TWI380973B

TWI380973B - Chemical compounds

Info

Publication number: TWI380973B
Application number: TW095123240A
Authority: TW
Inventors: Jianghe Deng; Jeffrey K Kerns; Qi Jin; Guoliang Lin; Xichen Lin; Michael Lindenmuth; Christopher E Neipp; Hong Nie; Sonia M Thomas; Katherine Louisa Widdowson
Original assignee: Smithkline Beecham Corp
Priority date: 2005-06-30
Filing date: 2006-06-28
Publication date: 2013-01-01
Also published as: NO20080457L; KR20080021077A; WO2007005534A2; WO2007005534A8; MA29566B1; MX2007016541A; AU2006266028A1; EA014083B1; EA200800183A1; PE20070173A1; ZA200709948B; UA99699C2; NZ563687A; JP2009500338A; EP1896014A4; CN101247804B; JP5059756B2; CA2613068A1; AR055343A1; WO2007005534A3

Description

Compound

本發明係有關某些吲哚羧醯胺化合物，其係激酶活性之抑制劑。更明確言之，該化合物為IKK2抑制劑。此等化合物適用於治療與IKK2(亦稱為IKKβ)活性不當有關之病變，如：類風濕關節炎、氣喘與COPD(慢性阻塞性肺病)。 The present invention relates to certain indole carboxamide compounds which are inhibitors of kinase activity. More specifically, the compound is an IKK2 inhibitor. These compounds are indicated for the treatment of conditions associated with inappropriate activity of IKK2 (also known as IKKβ), such as rheumatoid arthritis, asthma and COPD (chronic obstructive pulmonary disease).

有一個重要之酵素家族為蛋白質激酶酵素家族。目前已知有約500種不同蛋白質激酶。然而，由於有3至4%人類基因組會編碼形成蛋白質激酶，因此人體仍會出現數千種獨特之不同激酶。蛋白質激酶之作用在於藉由轉移ATP-Mg²⁺複合物之γ-磷酸根至不同蛋白質之胺基酸側鏈，來催化該胺基酸側鏈之磷酸化反應。此等酵素控制細胞內大多數訊號途徑，藉以透過蛋白質之絲胺酸、蘇胺酸與酪胺酸殘基之羥基之可逆性磷酸化反應，管控細胞功能、生長、分化與破壞(凋亡)。研究顯示，蛋白質激酶為許多細胞功能關鍵性調節劑，包括訊號轉導、轉錄性調節、細胞活動與細胞分化。已知有數種致癌基因會編碼蛋白質激酶，此表示激酶在致癌過程中扮演某種角色。此等過程受到複雜之交叉途徑調節，其中各激酶本身即受一種或多種激酶調節。因此，蛋白質激酶活性不當或異常均會造成與此等異常激酶活性有關之疾病。基於其生理相關性、變異性與普遍性，蛋白質激酶已成為生化與醫學研究之最重要且廣泛應用之酵素家族。 An important family of enzymes is the family of protein kinase enzymes. There are currently about 500 different protein kinases known. However, since 3 to 4% of the human genome encodes protein kinases, thousands of unique and distinct kinases still appear in humans. The role of protein kinases is to catalyze the phosphorylation of the amino acid side chain by transferring the gamma-phosphate of the ATP-Mg ²⁺ complex to the amino acid side chain of the different proteins. These enzymes control most of the signal pathways in the cell, thereby regulating cell function, growth, differentiation and destruction (apoptosis) through the reversible phosphorylation of the hydroxyl groups of the protein's serine, threonine and tyrosine residues. . Studies have shown that protein kinases are key regulators of many cellular functions, including signal transduction, transcriptional regulation, cell activity and cell differentiation. Several oncogenes are known to encode protein kinases, suggesting that kinases play a role in carcinogenesis. These processes are regulated by complex cross-pathways in which each kinase is itself regulated by one or more kinases. Therefore, inappropriate or abnormal protein kinase activity can cause diseases associated with these abnormal kinase activities. Based on its physiological relevance, variability and universality, protein kinase has become the most important and widely used family of enzymes in biochemical and medical research.

酵素之蛋白質激酶家族依據其所磷酸化之胺基酸殘基，典型地分成兩大次族群：蛋白質酪胺酸激酶與蛋白質絲胺酸/蘇胺酸激酶。絲胺酸/蘇胺酸激酶(PSTK)包括依賴環狀AMP-與環狀GMP-之蛋白質激酶、依賴鈣與磷脂之蛋白質激酶、依賴鈣-與攜鈣素之蛋白質激酶、酪蛋白激酶、細胞分化循環蛋白質激酶，等等。此等激酶通常在細胞質中，或與細胞之粒狀部份結合，可能利用蛋白質固定。蛋白質絲胺酸/蘇胺酸激酶活性異常涉及或疑似涉及許多種病理，如：類風濕關節炎、乾癬、敗血性休克、骨質流失、許多種癌症與其他增生性疾病。因此，絲胺酸/蘇胺酸激酶與其訊號轉導途徑即為藥物設計之重要目標。酪胺酸激酶磷酸化酪胺酸殘基。酪胺酸激酶同樣在細胞調節中扮演重要角色。此等激酶包括如：生長因子與激素之數種受體，包括上皮生長因子受體、胰島素受體、血小板衍生之生長因子受體，等等。研究顯示，許多種酪胺酸激酶為穿膜蛋白質，其受體功能部位位在細胞外面，而其激酶功能部位則在裏面。目前亦有許多工作在判別酪胺酸激酶之調節劑。 The protein kinase family of enzymes is typically divided into two major subpopulations based on the phosphorylated amino acid residues: protein tyrosine kinase and protein serine/threonine kinase. Serine/threonine kinase (PSTK) includes cyclic AMP- and cyclic GMP-dependent protein kinases, calcium and phospholipid-dependent protein kinases, calcium- and calciton-dependent protein kinases, casein kinases, cells Differentiating circulating protein kinases, and so on. These kinases are usually in the cytoplasm or bind to the granular part of the cell and may be fixed by protein. Abnormal protein leucine/threonine kinase activity involves or is suspected of involving many pathologies such as rheumatoid arthritis, dryness, septic shock, bone loss, many types of cancer and other proliferative diseases. Therefore, serine/threonine kinase and its signal transduction pathway are important targets for drug design. Tyrosine kinase phosphorylates tyrosine residues. Tyrosine kinase also plays an important role in cell regulation. Such kinases include, for example, several receptors for growth factors and hormones, including epidermal growth factor receptors, insulin receptors, platelet-derived growth factor receptors, and the like. Studies have shown that many tyrosine kinases are transmembrane proteins whose receptor functional sites are located outside the cell and whose kinase functional sites are located. There are also many work to determine the regulator of tyrosine kinase.

核因子κB(NF-κB)屬於由多肽之Rel/NF-κB家族之不同組合組成之極相近之二聚體轉錄因子複合物家族。該家族包括哺乳動物之5種個別基因產物：RelA(p65)、NF-κB1(p50/p105)、NF-κB2(p49/p100)、c-Rel與RelB，其均可形成雜-或均二聚體。此等蛋白質之共通點為高度同質性之300個胺基酸“Rel同質性功能部位”，其中包含DNA結合性與二聚化功能部位。在Rel同質功能部位之C-末端為核轉位序列，對NF-κB自細胞質運送至細胞核之過程很重要。此外，p65與cRel在其C-末端具有強力轉活化功能部位。 Nuclear factor kappa B (NF-κB) belongs to a family of very similar dimeric transcription factor complexes composed of different combinations of the Rel/NF-κB family of polypeptides. This family includes five individual gene products of mammals: RelA (p65), NF-κB1 (p50/p105), NF-κB2 (p49/p100), c-Rel and RelB, all of which can form hetero- or homogenous Polymer. The common point of these proteins is the highly homogenous 300 amino acid "Rel homogenous functional site", which contains DNA binding and dimerization functional sites. Nuclear translocation at the C-terminus of the Rel homofunctional part The sequence is important for the process by which NF-κB is transported from the cytoplasm to the nucleus. In addition, p65 and cRel have potent transactivation functional sites at their C-terminus.

NF-κB之活性受到其與蛋白質之抑制劑IκB家族成員之一之交互作用之調節。此交互作用有效阻斷NF-κB蛋白質上核定位序列，因此防止二聚體移動至核內。許多種刺激會透過似乎為多重訊號轉導途徑來活化NF-κB。包括細菌產物(LPS)、有些病毒(HIV-1、HTLV-1)、發炎細胞素(TNFα、IL-1)、環境與氧化壓力及DNA傷害劑。然而，所有刺激之共同點似乎為磷酸化反應及接續之IκB降解。IκB利用近來判別出之IκB激酶(IKK-α與IKK-β)對兩個N-末端絲胺酸進行磷酸化。IKK-β亦稱為IKK2。定點誘變法研究顯示，此等磷酸化反應對接續之NF-κB活化作用很重要，因為一旦磷酸化後，蛋白質即被貼上標記，會經由泛素-蛋白降解體途徑降解。沒有IκB之活性NF-κB複合物可以轉移至細胞核中，在此以選擇方式優先與基因專一性促進子序列結合。受NF-κB調節之基因包括許多種細胞素與化學激動素、細胞附著分子、急性期蛋白質、免疫調節蛋白質、類花生酸代謝酵素與抗細胞凋亡基因。 The activity of NF-κB is regulated by its interaction with one of the IκB family members of the protein inhibitor. This interaction effectively blocks the nuclear localization sequence of the NF-κB protein, thus preventing the dimer from moving into the nucleus. Many types of stimuli activate NF-κB through a pathway that appears to be a multiple signal transduction. These include bacterial products (LPS), some viruses (HIV-1, HTLV-1), inflammatory cytokines (TNFα, IL-1), environmental and oxidative stress, and DNA damaging agents. However, the common denominator of all stimuli appears to be phosphorylation and subsequent IκB degradation. IκB phosphorylates two N-terminal serine acids using the recently identified IκB kinase (IKK-α and IKK-β). IKK-β is also known as IKK2. Site-directed mutagenesis studies have shown that these phosphorylation reactions are important for the subsequent activation of NF-κB, since once phosphorylated, the protein is labeled and degraded via the ubiquitin-protein degradation pathway. The NF-κB complex without IκB activity can be transferred to the nucleus where it preferentially binds to the gene-specific promoter sequence in a selective manner. The genes regulated by NF-κB include many kinds of cytokines and chemical actin, cell adhesion molecules, acute phase proteins, immunoregulatory proteins, eicosanoid metabolizing enzymes and anti-apoptotic genes.

已知NF-κB在調節許多種促炎媒介物之表現上扮演重要角色，包括細胞素，如：TNF、IL-1β、IL-6與IL-8，細胞附著分子，如：ICAM與VCAM，與可誘發之氧化氮合成酶(iNOS)。已知此等媒介物在發炎位置補充白血球與iNOS上扮演重要角色，可能造成某些發炎與自體免疫疾病之器官破壞。 NF-κB is known to play an important role in regulating the performance of many proinflammatory mediators, including cytokines such as TNF, IL-1β, IL-6 and IL-8, cell attachment molecules such as ICAM and VCAM, And inducible nitric oxide synthase (iNOS). These vehicles are known to play an important role in supplementing white blood cells and iNOS in inflamed locations, possibly causing destruction of certain inflammatory and autoimmune diseases.

NF-κB於炎症中之重要性進一步由呼吸道發炎(包括氣喘)研究中證實，其中顯示NF-κB已活化。此活化作用造成此等疾病之細胞素生產增加與白血球浸潤之特性。此外，已知吸入性類固醇會降低呼吸道之過度反應，並壓抑氣喘之呼吸道之發炎反應。基於近來有關糖皮質激素抑制NF-κB之發現，可推論此等效應係透過抑制NF-κB所媒介。 The importance of NF-κB in inflammation was further confirmed by studies of respiratory inflammation, including asthma, which showed that NF-κB has been activated. This activation results in increased cytokine production and leukocyte infiltration characteristics of these diseases. In addition, inhaled steroids are known to reduce excessive reactions in the respiratory tract and suppress the inflammatory response of the respiratory tract. Based on recent findings regarding the inhibition of NF-κB by glucocorticoids, it can be inferred that these effects are mediated by inhibition of NF-κB.

進一步有關NF-κB於炎症中角色之證據來自類風濕滑膜之研究。雖然NF-κB通常呈無活性之細胞質複合物，但近來之免疫化學研究顯示，NF-κB出現在細胞核中，因此在包含類風濕滑膜之細胞中具有活性。此外，已知NF-κB於人類滑液細胞中，因應TNF-α或IL-1β之刺激而活化。此等分佈可能為此組織出現細胞素及類花生酸提高生產之特性之原因。參見Roshak,A.K.等人之J.Biol.Chem.,271,31496-31501(1996)。已知IKK-β之表現出現在類風濕關節炎患者之滑液細胞中，由基因轉移研究證實IKK-β於此等細胞中刺激發炎媒介物產生之中心角色。參見Aupperele等人之J.Immunology 1999.163：427-433與Aupperle等人之J.Immunology 2001；166：2705-11。更近來，在關節內投與野生型IKK-β腺病毒構築體時，顯示會造成足部腫大，而在關節內投與顯型-陰性IKK-β時，可抑制輔劑所誘發大鼠之關節炎。參見Tak等人之Arthritis and Rheumatism 2001,44：1897-1907。 Further evidence of the role of NF-κB in inflammation comes from the study of rheumatoid synovium. Although NF-κB is usually an inactive cytoplasmic complex, recent immunochemical studies have shown that NF-κB is present in the nucleus and is therefore active in cells containing a rheumatoid synovium. Furthermore, NF-κB is known to be activated in human synovial cells in response to stimulation with TNF-α or IL-1β. These distributions may be responsible for the increased production characteristics of cytokines and eicosanoids in this tissue. See Roshak, AK et al., J. Biol. Chem., 271, 31496-31501 (1996). IKK-β is known to be present in synovial cells of patients with rheumatoid arthritis, and gene transfer studies have confirmed the central role of IKK-β in stimulating the production of inflammatory mediators in these cells. See Aupperele et al., J. Immunology 1999. 163: 427-433 and Aupperle et al., J. Immunology 2001; 166: 2705-11. More recently, when the wild-type IKK-β adenovirus construct was administered intra-articularly, it was shown to cause swelling of the foot, and when the pheno-negative IKK-β was administered intra-articularly, the adjuvant-induced rat was inhibited. Arthritis. See Tak et al. Arthritis and Rheumatism 2001, 44: 1897-1907.

NF-κB/Rel與IκB蛋白質似乎亦在新生贅瘤轉形與癌轉移上扮演關鍵角色。該家族成員在活體內與活體外因過度表現、基因擴增、基因重組或移位而與細胞轉形相關。此外，編碼此等蛋白質之基因之重組與/或擴增出現在20-25%某些人類淋巴腫瘤中。此外，NF-κB受致癌基因ras活化，其係人類腫瘤最常見之缺陷，且封阻NF-κB活化可抑制ras所媒介細胞轉形作用。此外，NF-κB於調節細胞凋亡上已證實之角色加強此轉錄因子於調節腫瘤細胞增生上之角色。已知TNF、離子化射線與DNA傷害劑均會活化NF-κB，進而向上調節數種抗細胞凋亡蛋白質之表現。反之，已知抑制NF-κB可加強此等製劑在數種腫瘤細胞中細胞凋亡-消滅作用。此點似乎代表腫瘤細胞抗拒化療法之主要機轉，因此NF-κB活化作用之抑制劑可能適用為化療劑，其可作為單一藥劑或作為輔助療法。近來之報告顯示，以NF-κB作為骨骼細胞分化作用之抑制劑及作為細胞素所誘發肌肉耗弱之調節劑(Guttridge等人之Science；2000；289：2363-2365.)，進一步支持NF-κB抑制劑作為新穎之癌症化療劑之潛力。 NF-κB/Rel and IκB proteins also appear to play a key role in neonatal tumor transformation and cancer metastasis. Members of this family are involved in cell transformation in vivo and in vitro due to overexpression, gene amplification, genetic recombination or translocation. In addition, recombination and/or amplification of genes encoding such proteins occurs in 20-25% of certain human lymphoid tumors. In addition, NF-κB is activated by the oncogene ras, which is the most common defect in human tumors, and blocking NF-κB activation can inhibit the transformation of ras-mediated cells. In addition, the role of NF-κB in regulating apoptosis has enhanced the role of this transcription factor in regulating tumor cell proliferation. It is known that TNF, ionizing radiation and DNA injury agents activate NF-κB, which in turn regulates the expression of several anti-apoptotic proteins. Conversely, inhibition of NF-κB is known to enhance the apoptosis-elimination of these agents in several tumor cells. This point seems to represent the main mechanism by which tumor cells resist chemotherapeutic therapy, so inhibitors of NF-κB activation may be suitable as chemotherapeutic agents, either as a single agent or as an adjunct therapy. Recent reports have shown that NF-κB is an inhibitor of skeletal cell differentiation and a regulator of muscle depletion induced by cytokines (Guttridge et al., Science ; 2000; 289: 2363-2365.), further supporting NF- The potential of κB inhibitors as novel cancer chemotherapeutic agents.

數種NF-κB抑制劑說明於C.Wahl等人之J.Clin.Invest.101(5),1163-1174(1998)、R.W.Sullivan等人之J.Med.Chem.41,413-419(1998)、J.W.Pierce等人之J.Biol.Chem.272,21096-21103(1997)。 Several NF-κB inhibitors are described in C. Wahl et al., J. Clin. Invest. 101 (5), 1163-1174 (1998), RWSullivan et al., J. Med. Chem. 41, 413-419 (1998), J. P. et al., J. Biol. Chem. 272, 21096-21103 (1997).

已知海中天然產物海蒙辛(hymenialdisine)可抑制NF-κB。Roshak,A.等人之JPET,283,955-961(1997)。Breton,J.J與Chabot-Fletcher,M.C.,JPET,282,459-466(1997)。 It is known that the natural product of the sea, hymenial disine, inhibits NF-κB. Roshak, A. et al., JPET , 283, 955-961 (1997). Breton, JJ and Chabot-Fletcher, MC, JPET , 282, 459-466 (1997).

