TW201425296A - Substituted heterocyclic derivatives - Google Patents

Substituted heterocyclic derivatives Download PDF

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TW201425296A
TW201425296A TW102142723A TW102142723A TW201425296A TW 201425296 A TW201425296 A TW 201425296A TW 102142723 A TW102142723 A TW 102142723A TW 102142723 A TW102142723 A TW 102142723A TW 201425296 A TW201425296 A TW 201425296A
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phenyl
methoxy
oxazol
acetamide
lower alkyl
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Simona M Ceccarelli
Ravi Jagasia
Roland Jakob-Roetne
Jens-Uwe Peters
Juergen Wichmann
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Hoffmann La Roche
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Abstract

The present invention relates to compounds of general formula wherein R1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH2)2-lower akoxy, O(CH2)2N(CH3)2, or O(CH2)-morpholinyl; R1' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH2)2-lower akoxy, O(CH2)2N(CH3)2, or O(CH2)-morpholinyl; with the proviso that both R1 and R1' may be simultaneously hydrogen, but only one of R1 and R1' is lower alkyl, lower alkoxy, halogen, O(CH2)2-lower akoxy, O(CH2)2N(CH3)2, or O(CH2)-morpholinyl; Het is a 5-or 6 membered heteroaryl group, wherein the heteroatom is selected from N, O or S; X is -CRR'-, -CRR'-NR'-, -C(O)-, -CH2-S-, -CH2-S(O)2-, CH2-O- or -CH2-CRR'-; R/R' are independently from each other hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may form together with the carbon atom to which they are attached a cyclopropyl ring; R2 is lower alkyl, -C(O)O-lower alkyl, C3-6-cycloalkyl optionally substituted by lower alkyl or =O, bridged cyclohexyl or C3-6-cycloalkenyl, or is a 5-membered heteroaryl group, wherein the heteroatom is selected from N, O or S and which is optionally substituted by one or more lower alkyl, or is pyridinyl, optionally substituted by halogen or lower alkoxy; or is phenyl, optionally substituted by one or more R2', selected from halogen, cyano, S(O)2-lower alkyl, lower alkyl, lower alkyl substituted by halogen, lower alkoxy, lower alkoxy substituted by halogen or amino, or is benzo[1, 3]dioxolyl, naphthyl, indolyl, benzo-isoxazolyl, 2, 3-dihydro-1H-indenyl, optionally substituted by lower alkoxy or by an oxo group, or is 3, 4-dihydro-2H-[1, 4]oxazinyl, optionally substituted by an oxo group, or is a five or six membered heterocycloalkyl group; or to a pharmaceutically acceptable acid addition salt, to a racemic mixture or to its corresponding enantiomer and/or optical isomers thereof. The compounds may be used for the treatment or prophylaxis of schizophrenia, obsessive-compulsive personality disorder, major depression, bipolar disorders, anxiety disorders, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognitive impairment, chemotherapy-induced cognitive dysfunction, Down syndrome, autism spectrum disorders, hearing loss, tinnitus, spinocerebellar ataxia, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, radiation therapy, chronic stress, abuse of neuro-active drugs, such as alcohol, opiates, methamphetamine, phencyclidine and ***e.

Description

經取代之雜環衍生物 Substituted heterocyclic derivative

本發明係關於以下通式之化合物，或其中R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；Het為5或6員雜芳基，其中雜原子係選自N、O或S；X為-CRR'-、-CRR'-NR'-、-C(O)-、-CH2-S-、-CH2-S(O)2-、CH2-O-或-CH2-CRR'-；R/R'彼此獨立地為氫、低碳烷基、羥基或苯基，或R及R'可連同其所連接之碳原子一起形成環丙基環；R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一 或多個低碳烷基取代，或為吡啶基，視情況經鹵素或低碳烷氧基取代，或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基，或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基(oxo)取代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基；或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體。 The present invention relates to a compound of the following formula, or Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) - morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 - lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl group, wherein the hetero atom is Selected from N, O or S; X is -CRR'-, -CRR'-NR'-, -C(O)-, -CH 2 -S-, -CH 2 -S(O) 2 -, CH 2 -O- or -CH 2 -CRR'-;R/R' are each independently hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may together with the carbon atom to which they are attached form a cyclopropyl group Ring; R 2 is lower alkyl, -C(O)O-lower alkyl, optionally substituted by lower alkyl or =0, C 3-6 cycloalkyl, bridged cyclohexyl or C 3-6 a cycloalkenyl group, or a 5-membered heteroaryl group, wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, Substituted with halogen or lower alkoxy, or phenyl, optionally 'substituted, the R 2' with one or more R 2 is selected from halo, cyano, S (O) 2 - lower alkyl , lower alkyl, halogen-substituted lower alkyl, lower alkoxy, halogen-substituted lower alkoxy, or amine, or benzo[1,3]dioxole , naphthyl, anthracenyl, benzoisoxazolyl, 2,3-dihydro-1H-indenyl, optionally substituted by lower alkoxy or by oxo, or 4-dihydro-2H-[1,4]oxazinyl, optionally substituted by pendant oxy, or 5 or 6 membered heterocycloalkyl; or a pharmaceutically acceptable acid addition salt thereof, exogenous A mixture or a corresponding enantiomer and/or optical isomer thereof.

目前已顯示，本發明化合物刺激神經幹細胞(NSC)之神經生成。神經生成在發育之腦中及成體腦中發生。在概念上，可將此神經生成過程分成四個步驟：(i)NSC之增殖；(ii)NSC之神經元命運確定；(iii)新神經元之存活及成熟；及(iv)新神經元功能整合成神經元網路。 It has now been shown that the compounds of the invention stimulate nerve production of neural stem cells (NSC). Neurogenesis occurs in the developing brain and in the adult brain. Conceptually, this neurogenic process can be divided into four steps: (i) proliferation of NSC; (ii) neuronal fate determination of NSC; (iii) survival and maturation of new neurons; and (iv) new neurons The function is integrated into a neural network.

成體神經生成為在成體腦之整個存活期中發生之發育過程，藉此由成體神經幹細胞產生新功能性神經元。組成性成體神經生成在生理條件下主要於兩個「神經性」腦區域中發生：1)海馬齒狀回中之顆粒下區(SGZ)，其中產生新齒狀顆粒細胞；2)側腦室之腦室下區(SVZ)，其中產生新神經元，接著經嘴側遷移流(RMS)遷移至嗅球而變為中間神經元。 Adult neurogenicity is a developmental process that occurs throughout the life of an adult brain, whereby new functional neurons are produced by adult neural stem cells. Constitutive adult neurogenesis occurs under physiological conditions mainly in two "neuropathic" brain regions: 1) subgranular region (SGZ) in the hippocampal dentate gyrus, in which new dentate granule cells are produced; 2) lateral ventricle The subventricular zone (SVZ), in which new neurons are produced, which then migrate to the olfactory bulb via the mouth-side migration flow (RMS) to become interneurons.

大量證據表明，海馬成體神經生成在認知及情緒狀態方面起重要作用，但確切功能仍未可知。已證明，相對少量之新生顆粒神經元即可影響全腦功能，此係因為其以神經支配齒狀回內之許多中間神經元，各中間神經元抑制數百成熟顆粒細胞，從而引起神經生成依賴性 反饋抑制。與發火之下限相結合，新生神經元觸發對環境中極微小變化之反應。此過程中之紊亂可能在行為上表現為與精神病相關之模式分離缺陷。舉例而言，成體海馬神經生成與認知及情緒能力有關，例如，體育運動、暴露於豐富環境及典型抗抑鬱劑伴隨地促進成體海馬神經生成及認知及/或情緒狀態，而慢性壓力、抑鬱症、睡眠剝奪及衰老會減少成體神經生成且與負面認知及/或情緒狀態相關聯(Neuron 70,2011年5月26日，第582-588頁及第687-702頁；WO 2008/046072)。有趣地，抗抑鬱劑促進海馬成體神經生成且其對某些行為之影響需要刺激神經生成。一般咸信，其他成體CNS區域中之神經生成在正常生理條件下極其受限，但在諸如中風及中樞及周邊腦損傷之損傷後可得以誘發。 A large body of evidence suggests that hippocampal adult neurogenesis plays an important role in cognitive and emotional states, but the exact function remains unclear. It has been shown that a relatively small number of new-granular neurons can affect whole-brain function because it innervates many interneurons within the dentate gyrus, and each interneuron inhibits hundreds of mature granulosa cells, thereby causing neurogenic dependence. Sex Feedback suppression. In combination with the lower limit of igniting, newborn neurons trigger a response to very small changes in the environment. Disorders in this process may behave as behavioral degenerative patterns associated with mental illness. For example, adult hippocampal neurogenesis is associated with cognitive and emotional abilities, such as physical activity, exposure to abundance of the environment, and typical antidepressants that promote adult hippocampal neurogenesis and cognitive and/or emotional states, while chronic stress, Depression, sleep deprivation, and aging reduce adult neurogenesis and are associated with negative cognitive and/or emotional states (Neuron 70, May 26, 2011, pp. 582-588 and 687-702; WO 2008/ 046072). Interestingly, antidepressants promote hippocampal adultergic neurogenesis and their effects on certain behaviors require stimulation of neurogenesis. It is generally believed that nerve formation in other adult CNS regions is extremely limited under normal physiological conditions, but can be induced after injury such as stroke and central and peripheral brain injury.

因此咸信，成體神經生成之刺激代表正常衰老及尤其多種神經退化及神經精神疾病之神經再生性治療目標，該等疾病包括精神***症、強迫性人格障礙、嚴重抑鬱症、躁鬱症、焦慮症、癲癇症、視網膜變性、創傷性腦損傷、脊髓損傷、創傷後壓力症、恐慌症、帕金森氏病(Parkinson's disease)、癡呆症、阿茲海默氏病(Alzheimer's disease)、輕度認知障礙、化學療法誘發之認知功能障礙(「化療腦(chemobrain)」)、唐氏症候群(Down syndrome)、自閉症譜系障礙、聽力損失(Neuroscience,167(2010)1216-1226；Nature Medicine，第11卷，第3期，(2005),271-276)、耳鳴、脊髓小腦失調、肌萎縮性側索硬化症、多發性硬化症、亨廷頓氏病(Huntington's disease)、中風及因放射線療法引起之紊亂、慢性壓力，或諸如酒精、鴉片劑、甲基***(methamphetamine)、苯環利定(phencyclidine)及***(***e)之神經活性藥物濫用(US 2012/0022096)。 Therefore, Xianxin, the stimulus of adult neurogenesis represents the target of nerve regeneration treatment for normal aging and especially a variety of neurodegenerative and neuropsychiatric diseases, including schizophrenia, obsessive-compulsive disorder, severe depression, bipolar disorder, anxiety Symptoms, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognition Obstacle, chemotherapy-induced cognitive dysfunction ("chemobrain"), Down syndrome, autism spectrum disorder, hearing loss (Neuroscience, 167 (2010) 1216-1226; Nature Medicine, Volume 11, Issue 3, (2005), 271-276), tinnitus, spinocerebellar disorders, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, and radiation therapy Disorder, chronic stress, or nerve activity such as alcohol, opiates, methamphetamine, phencyclidine, and ***e Drug abuse (US 2012/0022096).

成體神經生成之刺激亦代表視神經病(S.Isenmann,A.Kretz,A.Cellerino,Progress in Retinal and Eye Research,22,(2003)483)及黃斑 部變性(G.Landa,O.Butovsky,J.Shoshani,M.Schwartz,A.Pollack,Current Eye Research 33,(2008)1011)之治療目標。 Stimulation of adult neurogenesis also represents optic neuropathy (S. Isenmann, A. Kretz, A. Cellerino, Progress in Retinal and Eye Research, 22, (2003) 483) and the macula The treatment target of G. Landa, O. Butovsky, J. Shoshani, M. Schwartz, A. Pollack, Current Eye Research 33, (2008) 1011.

因此，成體神經生成之化學刺激提供新的再生渠道及機會以開發治療神經疾病及神經精神異常之新穎藥物。 Therefore, chemical stimulation of adult neurogenesis provides new channels of regeneration and opportunities to develop novel drugs for the treatment of neurological disorders and neuropsychiatric disorders.

因此，本發明之目的為鑑別調節神經生成之化合物。已發現，式I化合物在此領域中具活性且其因此可用於治療精神***症、強迫性人格障礙、抑鬱症、躁鬱症、焦慮症、正常衰老、癲癇症、視網膜變性、創傷性腦損傷、脊髓損傷、創傷後壓力症、恐慌症、帕金森氏病、癡呆症、阿茲海默氏病、輕度認知障礙、化學療法誘發之認知功能障礙(「化療腦」)、唐氏症候群、自閉症譜系障礙、聽力損失、耳鳴、脊髓小腦失調、肌萎縮性側索硬化症、多發性硬化症、亨廷頓氏病、中風及因放射線療法引起之紊亂、慢性壓力、視神經病或黃斑部變性，或諸如酒精、鴉片劑、甲基***、苯環利定或***之神經活性藥物濫用。 Accordingly, it is an object of the present invention to identify compounds that modulate neurogenicity. It has been found that the compounds of formula I are active in this field and are therefore useful in the treatment of schizophrenia, obsessive-compulsive disorder, depression, bipolar disorder, anxiety, normal aging, epilepsy, retinal degeneration, traumatic brain injury, Spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognitive impairment, chemo-induced cognitive dysfunction ("chemotherapy brain"), Down syndrome, self Autism spectrum disorder, hearing loss, tinnitus, spinocerebellar disorders, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke and disturbances caused by radiation therapy, chronic stress, optic neuropathy or macular degeneration, Or neuroactive drug abuse such as alcohol, opiates, methamphetamine, phencyclidine or ***e.

式I化合物之最佳適應症為阿茲海默氏病、抑鬱症、焦慮症及中風。 The best indication for the compound of formula I is Alzheimer's disease, depression, anxiety and stroke.

本發明係關於式I化合物及其醫藥學上可接受之鹽(在此適用於對映異構體或非對映異構體或其對映異構純或非對映異構純形式之混合物的情況下)、作為醫藥學活性物質之此等化合物、其製備方法以及在治療或預防以下與神經生成有關之病症的用途：精神***症、強迫性人格障礙、抑鬱症、躁鬱症、焦慮症、正常衰老、癲癇症、視網膜變性、創傷性腦損傷、脊髓損傷、創傷後壓力症、恐慌症、帕金森氏病、癡呆症、阿茲海默氏病、輕度認知障礙、化學療法誘發之認知功能障礙(「化療腦」)、唐氏症候群、自閉症譜系障礙、聽力損失、耳鳴、脊髓小腦失調、肌萎縮性側索硬化症、多發性硬化症、亨廷頓氏病、中風及因放射線療法引起之紊亂、慢性壓力、視神經病或黃斑部 變性，或諸如酒精、鴉片劑、甲基***、苯環利定或***之神經活性藥物濫用。 The present invention relates to a compound of the formula I and a pharmaceutically acceptable salt thereof (here suitable for use as a mixture of enantiomers or diastereomers or enantiomerically pure or diastereomerically pure forms thereof) In the case of the pharmaceutically active substance, the preparation method thereof, and the use thereof for treating or preventing the following disorders related to nerve production: schizophrenia, obsessive-compulsive disorder, depression, bipolar disorder, anxiety , normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognitive impairment, chemotherapy induced Cognitive dysfunction ("chemotherapy brain"), Down syndrome, autism spectrum disorder, hearing loss, tinnitus, spinocerebellar disorders, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke, and radiation Treatment-induced disorder, chronic stress, optic neuropathy or macula Degeneration, or neuroactive drug abuse such as alcohol, opiates, methamphetamine, phencyclidine or ***e.

且係關於含有式I化合物之醫藥組合物。 It is also a pharmaceutical composition containing a compound of formula I.

與所討論之術語單獨出現或組合出現無關，本說明書中所用之通用術語的以下定義均適用。 Regardless of the occurrence or combination of the terms in question, the following definitions of the general terms used in this specification apply.

如本文所用之術語「低碳烷基」表示飽和，亦即脂族烴基，其包括具有1-4個碳原子之直鏈或分支鏈碳鏈。「烷基」之實例為甲基、乙基、正丙基及異丙基。 The term "lower alkyl" as used herein denotes a saturated, ie aliphatic, hydrocarbon group which includes a straight or branched chain carbon chain having from 1 to 4 carbon atoms. Examples of "alkyl" are methyl, ethyl, n-propyl and isopropyl.

術語「經鹵素取代之低碳烷基」表示至少一個氫原子經鹵素置換之如上文所定義之烷基。 The term "lower alkyl substituted by halogen" means an alkyl group as defined above wherein at least one hydrogen atom is replaced by a halogen.

術語「低碳烷氧基」表示基團O-R'，其中R'為如上文所定義之低碳烷基。 The term "lower alkoxy" denotes the group O-R', wherein R' is lower alkyl as defined above.

術語「經鹵素取代之低碳烷基」表示如上文所定義且其中至少一個氫原子經鹵素置換之低碳烷基。 The term "lower alkyl substituted by halogen" means a lower alkyl group as defined above and wherein at least one hydrogen atom is replaced by a halogen.

術語「環烷基」表示含有3至6個環碳原子之環狀烷基。 The term "cycloalkyl" means a cyclic alkyl group having 3 to 6 ring carbon atoms.

術語「環烯基」表示含有3至6個環碳原子且環原子之間的一個鍵為雙鍵之環狀烷基。 The term "cycloalkenyl" means a cyclic alkyl group having 3 to 6 ring carbon atoms and a bond between ring atoms being a double bond.

術語「鹵素」表示氯、溴、氟或碘。 The term "halogen" means chloro, bromo, fluoro or iodo.

橋連環己基為雙環[2.2.1]庚-2-基。 The bridged cyclohexyl group is a bicyclo [2.2.1] hept-2-yl group.

術語「5或6員雜環烷基」表示含有5或6個碳環原子之環烷基環，其中至少一個碳原子經N、O或S原子置換，例如哌嗪基、哌啶基、嗎啉基、四氫哌喃基、四氫呋喃基或1,1-二側氧基-四氫-1λ6-噻吩基。 The term "5 or 6 membered heterocycloalkyl" means a cycloalkyl ring containing 5 or 6 carbon ring atoms in which at least one carbon atom is replaced by an N, O or S atom, such as piperazinyl, piperidinyl, or Orolinyl, tetrahydropyranyl, tetrahydrofuranyl or 1,1-di-oxy-tetrahydro-1λ 6 -thienyl.

「其中雜原子係選自N、O或S」之術語5或6員雜芳基表示以下基團：噁唑基、噻吩基、異噁唑基、噻唑基、噁二唑基、***基、吡啶基、吡唑基或1,2,4-***基。 The term "heteroatom is selected from N, O or S" is a 5- or 6-membered heteroaryl group which represents the following groups: oxazolyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, triazolyl. , pyridyl, pyrazolyl or 1,2,4-triazolyl.

術語「醫藥學上可接受之鹽」或「醫藥學上可接受之酸加成鹽」涵蓋與無機及有機酸形成之鹽，該等酸為諸如鹽酸、硝酸、硫酸、磷酸、檸檬酸、甲酸、反丁烯二酸、順丁烯二酸、乙酸、丁二酸、酒石酸、甲烷磺酸、對甲苯磺酸及其類似酸。 The term "pharmaceutically acceptable salts" or "pharmaceutically acceptable acid addition salts" encompasses salts with inorganic and organic acids such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, and formic acid. , fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid and the like.

本發明之一個實施例為下式化合物 One embodiment of the invention is a compound of the formula

其中R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；Het為5或6員雜芳基，其中雜原子係選自N、O或S；X為-CRR'-、-CRR'-NR'-、-C(O)-、-CH2-S-、-CH2-S(O)2-、CH2-O-或-CH2-CRR'-；R/R'彼此獨立地為氫、低碳烷基、羥基或苯基，或R及R'可連同其所連接之碳原子一起形成環丙基環；R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一或多個低碳烷基取代，或為吡啶基，視情況經鹵素或低碳烷氧基取代， 或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基，或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基取代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基；或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體。 Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) - morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 - lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl group, wherein the hetero atom is Selected from N, O or S; X is -CRR'-, -CRR'-NR'-, -C(O)-, -CH 2 -S-, -CH 2 -S(O) 2 -, CH 2 -O- or -CH 2 -CRR'-;R/R' are each independently hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may together with the carbon atom to which they are attached form a cyclopropyl group Ring; R 2 is lower alkyl, -C(O)O-lower alkyl, optionally substituted by lower alkyl or =0, C 3-6 cycloalkyl, bridged cyclohexyl or C 3-6 a cycloalkenyl group, or a 5-membered heteroaryl group, wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, Substituted with halogen or lower alkoxy, or phenyl, optionally 'substituted, the R 2' with one or more R 2 is selected from halo, cyano, S (O) 2 - lower alkyl , lower alkyl, halogen-substituted lower alkyl, lower alkoxy, halogen-substituted lower alkoxy, or amine, or benzo[1,3]dioxole Base, naphthyl, anthracenyl, benzoisoxazolyl, 2,3-dihydro-1H-indenyl, optionally substituted by lower alkoxy or by pendant oxy, or 3,4-di Hydrogen-2H-[1,4]oxazinyl, optionally substituted by pendant oxy, or 5 or 6 membered heterocycloalkyl; or a pharmaceutically acceptable acid addition salt, racemic mixture thereof or Its corresponding enantiomers and/or optical isomers.

本發明之另一個實施例為下式化合物 Another embodiment of the invention is a compound of the formula

其中R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；Het為5或6員雜芳基，其中雜原子係選自N、O或S；X為-CRR'-、-CRR'-NR'-、-C(O)-、-CH2-S-、-CH2-S(O)2-、CH2-O-或-CH2-CRR'-；R/R'彼此獨立地為氫、低碳烷基、羥基或苯基，或R及R'可連同其所連接之碳原子一起形成環丙基環； R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一或多個低碳烷基取代，或為吡啶基，視情況經鹵素或低碳烷氧基取代，或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基，或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基取代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基；或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體。 Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) - morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 - lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl group, wherein the hetero atom is Selected from N, O or S; X is -CRR'-, -CRR'-NR'-, -C(O)-, -CH 2 -S-, -CH 2 -S(O) 2 -, CH 2 -O- or -CH 2 -CRR'-;R/R' are each independently hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may together with the carbon atom to which they are attached form a cyclopropyl group Ring; R 2 is lower alkyl, -C(O)O-lower alkyl, optionally substituted by lower alkyl or =0, C 3-6 cycloalkyl, bridged cyclohexyl or C 3-6 a cycloalkenyl group, or a 5-membered heteroaryl group, wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, Halogen or optionally substituted lower alkoxy, or phenyl, optionally 'substituted, the R 2' with one or more R 2 is selected from halo, cyano, S (O) 2 - lower alkoxy a lower alkyl group, a halogen-substituted lower alkyl group, a lower alkoxy group, a halogen-substituted lower alkoxy group, or an amine group, or a benzo[1,3]dioxole Alkenyl, naphthyl, anthracenyl, benzoisoxazolyl, 2,3-dihydro-1H-indenyl, optionally substituted by lower alkoxy or by pendant oxy, or 3,4- Dihydro-2H-[1,4]oxazinyl, optionally substituted by pendant oxy, or 5 or 6 membered heterocycloalkyl; or a pharmaceutically acceptable acid addition salt, racemic mixture thereof Or its corresponding enantiomers and/or optical isomers.

本發明之一個實施例為其他下式化合物 或 One embodiment of the present invention is another compound of the formula or

其中R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基； Het為5或6員雜芳基，其中雜原子係選自N、O或S；R/R'彼此獨立地為氫、低碳烷基、羥基或苯基，或R及R'可連同其所連接之碳原子一起形成環丙基環；R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一或多個低碳烷基取代，或為吡啶基，視情況經鹵素或低碳烷氧基取代，或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基，或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基取代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基；或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體，例如以下化合物。 Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) - morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 - lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl, wherein the hetero atom is Selected from N, O or S; R/R' are each independently hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may together with the carbon atom to which they are attached form a cyclopropyl ring; R 2 a lower alkyl, -C(O)O-lower alkyl, C 3-6 cycloalkyl, bridged cyclohexyl or C 3-6 cycloalkenyl, optionally substituted by lower alkyl or =O, Or a 5-membered heteroaryl group wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, optionally halogen or lower alkoxy Substituted, or phenyl, as the case may be taken by one or more R 2 ' The R 2 ' is selected from the group consisting of halogen, cyano, S(O) 2 -lower alkyl, lower alkyl, halogen substituted lower alkyl, lower alkoxy, halogen substituted Carboalkoxy, or amine group, or benzo[1,3]dioxolyl, naphthyl, anthracenyl, benzoisoxazolyl, 2,3-dihydro-1H-indole a group, optionally substituted by a lower alkoxy group or by a pendant oxy group, or a 3,4-dihydro-2H-[1,4]oxazinyl group, optionally substituted with a pendant oxy group, or 5 or 6 Heterocycloalkyl; or a pharmaceutically acceptable acid addition salt, racemic mixture thereof or the corresponding enantiomers and/or optical isomers thereof, for example, the following compounds.

N-(3-甲氧基-4-噁唑-5-基-苯基)-2-(3-甲氧基-苯基)-乙醯胺 N-(3-methoxy-4-oxazol-5-yl-phenyl)-2-(3-methoxy-phenyl)-acetamide

N-(3-甲氧基-4-噁唑-5-基-苯基)-2-間甲苯基-乙醯胺 N-(3-methoxy-4-oxazol-5-yl-phenyl)-2-m-tolyl-acetamide

N-(3-甲氧基-4-噁唑-5-基-苯基)-2-吡啶-2-基-乙醯胺 N-(3-methoxy-4-oxazol-5-yl-phenyl)-2-pyridin-2-yl-acetamide

2-(2-胺基苯基)-3'-甲氧基-4'-(5-噁唑基)乙醯苯胺 2-(2-Aminophenyl)-3'-methoxy-4'-(5-oxazolyl)acetanilide

2-(2,5-二甲氧基苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(2,5-Dimethoxyphenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(3-(二氟甲氧基)苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(3-(Difluoromethoxy)phenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(2-(三氟甲基)苯基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide

2-(2,4-二氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(2,4-Dichlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(4-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(4-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(3-溴苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(3-bromophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(4-溴苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(4-bromophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(苯并[d][1,3]二氧雜環戊烯-5-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(Benzo[d][1,3]dioxol-5-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(2-氯-6-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(2-chloro-6-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(2,6-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(2,6-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(2-(二氟甲氧基)苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(2-(Difluoromethoxy)phenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(2-(三氟甲氧基)苯基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(2-(trifluoromethoxy)phenyl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(2-甲氧基苯基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(2-methoxyphenyl)acetamide

2-(4-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(4-Fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-對甲苯基乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-p-tolylacetamide

2-(2-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(2-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-鄰甲苯基乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-o-tolylacetamide

2-(2-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(2-Fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-(三氟甲基)苯基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide

2-(3,5-二甲基苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(3,5-Dimethylphenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(萘-1-基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(naphthalen-1-yl)acetamide

2-(3-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(3-Chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(3,5-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(3,5-Difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(3-氟-5-(三氟甲基)苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(3-Fluoro-5-(trifluoromethyl)phenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(2,4-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(2,4-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(4-(甲基磺醯基)苯基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-(methylsulfonyl)phenyl)acetamide

2-(3,4-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(3,4-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(3-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(3-Fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(2,5-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(2,5-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(2,3-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(2,3-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(3-氯-4-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(3-Chloro-4-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(3-氰基苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(3-cyanophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(5-氯-2-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(5-chloro-2-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(呋喃-2-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(furan-2-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(5-氟吡啶-2-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(5-fluoropyridin-2-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(噻吩-2-基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(thiophen-2-yl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(噻吩-3-基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(thiophen-3-yl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(吡啶-4-基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(pyridin-4-yl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(1-甲基-1H-吲哚-3-基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(1-methyl-1H-indol-3-yl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(吡啶-3-基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(pyridin-3-yl)acetamide

2-(1H-吲哚-3-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(1H-indol-3-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(苯并[d]異噁唑-3-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(Benzo[d]isoxazol-3-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲基異噁唑-5-基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methylisoxazol-5-yl)acetamide

2-(2,4-二甲基噻唑-5-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(2,4-Dimethylthiazol-5-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(5-甲基噻吩-2-基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(5-methylthien-2-yl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)戊醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)pentanamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)丙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)propanamide

2-環己烯基-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-cyclohexenyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-環己基-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-cyclohexyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-環丙基-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-cyclopropyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-環戊基-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-cyclopentyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(4-甲基環己基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-methylcyclohexyl)acetamide

2-(雙環[2.2.1]庚-2-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(Bicyclo[2.2.1]hept-2-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(6-甲氧基-3-側氧基-2,3-二氫-1H-茚-1-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(6-Methoxy-3-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-methoxy-4-(oxazol-5-yl) Phenyl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(四氫-2H-哌喃-4-基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(tetrahydro-2H-piperidin-4-yl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(四氫呋喃-2-基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(tetrahydrofuran-2-yl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(四氫-2H-哌喃-2-基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(tetrahydro-2H-piperidin-2-yl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-側氧基-3,4-二氫-2H-苯并[b][1,4]噁嗪-2-基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-olyl-3,4-dihydro-2H-benzo[b][1,4 Oxazin-2-yl)acetamide

2-(1,1-二側氧基-四氫-1λ6-噻吩-3-基)-N-(3-甲氧基-4-噁唑-5-基-苯基)-乙醯胺 2-(1,1-di-oxy-tetrahydro-1λ 6 -thiophen-3-yl)-N-(3-methoxy-4-oxazol-5-yl-phenyl)-acetamide

2-環丁基-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-cyclobutyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(4-側氧基環己基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-oxocyclohexyl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-苯基丙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-phenylpropanamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-3,3-二甲基丁醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3,3-dimethylbutyramine

N-(3-氯-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基)乙醯胺 N-(3-chloro-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenyl)acetamide

2-(3-甲氧基苯基)-N-(3-甲基-4-(噁唑-5-基)苯基)乙醯胺 2-(3-methoxyphenyl)-N-(3-methyl-4-(oxazol-5-yl)phenyl)acetamide

2-(3-甲氧基-苯基)-N-(3-甲氧基-4-噻唑-5-基-苯基)-乙醯胺 2-(3-methoxy-phenyl)-N-(3-methoxy-4-thiazol-5-yl-phenyl)-acetamide

N-(3-甲氧基-4-[1,3,4]噁二唑-2-基-苯基)-2-(3-甲氧基-苯基)-乙醯胺 N-(3-methoxy-4-[1,3,4]oxadiazol-2-yl-phenyl)-2-(3-methoxy-phenyl)-acetamide

2-(3-甲氧基-苯基)-N-(3-甲氧基-4-[1,2,4]***-1-基-苯基)-乙醯胺 2-(3-methoxy-phenyl)-N-(3-methoxy-4-[1,2,4]triazol-1-yl-phenyl)-acetamide

3-甲氧基-N-(3-甲氧基苯甲基)-4-(噁唑-5-基)苯甲醯胺 3-methoxy-N-(3-methoxybenzyl)-4-(oxazol-5-yl)benzamide

N-(4-氯苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺 N-(4-chlorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

N-(4-氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺 N-(4-fluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

3-甲氧基-4-(噁唑-5-基)-N-(2-(三氟甲基)苯甲基)苯甲醯胺 3-methoxy-4-(oxazol-5-yl)-N-(2-(trifluoromethyl)benzyl)benzamide

N-(2-氯苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺 N-(2-chlorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

3-甲氧基-N-(2-甲基苯甲基)-4-(噁唑-5-基)苯甲醯胺 3-methoxy-N-(2-methylbenzyl)-4-(oxazol-5-yl)benzamide

N-(2-氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺 N-(2-fluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

N-(3-氯苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺 N-(3-chlorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

N-(3,5-二氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺 N-(3,5-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

N-(2,4-二氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺 N-(2,4-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

N-(3-氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺 N-(3-fluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

N-(2,5-二氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺 N-(2,5-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

N-(2,3-二氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺 N-(2,3-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

3-甲氧基-4-(噁唑-5-基)-N-(噻吩-2-基甲基)苯甲醯胺 3-methoxy-4-(oxazol-5-yl)-N-(thiophen-2-ylmethyl)benzamide

N-(2-氟-3-甲氧基苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺 N-(2-Fluoro-3-methoxybenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

N-(5-氯-2-氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺 N-(5-chloro-2-fluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

3-甲氧基-N-((6-甲氧基吡啶-2-基)甲基)-4-(噁唑-5-基)苯甲醯胺 3-methoxy-N-((6-methoxypyridin-2-yl)methyl)-4-(oxazol-5-yl)benzamide

2-(3-甲氧基苯基)-N-(4-(噁唑-5-基)苯基)乙醯胺 2-(3-methoxyphenyl)-N-(4-(oxazol-5-yl)phenyl)acetamide

N-(3-甲氧基苯甲基)-4-(噁唑-5-基)苯甲醯胺 N-(3-methoxybenzyl)-4-(oxazol-5-yl)benzamide

2-(3-甲氧基苯基)-N-(4-(吡啶-4-基)苯基)乙醯胺 2-(3-methoxyphenyl)-N-(4-(pyridin-4-yl)phenyl)acetamide

N-(3-甲氧基苯甲基)-4-(吡啶-4-基)苯甲醯胺 N-(3-methoxybenzyl)-4-(pyridin-4-yl)benzamide

2-(2-氯苯基)-N-(3-甲氧基-4-(吡啶-4-基)苯基)乙醯胺 2-(2-chlorophenyl)-N-(3-methoxy-4-(pyridin-4-yl)phenyl)acetamide

N-(2-氯苯甲基)-3-甲氧基-4-(吡啶-4-基)苯甲醯胺 N-(2-chlorobenzyl)-3-methoxy-4-(pyridin-4-yl)benzamide

2-(2-氯苯基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)乙醯胺 2-(2-Chlorophenyl)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)acetamide

2-(2-氯苯基)-N-(2-甲氧基-4-(1H-吡唑-4-基)苯基)乙醯胺 2-(2-chlorophenyl)-N-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)acetamide

N-(2-氯苯甲基)-2-甲氧基-4-(1H-吡唑-4-基)苯甲醯胺 N-(2-chlorobenzyl)-2-methoxy-4-(1H-pyrazol-4-yl)benzamide

N-(2-氯苯甲基)-3-甲氧基-4-(1H-吡唑-4-基)苯甲醯胺 N-(2-chlorobenzyl)-3-methoxy-4-(1H-pyrazol-4-yl)benzamide

2-(2-氯苯基)-N-(3-甲氧基-4-(1H-1,2,4-***-1-基)苯基)乙醯胺 2-(2-Chlorophenyl)-N-(3-methoxy-4-(1H-1,2,4-triazol-1-yl)phenyl)acetamide

2-(2-氯苯基)-N-(2-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(2-chlorophenyl)-N-(2-methoxy-4-(oxazol-5-yl)phenyl)acetamide

2-(2-氯苯基)-N-(4-(噁唑-5-基)苯基)乙醯胺 2-(2-chlorophenyl)-N-(4-(oxazol-5-yl)phenyl)acetamide

N-(2-氯苯甲基)-2-甲氧基-4-(噁唑-5-基)苯甲醯胺 N-(2-chlorobenzyl)-2-methoxy-4-(oxazol-5-yl)benzamide

N-(4-(1H-吡唑-4-基)苯基)-2-(2-氯苯基)乙醯胺 N-(4-(1H-pyrazol-4-yl)phenyl)-2-(2-chlorophenyl)acetamide

2-(2-氯苯基)-N-(4-(吡啶-4-基)苯基)乙醯胺 2-(2-chlorophenyl)-N-(4-(pyridin-4-yl)phenyl)acetamide

2-(2-氯苯基)-N-(2-(2-(二甲基胺基)乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺 2-(2-Chlorophenyl)-N-(2-(2-(dimethylamino)ethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamide

2-(2-氯苯基)-N-(3-甲氧基-4-(4-甲基噁唑-5-基)苯基)乙醯胺 2-(2-chlorophenyl)-N-(3-methoxy-4-(4-methyloxazol-5-yl)phenyl)acetamide

1-(2-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)環丙烷甲醯胺 1-(2-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)cyclopropanecarbamide

2-(2-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-甲基丙醯胺 2-(2-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-methylpropanamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基)-2-甲基丙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenyl)-2-methylpropanamide

2-(2-氯苯基)-N-(3-(2-(二甲基胺基)乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺2,2,2-三氟乙酸鹽 2-(2-chlorophenyl)-N-(3-(2-(dimethylamino)ethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamidamine 2, 2,2-trifluoroacetate

2-(2-氯苯基)-N-(2-(2-(N-嗎啉基乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺 2-(2-Chlorophenyl)-N-(2-(2-(N-morpholinylethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamide

2-(2-氯苯基)-N-(3-(2-(N-嗎啉基乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺2,2,2-三氟乙酸鹽 2-(2-Chlorophenyl)-N-(3-(2-(N-morpholinylethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamidamine 2,2 2-trifluoroacetate

2-(2-氯苯基)-N-(2-(2-甲氧基乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺 2-(2-chlorophenyl)-N-(2-(2-methoxyethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamide

2-(2-氯苯基)-N-(3-(2-甲氧基乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺 2-(2-chlorophenyl)-N-(3-(2-methoxyethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamide

2-羥基-N-[3-甲氧基-4-(1H-吡唑-4-基)苯基]-2-苯基乙醯胺或 2-(2-氯苯基)-2-羥基-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)乙醯胺。 2-hydroxy- N- [3-methoxy-4-(1 H -pyrazol-4-yl)phenyl]-2-phenylacetamide or 2-(2-chlorophenyl)-2- Hydroxy-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)acetamide.

本發明之另一個實施例為下式化合物或 Another embodiment of the invention is a compound of the formula or

其中R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；Het為5或6員雜芳基，其中雜原子係選自N、O或S； R/R'彼此獨立地為氫、低碳烷基、羥基或苯基，或R及R'可連同其所連接之碳原子一起形成環丙基環；R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一或多個低碳烷基取代，或為吡啶基，視情況經鹵素或低碳烷氧基取代，或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基，或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基取代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基；或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體，例如以下化合物：[(RS)-[[[3-甲氧基-4-(5-噁唑基)苯基]胺甲醯基]苯基]-(甲基)]胺基甲酸第三丁酯 Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) - morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 - lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl group, wherein the hetero atom is Selected from N, O or S; R/R' are each independently hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may together with the carbon atom to which they are attached form a cyclopropyl ring; R 2 a lower alkyl, -C(O)O-lower alkyl, C 3-6 cycloalkyl, bridged cyclohexyl or C 3-6 cycloalkenyl, optionally substituted by lower alkyl or =O, Or a 5-membered heteroaryl group wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, optionally halogen or lower alkoxy Substituted, or phenyl, as the case may be taken by one or more R 2 ' The R 2 ' is selected from the group consisting of halogen, cyano, S(O) 2 -lower alkyl, lower alkyl, halogen substituted lower alkyl, lower alkoxy, halogen substituted Carboalkoxy, or amine group, or benzo[1,3]dioxolyl, naphthyl, anthracenyl, benzoisoxazolyl, 2,3-dihydro-1H-indole a group, optionally substituted by a lower alkoxy group or by a pendant oxy group, or a 3,4-dihydro-2H-[1,4]oxazinyl group, optionally substituted with a pendant oxy group, or 5 or 6 a heterocycloalkyl group; or a pharmaceutically acceptable acid addition salt, racemic mixture or the corresponding enantiomer and/or optical isomer thereof, for example, the following compound: [(RS)-[[ [3-Methoxy-4-(5-oxazolyl)phenyl]amine-carbamoyl]phenyl]-(methyl)]carbamic acid tert-butyl ester

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-((3-甲氧基苯基)(甲基)胺基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-((3-methoxyphenyl)(methyl)amino)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基胺基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylamino)acetamide

N-(3-甲氧基-4-噁唑-5-基-苯基)-2-苯基胺基-乙醯胺 N-(3-methoxy-4-oxazol-5-yl-phenyl)-2-phenylamino-acetamide

2-(4-氯苯基胺基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(4-Chlorophenylamino)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-(三氟甲基)苯基胺基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-(trifluoromethyl)phenylamino)acetamide

2-(4-氟苯基胺基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(4-Fluorophenylamino)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

N-(4-(噁唑-5-基)苯基)-2-(苯基胺基)乙醯胺 N-(4-(oxazol-5-yl)phenyl)-2-(phenylamino)acetamide

2-(4-氟苯基胺基)-N-(4-(噁唑-5-基)苯基)乙醯胺 2-(4-Fluorophenylamino)-N-(4-(oxazol-5-yl)phenyl)acetamide

N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-((3-甲氧基苯基)(甲基)胺基)乙醯胺 N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-2-((3-methoxyphenyl)(methyl)amino)acetamide

N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-(3-甲氧基苯基胺基)乙醯胺 N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-2-(3-methoxyphenylamino)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基胺基)-2-甲基丙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylamino)-2-methylpropanamide

2-(2-氯苯基胺基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-甲基丙醯胺 2-(2-Chlorophenylamino)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-2-methylpropanamide

2-(2-氯苯基胺基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)乙醯胺 2-(2-Chlorophenylamino)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-1-(3-甲氧基苯基胺基)環丙烷甲醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-1-(3-methoxyphenylamino)cyclopropanecarbamide

N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-甲基-2-(苯基胺基)丙醯胺 N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-2-methyl-2-(phenylamino)propanamide

1-(2-氯苯基胺基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)環丙烷甲醯胺 1-(2-Chlorophenylamino)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)cyclopropanecarbamide

N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-(3-甲氧基苯基胺基)-2-甲基丙醯胺或1-(2-氯苯基胺基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)環丙烷甲醯胺。 N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-2-(3-methoxyphenylamino)-2-methylpropanamine or 1-( 2-Chlorophenylamino)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)cyclopropanecarbamide.

本發明之另一個實施例為下式化合物 或 Another embodiment of the invention is a compound of the formula or

其中R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基； 其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；Het為5或6員雜芳基，其中雜原子係選自N、O或S；R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一或多個低碳烷基取代，或為吡啶基，視情況經鹵素或低碳烷氧基取代，或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基，或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基取代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基；或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體，例如以下化合物：N-[3-甲氧基-4-(5-噁唑基)苯基]-3,3-二甲基-2-側氧基丁醯胺。 Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) - morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 - lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl group, wherein the hetero atom is Selected from N, O or S; R 2 is lower alkyl, -C(O)O-lower alkyl, optionally substituted by lower alkyl or =0, C 3-6 cycloalkyl, bridged ring A hexyl or C 3-6 cycloalkenyl group, or a 5-membered heteroaryl group, wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, halogen or optionally substituted lower alkoxy, or phenyl, optionally 'substituted, the R 2' with one or more R 2 is selected from halo, cyano, S (O) 2 - lower alkoxy Base, lower alkyl, halogen substituted lower alkyl, lower alkoxy, Halogen substituted lower alkoxy, or amine, or benzo[1,3]dioxolyl, naphthyl, anthracenyl, benzoisoxazolyl, 2,3-dihydro a -1H-indenyl group, optionally substituted by a lower alkoxy group or by a pendant oxy group, or a 3,4-dihydro-2H-[1,4]oxazinyl group, optionally substituted with a pendant oxy group, or Is a 5- or 6-membered heterocycloalkyl; or a pharmaceutically acceptable acid addition salt, racemic mixture or the corresponding enantiomer and/or optical isomer thereof, for example the following compound: N-[ 3-methoxy-4-(5-oxazolyl)phenyl]-3,3-dimethyl-2-oxobutanamine.

