TW200906818A - Chemical compounds - Google Patents

Abstract

The present invention relates to compounds of Formula (I): and to their salts, pharmaceutical compositions, methods of use, and methods for their preparation. These compounds provide a treatment for myeloproliferative disorders and cancer.

Description

Translated fromChinese

200906818 九、發明說明： 【發明所屬之技術領域】 本發明係關於新穎化合物，其醫藥組合物及使用方法。 此外本發明係關於治療與預防癌症之治療方法，及此等 化口物在藥劑製造上之用途，該藥劑係用於骨髓增生病症 與癌症之治療與預防。 【先前技術】 MK (與Janus有關聯之激酶）/stat (訊息轉導物與活化劑 或轉錄)發出訊息途徑係涉及多種過高增生性與癌症相關 k程包括免疫系統之細胞循環進展、細胞〉周零、血管生 成侵入、轉移及逃避（Haura等人，自然臨床實務腫瘤學， ’⑹’ 315_324，Vema等人，癌症與轉移回顧，獅3，22, 423-434)。 JAK族群係由四種非受體酪胺酸激酶Tyk2、JAK1、JAK2 及JAK3所組成’其在細胞活素-與生長因子所媒介之訊息轉 導中係扮次-項關鍵角色。結合至細胞表面受體之細胞 ’舌素及/或生長因子，係藉由自磷醯化作用，促進受體二聚 合作用’且幫助受體有關聯JAK之活化作用。'經活化之皿 會璘醯基化該受體，建立供含SH2功能部位之發出訊息蛋 白質，特別是蛋白質之STAT族群（STAT1、2、3、4、5a、5b 及6)用之停泊位置。受體結合之STAT本身係藉由jak碌酸基 =，促進其自受體解離，及後續二聚合作用，與移位至核。 1在核中，STAT會結合眶，且與其他轉錄因子協力以 ㈣許多基因之表現’包括-些基因’其係為細胞调零抑 133151 200906818 制劑（例如Bcl-XL、Mcl-l)與細胞循環調節劑（例如環素 D1/D2、c-myc) (Haura等人，自然臨床實務腫瘤學，2005，2(6)， 315-324 ; Vema 等人，癌症與轉移回顧，2003, 22, 423-434)。 於過去十年來，已發表相當大量科學文獻，將構成JAK 及/或STAT發出訊息與過高增生性病症及癌症連結。STAT 族群之構成活化作用，特別是STAT3與STAT5，已在廣範圍 癌症與過高增生病症中被檢出（Haura等人，自然臨床實務 腫瘤學，2005, 2(6), 315-324) »再者，JAK/STAT途徑之迷行活化 作用係提供許多激酶（例如Flt3、EGFR)下游之重要增生及/ 或抗細胞凋零驅動力，其構成活化作用已在多種癌症與過 高增生病症中被牽連為主要驅動器（Tibes等人，Annu Rev Pharmacol Toxicol 2550, 45, 357-384 ; Choudhary 等人，國際金液學 期刊 2005, 82(2)，93-99; Sordella 等人，Science 2004, 305, 1163-1167)。 此外，負型調節蛋白質之損害，譬如細胞活素發出訊息 (SOCS)蛋白質之抑制劑，亦可影響JAK/STAT發出訊息途徑在 疾病中之活化作用狀態（JC Tan與Rabkin R,兒科腎病學，2005, 20, 567-575)。 JAK2之數種突變形式已在多種疾病環境中被確認。例如， 會造成JAK2激酶功能部位與募聚合功能部位融合之移位作 用，TEL-JAK2、Bcr-JAK2及PCM1-JAK2，已被牽連在各種血 液學惡性病症之發病原理上（SD Turner與Alesander DR,白血 病，2006, 20, 572-582)。最近，一種會使JAK2中之纈胺酸-對-苯丙胺酸（V617F)取代編碼之獨特後天突變型，係在可觀數 目之真性紅企球增多症、自發性企小板增多症及原發性骨 133151 200906818 髓纖維變性病患中檢出，而在數種其他疾病中達較少程度。 突變JAK2蛋白質係能夠於細胞活素刺激不存在下活化下游 發出訊息，而造成自律生長及/或對細胞活素之過敏性，且 咸認在驅動此等疾病上扮演一項角色（MJ Percy與McMullin MF,血液學腫瘤學 2005, 23(3-4)，91-93)。 退變淋巴瘤激酶（ALK)為在染色體2p23上被ΙίΧ基因編碼 之200kd受體酪胺酸激酶。ALK係歸屬於胰島素受體超族群。 ALK之正常表現係緊密地被控制，且受限於睪丸、腸之神 經節細胞及神經組織。此功能並未充分被明瞭，因無ALK 之老鼠顯示正常表現型，但是，最新資料指出ALK係涉及 神經元細胞分化與再生作用、胞突接合形成及肌細胞潛移。 ALK最初係在與一些大細胞淋巴退變瘤（ALCL)有關聯之 染色體移位作用中被確認。大約50-60%之情況係與t(2;2) (p23;q35)染色體移位作用有關聯，其係產生雜種基因，包含 與核填素（nucleophosmin)(NPM)並列之ALK酷·胺酸激酶受體之 胞内功能部位，該核磷素為一種涉及穿梭核糖核蛋白之核 仁蛋白質。所形成之融合蛋白質NPM-ALK具有構成激酶活 性，且於活體外轉變多種不滅細胞系，及在活體内藉由控 制主要細胞過程，譬如細胞循環進展、生存、細胞潛移及 細胞成形，以支持腫瘤形成（Chiarle等人，Nature Reviews Cancer， 8 : 11-23, 2008)。同樣地，在轉基因老鼠中，藉由CD4啟動子 所驅動之NPM-ALK表現會造成多重來源之強勢淋巴瘤之發 展。數種發出訊息途徑係牽連NPM-ALK陽性ALCL之發病。 NPM-ALK已被証實會活化轉錄之訊息轉導物與活化劑 133151 200906818 (STAT)族群之數個成員’包括STAT3與STAT5，以及磷脂酶C-7*與PI3-激酶/AKT途徑。 其他ALK融合配對物，除了 CD30-陰性擴散大細胞淋巴瘤 之外，已被報告於ALCL中’惟具有較低頻率。ALK融合蛋 白質亦已在炎性肌成纖維細胞腫瘤、食管鱗狀細胞癌瘤中 被檢出，而又最近係在大約6%非小細胞肺癌（NSCLC)中被檢 出（Soda 等人，Nature, 448 : 561-566, 2007)。在 NSCLC 中，係首先 確認一種新穎移位作用，其中在染色體2p内之小轉化係造 成形成融合基因，其包含棘皮動物微管有關聯蛋白質狀4 (EML4)之部份，與ALK基因。此融合蛋白質在老鼠3T3成纖 維細胞中之表現，會造成在老鼠之培養物與腫瘤中產生經 轉變之病灶。ALK抑制劑亦已經報告會於活體外與活體内 抑制含有EML4-ALK蛋白質融合物之一些NSCLC細胞之生長 (McDermott 等人，Cancer Res. 68 : 3389-3395, 2008 ; Koivunen 等人， AACR年會2008)。其他融合配對物亦已在NSCLC中報告或提 出（Rikova 等人，Cell 131 : 1190-1203, 2007 ; Pemer 等人，贅瘤形 成 10 : 298-302, 2008)。 ALK之迷行表現可代表ALK活化作用之替代機制，其可 助長腫瘤生成。全長ALK之迷行不規則表現及/或擴大已被 記載於B細胞NHL甲，於神經系統衍生之人類癌細胞系與原 發性腫瘤中，包括神經胚細胞瘤、神經膠質母細胞瘤及視 網膜胚細胞瘤，衍生自外胚層來源之固態腫瘤之細胞系， 該固態腫瘤包括黑色素瘤與乳房癌及NSCLC (Chiarle等人， Nature Reviews Cancer，8 : 11-23, 2008)。 133151 200906818 【發明内容】200906818 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to novel compounds, pharmaceutical compositions thereof and methods of use thereof. Further, the present invention relates to a method for treating and preventing cancer, and the use of such a substance in the manufacture of a medicament for the treatment and prevention of myeloproliferative disorders and cancer. [Prior Art] MK (Janus-associated kinase)/stat (information transducer and activator or transcription) signaling pathway involves a variety of hyperproliferative and cancer-related k-paths including cell cycle progression of the immune system, cells 〉Zhou zero, angiogenesis invasion, metastasis and escape (Haura et al., Natural Clinical Practice Oncology, '(6)' 315_324, Vema et al., Cancer and Metastasis Review, Lions 3, 22, 423-434). The JAK group consists of four non-receptor tyrosine kinases, Tyk2, JAK1, JAK2, and JAK3, which play a minor role in the cytokine- and growth factor-mediated message transduction. The cells that bind to the cell surface receptors, 'the phage and/or growth factor, promote receptor dimerization by self-phosphorylation' and help the receptor to be associated with the activation of JAK. 'The activated dish will thiolize the receptor and establish a docking position for the signaling protein containing the SH2 functional site, especially the STAT group of proteins (STAT1, 2, 3, 4, 5a, 5b and 6). . The receptor-bound STAT itself promotes its self-receptor dissociation, and subsequent dimerization, and shifts to the nucleus by the jak acid group. 1 In the nucleus, STAT binds to 眶 and cooperates with other transcription factors to (4) the performance of many genes 'including some genes' which are cell-regulated 133151 200906818 preparations (eg Bcl-XL, Mcl-1) and cells Circulatory modulators (eg, cyclin D1/D2, c-myc) (Haura et al., Nature Clinical Practice Oncology, 2005, 2(6), 315-324; Vema et al., Cancer and Metastasis Review, 2003, 22, 423-434). Over the past decade, a considerable amount of scientific literature has been published that will link JAK and/or STAT messages to hyperproliferative disorders and cancer. Activation of the STAT population, particularly STAT3 and STAT5, has been detected in a wide range of cancers and hyperproliferative disorders (Haura et al., Nature Clinical Practice Oncology, 2005, 2(6), 315-324) » Furthermore, the aberrant activation of the JAK/STAT pathway provides important proliferation downstream of many kinases (eg, Flt3, EGFR) and/or anti-cell dysfunction, which has been activated in a variety of cancers and hyperproliferative disorders. Implicated as the primary driver (Tibes et al., Annu Rev Pharmacol Toxicol 2550, 45, 357-384; Choudhary et al., International Journal of Liquid Chemistry 2005, 82(2), 93-99; Sordella et al., Science 2004, 305, 1163-1167). In addition, negative-regulated protein damage, such as inhibitors of cytokine signaling (SOCS) proteins, can also affect the activation of JAK/STAT signaling pathways in disease (JC Tan and Rabkin R, Pediatric Nephrology, 2005, 20, 567-575). Several mutant forms of JAK2 have been identified in a variety of disease settings. For example, STR-JAK2, Bcr-JAK2, and PCM1-JAK2, which are involved in the dysfunction of JAK2 kinase functional sites, have been implicated in the pathogenesis of various hematological malignancies (SD Turner and Alesander DR). , Leukemia, 2006, 20, 572-582). Recently, a unique acquired mutant that encodes a proline-p-phenylalanine (V617F) substitution in JAK2 is associated with a significant number of true red globulins, spontaneous stenosis, and primary Bone 133151 200906818 was detected in patients with myelin degeneration, but to a lesser extent in several other diseases. The mutant JAK2 protein line is capable of signaling downstream activation in the absence of cytokine stimulation, resulting in autonomous growth and/or cytokine sensitization, and suspicion plays a role in driving these diseases (MJ Percy and McMullin MF, Hematology Oncology 2005, 23(3-4), 91-93). Degenerative lymphoma kinase (ALK) is a 200 kd receptor tyrosine kinase encoded by the ΙίΧ gene on chromosome 2p23. The ALK family is assigned to the insulin receptor supergroup. The normal expression of ALK is tightly controlled and is limited by the testis cells, the ganglion cells of the intestines, and the nervous tissues. This function is not fully understood, as mice without ALK show normal phenotype, but recent data indicate that ALK is involved in neuronal cell differentiation and regeneration, cell formation and myocyte migration. ALK was originally identified in chromosomal translocation associated with some large cell lymphoid degeneration tumors (ALCL). Approximately 50-60% of the cases are associated with t(2;2) (p23;q35) chromosomal translocation, which produces a hybrid gene containing ALK cool amines juxtaposed with nucleophosmin (NPM) The intracellular functional site of the acid kinase receptor, a nuclear protein involved in the shuttle ribonucleoprotein. The resulting fusion protein NPM-ALK has kinase activity and transforms multiple immortal cell lines in vitro, and supports in vivo by controlling major cellular processes such as cell cycle progression, survival, cell migration, and cell formation. Tumor formation (Chiarle et al, Nature Reviews Cancer, 8: 11-23, 2008). Similarly, in transgenic mice, NPM-ALK expression driven by the CD4 promoter causes the development of multiple sources of strong lymphoma. Several signaling pathways are implicated in the pathogenesis of NPM-ALK-positive ALCL. NPM-ALK has been shown to activate transcriptional message transducers and activators 133151 200906818 (STAT) population of several members' including STAT3 and STAT5, as well as phospholipase C-7* and PI3-kinase/AKT pathways. Other ALK fusion partners, except for CD30-negatively diffuse large cell lymphoma, have been reported in ALCL with only lower frequencies. ALK fusion proteins have also been detected in inflammatory myofibroblastic tumors, esophageal squamous cell carcinomas, and recently detected in approximately 6% of non-small cell lung cancer (NSCLC) (Soda et al., Nature , 448: 561-566, 2007). In NSCLC, a novel translocation effect was first identified in which a small transformation line within chromosome 2p resulted in the formation of a fusion gene comprising a portion of Echinoderm microtubules associated with proteinaceous 4 (EML4), and the ALK gene. The expression of this fusion protein in mouse 3T3 fibroblasts results in a transformed lesion in cultures and tumors in mice. ALK inhibitors have also been reported to inhibit the growth of some NSCLC cells containing EML4-ALK protein fusions in vitro and in vivo (McDermott et al, Cancer Res. 68: 3389-3395, 2008; Koivunen et al., AACR Annual Meeting) 2008). Other fusion partners have also been reported or raised in NSCLC (Rikova et al, Cell 131: 1190-1203, 2007; Pemer et al., Tumor Formation 10: 298-302, 2008). The awkward performance of ALK represents an alternative mechanism of ALK activation that can contribute to tumor formation. Irregular manifestations and/or enlargement of full-length ALK have been documented in B-cell NHL A, in neuronal-derived human cancer cell lines and primary tumors, including neuroblastoma, glioblastoma, and retina A blastoma, a cell line derived from a solid tumor derived from ectodermal, including melanoma and breast cancer and NSCLC (Chiarle et al., Nature Reviews Cancer, 8: 11-23, 2008). 133151 200906818 [Summary content]

或其藥學上可接受之鹽。 預期典型式（I)化合物具有有利之有效性、代謝及/或藥效 性質。 成^、型式（I)化合物具有JAK激酶抑制活性，且因此可 :於其抗増生及/或前細胞祠零活性，及人類或動物身體之 /療方法中。本發明亦關於製造該化合物或其藥學上可接 方法3有彼等之醫藥組合物，及其在藥劑製造上 i.. :用途，以在溫血動物譬如人類中，產生抗增生及/或前細 月匕凋零作用。而且，根據本發明，申d A 合物或其藥學上可接…，二供使用該化 發育不良徵候襄及癌症之方*。 爾 她合物之性質，於治療骨髓增生病症、脊髓發 :酶及癌症上是有價值的，其方式是抑制路胺酸 、】疋胤族群，且更特JAK2 路胺酸激酶活性為標的，特別a璧㈣壬祕 係以 B 竹⑴疋JAK私群活性，且更肚 疋K2活性，其係涉及多種骨髓增生病症、脊髓發育不良 133151 10 200906818 徵候簇及癌症相關過程。因&，預祕胺酸激酶，特別是 MK知群且更特別是ίΑΚ2之抑制劑，係具有抵抗骨髓増生 病症之活性，譬如慢性髓樣白血病、真性紅血球增多症、 自發性血小板增多纟、伴隨著骨髓纖維變性之髓樣化生、 原發性骨髓纖維變性、慢性骨髓單核血球白血病與嗜伊紅 ，血球過多症徵候簇、脊髓發育不良徵候簇及贅瘤疾病， 譬如孔房、卵巢、肺臟、結腸、前列腺或其他組織之癌症， 以及白血病、骨髓細胞瘤及淋巴瘤，中樞與末梢神經系統 之腫瘤’ Α其他腫瘤類型’譬如黑色素瘤、纖維肉瘤及骨 肉瘤。亦預期㈣酸激酶抑制劑，特別是皿族群抑制劑， 且更特別是JAK2抑制劑，可用於治療其他增生疾病，包括 自身免疫、炎性、神經病及心血管疾病。 私再者，職式(I)化合物或其藥學上可接受之鹽，在抵抗 骨髓增生病症之治療或預防上是有價值的，該病症選自慢 性髓樣白血病 '真性紅血球增多症、自發性血小板增多症、Or a pharmaceutically acceptable salt thereof. The compounds of formula (I) are expected to have advantageous potency, metabolic and/or pharmacodynamic properties. The compound of the formula (I) has JAK kinase inhibitory activity, and thus can be used in its anti-tuberculosis and/or pro-cell 祠 zero activity, and in human or animal body/treatment methods. The invention also relates to the manufacture of the compound or a pharmaceutically acceptable method thereof, to a pharmaceutical composition thereof, and to the use thereof in the manufacture of a medicament for the production of anti-proliferation and/or in a warm-blooded animal such as a human. Before the fine moon 匕 匕 作用. Moreover, according to the present invention, the compound or its pharmaceutically acceptable substance is used for the purpose of the developmental dysplasia and cancer*. The nature of her compound is valuable in the treatment of myeloproliferative disorders, spinal cord: enzymes and cancer, in the form of inhibition of glutamate, sputum group, and more specific JAK2 glutamate kinase activity. In particular, a 璧 (4) 壬 secret system is B (1) 疋 JAK private group activity, and more intestine K2 activity, which is related to a variety of myeloproliferative disorders, spinal dysplasia 133151 10 200906818 syndrome and cancer-related processes. Because of &, pre-aminic acid kinases, particularly MK-known and more particularly inhibitors of ΑΚ2, are active against bone marrow atrophy, such as chronic myeloid leukemia, polycythemia vera, spontaneous thrombocytopenia, Myeloid metaplasia with bone marrow fibrosis, primary myelofibrosis, chronic bone marrow mononuclear leukemia and eosinophilia, hyperglobulin syndrome, spinal dysplasia syndrome and neoplastic disease, such as the chamber, ovary , cancer of the lungs, colon, prostate or other tissues, as well as leukemia, myeloma and lymphoma, tumors of the central and peripheral nervous system 'Α other tumor types' such as melanoma, fibrosarcoma and osteosarcoma. It is also contemplated that (iv) acid kinase inhibitors, particularly dish group inhibitors, and more particularly JAK2 inhibitors, can be used to treat other proliferative diseases, including autoimmune, inflammatory, neurological, and cardiovascular diseases. In addition, the compound of the formula (I) or a pharmaceutically acceptable salt thereof is valuable in the treatment or prevention against a myeloproliferative disorder selected from the group consisting of chronic myeloid leukemia 'true erythrocytosis, spontaneous Thrombocytopenia,

:隨著骨髓纖維變性之髓樣化生、原發性骨髓纖維變性、 慢，骨髓單核血球白血病與嗜伊紅性血球過多症徵候藤、 脊髓發月不良徵候簇’及癌症，選自食管癌、骨髓細胞瘤， 肝細胞、月夷、子宮頸癌，尤汉氏肉瘤、神經胚細胞瘤、卡 波西氏肉瘤、印巢癌、乳癌、結腸直腸癌、前列腺癌、膀 Μ '黑色素瘤'肺癌_非小細胞肺癌（NSCLQ與小細胞肺 ’（SCLC)、胃癌、頭部與頸部癌、間皮瘤、腎癌、淋巴瘤 ^白金病；特別是骨髓細胞瘤、白血病、#巢癌、乳癌及 月1J列腺癌。 133151 -11- 200906818 發明詳述 本發明係關於式（I)化合物：: with myelofibrosis of myelofibrosis, primary myelofibrosis, slow, bone marrow mononuclear leukemia and eosinophilic stagnation vines, spinal cord dystrophic syndrome 'and cancer, selected from the esophagus Cancer, myeloid cell tumor, liver cell, stagnation, cervical cancer, Youhan's sarcoma, neuroblastoma, Kaposi's sarcoma, Indian cancer, breast cancer, colorectal cancer, prostate cancer, bladder 'melanoma 'Lung cancer _ non-small cell lung cancer (NSCLQ and small cell lung ' (SCLC), gastric cancer, head and neck cancer, mesothelioma, kidney cancer, lymphoma ^ platinum disease; especially myeloma, leukemia, #巢Cancer, breast cancer, and adenocarcinoma of the month 1J. 133151 -11- 200906818 DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a compound of formula (I):

或其藥學上可接受之鹽，其中： 環A可為雜環基中該雜環基可視情況在碳上被一或多 個R取代’且其中該雜環基之任何_NH_部份基團可視情況 被R2#取代； 環B可選自碳環基與雜環基，其中該碳環基與雜環基可視 情況在碳上被-或多個R4取代，且其中該雜環基之任何 -NH-部份基團可視情況被R4*取代； X 可選自-Ο-、-NH-及-S-; β可選自H'mN、Ci.6烧基、h烯基、CM块基、 碳環基、雜環基、_QRU、_SRla、_N(Rla)2、_N(Rla)c(〇)Rib、 -N(Rla)N(Rla)2、_Nq2、_N(Rla)QRla、⑽(r、、_c(〇)H、 C(0)R > -C(0)2Ria , -C(0)N(Rla)2 . -C(0)N(Rla)(〇Ria), 0C(0)N(R )2、_N(Ria)c(Q)2Rla、_N(Ria)c(〇)N(Ria)2、 0C(0)R、_S(Q)R b、_s⑼2 Rl b、_S(Q)2 n(r1 a )2、_罐〗& )s(〇)2 ^ b、 -C(R^)=N(Ria)A.C(Rla)=N(〇Rla) , ^ t ^ C2 6^ 基A_6炔基*反％基及雜環基可視情況在碳上被一或多 133151 200906818 個R取代，且其中該雜環基之任何-簡·部份基團可視情況 被R1 G111取代； R，於各存在處’可獨立選自Η、。卜6烷基、碳環基及雜 %基’其中该（：卜6炫基、碳環基及雜環基，於各存在處， 可視情況且獨立地在碳上被一或多個Rl〇取代，且其中該雜 環基之任何-NH-部份基團可視情況被Rl()*取代；Or a pharmaceutically acceptable salt thereof, wherein: ring A may be a heterocyclic group which may optionally be substituted on the carbon by one or more R' and wherein any _NH_ moiety of the heterocyclic group The group may be optionally substituted by R2#; ring B may be selected from a carbocyclic group and a heterocyclic group, wherein the carbocyclic group and the heterocyclic group may be optionally substituted on the carbon by - or a plurality of R4, and wherein the heterocyclic group Any -NH- moiety may be optionally substituted by R4*; X may be selected from -Ο-, -NH- and -S-; β may be selected from H'mN, Ci.6 alkyl, h-alkenyl, CM Block group, carbocyclic group, heterocyclic group, _QRU, _SRla, _N(Rla)2, _N(Rla)c(〇)Rib, -N(Rla)N(Rla)2, _Nq2, _N(Rla)QRla, (10) (r, _c(〇)H, C(0)R > -C(0)2Ria , -C(0)N(Rla)2 . -C(0)N(Rla)(〇Ria), 0C(0)N(R )2, _N(Ria)c(Q)2Rla, _N(Ria)c(〇)N(Ria)2, 0C(0)R, _S(Q)R b, _s(9)2 Rl b , _S(Q)2 n(r1 a )2, _ canister & )s(〇)2 ^ b, -C(R^)=N(Ria)AC(Rla)=N(〇Rla) , ^ t ^ C2 6^ Group A_6 alkynyl group *invertyl group and heterocyclic group may be optionally substituted on the carbon by one or more 133151 200906818 R, and any -succinic group of the heterocyclic group may be Substituted R1 G111; R, at each occurrence 'may be independently selected Η ,. a 6-alkyl group, a carbocyclic group, and a hetero-based group wherein the (:6, cyclyl, carbocyclyl and heterocyclic groups, in each presence, optionally and independently on the carbon, are one or more R1〇 Substituted, and wherein any -NH- moiety of the heterocyclic group is optionally substituted by Rl()*;

Rlb，於各存在處，可選自Ci_6炫基、C2 6稀基、CM块基、 r碳環基及料基，其巾該Cl.6絲、C2 6烯基、C2 6快基、 碳環基及雜環基，於各存在處，可視情況且獨立地在碳上 被一或多個R10取代，且其中該雜環基之任何部份基團 可視情況被R1 G *取代； R2可選自H、鹵基、_CN、C卜6烷基、C2-6烯基、。2_6炔基、 礙環基、雜環基、_〇R2a、_SR2a、_N(R2a)2、_N(R2a)c(〇)R2b、 -N(R a)N(R2a)2 > -N〇2 s -N(R2a)〇R2a N -〇N(R2a)2 ^ -C(0)H ^ -C(0)R2b ^ -C(0)2R2a , -C(〇)N(R2a)2 ^ -C(0)N(R2a)(〇R2a). 1, 〇C(〇)N(R2 a )2、_N(R2 a )c(0)2 R2 a、-N(R2 a )C(0)N(r2 a )2、_〇c(〇)r2 b ' -S(0)R2b . -S(〇)2R2b . -S(〇)2N(R2a)2 , -N(R2 a )S(〇)2 R2 b , ”N(R力及_c(R2a)哪R2a)，其中該烧基、婦 基、C2_6炔基、碳環基及雜環基可視情況在碳上被一或多 個R20取代，且其中該雜環基之任何福-部份基團可視情況 被R2G*取代； 於各存在處，可獨立選自Ci 6烷基、碳環基、雜環基、 C(0)H -C(0)R > -C(0)2 R2 c n .C(〇)N(R2 a )2 ' -S(0)R2 b Λ _S(〇)2 R2 b > -S(0)2N(R2a)2、-C(R2a)=N(R2a^_c(R2a)=N(〇R2a)，其中該 Ci_6 133151 •13- 200906818 烷基、碳環基及雜環基，於各 ,^ 仔在處可視情況且獨立地 在反上被-或多個F取代’且其中該雜環基之任何姻 伤基團可視情況被R2 0 *取代；Rlb, in each of the presences, may be selected from the group consisting of Ci-6 thiol, C6 6 dilute, CM block, r carbocyclic and base, and the Cl.6 filament, C2 6 alkenyl, C2 6 fast radical, carbon The cyclic group and the heterocyclic group are optionally substituted on the carbon by one or more R10 at each position, and wherein any part of the heterocyclic group may be optionally substituted by R1 G*; It is selected from the group consisting of H, halo, _CN, C 6 alkyl, C 2-6 alkenyl. 2_6 alkynyl, hindered cyclic, heterocyclic, 〇R2a, _SR2a, _N(R2a)2, _N(R2a)c(〇)R2b, -N(R a)N(R2a)2 > -N〇 2 s -N(R2a)〇R2a N -〇N(R2a)2 ^ -C(0)H ^ -C(0)R2b ^ -C(0)2R2a , -C(〇)N(R2a)2 ^ -C(0)N(R2a)(〇R2a). 1, 〇C(〇)N(R2 a )2, _N(R2 a )c(0)2 R2 a, -N(R2 a )C(0 N(r2 a )2, _〇c(〇)r2 b ' -S(0)R2b . -S(〇)2R2b . -S(〇)2N(R2a)2 , -N(R2 a )S( 〇) 2 R2 b , "N (R force and _c(R2a) which R2a), wherein the alkyl group, the banyl group, the C2_6 alkynyl group, the carbocyclic group and the heterocyclic group may optionally be one or more on the carbon R20 is substituted, and wherein any of the Fu-partic groups of the heterocyclic group may be optionally substituted by R2G*; at each position, independently selected from Ci 6 alkyl, carbocyclyl, heterocyclyl, C(0) H -C(0)R > -C(0)2 R2 cn .C(〇)N(R2 a )2 ' -S(0)R2 b Λ _S(〇)2 R2 b > -S(0 2N(R2a)2, -C(R2a)=N(R2a^_c(R2a)=N(〇R2a), wherein the Ci_6 133151 •13- 200906818 alkyl group, carbocyclic group and heterocyclic group, ^ Aberdeen may be optionally replaced by - or a plurality of F's in the opposite case and wherein any of the heterocyclic groups of the heterocyclic group may be R2 0 as appropriate *replace;

Ra，於各存在處，可獨立選自H、 卢I ^ 卜6況基 基及雜 環基，其中該q.6縣、碳環基及雜環基，於各存在處， 可視情況且獨立地在碳上被_或多個R2G取代，且其^雜 環基之任何-NH-部份基團可視情況被R2 G *取代； 'Ra, in each presence, may be independently selected from the group consisting of H, Lu I ^ 6 and a heterocyclic group, wherein the q.6 county, carbocyclyl and heterocyclic group, in each presence, may be independent and independent The ground is substituted with _ or more R 2 G on the carbon, and any -NH- moiety of the heterocyclyl group may be optionally substituted by R 2 G *;

於各存在處，可選自Cl.6院基、C2 6烯基、eh块基 碳環基及雜環基，其中該。·6烷基、C2·6烯基、c2 6炔基、 厌％基及雜％基，於各存在處，可視情況且獨立地在碳上 被一或多個R20取代，且其中該雜環基之任何-NH-部份^團 可視情況被R20*取代； 土 R2c，於各存在處，可獨立選自c]—烷基、碳環基及雜環基， 其中該q—6烷基、碳環基及雜環基，於各存在處，可視情 況且獨立地在碳上被一或多個尺2〇取代，且其中該雜環基之 任何-ΝΉ-部份基團可視情況被R2 〇 *取代； R3可選自H、鹵基、_CN、C卜6烷基、C2_6烯基、c2_6炔基、 石厌續基、雜環基、-〇R3a、_SR3a、_N(R3a)2、_N(R3a)c(〇)R3b、 _N(R3a)N(R3a)2、_N〇2、_N(R3a)_〇R3a、_〇 N(R3a)2、_c(〇)h、 -C(〇)R3b . -C(0)2R3^ , -C(〇)N(R3a)2 ' -C(0)N(R3a)(〇R3a}. -〇C(〇)N(R3a)2 > -N(R3a)C(〇)2R3 , -N(R3a)C(0)N(R3a)2 , -〇C(〇)R3b ^ -S(0)R3b . -S(0)2R3b , -S(0)2N(R3a)2 ' -N(R3a)S(〇)2R3b . -C(Rh)=N(R3a)及 _c(R3a)=N(〇R3a)，其中該 烧基、A、稀 基、C2·6炔基、碳環基及雜環基可視情況在碳上被一或多 133151 -14- 200906818 個R3°取代’且其巾該雜環基之任何_NH•部份 被R3。*取代； "見障况 :3a ’於各存在處，可獨立選自H、Ci6烷基、碳環基及雜 環基，其中該Ch燒基、碳環基及雜環基，於各存在處， 可視情況且獨立地在碳上被一或多個r3〇取代，且其中=雜 環基之任何-NH-部份基團可視情況被r3G*取代； R3b，於各存在處，可選自Ci 6烧基、C2 6稀基、A、块基、 厂 碳裱基及雜環基，其中該。6烷基、q·6烯基、CM炔基、 碳環基及雜環基，於各存在處，可視情況且獨立地在碳上 被一或多個R3〇取代，且其中該雜環基之任何-NH-部份基團 可視情況被R30*取代； R4可選自Η、函基、_CN、q_6烧基、c2.6烯基、^块基、 碳環基、雜環基、-〇R4a、-SR4a、_N<R4a)2、_N(R4a)(：^R4b、In each of the presences, it may be selected from the group consisting of Cl.6, C2 6 alkenyl, eh block carbocyclyl and heterocyclyl. • a 6 alkyl group, a C 2·6 alkenyl group, a c 2 6 alkynyl group, an anisole group, and a hetero aryl group, optionally in each case, independently and independently substituted on the carbon by one or more R 20 , and wherein the heterocyclic ring Any -NH- moiety may be optionally substituted by R20*; the soil R2c, in each presence, may be independently selected from the group consisting of c]-alkyl, carbocyclyl and heterocyclyl, wherein the q-6 alkyl , carbocyclyl and heterocyclyl, at each occurrence, optionally and independently substituted on the carbon by one or more ampules, and wherein any -ΝΉ- moiety of the heterocyclic group may be R2 〇* substituted; R3 may be selected from H, halo, _CN, C6-6 alkyl, C2_6 alkenyl, c2_6 alkynyl, sulphate, heterocyclyl, -R3a, _SR3a, _N(R3a)2 , _N(R3a)c(〇)R3b, _N(R3a)N(R3a)2, _N〇2, _N(R3a)_〇R3a, _〇N(R3a)2, _c(〇)h, -C( 〇)R3b . -C(0)2R3^ , -C(〇)N(R3a)2 ' -C(0)N(R3a)(〇R3a}. -〇C(〇)N(R3a)2 > -N(R3a)C(〇)2R3 , -N(R3a)C(0)N(R3a)2 , -〇C(〇)R3b ^ -S(0)R3b . -S(0)2R3b , -S (0) 2N(R3a)2 ' -N(R3a)S(〇)2R3b . -C(Rh)=N(R3a) and _c(R3a)=N(〇R3a), wherein the alkyl group, A, Dilute base, C The 2·6 alkynyl group, the carbocyclic group and the heterocyclic group may be optionally substituted on the carbon by one or more 133151 -14-200906818 R3° and the _NH• moiety of the heterocyclic group is R3.* Substituting; "seeing a disorder: 3a' may be independently selected from H, Ci6 alkyl, carbocyclyl and heterocyclic groups, wherein the Ch alkyl group, the carbocyclic group and the heterocyclic group exist in each Wherein, optionally and independently, substituted on the carbon by one or more r3〇, and wherein any -NH- moiety of the heterocyclyl group may be optionally substituted by r3G*; R3b, optionally present, From Ci 6 alkyl, C 2 6 dilute, A, a block, a carbhydryl group and a heterocyclic group, wherein the 6 alkyl group, the q 6 alkenyl group, the CM alkynyl group, the carbocyclic group and the heterocyclic group, Where present, optionally and independently substituted on the carbon by one or more R 3 , and wherein any -NH- moiety of the heterocyclic group may be optionally substituted by R 30 *; R 4 may be selected from hydrazine, Chungyl group, _CN, q_6 alkyl group, c2.6 alkenyl group, ^ block group, carbocyclic group, heterocyclic group, -〇R4a, -SR4a, _N<R4a)2, _N(R4a)(:^R4b,

-N(R4a)N(R4a)2、-N〇2、-N(R,_〇R4a、_〇_n(R4”2、c(〇)H -C(0)R4b、-C(0)2R4a、_c(〇)N(R4a)2、_c(〇)N(R4a)(〇R4a)、 (;-〇C(0)N(R4a)2 ' -N(R4a)C(〇)2R4a . -N(R4a)C(0)N(R4a)2 ^ 0C(0)R4b、-S(〇)R4b、_S(〇)2R4b、_s(〇)2N(R4a)2、_N(R4a)s(〇)2R4b、 -C(R4a)=N(R4a)及-C(R4a)=N(〇R4a)，其中該Ci6 烧基、&_6稀 基、C2-6炔基、碳環基及雜環基可視情況在碳上被一或多 個R4 0取代’且其中該雜環基之任何-部份基團可視情況 被RW取代； R4，於各存在處’可獨立選自Ci _6烷基、碳環基、雜環基、 -C(0)H ' -C(0)R4b ^ -C(0)2R4c ^ -C(0)N(R4a)2 ' -S(0)R4b ^ -S(0)2R4b ' -S(0)2N(R4a)2、-C(R4a)=N(R4a)及-C(R4a)=N(OR4a)，其中該（V6 133151 •15- 200906818 烷基、妷％基及雜環基，於各 ^ ^ 存在處，可視情况且獨立地 在石厌上被一或多個R4〇取代， 獨立地 於贫闹 且其中該雜環基之任何-NH-邱 伤基團可視情況被R4〇*取代； Γ基於::广可獨立選自h、ci‘基、碳環㈣ ^ 4_6&基、碳環基及雜環基，於各存在處， 可視情況且獨立地在碳上被—或多個R4G取代，且其中該雜 %基之任何-NH-部份基團可視情況被R4G*取代；-N(R4a)N(R4a)2, -N〇2, -N(R,_〇R4a, _〇_n(R4"2, c(〇)H -C(0)R4b, -C(0 2R4a, _c(〇)N(R4a)2, _c(〇)N(R4a)(〇R4a), (;-〇C(0)N(R4a)2 '-N(R4a)C(〇)2R4a -N(R4a)C(0)N(R4a)2^0C(0)R4b, -S(〇)R4b, _S(〇)2R4b, _s(〇)2N(R4a)2, _N(R4a)s (〇) 2R4b, -C(R4a)=N(R4a) and -C(R4a)=N(〇R4a), wherein the Ci6 alkyl group, &_6 dilute group, C2-6 alkynyl group, carbocyclic group and The heterocyclic group may be optionally substituted on the carbon by one or more R.sup.4 and wherein any of the heterocyclic groups may be optionally substituted by RW; R4, at each position, may be independently selected from Ci-6 alkyl. , carbocyclyl, heterocyclyl, -C(0)H ' -C(0)R4b ^ -C(0)2R4c ^ -C(0)N(R4a)2 ' -S(0)R4b ^ - S(0)2R4b ' -S(0)2N(R4a)2, -C(R4a)=N(R4a) and -C(R4a)=N(OR4a), wherein (V6 133151 •15- 200906818 alkyl , 妷%, and heterocyclyl, in the presence of each ^^, optionally and independently, on the anthracene, substituted by one or more R4〇, independently of the stagnation and wherein any -NH- of the heterocyclic group The Qiu injury group can be replaced by R4〇* as the case may be; Γ based on:: Guang can be independently selected from h, ci' base, Carbocyclic (tetra) ^ 4_6 & base, carbocyclyl and heterocyclyl, in each presence, optionally and independently substituted on carbon by - or multiple R4G, and wherein any -NH- moiety of the hetero-group The group may be replaced by R4G* as appropriate;

於各存在處’可選自Ci 6燒基、C“烯基、C“块基、 石炭環基及雜環基，其中叫旧基U基、eh块基、 碳環基及雜環基，於久在太走 -r. | 不土於各存在處，可視情況且獨立地在碳上 被或夕個R取代，且其中該雜環基之任何-腿·部份基團 可視情況被R40*取代； 於各存在處，可獨立選自Ch烧基、碳環基及雜環基， 其中該C!·6烷基、碳環基及雜環基，於各存在處，可視情 況且獨立地在碳上被一或多個r4〇取代，且其中該雜環基之 任何-NH-部份基團可視情況被R4〇*取代； R10，於各存在處，可獨立選自鹵基、_CN、c〗_6烷基、C2_6 烯基、C2-6 炔基、碳環基、雜環基、_〇RlGa、_SRlGa、_N(RlGa)2、 -N(R10a)C(O)R10b、_N(R1()a)N(R10a)2、-N02、-N(R10a)-〇R10a、 _〇-N(R10a)2、-C(0)H、-C(O)R10b、-C(O)2R10a、-C(O)N(R10a)2、 -C(O)N(R10a)(OR10a) ^ -〇C(O)N(R10a)2 > -NCR1 0a)C(0)2R1 0a ^ -N(R10a)C(O)N(R10a)2、_OC(〇)Ri〇b、_s(〇)Ri〇b、_s(〇)2Rl0b、 -S(0)2N(R] 0a)2 、 -N(R10a)S(O)2Rl0b 、 -C(R10a)=N(R1()a)及 -C(R1()a)=N(OR1()a) ’ 其中該Cl_6烷基、C2-6烯基、C26 炔基、 133151 -16- 200906818 碳環基及雜環基，於各存在處，可視情況且獨立地在碳上 被-或多㈣取代’且其中該雜環基之任何.部份基團 可視情況被Ra*取代； 於各存在處，可獨立選自院基、碳環基、雜環基、 -C(0)H ^ -C(0)R-b ^ -C(0)2Ri〇c , .C(0)N(R-a)2 . _S(〇)Rl0b ^ -S(〇)2R^- >-S(0)2N(R-a)2 ^-C(R1 〇a)=N(Rl 〇a) A _C(RI 〇a)=N(〇Rl 0a) ’其中該CV6烧基、碳環基及雜環基，於各存在處，可視'wherein' may be selected from a Ci 6 alkyl group, a C "alkenyl group, a C" block group, a carbolic ring group and a heterocyclic group, which are called an old group U group, an eh block group, a carbocyclic group and a heterocyclic group.久久在走-r. | Not in each place, can be replaced by carbon or by R on the carbon, and any of the leg-partial groups of the heterocyclic group can be R40 as appropriate. *Substituted; at each position, independently selected from the group consisting of a C alkyl group, a carbocyclic group and a heterocyclic group, wherein the C!·6 alkyl group, a carbocyclic group and a heterocyclic group are optionally present and independent Substituted on the carbon by one or more r4〇, and wherein any -NH- moiety of the heterocyclic group may be optionally substituted by R4〇*; R10, in each presence, may be independently selected from halo, _CN, c _6 alkyl, C2_6 alkenyl, C2-6 alkynyl, carbocyclyl, heterocyclic, 〇RlGa, _SRlGa, _N(RlGa)2, -N(R10a)C(O)R10b, _N (R1()a)N(R10a)2, -N02, -N(R10a)-〇R10a, _〇-N(R10a)2, -C(0)H, -C(O)R10b, -C( O) 2R10a, -C(O)N(R10a)2, -C(O)N(R10a)(OR10a) ^ -〇C(O)N(R10a)2 > -NCR1 0a)C(0)2R1 0a ^ -N(R10a)C(O)N(R10a)2, _OC(〇)Ri〇b, _s(〇)Ri〇b, _s(〇)2Rl0b, -S(0)2N(R) 0a)2, -N(R10a)S(O)2Rl0b, -C(R10a)=N(R1()a And -C(R1()a)=N(OR1()a) ' wherein the Cl_6 alkyl group, the C2-6 alkenyl group, the C26 alkynyl group, the 133151-16-200906818 carbocyclic group and the heterocyclic group are each Where present, optionally and independently substituted on carbon by - or multiple (four) ' and wherein any of the heterocyclic groups may be optionally substituted by Ra*; in each presence, may be independently selected from the group, Carbocyclyl, heterocyclic, -C(0)H^-C(0)Rb^-C(0)2Ri〇c, .C(0)N(Ra)2 . _S(〇)Rl0b ^ -S (〇)2R^- >-S(0)2N(Ra)2 ^-C(R1 〇a)=N(Rl 〇a) A _C(RI 〇a)=N(〇Rl 0a) 'Where CV6 alkyl, carbocyclic and heterocyclic groups, visible at each location

情況且獨立地在碳上被一或多個Ra取代，且其十該雜環基 之任何-NH-部份基團可視情況被r3 *取代； R10a，於各存在處，可獨立選自H、Ci6燒基、碳環基及雜 環基，其中該。-6烷基、碳環基及雜環基，於各存在處， 可視情況且獨立地在碳上被一或多個Ra取代，且其中該雜 環基之任何-NH-部份基團可視情況被Ra*取代； R10b ’於各存在處，可獨立選自Cu烷基、烯基、。6 炔基、碳環基及雜環基’其中該Ci_6烷基、C2_6烯基、 炔基、碳環基及雜環基，於各存在處’可視情況且獨立2地6 在碳上被一或多個Ra取代，且其中該雜環基之任何__-部 份基團可視情況被Ra*取代； R10e’於各存在處，可獨立選自q_6烷基、碳環基及雜環基， 其中該烧基、碳環基及雜環基，於各存在處，可視情 況且獨立地在碳上被一或多個Ra取代，且其中該雜環基之 任何-NH-部份基團可視情況被Ra *取代； R20 ’於各存在處，可獨立選自il基、-CN、Cl_6燒基、& 6 烯基、C2-6炔基、碳環基、雜環基、_〇R2〇a、_SR2Ga、七 133151 200906818 -N(R20a)C(O)R20b ' -N(R2〇a)N(R2 0a)2 , _n〇2 > .N(R2〇a).〇R2 0a . -0-N(R2°a)2、-C(0)H、-C(0)R2°b、_c(O)2R20a、-C(0)N(R2°a)2、 -C(O)N(R20a)(OR20a) ' -〇C(O)N(R20a)2、-N(R20a)C(O)2R20a、 -N(R2°a)C(O)N(R20a)2、_〇C(0)R2〇b、_s(〇)R2〇b、_s(〇)2R20b、 -S(O)2N(R20a)2、-N(R2〇a)s(〇)2R20b、_C(R2〇a)=N(R2〇a)及 -C(R2h)=N(OR2〇a)，其中該Ci_6烷基、C2 6烯基、C2-6炔基、 碳環基及雜環基，於各存在處，可視情況且獨立地在碳上 f 被一或多個Rb取代，且其中該雜環基之任何_他_部份基團 可視情況被Rb*取代； R20*，於各存在處，可獨立選自Ci 0烷基、碳環基、雜環基、 -C(0)H ^ -C(O)R2 0b . -C(〇)2R2〇c . .C(0)N(R2〇a)2 , _S(〇)R20b ^ -s(〇)2R20、s(o)2N(R2,2、_c(R20a)=N_ ’其中該烧基、碳環基及雜環基，於各存在處，可視 情況且獨立地在碳上被—或多個Rb取代，且其中該雜環基 之任何-NH-部份基團可視情況被Rb*取代； 各存在處，可獨立選自H、C16烧基、碳環基及雜 衣土 /、巾叫_6院基、碳環基及雜環基，於各存在處， 可視情況且獨立地在碳上祜_ 产其… 反上被或多個Rb取代’且其中該雜 壤基之W部份基时視情況㈣*取代； R0b’於各存在處，可獨 块基、碳環基及雜環基⑽ 块基、碳環基及雜環基，，於各二基、^稀基、^ 在碳上被—或多個Rb取代，且：視清况且獨立地 份基團可視情況被Rb、代；雜％基之任何姻-部 133151 •18- 200906818 R e ’於各存在處，可獨立選自Ci 6烷基、碳環基及雜環基， 其中該C^6烷基、碳環基及雜環基，於各存在處，可視情 況且獨立地在碳上被_或多個Rb取代，且其中該雜環基之 任何-NH-部份基團可視情況被Rb*取代； R30 ’於各存在處，可獨立選自函基、-CN、Cl_6烷基、C2_6 烯基、C2_6炔基、碳環基、雜環基、_〇R3Ga、_SR3〇a、_N(R3()a)2、 -N(R3〇a)C(〇)R3〇b . -N(R3〇a)N(R3〇a)2 . .N〇2 , _N(R3 0 a 0 a ,And independently and independently substituted on the carbon by one or more Ra, and any of the -NH- moiety of the heterocyclic group may be optionally substituted by r3*; R10a, in each presence, may be independently selected from H , Ci6 alkyl, carbocyclic and heterocyclic, of which. a -6 alkyl group, a carbocyclic group and a heterocyclic group, each optionally, optionally and independently substituted on the carbon by one or more Ra, and wherein any -NH- moiety of the heterocyclic group is visible The situation is replaced by Ra*; R10b' can be independently selected from Cu alkyl, alkenyl, at each point of existence. 6 alkynyl, carbocyclyl and heterocyclyl' wherein the Ci_6 alkyl, C2_6 alkenyl, alkynyl, carbocyclyl and heterocyclic groups are present in each case as appropriate and independently 2 on the carbon Or a plurality of Ra substitutions, and wherein any __- moiety of the heterocyclic group may be optionally substituted by Ra*; R10e' may be independently selected from the group consisting of q-6 alkyl, carbocyclic and heterocyclic groups Wherein the alkyl, carbocyclyl and heterocyclic groups are optionally substituted on the carbon by one or more Ra at each of the positions, and wherein any -NH- moiety of the heterocyclic group Optionally, substituted by Ra*; R20' may be independently selected from the group consisting of il, -CN, Cl_6 alkyl, & 6 alkenyl, C2-6 alkynyl, carbocyclyl, heterocyclyl, _〇 R2〇a, _SR2Ga, 七 151151 200906818 -N(R20a)C(O)R20b ' -N(R2〇a)N(R2 0a)2 , _n〇2 > .N(R2〇a).〇R2 0a -0-N(R2°a)2, -C(0)H, -C(0)R2°b, _c(O)2R20a, -C(0)N(R2°a)2, -C( O)N(R20a)(OR20a) ' -〇C(O)N(R20a)2, -N(R20a)C(O)2R20a, -N(R2°a)C(O)N(R20a)2 _〇C(0)R2〇b, _s(〇)R2〇b, _s(〇)2R20b, -S(O)2N(R20a)2, -N(R2〇a) s(〇)2R20b, _C(R2〇a)=N(R2〇a) and -C(R2h)=N(OR2〇a), wherein the Ci_6 alkyl group, the C2 6 alkenyl group, the C2-6 alkynyl group, Carbocyclyl and heterocyclyl, at each occurrence, optionally and independently, on the carbon, f is substituted by one or more Rb, and wherein any _he moiety of the heterocyclic group may be Rb* as appropriate Substituent; R20*, at each position, independently selected from Ci0 alkyl, carbocyclyl, heterocyclyl, -C(0)H^-C(O)R2 0b. -C(〇)2R2〇c .C(0)N(R2〇a)2 , _S(〇)R20b ^ -s(〇)2R20, s(o)2N(R2,2,_c(R20a)=N_ 'where the alkyl group, carbon a cyclic group and a heterocyclic group, each optionally present, independently and independently substituted on the carbon by - or a plurality of Rb, and wherein any -NH- moiety of the heterocyclic group may be optionally substituted by Rb*; Each of the existing sites may be independently selected from the group consisting of H, C16 alkyl, carbocyclic, and miscellaneous soils, and towels, -6 groups, carbocyclic groups, and heterocyclic groups, in each presence, optionally and independently in carbon. The upper 祜 _ produces its ... is reversed by or multiple Rb' and the W part of the heterogeneous base is replaced by the case of the fourth (4) *; R0b' can be mono- and carbocyclic at each a cyclic group (10) a block group, a carbocyclic group and a heterocyclic group, which are substituted on each of the two groups, a dilute group, or a plurality of Rbs on the carbon, and: depending on the condition and independently, the group may be Rb as the case may be. Any of the singularities of the heterozygous 133151 • 18- 200906818 R e 'in each of the respective positions, independently selected from a Ci 6 alkyl group, a carbocyclic group and a heterocyclic group, wherein the C 6 alkyl group, carbon a cyclic group and a heterocyclic group, each optionally, optionally and independently substituted on the carbon by _ or a plurality of Rb, and wherein any -NH- moiety of the heterocyclic group may be optionally substituted by Rb*; R30' may be independently selected from the group, -CN, Cl_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, carbocyclyl, heterocyclyl, _R3Ga, _SR3〇a, _N(R3() a) 2, -N(R3〇a)C(〇)R3〇b. -N(R3〇a)N(R3〇a)2 . .N〇2 , _N(R3 0 a 0 a ,

-O-N(R30a)2、-C(0)H、-C(0)R3〇b、_c(〇)2R3 0a ' c(〇)N(R30a)2 ' -C(O)N(R30a)(〇R30a) . -OC(O)N(R30a)2 ' -N(R3 0 ^ )C(〇)2 r3 〇 a -N(R3〇a)C(〇)N(R3〇a)2 , .〇C(〇)R3〇b Λ .S(〇)R3 0b . .S(〇)2R3 0b-ON(R30a)2, -C(0)H, -C(0)R3〇b, _c(〇)2R3 0a ' c(〇)N(R30a)2 ' -C(O)N(R30a)( 〇R30a) . -OC(O)N(R30a)2 ' -N(R3 0 ^ )C(〇)2 r3 〇a -N(R3〇a)C(〇)N(R3〇a)2 , . 〇C(〇)R3〇b Λ .S(〇)R3 0b . .S(〇)2R3 0b

-S(O)2N(R30a)2、-N(R3〇a)s(〇)2R30b、_c(R30a)=N(R3〇a) C(R ) N(OR )，其中該c卜6烧基、Ch稀基、块基 奴％基及雜環基，於各存在處，可視情況且獨立地在碳上 被一或多個Μ取代，且其中該雜環基之任何—^-部份基團 可視情況被Rc*取代； R3〇，於各存在處，可獨立選自Ci_6烷基、碳環基、雜環基、 -C(0)H ' -C(O)R30b ' -C(〇)2R3〇c λ -C(〇)N(R30a)2 ^ -S(0)R3〇b , -s(〇)2R 鳩、-S(o)2N(Rw)2、_c(R30a)=N(R30a)LC(R30a)=N(〇R30a) ，其中該(^-6烷基、碳環基及雜環基，於各存在處，可視 情況且獨立地在m或多個Re取代，且其中該雜環基 之任何-NH-部份基團可視情況被RC *取代； e，於各存在處，可獨立選自Η、Cl.6烧基、碳環基及雜 環基’其中該Ch院基、碳環基及雜環基，於各存在處， 可視情況且獨立地在碳上被_或多個RC取代，且其中該雜 133151 -19- 200906818 壞基之任何_NH_部份基團可視情況被Re* R3 0b ,於夂 叭， 於各存在處’可獨立選自Ci 6烧基 炔基、碳環基及雜環基，直中 2 6 衣暴/、中0亥Cl_6说基、c2-6烯基、c2.6 快基、碳環基及雜環基，於各在名虎^ 衣丞於各存在處，可視情況且獨立地 在碳上被-或多個Re取代，且其中該雜環基之任何抓部 份基團可視情況被Rc*取代； f-S(O)2N(R30a)2, -N(R3〇a)s(〇)2R30b, _c(R30a)=N(R3〇a) C(R ) N(OR ), wherein the c a base, a Ch group, a block base, and a heterocyclic group, which may be optionally substituted on the carbon by one or more hydrazines, and wherein any of the heterocyclic groups The group may be optionally substituted by Rc*; R3〇, at each position, may be independently selected from Ci-6 alkyl, carbocyclyl, heterocyclyl, -C(0)H '-C(O)R30b '-C ( 〇) 2R3〇c λ -C(〇)N(R30a)2 ^ -S(0)R3〇b , -s(〇)2R 鸠, -S(o)2N(Rw)2, _c(R30a)= N(R30a)LC(R30a)=N(〇R30a), wherein the (^-6 alkyl, carbocyclyl and heterocyclic group, in each presence, may optionally be substituted with m or more Re, And wherein any -NH- moiety of the heterocyclic group may be optionally substituted by RC*; e, in each presence, may be independently selected from the group consisting of hydrazine, Cl.6 alkyl, carbocyclic and heterocyclic The Ch-based, carbocyclic, and heterocyclic groups are optionally substituted on the carbon by _ or a plurality of RCs, and any _NH_ of the 133151 -19-200906818 bad bases Some groups may be Re* R3 0b depending on the situation. The sputum, in each of its existences, can be independently selected from Ci 6 alkyl alkynyl, carbocyclic and heterocyclic groups, straight 2 6 clothing storms, medium 0 hai Cl_6 base, c2-6 alkenyl, c2. 6 a fast-radical, carbocyclic, and heterocyclic group, each of which is optionally substituted on the carbon by - or a plurality of Re, and wherein any of the heterocyclic groups are The group may be replaced by Rc* as appropriate; f

R30\於各存減’可獨立選自Ci 6院基、碳環基及雜環基， 其中該基 '碳環基及雜環基，於各存在處，可視情 況且獨立地在碳上被一或多㈣取代，且其中該雜環基之 任何-NH-部份基團可視情況被RC *取代； R40 ’於各存在處，可獨立選自鹵基、_CN、Ci 6烧基、k 烯基、<：2_6炔基、碳環基、雜環基、_〇R4〇a、视…、_N(R4Ga)2、 -N(R4^)C(〇)R40b . .N(R40a)N(R4〇a)2 . , .N(R4 0 a >〇r4 〇 a" ^ -〇-N(R4〇a)2 . -C(〇)H ^ -C(O)R40b , .C(〇)2R4〇a . .C(〇)N(R40a)2 , -Ο(Ο)Ν(Κ^3)(〇Κ4 03) . .〇C(〇)N(R4〇a)2 , -N(R4 0a)C(〇)2R40a ^ -N(R4h)C(〇)N(R4〇a)2、_〇C(〇)R40b、_s(〇)R40b、_s(〇)2R4〇b、 -S(0)2N(R4❹ a)2、-N(R4〇a)S(〇)2R40b、_c(R4〇a)=N(R4〇a)及 -C(R4〇a)=N(OR4〇a)，其中該Ci—6烧基、c2 6稀基、C2 6缺基、 環基及雜環基，於各存在處，可視情況且獨立地在碳上 被一或多個Rd取代’且其中該雜環基之任何_冊_部份基團 可視情況被Rd#取代； R40，於各存在處，可獨立選自C! _6烷基、碳環基、雜環基、 -C(0)H、-C(O)R40b、-C(0)2R4〇c、_c(〇)N(R4〇a)2、_s(〇)R40b、 -S(0)2 R4。b、-S(0)2 N(R4 0 a )2、-C(R4 0 a )=N(R4 0 a)及-C(R4 0 a )=N(OR4 0 a) 133151 -20- 200906818 1其中該Ci·6烷基、碳環基及雜環基，於各存在處，可視 b况且獨立地在碳上被_或多個Rd取代，且其中該雜環某 =何舰部份基團可視情況被Rd*取代； ^ ^，於各存在處，可獨立選自η、C!-6烧基、碳環基及雜 %基’其中該Ci6燒基、碳環基及雜環基’於各存在處， 可視情況且獨立地在碳上被—或多個Rd取代，且其中該雜 %基之任何-NH-部份基團可視情況被Rd*取代； fR30\ can be independently selected from the group consisting of Ci 6 and carbocyclyl, and the heterocyclyl, wherein the carbocyclyl and heterocyclyl are optionally present on the carbon. One or more (four) substitutions, and wherein any -NH- moiety of the heterocyclic group may be optionally substituted by RC*; R40' may be independently selected from halo, _CN, Ci 6 alkyl, k Alkenyl, <: 2_6 alkynyl, carbocyclyl, heterocyclyl, 〇R4〇a, ...N, _N(R4Ga)2, -N(R4^)C(〇)R40b . .N(R40a) N(R4〇a)2 . , .N(R4 0 a >〇r4 〇a" ^ -〇-N(R4〇a)2 . -C(〇)H ^ -C(O)R40b , .C (〇) 2R4〇a . .C(〇)N(R40a)2 , -Ο(Ο)Ν(Κ^3)(〇Κ4 03) . .〇C(〇)N(R4〇a)2 , - N(R4 0a)C(〇)2R40a ^ -N(R4h)C(〇)N(R4〇a)2, _〇C(〇)R40b, _s(〇)R40b, _s(〇)2R4〇b, -S(0)2N(R4❹ a)2, -N(R4〇a)S(〇)2R40b, _c(R4〇a)=N(R4〇a) and -C(R4〇a)=N(OR4 〇a), wherein the Ci-6 alkyl group, the c2 6 dilute group, the C6 6 yl group, the cyclic group and the heterocyclic group are optionally substituted on the carbon by one or more Rd at each presence. And any of the heterocyclic groups The group may be optionally substituted by Rd#; R40, at each position, may be independently selected from C! -6 alkyl, carbocyclyl, heterocyclyl, -C(0)H, -C(O)R40b, - C(0)2R4〇c, _c(〇)N(R4〇a)2, _s(〇)R40b, -S(0)2 R4.b, -S(0)2 N(R4 0 a )2 -C(R4 0 a )=N(R4 0 a) and -C(R4 0 a )=N(OR4 0 a) 133151 -20- 200906818 1 wherein the Ci·6 alkyl group, carbocyclic group and heterocyclic group , in each place, can be replaced by _ or more Rd on the carbon, and wherein the heterocyclic group = He part of the group can be replaced by Rd*; ^ ^, in each place, It may be independently selected from the group consisting of η, C!-6 alkyl, carbocyclyl and heteropoly' wherein the Ci6 alkyl, carbocyclyl and heterocyclyl are present, optionally and independently on carbon. Or a plurality of Rd substitutions, and wherein any -NH- moiety of the hetero-group is optionally substituted by Rd*;

R4°b ’於各存在處，可獨立選自Ci 6烷基、CH烯基、 炔基、奴環基及雜環基，其中該^、烧基、C2_6稀基、Cy 快基、碳m基及雜環&，於各存纟處m兄且獨立地6 在奴上被一或多個Rd取代，且其中該雜環基之任何部 份基團可視情況被Rd *取代； R4〇t，於各存在處，可獨立選自C^6烷基、碳環基及雜環基， 其中該烷基、碳環基及雜環基，於各存在處，可視情 況且獨立地在碳上被一或多個Rd取代，且其中該雜環基之 任何-NH-部份基團可視情況被Rd*取代；R4°b' may be independently selected from the group consisting of Ci 6 alkyl, CH alkenyl, alkynyl, cyclyl and heterocyclic groups, wherein the group, the alkyl group, the C2_6 group, the Cy group, the carbon m And heterocycles &, at each of the sites, and independently 6 are substituted on the slave by one or more Rd, and wherein any part of the heterocyclyl group may be substituted by Rd*; R4〇 And, in each presence, independently selected from the group consisting of C1-6 alkyl, carbocyclyl and heterocyclyl, wherein the alkyl, carbocyclyl and heterocyclyl are, where appropriate, optionally and independently in the carbon Substituted by one or more Rd, and wherein any -NH- moiety of the heterocyclic group may be optionally substituted by Rd*;

Ra，Rb，Re及Rd，於各存在處，可獨立選自鹵基、_CN、 1 * 0 烷基、C2.6烯基、C2-6炔基、碳環基、雜環基、_〇Rm、_SRm、 -N(Rm)2、-N(Rm)C(0)Rn、-N(Rm)N(Rm)2、-N02、-N(Rm)-〇Rm、 -0-N(Rm)2、-C(0)H、-C(0)Rn、-C(0)2Rm、-C(〇)N(Rm)2、 -C(0)N(Rm)(ORm) 、 -〇C(0)N(Rm)2 、 -N(Rm)C(0)2Rm 、 -N(Rm)C(0)N(Rm)2、-〇C(〇)Rn、-S(0)Rn、-S(0)2Rn、-S(〇)2N(Rm)2、 -N(Rm)S(0)2Rn、-C(Rm)=N(Rm)及-C(Rm)=N(ORm);Ra, Rb, Re and Rd, in each presence, may be independently selected from halo, _CN, 1*0 alkyl, C2.6 alkenyl, C2-6 alkynyl, carbocyclyl, heterocyclyl, _〇 Rm, _SRm, -N(Rm)2, -N(Rm)C(0)Rn, -N(Rm)N(Rm)2, -N02, -N(Rm)-〇Rm, -0-N( Rm)2, -C(0)H, -C(0)Rn, -C(0)2Rm, -C(〇)N(Rm)2, -C(0)N(Rm)(ORm), - 〇C(0)N(Rm)2, -N(Rm)C(0)2Rm, -N(Rm)C(0)N(Rm)2, -〇C(〇)Rn, -S(0) Rn, -S(0)2Rn, -S(〇)2N(Rm)2, -N(Rm)S(0)2Rn, -C(Rm)=N(Rm), and -C(Rm)=N( ORm);

Ra*，Rb*，Rc*及Rd*，於各存在處，可獨立選自Ci6烧基、碳 133151 •21 · 200906818 環基、雜環基、-C(〇)H、-C(0)Rn、-C(0)2R。、_CCC〇N〇RH(〇)Ri •S(0)2Rn , -S(0)2N(Rm)2 ' -C(Rm)=N(Rm)^-C(Rm)=N(〇Rm)； R於各存在處，可獨立選自H、C】_6烷基、碳環基及雜 環基； βRa*, Rb*, Rc* and Rd*, in each position, may be independently selected from Ci6 alkyl, carbon 133151 • 21 · 200906818 cyclic, heterocyclic, -C(〇)H, -C(0) Rn, -C(0)2R. , _CCC〇N〇RH(〇)Ri •S(0)2Rn , -S(0)2N(Rm)2 ' -C(Rm)=N(Rm)^-C(Rm)=N(〇Rm) ; R at each position, independently selected from H, C] _6 alkyl, carbocyclyl and heterocyclic;

Rn，於各存在處，可獨立選自C1_6烷基、Ch6烯基、& 6炔 基、碳環基及雜環基；且 R0，於各存在處，可獨立選自Ci烷基、碳環基及雜環基。 Γ k. 在本專利說明書中，字首Cx y，當使用於術語譬如G y 烷基等（其中x與y為整數）中時，係指示存在於該基團中 碳原子數字範圍；例如，C1_4烷基包括q烷基（曱基）、Q 烷基（乙基）、cs烷基（丙基與異丙基）及Q烷基（丁基、卜甲 基丙基、2-甲基丙基及第三-丁基）。 燒基-當於本文中使用時，"烧基"一詞係指直鍵與分枝鍵 飽和烴基兩者，具有所指定之碳原子數。 包括-些基團，譬如Cl.5稀基、CH烯基、甲基、:、土丙 基、異丙基、丁基、第三-丁美、呙其 χ ^ ^ j丞丙基、正-丙基及己基。對 個別烷基譬如”丙基"之指稱，係僅鼻 你惶寻才曰直鏈變型，而對個 別分枝鏈烷基譬如”異丙基”之沪盤，总找击〜 !之彳日稱，係僅專指分枝鏈變型。 稀基-當於本文中使用時，"嫌其，，+ ^琊基一阙係指直鏈與分枝鏈 fe基兩者’具有所指定之後S子數曰人 灭屌于數，且含有至少一個碳— 碳雙鍵。例如，”C2-6烯基"包括一此i 彷些暴團，譬如c2_5烯基、 C2_4稀基、乙稀基、2-丙稀基、2甲其 2甲基-2-丙烯基、3_丁烯基、 4-戊稀基及5-己烯基。 炔基-當於本文中使用時，”炔芙，，一 炔基巧係指直鏈與分枝鏈 133151 -22- 200906818 子數，且含有至少一個碳 —些基團，譬如C2_5炔基、 -甲基-2-丙炔基、3_丁炔基、 煙基兩者，具有所指定之碳原 碳參鍵。例如’ "c：2·6炔基”包括 〇2·4炔基、乙炔基、2-丙炔基、2 4-戊炔基及5-己炔基。 囡丞-當於本文 、自A ώ # 土 ㈣你指氟基、氯基、 ΓΓ 面’"鹵基’，一詞可指氟基、氯基及淳 基。於另-方面基詞可指氣基與氣基。、 eRn, at each position, may be independently selected from C1_6 alkyl, Ch6 alkenyl, & 6 alkynyl, carbocyclyl and heterocyclyl; and R0, in each presence, may be independently selected from Ci alkyl, carbon a cyclic group and a heterocyclic group. Γ k. In this patent specification, the prefix Cx y, when used in a term such as G y alkyl or the like (wherein x and y are integers), indicates the range of carbon atoms present in the group; for example, C1_4 alkyl includes q alkyl (indenyl), Q alkyl (ethyl), cs alkyl (propyl and isopropyl), and Q alkyl (butyl, methylpropyl, 2-methylpropyl and Third-butyl). Burning Base - As used herein, the term "burning base" refers to both a straight bond and a branched bond saturated hydrocarbon group having the specified number of carbon atoms. Including some groups, such as Cl.5 dilute, CH alkenyl, methyl, :, propyl, isopropyl, butyl, tri-butyl, ruthenium ^ ^ j propyl, positive -propyl and hexyl. For the reference of individual alkyl hydrazines such as "propyl", it is only the nose that you look for in a straight-chain variant, but for the individual branched-chain alkyl groups such as "isopropyl", it is always looking for ~! Japanese said that the system only refers to the branch chain variant. Thin base - when used in this article, "supplement, + ^ 琊 阙 阙 means both linear and branched chain fe base 'has been specified After that, the number of S is annihilated and contains at least one carbon-carbon double bond. For example, "C2-6 alkenyl" includes one such i-like violent group, such as c2_5 alkenyl, C2_4, and B. Dilute, 2-propenyl, 2-methyl 2-methyl-2-propenyl, 3-butenyl, 4-pentyl and 5-hexenyl. Alkynyl - as used herein, "acetylene", alkynyl refers to the number of straight and branched chains 133151 -22- 200906818 and contains at least one carbon group, such as a C2_5 alkynyl group, - a methyl 2-propynyl group, a 3-butynyl group, a nicotyl group, having the specified carbon-based carbon ginseng bond. For example, ' "c:2·6 alkynyl group” includes 〇2·4 alkynyl group , ethynyl, 2-propynyl, 2 4-pentynyl and 5-hexynyl.囡丞 - In this article, from A ώ #土 (4) you mean fluoro, chloro, ’ ’ '" The other terms may refer to a gas base and a gas base. , e

碳環基-當於本文中使用時，"碳環基”―詞係指飽和、部 份飽和或不飽和，單或雙環狀碳環，其含有3至12個環原子 其中-細偶-基團可視情況被相應數目之麟基團 置換。”碳環基”之說明例包括金剛烧基、環丙基、環丁某、 環戊基、環戊稀基、環己基、環己烯基、氫 酮基環戊基、㈣基氫印基'笨基及四氫茶基。 3-至6-員碳環基·於一方面’ ”碳環基，，可為"…員碳環 基，|。”3-至6-員碳環基.，一詞係指含有⑴個環原子之飽 和、部份飽和或*飽和單環狀碳環，其中—或多個偶-基 團可視情況被相應數目之_C叫基團置換。"3_至6·員碳絲 "之說明例包括環丙基、環丁基、環戊基、㈣基環戊基、環 戊烯基、環己基及笨基。 雜環基-當於本文中使用時，"雜環基” 一詞係指飽和、部 份飽和或不飽和，單或雙環狀環，含有4至12個環原子’其 中至少一個環原子係選自氮、硫及氧，且除非另有指明了 否則其可經碳或氮連接，及其中_CH2_基團可視情況被 -CXO)-置換。環硫原子可視情況被氧化以形成s_氧化物。環 133151 -23- 200906818 氮原子可視情況被氧化以形成>^•氧化物。"雜環基”一詞 說明例包括i,3-苯并二氧伍圜烯基、3,5_二酮基六^比咬基之 呋喃基、咪唑基、吲哚基、異喳啉基、異噻唑基、異^唑 基、嗎福啉基、2-氧-5-氮雙環并[2.2.1;|庚_5_基、嘮唑基、2 嗣基四氫料基、嗣基.㈣如定基、六氫Μ基、六^ 。定基、2Η-喊鳴基、峨唾基、峨啶基、峨咯基、四氯咐嘻基、 口街咬基、t井基、塔口井基、4_ρ比咬酉同基、如林基、四氣咬 喃基、四氫哌喃基、噻唑基、嘧二唑基、嘧唑啶基、硫代 嗎祸啉基、硫苯基、吡啶_Ν_氧化基及喹啉_Ν_氧化基。 非芳族雜環基-於一方面，”雜環基”可為，，非芳族雜環基” ，其係指飽和或部份飽和，單或雙環狀非芳族環含有* 至12個環原子，其中至少—個環原子係選自氮、硫及氧， 且除非另有指明，否則其可經碳或氮連接，及其中義 團—可視情況被-(：(〇)_置換。環硫原子可視情況被氧化以形成 =乳化物。環氮原子可視情況被氧化以形成n_氧化物。 芳族雜環基” 一詞之說明例包括3,5_二_基六氫心定基、嗎 細啉基、2-氧-5-氮雙環并[2 21]庚·5_基、2_酮基四氫吡咯基、 酉同基-1，3〜塞。坐咬基、六氫咕p井基、六氫峨咬基、2H_味喃基、 四虱吡咯基、四氫呋喃基、四氫哌喃基、硫代嗎福啉基及 喧哇π定基。 環：或6-員雜環基，另一方面，"雜環基"可為'或卜員雜 衣土 ，其係指飽和、部份飽和或不飽和單環狀環，含有5 個環原子’其中至少—個環原子係選自氮、硫及氧，且 其中'CH2_基團可視情況被-C(0)-基團置換。除非另有指明， 133151 -24- 200906818 :則：或6-員雜環基”可經碳或氮連結。環氮原子可視情況 :::开:成N_氧化物。環硫原子可視情況被氧化㈣^ 氧 5_或6-員雜環基”之說明例包括3,5-二酮基六氫吡 :基 < 喃基、㈣基、異㉝。坐基、異十坐基、嗎福咕基' 哼唑士：2,基四氫吡咯基、酮基-U-嘧唑啶基、六氫吡畊 氣比咬基、2H-嗓喃基、吡唑基、吡啶基、吡咯基、 四氫吡咯基、四氫吡咯基、嘧啶基、吡畊基、吡唑基"乂Carbocyclyl - as used herein, "carbocyclyl" means a saturated, partially saturated or unsaturated, mono or bicyclic carbocyclic ring containing from 3 to 12 ring atoms. - The group may be replaced by a corresponding number of lining groups as appropriate. Examples of "carbocyclyl" include adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentyl, cyclohexyl, cyclohexene a ketone, a hydrocarbyl cyclopentyl group, a (tetra)ylhydroprinting group, a strepyl group, and a tetrahydrofuran group. A 3- to 6-membered carbocyclic group, on the one hand, a carbocyclic group, which can be a carbon Ring base, |. The term "3- to 6-membered carbocyclyl." refers to a saturated, partially saturated or *saturated monocyclic carbocyclic ring containing (1) ring atoms, wherein - or a plurality of even-groups may be correspondingly numbered _C is a group substitution. Examples of "3_ to 6·member carbon wire" include cyclopropyl, cyclobutyl, cyclopentyl, (tetra)cyclopentyl, cyclopentenyl, cyclohexyl and Heterocyclyl. Heterocyclyl - as used herein, the term "heterocyclyl" refers to saturated, partially saturated or unsaturated, mono- or bicyclic rings containing from 4 to 12 ring atoms. One ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen, and unless otherwise indicated, may be attached via carbon or nitrogen, and wherein the _CH2_ group may be replaced by -CXO)- as appropriate. The ring sulfur atom may optionally be oxidized to form an s-oxide. Ring 133151 -23- 200906818 The nitrogen atom may be oxidized as appropriate to form > Examples of the term "heterocyclyl" include i,3-benzodioxanthyl, 3,5-dione, hexyl, furyl, imidazolyl, fluorenyl, isoporphyrin Base, isothiazolyl, isoxazolyl, morpholinyl, 2-oxo-5-azabicyclo[2.2.1;|g- 5-yl, carbazolyl, 2 fluorenyltetrahydrocarbyl, hydrazine (4) such as fixed base, hexahydroindenyl, hexa. fixed base, 2 Η- shouting base, 峨 基 峨, acridinyl, fluorenyl, tetrachloro fluorenyl, mouth street bite base, t well base, tower Well base, 4_ρ than biting the same base, such as forest base, tetrachatopyranyl, tetrahydropyranyl, thiazolyl, pyrimazolyl, pyrazolidine, thiophene, thiophenyl , pyridine Ν 氧化 oxidized group and quinoline Ν 氧化 oxidized group. Non-aromatic heterocyclic group - in one aspect, "heterocyclic group" may be, non-aromatic heterocyclic group, which means saturated or partially a saturated, mono- or bicyclic non-aromatic ring containing from * to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur and oxygen, and may be linked via carbon or nitrogen unless otherwise indicated, And its neutral group - can be replaced by -(:(〇)_ depending on the situation. The ring sulfur atom can be oxidized as the case may be. To form = emulsifier. The ring nitrogen atom may be oxidized as appropriate to form an n-oxide. The illustrative examples of the term "aromatic heterocyclic group" include 3,5-di-hexylhexyl-hydrogenyl, morphinoline, 2 - Oxy-5-azabicyclo[2 21]hept-5-yl, 2-ketotetrahydropyrrolyl, fluorenyl-1,3~ plug. Sit, hexahydropurine, hexahydro a thiol group, a 2H-flamolyl group, a tetrahydropyrrolyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a thiomorphine group, and a fluorenyl group. A ring: or a 6-membered heterocyclic group, on the other hand, "Heterocyclyl" may be 'or a cloaked soil, which means a saturated, partially saturated or unsaturated monocyclic ring containing 5 ring atoms' wherein at least one of the ring atoms is selected from nitrogen, Sulfur and oxygen, and wherein the 'CH2_ group may be optionally replaced by a -C(0)- group. Unless otherwise indicated, 133151 -24-200906818: then: or a 6-membered heterocyclic group may pass carbon or nitrogen Linkage. Ring nitrogen atom can be viewed as follows::: On: N_oxide. The ring sulfur atom can be oxidized as appropriate (IV) ^ Oxygen 5_ or 6-membered heterocyclic group" Examples include 3,5-dione-based Hydropyridyl: group < thiol, (tetra)yl, hetero-33. Sodium, sulphonyl' oxazoline: 2, phenyltetrahydropyrrolyl, keto-U-pyrazolidine, hexahydropyrazine gas, bite, 2H-furanyl, pyrazolyl, pyridine Base, pyrrolyl, tetrahydropyrrolyl, tetrahydropyrrolyl, pyrimidinyl, pyridinyl, pyrazolyl "

呼基、心比相基、四氫咳喃基、四氫味喃基”塞唾基、 塞一坐基嘍唑啶基、硫代嗎福啉基、硫苯基及吡啶_N_氧 化基。 4-至6-員雜環基_ ”4_至6_員雜環基π 一詞係指飽和、部份飽 和或不飽和單環狀環，含有4至6個環原子，其中至少一個 %原子係選自t、硫及氧’且其中_CH2基團可視情況被 -C(O)-基團置換。除非另有指明’否則，，4_至6項雜環基"可 經碳或氮連結。環氮原子可視情況被氧化以形成队氧化物。 %硫原子可視情況被氧化以形成^氧化物。％至6_員雜環基 "之說明例包括一氮四圜小基、二氧化四氫硫苯基、2斗二 酮基咪唑咬基、3,5-二酮基六氫吡啶基、呋喃基、咪唑基、 異嘍唑基、異啰唑基、嗎福啉基、哼唑基、環氧丙烷基、 酮基咪唑啉啶基、3-酮基小六氫吡畊基、2-酮基四氫吡咯 基、2_酮基四氫呋喃基、酮基-1,3-4唑啶基 '六氫吡畊基、 六氫吡啶基、2H-哌喃基、吡唑基、吡啶基、吡咯基、四氫 吡咯基、嘧啶基、吡畊基、吡唑基、嗒畊基、4_吡啶酮基、 四氫味喃基、四氫哌喃基、嘍唑基、^4-噹二唑基、p塞唾 133151 -25 200906818 啶基、硫代嗎福啉基、硫苯基、购，2,4_三唑基及咐咬_ 化基。 6·員雜環基-於又另一方面，"雜環基"與，，5_或6_員雜環基” 可為"6-員雜環基"，其係指飽和、部份飽和或不飽和單環狀 :，含有6個環原子’其中至少一個環原子係選自氮、琉及 軋，且其中-CH2-基團可視情況被七(〇)_基團置換。除非另 :=氡!·則"6:員雜環基”可經碳或氮連結。環氮原子可視 形成s氧化以形成N_氧化物。環硫原子可視情況被氧化以 唆基、嗎福二=說明例包括-二，基心 蝴…井；基、六氯㈣基、叫南基、 。井基、吡啶基及嘧啶基。 6-員雜♦基-於又里2 基,,及” 方面，"雜環基"L·員雜環 負心基”可為"6_員雜芳基"。 意欲指稱含有6個環原子之單環狀環方f —詞係 有指明，否則，，6_員雜芸且” 方族雜銥基％。除非另 情況被氧化以形成可經碳或氮連結。環氮原子可視 形成s-氧化物。”6。物。環硫原子可視情况被氧化以 基、《基及芳基”之說明例包括則基 5或員非芳埃雜環基於進_ 族雜環基”、”5-或6-員雜環基”可^ 雜環基，·、，，非芳 ”5-或6-員非芳埃雜環一 ^ S -貝非方族雜環基"。 單環狀非芳族雜環一詞係意欲指稱飽和或部份飽和， 個環原子係選自氮、：含有5或6個環原子，其中至少— 經碳或氮連接，及二’且除非另有指明，否則其可 133151 r基團可視情況被_C(〇>置換。 -26- 200906818 環硫原子可視情況被氧化以形成s_氧化物 情況被氧化以形成N_氧化物。，，5或 衣氮原子可視 a 0貝非方族雜環基" 明例包括3,5-二酮基六氫吡啶基 '嗎福 ° λ· «· 林基、2-酮基四氫口比 咯基、酮基-I，3-嘍唑啶基、六氫吡丄 w 土甘" 丞，、虱吡啶基、2Η- 辰喃基、四氣咐嘻基、四氯啥喃基、四氯 福啉基及嘧唑啶基。 代馬 6_員非芳族雜環基-又再進一步方φ，”雜環基” /· i. 族雜環基，，、，，5-或6_員雜環基，，及”5或 方 尺貝非方族雜環基"可 =貝^族雜環基。㈣非芳族雜環基”—詞係意欲指稱 飽和或㈣飽和，單環狀非芳族雜環基環，含有6個環原子， 其中至卜個環原子係選自氮、硫及氧，且除非另有指明， 否則其可經碳或氮連接，及其中 ^ 叫基團可視情況被 ’置換。壤碗原子可視情況被氧化以形成s_氧化物。環 =原子可視情況被氧化以形成N_氧化物。％員非芳族雜環 基之祝明丫列包括3,5-二酮基六氫峨唆基、嗎福琳基、六氯 X基、六氯_基、2时喃基 '四氫味喃基及硫代嗎福 啡基。 在特定R基團（例如Ru，Rl〇等）係於式⑴化合物中存在超 過一次之情況下，所意欲的是，對該R基團之各選擇在任 何其他存在處之任何選擇之每—存在處料獨立。例如， 娜)2基團係意欲涵蓋：υ其中兩似取代基為相同之綱 基團’譬如其中兩做取代基均為例如^烧基者；盘料 :各汉取代基係為不同之刪2基團，譬如其中—似取代 基為例如Η ’ 個R取代基為例如石炭環基者。 133151 -27- 200906818 除非特別地敘述’否則—個基團之結合原 之任何適當原子；例如，丙基包括丙小基與丙从團 有效量-當於本文中使用時，”有效量，，措辭係意 或組合物之量，其足以充分顯著且正面地改變欲被治紅 病徵及/或症狀（例如提供正臨床回應小供使用於醫藥^ 物之活性成份之有效量將會隨著被治療之特定症狀、、症: 之戚重性、治療之延續時間、同時療法之性質、所採用之 特定活性成份、所使用之特定藥學上可接受之賦形劑 及在負責醫師之知識與專門技術内之類似因素而改變。 寺足》之4 (I)化合物供使用於治療癌症之有效量，係 為足以在溫血動物譬如人類中於徵狀上舒解癌症與骨髓增 生疾病之病徵，減緩癌症與骨髓增生疾病之進展，或在串 有癌症與骨髓增生疾病徵候之病人中降低變得更壞之纽 之量。 —脫離基·當於本文中使用時’”脫離基”措辭係意欲指稱可 谷易地被親核基團，譬如胺親核基團與醇親核基團或硫醇 親核基團置換之基團。適當脫離基之實例包括齒基，譬如 亂基與，及續醯氧基，譬如甲院續醯氧基與甲苯本續 酿氧i基。 視清况經取代-當於本文中使用時，，，視情況經取代"措辭 係表示取代為選用，因此對於所指定之基團可為無論是經 取代或未經取代。在需要取代之情況中，於所指定基團上 之任何數目之氫可被選自所指示之取代基置換，其條件是 不得超過特定取代基上之原子之正常價鍵，且此取代會造 133151 -28- 200906818 成安定化合物。 於一方面，當特定基圓係被指定為視情況被”一或多個” 取代基取代時，此特定基團可為未經取代。於另一方面， :寺定基圓可帶有一個取代基。於另一方面，特定取代基可 τ有兩個取代基。於又另一方面，特定基團可帶有三個取 代基於又另一方面，特定基團可帶有四個取代基。於進 V方面，特疋基團可帶有一個或兩個取代基。於又再進 f · 一步方面，特定基團可為未經取代，或可帶有一個或兩個 v 取代基。 藥學上可接受_當於本文中使用時，，，藥學上可接受"一 詞，係指此等化合物、物質、組合物及/或劑型係在安全可 靠醫學判斷之範圍内，適用於與人類及動物之組織接觸， 而無過度毒性、刺激性、過敏性回應或其他問題或併發症， 伴隨著合理利益/風險比。 保護基-當於本文中使用時，”保護基”一詞係意欲指稱用 I 以防止經選擇之反應性基團（譬如羧基、胺基、羥基及巯基） 遭受不想要反應之基團。 關於羥基之適當保護基之說明例包括醯基；烷醯基，譬 如乙醯基；芳醯基，譬如苯曱醯基；矽烷基，譬如三曱基 夕烷基’及芳基曱基’譬如苄基。關於上文羥基保護基之 去除保護條件，將必須隨著保護基之選擇而改變。因此， 例如醯基，譬如烷醯基或芳醯基，可例如以適當鹼，譬如 鹼金屬氫氧化物，例如氫氧化鋰或鈉，藉由水解作用而被 移除。或者，矽烷基，譬如三甲基矽烷基，可例如藉由氟 133151 -29· 200906818 化物或藉由含水酸而被移除；或芳基τ基，譬如爷基可 例如於觸媒存在下’譬如鈀/碳，藉由氫化作用移除。 關於胺基之適當保護基之說明例包括醯基；炫醯基，譬 如乙醯基；烷氧羰基，譬如甲氧羰基、乙氧羰基及第三_ 丁氧羰基；芳基甲氧羰基，譬如芊氧羰基；及芳醯基，譬 如苯甲醯基。關於上文胺基保護基之去除保護條件必須隨 著保護基之選擇而改變。因此’例如醯基，譬如烷醯基或 烷氧羰基或芳醯基，可例如以適當鹼，譬如鹼金屬氫氧化 物，例如氫氧化鋰或鈉，藉由水解作用移除。或者，醯基， 譬如第二-丁氧羰基，可例如經由以適當酸譬如鹽酸、硫 酸、磷酸或三氟醋酸處理而被移除，及芳基甲氧羰基，譬 如苄氧羰基，可例如於觸媒譬如鈀/碳上，藉由氫化作用， 或經由以路易士酸例如三氯化删處理而被移除。關於一級 胺基之適當替代保護基係為例如酞醯基，其可經由以烷基 胺，例如二甲胺基丙胺或2_經乙胺，或以肼處理而被移除。 關於胺之另一種適當保護基係為例如環狀鍵，譬如四氫呋 南八可、.工由以適虽酸譬如三氣醋酸處理而被移除。 保瘦基可在合成中> /人 你口取甲之任何合宜階段下，使用化學技藝上 習知之習用技術移除，赤甘1" “ 或其可在稍後反應步驟或處理期間 被移除。 參考取代基R1以達說明目的’下列取代基定義具有 示之意義： 曰 133151 >30- 200906818 、1a -N(R1”2 R'、，N、R1a -N(R1a)C(0)R1bRespiratory group, heart-specific phase group, tetrahydroc-butyl group, tetrahydro-glycolyl group, sialyl group, succinyl oxazolidinyl group, thiomorpholine group, thiophenyl group and pyridine_N_oxide group The 4- to 6-membered heterocyclic group _ "4_ to 6_membered heterocyclic group π" means a saturated, partially saturated or unsaturated monocyclic ring containing 4 to 6 ring atoms, at least one of which The % atomic system is selected from the group consisting of t, sulfur and oxygen ' and wherein the _CH2 group may be replaced by a -C(O)- group, as appropriate. Unless otherwise indicated 'otherwise, 4 to 6 heterocyclyl groups" may be bonded via carbon or nitrogen. The ring nitrogen atom can be oxidized as appropriate to form a group oxide. The % sulfur atom may optionally be oxidized to form an oxide. Illustrative examples of the % to 6-membered heterocyclic group include a azofluorenyl group, a tetrahydrothiophenyl diphenylate, a 2-piperidinyl imidazolium group, a 3,5-dione hexahydropyridyl group, Furanyl, imidazolyl, isoxazolyl, isoxazolyl, morpholinyl, oxazolyl, propylene oxide, ketoimidazolidinyl, 3-keto hexahydropyranyl, 2- Ketotetrahydropyrrolyl, 2-ketotetrahydrofuranyl, keto-1, 3-4oxazolidinyl hexahydropyrrole, hexahydropyridyl, 2H-piperidyl, pyrazolyl, pyridyl, Pyrrolyl, tetrahydropyrrolyl, pyrimidinyl, pyridinyl, pyrazolyl, hydrazine, 4-pyridino, tetrahydrofuranyl, tetrahydropyranyl, oxazolyl, ^4- Azolyl, p-plug 133151 -25 200906818 pyridine, thiomorpholine, thiophenyl, commercially available, 2,4-triazolyl and bite-based. 6. Heterocyclyl-on the other hand, "heterocyclyl" and, 5 or 6-membered heterocyclic group may be "6-membered heterocyclic group", which means saturation a partially saturated or unsaturated monocyclic ring containing 6 ring atoms wherein at least one of the ring atoms is selected from the group consisting of nitrogen, ruthenium and rolling, and wherein the -CH2- group may be replaced by a seven (〇) group. Unless otherwise: = 氡! · then "6: member heterocyclic group" can be linked by carbon or nitrogen. The ring nitrogen atom can be oxidized to form s to form an N-oxide. The ring sulfur atom may be oxidized as the sulfhydryl group, the ruthenium II = illustrative examples include - two, the base heart butterfly, the base, the hexachloro (tetra) group, and the south base. Well base, pyridyl and pyrimidinyl. 6-members ♦ BASE-Yu-Li 2 base, and, in terms of, "heterocyclic group"L·member heterocycle negative core group, can be "6_member heteroaryl". It is intended to refer to a single cyclic ring containing six ring atoms. The word f is indicated, otherwise, 6_members are heterozygous and have a % of the family of heterocyclic groups. Unless otherwise oxidized to form a carbon or nitrogen link The ring nitrogen atom can be formed into an s-oxide." Things. The ring sulfur atom may be oxidized by a group, and the "base and aryl group" examples include a group 5 or a non-aryl heterocyclic ring based on a heterocyclic group, a 5- or 6-membered heterocyclic group. a heterocyclic group, a, or a non-aromatic "5- or 6-membered non-aryl heterocycle-S-befetyl heterocyclic group". The term monocyclic non-aromatic heterocyclic ring is intended Sufficiently saturated or partially saturated, each ring atom is selected from nitrogen, containing 5 or 6 ring atoms, at least - linked via carbon or nitrogen, and two' and unless otherwise indicated, it may be visible as 133151 r group The condition is replaced by _C(〇> -26- 200906818. The ring sulfur atom may be oxidized to form an s_oxide, which is oxidized to form an N_oxide., 5 or a nitrogen atom may be a 0. Family heterocyclic group " Examples include 3,5-diketopyl hexahydropyridyl '?? λ· «· Lin, 2-ketotetrahydropyryl, keto-I,3-喽An oxazolidinyl group, a hexahydropyridinium, a ruthenium, an anthracene, a pyridyl group, a 2-fluorenyl group, a tetrahydrofuranyl group, a tetrachloroporphyrin group, and a pyrazolidine group. Ma 6_member non-aromatic heterocyclic group - again One-step φ, "heterocyclic group" /· i. a heterocyclic group, a group, a 5-, or a 6-membered heterocyclic group, and a "5 or a square-footed non-aromatic heterocyclic group" (a) non-aromatic heterocyclic group" - the word system is intended to mean a saturated or (tetra) saturated, monocyclic non-aromatic heterocyclic ring containing 6 ring atoms, wherein the ring atoms are selected from Nitrogen, sulfur and oxygen, and unless otherwise indicated, may be attached via carbon or nitrogen, and wherein the group may be 'substituted. The soil of the bowl may be oxidized to form s_oxide. Ring = atom It may be oxidized as appropriate to form N-oxide. The list of non-aromatic heterocyclic groups includes 3,5-dione hexahydroindenyl, morphine, hexachloroX, hexachloro _ base, 2 butyl group 'tetrahydromyranyl group and thiomorphinyl group. In the case where a specific R group (for example, Ru, Rl〇, etc.) is present in the compound of formula (1) more than once, the intended Yes, the choice of the R group is independent of any choice in any other place of existence. For example, the nal 2 group is intended to cover: υ two of the substituents are The same group 'such as two of which are substituents are, for example, those of the group; the disk: each of the substituents of the group is a different group, for example, wherein the substituent is, for example, Η 'R substituent For example, those of the charcoal ring base. 133151 -27- 200906818 Unless otherwise specified, 'others are a combination of any suitable atom of the group; for example, propyl includes a small amount of propyl group and a group of propylene groups - as used herein The "effective amount," or the amount of the composition, which is sufficient to substantially and positively alter the symptoms and/or symptoms to be treated (eg, to provide a positive clinical response for the active ingredients of the pharmaceutical product) The effective amount will vary with the particular condition being treated, the severity of the treatment, the duration of the treatment, the nature of the concurrent therapy, the particular active ingredient employed, the particular pharmaceutically acceptable excipients employed, and It changes with similar factors within the knowledge and expertise of the physician. 4 (I) Compounds for the treatment of cancer are effective in relieving cancer and myeloproliferative disorders in warm-blooded animals such as humans, slowing the progression of cancer and myeloproliferative diseases. , or reduce the amount of worsening in patients with signs of cancer and myeloproliferative disorders. - Detaminating base - As used herein, the term "exclusive base" is intended to mean that the nucleophilic group, such as an amine nucleophilic group, and an alcohol nucleophilic group or a thiol nucleophilic group, are replaced by a nucleophilic group. Group. Examples of suitable exfoliating bases include a dentate group, such as a chaotic group, and a decyloxy group, such as a sulfonate and a toluene. Substituting the condition as it is used - when used herein, as the case may be substituted, the wording indicates substitution is optional, and thus the specified group may be either substituted or unsubstituted. In the case where substitution is desired, any number of hydrogens on the specified group may be replaced by a substituent selected from the indicated substituents, provided that the normal valence bond of the atom on the particular substituent is not exceeded and the substitution 133151 -28- 200906818 Compounds. In one aspect, when a particular base is designated as being substituted with one or more substituents as appropriate, the particular group can be unsubstituted. On the other hand, the temple base can have a substituent. In another aspect, a particular substituent can have two substituents. In yet another aspect, a particular group can be based on three substitutions and on the other hand, a particular group can carry four substituents. In the case of V, the thiol group may have one or two substituents. Further, in a step, the specific group may be unsubstituted or may have one or two v substituents. Pharmaceutically acceptable - as used herein, pharmaceutically acceptable "the term means that such compounds, substances, compositions and/or dosage forms are within the scope of safe and reliable medical judgment and are applicable to Human and animal tissue exposure without excessive toxicity, irritation, allergic response or other problems or complications is accompanied by a reasonable benefit/risk ratio. Protecting Group - As used herein, the term "protecting group" is intended to refer to a group that is used to prevent unwanted reactive groups (such as carboxyl groups, amine groups, hydroxyl groups, and sulfhydryl groups) from undergoing unwanted reactions. Illustrative examples of suitable protecting groups for hydroxy groups include mercapto groups; alkyl groups, such as ethyl, aryl groups, such as phenyl groups; alkyl groups, such as trisyl and aryl groups, such as Benzyl. With regard to the removal protection conditions of the above hydroxy protecting groups, it will necessarily vary with the choice of protecting group. Thus, for example, an anthracenyl group such as an alkanoyl group or an aryl group can be removed by hydrolysis, for example, with a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium. Alternatively, a decyl group, such as a trimethyl decyl group, may be removed, for example, by fluorine 133151 -29. 200906818 or by an aqueous acid; or an aryl τ group, such as, for example, in the presence of a catalyst. For example, palladium/carbon is removed by hydrogenation. Illustrative examples of suitable protecting groups for the amine group include anthracenyl; a fluorenyl group such as an ethoxy group; an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group and a third-butoxycarbonyl group; an arylmethoxycarbonyl group such as An oxocarbonyl group; and an aryl group, such as a benzyl group. The removal protection conditions for the above amine protecting groups must vary with the choice of protecting group. Thus, for example, an anthracenyl group such as an alkoxy group or an alkoxycarbonyl group or an aryl group can be removed by hydrolysis, for example, with a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium. Alternatively, a mercapto group, such as a second-butoxycarbonyl group, may be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group, such as a benzyloxycarbonyl group, for example The catalyst is removed, for example, by palladium on carbon, by hydrogenation, or by treatment with Lewis acid such as trichlorination. Suitable alternative protecting groups for the primary amine group are, for example, sulfhydryl groups which may be removed via treatment with an alkylamine such as dimethylaminopropylamine or 2-ethylamine or by treatment with hydrazine. Another suitable protecting group for the amine is, for example, a cyclic bond, such as tetrahydrofuran, which can be removed by treatment with a suitable acid such as tri-acetic acid. The thin base can be removed in the synthesis stage / using any customary technique known in the chemical art, and the red sugar can be removed during the later reaction step or treatment. Reference to the substituent R1 for illustrative purposes 'The following substituent definitions have the meanings indicated: 曰133151 >30- 200906818, 1a -N(R1"2 R',,N,R1a -N(R1a)C(0 )R1b

13 O k1b13 O k1b

R1a O R1a )I II I >——N 11 -N—FR1a O R1a )I II I >——N 11 -N-F

R R1a > I I , )——N—N—R OR R1a > I I , )——N—N—R O

-N(R1a)C(0)N(Ria)2 -N(R1a)C(0)2R1a = -N(R1a)S(0)2R1b = -N(R1a)N(R1a)2 = -C(0)R1b = 〇 -C(0)2R1a = \—L〇R1a -C(0)N(R1”2 = -0C(0)N(R1a)2 = -0C(0)R1a = -S(0)R1b = -S(0)2R1b = -S(0)2N(R^)2 = \/vs/ o-N(R1a)C(0)N(Ria)2 -N(R1a)C(0)2R1a = -N(R1a)S(0)2R1b = -N(R1a)N(R1a)2 = -C( 0) R1b = 〇-C(0)2R1a = \—L〇R1a -C(0)N(R1"2 = -0C(0)N(R1a)2 = -0C(0)R1a = -S(0 )R1b = -S(0)2R1b = -S(0)2N(R^)2 = \/vs/ o

OHSOHS

RINRIN

RR

R丨NR丨N

RR

a 1Ra 1R

R R,bI onsnoR R, bI onsno

a 1R N I onsnoa 1R N I onsno

R 133151 -3l · 200906818 -C(R1a)=N(ORi” -C(R1a)=N(R1a)R 133151 -3l · 200906818 -C(R1a)=N(ORi" -C(R1a)=N(R1a)

本文中所討論之化合物在許多情況十係使用ACD/Labs®之 ACD/Name命名及/或確認。 式（I)化合物可形成安定藥學上可接受之酸或鹼鹽，而在 此種情況中，化合物以鹽之投藥可為適當的。酸加成鹽之 實例，包括醋酸鹽、己二酸鹽、抗壞血酸鹽、苯甲酸鹽、 苯磺酸鹽、重碳酸鹽、酸性硫酸鹽、丁酸鹽、樟腦酸鹽、 樟腦磺酸鹽、膽鹼、擰檬酸鹽、環己基胺基磺酸鹽、二乙 二胺、乙烷磺酸鹽、反丁烯二酸鹽、麩胺酸鹽、乙醇酸鹽、 半硫酸鹽、2-羥乙基磺酸鹽、庚酸鹽、己酸鹽、鹽酸鹽、 氫溴酸鹽、氫碘酸鹽、羥基順丁烯二酸鹽、乳酸鹽、蘋果 酸鹽、順丁烯二酸鹽、曱烷磺酸鹽、葡甲胺、2-莕磺酸鹽、 硝酸鹽、草酸鹽、雙羥苯酸鹽、過硫酸鹽、苯基醋酸鹽、 磷酸鹽、二磷酸鹽、苦味酸鹽、三甲基醋酸鹽、丙酸鹽、 金雞鈉酸鹽、柳酸鹽、硬脂酸鹽、琥珀酸鹽、胺基磺酸鹽、 磺胺酸鹽、硫酸鹽、酒石酸鹽、甲苯磺酸鹽（對-甲苯磺酸 鹽）、三氟醋酸鹽及Η —烧酸鹽。驗鹽之實例包括銨鹽；驗 金屬鹽，譬如納、鋰及釺鹽；驗土金屬鹽，譬如銘、躬及 鎂鹽；與有機鹼之鹽，譬如二環己基胺鹽與Ν-甲基-D-葡萄 糖胺鹽；及與胺基酸譬如精胺酸、離胺酸、鳥胺酸之鹽等 等。鹼性含氮基團亦可以一些作用劑四級化，譬如：低碳 133151 -32- 200906818 烧基鹵化物，嬖^ ~ 甲基、乙基、丙基及丁基_化物，·二沪 基硫酸鹽’譬如二- —% 甲基、一乙基、二丁基、二戊基硫酸鹽 長鏈鹵化物，壁如八# 皿’ ^ S六基、月桂基、肉豆蔻基及硬脂基鹵化 物，芳烧基_介私 _* ^ 物，4如溴化苄及其他。無毒性生理學上 可接又之ί係為較佳，惟其他鹽可使用，譬如在單離或純 化產物上。 此鹽類可藉由@ + ί S用方式形成，譬如經由使產物之自由熊 驗形式與一或冬告旦丄 * ， 次多虽里之適當酸反應，在其中該鹽為不溶性 之溶劑或媒質中，舔太链 + 次在·#如水之溶劑中，其係於真空中 藉由殊乾移除，或藉出丨ν ϊ;目士_ _ ^ 飞鞛由以現有鹽之陰離子交換適當離子交 換樹脂上之另一種陰離子。 一些式⑴化合物可具㈣"d/线何異構中心佐 2異構物），且應明瞭的是，本發明係涵蓋所有此種光學、 2映異構物及幾何異構物。本發明係進—步關於式(1)化 σ物之任何及所有互變異構形式。The compounds discussed herein are named and/or confirmed using ACD/Name of ACD/Labs® in many cases. The compound of the formula (I) can form a stable pharmaceutically acceptable acid or base salt, and in this case, the compound can be administered as a salt. Examples of acid addition salts include acetates, adipates, ascorbates, benzoates, besylates, bicarbonates, acid sulfates, butyrates, camphorates, camphorsulfonates, Choline, citrate, cyclohexylamine sulfonate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxy Ethyl sulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxy maleate, lactate, malate, maleate, a decane sulfonate, meglumine, 2-anthracene sulfonate, nitrate, oxalate, bishydroxybenzoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, Trimethylacetate, propionate, cinnabarate, salicylate, stearate, succinate, amine sulfonate, sulfonate, sulfate, tartrate, tosylate -tosylate), trifluoroacetate and guanidinium. Examples of salt tests include ammonium salts; metal salts such as sodium, lithium and barium salts; soil metal salts, such as sulphur, magnesium and magnesium salts; salts with organic bases such as dicyclohexylamine and barium-methyl -D-glucosamine salt; and a salt with an amino acid such as arginine, lysine, ornithic acid, and the like. Alkaline nitrogen-containing groups can also be quaternized by some agents, such as: low carbon 133151 -32- 200906818 alkyl halide, 嬖^ ~ methyl, ethyl, propyl and butyl _, · · · Sulfate's such as di--% methyl, monoethyl, dibutyl, dipentyl sulfate long-chain halides, such as 八# 皿 ' ^ S hexyl, lauryl, myristyl and stearyl Halides, aryl groups _ _ _ ^ ^ things, 4 such as benzyl bromide and others. Non-toxic physiology is preferred, but other salts may be used, such as on isolated or purified products. This salt can be formed by @ + ί S, for example, by reacting the free bear form of the product with a suitable acid, in which the salt is an insoluble solvent or In the medium, the 舔太chain+ times in the solvent such as water, it is removed by vacuum in the vacuum, or borrowed 丨ν ϊ; the _ _ ^ ^ fly hopper is exchanged by the anion of the existing salt Another anion on the ion exchange resin. Some of the compounds of formula (1) may have (iv) "d/line"heteroisomers; and it is to be understood that the invention encompasses all such optical, diastereomers and geometric isomers. The present invention is directed to any and all tautomeric forms of the sigma of formula (1).

ί \ 'X 亦應明瞭的是，草此古m ^卜人 、.… ¥二式⑴化合物可以已溶劑化合以及未 岭劑化合形式例如水合形式存 牡應明瞭的是，本發明係 成盖所有此種溶劑化合形式。 本發明之其他具體實施例如 Μ ^ , ,τλ 下此專其他具體實施例係 合物及其藥學上可接受之鹽。此種特定取代基 情況下，與前文或後文所界定之任何定義、請求 項或具體實施例一起使用。ί \ 'X should also be clear that the compound of the formula (1) can be solvated and unblended, such as hydrated form, it should be clear that the present invention is a cover All such solvated forms. Other embodiments of the invention are, for example, Μ ^ , , τλ, such other specific embodiment compounds and pharmaceutically acceptable salts thereof. Such specific substituents are used with any definition, claim or specific embodiment as defined above or hereinafter.

環A 於—方面 環可為雜％基，其中該雜環基可視情況 133151 -33- 200906818 碳上被一或多個R2取代’且其中該雜卢Α λ τ你雜％基之任何_nh-部份 基團可視情況被R2*取代； C2-6烯基、C2_6炔基、 R2可選自Η、鹵基、-CN、q _ 6烷基 碳環基、雜環基、-Om-SRh、_N(R2a)2、_N(R2a)_R2b、 -N(R2a)N(R2a)2 , .n〇2 , _N(R2a)〇R2a ^ _〇N(R2a)2 ^ _c^H ^ C(0)R -C(0)2R ' -C(0)N(R2a)2 λ -C(0)N(R2a)(0R2a)- 0C(0)N(R-)2 ^ -N(R2a)C(〇)2R2a . -N(R2a)C(〇)N(R2a)2 ^ _〇c(〇)R2b , f -S(0)R- ^ -S(0)2R- . -S(0)2N(R2a)2 . .N(R2a)S(〇)2R2b . -c(i^)=N(R2a)及_c(R2a)=N(OR2a)，其中該Ci 6院基、心6稀 基、Q_6炔基、碳環基及雜環基可視情況在碳上被一或多 個R2〇取代，且其中該雜環基之任何___部份基團可視情況 被R2G*取代； R2*，於各存在處，可獨立選自Ci_6烷基、碳環基、雜環基、 -C(0)H ^ -C(0)R2b . -C(〇)2R2c. .C(〇)N(R2a)2 . _S(〇)R2b ^ _S(〇)2R2b , -8(0)2聯23)2、_〇：(1^)=離23)及_(：(圮3)，〇心），其中該^6 烷基、碳環基及雜環基，於各存在處，可視情況且獨立地 在％上被一或多個R2〇取代，且其中該雜環基之任何_NH-部 份基團可視情況被r2〇*取代； R2a，於各存在處，可獨立選自Η、Ci_6烷基、碳環基及雜 環基，其中該^—6烷基、碳環基及雜環基，於各存在處， 可視情況且獨立地在碳上被一或多個R2〇取代，且其中該雜 環基之任何-NH-部份基團可視情況被R2〇*取代； R2b ’於各存在處，可選自C〖_6烷基、C2·6烯基、c2_6炔基、 碳環基及雜環基，其中該^·6烷基、ό烯基、C2 6炔基、 133151 -34· 200906818 碳環基及雜環基，於久左产老 , 、 於各存在處，可視情況且獨立地在碳上 被一或多個R2 0取代，且盆中_魏$糞少乂工7 儿，、甲該雜％基之任何-NH_部份基團 可視情況被R2 G *取代； R2c’於各存在處，可獨立選自q.6m環基及雜環基， 其中該CJ基1環基及雜環基，於各存在處，可視情 況且獨立地在碳上被一或多個圮。取代，且其中該雜環基之 任何-NH-部份基團可視情況被R2〇*取代； ·/. R20’於各存在處，可獨立選自_基、_CN、Ci㈤基、Ch 烯基、C2-6炔基、碳環基、雜環基、_〇R2Ga、_SR2Ga、_N(R2Ga)2、 -N(R2〇a)C(〇)R2〇b、娜20a難2〇a)2、_n〇2、娜“a)—。，、 -O-N(R20^)2 . _C(〇)H . -C(〇)R2〇b , _C(〇)2R2 0a , _C(0)N(R20a)2 . -C(O)N(R2 0a)(〇R2 0a) ^ _〇C(〇)N(R2 0a)2 . .N(R2 〇 a )C(〇)2R20 a , -N(R2°a)C(〇)N(R2〇a)2 ' _〇c(〇)R2()b、_s(〇)R2()b ' _s ⑼ 2R20b、 -S(〇)2N(R2〇a)2、~N(R20a)S(O)2R20b、-C(R2〇a)=N(R2〇a)及 -C(R20a)=N(〇R2〇a)； R ，於各存在處，可獨立選自Cl_6烷基、碳環基、雜環基、 -C(0)H、-C(0)R2〇b、_c(〇lr20c、_c⑼雕2〇、、_s(〇)R2〇b、 -S(0)2 R2 0 b、-S(0)2 N(R2。a )2、_C(R2。，雕2 0 ” 及-c(r2。a 〇 a ); R20a，於各存在處，可獨立選自Η、Ci·6烷基、碳環基及雜 環基； ，於各存在處，可獨立選自Ci6烷基、C26烯基、C2_6 炔基、碳環基及雜環基；且 R20e’於各存在處’可獨立選自q·6烷基、碳環基及雜環基。 於另方面’環A為4-至6-員雜環基’其中該4-至6-員雜 133151 -35 - 200906818 環基係視情況在碳上被一或多個R2取代’且其中該4_至6_ 員雜環基之任何-NH-部份基團係視情況被R2 *取代； R ’於各存在處’係獨立選自鹵基、_CN、C! - 6烧基、-OR2 a、 -N(R2a)2、_C⑼N(R2a)2、_N(R2a)c(〇)R2bA _N(R2a)c(〇)2R2a，其 中該Ci _6烷基係視情況被一或多個R2 0取代； R2*為（ν6烷基； R2a ’於各存在處，係獨立選自11與（：1-6烷基； 烷基；Ring A can be a hetero group in the ring, wherein the heterocyclic group can be substituted by one or more R 2 on the carbon 133151 -33 - 200906818 and the _nh of the heterocyclic λ τ - a part of the group may be optionally substituted by R2*; C2-6 alkenyl, C2_6 alkynyl, R2 may be selected from fluorene, halo, -CN, q-6 alkylcarbocyclyl, heterocyclyl, -Om- SRh, _N(R2a)2, _N(R2a)_R2b, -N(R2a)N(R2a)2, .n〇2, _N(R2a)〇R2a^ _〇N(R2a)2 ^ _c^H ^ C (0)R -C(0)2R ' -C(0)N(R2a)2 λ -C(0)N(R2a)(0R2a)- 0C(0)N(R-)2 ^ -N(R2a C(〇)2R2a . -N(R2a)C(〇)N(R2a)2 ^ _〇c(〇)R2b , f -S(0)R- ^ -S(0)2R- . -S( 0) 2N(R2a)2 . .N(R2a)S(〇)2R2b . -c(i^)=N(R2a) and _c(R2a)=N(OR2a), where the Ci 6 yard base, heart 6 dilute, Q 6 alkynyl, carbocyclyl and heterocyclyl may be optionally substituted on the carbon with one or more R 2 , and wherein any of the ___ moieties of the heterocyclyl may be replaced by R 2 G * ; R2*, at each position, independently selected from Ci-6 alkyl, carbocyclyl, heterocyclyl, -C(0)H^-C(0)R2b. -C(〇)2R2c. .C(〇 N(R2a)2 . _S(〇)R2b ^ _S(〇)2R2b , -8(0)2 in 23)2, _〇:(1 ^) = from 23) and _ (: (圮3), 〇), wherein the ^6 alkyl group, carbocyclyl group and heterocyclic group are optionally present at each %, or independently a plurality of R 2 〇 substituted, and wherein any _NH- moiety of the heterocyclic group may be optionally substituted by r 2 〇 *; R 2a, in each presence, may be independently selected from hydrazine, Ci-6 alkyl, carbocyclyl and a heterocyclic group, wherein the 1-6 alkyl group, the carbocyclic group and the heterocyclic group are optionally substituted at the carbon, by one or more R 2 在 on the carbon, and wherein any of the heterocyclic groups The -NH- moiety may be optionally substituted by R 2 〇 *; R 2b ' may be selected from the group consisting of C -6 alkyl, C 2 · 6 alkenyl, c 2 - 6 alkynyl, carbocyclyl and heterocyclyl, wherein The alkyl group, the decyl group, the C2 6 alkynyl group, the 133151 -34·200906818 carbocyclic group and the heterocyclic group are produced in the long-term, and in each place, optionally and independently on the carbon. One or more R2 0 substitutions, and in the pot _ Wei $ feces less than 7 children, any -NH_ part of the group of the heterozygous group may be replaced by R2 G *; R2c' in each place , independently selected from the group consisting of a q.6m ring group and a heterocyclic group, Wherein the CJ-l 1 ring group and the heterocyclic group are optionally present on the carbon and one or more on the carbon, respectively. Substituted, and wherein any -NH- moiety of the heterocyclic group may be optionally substituted by R2〇*; R20' may be independently selected from the group consisting of _ group, _CN, Ci(5) group, Ch alkenyl group , C2-6 alkynyl, carbocyclyl, heterocyclic, 〇R2Ga, _SR2Ga, _N(R2Ga)2, -N(R2〇a)C(〇)R2〇b, Na 20a difficult 2〇a)2 , _n〇2, Na "a) -., -ON(R20^)2 . _C(〇)H . -C(〇)R2〇b , _C(〇)2R2 0a , _C(0)N(R20a 2 . -C(O)N(R2 0a)(〇R2 0a) ^ _〇C(〇)N(R2 0a)2 . .N(R2 〇a )C(〇)2R20 a , -N(R2 °a)C(〇)N(R2〇a)2 ' _〇c(〇)R2()b, _s(〇)R2()b ' _s (9) 2R20b, -S(〇)2N(R2〇a) 2. ~N(R20a)S(O)2R20b, -C(R2〇a)=N(R2〇a) and -C(R20a)=N(〇R2〇a); R, in each presence, Independently selected from the group consisting of Cl_6 alkyl, carbocyclyl, heterocyclic, -C(0)H, -C(0)R2〇b, _c(〇lr20c, _c(9), 2〇, _s(〇)R2〇b, -S(0)2 R2 0 b, -S(0)2 N(R2.a)2, _C(R2., eagle 2 0 ” and -c(r2.a 〇a ); R20a, at each place , which may be independently selected from the group consisting of hydrazine, Ci. 6 alkyl, carbocyclyl and heterocyclic; and, in each presence, may be independently selected from Ci6 alkyl, C26 alkenyl C2_6 alkynyl, carbocyclyl and heterocyclic; and R20e' may be independently selected from the group consisting of q.6 alkyl, carbocyclyl and heterocyclic in each presence. In another aspect, ring A is 4- to 6- A heterocyclic group wherein the 4- to 6-membered porridge 133151 -35 - 200906818 cyclic group is optionally substituted on the carbon by one or more R 2 ' and wherein the -4 to 6-membered heterocyclic group is any -NH - some of the groups are optionally substituted by R2*; R'in each of the 'existence' is independently selected from halo, _CN, C!-6 alkyl, -OR2 a, -N(R2a)2, _C(9)N (R2a 2, _N(R2a)c(〇)R2bA_N(R2a)c(〇)2R2a, wherein the Ci_6 alkyl group is optionally substituted by one or more R20; R2* is (ν6 alkyl; R2a' In each presence, independently selected from 11 and (: 1-6 alkyl; alkyl;

R20，於各存在處，係獨立選自鹵基、-CN、4-至6-員雜環基、 -OR2 0 a ' -N(R2 0 a )2 . _C(〇)2 r2 o a , _c(〇)N(R2 0 a )2 > -N(R2 0 a )C(0)2 R2 0 a &-N(R2°a)S(0)2Me;& R2〇a，於各存在處，係獨立選自H與Cu烷基。 於又另一方面，環A可為6_員雜環基，其中該6_員雜環基可 視情況在礙上被一或多個R2取代，且其中該6_員雜環基之 任何-NH-部份基團可視情況被R2*取代； R2可選自Η、鹵基、_CN、。卜6烷基、c2 6烯基、6炔基、 碳環基、雜環基、-0R2a、_SR2a、_N(R2a)2、_N(R2a)c(〇)R2b、 -N(R2a)N(R2a)2、_N〇2 -C(0)R2 b 、-C(〇)2 R2 a -N(R2a)〇R2a、_〇N(R2a)2、_c(〇)H、 -C(0)N(R2a)2 、 -C(0)N(R2a)(〇R2a)- 0C(0)N(R2a)2 ' -N(R2a)C(〇^R2a Λ -N(R2a)C(0)N(R2a)2 > -0C(0)R2b ' -S(0)R2b ' -S(0)2R2b , _S(〇)2N(R2a)2 % -N(R2a)S(0)2R2b > -C〇^=N(R2M_c(R2a)=N(〇R2a)，其中該Ch院基、k 稀 基、C2_6炔基、碳環基及雜環基可視情況在碳上被一或多 個R20取代，且其中該雜環基之任何___部份基團可視情況 133151 -36 - 200906818 被R2 G *取代； W ’於各存在處，可獨立選自、碳環基、雜環基 -C(〇)H ^ -C(〇)R2K .C(0)2r2c . _C(〇)N(R2a)2 ^ _S(〇)r2k _s(〇)2R2b ^ -S(〇)2N(R2a)2 . -€(Κ^)=Ν(Κ23)^_€(κ23)=Ν(〇κ23) 5 ^ t 6 燒基核基及雜環基’於各存在處，可視情況且獨立地 在碳上被一或多個RM取代，且其中該雜環基之任何_ΝΗ·部 份基團可視情況被R20*取代； R:，於各存在處，可獨立選自H、Ch烷基、碳環基及雜 %基’其中該Ci —院基、碳環基及雜環基，於各存在處， 可視情況且獨立地在碳上被—或多個R2〇取代，且其中該雜 環基之任何-NH-部份基團可視情況被RU*取代； R2b，於各存在處，可選自16烧基、C2 6稀基、Ch快基、 =基及雜環基，其中該^燒基、&烯基、&快基、 炭衣基及雜％基，於各存在處，可視情況且獨立地在碳上 被或多個R2〇取代，且其中該雜環基之任何-νη_部份基團 可視情況被R2G*取代； R2<： ’於各存在處，可獨立選自Ch烷基、碳環基及雜環 基，其中該C!—6烷基、碳環基及雜環基，於各存在處，可 視情況且獨立地在碳上被—或多個r2g取代，且其中該雜環 基之任何-NH-部份基團可視情況被R2Q *取代； R20 ’於各存在處，可獨立選自齒基、_CN、Ci 6院基、〔Μ 烯基、C2·6炔基、碳環基、雜環基、-〇R20a、-SR2()a、-N(R2〇a)2、 -N(R 〇a)c(Q)R2Gb、_N(R2Ga)N(R2Ga)2、、_N(R2Qa)_〇R2〇a、 〇N(R )2 . -C(0)H ' -C(〇)R2〇b % _C(〇)2R20a > -C(〇)N(R2〇a)2 , 133151 •37· 200906818 -C(0)N(R2°a)(〇R2°a)、_〇c(〇)N(R2°a)2、-N(R2〇a)c(〇)2R2〇a、 -N(R20a)C(O)N(R20a)2 . -〇C(O)R20b > -S(O)R20b，-S(O)2R20b > -S(O)2N(R20a)2 、-N(R20a)S(O)2R20b 、-C(R2 〇 a )=N(R2 o a)及 -C(R20a)=N(OR20a); r2〇，於各存在處，可獨立選自Ci_6烷基、碳環基、雜環基、 -C(0)H、-C(〇)R2°b、_C(〇)2R2〇C、_c(〇)N(R2〇a)2、_s(〇)R2〇b、 -S(O)2R20b、-S(〇)2N(R20a)2、-C(R20a)=N(R20a)及-C(R2〇a)=N(〇R2〇a); R20a,於各存在處，可獨立選自H、Cl_6烷基'碳環基及雜 環基； R2〇b，於各存在處，可獨立選自Ch烷基、烯基、C2 6 快基、碳壤基及雜環基；且 R20e，於各存在處’可獨立選自c] 6烷基、碳環基及雜環基。 ;再另方φ ’環A可為雜環基，其中該雜環基之任 何-NH-部份基團可視情況被r2*取代；且 R2 ，於各存在處，可獨立選自Ci 6烷基。 =步方面’環A可為5_或6_員雜環基，其中該&或、 ' :、衣土之任何姻-部份基團可視情況被R2*取代；且 R2 ，於各存在處，可獨立選自C16烷基。 於又再進一步方面，環 中了為5_或6_員非芳族雜環基，其 人5 、卩方族雜環基之任何-NH-部份臭ϋ τ、s # 被R2*取代；且 切基團可視情況 R2 ’於各存在處，可獨立選自Ci 6烧基。R20, at each position, is independently selected from halo, -CN, 4- to 6-membered heterocyclic, -OR2 0 a ' -N(R2 0 a )2 . _C(〇)2 r2 oa , _c (〇)N(R2 0 a )2 > -N(R2 0 a )C(0)2 R2 0 a &-N(R2°a)S(0)2Me;& R2〇a, in each Where present, they are independently selected from the group consisting of H and Cu alkyl. In yet another aspect, Ring A can be a 6-membered heterocyclic group, wherein the 6-membered heterocyclic group can be optionally substituted by one or more R 2 , and wherein any of the 6-membered heterocyclic groups is - The NH- moiety may be optionally substituted by R2*; R2 may be selected from the group consisting of hydrazine, halo, and _CN. 6 alkyl, c2 6 alkenyl, 6 alkynyl, carbocyclyl, heterocyclyl, -0R2a, _SR2a, _N(R2a)2, _N(R2a)c(〇)R2b, -N(R2a)N( R2a)2, _N〇2 -C(0)R2 b, -C(〇)2 R2 a -N(R2a)〇R2a, _〇N(R2a)2, _c(〇)H, -C(0) N(R2a)2, -C(0)N(R2a)(〇R2a)- 0C(0)N(R2a)2 ' -N(R2a)C(〇^R2a Λ -N(R2a)C(0) N(R2a)2 > -0C(0)R2b ' -S(0)R2b ' -S(0)2R2b , _S(〇)2N(R2a)2 % -N(R2a)S(0)2R2b > -C〇^=N(R2M_c(R2a)=N(〇R2a), wherein the Ch-based, k-dilute, C2_6 alkynyl, carbocyclic and heterocyclic groups may optionally be one or more R20 on the carbon Substituted, and wherein any of the __- moiety of the heterocyclic group may be substituted by R 2 G * as the case may be, 133151 -36 - 200906818; W' may be independently selected from the group, carbocyclyl, heterocyclic group - C(〇)H ^ -C(〇)R2K .C(0)2r2c . _C(〇)N(R2a)2 ^ _S(〇)r2k _s(〇)2R2b ^ -S(〇)2N(R2a)2 -€(Κ^)=Ν(Κ23)^_€(κ23)=Ν(〇κ23) 5 ^ t 6 The ketone group and the heterocyclic group are present at each, optionally and independently on carbon Substituted by one or more RM, and wherein any of the _ΝΗ· groups of the heterocyclic group may be R20* as appropriate Substituting; R: at each position, independently selected from H, Ch alkyl, carbocyclyl and hetero-l', wherein the Ci-hospital, carbocyclic and heterocyclic groups, in each presence, as appropriate And independently substituted on the carbon by - or a plurality of R 2 , and wherein any -NH- moiety of the heterocyclic group may be optionally substituted by RU*; R 2b, in each presence, may be selected from the group consisting of 16 alkyl , C 2 6 dilute group, Ch fast group, = group and heterocyclic group, wherein the alkyl group, & alkenyl group, & fast group, carbon-based group and hetero-based group, in each presence, may be independent and independent Is substituted on the carbon by a plurality of R 2 ,, and wherein any -νη_ moiety of the heterocyclic group may be optionally substituted by R 2 G *; R 2 <: ' at each position, independently selected from a C alkyl group a carbocyclic group and a heterocyclic group, wherein the C!-6 alkyl group, the carbocyclic group and the heterocyclic group are optionally substituted on the carbon by - or a plurality of r2g, respectively, and wherein Any -NH- moiety of the heterocyclic group may be optionally substituted by R2Q*; R20' may be independently selected from the group consisting of a dentate group, a _CN, a Ci 6 substituent, a [nonenyl group, a C2·6 alkynyl group. Carbocyclic group Heterocyclic group, -〇R20a, -SR2()a, -N(R2〇a)2, -N(R 〇a)c(Q)R2Gb, _N(R2Ga)N(R2Ga)2, _N(R2Qa )_〇R2〇a, 〇N(R )2 . -C(0)H ' -C(〇)R2〇b % _C(〇)2R20a > -C(〇)N(R2〇a)2 , 133151 •37· 200906818 -C(0)N(R2°a)(〇R2°a), _〇c(〇)N(R2°a)2, -N(R2〇a)c(〇)2R2〇 a, -N(R20a)C(O)N(R20a)2 . -〇C(O)R20b > -S(O)R20b, -S(O)2R20b > -S(O)2N(R20a) 2, -N(R20a)S(O)2R20b, -C(R2 〇a )=N(R2 oa) and -C(R20a)=N(OR20a); r2〇, in each place, can be independently selected Ci_6 alkyl, carbocyclyl, heterocyclic, -C(0)H, -C(〇)R2°b, _C(〇)2R2〇C, _c(〇)N(R2〇a)2, _s( 〇)R2〇b, -S(O)2R20b, -S(〇)2N(R20a)2, -C(R20a)=N(R20a), and -C(R2〇a)=N(〇R2〇a) R20a, in each presence, may be independently selected from H, Cl-6 alkyl-carbocyclyl and heterocyclic; R2〇b, in each position, may be independently selected from the group consisting of Ch alkyl, alkenyl, C2 6 fast radicals a carbon-based base and a heterocyclic group; and R20e, in each of the presences, may be independently selected from the group consisting of c] 6 alkyl, carbocyclic and heterocyclic. Further, φ 'ring A may be a heterocyclic group, wherein any -NH- moiety of the heterocyclic group may be optionally substituted by r2*; and R2, in each presence, may be independently selected from Ci 6 alkane. base. = step aspect 'ring A' may be a 5_ or 6_ member heterocyclic group, wherein the & or, ':, any of the marriage-partial groups of the soil may be replaced by R2*; and R2 exists in each It can be independently selected from C16 alkyl. In still another aspect, the ring is a 5- or 6-membered non-aromatic heterocyclic group, and any -NH- moiety skunk τ, s # of the human 5, anthracene heterocyclic group is replaced by R2* And the cleavage group can be independently selected from the Ci 6 alkyl group, where R2' is present at each position.

於又再進·一 JLfc^ -JK 乂 面，環A係選自一氮四圓其 μ-氧氮七圜烷基… 虱四圜基、嗎福啉基、 基六蝴基、六氣吨。定基及四祕 133151 •38- 200906818 基，其中該一氮四圜基、嗎福啉基、1,4-氧氮七圜烷基、六 氫p井基、六氫0比σ定基、四氫P比嘻基係視情況在碳上被一 或多個R2取代，且其中該六氫吡畊基之任何-ΝΗ-部份基團 係視情況被R2 *取代； R2為鹵基、-CN、Cu烷基、-N(R2a)2、-OR2a、-C(0)N(R2a)2、 -N(H)C(0)R2b及-N(R2a)c(〇)2R2a，其中該心^烷基，於各存在 處’係視情況且獨立地被一或多個R2 Q取代； R2a ’於各存在處’係獨立選自Η與q_6烷基； 烷基； 烷基； R20，於各存在處，係獨立選自鹵基、_CN、一氮四圜基、 -OR2 0 a、_N(R2 〇 a )2、_c⑼2 r2 〇 a、_c(〇)n(r2 〇 a )2、_n(h)c(〇)2 r2 〇 a 及-N(H)S(O)2R20b ; R a，於各存在處，係獨立選自H與c卜6烷基；且 ”“為^巧烷基。 於方面’環人可選自嗎福啉基與六氫吡畊基，其中該 馬福琳基與六氫峨P井基之任何视.部份基團可視情況被 R2%取代；且 R2<：可獨立選自C!-6烷基。 /另-方面’環A可選自嗎福b林基與六氫七井基，其中 <馬細'林基與六氫井基之任何.丽_心分基團彳視情況被 F取代；且 R2 a可獨立選自曱基。 於又另-方φ，環A係選自3_(乙酿胺基卜氣四園小基、 133151 -39- 200906818 3_(乙醯胺基）四氫吡咯-1-基、3-(胺基甲基）六氫吡啶-1-基、3-胺基/、氯卩比咬_1_基、2_(一氮四圜_丨_基甲基）嗎福琳_4_基、3_ 氰基一氮四圜+基、2-(氰基甲基）嗎福啉-4-基、3-(氰基甲基） 嗎福淋冰基、2_(氰基甲基）六氫吡啶-1-基、3-氰基六氫吡啶-1-基、4_氛基六氫吡啶-1-基、2-[(二乙胺基）甲基]嗎福啉-4-基、 3,3-二氣一氮四園小基、2仁氟甲基）嗎福啉_4_基、3_(二氟甲 3,3-二氟六氫p比咬-1-基、4,4-二氟六氫p比咬-1- 基、3,3-二I四氫吡咯-1·基、3-(二甲胺基）一氮四圜-1-基、3-[(二 曱胺基）羰基]甲基嗎福啉_4_基、二曱胺基）羰基]嗎福啉_4_ 基、3-[(一甲胺基）曱基]六氫吡啶小基、3 (二曱胺基）四氫吡 洛-1-基、2,2-二甲基嗎福琳_4_基、2,6_二甲基嗎福琳_4_基、3,3_ 一曱基嗎福啉_4_基、3_{[(乙氧羰基）胺基]甲基丨嗎福啉_4_基、 2-乙基嗎福琳_4_基、3_乙基嗎福琳冰基、3_乙氧基四氫吡咯 小基、3·氟基一氮四圜小基、3_氟基六氫吡啶小基、本氟基 六虱吡啶-1-基、3-羥基—氮四圜小基、3_(2-羥乙基）嗎福啉斗 基、2-(經甲基）一氮四園]•基' 3_經基各甲基—氮四園+基、 2-(羥甲基）嗎福啉-4-基、 3 (%甲基）嗎福p林_4_基、3-經基_3_甲Further re-into a JLfc^-JK kneading surface, ring A is selected from the group consisting of a nitrogen-tetracycline, its μ-oxygen-7-nonylalkyl group, 虱tetradecyl, morpholinyl, hexamyl, six gas ton .基基和四秘 133151 •38- 200906818 base, wherein the nitrotetradecyl group, morpholinyl group, 1,4-oxazolodecenyl group, hexahydro-p-well group, hexahydro- 0-sigma group, tetrahydrogen P is more optionally substituted on the carbon by one or more R2, and wherein any -ΝΗ-part group of the hexahydropyrrole is optionally substituted by R2*; R2 is halo, -CN , Cu alkyl, -N(R2a)2, -OR2a, -C(0)N(R2a)2, -N(H)C(0)R2b, and -N(R2a)c(〇)2R2a, wherein The heart alkyl group, at each position, is optionally substituted with one or more R 2 Qs; R 2a 'in each presence' is independently selected from the group consisting of hydrazine and q_6 alkyl; alkyl; alkyl; R20, In each place, it is independently selected from a halogen group, _CN, a nitrogen tetradecyl group, -OR2 0 a, _N(R2 〇a )2, _c(9)2 r2 〇a, _c(〇)n(r2 〇a )2. _n(h)c(〇)2 r2 〇a and -N(H)S(O)2R20b ; R a , in each presence, independently selected from H and c 6 alkyl; and "" alkyl. In the aspect, the ring can be selected from the group consisting of morpholinyl and hexahydropyrrole, wherein any of the groups of the moffinyl and hexahydropyrene P groups can be optionally substituted by R2%; and R2<: Independently selected from C!-6 alkyl. /Alternatively, 'ring A' may be selected from the group consisting of ruthenium b-based and hexahydro-seven-pile, wherein any of the <Ma's 'linyl and hexahydro-well groups are replaced by F; And R2a can be independently selected from the group consisting of sulfhydryl groups. Further, the other side is φ, and the ring A is selected from the group consisting of 3_(Ethylamine, Buqi, Siyuan, Xiaoji, 133151-39-200906818 3_(ethylamino)tetrahydropyrrol-1-yl, 3-(amino group) Methyl) hexahydropyridin-1-yl, 3-amino/, chlorohydrazine ratio _1_yl, 2_(mononitrotetradecyl-fluorenylmethyl) carbaryl _4-yl, 3-cyano Nitrotetradecyl+yl, 2-(cyanomethyl)norfosolin-4-yl, 3-(cyanomethyl) whufate, 2-((cyanomethyl)hexahydropyridine-1- , 3-cyanohexahydropyridin-1-yl, 4-ylhexahydropyridin-1-yl, 2-[(diethylamino)methyl]norfosolin-4-yl, 3,3- Diqi, Nitrogen, 4 Park, Small, 2, Fluoromethyl), Florox, 4, 4-(3,3-difluoromethyl 3,3-difluorohexahydrop, butyl-1-yl, 4,4-difluoro Hexahydro-p-buty-1-yl, 3,3-di-I-tetrahydropyrrole-1·yl, 3-(dimethylamino)-azinotetradec-1-yl, 3-[(didecylamino) Carbonyl]methylmorpholine-4-yl, bis-amino)carbonyl]norfosolin-4-yl, 3-[(monomethylamino)indolyl]hexahydropyridine, 3 (diamylamine) ) tetrahydropyrrol-1-yl, 2,2-dimethylmorphine _4_yl, 2,6-dimethylmorphin _4_yl, 3,3_indolyl porphyrin _ 4_based, 3_{[(ethoxycarbonyl) Methyl hydrazinoline _4_ group, 2-ethyl phoxalin _4 yl group, 3-ethyl phenoline aryl group, 3 ethoxytetrahydropyrrole group, 3 · fluoro group Nitrogen tetramethylene small group, 3-fluorohexahydropyridine small group, present fluoro hexamidine pyridin-1-yl, 3-hydroxy-nitrotetradecyl small group, 3-(2-hydroxyethyl) porphyrin Base, 2-(methyl)-nitrogen four-potassium]•yl' 3_yl-methyl-nitrogen tetra-carboxyl, 2-(hydroxymethyl)norfosolin-4-yl, 3 (%A基)福福p林_4_基,3-经基_3_甲

基）幾基]嗎福淋斗基、3h -、3·(甲胺基）一氮四圜-1-基、3-[(甲胺 3_(甲胺基）四氫吡咯-1-基、2-曱基嗎福 133151 -40- 200906818 琳-4-基、3-甲基嗎福啦_4.基、4_甲基-3_酮基六氫峨p井基、 3_{[(甲石頁醯基）胺基]甲基}嗎福啉_4_基、嗎福啉_4_基、4_甲基 六氫吡畊-1-基、1，4-氧氮七圓_4_基、3_{[(第三_丁氧羰基）胺基] 甲基}六氫吡啶小基及3-[(第三丁氧羰基）胺基]六氫吡啶-l 基。a group of sulfonyl, 3h-, 3-(methylamino)-azinotetradec-1-yl, 3-[(methylamine 3-(methylamino)tetrahydropyrrole-1-yl, 2-曱基吗福133151 -40- 200906818 lin-4-yl, 3-methyl-fro- _4. yl, 4-methyl-3-keto hexahydroindole p well base, 3_{[(A石 ) ) ) ) ) ) ) ) ) ) ) ) ) 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 _ group, 3_{[(tris-butoxycarbonyl)amino]methyl}hexahydropyridine small group and 3-[(tatabutoxycarbonyl)amino]hexahydropyridine-1 group.

