine (8_0 mL, 45.94 mmol) in anhydrous dichloromethane (50 mL). The reaction mixture was stirred for 3 hours, diluted with dioxane (5 〇 'mL) and then quenched with water (20 mL). The phases were separated, the organics and layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by hydrazine gel column chromatography using hexane: ethyl acetate = 9 </ RTI> </ RTI> </ RTI> to afford the desired product, 7.29 g (79.7%). !H NMR (400 MHz, CDC13) δ (ppm) 7.30 (t, 1 Η) 7.09 (d, 1 Η) 6.95 (d, 1 Η) 5.18 (s, 2 Η) 4.38 (q, 2 Η) 4.14 ( q, 2 Η)

3.66 (s，2 Η) 3.48 (s，3 Η) 1.37 (t，3 Η) 1.24 (t，3 H)。MS (ESI) w/z 297[M+H]。 實例1-23 ◎ 2-(1-溴-2-乙氧基-2-側氧基乙基）_6-(甲氧基甲氧基）苯甲酸 乙醋3.66 (s, 2 Η) 3.48 (s, 3 Η) 1.37 (t, 3 Η) 1.24 (t, 3 H). MS (ESI) w/z 297 [M+H]. Example 1-23 ◎ 2-(1-Bromo-2-ethoxy-2-oxoethyl)-6-(methoxymethoxy)benzoic acid Ethyl vinegar

中間物23 將 N-溴丁 二醯胺（6.2 g ’ 31.47 mmol)及2,2，-偶氮雙（2_ 甲 基丙腈）（1.1 g)依次添加至2-(2-乙氧基-2-側氧基乙基 140374.doc •47· 201000446 (甲氧基甲氧基）笨曱酸乙酯（6·〇 g，20·24 mm〇1)於四氯化 碳（100 ml)中之溶液中。使反應混合物回流15小時，隨後 冷卻至室溫’過濾且在減壓下濃縮。藉由矽膠管柱層析藉 由使用己烧：乙酸乙醋=100:0至95:5作為梯度來純化粗殘 餘物，從而產生所需產物，4.6 g(79°/〇)。 JH NMR (400 MHz, CDC13) δ (ppm) 7.44-7.53 (m, 1 Η) 7 38 (t, 1 Η) 7.15 (d, 1 Η) 5.49 (s, 1 Η) 5.19 (s, 2 Η) 4.44 (q, 2 Η) 4.16-4.36 (m, 2 Η) 3.48 (s, 3 Η) 1.40 (t, 3 Η) 1 27 (t 3 H)。MS (ESI) m/z 376 [M+H]。 實例1-24 4-(甲氧基甲氧基）-3-側氧基-2-(四氫- 2H-娘喃_4_基）異11弓丨吟 啉-1-甲酸乙酯Intermediate 23 N-bromobutaneamine (6.2 g '31.47 mmol) and 2,2,-azobis(2-methylpropionitrile) (1.1 g) were added sequentially to 2-(2-ethoxy- 2-sided oxyethyl 140374.doc •47· 201000446 (methoxymethoxy)ethyl decanoate (6·〇g, 20·24 mm〇1) in carbon tetrachloride (100 ml) The reaction mixture was refluxed for 15 hours, then cooled to room temperature 'filtered and concentrated under reduced pressure. by column chromatography by using hexane: ethyl acetate = 100:0 to 95:5 Gradient to purify the crude residue to give the desired product, 4.6 g (79° / 〇). JH NMR (400 MHz, CDC13) δ (ppm) 7.44-7.53 (m, 1 Η) 7 38 (t, 1 Η 7.15 (d, 1 Η) 5.49 (s, 1 Η) 5.19 (s, 2 Η) 4.44 (q, 2 Η) 4.16-4.36 (m, 2 Η) 3.48 (s, 3 Η) 1.40 (t, 3 Η) 1 27 (t 3 H). MS (ESI) m/z 376 [M+H]. Example 1-24 4-(methoxymethoxy) - 2H-Nymidine_4_yl)iso 11 oxoline-1-carboxylate

根據關於中間物1所述之程序自乙腈（20 mL)中之2_(1_ 溴-2-乙氧基-2-側氧基乙基）-6-(曱氧基甲氧基）苯曱酸乙酯 (1_4 g，3.73 mmol)、4-胺基四氫哌喃376 经，3 72 mmol)及三乙胺（1.03 mL ’ 7.43 mmol)製備標題化合物。固 體，900 mg(69%) ° ]H NMR (400 MHz, CDC13) δ (ppm) 7.46 (t, 1 H) 7.21 (d i H) 7.15 (d, 1 H) 5.36 (s, 2 H) 5.12 (s5 1 H) 4.13-4.40 (m,' 140374.doc •48- 201000446 Η) 3.94-4.12 (m, 2 Η) 3.40-3.63 (m, 5 Η) 1.75-2.02 (m, 4 Η) 1_29 (t，3 Η)。Ms (ESI) w/z 35〇 [Μ+Η]。 實例1-25 4-(甲氧基甲氧基侧氧基_2_(四氳_2Η哌喃_4基）異吲哚 啉-1-甲酸2-(1_Bromo-2-ethoxy-2-oxoethyl)-6-(decyloxymethoxy)benzoic acid in acetonitrile (20 mL) according to the procedure described for Intermediate 1 The title compound was prepared from EtOAc (EtOAc m. Solid, 900 mg (69%) ° ]H NMR (400 MHz, CDC13) δ (ppm) 7.46 (t, 1 H) 7.21 (di H) 7.15 (d, 1 H) 5.36 (s, 2 H) 5.12 ( S5 1 H) 4.13-4.40 (m,' 140374.doc •48- 201000446 Η) 3.94-4.12 (m, 2 Η) 3.40-3.63 (m, 5 Η) 1.75-2.02 (m, 4 Η) 1_29 (t , 3 Η). Ms (ESI) w/z 35〇 [Μ+Η]. Example 1-25 4-(methoxymethoxy-oxo-oxy-2_(tetrahydro-2-indole-4-yl)isoindoline-1-carboxylic acid

在室溫下，將氫氧化鐘（0.113 g，4 72職〇1)於水（1叫 中之溶液添加至4_(甲氧基甲氧基）_3_側氧基_2_(四氫_2h_ 旅喃-4-基）異叫卜朵琳小甲酸乙醋（11 g，3i5匪叫於四氮 吱咕（5 mL)及甲醇（5 mL)中之授掉溶液中。將反應混合物 授拌3 j f &amp;後在冑$中濃、缩。將粗殘餘物溶解於水（1 〇 mL)中，用6 N 化，且用乙酸乙酯（3χ5〇 萃取。 將經組合之有機萃取物用鹽水（5〇 mL)洗務，、經無水硫酸 鈉乾燥，㉟渡且在減壓下濃縮以生成所需產物，8〇〇 mg(79%) 〇 ]H NMR (400 MHz, CDC13) δ (ppm) 7.46 (t, 1 H) 7 21 (d 1 H) 7.15 (d, 1 H) 5.36 (s, 2 H) 5.21 (s, 1 H) 4.13-4.40 (m, 3 H) 3.40-3.63 (m, 5 H) 1.75-2.02 (m, 4 H) 〇 Ms (ESI) w/z 322 [M+H]。 實例1-26 140374.doc -49- 201000446 2-(4,4-二氟環己基）_4•(甲氧基曱氧基）_3_側氧基異吲哚啉 1-甲酸乙酯 /〇At room temperature, the hydrazine clock (0.113 g, 4 72) 1 in water (1 solution was added to 4_(methoxymethoxy)_3_sideoxy_2_(tetrahydro-2h_)喃 -4- -4- ) 异 卜 卜 朵 朵 朵 朵 朵 朵 卜 卜 -4- -4- -4- ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 3 jf &amp;; then concentrated and reduced in 胄$. The crude residue was dissolved in water (1 mL), taken with 6 N and extracted with ethyl acetate (3 χ 5 。. Brine (5 〇 mL) was washed, dried over anhydrous sodium sulfate, EtOAc EtOAc (EtOAc m. Ppm) 7.46 (t, 1 H) 7 21 (d 1 H) 7.15 (d, 1 H) 5.36 (s, 2 H) 5.21 (s, 1 H) 4.13-4.40 (m, 3 H) 3.40-3.63 ( m, 5 H) 1.75-2.02 (m, 4 H) 〇Ms (ESI) w/z 322 [M+H]. Example 1-26 140374.doc -49- 201000446 2-(4,4-difluoro ring Hexyl)_4•(methoxy methoxy)_3_ pendant oxyisoindoline 1-carboxylate/〇

中間物26 根據關於中間物1所述之程序自乙腈（2〇 mL)中之2_(i _ 溴-2-乙氧基-2-側氧基乙基）-6-(曱氧基曱氧基）苯甲酸乙酯 (2.8 g，7.47 mmol)、4,4-二氟環己胺（1.35 g，1〇 〇 mm〇1) 及二乙胺（2.5 mL，1 8.0 mmol)製備標題化合物。固體， 1.67 g(58.60/〇)。 MS(ESI) m/z 384[M+H] ° 實例1-27 2-(4,4-二氟環己基）_4_(甲氧基甲氧基）_3_側氧基異吲哚啉_ 1-甲酸Intermediate 26 2-(i _ bromo-2-ethoxy-2-oxoethyl)-6-(methoxy oxime) in acetonitrile (2 mL) according to the procedure described for Intermediate 1 The title compound was prepared from ethyl benzoate (2.8 g, 7.47 mmol), 4,4-difluorocyclohexylamine (1.35 g, 1 〇〇mm 〇1) and diethylamine (2.5 mL, 1 8.0 mmol). Solid, 1.67 g (58.60 / 〇). MS (ESI) m / z 384 [M + H] ° Example 1-27 2-(4,4-difluorocyclohexyl)_4_(methoxymethoxy)_3_ pendant oxyisoporphyrin _ 1 -formic acid

根據關於實例25所述之方法使用於四氫呋喃/曱醇（5/5 mL)中之2-(4,4-二氟環己基）-4-(曱氧基甲氧基）_3_側氧基異 140374.doc -50- 201000446 吲哚啉-1-曱酸乙酯（650 mg，1_69 mmol)及於水（1 mL)中之 氫氧化鋰（81 mg，3 ·37 mmol)製備標題化合物。固體，35〇 mg(600/〇)。 MS (ESI) m/z 356 [M+H]。 實例1(通用程序1) 2-(D惡烧-4-基）-3-側氧基-N-[【4-(三氟甲氧基）苯基】甲基卜 1H-異吲哚-1-甲醢胺2-(4,4-Difluorocyclohexyl)-4-(decyloxymethoxy)_3_sideoxyl in tetrahydrofuran/nonanol (5/5 mL) according to the method described in Example 25. The title compound was prepared as the title compound (yield: EtOAc, EtOAc, EtOAc (EtOAc) Solid, 35 〇 mg (600/〇). MS (ESI) m/z 356 [M+H]. Example 1 (general procedure 1) 2-(Doxa-4-yl)-3-oxo-N-[[4-(trifluoromethoxy)phenyl]methyl b 1H-isoindole- 1-methylamine

向2 -甲酿基苯甲酸（45 mg’ 0.3 mmol)於甲醇（2 mL)中之溶 液中添加四虱-2H-0辰喃-4-胺（3 0 pL，0.3 0 mmol)，繼而添加 1-(異氰基甲基）-4-(三氟甲氧基）苯（57 mg，0.29 mmol)。將混 合物在環境溫度下擾拌隔夜’隨後將其過濾、且使用製備型液 相層析進行純化。彙集含產物之溶離份且在真空中移除乙 腈。用乙酸乙酯萃取水溶液。將有機層經硫酸鎂乾燥且濃縮 以生成呈白色固體狀之標題化合物，78 mg(60%)。 H NMR (400 MHz, DMSO-c?6) δ ppm 9.12-9.19 (m, 1 Η) 7 67-7.72 (m, 1 Η), 7.57-7.62 (m, 1 Η), 7.51-7.55 (m, 1 Η), 7.46-7.51 (m, 1 Η), 7.30-7.41 (m, 4 Η), 5.32 (s, 1 Η), 4.34 (d, 2 Η), 4.06-4.17 (m, 1 Η), 3.86-3.92 (m, 1 Η), 3.77-3.84 (m, 1 Η), 3.33-3.41 (m, 2 Η), 1.77-1.91 (m, 1 Η), 1.63-1.73 (m, 3 Η) ; MS (ESI) m/z 435 [M+H]，MS (ESI) m/z 433 [M-H]。 -51 - 140374.doc 201000446 實例2 2-(噁烷-4-基）_3_側氧基_N_[[4_(三氟甲氧基）苯基]曱基卜 1H-異吲哚4·曱醯胺，異構物2To a solution of 2-methyl-bromobenzoic acid (45 mg of 0.3 mmol) in methanol (2 mL) was added tetras--2H-0-c-butyl-4-amine (3 0 pL, 0.30 mmol), followed by addition 1-(Isocyanomethyl)-4-(trifluoromethoxy)benzene (57 mg, 0.29 mmol). The mixture was scrambled overnight at ambient temperature&apos; then it was filtered and purified using preparative liquid chromatography. The product-containing fractions were pooled and the acetonitrile was removed in vacuo. The aqueous solution was extracted with ethyl acetate. The organic layer was dried (MgSO4) H NMR (400 MHz, DMSO-c?6) δ ppm 9.12-9.19 (m, 1 Η) 7 67-7.72 (m, 1 Η), 7.57-7.62 (m, 1 Η), 7.51-7.55 (m, 1 Η), 7.46-7.51 (m, 1 Η), 7.30-7.41 (m, 4 Η), 5.32 (s, 1 Η), 4.34 (d, 2 Η), 4.06-4.17 (m, 1 Η), 3.86-3.92 (m, 1 Η), 3.77-3.84 (m, 1 Η), 3.33-3.41 (m, 2 Η), 1.77-1.91 (m, 1 Η), 1.63-1.73 (m, 3 Η); MS (ESI) m/z 435 [M+H], MS (ESI) -51 - 140374.doc 201000446 Example 2 2-(oxo-4-yl)_3_sideoxy_N_[[4_(trifluoromethoxy)phenyl]indolyl 1H-isoindole 4·曱Indoleamine, isomer 2

異構物2 b=未知絕對構型Isomer 2 b = unknown absolute configuration

由使用 SFC Berger Multigram II 系統（管枝· 21.2x250 mm ’ 10 _ ;移動相：％ 乙醇 /I 藉 AD ， CO〆流動速率：50 mL/min，約15 mg/inj)對掌性分離外 消旋化合物2-(噁烷-4-基）-3-側氧基_N_[[4_(三氟甲氧基）苯 基]甲基]-1Η-異吲哚-1-甲醯胺而獲得對映異構純化合物。 根據滯留時間收集溶離份，從而產生作為第二溶離份之異 構物2。將溶離份在23-25°C下蒸發以避免熱致外消旋且分 別處理。使用 Berger SFC Analytix(管柱：（：^1^11^八0-H , 4.6x250 mm，5 μιη ;移動相：25°/〇 乙醇/75% C02 ;流 動速率：2 11^/111丨11)來進行分析型1^分析；異構物2(6.20 min) ’ 26 mg ’對映異構純度：99%。 4 NMR (400 MHz，DMSO-c/6) δ ppm 9·15 (t，1 H), 7.69 (d, 1 Η), 7.60 (td, 1 Η), 7.46-7.55 (m, 2 Η), 7.35-7.41 (m, 2 Η), 7,30-7.35 (m, 2 Η), 5_32 (s，1 η), 4.34 (d, 2 Η), 4.06-4.16 (m, 1 H), 3.89 (dd, 1 H), 3.76-3.84 (m, 1 H), 3.33-3.40 (m, 140374.doc -52. 201000446 2 H)? 1.78-1.90 (m, 1 H), 1.64-1.73 (m, 3 H) ； MS (ESI) m/z 435[Μ+Η], MS (ESI) w/z 433 [M-H]。 實例3(通用程序2) 2-(4,4-二氟環己基）-3-側氧基-N-[4-(三氟甲氧基）苯甲基】異 β弓丨嘴淋-1-甲酿胺Separation of palmarity by SFC Berger Multigram II system (tube branch · 21.2x250 mm ' 10 _ ; mobile phase: % ethanol / I by AD, CO〆 flow rate: 50 mL/min, approx. 15 mg/inj) Obtaining the compound 2-(oxo-4-yl)-3-oxooxy_N_[[4-(trifluoromethoxy)phenyl]methyl]-1Η-isoindole-1-carboxamide Enantiomerically pure compound. The dissolved fraction is collected according to the residence time to produce the isomer 2 as the second dissolved component. The dissolved fractions were evaporated at 23-25 ° C to avoid thermal racemization and separate treatment. Use Berger SFC Analytix (column: (:^1^11^8-H, 4.6x250 mm, 5 μιη; mobile phase: 25°/〇 ethanol/75% C02; flow rate: 2 11^/111丨11 Analytical type 1 analysis; isomer 2 (6.20 min) '26 mg' enantiomeric purity: 99%. 4 NMR (400 MHz, DMSO-c/6) δ ppm 9·15 (t, 1 H), 7.69 (d, 1 Η), 7.60 (td, 1 Η), 7.46-7.55 (m, 2 Η), 7.35-7.41 (m, 2 Η), 7,30-7.35 (m, 2 Η ), 5_32 (s,1 η), 4.34 (d, 2 Η), 4.06-4.16 (m, 1 H), 3.89 (dd, 1 H), 3.76-3.84 (m, 1 H), 3.33-3.40 ( m, 140374.doc -52. 201000446 2 H)? 1.78-1.90 (m, 1 H), 1.64-1.73 (m, 3 H) ; MS (ESI) m/z 435[Μ+Η], MS (ESI ) w/z 433 [MH]. Example 3 (general procedure 2) 2-(4,4-difluorocyclohexyl)-3-oxo-N-[4-(trifluoromethoxy)benzyl 】iso-β 丨 淋 -1- -1- 酿 胺

在氬氣氣氛下向2-(4,4-二氟環己基）-3-側氧基異吲哚琳_ 1-曱酸（74 mg ’ 0.2 5 mmol)於DMF(2 mL)中之溶液中依次 添加三乙胺（139 μί’ 1·〇〇 mmol)及六氟磷酸氟-Ν,Ν,Ν',Ν'- 四甲基甲脎鑌（99 mg ’ 〇·38 mmol)。將反應混合物在環境 溫度下攪拌2分鐘。添加（4-(三氟甲氧基）苯基）甲胺（96 gL，0·50 mmol) ’且將反應混合物在45t下攪拌隔夜。將 混合物過濾且使用製備型液相層析進行純化。彙集含產物 之浴離份且在真空中移除乙腈。用碳酸氫鈉之飽和溶液使 水溶液鹼化且用乙酸乙酯萃取。 將有機層用鹽水洗滌，經A solution of 2-(4,4-difluorocyclohexyl)-3-oxo-iso-indolyl-1-pyruic acid (74 mg '0.25 mmol) in DMF (2 mL) under argon Triethylamine (139 μί'1·〇〇mmol) and fluoro-fluorophosphonium hexafluorophosphate, Ν, Ν', Ν'-tetramethylformamidine (99 mg '〇·38 mmol) were added in this order. The reaction mixture was stirred at ambient temperature for 2 minutes. (4-(Trifluoromethoxy)phenyl)methanamine (96 g, 0.50 mmol) was added and the mixture was stirred overnight at 45t. The mixture was filtered and purified using preparative liquid chromatography. The bath containing the product was pooled and the acetonitrile was removed in vacuo. The aqueous solution was basified with a saturated solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was washed with brine and passed through

合物，8 mg(7%)。Compound, 8 mg (7%).