本發明之另一個目的為下式化合物 或 或或 Another object of the invention is a compound of the formula or or or

其中 R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；Het為5或6員雜芳基，其中雜原子係選自N、O或S；R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一或多個低碳烷基取代，或為吡啶基，視情況經鹵素或低碳烷氧基取代，或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基，或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基取代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基；或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體，例如以下化合物：2-(苯磺醯基)-3'-甲氧基-4'-(5-噁唑基)乙醯苯胺 Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) - morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 - lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl group, wherein the hetero atom is Selected from N, O or S; R 2 is lower alkyl, -C(O)O-lower alkyl, optionally substituted by lower alkyl or =0, C 3-6 cycloalkyl, bridged ring A hexyl or C 3-6 cycloalkenyl group, or a 5-membered heteroaryl group, wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, halogen or optionally substituted lower alkoxy, or phenyl, optionally 'substituted, the R 2' with one or more R 2 is selected from halo, cyano, S (O) 2 - lower alkoxy Base, lower alkyl, halogen substituted lower alkyl, lower alkoxy, Halogen substituted lower alkoxy, or amine, or benzo[1,3]dioxolyl, naphthyl, anthracenyl, benzoisoxazolyl, 2,3-dihydro a -1H-indenyl group, optionally substituted by a lower alkoxy group or by a pendant oxy group, or a 3,4-dihydro-2H-[1,4]oxazinyl group, optionally substituted with a pendant oxy group, or Is a 5- or 6-membered heterocycloalkyl; or a pharmaceutically acceptable acid addition salt, racemic mixture or the corresponding enantiomer and/or optical isomer thereof, for example, the following compound: 2-( Phenylsulfonyl)-3'-methoxy-4'-(5-oxazolyl)acetanilide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(苯硫基)乙醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(phenylthio)acetamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯硫基)乙醯胺或 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基磺醯基)乙醯 胺。 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylthio)acetamide or N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylsulfonyl)acetamidine amine.

本發明之另一個目的為下式化合物或 Another object of the invention is a compound of the formula or

其中R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；Het為5或6員雜芳基，其中雜原子係選自N、O或S；R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一或多個低碳烷基取代，或為吡啶基，視情況經鹵素或低碳烷氧基取代，或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基，或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基取代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基； 或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體，例如以下化合物：N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-苯氧基乙醯胺。 Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) - morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 - lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl group, wherein the hetero atom is Selected from N, O or S; R 2 is lower alkyl, -C(O)O-lower alkyl, optionally substituted by lower alkyl or =0, C 3-6 cycloalkyl, bridged ring A hexyl or C 3-6 cycloalkenyl group, or a 5-membered heteroaryl group, wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, halogen or optionally substituted lower alkoxy, or phenyl, optionally 'substituted, the R 2' with one or more R 2 is selected from halo, cyano, S (O) 2 - lower alkoxy Base, lower alkyl, halogen substituted lower alkyl, lower alkoxy, Halogen substituted lower alkoxy, or amine, or benzo[1,3]dioxolyl, naphthyl, anthracenyl, benzoisoxazolyl, 2,3-dihydro a -1H-indenyl group, optionally substituted by a lower alkoxy group or by a pendant oxy group, or a 3,4-dihydro-2H-[1,4]oxazinyl group, optionally substituted with a pendant oxy group, or Is a 5- or 6-membered heterocycloalkyl; or a pharmaceutically acceptable acid addition salt, racemic mixture or the corresponding enantiomer and/or optical isomer thereof, for example the following compound: N-( 3-methoxy-4-(oxazol-5-yl)phenyl)-2-phenoxyacetamide.

本發明之另一個目的為下式化合物 或 Another object of the invention is a compound of the formula or

其中R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；Het為5或6員雜芳基，其中雜原子係選自N、O或S；R/R'彼此獨立地為氫、低碳烷基、羥基或苯基，或R及R'可連同其所連接之碳原子一起形成環丙基環；R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一或多個低碳烷基取代，或為吡啶基，視情況經鹵素或低碳烷氧基取代，或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基， 或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基取代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基；或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體，例如以下化合物：N-(3-甲氧基-4-(噁唑-5-基)苯基)-3-苯基丙醯胺 Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) - morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 - lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl group, wherein the hetero atom is Selected from N, O or S; R/R' are each independently hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may together with the carbon atom to which they are attached form a cyclopropyl ring; R 2 a lower alkyl, -C(O)O-lower alkyl, C 3-6 cycloalkyl, bridged cyclohexyl or C 3-6 cycloalkenyl, optionally substituted by lower alkyl or =O, Or a 5-membered heteroaryl group wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, optionally halogen or lower alkoxy substituted, or is phenyl, optionally substituted with one or more R 2 'taken The R 2 'is selected from halo, cyano, S (O) 2 - lower alkyl, lower alkyl, lower alkyl substituted with halogen, lower alkoxy, halogen substituted lower the Alkoxy, or an amine group, or a benzo[1,3]dioxolyl, naphthyl, anthracenyl, benzisoxazolyl, 2,3-dihydro-1H-indenyl group , optionally substituted by a lower alkoxy group or by a pendant oxy group, or 3,4-dihydro-2H-[1,4]oxazinyl, optionally substituted by a pendant oxy group, or 5 or 6 members Heterocycloalkyl; or a pharmaceutically acceptable acid addition salt, racemic mixture or the corresponding enantiomer and/or optical isomer thereof, for example, the following compound: N-(3-methoxy -4-(oxazol-5-yl)phenyl)-3-phenylpropanamide

N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺 N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide

3-(4-氯苯基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)丙醯胺 3-(4-chlorophenyl)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)propanamide

3-(3-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)丙醯胺 3-(3-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)propanamide

3-(2-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)丙醯胺 3-(2-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)propanamide

N-(3-甲氧基-4-(吡啶-4-基)苯基)-3-苯基丙醯胺 N-(3-methoxy-4-(pyridin-4-yl)phenyl)-3-phenylpropanamide

N-(4-(1H-吡唑-4-基)苯基)-3-(2-氯苯基)丙醯胺 N-(4-(1H-pyrazol-4-yl)phenyl)-3-(2-chlorophenyl)propanamide

N-(4-(1H-吡唑-4-基)苯基)-3-(3-氯苯基)丙醯胺 N-(4-(1H-pyrazol-4-yl)phenyl)-3-(3-chlorophenyl)propanamide

N-(4-(1H-吡唑-4-基)苯基)-3-(4-氯苯基)丙醯胺 N-(4-(1H-pyrazol-4-yl)phenyl)-3-(4-chlorophenyl)propanamide

N-(3-氟-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺 N-(3-Fluoro-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide

N-(3-氯-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺 N-(3-chloro-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide

N-(2-氯-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺 N-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide

N-(3-甲基-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺 N-(3-methyl-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide

N-(2-甲基-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺 N-(2-methyl-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide

N-(2-甲氧基-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺 N-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide

3-甲氧基-N-苯乙基-4-(1H-吡唑-4-基)苯甲醯胺 3-methoxy-N-phenethyl-4-(1H-pyrazol-4-yl)benzamide

N-(3-甲氧基-4-(噁唑-5-基)苯基)-3-甲基-3-苯基丁醯胺 N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3-methyl-3-phenylbutyramine

N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-甲基-3-苯基丁醯胺 N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-methyl-3-phenylbutyramine

N-(4-(1H-吡唑-4-基)苯基)-3-甲基-3-苯基丁醯胺 N-(4-(1H-pyrazol-4-yl)phenyl)-3-methyl-3-phenylbutyramine

N-(3-甲氧基-4-(吡啶-4-基)苯基)-3-甲基-3-苯基丁醯胺 N-(3-methoxy-4-(pyridin-4-yl)phenyl)-3-methyl-3-phenylbutyramine

N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-苯基丁醯胺 N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-phenylbutyramine

3-(4-氯苯基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-甲基丁醯胺 3-(4-Chlorophenyl)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-methylbutyramine

3-羥基-N-(3-甲氧基-4-(噁唑-5-基)苯基)-3-苯基丁醯胺 3-hydroxy-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3-phenylbutyramine

N-(4-(1H-吡唑-4-基)苯基)-3-(4-氯苯基)-3-甲基丁醯胺 N-(4-(1H-pyrazol-4-yl)phenyl)-3-(4-chlorophenyl)-3-methylbutyramine

3-(3-氯苯基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-甲基丁醯胺 3-(3-Chlorophenyl)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-methylbutanamine

N-(4-(1H-吡唑-4-基)苯基)-3-(3-氯苯基)-3-甲基丁醯胺 N-(4-(1H-pyrazol-4-yl)phenyl)-3-(3-chlorophenyl)-3-methylbutyramine

3-(2-氯苯基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-甲基丁醯胺 3-(2-chlorophenyl)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-methylbutyramine

N-(4-(1H-吡唑-4-基)苯基)-3-(2-氯苯基)-3-甲基丁醯胺 N-(4-(1H-pyrazol-4-yl)phenyl)-3-(2-chlorophenyl)-3-methylbutyramine

3-羥基-N-[4-(1,3-噁唑-5-基)苯基]-3-苯基丁醯胺 3-hydroxy- N- [4-(1,3-oxazol-5-yl)phenyl]-3-phenylbutyramine

3-羥基-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-苯基丁醯胺或 N-(4-(1H-吡唑-4-基)苯基)-3-羥基-3-苯基丁醯胺。 3-hydroxy-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-phenylbutyramine or N-(4-(1H-pyrazol-4-yl)phenyl)-3-hydroxy-3-phenylbutanamine.

本發明之另一個實施例為Het為噁唑基之化合物。 Another embodiment of the invention is a compound wherein Het is an oxazolyl group.

本發明之另一個實施例為Het為噻唑基之化合物。 Another embodiment of the invention is a compound wherein Het is a thiazolyl group.

本發明之另一個實施例為Het為噁二唑基之化合物。 Another embodiment of the invention is a compound wherein Het is an oxadiazolyl group.

本發明之另一個實施例為Het為吡啶基之化合物。 Another embodiment of the invention is a compound wherein Het is a pyridyl group.

本發明之另一個實施例為Het為吡唑基之化合物。 Another embodiment of the invention is a compound wherein Het is pyrazolyl.

本發明之另一個實施例為Het為噻吩基之化合物。 Another embodiment of the invention is a compound wherein Het is a thienyl group.

本發明之另一個實施例為Het為異噁唑基之化合物。 Another embodiment of the invention is a compound wherein Het is isoxazolyl.

本發明之另一個實施例為Het為1,2,4-***基之化合物。 Another embodiment of the invention is a compound wherein Het is a 1,2,4-triazolyl group.

本發明之式I化合物及其醫藥上可接受之鹽可藉由此項技術中已知之方法，例如藉由下文所述之製程來製備，該製程包含a)使下式化合物 The compounds of the formula I according to the invention and their pharmaceutically acceptable salts can be prepared by processes known in the art, for example by the processes described below, which comprise a) a compound of the formula

與下式化合物 Compound with

在EDC或HATU存在下反應 React in the presence of EDC or HATU

得到下式化合物 其中定義如上文所述，或b)使下式化合物 Obtaining a compound of the formula Wherein the definition is as described above, or b) the compound of the formula

與下式化合物 Compound with

在EDC或HATU存在下反應 React in the presence of EDC or HATU

得到下式化合物 Obtaining a compound of the formula

其中取代基如上文所述，且必要時使所獲得之化合物轉化為醫藥學上可接受之酸加成鹽。 Wherein the substituent is as described above, and if necessary, the obtained compound is converted into a pharmaceutically acceptable acid addition salt.

本發明之式I化合物的製備可依連續或彙集合成途徑進行。本發明化合物之合成示於以下流程1-7中。進行所得產物之反應及純化所需之技術為熟習此項技術者所知。除非有相反指示，否則以下製程描述中所用之取代基及指數具有本文先前所給出之含義。 The preparation of the compounds of formula I of the present invention can be carried out according to a continuous or pooled synthetic route. The synthesis of the compounds of the invention is shown in Schemes 1-7 below. The techniques required to carry out the reaction and purification of the resulting product are known to those skilled in the art. Unless otherwise indicated, the substituents and indices used in the following process descriptions have the meanings previously given herein.

更詳言之，式I化合物可藉由下文所給出之方法、藉由實例中所給出之方法或藉由類似方法來製造。個別反應步驟之適當反應條件為 熟習此項技術者所知。然而，反應順序並不限於流程1-7中所展示之順序，反應步驟之順序可視起始物質及其各別反應性而自由地改變。起始物質可購得或可藉由類似於下文所給出之方法的方法、藉由說明書或實例中所引用之參考文獻中所述之方法或藉由此項技術中已知之方法來製備。 More specifically, the compounds of formula I can be made by the methods given below, by the methods given in the examples or by analogous methods. Suitable reaction conditions for the individual reaction steps are known to those skilled in the art. However, the order of the reactions is not limited to the order shown in Schemes 1-7, and the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivity. The starting materials are either commercially available or can be prepared by methods analogous to those exemplified below, by methods described in the references cited in the specification or examples, or by methods known in the art.

通式I-1之化合物可根據此項技術中熟知之方法藉由使通式3之胺與酸4偶合來製備，例如藉由使用(3-二甲基胺基-丙基)-乙基-碳化二亞胺(EDC)或(六氟磷酸2-(7-氮雜-1H-苯并***-1-基)-1,1,3,3-四甲基)(HATU)及二異丙基乙胺作為偶合劑。通式3之胺可藉由還原硝基衍生物2來製備，硝基衍生物2係藉由相應醛1與甲苯-4-磺醯基甲基胩(TOSMIC)及鹼反應而產生。醛1係藉由此項技術中熟知之方法產生或獲自商業供應商。 The compound of formula I-1 can be prepared by coupling an amine of formula 3 with acid 4 according to methods well known in the art, for example by using (3-dimethylamino-propyl)-ethyl. - carbodiimide (EDC) or (2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyl hexafluorophosphate (HATU) and diisopropylethylamine as coupling agents. 3 of the amine of general formula 2 can be prepared by reduction of the nitro derivative, 2-nitro derivatives by reaction of the corresponding aldehyde 1-based and toluene-4-sulfonic acyl methyl isocyanide (TOSMIC) and a base to produce. Aldehyde 1 is produced or obtained from commercial suppliers by methods well known in the art.

通式I-1之化合物可如上文所述藉由使通式7之胺與通式4之羧酸偶合來製備。通式7之胺可由相應硝基衍生物6製備，硝基衍生物6係藉由在鈀催化劑及鹼(例如Pd(PPh3)4及乙酸鉀)存在下溴衍生物5與噻唑反應而產生。 The compound of formula I-1 can be prepared by coupling an amine of formula 7 with a carboxylic acid of formula 4 as described above. 7 of the amine of general formula 6 can be prepared from the corresponding nitro derivative, a nitro-based derivative 6 by reaction in the presence of 5-bromo-thiazole derivative of a palladium catalyst and a base (e.g. Pd (PPh 3) 4 and potassium acetate) to produce .

通式I-1之化合物可如上文所述藉由使通式12之胺與通式4之羧酸偶合來製備。通式12之胺可由相應硝基衍生物11製備。硝基衍生物11之合成係由以下方式實現：在例如EDC之偶合劑存在下用肼基甲酸第三丁酯處理通式8之羧酸，繼而在酸性條件下移除第三丁基保護基，得到醯肼10，接著在酸性催化下使醯肼10與原甲酸三乙酯縮合，得到通式11之化合物。 The compound of formula I-1 can be prepared by coupling an amine of formula 12 with a carboxylic acid of formula 4 as described above. The amine of formula 12 can be prepared from the corresponding nitro derivative 11 . The synthesis of the nitro derivative 11 is carried out by treating the carboxylic acid of the formula 8 with a third butyl carbazate in the presence of a coupling agent such as EDC, followed by removal of the t-butyl protecting group under acidic conditions.醯肼10 is obtained, followed by condensation of hydrazine 10 with triethyl orthoformate under acidic catalysis to give a compound of formula 11 .

通式I-1之化合物可如上文所述藉由使通式15之胺與通式4之羧酸偶合來製備。通式15之胺可由相應硝基衍生物14製備，硝基衍生物14係藉由在鹼存在下氟衍生物13與1H-1,2,4-***反應而產生。 The compound of formula I-1 can be prepared by coupling an amine of formula 15 with a carboxylic acid of formula 4 as described above. The amine of general formula 15 14 prepared from the corresponding nitro derivative, a nitro-based derivatives, 14-fluoro derivative by IH-1,2,4-triazole 13 is generated in the presence of a base.

通式I-2之化合物係根據上文所述之通用條件藉由使通式18之酸 與胺19偶合而產生。酸18可如上文針對通式I之化合物所述藉由相應酯醛16與TOSMIC反應，繼而對酯進行水解來獲得。通式16之醛可藉由此項技術中熟知之方法合成或獲自商業供應商。 The compound of formula I-2 is produced by coupling the acid of formula 18 with amine 19 according to the general conditions described above. Acid 18 can be obtained by reacting the corresponding ester aldehyde 16 with TOSMIC, followed by hydrolysis of the ester, as described above for the compound of formula I. The aldehyde of formula 16 can be synthesized by methods well known in the art or obtained from commercial suppliers.

與上文所述之方法類似，其他所主張之化合物可藉由使用通式4及19未涵蓋之其他酸及胺來合成。 Similar to the methods described above, other claimed compounds can be synthesized by using other acids and amines not encompassed by Formulas 4 and 19 .

通式I-2之化合物係根據此項技術中熟知之方法藉由在鈀催化劑及鹼存在下使通式21之芳基溴化物與通式22之酸或酸酯衍生物偶合而產生。通式21之芳基溴化物可如上文所述由相應胺20及酸4獲得。 The compound of the formula I-2 is obtained by reacting an aryl bromide of the formula 21 with a formula 22 in the presence of a palladium catalyst and a base according to a method well known in the art. Acid or The acid ester derivative is produced by coupling. The aryl bromide of formula 21 can be obtained from the corresponding amine 20 and acid 4 as described above.

通式I-2之化合物係根據此項技術中熟知之方法藉由在鈀催化劑及鹼存在下使通式24之芳基溴化物與通式22之酸或酸酯衍生物偶 合而產生。通式24之芳基溴化物可如上文所述由相應酸23及胺19獲得。 The compound of the formula I-2 is obtained by reacting an aryl bromide of the formula 24 with a formula 22 in the presence of a palladium catalyst and a base according to a method well known in the art. Acid or The acid ester derivative is produced by coupling. The aryl bromide of formula 24 can be obtained from the corresponding acid 23 and amine 19 as described above.

化合物之離析及純化Separation and purification of compounds

必要時，可藉由任何適合之分離或純化程序，諸如過濾、萃取、結晶、管柱層析、薄層層析、厚層層析、製備型低壓或高壓液相層析或此等程序之組合來實現本文所述之化合物及中間物之離析及純化。適合之分離及離析程序之特定說明可藉由參考下文之製備及實例而進行。然而，當然亦可使用其他等效分離或離析程序。對掌性式I化合物之外消旋混合物可使用對掌性HPLC來分離。 If necessary, by any suitable separation or purification procedure, such as filtration, extraction, crystallization, column chromatography, thin layer chromatography, thick layer chromatography, preparative low pressure or high pressure liquid chromatography or such procedures Combining to effect isolation and purification of the compounds and intermediates described herein. Specific instructions for suitable separation and isolation procedures can be made by reference to the preparations and examples below. However, it is of course also possible to use other equivalent separation or isolation procedures. Racemic mixtures of the palmitic formula I compounds can be separated using palmitic HPLC.

式I化合物之鹽Salt of a compound of formula I

式I化合物呈鹼性且可轉化為相應酸加成鹽。轉化係藉由用至少化學計量之量的適當酸處理來實現，該酸為諸如鹽酸、氫溴酸、硫酸、硝酸、磷酸及其類似酸，及有機酸，諸如乙酸、丙酸、乙醇酸、丙酮酸、草酸、蘋果酸、丙二酸、丁二酸、順丁烯二酸、反丁烯二酸、酒石酸、檸檬酸、苯甲酸、肉桂酸、杏仁酸、甲烷磺酸、乙烷磺酸、對甲苯磺酸、水楊酸及其類似酸。通常，將游離鹼溶解於諸如***、乙酸乙酯、氯仿、乙醇或甲醇及其類似物之惰性有機溶劑中，且將酸添加於類似溶劑中。使溫度維持於0℃與50℃之間。所得鹽自發沈澱或可用較小極性之溶劑自溶液中產生。 The compounds of formula I are basic and can be converted to the corresponding acid addition salts. Conversion is achieved by treatment with at least a stoichiometric amount of a suitable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, Pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid , p-toluenesulfonic acid, salicylic acid and similar acids. Usually, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid is added to a similar solvent. The temperature is maintained between 0 ° C and 50 ° C. The resulting salt spontaneously precipitates or can be produced from the solution with a less polar solvent.

鹼性式I化合物之酸加成鹽可藉由用至少化學計量當量之適合鹼處理而轉化為相應游離鹼，該鹼為諸如氫氧化鈉或氫氧化鉀、碳酸鉀、碳酸氫鈉、氨及其類似物。 The acid addition salt of a basic formula I compound can be converted to the corresponding free base by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium hydrogencarbonate, ammonia and Its analogues.

式I化合物及其醫藥學上可用之加成鹽具有有價值之藥理特性。特定言之，已發現本發明化合物具有作為神經性藥劑之活性。 The compounds of formula I and their pharmaceutically acceptable addition salts have valuable pharmacological properties. In particular, it has been found that the compounds of the invention have activity as neurological agents.

根據下文所給出之測試研究該等化合物。 The compounds were studied according to the tests given below.

神經生成分析Neurogenic analysis 神經幹細胞增殖分析Neural stem cell proliferation analysis

基於如先前所述(Chambers,S.M.等人，Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling,Nature biotechnology,2009.27(3)：第275-80頁)經由雙重smad抑制而得到之源自人類胚胎幹細胞之神經幹細胞(NSC)增殖來測定小分子之神經性特性。 Based on double smad inhibition as described previously (Chambers, SM et al, Highly efficient neural conversion of human ES and iPS cells by dual inhibition of SMAD signaling, Nature biotechnology, 2009. 27 (3): pp. 275-80) The neural stem cells (NSC) derived from human embryonic stem cells are obtained to determine the neurological properties of small molecules.

在4天之培育期之後基於ATP含量(Promega：CellTiterGlo®)由細胞之增加來量測化合物反應。 The compound response was measured by an increase in cells based on ATP content (Promega: CellTiterGlo®) after a 4-day incubation period.

將NSC解凍且擴充3個繼代。第14天，將NSC於38μl之培養基體積中以21,000個細胞/平方公分之細胞密度接種於經多鳥胺酸/層黏連蛋白(Polyornithin/Laminin)塗佈之384孔板中。 The NSC was thawed and expanded for 3 passages. On day 14, NSCs were seeded in a polyornithine/Laminin coated 384 well plate at a cell density of 21,000 cells/cm 2 in a 38 μl medium volume.

在細胞接種之後4小時，添加2μl體積之化合物溶液。稀釋化合物之儲備溶液(水，5% DMSO)，獲得在8μM至8nM範圍內之劑量反應(11個點，稀釋因子為2)。操作對照以一致地測定細胞之神經性特性：陰性(中性)對照為細胞培養基(最終DMSO濃度：0.25%)。 Four hours after the cell seeding, a 2 μl volume of the compound solution was added. A stock solution of the compound (water, 5% DMSO) was diluted to obtain a dose response (11 points, dilution factor of 2) in the range of 8 μM to 8 nM. Controls were run to consistently determine the neurological properties of the cells: the negative (neutral) control was the cell culture medium (final DMSO concentration: 0.25%).

陽性對照為： The positive control is:

1. 細胞培養基+100ng/ml FGF2(最終DMSO濃度：0.1%) 1. Cell culture medium + 100 ng / ml FGF2 (final DMSO concentration: 0.1%)

2. 細胞培養基+20ng/ml EGF(最終DMSO濃度：0.1%) 2. Cell culture medium + 20 ng/ml EGF (final DMSO concentration: 0.1%)

3. 細胞培養基+100ng/ml Wnt3a(最終DMSO濃度：0.1%) 3. Cell culture medium + 100 ng/ml Wnt3a (final DMSO concentration: 0.1%)

在37℃、5% CO2下培育4天之後，定量每孔之ATP量。ATP濃度與細胞數目成比例。藉由使用Promega CellTiterGlo®套組定量ATP。CellTiterGlo®試劑含有細胞溶解緩衝液、熱穩定螢光素酶(UltraGloTM重組螢光素酶)、鎂及螢光素。螢光素與ATP反應產生氧化螢光素、AMP及光。發光信號與ATP含量成比例。 After incubation for 4 days at 37 ° C, 5% CO 2 , the amount of ATP per well was quantified. The ATP concentration is proportional to the number of cells. ATP was quantified by using the Promega CellTiterGlo® kit. CellTiterGlo® reagent containing lysis buffer, thermostable luciferase (UltraGlo TM recombinant luciferase), magnesium and luciferase. Luciferin reacts with ATP to produce oxyluciferin, AMP, and light. The luminescent signal is proportional to the ATP content.

藉由獲取16個陰性對照孔之平均值來測定各分析板之陰性(中性) 對照之值。以(化合物/陰性對照)×100計算各化合物之神經性化合物反應。 Negative (neutral) of each assay plate was determined by taking the average of 16 negative control wells The value of the comparison. The neurological compound reaction of each compound was calculated as (compound/negative control) x 100.

自劑量反應曲線測定各測試化合物之EC150值。EC150為達到對照活性(100%)之150%之化合物濃度。 The EC 150 values of each test compound were determined from the dose response curve. EC 150 is the concentration of the compound that achieves 150% of the control activity (100%).

如下表所示，較佳化合物展示在<10μM範圍內之EC150(μM)。 Preferred compounds show EC 150 (μM) in the range <10 μM as shown in the table below.

實例及ECExamples and EC 150150 數據之列表List of data

式(I)化合物及其醫藥學上可接受之鹽可用作藥劑，例如呈醫藥製劑之形式。醫藥製劑可經口投與，例如以錠劑、包衣錠劑、糖衣藥丸、硬明膠膠囊及軟明膠膠囊、溶液、乳液或懸浮液之形式。然而，亦可經直腸達成投藥，例如以栓劑之形式，或可非經腸達成投藥，例如以注射溶液之形式。 The compound of the formula (I) and its pharmaceutically acceptable salt can be used as a medicament, for example in the form of a pharmaceutical preparation. The pharmaceutical preparations can be administered orally, for example, in the form of lozenges, coated lozenges, dragees, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions. However, it can also be administered rectally, for example in the form of a suppository, or it can be administered parenterally, for example in the form of an injectable solution.

式(I)化合物及其醫藥學上可接受之鹽可用醫藥學上惰性之無機或有機載劑處理以產生醫藥製劑。乳糖、玉米澱粉或其衍生物、滑石、硬脂酸或其鹽及其類似物可用作例如該等用於錠劑、包衣錠劑、糖衣藥丸及硬明膠膠囊之載劑。適用於軟明膠膠囊之載劑為例如植物油、蠟、脂肪、半固體及液體多元醇及其類似物；然而，視活性物質之性質而定，在軟明膠膠囊之情況下，通常不需要載劑。適用於產生溶液及糖漿之載劑為例如水、多元醇、蔗糖、轉化糖、葡萄糖及其類似物。諸如醇、多元醇、甘油、植物油及其類似物之佐劑可用於式(I)化合物之水溶性鹽的注射水溶液，但通常並非必需的。適用於栓劑之載劑為例如天然油或硬化油、蠟、脂肪、半液體或液體多元醇及其類似物。 The compound of formula (I) and its pharmaceutically acceptable salts can be treated with a pharmaceutically inert inorganic or organic carrier to produce a pharmaceutical preparation. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for lozenges, coated lozenges, dragees and hard gelatin capsules. Carriers suitable for use in soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like; however, depending on the nature of the active substance, in the case of soft gelatin capsules, carriers are generally not required. . Carriers suitable for use in the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, and the like. Adjuvants such as alcohols, polyols, glycerol, vegetable oils and the like can be used in the aqueous injection solutions of the water-soluble salts of the compounds of formula (I), but are generally not necessary. Carriers suitable for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

另外，醫藥製劑可含有防腐劑、增溶劑、穩定劑、濕潤劑、乳化劑、甜味劑、著色劑、調味劑、用於改變滲透壓之鹽、緩衝劑、遮蔽劑或抗氧化劑。其亦可含有其他治療上有價值之物質。 Further, the pharmaceutical preparation may contain a preservative, a solubilizer, a stabilizer, a wetting agent, an emulsifier, a sweetener, a coloring agent, a flavoring agent, a salt for changing the osmotic pressure, a buffering agent, a masking agent or an antioxidant. It may also contain other therapeutically valuable substances.

如早先所提及，含有式(I)化合物或其醫藥學上可接受之鹽及治療上惰性之賦形劑的藥劑亦為本發明之一個目的，用於產生該等藥劑之製程同樣為本發明之一個目的，該製程包含使一或多種式I化合物或其醫藥學上可接受之鹽及必要時一或多種其他治療上有價值之物質與一或多種治療上惰性之載劑一起形成蓋倫劑型(galenical dosage form)。 As mentioned earlier, an agent comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, and a therapeutically inert excipient is also an object of the invention, and the process for producing the agent is also For one purpose of the invention, the process comprises forming one or more compounds of formula I or a pharmaceutically acceptable salt thereof, and optionally one or more other therapeutically valuable substances, together with one or more therapeutically inert carriers. Galenical dosage form.

如早先另外所提及，使用式(I)化合物製備適用於預防及/或治療 上述疾病之藥劑亦為本發明之一個目的。 As mentioned earlier, the preparation of the compounds of formula (I) is suitable for the prevention and/or treatment The agent for the above diseases is also an object of the present invention.

劑量可在寬限度內變化，且當然應適於在各種特定情況下之個體需求。一般而言，經口或非經腸投藥之有效劑量介於0.01-20毫克/公斤/天之間，對於所有所述適應症而言，0.1-10毫克/公斤/天之劑量較佳。對於重量為70kg之成人，日劑量相應地介於每天0.7-1400mg之間，較佳介於每天7mg與700mg之間。 The dosage can vary within wide limits and, of course, should be adapted to the individual needs in the particular circumstances. In general, an effective dose for oral or parenteral administration is between 0.01 and 20 mg/kg/day, and for all of the indications, a dose of 0.1 to 10 mg/kg/day is preferred. For an adult weighing 70 kg, the daily dose is correspondingly between 0.7 and 1400 mg per day, preferably between 7 and 700 mg per day.

包含本發明化合物之醫藥組合物：錠劑配方(濕式造粒)Pharmaceutical composition comprising a compound of the invention: lozenge formulation (wet granulation)

製造程序Manufacturing process

1. 將條目1、2、3及4混合且用純水造粒。 1. Mix items 1, 2, 3 and 4 and granulate with pure water.

2. 在50℃下乾燥顆粒。 2. Dry the granules at 50 °C.

3. 使顆粒通過適合之研磨設備。 3. Pass the particles through the appropriate grinding equipment.

4. 添加條目5且混合三分鐘；在適合之壓力機上壓實。 4. Add item 5 and mix for three minutes; compact on a suitable press.

膠囊配方Capsule formula

製造程序Manufacturing process

1. 在適合之混合器中混合條目1、2及3，持續30分鐘。 1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.

2. 添加條目4及5且混合3分鐘。 2. Add entries 4 and 5 and mix for 3 minutes.

3. 填充至適合膠囊中。 3. Fill to fit the capsule.

實驗部分Experimental part 中間物Intermediate 中間物1：3-甲氧基-4-噁唑-5-基-苯基胺Intermediate 1: 3-methoxy-4-oxazol-5-yl-phenylamine

步驟A Step A

使2-甲氧基-4-硝基苯甲醛(5.064g，27.1mmol)、甲苯-4-磺醯基甲基胩(TOSMIC，5.4g，27.1mmol)及碳酸鉀(3.75g，27.1mmol)與甲醇(55ml)組合，得到濃稠懸浮液。加熱反應混合物至80℃，屆時可進行攪拌。在80℃下攪拌混合物3小時且在室溫下攪拌隔夜。藉由過濾收集沈澱之固體，用少量***洗滌且在真空下乾燥。獲得呈黃色固體狀之5-(2-甲氧基-4-硝基-苯基)-噁唑(5.12g，84.1%)；MS(ISN)m/z=221.05[(M+H)+]。 2-methoxy-4-nitrobenzaldehyde (5.064 g, 27.1 mmol), toluene-4-sulfonylmethyl hydrazine (TOSMIC, 5.4 g, 27.1 mmol) and potassium carbonate (3.75 g, 27.1 mmol) In combination with methanol (55 ml), a thick suspension was obtained. The reaction mixture was heated to 80 ° C, at which time stirring was possible. The mixture was stirred at 80 ° C for 3 hours and stirred at room temperature overnight. The precipitated solid was collected by filtration, washed with diethyl ether and dried under vacuum. Obtained 5-(2-methoxy-4-nitro-phenyl)-oxazole as a yellow solid (5.12 g, 84.1%); MS (ISN) m/z = 221.05 [(M+H)+ ].

步驟B Step B

將5-(2-甲氧基-4-硝基-苯基)-噁唑(10g，45.4mmol)溶解於四氫呋喃(185ml)及乙醇(37ml)中。將混合物置於氬氣氛圍下，隨後添加催化Pd/C(2.0g，1.88mmol)。用氫氣吹洗混合物，接著劇烈攪拌隔 夜。濾除催化劑且用四氫呋喃及乙醇洗滌。蒸發得到油狀物，其在數小時後結晶。獲得呈黃色固體狀之3-甲氧基-4-噁唑-5-基-苯基胺(8.54g，97%)；MS(ISN)m/z=191.08[(M+H)+]。 5-(2-Methoxy-4-nitro-phenyl)-oxazole (10 g, 45.4 mmol) was dissolved in tetrahydrofuran (185 ml) and ethanol (37 ml). The mixture was placed under an argon atmosphere, followed by the addition of catalyzed Pd/C (2.0 g, 1.88 mmol). Purge the mixture with hydrogen followed by vigorous agitation night. The catalyst was filtered off and washed with tetrahydrofuran and ethanol. Evaporation gave an oil which crystallized after a few hours. 3-Methoxy-4-oxazol-5-yl-phenylamine (8.54 g, 97%) was obtained as a yellow solid. MS (ISN) m/z=191.08 [(M+H)+].

中間物2：3-氯-4-噁唑-5-基-苯基胺Intermediate 2: 3-chloro-4-oxazol-5-yl-phenylamine

與中間物1類似，以兩個步驟由2-氯-4-硝基苯甲醛製備3-氯-4-噁唑-5-基-苯基胺，橙色固體，MS(ISN)m/z=195.1[(M+H)+]。 Similar to Intermediate 1, 3-chloro-4-oxazol-5-yl-phenylamine was prepared from 2-chloro-4-nitrobenzaldehyde in two steps, orange solid, MS (ISN) m/z = 195.1 [(M+H)+].

中間物3：3-甲基-4-噁唑-5-基-苯基胺Intermediate 3: 3-methyl-4-oxazol-5-yl-phenylamine

與中間物1類似，以兩個步驟由2-甲基-4-硝基苯甲醛製備3-甲基-4-噁唑-5-基-苯基胺。根據以下程序製備2-甲基-4-硝基苯甲醛： 將2-甲基-4-硝基苯甲腈(1g，6.17mmol)溶解於無水甲苯(24.0ml)中。冷卻至0℃之後，經10分鐘逐滴添加DIBAL-H(4.35ml，7.4mmol)於甲苯中之溶液。在0℃下攪拌混合物2小時。在0℃下藉由添加2N HCl(1ml)淬滅混合物。升溫至室溫且再添加2N HCl(1ml)之後，在劇烈攪拌下添加硫酸鈉。過濾固體且蒸發得到粗物質，藉由急驟層析(庚烷/AcOEt)純化該粗物質，得到呈橙色固體狀之2-甲基-4-硝基苯甲醛(0.68g，67%) Similarly to Intermediate 1, 3-methyl-4-oxazol-5-yl-phenylamine was prepared from 2-methyl-4-nitrobenzaldehyde in two steps. Prepare 2-methyl-4-nitrobenzaldehyde according to the following procedure: 2-Methyl-4-nitrobenzonitrile (1 g, 6.17 mmol) was dissolved in anhydrous toluene (24.0 mL). After cooling to 0 ° C, a solution of DIBAL-H (4.35 ml, 7.4 mmol) in toluene was added dropwise over 10 min. The mixture was stirred at 0 ° C for 2 hours. The mixture was quenched by the addition of 2N HCl (1 mL). After warming to room temperature and further adding 2N HCl (1 mL), sodium sulfate was added with vigorous stirring. The solid was filtered and evaporated to give crystals crystals crystals crystals crystals crystals

中間物4：3-甲氧基-4-噁唑-5-基-苯甲酸Intermediate 4: 3-methoxy-4-oxazol-5-yl-benzoic acid

步驟A Step A

在250mL圓底燒瓶中，使4-(溴甲基)-3-甲氧基苯甲酸甲酯(3.48 g，13.4mmol)與二甲基甲醯胺(50ml)組合，得到無色溶液。添加乙酸鈉(2.2g，26.9mmol)。攪拌反應混合物20小時，接著經燒結玻璃過濾。添加水且用乙酸乙酯萃取反應混合物。經硫酸鈉乾燥合併之有機層且過濾並在真空中移除溶劑，得到呈白色固體狀之4-(乙醯氧基甲基)-3-甲氧基苯甲酸甲酯(3.1g，97%)，其以粗物質形式使用。 Methyl 4-(bromomethyl)-3-methoxybenzoate (3.48) in a 250 mL round bottom flask g, 13.4 mmol) combined with dimethylformamide (50 ml) gave a colourless solution. Sodium acetate (2.2 g, 26.9 mmol) was added. The reaction mixture was stirred for 20 hours and then filtered through a sintered glass. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layer was dried with EtOAcjjjjjjjjjjjjj ), which is used in the form of a crude substance.

步驟B Step B

在250mL圓底燒瓶中，使4-(乙醯氧基甲基)-3-甲氧基苯甲酸甲酯(3.0g，12.6mmol)與甲醇(80ml)組合，得到無色溶液。添加飽和HCl於***中之溶液(12.0g，10ml)。加熱反應混合物至80℃且攪拌1小時。在真空中濃縮粗反應混合物，得到呈白色固體狀之4-(羥甲基)-3-甲氧基苯甲酸甲酯(1.9g，86%)；MS(ISN)m/z=197.1[(M+H)+]。 In a 250 mL round bottom flask, methyl 4-(ethyloxymethyl)-3-methoxybenzoate (3.0 g, 12.6 mmol) was combined with methanol (80 mL) to give a colourless solution. A solution of saturated HCl in diethyl ether (12.0 g, 10 mL). The reaction mixture was heated to 80 ° C and stirred for 1 hour. The crude reaction mixture was concentrated EtOAc mjjjjjjjjjjjj M+H)+].

步驟C Step C

在250mL圓底燒瓶中，使4-(羥甲基)-3-甲氧基苯甲酸甲酯(2.24g，11.4mmol)與二氯甲烷(150ml)組合，得到無色溶液。添加二氧化錳(7.94g，91.3mmol)。加熱反應混合物至45℃且攪拌15小時。經矽藻土過濾反應混合物且在真空中濃縮，得到呈白色固體狀之4-甲醯基-3-甲氧基苯甲酸甲酯(1.9g，86%)；MS(ISN)m/z=195.1[(M+H)+]。 In a 250 mL round bottom flask, methyl 4-(hydroxymethyl)-3-methoxybenzoate (2.24 g, 11.4 mmol) was combined with dichloromethane (150 ml). Manganese dioxide (7.94 g, 91.3 mmol) was added. The reaction mixture was heated to 45 ° C and stirred for 15 hours. The reaction mixture was filtered with EtOAc (EtOAc) (EtOAcjjjjjj 195.1 [(M+H)+].

步驟D Step D

在50mL圓底燒瓶中，使4-甲醯基-3-甲氧基苯甲酸甲酯(1.9g，9.78mmol)與甲醇(20ml)組合，得到無色溶液。添加甲苯-4-磺醯基甲基胩(TOSMIC，1.91g，9.78mmol)及碳酸鉀(1.35g，9.78mmol)。加熱反應混合物至80℃且攪拌2小時，接著冷卻至室溫。添加水，接著用二氯甲烷萃取反應混合物。經硫酸鈉乾燥合併之有機層，過濾且在真空下移除溶劑。藉由急驟層析(矽膠，40g，含0%至100% EtOAc之庚烷)純化粗物質，得到呈白色固體狀之3-甲氧基-4-(噁唑-5-基)-苯甲 酸甲酯(1.43g，62.5%)；MS(ISN)m/z=233.9[(M+H)+]。 Methyl 4-methylamido-3-methoxybenzoate (1.9 g, 9.78 mmol) was combined with methanol (20 mL) in a 50 mL round bottom flask to give a colourless solution. Toluene-4-sulfonylmethylhydrazine (TOSMIC, 1.91 g, 9.78 mmol) and potassium carbonate (1.35 g, 9.78 mmol) were added. The reaction mixture was heated to 80 ° C and stirred for 2 hours, then cooled to room temperature. Water was added, followed by extraction of the reaction mixture with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and evaporated in vacuo. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut elut Methyl ester (1.43 g, 62.5%); MS (ISN) m/z = 233.9 [(M+H)+].

步驟E Step E

在10mL圓底燒瓶中，使3-甲氧基-4-(噁唑-5-基)-苯甲酸甲酯(300mg，1.29mmol)與四氫呋喃(2ml)及甲醇(2ml)組合，得到無色溶液。添加1M NaOH(4ml，4.00mmol)且在室溫下攪拌反應混合物2小時。添加濃HCl(4.8g，4mL)，且過濾白色沈澱物並在高真空下乾燥，得到呈白色固體狀之3-甲氧基-4-(噁唑-5-基)-苯甲酸(266mg，94.3%)；MS(ISN)m/z=220.3[(M+H)+]。 In a 10 mL round bottom flask, 3-methoxy-4-(oxazol-5-yl)-benzoic acid methyl ester (300 mg, 1.29 mmol) was combined with tetrahydrofuran (2 ml) and methanol (2 ml) to give a colorless solution. . 1 M NaOH (4 ml, 4.00 mmol) was added and the mixture was stirred at room temperature for 2 hr. Concentrated HCl (4.8 g, 4 mL) was obtained,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 94.3%); MS (ISN) m/z = 220.3 [(M+H)+].