此外，專利申請案已提出IKK2之胺基噻吩抑制劑，參見Callahan等人之WO 2002030353；Baxter等人之WO 2001058890；Faull等人之WO 2003010158；Griffiths等人之WO2003010163；Fancelli等人之WO 200198290；Granetto等人之WO 2003037886；IKK2之咪唑抑制劑，參見Callahan等人之WO 200230423；IKK2之苯胺基苯基嘧啶抑制劑，參見Kois等人之WO 2002046171；IKK2之β-咔啉抑制劑，參見Ritzeler等人之WO 2001068648,Ritzeler等人之EP 1134221；Nielsch等人之DE 19807993；Ritzeler等人之EP 1209158；IKK2之吲哚抑制劑，參見Ritzeler等人之WO 2001030774；IKK2之苯并咪唑抑制劑，參見Ritzeler等人之DE 19928424；Ritzeler等人之WO 2001000610；Ritzeler等人之WO 2004022553；IKK2之胺基吡啶抑制劑，參見Lewinger等人之WO 2002024679；Murata等人之WO 2002024693；Murata等人之WO 2002044153；IKK2之胺基嘧啶抑制劑，參見Bollbuck等人之WO 2004089913；IKK2之吡唑抑制劑，參見Bergmanis等人之WO 2003024935；Metz等人之WO 2003024936；Geng等人之WO 2003027075；Stealey等人之WO 2003035625；Xu等人之WO 200307076；Lennon等人之WO 2003095430；IKK2之吡酮抑制劑，參見Boys等人之WO 2005035527；IKK2之吡唑喹唑啉抑制劑，參見Beaulieu等人之WO 2002028860；Burke等人之WO 2002060386；Burke等人之US 20030022898；IKK2之噻吩三環抑制劑，參見Belema等人之WO 2003084959；IKK2之吡唑并嘌呤抑制劑，參見Qiu等人之WO 2004075846；IKK2之唑并與噻唑并吡啶抑制劑，參見Pitts等人之WO 2004106293；IKK2之喹啉抑制劑；Browner等人之WO2002041843；Browner等人之US 20020161004與IKK2之吡啶基氰基胍抑制劑，參見Bjorkling等人之WO 2002094813、Binderup等人之WO 2002094322與Madsen等人之WO 200294265；IKK2之噻吩并吡啶抑制劑，參見Cywin等人之WO 2003103661；Liu等人之WO 2005035537；IKK2之苯并噻吩抑制劑，參見Chen等人之WO 2005012283。已知天然產物星形胞菌素、檞皮黃酮、K252a與K252b為IKK2抑制劑，參見Peet,G.W.與Li之J.J.Biol.Chem.,274,32655-32661(1999)與Wisniewski,D.等人之Analytical Biochem.274,220-228(1999)。亦有文獻說明合成之IKK2之抑制劑，參見Burke等人之J.Biol.Chem.,278,1450-1456(2003)、Murata等人之Bioorg.Med.Chem.Lett.,13,913-198(2003)、Murata等人之Bioorg.Med.Chem.Lett.,14,4013-4017(2004)與Murata等人之Bioorg.Med.Chem.Lett.,14,4019-4022(2004)已說明之IKK2抑制劑。 In addition, the patent application has proposed an aminothiophene inhibitor of IKK2, see WO 2002030353 to Callahan et al.; WO 2001058890 to Baxter et al; WO 2003010158 to Faul et al; WO2003010163 to Griffiths et al; WO 200198290 to Fancelli et al; WO 101037886 to Granetto et al.; imidazole inhibitors of IKK2, see WO 200230423 to Callahan et al; aniline phenylpyrimidine inhibitors of IKK2, see WO 2002046171 by Kois et al; β-porphyrin inhibitors of IKK2, see Ritzeler WO 2001068648, Ritzeler et al., EP 1134221; Nielsch et al., DE 19807993; Ritzeler et al., EP 1209158; inhibitors of IKK2, see Ritzeler et al., WO 2001030774; IKKIM benzimidazole inhibitors, See, Ritzeler et al., DE 19928424; Ritzeler et al., WO 2001000610; Ritzeler et al., WO 2004022553; IKK2 aminopyridine inhibitors, see Lewinger et al., WO 2002024679; Murata et al., WO 2002024693; Murata et al. 2002044153; Aminopyrimidine inhibitors of IKK2, see Bollbuck et al., WO 2004089913; IKK2 pyrazole inhibitors, see Bergmanis et al. The WO 2003024935; Metz et al.'S WO 2003024936; Geng et al.'S WO 2003027075; Stealey et al.'S WO 2003035625; Xu et al.'S WO 200307076; Lennon et al.'S WO 2003095430; IKK2 of pyrazole Ketone inhibitors, see Boys et al., WO 2005035527; IKK2 pyrazole quinazoline inhibitors, see Beaulieu et al., WO 2002028860; Burke et al., WO 2002060386; Burke et al., US 20030022898; IKK2, thiophene tricyclic inhibition For agents, see Belema et al., WO 2003084959; IKK2 pyrazolopyrene inhibitors, see Qiu et al., WO 2004075846; IKK2 For oxazolidine and thiazolopyridine inhibitors, see Pitts et al., WO 2004106293; IKK2 quinoline inhibitors; Browner et al., WO2002041843; Browner et al., US20020161004, and IKK2 pyridyl cyanoguanidine inhibitors, see Bjorkling et al. WO 2002094813, Binderup et al. WO 2002094322 and Madsen et al. WO 200294265; IKK2 thienopyridine inhibitors, see Cywin et al. WO 2003103661; Liu et al. WO 2005035537; IKK2 benzothiophene inhibitors, See WO 2005012283 by Chen et al. The natural products of streptomycin, quercetin, K252a and K252b are known as IKK2 inhibitors, see Peet, GW and Li JJ Biol. Chem. , 274, 32655-32661 (1999) and Wisniewski, D. et al. Analytical Biochem. 274, 220-228 (1999). There are also literatures describing inhibitors of synthetic IKK2, see Burke et al . , J. Biol. Chem. , 278, 1450-1456 (2003), Murata et al . , Bioorg. Med. Chem. Lett. , 13, 913-198 (2003) . ), Murata et al . , Bioorg. Med. Chem. Lett. , 14, 4013-4017 (2004) and Murata et al . , Bioorg. Med. Chem. Lett. , 14, 4019-4022 (2004) . Agent.

因此，已有人試圖製備可抑制IKK2活性之化合物且相關技藝已說明許多此等化合物。然而，由於IKK2媒介許多種病理反應，因此仍舊需要可用於治療多種疾病之IKK2之抑制劑。 Thus, attempts have been made to prepare compounds which inhibit the activity of IKK2 and a number of such compounds have been described in the related art. However, due to the many pathological reactions of IKK2 media, there is still a need for inhibitors of IKK2 that can be used to treat a variety of diseases.

本發明者已發現新穎之吲哚羧醯胺化合物，其係激酶活性(特定言之不當IKK2活性)之抑制劑。此等吲哚羧醯胺衍生物因此適用於治療與不當激酶(特定言之不當IKK2)活性有關之疾病，特定言之治療與預防由IKK2機轉所媒介之疾病，包括發炎與組織修復病變，特定言之類風濕關節炎、發炎性腸部疾病、氣喘與COPD(慢性阻塞性肺病)；骨關節炎、骨質疏鬆症與纖維變性疾病；皮膚病，包括乾癬、異位性皮膚炎與紫外線(UV)所誘發皮膚傷害；自體免疫疾病，包括全身紅斑性狼瘡、多發性硬化、乾癬性關節炎、僵直性脊椎炎、組織與器官排斥、阿茲海默氏症、中風、動脈粥樣硬化、術後再狹窄、糖尿病、腎小球腎炎、癌症，包括霍金氏症、惡病質、與感染及某些病毒感染有關之發炎，包括後天免疫缺乏症候群(AIDS)、成人呼吸窘迫症候群與共濟失調-毛細血管擴張症(Ataxia Telangiestasia)。 The present inventors have discovered novel indole carboxamide compounds which are inhibitors of kinase activity (specifically, improper IKK2 activity). These guanidinium derivatives are therefore suitable for the treatment of diseases associated with the activity of inappropriate kinases (specifically inappropriate IKK2), in particular the treatment and prevention of the disease by the IKK2 machine. Diseases, including inflammation and tissue repair lesions, rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease); osteoarthritis, osteoporosis and fibrotic diseases; skin diseases, including dryness , atopic dermatitis and ultraviolet (UV) induced skin damage; autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, dry arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer Disease, stroke, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, including Hodgkin's disease, cachexia, inflammation associated with infections and certain viral infections, including acquired immunodeficiency syndrome (AIDS) Adult respiratory distress syndrome and ataxia - telangiectasia (Ataxia Telangiestasia).

本發明係有關新穎之吲哚羧醯胺衍生物。明確言之，本發明係有關一種式(I)化合物：其中R1、R2、R3、U與V如下文中定義，及其醫藥上可接受之鹽。 The present invention relates to novel indole carboxamide derivatives. In particular, the invention relates to a compound of formula (I): Wherein R1, R2, R3, U and V are as defined below, and pharmaceutically acceptable salts thereof.

本發明化合物為IKK2之抑制劑，適用於治療與不當IKK2(亦稱為IKKβ)活性有關之疾病，如：類風濕關節炎、氣喘與COPD(慢性阻塞性肺病)。因此，本發明進一步有關一種包含本發明化合物之醫藥組合物。本發明進一步亦有關一種抑制IKK2活性及使用本發明化合物或包含本發明化合物之醫藥組合物治療與其相關病變之方法。 The compounds of the present invention are inhibitors of IKK2 and are useful for the treatment of diseases associated with inappropriate IKK2 (also known as IKKβ) activity, such as rheumatoid arthritis, asthma and COPD (chronic obstructive pulmonary disease). Accordingly, the invention is further directed to a pharmaceutical composition comprising a compound of the invention. The invention is further related A method of inhibiting IKK2 activity and treating a disease associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

本發明係有關一種式(I)化合物：其中R1為基團-XYZ或或；X 為苯基、雜芳基、1,2,3,4-四氫萘基或2,3-二氫-1H-茚基，其中該苯基、雜芳基、1,2,3,4-四氫萘基與2,3-二氫-1H-茚基可視需要經1或2個分別獨立選自下列之取代基取代：1)鹵基，2)硝基，3)氰基，4)-NR7R8，5)C₁-C₆-烷基，6)CHO，7)CONH₂，與 8)-OR4，其中該C₁-C₆-烷基可視需要經一個-NR4R5基團取代；Y 為一鍵結或C₁-C₆伸烷基，其中C₁-C₆伸烷基可視需要經1或2個分別獨立選自下列之取代基取代：1)C₁-C₃-烷基，其可視需要經一個OR4基團取代，2)C₃-C₇-環烷基，3)甲氧基，4)羥基，與5)雜芳基；Z 為-NR4R5或雜環烷基，其中該雜環烷基可視需要經1或2個分別獨立選自下列之取代基取代：1)C₁-C₆-烷基，其可視需要經一個OR4或一個雜環烷基取代，2)C₃-C₇-環烷基，3)甲氧基，4)-CONH₂，5)羥基，6)雜芳基，7)CF₃，8)苯基，9)雜環烷基，與10)N(CH₃)₂； R2係選自：1)H，2)氟，與3)氯；R3係選自：1)H，2)氟，與3)氯；R4係選自：1)H，與2)C₁-C₆-烷基，其中該C₁-C₆-烷基可視需要經一個羥基或一個甲氧基取代；R5係選自：1)H，2)C₅-C₆-雜環烷基，3)-CO₂Et，4)C₁-C₆-烷氧基，5)C₃-C₇-環烷基，6)C₁-C₆-烷基，7)-SO₂R10，與8)-C(O)R10，其中該C₃-C₇-環烷基與C₁-C₆-烷基可視需要經1至3個選自R6之取代基取代；各R6分別獨立選自：1)-NR7R8，2)-SO₂R7，3)-CONH₂，4)-CF₃，5)-CN，6)-CO₂R7，7)-OCH₂CH₂OR7，8)-SR5，9)C3-C4烯基，10)OH，11)C₁-C₆-烷氧基，12)雜芳基，13)C₃-C₇-環烷基，14)苯基，15)雜環烷基，與16)鹵基，其中該雜芳基、環烷基、苯基與雜環烷基可視需要經1至2個選自R9之取代基取代；R7係選自：1)H，2)C₁-C₃-烷基，與3)苯基；R8係選自： 1)H，2)C₁-C₃-烷基，與3)-C(O)R4；各R9分別獨立選自：1)羥基，2)-OMe，3)硝基，4)C₁-C₆-烷基，5)NH₂，6)鹵基，7)CF₃，8)C₁-C₆-烷氧基，與9)CN；R10係選自：1)H，2)C₁-C₆-烷基，3)苯基，4)C₃-C₇-環烷基，5)雜芳基，6)C₁-C₆-雜芳基，與7)雜環烷基，其中該C₁-C₆-烷基可視需要經1或2個分別獨立選自C₃-C₇-環烷基與-S-R7之取代基取代；其中該雜環烷基可視需要經一個-C(O)R7基團取代；及其中該苯基、雜芳基與C₁-C₆-雜芳基可視需要經1至2個選自R11之取代基取代；各R11分別獨立選自：1)H，2)C₁-C₆-烷基，與3)鹵基；U 為一鍵結，C₁-C₆伸烷基或C₂-C₆伸烯基；V 為苯基、5或6員雜芳基、5-7員雜環烷基、C₅-C₇環烷基，或C₅-C₇環烯基，其分別經-N(R7)S(O)_mR12、-S(O)_mN(R7)R12、-S(O)_mR12，或-C(O)R12取代；m 為1或2；及R12為C₁-C₆-烷基、C₃-C₇環烷基、C₁-C₆-烷基-C₃-C₇環烷基，或C₁-C₆-烷基-苯基；或其醫藥上可接受之鹽。 The invention relates to a compound of formula (I): Wherein R1 is a group -XYZ or or X is phenyl, heteroaryl, 1,2,3,4-tetrahydronaphthyl or 2,3-dihydro-1 H -indenyl, wherein the phenyl, heteroaryl, 1, 2, 3 , 4-tetrahydronaphthyl and 2,3-dihydro-1 H -fluorenyl may be optionally substituted by 1 or 2 substituents each independently selected from the group consisting of: 1) halo, 2) nitro, 3) cyanide a group, 4)-NR7R8,5)C ₁ -C ₆ -alkyl, 6)CHO,7)CONH ₂ , and 8)-OR4, wherein the C ₁ -C ₆ -alkyl group may optionally undergo a -NR 4 R 5 group Substituted; Y is a bond or a C ₁ -C ₆ alkyl group, wherein the C ₁ -C ₆ alkyl group may be substituted with 1 or 2 substituents each independently selected from the group consisting of: 1) C ₁ -C ₃ -alkyl, which may optionally be substituted by an OR4 group, 2) C ₃ -C ₇ -cycloalkyl, 3) methoxy, 4) hydroxy, and 5) heteroaryl; Z is -NR4R5 or hetero a cycloalkyl group, wherein the heterocycloalkyl group may be optionally substituted with 1 or 2 substituents each independently selected from the group consisting of 1) C ₁ -C ₆ -alkyl, which may optionally be subjected to an OR 4 or a heterocycloalkyl group. Substituted, 2) C ₃ -C ₇ -cycloalkyl, 3) methoxy, 4)-CONH ₂ , 5) hydroxy, 6) heteroaryl, 7) CF ₃ , 8) phenyl, 9) heterocyclic An alkyl group, and 10) N(CH ₃ ) ₂ ; R ₂ is selected from the group consisting of: 1) H, 2) fluorine, And 3) chlorine; R3 is selected from the group consisting of: 1) H, 2) fluorine, and 3) chlorine; R4 is selected from the group consisting of: 1) H, and 2) C ₁ -C ₆ -alkyl, wherein the C ₁ -C _{The 6} -alkyl group may be optionally substituted by a hydroxyl group or a methoxy group; R5 is selected from the group consisting of: 1) H, 2) C ₅ -C ₆ -heterocycloalkyl, 3)-CO ₂ Et, 4) C ₁ - C ₆ -alkoxy, 5)C ₃ -C ₇ -cycloalkyl, 6)C ₁ -C ₆ -alkyl, 7)-SO ₂ R10, and 8)-C(O)R10, wherein the C ₃ -C ₇ -cycloalkyl and C ₁ -C ₆ -alkyl may be optionally substituted with 1 to 3 substituents selected from R 6 ; each R 6 is independently selected from: 1) -NR ₇ R 8 , ₂ ) - SO ₂ R 7 , 3)-CONH ₂ ,4)-CF ₃ ,5)-CN,6)-CO ₂ R7,7)-OCH ₂ CH ₂ OR7,8)-SR5,9)C3-C4 alkenyl,10)OH , 11) C ₁ -C ₆ -alkoxy, 12)heteroaryl, 13)C ₃ -C ₇ -cycloalkyl, 14)phenyl, 15)heterocycloalkyl, and 16)halo, wherein The heteroaryl, cycloalkyl, phenyl and heterocycloalkyl groups may be optionally substituted with 1 to 2 substituents selected from R9; R7 is selected from: 1) H, 2) C ₁ -C ₃ -alkyl And 3) phenyl; R8 is selected from the group consisting of: 1) H, 2) C ₁ -C ₃ -alkyl, and 3)-C(O)R4; each R9 is independently selected from: 1) hydroxyl, 2) -OMe, 3) nitro, 4) C ₁ -C ₆ - alkyl, 5) NH _2, 6) _{Group, 7) CF 3, 8)} C 1 -C 6 - alkoxy, and 9) CN; R10 is selected from: 1) H, 2) C 1 -C 6 - alkyl, 3) phenyl, 4 C ₃ -C ₇ -cycloalkyl, 5)heteroaryl, 6)C ₁ -C ₆ -heteroaryl, and 7)heterocycloalkyl, wherein the C ₁ -C ₆ -alkyl group may be 1 or 2 substituents each independently selected from a C ₃ -C ₇ -cycloalkyl group and -S-R7; wherein the heterocycloalkyl group may be optionally substituted with a -C(O)R7 group; The phenyl group, the heteroaryl group and the C ₁ -C ₆ -heteroaryl group may be optionally substituted with 1 to 2 substituents selected from R 11 ; each R 11 is independently selected from the group consisting of: 1) H, 2) C ₁ -C ₆ - Alkyl, with 3) halo; U is a bond, C ₁ -C ₆ alkyl or C ₂ -C ₆ alkylene; V is phenyl, 5 or 6 membered heteroaryl, 5-7 member Heterocycloalkyl, C ₅ -C ₇ cycloalkyl, or C ₅ -C ₇ cycloalkenyl, which are respectively -N(R7)S(O) _m R12, -S(O) _m N(R7)R12 , -S(O) _m R12, or -C(O)R12 substituted; m is 1 or 2; and R12 is C ₁ -C ₆ -alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₆ An alkyl-C ₃ -C ₇ cycloalkyl group, or a C ₁ -C ₆ -alkyl-phenyl group; or a pharmaceutically acceptable salt thereof.

本發明一項具體實施例為式(I)化合物：其中R1為基團-XYZ；X 為苯基或雜芳基，其中該苯基與雜芳基可視需要經1或2個分別獨立選自下列之取代基取代：1)鹵基，2)硝基，3)氰基，4)-NR7R8，5)C₁-C₆-烷基， 6)CHO，7)CONH₂，與8)-OR4，其中該C₁-C₆-烷基可視需要經一個-NR4R5基團取代；Y為一鍵結或C₁-C₆伸烷基，其中C₁-C₆伸烷基為可視需要經1或2個分別獨立選自下列之取代基取代：1)C₁-C₃-烷基，其可視需要經一個OR4基團取代，2)C₃-C₇-環烷基，3)甲氧基，4)羥基，與5)雜芳基；Z為-NR4R5或雜環烷基，其中該雜環烷基為可視需要經1或2個分別獨立選自下列之取代基取代：1)C₁-C₆-烷基，其可視需要經一個OR4基團取代，2)C₃-C₇-環烷基，3)甲氧基，4)羥基，與5)雜芳基；R2係選自：1)H，2)氟，與3)氯； R3係選自：1)H，2)氟，與3)氯；R4係選自：1)H，與2)C₁-C₆-烷基，其中該C₁-C₆-烷基可視需要經一個羥基或一個甲氧基取代；R5係選自：1)H，2)C₁-C₆-烷氧基，3)C₃-C₇-環烷基、4)C₁-C₆-烷基，5)-SO₂R10，與6)-C(O)R10，其中該C₃-C₇-環烷基與C₁-C₆-烷基可視需要經1至3個選自R6之取代基取代；各R6分別獨立選自：1)-NR7R8，2)-SO₂R7，3)OH，4)甲氧基，5)雜芳基， 6)C₃-C₇-環烷基，7)苯基，8)雜環烷基，與9)鹵基，其中該雜芳基、環烷基、苯基與雜環烷基可視需要經1至2個選自R9之取代基取代；R7係選自：1)H，與2)C₁-C₃-烷基；R8係選自：1)H，與2)C₁-C₃-烷基；各R9分別獨立選自：1)羥基，2)硝基，3)C₁-C₆-烷基，4)NH₂，5)鹵基，6)CF₃，7)C₁-C₆-烷氧基，與8)CN；R10係選自：1)H，2)C₁-C₆-烷基， 3)苯基，4)C₃-C₇-環烷基，與5)雜芳基，其中該C₁-C₆-烷基可視需要經1或2個分別獨立選自C₃-C₇-環烷基與-S-R7之取代基取代；其中該雜環烷基可視需要經一個-C(O)R7基團取代；且其中該苯基與雜芳基可視需要經1至2個選自R11之取代基取代；各R11分別獨立選自：1)H，2)C₁-C₆-烷基，與3)鹵基；U 為一鍵結，C₁-C₆伸烷基或C₂-C₆伸烯基；V 為苯基、5或6員雜芳基、5-7員雜環烷基、C₅-C₇環烷基或C₅-C₇環烯基，其分別經-N(R7)S(O)_mR12、-S(O)_mN(R7)R12、-S(O)_mR12，或-C(O)R12取代；m 為1或2；及R12為C₁-C₆-烷基、C₃-C₇環烷基、C₁-C₆-烷基-C₃-C₇環烷基，或C₁-C₆-烷基-苯基；或其醫藥上可接受之鹽。 A particular embodiment of the invention is a compound of formula (I): wherein R1 is a group -XYZ; X is phenyl or heteroaryl, wherein the phenyl and heteroaryl groups are optionally independently selected from 1 or 2, respectively. Substituted by the following substituents: 1) halo, 2) nitro, 3) cyano, 4) - NR7R8, 5) C ₁ -C ₆ -alkyl, 6) CHO, 7) CONH ₂ , and 8)- OR4, wherein the C ₁ -C ₆ -alkyl group may be optionally substituted with a -NR 4 R 5 group; Y is a bond or a C ₁ -C ₆ alkyl group, wherein the C ₁ -C ₆ alkyl group is as visible 1 or 2 substituents each independently selected from the group consisting of 1) C ₁ -C ₃ -alkyl, which may optionally be substituted by an OR4 group, 2) C ₃ -C ₇ -cycloalkyl, 3) A Oxy, 4) hydroxy, and 5) heteroaryl; Z is -NR4R5 or heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted by 1 or 2 substituents each independently selected from the group consisting of: 1) C ₁ -C ₆ -alkyl, which may optionally be substituted by an OR4 group, 2) C ₃ -C ₇ -cycloalkyl, 3) methoxy, 4) hydroxy, and 5) heteroaryl; R 2 Selected from: 1) H, 2) fluorine, and 3) chlorine; R3 is selected from: 1) H, 2) fluorine, and 3) chlorine; R4 is selected from: 1) H, and 2) C ₁ -C ₆ - alkyl, wherein C ₁ -C ₆ - alkyl optionally substituted with one hydroxyl group or a methoxy group; R5 is selected from: 1) H, 2) C 1 -C 6 - alkoxy, ₃₎ C 3 -C ₇ - cycloalkyl An alkyl group, 4) C ₁ -C ₆ -alkyl, 5)-SO ₂ R10, and 6)-C(O)R10, wherein the C ₃ -C ₇ -cycloalkyl group and the C ₁ -C ₆ -alkane The base may be substituted with 1 to 3 substituents selected from R6; each R6 is independently selected from the group consisting of: 1) -NR7R8, ₂ )-SO ₂ R7, 3) OH, 4) methoxy, 5) heteroaryl , 6) C ₃ -C ₇ -cycloalkyl, 7) phenyl, 8) heterocycloalkyl, and 9) halo, wherein the heteroaryl, cycloalkyl, phenyl and heterocycloalkyl are optionally required Substituted by 1 to 2 substituents selected from R9; R7 is selected from: 1) H, and 2) C ₁ -C ₃ -alkyl; R8 is selected from: 1) H, and 2) C ₁ -C ₃ -alkyl; each R9 is independently selected from the group consisting of: 1) hydroxy, 2) nitro, 3) C ₁ -C ₆ -alkyl, 4) NH ₂ , 5) halo, 6) CF ₃ , 7) C ₁ -C ₆ -alkoxy, and 8)CN; R10 is selected from the group consisting of: 1) H, 2) C ₁ -C ₆ -alkyl, 3) phenyl, 4) C ₃ -C ₇ -cycloalkyl And 5) a heteroaryl group, wherein the C ₁ -C ₆ -alkyl group may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of C ₃ -C ₇ -cycloalkyl and -S-R7; Heterocycloalkyl Substituting a -C(O)R7 group as needed; and wherein the phenyl group and the heteroaryl group may be optionally substituted with 1 to 2 substituents selected from R11; each R11 is independently selected from: 1) H, 2 C ₁ -C ₆ -alkyl, and 3)halo; U is a bond, C ₁ -C ₆ alkyl or C ₂ -C ₆ alkylene; V is phenyl, 5 or 6 hetero Aryl, 5-7 membered heterocycloalkyl, C ₅ -C ₇ cycloalkyl or C ₅ -C ₇ cycloalkenyl, which are respectively -N(R7)S(O) _m R12, -S(O) _m N(R7)R12, -S(O) _m R12, or -C(O)R12 substituted; m is 1 or 2; and R12 is C ₁ -C ₆ -alkyl, C ₃ -C ₇ cycloalkyl And a C ₁ -C ₆ -alkyl-C ₃ -C ₇ cycloalkyl group, or a C ₁ -C ₆ -alkyl-phenyl group; or a pharmaceutically acceptable salt thereof.