環B 於一方面，環B可選自碳環基與雜環基，其中該碳環基 ( '與雜環基可視情況在碳上被一或多個R4取代，且其中該雜 環基之任何-NH-部份基團可視情況被R4*取代； R4可選自Η、豳基、-CN、Ci6烷基、c26烯基、c26炔基、 石炭環基、雜環基、-〇R4a、_SR4a、_N(R4a)2、_N(R4a)c(〇)R4b、 -N(R4a)N(R4a)2 ^ -N02 ^ -Ν(Κ^).〇Κ4α % _〇.N(R4a)2 N _C(〇)H Λ -C(0)R b > -C(0)2R4a > -C(〇)N(R4a)2 . -C(0)N(R4 a )(〇R4 a 〇C(0)N(R4a)2 ^ -N(R4a)C(〇)2R4a Λ -N(R4^)C(0)N(R4a)2 ^ -0C(0)R4b , -S(0)R4b . -S(〇)2R4b . -S(〇)2N(R4-)2 > -N(R4^)S(0)2R4b , (-咖3)傳43)及你3)，〇^)，其中該Cl-6院基、c2.6烯 基、C2_6炔基、碳環基及雜環基可視情況在碳上被一或多 個R40取代，且其中該雜環基之任何_NH_部份基團可視情況 被R40*取代； R4*，於各存在處，可獨立選自Ci —烷基、碳環基、雜環基、 -C(0)H、·(：⑼R4b、_C(Q)2R4e、_c(Q)N(R4a)2、娜⑽、s(%R4b、 -S(0)2 N(R4 a )2 ' _C(R4 a )=n(r4 a )及 _c(r4 a )=N(〇R4 a )，其中該 q · 6 院基、碳環基及雜環基，於各存在處，可視情況且獨立地 在碳上被-或多個_取代，且其中該雜環基之任何·部 133151 -41 · 200906818 份基團可視情況被R40*取代； Γ，於各存在處，可獨立選自H、Ch烧基、碳環基及雜 %基’其中g Cl ·6炫基、碳環基及雜環基於各存在處： 可視h况且獨立地在碳上被—或多個r4〇取代’且其中該雜 環基之任何-NH-部份基團可視情況被R4 〇 *取代丨 ‘ R4b ’於各存在處，可選自Cl.6燒基、c2 6稀基、c2 6块基、 =基及雜環基，其中該基、c2.6烯基、C2.6炔基、Ring B In one aspect, Ring B can be selected from a carbocyclic group and a heterocyclic group, wherein the carbocyclic group ('and a heterocyclic group are optionally substituted on the carbon by one or more R4, and wherein the heterocyclic group Any -NH- moiety may be optionally substituted by R4*; R4 may be selected from fluorene, fluorenyl, -CN, Ci6 alkyl, c26 alkenyl, c26 alkynyl, carbolic ring, heterocyclyl, -R4a , _SR4a, _N(R4a)2, _N(R4a)c(〇)R4b, -N(R4a)N(R4a)2^-N02^-Ν(Κ^).〇Κ4α % _〇.N(R4a) 2 N _C(〇)H Λ -C(0)R b > -C(0)2R4a > -C(〇)N(R4a)2 . -C(0)N(R4 a )(〇R4 a 〇C(0)N(R4a)2 ^ -N(R4a)C(〇)2R4a Λ -N(R4^)C(0)N(R4a)2 ^ -0C(0)R4b , -S(0) R4b . -S(〇)2R4b . -S(〇)2N(R4-)2 > -N(R4^)S(0)2R4b , (-C3) Pass 43) and you 3),〇^) Wherein the Cl-6, c2.6 alkenyl, C2_6 alkynyl, carbocyclyl and heterocyclyl are optionally substituted on the carbon by one or more R40, and wherein any _NH_ of the heterocyclic group Some of the groups may be substituted by R40* as appropriate; R4*, in each position, may be independently selected from Ci-alkyl, carbocyclyl, heterocyclyl, -C(0)H, ·(:(9)R4b, _C( Q) 2R4e, _c(Q)N(R4a)2, Na(10), s(% R4b, -S(0)2 N(R4 a )2 ' _C(R4 a )=n(r4 a ) and _c(r4 a )=N(〇R4 a ), wherein the q · 6 yard base, carbon The cyclic group and the heterocyclic group are optionally substituted on the carbon by - or a plurality of _ at each position, and wherein any of the 133151 -41 · 200906818 groups of the heterocyclic group may be R40 as the case may be. *Substitution; Γ, at each position, may be independently selected from H, Ch alkyl, carbocyclyl and hetero-l' wherein gCl.6 leuco, carbocyclyl and heterocycle are based on their presence: Independently substituted on carbon by - or a plurality of r4 ' ' and wherein any -NH- moiety of the heterocyclic group may be optionally substituted by R 4 〇 * 丨 ' R 4b ' at each position, may be selected from Cl. 6 alkyl, c2 6 dilute, c 2 6 block, = base and heterocyclic group, wherein the group, c2.6 alkenyl, C2.6 alkynyl,

V 碳環基及雜環基’於各存在處，可視情況且獨立地在碳上 被一或多個R40取代，且其中該雜環基之任何-丽-部份基團 可視情況被R4Q*取代； R4c，於各存在處，可獨立選，自Ci 6烷基、碳環基及雜環基， 其中該q_6烷基、碳環基及雜環基，於各存在處，可視情 況且獨立地在碳上被一或多個r4〇取代，且其中該雜環基之 任何-NH-部份基團可視情況被R4〇*取代； R40’於各存在處，可獨立選自鹵基、-CN、C卜6烷基、c2_6 烯基、C2-6炔基、碳環基、雜環基、_〇R4Ga、_SR4Qa、_N(R4Ga)2、 -N(R40a)C(O)R40b、_N(R4〇a)N(R40a)2、_N〇2、_N(R40a)，〇R40a、 0_N(R4Qa)2、-C(0)H、-C(0)R4Qb、-C(O)2R40a、-C(0)N(R4()a)2、 -C(O)N(R40a)(〇R40”、_〇c⑼N(R4〇”2、_N(R4〇a)c(〇)2R40a、 -N(R40a)C(O)N(R40a)2、-〇c(〇)R4 0b、_s(〇)R4〇b、_s(〇)2R40b、 -S(O)2N(R40a)2、-N(R40a)S(O)2R40b、_C(R4 ° a )=N(R4 o a)及 -C(R40a)=N(OR40a); R40，於各存在處，可獨立選自Cu炫基、碳環基、雜環基、 -C(0)H、-C(O)R40b、_c(O)2R40c、-C(O)N(R40a)2、_s(〇)R4〇b、 133151 -42- 200906818 -S(O)2R40b、-S(0)2N(R4〇a)2、_c(R40a)=N(R40a)及 _c(R4〇a)=N(⑽〇a); C ’於各存在處，可獨立選自H、CH燒基、碳環基及雜 環基； R4〇b，於各存在處，可獨立選自Ch院基、C2_6烯基、C2 6 炔基、碳環基及雜環基；且 R40c，於各存在處，可獨立選自6烧基、碳環基及雜環基。 於另-方面’環B可為雜環基，其中該雜環基可視情況V Carbocyclyl and Heterocyclyl 'in each occurrence, optionally and independently substituted on the carbon by one or more R40, and wherein any -Li-partyl group of the heterocyclic group may be optionally R4Q* Substituted; R4c, in each position, independently selected from Ci 6 alkyl, carbocyclyl and heterocyclic, wherein the q-6 alkyl, carbocyclyl and heterocyclyl are, where appropriate, optionally and independently Substituted on the carbon by one or more r4〇, and wherein any -NH- moiety of the heterocyclic group may be optionally substituted by R4〇*; R40' may be independently selected from the group consisting of halo, -CN, C hexaalkyl, c2_6 alkenyl, C 2-6 alkynyl, carbocyclyl, heterocyclyl, 〇R4Ga, _SR4Qa, _N(R4Ga)2, -N(R40a)C(O)R40b, _N(R4〇a)N(R40a)2, _N〇2, _N(R40a), 〇R40a, 0_N(R4Qa)2, -C(0)H, -C(0)R4Qb, -C(O)2R40a , -C(0)N(R4()a)2, -C(O)N(R40a)(〇R40", _〇c(9)N(R4〇"2, _N(R4〇a)c(〇)2R40a, -N(R40a)C(O)N(R40a)2, -〇c(〇)R4 0b, _s(〇)R4〇b, _s(〇)2R40b, -S(O)2N(R40a)2, - N(R40a)S(O)2R40b, _C(R4 ° a )=N(R4 oa) and -C(R40a)=N(OR40a); R40, present in each , which may be independently selected from Cu thio, carbocyclyl, heterocyclyl, -C(0)H, -C(O)R40b, _c(O)2R40c, -C(O)N(R40a)2, _s( 〇)R4〇b, 133151 -42- 200906818 -S(O)2R40b, -S(0)2N(R4〇a)2, _c(R40a)=N(R40a) and _c(R4〇a)=N ((10)〇a); C' may be independently selected from the group consisting of H, CH alkyl, carbocyclyl and heterocyclic; R4〇b, in each presence, may be independently selected from the group consisting of Ch, C2_6 a group, a C2 6 alkynyl group, a carbocyclic group and a heterocyclic group; and R40c, in each of the above, may be independently selected from the group consisting of a 6 alkyl group, a carbocyclic group and a heterocyclic group. In another aspect, the ring B may be a heterocyclic ring. Base, wherein the heterocyclic group can be used as the case may be

在碳上被一或多個R4取代，且其中該雜環基之任何·阳-部 份基團可視情況被R4 *取代； R4可選自Η、鹵基、CN、Ci 6烷基、c“烯基、炔基、 碳環基、雜環基、领“、_SR4a、_N(R4a)2、_N(R4a)c(〇)R4b、 -N(R4a)N(R4^)2 > .N02 , .N(R4a).〇R4a , _〇_N(R4a)2 x _C(〇)H ^ "C(〇)R4b ' -C(〇)2R4a ' -C(0)N(R4a)2 . ^(0)Ν(Κ^)(ΟΚ43). 〇C(0)N(R )2、_N(R4 a )C(〇)2 R4 a、_n(r4 a )c(〇)n(r4 a )2、_〇c(〇)r4 b、 -S(〇)R4b > -S(〇)2R4b . .S(〇)2N(R4a)2 . -N(R4a)S(〇)2R4b . -CXR，N(R“）及-C(R4a)哪R4a)，其中該 Ci6 院基、& 6 稀 土 2 -6块基奴環基及雜環基可視情況在碳上被一或多 個R取&且其中该雜環基之任何视·部份基围可視情況 被R4G*取代； R4 ’於各存在處’可獨立選自Ci 6烷基、碳環基、雜環基、 -C(〇)H ^ -C(0)R4K ,C(〇)2R4c. .C(〇)N(R4a)2 ^ _S(〇)r4K _s(〇)2R4b ^ -S(0)2N(R4a)2、_c(R4a)=N(R4a)及 _c(R4a㈣〇R4”，其中該 k … 炭I基及雜環基，於各存在處，可視情況且獨立地 在碳上被一或多個R4 0取代， 且其中該雜環基之任何-NH-部 133151 43- 200906818 份基團可視情況被R40*取代； =，於各存在處，可獨立選自H、Ci㈤基、碳環基及雜 %基’其中該Cl·6烧基、碳環基及雜環基，於各存在處， 可視情況且獨立地在碳上被—或多個r4g取代，且其中該雜 環基之任何-NH-部份基團可視情況被圮❶*取代； 心，於各存在處，可選自基、c2.6烯基、c2_6炔基、 碳環基及雜環基，其中叫4基、Ch稀基、C2 6快基、 碳環基及雜環基，於各存在處，可視情況且獨立地在碳上 被一或多個R40取代，且其中該雜環基之任何NH-部份基團 可視情況被R4G*取代； R4c，於各存在處，可獨立選自Ci —烷基、碳環基及雜環基， 其中該c^6烧基、碳環基及雜環基，於各存在處，可視情 況且獨立地在碳上被一或多個R4〇取代，且其中該雜環基之 任何-NH-部份基團可視情況被r4g *取代；R4〇，於各存在處， 可獨立選自li基、-CN、Cl_6烷基、c2_6烯基、&炔基、 碳環基、雜環基 ' -OR4 0 a、-SR4 G a、-N(；R4 0 a )2、-N(；R4 0 a 0 b、 -N(R4°a)N(R4°a)2、_N02、-N(R4°a)-〇R4()a、-〇-N(R4°a)2、-C(〇)H、 -C(O)R40b、_C(O)2R40a、-C(〇)N(R40a)2、-C(O)N(R40a)(〇R40a)、 -〇C(0)N(R4°a)2、-N(R40a)C(O)2R4()a、-N(R4°a)C(〇)N(R4°a)2、 -OC(0)R4〇b 、 -S(0)R4〇b 、 _S(0)2R4〇b 、 _s(〇)2N(R4〇a)2 、 -N(R4°a)S(0)2R4°b、-C(R4°a)=N(R40a)及-C(R40a)=N(OR40a); R40* ’於各存在處’可獨立選自Cl 6烷基、碳環基、雜環基、 -C(0)H、-C(O)R40b、-C(O)2R40c、-C(O)N(R40a)2、_s(O)R40b、 -S(O)2R40b、-S(O)2N(R4()a)2、-C(R4°a)=N(R40a)及-C(R4〇a)=N(OR4〇a); 133151 -44- 200906818 R4 0 a，於各存在處 環基； 可獨立選自Η、Ci_6烷基 碳環基及雜 R ’於各存在處，可獨立選自烧基、C2-6烯基、C-炔基、碳環基及雜環基；且 R C，於各存在處，可獨立選自Ch烷基、碳環基及雜環基。 ;另方面，環B可為6-員雜環基，其中該6_員雜環基 可視情況在碳上被—❹個r4取代，且其中該雜環基之^ 何-NH-部份基團可視情況被R4*取代； R可選自H、鹵基、_CN、Ch烷基、C2_6烯基、c2 6炔基、 碳環基、雜環基、_〇R4a、观4a、_N(R4a)2、娜“剛心、 -N(R )N(R“)2、_Nq2、N(R4a)_〇R4a、·⑽(r4、、_c(〇)h、 -C(0)R4b、_c(〇)2R4a、_c 綱 η、_c ⑼聰 “)(〇卜)_ 0C(0)N(R4a)2、_N(R4a)c(〇)2R4a、_N(R4a)c⑼N(R4a)n⑼^、 'S(〇)R4b ' -S^〇)2R4b ' -S(〇)2N(R^)2 . -N(R4a)S(〇)2R4b . 傳及谓4a)=N(OR4a)，其中該CH烧基、^婦Substituted by one or more R4 on the carbon, and wherein any cation-partial group of the heterocyclic group may be optionally substituted by R4*; R4 may be selected from fluorene, halo, CN, Ci6 alkyl, c "Alkenyl, alkynyl, carbocyclyl, heterocyclyl, collar", _SR4a, _N(R4a)2, _N(R4a)c(〇)R4b, -N(R4a)N(R4^)2 > N02 , .N(R4a).〇R4a , _〇_N(R4a)2 x _C(〇)H ^ "C(〇)R4b ' -C(〇)2R4a ' -C(0)N(R4a) 2. ^(0)Ν(Κ^)(ΟΚ43). 〇C(0)N(R )2, _N(R4 a )C(〇)2 R4 a, _n(r4 a )c(〇)n( R4 a )2, _〇c(〇)r4 b, -S(〇)R4b > -S(〇)2R4b . .S(〇)2N(R4a)2 . -N(R4a)S(〇)2R4b -CXR, N(R") and -C(R4a), which R4a), wherein the Ci6, and the <6 rare earth 2 -6 gram cyclyl and heterocyclic group may be one or more on carbon And R may be substituted by R4G*; R4 'in each presence' may be independently selected from Ci 6 alkyl, carbocyclyl, heterocyclyl, -C(〇)H ^ -C(0)R4K ,C(〇)2R4c. .C(〇)N(R4a)2 ^ _S(〇)r4K _s(〇)2R4b ^ -S(0)2N(R4a 2, _c (R4a) = N (R4a) and _c (R4a (four) 〇 R4", wherein the k ... carbon I base And a heterocyclic group, at each position, optionally and independently substituted on the carbon by one or more R40, and wherein any -NH- moiety of the heterocyclic group 133151 43-200906818 of the group may be optionally R40 *Substituted; =, at each position, independently selected from H, Ci(5), carbocyclyl and heteropoly', wherein the Cl6, carbocyclyl and heterocyclyl are present at each position, as appropriate And independently substituted on the carbon by - or a plurality of r4g, and wherein any -NH- moiety of the heterocyclic group may be optionally substituted by 圮❶*; the heart, at each presence, may be selected from the group, c2 .6 alkenyl, c2_6 alkynyl, carbocyclyl and heterocyclic, wherein 4, Ch, C2, carbyl, carbocyclyl and heterocyclyl are present, optionally, independently Substituting carbon for one or more R40, and wherein any NH-partic group of the heterocyclic group may be optionally substituted by R4G*; R4c, in each presence, may be independently selected from Ci-alkyl, carbocyclyl And a heterocyclic group, wherein the c6 alkyl group, the carbocyclic group and the heterocyclic group are optionally substituted on the carbon by one or more R4〇, and wherein Any -NH- moiety of the ring group may be optionally substituted by r4g*; R4〇, at each position, may be independently selected from the group consisting of li, -CN, Cl_6 alkyl, c2_6 alkenyl, & alkynyl, carbon Ring group, heterocyclic group '-OR4 0 a, -SR4 G a, -N(;R4 0 a )2, -N(;R4 0 a 0 b, -N(R4°a)N(R4°a) 2, _N02, -N(R4°a)-〇R4()a, -〇-N(R4°a)2, -C(〇)H, -C(O)R40b, _C(O)2R40a,- C(〇)N(R40a)2, -C(O)N(R40a)(〇R40a), -〇C(0)N(R4°a)2, -N(R40a)C(O)2R4() a, -N(R4°a)C(〇)N(R4°a)2, -OC(0)R4〇b, -S(0)R4〇b, _S(0)2R4〇b, _s(〇 2N(R4〇a)2, -N(R4°a)S(0)2R4°b, -C(R4°a)=N(R40a) and -C(R40a)=N(OR40a); R40* 'in each occurrence' may be independently selected from Cl 6 alkyl, carbocyclyl, heterocyclyl, -C(0)H, -C(O)R40b, -C(O)2R40c, -C(O)N (R40a)2, _s(O)R40b, -S(O)2R40b, -S(O)2N(R4()a)2, -C(R4°a)=N(R40a) and -C(R4〇 a)=N(OR4〇a); 133151 -44- 200906818 R4 0 a, ring group at each position; independently selected from hydrazine, Ci_6 alkyl carbocyclyl and hetero-R' in each position, independently selected Self-alkylating group, C2-6 alkenyl group, C-alkynyl group, carbocyclic group and hetero Group; and R C, at each occurrence, is independently selected from alkyl Ch, carbocyclic group and heterocyclic group. In another aspect, Ring B can be a 6-membered heterocyclic group, wherein the 6-membered heterocyclic group can be optionally substituted on the carbon by ❹-r4, and wherein the hetero--------- The group may be optionally substituted by R4*; R may be selected from H, halo, _CN, Ch alkyl, C2_6 alkenyl, c2 6 alkynyl, carbocyclyl, heterocyclyl, 〇R4a, 4a, _N (R4a) 2, Na "heart", -N(R)N(R")2, _Nq2, N(R4a)_〇R4a, ·(10)(r4, _c(〇)h, -C(0)R4b, _c (〇) 2R4a, _c η, _c (9) Sat ") (〇) _ 0C(0)N(R4a)2, _N(R4a)c(〇)2R4a, _N(R4a)c(9)N(R4a)n(9)^, 'S(〇)R4b ' -S^〇)2R4b ' -S(〇)2N(R^)2 . -N(R4a)S(〇)2R4b . and 4a)=N(OR4a), where CH burning base, ^ woman

土 2_6炔基石反環基及雜環基可視情況在碳上被一或多 個&取代’且其中該雜環基之任何-NH-部份基團可視情況 被R40*取代； R4*’於各存在處，可獨立選自Ci 6炫基、碳環基、雜環基、 -C(〇)H ^ -C(0)R- . -C(〇)2R4c . .C(0)N(R4a)2 . _S(〇)r4K _S(〇)2R4b ^ -S(0)2N(R4a)2、_C(R4a)=N(R4a)及-c(R4a)=N(〇R4a)，其中該b 院基、碳環基及雜環基，於各存在處，可視情況且獨立地 在碳上被-或多個⑽取代’且其中該雜環基之任何喜部 份基團可視情況被R4〇*取代； 133151 -45- 200906818 =a’於各存在處，可獨立選自H、Ci6烧基、碳環基及雜 %基’其中該Ch燒基 '碳環基及雜環基，於各存在處， :視情況且獨立地在碳上被—或多個R4。取代，且其中該雜 環基之任何-NH-部份基團可視情況被R4Q*取代； R4b，於各存在處，可選自Ci 6院基、烯基、^快基、 T環基及雜環基，其中該心6烷基、A6烯基、hi炔基、 石反％基及雜環基，於各存在處，可視情況且獨立地在碳上The soil 2_6 alkynyl sulfocyclic and heterocyclic group may optionally be substituted on the carbon by one or more & ' and wherein any -NH- moiety of the heterocyclic group may be optionally substituted by R40*; R4*' In each position, it may be independently selected from Ci 6 leumino, carbocyclyl, heterocyclic, -C(〇)H ^ -C(0)R- . -C(〇)2R4c . .C(0)N (R4a)2 . _S(〇)r4K _S(〇)2R4b ^ -S(0)2N(R4a)2, _C(R4a)=N(R4a) and -c(R4a)=N(〇R4a), wherein The b-membered, carbocyclic, and heterocyclic groups may be optionally substituted on the carbon by one or more (10) at each position and wherein any of the preferred groups of the heterocyclic group may be R4〇*substituted; 133151 -45- 200906818 =a', in each of the respective positions, may be independently selected from H, Ci6 alkyl, carbocyclyl and hetero-l', wherein the Ch-carbocyclyl and heterocyclic, At each occurrence, : as appropriate and independently on the carbon - or a plurality of R4. Substituted, and wherein any -NH- moiety of the heterocyclic group may be optionally substituted by R4Q*; R4b, in each presence, may be selected from the group consisting of Ci 6, alkenyl, ketone, T, and a heterocyclic group wherein the core 6 alkyl group, A6 alkenyl group, hi alkynyl group, fluorenyl group and heterocyclic group are present, optionally, independently on carbon

被或多個R40取代，且其中該雜環基之任何部份基團 可視情況被R4G*取代； R4c，於各存在處，可獨立選自q —烷基、碳環基及雜環基， 其中該C】·6烷基、碳環基及雜環基，於各存在處，可視情 況且獨立地在碳上被一或多個r4〇取代，且其中該雜環基之 任何-NH-部份基團可視情況被R4〇*取代； R40 ’於各存在處，可獨立選自鹵基、_CN、Ci 6烷基、c2 6 烯基、C2_6炔基、碳環基、雜環基、_〇R40a、_SR4〇a、_N(R4〇a)2、 -N(R40a)C(O)R40b、-N(R4〇a)N(R4〇a)2、_N〇2、_N(R40a)_〇R40a、 -0-N(R4()a)2、-C(0)H、-C(O)R40b、-C(0)2R4()a、-C(〇)N(R40a)2、 -C(O)N(R40a)(〇R40a) > -〇C(O)N(R40a)2 ' -N(R40a)C(〇)2r4〇a , -N(R40a)C(O)N(R40a)2 > -〇C(O)R40b ' -S(O)R40b . -S(O)2R40b ^ -S(O)2N(R40a)2、-N(R40a)S(O)2R40b、-C(R4 ° a )=n(R4 0 a)及 -C(R40a)=N(OR40a); R40* ’於各存在處’可獨立選自Cl_6烷基、碳環基、雜環基、 -C(0)H、-C(O)R40b、-c(〇)2R40c、-C(O)N(R40a)2、-s(〇)R40b、 -S(0)2R4°b、-S(0)2N(R4〇a)2、_C(R4〇a)=N(R4” 及 _C(R4〇a)=N(〇R4〇a); 133151 •46- 200906818 R’於各存在處，可獨立選自H 環基；Substituted by a plurality of R40, and wherein any part of the heterocyclic group may be optionally substituted by R4G*; R4c, in each presence, may be independently selected from the group consisting of q-alkyl, carbocyclyl and heterocyclic, Wherein the C -6 alkyl, carbocyclyl and heterocyclyl groups, where present, optionally and independently substituted on the carbon by one or more r 4 ,, and wherein any -NH- of the heterocyclic group Some of the groups may be optionally substituted by R4〇*; R40' may be independently selected from the group consisting of halo, _CN, Ci6 alkyl, c2 6 alkenyl, C2_6 alkynyl, carbocyclyl, heterocyclyl, _〇R40a, _SR4〇a, _N(R4〇a)2, -N(R40a)C(O)R40b, -N(R4〇a)N(R4〇a)2, _N〇2, _N(R40a) _〇R40a, -0-N(R4()a)2, -C(0)H, -C(O)R40b, -C(0)2R4()a, -C(〇)N(R40a)2 -C(O)N(R40a)(〇R40a) > -〇C(O)N(R40a)2 ' -N(R40a)C(〇)2r4〇a , -N(R40a)C(O) N(R40a)2 > -〇C(O)R40b ' -S(O)R40b . -S(O)2R40b ^ -S(O)2N(R40a)2, -N(R40a)S(O)2R40b , -C(R4 ° a )=n(R4 0 a) and -C(R40a)=N(OR40a); R40* 'in each of the places' may be independently selected from a C1-6 alkyl group, a carbocyclic group, a heterocyclic group. , -C(0)H, -C(O)R40b, -c( 2R40c, -C(O)N(R40a)2, -s(〇)R40b, -S(0)2R4°b, -S(0)2N(R4〇a)2, _C(R4〇a)= N(R4" and _C(R4〇a)=N(〇R4〇a); 133151 •46- 200906818 R', in each presence, may be independently selected from the H ring group;

Cu烷基 碳環基及雜 C2-6烯基、C2Cu alkyl carbocyclic group and hetero C2-6 alkenyl group, C2

R c，於各存在處，可獨立選自c 於又再另-方面，環B可為雜 情況在碳上被一或多個％取代. R4可為齒基。 -6燒基、碳環基及雜環基。 環基，其中該雜環基可視 且 於進-步方面，環B可為6_員 可視情況在碳上被一或多個妒取，、 §亥6_員雜環基 R4可為鹵基。 代’且 於又再進一步方面， 芳基可在碳上被至少一 R4可為_基。 環8可為6-員雜芳基 個R4取代；且 其中該6-員雜R c , in each presence, may be independently selected from c and yet another aspect, and ring B may be substituted on the carbon by one or more % for heterogeneous conditions. R 4 may be a dentate group. -6 alkyl, carbocyclic and heterocyclic groups. a cyclic group wherein the heterocyclic group is visible and in the aspect of the step, the ring B may be 6-membered, and may be taken by one or more on the carbon, and the heterocyclic group R4 may be a halogen group. . In another aspect, and in still further aspects, the aryl group can be at least one R4 on the carbon. Ring 8 may be a 6-membered heteroaryl R4 substituted; and wherein the 6-member is heterozygous

於又再進-步方®，環B -« 1 吟6_貝雜芳基，直Φ与^。… 方基可在碳上被一或多個r4取代· ，、中該6-貝雜 R4可為鹵基。 ’且 ~黍興嘧啶· 與嘧啶基可視情況在碳上 把可為，基。 或多個R4 其中該p比α定基 ;且 於另一方面，環Β可選自吡 基與嘧啶基可視情況被—或多 R4可為氟基。 咬基與鳴。定基， 個R4取代；且 其中該Ρ比Π定 於又另一方面，環Β可 為吡啶基 其中該吡啶基可视情 133151 200906818 況在碳上被—或多個R4取代；且 R4可為鹵基。 ’Further re-entry - step square ®, ring B - « 1 吟 6_ beheteroaryl, straight Φ and ^. The square group may be substituted by one or more r4 on the carbon, and the 6-shell heterocyclic R4 may be a halogen group. 'And ~ 黍 嘧啶 pyrimidine · and pyrimidinyl groups can be used on the carbon. Or a plurality of R4 wherein the p is a group of α; and, in another aspect, the ring oxime may be selected from a pyridyl group and a pyrimidinyl group as the case may be - or a plurality of R4 may be a fluorine group. Bite the base and sing. a group, R4 is substituted; and wherein the oxime is determined on the other hand, the guanidine may be a pyridyl group, wherein the pyridyl group is substituted on the carbon by a plurality of R4, and R4 may be Halogen. ’

於又再另―_ 士 I 其中該嘧啶基可視 方面，環B可為嘧啶基 情況在碳上被—或多個R4取代；且 R4可為鹵基。 於進一步方面， §亥p比n定-2-基與嘴σ定 R4為氟i基。 環B係選自吡啶-2-基與嘧啶_2_基，其中 -2-基係視情況被一或多個R4取代；且 於又再進一步方而 Tff y- 面，環B係選自3,5-二氟吡啶-2-基、5-氟 基吡啶-2-基及5_氟基嘧啶_2_基。 ；再進v方面，環B可選自5-氟基吡啶-2-基與5-氟基 嘧啶-2-基。 於一方面，環B可為5_氣基峨„定_2_基。 於另一方面，環B可為5_氟基嘧啶_2_基。 於一方面’ X可為經選擇之_〇與。 於另一方面，X可為_〇·。 於又另一方面，X可為-NH-。 R1 於一方面，R1可選自H、鹵基、_CN、Ci6烷基、C2-6. 基、C2_6 炔基、碳環基、雜環基、_〇Rla、_SRla、_N(Rla)2、 -i^R1 3)(:(0)111 b、-Ν(Κ； a)N(Rl a)2、_N〇2、_N(R1 a)〇Rl a、_〇N(Rl a)2、 -C(0)H、-(XO)R1 b、-qOLR1 a、-C(0)N(R] a)2、-CCOMR1 lOR1 a)、 -0C(0)N(Rla)2 、-N(Rla)C(0)2Rla、-NCR1 a )0(0)^^a )2 、 133151 -48· 200906818 -〇C(〇)Rl b . .S(〇)Rl b . _S(〇)2 R1 b ^ N(R1 a ^ ^ ^ a ^ ^ ^ :(Rla)哪1 M_C(R，擎 ^ ^ 土、C2-6炔基、碳環基及雜環基可視情況在碳上被一或多 個R1 0取代，且J：中钕M w 甲该雜核基之任何_NH_部份基團可視情況 被R1G*取代； r W ’於各存在處，可獨立選自H、CH烧基、碳環基及雜 %基’其中該q_6烷基、碳環基及雜環基，於各存在處， 可視情況且獨立地在碳上被一或多個Rl 〇取代，且其中該雜 %基之任何-NH-部份基團可視情況被RlG*取代；Further, in the case of the pyrimidinyl group, the ring B may be a pyrimidinyl group in the case of a carbon- or a plurality of R4 groups; and R4 may be a halogen group. In a further aspect, the §Hp ratio is n-but-2-yl and the mouth σ is determined to be a fluoroi group. Ring B is selected from the group consisting of pyridin-2-yl and pyrimidin-2-yl, wherein the-2-yl group is optionally substituted by one or more R4; and further to the Tff y-plane, the ring B is selected from 3,5-Difluoropyridin-2-yl, 5-fluoropyridin-2-yl and 5-fluoropyrimidin-2-yl. Further, in terms of v, ring B may be selected from the group consisting of 5-fluoropyridin-2-yl and 5-fluoropyrimidin-2-yl. In one aspect, ring B can be a 5-fluoro group, and on the other hand, ring B can be a 5-fluoropyrimidin-2-yl group. On the one hand, 'X can be selected _ In another aspect, X can be _〇·. In another aspect, X can be -NH-. R1 In one aspect, R1 can be selected from the group consisting of H, halo, _CN, Ci6 alkyl, C2- 6. Group, C2_6 alkynyl, carbocyclyl, heterocyclic, 〇Rla, _SRla, _N(Rla)2, -i^R1 3)(:(0)111 b, -Ν(Κ; a)N (Rl a)2, _N〇2, _N(R1 a)〇Rl a, _〇N(Rl a)2, -C(0)H, -(XO)R1 b, -qOLR1 a, -C(0 N(R] a)2, -CCOMR1 lOR1 a), -0C(0)N(Rla)2, -N(Rla)C(0)2Rla, -NCR1 a )0(0)^^a )2 , 133151 -48· 200906818 -〇C(〇)Rl b . .S(〇)Rl b . _S(〇)2 R1 b ^ N(R1 a ^ ^ ^ a ^ ^ ^ :(Rla) Which 1 M_C( R, ^^^, C2-6 alkynyl, carbocyclyl and heterocyclyl may be substituted on the carbon by one or more R1 0, and J: 钕M w A any of the heteronuclear groups The _ moiety may be optionally substituted by R1G*; r W ' may be independently selected from the group consisting of H, CH alkyl, carbocyclyl and heteropoly', wherein the q_6 alkyl, carbocyclic and heterocyclic ring Base At, optionally and independently substituted on carbon by one or more Rl billion, and wherein the heteroaryl group% of any -NH- moiety is optionally substituted RlG *;

Rlb，於各存在處，可選自Ci_6烷基、c2 6烯基、C24炔基、 碳環基及雜環基，其中該。6烷基、c2 6烯基、c2 6炔基、 石反環基及雜環基，於各存在處，可視情況且獨立地在碳上 被一或多個R10取代，且其中該雜環基之任何-部份基團 可視情況被R1 G *取代； R10，於各存在處’可獨立選自鹵基、_CN、q_6烷基、C26 烯基、C〗-6快基、碳環基、雜環基、-OR1 Q a、-SR1。a、_n(r1❶a )2、 -N(R1〇a)C(0)Ri〇b , -N(R10a)N(R10a)2 ' -N02 ' -K(R10a)-〇Ri〇a . -0-N(R1Ga)2、-C(0)H、-C(0)R1()b、-C(0)2R1()a、-C(〇)N(R1<)a)2、 -C^NC^^XOR1»^ % -〇C(O)N(R10a)2 ' -N(R1〇a)C(〇)2Ri〇a , -N(R10a)C(O)N(R10a)2、-〇C(O)R10b、4(0)1110b、_s(〇)2Ri〇b、 -S(O)2N(R10a)2 、-N(R10a)S(O)2R10b 、-C^R10 a )=N(Ri 0 a)及 -C(R10a)=N(OR10a)； R1(^，於各存在處，可獨立選自q _6烷基、碳環基、雜環基、 -C(0)H、-C(O)R10b、-C(O)2R10c、-C(O)N(R10a)2、_S(0)Ri〇b、 133151 -49- 200906818 -S(〇)2R»〇b,.S(〇)2N(Rl〇a)2 ..C(Rl〇a)=N(Rl〇am 1〇 R1。，於 ；1N^UK )， 環基；存在處’可獨立選自H、Ch貌基、碳環基及雜 =’：各存在處’可獨立選自Ci_6院基〜稀基、h 炔基、碳環基及雜環基；且Rlb, in each presence, may be selected from the group consisting of Ci-6 alkyl, c2 6 alkenyl, C24 alkynyl, carbocyclyl and heterocyclyl, of which. a 6 alkyl group, a c2 6 alkenyl group, a c2 6 alkynyl group, a fluorenyl group and a heterocyclic group, optionally in each case, independently and independently substituted on the carbon by one or more R 10 , and wherein the heterocyclic group Any of the -groups may be optionally substituted by R1 G*; R10, at each position, may be independently selected from halo, _CN, q_6 alkyl, C26 alkenyl, C-6-6, carbocyclyl, Heterocyclic group, -OR1 Q a, -SR1. a, _n(r1❶a)2, -N(R1〇a)C(0)Ri〇b, -N(R10a)N(R10a)2 ' -N02 ' -K(R10a)-〇Ri〇a . -0 -N(R1Ga)2, -C(0)H, -C(0)R1()b, -C(0)2R1()a, -C(〇)N(R1<)a)2, -C ^NC^^XOR1»^ % -〇C(O)N(R10a)2 ' -N(R1〇a)C(〇)2Ri〇a , -N(R10a)C(O)N(R10a)2 -〇C(O)R10b, 4(0)1110b, _s(〇)2Ri〇b, -S(O)2N(R10a)2, -N(R10a)S(O)2R10b, -C^R10 a ) =N(Ri 0 a) and -C(R10a)=N(OR10a); R1(^, in each presence, may be independently selected from q-6 alkyl, carbocyclyl, heterocyclyl, -C(0) H, -C(O)R10b, -C(O)2R10c, -C(O)N(R10a)2, _S(0)Ri〇b, 133151 -49- 200906818 -S(〇)2R»〇b, .S(〇)2N(Rl〇a)2 ..C(Rl〇a)=N(Rl〇am 1〇R1., in; 1N^UK ), a ring group; the presence 'can be independently selected from H, Chmorphyl, carbocyclyl and hetero=': each present' can be independently selected from Ci_6-derived to dilute, h alkynyl, carbocyclyl and heterocyclic;

Rl〇C’於各存在處，可獨立選自Ci‘基、碳環基及雜環基。 f ΐ κ ;另^方面，R係選自Q-6烧基、3-至6-員碳環基及5•或 班貝雜％基’其中該Ch烧基、3至6員碳環基及$•或6項雜 環基係視情況在碳上被一或多個r1 G取代； R二於各存在處，係獨立選㈣基、3-至6-員碳環基、5_ 或6·員雜環基及_〇Ri 0a，1 ^ 八甲口哀3·至6-貝石厌J衣基與5-或6-員雜 %基’於各存在處’係視情況且獨立地在碳上被 Ra取代； R10a為3-至6-員碳環基； 粑，於各存在處，係獨立選自鹵基與-ORm ;且 Rm為C卜6燒基。 又再_方自，R1係選自環丙基、乙基、甲基、苯基及 石：本基’纟中該環丙基、乙基、甲基、苯基及硫苯基係視 情況被一或多個R1 0取代；Rl〇C' may be independently selected from the group consisting of Ci' group, carbocyclic group and heterocyclic group. f ΐ κ ; in another aspect, R is selected from the group consisting of Q-6 alkyl, 3- to 6-membered carbocyclic group, and 5 or bamene-based group, wherein the Ch-based, 3- to 6-membered carbocyclic group And the ? or 6 heterocyclic groups are optionally substituted on the carbon by one or more r1 G; R is in each of the respective positions, independently selected (tetra), 3- to 6-membered carbocyclyl, 5 or 6 · Member heterocyclic group and _〇Ri 0a,1 ^ 八甲口哀3· to 6-Beyite JJ clothing base and 5- or 6-membered 基基基 'in each place' as appropriate and independently Substituted by Ra on carbon; R10a is a 3- to 6-membered carbocyclic group; hydrazine, in each presence, is independently selected from the group consisting of halo and -ORm; and Rm is C. Further, R1 is selected from the group consisting of cyclopropyl, ethyl, methyl, phenyl and stone: the cyclopropyl, ethyl, methyl, phenyl and thiophenyl groups in the present group are as appropriate. Substituted by one or more R1 0;

Rl0 ’於各存在處’係獨立選自氟基、-ORl〇a、環己基、咪 :基、本基及吡啶基，#中該環己基、咪唑基、苯基及吡 於各存在處，係視情況且獨立地在碳上被一或多個 Ra取代； R 於各存在處，係獨立選自甲基與苯基；且 133151 -50- 200906818Rl0 'in each of the positions' is independently selected from the group consisting of a fluorine group, -ORl〇a, a cyclohexyl group, a mercapto group, a benzyl group and a pyridyl group, and in the #, the cyclohexyl group, the imidazolyl group, the phenyl group and the pyridyl group are present at each. Depending on the case and independently substituted with one or more Ra on the carbon; R is independently selected from the group consisting of methyl and phenyl; and 133151 -50- 200906818

Ra’於各存在處，係獨立選自氟基與甲氧基。 於又再另一方面，R1係選自2-環己基乙基、環丙基、2-(2,4-二氟苯基）乙基、2-(2,6-二氟苯基）乙基、2-(3,4-二氟苯基）乙 基、2-(3,5-二氟苯基）乙基、2-(3,5-二甲氧基苯基）乙基、4-氟苯 基、2-(3-氟苯基）乙基、2-(4-氟苯基）乙基、2-(1Η-咪唑-2-基）乙 基、4-甲乳本基、甲基、2-苯基乙基、苯基氧基甲基、2-ρ比 咬-4-基乙基及p塞吩-2-基。Ra' is independently selected from the group consisting of a fluoro group and a methoxy group. In still another aspect, R1 is selected from the group consisting of 2-cyclohexylethyl, cyclopropyl, 2-(2,4-difluorophenyl)ethyl, 2-(2,6-difluorophenyl)B. , 2-(3,4-difluorophenyl)ethyl, 2-(3,5-difluorophenyl)ethyl, 2-(3,5-dimethoxyphenyl)ethyl, 4 -fluorophenyl, 2-(3-fluorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2-(1Η-imidazol-2-yl)ethyl, 4-methyllacyl, Methyl, 2-phenylethyl, phenyloxymethyl, 2-ρ butyl-4-ylethyl and p-cephen-2-yl.

於進一步方面，R1可為(^_6烷基。 於又再進一步方面，Ri可為曱基。 R3 於一方面，R3可選自Η、_基、-CN、（：卜6烷基、C2_6烯 基、C2_6快基、碳環基 '雜環基、_〇R3a、_sR3a、_N(R3a\、 -N(R3a)C(0)R3b、-N(R3a)N(R3a)2、-N02、-N(R3a)-〇R3a、 -0-N(R3a)2 ^ -C(0)H ^ -C(0)R3b ^ -C(0)2R3a > -C(0)N(R3a)2 > -C(0)N(R3a)(0R3a) 、.〇C(〇)N(R3a)2 、_N(R3 ar3 、 -N(R3a)C(0)N(R3a)2 ^ -OC(0)R^ . -S(0)R3b . -S(〇)2r3 及 碳 -S(0)2N(Rh)2 、_N(R3a 剛2R3b 、_c(R3a)哪3a) -C(Rh)=N(0R3a)，其中該Ci6烧基、c26稀基、快基 %基及雜裱基可視情況在碳上被一或多個R3 〇取代，且其中 遠雜環基之任何-ΝΗ-部份基團可視情況被R3〇*取代； R3a，於各存在處，可獨立選自Η、Ch院基、碳環基及雜 %基，其中該Cl 6烷基、碳環基及雜環基，於各存在處， 可視情況且獨立地在碳上被一或多個圮〇取代，且其中該雜 環基之任何-NH-部份基團可視情況被R3〇*取代； 133151 -51 · 200906818 R3b，於各存在處，可選自Cl·6烷基、C2 6烯基、C2 6炔基、 碳環基及雜環基，其中該〇1_6烷基、c2 6烯基、c2 6炔基、 碳％基及雜環基，於各存在處，可視情況且獨立地在碳上 被一或多個R30取代，且其中該雜環基之任何___部份基團 可視情況被R3 G *取代； R30，於各存在處，可獨立選自鹵基、-CN、C卜6烷基、c2_6 烯基、c2-6炔基、碳環基、雜環基、_〇R3Qa、_SR3Ga、_N(R3Ga^ ' -N(R30a)C(O)R30b、-N(R30a)N(R30a)2、_n〇2、-N(R30a)-〇R3〇a、 -O-N(R30a)2 . -C(0)H > -C(〇)R3 0b . .C(〇)2R3〇a . .C(〇)N(R3〇a)2 . -C(O)N(R30a)(〇R3 0”、_〇c⑼N(R3〇a)2、_N(R30a)c(〇hR3〇a、 -N(R30a)C(O)N(R30a)2、-〇c(〇)R30b、_s(〇)R30b、_s(〇)2R30b、 -S(O)2N(R30a)2 、 -N(R3〇a)S(〇)2R3〇b . _C(R3〇a)=N(R30a)及 -C(R30a)=N(〇R30a); R3〇，於各存在處，可獨立選自Ci I烷基、碳環基、雜環基、 -C(0)H > -C(0)R3〇b , -C(〇)2R30c ' -C(O)N(R30a)2 x -S(〇)R3〇b , -S(O)2R30b、-S(〇)2N(R3°a)2、_c(R3°a)=N(R30a)及-C(R3Qa)=N(〇R30a); R30a，於各存在處，可獨立選自H、Ci_6烷基、碳環基及雜 環基； R3〇b，於各存在處，可獨立選自Ch烷基、c2_6烯基、C2_6 炔基、碳環基及雜環基；且 R3〇e，於各存在處，可獨立選自Ci·6烷基、碳環基及雜環基。 於另方面，R3係選自Ci ·6烷基，其中該q. 6烷基係視情 況被一或多個R3 〇取代； R ’於各存在處’係獨立選自鹵基、-CN、_〇R3 0a、 133151 -52- 200906818 -C(0)N(R3〇”2、_s(〇)2R3〇b、_s(〇)2N(R30a)2 ; R3〇a，於各存在處，係獨立選自H與Ch6烷基丨且 R301^^、烷基。 於又另一方面，R3係選自甲基與乙基，其中該曱基與乙 基係視情況被一或多個R3 0取代， R30 ’於各存在處，係獨立選自氟基、-CN及-OR3〇a、 -c(o)n(r3〇”2、_s(o)2N(R30a)2、_s⑼2Me ;且 R30a，於各存在處，係獨立選自H、曱基及乙基。 於又再另一方面，R3可為q_6烷基。 於更另—方面，R3可為甲基。 於又再進一步方面’ R3係選自（胺基幾基）曱基、氰基甲 基' U-二氟-2-經乙基、[(二曱胺基德基]甲基、（二甲胺基錯 醢基）甲基、乙氧基乙基、2_經乙基、^氧基乙 基曱氧基曱基、甲基、[(甲胺基）幾基]甲基及（甲績酿基 甲基。 環 A、環 B、X、R1及 R3 於一方面’環A可為雜環其，甘士吟*, * 其中該雜環基可視情況在 碳上被一或多個R2取代，且1中 /、T该雜％基之任何-NH-部 基團可視情況被R2*取代； 環B可為雜環基，其中該雜環基可視情況在碳上被一或多 個R4取代，且其中該雜環基 取代； 之㈣姻·部份基團可視情況 X可為經選擇之_〇_與-NH-; C2-6稀基、C2_6炔基 R1可選自H、鹵基、-CN、Ci.6烧基 133151 -53、 200906818 碳環基、雜環基、-ORU、_SRla、_N(Rla)2、_N(Rla)c(〇)Rib、 -N(R )N(R )2、·ν〇2、MRUpRia、_〇N(Rla)2、_c(〇)h、 -C(〇.)R ' -C(0)2Ria , -C(0)N(Rla)2 . -C(0)N(Rla)(〇Ria), 0C(0)N(R )2、_N(Ria)c(〇)2Rla、_N(Rla)c(〇)N(Rla)2、 -OC^R1 b ' -S(0)Ri b , _S(〇)2r1 b , -SCO^NCR1 a)2 ^ -N(R! a )S(0)2 R1 b , -C(R，N(Rla)及 _C(Rla)=N(〇Rla)，其中該Cm 炫基、c24 基、C2_6炔基、碳環基及雜環基可視情況在碳上被一或多 個R取代，且其中該雜環基之任何__-部份基團可視情況 被R1Q*取代；In a further aspect, R1 can be (^_6 alkyl. In yet a further aspect, Ri can be a fluorenyl group. R3 In one aspect, R3 can be selected from the group consisting of hydrazine, _ group, -CN, (: 6 alkyl group, C2_6) Alkenyl, C2_6 fast radical, carbocyclyl 'heterocyclyl, 〇R3a, _sR3a, _N(R3a\, -N(R3a)C(0)R3b, -N(R3a)N(R3a)2, -N02 , -N(R3a)-〇R3a, -0-N(R3a)2 ^ -C(0)H ^ -C(0)R3b ^ -C(0)2R3a > -C(0)N(R3a) 2 > -C(0)N(R3a)(0R3a) , .〇C(〇)N(R3a)2 , _N(R3 ar3 , -N(R3a)C(0)N(R3a)2 ^ -OC (0)R^ . -S(0)R3b . -S(〇)2r3 and carbon-S(0)2N(Rh)2, _N(R3a just 2R3b, _c(R3a) which 3a) -C(Rh) =N(0R3a), wherein the Ci6 alkyl group, the c26 dilute group, the fast group % group and the heterofluorenyl group are optionally substituted on the carbon by one or more R3 〇, and any -ΝΗ-part of the far heterocyclic group The radical may be optionally substituted by R3〇*; R3a, at each position, may be independently selected from the group consisting of fluorene, Ch, a carbocyclic group, and a heterocyclic group, wherein the C6 alkyl group, the carbocyclic group and the heterocyclic group are present. , in each presence, optionally and independently substituted on the carbon by one or more deuteriums, and wherein any -NH- moiety of the heterocyclic group may be R3 as appropriate *substituted; 133151 -51 · 200906818 R3b, in each presence, may be selected from the group consisting of Cl.6 alkyl, C2 6 alkenyl, C2 6 alkynyl, carbocyclyl and heterocyclic, wherein the 〇1_6 alkyl, c2 6 alkenyl, c 2 6 alkynyl, carbon henyl and heterocyclyl, each optionally, independently and independently substituted on the carbon by one or more R30, and wherein any __- moiety of the heterocyclic group The moiety may be optionally substituted by R3 G*; R30, in each presence, may be independently selected from halo, -CN, C6-6, c2-6 alkenyl, c2-6 alkynyl, carbocyclyl, heterocycle Base, _〇R3Qa, _SR3Ga, _N(R3Ga^ ' -N(R30a)C(O)R30b, -N(R30a)N(R30a)2, _n〇2, -N(R30a)-〇R3〇a, -ON(R30a)2 . -C(0)H > -C(〇)R3 0b . .C(〇)2R3〇a . .C(〇)N(R3〇a)2 . -C(O) N(R30a)(〇R3 0", _〇c(9)N(R3〇a)2, _N(R30a)c(〇hR3〇a, -N(R30a)C(O)N(R30a)2, -〇c( 〇) R30b, _s(〇)R30b, _s(〇)2R30b, -S(O)2N(R30a)2, -N(R3〇a)S(〇)2R3〇b. _C(R3〇a)=N (R30a) and -C(R30a)=N(〇R30a); R3〇, at each position, may be independently selected from Ci I alkyl, carbocyclyl, heterocyclyl, -C(0)H > C(0)R3〇b , -C( ) 2R30c ' -C(O)N(R30a)2 x -S(〇)R3〇b , -S(O)2R30b, -S(〇)2N(R3°a)2, _c(R3°a)= N(R30a) and -C(R3Qa)=N(〇R30a); R30a, in each position, may be independently selected from H, Ci-6 alkyl, carbocyclyl and heterocyclic; R3〇b, in each presence , which may be independently selected from the group consisting of a C alkyl group, a c 2_6 alkenyl group, a C 2_6 alkynyl group, a carbocyclic group and a heterocyclic group; and R 3 〇 e may be independently selected from the group consisting of Ci. 6 alkyl, carbocyclic and hetero Ring base. In another aspect, R 3 is selected from Ci 6 alkyl, wherein the q. 6 alkyl group is optionally substituted with one or more R 3 〇; R 'in each presence' is independently selected from halo, -CN, _〇R3 0a, 133151 -52- 200906818 -C(0)N(R3〇"2, _s(〇)2R3〇b, _s(〇)2N(R30a)2; R3〇a, at each place, Independently selected from H and Ch6 alkyl hydrazine and R301^^, alkyl. In yet another aspect, R3 is selected from the group consisting of methyl and ethyl, wherein the thiol and ethyl are optionally one or more R3 0 Substituted, R30' is independently selected from the group consisting of fluorine group, -CN and -OR3〇a, -c(o)n(r3〇"2, _s(o)2N(R30a)2, _s(9)2Me; and R30a And in each of the places, independently selected from H, decyl and ethyl. In still another aspect, R3 may be q_6 alkyl. In a further aspect, R3 may be methyl. In yet further aspects' R3 is selected from (amino) fluorenyl, cyanomethyl 'U-difluoro-2-ethyl, [(didecylamino)methyl, (dimethylamino) Methyl, ethoxyethyl, 2_ethyl, ethoxyethyl decyl fluorenyl, methyl, [(methylamino) benzyl] methyl and Ring A, Ring B, X, R1 and R3 In one aspect, Ring A can be a heterocyclic ring, and a glycoside, wherein the heterocyclic group can be optionally substituted on the carbon by one or more R 2 , and Any -NH- moiety of 1/, T of the hetero-group may be optionally substituted by R2*; ring B may be a heterocyclic group, wherein the heterocyclic group may optionally be substituted on the carbon by one or more R4, And wherein the heterocyclic group is substituted; the (four) marriage moiety may optionally be selected _〇_ and -NH-; C2-6 dilute, C2_6 alkynyl R1 may be selected from H, halo, -CN, Ci.6 alkyl 133151 -53, 200906818 carbocyclyl, heterocyclic, -ORU, _SRla, _N(Rla)2, _N(Rla)c(〇)Rib, -N(R)N(R 2, ν 〇 2, MRUpRia, _ 〇 N (Rla) 2, _c (〇) h, -C (〇.) R ' - C (0) 2 Ria , -C (0) N (Rla) 2 . -C(0)N(Rla)(〇Ria), 0C(0)N(R)2, _N(Ria)c(〇)2Rla, _N(Rla)c(〇)N(Rla)2, -OC ^R1 b ' -S(0)Ri b , _S(〇)2r1 b , -SCO^NCR1 a)2 ^ -N(R! a )S(0)2 R1 b , -C(R,N(Rla And _C(Rla)=N(〇Rla), wherein the Cm thiol group, the c24 group, the C2_6 alkynyl group, the carbocyclic group and the heterocyclic group are optionally substituted on the carbon by one or more R, and wherein miscellaneous Any group of __- moiety is optionally substituted with R1Q *;

Rla，於各存在處，可獨立選自H、Ci6烷基、碳環基及雜 %基，其中該Ci -6烷基、碳環基及雜環基，於各存在處， 了視情況且獨立地在碳上被—或多個Rl 〇取代，且其中該雜 環基之任何-NH-部份基團可視情況被R1G *取代；Rla, in each presence, may be independently selected from the group consisting of H, Ci6 alkyl, carbocyclyl and heteropoly, wherein the Ci-6 alkyl, carbocyclyl and heterocyclyl are present, as appropriate, and Independently substituted on the carbon by - or a plurality of R1 ,, and wherein any -NH- moiety of the heterocyclic group may be optionally substituted by R1G*;

Rlb，於各存在處，可選gCi·6烷基、c2_6烯基、c2 6炔基、 碳環基及雜環基，其中該心.6烷基、C2 6烯基、C2 6炔基、 碳環基及雜環基，於各存在處，可視情況且獨立地在碳上 被一或多個R10取代，且其中該雜環基之任何_见^部份基團 可視情況被R1G*取代； R可選自Η、鹵基、-CN、（：卜6烷基、c2 6烯基、c2 6炔基、 石反環基、雜環基、-OR2 a、_SR2 a、_n(r2 a )2、_n(r2 a )c(〇)r2 b、 'N(R2a)N(R2a)2 , „N〇2 . .N(R2a)〇R2a , _〇N(R2a)2 . _c(〇)H ^ -C(0)R2b、.C(〇)2R2a , -C(0)N(R2-)2 . -C(0)N(R^)(〇R2a). 〇C(〇)N(R2a)2、_N(R2a)C(〇)2R2a、-N(R2a)C(〇)N(R2a)2、-0C(0)R2b、 ~S(0)R2b , _S(0)2R2b ' -S(0)2N(R2^)2 > -N(R2a)S(0)2R2b . 133151 -54- 200906818 -C(R2a)=N(R2a)及 _C(R2a)=N(〇R2a)，其中該 烧基、[Η 婦 基、A—6炔基、碳環基及雜環基可視情況在碳上被一或6多 個R20取代，且其中該雜環基之任何·ΝΗ·部份基團可視情況 被R2 G #取代； R2，於各存在處，可獨立選自C〗6烷基、碳環基、雜環基、 -C(0)H > -C(0)R2b . -C(〇)2R2c . -C(〇)N(R2a)2 , .S(0)R2 b , .5^ r2 b ^ -S(0)2N(Rh)2、_C(R2a)=N(R2a)及_c(R2a)=N(〇R2a)，其中該q 烷基、碳環基及雜環基，於各存在處，可視情況且獨立地6 在碳上被一或多個R2〇取代，且其中該雜環基之任何·部 份基團可視情況被r2〇*取代； R2a ’於各存在處，可獨立選自Η、Ci·6烷基、碳環基及雜 環基，其中該C〗_6烷基、碳環基及雜環基，於各存在處， 可視情況且獨立地在碳上被一或多個r2〇取代，且其中該雜 環基之任何-NH-部份基團可視情況被R2〇*取代； R2b ’於各存在處，可選自Cl.6烧基、Ch稀基、C2 6快基、 碳環基及雜環基，其中該Cl_6烷基、A 6烯基、hi炔基、 石反％基及雜環基，於各存在處，可視情況且獨立地在碳上 被一或多個R2〇取代，且其中該雜環基之任何___部份基團 可視情況被R2G*取代； 於各存在處，可獨立選自Cw烧基、碳環基及雜環基， 其中該c】_6烷基、碳環基及雜環基，於各存在處，可視情 況且獨立地在碳上被-或多個R2Q取代，且其中該雜環基之 任何-NH-部份基團可視情況被R2 〇 *取代； 於可選自Η、函基、-CN、Ci_6燒基、Cm烤基、CM快基、 133151 •55· 200906818 石反 ％ 基雜 ％ 基、_〇R3a、_SR3a、_N(R3a)2、_N(R3a)c(〇)R3b、 -N(R )N(R )2、_NG2、_N(R3a)_QR3a、_〇_N(R3a)2、c(〇)h、 -C(0)R > -C(0)2R3a Λ -C(0)N(R3a)2 > -C(0)N(R3a)(〇R3a), -0C(0)N(R )2、-N(R3 ”c(〇)2 r3、_n(r3 ”c⑼n(r3 a 乂、〇c⑼r3 b、 S(0)R ' -S(0)2R3b , -S(0)2N(R3a)2 > -N(R3a)S(0)2R3b ^ -C(R3a)=N(R3a)及 _C(R3a)=N(〇R3a)，其中該Ci6烧基、稀 基、C：2·6炔基、碳環基及雜環基可視情況在碳上被一或多 (個R 〇取代，且其中該雜環基之任何-NH-部份基團可視情況 被R3G*取代； R3a，於各存在處，可獨立選自H、Ci 6烧基、碳環基及雜 環基，其中該心―6烷基、碳環基及雜環基，於各存在處， 可視情況且獨立地在碳上被一或多個尺3〇取代，且其中該雜 環基之任何-NH-部份基團可視情況被R3〇*取代； R3b ’於各存在處，可選自Cl_6烷基、C2 6烯基、。纟炔基、 碳環基及雜環基，其中該Cl_e烷基、C2 6烯基、C2 6炔基、 、 碳1农基及雜裱基，於各存在處，可視情況且獨立地在碳上 被一或多個R3〇取代，且其中該雜環基之任何-部份基團 可視情況被R3 G *取代； R4可選自Η、自基、-CN、Cl.6烧基、C2 6稀基、C2 6快基、 石反環基、雜環基、-OR4a、_SR4a、_N(R4a；)2、-N(；R4a；)C(0)Il4b、 -N(R4a)N(R4a)2、-N〇2、-N(R4a)_0R4a、〇_N(R4a)2、_c(〇)H、 -C(0)R4b v -C(0)2R4a ' -C(〇)N(R4a)2 . -C(0)N(R4a)(〇R4a). 〇C(〇)N(R4a)2 ^ -N(R4a)C(0)2R4a , -N(R4a)C(0)N(R4a)2 > -0C(0)R4b Λ -S(〇)R4b、_S(〇)2R4b、-S(〇)2N(R4a)2、_N(R4a)S(〇)2R4b、 133151 -56 - 200906818 -C(R“)=N(R“）及·c(R4a)哪R4a)，其中該ci 6燒基、c24 基、Q-6炔基、碳環基及雜環基可視情況在碳上被一或多 個R 0取代，且其中該雜環基之任何遞.部份基團可視情況 被R4G*取代； ' 妒*’於各存在處，可獨立選自烷基、碳環基、雜環基、 -C(0)H、-C(0)R4b、_c(〇)2R4e、_c(〇)N(R4a 卜啊R4b、卻)广、 -S(0)2N(R4a)2、-C(R4a)=N(R4a)及 _c(R4a)=N(〇R4。，其中該q 6 『烧I炭環基及雜環基’於各存在處，可視情況且獨立地 在碳上被一或多個r4〇取代，且其中該雜環基之任何__-部 份基團可視情況被R4 〇 *取代； ’於各存在處’可獨立選自H、Ci 6烷基、碳環基及雜 %基，其中該Ci 6烷基、碳環基及雜環基，於各存在處， 可視情況且獨立地在碳上被一或多個圮0取代，且其中該雜 %基之任何-NH-部份基團可視情況被R4〇*取代； R4b，於各存在處，可選ICl·6烷基、eh烯基、c2 6炔基、 《 碳環基及雜環基，其中該CHm2 6稀基、Ch块基、 石厌核基及雜環基，於各存在處，可視情況且獨立地在碳上 被一或多個R40取代，且其中該雜環基之任何-部份基團 可視情況被R4G*取代； R4c’於各存在處，可獨立選自Cl，6烷基、碳環基及雜環基， 其中該Ci-6烷基、碳環基及雜環基，於各存在處，可視情 況且獨立地在碳上被一或多個R4 〇取代，且其中該雜環基之 任何-NH-部份基團可視情況被R4〇*取代； R10’於各存在處，可獨立選自_基、_CN、烷基、C2_6 133151 -57- 200906818 浠基、C2 _ 6炔基、碳環基、雜環基、_〇Rl 0 a、_SRi 〇 a、_N(Rl 〇 %、 -N(R1Qa)C(0)R1()b、-N(Rl〇a)N(R10a)2、_N〇2、_N(Rl〇a)_〇Rl〇a、 -O-N(R10a)2、-C(〇)H、-C(O)R10b、-C(O)2R10a、-C(O)N(R10a)2、 -C(0)N(R10a)(〇Ri〇a)、_〇c⑼N(Rl0”2、_N(Rl0”c(〇hRl0a、 -N(R10a)C(O)N(R10a)2、_OC(0)Ri〇b、-S(〇)Ri〇b、_s(〇)2Rl0b、 -S(O)2N(R10a)2 、 -N(R10a)S(O)2R10b 、 -C^R1 0 a 0 a)及 -C(R10a)=N(〇Ri〇a); R10* ’於各存在處’可獨立選自Ci 6烷基、碳環基、雜環基、 -C(0)H ' -C(O)R10b . -C(O)2R10c ' -C(O)N(R10a)2 > -S(O)R10b ^ -S(0)2 R1 0 b、-S(〇)2 N(R； 0 a )2、_C(R1 0 a )=N(R1 0 a)及 _C(R1 0 a )=N(〇Rl 〇 a ); R10a，於各存在處，可獨立選自H、Cl_6烷基、碳環基及雜 環基；Rlb, in each of the places, may be selected from the group consisting of gCi.6 alkyl, c2_6 alkenyl, c2 6 alkynyl, carbocyclyl and heterocyclic, wherein the heart is a 6 alkyl group, a C2 6 alkenyl group, a C2 6 alkynyl group, Carbocyclyl and heterocyclyl, at each occurrence, optionally and independently substituted on the carbon by one or more R10, and wherein any of the heterocyclic groups may be replaced by R1G*, as appropriate R may be selected from the group consisting of hydrazine, halo, -CN, (: 6 alkyl, c2 6 alkenyl, c2 6 alkynyl, fluorenyl, heterocyclyl, -OR2 a, _SR2 a, _n (r2 a 2, _n(r2 a )c(〇)r2 b, 'N(R2a)N(R2a)2 , „N〇2 . .N(R2a)〇R2a , _〇N(R2a)2 . _c(〇 H ^ -C(0)R2b, .C(〇)2R2a , -C(0)N(R2-)2 . -C(0)N(R^)(〇R2a). 〇C(〇)N (R2a)2, _N(R2a)C(〇)2R2a, -N(R2a)C(〇)N(R2a)2, -0C(0)R2b, ~S(0)R2b, _S(0)2R2b ' -S(0)2N(R2^)2 > -N(R2a)S(0)2R2b . 133151 -54- 200906818 -C(R2a)=N(R2a) and _C(R2a)=N(〇R2a Wherein the alkyl group, the oxime group, the A-6 alkynyl group, the carbocyclic group and the heterocyclic group are optionally substituted on the carbon by one or more than R20, and wherein any of the heterocyclic groups is Some groups may be taken by R2 G # depending on the situation. R2, at each position, may be independently selected from C 6 alkyl, carbocyclyl, heterocyclyl, -C(0)H > -C(0)R2b . -C(〇)2R2c . C(〇)N(R2a)2 , .S(0)R2 b , .5^ r2 b ^ -S(0)2N(Rh)2, _C(R2a)=N(R2a) and _c(R2a) =N(〇R2a), wherein the q alkyl, carbocyclyl and heterocyclyl are, at each occurrence, optionally and independently 6 substituted on the carbon by one or more R 2 , wherein the heterocyclic group Any of the partial groups may be optionally substituted by r2〇*; R2a' may be independently selected from the group consisting of hydrazine, Ci.6 alkyl, carbocyclic and heterocyclic groups, wherein the C -6 alkyl group, Carbocyclyl and heterocyclyl, at each occurrence, may be optionally substituted on the carbon by one or more r2?, and wherein any -NH- moiety of the heterocyclic group may be R2 by- *Substituted; R2b' may be selected from the group consisting of Cl.6 alkyl, Ch dibasic, C6 6 fast radical, carbocyclyl and heterocyclyl, wherein the Cl 6 alkyl, A 6 alkenyl, hi alkynyl And a heterocyclyl group, at each position, optionally and independently substituted on the carbon by one or more R 2 , and wherein any ___ moiety of the heterocyclic group Optionally, it is substituted by R2G*; at each position, it may be independently selected from a Cw alkyl group, a carbocyclic group and a heterocyclic group, wherein the c]-6 alkyl group, a carbocyclic group and a heterocyclic group are visible at each point of existence. And independently and independently substituted on the carbon by - or a plurality of R 2 Q, and wherein any -NH- moiety of the heterocyclic group may be optionally substituted by R 2 〇 *; may be selected from fluorene, a functional group, -CN, Ci_6 base, Cm base, CM fast base, 133151 •55· 200906818 stone inverse % base hetero group, _〇R3a, _SR3a, _N(R3a)2, _N(R3a)c(〇)R3b, -N( R ) N(R )2, _NG2, _N(R3a)_QR3a, _〇_N(R3a)2, c(〇)h, -C(0)R > -C(0)2R3a Λ -C(0 N(R3a)2 > -C(0)N(R3a)(〇R3a), -0C(0)N(R )2, -N(R3 ”c(〇)2 r3, _n(r3 ”c(9)n (r3 a 乂, 〇c(9)r3 b, S(0)R ' -S(0)2R3b , -S(0)2N(R3a)2 > -N(R3a)S(0)2R3b ^ -C(R3a) =N(R3a) and _C(R3a)=N(〇R3a), wherein the Ci6 alkyl group, the dilute group, the C:2·6 alkynyl group, the carbocyclic group and the heterocyclic group may be optionally on the carbon or Multiple (R 〇 substituted, and wherein any -NH- moiety of the heterocyclic group may be substituted by R3G* as appropriate; R3a, in each presence, Is selected from the group consisting of H, Ci 6 alkyl, carbocyclyl and heterocyclic groups, wherein the heart is a 6-alkyl group, a carbocyclic group and a heterocyclic group, which are optionally present on the carbon and/or independently A plurality of ruthenium 3 〇 are substituted, and wherein any -NH- moiety of the heterocyclic group may be optionally substituted by R 3 〇 *; R 3b ' may be selected from the group consisting of Cl 6 alkyl, C 2 6 alkenyl. a decynyl group, a carbocyclic group, and a heterocyclic group, wherein the Cl_e alkyl group, the C2 6 alkenyl group, the C2 6 alkynyl group, the carbon 1 agroyl group, and the heterofluorenyl group are present at each, optionally and independently in the carbon Substituted by one or more R 3 ,, and wherein any - part of the heterocyclic group may be optionally substituted by R 3 G *; R 4 may be selected from fluorene, from the group, -CN, Cl.6 alkyl, C2 6 dilute, C 2 6 fast radical, fluorenyl, heterocyclyl, -OR4a, _SR4a, _N(R4a;)2, -N(;R4a;)C(0)Il4b, -N(R4a)N( R4a)2, -N〇2, -N(R4a)_0R4a, 〇_N(R4a)2, _c(〇)H, -C(0)R4b v -C(0)2R4a ' -C(〇)N (R4a)2 . -C(0)N(R4a)(〇R4a). 〇C(〇)N(R4a)2 ^ -N(R4a)C(0)2R4a , -N(R4a)C(0) N(R4a)2 > -0C(0)R4b Λ -S(〇)R4b, _S(〇)2R4b, -S(〇)2N(R4a)2, _N(R4a)S(〇)2R4b, 133151 - 56 - 200906818 -C(R")=N(R") and ·c(R4a), wherein R4a), wherein the ci 6 alkyl group, the c24 group, the Q-6 alkynyl group, the carbocyclic group and the heterocyclic group may be used as the case may be. Substituting one or more R 0 on the carbon, and wherein any of the moiety of the heterocyclic group may be optionally substituted by R 4 G *; ' 妒 * ' at each position may be independently selected from alkyl, carbon Base, heterocyclic group, -C(0)H, -C(0)R4b, _c(〇)2R4e, _c(〇)N(R4a 卜R4b, but) wide, -S(0)2N(R4a) 2. -C(R4a)=N(R4a) and _c(R4a)=N(〇R4., wherein the q 6 "burning I carbon ring group and heterocyclic group" are present at each position, optionally and independently Substituted on the carbon by one or more r4〇, and wherein any __- moiety of the heterocyclic group may be optionally substituted by R4 〇*; 'in each presence' may be independently selected from H, Ci 6 alkane a carbyl group, a carbocyclic group and a hetero aryl group, wherein the Ci 6 alkyl group, the carbocyclic group and the heterocyclic group are optionally substituted on the carbon by one or more 圮0, respectively, and wherein Any -NH- moiety of the hetero-amino group may be optionally substituted by R4〇*; R4b, in each of the groups, may be selected from the group consisting of ICl.6 alkyl, eh-alkenyl, c2 6 alkynyl, carbocyclyl and hetero a cyclic group wherein the CHm 2 6 dilute group, the Ch block group, the stone anodic group, and the heterocyclic group are optionally substituted on the carbon by one or more R 40 at each position, and wherein the heterocyclic group Any of the -groups may be replaced by R4G* as appropriate; R4c' may be independently selected from the group consisting of Cl, 6 alkyl, carbocycle And a heterocyclic group, wherein the Ci-6 alkyl group, the carbocyclic group and the heterocyclic group are optionally substituted on the carbon by one or more R 4 〇 at each presence, and wherein the heterocyclic group Any -NH- moiety may be optionally substituted by R4〇*; R10' may be independently selected from the group consisting of _ group, _CN, alkyl group, C2_6 133151 -57- 200906818 fluorenyl group, C2 _ 6 alkynyl group , carbocyclyl, heterocyclyl, _〇Rl 0 a, _SRi 〇a, _N(Rl 〇%, -N(R1Qa)C(0)R1()b, -N(Rl〇a)N(R10a) 2, _N〇2, _N(Rl〇a)_〇Rl〇a, -ON(R10a)2, -C(〇)H, -C(O)R10b, -C(O)2R10a, -C(O N(R10a)2, -C(0)N(R10a)(〇Ri〇a), _〇c(9)N(R10)2, _N(Rl0"c(〇hRl0a, -N(R10a)C(O)N (R10a)2, _OC(0)Ri〇b, -S(〇)Ri〇b, _s(〇)2R10b, -S(O)2N(R10a)2, -N(R10a)S(O)2R10b, -C^R1 0 a 0 a) and -C(R10a)=N(〇Ri〇a); R10* 'in each of the places' may be independently selected from Ci 6 alkyl, carbocyclic, heterocyclic, C(0)H ' -C(O)R10b . -C(O)2R10c ' -C(O)N(R10a)2 > -S(O)R10b ^ -S(0)2 R1 0 b,- S(〇)2 N(R; 0 a )2, _C(R1 0 a )=N(R1 0 a) and _C(R1 0 a )=N(〇Rl 〇a R10a, at each position, may be independently selected from the group consisting of H, Cl-6 alkyl, carbocyclyl and heterocyclyl;

Rl〇b，於各存在處，可獨立選自CV6烷基、C2-6烯基、c2_6 炔基、碳環基及雜環基； R10e，於各存在處，可獨立選自H、Ci 6烷基 '碳環基及雜 環基； R20’於各存在處’可獨立選自鹵基、_CN、烷基、Cm 烯基、C2_6 炔基、碳環基、雜環基、_〇R20a、_SR2〇a、_N(R2〇a)2、 -N(R20a)C(〇)R2〇b、_N(R20a)N(R20”2、_N〇2、_N(R2〇a>〇R2〇a、 -O-N(R20a)2 . -C(〇)H ^ -C(O)R20b ' -C(O)2R20a > -C(0)N(R2 0 a )2 > -C(0)N(R2〇a)(〇R2〇a)、_〇c(〇)N(R20a)2、_N(R2〇a)c(〇)2R2〇a、 -N(R20a)C(〇)N(R20a)2 > -〇C(〇)R20b ^ -S(O)R20b ' -S(O)2R20b ^ -S(0)2N(R2〇a)2 、_N(R20a)s(〇)2R20b 、_c(R20a)=N(R2〇a)及 -C(R20a)=N(〇R2〇a); 133151 -58- 200906818 :各存在處，可獨立選自c】·6烧基、碳環基、雜環基、 -C(0)H ^ -C(0)R2〇b , _C(〇)2R2〇c , _C(〇)N(R20a)2 . -S(O)R20b ^ -S(0)2R2°b、-S(0)2N(Il2〇a)2、_c(R2〇a)==N(R2〇a)及 _c(R20a)=N(〇R20a); R20a，於各存在處，可獨立選自H、Ci 6烷基、碳環基及雜 環基； R20b ,於各存在處，可獨立選自Ci 6烷基、c2 6烯基、c2 6 炔基、碳環基及雜環基； R20e，於各存在處，可獨立選自H、Ci_6烷基、碳環基及雜 環基； R30，於各存在處，可獨立選自鹵基、-CN、C卜6烷基' c2-6 烯基、C2·6炔基、碳環基、雜環基、_〇R3〇a、服…、_N(R3Ga)2、 -N(R3°a)C(〇)R3〇b、_N(R30a)N(R30a)2、_N〇2、_難3〇a)-⑽〇a、Rl〇b, at each position, may be independently selected from CV6 alkyl, C2-6 alkenyl, c2_6 alkynyl, carbocyclyl and heterocyclic; R10e, in each presence, may be independently selected from H, Ci 6 Alkyl 'carbocyclyl and heterocyclic; R20' may be independently selected from halo, -CN, alkyl, Cm alkenyl, C2-6 alkynyl, carbocyclyl, heterocyclyl, 〇R20a, _SR2〇a, _N(R2〇a)2, -N(R20a)C(〇)R2〇b, _N(R20a)N(R20"2, _N〇2, _N(R2〇a>〇R2〇a, -ON(R20a)2 . -C(〇)H ^ -C(O)R20b ' -C(O)2R20a > -C(0)N(R2 0 a )2 > -C(0)N( R2〇a)(〇R2〇a), _〇c(〇)N(R20a)2, _N(R2〇a)c(〇)2R2〇a, -N(R20a)C(〇)N(R20a) 2 > -〇C(〇)R20b ^ -S(O)R20b ' -S(O)2R20b ^ -S(0)2N(R2〇a)2 , _N(R20a)s(〇)2R20b, _c( R20a)=N(R2〇a) and -C(R20a)=N(〇R2〇a); 133151 -58- 200906818 : each being present, independently selected from c]·6 alkyl, carbocyclic, hetero Ring group, -C(0)H ^ -C(0)R2〇b , _C(〇)2R2〇c , _C(〇)N(R20a)2 . -S(O)R20b ^ -S(0)2R2 °b, -S(0)2N(Il2〇a)2, _c(R2〇a)==N(R2〇a) and _c(R20a)=N(〇R20a); R20a, at each place, Can be independent Lie to H, Ci 6 alkyl, carbocyclyl and heterocyclic; R20b, in each presence, independently selected from Ci 6 alkyl, c 2 6 alkenyl, c 2 6 alkynyl, carbocyclyl and heterocyclic R20e, at each position, may be independently selected from H, Ci-6 alkyl, carbocyclyl and heterocyclic; R30, in each presence, may be independently selected from halo, -CN, Cb6 alkyl' C2-6 alkenyl, C2·6 alkynyl, carbocyclyl, heterocyclic, 〇R3〇a, s..., _N(R3Ga)2, -N(R3°a)C(〇)R3〇b, _N(R30a)N(R30a)2, _N〇2, _hard 3〇a)-(10)〇a,

-O-N(R30a)2 > -C(0)H ^ -C(O)R30b > -C(O)2R30a > -C(0)N(R3 0 a )2 ^ -C(0)N(R3〇a)(〇R3 0a^ N -〇C(〇)N(R30a)2 ' -N(R3〇a)C(〇)2R3〇a N -N(R30a)C(〇)N(R30a)2 > -〇C(〇)R30b ^ -S(O)R30b > -S(O)2R30b > -S(0)2N(R3〇a)2 、 _N(R3°a)S(〇)2R30b 、 -C(R3 0 a )=n(R3 0 a)及 -C(R30a)=N(OR30a); R3〇，於各存在處，可獨立選自Ci I烷基、碳環基、雜環基、 -C(0)H ^ -C(0)R3〇b , _C(〇)2R3〇c , _C(〇)N(R30a)2 . -S(〇)R3〇b , -S(0)2R30b、-S(〇)2N(R3〇a)2、_c(R3〇a)=N(R3〇a)及 _c(R3〇a)=N(〇R30a); R30a，於各存在處，可獨立選自H、Ci_6烷基、碳環基及雜 環基； R3〇b，於各存在處，可獨立選自Ci-6烷基、c2_6烯基、c2_6 炔基、碳環基及雜環基；且 133151 -59- 200906818 R3 〇 e ’於各存在處’可獨立選自& ·6烷基、碳環基及雜環基； R40，於各存在處，可獨立選自鹵基、-CN、Ch烷基、C2-6 烯基、C2 - 6 快基、碳環基、雜環基、-〇R4 G a、_SR4 Q a、_N(R4 Q a)2、 -N(R40a)C(O)R40b、-N(R4〇a)N(R40a)2、-N〇2、-N(R40a)-〇R40a、 -O-N(R40a)2、-C(0)H、-C(〇)R40b、-C(O)2R40a、-C(O)N(R40a)2、 -C(O)N(R40a)(〇R4°a) . -〇C(O)N(R40a)2 ' -N(R40a)C(〇)2R40a .-ON(R30a)2 > -C(0)H ^ -C(O)R30b > -C(O)2R30a > -C(0)N(R3 0 a )2 ^ -C(0)N (R3〇a)(〇R3 0a^ N -〇C(〇)N(R30a)2 ' -N(R3〇a)C(〇)2R3〇a N -N(R30a)C(〇)N(R30a ) 2 > -〇C(〇)R30b ^ -S(O)R30b > -S(O)2R30b > -S(0)2N(R3〇a)2 , _N(R3°a)S(〇 2R30b, -C(R3 0 a )=n(R3 0 a) and -C(R30a)=N(OR30a); R3〇, at each position, may be independently selected from Ci I alkyl, carbocyclyl, Heterocyclic group, -C(0)H ^ -C(0)R3〇b , _C(〇)2R3〇c , _C(〇)N(R30a)2 . -S(〇)R3〇b , -S( 0) 2R30b, -S(〇)2N(R3〇a)2, _c(R3〇a)=N(R3〇a), and _c(R3〇a)=N(〇R30a); R30a, exist in each Wherein, independently selected from the group consisting of H, Ci-6 alkyl, carbocyclyl and heterocyclic; R3〇b, in each presence, independently selected from Ci-6 alkyl, c2-6 alkenyl, c2-6 alkynyl, carbocyclyl And a heterocyclic group; and 133151 -59- 200906818 R3 〇e 'in each of the 'wherein' can be independently selected from & 6 alkyl, carbocyclyl and heterocyclic; R40, in each presence, can be independently selected from Halo, -CN, Ch alkyl, C2-6 alkenyl, C2-6 fast radical, carbocyclyl, heterocyclyl, -〇R4 G a, _SR4 Q a, _N(R 4 Q a)2, -N(R40a)C(O)R40b, -N(R4〇a)N(R40a)2, -N〇2, -N(R40a)-〇R40a, -ON(R40a)2 , -C(0)H, -C(〇)R40b, -C(O)2R40a, -C(O)N(R40a)2, -C(O)N(R40a)(〇R4°a) . 〇C(O)N(R40a)2 '-N(R40a)C(〇)2R40a .

-N(R40a)C(O)N(R40a)2 > -〇C(O)R40b - -S(O)R40b ^ -S(O)2R40b > -S(O)2N(R40a)2、-N(R4〇a)s(〇)2R4〇b、_c(R4〇a)=N(R4()a)及 -C(R40a)=N(OR40a); r40*，於各存在處，可獨立選自C!_6烷基、碳環基、雜環基、 -C(0)H > -C(0)R4〇b . -C(〇)2R4〇c . .C(0)N(R4〇a)2 , _S(〇)R4〇b , -S(O)2R40b >-S(〇)2N(R4〇a)2 >-C(R4〇a)=N(R4〇a) A -C(R4〇a)=N(〇R4〇a); R40a，於各存在處，可獨立選自H、Ci6烷基、碳環基及雜 環基； R4〇b ’於各存在處，可獨立選自q.6烧基、c2_6稀基、c2 6 炔基、碳環基及雜環基；且 R4°C’於各存在處’可獨立選自Ch烷基、碳環基及雜環基。 立於另方面’環A可為雜環基，其中該雜環基之任何棚_ 部份基團可視情況被R2*取代； 環B可為雜環基 個R4取代； 其中該雜環基可視情況在碳上被一或多 X可為經選擇之_〇_與___ ·， Rl可為烷基； R2* 於各存在處， 可獨立選自Cl_6烷基； 133151 200906818 r3可為烷基；且 R4可為鹵基。 於又另一方面，環a可選自嗎福啉基與六氫吡畊基，其中 該嗎福琳基與六氫吡畊基之任何-NH-部份基團可視情況被 R2"取代； 環B可選自吡啶基與嘧啶基，其中該吡啶基與嘧啶基可視 情況在碳上被一或多個R4取代； X可為經選擇之_〇_與_Nh_ ; R1可為甲基； R2*，於各存在處，可獨立選自曱基； R3可為甲基；且 R4可為氟基。 於又再另一方面，環A可選自嗎福啉冰基與4_甲基六氫吡 畊-1-基； 環B可選自5-氟基吡啶-2-基與5-氟基嘧啶_2_基； X可為經選擇之-〇-與-NH-; R1可為曱基；且 R3可為甲基。-N(R40a)C(O)N(R40a)2 > -〇C(O)R40b - -S(O)R40b ^ -S(O)2R40b > -S(O)2N(R40a)2 -N(R4〇a)s(〇)2R4〇b, _c(R4〇a)=N(R4()a) and -C(R40a)=N(OR40a); r40*, in each presence, Independently selected from C!_6 alkyl, carbocyclyl, heterocyclyl, -C(0)H > -C(0)R4〇b. -C(〇)2R4〇c . .C(0)N( R4〇a)2 , _S(〇)R4〇b , -S(O)2R40b >-S(〇)2N(R4〇a)2 >-C(R4〇a)=N(R4〇a) A -C(R4〇a)=N(〇R4〇a); R40a, at each position, may be independently selected from H, Ci6 alkyl, carbocyclyl and heterocyclic; R4〇b' is present at each , which may be independently selected from the group consisting of a q.6 alkyl group, a c2_6 dilute group, a c2 6 alkynyl group, a carbocyclic group and a heterocyclic group; and R 4 ° C 'in each of the places' may be independently selected from a C alkyl group, a carbocyclic group and Heterocyclic group. In another aspect, Ring A can be a heterocyclic group, wherein any of the sulfonyl groups of the heterocyclic group may be optionally substituted by R2*; Ring B may be substituted by a heterocyclic group of R4; wherein the heterocyclic group may be The case may be one or more X on the carbon, which may be selected _〇_ and ___, and R1 may be an alkyl group; R2* may be independently selected from a C1-6 alkyl group at each position; 133151 200906818 r3 may be an alkyl group And R4 may be a halogen group. In yet another aspect, the ring a can be selected from the group consisting of morpholinyl and hexahydropyridinyl, wherein any -NH- moiety of the wheylinyl and hexahydropyrrole can be optionally replaced by R2"; Ring B may be selected from pyridyl and pyrimidinyl, wherein the pyridyl and pyrimidinyl may be optionally substituted on the carbon with one or more R4; X may be selected _〇_ and _Nh_; R1 may be methyl; R2*, in each presence, may be independently selected from the group consisting of fluorenyl; R3 may be methyl; and R4 may be fluoro. In yet another aspect, Ring A can be selected from the group consisting of morphine and benzyl hexahydropyranin-1-yl; ring B can be selected from the group consisting of 5-fluoropyridin-2-yl and 5-fluoro Pyrimidine_2-yl; X may be selected - 〇- and -NH-; R1 may be a fluorenyl group; and R3 may be a methyl group.

133151 ，式（1)化合物可為式（la)化合物： N、133151, the compound of formula (1) may be a compound of formula (la): N,

、NH 式（la) -61 - 200906818 或其藥學上可接受之鹽。, NH (la) -61 - 200906818 or a pharmaceutically acceptable salt thereof.

於又再進一步方1¾ I ，本發明係提供式（I)化合物或其藥學 上可接受之鹽，如藉由每7丨 由貝例所說明，其每一個係提供本發 明之進一步獨立方面。 利用性 咸認典型式⑴化人4 ° 八有藉由抑制JAK酪胺酸激酶，特 別是JAK2族群，以户·底典财_ ^ α療月髓增生病症、脊髓發育不良徵 簇及癌症之利用性。，、Λ达+ 、 〜療方法係以酪胺酸激酶活性，特 疋JAK族群活性，且更特別是觸活性為標的，該活性係 涉及多種骨题增生病症、脊髓發育不良徵候鎮及癌症相關 過程。因& ’預期赂胺酸激酶，特別是族群，且更特 別是JAK2之抑制劑，係呈有 你”有抵抗骨髓增生病症之活性，孽 如慢性髓樣白血病、直性έ ‘七 & 具性紅血球增多症、自發性血小板增 多症、伴隨著骨趫纖維變性縣 曰 取再吏r生之叙樣化生、原發性骨髓 變性、慢性骨髓單核血球白血病愈 八炳興《伊紅性血球過多症徵 候簇、脊髓發育不良徵候簇，及贅瘤疾病，譬如乳房、即 巢、肺臟、結腸、前列腺或其他組織之癌症，以及白血病P 骨髓細胞瘤與淋巴瘤、中樞與末梢神經系統之腫瘤，二 他腫瘤類型’譬如黑色素瘤、纖維肉瘤及骨肉瘤。亦預期 酪胺酸激酶抑制劑，特別是JAK族群抑制劑，且更特別θ 皿2抑制劑，可用於治療其他增生疾病，包括但不限於7 身免疫、炎性、神經病及心血管疾病。 、 當藉由本文中所述之JAK2檢測法測定時，已証實式⑺化 合物會抑制酪胺酸激酶，特別是JAK族 ^ 且更特別是 133151 -62- 200906818 JAK2 ° 式（I)化合物亦應可作為標準物與試劑，用於測定潛在醫 藥抑制酪胺酸激酶，特別是JAK族群，且更特別是JAK2之 能力。其係被提供於包含本發明化合物之市售套件中。 JAK2激酶活性可使用放大發光親近檢測（Alphascreen)技術 (PerkinElmer，549 Albany Street, Boston，MA)，藉由度量此激酶使 一般性多肽受質内之合成酪胺酸殘基磷醯基化之能力而測 得。 為度量JAK2激酶活性，可使用市購可得之經純化酵素。 此酵素可為C-末端His6-標記之重組人類JAK2，胺基酸808-末 端（基因銀行收受號碼NM 004972)，藉由桿狀病毒表現於Sf21 細胞（Upstate生物技術，ΜΑ)中。在激酶以生物素化之受質及 腺苷三磷酸（ΑΤΡ)於室溫下培養60分鐘後，藉由添加30 mM 乙二胺四醋酸（EDTA)可使激酶反應停止。反應可在384井微 滴定板中進行，且反應產物可於室溫下過夜培養後，使用 EnVision多標記板讀取器，藉由添加經鏈黴胺基酸塗覆之供 體珠粒與磷酸酪胺酸專一抗體塗覆之受體珠粒進行偵測。 "Tween 20”為ICI美國公司之註冊商標。 肽受質 TYK2 (Tyr 1054/1055生物素化肽）細胞發出訊 息技術#2200B. 402 /^Μ儲備液. ATP Km 30 μΜ 檢測條件 300pM JAK2 酵素，5 mM ATP, 80nM Tyk2, 10mM MgCl2, 50mM Hepes 緩衝劑 pH 7.5，ImM DTT, 0.01% Tween 20®. 培養 60分鐘，室溫 133151 -63· 200906818 終止/偵測條件 6.3mM HEPES，30 mM EDTA，525 微克 / 毫升 BSA, 40 mM NaCl, 0_〇〇7% Triton®X-100, 12 毫微克 / 毫 升供體珠粒，12毫微克/毫升受體珠粒 偵測培養 ^過夜，室溫 螢光計設定 激發=680毫微米，發射=570毫微米，激發 時間=180 ms,總度量時間=550 ms 雖然式（i)化合物之藥理學性質可隨著結構變化而改變， 但咸認典型式（I)化合物在IC5Q濃度（達成50%抑制作用之濃 度）下，或在含量低於1〇 _之劑量下，具有JAK抑制活性。 f 當在上述活體外檢測中測試時，下述實例之JAK抑制活 性係在下列IC5()下度量。 實例 icso (幽 1 0.003 2 0.003 3 0.003 4 0.003 5 0.003 因此，於一方面，係提供式（1)化合物或其藥學上可接受 之鹽，作為藥劑使用。 於另一方面，係提供式（I)化合物或其藥學上可接受之鹽 於藥劑製造上之用途，該藥劑係在溫血動物譬如人類中治 療或預防骨髓增生病症、脊髓發育不良徵候簇及癌症。 於又另一方面，係提供式（I)化合物或其藥學上可接受之 鹽於藥劑製造上之用途，該藥劑係在溫血動物譬如人類中 治療或預防骨髓增生病症、脊髓發育不良徵候簇及癌症（固 態與血液學腫瘤）、纖維增生與分化病症、牛皮癬、風濕性 133151 -64 - 200906818 關郎炎、卡波西氏肉瘤、金管瘤、急性與慢性腎病、動脈 粥瘤、動脈粥瘤硬化、動脈再狹窄、自身免疫疾病、肢端 肥大病、急性與慢性發炎、骨質疾病及伴隨著視網膜血管 增生之眼部疾病。 、 ;又再另方面，係提供式（I)化合物或其藥學上可接為 之I於藥劑製造上之用途，該藥劑係在溫血動物馨如人類 中治療慢性髓樣白血病、真性紅血球增多症、自發性到、、 板增多症、伴隨著骨髓纖維變性之髓樣化生、原發性骨髓 雇、准羞I·生、慢性骨趙單核血球白血病與唁伊紅性血球過多 徵候簇、脊髓發育不良徵候襄’及癌症’選自食管癌、骨 髓細胞瘤’肝細胞、胰、子宮頸癌，尤汉氏肉瘤 '神經胚 、、-田胞瘤、卡波西氏肉瘤、印巢癌、乳癌、結腸直腸癌 '前 列腺癌、膀胱癌、黑色素瘤、肺癌_非小細胞肺癌（NSCLC) 舁1、’’田胞肺癌(SCLC)、胃癌、頭部與頸部癌、間皮瘤、腎 癌、淋巴瘤及白血病。 於進步方面，係提供式（I)化合物或其藥學上可接受之 鹽於藥劑制μ + m、八 、以上之用途’該藥劑係在溫血動物譬如人類中 產生抗增生作用。 ''又進步方面，係提供式（I)化合物或其藥學上可接受 ;藥诏製造上之用途，該藥劑係用於產生JAK抑制作 用。 ； 再進步方面’係提供式（I)化合物或其藥學上可接 受之鹽於藥劑製造上之用途，該藥劑係用於治療癌症。In a further aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, as illustrated by the shellfish, each of which provides further independent aspects of the invention. The use of sexual salt to recognize the typical formula (1) to human 4 ° 八 has to inhibit JAK tyrosine kinase, especially the JAK2 group, to the end of the family _ _ ^ α treatment of myeloid hyperplasia, spinal dysplasia and cancer Utilization. , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , 〜 疗 〜 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗 疗process. Because & 'expects glycosylkinase, especially the ethnic group, and more particularly the inhibitor of JAK2, is your activity against bone marrow hyperplasia, such as chronic myeloid leukemia, straight έ 'seven & Sexual erythrocytosis, spontaneous thrombocytosis, accompanied by osteophyte fiber degeneration, recapture, recurrence, primary metabolite, primary bone marrow degeneration, chronic bone marrow mononuclear leukemia, more than eight Bingxing Hypertrophic syndrome, spinal dysplasia syndrome, and neoplastic disease, such as breast, nest, lung, colon, prostate or other tissue cancer, and leukemia P myeloma and lymphoma, central and peripheral nervous system Tumor, two tumor types such as melanoma, fibrosarcoma and osteosarcoma. Tyrosine kinase inhibitors, especially JAK group inhibitors, and more particularly θ 2 inhibitors, are also expected to be useful in the treatment of other proliferative diseases, including However, it is not limited to 7 immune, inflammatory, neurological, and cardiovascular diseases. When determined by the JAK2 assay described herein, the formula (7) has been confirmed. It inhibits tyrosine kinases, particularly the JAK family and more particularly 133151 -62- 200906818 JAK2 ° The compounds of formula (I) should also be used as standards and reagents for the determination of potential pharmaceutical inhibitory tyrosine kinases, especially The ability of the JAK population, and more particularly JAK2, is provided in a commercially available kit comprising a compound of the invention. JAK2 kinase activity can be performed using the Alphascreen technique (PerkinElmer, 549 Albany Street, Boston, MA). By measuring the kinase, the general polypeptide is determined by the ability to phosphorylate the synthetic tyrosine residue in the plastid. To measure JAK2 kinase activity, commercially available purified enzymes can be used. The C-terminal His6-tagged recombinant human JAK2, the amino acid 808-terminus (Gene Bank Acceptance No. NM 004972), is expressed in Sf21 cells (Upstate Biotechnology, ΜΑ) by baculovirus. After the culture and adenosine triphosphate (ΑΤΡ) were incubated at room temperature for 60 minutes, the kinase reaction was stopped by adding 30 mM ethylenediaminetetraacetic acid (EDTA). The reaction was carried out in a 384 well microtiter plate. The reaction product was carried out overnight at room temperature and then coated with a specific antibody coated with streptavidin-coated donor beads and phosphotyrosine using an EnVision multi-label plate reader. Body beads are detected. "Tween 20" is a registered trademark of ICI America. Peptide-derived TYK2 (Tyr 1054/1055 biotinylated peptide) cells emit message technology #2200B. 402 /^Μ stock solution. ATP Km 30 μΜ Detection conditions 300pM JAK2 enzyme, 5 mM ATP, 80nM Tyk2, 10mM MgCl2, 50mM Hepes Buffer pH 7.5, ImM DTT, 0.01% Tween 20®. Culture for 60 minutes, room temperature 133151 -63· 200906818 Termination/detection conditions 6.3 mM HEPES, 30 mM EDTA, 525 μg/ml BSA, 40 mM NaCl, 0_ 〇〇7% Triton®X-100, 12 ng/ml donor beads, 12 ng/ml acceptor beads detection culture overnight, room temperature fluorometer set excitation = 680 nm, emission = 570 nm , excitation time = 180 ms, total measurement time = 550 ms Although the pharmacological properties of the compound of formula (i) may vary with the structure, the compound of formula (I) is recognized at IC5Q concentration (50% inhibition is achieved). At a concentration, or at a dose of less than 1 〇, it has JAK inhibitory activity. f When tested in the above in vitro assay, the JAK inhibitory activity of the following examples was measured under the following IC5(). Example icso (幽1 0.003 2 0.003 3 0.003 4 0.003 5 0.003 Thus, in one aspect, a compound of formula (1) or a pharmaceutically acceptable salt thereof is provided for use as a medicament. In another aspect, a formula (I) is provided a use of a compound or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment or prevention of myeloproliferative disorders, myelodysplastic syndromes and cancer in a warm-blooded animal such as a human. In yet another aspect, Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing myeloproliferative disorders, myelodysplastic syndromes and cancer (solid and hematological tumors) in a warm-blooded animal such as a human ), fibroproliferation and differentiation disorders, psoriasis, rheumatism 133151 -64 - 200906818 Guan Langyan, Kaposi's sarcoma, tumor, acute and chronic kidney disease, atheroma, atherosclerosis, arterial restenosis, autoimmune Disease, acromegaly, acute and chronic inflammation, bone disease and eye diseases associated with retinal vascular hyperplasia. Providing a compound of formula (I) or a pharmaceutically acceptable agent thereof for use in the manufacture of a medicament for treating chronic myeloid leukemia, polycythemia vera, spontaneity, in a warm-blooded animal such as a human Plate hyperplasia, myeloid metaplasia with bone marrow fibrosis, primary bone marrow employment, quasi-shame I. Health, chronic bone marrow mononuclear leukemia and sputum red blood cell hypertrophy, spinal dysplasia 襄And cancer 'selected from esophageal cancer, myeloid cell tumor 'hepatocytes, pancreas, cervical cancer, Youhan's sarcoma' nerve embryo, - cytoma, Kaposi's sarcoma, India, breast cancer, colorectal cancer 'Prostate cancer, bladder cancer, melanoma, lung cancer _ non-small cell lung cancer (NSCLC) 舁 1, ''Field cell lung cancer (SCLC), gastric cancer, head and neck cancer, mesothelioma, kidney cancer, lymphoma and Leukemia. In terms of progress, the invention provides a compound of the formula (I) or a pharmaceutically acceptable salt thereof for use in the preparation of μ + m, VIII or more of the medicament. The agent produces an anti-proliferative effect in a warm-blooded animal such as a human. 'And progress, the Department provides (I) a compound or a pharmaceutically acceptable agent thereof; for use in the manufacture of a medicinal tract for the production of a JAK inhibitory effect; a further improvement in the provision of a compound of formula (I) or a pharmaceutically acceptable salt thereof For manufacturing purposes, the agent is used to treat cancer.

^ XIM 、 ’係提供一種在溫血動物譬如人類中治療骨髓 133151 -65- 200906818 增生病症、脊鈿發育不良徵候簇及癌症之方法，該方法包 括對該動物投予有效量之式①化合物，或其藥學上可接= 之鹽。 於另一方面，係提供一種在溫血動物譬如人類中治療骨 髓增生病症、脊髓發育不良徵候簇及癌症（固態與血液學腫 瘤）、纖維增生與分化病症、牛皮癬、風濕性關節炎、卡波 西氏肉瘤、血管瘤、急性與慢性腎病、動脈粥瘤、動脈粥 瘤硬化、動脈再狹窄、自身免疫疾病、肢端肥大病、急性 與慢性發炎、骨質疾病及伴隨著視網膜血管增生之眼部疾 病之方法’該方法包括對該動物投予有效量之式(ι)化合物， 或其藥學上可接受之鹽。 於又另一方面，係提供一種在溫血動物譬如人類中治療 慢性髓樣白灰病'真性紅4球增多症、自發性血小板增多 症、伴隨著骨髓纖維變性之髓樣化生、原發性骨髓纖維變 性、慢性骨髓單核灰球白血病與嘻伊紅性血球過多徵候 鎮、脊髓發育不良徵候蔟’及癌症，選自食管癌、骨髓細 胞瘤，肝細胞、胰、子宮頸癌，尤汉氏肉广留、神經胚細胞 瘤、卡波西氏肉瘤、印巢癌、乳癌、結腸直腸癌、前列腺 癌膀胱癌黑色素瘤、肺癌_非小細胞肺癌與小 細胞肺癌(SCLC)、胃癌' 頭部與頸部癌、間皮瘤、腎癌、 淋巴瘤及白A病之方法，該方法包括㈣㈣0㈣f 之式（I)化合物，或其藥學上可接受之鹽。 ' 方面係提供一種在溫血動物譬如人類中產 生抗增生作用之方法，該方法包括對該動物投予有效量之 133151 -66 - 200906818 式（i)化合物，或其藥學上可接受之鹽。 於進一步方面，係提供一種在溫血動物譬如 ° 頸中產生 JAK抑制作用之方法，該方法包括對該動物投 】頁效量之 式（I)化合物，或其藥學上可接受之鹽。 於又進一步方面’係提供一種在溫血動物嬖如 D 3人類中治 療癌症之方法，該方法包括對該動物投予有效量之式①化 合物，或其藥學上可接受之鹽。 ( 於又再進一步方面，係提供式（I)化合物或其藥學上可接 受之鹽在溫血動物譬如人類中用於治療骨髓増生病症、脊 髓發育不良徵候簇及癌症。 於一方面，係提供式（I)化合物或其藥學上可接受之趟在 溫血動物譬如人類中用於治療骨髓增生病症、脊越發育不 良破候蔟及癌症（固態與血液學腫瘤）、纖維増生與八化广 症、牛皮癣、風濕性關節炎、卡波西氏肉瘤、血管瘤、急 性與慢性腎病、動脈粥瘤、動脈粥瘤硬化、動脈再狹窄、 ί .. 自身免疫疾病、肢端肥大病、急性與慢性發炎、骨質疾广 及伴隨著視網膜血管增生之眼部疾病。 於另一方面，係提供式①化合物或其藥學上可接受之鹽 在溫血動物譬如人類中用於治療慢性髓樣白血病、真性紅 血球增多症、自發性血小板增多症、伴隨著骨趙纖維變性 之髓樣化生、原發性骨髓纖維變性、慢性骨髓單核血球白 血病與嗜伊紅性血球過多徵候簇、脊髓發育不良徵候簇， 及癌症，選自食管癌、骨髓細胞瘤’肝細胞、胰、子宮頸 癌，尤汶氏肉瘤、神經胚細胞瘤、卡波西氏肉瘤、卵巢癌、 133151 -67· 200906818 乳癌、結腸直腸癌、前列腺癌、膀胱癌、黑色素瘤、肺癌-非小細胞肺癌（NSCLC)與小細胞肺癌（SCLC)、胃癌、頭部與 頸部癌、間皮瘤、腎癌、淋巴瘤及白血病。 於又另一方面’係提供式⑴化合物或其藥學上可接受之 鹽在溫血動物譬如人類中用於產生抗增生作用。 於又再另一進一步方面，係提供式⑴化合物或其藥學上 可接受之鹽在溫血動物譬如人類中用於產生JAK抑制作 用。 於進一步方面’係提供式①化合物或其藥學上可接受之 鹽在溫企動物譬如人類中用於治療癌症。^XIM, 'A method for treating a bone marrow 133151-65-200906818 proliferative disorder, spinal dysplasia syndrome, and cancer in a warm-blooded animal such as a human, the method comprising administering to the animal an effective amount of a compound of formula 1, Or a pharmaceutically acceptable salt thereof. In another aspect, the invention provides a method for treating myeloproliferative disorders, spinal dysplasia syndromes and cancers (solid and hematological tumors), fibroproliferation and differentiation disorders, psoriasis, rheumatoid arthritis, and Kaposbo in warm-blooded animals such as humans. Western sarcoma, hemangioma, acute and chronic kidney disease, atheroma, atherosclerosis, arterial restenosis, autoimmune disease, acromegaly, acute and chronic inflammation, bone disease and eye with retinal vascular proliferation Method of Disease 'This method comprises administering to the animal an effective amount of a compound of formula (i), or a pharmaceutically acceptable salt thereof. On the other hand, it provides a treatment for chronic myeloid white ash disease in patients with chronic myeloid white ash, true red thrombocytosis, spontaneous thrombocytosis, myeloid metaplasia accompanied by myelofibrosis, primary Bone marrow fiber degeneration, chronic bone marrow mononuclear gray leukemia and sputum red blood cell hypertrophy syndrome, spinal cord dysplasia 蔟 ' and cancer, selected from esophageal cancer, myeloid cell tumor, liver cells, pancreas, cervical cancer, Youhan Meat, blastocytoma, Kaposi's sarcoma, Indian cancer, breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer, non-small cell lung cancer, small cell lung cancer (SCLC), gastric cancer And a method of cervical cancer, mesothelioma, renal cancer, lymphoma, and white A disease, the method comprising (d) (d) 0 (tetra) f a compound of formula (I), or a pharmaceutically acceptable salt thereof. The aspect provides a method of producing an anti-proliferative effect in a warm-blooded animal such as a human, which comprises administering to the animal an effective amount of a compound of formula (i), 133151 - 66 - 200906818, or a pharmaceutically acceptable salt thereof. In a further aspect, there is provided a method of producing JAK inhibition in a warm-blooded animal such as a neck comprising administering to the animal a compound of formula (I), or a pharmaceutically acceptable salt thereof. In yet a further aspect, a method of treating cancer in a warm-blooded animal such as D3 human is provided, the method comprising administering to the animal an effective amount of a compound of formula 1, or a pharmaceutically acceptable salt thereof. (A still further aspect provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a warm-blooded animal such as a human for the treatment of a myelodysplastic disorder, a syndrome of myelodysplasia, and cancer. A compound of formula (I) or a pharmaceutically acceptable hydrazine thereof for use in the treatment of myeloproliferative disorders, dysplasia, and cancer (solid and hematological tumors), fibrosis and octagonal Symptoms, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, hemangioma, acute and chronic kidney disease, atheroma, atherosclerosis, arterial restenosis, 自身. autoimmune disease, acromegaly, acute and Chronic inflammation, extensive bone disease, and ocular diseases associated with retinal vascular proliferation. In another aspect, the compound of Formula 1 or a pharmaceutically acceptable salt thereof is provided for use in treating chronic myeloid leukemia in a warm-blooded animal such as a human, True polycythemia, spontaneous thrombocytosis, myeloid metaplasia with bone fiber degeneration, primary myelofibrosis, chronic bone marrow mononuclear blood Ball leukemia and eosinophilic hypertrophy syndrome, spinal dysplasia syndrome, and cancer, selected from esophageal cancer, myeloid cell tumor 'hepatocytes, pancreas, cervical cancer, You Wen's sarcoma, neuroblastoma, card Persian sarcoma, ovarian cancer, 133151 -67· 200906818 Breast cancer, colorectal cancer, prostate cancer, bladder cancer, melanoma, lung cancer-non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), gastric cancer, head and Cervical cancer, mesothelioma, renal cancer, lymphoma, and leukemia. In another aspect, the compound of formula (1) or a pharmaceutically acceptable salt thereof is used to produce an anti-proliferative effect in a warm-blooded animal such as a human. In still a further aspect, there is provided a compound of formula (1), or a pharmaceutically acceptable salt thereof, for use in the production of JAK inhibition in a warm-blooded animal such as a human. In a further aspect, the compound of formula 1 or a pharmaceutically acceptable compound thereof is provided Salt is used to treat cancer in warm animals such as humans.

於又進一步方面’在指稱治療（或預防）癌症之情況下， 其可特別地指治療（或預防）中胚層腎瘤、間皮瘤、急性骨 髓胚細胞白血病、急性淋巴球白血病、多發性骨髓瘤、食 营癌、骨髓細胞瘤，肝細胞、胰、子宮頸癌，尤汶氏肉瘤、 神經胚細胞瘤、卡波西氏肉瘤、卵巢癌、包括分泌乳癌之 乳癌、、结腸n癌、心激素反掏前列腺癌之前列腺癌、 膀脱癌、黑色素瘤、肺癌·非小細胞肺癌（NSCLC)與小細胞 肺癌(SCLC)、胃癌、頭部與頸部癌、腎癌、淋巴瘤、包括 礼頭甲狀腺癌之甲狀腺癌、間皮瘤、白友病、中樞與末梢 神經系統之腫瘤、里A主士 ， l “、、色素瘤 '包括先天性纖維肉瘤之酿維 肉瘤及骨肉瘤。更輯定" 文将疋吕之，其係指前列腺癌。此外，更 特疋 § 之，其係指 SCLC、P ere * ge ^ JNbLLC、結齡直腸癌、即巢癌及/ 或乳癌。於進一步方 万面’其可指激素反抛前列腺癌。 於又再進一步方vt» >> ’係提供一種醫藥組合物，其包含式 133151 •68· 200906818 (i)化合物或其藥學上可接受之鹽，及至少—種藥學 受之載劑、稀釋劑或賦形劑。 或提供一種醫藥組合物，其包含式①化合物 〆、 '予 接文之鹽，及至少一種藥學上可接受之載 劑、稀釋劑或賦形劑。 /In a further aspect, in the context of alleged treatment (or prevention) of cancer, it may specifically refer to the treatment (or prevention) of mesoderm nephroma, mesothelioma, acute myeloid leukemia, acute lymphocytic leukemia, multiple bone marrow Tumor, food camp cancer, myeloid cell tumor, liver cell, pancreas, cervical cancer, You Wen's sarcoma, neuroblastoma, Kaposi's sarcoma, ovarian cancer, breast cancer including breast cancer, colon cancer, Heart hormone ruminant prostate cancer prostate cancer, bladder cancer, melanoma, lung cancer · non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), gastric cancer, head and neck cancer, kidney cancer, lymphoma, including Thyroid cancer, thyroid cancer, mesothelioma, white funeral disease, central and peripheral nervous system tumors, Li A, Shi, ", pigmentoma" including congenital fibrosarcoma, sarcoma and osteosarcoma. The definition of "quote" will refer to Lu Zhi, which refers to prostate cancer. In addition, it is more specifically §, which refers to SCLC, P ere * ge ^ JNbLLC, colorectal cancer, that is, nest cancer and / or breast cancer. Fang Wanmian' Refers to hormones that reverse prostate cancer. Further, vt» >> ' provides a pharmaceutical composition comprising formula 133151 •68· 200906818 (i) a compound or a pharmaceutically acceptable salt thereof, and at least Or a pharmaceutically acceptable carrier, diluent or excipient. Or a pharmaceutical composition comprising a compound of formula 1, hydrazine, and at least one pharmaceutically acceptable carrier, diluent or Shape agent. /

本發明之組合物可呈適合口服使用（例如作成片劑、錠 劑、、硬或軟膠囊、水性或油性懸浮液、乳化液、可分散粉 末或顆粒、糖漿或酏劑）、局部使用（例如作成乳膏、軟膏、 凝膠或水性或油性溶液或懸浮液）、藉吸入投藥（例如作成 ”、田刀私末或液體氣溶膠）、藉吹入投藥（例如作成細分粉末） 或非經腸投藥（例如作成無菌水性或油性溶液供靜脈内、皮 下、肌内或肌内服藥’或作成栓劑供直腸服藥）形式。 本發明之組合物可藉由習用程序，使用此項技藝中所習 知=習用醫藥賦形劑獲得。因此，欲供口服使用之組合物 可含有例如一或多種著色、增甜、矯味及/或防腐劑。 在供片劑配方用之適當藥學上可接受之賦形劑，包括例如 h f稀釋劑:如乳糖、碳酸納、填酸雀弓或碳酸碎，粒化 /、朋解d s如玉米丨殿粉或海藻酸；黏合劑，譬如丨殿粉； 潤π劑，譬如硬脂酸鎂、硬脂酸或滑石；防腐劑，譬如對· 羥基本甲酸乙酯或丙酯；及抗氧化劑，譬如抗壞血酸。片 劑配方可未經塗覆或經塗覆，無論是為改變其崩解作用， 及活性成份在胃腸道中之隨後吸收，或為改良其安定性及/ 或外觀，在任一情況中’係使用此項技藝中所習知之習用 塗覆劑與程序。 133151 -69- 200906818 供口服使用之組合物可呈硬明膠膠囊形式，其中活性成 份係與惰性固體稀釋劑混合，例如碳酸鈣、磷酸鈣或高嶺 土 ’或作成軟明膠膠囊’其中活性成份係與水或油譬如花 生油'液態石蠟或橄欖油混合。 含水懸浮液通常含有呈微細粉末形式或呈毫微或微粉化 粒子形式之活性成份’伴隨著一或多種懸浮劑，譬如羧曱 基纖維素鈉、甲基纖維素、羥丙甲基纖維素、海藻酸鈉、 聚乙稀基四氫晚洛酮、西黃蓍樹膠及阿拉伯膠；分散或潤 濕劑，譬如卵磷脂，或氧化烯與脂肪酸類之縮合產物（例如 聚氧化乙烯硬脂酸酯）’或環氧乙烷與長鏈脂族醇之縮合產 物，例如十七氧化乙烯鯨蠟醇，或環氧乙烷與衍生自脂肪 酸類與己糖醇之部份酯類之縮合產物，譬如聚氧化乙烯單 油酸花楸醇酯，或環氧乙烷與長鏈脂族醇之縮合產物，例 如十七氧化乙烯鯨蠟醇，或環氧乙烷與衍生自脂肪酸類與 己糖醇之部份酯類之縮合產物，譬如聚氧化乙烯單油酸花 楸醇酯，或環氧乙烷與衍生自脂肪酸類與己糖醇酐類之部 份酯類之縮合產物，例如聚乙烯單油酸花楸聚糖酯。此含 水懸浮液亦可含有一或多種防腐劑’譬如對_經基苯甲酸乙 酿或丙s旨；抗氧化冑，譬如抗壞血酸；著色劑；矯味劑； 及/或增甜劑，譬如蔗糖、糖精或天冬醯苯丙胺酸甲酯。 油性懸浮液可經由使活性成份懸浮在植物油，譬如^生 油、橄欖油、芝麻油或椰子油，或在礦油譬如液態石$中 進行調配。油性懸浮液亦可含有增稠劑，譬如蜂蠟、硬石 蠟或鯨蠟醇。可添加增甜劑，譬如上文所陳述者， 石 133151 •70· 200906818 劑，以提供美味口服製劑。此等組合物可藉由添加抗氧化 劑4如抗壞血酸保存著。 適用於藉由添加纟以製備含水懸浮液之可分散粉末與顆 粒，通常含有活性成份，伴隨著分散或潤濕劑、懸浮劑及 -或多種防腐劑。適當分散或潤濕劑及懸浮劑之實例為已 於上文提及者。其他賦形劑，譬如增甜、矯味及著色劑， 亦可存在。 I贫明之醫藥組合物 ， ，一叫，卜十I '土礼狄爻形式。 油相可為植物油，譬如撖欖油或花生油，或礦油，例如液 態石蠛，或任何此等之混合物。適當乳化劑可為例如天缺 ί成：膠質’譬如阿拉伯膠或西黃箸樹膠，天然生成之磷 …如大豆、卵碟脂、衍生自脂肪酸類與己糖 酯類或部份酯類Γ你丨‘ „ .丄α 又 環氧乙院之缩入產物早Γ 聚糖醋）及該部份醋類與 醋。乳化液亦；含如聚氧化乙稀單油酸花楸聚糖 有立曰甜、矯味及防腐劑。 i 糖聚與驰齋丨可说t 醇、天久醯配’譬如甘油、丙二醇、花揪 糾德去 甲酯或蔗糖，且亦可含有和潤劑、防 腐劑、矯味及/或著色劑。 防 醫藥組合物亦可呈盔 其可根據已知程序，^ 或油性懸浮液形式， 散或潤濕劑與縣竿心一或多種已於上文提及之適當分 注射溶液或懸浮液m广射U亦了為無菌可 溶劑中，例如在η 上可接受之稀釋劑或 Μ 如在丁二醇中之溶液。 供吸入投藥用之組入 ' σ物了呈習用加i氣溶膠形式，經安 133151 200906818 細分固體或液滴之氣 如揮發性氟化烴類或 ’以分配經計量之活 排以分配活性成份’無論是作成含有 溶膠。可使用習用氣溶膠推進劑，馨 烴類，且氣溶膠裝置可合宜地經安排 性成份量。The compositions of the present invention may be suitable for oral use (for example, as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example) To make a cream, ointment, gel or aqueous or oily solution or suspension), by inhalation (for example, "made", field knife or liquid aerosol), by insufflation (for example, into a fine powder) or parenteral Administration (for example, as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular administration or as a suppository for rectal administration). The compositions of the present invention can be used in the art by conventional procedures. = conventional pharmaceutical excipients are obtained. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavoring and/or preservatives. Suitable pharmaceutically acceptable forms for tablet formulations Agents, including, for example, hf diluents: such as lactose, sodium carbonate, acid gelatin or carbonic acid granules, granulation /, dens ds such as corn glutinous rice powder or alginic acid; adhesives, such as 丨 丨 粉 powder; Agents such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl hydroxybenzoate; and antioxidants such as ascorbic acid. Tablet formulations may be uncoated or coated, regardless of In order to alter its disintegration, and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve its stability and/or appearance, in either case, conventional coating agents and procedures are known in the art. 133151 -69- 200906818 The composition for oral use can be in the form of a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin or as a soft gelatin capsule wherein the active ingredient is water Or oily oysters such as peanut oil 'liquid paraffin or olive oil. The aqueous suspension usually contains the active ingredient in the form of a fine powder or in the form of nano or micronized particles' accompanied by one or more suspending agents, such as sodium carboxymethyl cellulose, Methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyltetrahydroacyptone, scutellaria and gum arabic; dispersing or wetting agent, Such as lecithin, or a condensation product of an alkylene oxide with a fatty acid (such as polyoxyethylene stearate) or a condensation product of ethylene oxide with a long-chain aliphatic alcohol, such as cetyl vinyl ether cetyl alcohol, or a ring a condensation product of oxyethane with a partial ester derived from a fatty acid and a hexitol, such as a polyoxyethylene monooleate, or a condensation product of ethylene oxide with a long-chain aliphatic alcohol, such as ten Cetyl sulphate, or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as a polyoxyethylene monooleate, or an ethylene oxide derived from a condensation product of a fatty acid with a partial ester of a hexitol anhydride, such as a polyethylene monooleate. The aqueous suspension may also contain one or more preservatives such as p-benzoic acid B. Stuffed or anti-oxidant, such as ascorbic acid; coloring agents; flavoring agents; and / or sweeteners, such as sucrose, saccharin or methyl aspartame. The oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid stone. The oily suspensions may also contain a thickening agent, such as beeswax, hard wax or cetyl alcohol. Sweeteners may be added, such as those set forth above, stone 133151 • 70· 200906818 to provide a delicious oral preparation. These compositions can be preserved by the addition of an antioxidant 4 such as ascorbic acid. Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of hydrazine, usually containing the active ingredient, together with dispersion or wetting agents, suspending agents and/or preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those already mentioned above. Other excipients, such as sweetening, flavoring, and coloring agents, may also be present. I poor pharmaceutical composition, one called, Bu Shi I 'Tu Li Di form. The oil phase may be a vegetable oil such as eucalyptus oil or peanut oil, or a mineral oil such as liquid sarcophagus, or a mixture of any of these. Suitable emulsifiers can be, for example, glutinous: gums such as gum arabic or scutellaria, naturally occurring phosphorus... such as soy, egg fat, derived from fatty acids and hexose esters or some esters.丨' „ . 丄α 环氧 又 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧 环氧Sweet, flavoring and preservatives. i Sugar and Chi Zhai can be said to be alcoholic, long-lasting with 'such as glycerin, propylene glycol, calyx to methyl ester or sucrose, and can also contain emollients, preservatives, flavor And/or coloring agent. The anti-pharmaceutical composition may also be in the form of a helmet which may be in accordance with known procedures, or in the form of an oily suspension, a dispersing or wetting agent and one or more of the appropriate sub-injections mentioned above. The solution or suspension m is also in a sterile solvent, such as a diluent acceptable for η or a solution such as in butanediol. The group for inhalation administration is 'study'. i aerosol form, by 133151 200906818 subdivided solid or liquid droplets such as volatile fluorinated hydrocarbons Or 'to dispense a metered discharge to dispense the active ingredient live' both made containing sol can be used with conventional aerosol propellants, Xin hydrocarbons, and the aerosol device may be arranged by the component amount of conveniently.

關於配方之進一步資訊，續土 A v貝凡6買者可參閱综合醫藥化學第5 卷第25.2章（Corwin Hansch;編委會主席），pergam〇n出版社觸。 與-或多種賦形劑合併以產生單一劑型之活性成份量， 將必須依待治療之宿主及特定投藥途徑而改變。例如，欲 供口服投予人類之配方，通常將含有例如G5毫克至4克活 性劑，與適當且合宜量之賦形劑摻配，該賦形劑可從全部 組合物重量之約5改變至約98%。劑量單位形式通常含有約 1毫克至約500毫克活性成份。關於投藥途徑與劑量服用法 之進一步資訊，讀者可參閱綜合醫藥化學第5卷第25·3章 (Corwin Hansch ;編委會主席），Pergam〇n 出版社 199〇。 如上述，治療或預防治療特定疾病狀態所需要之劑量大Further information on the formula, renewed soil A V Bevan 6 buyers can refer to the comprehensive medical chemistry volume 5 chapter 25.2 (Corwin Hansch; editorial board chairman), pergam〇n press. The amount of active ingredient combined with - or a plurality of excipients to produce a single dosage form will necessarily vary depending upon the host to be treated and the particular route of administration. For example, a formulation intended for oral administration to humans will typically contain, for example, G5 mg to 4 g of active agent, in admixture with suitable and suitable amounts of excipients which may vary from about 5 to about the total weight of the composition. About 98%. Dosage unit forms will generally contain from about 1 mg to about 500 mg of active ingredient. For further information on the route of administration and dosage regimen, the reader is referred to Chapter 25, Chapter 3 of the Journal of Integrated Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergam〇n Press, 199. As mentioned above, the dose required to treat or prevent a particular disease state is large

小’係必須依待治療之宿主、投藥途徑及被治療疾病之嚴 重性而改變。較佳係採用丨-50毫克/公斤範圍内之日服劑 量。因此，最適宜劑量可由正在治療任何特定病患之執業 醫師決定。 於本文中定義之抗癌治療可以單獨療法應用，或除了本 發明化合物以外，可涉及習用手術或放射療法或化學療 法。此種化學療法可包含一或多種下列種類之抗腫瘤劑： (i)如使用於醫療腫瘤學中之抗增生/抗贅瘤藥物及其組 合，譬如烷基化劑（例如順氯胺鉑、碳氣胺鉑、環磷醯 133151 -72- 200906818 胺、氮界、苯丙胺酸氮齐、苯丁酸氮芬（chl〇rambucil)、 白血福恩（busulphan)及亞硝基脲）；抗代謝物（例如抗葉 I鹽，譬如氟基嘧啶，包括5-氟尿嘧啶與提佳弗（tegafUr) ，瑞提崔斯得（raltitrexed)、胺甲喋呤、阿拉伯糖胞苷及 經基服），抗腫瘤抗生素（例如萬環素，嬖如亞德里亞 徽素、博來黴素、多克索紅菌素、道諾黴素、表紅菌 素、依達紅菌素、絲裂黴素-C、達克汀黴素及光神黴 素）；抗有絲分裂劑（例如長春花植物鹼，譬如長春新 驗、長春花鹼、長春花素及威諾賓（vinorelbine)，與類紅 豆杉物質，譬如紅豆杉醇與紅豆杉帖里（tax〇tere));及拓 樸異構酶抑制劑（例如表鬼臼脂素，譬如衣托糖嘗 (etoposide)與天尼苷（teniposide)、阿姆薩素（amsacrine)、拓 波提肯（topotecan)及喜樹驗）；以及蛋白體抑制劑（例如博 替左米（bortezomib) [Velcade®]);及藥劑安臬葛來得 (anegrilide) [Agrylin®];以及 d-干擾素； (ii) 細胞抑制劑，譬如抗雖激素（例如他摩西吩（tamoxifen)、 托里米吩（toremifene)、瑞洛西吩（raloxifene)、卓洛西吩 (droloxifene)及峨氧吩（iodoxyfene))、雌激素受體向下調節 劑（例如弗爾威斯傳（fiilvestrant))、抗雄激素物質（例如二 卡如醯胺（bicalutamide)、弗如酿胺（flutamide)、尼如醯胺 (nilutamide)及環丙氯地孕酮醋酸鹽）、LHRH拮抗劑或 LHRH催動劑（例如郭捨瑞林（goserelin)、留普瑞林 (leuprorelin)及布捨瑞林（buserelin))、孕激素類（例如曱地 孕酮1醋酸鹽）、芳香酶抑制劑（例如安那史唾（anastrozole) 133151 -73- 200906818 、列特羅嗤（letrozole)、玻拉唾（vorazole)及約克美斯烧 (exemestane))，及5 α-還原酶之抑制劑，譬如菲那史替來 (finasteride)； (iii) 抑制癌細胞侵襲之藥劑（例如金屬蛋白酶抑制劑，譬如 馬利制菌素（marimastat)，與尿激酶血纖維蛋白溶酶原活 化劑受體功能之抑制劑）； (iv) 生長因子功能抑制劑，例如此種抑制劑，包括生長因 子抗體、生長因子受體抗體（例如抗-erbb2抗體搓史圖 諸馬伯（trastuzumab)[HerceptinTM]與抗-erbbl抗體些圖西馬 伯（Cetuximab)[C225])、法呢基轉移酶抑制劑、酷·胺酸激 酶抑制劑及絲胺酸/蘇胺酸激酶抑制劑，例如表皮生長 因子族群之抑制劑（例如EGFR族群酪胺酸激酶抑制 劑，譬如N-(3-氣基-4-氟苯基）-7-曱氧基-6-(3-嗎福p林基丙 氧基 >奎唑琳-4-胺（吉非汀尼伯（gefitinib)，AZD1839)、N-(3-乙炔基苯基）-6,7-雙（2-甲氧基乙氧基奎坐p林_4_胺（啊羅 提尼伯（erlotinib) ’ OSI-774)及6-丙烯醯胺基-N-(3-氣基-4-氟苯基）-7-(3-嗎福啉基丙氧基）喹唑啉-4-胺（CI1033))，例 如血小板衍生之生長因子族群抑制劑，與例如肝細胞 生長因子族群之抑制劑，例如磷脂醯肌醇3-激酶（PI3K) 之抑制劑，及例如有絲分裂原活化蛋白質激酶（MEK1/2) 之抑制劑，與例如蛋白質激酶B (PKB/Akt)之抑制劑，例 如Src酪胺酸激酶族群及/或Abelson (Abl)酪胺酸激酶族 群之抑制劑，譬如AZD0530與達沙汀尼伯（dasatinib) (BMS-354825)及愛馬汀尼伯（imatinib)甲烷磺酸鹽 133151 -74· 200906818 (GleevecTM);以及任何會修改STAT發出訊息之藥劑； (v) 抗血管生成劑，譬如會抑制血管内皮生長因子作用者 (例如抗血管内皮細胞生長因子抗體貝發西馬伯 (bevacizumab)[AvastinTM]，譬如在國際專利申請案WO 97/22596, WO 97/30035, WO 97/32856 及 WO 98/13354 中所揭 示之化合物），及藉由其他機制發生作用之化合物（例 如里諾醯胺（linomide)、整合素αν 功能之抑制劑及制 血管生成素）； (vi) 血管傷害劑，譬如風車子制菌素Α4，及在國際專利申 請案 WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434及WO 02/08213中所揭示之化合物； (vii) 反有意義療法，例如針對上文所列示標的者，譬如ISIS 2503、抗ras反有意義劑； (viii) 基因療法途徑，包括例如置換迷行基因譬如迷行p53 或迷行BRCA1或BRCA2之途徑，GDEPT (基因導引酶前 體藥物療法）途徑，譬如使用胞嘧啶脫胺基酶、胸腺核 嘗激酶或細菌硝基還原酶者，及增加病患對化學療法 或放射療法之容許度之途徑，譬如多抗藥性基因療法； (ix) 免疫療法途徑，包括例如增加病患腫瘤細胞之致免疫 性之活體外與活體内途徑，譬如以細胞活素譬如間白 血球活素2、間白血球活素4或粒性細胞-巨噬細胞菌 落刺激因子轉移感染，降低T-細胞能之途徑，使用轉 染之免疫細胞譬如細胞活素轉染之樹突細胞之途徑， 使用細胞活素轉染之腫瘤細胞系之途徑，及使用抗遺 133151 -75· 200906818 傳性型抗體之途徑，以及使用免疫調制藥物酞胺哌啶 酮與連那利多麥（lenalidomide)[Revlimid® ]之途徑；及 ⑻其他治療體系，包括：地塞米松、蛋白質降解體抑制 劑（包括博替左米（bortezomib))、異崔替諾因（isotretinoin) (13-順式視黃酸）、g太胺喊咬酮、瑞維米得（revemid)、利 圖沙馬伯（Rituxamab)、ALIMTA、Cephalon氏激酶抑制劑 CEP-701與CEP-2563、抗-Trk或抗-NGF單株抗體，使用1311-間碘基苄基胍（131I-MIBG)之標的放射療法，在化學療法 之後，使用或未使用粒性細胞-巨噬細胞菌落-刺激因 子（GM-CSF)之抗-G(D2)單株抗體療法。 此種共同治療可以同時、相繼或個別服用治療之個別成 份之方式達成。此種組合產物係採用前文所述劑量範圍内 之本發明化合物或其藥學上可接受之鹽，與其許可劑量範 圍内之另一種具醫藥活性藥劑。 式（I)化合物及其藥學上可接受之鹽，除了其在治療醫藥 上之用途以外，亦可在活體外與活體内試驗系統之發展與 標準化中作為藥理學工具使用，以評估JAK2抑制劑在實驗 室動物中之作用，譬如貓、狗、兔子、猴子、大白鼠及老 鼠，作為搜尋新穎治療劑之一部份。 在本發明之任何上文所提及之醫藥組合物、製程、方法、 用途、藥劑及製造特徵中，本文中所述本發明化合物之任 何替代具體實施例亦適用。 於一方面，JAK活性之抑制特別是指JAK2活性之抑制。 方法 133151 -76- 200906818 右不犯市購取得，則供此等程序用之必須起始物質，譬 士口 卜-支十、 —兴如 ^ ’可藉由一些程序製成，其係選自標準有機化學技 術’類似合成已知而於結構上類似化合物之技術，或類似 所述程序或實例中所述程序之技術。 應注意的是’關於如上文所述合成方法之許多起始物質 係為市購可得及/或廣泛地報告於科學文獻中，或可使用科 子文獻中所報告方法之修改，製自市購可得化合物。讀者 可進一步參考高事有襪允學，第5版，由JenyMarch與Michael SrmA者’由j〇hn Wiley & 8〇仍於2〇〇1年出版，關於反應條件 與試劑之一般指引。The small line must be altered depending on the host to be treated, the route of administration, and the severity of the condition being treated. It is preferred to use a daily dose in the range of 丨-50 mg/kg. Therefore, the optimum dose can be determined by the practitioner who is treating any particular patient. The anti-cancer treatment as defined herein may be applied alone or in addition to the compounds of the invention, may involve conventional surgery or radiation therapy or chemotherapy. Such chemotherapy may comprise one or more of the following classes of anti-tumor agents: (i) anti-proliferative/anti-tumor drugs and combinations thereof such as those used in medical oncology, such as alkylating agents (eg, cisplatin, Carbon gas amine platinum, cyclophosphonium 133151 -72- 200906818 amine, nitrogen boundary, amphetamine, chlorambucil, chul〇rambucil, busulphan and nitrosourea; antimetabolite (eg anti-leaf I salt, such as fluoropyrimidine, including 5-fluorouracil and tegafUr, raltitrexed, amidoxime, arabinose and base), anti-tumor Antibiotics (eg, cyclaline, such as Adria, bleomycin, erythromycin, daunorubicin, erythromycin, idadamycin, mitomycin-C, Dakectin and mithramycin; anti-mitotic agents (such as vinca alkaloids, such as Changchun new test, vinblastine, vinca, and vinorelbine, and yew-like substances, such as red beans Cedar and taxus (tax〇tere); and topoisomerase inhibitors (eg table peony Such as etoposide and teniposide, amsacrine, topotecan and hi-tree test; and proteosome inhibitors (such as botezomib) (bortezomib) [Velcade®]); and anegrilide [Agrylin®]; and d-interferon; (ii) cytostatics, such as anti-hormone (eg, tamoxifen, 托Tormifene, raloxifene, droloxifene, and iodoxyfene, estrogen receptor downregulators (eg, fiilvestrant) , antiandrogens (eg, bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH activators (eg, goserelin, leuprorelin, and buserelin), progesterones (eg, gesticillin 1 acetate), aromatase inhibitors (eg, Anath Saliva (anastrozole) 133151 -73- 200906818 , letrozole, lela saliva (v Orazole) and yumestane (exemestane), and 5 α-reductase inhibitors, such as finasteride (finasteride); (iii) agents that inhibit cancer cell invasion (eg, metalloproteinase inhibitors, such as horses) Marimastat, an inhibitor of urokinase plasminogen activator receptor function); (iv) growth factor function inhibitors, such as such inhibitors, including growth factor antibodies, growth factors Antibody (eg anti-erbb2 antibody, trastuzumab [HerceptinTM] and anti-erbbl antibody, some Cetuximab [C225]), farnesyl transferase inhibitor, cool amine acid Kinase inhibitors and serine/threonine kinase inhibitors, such as inhibitors of the epidermal growth factor population (eg, EGFR group tyrosine kinase inhibitors, such as N-(3-carbyl-4-fluorophenyl)- 7-decyloxy-6-(3-moffyl-p-l-propoxy)> quetioline-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl) )-6,7-bis(2-methoxyethoxy quinone-p-line_4_amine (erlotinib 'OSI-774) and 6-acrylamide -N-(3-carbyl-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI1033)), such as platelet-derived growth factor population inhibitors And inhibitors such as the hepatocyte growth factor population, such as inhibitors of phospholipid inositol 3-kinase (PI3K), and inhibitors such as mitogen-activated protein kinase (MEK1/2), for example, protein kinase B (PKB) /Akt) inhibitors, such as the Src tyrosine kinase group and/or Abelson (Abl) tyrosine kinase group inhibitors, such as AZD0530 and dasatinib (BMS-354825) and Amartini Imatinib methanesulfonate 133151 -74· 200906818 (GleevecTM); and any agent that modifies the message of STAT; (v) anti-angiogenic agents, such as those that inhibit vascular endothelial growth factor (eg, anti-vascular endothelial cells) The growth factor antibody bevacizumab [AvastinTM], such as the compounds disclosed in the international patent application WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354, and by Compounds that act on other mechanisms (eg, linomide) ), an inhibitor of integrin αν function and angiopoietin); (vi) a vascular injury agent, such as a windmill sputum Α 4, and in the international patent application WO 99/02166, WO 00/40529, WO 00/ a compound disclosed in 41669, WO 01/92224, WO 02/04434 and WO 02/08213; (vii) an antisense therapy, such as for those listed above, such as ISIS 2503, an anti-ras antisense agent; Viii) gene therapy pathways, including, for example, replacement of mimetic genes such as the p53 or the pathway of BRCA1 or BRCA2, the GDEPT (gene-directed enzyme prodrug therapy) pathway, such as the use of cytosine deaminase, thymic nuclear taste Kinase or bacterial nitroreductase, and ways to increase patient tolerance to chemotherapy or radiation therapy, such as multidrug resistance gene therapy; (ix) immunotherapeutic pathways, including, for example, increasing the immunity of tumor cells in patients In vitro and in vivo pathways, such as cytokines such as interleukin-2, interleukocytokinin 4 or granulocyte-macrophage colony stimulating factor transfer infection, reduce T-cell energy pathway, use transfection It The pathway of cytokines such as cytokine-transfected dendritic cells, the pathway of cytokine-transfected tumor cell lines, and the use of anti-legal antibodies 133151 -75· 200906818, and the use of immunomodulatory drugs Amlididone and lenalidomide [Revlimid®] pathway; and (8) other therapeutic systems, including: dexamethasone, protein degrading inhibitors (including bortezomib), isochromia Isoretinoin (13-cis retinoic acid), g-amine ketone, revemid, Rituxamab, ALIMTA, Cephalon kinase inhibitor CEP-701 CEP-2563, anti-Trk or anti-NGF monoclonal antibody, using radiotherapy with 1311-m-iodobenzylhydrazine (131I-MIBG), after chemotherapy, with or without granulocyte-macrophages Colony-stimulator (GM-CSF) anti-G (D2) monoclonal antibody therapy. Such co-therapy can be achieved by administering the individual components of the treatment simultaneously, sequentially or individually. Such a combination product is a compound of the present invention, or a pharmaceutically acceptable salt thereof, in a dosage range as hereinbefore described, and another pharmaceutically active agent within the permissible dosage range. The compound of the formula (I) and a pharmaceutically acceptable salt thereof, in addition to its use in therapeutic medicine, can also be used as a pharmacological tool in the development and standardization of in vitro and in vivo test systems to evaluate JAK2 inhibitors. The role of animals in laboratory animals, such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for novel therapeutic agents. In any of the above-mentioned pharmaceutical compositions, processes, methods, uses, medicaments and manufacturing characteristics of the present invention, any of the alternative embodiments of the compounds of the invention described herein are also applicable. In one aspect, inhibition of JAK activity refers specifically to inhibition of JAK2 activity. Method 133151 -76- 200906818 If the right is not obtained by the market, the necessary starting materials for these procedures, the gentleman's mouth - branch 10, - Xingru ^ ' can be made by some procedures, which are selected from the standard Organic chemistry techniques are similar to techniques for synthesizing known compounds that are structurally similar to compounds, or techniques similar to those described in the procedures or examples. It should be noted that 'many of the starting materials for the synthetic methods as described above are commercially available and/or widely reported in the scientific literature, or may be modified using the methods reported in the literature. Available compounds are available. Readers can refer to the high-level hosiery, the fifth edition, published by JenyMarch and Michael SrmA by j〇hn Wiley & 8〇, still published in 2002, general guidelines on reaction conditions and reagents.