中間物5：3-甲氧基-4-噻唑-5-基-苯基胺Intermediate 5: 3-methoxy-4-thiazol-5-yl-phenylamine

步驟A Step A

在密封管中，用氬氣淨化2-溴-5-硝基苯甲醚(150mg，0.65mmol)、乙酸鉀(96mg，0.97mmol))及Pd(PPh3)4(38mg，0.03mmol)於二甲基乙醯胺(4ml)中之混合物。接著向此混合物中添加噻唑(0.230ml，3.23mmol)。再用氬氣淨化所得混合物，接著加熱至160℃維持3小時。使反應混合物冷卻至25℃，用水稀釋且用乙酸乙酯(3×30ml)萃取。用鹽水洗滌合併之有機層，經無水硫酸鈉乾燥，過濾且在真空中濃縮。藉由管柱層析(40% EtOAc/己烷)純化，得到呈黃色固體狀之5-(2-甲氧基-4-硝基-苯基)-噻唑(65mg，42.56%)。 Purification of 2-bromo-5-nitroanisole (150 mg, 0.65 mmol), potassium acetate (96 mg, 0.97 mmol) and Pd(PPh 3 ) 4 (38 mg, 0.03 mmol) in argon. A mixture of dimethylacetamide (4 ml). Thiazole (0.230 ml, 3.23 mmol) was then added to this mixture. The resulting mixture was again purged with argon and then heated to 160 ° C for 3 hours. The reaction mixture was cooled to 25 &lt;0&gt;C, diluted with EtOAc EtOAc. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate Purification by column chromatography (40% EtOAc /EtOAc)

步驟B Step B

使5-(2-甲氧基-4-硝基-苯基)-噻唑(160mg，0.68mmol)及二氯化亞錫(655mg，3.39mmol)於乙醇(10ml)中之混合物回流75分鐘。在真空中移除溶劑，且將所得殘餘物溶解於乙酸乙酯(20ml)中。相繼用2N NaOH及鹽水洗滌有機層，經無水硫酸鈉乾燥，過濾且在真空中 濃縮。用二氯甲烷(20ml)稀釋由此獲得之粗物質且過濾。在減壓下移除濾液，得到呈橙色油狀之3-甲氧基-4-噻唑-5-基-苯基胺(107mg，76.6%)。LC-MS(ESI)：207[(M+H)+]。 A mixture of 5-(2-methoxy-4-nitro-phenyl)-thiazole (160 mg, 0.68 mmol) and stannous chloride (655 mg, 3.39 mmol) in ethanol (10 ml) was refluxed for 75 min. The solvent was removed in vacuo and EtOAcqqqqqqq The organic layer was washed successively with 2N NaOH and brine, dried over anhydrous sodium sulfate, filtered and evaporated. concentrate. The crude material thus obtained was diluted with dichloromethane (20 ml) and filtered. The filtrate was removed under reduced pressure to give 3-methoxy-4-thiazol-5-yl-phenylamine (107 mg, 76.6%). LC-MS (ESI): 207 [ (M+H)+].

中間物6：3-甲氧基-4-[1,3,4]噁二唑-2-基-苯基胺Intermediate 6: 3-methoxy-4-[1,3,4]oxadiazol-2-yl-phenylamine

步驟A Step A

在0℃下，向2-甲氧基-4-硝基-苯甲酸(1g，5.077mmol)於二氯甲烷(30ml)中之溶液中添加肼基甲酸第三丁酯(670mg，5.07mmol)及EDCI.HCl(1.167g，6.09mmol)。在25℃下攪拌反應混合物6小時。用水淬滅反應混合物，且用飽和NaHCO3水溶液(10ml)及鹽水洗滌有機層，經無水硫酸鈉乾燥，過濾且在真空中蒸發，得到呈黃色固體狀之N'-(2-甲氧基-4-硝基-苯甲醯基)-肼甲酸第三丁酯(1.3g，82.33%)。LC-MS(ESI)：312[(M+H)+]。 To a solution of 2-methoxy-4-nitro-benzoic acid (1 g, 5.077 mmol) in dichloromethane (30 mL), EtOAc EtOAc EtOAc And EDCI.HCl (1.167 g, 6.09 mmol). The reaction mixture was stirred at 25 ° C for 6 hours. The reaction mixture was quenched with water, and the organic layer was washed with brine, saturated aqueous NaHCO 3 (10ml) and dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give a yellow solid of N '- (2- methoxy - 4-Nitro-benzimidyl)-hydrazinic acid tert-butyl ester (1.3 g, 82.33%). LC-MS (ESI): 312 [ (M+H)+].

步驟B Step B

在0℃下，向N'-(2-甲氧基-4-硝基-苯甲醯基)-肼甲酸第三丁酯(1.3g，4.18mmol)於二噁烷(10ml)中之溶液中逐滴添加HCl於二噁烷中之溶液(4N；33ml)。在25℃下攪拌反應混合物12小時。在真空中移除揮發物，且用乙酸乙酯於己烷中之混合物洗滌所得粗物質，得到呈黃色固體狀之2-甲氧基-4-硝基-苯甲酸醯肼(750mg，84.96%)。LC-MS(ESI)：212[(M+H)+]。 A solution of N'-(2-methoxy-4-nitro-benzoguanidino)-indolecarboxylic acid tert-butyl ester (1.3 g, 4.18 mmol) in dioxane (10 ml) at 0 °C A solution of HCl in dioxane (4N; 33 mL) was added dropwise. The reaction mixture was stirred at 25 ° C for 12 hours. The volatiles were removed in vacuo <RTI ID=0.0> ). LC-MS (ESI): 212 [ (M+H)+].

步驟C Step C

在120℃下，於密封管中，將2-甲氧基-4-硝基-苯甲酸醯肼(600mg，2.84mmol)、原甲酸三乙酯(4.73ml，28.4mmol)及催化量之對甲苯磺酸於二噁烷(10ml)中之溶液加熱24小時。在真空中移除揮發 物。藉由管柱層析(50% EtOAc/己烷)純化所得粗物質，得到呈黃色固體狀之2-(2-甲氧基-4-硝基-苯基)-[1,3,4]噁二唑(470mg，74.73%)。 2-methoxy-4-nitro-benzoic acid hydrazine (600 mg, 2.84 mmol), triethyl orthoformate (4.73 ml, 28.4 mmol) and a catalytic amount in a sealed tube at 120 ° C A solution of toluenesulfonic acid in dioxane (10 ml) was heated for 24 hours. Remove volatilization in vacuum Things. The crude material was purified by column chromatography eluting elut elut elut elut Oxadiazole (470 mg, 74.73%).

步驟D. 在氮氣下，向2-(2-甲氧基-4-硝基-苯基)-[1,3,4]噁二唑(400mg，1.81mmol)於乙醇與乙酸乙酯之混合物(1：1；6ml)中之經脫氣溶液中添加催化量之5% Pd-C(20mg)。將反應混合物置於氫氣氛圍下且在25℃下攪拌24小時。經矽藻土床過濾混合物，且用甲醇(10ml)洗滌殘餘物。在真空中蒸發合併之濾液，得到呈黃色固體狀之3-甲氧基-4-[1,3,4]噁二唑-2-基-苯基胺(190mg，55.07%)。LC-MS(ESI)：192[(M+H)+]。 Step D. To a mixture of 2-(2-methoxy-4-nitro-phenyl)-[1,3,4]oxadiazole (400 mg, 1.81 mmol) in ethanol and ethyl acetate under nitrogen. A catalytic amount of 5% Pd-C (20 mg) was added to the degassed solution in (1:1; 6 ml). The reaction mixture was placed under a hydrogen atmosphere and stirred at 25 ° C for 24 hours. The mixture was filtered through a pad of celite and washed with methanol (10ml). The combined filtrate was evaporated <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> </RTI> <RTIgt; LC-MS (ESI): 192 [ (M+H)+].

中間物7：3-甲氧基-4-[1,2,4]***-1-基-苯基胺Intermediate 7: 3-methoxy-4-[1,2,4]triazol-1-yl-phenylamine

步驟A Step A

在110℃下，於密封管中，將1-氟-2-甲氧基-4-硝基苯(3g，17.27mmol)、1H-1,2,4-***(1.19g，17.27mmol)及K2CO3(2.38g，17.27mmol)於二甲基甲醯胺(20ml)中之混合物攪拌2小時。使反應混合物冷卻至25℃，傾倒至冰冷水中且用乙酸乙酯萃取。用鹽水洗滌合併之有機層且經無水硫酸鈉乾燥，過濾，且在真空中蒸發。用DMSO稀釋由此獲得之粗物質且過濾。用水及己烷洗滌固體殘餘物。藉由製備型HPLC純化濾液且與固體合併，得到呈淺黃色固體狀之4-(2-甲氧基-4-硝基-苯基)-4H-[1,2,4]***(650mg，19%)。LC-MS(ESI)：221[(M+H)+]。 1-Fluoro-2-methoxy-4-nitrobenzene (3 g, 17.27 mmol), 1H-1,2,4-triazole (1.19 g, 17.27 mmol) at 110 ° C in a sealed tube A mixture of K 2 CO 3 (2.38 g, 17.27 mmol) in dimethylformamide (20 mL) was stirred for 2 hr. The reaction mixture was cooled to 25 &lt;0&gt;C, poured into ice cold water andEtOAc. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The crude material thus obtained was diluted with DMSO and filtered. The solid residue was washed with water and hexanes. The filtrate was purified by preparative HPLC and combined with solid to give 4-(2-methoxy-4-nitro-phenyl)-4H-[1,2,4]triazole as a pale yellow solid (650 mg , 19%). LC-MS (ESI): 221 [ (M+H)+].

步驟B Step B

遵循與製備3-甲氧基-4-[1,3,4]噁二唑-2-基-苯基胺所採用之方法相同之方法，將1-(2-甲氧基-4-硝基-苯基)-1H-[1,2,4]***(330mg， 1.49mmol)氫化，得到呈淺棕色固體狀之3-甲氧基-4-[1,2,4]***-1-基-苯基胺(207mg，72.62%)。LC-MS(ESI)：191[(M+H)+]。 Following the same procedure as that used to prepare 3-methoxy-4-[1,3,4]oxadiazol-2-yl-phenylamine, 1-(2-methoxy-4-nitrate) Phenyl-phenyl)-1H-[1,2,4]triazole (330 mg, Hydrogenation of 1.49 mmol) gave 3-methoxy-4-[1,2,4]triazol-1-yl-phenylamine (207 mg, 72.62%). LC-MS (ESI): 191 [ (M+H)+].

中間物8：N-(4-溴-3-甲氧基-苯基)-2-(2-氯-苯基)-乙醯胺Intermediate 8: N-(4-bromo-3-methoxy-phenyl)-2-(2-chloro-phenyl)-acetamide

使4-溴-3-甲氧基苯胺(1g，4.95mmol)及2-(2-氯苯基)乙酸(887mg，5.2mmol)與二氯甲烷(20ml)組合。冷卻至0℃之後，添加EDC(996mg，5.2mmol)。在0℃下攪拌混合物30分鐘，接著返回至室溫維持1.5小時。出現白色懸浮液，將其過濾且用二氯甲烷洗滌。獲得呈白色固體狀之標題化合物(1.2g，66%)。LC-MS(ESI)：356.3[(M+H)+]。 4-Bromo-3-methoxyaniline (1 g, 4.95 mmol) and 2-(2-chlorophenyl)acetic acid (887 mg, 5.2 mmol) were combined with dichloromethane (20 mL). After cooling to 0 °C, EDC (996 mg, 5.2 mmol) was added. The mixture was stirred at 0 ° C for 30 minutes and then returned to room temperature for 1.5 hours. A white suspension appeared which was filtered and washed with dichloromethane. The title compound (1.2 g, 66%) was obtained. LC-MS (ESI): 356.3 [ (M+H)+].

中間物9：N-(4-溴-2-甲氧基-苯基)-2-(2-氯-苯基)-乙醯胺Intermediate 9: N-(4-bromo-2-methoxy-phenyl)-2-(2-chloro-phenyl)-acetamide

與中間物8類似，使用4-溴-2-甲氧基苯胺作為起始物質獲得標題化合物。灰白色固體，LC-MS(ESI)：356.3[(M+H)+]。 Similar to Intermediate 8 , the title compound was obtained using 4-bromo-2-methoxyaniline as starting material. An off-white solid, LC-MS (ESI): 356.3 [(M+H)+].

中間物10：4-溴-N-(2-氯-苯甲基)-2-甲氧基-苯甲醯胺Intermediate 10: 4-bromo-N-(2-chloro-benzyl)-2-methoxy-benzamide

使(2-氯苯基)甲胺(500mg，426μl，3.53mmol)及4-溴-2-甲氧基苯甲酸(938mg，4.06mmol)與二氯甲烷(10ml)組合。使反應物冷卻至0℃且添加EDC(778mg，4.06mmol)。在0℃下攪拌反應物30分鐘，接著在室溫下攪拌48小時。用飽和NaHCO3洗滌反應混合物，經Na2SO4乾燥，過濾且蒸發。標題化合物以粗物質形式使用，灰白色固體(1.14g，91%)。LC-MS(ESI)：356.3[(M+H)+]。 (2-Chlorophenyl)methylamine (500 mg, 426 μl, 3.53 mmol) and 4-bromo-2-methoxybenzoic acid (938 mg, 4.06 mmol) were combined with dichloromethane (10 ml). The reaction was cooled to 0.degree. C. and EDC ( 778 g, 4.06 mmol). The reaction was stirred at 0 °C for 30 minutes and then at room temperature for 48 hours. The reaction mixture was washed with saturated NaHCO 3, dried over Na 2 SO 4, filtered and evaporated. The title compound was used as a crude material as a white solid (1. 4 g, 91%). LC-MS (ESI): 356.3 [ (M+H)+].

中間物11：4-溴-N-(2-氯-苯甲基)-3-甲氧基-苯甲醯胺Intermediate 11: 4-bromo-N-(2-chloro-benzyl)-3-methoxy-benzamide

與中間物9類似，使用4-溴-3-甲氧基苯甲酸作為起始物質獲得標題化合物。灰白色固體，LC-MS(ESI)：356.3[(M+H)+]。 Similar to Intermediate 9, the title compound was obtained using 4-bromo-3-methoxybenzoic acid as starting material. An off-white solid, LC-MS (ESI): 356.3 [(M+H)+].

實例1 Example 1 N-(3-甲氧基-4-噁唑-5-基-苯基)-2-(3-甲氧基-苯基)-乙醯胺N-(3-methoxy-4-oxazol-5-yl-phenyl)-2-(3-methoxy-phenyl)-acetamide

使3-甲氧基-4-噁唑-5-基-苯基胺(中間物1)(3.792g，19.9mmol)及2-(3-甲氧基苯基)乙酸(5.3g，31.9mmol)與二氯甲烷(200ml)組合。使混合物冷卻至0℃且用(3-二甲基胺基-丙基)-乙基-碳化二亞胺(6.12g，31.9mmol)處理。在0℃下攪拌混合物30分鐘，接著在室溫下攪拌23小時。用飽和碳酸氫鈉洗滌混合物。經硫酸鈉乾燥有機相，過濾且蒸發。使所得黃色固體(8.2g)懸浮於乙酸乙酯中且過濾固體並洗滌。蒸發濾液且藉由急驟層析(庚烷/乙酸乙酯)純化且與固體合併，得到呈白色固體狀之N-(3-甲氧基-4-噁唑-5-基-苯基)-2-(3-甲氧基-苯基)-乙醯胺(5.4g，80.3%)。MS(ISN)m/z=339.5[(M+H)+]。 3-methoxy-4-oxazol-5-yl-phenylamine (Intermediate 1) (3.792 g, 19.9 mmol) and 2-(3-methoxyphenyl)acetic acid (5.3 g, 31.9 mmol) ) combined with dichloromethane (200 ml). The mixture was cooled to 0 ° C and treated with (3-dimethylamino-propyl)-ethyl-carbodiimide (6.12 g, 31.9 mmol). The mixture was stirred at 0 ° C for 30 minutes, followed by stirring at room temperature for 23 hours. The mixture was washed with saturated sodium bicarbonate. The organic phase was dried over sodium sulfate, filtered and evaporated. The resulting yellow solid (8.2 g) was suspended in ethyl acetate and filtered and washed. The filtrate was evaporated and purified by flash chromatography (EtOAc EtOAc EtOAc) 2-(3-Methoxy-phenyl)-acetamide (5.4 g, 80.3%). MS (ISN) m/z = 339.5 [(M+H)+].

實例2 Example 2 N-(3-甲氧基-4-噁唑-5-基-苯基)-2-間甲苯基-乙醯胺N-(3-methoxy-4-oxazol-5-yl-phenyl)-2-m-tolyl-acetamide

將2-(3-甲基苯基)乙酸(21.5mg，0.14mmol)於二甲基甲醯胺(0.3ml)中之溶液用0.47mM(六氟磷酸2-(7-氮雜-1H-苯并***-1-基)-1,1,3,3-四甲基)(HATU)溶液(0.3mL，0.14mmol)處理。將二異丙基乙胺(18.5mg，0.024mL，0.14mmol)添加至反應混合物中。將0.52mM 3-甲氧基-4-噁唑-5-基-苯基胺(中間物1)溶液(0.3mL，0.16mmol) 添加至反應混合物中。在室溫下攪拌混合物48小時，接著藉由直接注入製備型HPLC中(管柱：製備型：Gemini Axia C18 5μ 110A 5微米100×30mm，分析型：Gemini NX 3μ 110A 50×4.6mm；溶劑A：水+(0.1%甲酸或0.1%三乙胺)；溶劑B：甲醇或乙腈；方法：梯度：20% B至95% B，流量：40ml/min；偵測器：UV/MS/ELSD)純化。蒸發相關溶離份，得到呈白色粉末狀之N-(3-甲氧基-4-噁唑-5-基-苯基)-2-間甲苯基-乙醯胺(28mg，60.7%)；MS(ISN)m/z=322.6[(M+H)+]。 A solution of 2-(3-methylphenyl)acetic acid (21.5 mg, 0.14 mmol) in dimethylformamide (0.3 ml) was used in 0.47 mM (2-(7-aza-1H-hexafluorophosphate) Benzotriazol-1-yl)-1,1,3,3-tetramethyl (HATU) solution (0.3 mL, 0.14 mmol). Diisopropylethylamine (18.5 mg, 0.024 mL, 0.14 mmol) was added to the reaction mixture. A solution of 0.52 mM 3-methoxy-4-oxazol-5-yl-phenylamine (Intermediate 1) (0.3 mL, 0.16 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 48 hours, then directly injected into preparative HPLC (column: preparative: Gemini Axia C18 5μ 110A 5 micron 100 x 30 mm, analytical: Gemini NX 3μ 110A 50 x 4.6 mm; solvent A : water + (0.1% formic acid or 0.1% triethylamine); solvent B: methanol or acetonitrile; method: gradient: 20% B to 95% B, flow rate: 40 ml/min; detector: UV/MS/ELSD) purification. The relevant fractions were evaporated to give N-(3-methoxy-4-oxazol-5-yl-phenyl)-2-m-tolyl-acetamide as a white powder (28 mg, 60.7%); (ISN) m/z = 322.6 [(M+H)+].

實例3 Example 3 N-(3-甲氧基-4-噁唑-5-基-苯基)-2-吡啶-2-基-乙醯胺N-(3-methoxy-4-oxazol-5-yl-phenyl)-2-pyridin-2-yl-acetamide

與實例2之通用方法類似，由吡啶-2-基-乙酸及中間物1製備標題化合物，白色固體(24mg，55%)，MS(ISP)m/z=310.3[(M+H)+]。 The title compound was prepared from pyridine-2-yl-acetic acid and Intermediate 1 (m. .

實例4 Example 4 2-(苯磺醯基)-3'-甲氧基-4'-(5-噁唑基)乙醯苯胺2-(phenylsulfonyl)-3'-methoxy-4'-(5-oxazolyl)acetanilide

與實例2之通用方法類似，由苯磺醯基-乙酸及中間物1製備標題化合物，白色固體，MS(ISP)m/z=373.3[(M+H)+]。 The title compound was obtained from phenylsulfonyl-acetic acid and intermediate 1 as a white solid, MS (ESI) m/z=373.3 [(M+H)+].

實例5Example 5 [(RS)-[[[3-甲氧基-4-(5-噁唑基)苯基]胺甲醯基]苯基]-(甲基)]胺基甲酸第三丁酯[(RS)-[[[3-methoxy-4-(5-oxazolyl)phenyl]amine-carbamoyl]phenyl]-(methyl)]carbamic acid tert-butyl ester

與實例2之通用方法類似，由(D,L)-第三丁氧基羰基-苯基甘胺酸 及中間物1製備標題化合物，白色固體，MS(ISP)m/z=424.5[(M+H)+]。 Similar to the general procedure of Example 2, from (D,L)-t-butoxycarbonyl-phenylglycine The title compound was obtained as a white solid. MS (ESI) m/z=424.5 [(M+H)+].

實例6 Example 6 2-(2-胺基苯基)-3'-甲氧基-4'-(5-噁唑基)乙醯苯胺2-(2-Aminophenyl)-3'-methoxy-4'-(5-oxazolyl)acetanilide

步驟1：與實例2之通用方法類似，由2-(2-硝基苯基)乙酸及中間物1製備N-(3-甲氧基-4-噁唑-5-基-苯基)-2-(2-硝基-苯基)-乙醯胺。 Step 1: Similarly to the general procedure of Example 2, N-(3-methoxy-4-oxazol-5-yl-phenyl)- was prepared from 2-(2-nitrophenyl)acetic acid and Intermediate 1. 2-(2-Nitro-phenyl)-acetamide.

步驟2：與製備中間物1之步驟B所說明之標準程序類似，藉由將N-(3-甲氧基-4-噁唑-5-基-苯基)-2-(2-硝基-苯基)-乙醯胺氫化來製備標題化合物，白色固體，MS(ISP)m/z=324.3[(M+H)+]。 Step 2: Similar to the standard procedure described in Step B of Preparation of Intermediate 1, by N-(3-methoxy-4-oxazol-5-yl-phenyl)-2-(2-nitro Hydrogenation of phenyl)-acetamide to give the title compound as a white solid. m.

實例7 Example 7 N-[3-甲氧基-4-(5-噁唑基)苯基]-3,3-二甲基-2-側氧基丁醯胺N-[3-methoxy-4-(5-oxazolyl)phenyl]-3,3-dimethyl-2-oxobutylbutamine

與實例2類似，可由三甲基-丙酮酸及中間物1製備標題化合物，MS(ISP)m/z=303.3[(M+H)+]。 The title compound was prepared from trimethyl-pyruvate and intermediate 1 in the same manner as in Example 2, MS (ESI) m/z=303.3 [(M+H)+].

實例8 Example 8 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-((3-甲氧基苯基)(甲基)胺基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-((3-methoxyphenyl)(methyl)amino)acetamide

與實例2之通用方法類似，由2-((3-甲氧基苯基)(甲基)胺基)乙酸及中間物1製備標題化合物，黃色固體(95mg，98.4%)，MS(ISP)m/z=368.1[(M+H)+]。 The title compound was prepared from 2-((3-methoxyphenyl)(methyl)amino)acetic acid and Intermediate 1 from EtOAc (EtOAc) m/z = 368.1 [(M+H)+].

實例9 Example 9 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基胺基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylamino)acetamide

在10mL圓底燒瓶中，使3-甲氧基-4-(噁唑-5-基)苯胺(中間物1)(50mg，0.263mmol)與二氯甲烷(2.0ml)組合，得到淺黃色溶液。添加溴乙醯溴(53.1mg，0.023ml，0.263mmol)，在室溫下攪拌反應混合物15分鐘。添加三乙胺(26.6mg，0.037ml，0.263mmol)。攪拌反應混合物15分鐘且添加3-甲氧基苯胺(64.7mg，0.526mmol)。用四氫呋喃稀釋混合物且在真空中部分移除二氯甲烷。加熱反應混合物至70℃且攪拌4小時。在真空中濃縮粗反應混合物。藉由急驟層析純化粗物質，得到呈黃色固體狀之標題化合物(47mg，50.6%)；MS(ISP)m/z=354.2[(M+H)+]。 In a 10 mL round bottom flask, 3-methoxy-4-(oxazol-5-yl)aniline (Intermediate 1) (50 mg, 0.263 mmol) was combined with dichloromethane (2. . Ethyl bromide bromide (53.1 mg, 0.023 ml, 0.263 mmol) was added and the mixture was stirred at room temperature for 15 min. Triethylamine (26.6 mg, 0.037 ml, 0.263 mmol) was added. The reaction mixture was stirred for 15 min and 3-methoxyaniline (64.7 mg, 0.526 mmol). The mixture was diluted with tetrahydrofuran and the dichloromethane was partially removed in vacuo. The reaction mixture was heated to 70 ° C and stirred for 4 hours. The crude reaction mixture was concentrated in vacuo. The title compound (47 mg, 50.6%) was obtainedjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

實例10 Example 10 N-(3-甲氧基-4-噁唑-5-基-苯基)-2-苯基胺基-乙醯胺N-(3-methoxy-4-oxazol-5-yl-phenyl)-2-phenylamino-acetamide

與實例9類似，可使用苯胺製備標題化合物，黃色固體，MS(ISP)m/z=324.3[(M+H)+]。 The title compound was prepared using aniline as a yellow solid. MS (ESI) m/z=324.3 [(M+H)+].

實例11 Example 11 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(苯硫基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(phenylthio)acetamide

與實例2之通用方法類似，由2-(苯硫基)乙酸及中間物1製備標題化合物，黃色固體(88mg，99%)，MS(ISP)m/z=341.1[(M+H)+]。 The title compound was prepared from 2-(phenylthio)acetic acid and Intermediate 1 (yield: yellow solid (88mg, 99%), MS (ISP) m/z = 341.1 [(M+H)+ ].

實例12 Example 12 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-苯氧基乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-phenoxyacetamide

與實例2之通用方法類似，由2-苯氧基乙酸及中間物1製備標題化合物，黃色固體(85mg，99%)，MS(ISP)m/z=325.0[(M+H)+]。 The title compound was prepared from 2-phenoxyacetic acid and intermediate 1 as a yellow solid (85 mg, 99%), MS (ESI) m/z=325.0 [(M+H)+].

實例13 Example 13 N-(3-甲氧基-4-(噁唑-5-基)苯基)-3-苯基丙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3-phenylpropanamide

與實例2之通用方法類似，由3-苯基丙酸及中間物1製備標題化合物，黃色固體(87mg，100%)，MS(ISP)m/z=323.0[(M+H)+]。 The title compound was obtained from EtOAc (EtOAc m.).

實例14 Example 14 2-(2,5-二甲氧基苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2,5-Dimethoxyphenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(2,5-二甲氧基苯基)乙酸及中間物1製備標題化合物，黃色固體(103mg，94%)，MS(ISP)m/z=369.0[(M+H)+]。 The title compound was prepared from 2-(2,5-dimethoxyphenyl)acetic acid and Intermediate 1 (yield: EtOAc, m. [(M+H)+].

實例15 Example 15 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯硫基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylthio)acetamide

與實例2之通用方法類似，由2-(3-甲氧基苯硫基)乙酸及中間物1製備標題化合物，黃色固體(96mg，99%)，MS(ISP)m/z=371.1[(M+H)+]。 The title compound was prepared from 2-(3-methoxyphenylthio)acetic acid and EtOAc (m.) M+H)+].

實例16 Example 16 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基磺醯基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylsulfonyl)acetamide

在50mL圓底燒瓶中，使N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯硫基)乙醯胺(96mg，0.26mmol)與甲醇(10ml)組合，得到黃色溶液。添加過硫酸氫鉀(oxone)(239mg，0.39mmol)。攪拌反應混合物15小時。經玻璃纖維紙過濾反應混合物，接著在真空中濃縮。藉由急驟層析純化粗物質，得到呈黃色固體狀之標題化合物(73mg，70%)；MS(ISP)m/z=403.0[(M+H)+]。 In a 50 mL round bottom flask, N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylthio)acetamide (96 mg, 0.26) Methyl) combined with methanol (10 ml) gave a yellow solution. Potassium hydrogen persulfate (oxone) (239 mg, 0.39 mmol) was added. The reaction mixture was stirred for 15 hours. The reaction mixture was filtered through a glass fiber paper then concentrated in vacuo. The title compound (73 mg, 70%) elut.

實例17 Example 17 2-(3-(二氟甲氧基)苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(3-(Difluoromethoxy)phenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(3-(二氟甲氧基)苯基)乙酸及中間物1製備標題化合物，黃色固體(45mg，76%)，MS(ISP)m/z=375.2[(M+H)+]。 The title compound was prepared from 2-(3-(difluoromethoxy)phenyl)acetic acid and Intermediate 1 (yield: EtOAc, m. 375.2 [(M+H)+].

實例18 Example 18 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(2-(三氟甲基)苯基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(2-(trifluoromethyl)phenyl)acetamide

與實例2之通用方法類似，由2-(2-(三氟甲基)苯基)乙酸及中間物1製備標題化合物，黃色固體(27mg，50%)，MS(ISP)m/z=377.0[(M+H)+]。 The title compound was prepared from 2-(2-(trifluoromethyl)phenyl)acetic acid and Intermediate 1 (yield: yellow solid (27 mg, 50%), MS (ISP) m/z = 377.0 [(M+H)+].

實例19 Example 19 2-(2,4-二氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2,4-Dichlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(2,4-二氯苯基)乙酸及中間物1製備標題化合物，黃色固體(15mg，27%)，MS(ISP)m/z=376.8[(M+H)+]。 The title compound was prepared from 2-(2,4-dichlorophenyl)acetic acid and Intermediate 1 (yield: yellow solid (15 mg, 27%), MS (ISP) m/z = 376.8 [ M+H)+].

實例20 Example 20 2-(4-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(4-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(4-氯苯基)乙酸及中間物1製備標題化合物，黃色固體(26mg，52%)，MS(ISP)m/z=343.4[(M+H)+]。 The title compound was prepared from 2-(4-chlorophenyl)acetic acid and Intermediate 1 (yield: yellow solid (26mg, 52%), MS (ISP) m/z = 343.4 [M+H )+].

實例21 Example 21 2-(3-溴苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(3-bromophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(3-溴苯基)乙酸及中間物1製備標題化合物，黃色固體(24mg，43%)，MS(ISP)m/z=386.6[(M+H)+]。 The title compound was prepared from 2-(3-bromophenyl)acetic acid and Intermediate 1 (yield (yield: 24 mg, 43%), MS (ISP) m/z = 386.6 [M+H )+].

實例22 Example 22 2-(4-溴苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(4-bromophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(4-溴苯基)乙酸及中間物1製備標題化合物，黃色固體(19mg，34%)，MS(ISP)m/z=386.5[(M+H)+]。 The title compound was prepared from 2-(4-bromophenyl)acetic acid and Intermediate 1 (yield: yellow solid (19 mg, 34%), MS (ISP) m/z = 386.5 [M+H )+].

實例23 Example 23 2-(苯并[d][1,3]二氧雜環戊烯-5-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(Benzo[d][1,3]dioxol-5-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(苯并[d][1,3]二氧雜環戊烯-5-基)乙酸及中間物1製備標題化合物，黃色固體(28mg，55%)，MS(ISP)m/z=352.9[(M+H)+]。 The title compound was prepared from 2-(benzo[d][1,3]dioxol-5-yl)acetic acid and Intermediate 1 as a yellow solid (28 mg, 55%). MS (ISP) m/z = 352.9 [(M+H)+].

實例24 Example 24 2-(2-氯-6-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2-chloro-6-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(2-氯-6-氟苯基)乙酸及中間物1製備標題化合物，黃色固體(28mg，54%)，MS(ISP)m/z=360.9[(M+H)+]。 The title compound was obtained from 2-(2-chloro-6-fluorophenyl)acetic acid and Intermediate 1 (yield: EtOAc, m. (M+H)+].

實例25 Example 25 2-(2,6-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2,6-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(2,6-二氟苯基)乙酸及中間物1製備標題化合物，黃色固體(34mg，70%)，MS(ISP)m/z=344.9[(M+H)+]。 The title compound was prepared from 2-(2,6-difluorophenyl)acetic acid and Intermediate 1 (yield: yellow solid (34 mg, 70%), MS (ESI) m/z = 344.9 [ M+H)+].

實例26 Example 26 2-(2-(二氟甲氧基)苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2-(Difluoromethoxy)phenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(2-(二氟甲氧基)苯基)乙酸及中間物1製備標題化合物，黃色固體(30mg，56%)，MS(ISP)m/z=375.4[(M+H)+]。 The title compound was prepared from 2-(2-(difluoromethoxy)phenyl)acetic acid and Intermediate 1 (yield: yellow solid (30 mg, 56%), MS (ISP) m/z = 375.4 [(M+H)+].

實例27 Example 27 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(2-(三氟甲氧基)苯基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(2-(trifluoromethoxy)phenyl)acetamide

與實例2之通用方法類似，由2-(2-(三氟甲氧基)苯基)乙酸及中間物1製備標題化合物，黃色固體(23mg，41%)，MS(ISP)m/z=392.7[(M+H)+]。 The title compound was prepared from 2-(2-(trifluoromethoxy)phenyl)acetic acid and Intermediate 1 (yield: EtOAc, m. 392.7 [(M+H)+].

實例28 Example 28 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(2-甲氧基苯基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(2-methoxyphenyl)acetamide

與實例2之通用方法類似，由2-(2-甲氧基苯基)乙酸及中間物1製備標題化合物，黃色固體(35mg，72%)，MS(ISP)m/z=338.7[(M+H)+]。 The title compound was prepared from 2-(2-methoxyphenyl)acetic acid and Intermediate 1 (yield: EtOAc, m. +H)+].

實例29 Example 29 2-(4-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(4-Fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(4-氟苯基)乙酸及中間物1製備標題化合物，黃色固體(32mg，69%)，MS(ISP)m/z=327.0[(M+H)+]。 The title compound was prepared from 2-(4-fluorophenyl)acetic acid and Intermediate 1 (yield: EtOAc, m. )+].

實例30 Example 30 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-對甲苯基乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-p-tolylacetamide

與實例2之通用方法類似，由2-對甲苯基乙酸及中間物1製備標題化合物，黃色固體(19.1mg，41%)，MS(ISP)m/z=323.6[(M+H)+]。 The title compound was prepared from 2-p-tolylacetic acid and Intermediate 1 (yield: yellow solid (19.1mg, 41%), MS (ISP) m/z = 323.6 [(M+H)+] .

實例31 Example 31 2-(2-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(2-氯苯基)乙酸及中間物1製備標題化合物，黃色固體(29mg，59%)，MS(ISP)m/z=343.4[(M+H)+]。 The title compound was prepared from 2-(2-chlorophenyl)acetic acid and Intermediate 1 (yield: yellow solid (29mg, 59%), MS (ISP) m/z = 343.4 [M+H )+].

實例32 Example 32 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-鄰甲苯基乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-o-tolylacetamide

與實例2之通用方法類似，由2-鄰甲苯基乙酸及中間物1製備標題化合物，黃色固體(33.4mg，72.5%)，MS(ISP)m/z=323.3[(M+H)+]。 The title compound was prepared from 2-o-tolyl acetic acid and Intermediate 1 as a general procedure of Example 2, as a yellow solid (33.4mg, 72.5%), MS (ISP) m/z = 323.3 [(M+H)+] .

實例33 Example 33 2-(2-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2-Fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(2-氟苯基)乙酸及中間物1製備標題化合物，黃色固體(28mg，60%)，MS(ISP)m/z=326.9[(M+H)+]。 The title compound was prepared from 2-(2-fluorophenyl)acetic acid and Intermediate 1 (yield: yellow solid (28mg, 60%), MS (ISP) m/z = 326.9 [(M+H) )+].

實例34 Example 34 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-(三氟甲基)苯基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide

與實例2之通用方法類似，由2-(3-(三氟甲基)苯基)乙酸及中間物1製備標題化合物，黃色固體(22mg，41%)，MS(ISP)m/z=377.0[(M+H)+]。 The title compound was prepared from 2-(3-(trifluoromethyl)phenyl)acetic acid and Intermediate 1 (yield: EtOAc, m. [(M+H)+].

實例35 Example 35 2-(3,5-二甲基苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(3,5-Dimethylphenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(3,5-二甲基苯基)乙酸及中間物1製備標題化合物，黃色固體(29mg，60%)，MS(ISP)m/z=337[(M+H)+]。 The title compound was prepared from 2-(3,5-dimethylphenyl)acetic acid and Intermediate 1 (yield: yellow solid (29 mg, 60%), MS (ESI) m. (M+H)+].

實例36 Example 36 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(萘-1-基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(naphthalen-1-yl)acetamide

與實例2之通用方法類似，由2-(萘-1-基)乙酸及中間物1製備標題化合物，黃色固體(28mg，54%)，MS(ISP)m/z=358.9[(M+H)+]。 The title compound was prepared from 2-(naphthalen-l-yl)acetic acid and Intermediate 1 (yield: yellow solid (28mg, 54%), MS (ISP) m/z=358.9 [(M+H) )+].

實例37 Example 37 2-(3-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(3-Chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(3-氯苯基)乙酸及中間物1製備標題化合物，黃色固體(30mg，61%)，MS(ISP)m/z=342.8[(M+H)+]。 The title compound was prepared from 2-(3-chlorophenyl)acetic acid and Intermediate 1 (yield: yellow solid (30 mg, 61%), MS (ISP) m/z = 342.8 [(M+H) )+].

實例38 Example 38 2-(3,5-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(3,5-Difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(3,5-二氟苯基)乙酸及中間物1製備標題化合物，黃色固體(30mg，60%)，MS(ISP)m/z=345.4[(M+H)+]。 The title compound was prepared from 2-(3,5-difluorophenyl)acetic acid and Intermediate 1 (yield: yellow solid (30mg, 60%), MS (ISP) m/z = 345.4 [ M+H)+].

實例39 Example 39 2-(3-氟-5-(三氟甲基)苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(3-Fluoro-5-(trifluoromethyl)phenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(3-氟-5-(三氟甲基)苯基)乙酸及中間物1製備標題化合物，黃色固體(25.3mg，45%)，MS(ISP)m/z=394.8[(M+H)+]。 The title compound was prepared from 2-(3-fluoro-5-(trifluoromethyl)phenyl)acetic acid and Intermediate 1 (15.3 g, 45%). m/z = 394.8 [(M+H)+].

實例40 Example 40 2-(2,4-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2,4-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(2,4-二氟苯基)乙酸及中間物1製備標題化合物，黃色固體(31mg，63%)，MS(ISP)m/z=344.8[(M+H)+]。 The title compound was prepared from 2-(2,4-difluorophenyl)acetic acid and Intermediate 1 (m.p. M+H)+].

實例41 Example 41 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(4-(甲基磺醯基)苯基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-(methylsulfonyl)phenyl)acetamide

與實例2之通用方法類似，由2-(4-(甲基磺醯基)苯基)乙酸及中間物1製備標題化合物，黃色固體(25mg，46%)，MS(ISP)m/z=387.3[(M+H)+]。 The title compound was prepared from 2-(4-(methylsulfonyl)phenyl)acetic acid and Intermediate 1 (yield: EtOAc, m. 387.3 [(M+H)+].

實例42 Example 42 2-(3,4-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(3,4-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(3,4-二氟苯基)乙酸及中間物1製備標題化合物，黃色固體(28mg，56%)，MS(ISP)m/z=345.0[(M+H)+]。 The title compound was prepared from 2-(3,4-difluorophenyl)acetic acid and Intermediate 1 (yield: yellow solid (28mg, 56%), MS (ISP) m/z = 345.0 [ M+H)+].

實例43 Example 43 2-(3-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(3-Fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(3-氟苯基)乙酸及中間物1製備標題化合物，黃色固體(25mg，53%)，MS(ISP)m/z=326.9[(M+H)+]。 The title compound was prepared from 2-(3-fluorophenyl)acetic acid and Intermediate 1 (yield: m.p. )+].

實例44 Example 44 2-(2,5-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2,5-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(2,5-二氟苯基)乙酸及中間物1製備標題化合物，黃色固體(30.5mg，62%)，MS(ISP)m/z=344.8[(M+H)+]。 The title compound was prepared from 2-(2,5-difluorophenyl)acetic acid and Intermediate 1 (yield: yellow solid (30.5mg, 62%), MS (ISP) m/z = 344.8 (M+H)+].

實例45 Example 45 2-(2,3-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2,3-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(2,3-二氟苯基)乙酸及中間物1製備標題化合物，黃色固體(30mg，60%)，MS(ISP)m/z=344.8[(M+H)+]。 The title compound was prepared from 2-(2,3-difluorophenyl)acetic acid and Intermediate 1 as a EtOAc (m.). M+H)+].

實例46 Example 46 2-(3-氯-4-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(3-Chloro-4-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(3-氯-4-氟苯基)乙酸及中間物1製備標題化合物，黃色固體(29mg，56%)，MS(ISP)m/z=360.8[(M+H)+]。 The title compound was prepared from 2-(3-chloro-4-fluorophenyl)acetic acid and Intermediate 1 (yield (yield: 29 mg, 56%) (M+H)+].

實例47 Example 47 2-(3-氰基苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(3-cyanophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(3-氰基苯基)乙酸及中間物1製備標題化合物，黃色固體(30mg，62.5%)，MS(ISP)m/z=333.9[(M+H)+]。 The title compound was prepared from 2-(3-cyanophenyl)acetic acid and Intermediate 1 (yield: yellow solid (30mg, 62.5%), MS (ISP) m/z = 333.9 [M+ H)+].

實例48 Example 48 2-(5-氯-2-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(5-chloro-2-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(5-氯-2-氟苯基)乙酸及中間物1製備標題化合物，黃色固體(25mg，48%)，MS(ISP)m/z=360.8[(M+H)+]。 The title compound was prepared from 2-(5-chloro-2-fluorophenyl)acetic acid and Intermediate 1 (yield: EtOAc, m. (M+H)+].

實例49 Example 49 2-(呋喃-2-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(furan-2-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(呋喃-2-基)乙酸及中間物1製備標題化合物，黃色固體(31.1mg，73%)，MS(ISP)m/z=299.1[(M+H)+]。 The title compound was prepared from 2-(furan-2-yl)acetic acid and Intermediate 1 (yield: yellow solid (31.1mg, 73%), MS (ISP) m/z=299.1 [M+ H)+].

實例50 Example 50 2-(5-氟吡啶-2-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(5-fluoropyridin-2-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(5-氟吡啶-2-基)乙酸及中間物1製備標題化合物，黃色固體(28mg，59%)，MS(ISP)m/z=328.1[(M+H)+]。 The title compound was prepared from 2-(5-fluoropyridin-2-yl)acetic acid and Intermediate 1 (yield: EtOAc, m. M+H)+].

實例51 Example 51 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(噻吩-2-基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(thiophen-2-yl)acetamide

與實例2之通用方法類似，由2-(噻吩-2-基)乙酸及中間物1製備標 題化合物，黃色固體(22mg，49%)，MS(ISP)m/z=314.8[(M+H)+]。 Similar to the general procedure of Example 2, the preparation of the standard from 2-(thiophen-2-yl)acetic acid and intermediate 1 Compound, yellow solid (22 mg, 49%), MS (ESI) m/z=314.8 [(M+H)+].