H), 5.12 (s, 1 H), 4.45 (dd, 5.12 (s，1 Η), 4.45 (dd，1 H)，4.29 (dd, 1 Η), 4.14-4.26 140374.doc 53 - 201000446 (m, 1 Η), 2.04-2.23 (m, 2 Η), 1.72-1.97 (m, 6 Η) ； MS (ESI) m/z 467 [M-H] 〇 實例4 2-(4,4-二氟環己基）_3·側氧基三氟甲氧基）苯甲基】異 吲哚啉-1-甲醯胺，異構物2H), 5.12 (s, 1 H), 4.45 (dd, 5.12 (s,1 Η), 4.45 (dd,1 H), 4.29 (dd, 1 Η), 4.14-4.26 140374.doc 53 - 201000446 (m , 1 Η), 2.04-2.23 (m, 2 Η), 1.72-1.97 (m, 6 Η); MS (ESI) m/z 467 [MH] 〇 Example 4 2-(4,4-difluorocyclohexyl )_3·Sideoxytrifluoromethoxy)benzyl]isoindoline-1-carboxamide, isomer 2

異構物2 b=未知絕對構型 藉由使用 SFC Berger Muhigram II 系統（管柱：Chiralpak AD 21·2χ250 mm ;移動相：25〇/〇 乙醇/75% c〇2 ;流動速 率：50 ml/min，4〇 mg/90〇 注射）對掌性分離外消旋化 s物2-(4,4-二氟環己基）_3_側氧基_ν_[4_(三氟甲氧基）苯甲 基]異吲哚啉-1_甲醯胺而獲得對映異構純化合物。根據滯 留％間收集溶離份，從而產生在3 .丨〇 min時溶離之異構物2 作為第二溶離份。將溶離份分別在23_25。〇下蒸發以避免 熱致外消旋。用 SFC Berger Analytix(管柱：Chiralpak AD ’ 4.6x250 mm ’ 5 μιη ;移動相：30% 乙醇/70% C02 ; 流動速率：2 1111/11^11)進行分析型1^(：分析；異構物2(2.93 min)，117 mg ’對映異構純度：99〇/。。 ]H NMR (400 MHz, DMSO-J6) δ ppm 9.18 (t, 1 Η), 7.69 (d, 1 Η), 7.60 (td, 1 Η), 7.52 (t, 1 Η), 7.45-7.49 (m, 1 Η), 7.36- 140374.doc -54- 201000446 7.41 (m, 2 Η), 7.30-7.35 (m, 2 Η), 5.31 (s, 1 Η), 4.27-4.41 (m, 2 Η), 4.00-4.11 (m, 1 Η), 1.78-2.10 (m, 7 Η), 1.61-1.76 (m, 1 Η) ； MS (ESI) m/z 469 [M+H], MS (ESI) m/z 467 [M-H]。 實例5 3-側氧基-2-[[(2S)-氧雜環戊-2·基]曱基】-N-[[4-(三氟甲氧 基）苯基]甲基]-1Η-異吲哚-1-甲醯胺Isomer 2 b = unknown absolute configuration by using the SFC Berger Muhigram II system (column: Chiralpak AD 21·2 χ 250 mm; mobile phase: 25 〇 / 〇 ethanol / 75% c 〇 2; flow rate: 50 ml / Min, 4〇mg/90〇 injection) for the separation of racemic s species 2-(4,4-difluorocyclohexyl)_3_sideoxy_ν_[4_(trifluoromethoxy)benzene The enantiomerically pure compound is obtained by iso-oxaline-1_carbamide. The dissolved fraction was collected according to % retention, thereby producing isomer 2 which was dissolved at 3. 丨〇 min as the second dissolved fraction. The dissolved fractions were respectively at 23-25. Evaporate under the arm to avoid thermal racemization. Analytical type 1 (: analysis; isomerization) with SFC Berger Analytix (column: Chiralpak AD ' 4.6x250 mm ' 5 μιη ; mobile phase: 30% ethanol / 70% C02 ; flow rate: 2 1111/11^11) 2 (2.93 min), 117 mg 'enantiomeric purity: 99 〇 / . . . H NMR (400 MHz, DMSO-J6) δ ppm 9.18 (t, 1 Η), 7.69 (d, 1 Η), 7.60 (td, 1 Η), 7.52 (t, 1 Η), 7.45-7.49 (m, 1 Η), 7.36- 140374.doc -54- 201000446 7.41 (m, 2 Η), 7.30-7.35 (m, 2 Η), 5.31 (s, 1 Η), 4.27-4.41 (m, 2 Η), 4.00-4.11 (m, 1 Η), 1.78-2.10 (m, 7 Η), 1.61-1.76 (m, 1 Η) MS (ESI) m/z 469 [M+H], MS (ESI) m/z 467 [MH]. N]]-N-[[4-(trifluoromethoxy)phenyl]methyl]-1Η-isoindole-1-carboxamide

根據實例1中所述之通用程序1自2-甲醯基苯甲酸（38 mg ’ 0.25 mmol)、（*S)-l-(四氫-咬喃-2-基）-曱基胺（27 pL， 0.25 mmol)及1-(異氰基甲基）-4-(三氟曱氧基）苯（50 mg， 0.25 mmol)合成標題化合物。白色固體，63 mg(59%；)。 ]H NMR (400 MHz, DMSO-J6) δ ppm 9.18-9.25 (m, 1 Η), 7.69-7.73 (m, 1 Η), 7.59-7.64 (m, 1 Η), 7.54-7.58 (m, 1 Η), 7.50-7.54 (m, 1 Η), 7.36-7.41 (m, 2 Η), 7.30-7.35 (m, 2 Η), 5.42 (d, 1 Η), 4.29-4.43 (m, 2 Η), 3.91-4.07 (m, 2 Η), 3.68- 3.76 (m, 1 Η), 3.54-3.67 (m, 1 Η), 2.81-3.16 (m, 1 Η), 1.84- 2.02 (m, 1 Η), 1.71-1.84 (m, 2 Η), 1.45-1.59 (m, 1 Η) ； MS (ESI) m/z 435 [M+H]，MS (ESI) m/z 433 [M-H]。 實例6 140374.doc -55- 201000446 N-[l-(4-氣苯基）乙基】-3-側氧基-2-[[(2S)-氧雜環戊_2-基]甲 基】-1H·異吲哚-1-甲醯胺General procedure 1 as described in Example 1 from 2-methylmercaptobenzoic acid (38 mg '0.25 mmol), (*S)-l-(tetrahydro-benzo-2-yl)-decylamine (27) The title compound was synthesized from EtOAc (EtOAc m. White solid, 63 mg (59%;). ]H NMR (400 MHz, DMSO-J6) δ ppm 9.18-9.25 (m, 1 Η), 7.69-7.73 (m, 1 Η), 7.59-7.64 (m, 1 Η), 7.54-7.58 (m, 1 Η), 7.50-7.54 (m, 1 Η), 7.36-7.41 (m, 2 Η), 7.30-7.35 (m, 2 Η), 5.42 (d, 1 Η), 4.29-4.43 (m, 2 Η) , 3.91-4.07 (m, 2 Η), 3.68- 3.76 (m, 1 Η), 3.54-3.67 (m, 1 Η), 2.81-3.16 (m, 1 Η), 1.84- 2.02 (m, 1 Η) , 1.71-1.84 (m, 2 Η), 1.45-1.59 (m, 1 Η); MS (ESI) m/z 435 [M+H], MS (ESI) m/z 433 [MH]. Example 6 140374.doc -55- 201000446 N-[l-(4-Phenylphenyl)ethyl]-3-indolyl-2-[[(2S)-oxe-2-yl]methyl 】-1H·isoindole-1-carboxamide

根據實例1中所述之通用程序1自2-曱醯基苯曱酸（3〇 mg ’ 0·20 mmol)、（5)-1-(四氫-呋喃-2-基）-甲基胺（21 pL， 0.20 mmol)及 1-氣- 4-(1-異鼠基乙基）苯（33 mg，0.20 mmol) 合成標題化合物。白色固體，47 mgi59%)。 ]H NMR (400 MHz, DMSO-〇f6) δ ppm 9.13-9.25 (m, 1 Η), 7.64-7.74 (m, 1 Η), 7.46-7.64 (m, 3 Η), 7.33-7.42 (m, 4 Η), 5.32-5.52 (m, 1 Η), 4.86-4.99 (m, 1 Η), 3.85-4.13 (m, 2 Η), 3.55-3.83 (m, 2 Η), 2.69-3.19 (m, 1 Η), 1.70-2.05 (m, 3 Η), 1.45-1.61 (m, 1 Η), 1.41 (d, 3 Η) ； MS (ESI) m/z 499 [M+H]。 實例7 3-側氧基-2-[[(2R)_氧雜環戊_2-基]甲基]三氟甲氧 基）苯基]曱基]-1H-異吲哚-1-曱醯胺General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (3 〇 mg '0·20 mmol), (5)-1-(tetrahydro-furan-2-yl)-methylamine (21 pL, 0.20 mmol) and 1-m- 4-(1-iso-l-ethyl)benzene (33 mg, 0.20 mmol) White solid, 47 mg i 59%). ]H NMR (400 MHz, DMSO-〇f6) δ ppm 9.13-9.25 (m, 1 Η), 7.64-7.74 (m, 1 Η), 7.46-7.64 (m, 3 Η), 7.33-7.42 (m, 4 Η), 5.32-5.52 (m, 1 Η), 4.86-4.99 (m, 1 Η), 3.85-4.13 (m, 2 Η), 3.55-3.83 (m, 2 Η), 2.69-3.19 (m, 1 Η), 1.70-2.05 (m, 3 Η), 1.45-1.61 (m, 1 Η), 1.41 (d, 3 Η); MS (ESI) m/z 499 [M+H]. Example 7 3-Phenoxy-2-[[(2R)-oxe-2-yl]methyl]trifluoromethoxy)phenyl]indolyl]-1H-isoindole-1-indole Guanamine

140374.doc -56- 201000446 根據實例1中所述之通用程序1自2-曱酿基苯甲酸（38 mg，0.25 mmol)、（幻-1-(四氫-呋喃-2_基）_甲基胺（27 μ]：， 0.25 mmol)及1-(異氰基曱基）-4-(三氟曱氧基）苯（5〇 mg， 0_25 mmol)合成標題化合物。白色固體，58 mg(53%)。 NMR (400 MHz, DMSO-i/g) δ ppm 9.17-9.25 (m, 1 Η), 7.71 (d, 1 Η), 7.59-7.65 (m, 1 Η), 7.50-7.58 (m, 2 Η), 7.36-7.41 (m, 2 Η), 7.30-7.36 (m, 2 Η), 5.42 (d, 1 Η), 4.29-4.44 (m, 2 Η), 3.99-4.06 (m, 1 Η), 3.91-3.99 (m, 1 Η), 3.68-3.76 (m, 1 Η), 3.54-3.66 (m, 1H), 2.82-3.18 (m, 1 H), 1.84-2.03 (m, 1 H), 1.71-1.84 (m, 2 H), 1.45-1.59 (m, 1 H) ； MS (ESI) m/z 435 [M+H]，MS (ESI) m/z 433 [M-H]。 實例8 N-[l-(4-氣苯基）乙基】-2-(噁烷-4-基）-3-側氧基-1H-異吲哚-1-甲醯胺140374.doc -56- 201000446 according to the general procedure 1 described in Example 1 from 2-branched benzoic acid (38 mg, 0.25 mmol), (phantom-1-(tetrahydro-furan-2-yl)- Synthesis of the title compound <RTI ID=0.0># </RTI> </RTI> </RTI> <RTIgt; 53%) NMR (400 MHz, DMSO-i/g) δ ppm 9.17-9.25 (m, 1 Η), 7.71 (d, 1 Η), 7.59-7.65 (m, 1 Η), 7.50-7.58 (m , 2 Η), 7.36-7.41 (m, 2 Η), 7.30-7.36 (m, 2 Η), 5.42 (d, 1 Η), 4.29-4.44 (m, 2 Η), 3.99-4.06 (m, 1 Η), 3.91-3.99 (m, 1 Η), 3.68-3.76 (m, 1 Η), 3.54-3.66 (m, 1H), 2.82-3.18 (m, 1 H), 1.84-2.03 (m, 1 H ), 1.71-1.84 (m, 2 H), 1.45-1.59 (m, 1 H); MS (ESI) m/z 435 [M+H], MS (ESI) m/z 433 [MH]. N-[l-(4-Phenylphenyl)ethyl]-2-(oxo-4-yl)-3-oxo-1H-isoindole-1-carboxamide

根據實例1中所述之通用程序1自2-曱醯基苯甲酸（45 mg，0.3 mmol)、四氫-2Η-π底喃-4-胺（30 pL，0.30 mmol)及 1-氯-4-(1-異氰基乙基）苯（47 mg，0.29 mmol)合成標題化 合物。白色固體，40 mg(33%)。 !H NMR (400 MHz, CDC13) δ ppm 7.75-7.82 (m, 1 H), 7.46- 140374.doc •57· 201000446 7.65 (m, 3 Η), 7.29-7.34, 7.06-7.13 (m+m, 2 Η), 7.20-7.25, 6.72-6.79 (m+m , 2 Η), 6.00, 5.94 (d+d, 1 Η), 5.11, 5.05 (s + s, 1H), 4.99-5.12 (m, 1 H), 4.39-4.49, 4.17-4.28 (m+m, 1 H), 4.03-4.12, 3.99, 3.86 (m+dd+dd, 2 H), 3.53, 3.30-3.46 (td+m, 2 H), 1.44-2.04 (m, 4 H), 1.41, 1.29 (d+d, 3 H) ； MS (ESI) m/z 399 [M+H]，MS (ESI) m/z 397 [M-H]。 實例9 3 -側氧基- 2- [2-(2 -側氧基°比洛咬-1-基）乙基】- N-【[4-(三氟甲 氧基）苯基]曱基]-1Η-異吲哚-1-曱醯胺General Procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (45 mg, 0.3 mmol), tetrahydro-2 Η-π-propan-4-amine (30 pL, 0.30 mmol) and 1-chloro- 4-(1-Isocyanoethyl)benzene (47 mg, 0.29 mmol). White solid, 40 mg (33%). !H NMR (400 MHz, CDC13) δ ppm 7.75-7.82 (m, 1 H), 7.46- 140374.doc •57· 201000446 7.65 (m, 3 Η), 7.29-7.34, 7.06-7.13 (m+m, 2 Η), 7.20-7.25, 6.72-6.79 (m+m , 2 Η), 6.00, 5.94 (d+d, 1 Η), 5.11, 5.05 (s + s, 1H), 4.99-5.12 (m, 1 H), 4.39-4.49, 4.17-4.28 (m+m, 1 H), 4.03-4.12, 3.99, 3.86 (m+dd+dd, 2 H), 3.53, 3.30-3.46 (td+m, 2 H) , 1.44-2.04 (m, 4 H), 1.41, 1.29 (d+d, 3H); MS (ESI) m/z 399 [M+H], MS (ESI) m/z 397 [MH]. Example 9 3 -Sideoxy-2 - [2-(2-o-oxyl-pyridyl-1-yl)ethyl]-N-[[4-(trifluoromethoxy)phenyl]indolyl ]-1Η-isoindol-1-amine

根據實例1中所述之通用程序1自2-曱醯基苯甲酸（45 mg，0.3 0 mmol)、1-(2-胺基乙基）吡咯啶-2-酮（38 pL，0.30 mmol)及1-(異氰基甲基）-4-(三氟曱氧基）苯（60 pL，0.30 mmol)合成標題化合物。白色固體，71 mg(5 1〇/〇)。 NMR (400 MHz, DMSO-J6) δ ppm 9.27-9.33 (m, 1 Η), 7.66-7.72 (m, 1 Η), 7.58-7.63 (m, 1 Η), 7.49-7.57 (m, 1 Η), 7.35-7.41 (m, 2 Η), 7.29-7.34 (m, 2 Η), 5.36 (s, 1 Η), 4.30-4.42 (m, 2 Η), 4.06-4.16 (m, 1 Η), 3.61-3.70 (m, 1 Η), 3.44-3.53 (m, 1 Η), 3.15-3.31 (m, 2 Η), 3.00-3.08 (m, 1 Η), 2.08-2.16 (m, 1 Η), 1.93-2.03 (m, 1 Η), 1.79-1.90 (m, 2 Η) ; MS (ESI) m/z 462 [M+H]，MS (ESI) m/z 460 [M-H]。 140374.doc -58- 201000446 實例ίο 3_(1_側氧基-3-H4-(三氟甲氧基）苯甲基】胺甲醯基}-1，3-二 氣-2H-異⑸嗓_2_基）„丫丁咬小甲酸第三丁酯General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (45 mg, 0.30 mmol), 1-(2-aminoethyl)pyrrolidin-2-one (38 pL, 0.30 mmol) The title compound was synthesized from 1-(isocyanomethyl)-4-(trifluoromethoxy)benzene (60 pL, 0.30 mmol). White solid, 71 mg (5 1 〇/〇). NMR (400 MHz, DMSO-J6) δ ppm 9.27-9.33 (m, 1 Η), 7.66-7.72 (m, 1 Η), 7.58-7.63 (m, 1 Η), 7.49-7.57 (m, 1 Η) , 7.35-7.41 (m, 2 Η), 7.29-7.34 (m, 2 Η), 5.36 (s, 1 Η), 4.30-4.42 (m, 2 Η), 4.06-4.16 (m, 1 Η), 3.61 -3.70 (m, 1 Η), 3.44-3.53 (m, 1 Η), 3.15-3.31 (m, 2 Η), 3.00-3.08 (m, 1 Η), 2.08-2.16 (m, 1 Η), 1.93 -2.03 (m, 1 Η), 1.79-1.90 (m, 2 Η); MS (ESI) m/z 462 [M+H], MS (ESI) m/z 460 [MH]. 140374.doc -58- 201000446 Examples ίο 3_(1_Sideoxy-3-H4-(trifluoromethoxy)benzyl}amine-methylmethyl}-1,3-dialdehyde-2H-iso(5)嗓_2_基) „ 丫 丁 bite small butyrate

根據實例3中所述之通用程序2自。[卜（第三丁氧基羰基） 吖丁啶-3-基]-3-側氧基異吲哚啉_丨_甲酸（83 mg，0.25 mmol)及（4-(三氟甲氧基）苯基）甲胺（96 μΙν，0.50 mmol)製 備標題化合物。固體，9 mg(7%)。 H NMR (400 MHz, CDCl3-d6) δ ppm 7.64-7.68 (m, 1 Η), 7.56-7.63 (m, 2 Η), 7.45 (t, 1 Η), 7.09-7.16 (m, 4 Η), 6.46-6.53 (m, 1 Η), 5.29 (s, 1 Η), 4.85-4.95 (m, 1 Η), 4.41-4.48 (m, 1H), 4.31-4.38 (m, 1 H), 4.18-4.27 (m, 2 H), 4.08-4.17 (m, 2 H), 1.46 (s, 9 H) ; MS (ESI) w/z 506 [M+H]，MS (ESI) m/z 504 [M-H]。 實例11 2-[l-(2-糠醯基）哌啶-4-基卜3-側氧基-N-[4-(三氟甲氧基）苯 曱基】異吲哚啉-1-曱醯胺According to the general procedure 2 described in Example 3. [Bu (t-butoxycarbonyl) azetidin-3-yl]-3-oxo-iso-isoindoline 丨-carboxylic acid (83 mg, 0.25 mmol) and (4-(trifluoromethoxy) The title compound was prepared from phenyl)methanolamine (EtOAc (EtOAc) Solid, 9 mg (7%). H NMR (400 MHz, CDCl3-d6) δ ppm 7.64-7.68 (m, 1 Η), 7.56-7.63 (m, 2 Η), 7.45 (t, 1 Η), 7.09-7.16 (m, 4 Η), 6.46-6.53 (m, 1 Η), 5.29 (s, 1 Η), 4.85-4.95 (m, 1 Η), 4.41-4.48 (m, 1H), 4.31-4.38 (m, 1 H), 4.18-4.27 (m, 2 H), 4.08-4.17 (m, 2 H), 1.46 (s, 9 H) ; MS (ESI) w/z 506 [M+H], MS (ESI) m/z 504 [MH] . Example 11 2-[1-(2-Mercapto)piperidin-4-ylbu 3-yloxy-N-[4-(trifluoromethoxy)benzoinyl]isoindoline-1- Guanamine

140374.doc -59- 201000446 根據實例3中所述之通用程序2自2-( 1 -(呋喃-2-羰基）哌 咬-4-基）-3 -側氧基異。引10朵°林-1-曱酸（89 mg，0.25 mmol)及 (4-(三氟甲氧基）苯基）甲胺（96 μι，0.50 mmol)製備標題化 合物。白色固體’ Π mg(8%)。 *H NMR (400 MHz, CDCl3-d6) δ ppm 7.74-7.80 (m, 1 Η), 7.59-7.62 (m, 2 Η), 7.48-7.55 (m, 2 Η), 7.06-7.12 (m, 4 Η), 7.03 (dd, 1 Η), 6.51 (dd, 1 Η), 6.14-6.20 (m, 1 Η), 5.12 (s, 1 Η), 4.67 (br. s., 2 H), 4.28-4.46 (m, 3 H), 2.97 (br. s., 2 H), 1.82-1.94 (m, 3 H), 1.79 (dd, 1 H) ； MS (ESI) m/z 528 [M+H], MS (ESI) m/z 526 [M-H]。 實例12 3-侧氧基-2-(1-嘧啶-2-基吖丁啶_3_基）_]^_[4_(三氟甲氧基） 苯曱基]異吲哚啉-1-甲醯胺140374.doc -59- 201000446 The general procedure 2 according to Example 3 was carried out from 2-(1-(furan-2-carbonyl)piperidin-4-yl)-3-oxooxy. The title compound was prepared from EtOAc (yield: EtOAc, EtOAc (EtOAc) White solid ' Π mg (8%). *H NMR (400 MHz, CDCl3-d6) δ ppm 7.74-7.80 (m, 1 Η), 7.59-7.62 (m, 2 Η), 7.48-7.55 (m, 2 Η), 7.06-7.12 (m, 4 Η), 7.03 (dd, 1 Η), 6.51 (dd, 1 Η), 6.14-6.20 (m, 1 Η), 5.12 (s, 1 Η), 4.67 (br. s., 2 H), 4.28- 4.46 (m, 3 H), 2.97 (br. s., 2 H), 1.82-1.94 (m, 3 H), 1.79 (dd, 1 H) ; MS (ESI) m/z 528 [M+H] , MS (ESI) m/z 526 [MH]. Example 12 3-Phenoxy-2-(1-pyrimidin-2-ylazetidine-3-yl)_]^_[4_(trifluoromethoxy)phenylindenyl]isoindoline-1- Formamide

根據實例3中所述之通用程序2自3-側氧基-2-(l_(嘧啶_2_ 基）吖丁啶-3-基）異吲哚啉甲酸（78 mg，〇 25 mm〇1)及（4_ (二氟曱氧基）苯基）曱胺（96 mg，〇.5〇 mm〇l)製備標題化合 物。白色固體，1〇 。 !H NMR (400 MHz, DMSO-^6) δ ppm 9.26 (t, 1 H), 8.38 (d, 2 H), 7.71 (d, 1 H)，7.61-7.66 (m，1 H), 7.51-7.59 (m，2 H)， 140374.doc -60· 201000446 7.29-7.35 (m, 2 Η), 7.20-7.25 (m, 2 Η), 6.72 (t, 1 Η), 5.57 (s, 1 Η), 4.91-5.00 (m, 1 Η), 4.20-4.41 (m, 6 Η) ； MS (ESI) m/z 484 [M+H], MS (ESI) m/z 482[M-H]。 實例13 2-(4,4-二氟環己基）-N-(4-甲氧基苯甲基）-3-側氧基異吲哚 啉-1-甲醢胺General procedure 2 as described in Example 3 from 3-oxo-2-(1-(pyrimidin-2-yl)azetidin-3-yl)isoindolinecarboxylic acid (78 mg, 〇25 mm 〇1) And (4_(difluorodecyloxy)phenyl)decylamine (96 mg, 〇.5〇mm〇l) gave the title compound. White solid, 1〇. !H NMR (400 MHz, DMSO-^6) δ ppm 9.26 (t, 1 H), 8.38 (d, 2 H), 7.71 (d, 1 H), 7.61-7.66 (m,1 H), 7.51- 7.59 (m,2 H), 140374.doc -60· 201000446 7.29-7.35 (m, 2 Η), 7.20-7.25 (m, 2 Η), 6.72 (t, 1 Η), 5.57 (s, 1 Η) , 4.91-5.00 (m, 1 Η), 4.20-4.41 (m, 6 Η); MS (ESI) m/z 484 [M+H], MS (ESI) m/z 482 [MH]. Example 13 2-(4,4-Difluorocyclohexyl)-N-(4-methoxybenzyl)-3-oxooxyisoindoline-1-carboxamide