亦應明瞭的是，在—些本文中所提及之反應中，可能必 須/想要保護化合物中之任何敏感性基團。其中保護係為必 須或想要之情況，係為熟諳此藝者所已知，其係為此種保 護之適當方法。習用保護基可根據標準實務使用（關於說 明，可參閱T.W. Greene，㈣合4、之保護名，由施观巧& Sons出版，1991)，且如上文所述。 下文所示之方法與圖式 於合成式（I)化合物之中 式（I)化合物可以多種方式製備。 係說明關於合成式（I)化合物及可用 間物之-些方法（其_除非另有定義，否則，環Β，χ，Μ 及R3均如上文定義）。在特定溶劑或試劑係示於圖式^在 伴隨文字中引述之情況下，應明瞭的I，一般熟諳此蔽之 化學師係能夠按需要修改該溶劑或試劑。此等方法與圖式 並非意欲呈現關於製備式(I)化合物方法之無遺漏清單；： 而是其中熟練化學師所知道之其他技術亦可用於^合物之 13315J -Π、 200906818 成月长項並非意欲受限於方法與圖式中所示之結構。 ^熟練：學師將能夠利用與修改上述參考資料内所包含與 :及2二，且伴隨著其十之實例，以及本文之實例與圖 式，以獲侍必須之起始物質與產物。 1)方法A -使式（A)化合物：It should also be understood that in some of the reactions mentioned herein, it may be necessary/want to protect any sensitive groups in the compound. Where protection is necessary or desirable, it is known to those skilled in the art and is an appropriate method of such protection. Conventional protecting groups can be used in accordance with standard practice (for a description, see T. W. Greene, (4), Protected Names, published by Shi Guanqiao & Sons, 1991), and as described above. The method and scheme shown below can be used to synthesize a compound of formula (I). The compound of formula (I) can be prepared in a variety of ways. Some methods for synthesizing the compound of the formula (I) and the usable materials (which_unless otherwise defined, the ring Β, χ, Μ and R3 are as defined above). Where a particular solvent or reagent is shown in the accompanying text in the accompanying text, it should be understood that the skilled chemist can modify the solvent or reagent as needed. These methods and schemes are not intended to present an exhaustive list of methods for preparing compounds of formula (I); but other techniques known to the skilled chemist may also be used for the compound 13315J-Π, 200906818 It is not intended to be limited to the structures shown in the methods and drawings. ^ Proficiency: The instructor will be able to utilize and modify the references contained in the above references: and 2, along with examples of ten, and examples and diagrams herein to obtain the necessary starting materials and products. 1) Method A - a compound of formula (A):

與武（B)化合物反應：Reacts with 武(B) compounds:

式Φ);或 2)方法B-使式（C)化合物：Formula Φ); or 2) Method B - Compound of formula (C):

式(C) 與式（D)化合物反應：Reaction of formula (C) with compound of formula (D):

式(D); 3)方法C-使式（C')化合物與環A反應： 133151 -78- 200906818Formula (D); 3) Method C - reacting a compound of formula (C') with ring A: 133151 -78- 200906818

接著，若必要則： i) 使式（I)化合物轉化成另一種式（I)化合物； ii) 移除任何保護基；及/或Next, if necessary: i) converting a compound of formula (I) to another compound of formula (I); ii) removing any protecting groups; and/or

iii) 形成藥學上可接受之鹽， 其中L於各存在處可為相同或不同，且係為如本文上述之 脫離基。 關於各方法A與B，應明瞭的是，當必要時，可使用保護 基。適用於方法A與B之脫離基包括齒基，譬如氯基。此等 方法係於下文更詳細地討論。 方法A -式⑷化合物與式(B)化合物可於適當溶劑存在 下-起反應，該溶劑之實例包括酮類，譬如丙_，醇類， 譬如乙醇與丁 SI，及芳族烴類，譬如甲苯與甲基四氯峨 嘻-2-1反應可有利地於適纽存在下發生，錢之實例 包括無機驗，譬如碳酸卸與碳酸鉋，及有機驗，譬如第三_ 丁醇鉀與第三_丁醇鈉。反應可有利地在叱至回流範圍内 之溫度下進行。加熱此反應可為特別有利。 於另-方面，式（Α)化合物與式⑼化合物可於標準 Buchwald條件（例如參閱仏.㈤兔⑽，7215 ;仏.㈤. 下，使用適當鹼一 如碳酸铯，與有機 *Soc·’ 119’ 8451 ; «/ 〇g. c/zem·，62, 1568 與 6066) 起反應。適當鹼之實例包括無機鹼，譬 133151 -79- 200906818 鹼，譬如第三-丁醇鉀。此種反應可有利地於鈀觸媒譬如醋 酸鈀存在下發生。適用於此種反應之溶劑之實例包括甲 苯、苯、二氧陸圜及二曱苯。式（B)化合物之-NH-部份基團 可有利地以適當保護基保護，其實例包括保護基，譬如第 三-丁氧羰基。 方法B -式（D)化合物與式（C)化合物可在類似關於式（A) 化合物與式（B)化合物之反應所述之條件下一起反應。 方法C -式（F)化合物及環A可在類似關於式（A)化合物與 式（B)化合物之反應所述之條件下一起反應。 式（A)化合物可根據圓式1製成： 圏式1Iii) forming a pharmaceutically acceptable salt, wherein L may be the same or different at each occurrence, and is a leaving group as described herein above. With regard to each of methods A and B, it should be understood that a protecting group can be used when necessary. Suitable excipients for methods A and B include a dentate group such as a chloro group. These methods are discussed in more detail below. Process A - The compound of the formula (4) and the compound of the formula (B) may be reacted in the presence of a suitable solvent, and examples of the solvent include ketones such as propylene, alcohols, such as ethanol and butyl SI, and aromatic hydrocarbons, such as The reaction of toluene with methyltetrachloroguanidine-2-1 can be advantageously carried out in the presence of a suitable one, and examples of the money include inorganic tests, such as carbonic acid unloading and carbonic acid planing, and organic tests, such as third potassium butoxide. Sodium butyrate. The reaction can advantageously be carried out at a temperature within the range of the reflux to the reflux. Heating this reaction can be particularly advantageous. In another aspect, the compound of formula (Α) and the compound of formula (9) can be used under standard Buchwald conditions (for example, see 仏. (5) rabbit (10), 7215; 仏. (5). Using a suitable base such as cesium carbonate, with organic *Soc·' 119' 8451; «/ 〇g. c/zem·, 62, 1568 and 6066) reacted. Examples of suitable bases include inorganic bases, cesium 133151-79-200906818 bases such as potassium third-butoxide. This reaction can advantageously take place in the presence of a palladium catalyst such as palladium acetate. Examples of the solvent suitable for such a reaction include toluene, benzene, dioxane, and dinonylbenzene. The -NH- moiety of the compound of the formula (B) can be advantageously protected with a suitable protecting group, and examples thereof include a protecting group such as a tri-butoxycarbonyl group. Process B - A compound of formula (D) and a compound of formula (C) can be reacted together under conditions similar to those described for the reaction of a compound of formula (A) with a compound of formula (B). Process C - The compound of formula (F) and ring A can be reacted together under conditions similar to those described for the reaction of a compound of formula (A) with a compound of formula (B). The compound of formula (A) can be made according to the round form 1: 圏 type 1

其中L於各存在處可為相同或不同，且係為如本文上述之 脫離基。Wherein L may be the same or different at each occurrence and is a leaving group as described herein above.

133151 -80 - 200906818 圖式2133151 -80 - 200906818 Figure 2

LL

H2NH2N

驗 R1 式(B)Test R1 formula (B)

脫離基。 芍如本文上述之 ( 式（Β)化合物與式（Ε)化合物 」於適當溶劑存在下一起反 應，該溶劑之實例包括_類， > 5如丙酮，醇類，嬖如乙醇 與丁醉，及芳族烴類，譬如甲苯 、iN r I四虱吡咯-2-酮。 有利地於適當驗存在下發生，該驗之實例包括無機 驗，*如碳酸卸與碳酸鉋，及有機驗，譬如第三-丁醇鉀盥 第三-丁醇納。反應係有利地在〇七至回流範圍内之溫度下 進行。Detached from the base. For example, the above (the compound of the formula (Β) and the compound of the formula (Ε) are reacted together in the presence of a suitable solvent, and examples of the solvent include a class, > 5 such as acetone, an alcohol, such as ethanol and diced, And aromatic hydrocarbons, such as toluene, iN r I tetrapyrrole-2-one. Advantageously occurring in the presence of an appropriate test, examples of which include inorganic tests, * such as carbonation and carbonation, and organic tests, such as Third-potassium butoxide potassium third-butanol. The reaction is advantageously carried out at temperatures ranging from seven to about reflux.

式（F)化合物可根據圓式3製成：The compound of formula (F) can be made according to round 3:

式（F) 圖式3 其中L於各存在處可為相同或不同，且係為如本文上述之 脫離基。 式（D)化合物與式（G)化合物可在類似關於式（A)化合物與 式（B)化合物之反應所述之條件下一起反應。 133151 •81 - 200906818 【實施方式】 實例 現在將進一步參照下述說明實例描述本發明，其中除非 另有述及，否則： (1)溫度係以攝氏度數（°c)表示；操作係在室溫或環境 溫度下進行，意即在18-25°C之範圍内； (i〇 有機溶液係以無水硫酸鎂脫水乾燥，除非另有述 及；有機溶劑之蒸發係使用迴轉式蒸發器在減壓 (4.5-30毫米Hg)下，以達到00°C之浴溫進行； (iU)層析係意謂於矽膠上之急驟式層析；薄層層析法 (TLC)係於矽膠板上進行； (iY) 一般而言，反應過程係藉TLC或液相層析法/質譜 (LC/MS)追縱’且給予反應時間僅供說明； (v) 最後產物具有令人滿意之質子核磁共振（nmr)光譜 及/或質譜數據； (vi) 給予產率僅供說明，而未必是可藉由費心製程發展 所獲得者；若需要較多物質，則重複製備； (vii) 當給予NMR數據時，其係呈主要診斷質子之5值形 式’以相對於作為内標準之四甲基矽烷（TMS)之每 百萬份之份數（PPm)表示，在300 MHz下，於DMSO-d6 中測定’除非另有述及；關於NMR，MeOD係指 CD4 OD，CH2 Cl2 係指 ce>2 cl2。 (viii) 化學符號具有其常用意義； (IX)溶劑比例係以體積：體積（v/v)術語表示； 133151 -82 - 200906818 (X) "ISCO"係指正相急驟式管柱層析，使用預填充之矽 膠藥筒（12克，40克等），根據製造者之說明書使用， 得自 ISCO 公司，4700 Superior Street Lincoln, NE，USA。 (xi) ”Gilson管柱"係指YMC-AQC18逆相HPLC管柱，具有 尺寸20毫米/100與50毫米/250，在具有0.1% TFA之 H2 O/MeCN中作為流動相，除非另有述及，且根據 製造者之說明書使用，得自Gilson公司，3000 Parmenter Street, Middleton, WI 53562-0027, U.S.A 〇 f ' (xii) "Biotage"係指正相急驟式管柱層析，使用預填充之 矽膠藥筒（12克、40克、80克等），根據製造者之說 明書使用，得自 Biotage 公司，1725 Discovery Drive Charlotteville, Virginia 22911，USA 〇 (xiii) "SFC (超臨界流體層析）”係指分析SFC (具有二極體 陣列偵測器之ASC-1000分析SFC系統）及/或預備SFC (APS-1000 AutoPrep預備SFC)，根據製造者之說明書使 , 用，得自 SFC Mettler Toledo AutoChem 公司，7075 Samuel l:Formula (F) Figure 3 wherein L may be the same or different at each occurrence, and is a leaving group as described herein above. The compound of the formula (D) and the compound of the formula (G) can be reacted together under conditions similar to those described for the reaction of the compound of the formula (A) with the compound of the formula (B). 133151 • 81 - 200906818 EXAMPLES The present invention will now be described with further reference to the following illustrative examples, wherein unless otherwise stated: (1) temperature is expressed in degrees Celsius (°c); operating system is at room temperature Or at ambient temperature, meaning in the range of 18-25 ° C; (i 〇 organic solution is dehydrated and dried with anhydrous magnesium sulfate, unless otherwise stated; evaporation of organic solvent using a rotary evaporator in decompression (4.5-30 mm Hg), at a bath temperature of 00 ° C; (iU) chromatography means flash chromatography on tannin; thin layer chromatography (TLC) is performed on a silicone board (iY) In general, the reaction process is traced by TLC or liquid chromatography/mass spectrometry (LC/MS) and the reaction time is given for illustrative purposes only. (v) The final product has satisfactory proton nuclear magnetic resonance. (nmr) spectroscopy and/or mass spectrometry data; (vi) The yield is given for illustrative purposes only, and is not necessarily obtained by laborious process development; if more material is required, the preparation is repeated; (vii) when NMR data is given At the time, the system is in the form of a 5-valued form that mainly diagnoses protons. The parts per million (ppm) of quasi-tetramethyl decane (TMS) is expressed in DMSO-d6 at 300 MHz 'unless otherwise stated; for NMR, MeOD means CD4 OD, CH2 Cl2 means ce>2 cl2. (viii) Chemical symbols have their usual meanings; (IX) Solvent ratios are expressed in terms of volume: volume (v/v); 133151 -82 - 200906818 (X) "ISCO" Phase-flash column chromatography using a pre-filled silicone cartridge (12 g, 40 g, etc.), according to the manufacturer's instructions, available from ISCO, 4700 Superior Street Lincoln, NE, USA. (xi) "Gilson Column " refers to a YMC-AQC18 reverse phase HPLC column having dimensions of 20 mm/100 and 50 mm/250 as mobile phase in H2O/MeCN with 0.1% TFA, unless otherwise stated, and Instructions for use by the manufacturer, available from Gilson, 3000 Parmenter Street, Middleton, WI 53562-0027, USA 〇f ' (xii) "Biotage" refers to normal phase flash column chromatography using pre-filled silicone cartridges (12g, 40g, 80g, etc.), used according to the manufacturer's instructions, from B Iotage Corporation, 1725 Discovery Drive Charlotteville, Virginia 22911, USA 〇(xiii) "SFC (Supercritical Fluid Chromatography)" refers to the analysis of SFC (ASC-1000 Analytical SFC System with Diode Array Detector) and / Or prepare SFC (APS-1000 AutoPrep Pre-SFC), according to the manufacturer's instructions, available from SFC Mettler Toledo AutoChem, 7075 Samuel l:

Morse Drive Columbia MD 21046, U.S.A。 (xiv) 關於預備SFC之條件（A):烘箱40°C ;流量：60毫升/ 分鐘；出口壓力：100巴；波長：254毫微米及/或220 毫微米，除非另有指定。 (xv) 關於對掌性測定之分析SFC之條件（B):烘箱35°C， 流量：5毫升/分鐘；出口壓力：120巴；關於e.e.測 定之波長：254毫微米及/或220毫微米，除非另有 述及。 133151 -83- 200906818 (xvi) 管柱與溶劑條件：AD (或AS或OJ或OD-)係相應於對 掌性管柱（參閱下文），數目1-4係相應於流動相改 質劑-數目（相應於流動相改質劑之％)。例如： AD-3-20表示具有20%曱醇、0.4%二甲基乙胺之 Chiralpak AD，用於對掌性純化或e.e.測定。 (xvii) 關於流動相改質劑：1=甲醇，2=異丙醇，3=甲醇、 0.4%二甲基乙胺，及4=異丙醇、0.4%二曱基乙胺。 (xviii) Chiralcel®OJ 與 0D 或 Chiralpak® AS、IA 及 AD 管柱係根 據製造者之說明書使用，得自對掌性技術公司，800 NorthFivePointsRoad Westchester, PA19380, USA 〇 (xix) 對於各個別對掌異構物之對掌異構物過量（e.e.):使 用在220毫微米或254毫微米下之面積百分比所計 算之>%。 (XX) 於對掌性純化之後，所有實例均具有e.e· >98%，除 非另有述及。 (xxi) 帕爾氫化器或帕爾振盪器類型氫化器為關於在觸 媒存在下，於壓力高達5大氣壓（60 psi)及溫度至80 °C下，以氳處理化學品之系統。 (xxii) ”H-立方體”係指由Thales Nanotechnology所製造之H-立 方體連續氳化作用裝備。 (xxiii) 已使用下列縮寫： DCM 二氯曱烷； HPLC 高性能液相層析法 DIPEA N，N-二異丙基乙胺 133151 -84- DMF N,N-二曱基甲醯胺； THF 四氫吱喃； DMAP 4-二甲胺基吡啶； DMSO 二甲亞颯； EtOAc 醋酸乙酯； Et20 乙醚； Boc2 0 第三-丁氧羰基酐； BINAP 2,2'-雙（二苯基膦基）-1,1'-聯莕； GC 氣相層析法； o/n 過夜； hr 小時； mins 分鐘； Pd2 (dba)3 參（二苯亞甲基丙酮）二鈀（0); NMP N-曱基四氫叶1：咯酮； dppf 1，Γ-雙（二苯基膦基）二環戊二烯鐵； DMAc Ν，Ν-二曱基乙醯胺； TEA 三乙胺 TFAA 三氟醋酸酐 TBME 第三-丁基曱基醚 iPrOH 異-丙醇 HATU 六氟磷酸0-(7-氮苯并三唑-1- 基）-N,N，NW-四甲基錁 200906818 黃磷（乂&1^}1〇3)9,9-二甲基-4,5-雙（二苯基膦基）二苯 并哌喃 133151 -85- 200906818 DAST 二氣化—乙胺基硫 LDA 鋰二異丙基胺 TMS 三曱基矽烷基 rac. 外消旋 Tosyl, Ts 對-甲苯磺醯基 SEM 1-((2-(三甲基矽烷基）乙氧基）曱基 中間物1 5-氟基嘧啶-2·曱腈 於10毫升微波小玻瓶中’添加2-氯基-5-氟基嘧啶（2.0克， 15.09 毫莫耳）、Pd2(dba)3 (0.549 克，0_6 毫莫耳）、dppf (0.67 克， 1.21毫莫耳）、氰化鋅（115克，9 81毫莫耳）及鋅粉（〇 237毫克， 3.62毫莫耳）。將燒瓶抽氣’並以n2與無水二曱基乙醯胺逆 充填。將小玻甑安裝在Personal Chemistry微波反應器上，且於 loo c下加熱ίο小時。將反應混合物以EtOAc稀釋，然後以 鹽水洗滌二次。獲得有機層，及蒸發至乾涸。使已乾燥之 殘留物藉矽膠層析純化（藉ISC0 Combiflash，使用梯度液 KOAc與己烧）’而得標題化合物，為乳黃色固體("〇克， 80%) 〇 GC-MS ： 123 [M], 1 H NMR (CDC13 ) (5 ： 8.80 (s, 2H). 中間物2 N-(l-(5-氟基嘧啶-2-基）乙烯基）乙醯胺 於0°C下，將THF (1〇毫升）中之5·氟基嘧啶_2•甲腈（中間物 1 ’ 1.0克，8，1毫莫耳）逐滴添加至MeMgBr (3 3毫升，9 J5毫 133151 -86- 200906818 莫耳）在中之溶液内。在添加後，使反應物溫熱至室溫， 於至/ϋπ·下授掉1小時’然後以DCM (10毫升）稀釋。以一份添 加醋酸酐（1.23毫升，13.0毫莫耳）。將反應物在室溫下擾拌i 小時’並於40°C下1小時。添加飽和碳酸氫鈉溶液（1〇毫升）， 且以EtOAc (2 X 20毫升）萃取。使合併之有機物質以硫酸鈉 脫水乾燥。在移除溶劑後，使所形成之殘留物藉管柱層析 純化（己烧-EtOAc = 2_5:1) ’而得標題化合物，為白色固體（〇 38 克，26%)。 NMR (400 MHz) 5 ： 9.34 (s, 1H), 8.95 (s, 2H), 6.25 (s, 1H), 6.03 (s, 1H), 2.11 (s, 3H). LC-MS ： 182 [M+H]+182. 中間物3 N-[(lS)-l-(5-氟基嘧啶-2-基）乙基】乙醢胺 於N-(l-(5-氟基嘧啶-2-基）乙烯基）乙醯胺（中間物2，〇 1〇克， 0.55毫莫耳）在MeOH (5毫升）中之溶液内，在乂下，添加 (+)-1,2-雙（(2S，5S)-2,5-二乙基填烷基）苯（環辛二烯）三氟甲烷石黃 酸铑（1)(0.04克，0.0055毫莫耳）。將溶液轉移至高壓彈形容器， 並裝填15 0 psi H2。將反應物於室溫下攪拌4小時。移除溶劑， 且使所形成之殘留物藉管柱層析純化（Et〇Ac)，而得標題化 合物，為白色固體（0.096克，95%)。 ' H NMR (400 MHz) 5 ： 8.84 (d, 2H), 8.34 (d, 1H), 5.00 (m, 1H), 1.84 (s, 3H), 1.37 (d, 3H). LC-MS : 184 [M+H]. 對掌異構物過量係藉SFC測定（Chimlpak IA ; 95:5 133151 -87- 200906818 >99% ee. 中間物4 [(lS)-l-(5-氟基嘧啶-2-基）乙基】胺基甲酸第三_丁酯 將THF (10毫升）中之基嘧啶_2_基）乙基]乙醯 胺（中間物3，0.20克，ΐ·〇9毫莫耳）、DMAp (〇 〇27克，〇 22毫 莫耳）及Boc2 Ο (0·60克，2.73毫莫耳）於5〇°c下攪拌4〇小時。 在冷卻至至溫後，添加氫氧化鋰單水合物（〇 〇94克，2 24毫Morse Drive Columbia MD 21046, U.S.A. (xiv) Conditions for preparing SFC (A): oven 40 ° C; flow rate: 60 ml / min; outlet pressure: 100 bar; wavelength: 254 nm and / or 220 nm, unless otherwise specified. (xv) Conditions for analysis of palmity determination SFC conditions (B): oven 35 ° C, flow rate: 5 ml / min; outlet pressure: 120 bar; wavelength for ee determination: 254 nm and / or 220 nm Unless otherwise stated. 133151 -83- 200906818 (xvi) Column and Solvent Conditions: AD (or AS or OJ or OD-) corresponds to the palm column (see below), and the number 1-4 corresponds to the mobile phase modifier - Number (corresponding to % of mobile phase modifier). For example: AD-3-20 represents Chiralpak AD with 20% sterol, 0.4% dimethylethylamine for palm purification or e.e. assay. (xvii) For mobile phase modifiers: 1 = methanol, 2 = isopropanol, 3 = methanol, 0.4% dimethylethylamine, and 4 = isopropanol, 0.4% dimercaptoethylamine. (xviii) Chiralcel® OJ and 0D or Chiralpak® AS, IA and AD columns are used according to the manufacturer's instructions, from the palm technology company, 800 NorthFivePointsRoad Westchester, PA19380, USA 〇(xix) for each pair The excess of the isomers (ee): >% calculated using the area percentage at 220 nm or 254 nm. (XX) After the palmitic purification, all examples have e.e. > 98% unless otherwise stated. (xxi) Parr hydrogenator or Parr oscillator type hydrogenators are systems for treating chemicals with rhodium in the presence of a catalyst at pressures up to 5 atm (60 psi) and temperatures up to 80 °C. (xxii) "H-Cube" means the H-cylinder continuous deuteration equipment manufactured by Thales Nanotechnology. (xxiii) The following abbreviations have been used: DCM dichlorodecane; HPLC High performance liquid chromatography DIPEA N,N-diisopropylethylamine 133151 -84- DMF N,N-dimercaptocaramine; THF Tetrahydrofuran; DMAP 4-dimethylaminopyridine; DMSO dimethyl hydrazine; EtOAc ethyl acetate; Et20 diethyl ether; Boc2 0 tert-butoxycarbonyl anhydride; BINAP 2,2'-bis(diphenylphosphine) Base)-1,1'-linked oxime; GC gas chromatography; o/n overnight; hr hour; mins minute; Pd2 (dba)3 gin (diphenylmethyleneacetone) dipalladium (0); NMP N-mercaptotetrahydroleafone: ropone; dppf 1, Γ-bis(diphenylphosphino)dicyclopentadienyl iron; DMAc Ν, Ν-dimercaptoacetamide; TEA triethylamine TFAA III Fluoroacetic anhydride TBME Tert-butyl decyl ether iPrOH Iso-propanol HATU hexafluorophosphate 0-(7-nitrobenzotriazol-1-yl)-N,N,NW-tetramethylguanidine 200906818 Yellow phosphorus (乂&1^}1〇3) 9,9-Dimethyl-4,5-bis(diphenylphosphino)dibenzopyran 133151 -85- 200906818 DAST Dimethylation-Ethylamine Sulfur LDA lithium diisopropylamine TMS tridecyl decyl rac. racemic Tosyl, Ts p-toluene Mercapto-based SEM 1-((2-(trimethyldecyl)ethoxy) decyl intermediate 1 5-fluoropyrimidine-2·phthalonitrile in the 10 ml microwave vial 'add 2-chloro- 5-fluoropyrimidine (2.0 g, 15.09 mmol), Pd2 (dba) 3 (0.549 g, 0_6 mmol), dppf (0.67 g, 1.21 mmol), zinc cyanide (115 g, 9 81) Millol) and zinc powder (〇237 mg, 3.62 mmol). The flask was evacuated' and backfilled with n2 and anhydrous decyl acetamide. The small glass crucible was mounted on a Personal Chemistry microwave reactor. The reaction mixture was heated with EtOAc (EtOAc) and EtOAc (EtOAc)EtOAc. The title compound was obtained as a creamy solid (" gram, 80%) 〇GC-MS : 123 [M], 1 H NMR (CDC13 ) (5: 8.80 (s, 2H) Intermediate 2 N-(l-(5-fluoropyrimidin-2-yl)vinyl)acetamidine 5 °F-fluoropyrimidine_2•A in THF (1 mL) at 0 °C Nitrile (intermediate 1 ' 1. 0 g, 8, 1 mmol was added dropwise to the solution of MeMgBr (3 3 ml, 9 J5 135151 -86 - 200906818 Mo). After the addition, the reaction was allowed to warm to rt. Add acetic anhydride (1.23 ml, 13.0 mmol) in one portion. The reaction was scrambled for 1 hour at room temperature and at 40 ° C for 1 hour. A saturated aqueous solution of sodium bicarbonate (1 mL) was added andEtOAc was evaporated. The combined organic materials were dried over sodium sulfate. After the solvent was removed, EtOAc m. NMR (400 MHz) 5 : 9.34 (s, 1H), 8.95 (s, 2H), 6.25 (s, 1H), 6.03 (s, 1H), 2.11 (s, 3H). LC-MS : 182 [M+ H]+182. Intermediate 3 N-[(lS)-l-(5-fluoropyrimidin-2-yl)ethyl]acetamidamine in N-(l-(5-fluoropyrimidin-2-yl) ) Vinyl) acetamide (Intermediate 2, 〇1 gram, 0.55 mmol) in MeOH (5 mL) in the underarm, add (+)-1,2-bis ((2S) , 5S)-2,5-Diethyl-terminated alkyl)benzene (cyclooctadiene) trifluoromethane phthalate (1) (0.04 g, 0.0055 mmol). The solution was transferred to a high pressure elastomeric vessel and filled with 150 psi H2. The reaction was stirred at room temperature for 4 hours. The solvent was removed, and the title compound was crystalljjjjjjjjjjjjjjj 'H NMR (400 MHz) 5 : 8.84 (d, 2H), 8.34 (d, 1H), 5.00 (m, 1H), 1.84 (s, 3H), 1.37 (d, 3H). LC-MS : 184 [ M+H]. The excess of palm isomers was determined by SFC (Chimlpak IA; 95:5 133151 -87- 200906818 >99% ee. Intermediate 4 [(lS)-l-(5-fluoropyrimidine- 2-yl)ethyl]aminocarbamic acid tert-butyl ester in THF (10 ml) based on pyrimidine-2-yl)ethyl]acetamide (intermediate 3, 0.20 g, ΐ·〇 9 mmol) Ear), DMAp (〇〇27 g, 〇22 mmol) and Boc2 Ο (0·60 g, 2.73 mmol) were stirred at 5 ° C for 4 hrs. After cooling to the temperature, add lithium hydroxide monohydrate (〇 94 g, 2 24 毫

莫耳）與水（10毫升）。將反應物於室溫下攪拌9小時。添加 醚（30毫升）’分離有機層，以鹽水（2〇毫升）洗滌，並以硫酸 鈉脫水乾燥。在移除溶劑後，使所形成之殘留物藉管柱層 析純化（己烧-EtOAc = 5:1)，而得標題化合物，為淡黃色油 (0.21 克，80%)。 1 H ^ (4〇° MHZ) 5 ： 8·84 2H), 7.24 (d, 1H), 4.74 (m, 1H), 1,5 (s, 12H). LC-MS ： 242 [M+H]. 中間物5 (lS)_l-(5-襄基，咬-2-基）乙胺鹽酸鹽 於氟基料_2_基）乙基]胺基甲酸第三_丁醋（中間 物卜⑽克’㈣毫莫耳沣職^毫升^之溶液内添 加二氧陸圜中之HC1 (1.3蒼弁，$ 9τγ、 、 ^笔开5·2毫莫耳）。將反應物於室 &gt;皿下擾掉3小時。移除溶劑，满媒辦日自儿人 于冷削獲仔糕碭化合物，為白色固體 (定量）。 LC-MS ： 142 [M+H]. 中間物6 133151 -88- 200906818 3_胺基_5_甲基-1H-吡唑-1-羧酸第三-丁酯 於5-甲基-1H-吡唑-3-胺（2.48克，17.6毫莫耳）在DCM (70毫 升）中之溶液内，在0°C下添加Boc20 (4.0克，18·5毫莫耳）， 接著為ΚΟΗ之4_5Μ溶液（31毫升，140.8毫莫耳）。將所形成之 混合物於環境溫度下攪拌過夜，以更多DCM稀釋。使合併 之有機層脫水乾燥（MgS04)，及蒸發，而得黃色油。藉管柱 層析純化（Biotage，20%-^ 30% EtOAc/己烧），獲得標題化合 物，為白色固體。 LC-MS ： 198 [M+H]. 中間物7 5-氟基p比咬-2-曱腈 將2-》臭基-5-氟^基p比咬（93·0克，528毫莫耳）、Zn粉（8.29克， 127毫莫耳）、氰化鋅（40.3克，343毫莫耳）、dppf (11_7克，21.1 毫莫耳）及PA dba3 (9.68克，10.6毫莫耳）在無水DMA (300毫升） 中之混合物於95X：下加熱3小時。在冷卻至室溫後，添加鹽 水（100毫升）與醚（500毫升）。藉過濾移除所形成之固體，並 以醚（300毫升）洗滌。分離有機層，以鹽水（2〇〇毫升）洗務， 且以硫酸鈉脫水乾燥，及濃縮。於移除溶劑後，使所形成 之殘留物藉管柱層析純化（己烷-DCM = 1:1)，而得標題化合 物，為白色固體（49克，72%)。 NMR (400 MHz) δ : 8.82 (d, 1H), 8.21 (dd, 1H), 8.05 (dd, 1H). 中間物8 N-(l-(5-氟基吡啶_2_基）乙烯基）乙醯胺 將MeMgBr (170·3毫升’ 510.98毫莫耳）在醚中之溶液以i7〇 133151 -89- 200906818 毫升無水THF稀釋，並冷卻至。逐滴添加胃（i7〇毫升） 中之5-氟基被咬-2-甲腈（中間物7，53 6克，425 82毫莫耳）。 將反應物於0 C下攪拌3〇分鐘，然後以DCM (17〇毫升）稀 釋。在o°c下逐滴添加DCM(100毫升）中之醋酸酐（48·3毫升， 510.98毫莫耳）。於添加後，使反應物溫熱至室溫，並在室 /凰下攪拌8小時。添加飽和碳酸氫鈉溶液（5〇毫升），且以 EtOAc (2 X 200毫升）萃取。將合併之有機物質以硫酸鈉脫水 乾燥。於移除溶劑後，使所形成之殘留物藉管柱層析純化 (己烧-EtOAc - 2.5:1)，而得標題化合物，為白色固體（266克， 35%) 〇 1 H NMR (400 MHz) δ : 9.37 (s, 1H), 8.57 (d, 1H)? 7.81 (m, 2H), 6.01 (s, 1H), 5.52 (s, 1H), 2.08 (s, 3H). LC-MS ： 181 [M+H]. 中間物9 N-[(lS)-l-(5-氟基吡啶-2-基）乙基]乙醢胺 於N-(l-(5-氟基吡啶-2-基）乙烯基）乙醯胺（中間物8，ιι 〇 克，61_1毫莫耳）在MeOH (120毫升）中之溶液内，在％下， 添加（+)-1,2-雙（(2S，5S)-2,5c乙基磷烷基）苯（環辛二稀）三氣甲 烷磺酸铑（IXOMi克，0.6U毫莫耳）。將溶液轉移至高壓彈形 容器’並裝填150psiH2。將反應物於室溫下攪拌，且在12〇15〇 psi間之壓力下保持7小時。移除溶劑，並使所形成之殘留 物藉管柱層析純化（EtOAc) ’而得標題化合物，為白色固體 (9.8 克，88%)。 1 H NMR (400 MHz) (5 ： 8.49 (d, J = 2.4 Hz, 1H), 8.32 (d, J = 7.6 Hz, 133151 •90· 200906818 1H)，7.66 (m, 1H)，7_39 (dd，J = 4.4 與 8.8 Hz，1H)，4.95 (m，1H)，1.85 (s, 3H), 1.34 (d, J = 7.2 Hz, 3H). LC-MS ： 183 [M+H]. 對掌異構物過量係藉HPLC測定（Chiralpak IA ; 70:30 C02/Me0H) 95.3% ee. 中間物10 [(lS)-l-(5-氟基吡啶-2-基）乙基】胺基甲酸第三-丁酯 將N-[(lS)-l-(5-氟^基p比咬-2-基）乙基]乙醯胺（中間物9，u.O 克，60.37毫莫耳）、DMAP (1·48克，12.07毫莫耳）及二碳酸二 -第三-丁酯（26.35克，120.7毫莫耳）在THF (1〇〇毫升）中之溶液 於50°C下攪拌20小時。在冷卻至室溫後，添加氫氧化鋰單 水合物（5.19克，123.8毫莫耳）與水（1〇〇毫升）。將反應物於室 溫下攪拌5小時，並以醚（200毫升）稀释。分離有機層，以 鹽水（100毫升）洗滌’及以硫酸鈉脫水乾燥。在移除溶劑後， 使所形成之殘留物藉管柱層析純化（己烷_Et〇Ac = 5:1)，而得 標題化合物’為淡黃色油（13.6克，94%)。 1 H NMR (400 MHz) &lt;5 : 8.46 (d，1H)，7.69 (m，1H)，7.35-7.41 (m，2H)， 4.67 (m, 1H), 1.37 (s, 9H), 1.32 (d, 3H). LC-MS ： 241 [M+H]. 中間物11 [(lS)-l-(5-氟基吡啶-2-基）乙基】胺 於[(lS)-l-(5-氟基吡啶-2-基）乙基]胺基甲酸第三_丁酯（中間 物10，12.8克，53.3毫莫耳）在DCM (100毫升）中之溶液内， 添加HC1/二氧陸圜溶液（1〇7毫升，4N，428毫莫耳）。將反應 133151 -91- 200906818 物於至下授拌3小時。移除溶劑，並添加5〇毫升飽和碳酸 氫鈉。將所形成之水溶液以醚（6 X 4〇〇毫升）萃取，以硫酸鈉 脫X乾燥及;辰縮，而得標題化合物（7.30克，98%)，為淡 黃色油。 1 H NMR (400 MHz) : 8.44 (d, 1H), 7.66 (m, 1H), 7.53 (m, 1H), 4.01 (q, 1H), 1.94 (b, 2H), 1.26 (d, 3H). LC-MS ： 141 [M+H]. 其鹽酸鹽可藉由使標題化合物溶於Me〇H中，並添加HC1/ 二氧陸園溶液而製成。蒸發溶劑，獲得標題化合物之鹽酸 鹽’為黃褐色固體。 中間物12 1_(5_氟基p比咬-2-基）乙醇 於5-氟基峨唆-2-羧甲搭（2_5克）在Et20 (50毫升）中之溶液 内’在(TC下’逐滴添加MeMgBr溶液（8毫升，3.0M，在Et20 中）。將所形成之溶液於此溫度下攪拌30分鐘，然後，使其 ’息熱至環境溫度，歷經1小時。以飽和nh4 C1水溶液使混合 物淬滅，並以Ε^Ο萃取。使有機萃液脫水乾燥，及蒸發， 獲得標題化合物（2.6克）。 'H NMR 5 8.43 (s, 1H), 7.69 (m, 1H), 7.55 (m, 1H), 5.40 (d, 1H), 4.71 (m, 1H), 1.33 (d, 3H). 中間物13 ^(5-氟基嘧啶-2-基）乙酮 於5-氟基嘧啶-2-曱腈（中間物1，2.5克）在Et20 (50毫升）中 之溶液内’在0°C下，逐滴添加MeMgBr溶液（12毫升，3.0M， 133151 -92- 200906818 在Et2〇中）。將所形成之溶液於此溫度下攪拌30分鐘，然 後，使其溫熱至環境溫度過夜。以飽和NH4C1水溶液使混合 物淬滅，並以Et2〇萃取。使有機萃液脫水乾燥，及蒸發， 獲得TT有顏色殘留物。藉管柱層析純化（ISC〇，3〇/。Mohr) with water (10 ml). The reaction was stirred at room temperature for 9 hours. The organic layer was separated by the addition of ether (30 ml), washed with brine (2 mL) and dried over sodium sulfate. After the solvent was removed, the title compound was crystalljjjjjjjjjjjjjjjjjjjjj 1 H ^ (4〇° MHZ) 5 : 8·84 2H), 7.24 (d, 1H), 4.74 (m, 1H), 1,5 (s, 12H). LC-MS : 242 [M+H] Intermediate 5 (lS)_l-(5-fluorenyl, butyl-2-yl)ethylamine hydrochloride in the fluorobase _2-yl)ethyl]aminocarboxylic acid third _ vinegar (intermediate substance (10) Add the HC1 (1.3 弁, $ 9τ γ, ^ pen open 5.2 mmol) to the solution of gram '(四) 毫莫耳沣^ml^. Put the reactants in the chamber&gt; Dissipate the dish for 3 hours. Remove the solvent and collect the cake compound from the cold-filled day to obtain a white solid (quantitative). LC-MS : 142 [M+H]. Intermediate 6 133151 - 88- 200906818 3_Amino-5-methyl-1H-pyrazole-1-carboxylic acid tert-butyl ester in 5-methyl-1H-pyrazol-3-amine (2.48 g, 17.6 mmol) Boc20 (4.0 g, 18.5 mmol) was added at 0 ° C in a solution of DCM (70 mL), followed by a solution of _4_5 ( (31 mL, 140.8 mmol). The mixture was stirred at ambient temperature overnight and diluted with EtOAc EtOAc (EtOAc m. Ge, 20%-^ 30% EtOAc / EtOAc (mjjjjjjjjjjjjjj -"Smelly 5--5-fluoro-based p-bite (93. 0 g, 528 mmol), Zn powder (8.29 g, 127 mmol), zinc cyanide (40.3 g, 343 mmol), A mixture of dppf (11_7 g, 21.1 mmol) and PA dba3 (9.68 g, 10.6 mmol) in anhydrous DMA (300 mL) was heated at 95X: for 3 hours. After cooling to room temperature, brine was added ( The solid formed was removed by filtration and washed with ether (300 mL). After concentrating, the residue was purified by EtOAc EtOAc (EtOAc) 400 MHz) δ : 8.82 (d, 1H), 8.21 (dd, 1H), 8.05 (dd, 1H). Intermediate 8 N-(l-(5-fluoropyridin-2-yl)vinyl)acetamidine A solution of MeMgBr (170·3 ml '510.98 mmol) in ether as i 7〇 133151 -89- 200906818 Dilute in anhydrous THF and cool to . The 5-fluoro group in the stomach (i7 ml) was bitten 2-acetonitrile (intermediate 7, 53, 6 g, 425 82 mmol). The reaction was stirred at 0 C for 3 min then diluted with DCM (17 mL). Acetic anhydride (48. 3 ml, 510.98 mmol) in DCM (100 mL) was added dropwise at EtOAc. After the addition, the reaction was allowed to warm to room temperature and stirred at room / pho. for 8 hours. A saturated aqueous solution of sodium bicarbonate (5 mL) was added andEtOAc was evaporated. The combined organic materials were dried over sodium sulfate and dried. After the solvent was removed, EtOAc EtOAc (EtOAc) MHz) δ : 9.37 (s, 1H), 8.57 (d, 1H)? 7.81 (m, 2H), 6.01 (s, 1H), 5.52 (s, 1H), 2.08 (s, 3H). LC-MS : 181 [M+H]. Intermediate 9 N-[(lS)-l-(5-fluoropyridin-2-yl)ethyl]acetamide in N-(l-(5-fluoropyridine-2 -()-vinyl)acetamide (intermediate 8, ιι, gram, 61_1 mmol) in MeOH (120 mL), at %, add (+)-1,2-bis(( 2S,5S)-2,5cethylphosphinoalkyl)benzene (cyclooctane disulfide) trigas methanesulfonate sulfonate (IXOMi gram, 0.6 U millimolar). The solution was transferred to a high pressure elastomeric container&apos; and filled with 150 psi H2. The reaction was stirred at room temperature and maintained at a pressure between 12 Torr and 15 psi for 7 hours. The solvent was removed and the residue was purified mjjjjjjjjjjj 1 H NMR (400 MHz) (5: 8.49 (d, J = 2.4 Hz, 1H), 8.32 (d, J = 7.6 Hz, 133151 • 90· 200906818 1H), 7.66 (m, 1H), 7_39 (dd, J = 4.4 and 8.8 Hz, 1H), 4.95 (m, 1H), 1.85 (s, 3H), 1.34 (d, J = 7.2 Hz, 3H). LC-MS : 183 [M+H]. The excess of the structure was determined by HPLC (Chiralpak IA; 70:30 C02/Me0H) 95.3% ee. Intermediate 10 [(lS)-l-(5-fluoropyridin-2-yl)ethyl]aminocarbamic acid Tri-butyl ester will be N-[(lS)-l-(5-fluoro)-p-but-2-yl)ethyl]acetamide (intermediate 9, uO g, 60.37 mmol), DMAP ( 1.48 g, 12.07 mmol, and di-tert-butyl dicarbonate (26.35 g, 120.7 mmol) in THF (1 mL) were stirred at 50 ° C for 20 h. After cooling to room temperature, lithium hydroxide monohydrate (5.19 g, 123.8 mmol) and water (1 mL) were added. The reaction was stirred at room temperature for 5 h and diluted with ether (200 mL) The organic layer was separated, washed with brine (100 mL) and dried over sodium sulfate. After the solvent was removed, the residue was purified by column chromatography (hexane) Et 〇Ac = 5:1), and the title compound was obtained as pale yellow oil (13.6 g, 94%). 1 H NMR (400 MHz) &lt;5: 8.46 (d, 1H), 7.69 (m, 1H) , 7.35-7.41 (m, 2H), 4.67 (m, 1H), 1.37 (s, 9H), 1.32 (d, 3H). LC-MS : 241 [M+H]. Intermediate 11 [(lS)- 1-(5-Fluoropyridin-2-yl)ethyl]amine in [(lS)-l-(5-fluoropyridin-2-yl)ethyl]carbamic acid tert-butyl ester (intermediate) 10,12.8 g, 53.3 mmoles) In a solution of DCM (100 ml), add a solution of HC1/dioxanthine (1 〇 7 mL, 4 N, 428 mmol). Reaction 133151 -91 - 200906818 The mixture was stirred for 3 hours, the solvent was removed, and 5 ml of saturated sodium bicarbonate was added. The formed aqueous solution was extracted with ether (6×4 mL), dried with sodium sulfate and dried. The title compound (7.30 g, 98%) was obtained as pale yellow oil. 1 H NMR (400 MHz): 8.44 (d, 1H), 7.66 (m, 1H), 7.53 (m, 1H), 4.01 (q , 1H), 1.94 (b, 2H), 1.26 (d, 3H). LC-MS: 141 [M+H]. The hydrochloride salt can be obtained by dissolving the title compound in Me〇H and adding HC1/ Made from a dioxic earth solution. Evaporation of the solvent gave the title compound <RTI ID=0.0> Intermediate 12 1_(5-fluoro-p-buty-2-yl)ethanol in a solution of 5-fluoroindole-2-carboxymethyl (2-5 g) in Et20 (50 ml) 'under (TC 'MeMgBr solution (8 ml, 3.0 M in Et20) was added dropwise. The resulting solution was stirred at this temperature for 30 minutes and then allowed to warm to ambient temperature over 1 hour to saturate nh4 C1 The aqueous solution was quenched with EtOAc (EtOAc) (EtOAc) (HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH (m, 1H), 5.40 (d, 1H), 4.71 (m, 1H), 1.33 (d, 3H). Intermediate 13^(5-fluoropyrimidin-2-yl)ethanone in 5-fluoropyrimidine -2-indene nitrile (intermediate 1, 2.5 g) in Et20 (50 ml) in solution - at 0 ° C, MeMgBr solution was added dropwise (12 ml, 3.0 M, 133151 -92 - 200906818 in Et2〇 The resulting solution was stirred at this temperature for 30 minutes, then allowed to warm to ambient temperature overnight. The mixture was quenched with saturated aqueous NH4C1 and extracted with Et.sub.2. Evaporate, get TT Color residue. Purification by column chromatography (ISC〇, 3〇 /.

Me0H/DCM)，而得標題化合物（800毫克）。 1 H NMR (CDC13) δ 8.75 (s, 2H), 2.77 (s, 3H). 中間物14 1-(5-氟基鳴咬-2-基）乙醇 於1-(5-氟基嘧啶-2-基）乙酮（中間物13，8〇〇毫克）在Me〇H (40毫升）中之溶液内，在〇〇c下，分次添加(12毫升， 3.0M ’在Et2〇中）。將所形成之溶液於室溫下攪拌3〇分鐘。 蒸發溶劑’並使殘留物在H20與DCM之間作分液處理。以 飽和ΝΙ^α水溶液、吒〇及鹽水洗滌有機層。使有機萃液脫 水乾燥’及蒸發’獲得標題化合物（33〇毫克）。 !H NMR (CDC13) 5 8.59 (s, 2H), 4.96 (m, 1H), 3.79 (br s, 1H), 1.54 (d, 3H). 中間物15 4_氣-N-(5-甲基-1H-吡唑_3_基）_6_嗎福淋基_1&gt;3,5_三畊_2胺 於100毫升圓底燒瓶中’添加乙醇（4〇·8毫升）中之4,6二氯 -N-(5-甲基·1H-吡唑-3-基）+3,5^啡_2_胺（中間物18，2克，8 16 毫莫耳）、EtsN (1.137毫升，8·ι6毫莫耳）及嗎福啉（〇 711毫升， 8.16毫莫耳）’獲得黃色懸浮液。將此懸浮液在〇它下攪拌1 小時’此時添加乙醚。過濾已沉澱之固體，並以Et〇Ac/乙 鍵（1/1 v/v)之混合物洗務。使合併之濾液在減壓下蒸發，而 133151 •93 - 200906818 得橘色油。藉管柱層析純化（ISC〇，5〇% Et〇Ac/己烷），獲得 標題化合物，為白色固體。 LC-MS : 296 [M+H]. 中間物16 (S)-6-氣-N2-(l_(5-氟基吡啶_2_基）乙基）_ν4·(5-甲基-1H-吡唑_3_ 基）-1,3,5-三呼-2,4-二胺 於500毫升圓底燒瓶中，添加乙醇（51 〇毫升）中之4,6_二氣 厂 -N-(5-曱基-1H-吡唑-3-基）-1，3,5-三畊-2-胺（中間物18，5克，20.40 毫莫耳）' (S)-l-(5-氟基吡啶-2-基）乙胺，2HC1 (中間物11，4 35 克’ 2〇.4〇毫莫耳）及N_乙基_N_異丙基丙_2_胺（7 91克，6121毫 莫耳），而得黃色溶液。將所形成之混合物在環境溫度下攪 拌24小時。蒸發，獲得標題化合物，將其使用於下一步驟 中，未進行任何進一步純化。 LC-MS ： 349 [M+H]. 中間物17 c.⑻冬氣-N2-(1-(5-氟基嘧啶-2-基）乙基）-N4-(5-曱基-1H_吡唑_3_ 基）-1，3,5-三喷-2,4-二胺 按照類似關於中間物16合成所述之程序，標題化合物係 自4,6-二氯_N-(5-曱基-1H-吡唑-3-基）-1，3,5-三畊_2_胺（中間物叫 與（S)-l-(5-氟基嘧啶_2_基）乙胺鹽酸鹽（中間物5)合成。藉管柱 層析純化（ISCO，EtOAc-己烷50%— EtOAc 1〇〇%、，湓以加 ν 筏侍標題化 合物，為白色泡沫物。 LC-MS ： 350 [Μ+Η]. 中間物18 133151 -94- 200906818 4,6-二氣-N-(5_曱基-lH-p比峻各基）·1，3,5-三啡_2-胺 於2,4,6-三氯-l，3,5-三畊（5克’ 27.11毫莫耳）在Et〇H (9〇毫升） 中之溶液内’在〇°C下’添加5-甲基-1H-U比η坐_3_胺（2.63克，27.11 毫莫耳）與EtsN (7.56毫升，54.23毫莫耳）。將所形成之溶液 於室溫下攪拌過夜。將混合物以EkO研製，並經由過濾收 集標題化合物，為灰白色固體（4_5克）。 LC-MS ： 245 [M+H], 中間物19 4-(4-氣基-6-(1-(5-氟基嘧啶-2-基）乙氧基）·ι，3,5-三畊-2-基）嗎福 11 林 於微波管件中，添加1-(5-氟基《•密唆-2-基）乙醇（中間物14， 290宅克，2.〇4毫莫耳）、3毫升t-BuOH及第三-丁醇鈉（196毫 克’ 2.04毫莫耳）’並將所形成之溶液在室溫及惰性大氣下 攪拌1小時。將上述溶液於〇°C下添加至4_(4,6-二氣_1，3,5-三p井 -2-基）嗎福4 (中間物20，600毫克，2.55毫莫耳）在1毫升 t-BuOH/0.5毫升THF中之溶液内，歷經1〇分鐘。將所形成之 反應混合物在室溫下攪拌過夜。於減壓下過濾反應物，及 在減壓下蒸發所收集之濾液，獲得帶有顏色殘留物。藉管 柱層析純化（ISCO，50% Et〇Ac/己烷），獲得530毫克標題化合 物。 LC-MS ： 341 [M+H]. 中間物20 4-(4,6-二氯-I，3,5-三畊-2-基）嗎福啉 於500毫升圓底燒瓶中，添加2〇〇毫升Et〇H中之2,4,6_三氣 133151 -95- 200906818 -1，3,5-三畊（10.77 克，58.40 毫莫耳）與 DIPEA (20.40 毫升，116.80 毫莫耳）’獲得白色乳化液。使溶液冷卻至-40°C，並在-40 C下，慢慢添加25毫升EtOH中之嗎福啉（5.11毫升，58.40毫 莫耳）。使所形成之混合物溫熱至環境溫度過夜。在減壓下 蒸發揮發性物質，而得殘留物，使其藉管柱層析純化 (ISCO，〇— 1〇% MeOH在DCM中）’而得標題化合物，為白色 固體（6.6克）。 LC-MS ： 236 [M+H]. 中間物21 N-[(5-氟基吡啶-2-基）亞甲基]_2·甲基丙烷_2_亞磺醯基醯胺 使5-氟基-2-甲醯基吡淀（5克，40毫莫耳）、外消旋第三-丁 基亞磺醯基醯胺（9.7克’ 80毫莫耳）溶於DCM (100毫升）中， 並添加CuS〇4(12.8克，8〇毫莫耳）。將反應混合物在室溫及 氮大氣下攪拌過夜。於藉TLC顯示反應完成後，使反應混 合物經過Celite®過濾，及以DCM洗滌。在真空中蒸發濾液， 獲得淡黃色油，使其藉管柱層析純化（己烷/EtOAc = 8〇:2〇), 提供標題化合物（7.2克，82%)，為白色固體。 LC-MS ： 229 [M+H] 中間物22 2-胺基-2-(5-氟基p比咬-2-基）-N，N-二甲基乙烧續酿胺鹽酸鹽 於N，N’-二甲基磺醯胺在2毫升無水THF中之溶液内，在_78 C下慢慢添加1.8M LDA。於-78t下攪拌30分鐘後，將N-[(5-氟基吡啶-2-基）亞甲基]_2_甲基丙烷_2_亞磺醯基醯胺（中間物 21)在1毫升無水THF中之溶液慢慢添加至反應混合物中，並 133151 -96- 200906818 在相同狐度下再攪拌2小時。以飽和氣化銨溶液使反應淬 滅’以Et〇AC萃取，然後脫水乾燥（Na2S〇4)。使所收集之有 機層於真空中濃縮，以提供褐色油。使此油再溶於臟c (1 〇 耄升）中，且在室溫下慢慢添加二氧陸圜中之4M hci。反應 混合物轉變成混濁溶液’接著，沉澱析出褐色固體。於室 溫下2小時後’添加乙鍵，以供完成所要產物之沉殿作用。 藉過濾收集所形成之固體，以乙醚洗滌，及在高真空下乾 燥’而得標題化合物，為灰白色粉末。 1 H NMR (500 MHz) 5 ppm 2.67 (s, 6H) 3.75 (dd, 1H) 3.84 (dd, 1H) 4.79 (m，1H) 7.70-7.72 (m，1H) 7.83-7.85 (m，1H) 8.69 (s，1H) 8.89 (寬廣 s， 2H). 中間物23 2-(4-氣基-6·(5-曱基-1H-吡唑-3-基胺基M，3,5_三畊·2_基胺基）2_ (5-氟基吡啶-2-基）-N，N-二甲基乙烷磺醯胺 於250毫升圓底燒瓶中，添加乙醇（13 6〇毫升）中之4,6_二氯 -N-(5-甲基-1H-峨嗤-3-基）-1，3,5-三畊-2_胺（中間物18，1克，4 〇8 毫莫耳）與2_胺基_2_(5_氟基吡啶冬基&gt;N，N_二甲基乙烷磺醯胺 鹽酸鹽（中間物22，1.158克’ 4.08毫莫耳），獲得白色懸浮液。 使混合物冷卻至0。〇，且經由注射器添加DIpEA(2l38毫升， 12.24毫莫耳），並注意（放熱反應）。在氣體（白色雲霧）釋出 停止後，將所形成之混合物於25t：下攪拌16小時。蒸發揮 發性物質，獲得黃色殘留物。藉管柱層析純化（5〇% Et〇Ae/ 己烷—100〇/。Et〇Ac)，而得標題化合物’為灰白色固體（ΐ5ι 克）。 133151 -97- 200906818 LC-MS ： 456, 457 [M+H]. 中間物23φ) (S)-N-(四氫p比洛_3·基）乙酿胺鹽酸鹽 於（S)-3-乙醯胺基四氫吡咯·丨·羧酸第三_丁酯（ι克，438毫莫 耳）在MeOH (15 *升）中之溶液内，在说下，留心、添加船 (2.190毫升，8.76毫莫耳）在二氧陸圜（4N)中之溶液。將所形 成之混合物於此溫度下攪拌！小時。在減壓下蒸發揮發性物 質’獲得（S)-N-(ra氫p比咯_3_基）乙醯胺Ηα。 中間物24 (R)-N-(四氩p比洛_3_基）乙醯胺鹽酸鹽 於（R)-3-乙醯胺基四氫吡咯小羧酸第三_丁酯（1克，4 38毫 莫耳）在MeOH (〜15毫升）中之溶液内，在以^下，留心添加 HC1 (2.190毫升，8·76毫莫耳）在二氧陸園（4N)中之溶液。將 所形成之混合物於此溫度下攪拌丨小時。在減壓下蒸發揮發 性物質，獲得標題產物。 中間物25 (R)-六氩吡啶-2-基甲醇鹽酸鹽 於（R)-2-(羥甲基）六氫吡啶_丨·羧酸第三_丁酯（1克，4 64毫莫 耳）在MeOH (15.48毫升）中之溶液内，在25〇c下，留心添加Ηα (1_161毫升’ 4.64耄莫耳）在二氧陸圜（4n)中之溶液。將所形 成之混合物於此溫度下攪拌1小時。在減壓下蒸發揮發性物 質，獲得標題產物，為白色黏性固體。 JH NMR (300 MHz, MeOD) δ ppm 1.40-2.09 (m, 6H) 2.98 (t, 1H) 3.l〇. 3.22 (m, 1H) 3.30-3.42 (m, 1H) 3.50-3.63 (m, 1H) 3.76 (dd, 1H). 133151 -98- 200906818 中間物26 (R)-一氮四圜-2-基甲醇鹽酸鹽 使用類似關於中間物25合成所述之程序，使（R&gt;2_(經甲基） 一氮四圜-1-羧酸第三-丁酯反應，提供標題產物。 中間物27 (S)-六氫吡啶-2-基甲醇鹽酸鹽 於（S)-2-(經甲基）六氫吡啶心囔酸第三-丁酯（5〇〇毫克，2.32 .. 毫莫耳）在Me0H (〜8毫升）中之溶液内，在25。(：下，留心添加 HC1 (1161微升，4.64毫莫耳）在二氧陸圜（4N)中之溶液。將所 形成之混合物於此溫度下攪拌丨小時。在減壓下蒸發揮發性 物質，獲得標題產物。 中間物28 3-甲基一氮四困-3-醇鹽酸鹽 在〇 C下，使3-羥基-3-甲基一氮四圜小羧酸第三丁酯（2〇〇 毫克，1.07毫莫耳）溶於Me〇H(1.〇68毫升）中，並添加二氧陸 (圜中之4MHC1(0.801毫升，毫莫耳）。然後，將反應物在 〇°C下授拌2小時，接著於25t口小時。然後，使反應混合 物在真空中濃縮，提供標題產物，為黃色油（132毫克）。 1 H NMR (300 MHz,二氯甲烧 _d2) 5 ppm 3 64 (s，2H) 3 42 (s，2H) 1.42 (s, 3H). 中間物29 3-氟基一氣四園鹽酸鹽 使1-二苯曱基-3-氟基—氮四圜鹽酸鹽（2〇〇毫克，〇72毫莫 耳）溶於Me〇H(50毫升）中，並經過&quot;H-Cube&quot;處理（10barr ’流 133151 •99- 200906818 率〜1毫升/分鐘，25°C，使用20重量％ Pd/碳藥筒）。在真空 中濃縮，獲得白色固體（187毫克）。在〇。〇下，使此物質溶於 二氧陸圜（2毫升）中，並添加二氧陸園中之4M HC1 (0.540亳 升’ 2_16毫莫耳）。然後’將反應物於25°C下授拌。1小時後， 使反應混合物在真空中濃縮，提供標題化合物，為透明半 固體（181毫克）。 中間物30 羥基-4-甲基六氫p比咬-1-叛酸第三-丁酯 f 使、;臭化甲基鎮（1.795克’ 15.06毫莫耳）（在喊中之3M溶液） 於乾冰浴中冷卻，將THF中之4-酮基六氫吡啶+羧酸第三_ 丁酯（3.00克，15.06毫莫耳）逐滴添加至反應混合物中。將反 應物在-78°C下攪拌1小時，並於相同溫度下以飽和溶 液使反應淬滅。添加醋酸乙酯，且分離有機相，以MgS〇4 脫水乾燥，及在減壓下濃縮。藉ISC〇純化（8〇克管柱，Μ% -65% EtOAc/己烷）’獲得1_86克標題化合物。 ( H NMR (300 MHz，二氯甲院斗）5 ppm 115 (s，3H) &amp; 阳) 1.37-1.46 (m, 4H) 2.92-3.24 (m, 2H) 3.46-3.66 (m, 2H) 中間物31 4-甲基六氫叶b咬-4_醇鹽酸鹽 使甲醇（10毫升）中之4_羥基斗甲基六氫吡啶+羧酸第三_ 丁酯（中間物30，1.82克，8.45毫莫耳）冷卻至叱。將驼〖a 毫升，4N，在二氧陸園中）添加至反應物中。移除冰浴， 並將反應物於室溫下攪拌2小時。在減壓下移除溶劑，而Γ 1.26克標題化合物之產物。 133151 •100、 200906818 1 H NMR (300 MHz,二氯曱烷 _d2) d ppm 0.66-0.93 (m，2H) 1.08-1.32 (m, 4H) 1.64-1.74 (m, 1H) 1.87-2.08 (m, 2H) 3.06-3.31 (m, 2H). 中間物32 六氫吡啶-4-甲腈鹽酸鹽 於甲醇（15毫升）中之4-氰基六氫吡啶-1-羧酸第三-丁酯 (2.100克，9.99毫莫耳）内，添加i-pr〇H中之HC1 (3毫升，5-6N 溶液）。將反應物在室溫下攪拌過夜。移除溶劑，獲得1.56 克標題化合物。將此物質直接使用於下一步驟反應，無需 進一步純化。 NMR (300 MHz, MeOD) δ ppm 1.82-2.03 (m, 2H) 2.04-2.21 (m, 2H) 3.00-3.15 (m, 3H) 3.17-3.32 (m, 2H). 中間物33 3-羥基-3-甲基六氫吡啶-1-叛酸第三-丁酯 於溴化曱基鎂（1M，在丁基醚中，12_5毫升）中，在_78°C 下’添加3-酮基六氫p比咬-1-叛酸第三-丁 g旨（586毫克，2.94毫 莫耳）在THF (5毫升）中之溶液。將反應混合物於_78。(3下授 拌2-3小時，接著，在-78°C下’逐滴以飽和NH4 C1溶液使反 應混合物淬滅。然後，使反應混合物溫熱至環境溫度，並 以醋酸乙酯萃取。將合併之有機層以MgS〇4脫水乾燥，過濾， 及濃縮’而得粗製殘留物，使其在ISCO系統上直接純化 (100%己烷至100%醋酸乙酯），獲得標題化合物。將此物質 (0.488克）直接取至下一步驟。 中間物34 甲基六氩峨啶-3-醇 133151 101 - 200906818 於5毫升曱醇中之3-羥基_3_甲其丄与 土〕T I 虱p比咬_ι_緩酸第三·丁 酿（中間物33，0.488克，2.27毫莫耳）内，添加n夜中之m HC1(1〇毫升）。將反應物在室溫下㈣一小時。然後，於減 壓下濃縮反應混合物，並在其晝办丁 说 1隹同異空下乾煉，而得標題化合 物。 中間物35 (R)-N，N_二甲基嗎福，林_3胃羧酿胺Me0H/DCM) gave the title compound (800 mg). 1 H NMR (CDC13) δ 8.75 (s, 2H), 2.77 (s, 3H). Intermediate 14 1-(5-fluoroheptin-2-yl)ethanol in 1-(5-fluoropyrimidine-2 Ethyl ketone (Intermediate 13, 8 〇〇 mg) in a solution of Me 〇 H (40 mL) was added in portions (12 mL, 3.0 M ' in Et 2 )). The resulting solution was stirred at room temperature for 3 minutes. The solvent was evaporated and the residue was partitioned between H20 and DCM. The organic layer was washed with a saturated aqueous solution of hydrazine, hydrazine and brine. The organic extract was dehydrated and evaporated to give the title compound (33 mg). !H NMR (CDC13) 5 8.59 (s, 2H), 4.96 (m, 1H), 3.79 (br s, 1H), 1.54 (d, 3H). Intermediate 15 4_ gas-N-(5-methyl -1H-pyrazole_3_yl)_6_fofopyl-1&gt;3,5_three tillage _2 amine in a 100 ml round bottom flask '4,6 of ethanol (4 〇·8 ml) Dichloro-N-(5-methyl·1H-pyrazol-3-yl)+3,5^morpho-2-amine (intermediate 18, 2 g, 8 16 mmol), EtsN (1.137 ml, 8·ι6 mmol) and morpholine (〇 711 ml, 8.16 mmol) were obtained as a yellow suspension. The suspension was stirred under it for 1 hour. At this time diethyl ether was added. The precipitated solid was filtered and washed with a mixture of Et 〇 Ac / B (1/1 v/v). The combined filtrate was evaporated under reduced pressure, and 133151.93 - 200906818 obtained orange oil. The title compound was obtained as a white solid. m. m. LC-MS: 296 [M+H]. Intermediate 16 (S)-6-V-N2-(l-(5-fluoropyridin-2-yl)ethyl)_ν4·(5-methyl-1H- Pyrazole_3_yl)-1,3,5-trih-2,4-diamine in a 500 ml round bottom flask, adding 4,6_diox-N-(in ethanol (51 ml) 5-mercapto-1H-pyrazol-3-yl)-1,3,5-trin-2-amine (intermediate 18,5 g, 20.40 mmol)' (S)-l-(5- Fluoropyridin-2-yl)ethylamine, 2HC1 (intermediate 11, 4 35 g '2〇.4〇 mmol) and N_ethyl_N_isopropylpropan-2-amine (7 91 g) , 6121 millimoles), and a yellow solution. The resulting mixture was stirred at ambient temperature for 24 hours. Evaporation gave the title compound which was used in the next step without further purification. LC-MS : 349 [M+H]. Intermediate 17 c. (8) Winter-N2-(1-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-mercapto-1H_ Pyrazole-3-yl)-1,3,5-tripenta-2,4-diamine The title compound is from 4,6-dichloro-N-(5-, according to procedures similar to those described for the synthesis of intermediate 16 Mercapto-1H-pyrazol-3-yl)-1,3,5-three tillage _2-amine (intermediate is called (S)-l-(5-fluoropyrimidin-2-yl)ethylamine salt The acid salt (Intermediate 5) was purified by EtOAc EtOAc (EtOAc:EtOAcEtOAc 350 [Μ+Η]. Intermediate 18 133151 -94- 200906818 4,6-digas-N-(5_mercapto-lH-p ratio)·1,3,5-triphthol_2- Add 5 to the amine in a solution of 2,4,6-trichloro-l,3,5-three tillage (5 g ' 27.11 mmol) in Et〇H (9 mL) -Methyl-1H-U was taken as _3_amine (2.63 g, 27.11 mmol) and EtsN (7.56 ml, 54.23 mmol). The resulting solution was stirred at room temperature overnight. The title compound was triturated with EtOAc (EtOAc). : 245 [M+H], Intermediate 19 4-(4-Alkyl-6-(1-(5-fluoropyrimidin-2-yl)ethoxy)·ι,3,5-三耕-2 - 基)福福11 Lin in the microwave tube, add 1-(5-fluoro-based "• 唆-2-yl) ethanol (intermediate 14, 290 house, 2. 〇 4 millimoles), 3 ml t-BuOH and sodium tributoxide (196 mg '2.04 mmol) and the resulting solution was stirred at room temperature under an inert atmosphere for 1 hour. Add the above solution to 4_(4) at 〇 ° C , 6-dioxane_1,3,5-tri-p-but-2-yl)offene 4 (intermediate 20,600 mg, 2.55 mmol) in 1 ml of t-BuOH/0.5 ml of THF After 1 minute, the resulting reaction mixture was stirred at room temperature overnight. The reaction was filtered under reduced pressure and the filtrate was evaporated under reduced pressure to give a color residue. Purification (ISCO, 50% EtOAc / hexanes) Three-till-2-yl) porphyrin in a 500 ml round bottom flask, adding 2 4 ml of Et〇H 2,4,6_three gas 133151 -95- 200906818 -1,3 , 5-three tillage (10.77 grams, 58.40 millimoles) and DIPEA (20.40 milliliters, 116.80 millimoles) to obtain a white emulsion. The solution was cooled to -40 ° C and 25 ml of morphine (5.11 mL, 58.40 mmol) in EtOH was slowly added at -40 C. The resulting mixture was allowed to warm to ambient temperature overnight. The volatiles were evaporated under reduced pressure to give crystals crystals crystals crystals LC-MS: 236 [M+H]. Intermediate 21 N-[(5-fluoropyridin-2-yl)methylene]-2·methylpropane-2_sulfinyl decylamine 5-fluoro Pyridyl-2-mercaptopyridinium (5 g, 40 mmol), racemic tris-butylsulfinylguanamine (9.7 g '80 mmol) dissolved in DCM (100 mL) And add CuS〇4 (12.8 g, 8 〇 millimolar). The reaction mixture was stirred at room temperature under nitrogen overnight. After completion of the reaction by TLC, the reaction mixture was filtered over Celite® and washed with DCM. The filtrate was evaporated in vacuo tolululululululululululululululu LC-MS: 229 [M+H] Intermediate 22 2-Amino-2-(5-fluoro-p-buty-2-yl)-N,N-dimethylethyl ether In a solution of N,N'-dimethylsulfonamide in 2 ml of anhydrous THF, 1.8 M LDA was slowly added at -78 C. After stirring at -78t for 30 minutes, N-[(5-fluoropyridin-2-yl)methylene]_2-methylpropane-2_sulfinylguanamine (intermediate 21) in 1 ml A solution of anhydrous THF was slowly added to the reaction mixture, and stirred for another 2 hours at the same fox degree from 133151 to 96-200906818. The reaction was quenched with a saturated ammonium hydride solution, extracted with Et 〇 AC, and then dried (Na 2 S 〇 4). The collected organic layers were concentrated in vacuo to provide a brown oil. The oil was redissolved in dirty c (1 耄 liter) and 4 M hci in dioxane was slowly added at room temperature. The reaction mixture was converted to a cloudy solution. Then, a brown solid precipitated. After 2 hours at room temperature, the B bond was added to complete the sinking effect of the desired product. The solid which formed was collected by filtration, washed with diethyl ether and dried under high vacuum to give the title compound as pale white powder. 1 H NMR (500 MHz) 5 ppm 2.67 (s, 6H) 3.75 (dd, 1H) 3.84 (dd, 1H) 4.79 (m,1H) 7.70-7.72 (m,1H) 7.83-7.85 (m,1H) 8.69 (s,1H) 8.89 (broad s, 2H). Intermediate 23 2-(4-carbyl-6·(5-mercapto-1H-pyrazol-3-ylamino M, 3,5_ three tillage · 2_ylamino) 2_(5-fluoropyridin-2-yl)-N,N-dimethylethanesulfonamide in a 250 ml round bottom flask, added with ethanol (13 6 ml) 4,6-Dichloro-N-(5-methyl-1H-indol-3-yl)-1,3,5-trinol-2-amine (intermediate 18, 1 g, 4 〇 8 mmol) Ear) with 2_Amino-2-(5-fluoropyridylpyridinyl)N,N-dimethylethanesulfonamide hydrochloride (Intermediate 22, 1.158 g '4.08 mmol), obtained white The suspension was allowed to cool to 0. 〇, and DIpEA (2l38 ml, 12.24 mmol) was added via syringe and noted (exothermic reaction). After the gas (white cloud) evolution ceased, the resulting mixture was 25t: stirred for 16 hours. Evaporation of the volatile material to give a yellow residue. Purified by column chromatography (5 〇% Et 〇 Ae / hexane - 100 〇 / Et Et) Color solid (ΐ5 克). 133151 -97- 200906818 LC-MS : 456, 457 [M+H]. Intermediate 23 φ) (S)-N-(tetrahydropyrlo-3·yl) ethylamine salt The acid salt is in the solution of (S)-3-acetamido-tetrahydropyrrole·quinonecarboxylic acid tert-butyl ester (ι克, 438 mmol) in MeOH (15 * liter). , carefully, add a solution of the boat (2.190 ml, 8.76 mmol) in dioxane (4N). The resulting mixture was stirred at this temperature for an hour. Evaporate the volatiles under reduced pressure to obtain ( S)-N-(ra hydrogen p is more than _3_yl) acetamidine Ηα. Intermediate 24 (R)-N-(tetra-argon p-bi _3_yl) acetamidine hydrochloride in (R -3-Ethylaminotetrahydropyrrole carboxylic acid tert-butyl ester (1 g, 4 38 mmol) in MeOH (~15 ml) in the solution, add HCl ( 2.190 ml, 8.76 mmoles of a solution in dioxane (4N). The resulting mixture was stirred at this temperature for a few hours. The volatile material was evaporated under reduced pressure to give the title product. 25(R)-hexafluoropyridin-2-ylmethanol hydrochloride in (R)-2-(hydroxymethyl)hexahydropyridine_ · A solution of the third-butyl ester of carboxylic acid (1 g, 4 64 mmol) in MeOH (15.48 ml), at 25 ° C, carefully add Ηα (1_161 ml ' 4.64 耄 Mo) in dioxane Solution in Lu (4n). The resulting mixture was stirred at this temperature for 1 hour. The volatiles were evaporated under reduced pressure to give the title product as a white solid. JH NMR (300 MHz, MeOD) δ ppm 1.40-2.09 (m, 6H) 2.98 (t, 1H) 3.l〇. 3.22 (m, 1H) 3.30-3.42 (m, 1H) 3.50-3.63 (m, 1H) 3.76 (dd, 1H). 133151 -98- 200906818 Intermediate 26 (R)-N-tetradecyl-2-ylmethanol hydrochloride using a procedure similar to that described for the synthesis of Intermediate 25, (R > 2_( The title product is obtained by the reaction of the methyl 3-aminotetramethylene-1-carboxylic acid tert-butyl ester. Intermediate 27 (S)-hexahydropyridin-2-ylmethanol hydrochloride in (S)-2-( In the solution of methyl hexahydropyridinium citrate tris-butyl ester (5 〇〇 mg, 2.32 .. millimolar) in Me0H (~8 ml), at 25. (:, pay attention to add HC1 (1161 μl, 4.64 mmol) in dioxane (4N). The resulting mixture was stirred at this temperature for hrs. The volatile material was evaporated under reduced pressure to give the title product. 28 3-methyl-azinotetrazole-3-ol hydrochloride under 〇C to give 3-hydroxy-3-methyl-azinotetracarboxylic acid carboxylic acid tert-butyl ester (2 〇〇 mg, 1.07 mmol) Ear) dissolved in Me〇H (1.〇68 ml) and added dioxane (4MHC1 in 圜(0.801 ml, millimolar) The reaction was then stirred at EtOAc for 2 h then EtOAc (EtOAc) EtOAc (EtOAc) , methylene chloride _d2) 5 ppm 3 64 (s, 2H) 3 42 (s, 2H) 1.42 (s, 3H). Intermediate 29 3-fluoro-based gas-tetrahydrochloride hydrochloride 1-diphenylhydrazine 3-Benzyl-nitro-tetrazepine hydrochloride (2 mg, 〇72 mmol) dissolved in Me〇H (50 mL) and subjected to &quot;H-Cube&quot; treatment (10 barr 'flow 133151 • 99- 200906818 rate ~ 1 ml / min, 25 ° C, using 20 wt% Pd / carbon cartridge). Concentrate in vacuo to give a white solid (187 mg). Dioxane (2 ml) was added with 4 M HC1 (0.540 liters '2_16 mmol) in dioxane. Then the reaction was stirred at 25 ° C. After 1 hour, the reaction mixture was allowed to Concentration in vacuo afforded the title compound as a semi-solid ( 181 mg). Intermediate 30 hydroxy-4-methyl hexahydro-p. 1.795 g '15.06 mmol) (3M solution in shout) Cooled in a dry ice bath with 4-ketohexahydropyridine + carboxylic acid tert-butyl ester in THF (3.00 g, 15.06 mmol) Add dropwise to the reaction mixture. The reaction was stirred at -78 °C for 1 hour and quenched with a saturated solution at the same temperature. Ethyl acetate was added, and the organic phase was separated, dried with MgSO4, and concentrated under reduced pressure. Purification by ISC (8 gram column, Μ% - 65% EtOAc/hexanes) afforded 1-86 g of the title compound. (H NMR (300 MHz, dichlorocarbyl) hopper 5 ppm 115 (s, 3H) &amp; yang) 1.37-1.46 (m, 4H) 2.92-3.24 (m, 2H) 3.46-3.66 (m, 2H) Compound 31 4-methylhexahydrofolate b-battery-4-alcohol hydrochloride salt 4_hydroxyindole methylhexahydropyridine + carboxylic acid third-butyl ester in methanol (10 ml) (intermediate 30, 1.82 g , 8.45 millimoles) cooled to 叱. Add a camel [a ml, 4N, in a dioxere) to the reaction. The ice bath was removed and the reaction was stirred at room temperature for 2 h. The solvent was removed under reduced pressure and 1.26 g of the title compound. 133151 •100, 200906818 1 H NMR (300 MHz, methylene chloride _d2) d ppm 0.66-0.93 (m,2H) 1.08-1.32 (m, 4H) 1.64-1.74 (m, 1H) 1.87-2.08 (m , 2H) 3.06-3.31 (m, 2H). Intermediate 32 hexahydropyridine-4-carbonitrile hydrochloride in methanol (15 ml) 4-cyanohexahydropyridine-1-carboxylic acid tert-butyl To the ester (2.100 g, 9.99 mmol), add HC1 (3 mL, 5-6 N solution) in i-pr〇H. The reaction was stirred at room temperature overnight. The solvent was removed to give 1.56 g of the title compound. This material was used directly in the next step without further purification. NMR (300 MHz, MeOD) δ ppm 1.82-2.03 (m, 2H) 2.04-2.21 (m, 2H) 3.00-3.15 (m, 3H) 3.17-3.32 (m, 2H). Intermediate 33 3-hydroxy-3 -Methylhexahydropyridine-1-teric acid tri-butyl ester in 3-mercaptohexylhydrogen bromide (1M in butyl ether, 12-5 ml), added at -78 °C p is a solution of the third-butylic acid (586 mg, 2.94 mmol) in THF (5 mL). The reaction mixture was taken at _78. The mixture was stirred for 2-3 hours, then the reaction mixture was quenched with a saturated NH.sub.4 C.sub.1 solution. The combined organic layers were dried with EtOAc EtOAc (EtOAc m. The material (0.488 g) was taken directly to the next step. Intermediate 34 methylhexahydroacridin-3-ol 133151 101 - 200906818 3-hydroxy_3_methylpyrene and soil] TI 虱 in 5 ml of decyl alcohol Adding HC HCl (1 〇 ml) in n nights, and adding the reactants at room temperature (four) for one hour. Then, the reaction mixture was concentrated under reduced pressure, and dried under reduced pressure to give the title compound. Intermediate 35 (R)-N, N-dimethyl phen _3 stomach carbamide

於DMF (5毫升）中之（RM_(第三·丁氧幾基）嗎福琳讀酸 (0.25克，1·〇8宅莫耳）内，添加二曱胺（1 62毫升，3 %毫莫 、DIPEA(0_566 毫升，3·24 毫莫耳）及HATU(〇452 克，ιΐ9毫莫 耳）。將反應混合物在室溫下攪拌過夜。以飽和^^丨溶液 與醋酸乙酯萃取反應混合物。收集有機層，以寧4脫水乾 燥’過濾，及濃縮，獲得粗製殘留物，使其在·系統上 純化(100%己⑥至職醋酸乙酯）。&quot;所要之溶離份，並 溶於甲醇中，於其中添加10毫升在乙鱗溶液中之2Ν Ηα。 將反應混合物在室溫下㈣2小時，接著濃縮反應混合物， 而得標題化合物，將其直接使用於下一步驟中。 中間物36 (R)-N，N-二甲基-2-(嗎福啉_3_基）乙醯胺 於DMF (5毫升）中之⑻_2·(4_(第三_丁氧羰基）嗎福啉各基） 醋鷇（0.35克，1_43毫莫耳）内，添加二甲胺（214毫升，428毫 莫耳）、DIPEA (0.498 毫升，2.85 毫莫耳）及 HATU (〇 597 克，丨 57 毫莫耳）。將反應混合物在室溫下攪拌過夜。以飽和 溶液與醋酸乙酯萃取反應混合物。收集有機層，以MgS〇4 133151 -102, 200906818In DMF (5 ml) (RM_(T3·butoxymethyl)), the acid was read (0.25 g, 1 〇8 house Mo), and diamine was added (1 62 ml, 3% Mo, DIPEA (0_566 ml, 3·24 mmol) and HATU (〇 452 g, ι 9 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with saturated ethyl acetate and ethyl acetate. The organic layer was collected, dehydrated and dried with Ning 4, and concentrated to obtain a crude residue, which was purified on a system (100% of ethyl acetate). &quot; In methanol, 10 ml of 2 Η 在α in hexanes solution was added thereto. The reaction mixture was stirred at room temperature (d) for 2 hours, then the reaction mixture was concentrated to give the title compound, which was used directly in the next step. (R)-N,N-Dimethyl-2-(morpholine-3-yl)acetamide (8)_2·(4_(T-butoxycarbonyl)fosfoline in DMF (5 ml) Base vinegar (0.35 g, 1_43 mmol), add dimethylamine (214 ml, 428 mmol), DIPEA (0.498 mL, 2.85 mmol) and H ATU (〇 597 g, 丨 57 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was extracted with a saturated solution and ethyl acetate. The organic layer was collected to MgS 〇 4 133151 -102, 200906818

脫水乾燥，過濾、，及濃縮，獲得粗製殘㈣，使立在腦 系統上純化（職己院至臟醋酸乙酯）。收集所要之溶離 份’並溶於甲醇中’於其中添加1〇毫升在乙醚溶液中之2N HC卜將反應混合物在室溫下_2小時，接著濃縮反應混 合物，而得標題化合物，將其直接使用於下一步驟中。 中間物37 (R) -N-甲基嗎福琳_3_幾酿胺 「 於DMF (5毫升）中之（R)_4_(第三_丁氧獄基）嗎福淋_3叛酸 (〇.431克，1.86毫莫耳）内，添加曱胺（2 8〇毫升，$ %毫莫耳）、 DIPEA (0.651毫升，3.73毫莫耳）及似见（〇 78〇克，2 〇5毫莫 耳）將反應此合物在室溫下攪拌過夜。以飽和]^4(：1溶液 與醋酸乙酯萃取反應混合物。收集有機層，以MgS〇4脫水乾 燥’過渡，及濃縮，獲得粗製殘留物，使其在ISC〇系統上 純化（100%己烷至100%醋酸乙酯）。收集所要之溶離份並 /谷於甲醇中，於其中添加1〇毫升在乙醚溶液中之讯^。 ( 將反應混合物在室溫下攪拌2小時，接著濃縮反應混合物’ 而得標題化合物，將其直接使用於下一步驟中。 中間物38 (S) -6-氣-N2-(5-環丙基-1H-吡唑_3_基）_]^4_(1_(5_氟基嘧啶_2基）乙 基）-1，3,5-三 p井-2,4-二胺 使用類似關於中間物17合成所述之程序，使4,6_二氯_N_(5_ 環丙基-1H-吡唑-3-基）-1，3,5-三畊_2_胺（中間物54)與（lS)-l-(5-氟 基嘧啶-2-基）乙胺鹽酸鹽（中間物5)反應，提供標題化合物。 LC-MS ： 376 [M+H]+. 133151 -103- 200906818 中間物39 2七、氫p比咬·2_基）乙猜鹽酸鹽 使2~(經甲基）六氫Ρ比σ定_1_教酿笛一丁此“ ^ 熳I第二-丁酯（400毫克，1.86毫 莫耳）溶於DCM(3毫升）中，並將Et3N(〇5i8毫升，π毫莫 耳)添加至其中。使混合物冷卻至吖，此時，在屹下逐滴 添加職（3毫升）中之Ts_cl(531毫克，2·79毫莫耳）。將反應 混合物於環境溫度下㈣過夜。以卿稀釋，且將有機相 以吒0洗滌（2x)’脫水乾燥，及在減壓下蒸發，獲得油狀物。 使此油溶於DMSO (5毫升）中，並添加恤^^ (273毫克，557 毫莫耳）。將反應混合物在8(rc下加熱48小時。使液相於 Et0Ac/H20之間分離。將有機層以h2〇洗務（2χ)，脫水乾燥， 及在減壓下蒸發，獲得油狀物。使此油溶於Me〇H (3毫升） 中，並添加HC1 (2M，在醚中，4毫升，8.00毫莫耳）。將反 應物於室溫下攪拌2小時，及在真空中蒸發，而得標題產物。 中間物40 6-氣-N2-(l-(3,5-二氟吡啶_2·基）乙基π4#·甲基-1H_吡唑_3_基)_ 1，3,5-三畊-2,4-二胺 使4,6-二氣-：^-(5-甲基-11^吡唑-3-基）-1,3,5-三畊-2-胺（中間物 18，1.409克，5_75毫莫耳）與ι_(3,5-二氟吡啶-2-基）乙胺（中間 物105，1克，6.32毫莫耳）溶於乙醇（16·42毫升）中，並添加 ΤΕΑ(1.602毫升，11.50毫莫耳）。然後，將反應物在25°c下授 拌過夜。使反應混合物於真空中濃縮，留下灰白色固體 (4.649克）。使此物質藉ISCO純化（0-10% MeOH/DCM)。收集標 題化合物’為黃色固體（2.195克）。 133151 •104- 200906818 LC-MS ： 367 [M+H]+ 中間物41 6_氣-N2-(l-(3,5-二氟吡唆_2_基）_2_甲氣甚 迅” T乳丞乙基）_N4_(5_甲基_m 咐唑-3-基）-1，3,5_三畊-2,4-二胺 在〇°C下，使4,6-二氯·Ν_(5·甲基_1H_吡唑_3·基）]3 5_三畊2 胺（中間物18，例毫克，2·24毫莫耳⑷似二氟咐咬_2_ 基）-2-甲氧基乙胺（中間物1〇2，422毫克，224毫莫耳）溶於乙 醇（6_407毫升）中，並添加TEA (0.938毫升，6.73毫莫耳）。然 後，將反應物在攻下授拌過夜。接著，使反應現合㈣ 真空中濃縮’冑下黃色固體⑽毫克）。使此物質藉咖純 化（0-10%MeOH/DCM)。在真空中濃縮溶離份，提供標題化合 物’為白色固體（653毫克）。 LC-MS ： 397 [M+H]+. 中間物42 (R)-6-氣-N2-(1-(3,5-二氟吡啶_2_基）_2_甲氧基乙基）_ν4·(5甲基 -1Η-吡唑-3-基）-1,3,5-三啡 _2,4-二胺 使4’6-二氯-N-(5-甲基_iH_吡唑_3_基）_ΐ53,5_三畊_2_胺（中間物 18，I·%4克，8.01毫莫耳）與氟吡啶_2_基）_2甲氧 基乙銨（R)-苯乙醇酸鹽（中間物95，3.0克，8.82毫莫耳）溶於 乙醇（22·90毫升）中，並添加TEA (4.47毫升，32.06毫莫耳）。 然後，將反應物在25t下攪拌過夜。接著，於真空中濃縮 反應混合物’留下淡黃色半固體（7.120克）。然後，使此物 質以〜L5克批料藉1SCO純化（50% EtOAc/己烷’ 10分鐘，60% EtOAc/己烷’ 20分鐘’ 70% EtOAc/己烷，1〇分鐘）。在真空中 133151 200906818 濃縮溶離份，以64%產率提供標題化合物，為白色固體（2 〇24 克）。 1H NMR (300 MHz, MeOD) δ ppm 8.38 (s, 1H) 7.58 (td, 1H) 6.22-6.55 (m，1H) 5_71 (t，1H) 3.63-3.95 (m，2H) 3_35 (s，3H) 2_26 (寬廣8_，311)· LC-MS ： 397 [M+H]+ 中間物43 (R)-3-(甲基確醯胺基甲基）嗎福淋_4_羧酸第三_丁酯 於10毫升小玻瓶中，將氣化甲烷磺醯（0.170毫升，2 2〇毫 莫耳）與（R)-3-(胺基甲基）嗎福啉-4-羧酸第三丁 s旨（〇 396克， 1.83毫莫耳）在THF (3.66毫升）中合併，獲得無色溶液。將反 應物於23°C下攪拌30分鐘，並倒入10% K：2HP〇4水溶液（20毫 升）中’及以EtOAc (2 X 20毫升）沖洗。合併有機溶離份，並 以鹽水（20毫升）沖洗’以Na2S〇4脫水乾燥，過濾，及在減壓 下漢縮，產生標題化合物，為橘色油。 中間物44 (R)-1NK嗎福啉_3_基甲基）甲烷磺醯胺鹽酸鹽 使（R)-3-(曱基磺醯胺基甲基）嗎福啉_4_羧酸第三_丁醋（中 間物43，539毫克，1_83毫莫耳）溶於MeOH (1.831毫升）中， 並添加二氧陸圜中之4M HC1 (1.831毫升，7.32毫莫耳）。然後， 將反應物在25°C下攪拌。2小時後，於真空中濃縮反應混合 物’留下標題化合物，為橘色固體（407毫克）。 中間物45 (R)-3-((乙氧羰基胺基）甲基）嗎福啉_4_羧酸第三·丁酯 於10毫升小玻瓶中，將氯曱酸乙酯（0.330毫升，3.36毫莫 133151 -106- 200906818 2)與（R)-3-(胺基甲基）嗎福啦领酸第三_丁 g旨（〇 6〇5克，謂 毫莫耳）在THF (5.59毫升）中合併，獲得無色溶液。將反應 物於23。(：下授拌3G分鐘，並倒人祕κ2Ηρ〇4水溶液㈣毫升） 中，且以EtOAc (2 X 20毫升）沖洗。合併有機溶離份，並以 鹽水（20毫升）沖洗，以Ν%5〇4脫水乾燥，過濾，及在減壓下 濃縮’產生標題化合物，為橘色油。 中間物46 (R)-嗎福琳_3_基甲基胺基甲酸乙g旨鹽酸鹽 使（R)-3-((乙氧羰基胺基）甲基）嗎福啉_4_羧酸第三-丁酯（中 間物45，807毫克，2·80毫莫耳）溶於Me〇H (2799毫升）中， 並添加二氧陸圜中之4MHC1(28〇毫升，112〇毫莫耳）。然後， 將反應物在25。〇下攪拌。2小時後，於真空中濃縮反應混合 物，留下標題化合物，為灰白色黏性固體（445毫克）。 中間物47 (R)-(4-(4-甲氧基芊基）嗎福p林_3_基）甲醇 於已溶於DMF (30毫升）中之（R&gt;嗎福啉_3_基甲醇鹽酸鹽 (1.7克’ 11毫莫耳）之溶液内，添加K2C〇3(3 82克，27毫莫 耳），接著為1-(溴基曱基)-4-甲氧基苯（2 33克，u 6毫莫耳）， 並在室溫下激烈攪拌，將混合物於環境溫度下攪拌過夜。 以EtOAc稀釋混合物，且將有機相以吒〇洗滌，及脫水乾燥。 藉 ISC0 純化（CH2 CVCH3 OH/NH4 OH : 100/0— 100/3/0.3)，獲得標 題化合物（2_65克）。 LC-MS ： [M+H] = 238 JH NMR (CH2C12) 5 7.21 (d, 2H), 6.87 (d, 2H), 4.04 (d, 1H), 3.88 (dd, 133151 -107- 200906818 1H)，3.78 (s，3H), 3·70 (m，1H)，3·60 (m，1H)，3.47 (m, 2H)，3.19 (s, 1H)， 187 (d, 1H), 2.67 (m, 1H), 2.51 (m, 2H), 2.26 (m, 1H). 中間物48 4·甲苯磺酸(S)-(4-(4·甲氧基苄基）嗎福啉_3_基）甲酯 /. \Dehydrated, filtered, and concentrated to obtain a crude residue (IV), which is purified on the brain system (from the hospital to the dirty ethyl acetate). The desired fractions were collected and dissolved in methanol. 1 mL of 2N HCl in diethyl ether solution was added. The reaction mixture was allowed to stand at room temperature for 2 hours, then the reaction mixture was concentrated to give the title compound. Used in the next step. Intermediate 37 (R) -N-Methyl-Florin _3_ 酿 胺 "" in DMF (5 ml) (R) _4_ (third _ butyl phenyl) rifampin _3 〇.431 g, 1.86 mmol), add guanamine (28 ml, $% millimolar), DIPEA (0.651 ml, 3.73 mmol) and resemble (〇78〇g, 2 〇5) The reaction mixture was stirred at room temperature overnight. The reaction mixture was extracted with a saturated solution of ethyl acetate. The organic layer was collected, dried and dried with &lt;RTI ID=0.0&gt; The crude residue was purified on an ISC(R) system (100% hexanes to 100% ethyl acetate). The desired fractions were collected and / / MeOH was added to methanol. (The reaction mixture is stirred at room temperature for 2 hours, then the reaction mixture is concentrated to give the title compound, which is used directly in the next step. Intermediate 38 (S) -6-gas-N2-(5-ring Propyl-1H-pyrazole_3_yl)_]^4_(1_(5-fluoropyrimidin-2-yl)ethyl)-1,3,5-tri-p--2,4-diamine is similar Regarding the procedure for synthesizing the intermediate 17 to make 4,6_dichloro_N_(5 _ cyclopropyl-1H-pyrazol-3-yl)-1,3,5-three tillage _2_amine (intermediate 54) and (lS)-l-(5-fluoropyrimidin-2-yl) Reaction of ethylamine hydrochloride (Intermediate 5) afforded the title compound. LC-MS: 376 [M+H]+. 133151 -103- 200906818 Intermediate 39 2 VII, Hydrogen p ratio bite 2_base) The hydrochloride salt makes 2~(methyl)hexahydroindole σ _1 _ _ _ _ _ _ _ _ 第二 I second-butyl ester (400 mg, 1.86 mmol) dissolved in DCM (3 ml In the middle, Et3N (〇5i8 ml, π mmol) was added thereto. The mixture was cooled to 吖, at this time, Ts_cl (531 mg, 2.79) in the occupation (3 ml) was added dropwise under the armpits. The reaction mixture was allowed to stand at ambient temperature (4) overnight, diluted with EtOAc, and the organic phase was washed with EtOAc (2×) and dried under reduced pressure to give an oil. In DMSO (5 ml), and added a broth (273 mg, 557 mM). The reaction mixture was heated at 8 (rc) for 48 hours. The liquid phase was separated between Et0Ac/H20. H2 〇 务 (2χ), dehydrated and dried, and evaporated under reduced pressure to obtain an oil. This oil was dissolved in EtOAc (3 mL), EtOAc (EtOAc (EtOAc) The title product was obtained. Intermediate 40 6-Gas-N2-(l-(3,5-difluoropyridin-2-yl)ethyl π4#·methyl-1H-pyrazole_3_yl)_ 1,3 ,5-three tillage-2,4-diamine makes 4,6-diqi-:^-(5-methyl-11^pyrazol-3-yl)-1,3,5-three tillage-2- The amine (intermediate 18, 1.409 g, 5_75 mmol) and i-(3,5-difluoropyridin-2-yl)ethylamine (intermediate 105, 1 g, 6.32 mmol) were dissolved in ethanol (16· In 42 ml), add ΤΕΑ (1.602 ml, 11.50 mmol). The reaction was then allowed to stir overnight at 25 °C. The reaction mixture was concentrated in vacuo to give a white crystallite. This material was purified by ISCO (0-10% MeOH / DCM). The title compound was collected as a yellow solid (2.195 g). 133151 •104- 200906818 LC-MS : 367 [M+H]+ Intermediate 41 6_Gas-N2-(l-(3,5-Difluoropyridin-2-yl)_2_甲气快迅” T Lactate ethyl)_N4_(5-methyl-m oxazol-3-yl)-1,3,5_tri-n--2,4-diamine at 4 ° C, 4,6-dichloro Ν_(5·methyl_1H_pyrazole_3·yl)]3 5_three tillage 2 amine (intermediate 18, mg, 2.24 millimolar (4) like difluoride bite_2_ base)-2 -Methoxyethylamine (intermediate 1 〇 2, 422 mg, 224 mmol) dissolved in ethanol (6-407 mL) and added TEA (0.938 mL, 6.73 mmol). The mixture was stirred overnight. Next, the reaction was combined (4) EtOAc (EtOAc) EtOAc (EtOAc) 'A white solid (653 mg). LC-MS: 397 [M+H]+. Intermediate 42 (R)-6- gas-N2-(1-(3,5-difluoropyridine-2-yl) _2_methoxyethyl)_ν4·(5methyl-1Η-pyrazol-3-yl)-1,3,5-trimorph-2,4-diamine makes 4'6-dichloro-N- (5-methyl_iH_pyrazole_3_yl)_ΐ53,5_three tillage_2_amine (intermediate 18, I·% 4 g, 8.01 millimoles) and fluoropyridine-2-yl)-2-methoxyethylammonium (R)-phenylglycolate (intermediate 95, 3.0 g, 8.82 mmol) dissolved in ethanol (22.90 ml) TEA (4.47 ml, 32.06 mmol) was added. The reaction was then stirred at 25t overnight. Then the reaction mixture was concentrated in vacuo to leave a pale yellow semi solid (7.120 g). Purified by 1 SCO in ~L5 g batch (50% EtOAc / hexanes &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&&&&&&&& The title compound was obtained as a white solid (2 〇24 g). NMR (300 MHz, MeOD) δ ppm 8.38 (s, 1H) 7.58 (td, 1H) 6.22-6.55 (m,1H) 5_71 (t,1H) 3.63-3.95 (m,2H) 3_35 (s,3H) 2_26 (broad 8_,311)· LC-MS : 397 [M+H]+ Intermediate 43 (R)-3-(A醯 醯 醯 甲基 ) _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ -3-(aminomethyl)norfosolin-4-carboxylic acid tertidine 396 g, 1.83 mmol) were combined in THF (3.66 mL) to give a colorless solution. The reaction was stirred at 23 &lt;0&gt;C for 30 min and poured into a 10% K: 2 EtOAc solution (20 mL) and rinsed with EtOAc (2 X 20 mL). The organic extracts were combined and dried with EtOAc EtOAc EtOAc EtOAc Intermediate 44 (R)-1NK morpholino _3_ylmethyl)methanesulfonamide hydrochloride (R)-3-(mercaptosulfonylaminomethyl)norfosin-4-carboxylic acid The third _ vinegar (intermediate 43, 539 mg, 1 - 83 mmol) was dissolved in MeOH (1.831 mL) and 4M HCl (1.831 mL, 7.32 mmol) in dioxane. The reaction was then stirred at 25 °C. After 2 hours, the reaction mixture was evaporated mjjjjjjjjjj Intermediate 45 (R)-3-((ethoxycarbonylamino)methyl)norfosin_4_carboxylic acid tert-butyl ester in 10 ml vial, ethyl chlorodecanoate (0.330 ml , 3.36 mA 133151 -106- 200906818 2) with (R)-3-(aminomethyl) sulphonic acid third _ ding g (〇 6 〇 5 g, said millimolar) in THF ( Combined in 5.59 ml), a colorless solution was obtained. The reaction was at 23. (: Mix for 3 g minutes and pour into a solution of κ2Ηρ〇4 in water (4 ml) and rinse with EtOAc (2×20 mL). The combined organic extracts were combined with EtOAc EtOAc EtOAc. Intermediate 46 (R)-Nalfolin_3_ylmethylaminocarbamic acid B g hydrochloride salt (R)-3-((ethoxycarbonylamino)methyl)norfosin_4_carboxylate The acid tert-butyl ester (intermediate 45, 807 mg, 2.80 mmol) was dissolved in Me〇H (2799 ml) and added to 4 MHC1 in dioxane (28 ml, 112 min. ear). Then, the reactant was at 25. Stir under the armpits. After 2 hours, the reaction mixture was evaporated mjjjjjjjjj Intermediate 47 (R)-(4-(4-methoxyindolyl) ruthenium _3_yl)methanol was dissolved in DMF (30 ml) (R &gt; In a solution of methanolic hydrochloride (1.7 g of '11 mmol), K2C〇3 (3 82 g, 27 mmol) was added followed by 1-(bromomethyl)-4-methoxybenzene ( 2 33 g, u 6 mmol), and stirred vigorously at room temperature, the mixture was stirred at ambient temperature overnight. The mixture was diluted with EtOAc, and the organic phase was washed with hydr. CH2CVCH3 OH/NH4 OH: 100/0 - 100/3/0.3), ield of the title compound (2: 65 g). LC-MS: [M+H] = 238 JH NMR (CH2C12) 5 7.21 (d, 2H), 6.87 (d, 2H), 4.04 (d, 1H), 3.88 (dd, 133151 -107- 200906818 1H), 3.78 (s, 3H), 3·70 (m, 1H), 3·60 (m, 1H) , 3.47 (m, 2H), 3.19 (s, 1H), 187 (d, 1H), 2.67 (m, 1H), 2.51 (m, 2H), 2.26 (m, 1H). Intermediate 48 4·Toluene Acid (S)-(4-(4.methoxybenzyl)morpholine-3-yl)methyl ester /.

將DCM (20毫升）中之（R)-(4-(4-曱氧基芊基）嗎福啉_3_基）甲 醇（中間物47，1.7克，7.16毫莫耳）以Et3N (3.99毫升，28.66 宅莫耳）處理’並將所形成之溶液於〇它下攪拌。分次添加 氯化4-甲苯+磺醯(2.73克，14.33毫莫耳），且將混合物在室 溫下攪拌1小時。使反應混合物於吒0與CH2C12之間作分液 處理。分離有機相，並以N^SO4脫水乾燥，及在減壓下蒸 發揮發性物質，獲得標題化合物。 中間物49 (R)_4-(4-甲氧基芊基)-3-(甲氧基甲基）嗎福琳 於4-甲苯石頁酸（S)-(4-(4-甲氧基苄基）嗎福啉各基）曱酯（中間 物48，1.2克，3.07毫莫耳）在無水CH3〇H (1〇毫升）中之溶液 内，添加粉末Na〇CH3(〇.497克，9·2〇毫莫耳）。將反應混合物(R)-(4-(4-decyloxyfluorenyl)fosfolin-3-yl)methanol (intermediate 47, 1.7 g, 7.16 mmol) in Et.sub.3 (. ML, 28.66 house Moule) was treated 'and the resulting solution was stirred under it. 4-Methyl chloride + sulfonium chloride (2.73 g, 14.33 mmol) was added in portions, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was partitioned between 吒0 and CH2C12. The organic phase was separated, dried over EtOAc (EtOAc) Intermediate 49 (R) 4-(4-methoxyindolyl)-3-(methoxymethyl)fosfosin in 4-toluene succinic acid (S)-(4-(4-methoxy) Add benzyl Na〇CH3 (〇.497 g, benzyl) phenanthroline) decyl ester (intermediate 48, 1.2 g, 3.07 mmol) in anhydrous CH 3 〇H (1 mL). 9·2〇mole). Reaction mixture

在室溫下攪拌1小時’然後於8〇。。下加熱4小時。在CHA 與Η2〇之間分配，並使合併之有機相於減壓下濃縮。藉㈣ 純化（己㈣2〇，具有1%Et3N = 1_—_2g),料標題化 合物（0.380 克，49.3%)。 LC-MS ： [M+H] = 252 4 NMR (CD2C12) 5 7_27 (d …μ 凡 2Η)，6.87 (d, 2Η)，4.01 (d，1Η)，3.78 (s， 3H), 3_62 (m，2H)，3·44 (m，3H)，3 32 is W、1 % μ 1U、〇 (s，3H)，3.26 (d，1H)，2.62 (m，2H)， 2.19 (m, 1H). ’ 133151 -108- 200906818 中間物50 (R) -3-(甲氧基甲基）嗎福淋鹽酸鹽 使(R)-4-(4-甲氧基苄基）-3-(曱氧基甲基）嗎福啉（中間物49， 440毫克，1.75毫莫耳）在CH3 OH (5毫升）中之溶液脫氣，並 添加Pd(OH)2/C (20% w，40亳克）。使所形成之混合物接受氲 大氣，及攪拌48小時。經由矽藻土過濾觸媒，並將所形成 之濾液以HC1處理。於攪拌30分鐘後，在減壓下蒸發揮發性 物質’獲得標題化合物。 中間物51 (S) -4_(4-甲氧基字基）嗎福”林_3_缓甲路 使DCM (8毫升）中之DMSO (1,669毫升，23.52毫莫耳）溶液 於-78°C下冷卻，並逐滴添加DCM (2毫升）中之氣化草醯 (1.029毫升，11.76毫莫耳）。將混合物於_7fC下攪拌15分鐘， 此時，在30分鐘内，添加（R)_(4_(4_曱氧基芊基）嗎福啉_3_基） 甲醇（中間物47，0.93克，3.92毫莫耳）在CH2C12(2毫升）中之 溶液。將所形成之混合物於-78°c下攪拌16小時，且在_78〇c 下逐滴添加EtgN (6.56毫升’ 47.03毫莫耳）。使所形成之混合 物溫熱至室溫，歷經30分鐘。使混合物於CH2C12與飽和 NaHC03水溶液之間作分液處理。分離有機相，及在減壓下 移除揮發性物質，獲得標題化合物。 中間物52 (S)-3·(二氟甲基）_4_(4_曱氧基苄基）嗎福啉Stir at room temperature for 1 hour' then at 8 Torr. . Heat for 4 hours. It was partitioned between CHA and Η2〇, and the combined organic phases were concentrated under reduced pressure. Purified by (iv) ((4) 2〇 with 1% Et3N = 1_-2 g), title compound (0.380 g, 49.3%). LC-MS : [M+H] = 252 4 NMR (CD2C12) 5 7_27 (d ... μ 2 Η), 6.87 (d, 2 Η), 4.01 (d, 1 Η), 3.78 (s, 3H), 3_62 (m , 2H), 3·44 (m, 3H), 3 32 is W, 1 % μ 1U, 〇 (s, 3H), 3.26 (d, 1H), 2.62 (m, 2H), 2.19 (m, 1H) ' 133151 -108- 200906818 Intermediate 50 (R) -3-(Methoxymethyl)ofaline hydrochloride makes (R)-4-(4-methoxybenzyl)-3-(曱Deoxygenation of oxymethyl)morphine (intermediate 49, 440 mg, 1.75 mmol) in CH3 OH (5 mL) and Pd(OH)2/C (20% w, 40 亳) Gram). The resulting mixture was allowed to stand in the atmosphere and stirred for 48 hours. The catalyst was filtered through diatomaceous earth and the resulting filtrate was treated with HCl. After stirring for 30 minutes, the volatile substance was evaporated under reduced pressure to give the title compound. Intermediate 51 (S) -4_(4-Methoxy-based) 福福"林_3_ 延甲路 DMSO (1,669 ml, 23.52 mmol) solution in DCM (8 ml) at -78° Cool down at C, and add the vaporized grasshopper (1.029 ml, 11.76 mmol) in DCM (2 mL) dropwise. The mixture was stirred at _7fC for 15 minutes, at this time, within 30 minutes, added (R) a solution of methanol (intermediate 47, 0.93 g, 3.92 mmol) in CH.sub.2Cl.sub.2 (2 mL). Stir at -78 ° C for 16 hours, and add EtgN (6.56 mL '47.03 mmol) dropwise at _78 ° C. The resulting mixture was allowed to warm to room temperature over 30 min. The mixture was treated with a saturated aqueous solution of NaHCO3. The organic phase was separated, and the volatile material was removed under reduced pressure to give the title compound. Intermediate 52 (S) -3 · (difluoromethyl) _4_ (4 曱Oxybenzyl)morphine

使CH2C12(12毫升）中之（s)-4-(4-甲氧基苄基）嗎福啉_3_羧甲 链（中間物51 ’ 〇_922克，3.92毫莫耳）冷卻至〇。(：，並於〇-5°C 133151 -109- 200906818 下逐滴添加DAST。將反應混合物在室溫下攪拌過夜。使混 合物於DCM/飽和NaHC〇3水溶液之間作分液處理。將有機層 以玛0洗滌，脫水乾燥，及在減壓下蒸發揮發性物質，獲 得殘留物。藉ISCO純化（己烧/Et〇Ac，具有1%Et3N=i〇〇/〇— 100/30)，獲得標題化合物（280毫克）。 LC-MS ： [M+H] = 258. 中間物53 (S)-3-(二氟甲基）嗎福啉鹽酸鹽 使（S)-3-(一氟曱基)-4-(4-甲氧基苄基）嗎福^林（中間物52，257 窀克，1.00毫莫耳）在CH3〇H(5毫升）中之溶液脫氣，並添加 Pd(OH)2/C (20% w，50毫克）。使所形成之混合物接受氫大氣， 且攪拌48小時。經由矽藻土過濾觸媒，並將所形成之濾液 以HC1處理。於攪拌30分鐘後，在減壓下蒸發揮發性物質， 獲得標題化合物。 中間物54 二氣-N-(5-環丙基-1H-吡唑_3_基）_ι，3,5_三啡_2_胺 使5-環丙基-1H-峨峻-3-胺（200毫克，丨.63毫莫耳）溶於乙醇 (4.648毫升）中，並冷卻至(TC。然後慢慢添加2,4,6_三氯m 三畊（300毫克，1_63毫莫耳）與tea (〇·453毫升，3·25毫莫耳）。 接著，將反應物於25°C下攪拌過夜。使反應混合物冷卻至〇 C，及過遽。收集淡頁色固體（I%毫克）。亦在真空中濃縮 濾液，並藉ISCO純化（15-50% EtOAc/己烷）。於真空中濃縮溶 離份，提供標題化合物，淡桃色固體（48毫克）。 LC-MS ： 272 [M+H]+ 133151 -110· 200906818 中間物55 (R)-6-氣-N2-(5-環丙基_1Η·吡唑_3_基）_n4_(1_(3,5_二氟吡啶冬基 2-甲氧基乙基）-1，3,5-三井-2,4-二胺 使4,6-—氯-N-(5-環丙基-1H-吡唑_3•基）畊_2_胺（中間 物54，184毫克，〇_68毫莫耳）與氟吡啶_2基)_2甲 氧基乙叙（R)-本乙醇酸鹽（中間物95，254毫克，0.75毫莫耳） /谷於乙醇（1.939毫升）中，並添加TEA (〇 378毫升，2 71毫莫 耳）。然後，將反應物在25°C下檀拌過夜。接著，於真空中 》辰縮反應混合物，留下淡黃色半固體（641毫克）。使此物質 藉 ISCO 純化（50% EtOAc/ 己烷，1〇 分鐘，6〇% Et〇Ac/ 己烷，2〇 分鐘，70% EtOAc/己烷，1〇分鐘）。在真空中濃縮溶離份， 提供標題化合物，為白色固體（2〇1毫克）。 LC-MS ： 423 [M+H]+. 中間物56 1-(3,5-二氟-4-(三甲基矽烷基）吨啶基）_2乙氧基乙酮 於3,5-二氟吡啶（2.99克，25.98毫莫耳）在四氫呋喃（87毫升） 中之溶液内，在-78t：下，添加LDA (14.43毫升，25.98毫莫 耳）。將所形成之混合物於此溫度下攪拌1小時，此時，添 加TMS-C1 (3.32毫升，25·98毫莫耳）。添加另外之LDA (14.43 毫升’ 25.98毫莫耳），並將混合物在_78它下授拌1小時，此 時’以一份添加2-乙氧基醋酸乙酯（3 54毫升，25 98毫莫耳）。 使混合物溫熱至室溫，歷經3〇分鐘，此時，添加C1 (飽 和）。以EtOAc稀釋混合物，並將有機相以〇、鹽水洗滌， 及脫水乾燥。在減壓下蒸發，獲得帶有顏色油。藉管柱層 -Ill - 133151 200906818 析純化（10%-30% EtOAc/己烷），獲得二氟斗(三曱基矽烷 基）吡啶-2-基）-2-乙氧基乙酮，為油狀物，其係於靜置時空氣 固化成黃褐色固體（5·3克）。 LC-MS ： 274 [Μ+Η]+ 中間物57 1-(3,5-一氟咐咬_2-基）-2-乙氧基乙嗣 使1-(3,5-二氟·4-(三甲基矽烷基）,比啶_2_基）_2•乙氧基乙酮 (中間物56，2·11克，7.72毫莫耳）溶於HC1 (2〇毫升，刚〇〇 毫莫耳）（5N)中，並將所形成之混合物加熱至6〇°c，歷經2 小時。使混合物冷卻至室溫’此時，慢慢添加NaHc〇3水溶 液（飽和）直到pH〜8為止。將水相以Et〇Ac萃取（3χ)，脫水乾 燥（MgS04)，及在減壓下蒸發揮發性物質，獲得工似二氣吨 咬-2-基)·2_乙氧基乙酮’為黃色油似克），將其使用於後續 步驟中’未進行任何進一步純化。 LC-MS : 200 [M-HJ+ 中間物58 1-(3,5-一氟V比咬基）_2_乙氧基乙網肪 於Κ3,5-二氣峨咬-2-基)·2·乙氧基乙酮（中間物57，15克， 毫莫耳）在乙醇(37.3毛升）中之溶液内，添加經胺鹽酸鹽 (〇.別克’ 7_46毫莫耳），接著為邮（1㈣毫升，以6毫莫 耳）。將所形成之帶有顏色溶液於抑下攪拌過夜。在減壓 下蒸發揮發性物質’並使所得之殘留物再溶於中。將 有機層以帥、鹽水洗滌，及脫水乾燥。藉⑽純化（1〇%_3〇% 驗/己烧）’提供H3,5_二氣棒2•基似氧基乙_，為 133151 -112- 200906818 黃色固體。將標題化合物以段2〇研製，並過濾，而得粒狀 白色固體。 1 H NMR (300 MHz，MeOD) (5 ppm 1.06 (t，3H) 3_49 (q，J = 7.03 Hz, 2H) 4.44 (s, 1H) 4.74 (s, 2H) 7.56-7.73 (m, 1H) 8.30-8.52 (m, 1H). 中間物59 1-(3,5-二氟吡啶-2·基）-2-乙氧基乙胺鹽酸鹽 於（Z)-l-(3,5-二氟吡啶_2-基）-2-乙氧基乙酮肟（中間物58，46〇 毫克，2.13毫莫耳）在水中之懸浮液内，以一份添加氫氧化 銨（829微升，21.28毫莫耳）與醋酸銨（197毫克，2 55毫莫耳）。 將混合物加熱至65°C，並以一份添加鋅（557毫克，8 51毫莫 耳）。將混合物在此溫度下攪拌3小時，此時，使其經由石夕 藻土過濾，且以EtOAc洗滌。以鹽水洗滌Et〇Ac萃液，及脫 水乾燥（MgS〇4)。使溶劑在減壓（水浴&lt;3〇°c )下蒸發至一體積 (〜20耄升）’並添加1〇毫升在二氧陸園中之Ηα (4N)。將混合 物於室溫下攪拌30分鐘。蒸發揮發性物質，獲得1(3,5二氟 叶匕咬-2-基）-2-乙氧基乙胺鹽酸鹽，為灰白色固體。 lB. NMR (300 MHz, MeOD) 5 ppm 1.23 (t, 3H) 3.50-3.68 (m, 2H) 3.72-3.93 (m, 2H) 4.82-4.94 (m, 1H) 7.65-7.86 (m, 1H) 8.45-8.53 (m, 1H) 中間物60 6-氣-N2-(l-(3,5-二氟吡啶_2_基）_2_乙氧基乙基）_n4_(5甲基_ιη· 吡唑-3-基）-1,3,5-三畊·2,4-二胺 於4,6-二氯-Ν-(5-甲基-1Η-吡唑-3_基）_1Λ5_三畊_2_胺（中間物 18，0.522克，2_13毫莫耳）在乙醇（7.1〇毫升）中之溶液内在 25°C下，添加1-(3,5-二氟吡啶_2_基）_2_乙氧基乙胺鹽酸鹽（中間 133151 •113· 200906818 物59，0.508克，2.13毫莫耳）與DIpEA (丨116毫升，6 39毫莫 耳）。將所形成之混合物於環境溫度下攪拌12小時。在減壓 下移除揮發性物質，並使殘留物藉ISC〇純化（5〇% Et〇Ac/己 烷—100〇/〇EtOAc)，而得標題化合物，為白色固體。 LC-MS : 411 [M+H]+. 中間物61 3-[(第三-丁基亞磺醢基）胺基】_3·(5氟基吡啶：基）丙酸乙酯 於LDA (26.7毫升，2Μ溶液，53.4毫莫耳）在無水ΤΒΜΕ (15〇 毫升）中之經攪拌溶液内，在_78。〇及氮大氣下，逐滴添加 EtOAc (4.47克，50.9毫莫耳）在ΤΒΜΕ (2〇毫升）中之溶液。在 攪拌30分鐘後，於其中逐滴添加队[(5_氟基吡啶丨基）亞甲 基]-2-甲基丙烧-2-亞磺醯基醯胺（中間物21，5 8克，25 43毫 莫耳）在ΤΒΜΕ (30毫升）中之溶液。在_78c&gt;c下攪拌2小時（如 藉TLC顯示反應完成）後，藉由飽和氯化銨使反應混合物淬 滅，並溫熱至室溫。分離有機層，且以Et〇Ac萃取（2χ)水層。 使合併之有機層脫水乾燥（NhSO4)，及蒸發，在藉管柱層析 純化（己烷· EtOAc = 50:50)後，提供標題化合物（5 2克，68%)， 為非對映異構物之混合物（較高Rf為主要，較低财為較少）。 LC-MS ： 317 [M+H]+ 中間物62 N-(2-氰基_1_(5_氟基吡啶_2_基）乙基)_2_甲基丙烷_2亞磺醯基醯胺 使用類似關於中間物61合成所述之程序，使^[(丨办卜氟 基吡啶-2-基）亞甲基]-2-甲基丙烷-2-亞磺醯基醯胺（中間物21) 與乙腈反應，提供標題化合物。 133151 -114- 200906818 LC-MS ： 270 [M+H]+ 中間物63 3-胺基-3-(5_氟基p比咬-2-基）丙腈鹽酸鹽 使用類似關於中間物75合成所述之程序，使n-(2-氰基 -1-(5-氟基吡啶-2-基）乙基）-2-甲基丙烷_2_亞磺醯基醯胺（中間 物62)反應，提供標題化合物。 LC-MS ： 219 [M+H]+ 中間物64 N-(l-(5-氟基p比咬-2-基）-2-(三曱基矽烷基）乙基）_2_甲基丙烷_2_ 亞磺醯基醯胺 使用類似關於中間物62合成所述之程序，使n-[(1E)-(5-氟 基吡啶-2-基）亞甲基]-2-曱基丙烷·2_亞磺醯基醯胺（中間物21) 與TMSCI^Li反應’提供標題化合物。 LC-MS ： 317 [M+H]+ 中間物65 H5-氟基吡啶-2-基)-2-(三甲基矽烷基）乙胺鹽酸鹽 使用類似關於中間物75合成所述之程序，使N_(i_(5_氟基 吡啶-2-基）-2-(二甲基矽烷基）乙基）_2_曱基丙烷_2_亞磺醯基醯 胺（中間物64)反應，提供標題化合物。 LC-MS ： 213 [M+H]+ 中間物66 Ν-(1·(5-氟基吡啶-2-基）-2-(甲磺醯基）乙基）_2甲基丙烷_2亞磺 酿基酿胺 使用類似關於中間物61合成所述之程序，使^[(丨印^孓氟 133151 -115- 200906818 基吡啶-2-基）亞甲基]-2-甲基丙烷_2_亞磺醯基醢胺（中間物21) 與二甲颯反應’提供標題化合物。 LC-MS ： 323 [M+H]+ 中間物67 1-(5-氟基比咬-2-基)-2-(甲確酿基）乙胺鹽酸鹽 使用類似關於中間物75合成所述之程序，使N_(i_(5_氟基 吡啶-2-基）-2-(曱磺醯基）乙基）_2_甲基丙烷_2_亞磺醯基醯胺 (中間物66)反應’提供標題化合物。 LC-MS ： 219 [M+H]+ 中間物68 3-(1,1-二甲基乙基亞磺醯基醯胺基)_3(5氟基吡啶_2基）丙醯胺 標題化合物係以N-(2-氰基小(5_氟基吡啶_2_基）乙基）·2_甲基 丙烷-2-亞磺醯基醯胺（中間物62)之合成之副產物獲得。 LC-MS ： 287 [M+H]+ 中間物69 3-胺基-3-(5-氟基p比咬-2_基）丙酿胺鹽酸鹽 使用類似關於中間物7S合成所述之程序，使3_(u •2-基）丙醯胺（中間物68) 乙基亞靖酿基酿胺基）-3-(5-^基p比σ定 反應，提供標題化合物。 LC-MS : 183 [M+H]+ 中間物70 二氟-3-(5-氟基吡啶-2-基）丙 3-[(第三-丁基亞確酿基）胺基]_2,2_二 酸乙酯(s)-4-(4-methoxybenzyl)porphyrin-3-3-carboxymethyl chain (intermediate 51 '〇_922 g, 3.92 mmol) in CH2C12 (12 mL) was cooled to 〇 . (:, and DAST was added dropwise at 〇-5 ° C 133151 -109- 200906818. The reaction mixture was stirred at room temperature overnight. The mixture was partitioned between DCM / sat. NaHC. The layer was washed with MAL0, dehydrated and dried, and the volatile material was evaporated under reduced pressure to give a residue, which was purified by ISCO (hexane/Et〇Ac, with 1% Et3N=i〇〇/〇-100/30). The title compound (280 mg) was obtained. LC-MS: [M+H] = 258. Intermediate 53 (S)-3-(difluoromethyl) Fluoromethyl)-4-(4-methoxybenzyl) oxalate (intermediate 52,257 g, 1.00 mmol) degassed in CH3〇H (5 mL) and added Pd(OH)2/C (20% w, 50 mg). The resulting mixture was subjected to a hydrogen atmosphere and stirred for 48 hours. The catalyst was filtered through celite and the formed filtrate was treated with HCl. After 30 minutes, the volatile material was evaporated under reduced pressure to give the title compound. Intermediates: </RTI> </ RTI> </ RTI> </ RTI> N-(5-cyclopropyl-1H-pyrazole-3-yl)_m,3,5-tri- 2_amine makes 5-cyclopropyl-1H-indole-3-amine (200 mg, 丨. 63 mM dissolved in ethanol (4.648 ml) and cooled to (TC. Then slowly add 2,4,6-trichlorom tri-farming (300 mg, 1_63 mmol) with tea (〇·453 The reaction mixture was stirred at 25 ° C overnight. The reaction mixture was cooled to EtOAc EtOAc (EtOAc). The filtrate was concentrated and purified with EtOAc EtOAc EtOAc (EtOAc) 110· 200906818 Intermediate 55 (R)-6-Gas-N2-(5-cyclopropyl_1Η·pyrazole_3_yl)_n4_(1_(3,5-difluoropyridyl-methylene 2-methoxy Ethyl)-1,3,5-triper-2,4-diamine gives 4,6-chloro-N-(5-cyclopropyl-1H-pyrazole-3-yl) cultivating _2_amine ( Intermediate 54, 184 mg, 〇_68 mmol) and fluoropyridin-2-yl) 2 methoxy ethidine (R)-the present glycolate (intermediate 95, 254 mg, 0.75 mmol) / valley Ethanol (1.939 mL) was added with TEA (〇 378 mL, 2 71 mmol). The reaction was then allowed to stand at 25 ° C overnight. The reaction mixture was triturated in vacuo to give a pale-yellow semi-solid (641 mg). The material was purified by ISCO (50% EtOAc/hexanes, 1 min, 2 min, 70% EtOAc/hexanes, 1 min). The title compound was obtained as a white solid (2·1 mg). LC-MS: 423 [M+H]+. Intermediate 56 1-(3,5-difluoro-4-(trimethyldecyl) oxalyl)-2 ethoxy ketone in 3,5- To a solution of fluoropyridine (2.99 g, 25.98 mmol) in tetrahydrofuran (87 mL) was added LDA (14.43 mL, 25.98 mmol). The resulting mixture was stirred at this temperature for 1 hour, at which time TMS-C1 (3.32 ml, 25.98 mmol) was added. Additional LDA (14.43 ml '25.98 mmol) was added and the mixture was mixed for 1 hour under _78 at this time 'addition of 2-ethoxyacetic acid ethyl ester (3 54 ml, 25 98 m) Moore). The mixture was allowed to warm to room temperature over 3 minutes, at which time C1 (saturated) was added. The mixture was diluted with EtOAc and the org. Evaporation under reduced pressure gave a colored oil. By column chromatography - Ill - 133151 200906818 purification (10% - 30% EtOAc / hexane) to give difluoro fluoro (tridecyl decyl) pyridin-2-yl)-2-ethoxyethyl ketone as An oil which solidified to a yellow-brown solid (5.3 g) upon standing. LC-MS : 274 [Μ+Η]+ Intermediate 57 1-(3,5-Fluoroguanidin-2-yl)-2-ethoxyacetamidine 1-(3,5-difluoro·4 -(trimethyldecyl), pyridine-2_yl)_2•ethoxyketone (intermediate 56, 2.11 g, 7.72 mmol) dissolved in HC1 (2 mL, just 〇〇 In a molar (5N), the resulting mixture was heated to 6 ° C for 2 hours. The mixture was allowed to cool to room temperature. At this time, a NaHc 3 aqueous solution (saturated) was slowly added until pH ～8. The aqueous phase was extracted with Et〇Ac (3χ), dehydrated and dried (MgS04), and the volatile matter was evaporated under reduced pressure to obtain a 2-diox-t-butyl-2-yl)·2-ethoxyethyl ketone Yellow oil like gram) was used in the next step 'without any further purification. LC-MS : 200 [M-HJ+ Intermediate 58 1-(3,5-Fluoro-V ratio bite base)_2_Ethoxyethyl net fat in Κ3,5-dioxin bite-2-yl)·2 · Ethoxyethyl ketone (intermediate 57, 15 g, millimolar) in a solution of ethanol (37.3 liters), added with amine hydrochloride (〇. Buick '7_46 mmol), followed by postal (1 (four) ml, to 6 mmol). The resulting colored solution was stirred overnight. The volatile material was evaporated under reduced pressure and the residue obtained was redissolved. The organic layer was washed with water, brine, and dried. By (10) purification (1〇%_3〇% test/hexilated)' provides H3,5_2 gas bar 2•yloxy-like B, which is 133151 -112- 200906818 yellow solid. The title compound was triturated in EtOAc (EtOAc) elute 1 H NMR (300 MHz, MeOD) (5 ppm 1.06 (t, 3H) 3_49 (q, J = 7.03 Hz, 2H) 4.44 (s, 1H) 4.74 (s, 2H) 7.56-7.73 (m, 1H) 8.30 -8.52 (m, 1H). Intermediate 59 1-(3,5-Difluoropyridin-2-yl)-2-ethoxyethylamine hydrochloride in (Z)-l-(3,5- Add a solution of ammonium hydroxide (829 μl, 21.28) in a suspension of fluoropyridin-2-yl)-2-ethoxyethanone oxime (intermediate 58, 46 mg, 2.13 mmol) in water. Millol) with ammonium acetate (197 mg, 2 55 mmol). Heat the mixture to 65 ° C and add zinc (557 mg, 8 51 mmol) in one portion. Stir the mixture at this temperature. After 3 hours, at this time, it was filtered through celite and washed with EtOAc. Et EtAc was washed with brine, and dried (MgS 〇 4). The solvent was decompressed (water bath &lt; 3 〇 ° c) Evaporate to a volume (~20 liters) and add 1 liter of Ηα (4N) in the dioxane. Stir the mixture at room temperature for 30 minutes. Evaporate the volatiles to obtain 1 (3,5) Difluorophyllin-2-yl)-2-ethoxyethylamine hydrochloride as an off-white solid. lB. NMR (300 MHz, MeOD) 5 ppm 1.23 (t, 3H) 3.50-3.68 (m, 2H) 3.72-3.93 (m, 2H) 4.82-4.94 (m, 1H) 7.65-7.86 (m, 1H) 8.45-8.53 (m, 1H) Intermediate 60 6-Gas-N2-(l-(3,5-difluoropyridin-2-yl)_2-ethoxyethyl)_n4_(5-methyl_ιη·pyrazol-3-yl)-1 , 3,5-three tillage · 2,4-diamine in 4,6-dichloro-indole-(5-methyl-1Η-pyrazole-3-yl)_1Λ5_three tillage_2_amine (intermediate 18, 0.522 g, 2_13 mmol) in a solution of ethanol (7.1 mL) at 25 ° C, adding 1-(3,5-difluoropyridin-2-yl)_2-ethoxyethylamine salt Acid salt (middle 133151 • 113 · 200906818 59, 0.508 g, 2.13 mmol) and DIpEA (丨 116 mL, 6 39 mmol). The resulting mixture was stirred at ambient temperature for 12 hours. The volatiles were removed and the residue was purified EtOAc EtOAcjjjjjjj H]+. Intermediate 61 3-[(Third-butylsulfinyl)amino]_3·(5fluoropyridine:yl)propionic acid ethyl ester in LDA (26.7 ml, 2 Μ solution, 53.4 mmol) Ear) in anhydrous ΤΒΜΕ (15 〇 ml In the stirred solution of the, at _78. A solution of EtOAc (4.47 g, 50.9 mmol) in EtOAc (2 mL) was then evaporated. After stirring for 30 minutes, the group [(5-fluoropyridinyl)methylene]-2-methylpropan-2-sulfinylguanamine (intermediate 21, 58 g) was added dropwise thereto. , 25 43 mM) solution in hydrazine (30 ml). After stirring at _78c &gt;c for 2 hours (as indicated by TLC), the reaction mixture was quenched with saturated ammonium chloride and warmed to room temperature. The organic layer was separated and the aqueous layer was extracted (2 EtOAc) with Et. The combined organic layers were dried <RTI ID=0.0>(</RTI> </RTI> <RTI ID=0.0> A mixture of structures (higher Rf is the main, lower is less). LC-MS : 317 [M+H]+ Intermediate 62 N-(2-Cyano-1~(5-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinyl decylamine Using a procedure similar to that described for the synthesis of intermediate 61, ^[(丨(卜) fluoropyridin-2-yl)methylene]-2-methylpropan-2-sulfinyl decylamine (Intermediate 21 Reaction with acetonitrile to provide the title compound. 133151 -114- 200906818 LC-MS: 270 [M+H]+ intermediate 63 3-amino-3-(5-fluoropyp-biti-2-yl)propanenitrile hydrochloride using similar to intermediate 75 The procedure described was carried out to give n-(2-cyano-1-(5-fluoropyridin-2-yl)ethyl)-2-methylpropan-2-sulfonylguanamine (intermediate 62 The reaction provides the title compound. LC-MS: 219 [M+H]+ Intermediate 64 N-(l-(5-fluoro-p-but-2-yl)-2-(tridecylidene)ethyl)-2-methylpropane _2_ sulfinyl decylamine using a procedure similar to that described for the synthesis of intermediate 62 to give n-[(1E)-(5-fluoropyridin-2-yl)methylene]-2-mercaptopropane 2_ sulfinyl decylamine (Intermediate 21) reacts with TMSCI^Li to provide the title compound. LC-MS: 317 [M+H] + Intermediate 65H5-fluoropyridin-2-yl)-2-(trimethylsulfanyl)ethylamine hydrochloride using procedures similar to those described for the synthesis of intermediate 75 , reacting N_(i_(5-fluoropyridin-2-yl)-2-(dimethylindenyl)ethyl)_2-mercaptopropane-2_sulfinylguanamine (intermediate 64), Provide the title compound. LC-MS: 213 [M+H]+ Intermediate 66 Ν-(1·(5-fluoropyridin-2-yl)-2-(methylsulfonyl)ethyl)-2-methylpropane-2 sulfin The brewing amine is similar to the procedure described for the synthesis of the intermediate 61, so that ^[(丨印^孓氟133151 -115- 200906818-pyridin-2-yl)methylene]-2-methylpropane_2_ Sulfhydryl decylamine (Intermediate 21) is reacted with dimethylhydrazine to provide the title compound. LC-MS: 323 [M+H]+ Intermediate 67 1-(5-Fluorobi-But-2-yl)-2-(methyl-furanyl)ethylamine hydrochloride. The procedure described is such that N_(i_(5-fluoropyridin-2-yl)-2-(indolyl)ethyl)-2-methylpropane-2-sulfonylguanamine (Intermediate 66) Reaction 'provides the title compound. LC-MS: 219 [M+H] + Intermediate 68 3-(1,1-dimethylethylsulfinylhydrazinyl)-3(5fluoropyridin-2-yl)propanamine title compound Obtained as a by-product of the synthesis of N-(2-cyano small (5-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinylguanamine (Intermediate 62). LC-MS: 287 [M+H] + intermediate 69 3-amino-3-(5-fluoro-p-bit-2-yl) propylamine hydrochloride using analogy for intermediate 7S synthesis Procedure to give 3_(u.2-yl)propanamide (intermediate 68) ethyl benzylidene amide)-3-(5-yl-p-pyridine to give the title compound. LC-MS : 183 [M+H]+ intermediate 70 difluoro-3-(5-fluoropyridin-2-yl)propan 3-[(t-butylarylene)amino]_2,2_2 Ethyl acetate