實例52 Example 52 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(噻吩-3-基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(thiophen-3-yl)acetamide

與實例2之通用方法類似，由2-(噻吩-3-基)乙酸及中間物1製備標題化合物，黃色固體(23.3mg，52%)，MS(ISP)m/z=315.0[(M+H)+]。 The title compound was prepared from 2-(thiophen-3-yl)acetic acid and Intermediate 1 from EtOAc (EtOAc: m. H)+].

實例53 Example 53 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(吡啶-4-基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(pyridin-4-yl)acetamide

與實例2之通用方法類似，由2-(吡啶-4-基)乙酸及中間物1製備標題化合物，黃色固體(30mg，67%)，MS(ISP)m/z=310.3[(M+H)+]。 The title compound was prepared from 2-(pyridin-4-yl)acetic acid and Intermediate 1 (yield: yellow solid (30 mg, 67%), MS (ISP) m/z = 310.3 [(M+H) )+].

實例54 Example 54 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(1-甲基-1H-吲哚-3-基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(1-methyl-1H-indol-3-yl)acetamide

與實例2之通用方法類似，由2-(1-甲基-1H-吲哚-3-基)乙酸及中間物1製備標題化合物，黃色固體(35.2mg，68%)，MS(ISP)m/z=362.0[(M+H)+]。 The title compound was prepared from 2-(1-methyl-1H-indol-3-yl)acetic acid and Intermediate 1 (yield (35.2mg, 68%), MS (ISP) m. /z=362.0[(M+H)+].

實例55 Example 55 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(吡啶-3-基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(pyridin-3-yl)acetamide

與實例2之通用方法類似，由2-(吡啶-3-基)乙酸及中間物1製備標題化合物，黃色固體(78.2mg，88%)，MS(ISP)m/z=309.8[(M+H)+]。 The title compound was prepared from 2-(pyridin-3-yl)acetic acid and Intermediate 1 (yield: yellow solid (78.2mg, 88%), MS (ISP) m/z = 309.8 [(M+) H)+].

實例56 Example 56 2-(1H-吲哚-3-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(1H-indol-3-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(1H-吲哚-3-基)乙酸及中間物1製備標題化合物，黃色固體(27mg，54%)，MS(ISP)m/z=348.0[(M+H)+]。 The title compound was prepared from 2-(1H-indol-3-yl)acetic acid and Intermediate 1 (yield: yellow solid (27mg, 54%), MS (ESI) m/z = 348.0 [ M+H)+].

實例57 Example 57 2-(苯并[d]異噁唑-3-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(Benzo[d]isoxazol-3-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(苯并[d]異噁唑-3-基)乙酸及中間物1製備標題化合物，黃色固體(25mg，50%)，MS(ISP)m/z=350.0[(M+H)+]。 The title compound was prepared from 2-(benzo[d]isoxazol-3-yl)acetic acid and intermediate 1 as a general procedure of Example 2, as a yellow solid (25 mg, 50%), MS (ISP) m/z =350.0[(M+H)+].

實例58 Example 58 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲基異噁唑-5-基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methylisoxazol-5-yl)acetamide

與實例2之通用方法類似，由2-(3-甲基異噁唑-5-基)乙酸及中間物1製備標題化合物，黃色固體(10.5mg，23.5%)，MS(ISP)m/z=314.3[(M+H)+]。 The title compound was prepared from 2-(3-methylisoxazol-5-yl)acetic acid and Intermediate 1 (10.5 mg, 23.5%), MS (ISP) m/z. =314.3[(M+H)+].

實例59 Example 59 2-(2,4-二甲基噻唑-5-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2,4-Dimethylthiazol-5-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(2,4-二甲基噻唑-5-基)乙酸及中間物1製備標題化合物，黃色固體(12.6mg，26%)，MS(ISP)m/z=344.0[(M+H)+]。 The title compound was prepared from 2-(2,4-dimethylthiazol-5-yl)acetic acid and Intermediate 1 as a mp. z = 344.0 [(M+H)+].

實例60 Example 60 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(5-甲基噻吩-2-基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(5-methylthien-2-yl)acetamide

與實例2之通用方法類似，由2-(5-甲基噻吩-2-基)乙酸及中間物1製備標題化合物，黃色固體(19.2mg，41%)，MS(ISP)m/z=329.0[(M+H)+]。 The title compound was prepared from 2-(5-methyl-thiophen-2-yl)acetic acid and Intermediate 1 (19.2 mg, 41%), MS (ESI) m/z=329.0 [(M+H)+].

實例61 Example 61 N-(3-甲氧基-4-(噁唑-5-基)苯基)戊醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)pentanamide

與實例2之通用方法類似，由戊酸及中間物1製備標題化合物，黃色固體(23mg，58%)，MS(ISP)m/z=275.1[(M+H)+]。 The title compound was prepared from valeric acid and intermediate 1 (yield: yellow solid (23mg, 58%), MS (ESI) m/z=275.1 [(M+H)+].

實例62 Example 62 N-(3-甲氧基-4-(噁唑-5-基)苯基)丙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)propanamide

與實例2之通用方法類似，由丙酸及中間物1製備標題化合物，黃色固體(22mg，62%)，MS(ISP)m/z=247.2[(M+H)+]。 The title compound was prepared from EtOAc (EtOAc m.).

實例63 Example 63 2-環己烯基-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-cyclohexenyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-環己烯基乙酸及中間物1製備標題化合物，黃色固體(32.3mg，72%)，MS(ISP)m/z=312.8[(M+H)+]。 The title compound was prepared from 2-cyclohexenylacetic acid and intermediate 1 as a yellow solid (32.3mg, 72%), MS (ISP) m/z = 312.8 [(M+H)+ ].

實例64 Example 64 2-環己基-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-cyclohexyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-環己基乙酸及中間物1製備標題化合物，黃色固體(11.3mg，25%)，MS(ISP)m/z=315.0[(M+H)+]。 The title compound was prepared from 2-cyclohexylacetic acid and intermediate 1 as a yellow solid (11.3 mg, 25%), MS (ISP) m/z = 315.0 [(M+H)+].

實例65 Example 65 2-環丙基-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-cyclopropyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-環丙基乙酸及中間物1製備標題化合物，黃色固體(20.7mg，53%)，MS(ISP)m/z=272.8[(M+H)+]。 The title compound was prepared from 2-cyclopropylacetic acid and intermediate 1 (yield: EtOAc, m.p. .

實例66 Example 66 2-環戊基-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-cyclopentyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-環戊基乙酸及中間物1製備標題化合物，黃色固體(27mg，62%)，MS(ISP)m/z=301.0[(M+H)+]。 The title compound was prepared from 2-cyclopentylacetic acid and intermediate 1 as a yellow solid (27 mg, 62%), MS (ESI) m/z=301.0 [(M+H)+].

實例67 Example 67 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(4-甲基環己基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-methylcyclohexyl)acetamide

與實例2之通用方法類似，由2-(4-甲基環己基)乙酸及中間物1製備標題化合物，黃色固體(25mg，53%)，MS(ISP)m/z=329.5[(M+H)+]。 The title compound was prepared from 2-(4-methylcyclohexyl)acetic acid and Intermediate 1 (yield: EtOAc, m.p. H)+].

實例68 Example 68 2-(雙環[2.2.1]庚-2-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(Bicyclo[2.2.1]hept-2-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(雙環[2.2.1]庚-2-基)乙酸及中間物1製備標題化合物，黃色固體(23mg，50%)，MS(ISP)m/z=326.8[(M+H)+]。 The title compound was prepared from 2-(bicyclo[2.2.1]heptan-2-yl)acetic acid and Intermediate 1 (yield: EtOAc, m. 326.8 [(M+H)+].

實例69 Example 69 2-(6-甲氧基-3-側氧基-2,3-二氫-1H-茚-1-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(6-Methoxy-3-oxo-2,3-dihydro-1H-indol-1-yl)-N-(3-methoxy-4-(oxazol-5-yl) Phenyl)acetamide

與實例2之通用方法類似，由2-(6-甲氧基-3-側氧基-2,3-二氫-1H-茚-1-基)乙酸及中間物1製備標題化合物，黃色固體(26mg，47%)，MS(ISP)m/z=392.9[(M+H)+]。 The title compound was prepared from 2-(6-methoxy-3-oxo-2,3-dihydro-1H-indol-1-yl)acetic acid and intermediate 1 as a yellow solid. (26 mg, 47%), MS (ISP) m/z = 392.9 [(M+H)+].

實例70 Example 70 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(四氫-2H-哌喃-4-基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(tetrahydro-2H-piperidin-4-yl)acetamide

與實例2之通用方法類似，由2-(四氫-2H-哌喃-4-基)乙酸及中間物1製備標題化合物，黃色固體(31mg，68%)，MS(ISP)m/z=316.9[(M+H)+]。 The title compound was prepared from 2-(tetrahydro-2H-pyran-4-yl)acetic acid and Intermediate 1 (yield: EtOAc, m. 316.9 [(M+H)+].

實例71 Example 71 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(四氫呋喃-2-基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(tetrahydrofuran-2-yl)acetamide

與實例2之通用方法類似，由2-(四氫呋喃-2-基)乙酸及中間物1製備標題化合物，黃色固體(20mg，46%)，MS(ISP)m/z=303.0[(M+H)+]。 The title compound was prepared from 2-(tetrahydrofuran-2-yl)acetic acid and Intermediate 1 (yield: EtOAc, m. )+].

實例72 Example 72 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(四氫-2H-哌喃-2-基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(tetrahydro-2H-piperidin-2-yl)acetamide

與實例2之通用方法類似，由2-(四氫-2H-哌喃-2-基)乙酸及中間物1製備標題化合物，黃色固體(27mg，60%)，MS(ISP)m/z=316.8[(M+H)+]。 The title compound was prepared from 2-(tetrahydro-2H-pyran-2-yl)acetic acid and Intermediate 1 (yield: yellow solid (27 mg, 60%), MS (ISP) m/z = 316.8 [(M+H)+].

實例73 Example 73 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-側氧基-3,4-二氫-2H-苯并[b][1,4]噁嗪-2-基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-olyl-3,4-dihydro-2H-benzo[b][1,4 Oxazin-2-yl)acetamide

與實例2之通用方法類似，由2-(3-側氧基-3,4-二氫-2H-苯并[b][1,4]噁嗪-2-基)乙酸及中間物1製備標題化合物，黃色固體(37mg，69%)，MS(ISP)m/z=369.9[(M+H)+]。 Similar to the general procedure of Example 2, prepared from 2-(3-o-oxy-3,4-dihydro-2H-benzo[b][1,4]oxazin-2-yl)acetic acid and intermediate 1 The title compound was obtained as a yellow solid (37 mg, 69%), MS (ESI) m/z = 369.9 [(M+H)+].

實例74 Example 74 2-(1,1-二側氧基-四氫-1λ2-(1,1-di-oxy-tetrahydro-1λ 66 -噻吩-3-基)-N-(3-甲氧基-4-噁唑-5-基-苯基)-乙醯胺-thiophen-3-yl)-N-(3-methoxy-4-oxazol-5-yl-phenyl)-acetamide

與實例2之通用方法類似，由(1,1-二側氧基-四氫-1λ*6*-噻吩-3-基)-乙酸及中間物1製備標題化合物，黃色固體(34mg，67%)，MS(ISP)m/z=350.7[(M+H)+]。 The title compound was prepared from (1,1-di- oxy-tetrahydro-1 λ*6*-thiophen-3-yl)-acetic acid and Intermediate 1 as a yellow solid (34 mg, 67%) ), MS (ISP) m / z = 350.7 [(M + H) +].

實例75 Example 75 2-環丁基-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-cyclobutyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由2-(3-側氧基-3,4-二氫-2H-苯并 [b][1,4]噁嗪-2-基)乙酸及中間物1製備標題化合物，黃色固體(25mg，60%)，MS(ISP)m/z=286.9[(M+H)+]。 Similar to the general procedure of Example 2, from 2-(3-o-oxy-3,4-dihydro-2H-benzo [b][1,4]oxazin-2-yl)acetic acid and intermediate 1 gave the title compound as a yellow solid (25 mg, 60%), MS (ISP) m/z=286.9 [(M+H)+] .

實例76 Example 76 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(4-側氧基環己基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-oxocyclohexyl)acetamide

與實例2之通用方法類似，由2-(4-側氧基環己基)乙酸及中間物1製備標題化合物，黃色固體(28mg，59%)，MS(ISP)m/z=328.7[(M+H)+]。 The title compound was prepared from 2-(4-oxo-cyclohexyl)acetic acid and Intermediate 1 (yield: EtOAc, m. +H)+].

實例77 Example 77 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-苯基丙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-phenylpropanamide

與實例2之通用方法類似，由2-苯基丙酸及中間物1製備標題化合物，黃色固體(34mg，73%)，MS(ISP)m/z=322.5[(M+H)+]。 The title compound was prepared from 2-phenylpropanoic acid and EtOAc (EtOAc: m.

實例78 Example 78 N-(3-甲氧基-4-(噁唑-5-基)苯基)-3,3-二甲基丁醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3,3-dimethylbutyramine

與實例2之通用方法類似，由3,3-二甲基丁酸及中間物1製備標題化合物，黃色固體(18mg，43.5%)，MS(ISP)m/z=289.0[(M+H)+]。 The title compound was prepared from 3,3-dimethylbutyric acid and intermediate 1 as a yellow solid (18 mg, 43.5%), MS (ISP) m/z=289.0 [(M+H) +].

實例79 Example 79 N-(3-氯-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基)乙醯胺N-(3-chloro-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenyl)acetamide

與實例2之通用方法類似，由2-(3-甲氧基苯基)乙酸及中間物2製備標題化合物，灰白色固體(30mg，29.4%)，MS(ISP)m/z=343.1[(M+H)+]。 The title compound was prepared from 2-(3-methoxyphenyl)acetic acid and Intermediate 2, m.p. (30 mg, 29.4%), MS (ISP) m/z=343.1 [M. +H)+].

實例80 Example 80 2-(3-甲氧基苯基)-N-(3-甲基-4-(噁唑-5-基)苯基)乙醯胺2-(3-methoxyphenyl)-N-(3-methyl-4-(oxazol-5-yl)phenyl)acetamide

與實例1之通用方法類似，由2-(3-甲氧基苯基)乙酸及中間物3製備標題化合物，灰白色固體(288mg，78%)，MS(ISP)m/z=323.3[(M+H)+]。 The title compound was prepared from 2-(3-methoxyphenyl)acetic acid and Intermediate 3, mjjjjjjjjjjjjjjjjjjj +H)+].

實例81 Example 81 2-(3-甲氧基-苯基)-N-(3-甲氧基-4-噻唑-5-基-苯基)-乙醯胺2-(3-methoxy-phenyl)-N-(3-methoxy-4-thiazol-5-yl-phenyl)-acetamide

與實例2之通用方法類似，由2-(3-甲氧基苯基)乙酸及中間物5製備標題化合物，淺黃色固體(89mg，57%)，LC-MS(ESI)=355.0[(M+H)+]。 The title compound was obtained from 2-(3-methoxyphenyl)acetic acid and EtOAc (m.) +H)+].

實例82 Example 82 N-(3-甲氧基-4-[1,3,4]噁二唑-2-基-苯基)-2-(3-甲氧基-苯基)-乙醯胺N-(3-methoxy-4-[1,3,4]oxadiazol-2-yl-phenyl)-2-(3-methoxy-phenyl)-acetamide

與實例2之通用方法類似，由2-(3-甲氧基苯基)乙酸及中間物6製 備標題化合物，白色固體(51mg，14.3%)，LC-MS(ESI)=340.0[(M+H)+]。 Similar to the general procedure of Example 2, made of 2-(3-methoxyphenyl)acetic acid and intermediate 6 The title compound was obtained as a white solid (jjjjjjjjj

實例83 Example 83 2-(3-甲氧基-苯基)-N-(3-甲氧基-4-[1,2,4]***-1-基-苯基)-乙醯胺2-(3-methoxy-phenyl)-N-(3-methoxy-4-[1,2,4]triazol-1-yl-phenyl)-acetamide

與實例2之通用方法類似，由2-(3-甲氧基苯基)乙酸及中間物7製備標題化合物，黃色固體(44mg，41%)，LC-MS(ESI)=338.0[(M+H)+]。 The title compound was prepared from 2-(3-methoxyphenyl)acetic acid and Intermediate 7 (yield: EtOAc (EtOAc) H)+].

實例84 Example 84 3-甲氧基-N-(3-甲氧基苯甲基)-4-(噁唑-5-基)苯甲醯胺3-methoxy-N-(3-methoxybenzyl)-4-(oxazol-5-yl)benzamide

在5mL圓底燒瓶中，使3-甲氧基-4-(噁唑-5-基)苯甲酸(中間物4，100mg，0.46mmol)、二異丙基乙胺(59.0mg，0.46mmol)及HATU(173mg，0.46mmol)與二甲基甲醯胺(3ml)組合，得到黃色溶液。攪拌反應混合物15分鐘。添加(3-甲氧基苯基)甲胺(62.6mg，0.46mmol)。攪拌反應混合物15小時。在真空中濃縮粗反應混合物且藉由急驟層析純化，得到呈白色固體狀之標題化合物(84mg，54.4%)，MS(ISP)m/z=339.3[(M+H)+]。 3-methoxy-4-(oxazol-5-yl)benzoic acid (intermediate 4, 100 mg, 0.46 mmol), diisopropylethylamine (59.0 mg, 0.46 mmol) in a 5 mL round bottom flask HATU (173 mg, 0.46 mmol) was combined with dimethylformamide (3 ml) to give a yellow solution. The reaction mixture was stirred for 15 minutes. (3-Methoxyphenyl)methanamine (62.6 mg, 0.46 mmol) was added. The reaction mixture was stirred for 15 hours. The crude reaction mixture was taken from EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

實例85 Example 85 N-(4-氯苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(4-chlorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

與實例84之通用方法類似，由(4-氯苯基)甲胺及中間物4製備標題化合物，白色固體(35mg，91%)，MS(ISP)m/z=343.0[(M+H)+]。 The title compound was prepared from (4-chlorophenyl)methylamine (m.p.) +].

實例86 Example 86 N-(4-氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(4-fluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

與實例84之通用方法類似，由(4-氟苯基)甲胺及中間物4製備標題化合物，白色固體(26mg，64%)，MS(ISP)m/z=327.1[(M+H)+]。 The title compound was obtained from EtOAc (m. +].

實例87 Example 87 3-甲氧基-4-(噁唑-5-基)-N-(2-(三氟甲基)苯甲基)苯甲醯胺3-methoxy-4-(oxazol-5-yl)-N-(2-(trifluoromethyl)benzyl)benzamide

與實例84之通用方法類似，由(2-三氟甲基)苯基)甲胺及中間物4製備標題化合物，白色固體(29mg，62%)，MS(ISP)m/z=377.3[(M+H)+]。 The title compound was obtained from (2-(2-trifluoromethyl)phenyl)methylamine (m.p. M+H)+].

實例88 Example 88 N-(2-氯苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(2-chlorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

與實例84之通用方法類似，由(2-氯苯基)甲胺及中間物4製備標題化合物，白色固體(35mg，81%)，MS(ISP)m/z=343.0[(M+H)+]。 The title compound was prepared from (2-chlorophenyl)methylamine (m.p.). +].

實例89 Example 89 3-甲氧基-N-(2-甲基苯甲基)-4-(噁唑-5-基)苯甲醯胺3-methoxy-N-(2-methylbenzyl)-4-(oxazol-5-yl)benzamide

與實例84之通用方法類似，由鄰甲苯基甲胺及中間物4製備標題化合物，白色固體(30mg，74%)，MS(ISP)m/z=323.0[(M+H)+]。 The title compound was prepared from o-tolylmethylamine &lt;RTI ID=0.0&gt;&gt;&gt;&gt;

實例90 Example 90 N-(2-氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(2-fluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

與實例84之通用方法類似，由(2-氟苯基)甲胺及中間物4製備標題化合物，白色固體(24mg，58%)，MS(ISP)m/z=327.3[(M+H)+]。 The title compound was prepared from (2-fluorophenyl)methylamine (m.) (m.p. +].

實例91 Example 91 N-(3-氯苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(3-chlorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

與實例84之通用方法類似，由(3-氯苯基)甲胺及中間物4製備標題化合物，白色固體(25mg，57%)，MS(ISP)m/z=343.0[(M+H)+]。 The title compound was prepared from (3-chlorophenyl)methylamine and Intermediate 4 (m.p. +].

實例92 Example 92 N-(3,5-二氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(3,5-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

與實例84之通用方法類似，由(3,5-二氟苯基)甲胺及中間物4製備標題化合物，白色固體(34mg，78%)，MS(ISP)m/z=345.1[(M+H)+]。 The title compound was prepared from (3,5-difluorophenyl)methanamine and intermediate 4, m.p. +H)+].

實例93 Example 93 N-(2,4-二氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(2,4-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

與實例84之通用方法類似，由(2,4-二氟苯基)甲胺及中間物4製備標題化合物，白色固體(33mg，76%)，MS(ISP)m/z=345.0[(M+H)+]。 The title compound was prepared from (2,4-difluorophenyl)methanamine and intermediate 4 as a white solid (3, <RTI ID=0.0>#</RTI> <RTIgt; +H)+].

實例94 Example 94 N-(3-氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(3-fluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

與實例84之通用方法類似，由(3-氟苯基)甲胺及中間物4製備標題化合物，白色固體(31mg，75%)，MS(ISP)m/z=327.3[(M+H)+]。 The title compound was prepared from (3-fluorophenyl)-methanolamine (m.p.). +].

實例95 Example 95 N-(2,5-二氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(2,5-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

與實例84之通用方法類似，由(2,5-二氟苯基)甲胺及中間物4製備 標題化合物，白色固體(32.5mg，75%)，MS(ISP)m/z=345.0[(M+H)+]。 Similar to the general procedure of Example 84, prepared from (2,5-difluorophenyl)methylamine and intermediate 4 The title compound was obtained as a white solid (32.5mg, 75%), MS (ESI) m/z = 345.0 [(M+H)+].

實例96 Example 96 N-(2,3-二氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(2,3-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

與實例84之通用方法類似，由(2,3-二氟苯基)甲胺及中間物4製備標題化合物，白色固體(32mg，74%)，MS(ISP)m/z=345.1[(M+H)+]。 The title compound was obtained from (2,3-difluorophenyl)methylamine and Intermediate 4, m.p. +H)+].

實例97 Example 97 3-甲氧基-4-(噁唑-5-基)-N-(噻吩-2-基甲基)苯甲醯胺3-methoxy-4-(oxazol-5-yl)-N-(thiophen-2-ylmethyl)benzamide

與實例84之通用方法類似，由噻吩-2-基甲胺及中間物4製備標題化合物，白色固體(35mg，88%)，MS(ISP)m/z=315.0[(M+H)+]。 The title compound was prepared from thiophen-2-ylmethylamine and Intermediate 4, m.p. .

實例98 Example 98 N-(2-氟-3-甲氧基苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(2-Fluoro-3-methoxybenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

與實例84之通用方法類似，由(2-氟-3-甲氧基苯基)甲胺氫溴酸鹽及中間物4製備標題化合物，白色固體(61mg，75%)，MS(ISP)m/z=357.1[(M+H)+]。 The title compound was prepared from (2-fluoro-3-methoxyphenyl)methanamine hydrobromide and intermediate 4 as a white crystals (yield: EtOAc) /z=357.1[(M+H)+].

實例99 Example 99 N-(5-氯-2-氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(5-chloro-2-fluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide

與實例84之通用方法類似，由(5-氯-2-氟苯基)甲胺氫溴酸鹽及中間物4製備標題化合物，白色固體(79mg，96%)，MS(ISP)m/z=361.0[(M+H)+]。 The title compound was prepared from (5-chloro-2-fluorophenyl)methylamine hydrobromide and intermediate 4, white solid (79 mg, 96%), MS (ISP) m/z =361.0[(M+H)+].

實例100 Example 100 3-甲氧基-N-((6-甲氧基吡啶-2-基)甲基)-4-(噁唑-5-基)苯甲醯胺3-methoxy-N-((6-methoxypyridin-2-yl)methyl)-4-(oxazol-5-yl)benzamide

與實例84之通用方法類似，由(6-甲氧基吡啶-2-基)甲胺鹽酸鹽及中間物4製備標題化合物，白色固體(61mg，78%)，MS(ISP)m/z=340.3[(M+H)+]。 The title compound was obtained from (6-methoxypyridin-2-yl)methylamine hydrochloride and m. =340.3[(M+H)+].

實例101 Example 101 2-(3-甲氧基苯基)-N-(4-(噁唑-5-基)苯基)乙醯胺2-(3-methoxyphenyl)-N-(4-(oxazol-5-yl)phenyl)acetamide

與實例2之通用方法類似，由4-(噁唑-5-基)苯胺及2-(3-甲氧基苯基)乙酸製備標題化合物，白色固體(23.2mg，38%)，MS(ISP)m/z=309.5[(M+H)+]。 The title compound was obtained from 4-(oxazol-5-yl)aniline and 2-(3-methoxyphenyl)acetic acid. m/z = 309.5 [(M+H)+].

實例102 Example 102 N-(3-甲氧基苯甲基)-4-(噁唑-5-基)苯甲醯胺N-(3-methoxybenzyl)-4-(oxazol-5-yl)benzamide

與實例84之通用方法類似，由4-(噁唑-5-基)苯甲酸及(3-甲氧基苯 基)甲胺製備標題化合物，白色固體(11.5mg，19%)，MS(ISP)m/z=309.5[(M+H)+]。 Similar to the general procedure of Example 84, from 4-(oxazol-5-yl)benzoic acid and (3-methoxybenzene) The title compound was obtained as a white solid (11.5 mg, 19%), MS (ESI) m/z=309.5 [(M+H)+].

實例103 Example 103 2-(3-甲氧基苯基)-N-(4-(吡啶-4-基)苯基)乙醯胺2-(3-methoxyphenyl)-N-(4-(pyridin-4-yl)phenyl)acetamide

與實例2之通用方法類似，由4-(吡啶-4-基)苯胺及2-(3-甲氧基苯基)乙酸製備標題化合物，白色固體(16mg，25%)，MS(ISP)m/z=319.5[(M+H)+]。 The title compound was obtained from 4-(pyridin-4-yl)aniline and 2-(3-methoxyphenyl)acetic acid, mp. /z=319.5[(M+H)+].

實例104 Example 104 N-(3-甲氧基苯甲基)-4-(吡啶-4-基)苯甲醯胺N-(3-methoxybenzyl)-4-(pyridin-4-yl)benzamide

與實例84之通用方法類似，由4-(吡啶-4-基)苯甲酸及(3-甲氧基苯基)甲胺製備標題化合物，白色固體(1.2mg，2%)，MS(ISP)m/z=319.5[(M+H)+]。 The title compound was prepared from 4-(pyridin-4-yl)benzoic acid and (3-methoxyphenyl)methylamine as a white solid (yield: m/z = 319.5 [(M+H)+].

實例105 Example 105 2-(2-氯苯基)-N-(3-甲氧基-4-(吡啶-4-基)苯基)乙醯胺2-(2-chlorophenyl)-N-(3-methoxy-4-(pyridin-4-yl)phenyl)acetamide

使N-(4-溴-3-甲氧基苯基)-2-(2-氯苯基)乙醯胺(中間物8)(200mg，564μmol)、吡啶-4-基酸(83.2mg，677μmol)、K2CO3(390mg，2.82mmol)及Pd(Ph3P)4(97.8mg，84.6μmol)在燒瓶中組合，且用氬氣吹洗五分鐘。添加甲苯(3ml)、乙醇(1.00ml)及水(500μl)之混 合物。在80℃下加熱反應物18.5小時。將反應混合物傾倒於水(20ml)上，用EtOAc(20ml)洗滌且分離有機相，用Na2SO4乾燥，過濾且在真空中濃縮。將粗物質(292.8mg)溶解於二氯甲烷中且藉由矽膠急驟層析(二氯甲烷/甲醇梯度)純化，得到呈白色固體狀之標題化合物(107mg，104%)，MS(ISP)m/z=353.4[(M+H)+]。 N-(4-bromo-3-methoxyphenyl)-2-(2-chlorophenyl)acetamide (Intermediate 8 ) (200 mg, 564 μmol), pyridin-4-yl Acid (83.2 mg, 677 μmol), K 2 CO 3 (390 mg, 2.82 mmol) and Pd(Ph 3 P) 4 (97.8 mg, 84.6 μmol) were combined in a flask and purged with argon for five minutes. A mixture of toluene (3 ml), ethanol (1.00 ml) and water (500 μl) was added. The reaction was heated at 80 ° C for 18.5 hours. The reaction mixture was poured onto water (20ml), with EtOAc (20ml) and the separated organic phase was washed, dried over Na 2 SO 4, filtered and concentrated in vacuo. The crude material (292.8 mg) was purified eluting elut elut elut elut elut elut elut /z=353.4[(M+H)+].

實例106 Example 106 N-(2-氯苯甲基)-3-甲氧基-4-(吡啶-4-基)苯甲醯胺N-(2-chlorobenzyl)-3-methoxy-4-(pyridin-4-yl)benzamide

與實例105類似，藉由使中間物11與吡啶-4-基酸組合來製備標題化合物，淺黃色固體(108mg，54%)，MS(ISP)m/z=353.4[(M+H)+]。 Similar to Example 105, by subjecting the intermediate 11 to pyridin-4-yl The title compound was obtained as a pale yellow solid (108 mg, 54%), MS (ESI) m/z=353.4 [(M+H)+].

實例107 Example 107 2-(2-氯苯基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)乙醯胺2-(2-Chlorophenyl)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)acetamide

與實例105類似，藉由使中間物8與4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑組合來製備標題化合物，淺黃色固體(16mg，8.6%)，MS(ISP)m/z=342.4[(M+H)+]。 Similar to Example 105, by making intermediate 8 and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron The title compound was obtained as a pale yellow solid (16 mg, 8.6%), MS (ESI) m/z = 342.4 [(M+H)+].

實例108 Example 108 2-(2-氯苯基)-N-(2-甲氧基-4-(1H-吡唑-4-基)苯基)乙醯胺2-(2-chlorophenyl)-N-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)acetamide

與實例105類似，藉由使中間物9與4-(4,4,5,5-四甲基-1,3,2-二氧 硼-2-基)-1H-吡唑組合來製備標題化合物，白色固體(48mg，17%)，MS(ISP)m/z=342.4[(M+H)+]。 Similar to Example 105, by using intermediate 9 with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron The title compound was prepared as a white solid (48 mg, 17%), MS (ESI) m/z=342.4 [(M+H)+].

實例109 Example 109 N-(2-氯苯甲基)-2-甲氧基-4-(1H-吡唑-4-基)苯甲醯胺N-(2-chlorobenzyl)-2-methoxy-4-(1H-pyrazol-4-yl)benzamide

與實例105類似，藉由使中間物10與4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑組合來製備標題化合物，白色固體(37.4mg，18%)，MS(ISP)m/z=342.4[(M+H)+]。 Similar to Example 105, by intermediate 10 with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron The title compound was obtained as a white solid (37.4 mg, 18%), MS (ESI) m/z=342.4 [(M+H)+].

實例110 Example 110 N-(2-氯苯甲基)-3-甲氧基-4-(1H-吡唑-4-基)苯甲醯胺N-(2-chlorobenzyl)-3-methoxy-4-(1H-pyrazol-4-yl)benzamide

與實例105類似，藉由使中間物11與4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑組合來製備標題化合物，白色固體(57mg，28%)，MS(ISP)m/z=342.4[(M+H)+]。 Similar to Example 105, by subjecting the intermediate 11 to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron The title compound was prepared as a white solid (57 mg, 28%), MS (ESI) m/z=342.4 [(M+H)+].

實例111 Example 111 N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide

步驟A. Step A.

在25mL圓底燒瓶中，使3-苯基丙酸(446mg，2.97mmol)與DMF(10ml)組合，得到無色溶液。添加六氟磷酸(V)2-(3H-[1,2,3]***并[4,5-b]吡啶-3-基)-1,1,3,3-四甲基異(1.88g，4.95mmol)及二異丙基 乙胺(959mg，1.3ml，7.42mmol)，且在室溫下攪拌反應混合物10分鐘。接著添加4-溴-3-甲氧基苯胺(500mg，2.47mmol)。在室溫下攪拌混合物4小時，接著傾倒至水中，且用乙酸乙酯萃取。合併有機層，用鹽水洗滌，經硫酸鈉乾燥且在真空中濃縮。藉由急驟層析(矽膠，20g，含0%至50%乙酸乙酯之庚烷)純化粗物質，得到呈白色粉末狀之N-(4-溴-3-甲氧基苯基)-3-苯基丙醯胺(792.2mg，95.8%)。MS(m/e)=336.4[M+H+]。 In a 25 mL round bottom flask, 3-phenylpropionic acid (446 mg, 2.97 mmol) was combined with DMF (10 mL). Addition of hexafluorophosphate (V) 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyliso (1.88 g, 4.95 mmol) and diisopropylethylamine (959 mg, 1.3 ml, 7.42 mmol), and the mixture was stirred at room temperature for 10 min. Then 4-bromo-3-methoxyaniline (500 mg, 2.47 mmol) was added. The mixture was stirred at room temperature for 4 hours, then poured into water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate The crude material was purified by EtOAc (EtOAc) eluting -Phenylpropionamide (792.2 mg, 95.8%). MS (m/e) = 336.4 [M+H + ].

步驟B. Step B.

在密封管中，使N-(4-溴-3-甲氧基苯基)-3-苯基丙醯胺(100mg，299μmol)及4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑-1-甲酸第三丁酯(88.0mg，299μmol)與二噁烷(2ml)組合，得到淺黃色溶液。添加碳酸鈉溶液(2M，299μl，598μmol)。使氬氣鼓泡通過溶液5分鐘。添加[1,1'-雙(二苯膦基)二茂鐵]二氯鈀(II)(10.9mg，15.0μmol)。再使氬氣鼓泡通過溶液5分鐘。加熱反應混合物至110℃且攪拌4天。接著將反應混合物傾倒至飽和NaHCO3溶液中且用乙酸乙酯萃取。經硫酸鈉乾燥有機層且在真空中濃縮。藉由製備型HPLC(Zorbax Eclipse XDB-C18 21.2×50mm，流量：25ml/min，梯度：乙腈/水(0.1%甲酸)=95%-5%至5%-95%)純化反應混合物，得到呈白色固體狀之N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺(11mg，11.4%，MS(m/e)=322.16[M+H+])。 In a sealed tube, N-(4-bromo-3-methoxyphenyl)-3-phenylpropanamide (100 mg, 299 μmol) and 4-(4,4,5,5-tetramethyl- 1,3,2-dioxaboron The 2-butyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (88.0 mg, 299 μmol) was combined with dioxane (2 ml) to give a pale yellow solution. Sodium carbonate solution (2M, 299 μl, 598 μmol) was added. Argon was bubbled through the solution for 5 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10.9 mg, 15.0 μmol) was added. Argon was bubbled through the solution for another 5 minutes. The reaction mixture was heated to 110 ° C and stirred for 4 days. The reaction mixture was poured into saturated NaHCO 3 solution and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The reaction mixture was purified by preparative HPLC (Zorbax Eclipse XDB-C18 21.2×50 mm, flow: 25 ml/min, gradient: acetonitrile/water (0.1% formic acid) = 95%-5% to 5%-95%). N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide as a white solid (11 mg, 11.4%, MS (m/e) = 322.16 [M+H + ]).

實例112 Example 112 3-(4-氯苯基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)丙醯胺3-(4-chlorophenyl)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)propanamide

與實例111類似，在步驟A中使用3-(4-氯苯基)丙酸來製備標題化 合物。獲得呈棕色粉末狀之化合物(MS(m/e)=356.12[M+H+])。 The title compound was prepared in the step A using 3-(4-chlorophenyl)propionic acid. The compound was obtained as a brown powder (MS (m/e) = 356.12 [M+H + ]).

實例113 Example 113 2-(2-氯苯基)-N-(3-甲氧基-4-(1H-1,2,4-***-1-基)苯基)乙醯胺2-(2-Chlorophenyl)-N-(3-methoxy-4-(1H-1,2,4-triazol-1-yl)phenyl)acetamide

與實例2之通用方法類似，由(2-氯-苯基)-乙酸及中間物7製備標題化合物，淺棕色固體(42mg，47%)，MS(m/e)=343.1[M+H+]。 Similar to the general procedure of Example 2, from (2-chloro - phenyl) - acetic acid and Intermediate 7 was prepared the title compound as a pale brown solid (42mg, 47%), MS (m / e) = 343.1 [M + H + ].

實例114 Example 114 2-(4-氯苯基胺基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(4-Chlorophenylamino)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

使3-甲氧基-4-(噁唑-5-基)苯胺(中間物1，50mg，263μmol)、2-(4-氯苯基胺基)乙酸(48.8mg，263μmol)及六氟磷酸(V)2-(3H-[1,2,3]***并[4,5-b]吡啶-3-基)-1,1,3,3-四甲基異(150mg，394μmol)與DMF(2.00ml)組合，得到淺棕色溶液。添加二異丙基乙胺(102mg，138μl，789μmol)。在室溫下攪拌反應混合物隔夜，且藉由製備型HPLC(Zorbax Eclipse XDB-C18 21.2×50mm，流量：25ml/min，梯度：乙腈/水(0.1%甲酸)=95%-5%至5%-95%)純化，得到呈淺棕色固體狀之標題化合物(25.6mg，27.2%，MS(m/e)=358.1[M+H+])。 3-methoxy-4-(oxazol-5-yl)aniline (intermediate 1,50 mg, 263 μmol), 2-(4-chlorophenylamino)acetic acid (48.8 mg, 263 μmol) and hexafluorophosphoric acid (V) 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyliso (150 mg, 394 μmol) combined with DMF (2.00 ml) gave a light brown solution. Diisopropylethylamine (102 mg, 138 μl, 789 μmol) was added. The reaction mixture was stirred overnight at room temperature and by preparative HPLC (Zorbax Eclipse XDB-C18 21.2 x 50 mm, flow: 25 ml/min, gradient: acetonitrile/water (0.1% formic acid) = 95% - 5% to 5% Purification of the title compound (25.6 mg, 27.2%, MS (m/e)=358.1 [M+H + ]).

實例115 Example 115 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-(三氟甲基)苯基胺基)乙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-(trifluoromethyl)phenylamino)acetamide

與實例114類似，使用2-(3-(三氟甲基)苯基胺基)乙酸來製備標題 化合物。獲得呈淺棕色固體狀之化合物(43.7mg，42.3%，MS(m/e)=392.12[M+H+])。 The title compound was prepared using 2-(3-(trifluoromethyl)phenylamino)acetic acid as in Example 114. The compound was obtained as a light brown solid (43.7 mg, 42.3%, MS (m/e) = 392.12 [M+H + ]).

實例116 Example 116 2-(4-氟苯基胺基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(4-Fluorophenylamino)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide

與實例114類似，使用2-(4-氟苯基胺基)乙酸來製備標題化合物。獲得呈淺棕色固體狀之化合物(33.6mg，37.4%，MS(m/e)=342.12[M+H+])。 The title compound was prepared using 2-(4-fluorophenylamino)acetic acid analogous to Example 114. The compound was obtained as a light brown solid (33.6 mg, 37.4%, MS (m/e) = 342.12 [M+H + ]).

實例117 Example 117 N-(4-(噁唑-5-基)苯基)-2-(苯基胺基)乙醯胺N-(4-(oxazol-5-yl)phenyl)-2-(phenylamino)acetamide

與實例114類似，使用4-(噁唑-5-基)苯胺及2-(苯基胺基)乙酸來製備標題化合物。獲得呈淺棕色固體狀之化合物(26.5mg，28.9%，MS(m/e)=294.13[M+H+])。 Analogously to Example 114, the title compound was prepared using 4-(oxazol-5-yl)aniline and 2-(phenylamino)acetic acid. The compound was obtained as a light brown solid (26.5 mg, 28.9%, MS (m/e) = 294.13 [M+H + ]).

實例118 Example 118 2-(4-氟苯基胺基)-N-(4-(噁唑-5-基)苯基)乙醯胺2-(4-Fluorophenylamino)-N-(4-(oxazol-5-yl)phenyl)acetamide

與實例114類似，使用4-(噁唑-5-基)苯胺及2-(4-氟苯基胺基)乙酸來製備標題化合物。獲得呈灰白色粉末狀之化合物(27.7mg，28.5%，MS(m/e)=312.12[M+H+])。 The title compound was prepared using 4-(oxazol-5-yl)aniline and 2-(4-fluorophenylamino)acetic acid. The compound was obtained as an off-white powder (27.7 mg, 28.5%, MS (m/e) = 312.12 [M+H + ]).

實例119 Example 119 3-(3-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)丙醯胺3-(3-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)propanamide

與實例114類似，使用3-(3-氯苯基)丙酸來製備標題化合物。獲得呈棕色固體狀之化合物(MS(m/e)=357.10[M+H+])。 Analogously to Example 114, the title compound was prepared using 3-(3-chlorophenyl)propionic acid. The compound was obtained as a brown solid (MS (m/e) = 357.10 [M+H + ]).

實例120 Example 120 3-(2-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)丙醯胺3-(2-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)propanamide

與實例114類似，在步驟A中使用3-(2-氯苯基)丙酸來製備標題化合物。獲得呈棕色固體狀之化合物(MS(m/e)=357.10[M+H+])。 The title compound was prepared in the step A using 3-(2-chlorophenyl)propionic acid. The compound was obtained as a brown solid (MS (m/e) = 357.10 [M+H + ]).

實例121 Example 121 N-(3-甲氧基-4-(吡啶-4-基)苯基)-3-苯基丙醯胺N-(3-methoxy-4-(pyridin-4-yl)phenyl)-3-phenylpropanamide

步驟A. Step A.

在氮氣氛圍下，在50mL圓底燒瓶中，使吡啶-4-基酸(1g，8.14mmol)、4-溴-3-甲氧基苯胺(1.64g，8.14mmol)、肆(三苯基膦)鈀(0)(18.8mg，16.3μmol)及碳酸鈉(3.02g，28.5mmol)與DMF(14ml)及水(4ml)組合，得到淺棕色懸浮液。在回流下攪拌反應物隔夜。添加水且用乙酸乙酯萃取反應混合物。經硫酸鈉乾燥合併之有機層且過濾，且在真空中移除溶劑。藉由管柱層析(矽膠，20g，含50%至100% EtOAc之庚烷)自殘餘物中分離出呈棕色固體狀之3-甲氧基-4-(吡啶-4-基)苯胺(240mg，15%，MS(m/e)=201.5[M+H+])。 Pyridin-4-yl in a 50 mL round bottom flask under a nitrogen atmosphere Acid (1 g, 8.14 mmol), 4-bromo-3-methoxyaniline (1.64 g, 8.14 mmol), hydrazine (triphenylphosphine) palladium (0) (18.8 mg, 16.3 μmol) and sodium carbonate (3.02 g) , 28.5 mmol) in combination with DMF (14 ml) and water (4 ml) gave a light brown suspension. The reaction was stirred at reflux overnight. Water was added and the reaction mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and filtered and solvent was evaporated in vacuo. Separation of 3-methoxy-4-(pyridin-4-yl)aniline as a brown solid from EtOAc (EtOAc (EtOAc:EtOAc) 240 mg, 15%, MS (m/e) = 201.5 [M+H + ]).