根據實例1中所述之通用程序1自2-甲醯基苯曱酸（35 mg ’ 0.23 mmol)、4,4-二氟環己胺（31 mg，0.23 mmol)及 1-(異氰基甲基）-4 -曱氧基苯（31 mg，0.21 mmol)合成標題化 合物以生成28 mg(29%)。MS (ESI) m/z 415 [M+H]。 U 實例14 N-[l-(3-氣苯基）乙基】-2-(4,4-二氟環己基）-3-側氧基異吲哚 啉-1-甲醯胺General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (35 mg '0.23 mmol), 4,4-difluorocyclohexylamine (31 mg, 0.23 mmol) and 1-(isocyano) The title compound was synthesized to give 28 mg (29%). MS (ESI) m/z 415 [M+H]. U Example 14 N-[l-(3-Phenylphenyl)ethyl]-2-(4,4-difluorocyclohexyl)-3-oxooxyisoindoline-1-carboxamide

140374.doc -61 · 201000446 根據實例1中所述之通用程序1自2-甲醯基苯甲酸（35 mg，0.23 mmol)、4,4-二氟環己胺（31 mg，0.23 mmol)及 1 -氣- 3-(1-異氰基乙基）苯（35 mg，0.21 mmol)合成標題化合 物以生成20 mg(20%)。 !H NMR (600 MHz, DMSO-c/6) δ ppm 9.19, 9.15 (d+d, 1 Η), 7.25-7.71 (m, 8 Η), 5.31 (s, 1 Η), 4.85-4.95 (m, 1 Η), 4.02-4.09 (m, 1 Η), 1.58-2.12 (m, 8 Η), 1.44, 1.42 (d+d, 3 Η) ； MS (ESI) m/z 433 [M+H] ° 實例15 N-[1-(3-氣苯基）乙基]-3-側氧基-2-(四氫-2H-哌喃-4-基）異 吲哚啉-1-甲醯胺140374.doc -61 · 201000446 according to the general procedure 1 described in Example 1 from 2-mercaptobenzoic acid (35 mg, 0.23 mmol), 4,4-difluorocyclohexylamine (31 mg, 0.23 mmol) and The title compound was synthesized to give 20 mg (20%). !H NMR (600 MHz, DMSO-c/6) δ ppm 9.19, 9.15 (d+d, 1 Η), 7.25-7.71 (m, 8 Η), 5.31 (s, 1 Η), 4.85-4.95 (m , 1 Η), 4.02-4.09 (m, 1 Η), 1.58-2.12 (m, 8 Η), 1.44, 1.42 (d+d, 3 Η) ; MS (ESI) m/z 433 [M+H] ° Example 15 N-[1-(3-Phenylphenyl)ethyl]-3-oxooxy-2-(tetrahydro-2H-piperidin-4-yl)isoindoline-1-carboxamide

根據實例1中所述之通用程序1自2-甲醯基苯甲酸（35 mg，0.23 mmol)、四氫-2Η-^°南-4-胺（23 mg，0.23 mmol) 及1-氯-3-(1-異氰基乙基）苯（35 mg，0.21 mmol)合成標題 化合物以生成34 mg(37%)。 NMR(600 MHz, DMSO-c?6) δ ppm 9.16, 9.11 (d+d, 1 Η), Ί.65-1.11 (m, 1 H), 7.54-7.64 (m, 1 H), 7.51-7.54 (m, 1 H), 7.42-7.51 (m, 1 H), 7.26-7.42 (m, 4 H), 5.31-5.32 (m, 1 H), 4.86-4.95 (m, 1 H), 4.05-4.15 (m, 1 H), 3.92, 3.78 (dd+dd, 1 H), 3.88 (dd, 1 H), 3.34-3.42 (m, 2 H), 1.54-1.91 (m，4 H), 1.44, 1.43 (d+d，3 H) ; MS (ESI) m/z 399 [M+H]。 140374.doc -62- 201000446 實例16 2-((3,3-二氟環丁基）甲基）-3-侧氧基-N-(4-(三氟甲氧基）苯 甲基）異吲哚啉-1-甲酿胺General Procedure 1 as described in Example 1 from 2-methylmercaptobenzoic acid (35 mg, 0.23 mmol), tetrahydro-2 Η-^°-N-amine (23 mg, 0.23 mmol) and 1-chloro- The title compound was synthesized from 3-(1-isocyanoethyl)benzene (35 mg, 0.21 mmol) to yield 34 mg (37%). NMR (600 MHz, DMSO-c?6) δ ppm 9.16, 9.11 (d+d, 1 Η), Ί.65-1.11 (m, 1 H), 7.54-7.64 (m, 1 H), 7.51-7.54 (m, 1 H), 7.42-7.51 (m, 1 H), 7.26-7.42 (m, 4 H), 5.31-5.32 (m, 1 H), 4.86-4.95 (m, 1 H), 4.05-4.15 (m, 1 H), 3.92, 3.78 (dd+dd, 1 H), 3.88 (dd, 1 H), 3.34-3.42 (m, 2 H), 1.54-1.91 (m, 4 H), 1.44, 1.43 (d+d, 3 H); MS (ESI) m/z 399 [M+H]. 140374.doc -62- 201000446 Example 16 2-((3,3-Difluorocyclobutyl)methyl)-3-oxo-N-(4-(trifluoromethoxy)phenylmethyl) Porphyrin-1-cartoamine

根據實例1中所述之通用程序1自2_曱醯基苯甲酸（66.9 mg , 0.45 mmol) ' 異氰基曱基）-4-(三氟曱氧基）苯（0.075 mL，0.45 mmol)及（3,3-二氟環 丁基）曱胺（54 mg，0.45 mmol)合成標題化合物。白色固體，22 mg( 11%)。 !H NMR (500 MHz, CDC13) δ (ppm) Ί.55-1.69 (m, 3 Η) 7.46 (t, 1 Η) 7.07-7.19 (m, 4 Η) 6.35 (t, 1 Η) 5.07 (s, 1 Η) 4.31-4.49 (m, 2 Η) 4.12 (dd, 1 Η) 3.30 (dd, 1 Η) 2.55-2.77 (m, 2 Η) 2·31-2·53 (m，3 Η)。MS (ESI) w/z 455 [Μ+Η]。 實例17(通用程序3) 2-(3,3-二氟環丁基）_3·側氧基-N-(4-(三氟甲氧基）苯甲基）異 吲哚琳-1 -甲醯胺General procedure 1 as described in Example 1 from 2 - mercaptobenzoic acid (66.9 mg, 0.45 mmol) 'isocyanoindolyl)-4-(trifluoromethoxy)benzene (0.075 mL, 0.45 mmol) The title compound was synthesized from (3,3-difluorocyclobutyl)decylamine (54 mg, 0.45 mmol). White solid, 22 mg (11%). !H NMR (500 MHz, CDC13) δ (ppm) Ί.55-1.69 (m, 3 Η) 7.46 (t, 1 Η) 7.07-7.19 (m, 4 Η) 6.35 (t, 1 Η) 5.07 (s , 1 Η) 4.31-4.49 (m, 2 Η) 4.12 (dd, 1 Η) 3.30 (dd, 1 Η) 2.55-2.77 (m, 2 Η) 2·31-2·53 (m, 3 Η). MS (ESI) w/z 455 [Μ+Η]. Example 17 (general procedure 3) 2-(3,3-Difluorocyclobutyl)_3. pendantoxy-N-(4-(trifluoromethoxy)benzyl)isoindol-1 - A Guanamine

使氯化3,3-二氟環丁銨（28.7 mg，0.20 mmol)及三乙胺 140374.doc -63- 201000446 (0.042 mL，0.3 0 mmol，注意在反應中推薦使用不超過2.0 當量之鹼）在曱醇（2 mL)中混合，且在5分鐘之後添加2_甲 醯基苯甲酸（30 mg，0.20 mmol)及1-(異氰基甲基），4-(三氣 曱氧基）笨（40_2 mg，0.20 mmol)。將混合物在環境溫度下 攪拌16小時’隨後將其過濾且使用製備型液相層析進行純 化。彙集含產物之溶離份且在真空中移除乙腈。用乙酸乙 醋萃取水溶液。將有機層經硫酸鎂乾燥且濃縮以生成呈黃 色固體狀之標題化合物，21mg(24%)。 H NMR (500 MHz, CDC13) δ (ppm) 7.63-7.68 (m, 1 H) 7.60 (t, 1 H) 7.49 (d, 1 H) 7.42 (t, 1 H) 7.09-7.19 (m, 4 H) 6.62 (t, 1 H) 5.16 (s, 1 H) 4.41-4.51 (m, 2 H) 4.30-4.39 (m, 1 H) 2.87-3.08 (m, 3 H) 2.81 (ddd, 1 H) ° MS (ESI) m/z 441 [M+H]。 實例18 2-(4,4,二氣環己基）_7_曱氧基-3側氧基-N(4(三氣甲氧基） 笨甲基）異吲哚啉_1_甲醯胺3,3-Difluorocyclobutylammonium chloride (28.7 mg, 0.20 mmol) and triethylamine 140374.doc -63- 201000446 (0.042 mL, 0.3 0 mmol, note that no more than 2.0 equivalents of base are recommended in the reaction) Mix in decyl alcohol (2 mL) and add 2-methylmercaptobenzoic acid (30 mg, 0.20 mmol) and 1-(isocyanomethyl), 4-(trimethyleneoxy) after 5 minutes. ) Stupid (40_2 mg, 0.20 mmol). The mixture was stirred at ambient temperature for 16 hours' then it was filtered and purified using preparative liquid chromatography. The product-containing fractions were pooled and the acetonitrile was removed in vacuo. The aqueous solution was extracted with ethyl acetate. The organic layer was dried with EtOAc EtOAcjjjjjjj H NMR (500 MHz, CDC13) δ (ppm) 7.63-7.68 (m, 1 H) 7.60 (t, 1 H) 7.49 (d, 1 H) 7.42 (t, 1 H) 7.09-7.19 (m, 4 H 6.62 (t, 1 H) 5.16 (s, 1 H) 4.41-4.51 (m, 2 H) 4.30-4.39 (m, 1 H) 2.87-3.08 (m, 3 H) 2.81 (ddd, 1 H) ° MS (ESI) m/z 441 [M+H]. Example 18 2-(4,4, Di-cyclohexyl)-7-methoxy-3-oxyl-N(4(trimethoxymethoxy)m-methyl)isoindoline-1-carboxamide

根據實例17中杯· 4+、+ 甲所返之通用程序3自氣化4,4-二氟環己銨 (57.2 mg，0.33 mm〇n、二， )~~1 乙胺（0.056 mL，0.40 mmol)、 3-羥基_4_甲氡美 土 ’、本开呋喃-1(3H)-酮（60 mg，0.33 140374.doc -64 - 201000446Self-gasification of 4,4-difluorocyclohexammonium (57.2 mg, 0.33 mm〇n, di, )~~1 ethylamine (0.056 mL, according to the general procedure 3 of Cup 4+, + A) 0.40 mmol), 3-hydroxy_4_ formazan, 'open-furan-1(3H)-one (60 mg, 0.33 140374.doc -64 - 201000446

備）、1-(異氰基曱基）-4-(三氟曱氧基）苯（67.〇 mg，〇33 mmol)合成標題化合物。白色固體，32 mg( 19%)。 NMR (400 MHz, CDC13) δ (ppm) 7.37-7.51 (m, 2 H) 7.21-7.30 (m, 2 H) 7.11-7.19 (m, 2 H) 7.00 (dd, 1 H) 6 22The title compound was synthesized from 1-(isocyanoindolyl)-4-(trifluoromethoxy)benzene (67. 〇 mg, 〇33 mmol). White solid, 32 mg (19%). NMR (400 MHz, CDC13) δ (ppm) 7.37-7.51 (m, 2 H) 7.21-7.30 (m, 2 H) 7.11-7.19 (m, 2 H) 7.00 (dd, 1 H) 6 22

(t，1 H) 5.07 (s，1 H) 4.32-4.56 (m, 2 H) 4.08-4.27 (m，1 h) 3_75 (s，3 H) 2.00-2.26 (m，3 H) 1.69-1.98 (m, 5 H)。MS (ESI) wi/z 499 [M+H]。 實例19 2-(4,4-二氟環己基）-7-甲基-3-側氧基三氟甲氧基）苯 曱基）異吲哚啉-1-甲醯胺(t,1 H) 5.07 (s,1 H) 4.32-4.56 (m, 2 H) 4.08-4.27 (m,1 h) 3_75 (s,3 H) 2.00-2.26 (m,3 H) 1.69-1.98 (m, 5 H). MS (ESI) wi/z 499 [M+H]. Example 19 2-(4,4-Difluorocyclohexyl)-7-methyl-3-oxooxytrifluoromethoxy)phenylindenyl)isoindoline-1-carboxamide

根據實例17中所述之通用程序3自氣化4,4-二氣環己錢 (31.4 mg，0.18 mmol)、三乙胺（〇.050 mL，〇 36 爪仿^)、 3-羥基-4-甲基異苯并呋喃酮（3〇 mg，〇 18 mmQl， 根據：Teira/ze办〇« 2002，43，7315中對於未經取代之 類似物所述之程序製備）及1-(異氰基曱基）_4_(三氟曱氧基） 苯（36.8 mg，〇· 18 mmol)合成標題化合物。將反應混合物 在至溫下攪拌4小時’隨後在50°C下授拌40小時。白色固 體，3 1 ·9 mg(36〇/〇) 0 140374.doc -65· 201000446 !H NMR (500 MHz, DMSO-i/e) δ (ppm) 9.25 (t, 1 H) 7.51 (d, 1 H) 7.39 (d, 3 H) 7.27-7.37 (m, 3 H) 5.26 (s, 1 H) 4.32-4.40 (m, 1 H) 4.23-4.31 (m, 1 H) 4.08 (t, 1 H) 2.23 (s, 3 H) 1.85-2.09 (m，5 H) 1.75 (br_ s.，1 H) 1.57-1.72 (m, 2 H)。 MS (ESI) m/z 483 [M+H]。 實例20 3-(4-曱基-1-側氧基- 3- (4-(三氟曱氧基）笨甲基胺甲醢基）異 吲哚啉-2·基）吖丁啶-1-甲酸第三丁酯Self-gasification of 4,4-dicyclohexanthene (31.4 mg, 0.18 mmol), triethylamine (〇.050 mL, 〇36 paw imitation ^), 3-hydroxy- according to the general procedure 3 described in Example 17. 4-methylisobenzofuranone (3 〇 mg, 〇18 mm Ql, according to: Teira/ze Office 2002 2002, 43, 7315 for the preparation of the unsubstituted analogue) and 1-(iso) The title compound was synthesized from cyanoindenyl)- 4 -(trifluoromethoxy)benzene (36.8 mg, EtOAc). The reaction mixture was stirred at room temperature for 4 hours and then stirred at 50 ° C for 40 hours. White solid, 3 1 ·9 mg (36〇/〇) 0 140374.doc -65· 201000446 !H NMR (500 MHz, DMSO-i/e) δ (ppm) 9.25 (t, 1 H) 7.51 (d, 1 H) 7.39 (d, 3 H) 7.27-7.37 (m, 3 H) 5.26 (s, 1 H) 4.32-4.40 (m, 1 H) 4.23-4.31 (m, 1 H) 4.08 (t, 1 H) ) 2.23 (s, 3 H) 1.85-2.09 (m, 5 H) 1.75 (br_ s., 1 H) 1.57-1.72 (m, 2 H). MS (ESI) m/z 483 [M+H]. Example 20 3-(4-Mercapto-1-yloxy-3-(4-(trifluoromethoxy)benzylaminocarbamoyl)isoindoline-2·yl)azetidine-1 -T-butyl formate

根據實例1中所述之通用程序1自3-羥基-4-甲基異笨并呋 口南-1(3H)-酮（30 mg，0.18 mmol，根據 reira/ze办〇« 2002，43，7315中對於未經取代之類似物所述之程序製 備）、3-胺基吖丁啶-1-甲酸第三丁酯（3 1.5 mg，0.18 mmol) 及1-(異氰基曱基）-4-(三氟曱氧基）苯（36,8 mg，0.18 mmol) 合成標題化合物。將反應混合物在50°C下攪拌60小時。白 色固體，33.4 mg(35%)。 *Η NMR (500 MHz, CDC13) δ (ppm) 7.55-7.65 (m, 1 H) 7.38-7.45 (m, 2 H) 7.13 (s, 4 H) 5.96 (t, 1 H) 5.25 (s, 1 H) 4.83-4.90 (m, 1 H) 4.37-4.43 (m，1 H) 4.28-4.35 (m, 1 H) 4.16-4.28 (m，3 Η) 4·1〇 (t, 1 H) 2.40 (s，3 H) 1.47 (s，9 H)。MS (ESI) m/z 418 [M-H]。 140374.doc -66- 201000446 實例21 3-側氧基-2-(四氫-2H-哌喃-4-基）-N-(l-(4-(三氟甲氧基）苯 基）乙基）異吲哚啉-1_甲醯胺，異構物4According to the general procedure 1 described in Example 1, from 3-hydroxy-4-methylisobenzofuran-1(3H)-one (30 mg, 0.18 mmol, according to reira/ze® 2002, 43, Preparation of the procedure described for the unsubstituted analog in 7315), 3-aminoazetidine-1-carboxylic acid tert-butyl ester (3 1.5 mg, 0.18 mmol) and 1-(isocyanoguanidino)- 4-(Trifluorodecyloxy)benzene (36,8 mg, 0.18 mmol). The reaction mixture was stirred at 50 ° C for 60 hours. White solid, 33.4 mg (35%). *Η NMR (500 MHz, CDC13) δ (ppm) 7.55-7.65 (m, 1 H) 7.38-7.45 (m, 2 H) 7.13 (s, 4 H) 5.96 (t, 1 H) 5.25 (s, 1 H) 4.83-4.90 (m, 1 H) 4.37-4.43 (m, 1 H) 4.28-4.35 (m, 1 H) 4.16-4.28 (m,3 Η) 4·1〇(t, 1 H) 2.40 ( s, 3 H) 1.47 (s, 9 H). MS (ESI) m/z 418 [M-H]. 140374.doc -66-201000446 Example 21 3-Phenoxy-2-(tetrahydro-2H-piperidin-4-yl)-N-(l-(4-(trifluoromethoxy)phenyl)B Isoporphyrin-1_carbamamine, isomer 4

〇=未知絕對構型 p=未知絕對構型 異構物4 根據實例1中所述之通用程序丨自2_甲醯基苯甲酸（〇.丨〇5 g， 0.70 mmol)、4-胺基四氫哌喃（〇 〇71 g，〇 7〇 顏〇1)及1(1_ 異氰基乙基）-4·(三氟曱氧基）苯⑶151 g，〇 7() mm〇1)合成 標題化合物。白色固體，118 mg(;37 6%)。藉由在Berger〇 = unknown absolute configuration p = unknown absolute configuration isomer 4 according to the general procedure described in Example 1 from 2 -methionine benzoic acid (〇.丨〇5 g, 0.70 mmol), 4-amino group Synthesis of tetrahydropyran (〇〇71 g, 〇7〇颜〇1) and 1(1_isocyanoethyl)-4·(trifluoromethoxy)benzene (3) 151 g, 〇7() mm〇1) Title compound. White solid, 118 mg (; 37 6%). By Berger

MuUigram Π SFC系統上執行之對掌性層析來分離非對映 異構混合物（118 1^’0.26細〇1)。管柱：1^〇8丨1_皿， 20x250 mm，1〇 μηι ,移動相：1〇%甲醇及 9〇% ;流動 速率· 50¾升/分鐘，提供在83分鐘時溶離之分離異構物 為異構物1，在9.4分鐘時溶離之分離異構物為異構物2， 在11分鐘時溶離之分離異構物為異構物3及在127分鐘時 溶離之分離異構物為異構物4。收集、蒸發且分別處理分 離之異構物。藉由HPLC使用SFC Berger AnaIytix(管柱： Repr〇sil-NR，4.6x250 mm，5 μιη ;移動相：2〇% 甲醇及 80% C〇2 ;流動速率：2毫升/分鐘）來分析樣品，異構物 140374.doc •67- 201000446 4(6.5分鐘），25 mg，對映異構純度：99°/〇。 在根據NMR及對掌性HPLC分離之後，異構物4緩慢地差 向異構化為異構物3。 ]H NMR (500 MHz, DMSO-J6) δ ppm 9.19 (d, 1 H), 7.65 (m, 2 H), 7.47 (m, 4 H), 7.33 (d, 2 H), 5.30 (s, 1 H), 4.93 (m, 1 H), 4-09 (m, 1 H), 3.86 (dd, 1 H), 3.71 (dd, 1 H), 1.71 (m5 2 H), 1-53 (m，2 H)，1.45 (m，3 H)。MS (ESI) w/z 449 [M+H]。 實例22 3-(1-側氧基-3-(1-(4-(三氟甲氧基）苯基）乙基胺甲醯基）異 °弓丨哚啉-2-基）吖丁啶-1-甲酸第三丁酯，異構物3及4The chiral chromatography performed on the MuUigram® SFC system separates the diastereomeric mixture (118 1^'0.26 fine 〇1). Column: 1^〇8丨1_ dish, 20x250 mm, 1〇μηι, mobile phase: 1〇% methanol and 9〇%; flow rate · 503⁄4 l/min, providing separation isomers dissolved at 83 minutes For isomer 1, the isolated isomer which was dissolved at 9.4 minutes was isomer 2, the separated isomer which was dissolved at 11 minutes was isomer 3 and the separated isomer was dissolved at 127 minutes. Structure 4. The separated isomers were collected, evaporated and separately treated. The sample was analyzed by HPLC using SFC Berger AnaIytix (column: Repr〇sil-NR, 4.6 x 250 mm, 5 μιη; mobile phase: 2% methanol and 80% C〇2; flow rate: 2 ml/min). Isomer 140374.doc • 67- 201000446 4 (6.5 minutes), 25 mg, enantiomeric purity: 99°/〇. Isomer 4 was slowly epimerized to isomer 3 after separation by NMR and palm-wise HPLC. H NMR (500 MHz, DMSO-J6) δ ppm 9.19 (d, 1 H), 7.65 (m, 2 H), 7.47 (m, 4 H), 7.33 (d, 2 H), 5.30 (s, 1 H), 4.93 (m, 1 H), 4-09 (m, 1 H), 3.86 (dd, 1 H), 3.71 (dd, 1 H), 1.71 (m5 2 H), 1-53 (m, 2 H), 1.45 (m, 3 H). MS (ESI) w/z 449 [M+H]. Example 22 3-(1-Phenoxy-3-(1-(4-(trifluoromethoxy)phenyl)ethylaminemethanyl)isophthyl-2-yl)azetidine 1-butylic acid tert-butyl ester, isomers 3 and 4