於鋅金屬（0.856， 133151 -116- 200906818 中之懸浮液内，添加2-溴基_2,2_二氟醋酸乙酯（2·67克，〗 毫莫耳）°使混合物溫熱至3()t，而造成激烈放熱反應。％ 分鐘後，移除油浴’並添加另外之2_溴基_2,2_二氣醋酸乙醋 (0.5毫升）’卩消耗殘留鋅。在冷卻至室溫後，添加挪中 之N-((5-氟^比唆-2-基）亞甲基&gt;2_甲基丙烧_2_亞績酿基酿胺 (中間物21，1克，4.38毫莫耳）。將反應物於室溫下攪拌以 小時。在EtOAc與飽和氯化銨水溶液之間作分液處理。將有 機相以吒0洗滌，脫水乾燥，及在減壓下蒸發，獲得粗產 物。使粗產物藉ISCO純化（Et0Ac/己烷0_90%)，而得標題化合 物（1.16克）。 σ LC-MS ： 353 [M+H]+. 中間物71 3-胺基-2,2-二氟-3·(5·氟基吡啶_2_基）丙小醇鹽酸鹽 於3-(1，1·二甲基乙基亞磺醯基醯胺基）_2,2_二氟_3_(5_氟基吡 啶-2-基）丙酸乙酯（中間物7〇，丨159克，3 29毫莫耳）中之丁取 (18毫升）溶液内，在(TCT添加硼氫化鋰（181〇毫升，丄62毫 莫耳）。使溶液慢慢溫熱3小時，於Et〇Ac與飽和氣化銨水溶 液之間作分液處理。將有機相以吒〇洗滌，脫水乾燥，及 在減壓下蒸發，而得粗產物。使粗產物藉ISC〇純化（Et〇Ac/ 己烷50%)，而得Ν·(2,2_二氟_1(5_氟基吡啶_2_基）_3_羥丙基）·2_ 甲基丙烷-2-亞磺醯基醯胺。使此化合物再溶於醋酸乙酯中， 接著添加二氧陸圜中之4N HC1。將所形成之溶液攪拌i小 時，及在減壓下蒸發揮發性物質，獲得標題化合物（〇 47〇 克）。 133151 -117- 200906818 中間物72 3-[(第三-丁基亞續酿基）胺基】-3-(5-氟基p比咬-2·基）丙酸 於3-[(第二-丁基亞&gt;ε頁酿基）胺基]·3·(5-氟1基p比。定_2_基）丙酸乙 酯（中間物61，1.2克，3.8毫莫耳）在MeOH (8毫升）與THF (8 毫升）中之經攪拌溶液内，添加LiOH (480毫克，20毫莫耳） 在Η2 Ο (4毫升）中之溶液。在室溫下攪拌2小時（如藉顯 示反應完成）後，以1M檸檬酸使反應混合物酸化，並以 EtOAc萃取（3X)。使合併之有機層脫水乾燥（Na2S〇4)，及蒸 發，獲得標題化合物（910毫克，84%)，為濃稠油。 LC-MS ： 289 [M+H]+ 中間物73 3-[(第二-丁基亞罐醯基）胺基]_3-(5-氟基p比咬_2_基）_n_甲基丙 醯胺 於3-[(第三-丁基亞磺醯基）胺基]_3_(5_氟基吡啶_2基）丙酸To the suspension of zinc metal (0.856, 133151 -116- 200906818, add 2-bromo-2,2-difluoroacetate (2·67 g, mM mmol) ° to warm the mixture to 3 ()t, causing a fierce exothermic reaction. After 1 minute, remove the oil bath' and add another 2_bromo 2,2_di-acetic acid ethyl acetate (0.5 ml)' to consume residual zinc. After room temperature, add N-((5-fluoro^-pyrimidin-2-yl)methylene group>2-methylpropane-branched _2_Azure-branched amine (intermediate 21, 1 g) The reaction was stirred at room temperature for hr. EtOAc (EtOAc) m. The title compound (1.16 g) was obtained. 2,2-Difluoro-3·(5·fluoropyridin-2-yl)propanol hydrochloride in 3-(1,1·dimethylethylsulfinylhydrazinyl)_2,2 _Difluoro_3_(5-fluoropyridin-2-yl)propionic acid ethyl ester (intermediate 7 〇, 丨 159 g, 3 29 mmol) Dilute (18 ml) solution, add (lithium borohydride (181 〇 ml, 丄62 mmol) to TCT. Allow the solution to warm slowly for 3 hours between Et〇Ac and saturated aqueous ammonium carbonate solution. The organic phase is washed with hydrazine, dehydrated and dried, and evaporated under reduced pressure to give a crude product. The crude product is purified by ISC (Et〇Ac / hexane 50%). (2,2_Difluoro_1(5-fluoropyridine-2-yl)_3_hydroxypropyl)·2_methylpropane-2-sulfinylguanamine. Resolving this compound in ethyl acetate Then, 4N HCl in dioxane was added, and the resulting solution was stirred for 1 hour, and the volatile substance was evaporated under reduced pressure to give the title compound ( 〇 47 gram). 133151 -117 - 200906818 Intermediate 72 3-[(Third-butyl sulfenyl)amino]-3-(5-fluorop-p-bit-2-yl)propionic acid on 3-[(second-butyl sub-&gt; ε page Alkyl]-3 (5-fluoro 1 -p-p.r. _2-yl)ethyl propionate (intermediate 61, 1.2 g, 3.8 mmol) in MeOH (8 mL) and THF ( Add LiOH (480 mg, 20 mmol) in a stirred solution of 8 ml) at Η2 Ο The solution was stirred at room temperature for 2 hours (as indicated by the completion of the reaction). The reaction mixture was acidified with EtOAc (EtOAc) The title compound (910 mg, 84%) was obtained as a thick oil. LC-MS : 289 [M+H]+ Intermediate 73 3-[(2-butylarylene]amino]-3-(5-fluoropyp~bit_2_yl)_n_methyl Propylamine in 3-[(t-butylsulfinyl)amino]_3_(5-fluoropyridin-2-yl)propionic acid

(中間物72 ’ 900毫克，3.12毫莫耳）、MeNH2 · HC1 (631毫克， 9.36毫莫耳）及haTU (2·37克，6.24毫莫耳）在無水DMF (3〇毫 升）中之經攪拌溶液内，添加DIPEA (5.13毫升，30毫莫耳）。 將反應混合物在室溫及氮大氣下授掉過夜。於藉Tlc顯示 反應完成後’將反應混合物以EtOAc稀釋，以％ 〇、飽和 NaHC〇3(水溶液）及鹽水洗滌。使有機層脫水乾燥（Na2s〇4), 及蒸發’而得殘留物（320毫克）。藉管柱層析純化(DCM/Me〇H =90:10) ’獲得標題化合物（28〇毫克，29%)，為白色固體。 LC-MS ： 302 [M+H]+ 中間物74 133151 -118· 200906818 3-(1,1-二甲基乙基亞磺醯基醯胺基）-3-(5-氟基吡咬基）_N N_ 二甲基丙醢胺 使用類似關於中間物73合成所述之程序，使3_[(第三_丁 A 亞磺醯基）胺基]-3-(5-氟基吡啶-2-基）丙酸（中間物72)與Me2NH •HC1反應，提供標題化合物。 LC-MS ： 316 [M+H]+ 中間物75 3-胺基-3-(5-氟基p比咬-2-基)-N-甲基丙酿胺鹽酸鹽 於3-[(第三-丁基亞磺醯基）胺基;]_3_(5_氟基吡啶_2_基甲 基丙醯胺（中間物73，280毫克，〇_73毫莫耳）在段〇&amp; (1〇毫 升）中之經攪拌溶液内，在氮大氣下添加4Μ Ηα (2M，在二 氧陸圜中）。將反應混合物於室溫下攪拌2小時，獲得沉澱 物。將反應混合物以TBME(1〇毫升）稀釋，並過滤沉澱物， 以TBME(1()毫升）洗滌，及乾燥過夜，獲得標題化合物鹽酸 鹽（丨75耄克，95%) ’為黃褐色固體。 LC-MS ： 198 [M+H]+. 1 Η 職（500 MH杉：2.48 (s，3Η)，2 85_2·77 ㈣ 2η), π]坤， 1H), 7.58 (dd, 1H), 7.76 (ddd, 1H), 8.14 (d, lH), 8.59 (s 1H) 中間物76 ’ KM-二甲基乙基亞續酿基酿_ 二甲基丙酿胺鹽酸鹽 使用類似關於中間物75合成所奸、— 战所：4之程序，使3_(u_二甲基 乙基亞磺醯基醯胺基）-3-(5-氟基咐 土比啶·2-基）-Ν,Ν-二甲基丙醯 胺（中間物74)反應，提供標題化合物。 133151 •119- 200906818 LC-MS : 212 [M+H]+ 中間物77 N-(2-(第三-丁基二甲基矽烷基氧基）亞乙基)-2_甲基丙烷-2-亞 磺醯基醯胺 於外消旋-2-甲基丙烷-2-亞磺醯基醯胺（3.10克，26毫莫耳） 與CuS04(8.3克，52毫莫耳）在60毫升DCM中之懸浮液内，在 室溫下，添加第三-丁基二甲基矽烷基氧基乙醛（5.0克，26 毫莫耳）。將混合物於室溫下攪拌18小時，然後經過Celite® 墊片過濾’接著以DCM洗滌。使濾液在真空中濃縮，然後 藉管柱層析純化（20至40% EtOAc/正-己烷），而得標題化合物 (6_59克，92%)，為淡黃色油。 中間物78 N-(2-(第三-丁基二甲基矽烷基氧基）4-(5•氟基吡啶_2_基）乙 基）-2-甲基丙烧-2-亞續醯基酿胺 於2-溴基-5-氟基p比咬（5.2克’ 29毫莫耳）在80毫升無水 MTBE中之溶液内，在-78°C下，慢慢添加LDA在戊烷中之 1·7Μ溶液（21毫升’ 36毫莫耳）。於-78°C下攪拌30分鐘後， 將N-(2-(第三-丁基二曱基矽烷基氧基）亞乙基）_2_甲基丙烷_2_ 亞磺醯基醯胺（中間物77，6.59克，24毫莫耳）在15毫升無水 MTBE中之溶液11¾ ’ 1¾添加至反應混合物中，並在相同溫度下. 再攪拌2小時。以飽和NIhCl水溶液使反應淬滅，以Et〇Ac 萃取’以無水Na〗SO4脫水乾燥。使所收集之有機層在真空 中濃縮，然後藉管柱層析純化（30% EtOAc/己烷），而得標題 化合物（8.0克，90%)，為黏稠油。 133151 •120· 200906818 LC-MS ： 375 [M+H]+ 中間物79 [1-(5-氟基p比咬-2-基）-2-經乙基】胺基甲酸第三_丁酯 於N-(2-(第三-丁基二甲基矽烷基氧基）小(5_氟基吡啶_2基） 乙基）-2-甲基丙烷_2-亞磺醯基醯胺（中間物78，丨％克，6毫 莫耳）在50毫升EtOAc中之溶液内，在室溫下，慢慢添加HC1 在二氧陸圜中之4M溶液（4_6毫升）。反應混合物轉變成混濁 ^ 溶液，然後白色固體開始沉澱析出。於室溫下2小時後，添 加乙醚（50毫升），以供完成所要產物之沉澱作用。在室溫 下靜置30分鐘後，將所形成之液體部份藉傾析移除。使殘 留固體部份在真空下乾燥，且使用於下一步驟。於室溫下， 將固體添加至20毫升水、40毫升THF及4_8毫升5N-NaOH中， 接著為B〇C2〇 (1.7克）中。在室溫下攪拌2小時後，將反應物 以EtOAc萃取，以無水Naz SO#脫水乾燥。使所收集之有機層 於真空中濃縮，然後藉管柱層析純化（4〇% Et〇Ac/己烷），而 ( 得標題化合物（1.29克，84%)，為淡黃色油。 LC-MS ： 257 [M+H]+ 中間物80 1-(5-氟基吡啶-2-基）-2-甲氧基乙胺鹽酸鹽 於[1-(5-氟基p比咬-2-基）-2-經乙基]胺基甲酸第三_丁醋（中間 物79，L27 ’ 5毫莫耳）在18毫升無水THF中之溶液内，在_15 °C下，慢慢添加THF中之20〇/。第三-丁醇鉀溶液。於相同溫 度下攪拌20分鐘後，添加0·32毫升Mel，然後，使其溫熱至 室溫。以飽和氯化銨溶液使反應混合物淬滅，以Et〇Ac萃取， 133151 •121- 200906818 以無水Na2S〇4脫水乾燥。使所收集之有機層在真空中濃縮， 接著’藉管柱層析純化（2〇_3〇% Et〇Ac/己烧），而得氣基 吡。疋-2-基）-2-甲氧基乙基]胺基甲酸第三_丁酯汍％克，45%)， 為黏稠油。使所形成之油溶於Et〇Ac (1〇毫升）中，並以二氧 陸圜中之4M HC1處理。在室溫下2小時後，添加乙键⑼毫 升）’以供完成所要產物之沉澱作用。於室溫下靜置3〇分鐘 後，將所形成之液體部份藉傾析移除。使殘留固體部份在 真空下乾秌，而得高度濕敏性標題化合物（267毫克，72%， 為單鹽酸鹽），為無色固體。 LC-MS ： 171 [M+H]+. !H NMR (500 MHz) 5 3.23 (s, 3H), 3.69 (d, 2H), 4.55 (m, 1H), 7.67 (m, 1H), 7.82 (m, 1H) 8.59 (d, 1H) 8.65 (br, 2H). 中間物81 N-[l-(5_氟基吡啶-2-基）-3-羥丙基]_2-甲基丙烷_2_亞磺醯基醯胺 使3-[(第三-丁基亞磺醯基）胺基]_3_(5_氟基吡啶_2_基）丙酸乙 醋（中間物61，1.6克，5.06毫莫耳）溶於thf (40毫升）中，並 冷卻至〇°C。於此溶液中，在氮大氣下，以小量分次添加 LiBH4(318毫克，15毫莫耳）。於室溫下攪拌過夜（如藉tlc 顯示反應完成）後，在0°C下以甲醇使反應混合物淬滅，並 以飽和NH4C1水溶液（5毫升）處理。於真空中移除有機溶劑， 且以EtOAc萃取(2x)。使合併之有機層脫水乾燥⑼七s〇d ,及 藉管柱層析純化（EtOAc/MeOH = 98:2)，而得標題化合物（92〇 毫克，66%)。 LC-MS : 275 [M+H]' 133151 -122- 200906818 中間物82 3-胺基-3-(5-氣基p比咬-2-基）丙_1_醇鹽酸鹽 使N-[l-(5-氟基吡啶-2-基）-3·經丙基]·2_曱基丙烷-2-亞磺醯基 醯胺（中間物81，920毫克，3.35毫莫耳）溶於EtOAc (20毫升） 中。於溶液中，在氮大氣下，添加4NHC1(5毫升/二氧陸園）。 將反應混合物於室溫下攪拌2小時’獲得沉澱物。以tbME (20毫升）稀釋反應混合物’並過濾沉澱物，以TBME (1〇毫升） 洗滌，及乾燥，提供標題化合物（56〇毫克，81%)，為白色固 體。 LC-MS : 171 [M+H]' ]H NMR (500 MHz) δ 1.88-1.94 (m, 1H), 2.01-2.05 (m, 1H), 3.23-3.25 (m, 1H), 3.36-3.39 (m, 1H), 4.46 (m, 1H), 7.63 (dd, 1H), 7.80 (ddd, 1H), 8·59 (d，1H)，8·60 (寬廣 s，2H). 中間物83 (2S)-l-(5-氟基吡啶-2-基)-2-甲氧基丙小醇 於200毫升圓底燒瓶中’添加乙醚（95毫升）中之2_溴基_5_ 氟基吡啶（5克，28.41毫莫耳），獲得無色溶液。使所形成之 此合物冷卻至-78 C ’並將混合物以t-BuLi溶液（33.4毫升， 56.82毫莫耳）處理20分鐘。將所形成之暗色混合物在此溫度 下攪拌20分鐘，此時，將（SH-)-2-甲氧基丙酸乙酯（3 75克， 28.41毫莫耳）在與〇 (2〇毫升）中之溶液添加至溶液中。將所 形成之黃色溶液於-78t：下攪拌2小時，此時，藉由添加餘 和NH4 C1 (水溶液）慢慢地使其淬滅，同時激烈授拌混合物。 使混合物於EtO Ac與Η? Ο之間作分液處理。將有機相以鹽水 133151 -123 - 200906818 洗務’及脫水乾燥。蒸發，獲得暗色油。藉管柱層析純化 (祕―40% EtOAc/己烧），而得⑻小(5·氟基吡啶2基甲氧基 丙小酮，為帶有顏色固體。LC_MS: 184 [_]+。使用類似 關於中間物85合成所述之程序，使⑻*(5氟基μ _2_基)-2_ 甲氧基丙-1-酮與NaBH4反應，提供標題化合物。 LC-MS ： 186 [M+H]+ 中間物84 (S)-2-(第三·丁基二甲基矽烷基氧基)4_(5_氟基吡啶_2基 &gt;丙·^酮 於200宅升圓底燒瓶_，添加乙醚（95毫升）中之2-溴基-5-氟基吡啶（5克，28.41毫莫耳），獲得無色溶液。使所形成之 混合物冷卻至-78t，並將混合物以t_BuLi溶液（33.4毫升， 56_82毫莫耳）處理20分鐘。將所形成之暗色混合物在此溫度 下攪拌20分鐘，此時’將㈠_2_(第三_丁基二甲基矽烷基_ 氧基）丙酸乙酯（7.55毫升，28.41毫莫耳）在Et2 〇 (20毫升）中之 溶液添加至溶液中。將所形成之黃色溶液於_78。〇下搜拌2 小時，此時’藉由添加飽和NH4 C1 (水溶液）慢慢地使其淬 滅’同時激烈攪拌混合物。使混合物在EtOAc與H20之間作 分液處理。將有機相以鹽水洗滌，及脫水乾燥。蒸發，獲 得暗色油。藉管柱層析純化（5%-&gt; 30% EtOAc/己烷），而得 (S)-2-(第三-丁基二曱基石夕烧基氧基）小(5-氟基p比咬_2_基）丙_ι_ 嗣，為油狀物。 LC-MS ： 284 [M+H]+ 中間物85 2S-2-(第三-丁基二甲基矽烷基氧基)小(5_氟基吡啶-2-基）丙小醇 133151 -124- 200906818 使（S)-2-(第三-丁基二甲基矽烷基氧基）-i_(5-氟基吡啶·2·基） 丙-1-酮（中間物84 ’ 500毫克，1.76毫莫耳）溶於MeOH (8.821 毫升）中，並冷卻至0°C。然後添加NaBH4(66.7毫克，1.76毫 莫耳），且將反應物在25°C下攪拌30分鐘。於真空中濃縮反 應混合物’留下黃色油。使此物質溶於EtOAc中，以NH4 C1 洗滌’及以Naz SO4脫水乾燥。在真空中濃縮，獲得黃色油（41〇 毫克）。使此物質藉ISCO純化（5-30% EtOAc/己烷）。在真空中 濃縮溶離份，提供標題化合物’為兩種非對映異構物之混 ( 合物：中間物85(a)，為透明油（64毫克），與中間物85(b)， 為透明油（27毫克）。此兩種物質之立體化學並未指定。 中間物86 乙氧基-1-(5-氣基p比咬_2_基）乙嗣 於200毫升圓底燒瓶中，添加Et2〇 (37 9毫升）中之2_溴基_5_ 氟基吡啶（2克，11.36毫莫耳），獲得無色溶液。使所形成之 混合物冷卻至-78°C，並將混合物以tBuLi溶液（13 37毫升， (22.73毫莫耳）處理20分鐘。將所形成之暗色混合物在此溫度 下攪拌20分鐘’此時’將乙氧基醋酸乙酯（丨54〇毫升，1136 笔莫耳）在Eh Ο (20毫升）中之溶液添加至溶液中。將所形成 之黃色溶液於-78X：下攪拌2小時，此時，藉由添加飽和 (水溶液）慢慢地使其淬滅，同時激烈攪拌混合物。使混合 物於EtOAc與氏0之間作分液處理。以鹽水洗滌有機相，及 脫水乾燥。蒸發，獲得暗色油。藉管柱層析純化（5%_3〇% EtOAc/己烷），而得2-乙氧基_丨_(5_氟基吡啶_2_基）乙酮，為油 狀物。 133151 •125- 200906818 LC-MS ： 184 [M+H]+. 中間物87 2-乙氧基-l-(5_氟基吡啶-2-基）乙酵 於2-乙氧基-1-(5-氟基吡啶-2-基）乙酮（中間物86，533毫克， 2.91毫莫耳）在MeOH (7274微升）與水（7274微升）中之溶液 内，在25。(：下，分次添加NaBHJllO毫克，2.91毫莫耳）。將 所形成之混合物於此溫度下攪拌3小時，此時，在減壓下移 除揮發性物質。以EtOAc稀釋所得之殘留物，並將有機相以 鹽水洗滌，及脫水乾燥。於減壓下蒸發’獲得2_乙氧基-丨#-I基n比咬-2-基）乙醇，為油狀物。 LC-MS : 186 [M+H]+_ 中間物88 2-(1-疊氮基-2-乙氧基乙基)_5_氟基吡啶 於2-乙氧基-1-(5-氟基吡啶_2_基）乙醇（中間物87，〇 539克， 2·91毫莫耳）在DCM (2.91毫升）中之溶液内，在〇(&gt;c下，添加(Intermediate 72 '900 mg, 3.12 mmol), MeNH2 · HC1 (631 mg, 9.36 mmol) and haTU (2.37 g, 6.24 mmol) in anhydrous DMF (3 mL) The solution was stirred and DIPEA (5.13 mL, 30 mmol) was added. The reaction mixture was allowed to stand overnight at room temperature under a nitrogen atmosphere. After the reaction was completed by Tlc, the reaction mixture was diluted with EtOAc and washed with EtOAc EtOAc EtOAc The organic layer was dried (Na 2 s 4) and evaporated to yield residue (320 mg). The title compound (28 mg, 29%). LC-MS: 302 [M+H]+ Intermediate 74 133151 -118· 200906818 3-(1,1-Diethylethylsulfinylhydrazinyl)-3-(5-fluoropyridyl) )_N N_Dimethylpropionamide using a procedure similar to that described for the synthesis of intermediate 73 to give 3_[(T-A-sulfinyl)amino]-3-(5-fluoropyridine-2- Propionate (Intermediate 72) is reacted with Me2NH•HC1 to provide the title compound. LC-MS: 316 [M+H]+ intermediate 75 3-amino-3-(5-fluoro-p-but-2-yl)-N-methylpropanamine hydrochloride in 3-[( Tert-butylsulfinylamino);]_3_(5-fluoropyridin-2-ylmethylpropanamide (intermediate 73, 280 mg, 〇_73 mmol) in 〇 〇 &amp; 4 Μα (2M in dioxane) was added to the stirred solution in (1 mL). The reaction mixture was stirred at room temperature for 2 hr to give a precipitate. (1 ml) was diluted and the precipitate was filtered, washed with EtOAc EtOAc EtOAc EtOAc EtOAc : 198 [M+H]+. 1 Η (500 MH: 2.48 (s, 3Η), 2 85_2·77 (4) 2η), π]kun, 1H), 7.58 (dd, 1H), 7.76 (ddd, 1H), 8.14 (d, lH), 8.59 (s 1H) Intermediate 76 'KM-dimethylethyl sulphate brewing _ Dimethyl propylamine hydrochloride is similar to the synthesis of intermediate 75 , - Warfare: 4 procedure, so that 3_(u_dimethylethylsulfinylhydrazinyl)-3-(5-fluoroazepine-pyridyl-2-yl)-Ν,Ν-二Methylpropanamide (Intermediate 74) is reacted to provide the title compound. 133151 •119- 200906818 LC-MS: 212 [M+H]+ Intermediate 77 N-(2-(T-butyldimethylmethylalkyloxy)ethylidene)-2-methylpropane-2 - sulfinyl decylamine in racemic 2-methylpropane-2-sulfinyl decylamine (3.10 g, 26 mmol) with CuS04 (8.3 g, 52 mmol) in 60 ml DCM In the suspension, tri-butyldimethylsilyloxyacetaldehyde (5.0 g, 26 mmol) was added at room temperature. The mixture was stirred at room temperature for 18 hours then filtered through a pad of Celite® and then washed with DCM. The filtrate was concentrated in EtOAc (EtOAc)EtOAc. Intermediate 78 N-(2-(Third-butyldimethylmethylalkyloxy) 4-(5•fluoropyridin-2-yl)ethyl)-2-methylpropan-2-ene Addition of LDA to pentane at -78 ° C in a solution of 2-bromo-5-fluoropyp-bit (5.2 g '29 mmol) in 80 mL of anhydrous MTBE 1·7Μ solution (21 ml '36 mmol). After stirring at -78 ° C for 30 minutes, N-(2-(tert-butyldidecylfluorenyloxy)ethylidene)-2-methylpropane-2_sulfinylguanamine (middle) Solution 77, 6.59 g, 24 mmol) was added to the reaction mixture in a solution of 15 mL anhydrous MTBE and stirred at the same temperature for a further 2 hours. The reaction was quenched with a saturated aqueous solution of EtOAc and dried over Et. The collected organic layer was concentrated with EtOAc EtOAcjjjjjjjj 133151 •120· 200906818 LC-MS : 375 [M+H]+ Intermediate 79 [1-(5-Fluoro-p-But-2-yl)-2-Ethyl]carbamic acid tert-butyl ester N-(2-(Third-butyl dimethyl decyloxy) small (5-fluoropyridin-2-yl)ethyl)-2-methylpropane-2-sulfinyl decylamine ( Intermediate 4, 丨% gram, 6 mmol) in a solution of 50 mL EtOAc, EtOAc (4-6 mL) in EtOAc. The reaction mixture was turned into a turbid solution, and then a white solid began to precipitate. After 2 hours at room temperature, diethyl ether (50 mL) was added to afford a desired product. After standing at room temperature for 30 minutes, the formed liquid portion was removed by decantation. The residual solid portion was dried under vacuum and used in the next step. The solid was added to 20 ml of water, 40 ml of THF and 4-8 ml of 5N-NaOH at room temperature, followed by B 〇 C2 〇 (1.7 g). After stirring at room temperature for 2 hours, the reaction was extracted with EtOAc and dried over anhydrous Naz. The collected organic layer was concentrated with EtOAc EtOAc (EtOAc) MS: 257 [M+H]+ Intermediate 80 1-(5-fluoropyridin-2-yl)-2-methoxyethylamine hydrochloride in [1-(5-fluoro-p-bit-2 -ethyl)-2-ethyl-aminocarbamic acid third-butyl vinegar (intermediate 79, L27 '5 mmol) in 18 ml of anhydrous THF, slowly added at _15 °C 20 〇 /. Third potassium butoxide solution in THF. After stirring at the same temperature for 20 minutes, add 0·32 ml of Mel, then warm to room temperature. Saturate the reaction mixture with saturated ammonium chloride solution. Quenching, extraction with Et〇Ac, 133151 • 121- 200906818 Dehydrated with anhydrous Na2S〇4. The collected organic layer was concentrated in vacuo and then purified by column chromatography (2 〇 〇 〇 〇 〇 Ac/hexane), which is a viscous oil. 疋-2-yl)-2-methoxyethyl]carbamic acid tert-butyl ester 汍% gram, 45%). The oil formed was dissolved in Et 〇Ac (1 mL) and treated with 4M HCl in dioxane. After 2 hours at room temperature, an ethyl bond (9) ml) was added to complete the precipitation of the desired product. After standing at room temperature for 3 minutes, the formed liquid portion was removed by decantation. The residue was dried under vacuum to give the title compound (yield: 267 mg, 72% as monohydrochloride) as a colorless solid. LC-MS : 171 [M+H]+. !H NMR (500 MHz) 5 3.23 (s, 3H), 3.69 (d, 2H), 4.55 (m, 1H), 7.67 (m, 1H), 7.82 ( m, 1H) 8.59 (d, 1H) 8.65 (br, 2H). Intermediate 81 N-[l-(5-Fluoropyridin-2-yl)-3-hydroxypropyl]_2-methylpropane_2 _ sulfinyl decylamine makes 3-[(t-butylsulfinyl)amino]_3_(5-fluoropyridine-2-yl)propanoic acid ethyl acetate (intermediate 61, 1.6 g, 5.06 Mol) was dissolved in thf (40 mL) and cooled to 〇 °C. In this solution, LiBH4 (318 mg, 15 mmol) was added in small portions under a nitrogen atmosphere. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The organic solvent was removed in vacuo and EtOAc (2x). The combined organic layers were dried <RTI ID=0.0></RTI> (jjjjjjjj LC-MS: 275 [M+H]' 133151 -122- 200906818 Intermediate 82 3-amino-3-(5-carbyl p-biti-2-yl)propan-1-ol hydrochloride [l-(5-Fluoropyridin-2-yl)-3. propyl]·2_mercaptopropane-2-sulfinyl decylamine (intermediate 81,920 mg, 3.35 mmol) In EtOAc (20 mL). 4NHC1 (5 ml / dioxane) was added to the solution under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours to give a precipitate. The reaction mixture was diluted with EtOAc (EtOAc)EtOAc. LC-MS : 171 [M+H]']H NMR (500 MHz) δ 1.88-1.94 (m, 1H), 2.01-2.05 (m, 1H), 3.23-3.25 (m, 1H), 3.36-3.39 ( m, 1H), 4.46 (m, 1H), 7.63 (dd, 1H), 7.80 (ddd, 1H), 8·59 (d, 1H), 8·60 (broad s, 2H). Intermediate 83 (2S -l-(5-Fluoropyridin-2-yl)-2-methoxypropanol in a 200 ml round bottom flask - 2 -bromo-5-fluoropyridine in diethyl ether (95 ml) 5 g, 28.41 mmol, obtained a colorless solution. The resulting mixture was cooled to -78 C ' and the mixture was treated with t-BuLi solution (33.4 mL, 56.82 mmol) for 20 min. The dark mixture formed was stirred at this temperature for 20 minutes at which time (SH-)-2-methoxypropionic acid ethyl ester (3 75 g, 28.41 mmol) was combined with hydrazine (2 mL). The solution in the solution is added to the solution. The resulting yellow solution was stirred at -78 t: for 2 hours, at which time it was slowly quenched by addition of &lt;RTI ID=0.0&gt; The mixture was subjected to liquid separation between EtO Ac and Η??. The organic phase was washed with brine 133151 -123 - 200906818 and dehydrated. Evaporate to obtain a dark oil. Purification by column chromatography (sec. 40% EtOAc / hexanes) afforded (8) s (5 fluoro pyridine yl methoxy propyl ketone as a colour solid. LC_MS: 184 [-]+. The title compound was obtained by reacting (8)*(5-fluoro-[pi]-[upsilon]-yl)-2-methoxypropan-1-one with NaBH4 using a procedure similar to the procedure for the synthesis of Intermediate 85. LC-MS: 186 [M+ H]+ intermediate 84 (S)-2-(t-butyl dimethyl decyloxy) 4_(5-fluoropyridine-2-yl) propyl ketone in 200 house liter round bottom flask _ 2-Bromo-5-fluoropyridine (5 g, 28.41 mmol) in diethyl ether (95 ml) was added to give a colorless solution. The resulting mixture was cooled to -78t, and the mixture was taken as a t-BuLi solution ( 33.4 ml, 56_82 mmol, treated for 20 minutes. The dark mixture formed was stirred at this temperature for 20 minutes, at which time '(_)_2_(tris-butyl-dimethyl dimethyl-alkyl)-propionic acid ethyl ester (7.55 ml, 28.41 mmol) solution in Et2 (20 ml) was added to the solution. The yellow solution formed was placed at _78. The mixture was mixed for 2 hours, at which time 'by adding saturated NH4 C1 (aqueous solution) slowly The mixture was quenched while stirring the mixture vigorously. The mixture was partitioned between EtOAc and H20. The organic phase was washed with brine and dried with EtOAc. -&gt; 30% EtOAc/hexane) to give (S)-2-(tert-butyl dimethyl fluorenyloxy) small (5-fluoro-p-bit _2-yl) propyl Io_ 嗣, as an oil. LC-MS: 284 [M+H]+ Intermediate 85 2S-2-(T-butyl dimethyl decyloxy) small (5-fluoropyridine-2- Propyl glycerol 133151 -124- 200906818 (S)-2-(Third-butyl dimethyl decyloxy)-i-(5-fluoropyridin-2-yl)propan-1-one ( The intermediate 84' 500 mg, 1.76 mmol was dissolved in MeOH (8.821 mL) and cooled to 0 ° C. then NaBH4 (66.7 mg, 1.76 mmol) was added and the reaction was taken at 25 ° C After stirring for 30 minutes, the reaction mixture was evaporated EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj This material was purified by ISCO (5-30% EtOAc / hexanes Concentration of the fractions in vacuo afforded the title compound 'as a mixture of two diastereomers: intermediate 85 (a) as a clear oil (64 mg), with intermediate 85 (b) , for clear oil (27 mg). The stereochemistry of these two substances is not specified. Intermediate 86 Ethoxy-1-(5-a gas-based p-bito-2_yl) acetamidine in a 200 ml round bottom flask, adding 2-bromo group _5_ fluoro group in Et2 hydrazine (37 9 ml) Pyridine (2 g, 11.36 mmol) gave a colorless solution. The resulting mixture was cooled to -78 ° C, and the mixture was treated with tBuLi solution (13 37 ml, (22.73 mmol) for 20 minutes. The resulting dark mixture was stirred at this temperature for 20 minutes 'at this time' A solution of ethyl ethoxyacetate (丨 54 mL, 1136 moles) in Eh Ο (20 mL) was added to the solution. The resulting yellow solution was stirred at -78 X: for 2 hours. The mixture was quenched slowly by the addition of saturated (aq.), and the mixture was stirred vigorously. The mixture was partitioned between EtOAc and EtOAc. The organic phase was washed with brine, dried and evaporated. Purification by column chromatography (5% _3 % EtOAc / hexanes) afforded 2- ethoxy </ </RTI> <RTIgt; (5-fluoropyridin-2-yl)ethanone as an oil. 125- 200906818 LC-MS : 184 [M+H]+. Intermediate 87 2-ethoxy-l-(5-fluoropyridin-2-yl)-ethyl ester in 2-ethoxy-1-(5) -Fluoropyridin-2-yl)ethanone (intermediate 86,533 mg, 2.91 mmol) in a solution of MeOH (7274 [mu]L) and water (7274 L), at 25: Graded NaBHJllO mg, 2.91 mmol. The resulting mixture was stirred at this temperature for 3 h at which time the volatiles were removed under reduced pressure. The residue was diluted with EtOAc. And dehydration drying. Evaporation under reduced pressure to obtain 2_ethoxy-oxime #-I-based n-bit-2-yl)ethanol as an oil. LC-MS: 186 [M+H]+_ Intermediate 88 2-(1-azido-2-ethoxyethyl)-5-fluoropyridine in 2-ethoxy-1-(5-fluoro Pyridyl-2-yl)ethanol (Intermediate 87, 〇 539 g, 2.91 mmol) in DCM (2.91 mL), added under 〇 (&gt;c)

EtgN (0.406毫升，2.91毫莫耳）與氯化甲烷磺醯（〇·227毫升， 2.91毫莫耳）。將所形成之混合物於環境溫度下攪拌2小時， 此時，使其在EtOAc與Η2〇之間作分液處理。使有機相脫水 乾燥，及在減壓下蒸發，獲得其相應之績酸甲§旨，將其使 用於後續步射，未進行任何進—步純化。使姐醋溶於 DMF(2.91毫升）中，並添加疊氮化鈉（讀克，I%毫莫耳 將混合物加熱至贼，歷經4小時。使混合物冷卻至室况° 並使其在驗與H2〇之間作分液處理。使有機相脫：乾 無，及在減壓下蒸發(不…1編勒之署麵心 133151 -126- 200906818 為）’獲得2-(1-疊氮基-2-乙氧基乙基）_5_氟基吡啶，為油狀 物，將其使用於下一步驟中’未進行任何進一步純化。 LC-MS ： 211 [Μ+Η]+. 中間物89 2-乙氧基-1-(5-氟基吡啶-2-基）乙胺 於2-(1-疊氮基-2-乙氧基乙基）-5-氟基吡咬（中間物88，〇 612 克，2.91宅莫耳）在四氫吱喃（7.28毫升）與水（7.28毫升）中之 /谷液内，添加PS (聚合體所承載）三苯膦（3.82克，14.55毫莫 耳）。將所形成之漿液加熱至60。(：，歷經6小時。過濾混合 物，以移除PS (聚合體所承載）三苯膦與氧化物，且揮發性 物質在減壓下之後續蒸發，獲得2_乙氧基氟基吡啶_2_ 基）乙胺，212毫克，為黃色油。將產物使用於後續步驟中， 未進行任何進一步純化。 LC-MS ： 185 [M+H]+. 中間物90 6氣-N _(2_乙氧基小(5_氟基吡咬_2_基）乙基）_N4 _(5_甲基_1H吡 唾-3-基）-1，3,5-三啡-2,4-二胺 於4,6-二氯-N-(5-甲基-1H_吡唑各基）_13,5三啡冬胺（中間物 Μ，282毫克，1.15毫莫耳）在乙醇（3836微升）中之溶液内， 添加2-乙氧基-Η5_氟基吡啶冬基）乙胺（中間物89，212毫克， 1.15毫莫耳）與Ε^Ν (481微升，3 45毫莫耳）。將所形成之淡 汽色洛液在25 C下攪拌過夜。於減壓下蒸發揮發性物質， 獲侍頁色殘留物。藉管柱層析純化（7〇%— 1〇〇% Et〇Ac/己烷” 而得6氣-N -(2-乙氧基小(5_氟基吡啶·2_基）乙基）_n4_(5_甲基 133151 •127- 200906818 -1H-吡唑-3-基）-l，3,5-三畊-2,4-二胺，為灰白色固體。 LC-MS ： 393 [M+H]+. 中間物91 1-(5-氟基嘧啶-2-基）-2·曱氧基乙醇EtgN (0.406 ml, 2.91 mmol) with methanesulfonyl chloride (〇·227 ml, 2.91 mmol). The resulting mixture was stirred at ambient temperature for 2 hours at which time it was partitioned between EtOAc and EtOAc. The organic phase was dried and dried, and evaporated under reduced pressure to give the corresponding acid, which was applied to the next step, without any further purification. The vinegar was dissolved in DMF (2.91 ml) and sodium azide was added (read gram, I% millimolar to heat the mixture to the thief for 4 hours. Allow the mixture to cool to room temperature and allow it to be tested H2〇 is treated as a liquid separation process. The organic phase is removed: dry and free, and evaporated under reduced pressure (not... 1 liters of the face 133151 -126- 200906818)) -2-Ethylethyl)-5-fluoropyridine as an oil which was used in the next step 'without any further purification. LC-MS: 211 [Μ+Η]+. Intermediate 89 2-Ethoxy-1-(5-fluoropyridin-2-yl)ethylamine in 2-(1-azido-2-ethoxyethyl)-5-fluoropyridine (intermediate 88 , 〇612 g, 2.91 house Moer) In the tetrahydrofuran (7.28 ml) and water (7.28 ml) in the / trough, add PS (polymer supported by) triphenylphosphine (3.82 g, 14.55 mmol) The resulting slurry was heated to 60. (:, over 6 hours. The mixture was filtered to remove PS (supported by the polymer) triphenylphosphine and oxide, and the subsequent evaporation of volatiles under reduced pressure , obtaining 2_ethoxyfluoropyridine_2_ Ethylamine, 212 mg, as a yellow oil. The product was used in the next step without any further purification. LC-MS: 185 [M+H]+. Intermediate 90 6 gas-N _ (2 ethoxy Small (5-fluoropyridin-2-yl)ethyl)_N4 _(5-methyl_1Hpyrazin-3-yl)-1,3,5-triphthyl-2,4-diamine 4,6-Dichloro-N-(5-methyl-1H-pyrazole each)_13,5-trianthramine (intermediate Μ, 282 mg, 1.15 mmol) in ethanol (3836 μl) To the solution, 2-ethoxy-indole-5-fluoropyridinyl)ethylamine (intermediate 89,212 mg, 1.15 mmol) was added with Ε^Ν (481 μL, 3 45 mmol). The resulting light color solution was stirred at 25 C overnight. The volatile matter was evaporated under reduced pressure to obtain a residue of the color. Purification by column chromatography (7〇% - 1〇〇% Et〇Ac/hexane) gave 6 gas-N-(2-ethoxy small (5-fluoropyridine-2-yl)ethyl) _n4_(5_methyl 133151 •127- 200906818 -1H-pyrazol-3-yl)-l,3,5-trinol-2,4-diamine, as an off-white solid. LC-MS: 393 [M+ H]+. Intermediate 91 1-(5-fluoropyrimidin-2-yl)-2.nonyloxyethanol

於100毫升圓底燒瓶中，添加MeOH (7137微升）中之5_氟基 -2-(環氧乙烷-2-基）嘧啶（中間物no，200毫克，1.43毫莫耳） 與外消旋-Co(II)-沙林〇Ts (111毫克，0.14毫莫耳）_製自p_Ts〇H 之添加於⑻，(S)-與（R，R)-Co-沙林在MeOH中之溶液内，歷經i | 、' 小時，在開放空氣中，及揮發性物質之後續蒸發（當起始物 質為橘色時，最後產物為綠色）_獲得綠色溶液。將混合物 於25 C下攪拌7天。蒸發揮發性物質，並使殘留物藉管柱層 析純化（ISCO，30% EtOAc/ 己烷 90% EtOAc/ 己烷），而得丨_(5_ 氟基嘧啶-2-基）-2-甲氧基乙醇，為暗色油。伴隨著產物，回 收5-氟基-2-(環氧乙烷_2_基）。密啶（200毫克，143毫莫耳）以及 微量二醇。 (1 H NMR (300 MHz，氯仿-d) 5 ppm 3.38 (s，3H) 3.74-3.87 (m，2H) 4.01 (s, 1H) 4.82-5.35 (m, 1H) 8.63 (s, 2H) 中間物92 (S)-6-氣-N2-(1-(3,5-二氟吡啶：基）乙基）_N4 _(5_ 甲基 _m 吡唑-3_ 基）-1,3,5-三 p井-2,4-二胺 將DIPEA (1.875毫升，Km毫莫耳）添加至4,6_二氯_N (5甲 基-1H-吡唑-3-基）-1，3,5-三畊冬胺（中間物18，877毫克，3別毫 莫耳）與（S)-l-(3,5-二氟吡啶_2_基）乙胺（R)_苯乙醇酸鹽（中間物 106 ’ 127毫克’ 〇·41毫莫耳）在乙醇（15毫升）中之溶液内。將 133151 -128· 200906818 反應混合物於室溫下攪拌24小時。過濾反應物，以移除固 體，並使殘留溶液在減壓下濃縮，留下黃色殘留物。使此 物質藉ISCO純化（〇_5% MeOH/DCM)，以提供380毫克標題化合 物。 LC-MS : 367 [M+H]+. 1 H NMR (400 MHz, MeOD) δ ppm 8.32-8.40 (m, 1H) 7.54-7.62 (m, 1H) 5.47-5.58 (m, 1H) 2.29 (d, 3H) 1.55 (s, 3H). 中間物93 1-(3,5-二氟吡啶-2-基）-2-甲氧基乙酮 使THF中之3,5-二氟吡啶（5.0克，43.45毫莫耳）冷卻至_72t： (外部-80°C )。逐滴添加LDA (23·9毫升，1.1當量），以致使在 添加期間内部溫度不會增加超過3。〇。反應物轉變成深褐色 濃稠相。將反應物攪拌30分鐘。以相對較快速方式逐滴添 加TMS-C1 (43·4毫升，43.45毫莫耳）。反應物變成透明且淡黃 色溶液。逐滴添加LDA (23·9毫升，1_1當量），並將反應物攪 拌2小時。經過注射器快速添加2_甲氧基醋酸甲酯（5 59毫 升’ 56.48毫莫耳）。於-78°C下，藉由添加20毫升飽和nh4C1 溶液使反應淬滅。在減壓下蒸發有機萃液，獲得帶有顏色 殘留物。藉ISCO純化（0-25% EtOAc/己烷），獲得標題化合物（3 克）。 LC-MS ： 188 [M+H]+ 中間物94 1-(3,5-二氟吡啶_2-基）-2-甲氧基乙酮肟 使1-(3,5-二氟吡啶-2-基）-2-曱氧基乙酮（中間物93)溶於乙醇 133151 -129- 200906818 (255毫升，ι〇份體積）中。添加羥胺鹽酸鹽（i422克，加^上 毫莫耳），接著逐滴為三乙胺（28 5毫升，2〇4.61毫莫耳）^將 所形成之帶有顏色混合物加熱至5〇。〇，歷經2小時。在減壓 下蒸發揮發性物質，並使留下之殘留物於水（255毫升）與醋 酸乙酯（255毫升）之間作分液處理。將已分離之水層在&amp;醋 酸乙酯（255毫升）中進一步萃取。將合併之有機萃液以水 (255毫升）、飽和鹽水（255毫升）洗滌，以MgS〇4脫水乾燥， 過濾，及在真空中濃縮，而得42克褐色油。藉管柱層析純 化（25-40% EtOAc在異己烷中），獲得32克標題化合物，為黃 色油性固體（異構物之〜3:1混合物）。於MTBE中研製，獲得 標題化合物（12.3克，60.84毫莫耳，44.6%，單一異構物），為 白色固體。在減壓下蒸發液體，並將殘留物使用前述條件 再裝管柱，接著以EtOAc/異己烷研製，而得另外之丨_(3,5_二 氟吡啶-2-基）-2-甲氧基乙酮肪（7.2克，35 62毫莫耳，261%)。 LC-MS : 203 [M+H]+. 中間物95 (11)-1-(3,5-二氟p比咬_2_基）_2_甲氧基乙胺（R)苯乙醇酸鹽 使1-(3,5-二氟峨啶_2_基）-2-甲氧基乙酮肟（中間物94)溶於 EtOAc(0.4M)中，接著，在帕爾氫化器（壓力$巴，在4叱下） 中，使其接受催化氫化作用（Pd/C)，歷經i小時。經由矽藻 土過濾觸媒，並將1-(3,5-二氟吡啶-2-基&gt;2-甲氧基乙胺之濾液 (0.4M，在醋酸乙酯中）（180毫升’ 72⑻毫莫耳）以⑻-苯乙醇 酸（5_81克，38.16毫莫耳）處理。幾乎同時發現沉澱作用且 將所形成之混合物攪拌過夜。經由過濾收集二氟吡 133151 -130- 200906818 啶-2-基）-2-甲氧基乙胺（R)-苯乙醇酸鹽（8.5克，69.4%)。在蒸發 母液後，回收另一種對掌異構物（S)-l-(3,5-二氟吡啶-2-基）-2-甲氧基乙胺（R)-苯乙醇酸鹽。 1 H NMR (400 MHz) δ ppm 8.6 (s, 1H) 8.01 (m, 1H) 7.41 (t, 2H) 7.36 (t, 2H) 7.19 (m, 1H) 4.81 (s, 1H) 4.50 (m, 1H) 3.57 (d, 2H) 3.23 (s, 3H). LC-MS ： 188 [M-H]+ 中間物96 3,5-二氟-2-肼基吡啶 於250毫升圓底燒瓶中，添加THF (150毫升）中之肼單水合 物（17.69毫升，563.61毫莫耳）與2,3,5-三氟吡啶（25.0克，187.87 毫莫耳），獲得無色溶液。將反應物在5(TC下加熱72小時。 濃縮移除THF，並添加EtOAc (80毫升）。過濾，獲得第一份 收取之產物，為固體’將其以水（50毫升）洗滌。以EtOAc (3 X 30毫升）萃取水層。濃縮有機層，獲得第二份收取之產物。 將粗產物裝填至矽膠層析上，及以EtOAc/己烷（30%)溶離。 使所收集之溶離份濃縮，而得產物（23.0克，84%產率）。 1 H NMR δ 4.09 (s, 2H), 7.62 (ddd, 1H), 7.75 (s, 1H), 7.96 (d, 1H). 中間物97 2-溴基-3,5-二氟吡啶 於500毫升圓底燒瓶中，添加CHC13 (158毫升）中之3,5-二氟 -2-肼基吡啶（中間物96 ’ 16.0克，110.26毫莫耳），獲得褐色 懸浮液。將反應物加熱至40。(3，並逐滴添加漠（14.20毫升， 275.65毫莫耳）’歷經15分鐘。使反應混合物在6〇。〇下回流1 小時。在冷卻至室溫後’將燒瓶置於冰浴中，且極慢地添 133151 • 131 - 200906818 加飽和NaHC〇3，以使反應淬滅。分配，以Dcm (2 χ 80毫升） 萃取，脫水乾燥（N^SO4)，及濃縮，而得粗產物。將粗產物 添加至矽膠管柱中，並以Et〇Ac/己烷（0_20%)溶離。使所收集 之溶離份濃縮，獲得產物（丨2.〇克，56%產率）。 NMR (5 8.18 (td, 1H), 8.46 (d, 1H). 中間物98 2-演基-3,5-一氟-4-(三甲基梦统基）p比咬 於250毫升圓底燒瓶中’添加胃（552毫升）中之2_溴基 _3,5_二氟吡啶（中間物97，5·35克，27.58毫莫耳），獲得黃色 溶液。使溶液冷卻至_78t，並添加LDA (22.98毫升，41.37毫 莫耳）。溶液立即轉變成暗色，且在室溫下攪拌1〇分鐘後， 添加氣基三甲基矽烷（3.66毫升，28.96毫莫耳）。〇.5小時後， 添加飽和ΝΗαι，以使反應淬滅。分配，以Et0Ac (2 χ 3〇毫 升）萃取’脫水乾燥（NaaSO4)，及濃縮，而得粗產物。將粗 產物添加至矽膠管柱中，並以Et0Ac/己烷（〇_2〇%)溶離。使所 收集之溶離份濃縮，獲得產物（5.90克，80%產率）。 ]H NMR δ 0.40 (s, 9H), 8.34 (s, 1H). 中間物99 N-(2-(第二-丁基二甲基碎烧基氧基）小(3,5_二氟_4_(三甲基妙 烧基）《»比咬-2-基）乙基）-2-甲基丙烧-2-亞確酿基醢胺 於250毫升圓底燒瓶中，添加THF (36 9毫升）中之2溴基 -3,5-一氟_4-(二甲基石夕烧基）p比咬（中間物98，5 9克m7毫 莫耳）’獲得黃色溶液。使溶液冷卻至_78。(：，並添加n_BuU (13.85毫升，22.17毫莫耳）。在該溫度下攪拌1〇分鐘後，添 133151 -132- 200906818 加N-(2-(第三-丁基二甲基石夕院基氧基）亞乙基）_2_甲基丙烧_2_ 亞確醯基酿胺（中間物77，7.38克，26.60毫莫耳）。將反應物 再攪拌20分鐘，且添加飽和Νί^α (40毫升），以使反應泮滅。 溫熱至室溫，分配’以EtOAc (2 X 20毫升）萃取，脫水乾燥 (Na2 SO4 )’及濃縮，而得粗產物。將粗產物添加至石夕膠管柱 中’並以EtOAC/己炫&gt; (0-60%)溶離。使所收集之溶離份濃縮， 獲得產物（5.0克，48.5%產率）。 1 H NMR (5 -0.17 (s, 3Η), -0.06 (s, 3H), 0.37 (s, 9H), 0.71 (s, 9H), 1.05 (s, 9H), 3.92 (m, 2H), 4.67 (m, 1H), 5.50 (d, J = 7.91 Hz, 1H), 8.44 (s, 1H). 中間物99亦可經由下述程序製成： 於500毫升圓底燒瓶中，添加四氫吱喃（147毫升）中之3,5-一氟p比咬（4_22克’ 36.67宅莫耳）’獲得無色溶液。使溶液冷 卻至-78°C，然後添加LDA (20.37毫升，36.67毫莫耳）。在-78 °C下保持10分鐘後，慢慢添加氣基三曱基矽烷（4 64毫升， 36_67毫莫耳）。使反應混合物於_78°c下再保持1〇分鐘，慢慢 添加LDA (50.9毫升，91.67毫莫耳），並將混合物攪拌〇 5小時， 接著添加THF (20毫升）中之N-(2-(第三-丁基二甲基矽烷基氧 基）亞乙基）-2-甲基丙烷-2-亞磺醯基醯胺（中間物77，1018克， 36.67毫莫耳）。〇_5小時後’添加飽和nh4C1 (8〇毫升），以使 反應淬滅。分配’以EtOAc (2 X 50毫升）萃取，脫水乾燥 (NasSCU) ’及濃縮’而得粗產物。將粗產物添加至矽膠管柱 中’並以EtOAc/己烧（0-40%)溶離。使所收集之溶離份濃縮， 以41.1%產率獲得產物。 中間物100 133151 -133 - 200906818 1-(3,5-二氟吡啶_2_基）_2_羥乙基胺基甲酸第三-丁輯 於200毫升圓底燒瓶中，添加甲醇（45毫升）中之N_(2_(第三 丁基一甲基石夕烧基氧基）-1-(3,5-二氟-4-(三曱基石夕院基）?比σ定 -2-基）乙基）-2-甲基丙烷_2_亞磺醢基醯胺（中間物99，5 〇克， 10.76毫莫耳），獲得褐色溶液。使溶液冷卻至〇它，並添加 HC1 (4M，在二氧陸園申）（1〇 76毫升，43 〇3毫莫耳）。將反應 物於0 C下授拌1小時。在250毫升圓底燒瓶中，使溶液濃縮， 而得殘留物（2.65克）。於殘留物中添加水（35毫升），獲得黃 色溶液。以THF(70毫升）稀釋反應混合物。在室溫下，添加 B〇C2〇 (3.00毫升，12.91毫莫耳）與NaOH (8.61毫升，5M水溶 液）。將反應物於室溫下攪拌1小時。以Et0Ac (2 χ 4〇毫升） 萃取’脫水乾燥（NasSO4)，及濃縮，而得粗產物。將粗產物 裝填至矽膠層析上，並以EtOAc/己烷（20-80%)溶離。使所收 集之溶離份濃縮，獲得產物（1_8〇克，61%產率）。 LC-MS (M+Na) = 297. 中間物101 1-(3,5-二氣p比咬-2-基)-2-甲氧基乙基胺基曱酸第三_丁醋 於200毫升圓底燒瓶中，添加thf (25毫升）中之1_(3,5_二說 吡啶-2-基）-2-經乙基胺基甲酸第三-丁酯（中間物100，18〇克， 6.60毫莫耳），獲得褐色溶液。使用NaC1_冰浴使溶液冷卻至 -15 C。添加第二-丁醇钾（1.481克，13_2毫莫耳）。使反應物 保持在該溫度下，並於20分鐘後，添加填甲烧（〇·4ΐ3毫升， 6.6宅莫耳）。將反應物在該溫度下授掉1.5小時。tlc監視器 顯示少量起始物質留下，添加另外之0.3克KOt-Bu，接著為 133151 -134· 200906818 0.05毫升碘甲烷。再ι〇分鐘後，添加飽和NH4C1，以處理反 應物。分配，萃取（EtOAc ’ 2x15毫升），脫水乾燥（Na2S〇4)， 及濃縮，而得粗產物。將粗產物添加至矽膠管柱中並以In a 100 ml round bottom flask, add 5-fluoro-2-(oxiran-2-yl)pyrimidine (intermediate no, 200 mg, 1.43 mmol) in MeOH (7137 μl) Racemic-Co(II)-Sharin Ts (111 mg, 0.14 mmol) from p_Ts〇H added to (8), (S)- and (R,R)-Co-sarin in MeOH In the solution, after i | , 'hours, in open air, and subsequent evaporation of volatile materials (when the starting material is orange, the final product is green) _ obtain a green solution. The mixture was stirred at 25 C for 7 days. The volatiles were evaporated, and the residue was purified eluting elut elut elut elut elut elut elut elut elut Oxyethanol, a dark oil. With the product, 5-fluoro-2-(oxirane-2-yl) was recovered. Mixidine (200 mg, 143 mmol) and trace diol. (1H NMR (300 MHz, chloroform-d) 5 ppm 3.38 (s,3H) 3.74-3.87 (m,2H) 4.01 (s, 1H) 4.82-5.35 (m, 1H) 8.63 (s, 2H) Intermediate 92 (S)-6-Gas-N2-(1-(3,5-difluoropyridyl:yl)ethyl)_N4 _(5-methyl-m pyrazole-3-yl)-1,3,5-three P-well-2,4-diamine adds DIPEA (1.875 ml, Km millimolar) to 4,6-dichloro-N (5-methyl-1H-pyrazol-3-yl)-1,3,5 - Three-till winter amine (intermediate 18,877 mg, 3 gram molar) and (S)-l-(3,5-difluoropyridin-2-yl)ethylamine (R)-phenylglycolate ( Intermediate 106' 127 mg '〇·41 mmol) in a solution of ethanol (15 ml). The reaction mixture was stirred at room temperature for 24 hours. The reaction was filtered to remove solids. The residue was concentrated under reduced pressure to give a crystallite. . 1 H NMR (400 MHz, MeOD) δ ppm 8.32-8.40 (m, 1H) 7.54-7.62 (m, 1H) 5.47-5.58 (m, 1H) 2.29 (d, 3H) 1.55 (s, 3H). 93 1-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl ketone 3,5-difluoropyridine (5.0 g, 43.45 mmol) in THF was cooled to _72t: (external - 80 ° C). LDA (23. 9 ml, 1.1 eq.) was added dropwise, so that The internal temperature did not increase by more than 3. During the addition, the reactants were converted to a dark brown thick phase. The reaction was stirred for 30 minutes. TMS-C1 (43. 4 mL, 43.45 mmol) was added dropwise in a relatively fast manner. The reaction became a clear, pale yellow solution. LDA (23. 9 mL, 1 1 eq.) was added dropwise, and the mixture was stirred for 2 hr. &lt;RTI ID=0.0&gt; 56.48 millimolar). The reaction was quenched by the addition of 20 mL of saturated nh 4 C1 solution at -78 ° C. The organic extract was evaporated under reduced pressure to give a color residue. Purified by ISCO (0-25% The title compound (3 g) was obtained from EtOAc / EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjj Ketooxime 1-(3,5-Difluoropyridin-2-yl)-2-decyloxyethanone (Intermediate 93) was dissolved in ethanol 133151 - 129 - 200906818 (255 mL, EtOAc). Hydroxylamine hydrochloride (i422 g, plus mM) was added followed by triethylamine (28 5 mL, 2 〇 4.61 mmol), and the resulting color mixture was heated to 5 Torr. Hey, it took 2 hours. The volatiles were evaporated under reduced pressure and the residue was partitioned between water (br. The separated aqueous layer was further extracted in &amp; ethyl acetate (255 ml). The combined organic extracts were washed with EtOAc EtOAc m. Purification by column chromatography (25-40%EtOAcEtOAcEtOAc) The title compound (12.3 g, 60.84 mmol, 44.6%, single. The liquid was evaporated under reduced pressure, and the residue was applied to EtOAc EtOAc EtOAc EtOAc EtOAc Oxyacetone (7.2 g, 35 62 mmol, 261%). LC-MS : 203 [M+H]+. Intermediate 95 (11)-1-(3,5-difluorop ratio bite_2_yl)_2-methoxyethylamine (R) phenylglycolate 1-(3,5-Difluoroacridin-2-yl)-2-methoxyethanone oxime (Intermediate 94) was dissolved in EtOAc (0.4M), then, then, Ba, under 4 )), subjected to catalytic hydrogenation (Pd/C) over an hour. The catalyst was filtered through celite and the filtrate of 1-(3,5-difluoropyridin-2-yl) 2-methoxyethylamine (0.4M in ethyl acetate) (180 mL &lt; Monomolar) was treated with (8)-phenylglycolic acid (5-81 g, 38.16 mmol). Precipitation was observed almost simultaneously and the resulting mixture was stirred overnight. Difluoropyrimidine 133151-130-200906818 pyridine-2- was collected via filtration. 2-methoxyethylamine (R)-phenylglycolate (8.5 g, 69.4%). After evaporation of the mother liquor, another palmate isomer (S)-l-(3,5-difluoropyridin-2-yl)-2-methoxyethylamine (R)-phenylglycolate was recovered. 1 H NMR (400 MHz) δ ppm 8.6 (s, 1H) 8.01 (m, 1H) 7.41 (t, 2H) 7.36 (t, 2H) 7.19 (m, 1H) 4.81 (s, 1H) 4.50 (m, 1H) 3.57 (d, 2H) 3.23 (s, 3H). LC-MS: 188 [MH]+ Intermediate 96 3,5-difluoro-2-mercaptopyridine in a 250 mL round bottom flask with THF (150) In liters of hydrazine monohydrate (17.69 ml, 563.61 mmol) and 2,3,5-trifluoropyridine (25.0 g, 187.87 mmol), a colorless solution was obtained. The reaction was heated with EtOAc (EtOAc) (EtOAc) The aqueous layer was extracted (3 x 30 mL). The organic layer was concentrated to afford a second product. The crude product was loaded on silica gel and eluted with EtOAc/hexane (30%). Concentrate to give the product (23.0 g, 84% yield). 1 H NMR δ 4.09 (s, 2H), 7.62 (ddd, 1H), 7.75 (s, 1H), 7.96 (d, 1H). 2-Bromo-3,5-difluoropyridine in a 500 ml round bottom flask was charged with 3,5-difluoro-2-mercaptopyridine in CHC13 (158 ml) (intermediate 96 '16.0 g, 110.26 m Moer), a brown suspension was obtained. The reaction was heated to 40. (3, and drip (14.20 ml, 275.65 mmol) was added dropwise for 15 minutes. The reaction mixture was allowed to stand at 6 Torr. After cooling to room temperature, the flask was placed in an ice bath and 133151 • 131 - 200906818 was added very slowly with saturated NaHC〇3 to quench the reaction. Dispensing to Dcm (2 χ 80 ml), extracted, dehydrated and dried (N^SO4), and concentrated to give a crude product. The crude product was added to a silica gel column and dissolved in Et 〇Ac/hexane (0-20%) to dissolve the collected. The product was concentrated to give the product (m.p., s., 56% yield). NMR (5 8.18 (td, 1H), 8.46 (d, 1H). Intermediate 98 2-exyl-3,5-fluoro- 4-(trimethylmethane)p is more than 2-bromo-based, 3,5-difluoropyridine (intermediate 97, 5.35 g in a stomach (552 ml) added to a 250 ml round bottom flask , 27.58 mmol, obtained a yellow solution. The solution was cooled to _78t, and LDA (22.98 ml, 41.37 mmol) was added. The solution was immediately converted to a dark color and stirred at room temperature for 1 hr. Trimethyl decane (3.66 ml, 28.96 mmol). After 5 hours, saturated ΝΗαι was added to quench the reaction, partitioned and extracted with Et0Ac (2 χ 3 〇 mL), dried (NaaSO4), And concentrated to give a crude product. The crude product was added to a silica gel column and eluted with Et0Ac/hexane (〇 2〇%). The collected fractions were concentrated to give the product (5.90 g, 80%) Rate)]H NMR δ 0.40 (s, 9H), 8.34 (s, 1H). Intermediate 99 N-(2-(2nd-butyldimethyl sulfhydryloxy) small (3,5_ Difluoro_4_(trimethylmethanol)»»Bist-2-yl)ethyl)-2-methylpropan-2-pyrrolidine in a 250 ml round bottom flask with THF In a (36 9 ml) solution of 2 bromo-3,5-fluoro- 4-(dimethyl sulphate) p was obtained as a yellow solution from the bite (intermediate 98, 59 g. m7 mmol). Allow the solution to cool to -78. (:, and add n_BuU (13.85 ml, 22.17 mmol). After stirring at this temperature for 1 〇, add 133151 -132- 200906818 plus N-(2-(Third-butyl dimethyl Shi Xiyuan) Alkoxy)ethylidene)_2_methylpropanone-2_ azine amide (intermediate 77, 7.38 g, 26.60 mmol). The reaction was stirred for a further 20 min and saturated Νί^α (40 ml) to quench the reaction. Warmed to EtOAc EtOAc (EtOAc (EtOAc) The oxime column was 'dissolved with EtOAC/Hyun> (0-60%). The collected fractions were concentrated to give the product (5.0 g, 48.5% yield). 1 H NMR (5 -0.17 (s) , 3Η), -0.06 (s, 3H), 0.37 (s, 9H), 0.71 (s, 9H), 1.05 (s, 9H), 3.92 (m, 2H), 4.67 (m, 1H), 5.50 (d , J = 7.91 Hz, 1H), 8.44 (s, 1H). Intermediate 99 can also be prepared by the following procedure: Add 3,5 of tetrahydrofuran (147 ml) to a 500 ml round bottom flask. -Fluorine p to obtain a colorless solution than bite (4_22 g '36.67 house Moules'. Allow the solution to cool to -78° C, then add LDA (20.37 ml, 36.67 mmol). After maintaining at -78 °C for 10 minutes, slowly add gas-based tridecyl decane (4 64 mL, 36-67 mmol). Hold at _78 °c for an additional 1 minute, slowly add LDA (50.9 ml, 91.67 mmol), and stir the mixture for 5 hours, then add N-(2-(third) in THF (20 mL) -butyldimethylmethylalkyloxy)ethylidene-2-methylpropane-2-sulfinylguanamine (intermediate 77, 1018 g, 36.67 mmol). 〇_5 hours later' Add saturated nh4C1 (8 mL) to quench the reaction. The mixture was extracted with EtOAc (2 X 50 mL), dried (NasSCU) and concentrated to give a crude product. 'And was dissolved in EtOAc / hexane (0-40%). The collected fractions were concentrated to give the product in 41.1% yield. Intermediate 100 133151 -133 - 200906818 1-(3,5-difluoropyridine 2_Base)_2_Hydroxyethylaminocarbamic acid 3D-butyl in a 200 ml round bottom flask, N_(2_(t-butyl-methyl-methyl sulphate) in methanol (45 ml) ) -1-(3,5-difluoro-4-(triterpene), succinyl-2-yl)ethyl)-2-methylpropane-2-sulfonyl decylamine 99,5 gram, 10.76 millimolar), obtained a brown solution. Allow the solution to cool to sputum and add HCl (4M in dioxin) (1 〇 76 mL, 43 〇 3 mmol). The reaction was stirred at 0 C for 1 hour. The solution was concentrated in a 250 mL round bottom flask to give a residue (2.65 g). Water (35 ml) was added to the residue to give a yellow solution. The reaction mixture was diluted with THF (70 mL). At room temperature, B〇C2〇 (3.00 ml, 12.91 mmol) and NaOH (8.61 ml, 5 M aqueous solution) were added. The reaction was stirred at room temperature for 1 hour. It was extracted with Et0Ac (2 χ 4 mL), dried (NasSO4), and concentrated to give a crude product. The crude product was loaded onto silica gel chromatography eluting with EtOAc/hexanes (20-80%). The collected fractions were concentrated to give the product (1-8 g, 61% yield). LC-MS (M+Na) = 297. Intermediate 101 1-(3,5-di- gas p-biti-2-yl)-2-methoxyethylamine decanoic acid _ butyl vinegar in 200 In a milliliter round bottom flask, add 1_(3,5-dipyridin-2-yl)-2-ethylaminocarbamic acid tert-butyl ester in thf (25 ml) (intermediate 100, 18 g) , 6.60 mmol, obtained a brown solution. The solution was cooled to -15 C using a NaC1_ ice bath. Potassium 2-butoxide (1.481 g, 13_2 mmol) was added. The reaction was kept at this temperature, and after 20 minutes, a formazan (〇·4ΐ3 ml, 6.6 house mole) was added. The reaction was allowed to pass at this temperature for 1.5 hours. The tlc monitor showed a small amount of starting material remaining, and an additional 0.3 g of KOt-Bu was added, followed by 133151 -134·200906818 0.05 ml of methyl iodide. After another 〇 minute, saturated NH4C1 was added to treat the reaction. Dispense, extract (EtOAc <RTI ID=0.0>: </RTI> <RTIgt; </RTI> <RTIgt; Add the crude product to the silicone column and

EtOAc/己烷（0-40%)溶離。使所收集之溶離份濃縮，獲得產物 (1.0 克，53%)。 1 H NMR 5 1.34 (s, 9H), 3.21 (s, 3H), 3.57 (d, 2H), 5.06 (d, 1H), 7.28 (d, 1H), 7.90 (m, 1H), 8.49 (m, 1H). 中間物102 l-(3,5-—氣p比咬_2_基）-2-甲氧基乙胺壅酸盥 於100毫升圓底燒瓶中，添加MeOH (5_0毫升）中之 氟吡啶-2-基）-2-甲氧基乙基胺基甲酸第三-丁酯（中間物1〇ι， 1.10克’ 3_82毫莫耳），獲得無色溶液。於溶液中，在室溫 下’添加二氧陸園中之HC1 (1_908毫升，7 63毫莫耳）。將反 應物在至溫下搜掉2小時。濃縮移除MeOH，並於殘留物中， 添加無水趟（10毫升）。傾析移除喊，及濃縮，獲得產物， 為固體（0.7克，97%)。 !H NMR 5 3.29 (s, 3H), 3.72 (m, 2H), 4.83 (s, 1H), 8.13 (m, 1H), 8.65 (m, 3H). 中間物103 1-(3,5-.一氣p比咬-2-基）乙網 將溴化甲基鎂（36.8毫升，117.78毫莫耳）在THF (50毫升）中 之溶液於N2下攪拌，並冷卻至_78它。以添液漏斗逐滴添加 THF (50毫升）中之3,5-二氟曱基吡啶腈（15.0克，107.07毫莫耳） ’其速率係致使内部溫度保持低於_4。(：。在添加完成後， 133151 •135· 200906818 將反應物倒入1MHC1(100毫升，於冰浴中急冷）中。將反應 物於0°C下攪拌30分鐘，並在室溫下30分鐘。於此溶液中， 添加150毫升EtOAc ’以萃取產物。以NaHC03使水相中和至 PH9 ’且以EtOAc(2x20毫升）萃取。合併有機層，及在減壓 下移除揮發性物質。藉ISC0純化（〇_1〇% EtOAc-己烷），獲得 標題化合物，為淡黃色油。 LC-MS : 158 [M+H]+ 中間物104 1-(3,5-二氟吡啶_2_基）乙酮肟 於1_(3,5-二氟p比α定-2-基）乙酮（中間物1〇3，12.91克，82.17毫 莫耳）在乙醇（164毫升）中之溶液内，添加經胺鹽酸鹽（8 56 克，123.25毫莫耳），接著為Et3N (17.18毫升，123.25毫莫耳）， 並將所形成之混合物於室溫下攪拌過夜。在減壓下移除揮 發性物質’且使所形成之殘留物於EtOAc/H2〇之間作分液處 理。將有機萃液以鹽水洗滌，及乾燥。獲得橘色黃色固體， 並藉ISCO純化（10% EtOAc/己烷-&gt; Μ% EtOAc/己烷），而得 1-(3,5-二氟吡啶-2-基）乙酮肪（9.73克，68_8%)，為黃色固體。 1H NMR (300 MHz, DMSO-d6) 5 ppm 2.19 (s，3H) 7·98 (ddd，J = 10.97, 8.81, 2.26 Hz, 1H) 8.55 (d, J = 2.26 Hz, 1H) 11.70 (s, 1H) LC-MS ： 173 [M+H]+ 中間物105 1-(3,5--«氣p比咬-2-基）乙胺 將1-(3,5-二氟叶(：咬-2-基）乙嗣月亏（中間物1〇4，9.73克，56.53 毫莫耳）添加至水（113毫升）中，以形成懸浮液。將氫氧化銨 133151 -136· 200906818 (22·〇1毫升，565·26毫莫耳），接著為醋酸銨（523克，π別毫 莫耳）添加至上述溶液中。將混合物在5(rc下加熱，接著分 次添加鋅（M.79克，mil毫莫耳），同時保持内部溫度低於 65°C。在添加完成後，將反應物於5〇t下攪拌3小時。添加 固體NaCl與EtOAe，以使反應淬滅，於室溫下授心小時， 然後’經過矽藻土墊過濾，並以Et〇Ac沖洗。將有機層以5 毫升2 _ 5 % Na0H (水溶液），接著以丨〇毫升_ 〇H洗滌。然後， 將有機層以鹽水洗滌，且以Ν%3〇4脫水乾燥。使有機層在 減壓下濃縮’獲得標題化合物，為淡黃色油。 1 H NMR (400 MHz, MeOD) &lt;5 ppm 1.62 (d, J = 6.82 Hz, 3H) 4.86 (q5 J = 6.82 Hz, 1H) 7.75 (ddd, J = 10.11, 8.34, 2.27 Hz, 1H) 8.49 (d, J = 2.27 Hz, 1H). 中間物106 (S)-l-(3,5-二氟吡啶-2-基）乙胺（R)_苯乙醇酸鹽 將1-(3,5-一 H说咬-2-基）乙酮辟（中間物，9.73克，56 53 毫莫耳）添加至水（113毫升）中，以形成懸浮液。將氫氧化銨 (22.01毫升，565.26毫莫耳），接著為醋酸銨（523克，6783毫 莫耳）添加至上述溶液中。將混合物在5(rc下加熱，接著分 次添加鋅（14.79克，226.11毫莫耳），同時保持内部溫度低於 65〇C 0 在添加完成後，將反應物於50°C下攪拌3小時。添加固體 NaCl與EtOAc，以使反應淬滅，在室溫下攪拌i小時，然後 經過矽藻土墊過濾，及以EtOAc沖洗。將有機層以5毫升2 5% NaOH(水溶液）’接著以1〇毫升洗滌。然後，將有機 133151 -137- 200906818 層以鹽水洗滌’並以Na2 S04脫水乾燥。使有機層在減壓下 濃縮，獲得標題化合物，為淡黃色油。 1 H NMR (400 MHz, MeOD) δ ppm 1.62 (d, J = 6.82 Hz, 3H) 4.86 (q, J = 6_82 Hz，1H) 7.75 (ddd, J = 10.11, 8.34, 2.27 Hz, 1H) 8.49 (d，J = 2.27 Hz， 1H). 將醋酸乙酯（10毫升）中之l-(3,5_二氟吡啶_2-基）乙胺（0.83 克’ 5.25宅莫耳）與（R)-2-經基-2-苯基醋酸（0.399克，2.62毫莫 耳）加熱至50°C。加熱數分鐘後，固體形成，且甚至在添加 另外5毫升EtOAc後’反應物並未溶解。將反應物於5〇〇C下 持續攪拌1小時。1小時後，使反應混合物冷卻至環境溫度。 經由重力過濾（無真空）收集固體，以醋酸乙酯洗滌，直到 橘色消失為止。固體（265毫克）係被碓認為標題化合物 (Crompak CR+ ’ 0_4 X 15 公分，98:2:0.1 H20:Me0H:TFA ’ 流率 1 毫升/分鐘，e.e &gt;98%)，為HC1鹽。關於e.e.測定之程序：將 5-10毫克（R)-苯乙醇酸鹽以數滴醚中之2N HC1處理，並濃縮， 接著，將EtOAc添加至此殘留物中。將所形成之白色固體 (HC1鹽）過濾，且利用以供e.e測定。 溶離時間：吸收峰1 ’ 3.19分鐘，吸收蜂2，4.46分鐘（標題 化合物）。 苯乙醇酸鹽： ^ NMR (300 MHz) &lt;5 ppm 1.6 (d, 3H) 4.4-4.6 (m, 2H) 7.5-7.8 (m, 5H) 8·0 (m，1H)，8.4 (寬廣 s_，1H). 中間物107 1-(3,5-二氟吡啶_2_基）乙醇 133151 -138· 200906818 於250毫升圓底燒瓶中，使ι_(3,5-二氟吡啶_2_基）乙酮（中間 物103 ’ 1_0克’ 6·36毫莫耳）溶於Me0H (3〇毫升）中辦得無 色溶液。冷卻至-10°C (在MeOH中之冰），並將硼氫化鈉（〇 〇6〇 克，1.59毫莫耳）於-10 C下添加至上述溶液中。將反應物攪 拌30分鐘。在減壓下濃縮移除MeOH，且於殘留物中，添加 飽和NaHC〇3，及以EtOAc萃取。將粗產物添加至矽膠管柱 中，並以EtOAc/DCM (20-50%)溶離。獲得標題化合物，為無 色油（600毫克）。 LC-MS : 160 [M+H]+ 中間物108 1·(3,5_ 一·氣p比咬_2·基）_2_甲氧基乙醇 使MeOH中之1-(3,5-二氟吡啶-2-基）-2-甲氧基乙酮（中間物 93 ’ 2.78克’ 14.85毫莫耳）冷卻至-7沈。分次添加NaBH4。 於添加NaBHU (藉TLC監測，25% EtOAc/己烷）後，反應幾乎同 時完成。添加NH4 C1溶液（1克，在2毫升Η2 Ο中），以使反應 淬滅。在減壓下移除溶劑，並使殘留物於DCM與Η2 Ο之間 作分液處理。使有機層以NazSO4脫水乾燥，及在減壓下濃 縮’而得黃色油。ISCO純化（25% EtOAc/己燒），獲得標題化 合物（2.0克）。 LC-MS ： 190 [M+H]+ 中間物109 5·氟基·2_乙稀基喊唆 於乙烯基三氟硼酸鉀（9.80克，73.19毫莫耳）、2-氣基-5-氟 基嘧啶（9.32毫升，73.19毫莫耳）、PPh3 (2.304克，8.78毫莫耳） 133151 -139- 200906818 及Cs2C03(71.5克，219.58毫莫耳）在THF (144毫升）與水（16毫 升）中之經攪拌溶液内，以一份添加PdCl2 (0.519克，2.93毫莫 耳）。將反應混合物加熱至85°C，歷經48小時。在冷卻後， 使反應混合物藉助於DCM (100毫升），經過矽藻土墊過濾。 將殘留在燒瓶中之固體以DCM研製，及過濾。使所形成之 濾液小心地濃縮，而得5-氟基-2-乙烯基嘧啶，為不均勻褐色 油，將其直接使用於下一步驟中。 NMR (400 MHz, CDC13) δ 5.70 (d, 1Η) 6.53 (dd, 1H) 6.86 (dd, 1H) 8.55 (s, 2H) ； LC-MS ： [M+H] = 124.36. 中間物110 敗基_2_(環氧乙烧基）0¾唆 於5-氟基-2-乙烯基嘧啶（中間物109，9.06克，73毫莫耳）、 (S,S)-(+)-N,Ν'-雙（3,5-二-第三-丁基亞柳基）-1,2-環己烷二胺基-氣 化錳（ΙΙΙ)(0·927克，1·46毫莫耳）與4-苯基丙基吡啶N-氧化物 (1.246克，5.84毫莫耳）及二鹽基性磷酸鈉（1.036克，7_30毫莫 耳）在水（76毫升）與DCM (106毫升）中之經攪拌溶液内，以一 份添加NaOCl溶液5.65-6% (380毫升，255.50毫莫耳）。將反應 混合物攪拌48小時。使反應物藉助於DCM經過矽藻土墊過 濾。以DCM萃取水層。使合併之有機萃液脫水乾燥（Na2S04)， 及濃縮。經由ISCO層析純化（0%至10%至20% EtOAc-己烷， DCM裝填量，Si02 )，獲得5-氟基-2-(環氧乙烷-2-基）嘧啶(2.80 克，27.4%)，為黃色油。 NMR (400 MHz, CDC13) δ 3.20 (ddd, 2Η) 4.12 (dd, 1H) 8.58 (s, 2H) ； LC-MS ： [M+H] = 140.61. 133151 -140- 200906818 中間物111 2-疊氮基-1-(5-氟基嘧啶-2-基）乙醇 於5-氟基-2_(環氧乙烷-2_基）嗜啶（中間物11〇，2.8克，19.98 毫莫耳）與氣化銨（1.817克，33.97毫莫耳）在Me〇H (2〇〇毫升） 中之經攪拌溶液内，以一份添加NaNg (3.25克，49.96毫莫耳）。 將反應混合物加熱至5〇。(： ’歷經8小時。在冷卻後，經由迴 轉式蒸發移除MeOH，並使所形成之固體於段〇^與鹽水之 間作分液處理。以EtOAc萃取水相，且使合併之有機層脫水 乾燥（Nas SO*)，及濃縮。經由JSCO層析純化（〇。/。至23%至50〇/〇 EtOAc-己烷，DCm裝填量，Si〇2)，獲得2_疊氮基_2_(5氟基嘧 啶-2-基）乙醇（0.500克，13.66%)與2-疊氮基氟基嘧啶_2_基） 乙醇（1.600克，43.7%)，為黃色油。 1H NMR (400 MHz, CDC13) δ 3.02 (t, 1Η) 4.07 (t, 2H) 4.74 (t, 1H) 8.64 (s, 2H) ； LC-MS ： [M-N2-H] = 154.42. 中間物112 2_(1-疊氮基-2-甲氧基乙基)_5·氟基嘧啶 於2-疊氮基-2-(5-氟基嘧啶_2_基）乙醇（中間物m，36〇毫克， h97耄莫耳）與質子-海綿（1，雙-(二甲胺基）-莕）(421毫克，1.97 宅莫耳）在DCM (19毫升）中之經攪拌溶液内，在〇〇c下，以 一份添加四氟硼酸三甲基鑕（291毫克，197毫莫耳）。藉tlc 監測反應。反應係進行至6〇%轉化率，然後陷入。添加另 外之質子-海綿（1，8-雙·(二甲胺基）_莕）(211毫克，〇 98毫莫耳） 與四氟硼酸二甲基錯（116毫克，〇 79毫莫耳）。反應係達到 85%轉化率。添加水，並使反應混合物於Et〇Ac與〇 5M (水溶 133151 -141 - 200906818 液）CuS〇4之間作分液處理’獲得部份乳化液。使此兩相混 合物藉助於EtOAc經過燒結漏斗過濾。分離液層，並以Et0Ac 萃取水相。使合併之有機物質脫水乾燥（Na2S〇4)，及濃縮。 經由ISCO層析純化（〇%至1〇%至20% EtOAc-己烷，DCM裝填 量，Si〇2)，獲得2-(1-疊氮基-2-甲氧基乙基）·5-氟基嘧啶（243 毫克，62.7%)，為無色油。 lH NMR (400 MHz, CDC13) δ 3.41 (s, 3Η) 3.85-3.94 (m, 2H) 4.80 (dd, 1H) 8.62 (s, 2H) ； LC-MS ： [M+H] = 198.01. 中間物113 1-(5-氟基嘧啶-2-基）-2-甲氧基乙胺鹽酸鹽 於2-(1-疊氮基·2-甲氧基乙基）各氟基嘧啶（中間物112，243 毫克’ 1.23毫莫耳）在THF (10.6毫升）與水（1.767毫升）中之經 攪拌溶液内，以一份添加4-二苯基膦基聚苯乙烯樹脂（998毫 克，1.85毫莫耳）。將反應混合物加熱至幻它，歷經2小時。 在冷卻後，將反應混合物藉助於EtOAc過濾，及濃縮，而得 K5-氟基嘧啶-2-基）-2-甲氧基乙胺（196毫克，93%)，為黃色 油，使用之而無需進一步純化。1H NMR (400 MHz, CDC13) 5 3.35 (s, 3H) 3.64 (dd, 1H) 3.76 (dd, 1H) 4.34 (dd, 1H) 8.57 (s, 2H)； LC-MS: [M+H] = m_82。其鹽酸鹽係藉由二氧陸圜中之4N Ha 添加至胺之甲醇性溶液中，接著蒸發溶劑至乾涸而製成。 中間物114 NK2-(第三·丁基二甲基發燒基氧基）小(5氟基峨咬_2基）乙 基)-2-甲基丙燒-2-亞確酿基酿胺 於2-溴基-5-氟基吡啶（5.2克，29毫莫耳）在8〇毫升無水 133151 •142- 200906818 MTBE中之溶液内，在-78°C下’慢慢添加LDA在戊燒中之 1.7M溶液（21毫升，36毫莫耳）。於_78t：下攪拌30分鐘後， 將N-(2-(第三-丁基二甲基矽烷基氧基）亞乙基）_2_曱基丙烷_2_ 亞磺醯基醯胺（中間物77，6.59克，24毫莫耳）在15毫升無水 MTBE中之〉谷液1(¾慢添加至反應混合物中，並在相同溫度下 再攪拌2小時。以飽和NH4C1水溶液使反應淬滅，以Et〇Ac 萃取，以無水Na2S〇4脫水乾燥。使所收集之有機層在真空 中》辰縮’然後藉管柱層析純化（3〇% EtOAc/己院），而得標題 化合物（8.0克，90%)，為黏稠油。 LC-MS ： 375 [M+H] 中間物115 [1-(5-氟基p比啶-2-基）-2-羥乙基]胺基甲酸第三_丁酯 於N-(2-(第三-丁基二甲基矽烷基氧基）_1(5_氟基吡啶冬基） 乙基）-2-甲基丙烷-2-亞磺醯基醯胺（中間物114，丨％克，6毫 莫耳）在50毫升Et0Ac中之溶液内，在室溫下，慢慢添加ΗαEtOAc/hexane (0-40%) was dissolved. The collected fractions were concentrated to give the product (1.0 g, 53%). 1 H NMR 5 1.34 (s, 9H), 3.21 (s, 3H), 3.57 (d, 2H), 5.06 (d, 1H), 7.28 (d, 1H), 7.90 (m, 1H), 8.49 (m, 1H). Intermediate 102 l-(3,5--gas p to bite_2_yl)-2-methoxyethylamine ruthenate in a 100 ml round bottom flask, add MeOH (5_0 ml) Tri-butyl fluoropyridin-2-yl)-2-methoxyethylcarbamate (intermediate 1 〇, 1.10 g '3_82 mmol) afforded a colorless solution. In the solution, add HC1 (1_908 ml, 7 63 mmol) in a dioxygen field at room temperature. The reaction was searched for 2 hours at the temperature. The MeOH was removed by concentration and EtOAc (EtOAc) The product was removed as a solid (0.7 g, 97%). !H NMR 5 3.29 (s, 3H), 3.72 (m, 2H), 4.83 (s, 1H), 8.13 (m, 1H), 8.65 (m, 3H). Intermediate 103 1-(3,5-. A solution of methylmagnesium bromide (36.8 ml, 117.78 mmol) in THF (50 mL) was stirred under N.sub.2 and cooled to _78. The 3,5-difluorodecylpyridinonitrile (15.0 g, 107.07 mmol) in THF (50 ml) was added dropwise with an addition funnel to keep the internal temperature below _4. (: After the addition was completed, 133151 • 135· 200906818 The reaction was poured into 1 MHC 1 (100 mL, quenched in an ice bath). The reaction was stirred at 0 ° C for 30 min and at room temperature for 30 min. To this solution, 150 ml of EtOAc was added to extract the product. The aqueous phase was neutralized to pH 9 ' with NaHC03 and extracted with EtOAc (2×20 mL). The title compound was obtained as a pale yellow oil. LC-MS: 158 [M+H]+ Intermediate 104 1-(3,5-difluoropyridine_2 Ethyl ketone oxime in a solution of 1_(3,5-difluorop than α-di-2-yl)ethanone (intermediate 1〇3, 12.91 g, 82.17 mmol) in ethanol (164 ml) The amine hydrochloride salt (8 56 g, 123.25 mmol) was added followed by Et3N (17.18 mL, 123.25 mmol), and the resulting mixture was stirred overnight at room temperature. Volatile material' and the resulting residue was partitioned between EtOAc/H.sub.2, and the organic extract was washed with brine and dried. Purification by ISCO (10% EtOAc / hexanes - &gt;&lt;RTIID=0.0&gt;&gt; Yellow solid. 1H NMR (300 MHz, DMSO-d6) 5 ppm 2.19 (s, 3H) 7·98 (ddd, J = 10.97, 8.81, 2.26 Hz, 1H) 8.55 (d, J = 2.26 Hz, 1H) 11.70 (s, 1H) LC-MS : 173 [M+H]+ Intermediate 105 1-(3,5--« gas p to bit-2-yl) ethylamine 1-(3,5-difluorofolate (: bite-2-yl) acetamidine loss (intermediate 1 〇 4, 9.73 g, 56.53 mmol) was added to water (113 ml) to form a suspension. Ammonium hydroxide 133151 -136· 200906818 (22·〇1 ml, 565·26 mmol), followed by ammonium acetate (523 g, π Åmol) added to the above solution. The mixture was heated at 5 (rc, followed by zinc addition ( M.79 g, mil millimolar while maintaining the internal temperature below 65 C. After the addition was complete, the reaction was stirred at 5 Torr for 3 hours. Solid NaCl and EtOAe were added to quench the reaction. Inoculate at room temperature for an hour, then 'filtered through a pad of diatomaceous earth and rinsed with Et〇Ac. The organic layer was 5 ml 2 _ 5 % Na 0H (aqueous solution), followed by washing with 丨〇ml_〇H. Then, the organic layer was washed with brine and dried with hydrazine. The organic layer was concentrated under reduced pressure to give the title compound as pale yellow oil. 1 H NMR (400 MHz, MeOD) &lt;5 ppm 1.62 (d, J = 6.82 Hz, 3H) 4.86 (q5 J = 6.82 Hz, 1H) 7.75 (ddd, J = 10.11, 8.34, 2.27 Hz, 1H) 8.49 (d, J = 2.27 Hz, 1H). Intermediate 106 (S)-l-(3,5-Difluoropyridin-2-yl)ethylamine (R)-phenylglycolate 1-(3,5 - One H said biti-2-yl) ethyl ketone (intermediate, 9.73 g, 56 53 mmol) was added to water (113 mL) to form a suspension. Ammonium hydroxide (22.01 ml, 565.26 mmol) followed by ammonium acetate (523 g, 6783 mmol) was added to the above solution. The mixture was heated at 5 (rc, followed by zinc addition (14.79 g, 226.11 mmol) while maintaining the internal temperature below 65 ° C 0. After the addition was complete, the reaction was stirred at 50 ° C for 3 hours. Solid NaCl and EtOAc were added to quench the reaction, which was stirred at room temperature for 1 hour, then filtered over a pad of celite and rinsed with EtOAc. The organic layer was then taken in 5 <RTIgt; The mixture was washed with 1 mL of EtOAc. EtOAc EtOAc EtOAc (EtOAc) , MeOD) δ ppm 1.62 (d, J = 6.82 Hz, 3H) 4.86 (q, J = 6_82 Hz, 1H) 7.75 (ddd, J = 10.11, 8.34, 2.27 Hz, 1H) 8.49 (d, J = 2.27 Hz , 1H). 1-(3,5-Difluoropyridin-2-yl)ethylamine (0.83 g ' 5.25 house moles) and (R)-2-yl group in ethyl acetate (10 ml) 2-Phenylacetic acid (0.399 g, 2.62 mmol) was heated to 50 ° C. After a few minutes of heating, a solid formed and the reaction was not dissolved even after the addition of another 5 mL of EtOAc. The reaction was stirred for 1 hour at 5 ° C. After 1 hour, the reaction mixture was cooled to ambient temperature. The solid was collected by gravity (without vacuum) and washed with ethyl acetate until the orange disappeared. 265 mg) is the title compound (Crompak CR+ '0_4 X 15 cm, 98:2:0.1 H20:Me0H:TFA 'flow rate 1 ml/min, ee &gt; 98%), which is the HCl salt. Procedure: 5-10 mg of (R)-phenylglycolate was treated with 2N of HCl in a few drops of ether and concentrated, then EtOAc was added to this residue. The white solid (HC1 salt) formed was filtered. And used for determination of ee. Dissolution time: absorption peak 1 ' 3.19 minutes, absorbed bee 2, 4.46 minutes (title compound). Parathionate: ^ NMR (300 MHz) &lt;5 ppm 1.6 (d, 3H) 4.4-4.6 (m, 2H) 7.5-7.8 (m, 5H) 8·0 (m, 1H), 8.4 (broad s_, 1H). Intermediate 107 1-(3,5-difluoropyridine_2-yl Ethanol 133151 -138· 200906818 In a 250 ml round bottom flask, make ι_(3,5-difluoropyridin-2-yl)ethanone (intermediate 103 '1_0g' 6·36 mmol) ) Was dissolved in Me0H (3〇 ml) to give a colorless solution do. It was cooled to -10 ° C (ice in MeOH) and sodium borohydride (5 克g, 1.59 mmol) was added to the above solution at -10 C. The reaction was stirred for 30 minutes. The MeOH was removed by EtOAc (EtOAc)EtOAc. The crude product was added to a silica gel column and was taken up in EtOAc / DCM (20-50%). The title compound was obtained as a colorless oil (600 mg). LC-MS : 160 [M+H]+ Intermediate 108 1·(3,5_一·gas p ratio bit_2·yl)_2_methoxyethanol to 1-(3,5-difluoro) in MeOH Pyridin-2-yl)-2-methoxyethanone (intermediate 93 ' 2.78 g ' 14.85 mmol) was cooled to -7. Add NaBH4 in several portions. After the addition of NaBHU (by TLC monitoring, 25% EtOAc/hexanes), the reaction was almost completed at the same time. NH4Cl solution (1 g in 2 mL Η2 Ο) was added to quench the reaction. The solvent was removed under reduced pressure and the residue was partitioned between DCM and EtOAc. The organic layer was dried over NazSO4 and concentrated under reduced pressure to give a yellow oil. ISCO was purified (25% EtOAc / EtOAc) LC-MS: 190 [M+H]+ Intermediate 109 5·Fluoro- 2-Ethyl group screamed with potassium trifluoroborate (9.80 g, 73.19 mmol), 2-carbyl-5- Fluoropyrimidine (9.32 ml, 73.19 mmol), PPh3 (2.304 g, 8.78 mmol) 133151 -139- 200906818 and Cs2C03 (71.5 g, 219.58 mmol) in THF (144 ml) with water (16 ml) In a stirred solution, PdCl2 (0.519 g, 2.93 mmol) was added in one portion. The reaction mixture was heated to 85 ° C over 48 hours. After cooling, the reaction mixture was filtered with EtOAc EtOAc. The solid remaining in the flask was triturated with DCM and filtered. The resulting filtrate was carefully concentrated to give 5-fluoro-2-vinylpyrimidine as a non-smooth brown oil which was used directly in the next step. NMR (400 MHz, CDC13) δ 5.70 (d, 1 Η) 6.53 (dd, 1H) 6.86 (dd, 1H) 8.55 (s, 2H) ; LC-MS : [M+H] = 124.36. Intermediate 110 _2_(epoxyethylidene) 03⁄4唆 in 5-fluoro-2-vinylpyrimidine (intermediate 109, 9.06 g, 73 mmol), (S,S)-(+)-N,Ν' - bis(3,5-di-t-butylarylene)-1,2-cyclohexanediamine-manganese hydride (ΙΙΙ) (0·927 g, 1.46 mmol) and 4-Phenylpropylpyridine N-oxide (1.246 g, 5.84 mmol) and dibasic sodium phosphate (1.036 g, 7-30 mmol) in water (76 mL) and DCM (106 mL) A solution of 5.65-6% (380 ml, 255.50 mmol) of NaOCl solution was added in one portion with stirring. The reaction mixture was stirred for 48 hours. The reaction was filtered through a pad of celite with DCM. The aqueous layer was extracted with DCM. The combined organic extracts were dried (Na2SO4) and concentrated. Purification by ISCO chromatography (0% to 10% to 20% EtOAc-hexanes, DCM, SiO2) afforded 5-fluoro-2-( ethane-2- yl) pyrimidine (2.80 g, 27.4 %) is a yellow oil. NMR (400 MHz, CDC13) δ 3.20 (ddd, 2 Η) 4.12 (dd, 1H) 8.58 (s, 2H) ; LC-MS : [M+H] = 140.61. 133151 -140- 200906818 Intermediate 111 2-fold Nitrol-1-(5-fluoropyrimidin-2-yl)ethanol in 5-fluoro-2-((oxiran-2-yl)isidine (intermediate 11 〇, 2.8 g, 19.98 mmol) NaNg (3.25 g, 49.96 mmol) was added in one portion with a stirred solution of ammonium sulfate (1.817 g, 33.97 mmol) in Me〇H (2 mL). The reaction mixture was heated to 5 Torr. (: 'After 8 hours. After cooling, the MeOH was removed via rotary evaporation and the solid formed was partitioned between EtOAc and brine. The aqueous phase was extracted with EtOAc. Dehydrated (Nas SO*), and concentrated. Purified by JSCO chromatography (〇·· to 23% to 50 〇/〇 EtOAc-hexane, DCm loading, Si 〇 2) to obtain 2-azide _ 2-(5-fluoropyrimidin-2-yl)ethanol (0.500 g, 13.66%) and 2-azidofluoropyrimidin-2-yl)ethanol (1.600 g, 43.7%) as a yellow oil. 1H NMR (400 MHz, CDC13) δ 3.02 (t, 1 Η) 4.07 (t, 2H) 4.74 (t, 1H) 8.64 (s, 2H) ; LC-MS : [M-N2-H] = 154.42. 112 2_(1-azido-2-methoxyethyl)_5·fluoropyrimidine in 2-azido-2-(5-fluoropyrimidin-2-yl)ethanol (intermediate m, 36〇) mM, h97 耄 Mo) with a proton-sponge (1, bis-(dimethylamino)- oxime) (421 mg, 1.97 house Moer) in a stirred solution in DCM (19 mL), in 〇〇 Under c, add trimethyl sulfonium tetrafluoroborate (291 mg, 197 mmol) in one portion. The reaction was monitored by tlc. The reaction was carried out to 6% conversion and then trapped. Add another proton-sponge (1,8-bis(dimethylamino)-oxime) (211 mg, 〇98 mmol) with dimethyl tetrafluoroborate (116 mg, 〇79 mmol) . The reaction system reached 85% conversion. Water was added, and the reaction mixture was subjected to liquid separation between Et 〇Ac and 〇 5M (water-soluble 133151 - 141 - 200906818) CuS 〇 4 to obtain a partial emulsion. The two phase mixture was filtered through a funnel using EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc. The combined organic materials were dried (Na2S 4) and concentrated. Purification by ISCO chromatography (〇% to 1% to 20% EtOAc-hexanes, DCM, &lt;RTI ID=0.0&gt; Fluoropyrimidine (243 mg, 62.7%) is a colorless oil. lH NMR (400 MHz, CDC13) δ 3.41 (s, 3 Η) 3.85-3.94 (m, 2H) 4.80 (dd, 1H) 8.62 (s, 2H) ; LC-MS : [M+H] = 198.01. 113 1-(5-Fluoropyrimidin-2-yl)-2-methoxyethylamine hydrochloride in 2-(1-azido-2-methoxyethyl)fluorofluoropyrimidine (intermediate) 112,243 mg ' 1.23 mmol) in a stirred solution of THF (10.6 mL) and water (1.767 mL), a portion of 4-diphenylphosphinopolystyrene resin (998 mg, 1.85 m) Moore). The reaction mixture was heated to phantom it over 2 hours. After cooling, the reaction mixture was applied EtOAcjjjjjjjjjjjjj No further purification is required. 1H NMR (400 MHz, CDC13) 5 3.35 (s, 3H) 3.64 (dd, 1H) 3.76 (dd, 1H) 4.34 (dd, 1H) 8.57 (s, 2H); LC-MS: [M+H] = M_82. The hydrochloride salt was prepared by adding 4N Ha in dioxane to a methanolic solution of the amine, followed by evaporation of the solvent to dryness. Intermediate 114 NK2-(Thr. Butyldimethylthioloxy) Small (5Fluoro-Butyl-2-yl)ethyl)-2-methylpropan-2-ol 2-Bromo-5-fluoropyridine (5.2 g, 29 mmol) in a solution of 8 mL of anhydrous 133151 • 142-200906818 MTBE, slowly add LDA in the burn at -78 °C 1.7 M solution (21 mL, 36 mmol). After stirring for 30 minutes at _78t:, N-(2-(t-butyl dimethyl decyloxy)ethylidene) 2 - decylpropane 2 sulfinyl decylamine (intermediate) 77, 6.59 g, 24 mmol.) In a 15 ml portion of anhydrous MTBE, the solution was slowly added to the reaction mixture and stirred at the same temperature for an additional 2 hours. The reaction was quenched with a saturated aqueous solution of NH4C1. The title compound (8.0 g) was obtained from EtOAc (EtOAc). , 90%), as a viscous oil. LC-MS: 375 [M+H] Intermediate 115 [1-(5-Fluoro-p-pyridin-2-yl)-2-hydroxyethyl]carbamic acid III _Butyl ester in N-(2-(t-butyldimethyl decyloxy)_1(5-fluoropyridinyl)ethyl)-2-methylpropane-2-sulfinyl hydrazide Amine (intermediate 114, 丨% gram, 6 mmol) in a solution of 50 ml of Et0Ac, slowly add Ηα at room temperature

在一氧陸圜中之4M溶液(4·6毫升）。反應混合物轉變成混濁 岭液，然後白色固體開始沉澱析出。於室溫下2小時後，添 以供完成所要產物之沉澱作用。在室溫 將所形成之液體部份藉傾析移除。使殘 加乙醚（50毫升）， 下靜置30分鐘後， 留固體部份在真空下乾燥，I用於下一步驟。在室溫下， 將口體&quot;』、、加至20笔升水、4〇毫升ΤΗρ及4 8毫升5N_Na〇H中， 接著為Boe2〇 (1.7克）中。於室溫下授拌2小時後，將反應物 XEtOAc萃取，以無水Na2S〇4脫水乾燥。使所收集之有機層 在”工中展細’然後藉管柱層析純化(肋μ己炫），而 133151 -143- 200906818 得標題化合物（1.29克’ 84%)，為淡黃色油。 LC-MS ： 257 [Μ+Η] 中間物116 1-(5-氟基吡啶-2-基）-2-甲氧基乙胺鹽酸鹽 於[1-(5-氟基吡啶-2-基）-2-羥乙基]胺基甲酸第三-丁醋（中間 物115，1.27克，5毫莫耳）在18毫升無水xhf中之溶液内， 在-15°C下’慢慢添加THF中之20%第三-丁醇鉀溶液。於相 同溫度下攪拌20分鐘後，添加〇j2毫升Mel，然後，使其溫 熱至室溫。以飽和氣化銨溶液使反應混合物淬滅，以Et〇Ac 萃取，以無水Naz SO4脫水乾燥。使所收集之有機層在真空 中濃縮，然後藉管柱層析純化（20-30% EtOAc/己烷），而得[1_(5_ 氟基叶b啶-2-基）-2-曱氧基乙基]胺基甲酸第三_丁酯（〇58克， 45%) ’為黏稠油。使所形成之油溶於Et〇Ac (1〇毫升）中，並 以二氧陸園中之4M HC1處理。在室溫下2小時後，添加乙醚 (20毫升）’以供完成所要產物之沉澱作用。於室溫下靜置 30分鐘後，將所形成之液體部份藉傾析移除。使殘留固體 部份在真空下乾燥’而得高度濕敏性標題化合物（267毫克， 72°/。’為單鹽酸鹽），為無色固體。 LC-MS ： 171 [M+H]. 1 H NMR (500 MHz) δ 3.23 (s, 3H), 3.69 (d, 2H), 4.55 (m, 1H), 7.67 (m, 1H), 7_82 (m, 1H) 8.59 (d, 1H) 8_65 (寬廣 s，2H). 中間物117 3-(4-氣基-6-(3-甲基-1H-吡唑-5-基胺基)-l，3,5-三畊-2-基胺基)_2,2-一氟-3-(5-氟基p比唆-2·基）丙-1-醇 133151 •144· 200906818 使用類似關於中間物17合成所述之程序，使3胺基_2 2-二 氟-3-(5-氟基吡啶-2-基）丙-1-醇鹽酸鹽（中間物71，273毫克， 1.54毫莫耳）與4,6-二氯-N-(5-甲基-1H-P比。坐-3-基）-i，3,5-三呼_2_ 胺（中間物18，500毫克，1.54毫莫耳）反應，提供標題化合 物。 LC-MS : 415 [Μ+Η]+· 中間物118 3-(4-氣基-6-(3-甲基-1Η-吡唑-5-基胺基w，％三畊_2•基胺基）_ 3-(5-氟基吡啶-2-基）丙醯胺 使用類似關於中間物17合成所述之程序，使3_胺基_3_(5_ 氟基吡啶-2-基）丙醯胺（中間物69，273毫克，1.54毫莫耳）與 4,6-二氯-N-(5-曱基-1H-吡唑-3-基）-1,3,5_三畊冬胺（中間物18， 500毫克，1.54毫莫耳）反應，提供標題化合物。 LC-MS ： 392 [M+H]+. 中間物119 (6-氯_N2-(1_(5-氟基嘧啶_2_基）-2•甲氧基乙基）_n4_(3甲基_ih吡 嗤-5-基）-1，3,5-三 p井-2,4-二胺 使用類似關於中間物17合成所述之程序，使i_(5_氟基嘧 啶-2-基）-2-甲氧基乙胺（中間物113)與4,6_二氣_N_(5_甲基_ih-吡 唑-3-基）-1，3,5-三畊-2-胺（中間物18)反應，提供標題化合物。 LC-MS ： 380 [M+H]+. 中間物120 3-(4-氣基-6-(3-曱基-1H_吡唑_5_基胺基三畊_2_基胺 基）各(5-氟基吡啶-2-基）鼻甲基丙醯胺 133151 -145- 200906818 ^類㈣於中間物17合成所述之程序，使3_胺基邻_ 氟基峨咬-2-基沖.甲基丙醯胺鹽酸鹽（中間物％，功 U4毫莫耳）與4,6_二氯-N-(5-甲基-1H-峨。坐-3-基M 3 5.三呼2 料中間物18，則毫克，W毫莫耳）反應，提供標題化合 物。 LC-MS ： 406 [M+H]+. 中間物121 3-(4-氣基-6-(3-甲基-m_吡唑冬基胺基三啩：基胺 基）-3-(5-氟基p比咬_2_基）丙腈 使用類似關於中間物17合成所述之程序，使3_胺基_3_(5_ 氟基峨。定-2-基）丙腈鹽酸鹽（中間物63，273毫克，i M毫莫 耳）與4,6-二氯-N-(5-甲基-1H-吡唑-3-基）·1，3,5-三畊劣胺（中間物 18，500毫克，1.54毫莫耳）反應，提供標題化合物。 LC-MS ： 374 [Μ+Η]+ 中間物122 3_(4-氯基-ό-Ρ-甲基-1Η-Ρ比吐_5_基胺基）-ΐ，3,5-三喷_2•基胺 基）-3-(5-氟基吡啶-2-基）-Ν，Ν-二甲基丙醯胺 使用類似關於中間物17合成所述之程序，使3_胺基_3_(5_ 氟基ρ比。定-2-基）-Ν，Ν-二曱基丙醯胺鹽酸鹽（中間物76)與4,6·二 氣-Ν-(5-甲基-1Η-吡唑-3-基)-1,3,5-三畊-2-胺（中間物18)反應，提 供標題化合物。 LC-MS ： 420 [M+H]+. 中間物124 6-氣-N-[5-(2-環己基乙基）·1Η-吡唑-3-基]-N，-[(lS)-l-(5-氟基嘧咬 133151 •146- 200906818 -2-基）乙基]-1，3,5-三畊-2,4-二胺 使用類似關於中間物17合成所述之程序，使（s)-l-(5-氟基 嘧啶-2-基）乙胺鹽酸鹽（中間物5，208毫克，U7毫莫耳）與 4.6- 二氣-N-(3-(2-環己基乙基）_1H-毗唑-5-基）-1，3,5-三畊_2_胺（中 間物155，400毫克，1_17毫莫耳）反應’提供標題化合物。 1 H NMR (300 MHz，MeOD) 5 ppm 8·72 (s，2H)吡唑 C-4,質子並非 顯而易見 5.34 (q，1Η) 2.66 (t，2Η) 0.92-1.89 (m, 16Η). LC-MS ： 447 [M+H]+ . 中間物125 6-氣-N-[(lS)-l-(5-氟基嘧啶-2-基）乙基]-Ν，-[5_(4·甲氧苯基 唑-3-基】-I，3,5-三畊-2,4-二胺 使用類似關於中間物17合成所述之程序，使⑻_1(5氣基 嘧啶-2-基）乙胺鹽酸鹽（中間物5，263毫克，1.48毫莫耳）與 4.6- 二氣-N-(3-(4-曱氧苯基HH-吡唑-5-基）-1,3,5-三呼-2-胺（中間 物156 , 500毫克，1.48毫莫耳）反應，提供標題化合物。 1H NMR (300 MHz, MeOD) 5 ppm 8.73 (s, 2H) 7.75 (d, 2H) 7.06 (d, 2H) 5.38 (q, 1H) 3.87 (s, 3H) 1.63 (d, 3H). LC-MS ： 442 [M+H]+ 中間物126 3_(4_氱基邻-f基_1H_P比4 _5_基胺基从於三呼基胺 基)-3-(5-氟基p比咬-2-基）丙·ι_醇 使用類似關於中間物17合成所述之程序，使3_胺基邻 氟基说咬·2-基）丙-i —醇鹽酸鹽（中間物82)與4,6•二氯邵-甲 基-m㈣-3-基Η，3»井·2_胺（中間物18)反應，提供標題化 133151 -147- 200906818 合物。 LC-MS ： 379 [M+H]+. 中間物127 6-氣-N2-(1-(5-氟基吡啶-2-基）-2-(曱磺醯基）乙基__(3_甲基仙· 吡唑-5-基）-1,3,5-三畊-2,4-二胺 使用類似關於中間物17合成所述之程序，使μ(5_氟基吡 啶-2-基）-2-(甲磺醯基）乙胺鹽酸鹽（中間物67)與4,6_二氣_N_(5_ 甲基-1H-吡唑-3-基）-1，3,5·三畔-2-胺（中間物18)反應，提供標題 化合物。 LC-MS ： 427 [Μ+Η]+. 中間物128 6-氣-Ν-[5-(4-氟苯基)-1Η-吡唑-3-基]-N，-[(lS)-l-(5-氟基嘧啶-2-基） 乙基]-1，3,5-三畊-2,4-二胺 使用類似關於中間物17合成所述之程序，使（§)_丨_(5_氟基 嘧啶-2-基）乙胺鹽酸鹽（中間物5，273毫克，i 54毫莫耳）與 4,6-二氯-N-(3-(4-氟苯基）_1H-吡唑-5-基）-1,3,5-三畊-2-胺（中間物 154 ’ 500毫克’ 1.54毫莫耳）反應’提供標題化合物。 lU NMR (300 MHz, MeOD) δ ppm 8.74 (s, 2H) 7.85 (m, 2H)7.20 (m, 2H)吡唑C-4’並非顯而易見5·37 (q，1H) Μ〗（d, SH) LC-MS ： 430 [M+H]+. 中間物129 6-氣-N-[(lS)-l-(5-氟基嘧啶_2_基）己基】_n，-(5-嘍吩-2-基-1H-吡唑 -3-基）-1,3,5-三哨· -2,4-二胺 使用類似關於中間物17合成所述之程序，使（s)-l-(5-氟基 133151 -148- 200906818 嘧啶-2-基）乙胺鹽酸鹽（中間物5，227毫克，i28毫莫耳）與 4,6-二氯-N-(3-(4% -2-基 HH4。坐錢 Η，3κ ,井 _2,胺（中間物 157，400毫克，L28毫莫耳）反應，提供標題化合物。 !H NMR (300 MHz, MeOD) ^ ppm 8.74 (s, 2H) 7.33-7.57 (m, 2H) 7.11 (m，1H)吡唑之C-4'質子並非顯而易見5 37 (q，1H) 163风3Η)· LC-MS ： 418 [M+H]+. 中間物130 2-(二氟甲基）嗎福啉 將DCM (20毫升）中之2_甲醯基嗎福啉斗羧酸第三-丁酯 (383笔克，1.78毫莫耳）添加於具有冷水冷凝器之二頸燒瓶 中，在0 C下以DAST (三氟化二乙胺基硫，〇 564毫升，4 27 毫莫耳）處理，其速率係致使内部溫度不超過高於〇_rc。使 此δ物’皿熱至室溫過夜。使液相在DCM與飽和水溶 液之間分離。將有機層以玛〇洗滌，脫水乾燥，及在減壓 下蒸發揮發性物質，獲得2_(二氟曱基）嗎福啉_4•羧酸第三_ 丁酯（〜420 毫克）；！ η NMR ⑷（MeOD) : 5·76 (m，1H)，3 79 (m，3H)， 3.47 (m’ 2H)’ 2.96 (m，2H)，L41 (s，9H)。使 2-(二氟甲基）嗎福啉 _4· 羧酸第三-丁酯溶於MeOH(3毫升）中，並添加Ηα(2Ν，在醚 中，5毫升，lo.oo毫莫耳）。將所形成之反應混合物於室溫 下攪拌2小時，及在減壓下蒸發揮發性物質，而得標題化合 物。 中間物131 N2 -(H5·氟基峨咬_2·基)_2_甲氧基乙基）_N4 _(5•甲基_m•吡唑） 基）_6-嗎福啉基-1，3,5-三畊_2,4-二胺 133151 -149- 200906818 使用類似關於中間物17合成所述之程序，使1-(5-氟基吡 啶-2-基）-2-甲氧基乙胺鹽酸鹽（中間物116)與4,6-二氣-N-(5-曱 基-111-吡唑-3-基）-1，3,5-三畊-2-胺（中間物18)反應，提供標題化 合物。 LC-MS ： 379 [M+H]+ 中間物132 (S)-4-氣-]\-(1-(5_氟基嘧啶-2-基）乙基)-6-嗎福啉基-1，3,5-三畊-2-胺 使乙醇（80毫升）中之2,4,6-三氯-1，3,5-三畊（3·69克，20毫莫 耳）冷卻至-78°C。在另一個燒瓶中，將乙醇（20毫升）中之 (S)-l-(5·氟基嘧啶-2-基）乙胺鹽酸鹽（中間物5，3.55克，2〇 〇〇 莫耳）以DIPEA (6_99毫升’ 40.00毫莫耳）處理，並將所形成 之混合物授拌30分鐘’此時，將其逐滴添加至含有預冷卻 至-78°C之乙醇（80毫升）中之2,4,6-三氣-1，3,5-三畊（3.69克，204M solution (4.6 mL) in monohydrate. The reaction mixture was converted to a turbid ridge, and then a white solid began to precipitate. After 2 hours at room temperature, it was added to complete the precipitation of the desired product. The formed liquid portion was removed by decantation at room temperature. After leaving diethyl ether (50 ml), the mixture was allowed to stand for 30 minutes, and then the solid portion was dried under vacuum. At room temperature, add the mouth &quot;,, to 20 liters of water, 4 liters of ΤΗρ and 48 ml of 5N_Na〇H, followed by Boe2〇 (1.7 g). After 2 hours of stirring at room temperature, the reactant X EtOAc was extracted and dried over anhydrous Na 2 EtOAc. The collected organic layer was subjected to "small work" and then purified by column chromatography (yield), and 133151 - 143 - 200906818 obtained the title compound (1.29 g ' 84%) as pale yellow oil. -MS: 257 [Μ+Η] Intermediate 116 1-(5-Fluoropyridin-2-yl)-2-methoxyethylamine hydrochloride in [1-(5-fluoropyridin-2-yl) ) 2-hydroxyethyl]aminocarbamic acid tert-butyl vinegar (intermediate 115, 1.27 g, 5 mmol) in 18 ml of anhydrous xhf, slowly adding THF at -15 °C 20% third potassium butoxide solution. After stirring at the same temperature for 20 minutes, add 2 ml of Mel, then warm to room temperature. The reaction mixture was quenched with saturated ammonium sulfate solution. Extracted by Et〇Ac, dried over anhydrous Naz SO4. The obtained organic layer was concentrated in vacuo and purified by column chromatography (20-30% EtOAc/hexane) to give [1_(5_ B-pyridine-2-yl)-2-nonyloxyethyl]carbamic acid tert-butyl ester (〇58 g, 45%) 'is a viscous oil. The resulting oil was dissolved in Et 〇Ac (1 〇 In ML) and treated with 4M HC1 in Dioxin. At room temperature 2 After that time, diethyl ether (20 ml) was added to complete the precipitation of the desired product. After standing at room temperature for 30 minutes, the formed liquid portion was removed by decantation. The residual solid portion was under vacuum. The title compound was obtained as a colorless solid (yield: 267 mg, EtOAc (yield: s). (s, 3H), 3.69 (d, 2H), 4.55 (m, 1H), 7.67 (m, 1H), 7_82 (m, 1H) 8.59 (d, 1H) 8_65 (broad s, 2H). Intermediate 117 3-(4-Alkyl-6-(3-methyl-1H-pyrazol-5-ylamino)-l,3,5-trin-2-ylamino)_2,2-fluoro- 3-(5-Fluoro-p-indol-2-yl)propan-1-ol 133151 •144· 200906818 Using a procedure similar to that described for the synthesis of intermediate 17, 3 amino-amino 2 2-difluoro-3- (5-Fluoropyridin-2-yl)propan-1-ol hydrochloride (intermediate 71, 273 mg, 1.54 mmol) and 4,6-dichloro-N-(5-methyl-1H- Reaction of P. -3-yl)-i,3,5-tri-h-_2-amine (Intermediate 18,500 mg, 1.54 mmol) afforded the title compound. LC-MS: 415 [Μ+Η] +· Intermediate 118 3-(4-Alkyl-6-(3-methyl-1Η-pyrazole) -5-ylamino group w, % tritonic _2 amino group) 3-(5-fluoropyridin-2-yl)propanamide using a procedure similar to that described for the synthesis of intermediate 17 to give 3_ Amino_3_(5-fluoropyridin-2-yl)propanamide (intermediate 69, 273 mg, 1.54 mmol) and 4,6-dichloro-N-(5-mercapto-1H-pyrazole Reaction of -3-yl)-1,3,5-tri-methanol (intermediate 18, 500 mg, 1.54 mmol) afforded the title compound. LC-MS: 392 [M+H]+. Intermediate 119 (6-chloro-N2-(1_(5-fluoropyrimidin-2-yl)-2 methoxyethyl)_n4_(3 methyl _ Ih(pyridin-5-yl)-1,3,5-tri-p--2,4-diamine using a procedure similar to that described for the synthesis of intermediate 17 to give i_(5-fluoropyrimidin-2-yl) 2-methoxyethylamine (intermediate 113) and 4,6_digas_N_(5-methyl-ih-pyrazol-3-yl)-1,3,5-trinyl-2-amine (Intermediate 18) reaction to give the title compound. LC-MS: 380 [M+H]+. Intermediate 120 3-(4-carbyl-6-(3-mercapto-1H-pyrazole-5-yl) Amine-based three-tillage __amino-amine) each (5-fluoropyridin-2-yl)-nasyl propyl guanamine 133151 -145- 200906818 ^ class (d) in the intermediate 17 synthesis of the described procedure, so that 3_ Amino- ortho-fluoro-indenyl-2-pyrene.methylpropanamide hydrochloride (intermediate %, work U4 millimolar) and 4,6-dichloro-N-(5-methyl-1H) - 峨. -3-M, M3, </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -(4-Alkyl-6-(3-methyl-m-pyrazolylaminotrimethyl:amino)-3-(5-fluoropyp-bito-2-yl)propanenitrile is similar About Intermediate 1 7 Synthesize the procedure to give 3-amino-3_(5-fluoroylindole-2-yl)propanenitrile hydrochloride (intermediate 63, 273 mg, i M millimoles) with 4,6- Reaction of dichloro-N-(5-methyl-1H-pyrazol-3-yl)·1,3,5-tribasic amine (18,500 mg, 1.54 mmol) afforded the title compound. LC-MS : 374 [Μ+Η]+ Intermediate 122 3_(4-Chloro-indole-indole-methyl-1Η-Ρ比吐_5_ylamino)-ΐ,3,5-三喷_ 2•Aminoamino)-3-(5-fluoropyridin-2-yl)-indole, hydrazine-dimethylpropionamide using a procedure similar to that described for the synthesis of intermediate 17 to give the 3-amino group _3_ (5_Fluoryl ρ ratio. Benz-2-yl)-indole, fluorenyl-dimercaptopropionamine hydrochloride (Intermediate 76) and 4,6·di- Ν-(5-methyl-1Η- Reaction of pyrazol-3-yl)-1,3,5-trinyl-2-amine (Intermediate 18) afforded the title compound: LC-MS: 420 [M+H]+. Intermediate 124 6 N-[5-(2-cyclohexylethyl)·1Η-pyrazol-3-yl]-N,-[(lS)-l-(5-fluoropyrimidine 133151 •146- 200906818 -2-yl Ethyl]-1,3,5-trin-2,4-diamine using a procedure similar to that described for the synthesis of intermediate 17 to give (s)-l-(5-fluoropyrimidin-2-yl) Ethylamine hydrochloride (Intermediate 5,208 mg, U7 mmol) and 4.6-di-gas-N-(3-(2-cyclohexylethyl)_1H-pyrazol-5-yl)-1,3,5-three tillage _2_amine (intermediate 155,400 mg, 1-17 mmol) reaction afforded the title compound. 1 H NMR (300 MHz, MeOD) 5 ppm 8·72 (s, 2H) pyrazole C-4, protons are not obvious 5.34 (q, 1 Η) 2.66 (t, 2 Η) 0.92-1.89 (m, 16 Η). LC -MS : 447 [M+H]+ . Intermediate 125 6-Gas-N-[(lS)-l-(5-fluoropyrimidin-2-yl)ethyl]-oxime,-[5_(4· Methoxyphenyl azole-3-yl]-I,3,5-trinol-2,4-diamine was prepared using a procedure similar to that described for the synthesis of intermediate 17 to give (8) _1 (5-hydroxypyrimidin-2-yl) Ethylamine hydrochloride (intermediate 5,263 mg, 1.48 mmol) and 4.6-di-gas-N-(3-(4-indolylphenylHH-pyrazol-5-yl)-1,3, Reaction of 5-triox-2-amine (Intermediate 156, 500 mg, 1.48 mmol) afforded the title compound. 1H NMR (300 MHz, MeOD) 5 ppm 8.73 (s, 2H) 7.75 (d, 2H) 7.06 (d, 2H) 5.38 (q, 1H) 3.87 (s, 3H) 1.63 (d, 3H). LC-MS : 442 [M+H]+ Intermediate 126 3_(4_氱-o-f-group_1H_P a procedure similar to that described for the synthesis of intermediate 17 using a ratio of 4 _5_ylamino group from tris-ylamino)-3-(5-fluorop-buty-2-yl)propanol _Amino- ortho-fluoro-based butyl 2-yl) propyl-i-alcohol hydrochloride (intermediate 82) and 4,6•dichloro-s-methyl-m(tetra)-3-ylindole, 3» well 2-Amine (Intermediate 18) is reacted to provide the title compound 133151-147-200906818. LC-MS: 379 [M+H]+. Intermediate 127 6-gas-N2-(1-(5-fluoro) Pyridin-2-yl)-2-(indolyl)ethyl__(3_methylxian·pyrazol-5-yl)-1,3,5-trin-2,4-diamine Using a procedure similar to that described for the synthesis of intermediate 17, a mixture of μ(5-fluoropyridin-2-yl)-2-(methylsulfonyl)ethylamine hydrochloride (Intermediate 67) with 4,6_2 Reaction of _N_(5-methyl-1H-pyrazol-3-yl)-1,3,5-tri-amyl-2-amine (Intermediate 18) afforded the title compound. LC-MS: 427 [Μ+Η ]+. Intermediate 128 6-Gas-Ν-[5-(4-fluorophenyl)-1Η-pyrazol-3-yl]-N,-[(lS)-l-(5-fluoropyrimidine- 2-yl)ethyl]-1,3,5-tri-n--2,4-diamine using a procedure similar to that described for the synthesis of intermediate 17 to give (§)_丨_(5-fluoropyrimidine-2 -yl)ethylamine hydrochloride (intermediate 5,273 mg, i 54 mmol) and 4,6-dichloro-N-(3-(4-fluorophenyl)_1H-pyrazol-5-yl -1,3,5-Tricotin-2-amine (intermediate 154 '500 mg '1.54 mmol) reaction provided the title compound. lU NMR (300 MHz, MeOD) δ ppm 8.74 (s, 2H) 7.85 (m, 2H) 7.20 (m, 2H) pyrazole C-4' is not obvious 5.37 (q,1H) Μ〗 (d, SH LC-MS : 430 [M+H]+. Intermediate 129 6-Gas-N-[(lS)-l-(5-Fluoropyrimidin-2-yl)hexyl]_n,-(5- porphin -2-yl-1H-pyrazol-3-yl)-1,3,5-trisole·-2,4-diamine using a procedure similar to that described for the synthesis of intermediate 17 to give (s)-l- (5-fluoro group 133151 -148- 200906818 pyrimidin-2-yl)ethylamine hydrochloride (intermediate 5,227 mg, i28 mmol) and 4,6-dichloro-N-(3-(4%) -2-yl HH4. Reaction of hydrazine, 3κ, well _2, amine ( intermediate 157,400 mg, L28 mmol) afforded the title compound.H NMR (300 MHz, MeOD) ^ ppm 8.74 (s , 2H) 7.33-7.57 (m, 2H) 7.11 (m,1H) pyrazole C-4' proton is not obvious 5 37 (q,1H) 163 wind 3Η)· LC-MS : 418 [M+H]+ Intermediate 130 2-(Difluoromethyl)fosfoline Addition of 2-methylglycosylporphyrin carboxylic acid tert-butyl ester (383 g, 1.78 mmol) in DCM (20 mL) In a two-necked flask with a cold water condenser, DAST (diethylammonium trifluoride, 〇564 m) at 0 C , 4 27 mM), the rate is such that the internal temperature does not exceed 〇_rc. The δ's dish is allowed to warm to room temperature overnight. The liquid phase is separated between DCM and a saturated aqueous solution. Wash with malt, dehydrate dry, and evaporate volatiles under reduced pressure to obtain 2_(difluoroindolyl) phenanthroline-4 carboxylic acid tert-butyl ester (~420 mg); η NMR (4) ( MeOD) : 5·76 (m, 1H), 3 79 (m, 3H), 3.47 (m' 2H)' 2.96 (m, 2H), L41 (s, 9H). 2-(difluoromethyl) The valproline _4·carboxylic acid tert-butyl ester was dissolved in MeOH (3 ml), and Ηα (2 Ν in ether, 5 ml, lo. oo m.) was added. After stirring at room temperature for 2 hours, and evaporation of the volatile material under reduced pressure, the title compound was obtained. Intermediate 131 N2 - (H5 · fluoro s s s s s s s s s s s s s s s s s s s s s s s s s s 5•Methyl_m•pyrazole)yl)_6-homofolinyl-1,3,5-three tillage _2,4-diamine 133151 -149- 200906818 Using a procedure similar to that described for the synthesis of intermediate 17 To make 1-(5-fluoropyridin-2-yl)-2-methoxyethylamine hydrochloride (middle 116) Reaction with 4,6-di-n-(5-fluorenyl-111-pyrazol-3-yl)-1,3,5-trin-2-amine (Intermediate 18) to provide the title compound . LC-MS: 379 [M+H]+ Intermediate 132 (S)-4-V------(1-(5-Fluoropyrimidin-2-yl)ethyl)-6-morpholinyl- 1,3,5-Tricotin-2-amine Cools 2,4,6-trichloro-1,3,5-three tillage (3·69 g, 20 mmol) in ethanol (80 ml) to -78 ° C. (S)-l-(5.Fluoropyrimidin-2-yl)ethylamine hydrochloride (Intermediate 5, 3.55 g, 2 Torr) in ethanol (20 mL) in a separate flask Treated with DIPEA (6_99 ml '40.00 mmol) and the resulting mixture was mixed for 30 minutes. At this point, it was added dropwise to ethanol (80 mL) containing pre-cooled to -78 °C. 2,4,6-three gas-1,3,5-three tillage (3.69 g, 20

毫莫耳）之燒瓶内。將反應物於-78°C下攪拌2小時。LC-MS 顯示完成’且完全轉化。使反應混合物再冷卻至，經 由注射器逐滴添加乙醇（1〇毫升）中之嗎福啉（1 742毫升， 20.00毫莫耳）與DIPEA(3.49毫升，20.00毫莫耳）。將反應物於 -78°C下攪拌2小時，接著在室溫下過夜。於減壓下移除揮 發性物質，並使殘留物在咏〇之間作分液處理。使 有機相脫水乾燥，及在真空中濃縮，產生標題化合物。 LC-MS ： 340 [M+H]+. 中間物133 2_(曱氧基曱基）嗎福啉鹽酸鹽 於2_(經甲基）嗎福啉_4_羧酸第三_丁酯（3〇〇毫克，1;38毫莫 133151 -150- 200906818 耳）在無水DMF(4毫升）中之溶液β，在此及氮氣下，添加 60%氫化鈉（83毫克，2.07毫莫耳），並將此懸浮液於室溫下 攪拌30分鐘。將碘甲烷（2舛毫克，2〇7毫莫耳）在〇。〇下添加 至反應混合物中，且於室溫下攪拌過夜。在真空中移除溶 劑，使殘留物溶於DCM (20毫升）中’以水（1〇毫升）洗滌，及 以NazSO4脫水乾燥。在減壓下蒸發揮發性物質，獲得殘留 物使其溶於甲醇（3毫升）中，接著添加二氧陸園中之4M (0.8毫升）。將所形成之混合物於室溫下攪拌2小時，及在減 壓下蒸發揮發性物質，而得標題化合物。Millions of flasks. The reaction was stirred at -78 °C for 2 h. LC-MS showed complete 'and complete conversion. The reaction mixture was again cooled to a solution of EtOAc (1 742 mL, 20.00 mmol) and DIPEA (3.49 mL, 20.00 mM) in ethanol (1 mL). The reaction was stirred at -78 °C for 2 hours then at room temperature overnight. The volatile material was removed under reduced pressure and the residue was partitioned between hydrazines. The organic phase was dried to dryness and concentrated in vacuo to give title compound. LC-MS: 340 [M+H]+. Intermediate 133 2 - (decyloxy decyl) phenanthroline hydrochloride in 2- _ (methyl) phenanthroline _ 4-carboxylic acid tert-butyl ester ( 3 mg, 1; 38 mmol 133151 -150- 200906818 ear) solution β in anhydrous DMF (4 ml), and 60% sodium hydride (83 mg, 2.07 mmol) was added thereto under nitrogen. The suspension was stirred at room temperature for 30 minutes. Methyl iodide (2 舛 mg, 2 〇 7 mmol) was added. The mixture was added to the reaction mixture under stirring and stirred at room temperature overnight. The solvent was removed in vacuo and the residue was taken-upjjjjjjjjjjjjj The volatiles were evaporated under reduced pressure to give crystals crystals crystals crystals crystals The resulting mixture was stirred at room temperature for 2 hours, and the volatile material was evaporated under reduced pressure to give the title compound.