本發明另一項具體實施例為式(I)化合物：其中R1為基團-XYZ或或； X 為苯基、雜芳基、1,2,3,4-四氫萘基，或2,3-二氫-1H-茚基；Y 為一鍵結或C₁-C₆伸烷基；Z 為-NR4R5或雜環烷基、其中該雜環烷基為可視需要經1或2個分別獨立選自下列之取代基取代：1)C₁-C₆-烷基，其可視需要經一個OR4或一個雜環烷基取代，2)C₃-C₇-環烷基，3)甲氧基，4)-CONH₂，5)羥基，6)雜芳基，7)CF₃，8)苯基，9)雜環烷基，與10)N(CH₃)₂；R2為H；R3為H；R4係選自：1)H，與2)C₁-C₆-烷基，其中該C₁-C₆-烷基可視需要經一個羥基或一個甲氧基取代； R5係選自：1)H，2)C₅-C₆-雜環烷基，3)-CO₂Et，4)C₁-C₆-烷氧基，5)C₃-C₇-環烷基，6)C₁-C₆-烷基，7)-SO₂R10，與8)-C(O)R10，其中該C₃-C₇-環烷基與C₁-C₆-烷基可視需要經1至3個選自R6之取代基取代；各R6分別獨立選自：1)-NR7R8，2)-SO₂R7，3)-CONH₂，4)-CF₃，5)-CN，6)-CO₂R7，7)-OCH₂CH₂OR7，8)-SR5，9)C₃-C₄烯基，10)OH，11)C₁-C₆-烷氧基，12)雜芳基， 13)C₃-C₇-環烷基，14)苯基，15)雜環烷基，與16)鹵基，其中該雜芳基、環烷基、苯基與雜環烷基可視需要經1至2個選自R9之取代基取代；R7係選自：1)H，2)C₁-C₃-烷基，與3)苯基；R8係選自：1)H，2)C₁-C₃-烷基，與3)-C(O)R4；各R9分別獨立選自：1)羥基，2)-OMe，3)硝基，4)C₁-C₆-烷基，5)NH₂，6)鹵基，7)CF₃，8)C₁-C₆-烷氧基，與9)CN； R10係選自：1)H，2)C₁-C₆-烷基，3)苯基，4)C₃-C₇-環烷基，5)雜芳基，6)C₁-C₆-雜芳基，與7)雜環烷基，其中該C₁-C₆-烷基可視需要經1或2個分別獨立選自C₃-C₇-環烷基與-S-R7之取代基取代；其中該雜環烷基可視需要經一個-C(O)R7基團取代；且其中該苯基、雜芳基與C₁-C₆-雜芳基可視需要經1至2個選自R11之取代基取代；各R11分別獨立選自：1)H，2)C₁-C₆-烷基，與3)鹵基；U 為一鍵結；V 為經-S(O)_mR12取代之5-7員雜環烷基；m 為1或2；及R12為C₁-C₆-烷基；或其醫藥上可接受之鹽。 Another embodiment of the invention is a compound of formula (I): wherein R1 is a group -XYZ or or X is phenyl, heteroaryl, 1,2,3,4-tetrahydronaphthyl, or 2,3-dihydro-1 H -indenyl; Y is a bond or C ₁ -C ₆ -alkylene Z is -NR4R5 or heterocycloalkyl, wherein the heterocycloalkyl group may be optionally substituted with 1 or 2 substituents independently selected from the group consisting of: 1) C ₁ -C ₆ -alkyl, as needed Substituted by an OR4 or a heterocycloalkyl group, 2) C ₃ -C ₇ -cycloalkyl, 3) methoxy, 4)-CONH ₂ , 5) hydroxy, 6) heteroaryl, 7) CF ₃ , 8) phenyl, 9) heterocycloalkyl, and 10) N(CH ₃ ) ₂ ; R ₂ is H; R ₃ is H; R 4 is selected from: 1) H, and 2) C ₁ -C ₆ -alkyl Wherein the C ₁ -C ₆ -alkyl group may be optionally substituted by a hydroxyl group or a methoxy group; R 5 is selected from the group consisting of: 1) H, 2) C ₅ -C ₆ -heterocycloalkyl, 3)-CO ₂ Et, 4) C ₁ -C ₆ -alkoxy, 5)C ₃ -C ₇ -cycloalkyl, 6)C ₁ -C ₆ -alkyl, 7)-SO ₂ R10, and 8)-C ( O) R10, wherein the C ₃ -C ₇ -cycloalkyl group and the C ₁ -C ₆ -alkyl group may be optionally substituted with 1 to 3 substituents selected from R 6 ; each R 6 is independently selected from: 1) -NR 7 R 8 , 2) -SO ₂ R7,3)-CONH ₂ ,4)-CF ₃ ,5)-CN,6)-CO ₂ R7,7)-OCH ₂ CH ₂ OR7,8)-SR5,9)C ₃ -C ₄ alkenyl, 10) OH 11) C ₁ -C ₆ - alkoxy, 12) heteroaryl, 13) C ₃ -C ₇ - cycloalkyl, 14) phenyl, 15) heterocycloalkyl, and 16) halo, wherein the The heteroaryl, cycloalkyl, phenyl and heterocycloalkyl groups may be optionally substituted with 1 to 2 substituents selected from R9; R7 is selected from the group consisting of: 1) H, 2) C ₁ -C ₃ -alkyl, And 3) phenyl; R8 is selected from the group consisting of: 1) H, 2) C ₁ -C ₃ -alkyl, and 3)-C(O)R4; each R9 is independently selected from: 1) hydroxyl, 2)- OMe, 3) nitro, 4) C ₁ -C ₆ -alkyl, 5) NH ₂ , 6) halo, 7) CF ₃ , 8) C ₁ -C ₆ -alkoxy, and 9) CN; R10 is selected from the group consisting of: 1) H, 2) C ₁ -C ₆ -alkyl, 3) phenyl, 4) C ₃ -C ₇ -cycloalkyl, 5) heteroaryl, 6) C ₁ -C ₆ a heteroaryl group, and 7) a heterocycloalkyl group, wherein the C ₁ -C ₆ -alkyl group may optionally be substituted by 1 or 2, respectively, independently selected from the group consisting of C ₃ -C ₇ -cycloalkyl and -S-R7 Substituent; wherein the heterocycloalkyl group may be substituted with a -C(O)R7 group; and wherein the phenyl, heteroaryl and C ₁ -C ₆ -heteroaryl groups may optionally be selected from 1 to 2 Substituted from a substituent of R11; each R11 is independently selected from: 1) H, 2) C ₁ -C ₆ -alkyl, and 3) halo; U is a bond; V is -S(O) _m R12 The 5-7 membered heterocycloalkyl; m is 1 or 2; and R12 is C ₁ -C ₆ - alkyl; or a pharmaceutically acceptable salt thereof.

本發明另一項具體實施例為式(I)化合物：其中R1為基團-XYZ；X 為苯基或雜芳基；Y 為一鍵結或C₁-C₆伸烷基； Z 為-NR4R5或雜環烷基，其中該雜環烷基為可視需要經1或2個分別獨立選自下列之取代基取代：1)C₁-C₆-烷基，其可視需要經一個OR4基團取代，2)C₃-C₇-環烷基，3)甲氧基，4)羥基，與5)雜芳基；R2為H；R3為H；R4係選自：1)H，與2)C₁-C₆-烷基，其中該C₁-C₆-烷基可視需要經一個羥基或一個甲氧基取代；R5係選自：1)H，2)C₁-C₆-烷氧基，3)C₃-C₇-環烷基，4)C₁-C₆-烷基，5)-SO₂R10，與6)-C(O)R10，其中該C₃-C₇-環烷基與C₁-C₆-烷基可視需要經1至3個選自R6之取代基取代；各R6分別獨立選自：1)NR7R8，2)SO₂R7，3)OH，4)甲氧基，5)雜芳基，6)C₃-C₇-環烷基，7)苯基，8)雜環烷基，與9)鹵基，其中該雜芳基、環烷基、苯基與雜環烷基可視需要經1至2個選自R9之取代基取代；R7係選自：1)H，與2)C₁-C₃-烷基；R8係選自：1)H與2)C₁-C₃-烷基；各R9分別獨立選自：1)羥基，2)硝基，3)C₁-C₆-烷基，4)NH₂，5)鹵基， 6)CF₃，7)C₁-C₆-烷氧基，與8)CN；R10係選自：1)H，2)C₁-C₆-烷基，3)苯基，4)C₃-C₇-環烷基，與5)雜芳基，其中該C₁-C₆-烷基可視需要經1或2個分別獨立選自C₃-C₇-環烷基與-S-R7之取代基取代；其中該雜環烷基可視需要經一個-C(O)R7基團取代；與其中該苯基與雜芳基可視需要經1至2個選自R11之取代基取代；各R11分別獨立選自：1)H，2)C₁-C₆-烷基，與3)鹵基；U 為一鍵結；V 為經-S(O)_mR12取代之5-7員雜環烷基；m 為1或2；及R12為C₁-C₆-烷基；或其醫藥上可接受之鹽。 Another particular embodiment of the present invention is a compound of formula Example (I): wherein R1 is the group -XYZ; X is phenyl or heteroaryl; Y is a bond or C ₁ -C ₆ alkylene; Z is - NR4R5 or heterocycloalkyl, wherein the heterocycloalkyl group may be optionally substituted by 1 or 2 substituents each independently selected from the group consisting of 1) C ₁ -C ₆ -alkyl, which may optionally undergo an OR 4 group. Substituted, 2) C ₃ -C ₇ -cycloalkyl, 3) methoxy, 4) hydroxy, and 5) heteroaryl; R 2 is H; R 3 is H; R 4 is selected from: 1) H, and 2 C ₁ -C ₆ -alkyl, wherein the C ₁ -C ₆ -alkyl group may be optionally substituted by one hydroxyl group or one methoxy group; R 5 is selected from: 1) H, 2) C ₁ -C ₆ -alkane Oxyk, 3) C ₃ -C ₇ -cycloalkyl, 4) C ₁ -C ₆ -alkyl, 5)-SO ₂ R10, and 6)-C(O)R10, wherein the C ₃ -C ₇ - cycloalkyl and C ₁ -C ₆ -alkyl may optionally be substituted with 1 to 3 substituents selected from R 6 ; each R 6 is independently selected from: 1) NR 7 R 8 , ₂ ) SO ₂ R 7 , 3) OH, 4 a methoxy group, 5) a heteroaryl group, 6) a C ₃ -C ₇ -cycloalkyl group, 7) a phenyl group, an 8) heterocycloalkyl group, and a 9) halo group, wherein the heteroaryl group, cycloalkyl group , phenyl and heterocycloalkyl may optionally have 1 to 2 substituents selected from R9 Generation; R7 is selected from: 1) H, and 2) C ₁ -C ₃ - alkyl; R8 is selected from: 1) H and 2) C ₁ -C ₃ - alkyl; each R9 is independently selected from: 1) hydroxy, 2) nitro, 3) C ₁ -C ₆ -alkyl, 4) NH ₂ , 5) halo, 6) CF ₃ , 7) C ₁ -C ₆ -alkoxy, and 8) CN; R10 is selected from the group consisting of: 1) H, 2) C ₁ -C ₆ -alkyl, 3) phenyl, 4) C ₃ -C ₇ -cycloalkyl, and 5) heteroaryl, wherein the C ₁ -C ₆ -alkyl may optionally be substituted by 1 or 2 substituents each independently selected from C ₃ -C ₇ -cycloalkyl and -S-R7; wherein the heterocycloalkyl may optionally be subjected to a -C(O) Wherein the R7 group is substituted; and wherein the phenyl group and the heteroaryl group are optionally substituted with 1 to 2 substituents selected from R11; each R11 is independently selected from the group consisting of: 1) H, 2) C ₁ -C ₆ -alkane And 3) a halogen group; U is a bond; V is a 5-7 membered heterocycloalkyl group substituted by -S(O) _m R12; m is 1 or 2; and R12 is C ₁ -C ₆ - An alkyl group; or a pharmaceutically acceptable salt thereof.

本發明另一項具體實施例為式(I)化合物，其中：其中R1為基團-XYZ； X 為2-或3-硫苯基；Y 為一鍵結或C₁-C₄伸烷基；Z 為-NR4R5或雜環烷基，1)C₁-C₆-烷基，其可視需要經一個OR4或一個雜環烷基取代，2)C₃-C₇-環烷基，3)甲氧基，4)-CONH₂，5)羥基，6)雜芳基；7)CF₃，8)苯基，9)雜環烷基，與10)N(CH₃)₂；R2為H；R3為H；R4係選自：1)H與2)C₁-C₆-烷基，其中該C₁-C₆-烷基可視需要經一個羥基或一個甲氧基取代；R5係選自：1)C₃-C₇-環烷基，2)C₁-C₆-烷基，其中該C₃-C₇-環烷基與C₁-C₆-烷基可視需要經1至3個選自R6之取代基取代；各R6分別獨立選自：1)-NR7R8，2)-CONH₂，3)-CN，4)-OCH₂CH₂OR7，5)C3-C4烯基，6)OH，7)C₁-C₆-烷氧基，8)雜芳基，9)C₃-C₇-環烷基，10)苯基，11)雜環烷基，與12)鹵基，其中該雜芳基、環烷基、苯基與雜環烷基可視需要經1至2個選自R9之取代基取代；R7係選自：1)H，2)C₁-C₃-烷基，與3)苯基；R8係選自：1)H，2)C₁-C₃-烷基，與 3)-C(O)R4；各R9分別獨立選自：1)C₁-C₆-烷基；U 為一鍵結；V 為經-S(O)₂R12取代之4-哌啶基；及R12為乙基或異丙基；或其醫藥上可接受之鹽。 Another particular embodiment of the present invention is a compound of formula Example (I), wherein: wherein R1 is the group -XYZ; X is 2- or 3-thiophenyl; Y is a bond or C ₁ -C ₄ alkylene Z is -NR4R5 or heterocycloalkyl, 1) C ₁ -C ₆ -alkyl, which may optionally be substituted by an OR4 or a heterocycloalkyl group, 2) C ₃ -C ₇ -cycloalkyl, 3) Methoxy, 4)-CONH ₂ , 5) hydroxy, 6) heteroaryl; 7) CF ₃ , 8) phenyl, 9) heterocycloalkyl, and 10) N(CH ₃ ) ₂ ; R ₂ is H R3 is H; R4 is selected from the group consisting of: 1) H and 2) C ₁ -C ₆ -alkyl, wherein the C ₁ -C ₆ -alkyl group may be optionally substituted with a hydroxyl group or a methoxy group; From: 1) C ₃ -C ₇ -cycloalkyl, 2) C ₁ -C ₆ -alkyl, wherein the C ₃ -C ₇ -cycloalkyl group and the C ₁ -C ₆ -alkyl group may be subjected to 1 to 3 substituents selected from R6; each R6 is independently selected from: 1) -NR7R8, ₂ )-CONH ₂ , 3)-CN, 4)-OCH ₂ CH ₂ OR7, 5) C3-C4 alkenyl, 6) OH, 7) C ₁ -C ₆ -alkoxy, 8)heteroaryl, 9)C ₃ -C ₇ -cycloalkyl, 10)phenyl, 11)heterocycloalkyl, and 12)halide a group wherein the heteroaryl group, cycloalkyl group, phenyl group and heterocycloalkyl group may be substituted with 1 to 2 substituents selected from R9 R7 is selected from: 1) H, 2) C 1 -C 3 - alkyl, and 3) phenyl; R8 is selected from: 1) H, 2) C 1 -C 3 - alkyl, and 3) - C(O)R4; each R9 is independently selected from the group consisting of: 1) C ₁ -C ₆ -alkyl; U is a bond; V is 4-piperidinyl substituted with -S(O) ₂ R12; and R12 It is an ethyl or isopropyl group; or a pharmaceutically acceptable salt thereof.

本發明另一項具體實施例為式(I)化合物，其中基團U-V為，及R12為乙基或異丙基。 Another embodiment of the invention is a compound of formula (I) wherein the group UV is And R12 is ethyl or isopropyl.

本發明另一項具體實施例為式(II)化合物其中R13為-NR14R15或雜環烷基其中該雜環烷基可視需要經1或2個選自下列之取代基取代：1)C₁-C₆-烷基，其可視需要經一個OR14基團取代，2)羥基， 3)甲氧基，與4)雜芳基；R14係選自：1)H，與2)C₁-C₆-烷基，其中該C₁-C₆-烷基可視需要經一個羥基或一個甲氧基取代；R15係選自：1)H，2)甲氧基，3)C₃-C₇環烷基，與4)C₁-C₆-烷基，其中該C₃-C₇環烷基與C₁-C₆-烷基可視需要經1至3個選自R16之取代基取代；各R16分別獨立選自：1)-NR17R18，2)-SO₂R17，3)OH，4)甲氧基，5)雜芳基，6)C₃-C₇環烷基，7)苯基，與8)雜環烷基，其中該雜芳基、環烷基、苯基與雜環烷基可視需要經1至3個選自R19之取代基取代；R17係選自：1)H，與2)C₁-C₃-烷基；R18係選自：1)H與2)C₁-C₃-烷基；R19係選自：1)羥基，2)硝基，3)C₁-C₆-烷基，4)NH₂，5)鹵基，6)CF₃，與7)C₁-C₆-烷氧基；及n 為1至3；或其醫藥上可接受之鹽。 Another embodiment of the invention is a compound of formula (II) Wherein R 13 is -NR 14 R 15 or heterocycloalkyl, wherein the heterocycloalkyl group may be substituted with 1 or 2 substituents selected from the group consisting of 1) C ₁ -C ₆ -alkyl, optionally via an OR 14 group; Substituting 2) hydroxy, 3) methoxy, and 4) heteroaryl; R14 is selected from: 1) H, and 2) C ₁ -C ₆ -alkyl, wherein the C ₁ -C ₆ -alkyl It may optionally be substituted by a hydroxyl group or a methoxy group; R15 is selected from the group consisting of: 1) H, 2) methoxy, 3) C ₃ -C ₇ cycloalkyl, and 4) C ₁ -C ₆ -alkyl, Wherein the C ₃ -C ₇ cycloalkyl group and the C ₁ -C ₆ -alkyl group may be optionally substituted with 1 to 3 substituents selected from R16; each R16 is independently selected from the group consisting of: 1) -NR17R18, 2)-SO ₂ R17,3)OH, 4) methoxy, 5) heteroaryl, 6) C ₃ -C ₇ cycloalkyl, 7) phenyl, and 8) heterocycloalkyl, wherein the heteroaryl, ring The alkyl group, the phenyl group and the heterocycloalkyl group may be optionally substituted with 1 to 3 substituents selected from R19; R17 is selected from the group consisting of: 1) H, and 2) C ₁ -C ₃ -alkyl; : 1) H and 2) C ₁ -C ₃ -alkyl; R19 is selected from the group consisting of: 1) hydroxy, 2) nitro, 3) C ₁ -C ₆ -alkyl, 4) NH ₂ , 5) halo , 6) CF ₃ , and 7) C ₁ -C ₆ -alkoxy; and n is 1 to 3; or A pharmaceutically acceptable salt.