異構物3及4 d=未知絕對構型 根據貫例1中所述之通用程序丨自2_曱醯基苯曱酸㈧·1〇5 gIsomers 3 and 4 d = unknown absolute configuration according to the general procedure described in Example 1 from 2_mercaptobenzoic acid (eight)·1〇5 g

140374.doc •68-140374.doc •68-

201000446 75%⑶2 ’ 7_H分鐘·· 35%異_及65% c〇2 ·流動速率： 50毫升/刀鐘，提供在5分鐘時溶離之分離異構物為異構物 1以及2 ’在6.6分鐘時溶離之分離異構物為異構物3及在98 分鐘時溶離之分離異構物為異構物4。收集、蒸發且分別 處理分離之異構物。藉由HPLC使用SFC Berger Analytix (管柱：RePr〇sil-NR，4_6x25〇 随，5 μπι;移動相：2〇% 甲醇及嶋C〇2 ;流動速率：2毫升/分鐘）來分析樣品。在 移除溶劑所需之時間内將異構物3差向異構化為異構物4, 從而產生異構物3及4(滯留時間分別為6·2分鐘及8 9分鐘） 之1:1混合物’ 40 mg ’ 1:1非對映異構混合物。 !H NMR (500 MHz, DMSO-rf6) δ (ppm) 9 33 (d, ! Η) 7.68 (d, 1 Η) 7.59 (m, 1 Η) 7.49 (m, 4 Η) 7.33 (d, 2 Η) 5.47 (s, 1 Η) 4.96 (m, 1 Η) 4.69 (m, 1 Η) 4.10 (m, 4 Η) 1.43 (d, 3 Η) 1.40 (s, 9 Η)。MS (ESI) m/z 518 [Μ-Η]。 實例23 2-(2-嗎啉基乙基）-3-側氧基-N-(4-(三氟甲氧基）苯甲基）異 吲哚琳-1 -曱醢胺201000446 75%(3)2 '7_H minutes·· 35% _ and 65% c〇2 · Flow rate: 50 ml / knives, providing separation isomers at 5 minutes for isomers 1 and 2 ' at 6.6 The isolated isomer which was dissolved in minutes was isomer 3 and the separated isomer which was dissolved at 98 minutes was isomer 4. The separated isomers are collected, evaporated and separately treated. The sample was analyzed by HPLC using SFC Berger Analytix (column: RePr〇sil-NR, 4_6x25〇, 5 μm; mobile phase: 2% methanol and 嶋C〇2; flow rate: 2 ml/min). Isomer 3 was isomerized to isomer 4 within the time required to remove the solvent, resulting in 1 of isomers 3 and 4 (residence time of 6.2 minutes and 8 9 minutes, respectively): 1 Mixture '40 mg' 1:1 diastereomeric mixture. !H NMR (500 MHz, DMSO-rf6) δ (ppm) 9 33 (d, ! Η) 7.68 (d, 1 Η) 7.59 (m, 1 Η) 7.49 (m, 4 Η) 7.33 (d, 2 Η 5.47 (s, 1 Η) 4.96 (m, 1 Η) 4.69 (m, 1 Η) 4.10 (m, 4 Η) 1.43 (d, 3 Η) 1.40 (s, 9 Η). MS (ESI) m/z 518 [Μ-Η]. Example 23 2-(2-Morpholinylethyl)-3-oxo-N-(4-(trifluoromethoxy)benzyl)isoindol-1 -nonylamine

根據實例1中所述之通用程序1自2-甲醯基苯曱酸（200 mg，1.3 3 mmol)、嗎琳基乙胺（172 mg，h33 mmol)及 1 - 140374.doc •69- 201000446 (異氰基曱基）-4-(三氟甲氧基）苯（267 mg，1.33 mmol)合成 標題化合物。藉由矽膠管柱層析使用二氯甲烷：甲醇 = 100:0至95:5作為梯度來純化粗產物。固體，220 mg(32.80/〇)。 lU NMR (400 MHz, CDC13) δ (ppm) 8.31 (t, 1 Η) 7.68 (d, 1 Η) 7.53 (t, 1 Η) 7.27 (t, 1 Η) 7.24-7.12 (m, 3 Η) 7.07 (d, 2 Η) 5.29 (s, 1 Η) 4.53-4.32 (m, 2 Η) 3.81 (dt5 1 Η) 3.65-3.46 (m，5 Η) 2.68-2.42 (m，4 Η) 2.38-2.21 (m，2 H)。MS (ESI) m/z 464 [M+H]。 實例24 3-側氧基-2-((四氫呋喃-3-基）甲基）_N-(4-(三氟甲氧基）苯曱 基）異吲哚啉-1-甲醯胺General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (200 mg, 1.33 mmol), morphineethylamine (172 mg, h33 mmol) and 1 - 140374.doc •69- 201000446 The title compound was synthesized from (isocyanoindolyl)-4-(trifluoromethoxy)benzene (267 mg, 1.33 mmol). The crude product was purified by hydrazine gel column chromatography using dichloromethane:methanol = 100:0 to 95:5. Solid, 220 mg (32.80 / 〇). lU NMR (400 MHz, CDC13) δ (ppm) 8.31 (t, 1 Η) 7.68 (d, 1 Η) 7.53 (t, 1 Η) 7.27 (t, 1 Η) 7.24-7.12 (m, 3 Η) 7.07 (d, 2 Η) 5.29 (s, 1 Η) 4.53-4.32 (m, 2 Η) 3.81 (dt5 1 Η) 3.65-3.46 (m,5 Η) 2.68-2.42 (m,4 Η) 2.38-2.21 ( m, 2 H). MS (ESI) m/z 464 [M+H]. Example 24 3-Phenoxy-2-((tetrahydrofuran-3-yl)methyl)_N-(4-(trifluoromethoxy)phenylhydrazinyl)isoindoline-1-carboxamide

根據實例1中所述之通用程序1自2-甲醯基苯甲酸（丨5〇 mg，1.00 mmol)、（四虱 〇夫鳴 _3-基）曱胺（101 mg，1 〇〇 mmol)及1-(異氰基甲基）·4-(三氟曱氧基）苯（2〇1 mg，！⑽ mmol)合成標題化合物。藉由矽膠管柱層析使用二氣 烷：甲醇= 100:0至95:5作為梯度來純化粗產物。固體，'1⑽ mg(34.6%)。非對映異構物之1:1混合物，對應於一種非8G 映異構物之1個質子將積分設為1個質子。 皆 140374.doc •70- 201000446 NMR (400 MHz, CDC13) δ (ppm) 8.28 (br· s., 2 Η) 7.61 (d, 2 H) 7.49 (t, 2 H) 7.21 (dd, 4 H) 7.16-7.02 (m, 6 H) 6.84-6.68 (m, 2 H) 5.13 (d, 2 H) 4.58-4.46 (m, 2 H) 4.46- 4.34 (m, 2 H) 4.01-3.87 (m, 2 H) 3.87-3.74 (m, 3 H) 3.74- 3.59 (m, 3 H) 3.55-3.38 (m, 2 H) 3.20-3.06 (m, 2 H) 2.67- 2.47 (m, 2 H) 2.12-1.94 (m, 1 H) 1.94-1.76 (m, 1 H) 1.64- 1_42 (m, 2 H)。MS (ESI) m/2 435 [M+H]。 實例25 2-(l_苯甲基哌啶-4_基）-3-側氧基_N-(4-(三氟甲氧基）苯甲 基）異吲哚啉-1-甲醯胺General procedure 1 as described in Example 1 from 2-methylmercaptobenzoic acid (丨5〇mg, 1.00 mmol), (tetrakis keto-3-yl) decylamine (101 mg, 1 〇〇 mmol) The title compound was synthesized from 1-(isocyanomethyl)- 4-(trifluoromethoxy)benzene (2 〇 1 mg, (10) mmol). The crude product was purified by silica gel column chromatography using dioxane:methanol = 100:0 to 95:5. Solid, '1 (10) mg (34.6%). A 1:1 mixture of diastereomers, the integral is set to 1 proton corresponding to one proton of one non-8G. All 140374.doc •70- 201000446 NMR (400 MHz, CDC13) δ (ppm) 8.28 (br· s., 2 Η) 7.61 (d, 2 H) 7.49 (t, 2 H) 7.21 (dd, 4 H) 7.16-7.02 (m, 6 H) 6.84-6.68 (m, 2 H) 5.13 (d, 2 H) 4.58-4.46 (m, 2 H) 4.46- 4.34 (m, 2 H) 4.01-3.87 (m, 2 H) 3.87-3.74 (m, 3 H) 3.74- 3.59 (m, 3 H) 3.55-3.38 (m, 2 H) 3.20-3.06 (m, 2 H) 2.67- 2.47 (m, 2 H) 2.12-1.94 (m, 1 H) 1.94-1.76 (m, 1 H) 1.64- 1_42 (m, 2 H). MS (ESI) m/2 435 [M+H]. Example 25 2-(l-Benzylmethylpiperidin-4-yl)-3-oxooxy_N-(4-(trifluoromethoxy)benzyl)isoindoline-1-carboxamide

根據實例1中所述之通用程序1自2-甲醯基笨甲酸（65 mg，0.43 mmol)、4 -胺基-1-苯甲基娘咬（0.089 mL，0.43 mmol)及1-(異氰基曱基）-4-(三氟甲氧基）苯（0.087 mL， 0·43 mmol)合成標題化合物。白色固體，61 mg(27%)。 'H NMR (500 MHz, DMSO-^6) δ (ppm) 9.16 (t, 1 H) 7.68 (d, 1 H) 7.59 (dt, 1 H) 7.51 (t, 1 H) 7.48-7.42 (m, 1 H) 7.41-7.35 (m, 2 H) 7.35-7.22 (m, 7 H) 5.30 (s, 1 H) 4.40-4.28 (m5 2 H) 3.93-3.84 (m, 1 H) 3.45 (s, 2 H) 2.85 (d, 1 H) 2.78 (d, 1 H) 2.03-1.92 (m, 2 H) 1.80 (qd，1 H) 1.72-1.62 (m, 3 H)。MS (ESI) m/z 524 [M+H]。 140374.doc •71 · 201000446 實例26 4-基）-Ν-(4-(三氟甲氧基） 7_氟·3_側氧基-2-(四氫_2u-哌喃_ 本曱基）異11引蜂琳甲酿胺General Procedure 1 as described in Example 1 from 2-methylmercaptobenzoic acid (65 mg, 0.43 mmol), 4-amino-1-phenylmethyl Ninja (0.089 mL, 0.43 mmol) and 1-(iso) The title compound was synthesized from cyanomethyl)-4-(trifluoromethoxy)benzene (0.087 mL, 0.43 mmol). White solid, 61 mg (27%). 'H NMR (500 MHz, DMSO-^6) δ (ppm) 9.16 (t, 1 H) 7.68 (d, 1 H) 7.59 (dt, 1 H) 7.51 (t, 1 H) 7.48-7.42 (m, 1 H) 7.41-7.35 (m, 2 H) 7.35-7.22 (m, 7 H) 5.30 (s, 1 H) 4.40-4.28 (m5 2 H) 3.93-3.84 (m, 1 H) 3.45 (s, 2 H) 2.85 (d, 1 H) 2.78 (d, 1 H) 2.03-1.92 (m, 2 H) 1.80 (qd, 1 H) 1.72-1.62 (m, 3 H). MS (ESI) m/z 564 [M+H]. 140374.doc •71 · 201000446 Example 26 4-yl)-indole-(4-(trifluoromethoxy) 7-fluoro·3_sideoxy-2-(tetrahydro-2-u-pyranyl) )11

[-氟-3 -經基異苯并咬喃_ 氫-2H-旅喃-4-胺（0.024 根據實例1中所述之通用程序1自4 1 (3Η)-酮（40 mg，0.24 mmol)、四; mL，0.24 mmol)及1-(異氰基甲基）_4_(三氟甲氧基）苯（〇.〇48 mL，0.24 mmol)合成標題化合物。白色固體，* mg(4%)。 NMR (400 MHz, CDC13) δ (ppm) 7.62 (m, 1 H) 7.51 (m, 1 H) 7.26 (m, 3 H) 7.16 (d, 2 H) 6.14 (br. s., 1 H) 5.20 (s, 1 H) 4.38-4.52 (ddd, 2 H) 4.26-4.39 (m, 1 H) 4.03 (dd, 1 H) 3.94 (dd, 1 H) 3.44-3.48 (m, 2 H) 1.99-2.09 (m, 1 H) 1.80-1.92 (m, 1 H) 1.70-1.76 (m，2 H)。MS (ESI) m/z 453 [M+H]。 實例27 4-氟-3-側氧基-2-(四氫-2H-哌喃-4-基）-N-(4-(三氟甲氧基） 苯甲基）異吲哚啉-1-曱醢胺[-Fluoro-3 -ylisobenzopyrene-hydrogen-2H-bromo-4-amine (0.024 according to the general procedure 1 described in Example 1 from 4 1 (3Η)-one (40 mg, 0.24 mmol The title compound was synthesized from the title compound: mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj White solid, * mg (4%). NMR (400 MHz, CDC13) δ (ppm) 7.62 (m, 1 H) 7.51 (m, 1 H) 7.26 (m, 3 H) 7.16 (d, 2 H) 6.14 (br. s., 1 H) 5.20 (s, 1 H) 4.38-4.52 (ddd, 2 H) 4.26-4.39 (m, 1 H) 4.03 (dd, 1 H) 3.94 (dd, 1 H) 3.44-3.48 (m, 2 H) 1.99-2.09 (m, 1 H) 1.80-1.92 (m, 1 H) 1.70-1.76 (m, 2 H). MS (ESI) m/z 453 [M+H]. Example 27 4-Fluoro-3-oxooxy-2-(tetrahydro-2H-piperidin-4-yl)-N-(4-(trifluoromethoxy)benzyl)isoindoline-1 - guanamine

-72- 140374.doc 201000446 根據實例1中所述之通用程序1自7_氟_經基異苯并吱 喃-1 (3H)-酮（3 5 mg ’ 0.2 1 mmol)、四氫-2H-旅喃-4-胺 (0.021 mL，0.21 mmol)及1-(異氰基曱基）-4-(三氟甲氧基） 苯（0-042 mL，0.21 mmol)合成標題化合物。白色固體’ 36 mg(38%) ° NMR (400 MHz, CDC13) δ (ppm) 7.56 (m, 1 Η) 7.42 (d, 1 Η) 7.33 (t, 1 Η) 7.18 (d, 2 Η) 7.10 (m, 2 Η) 5.12 (s, 1 Η) 4.41-4.47 (dd, 1 Η) 4.30-4.36 (dd, 1 Η) 4.17 (m, 1 Η) 3.89-3.97 (m, 2 H) 3.31-3.37(m, 2 Η) 1.77-1.84 (m, 3 Η) 1.63-1.76 (m, 2 H)。MS (ESI) m/z 453 [M+H]。 實例28 3-側氧基-N-(4-(三氟甲氧基）苯曱基）-2-(1-(3,3,3-三氟丙醯 基）吖丁啶-3-基）異吲哚啉-1-甲醯胺-72- 140374.doc 201000446 according to the general procedure 1 described in Example 1 from 7-fluoro-pyridylbenzopyran-1 (3H)-one (3 5 mg '0.2 1 mmol), tetrahydro-2H The title compound was synthesized from bromo-4-amine (0.021 mL, 0.21 mmol) and 1-(isocyanoindolyl)-4-(trifluoromethoxy)benzene (0-042 mL, 0.21 mmol). White solid ' 36 mg (38%) ° NMR (400 MHz, CDC13) δ (ppm) 7.56 (m, 1 Η) 7.42 (d, 1 Η) 7.33 (t, 1 Η) 7.18 (d, 2 Η) 7.10 (m, 2 Η) 5.12 (s, 1 Η) 4.41-4.47 (dd, 1 Η) 4.30-4.36 (dd, 1 Η) 4.17 (m, 1 Η) 3.89-3.97 (m, 2 H) 3.31-3.37 (m, 2 Η) 1.77-1.84 (m, 3 Η) 1.63-1.76 (m, 2 H). MS (ESI) m/z 453 [M+H]. Example 28 3-Phenoxy-N-(4-(trifluoromethoxy)benzoinyl)-2-(1-(3,3,3-trifluoropropenyl)azetidin-3-yl Isoindolin-1-carboxamide

步驟1 : 將3-(1-侧氧基-3-(4-(三氟甲氧基）笨甲基胺曱醯基）異吲 木琳2基）吖丁 〇疋_1_甲酸第三丁酯（76 ，〇 15 溶 解於一氯曱烷（2 mL)中且添加三氟乙酸（0.070 mL· , 0.90 mm〇1)。將混合物攪拌16小時。向混合物中再添加三氟乙 酸（〇_〇3 mL)且在4〇°C下攪拌2小時。隨後添加甲苯（2 mL)，且在真空中移除揮發物。將該程序再重複一次，從 140374.doc -73- 201000446 而產生灰色油狀物（78 mg，1 〇〇%)，其無需進—步純化即 用於下一步驟。MS (ESI) m/z 406 [M+H]。 步驟2 : 使2,2,2-二氣乙酸;3-(1-側氧基_3-(4-(三I曱氧基）苯曱基 胺甲醯基）異吲哚啉-2-基）吖丁啶鑌（78 mg，〇.15 mm〇1)及 二乙胺（0.084 mL，0.60 mmol)在二氯曱院（2 mL)中混合， 且在5分鐘之後添加3,3,3-三氟丙醯氯（33.0 mg，0.23 mmol)。將混合物在室溫下搜拌i 6小時。在真空中移除溶 劑且藉由製備型HPLC進行純化《彙集含產物之溶離份且 在真空中移除乙腈。用乙酸乙酯萃取水溶液。將有機層經 無水硫酸鈉乾燥且濃縮以生成呈黃色泡沫狀之標題化合物 (旋轉異構物之2:1混合物），37 mg(48%)。 !H NMR (400 MHz, CDC13) δ (ppm) 7.52-7.65 (m, 3 Η) 7.35-7.46 (m, 1 Η) 7.22 (t, 2 Η) 7.10-7.18 (m, 3 Η) 5.27 (d, 1 Η) 4.85 (d, 1 Η) 4.34-4.62 (m, 5 Η) 4.21-4.33 (m, 1 Η) 2.93 (qd, 2 H)。MS (ESI) m/z 516 [M+H]。 實例29 2-(1-(甲基磺醯基）吖丁啶-3-基）-3-側氧基-N-(4-(三氟甲氡 基）苯甲基）異吲哚啉-1-曱醢胺Step 1: 3 - (1-Alkyloxy-3-(4-(trifluoromethoxy) benzylamino) sulfhydryl) 2 吖 〇疋 〇疋 _ _ carboxylic acid third Butyl ester (76, hydrazine 15 was dissolved in monochloromethane (2 mL) and trifluoroacetic acid (0.070 mL·, 0.90 mm 〇1) was added. The mixture was stirred for 16 hours. Additional trifluoroacetic acid was added to the mixture. _ 〇 3 mL) and stirred for 2 hours at 4 ° C. Then add toluene (2 mL) and remove the volatiles in vacuo. This procedure was repeated once more, from 140374.doc -73- 201000446 Gray oil (78 mg, 1%) which was used in the next step without further purification. MS (ESI) m/z 406 [M+H]. Step 2: 2,2,2 - di-glycolic acid; 3-(1-trioxy-3-(4-(tri-I-oxy)phenylhydrazinylmethyl hydrazino)isoindoline-2-yl)azetidine oxime (78 mg, hydrazine) .15 mm〇1) and diethylamine (0.084 mL, 0.60 mmol) were mixed in a dichlorohydrazine (2 mL), and after 3 minutes, 3,3,3-trifluoropropionyl chloride (33.0 mg, 0.23 mmol). Mix the mixture for 6 hours at room temperature. Remove the solvent in vacuo and purify by preparative HPLC. The title compound (2:1 mixture of rotamers) was obtained as a yellow foam. 37 mg (48%). !H NMR (400 MHz, CDC13) δ (ppm) 7.52-7.65 (m, 3 Η) 7.35-7.46 (m, 1 Η) 7.22 (t, 2 Η) 7.10-7.18 (m , 3 Η) 5.27 (d, 1 Η) 4.85 (d, 1 Η) 4.34-4.62 (m, 5 Η) 4.21-4.33 (m, 1 Η) 2.93 (qd, 2 H). MS (ESI) m/ z 516 [M+H]. Example 29 2-(1-(Methylsulfonyl)azetidin-3-yl)-3-yloxy-N-(4-(trifluoromethyl decyl)benzene Methyl)isoindoline-1-decylamine