1 H NMR (300 MHz, MeOD) 5 ppm 4.72 (d, J = 11.11 Hz, 2H), 4.58 (t, J =11.87 Hz, 1H), 4.17 (m, 2H), 4.05 (s, 3H), 3.94 (m, 2H), 3.72 (t, J = 9.70 Hz, 1H), 3.56 (q, J = l〇.86 Hz, 1H). 中間物134 2-(—氮四園-1-基甲基）嗎福淋鹽酸鹽 於至皿下，將二乙醯氧基棚氫化納（mi毫克，2_52毫莫耳） 添加至2-甲醯基嗎福啉_4_羧酸第三_丁酯（181毫克，〇·84毫莫 耳）與一氮四園（57_6毫克，1.01毫莫耳）在以-二氣乙烷（3毫 升）中之溶液内。將混合物在室溫下攪拌24小時，以飽和氯 化銨水溶液使反應淬滅，以DCM萃取，並以Na2S〇4脫水乾 燥。於減壓下蒸發揮發性物質，獲得無色固體，使其溶於 甲醇（3毫升）中，且添加二氧陸圜中之4河HC1 (〇 8毫升）。將 所形成之混合物在室溫下授拌2小時，蒸發，而得標題化合 物。 NMR (300 MHz, MeOD) &lt;5 ppm 4.21 (m, 4H), 3.96 (t, J = 11.87 Hz, 133151 151 - 200906818 1H), 3.67 (m, 2H), 3.43 ( ^ ^ s.} 1H), 3.33 (d, J = 1.32 Hz, 2H), 3.23 (d, J = 12.06 Hz, 1H), 3.05 ( t ^ s.} 1H), 2.64 (d, J = 7.91 Hz, 1H), 2.45 ( % 廣 s., 1H)，1.39 (m，1H) 中間物135 2-(嗎福p林-2-基）乙赌鹽酸鹽 將氰化鉀（158毫克，2_42毫莫耳）添加至2_(甲苯磺醯基氧 基曱基）嗎福啉-4-羧酸第三-丁酯（3〇〇毫克，〇 81毫莫耳）在 EtOH (5毫升）中之溶液内，將混合物於8〇°c下授拌2天然 後冷卻至室溫，並經過矽藻土過濾。在減壓下蒸發揮發性 物質，獲得無色固體，使其溶於甲醇（3毫升）中，且添加二 氧陸圜中之4M HC1 (0.8毫升）。將所形成之混合物在室溫下 攪拌2小時’蒸發’而得標題化合物。 !H NMR (300 MHz, CDC13) δ ppm 4.07 (m, 1H), 3.85 (m, 3H), 3.61 (m, 2H), 3.41 (m, 2H), 2.90 (t, J = 11.40 Hz, 1H), 2.67 (m, 1H) 中間物136 (R) -2_(4-(3,4_二甲氧基爷基）嗎福n林_3_基）乙腈 使用類似關於中間物135合成所述之程序，使4_曱苯續酸 (S) -(4-(3,4-.一曱氧基卞基）嗎福p林-3-基）甲g旨（中間物138，1 657 克’ 3.93¾莫耳）與NaCN(0.636克，12.97毫莫耳）反應，提供 標題化合物。 ]H NMR (CD2C12) δ 6.94 (s, 1H), 6.82 (m, 2H), 3.83 (s, 3H), 3.82 (m, 1H), 3.80 (s, 3H), 3.75 (d, 1H), 3.66 (m, 3H), 3.34 (d, 1H), 2.86 (m, 1H), 2.80 (dd, 1H), 2.64 (m, 1H), 2.54 (dd, 1H), 2.34 (m, 1H). LC-MS ： 277 [M+H]+ 133151 -152- 200906818 中間物137 (R)-2-(嗎福啉-3-基）乙腈，TFA鹽 使用類似關於中間物50合成所述之程序，使（(r)_2-(4-(3,4- 二甲氧基苄基）嗎福啉-3-基）乙腈（中間物136)反應，提供標題 化合物。 中間物138 2-(甲苯績酿基氧基甲基）嗎福淋-4-叛酸第三-丁酯 於2-(羥曱基）嗎福啉-4-羧酸第三-丁酯（中間物134，1〇〇毫 克’ 0.46毫莫耳）在3毫升DCM中之溶液内，添加Bel與 DMAP。在冷卻至〇°c後，添加TEA，並使混合物溫熱至室 /si過仪’然後置於20宅升水與2毫升飽和碳酸钟中。以dcm (3 X 10毫升）萃取，脫水乾燥，及揮發性物質在減壓下之後 續蒸發’獲得殘留物。於矽膠上純化，以Et〇Ac/己烷（1/2 v/v) 溶離，而得標題化合物（131毫克，77%)。 1 H NMR (300 MHz,氣仿-d) (5 ppm 7.71 (m，J = 8.29 Hz，2H)，7.27 (m， J = 8.10 Hz, 2H), 3.93 (m, 2H), 3.74 (dd, J = 11.21, 2.54 Hz, 3H), 3.52 (m, J = 10.24, 4.97, 2.54, 2.40 Hz, 1H), 3.37 (td, J = ll.59s 2.64 Hz, 1H), 2.81 (t, J - 11.11 Hz, 1H), 2.58 (寬廣 s” 1H), 2.37 (s, 3H)，1.37 (s, 9H)_ LC-MS ： 272.2 [M+H]+ 中間物139 6-氣-N-[(lS)-l-(5-氟基嘧啶_2-基）乙基]苯氧基曱基）_1H_ 吡唑各基]-1，3,5_三畊-2,4-二胺 使用類似關於中間物17合成所述之程序，使⑻+(5敗基 鳴咬-2-基）乙胺鹽酸鹽（中間物5，263毫克，ι ·48毫莫耳）與 133151 •153- 200906818 4,6-二氣-N-(3-(苯氧基甲基）-lH-w：l：。坐-5-基）-l，3,5-三啡_2_胺（中間 物178 ’ 500毫克’ 1_48毫莫耳）反應，提供標題化合物。 !H NMR (300 MHz, MeOD) δ ppm 8.73 (s, 2H) 7.32 (d, 2H) 6 92-7 11 (m, 3H) 5.31 (q, 1H) 5.10 (s, 2H) 1.62 (d, 3H). LC-MS ： 442 [M+H]+ 中間物140-147係使用類似關於中間物π合成所述之程序 製成。 中間物140 (S)-6-氯-N2-(l-(5氟基嘧啶-2-基）乙基）-N4-(5-苯乙基 _1Η_ρΛ 峻 _3_ 基）-1，3,5-三畊-2,4-二胺 起始物質：4,6-二氣-Ν-(5-苯乙基-1Η-吡唑-3-基）_l53,5_三呼_2_ 胺（中間物148)與（S)-l-(5-氟基嘧啶-2-基）乙胺鹽酸鹽（中間物 5)。 LC-MS : 440 [M+H]+ · 中間物141 (S)_6_氣-N2-(5-(4_氣基苯乙基）-lH-峨唾-3-基）-N4-(l-(5-|L 基，咬 -2-基）乙基）-l，3,5-三 11 井-2,4-二胺 起始物質：4,6-二氯-N-(5-(4-|t基苯乙基）-1Η-ρ比嗤-3-基）-l,3,5- 三畊-2-胺（中間物149)與（S)-l-(5-氟基嘧啶_2-基）乙胺鹽酸鹽 (中間物5)。 LC-MS ： 458 [M+H]+. 中間物142 (S)-6-氣-N2-(5-(3-氟基苯乙基比嗤-3-基）-N4-(l-(5-氟基嘧咬 -2-基）乙基）_ι，3,5-三 11 井-2,4-二胺 133151 -154- 200906818 起始物質：4,6-二氣-N-(5-(3-氟基苯乙基）-1Η-ρ比唾-3-基 ζ 畊 -2-胺 （ 中間物 150) 與⑻-1-(5-氟基嘧 。定 -2-基）乙胺 鹽酸鹽 (中間物5)。 LC-MS ： 458 [M+H]+. 中間物143 (S)_6_ 氣-N2-(5-(3,5-二氟苯乙基）-1Η·ρ比峻-3-基）-Ν4-(1-(5-氟基, 啶-2-基）乙基）-1,3,5-三畊-2,4-二胺1 H NMR (300 MHz, MeOD) 5 ppm 4.72 (d, J = 11.11 Hz, 2H), 4.58 (t, J = 11.87 Hz, 1H), 4.17 (m, 2H), 4.05 (s, 3H), 3.94 (m, 2H), 3.72 (t, J = 9.70 Hz, 1H), 3.56 (q, J = l〇.86 Hz, 1H). Intermediate 134 2-(-aza-tetra-l-yl-methyl) The hydrazine hydrochloride is added to the dish, and the diethyl hydrazine hydride sodium (mi mg, 2_52 mmol) is added to the 2-methyl hydrazinofosino-4 carboxylic acid tert-butyl ester ( 181 mg, 〇·84 mmoles) and a solution of a nitrogen tetragen (57_6 mg, 1.01 mmol) in a solution of di-hexane (3 mL). The mixture was stirred at room temperature for 24 hours. The reaction was quenched with EtOAc EtOAc. The volatiles were evaporated under reduced pressure to give a white solid crystals. The resulting mixture was stirred at room temperature for 2 hours and evaporated to give the title compound. NMR (300 MHz, MeOD) &lt;5 ppm 4.21 (m, 4H), 3.96 (t, J = 11.87 Hz, 133151 151 - 200906818 1H), 3.67 (m, 2H), 3.43 ( ^ ^ s.} 1H) , 3.33 (d, J = 1.32 Hz, 2H), 3.23 (d, J = 12.06 Hz, 1H), 3.05 ( t ^ s.} 1H), 2.64 (d, J = 7.91 Hz, 1H), 2.45 ( %广s., 1H), 1.39 (m, 1H) Intermediate 135 2-(Hofopin-2-yl)Betylamine hydrochloride Add potassium cyanide (158 mg, 2_42 mmol) to 2_( Toluenesulfonyloxyindolyl) phenanthroline-4-carboxylic acid tert-butyl ester (3 mg, 〇81 mmol) in EtOH (5 mL), the mixture was taken at 8 〇 The mixture was stirred at °c for 2 days and then cooled to room temperature and filtered through diatomaceous earth. The volatiles were evaporated under reduced pressure to give EtOAc (EtOAc m. The resulting mixture was stirred at room temperature for 2 hours to evaporate to give the title compound. !H NMR (300 MHz, CDC13) δ ppm 4.07 (m, 1H), 3.85 (m, 3H), 3.61 (m, 2H), 3.41 (m, 2H), 2.90 (t, J = 11.40 Hz, 1H) , 2.67 (m, 1H) Intermediate 136 (R) -2_(4-(3,4_Dimethoxy)yl) n- _3_yl) acetonitrile is used in a similar manner to the synthesis of intermediate 135 Procedure to make 4_nonylbenzene acid (S)-(4-(3,4-.-indolyloxy) ruthenium p--3-yl) A g (intermediate 138, 1 657 g' 3.933⁄4 mol) was reacted with NaCN (0.636 g, 12.97 mmol) to afford the title compound. H NMR (CD2C12) δ 6.94 (s, 1H), 6.82 (m, 2H), 3.83 (s, 3H), 3.82 (m, 1H), 3.80 (s, 3H), 3.75 (d, 1H), 3.66 (m, 3H), 3.34 (d, 1H), 2.86 (m, 1H), 2.80 (dd, 1H), 2.64 (m, 1H), 2.54 (dd, 1H), 2.34 (m, 1H). LC- MS: 277 [M+H]+ 133151 -152 - 200906818 Intermediate 137 (R)-2-(m-fosolin-3-yl)acetonitrile, TFA salt using a procedure similar to that described for the synthesis of intermediate 50, (r) 2-(4-(3,4-Dimethoxybenzyl)fosfolin-3-yl)acetonitrile (Intermediate 136) gave the title compound. Intermediate 138 2- (Toluene) Oxy-methyl)ofafox-4-reacidic third-butyl ester in 2-(hydroxyindole)norfosolin-4-carboxylic acid tert-butyl ester (intermediate 134, 1 〇〇 mg' 0.46 In a solution of 3 ml of DCM, add Bel and DMAP. After cooling to 〇°c, add TEA and warm the mixture to room/si. Then place in 20 liters of water and 2 ml. In a saturated carbonic acid clock, extracting with dcm (3×10 ml), dehydration drying, and subsequent evaporation of the volatile material under reduced pressure afforded residue. Purified on silica gel to Et EtOAc / hexane (1/2) v/v) dissolve The title compound (131 mg, 77%). 1H NMR (300 MHz, EMI-D) (5 ppm 7.71 (m, J = 8.29 Hz, 2H), 7.27 (m, J = 8.10 Hz, 2H ), 3.93 (m, 2H), 3.74 (dd, J = 11.21, 2.54 Hz, 3H), 3.52 (m, J = 10.24, 4.97, 2.54, 2.40 Hz, 1H), 3.37 (td, J = ll.59s 2.64 Hz, 1H), 2.81 (t, J - 11.11 Hz, 1H), 2.58 (broad s) 1H), 2.37 (s, 3H), 1.37 (s, 9H)_ LC-MS : 272.2 [M+H] + intermediate 139 6-gas-N-[(lS)-l-(5-fluoropyrimidin-2-yl)ethyl]phenoxyindenyl)_1H_pyrazole each]-1,3,5_ Trisin-2,4-diamine was used in a procedure similar to that described for the synthesis of intermediate 17 to give (8) + (5 ungrouped ketone-2-yl) ethylamine hydrochloride (intermediate 5,263 mg, ι 48 mM) and 133151 • 153- 200906818 4,6-di-gas-N-(3-(phenoxymethyl)-lH-w:l:. Reaction with -5,3,5-trimorph-2-amine (intermediate 178 '500 mg' 1 - 48 mmol) afforded the title compound. !H NMR (300 MHz, MeOD) δ ppm 8.73 (s, 2H) 7.32 (d, 2H) 6 92-7 11 (m, 3H) 5.31 (q, 1H) 5.10 (s, 2H) 1.62 (d, 3H LC-MS: 442 [M+H]+ Intermediate 140-147 was prepared using procedures similar to those described for intermediate π synthesis. Intermediate 140 (S)-6-Chloro-N2-(l-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-phenethyl_1Η_ρΛ __3_ base)-1,3, 5-trinol-2,4-diamine starting material: 4,6-diqi-indole-(5-phenethyl-1Η-pyrazol-3-yl)_l53,5_threeh_2_amine Intermediate 148) with (S)-l-(5-fluoropyrimidin-2-yl)ethylamine hydrochloride (Intermediate 5). LC-MS: 440 [M+H]+ · Intermediate 141 (S)_6_ gas-N2-(5-(4-carbophenethyl)-lH-indole-3-yl)-N4-( L-(5-|L-based, keto-2-yl)ethyl)-l,3,5-tri-11 well-2,4-diamine starting material: 4,6-dichloro-N-(5 -(4-|t-phenylethyl)-1Η-ρ than indole-3-yl)-l,3,5-trinyl-2-amine (intermediate 149) and (S)-l-(5- Fluoropyrimidin-2-yl)ethylamine hydrochloride (Intermediate 5). LC-MS: 458 [M+H]+. Intermediate 142 (S)-6-V-N2-(5-(3-fluorophenylethylethyl)-3-yl)-N4-(l-( 5-fluoropyrimidin-2-yl)ethyl)_ι,3,5-tri-11 Well-2,4-diamine 133151 -154- 200906818 Starting material: 4,6-digas-N-(5 -(3-fluorophenylethyl)-1Η-ρ than sani-3-yl hydrazine-2-amine (intermediate 150) and (8)-1-(5-fluoropyrimidin-2-yl) Amine hydrochloride (Intermediate 5) LC-MS: 458 [M+H]+. Intermediate 143 (S) _6_ gas-N2-(5-(3,5-difluorophenethyl)-1Η· ρ 比峻-3-yl)-Ν4-(1-(5-fluoro,pyridin-2-yl)ethyl)-1,3,5-trin-2,4-diamine

起始物質：4,6-二氯-N-(5-(3,5-二氟苯乙基）_ih_^吐_3_ 基）-1，3,5-三畊-2-胺（中間物151)與（S)-l-(5-氟基嘧啶冬基）乙胺 鹽酸鹽（中間物5)。 LC-MS : 476 [Μ+Η]+· 中間物144 (S)-6-氣-Ν2_(5·(2,4_二氟苯乙基）m_p比峻 _3 基）_ν4_(ι_(5_氟基喷 咬-2-基）乙基）-1，3,5-三 _ -2,4-二胺 起始物質：4,6-二氯鄉_(2,4_二ι苯乙基）_ΐΗ_吡唑各 基）-1，3,5-三哜_2_胺（中間物152)與⑻小(5_氟基嘧啶冬基 鹽酸鹽（中間物5)。 土 LC-MS : 476 [Μ+Η]' t間物145 唆-2-基）乙基）_1，3,5-三畊_2,4_二胺 二始5物^ Μ-二氯·N-(3-(3,4_二氟苯乙基)*吨。“ 基)-，，_二__2_胺（巾間物⑸)與⑻邻_氟基” 鹽酸鹽（中間物5)。 基）乙月女 133151 -155- 200906818 LC-MS ： 476 [M+H]+. 中間物146 6-氣-N-{3-[2-(2,6-二氟苯基）乙基】-1H-吡唾-5-基}-N，-[(lS)-l-(5-氟 基嘧啶_2·基）乙基】-1，3,5-三畊_2,4-二胺 起始物質：4,6-二氣-N-{3-[2-(2,6-二氟苯基）乙基]-1H-吡唑-5-基}-1，3,5-三畊-2-胺（中間物158)與（S)-l-(5-氟基嘧啶-2-基）乙胺 鹽酸鹽（中間物5)。 LC-MS : 476 [M+H]+_ 中間物147 (S)-6-氣-N2-(5-(3,4-二甲氧苯乙基）·1Η-吡唑-3-基）-N4-(1-(5-氟基 嘧啶-2-基）乙基）-1，3,5-三畊_2,4·二胺 起始物質：4,6-二氣-N-(5-(3,4-二甲氧苯乙基）-lH-吡唑-3-基）-1,3,5-三畔-2-胺（中間物159)與（S)-l-(5-氟基嘧啶-2-基）乙胺 鹽酸鹽（中間物5)。 LC-MS ： 500 [M+H]+. 下列中間物148-157係使用類似關於中間物18所述之程序 製成。 中間物148 4.6- 二氣-N-(5-苯乙基-1H-吡唑-3-基）-1,3,5-三畊-2-胺 起始物質·· 5-苯乙基-1H-吡唑-3-胺（中間物162)與2,4,6-三氯 -1,3,5-三畊。 LC-MS : 336 [M+H]+. 中間物149 4.6- 二氯-义(5-(4-氟基苯乙基)-111-吡唑-3-基)-1，3,5-三啡-2-胺 133151 •156- 200906818 起始物質·· 5-(4-氟基苯乙基）-1Η-吡唑-3-胺（中間物163)與 2.4.6- 三氯-1,3,5-三畊。 LC-MS ： 354 [M+H]+. 中間物150 4.6- 二氯-Ν-(5-(3·氟基苯乙基）-1Η-吡唑-3-基H，3，S-三呼_2_胺 起始物質：5-(3-氟基苯乙基）-1Η·ρ比哇-3-胺（中間物164)與 2.4.6- 三氯-1，3,5-三畊。 LC-MS : 354 [Μ+Η]+. 中間物151 4.6- 二氣-Ν-(5-(3,5-二氟苯乙基）-1Η-吡唑 _3_基）-1，3,5_三喷 _2_胺 起始物質：5-(3,5-二氟苯乙基）-1Η-吡唑-3-胺（中間物165)與 2.4.6- 三氣-1，3,5-三 口井。 LC-MS ： 372 [Μ+Η]+. 中間物152 — 氣-Ν-(5-(2,4-一氧苯乙基）-1Η-ρ比唆-3-基）-1，3,5-三 ρ井-2-胺 起始物質：5-(2,4-二氟苯乙基）-1Η-吡唑-3·胺（中間物166)與 2.4.6- 三氯-1，3,5-三畊。 LC-MS ： 372 [Μ+Η]+. 中間物153 4.6- 二氣-Ν-(3-(3,4-二氣苯乙基）-1Η-ρ比峻-5_基）-1，3,5-三 ρ井-2-胺 起始物質：3-(3,4-二氟苯乙基）-lH-毗唑-5-胺（中間物167)與 2.4.6- 三氯-1,3,5-三畊。 LC-MS ： 372 [Μ+Η]+. 中間物154 133151 -157- 200906818 4.6- 二氣-N-(5-(4-氟苯基）-1Η-吡唑-3-基）-l，3,5-三畊·2·胺 起始物質：5-(4-氟苯基）-1Η-吡唑-3-胺與2,4,6-三氯-1，3,5-三 畊。 LC-MS ： 326 [Μ+Η]+. 中間物155 4.6- 二氣-Ν-(5_(2-環己基乙基）-1Η-ρ比唾-3-基）-l，3,5-三味-2-胺 起始物質：5-(2-環己基乙基）-1Η-吡唑-3-胺與2,4,6-三氣-1,3,5- 三畊。 LC-MS ： 342 [Μ+Η]+. 中間物156 4,6·二氣-Ν-(5-(4_甲氧苯基)-1Η-吡唑-3-基)-1,3,5-三畊-2-胺 起始物質：5-(4-甲氧苯基）-1Η-吡唑-3-胺與2,4,6-三氯-1,3,5- 三畊。 LC-MS : 338 [Μ+Η]+· 中間物157 4,6·二氣-Ν-(5_(ρ塞吩 _2_基）-1Η-ρ比嗤-3-基）-1，3,5-三，井-2-胺 起始物質：5七塞吩-2-基）-1!1-吡唑-3-胺與2,4,6-三氣-1，3,5-三 畊。 LC-MS ： 314 [Μ+Η]+. 中間物158 4,6·二氣-Ν-{3-[2-(2,6-二氟苯基）乙基】-1Η-吡唑-5-基}-1,3,5-三呼 -2-胺 起始物質：3-[2-(2,6-二氟苯基）乙基]-1Η-吡唑-5-胺（中間物 169)與 2,4,6-三氯-1，3,5-三畊。 133151 -158- 200906818 LC-MS ： 372 [M+H]+. 中間物159 4,6-二氣-N-(5-(3,4-二曱氧苯乙基比唑-3-基）-l，3,5-三畊 _2胺 起始物質：5-(3,4-二曱氧苯乙基）-1Η-吡唑-3-胺（中間物no) 與2,4,6-三氣-1，3,5-三畊。 LC-MS ： 396 [M+H]+. 中間物160 3-酮基-4-苯氧基丁腈 使乙腈（1.998毫升’ 38.26毫莫耳）溶於無水二氧陸圜（5〇毫 升）中，接著添加NaH (1.808克，41.45毫莫耳）。將所形成之 反應混合物於室溫下攪拌0.5小時。添加2-苯氧基醋酸乙醋 (5毫升，31.88毫莫耳），並將所形成之溶液在85〇c下加熱24 小時。蒸發溶液，於醋酸乙酯與水之間分離。藉由2Ν Ηα 使水層酸化，然後，以EtOAc萃取（2x)，且使合併之有機層 脫水乾燥。在減壓下蒸發揮發性物質，獲得標題化合物（〇 88 克）。 中間物161 3-(苯氧基甲基）-1Η-吡唑-5-胺 使3-酮基-4-苯氧基丁腈（中間物156，〇 88克，5 〇2毫莫耳） 溶於乙醇（ίο毫升）中，並添加胼（〇 189毫升，6 〇3毫莫耳）。 將反應混合物在室溫下攪拌1〇分鐘，然後於85&lt;&gt;c下加熱牝 小時。在減壓下条發揮發性物質，獲得殘留物，使其藉isc〇 純化（MeOH/DCM 丨5%) ’而得標題化合卿泌克）。 LC-MS ： 190 [M+H]+ 133151 -159、 200906818 中間物162-170係使用類似關於 中間物161合成所 序製成。 中間物162 5-苯乙基-1H-吡唑-3-胺 起始物質：3-酮基-5-苯基戊腈與肼 LC-MS ： 188 [Μ+Η]+· 中間物163 5-(4-氟基苯乙基）-1Η-吡唑-3-胺 起始物質：5-(4-氟苯基）-3-酮基戊腈與肼 LC-MS ： 206 [M+H]+. 中間物164 5-(3·氟基苯乙基）-1Η-吡唑-3-胺 起始物質：5-(3-氟苯基)-3-酮基戊腈與肼 LC-MS ： 206 [M+H]+. 中間物165 5-(3,5-二氟苯乙基）-lH-吡唑-3-胺 起始物質：5-(3,5-二氟苯基）-3-酮基戊腈與肼 LC-MS : 224 [M+H]+_ 中間物166 5-(2,4-二氟苯乙基）_1H-吡唑-3-胺 起始物質：5-(2,4-二氟苯基）-3-酮基戊腈與肼 LC-MS ： 224 [M+H]+. 中間物167 3-CM-二氟苯乙基）-1Η-吡唑-5-胺 133151 -160- 200906818 起始物質：3-(3,4-二氟苯基)-3-S同基戊腈與月井 LC-MS ： 224 [M+H]+. 中間物168 3-(2-(吡啶-4-基）乙基）-1Η-吡唑-5-胺 起始物質：3-酮基-5-(p比》定-4-基）戊腈與月井 LC-MS: 189[Μ+Η]+. 中間物169 3-【2-(2,6-二氟苯基）乙基]-1Η-吡唑-5-胺 起始物質.5-(2,6-二氟苯基）-3-酮基戊腈與胼 LC-MS ： 224 [M+H]+. 中間物170 5-(3,4-二甲氧苯乙基）-1Η-吡唑-3-胺 起始物質：5-(3,4-二曱氧基苯基）-3-酮基戊腈與月井 LC-MS : 248 [Μ+Η]+· 其相應之腈類係根據類似WO 2008/001070中所述之程序製 成。 中間物171 6·氯-N-[(lS)-l-(5-氟基，唆·2·基）乙基】(三甲基發 烧基）乙氧基】甲基}-1Η-味嗤-2-基）乙基]-lH-p比嗤_5·基卜ι，3,5-三 啡-2,4-二胺 使用類似關於中間物17合成所述之程序，使4,6_二氣 -Ν-{3-[2-(1-{[2-(三甲基石夕烧基）乙氧基；]甲基}_1Η，。坐_2_基）乙 基]-1Η-吡唑-5-基}-1,3,5-三畊-2-胺（中間物172)與（S)-l-(5-氟基 嘧啶-2-基）乙胺鹽酸鹽（中間物5)反應，提供標題化合物。 133151 • 161 - 200906818 LCMS ： 561 [M+H]+. 中間物172 4,6-二氣-Ν_{3-[2·(1-{[2-(三甲基矽烷基）乙氧基】甲基}-lH·咪唑-2-基）乙基】-1Η-吡唑-5-基}-1，3,5-三畊-2-胺 使用類似關於中間物18合成所述之程序，使3-(2-(1-((2-(三 曱基石夕烧基）乙氧基）甲基）-1Η-_嗤-2-基）乙基）-1Η-ρ比。坐-5-胺 (中間物173)與2,4,6-三氯-1,3,5-三畊反應，提供標題化合物。 LCMS : 456 [M+H]+. 中間物173 3-(2-(1-((2-(三甲基矽烷基）乙氧基）甲基&gt;1H_咪唑_2_基）乙基 1H-P比唾-5-胺 使3-酮基-5-(1-((2-(三甲基矽烷基）乙氧基）甲基）_1H_咪唑_2_ 基）戍腈（中間物174 ’ 2·95克，10.05毫莫耳）溶於乙醇（5〇毫升） 中’並添加肼（0.338克，10.56毫莫耳）。將反應混合物在85 C下加熱3小時。在減壓下蒸發溶劑，而得殘留物。藉ISC〇 管柱純化，獲得標題化合物（3·〇克），為油狀物。 LCMS ： 308 [M+H]+ 中間物174 3-嗣基-5-(1-((2-(三曱基矽烷基）乙氧基）曱基）_1H咪唑_2_基）戊 腈 使乙腈（1.197毫升，22·92毫莫耳）溶於無水二氧陸圜（1〇〇 毫升）中，此時，添加氫化鈉（1〇克，22.92毫莫耳），並將反 應混合物在室溫下攪拌0.5小時。添加3-(1-((2-(三曱基矽烷基） 乙氧基）甲基）-1Η-咪唑_2_基）丙酸乙酯（中間物17S，5 7克， 133151 -162- 200906818 19.10毫莫耳），將所形成之溶液於幻它下加熱3小時。蒸發 洛液，在醋酸乙酯與水之間分離。藉由2N HC1使水層酸化， 並經由醋酸乙酯萃取。蒸發有機層，而得標題化合物，將 其使用於下一步驟中，未進行任何進一步純化。 LCMS ： 294 [M+H]+ 中間物175 3-(1·((2_(三曱基矽烷基）乙氧基）甲基）1H咪唑_2_基）丙酸乙酯 使（E)-3-(l-((2-(二曱基矽烷基）乙氧基）甲基）_1H咪唑_2_基）丙 稀酸乙醋（中間物Π6 ’ 5·995克，2〇_22毫莫耳）溶於设〇&amp; (1〇〇 毫升）中，並添加鈀/碳（L2克，U3毫莫耳）。將反應混合物 在氫大氣下攪拌過夜。經過矽藻土過濾觸媒，接著在減壓 下蒸發揮發性物質，獲得標題化合物（5 7克）。 LCMS ： 299 [M+H]+ 中間物176 (Ε)-3-(1-((2·(三甲基矽烷基）乙氧基）甲基）_1H_味唑_2基）丙烯酸 乙酯 使（二苯基亞正膦基）醋酸乙酯（9 〇1克，25 85毫莫耳）與 1-((2_(_三曱基矽烷基）乙氧基）甲基）_m咪唑冬羧甲醛（中間 物Π7，5.319克，23.50毫莫耳）溶於thf (1〇〇毫升）中，並將 所形成之溶液授拌過夜。在減壓下蒸發揮發性物質。將醋 酸乙酯/己烷（100毫升，5%)添加至粗製油中，並使白色固 體沉澱，過濾，及在減壓下蒸發濾液。藉管柱層析純化 (ISCO)，獲得標題化合物（6 0克）。 1H NMR (300 MHz, DMSO) δ ppm 7.64 (d, 1H) 7.60 (s, 1H) 7.17 (s, iH) 133151 -163- 200906818 6.67 (d, 1H) 5.58 (s, 2H) 4.26 (q, 2H) 3.54 (t, 2H) 1.32 (t, 3H) 0.90 (t, 2H) 0.0 (s, 9H) LCMS ： 297 [M+H]+ 中間物177 1-((2-(三甲基矽烷基）乙氧基）甲基)-1Η-咪唑-2-羧甲醛 使1H-咪峻-2-羧甲搭（5克，52.04毫莫耳）溶於THF (200毫升） 中，並添加氫化納（2·384克，54.64毫莫耳）。將所形成之反 應混合物於室溫下攪拌0.5小時。反應似乎沒有進展，故添 加4〇毫升DMF。將所形成之溶液授拌1小時，此時，其係變 成透明溶液’且添加SEM-C1 (10.15毫升，57.24毫莫耳）。將 反應混合物攪拌15分鐘’接著在減壓下蒸發揮發性物質。 藉ISCO純化，產生標題化合物（5.32克）。 NMR (300 MHz, CDC13) δ ppm 9.86 (s, 1H) 7.39 (s, 1H) 7.36 (s, 1H) 5.81 (s, 2H) 3.58 (t, 2H) 0.946 (t, 2H) 0.0 (s3 9H) LCMS : 227 [M+H]+ 中間物178 二氣-N-(3-(苯氧基曱基)_ih-吡唑_5·基从於三p井_2胺 使用類似關於中間物15合成所述之程序，使(苯氧美甲 基）-1Η-吡唑-5-胺（中間物161)與2,4,6_三氣_丨，3,5-三畊反應，提 供標題化合物。 LC-MS : 338 [M+H]+ 實例1 (S)-N2 -(1-(5-氟基吡啶_2·基）乙基）·]^ _(5·曱基·m•吡唑各基）6 (4 曱基六氫p比畊-1-基）-1，3,5_三畊_2,4·二胺 133151 -164、 200906818 於5〇毫升圓底燒瓶中’添加n_BuOH (3.23毫升）中之（s)_6_ 氯-N2-(l-(5-氟基吡啶-2-基）乙基）·ν4-(5-甲基-1H-吡唑_3_基 1,3,5-三畊-2,4-二胺（中間物16,〇.338克，0.97毫莫耳），獲得 黃色溶液。然後添加1-曱基六氫吡畊（〇 486克，4.85毫莫耳）， 並將所形成之溶液加熱至回流，歷經30分鐘。在減壓下蒸 發揮發性物質’而得橘色油。藉Gils〇n純化（5%— 95% MeCN/ &amp; Ο ’具有0.1。/。甲酸）’獲得標題化合物（溶離時間t = 8分 鐘，52毫克，在以飽和NaHC〇3水溶液移除甲酸後，成為自 由態驗）。 !H NMR (300 MHz, MeOD) δ 1.40 (d, 3Η) 2.15 (s, 3H) 2.40 (s, 3H) 2.50-2.72 (m, 4H) 3.72 (m, 4H) 4.96-5.14 (m, 1H) 5.83-6.02 (m, 1H) 7.37 (dd, 1H) 7.42-7.52 (m, 1H) 8.23-8.40 (m, 2H). LC-MS ： 413 [M+H]. 實例2 (S)-N2-(l-(5-氟基嘧啶-2-基）乙基)-N4-(5_甲基·m_吡唑·3_基)6嗎 福啉基-I,3,5-三畊-2,4-二胺 於250毫升圓底燒瓶中，添加Et〇H中之（s)_6_氯以^丨七-氟 基°治。定-2-基）乙基）-N4-(5-甲基-lH-p比唾-3-基）_ι，3,5-三_ _2 4-二 胺（中間物17，300毫克）與嗎福啉（1 385毫升，15 9〇毫莫耳）， 獲得黃色溶液。將混合物在室溫下攪拌過夜。於減壓下蒸 發揮發性物質，而得橘色殘留物。使殘留物經由Gils〇n純化 (5%— 95% MeCN/H20，具有 0.1% HC〇〇H，4〇 分鐘，在 t = 7 $ 分鐘下收集）’獲得標題化合物，為黃褐色固體。使此鹽溶 於Et〇Ac中，以飽*NaHC〇3水溶液洗滌有機層，脫水乾燥， 133151 •165· 200906818 及揮發性物質在減壓下之後續蒸發後，獲得不含酸之化合 物。 !H NMR (300 MHz, MeOD) δ ppm 1.58 (d, 3H) 2.25 (s, 3H) 3.47-3.95 (m, 8H) 5.11-5.45 (m, 1H) 5.98-6.22 (m, 1H) 8.71 (s, 2H) LC-MS ： 401 [M+H]. 實例3 (S)-N2 -(1-(5-氣基p比咬-2-基）乙基)-N4 -(5_曱基-lH-p比峻-3-基)-6-嗎 福啉基·1，3,5-三畊·2,4-二胺 將（S)-6-氯-N2-(l-(5-氟基ϊ1比咬-2-基）乙基）-Ν4-(5-甲基-1Η-Ι»比β坐 -3-基）-1，3,5-三畊-2,4-二胺（中間物16，550毫克，1_58毫莫耳） 在嗎福淋（4122微升’ 47.31毫莫耳）中之溶液於室溫下授拌過 夜。蒸發揮發性物質，獲得橘色油。藉管柱層析純化（7〇% EtOAc-己烷至100% EtOAc，具有0.2% TEA)，而得標題化合物 (625.5毫克），為白色固體。 ]H NMR (300 MHz) 5 1.49 (d, 3H) 2.27 (s, 3H) 3.51-3.89 (m, 8H) 5.05- 5.33 (m, 1H) 5.91 (s, 1H) 7.55 (dd, 1H) 7.65-7.96 (m, 1H) 8.55 (d, 1H) LC-MS ： 400 [M+H] 實例4 4-(l_(5-氣基咐啶-2-基）乙氧基）·Ν_(5_甲基_m吡唑_3_基）_6_嗎福 林基-1,3,5-三啡-2-胺 於1〇〇毫升圓底燒瓶中，添加t-Bu0H (5918微升）中之ι_(5_ 氟基峨咬-2-基）乙醇（中間物12，251毫克，丨78毫莫耳）與第 三-丁醇鈉（341毫克，3·55毫莫耳），獲得黃褐色溶液。將混 合物攪拌1小時，此時，添加冬氯_N_(5_甲基_1H_吡唑冰基）_卜 133151 -166· 200906818 嗎福啉基-1，3,5-三畊-2-胺（中間物15，35〇毫克，118毫莫耳）。 將所形成之紅色混合物於環境溫度下攪拌48小時。蒸發揮 發性物質’及藉Gilson純化（5%—%% MeCN/H2〇，υ分鐘操 作，溶離時間〜6·5分鐘），獲得標題化合物，為對掌異構物 之混合物。 lH NMR (300 MHz, MeOD) δ 1.72 (d, 3Η) 2.38 (s5 3H) 3.63-3.87 (m 8H) 6.07 (s, 1H) 6.18 (q, 1H) 7.50-7.79 (m, 2H) 8.46 (d, 1H). LC-MS ： 400 [M+H]. 標題化合物係使用對掌性HPLC進行對掌性純化：Starting material: 4,6-dichloro-N-(5-(3,5-difluorophenethyl)_ih_^ spit_3_yl)-1,3,5-three tillage-2-amine (intermediate) 151) with (S)-l-(5-fluoropyrimidinyl)ethylamine hydrochloride (Intermediate 5). LC-MS : 476 [Μ+Η]+· Intermediate 144 (S)-6-Gas-Ν2_(5·(2,4-difluorophenethyl)m_p ratio Jun_3 base)_ν4_(ι_(5 _Fluoro-based acetophenone-2-yl)ethyl)-1,3,5-tris-2,4-diamine starting material: 4,6-dichloro _(2,4_2 benzene Base)-ΐΗ-pyrazole each)-1,3,5-trioxin-2-amine (intermediate 152) and (8) small (5-fluoropyrimidinyl hydrochloride (intermediate 5). Soil LC- MS : 476 [Μ+Η]'t intervening substance 145 唆-2-yl)ethyl)_1,3,5-three tillage _2,4-diamine two starting materials Μ-dichloro-N-( 3-(3,4-difluorophenethyl)* ton. "Bisyl"-,,-di-2-_2-amine (cloth (5)) and (8) o-fluoro" hydrochloride (intermediate 5).基)乙月女133151 -155- 200906818 LC-MS : 476 [M+H]+. Intermediate 146 6-Gas-N-{3-[2-(2,6-Difluorophenyl)ethyl] -1H-pyridin-5-yl}-N,-[(lS)-l-(5-fluoropyrimidin-2-yl)ethyl]-1,3,5-three tillage_2,4-di Amine starting material: 4,6-di-gas-N-{3-[2-(2,6-difluorophenyl)ethyl]-1H-pyrazole-5-yl}-1,3,5- Tricotin-2-amine (intermediate 158) and (S)-l-(5-fluoropyrimidin-2-yl)ethylamine hydrochloride (Intermediate 5). LC-MS: 476 [M+H]+_ Intermediate 147 (S)-6-V-N2-(5-(3,4-Dimethoxyphenethyl)·1Η-pyrazol-3-yl) -N4-(1-(5-fluoropyrimidin-2-yl)ethyl)-1,3,5-three tillage _2,4.diamine starting material: 4,6-digas-N-( 5-(3,4-Dimethoxyphenethyl)-lH-pyrazol-3-yl)-1,3,5-tri-anthran-2-amine (Intermediate 159) and (S)-l-( 5-Fluoropyrimidin-2-yl)ethylamine hydrochloride (Intermediate 5). LC-MS: 500 [M+H]+. The following intermediates 148-157 were prepared using procedures similar to those described for Intermediate 18. Intermediate 148 4.6-Di-N-(5-phenethyl-1H-pyrazol-3-yl)-1,3,5-trin-2-amine starting material · 5-phenylethyl- 1H-pyrazol-3-amine (intermediate 162) and 2,4,6-trichloro-1,3,5-three tillage. LC-MS: 336 [M+H]+. Intermediate 149 4.6-dichloro-yis(5-(4-fluorophenylethyl)-111-pyrazol-3-yl)-1,3,5- Trimorph-2-amine 133151 • 156- 200906818 Starting material · 5-(4-Fluorophenethyl)-1Η-pyrazol-3-amine (Intermediate 163) and 2.4.6- Trichloro-1 , 3, 5 - three tillage. LC-MS: 354 [M+H]+. Intermediate 150 4.6-dichloro-indole-(5-(3·fluorophenylethyl)-1Η-pyrazol-3-yl H,3,S- _2_2_amine starting material: 5-(3-fluorophenylethyl)-1Η·ρbiw-3-amine (intermediate 164) and 2.4.6-trichloro-1,3,5-three LC-MS : 354 [Μ+Η]+. Intermediate 151 4.6- Digas-Ν-(5-(3,5-difluorophenethyl)-1Η-pyrazole_3_yl)-1 , 3,5_three spray_2_amine starting material: 5-(3,5-difluorophenethyl)-1Η-pyrazol-3-amine (intermediate 165) and 2.4.6-three gas- 1,3,5-three wells LC-MS: 372 [Μ+Η]+. Intermediate 152 — gas-Ν-(5-(2,4-oxophenethyl)-1Η-ρ than 唆- 3-yl)-1,3,5-triphle-2-amine starting material: 5-(2,4-difluorophenethyl)-1Η-pyrazole-3.amine (intermediate 166) 2.4.6- Trichloro-1,3,5-three tillage LC-MS : 372 [Μ+Η]+. Intermediate 153 4.6- 二气-Ν-(3-(3,4-二气苯乙乙Base)-1Η-ρ ratio -5-5_yl)-1,3,5-triphle-2-amine starting material: 3-(3,4-difluorophenethyl)-lH-pyrazole- 5-amine (intermediate 167) and 2.4.6- trichloro-1,3,5-three tillage LC-MS: 372 [Μ+Η]+. Intermediate 154 133151 -157- 200906818 4.6- 二气- N-(5-(4- Fluorophenyl)-1Η-pyrazol-3-yl)-l,3,5-tri-indene-2 amine starting material: 5-(4-fluorophenyl)-1Η-pyrazol-3-amine 2,4,6-trichloro-1,3,5-three tillage LC-MS : 326 [Μ+Η]+. Intermediate 155 4.6- Digas-Ν-(5_(2-cyclohexylethyl) -1Η-ρ than sial-3-yl)-l,3,5-tris-2-amine starting material: 5-(2-cyclohexylethyl)-1 Η-pyrazol-3-amine and 2,4 , 6-three gas-1,3,5-three tillage. LC-MS : 342 [Μ+Η]+. Intermediate 156 4,6·digas-Ν-(5-(4-methoxyphenyl) -1Η-pyrazol-3-yl)-1,3,5-three-till-2-amine starting material: 5-(4-methoxyphenyl)-1Η-pyrazol-3-amine and 2,4 ,6-trichloro-1,3,5-three tillage. LC-MS : 338 [Μ+Η]+· Intermediate 157 4,6·二气-Ν-(5_(ρ塞特_2_基) -1Η-ρ than 嗤-3-yl)-1,3,5-three, well-2-amine starting material: 5 heptaphen-2-yl)-1!1-pyrazol-3-amine 2,4,6-three gas-1,3,5-three tillage. LC-MS: 314 [Μ+Η]+. Intermediate 158 4,6·di- Ν-{3-[2-(2,6-difluorophenyl)ethyl]-1Η-pyrazole-5 -yl}-1,3,5-tris-2-amine starting material: 3-[2-(2,6-difluorophenyl)ethyl]-1Η-pyrazole-5-amine (intermediate) 169) with 2,4,6-trichloro-1,3,5-three tillage. 133151 -158- 200906818 LC-MS : 372 [M+H]+. Intermediate 159 4,6-di-gas-N-(5-(3,4-dioxalylphenidin-3-yl) -l,3,5-three tillage _2 amine starting material: 5-(3,4-dioxanphenethyl)-1 Η-pyrazol-3-amine (intermediate no) with 2,4,6 - three gas-1,3,5-three tillage. LC-MS: 396 [M+H]+. Intermediate 160 3-keto-4-phenoxybutyronitrile to make acetonitrile (1.998 ml ' 38.26 mmol) Dissolved in anhydrous dioxane (5 ml), followed by NaH (1.808 g, 41.45 mmol). The resulting reaction mixture was stirred at room temperature for 0.5 h. 2-phenoxyacetic acid B was added. Vinegar (5 ml, 31.88 mmol), and the resulting solution was heated at 85 ° C for 24 hours. The solution was evaporated and separated between ethyl acetate and water. The aqueous layer was acidified by 2 Ν Ηα, then The mixture was extracted with EtOAc (EtOAc) (EtOAcjjjjjjjjjjj Zylo-5-amine is soluble in 3-keto-4-phenoxybutyronitrile (intermediate 156, 〇88 g, 5 〇 2 mmol) in ethanol ( ο ml), and add 胼 (〇 189 ml, 6 〇 3 mmol). The reaction mixture was stirred at room temperature for 1 Torr, then heated at 85 ° &gt; c for a few hours. Volatile material was obtained, and the residue was obtained, which was purified by EtOAc (MeOH/DCM 5%). LC-MS: 190 [M+H]+ 133151 -159, 200906818 Intermediate 162-170 was prepared using a procedure similar to the synthesis of intermediate 161. Intermediate 162 5-Phenyl-1H-pyrazol-3-amine Starting material: 3-keto-5-phenylpentanenitrile and hydrazine LC-MS: 188 [Μ+Η]+· Intermediate 163 5 -(4-fluorophenylethyl)-1 Η-pyrazol-3-amine Starting material: 5-(4-fluorophenyl)-3-ketovaleronitrile with hydrazine LC-MS: 206 [M+H ]+. Intermediate 164 5-(3·Fluorophenethyl)-1Η-pyrazol-3-amine Starting material: 5-(3-fluorophenyl)-3-ketopopentanonitrile with hydrazine LC- MS: 206 [M+H]+. Intermediate 165 5-(3,5-difluorophenethyl)-lH-pyrazol-3-amine starting material: 5-(3,5-difluorophenyl )-3-ketovaleronitrile and hydrazine LC-MS : 224 [M+H]+_ Intermediate 166 5-(2,4-Difluorophenethyl)_1H-pyrazol-3-amine Starting material: 5-(2,4-Difluorophenyl)-3-ketovaleronitrile with hydrazine LC-MS : 224 [M+H]+. Intermediate 167 3-CM-difluorophenethyl)-1Η-pyridin Azole-5-amine 133151 -160- 200906818 Starting material: 3-(3,4-difluorophenyl)-3-S with valeronitrile and moon well LC-MS: 224 [M+H]+. 168 3-(2-(pyridin-4-yl)ethyl)-1Η-pyrazole-5-amine Starting material: 3-keto-5-(p-r-but-4-yl)pentanenitrile月井LC-MS: 189[Μ+Η]+. Intermediate 169 3-[2-(2,6-Difluorophenyl)ethyl]-1Η-pyridyl -5-Amine starting material. 5-(2,6-Difluorophenyl)-3-ketovaleronitrile with hydrazine LC-MS: 224 [M+H]+. Intermediate 170 5-(3,4 -Dimethoxyphenethyl)-1Η-pyrazole-3-amine Starting material: 5-(3,4-dimethoxyphenyl)-3-ketovaleronitrile with Yuejing LC-MS : 248 [Μ+Η]+· The corresponding nitriles are made according to procedures similar to those described in WO 2008/001070. Intermediate 171 6·Chloro-N-[(lS)-l-(5-fluoro, 唆·2·yl)ethyl](trimethylpropenyl)ethoxy]methyl}-1Η-flavor嗤-2-yl)ethyl]-lH-p is more specific than 嗤_5· kib, 3,5-triphthyl-2,4-diamine using a procedure similar to that described for the synthesis of intermediate 17, 6_二气-Ν-{3-[2-(1-{[2-(trimethylglyoxime)ethoxy);]methyl}_1Η,. _2_yl)ethyl]-1Η- Pyrazol-5-yl}-1,3,5-trinyl-2-amine (intermediate 172) and (S)-l-(5-fluoropyrimidin-2-yl)ethylamine hydrochloride (middle) Reaction 5) provides the title compound. 133151 • 161 - 200906818 LCMS : 561 [M+H]+. Intermediate 172 4,6-di-gas-Ν_{3-[2·(1-{[2-(trimethyldecyl)ethoxy) Methyl}-lH.imidazol-2-yl)ethyl]-1Η-pyrazol-5-yl}-1,3,5-trinyl-2-amine is prepared using a procedure similar to that described for the synthesis of intermediate 18, 3-(2-(1-(2-(trimethylsulfanyl)ethoxy)methyl)-1Η--indol-2-yl)ethyl)-1Η-ρ ratio. The reaction of the 5-amine (Intermediate 173) with 2,4,6-trichloro-1,3,5-trin was afforded the title compound. LCMS: 456 [M+H] +. Intermediate 173 3-(2-((2-(trimethylmethyl) ethoxy)methyl) &lt;1H_imidazol-2-yl)ethyl 1H-P is a 3-keto-5-(1-((2-(trimethyldecyl)ethoxy)methyl)_1H-imidazol-2-yl)carbonitrile (intermediate) compared to sal-5-amine 174 '2·95 g, 10.05 mmol) dissolved in ethanol (5 mL) and added hydrazine (0.338 g, 10.56 mmol). The reaction mixture was heated at 85 C for 3 hours under reduced pressure. Evaporation of the solvent to give a crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 1-((2-(tridecyldecyl)ethoxy)indolyl)_1H-imidazole-2-yl)pentanenitrile acetonitrile (1.197 ml, 22.92 mmol) dissolved in anhydrous dioxane ( In 1 mL, at this time, sodium hydride (1 gram, 22.92 mmol) was added, and the reaction mixture was stirred at room temperature for 0.5 hour. 3-(1-((2-(trimethyl)) was added. Ethylalkyl)ethoxy)methyl)-1Η-imidazole-2-yl)propionic acid ethyl ester (intermediate 17S, 5 7 g, 133151 -162- 200906818 19.10 mmol) The resulting solution was heated under the illusion for 3 hours. The mixture was evaporated and separated between ethyl acetate and water. The aqueous layer was acidified with 2N HCl and extracted with ethyl acetate. The title compound was used in the next step without any further purification. LCMS: 294 [M+H]+ Intermediate 175 3-(1·((2-(tridecyl)alkyl)ethoxy) (E)-3-(l-((2-(didecyldecyl)ethoxy)methyl)_1H imidazolium-2-yl) propylene Ethyl acetate (intermediate Π 6 '5·995 g, 2 〇 _22 mmol) was dissolved in 〇 &amp; (1 〇〇 ml) and palladium/carbon (L2 g, U3 mmol) was added. The reaction mixture was stirred with EtOAc EtOAc (EtOAc) (EtOAc) Ethyl (3-phenylphosphoryl)ethyl acetate (9 〇 1 gram, 25 85 millimoles) and 1-((2_(_三曱) The decylalkyl)ethoxy)methyl)-m-imidazolecarboxaldehyde (intermediate Π7, 5.319 g, 23.50 mmol) was dissolved in thf (1 mL) and the resulting solution was stirred overnight. The volatiles were evaporated under reduced pressure. Ethyl acetate/hexane (100 ml, 5%) was added to a crude oil, and a white solid was precipitated, filtered, and evaporated. Purification by column chromatography (ISCO) gave the title compound (60 g). 1H NMR (300 MHz, DMSO) δ ppm 7.64 (d, 1H) 7.60 (s, 1H) 7.17 (s, iH) 133151 -163- 200906818 6.67 (d, 1H) 5.58 (s, 2H) 4.26 (q, 2H 3.54 (t, 2H) 1.32 (t, 3H) 0.90 (t, 2H) 0.0 (s, 9H) LCMS: 297 [M+H]+ Intermediate 177 1-((2-(trimethyldecyl) Ethoxy)methyl)-1Η-imidazole-2-carboxaldehyde was dissolved in 1H-methylene-2-carboxylate (5 g, 52.04 mmol) in THF (200 mL) with sodium hydride ( 2·384 grams, 54.64 millimoles). The resulting reaction mixture was stirred at room temperature for 0.5 hours. The reaction did not seem to progress, so 4 ml of DMF was added. The resulting solution was stirred for 1 hour at which time it became a clear solution&apos; and SEM-C1 (10.15 mL, 57.24 mmol) was added. The reaction mixture was stirred for 15 minutes' and then the volatiles were evaporated under reduced pressure. Purification by ISCO gave the title compound (5.32 g). NMR (300 MHz, CDC13) δ ppm 9.86 (s, 1H) 7.39 (s, 1H) 7.36 (s, 1H) 5.81 (s, 2H) 3.58 (t, 2H) 0.946 (t, 2H) 0.0 (s3 9H) LCMS: 227 [M+H]+ intermediate 178 dioxin-N-(3-(phenoxyindolyl)-ih-pyrazole _5·yl group from the three p well _2 amines similar to the synthesis of intermediate 15 The procedure for reacting (phenoxymethyl)-1Η-pyrazole-5-amine (intermediate 161) with 2,4,6_trioxane, 3,5-trin, to provide the title compound LC-MS : 338 [M+H]+ Example 1 (S)-N2 -(1-(5-fluoropyridin-2-yl)ethyl)·]^ _(5·曱基·m•py Oxazol)6 (4 fluorenyl hexahydrop to plough-1-yl)-1,3,5_three tillage _2,4·diamine 133151 -164, 200906818 Add in 5 〇 ml round bottom flask (s)_6_Chloro-N2-(l-(5-fluoropyridin-2-yl)ethyl)·ν4-(5-methyl-1H-pyrazole_3_yl 1 in n_BuOH (3.23 ml) , 3,5-three tillage-2,4-diamine (intermediate 16, 〇.338 g, 0.97 mmol), obtained a yellow solution. Then add 1-mercaptohexahydropyrazine (〇486 g, 4.85) Millol), and the resulting solution is heated to reflux for 30 minutes. Evaporate volatiles under reduced pressure to obtain orange Oil. Purified by Gils 〇n (5% - 95% MeCN / & Ο 'with 0.1% carboxylic acid)' to obtain the title compound (dissolution time t = 8 min, 52 mg, removed in saturated aqueous NaHC 3) After formic acid, it becomes a free state.) !H NMR (300 MHz, MeOD) δ 1.40 (d, 3Η) 2.15 (s, 3H) 2.40 (s, 3H) 2.50-2.72 (m, 4H) 3.72 (m, 4H 4.96-5.14 (m, 1H) 5.83-6.02 (m, 1H) 7.37 (dd, 1H) 7.42-7.52 (m, 1H) 8.23-8.40 (m, 2H). LC-MS : 413 [M+H] Example 2 (S)-N2-(l-(5-Fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl·m-pyrazole·3-yl)6-formoline- I,3,5-tripering-2,4-diamine in a 250 ml round bottom flask, adding (s)_6_chloro in Et〇H to determine the β-fluoro group. Ethyl)-N4-(5-methyl-lH-ppyraz-3-yl)_ι,3,5-tris-2-didiamine (intermediate 17,300 mg) and morphine (1) 385 ml, 15 9 Torr, obtained a yellow solution. The mixture was stirred at room temperature overnight. The volatile material was evaporated under reduced pressure to give an orange residue. The residue was purified with EtOAc (EtOAc EtOAc:EtOAc: The salt was dissolved in Et 〇Ac, and the organic layer was washed with a saturated aqueous solution of NaHCO3, dehydrated and dried, 133151 • 165 · 200906818, and the subsequent evaporation of the volatile substance under reduced pressure gave an acid-free compound. !H NMR (300 MHz, MeOD) δ ppm 1.58 (d, 3H) 2.25 (s, 3H) 3.47-3.95 (m, 8H) 5.11-5.45 (m, 1H) 5.98-6.22 (m, 1H) 8.71 (s , 2H) LC-MS: 401 [M+H]. Example 3 (S)-N2 -(1-(5-aero-p-p-but-2-yl)ethyl)-N4 -(5_mercapto- lH-p than jun-3-yl)-6-morpholinyl·1,3,5-three tillage·2,4-diamine (S)-6-chloro-N2-(l-(5- Fluoropyrene 1 is more specific than 2-amino)ethyl)-indole 4-(5-methyl-1Η-Ι) than β--3-yl)-1,3,5-trin-2,4-diamine (Intermediate 16, 550 mg, 1 - 58 mmol) The solution in wholidine (4122 μl '47.31 mmol) was stirred overnight at room temperature. The volatiles were evaporated to give an orange oil. The title compound (625.5 mg) was obtained elute ]H NMR (300 MHz) 5 1.49 (d, 3H) 2.27 (s, 3H) 3.51-3.89 (m, 8H) 5.05- 5.33 (m, 1H) 5.91 (s, 1H) 7.55 (dd, 1H) 7.65- 7.96 (m, 1H) 8.55 (d, 1H) LC-MS: 400 [M+H] Example 4 4-(l-(5-Alkyl acridine-2-yl)ethoxy)·Ν_(5_A Base_mpyrazole_3_yl)_6_folinin-1,3,5-tri-ephthyl-2-amine in a 1 liter round bottom flask, added t-Bu0H (5918 μl) Io_(5_Fluorobenzoin-2-yl)ethanol (intermediate 12,251 mg, 丨78 mmol) and sodium tributoxide (341 mg, 3·55 mmol) to obtain a tan solution . The mixture was stirred for 1 hour, at which time, winter chloride_N_(5-methyl-1H-pyrazole ice-based)_Bu 133151-166·200906818 oxalinolyl-1,3,5-three tillage-2- Amine (intermediate 15, 35 mg, 118 mmol). The resulting red mixture was stirred at ambient temperature for 48 hours. The title compound was obtained as a mixture of the palmeal isomers by purifying the starting material' and purifying by Gilson (5%-%% MeCN/H2 〇, υmin operation, solute time ~ 6.5 min). lH NMR (300 MHz, MeOD) δ 1.72 (d, 3Η) 2.38 (s5 3H) 3.63-3.87 (m 8H) 6.07 (s, 1H) 6.18 (q, 1H) 7.50-7.79 (m, 2H) 8.46 (d , 1H). LC-MS: 400 [M+H].

管柱：Chirapak AD 尺寸：250 X 20毫米，10以 流動相：80%己烧，20% 1:1乙醇：甲醇，ο]%二乙胺（v/v/v) 流率（毫升/分鐘）：20 偵測（毫微米）：254 第一個溶離峰，實例4⑻ !H NMR (300 MHz, MeOD) 5 1.72 (d, 3H) 2.38 (s, 3H) 3.63-3.87 (m, 8H) 6.07 (s, 1H) 6.18 (q, 1H) 7.50-7.79 (m, 2H) 8.46 (d, 1H). 第二個溶離峰，實例4(b) ]H NMR (300 MHz, MeOD) δ 1.72 (d, 3H) 2.38 (s, 3H) 3.63-3.87 (m, 8H) 6.07 (s, 1H) 6.18 (q, 1H) 7.50-7.79 (m, 2H) 8.46 (d, 1H). 實例5 (S)-4-(l-(5-氟基嘧啶-2-基）乙氧基)-N-(5-甲基-1H-吡唑-3-基)-6-嗎 福啉基-1，3,5-三畊-2-胺 於微波容器中，添加4-(4-氣基-6-(1-(5-氟基嘧啶-2-基）乙氧 133151 -167- 200906818 基）-l，3,5-三畊-2-基）嗎福啉（中間物19，253毫克，〇 74毫莫 耳）、3-胺基-5-甲基-1H-吡唑小羧酸第三·丁酯（中間物6，220 毫克，1.11毫莫耳）、BINAP (46.2毫克）、Cs2C03 (605毫克）及 Pd；2 (dba)3 (34.0毫克），接著為二氧陸圜（2毫升），並將所形成 之混合物以氬滌氣20分鐘。將反應混合物加熱至1〇〇它，歷 經4小時，此時，添加MeOH，且將所形成之混合物於室溫 下攪拌3小時。過滤混合物，及以DCM洗滌數次。在減壓 下蒸發揮發性物質，獲得深褐色殘留物。藉管柱層析純化 (ISCO 3% MeOH，0.3% NH4 OH在DCM中），而得標題化合物， 為淡黃色粉末。 LC-MS : 402 [M+H]. 標題化合物係使用條件（A)與OD-4-20 (具有0.1%二曱基乙 胺）進行對掌性純化 管柱粒子大小（y) : 5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗 試樣純度係使用條件（B)與AD-4-20確認 第一個吸收峰（滯留時間：分鐘）2·06 第二個吸收峰（滯留時間：分鐘）2.91 第一個溶離峰，實例5⑻ 1H NMR (400 MHz, MeOD) δ ppm 8.69 (s, 2H) 6.23 (s, 1H) 6.02 (q, J = 6.57 Hz, 1H) 3.61 (m, 8H) 2.24 (s, 3H) 1.67 (d, J = 6.82 Hz, 3H). 第二個溶離峰，實例5(b) 1H NMR (400 MHz, MeOD) δ ppm 8.69 (s, 2H) 6.23 (s, 1H) 6.02 (q, J = 133151 • 168- 200906818 6.57 Hz, 1H) 3.64 (m, 8H) 2.24 (s, 3H) 1.68 (d, J = 6.57 Hz, 3H). 實例6 6-((R)-3-(二甲胺基）四氫吡咯-1-基)_N2·(⑻小(5_氟基嘧啶_2-基） 乙基）-N4-(5-甲基-1H-吡唑-3-基）·1，3,5_三畊-2,4-二胺 使用類似關於實例11合成所述之程序，使（S)-6-氣-Ν2 -(1-(5-氟基嘧啶-2-基）乙基）-Ν4·(5-曱基-1H-吡唑-3-基）-1，3,5-三畊-2,4-二胺（中間物17)與（R)-N，N-二甲基四氫吡咯_3_胺反應，提供 標題化合物。 1 H NMR (300 MHz, MeOD) δ ppm 1.30 (d, J = 6.59 Hz, 3H) 1.58 (s, 3H) 1.72-1.98 (m, 1H) 2.12-2.45 (m, 10H) 2.75-2.95 (m, 1H) 3.72-3.99 (m, 1H) 5.15-5.42 (m, 1H) 5.53-5.75 (m, 1H) 8.71 (s, 2H). LC-MS ： 428 [M+H]+. 實例7 2-(5氟基吡啶-2-基）-N,N-二曱基-2-(4-(5-曱基-1H-吡唑-3-基胺 基）-6-嗎福啉基-1,3,5-三畊-2-基胺基）乙烷磺醯胺 於250毫升圓底燒瓶中，添加EtOH (3.29毫升）中之2-(4-氯基 -6-(5-甲基-1H-吡唑-3-基胺基）-1,3,5-三啡-2-基胺基）-2-(5-氟基吡 咬-2-基）-N，N-二甲基乙烧績醯胺（中間物23，1_5克，3.29毫莫 耳）與嗎福啉（1.720毫升，19.74毫莫耳），獲得黃色溶液。將 所形成之混合物在25°C下攪拌1小時。於減壓下蒸發揮發性 物質，獲得油狀物。藉管柱層析純化（ISCO，5% MeOH/DCM)， 而得標題化合物，為對掌異構物之混合物。 LC-MS ： 507 [M+H]. !H NMR (300 MHz, MeOD) &lt;5 ppm 2.25 (s, 3H) 2.81 (s, 6H) 2.82-2.89 133151 -169- 200906818 (m, 2H) 3.53-3.87 (m, 8H) 5.73 (t, J = 6.41 Hz, 1H) 6.38 (s, 1H) 7.29-7.79 (m, 2H) 8.47 (s, 1H). 標題化合物係使用條件（A)與OD-4-20進行對掌性純化 管柱粒子大小（〆)：5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗 試樣純度係使用條件（B)與OD-4-20確認 f 管柱尺寸（毫米）：100 X 4·6 管柱粒子大小（〆）：5 第一個吸收峰（滯留時間：分鐘）20.5 第二個吸收峰（滯留時間：分鐘）24.1 第一個溶離峰，實例7(a) lU NMR (300 MHz, MeOD) δ ppm 2.14 (s, 3H) 2.71 (s, 6H) 3.43-3.80 (m, 10H) 5.48-5.68 (m, 1H) 5.99 (s, 1H) 7.11-7.72 (m, 2H) 8.37 (s, 2H) 第二個溶離峰，實例7(b) ( NMR (300 MHz, MeOD) &lt;5 ppm 2.14 (s, 3H) 2.71 (s, 6H) 3.42-3.67 (m, 10H) 5.45-5.65 (m, 1H) 5.99 (s, 1H) 7.18-7.68 (m, 2H) 8.37 (d, J = 1.70 Hz, 1H) 實例8 6-((S)-3-(二甲胺基）四氫吡咯_i_基）_n2-((S)-1-(5-氟基嘧啶-2-基） 乙基）-N4-(5-甲基-lH-t*比峻-3-基）-1，3,5-三畊-2,4-二胺 使用類似關於實例11合成所述之程序，使（S)-6-氯-N2 -(1-(5-氟基嘧啶-2-基）乙基）-：^-(5-曱基-111-吡唑-3-基）-1,3,5-三畊-2,4-二胺（中間物17)與（S)-N，N-二曱基四氫吡咯-3-胺反應，提供標 133151 -170- 200906818 題化合物。 1 H NMR (300 MHz, MeOD) δ ppm 1.25 (d, J = 6.41 Hz, 3H) 1.58 (s, 3H) 1.75-1.89 (m, 1H) 2.22-2.28 (m, 1H) 2.33 (s, 6H) 2.72-2.92 (m, 1H) 3.40-3.59 (m, 1H) 3.66-4.13 (m, 2H) 5.17-5.44 (m, 1H) 5.50-5.82 (m, 1H) 6.45 (s, 1H) 8.71 (s, 2H). LC-MS : 428 [M+H]+ · 實例9 N-(l-(4-((S)-l-(5-氟基嘧啶-2-基）乙胺基）·6_(5·甲基_m-吡唑_3-基 胺基）-1，3,5_三？井_2_基）四氫u比洛-3-基）乙酿胺 使用類似關於實例11合成所述之程序，使（S)-6-氣-N2 -(1-(5-氟基嘧啶-2-基）乙基）-&gt;14-(5-甲基-111-吡唑-3-基）-1,3,5-三畊-2,4-二胺（中間物17)與N-(四氫吡咯-3-基）乙醯胺反應，提供標題 化合物，為非對映異構物之混合物。 1 H NMR (300 MHz, MeOD) δ ppm 1.37 (d, J = 6.59 Hz, 3H) 1.58 (s, 3H) 1.96 (s, 3H) 3.44-3.89 (m, 4H) 4.23-4.50 (m, 1H) 5.22-5.41 (m, 1H) 5.50-5.82 (m, 1H) 8.71 (s, 2H). LC-MS : 442 [M+H]+. 實例10 $-((8)-1-(5-氟基嘧啶-2-基）乙基）_]\4-(5-甲基-111-吡唑_3-基）-6-((R)_3·(甲胺基）四氫p比洛-1·基）_1，3,5_三呼_2,4_二胺 使用類似關於實例11合成所述之程序，使⑸_6_氯_Ν2 _(丨_(5_ 氟基嘧啶-2-基）乙基）-Ν4-(5-曱基-1Η-吡唑-3-基）-1,3,5-三畊_2,4_ 二胺（中間物17)與（R)-N-甲基四氫P比B各_3_胺反應，提供標題 化合物。 133151 -171 · 200906818 lU NMR (300 MHz, MeOD) δ ppm 1.58 (d, 3H) 1.74-1.93 (m, 1H) 2.18-2.26 (m, 4H) 2.41 (s, 3H) 3.11-3.32 (m, 2H) 3.46-3.89 (m, 2H) 5.22-5.44 (m, 1H) 5.50-5.74 (m, 1H) 6.45 (s, 1H) 8.71 (s, 2H). LC-MS ： 414 [M+H]+. 實例11 6-(3-乙氧基四氫吡咯小基）_N2·(⑻小(5_氟基嘧啶_2_基）乙 基）-N4-(5-甲基-1H-U比峻-3-基）-1,3,5-三 井-2,4-二胺 於（S)-6-氯-N2-(l-(5-氟基嘧啶_2·基）乙基）_n4-(5-甲基-1H-吡唑 -3-基）-1,3,5-三畊-2,4-二胺（中間物π，100毫克，〇_29毫莫耳） 在EtOH (572微升）中之溶液内，添加3_乙氧基四氫吡咯鹽酸 鹽（43.4毫克’ 0.29毫莫耳）與DIPEA (49.9微升，0.29毫莫耳）。 將所形成之混合物於25。(：下攪拌16小時。在減壓下蒸發揮 發性物質’獲得黃色殘留物。藉管柱層析純化(ISC〇，5%_1〇0/。 MeOH/DCM)，而得6-(3-乙氧基四氫峨n各小基）_N2_((S)]_(5_氣基 嘧啶-2-基）乙基）-]^4-(5-甲基-111-吡唑-3-基）-1,3,5-三畊-2,4-二胺 (87毫克’ 71.0%)，為非對映異構物之混合物。 JH NMR (300 MHz, MeOD) δ ppm 0.98-1.14 (m, 2H) 1.21-1.33 (m, 3H) 1.46 (t, J = 6.97 Hz, 3H) 1.79-1.99 (m, 2H) 2.14 (s, 3H) 3.34-3.54 (m, 4H) 3.87-4.20 (m, 1H) 4.99-5.35 (m, 1H) 5.96 (s, 1H) 8.62 (s, 2H). LC-MS ： 429 [M+H]+ 實例12 (S)-N-(l-(4-(l-(5-氟基嘧啶-2·基）乙胺基甲基_m吡唑_3基 胺基）-1，3,5-三p井-2-基）一氮四園_3_基）乙酿胺 使用類似關於實例11合成所述之程序，使⑻_6_氯_n2_(1_(5_ 133151 -172· 200906818 氟基嘴啶-2-基）乙基）_n4-(5-甲基-1H-吡唑-3-基）-l，3,5-三畊-2,4- 二胺（中間物17)與N-(—氮四圜-3-基）乙醯胺反應，提供標題 化合物。 ^ NMR (300 MHz, MeOD) δ ppm 1.36-1.53 (m, 3H) 1.86 (s, 3H) 2.14 (s, 3H) 3.68-3.96 (m, 2H) 4.09-4.35 (m, 2H) 4.40-4.61 (m, 1H) 5.08-5.37 (m, 1H) 6.12 (sJ = 6.00 Hz, 1H) 8.61 (s, 2H). LC-MS : 428 [M+H]' 實例13 N-((S)-l-(4-((S)-l-(5-氟基嘧啶-2-基）乙胺基）-6-(5-甲基-1H-吡唑-3-基胺基)-1，3,5-三畊-2-基）四氩吡洛_3_基）乙酿胺 使用類似關於實例11合成所述之程序，使（8)_6_氣_N2 _(丨_(5_ 氟基'*岔、咬-2-基）乙基）-N4-(5-曱基°圭-3-基）-1,3,5-三 p井-2,4· 二胺（中間物17)與（S)-N-(izg氫吡咯_3_基）乙醯胺HC1 (中間物 23b)反應，提供標題化合物。 1 H NMR (300 MHz, MeOD) δ ppm 1.46 (d, 3H) 1.83 (s, 3H) 2.14 (s, 3H) 3.27-3.79 (m, 4H) 4.14-4.44 (m, 1H) 5.05-5.44 (m, 1H) 5.90-6.45 (m, 1H) 8.60 (s，2H). LC-MS ： 442 [M+H]+. 實例14 N-((R)-l-(4-((S)-l-(5-氟基嘧啶-2-基）乙胺基）_6_(5_ 甲基 _ih-吡唑-3-基胺基）-1,3,5-三畊-2-基）四氫峨略_3_基）乙酿胺 使用類似關於實例11合成所述之程序，使（幻_6_氣_N2 氟基嘧啶-2-基）乙基）-1^4-(5-甲基_111_吡唑_3_基）_1，3,5_三畊_2,4_ 二胺（中間物17)與（R)-N-(四氩吡咯_3_基）乙醯胺（中間物24) 133151 -173 - 200906818 反應，提供標題化合物。 1 H NMR (300 MHz, MeOD) δ ppm 1.46 (d, 3H) 1.83 (s, 3H) 2.14 (s, 3H) 3.27-3.79 (m, 4H) 4.14-4.44 (m, 1H) 5.05-5.44 (m, 1H) 5.90-6.45 (m, 1H) 8.60 (s, 2H). LC-MS ： 442 [M+H]+. 實例15 ((R)-l-(4-((S)-l-(5-氟基，咬-2-基）乙胺基）_6-(5_ 甲基·ih-p比嗤-3-基胺基）-l，3,5-三p井-2-基）六氫?比咬-2-基）甲醇 使用類似關於實例62合成所述之程序，使（s)-6-氣-N2 -(1-(5-氟基嘧啶-2-基）乙基）-N4-(5-甲基-1H-吡唑-3-基）-1,3,5-三喷-2,4-一胺（中間物17)與（R)-六氫p比咬-2-基甲醇鹽酸鹽（中間物25) 反應，提供標題化合物。 LC-MS ： 429 [M+H]. NMR (300 MHz, MeOD) δ ppm 1.45 (d, J = 6.78 Hz, 10H) 1.45-1.73 (m, 5H) 1.67-1.83 (m, 1H) 2.13 (s, 3H) 2.53-2.81 (m, 1H) 3.37-3.85 (m, 2H) 4.22-4.63 (m, 1H) 4.64-4.77 (m, 1H) 5.01-5.30 (m, 1H) 6.20 (s, 1H) 8.59 (s, 2H) 實例16 ((R)-l_(4-((S)-l-(5-氟基嘧啶·2_基）乙胺基）-6-(5_ 甲基-1H_吡唑·3_ 基胺基）-1，3,5-三》1井-2-基）一氣四園-2-基）曱醇 使用類似關於實例62合成所述之程序，使（S)-6-氯-Ν2 -(1-(5-氟基嘧啶-2-基）乙基）_Ν4·(5_甲基-1H-吡唑-3-基）-1,3,5-三喷_2,4_ 二胺（中間物17)與（R)_一氮四圜-2-基甲醇鹽酸鹽（中間物26) 反應’提供標題化合物。 133151 -174- 200906818 NMR (300 MHz, MeOD) δ ppm 1.46 (d, J = 6.41 Hz, 3H) 1.95-2.37 (m, 2H) 2.13 (s, 3H) 3.53-3.75 (m, 2H) 3.74-3.91 (m, 2H) 4.13-4.49 (m, 1H) 5.05-5.22 (m, 1H) 5.88 (s, 1H) 8.60 (s, 2H). LC-MS : 40 [M+H] 實例17 ((S)-l-(4-((S)-l-(5-氟基嘧啶-2-基）乙胺基）-6-(5-曱基-1H-吡唑-3-基 胺基）-1，3,5_三畊-2-基）六氫吡啶-2-基）甲醇 使用類似關於實例62合成所述之程序，使（s)-6-氣-N2 -(1-(5-氟基嘧啶-2-基）乙基）-N4-(5-甲基-1H-吡唑-3-基）-1,3,5-三畊-2,4-二胺（中間物17)與（S)-六氫吡啶-2-基甲醇HC1 (中間物27)反 應，提供標題化合物。 !H NMR (300 MHz, MeOD) δ ppm 1.17-1.30 (m, 2H) 1.45 (d, J = 6.97 Hz, 3H) 1.48-1.62 (m, 4H) 1.68-1.93 (m, 1H) 2.13 (s, 3H) 2.52-2.84 (m, 1H) 3.51-3.78 (m, 2H) 4.26-4.62 (m, 1H) 5.04-5.29 (m, 1H) 5.36-6.34 (m, 1H) 8.60 (s, 2H). LC-MS ： 429 [M+H] 實例18 (S)-6-(3-(二甲胺基）一氮四園_1·基）_ν2-(1·(5-氟基嘧啶-2-基）乙 基）-N4-(5-甲基-1H-吡唑 _3_基）-13,5-三畊-2,4_ 二胺 使用類似關於實例11合成所述之程序，使（S)-6-氯-N2-(1-(5-鼠基喂°定-2-基）乙基）-1^4-(5-甲基-11^-11比°坐-3-基）-1,3,5-三11井-2,4-二胺（中間物17)與N，N-二甲基一氮四圜-3-胺，2HC1反應，提 供標題化合物。 1H NMR (300 MHz, MeOD) &lt;5 ppm 1.56 (t, 3H) 2.26 (s, 3H) 2.33 (s, 6H) 133151 -175 - 200906818 3.79-3.99 (m, 2H) 4.03-4.31 (m, 2H) 4.81-4.88 (m, 1H) 5.16-5.43 (m, 1H) 6.12 (s, 1H) 8.73 (s, 2H). LC-MS : 414 [M+H] 實例19 (S)-N2-(l-(5-氟基，啶-2-基）乙基）_ν4·(5-甲基 嗤 _3_基 (3-(甲胺基）一氮四困-1-基）-1，3,5·三呼-2,4_二胺鹽酸鹽 於（S)-6-氣-N2-(l-(5-氟基嘧啶-2-基）乙基）_N4_(5_曱基_m•峨嗤 -3-基）-1，3,5-三畊-2,4-二胺（中間物Π，1〇〇毫克，〇 29毫莫耳） 在EtOH (953微升）中之落液内’添加一氮四圜_3_基（甲基）胺 基曱酸第三-丁酯（53.3毫克，0.29毫莫耳）與Et3N (12〇微升， 0_86毫莫耳）。將所形成之混合物在25°C下擾拌16小時。於 減壓下蒸發揮發性物質，獲得黃色殘留物。藉管柱層析純 化（ISCO ’ 5%-10% MeOH/DCM) ’而得中間物Boc產物，為白 色固體。使Boc產物溶於MeOH (1毫升）中，並冷卻至〇艺。 添加HC1在二氧陸圜中之溶液（4N，1毫升）。使混合物溫熱 至室溫，且攪拌30分鐘。蒸發揮發性物質，獲得（s)_n2 -(1-(5-氟基嘧啶-2-基）乙基）-N4-(5-甲基-1H-吡唑-3-基）-6-(3-(甲胺基）一 氮四圜-1-基）-1,3,5-三畊-2,4-二胺（20.00 毫克，17.51%)，為 HC1 鹽。自由態鹼係藉由使固體溶於EtOAc中，並以飽和NaHC03 水溶液洗滌（2x)有機層而獲得。 LC-MS ： 400 [M+H]. 1H NMR (300 MHz, MeOD) δ ppm 1.45 (d, 3H) 2.14 (s, 3H) 2.29 (s, 3H) 3.52-3.93 (m, 2H) 3.93-4.24 (m, 2H) 4.73-4.80 (m, 1H) 5.03-5.40 (m, 1H) 8.61 (s, 2H). 133151 -176- 200906818 實例20 (S)-6-(3,3-二氟一氮四圓-1-基）_Ν2_(1·(5_氟基嘧啶_2基）乙基) n4_ (5_ 曱基-1Η-!»比唾 _3_基）-1，3,5·三 \»井 _2,4_二胺 使用類似關於實例11合成所述之程序，使⑻_6_氯_N2 A#- 氟基嘧啶-2-基）乙基）-N4-(5-甲基-1H-吡唾-3-基）-1,3,5-三啡-2,4- 二胺（中間物17，200毫克，0.57毫莫耳）與3,3_二氟一氮四圜 鹽酸鹽（81毫克’ 0.63毫莫耳）反應，提供標題化合物。 ^ H NMR (300 MHz, MeOD) &lt;5 ppm 8.71 (s，2H) 6.07 (寬廣 s.，1H) 5.29 (q, 1H) 3.98-4.55 (m, 4H) 2.25 (s, 3H) 1.57 (d, 3H). LC-MS : 407 [M+H]+ 實例21 (8)-6-(3,3-二氟四氫p比洛-1-基)-N2 -(1-(5-氣基嘴咬_2_基）乙基)_ (5_ 甲基-lH-v比嗤-3-基）-1,3,5-三 _ -2,4-二胺 使用類似關於實例11合成所述之程序，使⑻_6_氯_ν2 -(ΐ-(5· 氟基〇治、唆-2-基）乙基）-N4-(5-甲基-1H-P比α坐-3-基）-i，3,5-三p井-2,4-I 二胺（中間物I7，200毫克，0.57毫莫耳）與3,3_二氟四氫吡咯 鹽酸鹽（90毫克，0.63毫莫耳）反應，提供標題化合物。 4 NMR (300 MHz，MeOD) &lt;5 ppm 8.71 (s，1H) 6.04 (寬廣 s_，1H) 5.29 (q, 1H) 3.59-4.03 (m, 4H) 2.30-2.58 (m, 2H) 2.25 (s, 3H) 1.57 (d, 3H). LC-MS ： 421 [M+H]+ 實例22 (S)-l-(4-(l-(5-氟基嘧啶_2-基）乙胺基）冬(5_甲基_1H_吡唑_3_基胺 基）-1，3,5_三_ -2-基）一氣四困-3·醇 使用類似關於實例11合成所述之程序，使⑻各氯_Ν2 _(丨_(5_ 133151 -177- 200906818 氟基嘧啶-2-基）乙基）·ν4_(5_甲基.吡唑_3_基H，3,5_三畊·2,4_ 二胺（中間物17，200毫克，〇·57毫莫耳）與一氮四圜斗醇鹽 酸鹽反應，提供標題化合物。 1H NMR (300 MHz, MeOD) (5 ppm 8.71 (s，2Η) 5.98 (寬廣 s_，1Η) 5.29 (d，1H) 4·6〇 (寬廣 s” 1H) 4·28 (寬廣 s” 2H) 3 84 (寬廣 s , 2H) 2 % &amp; 3H) 1.57 (d, 3H). LC-MS ： 387 [M+H]+. 實例23 i N2-((S)-l-(5-氟基嘧啶-2-基）乙基）·ν4·(5-甲基_ih_吡唑-3-基）-6- ((S)-3-曱基嗎福β林基）_ι，3,5_三井_2,4»二胺 使用類似關於實例62合成所述之程序，使⑸_6_氣_Ν2 氟基嘧啶-2-基）乙基）-N4-(5-甲基-lH-p比唾-3-基）-l，3,5-三喷-2,4_ 二胺（中間物17，200毫克，〇_57毫莫耳）與（s)-3-甲基嗎福啉 (63.6毫克，0.63毫莫耳）反應，提供標題化合物。 1H NMR (300 MHz, MeOD) δ ppm 8.70 (s，2H) 5J6 (寬廣 s.，1H) ( 4.98-5.40 (m，1H) 4.40-4.76 (m, 1H) 4.03-4.39 (m，1H) 3.86 (d，1H) 3.51-3.78 (m，2H) 2.94-3.23 (m，1H) 2.24 (s，3H) 1.55 (d, 3H) 1.32 (寬廣 s·，2H) 0.95 (寬廣8.，211)· LC-MS ： 415 [M+H]+. 實例24 (S)-l-(4-(l-(5-氟基嘧啶-2-基）乙胺基）_6·(5_甲基-1H-吡唑-3-基胺 基）-1，3,5·三味-2-基）·3_曱基一氮四園_3_醇 使用類似關於實例11合成所述之程序，使（S)-6-氣-Ν2 -(1-(5-氟基嘧啶-2-基）乙基）-N4-(5-甲基-1H-吡唑-3-基）-1,3,5-三畊-2,4- 133151 -178- 200906818 二胺（中間物17 ’ 340毫克’ 0.97毫莫耳）與3-甲基一氮四圜_3-醇鹽酸鹽（中間物28，132毫克’ 1·〇7毫莫耳）反應，提供標 題化合物。 1 H NMR (300 MHz，MeOD) 5 ppm 8.71 (s，2Η) 6.15 (寬廣 s·, 1Η) 5.28 (m, 1H) 3.73-4.04 (m, 4H) 2.24 (s, 3H) 1.36-1.71 (m, 6H). LC-MS ： 401 [M+H]+. 實例25 (S)-l-(4-(l-(5-氣基，咬-2-基）乙胺基）-6-(5-甲基-1Η-ϊ»比峻-3-基胺 基）-1，3,5-三p井-2-基）一氮四園-3-曱腈 使用類似關於實例11合成所述之程序，使（S)-6-氯-N2 -(1-(5-乾基0密咬-2-基）乙基）-N4-(5-曱基-1H-P比唾-3-基）-1，3,5-三口井-2,4-二胺（中間物17，200毫克，0.57毫莫耳）與一氮四圜_3_曱腈 鹽酸鹽（74·6毫克’ 0_63毫莫耳）反應，提供標題化合物。 lH NMR (300 MHz, MeOD) δ ppm 8.70 (s, 2H) 6.19-6.61 (m, 1H) 5.59 (m, 1H) 5.28 (m, 1H) 3.87-4.52 (m, 2H) 3.60-3.86 (m, 2H) 2.24 (d, 3H) 1.55 (d, 3H). LC-MS : 396 [M+H]+. 實例26 (S)-6-(3-氟基一氮四圓_i_基）_]^_(1_(5_氟基嘧啶：基）乙基)_N4_ (5_ 曱基-lH-p比嗤 _3_基）-1，3,5_三 **井-2,4·二胺 使用類似關於實例11合成所述之程序，使（8)_6_氯_N2 氟基嘧啶-2-基）乙基）~^4-(5-甲基-1沁吡唑-3-基）-1,3,5-三呼_2,4-二胺（中間物17，228毫克，0.65毫莫耳）與3-氟基一氮四圜鹽 酸鹽（中間物29，80毫克，0.72毫莫耳）反應，提供標題化合 133151 •179- 200906818 物。 H NMR (300 MHz, Me〇D) 5 ppm 8.70 (s, 2H) 6.16 (寬廣 s.，1H) 5 47 (m, 1H) 5.27 (m, 1H) 3.69-4.57 (m, 4H) 2.24 (s, 3H) 1.56 (d, 3H). LC-MS : 389 [M+H]+ 實例27 (S)-6-(4,4-二氟六氫吡啶-1-基）_N2 _(1·(5·氟基嘧啶_2基）乙基)_N4 _ (5_ 曱基-ΙΗ-ι»比唾-3-基）-1，3,5-三啡-2,4-二胺 使用類似關於實例11合成所述之程序，使⑻-6-氣-N2-(1-(5-風1基°密。定-2-基）乙基）-]^4-(5-曱基-111^比。坐-3-基）-1,3,5-三11井-2 4-二胺（中間物17 ’ 200毫克’ 〇·57毫莫耳）與4,4-二氟六氫吡咬 鹽酸鹽（99毫克，0_63毫莫耳）反應，提供標題化合物。 1H NMR (300 MHz，MeOD) d ppm 8.70 (s，2H) 6.05 (寬廣 s” 1H) 5.12-5.41 (m, 1H) 3.82 (d, 4H) 2.26 (s, 3H) 1.98 (m, 4H) 1.52 (d, 3H). LC-MS ： 435 [M+H]+ 實例28 (S)-l-(4-(l-(5-氣基喊咬-2_基）乙胺基）-6-(5-曱基-iH-p比峻-3-基胺 基）-1,3,5-三味-:2-基）六氫p比咬-4-醇 使用類似關於實例11合成所述之程序，使（S)-6-氣-N2-(1-(5- 氟基。密咬-2-基）乙基）-N4-(5-甲基-1H-P比唾-3-基）-1，3,5-三ϋ井-2,4_ 一胺（中間物17，200耄克’ 0.57毫莫耳）與六氫ρ比咬_4_醇（63.6 毫克’ 0.63毫莫耳）反應’提供標題化合物。 1H NMR (300 MHz, MeOD) 5 ppm 8.69 (s，2Η) 6.03 (寬廣 s·，1Η) 5.06-5.41 (m, 1H) 4.03-4.54 (m, 2H) 3.79 (m, 1H) 2.90-3.26 (m, 2H) 2.25 (s, 3H) 1.78 (m, 2H) 1.56 (d, 3H) 1.34 (m, 2H). 133151 -180- 200906818 LC-MS ： 415 [M+H]+ 實例29 (S)-6-(4-氟基六氫p比咬-1-基）—]^_(1_(5_氟基嘧啶_2_基）乙基）_n4_ (5-甲基-lH-p比嗅-3-基）-1,3,5-三 p井 _2,4-二胺 使用類似關於實例11合成所述之程序，使⑻_6_氯_Ν2 -(^(孓 氟基嘴咬-2-基）乙基）-N4-(5-曱基_iH-p比嗤_3_基）_ι，3,5-三呼-2,4· 一胺（200毫克，0_57毫莫耳）（中間物17)與4_氟基六氫吡啶鹽 酸鹽（88毫克’ 0.63毫莫耳）反應，提供標題化合物。 4 NMR (300 MHz, MeOD) 5 ppm 8.69 (s，邱 6 〇6 (寬廣 s，m) 5.09-5.40 (m, 1H) 4.70 (m, 1H) 3.46-4.10 (m, 4H) 2.23 (s, 3H) 1.61-2.02 (m, 4H) 1.55 (d, 3H). LC-MS ： 417 [M+H]+ 實例30 (S)-N2 -(1-(5-氣基痛咬-2-基）乙基）_6·(3_甲氧基一氮四園小基）_ Ν4-(5-甲基-1Η-Ϊ»比唾-3-基）-1,3,5-三哨 -2,4-二胺 使用類似關於實例11合成所述之程序，使（8)_6_氯_N2 _(丨-(5_ 氟基哺'1定-2-基）乙基）-1''14-(5-甲基-出-?比峻-3-基）-1,3,5-三'1井-2,4-二胺（中間物17，200毫克，0.57毫莫耳）與3_曱氧基一氮四圜 鹽酸鹽（78毫克，0.63毫莫耳）反應，提供標題化合物。 1 H NMR (300 MHz，氯仿-d) &lt;5 ppm 8.56 (寬廣 s.，2H) 5.55-6.61 (m， 1H) 5.39 (見廣 s，1H) 4.26 (m，3H) 3_98 (m, 2H) 3.32 (s, 3H) 2.29 (寬 廣 s·，3H) 1.57 (d, 3H). LC-MS ： 401 [M+H]+ 實例31 133151 -181 - 200906818 (S)-l-(4-(l-(5-氟基嘴咬-2-基）乙胺基）-6-(5-曱基·ιη-ρ比哇_3_基胺 基）-1，3,5_三呼_2_基）_4_甲基六氫ρ比咬-4-醇 使用類似關於實例11合成所述之程序，使（8)_6_氣_Ν2 _(丨_(5_ 氟基°密σ定-2-基）乙基）-Ν4-(5-曱基-lH-p比。垒-3-基）-ΐ,3,5-三ρ井_2 4-二胺（200毫克，0.57毫莫耳）（中間物17)與4_甲基六氫吡啶_4_ 醇鹽酸鹽（中間物31 ’ 95毫克’ 0.63毫莫耳）反應，提供標題 化合物。 1 H NMR (300 MHz，MeOD) (5 ppm 8.69 (s，2H) 6.18 (寬廣 s·，1H) 5.21 (m, 1H) 3.81-4.38 (m, 2H) 3.34-3.53 (m, 1H) 2.23 (s, 3H) 1.35-1.69 (m, 7H) 1.13-1.29 (m, 4H). LC-MS ： 429 [M+H]+ 實例32 (S)-N2 -(1-(5-氟基嘧啶-2-基）乙基）-6-(4-甲氧基六氫吡啶小基）_ 1^4-(5-甲基-111-吡唑-3-基）-1，3,5_三畊-2,4-二胺 使用類似關於實例11合成所述之程序，使⑻_6_氯-N2 -(1-(5-氟基喷咬-2-基）乙基）-1^4-(5-甲基-11^比》坐-3-基）-1,3,5-三'1井-2,4-二胺（200毫克，0.57毫莫耳）（中間物17)與4-曱氧基六氫吡啶 鹽酸鹽（95毫克，0.63毫莫耳）反應，提供標題化合物。 1 H NMR (300 MHz, MeOD) 5 ppm 8.69 (s，2H) 6_05 (寬廣 s·，1H) 5.20 (m, 1H) 3.89-4.41 (m, 2H) 3.43 (m, 1H) 3.35 (s, 3H) 3.09-3.27 (m, 1H) 2.23 (s, 3H) 1.77 (m, 2H) 1.55 (d, 3H) 1.37 (m, 2H). LC-MS : 429 [M+H]+ 實例33 (S)-4-(4-(l-(5-氟基嘧啶-2-基）乙胺基）-6-(5-甲基-1H-吡唑-3-基胺 133151 -182- 200906818 基二p井-2-基）-1-甲基六氮ι»比p井-2-嗣 使用類似關於實例11合成所述之程序，使（8)_6_氣_n2 氟基°密η定-2-基）乙基）-N4-(5-曱基-lH-p比嗤-3-基）-1,3 5-三p井2 4 二胺（中間物17 ’ 200毫克，0_57毫莫耳甲基六氫吨呼_2· 酮鹽酸鹽（95毫克，〇_63毫莫耳）反應，提供標題化合物。 1 H NMR (300 MHz，MeOD) &lt;5 ppm 8.69 (寬廣 s” 2H) 6.11 (寬廣 s 1H) 5.12-5.39 (m, 1H) 4.07-4.48 (m, 2H) 3.69-4.06 (m, 2H) 3.41 (m, 1H) 2.96 (寬廣 s” 3H) 2·24 (s，3H) 1.56 (d，3H) LC-MS ： 428 [M+H]+ 實例34 (S)_l-(4-(l-(5-氟基嘴咬-2-基）乙胺基）-6-(5-甲基-lH-p比峻-3_基胺 基）-l，3,5-三畊-2-基）六氫吡啶-4-曱腈 使用類似關於實例11合成所述之程序，使（S)-6-氯-N2 -〇(5-氟基°密σ定-2-基）乙基）-N4-(5-曱基-lH-p比唾-3-基）-1,3,5-三p井-2 4_ 二胺（中間物17 ’ 200毫克，〇_57毫莫耳）與六氫吡啶斗甲腈 鹽酸鹽（中間物32 ’ 92毫克，0.63毫莫耳）反應，提供標題化 合物。 1 H NMR (300 MHz, MeOD) &lt;5 ppm 8_69 (s，2H) 6.06 (寬廣 s·，1H) 5.10-5.42 (m, 1H) 3.78-4.35 (m, 2H) 3.35-3.63 (m, 2H) 2.97 (m, 1H) 2.24 (s, 3H) 1.61-1.99 (m, 4H) 1.55 (d, 3H). LC-MS ： 424 [M+H]+ 實例35 l-(4-((S)-l-(5-氟基嘧啶-2-基）乙胺基）-6-(5-曱基-1H-吡唑-3-基胺 基)-1，3,5-三畊_2-基）六氫吡啶-3-甲腈 133151 -183 - 200906818 使用類似關於實例11合成所述之程序，使（S)-6-氯-N2 -(1-(5-氟基嘧啶-2-基）乙基）-N4-(5-曱基-1H-吡唑-3-基）-1,3,5-三畊-2,4-二胺（中間物17)與六氫吡啶-3-甲腈反應，提供標題化合物， 為非對映異構物之混合物。 NMR (5 ppm 8.69 (m, 2H), 6.33 (m, 1H), 5.19 (m, 1H), 4.10 (m, 1H), 3.88 (m, 3H), 2.84 (m, 1H), 2.26 (m, 3H), 1.95 (m, 2H), 1.53 (m, 5H). LC-MS : 424 [M+H]+ _ 兩種非對映異構物係使用條件（A)與AS-3-25分離 管柱粒子大小（μ): 5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗 試樣純度係使用條件（Β)與AD-3-25確認 管柱尺寸：4.6 X 250毫米，10微米 流率：3毫升/分鐘 第一個吸收峰（滯留時間：分鐘）8.59 第二個吸收峰（滯留時間：分鐘）11.21 第一個溶離峰，實例35(a) NMR δ ppm 8.66 (m, 2H), 6.35 (m, 1H), 5.19 (m, 1H), 4.08 (m, 1H), 3.88 (m, 3H), 2.83 (m, 1H), 2.23 (m, 3H), 1.93 (m, 2H), 1.55 (m, 5H). LC-MS ： 424 [M+H]+. 第二個溶離峰，實例35(b) NMR δ ppm 8.70 (s, 2H), 5.99 (m, 1H), 5.23 (m, 1H), 4.08 (m, 1H), 3.90 (m, 3H), 2.85 (m, 1H), 2.24 (s, 3H), 1.98 (m, 3H), 1.56 (d, 4H). LC-MS : 424 [M+H]+ · 133151 -184- 200906818 實例36 N2 -((S)-l-(5-氟基嘧啶-2-基）乙基）_6_(3_甲氧基六氫吡啶小基）_ …-(七甲基-讯-吡唑净基从^三啩^二胺 使用類似關於實例11合成所述之程序，使⑻各氯_N2 -…(^ 氟基嘧啶-2-基）乙基）-N4-(5-曱基]H_吡唑_3_基）_13,5_三畊_2,4_ 一胺（中間物17)與3-甲氧基六氫吡啶反應，提供標題化合 物’為非對映異構物之混合物。 ]H NMR (5 ppm 8.68 (s, 2H), 6.35 (br s, 1H), 5.21 (m, 1H), 4.11 (m, iH), 3.87 (m, 1H), 3.36 (m, 6H), 2.22 (m, 3H), 1.94 (m, 1H), 1.72 (m, 1H), 1.55 (m, 4H), 1.39 (m, 1H). LC-MS ： 429 [M+H]+. 兩種非對映異構物係使用條件（A)與〇j_3_1〇分離 管柱粒子大小（μ) : 5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗 試樣純度係使用條件（Β)與〇j_3_i5確認 管柱尺寸：4.6 X 250毫米，1〇微米 流率：3毫升/分鐘 偵測：220毫微米 第一個吸收峰（滯留時間：分鐘）5 〇7 第二個吸收峰（滯留時間：分鐘）6·57 第一個溶離之化合物，實例36⑻ 1H NMR (5 ppm 8.68 (s, 2H), 6.35 (br s, 1H), 5.21 (m, 1H), 3.90 (m, 2H), 3.36 (m, 6H), 2.22 (m, 3H), 1.94 (m5 1H), 1.55 (m, 5H), 1.40 (m, 1H). 133151 -185- 200906818 LC-MS : 429 [M+H]+. 第二個溶離之化合物，實例36φ) NMR 5 ppm 8.68 (s, 2H), 6.33 (br s, 1H), 5.23 (m, 1H), 4.13 (m, 1H), 3.80 (m, 1H), 3.36 (m, 6H), 2.22 (m, 3H), 1.93 (m, iH), 1.69 (m, 1H), 1.55 (m, 5H). LC-MS ： 429 [M+H]+. 實例37 l-(4-((S)-l-(5-氟基鳴咬-2-基）乙胺基)_6-(5_甲基_m_吡唑_3_基胺 基)-1,3,5-三畊-2-基)-3-甲基六氩峨咬_3_醇 使用類似關於實例11合成所述之程序，使（s)_6•氣_N2 _(1_(5_ 鼠基鳴。疋-2-基）乙基）-N4 -(5_甲基-lH-p比唾_3_基）_ι 3 5-三呼-2,4_ 二胺（中間物17)與3-甲基六氫吡啶氺醇（中間物34)反應，提 供標題化合物。 !H NMR 5 ppm 8.69 (s, 2H), 6.02 (m, 1H), 5.25 (m, 1H), 3.80 (m, 1H), 3.64 (m, 1H), 3.51 (m, 2H), 2.23 (s, 3H), 1.63 (m, 4H), 1.54 (m, 3H), 1.15 (m, 3H). LC-MS ： 429 [M+H]+. 兩種非對映異構物係使用條件（A)與AD_3_2〇分離 管柱粒子大小（μ) : 5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗： 試樣純度係使用條件（Β)與AD-3-20確認 官柱尺寸：4.6 X 1〇〇毫米，1〇微米 流率：3毫升/分鐘 133151 •186- 200906818 偵測：254毫微米 第一個吸收峰（滯留時間：分鐘）213 第二個吸收峰（滯留時間··分鐘）3 ls 第一個溶離之化合物，實例37(a). Ή NMR 5 ppm 8.68 (s, 2H), 6.38 (m, 1H)5 5.24 (m, 1H), 3.80 (m&gt; 1H), 3.64 (m, 1H), 3.51 (m, 2H), 2.24 (m, 3H), 1.63 (m, 4H), 1.54 (m, 3H), 1.15 (m, 3H). LC-MS ： 429 [M+H]+. 第二個溶離之化合物，實例37(b). !H NMR ά ppm 8.68 (s, 2H), 6.35 (m, 1H), 5.24 (m, 1H), 3.86 (m, 1H), 3.69 (m, 1H), 3.50 (m, 2H), 2.25 (m, 3H), 1.61 (m, 4H), 1.55 (m, 3H), 1.15 (m, 3H). LC-MS ： 429 [M+H]+. 實例38 (R)-l-(4-((S)-l-(5·氟基嘧啶_2-基）乙胺基)各(5-甲基-1H-吡唑-3-基 胺基）_1，3,5_三畊-2-基）六氫吡啶_3_基胺基甲酸第三-丁酯 使用類似關於實例11合成所述之程序，使（§)_6_氣_N2 _(45_ 氟基哺°定-2-基）乙基）-1\[4-(5-甲基-11&quot;1-11比嗤-3-基）-1,3,5-三11井-2,4-二胺（中間物17)與（R)-六氫吡啶_3_基胺基曱酸第三_丁酯反 應’提供標題化合物。 ^ NMR δ ppm 8.67 (m, 2H), 6.40 (m, 1H), 5.24 (m, 1H), 4.31 (m, 2H), 2.97 (m, 2H), 2.25 (m, 3H), 1.94 (m, 1H), 1.44 (m, 16H). LC-MS : 514 [M+H]' 實例39 133151 -187- 200906818 6-((R)_3-胺基六氫峨咬_1_基基嘧啶_2_基）乙基）_ Ν4·(5·甲基-1H-吡嗤-3-基）-1，3,5_三畊_2,4_二胺鹽酸鹽 使⑻-l-(4-((S)-l-(5-氟基嘧啶_2_基）乙胺基）·6_(5_甲基·ιη-吡唑 -3-基胺基）-1，3,5-三畊-2-基）六氫吡啶_3_基胺基甲酸第三_丁酯 (實例38)溶於甲醇中，並以1〇毫升在乙鱗溶液中之2N HC1 處理。將反應混合物授拌四小時，於減壓下濃縮，並在真 空烘箱中’於50°C下乾燥，而得標題化合物。 !H NMR 5 ppm 8.76 (m, 2H), 5.88 (m, 1H), 5.34 (m, 1H), 4.23 (m, 1H), 3.96 (m, 1H), 3.65 (m, 2H), 2.39 (m, 1H), 2.32 (m, 3H), 2.11 (m, 1H), 1.63 (m, 6H). LC-MS : 414 [M+H]+. 實例40 (S)-l-(4-((S)-l-(5-氟基嘴咬_2_基）乙胺基)·6·(5甲基_1H吡唑各基 胺基)-1,3,5-三畊-2-基）六氫吡啶_3_基胺基甲酸第三-丁酯 使用類似關於實例11合成所述之程序，使（s)_6_氣 氟基嘧啶-2-基）乙基）-N4-(5-甲基·1H_吡唑_3_基）_13,5-三畊_2,4_ 二胺（中間物Π)與（S)-六氫吡啶_3_基胺基甲酸第三-丁酯反 應，提供標題化合物。 1 H NMR (5 ppm 8.67 (m, 2H), 6.39 (m, 1H), 5.22 (m, 1H), 4.31 (m, 2H), 2.91 (m，2H)，2.23 (m，3H)，1.90 (m, m)，155 (m, 7H)，143 ㈣ 9H) LC-MS ： 514 [M+H]+. 實例41 6-((S)_3-胺基六氫吡啶小基(⑻小(5氣基嘧啶_2基）乙基）_ N4-(5-甲基-1Η-Τ»比唑-3-基）-i，3，S_三畊_2,4_二胺鹽酸鹽 133151 • 18δ· 200906818 使（S)-l-(4-((S)-l-(5·氟基嘧啶冬基）乙胺基）_6 (5_甲基_m吡唑 -3-基胺基）-1，3,5-三畊-2-基）六氫吡啶_3_基胺基甲酸第三_丁酯 (實例40) &gt;谷於甲醇中，並以1〇毫升在乙醚溶液中之2Ν Ηα 處理。將反應混合物攪拌四小時，在減壓下濃縮，並於真 空烘箱中，在50°C下乾燥，而得標題產物。 ^ NMR 5 ppm 8.76 (m, 2H), 5.91 (m5 1H)5 5.30 (m, 1H), 4.42 (m, 1H), 3.95 (m, 1H), 3.58 (m, 2H), 2.33 (m, 3H), 2.17 (m, 1H), 1.87 (m, 1H), 1.64 (m, 5H), 1.39 (m, 1H). LC-MS ： 414 [M+H]+. 實例42 (R) -l-(4-((S)-l-(5•氟基嘧啶-2-基）乙胺基甲基_1H•吡唑_3_基 胺基）-1，3,5_三呼_2_基）六氫u比咬_3_醇 使用類似關於實例11合成所述之程序，使（s)_6_氯_N2 _(丨_(5_ 氟基嘧啶-2-基）乙基）-N4-(5-甲基-1H-吡唑-3-基）-l，3,5-三畊-2,4-二胺（中間物17)與（R)-六氫吡啶-3_醇反應，提供標題化合物。 NMR 5 ppm 8.68 (s, 2H), 6.35 (m, 1H), 5.23 (m, 1H), 4.26 (m, 2H), 3.54 (m, 1H), 2.96 (m, 2H), 2.23 (m, 3H), 1.95 (m, 1H), 1.54 (m, 3H), 1.43 (m, 3H). LC-MS ： 415 [M+H]+. 實例43 (S) -l-(4-((S)-l-(5-氟基峨咬-2-基）乙胺基)-6-(5-甲基-lH-p比唾-3-基 胺基）-1,3,5-三啼-2-基）六氩吡啶-3-醇 使用類似關於實例11合成所述之程序，使（S)-6-氣-N2 -(1-(5-氟基嘴17定-2-基）乙基）-N4-(5-甲基-lH-p比。坐-3-基）-1,3,5-三p井-2,4- 133151 -189- 200906818 二胺（中間物17)與（S)-六氫吡啶_3_醇反應，提供標題化合物。 H NMR δ ppm 8.68 (s, 2H), 6.34 (m, 1H), 5.23 (m, 1H), 4.38 (m, 1H), 4.22 (m, 2H), 3.53 (m, 1H), 2.93 (m, 2H), 2.23 (m, 3H), 1.98 (m, 1H), 1.72 (m, 1H), 1.55 (m, 3H), 1.45 (m, 1H). LC-MS ： 415 [M+H]+. 實例44 N2-((S)-l-(5-氟基嘧啶-2-基）乙基甲氧基甲基）六氫吡啶 -1-基）-N4-(5-甲基-1H-P比峻-3-基）-1，3,5-三？井-2,4-二胺 使用類似關於實例11合成所述之程序，使（S)-6-氣-N2 -(1-(5-氟基嘧啶-2-基）乙基）-&gt;^4-(5-甲基-111-吡唑-3-基）-1,3,5-三畊-2,4-二胺（中間物17)與3-(甲氧基甲基）六氫吡啶反應，提供標題 化合物’為非對映異構物之混合物。 ]H NMR δ ppm 8.68 (m, 2H), 6.39 (m, 1H), 5.22 (m, 1H), 4.62 (m, 1H), 4.42 (m, 1H), 3.23 (m, 5H), 2.87 (m, 1H), 2.69 (m, 1H), 2.22 (m, 3H), 1.76 (m, 3H), 1.54 (m, 3H), 1.29 (m, 2H). LC-MS ： 443 [M+H]+. 兩種非對映異構物係使用條件（A)與OD-3-15分離 管柱粒子大小（〆)：5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗： 試樣純度係使用條件（B)與AD-4-25確認 管柱尺寸：4.6 X 100毫米，10微米 偵測：254毫微米 第一個吸收峰（滯留時間：分鐘）2.21 133151 -190· 200906818 第二個吸收峰（滯留時間：分鐘）3 〇7 第一個溶離之化合物，實例44(a) 5-22 (m, 1H), 4.48 (m, 1H), ]H NMR (δ ) 8.69 (m, 2H), 6.36 (m, 1H), (m，1H)，2.22 (m，3H)，1.75 4.27 (m，1H)，3_25 (m，5H)，2.89 (m，1H)，2 65 (m, 3H), 1.55 (m, 3H), 1.27 (m, 2H). LC-MS : 443 [M+H]+ · 第二個溶離之化合物，實例44(b). lH NMR (5) 8 68 ㈣ 2H)，636 ㈣邱，5.23 (m，1H)，4.45 (m 2H) 3.23 (m，5H)，2.89 (m，1H)，2.72 (m，1H)，2 22 (m，3h), i % ㈣邱】％ (m, 3H), 1.28 (m, 2H). ’ LC-MS : 443 [M+H]+. 實例45 6-㈣二乙胺基）甲基）嗎福啉基)_N2调小(I氟基嘧啶：基）乙 基)Μ#-甲基-1H-吨唾_3_基)畊_2,心二胺Column: Chirapak AD Size: 250 X 20 mm, 10 with mobile phase: 80% hexane, 20% 1:1 ethanol: methanol, ο]% diethylamine (v/v/v) flow rate (ml/min) ): 20 detection (nm): 254 first dissolution peak, example 4 (8) !H NMR (300 MHz, MeOD) 5 1.72 (d, 3H) 2.38 (s, 3H) 3.63-3.87 (m, 8H) 6.07 (s, 1H) 6.18 (q, 1H) 7.50-7.79 (m, 2H) 8.46 (d, 1H). Second Dissolved Peak, Example 4(b) ]H NMR (300 MHz, MeOD) δ 1.72 (d , 3H) 2.38 (s, 3H) 3.63-3.87 (m, 8H) 6.07 (s, 1H) 6.18 (q, 1H) 7.50-7.79 (m, 2H) 8.46 (d, 1H). Example 5 (S)- 4-(l-(5-Fluoropyrimidin-2-yl)ethoxy)-N-(5-methyl-1H-pyrazol-3-yl)-6-morpholinyl-1,3, 5-trinyl-2-amine in a microwave container, 4-(4-(yl)fluoro-6-(1-(5-fluoropyrimidin-2-yl)ethoxyl 133151-167- 200906818 base)-l, 3,5-three tillage-2-yl)porphyrin (intermediate 19,253 mg, 〇74 mmol), 3-amino-5-methyl-1H-pyrazole small carboxylic acid third·ding Ester (intermediate 6,220 mg, 1.11 mmol), BITAP (46.2 mg), Cs2C03 (605 mg) and Pd; 2 (dba) 3 (34.0 mg) followed by dioxane The land was rubbed (2 ml) and the resulting mixture was degassed with argon for 20 minutes. The reaction mixture was heated to 1 Torr for 4 h at which time MeOH was added and mixture was stirred at room temperature for 3 hr. The mixture was filtered and washed several times with DCM. The volatiles were evaporated under reduced pressure to give a dark brown residue. The title compound was obtained as a pale yellow powder. LC-MS: 402 [M+H]. The title compound was obtained using conditions (A) and OD-4-20 (with 0.1% dimercaptoethylamine) for the purification of the column. Particle size (y): 5 tubes Column size (mm): 21 X 250 Purity test purity after purification. Conditions of use (B) and AD-4-20 confirm the first absorption peak (residence time: minute) 2·06 Second absorption peak (stagnation) Time: min) 2.91 First Dissolved Peak, Example 5(8) 1H NMR (400 MHz, MeOD) δ ppm 8.69 (s, 2H) 6.23 (s, 1H) 6.02 (q, J = 6.57 Hz, 1H) 3.61 (m, 8H) 2.24 (s, 3H) 1.67 (d, J = 6.82 Hz, 3H). Second elution peak, Example 5(b) 1H NMR (400 MHz, MeOD) δ ppm 8.69 (s, 2H) 6.23 (s , 1H) 6.02 (q, J = 133151 • 168- 200906818 6.57 Hz, 1H) 3.64 (m, 8H) 2.24 (s, 3H) 1.68 (d, J = 6.57 Hz, 3H). Example 6 6-((R )-3-(dimethylamino)tetrahydropyrrol-1-yl)_N2·((8) small (5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazole -3-yl)·1,3,5_three tillage-2,4-diamine using a procedure similar to that described for the synthesis of Example 11 to give (S)-6-gas-Ν2- (1-(5-fluoro) Pyrimidin-2-yl)ethyl)-Ν4·(5-mercapto-1H-pyridyl -3-yl)-1,3,5-trinyl-2,4-diamine (intermediate 17) is reacted with (R)-N,N-dimethyltetrahydropyrrole-3-amine to provide the title compound . 1 H NMR (300 MHz, MeOD) δ ppm 1.30 (d, J = 6.59 Hz, 3H) 1.58 (s, 3H) 1.72-1.98 (m, 1H) 2.12-2.45 (m, 10H) 2.75-2.95 (m, 1H) 3.72-3.99 (m, 1H) 5.15-5.42 (m, 1H) 5.53-5.75 (m, 1H) 8.71 (s, 2H). LC-MS : 428 [M+H]+. Example 7 2-( 5-fluoropyridin-2-yl)-N,N-dimercapto-2-(4-(5-fluorenyl-1H-pyrazol-3-ylamino)-6-morpholinyl-1, 3,5-Triton-2-ylamino)ethanesulfonamide in a 250 ml round bottom flask with 2-(4-chloro-6-(5-methyl-) in EtOH (3.29 mL) 1H-pyrazol-3-ylamino)-1,3,5-tricyano-2-ylamino)-2-(5-fluoropyridin-2-yl)-N,N-dimethyl Ethylene amide (intermediate 23, 1-5 g, 3.29 mmol) and morpholine (1.720 ml, 19.74 mmol) were obtained as a yellow solution. The resulting mixture was stirred at 25 ° C for 1 hour. The volatiles were evaporated under reduced pressure to give an oil. Purification by column chromatography (ISCO, EtOAc /EtOAc) LC-MS: 507 [M+H]. !H NMR (300 MHz, MeOD) &lt;5 ppm 2.25 (s, 3H) 2.81 (s, 6H) 2.82-2.89 133151 -169- 200906818 (m, 2H) 3.53-3.87 (m, 8H) 5.73 (t, J = 6.41 Hz, 1H) 6.38 ( s, 1H) 7.29-7.79 (m, 2H) 8.47 (s, 1H). The title compound is used for the purification of the column particle size (〆) using conditions (A) and OD-4-20: 5 column size (mm): 21 X 250 Purity test purity after purification. Conditions of use (B) and OD-4-20 confirmed f Column size (mm): 100 X 4·6 Column particle size (〆): 5 One absorption peak (residence time: minute) 20.5 Second absorption peak (residence time: minute) 24.1 First dissolution peak, Example 7(a) lU NMR (300 MHz, MeOD) δ ppm 2.14 (s, 3H) 2.71 (s, 6H) 3.43-3.80 (m, 10H) 5.48-5.68 (m, 1H) 5.99 (s, 1H) 7.11-7.72 (m, 2H) 8.37 (s, 2H) Second Dissolved Peak, Example 7 (b) ( NMR (300 MHz, MeOD) &lt;5 ppm 2.14 (s, 3H) 2.71 (s, 6H) 3.42-3.67 (m, 10H) 5.45-5.65 (m, 1H) 5.99 (s, 1H) 7.18-7.68 (m, 2H) 8.37 (d, J = 1.70 Hz, 1H) Example 8 6-((S)-3-(Dimethylamino)tetrahydropyrrole_i_yl)_n2-((S)-1-(5-fluoropyrimidin-2- Ethyl)-N4-(5-methyl-lH-t* than quaternary-3-yl)-1,3,5-trinol-2,4-diamine was synthesized analogously to Example 11 Procedure, (S)-6-chloro-N2-(1-(5-fluoropyrimidin-2-yl)ethyl)-:^-(5-fluorenyl-111-pyrazol-3-yl)- 1,3,5-Tricotin-2,4-diamine (intermediate 17) is reacted with (S)-N,N-dimercaptotetrahydropyrrol-3-amine to provide the title compound 133151 -170- 200906818 . 1 H NMR (300 MHz, MeOD) δ ppm 1.25 (d, J = 6.41 Hz, 3H) 1.58 (s, 3H) 1.75-1.89 (m, 1H) 2.22-2.28 (m, 1H) 2.33 (s, 6H) 2.72-2.92 (m, 1H) 3.40-3.59 (m, 1H) 3.66-4.13 (m, 2H) 5.17-5.44 (m, 1H) 5.50-5.82 (m, 1H) 6.45 (s, 1H) 8.71 (s, 2H). LC-MS: 428 [M+H] + · Example 9 N-(l-(4-((S)-l-(5-fluoropyrimidin-2-yl)ethylamino). 5·Methyl_m-pyrazole-3-ylamino)-1,3,5_III? Well_2_yl)tetrahydrou-bi-3-yl) Ethylamine was synthesized similarly to Example 11 The procedure described is such that (S)-6-gas-N2-(1-(5-fluoropyrimidin-2-yl)ethyl)-&gt;14-(5-methyl-111-pyrazole-3 -Based -1,3,5-Tricotin-2,4-diamine (Intermediate 17) is reacted with N-(tetrahydropyrrol-3-yl)acetamide to provide the title compound as diastereomeric a mixture of structures. 1 H NMR (300 MHz, MeOD) δ ppm 1.37 (d, J = 6.59 Hz, 3H) 1.58 (s, 3H) 1.96 (s, 3H) 3.44-3.89 (m, 4H) 4.23-4.50 (m, 1H) 5.22-5.41 (m, 1H) 5.50-5.82 (m, 1H) 8.71 (s, 2H). LC-MS: 442 [M+H]+. Example 10 $-((8)-1-(5-fluoro Pyrimidin-2-yl)ethyl)_]\4-(5-methyl-111-pyrazole-3-yl)-6-((R)_3·(methylamino)tetrahydro-p-lo- 1·基)_1,3,5_三呼_2,4_Diamine using a procedure similar to that described in Example 11 for (5)_6_chloro-Ν2 _(丨_(5-fluoropyrimidin-2-yl) Ethyl)-indole 4-(5-mercapto-1Η-pyrazol-3-yl)-1,3,5-three tillage _2,4-diamine (intermediate 17) and (R)-N-methyl TetrahydroP is reacted with each of the _3_amines to provide the title compound. 133151 -171 · 200906818 lU NMR (300 MHz, MeOD) δ ppm 1.58 (d, 3H) 1.74-1.93 (m, 1H) 2.18-2.26 (m, 4H) 2.41 (s, 3H) 3.11-3.32 (m, 2H) 3.46-3.89 (m, 2H) 5.22-5.44 (m, 1H) 5.50-5.74 (m, 1H) 6.45 (s, 1H) 8.71 (s, 2H). LC-MS : 414 [M+H]+. Example 11 6-(3-Ethoxytetrahydropyrrole small group)_N2·((8) small (5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-U ratio-- 3-yl)-1,3,5-triper-2,4-diamine in (S)-6-chloro-N2-(l-(5-fluoropyrimidin-2-yl)ethyl)_n4-( 5-methyl-1H-pyrazol-3-yl)-1,3,5-trinol-2,4-diamine (intermediate π, 100 mg, 〇_29 mmol) at EtOH (572 micro In the solution of liter), 3_ethoxytetrahydropyrrole hydrochloride (43.4 mg '0.29 mmol) and DIPEA (49.9 μl, 0.29 mmol) were added. The resulting mixture was at 25. (: stirring for 16 hours. Evaporating the volatile material under reduced pressure to give a yellow residue. Purified by column chromatography (ISC 〇, 5% 〇0 / MeOH / DCM) to give 6-(3- Each small group of ethoxytetrahydroanthracene)_N2_((S)]_(5_aphthylpyrimidin-2-yl)ethyl)-]^4-(5-methyl-111-pyrazole-3- -1,3,5-Tricotin-2,4-diamine (87 mg '71.0%) as a mixture of diastereomers. JH NMR (300 MHz, MeOD) δ ppm 0.98-1.14 ( m, 2H) 1.21-1.33 (m, 3H) 1.46 (t, J = 6.97 Hz, 3H) 1.79-1.99 (m, 2H) 2.14 (s, 3H) 3.34-3.54 (m, 4H) 3.87-4.20 (m , 1H) 4.99-5.35 (m, 1H) 5.96 (s, 1H) 8.62 (s, 2H). LC-MS : 429 [M+H]+ Example 12 (S)-N-(l-(4-( L-(5-Fluoropyrimidin-2-yl)ethylaminomethyl-m-pyrazole-3-ylamino)-1,3,5-tri-p--2-yl)-nitrogen four-park_3_ Ethylamine using a procedure similar to that described for the synthesis of Example 11 to give (8)_6_chloro_n2_(1_(5_133151-172·200906818 fluoroyl)-2-)ethyl)_n4-(5-methyl -1H-pyrazol-3-yl)-l,3,5-trinyl-2,4-diamine (intermediate 17) is reacted with N-(-azaindole-3-yl)acetamide to provide Title compound. ^ NMR (300 MHz, MeOD) δ ppm 1.36-1.53 (m, 3H) 1.86 (s, 3H) 2.14 (s, 3H) 3.68-3.96 (m, 2H) 4.09-4.35 (m, 2H) 4.40-4.61 (m, 1H) 5.08- 5.37 (m, 1H) 6.12 (sJ = 6.00 Hz, 1H) 8.61 (s, 2H). LC-MS : 428 [M+H]' Example 13 N-((S)-l-(4-((S )-l-(5-fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-1,3,5-three tillage-2 -Based on tetrahydropyrrolyl-3-yl)benzamine using a procedure similar to that described for the synthesis of Example 11 to give (8)_6_gas_N2 _(丨_(5_fluoroyl'*岔, bite-2 -yl)ethyl)-N4-(5-fluorenyl-methyl-3-yl)-1,3,5-tri-p--2,4.diamine (intermediate 17) and (S)-N- (izg Hydropyrrole_3_yl)acetamide HC1 (Intermediate 23b) was reacted to afford the title compound. 1 H NMR (300 MHz, MeOD) δ ppm 1.46 (d, 3H) 1.83 (s, 3H) 2.14 (s, 3H) 3.27-3.79 (m, 4H) 4.14-4.44 (m, 1H) 5.05-5.44 (m , 1H) 5.90-6.45 (m, 1H) 8.60 (s, 2H). LC-MS: 442 [M+H]+. Example 14 N-((R)-l-(4-((S)-l -(5-fluoropyrimidin-2-yl)ethylamino)_6_(5-methyl-ih-pyrazol-3-ylamino)-1,3,5-trin-2-yl)tetrahydroindole _3_yl) ethanoamine using a procedure similar to that described in the synthesis of Example 11 to give (Fantasy_6_qi_N2 fluoropyrimidin-2-yl)ethyl)-1^4-(5-methyl _111_pyrazole_3_yl)_1,3,5_three tillage_2,4_diamine (intermediate 17) and (R)-N-(tetrahydropyrrole_3_yl)acetamide (middle (24) 133151 -173 - 200906818 Reaction, providing the title compound. 1 H NMR (300 MHz, MeOD) δ ppm 1.46 (d, 3H) 1.83 (s, 3H) 2.14 (s, 3H) 3.27-3.79 (m, 4H) 4.14-4.44 (m, 1H) 5.05-5.44 (m , 1H) 5.90-6.45 (m, 1H) 8.60 (s, 2H). LC-MS: 442 [M+H]+. Example 15 ((R)-l-(4-((S)-l-( 5-fluoro, n-yl-2-yl)ethylamino)_6-(5-methyl·ih-p than indol-3-ylamino)-l,3,5-tri-p-yl-2-yl) Hydrogen is used in a procedure similar to that described in Example 62 for the synthesis of (s)-6-gas-N2-(1-(5-fluoropyrimidin-2-yl)ethyl)- N4-(5-Methyl-1H-pyrazol-3-yl)-1,3,5-tripenta-2,4-monoamine (intermediate 17) and (R)-hexahydrop ratio bite-2 -Methanol HCl hydrochloride (Intermediate 25) was reacted to afford the title compound. LC-MS: 429 [M+H]. NMR (300 MHz, MeOD) δ ppm 1.45 (d, J = 6.78 Hz, 10H) 1.45-1.73 (m, 5H) 1.67-1.83 (m, 1H) 2.13 (s , 3H) 2.53-2.81 (m, 1H) 3.37-3.85 (m, 2H) 4.22-4.63 (m, 1H) 4.64-4.77 (m, 1H) 5.01-5.30 (m, 1H) 6.20 (s, 1H) 8.59 (s, 2H) Example 16 ((R)-l_(4-((S)-l-(5-fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl-1H-pyrazole) · 3_ arylamino)-1,3,5-tri"1 well-2-yl)-gas tetram-2-yl)sterol using a procedure similar to that described for the synthesis of Example 62, (S)-6- Chloro-indole 2 -(1-(5-fluoropyrimidin-2-yl)ethyl)-indole 4·(5-methyl-1H-pyrazol-3-yl)-1,3,5-three-spray_2, 4_ Diamine (Intermediate 17) is reacted with (R)-monotetradec-2-ylmethanol hydrochloride (Intermediate 26) to provide the title compound. 133151 -174- 200906818 NMR (300 MHz, MeOD) δ ppm 1.46 (d, J = 6.41 Hz, 3H) 1.95-2.37 (m, 2H) 2.13 (s, 3H) 3.53-3.75 (m, 2H) 3.74-3.91 (m, 2H) 4.13-4.49 (m, 1H) 5.05-5.22 (m, 1H) 5.88 (s, 1H) 8.60 (s, 2H). LC-MS : 40 [M+H] Example 17 ((S) -l-(4-((S)-l-(5-fluoropyrimidin-2-yl)ethylamino)-6-(5-fluorenyl-1H-pyrazol-3-ylamino)-1 , 3,5_Triton-2-yl)hexahydropyridin-2-yl)methanol using a procedure similar to that described for the synthesis of Example 62 to give (s)-6-gas-N2-(1-(5-fluoro) Pyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl)-1,3,5-trinol-2,4-diamine (intermediate 17) (S)-Hexahydropyridin-2-ylmethanol HC1 (Intermediate 27) was reacted to afford the title compound. !H NMR (300 MHz, MeOD) δ ppm 1.17-1.30 (m, 2H) 1.45 (d, J = 6.97 Hz, 3H) 1.48-1.62 (m, 4H) 1.68-1.93 (m, 1H) 2.13 (s, 3H) 2.52-2.84 (m, 1H) 3.51-3.78 (m, 2H) 4.26-4.62 (m, 1H) 5.04-5.29 (m, 1H) 5.36-6.34 (m, 1H) 8.60 (s, 2H). LC -MS: 429 [M+H] Example 18 (S)-6-(3-(Dimethylamino)-nitrogentetracycline-1-yl)_ν2-(1·(5-fluoropyrimidin-2-yl) Ethyl)-N4-(5-methyl-1H-pyrazole-3-yl)-13,5-trinol-2,4-diamine was prepared using a procedure similar to that described in Example 11 for (S) -6-Chloro-N2-(1-(5-murine-based)-2-yl)ethyl)-1^4-(5-methyl-11^-11 ratio °-3-yl)- The 1,3,5-tri-11,-2,4-diamine (Intermediate 17) is reacted with N,N-dimethylnazatetradec-3-amine, 2HC1 to provide the title compound. 1H NMR (300 MHz, MeOD) &lt;5 ppm 1.56 (t, 3H) 2.26 (s, 3H) 2.33 (s, 6H) 133151 -175 - 200906818 3.79-3.99 (m, 2H) 4.03-4.31 (m, 2H) 4.81-4.88 (m, 1H 5.16-5.43 (m, 1H) 6.12 (s, 1H) 8.73 (s, 2H). LC-MS: 414 [M+H] Example 19 (S)-N2-(l-(5-fluoro, pyridine -2-yl)ethyl)_ν4·(5-methylindole_3_yl(3-(methylamino)-nitrogentetrahydro-1-yl)-1,3,5·three-h-2,4 _Diamine hydrochloride in (S)-6-gas-N2-(l-(5-fluoropyrimidin-2-yl)ethyl)_N4_(5-fluorenyl-m•indol-3-yl) -1,3,5-three tillage-2,4-diamine (intermediate Π, 1 〇〇 mg, 〇29 mmol) Add a nitrogen tetramine in the drop in EtOH (953 μL) _3_yl (meth)amine decanoic acid tert-butyl ester (53.3 mg, 0.29 mmol) and Et3N (12 〇 microliter, 0-86 mmol). The resulting mixture was at 25 ° C. The mixture was stirred for 16 hours. The title compound was obtained eluted eluted eluted elution elution The Boc product was dissolved in MeOH (1 mL) and cooled to dryness. Add a solution of HC1 in dioxane (4) N, 1 ml). The mixture was allowed to warm to room temperature and stirred for 30 minutes. The volatile material was evaporated to give (s)_n2-(1-(5-fluoropyrimidin-2-yl)ethyl)-N4- (5-Methyl-1H-pyrazol-3-yl)-6-(3-(methylamino)-azatetraindole-1-yl)-1,3,5-three tillage-2,4-di The amine (20.00 mg, 17.51%) was obtained as the HCl salt. The free base was obtained by dissolving the solid in EtOAc and washing (2×) organic layer with saturated aqueous NaHC03. LC-MS: 400 [M+H] 1H NMR (300 MHz, MeOD) δ ppm 1.45 (d, 3H) 2.14 (s, 3H) 2.29 (s, 3H) 3.52-3.93 (m, 2H) 3.93-4.24 (m, 2H) 4.73-4.80 (m , 1H) 5.03-5.40 (m, 1H) 8.61 (s, 2H). 133151 -176- 200906818 Example 20 (S)-6-(3,3-difluoro-nitrogen-tetra-l-yl)_Ν2_(1 ·(5_Fluoropyrimidin-2-yl)ethyl) n4_ (5_ fluorenyl-1Η-!» than salivation_3_yl)-1,3,5·three\» Well _2,4-diamine use The procedure described for the synthesis of Example 11 was carried out such that (8)_6_chloro-N2 A#-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyran-3-yl)-1, 3,5-triphthyl-2,4-diamine (intermediate 17,200 mg, 0.57 mmol) and 3,3-difluoronitrozatetrahydrochloride (81 mg' The reaction was carried out in 0.63 mmol to give the title compound. ^ H NMR (300 MHz, MeOD) &lt;5 ppm 8.71 (s, 2H) 6.07 (broad s., 1H) 5.29 (q, 1H) 3.98-4.55 (m, 4H) 2.25 (s, 3H) 1.57 (d, 3H). LC-MS : 407 [M+H]+ Example 21 (8)-6-(3,3-Difluorotetrahydrop-pyr-1-yl)-N2 -(1-(5-gas-based mouth bite_2_yl)B Base)_(5-methyl-lH-v is more than indole-3-yl)-1,3,5-tris-2,4-diamine using a procedure similar to that described for the synthesis of Example 11 to give (8)_6_chloro_ Ν2 -(ΐ-(5·fluoro-based, 唆-2-yl)ethyl)-N4-(5-methyl-1H-P than α--3-yl)-i,3,5-three Reaction of p--2,4-I diamine (intermediate I7, 200 mg, 0.57 mmol) with 3,3-difluorotetrahydropyrrole hydrochloride (90 mg, 0.63 mmol) afforded title compound . 4 NMR (300 MHz, MeOD) &lt;5 ppm 8.71 (s,1H) 6.04 (broad s_,1H) 5.29 (q, 1H) 3.59-4.03 (m, 4H) 2.30-2.58 (m, 2H) 2.25 (s, 3H) 1.57 (d, 3H LC-MS: 421 [M+H]+ Example 22 (S)-l-(4-(l-(5-Fluoropyrimidin-2-yl)ethylamino) Winter (5-Methyl-1H) _Pyrazole_3_ylamino)-1,3,5_tri--2-yl)-gas tetrad-3-alcohol using a procedure similar to that described for the synthesis of Example 11 to give (8) each chlorine_Ν2 _(丨_(5_ 133151 -177- 200906818 fluoropyrimidin-2-yl)ethyl)·ν4_(5-methyl.pyrazole_3_yl H,3,5_three tillage·2,4_diamine (middle Reaction of 1,4 mg, 〇·57 mmoles with nitro-tetrahydrofuran hydrochloride afforded the title compound. 1H NMR (300 MHz, MeOD) (5 ppm 8.71 (s, 2 Η) 5.98 (broad s_) ,1Η) 5.29 (d,1H) 4·6〇(broad s) 1H) 4·28 (broad s) 2H) 3 84 (broad s, 2H) 2 % &amp; 3H) 1.57 (d, 3H). LC -MS: 387 [M+H]+. Example 23 i N2-((S)-l-(5-fluoropyrimidin-2-yl)ethyl)·ν4·(5-methyl_ih_pyrazole -3-yl)-6-((S)-3-indolyl-based β-linyl)_ι, 3,5_三井_2,4»diamine using a procedure similar to that described for the synthesis of Example 62, (5)_6 _气_Ν2 Pyrimidin-2-yl)ethyl)-N4-(5-methyl-lH-ppyraz-3-yl)-l,3,5-tripentene-2,4-diamine (intermediate 17,200 Reaction of (s)-3-methylmorpholine (63.6 mg, 0.63 mmol) afforded the title compound. 1H NMR (300 MHz, MeOD) δ ppm 8.70 (s, 2H) 5J6 (broad s., 1H) ( 4.98-5.40 (m, 1H) 4.40-4.76 (m, 1H) 4.03-4.39 (m,1H) 3.86 (d,1H) 3.51-3.78 (m,2H) 2.94-3.23 (m,1H) 2.24 (s,3H) 1.55 (d, 3H) 1.32 (broad s·, 2H) 0.95 (broad 8.,211)· LC-MS: 415 [M+H] +. s. 24 (S)-l-(4-(l-(5-fluoropyrimidin-2-yl)ethylamino) -6 (5-methyl-1H) -pyrazol-3-ylamino)-1,3,5·tris-2-yl)·3_fluorenyl-nitrogen tetra- 3-3-ol was synthesized using a procedure similar to that described in Example 11 to make (S -6-Gas-Ν2-(1-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl)-1,3,5-三耕-2,4- 133151 -178- 200906818 Diamine (intermediate 17 ' 340 mg '0.97 mmol) with 3-methyl-azinotetramine-ol hydrochloride (intermediate 28,132 mg '1·〇7 mmoles of reaction, providing the title compound. 1 H NMR (300 MHz, MeOD) 5 ppm 8.71 (s, 2 Η) 6.15 (broad s·, 1 Η) 5.28 (m, 1H) 3.73-4.04 ( m, 4H) 2.24 (s, 3H) 1.36-1.71 (m, 6H). LC-MS: 401 [M+H]+. Example 25 (S)-l-(4-(l-(5-) , bit-2-yl)ethylamino)-6-(5-methyl -1Η-ϊ»比峻-3-ylamino)-1,3,5-tri-p--2-yl)-nitrogen tetra--3-carbonitrile was synthesized using a procedure similar to that described in Example 11 (S)-6-chloro-N2 -(1-(5-dry-based 0-denyl-2-yl)ethyl)-N4-(5-mercapto-1H-P than spani-3-yl)-1 , 3,5-three wells-2,4-diamine (intermediate 17,200 mg, 0.57 mmol) and nitrotetracycline_3_indole nitrile hydrochloride (74·6 mg ' 0_63 mmol) Reaction, the title compound is provided. lH NMR (300 MHz, MeOD) δ ppm 8.70 (s, 2H) 6.19-6.61 (m, 1H) 5.59 (m, 1H) 5.28 (m, 1H) 3.87-4.52 (m, 2H 3.60-3.86 (m, 2H) 2.24 (d, 3H) 1.55 (d, 3H). LC-MS: 396 [M+H]+. Example 26 (S)-6-(3-fluoro-nitrogen-tetra _i_基)_]^_(1_(5_Fluoropyrimidinyl)ethyl)_N4_ (5_ fluorenyl-lH-p than 嗤_3_yl)-1,3,5_three** Well-2,4.diamine was prepared using a procedure similar to that described for the synthesis of Example 11 to give (8)_6_chloro-N2 fluoropyrimidin-2-yl)ethyl)~^4-(5-methyl-1 Pyridoxazole-3-yl)-1,3,5-trioxo-2,4-diamine (intermediate 17,228 mg, 0.65 mmol) and 3-fluoronorzine tetrahydrochloride hydrochloride ( Intermediate 29, 80 mg, 0.72 mmol, reaction, For the title compound 133151 • 179- 200906818 matter. H NMR (300 MHz, Me〇D) 5 ppm 8.70 (s, 2H) 6.16 (broad s., 1H) 5 47 (m, 1H) 5.27 (m, 1H) 3.69-4.57 (m, 4H) 2.24 (s , 3H) 1.56 (d, 3H). LC-MS: 389 [M+H]+ Example 27 (S)-6-(4,4-difluorohexahydropyridin-1-yl)_N2 _(1·( 5·Fluoropyrimidin-2-yl)ethyl)_N4 _ (5_ fluorenyl-ΙΗ-ι» than sial-3-yl)-1,3,5-triphthyl-2,4-diamine is similarly used 11 synthesize the procedure to make (8)-6-gas-N2-(1-(5-wind 1 dimethyl thiophenan-2-yl)ethyl)-]^4-(5-mercapto-111^ Ratio. sit -3-base)-1,3,5-triple 11 well-2 4-diamine (intermediate 17 '200 mg' 〇·57 mmol) with 4,4-difluorohexahydropyridine The hydrochloride salt (99 mg, 0-63 mmol) was reacted to afford the title compound. 1H NMR (300 MHz, MeOD) d ppm 8.70 (s, 2H) 6.05 (broad s) 1H) 5.12-5.41 (m, 1H) 3.82 (d, 4H) 2.26 (s, 3H) 1.98 (m, 4H) 1.52 (d, 3H). LC-MS: 435 [M+H]+ Example 28 (S)-l-(4-(l-(5-methane-based)-ethylamino)-6- (5-Mercapto-iH-p than tern-3-aminol)-1,3,5-tris-:2-yl)hexahydro-p-biti-4-ol was synthesized analogously to the synthesis of Example 11. Procedure for making (S)-6-gas-N2-(1-(5-fluoro-. dimethyl-2-yl)ethyl)-N4-(5-methyl-1H-P than spyr-3-yl )-1,3,5-Sanchajing-2,4_-amine (intermediate 17,200 gram '0.57 mmol) and hexahydro ρ ratio _4-alcohol (63.6 mg '0.63 mmol) Reaction 'Provides the title compound. 1H NMR (300 MHz, MeOD) 5 ppm 8.69 (s, 2 Η) 6.03 (broad s·, 1 Η) 5.06-5.41 (m, 1H) 4.03-4.54 (m, 2H) 3.79 (m, 1H) 2.90-3.26 (m, 2H) 2.25 (s, 3H) 1.78 (m, 2H) 1.56 (d, 3H) 1.34 (m, 2H). 133151 -180- 200906818 LC-MS : 415 [M+H] + Example 29 (S)-6-(4-Fluorohexahydrop to bit-1-yl)-]^_(1_(5-fluoropyrimidin-2-yl)ethyl)_n4_ (5-methyl -lH-p is similar to s--3-yl)-1,3,5-tri-p well _2,4-diamine The procedure described in Example 11 was synthesized such that (8)_6_chloro-Ν2 -(^(孓-fluoroyl-n-butyl-2-yl)ethyl)-N4-(5-fluorenyl-iH-p is 嗤_3_yl )_ι,3,5-triplo-2,4·monoamine (200 mg, 0_57 mmol) (intermediate 17) and 4-fluorohexahydropyridine hydrochloride (88 mg '0.63 mmol) Reaction, the title compound is provided. 4 NMR (300 MHz, MeOD) 5 ppm 8.69 (s, Qiu 6 〇6 (broad s, m) 5.09-5.40 (m, 1H) 4.70 (m, 1H) 3.46-4.10 (m, 4H) 2.23 (s, 3H) 1.61-2.02 (m, 4H) 1.55 (d, 3H). LC-MS: 417 [M+H]+ Example 30 (S)-N2 -(1-(5-) Pain-2-yl)ethyl)_6·(3_methoxy-nitrogen tetramyl) Ν4-(5-methyl-1Η-Ϊ» than sal-3-yl)-1,3, 5-Trisex-2,4-diamine was prepared using a procedure similar to that described for the synthesis of Example 11 to give (8)_6_chloro-N2 _(丨-(5- fluoroyl-n-butyl-2-yl)ethyl )-1''14-(5-methyl-ex-?-jun-3-yl)-1,3,5-tri'1 well-2,4-diamine (intermediate 17,200 mg, 0.57) Reaction with 3-methoxyl-tetrazepine hydrochloride (78 mg, 0.63 mmol) afforded the title compound. 1 H NMR (300 MHz, chloroform-d) &lt;5 ppm 8.56 (broad s., 2H) 5.55-6.61 (m, 1H) 5.39 (see wide s, 1H) 4.26 (m, 3H) 3_98 (m, 2H) 3.32 (s, 3H) 2.29 (broad s ·, 3H) 1.57 (d, 3H). LC-MS: 401 [M+H]+ Example 31 133151 -181 - 200906818 (S)-l-(4-(l-(5-Fluoro-mouth bite-2 -yl)ethylamino)-6-(5-fluorenyl·ιη-ρ than wow_3_ylamino)-1,3,5-trih_2_yl)_4_methylhexahydro-p ratio The bite-4-ol was prepared using a procedure similar to that described for the synthesis of Example 11 to give (8)_6_gas_Ν2 _(丨_(5_ fluoroyl) succinyl-2-yl)ethyl)-Ν4-(5 - mercapto-lH-p ratio. base-3-yl)-oxime, 3,5-tri-p-well _2 4-diamine (200 mg, 0.57 mmol) (intermediate 17) and 4-methyl The reaction of the hexahydropyridine _4_ alkanoate (Intermediate 31 '95 mg '0.63 mmol) afforded the title compound. 1 H NMR (300 MHz, MeOD) (5 ppm 8.69 (s, 2H) 6.18 (broad s·, 1H) 5.21 (m, 1H) 3.81-4.38 (m, 2H) 3.34-3.53 (m, 1H) 2.23 ( s, 3H) 1.35-1.69 (m, 7H) 1.13-1.29 (m, 4H). LC-MS: 429 [M+H]+ Example 32 (S)-N2 -(1-(5-fluoropyrimidine- 2-yl)ethyl)-6-(4-methoxyhexahydropyridine small)_1^4-(5-methyl-111-pyrazol-3-yl)-1,3,5_3 Plowing the 2,4-diamine using a procedure similar to that described for the synthesis of Example 11 to give (8) _6_chloro-N2-(1-(5-fluoropiped-2-yl)ethyl)-1^4-( 5-methyl-11^ ratio "sit-3-yl)-1,3,5-tri'1 well-2,4-diamine (200 mg, 0.57 mmol) (intermediate 17) and 4- Reaction of the decyloxy hexahydropyridine hydrochloride (95 mg, 0.63 mmol) afforded the title compound. 1 H NMR (300 MHz, MeOD) 5 ppm 8.69 (s, 2H) 6_05 (broad s·, 1H) 5.20 (m, 1H) 3.89-4.41 (m, 2H) 3.43 (m, 1H) 3.35 (s, 3H) 3.09-3.27 (m, 1H) 2.23 (s, 3H) 1.77 (m, 2H) 1.55 (d, 3H) 1.37 (m, 2H). LC-MS: 429 [M+H] + s. 33 (S)-4-(4-(l-(5-fluoropyrimidin-2-yl)ethylamino)-6 -(5-methyl-1H-pyrazol-3-ylamine 133151 -182- 200906818 base two p-form-2-yl)-1- The hexamethylene ι» is similar to the p-well 嗣 using a procedure similar to that described for the synthesis of Example 11 to give (8) _6_gas_n2 fluoroyl-denyl-2-yl)ethyl)-N4-( 5-mercapto-lH-p is more than 嗤-3-yl)-1,3 5-tri-p well 2 4 diamine (intermediate 17 '200 mg, 0_57 mmole hexahydro ton hr 2· ketone Reaction with the hydrochloride salt (95 mg, EtOAc EtOAc) &lt;5 ppm 8.69 (broad s) 2H) 6.11 (broad s 1H) 5.12-5.39 (m, 1H) 4.07-4.48 (m, 2H) 3.69-4.06 (m, 2H) 3.41 (m, 1H) 2.96 (wide) s" 3H) 2·24 (s,3H) 1.56 (d,3H) LC-MS : 428 [M+H]+ Example 34 (S)_l-(4-(l-(5-Fluoro-bite bite- 2-yl)ethylamino)-6-(5-methyl-lH-p than ternary-3-amino)-l,3,5-trin-2-yl)hexahydropyridin-4-indole The nitrile was used in a procedure similar to that described for the synthesis of Example 11 to give (S)-6-chloro-N2-indole (5-fluoroyl succinyl-2-yl)ethyl)-N4-(5-fluorenyl- lH-p is more than spyr-3-yl)-1,3,5-tri-p--2 4-diamine (intermediate 17 '200 mg, 〇_57 mmol) and hexahydropyridine carbonitrile hydrochloride (Intermediate 32 '92 mg, 0.63 mmol) reaction afforded the title compound. 1 H NMR (300 MHz, MeOD) &lt;5 ppm 8_69 (s, 2H) 6.06 (broad s·, 1H) 5.10-5.42 (m, 1H) 3.78-4.35 (m, 2H) 3.35-3.63 (m, 2H) 2.97 (m, 1H) 2.24 ( s, 3H) 1.61-1.99 (m, 4H) 1.55 (d, 3H). LC-MS: 424 [M+H] + Example 35 l-(4-((S)-l-(5-fluoropyrimidine) -2-yl)ethylamino)-6-(5-mercapto-1H-pyrazol-3-ylamino)-1,3,5-trinyl-2-yl)hexahydropyridine-3-methyl Nitrile 133151 -183 - 200906818 Using a procedure similar to that described for the synthesis of Example 11, (S)-6-chloro-N2-(1-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5 - mercapto-1H-pyrazol-3-yl)-1,3,5-trinyl-2,4-diamine (intermediate 17) is reacted with hexahydropyridine-3-carbonitrile to provide the title compound as a mixture of diastereomers. NMR (5 ppm 8.69 (m, 2H), 6.33 (m, 1H), 5.19 (m, 1H), 4.10 (m, 1H), 3.88 (m, 3H), 2.84 (m, 1H), 2.26 (m, 3H), 1.95 (m, 2H), 1.53 (m, 5H). LC-MS: 424 [M+H]+ _ Separation of two diastereomers using conditions (A) and AS-3-25 Column particle size (μ): 5 Column size (mm): 21 X 250 Purity test purity after purification. Conditions of use (Β) and AD-3-25 Confirmation of column size: 4.6 X 250 mm, 10 μm Flow rate: 3 ml/min first absorption peak (residence time: minute) 8.59 second absorption peak (residence time: minute) 11.21 first dissolution peak, example 35 (a) NMR δ ppm 8.66 (m, 2H ), 6.35 (m, 1H), 5.19 (m, 1H), 4.08 (m, 1H), 3.88 (m, 3H), 2.83 (m, 1H), 2.23 (m, 3H), 1.93 (m, 2H) , 1.55 (m, 5H). LC-MS: 424 [M+H]+. Second elution peak, Example 35(b) NMR δ ppm 8.70 (s, 2H), 5.99 (m, 1H), 5.23 ( m, 1H), 4.08 (m, 1H), 3.90 (m, 3H), 2.85 (m, 1H), 2.24 (s, 3H), 1.98 (m, 3H), 1.56 (d, 4H). LC-MS : 424 [M+H]+ · 133151 -184- 200906818 Example 36 N2 -((S)-l-(5-Fluoropyrimidin-2-yl)ethyl)_6_(3_methoxy-6 Hydropyridine small base) _ ...-(heptamethyl-indole-pyrazole net group from ^3啩^ diamine using a procedure similar to that described in Example 11 for the synthesis of (8) each chlorine_N2 -...(^ fluoropyrimidine -2-yl)ethyl)-N4-(5-fluorenyl)H_pyrazole_3_yl)_13,5_three tillage _2,4_monoamine (intermediate 17) and 3-methoxy six Hydropyridine reaction, providing the title compound as a mixture of diastereomers.]H NMR (5 ppm 8.68 (s, 2H), 6.35 (br s, 1H), 5.21 (m, 1H), 4.11 (m, iH), 3.87 (m, 1H), 3.36 (m, 6H), 2.22 (m, 3H), 1.94 (m, 1H), 1.72 (m, 1H), 1.55 (m, 4H), 1.39 (m, 1H) LC-MS : 429 [M+H]+. Two diastereoisomers using conditions (A) and 〇j_3_1〇 separation column particle size (μ): 5 column size (mm): 21 Purity test purity after X 250 purification The conditions of use (Β) and 〇j_3_i5 confirm the column size: 4.6 X 250 mm, 1 〇 micron flow rate: 3 ml / min Detection: 220 nm first absorption peak ( Retention time: minute) 5 〇7 Second absorption peak (residence time: minute) 6.57 First dissolved compound, Example 36(8) 1H NMR (5 ppm 8.68 (s, 2H), 6 .35 (br s, 1H), 5.21 (m, 1H), 3.90 (m, 2H), 3.36 (m, 6H), 2.22 (m, 3H), 1.94 (m5 1H), 1.55 (m, 5H), 1.40 (m, 1H). 133151 -185- 200906818 LC-MS: 429 [M+H]+. Second dissolved compound, Example 36φ) NMR 5 ppm 8.68 (s, 2H), 6.33 (br s, 1H ), 5.23 (m, 1H), 4.13 (m, 1H), 3.80 (m, 1H), 3.36 (m, 6H), 2.22 (m, 3H), 1.93 (m, iH), 1.69 (m, 1H) , 1.55 (m, 5H). LC-MS: 429 [M+H]+. Example 37 l-(4-((S)-l-(5-Fluoroheptin-2-yl)ethylamine) _6-(5_methyl_m_pyrazole-3-ylamino)-1,3,5-trin-2-yl)-3-methylhexafluoroquinone _3_alcohol is similar to the example 11 Synthesize the program so that (s)_6•gas_N2 _(1_(5_ rat base). Indole-2-yl)ethyl)-N4-(5-methyl-lH-p than salivation_3_yl)_ι 3 5-trih-2,4-diamine (intermediate 17) and 3-methyl The hexahydropyridinol (Intermediate 34) is reacted to provide the title compound. !H NMR 5 ppm 8.69 (s, 2H), 6.02 (m, 1H), 5.25 (m, 1H), 3.80 (m, 1H), 3.64 (m, 1H), 3.51 (m, 2H), 2.23 (s , 3H), 1.63 (m, 4H), 1.54 (m, 3H), 1.15 (m, 3H). LC-MS: 429 [M+H]+. Conditions for use of two diastereomers (A Separation column particle size (μ) with AD_3_2〇: 5 Column size (mm): 21 X 250 Purity test after purification: Sample purity conditions (Β) and AD-3-20 confirmation column size: 4.6 X 1〇〇mm, 1〇micron flow rate: 3ml/min 133151 •186- 200906818 Detection: 254 nm first absorption peak (residence time: minute) 213 second absorption peak (residence time·minutes 3 ls first dissolved compound, Example 37(a). NMR NMR 5 ppm 8.68 (s, 2H), 6.38 (m, 1H)5 5.24 (m, 1H), 3.80 (m> 1H), 3.64 ( m, 1H), 3.51 (m, 2H), 2.24 (m, 3H), 1.63 (m, 4H), 1.54 (m, 3H), 1.15 (m, 3H). LC-MS : 429 [M+H] +. The second dissolved compound, Example 37(b). !H NMR ά ppm 8.68 (s, 2H), 6.35 (m, 1H), 5.24 (m, 1H), 3.86 (m, 1H), 3.69 ( m, 1H), 3.50 (m, 2H), 2.25 (m, 3H), 1.61 (m, 4H), 1.55 (m, 3H), 1.15 (m, 3H). LC-MS: 429 [M+H]+. Example 38 (R)-l-(4-((S)-l-(5-fluoropyrimidin-2-yl)ethylamine Each of (5-methyl-1H-pyrazol-3-ylamino)_1,3,5-triton-2-yl)hexahydropyridine-3-ylaminocarboxylic acid tert-butyl ester is similar For the synthesis of the procedure described in Example 11, let (§)_6_gas_N2_(45_ fluoromethyl-but-2-yl)ethyl)-1\[4-(5-methyl-11&quot;1- 11 to indole-3-yl)-1,3,5-tri-11 well-2,4-diamine (intermediate 17) and (R)-hexahydropyridine-3-ylamino decanoic acid The ester reaction 'provides the title compound. ^ NMR δ ppm 8.67 (m, 2H), 6.40 (m, 1H), 5.24 (m, 1H), 4.31 (m, 2H), 2.97 (m, 2H), 2.25 (m, 3H), 1.94 (m, 1H), 1.44 (m, 16H). LC-MS: 514 [M+H]' Example 39 133151 -187- 200906818 6-((R)_3-Amino hexahydropurine _1_ylpyrimidine_2 _yl)ethyl)_Ν4·(5·methyl-1H-pyridin-3-yl)-1,3,5_three tillage _2,4-diamine hydrochloride makes (8)-l-(4 -((S)-l-(5-fluoropyrimidin-2-yl)ethylamino)·6_(5-methyl·ιη-pyrazol-3-ylamino)-1,3,5-three Tern-2-yl)hexahydropyridine-3-ylaminocarbamic acid tert-butyl ester (Example 38) was dissolved in methanol and treated with 1 mL of 2N HCl in hexanes. The reaction mixture was stirred for four hours, concentrated under reduced pressure and dried <RTI ID=0.0> !H NMR 5 ppm 8.76 (m, 2H), 5.88 (m, 1H), 5.34 (m, 1H), 4.23 (m, 1H), 3.96 (m, 1H), 3.65 (m, 2H), 2.39 (m , 1H), 2.32 (m, 3H), 2.11 (m, 1H), 1.63 (m, 6H). LC-MS : 414 [M+H]+. Example 40 (S)-l-(4-(( S)-l-(5-fluoro-based mouth bite 2_yl)ethylamine)·6·(5-methyl-1Hpyrazolylamino)-1,3,5-trin-2-yl </RTI> hexahydropyridine _3_ylaminocarbamic acid tert-butyl ester using a procedure similar to that described for the synthesis of Example 11 to give (s) _6_fluorofluoropyrimidin-2-yl)ethyl)-N4-(5 -methyl·1H_pyrazole_3_yl)_13,5-three tillage _2,4-diamine (intermediate ruthenium) and (S)-hexahydropyridine -3-aminocarbamic acid tert-butyl ester The reaction provides the title compound. 1 H NMR (5 ppm 8.67 (m, 2H), 6.39 (m, 1H), 5.22 (m, 1H), 4.31 (m, 2H), 2.91 (m, 2H), 2.23 (m, 3H), 1.90 ( m, m), 155 (m, 7H), 143 (4) 9H) LC-MS: 514 [M+H]+. Example 41 6-((S)_3-aminohexahydropyridine small group ((8) small (5 Vetylpyrimidin-2-yl)ethyl)_N4-(5-methyl-1Η-Τ»pyrazol-3-yl)-i,3,S_three-plowed _2,4-diamine hydrochloride 133151 • 18δ· 200906818 (S)-l-(4-((S)-l-(5.Fluoropyrimidyl)ethylamino)-6 (5-methyl-m-pyrazol-3-ylamino) -1,3,5-Triton-2-yl)hexahydropyridine-3-ylaminocarbamic acid tert-butyl ester (Example 40) &gt; Valley in methanol, and 1 mL in ether solution 2 Ν 处理 处理 。 反应 反应 反应 反应 反应 反应 反应 反应 反应 反应 ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ 1H)5 5.30 (m, 1H), 4.42 (m, 1H), 3.95 (m, 1H), 3.58 (m, 2H), 2.33 (m, 3H), 2.17 (m, 1H), 1.87 (m, 1H) ), 1.64 (m, 5H), 1.39 (m, 1H). LC-MS: 414 [M+H]+. Example 42 (R) -l-(4-((S)-l-(5•Fluorine Pyrimidin-2-yl)ethylaminomethyl_1H•pyrazole-3-ylamine Base)-1,3,5_three-hook_2_yl)hexahydro-u-bite_3_alcohol using a procedure similar to that described in Example 11 synthesis, such that (s)_6_chloro_N2 _(丨_( 5-_Fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl)-l,3,5-trinol-2,4-diamine (intermediate 17 Reaction with (R)-hexahydropyridin-3-ol to provide the title compound. NMR 5 ppm 8.68 (s, 2H), 6.35 (m, 1H), 5.23 (m, 1H), 4.26 (m, 2H), 3.54 (m, 1H), 2.96 (m, 2H), 2.23 (m, 3H), 1.95 (m, 1H), 1.54 (m, 3H), 1.43 (m, 3H). LC-MS : 415 [M+ H]+. Example 43 (S) -l-(4-((S)-l-(5-fluoroguanidin-2-yl)ethylamino)-6-(5-methyl-lH-p Use of a procedure similar to that described in Example 11 for the synthesis of (S)-6-gas-pyrazine-pyran-3-ylamino)-1,3,5-triazin-2-yl)hexafluoropyridin-3-ol N2 -(1-(5-Fluoro) 17-yl-2-yl)ethyl)-N4-(5-methyl-lH-p ratio. Sodium-3-yl)-1,3,5-tri-p--2,4-133151-189- 200906818 Diamine (Intermediate 17) is reacted with (S)-hexahydropyridine-3-ol to provide the title compound . H NMR δ ppm 8.68 (s, 2H), 6.34 (m, 1H), 5.23 (m, 1H), 4.38 (m, 1H), 4.22 (m, 2H), 3.53 (m, 1H), 2.93 (m, 2H), 2.23 (m, 3H), 1.98 (m, 1H), 1.72 (m, 1H), 1.55 (m, 3H), 1.45 (m, 1H). LC-MS : 415 [M+H]+. Example 44 N2-((S)-l-(5-Fluoropyrimidin-2-yl)ethylmethoxymethyl)hexahydropyridin-1-yl)-N4-(5-methyl-1H-P More than -3--3-yl)-1,3,5-three? Well-2,4-diamine was prepared using a procedure similar to that described for the synthesis of Example 11 to give (S)-6- gas-N2-(1-(5-fluoropyrimidin-2-yl)ethyl)-&gt; ^4-(5-Methyl-111-pyrazol-3-yl)-1,3,5-trinyl-2,4-diamine (intermediate 17) and 3-(methoxymethyl)hexa Hydropyridine reaction provides the title compound as a mixture of diastereomers. ]H NMR δ ppm 8.68 (m, 2H), 6.39 (m, 1H), 5.22 (m, 1H), 4.62 (m, 1H), 4.42 (m, 1H), 3.23 (m, 5H), 2.87 (m , 1H), 2.69 (m, 1H), 2.22 (m, 3H), 1.76 (m, 3H), 1.54 (m, 3H), 1.29 (m, 2H). LC-MS : 443 [M+H]+ . Conditions for use of two diastereomers (A) and OD-3-15 Separation Column particle size (〆): 5 Column size (mm): 21 X 250 Purity after purification Purification: Sample purity Use conditions (B) and AD-4-25 to confirm the column size: 4.6 X 100 mm, 10 μm detection: 254 nm first absorption peak (residence time: minute) 2.21 133151 -190· 200906818 second absorption Peak (retention time: minute) 3 〇7 First dissolved compound, Example 44(a) 5-22 (m, 1H), 4.48 (m, 1H), ]H NMR (δ) 8.69 (m, 2H) , 6.36 (m, 1H), (m, 1H), 2.22 (m, 3H), 1.75 4.27 (m, 1H), 3_25 (m, 5H), 2.89 (m, 1H), 2 65 (m, 3H) , 1.55 (m, 3H), 1.27 (m, 2H). LC-MS: 443 [M+H]+ · The second dissolved compound, Example 44(b). lH NMR (5) 8 68 (4) 2H) , 636 (four) Qiu, 5.23 (m, 1H), 4.45 (m 2H) 3.23 (m, 5H), 2.89 (m, 1H), 2.72 (m 1H), 2 22 (m, 3h), i % (four) Qiu]% (m, 3H), 1.28 (m, 2H). ' LC-MS : 443 [M+H]+. Example 45 6-(4) 2 Amino)methyl)norfolinyl)_N2 small (I-fluoropyrimidine:yl)ethyl)oxime #-methyl-1H-ton sal _3_yl) cultivating _2, cardiac diamine