步驟B. Step B.

在密封管中，使3-甲氧基-4-(吡啶-4-基)苯胺(60mg，300μmol)、3-苯基丙酸(45.0mg，300μmol)及DIPEA(65.8mg，89.0μl，509μmol)與DMF(500μl)組合。接著添加HATU(194mg，509μmol，1.7當量)。在室溫下攪拌混合物5天。藉由製備型HPLC(管柱：zorbax C18 21.2×50mm，流量：20ml/min，梯度：在8分鐘內，乙腈/水(+0.1%甲酸)=(95%-5%至5%-95%))純化粗物質，得到呈黃色固體狀之N-(3-甲氧基-4-(吡啶-4-基)苯基)-3-苯基丙醯胺(34.7mg，34.8%，MS(m/e)=333.16[M+H+])。 3-methoxy-4-(pyridin-4-yl)aniline (60 mg, 300 μmol), 3-phenylpropionic acid (45.0 mg, 300 μmol) and DIPEA (65.8 mg, 89.0 μl, 509 μmol) in a sealed tube ) combined with DMF (500 μl). Then HATU (194 mg, 509 μmol, 1.7 equivalents) was added. The mixture was stirred at room temperature for 5 days. By preparative HPLC (column: zorbax C18 21.2 x 50 mm, flow: 20 ml/min, gradient: acetonitrile / water (+0.1% formic acid) = (95% - 5% to 5% - 95% in 8 minutes) The crude material was purified to give N-(3-methoxy-4-(pyridin-4-yl)phenyl)-3-phenylpropanamine as a yellow solid (34.7 mg, 34. m/e) = 333.16 [M + H + ]).

實例122 Example 122 N-(4-(1H-吡唑-4-基)苯基)-3-(2-氯苯基)丙醯胺N-(4-(1H-pyrazol-4-yl)phenyl)-3-(2-chlorophenyl)propanamide

步驟A. Step A.

向1-溴-4-硝基-苯(2g，9.90mmol)於二噁烷(160ml)及水(40ml)中之溶液中添加碳酸鉀(4.10mg，29.70mmol)，且用氬氣淨化反應混合物10分鐘。將[1-(第三丁氧基羰基)-1H-吡唑-4-基]酸頻哪醇酯(4.36g，14.85mmol)及Pd(dppf)2Cl2．CH2Cl2(323mg，0.39mmol)添加至反應混合物中，且再用氬氣淨化10分鐘。加熱反應混合物至80℃維持16小時。在減壓下蒸發溶劑，且用水(60ml)稀釋所得粗物質，且用二氯甲烷(2×80ml)萃取。經無水硫酸鈉乾燥合併之有機層，過濾且在真空中蒸發。藉由管柱層析(矽膠，50-60%乙酸乙酯/己烷)純化所得粗物質，得到呈黃色固體狀之4-(4-硝基-苯基)-1H-吡唑(1.86g，99.41%)。MS：190.0(M+H+)。 Potassium carbonate (4.10 mg, 29.70 mmol) was added to a solution of 1-bromo-4-nitro-benzene (2 g, 9.90 mmol) in dioxane (160 ml) and water (40 ml). The mixture was allowed to stand for 10 minutes. [1-(Tertibutoxycarbonyl)-1H-pyrazol-4-yl] Acid pinacol ester (4.36g, 14.85mmol) and Pd(dppf) 2 Cl 2 . CH 2 Cl 2 (323 mg, 0.39 mmol) was added to the reaction mixture and then purified with argon for 10 min. The reaction mixture was heated to 80 ° C for 16 hours. The solvent was evaporated under reduced pressure and EtOAc m. The combined organic layers were dried with anhydrous sodium sulfate, filtered and evaporated in vacuo. The crude material was purified by column chromatography eluting elut elut elut elut elut elut elut elut elut , 99.41%). MS: 190.0 (M + H + ).

步驟B. Step B.

向4-(4-硝基-苯基)-1H-吡唑(3.98g，21.05mmol)於THF(150ml)中之溶液中添加三乙胺(4.40ml，31.58mmol)及(Boc)2O(7.25ml，31.58mmol)，且在25℃下攪拌反應混合物16小時。在真空中蒸發溶劑，且藉由管柱層析(矽膠，20-30%乙酸乙酯/己烷)純化所得粗物質，得到呈白色固體狀之4-(4-硝基苯基)-1H-吡唑-1-甲酸第三丁酯(4g，65.66%)。MS：290.2(M+H+)。 Triethylamine (4.40ml, 31.58mmol) and (Boc) 2 O in the -1H- pyrazole (3.98g, 21.05mmol) in THF (150ml) solution - a solution of 4- (4-nitro-phenyl) (7.25 ml, 31.58 mmol), and the reaction mixture was stirred at 25 ° C for 16 h. The solvent was evaporated in vacuo and EtOAcqqqqqqqq Pyrazole-1-carboxylic acid tert-butyl ester (4 g, 65.66%). MS: 290.2 (M + H + ).

步驟C. Step C.

向4-(4-硝基苯基)-1H-吡唑-1-甲酸第三丁酯(2g，6.92mmol)於MeOH(190ml)中之溶液中添加10% Pd/C(100mg)，且在25℃下於H2氣球氛圍下攪拌反應混合物3小時。過濾混合物，且在減壓下蒸發濾液，得到呈灰白色固體狀之4-(4-胺基苯基)-1H-吡唑-1-甲酸第三丁酯(1.75g，97.8%)。MS：260.0(M+H+)。 To a solution of 4-(4-nitrophenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (2 g, 6.92 mmol) in MeOH (190 ml), 10% Pd / C (100 mg) The reaction mixture was stirred at 25 ° C under a H 2 balloon atmosphere for 3 hours. The mixture was filtered, and the filtrate was evaporated,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS: 260.0 (M+H + ).

步驟D. Step D.

在密封管中，使4-(4-胺基苯基)-1H-吡唑-1-甲酸第三丁酯(120mg，463μmol)、3-(2-氯苯基)丙酸(85.4mg，463μmol)及DIPEA(102mg，137μl，787μmol)與DMF(1ml)組合。接著添加HATU(264mg，694μmol)。在室溫下攪拌混合物隔夜，接著傾倒至30ml乙酸乙酯中且用水(3×15mL)及鹽水萃取。經硫酸鈉乾燥有機層且在真空中濃縮。獲得呈淺棕色泡沫狀之4-(4-(3-(2-氯苯基)丙醯胺基)苯基)-1H-吡唑-1-甲酸第三丁酯(240mg，97.4%)。MS(m/e)=326.5。 In the sealed tube, 4-(4-aminophenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (120 mg, 463 μmol), 3-(2-chlorophenyl)propionic acid (85.4 mg, 463 μmol) and DIPEA (102 mg, 137 μl, 787 μmol) were combined with DMF (1 ml). Then HATU (264 mg, 694 μmol) was added. The mixture was stirred at room temperature overnight then poured into 30 mL EtOAc EtOAc. The organic layer was dried over sodium sulfate and concentrated in vacuo. 4-(4-(3-(2-Chlorophenyl)propanamido)phenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (240 mg, 97.4%) was obtained as a light brown foam. MS (m/e) = 326.5.

步驟E. Step E.

在氮氣氛圍下，在25mL圓底燒瓶中，使4-(4-(3-(2-氯苯基)丙醯胺基)苯基)-1H-吡唑-1-甲酸第三丁酯(240mg，451μmol)與CH2Cl2(2ml)組合，得到淺棕色溶液。接著緩慢添加三氟乙酸(1.03g，695μl，9.02mmol)。在室溫下攪拌混合物1小時。在真空中濃縮粗反應混合物且藉由製備型HPLC(zorbax C18 21.2×50mm，流量：20ml/min， 梯度：在8分鐘內，乙腈/水(+0.1%甲酸)=(95%-5%至5%-95%))純化。獲得呈灰白色固體狀之N-(4-(1H-吡唑-4-基)苯基)-3-(2-氯苯基)丙醯胺(49.9mg，34.0%)。MS(m/e)=326.10[M+H+]。 4-(4-(3-(2-chlorophenyl)propanamido)phenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (25%) in a 25 mL round bottom flask under nitrogen atmosphere ( 240 mg, 451 μmol) combined with CH 2 Cl 2 (2 ml) gave a light brown solution. Trifluoroacetic acid (1.03 g, 695 μl, 9.02 mmol) was then added slowly. The mixture was stirred at room temperature for 1 hour. The crude reaction mixture was concentrated in vacuo and purified by preparative HPLC ( </ RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI></RTI><RTIgt; 5%-95%)) purified. N-(4-(1H-pyrazol-4-yl)phenyl)-3-(2-chlorophenyl)propanamide (49.9 mg, 34.0%) was obtained as a white solid. MS (m/e) = 326.10 [M+H + ].

實例123 Example 123 N-(4-(1H-吡唑-4-基)苯基)-3-(3-氯苯基)丙醯胺N-(4-(1H-pyrazol-4-yl)phenyl)-3-(3-chlorophenyl)propanamide

與實例122類似，在步驟D中使用3-(3-氯苯基)丙酸來製備標題化合物。MS(m/e)=326.1[M+H+]。 The title compound was prepared in the step D using 3-(3-chlorophenyl)propionic acid. MS (m/e) = 326.1 [M+H + ].

實例124 Example 124 N-(4-(1H-吡唑-4-基)苯基)-3-(4-氯苯基)丙醯胺N-(4-(1H-pyrazol-4-yl)phenyl)-3-(4-chlorophenyl)propanamide

與實例122類似，在步驟D中使用3-(4-氯苯基)丙酸來製備標題化合物。MS(m/e)=326.11[M+H+]。 The title compound was prepared in the step D using 3-(4-chlorophenyl)propionic acid. MS (m/e) = 326.11 [M+H + ].

實例125 Example 125 N-(3-氟-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺N-(3-Fluoro-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide

步驟A. Step A.

在密封管中，使4-溴-3-氟苯胺(150mg，789μmol)、3-苯基丙酸(119mg，789μmol)及DIPEA(173mg，234μl，1.34mmol)與DMF(1.5ml)組合。接著添加HATU(450mg，1.18mmol)且在室溫下攪拌混合物隔夜。將反應混合物傾倒至乙酸乙酯中且用水萃取。經硫酸鈉 乾燥有機層且在真空中濃縮。藉由製備型HPLC(zorbax C18 21.2×50mm，流量：20ml/min，梯度：在8分鐘內，乙腈/水(+0.1%甲酸)=(95%-5%至5%-95%))純化粗物質。獲得呈淺棕色固體狀之N-(4-溴-3-氟苯基)-3-苯基丙醯胺(180mg，70.8%)。MS(m/e)=322.4[M+H+]。 4-bromo-3-fluoroaniline (150 mg, 789 μmol), 3-phenylpropionic acid (119 mg, 789 μmol) and DIPEA (173 mg, 234 μl, 1.34 mmol) were combined with DMF (1.5 ml). Then HATU (450 mg, 1.18 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ethyl acetate and extracted with water. The organic layer was dried over sodium sulfate and concentrated in vacuo. Purified by preparative HPLC (zorbax C18 21.2×50 mm, flow: 20 ml/min, gradient: acetonitrile/water (+0.1% formic acid) = (95%-5% to 5%-95%) in 8 minutes) Crude material. N-(4-Bromo-3-fluorophenyl)-3-phenylpropanamide (180 mg, 70.8%) was obtained as a pale brown solid. MS (m/e) = 322.4 [M+H + ].

步驟B. Step B.

在密封管中，使N-(4-溴-3-氟苯基)-3-苯基丙醯胺(100mg，310μmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑-1-甲酸第三丁酯(91.3mg，310μmol)及碳酸鈉(776μl，1.55mmol)與二噁烷(5ml)組合。使氬氣鼓泡通過反應混合物5分鐘。接著添加1,1'-雙(二苯膦基)二茂鐵-二氯化鈀(II)二氯甲烷複合物(25.3mg，31.0μmol)。再使氬氣鼓泡通過反應混合物5分鐘。在85℃下攪拌反應物隔夜。將反應混合物傾倒至乙酸乙酯中且用水萃取。經硫酸鈉乾燥有機層且在真空中濃縮。藉由製備型HPLC(zorbax C18 21.2×50mm，流量：20ml/min，梯度：在8分鐘內，乙腈/水(+0.1%甲酸)=(95%-5%至5%-95%))純化粗物質。獲得呈棕色固體狀之N-(3-氟-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺(13.4mg，14.0%)。MS(m/e)=310.13[M+H+]。 In a sealed tube, N-(4-bromo-3-fluorophenyl)-3-phenylpropanamide (100 mg, 310 μmol), 4-(4,4,5,5-tetramethyl-1, 3,2-dioxaboron 2-Benzyl-1H-pyrazole-1-carboxylic acid tert-butyl ester (91.3 mg, 310 μmol) and sodium carbonate (776 μl, 1.55 mmol) were combined with dioxane (5 ml). Argon was bubbled through the reaction mixture for 5 minutes. Next, 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) chloride dichloride complex (25.3 mg, 31.0 μmol) was added. Argon was bubbled through the reaction mixture for another 5 minutes. The reaction was stirred at 85 ° C overnight. The reaction mixture was poured into ethyl acetate and extracted with water. The organic layer was dried over sodium sulfate and concentrated in vacuo. Purified by preparative HPLC (zorbax C18 21.2×50 mm, flow: 20 ml/min, gradient: acetonitrile/water (+0.1% formic acid) = (95%-5% to 5%-95%) in 8 minutes) Crude material. N-(3-Fluoro-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide (13.4 mg, 14.0%) was obtained as a brown solid. MS (m/e) = 310.13 [M+H + ].

實例126 Example 126 N-(3-氯-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺N-(3-chloro-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide

與實例122類似，在步驟A中使用4-溴-3-氯-苯胺來製備標題化合物。MS(m/e)=326.10[M+H+]。 The title compound was prepared in the step A using 4-bromo-3-chloro-phenylamine. MS (m/e) = 326.10 [M+H + ].

實例127 Example 127 N-(2-氯-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺N-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide

與實例122類似，在步驟A中使用4-溴-2-氯-苯胺來製備標題化合物。MS(m/e)=326.10[M+H+]。 The title compound was prepared in the step A using 4-bromo-2-chloro-phenylamine. MS (m/e) = 326.10 [M+H + ].

實例128 Example 128 N-(3-甲基-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺N-(3-methyl-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide

與實例122類似，在步驟A中使用4-溴-3-甲基-苯胺來製備標題化合物。MS(m/e)=306.16[M+H+]。 Analogously to Example 122, 4-bromo-3-methyl-phenylamine was used in Step A to give the title compound. MS (m/e) = 306.16 [M+H + ].

實例129 Example 129 N-(2-甲基-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺N-(2-methyl-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide

與實例122類似，在步驟A中使用4-溴-2-甲基-苯胺來製備標題化合物。MS(m/e)=306.16[M+H+]。 The title compound was prepared in the step A using 4-bromo-2-methyl-phenylamine. MS (m/e) = 306.16 [M+H + ].

實例130 Example 130 N-(2-甲氧基-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺N-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide

與實例122類似，在步驟A中使用4-溴-2-甲氧基-苯胺來製備標題化合物。MS(m/e)=322.16[M+H+]。 Analogously to Example 122, 4-bromo-2-methoxy-phenylamine was used in Step A to give the title compound. MS (m/e) = 322.16 [M+H + ].

實例131 Example 131 3-甲氧基-N-苯乙基-4-(1H-吡唑-4-基)苯甲醯胺3-methoxy-N-phenethyl-4-(1H-pyrazol-4-yl)benzamide

步驟A. Step A.

在密封管中，使4-溴-3-甲氧基苯甲酸(500mg，2.16mmol)、2-苯基乙胺(262mg，272μl，2.16mmol)及六氟磷酸(V)2-(3H-[1,2,3]***并[4,5-b]吡啶-3-基)-1,1,3,3-四甲基異(1.23g，3.25mmol)與DMF(10ml)組合，得到淺棕色溶液。添加二異丙基乙胺(839mg，1.13ml，6.49mmol)。在室溫下攪拌反應混合物隔夜。接著將反應混合物傾倒至水中且用乙酸乙酯萃取。經硫酸鈉乾燥有機層且在真空中濃縮。藉由急驟層析(矽膠，50g，含0%至50% EtOAc之庚烷)純化粗物質，得到呈淺黃色固體狀之4-溴-3-甲氧基-N-苯乙基苯甲醯胺(0.58g，77.4%，MS(m/e)=334.4[M+H+])。 4-bromo-3-methoxybenzoic acid (500 mg, 2.16 mmol), 2-phenylethylamine (262 mg, 272 μl, 2.16 mmol) and hexafluorophosphate (V) 2-(3H- in a sealed tube. [1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethyliso (1.23 g, 3.25 mmol) in combination with DMF (10 mL) gave a pale brown solution. Diisopropylethylamine (839 mg, 1.13 ml, 6.49 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography eluting elut elut elut elut elut elut elut elut Amine (0.58 g, 77.4%, MS (m/e) = 334.4 [M+H + ]).

步驟B. Step B.

在密封管中，使4-溴-3-甲氧基-N-苯乙基苯甲醯胺(250mg，748μmol)及4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑-1-甲酸第三丁酯(220mg，748μmol)與二噁烷(5ml)組合，得到淺黃色溶液。添加碳酸鈉溶液(2M，748μl，1.5mmol)。使氬氣鼓泡通過溶液5分鐘。添加[1,1'-雙(二苯膦基)二茂鐵]二氯鈀(II)(27.4mg，37.4μmol)，且再使氬氣鼓泡通過溶液5分鐘。加熱反應混合物至85℃經週末，接著傾倒至飽和NaHCO3中且用乙酸乙酯萃取。經硫酸鈉乾燥有機層且在真空中濃縮。藉由製備型HPLC(Zorbax Eclipse XDB-C18 21.2×50mm，流量：25ml/min，梯度：乙腈/水(0.1%甲酸)=95%-5%至5%-95%)純化反應混合物，得到呈白色固體狀之3-甲氧基-N-苯乙基-4-(1H-吡唑-4-基)苯甲醯胺(63mg，26%，MS(m/e)=322.16[M+H+]。 In a sealed tube, 4-bromo-3-methoxy-N-phenethylbenzamide (250 mg, 748 μmol) and 4-(4,4,5,5-tetramethyl-1,3, 2-diboron The 2-butyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (220 mg, 748 μmol) was combined with dioxane (5 ml) to give a pale yellow solution. Sodium carbonate solution (2M, 748 [mu]l, 1.5 mmol) was added. Argon was bubbled through the solution for 5 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (27.4 mg, 37.4 μmol) was added, and argon was bubbled through the solution for 5 minutes. The reaction mixture was heated to 85 ℃ over the weekend, then poured into saturated NaHCO 3 and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo. The reaction mixture was purified by preparative HPLC (Zorbax Eclipse XDB-C18 21.2×50 mm, flow: 25 ml/min, gradient: acetonitrile/water (0.1% formic acid) = 95%-5% to 5%-95%). 3-methoxy-N-phenethyl-4-(1H-pyrazol-4-yl)benzamide as a white solid (63 mg, 26%, MS (m/e) = 322.16 [M+H + ].

實例132 Example 132 2-(2-氯苯基)-N-(2-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2-chlorophenyl)-N-(2-methoxy-4-(oxazol-5-yl)phenyl)acetamide

步驟A. Step A.

使3-甲氧基-4-硝基苯甲醛(CAS 80410-57-7，500mg，2.76mmol)、4-甲苯基磺醯基-甲基胩(TosMIC，539mg，2.76mmol)及碳酸鉀(381mg，2.76mmol)與甲醇(5.5ml)組合。在80℃下攪拌反應混合物3小時，接著在室溫下攪拌隔夜。過濾反應混合物且將固體溶解於二氯甲烷(40ml)中，依序用水(30ml)、鹽水(30ml)洗滌。經硫酸鈉乾燥有機相且在真空中濃縮，得到呈橙色固體狀之5-(3-甲氧基-4-硝基苯基)噁唑(403mg，66%)。MS：m/e=221.4[M+H]+。 3-methoxy-4-nitrobenzaldehyde (CAS 80410-57-7, 500 mg, 2.76 mmol), 4-tolylsulfonyl-methylhydrazine (TosMIC, 539 mg, 2.76 mmol) and potassium carbonate ( 381 mg, 2.76 mmol) was combined with methanol (5.5 ml). The reaction mixture was stirred at 80 ° C for 3 hours, then stirred at room temperature overnight. The reaction mixture was filtered and EtOAc (EtOAc m. The organic phase was dried <RTI ID=0.0>(~~~~~~~~~~~ MS: m/e = 221.4 [M + H] + .

步驟B. Step B.

在兩頸容器中，用四氫呋喃(8ml)/乙醇(1.6ml)稀釋5-(3-甲氧基-4-硝基苯基)噁唑(397mg，1.80mmol)。在氬氣氛圍下添加鈀(10%，於碳上，79.4mg，74.6μmol)。在氫氣氛圍下攪拌反應混合物隔夜。過濾反應混合物，用乙醇洗滌且在真空中濃縮液相，得到呈黃色固體狀之2-甲氧基-4-(噁唑-5-基)苯胺(342mg；99.8%)。MS：m/e=191.5[M+H]+。 5-(3-methoxy-4-nitrophenyl)oxazole (397 mg, 1.80 mmol) was diluted with tetrahydrofuran (8 ml) / ethanol (1.6 ml). Palladium (10% on carbon, 79.4 mg, 74.6 μmol) was added under argon. The reaction mixture was stirred overnight under a hydrogen atmosphere. The reaction mixture was filtered, washed with EtOAc EtOAcjjjjjjjj MS: m/e = 191.5 [M + H] + .

步驟C. Step C.

使2-甲氧基-4-(噁唑-5-基)苯胺(150mg，789μmol)與二氯甲烷(7.3ml)組合。添加2-(2-氯苯基)乙酸(215mg，1.26mmol)。使混合物冷卻至0℃。添加N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(242mg，1.26mmol)。在0℃下攪拌反應混合物30分鐘，接著在室溫下攪拌隔夜。用二氯甲烷(20ml)稀釋反應混合物，用飽和碳酸氫鈉水溶液(20ml)及鹽水(20ml)洗滌。經硫酸鈉乾燥有機相，且過濾並在真空中濃縮。藉由層析(矽膠，乙酸乙酯/庚烷=0：100至70：30)純化，得到呈白色固體狀之2-(2-氯苯基)-N-(2-甲氧基-4-(噁唑-5-基)苯基)乙醯胺(243mg，90%)。MS：m/e=343.4[M+H]+。 2-Methoxy-4-(oxazol-5-yl)aniline (150 mg, 789 μmol) was combined with dichloromethane (7.3 mL). 2-(2-Chlorophenyl)acetic acid (215 mg, 1.26 mmol) was added. The mixture was allowed to cool to 0 °C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (242 mg, 1.26 mmol) was added. The reaction mixture was stirred at 0 °C for 30 min then stirred at rt overnight. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. The organic phase was dried over sodium sulfate and filtered and concentrated in vacuo. Purification by chromatography (ethyl acetate / EtOAc / EtOAc /EtOAc) - (oxazol-5-yl)phenyl)acetamidine (243 mg, 90%). MS: m/e = 343.4 [M + H] + .

實例133 Example 133 2-(2-氯苯基)-N-(4-(噁唑-5-基)苯基)乙醯胺2-(2-chlorophenyl)-N-(4-(oxazol-5-yl)phenyl)acetamide

使4-(噁唑-5-基)苯胺(150mg，936μmol)及2-(2-氯苯基)乙酸(256mg，1.5mmol)與二氯甲烷(9ml)組合。在0℃下添加N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(287mg，1.5mmol)。在0℃下攪拌反應混合物30分鐘，接著返回至室溫且攪拌隔夜。用二氯甲烷(20ml)稀釋反應混合物且用飽和碳酸氫鈉水溶液(15ml)洗滌。經硫酸鈉乾燥有機相，過濾且在真空中濃縮。層析(矽膠，乙酸乙酯/庚烷=0：100至80)得到呈黃色固體狀之2-(2-氯苯基)-N-(4-(噁唑-5-基)苯基)乙醯胺(146mg，50%)。MS：m/e=313.4[M+H]+。 4-(oxazol-5-yl)aniline (150 mg, 936 μmol) and 2-(2-chlorophenyl)acetic acid (256 mg, 1.5 mmol) were combined with dichloromethane (9 mL). N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (287 mg, 1.5 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min then returned to rt and stirred overnight. The reaction mixture was diluted with dichloromethane (20 mL)EtOAc The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography (ethyl acetate / EtOAc / EtOAc / EtOAc / EtOAc) Acetamide (146 mg, 50%). MS: m/e = 313.4 [M + H] + .

實例134 Example 134 N-(2-氯苯甲基)-2-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(2-chlorobenzyl)-2-methoxy-4-(oxazol-5-yl)benzamide

步驟A. Step A.

使4-甲醯基-2-甲氧基苯甲酸甲酯(CAS 55204-14-3，444mg，2.29mmol)與甲醇(4.7ml)組合。添加4-甲苯基磺醯基-甲基胩(447mg，2.29mmol)及碳酸鉀(316mg，2.29mmol)。在80℃下加熱反應混合物2小時且在室溫下攪拌隔夜。將反應混合物傾倒於水上且用二氯甲烷(3×20ml)萃取且用鹽水(15ml)洗滌。經硫酸鈉乾燥有機相，過濾且在真空中濃縮並乾燥，得到呈橙色固體狀之2-甲氧基-4-(噁唑-5-基)苯甲酸甲酯(472mg，88%)。MS：m/e=234.5[M+H]+。 Methyl 4-mercapto-2-methoxybenzoate (CAS 55204-14-3, 444 mg, 2.29 mmol) was combined with methanol (4.7 mL). 4-Tolylsulfonyl-methyloxime (447 mg, 2.29 mmol) and potassium carbonate (316 mg, 2.29 mmol) were added. The reaction mixture was heated at 80 °C for 2 hours and stirred at room temperature overnight. The reaction mixture was poured onto water and extracted with dichloromethane (3×20 mL) and brine. The organic phase was dried with EtOAc EtOAc m. MS: m/e = 234.5 [M + H] + .

步驟B. Step B.

使2-甲氧基-4-(噁唑-5-基)苯甲酸甲酯(467mg，2.00mmol)與甲醇(3.2ml)及四氫呋喃(3.2ml)組合。添加氫氧化鈉水溶液(1N，6.79ml，6.79mmol)。攪拌反應混合物1小時。添加鹽酸(1N，6.79ml，6.79mmol)。過濾沈澱物且在真空中乾燥，得到呈黃色固體狀之2-甲氧基-4-(噁唑-5-基)苯甲酸(369mg，84%)。MS：m/e=220.4[M+H]+。 Methyl 2-methoxy-4-(oxazol-5-yl)benzoate (467 mg, 2.00 mmol) was combined with methanol (3.2 ml) and tetrahydrofurane (3.2 ml). Aqueous sodium hydroxide (1 N, 6.79 ml, 6.79 mmol) was added. The reaction mixture was stirred for 1 hour. Hydrochloric acid (1 N, 6.79 ml, 6.79 mmol) was added. The precipitate was filtered and dried <RTI ID=0.0> MS: m/e = 220.4 [M + H] + .

步驟C. Step C.

使2-甲氧基-4-(噁唑-5-基)苯甲酸(150mg，684μmol)及(2-氯苯基)甲胺(102mg，86.7μl，719μmol)與二氯甲烷(7.3ml)組合。使反應混合物冷卻至0℃且添加N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(138mg，719μmol)。在0℃下攪拌反應混合物40分鐘，接著在室溫下攪拌隔夜。用二氯甲烷(20ml)稀釋反應混合物且用飽和碳酸氫鈉水溶液(20ml)洗滌。經硫酸鈉乾燥有機層，過濾且在真空中濃縮。層析(矽膠，乙酸乙酯/庚烷=0：100至100：0)得到呈白色固體狀之N-(2-氯苯甲基)-2-甲氧基-4-(噁唑-5-基)苯甲醯胺(176mg，75%)。MS：m/e=343.4[M+H]+。 2-methoxy-4-(oxazol-5-yl)benzoic acid (150 mg, 684 μmol) and (2-chlorophenyl)methylamine (102 mg, 86.7 μl, 719 μmol) and dichloromethane (7.3 ml) combination. The reaction mixture was cooled to 0 ° C and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (138 mg, 719. The reaction mixture was stirred at 0 °C for 40 min then stirred at rt overnight. The reaction mixture was diluted with dichloromethane (20 mL)EtOAcEtOAc The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. Chromatography (ethyl acetate / EtOAc / EtOAc / EtOAc / EtOAc / EtOAc) -yl)benzamide (176 mg, 75%). MS: m/e = 343.4 [M + H] + .

RO6924780-000-001 RO6924780-000-001

實例135 Example 135 N-(4-(1H-吡唑-4-基)苯基)-2-(2-氯苯基)乙醯胺N-(4-(1H-pyrazol-4-yl)phenyl)-2-(2-chlorophenyl)acetamide

將N-(4-溴苯基)-2-(2-氯苯基)乙醯胺(CAS 847938-76-5，200mg，616μmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑(239mg，1.23mmol)、Pd(Ph3P)4(107mg，92.4μmol)及碳酸鉀(426mg，3.08mmol)用氬氣吹洗五分鐘，接著添加二噁烷(8.22ml)及水(2.05ml)。在95℃下於氬氣下攪拌反應混合物隔夜。將反應混合物傾倒於水(20ml)上且用乙酸乙酯萃取。部分蒸餾出有機相且使用燒結玻璃漏斗過濾。在真空中乾燥白色固體，得到N-(4-(1H-吡唑-4-基)苯基)-2-(2-氯苯基)乙醯胺(39mg，21%)。MS：m/e=312.5[M+H]+。 N-(4-bromophenyl)-2-(2-chlorophenyl)acetamide (CAS 847938-76-5, 200 mg, 616 μmol), 4-(4,4,5,5-tetramethyl -1,3,2-dioxaboron 2-yl)-1H-pyrazole (239 mg, 1.23 mmol), Pd(Ph 3 P) 4 (107 mg, 92.4 μmol) and potassium carbonate (426 mg, 3.08 mmol) were purged with argon for five minutes, followed by two Oxane (8.22 ml) and water (2.05 ml). The reaction mixture was stirred at 95 ° C under argon overnight. The reaction mixture was poured with water (20 mL) The organic phase was partially distilled off and filtered using a sintered glass funnel. The white solid was dried <RTI ID=0.0></RTI> in vacuo to give N-(4-(1H-pyrazol-4-yl)phenyl)-2-(2-chlorophenyl)acetamide (39 mg, 21%). MS: m/e = 312.5 [M + H] + .

實例136 Example 136 2-(2-氯苯基)-N-(4-(吡啶-4-基)苯基)乙醯胺2-(2-chlorophenyl)-N-(4-(pyridin-4-yl)phenyl)acetamide

組合N-(4-溴苯基)-2-(2-氯苯基)乙醯胺(CAS 847938-76-5，200mg，616μmol)、吡啶-4-基酸(90.9mg，739μmol)、碳酸鉀(426mg，3.08mmol)及Pd(Ph3P)4(107mg，92.4μmol)，且用氬氣吹洗五分鐘。添加甲苯(3ml)、乙醇(1.00ml)及水(500μl)且在80℃下攪拌反應混合物隔夜。將反應混合物傾倒於水(20ml)上且用AcOEt(2×20ml)萃取。經硫酸鈉乾燥有機層，過濾且在真空中濃縮。層析(矽膠，甲醇/二氯甲烷=0：100至5：95)得到呈白色固體狀之2-(2-氯苯基)-N-(4-(吡啶-4-基)苯基)乙醯胺(74.7mg，38%)。MS：m/e=323.4[M+H]+。 Combination of N-(4-bromophenyl)-2-(2-chlorophenyl)acetamide (CAS 847938-76-5, 200 mg, 616 μmol), pyridin-4-yl Acid (90.9 mg, 739 μmol), potassium carbonate (426 mg, 3.08 mmol) and Pd(Ph 3 P) 4 (107 mg, 92.4 μmol) were eluted with argon for five minutes. Toluene (3 ml), ethanol (1.00 ml) and water (500 μl) were added and the reaction mixture was stirred at 80 ° C overnight. The reaction mixture was poured onto water (20 mL) andEtOAc. The organic layer was dried with sodium sulfate, filtered and concentrated in vacuo. Chromatography (silica gel, methanol / methylene chloride = 0: 100 to 5: 95) to give 2-(2-chlorophenyl)-N-(4-(pyridin-4-yl)phenyl) as a white solid. Acetamide (74.7 mg, 38%). MS: m/e = 323.4 [M + H] + .

實例137 Example 137 2-(2-氯苯基)-N-(2-(2-(二甲基胺基)乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺2-(2-Chlorophenyl)-N-(2-(2-(dimethylamino)ethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamide

步驟A. Step A.

使4-溴-2-(2-(二甲基胺基)乙氧基)苯胺(CAS 1072906-05-8，130mg，503μmol)與二甲基甲醯胺(3.7ml)組合。添加2-(2-氯苯基)乙酸(103mg，603μmol)、四氟硼酸O-(苯并***-1-基)-N,N,N',N'-四甲基(TBTU，258mg，804μmol)及N,N-二異丙基乙胺(162mg，215μl，1.26mmol)。在室溫下攪拌反應混合物3小時。將反應混合物傾倒 於水(10ml)上，添加飽和碳酸氫鈉水溶液(10ml)且使用EtOAc(2×10ml)進行萃取。用水(2×10ml)洗滌有機相且經硫酸鈉乾燥，過濾，在真空中濃縮且在真空中乾燥，得到呈粉紅色固體狀之N-(4-溴-2-(2-(二甲基胺基)乙氧基)苯基)-2-(2-氯苯基)乙醯胺(238mg，定量)。MS：m/e=413.3[M+H]+。 4-Bromo-2-(2-(dimethylamino)ethoxy)phenylamine (CAS 1072906-05-8, 130 mg, 503 μmol) was combined with dimethylformamide (3.7 ml). Add 2-(2-chlorophenyl)acetic acid (103 mg, 603 μmol), O- (benzotriazol-1-yl) -N,N,N',N' -tetramethyltetrafluoroborate (TBTU, 258 mg, 804 μmol) and N,N-diisopropylethylamine (162 mg, 215 μl, 1.26 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured with EtOAc (EtOAc) (EtOAc) The organic phase was washed with water (2×10 mL) EtOAc. Amino)ethoxy)phenyl)-2-(2-chlorophenyl)acetamide (238 mg, quantitative). MS: m/e = 413.3 [M + H] + .

步驟B. Step B.

組合N-(4-溴-2-(2-(二甲基胺基)乙氧基)苯基)-2-(2-氯苯基)乙醯胺(196.2mg，477μmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑(185mg，953μmol)、Pd(Ph3P)4(82.6mg，71.5μmol)及碳酸鉀(329mg，2.38mmol)，且用氬氣吹洗五分鐘。添加二噁烷(3.18ml)及水(794μl)且用氬氣吹洗。在95℃下攪拌反應混合物隔夜。將反應混合物傾倒於水(20ml)上且用乙酸乙酯(2×20ml)萃取。層析(矽膠，甲醇/二氯甲烷=0：100至23：77)得到呈灰白色固體狀之2-(2-氯苯基)-N-(2-(2-(二甲基胺基)乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺(43.5mg，23%)。MS：m/e=399.5[M+H]+。 Combination of N-(4-bromo-2-(2-(dimethylamino)ethoxy)phenyl)-2-(2-chlorophenyl)acetamide (196.2 mg, 477 μmol), 4-( 4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-1H-pyrazole (185 mg, 953 μmol), Pd(Ph 3 P) 4 (82.6 mg, 71.5 μmol) and potassium carbonate (329 mg, 2.38 mmol), and purged with argon for five minutes. Dioxane (3.18 ml) and water (794 μl) were added and flushed with argon. The reaction mixture was stirred at 95 ° C overnight. The reaction mixture was poured with water (20 mL)EtOAc. Chromatography (silica gel, methanol / methylene chloride = 0: 100 to 23: 77) to give 2-(2-chlorophenyl)-N-(2-(2-(dimethylamino)) Ethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamide (43.5 mg, 23%). MS: m/e = 399.5 [M + H] + .

實例138 Example 138 2-(2-氯苯基)-N-(3-甲氧基-4-(4-甲基噁唑-5-基)苯基)乙醯胺2-(2-chlorophenyl)-N-(3-methoxy-4-(4-methyloxazol-5-yl)phenyl)acetamide

使3-甲氧基-4-(4-甲基噁唑-5-基)苯胺(CAS 1239719-44-8，23.5mg，115μmol)與二氯甲烷(1.15ml)組合。添加2-(2-氯苯基)乙酸(31.4 mg，184μmol)。使反應混合物冷卻至0℃且添加N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(35.3mg，184μmol)。攪拌反應混合物30分鐘，且升溫至室溫維持3小時。用二氯甲烷(10ml)稀釋反應混合物且用飽和碳酸氫鈉水溶液(10ml)及鹽水(10ml)洗滌。合併有機相且在真空中濃縮。層析(矽膠，乙酸乙酯/庚烷=0：100至80：20)得到呈蠟狀黃色固體狀之2-(2-氯苯基)-N-(3-甲氧基-4-(4-甲基噁唑-5-基)苯基)乙醯胺(38.4mg，94%)。MS：m/e=357.4[M+H]+。 3-Methoxy-4-(4-methyloxazol-5-yl)aniline (CAS 1239719-44-8, 23.5 mg, 115 μmol) was combined with dichloromethane (1.15 mL). 2-(2-Chlorophenyl)acetic acid (31.4 mg, 184 μmol) was added. The reaction mixture was cooled to 0 ° C and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (35.3 mg, 184. The reaction mixture was stirred for 30 minutes and warmed to room temperature for 3 h. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) The organic phases were combined and concentrated in vacuo. Chromatography (ethyl acetate / EtOAc / EtOAc / EtOAc / EtOAc / EtOAc) 4-Methyloxazol-5-yl)phenyl)acetamide (38.4 mg, 94%). MS: m/e = 357.4 [M + H] + .

實例139 Example 139 N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-((3-甲氧基苯基)(甲基)胺基)乙醯胺N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-2-((3-methoxyphenyl)(methyl)amino)acetamide

步驟A. Step A.

使4-溴-3-甲氧基苯胺(150mg，742μmol)與二氯甲烷(3ml)組合。添加2-((3-甲氧基苯基)(甲基)胺基)乙酸(CAS 1247372-54-8，210mg，1.08mmol)。使反應混合物冷卻至0℃。添加N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(206mg，1.08mmol)。在0℃下攪拌反應混合物30分鐘，接著升溫至室溫。3小時後，用二氯甲烷(10ml)稀釋反應混合物且用飽和碳酸氫鈉水溶液(10ml)洗滌。層析(矽膠，乙酸乙酯/庚烷=0：100至55：45)得到呈黃色油狀之N-(4-溴-3-甲氧基苯基)-2-((3-甲氧基苯基)(甲基)胺基)乙醯胺(228mg，81%)。MS：m/e=379.5[M+H]+。 4-Bromo-3-methoxyaniline (150 mg, 742 μmol) was combined with dichloromethane (3 mL). 2-((3-Methoxyphenyl)(methyl)amino)acetic acid (CAS 1247372-54-8, 210 mg, 1.08 mmol) was added. The reaction mixture was cooled to 0 °C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (206 mg, 1.08 mmol) was added. The reaction mixture was stirred at 0 ° C for 30 minutes and then warmed to room temperature. The reaction mixture was diluted with EtOAc (EtOAc) (EtOAc) Chromatography (ethyl acetate, ethyl acetate / heptane = 0: 100 to 55:45) afforded N-(4-bromo-3-methoxyphenyl)-2-((3-methoxy) as a yellow oil. Phenylphenyl)(methyl)amino)acetamide (228 mg, 81%). MS: m/e = 379.5 [M + H] + .

步驟B. Step B.

組合N-(4-溴-3-甲氧基苯基)-2-((3-甲氧基苯基)(甲基)胺基)乙醯胺(225mg，594μmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑(230mg，1.19mmol)、Pd(Ph3P)4(103mg，89.0μmol)及碳酸鉀(410mg，2.97mmol)，且用氬氣淨化5分鐘。添加二噁烷(7.36ml)及水(1.84ml)且用氬氣淨化反應混合物，接著在95℃下攪拌隔夜。使反應混合物冷卻至室溫。將反應混合物傾倒於水(20ml)上，用乙酸乙酯(2×20ml)洗滌，經硫酸鈉乾燥，過濾且在真空中濃縮。層析(矽膠，甲醇/二氯甲烷=0：100至8：92)且在***中沈澱，得到呈灰白色固體狀之N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-((3-甲氧基苯基)(甲基)胺基)乙醯胺(2.8mg，1.3%)。MS：m/e=367.2[M+H]+。 Combining N-(4-bromo-3-methoxyphenyl)-2-((3-methoxyphenyl)(methyl)amino)acetamide (225 mg, 594 μmol), 4-(4, 4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-1H-pyrazole (230 mg, 1.19 mmol), Pd(Ph 3 P) 4 (103 mg, 89.0 μmol), and potassium carbonate (410 mg, 2.97 mmol), and purified with argon for 5 min. Dioxane (7.36 ml) and water (1.84 ml) were added and the reaction mixture was purified with argon, then stirred at 95 ° C overnight. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured with EtOAc EtOAc. Chromatography (silica gel, methanol / methylene chloride = 0: 100 to 8:92) Phenyl)-2-((3-methoxyphenyl)(methyl)amino)acetamide (2.8 mg, 1.3%). MS: m/e = 367.2 [M + H] + .

實例140 Example 140 N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-(3-甲氧基苯基胺基)乙醯胺N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-2-(3-methoxyphenylamino)acetamide

步驟A. Step A.

使4-溴-3-甲氧基苯胺(150mg，742μmol)與二氯甲烷(3ml)組合。添加2-(3-甲氧基苯基胺基)乙酸(195mg，1.08mmol)。使反應混合物冷卻至0℃。添加N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(206mg，1.08mmol)。在0℃下攪拌反應混合物30分鐘，接著升溫至室溫維持3小時。層析(矽膠，乙酸乙酯/庚烷=0：100至70：30)得到呈 淺棕色油狀之N-(4-溴-3-甲氧基苯基)-2-(3-甲氧基苯基胺基)乙醯胺(185mg，68%)。MS：m/e=367.4[M+H]+。 4-Bromo-3-methoxyaniline (150 mg, 742 μmol) was combined with dichloromethane (3 mL). 2-(3-Methoxyphenylamino)acetic acid (195 mg, 1.08 mmol) was added. The reaction mixture was cooled to 0 °C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (206 mg, 1.08 mmol) was added. The reaction mixture was stirred at 0 ° C for 30 minutes and then warmed to room temperature for 3 hours. Chromatography (ethyl acetate, ethyl acetate / heptane = 0: 100 to 70: 30) afforded N-(4-bromo-3-methoxyphenyl)-2-(3-methoxy) as a light brown oil. Phenylamino)acetamide (185 mg, 68%). MS: m/e = 367.4 [M + H] + .