140374.doc -74- 201000446 步驟1 : 將3-(1-側氧基-3-(4-(三氟曱氧基）苯曱基胺甲醯基）異^弓丨 喝啉-2-基）吖丁啶-1-甲酸第三丁酯（實例1〇，53〇 ，丨〇5 mmol)溶解於二氯甲烷（1〇 mL)中，添加三氟乙酸（2 mL)， 且將所得反應混合物在室溫下攪拌3小時。用二氯甲烧（3〇 mL)及水（10 mL)稀釋混合物’隨後在劇烈攪拌下小心地添 加2 Μ氫氧化鈉水溶液（1〇 mL)(pH值為約12)。分離各相， 且將水層用一風曱烧卒取兩次。將經組合之有機相用鹽水 洗滌，經無水硫酸鎂乾燥，過濾且蒸發以生成呈乾膜狀之 胺，332 mg(78〇/〇) ° ]H NMR (400 MHz, CDC13) δ (ppm) 7.56-7.66 (m, 3 Η) 7.45 (t, 1 Η) 7.15 (d, 2 Η) 7.09 (d, 2 Η) 6.87 (br.s., 1 Η) 5.35 (d, 1 Η) 4.99-5.07 (m, 1 Η) 4.44 (dd, 1 Η) 4.30 (dd, 1 Η) 4.09 (t，1 Η) 4.01 (t，1 Η) 3.87 (t，1 Η) 3.80 (t, 1 Η) 2.23 (br.s.， 1 H)。MS (ESI) m/z 406 [M+H]。 步驟2 : 將2-(吖丁啶-3-基）-3-側氧基-N-(4-(三氟甲氧基）苯曱基） 異α引°朵琳-1 -曱醯胺（66 mg，〇. 1 6 mmol)溶解於無水二氣曱 烧（2 mL)中，添加Ν,Ν-二異丙基乙胺（0.057 mL，0.33 mmol) 及曱烷磺醯氣（0·019 mL ’ 0.24 mmol)。將所得溶液在室溫 下攪拌16小時。藉由添加二乙胺（0.120 mL)來中止反應。 彙集含產物之溶離份且在真空中移除乙腈。用二氣曱烷萃 取水溶液。將有機層經無水硫酸鈉乾燥且濃縮以生成呈乾 膜狀之標題化合物，25 mg(32%)。 140374.doc -75- 201000446 NMR (400 MHz，CDC13) δ (ppm) 7.58 (d，2 Η) 7.40 (d, 2 H) 7.21 (d, 2 H) 7.13 (d, 2 H) 6.84 (br.s., 1 H) 5.22 (d5 1 H) 4.74-4.82 (m, 1 H) 4.38-4.50 (m, 4 H) 4.06 (dt, 2 H) 2.96 (s, 3 H)。MS (ESI) w/z 484 [M+H] 〇 實例30 3-(1-側氧基-3-(4-(三氟曱氧基）苯甲基胺甲醯基）異吲哚啉_ 2-基）吖丁啶-1-甲酸異丙酯140374.doc -74- 201000446 Step 1: 3-(1-Phenoxy-3-(4-(trifluoromethoxy)phenylhydrazinylmethyl)-yl) Azetidine-1-carboxylic acid tert-butyl ester (Example 1 〇, 53 〇, 丨〇 5 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (2 mL) was added, and the obtained reaction The mixture was stirred at room temperature for 3 hours. The mixture was diluted with methylene chloride (3 〇 mL) and water (10 mL). Then, 2 Μ aqueous sodium hydroxide (1 〇 mL) (pH about 12) was carefully added under vigorous stirring. The phases were separated and the aqueous layer was scooped twice with a wind. The combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give ssssssssssssssssssssssssssssssssssssssssssssssssss 7.56-7.66 (m, 3 Η) 7.45 (t, 1 Η) 7.15 (d, 2 Η) 7.09 (d, 2 Η) 6.87 (br.s., 1 Η) 5.35 (d, 1 Η) 4.99-5.07 (m, 1 Η) 4.44 (dd, 1 Η) 4.30 (dd, 1 Η) 4.09 (t,1 Η) 4.01 (t,1 Η) 3.87 (t,1 Η) 3.80 (t, 1 Η) 2.23 ( Br.s., 1 H). MS (ESI) m/z 406 [M+H]. Step 2: 2-(Azetidin-3-yl)-3-oxo-N-(4-(trifluoromethoxy)benzoinyl)iso-α is introduced as a linal-1-nonylamine (66 mg, 〇. 1 6 mmol) was dissolved in anhydrous sulphur (2 mL), hydrazine, hydrazine-diisopropylethylamine (0.057 mL, 0.33 mmol) and decane sulfonium (0·) 019 mL '0.24 mmol). The resulting solution was stirred at room temperature for 16 hours. The reaction was quenched by the addition of diethylamine (0.120 mL). The product-containing fractions were pooled and the acetonitrile was removed in vacuo. The aqueous solution was extracted with dioxane. The organic layer was dried over anhydrous sodium sulfate and evaporated 140374.doc -75- 201000446 NMR (400 MHz, CDC13) δ (ppm) 7.58 (d, 2 Η) 7.40 (d, 2 H) 7.21 (d, 2 H) 7.13 (d, 2 H) 6.84 (br. s., 1 H) 5.22 (d5 1 H) 4.74-4.82 (m, 1 H) 4.38-4.50 (m, 4 H) 4.06 (dt, 2 H) 2.96 (s, 3 H). MS (ESI) w/z 484 [M+H] </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; 3-(1- </RTI> </RTI> <RTIgt; 2-based) isopropyl butyrate-1-isopropylate

根據關於實例29所給出之方法使用2-(吖丁啶-3-基）-3-側 氧基善(4-(三氟甲氧基）苯甲基)異。引哚啉曱醯胺(〇 〇66 g，〇 16 mmol)、無水〇比啶(〇」mL)、氣甲酸異丙醋（於甲苯中1 μ溶液， 〇·244 mL ’ 0·24 mmol)製備標題化合物。乾膜，34 mg(42°/〇)。 !H NMR (400 MHz, CDC13) δ (ppm) 7.64 (d, 1 Η) 7.59 (d, 1 Η) 7.36-7.42 (m, 2 Η) 7.12-7.18 (m, 4 Η) 6.75 (br.s., 1 Η) 5.28 (s, 1 Η) 4.85-4.95 (m, 2 Η) 4.35-4.48 (m, 2 Η) 4.14- 4.31 (m，4 Η) 1.24 (d，6 H)。MS (ESI) m/z 492 [M+H]。 實例31 4-(l_側氧基-3_(4-(三氟甲氧基）苯甲基胺甲醢基）異吲哚啉_ 2-基）旅咬-1-甲酸第三丁酯 140374.doc •76· 2010004462-(Azetidin-3-yl)-3-oxo-oxy-(4-(trifluoromethoxy)benzyl)iso was used according to the procedure given for Example 29. Porphyrin guanamine (〇〇66 g, 〇16 mmol), anhydrous hydrazine (〇) mL, isopropyl isopropyl vinegar (1 μ solution in toluene, 〇·244 mL '0·24 mmol) The title compound was prepared. Dry film, 34 mg (42 ° / 〇). !H NMR (400 MHz, CDC13) δ (ppm) 7.64 (d, 1 Η) 7.59 (d, 1 Η) 7.36-7.42 (m, 2 Η) 7.12-7.18 (m, 4 Η) 6.75 (br.s ., 1 Η) 5.28 (s, 1 Η) 4.85-4.95 (m, 2 Η) 4.35-4.48 (m, 2 Η) 4.14- 4.31 (m, 4 Η) 1.24 (d, 6 H). MS (ESI) m/z 492 [M+H]. Example 31 4-(l_Sideoxy-3_(4-(trifluoromethoxy)benzylaminecarbamoyl)isoindoline-2-yl) britium-1-carboxylic acid tert-butyl ester 140374 .doc •76· 201000446

FF

很像貫 mg 3 曱醯基苯甲酸（3 15 ，2· 10 mmol)、4-胺基 α底。定 _甲酸第三丁酯（420 mg， 2.10 mmol)及1-(異氰基甲基）&gt;Much like mg 3 mercaptobenzoic acid (3 15 , 2·10 mmol), 4-aminol base. D-butyl butyrate (420 mg, 2.10 mmol) and 1-(isocyanomethyl)&gt;

1二氟曱氧基）苯（0 422 mL，2.10 mmol)合成標題化合物 藉由矽膠層析使用庚 烷：乙酸乙酯=80··20至50:50作失极+ …、梯度來純化粗產物。白色 固體，773 mg(69%)。 NMR (400 MHz, CDC13) δ fnnm\ η ^ ^ V VPpm) 7.57-7.64 (m, 3 Η) 7.46 (t，lH)7.10(s，4H)6.39(br.s.，lH)5.10(s，lH)4.27_ 4.39 (m, 2 Η) 4.17-4.24 (m, 3 Η) 2.70-2.80 (m, 2 Η) 1.70-1.77 (m，4 Η) 1·48 (s，9 Η)。MS (ESI)仍/z 534 [Μ+Η]。 實例32 3-側氧基-2-(1-丙醢基哌啶·4-基）-Ν-(4-(三氟甲氧基）苯甲 基）異吲哚啉-1-曱醯胺Synthesis of the title compound by dithilyloxy)benzene (0 422 mL, 2.10 mmol). Purified crude by chromatography using hexanes: ethyl acetate=80··20 to 50:50 as a gradient. product. White solid, 773 mg (69%). NMR (400 MHz, CDC13) δ fnnm\ η ^ ^ V VPpm) 7.57-7.64 (m, 3 Η) 7.46 (t,lH)7.10(s,4H)6.39(br.s.,lH)5.10(s, lH) 4.27_ 4.39 (m, 2 Η) 4.17-4.24 (m, 3 Η) 2.70-2.80 (m, 2 Η) 1.70-1.77 (m, 4 Η) 1·48 (s, 9 Η). MS (ESI) is still /z 534 [Μ+Η]. Example 32 3-Phenoxy-2-(1-propionylpiperidine-4-yl)-indole-(4-(trifluoromethoxy)benzyl)isoindolin-1-ylidene

步驟1 : 140374.doc 77- 201000446 將4-(1-側氧基-3-(4-(三氟曱氧基）苯甲基胺曱醯基）異吲 哚啉-2-基）哌啶-1-甲酸第三丁酯（620 mg，1.16 mmol)溶解 於乙酸（10 mL)及水（2 mL)之混合物中’且將溶液加熱至 80°C且授拌1 6小時。隨後蒸發反應混合物，將殘餘物溶解 於二氣曱垸中且用飽和NaHC〇3水溶液洗務。將有機相用 鹽水萃取且經無水硫酸鎂乾燥，過濾且濃縮以生成呈固體 狀之胺中間物3 -側氧基-2-(〇底咬-4 -基）-N-(4-(三氣甲氧基） 苯曱基）異吲哚啉-1-甲醯胺（485 mg，96%)。 NMR (400 MHz, CDC13) δ (ppm) 7.54-7.61 (m, 3 Η) 7.41 (t 1 Η) 7.06-7.13 (m, 4 Η) 6.69 (br. s„ 1H)5.13 (s, 1 H) 4.30-4.43 (m, 2 H) 4.17-4.24 (m, 1H)3.11 (t, 2 H) 2.60-2.69 (m, 2 H) 2 5 (br. s., 2 H) 1.70-1.80 (m, 4 H) 〇 MS (ESI) m/z 434 [M+H] 〇 步驟2 : 將胺中間物（56 mg，0.13 mmol)溶解於無水二氯甲烷( mL)中且攪拌2分鐘，隨後添加無水吡啶（〇 〇13 mL，〇 i mm〇1)及丙酸酐（ο· mL，〇.16 _〇1)，且將所得溶液4 室溫下攪拌i小時。藉由添加二乙胺（〇 ι〇爪乙）來中止^ 應。蒸發粗反應混合物，將殘餘物溶解於曱醇中且藉由^ 備型液相層析進行純化。彙集適當溶離份且濃縮 ^體積且用二氯甲烧萃取。將有機相經無水硫酸⑸ 煉’過濾且濃縮以生成呈白色固體狀之產物醯胺，^ mg(620/〇) ° (PPm) 9.13 (m, 1 H), 7.70 H) 7·48 (t，1 H) 7.36 (d，2 'H NMR (4〇〇 MHz, DMSO-c/6) δ (d，1 Η) 7.60 (t，1 Η) 7.52 (d，1 140374.doc -78- 201000446 Η) 7.30 (d, 2 Η) 5.30 (d, 1 Η) 4.25-4.52 (m5 3 Η) 4.00-4.21 (m, 1 Η) 3.86 (dd, 1 Η) 3.04 (t, 1 Η), 2.52 (m, 1 Η) 2.25- 2.37 (m，2 Η) 2.72-2.90 (d，2 Η) 1.45-1.70 (m, 2 Η) 0.98 (t, 3 Η)。MS (ESI) w/z 490 [Μ+Η] ο 實例33 3-側氧基-2-(2-(四氫-：2H-旅淹_4_基）乙基）_N_(4_(三氟甲氧 基）苯甲基）異吲哚啉-1-甲醯胺Step 1: 140374.doc 77- 201000446 4-(1-Phenoxy-3-(4-(trifluoromethoxy)benzylamine)-isoindolin-2-yl)piperidine The 1-butylic acid tert-butyl ester (620 mg, 1.16 mmol) was dissolved in a mixture of acetic acid (10 mL) and water (2 mL) and the solution was heated to 80 ° C and stirred for 16 hours. The reaction mixture was then evaporated and the residue was taken in EtOAc EtOAc m. The organic phase is extracted with brine and dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound Gas methoxy) phenylhydrazino)isoindoline-1-carboxamide (485 mg, 96%). NMR (400 MHz, CDC13) δ (ppm) 7.54-7.61 (m, 3 Η) 7.41 (t 1 Η) 7.06-7.13 (m, 4 Η) 6.69 (br. s„ 1H)5.13 (s, 1 H) 4.30-4.43 (m, 2 H) 4.17-4.24 (m, 1H)3.11 (t, 2 H) 2.60-2.69 (m, 2 H) 2 5 (br. s., 2 H) 1.70-1.80 (m, 4 H) 〇MS (ESI) m/z 434 [M+H] 〇 Step 2: The amine intermediate (56 mg, 0.13 mmol) was dissolved in anhydrous dichloromethane (mL) and stirred for 2 min, then anhydrous Pyridine (〇〇13 mL, 〇i mm〇1) and propionic anhydride (ο·mL, 〇.16 _〇1), and the resulting solution 4 was stirred at room temperature for 1 hour by adding diethylamine (〇ι The crude reaction mixture was evaporated, and the residue was dissolved in decyl alcohol and purified by preparative liquid chromatography. The appropriate fractions were concentrated and concentrated to volume and extracted with dichloromethane. The organic phase was filtered and concentrated with anhydrous sulfuric acid (5) to give the product decylamine as a white solid, &lt;RTI ID=0.0&gt;&gt;&&&&&&&&&&&&&&&&& t,1 H) 7.36 (d,2 'H NMR (4〇〇MHz, DMSO-c/6) δ (d,1 Η) 7.60 (t,1 Η) 7.52 (d,1 140374.doc -78- 201000446 Η) 7.30 (d , 2 Η) 5.30 (d, 1 Η) 4.25-4.52 (m5 3 Η) 4.00-4.21 (m, 1 Η) 3.86 (dd, 1 Η) 3.04 (t, 1 Η), 2.52 (m, 1 Η) 2.25- 2.37 (m, 2 Η) 2.72-2.90 (d, 2 Η) 1.45-1.70 (m, 2 Η) 0.98 (t, 3 Η). MS (ESI) w/z 490 [Μ+Η] ο Example 33 3-Phenoxy-2-(2-(tetrahydro-:2H-jursing_4_yl)ethyl)_N_(4-(trifluoromethoxy)benzyl)isoindolin-1- Formamide

根據實例1中所述之通用程序1自2-曱醯基笨甲酸（0.038 g， 0.25 mmol)、2-(四氫-2H-n底喃-4-基）乙胺（0.032 mL，0.25 mmol)及1-(異氰基曱基）-4-(三氟曱氧基）笨（0.048 mL , 0_24 mmol)合成標題化合物。白色固體，81 mg(70%)。 ]H NMR (400 MHz, DMSO-J6) δ (ppm) 9.19 (t, 1 Η) 7.67-7.73 (m, 1 Η) 7.58-7.64 (m, 1 Η) 7.50-7.57 (m, 2 Η) 7.36-7.41 (m, 2 Η) 7.30-7.36 (m, 2 Η) 5.27 (s, 1 Η) 4.35 (d, 2 Η) 3.83-3.93 (m, 1 Η) 3.75-3.82 (m, 2 Η) 3.16-3.27 (m, 2 Η) 2.95-3.06 (m, 1 Η) 1.52-1.64 (m, 2 Η) 1.36-1.52 (m，3 Η) 1.02-1.21 (m, 2 H)。MS (ESI) m/z 463 [M+H]。 實例34 3_(1-侧氧基-3-(3-(三氟甲氧基）苯甲基胺甲醢基）異吲哚琳_ 2-基）吖丁啶-1-甲酸第三丁酯 140374.doc -79- 201000446General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (0.038 g, 0.25 mmol), 2-(tetrahydro-2H-n- s- s- yl)ethylamine (0.032 mL, 0.25 mmol The title compound was synthesized from 1-(isocyanoindolyl)-4-(trifluoromethoxy)phenyl (0.048 mL, EtOAc). White solid, 81 mg (70%). ]H NMR (400 MHz, DMSO-J6) δ (ppm) 9.19 (t, 1 Η) 7.67-7.73 (m, 1 Η) 7.58-7.64 (m, 1 Η) 7.50-7.57 (m, 2 Η) 7.36 -7.41 (m, 2 Η) 7.30-7.36 (m, 2 Η) 5.27 (s, 1 Η) 4.35 (d, 2 Η) 3.83-3.93 (m, 1 Η) 3.75-3.82 (m, 2 Η) 3.16 -3.27 (m, 2 Η) 2.95-3.06 (m, 1 Η) 1.52-1.64 (m, 2 Η) 1.36-1.52 (m,3 Η) 1.02-1.21 (m, 2 H). MS (ESI) m/z 467 [M+H]. Example 34 3_(1-Sideoxy-3-(3-(trifluoromethoxy)benzylaminecarbamoyl)isoindolin-2-yl)azetidine-1-carboxylic acid tert-butyl ester 140374.doc -79- 201000446

FF

根據實例1中所述之通用程序1自2-曱醯基苯曱酸（0.060 g，0.40 mmol)、3 -胺基α丫丁咬-1-甲酸第三丁酉旨（0.069 mL，0.40 mmol)及1-(異氰基甲基）-3-(三氟甲氧基）苯 (0.080 g，0.40 mmol)合成標題化合物。白色固體，21.4 mg( 10〇/〇)。 !H NMR (500 MHz, DMSO-J6) δ (ppm) 9.25 (t, 1 Η) 7.71 (d, 1 Η) 7.62 (dt, 1 Η) 7.59-7.52 (m, 2 Η) 7.45 (t, 1 Η) 7.26 (t, 2 Η) 7.18 (s, 1 Η) 5.51 (s, 1 Η) 4.66 (m, 1 Η) 4.36 (d, 2 Η) 4.20 (dd, 1 Η) 4.07-3.95 (m, 2 Η) 1.38 (s，9 H)。MS (ESI) m/z 504 [M-Η]。 實例35 3-(1-(2-甲基-4-(三氟甲氧基）苯甲基胺甲醯基）-3-側氧基異 吲哚啉-2-基）吖丁啶-1-甲酸第三丁酯General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (0.060 g, 0.40 mmol), 3-amino-sodium-butyrate 1-carboxylic acid tert-butylate (0.069 mL, 0.40 mmol) The title compound was synthesized from 1-(isocyanomethyl)-3-(trifluoromethoxy)benzene (0.080 g, 0.40 mmol). White solid, 21.4 mg (10 〇 / 〇). !H NMR (500 MHz, DMSO-J6) δ (ppm) 9.25 (t, 1 Η) 7.71 (d, 1 Η) 7.62 (dt, 1 Η) 7.59-7.52 (m, 2 Η) 7.45 (t, 1 Η) 7.26 (t, 2 Η) 7.18 (s, 1 Η) 5.51 (s, 1 Η) 4.66 (m, 1 Η) 4.36 (d, 2 Η) 4.20 (dd, 1 Η) 4.07-3.95 (m, 2 Η) 1.38 (s, 9 H). MS (ESI) m/z 504 [M-Η]. Example 35 3-(1-(2-Methyl-4-(trifluoromethoxy)benzylaminecarbamyl)-3-oxoisoindoline-2-yl)azetidine-1 -T-butyl formate

140374.doc -80- 201000446 根據實例1中所述之通用程序1自2_曱酿基笨曱酸（37.5 mg，0.25 mmol)、3 -胺基。丫丁咬-1-曱酸第二丁醋（43.1 mg，0.25 mmol)及1_(異氰基曱基）-2_曱基_4_(三氣曱氧基） 苯（53.8 mg，0.25 mmol)合成標題化合物。白色固體，0.5 mg(0.40/〇)。 !H NMR (500 MHz, CD3OD) δ (ppm) 7.80 (d, 1 Η) 7.65 (m, 1 H) 7_57 (m，2 Η) 7.29 (d，1 Η) 7·12 (s，1 Η) 7.07 (d，1 Η) 5.43 (s, 1 Η) 4.75 (m, 1 Η) 4.45 (s, 2 Η) 4.37 (dd, 2 Η) 4.19 (m, 2 Η) 2.36 (s，3 H) 1_46 (s, 9 H)。MS (ESI) w/z 518 [M-H]。 實例36 2-(4,4-二氟環己基）-3-側氧基-]^-(4-(2,2,2-三氟乙基）苯甲 基）異吲哚啉-1-甲醯胺140374.doc -80- 201000446 The general procedure 1 described in Example 1 was carried out from 2_branched acid (37.5 mg, 0.25 mmol), 3-amino group. Butadiene bite-1-decanoic acid second vinegar (43.1 mg, 0.25 mmol) and 1_(isocyanoindolyl)-2_indolyl_4_(trioxanoxy)benzene (53.8 mg, 0.25 mmol) The title compound was synthesized. White solid, 0.5 mg (0.40/〇). !H NMR (500 MHz, CD3OD) δ (ppm) 7.80 (d, 1 Η) 7.65 (m, 1 H) 7_57 (m, 2 Η) 7.29 (d,1 Η) 7·12 (s,1 Η) 7.07 (d,1 Η) 5.43 (s, 1 Η) 4.75 (m, 1 Η) 4.45 (s, 2 Η) 4.37 (dd, 2 Η) 4.19 (m, 2 Η) 2.36 (s,3 H) 1_46 (s, 9 H). MS (ESI) w/z 518 [M-H]. Example 36 2-(4,4-Difluorocyclohexyl)-3-yloxy-]^-(4-(2,2,2-trifluoroethyl)benzyl)isoindolin-1- Formamide