使用類似關於實合朗述之程序，使⑻錢_n2_(i_(5_ 氟基嘧啶-2-基）乙基）_ν4·(5_甲基吡唑冰基H，3,5^ _ _2,4_ 一胺（中間物17)與N-乙基-Ν·(嗎福啉_2_基甲基）乙胺反應，提 供標題化合物，為非對映異構物之混合物。 !H NMR δ ppm 8.69 (m, 2H), 6.35 (m, 1H), 5.24 (m, 1H), 4.49 (m, 2H), 3.90 (m, 1H), 3.54 (m, 2H), 2.89 (m, 1H), 2.67 (m, 7H), 2.23 (m, 3H), 1.55 (m, 3H), 1.07 (m, 6H). LC-MS : 486 [M+H]' 兩種非對映異構物係使用條件（A)與AS_3_3〇分離 管柱粒子大小（：5Using a procedure similar to the actual description, make (8) money _n2_(i_(5_fluoropyrimidin-2-yl)ethyl)_ν4·(5-methylpyrazole ice-based H,3,5^ _2, Reaction of 4 -monoamine (Intermediate 17) with N-ethyl-indole (morpholin-2-ylmethyl)ethylamine afforded the title compound as a mixture of diastereomers. !H NMR δ ppm 8.69 (m, 2H), 6.35 (m, 1H), 5.24 (m, 1H), 4.49 (m, 2H), 3.90 (m, 1H), 3.54 (m, 2H), 2.89 (m, 1H), 2.67 (m, 7H), 2.23 (m, 3H), 1.55 (m, 3H), 1.07 (m, 6H). LC-MS: 486 [M+H]' Conditions for the use of two diastereomers ( A) Separation column particle size with AS_3_3〇 (: 5

• 19U 133151 200906818 管柱尺寸（毫米）：21 χ 250 純化後純度檢驗： 試樣純度係使用條件（B)與AS_3_3〇確認 管柱尺寸：4_6x 100毫米，1〇微米 偵測：220毫微米 第一個吸收峰（滯留時間：分鐘）〇·64 第二個吸收峰（滯留時間：分鐘）i u 第一個溶離之化合物，實例45(a). NMR (5 ppm 8.68 (m, 2H), 6.35 (m, 1H), 5.23 (m, 1H), 4.49 (m, 2H), 3.87 (m, 1H), 3.50 (m, 2H), 2.90 (m, iH)s 2.61 (m, 7H), 2.23 (m, 3H), 1.55 (m, 3H), 1.06 (m, 6H). LC-MS ： 486 [M+H]+. 第二個溶離之化合物，實例45(b) NMR (δ ) 8.69 (m, 2H), 6.34 (m, 1H), 5.25 (m, 1H), 4.44 (m, 2H), 3.89 (m, 1H), 3.49 (m, 2H), 2.92 (m, 1H), 2.62 (m, 7H), 2.23 (m, 3H), 1.55 (m, 3H), 1.05 (m, 6H). LC-MS ： 486 [M+H]+. 實例46 (R)_4_(4-((S)-1-(5-氣基，咬_2_基）乙胺基）6 (5甲基_m_吡唑_3_基 胺基）-l，3,5-三畊-2_基）_N，N_:甲基嗎福啉各羧醯胺 使用類似關於實例62合成所述之程序，使（8)_6_氯_ν2_(1_(5· 氟基㈣-2-基）乙基）·Ν4分甲基_1Η_ρ比哇_3_基三啼-2,4· 一胺（中間物17)與（R)-N，N-二甲基嗎福啉_3_羧醯胺（中間物 35)反應’提供標題化合物。 133151 -192- 200906818 1 H NMR δ ppm 8.69 (m, 2H), 6.29 (m, 1H), 5.34 (m, 1H), 4.25 (m, 1H), 4.15 (m, 2H), 3.93 (m, 1H), 3.78-3.53 (m, 3H), 3.11 (m, 3H), 2.91 (m, 3H), 2.23 (m, 3H), 1.54 (m, 3H). LC-MS ： 472 [M+H]+. 實例47 2-((R)-4-(4-((S)-l-(5-氟基嘴咬-2-基）乙胺基）-6-(5-甲基-1Η·ϊ»比嗤-3-基胺基）-1,3,5-三畊-2-基）嗎福啉-3-基）-N，N-二甲基乙醯胺 使用類似關於實例62合成所述之程序，使（S)-6-氣-N2 -(1-(5-氟基嘧啶-2-基）乙基）-N4-(5-甲基-1H-吡唑-3-基）-1，3,5-三畊-2,4-二胺（中間物17)與（R)-N,N-二甲基-2-(嗎福啉-3-基）乙醯胺（中 間物36)反應，提供標題化合物。 1 H NMR δ ppm 8.68 (m, 2H), 6.32 (m, 1H), 5.22 (m, 1H), 4.92 (m, 1H), 4.34 (m, 1H), 3.87 (m, 3H), 3.60 (m, 1H), 3.46 (m, 1H), 3.08 (m, 4H), 2.87 (m, 3H), 2.52 (m, 1H), 2.22 (m, 3H), 1.54 (m, 3H). LC-MS : 486 [M+H]+. 實例48 (R)-4-(4-((S)-l-(5-氟基嘧啶_2-基）乙胺基）_6·(5·曱基-1H-吡唑-3-基 胺基）-1,3,5-三畊-2-基）-N-甲基嗎福淋-3-叛醢胺 使用類似關於實例62合成所述之程序，使（S)-6-氣-N2-(1-(5-氟基嘧啶-2-基）乙基）-：^4-(5-甲基-1沁吡唑-3-基）-1,3,5-三畊-2,4-二胺（中間物17)與（R)-N-甲基嗎福啉-3-羧醯胺（中間物37)反 應，提供標題化合物。 !H NMR δ ppm 8.64 (m, 2H), 6.34 (m, 1H), 5.29 (m, 1H), 5.03 (m, 1H), 4.43 (m, 2H), 3.80 (m, 1H), 3.53 (m, 2H), 2.73 (m, 2H), 2.57 (m, 2H), 2.24 133151 -193- 200906818 (m, 3H), 1.53 (m, 3H). LC-MS ： 458 [M+H]+. 實例49 ⑻_6_(3,3_二氟六氫吡啶-1-基）-N2-(1-(3,5-二氟吡啶-2-基)-2-甲氧 基乙基）-N4-(5-甲基-ΙΗβ比唾-3-基）-l，3,5-三命-2,4-二胺 使用類似關於實例11合成所述之程序，使（R)_6_氯 -N2-(l-(3,5-二氟吡啶-2-基）-2-曱氧基乙基）_n4_(5_甲基_1H-吡唑 -3-基）-1，3,5-三畊-2,4-二胺（中間物42)與3,3-二氟六氫吡啶鹽酸 鹽反應，提供標題化合物。 1 H NMR δ ppm 8.34 (m5 1H), 7.54 (m, 1H), 6.01 (m, 1H), 5.62 (m, 1H), 4.01 (m, 2H), 3.79 (m, 4H), 3.35 (m, 3H), 2.23 (s, 3H), 2.04 (m, 2H), 1.71 (m, 2H). LC-MS : 482 [M+H]+. 實例50 (r)-n2-(i-(3,5-二氟吡啶_2_基)_2·甲氧基乙基)_6_(2,2_二曱基嗎福 B林基）-N4-(5-曱基比峻-3·基）-l，3,5-三呀-2,4·二胺 使用類似關於實例11合成所述之程序，使（R)_6_氣 -N2-(1-(3,5-二氟吡啶-2-基）-2-甲氧基乙基）_n4-(5-甲基-1H-吡唑 -3-基）-1，3,5-三畊-2,4-二胺（中間物42)與2,2-二甲基嗎福啉鹽酸 鹽反應，提供標題化合物。 TH NMR δ ppm 8.35 (s, 1H), 7.59 (m, 1H), 6.36 (br s, 1H), 5.63 (m, 1H), 3.71 (m, 8H), 3.34 (m, 3H), 2.26 (br s, 3H), 1.19 (m, 6H). LC-MS ： 476 [M+H]+. 實例51 133151 -194- 200906818 N2-((R)-l-(3,5-二氣p比咬-2-基）-2-甲氧基乙基）-6-(3-氣基六氮p比 啶-1-基）-N4-(5-甲基-1H-吡唑-3-基）-1,3,5-三啩-2,4-二胺 使用類似關於實例11合成所述之程序，使（R)-6-氯-N2-(l-(3,5-二氟吡啶-2-基）-2-曱氧基乙基）-N4 -(5-甲基-1H-吡唑-3-基）-1,3,5-三畊-2,4-二胺（中間物42)與3-氟基六氳吡啶鹽酸鹽反 應，提供標題化合物，為非對映異構物之混合物。 兩種非對映異構物係使用條件（A)與AS-3-20分離 管柱粒子大小（//) : 5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗： 試樣純度係使用條件（B)與AS-3-15確認 管柱尺寸：4.6 X 100毫米，10微米 偵測：254毫微米 第一個吸收峰（滯留時間：分鐘）1.75 第二個吸收峰（滯留時間：分鐘）2.50 第一個溶離之化合物，實例51(a). NMR (δ ) 8.35 (m, 1H), 7.54 (m, 1H), 6.37 (m, 1H), 5.65 (m, 1H), 3.81 (m, 6H), 3.61 (m, 1H), 3.31 (m, 3H), 2.25 (m, 3H), 1.87 (m, 3H), 1.53 (m, 1H). LC-MS ： 464 [M+H]+ . 第二個溶離之化合物，實例51(b). ]H NMR (δ ) 8.34 (m, 1H), 7.53 (m, 1H), 6.36 (m, 1H), 5.63 (m, 1H), 4.50 (m, 1H), 3.78 (m, 5H), 3.58 (m, 1H), 3.35 (m, 3H), 2.26 (m, 3H), 1.88 (m, 3H), 1.48 (m, 1H). 133151 -195 - 200906818 LC-MS ： 464 [M+H]+. 實例52 (R)-l-(4-((R)-l-(3,5_二氟吡啶_2-基）_2-曱氧基乙胺基）-6-(5-甲基 -1H-P比岐-3-基胺基）-1，3,5·三》井-2-基）六氫咐唆_3_醇 使用類似關於實例11合成所述之程序，使（R)_6_氣 -N2-(l-(3,5-二氟吡啶-2-基）-2-甲氧基乙基）_n4_(5_甲基-1H-吡唑 -3-基）-1，3,5-三畊-2,4-二胺（中間物42)與（R)·六氫吡啶-3-醇鹽酸 鹽反應，提供標題化合物。 !H NMR (5 ) 8.35 (s, 1H), 7.54 (m, 1H), 6.09 (br s, 1H), 5.67 (m, 1H), 4.39 (m, 1H), 4.23 (m, 1H), 3.77 (m, 2H), 3.34 (s, 3H), 3.07 (m, 3H), 2.23 (s, 3H), 1.99 (m, 1H), 1.76 (m, 1H), 1.46 (m, 2H). LC-MS ： 462 [M+H]+. 實例S3 N2-((R)-l-(3,5-二氟吡啶_2·基）_2_甲氧基乙基）_6_(2_乙基嗎福啉 基）_N4-(5-甲基·1ΙΚ 唾-3-基）·1，3,5-三呼-2,4-二胺 使用類似關於實例11合成所述之程序，使（尺)_6_氯—NIG· (3,5-二氟吡啶-2·基）-2-甲氧基乙基）_Ν4 _(5_曱基_m•吡唑_3基）_ 1，3’5-二畊-2,4·二胺（中間物42)與2_乙基嗎福啉反應，提供標 題化合物’為非對映異構物之混合物。 兩種非對映異構物係使用條件（Α)與〇J_3_1〇分離 管柱粒子大小（从）：5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗： 試樣純度係使用條件⑼與AD_4_1〇確認 133151 -196- 200906818 管柱尺寸：4.6 x 100毫米，10微米 偵測：254毫微米 第一個吸收峰（滯留時間：分鐘）Π·77 第二個吸收峰（滯留時間：分鐘）22.55 第一個溶離之化合物，實例53(a) NMR (δ ) 8.35 (s, 1H), 7.54 (m, 1H), 6.35 (br s, 1H), 5.65 (m, 1H), 4.51 (m, 2H), 3.89 (m, 2H), 3.76 (m, 2H), 3.52 (m, 1H), 3.33 (m, 3H), 2.93 (m, 1H), 2.61 (m, 1H), 2.25 (m, 3H), 1.53 (m, 2H), 0.98 (t, 3H). LC-MS ： 476 [M+H]+. 第二個溶離之化合物，實例53(b) 1 H NMR (&lt;5 ) 8.35 (s, 1H), 7.55 (m, 1H), 6.36 (m, 1H), 5.66 (m, 1H), 4.50 (m, 2H), 3.88 (m, 2H), 3.76 (m, 3H), 3.34 (m, 3H), 2.95 (m, 1H), 2.61 (m, 1H), 2.25 (m, 3H), 1.52 (m, 2H), 0.98 (t, 3H). LC-MS : 476 [M+H]+ 實例54 (R)-l-(4-((R)-l-(3,5-二氟吡啶-2-基）-2-甲氧基乙胺基）-6-(5_甲基 -1H-吡唑-3-基胺基）-1,3,5-三畊-2-基）六氫毗啶-3-醇 使用類似關於實例11合成所述之程序，使（R)-6-氯-N2-(l-(3,5-二氟吡啶-2-基）-2-甲氧基乙基）-N4-(5-曱基-1H-吡唑-3-基）-1,3,5-三畊-2,4-二胺（中間物42)與（R)-六氫吡啶-3-醇鹽酸鹽反 應，提供標題化合物。 !H NMR (δ ) 8.35 (s, 1H), 7.54 (m, 1H), 6.09 (br s, 1H), 5.67 (m, 1H), 4.39 (m, 1H), 4.23 (m, 1H), 3.77 (m, 2H), 3.34 (s, 3H), 3.07 (3H), 2.23 (s, 3H), 1.99 (m, 1H), 1.76 (m, 1H), 1.46 (m, 2H). 133151 -197- 200906818 LC-MS ： 462 [M+H]+. 實例55 N2-((R)_l-(3,5-二氟吡啶_2_基）_2_甲氧基乙基）_ν4_(5·甲基仙-吡 唑-3-基）_6_(2_甲基嗎福啉基）4,3+三畊_2,4•二胺 使用類似關於實例11合成所述之程序，使⑻_6_氯 -&gt;12-(1-(3,5-二氟吡啶-2-基）_2_甲氧基乙基）_^4_(5_曱基_111_吡唑 -3-基）-1，3,5-三畊-2,4-二胺（中間物42)與2_甲基嗎福啉反應，提 供標題化合物，為非對映異構物之混合物。 ( &quot; 兩種非對映異構物係使用條件（A)與OJ-3-15分離 管柱粒子大小（//)·· 5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗 試樣純度係使用條件（B)與OJ-3-10確認 管柱尺寸：4.6 X 100毫米，10微米 偵測：254毫微米 ( 流率：5毫升/分鐘 偵測·· 220毫微米 第一個吸收峰（滯留時間：分鐘）1_64 第二個吸收峰（滯留時間：分鐘）3.24 第一個溶離之化合物，實例55(a). ]HNMR (¢5 ) 8.35 (s, 1H), 7.55 (m, 1H), 6.36 (m, 1H), 5.63 (m, 1H), 4.49 (m, 2H), 3.88 (m, 2H), 3.76 (m, 2H), 3.52 (m, 1H), 3.33 (m, 3H), 2.92 (m, 1H), 2.58 (m, 1H), 2.26 (m, 3H), 1.17 (d, 3H). LC-MS : 462 [M+H]+. 133151 -198- 200906818 第二個溶離之化合物，實例55(b) 1 H NMR (δ ) 8.34 (s, 1H), 7.55 (m, 1H), 6.35 (m, 1H), 5.64 (m, 1H), 4.48 (m, 2H), 3.85 (m, 4H), 3.50 (m, 1H), 3.34 (m5 3H), 2.93 (m, 1H), 2.56 (m, 1H), 2.25 (m, 3H), 1.17 (d, 3H). LC-MS ： 462 [M+H]+. 實例56 (S)-N2-(5-環丙基-1H-吡嗤-3-基）-Ν4-(1·(5-氟基嘧啶_2-基）乙基)-6-嗎福啉基-1,3,5-三畊-2,4-二胺 使用類似關於實例11合成所述之程序，使（s)_6_氯_N2 _(5_ 環丙基-1H-吡唑-3-基）-N4-(l-(5-氟基嘧啶_2_基）乙基）三畊 -2,4-二胺（中間物38)與嗎福啉反應，提供標題化合物。 LC-MS ： 427 [Μ+Η]+ 1H(300 MHz, MeOD) δ ppm 8.60 (s, 2H), 5.13-5.15 (m, 1H), 3.48-3.61 (m, 8H), 3.25 (s, 1H), 1.75-1.82 (m, 1H), 1.46 (d, 3H), 0.83-0.88 (m, 2H), 0.62 (bs, 2H). 實例57 N2 -((S)-l-(S·氟基嘧啶 _2·基）乙基)_n4-(5-甲基-1H-吡唑-3-基)-6-(2-甲基嗎福啉基）-1,3,5-三畊-2,4-二胺 使用類似關於實例11合成所述之程序’使⑻_6_氣_N2 _(丨_(5_ 說基鳴咬-2-基）乙基）_n4_(5_甲基_识_吡唑_3_基三畊_2,4_ 一胺（中間物17)與2-甲基嗎福啉反應，提供標題化合物，為 非對映異構物之混合物。 H NMR ((5 ) 8.71 (s, 2H), 6.37 (m, 1H), 5.24 (m, 1H), 4.38 (m, 2H), 3.86 (m, 1H), 3.49 (m, 2H), 2.92 (m, 1H), 2.57 (m, 1H), 2.27 (m, 3H), 1.56 (m, 133151 -199- 200906818 3H)，1.17 (m，3H). LC-MS ： 415 [M+H]+. 兩種非對映異構物係使用條件與〇J_3_4〇分離 管柱粒子大小（//) : 5 管柱尺寸（毫米）：21 X 250 第一個溶離峰，實例57⑻ 1 H NMR (5 ) 8.69 (s, 2H), 6.19 (m, 1H), 5.21 (m, ih)5 4.38 (m, 2H), 3.85 (m, 1H), 3.47 (m, 2H), 2.89 (m, 1H), 2.51 (m, 1H), 2.22 (s, 3H), 1.54 (m, 3H), 1.17 (m, 3H). LC-MS ： 415 [M+H]+. 第二個溶離峰，實例57(b) 1 H NMR ((5 ) 8.69 (s, 2H), 6.03 (m, 1H), 5.21 (m, 1H), 4.36 (m, 2H), 3.84 (m, 1H), 3.48 (m, 2H), 2.89 (m5 1H), 2.56 (m, 1H), 2.23 (s, 3H), 1.55 (m, 3H), 1.15 (d, 3H). LC-MS ： 415 [M+H]+. 實例58 (4-(4-((S)-l-(5·氟基嘧啶_2-基）乙胺基）_6_(5·甲基_m_吡唑_3_基胺 基）_1，3,5-三畊_2-基）嗎福啉_2_基）甲醇 使用類似關於實例U合成所述之程序，使（幻_6_氯_N2 _(丨_(5_ 氟基鳴唆-2-基）乙基）_Ν4_(5·甲基_出_吡唑净基Η，3,5·三畊_2,4_ 二胺（中間物17)與嗎福啉-2-基曱醇反應，提供標題化合物， 為非對映異構物之混合物。 1 H NMR ( 5 ) 8.71 (S, 2H), 6.26 (bs, 1H), 5.25 (m, 1H), 4.46 (m, 2H), 3.93 (m, 1H), 3.57 (m, 4H), 2.72-2.92 (m, 2H), 2.25 (m, 3H), 1.57 (m, 3H). 133151 •200· 200906818 LC-MS ： 431, 432 [M+H]+. 兩種非對映異構物係使用條件（A)與〇j_3_3〇分離 管柱粒子大小: 5 管柱尺寸（毫米）：21 X 250 第一個溶離峰：實例58(a) NMR (5 ) 8.68 (s, 2H), 6.26 (bs, 1H), 5.23 (m, 1H), 4.48 (m, 2H), 3.90 (m5 1H), 3.55 (m, 4H), 2.81 (m, 2H), 2.51 (m, 1H), 2.23 (s, 3H), 1.54 (m, 3H). LC-MS ： 431 [M+H]+. 第二個溶離峰：實例58(b) 1 H NMR ( 5 ) 8.68 (s, 2H), 6.06 (bs5 1H), 5.23 (m, 1H), 4.44 (m, 2H), 3.89 (m, 1H), 3.56 (m, 4H), 2.84 (m, 2H), 2.51 (m, 1H), 2.23 (s, 3H), 1.54 (m, 3H). LC-MS : 431 [M+H]' 實例59 6-(2-乙基嗎福啉基）_N2 _(⑻小(5_氟基嘧啶_2基）乙基）N4 _(s_甲 基-1H-吡唑-3-基）-1,3,5-三畊-2,4-二胺 使用類似關於實例11合成所述之程序，使⑻_6_氯_N2 _(丨 氟基嘧啶-2-基）乙基）_N4_(5_甲基_1H-吡唑_3_基h,3,5j呼_2,4_ 一胺（中間物17)與2-乙基嗎福啉反應，提供標題化合物，為 非對映異構物之混合物。 4 NMR (5 ) 8.68 (m，2H)，6.33 (m，1H)，5.21 (m，1H)，4.42 (m，2H)， 3.86 (m, 1H), 3.48 (m, 1H), 2.91 (m, 2H), 2.58 (m, 1H), 2.27 (m, 3H), 1.53 (m, 5H), 0.97 (m, 3H). 133151 -201 - 200906818 LC-MS : 429 [M+H]+ · 兩種非對映異構物係使用對掌性HPLC分離• 19U 133151 200906818 Column size (mm): 21 χ 250 Purity after purification: Sample purity is determined using conditions (B) and AS_3_3〇 Column size: 4_6x 100 mm, 1 〇 micron detection: 220 nm One absorption peak (residence time: minute) 〇·64 second absorption peak (residence time: minute) iu first dissolved compound, example 45(a). NMR (5 ppm 8.68 (m, 2H), 6.35 (m, 1H), 5.23 (m, 1H), 4.49 (m, 2H), 3.87 (m, 1H), 3.50 (m, 2H), 2.90 (m, iH)s 2.61 (m, 7H), 2.23 ( m, 3H), 1.55 (m, 3H), 1.06 (m, 6H). LC-MS: 486 [M+H]+. The second dissolved compound, Example 45(b) NMR (δ ) 8.69 (m , 2H), 6.34 (m, 1H), 5.25 (m, 1H), 4.44 (m, 2H), 3.89 (m, 1H), 3.49 (m, 2H), 2.92 (m, 1H), 2.62 (m, 7H), 2.23 (m, 3H), 1.55 (m, 3H), 1.05 (m, 6H). LC-MS: 486 [M+H]+. Example 46 (R)_4_(4-((S)- 1-(5-a gas, bit _2_yl)ethylamino)6 (5-methyl-m-pyrazole-3-ylamino)-l,3,5-three tillage-2_yl)_N , N_: methylmorpholine each carboguanamine using a procedure similar to that described for the synthesis of Example 62, such that (8)_6_chloro_ν2_(1_(5·fluoro (4)-2-yl)ethyl)·Ν4:methyl_1Η_ρ than wow_3_yltris-2,4·monoamine (intermediate 17) and (R)-N,N-dimethylorfo The porphyrin_3_carboxamide (intermediate 35) was reacted to provide the title compound. 133151 - 192 - 200906818 1 H NMR δ ppm 8.69 (m, 2H), 6.29 (m, 1H), 5.34 (m, 1H), 4.25 (m, 1H), 4.15 (m, 2H), 3.93 (m, 1H), 3.78-3.53 (m, 3H), 3.11 (m, 3H), 2.91 (m, 3H), 2.23 (m, 3H), 1.54 (m, 3H). LC-MS: 472 [M+H]+. EXAMPLE 47 2-((R)-4-(4-((S)-l-(5-Fluoro-bite bite-2- Ethylamino)-6-(5-methyl-1Η·ϊ» than indol-3-ylamino)-1,3,5-trin-2-yl)norfolin-3-yl) -N,N-dimethylacetamide using a procedure similar to that described for the synthesis of Example 62 to give (S)-6-gas-N2-(1-(5-fluoropyrimidin-2-yl)ethyl) -N4-(5-methyl-1H-pyrazol-3-yl)-1,3,5-trin-2,4-diamine (intermediate 17) and (R)-N,N-dimethyl Reaction of benzyl-2-(morpholine-3-yl)acetamide (Intermediate 36) afforded the title compound. 1 H NMR δ ppm 8.68 (m, 2H), 6.32 (m, 1H), 5.22 (m, 1H), 4.92 (m, 1H), 4.34 (m, 1H), 3.87 (m, 3H), 3.60 (m , 1H), 3.46 (m, 1H), 3.08 (m, 4H), 2.87 (m, 3H), 2.52 (m, 1H), 2.22 (m, 3H), 1.54 (m, 3H). LC-MS : 486 [M+H]+. Example 48 (R)-4-(4-((S)-l-(5-Fluoropyrimidin-2-yl)ethylamino)_6·(5·indolyl-1H -pyrazol-3-ylamino)-1,3,5-trin-2-yl)-N-methylmorphine-3-treazone using a procedure similar to that described for the synthesis of Example 62 (S)-6-gas-N2-(1-(5-fluoropyrimidin-2-yl)ethyl)-:^4-(5-methyl-1oxapyrazol-3-yl)-1, 3,5-Tricotin-2,4-diamine (Intermediate 17) is reacted with (R)-N-methylmorpholine-3-carboxamide (Intermediate 37) to provide the title compound. !H NMR δ ppm 8.64 (m, 2H), 6.34 (m, 1H), 5.29 (m, 1H), 5.03 (m, 1H), 4.43 (m, 2H), 3.80 (m, 1H), 3.53 (m , 2H), 2.73 (m, 2H), 2.57 (m, 2H), 2.24 133151 -193- 200906818 (m, 3H), 1.53 (m, 3H). LC-MS : 458 [M+H]+. 49 (8)_6_(3,3-difluorohexahydropyridin-1-yl)-N2-(1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5 -Methyl-ΙΗβ than spani-3-yl)-l,3,5-tris-2,4-diamine using a procedure similar to that described for the synthesis of Example 11 to give (R)_6_chloro-N2-( L-(3,5-Difluoropyridin-2-yl)-2-decyloxyethyl)_n4_(5-methyl-1H-pyrazol-3-yl)-1,3,5-three tillage- The 2,4-diamine (Intermediate 42) is reacted with 3,3-difluorohexahydropyridine hydrochloride to provide the title compound. 1 H NMR δ ppm 8.34 (m5 1H), 7.54 (m, 1H), 6.01 (m, 1H), 5.62 (m, 1H), 4.01 (m, 2H), 3.79 (m, 4H), 3.35 (m, 3H), 2.23 (s, 3H), 2.04 (m, 2H), 1.71 (m, 2H). LC-MS: 482 [M+H]+. Example 50 (r)-n2-(i-(3, 5-difluoropyridin-2-yl)_2.methoxyethyl)_6_(2,2-diindolyl b-based B-based)-N4-(5-fluorenyl-thin-3)-l , 3,5-tride-2,4.diamine using a procedure similar to that described for the synthesis of Example 11 to give (R)_6_gas-N2-(1-(3,5-difluoropyridin-2-yl) )-2-methoxyethyl)_n4-(5-methyl-1H-pyrazol-3-yl)-1,3,5-trinol-2,4-diamine (intermediate 42) and 2 2-Dimethylmorpholine hydrochloride is reacted to provide the title compound. TH NMR δ ppm 8.35 (s, 1H), 7.59 (m, 1H), 6.36 (br s, 1H), 5.63 (m, 1H), 3.71 (m, 8H), 3.34 (m, 3H), 2.26 (br s, 3H), 1.19 (m, 6H). LC-MS : 476 [M+H]+. Example 51 133151 -194- 200906818 N2-((R)-l-(3,5-two gas p ratio bite -2-yl)-2-methoxyethyl)-6-(3-carbylhexanitro-p-pyridin-1-yl)-N4-(5-methyl-1H-pyrazol-3-yl) -1,3,5-tris-2,4-diamine using a procedure similar to that described for the synthesis of Example 11 to give (R)-6-chloro-N2-(l-(3,5-difluoropyridine- 2-yl)-2-decyloxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)-1,3,5-trinol-2,4-diamine (intermediate) 42) Reaction with 3-fluorohexapyridine pyridine hydrochloride to provide the title compound as a mixture of diastereomers. Separation of two diastereomers using conditions (A) and AS-3-20 Separation column particle size (//): 5 Column size (mm): 21 X 250 Purity after purification Purification: Sample purity Use conditions (B) and AS-3-15 to confirm the column size: 4.6 X 100 mm, 10 μm detection: 254 nm first absorption peak (residence time: minute) 1.75 Second absorption peak (residence time: Minutes) 2.50 First Dissolved Compound, Example 51(a). NMR (δ) 8.35 (m, 1H), 7.54 (m, 1H), 6.37 (m, 1H), 5.65 (m, 1H), 3.81 ( m, 6H), 3.61 (m, 1H), 3.31 (m, 3H), 2.25 (m, 3H), 1.87 (m, 3H), 1.53 (m, 1H). LC-MS : 464 [M+H] The second dissolved compound, Example 51(b). ]H NMR (δ ) 8.34 (m, 1H), 7.53 (m, 1H), 6.36 (m, 1H), 5.63 (m, 1H), 4.50 (m, 1H), 3.78 (m, 5H), 3.58 (m, 1H), 3.35 (m, 3H), 2.26 (m, 3H), 1.88 (m, 3H), 1.48 (m, 1H). 133151 - 195 - 200906818 LC-MS: 464 [M+H]+. Example 52 (R)-l-(4-((R)-l-(3,5-difluoropyridin-2-yl)_2-oxime Ethylethylamino)-6-(5-methyl-1H-P than indole-3-ylamino)-1,3,5·three"well-2-yl)hexahydroindole_3_ol Using a procedure similar to that described for the synthesis of Example 11, (R)_6_gas-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)_n4_(5_ Methyl-1H-pyrazol-3-yl)-1,3,5-trinyl-2,4-diamine (intermediate 42) is reacted with (R)·hexahydropyridin-3-ol hydrochloride, Provide the title compound. !H NMR (5 ) 8.35 (s, 1H), 7.54 (m, 1H), 6.09 (br s, 1H), 5.67 (m, 1H), 4.39 (m, 1H), 4.23 (m, 1H), 3.77 (m, 2H), 3.34 (s, 3H), 3.07 (m, 3H), 2.23 (s, 3H), 1.99 (m, 1H), 1.76 (m, 1H), 1.46 (m, 2H). LC- MS: 462 [M+H]+. Example S3 N2-((R)-l-(3,5-difluoropyridin-2-yl)_2-methoxyethyl)_6_(2_ethyl? Phytyl)_N4-(5-methyl·1ΙΚ-sial-3-yl)·1,3,5-trih-2,4-diamine was synthesized using a procedure similar to that described in Example 11 to give (foot) _6 _Chlorine-NIG·(3,5-difluoropyridin-2-yl)-2-methoxyethyl)_Ν4 _(5_mercapto_m•pyrazole_3yl)_ 1,3'5- The second compound - 2,4. diamine (intermediate 42) is reacted with 2-ethylphenanthroline to provide the title compound as a mixture of diastereomers. Separation of two diastereoisomeric conditions (Α) and 〇J_3_1〇 separation column particle size (from): 5 column size (mm): 21 X 250 Purity after purification purity test: sample purity conditions (9) Confirm with AD_4_1〇 133151 -196- 200906818 Column size: 4.6 x 100 mm, 10 micron detection: first absorption peak of 254 nm (residence time: minute) Π·77 second absorption peak (residence time: minute ) 22.55 First Dissolved Compound, Example 53 (a) NMR (δ ) 8.35 (s, 1H), 7.54 (m, 1H), 6.35 (br s, 1H), 5.65 (m, 1H), 4.51 (m) , 2H), 3.89 (m, 2H), 3.76 (m, 2H), 3.52 (m, 1H), 3.33 (m, 3H), 2.93 (m, 1H), 2.61 (m, 1H), 2.25 (m, 3H), 1.53 (m, 2H), 0.98 (t, 3H). LC-MS: 476 [M+H]+. Second Dissolved Compound, Example 53(b) 1 H NMR (&lt;5) 8.35 (s, 1H), 7.55 (m, 1H), 6.36 (m, 1H), 5.66 (m, 1H), 4.50 (m, 2H), 3.88 (m, 2H), 3.76 (m, 3H), 3.34 ( m, 3H), 2.95 (m, 1H), 2.61 (m, 1H), 2.25 (m, 3H), 1.52 (m, 2H), 0.98 (t, 3H). LC-MS : 476 [M+H] + Example 54 (R)-l-(4-((R)-l-(3,5-Difluoropyridin-2-yl)-2-methoxyethylamine -6-(5-methyl-1H-pyrazol-3-ylamino)-1,3,5-trin-2-yl)hexahydropyridin-3-ol was synthesized analogously to Example 11 The procedure described is such that (R)-6-chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-fluorenyl- 1H-pyrazol-3-yl)-1,3,5-trinyl-2,4-diamine (intermediate 42) is reacted with (R)-hexahydropyridin-3-ol hydrochloride to provide the title compound . !H NMR (δ ) 8.35 (s, 1H), 7.54 (m, 1H), 6.09 (br s, 1H), 5.67 (m, 1H), 4.39 (m, 1H), 4.23 (m, 1H), 3.77 (m, 2H), 3.34 (s, 3H), 3.07 (3H), 2.23 (s, 3H), 1.99 (m, 1H), 1.76 (m, 1H), 1.46 (m, 2H). 133151 -197- 200906818 LC-MS: 462 [M+H]+. Example 55 N2-((R)_l-(3,5-difluoropyridin-2-yl)_2-methoxyethyl)_ν4_(5·methyl Sin-pyrazol-3-yl)_6_(2-methylnorfosyl) 4,3+three-till _2,4•diamine was prepared using a procedure similar to that described in Example 11 to give (8)_6_chloro-&gt ; 12-(1-(3,5-difluoropyridin-2-yl)_2-methoxyethyl)_^4_(5-fluorenyl-111-pyrazol-3-yl)-1,3, 5-Trito-2,4-diamine (Intermediate 42) was reacted with 2-methyl-m-propofol to afford the title compound as a mixture of diastereomers. ( &quot; Two diastereoisomers use conditions (A) and OJ-3-15 separation column particle size (/ /) · · 5 column size (mm): 21 X 250 purification test after purification Sample purity conditions (B) and OJ-3-10 confirmed column size: 4.6 X 100 mm, 10 micron detection: 254 nm (flow rate: 5 ml / min detection · · 220 nm first Absorption peak (residence time: minute) 1_64 Second absorption peak (residence time: minute) 3.24 First dissolved compound, Example 55(a). ]HNMR (¢5) 8.35 (s, 1H), 7.55 (m , 1H), 6.36 (m, 1H), 5.63 (m, 1H), 4.49 (m, 2H), 3.88 (m, 2H), 3.76 (m, 2H), 3.52 (m, 1H), 3.33 (m, 3H), 2.92 (m, 1H), 2.58 (m, 1H), 2.26 (m, 3H), 1.17 (d, 3H). LC-MS : 462 [M+H]+. 133151 -198- 200906818 A solution of the compound, Example 55(b) 1 H NMR (δ ) 8.34 (s, 1H), 7.55 (m, 1H), 6.35 (m, 1H), 5.64 (m, 1H), 4.48 (m, 2H) , 3.85 (m, 4H), 3.50 (m, 1H), 3.34 (m5 3H), 2.93 (m, 1H), 2.56 (m, 1H), 2.25 (m, 3H), 1.17 (d, 3H). LC -MS : 462 [M+H]+. Example 56 (S)-N2-(5-cyclopropyl-1H-pyridin-3-yl)-indole 4 -(1.(5-Fluoropyrimidin-2-yl)ethyl)-6-morpholinyl-1,3,5-trinol-2,4-diamine was synthesized similarly to the synthesis of Example 11. Procedure for (s)_6_chloro_N2 _(5_cyclopropyl-1H-pyrazol-3-yl)-N4-(l-(5-fluoropyrimidin-2-yl)ethyl) 2,4-Diamine (Intermediate 38) was reacted with morpholine to provide the title compound. LC-MS: 427 [Μ+Η]+ 1H (300 MHz, MeOD) δ ppm 8.60 (s, 2H), 5.13- 5.15 (m, 1H), 3.48-3.61 (m, 8H), 3.25 (s, 1H), 1.75-1.82 (m, 1H), 1.46 (d, 3H), 0.83-0.88 (m, 2H), 0.62 ( Bs, 2H). Example 57 N2 -((S)-l-(S.Fluoropyrimidin-2-yl)ethyl)-n4-(5-methyl-1H-pyrazol-3-yl)-6- (2-Methylmorpholine)-1,3,5-Tricotin-2,4-diamine was synthesized using a procedure similar to that described in Example 11 '[8)_6_气_N2 _(丨_(5_说Keither-2-yl)ethyl)_n4_(5_methyl___pyrazole_3_yltrinyl-2,4_monoamine (intermediate 17) is reacted with 2-methylmorpholine to provide The title compound is a mixture of diastereomers. H NMR ((5 ) 8.71 (s, 2H), 6.37 (m, 1H), 5.24 (m, 1H), 4.38 (m, 2H), 3.86 (m, 1H), 3.49 (m, 2H), 2.92 ( m, 1H), 2.57 (m, 1H), 2.27 (m, 3H), 1.56 (m, 133151 -199- 200906818 3H), 1.17 (m,3H). LC-MS : 415 [M+H]+. Separation of two diastereomeric systems with 〇J_3_4〇 separation column particle size (//): 5 column size (mm): 21 X 250 first dissolved peak, example 57 (8) 1 H NMR (5 ) 8.69 (s, 2H), 6.19 (m, 1H), 5.21 (m, ih)5 4.38 (m, 2H), 3.85 (m, 1H), 3.47 (m, 2H), 2.89 (m, 1H), 2.51 (m, 1H), 2.22 (s, 3H), 1.54 (m, 3H), 1.17 (m, 3H). LC-MS: 415 [M+H]+. Second Dissolved Peak, Example 57(b) 1 H NMR ((5 ) 8.69 (s, 2H), 6.03 (m, 1H), 5.21 (m, 1H), 4.36 (m, 2H), 3.84 (m, 1H), 3.48 (m, 2H), 2.89 (m5 1H), 2.56 (m, 1H), 2.23 (s, 3H), 1.55 (m, 3H), 1.15 (d, 3H). LC-MS : 415 [M+H]+. Example 58 (4- (4-((S)-l-(5.Fluoropyrimidin-2-yl)ethylamino)_6_(5·methyl_m_pyrazole_3_ylamino)_1,3,5-three Ploughing 2 -yl)norfosin-2-yl)methanol using a procedure similar to that described for the synthesis of Example U, making (幻_6_氯_N2 _( _(5_ Fluoropyrazine-2-yl)ethyl)_Ν4_(5·methyl_出_pyrazolyl hydrazine, 3,5·three tillage _2,4_diamine (intermediate 17) and bluff Reaction of the oxol-2-yl sterol to provide the title compound as a mixture of diastereomers. 1 H NMR ( 5 ) 8.71 (S, 2H), 6.26 (bs, 1H), 5.25 (m, 1H), 4.46 (m, 2H), 3.93 (m, 1H), 3.57 (m, 4H), 2.72-2.92 (m, 2H), 2.25 (m, 3H), 1.57 (m, 3H). 133151 •200· 200906818 LC -MS : 431, 432 [M+H]+. Two diastereomeric systems are used under conditions (A) and 〇j_3_3 〇 separation column particle size: 5 column size (mm): 21 X 250 first Dissolved peaks: Example 58(a) NMR (5) 8.68 (s, 2H), 6.26 (bs, 1H), 5.23 (m, 1H), 4.48 (m, 2H), 3.90 (m5 1H), 3.55 (m) , 4H), 2.81 (m, 2H), 2.51 (m, 1H), 2.23 (s, 3H), 1.54 (m, 3H). LC-MS : 431 [M+H]+. Example 58(b) 1 H NMR ( 5 ) 8.68 (s, 2H), 6.06 (bs5 1H), 5.23 (m, 1H), 4.44 (m, 2H), 3.89 (m, 1H), 3.56 (m, 4H) ), 2.84 (m, 2H), 2.51 (m, 1H), 2.23 (s, 3H), 1.54 (m, 3H). LC-MS: 431 [M+H]' Example 59 6-(2-ethyl吗福olinyl)_N2 _((8) small (5-fluoropyrimidine) Pyridin-2-yl)ethyl)N4_(s_methyl-1H-pyrazol-3-yl)-1,3,5-trinol-2,4-diamine was synthesized analogously to Example 11 Procedure, such that (8)_6_chloro_N2 _(fluorenylpyrimidin-2-yl)ethyl)_N4_(5-methyl_1H-pyrazole_3_yl h,3,5jh_2,4_monoamine ( The intermediate 17) is reacted with 2-ethylmorpholine to provide the title compound as a mixture of diastereomers. 4 NMR (5 ) 8.68 (m, 2H), 6.33 (m, 1H), 5.21 (m, 1H), 4.42 (m, 2H), 3.86 (m, 1H), 3.48 (m, 1H), 2.91 (m , 2H), 2.58 (m, 1H), 2.27 (m, 3H), 1.53 (m, 5H), 0.97 (m, 3H). 133151 -201 - 200906818 LC-MS : 429 [M+H]+ · Two Diastereomers are separated by palmitic HPLC

管柱：Chirapak AD 尺寸：250 X 20毫米，10 # 流動相：90%己烧’ 10%異丙醇，〇·ΐ%二乙胺（v/v/v) 流率（毫升/分鐘）：20 偵測（毫微米）：220 第一個溶離峰，實例59⑻ 1 H NMR ( δ ) 8.71 (s, 2H), 6.35 (bs, 1H), 5.24 (m, 1H), 4.43 (m, 2H), 3.89 (m, 1H), 3.47 (m, 1H), 2.93 (m, 2H), 2.56 (m, 1H), 2.26 (m, 3H), 1.56 (m, 5H), 0.99 (t, 3H). LC-MS : 429 [M+H]' 第二個溶離峰，實例59(b) 1 H NMR (5 ) 8.68 (s, 2H), 6.29 (bs, 1H), 5.21 (m, 1H), 4.43 (m, 2H), 3.85 (m, 1H), 3.49 (m, 1H), 2.90 (m, 2H), 2.58 (m, 1H), 2.22 (s, 3H), 1.54 (m, 5H), 0.97 (t, 3H). LC-MS ： 429 [M+H]+. 實例60 2-(1-(4-((8)-1-(5-1基鳴啶_2_基）乙胺基甲基·m吡唑_3基 胺基)-l,3,5-二味_2_基）六氫p比咬_2_基）乙腈 使用類似關於實例62合成所述之程序，使⑸各氣_N2 _(丨_(5_ 氣基响。定-2-基）乙基&gt;N4_(5_甲基_出_吡唑各基）]，3,5_三畊_2,4_ 二胺（中間物17)與2-(六氫吡啶丨基）乙腈（中間物39)反應，提 供標題化合物，為非對映異構物之混合物。 133151 •202- 200906818 H NMR ((5 ) 8·69 (s，2H)，6.03 (m，1H)，5 23 (m，1H)，4 57 (m，1H)，2 % (m，3H)’ 2_23 (s，3H)，1.92 (m，1H)，丨 81 (m, lH)，丨说㈣ 4H)，i % ㈣ 3H), 1.40 (m, 1H). LC-MS : 438 [M+H]+. 實例61 NMK3,5_二氟峨咬_2_基）乙基) n4 (5甲基胸匕㊃基)·6嗎 福ρ林基-1，3,5-三呼-2,4-二胺Column: Chirapak AD Size: 250 X 20 mm, 10 # Mobile phase: 90% burned '10% isopropanol, 〇·ΐ% diethylamine (v/v/v) Flow rate (ml/min): 20 Detection (nm): 220 First Dissolved Peak, Example 59(8) 1 H NMR ( δ ) 8.71 (s, 2H), 6.35 (bs, 1H), 5.24 (m, 1H), 4.43 (m, 2H) , 3.89 (m, 1H), 3.47 (m, 1H), 2.93 (m, 2H), 2.56 (m, 1H), 2.26 (m, 3H), 1.56 (m, 5H), 0.99 (t, 3H). LC-MS: 429 [M+H]' second eluting peak, Example 59 (b) 1 H NMR (5 ) 8.68 (s, 2H), 6.29 (bs, 1H), 5.21 (m, 1H), 4.43 (m, 2H), 3.85 (m, 1H), 3.49 (m, 1H), 2.90 (m, 2H), 2.58 (m, 1H), 2.22 (s, 3H), 1.54 (m, 5H), 0.97 ( t, 3H). LC-MS: 429 [M+H]+. Example 60 2-(1-(4-((8)-1-(5-1- yl))) ··mpyrazole-3-ylamino)-l,3,5-di-sodium-2-yl)hexahydro-p-bito-2_yl)acetonitrile using a procedure similar to that described for the synthesis of Example 62, (5) Gas_N2 _(丨_(5_气基响.定-2-yl)ethyl&gt;N4_(5_methyl_出_pyrazole each)],3,5_three tillage_2,4_ two Reaction of the amine (intermediate 17) with 2-(hexahydropyridinyl)acetonitrile (intermediate 39), For the title compound, a mixture of diastereomers. 133151 • 202- 200906818 H NMR ((5 ) 8·69 (s, 2H), 6.03 (m, 1H), 5 23 (m, 1H), 4 57 (m,1H),2 % (m,3H)' 2_23 (s,3H),1.92 (m,1H),丨81 (m, lH),丨 (4) 4H),i % (4) 3H), 1.40 (m, 1H). LC-MS: 438 [M+H]+. Example 61 NMK3,5_difluorobite_2_yl)ethyl) n4 (5-methyl-thioniumtetrayl)·6 Ρ-lin-1,3,5-trih-2,4-diamine

使6氯Ν _(1-(3,5·—氟吨„定_2_基）乙齡Ν4_(5_甲基]如比嗤各 基）-1，3,5·三_ -2,4-二胺（中間物4〇，i规克，2 98毫莫耳）溶於 乙醇（3.91毫升）中，並添加嗎福啉（9 〇8毫升，ι〇4 21毫莫耳）。 將反應混合物在25t下㈣i小時。接著，使反應混合物於 真二中/辰縮甾下丙色半固體（3.143克）。使此物質藉ISC〇 純化（0-15% MeOH/DCM)。收集標題化合物，對掌異構物之混 合物，為黃色固體（1.240克），99%產率。 ]H NMR (300 MHz, MeOD) δ ppm 8.33 (s, 1H) 7.41-7.66 (m, 1H) 6.34 (寬廣 s” 1H) 5.29-5.74 (m，1H) 3.49-3.87 (m, 8H) 2·23 (d，3H) 1.51 (寬 廣 s.，3H). LC-MS ： 418 [M+H]+ 管柱與溶劑條件 標題化合物係使用條件（A)與AD-3-20進行對掌性純化 管柱粒子大小（〆）：5 管柱尺寸（毫米）：21 X 250 偵測：220毫微米 純化後純度檢驗： 133151 •203 · 200906818 試樣純度係使用條件（B)與OJ-3-20確認 管柱尺寸：4.6 X 100毫米 偵測：220毫微米 第一個吸收峰（滯留時間：分鐘）〇·58 第二個吸收峰（滯留時間：分鐘）U7 第一個溶離峰，實例61⑻ lU NMR (300 MHz, MeOD) δ ppm 8.33 (s, 1H) 7.41-7.66 (m, 1H) 6.34 (寬廣 s·，1H) 5.29-5.74 (m，1H) 3.49-3.87 (m，8H) 2.23 (d，3H) 1.51 (寬 ( 廣 s_，3H) LC-MS ： 418 [M+H]+ 第二個溶離峰，實例61(b) ^ NMR (300 MHz, MeOD) δ ppm 8.33 (d, 1H) 7.40-7.65 (m, 1H) 6.34 (寬廣 s·，0_5H) 5.59 (寬廣 s.，〇.5H) 5.38-5.49 (m，1H) 3.48-3.84 (m，8H) 2.09-2.38 (m, 3H) 1.50 (d, 3H) LC-MS ： 418 [M+H]+ ( 實例62 1 ((R)-4-(4_(l-(3,5-二氟吡啶 基）乙胺基）·6_(5·甲基 _1H峨唑 _3_基 胺基)-1,3,5-三畊·2-基）嗎福啉_3_基）曱醇 使6-氣-N2-(l-(3,5-二氟吡啶_2_基）乙基）_n4_(5_甲基_出_吡唑_3_ 基）-1，3,5-二畊-2,4-二胺（中間物4〇，2〇〇毫克，〇 55毫莫耳）與 ⑻-嗎福啉-3-基甲醇鹽酸鹽（92毫克，〇 6〇毫莫耳）溶於Bu〇H (2毫升）中，並添加DIPEA (〇·286毫升，164毫莫耳）。然後， 將反應物在100°C下加熱過夜。接著，使反應混合物於真空 中痕縮，留下黃色油。然後，將此物質在Et〇Ac與水之間分 133151 •204· 200906818 離’且於真空中濃縮有機物質，@下淡黃色固體(240毫 克）。使此物質藉！SC0純化（2_15% Me〇H/DCM)。在真空中濃 ，’宿/合離伤，提供標題化合物，非對映異構物之混合物，為 灰白色固體（209毫克）。 H NMR (300 MHz, MeOD)占 ppm 8.32 (s, 1H) 7.54 (t，1H) 6.36 (寬廣 s·，1H) 5·32-5_76 (m，1H) 4.55 (寬廣 s.，1H) 4·35 (d，1H) 4.08 (d，m) 3 88 (d，2H) 3.37-3.72 (m，3H) 2.98-3.22 (m，1H) 2·25 (寬廣 s.，3H) 1_50 (d， 3H). LC-MS ： 448 [M+H]+ 管柱與溶劑條件 兩種非對映異構物係使用條件（A)與AD 3 3〇純化 管柱粒子大小（: 5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗： δ式樣純度係使用條件（B)與ad_3_3〇確認 管柱尺寸：4.6 X 1〇〇毫米 偵測：254毫微米 第一個吸收峰（滯留時間：分鐘）123 第二個吸收峰（滯留時間：分鐘）丨S9 第一個溶離峰，實例62(a) 1H NMR (300 MHz, MeOD) δ ppm 8.32 (s，1H) 7.54 (t，1H) 6.36 (寬廣 s·，1H) 5.32-5.76 (m，1H) 4.55 (寬廣 s.，1H) 4.35 (d，1H) 4·08 (d，1H) 3.88 (d，2H) 3.37-3.72 (m，3H) 2.98-3.22 (m，1H) 2.25 (寬廣 s., 3H) 1.50 (d， 3H). 133151 -205 - 200906818 LC-MS : 448 [M+H]+ 第二個溶離峰，實例62(b) 1 H NMR (300 MHz，MeOD) ppm 8_32 (s，1H) 7_54 (t, 1H) 6.36 (寬廣 s.，1H) 5.32-5.76 (m，1H) 4.55 (寬廣 s., 1H) 4.35 (d，1H) 4.08 (d，1H) 3.88 (d，2H) 3.37-3.72 (m, 3H) 2.98-3.22 (m，1H) 2.25 (寬廣 s·，3H) 1.50 (d， 3H). LC-MS ： 448 [M+H]+ 實例63 f X N2 -(Η3,5·二氟吡啶-2-基）乙基）-6-(3-氟基一氮四圓-1·基）_N4 -(5_ 曱基-1H-吡唑-3-基）-1,3,5-三畊-2,4-二胺 使用類似關於實例11合成所述之程序，使6_氣-n2_(1_(3,5_ 二氟'1比。定-2-基）乙基）-：^4-(5-甲基-111-峨嗤-3-基）-1,3,5-三畊-2,4-二胺（中間物40，136毫克，0_37毫莫耳）與3-氟基一氮四圜鹽 酸鹽（中間物29，45.5毫克，0.41毫莫耳）反應，提供標題化 合物’為對掌異構物之混合物。 ( 1 H NMR (300 MHz, MeOD) 6 ppm 8.33 (寬廣 s·，1H) 7.41-7.69 (m, 1H) 6.22 (寬廣 s.，1H) 5_47 (m，1H) 5.28 (m，1H) 3.84-4.53 (m，4H) 2·23 (寬 廣 s.，3H) 1.50 (d, 3H) LC-MS ： 406 [M+H]+. 管柱與溶劑條件 兩種對掌異構物係使用對掌性HPLC純化6 Ν Ν ( 使 1- 1- 1- ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 4-Diamine (intermediate 4 〇, i gram, 2 98 mmol) was dissolved in ethanol (3.91 mL) and added with morpholine (9 〇 8 mL, ι〇 4 21 mmol). The reaction mixture was quenched at 25 s for four hours. Then, the reaction mixture was taken to a hexanes semi-solid (3.143 g). The material was purified by I.sub. Compound, a mixture of palmomers, as a yellow solid (1.240g), 99% yield.]H NMR (300 MHz, MeOD) δ ppm 8.33 (s, 1H) 7.41-7.66 (m, 1H) 6.34 ( Broad s" 1H) 5.29-5.74 (m, 1H) 3.49-3.87 (m, 8H) 2·23 (d, 3H) 1.51 (broad s., 3H). LC-MS : 418 [M+H]+ tube Column and Solvent Conditions The title compound was used under conditions (A) and AD-3-20 for palm purification. Column particle size (〆): 5 Column size (mm): 21 X 250 Detection: 220 nm after purification Purity test: 133151 •203 · 200906818 Sample purity is determined by using conditions (B) and OJ-3-20. Column size: 4 .6 X 100 mm detection: 220 nm first absorption peak (residence time: minute) 〇·58 second absorption peak (residence time: minute) U7 first dissolution peak, example 61(8) lU NMR (300 MHz , MeOD) δ ppm 8.33 (s, 1H) 7.41-7.66 (m, 1H) 6.34 (broad s·, 1H) 5.29-5.74 (m,1H) 3.49-3.87 (m,8H) 2.23 (d,3H) 1.51 (Wide (wide s_, 3H) LC-MS: 418 [M+H]+ second elution peak, example 61(b) ^ NMR (300 MHz, MeOD) δ ppm 8.33 (d, 1H) 7.40-7.65 ( m, 1H) 6.34 (broad s·, 0_5H) 5.59 (broad s., 〇.5H) 5.38-5.49 (m,1H) 3.48-3.84 (m,8H) 2.09-2.38 (m, 3H) 1.50 (d, 3H) LC-MS: 418 [M+H] + ( </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> ((R)-4-(4-(l-(3,5-difluoropyridinyl)ethylamino)). _1H carbazole _3_ylamino)-1,3,5-three cultivating 2-yl)porphyrin _3_yl) decyl alcohol makes 6-gas-N2-(l-(3,5- Difluoropyridin-2-yl)ethyl)_n4_(5-methyl-exo-pyrazole-3-yl)-1,3,5-diplough-2,4-diamine (intermediate 4〇, 2〇) 〇mg, 〇55 mM) and (8)-morpholin-3-ylmethanol hydrochloride (92 mg, 〇6 〇 mmol) dissolved in Bu〇H (2 mL) And added DIPEA (286 ml · square, 164 mmol). The reaction was then heated at 100 °C overnight. Next, the reaction mixture was allowed to condense in vacuo to leave a yellow oil. Then, this material was partitioned between Et 〇Ac and water by 133151 • 204· 200906818 and the organic material was concentrated in vacuo to give a pale yellow solid (240 m). Let this material borrow! SC0 purification (2_15% Me〇H/DCM). Concentration in vacuo, &lt;RTI ID=0.0&gt;&gt;&gt;&gt; H NMR (300 MHz, MeOD) in ppm 8.32 (s, 1H) 7.54 (t, 1H) 6.36 (broad s·, 1H) 5·32-5_76 (m, 1H) 4.55 (broad s., 1H) 4· 35 (d,1H) 4.08 (d,m) 3 88 (d,2H) 3.37-3.72 (m,3H) 2.98-3.22 (m,1H) 2·25 (broad s.,3H) 1_50 (d, 3H LC-MS : 448 [M+H]+ Column and solvent conditions Diastereomers Conditions of use (A) and AD 3 3〇 Purified column particle size (: 5 column size (mm) ): 21 X 250 Purity test after purification: δ pattern purity system conditions (B) and ad_3_3〇 Confirmation column size: 4.6 X 1〇〇mm Detection: 254 nm first absorption peak (residence time: minute) 123 second absorption peak (residence time: minute) 丨S9 first dissolution peak, example 62(a) 1H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1H) 7.54 (t, 1H) 6.36 (wide) s·,1H) 5.32-5.76 (m,1H) 4.55 (broad s.,1H) 4.35 (d,1H) 4·08 (d,1H) 3.88 (d,2H) 3.37-3.72 (m,3H) 2.98 -3.22 (m,1H) 2.25 (broad s., 3H) 1.50 (d, 3H). 133151 -205 - 200906818 LC-MS : 448 [M+H]+ second elution peak, example 62(b) 1 H NMR ( 300 MHz, MeOD) ppm 8_32 (s, 1H) 7_54 (t, 1H) 6.36 (broad s., 1H) 5.32-5.76 (m, 1H) 4.55 (broad s., 1H) 4.35 (d, 1H) 4.08 ( d,1H) 3.88 (d,2H) 3.37-3.72 (m, 3H) 2.98-3.22 (m,1H) 2.25 (broad s·,3H) 1.50 (d, 3H). LC-MS : 448 [M+H ]+ Example 63 f X N2 -(Η3,5·difluoropyridin-2-yl)ethyl)-6-(3-fluoro-nitrogen tetra-l-yl)-N4-(5- decyl-1H- Pyrazol-3-yl)-1,3,5-trinol-2,4-diamine was prepared using a procedure similar to that described for the synthesis of Example 11 to give 6-gas-n2_(1_(3,5-difluoro'1 ratio. Ding-2-yl)ethyl)-:^4-(5-methyl-111-indol-3-yl)-1,3,5-trin-2,4-diamine (intermediate 40, 136 mg (0-37 mmol) was reacted with 3-fluoro-nitrozinium tetrahydrochloride (intermediate 29, 45.5 mg, 0.41 mmol) to afford the title compound as a mixture. ( 1 H NMR (300 MHz, MeOD) 6 ppm 8.33 (broad s·, 1H) 7.41-7.69 (m, 1H) 6.22 (broad s., 1H) 5_47 (m,1H) 5.28 (m,1H) 3.84- 4.53 (m, 4H) 2·23 (broad s., 3H) 1.50 (d, 3H) LC-MS: 406 [M+H]+. Two different pairs of palm isomers used in the column and solvent conditions HPLC purification

管柱：Chirapak IA 尺寸：250 X 20毫米，5 // 流動相：90%己烷，l〇〇/0 ι:1乙醇：曱醇，〇1%二乙胺（v/v/v) 133151 -206- 200906818 流率（毫升/分鐘）：20 偵測（毫微米）：220 純化後純度檢驗： 試樣純度係使用Chiralpak IA確認 管柱尺寸：4.6 X 250毫米 流動相：90:10:0.1己烷：乙醇/曱醇（1:1):二乙胺 流率：1毫升/分鐘 偵測：220毫微米Column: Chirapak IA Size: 250 X 20 mm, 5 // Mobile phase: 90% hexane, l〇〇/0 ι: 1 Ethanol: decyl alcohol, 〇1% diethylamine (v/v/v) 133151 -206- 200906818 Flow rate (ml/min): 20 Detection (nm): 220 Purity test after purification: Sample purity is confirmed by Chiralpak IA Column size: 4.6 X 250 mm Mobile phase: 90:10:0.1 Hexane: Ethanol/Decanol (1:1): Diethylamine flow rate: 1 ml/min Detection: 220 nm

C 第一個吸收峰（滯留時間：分鐘）16.99 第二個吸收峰（滯留時間：分鐘）20.61 第一個溶離峰，實例63⑷ 1 H NMR (300 MHz, MeOD) 5 ppm 8.33 (寬廣 s” 1H) 7.41-7.69 (m，1H) 6_22 (寬廣 s·，1H) 5.47 (m，1H) 5.28 (m，1H) 3.84-4.53 (m, 4H) 2.23 (寬 廣 s., 3H) 1.50 (d，3H) LC-MS : 406 [M+H]+ , 第二個溶離峰，實例63(b) 1 H NMR (300 MHz, MeOD) δ ppm 8.33 (寬廣 s” 1H) 7.41-7.69 (m，1H) 6.22 (寬廣 s·, 1H) 5.47 (m，1H) 5_28 (m，1H) 3.84-4.53 (m，4H) 2.23 (寬 廣 s·，3H) 1.50 (d, 3H) LC-MS ： 406 [M+H]+ 實例64 1-(4-(1-(3,5-二氟吡啶-2-基）乙胺基）-6-(5-曱基-1H-吡唑-3-基胺 基）-1，3,5-三畊-2-基）-4·甲基六氫吡啶-4·醇 使用類似關於實例11合成所述之程序，使6-氯-N2-(l-(3,5- 133151 207· 200906818 二 m2-基）乙基）_N4_(5_ 甲基-1H_ 吡唑 _3_ 基）_u,5_三畊 _2,4_ 一胺（中間物40，200毫克，0.55毫莫耳）與4-曱基六氫吡啶_ζμ 醇鹽酸鹽（中間物31，91毫克，0.60毫莫耳）反應，提供標題 化合物’為對掌異構物之混合物。 JH NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1H) 7.41-7.67 (m, 1H) 6.34 (寬廣 s·，1H) 5.15-5.93 (m, 1H) 4.15 (m，2H) 3.35 (m，2H) 2.23 (m，4H) 1.50 (d，7H) 1.22 (寬廣 s.，3H) LC-MS ： 446 [M+H]+ (' 管柱與溶劑條件 兩種對掌異構物係使用條件（A)與OJ-3-20純化 管柱粒子大小（〆）：5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗： 試樣純度係使用條件（B)與OJ-3-20確認 流率：3毫升/分鐘 , 偵測：220毫微米C First absorption peak (residence time: minute) 16.99 Second absorption peak (residence time: minute) 20.61 First dissolved peak, Example 63(4) 1 H NMR (300 MHz, MeOD) 5 ppm 8.33 (broad s) 1H ) 7.41-7.69 (m,1H) 6_22 (broad s·,1H) 5.47 (m,1H) 5.28 (m,1H) 3.84-4.53 (m, 4H) 2.23 (broad s., 3H) 1.50 (d,3H LC-MS : 406 [M+H]+ , second elution peak, example 63(b) 1 H NMR (300 MHz, MeOD) δ ppm 8.33 (broad s) 1H) 7.41-7.69 (m,1H) 6.22 (broad s·, 1H) 5.47 (m,1H) 5_28 (m,1H) 3.84-4.53 (m,4H) 2.23 (broad s·,3H) 1.50 (d, 3H) LC-MS : 406 [M+ H]+ Example 64 1-(4-(1-(3,5-Difluoropyridin-2-yl)ethylamino)-6-(5-fluorenyl-1H-pyrazol-3-ylamino) -1,3,5-Triton-2-yl)-4.methylhexahydropyridin-4-ol using a procedure similar to that described for the synthesis of Example 11 to give 6-chloro-N2-(l-(3, 5- 133151 207· 200906818 Dim2-yl)ethyl)_N4_(5_methyl-1H_pyrazole_3_yl)_u,5_three tillage_2,4_monoamine (intermediate 40,200 mg, 0.55 mmol) Ear) with 4-mercaptohexahydropyridine_ζμ alkoxide hydrochloride (intermediate 31,91 mg) , 0.60 millimolar) reaction, providing the title compound 'as a mixture of palmomers. JH NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1H) 7.41-7.67 (m, 1H) 6.34 (broad s·, 1H) 5.15-5.93 (m, 1H) 4.15 (m, 2H) 3.35 (m, 2H) 2.23 (m,4H) 1.50 (d,7H) 1.22 (broad s.,3H) LC-MS : 446 [M+H]+ ('The conditions for the use of two different pairs of palms and solvent conditions (A) and OJ-3-20 Purified column particle size (〆): 5 Column size (mm): 21 X 250 Purity test after purification: Sample purity is confirmed by conditions (B) and OJ-3-20 Flow rate: 3 ml / min, detection: 220 nm

I 第一個吸收峰（滯留時間：分鐘）2.0 第二個吸收峰（滯留時間：分鐘）4_19 第一個溶離峰，實例64(a) !H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1H) 7.41-7.67 (m, 1H) 6.34 (寬廣 s_，1H) 5.15-5.93 (m, 1H) 4.15 (m，2H) 3.35 (m，2H) 2_23 (m，4H) 1.50 (d，7H) 1.22 (寬廣 s·，3H) LC-MS ： 446 [M+H]+ 第二個溶離峰，實例64(b) 133151 -208· 200906818 lH NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1H) 7.41-7.67 (m, 1H) 6.34 (寬廣 s·，1H) 5」5-5_93 (m，1H) 4.I5 (m, 2H) 3.35 (m，2H) 2.23 (m, 4H) 1.50 (d，7H) 1.22(寬廣 S.，3H) LC-MS ： 446 [M+H]+ 實例65 N2-(1-(3,5-二氟吡啶-2-基）乙基）-6-(4-曱氧基六氫吡啶小基）_ N4-(5-甲基-1H-吡唑-3-基）-1,3,5-三啩·2,4-二胺 使用類似關於實例11合成所述之程序，使6-氯-Ν2-(1-(3,5-一乱p比。定-2-基）乙基）-N4-(5-曱基-1H-P比吐-3-基）-1,3,5-三11 井-2,4-二胺（中間物40，200毫克’ 0.55毫莫耳）與4-甲氧基六氫吡啶 鹽酸鹽（91毫克，0·60毫莫耳）反應，提供標題化合物，為對 掌異構物之混合物。 ]H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1H) 7.42-7.69 (m, 1H) 6.35 (寬廣 s.，1H) 5.30-5.83 (m, 1H) 4.17 (m，3H) 3_47 (m，1H) 3.36 (s，3H) 2·24 (寬廣 s” 3H) 1.86 (m，2H) l_〇5_1.69 (m, 6H). LC-MS : 446 [M+H]+ 管柱與溶劑條件 兩種對掌異構物係使用條件（A)與OJ-3-20純化 管柱粒子大小（μ) : 5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗： 試樣純度係使用條件（Β)與OJ-3-20確認 流率：3毫升/分鐘 偵測：220毫微米 133151 •209- 200906818 第一個吸收峰（滯留時間：分鐘）215 第二個吸收峰（滯留時間：分鐘）4.46 第一個溶離峰’實例65(a) 1 H NMR (300 MHz, MeOD) 5 ppm 8.32 (s, 1H) 7.42-7.69 (m, 1H) 6.35 (寬廣 s” 1H) 5.30-5.83 (m，1H) 4_17 (m，3H) 3·47 (m，1H) 3.36 (s，3H) 2.24 (寬廣 s.，3H) 1·86 (m，2H) 1.05-1.69 (m，6H)_ LC-MS ： 446 [M+H]+ 第'一個溶離峰’實例65(b) 1 H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1H) 7.42-7.69 (m, 1H) 6.35 (寬廣 s” 1H) 5.30-5.83 (m，1H) 4.17 (m，3H) 3.47 (m，1H) 3.36 (s，3H) 2.24 (寬廣 s., 3H) 1.86 (m，2H) 1.05-1.69 (m，6H). LC-MS : 446 [M+H]+ 實例66 1-(4-(1-(3,5·二氟吡啶-2-基）乙胺基）-6-(5-甲基-1H-吡唑-3-基胺 基)-1，3,5-三畊_2-基）六氫毗啶-4-曱腈 使用類似關於實例11合成所述之程序，使6-氣-N2 -(1-(3,5-二氟吡啶-2-基）乙基）-N4-(5-甲基-1H-吡唑-3-基）-1，3,5-三畊-2,4-二胺（中間物40，200毫克，0.55毫莫耳）與六氫吡啶_4·甲腈 鹽酸鹽（中間物32，88毫克’ 0.60毫莫耳）反應，提供標題化 合物，為對掌異構物之混合物。 1H NMR (300 MHz, MeOD) &lt;5 ppm 8·33 (s，1H) 7.55 (ddd，1H) 6.34 (寬 廣 s.，1H) 5.25-5.78 (m，1H) 4.07 (m，2H) 3.52 (m, 2H) 3.06 (m，1H) 2·24 (m, 3H) 1.57-2.06 (m, 4H) 1.51 (d, 3H). LC-MS ： 441 [M+H]+. 133151 •210· 200906818 管柱與溶劑條件 兩種對掌異構物係使用條件（A)與OJ_3-15純化 管柱粒子大小: 5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗： 試樣純度係使用條件（B)與OJ-3-20確認 管柱尺寸：4·6 X 250毫米 流率：3毫升/分鐘 偵測：220毫微米 第一個吸收峰（滯留時間：分鐘）2_60 第二個吸收峰（滯留時間：分鐘）3.61 第一個溶離峰，實例66⑻ 1H NMR (300 MHz，MeOD) 5 ppm 8.33 (s，1Η) 7.55 (ddd，1Η) 6.34 (寬 廣 s·，1H) 5.25-5.78 (m，1H) 4.07 (m，2H) 3.52 (m，2H) 3.06 (m，1H) 2.24 (m, 3H) 1.57-2.06 (m, 4H) 1.51 (d, 3H). LC-MS ： 441 [M+H]+ 第二個溶離峰，實例66(b) 1 H NMR (300 MHz, MeOD) (5 ppm 8.33 (s，1H) 7.55 (ddd, 1H) 6·34 (寬 廣 s.，1H) 5.25-5.78 (m, 1H) 4.07 (m，2H) 3.52 (m，2H) 3_06 (m，1H) 2.24 (m, 3H) 1.57-2.06 (m, 4H) 1.51 (d, 3H). LC-MS : 441 [M+H]+ 實例67 N2-(l-(3,5-二氣p比唆-2-基）乙基）-6_(4_氣基六氫p比咬-1-基）_N4-(5-甲基-111~'1比嗤-3-基）-1，3,5-三'1井-2,4-二胺 133151 -211 · 200906818 使用類似關於實例11合成所述之程序，使6_氯_N2_(1_(3,5_ 一氟p比口疋-2·基）乙基）-N4-(5_甲基-1H-P比〇坐_3_基）]，3,5_三畊_2,4_ 二胺（中間物40’ 200毫克，〇_55毫莫耳）與4_氟基六氫吡啶鹽 酸鹽（84毫克，0.60毫莫耳）反應，提供標題化合物，為對掌 異構物之混合物。 1 H NMR (300 MHz, MeOD) &lt;5 ppm 8.32 (s, 1H) 7.38-7.69 (m, 1H) 6.35 (見廣 s” 1H) 5.31-5.75 (m, 1H) 4.73 (m, 1H) 3.60-4.05 (m, 4H) 2.07-2.42 (m, 3H) 1.58-2.05 (m, 4H) 1.52 (d, 3H). LC-MS ： 434 [M+H]+. 管柱與溶劑條件 兩種對掌異構物係使用條件（A)與〇J_3_2〇純化 管柱粒子大小（〆）：5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗： 試樣純度係使用條件（B)與OJ-3-20確認 管柱尺寸：4.6 X 250毫米 流率：3毫升/分鐘 偵測：220毫微米 第一個吸收峰（滯留時間：分鐘）2.19 第二個吸收峰（滯留時間：分鐘）3.97 第一個溶離峰，實例67⑷ ]H NMR (300 MHz, MeOD) 5 ppm 8.32 (s, 1H) 7.38-7.69 (m, 1H) 6.35 (寬廣 s” 1H) 5.31-5.75 (m，1H) 4.73 (m，1H) 3.60-4.05 (m，4H) 2.07-2.42 (m, 3H) 1.58-2.05 (m, 4H) 1.52 (d, 3H). 133151 -212- 200906818 LC-MS ： 434 [M+H]+ 第二個溶離峰，實例67(b) 1 H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1H) 7.38-7.69 (m, 1H) 6.35 (寬廣 s.，1H) 5·31-5.75 (m，1H) 4.73 (m，1H) 3.60_4.05 (m，4H) 2.07-2.42 (m, 3H) 1.58-2.05 (m, 4H) 1.52 (d, 3H). LC-MS ： 434 [M+H]+ 實例68 6-(4,4-二氟六氫吡啶-1-基）-N2-(l-(3,5-二氟吡啶-2-基）乙基）- { N4 -(5_ 甲基-1H-吡唑-3-基）-1,3,5-三畊·2,4·二胺 使用類似關於實例11合成所述之程序，使6-氣-Ν2 -(1-(3,5-二氟11比'1定-2-基）乙基）-1^4-(5-曱基-111-1»比吐-3-基）-1,3,5-三'1井-2,4-二胺（中間物40 ’ 200毫克，〇·55毫莫耳）與4,4-二氟六氫吡啶 鹽酸鹽（95毫克，0.60毫莫耳）反應，提供標題化合物，為對 掌異構物之混合物。 1 H NMR (300 MHz, MeOD) ά ppm 8.33 (s，1H) 7_55 (ddd，1H) 6_34 (寬 ( 廣 s” 1H) 5.25-5.82 (m，1H) 3.87 (寬廣 s” 4H) 2.24 (寬廣 s., 3H) 1.68-2.08 (m，4H) 1.51 (d，3H). LC-MS ： 452 [M+H]+. 管柱與溶劑條件 兩種對掌異構物係使用條件（A)與〇j_3_i5純化 管柱粒子大小（〆)：5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗： 試樣純度係使用條件（B)與OJ-3-20確認 133151 •213 - 200906818 管柱尺寸：4.6 x 250毫米 流率：3毫升/分鐘 偵測：220毫微米 第一個吸收峰（滯留時間：分鐘）199 第二個吸收峰（滯留時間：分鐘）314 第一個溶離之化合物，實例68⑻ 1H NMK ’ MHz’ MeOD) &lt;5 ppm 833 (s，1H) 7_55 (ddd，1H) 6.34 (寬 廣 s_，1H) 5.25-5.82 (m，1H) 3.87 (寬廣 s” 4H) 2.24 (寬廣 s.，3H) 1.68-2.08 (m, 4H) 1.51 (d, 3H) LC-MS ： 452 [M+H]+ 第二個溶離之化合物，實例68(b) 第二個溶離之化合物具有滯留時間為3 14分鐘，&gt;98% ee H NMR (300 MHz, MeOD) 5 ppm 8.33 (s，1H) 7.55 (ddd, 1H) 6.34 (寬 廣 s.，1H) 5.25-5.82 (m，1H) 3.87 (寬廣 s·，4H) 2.24 (寬廣3_，3幵）1.68- 2.08 (m, 4H) 1.51 (d, 3H). LC-MS ： 452 [M+H]+ 實例69 N2-(H3,5·二氟比咬_2_基）乙基）-6-(3-甲氧基一氮四困小基）_ Ν4·(5-甲基-1H-P比唾-3·基）-1，3,5-三》»井-2,4-二胺 使用類似關於實例11合成所述之程序，使6_氯_N2 _(丨_(3 5_ 一氟51比咬-2-基）乙基）-N4-(5-曱基-lH-p比嗤-3-基）_1，3,5_三p井_2 4_ 二胺（中間物40 ’ 200毫克，0·55毫莫耳）與3_甲氧基一氮四圜 鹽酸鹽（74.1毫克，0.60毫莫耳）反應，提供標題化合物，為 對掌異構物之混合物。 133151 •214- 200906818 1 H NMR (300 MHz，MeOD) (5 ppm 8.33 (寬廣 s_，1Η) 7·40-7·69 (m，1H) 6.40 (寬廣 s·，1H) 5.27-5.78 (m, 1H) 4.01-4.43 (m，3H) 3_62-4·01 (m，2H) 2.43 (寬廣 s·, 3H) 1.49 (d，3H) LC-MS : 418 [M+H]+ 管柱與溶劑條件 兩種對掌異構物係使用條件（A)與OJ-3-20純化 官柱粒子大小（W : 5 管柱尺寸（毫米）：21 X 250 ί &quot; 純化後純度檢驗： 試樣純度係使用條件（Β)與OJ-3-20確認 管柱尺寸：4.6 X 250毫米 流率：3毫升/分鐘 偵測：220毫微米 第一個吸收峰（滞留時間：分鐘）1.78 第二個吸收峰（滞留時間：分鐘）3.13 《 第一個溶離之化合物，實例69(a) 1H NMR (300 MHz，MeOD)占 ppm 8.33 (寬廣 s_, 1Η) 7.40-7.69 (m，1Η) 6_40 (寬廣 s·，1H) 5.27-5.78 (m，1H) 4.01-4.43 (m, 3H) 3.62-4.01 (m，2H) 2.43 (寬廣8_，3印1.49((1，311)· LC-MS : 418 [M+H]+ 第二個溶離之化合物，實例69(b) 4 NMR (300 MHz, MeOD) (5 ppm 8.33 (寬廣 s.，1H) 7.40-7.69 (m，1H) 6.40 (寬廣 s” 1H) 5.27-5.78 (m, 1H) 4.01-4.43 (m，3H) 3.62-4.01 (m, 2H) 2.43 (寬廣 s_，3H) 1.49 (d, 3H). 133151 -215- 200906818 LC-MS ： 418 [M+H]+. 實例70 N2-(1-(3,5-二氟吡啶-2-基）-2-甲氧基乙基）_6_(3_氟基一氮四困小 基）-N4-(5-甲基-1H-吡唑-3-基H，3,5-三畊-2,4-二胺 使用類似關於實例11合成所述之程序，使6_氣_N2 -(1-(3,5-一氟p比咬-2-基）-2-甲氧基乙基）-N4-(5-甲基-lH-p比嗤_3_基）-1,3,5-三畊-2,4-二胺（中間物41，166毫克，0.42毫莫耳）與3-氟基一 氮四圜鹽酸鹽（中間物29，51.3毫克，0.46毫莫耳）反應，提 供^ 化合物’為對掌異構物之混合物。 1H NMR (300 MHz，MeOD) 5 ppm 8.36 (寬廣 s., 1Η) 7.41-7.67 (m，1Η) 6.41 (寬廣 s” 1H) 5.54-5.85 (m, 1H) 5_49 (m，1H) 5.28 (m, 1H) 4.19-4.50 (m，2H) 3.89-4.20 (m，1H) 3.61-3.89 (m，2H) 3_34 (寬廣 s·，3H) 2.27 (寬 廣 s., 3H). LC-MS ： 436 [M+H]+. 管柱與溶劑條件 兩種對掌異構物係使用條件（A)與AD-3-20純化 管柱粒子大小（从）：5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗： 試樣純度係使用條件（B)與AD-3-20碎認 管柱尺寸：4.6 X 250毫米 流率：3毫升/分鐘 偵測：220毫微米 第一個吸收峰（滞留時間：分鐘）2·34 133151 -216· 200906818 第二個吸收峰（滯留時間：分鐘）3.40, 95.9% ee. 第一個溶離峰，實例70⑻ 1 H NMR (300 MHz, MeOD) &lt;5 ppm 8.36 (寬廣 s_，1H) 7.41-7.67 (m，1H) 6·41 (寬廣 s·，1H) 5.54-5.85 (m, 1H) 5.49 (m，1H) 5_28 (m，1H) 4.19-4.50 (m，2H) 3.89-4.20 (m，1H) 3.61-3.89 (m，2H) 3.34 (寬廣 s·，3H) 2_27 (寬 廣 s·, 3H). LC-MS : 436 [M+H]+ 第二個溶離峰，實例70(b) 1 H NMR (300 MHz，MeOD) (5 ppm 8.36 (寬廣 s.，1H) 7.41-7.67 (m，1H) 6.41 (寬廣 s.，1H) 5·54_5·85 (m，1H) 5_49 (m，1H) 5_28 (m, 1H) 4.19-4.50 (m，2H) 3.89-4.20 (m，1H) 3.61-3.89 (m，2H) 3.34 (寬廣 s.，3H) 2.27 (寬 廣 s·，3H). LC-MS : 436 [M+H]+ 實例71 N2 -(1-(3，S-二氟吡啶_2-基）-2-甲氧基乙基)-6-(4-甲氧基六氫吡啶 -1-基）-N4-(5-甲基-1H-吡唑-3-基)-1，3,5-三畊-2,4-二胺 使用類似關於實例11合成所述之程序，使6_氯_n2_(1_(3,5_ 二氟峨咬-2-基）-2-曱氧基乙基）_n4-(5-曱基-1H-吡唑-3-基）-l,3,5-二 1•井 -2,4-一胺 （ 中間物 41 ， 15〇 毫克， 〇·38 毫莫耳 ） 與 4- 甲氧基 六氫吡啶鹽酸鹽（63.1毫克’ 〇_42毫莫耳）反應，提供標題化 合物，為對掌異構物之混合物。 4 NMR (300 MHz，MeOD) (5 ppm 8.36 (寬廣 s” 1Η) 7.42-7.68 (m，1Η) 6_36 (寬廣 s·，1H) 5.65 (t，1H) 4.20 (d，邱 3_64-3·95 (m, 2H) 3.41-3.53 (m，1H) 3·37 (s，3H) 3.35 (s，3H) 2.23 (m，3H) 1.87 (寬廣 s·，2H) 1.36 (m， 133151 -217- 200906818 3H). LC-MS : 476 [M+H]+ 標題化合物係使用對掌性HPLC進行對掌性純化I First absorption peak (residence time: minute) 2.0 Second absorption peak (residence time: minute) 4_19 First dissolved peak, Example 64(a) !H NMR (300 MHz, MeOD) δ ppm 8.32 (s , 1H) 7.41-7.67 (m, 1H) 6.34 (broad s_, 1H) 5.15-5.93 (m, 1H) 4.15 (m, 2H) 3.35 (m, 2H) 2_23 (m, 4H) 1.50 (d, 7H) 1.22 (broad s·, 3H) LC-MS: 446 [M+H]+ second eluting peak, example 64(b) 133151 -208· 200906818 lH NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1H ) 7.41-7.67 (m, 1H) 6.34 (broad s·, 1H) 5"5-5_93 (m, 1H) 4.I5 (m, 2H) 3.35 (m, 2H) 2.23 (m, 4H) 1.50 (d , 7H) 1.22 (broad S., 3H) LC-MS: 446 [M+H] + Example 65 N2-(1-(3,5-difluoropyridin-2-yl)ethyl)-6-(4 -decyloxyhexahydropyridine small group)_N4-(5-methyl-1H-pyrazol-3-yl)-1,3,5-trisyl 2,4-diamine was synthesized analogously to Example 11 The procedure described is such that 6-chloro-indole 2-(1-(3,5-a chaotic p ratio.din-2-yl)ethyl)-N4-(5-mercapto-1H-P ratio spit-3 -yl)-1,3,5-tri-11 well-2,4-diamine (intermediate 40,200 mg '0.55 mmol) with 4-methoxyhexahydropyridine hydrochloride (91 mg, 0 60 mmol) to provide the title compound as a mixture of isomers of the palm. ]H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1H) 7.42-7.69 (m, 1H) 6.35 (broad s.,1H) 5.30-5.83 (m, 1H) 4.17 (m,3H) 3_47 (m ,1H) 3.36 (s,3H) 2·24 (broad s) 3H) 1.86 (m,2H) l_〇5_1.69 (m, 6H). LC-MS : 446 [M+H]+ Solvent conditions Two pairs of palm isomers Conditions of use (A) and OJ-3-20 Purified column particle size (μ): 5 Column size (mm): 21 X 250 Purity after purification Purification: Sample purity Conditions of use (Β) and OJ-3-20 Confirm flow rate: 3 ml/min Detection: 220 nm 133151 •209- 200906818 First absorption peak (residence time: minute) 215 Second absorption peak (residence time) : min) 4.46 First Dissolved Peak 'Example 65(a) 1 H NMR (300 MHz, MeOD) 5 ppm 8.32 (s, 1H) 7.42-7.69 (m, 1H) 6.35 (broad s) 1H) 5.30-5.83 (m,1H) 4_17 (m,3H) 3·47 (m,1H) 3.36 (s,3H) 2.24 (broad s.,3H) 1·86 (m,2H) 1.05-1.69 (m,6H)_ LC-MS: 446 [M+H]+ </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; s" 1H) 5.30-5.83 (m, 1 H) 4.17 (m,3H) 3.47 (m,1H) 3.36 (s,3H) 2.24 (broad s., 3H) 1.86 (m,2H) 1.05-1.69 (m,6H). LC-MS : 446 [M +H]+ Example 66 1-(4-(1-(3,5·Difluoropyridin-2-yl)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino) -1,3,5-three tillage 2 -yl)hexahydropyridin-4-indeneonitrile using a procedure similar to that described for the synthesis of Example 11 to give 6-gas-N2 -(1-(3,5- Difluoropyridin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl)-1,3,5-trinyl-2,4-diamine (intermediate 40, Reaction with hexahydropyridine _4. carbonitrile hydrochloride (Intermediate 32, 88 mg '0.60 mmol) afforded the title compound as a mixture. 1H NMR (300 MHz, MeOD) &lt;5 ppm 8·33 (s,1H) 7.55 (ddd,1H) 6.34 (broad s.,1H) 5.25-5.78 (m,1H) 4.07 (m,2H) 3.52 ( m, 2H) 3.06 (m,1H) 2·24 (m, 3H) 1.57-2.06 (m, 4H) 1.51 (d, 3H). LC-MS : 441 [M+H]+. 133151 •210· 200906818 Column and solvent conditions Two pairs of palm isomers Conditions of use (A) and OJ_3-15 Purified column particle size: 5 Column size (mm): 21 X 250 Purity after purification Purification: Sample purity conditions (B) Confirmation of column size with OJ-3-20: 4·6 X 250 mm flow rate: 3 ml/min Detection: 220 nm first absorption peak (residence time: minute) 2_60 second absorption peak (Retention time: minute) 3.61 First elution peak, Example 66(8) 1H NMR (300 MHz, MeOD) 5 ppm 8.33 (s, 1Η) 7.55 (ddd, 1Η) 6.34 (broad s·, 1H) 5.25-5.78 (m ,1H) 4.07 (m,2H) 3.52 (m,2H) 3.06 (m,1H) 2.24 (m, 3H) 1.57-2.06 (m, 4H) 1.51 (d, 3H). LC-MS : 441 [M+ H]+ second elution peak, example 66(b) 1 H NMR (300 MHz, MeOD) (5 ppm 8.33 (s, 1H) 7.55 (ddd, 1H) 6.34 (broad s., 1H) 5.25- 5 .78 (m, 1H) 4.07 (m,2H) 3.52 (m,2H) 3_06 (m,1H) 2.24 (m, 3H) 1.57-2.06 (m, 4H) 1.51 (d, 3H). LC-MS : 441 [M+H]+ Example 67 N2-(l-(3,5-di-gas p-purin-2-yl)ethyl)-6_(4_alkylhexahydrop-biti-1-yl)_N4 -(5-methyl-111~'1 than indol-3-yl)-1,3,5-tri'1 well-2,4-diamine 133151 -211 · 200906818 using a similar synthesis as described in Example 11 Procedure, such that 6_chloro_N2_(1_(3,5_monofluorop is more than 疋-2.yl)ethyl)-N4-(5-methyl-1H-P is more than 〇3_yl)], 3,5_three tillage _2,4_ diamine (intermediate 40' 200 mg, 〇_55 mmol) reacted with 4-fluorohexahydropyridine hydrochloride (84 mg, 0.60 mmol) to provide The title compound is a mixture of palmomers. 1 H NMR (300 MHz, MeOD) &lt;5 ppm 8.32 (s, 1H) 7.38-7.69 (m, 1H) 6.35 (see wide s" 1H) 5.31-5.75 (m, 1H) 4.73 (m, 1H) 3.60 -4.05 (m, 4H) 2.07-2.42 (m, 3H) 1.58-2.05 (m, 4H) 1.52 (d, 3H). LC-MS: 434 [M+H]+. Palm isomer system conditions (A) and 〇J_3_2〇 Purified column particle size (〆): 5 Column size (mm): 21 X 250 Purity after purification Purification: Sample purity conditions (B) and OJ -3-20 Confirmation of column size: 4.6 X 250 mm Flow rate: 3 ml/min Detection: 220 nm first absorption peak (residence time: minute) 2.19 Second absorption peak (residence time: minute) 3.97 First Dissolved Peak, Example 67(4) ]H NMR (300 MHz, MeOD) 5 ppm 8.32 (s, 1H) 7.38-7.69 (m, 1H) 6.35 (broad s) 1H) 5.31-5.75 (m,1H) 4.73 ( m,1H) 3.60-4.05 (m,4H) 2.07-2.42 (m, 3H) 1.58-2.05 (m, 4H) 1.52 (d, 3H). 133151 -212- 200906818 LC-MS : 434 [M+H] + second elution peak, example 67(b) 1 H NMR (300 MHz, MeOD) δ ppm 8.32 (s, 1H) 7.38-7.69 (m, 1H) 6.35 (broad s., 1H) 5·31-5.75(m,1H) 4.73 (m,1H) 3.60_4.05 (m,4H) 2.07-2.42 (m, 3H) 1.58-2.05 (m, 4H) 1.52 (d, 3H). LC-MS : 434 [M +H]+ Example 68 6-(4,4-Difluorohexahydropyridin-1-yl)-N2-(l-(3,5-difluoropyridin-2-yl)ethyl)- { N4 -( 5_Methyl-1H-pyrazol-3-yl)-1,3,5-trinol-2,4-diamine was prepared using a procedure similar to that described in Example 11 to give 6-gas-Ν2- (1- (3,5-difluoro-11 is more than '1 defen-2-yl)ethyl)-1^4-(5-fluorenyl-111-1»pyr-3-yl)-1,3,5-three '1 Well-2,4-diamine (intermediate 40 '200 mg, 〇·55 mmol) was reacted with 4,4-difluorohexahydropyridine hydrochloride (95 mg, 0.60 mmol) to provide The title compound is a mixture of palmomers. 1 H NMR (300 MHz, MeOD) ά ppm 8.33 (s, 1H) 7_55 (ddd, 1H) 6_34 (width (wide s) 1H) 5.25-5.82 (m, 1H) 3.87 (wide s) 4H) 2.24 (wide) s., 3H) 1.68-2.08 (m,4H) 1.51 (d,3H). LC-MS : 452 [M+H]+. Conditions for use of column and solvent conditions (A) Purification column particle size with 〇j_3_i5 (〆): 5 Column size (mm): 21 X 250 Purity after purification Purification: Sample purity conditions (B) and OJ-3-20 confirmation 133151 •213 - 200906818 Column size: 4.6 x 250 mm Flow rate: 3 ml/min Detection: 220 nm first absorption peak (residence time: minute) 199 second absorption peak (residence time: minute) 314 first dissolved compound , Example 68(8) 1H NMK 'MHz' MeOD) &lt;5 ppm 833 (s,1H) 7_55 (ddd,1H) 6.34 (broad s_,1H) 5.25-5.82 (m,1H) 3.87 (broad s) 4H) 2.24 ( Broad s., 3H) 1.68-2.08 (m, 4H) 1.51 (d, 3H) LC-MS: 452 [M+H]+ second dissolved compound, example 68(b) second dissolved compound The residence time is 3 14 minutes, &gt;98% ee H NMR (300 MHz, MeOD) 5 ppm 8.33 (s, 1H) 7.55 (ddd, 1H) 6.34 (broad s., 1H) 5.25-5.82 (m, 1H) 3.87 (broad s·, 4H) 2.24 (broad 3_, 3幵) 1.68- 2.08 (m, 4H) 1.51 (d, 3H). LC-MS: 452 [M+H]+ Example 69 N2-(H3,5·difluoro-bito-2-yl)ethyl)-6-(3 -Methoxy-nitrogen tetra-small base) _ Ν4·(5-methyl-1H-P than sal-3)--1,3,5-three»» Well-2,4-diamine is similar For the procedure described in Example 11 synthesis, 6_chloro_N2 _(丨_(3 5_ fluoro 51 butyl-2-yl)ethyl)-N4-(5-fluorenyl-lH-p 嗤- 3-yl)_1,3,5_tri-p well_2 4_diamine (intermediate 40 '200 mg, 0·55 mmol) and 3-methoxy-tetrazinidine hydrochloride (74.1 mg, The reaction was carried out to give the title compound as a mixture. 133151 •214- 200906818 1 H NMR (300 MHz, MeOD) (5 ppm 8.33 (broad s_,1Η) 7·40-7·69 (m,1H) 6.40 (broad s·,1H) 5.27-5.78 (m, 1H) 4.01-4.43 (m,3H) 3_62-4·01 (m,2H) 2.43 (broad s·, 3H) 1.49 (d,3H) LC-MS : 418 [M+H]+ Column and solvent conditions Two pairs of palm isomers use conditions (A) and OJ-3-20 purified column particle size (W: 5 column size (mm): 21 X 250 ί &quot; Purification purity test: sample purity system Conditions of use (Β) and OJ-3-20 Confirmation of column size: 4.6 X 250 mm Flow rate: 3 ml/min Detection: 220 nm first absorption peak (residence time: minute) 1.78 Second absorption peak (Retention time: minute) 3.13 "The first dissolved compound, Example 69 (a) 1H NMR (300 MHz, MeOD) in ppm 8.33 (broad s_, 1 Η) 7.40-7.69 (m, 1 Η) 6_40 (wide s· ,1H) 5.27-5.78 (m,1H) 4.01-4.43 (m, 3H) 3.62-4.01 (m,2H) 2.43 (wide 8_, 3 printed 1.49 ((1,311)· LC-MS : 418 [M+ H]+ second dissolved compound, example 69(b) 4 NMR (300 MHz, MeOD) (5 ppm 8.33 (broad s., 1H) 7.40-7.69 ( m,1H) 6.40 (broad s) 1H) 5.27-5.78 (m, 1H) 4.01-4.43 (m,3H) 3.62-4.01 (m, 2H) 2.43 (broad s_,3H) 1.49 (d, 3H). 133151 -215- 200906818 LC-MS: 418 [M+H]+. Example 70 N2-(1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)_6_ (3 -N4-(5-methyl-1H-pyrazol-3-yl H,3,5-trinol-2,4-diamine using a procedure similar to that described for the synthesis of Example 11 , 6_ gas_N2 -(1-(3,5-fluoro-p-but-2-yl)-2-methoxyethyl)-N4-(5-methyl-lH-p than 嗤_ 3_yl)-1,3,5-three tillage-2,4-diamine (intermediate 41,166 mg, 0.42 mmol) and 3-fluoro-nitrozinidine hydrochloride (Intermediate 29, 51.3 mg, 0.46 mmoles of reaction, providing ^ compound 'as a mixture of palmomers. 1H NMR (300 MHz, MeOD) 5 ppm 8.36 (broad s., 1Η) 7.41-7.67 (m,1Η) 6.41 (broad s) 1H) 5.54-5.85 (m, 1H) 5_49 (m,1H) 5.28 (m , 1H) 4.19-4.50 (m, 2H) 3.89-4.20 (m, 1H) 3.61-3.89 (m, 2H) 3_34 (broad s·, 3H) 2.27 (broad s., 3H). LC-MS : 436 [ M+H]+. Column and solvent conditions Two pairs of palm isomers use conditions (A) and AD-3-20 purification column particle size (from): 5 column size (mm): 21 X 250 Purity test after purification: Sample purity is the use condition (B) and AD-3-20 fragmentation column size: 4.6 X 250 mm flow rate: 3 ml / min Detection: 220 nm first absorption peak (stagnation Time: minute) 2·34 133151 -216· 200906818 Second absorption peak (residence time: minute) 3.40, 95.9% ee. First elution peak, example 70(8) 1 H NMR (300 MHz, MeOD) &lt;5 ppm 8.36 (broad s_,1H) 7.41-7.67 (m,1H) 6·41 (broad s·,1H) 5.54-5.85 (m, 1H) 5.49 (m,1H) 5_28 (m,1H) 4.19-4.50 (m , 2H) 3.89-4.20 (m, 1H) 3.61-3.89 (m, 2H) 3.34 (broad s·, 3H) 2_27 (broad s·, 3H). LC-MS : 436 [M+H]+ Second Dissolved Peak, Example 70(b) 1 H NMR (300 MHz, MeOD) (5 ppm 8.36 (broad s., 1H) 7.41-7.67 (m, 1H) 6.41 (broad s., 1H) 5·54_5 ·85 (m,1H) 5_49 (m,1H) 5_28 (m, 1H) 4.19-4.50 (m,2H) 3.89-4.20 (m,1H) 3.61-3.89 (m,2H) 3.34 (broad s.,3H 2.27 (broad s·, 3H). LC-MS: 436 [M+H] + EXAMPLE 71 N2 -(1-(3,S-difluoropyridin-2-yl)-2-methoxyethyl) -6-(4-methoxyhexahydropyridin-1-yl)-N4-(5-methyl-1H-pyrazol-3-yl)-1,3,5-trin-2,4-di The amine was used in a procedure similar to that described for the synthesis of Example 11 to give 6-chloro-n2_(1_(3,5-difluoroindol-2-yl)-2-oxiranylethyl)-n4-(5-fluorenyl- 1H-pyrazol-3-yl)-l,3,5-di-1•-2,4-amine (intermediate 41, 15 mg, 〇·38 mmol) with 4-methoxy-6 Hydropyridine salt (63.1 mg of '〇_42 mmol) was reacted to provide the title compound as a mixture. 4 NMR (300 MHz, MeOD) (5 ppm 8.36 (broad s) 1Η) 7.42-7.68 (m, 1Η) 6_36 (broad s·, 1H) 5.65 (t,1H) 4.20 (d, Qiu 3_64-3·95 (m, 2H) 3.41-3.53 (m, 1H) 3·37 (s, 3H) 3.35 (s, 3H) 2.23 (m, 3H) 1.87 (broad s·, 2H) 1.36 (m, 133151 -217- 200906818 3H). LC-MS: 476 [M+H]+ The title compound was purified by palm chromatography