步驟B. Step B.

使N-(4-溴-3-甲氧基苯基)-2-(3-甲氧基苯基胺基)乙醯胺(184.6mg，505μmol)、雙(二苯膦基)二茂鐵-二氯化鈀(II)(18.5mg，25.3μmol)及4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑(98.1mg，505μmol)與二噁烷(17ml)及水(1.7ml)組合。在95℃下攪拌反應混合物隔夜。層析(矽膠，乙酸乙酯/庚烷=0：100至50：50)且用***/戊烷沈澱，得到呈灰白色固體狀之N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-(3-甲氧基苯基胺基)乙醯胺(13.4mg，7.5%)。MS：m/e=353.2[M+H]+。 N-(4-bromo-3-methoxyphenyl)-2-(3-methoxyphenylamino)acetamide (184.6 mg, 505 μmol), bis(diphenylphosphino)ferrocene -Palladium(II) dichloride (18.5 mg, 25.3 μmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-1H-pyrazole (98.1 mg, 505 μmol) was combined with dioxane (17 ml) and water (1.7 ml). The reaction mixture was stirred at 95 ° C overnight. Chromatography (ethyl acetate / EtOAc / EtOAc / EtOAc /EtOAc) 4-yl)phenyl)-2-(3-methoxyphenylamino)acetamide (13.4 mg, 7.5%). MS: m/e = 353.2 [M + H] + .

實例141 Example 141 1-(2-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)環丙烷甲醯胺1-(2-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)cyclopropanecarbamide

使1-(2-氯苯基)環丙烷甲酸(414mg，2.1mmol)與二氯甲烷(10ml)組合。添加兩滴二甲基甲醯胺。在0℃下添加乙二醯氯(2.00g，1.38ml，15.8mmol)。攪拌反應混合物2小時。在真空中濃縮反應混合物，溶解於甲苯中且在真空中濃縮。將混合物溶解於二氯甲烷(5ml)中，且緩慢添加至3-甲氧基-4-(噁唑-5-基)苯胺(中間物1，200mg，1.05mmol)及三乙胺(223mg，308μl，2.21mmol)於二氯甲烷(10ml)中之溶液中。在室溫下攪拌反應混合物隔夜。將反應混合物傾倒於水(20ml)上且用二氯甲烷(2×20ml)萃取。藉由層析(矽膠，乙酸乙 酯/庚烷=0：100至50：50)純化，得到呈灰白色固體狀之1-(2-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)環丙烷甲醯胺(13.6mg，3.5%)。MS：m/e=369.4[M+H]+。 1-(2-Chlorophenyl)cyclopropanecarboxylic acid (414 mg, 2.1 mmol) was combined with dichloromethane (10 mL). Two drops of dimethylformamide were added. Ethylene dichloride (2.00 g, 1.38 ml, 15.8 mmol) was added at 0 °C. The reaction mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo, dissolved in toluene and concentrated in vacuo. The mixture was dissolved in dichloromethane (5 ml) and slowly added to 3-methoxy-4-(oxazol-5-yl)phenylamine (1,200 mg, 1.05 mmol) and triethylamine (223 mg, 308 μl, 2.21 mmol) in dichloromethane (10 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured with water (20 mL) Purification by chromatography (ethyl acetate / EtOAc / EtOAc / EtOAc /EtOAc /EtOAc - (oxazol-5-yl)phenyl)cyclopropanecarbamide (13.6 mg, 3.5%). MS: m/e = 369.4 [M + H] + .

實例142 Example 142 2-(2-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-甲基丙醯胺2-(2-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-methylpropanamide

與實例141之通用方法類似，由2-(2-氯苯基)-2-甲基丙酸及中間物1製備標題化合物，灰白色固體(11mg，2.7%)，MS(ISP)m/z=371.4[(M+H)+]。 The title compound was prepared from 2-(2-chlorophenyl)-2-methylpropanoic acid and EtOAc (m.) 371.4 [(M+H)+].

實例143 Example 143 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基)-2-甲基丙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenyl)-2-methylpropanamide

與實例141之通用方法類似，由2-(3-甲氧基苯基)-2-甲基丙酸及中間物1製備標題化合物，灰白色固體(25mg，13%)，MS(ISP)m/z=367.5[(M+H)+]。 The title compound was prepared from 2-(3-methoxyphenyl)-2-methylpropanoic acid and Intermediate 1 (m.p. z = 367.5 [(M+H)+].

實例144 Example 144 N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基胺基)-2-甲基丙醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylamino)-2-methylpropanamide

使3-甲氧基-4-(噁唑-5-基)苯胺(中間物1，200mg)、2-(3-甲氧基苯基胺基)-2-甲基丙酸(264mg，1.26mmol)及二異丙基乙胺(231mg，312μl，1.79mmol)與二甲基甲醯胺(10ml)組合。在室溫下於氬氣氛 圍下攪拌反應混合物。添加六氟磷酸O-(7-氮雜苯并***-1-基)-N,N,N',N'-四甲基(HATU，680mg，1.79mmol)。在室溫下攪拌反應混合物隔夜。將反應混合物傾倒於水上且用二氯甲烷萃取。層析(矽膠，乙酸乙酯/庚烷=33：67至75：25)得到呈灰白色固體狀之N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基胺基)-2-甲基丙醯胺(246mg，62%)。MS：m/e=382.5[M+H]+。 3-methoxy-4-(oxazol-5-yl)aniline (intermediate 1,200 mg), 2-(3-methoxyphenylamino)-2-methylpropanoic acid (264 mg, 1.26) Methyl) and diisopropylethylamine (231 mg, 312 [mu]l, 1.79 mmol) were combined with dimethylformamide (10 ml). The reaction mixture was stirred at room temperature under an argon atmosphere. Add O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl hexafluorophosphate (HATU, 680 mg, 1.79 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured onto water and extracted with dichloromethane. Chromatography (ethyl acetate, ethyl acetate / heptane = 33:67 to 75:25) afforded N-(3-methoxy-4-(oxazol-5-yl)phenyl) -(3-Methoxyphenylamino)-2-methylpropanamide (246 mg, 62%). MS: m/e = 382.5 [M + H] + .

實例145 Example 145 2-(2-氯苯基胺基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-甲基丙醯胺2-(2-Chlorophenylamino)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-2-methylpropanamide

步驟A. Step A.

使4-溴-3-甲氧基苯胺(380mg，1.88mmol)、2-(2-氯苯基胺基)-2-甲基丙酸(482mg，2.26mmol)及二異丙基乙胺(413mg，558μl，3.2mmol)與二甲基甲醯胺(15ml)組合。添加六氟磷酸O-(7-氮雜苯并***-1-基)-N,N,N',N'-四甲基(HATU，1.22g，3.2mmol)。在室溫下攪拌反應混合物隔夜。將反應混合物傾倒於水上且用二氯甲烷萃取。層析(矽膠，乙酸乙酯/庚烷=20：80至50：50)得到呈棕色固體狀之N-(4-溴-3-甲氧基苯基)-2-(2-氯苯基胺基)-2-甲基丙醯胺(457mg，61%)。MS：m/e=399.3[M+H]+。 4-Bromo-3-methoxyaniline (380 mg, 1.88 mmol), 2-(2-chlorophenylamino)-2-methylpropanoic acid (482 mg, 2.26 mmol) and diisopropylethylamine ( 413 mg, 558 μl, 3.2 mmol) was combined with dimethylformamide (15 ml). Add O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl hexafluorophosphate (HATU, 1.22 g, 3.2 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured onto water and extracted with dichloromethane. Chromatography (ethyl acetate, ethyl acetate / heptane = 20: 80 to 50: 50) to give N-(4-bromo-3-methoxyphenyl)-2-(2-chlorophenyl) as a brown solid. Amino)-2-methylpropanamide (457 mg, 61%). MS: m/e = 399.3 [M + H] + .

步驟B. Step B.

使N-(4-溴-3-甲氧基苯基)-2-(2-氯苯基胺基)-2-甲基丙醯胺(200 mg，503μmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑(111mg，553μmol)及碳酸銫(180mg，553μmol)與二噁烷(10ml)及水(1.0ml)組合。在氬氣氛圍下，添加雙(二苯膦基)二茂鐵-二氯化鈀(II)(73.6mg，101μmol)。在85℃下攪拌反應混合物經週末。在真空中濃縮混合物且藉由層析(矽膠，甲醇/二氯甲烷=0：100至5：95；接著進行製備型HPLC，Gemini NX 3μ 50×4.6mm，C18逆相，甲醇/甲酸=98：2)純化，得到呈灰白色固體狀之2-(2-氯苯基胺基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-甲基丙醯胺(23.3mg，12%)。MS：m/e=385.4[M+H]+。 N-(4-bromo-3-methoxyphenyl)-2-(2-chlorophenylamino)-2-methylpropanamide (200 mg, 503 μmol), 4-(4,4, 5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-1H-pyrazole (111 mg, 553 μmol) and cesium carbonate (180 mg, 553 μmol) were combined with dioxane (10 ml) and water (1.0 ml). Bis(diphenylphosphino)ferrocene-palladium(II) chloride (73.6 mg, 101 μmol) was added under an argon atmosphere. The reaction mixture was stirred at 85 ° C over the weekend. The mixture was concentrated in vacuo and chromatographed (EtOAc,MeOH/dichloromethane = 0:100 to 5:95; followed by preparative HPLC, Gemini NX 3μ 50 x 4.6 mm, C18 reverse phase, methanol/formic acid = 98 : 2) Purification to give 2-(2-chlorophenylamino)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-2- Methyl acrylamide (23.3 mg, 12%). MS: m/e = 385.4 [M + H] + .

實例146 Example 146 2-(2-氯苯基胺基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)乙醯胺2-(2-Chlorophenylamino)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)acetamide

步驟A. Step A.

使2-(2-氯苯基胺基)乙酸(150mg，808μmol)及4-溴-3-甲氧基苯胺(171mg，849μmol)與二氯甲烷(10ml)組合。在0℃下添加N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(163mg，849μmol)。在0℃下攪拌反應混合物30分鐘，接著在室溫下攪拌隔夜。將混合物傾倒於水(20ml)上且用二氯甲烷(3×15ml)萃取。層析(矽膠，乙酸乙酯/庚烷=20：80至50：50)得到呈黃色固體狀之N-(4-溴-3-甲氧基苯基)-2-(2-氯苯基胺基)乙醯胺(225mg，75%)。MS：m/e=371.1[M+H]+。 2-(2-Chlorophenylamino)acetic acid (150 mg, 808 μmol) and 4-bromo-3-methoxyaniline (171 mg, 849 μmol) were combined with dichloromethane (10 ml). N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (163 mg, 849 μmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min then stirred at rt overnight. The mixture was poured onto water (20 mL) andEtOAc was evaporated. Chromatography (ethyl acetate / EtOAc /Heptane = 20: 80 to 50: 50) to afford N-(4-bromo-3-methoxyphenyl)-2-(2-chlorophenyl) as a yellow solid. Amino) acetamide (225 mg, 75%). MS: m/e = 371.1 [M + H] + .

步驟B. Step B.

在氬氣氛圍下，使N-(4-溴-3-甲氧基苯基)-2-(2-氯苯基胺基)乙醯胺(220mg，595μmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑(134mg，655μmol)及雙(二苯膦基)二茂鐵-二氯化鈀(II)(43.5mg，59.5μmol)及碳酸銫(213mg，655μmol)與二噁烷(10ml)/水(1.00ml)組合。加熱反應混合物至80℃且攪拌隔夜。用製備型HPLC(Gemini NX 3μ 50×4.6mm，C18逆相，甲醇/甲酸=98：2)純化混合物，得到呈棕色固體狀之2-(2-氯苯基胺基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)乙醯胺(6mg，2.8%)。MS：m/e=357.4[M+H]+。 N-(4-bromo-3-methoxyphenyl)-2-(2-chlorophenylamino)acetamide (220 mg, 595 μmol), 4-(4,4, under argon atmosphere 5,5-tetramethyl-1,3,2-dioxaboron 2-yl)-1H-pyrazole (134 mg, 655 μmol) and bis(diphenylphosphino)ferrocene-palladium(II) dichloride (43.5 mg, 59.5 μmol) and cesium carbonate (213 mg, 655 μmol) Dioxane (10 ml) / water (1.00 ml) combination. The reaction mixture was heated to 80 ° C and stirred overnight. The mixture was purified by preparative HPLC (EtOAc EtOAc (EtOAc (EtOAc). -Methoxy-4-(1H-pyrazol-4-yl)phenyl)acetamide (6 mg, 2.8%). MS: m/e = 357.4 [M + H] + .

實例147 Example 147 N-(3-甲氧基-4-(噁唑-5-基)苯基)-1-(3-甲氧基苯基胺基)環丙烷甲醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-1-(3-methoxyphenylamino)cyclopropanecarbamide

在氬氣氛圍下，使1-(3-甲氧基苯基胺基)環丙烷甲酸(54.5mg，263μmol)、3-甲氧基-4-(噁唑-5-基)苯胺(中間物1，50mg，263μmol)及二異丙基乙胺(57.8mg，78.1μl，447μmol)與二甲基甲醯胺(10ml)組合。添加六氟磷酸O-(7-氮雜苯并***-1-基)-N,N,N',N'-四甲基(HATU，170mg，447μmol)。在室溫下攪拌反應混合物隔夜。藉由製備型HPLC(Gemini NX 3μ 50×4.6mm，C18逆相，甲醇/甲酸=98：2)純化且在***及庚烷中沈澱，得到呈灰白色固體狀之標題化合物RO6959544-000-001(9.5mg；9.5%)。MS：m/e=380.4[M+H]+。 1-(3-Methoxyphenylamino)cyclopropanecarboxylic acid (54.5 mg, 263 μmol), 3-methoxy-4-(oxazol-5-yl)aniline (intermediate) under argon atmosphere 1,50 mg, 263 μmol) and diisopropylethylamine (57.8 mg, 78.1 μl, 447 μmol) were combined with dimethylformamide (10 ml). Add O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl hexafluorophosphate (HATU, 170 mg, 447 μmol). The reaction mixture was stirred at room temperature overnight. The title compound RO6959544-000-001 was obtained as a white solid (yield: EtOAc: EtOAc (EtOAc) 9.5 mg; 9.5%). MS: m/e = 380.4 [M + H] + .

實例148 Example 148 N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-甲基-2-(苯基胺基)丙醯胺N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-2-methyl-2-(phenylamino)propanamide

步驟A. Step A.

使2-甲基-2-(苯基胺基)丙酸(106mg，594μmol)、4-溴-3-甲氧基苯胺(100mg，495μmol)及二異丙基乙胺(109mg，147μl，841μmol)與二甲基甲醯胺(10ml)組合。在氬氣氛圍下添加六氟磷酸O-(7-氮雜苯并***-1-基)-N,N,N',N'-四甲基(HATU，320mg，841μmol)。在室溫下攪拌反應混合物隔夜。在真空中濃縮反應混合物且傾倒於水(20ml)上且用乙酸乙酯(3×20ml)萃取。收集有機相且經MgSO4乾燥且在真空中濃縮。藉由層析(矽膠，乙酸乙酯/庚烷=20：80至50：50)純化，得到呈橙色蠟狀固體狀之N-(4-溴-3-甲氧基苯基)-2-甲基-2-(苯基胺基)丙醯胺(112mg；62%)。MS：m/e=363.4[M+H]+。 2-Methyl-2-(phenylamino)propionic acid (106 mg, 594 μmol), 4-bromo-3-methoxyaniline (100 mg, 495 μmol) and diisopropylethylamine (109 mg, 147 μl, 841 μmol) ) in combination with dimethylformamide (10 ml). Add O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl hexafluorophosphate under argon atmosphere (HATU, 320 mg, 841 μmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated with EtOAc EtOAc m. 4 and the organic phase was collected and concentrated in vacuo dried over MgSO. Purification by chromatography (ethyl acetate / EtOAc / EtOAc /EtOAc /EtOAc) Methyl-2-(phenylamino)propanamide (112 mg; 62%). MS: m/e = 363.4 [M + H] + .

步驟B. Step B.

在25ml圓底燒瓶中，使N-(4-溴-3-甲氧基苯基)-2-甲基-2-(苯基胺基)丙醯胺(100mg，275μmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑-1-甲酸第三丁酯(162mg，551μmol)及碳酸銫(179mg，551μmol)與二噁烷(10ml)/水(1ml)組合。在氬氣下添加雙(二苯膦基)二茂鐵-二氯化鈀(II)(40.3mg，55.1μmol)。在70℃下攪拌反應混合物2小時。在真空中濃縮混合物且藉由層析(矽膠，乙酸乙酯/庚烷= 0：100至20：80)純化，得到呈無色蠟狀固體狀之4-(2-甲氧基-4-(2-甲基-2-(苯基胺基)丙醯胺基)苯基)-1H-吡唑-1-甲酸第三丁酯(91mg，73%)。MS：m/e=451.5[M+H]+。 In a 25 ml round bottom flask, N-(4-bromo-3-methoxyphenyl)-2-methyl-2-(phenylamino)propanamide (100 mg, 275 μmol), 4-(4) ,4,5,5-tetramethyl-1,3,2-dioxaboron 2-Benzyl-1H-pyrazole-1-carboxylic acid tert-butyl ester (162 mg, 551 μmol) and cesium carbonate (179 mg, 551 μmol) were combined with dioxane (10 ml) / water (1 ml). Bis(diphenylphosphino)ferrocene-palladium(II) chloride (40.3 mg, 55.1 μmol) was added under argon. The reaction mixture was stirred at 70 ° C for 2 hours. The mixture was concentrated in vacuo and purified by EtOAc (EtOAc:EtOAcHHHHHHH 2-Methyl-2-(phenylamino)propanylamino)phenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (91 mg, 73%). MS: m/e = 451.5 [M + H] + .

步驟C. Step C.

在25ml圓底燒瓶中，使4-(2-甲氧基-4-(2-甲基-2-(苯基胺基)丙醯胺基)苯基)-1H-吡唑-1-甲酸第三丁酯(30mg，66.6μmol，1.00當量)與二氯甲烷(10ml)組合。在0℃下添加三氟乙酸(11.4mg，7.7μl，99.9μmol)且在0℃下攪拌1小時，接著在室溫下攪拌3小時。將反應混合物傾倒於水(10ml)上且用二氯甲烷(3×10ml)萃取且用飽和碳酸氫鈉水溶液(15ml)洗滌。藉由層析(矽膠，甲醇/二氯甲烷=0：100至10：90)純化反應混合物，得到呈灰白色固體狀之N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-甲基-2-(苯基胺基)丙醯胺(17.5mg，75%)。MS：m/e=351.5[M+H]+。 In a 25 ml round bottom flask, 4-(2-methoxy-4-(2-methyl-2-(phenylamino)propanyl)phenyl)-1H-pyrazole-1-carboxylic acid The third butyl ester (30 mg, 66.6 μmol, 1.00 equivalent) was combined with dichloromethane (10 ml). Trifluoroacetic acid (11.4 mg, 7.7 μl, 99.9 μmol) was added at 0 ° C and stirred at 0 ° C for 1 hour, followed by stirring at room temperature for 3 hours. The reaction mixture was poured with EtOAc EtOAc (EtOAc) The reaction mixture was purified by EtOAc EtOAc (EtOAc:EtOAc:EtOAc Phenyl)-2-methyl-2-(phenylamino)propanamide (17.5 mg, 75%). MS: m/e = 351.5 [M + H] + .

實例149 Example 149 1-(2-氯苯基胺基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)環丙烷甲醯胺1-(2-Chlorophenylamino)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)cyclopropanecarbamide

在25mL圓底燒瓶中，使1-(2-氯苯基胺基)環丙烷甲酸(100mg，473μmol)、3-甲氧基-4-(噁唑-5-基)苯胺(中間物1，75mg，394μmol)及六氟磷酸O-(7-氮雜苯并***-1-基)-N,N,N',N'-四甲基(HATU，255mg，670μmol)與二甲基甲醯胺(5ml)組合。添加二異丙基乙胺(86.6mg，117μl，670μmol)。在室溫下攪拌反應混合物隔夜。在真空中濃縮混合物。將反應混合物傾倒於水(50ml)上且用乙酸乙酯(3×30ml) 萃取。用飽和碳酸氫鈉水溶液(20mL)洗滌有機相。藉由層析(製備型HPLC，Gemini NX 3μ 50×4.6mm，C18逆相，甲醇/甲酸=98：2；接著，矽膠，乙酸乙酯/庚烷=0：100至50：50)純化，得到呈灰白色固體狀之1-(2-氯苯基胺基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)環丙烷甲醯胺(64.3mg；43%)。MS：m/e=384.5[M+H]+。 In a 25 mL round bottom flask, 1-(2-chlorophenylamino)cyclopropanecarboxylic acid (100 mg, 473 μmol), 3-methoxy-4-(oxazol-5-yl)aniline (Intermediate 1, 75 mg, 394 μmol) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl hexafluorophosphate (HATU, 255 mg, 670 μmol) was combined with dimethylformamide (5 ml). Diisopropylethylamine (86.6 mg, 117 μl, 670 μmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The reaction mixture was poured into water (50 mL)EtOAc. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate (20 mL). Purified by chromatography (preparative HPLC, Gemini NX 3μ 50×4.6 mm, C18 reverse phase, methanol/formic acid = 98:2; then, EtOAc, ethyl acetate/heptane = 0:100 to 50:50). 1-(2-Chlorophenylamino)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)cyclopropanecarbamide (64.3 mg; 43) %). MS: m/e = 384.5 [M + H] + .

實例150 Example 150 2-(2-氯苯基)-N-(3-(2-(二甲基胺基)乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺2,2,2-三氟乙酸鹽2-(2-chlorophenyl)-N-(3-(2-(dimethylamino)ethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamidamine 2, 2,2-trifluoroacetate

步驟A. Step A.

在25mL圓底燒瓶中，使4-溴-3-(2-(二甲基胺基)乙氧基)苯胺(CAS 170230-19-0，170mg，656μmol)及2-(2-氯苯基)乙酸(134mg，787μmol)與二氯甲烷(5ml)組合。在0℃下添加N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(151mg，787μmol)且在0℃下攪拌反應混合物15分鐘且在室溫下攪拌隔夜。將反應混合物傾倒於水(20ml)上且用二氯甲烷(3×20ml)萃取。合併有機相且用飽和碳酸氫鈉水溶液(20ml)洗滌。層析(矽膠，甲醇/二氯甲烷=0：100至10：90)得到呈蠟狀白色固體狀之N-(4-溴-3-(2-(二甲基胺基)乙氧基)苯基)-2-(2-氯苯基)乙醯胺(90.8mg，34%)。MS：m/e=413.2[M+H]+。 In a 25 mL round bottom flask, 4-bromo-3-(2-(dimethylamino)ethoxy)phenylamine (CAS 170230-19-0, 170 mg, 656 μmol) and 2-(2-chlorophenyl) Acetic acid (134 mg, 787 μmol) was combined with dichloromethane (5 ml). N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (151 mg, 787 μmol) was added at 0 ° C and the reaction mixture was stirred at 0 ° C for 15 min at room temperature Stir under night. The reaction mixture was poured with water (20 mL) The organic phase was combined and washed with aq. Chromatography (silica gel, methanol/dichloromethane = 0: 100 to 10:90) afforded N-(4-bromo-3-(2-(dimethylamino)ethoxy) as a white solid as a wax. Phenyl)-2-(2-chlorophenyl)acetamide (90.8 mg, 34%). MS: m/e = 413.2 [M + H] + .

步驟B. Step B.

在25mL圓底燒瓶中，使N-(4-溴-3-(2-(二甲基胺基)乙氧基)苯基)-2-(2-氯苯基)乙醯胺(90mg，219μmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑-1-甲酸第三丁酯(77.2mg，262μmol)及雙(二苯膦基)二茂鐵-二氯化鈀(II)(32.0mg，43.7μmol)與二噁烷(5ml)及水(500μl)組合。在70℃下攪拌反應混合物隔夜。在真空中濃縮反應混合物且藉由層析(矽膠，甲醇/二氯甲烷=0：100至10：90)純化，得到呈蠟狀棕色固體狀之4-(4-(2-(2-氯苯基)乙醯胺基)-2-(2-(二甲基胺基)乙氧基)苯基)-1H-吡唑-1-甲酸第三丁酯(76.5mg，70%)。MS：m/e=499.6[M+H]+。 In a 25 mL round bottom flask, N-(4-bromo-3-(2-(dimethylamino)ethoxy)phenyl)-2-(2-chlorophenyl)acetamide (90 mg, 219 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (77.2 mg, 262 μmol) and bis(diphenylphosphino)ferrocene-palladium (II) chloride (32.0 mg, 43.7 μmol) Combined with dioxane (5 ml) and water (500 μl). The reaction mixture was stirred at 70 ° C overnight. The reaction mixture was concentrated in vacuo and purified by chromatography (jjjjjjjjjjjjjj Phenyl)acetamido)-2-(2-(dimethylamino)ethoxy)phenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (76.5 mg, 70%). MS: m/e = 499.6 [M + H] + .

步驟C. Step C.

在25mL圓底燒瓶中，使4-(4-(2-(2-氯苯基)乙醯胺基)-2-(2-(二甲基胺基)乙氧基)苯基)-1H-吡唑-1-甲酸第三丁酯(75mg，150μmol)及三氟乙酸(17.1mg，11.6μl，150μmol)與二氯甲烷(5ml)組合，且在室溫下攪拌隔夜。添加三氟乙酸(17.1mg，11.6μl，150μmol)且在50℃下攪拌反應混合物4小時。在真空中濃縮反應混合物。藉由層析(矽膠，甲醇/二氯甲烷=0：100至20：80)純化且在***及戊烷中沈澱，得到呈灰白色固體狀之2-(2-氯苯基)-N-(3-(2-(二甲基胺基)乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺2,2,2-三氟乙酸鹽(57.3mg，74%)。MS： m/e=399.2[M+H]+。 In a 25 mL round bottom flask, 4-(4-(2-(2-chlorophenyl)acetamido)-2-(2-(dimethylamino)ethoxy)phenyl)-1H Pyrazole-1-carboxylic acid tert-butyl ester (75 mg, 150 μmol) and trifluoroacetic acid (17.1 mg, 11.6 μl, 150 μmol) were combined with dichloromethane (5 ml) and stirred at room temperature overnight. Trifluoroacetic acid (17.1 mg, 11.6 μl, 150 μmol) was added and the reaction mixture was stirred at 50 ° C for 4 hours. The reaction mixture was concentrated in vacuo. Purification by chromatography (methylene chloride, methylene chloride / methylene chloride = EtOAc: EtOAc: EtOAc) 3-(2-(Dimethylamino)ethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamidamine 2,2,2-trifluoroacetate (57.3 mg, 74 %). MS: m/e = 399.2 [M+H] + .

實例151 Example 151 N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-(3-甲氧基苯基胺基)-2-甲基丙醯胺N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-2-(3-methoxyphenylamino)-2-methylpropanamide

步驟A. Step A.

使N-(4-溴-3-甲氧基苯基)-2-(3-甲氧基苯基胺基)-2-甲基丙醯胺(50mg，127μmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑-1-甲酸第三丁酯(63.6mg，216μmol)及碳酸銫(70.4mg，216μmol)與二噁烷(5ml)/水(0.5ml)組合。添加雙(二苯膦基)二茂鐵-二氯化鈀(II)(18.6mg，25.4μmol)。在75℃下加熱反應混合物隔夜。在真空中濃縮混合物且藉由層析(矽膠，乙酸乙酯/庚烷=0：100至50：50)純化，得到呈灰白色固體狀之4-(2-甲氧基-4-(2-(3-甲氧基苯基胺基)-2-甲基丙醯胺基)苯基)-1H-吡唑-1-甲酸第三丁酯(23.5mg，31%)。MS：m/e=481.5[M+H]+。 N-(4-bromo-3-methoxyphenyl)-2-(3-methoxyphenylamino)-2-methylpropanamide (50 mg, 127 μmol), 4-(4,4) ,5,5-tetramethyl-1,3,2-dioxaboron 2-Benzyl-1H-pyrazole-1-carboxylic acid tert-butyl ester (63.6 mg, 216 μmol) and cesium carbonate (70.4 mg, 216 μmol) were combined with dioxane (5 ml) / water (0.5 ml). Bis(diphenylphosphino)ferrocene-palladium(II) chloride (18.6 mg, 25.4 μmol) was added. The reaction mixture was heated at 75 ° C overnight. The mixture was concentrated in vacuo and purified by EtOAc (EtOAcEtOAcEtOAcEtOAc (3-Methoxyphenylamino)-2-methylpropionamido)phenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (23.5 mg, 31%). MS: m/e = 481.5 [M + H] + .

步驟B. Step B.

在25mL圓底燒瓶中，使4-(2-甲氧基-4-(2-(3-甲氧基苯基胺基)-2-甲基丙醯胺基)苯基)-1H-吡唑-1-甲酸第三丁酯(23.5mg，48.9μmol)及 三氟乙酸(6.69mg，4.52μl，58.7μmol)與二氯甲烷(5ml)組合。在室溫下攪拌反應混合物隔夜。在真空中濃縮混合物。藉由層析(矽膠，乙酸乙酯/庚烷=0：100至75：25；及矽膠，甲醇/二氯甲烷=0：100至5：95)純化，得到呈灰白色固體狀之N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-(3-甲氧基苯基胺基)-2-甲基丙醯胺(6.4mg，34%)。MS：m/e=381.3[M+H]+。 In a 25 mL round bottom flask, 4-(2-methoxy-4-(2-(3-methoxyphenylamino)-2-methylpropionamido)phenyl)-1H-pyridin Triazole ester of azole-1-carboxylic acid (23.5 mg, 48.9 μmol) and trifluoroacetic acid (6.69 mg, 4.52 μl, 58.7 μmol) were combined with dichloromethane (5 ml). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. Purification by chromatography (ethyl acetate, ethyl acetate / heptane = 0: 100 to 75: 25; and silica gel, methanol / methylene chloride = 0: 100 to 5: 95) affords N- 3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-2-(3-methoxyphenylamino)-2-methylpropanamide (6.4 mg, 34%) . MS: m/e = 381.3 [M + H] + .

實例152 Example 152 2-(2-氯苯基)-N-(2-(2-(N-嗎啉基乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺2-(2-Chlorophenyl)-N-(2-(2-(N-morpholinylethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamide

步驟A. Step A.

在50mL圓底燒瓶中，使4-溴-2-(2-(N-嗎啉基乙氧基)苯胺(CAS 1219728-38-7，526mg，1.75mmol)及2-(2-氯苯基)乙酸(358mg，2.1mmol)與二氯甲烷(10ml)組合。在0℃下添加N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(402mg，2.1mmol)。在0℃下攪拌溶液15分鐘，接著在室溫下攪拌隔夜。將反應混合物傾倒於水(20ml)上且用二氯甲烷(3×20ml)萃取。合併有機相且用飽和碳酸氫鈉水溶液(20ml)洗滌。用硫酸鎂乾燥有機相，過濾且在真空中濃縮，得到呈粉紅色固體狀之N-(4-溴-2-(2-(N-嗎啉基乙氧基)苯基)-2-(2-氯苯基)乙醯胺(741mg，94%)。MS：m/e=455.5[M+H]+。 In a 50 mL round bottom flask, 4-bromo-2-(2-(N-morpholinylethoxy)aniline (CAS 1219728-38-7, 526 mg, 1.75 mmol) and 2-(2-chlorophenyl) Acetic acid (358 mg, 2.1 mmol) in combination with dichloromethane (10 ml). Add N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (402 mg) at 0 °C The mixture was stirred at 0 ° C for 15 min, then stirred at rt overnight. The mixture was poured on water (20 mL) eluting with dichloromethane (3×20 ml). The organic phase was dried over MgSO4, filtered and evaporatedEtOAcjjjjjjjjjjjjjjjjjjj Phenyl)-2-(2-chlorophenyl)acetamidamine (741 mg, 94%). MS: m/e=455.5 [M+H] + .

步驟B. Step B.

在25mL圓底燒瓶中，使N-(4-溴-2-(2-(N-嗎啉基乙氧基)苯基)-2-(2-氯苯基)乙醯胺(100mg，220μmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑-1-甲酸第三丁酯(77.8mg，264μmol)及碳酸銫(86.2mg，264μmol)與二噁烷(10ml)及水(1.0ml)組合。添加雙(二苯膦基)二茂鐵-二氯化鈀(II)(32.3mg，44.1μmol)且在70℃下攪拌反應混合物1小時。藉由層析(矽膠，甲醇/二氯甲烷=0：100至10：90)純化反應混合物，得到呈棕色固體狀之4-(4-(2-(2-氯苯基)乙醯胺基)-3-(2-(N-嗎啉基乙氧基)苯基)-1H-吡唑-1-甲酸第三丁酯(104mg，87%)。MS：m/e=541.6[M+H]+。 In a 25 mL round bottom flask, N-(4-bromo-2-(2-(N-morpholinylethoxy)phenyl)-2-(2-chlorophenyl)acetamide (100 mg, 220 μmol) ), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) 2-Butyl-1H-pyrazole-1-carboxylic acid tert-butyl ester (77.8 mg, 264 μmol) and cesium carbonate (86.2 mg, 264 μmol) were combined with dioxane (10 ml) and water (1.0 ml). Bis(diphenylphosphino)ferrocene-palladium(II) chloride (32.3 mg, 44.1 μmol) was added and the reaction mixture was stirred at 70 ° C for 1 hour. The reaction mixture was purified by chromatography (jjjjjjjjjjjjjjjjjjjj -3-(2-(N-morpholinylethoxy)phenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (104 mg, 87%). MS: m/e = 541.6 [M+ H] + .

步驟C. Step C.

在50mL圓底燒瓶中，使4-(4-(2-(2-氯苯基)乙醯胺基)-3-(2-(N-嗎啉基乙氧基)苯基)-1H-吡唑-1-甲酸第三丁酯(100mg，185μmol)及三氟乙酸(25.3mg，17.1μl，222μmol)與二氯甲烷(5ml)組合。在室溫下攪拌混合物隔夜，接著在50℃下攪拌4小時。在真空中濃縮反應混合物。藉由層析(矽膠，甲醇/二氯甲烷=5：95至10：90；及矽膠，甲醇/二氯甲烷=0：100至5：95)純化，得到呈灰白色固體狀之2-(2-氯苯基)-N-(2-(2-(N-嗎啉基乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺(33.8mg， 42%)。MS：m/e=441.3[M+H]+。 In a 50 mL round bottom flask, 4-(4-(2-(2-chlorophenyl)acetamido)-3-(2-(N-morpholinylethoxy)phenyl)-1H- Pyrazole-1-carboxylic acid tert-butyl ester (100 mg, 185 μmol) and trifluoroacetic acid (25.3 mg, 17.1 μl, 222 μmol) were combined with dichloromethane (5 ml). The mixture was stirred at room temperature overnight, then at 50 ° C Stir for 4 hours. Concentrate the reaction mixture in vacuo. Purify by chromatography (EtOAc, methylene chloride / methylene chloride = 5:95 to 10:90; and hexane, methanol/dichloromethane = 0:100 to 5:95) , 2-(2-chlorophenyl)-N-(2-(2-(N-morpholinylethoxy)-4-(1H-pyrazol-4-yl)phenyl) Ethylamine (33.8 mg, 42%). MS: m/e = 441.3 [M+H] + .

實例153 Example 153 1-(2-氯苯基胺基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)環丙烷甲醯胺1-(2-Chlorophenylamino)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)cyclopropanecarbamide

步驟A. Step A.

在25mL圓底燒瓶中，使1-(2-氯苯基胺基)環丙烷甲酸(201mg，950μmol)、4-溴-3-甲氧基苯胺(160mg，792μmol)及六氟磷酸O-(7-氮雜苯并***-1-基)-N,N,N',N'-四甲基(HATU，512mg，1.35mmol)與二甲基甲醯胺(10ml)組合。添加二異丙基乙胺(174mg，235μl，1.35mmol)。在室溫下攪拌反應混合物隔夜。在真空中濃縮混合物。將反應混合物傾倒於水(50ml)上且用乙酸乙酯(3×30ml)萃取。用飽和碳酸氫鈉水溶液(20ml)洗滌有機相。藉由層析(矽膠，乙酸乙酯/庚烷=0：100至50：50)純化，得到呈灰白色固體狀之N-(4-溴-3-甲氧基苯基)-1-(2-氯苯基胺基)環丙烷甲醯胺(148mg，47%)。MS：m/e=397.4[M+H]+。 In a 25 mL round bottom flask, 1-(2-chlorophenylamino)cyclopropanecarboxylic acid (201 mg, 950 μmol), 4-bromo-3-methoxyaniline (160 mg, 792 μmol) and hexafluorophosphate O- ( 7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyl (HATU, 512 mg, 1.35 mmol) was combined with dimethylformamide (10 ml). Diisopropylethylamine (174 mg, 235 μl, 1.35 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo. The reaction mixture was poured with water (50 mL)EtOAc. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate (20 mL). Purification by chromatography (ethyl acetate / EtOAc / EtOAc / EtOAc /EtOAc /EtOAc -Chlorophenylamino)cyclopropanecarbamide (148 mg, 47%). MS: m/e = 397.4 [M + H] + .

步驟B. Step B.

在25mL圓底燒瓶中，使N-(4-溴-3-甲氧基苯基)-1-(2-氯苯基胺基)環丙烷甲醯胺(140mg，354μmol)、4-(4,4,5,5-四甲基-1,3,2-二氧 硼-2-基)-1H-吡唑-1-甲酸第三丁酯(125mg，425μmol)及碳酸銫(231mg，708μmol)與二噁烷(5ml)及水(0.5ml)組合。在氬氣氛圍下添加雙(二苯膦基)二茂鐵-二氯化鈀(II)(51.8mg，70.8μmol)。在70℃下加熱反應混合物隔夜。在真空中濃縮反應混合物且藉由層析(矽膠，乙酸乙酯/庚烷=0：100至25：75)純化，得到呈灰白色固體狀之4-(4-(1-(2-氯苯基胺基)環丙烷甲醯胺基)-2-甲氧基苯基)-1H-吡唑-1-甲酸第三丁酯(110mg，52%)。MS：m/e=483.2[M+H]+。 In a 25 mL round bottom flask, N-(4-bromo-3-methoxyphenyl)-1-(2-chlorophenylamino)cyclopropanecarbamide (140 mg, 354 μmol), 4-(4) ,4,5,5-tetramethyl-1,3,2-dioxaboron 2-Butyl-1H-pyrazole-1-carboxylic acid tert-butyl ester (125 mg, 425 μmol) and cesium carbonate (231 mg, 708 μmol) were combined with dioxane (5 ml) and water (0.5 ml). Bis(diphenylphosphino)ferrocene-palladium(II) chloride (51.8 mg, 70.8 μmol) was added under an argon atmosphere. The reaction mixture was heated at 70 ° C overnight. The reaction mixture was concentrated in EtOAc (EtOAc m.) Aminobutyl)cyclopropanecarbamoyl)-2-methoxyphenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (110 mg, 52%). MS: m/e = 483.2 [M + H] + .

步驟C. Step C.

在50mL圓底燒瓶中，使4-(4-(1-(2-氯苯基胺基)環丙烷甲醯胺基)-2-甲氧基苯基)-1H-吡唑-1-甲酸第三丁酯(100mg，207μmol)及三氟乙酸(23.7mg，16μl，208μmol)與二氯甲烷(5ml)組合且在室溫下攪拌隔夜。添加三氟乙酸(23.7mg，16μl，208μmol)且在70℃下攪拌反應混合物4小時。用飽和碳酸氫鈉水溶液(10ml)洗滌反應混合物且用二氯甲烷(2×20ml)萃取。用MgSO4乾燥有機相，過濾且在真空中濃縮，得到呈灰白色固體狀之1-(2-氯苯基胺基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)環丙烷甲醯胺(57.2mg，72%)。MS：m/e=483.2[M+H]+。 4-(4-(1-(2-chlorophenylamino)cyclopropanecarbamoyl)-2-methoxyphenyl)-1H-pyrazole-1-carboxylic acid in a 50 mL round bottom flask The third butyl ester (100 mg, 207 μmol) and trifluoroacetic acid (23.7 mg, 16 μl, 208 μmol) were combined with dichloromethane (5 ml) and stirred at room temperature overnight. Trifluoroacetic acid (23.7 mg, 16 μl, 208 μmol) was added and the reaction mixture was stirred at 70 ° C for 4 hours. The reaction mixture was washed with aq. EtOAc (EtOAc) The organic phase was dried with MgSO 4, filtered and concentrated in vacuo to give an off-white solid of 1- (2-chlorophenyl amino) -N- (3- methoxy -4- (1H- pyrazol -4 -yl)phenyl)cyclopropanecarbamide (57.2 mg, 72%). MS: m/e = 483.2 [M + H] + .

實例154 Example 154 2-(2-氯苯基)-N-(3-(2-(N-嗎啉基乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺2,2,2-三氟乙酸鹽2-(2-Chlorophenyl)-N-(3-(2-(N-morpholinylethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamidamine 2,2 2-trifluoroacetate

步驟A. Step A.

在50mL圓底燒瓶中，使2-溴-5-硝基苯酚(500mg，2.18mmol)及碳酸銫(1.06g，3.27mmol)與二甲基甲醯胺(20ml)組合，且在室溫下攪拌15分鐘。添加4-(2-氯乙基)嗎啉(391mg，360μl，2.61mmol)且在室溫下攪拌反應混合物經週末。加熱反應混合物至70℃且攪拌1小時。在真空中濃縮反應混合物且傾倒於水(10ml)上。用2M HCl水溶液酸化混合物且用乙酸乙酯(3×20ml)洗滌。用飽和碳酸氫鈉水溶液鹼化水溶液，且用乙酸乙酯(3×30ml)萃取。經硫酸鎂乾燥有機相且在真空下濃縮，得到呈黃色油狀之4-(2-(2-溴-5-硝基苯氧基)乙基)嗎啉(762mg，定量)。MS：m/e=333.1[M+H]+。 In a 50 mL round bottom flask, 2-bromo-5-nitrophenol (500 mg, 2.18 mmol) and cesium carbonate (1.06 g, 3.27 mmol) were combined with dimethylformamide (20 ml) at room temperature Stir for 15 minutes. 4-(2-Chloroethyl)morpholine (391 mg, 360 μl, 2.61 mmol) was added and the reaction mixture was stirred at room temperature over the weekend. The reaction mixture was heated to 70 ° C and stirred for 1 hour. The reaction mixture was concentrated in vacuo and poured onto water (10 mL). The mixture was acidified with aq. EtOAc (EtOAc) The aqueous solution was basified with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×30 mL). The organic phase was dried <RTI ID=0.0></RTI> MS: m/e = 333.1 [M + H] + .

步驟B. Step B.