根據實例17中所述之通用程序3自氣化4,4_二氟環己銨 (51.5 mg，0.30 mmol)、三乙胺（0.05 mL，〇 36 mm〇1) ' 孓 曱醯基苯甲酸（45 mg，0.30 mm〇i)&amp; 異氰基曱基-4_ (2,2,2-二氟乙基）苯（60 mg，〇 3〇 mm〇i)合成標題化合物。 藉由矽膠管柱層析使用二氯曱烷：曱醇=1〇〇:〇至95:5作為 梯度來純化粗產物。淺黃色固體，88 mg(63〇/〇)。 H NMR (400 MHz, CDC13) δ (ppm) 7.75 (d, 1H) 7.56-7.63 140374.doc -81 - 201000446 (m, 2 Η) 7.47-7.52 (m, 1 Η) 7.19 (d, 2H)7.08(d, 2H)6.12(m, lH)5.10(s, 1 H) 4.48 (dd, 1 H) 4.25 (dd, 1H)4.11-4.21 (m, 1 H) 3_32 (q，2 H) 2.03-2.20 (m, 2 H) 1.70-1.96 (m, 6 H)。19F NMR (400 MHz, CDC13) δ (ppm) -66.33、-66_36、-66.39、 -93.93、-94.57。MS (ESI) m/z 467 [M+H]。 實例37 N-(3,4-二曱基苯甲基）-3-側氧基-2-(四氫-2H-哌喃-4-基）異 吲哚啉_1-甲醯胺Self-gasification of 4,4-difluorocyclohexylammonium (51.5 mg, 0.30 mmol), triethylamine (0.05 mL, 〇36 mm〇1) ' mercaptobenzoic acid according to the general procedure 3 described in Example 17. (45 mg, 0.30 mm 〇i) &amp; Isocyanoindol-4-(2,2,2-difluoroethyl)benzene (60 mg, 〇3〇mm〇i). The crude product was purified by silica gel column chromatography using dichloromethane: dec. Light yellow solid, 88 mg (63 〇 / 〇). H NMR (400 MHz, CDC13) δ (ppm) 7.75 (d, 1H) 7.56-7.63 140374.doc -81 - 201000446 (m, 2 Η) 7.47-7.52 (m, 1 Η) 7.19 (d, 2H)7.08 (d, 2H) 6.12(m, lH)5.10(s, 1 H) 4.48 (dd, 1 H) 4.25 (dd, 1H)4.11-4.21 (m, 1 H) 3_32 (q,2 H) 2.03-2.20 (m, 2 H) 1.70-1.96 (m, 6 H). 19F NMR (400 MHz, CDC13) δ (ppm) - 66.33, -66_36, -66.39, -93.93, -94.57. MS (ESI) m/z 467 [M+H]. Example 37 N-(3,4-Dimercaptobenzyl)-3-oxo-2-(tetrahydro-2H-pyran-4-yl)isoporphyrin-1-carboxamide

在室溫下，將1-(3-二曱基胺基丙基）_3_乙基碳化二亞胺 鹽酸鹽（150 mg ’ 0.785 mmol)及1-羥基苯并三唑水合物 (105 mg ’ 0.785 mmol)添加至（3，4-二曱基苯基）甲胺（6〇 mg, 0.44 mmol)及 3-側氧基-2-(四氫 琳-1 -曱酸（1 00 mg，0.383 mmol)於無水四氫〇夫喃（1 〇 mL)中 之溶液中。將反應混合物攪拌i 6小時，隨後在真空中濃 縮。將粗殘餘物溶解於乙酸乙酯（3〇 mL)中，用水（2〇 mL)、鹽水（20 mL)洗滌，經無水硫酸鈉乾燥，過濾且在減 壓下濃縮。藉由矽膠管柱層析使用庚烷：乙酸乙酯=5〇:5〇 至30:70%來純化粗化合物’從而提供呈固體狀之標題化合 物，63 mg(690/〇) 〇 140374.doc -82- 201000446 】H NMR (400 MHz CDn ^ x ^ 5 ^UC13) δ (ppm) 7.62-7.72 (m5 1 H) 7.53-7.62 (m, 2 H) 7 42 ft i uw Λ )1 H) 6.99 (d, 1 H) 6.74-6.89 (m, 2 H) 6.42 (t, 1 H) 5 12 1 u、， } 1 H) 4.32-4.48 (m, 1 H) 4.17-1-(3-Dimercaptoaminopropyl)_3_ethylcarbodiimide hydrochloride (150 mg '0.785 mmol) and 1-hydroxybenzotriazole hydrate (105 mg) at room temperature '0.785 mmol) was added to (3,4-dimercaptophenyl)methanamine (6 mg, 0.44 mmol) and 3-oxo-2-(tetrahydrolin-1 -nonanoic acid (1 00 mg, 0.383 mmol), EtOAc (3 mL EtOAc) Washed with water (2 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered and evaporated. : 70% to purify the crude compound' to provide the title compound as a solid, 63 mg (690 / 〇) 〇 140374.doc -82 - 201000446 】H NMR (400 MHz CDn ^ x ^ 5 ^UC13) δ (ppm) 7.62-7.72 (m5 1 H) 7.53-7.62 (m, 2 H) 7 42 ft i uw Λ )1 H) 6.99 (d, 1 H) 6.74-6.89 (m, 2 H) 6.42 (t, 1 H) 5 12 1 u,, } 1 H) 4.32-4.48 (m, 1 H) 4.17-

4.32 (m,2H)3.97 (td, 2 H) 3.31.3.52 (m, 2 H) 2.19 (s, 3 H) 2.14 (s, 3 H) 1.80-2.00 (m, 2 H) 1.62-1.80 (m, 2 H) 〇 MS (ESI) w/z 379 [M+H]。 實例384.32 (m,2H)3.97 (td, 2 H) 3.31.3.52 (m, 2 H) 2.19 (s, 3 H) 2.14 (s, 3 H) 1.80-2.00 (m, 2 H) 1.62-1.80 (m , 2 H) 〇MS (ESI) w/z 379 [M+H]. Example 38

3-側氧基-2-(四氫_2H“底味_4_基）娜_(4 (三氟甲基）苯基) 環丙基）異吲哚啉-1_甲醯胺3-Sideoxy-2-(tetrahydro-2H "bottom _4_yl) Na_(4(trifluoromethyl)phenyl)cyclopropyl)isoindoline-1_carboxamide

根據關於實例37所述之方法自無水四氫呋喃mL)中之 3-側氧基-2-(四氫-2H-哌喃-4-基）異吲哚啉_卜曱酸（1〇〇 mg’ 0.383 mmol)、三氟曱基）苯基）環丙胺（6〇 mg， 0.407 mmol)、l-(3-二曱基胺基丙基）_3乙基碳化二亞胺鹽 酸鹽（100 mg，0.523 mmol)及1-羥基苯并三唑水合物（1〇〇 mg，0_74 mmol)合成標題化合物。固體，33 mg(22%)。 H NMR (400 MHz, CDC13) δ (ppm) 7.66 (d, 1 Η) 7.65-7.47 (m，3 Η) 7.40 (d，2 Η) 7.06-6.93 (m，3 Η) 5.10 (s, 1 Η) 4.45-4.28 (m, 1 Η) 4.06-3.89 (m, 2 Η) 3.51-3.37 (m, 2 Η) 1.93-1.68 (m, 4 Η) 1.44-1.32 (m, 1 Η) 1.32-1.23 (m, 1 Η) 1.23-1.08 (m, 2 H)。MS (ESI) m/z 445 [M+H]。 140374.doc •83- 201000446 實例39 4-經基-3-側氧基_2-(四氫_2H_哌喃_4_基）_N_(4_(三氟甲氧 基）苯甲基）異吲哚琳甲酿胺3-Phenoxy-2-(tetrahydro-2H-pyran-4-yl)isoindoline-dibenzoic acid (1 mg) from anhydrous tetrahydrofuran (mL) according to the procedure described in Example 37 0.383 mmol), trifluoromethyl)phenyl)cyclopropylamine (6 mg, 0.407 mmol), l-(3-didecylaminopropyl)_3 ethylcarbodiimide hydrochloride (100 mg, The title compound was synthesized from 0.523 mmol) and 1-hydroxybenzotriazole hydrate (1 mg, 0-74 mmol). Solid, 33 mg (22%). H NMR (400 MHz, CDC13) δ (ppm) 7.66 (d, 1 Η) 7.65-7.47 (m,3 Η) 7.40 (d,2 Η) 7.06-6.93 (m,3 Η) 5.10 (s, 1 Η ) 4.45-4.28 (m, 1 Η) 4.06-3.89 (m, 2 Η) 3.51-3.37 (m, 2 Η) 1.93-1.68 (m, 4 Η) 1.44-1.32 (m, 1 Η) 1.32-1.23 ( m, 1 Η) 1.23-1.08 (m, 2 H). MS (ESI) m/z 445 [M+H]. 140374.doc •83- 201000446 Example 39 4-Thryl-3-oxooxy-2-(tetrahydro-2H-pyran-4-yl)_N_(4-(trifluoromethoxy)phenylmethyl)吲哚琳甲甲胺

步驟1 : 根據關於實例37所述之方法自四氫呋喃（1〇 mL)中之4-(甲氧基甲氧基）-3-側氧基_2_(四氫_2H_哌喃_4_基）異吲哚 啉-1-曱酸（200 mg，〇.623 mm〇1)、（4_(三氟曱氧基）苯基）甲 胺（170 mg，0.889 mm〇i)、bp·二曱基胺基丙基）_3_乙基 碳化二亞胺鹽酸鹽（2〇〇 mg，1 〇4 mni〇l)及1-羥基苯并三唑 水合物（100 mg，0.74 mmol)合成4-(甲氧基甲氧基）_3_側氧 基-2-(四氫-2H-哌喃-4-基）-N-(4-(三氟曱氧基）苯曱基）異吲 °朵啉-1 -曱醯胺。固體，i 〇 mg(3 5 · 8%)。 步驟2 : 將4-(曱氧基曱氧基）_3-側氧基-2-(四氫-2H-哌喃_4-基）_ N-(4-(三氟曱氧基）苯曱基）異吲哚啉-i -曱醯胺（11〇 ， 0.22 mmol)之無水四氫呋喃（1〇 mL)溶液置於氮氣氣氛下且 冷卻至0°C。使HC1氣體在反應混合物中鼓泡5分鐘，隨後 在室溫下擾拌1小時。在真空中移除溶劑且藉由石夕膠管柱 層析使用己烧··乙酸乙醋=100:0至30:70作為梯度來純化粗 140374.doc • 84- 201000446 產物以生成所需化合物，4〇 mg(40%)。 H NMR (400 MHz, CDC13) δ (ppm) 8.32 (s, 1 Η) 7.42-7.61 (m, 3 Η) 7.20 (d, 2 Η) 7.07 (d, 1 Η) 6.93 (d, 1 Η) 6.13 (br. s., 1 H) 5.13 (s, 1 H) 4.32-4.56 (m, 2 H) 4.23 (t, 1 H) 3.86- 4.10 (m, 2 H) 3.43 (q, 2 H) 1.76-2.06 (m, 2 H) 1.69 (br. s., 2 H) ° MS (ESI) m/z 451 [M+H] ° 實例40 4-羥基·Ν-(4-異丙基苯甲基）_3·側氧基_2 (四氫_2H_哌喃_4_ 基）異吲哚琳-1-甲醯胺Step 1: 4-(methoxymethoxy)-3-oxo-2-(4-tetrahydro-2H-pyran-4-yl) from tetrahydrofuran (1 mL) according to the procedure described in Example 37 Isoporphyrin-1-decanoic acid (200 mg, 〇.623 mm〇1), (4_(trifluorodecyloxy)phenyl)methanamine (170 mg, 0.889 mm〇i), bp·dioxin Synthesis of 4-amino-propyl)_3_ethylcarbodiimide hydrochloride (2〇〇mg, 1 〇4 mni〇l) and 1-hydroxybenzotriazole hydrate (100 mg, 0.74 mmol) (methoxymethoxy)_3_sideoxy-2-(tetrahydro-2H-piperidin-4-yl)-N-(4-(trifluoromethoxy)phenylindenyl)isoindole Porphyrin-1 - decylamine. Solid, i 〇 mg (3 5 · 8%). Step 2: 4-(decyloxymethoxy)_3-o-oxy-2-(tetrahydro-2H-pyran-4-yl)_N-(4-(trifluorodecyloxy)phenylhydrazine A solution of isoporphyrin-i-guanamine (11 〇, 0.22 mmol) in dry tetrahydrofuran (1 mL) was placed under nitrogen and cooled to 0 °C. The HC1 gas was bubbled through the reaction mixture for 5 minutes and then scrambled for 1 hour at room temperature. The solvent was removed in vacuo and the crude 140374.doc • 84- 201000446 product was purified by a sulphuric acid-ethyl acetate = 100:0 to 30:70 gradient to afford the desired compound. 4〇mg (40%). H NMR (400 MHz, CDC13) δ (ppm) 8.32 (s, 1 Η) 7.42-7.61 (m, 3 Η) 7.20 (d, 2 Η) 7.07 (d, 1 Η) 6.93 (d, 1 Η) 6.13 (br. s., 1 H) 5.13 (s, 1 H) 4.32-4.56 (m, 2 H) 4.23 (t, 1 H) 3.86- 4.10 (m, 2 H) 3.43 (q, 2 H) 1.76- 2.06 (m, 2 H) 1.69 (br. s., 2 H) ° MS (ESI) m/z 451 [M+H] ° Example 40 4-hydroxy-indole-(4-isopropylbenzyl) _3·Sideoxy-2 (tetrahydro-2H_pyranyl-4-yl)isoindolin-1-carboxamide

根據關於貫例39所述之方法自四氫吱喃（7 mL)中之4_(曱 氧基曱氧基）-3-侧氧基-2-(四氫-2H-哌喃-4-基）異吲哚啉_ι_ 甲酸（150 mg，0.466 mmol)、（4-異丙基苯基）曱胺（1〇〇 mg，0.669 mmol)、1-(3-二甲基胺基丙基）_3_乙基碳化二亞 胺鹽酸鹽（150 mg ’ 0.785 mmol)及1-羥基苯并三唑水合物 (75 mg，0.555 mmol)合成標題化合物。固體，71 mg(78.9%)。 ]H NMR (400 MHz, CDC13) δ (ppm) 8.33 (s, 1 H) 7.46 (t, 1 H) 7.08-7.19 (m, 3 H) 6.99-7.08 (m, 2 H) 6.92 (d, 1 H) 5.81-5.95 (m, 1 H)5.10(s, 1 H) 4.47 (dd, 1 H) 4.10-4.29 (m, 140374.doc -85- 201000446 2 Η) 3.88-4.08 (m, 2 Η) 3.41 (q, 2 Η) 2.87 (dt, 1 Η) 1.76-2.06 (m, 2 Η) 1.66 (td, 2 Η) 1.22 (d，6 Η)。MS (ESI) w/z 407 [M-H]。 實例41 2-(4,4-二氟環己基）-4-羥基-3-側氧基-N-(4-(三氟甲基）苯甲 基）異吲哚啉-1-甲醯胺4_(decyloxydecyloxy)-3-oxooxy-2-(tetrahydro-2H-pyran-4-yl) from tetrahydrofuran (7 mL) according to the method described in Example 39 Isoporphyrin_ι_ formic acid (150 mg, 0.466 mmol), (4-isopropylphenyl)decylamine (1 mg, 0.669 mmol), 1-(3-dimethylaminopropyl) _3_Ethylcarbodiimide hydrochloride (150 mg '0.785 mmol) and 1-hydroxybenzotriazole hydrate (75 mg, 0.555 mmol). Solid, 71 mg (78.9%). ]H NMR (400 MHz, CDC13) δ (ppm) 8.33 (s, 1 H) 7.46 (t, 1 H) 7.08-7.19 (m, 3 H) 6.99-7.08 (m, 2 H) 6.92 (d, 1 H) 5.81-5.95 (m, 1 H) 5.10(s, 1 H) 4.47 (dd, 1 H) 4.10-4.29 (m, 140374.doc -85- 201000446 2 Η) 3.88-4.08 (m, 2 Η) 3.41 (q, 2 Η) 2.87 (dt, 1 Η) 1.76-2.06 (m, 2 Η) 1.66 (td, 2 Η) 1.22 (d,6 Η). MS (ESI) w/z 407 [M-H]. Example 41 2-(4,4-Difluorocyclohexyl)-4-hydroxy-3-oxo-N-(4-(trifluoromethyl)benzyl)isoindoline-1-carboxamide

FF

根據關於實例39所述之方法自四氫呋喃（10 mL)中之2-(4,4-二氟環己基）-4-(曱氧基曱氧基）-3-側氧基異吲哚啉-曱酸（130 mg，0.366 mmol)、（4-(三氟曱基）苯基）甲胺（1〇〇 mg ’ 0.571 mmol)、1-(3-二甲基胺基丙基）-3 -乙基碳化二亞胺 鹽酸鹽（150 mg’ 0.785 mmol)及1-經基苯并三峻水合物（1〇〇 mg，0.740 mmol)合成標題化合物。固體，47.7 mg(；58%)。 !HNMR (400 MHz, CDC13)6 (ppm) 8.31 (s, 1 H) 7.41-7.60 (m, 3 H) 7.15-7.35 (m, 2 H) 7.06 (d, 1 H) 6.94 (d, 1H) 6.02 (br. s., 1 H) 5.10 (s, 1 H) 4.31-4.57 (m, 2 H) 4.10 (br. S.s 1 H) 2.03-2.20 (m，2 H) 1.70-1.96 (m，6 H)。MS (ESI) m/z 469 [M+H]。 實例42 N-(4-溴苯甲基）-3-側氧基-2-(四氫-2H-哌喃_4_基）異e引嗓 啉-1-甲醯胺 140374.doc •86· 2010004462-(4,4-Difluorocyclohexyl)-4-(decyloxydecyloxy)-3-oxooxyisoindoline in tetrahydrofuran (10 mL) according to the procedure described in Example 39 Capric acid (130 mg, 0.366 mmol), (4-(trifluoromethyl)phenyl)methanamine (1 〇〇 mg '0.571 mmol), 1-(3-dimethylaminopropyl)-3 - The title compound was synthesized from ethyl carbodiimide hydrochloride (150 mg &lt;RTI ID=0.0&gt; Solid, 47.7 mg (; 58%). !HNMR (400 MHz, CDC13)6 (ppm) 8.31 (s, 1 H) 7.41-7.60 (m, 3 H) 7.15-7.35 (m, 2 H) 7.06 (d, 1 H) 6.94 (d, 1H) 6.02 (br. s., 1 H) 5.10 (s, 1 H) 4.31-4.57 (m, 2 H) 4.10 (br. Ss 1 H) 2.03-2.20 (m, 2 H) 1.70-1.96 (m, 6 H). MS (ESI) m/z 469 [M+H]. Example 42 N-(4-Bromobenzyl)-3-oxooxy-2-(tetrahydro-2H-pyran-4-yl)iso-e-pilinolin-1-carboxamide 140374.doc •86 · 201000446

根據實例1中所述之通用程序1自2-曱醯基苯甲酸（0.113 g， 0.75 mmol)、四氫_2η_π底喃 _4_ 胺（〇·〇76 mL，0.75 mmol)及 臭異氰基曱基）笨（〇·140 g，0.71 mmol)合成標題化合 物。白色固體，128 mg(40%)。 丨H NMR (400 MHz，DMSO-A) δ (ppm) 9.16 (t，1 H) 7.67-7.72 (m, 1 H) 7.57-7.63 (m, 1 H) 7.49-7.55 (m, 3 H) 7.45-7.49 (m, 1 H) 7.18-7.25 (m, 2 H) 5.32 (s, 1 H) 4.29 (d, 2 H) 4.06-4.17 (m, 1 H) 3.89 (dd, 1 H) 3.78-3.86 (m, 1 H) 3.35-3.41 (m, 2 H) 1.76-1.92 (m, 1 H) 1.63-1.74 (m，3 H)。MS (ESI) w/z 430 [M+H]。 實例43 N-(4-溴苯甲基）-3-側氧基-2-(四氫-2H-哌喃_4_基）異吲鳴 啉-1-甲醯胺，異構物2General procedure 1 as described in Example 1 from 2-mercaptobenzoic acid (0.113 g, 0.75 mmol), tetrahydro-2η_π- s- _4_amine (〇·〇76 mL, 0.75 mmol) and odorous cyano The title compound was synthesized as a succinimide (yield: 140 g, 0.71 mmol). White solid, 128 mg (40%).丨H NMR (400 MHz, DMSO-A) δ (ppm) 9.16 (t, 1 H) 7.67-7.72 (m, 1 H) 7.57-7.63 (m, 1 H) 7.49-7.55 (m, 3 H) 7.45 -7.49 (m, 1 H) 7.18-7.25 (m, 2 H) 5.32 (s, 1 H) 4.29 (d, 2 H) 4.06-4.17 (m, 1 H) 3.89 (dd, 1 H) 3.78-3.86 (m, 1 H) 3.35-3.41 (m, 2 H) 1.76-1.92 (m, 1 H) 1.63-1.74 (m, 3 H). MS (ESI) w/z 430 [M+H]. Example 43 N-(4-Bromobenzyl)-3-oxo-2-(tetrahydro-2H-pyran-4-yl)isoindolin-1-carbamide, isomer 2