管柱：Chiralpak IB 尺寸：250 X 20毫米，10 # 流動相：93%己烷，7% 1:1乙醇：曱醇，0.1%二乙胺（v/v/v) 流率（毫升/分鐘）：20 偵測（毫微米）：254 純化後純度檢驗： 試樣純度係使用下列條件確認： 管柱：Chiralpak IB，4.6 X 250 毫米，5 微米 流動相：93:7:0.1己烷：乙醇/甲醇（1:1):二乙胺 流率：1毫升/分鐘 偵測：254毫微米 第一個吸收峰（滯留時間：分鐘）17.03 第二個吸收峰（滯留時間：分鐘）丨9·59, 96.2% ee. 實例71(a)，第一個溶離峰 1H NMR (300 MHz，MeOD) 5 ppm 8.36 (寬廣 s·，1H) 7.42-7.68 (m，1H) 6.36 (寬廣 s., 1H) 5_65 (t，1H) 4.20 (d，2H) 3.64-3.95 (m，2H) 3.41-3.53 (m, 1H) 3.37 (s，3H) 3.35 (s，3H) 2.23 (m, 3H) 1.87 (寬廣 s.，2H) 1.36 (m， 3H). LC-MS ： 476 [M+H]+ 實例71(b)，第二個溶離峰 1 H NMR (300 MHz, MeOD) (5 ppm 8.36 (寬廣 s·，1H) 7.42-7.68 (m，1H) 133151 -218- 200906818 6.36 (寬廣 s.，1Η) 5·65 (t，1H) 4.20 (d，2H) 3.64-3.95 (m，2H) 3.41-3.53 (m，1H) 3.37 (s，3H) 3.35 (s，3H) 2_23 (m, 3H) 1.87 (寬廣 s.，2H) U6 (m， 3H). LC-MS ： 476 [M+H]+ 實例72 N2-(l-(3,5·二氟比咬-2-基）·2_甲氧基乙基)-6-(3-甲氧基一氮四園 -1-基）-N4-(5-甲基-1H-吡唑-3-基）-1，3,5-三畊 _2,4_二胺 使用類似關於實例11合成所述之程序，使6-氯-N2 -(1-(3,5- f 一氟p比咬-2-基）-2-甲氧基乙基）-N4-(5-甲基-lH-p比唾-3-基）-1，3,5· 二呼-2,4-二胺（中間物41 ’ 170毫克，0.43毫莫耳）與3-甲氧基 一氮四圜鹽酸鹽（52_9毫克’ 0.43毫莫耳）反應，提供標題化 合物，為對掌異構物之混合物。 !H NMR (300 MHz, MeOD) 5 ppm 8.39 (s, 1H) 7.56-7.74 (m, 1H) 5.83 (寬廣 s·，1H) 5.59_5_76 (m，1H) 3·90-4·58 (m, 5H) 3.62-3.91 (m, 2H) 3.38 (s, 3H) 3.37 (s, 3H) 2.31 (s, 3H). # LC-MS ： 448 [M+H]+ 管柱與溶劑條件 兩種對掌異構物係使用條件（A)與AD-3-20純化 管柱粒子大小（//) : 5 管柱尺寸（毫米广21 X 250 純化後純度檢驗： 試樣純度係使用條件（B)與AD-3-20確認 官柱尺寸：4·6 X 250毫米 在率：3毫升/分鐘 133151 -219- 200906818 偵測：220毫微米 第一個吸收峰（滞留時間：分鐘）1.69 第二個吸收峰（滯留時間：分鐘）2.18 實例72⑻，第一個溶離峰 !H NMR (300 MHz, MeOD) δ ppm 8.39 (s, 1H) 7.56-7.74 (m, 1H) 5.83 (寬廣 s” 1H) 5.59-5.76 (m，1H) 3.90-4.58 (m，5H) 3.62-3.91 (m，2H) 3.38 (s, 3H) 3.37 (s, 3H) 2.31 (s, 3H). LC-MS : 448 [M+H]+ / ' 實例72(b)，第二個溶離峰 1 H NMR (300 MHz, MeOD) δ ppm 8.39 (s, 1H) 7.56-7.74 (m, 1H) 5.83 (寬廣 s., 1H) 5.59-5.76 (m, 1H) 3.90-4.58 (m，5H) 3.62-3.91 (m，2H) 3.38 (s, 3H) 3.37 (s, 3H) 2.31 (s, 3H). LC-MS ： 448 [M+H]+ 實例73 ((R)-4-(4-((R)-l-(3,5-二氟吡啶 _2·基）_2_ 甲氧基乙胺基）-6-(5-甲基 &lt; -1H-吡唑-3-基胺基）-l，3,5-三畊-2-基）嗎福啉-3-基）甲醇，TFA鹽 使用類似關於實例62合成所述之程序，使（r)_6_氯-N2 -(1-(3,5-二氟吡啶-2-基）-2-甲氧基乙基）-N4-(5-曱基-1H-吡唑-3-基）-1，3,5-三啡-2,4-二胺（中間物42，100毫克，0.25毫莫耳）與（R)_ 嗎福啉-3-基甲醇鹽酸鹽（42_6毫克，〇·28毫莫耳）反應，提供 標題化合物。 lU NMR (300 MHz, MeOD) δ ppm 8.40 (s, 1H) 7.63 (t, 1H) 5.80-6.04 (m, 1H) 5.58-5.80 (m, 1H) 4.54-4.73 (m, 1H) 4.46 (d, 1H) 3.40-4.15 (m, 10H) 3.41 (s, 3H) 2.32 (s, 3H). 133151 -220- 200906818 LC-MS : 478 [M+H]+ 實例74 (R)小(4-(1-(3,5-二氣峨咬I基）_2_甲氧基乙胺基）6 (5甲基· 吡唑-3-基胺基）-1，3,5·三畊_2-基）_4_曱基六氫吡啶_4_醇，TFA鹽 使用類似關於實例11合成所述之程序，使⑻_6_氣_N2·^ (3,5-二氟吡啶-2-基）_2_曱氧基乙基）_N4_(5_曱基_出_吡唑_3_基）_ 1，3,5-二啡-2,4-二胺（中間物42，1〇〇毫克，〇 25毫莫耳）與4_甲 基六氫吡啶-4-醇鹽酸鹽（中間物31，42 〇毫克，〇.28毫莫耳） 反應’提供標題化合物。 lH NMR (300 MHz, MeOD) δ ppm 8.39 (s, 1H) 7.63 (t, 1H) 5.75-5.99 (m, 1H) 5.58-5.74 (m, 1H) 4.13-4.55 (m, 2H) 3.63-3.98 (m, 2H) 3.41-3.57 (m, 2H) 3_39 (s，3H) 2.31 (s，3H) 1_61 (寬廣 s·，3H) 1.24 (d，3H)_ LC-MS ： 476 [M+H]+ 實例75 (R)-l-(4-(l-(3,5-二氟吡啶-2-基）-2-甲氧基乙胺基）-6-(5-甲基-1H-吡唑-3-基胺基）-l，3,5-三啡-2-基）六氫吡啶-4-甲腈，TFA鹽 使用類似關於實例11合成所述之程序，使（r)_6_氣 -N2-(1-(3,5-二氟吡啶-2-基）-2-甲氧基乙基）-N4-(5-曱基-1H-吡唑 -3-基）-1，3,5-三畊-2,4-二胺（中間物42，100毫克，0.25毫莫耳） 與六氫吡啶-4-甲腈鹽酸鹽（中間物32，40.6毫克，0.28毫莫耳） 反應’提供標題化合物。 4 NMR (300 Nfflz，MeOD) δ ppm 8_40 (s, 1H) 7.65 (寬廣 s” 1H) 5.84 (寬廣 s” 1H) 5.59-5.76 (m, 1H) 4.00-4.35 (m, 2H) 3.46-3.98 (m, 4H) 3.37 (s, 3H) 3.02-3.20 (m, 1H) 2.32 (s, 3H) 1.49-2.14 (m, 4H). 133151 -221 - 200906818 LC-MS ： 471 [M+H]+ 實例76 (R)-N2-(i-(3,5_二氟吡啶：基）_2_甲氧基乙基）_6_(4_氟基六氫吡 咬-1-基）-N4-(5-甲基 _1H_吡唑 _3_基）ns 畊 _2,4_二胺，tfa 鹽 使用類似關於實例11合成所述之程序，使⑻各氯 (3’5-二氟吡啶-2·基）-2-甲氧基乙基）_N4 _(5_甲基_出_吡唑_3_基 1，3,5-二喷-2,4-二胺（中間物42，1〇〇毫克，0·25毫莫耳）與4說 基六氫吡啶鹽酸鹽（38.7毫克，〇.28毫莫耳）反應，提供標題 化合物。 1 H NMR (300 MHz, MeOD) δ ppm 8.39 (s, 1H) 7.55-7.74 (m, 1H) 5.83 (寬廣 s” 1H) 5.66 (t，1H) 3.63-4.29 (m，7H) 3.38 (s, 3H) 2_32 (s, 3H) 1.53-2.11 (m, 4H). LC-MS ： 464 [M+H]+ 實例77 (R)-6-(4,4-二氟六氫 p比咬-l-基)_n2-(1-(3,5-二氟 u比咬-2-基)-2-甲氧 基乙基）-Ν4-(5·甲基-lH-p比嗤-3-基）-l，3,5-三》•井-2,4-二胺，TFA鹽 使用類似關於實例11合成所述之程序，使（尺)_6_氯 (3,5-—氟p比咬-2-基）-2-甲氧基乙基）-N4-(5-甲基-lH-p比唾-3-基）_ 1，3,5-三畊-2,4-二胺（中間物42，100毫克，〇_25毫莫耳）與4,4_ 二氟六氫吡啶鹽酸鹽（43_7毫克’ 0.28毫莫耳）反應，提供標 題化合物。 !H NMR (300 MHz, MeOD) δ ppm 8.40 (s, 1H) 7.65 (ddd, 1H) 5.85 (s, 1H) 5.68 (t, 1H) 3.65-4.21 (m, 4H) 3.42 (s, 3H) 2.33 (s, 3H) 1.81-2.15 (m, 4H). 133151 -222- 200906818 LC-MS ： 482 [M+H]+ 實例78 N2-((R)-l-(3,5-二氟吡啶-2-基）-2-甲氧基乙基）-6-((2S，6R)-2,6-二甲 基嗎福淋基）-]\4-(5-甲基-111-1»比峻-3-基）-1，3,5-三呼-2,4-二胺 使用類似關於實例11合成所述之程序，使（r)_6_氣_N2-(1_ (3,5-二氟吡啶-2-基）-2-甲氧基乙基）_n4-(5-甲基-1H-吡唑-3-基）-1,3,5-二11 井-2,4-·一胺（中間物42，100毫克，〇·25毫莫耳）與順式 -2,6-二甲基嗎福啉（0.034毫升，0.28毫莫耳）反應，提供標題 化合物。 4 NMR (300 MHz，MeOD) d ppm 8.36 (寬廣 s·，1H) 7.56 (ddd，1H) 6.34 (寬廣 s” 1H) 5.51-5.87 (m，1H) 4.53 (d，2H) 3.65-3.91 (m，2H) 3·42-3.65 (m，2H) 3.35 (s，3H) 2.48 (t，2H) 2_23 (寬廣 s.，3H) l.2〇 (d， 6H). LC-MS ： 476 [M+H]+ 實例79 (R)-N2-(l-(3,5-二氟吡啶-2-基）-2-甲氧基乙基）_n4_(5_曱基仙-吡 唑-3-基）-6-(1，4-氧氮七園_4_基）-1，3,5_三呼_2,4_二胺 使用類似關於實例11合成所述之程序，使（尺)_6_氣 (3,5-一氟吡啶-2-基）-2-曱氧基乙基）_N4 _(5_曱基_出_吡唑_3_基）_ 1，3,5-二畊-2,4-二胺（中間物42，1〇〇毫克，〇 25毫莫耳）與 氧氮七圜烷鹽酸鹽（38.1毫克，0.28毫莫耳）反應，提供標題 化合物。 NMR (300 MHz, MeOD) 5 ppm 8.36 (s, 1H) 7.47-7.64 (m, 1H) 6.36 (寬廣 S” 1H) 5.66 (寬廣 s” 1H) 3.42-4.12 (m，11H) 3.34 (s, 3H) 2.23 133151 -223 - 200906818 (寬廣 s·，3H) 1.82-2.00 (m，2H) 1.72 (寬廣 s·，1H). LC-MS ： 462 [M+H]+ 實例80 N2-(l-(3,5-二氟峨咬·2_基）_2·曱氧基乙基）_N4 _(s_甲基邮哺嗤 -3-基）_6_嗎福p林基-i，3,5-三p井-2,4·二胺 在〇°C下，使6-氯-Ν2-(1-(3,5-二氟吡啶-2-基）_2_曱氧基 基）-Ν4-(5-曱基-1Η-吡唑-3·基）-丨，^三畊_2,4_二胺（中間物41， 653毫克，1.65毫莫耳）溶於乙醇（2194毫升）中，並添加嗎福 啉（5.02毫升，57.60毫莫耳）。將反應物於25°c下攪拌i小時。 使反應混合物在真空中濃縮，留下黃色半固體（1 633克）。 使此物質藉ISCO純化（0-10% MeOH/DCM)。於真空中濃縮溶離 份’提供標題化合物，對掌異構物之混合物，為白色固體 (610毫克）。 管柱與溶劑條件 兩種對掌異構物係使用條件（A)與OJ-3-20純化 管柱粒子大小: 5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗： 試樣純度係使用條件（B)與AD-3-20確認 管柱尺寸：4.6 X 1〇〇毫米 流率：5毫升/分鐘 第一個吸收峰（滯留時間：分鐘）0.56 第二個吸收峰（滯留時間：分鐘）0.87 實例80⑻’第一個溶離峰 133151 -224- 200906818 LC-MS ： 448 [M+H]+ 實例80(b)，第二個溶離峰 JH NMR (300 MHz, MeOD) 5 ppm 8.36 (d, 1H) 7.38-7.74 (m, 1H) 6.36 廣 s” 0.5H) 5.42-5.88 (m，1.5H) 3.48-3.98 (m，10H) 3 34 (s 3H) 2.05-2.41 (m, 3H). LC-MS ： 448 [M+H]+ . 關於標題化合物之R-對掌異構物之對掌性合成，參考實 例 113。 實例81 N-(((R)_4-(4-((R)-l-(3,5-二氟吡啶·2_基）·2_ 甲氧基乙胺基）_6_(5 甲 基-1Η-吡唑-3-基胺基）-1,3,5-三畊-2-基）嗎福啉_3基）甲基）曱燒 磺醢胺 使用類似關於實例62合成所述之程序，使⑻冬氣挪分 (3,5-二氟ρ比。定-2-基）-2-曱氧基乙基）_n4 -(5-曱基-lH-p比。坐-3-基）· 1，3,5-三畊-2,4-二胺（中間物42 ’ 1〇〇毫克，〇 25毫莫耳）與 (R)-N-(嗎福淋-3-基曱基）甲烧續醯胺鹽酸鹽（中間物44，58」 毫克，0.25毫莫耳）反應，提供標題化合物。 1 H NMR (300 MHz，MeOD) &lt;5 ppm 8.36 (s，1H) 7.55 (t，1H) 6.38 (寬廣 s., 1H) 5.73 (m, 1H) 4.69 (m, 1H) 4.41 (d, 1H) 4.01 (d, 1H) 3.90 (d, 1H) 3.64-3.85 (m, 2H) 3.37-3.64 (m, 4H) 3.34 (s, 3H) 3.05-3.26 (m, 1H) 2.94 (寬廣 s.，3H) 2.25 (寬廣 s_, 3H). LC-MS : 555 [M+H]+ 實例82 ((R)-4-(4-((R)-l-(3,5_二氟吡啶：基）_2_甲氧基乙胺基）_6_(5_甲基 133151 -225 - 200906818 -lH-p比也-3-基胺基）-l，3,5-三《•井-2-基）嗎福琳_3-基）甲基胺基甲 酸乙酯 使用類似關於實例62合成所述之程序，使（尺)_6_氯_N2 (3,5-一乱p比唆-2-基）-2-甲氧基乙基）_n4-(5-甲基-lH-p比唾-3-基）_ I，3,5-三畊-2,4-二胺（中間物42，100毫克，0.25毫莫耳）與 嗎福π林-3-基甲基胺基甲酸乙酯鹽酸鹽（中間物46，56.6毫 克’ 0.25宅莫耳）反應’提供標題化合物。 ]H NMR (300 MHz, MeOD) δ ppm 8.36 (s, 1H) 7.44-7.68 (m, 1H) 6.39 (寬廣 s.，1H) 5.42-5.90 (m，1H) 4_76 (寬廣 s_，1H) 4.39 (寬廣 s.，1H) 3.39-4.19 (m，10H) 3_34 (s，3H) 3.09-3.26 (m，1H) 2.28 (寬廣 s·，3H) 1.26 (寬廣 s·，3H). LC-MS ： 549 [M+H]+ 實例83 N2 -((叫-1-(3,5-二氟吡啶_2·基)_2_甲氧基乙基）冬((2R，6R)_2,6二甲 基嗎福琳基）-N4 -(5-甲基-1H-吡唑-3-基）-1,3,5-三畊-2,4-二胺 使用類似關於實例11合成所述之程序，使（11)_6_氣_N2_(1_ (3,5-二氟吨啶-2-基）_2_甲氧基乙基）_n4_(5_甲基-肝吡唑_3_基）_ 1，3,5-二畊-2,4-二胺（中間物42，150毫克，〇_38毫莫耳）與2,6- 二甲基嗎福啉（反式_，順式-混合物）(43.5毫克，〇 38毫莫耳） 反應’提供標題化合物，為立體異構物之混合物。將異構 物藉由Gilson (NH4 OAc/MeOH)分離。在真空中濃縮溶離份， 獲知非對映異構物之混合物，為白色固體。 lU NMR (300 MHz, MeOD) δ ppm 8.36 ( X： ^ s., 1Η) 7.56 (ddd, 2.35 Hz, 1H) 5.85-6.24 (m, 1H) 5.54-5.79 (m, 1H) 3.63-4.15 (m, 7H) 3.40-3.62 133151 -226- 200906818 (m，2H) 3.35 (s，3H) 2.23 (s，3H) U7 (寬廣 s.，6H). LC-MS : 476 [M+H]+，伴隨著 N2-((R)-l-(3,5-二氟吡啶-2-基）-2-曱 氧基乙基）-6-((2S，6R)-2,6-二曱基嗎福p林基）-N4-(5-甲基-1H-吡唑 -3-基）-1,3,5-三畊-2,4-二胺（實例 78)。 管柱與溶劑條件 兩種非對映異構物係使用HPLC分離 管柱：XBridge C18管柱 流動相：lOmMM^OAc 在H2〇(具有 5%MeCN)中，pH8，使 用MeOH，梯度液60至75%。 管柱粒子大小（^) : 5 管柱尺寸（毫米）：19 X 100 實例84 N2 -((R)-l-(3,5-二氟吡啶-2-基)-2-甲氧基乙基)_6-((R)-3-(甲氧基甲 基）嗎福琳基）-N4 -(5-甲基-1H-吡唑_3_基）-l，3,5-三畊-2,4-二胺 使用類似關於實例62合成所述之程序，使（R)_6_氯 -N2-(l-(3,5-二氟吡啶-2-基）-2-甲氧基乙基）-Ν4_(5·甲基_出_吡唑 -3-基）-1，3,5-三畊-2,4-二胺（中間物42，0.207克，0.52毫莫耳） 與(R)-3-(曱氧基甲基）嗎福啉（中間物5〇，〇 〇76克，〇 %毫莫耳） 反應’提供標題化合物。 LC-MS : 493 [Μ]+· lU NMR (MeOD) δ 8.24 (s, 1H), 7.41 (t, 1H), 6.27 ( M s, 1H), 5.62 (m，1H)，4.54 (m，1H)，4.29 (m，1H)，3.90 (m，1H)，3.78 (m, 1H), 3.69 (m， 1H), 3.64 (m, 2H), 3.36 (m, 2H), 3.27 (m, 1H), 3.21 (s, 3H), 3.98 (m, 1H), 2.12 (s, 3H). 133151 -227- 200906818 ⑻-6-丁氧基-來(1-(3,5-二氟吡啶_2_基）_2_甲氧基乙基）_N4_(5_ 曱基-1H-吡唑-3-基）-1,3,5-三畊-2,4-二胺係以副產物單離。 1 H NMR (MeOD) 5 8.25 (s, 1H), 7.47 (t, 1H), 5.61 (m, 1H), 4.17 (m, 2H), 3.69 (m, 2H), 3.26 (m, 3H), 3.24 (s, 3H), 2.17 (d, 3H), 1.59 (m, 2H), 1.35 (m, 2H), 0.85 (t, 3H). LC-MS : 493 [M+H]+. 實例85 6-((S)-3-(二氟甲基）嗎福啉基氟吡啶_2基）_2_ 甲氧基乙基）-N4-(5-甲基-1Η·吡唑-3-基）-1，3,5-三畊_2,4_二胺 使用類似關於實例62合成所述之程序，使（尺)_6_氯_N2 _(l (3,5-二氟吡啶-2-基）-2-曱氧基乙基）_n4-(5-甲基-1H-吡唑-3-基）-1,3,5-二啡-2,4-二胺（中間物42’〇.188克，〇_48毫莫耳）與 (S)-3-(二氟甲基）嗎福啉（中間物53，〇 〇69克，〇·5毫莫耳）反應， 提供標題化合物。 LC_MS : 498 [Μ+Η]+. 1 H NMR (MeOD) 5 8.32 (s, 1H), 7.51 (t, 1H), 6.20 (m, 1H), 5.60 (m, 1H), 4.78 (m, 1H), 4.47 (m, 1H)5 4.10 (d, 1H), 3.90 (m, 1H), 3.75 (m, 1H), 3.68 (m，1H)，3.55 (m, 1H)，3.47 (m，1H)，3.25 (s, 3H)，3·19 (m，1H)，2.20 (寬 廣 s，3H). 實例86 (R)-N2-(5-環丙基-1H-吡唑-3-基）-N4-(l-(3,5-二氟吡啶-2-基）_2-甲 氧基乙基）·6_嗎福啉基_1，3,5_三畊_2,4_二胺 使（R)-6-氯-N2-(5-環丙基-lH-p比峻-3-基）-N4-(l-(3,5-二氟？比。定 -2-基）-2-甲氧基乙基）—us三畊_2,4_二胺（中間物55，2〇1毫 133151 -228· 200906818 克，0_48毫莫耳）溶於乙醇（ο ·毫升）中，並添加嗎福啉（145〇 毫升’ 16.64毫莫耳）。將反應混合物在25°c下攪拌1小時。 接著，使反應混合物於真空中濃縮，留下透明半固體（4〇2 毫克）。使此物質藉ISCO純化（2-10% MeOH/DCM)。在真空中 濃縮溶離份，提供標題化合物，為白色固體（194.5毫克）。 1 H NMR (300 MHz，MeOD) (5 ppm 8.35 (寬廣 s·，1H) 7.45-7.63 (m，1H) 6.29 (寬廣 s” 1H) 5.31-5.89 (m，1H) 3.52-3.94 (m，11H) 3.34 (s，3H) 1.87 (寬廣 s·，1H) 0.93 (寬廣 s·，2H) 0.69 (寬廣 s.，2H)· LC-MS ： 474 [M+H]+ 實例87 N2-(1-(3,5-二氟吡啶-2-基）-2-乙氧基乙基）-N4-(5-甲基-1H-吡唑 -3-基）-6-嗎福《•林基-1，3,5_三畊-2,4-二胺 於100毫升圓底燒瓶中，添加乙醇（974微升）中之6-氣 -N2-(1-(3,5-二氟吡啶-2-基）-2-乙氧基乙基）_N4-(5-曱基-1H-吡唑 -3-基）-1,3,5-三畊-2,4-二胺（中間物60，200毫克，〇_49毫莫耳） 與嗎福啉（42·4微升，0.49毫莫耳），獲得黃色溶液。將溶液 在此溫度下授拌3小時，此時，於減壓下蒸發揮發性物質。 藉管柱層析純化（ISCO，5%-10% MeOH/DCM)，獲得 N2-(1-(3,5-二氟吡啶-2-基）-2-乙氧基乙基）_N4-(5-甲基-1H-吡唑-3-基）-6-嗎 福啉基-1，3,5-三畊-2,4-二胺（61_0毫克，27.2%)，為對掌異構物 之混合物。 1H NMR (300 MHz, MeOD) δ ppm 1.17 (t, J = 7.06 Hz, 3H) 2.34 (s, 3H) 3.57 (q, J - 7.10 Hz, 2H) 3.65-4.04 (m, 10H) 5.68 (t, J = 6.59 Hz, 1H) 5.86 (寬廣 s.，1H) 7_64 (ddd, J = 9.80, 8.67, 2.26 Hz，1H) 8·41 (d, J = 2.26 Hz, 133151 -229- 200906818 1H). LC-MS · 462 [M+H]+ 管柱與溶劑條件 標題化合物之兩種對掌異構物係使用條件（A)與OJ-3-20分離 管柱粒子大小（β: 5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗 試樣純度係使用條件（Β)與OJ-3-20確認 1 管柱粒子大小〇) : 5 管柱尺寸（毫米）：4.6 X 250 溶離時間：15分鐘 第一個吸收峰（滯留時間：分鐘）2.1〇 第二個吸收峰（滯留時間：分鐘）3.43 實例87(a)，第一個溶離峰 4 NMR (300 MHz，MeOD) &lt;5 ppm 1.13 (t，J = 6.97 Hz, 3Η) 2.28 (寬 # 廣 s” 3H) 3.45-3.92 (m，12H) 5.46-5.88 (m, 1H) 6·37 (寬廣 s.，1H) \ 7.38- 7.75 (m, 1H) 8.38 (s, 1H) 實例87(b)，第二個溶離峰 4 NMR (300 MHz，MeOD) δ ppm 1.13 (t, J = 6.97 Hz, 3H) 2·28 (寬 廣 s·，3H) 3.45-3,92 (m，12H) 5.46-5.88 (m, 1H) 6·37 (寬廣 s., 1H) 7.38- 7.75 (m, 1H) 8.38 (s, 1H) 實例88 2S-l-(5-氟基吡啶-2-基）-1-(4-(5-曱基-1H-吡唑-3-基胺基）-6-嗎福 啉基-1,3,5-三，井-2-基氧基）丙-2-醇鹽酸鹽，對掌異構物（A) 133151 -230- 200906818 使4-氯·Ν-(5-甲基_1H-吡唑_3·基）_6•嗎福啉基-〗，3,5_三畊_2_胺 (中間物15，66.3毫克，0.22毫莫耳）與28_2(第三-丁基二甲基 矽烷基氧基）-1-(5-氟基吡啶_2_基）丙_丨_醇（中間物8S (Aa)，64亳 克，0.22毫莫耳）溶於tBuOH(2毫升）中，並添加^加〇1^(431 毫克，0.45毫莫耳）。然後，將反應物在25&lt;&gt;c下攪拌過夜。 LC/MS顯示僅18%轉化成產物，故添加另一當量之第三-丁醇 鈉，且將反應物於25°C下再一次搅拌過夜。接著，使反應 混合物在真空中濃縮，留下灰白色固體（191毫克）。使此物 質藉ISCO純化（80-100% EtOAc/己烷）。於真空中濃縮溶離份， 獲得透明油（51毫克）。使此物質溶於Me〇H (丨毫升）中，並添 加二氧陸圜中之4M HC1 (0.093毫升，〇_37毫莫耳）。然後，將 反應物在25 C下授拌2小時。使反應混合物於真空中濃縮， 留下透明油。使此物質藉ISCO純化（〇_1〇% Me0H/DCMp在真 空中濃縮溶離份，提供標題化合物，為白色固體（17·5毫克）。 NMR (300 MHz, MeOD) &lt;5 ppm 8.28-8.60 (m, 1H) 7.39-7.79 (m, 2H) 6.17 (寬廣 s” 1H) 5.67-5.95 (m, 1H) 4.09-4.37 (m, 1H) 3.42-3.94 (m，8H) 2.26 (s, 3H) 1.03-1.50 (m, 3H). LC-MS ： 431 [M+H]+ 實例89 2S-1_(5-氟基吡啶-2-基）小(4-(5-甲基-1H-吡唑-3-基胺基）-6·嗎福 啉基-1，3,5-三畊-2-基氧基）丙_2_醇鹽酸鹽，對掌異構物⑼ 使用類似關於實例88合成所述之程序，使4-氯-Ν-(5-甲基 -1Η-吡唑-3-基）-6-嗎福啉基_l，3,5-三畊-2-胺（中間物15，06.3毫 克’ 0.22毫莫耳）與2S-2-(第三-丁基二曱基矽烷基氧基)小(5_ 133151 -231 · 200906818 氟基P比咬-2-基）丙-1-醇（中間物85(b)，64毫克，〇_22毫莫耳） 反應，提供標題化合物。 H NMR (300 MHz, MeOD) δ ppm 8.31-8.57 (m, 1H) 7.42-7.77 (m, 2H) 6.24 (寬廣 s·，1H) 5.79 (d，1H) 4.21 (dq，1H) 3.45-3.96 (m，8H) 2.26 (s， 3H) 1.36-1.50 (m, 3H). LC-MS ： 431 [M+H]+ 實例90 N2 -(2-乙氧基-1-(5-氣基，比咬_2_基）乙基）_N4 _(5_曱基_m吡唑各 基）-6-嗎福林基-i，3,5-三喷-2,4-二胺 於6-氯-N2-(2-乙氧基_ι_(5_氟基吡啶_2_基）乙基）_N4_(5_甲基 -1H-H3-基）-1，3,5-三畊 _2,4_二胺（中間物 90，〇 452 克，i 15 毫莫耳）在乙醇（2.300毫升）中之溶液内，添加嗎福啉（3〇1毫 升，34.50毫莫耳）。將所形成之混合物於環境溫度下攪拌3 小時。在減壓下蒸發揮發性物質，獲得黃色殘留物。藉管 柱層析純化（ISCO，5%-l〇%Me〇H/DCM)，獲得標題化合物， 為對掌異構物之混合物。 LC-MS : 444 [M+H]+. lH 麵1 (細麻，Me0D) ^ PPm 1.15 (t，3H) 2_25 (s，3H) 3.43-3.90 (m, 12H) 5.12-5.42 (m, 1H) 5.60 (s, 1H) 7.37-7.77 (m, 2H) 8.48 (s, 1H) 管柱與溶劑條件 ’ 標題化合物係使用條件（A)與AD_3_4〇進行對掌性純化 管柱粒子大小（#) : 5 管柱尺寸（毫米）：19 X 1〇〇 純化後純度檢驗 133151 -232- 200906818 試樣純度係使用條件（B)與AD-3-40確認 管柱粒子大小（〆）：5 管柱尺寸（毫米）·· 4.6 X 100 第一個吸收峰（滯留時間：分鐘）0.97 第二個吸收峰（滯留時間：分鐘）2.13 實例90⑻，第一個溶離峰 1 H NMR (300 MHz, MeOD) δ ppm 1.16 (t, J = 7.06 Hz, 3H) 2.25 (s, 3H) 3.46-3.98 (m, 12H) 5.19-5.41 (m, 1H) 5.48-6.50 (m, 1H) 7.35-7.76 (m, 2H) 8.42 (s, 1H). 實例90(b)，第二個溶離峰 1 H NMR (300 MHz, MeOD) δ ppm 1.05 (t, J - 6.97 Hz, 3H) 2.14 (s, 3H) 3.36-3.81 (m, 12H) 5.03-5.26 (m, 1H) 5.42-6.44 (m, 1H) 7.30-7.66 (m, 2H) 8.31 (s，1H). 實例91 (l-(4-((S)-l-(5-氣基p比咬-2-基）乙胺基）-6-(5-甲基-lH-i*比峻-3-基胺 基）-1，3,5-三哜-2-基）六氫吡啶_2_基）甲醇 於（S)-6-氯-N2-(l-(5-氣基吡啶·2·基）乙基）-N4-(5-甲基-1H-吡唑 -3-基）-1，3,5-三畊-2,4-二胺（中間物16，222毫克，0.64毫莫耳） 在EtOH (1061微升）與n-BuOH (1061微升）中之溶液内，添加六 氫说σ定-2-基曱醇（73.3毫克，0.64毫莫耳）與DIPEA (111微升， 0.64毫莫耳）。將所形成之混合物加熱至i〇〇°c，歷經ι6小 時。在減壓下蒸發揮發性物質，獲得黃色殘留物。藉管柱 層析純化（ISCO ’ 5%-10% MeOH/DCM)，而得標題化合物（191 毫克，70.2%)，為白色固體。 133151 -233 - 200906818 LC-MS ： 428 [M+H]. ^ NMR (300 MHz, MeOD) δ ppm 1.41 (d, J = 6.97 Hz, 3H) 1.44-1.61 (m, 4H) 1.63-1.86 (m, 1H) 2.12 (s, 3H) 2.51-2.84 (m, 1H) 3.46-3.74 (m, 2H) 4.27-4.59 (m, 2H) 4.70-4.80 (m, 1H) 4.96-5.23 (m, 1H) 6.28 (s, 1H) 7.17-7.74 (m, 2H) 8.27 (s, 1H) 實例92 ((S)-4-(4-((S)-l-(5-氟基吡啶-2-基）乙胺基）_6-(5_甲基-1H-吡唑-3-基 胺基）-1,3,5-三畊-2-基）嗎福啉-3-基）甲醇 使用類似關於實例91合成所述之程序，使⑸_6_氯_N2 _(丨_(5_ 氟基卩比咬-2-基）乙基）-&gt;14-(5-曱基-111-1»比唾-3-基）-1,3,5-三'(*井-2,4-二胺（中間物16 ’ 200毫克，0.57毫莫耳）與（S)-嗎福啉-3-基甲 醇（73·9毫克，0.63毫莫耳）反應，提供標題化合物。 1H NMR (300 MHz，MeOD) &lt;5 ppm 8.37 (寬廣 s.，1Η) 7.28-7.70 (m，2Η) 6.03 (寬廣 s” 1H) 5.16 (q, 1H) 4.17-4.69 (m，2H) 4_08 (d，1H) 3·87 (m， 2H) 3.36-3.71 (m，2H) 2.77-3.19 (m，2H) 2.19 (s, 3H) 1.54 (d, 3H). LC-MS ： 430 [M+H]+ 實例93 ((R)-4_(4-((S)-l-(5-氣基峨咬 _2_基）乙胺基）_6·(5·甲基·ιη-ι»比吐-3-基胺基）-1，3,5-三啡-2-基）嗎福啉-3-基）甲醇 使用類似關於實例91合成所述之程序，使⑸_6-氯-Ν2-(1-(5-氟基峨11定-2-基）乙基）-1&lt;!4-(5-曱基-11&quot;1-3比。垒-3-基）-1,3,5-三'1井-2,4-二胺（中間物16，200毫克，0.57毫莫耳）與（R)·嗎福啉_3-基甲 醇鹽酸鹽（97毫克’ 0.63毫莫耳）反應，提供標題化合物。 1 H NMR (300 MHz，MeOD) &lt;5 ppm 8.37 (寬廣 s·，1H) 7.32-7.70 (m，2H) 133151 - 234 - 200906818 5.87-6.69 (m，0.5H) 5.58 (寬廣 s·, 0.5H) 5.15 (q，1H) 4.18-4.74 (m，2H) 4.04 (d, 1H) 3.72-3.97 (m, 2H) 3.35-3.72 (m, 2H) 2.72-3.21 (m5 2H) 2.23 (寬廣 s·, 3H) 1.51 (d，3H). LC-MS ： 430 [M+H]+ 實例94 2-(4-(4-((S)-l-(5-氟基p比咬-2_基）乙胺基）-6-(5-甲基-lH-p比峡-3_基 胺基）-l，3,5-三畊-2-基）嗎福啉-3-基）醋酸甲酯 於250毫升圓底燒瓶中，添加EtOH (2867微升）中之（S)-6-氯 -N2-(l-(5-氟基 p比咬-2-基）乙基）-N4-(5-甲基-lH-p比唾-3-基）-l,3,5-三畊-2,4-二胺（中間物16,300毫克，0·86毫莫耳）與2-(嗎福啉 -3-基）醋酸甲酯（137毫克，0.86毫莫耳），而得黃色溶液。將 所形成之混合物在100°C下加熱12小時。於減壓下蒸發揮發 性物質，獲得油狀物。藉管柱層析純化（ISC0，5% MeOH/ DCM)，而得標題化合物。 LC-MS ： 472 [M+H]+ 實例95 2-(4-(4-((S)-l-(5_氟基p比咬_2_基）乙胺基）-6-(5-曱基-lH-p比峻-3-基 胺基）-1，3,5-三喷-2-基）嗎福p林-3-基）乙醇 於2-(4-(4-((S)-l-(5-氟基吡啶-2-基）乙胺基）_6_(5-甲基-iH-p比唑 -3-基胺基）-1，3,5-三畊-2-基）嗎福啉-3-基）醋酸曱酯（實例94,200 ^:克，0·42宅莫耳）在四氫吱π南（1.4毫升）中之溶液内，在〇 。(：下’逐滴添加LiBH4(636微升，1.27毫莫耳）在THF中之2Μ ;谷液。於氣體釋出停止後，將所形成之混合物在環境溫度 下攪拌1小時。使混合物冷卻至(TC，並慢慢添加MeOH (注 133151 - 235 - 200906818 意：放熱），以使過量LiBH4淬滅。在減壓下蒸發揮發性物 質，且使留下之殘留物溶於Et0Ac中。將有機相以H2〇、鹽 水洗滌，及脫水乾燥。蒸發，獲得黃色殘留物。藉管柱層 析純化（ISCO，5%-1〇% MeOH/DCM)，而得 2-(4-(4-((s)-l-(5_氟美 叶匕啶-2-基）乙胺基）-6-(5-甲基-1H-吡唑-3-基胺基”二^三命_2_ 基）嗎福啉-3-基）乙醇（80毫克，42·5°/〇) ’為非對映異構物之混 合物。 lR NMR (300 MHz, DMSO-d6) δ ppm 1.44 (d, 6H) 1.67-1.94 (m, 4H) 2.15 (s, 6H) 2.73-4.83 (m, 18H) 5.75-6.58 (m, 2H) 7.20-7.96 (m, 4H) 8.49 (s, 2H) 9.13 (s, 1H) 9.46 (s, 1H). LC-MS ： 444 [M+H] 實例96 (S)-l-(4-(l-(5-氟基吡啶-2-基）乙胺基）_6_(5_甲基_1H_吡唑_3_基胺 基）-l，3,5-三畊_2_基）一氮四圓_3-醇 使用類似關於實例11合成所述之程序，使（8)_6_氯_N2 _(丨_(5_ 氟基卩比α定-2-基）乙基）-N4-(5-甲基-lH-p比唉-3-基）-l，3,5-三喷-2,4_ 二胺（中間物16，200毫克’ 0.57毫莫耳）與—氮四園_3_醇鹽 酸鹽（69_1毫克，0_63毫莫耳）反應，提供標題化合物。 1 H NMR (300 MHz, MeOD) δ ppm 8.24-8.60 (m, 1H) 7.34-7.73 (m, 2H) 6.06 (寬廣 s·，1H) 5_17 (q，1H) 4.61 (m，1H) 3.97-4.40 (m, 2H) 3.58-3.96 (m, 2H) 2.23 (s, 3H) 1.51 (d, 3H). LC-MS ： 386 [M+H]+ 實例97 (S)-N2-(l-(3,5-二氟吡啶-2-基）乙基）·6_(2,2_二曱基嗎福琳基)-N4- 133151 •236. 200906818 (5-甲基-1Η_吡唑-3-基）-i，3,5-三畊-2,4_二胺Column: Chiralpak IB Size: 250 X 20 mm, 10 # Mobile phase: 93% hexane, 7% 1:1 Ethanol: decyl alcohol, 0.1% diethylamine (v/v/v) Flow rate (ml/min) ): 20 Detection (nm): 254 Purity test after purification: Sample purity is confirmed using the following conditions: Column: Chiralpak IB, 4.6 X 250 mm, 5 μm mobile phase: 93:7: 0.1 Hexane: Ethanol /Methanol (1:1): Diethylamine flow rate: 1 ml/min Detection: 254 nm first absorption peak (residence time: minute) 17.03 Second absorption peak (residence time: minute) 丨9· 59, 96.2% ee. Example 71(a), first dissolution peak 1H NMR (300 MHz, MeOD) 5 ppm 8.36 (broad s·, 1H) 7.42-7.68 (m, 1H) 6.36 (broad s., 1H 5_65 (t,1H) 4.20 (d,2H) 3.64-3.95 (m,2H) 3.41-3.53 (m, 1H) 3.37 (s,3H) 3.35 (s,3H) 2.23 (m, 3H) 1.87 (wide) s., 2H) 1.36 (m, 3H). LC-MS: 476 [M+H]+ Example 71(b), second elution peak 1 H NMR (300 MHz, MeOD) (5 ppm 8.36 (broad s ·, 1H) 7.42-7.68 (m, 1H) 133151 -218- 200906818 6.36 (broad s., 1Η) 5·65 (t, 1H) 4.20 (d, 2H) 3.6 4-3.95 (m,2H) 3.41-3.53 (m,1H) 3.37 (s,3H) 3.35 (s,3H) 2_23 (m, 3H) 1.87 (broad s.,2H) U6 (m, 3H). LC -MS: 476 [M+H]+ Example 72 N2-(l-(3,5·difluorobuty-2-yl)·2-methoxyethyl)-6-(3-methoxy- Nitrogen tetra-l-yl)-N4-(5-methyl-1H-pyrazol-3-yl)-1,3,5-tri-n-tano-2,4-diamine was synthesized analogously to Example 11 Procedure for 6-chloro-N2-(1-(3,5-f-fluoro-p-but-2-yl)-2-methoxyethyl)-N4-(5-methyl-lH-p Than sial-3-yl)-1,3,5·dih-2,4-diamine (intermediate 41 '170 mg, 0.43 mmol) and 3-methoxy-azinotetramine hydrochloride ( 52_9 mg of '0.43 mmol' of reaction provided the title compound as a mixture of the palmomers. !H NMR (300 MHz, MeOD) 5 ppm 8.39 (s, 1H) 7.56-7.74 (m, 1H) 5.83 (broad s·, 1H) 5.59_5_76 (m,1H) 3·90-4·58 (m, 5H) 3.62-3.91 (m, 2H) 3.38 (s, 3H) 3.37 (s, 3H) 2.31 (s, 3H). # LC-MS : 448 [M+H]+ tube and solvent conditions Isomer system use conditions (A) and AD-3-20 purification column particle size (//): 5 column size (mm 2 21 X 250 Purification purity test: sample purity system conditions (B) and AD-3-20 confirmed column size: 4·6 X 250 mm at rate: 3 ml/min 133151 -219- 200906818 Detection: 220 nm first absorption peak (residence time: minute) 1.69 second absorption Peak (retention time: minute) 2.18 Example 72 (8), first dissolved peak! H NMR (300 MHz, MeOD) δ ppm 8.39 (s, 1H) 7.56-7.74 (m, 1H) 5.83 (broad s) 1H) 5.59- 5.76 (m,1H) 3.90-4.58 (m,5H) 3.62-3.91 (m,2H) 3.38 (s, 3H) 3.37 (s, 3H) 2.31 (s, 3H). LC-MS : 448 [M+H ] + / ' Example 72(b), second dissolved peak 1 H NMR (300 MHz, MeOD) δ ppm 8.39 (s, 1H) 7.56-7.74 (m, 1H) 5.83 (broad s., 1H) 5.59- 5.76 (m, 1H) 3.90-4.58 (m,5H) 3.62-3.91 (m,2H) 3.38 (s, 3H) 3.37 (s, 3H) 2.31 (s, 3H). LC-MS : 448 [M+H]+ Example 73 ((R)- 4-(4-((R)-l-(3,5-difluoropyridin-2-yl)_2-methoxyethylamino)-6-(5-methyl&lt;-1H-pyrazole-3 -ylamino)-l,3,5-triton-2-yl)norfosin-3-yl)methanol, TFA salt was used in a procedure similar to that described for the synthesis of Example 62 to give (r) _6 _ chloro N2-(1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-fluorenyl-1H-pyrazol-3-yl)-1,3, 5-triphthyl-2,4-diamine (intermediate 42,100 mg, 0.25 mmol) and (R)-norfosolin-3-ylmethanol hydrochloride (42_6 mg, 〇·28 mmol) The reaction provides the title compound. lU NMR (300 MHz, MeOD) δ ppm 8.40 (s, 1H) 7.63 (t, 1H) 5.80-6.04 (m, 1H) 5.58-5.80 (m, 1H) 4.54-4.73 (m, 1H) 4.46 (d, 1H) 3.40-4.15 (m, 10H) 3.41 (s, 3H) 2.32 (s, 3H). 133151 -220- 200906818 LC-MS : 478 [M+H]+ Example 74 (R) Small (4-(1 -(3,5-two gas bite I base)_2_methoxyethylamino)6 (5-methyl-pyrazol-3-ylamino)-1,3,5·three tillage_2-based _4_decyl hexahydropyridine _4-alcohol, TFA salt using a procedure similar to that described for the synthesis of Example 11 to give (8) _6_gas_N2·^(3,5-difluoropyridin-2-yl)_2_曱Oxyethyl)_N4_(5_fluorenyl-out-pyrazole-3-yl)- 1,3,5-dimorph-2,4-diamine (intermediate 42, 1 〇〇 mg, 〇 25 毫Reaction of 4-Methylhexahydropyridin-4-ol hydrochloride (Intermediate 31, 42 mg, 〇. 28 mmol) afforded the title compound. lH NMR (300 MHz, MeOD) δ ppm 8.39 (s, 1H) 7.63 (t, 1H) 5.75-5.99 (m, 1H) 5.58-5.74 (m, 1H) 4.13-4.55 (m, 2H) 3.63-3.98 ( m, 2H) 3.41-3.57 (m, 2H) 3_39 (s, 3H) 2.31 (s, 3H) 1_61 (broad s·, 3H) 1.24 (d,3H)_ LC-MS : 476 [M+H]+ Example 75 (R)-l-(4-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethylamino)-6-(5-methyl-1H-pyrazole) -3-ylamino)-l,3,5-tri- morphin-2-yl)hexahydropyridine-4-carbonitrile, the TFA salt was similar to the procedure described for the synthesis of Example 11 to give (r) _6_ -N2-(1-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-fluorenyl-1H-pyrazol-3-yl)-1,3 , 5-trin-2,4-diamine (intermediate 42,100 mg, 0.25 mmol) and hexahydropyridine-4-carbonitrile hydrochloride (intermediate 32, 40.6 mg, 0.28 mmol) Reaction 'provides the title compound. 4 NMR (300 Nfflz, MeOD) δ ppm 8_40 (s, 1H) 7.65 (broad s) 1H) 5.84 (broad s) 1H) 5.59-5.76 (m, 1H) 4.00-4.35 (m, 2H) 3.46-3.98 ( m, 4H) 3.37 (s, 3H) 3.02-3.20 (m, 1H) 2.32 (s, 3H) 1.49-2.14 (m, 4H). 133151 -221 - 200906818 LC-MS : 471 [M+H]+ Example 76(R)-N2-(i-(3,5-difluoropyridyl:yl)_2-methoxyethyl)_6_(4-fluorohexahydropyridin-1-yl)-N4-(5- Methyl-1H_pyrazole_3_yl)ns cultivating _2,4-diamine, tfa salt using a procedure similar to that described for the synthesis of Example 11 to give (8) each chlorine (3'5-difluoropyridine-2) ))-2-methoxyethyl)_N4 _(5-methyl-exo-pyrazole_3_yl 1,3,5-dipenta-2,4-diamine (intermediate 42, 1 〇〇) Reaction of 4 hexahydropyridine hydrochloride (38.7 mg, 〇.28 mmol) afforded the title compound. 1 H NMR (300 MHz, MeOD) δ ppm 8.39 (s , 1H) 7.55-7.74 (m, 1H) 5.83 (broad s) 1H) 5.66 (t,1H) 3.63-4.29 (m,7H) 3.38 (s, 3H) 2_32 (s, 3H) 1.53-2.11 (m, 4H). LC-MS: 464 [M+H]+ Example 77 (R)-6-(4,4-difluorohexahydrop to bite-l-yl)_n2-(1-(3,5-di) Fluorine u than bit-2-yl)-2 -Methoxyethyl)-indole 4-(5·methyl-lH-p than indole-3-yl)-l,3,5-tri"• Well-2,4-diamine, TFA salt is similar to Example 11 synthesizes the procedure described to give (s) _6_chloro(3,5--fluorop to butyl-2-yl)-2-methoxyethyl)-N4-(5-methyl-lH- p is more than spani-3-yl)-1,3,5-trin-2,4-diamine (intermediate 42,100 mg, 〇25 mmol) and 4,4-difluorohexahydropyridine hydrochloride Reaction of the salt (43_7 mg '0.28 mmol) afforded the title compound.H NMR (300 MHz, MeOD) δ ppm 8.40 (s, 1H) 7.65 (ddd, 1H) 5.85 (s, 1H) 5.68 (t, 1H 3.65-4.21 (m, 4H) 3.42 (s, 3H) 2.33 (s, 3H) 1.81-2.15 (m, 4H). 133151 -222- 200906818 LC-MS : 482 [M+H]+ Example 78 N2- ((R)-l-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl)-6-((2S,6R)-2,6-dimethylmorphinyl )-]\4-(5-methyl-111-1»pyrim-3-yl)-1,3,5-trih-2,4-diamine was prepared using a procedure similar to that described for the synthesis of Example 11, (r)_6_gas_N2-(1_(3,5-difluoropyridin-2-yl)-2-methoxyethyl)_n4-(5-methyl-1H-pyrazol-3-yl )-1,3,5-II 11 Well-2,4-·monoamine (intermediate 42,100 mg, 〇· Reaction with cis- 2,6-dimethylmorpholine (0.034 mL, 0.28 mmol) afforded the title compound. 4 NMR (300 MHz, MeOD) d ppm 8.36 (broad s·, 1H) 7.56 (ddd, 1H) 6.34 (broad s) 1H) 5.51-5.87 (m,1H) 4.53 (d,2H) 3.65-3.91 (m ,2H) 3·42-3.65 (m,2H) 3.35 (s,3H) 2.48 (t,2H) 2_23 (broad s.,3H) l.2〇(d, 6H). LC-MS : 476 [M +H]+ Example 79 (R)-N2-(l-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl)_n4_(5_indolyl-pyrazole-3- Base)-6-(1,4-oxo-nitrogen-7___yl)-1,3,5-trih_2,4-diamine using a procedure similar to that described for the synthesis of Example 11, _6_ gas (3,5-fluoropyridin-2-yl)-2-nonyloxyethyl)_N4 _(5_mercapto_out_pyrazole_3_yl)_ 1,3,5-di The cultivar-2,4-diamine (intermediate 42, 1 mg, 〇 25 mmol) was reacted with oxynitrile decane hydrochloride (38.1 mg, 0.28 mmol) to afford the title compound. 300 MHz, MeOD) 5 ppm 8.36 (s, 1H) 7.47-7.64 (m, 1H) 6.36 (broad S) 1H) 5.66 (broad s) 1H) 3.42-4.12 (m,11H) 3.34 (s, 3H) 2.23 133151 -223 - 200906818 (broad s·, 3H) 1.82-2.00 (m, 2H) 1.72 (broad s·, 1H). LC-MS : 462 [M+H]+ Example 80 N2-(l-(3, 5-difluoro Bite·2_base)_2·曱oxyethyl)_N4 _(s_methyl-mail 嗤-3-yl)_6_?福普林基-i,3,5-三p well-2, 4. Diamine at 6 ° C, 6-chloro-indole 2-(1-(3,5-difluoropyridin-2-yl)_2_decyloxy)-indole 4-(5-mercapto-1Η -pyrazole-3·yl)-oxime, ^3 plough _2,4-diamine (intermediate 41, 653 mg, 1.65 mmol) dissolved in ethanol (2194 ml) with the addition of morphine (5.02) The reaction was stirred at 25 ° C for 1 h. The reaction mixture was concentrated in vacuo to leave a yellow semi solid (1 633 g). MeOH/DCM). Concentrate in vacuo to give the title compound as a white solid ( 610 mg). The column and solvent conditions. Purification column particle size with OJ-3-20: 5 Column size (mm): 21 X 250 Purity after purification Purification: Sample purity conditions (B) and AD-3-20 Confirmation Column size: 4.6 X 1〇〇mm flow rate: 5ml/min first absorption peak (residence time: minute) 0.56 second Peak (residence time: minute) 0.87 Example 80 (8) 'First dissolution peak 133151 -224- 200906818 LC-MS : 448 [M+H]+ Example 80(b), second dissolution peak JH NMR (300 MHz, MeOD) 5 ppm 8.36 (d, 1H) 7.38-7.74 (m, 1H) 6.36 wide s" 0.5H) 5.42-5.88 (m, 1.5H) 3.48-3.98 (m, 10H) 3 34 (s 3H) 2.05- 2.41 (m, 3H). LC-MS: 448 [M+H]+. For the palm compound of the R-p. Example 81 N-(((R)_4-(4-((R)-l-(3,5-difluoropyridine)-2-yl)-2-methoxyethylamino)-6-(5-methyl-1 hydrazide) -pyrazol-3-ylamino)-1,3,5-trin-2-yl)norfosin-3-yl)methyl)indolesulfonamide using a procedure similar to that described for the synthesis of Example 62, (8) Winter gas fractionation (3,5-difluoroρ ratio. deacetyl-2-yl)-2-decyloxyethyl)_n4 -(5-fluorenyl-lH-p ratio. sit-3-yl) · 1,3,5-three tillage-2,4-diamine (intermediate 42 '1 mg, 〇25 mmol) and (R)-N-(moffolin-3-yl fluorenyl) The reaction was continued with the title compound as the title compound. 1 H NMR (300 MHz, MeOD) &lt;5 ppm 8.36 (s, 1H) 7.55 (t, 1H) 6.38 (broad s., 1H) 5.73 (m, 1H) 4.69 (m, 1H) 4.41 (d, 1H ) 4.01 (d, 1H) 3.90 (d, 1H) 3.64-3.85 (m, 2H) 3.37-3.64 (m, 4H) 3.34 (s, 3H) 3.05-3.26 (m, 1H) 2.94 (broad s., 3H) 2.25 (broad s_, 3H). LC-MS: 555 [M+H]+ Example 82 ((R)-4-(4-((R)-l-(3,5-difluoropyridine: yl)) _2_methoxyethylamino)_6_(5-methyl 133151 -225 - 200906818 -lH-p than also 3-ylamino)-l,3,5-three "•-2-yl" Flint-3-yl)ethyl methyl carbamate used a procedure similar to that described for the synthesis of Example 62 to give (s) _6_chloro_N2 (3,5-a chaotic p to 唆-2-yl)- 2-methoxyethyl)_n4-(5-methyl-lH-p than spani-3-yl)_ I,3,5-trin-2,4-diamine (intermediate 42,100 mg, The title compound was obtained by the reaction of EtOAc (m.p., </RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; ]H NMR (300 MHz, MeOD) δ ppm 8.36 (s, 1H) 7.44-7.68 (m, 1H) 6.39 (broad s., 1H) 5.42-5.90 (m, 1H) 4_76 (broad s_, 1H) 4.39 ( Broad s.,1H) 3.39-4.19 (m,10H) 3_34 (s,3H) 3.09-3.26 (m,1H) 2.28 (broad s·,3H) 1.26 (broad s·,3H). LC-MS : 549 [M+H]+ Example 83 N2 -((called 1-(3,5-difluoropyridin-2-yl)_2-methoxyethyl) winter ((2R,6R)_2,6 dimethyl [Nufrinyl)-N4-(5-methyl-1H-pyrazol-3-yl)-1,3,5-trinol-2,4-diamine was prepared using a procedure similar to that described for the synthesis of Example 11, (11)_6_Gas_N2_(1_(3,5-Difluorotomyridin-2-yl)_2-methoxyethyl)_n4_(5-methyl-heparidazole_3_yl)_ 1 , 3,5-two tillage-2,4-diamine (intermediate 42,150 mg, 〇38 mmol) and 2,6-dimethylmorpholine (trans-, cis-mixture) (43.5 mg, 〇38 mmol) Reaction provided the title compound as a mixture of stereoisomers. The isomers were separated by Gilson (NH4OAc/MeOH). a mixture of isomers as a white solid. lU NMR (300 MHz, MeOD) δ ppm 8.36 ( X: ^ s ., 1Η) 7.56 (ddd, 2.35 Hz, 1H) 5.85-6.24 (m, 1H) 5.54-5.79 (m, 1H) 3.63-4.15 (m, 7H) 3.40-3.62 133151 -226- 200906818 (m, 2H) 3.35 (s,3H) 2.23 (s,3H) U7 (broad s.,6H). LC-MS : 476 [M+H]+, accompanied by N2-((R)-l-(3,5-two Fluoridin-2-yl)-2-decyloxyethyl)-6-((2S,6R)-2,6-dimercaptopurine p-linyl)-N4-(5-methyl-1H- Pyrazol-3-yl)-1,3,5-trin-2,4-diamine (Example 78). Column and solvent conditions. Two diastereomers using HPLC separation column: XBridge C18 Column mobile phase: lOmMM^OAc in H2〇 (with 5% MeCN), pH 8, using MeOH, gradient solution 60 to 75%. Column particle size (^): 5 Column size (mm): 19 X 100 Example 84 N2 -((R)-l-(3,5-Difluoropyridin-2-yl)-2-methoxyethyl)_6-((R)-3-(methoxymethyl)? Folinyl)-N4-(5-methyl-1H-pyrazole-3-yl)-l,3,5-trinol-2,4-diamine was prepared using a procedure similar to that described for the synthesis of Example 62. (R)_6_Chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-indole 4-(5-methyl-exo-pyrazol-3-yl )-1,3,5-three tillage-2,4-diamine (intermediate 42,0. 207 g, 0.52 mmol, reacted with (R)-3-(decyloxymethyl)morpholine (intermediate 5 〇, 〇 76 g, 〇 % mmol) to afford the title compound. LC-MS: 493 [Μ]+················· ), 4.29 (m, 1H), 3.90 (m, 1H), 3.78 (m, 1H), 3.69 (m, 1H), 3.64 (m, 2H), 3.36 (m, 2H), 3.27 (m, 1H) , 3.21 (s, 3H), 3.98 (m, 1H), 2.12 (s, 3H). 133151 -227- 200906818 (8)-6-butoxy-la (1-(3,5-difluoropyridine_2_) Base)_2_methoxyethyl)_N4_(5-decyl-1H-pyrazol-3-yl)-1,3,5-trin-2,4-diamine is isolated as a by-product. 1 H NMR (MeOD) 5 8.25 (s, 1H), 7.47 (t, 1H), 5.61 (m, 1H), 4.17 (m, 2H), 3.69 (m, 2H), 3.26 (m, 3H), 3.24 (s, 3H), 2.17 (d, 3H), 1.59 (m, 2H), 1.35 (m, 2H), 0.85 (t, 3H). LC-MS: 493 [M+H]+. Example 85 6- ((S)-3-(Difluoromethyl)morpholinefluoropyridine-2-yl)_2_methoxyethyl)-N4-(5-methyl-1Η-pyrazol-3-yl)-1 , 3,5-three tillage _2,4-diamine using a procedure similar to that described for the synthesis of Example 62, giving (foot) _6_chloro_N2 _(l (3,5-difluoropyridin-2-yl) -2-decyloxyethyl)_n4-(5-methyl-1H-pyrazol-3-yl)-1,3,5-dimorph-2,4-diamine (intermediate 42'〇.188 </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; LC_MS : 498 [Μ+Η]+. 1 H NMR (MeOD) 5 8.32 (s, 1H), 7.51 (t, 1H), 6.20 (m, 1H), 5.60 (m, 1H), 4.78 (m, 1H) ), 4.47 (m, 1H)5 4.10 (d, 1H), 3.90 (m, 1H), 3.75 (m, 1H), 3.68 (m, 1H), 3.55 (m, 1H), 3.47 (m, 1H) , 3.25 (s, 3H), 3·19 (m, 1H), 2.20 (broad s, 3H). Example 86 (R)-N2-(5-cyclopropyl-1H-pyrazol-3-yl)- N4-(l-(3,5-Difluoropyridin-2-yl)_2-methoxyethyl)·6-norfosolinyl-1,3,5_three tillage _2,4-diamine (R)-6-chloro-N2-(5-cyclopropyl-lH-p than quaternary-3-yl)-N4-(l-(3,5-difluoro? ratio: 1,4-yl)- 2-methoxyethyl)-us three tillage _2,4_diamine (intermediate 55, 2〇1 135151 -228· 200906818 g, 0_48 mmol) dissolved in ethanol (ο · ml), And add morphine (145 〇 ml ' 16.64 mmol). The reaction mixture was stirred at 25 ° C for 1 hour. The reaction mixture was then concentrated in vacuo to leave a clear semi-solid (4 EtOAc). This material was purified by ISCO (2-10% MeOH / DCM). The title compound was obtained as a white solid (194.5 mg). 1 H NMR (300 MHz, MeOD) (5 ppm 8.35 (broad s·, 1H) 7.45-7.63 (m, 1H) 6.29 (broad s) 1H) 5.31-5.89 (m,1H) 3.52-3.94 (m,11H ) 3.34 (s, 3H) 1.87 (broad s·, 1H) 0.93 (broad s·, 2H) 0.69 (broad s., 2H)· LC-MS : 474 [M+H]+ Example 87 N2-(1- (3,5-Difluoropyridin-2-yl)-2-ethoxyethyl)-N4-(5-methyl-1H-pyrazol-3-yl)-6-? 1,3,5_three tillage-2,4-diamine in a 100 ml round bottom flask, adding 6-gas-N2-(1-(3,5-difluoropyridine) in ethanol (974 μl) 2-yl)-2-ethoxyethyl)-N4-(5-fluorenyl-1H-pyrazol-3-yl)-1,3,5-trinol-2,4-diamine (intermediate 60 , 200 mg, 〇_49 mmol) with morphine (42. 4 μl, 0.49 mmol), a yellow solution was obtained. The solution was stirred at this temperature for 3 hours at this time under reduced pressure. Evaporation of volatiles. Purification by column chromatography (ISCO, 5% - 10% MeOH / DCM) to afford N2-(1 - (3,5-difluoropyridin-2-yl)-2-ethoxy _N4-(5-Methyl-1H-pyrazol-3-yl)-6-morpholinyl-1,3,5-trinol-2,4-diamine (61_0 mg, 27.2%), For the palm of the isomer 1H NMR (300 MHz, MeOD) δ ppm 1.17 (t, J = 7.06 Hz, 3H) 2.34 (s, 3H) 3.57 (q, J - 7.10 Hz, 2H) 3.65-4.04 (m, 10H) 5.68 (t, J = 6.59 Hz, 1H) 5.86 (broad s., 1H) 7_64 (ddd, J = 9.80, 8.67, 2.26 Hz, 1H) 8·41 (d, J = 2.26 Hz, 133151 -229- 200906818 1H LC-MS · 462 [M+H]+ Column and solvent conditions The title compound is used in two conditions. (A) and OJ-3-20 Separation column particle size (β: 5 tubes) Column size (mm): 21 X 250 Purity test purity after purification. Conditions of use (Β) and OJ-3-20 confirmed 1 column particle size 〇): 5 Column size (mm): 4.6 X 250 Dissolution time : 15 min first absorption peak (residence time: minute) 2.1 〇 second absorption peak (residence time: minute) 3.43 Example 87 (a), first dissolving peak 4 NMR (300 MHz, MeOD) &lt;5 Ppm 1.13 (t, J = 6.97 Hz, 3Η) 2.28 (width #广s) 3H) 3.45-3.92 (m,12H) 5.46-5.88 (m, 1H) 6·37 (broad s.,1H) \ 7.38- 7.75 (m, 1H) 8.38 (s, 1H) Example 87(b), second dissolved peak 4 NMR (300 MHz, MeOD) δ ppm 1.13 (t, J = 6.97 Hz, 3H) 2·28 (broad s·, 3H) 3.45-3,92 (m,12H) 5.46-5.88 (m, 1H) 6·37 (broad s., 1H) 7.38- 7.75 (m, 1H) 8.38 (s, 1H) Example 88 2S-l-(5-Fluoropyridin-2-yl)-1-(4-(5-fluorenyl-1H-pyrazol-3-ylamino)-6- Tropoline 1,3,5-tri, well-2-yloxy)propan-2-ol hydrochloride, palmate isomer (A) 133151 -230- 200906818 4-chloro-indole- (5-methyl-1H-pyrazole _3·yl)_6•norfosolinyl-, 3,5_three tillage _2_amine (intermediate 15,66.3 mg, 0.22 mmol) and 28_2 ( Tert-Butyldimethylmercaptooxy)-1-(5-fluoropyridine-2-yl)propanol-ol (Intermediate 8S (Aa), 64 g, 0.22 mmol) In tBuOH (2 ml), add ^ plus ^ 1^ (431 mg, 0.45 mmol). The reaction was then stirred at 25 &lt;&gt;c overnight. LC/MS showed only 18% conversion to product, so another equivalent of sodium tris-butoxide was added and the reaction was stirred again at 25 °C overnight. The reaction mixture was then concentrated in vacuo to leave a pale white solid (191 mg). This material was purified by ISCO (80-100% EtOAc/hexanes). The fraction was concentrated in vacuo to give abronic oil (51 mg). This material was dissolved in Me 〇H (丨 ml) and 4M HCl (0.093 mL, 〇 _ 37 mmol) in dioxin. The reaction was then stirred at 25 C for 2 hours. The reaction mixture was concentrated in vacuo to leave a clear oil. The title compound was obtained as a white solid (17·5 mg). NMR (300 MHz, MeOD) &lt;5 ppm 8.28-8.60 </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; (m, 1H) 7.39-7.79 (m, 2H) 6.17 (broad s) 1H) 5.67-5.95 (m, 1H) 4.09-4.37 (m, 1H) 3.42-3.94 (m,8H) 2.26 (s, 3H) 1.03-1.50 (m, 3H). LC-MS: 431 [M+H]+ Example 89 2S-1_(5-fluoropyridin-2-yl) small (4-(5-methyl-1H-pyrazole) -3-ylamino)-6·morpholinyl-1,3,5-trinol-2-yloxy)propan-2-ol hydrochloride, used for palmo isomer (9) Similar to Example 88 The procedure described was carried out to give 4-chloro-indole-(5-methyl-1 Η-pyrazol-3-yl)-6-morpholinyl-l,3,5-trin-2-amine (middle 15,06.3 mg '0.22 mmol> and 2S-2-(tris-butyldidecylfluorenyloxy) small (5_133151-231 · 200906818 fluoro-P-Bitter-2-yl)-C- 1-Alcohol (Intermediate 85(b), 64 mg, 〇 _22 mmol) reaction afforded the title compound H NMR (300 MHz, MeOD) δ ppm 8.31-8.57 (m, 1H) 7.42-7.77 (m , 2H) 6.24 (broad s·, 1H) 5.79 (d, 1H) 4.21 (dq, 1H) 3.45-3.96 (m 8H) 2.26 (s, 3H) 1.36-1.50 (m, 3H). LC-MS: 431 [M+H]+ Example 90 N2 -(2-Ethoxy-1-(5-gas-based, than bite_ 2_yl)ethyl)_N4 _(5_fluorenyl-mpyrazole each)-6-folinin-i,3,5-tripentene-2,4-diamine in 6-chloro-N2 -(2-ethoxyoxy_ι_(5-fluoropyridine-2-yl)ethyl)_N4_(5-methyl-1H-H3-yl)-1,3,5-three tillage_2,4_ To a solution of the diamine (intermediate 90, 〇 452 g, i 15 mmol) in ethanol (2.300 mL), add florin (3 〇 1 mL, 34.50 mmol). Stir at ambient temperature for 3 hours. Evaporate the volatile material under reduced pressure to give a yellow residue. m. m. m. a mixture of isomers LC-MS: 444 [M+H]+. lH No. 1 (fine hemp, Me0D) ^ PPm 1.15 (t,3H) 2_25 (s,3H) 3.43-3.90 (m, 12H) 5.12 -5.42 (m, 1H) 5.60 (s, 1H) 7.37-7.77 (m, 2H) 8.48 (s, 1H) Column and solvent conditions ' Title compound is used for conditions of use (A) and AD_3_4〇 for palm purification tubes Column Particle Size (#): 5 Column Size (mm): Purity test after purification of 19 X 1〇〇 133151 -232- 200906818 Sample purity is determined by using conditions (B) and AD-3-40. Column particle size (〆): 5 Column size (mm)·· 4.6 X 100 First absorption peak (residence time: minute) 0.97 Second absorption peak (residence time: minute) 2.13 Example 90 (8), first dissolution peak 1 H NMR (300 MHz, MeOD) δ ppm 1.16 (t, J = 7.06 Hz, 3H) 2.25 (s, 3H) 3.46-3.98 (m, 12H) 5.19-5.41 (m, 1H) 5.48-6.50 (m, 1H) 7.35-7.76 (m, 2H) 8.42 (s, 1H). 90(b), second dissolved peak 1 H NMR (300 MHz, MeOD) δ ppm 1.05 (t, J - 6.97 Hz, 3H) 2.14 (s, 3H) 3.36-3.81 (m, 12H) 5.03-5.26 ( m, 1H) 5.42-6.44 (m, 1H) 7.30-7.66 (m, 2H) 8.31 (s, 1H). Example 91 (l-(4-((S)-l-(5-gas-based p-biting) -2-yl)ethylamino)-6-(5-methyl-lH-i*pyran-3-ylamino)-1,3,5-trian-2-yl)hexahydropyridine_2 _ base)methanol to (S)-6-chloro-N2-(l-(5-aylpyridin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl) -1,3,5-three tillage-2,4-diamine (intermediate 16,222 mg, 0.64 mmol) in EtOH (1061 μl) with n-Bu To the solution in OH (1061 μl), hexahydro sigma-2-yl sterol (73.3 mg, 0.64 mmol) and DIPEA (111 μL, 0.64 mmol) were added. The resulting mixture was heated to i 〇〇 ° c for ι 6 hours. The volatiles were evaporated under reduced pressure to give a yellow residue. The title compound (191 mg, 70.2%). 133151 -233 - 200906818 LC-MS : 428 [M+H]. ^ NMR (300 MHz, MeOD) δ ppm 1.41 (d, J = 6.97 Hz, 3H) 1.44-1.61 (m, 4H) 1.63-1.86 (m , 1H) 2.12 (s, 3H) 2.51-2.84 (m, 1H) 3.46-3.74 (m, 2H) 4.27-4.59 (m, 2H) 4.70-4.80 (m, 1H) 4.96-5.23 (m, 1H) 6.28 (s, 1H) 7.17-7.74 (m, 2H) 8.27 (s, 1H) Example 92 ((S)-4-(4-((S)-l-(5-fluoropyridin-2-yl)) Amino) 6-(5-methyl-1H-pyrazol-3-ylamino)-1,3,5-trin-2-yl)norfolin-3-yl)methanol was used similarly to Example 91 The procedure described is carried out such that (5)_6_chloro_N2_(丨_(5_fluoroylpyridinyl)-2-yl)ethyl)-&gt;14-(5-mercapto-111-1) than saliva-3 -yl)-1,3,5-tri' (*well-2,4-diamine (intermediate 16 '200 mg, 0.57 mmol) and (S)-morpholin-3-ylmethanol (73 · 9 mg, 0.63 mmol, provided the title compound. 1H NMR (300 MHz, MeOD) &lt;5 ppm 8.37 (broad s., 1 Η) 7.28-7.70 (m, 2 Η) 6.03 (broad s) 1H) 5.16 (q, 1H) 4.17-4.69 (m,2H) 4_08 (d,1H) 3·87 (m, 2H) 3.36-3.71 (m,2H) 2.77-3.19 (m,2H) 2.19 (s, 3H) 1.54 (d, 3H). LC-MS : 430 [M+H]+ Example 93 ((R)-4_(4-((S)-l-(5-Gas-based bite_2_yl)ethylamino)_6·(5·methyl·ιη-ι»比吐-3 -ylamino)-1,3,5-trimorph-2-yl)norfolin-3-yl)methanol was prepared using a procedure similar to that described for the synthesis of Example 91 to give (5) -6-chloro-indole 2-(1-( 5-Fluoroindole 11-denyl-2-yl)ethyl)-1&lt;! 4-(5-fluorenyl-11&quot;1-3 ratio. -3-yl)-1,3,5-tri'1 Well-2,4-diamine (intermediate 16,200 mg, 0.57 mmol) was reacted with (R)·norfosolin-3-ylmethanol hydrochloride (97 mg '0.63 mmol) to provide the title Compound 1 H NMR (300 MHz, MeOD) &lt; 5 ppm 8.37 (broad s·, 1H) 7.32-7.70 (m, 2H) 133151 - 234 - 200906818 5.87-6.69 (m, 0.5H) 5.58 (broad s· , 0.5H) 5.15 (q,1H) 4.18-4.74 (m,2H) 4.04 (d, 1H) 3.72-3.97 (m, 2H) 3.35-3.72 (m, 2H) 2.72-3.21 (m5 2H) 2.23 (wide) s·, 3H) 1.51 (d,3H). LC-MS : 430 [M+H]+ Example 94 2-(4-(4-((S)-l-(5-fluoro-p-bit-2) _yl)ethylamino)-6-(5-methyl-lH-p than gorge-3-ylamino)-l,3,5-trin-2-yl)norfolin-3-yl) Methyl acetate in a 250 ml round bottom flask with EtOH (2867 μl (S)-6-Chloro-N2-(l-(5-fluorop-p-but-2-yl)ethyl)-N4-(5-methyl-lH-p than spani-3-yl) -l,3,5-three tillage-2,4-diamine (intermediate 16,300 mg, 0·86 mmol) and methyl 2-(morpholine-3-yl)acetate (137 mg, 0.86 m Mohr), and got a yellow solution. The resulting mixture was heated at 100 ° C for 12 hours. The volatile matter was evaporated under reduced pressure to give an oil. Purification by column chromatography (EtOAc, EtOAc /EtOAc) LC-MS: 472 [M+H] + EXAMPLE 95 2-(4-(4-((S)-l-(5-Fluoro-p-bito-2-yl)ethylamino)-6-(5 - mercapto-lH-p than jun-3-ylamino)-1,3,5-tripent-2-yl)), p-lin-3-yl)ethanol in 2-(4-(4-( (S)-l-(5-fluoropyridin-2-yl)ethylamino)_6_(5-methyl-iH-ppyrazol-3-ylamino)-1,3,5-three tillage- 2-Benzyl)fosfolin-3-yl)acetate (Example 94, 200^: gram, 0·42 house mole) in a solution of tetrahydroanthracene π (1.4 ml) in hydrazine. (The following was added dropwise LiBH4 (636 μl, 1.27 mmol) in THF; gluten solution. After the gas evolution ceased, the resulting mixture was stirred at ambient temperature for 1 hour. To (TC, and slowly add MeOH (Note 133151 - 235 - 200906818 means: exotherm) to quench excess LiBH4. Evaporate the volatiles under reduced pressure and leave the residue in Et0Ac. The organic phase was washed with H.sub.2 H.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss ((s)-l-(5_Fluomeidin-2-yl)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)"^^^^^ (R) oxaline-3-yl)ethanol (80 mg, 42·5 ° / 〇) 'is a mixture of diastereomers. lR NMR (300 MHz, DMSO-d6) δ ppm 1.44 (d, 6H ) 1.67-1.94 (m, 4H) 2.15 (s, 6H) 2.73-4.83 (m, 18H) 5.75-6.58 (m, 2H) 7.20-7.96 (m, 4H) 8.49 (s, 2H) 9.13 (s, 1H) </ RTI> <RTIgt; _methyl_1H_pyrazole_3_ base Base)-l,3,5-three tillage_2_base)-nitrogen tetra-ring_3-alcohol using a procedure similar to that described in Example 11 synthesis, such that (8)_6_chloro_N2 _(丨_(5_ Fluoropyridinium ratio α-di-2-yl)ethyl)-N4-(5-methyl-lH-p-p--3-yl)-l,3,5-tripentene-2,4-diamine (middle The title compound was obtained by the reaction of <RTI ID=0.0># </RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -8.60 (m, 1H) 7.34-7.73 (m, 2H) 6.06 (broad s·, 1H) 5_17 (q,1H) 4.61 (m,1H) 3.97-4.40 (m, 2H) 3.58-3.96 (m, 2H) ) 2.23 (s, 3H) 1.51 (d, 3H). LC-MS: 386 [M+H] + s. 97 (S)-N2-(l-(3,5-difluoropyridin-2-yl) Base)·6_(2,2_dimercapto-florinyl)-N4- 133151 •236. 200906818 (5-methyl-1Η-pyrazol-3-yl)-i,3,5-three tillage- 2,4_diamine

於乙醇（1毫升）中之⑻_6_氯冰_(1_(3,5_二氟吡啶_2_基）乙 基）-N4-(5-甲基-1H-吡唑-3-基）-1，3,5-三畊-2,4-二胺（中間物92， 100毫克’ 0.27毫莫耳）内，添加2,2_二甲基嗎福啉鹽酸鹽（45.5 毫克，0_30毫莫耳）與DIPEA (0.143毫升，0.82毫莫耳）。將反 應混合物在室溫下攪拌過夜。使粗製反應混合物於減壓下 濃縮’並在ISCO系統上直接純化（0_2% Me〇H，0.2% NH4OH 在DCM中），獲得所要之產物，ι〇6毫克，為白色固體。 LC-MS ： 446 [M+H]+. 1 H NMR (400 MHz, MeOD) &lt;5 ppm 8.22 (s, 1H) 7.44 (t, J = 8.46 Hz, 1H) (吡唑 C-4 並非極為可見）5.35 (m，iH) 3 6〇 (d, j = 6·57 Hz, 2H) 3.43-3.55 (m, 4H) 2.13 (s, 3H) 1.40 (d, J = 6.57 Hz, 3H) 1.12 (m, 3H) 0.93 (s, 3H). 實例98 N2-((S)-l-(3,5-二氟吡啶-2-基）乙基)-6-((2S,6R)-2,6-二甲基嗎福啉 基）-N4 -(5-甲基-1H-吡唑-3-基）-l，3,5-三畊-2,4-二胺 使用類似關於實例97合成所述之程序，使（S)-6-氣 -N2-(1-(3,5-二氟吡啶-2-基）乙基）-N4-(5-曱基-1H-吡唑-3-基）-1,3,5-三畊-2,4-二胺（中間物92)與順式-2,6-二曱基嗎福啉反應，提 供標題化合物，為白色固體。 LC-MS ： 446 [M+H]+. 4 NMR (400 MHz，MeOD) 5 ppm 8.33 (s，1H) 7.52-7.59 (m，1H)(吡 唑 C-4'並非顯而易見）4_53 (m，2H) 3.58-3.68 (m，1H) 3.55 (m，1H) 2.87 (d, 2H) 2.42 (m, 2H) 2.25 (s, 3H) 1.16-1.22 (m, 6H) 1.13 (d, 3H) 133151 •237· 200906818 實例99 (S)-N2 -(l-(3,5-二氟吡啶_2_基）乙基）_N4 _(5甲基_m吡唑_3基）冬 (1，4_氧氣七園·4·基）-i，3,5-三p井·2,4-二胺 使用類似關於實例97合成所述之程序，使⑻_6_氯 -N2-(1-(3,5c 敦峨咬 _2·基）乙基）_Ν4_(5_甲基-1Η_吡唑 _3_基 η，3,5· 三畊-2,4-二胺（中間物92)與丨，4_氧氮七圜烷鹽酸鹽反應，提供 標題化合物，為白色固體。 LC-MS ： 432 [Μ+Η]+. !H NMR (400 MHz, MeOD) ¢5 ppm 8.22 (s, 1H) 7.39-7.48 (m, 1H) ( 唑 C-4’ 並非顯而易見）5 35 (m，3 J3 (m，邱 3 &amp; 扣，2H) 3 52_ 3.63 (m, 3H) 2.13 (s, 3H) 1.81 (m, 2H) 1.40 (d, J = 6.57 Hz, 3H). 實例100 4-[l-(3,5-二氟峨咬_2_基)-2-甲氧基乙氧基】_N_(5_甲基_m_吡唑各 基)-6-嗎福淋-4·基-1，3,5·三味·2·胺 使第二-丁醇鈉（5〇8毫克，5.29毫莫耳）溶於t_Bu〇H (13毫升） 中，並將所形成之落液在6〇它下加熱，接著添加丨_(3,5_二氟 叶匕咬-2-基）-2-曱氧基乙醇（中間物ι〇8，500毫克，2 64毫莫 耳）。於攪拌30分鐘後，使混合物冷卻至環境溫度，且添加 4-氯-N-(3-甲基-1H-吡唑-5-基）-6-嗎福啉基-us三畊_2_胺（中間 物15 ’ 782毫克，2.64毫莫耳）。將溶液在室溫下擾拌過夜。 瘵發揮發性物質，獲得殘留物，使其藉ISC〇純化（〇_1〇% MeOH/DCM) ’而得標題化合物（75〇毫克），為對掌異構物之 混合物。 ^ NMR (300 MHz, MeOD) &lt;5 ppm 8.37 (s, 1H) 7.63 (t, 1H) 6.31 (s, 1H) 133151 -238- 200906818 4.00 (t, 1H) 3.62-3.82 (m, 10H) 3.41 (s, 3H) 2.29 (s, 3H). LC-MS ： 449 [M+H]+ 管柱與溶劑條件 標題化合物係使用條件（A)與OJ-3-20進行對掌性純化 管柱粒子大小（#) : 5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗： 試樣純度係使用條件（B)與OJ-3-20確認 管柱尺寸：4.6 X 100毫米 偵測：220毫微米 第一個吸收峰（滞留時間：分鐘）1.14 第二個吸收峰（滞留時間：分鐘）1.65 實例100(a)，第一個溶離峰 NMR (300 MHz, MeOD) δ ppm 8.37 (s, 1H) 7.63 (t, 1H) 6.31 (s, 1H) 4.00 (t, 1H) 3.62-3.82 (m, 10H) 3.41 (s, 3H) 2.29 (s, 3H). LC-MS : 449 [M+H]+ 實例100(b)，第二個溶離峰 1H NMR (300 MHz, MeOD) δ ppm 8.37 (s, 1H) 7.63 (t, 1H) 6.31 (s, 1H) 4.00 (t, 1H) 3.62-3.82 (m, 10H) 3.41 (s, 3H) 2.29 (s, 3H). LC-MS : 449 [M+H]+ 實例101 2,2-二氟-3-(5-氟基吡啶-2-基）-3-({4-[(5-甲基-1H-吡唑-3-基）胺 基]-6-嗎福ρ林-4-基-1，3,5_二'•井_2-基}胺基）丙-1-醇 使用類似關於實例11合成所述之程序，使3-(4-氯基-6-(3- 133151 -239 - 200906818 甲基-1H-吡唑-5-基胺基）-1,3,5-三畊-2-基胺基）_2,2-二氟 基吡啶-2-基）丙-1-醇（中間物117，466毫克，1.12毫莫耳）與嗎 福啉反應，提供標題化合物，為對掌異構物之混合物。 !H NMR (300 MHz, MeOD) δ ppm 8.52 (s, 1H) 7.62-7.71 (m., 2H) 5.98 (t5 1H) 5.89 (s, 1H) 3.65-3.91 (m, 10H) 2.35 (s, 3H). LC-MS ： 466 [M+H]+ 管柱與溶劑條件 標題化合物係使用條件（A)與AD-3-30進行對掌性純化 管柱粒子大小（μ): 5 管柱尺寸（毫米）：21 X 250 實例101(a)，第一個溶離峰 !H NMR (300 MHz, MeOD) &lt;5 ppm 8.52 (s, 1H) 7.62-7.71 (m., 2H) 5.98 (t, 1H) 5.89 (s, 1H) 3.65-3.91 (m, 10H) 2.35 (s, 3H). LC-MS : 466 [M+H]+. 實例101(b)，第二個溶離峰 ^ NMR (300 MHz, MeOD) &lt;5 ppm 8.52 (s, 1H) 7.62-7.71 (m., 2H) 5.98 (t, 1H) 5.89 (s, 1H) 3.65-3.91 (m, 10H) 2.35 (s, 3H). LC-MS : 466 [M+H]+. 實例102 3-(5-氟基吡啶-2-基）-3-({4-[(5-甲基-1H-吡唑-3-基）胺基]-6-嗎福 p林-4-基-1,3,5-三p井-2-基}胺基）丙酿胺 使用類似關於實例11合成所述之程序，使3-(4-氯基-6-(3-曱基-1H-吡唑-5-基胺基）-1,3,5-三畊-2-基胺基）-3-(5-氟基吡啶-2-基）丙醯胺（中間物118)與嗎福啉（2毫升）反應，提供標題化 133151 -240- 200906818 合物，為對掌異構物之混合物。 1 H NMR (300 MHz, MeOD) δ ppm 8.47 (s, 1H) 7.48-7.64 (m., 2H) 5.86 (寬廣 s，1H) 5.66 (t, 1H) 3.65-3.89 (m, 8H) 2.91-2.95 (m, 2H) 2.33 (s， 3H). LC-MS : 443 [M+H]+ 管柱與溶劑條件 標題化合物係使用對掌性HPLC進行對掌性分離 管柱：Chirapak AD 4 尺寸：250 X 20 毫米，10 // 流動相：50%己烷，50%異丙醇，0.1%二乙胺（v/v/v) 流率（毫升/分鐘）：20 偵測（毫微米）：220 實例102⑻，第一個溶離峰 NMR (300 MHz, MeOD) 5 ppm 8.47 (s, 1H) 7.48-7.64 (m., 2H) 5.86 (寬廣 s，1H) 5_66 (t, 1H) 3.65-3.89 (m, 8H) 2.91-2.95 (m，2H) 2_33 (s， / 3H). \ LC-MS ： 443 [M+H]+ 實例102(b)，第二個溶離峰 !Η NMR (300 MHz, MeOD) δ ppm 8.47 (s, 1H) 7.48-7.64 (m., 2H) 5.86 (寬廣 s, 1H) 5.66 (t，1H) 3.65-3.89 (m, 8H) 2.91-2.95 (m，2H) 2.33 (s, 3H). LC-MS ： 443 [M+H]+ 實例103 N-[(lS)-l-(5-氟基嘧啶-2-基）乙基]-6-嗎福啉-4-基-N’-[5-(2-苯基乙 133151 •241 - 200906818 基比咕-3-基】-1，3,5-三喷_2,4_二胺 使用類似關於實例:α合成所述之程序，使（sh_氯格(吵 敦基嘯咬-2-基）乙基）抓(3_苯乙n比嗤_5_基）七$三呼 -2,4-二胺（中間物:UO’M克，αΐ6毫莫耳）與嗎福料毫 升，23.0毫莫耳）反應’提供標題化合物。 1H NMR (300 MHz，MeOD) (5 ppm 8.71 (s 2m 7 】m 、，2H) 7.15-7.28 (m, 5H) 5.50 (q，1H) 3.61-3.74 (m，8H) 2.58-3.02 (m，4H) 1.58 (d，3H) LC-MS ： 491 [M+H]+ 實例104 6-(3-乙基嗎福琳·4_基）_N_[⑽小(5_氟基嘧啶_2基）乙基】_N，你 甲基-1H-吡唑-3-基）-1,3,5-三畊-2,4-二胺 使用類似關於實例62合成所述之程序，使⑹_6_氣_N2 _(1_(5_ 氟基嘧啶-2-基）乙基）-N4-(3-甲基-出_吡唑-5-基）_1，3,5_三畊_2 4 二胺（中間物17 , 200毫克，0.57毫莫耳）與3_乙基嗎福啉鹽酸 鹽（87毫克，0.57毫莫耳）反應，提供標題化合物，為非對映 異構物之混合物。 NMR (300 MHz, MeOD) &lt;5 ppm 8.76 (s，2H) 5.89 (寬廣 s, 1H) 5.32 (q, 1H) 3.61-4.43 (m, 2H) 3.21-3.86 (m, 5H) 2.34 (s, 3H) 1.80-2.02 (m, 2H) 1.64 (d, 3H) 1.39 (t, 3H). LC-MS ： 429 [M+H]+. 管柱與溶劑條件 標題化合物之非對映異構物係使用對掌性HPLC分離(8)_6_Chlorine ice-(1_(3,5-difluoropyridin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl)- in ethanol (1 ml) 1,3,5-three tillage-2,4-diamine (intermediate 92, 100 mg '0.27 mmol), 2,2-dimethyl morpholine hydrochloride (45.5 mg, 0-30 ml) Mohr) with DIPEA (0.143 ml, 0.82 mmol). The reaction mixture was stirred at room temperature overnight. The crude reaction mixture was concentrated EtOAc EtOAc (EtOAc) LC-MS: 446 [M+H]+. 1 H NMR (400 MHz, MeOD) &lt;5 ppm 8.22 (s, 1H) 7.44 (t, J = 8.46 Hz, 1H) (pyrazole C-4 is not extremely Visible) 5.35 (m, iH) 3 6〇 (d, j = 6·57 Hz, 2H) 3.43-3.55 (m, 4H) 2.13 (s, 3H) 1.40 (d, J = 6.57 Hz, 3H) 1.12 ( m, 3H) 0.93 (s, 3H). Example 98 N2-((S)-l-(3,5-difluoropyridin-2-yl)ethyl)-6-((2S,6R)-2, 6-Dimethylmorpholino)-N4-(5-methyl-1H-pyrazol-3-yl)-l,3,5-trinol-2,4-diamine was synthesized analogously to Example 97. The procedure described is such that (S)-6-gas-N2-(1-(3,5-difluoropyridin-2-yl)ethyl)-N4-(5-mercapto-1H-pyrazole-3 -1,3,5-Tricotin-2,4-diamine (Intermediate 92) was reacted with cis-2,6-dimercaptophyrin to afford the title compound as a white solid. LC-MS: 446 [M+H]+. 4 NMR (400 MHz,MeOD) 5 ppm 8.33 (s,1H) 7.52-7.59 (m,1H) (pyrazole C-4' is not obvious) 4_53 (m, 2H) 3.58-3.68 (m,1H) 3.55 (m,1H) 2.87 (d, 2H) 2.42 (m, 2H) 2.25 (s, 3H) 1.16-1.22 (m, 6H) 1.13 (d, 3H) 133151 • 237· 200906818 Example 99 (S)-N2 -(l-(3,5-Difluoropyridin-2-yl)ethyl)_N4 _(5 methyl_mpyrazole-3-yl) Winter (1,4_ Oxygen seven gardens · 4 · base) -i, 3,5-tri-p well · 2,4-diamine using a procedure similar to that described in Example 97 synthesis, such that (8)_6_chloro-N2-(1-(3,5c)峨 峨 · · · _2 _2 _2 _2 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 4 4 4 4 4 4 4 4 Reaction of oxazolidine decane hydrochloride afforded the title compound as a white solid. LC-MS: 432 [Μ+Η]+. !H NMR (400 MHz, MeOD) ¢5 ppm 8.22 (s, 1H) 7.39 -7.48 (m, 1H) (azole C-4' is not obvious) 5 35 (m,3 J3 (m, Qiu 3 &amp; buckle, 2H) 3 52_ 3.63 (m, 3H) 2.13 (s, 3H) 1.81 ( m, 2H) 1.40 (d, J = 6.57 Hz, 3H). Example 100 4-[l-(3,5-Difluorobite-2-yl)-2-methoxyethoxy]_N_(5 _methyl_m_pyrazole - 6- oxafluran-4-yl-1,3,5·three-flavors·2·amines solubilized sodium 2-butoxide (5〇8 mg, 5.29 mmol) in t_Bu〇H (13 ml) Medium, and the resulting liquid is heated under 6 Torr, followed by the addition of 丨_(3,5-difluorophyllin-2-yl)-2-methoxyethanol (intermediate ι〇8,500 Mg, 2 64 mmol. After stirring for 30 minutes, the mixture was allowed to cool to ambient temperature and 4-chloro-N-(3-methyl-1H-pyrazol-5-yl)-6-? Phytyl-us three-tillage __amine (intermediate 15 '782 mg, 2.64 mmol). The solution was scrambled overnight at room temperature. Volatile matter was obtained and the residue was obtained and purified by ISC. (〇_1〇% MeOH/DCM) 'The title compound (75 mg) was obtained as a mixture of ss.. NMR (300 MHz, MeOD) &lt;5 ppm 8.37 (s, 1H) 7.63 ( t, 1H) 6.31 (s, 1H) 133151 -238- 200906818 4.00 (t, 1H) 3.62-3.82 (m, 10H) 3.41 (s, 3H) 2.29 (s, 3H). LC-MS : 449 [M+ H]+ Column and Solvent Conditions Title Compounds Conditions for use (A) and OJ-3-20 for palmar purification Column particle size (#): 5 Column size (mm) 21 X 250 Purity test after purification: Sample purity is determined by using conditions (B) and OJ-3-20. Column size: 4.6 X 100 mm Detection: 220 nm first absorption peak (residence time: minute) 1.14 Second absorption peak (residence time: minute) 1.65 Example 100 (a), first dissolution peak NMR (300 MHz, MeOD) δ ppm 8.37 (s, 1H) 7.63 (t, 1H) 6.31 (s, 1H) 4.00 (t, 1H) 3.62-3.82 (m, 10H) 3.41 (s, 3H) 2.29 (s, 3H). LC-MS : 449 [M+H]+ Example 100(b), second dissolved peak 1H NMR (300 MHz, MeOD) δ ppm 8.37 (s, 1H) 7.63 (t, 1H) 6.31 (s, 1H) 4.00 (t, 1H) 3.62-3.82 (m, 10H) 3.41 (s, 3H) 2.29 (s , 3H). LC-MS: 449 [M+H] + Example 101 2,2-difluoro-3-(5-fluoropyridin-2-yl)-3-({4-[(5-methyl) -1H-pyrazol-3-yl)amino]-6-rhofolin-4-yl-1,3,5-di'•well_2-yl}amino)propan-1-ol The procedure described in the synthesis of Example 11 was carried out to give 3-(4-chloro-6-(3- 133151 -239 - 200906818 methyl-1H-pyrazol-5-ylamino)-1,3,5-tri Plant-2-ylamino) 2,2-difluoropyridin-2-yl)propan-1-ol (intermediate 117, 466 mg, 1.12 mmol) and The reaction morpholine to provide the title compound as a mixture of isomers of the palm. !H NMR (300 MHz, MeOD) δ ppm 8.52 (s, 1H) 7.62-7.71 (m., 2H) 5.98 (t5 1H) 5.89 (s, 1H) 3.65-3.91 (m, 10H) 2.35 (s, 3H) LC-MS : 466 [M+H]+ Column and Solvent Conditions The title compound is used for the purification of the column particle size (μ) using conditions (A) and AD-3-30: 5 column size ( Mm): 21 X 250 Example 101(a), first dissolved peak! H NMR (300 MHz, MeOD) &lt;5 ppm 8.52 (s, 1H) 7.62-7.71 (m., 2H) 5.98 (t, 1H 5.89 (s, 1H) 3.65-3.91 (m, 10H) 2.35 (s, 3H). LC-MS: 466 [M+H]+. Example 101(b), second elution peak NMR (300 MHz) , MeOD) &lt;5 ppm 8.52 (s, 1H) 7.62-7.71 (m., 2H) 5.98 (t, 1H) 5.89 (s, 1H) 3.65-3.91 (m, 10H) 2.35 (s, 3H). LC -MS: 466 [M+H]+. Example 102 3-(5-fluoropyridin-2-yl)-3-({4-[(5-methyl-1H-pyrazol-3-yl)amine ]--6-?-fu-p-lin-4-yl-1,3,5-tri-p--2-yl}amino) propylamine using a procedure similar to that described in Example 11 for the synthesis of 3-(4 -Chloro-6-(3-indolyl-1H-pyrazol-5-ylamino)-1,3,5-trin-2-ylamino)-3-(5-fluoropyridine-2 -yl)propanamide (intermediate 118) opposite to morphine (2 ml) To provide the title compound -240-200906818 133 151, as a mixture of isomers of the palm. 1 H NMR (300 MHz, MeOD) δ ppm 8.47 (s, 1H) 7.48-7.64 (m., 2H) 5.86 (broad s, 1H) 5.66 (t, 1H) 3.65-3.89 (m, 8H) 2.91-2.95 (m, 2H) 2.33 (s, 3H). LC-MS: 443 [M+H]+ Columns and solvent conditions The title compound was applied to the palm of the hand using the palm of the hand: Chirapak AD 4 Size: 250 X 20 mm, 10 // mobile phase: 50% hexane, 50% isopropanol, 0.1% diethylamine (v/v/v) Flow rate (ml/min): 20 Detection (nm): 220 Example 102(8), first dissolution peak NMR (300 MHz, MeOD) 5 ppm 8.47 (s, 1H) 7.48-7.64 (m., 2H) 5.86 (broad s, 1H) 5_66 (t, 1H) 3.65-3.89 (m , 8H) 2.91-2.95 (m, 2H) 2_33 (s, / 3H). \ LC-MS : 443 [M+H]+ Example 102(b), second dissolved peak! NMR (300 MHz, MeOD δ ppm 8.47 (s, 1H) 7.48-7.64 (m., 2H) 5.86 (broad s, 1H) 5.66 (t,1H) 3.65-3.89 (m, 8H) 2.91-2.95 (m,2H) 2.33 (s , 3H). LC-MS: 443 [M+H] + Example 103 N-[(lS)-l-(5-fluoropyrimidin-2-yl)ethyl]-6-hofolin-4-yl -N'-[5-(2-phenylethyl 133151 •241 - 200906818 bispyrimidin-3-yl)-1,3,5-trisole_2,4-diamine Similar to the example: the procedure of α synthesis, so that (sh_ 氯 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 4-Diamine (Intermediate: UO 'M gram, ΐ6 mmol) and reaction with ML, 23.0 mmol. 1H NMR (300 MHz, MeOD) (5 ppm 8.71 (s 2m 7 ) m , , 2H) 7.15-7.28 (m, 5H) 5.50 (q,1H) 3.61-3.74 (m,8H) 2.58-3.02 (m, 4H) 1.58 (d,3H) LC-MS: 491 [M+H]+ Example 104 6-(3-Ethyl-Fophenin-4-yl)_N_[(10) small (5-fluoropyrimidin-2-yl) Ethyl]_N, your methyl-1H-pyrazol-3-yl)-1,3,5-trinol-2,4-diamine was prepared using a procedure similar to that described in Example 62, to give (6)_6_qi_ N2 _(1_(5-fluoropyrimidin-2-yl)ethyl)-N4-(3-methyl-exo-pyrazol-5-yl)_1,3,5_three tillage _2 4 diamine (middle Reaction of 3, ethyl phenanthroline hydrochloride (87 mg, 0.57 mmol) afforded the title compound as a mixture of diastereomers. NMR (300 MHz, MeOD) &lt;5 ppm 8.76 (s, 2H) 5.89 (broad s, 1H) 5.32 (q, 1H) 3.61-4.43 (m, 2H) 3.21-3.86 (m, 5H) 2.34 (s, 3H) 1.80-2.02 (m, 2H) 1.64 (d, 3H) 1.39 (t, 3H). LC-MS: 429 [M+H]+. Columns and solvent conditions, title compound, diastereomers Separation using palmar HPLC

管柱：Chirapak AD 尺寸：250 X 20毫米，1〇 g 133151 -242- 200906818 流動相：80%己烷，20% 1:1乙醇：甲醇，〇·1〇/0二乙胺 流率（毫升/分鐘）：20 偵測（毫微米）：254 實例104⑻，第一個溶離峰 4 NMR (300 MHz, MeOD) 5 ppm 8.60 (s, 2Η) 5.89 (宽廣 s，1Η) 5.13 (q, 1H) 3.27-4.43 (m, 7H) 2.13 (s, 3H) 1.50-1.78 (m, 2H) 1.57 (d, 3H) 0.90 (t, 3H). LC-MS : 429 [M+H]+. ( K 實例104(b)，第二個溶離峰 1 H NMR (300 MHz, MeOD) δ ppm 8.71 (s, 2H) 5.24 (q, 1H) 3.40-4.41 (m，7H) 2.25 (寬廣8,311) 1.80-2.02 (111，211)1.64((1，3印1.39(1,311)· LC-MS ： 429 [M+H]+. 實例105 N-[l_(5-氟基嘧啶-2·基）-2-甲氧基乙基]-Ν·-(5-甲基-iH_吡唑_3_ 基）-6-嗎福琳-4-基-1,3,5-三畊-2,4-二胺 ， 使用類似關於實例11合成所述之程序，使（6-氣-N2-(1-(5- 氟基嘧啶-2-基）-2-甲氧基乙基）-N4-(3-甲基-1H-吡唑_5_基）·!％· 三_-2,4-二胺（中間物119，363毫克’ 〇·96毫莫耳）與嗎福啉（2 毫升’ 23_0毫莫耳）反應’提供標題化合物，為對掌異構物 之混合物。 1H NMR (300 MHz, MeOD) (5 ppm 8.73 (s，2Η)(吡唑 C：_4I 質子並非 顯而易見）5.45 (t，1H) 3_90 (d，2H) 3.63-3.80 (m, 8H) 3.33 (s，3H) 2.28 (s, 3H). LC-MS : 431 [M+H]+ 133151 243 - 200906818 管柱與溶劑條件 標題化合物係使用對掌性HPLC進行對掌性純化Column: Chirapak AD Size: 250 X 20 mm, 1〇g 133151 -242- 200906818 Mobile phase: 80% hexane, 20% 1:1 Ethanol: methanol, 〇·1〇/0 diethylamine flow rate (ml /min): 20 detection (nm): 254 Example 104 (8), first dissolution peak 4 NMR (300 MHz, MeOD) 5 ppm 8.60 (s, 2 Η) 5.89 (broad s, 1 Η) 5.13 (q, 1H 3.27-4.43 (m, 7H) 2.13 (s, 3H) 1.50-1.78 (m, 2H) 1.57 (d, 3H) 0.90 (t, 3H). LC-MS : 429 [M+H]+. ( K Example 104(b), second elution peak 1 H NMR (300 MHz, MeOD) δ ppm 8.71 (s, 2H) 5.24 (q, 1H) 3.40-4.41 (m, 7H) 2.25 (broad 8,311) 1.80-2.02 (111, 211) 1.64 ((1, 3 imprints 1.39 (1, 311)· LC-MS: 429 [M+H]+. Example 105 N-[l_(5-fluoropyrimidin-2-yl)-2-yl Oxyethyl]-indole-(5-methyl-iH-pyrazole-3-yl)-6-moffin-4-yl-1,3,5-trin-2,4-diamine, Using a procedure similar to that described for the synthesis of Example 11, (6-Gas-N2-(1-(5-fluoropyrimidin-2-yl)-2-methoxyethyl)-N4-(3-methyl -1H-pyrazole_5_yl)·!%· Tris-2,4-diamine (intermediate 119, 363 mg '〇·96 mmol) and morphine (2 mM) '23_0 millimolar reaction' provides the title compound as a mixture of palmomers. 1H NMR (300 MHz, MeOD) (5 ppm 8.73 (s, 2 Η) (pyrazole C: _4I proton is not obvious) 5.45 ( t,1H) 3_90 (d,2H) 3.63-3.80 (m, 8H) 3.33 (s,3H) 2.28 (s, 3H). LC-MS : 431 [M+H]+ 133151 243 - 200906818 Column and solvent Conditional title compound was purified by palmitic HPLC

管柱：Chiralcel OJ 尺寸：250 X 20毫米，10 /z 流動相：20%己烷，80% 1:1乙醇：曱醇，0.1%二乙胺（v/v/v) 流率（毫升/分鐘）：10 偵測（毫微米）：220 純化後純度檢驗： / 1 試樣純度係使用下列條件確認： 管柱：Chiralcel OJ，4.6 X 250 毫米，10 // 流動相：20%己烷，80% 1:1乙醇：曱醇，0.1%二乙胺 流率：0.5毫升/分鐘 偵測：220毫微米 第一個吸收峰（滯留時間：分鐘）10.7 第二個吸收峰（滯留時間：分鐘）18.8 實例105(a)，第一個溶離峰 ί 第一個溶離之化合物具有滯留時間為10.7分鐘，&gt;98°/(^6· 1 H NMR (300 MHz, MeOD) δ ppm 8.73 (s，2Η)(吡唑 C-41)質子並非 顯而易見）5.45 (t, 1H) 3.90 (d, 2H) 3.63-3.80 (m，8H) 3.33 (s, 3H) 2_28 (s, 3H). LC-MS ： 431 [M+H]+. 實例105(b)，第二個溶離峰 第二個溶離之化合物具有滯留時間為18.8分鐘，&gt;98% ee. 1H NMR (300 MHz，MeOD) (5 ppm 8.73 (s, 2H)(吡唑 C-41)質子並非 133151 -244 - 200906818 顯而易見）5.45 (t，1H) 3.90 (d，2H) 3.63-3.80 (m, 8H) 3.33 (s, 3H) 2.28 (s, 3H). LC-MS ： 431 [M+H]+. 實例106 6-(2,2-二甲基嗎福淋_4_基）_队【(18)_1_(5_氟基嘧啶_2_基）乙基】_ Ν’·(5-甲基-1H-吡唑-3-基）-l，3,5-三畊·2,4·二胺 使用類似關於實例11合成所述之程序，使（s)_6氣_Ν2 _(丨_(5_ II基0密0定-2-基）乙基）-Ν4-(3-曱基-1Η-口比嗤-5-基）-1，3,5-三ρ井-2,4_ 二胺（中間物17，200毫克，〇.57毫莫耳）與2,2_二曱基嗎福啉 鹽酸鹽（87毫克，0.57毫莫耳）反應，提供標題化合物。 H NMR_ (300 MHz’ MeOD) 5 ppm 8·77 (s，2Η) 5.87 (寬廣 s，1Η) 5.30 (q, 1H) 3.44-3.77 (m, 6H) 2.34 (s, 3H) 1.64 (s, 3H) 1.21 (s, 3H) 0.97 (s, 3H). LC-MS ： 429 [M+H]+ 實例107 4-[l-(5-氟基吡啶-2-基）-2-甲氧基乙氧基】_N_(5_甲基·1Η吡唑·3_ 基）-6-嗎福淋_4·基-1，3,5-三呼-2_胺 使用類似關於實例100合成所述之程序，使^(5氟基吡啶 -2-基）-2-曱氧基乙醇（中間物80，750毫克，4·38毫莫耳）與4_ 氯-Ν-(3-甲基-1Η-吡唑-5-基）-6-嗎福啉基4,3,5-三畊冬胺（中間 物15，864毫克，2.92毫莫耳）反應，提供標題化合物，為對 掌異構物之混合物。 1H NMR (300 MHz, MeOD) δ ppm 8.46 (s, 1H) 7.48-7.62 (m, 2H) 5.19-6.42 (m, 2H) 3.87 (d, 2H) 3.56-3.83 (m, 8H) 3.40 (s, 3H) 2.29 (s, 3H). 133151 -245 · 200906818 LC-MS ： 431 [M+H]+. 管柱與溶劑條件 標題化合物係使用條件（A)與OD-4-40進行對掌性純化 管柱粒子大小（从）：5 管柱尺寸（毫米）：21 X 250 實例l〇7(a)，第一個溶離峰 1H NMR (300 MHz, MeOD) δ ppm 8.46 (s, 1H) 7.48-7.62 (m, 2H) 5.19- 6.42 (m, 2H) 3.87 (d, 2H) 3.56-3.83 (m, 8H) 3.40 (s, 3H) 2.29 (s, 3H). / LC-MS ： 431 [M+H]+. 實例107(b)，第二個溶離峰 1H NMR (300 MHz, MeOD) δ ppm 8.46 (s, 1H) 7.48-7.62 (m, 2H) 5.19- 6.42 (m, 2H) 3.87 (d, 2H) 3.56-3.83 (m, 8H) 3.40 (s, 3H) 2.29 (s, 3H). LC-MS ： 431 [M+H]+. 實例108 3-(5-氟基吡啶-2-基）-N-甲基-3-({4-[(5_甲基_1H-吡唑-3-基）胺 基]-6_嗎福啉_4_基-I，3,5-三畊_2-基}氧基）丙醢胺 V .. 使用類似關於實例11合成所述之程序，使3-(4-氣基-6-(3-甲基-1H-吡唑-5-基胺基）-1，3,5-三畊-2-基胺基）-3-(5-氟基吡啶-2-基）-N-曱基丙醯胺（中間物120)與嗎福啉（3毫升）反應，提供 標題化合物，為對掌異構物之混合物。 !H NMR (300 MHz, MeOD) &lt;5 ppm 8.51 (s, 1H) 7.57-7.62 (m, 2H) (ρΛ 唑 C4'-H 信號並非顯而易見）5.57 (t，1H) 3.56-3.80 (m，8H) 3.05 (d, 2H) 2.66 (s, 3H) 2.25 (s, 3H). LC-MS ： 457 [M+H]+ 133151 •246 · 200906818 管柱與溶劑條件 標題化合物係使用條件（A)與IA-3-40進行對掌性純化 管柱粒子大小（〆）：5 管柱尺寸（毫米）：21 X 250 實例108(a) ’第一個溶離之化合物 1 H NMR (300 MHz, MeOD) δ ppm 8.51 (s, 1H) 7.57-7.62 (m, 2H) ( 唑 CV-H 信號並非顯而易見）5.57 (t，ih) 3.56-3.80 (m, 8H) 3.05 (d， 2H) 2.66 (s, 3H) 2.25 (s, 3H). LC-MS ： 431 [M+H]+. 實例108(b)，第二個溶離之化合物 4 NMR (300 MHz, MeOD) 5 ppm 8.51 (s，1H) 7.57-7.62 (m, 2H)(吡 唑 CV-H 信號並非顯而易見）5·57 (t，ih) 3.56-3.80 (m，8H) 3.05 (d, 2H) 2.66 (s, 3H) 2.25 (s, 3H). LC-MS ： 431 [M+H]+. 實例109 3-(5-氟基p比淀-2-基）-3-({4-[(5-曱基-IH-吡咬-3-基）胺基卜6嗎福 琳-4-基-1，3,5·三ρ井-2-基}胺基）丙腈 使用類似關於實例11合成所述之程序，使3_(4_氯基_6_(3_ 甲基-1Η-吡唑-5-基胺基）-1，3,5-三呼-2-基胺基）_3_(5·氟基吡啶_2_ 基）丙腈（中間物121 ’ 110毫克，0.29毫莫耳）與嗎福啉(2毫升， 22_96毫莫耳）反應’提供標題化合物，為對掌異構物之混合 物。 1 H NMR (300 MHz, MeOD) δ ppm 8.42 (s, IH) 7.46-7.59 (m, 2H) ( 嗤CV-H信號並非顯而易見）5·58 (t，1H) 3 %㈣4H) 3 6S㈣仰 133151 -247- 200906818 3.22 (d, 2H) 2.27 (s, 3H). LC-MS ： 425 [M+H]+. 管柱與溶劑條件 標題化合物係使用對掌性HPLC進行對掌性純化Column: Chiralcel OJ Size: 250 X 20 mm, 10 /z Mobile phase: 20% hexane, 80% 1:1 Ethanol: decyl alcohol, 0.1% diethylamine (v/v/v) Flow rate (ml/ Minutes): 10 Detection (nm): 220 Purity after purification: / 1 The purity of the sample is confirmed using the following conditions: Column: Chiralcel OJ, 4.6 X 250 mm, 10 // Mobile phase: 20% hexane, 80% 1:1 ethanol: decyl alcohol, 0.1% diethylamine flow rate: 0.5 ml/min Detection: 220 nm first absorption peak (residence time: minute) 10.7 second absorption peak (residence time: minute 18.8 Example 105(a), the first dissolution peak ί The first dissolved compound has a residence time of 10.7 minutes, &gt;98°/(^6·1 H NMR (300 MHz, MeOD) δ ppm 8.73 (s , 2Η) (pyrazole C-41) proton is not obvious) 5.45 (t, 1H) 3.90 (d, 2H) 3.63-3.80 (m, 8H) 3.33 (s, 3H) 2_28 (s, 3H). LC-MS : 431 [M+H]+. Example 105(b), second elution peak The second dissolved compound has a residence time of 18.8 minutes, &gt;98% ee. 1H NMR (300 MHz, MeOD) (5 ppm 8.73 (s, 2H) (pyrazole C-41) proton is not 133151 -244 - 200906818 Obviously) 5.45 (t,1H) 3.90 (d,2H) 3.63-3.80 (m, 8H) 3.33 (s, 3H) 2.28 (s, 3H). LC-MS : 431 [M+H]+. Example 106 6-(2,2-Dimethylfuran _4_yl)_Team [(18)_1_(5-fluoropyrimidin-2-yl)ethyl]_ Ν'·(5-methyl-1H -pyrazol-3-yl)-l,3,5-tri-n.2,4.diamine using a procedure similar to that described for the synthesis of Example 11 to give (s) _6 gas _ Ν 2 _ (丨_(5_ II基0密0定-2-yl)ethyl)-Ν4-(3-indolyl-1Η-oral 嗤-5-yl)-1,3,5-tri-p--2,4-diamine (middle Reaction of 2,2-dimercaptophyrin hydrochloride (87 mg, 0.57 mmol) afforded the title compound. H NMR_ (300 MHz' MeOD) 5 ppm 8·77 (s, 2Η) 5.87 (broad s, 1Η) 5.30 (q, 1H) 3.44-3.77 (m, 6H) 2.34 (s, 3H) 1.64 (s, 3H) 1.21 (s, 3H) 0.97 (s, 3H). LC-MS: 429 [M+H] + </ RTI> </ RTI> </ RTI> 4-[l-(5-fluoropyridin-2-yl)-2-methoxy Oxy] _N_(5-methyl·1 Ηpyrazole·3_yl)-6-norfos _4·yl-1,3,5-trih-2-amine using procedures similar to those described for the synthesis of Example 100 , (5-fluoropyridin-2-yl)-2-methoxyethanol (intermediate 80, 750 mg, 4. 38 mmol) and 4 chloro-indole-(3-methyl-1 Η-pyridyl) Reaction of oxazol-5-yl)-6-morpholinyl 4,3,5-trimethanol (intermediate 15,864 mg, 2.92 mmol) afforded the title compound as a mixture . 1H NMR (300 MHz, MeOD) δ ppm 8.46 (s, 1H) 7.48-7.62 (m, 2H) 5.19-6.42 (m, 2H) 3.87 (d, 2H) 3.56-3.83 (m, 8H) 3.40 (s, 3H) 2.29 (s, 3H). 133151 -245 · 200906818 LC-MS : 431 [M+H]+. Column and solvent conditions The title compound was used for the purification of palms using conditions (A) and OD-4-40. Column particle size (from): 5 Column size (mm): 21 X 250 Example l〇7(a), first dissolved peak 1H NMR (300 MHz, MeOD) δ ppm 8.46 (s, 1H) 7.48- 7.62 (m, 2H) 5.19- 6.42 (m, 2H) 3.87 (d, 2H) 3.56-3.83 (m, 8H) 3.40 (s, 3H) 2.29 (s, 3H). / LC-MS : 431 [M+ H]+. Example 107(b), second elution peak 1H NMR (300 MHz, MeOD) δ ppm 8.46 (s, 1H) 7.48-7.62 (m, 2H) 5.19- 6.42 (m, 2H) 3.87 (d , 2H) 3.56-3.83 (m, 8H) 3.40 (s, 3H) 2.29 (s, 3H). LC-MS: 431 [M+H]+. Example 108 3-(5-fluoropyridin-2-yl -N-methyl-3-({4-[(5-methyl_1H-pyrazol-3-yl)amino]-6_morpholine_4_yl-I,3,5-three Cultivating 2-(yl)oxy)propanamine V.. Using a procedure similar to that described for the synthesis of Example 11, 3-(4-carbyl-6-(3-methyl-1H-pyrazole-5-) was used. Amino group)-1,3,5-three </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; a mixture of palmomers. !H NMR (300 MHz, MeOD) &lt;5 ppm 8.51 (s, 1H) 7.57-7.62 (m, 2H) (ρΛ azole C4'-H signal is not obvious) 5.57 (t,1H) 3.56-3.80 (m, 8H) 3.05 (d, 2H) 2.66 (s, 3H) 2.25 (s, 3H). LC-MS : 457 [M+H]+ 133151 •246 · 200906818 Column and solvent conditions The title compound is used (A) Purification of column particle size with IA-3-40 (〆): 5 Column size (mm): 21 X 250 Example 108 (a) 'First dissolved compound 1 H NMR (300 MHz, MeOD δ ppm 8.51 (s, 1H) 7.57-7.62 (m, 2H) (The azole CV-H signal is not obvious) 5.57 (t, ih) 3.56-3.80 (m, 8H) 3.05 (d, 2H) 2.66 (s, 3H) 2.25 (s, 3H). LC-MS: 431 [M+H]+. Example 108 (b), second dissolved compound 4 NMR (300 MHz, MeOD) 5 ppm 8.51 (s, 1H) 7.57 -7.62 (m, 2H) (pyrazole CV-H signal is not obvious) 5·57 (t,ih) 3.56-3.80 (m,8H) 3.05 (d, 2H) 2.66 (s, 3H) 2.25 (s, 3H) LC-MS: 431 [M+H]+. Example 109 3-(5-fluoro-p-p-but-2-yl)-3-({4-[(5-fluorenyl-IH-pyrobitone) 3-yl)aminopurine 6 phenanthene-4-yl-1,3,5·trisole-2-yl}amino)propyl The nitrile was used in a procedure similar to that described for the synthesis of Example 11 to give 3_(4-dichloro-6-(3-methyl-1 -pyrazol-5-ylamino)-1,3,5-tris-2-yl Amino)_3_(5·fluoropyridin-2-yl)propanenitrile (Intermediate 121 '110 mg, 0.29 mmol) was reacted with morpholine (2 mL, 22-96 mmol) to afford title compound. a mixture of palmomers. 1 H NMR (300 MHz, MeOD) δ ppm 8.42 (s, IH) 7.46-7.59 (m, 2H) (嗤CV-H signal is not obvious) 5·58 (t,1H) 3 %(4)4H) 3 6S(4) 133151 -247- 200906818 3.22 (d, 2H) 2.27 (s, 3H). LC-MS: 425 [M+H]+. Column and solvent conditions The title compound was purified by palm chromatography

管柱：Chirapak AD 尺寸：250 X 20毫米，10 μ 流動相：50%乙醇，50%甲醇，0.1%二乙胺（ν/νΛ^ 流率（毫升/分鐘）：20 偵測（毫微米）：220 實例109(a)，第一個溶離之化合物 1 H NMR (300 MHz, MeOD) δ ppm 8.42 (s, 1H) 7.46-7.59 (m, 2H) ( ni 。坐 CV-H 信號並非顯而易見）5.58 (t，1H) 3.78 (m, 4H) 3.65 (m, 4H) 3.22 (d, 2H) 2.27 (s, 3H). LC-MS ： 425 [M+H]+. 實例109(b)，第二個溶離之化合物 1 H NMR (300 MHz, MeOD) δ ppm 8.42 (s，1H) 7.46-7.59 (m，2H)(吡 唑 CV-H 信號並非顯而易見）5,58 (t, 1H) 3.78 (m，4H) 3.65 (m, 4H) 3.22 (d, 2H) 2.27 (s, 3H). LC-MS ： 425 [M+H]+. 實例110 4-【l-(5-氟基嘧啶-2-基)-2-甲氧基乙氧基】_N-(5-甲基-1H-吡唑-3-基）_6_嗎福淋_4_基·1，3,5_三畊_2•胺 使用類似關於實例100合成所述之程序，使1-(5-氟基嘧啶 -2-基）-2-甲氧基乙醇（中間物91，366毫克，2.13毫莫耳）與4-133151 -248 - 200906818 氯-N-(3-甲基-1H-吡唑-5-基）-6-嗎福啉基-1,3,5-三畊-2-胺（中間 物15)反應，提供標題化合物，為對掌異構物之混合物。 NMR (300 MHz, MeOD) δ ppm 8.78 (s, 2H) 6.19-6.22 (m, 1H) 6.08 (t, 1H) 3.94-4.05 (m, 2H) 3.56-3.82 (m, 8H) 3.42 (s, 3H) 2.38 (s, 3H). LC-MS ： 432 [M+H]+. 管柱與溶劑條件 標題化合物係使用條件（A)與OD-3-40進行對掌性純化 管柱粒子大小（^) : 5 管柱尺寸（毫米）：21 X 250 實例110(a)，第一個溶離之化合物 !H NMR (300 MHz, MeOD) δ ppm 8.78 (s, 2H) 6.19-6.22 (m5 1H) 6.08 (t, 1H) 3.94-4.05 (m, 2H) 3.56-3.82 (m, 8H) 3.42 (s, 3H) 2.38 (s, 3H). LC-MS : 432 [M+H]+ · 實例110(b)，第二個溶離之化合物 !H NMR (300 MHz, MeOD) (5 ppm 8.78 (s, 2H) 6.19-6.22 (m, 1H) 6.08 (t, 1H) 3.94-4.05 (m, 2H) 3.56-3.82 (m, 8H) 3.42 (s, 3H) 2.38 (s, 3H). LC-MS : 432 [M+H]+ · 實例111 3-(5-氟基吡啶-2-基)-N，N-二甲基-3-({4-[(5-曱基-1H-吡唑-3-基）胺 基】-6-嗎福林-4-基-1，3,5-三？井-2-基}胺基）丙酿胺 使用類似關於實例11合成所述之程序，使3-(4-氯基-6-(3-曱基-1H-吡唑-5-基胺基）-1,3,5-三畊-2-基胺基）-3-(5-氟基吡啶_2-基）-N，N-二曱基丙醯胺（中間物122，410毫克，0.98毫莫耳） 與嗎福啉（4毫升，46毫莫耳）反應，提供標題化合物，為對 133151 -249 - 200906818 掌異構物之混合物。 1 H NMR (300 MHz, MeOD) δ ppm 8.42 (s, 1H) 7.46-7.59 (m&gt; 2H) 5 58 (t, 1H) 3.78 (m, 4H) 3.65 (m, 4H) 3.22 (s, 6H) 2.27 (s, 3H). LC-MS ： 471 [M+H]+. 管柱與溶劑條件 標題化合物係使用條件（A)與AD-3-50進行對掌性純化 管柱粒子大小（的：5 管柱尺寸（毫米）：21 X 250 實例111(a)，第一個溶離之化合物 1 H NMR (300 MHz, MeOD) &lt;5 ppm 8.42 (s, 1H) 7.46-7.59 (m, 2H) 5 58 (t, 1H) 3.78 (m5 4H) 3.65 (m, 4H) 3.22 (s, 6H) 2.27 (s, 3H) LC-MS : 471 [M+H]+. 實例111(b)，第二個溶離之化合物 1H NMR (300 MHz, MeOD) &lt;5 ppm 8.42 (s, 1H) 7.46-7.59 (m, 2H) 5 58 (t, 1H) 3.78 (m, 4H) 3.65 (m, 4H) 3.22 (s, 6H) 2.27 (s, 3H) LC-MS ： 471 [M+H]+. 實例112 6-(3,3-二甲基嗎福啉-4-基）-]\-[(18)-1-(5_氟基嘧啶-2-基）乙基】· 1\’-(5-甲基-111-叶1:嗤-3-基）-1，3,5_三》»井_2,4_二胺 使用類似關於實例62合成所述之程序，使⑸_6_氯_N2_(1_(5_ 氟基嘴咬-2-基）乙基）-N4-(3-甲基-iH-p比唾-5-基）-1，3,5-三11 井-24_ 二胺（中間物17，200毫克，〇·57毫莫耳）與3,3二甲基嗎福啉 鹽酸鹽（87毫克，0.57毫莫耳）反應，提供標題化合物。 1 H NMR (300 MHz, MeOD) &lt;5 ppm 8.76 (s, 2H) 5_87 (s，1H) 5.34 (q，1H) 133151 -250- 200906818 3.50-3.86 (m, 9H) 2.34 (s, 3H) 1.66 (d, 3H) 1.54 (s, 3H). LC-MS ： 429 [M+H]+. 實例113 (扣-]^-(1-(3,5-二氟吡啶-2-基）-2-甲氧基乙基）_妒_(5_甲基_111_峨 唑各基）_6_嗎福啉基-1，3，S-三畊-2,4-二胺 使（R)-6-氣-N2-(l-(3,5-二氟ρ比0定-2-基）-2-甲氧基乙基）_n4_(5-甲 基-1H-吡唑-3-基）-1,3,5-三畊-2,4-二胺（中間物42，574毫克，1_45 毫莫耳）溶於乙醇（3_5毫升）中，並添加嗎福啉（4.41毫升， 50.63毫莫耳）。將反應混合物在25°C下攪拌1小時。接著， 使反應混合物於真空中濃縮，留下透明半固體（1 374克）。 使此物質藉ISC◦純化（2-10% MeOH/DCM)。在真空中濃縮溶離 份，提供標題化合物，為白色固體（591.7毫克）。 1 H NMR (300 MHz, MeOD) δ ppm 8.36 (d, 1H) 7.38-7.74 (m5 1H) 6.36 (寬廣 s” 0.5H) 5.42-5.88 (m，1.5H) 3.48-3.98 (m, l〇H) 3.34 (s，3H) 2.05-2.41 (m, 3H). LC-MS ： 448 [M+H]+. 試樣純度係使用Chiralcel OJ-H測定。 管柱尺寸：4.6 x 100毫米 流動相：20% MeOH/二甲基乙胺 流率：5毫升/分鐘 壓力：120巴 烘箱温度：35°C 偵測：220毫微米 化合物具有滯留時間為0.92分鐘，97.5% ee. 133151 -251 - 200906818 實例114 N-【5-(2-環己基乙基）_m_吡唑_3_基]_N，_[(1S)小沙氟基嘧啶·2基） 乙基】-6-嗎福啉_4-基-1,3,5-三畊-2,4-二胺 使用類似關於實例11合成所述之程序，使（s)_6_氯_Ν2 _(3_(2_ 環己基乙基）-1Η-吡唑-5-基）-N4-(l-(5-氟基嘧啶-2-基）乙基）-l，3,5-二畊-2,4-二胺（中間物124，363毫克，〇 81毫莫耳）與嗎福啉 (4毫升’ 45.91毫莫耳）反應，提供標題化合物。 1H NMR (300 MHz，MeOD) &lt;5 ppm 8.70 (s，2Η)吡唑 C-4·質子並非 顯而易見 5_25 (t，1H) 3.57-3.75 (m，8H) 2_62 (t, 2H) 0.90-1.83 (m，16H). LC-MS : 497 [M+H]+ 實例115 N-[(lS)-l-(5-氟基响咬_2_基）乙基卜n’_[5_(4•甲氧苯基）_1H_p比吐_3_ 基】-6_嗎福啉-4-基-1，3,5-三畊-2,4_二胺 使用類似關於實例11合成所述之程序，使（8)_6_氯_ν2 _(ι_(5_ 氟基嘧啶-2-基）乙基）_n4-(3-(4-甲氧苯基）-iH-吡唑-5-基）-1,3,5-三 p井-2,4-二胺（中間物125，510毫克，1.15毫莫耳）與嗎福4 (5 毫升，57.39毫莫耳）反應，提供標題化合物。 1H NMR (300 MHz, MeOD) δ ppm 8.76 (s, 2H) 7.67 (d, 2H) 7.06 (d, 2H)峨嗅 C-4’ 質子並非顯而易見 5.36 (q，ih) 3.87 (s，3H) 3.68-3.76 (m, 8H) 1.66 (d, 3H). LC-MS ： 493 [M+H]+. 實例116 3-(5-氟基吡啶-2-基&gt;3-({4-[(5-曱基-1H-吡唑-3-基）胺基】-6-嗎福 啉斗基-1，3,5-三畊-2-基}胺基）丙4•醇 J33151 -252· 200906818 使用類似關於實例11合成所述之程序，使3-(4-氯基-6-(3-曱基-1H-吡唑-5-基胺基）-1,3,5-三畊-2-基胺基）-3-(5-氟基吡啶-2-基）丙-1-醇（中間物126，110毫克，0.29毫莫耳）與嗎福啉(2毫 升，22.96毫莫耳）反應，提供標題化合物，為對掌異構物之 混合物。 1 H NMR (300 MHz, MeOD) (5 ppm 8.47 (d，1H) 7.51-7.65 (m，2H)吡唑 C-4,質子並非顯而易見 5.85 (q，1H) 5·37 (t, 1H) 3.66-3.88 (m，8H) 2.33 (s, 3H) 2.12-2.18 (m, 2H). 、 LC-MS : 430 [M+H]+_ 管柱與溶劑條件 標題化合物係使用對掌性HPLC進行對掌性純化Column: Chirapak AD Size: 250 X 20 mm, 10 μ Mobile phase: 50% ethanol, 50% methanol, 0.1% diethylamine (ν/νΛ^ flow rate (ml/min): 20 detection (nm) : 220 Example 109(a), the first dissolved compound 1 H NMR (300 MHz, MeOD) δ ppm 8.42 (s, 1H) 7.46-7.59 (m, 2H) (ni. Sitting CV-H signal is not obvious) 5.58 (t,1H) 3.78 (m, 4H) 3.65 (m, 4H) 3.22 (d, 2H) 2.27 (s, 3H). LC-MS : 425 [M+H]+. Example 109(b), Two dissolved compounds 1 H NMR (300 MHz, MeOD) δ ppm 8.42 (s, 1H) 7.46-7.59 (m, 2H) (pyrazole CV-H signal is not obvious) 5,58 (t, 1H) 3.78 ( m,4H) 3.65 (m, 4H) 3.22 (d, 2H) 2.27 (s, 3H). LC-MS: 425 [M+H]+. Example 110 4-[1-(5-fluoropyrimidine-2 -yl)-2-methoxyethoxy]_N-(5-methyl-1H-pyrazol-3-yl)_6_? 福福____1·3,5_three tillage_2 • Amine was used in a procedure similar to that described for the synthesis of Example 100 to give 1-(5-fluoropyrimidin-2-yl)-2-methoxyethanol (intermediate 91, 366 mg, 2.13 mmol) with 4- 133151 -248 - 200906818 Chloro-N-(3-methyl-1H-pyrazol-5-yl)-6-? Reaction of the morphyl-1,3,5-trinyl-2-amine (Intermediate 15) afforded the title compound as a mixture of ss. NMR (300 MHz, MeOD) δ ppm 8.78 (s, 2H) 6.19-6.22 (m, 1H) 6.08 (t, 1H) 3.94-4.05 (m, 2H) 3.56-3.82 (m, 8H) 3.42 (s, 3H) 2.38 (s, 3H). LC-MS : 432 [M +H]+. Column and Solvent Conditions The title compound is used for the purification of the column particle size (^) using conditions (A) and OD-3-40: 5 Column size (mm): 21 X 250 Example 110 (a), the first dissolved compound! H NMR (300 MHz, MeOD) δ ppm 8.78 (s, 2H) 6.19-6.22 (m5 1H) 6.08 (t, 1H) 3.94-4.05 (m, 2H) 3.56- 3.82 (m, 8H) 3.42 (s, 3H) 2.38 (s, 3H). LC-MS: 432 [M+H]+ · Example 110(b), the second dissolved compound! H NMR (300 MHz, MeOD) (5 ppm 8.78 (s, 2H) 6.19-6.22 (m, 1H) 6.08 (t, 1H) 3.94-4.05 (m, 2H) 3.56-3.82 (m, 8H) 3.42 (s, 3H) 2.38 (s , 3H). LC-MS: 432 [M+H] + · Example 111 3-(5-fluoropyridin-2-yl)-N,N-dimethyl-3-({4-[(5- Mercapto-1H-pyrazol-3-yl)amino]-6-norfosolin-4-yl-1,3,5-tri? Well-2-yl}amino) propylamine using a procedure similar to that described for the synthesis of Example 11 to give 3-(4-chloro-6-(3-indolyl-1H-pyrazol-5-ylamino) -1,3,5-Triton-2-ylamino)-3-(5-fluoropyridine-2-yl)-N,N-dimercaptopropanamide (intermediate 122,410 mg, Reaction with morphine (4 ml, 46 mmol) afforded the title compound as a mixture of 133151 -249 - 200906818. 1 H NMR (300 MHz, MeOD) δ ppm 8.42 (s, 1H) 7.46-7.59 (m&gt; 2H) 5 58 (t, 1H) 3.78 (m, 4H) 3.65 (m, 4H) 3.22 (s, 6H) 2.27 (s, 3H). LC-MS: 471 [M+H]+. Column and solvent conditions The title compound was used for the purification of the column particle size using conditions (A) and AD-3-50. 5 Column size (mm): 21 X 250 Example 111(a), first dissolved compound 1 H NMR (300 MHz, MeOD) &lt;5 ppm 8.42 (s, 1H) 7.46-7.59 (m, 2H) 5 58 (t, 1H) 3.78 (m5 4H) 3.65 (m, 4H) 3.22 (s, 6H) 2.27 (s, 3H) LC-MS : 471 [M+H]+. Example 111(b), second 1H NMR (300 MHz, MeOD) &lt;5 ppm 8.42 (s, 1H) 7.46-7.59 (m, 2H) 5 58 (t, 1H) 3.78 (m, 4H) 3.65 (m, 4H) 3.22 (s, 6H) 2.27 (s, 3H) LC-MS: 471 [M+H]+. Example 112 6-(3,3-Dimethyl-propofolin-4-yl)-]\-[(18 )-1-(5-fluoropyrimidin-2-yl)ethyl]·1\'-(5-methyl-111-leaf:indol-3-yl)-1,3,5_three"» Well _2,4-diamine was prepared using a procedure similar to that described for the synthesis of Example 62 to give (5)_6_chloro_N2_(1_(5-fluoroyl-n-butyl-2-yl)ethyl)-N4-(3-methyl- iH-p is more than salivary-5-yl)-1,3,5- Reaction of 3,13--24-diamine (intermediate 17,200 mg, 〇·57 mmol) with 3,3 dimethyl morpholine hydrochloride (87 mg, 0.57 mmol) afforded the title compound. 1 H NMR (300 MHz, MeOD) &lt;5 ppm 8.76 (s, 2H) 5_87 (s,1H) 5.34 (q,1H) 133151 -250- 200906818 3.50-3.86 (m, 9H) 2.34 (s, 3H) 1.66 (d, 3H) 1.54 (s, 3H). LC-MS: 429 [M+H]+. Example 113 (----^^-(1-(3,5-difluoropyridin-2-yl)- 2-methoxyethyl)_妒_(5-methyl_111_carbazole group)_6_morpholinyl-1,3,S-trinyl-2,4-diamine (R) -6-gas-N2-(l-(3,5-difluoroρ~0-but-2-yl)-2-methoxyethyl)_n4_(5-methyl-1H-pyrazol-3-yl -1,3,5-three tillage-2,4-diamine (intermediate 42,574 mg, 1_45 mmol) dissolved in ethanol (3_5 ml) with the addition of morpholine (4.41 ml, 50.63 m) Moore). The reaction mixture was stirred at 25 ° C for 1 hour. The reaction mixture was then concentrated in vacuo to leave a clear semi solid (1 374 g). This material was purified by ISC (2-10% MeOH / DCM). The title compound was obtained as a white solid (yield: 591.7 mg). 1 H NMR (300 MHz, MeOD) δ ppm 8.36 (d, 1H) 7.38-7.74 (m5 1H) 6.36 (broad s) 0.5H) 5.42-5.88 (m, 1.5H) 3.48-3.98 (m, l〇H 3.34 (s,3H) 2.05-2.41 (m, 3H). LC-MS: 448 [M+H]+. The purity of the sample is determined using Chiralcel OJ-H. Column size: 4.6 x 100 mm mobile phase: 20% MeOH/dimethylethylamine flow rate: 5 ml/min Pressure: 120 bar Oven temperature: 35 ° C Detection: 220 nm compound with retention time 0.92 minutes, 97.5% ee. 133151 -251 - 200906818 Examples 114 N-[5-(2-cyclohexylethyl)_m_pyrazole_3_yl]_N,_[(1S)sodium fluoropyrimidinyl-2-yl)ethyl]-6-morpholine_4 -Base-1,3,5-Tricotin-2,4-diamine using a procedure similar to that described for the synthesis of Example 11 to give (s)_6_chloro-Ν2 _(3_(2_cyclohexylethyl)-1Η -pyrazol-5-yl)-N4-(l-(5-fluoropyrimidin-2-yl)ethyl)-l,3,5-diplough-2,4-diamine (intermediate 124,363 </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; · Proton is not obvious 5_25 (t 1H) 3.57-3.75 (m,8H) 2_62 (t, 2H) 0.90-1.83 (m,16H). LC-MS: 497 [M+H]+ Example 115 N-[(lS)-l-(5- Fluorine-based biting_2_yl)ethyl b-n'_[5_(4•methoxyphenyl)_1H_p than spit_3_yl]-6_morpholine-4-yl-1,3,5-three Plowing the 2,4-diamine using a procedure similar to that described for the synthesis of Example 11 to give (8)_6_chloro_ν2 _(ι_(5-fluoropyrimidin-2-yl)ethyl)_n4-(3-( 4-methoxyphenyl)-iH-pyrazol-5-yl)-1,3,5-tri-p--2,4-diamine (intermediate 125,510 mg, 1.15 mmol) and oxime Reaction of 4 (5 ml, 57.39 mmol) afforded the title compound. 1H NMR (300 MHz, MeOD) δ </ RTI> </ RTI> 8.76 (s, 2H) 7.67 (d, 2H) 7.06 (d, 2H) 峨 sniffing C-4' Protons are not obvious 5.36 (q,ih) 3.87 (s,3H) 3.68-3.76 (m, 8H) 1.66 (d, 3H). LC-MS: 493 [M+H]+. Example 116 3-(5-Fluorine Pyridin-2-yl&gt;3-({4-[(5-fluorenyl-1H-pyrazol-3-yl)amino]-6-morpholine bucket base-1,3,5-three tillage -2-yl}amino)propanol • alcohol J33151 -252· 200906818 Using a procedure similar to that described for the synthesis of Example 11, 3-(4-chloro-6-(3-mercapto-1H-pyrazole- 5-aminoamino)-1,3,5-trin-2-yl 3-(5-fluoropyridin-2-yl)propan-1-ol (intermediate 126, 110 mg, 0.29 mmol) was reacted with morpholine (2 mL, 22.96 mmol). The title compound is a mixture of palmomers. 1 H NMR (300 MHz, MeOD) (5 ppm 8.47 (d, 1H) 7.51-7.65 (m, 2H) pyrazole C-4, protons are not obvious 5.85 (q, 1H) 5·37 (t, 1H) 3.66 -3.88 (m,8H) 2.33 (s, 3H) 2.12-2.18 (m, 2H)., LC-MS: 430 [M+H]+_ Column and solvent conditions The title compound was applied to the palm of the HPLC. Palm purification

管柱：Chirapak AD 尺寸：250 X 20毫米，10 // 流動相：70%己烷，30%異丙醇，0.1%二乙胺（v/v/v) 流率（毫升/分鐘）：20 偵測（毫微米）：220 \ 實例116(a)，第一個溶離之化合物 1 H NMR (300 MHz，MeOD) 5 ppm 8_47 (d, 1H) 7.51-7.65 (m，2H)吡唑 C-4·質子並非顯而易見 5.85 (q, 1H) 5.37 (t, 1H) 3.66-3.88 (m，8H) 2.33 (s, 3H) 2.12-2.18 (m, 2H). LC-MS ： 430 [M+H]+. 實例116(b)，第二個溶離之化合物 1 H NMR (300 MHz, MeOD) (5 ppm 8.47 (d, 1H) 7.51-7.65 (m，2H)吡唑 C-41 質子並非顯而易見 5.85 (q，1H) 5.37 (t, 1H) 3.66-3.88 (m, 8H) 133151 - 253 - 200906818 2.33 (s, 3H) 2.12-2.18 (m，2H). LC-MS ： 430 [M+H]+. 實例117 N-[l_(5_氟基吡啶-2-基）-2-(曱磺醯基）乙基]_N，_(5曱基_lH吡唑 3-基)-6-嗎福〃林·4-基-1，3,5-三 p井-2,4-二胺 使用類似關於實例11合成所述之程序，使6_氯_Ν2_(1·(5_1 基被啶-2-基）-2-(曱磺醯基）乙基）_ν4_(3_甲基_1Η〇比峻-5_ 基）-1,3,5-二ρ井-2,4-一胺（中間物127，407毫克，0.95毫莫耳）與 ' 嗎福啉反應，提供標題化合物，為對掌異構物之混合物。 1 H NMR (300 MHz, MeOD) δ ppm 8.54 (s, 1H) 7.62-7.66 (m, 2H) 5.95 (t，1H) 5_87 (寬廣 s，1H) 3.71-4.04 (m，10H) 3.00 (s，3H) 2.33 (s 3H) LC-MS : 478 [M+H]+. 管柱與溶劑條件 標題化合物係使用條件（A)與IA管柱進行對掌性純化 改質劑：50%異丙醇，〇_2% TFA，0.2%二甲基乙胺 管柱粒子大小（〆)：5 i. 管柱尺寸（毫米）：21 X 250 實例lH(a)，第一個溶離之化合物 1 H NMR (300 MHz, MeOD) δ ppm 8.54 (s, 1H) 7.62-7.66 (m, 2H) 5.95 (t，1H) 5.87 (寬廣 s，1H) 3.71-4.04 (m，10H) 3.00 (s, 3H) 2.33 (s，3H). LC-MS : 478 [M+H]+ 實例117(b)，第二個溶離之化合物 NMR (300 MHz, MeOD) δ ppm 8.54 (s, 1H) 7.62-7.66 (m, 2H) 5.95 (t，1H) 5.87 (寬廣 s，1H) 3.71-4.04 (m，10H) 3.00 (s, 3H) 2.33 (s，3H). 133151 -254 - 200906818 LC-MS : 478 [M+H]+ 實例118 N-[5-(4-氟苯基）-1Η·咐4各基】_N，_[叫^-敗基^ -2·基）乙 基】·6·嗎福淋_4_基-1，3,5-三呼-2,4-二胺 使用類似關於實例11合成所述之程序，使⑻_6_氣_n2 _(3_(4_ 氟苯基基）抓(1_(5_氟基喷啶_2_基）乙基三畊 -2,4-二胺（中間物128,310毫克，〇72毫莫耳）與嗎福淋反應， 提供標題化合物。 / 屮 NMR (300 MHz，MeOD) d ppm 8 77 (s，2Η) π·㈣ 2H) 7.23-7.30 (m, 2H) 6.38 ( ^ ^ s, 1H) 5.36 (q, 1H) 3.61-3.87 (m, 8H) 1.66 (d, 3H). LC-MS ： 481 [M+H]+ 實例119 4-{【(2S)-l-(5-氟基峨咬-2-基)-2-甲氧基丙基】氧基}_N (5甲基_m_ 吡唑-3-基）-6-嗎福啉-4-基-1，3,5-三啡_2_胺Column: Chirapak AD Size: 250 X 20 mm, 10 // Mobile phase: 70% hexane, 30% isopropanol, 0.1% diethylamine (v/v/v) Flow rate (ml/min): 20 Detection (nm): 220 \ Example 116 (a), first dissolved compound 1 H NMR (300 MHz, MeOD) 5 ppm 8_47 (d, 1H) 7.51-7.65 (m, 2H) pyrazole C- 4. Protons are not obvious 5.85 (q, 1H) 5.37 (t, 1H) 3.66-3.88 (m, 8H) 2.33 (s, 3H) 2.12-2.18 (m, 2H). LC-MS : 430 [M+H] +. Example 116(b), the second dissolved compound 1 H NMR (300 MHz, MeOD) (5 ppm 8.47 (d, 1H) 7.51-7.65 (m, 2H) pyrazole C-41 proton is not obvious 5.85 ( q,1H) 5.37 (t, 1H) 3.66-3.88 (m, 8H) 133151 - 253 - 200906818 2.33 (s, 3H) 2.12-2.18 (m,2H). LC-MS : 430 [M+H]+. Example 117 N-[l_(5-Fluoropyridin-2-yl)-2-(indolyl)ethyl]-N,-(5-mercapto-1H-pyrazole-3-yl)-6-isfosin Lin 4-yl-1,3,5-tri-p--2,4-diamine was prepared using a procedure similar to that described for the synthesis of Example 11 to give 6_chloro-Ν2_(1·(5_1 yl) Base)-2-(indolyl)ethyl)_ν4_(3_methyl_1Η〇比峻-5_yl)-1,3,5-two-ρ well -2,4-Amine (Intermediate 127, 407 mg, 0.95 mmol) was reacted with &lt;RTI ID=0.0&gt;&gt;&gt; Ppm 8.54 (s, 1H) 7.62-7.66 (m, 2H) 5.95 (t, 1H) 5_87 (broad s, 1H) 3.71-4.04 (m, 10H) 3.00 (s, 3H) 2.33 (s 3H) LC-MS : 478 [M+H]+. Column and Solvent Conditions The title compound is used under conditions (A) and IA column for palm-like purification. Modifier: 50% isopropanol, 〇_2% TFA, 0.2% Methylethylamine column particle size (〆): 5 i. Column size (mm): 21 X 250 Example lH(a), first dissolved compound 1 H NMR (300 MHz, MeOD) δ ppm 8.54 ( s, 1H) 7.62-7.66 (m, 2H) 5.95 (t,1H) 5.87 (broad s, 1H) 3.71-4.04 (m,10H) 3.00 (s, 3H) 2.33 (s,3H). LC-MS : 478 [M+H]+ Example 117(b), second dissolved compound NMR (300 MHz, MeOD) δ ppm 8.54 (s, 1H) 7.62-7.66 (m, 2H) 5.95 (t,1H) 5.87 ( Broad s, 1H) 3.71-4.04 (m, 10H) 3.00 (s, 3H) 2.33 (s, 3H). 133151 -254 - 200906818 LC-MS : 478 [M+H]+ Example 118 N-[5-( 4-fluorophenyl)-1Η·咐4 groups 】 _N, _ [called ^ - defeat base ^ - 2 · base) ethyl] · 6 · whuple _4_ base -1,3,5-trih-2,4-diamine use similar to example 11 Synthesize the procedure to make (8)_6_gas_n2 _(3_(4_fluorophenyl) grab (1_(5-fluoroylpyridin-2-yl)ethyltrin-2,4-diamine (middle The compound, 128, 310 mg, 〇72 mmol, was reacted with miramide to provide the title compound. / 屮 NMR (300 MHz, MeOD) d ppm 8 77 (s, 2Η) π·(4) 2H) 7.23-7.30 (m, 2H) 6.38 ( ^ ^ s, 1H) 5.36 (q, 1H) 3.61-3.87 (m , 8H) 1.66 (d, 3H). LC-MS: 481 [M+H]+ Example 119 4-{[(2S)-l-(5-Fluorobenzoin-2-yl)-2-methoxy Propyl]oxy}_N (5-methyl-m-pyrazol-3-yl)-6-morpholine-4-yl-1,3,5-trimorph-2-amine