本發明化合物之明確實例包括下列：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(1-哌啶基甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(1-哌基甲基)苯基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(4-嗎啉基甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({甲基[2-(甲基磺醯基)乙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；5-(3-{[[2-(二甲基胺基)乙基](甲基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(4-{2-[(2-羥基乙基)氧]乙基}-1-哌基)甲基]苯基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[3-(羥基甲基)-1-哌啶基]甲基}苯基)-1H-吲哚-7-羧醯胺；5-[3-({雙[2-(甲基氧)乙基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{3-[(2,6-二甲基-4-嗎啉基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[2-(1,3-噻唑-2-基)-1-吡咯啶基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[2-(2-噻吩基)-1-吡咯啶基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-羥基-2-苯基乙基)(甲基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；5-(3-{[乙基(甲基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[3-(胺基甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺； 5-{3-[(環戊基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[3-({[(3,4-二羥苯基)甲基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-噻吩基甲基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(2S)-2-(羥基甲基)-3-甲基丁基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-羥基-1-甲基乙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(反式-4-羥基環己基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[({[1-(1-哌啶基)環己基]甲基}胺基)甲基]苯基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(2S)-2-羥基丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；5-{3-[(乙基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(丙基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(1-甲基乙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；5-(3-{[(1-乙基丙基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(1-哌啶基甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(1-哌啶基甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(4-嗎啉基甲基)苯基]-1H-吲哚-7-羧醯胺；5-[4-(胺基甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(4-嗎啉基甲基)苯基]-1H-吲哚-7-羧醯胺；5-{3-[(環丙基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{3-[(環丁基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-(1-{[3-(二甲基胺基)丙基]磺醯基}-4-哌啶基)-5-[4-(1-哌啶基甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(2-甲基丙基)胺基]-2,3-二氫-1H-茚-5-基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{8-[(2-甲基丙基)胺基]-5,6,7,8-四氫-2-萘基}-1H-吲哚-7-羧醯胺；5-(5-{[(2-氰基乙基)胺基]甲基}-2-氟苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-氟-5-{[(2,2,2-三氟乙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(1,2,3,4-四氫-7-異喹啉基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2,2,2-三氟乙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；5-(3-{[(2-胺基-2-氧代乙基)(甲基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-{[(2,2,2-三氟乙基)胺基]甲基}-1,3-噻唑-4-基)-1H-吲哚-7-羧醯胺；5-(3-氰基-5-{[(2,2,2-三氟乙基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(1-甲基-4-哌啶基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；5-(5-{[(2-氰基乙基)(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[(2-胺基-2-氧代乙基)(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({甲基[2-(苯基磺醯基)乙基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-苯基-1-吡咯啶基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[2-(1-哌啶基甲基)-1-吡咯啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺； 5-(5-{[(2R)-2-(胺基羰基)-1-吡咯啶基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[(2S)-2-(二甲基胺基)-1-吡咯啶基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(1-{2-[4-(二甲基胺基)-1-哌啶基]乙基}-1H-吡唑-4-基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[3-[(二甲基胺基)甲基]-4,5-雙(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[3,4-雙(甲基氧)-5-(4-嗎啉基甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-{[(1-甲基乙基)胺基]甲基}-4,5-雙(甲基氧)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-{[(1-甲基乙基)胺基]甲基}-4,5-雙(甲基氧)苯基]-1H-吲哚-7-羧醯胺；5-[3-{[(2,2-二甲基丙基)胺基]甲基}-4,5-雙(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-{[(2-羥基乙基)(甲基)胺基]甲基}-4,5-雙(甲基氧)苯基]-1H-吲哚-7-羧醯胺；5-[3,4-雙(甲基氧)-5-(1-吡咯啶基甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{4-[(二甲基胺基)甲基]-2,3-二氫-1-苯并呋喃-6-基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(1-甲基乙基)胺基]甲基}-2,3-二氫-1-苯并呋喃-6-基)-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(4-嗎啉基甲基)-2,3-二氫-1-苯并呋喃-6-基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[1-甲基-2-(甲基氧)乙基]胺基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺；5-(5-{[(2-氰基乙基)胺基]甲基}-3-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2,2,2-三氟乙基)胺基]甲基}-3-吡啶基)-1H-吲哚-7-羧醯胺；5-{3-[(二甲基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[[2-(二乙基胺基)乙基](甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[丁基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；5-(5-{[[2-(二甲基胺基)乙基](甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[[3-(二甲基胺基)丙基](甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[環戊基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(戊基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(2-甲基丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(苯基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-羥基乙基)(甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({甲基[2-(2-吡啶基)乙基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-呋喃基甲基)(甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(4-吡啶基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(甲基{[1-(1-甲基乙基)-3-吡咯啶基]甲基}胺基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺；；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(2-噻吩基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({甲基[1-(2-噻吩基)乙基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(3-噻吩基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(四氫-2H-吡喃-4-基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；三氟乙酸鹽3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(3-吡啶基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；三氟乙酸鹽3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(4-嘧啶基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({甲基[2-(甲基氧)乙基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺；5-{3-[(二甲基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(1-甲基乙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-丙基-1-吡咯啶基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[2-(3-吡啶基)-1-吡咯啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；5-(5-{[2-(1,1-二甲基乙基)-1-吡咯啶基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{5-[(2-乙基-1-吡咯啶基)甲基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[2-(2-甲基丙基)-1-吡咯啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[2-(1-甲基乙基)-1-吡咯啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({(2S)-2-[(甲基氧)甲基]-1-吡咯啶基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺；5-(5-{[環己基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[2-(2-甲基丙基)-1-吡咯啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}5-(5-{[甲基(丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺；3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-5-[5-({甲基[2-(甲基氧)乙基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(甲基胺基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-甲基-1-吡咯啶基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(丙基胺基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺；5-{5-[(二乙基胺基)甲基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[(2R,5R)-2,5-二甲基-1-吡咯啶基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{5-[(環丙基胺基)甲基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{5-[(環丁基胺基)甲基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{5-[(二甲基胺基)甲基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[(環戊基甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[5-({[(1R)-1,2-二甲基丙基]胺基}甲基)-3-噻吩基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{5-[(環戊基胺基)甲基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[(環丙基甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[5-({[(1S)-1,2-二甲基丙基]胺基}甲基)-3-噻吩基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[(2,2-二甲基丙基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(苯基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(四氫-2H-吡喃-4-基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；5-{5-[(丁基胺基)甲基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[(2R)-四氫-2-呋喃基甲基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({(2S)-2-[(甲基氧)甲基]-1-吡咯啶基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({(2R)-2-[(甲基氧)甲基]-1-吡咯啶基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-[2-(甲基胺基)乙基]苯基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-[2-(丙基胺基)乙基]苯基}-1H-吲哚-7-羧醯胺；5-{4-[2-(乙基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{4-[({[1-(1,1-二甲基乙基)-3-甲基-1H-吡唑-5-基]羰基}胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(4-吡啶基羰基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；5-(4-{[(環戊基羰基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(2-呋喃基羰基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；5-{4-[2-(乙醯基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{2-[(甲基磺醯基)胺基]乙基}苯基)-1H-吲哚-7-羧醯胺；5-(4-{2-[(環丁基羰基)胺基]乙基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(4-{2-[(環己基羰基)胺基]乙基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{2-[(甲基磺醯基)胺基]乙基}苯基)-1H-吲哚-7-羧醯胺；5-(3-{2-[(環己基羰基)胺基]乙基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[6-(1-哌基)-3-吡啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽；5-[6-(4-乙基-1-哌基)-3-吡啶基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(1-哌啶基甲基)苯基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(1-哌啶基甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(1-甲基乙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-[(丙基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺；5-(4-{[(1-乙基丙基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{4-[(環戊基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{4-[(環丁基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{4-[(乙基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{4-[(二甲基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{4-[(二乙基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(4-嗎啉基甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(1-吡咯啶基甲基)苯基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-({[(1S)-2-羥基-1-甲基乙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-({[(1R)-2-羥基-1-甲基乙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-({[(2R)-2-羥基丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-({[2-羥基-1-(羥基甲基)乙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(1-甲基丁基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(1R)-1-甲基丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-甲基丙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(1S)-1-甲基丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；5-{4-[(乙醯基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-[(丙醯基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺；5-(4-{[(環丙基羰基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(4-{[(環丁基羰基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(2-噻吩基乙醯基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；5-[4-({[(1S)-1,2-二甲基丙基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{4-[(丁醯基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(2-甲基丙醯基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(3-甲基丁醯基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(甲基磺醯基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；5-[3-({[(1R)-1,2-二甲基丙基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(4-{[(乙基磺醯基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(4-{[(丁基磺醯基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-({[(1-甲基乙基)磺醯基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；5-(6-胺基-2-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(1H-吡唑-1-基)苯基]-1H-吲哚-7-羧醯胺； 5-[4-(二甲基胺基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(3-胺基苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-甲基-1-吡咯啶基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺；5-{5-[(乙基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(1-甲基乙基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺；5-{5-[(環丙基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[(2,2-二甲基丙基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[(環丙基甲基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[(環丙基甲基)胺基]甲基}-3-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[2-(甲基氧)乙基]胺基}甲基)-3-吡啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[3-(甲基氧)丙基]胺基}甲基)-3-吡啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(4-嗎啉基甲基)-3-吡啶基]-1H-吲哚-7-羧醯胺； 5-{5-[(乙基胺基)甲基]-3-吡啶基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{5-[(二甲基胺基)甲基]-3-吡啶基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-甲基-1-吡咯啶基)甲基]-3-吡啶基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丙基)胺基]甲基}-3-吡啶基)-1H-吲哚-7-羧醯胺；5-(5-{[(2,2-二甲基丙基)胺基]甲基}-3-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丁基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺；5-[5-({[(1R)-1,2-二甲基丙基]胺基}甲基)-2-噻吩基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(戊基胺基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[(2S)-2-甲基丁基]胺基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(1-甲基丁基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺；5-{5-[(丁基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[2-(甲基氧)乙基]胺基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺； 5-{5-[(環戊基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(3-甲基丁基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(1-甲基乙基)胺基]甲基}-3-吡啶基)-1H-吲哚-7-羧醯胺；5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[5-({[3-(乙基氧)丙基]胺基}甲基)-2-噻吩基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[3-(甲基氧)丙基]胺基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺；5-(5-{[(環己基甲基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[({3-[(1-甲基乙基)氧]丙基}胺基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺；5-[5-({[2-(乙基氧)乙基]胺基}甲基)-2-噻吩基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[3-(丙基氧)丙基]胺基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺；5-(5-{[(3,3-二甲基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[(1S)-1,2,2-三甲基丙基]胺基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(己基胺基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-[(甲基磺醯基)胺基]苯基}-1H-吲哚-7-羧醯胺；5-[2-(二甲基胺基)-4-吡啶基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(1-吡咯啶基)-4-吡啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(4-嗎啉基)-4-吡啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{2-[(2-甲基丙基)胺基]-4-吡啶基}-1H-吲哚-7-羧醯胺；5-{2-[(2,2-二甲基丙基)胺基]-4-吡啶基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(丙基胺基)-4-吡啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-[(甲基胺基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(1-吡咯啶基甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(2-甲基丙基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺；5-{4-[(二甲基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(1S)-1-(1-吡咯啶基)乙基]-3-噻吩基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(1R)-1-(1-吡咯啶基)乙基]-3-噻吩基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-({[3-(甲基氧)丙基]胺基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-({(2S)-2-[(甲基氧)甲基]-1-吡咯啶基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺；5-(4-{[(2R,5R)-2,5-二甲基-1-吡咯啶基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2S)-2-甲基-1-吡咯啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2R)-2-甲基-1-吡咯啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[1-(1-吡咯啶基)丙基]-3-噻吩基}-1H-吲哚-7-羧醯胺；5-{5-[(二甲基胺基)甲基]-3-噻吩基}-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺；5-[5-(胺基甲基)-3-噻吩基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{2-[(2-甲基丙基)胺基]乙基}-3-噻吩基)-1H-吲哚-7-羧醯胺；5-{5-[2-(二甲基胺基)乙基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-[6-(1-吡咯啶基)-3-吡啶基]-1H-吲哚-7-羧醯胺；5-{6-[乙基(甲基)胺基]-3-吡啶基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[6-(二甲基胺基)-3-吡啶基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[6-(丙基胺基)-3-吡啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{6-[(1-甲基乙基)胺基]-3-吡啶基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[6-(4-嗎啉基)-3-吡啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(甲基胺基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(1-甲基乙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(1-吡咯啶基甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺；5-{5-[(乙基胺基)甲基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[(1R)-2-羥基-1-甲基乙基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(1-哌啶基甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(4-嗎啉基甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(甲基胺基)甲基]-3-呋喃基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[1-(1-吡咯啶基)乙基]-3-噻吩基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(1-吡咯啶基甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺；5-{5-[(二甲基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(丙基胺基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺；5-{5-[(二乙基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丙基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺；5-(5-{[(2,2-二甲基丙基)胺基]甲基}-3-呋喃基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丙基)胺基]甲基}-3-呋喃基)-1H-吲哚-7-羧醯胺；5-(5-{[(環戊基甲基)胺基]甲基}-3-呋喃基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(1-吡咯啶基甲基)-3-呋喃基]-1H-吲哚-7-羧醯胺； 5-{5-[(二乙基胺基)甲基]-3-呋喃基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(1-吡咯啶基甲基)-1,3-噻唑-2-基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[2-甲基-1-(1-吡咯啶基)丙基]-3-噻吩基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(1-吡咯啶基甲基)-1,3-噻唑-2-基]-1H-吲哚-7-羧醯胺；5-{1-[2-(二甲基胺基)乙基]-1H-吡唑-4-基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{1-[2-(1-吡咯啶基)乙基]-1H-吡唑-4-基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{1-[2-(4-嗎啉基)乙基]-1H-吡唑-4-基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(1-{2-[(2-羥基乙基)胺基]乙基}-1H-吡唑-4-基)-1H-吲哚-7-羧醯胺；5-{1-[2-(丁基胺基)乙基]-1H-吡唑-4-基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{1-[2-(環丁基胺基)乙基]-1H-吡唑-4-基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[1-(2-{[2-(二乙基胺基)乙基]胺基}乙基)-1H-吡唑-4-基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(1-{2-[(1-甲基乙基)胺基]乙基}-1H-吡唑-4-基)-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-(1-{2-[(2-甲基丙基)胺基]乙基}-1H-吡唑-4-基)-1H-吲哚-7-羧醯胺；5-(1-{2-[(環戊基甲基)胺基]乙基}-1H-吡唑-4-基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(甲基氧)-3-(1-吡咯啶基甲基)苯基]-1H-吲哚-7-羧醯胺；5-[3-[(二甲基胺基)甲基]-4-(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(甲基氧)-3-(4-嗎啉基甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-{[(1-甲基乙基)胺基]甲基}-4-(甲基氧)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-[(甲基胺基)甲基]-4-(甲基氧)苯基]-1H-吲哚-7-羧醯胺；5-[3-{[(2,2-二甲基丙基)胺基]甲基}-4-(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(1-{2-[(2-羥基乙基)(甲基)胺基]乙基}-1H-吡唑-4-基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-氟-3-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺；5-{3,5-雙[(甲基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{3-[(乙基胺基)甲基]-4-氟苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-氟-3-({[2-羥基-1-(羥基甲基)乙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-氟-3-({[(1S)-2-羥基-1-甲基乙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；5-{3-[(環丙基胺基)甲基]-4-氟苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{3-[(環丁基胺基)甲基]-4-氟苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(1-吡咯啶基甲基)苯基]-1H-吲哚-7-羧醯胺；5-{3,5-雙[(乙基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{3,5-雙[(二甲基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(2-哌啶基)苯基]-1H-吲哚-7-羧醯胺；5-{3-[1-(乙基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{3-[1-(二甲基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺；5-{3-[(乙基胺基)甲基]-5-氟苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-氟-5-[(丙基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-{[(1-甲基乙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-{[(2-甲基丙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；5-{3-[(環丁基胺基)甲基]-5-氟苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{3-[(二甲基胺基)甲基]-5-氟苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-(1-吡咯啶基甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-(4-嗎啉基甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-(1-哌啶基甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[1-(甲基胺基)乙基]苯基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{1-[(1-甲基乙基)胺基]乙基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{1-[(2-甲基丙基)胺基]乙基}苯基)-1H-吲哚-7-羧醯胺；5-{3-[1-(環丁基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[1-(1-吡咯啶基)乙基]苯基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(3-硫嗎啉基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(2-哌基)-2-噻吩基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(2-哌基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(2-哌基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[6-(4-嗎啉基)-3-嗒基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[6-(1-吡咯啶基)-3-嗒基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{2-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-噻吩基甲基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(5-甲基-2-呋喃基)甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(2R)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺； 5-(3-{[(2,2-二甲基丙基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-甲基丁基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(2S)-2-甲基丁基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(1R)-1,2,2-三甲基丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2R)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；5-[3-({[(1S)-1,2-二甲基丙基]胺基}甲基)-5-氟苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[3-({[(1R)-1,2-二甲基丙基]胺基}甲基)-5-氟苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-{[(1-甲基丙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(1S)-1,2,2-三甲基丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-2-甲基丁基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-{[(2-甲基丁基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(1R)-1,2,2-三甲基丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；5-(3-{[(2,2-二甲基丙基)胺基]甲基}-5-氟苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(3-{[(環丙基甲基)胺基]甲基}-5-氟苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(3-{[(環戊基甲基)胺基]甲基}-5-氟苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-{[(四氫-2H-吡喃-4-基甲基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-{[(2-噻吩基甲基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[2-(甲基氧)乙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[3-(甲基氧)丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-{[(2-呋喃基甲基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-{[(3-甲基丁基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(5-甲基-2-呋喃基)甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-甲基丙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(2-吡咯啶基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{2-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{2-氟-5-[(丙基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-氟-5-{[(2-甲基丙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；5-(5-{[(2,2-二甲基丙基)胺基]甲基}-2-氟苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[5-({[(1S)-1,2-二甲基丙基]胺基}甲基)-2-氟苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[5-({[(1R)-1,2-二甲基丙基]胺基}甲基)-2-氟苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[(環丙基甲基)胺基]甲基}-2-氟苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-氟-5-(1-吡咯啶基甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-氟-5-(4-嗎啉基甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-氟-5-({[2-(甲基氧)乙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-氟-5-({[3-(甲基氧)丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(1-甲基-2-吡咯啶基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{2-[(2-甲基丙基)胺基]乙基}苯基)-1H-吲哚-7-羧醯胺；5-{3-[2-(乙基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[2-(丙基胺基)乙基]苯基}-1H-吲哚-7-羧醯胺；5-{3-[2-(二甲基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{3-[2-(二丙基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[3-({[2-(3,5-二甲基-1H-吡唑-1-基)乙基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(4-嗎啉基甲基)-1,3-噻唑-4-基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-{[(2-甲基丙基)胺基]甲基}-1,3-噻唑-4-基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(1-吡咯啶基甲基)-1,3-噻唑-4-基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(1-哌啶基甲基)-1,3-噻唑-4-基]-1H-吲哚-7-羧醯胺；5-{2-[(二甲基胺基)甲基]-1,3-噻唑-4-基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺； 5-(2-{[乙基(甲基)胺基]甲基}-1,3-噻唑-4-基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(3-氰基-5-{[(2-甲基丙基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{3-氰基-5-[(二甲基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(甲基磺醯基)胺基]苯基}-1H-吲哚-7-羧醯胺；5-[4-(乙醯基胺基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[3-(乙醯基胺基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(4-嗎啉基甲基)苯基]-1H-吲哚-7-羧醯胺；5-{3-[(乙醯基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(甲基磺醯基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；5-{3-[(丁醯基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(4-氟苯基)羰基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-甲基丙醯基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-呋喃基羰基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；5-(3-{[(環戊基羰基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(戊醯基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺；5-(3-{[(2-乙基丁醯基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(3-{[(1-苯并噻吩-2-基羰基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[3-({[(1-乙醯基-4-哌啶基)羰基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(1-甲基-1H-吡咯-2-基)羰基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(3-甲基-2-丁烯醯基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(庚醯基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(辛醯基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-甲基戊醯基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(3-甲基丁醯基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-噻吩基乙醯基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(己醯基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-甲基丁醯基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；5-(3-{[(環丁基羰基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(3-{[(環丙基羰基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(丙醯基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺；5-(3-{[(環戊基乙醯基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[3-(甲基硫)丙醯基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(1-甲基乙基)磺醯基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；5-(3-{[(環丙基磺醯基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[3-({[(2,5-二氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[3-({[(4-溴苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺； 