異構物2 b=未知絕對構型 對外消旋N-(4-溴苯甲基）-3-側氧基-2-(四氫_2H_哌喃_4_ 140374.doc •87- 201000446 基）異°引°朵啉-1-曱醯胺（128 mg，0 3 mmol)進行在Berger Multlgram 11系統上執行之對映異構分離。管柱：Chiralpak AD， 21·2χ250 mm ;移動相：40%乙醇及60% C02 ;流動速率： 50毫升/分鐘，提供兩種分離之異構物，其為在4.2分鐘時 溶離之異構物1及在6.8分鐘時溶離之異構物2。收集、蒸 發且分別處理分離之異構物。藉由HPLC使用SFC BergerIsomer 2 b = unknown absolute configuration racemic N-(4-bromobenzyl)-3-oxo-2-(tetrahydro-2H_pyranyl-4_140374.doc •87- 201000446 base Enantiomeric separation performed on a Berger Multlgram 11 system was carried out by iso-oxo-l-indoleamine (128 mg, 0 3 mmol). Column: Chiralpak AD, 21·2χ250 mm; mobile phase: 40% ethanol and 60% C02; flow rate: 50 ml/min, providing two separated isomers, which are isomers dissolved at 4.2 minutes 1 and isomer 2 dissolved at 6.8 minutes. The separated isomers are collected, evaporated and separately treated. Use SFC Berger with HPLC

Analytix(管柱：Repr〇sil_AM(AD)，4 6χ25〇 mrn，5 μηι ; 移動相：40。/。乙醇及60% c〇2 ;流動速率：2毫升/分鐘）來 分析樣品，異構物2(6.2分鐘），41 mg，對映異構純度： 99%。 'H NMR (400 MHz, DMSO-J6) δ (ppm) 9.16 (t, 1 H) 7.67- 7-72 (m, 1 H) 7.57-7.63 (m, 1 H) 7.49-7.55 (m, 3 H) 7.45. 7.49 (m, 1 H) 7.18-7.25 (m, 2 H) 5.32 (s, 1 H) 4.29 (d, 2 H) 4.06-4.17 (m, 1 H) 3.89 (dd, 1 H) 3.78-3.86 (m, 1 H) 3.35.Analytix (column: Repr〇sil_AM (AD), 4 6χ25〇mrn, 5 μηι; mobile phase: 40% ethanol and 60% c〇2; flow rate: 2 ml/min) to analyze samples, isomers 2 (6.2 min), 41 mg, enantiomeric purity: 99%. 'H NMR (400 MHz, DMSO-J6) δ (ppm) 9.16 (t, 1 H) 7.67- 7-72 (m, 1 H) 7.57-7.63 (m, 1 H) 7.49-7.55 (m, 3 H 7.45. 7.49 (m, 1 H) 7.18-7.25 (m, 2 H) 5.32 (s, 1 H) 4.29 (d, 2 H) 4.06-4.17 (m, 1 H) 3.89 (dd, 1 H) 3.78 -3.86 (m, 1 H) 3.35.

3.41 (m, 2 H) 1.76-1.92 (m, 1 H) 1.63-1.74 (m, 3 H) 〇 MS (ESI) m/z 430 [M+H]。 生物測試 電壓閘控鈉通道在細胞系中之表現： 如此項技術中所熟知，將編碼所關注之電壓閘控鈉通道 之全長蛋白的基因在合適啟動子下選殖且表現於合適細胞系 中。使用如此建構之穩定細胞系來進行篩選檢定以鑑別對電 壓閘控鈉通道有效之合適化合物。合適篩選檢定如下。3.41 (m, 2 H) 1.76-1.92 (m, 1 H) 1.63-1.74 (m, 3 H) 〇 MS (ESI) m/z 430 [M+H]. Biological test voltage-gated sodium channel performance in cell lines: As is well known in the art, a gene encoding a full-length protein of a voltage-gated sodium channel of interest is selected under a suitable promoter and expressed in a suitable cell line. . Screening assays are performed using such constructed stable cell lines to identify suitable compounds that are effective for voltage-gated sodium channels. A suitable screening assay is as follows.

Li +流入量檢定 將表現所關注之電壓閘控鈉通道之細胞系以合適細胞密 140374.doc -88- 201000446 度塗於習知96或384孔組織培養盤中（細胞密度例如在96孔 培養盤中40000個細胞/孔或在384孔培養盤中20000個細胞/ 孔）。隨後’使用合適的市售洗滌器（例如EL-405洗滌器）用 合適無Na緩衝液反覆洗滌細胞，直至所有組織培養基均自 孔中移除。合適之無鈉緩衝液可具有以下組成（mM):氯 化膽鹼 137、KC1 5.4、MgS04 0·81、CaCl2 0.95、葡萄糖 5.5 5及取？£3 25化117_4)，但其亦可具有其他合適組成。 在完成所有洗滌步驟之後，將細胞在合適之無鈉緩衝液中 培月1 5 min。隨後，將無鈉緩衝液移除且將細胞在3下 用虽含LiCl之緩衝液培育60 min。LiCl緩衝液亦富含鉀離 子’從而對細胞產生去極化刺激。該緩衝液可具有以下組 成（mM) : UC1 1〇〇、KC1 50、MgS04 0.81、CaCl2 0.95、 葡萄糖5.55及HEPES 25(pH 7.4) ’但其亦可具有其他合適 組成。為增強信號雜訊比，可向培養基中添加有效濃度 (例如100 μΜ)之電壓閘控鈉通道開放劑藜蘆定（veratridine) U 或任何其他合適的電壓閘控鈉通道開放劑以增強信號偵 測。此外，且亦為了增強信號雜訊比，亦可向培養基中添 加有效濃度（例如10 pg/ml)之合適蠍子毒，以延緩通道失 活。為發現所關注電壓閘控鈉通道之調節劑，可在檢定中 補充來自化合物庫之化合物。將所關注化合物添加至富含 。之溶液中，每孔一種化合物。在培育期結束時，用無鈉 緩衝液反覆洗滌細胞，直至移除所有細胞nLicl。經由使 細胞與曲拉通（trit〇n)( 1 %) —起培育丨5 min或任何其他合適 方法獲得溶胞物。隨後，將所得溶胞物引入原子吸收分光 H0374.doc -89- 201000446 光度計中，由此定量上述程序期間之Li流入量。 所述檢定可用任何原子吸收分光光度計使用96孔形式、 3 84孔形式之培養盤或任何其他習知培養盤形式來進行。 所述檢定可用於表現所指定的任何一或多個電壓閘控鈉通 道α亞單位以及一個電壓閘控a亞單位與任何一或多個β亞 單位之任何指定組合的細胞系。 若需要，則藉由短暫性共轉染或經由建立穩定共轉染細 胞系來表現合適鉀漏離子通道（例如TREK-1 )，從而可另外 使所選細胞系超極化。可在全細胞膜片鉗、穿孔膜片鉗或 習知兩電極電壓鉗中使用傳統細胞内電生理學來證實漏K 電流之成功表現。如上所述，隨後可使用經改良以成功表 現所關注電壓閘控鈉通道以及所轉染之合適鉀漏離子通道 的所選細胞系以使用原子吸收光譜法進行篩選。 全細胞電壓甜電生理學檢定 穩定表現所關注電壓閘控鈉通道之細胞中鈉電流的電生 理學記錄證實有效且提供特異性影響該等通道之化合物的 效能之功能量度。 電生理學研究可使用自動膜片鉗電生理學平台（如 IonWorks HT、IonWorks Quattro、PatchXpress)或任何其他合 適平台來執行。將表現所關注電壓閘控鈉通道之細胞系塗 於如自動膜片鉗平台之製造商所提供的適當孔組織培養盤 中。根據自動膜片鉗平台之製造商所提供之說明來使用該 等實驗之合適細胞外及細胞内緩衝液。經由整合於平台中 之微量分注系統（pipetting system)將表現所關注電壓閘控 140374.doc -90- 201000446 鈉通道蛋白之細胞暴露於藥物。使用合適㈣刺激方案來 活化所關，主之電屢㈣鈉通道蛋白。合適刺激方案可由八 個电歷脈衝組成，該人個電壓脈衝各自達，⑽且長度為 50 ms ’且在’ mV或·65 mv之電勢下彼此間隔别咖， 但其亦可具有其他合適參數。 電生理學研究亦可如文獻中所述使用標準膜片鉗技術之 全細胞構型來執行。在該檢定中，藉由習知微灌注系統將Li + influx assay The cell line expressing the voltage-gated sodium channel of interest is applied to a conventional 96 or 384-well tissue culture dish at a suitable cell density of 140374.doc -88 - 201000446 (cell density, for example, in 96-well culture) 40,000 cells/well in the dish or 20,000 cells/well in a 384-well plate). The cells are then washed repeatedly with a suitable commercially available scrubber (e.g., an EL-405 scrubber) with a suitable Na-free buffer until all tissue culture medium is removed from the wells. A suitable sodium-free buffer may have the following composition (mM): choline chloride 137, KC1 5.4, MgS04 0·81, CaCl2 0.95, glucose 5.5 5 and taken? £3 25 117_4), but it may also have other suitable compositions. After all washing steps have been completed, the cells are incubated for 15 minutes in a suitable sodium-free buffer. Subsequently, the sodium-free buffer was removed and the cells were incubated with 3 buffers containing LiCl for 60 min. LiCl buffer is also rich in potassium ions&apos; to produce depolarizing stimulation of the cells. The buffer may have the following composition (mM): UC1 1〇〇, KC1 50, MgS04 0.81, CaCl2 0.95, glucose 5.55, and HEPES 25 (pH 7.4)' but it may have other suitable compositions. To enhance the signal-to-noise ratio, an effective concentration (eg, 100 μΜ) of voltage-gated sodium channel opener veratridine U or any other suitable voltage-gated sodium channel opener can be added to the medium to enhance signal detection. Measurement. In addition, in order to enhance the signal-to-noise ratio, an appropriate concentration of scorpion venom (e.g., 10 pg/ml) may be added to the medium to delay channel inactivation. In order to find a regulator of the voltage-gated sodium channel of interest, the compound from the compound library can be supplemented in the assay. Add the compound of interest to the rich. In the solution, one compound per well. At the end of the incubation period, the cells were washed repeatedly with sodium-free buffer until all cells were removed from nLicl. The lysate is obtained by incubating the cells with trit〇n (1%) for 5 min or any other suitable method. Subsequently, the obtained lysate was introduced into an atomic absorption spectrophotometer H0374.doc -89 - 201000446 luminometer, whereby the amount of Li inflow during the above procedure was quantified. The assay can be carried out using any atomic absorption spectrophotometer using a 96 well format, 3 84 well format plate or any other conventional culture plate format. The assay can be used to represent any one or more of the voltage-gated sodium channel alpha subunits specified, as well as a cell line of any given combination of voltage gated a subunits and any one or more beta subunits. If desired, the appropriate potassium leakage channel (e.g., TREK-1) can be expressed by transient co-transfection or by establishing a stable co-transfected cell line, thereby additionally hyperpolarizing the selected cell line. Traditional intracellular electrophysiology can be used in whole cell patch clamps, perforated patch clamps or conventional two-electrode voltage clamps to confirm the successful performance of the leakage K current. As described above, selected cell lines modified to successfully represent the voltage-gated sodium channel of interest and the appropriate potassium-leakage channel transfected can be used for screening using atomic absorption spectroscopy. Whole-Cell Voltage Sweet Electrophysiological Assays Electrophysiological recordings of sodium currents in cells stably expressing the voltage-gated sodium channel of interest are validated and provide functional measures that specifically affect the potency of the compounds of the channels. Electrophysiological studies can be performed using an automated patch clamp electrophysiology platform (such as IonWorks HT, IonWorks Quattro, PatchXpress) or any other suitable platform. The cell line expressing the voltage-gated sodium channel of interest is applied to a suitable well tissue culture dish as provided by the manufacturer of the automated patch clamp platform. The appropriate extracellular and intracellular buffers for these experiments were used according to the instructions provided by the manufacturer of the automated patch clamp platform. Cells expressing the sodium gate protein of interest are exposed to the drug via a micropipetting system integrated into the platform. Use the appropriate (four) stimulation protocol to activate the activated, the main electricity (four) sodium channel protein. A suitable stimulation scheme may consist of eight electrical pulse pulses, each of which has a voltage pulse of (10) and a length of 50 ms ' and is spaced apart from each other at a potential of 'mV or · 65 mv, but may have other suitable parameters . Electrophysiological studies can also be performed as described in the literature using a whole cell configuration of standard patch clamp techniques. In this test, by the conventional micro-perfusion system

表現所關注之人類電壓閘控鈉通道蛋白之細胞暴露於藥物 且使用合適電壓刺激方案來活化電壓閘控鈉通道。 活體内實驗 當藉由全身性注射將本發明化合物給予小鼠或大鼠時， 該化合物可特異性減少福馬林（formalin)測試中之疼痛行 為°亥測°式為人類臨床疼痛之已接受模型，包括疼痛感受 器活化、發炎、末梢致敏及中樞致敏之成員（A Tj0lsen等 人，尸⑴7外2, 51, 5)。因此，可推斷本發明化合物適用 作緩解各種來源之疼痛的治療劑。 式I化合物可在大鼠關節内FCA(佛氏完全佐劑（Freund,s complete adjuvant))測試（發炎疼痛模型）(/β而⑺&amp;等人， 7PS5，W, 205-72)及大鼠 Chung神經損傷測 〇式（神’Ik痛模型）（幻w及50, 355)中展示止 痛活性。在給藥後可在動物模型中獲得止痛作用，其並不 產生阻斷神經纖維中之傳導之組織濃度。因此，Kornet及 Thio之公開案中所提及之該等化合物之局部麻醉特性不能 說明止痛作用。全身性投與之後的止痛功效並非具有局部 140374.doc •91 · 201000446 麻醉作用之藥物的一般特性（心0&quot;等人，召nj&lt;Cells expressing human voltage-gated sodium channel proteins of interest are exposed to the drug and a voltage-stimulated sodium channel is activated using a suitable voltage stimulation protocol. In vivo experiments When a compound of the present invention is administered to a mouse or a rat by systemic injection, the compound specifically reduces the pain behavior in the formalin test. The accepted model is a accepted model of human clinical pain. , including members of pain receptor activation, inflammation, peripheral sensitization, and central sensitization (A Tj0lsen et al., corpse (1) 7 outside 2, 51, 5). Therefore, it can be inferred that the compounds of the present invention are useful as therapeutic agents for relieving pain from various sources. The compound of formula I can be tested in rat intra-articular FCA (Freund, s complete adjuvant) (inflamed pain model) (/β and (7) &amp; et al, 7PS5, W, 205-72) and rats The analgesic activity is shown in the Chung nerve injury test (God's Ik pain model) (Fantasy w and 50, 355). Analgesic effects can be obtained in animal models after administration, which do not produce tissue concentrations that block conduction in nerve fibers. Therefore, the local anesthetic properties of the compounds mentioned in the Kornet and Thio publications do not account for analgesic effects. The analgesic effect after systemic administration is not local. 140374.doc •91 · 201000446 General characteristics of anesthetic drugs (heart 0) et al., call nj&lt;

Anaesthesia 1988，61，165-8)。 一般而言，本發明之化合物在以上全細胞電壓鉗電生理 學檢定中有效，其中IC5。值小於1() μΜ。在本發明之一態 樣中’ IC50值小於1 μΜ。 隹上述全 Β 疋Υ硎式以上實例之損 題化合物。IC5〇值表示50%抑制所兩 » . _ ., 吊之化合物濃度。試;f| 結果在下表中以？1(：50值（亦即」 运、比5〇))之來爷&amp; — 此，pIC5〇值愈大’化合物愈有效。與彳 舉例而言，6 4之Dir 值表明10-64M之IC50值。 之PIC5Anaesthesia 1988, 61, 165-8). In general, the compounds of the invention are effective in the above whole cell voltage clamp electrophysiological assay, wherein IC5. The value is less than 1 () μΜ. In one aspect of the invention, the 'IC50 value is less than 1 μΜ.损 All of the above-mentioned damage compounds of the above examples. The IC5 〇 value indicates 50% inhibition of both » . _ ., hanging compound concentration. Try; f| results in the table below? 1 (: 50 value (ie, "transport, than 5 〇)) 来 &&amp; - The greater the pIC5 〇 value, the more effective the compound. For example, a Dir value of 64 indicates an IC50 value of 10-64M. PIC5

140374.doc -92-140374.doc -92-

Claims (1)