在50mL圓底燒瓶中，使4-(2-(2-溴-5-硝基苯氧基)乙基)嗎啉(350mg，1.06mmol)及鐵(413mg，7.4mmol)與甲醇(14ml)及鹽酸(37%，1.4ml)組合。在80℃下攪拌反應混合物隔夜。使用淡水矽藻土(dicalite)過濾混合物且在真空中濃縮。將混合物傾倒於水(20ml)上且 使用乙酸乙酯(3×25ml)萃取。用碳酸氫鈉將水相鹼化至pH 8且形成固體沈澱物。過濾混合物且用乙酸乙酯(3×25ml)萃取液相。合併有機相，用硫酸鎂乾燥，過濾且在真空中濃縮，得到呈橙色黏性橙色油狀之4-溴-3-(2-(N-嗎啉基乙氧基)苯胺(266mg，83%)。MS：m/e=301.1[M+H]+。 In a 50 mL round bottom flask, 4-(2-(2-bromo-5-nitrophenoxy)ethyl)morpholine (350 mg, 1.06 mmol) and iron (413 mg, 7.4 mmol) and methanol (14 ml) And a combination of hydrochloric acid (37%, 1.4 ml). The reaction mixture was stirred at 80 ° C overnight. The mixture was filtered using fresh water dicalite and concentrated in vacuo. The mixture was poured onto water (20 mL) andEtOAc was evaporated. The aqueous phase was basified to pH 8 with sodium bicarbonate and a solid precipitate formed. The mixture was filtered and the liquid was extracted with ethyl acetate (3×25 mL). The combined organics were dried with EtOAc EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH MS: m/e = 301.1 [M + H] + .

步驟C. Step C.

在25mL圓底燒瓶中，使4-溴-3-(2-(N-嗎啉基乙氧基)苯胺(250mg，830μmol)及2-(2-氯苯基)乙酸(170mg，996μmol)與二氯甲烷(10ml)組合。在0℃下添加N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(191mg，996μmol)。在室溫下攪拌反應混合物2小時。將反應混合物傾倒於水(20ml)上且用二氯甲烷(3×20ml)萃取。合併有機相且經硫酸鎂乾燥且在真空中濃縮。藉由層析(矽膠，甲醇/乙酸乙酯=0：100至5：95)純化，得到呈灰白色固體狀之N-(4-溴-3-(2-(N-嗎啉基乙氧基)苯基)-2-(2-氯苯基)乙醯胺(214mg，57%)。MS：m/e=455.1[M+H]+。 In a 25 mL round bottom flask, 4-bromo-3-(2-(N-morpholinylethoxy)phenylamine (250 mg, 830 μmol) and 2-(2-chlorophenyl)acetic acid (170 mg, 996 μmol) Methylene chloride (10 ml) was combined. N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (191 mg, 996 μmol) was added at 0 ° C. Stirring at room temperature The reaction mixture was poured into water (20 ml) and EtOAc (EtOAc (EtOAc)EtOAc. Purification with ethyl acetate = 0: 100 to 5: 95) afforded N-(4-bromo-3-(2-(N-morpholinylethoxy)phenyl)-2-(2) - chlorophenyl)acetamide (214 mg, 57%). MS: m / e = 455.1 [M+H] + .

步驟D. Step D.

在25mL圓底燒瓶中，使N-(4-溴-3-(2-(N-嗎啉基乙氧基)苯基)-2-(2-氯苯基)乙醯胺(200mg，441μmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼-2-基)-1H-吡唑-1-甲酸第三丁酯(194mg，661μmol)及碳酸銫 (215mg，661μmol)與二噁烷(10ml)及水(1ml)組合。在氬氣氛圍下添加雙(二苯膦基)二茂鐵-二氯化鈀(II)(96.8mg，132μmol)。在70℃下攪拌反應混合物4小時。在真空中濃縮反應混合物且藉由層析(矽膠，甲醇/二氯甲烷=0：100至5：95，接著藉由製備型HPLC，Gemini NX 3μ 50×4.6mm，C18逆相，乙腈/三乙胺=98：2)純化，得到呈蠟狀棕色固體狀之4-(4-(2-(2-氯苯基)乙醯胺基)-2-(2-(N-嗎啉基乙氧基)苯基)-1H-吡唑-1-甲酸第三丁酯(111mg，47%)。MS：m/e=541.4[M+H]+。 In a 25 mL round bottom flask, N-(4-bromo-3-(2-(N-morpholinylethoxy)phenyl)-2-(2-chlorophenyl)acetamide (200 mg, 441 μmol) ), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) 2-Butyl-1H-pyrazole-1-carboxylic acid tert-butyl ester (194 mg, 661 μmol) and cesium carbonate (215 mg, 661 μmol) were combined with dioxane (10 ml) and water (1 ml). Bis(diphenylphosphino)ferrocene-palladium(II) chloride (96.8 mg, 132 μmol) was added under an argon atmosphere. The reaction mixture was stirred at 70 ° C for 4 hours. The reaction mixture was concentrated in vacuo and chromatographed (EtOAc,MeOH/dichloromethane = 0:100 to 5:95, followed by preparative HPLC, Gemini NX 3μ 50 x 4.6 mm, C18 reverse phase, acetonitrile / tris Purification of ethylamine = 98:2) to give 4-(4-(2-(2-chlorophenyl)ethylamino)-2-(2-(N-morpholinyl) Oxy)phenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (111 mg, 47%). MS: m / e = 541.4 [M+H] + .

步驟E. Step E.

在25mL圓底燒瓶中，使4-(4-(2-(2-氯苯基)乙醯胺基)-2-(2-(N-嗎啉基乙氧基)苯基)-1H-吡唑-1-甲酸第三丁酯(100mg，185μmol)及三氟乙酸(42.1mg，28.5μl，370μmol)與二氯甲烷(5ml)組合，得到橙色溶液。在室溫下攪拌反應混合物2小時。添加三氟乙酸(42.1mg，28.5μl，370μmol)且在50℃下加熱反應混合物2小時。添加三氟乙酸(1ml)且在50℃下攪拌反應混合物30分鐘。在真空中濃縮反應混合物。藉由急驟管柱層析(矽膠，甲醇/二氯甲烷=2：98至10：90)純化且濕磨，得到呈灰白色固體狀之2-(2-氯苯基)-N-(3-(2-(N-嗎啉基乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺2,2,2-三氟乙酸鹽(30.5mg，30%)。MS：m/e=441.2[M+H]+。 In a 25 mL round bottom flask, 4-(4-(2-(2-chlorophenyl)acetamido)-2-(2-(N-morpholinylethoxy)phenyl)-1H- Pyrazole-1-carboxylic acid tert-butyl ester (100 mg, 185 μmol) and trifluoroacetic acid (42.1 mg, 28.5 μl, 370 μmol) were combined with dichloromethane (5 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2 hours. Trifluoroacetic acid (42.1 mg, 28.5 μl, 370 μmol) was added and the reaction mixture was heated at 50 ° C for 2 hours. Trifluoroacetic acid (1 ml) was added and the reaction mixture was stirred at 50 ° C for 30 min. The reaction mixture was concentrated in vacuo. Purification by flash column chromatography (methylene chloride, methylene chloride / methylene chloride = 2:98 to 10:90) and wet-purified to give 2-(2-chlorophenyl)-N-(3- (2-(N-Morpholinylethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamide 2,2,2-trifluoroacetate (30.5 mg, 30%). MS: m/e = 441.2 [M + H] + .

實例155 Example 155 2-(2-氯苯基)-N-(2-(2-甲氧基乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺2-(2-chlorophenyl)-N-(2-(2-methoxyethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamide

步驟A. Step A.

在25mL圓底燒瓶中，使4-溴-2-(2-甲氧基乙氧基)苯胺(CAS 1219730-72-9，100mg，406μmol)及2-(2-氯苯基)乙酸(83.2mg，488μmol)與二氯甲烷(5ml)組合，得到淺黃色溶液。在0℃下添加N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(93.5mg，488μmol)。在0℃下攪拌反應混合物30分鐘，接著在室溫下攪拌經週末。將反應混合物傾倒於水(20ml)上且用乙酸乙酯(3×20ml)萃取。合併有機相，用硫酸鎂乾燥，過濾且在真空中濃縮，得到呈灰白色固體狀之N-(4-溴-2-(2-甲氧基乙氧基)苯基)-2-(2-氯苯基)乙醯胺(185mg，定量)。MS：m/e=400.1[M+H]+。 In a 25 mL round bottom flask, 4-bromo-2-(2-methoxyethoxy)aniline (CAS 1219730-72-9, 100 mg, 406 μmol) and 2-(2-chlorophenyl)acetic acid (83.2) The combination of methylene chloride (5 ml) gave a pale yellow solution. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (93.5 mg, 488 μmol) was added at 0 °C. The reaction mixture was stirred at 0 ° C for 30 minutes, then stirred at room temperature over the weekend. The reaction mixture was poured with water (20 mL) The combined organics were dried with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH Chlorophenyl) acetamide (185 mg, quantitative). MS: m/e = 400.1 [M + H] + .

步驟B. Step B.

在25mL圓底燒瓶中，使N-(4-溴-2-(2-甲氧基乙氧基)苯基)-2-(2-氯苯基)乙醯胺(80mg，201μmol)、4-(4,4,5,5-四甲基-1,3,2-二氧硼- 2-基)-1H-吡唑-1-甲酸第三丁酯(70.8mg，241μmol)及碳酸銫(98.1mg，301μmol)與二噁烷(5ml)及水(500μl)組合，得到淺黃色溶液。在氬氣氛圍下添加雙(二苯膦基)二茂鐵-二氯化鈀(II)(29.4mg，40.1μmol)。加熱反應混合物至70℃維持1小時。在真空中濃縮反應混合物且藉由層析(矽膠，乙酸乙酯/庚烷=0：100至50：50)純化，得到呈蠟狀白色固體狀之4-(4-(2-(2-氯苯基)乙醯胺基)-3-(2-甲氧基乙氧基)苯基)-1H-吡唑-1-甲酸第三丁酯(28.1mg，29%)。MS：m/e=386.2[M+H]+。 In a 25 mL round bottom flask, N-(4-bromo-2-(2-methoxyethoxy)phenyl)-2-(2-chlorophenyl)acetamide (80 mg, 201 μmol), 4 -(4,4,5,5-tetramethyl-1,3,2-dioxaboron -2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (70.8 mg, 241 μmol) and cesium carbonate (98.1 mg, 301 μmol) combined with dioxane (5 ml) and water (500 μl) to give a pale yellow Solution. Bis(diphenylphosphino)ferrocene-palladium(II) chloride (29.4 mg, 40.1 μmol) was added under an argon atmosphere. The reaction mixture was heated to 70 ° C for 1 hour. The reaction mixture was concentrated in vacuo and purified by chromatography (jjjjjjjjjjjj Chlorophenyl)ethylamino)-3-(2-methoxyethoxy)phenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (28.1 mg, 29%). MS: m/e = 386.2 [M + H] + .

步驟C. Step C.

在25mL圓底燒瓶中，使4-(4-(2-(2-氯苯基)乙醯胺基)-3-(2-甲氧基乙氧基)苯基)-1H-吡唑-1-甲酸第三丁酯(28mg，57.6μmol)及三氟乙酸(19.7mg，13.3μl，173μmol)與二氯甲烷(2ml)組合，得到淺黃色溶液。在40℃下加熱反應混合物1小時。添加三氟乙酸(1ml)。在40℃下攪拌反應混合物30分鐘。使反應混合物冷卻至室溫。用二氯甲烷(20ml)稀釋反應混合物且用飽和碳酸氫鈉水溶液(20ml)洗滌。合併有機相且用硫酸鎂乾燥，過濾且在真空中濃縮，得到呈白色固體狀之2-(2-氯苯基)-N-(2-(2-甲氧基乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺(14.4mg，65%)。MS：m/e=386.2[M+H]+。 In a 25 mL round bottom flask, 4-(4-(2-(2-chlorophenyl)acetamido)-3-(2-methoxyethoxy)phenyl)-1H-pyrazole- Tributyl 1-formate (28 mg, 57.6 μmol) and trifluoroacetic acid (19.7 mg, 13.3 μl, 173 μmol) were combined with dichloromethane (2 ml) to give a pale yellow solution. The reaction mixture was heated at 40 ° C for 1 hour. Trifluoroacetic acid (1 ml) was added. The reaction mixture was stirred at 40 ° C for 30 minutes. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with dichloromethane (20 mL)EtOAcEtOAc The combined organics were dried with EtOAc EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH (1H-pyrazol-4-yl)phenyl)acetamide (14.4 mg, 65%). MS: m/e = 386.2 [M + H] + .

實例156 Example 156 2-(2-氯苯基)-N-(3-(2-甲氧基乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺2-(2-chlorophenyl)-N-(3-(2-methoxyethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamide

步驟A. Step A.

在25mL圓底燒瓶中，使2-溴-5-硝基苯酚(600mg，2.75mmol，1.00當量)、碳酸銫(1.35g，4.13mmol，1.5當量)及碘化鉀(91.4mg，550μmol，0.2當量)與二甲基甲醯胺(10ml)組合，且在氬氣下添加1-溴-2-甲氧基乙烷(574mg，388μl，4.13mmol，1.5當量)。在30℃下攪拌反應混合物2小時。在真空中濃縮反應混合物且添加水(40ml)。用乙酸乙酯(3×30ml)萃取反應混合物。經硫酸鎂乾燥有機相且在真空中濃縮，得到呈棕色固體狀之1-溴-2-(2-甲氧基乙氧基)-4-硝基苯(748mg，98%)。1H-NMR(ppm,300MHz,CDCl3)：7.76-7.77(m,1H),7.72-7.73(m,2H),4.29(t,2H),3.85(t,2H),3.49(s,3H)。 In a 25 mL round bottom flask, 2-bromo-5-nitrophenol (600 mg, 2.75 mmol, 1.00 equiv), cesium carbonate (1.35 g, 4.13 mmol, 1.5 eq.) and potassium iodide (91.4 mg, 550 [mu]mol, 0.2 eq.) In combination with dimethylformamide (10 ml), 1-bromo-2-methoxyethane (574 mg, 388 μl, 4.13 mmol, 1.5 eq.) was added under argon. The reaction mixture was stirred at 30 ° C for 2 hours. The reaction mixture was concentrated in vacuo and water (40 mL) was evaporated. The reaction mixture was extracted with ethyl acetate (3×30 mL). The organic phase was dried <RTI ID=0.0></RTI> 1 H-NMR (ppm, 300 MHz, CDCl 3 ): 7.76-7.77 (m, 1H), 7.72-7.73 (m, 2H), 4.29 (t, 2H), 3.85 (t, 2H), 3.49 (s, 3H) ).

步驟B. Step B.

在50mL圓底燒瓶中，使1-溴-2-(2-甲氧基乙氧基)-4-硝基苯(200mg，724μmol)及鐵(283mg，5.07mmol)與甲醇(5ml)組合。緩慢添加鹽酸(37%，500μl)。在70℃下攪拌反應混合物4小時。使反應混合物冷卻至室溫且經淡水矽藻土過濾且在真空中濃縮。藉由層析(矽膠，甲醇/二氯甲烷=2：98至5：95)純化，得到呈棕色油狀之4-溴-3-(2-甲氧基乙氧基)苯胺(85mg，48%)。MS：m/e=248.1[M+H]+。 1-Bromo-2-(2-methoxyethoxy)-4-nitrobenzene (200 mg, 724 μmol) and iron (283 mg, 5.07 mmol) were combined with methanol (5 ml) in a 50 mL round bottom flask. Hydrochloric acid (37%, 500 μl) was added slowly. The reaction mixture was stirred at 70 ° C for 4 hours. The reaction mixture was cooled to rt and filtered over EtOAc EtOAc. Purification by chromatography (methylene chloride, methylene chloride / methylene chloride = 2:98 to 5:95) afforded 4-bromo-3-(2-methoxyethoxy)aniline as a brown oil (85 mg, 48 %). MS: m/e = 248.1 [M + H] + .

步驟C. Step C.

在25mL圓底燒瓶中，使4-溴-3-(2-甲氧基乙氧基)苯胺(85mg，345μmol)及2-(2-氯苯基)乙酸(70.7mg，414μmol)與二氯甲烷(5ml)組合。在0℃下添加N-(3-二甲基胺基丙基)-N'-乙基碳化二亞胺鹽酸鹽(79.5mg，414μmol)。在0℃下攪拌反應混合物30分鐘，接著在室溫下攪拌隔夜。將反應混合物傾倒於水(20ml)上且用二氯甲烷(2×20ml)萃取，且合併有機相且用飽和碳酸氫鈉水溶液洗滌。用硫酸鎂乾燥有機相，過濾且在真空中濃縮。在甲醇中沈澱得到固體，其為純N-(4-溴-3-(2-甲氧基乙氧基)苯基)-2-(2-氯苯基)乙醯胺(81.4mg；59.1%)，灰白色固體。MS：m/e=400.1[M+H]+。 In a 25 mL round bottom flask, 4-bromo-3-(2-methoxyethoxy)aniline (85 mg, 345 μmol) and 2-(2-chlorophenyl)acetic acid (70.7 mg, 414 μmol) and dichloro Methane (5ml) combination. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (79.5 mg, 414 μmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 min then stirred at rt overnight. The reaction mixture was poured with EtOAc (EtOAc)EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. Precipitation in methanol gave a solid as pure N-(4-bromo-3-(2-methoxyethoxy)phenyl)-2-(2-chlorophenyl)acetamide (81.4 mg; 59.1 %), off-white solid. MS: m/e = 400.1 [M + H] + .

步驟D. Step D.

在25mL圓底燒瓶中，使N-(4-溴-3-(2-甲氧基乙氧基)苯基)-2-(2-氯苯基)乙醯胺(80mg，201μmol)、4-(4,4,5,5-四甲基-1,3-二氧雜環戊烷-2-基)-1H-吡唑-1-甲酸第三丁酯(71.4mg，241μmol)及碳酸銫(98.1mg，301μmol)與二噁烷(5ml)及水(500μl)組合。在氬氣氛圍下添加雙(二苯膦基)二茂鐵-二氯化鈀(II)(29.4mg，40.1μmol)。加熱反應混合物至70℃維持1小時。添加雙(二苯膦基)二茂鐵-二氯化鈀(II)(29.4mg，40.1μmol)及4-(4,4,5,5-四甲基-1,3-二氧雜環戊烷-2-基)-1H-吡唑-1-甲酸第三丁酯(29.7mg，100μmol)。在70℃下加熱反應混合物隔夜。在真空中濃縮反應混合物且藉由層析(矽膠，乙酸乙酯/庚烷=0：100至50：50)純化，得到呈黃色固體狀之4-(4-(2-(2-氯苯基)乙醯胺基)-2-(2-甲氧基乙氧基)苯基)-1H-吡唑-1-甲酸第三丁酯(57.6mg，59%)。MS：m/e=386.2[M-BOC+H]+。 In a 25 mL round bottom flask, N-(4-bromo-3-(2-methoxyethoxy)phenyl)-2-(2-chlorophenyl)acetamide (80 mg, 201 μmol), 4 -(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (71.4 mg, 241 μmol) and carbonic acid Ruthenium (98.1 mg, 301 μmol) was combined with dioxane (5 ml) and water (500 μl). Bis(diphenylphosphino)ferrocene-palladium(II) chloride (29.4 mg, 40.1 μmol) was added under an argon atmosphere. The reaction mixture was heated to 70 ° C for 1 hour. Addition of bis(diphenylphosphino)ferrocene-palladium(II) dichloride (29.4 mg, 40.1 μmol) and 4-(4,4,5,5-tetramethyl-1,3-dioxane Pentane-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (29.7 mg, 100 μmol). The reaction mixture was heated at 70 ° C overnight. The reaction mixture was concentrated in vacuo and purified eluting elut elut elut elut elut elut elut elut (Ethylamino)-2-(2-methoxyethoxy)phenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (57.6 mg, 59%). MS: m / e = 386.2 [M - BOC + H] + .

步驟E. Step E.

在25mL圓底燒瓶中，使4-(4-(2-(2-氯苯基)乙醯胺基)-2-(2-甲氧基乙氧基)苯基)-1H-吡唑-1-甲酸第三丁酯(55mg，113μmol)及三氟乙酸(1.48g，1ml，13.0mmol)與二氯甲烷(2ml)組合，得到橙色溶液。在40℃下攪拌反應混合物1小時。使用飽和碳酸氫鈉水溶液鹼化反應混合物，且用二氯甲烷(3×20ml)萃取。用硫酸鎂乾燥有機相，過濾且在真空中濃縮。用***及戊烷濕磨固體，得到呈灰白色固體狀之2-(2-氯苯基)-N-(3-(2-甲氧基乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺(31.7mg，73%)。MS：m/e=386.2[M+H]+。 In a 25 mL round bottom flask, 4-(4-(2-(2-chlorophenyl)acetamido)-2-(2-methoxyethoxy)phenyl)-1H-pyrazole- 1-Chloric acid tert-butyl ester (55 mg, 113 μmol) and trifluoroacetic acid (1.48 g, 1 ml, 13.0 mmol) were combined with dichloromethane (2 ml) to give an orange solution. The reaction mixture was stirred at 40 ° C for 1 hour. The reaction mixture was basified with saturated aqueous sodium bicarbonate and extracted with dichloromethane (3×20 mL). The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The solid was triturated with diethyl ether and pentane to give 2-(2-chlorophenyl)-N-(3-(2-methoxyethoxy)-4-(1H-pyrazole-4) as a white solid. -yl)phenyl)acetamide (31.7 mg, 73%). MS: m/e = 386.2 [M + H] + .

實例157 Example 157 N-(3-甲氧基-4-(噁唑-5-基)苯基)-3-甲基-3-苯基丁醯胺N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3-methyl-3-phenylbutyramine

與實例1類似，使用3-甲基-3-苯基-丁酸來製備標題化合物。獲得呈棕色膠狀之化合物(MS(m/e)=351.17[M+H+])。 Analogously to Example 1, 3-methyl-3-phenyl-butyric acid was used to prepare the title compound. The compound was obtained as a brown gum (MS (m/e) = 351.17 [M+H + ]).

實例158 Example 158 N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-甲基-3-苯基丁醯胺N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-methyl-3-phenylbutyramine

與實例111類似，在步驟A中使用3-甲基-3-苯基丁酸來製備標題化合物。獲得呈棕色固體狀之化合物(MS(m/e)=350.19[M+H+])。 Analogously to Example 111, the title compound was prepared using 3-methyl-3-phenylbutyric acid in Step A. The compound was obtained as a brown solid (MS (m/e) = 350.19 [M+H + ]).

實例159 Example 159 N-(4-(1H-吡唑-4-基)苯基)-3-甲基-3-苯基丁醯胺N-(4-(1H-pyrazol-4-yl)phenyl)-3-methyl-3-phenylbutyramine

與實例122類似，在步驟D中使用3-甲基-3-苯基丁酸來製備標題化合物。獲得呈棕色固體狀之化合物(MS(m/e)=320.17[M+H+])。 The title compound was prepared in the step D using 3-methyl-3-phenylbutyric acid. The compound was obtained as a brown solid (MS (m/e) = 320.17 [M+H + ]).

實例160 Example 160 N-(3-甲氧基-4-(吡啶-4-基)苯基)-3-甲基-3-苯基丁醯胺N-(3-methoxy-4-(pyridin-4-yl)phenyl)-3-methyl-3-phenylbutyramine

與實例121類似，在步驟B中使用3-甲基-3-苯基丁酸來製備標題化合物。獲得呈棕色膠狀之化合物(MS(m/e)=361.19[M+H+])。 Similarly to Example 121, the title compound was prepared using 3-methyl-3-phenylbutyric acid in Step B. The compound was obtained as a brown gum (MS (m/e) = 361.19 [M+H + ]).

實例161 Example 161 N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-苯基丁醯胺N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-phenylbutyramine

與實例111類似，在步驟D中使用3-苯基丁酸來製備標題化合物。獲得呈棕色固體狀之化合物(MS(m/e)=336.17[M+H+])。 Analogously to Example 111, the title compound was prepared using 3-phenylbutyric acid in Step D. The compound (MS (m/e) = 336.17 [M+H + ]) was obtained as a brown solid.

實例162 Example 162 3-(4-氯苯基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-甲基丁醯胺3-(4-Chlorophenyl)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-methylbutyramine

與實例111類似，在步驟D中使用3-(4-氯苯基)-3-甲基丁酸來製備標題化合物。獲得呈棕色固體狀之化合物(MS(m/e)=384.15 [M+H+])。 The title compound was prepared in the step D using 3-(4-chlorophenyl)-3-methylbutyric acid. Compound (MS (m/e) = 384.15 [M+H + ]).

實例163 Example 163 3-羥基-N-(3-甲氧基-4-(噁唑-5-基)苯基)-3-苯基丁醯胺3-hydroxy-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3-phenylbutyramine

與實例1類似，使用3-羥基-3-苯基丁酸來製備標題化合物。獲得呈棕色半固體狀之化合物(MS(m/e)=353.1[M+H+])。 Analogously to Example 1, the title compound was prepared using 3-hydroxy-3-phenylbutyric acid. The compound was obtained as a brown semi-solid (MS (m/e) = 353.1 [M+H + ]).

實例164 Example 164 N-(4-(1H-吡唑-4-基)苯基)-3-(4-氯苯基)-3-甲基丁醯胺N-(4-(1H-pyrazol-4-yl)phenyl)-3-(4-chlorophenyl)-3-methylbutyramine

與實例122類似，在步驟D中使用3-(4-氯苯基)-3-甲基丁酸來製備標題化合物。獲得呈白色粉末狀之化合物(MS(m/e)=354.14[M+H+])。 The title compound was prepared in the step D using 3-(4-chlorophenyl)-3-methylbutanoic acid. The compound was obtained as a white powder (MS (m/e) = 354.14 [M+H + ]).

實例165 Example 165 3-(3-氯苯基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-甲基丁醯胺3-(3-Chlorophenyl)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-methylbutanamine

與實例111類似，在步驟D中使用3-(3-氯苯基)-3-甲基丁酸來製備標題化合物。獲得呈淺黃色固體狀之化合物(MS(m/e)=384.15[M+H+])。 The title compound was prepared in the step D using 3-(3-chlorophenyl)-3-methylbutanoic acid. The compound (MS (m/e) = 384.15 [M+H + ]) was obtained as a pale yellow solid.

實例166 Example 166 N-(4-(1H-吡唑-4-基)苯基)-3-(3-氯苯基)-3-甲基丁醯胺N-(4-(1H-pyrazol-4-yl)phenyl)-3-(3-chlorophenyl)-3-methylbutyramine

與實例122類似，在步驟D中使用3-(3-氯苯基)-3-甲基丁酸來製備標題化合物。獲得呈白色粉末狀之化合物(MS(m/e)=354.13[M+H+])。 The title compound was prepared in the step D using 3-(3-chlorophenyl)-3-methylbutyric acid. The compound was obtained as a white powder (MS (m/e) = 354.13 [M+H + ]).

實例167 Example 167 3-(2-氯苯基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-甲基丁醯胺3-(2-chlorophenyl)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-methylbutyramine

與實例111類似，在步驟D中使用3-(2-氯苯基)-3-甲基丁酸來製備標題化合物。獲得呈白色粉末狀之化合物(MS(m/e)=384.15[M+H+])。 The title compound was prepared in the step D using 3-(2-chlorophenyl)-3-methylbutyric acid. The compound was obtained as a white powder (MS (m/e) = 384.15 [M+H + ]).

實例168 Example 168 N-(4-(1H-吡唑-4-基)苯基)-3-(2-氯苯基)-3-甲基丁醯胺N-(4-(1H-pyrazol-4-yl)phenyl)-3-(2-chlorophenyl)-3-methylbutyramine

與實例122類似，在步驟D中使用3-(2-氯苯基)-3-甲基丁酸來製備標題化合物。獲得呈白色粉末狀之化合物(MS(m/e)=354.14[M+H+])。 The title compound was prepared in the step D using 3-(2-chlorophenyl)-3-methylbutanoic acid. The compound was obtained as a white powder (MS (m/e) = 354.14 [M+H + ]).

實例169 Example 169 3-羥基-N-[4-(1,3-噁唑-5-基)苯基]-3-苯基丁醯胺3-hydroxy- N- [4-(1,3-oxazol-5-yl)phenyl]-3-phenylbutyramine

與實例114類似，使用4-(噁唑-5-基)苯胺及3-羥基-3-苯基丁酸來 製備標題化合物。獲得呈淺黃色泡沫狀之化合物(92mg，76%，MS(m/e)=323.14[M+H+])。 The title compound was prepared using 4-(oxazol-5-yl)aniline and 3-hydroxy-3-phenylbutyric acid analogously to Example 114. The compound was obtained as a pale yellow foam (92 mg, 76%, MS (m/e) = 323.14 [M+H + ]).

實例170 Example 170 3-羥基-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-苯基丁醯胺3-hydroxy-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-phenylbutyramine

與實例111類似，使用3-羥基-3-苯基丁酸來製備標題化合物。獲得呈棕色粉末狀之化合物(MS(m/e)=352.16[M+H+])。 Analogously to Example 111, the title compound was prepared using 3-hydroxy-3-phenylbutyric acid. The compound was obtained as a brown powder (MS (m/e) = 352.16 [M+H + ]).

實例171 Example 171 N-(4-(1H-吡唑-4-基)苯基)-3-羥基-3-苯基丁醯胺N-(4-(1H-pyrazol-4-yl)phenyl)-3-hydroxy-3-phenylbutyramine

與實例122類似，在步驟D中使用3-羥基-3-苯基丁酸來製備標題化合物。獲得呈淺棕色固體狀之化合物(MS(m/e)=322.16[M+H+])。 Analogously to Example 122, the title compound was prepared using 3-hydroxy-3-phenylbutyric acid in Step D. The compound was obtained as a light brown solid (MS (m/e) = 322.16 [M+H + ]).

實例172 Example 172 2-羥基-N-[3-甲氧基-4-(1H-吡唑-4-基)苯基]-2-苯基乙醯胺2-hydroxy- N- [3-methoxy-4-(1 H -pyrazol-4-yl)phenyl]-2-phenylacetamide

步驟A. Step A.

向1-溴-2-甲氧基-4-硝基-苯(200mg，0.86mmol)於二噁烷(160ml)及H2O(40ml)中之溶液中添加K2CO3(357.4mg，2.58mmol)，且用氬氣淨化反應混合物10分鐘。將[1-(第三丁氧基羰基)-1H-吡唑-4-基]酸頻哪醇酯(380mg，1.29mmol)及Pd(dppf)2Cl2．DCM(323mg， 0.39mmol)添加至反應混合物中，且再用氬氣淨化10分鐘。在80℃下加熱反應混合物16小時。在減壓下蒸發溶劑，且用水(60ml)稀釋所得粗物質，且用DCM(2×80ml)萃取。經無水Na2SO4乾燥合併之有機層，過濾且在真空中蒸發。藉由矽膠管柱層析(50-60% EtOAc/己烷)純化所得粗物質，得到呈綠色固體狀之4-(2-甲氧基-4-硝基-苯基)-1H-吡唑(1.86g，99.41%)(130mg，68%)。MS(m/e)=220.0(M+H+)。 K 2 CO 3 (357.4 mg, added to a solution of 1-bromo-2-methoxy-4-nitro-benzene (200 mg, 0.86 mmol) in dioxane (160 ml) and H 2 O (40 ml) 2.58 mmol) and the reaction mixture was purged with argon for 10 min. [1-(Tertibutoxycarbonyl)-1H-pyrazol-4-yl] Acid pinacol ester (380 mg, 1.29 mmol) and Pd(dppf) 2 Cl 2 . DCM (323 mg, 0.39 mmol) was added to the reaction mixture and then purified with argon for 10 min. The reaction mixture was heated at 80 ° C for 16 hours. The solvent was evaporated under reduced pressure and EtOAc m. 2 SO 4 organic layers were dried over anhydrous of Na, filtered and evaporated in vacuo. The crude material was purified by EtOAc EtOAc EtOAc (EtOAc) (1.86 g, 99.41%) (130 mg, 68%). MS (m/e) = 220.0 (M + H + ).

步驟B. Step B.

向4-(2-甲氧基-4-硝基-苯基)-1H-吡唑(3.98g，21.05mmol)於THF(150ml)中之溶液中添加TEA(4.40ml，31.58mmol)及(boc)2O(7.25ml，31.58mmol)，且在25℃下攪拌反應混合物16小時。在真空中蒸發溶劑，且藉由矽膠管柱層析(20-30% EtOAc/己烷)純化所得粗物質，得到呈白色固體狀之4-(2-甲氧基-4-硝基苯基)-1H-吡唑-1-甲酸第三丁酯(4g，66.27%)。 To a solution of 4-(2-methoxy-4-nitro-phenyl)-1H-pyrazole (3.98 g, 21.05 mmol) in THF (150 mL Boc) 2 O (7.25 ml, 31.58 mmol), and the reaction mixture was stirred at 25 ° C for 16 hours. The solvent was evaporated in vacuo to give EtOAcqqqqqqq -1H-pyrazole-1-carboxylic acid tert-butyl ester (4 g, 66.27%).

步驟C. Step C.

向4-(2-甲氧基-4-硝基苯基)-1H-吡唑-1-甲酸第三丁酯(2g，6.92mmol)於MeOH(190ml)中之溶液中添加10% Pd/C(100mg)，且在25℃下於H2氛圍下攪拌反應混合物3小時。過濾混合物，且在減壓下蒸發濾液，得到呈灰白色固體狀之4-(4-胺基-2-甲氧基苯基)-1H-吡唑-1-甲酸第三丁酯(1.75g，97.8%)。MS(m/e)=260.0(M+H+)。 Add 10% Pd/ to a solution of 4-(2-methoxy-4-nitrophenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (2 g, 6.92 mmol) in MeOH (190 mL) C (100 mg), and the reaction mixture was stirred at 25 ° C under H 2 atmosphere for 3 hr. The mixture was filtered, and the filtrate was evaporatedjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 97.8%). MS (m/e) = 260.0 (M + H + ).

步驟D. Step D.

使4-(4-胺基-2-甲氧基苯基)-1H-吡唑-1-甲酸第三丁酯(150mg，518μmol)及2-羥基-2-苯基乙酸(78.9mg，518μmol)與DMF(2ml)組合，得到淺棕色溶液。添加DIPEA(201mg，1.56mmol)及六氟磷酸(V)2-(3H-[1,2,3]***并[4,5-b]吡啶-3-基)-1,1,3,3-四甲基異(296mg，778μmol)。在室溫下攪拌反應混合物隔夜。藉由製備型HPLC(管柱：Zorbax Eclipse XDB-C18 21.2×50mm，流量：25ml/min，梯 度：乙腈/水(0.1%甲酸)=(95%-5%至5%-95%)作為溶離劑)純化反應混合物，得到呈橙色固體狀之標題化合物(73mg，28.2%)。 4-(4-Amino-2-methoxyphenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (150 mg, 518 μmol) and 2-hydroxy-2-phenylacetic acid (78.9 mg, 518 μmol) In combination with DMF (2 ml), a light brown solution was obtained. Add DIPEA (201 mg, 1.56 mmol) and hexafluorophosphate (V) 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3, 3-tetramethyliso (296 mg, 778 μmol). The reaction mixture was stirred at room temperature overnight. By preparative HPLC (column: Zorbax Eclipse XDB-C18 21.2×50 mm, flow rate: 25 ml/min, gradient: acetonitrile/water (0.1% formic acid) = (95%-5% to 5%-95%) as dissolution The title compound (73 mg, 28.2%) was obtained.

步驟E. Step E.

使4-(4-(2-羥基-2-苯基乙醯胺基)-2-甲氧基苯基)-1H-吡唑-1-甲酸第三丁酯(73mg，146μmol)與DCM(1ml)組合，得到淺棕色溶液。添加2,2,2-三氟乙酸(75μl)。在室溫下攪拌反應混合物隔夜。在真空中濃縮粗反應混合物。藉由製備型HPLC(管柱：Zorbax Eclipse XDB-C18 21.2×50mm，流量：25ml/min，梯度：乙腈/水(0.1%甲酸)=(95%-5%至5%-95%)作為溶離劑)純化反應混合物，得到呈淺棕色固體狀之標題化合物(13.1mg，27.7%，MS(m/e)=324.13[M+H]+)。 3-(4-(2-Hydroxy-2-phenylethylamino)-2-methoxyphenyl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (73 mg, 146 μmol) and DCM ( 1 ml) combined to give a light brown solution. 2,2,2-Trifluoroacetic acid (75 μl) was added. The reaction mixture was stirred at room temperature overnight. The crude reaction mixture was concentrated in vacuo. By preparative HPLC (column: Zorbax Eclipse XDB-C18 21.2×50 mm, flow rate: 25 ml/min, gradient: acetonitrile/water (0.1% formic acid) = (95%-5% to 5%-95%) as dissolution The title compound (13.1 mg, 27.7%, MS (m/e) = 324.13 [M+H] + ) was obtained as a light brown solid.

實例173 Example 173 2-(2-氯苯基)-2-羥基-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)乙醯胺2-(2-chlorophenyl)-2-hydroxy-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)acetamide

與實例172類似，在步驟D中使用2-(2-氯苯基)-2-羥基乙酸來製備標題化合物。獲得呈白色固體狀之化合物(MS(m/e)=358.09[M+H+])。 The title compound was prepared in the step D using 2-(2-chlorophenyl)-2-hydroxyacetic acid. The compound (MS (m/e) = 358.09 [M+H + ]) was obtained as a white solid.