5-[3-({[(4-氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(3-氟苯基)磺醯基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；5-[3-({[(2-氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[3-({[(2,5-二氯-3-噻吩基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[3-({[(2-氯-6-甲基苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(5-氟-2-甲基苯基)磺醯基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；5-[3-({[(1,2-二甲基-1H-咪唑-4-基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(丙基磺醯基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；5-(3-{[(丁基磺醯基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(苯基磺醯基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(4-氟苯基)磺醯基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺；5-[3-({[(4-溴-2-乙基苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺； 5-(3-{[(1-苯并噻吩-3-基磺醯基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-{3-[({[4-(1,1-二甲基乙基)苯基]磺醯基}胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-[3-({[(3,4-二氟苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(3-{[(乙基磺醯基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(3-{[(2,1,3-苯并二唑-4-基磺醯基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(四氫-3-呋喃基羰基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；5-{4-[(環戊基磺醯基)胺基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(4-甲基-2-氧代-1-哌基)苯基]-1H-吲哚-7-羧醯胺；5-[6-(4-乙醯基-1-哌基)-3-吡啶基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(甲基氧)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(甲基氧)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[4-(1-吡咯啶基)-1-哌啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2S)-2-(三氟甲基)-1-吡咯啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；5-(5-{[(2R)-2-(羥基甲基)-1-吡咯啶基]甲基}-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺；5-(5-{[(3S)-3-羥基-1-吡咯啶基]甲基}-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺；5-(5-{[環戊基(甲基)胺基]甲基}-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺；5-(5-{[(2-羥基乙基)(甲基)胺基]甲基}-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺；5-(5-{[(2-胺基-2-氧代乙基)(甲基)胺基]甲基}-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(2-丙烯-1-基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；5-(5-{[[(3,5-二甲基-1H-吡唑-4-基)甲基](甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[(氰基甲基)(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(1-甲基丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；5-(5-{[[2-(乙基氧)乙基](甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[環丁基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({2-[(甲基氧)甲基]-1-吡咯啶基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺；5-(5-{[(1,1-二甲基乙基)(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[3-(三氟甲基)-1-哌啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[(1S)-2-羥基-1-甲基乙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；5-(5-{[(環丙基甲基)(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；5-(5-{[[2-(乙醯基胺基)乙基](甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[(1R,2R)-2-羥基環戊基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；5-(5-{[(1,1-二甲基丙基)(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[(2S)-2-羥基丙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({甲基[(2R)-四氫-2-呋喃基甲基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[{2-[(2-羥基乙基)氧]乙基}(甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(1-{甲基[2-(甲基氧)乙基]胺基}乙基)-3-噻吩基]-1H-吲哚-7-羧醯胺； 3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{1-[甲基(丙基)胺基]乙基}-3-噻吩基)-1H-吲哚-7-羧醯胺；3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[(1S)-2-羥基-1-甲基乙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺；及5-(5-{[(1,1-二氧撐基四氫-3-噻吩基)(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺；或其醫藥上可接受之鹽。 Specific examples of the compound of the present invention include the following: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperidylmethyl)phenyl]-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-pipeper Methyl)phenyl]-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinylmethyl)phenyl]-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({methyl[2-(methylsulfonyl)) Amino]methyl)phenyl]-1 H -吲哚-7-carboxyguanamine; 5-(3-{[[2-(dimethylamino)ethyl](methyl)amino]methyl}phenyl)-3-[1-( Ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(4-{2-[(2-hydroxyethyl)) Oxy]ethyl}-1-piperidone Methyl]phenyl}-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[3-(hydroxymethyl)-1-piperidinyl ]methyl}phenyl)-1 H -吲哚-7-carboxyguanamine; 5-[3-({bis[2-(methyloxy)ethyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1 H -吲哚-7-carboxyguanamine; 5-{3-[(2,6-dimethyl-4-morpholinyl)methyl]phenyl}-3-[1-(ethylsulfonyl) -4-piperidinyl]-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[2-(1,3-thiazol-2-yl)) -1-pyrrolidinyl]methyl}phenyl)-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[2-(2-thienyl)-1-pyrrolidine Methyl}phenyl)-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-hydroxy-2-phenylethyl)( Methyl)amino]methyl}phenyl)-1 H -吲哚-7-carboxyguanamine; 5-(3-{[ethyl(methyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidine Base]-1 H -吲哚-7-carboxyguanamine; 5-[3-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxyguanamine; 5-{3-[(cyclopentylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxyguanamine; 5-[3-({[(3,4-dihydroxyphenyl)methyl]amino}methyl)phenyl]-3-[1-(ethyl sulfonate) Mercapto)-4-piperidinyl]-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl }phenyl)-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2) S )-2-(hydroxymethyl)-3-methylbutyl]amino}methyl)phenyl]-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-hydroxy-1-methylethyl)amine Methyl}phenyl)-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(trans-4-hydroxycyclohexyl)amino] Methyl}phenyl)-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[({[1-(1-piperidyl)cyclohexyl) Methyl}amino)methyl]phenyl}-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2) S )-2-hydroxypropyl]amino}methyl)phenyl]-1 H -吲哚-7-carboxyguanamine; 5-{3-[(ethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(propylamino)methyl]phenyl}-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(1-methylethyl)amino]methyl }phenyl)-1 H -吲哚-7-carboxyguanamine; 5-(3-{[(1-ethylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4- Piperidinyl]-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperidinylmethyl)phenyl]-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(1-piperidinylmethyl)phenyl]-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(methylamino)methyl]phenyl}-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-morpholinylmethyl)phenyl]-1 H -吲哚-7-carboxyguanamine; 5-[4-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinylmethyl)phenyl]-1 H -吲哚-7-carboxyguanamine; 5-{3-[(cyclopropylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxyguanamine; 5-{3-[(cyclobutylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxyguanamine; 3-(1-{[3-(dimethylamino)propyl]sulfonyl}-4-piperidinyl)-5-[4-(1-pipe Pyridylmethyl)phenyl]-1 H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(2-methylpropyl)amino]-2, 3-dihydro-1H-indol-5-yl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{8- [(2-methylpropyl)amino]-5,6,7,8-tetrahydro-2-naphthalenyl}-1H-indole-7-carboxamide; 5-(5-{[(2) -Cyanoethyl)amino]methyl}-2-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide ; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-{[(2,2,2-trifluoroethyl)amino]methyl} Phenyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1,2,3,4-tetrahydro-7 -isoquinolyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2,2, 2-trifluoroethyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 5-(3-{[(2-amino-2-oxoethyl)) Amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(B Sulfosyl)-4-piperidinyl]-5-(2-{[(2,2,2-trifluoroethyl)amino]methyl}-1,3-thiazol-4-yl)- 1H-吲哚-7-carboxyguanamine; 5-(3-cyano-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-3-[1- (ethyl sulfonate) 4-(piperidinyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl (1-methyl-4-piperidinyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 5-(5-{[(2-cyanoethyl) (methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5 -(5-{[(2-Amino-2-oxoethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4 -piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[2-( Phenylsulfonyl)ethyl]amino}methyl)-3-thienyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidine 5-[5-[(2-Phenyl-1-pyrrolidinyl)methyl]-3-thienyl}-1H-indole-7-carboxamide; 3-[1-(ethyl Sulfomethyl)-4-piperidinyl]-5-(5-{[2-(1-piperidylmethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-1H-indole哚-7-carboxyguanamine; 5-(5-{[(2R)-2-(aminocarbonyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-[1-(B 5-sulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[(2S)-2-(dimethylamino)-1-pyrrolidinyl) ]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidin -1H-indole-7-carboxamide; 5-(1-{2-[4-(dimethylamino)-1-piperidinyl]ethyl}-1H-pyrazole-4- 3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-[3-[(dimethylamino)methyl] -4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-[3 ,4-bis(methyloxy)-5-(4-morpholinylmethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole- 7-Carboguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-{[(1-methylethyl)amino]methyl}-4, 5-bis(methyloxy)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-{[ (1-methylethyl)amino]methyl}-4,5-bis(methyloxy)phenyl]-1H-indole-7-carboxamide; 5-[3-{[(2, 2-Dimethylpropyl)amino]methyl}-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-{[(2-hydroxyethyl)(methyl)amino ]methyl}-4,5-bis(methyloxy)phenyl]-1H-indole-7-carboxamide; 5-[3,4-bis(methyloxy)-5-(1-pyrrole) Pyridylmethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxylate Amine; 5-{4-[(dimethylamino)methyl]-2,3-dihydro-1-benzofuran-6-yl}-3-[1-(ethylsulfonyl)- 4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(1-methyl) Ethyl)amino]methyl}-2,3-dihydro-1-benzofuran-6-yl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl) )-4-piperidinyl]-5-[4-(4-morpholinomethyl)-2,3-dihydro-1-benzofuran-6-yl]-1H-indole-7-carboxylate Indoleamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[1-methyl-2-(methyloxy)ethyl]amino}} 2-thiophenyl]-1H-indole-7-carboxamide; 5-(5-{[(2-cyanoethyl)amino]methyl}-3-pyridyl)-3- [1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5 -(5-{[(2,2,2-trifluoroethyl)amino]methyl}-3-pyridyl)-1H-indole-7-carboxamide; 5-{3-[(two Methylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[ Ethyl (methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[[2-(diethylamino)ethyl](methyl)amino]methyl}-3- Benzyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[butyl(methyl)amino) ]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethyl Sulfomethyl)-4-piperidinyl]-5-(5-{[methyl(propyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 5 -(5-{[[2-(Dimethylamino)ethyl](methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4 -piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[[3-(dimethylamino)propyl](methyl)amino]methyl}-3- Thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[cyclopentyl (methyl)amine Methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(B Sulfosyl)-4-piperidinyl]-5-(5-{[methyl(pentyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(2-methylpropyl)amino]methyl}-3-thienyl)- 1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(phenylmethyl)amino]- -3-}-3-thienyl-1H-indole-7-carboxamide 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-hydroxyethyl)(methyl)amino]methyl}-3-thienyl) -1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[2-(2-pyridyl)) Ethyl]amino}methyl)-3-thienyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5- 5-{[(2-furylmethyl)(methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonate) 4-piperidinyl]-5-(5-{[methyl(4-pyridylmethyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide ;3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methyl{[1-(1-methylethyl)-3-pyrrolidinyl]- Amino]methyl]-3-thienyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5- 5-{[methyl(2-thienylmethyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl) 4-piperidinyl]-5-[5-({methyl[1-(2-thienyl)ethyl]amino}methyl)-3-thienyl]-1H-indole-7-carboxylate Indoleamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(3-thienylmethyl)amino]methyl}-3-thiophene Base)-1H-吲哚-7-carboxyguanamine; 3 -[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl}- 3-thienyl)-1H-indole-7-carboxamide; trifluoroacetate 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl (3-pyridylmethyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; trifluoroacetate 3-[1-(ethylsulfonyl)-4 -piperidinyl]-5-(5-{[methyl(4-pyrimidinylmethyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[ 1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[2-(methyloxy)ethyl]amino}methyl)-3-thienyl]- 1H-吲哚-7-carboxyguanamine; 5-{3-[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl] -1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylethyl)amine Methyl]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[( 2-propyl-1-pyrrolidinyl)methyl]-3-thienyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl 5-(5-{[2-(3-pyridyl)-1-pyrrolidinyl]methyl}-3-thienyl)-1H-indole-7-carboxamide; 5-(5- {[2-(1,1-dimethylethyl)-1 -pyrrolidinyl]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-{5 -[(2-ethyl-1-pyrrolidinyl)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7 Carboxylamidine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(2-methylpropyl)-1-pyrrolidinyl]- }}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-( 1-methylethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4- Piperidinyl]-5-[5-({(2S)-2-[(methyloxy)methyl]-1-pyrrolidinyl}methyl)-3-thienyl]-1H-indole-7 - Carboxylamidine; 5-(5-{[cyclohexyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl] -1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(2-methylpropyl)- 1-pyrrolidinyl]methyl}-3-thienyl)-1H-indole-7-carboxamide; 5-(5-{[ethyl(methyl)amino]methyl}-3-thiophene 3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-5-(5-{[methyl(propyl)amino]methyl}-3-吩))-1H-吲哚-7-carboxyguanamine; 3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}5-(5-{[methyl ( Propyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 5-(5-{[ethyl(methyl)amino]methyl}-3-thiophene -3{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide; 3-{1-[(1-A Benzyl)sulfonyl]-4-piperidinyl}-5-[5-({methyl[2-(methyloxy)ethyl]amino}methyl)-3-thienyl]-1H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-2-thienyl }-1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl) )methyl]-3-thienyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[( 2-methylpropyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl] -5-{5-[(propylamino)methyl]-3-thienyl}-1H-indole-7-carboxamide; 5-{5-[(diethylamino)methyl] 3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[(2R,5R)) -2,5-dimethyl-1-pyrrolidinyl]methyl}-3-thienyl)-3- [1-(Ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-{5-[(cyclopropylamino)methyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-{5-[(cyclobutylamino)methyl]- 3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-{5-[(dimethylamino) Methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[(ring) Amylmethyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5 -[5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-3-thienyl]-3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-1H-indole-7-carboxamide; 5-{5-[(cyclopentylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl) 4-piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-[5-({[(1S)-1,2-dimethylpropyl]amine) }}methyl)-3-thienyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[ (2,2-dimethylpropyl)amino]methyl}-3-thienyl)-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5- 5-{[(phenylmethyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-5-[5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)-3-thienyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl}-3 -thienyl)-1H-indole-7-carboxamide; 5-{5-[(butylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl) 4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[(2R)) -tetrahydro-2-furanylmethyl]amino}methyl)-3-thienyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4- Piperidinyl]-5-[5-({(2S)-2-[(methyloxy)methyl]-1-pyrrolidinyl}methyl)-3-thienyl]-1H-indole-7 Carboxylamidine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({(2R)-2-[(methyloxy)methyl]-1- Pyrrrolidinyl}methyl)-3-thienyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4- [2-(Methylamino)ethyl]phenyl}-1H-indole-7-carboxamide 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[2-(propylamino)ethyl]phenyl}-1H-indole-7-carboxyindole Amine; 5-{4-[2-(ethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7- Carboxylamidine; 5-{4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]benzene -3-[-3-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-5-(4-{[(4-pyridylcarbonyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 5-(4-{[(cyclopentyl) Carbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(B Sulfosyl)-4-piperidinyl]-5-(4-{[(2-furylcarbonyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 5- {4-[2-(Ethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{2-[(methylsulfonyl)amino]ethyl}phenyl)-1H-indole哚-7-carboxyguanamine; 5-(4-{2-[(cyclobutylcarbonyl)amino]ethyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidine -1H-吲哚-7-carboxyguanamine; 5-(4-{2-[(cyclohexyl) Carbonyl)amino]ethyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(B Sulfosyl)-4-piperidinyl]-5-(3-{2-[(methylsulfonyl)amino]ethyl}phenyl)-1H-indole-7-carboxamide; 5-(3-{2-[(cyclohexylcarbonyl)amino]ethyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7 - Carboxylamidine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-piperider ))-3-pyridyl]-1H-indole-7-carboxamide guanamine trifluoroacetate; 5-[6-(4-ethyl-1-piperidin 3-(1-pyridyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonate) 4-(piperidinyl)-5-[4-(1-piperidinylmethyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl) )-4-piperidinyl]-5-[3-(1-piperidinylmethyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl) 4-piperidinyl]-5-{4-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl) 4-piperidinyl]-5-(4-{[(1-methylethyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-( Ethylsulfonyl)-4-piperidinyl]-5-{4-[(propylamino)methyl]phenyl}-1H-indole-7-carboxamide; 5-(4-{ [(1-Ethylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-{4-[(cyclopentylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide ;5-{4-[(cyclobutylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxyindole Amine; 5-{4-[(ethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxyindole Amine; 5-{4-[(dimethylamino)methyl]phenyl}-3-[1-( 5-sulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-{4-[(diethylamino)methyl]phenyl}-3-[1-( Ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4- (4-morpholinylmethyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-( 1-pyrrolidinylmethyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({ [(1S)-2-hydroxy-1-methylethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)- 4-piperidinyl]-5-[4-({[(1R)-2-hydroxy-1-methylethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide ;3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[(2R)-2-hydroxypropyl]amino}methyl)phenyl]-1H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[2-hydroxy-1-(hydroxymethyl)) Amino]methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[ (1-methylbutyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5 -[3-({[(1R)-1-methylpropyl]amino}methyl)phenyl]-1 H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylpropyl)amino]- Benzyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1S)-1) -methylpropyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 5-{4-[(ethylamino)methyl]phenyl}-3-[ 1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5- {4-[(Propylamino)methyl]phenyl}-1H-indole-7-carboxamide; 5-(4-{[(cyclopropylcarbonyl)amino]methyl}phenyl -3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(4-{[(cyclobutylcarbonyl)amino]- Benzyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)- 4-piperidinyl]-5-(4-{[(2-thienylethyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 5-[4-( {[(1S)-1,2-dimethylpropyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole -7-carboxyguanamine; 5-{4-[(butylammonio)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole- 7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidin 5-(4-{[(2-methylpropionyl)amino]methyl}phenyl)-1H-indole-7-carboxamide 3-[1-(ethylsulfonyl) )-4-piperidinyl]-5-(4-{[(3-methylbutylidene)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-( Ethylsulfonyl)-4-piperidinyl]-5-(4-{[(methylsulfonyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 5 -[3-({[(1R)-1,2-dimethylpropyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl] -1H-吲哚-7-carboxyguanamine; 5-(4-{[(ethylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4 -piperidinyl]-1H-indole-7-carboxamide; 5-(4-{[(butylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonate) Mercapto)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[ (1-methylethyl)sulfonyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 5-(6-amino-2-pyridyl)-3-[ 1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5- [3-(1H-pyrazol-1-yl)phenyl]-1H-indole-7-carboxamide; 5-[4-(dimethylamino)phenyl]-3-[1-( Ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5 -(3-aminophenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonate) Mercapto)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl}-1H-indole-7-carboxamide; 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxylate Indoleamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-2-thienyl) -1H-吲哚-7-carboxyguanamine; 5-{5-[(cyclopropylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4- Piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-2-thienyl)-3-[ 1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[(cyclopropylmethyl)amino]methyl}-2 -thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[(cyclopropylmethyl)) Amino]methyl}-3-pyridyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-( Ethylsulfonyl)-4-piperidinyl]-5-[5-({[2-(methyloxy)ethyl]amino}methyl)-3-pyridyl]-1H-indole- 7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5- [5-({[3-(methyloxy)propyl]amino}methyl)-3-pyridyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonate) 4-)piperidinyl]-5-[5-(4-morpholinylmethyl)-3-pyridyl]-1H-indole-7-carboxamide; 5-{5-[(B Amino)methyl]-3-pyridyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-{5- [(Dimethylamino)methyl]-3-pyridyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3 -[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-3-pyridyl}-1H-indole哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}- 3-pyridyl)-1H-indole-7-carboxamide; 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-pyridyl)-3- [1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5 -(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide; 5-[5-({[(1R)-) 1,2-dimethylpropyl]amino}methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7- Carboxylamidine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(penta Amino)methyl]-2-thienyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-( {[(2S)-2-methylbutyl]amino}methyl)-2-thienyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)- 4-piperidinyl]-5-(5-{[(1-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide; 5-{5 -[(butylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3 -[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[2-(methyloxy)ethyl]amino}methyl)-2-thienyl]- 1H-吲哚-7-carboxyguanamine; 5-{5-[(cyclopentylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperider Pyridyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(3-methylbutyl) Amino]methyl}-2-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{ [(1-methylethyl)amino]methyl}-3-pyridyl)-1H-indole-7-carboxamide; 5-(5-{[(2-ethylbutyl))amino group ]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-[5-({[ 3-(ethyloxy)propyl]amino}methyl)-2-thienyl]-3-[1-( 3-sulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-( {[3-(Methyloxy)propyl]amino}methyl)-2-thienyl]-1H-indole-7-carboxamide; 5-(5-{[(cyclohexylmethyl)amine Methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(B Sulfosyl)-4-piperidinyl]-5-{5-[({3-[(1-methylethyl)oxy)propyl)amino)methyl]-2-thienyl}- 1H-吲哚-7-carboxyguanamine; 5-[5-({[2-(ethyloxy)ethyl]amino}methyl)-2-thienyl]-3-[1-(ethyl Sulfhydryl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({ [3-(propyloxy)propyl]amino}methyl)-2-thienyl]-1H-indole-7-carboxamide; 5-(5-{[(3,3-dimethyl) Butyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[ 1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({[(1S)-1,2,2-trimethylpropyl]amino}methyl)-2- Thienyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(hexylamino)methyl]- 2-thienyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl) )-4-piperidinyl]-5-{4-[(methylsulfonyl)amino]phenyl}-1H-indole-7-carboxamide; 5-[2-(dimethylamine) 4-pyridyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonate) 4-(piperidinyl)-5-[2-(1-pyrrolidinyl)-4-pyridyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonate) 4-(piperidinyl)-5-[2-(4-morpholinyl)-4-pyridyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonate) 4-(piperidinyl)-5-{2-[(2-methylpropyl)amino]-4-pyridyl}-1H-indole-7-carboxamide; 5-{2- [(2,2-Dimethylpropyl)amino]-4-pyridyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxylate Indoleamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(propylamino)-4-pyridyl]-1H-indole-7-carboxyindole Amine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1H-indole-7 - Carboxylamidine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(1-pyrrolidinylmethyl)-2-thienyl]-1H-indole -7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-methylpropyl)amino]methyl}-2 -thienyl)-1H-indole-7-carboxamide; 5-{4-[(dimethylamino) Methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonate) Mercapto)-4-piperidinyl]-5-{5-[(1S)-1-(1-pyrrolidinyl)ethyl]-3-thienyl}-1H-indole-7-carboxamide 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(1R)-1-(1-pyrrolidinyl)ethyl]-3-thienyl}- 1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[3-(methyloxy)propyl]amine) (methyl)-2-thienyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({ (2S)-2-[(methyloxy)methyl]-1-pyrrolidinyl}methyl)-2-thienyl]-1H-indole-7-carboxamide; 5-(4-{[ (2R,5R)-2,5-Dimethyl-1-pyrrolidinyl]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2S)-2-methyl-1-pyrrole Pyridyl]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{ [(2R)-2-methyl-1-pyrrolidinyl]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)- 4-piperidinyl]-5-{5-[1-(1-pyrrolidinyl)propyl]-3-thienyl}-1H-indole-7- Carboxylamidine; 5-{5-[(dimethylamino)methyl]-3-thienyl}-3-{1-[(1-methylethyl)sulfonyl]-4-piperidine }}-1H-吲哚-7-carboxyguanamine; 5-[5-(aminomethyl)-3-thienyl]-3-[1-(ethylsulfonyl)-4-piperidinyl -1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{2-[(2-methylpropyl)) Amino]ethyl}-3-thienyl)-1H-indole-7-carboxamide; 5-{5-[2-(dimethylamino)ethyl]-3-thienyl}-3 -[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]- 5-[6-(1-pyrrolidinyl)-3-pyridyl]-1H-indole-7-carboxamide; 5-{6-[ethyl(methyl)amino]-3-pyridyl }-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-[6-(dimethylamino)-3-pyridyl ]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidine 5-[6-(propylamino)-3-pyridyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl ]-5-{6-[(1-methylethyl)amino]-3-pyridyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)- 4-piperidinyl]-5-[6-(4-morpholinyl)-3-pyridyl]-1H-哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-3-thienyl}- 1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]- }}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidine) Methyl)-3-thienyl]-1H-indole-7-carboxamide; 5-{5-[(ethylamino)methyl]-3-thienyl}-3-[1-( Ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5- ({[(1R)-2-hydroxy-1-methylethyl]amino}methyl)-3-thienyl]-1H-indole-7-carboxamide; 3-[1-(ethyl Sulfomethyl)-4-piperidinyl]-5-[5-(1-piperidylmethyl)-3-thienyl]-1H-indole-7-carboxamide; 3-[1-( Ethylsulfonyl)-4-piperidinyl]-5-[5-(4-morpholinomethyl)-3-thienyl]-1H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-3-furanyl}-1H-indole-7-carboxamide; 3 -[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[1-(1-pyrrolidinyl)ethyl]-3-thienyl}-1H-indole-7 Carboxylamidine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[ 5-(1-pyrrolidinylmethyl)-2-thienyl]-1H-indole-7-carboxamide; 5-{5-[(dimethylamino)methyl]-2-thienyl }-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidine 5-[5-[(propylamino)methyl]-2-thienyl}-1H-indole-7-carboxamide; 5-{5-[(diethylamino) A 4-thiophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonate) 4-)piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide; 5 -(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]- }}-3-furanyl)-1H-indole-7-carboxamide; 5-(5-{[(cyclopentylmethyl)amino]methyl}-3-furanyl)-3-[ 1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5- [5-(1-Pyrrolidinylmethyl)-3-furanyl]-1H-indole-7-carboxamide; 5-{5-[(diethylamino)methyl]-3-furan }}-3-[1-(ethylsulfonyl)-4-piperidine -1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-1, 3-thiazol-2-yl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[2-methyl 1-(1-pyrrolidinyl)propyl]-3-thienyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl] -5-[4-(1-pyrrolidylmethyl)-1,3-thiazol-2-yl]-1H-indole-7-carboxamide; 5-{1-[2-(dimethyl) Amino)ethyl]-1H-pyrazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3- [1-(Ethylsulfonyl)-4-piperidinyl]-5-{1-[2-(1-pyrrolidinyl)ethyl]-1H-pyrazol-4-yl}-1H-indole哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{1-[2-(4-morpholinyl)ethyl]-1H-pyridyl Zin-4-yl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2- Hydroxyethyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-indole-7-carboxamide; 5-{1-[2-(butylamino)ethyl]- 1H-pyrazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-{1-[2-( Cyclobutylamino)ethyl]-1H-pyrazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7- Carboxylamidine; 5-[1-(2-{[2-(diethylamino)ethyl]amino}ethyl)-1H-pyrazol-4-yl]-3-[1-(B 3-sulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{ 2-[(1-methylethyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl) )-4-piperidinyl]-5-(1-{2-[(2-methylpropyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-indole-7- Carboxylamidine; 5-(1-{2-[(cyclopentylmethyl)amino]ethyl}-1H-pyrazol-4-yl)-3-[1-(ethylsulfonyl)- 4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(methyloxy)-3 -(1-pyrrolidinylmethyl)phenyl]-1H-indole-7-carboxamide; 5-[3-[(dimethylamino)methyl]-4-(methyloxy)benzene 3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-5-[4-(methyloxy)-3-(4-morpholinylmethyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonate) Mercapto)-4-piperidinyl]-5-[3-{[(1-methylethyl)amino]methyl}-4-(methyloxy)phenyl]-1H-indole-7 - Carboxylamamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-[(methylamino) A ]-4-(methyloxy)phenyl]-1H-indole-7-carboxamide; 5-[3-{[(2,2-dimethylpropyl)amino]methyl}-4 -(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonate) Mercapto)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)(methyl)amino]ethyl}-1H-pyrazol-4-yl)-1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-fluoro-3-[(methylamino)methyl]phenyl }-1H-吲哚-7-carboxyguanamine; 5-{3,5-bis[(methylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4- Piperidinyl]-1H-indole-7-carboxamide; 5-{3-[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-fluoro-3-( {[2-hydroxy-1-(hydroxymethyl)ethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)- 4-piperidinyl]-5-[4-fluoro-3-({[(1S)-2-hydroxy-1-methylethyl]amino}methyl)phenyl]-1H-indole-7 - Carboxylamidine; 5-{3-[(cyclopropylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H -吲哚-7-carboxyguanamine; 5-{3-[(cyclobutylamino)methyl]-4-fluorophenyl} -3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl ]-5-[3-(1-pyrrolidylmethyl)phenyl]-1H-indole-7-carboxamide; 5-{3,5-bis[(ethylamino)methyl]benzene -3-}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-{3,5-bis[(dimethylamino) Methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl) 4-piperidinyl]-5-[3-(2-piperidinyl)phenyl]-1H-indole-7-carboxamide; 5-{3-[1-(ethylamino)B Phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-{3-[1-(dimethylamine) Ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonate) 4-)piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide; 5-{3-[ (ethylamino)methyl]-5-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3- [1-(Ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(propylamino)methyl]phenyl}-1H-indole-7-carboxyindole Amine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(1- Ethylethyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3- Fluor-5-{[(2-methylpropyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 5-{3-[(cyclobutylamino)methyl ]-5-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-{3-[(dimethyl) Amino)methyl]-5-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1- (ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-(1-pyrrolidinylmethyl)phenyl]-1H-indole-7-carboxamide; 3- [1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-(4-morpholinylmethyl)phenyl]-1H-indole-7-carboxamide 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-(1-piperidinylmethyl)phenyl]-1H-indole-7- Carboxylamidine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[1-(methylamino)ethyl]phenyl}-1H-indole- 7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(1-methylethyl)amino]ethyl}benzene -1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(2-methylpropyl) Amino]ethyl}phenyl)-1H-indole-7-carboxamide; 5-{3-[1-(cyclobutane) Amino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonate) Mercapto)-4-piperidinyl]-5-{3-[1-(1-pyrrolidinyl)ethyl]phenyl}-1H-indole-7-carboxamide; 3-[1-( Ethylsulfonyl)-4-piperidinyl]-5-[3-(3-thiomorpholinyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethyl Sulfomethyl)-4-piperidinyl]-5-[5-(2-piperidin 2-thiophenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(2-piperidin Phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperidin Phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(4-morpholinyl)- 3-嗒 -1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-pyrrolidinyl)-3-anthracene -1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-[(methylamino)methyl]benzene }}-1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amine Methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(5) -methyl-2-furyl)methyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidine 5-[3-({[(2R)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-吲哚-7-carboxyguanamine; 5-(3-{[(2,2-dimethylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)- 4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methyl) Butyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-( {[(2S)-2-methylbutyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-5-[3-({[(1R)-1,2,2-trimethylpropyl]amino} Phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S) )-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidine 5-[3-fluoro-5-({[(2R)-tetrahydro-2-furylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 5-[3-({[(1S)-1,2-dimethylpropyl]amino}methyl)-5-fluorophenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl]-1H-indole-7-carboxamide; 5-[3-({[(1R)-1,2-dimethylpropyl]amino}methyl)-5-fluorobenzene 3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-5-(3-fluoro-5-{[(1-methylpropyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-( Ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(1S)-1,2,2-trimethylpropyl]amino}methyl)phenyl) -1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-2) -methylbutyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5- 3-fluoro-5-{[(2-methylbutyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-(B Sulfomethyl)-4-piperidinyl]-5-[3-fluoro-5-({[(1R)-1,2,2-trimethylpropyl]amino}methyl)phenyl]- 1H-吲哚-7-carboxyguanamine; 5-(3-{[(2,2-dimethylpropyl)amino]methyl}-5-fluorophenyl)-3-[1-(B 5-sulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(3-{[(cyclopropylmethyl)amino]methyl}-5-fluorophenyl -3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(3-{[(cyclopentylmethyl)amino] Methyl}-5-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethyl Sulfomethyl)-4-piperidinyl]-5-(3-fluoro-5-{[(tetrahydro-2H-pyran-4-ylmethyl)amino]methyl}phenyl)-1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-thienylmethyl)amino ]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({ [2-(Methyloxy)ethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl ]-5-[3-Fluoro-5-({[3-(methyloxy)propyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1- (Ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-furylmethyl)amino] Benzyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(3 -methylbutyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[ 3-fluoro-5-({[(5-methyl-2-furyl)methyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-( Ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylpropyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-pyrrolidinyl)phenyl]-1H-indole-7-carboxamide; 3-[ 1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole-7-carboxamide ;3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(propylamino)methyl]phenyl}-1H-indole-7 Carboxylamidine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-{[(2-methylpropyl)amino]methyl} Phenyl)-1H-indole-7-carboxamide; 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-2-fluorophenyl)-3-[ 1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-[5-({[(1S)-1,2-dimethylpropyl] Amino}methyl)-2-fluorophenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-哚-7-carboxyguanamine; 5-[5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-fluorophenyl]-3-[1-( Ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[(cyclopropylmethyl)amino]methyl}-2-fluorobenzene 3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-5-[2-fluoro-5-(1-pyrrolidinylmethyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)- 4-piperidinyl]-5-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonate) 4-piperidinyl]-5-[2-fluoro-5-({[2-(methyloxy)ethyl]amino}methyl)phenyl]-1H-indole-7-carboxylate Indoleamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-({[3-(methyloxy)propyl]amino}methyl) Phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-methyl-2-pyrrole) Pyridyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{2-[(2- Methylpropyl)amino]ethyl}phenyl)-1H-indole-7-carboxamide; 5-{3-[2-(ethylamino)ethyl]phenyl}-3-[ 1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethyl Mercapto)-4-piperidinyl]-5-{3-[2-(propylamino)ethyl]phenyl}-1H-indole-7-carboxamide; 5-{3-[2 -(dimethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-{3 -[2-(dipropylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5 -[3-({[2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl]amino}methyl)phenyl]-3-[1-(ethylsulfonate) (4-)piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(4-? Lolinylmethyl)-1,3-thiazol-4-yl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5- (2-{[(2-methylpropyl)amino]methyl}-1,3-thiazol-4-yl)-1H-indole-7-carboxamide; 3-[1-(ethyl Sulfomethyl)-4-piperidinyl]-5-[2-(1-pyrrolidinylmethyl)-1,3-thiazol-4-yl]-1H-indole-7-carboxamide; 3 -[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-piperidinylmethyl)-1,3-thiazol-4-yl]-1H-indole- 7-carboxyguanamine; 5-{2-[(dimethylamino)methyl]-1,3-thiazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-1H-indole-7-carboxamide; 5-(2-{[ethyl(methyl)amino]methyl}-1,3-thiazole-4- 3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(3-cyano-5-{[(2-A) Propyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-{3- Cyano-5-[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{3-[(methylsulfonyl)amino]phenyl}-1H-indole-7-carboxyindole Amine; 5-[4-(ethylhydrazino)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; -[3-(ethylhydrazino)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinomethyl)phenyl]-1H-indole-7-carboxamide; 5-{3- [(Ethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(methylsulfonyl)amino]methyl}phenyl)-1H-indole-7-carboxamide 5-{3-[(Budecylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-( {[(4-Fluorophenyl)carbonyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl -5-(3-{[(2-methylpropenyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl) )-4-piperidinyl]-5-(3-{[(2-furylcarbonyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 5-(3-{ [(Cyclopentylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxyguanamine 3-[ 1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentamnessylamino)methyl]phenyl}-1H-indole-7-carboxamide; 5- (3-{[(2-ethylbutylidene)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxylate Indoleamine; 5-(3-{[(1-benzothiophen-2-ylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl -1H-吲哚-7-carboxyguanamine; 5-[3-({[(1-ethylindolyl-4-piperidyl)carbonyl]amino}methyl)phenyl]-3-[1 -(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[ 3-({[(1-methyl-1H-pyrrol-2-yl)carbonyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethyl Sulfhydryl)-4-piperidinyl]-5-(3-{[( 3-methyl-2-butenyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidine 5-[3-[(heptylamino)methyl]phenyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-5-{3-[(octylamino)methyl]phenyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidine 5-[3-([2-methylpentamyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonate) 4-(piperidinyl)-5-(3-{[(3-methylbutylidene)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1- (ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylethenyl)amino]methyl}phenyl)-1H-indole-7-carboxyindole Amine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(hexylamino)methyl]phenyl}-1H-indole-7-carboxylate Indoleamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylbutylidene)amino]methyl}phenyl)-1H-indole哚-7-carboxyguanamine; 5-(3-{[(cyclobutylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl] -1H-吲哚-7-carboxyguanamine; 5-(3-{[(cyclopropylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4- Piperidinyl]-1H-吲哚-7- Carboxylamidine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(propionylamino)methyl]phenyl}-1H-indole-7 - Carboxylamidine; 5-(3-{[(cyclopentylethyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1H-吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[3-(methylthio)propenyl)] Amino}methyl)phenyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[( 1-methylethyl)sulfonyl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 5-(3-{[(cyclopropylsulfonyl)amino] Methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-[3-({[(2,5) -dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide ; 5-[3-({[(4-bromophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1H-吲哚-7-carboxyguanamine; 5-[3-({[(4-chlorophenyl)sulfonyl)amino}methyl)phenyl]-3-[1-(ethylsulfonate) (4-)piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[( 3-fluorophenyl)sulfonyl]amino}methyl)phenyl]-1H-indole -7-carboxyguanamine; 5-[3-({[(2-chlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl]-1H-indole-7-carboxamide; 5-[3-({[(2,5-dichloro-3-thienyl))sulfonyl]amino}methyl)phenyl ]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-[3-({[(2-chloro-6-methyl) Phenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3- [1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-({[(5-fluoro-2-methylphenyl)sulfonyl]amino}methyl)phenyl -1H-吲哚-7-carboxyguanamine; 5-[3-({[(1,2-dimethyl-1H-imidazol-4-yl)sulfonyl]amino}methyl)phenyl ]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidine 5-(3-{[(propylsulfonyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 5-(3-{[(butylsulfonate) Amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(B Sulfosyl)-4-piperidinyl]-5-(3-{[(phenylsulfonyl)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3- [1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-({[(4-fluorobenzene) Sulfhydryl]amino}methyl)phenyl]-1H-indole-7-carboxamide; 5-[3-({[(4-bromo-2-ethylphenyl)sulfonyl)] Amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(3-{[(1) -benzothiophen-3-ylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxylate Indoleamine; 5-{3-[({[4-(1,1-dimethylethyl)phenyl)sulfonyl}amino)methyl]phenyl}-3-[1-(ethyl Sulfhydryl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-[3-({[(3,4-difluorophenyl)sulfonyl]amino}methyl) Phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(3-{[(ethylsulfonyl) Amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(3-{[(2) , 1,3-benzoic acid Zin-4-ylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(tetrahydro-3-furanylcarbonyl)amino]methyl}phenyl)-1H-indole哚-7-carboxyguanamine; 5-{4-[(cyclopentylsulfonyl)amino]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-methyl-2-oxo-1-piperider Phenyl]-1H-indole-7-carboxamide; 5-[6-(4-ethenyl-1-piperidin 3-(1-pyridyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonate) 4-(piperidinyl)-5-(4-{[(methyloxy)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1-(B Sulfosyl)-4-piperidinyl]-5-(3-{[(methyloxy)amino]methyl}phenyl)-1H-indole-7-carboxamide; 3-[1 -(ethylsulfonyl)-4-piperidinyl]-5-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}-3-thienyl)-1H -吲哚-7-carboxyguanamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2S)-2-(trifluoromethyl)- 1-pyrrolidinyl]methyl}-3-thienyl)-1H-indole-7-carboxamide; 5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidine Methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide; 5 -(5-{[(3S)-3-hydroxy-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4 -piperidinyl}-1H-indole-7-carboxamide; 5-(5-{[cyclopentyl(methyl)amino]methyl}-3-thienyl)-3-{1-[ (1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide; 5-(5-{[(2-hydroxyethyl)(methyl)amine Methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4 -piperidinyl}-1H-indole-7-carboxamide; 5-(5-{[(2-amino-2-oxoethyl)(methyl)amino]methyl}-3- Thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide; 3-[1-(ethylsulfonate) Mercapto)-4-piperidinyl]-5-(5-{[methyl(2-propen-1-yl)amino]methyl}-3-thienyl)-1H-indole-7-carboxylate Indoleamine; 5-(5-{[[(3,5-dimethyl-1H-pyrazol-4-yl)methyl](methyl)amino]methyl}-3-thienyl)-3 -[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[(cyanomethyl)(methyl)amino] Methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethyl sulfonate) Mercapto)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxyindole Amine; 5-(5-{[[2-(ethyloxy)ethyl](methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)- 4-piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[cyclobutyl(methyl)amino]methyl}-3-thienyl)-3-[1- (ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5 -({2-[(methyloxy)methyl]-1-pyrrolidinyl}methyl)-3-thiophene -1H-indole-7-carboxamide; 5-(5-{[(1,1-dimethylethyl)(methyl)amino]methyl}-3-thienyl)-3 -[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]- 5-(5-{[3-(trifluoromethyl)-1-piperidinyl]methyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(B Sulfosyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]methyl}-3-thiophene -1H-indole-7-carboxamide; 5-(5-{[(cyclopropylmethyl)(methyl)amino]methyl}-3-thienyl)-3-[1- (ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 5-(5-{[[2-(ethinyl))ethyl](methyl) Amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-( Ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1R,2R)-2-hydroxycyclopentyl](methyl)amino]methyl}-3-thienyl -1H-吲哚-7-carboxyguanamine; 5-(5-{[(1,1-dimethylpropyl)(methyl)amino]methyl}-3-thienyl)-3- [1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5 -(5-{[[(2S)-2-hydroxypropyl](methyl)amino]methyl}-3-thiophene -1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[(2R)-tetrahydro) 2-furylmethyl]amino}methyl)-3-thienyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl ]-5-(5-{[{2-[(2-hydroxyethyl)oxy)ethyl}(methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxylate Indoleamine; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-{methyl[2-(methyloxy)ethyl]amino}ethyl -3-thienyl]-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{1-[methyl (propyl)amino]ethyl}-3-thienyl)-1H-indole-7-carboxamide; 3-[1-(ethylsulfonyl)-4-piperidinyl]-5- (5-{[[(1 S )-2-hydroxy-1-methylethyl](methyl)amino]methyl}-3-thienyl)-1 H -吲哚-7-carboxyguanamine; and 5-(5-{[(1,1-dioxytetrahydro-3-thienyl)(methyl)amino]methyl}-3-thienyl )-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H - 吲哚-7-carboxamide; or a pharmaceutically acceptable salt thereof.