201000446 七、申請專利範圍： 1. 一種式I化合物：201000446 VII. Patent application scope: 1. A compound of formula I: 其中 R1為氫、C!-3炫基、Cw烧氧基、氰基、羥基或鹵基； 且其中該C 1 - 3院基視情況經一或多個獨立地選自經基、 C!·3烧氧基及氟基之取代基取代；且該Cu烧氧基視情況 經一或多個I基取代； m為1或2 ; R2及R3係各自且獨立地選自氫、Cl_4鹵烷基、Cl-4鹵烷 氧基、齒基、Cw烷氧基、Cl_4烷基及C3_7環烷氧基；其 中該CM環烷氧基視情況經一或多個氟基取代； 且R2及R3不可同時為氫； D為CM%烧基或C3·7雜環烷基；且其中該c37環烷基 或該&lt;C3_7雜環烷基可視情況經一或多個X4取代； X為鹵基、Cy烷基、Ci 3烷基〇Ci 3烷基、3烷氧 基苯甲基、ci-4烷基磺醯基、側氧基、R4〇(c=⑺、 〇)或C5_6雜芳基；其中該Cl]烧基、該h烧基〇Cu 140374.doc 201000446 烷基、該C!_3烷氧基及該Cl_4烷基磺醯基視情況經一或多 個氟基取代； 以為匚“烷基、cl4烷基OCi4烷基、c56環烷基或芳 基； ^為匚〗-4烧基、Cl4氟烷基或c5_6雜芳基； Li為Cw伸烧基或一鍵； 1^2為cN3伸烷基； 其中以下化合物除外： 2-(環己基甲基）_3_側氧基_N_[2_(三氟甲基）苯曱基]異 吲哚啉-1 _甲醯胺； 以及其醫藥學上可接受之鹽或異構物或該異構物之 鹽。 2 ·如請求項1之化合物，其中： Rl為氫、Ch烷基、Cn3烷氧基、鹵基或羥基； m為1 ; R係選自氫、Ci-4烷基、Cl_4鹵烷基、鹵基、Cl_4烧氧 基及烷氧基； R3為氫、C〗·4烷基、鹵基或Cl 4鹵烷氧基； 且R2及R3不可同時為氫； D為C4-6環烷基或Ch雜環烷基；其中C4_6環烷基或c4 f 雜環燒基視情況經一或多個X4取代； X4為i基、側氧基、R4〇(C = 〇)、R5(C =⑺或c5 6雜芳 基； / r4為Cw烷基； 140374.doc 201000446 R為c5.6雜芳基； Li為Cl-2伸烷基或一鍵；且 L2為CN2伸烧基。 3 ·如請求項1或2之化合物，其中m為1。 4.如請求項丨至3中任一項之化合物，其_ 5·如請求項丨至3中任一項之化合物，其y 6.如請求項1至3中任一項之化合物，其$ 7·如請求項1至3中任一項之化合物，其c 8·如請求項1至3中任一項之化合物，其t 9.如請求項1至8中任一項之化合物，其d 1 〇_如請求項1至8中任一項之化合物，j 基。 11.如請求項1至8中任一項之化合物，其t 1 2.如請求項1至8中任一項之化合物，其 CF3。 1 3 .如請求項丨至8中任一項之化合物，其c 1 4.如請求項！至8中任一項之化合物，其t 1 5 ·如請求項i至丨4中任一項之化合物，其 16. 如請求項1至14中任一項之化合物，其 17. 如請求項！至14中任一項之化合物，其 18. 如請求項1至14中任一項之化合物，其 1 9.如請求項丨至丨8中任一項之化合物，其 20 ·如請求項1至丨8中任一項之化合物，其 2 1.如請求項1至〗8中任一項之化合物，其 140374.doc ’ Rl為氫。 ^ Rl為甲基 fRl為甲氧基。 'Rl為氟基。 R為經基。 R2為·o_cf3。 _ + R2為氯基或溴 ^R2為甲氧基。 中 R2為 cf3 或-ch2- ^ r2為曱基。 R為異丙基。 中R3為氫。 中R為甲基。 中R3為氣基。 中 R3為-〇CF3。 中L1為一鍵。 中L!為亞曱基。 中1^為伸乙基。 201000446 22 ·如請求項1至2 1中任一項之化合物，其中為亞甲美。 23. 如請求項1至21中任一項之化合物，其中。 24. 如請求項1至2 1中任一項之化合物，其中q為伸場丙 基。 &quot; 25. 如請求項1至24中任一項之化合物，其中D係選自以下任 一者：吖丁啶基、四氫哌喃基、四氫呋喃基、π比嘻咬 基、吡咯啶基-2-酮、哌啶基及嗎啉基。 26. 如請求項1至24中任一項之化合物，其中d為環丁基咬产 己基。 、 27. 如請求項1至24中任一項之化合物，其中d係經X4 _取 代。 28_如請求項1至27中任一項之化合物，其中X4為氟基。 29.如請求項1至27中任一項之化合物，其中X4為_c(〇)_〇 C(CH3)3。 30·如請求項1至27中任一項之化合物，其中χ4為_c(〇)_〇_ ch(ch3)2。 31. 如請求項1至27中任—項之化合物，其中\4為_c(〇)-CHr CH3。 32. 如請求項丄至”中任—項之化合物’其中χ4為_c(〇)_cH2_ CF3。 33·如請求項i至27中任一項之化合物，其中χ4為_s〇2_ CH3。 34.如請求項丄至”中任—項之化合物，其中X4為嘧啶基。 140374.doc 201000446Wherein R1 is hydrogen, C!-3 leucoyl, Cw alkoxy, cyano, hydroxy or halo; and wherein the C1-3 parenter is optionally selected from the group consisting of a thiol group, C! a substituent substituted with 3 alkoxy groups and a fluorine group; and the Cu alkoxy group is optionally substituted with one or more I groups; m is 1 or 2; R 2 and R 3 are each independently and independently selected from hydrogen, Cl 4 halogen An alkyl group, a Cl-4 haloalkoxy group, a dentate group, a Cw alkoxy group, a C1-4 alkyl group, and a C3_7 cycloalkoxy group; wherein the CM cycloalkoxy group is optionally substituted with one or more fluorine groups; and R2 and R3 may not be hydrogen at the same time; D is CM% alkyl or C3.7 heterocycloalkyl; and wherein the c37 cycloalkyl or the &lt;C3_7 heterocycloalkyl is optionally substituted by one or more X4; X is halo , Cy alkyl, Ci 3 alkyl hydrazine Ci 3 alkyl, 3 alkoxybenzyl, ci-4 alkylsulfonyl, pendant oxy, R 4 〇 (c = (7), 〇) or C5_6 heteroaryl a base; wherein the Cl] group, the h group 〇Cu 140374.doc 201000446 alkyl, the C!_3 alkoxy group and the Cl 4 alkylsulfonyl group are optionally substituted by one or more fluorine groups; "Alkyl, cl4 alkyl OSi4 alkyl, c56 cycloalkyl or aryl; ^ is 匚〗 4 a group, a C4 fluoroalkyl group or a C5_6 heteroaryl group; Li is a Cw stretching group or a bond; 1^2 is a cN3 alkyl group; wherein the following compounds are excluded: 2-(cyclohexylmethyl)_3_sideoxy_ N_[2_(trifluoromethyl)phenylindenyl]isoindoline-1 _forminamine; and a pharmaceutically acceptable salt or isomer thereof or a salt of the same. A compound of 1, wherein: R1 is hydrogen, Ch alkyl, Cn3 alkoxy, halo or hydroxy; m is 1; R is selected from the group consisting of hydrogen, Ci-4 alkyl, Cl-4 haloalkyl, halo, Cl_4 Oxyl and alkoxy; R3 is hydrogen, C. 4 alkyl, halo or Cl 4 haloalkoxy; and R 2 and R 3 are not simultaneously hydrogen; D is C 4-6 cycloalkyl or ch heterocycloalkane Wherein a C4_6 cycloalkyl or c4f heterocycloalkyl group is optionally substituted by one or more X4; X4 is i group, pendant oxy group, R4 〇 (C = 〇), R5 (C = (7) or c5 6 hetero Aryl; /r4 is Cw alkyl; 140374.doc 201000446 R is c5.6 heteroaryl; Li is Cl-2 alkyl or one bond; and L2 is CN2 extension. 3 · As claimed in claim 1 or a compound of 2, wherein m is 1. 4. A compound according to any one of claims 3 to 3, wherein The compound of any one of claims 1 to 3, wherein the compound of any one of claims 1 to 3, such as c 8 · The compound of any one of claims 1 to 3, wherein the compound of any one of claims 1 to 8 is a compound of any one of claims 1 to 8, a j group. The compound of any one of claims 1 to 8, wherein the compound is a compound of any one of claims 1 to 8, which is CF3. 1 3. A compound according to any one of claims 8 to 5, c 1 4. If requested! The compound of any one of claims 1 to 4, wherein the compound of any one of claims 1 to 14 is the same as the compound of any one of claims 1 to 14, wherein ! The compound of any one of claims 1 to 14, wherein the compound of any one of claims 1 to 14, wherein the compound of any one of claims 1 to 20, The compound of any one of claims 1 to 8, wherein 140374.doc ' Rl is hydrogen. ^ Rl is methyl fRl is methoxy. 'Rl is a fluorine group. R is a radical. R2 is ·o_cf3. _ + R2 is chloro or bromo. R2 is methoxy. Where R2 is cf3 or -ch2-^r2 is a sulfhydryl group. R is an isopropyl group. Medium R3 is hydrogen. Where R is a methyl group. Medium R3 is a gas base. Medium R3 is -〇CF3. L1 is a key. L! is the Aachen. 1^ is an ethyl group. The compound of any one of claims 1 to 2, wherein is a methylene-amid. 23. The compound of any one of claims 1 to 21, wherein. The compound of any one of claims 1 to 21, wherein q is an exchanging propyl group. The compound according to any one of claims 1 to 24, wherein the D is selected from the group consisting of azetidinyl, tetrahydropyranyl, tetrahydrofuranyl, pi-pyridyl, pyrrolidinyl-2 a ketone, piperidinyl and morpholinyl. 26. The compound of any one of claims 1 to 24, wherein d is cyclobutyl hexanyl. The compound of any one of claims 1 to 24, wherein d is substituted by X4_. The compound according to any one of claims 1 to 27, wherein X4 is a fluorine group. The compound of any one of claims 1 to 27, wherein X4 is _c(〇)_〇 C(CH3)3. The compound according to any one of claims 1 to 27, wherein χ4 is _c(〇)_〇_ch(ch3)2. 31. The compound of any one of claims 1 to 27, wherein \4 is _c(〇)-CHr CH3. 32. The compound of any one of the claims i to 27, wherein χ4 is _s〇2_CH3, wherein the 请求4 is a compound of any one of the claims i to 27, wherein χ4 is _c(〇)_cH2_CF3. 34. The compound of claim 1, wherein X4 is pyrimidinyl. 140374.doc 201000446 35.如請求項1至27中任一 J 、之化合物，其中χ4為1 3 6.如請求項1至2 7中任一頂夕儿Λ 〆 、， η壬項之化合物，其中X4為苯甲基。 3 7 ·如前述請求項中任一項 之化合物，其係選自以下任一 者： (^烷4基）_3_側氧基幕[[心（三氣甲氧基）苯基]甲 基]-1Η-異吲哚__丨_曱醯胺；35. The compound according to any one of claims 1 to 27, wherein χ4 is 1 3 6. The compound of any one of claims 1 to 27, η壬, η壬, wherein X4 is benzene methyl. The compound according to any one of the preceding claims, which is selected from any one of the following: (^ alk 4) _3_ side oxygen curtain [[heart (tris methoxy) phenyl] methyl) ]-1Η-isoindole__丨_曱醯amine; (，己基）_3_側氧基-Ν-[4-(三氟甲氧基）苯甲 基]異吲哚琳-1 -曱醯胺； —3-側氧基·2_[[(2δ)_氧雜環〇•基]曱基]善[[4_(三氣甲 氧基）笨基]甲基]-1Η-異吲哚_丨_甲醯胺； N-[l-(4-氣苯基）乙基]_3_側氧基_2_[[(2s)·氧雜環戊j — 基]甲基]-1H-異吲哚-1 -甲酸胺； 3-側氧基-2-[[(2R)-氧雜環戊_2_基]曱基]_n_[[4_(三氟曱 氧基）苯基]曱基]-1H-異吲哚-^甲醯胺； N-[l-(4-氯苯基）乙基]-2-(噁烷_4_基）_3_側氣基_ih-異 吲哚-1 -曱醯胺； ' 3-側氧基-2-[2-(2_側氧基^比咯啶·丨_基）乙基pN_[[4_(三 氟曱氧基）苯基]甲基]-1H-異η引。朵_1_甲酸胺； 3-(1-側氧基-3-{[4-(三氟甲氧基）苯甲基]胺甲醯基卜 1,3-二氫-2H-異吲哚_2-基）η丫丁咬+曱酸第三丁騎. 2- [1-(2-糠醯基）哌啶-4-基]_3_側氧基_Ν_[4γ三氟甲氧 基）苯曱基]異吲哚啉-1-曱酿胺； 3- 側氧基-2-(卜嘧啶-2-基吖丁啶_3_基）_Ν_[4_(三氟甲氧 140374.doc 201000446 基）苯曱基]異吲哚啉-1 -曱醯胺； 2-(4,4-二氟環己基）_N_(4_曱氧基笨甲基分3_側氧基異 °引D朵琳-1 -甲酿胺； N_[ 1-(3-氯笨基）乙基]_2_(4,4_二氟環己基）_3_側氧基異 °引D木琳-1 -曱酸胺； N [1_(3-氯苯基）乙基]-3-側氧基_2_(四氫-2H-哌喃-4-基）異°引n朵琳_ 1 _曱醯胺； 2七3,3-二氟環丁基）甲基）_3-側氧基_N_(4_(三氟曱氧 基）苯曱基）異吲哚啉-1 -甲醯胺； (3’3 —氟環丁基）-3-側氧基-N-(4-(三氟曱氧基）苯曱 基）異吲哚琳-1 -曱醯胺； 2~(4,4-二氟環己基）_7_曱氧基·3·側氧基_N_(4_(三氟曱 氧基）笨甲基）異吲哚琳-1 -甲醯胺； 2 - Γ 4 4 — ^ _ (,軋％己基）-7-甲基·3_側氧基_N_(4_(三氟曱氧 基）苯甲基）異吲哚啉-1-甲醯胺； (甲基1 ~側氧基-3-(4-(三氟甲氧基）苯曱基胺甲醯 基）異吲哚啉-2-基）吖丁啶_丨_曱酸第三丁酯； 側氧基(四氫-2H_哌喃_4·基）-N-(l-(4-(三氟甲氧 基）苯基）乙旬異十朵琳小甲酷胺，異構物4 ; ( 氧基-3_(丨-(4-(二氟甲氧基）苯基）乙基胺曱酸基） 異吲哚啉_2-基、σΥ 丁 +」m » 丞）吖丁。疋-1·甲酸第三丁酯，異構物3及4 ; 2_(2_嗎啉基乙基）_3_側氧基-N-(4-(三氟曱氧基）苯曱 基）異吲哚啉-1-甲醯胺； 3-側乳基-2_((四氫吱喃_3_基）曱基）_ν·(4·(三氣甲氧基） 140374.doc 201000446 苯甲基）異吲哚啉-1 _曱醯胺； 2 (1苯甲基娘κ基）_3_側氧基三氟曱氧基）苯 曱基）異吲哚琳-1 -曱酿胺； 7氟3側氧基·2·(四氫-2H-派喃-4-基）-N-(4-(三氟曱氧 基）苯甲基）異吲哚啉-丨_甲醢胺； 4-氟-3-側氧基_2_(四氫·2H_派喃_4_基）_n_(4_(三氟甲氧 基）笨曱基）異吲哚琳_ 1 -曱醯胺； 3-側氧基-N-(4-(三氟曱氧基）苯曱基）_2_(1_(3,3,3_三氟 丙醯基）吖丁啶-3 -基）異吲哚啉_丨_甲醯胺； 2- (1-(甲基磺醯基）吖丁啶_3_基）_3_側氧基_N_(4_(三氟 曱氧基）笨曱基）異吲哚啉_ i _曱醯胺； 3- (1-側氧基-3-(4-(三氟甲氧基）苯甲基胺曱醯基）異吲 哚啉-2-基）吖丁啶甲酸異丙酯； 4- (1-側氧基-3-(4-(三氤曱氧基）笨曱基胺甲醯基）異吲 °朵琳-2-基）派咬-1-曱酸第三丁酯； 3-側氧基-2-(1-丙酿基D辰咬_4-基）_N-(4-(三氟曱氧基）苯 曱基）異°引°朵°林-1 -甲醢胺； 3-側氧基-2-(2-(四氫-2H-派喃_4_基）乙基）_n-(4-(三氟 甲氧基）苯甲基）異吲哚啉-1 -甲醯胺； 3-(1-側氧基-3-(3-(三氟曱氧基）苯甲基胺甲醯基）異吲 哚啉-2-基）吖丁啶-1-甲酸第三丁酯； 3-(1-(2-甲基-4-(三氟甲氧基）苯甲基胺甲醯基）_3_側氧 基異吲哚啉-2-基）吖丁啶-1-甲酸第三丁酯； 2 - (4,4-二氟環己基）-3-側氧基_N-(4-(2,2,2-三氟乙基）苯 140374.doc 201000446 曱基）異吲哚啉-1 -甲醯胺； N-(3,4-二曱基苯甲基）_3_側氧基_2•(四氫_211_哌喃-4_ 基）異吲哚琳-1 -甲醯胺； 3- 側氧基-2-(四氫-2H-哌喃_4_基）-N-(l-(4-(三氟曱基） 苯基）環丙基）異吲哚淋-1 -甲醯胺； 4- 羥基-3-側氧基-2-(四氫-2H-哌喃-4-基）_N_(4_(三氟曱 氧基）本甲基）異η引π朵淋-1 _曱酸胺； 4-羥基-Ν-(4-異丙基苯曱基）_3_侧氧基_2_(四氫_2士哌 喃-4 -基）異》引D朵啦-1 _甲醢胺； 2-(4,4-二氟環己基）·ζμ羥基_3_側氧基_N_(4_(三氟甲基） 苯甲基）異吲哚啉_ 1 -甲醯胺； N (4 ’臭本曱基）_3-側氧基_2_(四氫_2h_0底喃_4_基）異口引 哚啉-1 -甲醯胺；及 N (4 /臭笨甲基）_3_側氧基_2_(四氫_2Η_α辰喃_4_基）異吲 哚啉-1 -甲醯胺，異構物2。 38. 39. 40. 41. 42. 如前述請求項中任一項之化合物，其係用於治療。 一種如請求項1至37中任—項之化合物之用途，其係用 於製造用於治療疼痛病症之藥物。 種療疼痛病症之方法，由此對需要該疼痛治 體投與如請求们㈣中任_項之化合物。 療之個 如請求項1至37中任一項之化合物 病症。 其係用於治療疼痛 一種醫藥組合物， 之賦形劑混合的如 具包含與醫藥學上及藥理學上 月求項1至37中任—項之化合物 受 140374.doc 201000446 四、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：(,hexyl)_3_sideoxy-indole-[4-(trifluoromethoxy)benzyl]isoindolin-1 -decylamine; -3-sideoxy·2_[[(2δ) _ oxacyclohexanyl] fluorenyl] good [[4_(trimethylmethoxy) phenyl]methyl]-1 Η-isoindole _ 丨 醯 醯 ;; N-[l-(4- gas Phenyl)ethyl]_3_sideoxy_2_[[(2s).oxacyclol-yl]methyl]-1H-isoindole-1 -carboxylic acid amine; 3-sided oxy-2- [[(2R)-oxo-2-yl]indolyl]_n_[[4_(trifluorodecyloxy)phenyl]indolyl]-1H-isoindole-^carboxamide; N-[ 1-(4-Chlorophenyl)ethyl]-2-(oxane-4-yl)_3_side gas group _ih-isoindole-1 -decylamine; '3-sideoxy-2- [2-(2_Phenoxy)pyrrolidinyl)ethyl pN_[[4_(trifluorodecyloxy)phenyl]methyl]-1H-isoη. 1-3 _ carboxylic acid amine; 3-(1- oxo-3-{[4-(trifluoromethoxy)benzyl]amine mercapto 1,3-dihydro-2H-isoindole _2-yl) η丫丁丁+曱酸三丁骑. 2- [1-(2-Mercapto)piperidin-4-yl]_3_sideoxy_Ν_[4γTrifluoromethoxy Phenylhydrazinyl]isoindoline-1-anthracene; 3-tertiaryoxy-2-(pyrimidin-2-ylazetidine_3_yl)_Ν_[4_(trifluoromethoxy 140374.doc 201000446 base) phenylhydrazinyl]isoindoline-1 -decylamine; 2-(4,4-difluorocyclohexyl)_N_(4_decyloxy benzyl group 3_side oxy group Dolly-1 - ketoamine; N_[ 1-(3-chlorophenyl)ethyl]_2_(4,4-difluorocyclohexyl)_3_sideoxy-iso-inducing D-Mullin-1 -Citrate Amine; N [1_(3-chlorophenyl)ethyl]-3-oxo-oxy-2_(tetrahydro-2H-pyran-4-yl)iso-n-n-n-lin _ 1 曱醯 曱醯amine; 2 Hepta-3,3-difluorocyclobutyl)methyl)_3-tertiaryoxy_N_(4_(trifluoromethoxy)phenylhydrazolyl)isoindoline-1 -carboxamide; (3'3 - Fluorocyclobutyl)-3-oxo-N-(4-(trifluorodecyloxy)phenylhydrazinyl)isoindol-1 -decylamine; 2~(4,4-difluorocyclohexyl )_7_曱oxy·3·sideoxy_N_(4_(trifluoromethoxy) Methyl)isoindolin-1 -carbamamine; 2 - Γ 4 4 — ^ _ (, rolled % hexyl)-7-methyl·3_sideoxy_N_(4_(trifluoromethoxy) Benzyl)isoindoline-1-carboxamide; (methyl 1 ~ pendant oxy-3-(4-(trifluoromethoxy)phenylhydrazinylmethyl hydrazino)isoindoline-2 -yl)azetidine_丨_decanoic acid tert-butyl ester; pendant oxy group (tetrahydro-2H_pyran-4-yl)-N-(l-(4-(trifluoromethoxy)phenyl) )Essence of ten different carbaryl, isomer 4; (oxy-3_(丨-(4-(difluoromethoxy)phenyl)ethylamine decanoic acid) isoporphyrin _ 2-Base, σΥ丁+”m » 丞)吖丁.疋-1·T-butyl formate, isomers 3 and 4; 2_(2-morpholinoethyl)_3_sideoxy-N- (4-(Trifluorodecyloxy)phenylhydrazinyl)isoindoline-1-carboxamide; 3-flank-2-((tetrahydrofuran-3-yl)indolyl)_ν·(4 · (Tri-methoxy) 140374.doc 201000446 Benzyl)isoindoline-1 _ decylamine; 2 (1 benzyl ketone κ) _3_ pendant oxytrifluoromethoxy) phenylhydrazine )) isoindene-1 - an amine; 7 fluoro 3 oxo · 2 · (tetrahydro-2H-pyran-4-yl)-N-(4-(trifluorodecyloxy)benzene Methyl)isoporphyrin-indole-carbamamine; 4-fluoro-3-indolyl_2_(tetrahydro-2H_pyranyl-4-yl)_n_(4_(trifluoromethoxy) alum )) 吲哚 吲哚 _ 1 - decylamine; 3- oxo-N-(4-(trifluoromethoxy)phenyl fluorenyl)_2_(1_(3,3,3-trifluoropropenyl) Azetidin-3-yl)isoporphyrin_丨_carbamamine; 2-(1-(methylsulfonyl)azetidine_3_yl)_3_sideoxy_N_(4_( Trifluorodecyloxy) alkaloid)isoporphyrin _ i _ decylamine; 3- (1-o-oxy-3-(4-(trifluoromethoxy)benzylamine fluorenyl) Iso-oxalin-2-yl)azetidinecarboxylic acid isopropyl ester; 4-(1-o-oxy-3-(4-(tris-methoxy)) oxanylaminocarbazyl)isoindole Lin-2-yl) sent bite-1-butyric acid tert-butyl ester; 3-sided oxy-2-(1-propyl aryl D-biting _4-yl) _N-(4-(trifluoroantimony) Benzyl phenyl) iso- ̄ ° ° ° Lin-1 - methotrexate; 3-sided oxy-2-(2-(tetrahydro-2H-pyrano-4-yl)ethyl)_n- ( 4-(trifluoromethoxy)benzyl)isoindoline-1 -carboxamide; 3-(1-oxo-3-(3-(trifluorodecyloxy)benzylamine A Mercapto)isoindoline-2-yl)azetidine-1-carboxylic acid tert-butyl ester; 3-(1-(2-methyl-4-(trifluoromethoxy)benzylaminecarbamyl)_3_p-oxyisoindoline-2-yl)azetidine-1-carboxylic acid Tributyl ester; 2 - (4,4-difluorocyclohexyl)-3-oxooxy_N-(4-(2,2,2-trifluoroethyl)benzene 140374.doc 201000446 thiol) Porphyrin-1 -carbamamine; N-(3,4-dimercaptobenzyl)_3_sideoxy-2•(tetrahydro-211-pyran-4-yl)isoindene-1 Methionine; 3-oxo-2-(tetrahydro-2H-piperidin-4-yl)-N-(l-(4-(trifluoromethyl)phenyl)cyclopropyl)isoindole淋-1 -carbamamine; 4-hydroxy-3-oxooxy-2-(tetrahydro-2H-piperidin-4-yl)_N_(4_(trifluoromethoxy)benylmethyl)iso η π朵淋-1 _ decanoic acid; 4-hydroxy-indole-(4-isopropylphenylhydrazino)_3_sideoxy-2_(tetrahydro-2 spiperidin-4-yl)iso"朵拉-1 _carbamamine; 2-(4,4-difluorocyclohexyl)·ζμhydroxy_3_sideoxy_N_(4_(trifluoromethyl)benzyl)isoporphyrin _ 1 -carbamamine; N (4 'smoke oxime) _3-side oxy-2_(tetrahydro-2h_0 oxime _4_yl) isoporazine quinoxaline-1 -carboxamide; and N (4 / Stinking methyl)_3_sideoxy_2_(tetrahydro-2Η_α辰喃_4_ ) Isoindoline-l - methanone Amides, isomer 2. 38. 40. The combination of any of the preceding claims is for use in therapy. A use of a compound according to any one of claims 1 to 37 for the manufacture of a medicament for the treatment of a pain condition. A method of treating a pain condition whereby a compound requiring the pain is administered to a compound as claimed in claim 4(4). A compound according to any one of claims 1 to 37. It is a pharmaceutical composition for treating pain, and the excipients are mixed, and the compounds which are included in the medicinal and pharmacological last month items 1 to 37 are accepted by 140374.doc 201000446. : (1) The representative representative of the case is: (none) (2) A brief description of the symbol of the representative figure: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 140374.doc140374.doc
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