使用類似關於實例100合成所述之程序，使（2$)_1_(5_氟基 吡啶-2-基）-2-甲氧基丙-1-醇（5〇5毫克，2.73毫莫耳）與4-氯-N-(3_ 甲基-1H-叶匕°坐-5-基）-6-嗎福口林基_i，3,5-三p井_2_胺（中間物is，538 毫克，1.82毫莫耳）反應，提供兩種不同之非對映異構物。 實例119⑻，非對映異構物a !H NMR (300 MHz, MeOD) δ ppm 8.45 (s, 1H) 7.66-7.71 (m, 2H) 5.89 (m, 1H) 4.81 (d, 1H) 3.66-3.93 (m, 11H) 2.33 (s, 3H) 1.05-1.11 (m, 3H). LC-MS ： 445 [M+H]+ 實例119(b)，非對映異構物b 133151 -255- 200906818 ]H NMR (300 MHz, MeOD) δ ppm 8.48 (s, 1H) 7.59-7.66 (m5 2H) 6.18 (寬廣 s, 1H) 6.07 (d，1H) 4.00 (s, 3H) 3.66-3.88 (m, 8H) 2.38 (s, 3H) 1.15-1.26 (m, 3H). LC-MS ： 445 [M+H]+ 實例120 N-[(lS)-l-(5-氟基，咬-2-基）乙基卜6_嗎福淋_冬基_n，_丨5_(苯氧基 甲基比峻-3_基】-1，3,5-三啡·2,4-二胺 使用類似關於實例11合成所述之程序，使（8)_6_氯_Ν2 氟基嘧啶-2-基）乙基）-Ν4-(3-(苯氧基曱基）_出_吡唑_5_基）4,3,5-三畊-2,4-二胺（中間物139，270毫克’ 0.61毫莫耳）與嗎福啉 反應，提供標題化合物。 ]H NMR (300 MHz, MeOD) ^ ppm 8.71 (s, 2H) 7.29 (t, 2H) 6.93-7.03 (m，3H) 比峻之C-4’質子並非顯而易見5·25 (q, m) 5〇4 (s，2H) 3.53-3.83 (m, 8H) 1.58 (d, 3H). LC-MS ： 493 [M+H]+ 實例121 N-[(lS)-l-(5-敗基’啶-2·基）乙基]嗎福淋冬基_N，_(5嘍吩_2基 -1H-P比也-3-基）-1，3,5-三 p井-2,4-二胺 使用類似關於實例11合成所述之程序，使（8)_6_氯_N2 氟基嘧啶-2-基）乙基）-N4-(3-〇塞吩_2_基）-1Η-吡唑-5-基）-l，3,5-三 吨-2,4-二胺（中間物129，310毫克，〇.74毫莫耳）與嗎福啉（2 毫升’ 22·96毫莫耳）反應’提供標題化合物。 1 H NMR (300 MHz, MeOD) δ ppm 8.76 (s, 2H) 7.55 (d, 1H) 7.51 (d, 1H) 7_17 (dd，1H) 6_29 (寬廣 s，1H) 5..35 (q, 1H) 3.60-3.86 (m, 8H) 1.66 (d， 133151 -256- 200906818 3H). LC-MS : 469 [M+H]+ 實例122 6-((2S，6R)-2,6-二甲基嗎福琳基&gt;n2 _((s)小(5氣基鳴咬_2基）乙 基）-N4-(5-甲基-1H-吡唑冬基）义％三畊_2,4_二胺 使用類似關於實例11合成所述之程序，使⑻_6_氯_N2 _(1_(5_ 齓基嘧啶-2-基）乙基）-N4-(5-甲基-1H_吡唑_3_基h,3,5_三畊_2,4_ 二胺（中與順式_2,6_二甲基嗎福#反應，提供標題化 合物。 1H NMR (5 ) 8.67 (s, 2H), 6.30 (bs, 1H), 5.20 (m, 1H), 4.44 (m, 2H), 3.53 (m, 2H), 2.44 (m, 2H), 2.22 (s, 3H), I.54 (m, 3H), 1.15 (m, 6H) LC-MS ： 429, 430 [M+H]+. 實例123 (K_R)_2,6-二甲基嗎福琳基)_Ν2 ·_(5·氟基㈣·2幻乙 基甲基·1Η·,比哇-3_基）三啩_2，心二胺 使用類似關於實⑽合成所述之料，使⑻_6_“_(1_(5_ 氟基㈣-2-基）乙基）·Ν4_(5_甲基]知比唾絲h，3,5_三_ _2,4-二胺（中間物聊，6-二甲基嗎福她式_與反式_之混合 物）反應’提供標題化合物，為兩種順式與反式之混合物。 使混合物藉GilS〇n進一步分離(PH 8，1〇 _ _ 〇Ac，勵/ H2〇3〇%—40%，15分鐘）’以提供標題化合物（較幻，伴隨 著6倘叫2,6-二甲基嗎福琳基)_N2倘小㈣基㈣_2·基）乙 基&gt;N4-(5-甲基_1H•十坐_3_基R3，h呼_2,4_二則實例即。 1 H NMR ( , ) 8.69 (s, 2H), 6,〇 (bs, 1H)? 5 2〇 (mj iH)s 3 8〇 3(mj 4h)j 133151 -257- 200906818 3.36 (m, 2H), 2.22 (s, 3H), 1.54 (m, 3H), 1.14 (m, 6H). LC-MS ： 429 [M+H]+. 實例124 6-(2-(二氟甲基）嗎福啉基）_N2_((S)小(5氟基嘧啶_2基）乙 基）-N4-(5-甲基-1H-吡唑-3-基）-l，3,5-三畊_2斗二胺 使用類似關於實例11合成所述之程序，使（8)_6_氯_N2 _(丨_(5一 氣基°密σ定-2-基）乙基）-N4-(5-甲基-1H-吡唑-3-基）-1，3,5-三畊-2,4- 一胺（中間物17)與2-(二氟甲基）嗎福啉（中間物13〇)反應，提 供標題化合物，為非對映異構物之混合物。 JH NMR (5 ) 8.73 (m, 2H), 5.84 (m, 2H), 5.31 (m, 1H), 4.36-4.67 (m&gt; 2H), 3.97 (m, 1H), 3.53 (m, 2H), 3.08 (m, 2H), 2.32 (s, 3H), 1.61 (m, 3H). LC-MS : 451，452 [M+H]+. 實例125 6-(2-(二氟甲基）嗎福啉基)_N2 _((R)1_(3,5二氟吡啶_2基甲氧 基乙基）-N4-(5-甲基_1Η·吡唑冰基）ns三畊j，4二胺 使用類似關於實例^合成所述之程序，使（11)_6_氯^2_(1_ (3,5-二氟吡啶-2-基）_2_甲氧基乙基&gt;Ν4 _(5_甲基_m-吡唑冰基）— 1，3,5-三畊-2,4-二胺（中間物42)與2仁氟甲基）嗎福啉（中間物 130)反應，提供標題化合物。 NMR (5 ) 8.34 (m5 1H)j 7.52 (m, 1H), 6.35 (m, 1H), 5.84 (m, 2H)5 4.64 (m, 1H), 4.48 (m, 1H), 3.96 (m, 1H), 3.53-3.71 (m, 4H), 3.34 (m&gt; 3H)j 3.15 (m, 2H), 2.25 (s, 3H). ， LC-MS ： 498 [M+H]+. 實例126 133151 258· 200906818 (S)-6-(3,3-二氟六氫p比咬_ι_基）_n2_(i_(5_氟基喊咬-2_基）乙基）-N4-(5-甲基-1H-吡唑-3-基）-1,3,5-三畊-2,4-二胺 使用類似關於實例11合成所述之程序，使（S)-6-氯-N2 -(1-(5-氟基嘧啶-2-基）乙基）-N4-(5-甲基-1H-吡唑-3-基:)·1，3,5-三畊-2,4-二胺（中間物17)與3,3-二氟六氫吡啶反應，提供標題化合物。 NMR (δ ) 8.66 (m, 2H), 6.37 (m, 1H), 5.16 (m, 1H), 4.00 (m, 2H), 3.77 (m, 1H), 3.49 (m, 1H), 2.25 (s, 3H), 2.03 (m, 2H), 1.57 (m, 5H). LC-MS ： 435, 436 [M+H]+. &quot; 實例127 6-(3-((二甲胺基）甲基）六氫吡啶-1-基）_N2-((S)-l-(5-氟基嘧啶-2-基）乙基）-N4-(5-甲基-1IK唑-3-基）-1,3,5-三畊-2,4-二胺 使用類似關於實例11合成所述之程序，使（8)_6_氣_N2 _(丨_(5_ 氟基嘧啶-2-基）乙基）-N4-(5-甲基-1H-吡唑-3-基）-1,3,5-三畊-2,4-一胺（中間物17)與N，N-二甲基-l_(六氫吡啶基）曱胺反應， 提供標題化合物，為非對映異構物之混合物。 ( 1 H NMR (5 ) 8.70 (s, 2H), 6.02 (m, 1H), 5.31 (m, 1H), 3.73 (m, 1H), 2.55 (m, 8H), 2.27 (s, 3H), 1.93 (s, 6H), 1.57 (d, 3H), 1.38 (m, 2H). LC-MS ： 456 [M+H]+. 標題化合物係使用對掌性hplc分離Using a procedure similar to that described for the synthesis of Example 100, (2$)_1_(5-fluoropyridin-2-yl)-2-methoxypropan-1-ol (5 〇 5 mg, 2.73 mmol) With 4-chloro-N-(3_methyl-1H-leaf 匕°-5-yl)-6- 福福口林基_i,3,5-threep well_2_amine (intermediate is, The reaction was carried out at 538 mg, 1.82 mmol, providing two different diastereomers. Example 119(8), diastereomer a!H NMR (300 MHz, MeOD) δ ppm 8.45 (s, 1H) 7.66-7.71 (m, 2H) 5.89 (m, 1H) 4.81 (d, 1H) 3.66-3.93 (m, 11H) 2.33 (s, 3H) 1.05-1.11 (m, 3H). LC-MS: 445 [M+H] + </RTI> 119 (b), diastereomers b 133151 -255- 200906818 ] H NMR (300 MHz, MeOD) δ ppm 8.48 (s, 1H) 7.59-7.66 (m5 2H) 6.18 (broad s, 1H) 6.07 (d,1H) 4.00 (s, 3H) 3.66-3.88 (m, 8H) 2.38 (s, 3H) 1.15-1.26 (m, 3H). LC-MS: 445 [M+H]+ Example 120 N-[(lS)-l-(5-Fluoro, Ben-2-yl) Kebu 6_? 福淋_冬基_n, _丨5_(phenoxymethyl than jun-3_yl)-1,3,5-triphthyl-2,4-diamine is similar to Example 11 The procedure described is carried out such that (8)_6_chloro-Ν2 fluoropyrimidin-2-yl)ethyl)-indole 4-(3-(phenoxyindenyl)-exo-pyrazole-5-yl)4 , 3,5-Tricotin-2,4-diamine (intermediate 139, 270 mg '0.61 mmol) was reacted with morpholine to afford the title compound. ]H NMR (300 MHz, MeOD) ^ ppm 8.71 (s, 2H) 7.29 (t, 2H) 6.93-7.03 (m,3H) Proton C-4' proton is not obvious 5·25 (q, m) 5 〇4 (s,2H) 3.53-3.83 (m, 8H) 1.58 (d, 3H). LC-MS: 493 [M+H]+ Example 121 N-[(lS)-l-(5---- Pyridin-2-yl)ethyl]norfosyl winter base_N,_(5喽-phen-2-yl-1H-P ratio also-3-yl)-1,3,5-tri-p--2,4 -Diamine using a procedure similar to that described for the synthesis of Example 11 to give (8)-6-chloro-N2 fluoropyrimidin-2-yl)ethyl)-N4-(3-dexexephen-2-yl)-1? -pyrazol-5-yl)-l,3,5-three tons-2,4-diamine (intermediate 129,310 mg, 〇.74 mmol) and morphine (2 ml '22·96) Millol) reaction to provide the title compound. 1 H NMR (300 MHz, MeOD) δ ppm 8.76 (s, 2H) 7.55 (d, 1H) 7.51 (d, 1H) 7_17 (dd, 1H) 6_29 (broad s, 1H) 5..35 (q, 1H) 3.60-3.86 (m, 8H) 1.66 (d, 133151 -256- 200906818 3H). LC-MS: 469 [M+H]+ Example 122 6-((2S,6R)-2,6-dimethyl福福琳基&gt;n2 _((s) small (5 gas-based biting _2 yl) ethyl)-N4-(5-methyl-1H-pyrazole winter) %% three tillage _2,4 _Diamine using a procedure similar to that described for the synthesis of Example 11 to give (8) _6_chloro-N2 _(1_(5- decylpyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazole _ 3_基h,3,5_三耕_2,4_Diamine (reacted with cis- 2,6-dimethyl-fylo# to provide the title compound. 1H NMR (5 ) 8.67 (s, 2H) , 6.30 (bs, 1H), 5.20 (m, 1H), 4.44 (m, 2H), 3.53 (m, 2H), 2.44 (m, 2H), 2.22 (s, 3H), I.54 (m, 3H) ), 1.15 (m, 6H) LC-MS: 429, 430 [M+H]+. Example 123 (K_R)_2,6-dimethylmorphinyl)_Ν2 ·_(5·Fluoro (4)·2 Fantasy ethylmethyl·1Η·, biwa-3_yl)triterpene-2-, diamine is similar to the material described in the actual (10) synthesis, so that (8)_6_“_(1_(5_fluoro)(4-)-2-yl )ethyl)·Ν4_(5_methyl) knows the ratio of saliva h,3,5_three_ _ 2,4-Diamine (intermediate chat, 6-dimethyl phlox her formula _ with a mixture of trans _) reaction 'provided the title compound, a mixture of two cis and trans. Bring the mixture to GilS〇 Further separation (PH 8, 1 〇 _ _ 〇 Ac, excitation / H2 〇 3 〇 % - 40%, 15 minutes) ' to provide the title compound (more magic, accompanied by 6 if 2,6-dimethyl? Fulin) _N2 if small (tetra)yl(tetra)_2·yl)ethyl&gt;N4-(5-methyl_1H•10 sitting_3_yl R3,hh_2,4_two is an example. 1 H NMR ( , ) 8.69 (s, 2H), 6, 〇 (bs, 1H)? 5 2〇(mj iH)s 3 8〇3(mj 4h)j 133151 -257- 200906818 3.36 (m, 2H), 2.22 ( s, 3H), 1.54 (m, 3H), 1.14 (m, 6H). LC-MS: 429 [M+H]+. Example 124 6-(2-(difluoromethyl) oxalinyl)_N2_ ((S) small (5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl)-l,3,5-three tillage _2 used diamine Similar to the procedure described in Example 11 for the synthesis of (8)_6_chloro-N2 _(丨_(5-gas-based succinyl-2-yl)ethyl)-N4-(5-methyl-1H- Pyrazol-3-yl)-1,3,5-trinol-2,4-monoamine (intermediate 17) and 2-(difluoromethyl)morpholine (intermediate 13〇) , To provide the title compound as a mixture of isomers of the diastereomers. JH NMR (5) 8.73 (m, 2H), 5.84 (m, 2H), 5.31 (m, 1H), 4.36-4.67 (m &gt; 2H), 3.97 (m, 1H), 3.53 (m, 2H), 3.08 (m, 2H), 2.32 (s, 3H), 1.61 (m, 3H). LC-MS: 451,452 [M+H]+. Example 125 6-(2-(difluoromethyl)morpholine Base)_N2 _((R)1_(3,5-difluoropyridin-2-ylmethoxyethyl)-N4-(5-methyl-l-pyridylpyrazole ice-based) ns three-ploughed j,4 diamine Similar to the procedure described for the synthesis of (11)_6_chloro^2_(1_(3,5-difluoropyridin-2-yl)_2-methoxyethyl&gt;Ν4 _(5-methyl <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; NMR (5) 8.34 (m5 1H)j 7.52 (m, 1H), 6.35 (m, 1H), 5.84 (m, 2H)5 4.64 (m, 1H), 4.48 (m, 1H), 3.96 (m, 1H) ), 3.53-3.71 (m, 4H), 3.34 (m&gt; 3H)j 3.15 (m, 2H), 2.25 (s, 3H). , LC-MS : 498 [M+H]+. Example 126 133151 258· 200906818 (S)-6-(3,3-Difluorohexahydrop to bite_ι_yl)_n2_(i_(5_Fluoro-spoken-2_yl)ethyl)-N4-(5-methyl -1H-pyrazol-3-yl)-1,3,5-trinol-2,4-diamine was synthesized analogously to Example 11 Procedure for (S)-6-chloro-N2-(1-(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazol-3-yl:) 1. 1,3,5-Tricotin-2,4-diamine (Intermediate 17) was reacted with 3,3-difluorohexahydropyridine to give the title compound. NMR (δ) 8.66 (m, 2H), 6.37 ( m, 1H), 5.16 (m, 1H), 4.00 (m, 2H), 3.77 (m, 1H), 3.49 (m, 1H), 2.25 (s, 3H), 2.03 (m, 2H), 1.57 (m , 5H). LC-MS: 435, 436 [M+H]+. &quot; Example 127 6-(3-((Dimethylamino)methyl)hexahydropyridin-1-yl)_N2-((S )-l-(5-Fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1IKoxazol-3-yl)-1,3,5-trin-2,4-diamine Using a procedure similar to that described for the synthesis of Example 11, (8)_6_gas_N2_(丨_(5-fluoropyrimidin-2-yl)ethyl)-N4-(5-methyl-1H-pyrazole) -3-yl)-1,3,5-trinyl-2,4-monoamine (Intermediate 17) is reacted with N,N-dimethyl-l-(hexahydropyridinyl)guanamine to provide the title compound. It is a mixture of diastereomers. ( 1 H NMR (5 ) 8.70 (s, 2H), 6.02 (m, 1H), 5.31 (m, 1H), 3.73 (m, 1H), 2.55 (m, 8H), 2.27 (s, 3H), 1.93 (s, 6H), 1.57 (d, 3H), 1.38 (m, 2H). LC-MS: 456 [M+H]+. The title compound is isolated using palm hplc

管柱：Chirapak AD 尺寸：250 x 20毫米，10 // 流動相：50%己烧，50%異丙醇，〇 ι〇/〇二乙胺（v/v/v) 流率（毫升/分鐘）：20 偵測（毫微米）：254 133151 -259- 200906818 實例127⑻，第一個溶離峰 1 H NMR (δ ) 8.69 (s, 2H), 6.25 (bs5 1H), 5.26 (m, 1H), 4.40 (m, 1H), 3.34 (m, 2H), 2.25 (m, 11H), 1.28-1.89 (m, 9H). LC-MS ： 456 [M+H]+. 實例127(b)，第二個溶離峰 1 H NMR (δ) 8.74 (s, 2Η), 5.88 (m, 1H), 5.28 (m, 1H), 4.53 (m, 1H), 3.37-4.12 (m, 1H), 2.97 (m, 9H), 2.32 (s, 3H), 1.99 (s, 3H), 1.22-1.63 (s, 6H)； LC-MS : 456 [M+H]+ . 實例128 ((S)-l-(4-((S)-l-(5-氟基嘧啶-2-基）乙胺基)各(5_甲基_1H-吡唑-3-基 胺基)-1,3,5-三畊-2-基）六氫吡啶_3_基）甲基胺基甲酸第三_丁酯 使用類似關於實例11合成所述之程序，使⑸_6_氣_N2 _(丨_(5_ 氟基嘧啶-2-基）乙基）-：^4-(5-曱基-111-吡唑-3-基）-1,3,5-三畊-2,4-二胺（中間物17)與⑻-六氫吡啶_3_基曱基胺基曱酸第三·丁 酯反應，提供標題化合物。 1 H NMR (&lt;5 ) 8.68 (s, 2H), 6.43 (bs, 1H), 5.26 (m, 1H), 3.81 (m, 2H), 3.20 (m, 1H), 2.89 (m, 2H), 2.21 (m, 3H), 1.72 (m, 3H), 1.54 (d, 3H), 1.39 (m, 12H). LC-MS ： 528 [M+H]+. 實例129 6-((S)-3-(胺基曱基）六氫吡啶小基_ __小(5氟基嘧啶_2基） 乙基）-N4-(5-曱基-1H-吡唑各基）-以七三畊_2,4_二胺鹽酸鹽 使用類似關於實例41合成所述之程序，使（⑸小^七幻小^ 氟基嘧啶-2-基）乙胺基）-6-(5-甲基-丨扎吡唑_3_基胺基”，^三 畊-2-基）六氫吡啶-3-基）曱基胺基甲酸第三-丁酯（實例128 , 133151 -260- 200906818 167毫克，〇_32毫莫耳）反應，提供標題化合物。 ^ NMR (5 ) 8.77 (m, 2H), 6.06 (m, 1H), 5.40 (m, 1H), 3.47 (m, 3H), 2.91 (m, 2H), 2.39 (m, 3H), 2.20 (m, 1H), 1.94 (m, 2H), 1.35-1.71 (m, 6H). LC-MS ： 428 [M+H]+. 實例130 ((R)小(4-((S)-H5_氟基嘧啶-2-基）乙胺基）-6-(5-甲基-1H-吡唑-3-基胺基)-1，3,5-三畊-2-基）六氫吡啶·3_基）甲基胺基甲酸第三丁酯 f 使用類似關於實例11合成所述之程序，使（S)-6-氯-N2 -(1-(5- 氟基嘧啶-2-基）乙基）_&gt;^4-(5-甲基-1凡吡唑_3-基）-1,3,5-三'1井-2,4-二胺（中間物17)與（S)-六氫吡啶-3_基甲基胺基甲酸第三丁 酯反應，提供標題化合物。 H NMR ( δ ) 8.70 (s, 2H), 6.41 (bs, 1H), 5.28 (m, 1H), 3.83 (m, 2H), 3.22 (m, 1H), 2.92 (m, 2H), 2.21 (m, 3H), 1.72 (m, 3H), 1.54 (d, 3H), 1.41 (m, 12H). LC-MS : 528 [M+H]+_ 7 實例131 \ 6-㈣-3-(胺基曱基）六氫吡咬小基）_N2_((s)小(5氟基嘧啶_2_基） 乙基）抓(5_?基_1H_P比4 _3_基M，冰三口井_2,4_二胺，似鹽 使用類似關於實例41合成所述之程序，使小(4_小(5_ 氟基嘧啶-2-基）乙胺基）各(5_甲基_出_吡唑各基胺基H，3,5三 畊-2-基）六氫吡啶·3_基）甲基胺基甲酸第三_丁酯（實例13〇)反 應，提供標題化合物。藉Gilson純化（MeCN/H2 〇，〇1% wa)， 獲得標題產物。 H NMR (5 ) 8.76 (m，2H)，5.99 (m，1H)，5 39 ㈣ 1H)，3 4〇 (m，3H)， 133151 -261 - 200906818 2.89 (m, 2H), 2.34 (m, 3H), 2.01 (m, 3H), 1.34-1.72 (m, 6H). LC-MS ： 428 [M+H]+ ； 實例132 l-(4_((S)_l-(5-氟基嘧咬-2-基）乙胺基）_6·(5_曱基比唑冬基胺 基)-1,3,5-三畊-2-基）六氫吡啶各基（甲基）胺基甲酸第三_丁酯 使用類似關於實例11合成所述之程序，使⑸_6_氯_Ν2 _(卜(5_ 氟基。t啶-2-基）乙基）-Ντ4-(5-甲基-1H-吡唑-3-基）-1,3,5-三畊-2,4-二胺（中間物17)與曱基（六氫吡啶_3_基）胺基甲酸第三-丁酯 反應，提供標題化合物。 NMR (δ ) 8.67 (m, 2H), 6.32 (m, 1H), 5.22 (m, 1H), 4.64 (m, 2H), 3.79 (m, 1H), 2.81 (m, 4H), 2.61 (m5 1H), 2.23 (m, 3H), 1.78 (m, 3H), 1.50 (m, 13H) ； LC-MS ： 528,529 [M+H]+. 標題化合物係使用條件（A)與AD-4-25分離 管柱粒子大小（//) : 5 管柱尺寸（毫米）：21 X 250 實例l32(a)，第一個溶離峰 1 H NMR (δ ) 8.67 (s, 2H), 6.32 (bs, 1H), 5.25 (m, 1H), 4.65 (m, 2H), 3.79 (m, 1H), 2.81 (m, 4H), 2.66 (m, 1H), 2.22 (s, 3H), 1.79 (m, 3H), 1.50 (m, 13H) ； LC-MS ： 528, 529 [M+H]+. 實例132(b)，第二個溶離峰 1 H NMR ((5 ) 8.67 (s, 2H), 6.32 (bs, 1H), 5.24 (m, 1H), 4.58 (m, 2H), 3.80 (m, 1H), 2.80 (m, 4H), 2.62 (m, 1H), 2.22 (s, 3H), 1.78 (m, 3H), 1.51 (m, 13H) ; LC-MS : 529 [M+H]+. 實例133 133151 • 262 · 200906818 4-(1-(3,5-二氟吡啶-2-基）乙氧基）_]^_(5_甲基_111_吡唑_3_基）_6_嗎 福啉基-1，3,5·三畊-2-胺 使用類似關於實例100合成所述之程序’使1_(3,5_二敗峨 咬-2-基）-2-曱氧基乙醇（中間物107)與4_氯_Ν_(3_曱基_m-吡唑 -5-基）-6-嗎福ρ林基-1，3,5-三畊-2-胺（中間物15)反應，提供標題 化合物，為對掌異構物之混合物。 H NMR (300 MHz, MeOD) δ ppm 1.69 (d, J = 6.59 Hz, 3H) 2.27 (s, 3H) 3.47- 4.02 (m, 8H) 6.11-6.44 (m, 2H), 7.61 (ddd, 1H) 8.35 (s, 1H). LC-MS ： 419 [M+Hf. 管柱與溶劑條件 標題化合物係使用條件（A)與AD-4-20進行對掌性純化 管柱粒子大小（#) : 5 管柱尺寸（毫米）：21 X 250 純化後純度檢驗： 試樣純度係使用條件（B)與AD-4-20確認 溶離時間（分鐘）：5 流率（毫升/分鐘）：5 第一個吸收峰（滯留時間：分鐘）1.87 第二個吸收峰（滯留時間：分鐘）2.53 實例133(a)，第一個溶離峰 1H NMR (300 MHz, MeOD) 5 ppm 1.69 (d, J = 6.59 Hz, 3H) 2.27 (s, 3H) 3.47- 4.02 (m, 8H) 6.11-6.44 (m, 2H), 7.61 (ddd, 1H) 8.35 (s, 1H). LC-MS ·· 419 [M+H]+. 實例133(b)，第二個溶離峰 133151 •263 · 200906818 1 H NMR (300 MHz, MeOD) &lt;5 ppm 1.69 (d, J = 6.59 Hz, 3H) 2.27 (s, 3H) 3.47-4.02 (m, 8H) 6.11-6.44 (m, 2H), 7.61 (ddd, 1H) 8.35 (s, 1H). LC-MS ： 419 [M+H]+. 實例134 N2-(l-(5-氟基吡啶-2-基）-2-甲氧基乙基）-N4-(S-曱基-1H-吡唑-3-基）-6-嗎福淋基-1,3,5-三畊-2,4-二胺 使用類似關於實例11合成所述之程序’使N2-(1-(5-氟基吡 啶-2-基）-2-甲氧基乙基）·Ν4 -(5-曱基-lH-p比唑-3-基）-6-嗎福琳基 -1，3,5-三畊-2,4-二胺（中間物131)與嗎福p林反應，提供標題化 合物，為對掌異構物之混合物。 lR NMR (300 MHz, MeOD) δ ppm 2.25 (s, 3H) 3.36 (s, 3H) 3.52-4.06 (m, 10H) 5.16-5.44 (m, 1H) 6.05 (s, 1H) 7.30-7.79 (m, 2H) 8.42 (s5 1H). LC-MS : 430 [M+H]+. 管柱與溶劑條件Column: Chirapak AD Dimensions: 250 x 20 mm, 10 // Mobile phase: 50% hexane, 50% isopropanol, 〇ι〇/〇 diethylamine (v/v/v) Flow rate (ml/min) ): 20 detection (nm): 254 133151 -259- 200906818 Example 127 (8), first dissolution peak 1 H NMR (δ ) 8.69 (s, 2H), 6.25 (bs5 1H), 5.26 (m, 1H), 4.40 (m, 1H), 3.34 (m, 2H), 2.25 (m, 11H), 1.28-1.89 (m, 9H). LC-MS : 456 [M+H]+. Example 127(b), second 1 H NMR (δ) 8.74 (s, 2Η), 5.88 (m, 1H), 5.28 (m, 1H), 4.53 (m, 1H), 3.37-4.12 (m, 1H), 2.97 (m, 9H), 2.32 (s, 3H), 1.99 (s, 3H), 1.22-1.63 (s, 6H); LC-MS: 456 [M+H]+ . Example 128 ((S)-l-(4- ((S)-l-(5-fluoropyrimidin-2-yl)ethylamine) each (5-methyl-1H-pyrazol-3-ylamino)-1,3,5-three tillage- 2-Based) hexahydropyridine-3-yl)methylaminocarbamic acid tert-butyl ester using a procedure similar to that described for the synthesis of Example 11 to give (5) _6_gas_N2 _(丨_(5-fluoropyrimidine-2) -yl)ethyl)-:^4-(5-fluorenyl-111-pyrazol-3-yl)-1,3,5-trinyl-2,4-diamine (intermediate 17) and (8)- Hexahydropyridine _3_ hydrazinyl decanoic acid tert-butyl ester It should provide the title compound. 1 H NMR (&lt;5) 8.68 (s, 2H), 6.43 (bs, 1H), 5.26 (m, 1H), 3.81 (m, 2H), 3.20 (m, 1H), 2.89 (m, 2H), 2.21 (m, 3H), 1.72 (m, 3H), 1.54 (d, 3H), 1.39 (m, 12H). LC-MS: 528 [M+H]+. Example 129 6-((S)-3 -(Aminoguanidino)hexahydropyridine small group ___small (5-fluoropyrimidin-2-yl)ethyl)-N4-(5-mercapto-1H-pyrazole each)- to seven or three tillage _ 2,4-diamine hydrochloride was used in a procedure similar to that described for the synthesis of Example 41 to give ((5) succinimide fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl- Terpene pyridazole _3_ylamino", triacetin-2-yl) hexahydropyridin-3-yl) decylaminocarbamic acid tert-butyl ester (Example 128, 133151-260-200906818 167 mg, The reaction was carried out to give the title compound. NMR (5) 8.77 (m, 2H), 6.06 (m, 1H), 5.40 (m, 1H), 3.47 (m, 3H), 2.91 (m, 2H), 2.39 (m, 3H), 2.20 (m, 1H), 1.94 (m, 2H), 1.35-1.71 (m, 6H). LC-MS: 428 [M+H]+. Example 130 ((R Small (4-((S)-H5-fluoropyrimidin-2-yl)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-1,3,5 -Tricotin-2-yl)hexahydropyridine·3_yl)methylaminocarbamic acid tert-butyl ester f Using a procedure similar to that described for the synthesis of Example 11, (S)-6-chloro-N2-(1-(5-fluoropyrimidin-2-yl)ethyl)_&gt;^4-(5-methyl- 1 Wherein pyrazole-3-yl)-1,3,5-tri'1 well-2,4-diamine (intermediate 17) and (S)-hexahydropyridin-3-ylmethylcarbamic acid Reaction of tributyl ester to provide the title compound. H NMR ( δ ) 8.70 (s, 2H), 6.41 (bs, 1H), 5.28 (m, 1H), 3.83 (m, 2H), 3.22 (m, 1H), 2.92 (m, 2H), 2.21 (m, 3H), 1.72 (m, 3H), 1.54 (d, 3H), 1.41 (m, 12H). LC-MS : 528 [M+H]+_ 7 Example 131 \ 6-(tetra)-3-(aminomercapto)hexahydropyridyl small base)_N2_((s) small (5-fluoropyrimidin-2-yl)ethyl) grab (5_? base_1H_P ratio 4 _3_ group M, ice three wells _2,4_diamine, salt-like using a procedure similar to that described for the synthesis of Example 41, making small (4_small (5-fluoropyrimidin-2-yl)ethylamine) each (5_ Methyl-ex-pyrazolylamino H,3,5 triton-2-yl)hexahydropyridine-3-yl)methylaminocarbamic acid tert-butyl ester (Example 13) reaction, providing the title Compound. Purified by Gilson (MeCN/H2 〇, 〇 1% wa) to give the title product. H NMR (5 ) 8.76 (m, 2H), 5.99 (m, 1H), 5 39 (4) 1H), 3 4 〇 (m, 3H), 133151 -261 - 200906818 2.89 (m, 2H), 2.34 (m, 3H), 2.01 (m, 3H), 1.34-1.72 (m, 6H). LC-MS: 428 [M+H]+; Example 132 l-(4_((S)_l-(5-fluoropyrimidine) -2-yl)ethylamino)_6·(5_mercaptozolamideylamino)-1,3,5-trin-2-yl)hexahydropyridyl (methyl)aminocarbamic acid Tri-butyl ester was prepared using a procedure similar to that described for the synthesis of Example 11 to give (5)_6_chloro-Ν2 _(Bu(5-fluoro.t.sub.2-yl)ethyl)-Ντ4-(5-methyl-1H- Pyrazol-3-yl)-1,3,5-trinyl-2,4-diamine (intermediate 17) is reacted with a decyl (hexahydropyridine-3-yl)carbamic acid tert-butyl ester, Provide the title compound. NMR (δ ) 8.67 (m, 2H), 6.32 (m, 1H), 5.22 (m, 1H), 4.64 (m, 2H), 3.79 (m, 1H), 2.81 (m, 4H), 2.61 (m5 1H ), 2.23 (m, 3H), 1.78 (m, 3H), 1.50 (m, 13H); LC-MS: 528,529 [M+H]+. The title compound is isolated from the use of AD-4-25. Column particle size (//) : 5 Column size (mm): 21 X 250 Example l32(a), first dissolved peak 1 H NMR (δ ) 8.67 (s, 2H), 6.32 (bs, 1H) , 5.25 (m, 1H), 4.65 (m, 2H), 3.79 (m, 1H), 2.81 (m, 4H), 2.66 (m, 1H), 2.22 (s, 3H), 1.79 (m, 3H), 1.50 (m, 13H); LC-MS: 528, 529 [M+H]+. Example 132(b), second elution peak 1 H NMR ((5 ) 8.67 (s, 2H), 6.32 (bs, 1H), 5.24 (m, 1H), 4.58 (m, 2H), 3.80 (m, 1H), 2.80 (m, 4H), 2.62 (m, 1H), 2.22 (s, 3H), 1.78 (m, 3H) ), 1.51 (m, 13H); LC-MS: 529 [M+H]+. Example 133 133151 • 262 · 200906818 4-(1-(3,5-difluoropyridin-2-yl)ethoxy) _]^_(5_methyl_111_pyrazole_3_yl)_6_hofolinyl-1,3,5·three tillage-2-amine using a procedure similar to that described for the synthesis of Example 100 1_(3,5_二败峨 bit-2-yl)-2-decyloxyethanol (intermediate 107) 4_Chloro-[Ν-(3_fluorenyl-m-pyrazol-5-yl)-6-morpho-p-linyl-1,3,5-trinyl-2-amine (intermediate 15) reaction, providing the title Compound, a mixture of palmomers. H NMR (300 MHz, MeOD) δ ppm 1.69 (d, J = 6.59 Hz, 3H) 2.27 (s, 3H) 3.47- 4.02 (m, 8H) 6.11-6.44 ( m, 2H), 7.61 (ddd, 1H) 8.35 (s, 1H). LC-MS: 419 [M+Hf. Column and solvent conditions. The title compound is used under conditions (A) and AD-4-20. Purified column particle size (#): 5 Column size (mm): 21 X 250 Purity after purification: Sample purity conditions (B) and AD-4-20 confirmed dissolution time (minutes): 5 streams Rate (ml/min): 5 first absorption peak (residence time: minute) 1.87 second absorption peak (residence time: minute) 2.53 Example 133(a), first dissolution peak 1H NMR (300 MHz, MeOD 5 ppm 1.69 (d, J = 6.59 Hz, 3H) 2.27 (s, 3H) 3.47- 4.02 (m, 8H) 6.11-6.44 (m, 2H), 7.61 (ddd, 1H) 8.35 (s, 1H). LC-MS ·· 419 [M+H]+. Example 133(b), second elution peak 133151 •263 · 200906818 1 H NMR (300 MHz, MeOD) &lt;5 ppm 1.69 (d, J = 6.59 Hz, 3H) 2.27 (s, 3H) 3.47-4.02 (m, 8H) 6.11-6.44 (m, 2H), 7.61 (ddd, 1H) 8.35 (s, 1H). LC-MS : 419 [M+H Example 134 N2-(l-(5-Fluoropyridin-2-yl)-2-methoxyethyl)-N4-(S-fluorenyl-1H-pyrazol-3-yl)-6 - morphine-1,3,5-trinol-2,4-diamine using a procedure similar to that described for the synthesis of Example 11 'N2-(1-(5-fluoropyridin-2-yl)- 2-methoxyethyl)·Ν4 -(5-fluorenyl-lH-p-pyrazol-3-yl)-6-moffolinyl-1,3,5-trin-2,4-diamine (Intermediate 131) is reacted with chloroform, providing the title compound as a mixture of the palmo isomers. lR NMR (300 MHz, MeOD) δ ppm 2.25 (s, 3H) 3.36 (s, 3H) 3.52-4.06 (m, 10H) 5.16-5.44 (m, 1H) 6.05 (s, 1H) 7.30-7.79 (m, 2H) 8.42 (s5 1H). LC-MS : 430 [M+H]+. Column and solvent conditions

標題化合物係使用對掌性HPLC進行對掌性純化 , 管柱：Chirapak ADThe title compound was purified by palmitic HPLC, column: Chirapak AD

I \ 尺寸：250 X 20毫米，10 # 流動相：10%己烷’ 90% 1:1乙醇：甲醇，〇·1%二乙胺（v/v/v) 流率（毫升/分鐘）：20 偵測（毫微米）：220 實例134(a)，第一個溶離峰 H NMR δ ppm 2,25 (s, 3H) 3.36 (s, 3H) 3.52-4.06 (m5 l〇H) 5 16-5 44 (m，1H) 6·05 (s，1H) 7.30-7.79 (m，2H) 8·42 (s，1H). LC-MS : 430 [M+H]+. 133151 -264 · 200906818 實例l34(b)，第二個溶離峰 !H NMR (300 MHz, MeOD) δ ppm 2.25 (s, 3H) 3.36 (s, 3H) 3.52-4.06 (m, 10H) 5.16-5.44 (m, 1H) 6.05 (s, 1H) 7.30-7.79 (m, 2H) 8.42 (s, 1H). LC-MS ： 430 [M+H]+ 實例135 6-(3-氟基六氫吡啶小基）_N2_((S)小(5_氟基嘧啶_2_基）乙基)_n4_ (5-甲基-1H-吡唑·3·基）-l，3,5-三畊-2,4-二胺 使用類似關於實例11合成所述之程序，使⑻_6_氣^-(丨分 氟基嘧啶-2-基）乙基）-N4-(5-曱基-1H-吡唑-3-基）-1,3,5-三畊-2,4-二胺（中間物17)與3-氟基六氫吡啶鹽酸鹽反應，提供標題化 合物，為對掌異構物之混合物。 1 H NMR ((5 ) 8.70 (s，2H), 6.39 (s，1H)，5.22 (m，1H)，4.55 (m，1H)，3.83 (m，4H)，2·25 (s，3H)，1.86 (m，3H)，1_57 (m，4H) ; LCMS : 417 [M+H]+. 管柱與溶劑條件 標題化合物係使用條件（A)與〇j_3_2〇分離 管柱粒子大小（μ) : 5 管柱尺寸（毫米）：21 X 250 實例135(a)，第一個溶離之化合物 1 H NMR ( 5 ) 8.68 (s, 2H), 5.99 (bs, 1H), 5.19 (m, 1H), 4.64 (m, 1H), 3.71 (m, 4H), 2.23 (s，3H), 1.84 (m，3H), 1.55 (m, 4H) ; LCMS : 417 [M+H]+· 實例135(b)，第二個溶離之化合物 !H NMR ) 8.66 (s, 2H), 6.10 (bs, 1H), 5.18 (m, 1H), 4.53 (m, 1H), 3.71 (m, 4H)，2.23 (s, 3H), 1.83 (m，3H), 1.55 (m, 4H) ; LCMS : 417 [M+H]+. 實例136 133151 •265- 200906818 (S)-N2-(l_(5-氣基’咬_2·基）乙基）_6_嗎福啉基_n4_(5 (2_(吡咬^ 基）乙基）-1Η-吡唑-3-基）-1,3,5-三畊-2,4-二胺 將（S)-4-氯氟基嘧啶-2-基）乙基&gt;6_嗎福啉基十“—三 畊-2-胺（中間物132，170毫克，〇.50毫莫耳）、5_(2 (吡啶冰基） 乙基）-1Η-吡唑-3-胺（中間物168，94亳克，〇·50亳莫耳）、BINAp (31.2 毫克，〇_〇5 毫莫耳）、Pd2(dba)3(2291 毫克，〇〇3 毫莫耳） 及Cs2C〇3 (408毫克，1.25毫莫耳）裝填於微波管件中，接著為 二氧陸圜（1.5毫升）。使混合物脫氣，並以％沖洗。將反應 物在95°C下加熱8小時。於減壓下蒸發揮發性物質，及藉 ISCO純化，獲得標題化合物（13毫克）。 實例137 N -((R)-l-(3,5-一炎p比咬-2-基)-2-甲氧基乙基)-6-(2-(甲氧基甲基） 嗎福淋基）-Ν4·(5-甲基-1H-P比唑-3-基）-1，3,5-三畊-2,4-二胺 使用類似關於實例11合成所述之程序’使（11)_6_氣_Ν2_(1_ (3,5-二氟吡啶-2-基）-2-甲氧基乙基）-N4-(5-曱基-1Η-吡唑-3-基）-I，3,5-三畊_2,4·二胺（中間物42，15〇毫克，〇 %毫莫耳）與2 (甲 氧基甲基）嗎福淋（59.5毫克，0.45毫莫耳）反應’提供標題化 合物，為非對映異構物之混合物。 4 NMR (300 MHz，MeOD) 6 ppm 8.26 (寬廣 s·，1H)，7.45 (m，1H)， 5.94 (寬廣 s.，1H)，5.55 (t, J = 6.50 Hz，1H), 4_46 (d，J = 12.62 Hz, 1H)， 4.36 (d, J = 13.56 Hz, 1H), 3.81 (d, J = 11.11 Hz, 1H), 3.67 (m, 2H), 3.41 (m, 4H), 3.29 (s, 3H), 3.25 (s, 3H), 2.92 (m5 1H), 2.66 (dd, J = 12.90, 10.83 Hz, 1H)，2_13 (寬廣5.，3印· LCMS ： 492.2 [M+H]+. 133151 -266- 200906818 管柱與溶劑條件 標題化合物係使用對掌性HPLC分離 管柱尺寸：AD 2 X 25公分，10微米 流動相：70%己烷，30%異丙醇，0.1%二乙胺 流率（毫升/分鐘）：20毫升/分鐘 偵測（毫微米）：254 純化後純度檢驗 試樣純度係使用Chiralcel OJ-H (對掌性HPLC)確認 管柱尺寸：4.6 X 100毫米 流動相：70%己烷，30%異丙醇，0.1%二乙胺 流率：5毫升/分鐘 壓力：120巴I \ Size: 250 X 20 mm, 10 # Mobile phase: 10% hexane '90% 1:1 Ethanol: methanol, 〇·1% diethylamine (v/v/v) Flow rate (ml/min): 20 Detection (nm): 220 Example 134(a), first dissolution peak H NMR δ ppm 2,25 (s, 3H) 3.36 (s, 3H) 3.52-4.06 (m5 l〇H) 5 16- 5 44 (m,1H) 6·05 (s,1H) 7.30-7.79 (m,2H) 8·42 (s,1H). LC-MS : 430 [M+H]+. 133151 -264 · 200906818 Examples L34(b), the second dissolved peak! H NMR (300 MHz, MeOD) δ ppm 2.25 (s, 3H) 3.36 (s, 3H) 3.52-4.06 (m, 10H) 5.16-5.44 (m, 1H) 6.05 (s, 1H) 7.30-7.79 (m, 2H) 8.42 (s, 1H). LC-MS: 430 [M+H]+ Example 135 6-(3-Fluorohexahydropyridinyl)_N2_((S ) small (5-fluoropyrimidin-2-yl)ethyl)_n4_ (5-methyl-1H-pyrazole·3·yl)-l,3,5-trinol-2,4-diamine is similar For the synthesis of the procedure described in Example 11, (8) _6_ gas^-(丨 fluoropyrimidin-2-yl)ethyl)-N4-(5-fluorenyl-1H-pyrazol-3-yl)-1, 3,5-Tricotin-2,4-diamine (Intermediate 17) is reacted with 3-fluorohexahydropyridine hydrochloride to provide the title compound as a mixture of the mixture. 1 H NMR ((5 ) 8.70 (s, 2H), 6.39 (s, 1H), 5.22 (m, 1H), 4.55 (m, 1H), 3.83 (m, 4H), 2·25 (s, 3H) , 1.86 (m, 3H), 1_57 (m, 4H) ; LCMS : 417 [M+H]+. Column and solvent conditions title compound used conditions (A) and 〇j_3_2 〇 separation column particle size (μ) : 5 Column Size (mm): 21 X 250 Example 135(a), the first dissolved compound 1 H NMR ( 5 ) 8.68 (s, 2H), 5.99 (bs, 1H), 5.19 (m, 1H) , 4.64 (m, 1H), 3.71 (m, 4H), 2.23 (s, 3H), 1.84 (m, 3H), 1.55 (m, 4H) ; LCMS : 417 [M+H]+· Example 135 (b ), the second dissolved compound!H NMR ) 8.66 (s, 2H), 6.10 (bs, 1H), 5.18 (m, 1H), 4.53 (m, 1H), 3.71 (m, 4H), 2.23 (s , 3H), 1.83 (m, 3H), 1.55 (m, 4H) ; LCMS : 417 [M+H]+. Example 136 133151 •265- 200906818 (S)-N2-(l_(5-gas-based 'bite _2·yl)ethyl)_6_morpholineyl_n4_(5 (2_(pyridyl)ethyl)-1Η-pyrazol-3-yl)-1,3,5-three tillage-2 , 4-diamine will be (S)-4-chlorofluoropyrimidin-2-yl)ethyl &gt; 6-norfosolinyl ten "-three tillage-2-amine (intermediate 132, 170 mg, 〇. 50 millimoles), 5_(2 (pyridyl) Ice-based) ethyl)-1Η-pyrazol-3-amine (intermediate 168,94 gram, 〇·50 亳 Mo), BINAp (31.2 mg, 〇_〇5 mM), Pd2 (dba) 3 (2291 mg, 〇〇3 mmol) and Cs2C〇3 (408 mg, 1.25 mmol) were filled in a microwave tube followed by dioxane (1.5 ml). The mixture was degassed and taken in % The reaction was heated at 95 ° C for 8 hours. The title compound (13 mg) was obtained. 5- inflammatory p-but-2-yl)-2-methoxyethyl)-6-(2-(methoxymethyl)norfos)-Ν4·(5-methyl-1H- P-pyrazol-3-yl)-1,3,5-trinol-2,4-diamine was synthesized using a procedure similar to that described in Example 11 '[11]_6_气_Ν2_(1_ (3,5 -difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-mercapto-1Η-pyrazol-3-yl)-I,3,5-three tillage_2,4· Diamine (intermediate 42, 15 mg, 〇% mmol) was reacted with 2 (methoxymethyl) miral (59.5 mg, 0.45 mmol) to provide the title compound as diastereomer. a mixture of things. 4 NMR (300 MHz, MeOD) 6 ppm 8.26 (broad s·, 1H), 7.45 (m, 1H), 5.94 (broad s., 1H), 5.55 (t, J = 6.50 Hz, 1H), 4_46 (d , J = 12.62 Hz, 1H), 4.36 (d, J = 13.56 Hz, 1H), 3.81 (d, J = 11.11 Hz, 1H), 3.67 (m, 2H), 3.41 (m, 4H), 3.29 (s , 3H), 3.25 (s, 3H), 2.92 (m5 1H), 2.66 (dd, J = 12.90, 10.83 Hz, 1H), 2_13 (wide 5., 3 marks · LCMS: 492.2 [M+H]+. 133151 -266- 200906818 Column and Solvent Conditions The title compound was isolated using a palmitic HPLC column size: AD 2 X 25 cm, 10 μm mobile phase: 70% hexane, 30% isopropanol, 0.1% diethylamine Flow rate (ml/min): 20 ml/min detection (nm): 254 Purity test purity after purification. Chiralcel OJ-H (for palmar HPLC) confirm column size: 4.6 X 100 mm mobile phase : 70% hexane, 30% isopropanol, 0.1% diethylamine flow rate: 5 ml / min Pressure: 120 bar

烘箱溫度：35°C 偵測：254毫微米 實例137(a)，第一個溶離峰 1 H NMR (300 MHz, CDC13) 5 ppm 8.51 (寬廣 s·, 1H)，8.26 (d，J = 1.88 Hz, 1H)，7.12 (t, J = 9.51 Hz, 1H), 6_10 (寬廣 s_，1H), 5.76 (寬廣 s” 1H)， 4.41 (m, 2H), 3.92 (m, 1H), 3.72 (m, 2H), 3.45 (m, 8H), 3.26 (s, 3H), 2.95 (q, J = 7.35 Hz, 2H), 2.79 (t, J = 11.77 Hz, 1H), 2.21 (s, 3H) LCMS : 492.2 [M+H]+ 實例137(b)，第二個溶離峰 1 H NMR (300 MHz,氯仿-d) 5 ppm 8.54 (寬廣 s” 1H), 8.26 (d，J = 1.70 Hz, 1H)，7_12 (t, J = 7.63 Hz，1H)，6·10 (寬廣 s·，1H), 5.76 (dd, J = 3.77, 1.13 Hz, 1H), 4.42 (m, 2H), 3.92 (d, J = 9.61 Hz, 1H), 3.72 (m, 2H), 133151 - 267- 200906818 3.54 (m, 2H), 3.39 (m, 6H), 3.27 (s, 3H), 2.97 (m, 2H), 2.70 (m5 1H), 2.17 (m, 3H). LC-MS ： 492.2 [M+H]+ 實例138 2-(4-(4-((R)-l-(3,5-二氟吡啶-2-基）-2-甲氧基乙胺基）-6-(5-甲基 -1H-吡唑-3-基胺基)，1，3,5_三畊-2-基)嗎福啉-2-基）乙腈 使用類似關於實例11合成所述之程序，使⑻各氯 -N2-(l-(3,5-二氟吡啶-2_基）-2-甲氧基乙基）-N4-(5-曱基-1H-吡哇 -3-基）-1，3,5-二p井-2,4-&gt;一月女（中間物42，150毫克，0.38毫莫耳） 與2-(嗎福啉_2-基）乙腈HC1 (中間物135，47.7毫克，0.38毫莫 耳）反應，提供標題化合物。 LC-MS ： 487.4 [M+H]+Oven temperature: 35 ° C Detection: 254 nm Example 137 (a), first dissolution peak 1 H NMR (300 MHz, CDC13) 5 ppm 8.51 (broad s·, 1H), 8.26 (d, J = 1.88 Hz, 1H), 7.12 (t, J = 9.51 Hz, 1H), 6_10 (broad s_, 1H), 5.76 (broad s) 1H), 4.41 (m, 2H), 3.92 (m, 1H), 3.72 (m , 2H), 3.45 (m, 8H), 3.26 (s, 3H), 2.95 (q, J = 7.35 Hz, 2H), 2.79 (t, J = 11.77 Hz, 1H), 2.21 (s, 3H) LCMS : 492.2 [M+H]+ Example 137(b), second elution peak 1 H NMR (300 MHz, chloroform-d) 5 ppm 8.54 (broad s) 1H), 8.26 (d, J = 1.70 Hz, 1H) , 7_12 (t, J = 7.63 Hz, 1H), 6·10 (broad s·, 1H), 5.76 (dd, J = 3.77, 1.13 Hz, 1H), 4.42 (m, 2H), 3.92 (d, J = 9.61 Hz, 1H), 3.72 (m, 2H), 133151 - 267- 200906818 3.54 (m, 2H), 3.39 (m, 6H), 3.27 (s, 3H), 2.97 (m, 2H), 2.70 (m5 1H), 2.17 (m, 3H). LC-MS: 492.2 [M+H] + EXAMPLE 138 2-(4-(4-((R)-l-(3,5-difluoropyridin-2-yl) )-2-methoxyethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino), 1,3,5-trin-2-yl)morpholine-2 -base) acetonitrile using a procedure similar to that described for the synthesis of Example 11 (8) each chloro-N2-(l-(3,5-difluoropyridin-2-yl)-2-methoxyethyl)-N4-(5-fluorenyl-1H-pyroxy-3-yl)- 1,3,5-two p well-2,4-&gt; January female (intermediate 42,150 mg, 0.38 mmol) with 2-(morpholine-2-yl)acetonitrile HC1 (intermediate 135 , 47.7 mg, 0.38 mmol, reaction afforded the title compound. LC-MS : 487.4 [M+H]+

1H NMR (300 MHz, MeOD) δ ppm 8.41 (d, J = 2.07 Hz, 1H), 7.65 (td, J =9.18, 2.35 Hz，1H)，5.88 (寬廣 s.，1H)，5_71 (寬廣 s·，1H)，4.67 (m， 1H)，4.52 (m，1H)，4.01 (dd，卜 10.36, 2.45 Hz，1H)，3.82 (m，2H), 3.64 (m, 2H), 3.40 (s, 3H), 3.19 (d, J = 14.88 Hz, 1H), 2.99 (m, 1H), 2.78 (d, J =5.84 Hz, 2H), 2.35 (s, 3H). 實例139 6·(2_(—氮四園-1-基甲基）嗎福啉基）_N2·㈣小(3,5_二氟吡啶·2_ 基）-2-甲氧基乙基)-IV4 -(5_甲基·1H_吡唑j·基”，於三畊_2,4_二胺 使用類似關於實例11合成所述之程序，使（尺)_6_氯_Ν2 -θα】-二 氟吡啶 -2-基 ）-2-甲氧 基乙基 ）_N4_(5_ 甲基 _出_吡 唑 基 ）· 1，3,5-三畊-2,4-二胺（中間物42，18〇毫克，〇 5〇毫莫耳）與2 (一 氮四圜-1-基甲基）嗎福啉鹽酸鹽（中間物134，93毫克’ 〇 6〇 133151 -268 - 200906818 毫莫耳）反應，提供標題化合物。 1 H NMR (300 MHz, MeOD) δ ppm 8.29 (m, 1H), 7.46 (m, 1H), 6.27 (m 1H)，5.61 (m，2H)，4.39 (t，J = 12.72 Hz, 2H)，3.80 (d, J = 10.93 Hz，1H) 3.66 (dd, 3H), 3.31 (m, 4H), 2.86 (m, 1H), 2.54 (m, 4H), 2.07 (m, 6H). 實例140 2-((R)_4-(4-((R)-l-(3,5-一 氣 p比咬-2-基)-2-甲氧基乙胺基)-6-(5-曱基 -1H-P比吐-3-基胺基）-1,3,5-三_ -2-基）嗎福淋-3-基）乙腈 使用類似關於實例62合成所述之程序，使（尺)_6_氣_N2 (3,5-二氟吡啶-2-基）-2-甲氧基乙基）_ν4-(5-甲基-1H-吡唑_3-基）_ 1，3,5-三畊-2,4-二胺（中間物42 ’ 180毫克，0.45毫莫耳）與 (R)-2-(嗎福啉-3-基）乙腈，TFA鹽（中間物137，218毫克，〇 91 毫莫耳）反應，提供標題化合物。 LC-MS : 487 [M+H]+. NMR (MeOD) 5 8.27 (s, 1H), 7.46 (t, 1H), 6.25 (br s, 1H), 5.57 (m, 1H), 4.83 (m, 1H), 4.29 (m, 1H), 3.85 (d, 2H), 3.71 (m, 1H), 3.66 (m, 1H), 3.54 (m, 1H), 3.40 (m, 1H), 3.26 (s, 3H), 3.04 (m, 1H), 2.89 (m, 1H), 2.73 (m, 1H), 2.16 (s, 3H). 實例Ml-lW係使用類似關於實例u合成所述之程序製 成。 實例141 N仰㈣苯祕基HH_5_基邮丨叫^基㈣_2_ 基）乙基】_6-嗎福啉_4_基畊_2,4二胺 起始物KS)-6|N2.(5普氟基苯乙基&gt;1H《口坐福)_n4_ (K5-氟基錢_2_基）乙基）义仏三_ %-二胺（中間物！叫與 133151 -269- 200906818 嗎福P林。 LC-MS ： 509 [M+H]+. JH NMR δ 8.75 (s, 2H) 7.19-7.23 (m, 2H) 7.01 (t, 2H) 5.83 (bs, 1H) 5.34 (q, 1H) 3.64-3.84 (m, 8H) 2.98 (m, 4H) 1.65 (d, 3H). 實例142 N-{3-[2-(3-氟苯基）乙基】-1H-吡唑-5-基}-N’-[(lS)-l-(5-氟基嘧啶_2-基）乙基】-6-嗎福啉_4_基-1，3,5-三啼-2,4_二胺 起始物質··（S)-6_氯-N2-(5-(3-氟基苯乙基）-1Η-吡唑_3-基）-N4-(1-(5-氟基嘧咬-2-基）乙基）-1，3,5-三_ _2,4·二胺（中間物142)與 嗎福V*林。 LC-MS ： 509 [M+H]+. 1 H NMR δ 8.69 (s, 2Η) 7.26 (dd, 1H) 6.86-7.03 (m, 3H), 5.23 (q, 1H) 3.54-3.71 (m, 8H) 2.84-3.01 (m, 4H) 1.56 (d, 3H). 實例143 N-{3-[2-(3,5-二氟苯基）乙基】-1H-吡唑-5-基}-N’-[(lS)-l-(5-氟基嘧 啶-2-基）6基]-6-嗎福啉-4-基-1，3,5-三畊-2,4-二胺 起始物質.（S)-6-氯-N2-(5-(3,5-二鼠苯乙基yiH-p比唾-3-基）-N4· (1-(5-氟基嘧啶-2-基）乙基）-1，3,5-三畊-2,4-二胺（中間物143)與 嗎福P林。 LC-MS ： 527 [M+H]+. NMR δ 8.71 (s, 2Η) 6.85 (d, 2H) 6.76 (dd, 1H) 5.25 (q, 1H) 3.58-3.74 (m, 8H) 2.90-3.03 (m, 4H) 1.58 (d, 3H). 實例144 N-{3-[2-(2,4-二氟苯基）乙基】-1H-吡唑 _5_基}-N’-[(lS)-l-(5-氟基嘧 133151 -270- 200906818 啶_2·基）乙基]·6_嗎福啉_4_基-1，3,5-三畊_2,4-二胺 起始物質：（8)-6-氣-1^2-(5-(2,4-二氟苯乙基）-1沁吡唑-3-基）-分-(1-(5_氟基0^ °定-2-基）乙基）-1，3,5-三喷-2,4-二胺（中間物144)與 嗎福p林。 LC-MS ： 527 [M+H]+. 1 H NMR δ 8.71 (s, 2Η) 7.21-7.28 (m, 1H) 6.85-6.94 (m, 2H) 5.21 (q, 1H) 3.55- 3.74 (m, 8H) 2.83-3.04 (m, 4H) 1.58 (d, 3H). 實例145 Ν-{3-[2-(3,4·二氟苯基）乙基]-1H-吡唑-5-基}-N，-[(lS)-l-(5-氟基嘴 咬-2-基）乙基】·6-嗎福p林-4-基·1，3,5-二喷-2,4_二胺 起始物質：⑻各氯-Ν2 -(3-(3,4-二氟苯乙基）-lH-吡唑-5-基）-Ν4 -(1-(5-氟基喂咬-2-基）乙基）-1，3,5-三ρ井-2,4-二胺（中間物145)與 嗎福淋。 LC-MS : 527 [Μ+Η]+. ]H NMR (J 8.71 (s, 2H) 7.10-7.21 (m, 2H) 7.01 (bs, 1H) 5.25 (q, 1H) 3.55- 3.74 (m, 8H) 2.82-3.0 (m, 4H) 1.58 (d, 3H). 實例146 N-{3-[2-(2,6-二氟苯基）乙基】-1H-吡唑-5_基}-N，-[(lS)-l-(5-氟基嘧 咬-2-基）乙基]-6·嗎福林_4_基-1，3,5_三啡-2,4·二胺 起始物質：6-氣-Ν-{3-[2·(2,6-二氟苯基）乙基]_ιη_吡唑_5-基}-]^'-[(18)-1-(5-|^基'1密17定-2-基）乙基]-1，3,5-三11井-2,4-二胺（中間 物146)與嗎福淋。 LC-MS ： 527 [Μ+Η]+. !H NMR (300 MHz, MeOD) δ ppm 8.71 (s, 2H) 7.19-7.29 (m, 1H) 133151 -271 · 200906818 6.88-6.93 (m，2H) 5.79 (寬廣 s，iH) 5.30 (q，1H) 3.52-3.82 (m, 8H) 2.93-3.05 (m, 4H) 1.60 (d, 3H). 實例147 (S)-N2-(5-(3,4·二甲氧苯乙基）_1H_吡唑_3-基）-N4-(l-(5-氟基嘧啶 -2-基）乙基）-6-嗎福淋基_i，3,5-三畊-2,4-二胺 起始物質：（(S)-6-氯-N2-(5-(3,4-二甲氧苯乙基）-1Η-吡唑-3-基）-N4-(l-(5-氟基嘧啶·2-基）乙基）-1,3,5-三畊-2,4-二胺（中間物 147)與嗎福啉。 LC-MS ： 551 [M+H]+. JH NMR (400 MHz, DMSO-d6) δ ppm 11.63 (s, 1H) 9.35 (s, 1H) 8.78 (s, 2H) 8.28 (s, 1H) 6.80-6.93 (m, 2H) 6.75 (dd, 1H) 6.28 (s, 1H) 5.24 (m, br, 1H) 3.68-3.77 (m, 6H) 3.58 (d, 8H) 2.87 (m, 4H) 1.52 (d, 3H). 實例148 N-[(lS)-l-(5-氟基嘧啶-2-基）乙基]-N，-{3-[2-(lH-咪唑-2-基）乙 基】-1Η-ρ比唑-5-基}冬嗎福淋_4_基-1，3,5-三畊-2,4-二胺 使用類似關於實例11合成所述之程序，使6_氯· 氟基嘧啶-2-基）乙基]-N’-{3-[2-(l-{p-(三曱基矽烷基）乙氧基]甲 基}-1Η-咪唑-2-基）乙基]-1H-吡唑-5-基}-1,3,5-三畊_2,4-二胺（中 間物171)與嗎福〇林反應，提供（s)-N2-(l-(5-l基u密咬_2_基）乙 基）-6-嗎福基-N4-(3-(2-(1-((2-(三甲基矽烧基）乙氧基）甲 基）-111-咪唑-2-基）乙基）-111-吡唑_5-基）-1，3,5-三啩-2,4-二胺。使 (S)-N2-(l-(5_氟基鳴。定-；2-基）乙基）冬嗎福3林基= 曱基矽烧基）乙氧基）曱基HH-咪唑-2-基）乙基&gt;1H_，比唾_5_ 基）-1,3,5-三_ -2,4-二胺溶於DCM中。將TFA與水添加至溶液 133151 -272· 200906818 中，並將反應物攪拌2小時。濃縮反應物，接著純化，獲得 標題化合物。 LCMS ： 481 [M+H]+ 1 H NMR (300 MHz, MeOD) &lt;5 ppm 8.75 (s, 2H) 7.49 (s, 2H) 5.31 (q, 1H) 3.59-3.86 (m, 8H) 3.08-3.26 (m, 4H) 1.63 (d, 3H). f 133151 -2731H NMR (300 MHz, MeOD) δ ppm 8.41 (d, J = 2.07 Hz, 1H), 7.65 (td, J = 9.18, 2.35 Hz, 1H), 5.88 (broad s., 1H), 5_71 (broad s) , 1H), 4.67 (m, 1H), 4.52 (m, 1H), 4.01 (dd, Bu 10.36, 2.45 Hz, 1H), 3.82 (m, 2H), 3.64 (m, 2H), 3.40 (s, 3H ), 3.19 (d, J = 14.88 Hz, 1H), 2.99 (m, 1H), 2.78 (d, J = 5.84 Hz, 2H), 2.35 (s, 3H). Example 139 6·(2_(-nitrogen four Park-1-ylmethyl)fosfolinyl)_N2·(tetra)small (3,5-difluoropyridin-2-yl)-2-methoxyethyl)-IV4 -(5-methyl·1H_pyridyl Azole j. group, in the three tillage _2,4-diamine using a procedure similar to that described in the synthesis of Example 11, to give (foot) _6_chloro-Ν2 - θα]-difluoropyridin-2-yl)-2 -methoxyethyl)_N4_(5-methyl-exo-pyrazolyl)· 1,3,5-trin-2,4-diamine (intermediate 42, 18 〇 mg, 〇 5 〇 millimol Reaction with 2 (azatetradec-1-ylmethyl) morpholine hydrochloride (Intermediate 134, 93 mg ' 〇 6 〇 133151 - 268 - 200906818 mM) provided the title compound. 1 H NMR (300 MHz, MeOD) δ ppm 8.29 (m, 1H), 7.46 (m, 1H), 6.27 (m 1H), 5.61 (m, 2H) ), 4.39 (t, J = 12.72 Hz, 2H), 3.80 (d, J = 10.93 Hz, 1H) 3.66 (dd, 3H), 3.31 (m, 4H), 2.86 (m, 1H), 2.54 (m, 4H), 2.07 (m, 6H). Example 140 2-((R)-4-(4-((R)-l-(3,5-a gas pbit-2-yl)-2-methoxy) Ethylamino)-6-(5-mercapto-1H-P than tola-3-ylamino)-1,3,5-tris-2-yl)moffolin-3-yl)acetonitrile is similar The procedure described for the synthesis of Example 62 was carried out to give (s) _6_gas_N2(3,5-difluoropyridin-2-yl)-2-methoxyethyl)_ν4-(5-methyl-1H- Pyrazole-3-yl)-1,3,5-trin-2,4-diamine (intermediate 42 '180 mg, 0.45 mmol) and (R)-2-(morpholin-3- Reaction of the acetonitrile, TFA salt ( Intermediate 137, 218 mg, s. LC-MS: 487 [M+H]+. NMR (MeOD) 5 8.27 (s, 1H), 7.46 (t, 1H), 6.25 (br s, 1H), 5.57 (m, 1H), 4.83 (m, 1H), 4.29 (m, 1H), 3.85 (d, 2H), 3.71 (m, 1H), 3.66 (m, 1H), 3.54 (m, 1H), 3.40 (m, 1H), 3.26 (s, 3H ), 3.04 (m, 1H), 2.89 (m, 1H), 2.73 (m, 1H), 2.16 (s, 3H). Example M1-lW was prepared using a procedure similar to that described for the synthesis of Example u. Example 141 N (4) Benzyl-based HH_5_-based 丨 ^ ^ (4)_2_ yl) ethyl] _6-morpholine _4_ _ _ 2, 4 diamine starting material KS) -6 | N2. (5 Pflufenylphenethyl &gt; 1H "mouth sitting blessing" _n4_ (K5-fluoroethanol 2_yl) ethyl) 仏 仏 _ %-diamine (intermediate! Called with 133151 -269- 200906818 P-L. LC-MS: 509 [M+H]+. JH NMR δ 8.75 (s, 2H) 7.19-7.23 (m, 2H) 7.01 (t, 2H) 5.83 (bs, 1H) 5.34 (q, 1H) 3.64-3.84 (m, 8H) 2.98 (m, 4H) 1.65 (d, 3H). Example 142 N-{3-[2-(3-fluorophenyl)ethyl]-1H-pyrazol-5-yl }-N'-[(lS)-l-(5-fluoropyrimidin-2-yl)ethyl]-6-morpholine_4_yl-1,3,5-triter-2,4_ Diamine starting material··(S)-6_Chloro-N2-(5-(3-fluorophenylethyl)-1Η-pyrazole-3-yl)-N4-(1-(5-fluoro) Pyrimidine-2-yl)ethyl)-1,3,5-tris-2,4.diamine (intermediate 142) and ruthenium V*. LC-MS: 509 [M+H]+. H NMR δ 8.69 (s, 2Η) 7.26 (dd, 1H) 6.86-7.03 (m, 3H), 5.23 (q, 1H) 3.54-3.71 (m, 8H) 2.84-3.01 (m, 4H) 1.56 (d, 3H). Example 143 N-{3-[2-(3,5-Difluorophenyl)ethyl]-1H-pyrazol-5-yl}-N'-[(lS)-l-(5- Fluoropyrimidin-2-yl)6-yl]-6 - morpholine-4-yl-1,3,5-tri-n--2,4-diamine starting material. (S)-6-chloro-N2-(5-(3,5-di-r-phenylene) yiH-p than sial-3-yl)-N4·(1-(5-fluoropyrimidin-2-yl)ethyl)-1,3,5-trin-2,4-diamine (intermediate 143) with phosphonin P. LC-MS: 527 [M+H]+. NMR δ 8.71 (s, 2 Η) 6.85 (d, 2H) 6.76 (dd, 1H) 5.25 (q, 1H) 3.58-3.74 ( m, 8H) 2.90-3.03 (m, 4H) 1.58 (d, 3H). Example 144 N-{3-[2-(2,4-difluorophenyl)ethyl]-1H-pyrazole_5_ }}-N'-[(lS)-l-(5-fluoropyrimidine 133151-270- 200906818 pyridine-2-yl)ethyl]·6_morpholine_4_yl-1,3,5- Three tillage 2,4-diamine starting material: (8)-6-gas-1^2-(5-(2,4-difluorophenethyl)-1沁pyrazol-3-yl)- Part-(1-(5-Fluoro0^°-2-yl)ethyl)-1,3,5-tripenta-2,4-diamine (intermediate 144) and phloem p. LC-MS : 527 [M+H]+. 1 H NMR δ 8.71 (s, 2 Η) 7.21-7.28 (m, 1H) 6.85-6.94 (m, 2H) 5.21 (q, 1H) 3.55- 3.74 (m, 8H) 2.83-3.04 (m, 4H) 1.58 (d, 3H). Example 145 Ν-{3-[2-(3,4·difluorophenyl)ethyl]-1H-pyrazol-5-yl} -N,-[(lS)-l-(5-fluoro-n-butyl-2-yl)ethyl]·6-?-fu-p-lin-4-yl·1,3,5-two-spray-2,4 _Diamine starting material: (8) each chloro-Ν2-(3-(3,4-difluorophenethyl)-lH-pyrazol-5-yl)-Ν4- (1-(5-fluoro-feeding bite) 2-yl)ethyl)-1,3,5-tri-p--2,4-diamine (intermediate 145) and whey. LC-MS : 527 [Μ+Η]+. ]H NMR (J 8.71 (s, 2H) 7.10-7.21 (m, 2H) 7.01 (bs, 1H) 5.25 (q, 1H) 3.55- 3.74 (m, 8H 2.82-3.0 (m, 4H) 1.58 (d, 3H). Example 146 N-{3-[2-(2,6-difluorophenyl)ethyl]-1H-pyrazole-5-yl}- N,-[(lS)-l-(5-fluoropyrimidin-2-yl)ethyl]-6·ofofolin_4_yl-1,3,5-tri-an-2,4·2 Amine starting material: 6-gas-Ν-{3-[2·(2,6-difluorophenyl)ethyl]_ιη_pyrazole_5-yl}-]^'-[(18)-1 -(5-|^-based '1 dimethyl 17-denyl-2-yl)ethyl]-1,3,5-tri-11 well-2,4-diamine (intermediate 146) and whollen. LC-MS : 527 [Μ+Η]+. !H NMR (300 MHz, MeOD) δ ppm 8.71 (s, 2H) 7.19-7.29 (m, 1H) 133151 -271 · 200906818 6.88-6.93 (m,2H) 5.79 (wide) s,iH) 5.30 (q,1H) 3.52-3.82 (m, 8H) 2.93-3.05 (m, 4H) 1.60 (d, 3H). Example 147 (S)-N2-(5-(3,4·2 Methoxyphenethyl)_1H_pyrazole-3-yl)-N4-(l-(5-fluoropyrimidin-2-yl)ethyl)-6-morphinyl _i,3,5-three Plowing 2,4-diamine starting material: ((S)-6-chloro-N2-(5-(3,4-dimethoxyphenethyl)-1Η-pyrazol-3-yl)-N4 -(l-(5-fluoropyrimidin-2-yl)ethyl)-1,3,5-trinol-2,4-diamine (middle 147) with morphine. LC-MS: 551 [M+H]+. JH NMR (400 MHz, DMSO-d6) δ ppm 11.63 (s, 1H) 9.35 (s, 1H) 8.78 (s, 2H) 8.28 (s, 1H) 6.80-6.93 (m, 2H) 6.75 (dd, 1H) 6.28 (s, 1H) 5.24 (m, br, 1H) 3.68-3.77 (m, 6H) 3.58 (d, 8H) 2.87 (m , 4H) 1.52 (d, 3H). Example 148 N-[(lS)-l-(5-fluoropyrimidin-2-yl)ethyl]-N,-{3-[2-(lH-imidazole- 2-yl)ethyl]-1Η-ρ-biazole-5-yl}wolfos _4_yl-1,3,5-trin-2,4-diamine was synthesized similarly to Example 11 Procedure for 6-chlorofluoropyrimidin-2-yl)ethyl]-N'-{3-[2-(l-{p-(tridecyldecyl)ethoxy]methyl}- 1Η-imidazol-2-yl)ethyl]-1H-pyrazol-5-yl}-1,3,5-three tillage 2,4-diamine (intermediate 171) reacted with rifampin (s)-N2-(l-(5-l-based urethane-2-yl)ethyl)-6-fosfosyl-N4-(3-(2-(1-((2-()) Ethyl pyridyl) ethoxy)methyl)-111-imidazol-2-yl)ethyl)-111-pyrazole-5-yl)-1,3,5-tritero-2,4-diamine . (S)-N2-(l-(5-Fluoryl- s-but-2-yl)ethyl) Winterfowl 3 linyl = fluorenyl fluorenyl) ethoxy) fluorenyl HH-imidazole 2-Based)ethyl&gt;1H_, is more soluble than saliv-5-yl-1,3,5-tris-2,4-diamine in DCM. TFA and water were added to solution 133151 - 272 · 200906818 and the reaction was stirred for 2 hours. The reaction was concentrated and purified to give the title compound. LCMS: 481 [M+H] + 1 H NMR (300 MHz, Me.) &lt;5 ppm 8.75 (s, 2H) 7.49 (s, 2H) 5.31 (q, 1H) 3.59-3.86 (m, 8H) 3.08- 3.26 (m, 4H) 1.63 (d, 3H). f 133151 -273

Claims (1)

Translated fromChinese

200906818 十、申請專利範圍： 1. 一種式⑴化合物：200906818 X. Patent application scope: 1. A compound of formula (1):或其藥學上可接受之鹽，其中 環A為雜環基’其中該雜環基係視情況在礙上被 況被R21&quot;取代； ⑽2取Γ’且其中該雜環基之任何抓部份基團係^ 環B為雜環基’其中該雜環基係視情況在碳上被—或多 個R4取代，且纟中該雜環基之任何擦部份錢係視二 況被取代； X 係選自-〇-、-NH-及-S-; R1係選自Η、i基、-CN、C&quot;烷基、c2 6烯基、c“炔 基、碳環基、雜環基、-ORi a、-SRi a、_N(R1 a ^、_N(Rl a )e(Q)R/b 、-N(Rla)N(Rla)2、-N02、-N(Rla)〇Ria、_〇N(Ria)2、_c(〇)H ' -C(0)Rlb、，C(0)2Rla、-C(0)N(Rla)2、-c(〇)N(Ria)(〇Rla)、 -0C(0)N(R1 a )2 ' -NCR1 a )C(0)2 R1 a ' ^(R1 a )C(0)N(R1 a )2 . -0C(0)Rlb 、-S(0)Rlb 、-S(0)2Rlb 、-S(〇)2N(Rla)2 、 -N(Rla)S(0)2Rlb、-C(Rla)=N(Rla)及-QRh^^oRia)，其中 該C! _6烧基、C2 _6稀基、C2 -6快基、碳環基及雜環基係 133151 200906818 視u況在碳上被—或多個RlQ取代，且其中該雜環基之 任何-NH-部份基團係視情況被Rl0*取代； Rla ’於各存在處，係獨立選自H、Ci_6烷基、碳環基及 &quot;f基其中该Α·6烧基、碳環基及雜環基，於各存在 處，係視情況且獨立地在碳上被一或多個RlQ取代，且 其中該雜環基之任何_NH_部份基團係視情況被ri〇*取 代； Rlb，於各存在處，係選自Cl_6烧基、c2 6稀基、^快 基、碳環基及雜環基，其中該。6烷基、C2 6烯基、C2 6 炔基、碳環基及雜環基，於各存在處，係視情況且獨 立地在碳上被一或多個R10取代，且其中該雜環基之任 何-NH-部份基團係視情況被Rl0*取代； R2係選自Η、i基、指、Cl_6烧基、c2 6婦基、^快 基、奴環基、雜環基、_〇R2 a、_SR2 a、_N(R2 a )2、_n(r2 a b 、-N(R2a)N(R2a)2、_N〇2、-N(R2a)OR2a、_ON(R2a)2、_c(〇)H、 -C(0)R2b . .C(〇)2R2a , _C(0)N(R2a)2 , -C(0)N(R2 a )(〇R2 a 0C(0)N(R2-)2 , -N(R2a)C(0)2R2a . -N(R2a)C(0)N(R2a)2 . -〇C(0)R2b、_s(〇)R2b、_s(〇)2R2b、s⑼雜、、 -N(R2a)S(0)2R2b、_C(R2a)=N(R2a)及 _c(R2a)=N(〇R2a)，其中 該匸!-6烧基、C2_6烯基、c：2 — 6炔基、碳環基及雜環基係 視情況在碳上被一或多個r2〇取代，且其中該雜環基之 任何-NH-部份基團係視情況被R2〇*取代； R2* ’於各存在處，係獨立選自q —烷基、碳環基、雜 環基、-C(0)H、-C(0)R2b、-C(0)2R2c、_c(0)N(R2a)2、-S(0)R2b、 133151 -2- 200906818 S(0)2 R、_S(〇)2 寧2 a )2、_c(r2 a )=n(r2 a )及 _c(r2 a )=n(〇r2 a ) ’其中該C丨-6烷基、碳環基及雜環基，於各存在處，係 視丨月况且獨立地在碳上被一或多個R20取代，且其中該 雜環基之任何_NH_部份基團係視情況被R2G*取代； R2a ’於各存在處，係獨立選自H、Ci 6烷基、碳環基及 雜％基，其中該Cl·6烷基、碳環基及雜環基，於各存在 處，係視情況且獨立地在碳上被一或多個取代，且 其中該雜環基之任何·ΝΗ_部份基團係視情況被R2〇*取 代； R2b ’於各存在處’係選自烧基、C2_6烯基、C2.6快 基、碳環基及雜環基，其中該院基、c2.6烯基、c2.6 炔基、碳環基及雜環基，於各存在處，係視情況且獨 立地在碳上被-或多個R2G取代，且其中該雜環基之任 何-NH-部份基團係視情況被R2〇*取代； Rm2C，於各存在處，係獨立選自Cl·6烷基、碳環基及雜 裱基，其中該Cl·6烷基、碳環基及雜環基，於各存在處， 係視情況且獨立地在碳上被一或多個”❶取代，且其中 該雜環基之任何·ΝΗ·部份基團係視情況被r2、代； R3係選自Η、鹵基、-CN、Cl_6烧基' c2 6稀基、^快 基、碳環基、雜環基、-0R3a、_SR3a、_N(Rn ' -N(R^)C(0)R3b . -N(R3a)N(R3a)2 . ,n〇2 ^ .N(R3a).〇R3a ^ -〇-N(R3a)2 . -C(0)H ^ -C(0)R3b . .C(〇)2R3a . _C(〇)N(R3a)2 . -C(〇)N(R3a)(OR3a) 、_〇c(〇)N(R3a)2 、_N(R3a)c(〇)2R3 、 -N(R3a)C(〇)N(R3a)2 . .〇C(0)R3 b . _S(〇)r3 b ^ _s(〇)2R3b ^ 133151 200906818 -S(〇)2N(R3a) 、 Nrp3aK N(R )S(〇)2R3b、-C(R3a)=N(R3a)及 _C(R3a)=N(〇R3 ^ j具中卜6燒基、C2-6烯基、C2.6炔基、 奴％基及雜環基係視情況在碳上被一或多個R3。取代， 且其中攻雜環基之任何_而_部份基團係視情況被R30* 取代； 化於各存在處，係獨立選自H、CH烧基、碳環基及 雜衣基’其中該C16院基、碳環基及雜環基，於各存在 處，係視情況且獨立地在碳上被一或多個R3G取代，且 其中該雜環基之任何_NH_部份基團係視情況被r3〇*取 代； R3b，於各存在處，係選自Cl 6院基、C2 6稀基、C2_^夬 基、奴％基及雜環基，其中該。^烷基、C2_6烯基、CM 炔基、奴裱基及雜環基，於各存在處，係視情況且獨 立地在碳上被一或多個圮〇取代，且其中該雜環基之任 何-NH-部份基團係視情況被R3〇*取代； R4係選自η、-基、_CN、。卜6烷基、。2 6烯基、一炔 基、碳環基、雜環基、_〇R4a、_SR4a、_N(R4a)2、 -N(R4a)C(〇)R4b、_N(R4a)N(R4a)2、_N〇2、_N(R4a)〇R4a ' _〇_N(R4a)2、-C(〇)H、-C(0)R4b、-C(〇)2R“、_C(0)N(R4a)2、 -C(0)N(R“)(OR4a&gt;〇c(〇)N(R4a)2 、 _N(R4a)C(〇)2R4a 、 -N(R4a)C(〇)N(R4a)2、_〇C(〇)R4b、_s(〇)R4b、s(〇)2R4b、 -S(0)2N(R4a)2 、 _N(R4a)S(〇)2R4b 、 _c(R4a)=N(R4a)及 ，其中該Ci 6烷基、c2 6烯基、c2-6炔基、 碳環基及雜環基係視情況在碳上被一或多個R4 G取代， 133151 200906818 且其中該雜環基之任何擺部份基團係視情況被r4〇* 取代； R4 ’於各存在處’係獨立選自Ci 6烧基、碳環基、雜 環基、-c_、_qo)R4b、_c(〇)2R4c、__、、_r4卜 ，2心、_s⑼2N(R4a)2、_c(R4a)哪4a)及撕a)哪内 ’其中該CV6㈣、碳環基及雜環基，於各存在處，係 視f月況且獨立地在碳上被一或多個R4〇取代，且其中該 雜4環基之任何-NH-部份基團係視情況被R4G*取代； t於各存在處，係獨立選自H、Cl·6院基、碳環基及 雜％基，其中該。I烷基、碳環基及雜環基於各存在 處，係視情況且獨立地在碳上被一或多個圮❹取代且 其中該雜環基之任何姻.部份基團係視情況被汉4 代：Or a pharmaceutically acceptable salt thereof, wherein ring A is a heterocyclic group, wherein the heterocyclic group is optionally substituted by R21&quot;; (10)2 is taken from 且' and wherein any of the heterocyclic groups The group B is a heterocyclic group wherein the heterocyclic group is optionally substituted on the carbon by a plurality of R 4 groups, and any moieties of the heterocyclic group in the oxime are substituted as appropriate; X is selected from the group consisting of -〇-, -NH-, and -S-; R1 is selected from the group consisting of fluorene, i-based, -CN, C&quot; alkyl, c2 6 alkenyl, c "alkynyl, carbocyclyl, heterocyclyl , -ORi a, -SRi a, _N(R1 a ^, _N(Rl a )e(Q)R/b , -N(Rla)N(Rla)2, -N02, -N(Rla)〇Ria, _〇N(Ria)2, _c(〇)H ' -C(0)Rlb,,C(0)2Rla, -C(0)N(Rla)2, -c(〇)N(Ria)(〇 Rla), -0C(0)N(R1 a )2 ' -NCR1 a )C(0)2 R1 a ' ^(R1 a )C(0)N(R1 a )2 . -0C(0)Rlb , -S(0)Rlb, -S(0)2Rlb, -S(〇)2N(Rla)2, -N(Rla)S(0)2Rlb, -C(Rla)=N(Rla), and -QRh^ ^oRia), wherein the C!-6 alkyl group, the C2_6 dilute group, the C2-6 fast group, the carbocyclic group and the heterocyclic group 133151 200906818 are replaced by a plurality of RlQ on the carbon, and wherein Any of the heterocyclic groups - The NH- moiety is optionally substituted by R10*; Rla' is independently selected from the group consisting of H, Ci-6 alkyl, carbocyclyl and &quot;f-based, wherein the 烧6 alkyl, carbocyclic group And a heterocyclic group, at each position, optionally substituted on the carbon by one or more R1Q, and wherein any _NH_ moiety of the heterocyclic group is optionally replaced by ri〇* Rlb, in each presence, is selected from the group consisting of a C 6 alkyl group, a c 2 6 dilute group, a fast group, a carbocyclic group, and a heterocyclic group, wherein the 6 alkyl group, the C 2 6 alkenyl group, the C 2 6 alkynyl group, and the carbon The cyclo and heterocyclic groups, where present, are optionally substituted on the carbon by one or more R10, and wherein any -NH- moiety of the heterocyclic group is optionally Rl0* Substituted; R2 is selected from the group consisting of hydrazine, i group, finger, Cl_6 alkyl group, c2 6 base group, ^ fast group, cyclyl group, heterocyclic group, _〇R2 a, _SR2 a, _N(R2 a )2, _n (r2 ab , -N(R2a)N(R2a)2, _N〇2, -N(R2a)OR2a, _ON(R2a)2, _c(〇)H, -C(0)R2b . .C(〇) 2R2a , _C(0)N(R2a)2 , -C(0)N(R2 a )(〇R2 a 0C(0)N(R2-)2 , -N(R2a)C(0)2R2a . -N (R2a)C(0)N(R2a)2 . -〇C(0)R2b, _s(〇)R2b , _s(〇)2R2b, s(9), , -N(R2a)S(0)2R2b, _C(R2a)=N(R2a), and _c(R2a)=N(〇R2a), wherein the 匸!-6 The alkyl group, the C2_6 alkenyl group, the c:2-6 alkynyl group, the carbocyclic group and the heterocyclic group are optionally substituted on the carbon by one or more r2〇, and wherein any -NH- moiety of the heterocyclic group The group is optionally substituted by R2〇*; R2*' is independently selected from the group consisting of q-alkyl, carbocyclyl, heterocyclyl, -C(0)H, -C(0)R2b, -C(0)2R2c, _c(0)N(R2a)2, -S(0)R2b, 133151 -2- 200906818 S(0)2 R, _S(〇)2 宁2 a)2, _c(r2 a)=n(r2 a ) and _c(r2 a )=n(〇r2 a ) ' wherein the C丨-6 alkyl group, the carbocyclic group and the heterocyclic group are present at each Independently substituted on the carbon by one or more R20, and wherein any _NH_ moiety of the heterocyclic group is optionally substituted by R2G*; R2a' is independently selected from H, Ci at each a 6 alkyl group, a carbocyclic group, and a hetero aryl group, wherein the Cl. 6 alkyl group, the carbocyclic group, and the heterocyclic group are each optionally substituted on the carbon by one or more, and Wherein any of the heterocyclic groups The group is optionally substituted by R2〇*; R2b 'in each of the positions' is selected from the group consisting of an alkyl group, a C2_6 alkenyl group, a C2.6 fast group, a carbocyclic group and a heterocyclic group, wherein the base group, c2.6 Alkenyl, c2.6 alkynyl, carbocyclyl and heterocyclyl, in each occurrence, are optionally substituted on the carbon by - or a plurality of R2G, and wherein any -NH- of the heterocyclic group Some of the groups are optionally substituted by R2〇*; Rm2C, at each position, is independently selected from the group consisting of Cl.6 alkyl, carbocyclyl and heterofluorenyl, wherein the Cl.6 alkyl, carbocyclyl and Heterocyclyl, at each occurrence, is optionally substituted on the carbon by one or more "❶", and wherein any of the heterocyclic groups are optionally employed by the formula; R3 is selected from the group consisting of hydrazine, halo, -CN, Cl_6 alkyl 'c2 6 dilute, ^ fast radical, carbocyclyl, heterocyclyl, -0R3a, _SR3a, _N(Rn ' -N(R^)C( 0) R3b . -N(R3a)N(R3a)2 . ,n〇2 ^ .N(R3a).〇R3a ^ -〇-N(R3a)2 . -C(0)H ^ -C(0) R3b . .C(〇)2R3a . _C(〇)N(R3a)2 . -C(〇)N(R3a)(OR3a) , _〇c(〇)N(R3a)2 , _N(R3a)c( 〇) 2R3 , -N(R3a)C(〇)N(R3a)2 . .〇C(0)R3 b . _S(〇)r3 b ^ _s(〇)2R3b ^ 133151 200906818 -S(〇)2N(R3a) , Nrp3aK N(R )S(〇)2R3b, -C(R3a)=N(R3a) and _C(R3a)=N(〇 R3^j has a hexyl group, a C2-6 alkenyl group, a C2.6 alkynyl group, a sulphonyl group and a heterocyclic group, optionally having one or more R3 groups on the carbon. Substituting, and wherein any of the _ and _ partial groups of the heterocyclic group are replaced by R30* as appropriate; and are independently selected from the group consisting of H, CH alkyl, carbocyclyl and clocheyl The C16, carbocyclyl and heterocyclyl, at each position, are optionally substituted on the carbon by one or more R3G, and wherein any _NH- moiety of the heterocyclic group It is optionally substituted by r3〇*; R3b, in each of its existence, is selected from the group consisting of Cl 6 , C 2 6, C 2 —, sulfhydryl, and heterocyclic. ^alkyl, C2_6 alkenyl, CM alkynyl, sulfenyl and heterocyclyl, in each case, optionally substituted on the carbon by one or more hydrazines, and wherein the heterocyclic group Any -NH- moiety is optionally substituted by R3〇*; R4 is selected from η, -yl, _CN. 6 alkyl,. 2 6 alkenyl, monoalkynyl, carbocyclyl, heterocyclic, 〇R4a, _SR4a, _N(R4a)2, -N(R4a)C(〇)R4b, _N(R4a)N(R4a)2 _N〇2, _N(R4a)〇R4a ' _〇_N(R4a)2, -C(〇)H, -C(0)R4b, -C(〇)2R", _C(0)N(R4a) 2. -C(0)N(R")(OR4a&gt;〇c(〇)N(R4a)2, _N(R4a)C(〇)2R4a, -N(R4a)C(〇)N(R4a)2 , _〇C(〇)R4b, _s(〇)R4b, s(〇)2R4b, -S(0)2N(R4a)2, _N(R4a)S(〇)2R4b, _c(R4a)=N(R4a And wherein the Ci 6 alkyl group, c2 6 alkenyl group, c2-6 alkynyl group, carbocyclic group and heterocyclic group are optionally substituted on the carbon by one or more R 4 G, 133151 200906818 and wherein the heterocyclic ring Any pendulum moiety of the group is optionally substituted by r4〇*; R4 'in each place' is independently selected from Ci 6 alkyl, carbocyclyl, heterocyclyl, -c_, _qo) R4b, _c ( 〇) 2R4c, __, _r4, 2 core, _s(9)2N(R4a)2, _c(R4a) which 4a) and tear a) where 'where CV6(tetra), carbocyclyl and heterocyclic group, in each presence, Depending on the condition of the month and independently substituted by one or more R 4 碳 on the carbon, and wherein any -NH- moiety of the hetero 4 ring group is optionally substituted by R 4 G *; t is independently selected from the group consisting of H, Cl.6, a carbocyclic group, and a heteropoly group, wherein. The I alkyl group, the carbocyclic group and the heterocyclic ring are each independently present, and are optionally substituted on the carbon by one or more hydrazines and wherein any of the aryl groups of the heterocyclic group are optionally Han 4 generation:各存在處’係選自Cl^基、C2.6稀基、C2-6块 基、石反環基及雜環基，其中該Ci 6烧基、c2 6婦基、Ch 炔基、碳環基及雜環基，於各存在處，係視情況且獨 立地在碳上被-或多個R4Q取代，且其中該雜環基之任 何-NH-部份基團係視情況被R4〇*取代； R:’於各存在處’係獨立選自Ch烷基、碳環基及雜 %基，其中該01_6烷基、碳環基及雜環基，於各存在處， 係視h况且獨立地在碳上被一或多個R4〇取代，且其中 該 10雜環基之任何播部份基團係視情況被产取代、； Rl0 ’於各存在處，係獨立選自A基、-CN、Cl.6烧基、 2 6烯基C2 _ 6炔基、碳環基、雜環基、—orm a、-sy 〇 a、 13315] 200906818 ^(R1 0a)2、-N(R10a)(:(0)111 〇b、_N(R10aMR1 0a)2、_n〇2、 -N(R10a)-OR10a、-O-N(R10a)2、-C(0)H、-C(O)RI0b、 -C(O)2R10a 、-C(O)N(R10a)2 、-C(0)N(R10a)(〇Ri〇a)、 -0C(0)N(R1 0 a )2 ' -NCR1 0 a )C(0)2 R10 a ^ -NCR1 0 a )C(0)N(R1 0 a )2， -OC(O)R10b、-S(0)R1〇b、_S(0)2Ri〇b、_s(〇)2N(Rl0a)2、 -NCR1 0 a )S(0)2 R1 0 b、-QR1 0 a )=N(R] 0 a )及-CXR1 ❶ a )=Ν(〇Ι^ 0 a)， 其中該C! -6烷基、C：2_6烯基、A _6炔基、碳環基及雜環 基，於各存在處，係視情況且獨立地在碳上被一或多 個Ra取代，且其中該雜環基之任何部份基團係視情 況被Ra +取代； R10 ，於各存在處，係獨立選自q Μ烷基、碳環基、雜 環基、-C(0)H、-C(0)Ri〇b、（(〇)2Κΐ〇。、_c⑼N(Rl0a)2、 -S(O)R10b &gt; -S(0)2Rl〇b , _S(〇)2N(R10a)2 Λ .C(Rl〇a)=N(Rl〇a) 及-C(〇=N(ORi〇a)，其中該Ci6烧基、碳環基及雜環 基，於各存在處，係視情況且獨立地在碳上被一或多 個Ra取代，且其巾該雜環基之任何_NH部份基團係視情 況被Ra*取代； R10a ’於各存在處’係獨立選自H、CH烷基、碳環基 及雜環基，其巾叫·旧基、碳環基及雜環基，於各存 在處，係視情況且獨立地在碳上被—或多個Ra取代，且 其中該雜環基之任何_料基團係視情況被r 代； R10b ’於各存在處，係獨立選自Ch烷基、c2-6烯基' C2_6快基、碳環基及雜環基，其中該院基、c2_6埽 133151 -6 - 200906818 基、c2.6块基、碳環基及雜環基，於各存在處，係視情 况且獨立地在碳上被一或多似a取代，i其中該雜環基 之任何-NH-部份基團係視情況被Ra*取代； R ’於各存在處’係、獨立選自q .6烧基、碳環基及雜 %基，其中該C! _6烷基、碳環基及雜環基，於各存在處， 係視t月況且獨立地在碳上被一或多個Ra取代，且其中該 雜％基之任何-NH-部份基團係視情況被Ra*取代； ( R20 ’於各存在處，係獨立選自鹵基、-CN ' C卜6烷基、 C2-6烯基、C2_6炔基、碳環基、雜環基、_〇R2()a、_SR2〇a、 -N(R20a)2、_N(R2°a)C(〇)R2〇b、_N(R2 0a)N(R2〇a)2、_N〇2、 -N(R20a)-〇R2〇a Λ -〇-N(R2〇a)2 % _C(〇)H ' -C(〇)R2〇b , -C(O)2R20a 、 -C(0)N(R2〇a)2 、-C(〇)N(R20a)(〇R2〇a)、 -OC(O)N(R20a)2 , -N(R20a)C(〇)2R2〇a , -N(R20a)C(〇)N(R20a)2 , -OC(O)R20b &gt; -S(0)R2〇b &gt; -S(O)2R20b &gt; -S(O)2N(R20a)2 &gt; -N(R2 0 a )S(0)2 R2 0 b、_c(R2 0 a )=n(R2 0 a)及-C(R2 0 a )=N(OR2 ° a)， l 其中该烧基、C2-6烯基、Cm炔基、碳環基及雜環 基，於各存在處’係視情況且獨立地在碳上被一或多 個R取代，且其中該雜環基之任何_NH_部份基團係視情 況被Rb*取代； R20 ，於各存在處，係獨立選自Ci Μ烷基、碳環基、雜 環基、-C(0)H、-C(O)R20b、_c(〇)2R20c、-c(〇)N(R2〇a)2、 -S(O)R20b、-S(O)2R20b、-S(〇)2N(R20a)2、-C(R2〇”=N(R2〇a) 及-C(R20a)=N(OR20a) ’其中該Cl —烷基、碳環基及雜環 基’於各存在處’係視情況且獨立地在碳上被一或多 133151 -7- 200906818 -NH-部份基團係視情 Ci - 6燒基、碳環基 個Rb取代，且其中該雜環基之任何 況被RM取代； R2〇a，於各存在處，係獨立選自H 、碳環基及雜環基，於各存 及雜環基，其中該烷基 在處，係視情況且獨立地在碳上被—或多個Rb取代，且 其中該雜環基之任何姻·部份基團係視情況被Rb*取 代； \Each of the present positions is selected from the group consisting of a Cl^ group, a C2.6 dilute group, a C2-6 block group, a stone anticyclic group, and a heterocyclic group, wherein the Ci 6 alkyl group, the c2 6 group, the Ch alkyn group, and the carbocyclic ring. And a heterocyclic group, at each position, are optionally substituted on the carbon by - or a plurality of R4Q, and wherein any -NH- moiety of the heterocyclic group is optionally R4〇* Substituting; R: 'in each place' is independently selected from the group consisting of a C alkyl group, a carbocyclic group and a hetero-based group, wherein the 01_6 alkyl group, a carbocyclic group and a heterocyclic group are present in each case, depending on the condition The ground is substituted on the carbon by one or more R4〇, and wherein any of the groups of the 10 heterocyclic group are substituted as appropriate; R10′ is independently selected from the group A, CN, Cl.6 alkyl, 2 6 alkenyl C 2 -6 alkynyl, carbocyclyl, heterocyclic, -orm a, -sy 〇a, 13315] 200906818 ^(R1 0a)2, -N(R10a) (:(0)111 〇b, _N(R10aMR1 0a)2, _n〇2, -N(R10a)-OR10a, -ON(R10a)2, -C(0)H, -C(O)RI0b, - C(O)2R10a, -C(O)N(R10a)2, -C(0)N(R10a)(〇Ri〇a), -0C(0)N(R1 0 a )2 ' -NCR1 0 a )C(0)2 R10 a ^ -NCR1 0 a )C(0)N(R1 0 a )2 , -OC(O)R10b, -S(0)R1〇b, _S(0)2Ri〇b, _s(〇)2N(Rl0a)2, -NCR1 0 a )S(0)2 R1 0 b,- QR1 0 a )=N(R] 0 a ) and -CXR1 ❶ a )=Ν(〇Ι^ 0 a), wherein the C! -6 alkyl group, C: 2_6 alkenyl group, A _6 alkynyl group, carbocyclic ring And a heterocyclic group, at each position, optionally substituted on the carbon by one or more Ra, and wherein any part of the heterocyclic group is optionally substituted by Ra + ; In each place, it is independently selected from the group consisting of q-alkyl, carbocyclyl, heterocyclyl, -C(0)H, -C(0)Ri〇b, ((〇)2Κΐ〇., _c(9)N(Rl0a) 2. -S(O)R10b &gt; -S(0)2Rl〇b , _S(〇)2N(R10a)2 Λ .C(Rl〇a)=N(Rl〇a) and -C(〇=N (ORi〇a), wherein the Ci6 alkyl, carbocyclyl and heterocyclic groups, in each presence, are optionally substituted on the carbon by one or more Ra, and the heterocyclic group Any _NH moiety is optionally substituted by Ra*; R10a 'in each presence' is independently selected from the group consisting of H, CH alkyl, carbocyclyl and heterocyclic, and the ring is called the old base or the carbocyclic group. And heterocyclic groups, in each presence, are optionally and on carbon Or a plurality of Ra substitutions, and wherein any of the substituent groups of the heterocyclic group are optionally substituted; R10b' is independently selected from the group consisting of a C alkyl group, a c2-6 alkenyl group, a C2_6 fast group, a carbocyclic group and a heterocyclic group, wherein the group, c2_6埽133151 -6 - 200906818 group, c2.6 block group, carbocyclic group and heterocyclic group are present in each case, depending on the case and independently on the carbon Substituted by one or more like a, i wherein any -NH- moiety of the heterocyclic group is optionally substituted by Ra*; R 'in each occurrence', independently selected from q.6 alkyl, carbon a cyclic group and a hetero-hydroxy group, wherein the C!-6 alkyl group, the carbocyclic group, and the heterocyclic group are each independently present, and are independently substituted on the carbon by one or more Ra, and wherein the hetero group Any -NH- moiety of the % group is optionally substituted by Ra*; (R20' is independently selected from the group consisting of halo, -CN 'C 6 alkyl, C 2-6 alkenyl, C 2_6 Alkynyl, carbocyclyl, heterocyclyl, _〇R2()a, _SR2〇a, -N(R20a)2, _N(R2°a)C(〇)R2〇b, _N(R2 0a)N( R2〇a)2, _N〇2, -N(R20a)-〇R2〇a Λ -〇-N(R2〇a)2 % _C(〇)H ' -C(〇)R2〇b , - C(O)2R20a, -C(0)N(R2〇a)2, -C(〇)N(R20a)(〇R2〇a), -OC(O)N(R20a)2, -N(R20a C(〇)2R2〇a , -N(R20a)C(〇)N(R20a)2, -OC(O)R20b &gt; -S(0)R2〇b &gt; -S(O)2R20b &gt; -S(O)2N(R20a)2 &gt; -N(R2 0 a )S(0)2 R2 0 b, _c(R2 0 a )=n(R2 0 a) and -C(R2 0 a )= N(OR2 ° a), wherein the alkyl group, C2-6 alkenyl group, Cm alkynyl group, carbocyclyl group and heterocyclic group are each optionally present on the carbon one or more R is substituted, and wherein any _NH_ moiety of the heterocyclic group is optionally substituted by Rb*; R20, in each presence, is independently selected from the group consisting of Ci alkyl, carbocyclyl, heterocyclyl, -C(0)H, -C(O)R20b, _c(〇)2R20c, -c(〇)N(R2〇a)2, -S(O)R20b, -S(O)2R20b, -S( 〇) 2N(R20a)2, -C(R2〇"=N(R2〇a) and -C(R20a)=N(OR20a) 'wherein the Cl-alkyl group, the carbocyclic group and the heterocyclic group' Where present, 'depending on the situation and independently substituted on the carbon by one or more 133151 -7-200906818 -NH-partial groups are optionally substituted with Ci-6 alkyl, carbocyclyl Rb, and wherein the heterocyclic group Any condition is replaced by RM; R2〇a, in each Wherein, independently selected from the group consisting of H, carbocyclyl and heterocyclyl, in each and a heterocyclic group, wherein the alkyl group is optionally substituted on the carbon by - or a plurality of Rb, and Wherein any of the aryl groups of the heterocyclic group is replaced by Rb* as appropriate;R20b，於各存在處，係獨立選自Ci 6烧基、C2 6稀基、 Cm快基、碳環基及雜環基，其中該Ci 6烧基、C2_4 基、A-6炔基、碳環基及雜環基，於各存在處，係視情 況且獨立地在碳上被一或多個Rb取代，且其中該雜環基 之任何-NH-部份基團係視情況被Rb*取代； R20e於各存在處，係獨立選自Ci 6烷基、碳環基及雜環 基，其中^Ci_6烷基、碳環基及雜環基，於各存在處， 係視情況且獨立地在碳上被一或多個Rb取代，且其中該 雜環基之任何-NH-部份基團係視情況被Rb*取代； R30，於各存在處，係獨立選自鹵基、_CN、c!-6烷基、 C2-6烯基、C2-6炔基、碳環基、雜環基、_〇R3Ga、_SR30a、 _N(R3〇a)2、-N(R30a)C(O)R30b、-N(R3Oa)N(R30a)2 ' -N〇2、 -N(R3 0 a )-〇R3 〇 a、_〇 N(R3 〇 a )2、_c(〇)H、_c(〇)r3 0 b、_c(〇)2 r3 〇 a 、-C(O)N(R30a)2、-C(〇)N(R30a)(〇R3〇”、_〇C(O)N(R30a)2、 _N(R3〇a)C(〇)2R30a、-N(R30a)C(O)N(R30a)2、-OC(O)R30b、 -S(〇)R3〇b、-S(O)2R30b、-S(O)2N(R30a)2、-N(R30a)S(O)2R30b、 -C(R3Ga)=N(R3〇a)及-c(R3〇a)=N(〇R30a)，其中該Ci6 烷基、 Ϊ33151 200906818 C2 — 6烯基、C2_6炔基、碳環基及雜環基，於各存在處， 係視情況且獨立地在碳上被一或多個RC取代，且其中該 雜環基之任何_NH-部份基團係視情況被RC*取代； R30 ’於各存在處，係獨立選自CV6烧基、碳環基、雜 環基、-C(0)H、-C(0)R3〇b、_c(〇)2R30c、七(〇)雕3、、 _S(O)R30b、_s(〇)2R3Qb、部)2N(R3Ga)2、-c(R3Qa)=N(R3〇a) 及-C(R3〇a)=N(OR3〇a)，其中該c]-6烧基、碳環基及雜環 ( 基，於各存在處，係視情況且獨立地在碳上被一或多 個Rc取代，且其中該雜環基之任何_NH-部份基團係視情 況被Re*取代； R3〇a，於各存在處，係獨立選自Η、Ch烧基、碳環基 及雜ί衣基’其中該Ci 6烷基、碳環基及雜環基，於各存 在處，係視情況且獨立地在碳上被一或多個RC取代，且 其中該雜環基之任何_NH_部份基團係視情況被rc*取 代； ( R3“ ’於各存在處’係獨立選自6烷基、C2_6烯基、 C2·6炔基、碳環基及雜環基，其中該^烧基、稀 基、C2·6炔基、碳環基及雜環基，於各存在處，係視情 况且獨立地在碳上被_或多個Re取代，且其中該雜環基 之3,何-NH-部份基團係視情況被RC*取代； f〇c，於各存在處，係獨立選自（V6烧基、碳環基及雜 %基，其中該Cl·6烷基、碳環基及雜環基，於各存在處， 係視t月況且獨立地在碳上被一或多個RC取代，且其中該 雜環基之任何-NH-部份基團係視情況被RC*取代；μ 133151 -9- 200906818 R40 ’於各存在處，係獨立選自鹵基、_CN、Ci 6烷基、 C2-6烯基、C2-6炔基、碳環基、雜環基、-〇R4Ga、_SR4〇a、 _N(R4〇a)2、_N(R40a)C(〇)R4〇b、_N(R4 0a)N(R4 0a)2、_N〇2、 -N(R4°a)-〇R4〇a、_〇-N(R4〇a)2、_c(〇)H、_c(〇)R4〇b、_c(〇)2R4〇a 、-C(〇)N(R40a)2、-C(〇)N(R4〇a)(〇R4〇a)、_〇C(〇)N(R4Qa)2、 -N(R40a)C(〇)2R40a、_N(R4〇a)c(〇)N(R4〇a)2、_〇C(〇)R4 0b、 -S(O)R40b、_s(O)2R40b、-S(〇)2N(R4°a)2、-N(R40a)S(O)2R40b、 -C(R40a)=N(R40a)及-C(R4〇a)=N(〇R4〇a)，其中該c〗_6 烷基、 C2·6烯基、C2_6炔基、碳環基及雜環基，於各存在處， 係視情況且獨立地在碳上被一或多個Rd取代，且其中該 雜環基之任何-NH-部份基團係視情況被Rd*取代； R40 ，於各存在處，係獨立選自Ci 6烷基、碳環基、雜 環基、_C(0)H、-C(0)R4〇b、_C(())2R4()C、、 -S(0)R4〇b、_s(〇)2R40b、_s(〇)2N(R4〇a)2、_c(R4〇a)=N(R4〇a) 及-C(R )-N(OR4Ga)，其中該q _6烧基、碳環基及雜環R20b, at each position, is independently selected from the group consisting of Ci 6 alkyl, C 2 6 weak, Cm fast, carbocyclic and heterocyclic, wherein the Ci 6 alkyl, C 2 4, A 6 alkynyl, carbon The cyclo and heterocyclic groups, where present, are optionally substituted on the carbon by one or more Rb, and wherein any -NH- moiety of the heterocyclic group is optionally Rb* Substituting; R20e is independently selected from the group consisting of Ci 6 alkyl, carbocyclyl and heterocyclic, wherein ^Ci_6 alkyl, carbocyclyl and heterocyclyl are, as appropriate, independently and independently Substituting one or more Rbs on the carbon, and wherein any -NH- moiety of the heterocyclic group is optionally substituted by Rb*; R30, in each presence, is independently selected from halo, _CN, c!-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, carbocyclyl, heterocyclyl, 〇R3Ga, _SR30a, _N(R3〇a)2, -N(R30a)C(O) R30b, -N(R3Oa)N(R30a)2 ' -N〇2, -N(R3 0 a )-〇R3 〇a, _〇N(R3 〇a )2, _c(〇)H, _c(〇 )r3 0 b, _c(〇)2 r3 〇a , -C(O)N(R30a)2, -C(〇)N(R30a)(〇R3〇", _〇C(O)N(R30a) 2, _N(R3〇a)C(〇)2R30a, -N(R30a)C(O)N(R 30a)2, -OC(O)R30b, -S(〇)R3〇b, -S(O)2R30b, -S(O)2N(R30a)2, -N(R30a)S(O)2R30b, - C(R3Ga)=N(R3〇a) and -c(R3〇a)=N(〇R30a), wherein the Ci6 alkyl group, Ϊ33151 200906818 C2-6 alkenyl group, C2_6 alkynyl group, carbocyclic group and heterocyclic ring a group, at each position, optionally substituted on the carbon by one or more RC, and wherein any _NH- moiety of the heterocyclic group is optionally substituted by RC*; R30' Each of the existing sites is independently selected from the group consisting of CV6 alkyl, carbocyclic, heterocyclic, -C(0)H, -C(0)R3〇b, _c(〇)2R30c, and seven (〇) carved 3, _S(O)R30b, _s(〇)2R3Qb, part)2N(R3Ga)2, -c(R3Qa)=N(R3〇a), and -C(R3〇a)=N(OR3〇a), where c]-6 alkyl, carbocyclyl and heterocyclic (in each case, optionally substituted on the carbon by one or more Rc, and wherein any _NH- moiety of the heterocyclic group The group is optionally substituted by Re*; R3〇a, at each position, is independently selected from the group consisting of ruthenium, Ch-alkyl, carbocyclyl and hetero-benzyl] wherein the Ci 6 alkyl, carbocyclyl and Heterocyclic groups, in each presence, as appropriate and independently in carbon Substituted by one or more RC, and wherein any _NH_ moiety of the heterocyclic group is optionally substituted by rc*; (R3 "'in each presence' is independently selected from 6 alkyl, C2_6 ene a group, a C2·6 alkynyl group, a carbocyclic group and a heterocyclic group, wherein the alkyl group, the dilute group, the C2·6 alkynyl group, the carbocyclic group and the heterocyclic group are present, as appropriate, independently and independently Substituted by _ or a plurality of Re on the carbon, and wherein the 3, Ho-NH- moiety of the heterocyclic group is optionally substituted by RC*; f〇c, at each position, is independently selected from ( a V6 alkyl group, a carbocyclic group, and a heterovalent group, wherein the Cl.6 alkyl group, the carbocyclic group, and the heterocyclic group are each independently present, and are independently substituted on the carbon by one or more RC And wherein any -NH- moiety of the heterocyclic group is optionally substituted by RC*; μ 133151 -9- 200906818 R40 'in each presence, independently selected from halo, _CN, Ci 6 alkyl , C2-6 alkenyl, C2-6 alkynyl, carbocyclyl, heterocyclyl, -〇R4Ga, _SR4〇a, _N(R4〇a)2, _N(R40a)C(〇)R4〇b, _N (R4 0a)N(R4 0a)2, _N〇2, -N(R4°a)-〇R4〇a, _〇-N(R4〇a)2, _c(〇)H, _c( 〇)R4〇b, _c(〇)2R4〇a, -C(〇)N(R40a)2, -C(〇)N(R4〇a)(〇R4〇a), _〇C(〇)N (R4Qa)2, -N(R40a)C(〇)2R40a, _N(R4〇a)c(〇)N(R4〇a)2, _〇C(〇)R4 0b, -S(O)R40b, _s(O)2R40b, -S(〇)2N(R4°a)2, -N(R40a)S(O)2R40b, -C(R40a)=N(R40a) and -C(R4〇a)=N (〇R4〇a), wherein the c--6 alkyl group, the C2·6 alkenyl group, the C2_6 alkynyl group, the carbocyclic group and the heterocyclic group are, as appropriate, independently and independently on the carbon. a plurality of Rd are substituted, and wherein any -NH- moiety of the heterocyclic group is optionally substituted by Rd*; R40, in each presence, is independently selected from Ci 6 alkyl, carbocyclic, heterocyclic Base, _C(0)H, -C(0)R4〇b, _C(())2R4()C,, -S(0)R4〇b, _s(〇)2R40b, _s(〇)2N(R4 〇 a)2, _c(R4〇a)=N(R4〇a) and -C(R)-N(OR4Ga), wherein the q -6 alkyl group, carbocyclic group and heterocyclic ring基，於各存在處，係視情況且獨立地在碳上被一或多 個R取代，且其中該雜環基之任何-__部份基團係視情 況被Rd *取代； R40a，於各存在處’係獨立選自H、Ci6院基、碳環基 及雜環基，其中該Ci_6院基、碳環基及雜環基，於各存 在處，係視情況且獨立地在碳上被一或多個Rd取代，且 其中該雜環基之任何·部份基團係視情況被Rd*取 代； R4 υ D 於 各存在處，係獨立選自Ci_6烷基、c2 6烯基 133151 •10· 200906818 Ch炔基、碳環基及雜環基，其中該Ci 6烧基、稀 基、C2 — 6炔基、碳環基及雜環基，於各存在處，係2視6情 況且獨立地在碳上被一或多個“取代，且其中該雜環基 之任何-NH-部份基團係視情況被Rd*取代； R40c，於各存在處，係獨立選自Ci 6院基、碳環基及雜 壞基，其中烷基、碳環基及雜環基，於各存在處， 係視情況且獨立地在碳上被一或多個Rd取代，且其中該 雜環基之任何-NH-部份基團係視情況被Rd*取代； Ra，Rb，Rd，於各存在處，係獨立選自鹵基、.、 CV6烷基、C2-6烯基、C2_6炔基、碳環基、雜環基、、 -SR&quot;、-Ν(π)2、_N(Rm)c(〇)Rn、·寧m)N(Rm)2、佩、 N(Rm)-〇Rm ' -°-N(Rm)2 ' -C(〇)H . -C(〇)Rn . .C(〇)2Rm . c(o)n(r™)2、_c(0)N(Rm)(〇Rm)、_〇c(〇)N(Rm)2、 -N(Rm)C(〇)2Rm ' _N(Rm)c(〇)N(Rm)2、_〇c(〇)Rn、_s⑼Rn、 -S(0)2Rn、_S(〇)2N(Rm)2、_N(Rm)s(〇)2Rn、_c(Rm)=N(Rm)及 -C(Rm)=N(〇Rm); R，R ，Re及Rd*，於各存在處，係獨立選自Ci6烷基、 石厌 基、雜環基、_C(〇)H、_C(〇)Rn、。、-c(〇)N(Rm)2、 -S(〇)Rn、-S(0)2Rn、-S(〇)2N(Rm)2、_c(Rm)=N(Rm)及 -C(Rm )=N(〇Rm )； Μ ’於各存在處，係獨立選自H、Cl-6炫基、碳環基及 雜環基； R，於各存在處，係獨立選自Ci_6烷基、c2 6烯基、c2 6 炔基、碳環基及雜環基；且 133151 200906818 R°，於各存在處，係獨立選自Cl·6烷基、碳環基及雜環 基。 ” 如叫求項1之式⑴化合物或其藥學上可接受之鹽，其中： 環A為4-至6-員雜環基，其中該4_至6_員雜環基係視情況 在石反上被一或多個R2取代，且其中該4-至6-員雜環基之 任何-NH-部份基團係視情況被R2 *取代； R2 ’於各存在處，係獨立選自鹵基、_CN、Ci 6烧基、 -〇R2a、_N(R2a)2、_c(〇)N(R2a)2、_N(R2a)c(〇)R2b 及 ~(R2a)C(〇)2R2a，其中該Ci 0烷基係視情況被一或多個 R20取代； R2為Ci-6烷基； R ，於各存在處，係獨立選自H與C丨-6烷基； R2b為。卜6烷基； R ，於各存在處，係獨立選自鹵基、-CN、4-至6-員雜 衣基、-OR20a、-N(R20a)2、-C(0)2R2〇a、_c⑼N(R20a)2、 _N(R2 0 a )C(〇)2 R2 0 a 及-N(R2 0 a )S(〇)2 R2 〇 b ; R ，於各存在處，係獨立選自只與^、烷基；且 R20、C卜6烷基。 如。月求項1或2 壬一項之式⑴化合&amp;或其藥學上可接受 之鹽，其中： 、為員雜環基，其中該6-員雜環基係視情況在碳上 被—或多個R4取代；且 R4為鹵基。 求項1至3中任一項之式（I)化合物或其藥學上可接受 133151 -12- 200906818 之鹽，其中： X係選自-〇-與-NH_。 5·如《月求項1至4中任—項之式（ι)化合物或其 之鹽，其中： 予上了接丈 ^係選自Cu烧基、3_至6_員碳環基及5_或6_員雜環基， 二中該q ·6烷基、3-至6-員碳環基及5_或6_員雜環基係視 情況在碳上被一或多個Rl0取代； R ，於各存在處，係獨立選自_基、3-至6-員碳環基、 員雜環基及_〇Rl0a，其中該3_至6_員碳環基與:或 6_員雜環基，於各存在處，係視情況且獨立地在碳上被 一或多個Ra取代； 圮〇{1為3-至6-員碳環基； W-V 〇 ’於各存在處，係獨立選自鹵基與_〇Rm ;且 R為c〗-6烧基。 士明求項1至5中任一項之式⑴化合物或其藥學上可接受 之鹽，其中： κ R3係選自q—6烷基，其中該Ci 6烷基係視情況被—或多 個R3 G取代； r3〇 ’於各存在處，係獨立選自鹵基、-CN、-OR3〇a、 •C(O)N(R30a)2、-S(〇)2R30 ^-8(0)2 N(R30 a )2 ; R3()a ’於各存在處’係獨立選自H與q_6烷基；且 以“為^、烷基。 7· —種式（I)化合物： 133151 -13- 200906818a group, at each position, optionally substituted on the carbon by one or more R, and wherein any -_- moiety of the heterocyclic group is optionally substituted by Rd*; R40a, Each of the 'existing positions' is independently selected from the group consisting of H, Ci6, carbocyclyl and heterocyclic, wherein the Ci_6, carbocyclyl and heterocyclic groups are present, as appropriate, independently on carbon. Substituted by one or more Rd, and wherein any part of the heterocyclic group is optionally substituted by Rd*; R4 υ D is independently selected from the group consisting of Ci-6 alkyl, c2 6 alkenyl 133151 • 10· 200906818 Ch alkynyl, carbocyclyl and heterocyclic group, wherein the Ci 6 alkyl group, the dilute group, the C 2 6 alkynyl group, the carbocyclic group and the heterocyclic group are in the presence of 2, 6 And independently substituted by one or more on the carbon, and wherein any -NH- moiety of the heterocyclic group is optionally substituted by Rd*; R40c, in each presence, is independently selected from Ci 6 a group, a carbocyclic group, and a heterocyclic group in which an alkyl group, a carbocyclic group, and a heterocyclic group are substituted, respectively, on the carbon by one or more Rds, as the case may be. And wherein any -NH- moiety of the heterocyclic group is optionally substituted by Rd*; Ra, Rb, Rd, in each presence, are independently selected from halo, .., C.sub.6 alkyl, C2-6 Alkenyl group, C2_6 alkynyl group, carbocyclic group, heterocyclic group, -SR&quot;, -Ν(π)2, _N(Rm)c(〇)Rn, ·Ning m)N(Rm)2, Pei, N (Rm)-〇Rm ' -°-N(Rm)2 ' -C(〇)H . -C(〇)Rn . .C(〇)2Rm . c(o)n(rTM)2, _c( 0) N(Rm)(〇Rm), _〇c(〇)N(Rm)2, -N(Rm)C(〇)2Rm ' _N(Rm)c(〇)N(Rm)2, _〇 c(〇)Rn, _s(9)Rn, -S(0)2Rn, _S(〇)2N(Rm)2, _N(Rm)s(〇)2Rn, _c(Rm)=N(Rm) and -C(Rm) =N(〇Rm); R, R, Re and Rd*, in each presence, are independently selected from the group consisting of Ci6 alkyl, oxalyl, heterocyclic, _C(〇)H, _C(〇)Rn. , -c(〇)N(Rm)2, -S(〇)Rn, -S(0)2Rn, -S(〇)2N(Rm)2, _c(Rm)=N(Rm), and -C( Rm )=N(〇Rm ); Μ 'in each presence, independently selected from H, Cl-6 leumino, carbocyclyl and heterocyclic; R, in each presence, independently selected from Ci-6 alkyl , c2 6 alkenyl, c 2 6 alkynyl, carbocyclyl and heterocyclic; and 133151 200906818 R°, in each presence, independently selected from Cl 6 alkyl, carbocyclic group and heterocyclic group. The compound of the formula (1) or the pharmaceutically acceptable salt thereof, wherein: the ring A is a 4- to 6-membered heterocyclic group, wherein the 4 to 6-membered heterocyclic group is optionally a stone Conversely substituted by one or more R2, and wherein any -NH- moiety of the 4- to 6-membered heterocyclic group is optionally substituted with R2*; R2' is independently selected from each Halogen, _CN, Ci 6 alkyl, -R2a, _N(R2a)2, _c(〇)N(R2a)2, _N(R2a)c(〇)R2b and ~(R2a)C(〇)2R2a, Wherein the Ci 0 alkyl group is optionally substituted by one or more R20; R2 is a Ci-6 alkyl group; and R, in each presence, is independently selected from H and C丨-6 alkyl groups; R2b is . Alkyl; R, in each presence, independently selected from halo, -CN, 4- to 6-membered lichenyl, -OR20a, -N(R20a)2, -C(0)2R2〇a, _c(9)N (R20a)2, _N(R2 0 a )C(〇)2 R2 0 a and -N(R2 0 a )S(〇)2 R2 〇b ; R , in each presence, are independently selected from only ^ And an alkyl group; and R20, C, a 6 alkyl group, such as a compound of the formula (1), or a pharmaceutically acceptable salt thereof, wherein: 6-membered heterocyclic group </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; X is selected from the group consisting of -〇- and -NH_. 5. The compound of the formula (1) of the formula (1), or the salt thereof, wherein the compound is selected from the group consisting of Cu-based a 3- to 6-membered carbocyclyl group and a 5 or 6-membered heterocyclic group, wherein the q·6 alkyl group, the 3- to 6-membered carbocyclic group, and the 5- or 6-membered heterocyclic group are Optionally substituted on the carbon by one or more R10; R, in each presence, independently selected from the group consisting of a _ group, a 3- to 6-membered carbocyclic group, a heterocyclic group, and a 〇R10a, wherein the 3_ To 6-membered carbocyclyl with: or 6-membered heterocyclic group, in each presence, optionally substituted with one or more Ra on carbon; 圮〇{1 is 3- to 6-member a carbocyclic group; WV 〇', in each of its existence, is independently selected from a halo group and _〇Rm; and R is a c -6 alkyl group. The compound of the formula (1) according to any one of items 1 to 5, or a pharmaceutically acceptable salt, wherein: κ R3 is selected from the group consisting of q-6 alkyl, wherein the Ci 6 alkyl group is optionally-- or more R3 G is substituted; r3〇' is present at each position and is independently selected from halo, -CN, -OR3〇a, C(O)N(R30a)2, -S(〇)2R30^-8(0 2 N(R30 a )2 ; R3()a 'in each presence' is independently selected from H and q_6 alkyl; and is ", ^, alkyl. 7. The compound of formula (I): 133151 -13- 200906818式(I) 或其藥學上可接受之鹽，其中： 環A係選自3-(乙醯胺基）一氮四圜基、3_(乙醯胺基）四 氫地&quot;各-1-基、3-(胺基甲基）六氫吡啶小基、3_胺基六氫咐 啶-1-基、2-(—氮四園_1_基甲基）嗎福啉冰基、3_氰基一氮 四圜-1-基、2-(氰基甲基）嗎福啉_4_基、3-(氰基甲基）嗎福 啉·4_基、2-(氰基曱基）六氫吡啶-1-基、3-氰基六氫吡咬+ 基、4-氰基六氫吡啶-i_基、2_[(二乙胺基）甲基]嗎福啉斗 基、3,3-二氟一氮四圜_1_基、2-(二氟甲基）嗎福啉_4_基、 3-(—敦曱基）嗎福淋-4-基、3,3-di氧基六氫说咬基、4 二氟六風11比。定-1-基、3,3-二氟四氫p比u各_1_基、3_(二甲胺 基）一氮四圜-1-基、3-[(二甲胺基）幾基]甲基嗎福啉_4•基、 3-[(·—曱胺基）&amp;基]嗎福淋-4·-基、3-[(二甲胺基）甲基]_i_氣 吡啶-1-基、3-(二甲胺基）四氫吡落_ι_基、2,2-二甲基嗎福 啉-4-基、2,6-二甲基嗎福啉-4-基、3,3-二甲基嗎福琳_4_基、 3-{[(乙氧幾基）胺基]曱基}嗎福淋-4-基、2-乙基嗎福淋4 基、3-乙基嗎福》林-4-基、3-乙氧基四氫u比嘻+基、3•氣爲 一氮四圜-1-基、3-氟基六氫吡啶-i_基、4-氟基六氫峨咬七 基、3-羥基一氮四圜-1-基、3-(2-羥乙基）嗎福啉_4_基、2_(_ 133151 •14- 200906818 甲基）一氮四圜-1-基、3-羥基-3-曱基一氮四園小基、2_(經 甲基）嗎福啉-4-基、3-(經曱基）嗎福啉-4-基、3-羥基_3-甲基 六氫吡啶-1-基、4-羥基-4-曱基六氫吡啶-1-基、2_(經甲基） 六氫吡啶-1-基、3-羥基六氫吡啶-1-基、4-羥基六氫吡咬·l 基、3-甲氧基一氮四圜小基、3-[(甲氧羰基）甲基]嗎福琳 -4-基、2-(甲氧基甲基）嗎福p林_4_基、3-(甲氧基甲基）嗎福 琳-4-基、3-(甲氧基甲基）六氫吡啶_1_基、3-甲氧基六氫咐 啶-1-基、4-甲氧基六氫吡啶-1-基、3-(甲胺基）一氮四圜+ 基、3-[(甲私基）|1炭基]嗎福p林-4-基、3-(甲胺基）四氫u比略_ι_ 基、2-甲基嗎福u林-4-基、3-曱基嗎福p林-4-基、4-曱基-3 酮基六氫吡畊-1-基、3-{[(甲磺醯基）胺基]甲基}嗎福啉斗 基、嗎福琳-4-基、4-甲基六氫p比畊-1-基、1，4_氧氮七圜_4_ 基、3-{[(第三-丁氧羰基）胺基]曱基}六氫吡啶_丨_基及3_[(第 三-丁氧羰基）胺基]六氫吡啶-1-基； 環B係選自3,5-二氟p比咬-2-基、5-氣基ρ比咬-2-基及5-氟基 嘧啶-2-基； X係選自-Ο-與-NH-; R1係選自2-環己基乙基、環丙基、2-(2,4-二氟苯基）乙基、 2-(2,6-二氟苯基）乙基、2-(3,4-二氟苯基）乙基、2·(3,5·二氟 苯基）乙基、2-(3,5-二甲氧基苯基）乙基、4_氟苯基、2_(3_ 氟苯基）乙基、2-(4-氟苯基）乙基、2-(1Η-咪唑-2-基）乙基、 4-甲氧苯基、甲基、2-苯基乙基、苯基氧基曱基、2_吡 淀-4-基乙基及p塞吩-2-基；且 R3係選自（胺基羰基）甲基、氰基甲基、u_二氟冬羥乙 133151 -15- 200906818 基龙[(二甲胺基）叛基]甲基、（二甲胺基確醯基）甲基、乙 基L羥乙基、2一羥乙基、1-甲氧基乙基、甲氧 基甲農、田甘 土 τ乳 甲基、[(甲胺基）幾基汴基及（甲磺醯基烀基。 〇·如蚺求項丨$ 中任一項之式①化合物或其藥學上可接受 现’其係作為藥劑使用。 =如明求項1至7中任一項之式⑴化合物或其藥學上可 ‘於藥劑製造上之用途’該藥劑係用於治療癌症。Or a pharmaceutically acceptable salt thereof, wherein: ring A is selected from the group consisting of 3-(ethylammonium)-nitrotetradecyl, 3-(ethylamino)tetrahydro-&quot; , 3-(aminomethyl)hexahydropyridine small group, 3-aminol hexahydroindol-1-yl, 2-(-nitrotetracycline-1-ylmethyl) porphyrin ice base, 3 _Cyano-nitrotetradec-1-yl, 2-(cyanomethyl)norfosin-4-yl, 3-(cyanomethyl)morpholine-4-yl, 2-(cyanoguanidine , hexahydropyridin-1-yl, 3-cyanohexahydropyridyl+, 4-cyanohexahydropyridine-i-yl, 2-[(diethylamino)methyl]fofoline 3,3-difluoro-azatetraindole-1-yl, 2-(difluoromethyl)norfosin-4-yl, 3-(-Denyl) whal-4-yl, 3,3 -dioxy hexahydro is said to bite, 4 difluoro 6 wind 11 ratio. Dec-1-yl, 3,3-difluorotetrahydrop, u1_1, dimethyl 3-(dimethylamino)-nitrotetradec-1-yl, 3-[(dimethylamino) Methylmorpholine _4• group, 3-[(·- guanyl) &amp; ki] whalolin-4·-yl, 3-[(dimethylamino)methyl]_i_pyridine -1-yl, 3-(dimethylamino)tetrahydropyridyl-yl, 2,2-dimethylmorpholine-4-yl, 2,6-dimethylmorpholine-4- , 3,3-dimethylmorphinyl _4_yl, 3-{[(ethoxyxo)amino]indolyl} oxaflu-4-yl, 2-ethyl fluprene 4 , 3-ethylonol, lin-4-yl, 3-ethoxytetrahydrou, 嘻+, 3, gas, nitrotetradec-1-yl, 3-fluorohexahydropyridine-i_ Base, 4-fluorohexahydroindole, heptayl, 3-hydroxy-azinotetradec-1-yl, 3-(2-hydroxyethyl)morpholine _4_yl, 2_(_ 133151 •14- 200906818 Methyl) nitrotetradec-1-yl, 3-hydroxy-3-indolyl-nitrogen tetrakisyl, 2-(methyl)norfosolin-4-yl, 3-(sulfenyl) ru啉-4-yl, 3-hydroxy-3-methylhexahydropyridin-1-yl, 4-hydroxy-4-mercaptohexahydropyridin-1-yl, 2-(methyl)hexahydropyridine-1- Base, 3-hydroxyhexahydropyridin-1-yl, 4-hydroxyhexahydropyridyl l base , 3-methoxymonocarbazinyl, 3-[(methoxycarbonyl)methyl]norfosin-4-yl, 2-(methoxymethyl)- ortho- p-linyl-4, 3-(methoxymethyl)norfosin-4-yl, 3-(methoxymethyl)hexahydropyridin-1-yl, 3-methoxyhexahydroacridin-1-yl, 4- Methoxyhexahydropyridin-1-yl, 3-(methylamino)-azatetraindole+yl, 3-[(methyl-yl)-1 carbon-based] pheno-p-lin-4-yl, 3-( Methylamino)tetrahydro-u ratio _ι_ group, 2-methyl-ofo-fu-lin-4-yl, 3-mercapto-purine p--4-yl, 4-mercapto-3 ketohexahydropyridyl Plung-1-yl, 3-{[(methylsulfonyl)amino]methyl}fosfolinin, carbaryl-4-yl, 4-methylhexahydrop, cultivating-1-yl, 1,4_oxyziridine-7_yl, 3-{[(tris-butoxycarbonyl)amino]fluorenyl}hexahydropyridine-indenyl and 3-[(tris-butoxycarbonyl)amino a hexahydropyridin-1-yl; a ring B is selected from the group consisting of 3,5-difluorop-biti-2-yl, 5-a-based ρ-but-2-yl and 5-fluoropyrimidin-2-yl; X is selected from the group consisting of -Ο- and -NH-; R1 is selected from the group consisting of 2-cyclohexylethyl, cyclopropyl, 2-(2,4-difluorophenyl)ethyl, 2-(2,6-di Fluorophenyl)ethyl, 2-(3,4-difluorophenyl)ethyl, 2·(3,5·difluorophenyl) Ethyl, 2-(3,5-dimethoxyphenyl)ethyl, 4-fluorophenyl, 2-(3-fluorophenyl)ethyl, 2-(4-fluorophenyl)ethyl, 2 -(1Η-imidazol-2-yl)ethyl, 4-methoxyphenyl, methyl, 2-phenylethyl, phenyloxyindenyl, 2-pyridyl-4-ylethyl and p-plug吩-2-yl; and R3 is selected from (aminocarbonyl)methyl, cyanomethyl, u-difluorobutanyl 133151 -15- 200906818 kelong [(dimethylamino) ruthenyl] methyl , (dimethylamino)-methyl, ethyl L-hydroxyethyl, 2-hydroxyethyl, 1-methoxyethyl, methoxy-camponic, tiangantu τ-methyl, [( Methylamino) mercaptoalkyl and (methylsulfonyl fluorenyl). The compound of the formula 1 according to any one of the items of the formula or its pharmaceutically acceptable present is used as a medicament. A compound of the formula (1) according to any one of the items 1 to 7 or a pharmaceutically acceptable use thereof for the manufacture of a medicament for treating cancer.:種在溫灰動物譬如人類中治療癌症之方法，該方法包括 對該動物投予有效量主 之如喷未項1至7中任一項之式（I)化 合物，或其藥學上可接受之鹽。 11·如請求項1至7 φτΕ ^ 一項之式（I)化合物或其藥學上可接受 之鹽係在溫血動物譬如人類中用於治療癌症。 12·—種醫藥組合物，豆包含 八匕3如蜎求項1至7中任一項之式（I) 化合物或其藥學上可接# 接又之鹽，及至少一種藥學上可接受 之載劑、稀釋劑或賦形劑。 13. —種製備如請求項1至7中任_ 上可接受鹽之方法，其中該方 方法A -使式（Α)化合物： 項之式（I)化合物或其藥學 法係選自：A method of treating cancer in a warm-blooded animal such as a human, the method comprising administering to the animal an effective amount of a compound of formula (I), such as any one of items 1 to 7, or a pharmaceutically acceptable compound thereof Salt. 11. A compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claims 1 to 7 φτΕ ^, for use in the treatment of cancer in a warm-blooded animal such as a human. 12. A pharmaceutical composition comprising: a compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable compound Carrier, diluent or excipient. 13. A process for the preparation of an acceptable salt according to any one of claims 1 to 7, wherein the process A - a compound of formula (I): or a pharmaceutically acceptable compound thereof is selected from the group consisting of:式(A&gt; 與式（B)化合物反應： 133151 • 16 * 200906818Formula (A&gt; reacts with a compound of formula (B): 133151 • 16 * 200906818式(B);或 方法B -使式（C)化合物：Formula (B); or Method B - to give a compound of formula (C):式(C) 與式（D)化合物反應 H—Xy /RFormula (C) reacts with compound of formula (D) H—Xy /R方法c -使式（σ)化合物與環a反應： ΗMethod c - reacting a compound of formula (σ) with ring a: Η丫ν、νη丫ν,νη式c，Formula c,接著，若必要則： i) 使式（I)化合物轉化成另一種式（I)化合物； ii) 移除任何保護基；及/或 iii) 形成藥學上可接受之鹽， 其中L於各存在處可為相同或不同，且係為如本文上述 之脫離基。 133151 -17- 200906818 七、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明: 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式：Next, if necessary: i) converting a compound of formula (I) to another compound of formula (I); ii) removing any protecting groups; and/or iii) forming a pharmaceutically acceptable salt, wherein L is present in each They may be the same or different and are de-based as described herein above. 133151 -17- 200906818 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the characteristics that can best display the invention. Chemical formula:133151133151