術語與定義Terms and definitions

“烷基”係指具有指定組員原子數之飽和烴鏈。例如：C₁-C₆烷基係指具有1至6個組員原子之烷基。烷基可視需要經一個或多個如本文定義之取代基取代。烷基可為直鏈或分支。代表性分支烷基具有1、2或3個分支。烷基包括甲基、乙基、丙基(正丙基與異丙基)、丁基(正丁基、異丁基與第三丁基)、戊基(正戊基、異戊基與新戊基)，與己基。 "Alkyl" means a saturated hydrocarbon chain having the specified number of members. For example, C ₁ -C ₆ alkyl means an alkyl group having from 1 to 6 member atoms. The alkyl group may optionally be substituted with one or more substituents as defined herein. The alkyl group can be straight or branched. Representative branched alkyl groups have 1, 2 or 3 branches. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl and tert-butyl), pentyl (n-pentyl, isopentyl and new) Amyl), with hexyl.

"伸烷基"當單獨使用或形成其他基團(如：C₁-C₆伸烷基-雜芳基、C₁-C₆伸烷基-雜環烷基、C₁-C₆伸烷基-C₄-C₇環烷基與C₁-C₆伸烷基-C₅-C₇環烯基基團)時，係指具有指定組員原子數之飽和二價烴鏈。例如：C₁-C₆伸烷基係指具有1至6個組員原子之伸烷基。伸烷基可視需要經一個或多個如本文定義之取代基取代。伸烷基可為直鏈或分支。代表性分支伸烷基具有1、2或3個分支。伸烷基包括亞甲基、伸乙基、伸丙基(伸正丙基與伸異丙基)、伸丁基(伸正丁基、伸異丁基，與伸第三丁基)、伸戊基(伸正戊基、伸異戊基與伸新戊基)，與伸己基。 "Alkyl" when used alone or to form other groups (eg, C ₁ -C ₆ alkyl-heteroaryl, C ₁ -C ₆ alkyl-heterocycloalkyl, C ₁ -C ₆ alkylene When the group -C ₄ -C ₇ cycloalkyl and C ₁ -C ₆ alkyl-C ₅ -C ₇ cycloalkenyl group), it means a saturated divalent hydrocarbon chain having the specified number of members. For example, a C ₁ -C ₆ alkylene group means an alkylene group having from 1 to 6 member atoms. The alkylene group may be optionally substituted with one or more substituents as defined herein. The alkyl group can be straight or branched. Representative branched alkyl groups have 1, 2 or 3 branches. The alkyl group includes methylene, ethyl, propyl (extended propyl and isopropyl), butyl (extended butyl, isobutyl, and butyl), and pentyl (Stretching the amyl group, stretching the isoamyl group and stretching the new amyl group), and extending the base.

“烯基”係指具有指定組員原子數且鏈中具有一個或多個碳-碳雙鍵之不飽和烴鏈。例如：C₂-C₆烯基係指具有2至6個組員原子之烯基。某些具體實施例中，烯基之鏈中具有一個碳-碳雙鍵。其他具體實施例中，烯基之鏈中具有一個以上碳-碳雙鍵。烯基可視需要經一個或多個如本文定義之取代基取代。烯基可為直鏈或分支。代表性分支烯基具有1、2或3個分支。烯基包括乙烯基、丙烯基、丁烯基、戊烯基與己烯基。 "Alkenyl" refers to an unsaturated hydrocarbon chain having the specified number of members and having one or more carbon-carbon double bonds in the chain. For example, C ₂ -C ₆ alkenyl refers to an alkenyl group having 2 to 6 member atoms. In certain embodiments, the alkenyl chain has a carbon-carbon double bond in the chain. In other embodiments, the alkenyl chain has more than one carbon-carbon double bond. The alkenyl group may optionally be substituted with one or more substituents as defined herein. The alkenyl group can be straight or branched. Representative branched alkenyl groups have 1, 2 or 3 branches. Alkenyl groups include ethenyl, propenyl, butenyl, pentenyl and hexenyl.

“伸烯基”係指具有指定組員原子數且鏈中具有一個或多個碳-碳雙鍵之不飽和二價烴鏈。例如：C₂-C₆伸烯基係指具有2至6個組員原子之伸烯基。某些具體實施例中，伸烯基之鏈中具有一個碳-碳雙鍵。其他具體實施例中，伸烯基之鏈中具有一個以上碳-碳雙鍵。伸烯基可視需要經一個或多個如本文定義之取代基取代。伸烯基可為直鏈或分支。代表性分支伸烯基具有1、2或3個分支。伸烯基包括伸乙烯基、伸丙烯基、伸丁烯基、伸戊烯基與伸己烯基。 "En stretched alkenyl" refers to an unsaturated divalent hydrocarbon chain having the specified number of members and having one or more carbon-carbon double bonds in the chain. For example: C ₂ -C ₆ alkenylene group refers to alkenylene groups having 2-6 members atoms. In certain embodiments, the alkenyl chain has a carbon-carbon double bond. In other embodiments, the chain extending to the alkenyl group has more than one carbon-carbon double bond. An alkenyl group may be optionally substituted with one or more substituents as defined herein. The alkenyl group can be straight or branched. Representative branched alkenyl groups have 1, 2 or 3 branches. The alkenyl group includes a vinyl group, a propylene group, a butenyl group, a pentenyl group and a hexenylene group.

“伸炔基”係指具有指定組員原子數且鏈中具有一個或多個碳-碳參鍵之不飽和二價烴鏈。例如：C₂-C₆伸炔基係指具有2至6個組員原子之伸炔基。某些具體實施例中，伸炔基之鏈中具有一個碳-碳參鍵。其他具體實施例中，伸炔基之鏈中具有一個以上碳-碳參鍵。為了釐清，鏈中具有一個或多個碳-碳參鍵且鏈中具有一個或多個碳-碳雙鍵之不飽和二價烴鏈亦為伸炔基。伸炔基可視需要經一個或多個如本文定義之取代基取代。伸炔基可為直鏈或分支。代表性分支伸炔基具有1、2或3個分支。伸炔基包括伸乙炔基、伸丙炔基、伸丁炔基、伸戊炔基與伸己炔基。 "Extend alkynyl" refers to an unsaturated divalent hydrocarbon chain having the specified number of members and having one or more carbon-carbon bonds in the chain. For example, a C ₂ -C ₆ alkynyl group refers to an alkynyl group having 2 to 6 member atoms. In certain embodiments, the alkynyl group has a carbon-carbon bond therein. In other embodiments, the alkynyl group has more than one carbon-carbon bond in the chain. For clarification, the unsaturated divalent hydrocarbon chain having one or more carbon-carbon bonds in the chain and having one or more carbon-carbon double bonds in the chain is also an alkynyl group. The alkynyl group may optionally be substituted with one or more substituents as defined herein. The alkynyl group can be straight or branched. Representative branched alkynyl groups have 1, 2 or 3 branches. The alkynyl group includes an ethynyl group, a propargyl group, a butynyl group, a pentynyl group and an extenylene group.

“芳基”係指芳香烴環。芳基為單環狀環系或雙環狀環系。單環狀芳基環係指苯基。雙環狀芳基環係指萘基及其中苯基與具有5、6或7個組員原子之環烷基或環烯基環稠合形成之環。芳基可視需要經一個或多個如本文定義之取代基取代。 "Aryl" means an aromatic hydrocarbon ring. The aryl group is a monocyclic ring system or a bicyclic ring system. A monocyclic aryl ring refers to a phenyl group. The bicyclic aryl ring means a naphthyl group and a ring in which the phenyl group is fused to a cycloalkyl or cycloalkenyl ring having 5, 6 or 7 member atoms. The aryl group may optionally be substituted with one or more substituents as defined herein.

“環烷基”係指具有指定組員原子數之飽和烴環。環烷基為單環狀環系。例如：C₃-C₆環烷基係指具有3至6個組員原子之環烷基。環烷基可視需要經一個或多個如本文定義之取代基取代。環烷基包括環丙基、環丁基、環戊基與環己基。 "Cycloalkyl" means a saturated hydrocarbon ring having the specified number of members. A cycloalkyl group is a monocyclic ring system. For example, a C ₃ -C ₆ cycloalkyl group means a cycloalkyl group having 3 to 6 member atoms. The cycloalkyl group may optionally be substituted with one or more substituents as defined herein. Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

“環烯基”係指具有指定組員原子數且環內具有碳-碳雙鍵之不飽和烴環。例如：C₃-C₆環烯基係指具有3至6個組員原子之環烯基。某些具體實施例中，環烯基之環內具有一個碳-碳雙鍵。其他具體實施例中，環烯基之環內具有一個以上碳-碳雙鍵。然而，環烯基環不為芳香系。環烯基為單環狀環系。環烯基可視需要經一個或多個如本文定義之取代基取代。環烯基包括環丙烯基、環丁烯基、環戊烯基與環己烯基。 "Cycloalkenyl" refers to an unsaturated hydrocarbon ring having the specified number of members and having a carbon-carbon double bond in the ring. For example, C ₃ -C ₆ cycloalkenyl refers to a cycloalkenyl group having 3 to 6 member atoms. In certain embodiments, the cycloalkenyl ring has a carbon-carbon double bond within the ring. In other embodiments, the cycloalkenyl ring has more than one carbon-carbon double bond within the ring. However, the cycloalkenyl ring is not an aromatic system. The cycloalkenyl group is a monocyclic ring system. The cycloalkenyl group may optionally be substituted with one or more substituents as defined herein. The cycloalkenyl group includes a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, and a cyclohexenyl group.

“高對映異構性”係指產物之對映異構性超量超過零。例如：高對映異構性係指產物之對映異構性超量超過50%ee，超過75%ee，與超過90% ee。 "High enantiomeric" means that the enantiomeric excess of the product exceeds zero. For example, high enantiomeric means that the product has an enantiomeric excess of more than 50% ee, more than 75% ee, and more than 90% ee.

"對映異構性超量"或"ee"為一種對映異構物之含量超過另一種對映異構物含量之百分比程度。結果消旋混合物中之兩種對映異構物呈等含量，因此對映異構性超量為零(0%ee)。然而，若其中一種對映異構物之含量高達產物之95%時，該對映異構性超量即為90%ee(高量對映異構物之含量95%減去另一種對映異構物之含量5%)。 "Enantiomeric excess" or "ee" is the degree to which one enantiomer is present in an amount greater than the other enantiomeric content. As a result, the two enantiomers in the racemic mixture were in an equivalent amount, so the enantiomeric excess was zero (0% ee). However, if the content of one of the enantiomers is as high as 95% of the product, the enantiomeric excess is 90% ee (the content of the high enantiomer is 95% minus the other. The content of the isomer is 5%).

“純對映異構性”係指產物之對映異構性超量為99% ee或以上。 "Pure enantiomeric" means that the product has an enantiomeric excess of 99% ee or more.

“半衰期”係指物質於活體內或活體外轉化一半量形成另一種不同化學物質時所需時間。 "Half-life" refers to the time it takes for a substance to be converted in vivo or in vitro to form another different chemical.

“鹵基”係指鹵素基團氟、氯、溴或碘。 " Halo " means a halogen group of fluorine, chlorine, bromine or iodine.

"鹵烷基"係指烷基中至少一個附接烷基內組員原子之氫原子被鹵基置換。鹵烷基包括三氟甲基。 "Haloalkyl" means that at least one of the hydrogen atoms of the alkyl group member in the alkyl group is replaced by a halo group. Haloalkyl groups include trifluoromethyl groups.

"雜芳基"係指包含1至4個雜原子作為環組員原子之芳香環。包含一個以上雜原子之雜芳基可能包含不同雜原子。雜芳基可視需要經一個或多個如本文定義之取代基取代。雜芳基為單環狀環系或稠合、螺形或橋連雙環狀環系。單環狀雜芳基環具有5或6個組員原子。雙環狀雜芳基環具有7至11個組員原子。雙環狀雜芳基環包括彼等環中，苯基與單環狀雜環烷基環附接形成之稠合、螺形或橋連雙環狀環系，與彼等環中，單環狀雜芳基環與附接之單環狀環烷基、環烯基、雜環烷基或雜芳基環形成之稠合、螺形或橋連雙環狀環系。雜芳基包括吡咯基、吡唑基、咪唑基、唑基、異唑基、噻唑基、異噻唑基、呋喃基、呋咱基、噻吩基、三唑基、吡啶基、嘧啶基、嗒基、吡基、三基、四基、吲哚基、異吲哚基、吲基、吲唑基、嘌呤基、喹啉基、異喹啉基、喹啉基、喹唑啉基、蝶啶基、噌啉基、苯并咪唑基、苯并吡喃基、苯并唑基、苯并呋喃基、異苯并呋喃基、苯并噻唑基、苯并噻吩基、呋喃并吡啶基與萘啶基。 "Heteroaryl" means an aromatic ring containing from 1 to 4 heteroatoms as ring member atoms. Heteroaryl groups containing more than one hetero atom may contain different heteroatoms. A heteroaryl group may optionally be substituted with one or more substituents as defined herein. Heteroaryl is a monocyclic ring system or a fused, helical or bridged bicyclic ring system. A monocyclic heteroaryl ring has 5 or 6 member atoms. The bicyclic heteroaryl ring has 7 to 11 member atoms. Bicyclic heteroaryl rings include fused, helical or bridged bicyclic ring systems in which the phenyl group is attached to a monocyclic heterocycloalkyl ring, and in the rings, single rings A fused, helical or bridged bicyclic ring system formed by a heterocyclic aryl ring with an attached monocyclic cycloalkyl, cycloalkenyl, heterocycloalkyl or heteroaryl ring. Heteroaryl includes pyrrolyl, pyrazolyl, imidazolyl, Azolyl, different Azyl, thiazolyl, isothiazolyl, furyl, furyl, thienyl, triazolyl, pyridyl, pyrimidinyl, anthracene Base Base, three Base, four Base, thiol, isothiol, hydrazine Base, carbazolyl, fluorenyl, quinolyl, isoquinolinyl, quin Lolinyl, quinazolinyl, pteridinyl, porphyrinyl, benzimidazolyl, benzopyranyl, benzo Azolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, furopyridinyl and naphthyridinyl.

“雜原子”係指氮、硫或氧原子。 "Hetero atom" means a nitrogen, sulfur or oxygen atom.

“雜環烷基”係指包含1至4個雜原子作為環組員原子之飽和或不飽和環。然而雜環烷基環不為芳香系。包含一個以上雜原子之雜環烷基可能包含不同雜原子。雜環烷基可視需要經一個或多個如本文定義之取代基取代。雜環烷基為具有4至7個組員原子之單環狀環系。某些具體實施例中，雜環烷基為飽和。其他具體實施例中，雜環烷基為不飽和，但不為芳香系。雜環烷基包括吡咯啶基、四氫呋喃基、二氫呋喃基、吡喃基、四氫吡喃基、二氫吡喃基、四氫噻吩基、吡唑啶基、唑啶基、噻唑啶基、哌啶基、高碳哌啶基、哌基、嗎啉基、噻嗎啉基、1,3-二茂烷基、1,3-二烷基、1,4-二烷基、1,3-氧硫戊環基、1,3-噻烷基、1,3-二噻烷基，與吖呾基。 "Heterocycloalkyl" means a saturated or unsaturated ring containing from 1 to 4 heteroatoms as ring member atoms. However, the heterocycloalkyl ring is not an aromatic system. Heterocycloalkyl groups containing more than one hetero atom may contain different heteroatoms. A heterocycloalkyl group may optionally be substituted with one or more substituents as defined herein. Heterocycloalkyl is a monocyclic ring system having from 4 to 7 member atoms. In certain embodiments, the heterocycloalkyl group is saturated. In other embodiments, the heterocycloalkyl group is unsaturated, but not aromatic. Heterocycloalkyl includes pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiophenyl, pyrazolyl, Zyridinyl, thiazolidinyl, piperidinyl, high carbon piperidinyl, piperazine Base, morpholinyl, thiamorpholinyl, 1,3-di Alkenyl, 1,3-di Alkyl, 1,4-two Alkyl, 1,3-oxathiolanyl, 1,3- Thiacyl, 1,3-dithiaalkyl, and fluorenyl.

"組員原子"係指形成鏈或環之組員。若鏈或環中出現一個以上組員原子時，各組員原子分別與鏈或環中相鄰組員原子共價鍵結。構成鏈或環上取代基之原子則不為該鏈或環之組員原子。 "Group member atom" means a member who forms a chain or a ring. If more than one group member atom is present in a chain or ring, each group member atom is covalently bonded to an adjacent group member atom in the chain or ring. The atom constituting the substituent on the chain or ring is not a member atom of the chain or ring.

"可視需要經取代"係指基團，如：烷基、烯基、炔基、芳基、環烷基、環烯基、雜環烷基或雜芳基可未經取代或經一個或多個如本文定義之取代基取代。基團中所提及"經取代"係指基團內附接組員原子之氫原子被置換。咸了解，術語"經取代"包括之限制條件為此等取代作用係依據經取代之原子與取代基容許之價數，且取代作用應產生安定化合物(亦即不會自發性進行轉形反應之化合物，如：重組、環化或消去反應)。某些具體實施例中，單一原子可能被一個以上取代基取代，只要原子之價數容許此等取代法即可。合適之取代基如本文中各經取代或可視需要經取代之基團之定義。 "Substituted as needed" means a group such as alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl or heteroaryl which may be unsubstituted or substituted by one or more Substituents substituted as defined herein. Reference to "substituted" in a group refers to the replacement of a hydrogen atom attached to a member atom within a group. It is understood that the term "substitution" includes the limitation that the substitution is based on the valence allowed by the substituted atom and the substituent, and the substitution should produce a stable compound (ie, does not spontaneously undergo a transformation reaction). a compound such as a recombination, cyclization or elimination reaction). In some embodiments, a single atom may be substituted with more than one substituent, as long as the valence of the atoms allows such substitution. Suitable substituents are as defined herein for each of the substituted or optionally substituted groups.

"醫藥上可接受"係指彼等化合物、材料、組合物與劑型在完整之醫學判斷下適合與人類及動物組織接觸，不會產生過度毒性、刺激、或其他問題或併發症，同時具有合理之效益/危險比例。 "Pharmaceutically acceptable" means that their compounds, materials, compositions and dosage forms are suitable for contact with humans and animal tissues under full medical judgment and do not cause excessive toxicity, irritation, or other problems or complications, and are reasonable. Benefit/hazard ratio.