Claims (22)

一種下式化合物，或其中R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；Het為5或6員雜芳基，其中雜原子係選自N、O或S；X為-CRR'-、-CRR'-NR'-、-C(O)-、-CH2-S-、-CH2-S(O)2-、CH2-O-或-CH2-CRR'-；R/R'彼此獨立地為氫、低碳烷基、羥基或苯基，或R及R'可連同其所連接之碳原子一起形成環丙基環；R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一或多個低碳烷基取代，或為吡啶基，視情況經鹵素或低碳烷氧基取代，或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、 低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基，或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基(oxo)取代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基；或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體。 a compound of the formula or Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) - morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 - lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl group, wherein the hetero atom is Selected from N, O or S; X is -CRR'-, -CRR'-NR'-, -C(O)-, -CH 2 -S-, -CH 2 -S(O) 2 -, CH 2 -O- or -CH 2 -CRR'-;R/R' are each independently hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may together with the carbon atom to which they are attached form a cyclopropyl group Ring; R 2 is lower alkyl, -C(O)O-lower alkyl, optionally substituted by lower alkyl or =0, C 3-6 cycloalkyl, bridged cyclohexyl or C 3-6 a cycloalkenyl group, or a 5-membered heteroaryl group, wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, Substituted with halogen or lower alkoxy, or phenyl, optionally 'substituted, the R 2' with one or more R 2 is selected from halo, cyano, S (O) 2 - lower alkyl , lower alkyl, halogen substituted lower alkyl, lower alkoxy, halogen substituted lower alkoxy, or amine, or benzo[1,3]dioxole , naphthyl, anthracenyl, benzoisoxazolyl, 2,3-dihydro-1H-indenyl, optionally substituted by lower alkoxy or by oxo, or 4-dihydro-2H-[1,4]oxazinyl, optionally substituted by pendant oxy, or 5 or 6 membered heterocycloalkyl; or a pharmaceutically acceptable acid addition salt thereof, exogenous A mixture or a corresponding enantiomer and/or optical isomer thereof. 如請求項1之化合物，其具有式I-1 其中R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；Het為5或6員雜芳基，其中雜原子係選自N、O或S；X為-CRR'-、-CRR'-NR'-、-C(O)-、-CH2-S-、-CH2-S(O)2-、CH2-O-或-CH2-CRR'-；R/R'彼此獨立地為氫、低碳烷基、羥基或苯基，或R及R'可連同其所連接之碳原子一起形成環丙基環；R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取 代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一或多個低碳烷基取代，或為吡啶基，視情況經鹵素或低碳烷氧基取代，或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基，或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基取代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基；或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體。 The compound of claim 1, which has the formula I-1 Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) - morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 - lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl group, wherein the hetero atom is Selected from N, O or S; X is -CRR'-, -CRR'-NR'-, -C(O)-, -CH 2 -S-, -CH 2 -S(O) 2 -, CH 2 -O- or -CH 2 -CRR'-;R/R' are each independently hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may together with the carbon atom to which they are attached form a cyclopropyl group Ring; R 2 is lower alkyl, -C(O)O-lower alkyl, optionally substituted by lower alkyl or =0, C 3-6 cycloalkyl, bridged cyclohexyl or C 3-6 a cycloalkenyl group, or a 5-membered heteroaryl group, wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, Substituted with halogen or lower alkoxy, or phenyl, optionally 'substituted, the R 2' with one or more R 2 is selected from halo, cyano, S (O) 2 - lower alkyl , lower alkyl, halogen-substituted lower alkyl, lower alkoxy, halogen-substituted lower alkoxy, or amine, or benzo[1,3]dioxole Base, naphthyl, anthracenyl, benzoisoxazolyl, 2,3-dihydro-1H-indenyl, optionally substituted by lower alkoxy or by pendant oxy, or 3,4-di Hydrogen-2H-[1,4]oxazinyl, optionally substituted by pendant oxy, or 5 or 6 membered heterocycloalkyl; or a pharmaceutically acceptable acid addition salt, racemic mixture thereof or Its corresponding enantiomers and/or optical isomers. 如請求項1之化合物，其具有式I-2 其中R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；Het為5或6員雜芳基，其中雜原子係選自N、O或S； X為-CRR'-、-CRR'-NR'-、-C(O)-、-CH2-S-、-CH2-S(O)2-、CH2-O-或-CH2-CRR'-；R/R'彼此獨立地為氫、低碳烷基、羥基或苯基，或R及R'可連同其所連接之碳原子一起形成環丙基環；R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一或多個低碳烷基取代，或為吡啶基，視情況經鹵素或低碳烷氧基取代，或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基，或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基取代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基；或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體。 The compound of claim 1, which has the formula I-2 Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) - morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 - lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl group, wherein the hetero atom is Selected from N, O or S; X is -CRR'-, -CRR'-NR'-, -C(O)-, -CH 2 -S-, -CH 2 -S(O) 2 -, CH 2 -O- or -CH 2 -CRR'-;R/R' are each independently hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may together with the carbon atom to which they are attached form a cyclopropyl group Ring; R 2 is lower alkyl, -C(O)O-lower alkyl, optionally substituted by lower alkyl or =0, C 3-6 cycloalkyl, bridged cyclohexyl or C 3-6 a cycloalkenyl group, or a 5-membered heteroaryl group, wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, Halogen or optionally substituted lower alkoxy, or phenyl, optionally 'substituted, the R 2' with one or more R 2 is selected from halo, cyano, S (O) 2 - lower alkoxy a lower alkyl group, a halogen-substituted lower alkyl group, a lower alkoxy group, a halogen-substituted lower alkoxy group, or an amine group, or a benzo[1,3]dioxole Alkenyl, naphthyl, anthracenyl, benzoisoxazolyl, 2,3-dihydro-1H-indenyl, optionally substituted by lower alkoxy or by pendant oxy, or 3,4- Dihydro-2H-[1,4]oxazinyl, optionally substituted by pendant oxy, or 5 or 6 membered heterocycloalkyl; or a pharmaceutically acceptable acid addition salt, racemic mixture thereof Or its corresponding enantiomers and/or optical isomers. 如請求項1之化合物，其具有式I-1A或I-2A或其中R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧 基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；Het為5或6員雜芳基，其中雜原子係選自N、O或S；R/R'彼此獨立地為氫、低碳烷基、羥基或苯基，或R及R'可連同其所連接之碳原子一起形成環丙基環；R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一或多個低碳烷基取代，或為吡啶基，視情況經鹵素或低碳烷氧基取代，或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基，或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基取代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基；或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體。 The compound of claim 1, which has the formula I-1A or I-2A or Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) - morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 - lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl group, wherein the hetero atom is Selected from N, O or S; R/R' are each independently hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may together with the carbon atom to which they are attached form a cyclopropyl ring; R 2 a lower alkyl, -C(O)O-lower alkyl, C 3-6 cycloalkyl, bridged cyclohexyl or C 3-6 cycloalkenyl, optionally substituted by lower alkyl or =O, Or a 5-membered heteroaryl group wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, optionally halogen or lower alkoxy substituted, or is phenyl, optionally substituted with one or more R 2 'taken The R 2 'is selected from halo, cyano, S (O) 2 - lower alkyl, lower alkyl, lower alkyl substituted with halogen, lower alkoxy, halogen substituted lower the Alkoxy, or amine group, or benzo[1,3]dioxolyl, naphthyl, anthracenyl, benzoisoxazolyl, 2,3-dihydro-1H-indenyl , optionally substituted by a lower alkoxy group or by a pendant oxy group, or 3,4-dihydro-2H-[1,4]oxazinyl, optionally substituted by a pendant oxy group, or 5 or 6 members Heterocycloalkyl; or a pharmaceutically acceptable acid addition salt, racemic mixture or the corresponding enantiomer and/or optical isomer thereof. 如請求項4之化合物，其中該等化合物為N-(3-甲氧基-4-噁唑-5-基-苯基)-2-(3-甲氧基-苯基)-乙醯胺N-(3-甲氧基-4-噁唑-5-基-苯基)-2-間甲苯基-乙醯胺N-(3-甲氧基-4-噁唑-5-基-苯基)-2-吡啶-2-基-乙醯胺2-(2-胺基苯基)-3'-甲氧基-4'-(5-噁唑基)乙醯苯胺 2-(2,5-二甲氧基苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(3-(二氟甲氧基)苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(2-(三氟甲基)苯基)乙醯胺2-(2,4-二氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(4-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(3-溴苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(4-溴苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(苯并[d][1,3]二氧雜環戊烯-5-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2-氯-6-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2,6-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2-(二氟甲氧基)苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(2-(三氟甲氧基)苯基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(2-甲氧基苯基)乙醯胺2-(4-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-對甲苯基乙醯胺2-(2-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-鄰甲苯基乙醯胺2-(2-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-(三氟甲基)苯基)乙醯胺2-(3,5-二甲基苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(萘-1-基)乙醯胺2-(3-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(3,5-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(3-氟-5-(三氟甲基)苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-(2,4-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(4-(甲基磺醯基)苯基)乙醯胺2-(3,4-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(3-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2,5-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2,3-二氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(3-氯-4-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(3-氰基苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(5-氯-2-氟苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(呋喃-2-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(5-氟吡啶-2-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(噻吩-2-基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(噻吩-3-基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(吡啶-4-基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(1-甲基-1H-吲哚-3-基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(吡啶-3-基)乙醯胺2-(1H-吲哚-3-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(苯并[d]異噁唑-3-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲基異噁唑-5-基)乙醯胺2-(2,4-二甲基噻唑-5-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(5-甲基噻吩-2-基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)戊醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)丙醯胺2-環己烯基-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-環己基-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-環丙基-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺 2-環戊基-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(4-甲基環己基)乙醯胺2-(雙環[2.2.1]庚-2-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(6-甲氧基-3-側氧基-2,3-二氫-1H-茚-1-基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(四氫-2H-哌喃-4-基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(四氫呋喃-2-基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(四氫-2H-哌喃-2-基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-側氧基-3,4-二氫-2H-苯并[b][1,4]噁嗪-2-基)乙醯胺2-(1,1-二側氧基-四氫-1λ*6*-噻吩-3-基)-N-(3-甲氧基-4-噁唑-5-基-苯基)-乙醯胺2-環丁基-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(4-側氧基環己基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-苯基丙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-3,3-二甲基丁醯胺N-(3-氯-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基)乙醯胺2-(3-甲氧基苯基)-N-(3-甲基-4-(噁唑-5-基)苯基)乙醯胺2-(3-甲氧基-苯基)-N-(3-甲氧基-4-噻唑-5-基-苯基)-乙醯胺N-(3-甲氧基-4-[1,3,4]噁二唑-2-基-苯基)-2-(3-甲氧基-苯基)-乙醯胺2-(3-甲氧基-苯基)-N-(3-甲氧基-4-[1,2,4]***-1-基-苯基)-乙醯胺3-甲氧基-N-(3-甲氧基苯甲基)-4-(噁唑-5-基)苯甲醯胺N-(4-氯苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(4-氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺3-甲氧基-4-(噁唑-5-基)-N-(2-(三氟甲基)苯甲基)苯甲醯胺 N-(2-氯苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺3-甲氧基-N-(2-甲基苯甲基)-4-(噁唑-5-基)苯甲醯胺N-(2-氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(3-氯苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(3,5-二氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(2,4-二氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(3-氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(2,5-二氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(2,3-二氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺3-甲氧基-4-(噁唑-5-基)-N-(噻吩-2-基甲基)苯甲醯胺N-(2-氟-3-甲氧基苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(5-氯-2-氟苯甲基)-3-甲氧基-4-(噁唑-5-基)苯甲醯胺3-甲氧基-N-((6-甲氧基吡啶-2-基)甲基)-4-(噁唑-5-基)苯甲醯胺2-(3-甲氧基苯基)-N-(4-(噁唑-5-基)苯基)乙醯胺N-(3-甲氧基苯甲基)-4-(噁唑-5-基)苯甲醯胺2-(3-甲氧基苯基)-N-(4-(吡啶-4-基)苯基)乙醯胺N-(3-甲氧基苯甲基)-4-(吡啶-4-基)苯甲醯胺2-(2-氯苯基)-N-(3-甲氧基-4-(吡啶-4-基)苯基)乙醯胺N-(2-氯苯甲基)-3-甲氧基-4-(吡啶-4-基)苯甲醯胺2-(2-氯苯基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)乙醯胺2-(2-氯苯基)-N-(2-甲氧基-4-(1H-吡唑-4-基)苯基)乙醯胺N-(2-氯苯甲基)-2-甲氧基-4-(1H-吡唑-4-基)苯甲醯胺N-(2-氯苯甲基)-3-甲氧基-4-(1H-吡唑-4-基)苯甲醯胺2-(2-氯苯基)-N-(3-甲氧基-4-(1H-1,2,4-***-1-基)苯基)乙醯胺2-(2-氯苯基)-N-(2-甲氧基-4-(噁唑-5-基)苯基)乙醯胺2-(2-氯苯基)-N-(4-(噁唑-5-基)苯基)乙醯胺 N-(2-氯苯甲基)-2-甲氧基-4-(噁唑-5-基)苯甲醯胺N-(4-(1H-吡唑-4-基)苯基)-2-(2-氯苯基)乙醯胺2-(2-氯苯基)-N-(4-(吡啶-4-基)苯基)乙醯胺2-(2-氯苯基)-N-(2-(2-(二甲基胺基)乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺2-(2-氯苯基)-N-(3-甲氧基-4-(4-甲基噁唑-5-基)苯基)乙醯胺1-(2-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)環丙烷甲醯胺2-(2-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-甲基丙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基)-2-甲基丙醯胺2-(2-氯苯基)-N-(3-(2-(二甲基胺基)乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺2,2,2-三氟乙酸鹽2-(2-氯苯基)-N-(2-(2-(N-嗎啉基乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺2-(2-氯苯基)-N-(3-(2-(N-嗎啉基乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺2,2,2-三氟乙酸鹽2-(2-氯苯基)-N-(2-(2-甲氧基乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺2-(2-氯苯基)-N-(3-(2-甲氧基乙氧基)-4-(1H-吡唑-4-基)苯基)乙醯胺2-羥基-N-[3-甲氧基-4-(1H-吡唑-4-基)苯基]-2-苯基乙醯胺或2-(2-氯苯基)-2-羥基-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)乙醯胺。 The compound of claim 4, wherein the compound is N-(3-methoxy-4-oxazol-5-yl-phenyl)-2-(3-methoxy-phenyl)-acetamide N-(3-methoxy-4-oxazol-5-yl-phenyl)-2-m-tolyl-acetamide N-(3-methoxy-4-oxazol-5-yl-benzene 2-(2-pyridin-2-yl-acetamide 2-(2-aminophenyl)-3'-methoxy-4'-(5-oxazolyl)acetanilide 2-(2, 5-dimethoxyphenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(3-(difluoromethoxy)phenyl) -N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2 -(2-(trifluoromethyl)phenyl)acetamide 2-(2,4-dichlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl Ethylamine 2-(4-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(3-bromophenyl)-N -(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(4-bromophenyl)-N-(3-methoxy-4-(oxazole-5) -yl)phenyl)acetamide 2-(benzo[d][1,3]dioxol-5-yl)-N-(3-methoxy-4-(oxazole-5) -yl)phenyl)acetamide 2-(2-chloro-6-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2- (2,6-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl) Acetylamine 2-(2-(difluoromethoxy)phenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide N-(3 -Methoxy-4-(oxazol-5-yl)phenyl)-2-(2-(trifluoromethoxy)phenyl)acetamide N-(3-methoxy-4-(acean) Zyrid-5-yl)phenyl)-2-(2-methoxyphenyl)acetamide 2-(4-fluorophenyl)-N-(3-methoxy-4-(oxazole-5) -yl)phenyl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-p-tolylacetamide 2-(2-chlorophenyl)- N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2- o-Tolylacetamide 2-(2-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide N-(3-methoxy- 4-(oxazol-5-yl)phenyl)-2-(3-(trifluoromethyl)phenyl)acetamide 2-(3,5-dimethylphenyl)-N-(3- Methoxy-4-(oxazol-5-yl)phenyl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(naphthalene-1- Acetylamine 2-(3-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(3,5-difluorobenzene -N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(3-fluoro-5-(trifluoromethyl)phenyl)-N-( 3-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(2,4-difluorophenyl)-N-(3-methoxy 4-(oxazol-5-yl)phenyl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-(methylsulfonate) Mercapto)phenyl)acetamide 2-(3,4-difluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamidamine 2-( 3-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(2,5-difluorophenyl)-N-(3- Methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(2,3-difluorophenyl)-N-(3-methoxy-4-(oxazole-5-) Phenyl) acetamidine 2-(3-chloro-4-fluorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamidamine 2-( 3-cyanophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(5-chloro-2-fluorophenyl)-N-( 3-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(furan-2-yl)-N-(3-methoxy-4-(oxazol-5-yl) Phenyl)acetamide 2-(5-fluoropyridin-2-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamidamine N-(3- Methoxy-4-(oxazol-5-yl)phenyl)-2-(thiophen-2-yl)acetamide N-(3-methoxy-4-(oxazole-5-yl)benzene 2-(thiophen-3-yl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(pyridin-4-yl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(1-methyl-1H-indol-3-yl)acetamide N-(3-methoxy base- 4-(oxazol-5-yl)phenyl)-2-(pyridin-3-yl)acetamide 2-(1H-indol-3-yl)-N-(3-methoxy-4- (oxazol-5-yl)phenyl)acetamide 2-(benzo[d]isoxazol-3-yl)-N-(3-methoxy-4-(oxazol-5-yl) Phenyl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methylisoxazol-5-yl)acetamidamine 2-( 2,4-Dimethylthiazol-5-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide N-(3-methoxy-4- (oxazol-5-yl)phenyl)-2-(5-methylthien-2-yl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl) Pentamidine N-(3-methoxy-4-(oxazol-5-yl)phenyl)propanamine 2-cyclohexenyl-N-(3-methoxy-4-(oxazole)- 5-yl)phenyl)acetamide 2-cyclohexyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-cyclopropyl-N-(3 -methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-cyclopentyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl) Indoleamine N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-methylcyclohexyl)acetamide 2-(bicyclo[2.2.1]hept-2 -yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamidine 2-(6-methoxy-3-oxirane-2,3-dihydro -1H-indol-1-yl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamidamine N-(3-A 4-(oxazol-5-yl)phenyl)-2-(tetrahydro-2H-piperidin-4-yl)acetamide N-(3-methoxy-4-(oxazole-5) -yl)phenyl)-2-(tetrahydrofuran-2-yl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(tetrahydro-2H- Piperan-2-yl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-trioxy-3,4-dihydro-2H -Benzo[b][1,4]oxazol-2-yl)acetamide 2-(1,1-di-oxy-tetrahydro-1λ*6*-thiophen-3-yl)-N- (3-methoxy-4-oxazol-5-yl-phenyl)-acetamide 2-cyclobutyl-N-(3-methoxy-4-(oxazol-5-yl)phenyl Ethylamine N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(4-oxocyclohexyl)acetamide N-(3-methoxy- 4-(oxazol-5-yl)phenyl)-2-phenylpropionamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3,3-dimethyl Butylamine N-(3-chloro-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenyl)acetamide 2-(3-methoxyphenyl) -N-(3-methyl-4-(oxazol-5-yl)phenyl)acetamido 2-(3-methoxy-phenyl)-N-(3-methoxy-4-thiazole -5-yl-phenyl)-acetamide N-(3-methoxy-4-[1,3,4]oxadiazol-2-yl-phenyl)-2-(3-methoxy -phenyl)-acetamide 2-(3-methoxy-phenyl)-N-(3-methoxy-4-[1,2,4]triazol-1-yl-benzene )-acetamide 3-methoxy-N-(3-methoxybenzyl)-4-(oxazol-5-yl)benzamide N-(4-chlorobenzyl)-3 -methoxy-4-(oxazol-5-yl)benzamide N-(4-fluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide 3-methoxy-4-(oxazol-5-yl)-N-(2-(trifluoromethyl)benzyl)benzamide N-(2-chlorobenzyl)-3-methyl Oxy-4-(oxazol-5-yl)benzamide-3-methoxy-N-(2-methylbenzyl)-4-(oxazol-5-yl)benzamide N -(2-fluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide N-(3-chlorobenzyl)-3-methoxy-4-( Oxazol-5-yl)benzamide N-(3,5-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide N-(2, 4-Difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide N-(3-fluorobenzyl)-3-methoxy-4-(evil Noxa-5-yl)benzamide N-(2,5-difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide N-(2,3 -difluorobenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide-3methoxy-4-(oxazol-5-yl)-N-(thiophene- 2-ylmethyl)benzamide N-(2-fluoro-3-methoxybenzyl)-3-methoxy-4-(oxazol-5-yl)benzamide N-( 5-chloro-2-fluorobenzyl)-3-methoxy-4-(oxazole- 5-yl)benzamide-5-methoxy-N-((6-methoxypyridin-2-yl)methyl)-4-(oxazol-5-yl)benzamide-5 3-methoxyphenyl)-N-(4-(oxazol-5-yl)phenyl)acetamide N-(3-methoxybenzyl)-4-(oxazol-5-yl) Benzoamide 2-(3-methoxyphenyl)-N-(4-(pyridin-4-yl)phenyl)acetamide N-(3-methoxybenzyl)-4- (pyridin-4-yl)benzamide 2-(2-chlorophenyl)-N-(3-methoxy-4-(pyridin-4-yl)phenyl)acetamide N-(2- Chlorobenzyl)-3-methoxy-4-(pyridin-4-yl)benzamide 2-(2-chlorophenyl)-N-(3-methoxy-4-(1H-pyridyl) Zyridin-4-yl)phenyl)acetamide 2-(2-chlorophenyl)-N-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)acetamide N -(2-chlorobenzyl)-2-methoxy-4-(1H-pyrazol-4-yl)benzamide N-(2-chlorobenzyl)-3-methoxy-4 -(1H-pyrazol-4-yl)benzamide 2-(2-chlorophenyl)-N-(3-methoxy-4-(1H-1,2,4-triazole-1- Ethyl) phenyl acetamide 2-(2-chlorophenyl)-N-(2-methoxy-4-(oxazol-5-yl)phenyl)acetamide 2-(2-chlorobenzene -N-(4-(oxazol-5-yl)phenyl)acetamide N-(2-chlorobenzyl)-2-methoxy-4-(oxazol-5-yl)benzene Methionine N-(4-(1H-pyrazol-4-yl)phenyl)-2-(2-chlorophenyl)acetamide 2-(2-chloro -N-(4-(pyridin-4-yl)phenyl)acetamide 2-(2-chlorophenyl)-N-(2-(2-(dimethylamino)ethoxy) 4-(1H-pyrazol-4-yl)phenyl)acetamide 2-(2-chlorophenyl)-N-(3-methoxy-4-(4-methyloxazole-5- Phenyl) acetamidine 1-(2-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)cyclopropanecarbamide 2-(2- Chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-methylpropionamide N-(3-methoxy-4-(oxazole)- 5-yl)phenyl)-2-(3-methoxyphenyl)-2-methylpropanamide 2-(2-chlorophenyl)-N-(3-(2-(dimethylamine) Ethyl)-4-(1H-pyrazol-4-yl)phenyl)acetamide 2,2,2-trifluoroacetate 2-(2-chlorophenyl)-N-(2- (2-(N-morpholinylethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamide 2-(2-chlorophenyl)-N-(3-(2- (N-morpholinylethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamide 2,2,2-trifluoroacetate 2-(2-chlorophenyl)-N -(2-(2-methoxyethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamide 2-(2-chlorophenyl)-N-(3-(2 -methoxyethoxy)-4-(1H-pyrazol-4-yl)phenyl)acetamide 2-hydroxy- N- [3-methoxy-4-(1 H -pyrazole-4 -yl)phenyl]-2-phenylacetamide or 2-(2-chlorophenyl)-2-hydroxy-N-(3-methoxy-4-(1H-pyrazole) 4-yl)phenyl)acetamide. 如請求項1之化合物，其具有式I-1B或I-2B或 其中R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；Het為5或6員雜芳基，其中雜原子係選自N、O或S；R/R'彼此獨立地為氫、低碳烷基、羥基或苯基，或R及R'可連同其所連接之碳原子一起形成環丙基環；R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一或多個低碳烷基取代，或為吡啶基，視情況經鹵素或低碳烷氧基取代，或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基，或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基取代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基；或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體。 The compound of claim 1, which has the formula I-1B or I-2B or Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) - morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 - lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl group, wherein the hetero atom is Selected from N, O or S; R/R' are each independently hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may together with the carbon atom to which they are attached form a cyclopropyl ring; R 2 a lower alkyl, -C(O)O-lower alkyl, C 3-6 cycloalkyl, bridged cyclohexyl or C 3-6 cycloalkenyl, optionally substituted by lower alkyl or =O, Or a 5-membered heteroaryl group wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, optionally halogen or lower alkoxy substituted, or is phenyl, optionally substituted with one or more R 2 'taken The R 2 'is selected from halo, cyano, S (O) 2 - lower alkyl, lower alkyl, lower alkyl substituted with halogen, lower alkoxy, halogen substituted lower the Alkoxy, or amine group, or benzo[1,3]dioxolyl, naphthyl, anthracenyl, benzoisoxazolyl, 2,3-dihydro-1H-indenyl , optionally substituted by a lower alkoxy group or by a pendant oxy group, or 3,4-dihydro-2H-[1,4]oxazinyl, optionally substituted by a pendant oxy group, or 5 or 6 members Heterocycloalkyl; or a pharmaceutically acceptable acid addition salt, racemic mixture or the corresponding enantiomer and/or optical isomer thereof. 如請求項6之化合物，其中該等化合物為 [(RS)-[[[3-甲氧基-4-(5-噁唑基)苯基]胺甲醯基]苯基]-(甲基)]胺基甲酸第三丁酯N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-((3-甲氧基苯基)(甲基)胺基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基胺基)乙醯胺N-(3-甲氧基-4-噁唑-5-基-苯基)-2-苯基胺基-乙醯胺2-(4-氯苯基胺基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-(三氟甲基)苯基胺基)乙醯胺2-(4-氟苯基胺基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)乙醯胺N-(4-(噁唑-5-基)苯基)-2-(苯基胺基)乙醯胺2-(4-氟苯基胺基)-N-(4-(噁唑-5-基)苯基)乙醯胺N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-((3-甲氧基苯基)(甲基)胺基)乙醯胺N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-(3-甲氧基苯基胺基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基胺基)-2-甲基丙醯胺2-(2-氯苯基胺基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-甲基丙醯胺2-(2-氯苯基胺基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-1-(3-甲氧基苯基胺基)環丙烷甲醯胺N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-甲基-2-(苯基胺基)丙醯胺1-(2-氯苯基胺基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)環丙烷甲醯胺N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-2-(3-甲氧基苯基胺基)-2- 甲基丙醯胺或1-(2-氯苯基胺基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)環丙烷甲醯胺。 The compound of claim 6, wherein the compound is [(RS)-[[[3-methoxy-4-(5-oxazolyl)phenyl]amine-carbamoyl]phenyl]-(methyl)]carbamic acid tert-butyl ester N-(( 3-methoxy-4-(oxazol-5-yl)phenyl)-2-((3-methoxyphenyl)(methyl)amino)acetamide N-(3-methoxy 4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylamino)acetamide N-(3-methoxy-4-oxazol-5-yl-benzene 2-phenylamino-acetamide 2-(4-chlorophenylamino)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-(trifluoromethyl)phenylamino)acetamide 2-(4-fluorophenyl Amino)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)acetamide N-(4-(oxazol-5-yl)phenyl)-2-(benzene Ethylamino)acetamide 2-(4-fluorophenylamino)-N-(4-(oxazol-5-yl)phenyl)acetamide N-(3-methoxy-4-( 1H-pyrazol-4-yl)phenyl)-2-((3-methoxyphenyl)(methyl)amino)acetamide N-(3-methoxy-4-(1H-pyridyl) Zin-4-yl)phenyl)-2-(3-methoxyphenylamino)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2 -(3-methoxyphenylamino)-2-methylpropionamide 2-(2-chlorophenylamino)-N-(3-methoxy-4-(1H-pyrazole-4) -yl)phenyl)-2-methylpropionamide 2-(2-chlorophenylamino)-N -(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-1 -(3-methoxyphenylamino)cyclopropanecarbamide N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-2-methyl-2-( Phenylamino)propanamine 1-(2-chlorophenylamino)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)cyclopropanecarbamide N-( 3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-2-(3-methoxyphenylamino)-2- Methyl acrylamide or 1-(2-chlorophenylamino)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)cyclopropanecarbamide. 如請求項1之化合物，其具有式I-1C或I-2C 或其中R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；Het為5或6員雜芳基，其中雜原子係選自N、O或S；R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一或多個低碳烷基取代，或為吡啶基，視情況經鹵素或低碳烷氧基取代，或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基，或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基取 代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基；或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體。 A compound of claim 1, which has the formula I-1C or I-2C or Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) - morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 - lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl group, wherein the hetero atom is Selected from N, O or S; R 2 is lower alkyl, -C(O)O-lower alkyl, optionally substituted by lower alkyl or =0, C 3-6 cycloalkyl, bridged ring A hexyl or C 3-6 cycloalkenyl group, or a 5-membered heteroaryl group, wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, halogen or optionally substituted lower alkoxy, or phenyl, optionally 'substituted, the R 2' with one or more R 2 is selected from halo, cyano, S (O) 2 - lower alkoxy Base, lower alkyl, halogen substituted lower alkyl, lower alkoxy, Halogen substituted lower alkoxy, or amine, or benzo[1,3]dioxolyl, naphthyl, anthracenyl, benzoisoxazolyl, 2,3-dihydro a -1H-indenyl group, optionally substituted by a lower alkoxy group or by a pendant oxy group, or a 3,4-dihydro-2H-[1,4]oxazinyl group, optionally substituted with a pendant oxy group, or Is a 5- or 6-membered heterocycloalkyl; or a pharmaceutically acceptable acid addition salt, racemic mixture or the corresponding enantiomer and/or optical isomer thereof. 如請求項8之化合物，其中該化合物為N-[3-甲氧基-4-(5-噁唑基)苯基]-3,3-二甲基-2-側氧基丁醯胺。 The compound of claim 8, wherein the compound is N-[3-methoxy-4-(5-oxazolyl)phenyl]-3,3-dimethyl-2-oxobutanamine. 如請求項1之化合物，其具有式I-1D及I-2D或I-1F或I-2F或或或其中R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；Het為5或6員雜芳基，其中雜原子係選自N、O或S；R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一或多個低碳烷基取代， 或為吡啶基，視情況經鹵素或低碳烷氧基取代，或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基，或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基取代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基；或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體。 The compound of claim 1, which has the formula I-1D and I-2D or I-1F or I-2F or or or Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) - morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 - lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl group, wherein the hetero atom is Selected from N, O or S; R 2 is lower alkyl, -C(O)O-lower alkyl, optionally substituted by lower alkyl or =0, C 3-6 cycloalkyl, bridged ring A hexyl or C 3-6 cycloalkenyl group, or a 5-membered heteroaryl group, wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, halogen or optionally substituted lower alkoxy, or phenyl, optionally 'substituted, the R 2' with one or more R 2 is selected from halo, cyano, S (O) 2 - lower alkoxy Base, lower alkyl, halogen substituted lower alkyl, lower alkoxy, Halogen substituted lower alkoxy, or amine, or benzo[1,3]dioxolyl, naphthyl, anthracenyl, benzoisoxazolyl, 2,3-dihydro a -1H-indenyl group, optionally substituted by a lower alkoxy group or by a pendant oxy group, or a 3,4-dihydro-2H-[1,4]oxazinyl group, optionally substituted with a pendant oxy group, or Is a 5- or 6-membered heterocycloalkyl; or a pharmaceutically acceptable acid addition salt, racemic mixture or the corresponding enantiomer and/or optical isomer thereof. 如請求項10之化合物，其中該等化合物為2-(苯磺醯基)-3'-甲氧基-4'-(5-噁唑基)乙醯苯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(苯硫基)乙醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯硫基)乙醯胺或N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-(3-甲氧基苯基磺醯基)乙醯胺。 The compound of claim 10, wherein the compound is 2-(phenylsulfonyl)-3'-methoxy-4'-(5-oxazolyl)acetanilide N-(3-methoxy- 4-(oxazol-5-yl)phenyl)-2-(phenylthio)acetamide N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-( 3-methoxyphenylthio)acetamide or N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-(3-methoxyphenylsulfonyl) Acetamide. 如請求項1之化合物，其具有式I-1G或I-2G或其中R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低 碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；Het為5或6員雜芳基，其中雜原子係選自N、O或S；R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一或多個低碳烷基取代，或為吡啶基，視情況經鹵素或低碳烷氧基取代，或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基，或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基取代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基；或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體。 A compound of claim 1, which has the formula I-1G or I-2G or Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) - morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 - lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl group, wherein the hetero atom is Selected from N, O or S; R 2 is lower alkyl, -C(O)O-lower alkyl, optionally substituted by lower alkyl or =0, C 3-6 cycloalkyl, bridged ring A hexyl or C 3-6 cycloalkenyl group, or a 5-membered heteroaryl group, wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, halogen or optionally substituted lower alkoxy, or phenyl, optionally 'substituted, the R 2' with one or more R 2 is selected from halo, cyano, S (O) 2 - lower alkoxy Base, lower alkyl, halogen substituted lower alkyl, lower alkoxy, Halogen substituted lower alkoxy, or amine, or benzo[1,3]dioxolyl, naphthyl, anthracenyl, benzoisoxazolyl, 2,3-dihydro a -1H-indenyl group, optionally substituted by a lower alkoxy group or by a pendant oxy group, or a 3,4-dihydro-2H-[1,4]oxazinyl group, optionally substituted with a pendant oxy group, or Is a 5- or 6-membered heterocycloalkyl; or a pharmaceutically acceptable acid addition salt, racemic mixture or the corresponding enantiomer and/or optical isomer thereof. 如請求項12之化合物，其中該化合物為N-(3-甲氧基-4-(噁唑-5-基)苯基)-2-苯氧基乙醯胺。 The compound of claim 12, wherein the compound is N-(3-methoxy-4-(oxazol-5-yl)phenyl)-2-phenoxyacetamide. 如請求項1之化合物，其具有式I-1H或I-2H或其中R1為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基； R1'為氫、低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；其限制條件為R1與R1'可同時為氫，但R1及R1'中僅一者為低碳烷基、低碳烷氧基、鹵素、O(CH2)2-低碳烷氧基、O(CH2)2N(CH3)2或O(CH2)-嗎啉基；Het為5或6員雜芳基，其中雜原子係選自N、O或S；R/R'彼此獨立地為氫、低碳烷基、羥基或苯基，或R及R'可連同其所連接之碳原子一起形成環丙基環；R2為低碳烷基、-C(O)O-低碳烷基、視情況經低碳烷基或=O取代之C3-6環烷基、橋連環己基或C3-6環烯基，或為5員雜芳基，其中雜原子係選自N、O或S，且其視情況經一或多個低碳烷基取代，或為吡啶基，視情況經鹵素或低碳烷氧基取代，或為苯基，視情況經一或多個R2'取代，該R2'係選自鹵素、氰基、S(O)2-低碳烷基、低碳烷基、經鹵素取代之低碳烷基、低碳烷氧基、經鹵素取代之低碳烷氧基、或胺基，或為苯并[1,3]二氧雜環戊烯基、萘基、吲哚基、苯并異噁唑基、2,3-二氫-1H-茚基，視情況經低碳烷氧基或經側氧基取代，或為3,4-二氫-2H-[1,4]噁嗪基，視情況經側氧基取代，或為5或6員雜環烷基；或其醫藥學上可接受之酸加成鹽、外消旋混合物或其相應對映異構體及/或光學異構體。 A compound of claim 1, which has the formula I-1H or I-2H or Wherein R 1 is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 ) -morpholinyl; R 1 ' is hydrogen, lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; the restriction is that R 1 and R 1 ' may be hydrogen at the same time, but only one of R 1 and R 1 ' is lower alkyl, lower alkoxy, halogen, O(CH 2 ) 2 -lower alkoxy, O(CH 2 ) 2 N(CH 3 ) 2 or O(CH 2 )-morpholinyl; Het is a 5 or 6 membered heteroaryl group, wherein the hetero atom is Selected from N, O or S; R/R' are each independently hydrogen, lower alkyl, hydroxy or phenyl, or R and R' may together with the carbon atom to which they are attached form a cyclopropyl ring; R 2 a lower alkyl, -C(O)O-lower alkyl, C 3-6 cycloalkyl, bridged cyclohexyl or C 3-6 cycloalkenyl, optionally substituted by lower alkyl or =O, Or a 5-membered heteroaryl group wherein the hetero atom is selected from N, O or S, and optionally substituted with one or more lower alkyl groups, or is pyridyl, optionally halogen or lower alkoxy Substituted, or phenyl, as the case may be taken by one or more R 2 ' The R 2 ' is selected from the group consisting of halogen, cyano, S(O) 2 -lower alkyl, lower alkyl, halogen substituted lower alkyl, lower alkoxy, halogen substituted Carboalkoxy, or amine group, or benzo[1,3]dioxolyl, naphthyl, anthracenyl, benzoisoxazolyl, 2,3-dihydro-1H-indole a group, optionally substituted by a lower alkoxy group or by a pendant oxy group, or a 3,4-dihydro-2H-[1,4]oxazinyl group, optionally substituted with a pendant oxy group, or 5 or 6 Heterocycloalkyl; or a pharmaceutically acceptable acid addition salt, racemic mixture or the corresponding enantiomer and/or optical isomer thereof. 如請求項14之化合物，其中該等化合物為N-(3-甲氧基-4-(噁唑-5-基)苯基)-3-苯基丙醯胺N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺3-(4-氯苯基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)丙醯胺 3-(3-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)丙醯胺3-(2-氯苯基)-N-(3-甲氧基-4-(噁唑-5-基)苯基)丙醯胺N-(3-甲氧基-4-(吡啶-4-基)苯基)-3-苯基丙醯胺N-(4-(1H-吡唑-4-基)苯基)-3-(2-氯苯基)丙醯胺N-(4-(1H-吡唑-4-基)苯基)-3-(3-氯苯基)丙醯胺N-(4-(1H-吡唑-4-基)苯基)-3-(4-氯苯基)丙醯胺N-(3-氟-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺N-(3-氯-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺N-(2-氯-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺N-(3-甲基-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺N-(2-甲基-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺N-(2-甲氧基-4-(1H-吡唑-4-基)苯基)-3-苯基丙醯胺3-甲氧基-N-苯乙基-4-(1H-吡唑-4-基)苯甲醯胺N-(3-甲氧基-4-(噁唑-5-基)苯基)-3-甲基-3-苯基丁醯胺N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-甲基-3-苯基丁醯胺N-(4-(1H-吡唑-4-基)苯基)-3-甲基-3-苯基丁醯胺N-(3-甲氧基-4-(吡啶-4-基)苯基)-3-甲基-3-苯基丁醯胺N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-苯基丁醯胺3-(4-氯苯基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-甲基丁醯胺3-羥基-N-(3-甲氧基-4-(噁唑-5-基)苯基)-3-苯基丁醯胺N-(4-(1H-吡唑-4-基)苯基)-3-(4-氯苯基)-3-甲基丁醯胺3-(3-氯苯基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-甲基丁醯胺N-(4-(1H-吡唑-4-基)苯基)-3-(3-氯苯基)-3-甲基丁醯胺3-(2-氯苯基)-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-甲基丁醯胺N-(4-(1H-吡唑-4-基)苯基)-3-(2-氯苯基)-3-甲基丁醯胺3-羥基-N-[4-(1,3-噁唑-5-基)苯基]-3-苯基丁醯胺 3-羥基-N-(3-甲氧基-4-(1H-吡唑-4-基)苯基)-3-苯基丁醯胺或N-(4-(1H-吡唑-4-基)苯基)-3-羥基-3-苯基丁醯胺。 The compound of claim 14, wherein the compound is N-(3-methoxy-4-(oxazol-5-yl)phenyl)-3-phenylpropanamine N-(3-methoxy 4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamine 3-(4-chlorophenyl)-N-(3-methoxy-4-(1H-pyrazole) 4-yl)phenyl)propanamine 3-(3-chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)propanamine 3-(2 -Chlorophenyl)-N-(3-methoxy-4-(oxazol-5-yl)phenyl)propanamine N-(3-methoxy-4-(pyridin-4-yl)benzene 3-phenylpropionamide N-(4-(1H-pyrazol-4-yl)phenyl)-3-(2-chlorophenyl)propanamine N-(4-(1H-pyridyl) Zin-4-yl)phenyl)-3-(3-chlorophenyl)propanamine N-(4-(1H-pyrazol-4-yl)phenyl)-3-(4-chlorophenyl) Propionamide N-(3-fluoro-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamine N-(3-chloro-4-(1H-pyrazole-4- Phenyl)-3-phenylpropionamide N-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide N-(3-methyl 4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamide N-(2-methyl-4-(1H-pyrazol-4-yl)phenyl)-3- Phenylpropionamide N-(2-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-phenylpropanamine 3-methoxy-N-phenylethyl-4 -(1H-pyrazol-4-yl)benzamide N-(3-methoxy-4-(oxazol-5-yl)phenyl )-3-methyl-3-phenylbutyramine N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-methyl-3-phenylbutane Amine N-(4-(1H-pyrazol-4-yl)phenyl)-3-methyl-3-phenylbutyramine N-(3-methoxy-4-(pyridin-4-yl) Phenyl)-3-methyl-3-phenylbutyramine N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-phenylbutyramine 3- (4-Chlorophenyl)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-methylbutanamine 3-hydroxy-N-(3-A Oxy-4-(oxazol-5-yl)phenyl)-3-phenylbutyramine N-(4-(1H-pyrazol-4-yl)phenyl)-3-(4-chlorobenzene 3-methylbutyramine 3-(3-chlorophenyl)-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-methylbutyl Indoleamine N-(4-(1H-pyrazol-4-yl)phenyl)-3-(3-chlorophenyl)-3-methylbutyramine 3-(2-chlorophenyl)-N- (3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-methylbutanamine N-(4-(1H-pyrazol-4-yl)phenyl)-3 -(2-chlorophenyl)-3-methylbutyramine 3-hydroxy- N- [4-(1,3-oxazol-5-yl)phenyl]-3-phenylbutanamine 3- Hydroxy-N-(3-methoxy-4-(1H-pyrazol-4-yl)phenyl)-3-phenylbutyramine or N-(4-(1H-pyrazol-4-yl) Phenyl)-3-hydroxy-3-phenylbutyramine. 一種製造如請求項1至15中任一項之式I-1或I-2化合物之方法，該方法包含a)使下式化合物 與下式化合物 在EDC或HATU存在下反應得到下式化合物 其中定義如上文所述，或b)使下式化合物 與下式化合物 在EDC或HATU存在下反應得到下式化合物 其中取代基如上文所述， 且必要時使所獲得之該等化合物轉化為醫藥學上可接受之酸加成鹽。 A method of producing a compound of the formula I-1 or I-2 according to any one of claims 1 to 15, which comprises a) a compound of the formula Compound with Reaction in the presence of EDC or HATU to give a compound of the formula Wherein the definition is as described above, or b) the compound of the formula Compound with Reaction in the presence of EDC or HATU to give a compound of the formula Wherein the substituents are as described above, and if necessary, the obtained compounds are converted into pharmaceutically acceptable acid addition salts. 如請求項1至15中任一項之化合物，其係藉由如請求項16之方法製造。 The compound of any one of claims 1 to 15 which is produced by the method of claim 16. 一種醫藥組合物，其包含如請求項1至15中任一項之化合物及醫藥學上可接受之載劑及/或佐劑。 A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier and/or adjuvant. 一種醫藥組合物，其包含如請求項1至15中任一項之化合物及醫藥學上可接受之載劑及/或佐劑，其係用於治療精神***症、強迫性人格障礙、抑鬱症、躁鬱症、焦慮症、正常衰老、癲癇症、視網膜變性、創傷性腦損傷、脊髓損傷、創傷後壓力症、恐慌症、帕金森氏病(Parkinson's disease)、癡呆症、阿茲海默氏病(Alzheimer's disease)、輕度認知障礙、化學療法誘發之認知功能障礙(「化療腦(chemobrain)」)、唐氏症候群(Down syndrome)、自閉症譜系障礙、聽力損失、耳鳴、脊髓小腦失調、肌萎縮性側索硬化症、多發性硬化症、亨廷頓氏病(Huntington's disease)、中風及因放射線療法引起之紊亂、慢性壓力、視神經病或黃斑部變性，或諸如酒精、鴉片劑、甲基***(methamphetamine)、苯環利定(phencyclidine)或***(***e)之神經活性藥物濫用。 A pharmaceutical composition comprising a compound according to any one of claims 1 to 15 and a pharmaceutically acceptable carrier and/or adjuvant for the treatment of schizophrenia, obsessive-compulsive disorder, depression , bipolar disorder, anxiety, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease (Alzheimer's disease), mild cognitive impairment, chemo-induced cognitive dysfunction ("chemobrain"), Down syndrome, autism spectrum disorder, hearing loss, tinnitus, spine cerebellar disorders, Amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke and disorders caused by radiation therapy, chronic stress, optic neuropathy or macular degeneration, or such as alcohol, opiates, methamphetamine Abuse of neuroactive drugs (methamphetamine), phencyclidine or ***e. 如請求項1至15中任一項之化合物，其係用作治療活性物質。 The compound of any one of claims 1 to 15 for use as a therapeutically active substance. 如請求項1至15中任一項之化合物，其係用作治療以下疾病之治療活性物質：精神***症、強迫性人格障礙、抑鬱症、躁鬱症、焦慮症、正常衰老、癲癇症、視網膜變性、創傷性腦損傷、脊髓損傷、創傷後壓力症、恐慌症、帕金森氏病、癡呆症、阿茲海默氏病、輕度認知障礙、化學療法誘發之認知功能障礙(「化療腦」)、唐氏症候群、自閉症譜系障礙、聽力損失、 耳鳴、脊髓小腦失調、肌萎縮性側索硬化症、多發性硬化症、亨廷頓氏病、中風及因放射線療法引起之紊亂、慢性壓力、視神經病或黃斑部變性，或諸如酒精、鴉片劑、甲基***、苯環利定或***之神經活性藥物濫用。 A compound according to any one of claims 1 to 15 for use as a therapeutically active substance for the treatment of schizophrenia, obsessive-compulsive disorder, depression, bipolar disorder, anxiety, normal aging, epilepsy, retina Degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognitive impairment, chemo-induced cognitive dysfunction ("chemotherapy brain") ), Down syndrome, autism spectrum disorder, hearing loss, Tinnitus, spinal cerebellar dysregulation, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke and disorders caused by radiation therapy, chronic stress, optic neuropathy or macular degeneration, or such as alcohol, opiates, nails Abuse of neuroactive drugs with genotypes, phencyclidine or ***e. 一種如請求項1至15中任一項之化合物之用途，其係用於製備用以治療性及/或預防性治療以下疾病之藥劑：精神***症、強迫性人格障礙、抑鬱症、躁鬱症、焦慮症、正常衰老、癲癇症、視網膜變性、創傷性腦損傷、脊髓損傷、創傷後壓力症、恐慌症、帕金森氏病、癡呆症、阿茲海默氏病、輕度認知障礙、化學療法誘發之認知功能障礙(「化療腦」)、唐氏症候群、自閉症譜系障礙、聽力損失、耳鳴、脊髓小腦失調、肌萎縮性側索硬化症、多發性硬化症、亨廷頓氏病、中風及因放射線療法引起之紊亂、慢性壓力、視神經病或黃斑部變性，或諸如酒精、鴉片劑、甲基***、苯環利定或***之神經活性藥物濫用。 Use of a compound according to any one of claims 1 to 15 for the preparation of a medicament for the therapeutic and/or prophylactic treatment of schizophrenia, obsessive-compulsive disorder, depression, bipolar disorder , anxiety, normal aging, epilepsy, retinal degeneration, traumatic brain injury, spinal cord injury, post-traumatic stress disorder, panic disorder, Parkinson's disease, dementia, Alzheimer's disease, mild cognitive impairment, chemistry Therapy-induced cognitive dysfunction ("chemotherapy brain"), Down's syndrome, autism spectrum disorder, hearing loss, tinnitus, spinocerebellar disorders, amyotrophic lateral sclerosis, multiple sclerosis, Huntington's disease, stroke And disorders caused by radiation therapy, chronic stress, optic neuropathy or macular degeneration, or neuroactive drug abuse such as alcohol, opiates, methamphetamine, phencyclidine or ***e.
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