本文在此等製法、反應圖及實例中所採用代號均符合現行科學文獻所採用者，例如：美國化學會期刊(Journal of the American Chemical Society)或生物化學期刊(Journal of Biological Chemistry)。通常使用標準單一字母或三字母縮寫代表胺基酸殘基，除非本文中另有說明，否則係指L-組態。除非本文中另有說明，否則所有起始物均得自商品，且未再純化即使用。明確言之，實例及本說明書全文中可使用下列縮寫： g(克)；mg(毫克)；L(升)；mL(毫升)；μL(微升)；psi(每平方吋磅數)；M(莫耳濃度)；mM(毫莫耳濃度)；i.v.(經靜脈內)；Hz(赫茲)；MHz(百萬赫茲)；mol(莫耳)；mmol(毫莫耳)；rt(室溫)；min(分鐘)；h(小時)；mp(熔點)；TLC(薄層層析法)；Tr(滯留時間)；RP(逆向)；MeOH(甲醇)；i-PrOH(異丙醇)；TEA(三乙基胺)；TFA(三氟乙酸)；TFAA(三氟乙酸酐)；THF(四氫呋喃)；DMSO(二甲亞碸)；AcOEt(乙酸乙酯)；DME(1,2-二甲氧乙烷)；DCM(二氯甲烷)；DCE(二氯乙烷)；DMF(N,N-二甲基甲醯胺)；DMPU(N,N'-二甲基伸丙基脲)；CDI(1,1-羰基二咪唑)；IBCF(氯甲酸異丁基酯)；HOAc(乙酸)；HOSu(N-羥基琥珀醯亞胺)；HOBT(1-羥基苯并三唑)；mCPBA(間氯過苯甲酸)；EDC(1-[3-二甲基胺基)丙基]-3-乙基碳化二亞胺鹽酸鹽)；BOC(第三丁基氧羰基)；FMOC(9-芴基甲氧基羰基)；DCC(二環己基碳化二亞胺)；CBZ(苯甲基氧羰基)；Ac(乙醯基)；atm(大氣壓)； TMSE(2-(三甲基矽烷基)乙基)；TMS(三甲基矽烷基)；TIPS(三異丙基矽烷基)；TBS(第三丁基二甲基矽烷基)；DMAP(4-二甲基胺基吡啶)；BSA(牛血清白蛋白)；ATP(腺苷三磷酸)；HRP(辣根過氧化酶)；DMEM(杜氏改良伊格氏培養基(Dulbecco’s modified Eagle medium))；HPLC(高壓液相層析法)；BOP(雙(2-氧代-3-唑啶基)次膦醯氯)；TBAF(四-正丁基銨化氟)；HBTU(O-苯并三唑-1-基-N,N,N’,N’-四甲基脲鎓六氟磷酸鹽)；HEPES(4-(2-羥基乙基)-1-哌乙烷磺酸)；DPPA(二苯基磷醯基疊氮化物)；fHNO₃(發煙HNO₃)；EDTA(乙二胺四乙酸)；TMEDA(N,N,N',N'-四甲基-1,2-乙二胺)；NBS(N-溴琥珀醯亞胺)；HATU(O-(7-氮雜苯并三唑-1-基)-N,N,N',N'-四甲基脲鎓六氟磷酸鹽)；DIPEA(二異丙基乙基胺)；Imes(1,3-雙(2,4,6-三甲基苯基)咪唑鎓氯化物)；dppf(1,1'-雙(二苯基膦基)二茂絡鐵)；MDAP(質量導向式自動製備法(Mass Directed AutoPrep))；CH₃CN(乙腈)； EtOAc(乙酸乙酯)；與NIS(N-碘琥珀醯亞胺)。 The codes used in these methods, reaction diagrams, and examples are consistent with those used in current scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry . Amino acid residues are typically represented using standard single letter or three letter abbreviations and are referred to as L-configuration unless otherwise indicated herein. All starting materials were obtained from commercial products and used without further purification unless otherwise stated herein. Specifically, the following abbreviations may be used throughout the examples and throughout the specification: g (grams); mg (mg); L (liters); mL (ml); μL (microliters); psi (pounds per square inch); M (mole concentration); mM (mole concentration); iv (intravenous); Hz (Hz); MHz (million Hz); mol (mole); mmol (mole); rt (room Temperature); min (minutes); h (hours); mp (melting point); TLC (thin layer chromatography); Tr (retention time); RP (reverse); MeOH (methanol); i- PrOH (isopropanol) ; TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); DMSO (dimethyl hydrazine); AcOEt (ethyl acetate); DME (1, 2) - Dimethoxyethane); DCM (dichloromethane); DCE (dichloroethane); DMF ( N , N -dimethylformamide); DMPU ( N , N' -dimethylpropyl) Urea); CDI (1,1-carbonyldiimidazole); IBCF (isobutyl chloroformate); HOAc (acetic acid); HOSu ( N -hydroxysuccinimide); HOBT (1-hydroxybenzotriazole) mCPBA (m-chloroperbenzoic acid); EDC (1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride); BOC (t-butyloxycarbonyl); FMOC (9-fluorenylmethoxycarbonyl); DCC (dicyclohexyl) Diimine); CBZ (benzyloxycarbonyl); Ac (ethenyl); atm (atmospheric pressure); TMSE (2-(trimethyldecyl)ethyl); TMS (trimethyldecyl) TIPS (triisopropyldecylalkyl); TBS (t-butyldimethylmethylalkyl); DMAP (4-dimethylaminopyridine); BSA (bovine serum albumin); ATP (adenosine triphosphate) HRP (horseradish peroxidase); DMEM (Dulbecco's modified Eagle medium); HPLC (high pressure liquid chromatography); BOP (double (2-oxo-3-) Zotrindyl)phosphinium chloride; TBAF (tetra-n-butylammonium fluoride); HBTU (O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium Hexafluorophosphate); HEPES (4-(2-hydroxyethyl)-1-piperider Ethanesulfonic acid); DPPA (diphenylphosphonium azide); fHNO ₃ (fuming HNO ₃ ); EDTA (ethylenediaminetetraacetic acid); TMEDA (N, N, N', N'-four Methyl-1,2-ethanediamine); NBS (N-bromosuccinimide); HATU (O-(7-azabenzotriazol-1-yl)-N,N,N',N '-Tetramethyluronium hexafluorophosphate); DIPEA (diisopropylethylamine); Imes (1,3-bis(2,4,6-trimethylphenyl)imidazolium chloride); Dppf (1,1'-bis(diphenylphosphino) ferrocene); MDAP (Mass Directed AutoPrep); CH ₃ CN (acetonitrile); EtOAc (ethyl acetate); With NIS (N-iodosuccinimide).

所有提及之醚均指乙醚，鹽水係指飽和NaCl水溶液。 All references to ether refer to diethyl ether and brine refers to saturated aqueous NaCl.

根據I-II化合物可能包含一個或多個不對稱中心(亦稱為對掌性中心)，因此可能出現個別對映異構物、非對映異構物或其他立體異構物，或出現其混合物。對掌性中心如：對掌性碳原子，亦可能出現在取代基中，如：烷基。若出現在式I-II或本文所示任何化學結構之對掌性中心之立體化學沒有明確說明時，該結構式係包括任何立體異構物與其所有混合物。因此，包含一個或多個對掌性中心之根據式I-II化合物可呈消旋混合物、高對映異構性混合物或純對映異構性之個別立體異構物使用。 Compounds according to I-II may contain one or more asymmetric centers (also known as palmar centers), so individual enantiomers, diastereomers or other stereoisomers may occur, or mixture. For the palm center, such as: for the palm carbon atom, it may also appear in the substituent, such as: alkyl. Where the stereochemistry of Formula I-II or the palm center of any of the chemical structures shown herein is not explicitly stated, the formula includes any stereoisomer and all mixtures thereof. Thus, a compound according to formula I-II comprising one or more palmitic centers can be used as a racemic mixture, a high enantiomeric mixture or an individual stereoisomer of pure enantiomeric.

包含一個或多個不對稱中心之根據式I-II化合物可利用習此相關技藝之人士習知之方法解析。例如：進行此等解析法時，可(1)形成非對映異構性鹽、錯化物或其他衍生物；(2)與立體異構物-專一性試劑進行選擇性反應，例如：酵素氧化法或還原法；或(3)於對掌性環境下進行氣相-液相或液相層析法，例如：於對掌性單體，如：矽石上，使用已結合之對掌性配位體或於對掌性溶劑之存在下進行。習此相關技藝之人士咸了解，若利用上述一種步驟轉化所需立體異構物形成另一種化學物質時，需要另一個步驟來釋出所需型式。或者，專一性立體異構物可利用不對稱合成法，使用光學活性試劑、受質、觸媒或溶劑合成，或利用不對稱轉形法，轉化一種對映異構物形成另一種。 Compounds of formula I-II comprising one or more asymmetric centers can be resolved by methods known to those skilled in the art. For example, when performing such analytical methods, (1) formation of diastereomeric salts, complexes or other derivatives; (2) selective reaction with stereoisomer-specific reagents, for example: enzyme oxidation Method or reduction method; or (3) performing gas-liquid phase or liquid phase chromatography in a palm environment, for example, on a palmitic monomer, such as a vermiculite, using a combined pair of palms The position is carried out in the presence of a palm solvent. It will be appreciated by those skilled in the art that if one of the above steps is used to convert the desired stereoisomer to form another chemical, another step is required to release the desired form. Alternatively, the specific stereoisomer can be synthesized by asymmetric synthesis using an optically active reagent, substrate, catalyst or solvent, or by asymmetric transformation to convert one enantiomer to another.

根據式I-II化合物可能亦包含雙鍵或其他幾何不對稱性中心。若式I-II或本文所示任何化學結構式出現幾何不對稱性中心之立體化學性時，若未明確說明，該結構式仍包括反式(E)幾何異構物、順式(Z)幾何異構物與其所有混合物。同樣地，所有互變異構型亦包括在式I-II中，不論此等互變異構物是否呈平衡型式或其中一種型式占優勢之型式。 The compounds according to formula I-II may also contain double bonds or other centers of geometric asymmetry. If Formula I-II or any of the chemical structural formulae shown herein exhibits the stereochemistry of the center of geometric asymmetry, if not explicitly stated, the structural formula still includes trans (E) geometric isomers, cis (Z) Geometric isomers and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula I-II, whether or not such tautomers are in equilibrium or one of the modes predominates.

習此相關技藝之人士咸了解，可製備根據式I-II化合物之醫藥上可接受之鹽類。事實上，本發明某些具體實施例中，根據式I-II化合物之醫藥上可接受之鹽類由於可為分子提供較高安定性或溶解度，藉以促進調配物形成劑型，因此優於其各游離鹼或游離酸型。因此，本發明進一步有關根據式I-II化合物之醫藥上可接受之鹽類。 It is understood by those skilled in the art that pharmaceutically acceptable salts of the compounds according to formula I-II can be prepared. In fact, in certain embodiments of the invention, the pharmaceutically acceptable salts according to the compounds of Formulas I-II are preferred over their pharmaceutically acceptable salts because they provide higher stability or solubility to the molecule, thereby facilitating the formulation of the formulation. Free base or free acid form. Accordingly, the invention further relates to pharmaceutically acceptable salts according to the compounds of formula I-II.

本文所採用術語"醫藥上可接受之鹽類"係指保留本化合物所需生物活性且具有最低不期望毒性之鹽類。此等醫藥上可接受之鹽類可在最後單離期間及純化化合物時，於原位製備，或另由呈其游離酸或游離鹼型之純化化合物分別與合適鹼或酸反應。 The term "pharmaceutically acceptable salts" as used herein refers to salts which retain the desired biological activity of the compound and which have the lowest undesired toxicity. Such pharmaceutically acceptable salts can be prepared in situ during the final isolation and when the compound is purified, or otherwise reacted with a suitable base or acid, respectively, of the purified compound in its free acid or free base form.

某些具體實施例中，根據式I-II化合物可能包含酸性官能基。合適之醫藥上可接受之鹽類包括此等酸性官能基之鹽類。代表性鹽類包括醫藥上可接受之金屬鹽，如：鈉、鉀、鋰、鈣、鎂、鋁與鋅鹽；醫藥上可接受之金屬陽離子(如：鈉、鉀、鋰、鈣、鎂、鋁與鋅)之碳酸鹽與碳酸氫鹽；醫藥上可接受之有機一級、二級與三級胺，包括脂系胺類、芳香系胺類、脂系二胺類與羥基烷基胺類，如：甲基胺、乙基胺、2-羥基乙基胺、二乙基胺、三乙基胺、乙二胺、乙醇胺、二乙醇胺與環己基胺。 In certain embodiments, a compound according to formula I-II may comprise an acidic functional group. Suitable pharmaceutically acceptable salts include the salts of such acidic functional groups. Representative salts include pharmaceutically acceptable metal salts such as: sodium, potassium, lithium, calcium, magnesium, aluminum and zinc salts; pharmaceutically acceptable metal cations (eg, sodium, potassium, lithium, calcium, magnesium, Aluminium and zinc) carbonates and hydrogencarbonates; pharmaceutically acceptable organic primary, secondary and tertiary amines, including aliphatic amines, aromatic amines, aliphatic diamines and hydroxyalkylamines, Such as: methylamine, ethyl Amine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine and cyclohexylamine.

某些具體實施例中，根據式I-II化合物可包含鹼性官能基，因此可經合適酸處理形成醫藥上可接受之酸加成鹽。合適酸包括醫藥上可接受之無機酸與醫藥上可接受之有機酸。代表性醫藥上可接受之酸加成鹽包括鹽酸鹽、氫溴酸鹽、硝酸鹽、甲基硝酸鹽、硫酸鹽、硫酸氫鹽、胺磺酸鹽、磷酸鹽、乙酸鹽、三氟乙酸鹽、羥基乙酸鹽、苯基乙酸鹽、丙酸鹽、丁酸鹽、異丁酸鹽、戊酸鹽、馬來酸鹽、羥基馬來酸鹽、丙烯酸鹽、富馬酸鹽、蘋果酸鹽、酒石酸鹽、檸檬酸鹽、水楊酸鹽、對胺基水楊酸鹽、乙醇酸鹽、乳酸鹽、庚酸鹽、酞酸鹽、草酸鹽、琥珀酸鹽、苯甲酸鹽、鄰-乙醯氧基苯甲酸鹽、氯苯甲酸鹽、甲基苯甲酸鹽、二硝基苯甲酸鹽、羥基苯甲酸鹽、甲氧基苯甲酸鹽、扁桃酸鹽、丹寧酸鹽、甲酸鹽、硬脂酸鹽、抗壞血酸鹽、棕櫚酸鹽、油酸鹽、丙酮酸鹽、雙羥萘酸鹽、丙二酸鹽、月桂酸鹽、戊二酸鹽、麩胺酸鹽、伊托酸鹽(estolate)、甲磺酸鹽(mesylate)、乙磺酸鹽(esylate)、2-羥基乙磺酸鹽、苯磺酸鹽(besylate)、對胺基苯磺酸鹽、對甲苯磺酸鹽(tosylate)與萘-2-磺酸鹽。 In certain embodiments, the compound according to formula I-II may comprise a basic functional group and thus may be treated with a suitable acid to form a pharmaceutically acceptable acid addition salt. Suitable acids include pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acids. Representative pharmaceutically acceptable acid addition salts include hydrochlorides, hydrobromides, nitrates, methyl nitrates, sulfates, hydrogen sulfates, amine sulfonates, phosphates, acetates, trifluoroacetic acids Salt, glycolate, phenylacetate, propionate, butyrate, isobutyrate, valerate, maleate, hydroxymaleate, acrylate, fumarate, malate , tartrate, citrate, salicylate, p-aminosalicylate, glycolate, lactate, heptanoate, citrate, oxalate, succinate, benzoate, o - ethoxylated benzoate, chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, mandelate, dan Nitrate, formate, stearate, ascorbate, palmitate, oleate, pyruvate, pamoate, malonate, laurate, glutarate, glutamine Acid salt, estolate, mesylate, esylate, 2-hydroxyethanesulfonate, besylate, p-aminobenzenesulfonate , Tosylate (as tosylate) and naphthalene-2-sulfonate.

本文所採用術語"本發明化合物"係指根據式I-II化合物與其醫藥上可接受之鹽類。 The term "compound of the invention" as used herein refers to a compound according to formula I-II and a pharmaceutically acceptable salt thereof.

本發明化合物可呈固態或液態型式。固態之本發明化合物可呈結晶或非結晶型，或呈其混合物。習此相關技藝之人士咸了解，結晶型之本發明化合物所形成之醫藥上可接受之鹽類可在結晶過程中納入溶劑分子至晶格中。溶劑可涉及非水性溶劑，如：乙醇、異丙醇、DMSO、乙酸、乙醇胺與乙酸乙酯，或其可能涉及使用可納入晶格中之水作為溶劑。以納入晶格中之水作為溶劑之溶合物典型地稱為"水合物"。水合物包括化學計量之水合物及包含不同水量之組合物。本發明包括所有此等溶劑。 The compounds of the invention may be in solid or liquid form. The solid compounds of the invention may be in crystalline or amorphous form, or in mixtures thereof. It is understood by those skilled in the art that the crystalline form of the compound of the invention forms a pharmaceutically acceptable Salts can incorporate solvent molecules into the crystal lattice during crystallization. The solvent may involve a non-aqueous solvent such as: ethanol, isopropanol, DMSO, acetic acid, ethanolamine and ethyl acetate, or it may involve the use of water which may be incorporated into the crystal lattice as a solvent. A solvate in which water incorporated into a crystal lattice is used as a solvent is typically referred to as a "hydrate." Hydrates include stoichiometric hydrates and compositions comprising different amounts of water. The invention includes all such solvents.

習此相關技藝之人士亦咸了解，某些呈結晶型(包括其不同溶合物型)之本發明化合物可能呈多晶型(亦即有能力出現不同結晶結構)。此等不同結晶型典型地稱為"多晶型"。本發明包括所有此等多晶型。多晶型具有相同化學組成，但結晶固體之填裝、幾何排列及其他敘述性質不同。因此多晶型可能具有不同物理性質，如：形狀、密度、硬度、變形性、安定性與溶解性質。多晶型典型地具有不同熔點、IR光譜與X-光粉末繞射圖形，其可用於判別。習此相關技藝之人士咸了解，製備化合物時，例如：改變或調整反應條件或試劑，可能產生多晶型。例如：改變溫度、壓力或溶劑時，可能產生多晶型。此外，一種多晶型可能在某些條件轉化成另一種多晶型。 It will also be appreciated by those skilled in the art that certain compounds of the invention in crystalline form (including their different solvate forms) may be polymorphic (i.e., capable of exhibiting different crystalline structures). These different crystalline forms are typically referred to as "polymorphs." The invention includes all such polymorphs. Polymorphs have the same chemical composition, but the filling, geometric arrangement, and other narrative properties of the crystalline solids are different. Polymorphs may therefore have different physical properties such as shape, density, hardness, deformability, stability and solubility properties. Polymorphs typically have different melting points, IR spectra, and X-ray powder diffraction patterns that can be used for discrimination. It will be appreciated by those skilled in the art that polymorphic forms may result when compounds are prepared, for example, by changing or adjusting the reaction conditions or reagents. For example, when changing temperature, pressure or solvent, polymorphism may result. In addition, one polymorph may be converted to another polymorph under certain conditions.

化合物製法Compound method

本發明化合物可依多種不同方法製備，包括標準化學法。任何前述代號均仍如前述定義，除非本文中另有說明。舉例說明之一般合成法如下示，本發明合物則如實例一節之方法製備。 The compounds of the invention can be prepared in a number of different ways, including standard chemical methods. Any of the foregoing symbols are still as defined above unless otherwise stated herein. The general synthetic methods exemplified are shown below, and the compounds of the present invention are prepared as in the method of the Examples section.

式I與II化合物可依據例如：下示反應圖1、2與3製備： 條件；a)(BOC)₂O，THF；b)s-BuLi，ClCO₂Me，TMEDA，Et₂O；c)N-溴琥珀醯亞胺，二氯甲烷；d)TFA；e)MnO₂，THF；f)LiOH，MeOH，水；g)R1B(OR)₂，Imes-HCl，Pd(OAc)₂，二烷/水；h)HATU，NH₃，DMF；i)RCHO(或)RC(O)R’，NaOMe，MeOH；j)Pd(OH)₂，H₂，HOAc，EtOH；k)R4Cl，TEA，二氯甲烷(或)(R4)₂O，DMAP，二氯甲烷 The compounds of the formulae I and II can be prepared, for example, according to the reaction schemes 1, 2 and 3 shown below: _{Conditions; a) (BOC) 2 O} , THF; b) s -BuLi, ClCO 2 Me, TMEDA, Et 2 O; c) N- bromosuccinimide (PEI), methylene chloride; d) TFA; e) MnO 2 , THF; f) LiOH, MeOH, water; g) R1B(OR) ₂ , Imes-HCl, Pd(OAc) ₂ , Alkane/water; h) HATU, NH ₃ , DMF; i) RCHO (or) RC(O)R', NaOMe, MeOH; j) Pd(OH) ₂ , H ₂ , HOAc, EtOH; k) R4Cl, TEA , dichloromethane (or) (R4) ₂ O, DMAP, dichloromethane

反應圖1代表製備根據式I與II中R2與R3為H、F或Cl，U為一鍵結或C₁-C₆伸烷基或C₂-C₆伸烯基，V為C₅-C₇環烷基或C₅-C₇環烯基或雜環烷基或雜環烯基之化合物之一般反應圖。反應圖1亦代表製備根據式I與II中U為C₁-C₆伸烷基或C₂-C₆伸烯基，V為芳基或雜芳基之化合物之之一般反應圖。反應圖1中，R1如上述定義，除非本文中另有說明。作為起始物之吲哚啉1係自商品取得。反應條件如上述反應圖所示；然而，習此相關技藝之人士咸了解，可能在所採用之反應條件與/或試劑上進行某些修飾。 Reaction Scheme 1 represents the preparation according to formulas I and II wherein R2 and R3 are H, F or Cl, U is a bond or a C ₁ -C ₆ alkylene group or a C ₂ -C ₆ alkylene group, and V is C ₅ - C ₇ cycloalkyl or C ₅ -C ₇ general reaction of the compound of FIG cycloalkenyl or heterocycloalkyl or heterocycloalkenyl it. Reaction Scheme 1 also represents a general reaction scheme for the preparation of compounds according to formulas I and II wherein U is a C ₁ -C ₆ alkylene group or a C ₂ -C ₆ alkylene group and V is an aryl or heteroaryl group. In Reaction Scheme 1, R1 is as defined above, unless otherwise stated herein. Porphyrin 1 as a starting material was obtained from a commercial product. The reaction conditions are as shown in the above reaction scheme; however, it will be apparent to those skilled in the art that certain modifications may be made to the reaction conditions and/or reagents employed.

由吲哚啉1於合適溶劑如：THF或二氯甲烷中，經二碳酸二-第三丁酯處理，產生所需BOC保護之產物。進一步轉形成所需溴化物2之方法為利用鋰化反應法，使用第二丁基鋰，於TMEDA之存在下反應，並以氯甲酸甲酯中止反應，然後與N-溴琥珀醯亞胺進行溴化反應。溴化物2經三氟乙酸處理後，使用二氧化錳氧化所得之吲哚啉，產生吲哚，然後水解甲酯，產生酸，得到所需之羧酸3。置入取代基R1之方法可利用過渡金屬所媒介之偶合法，使用適當觸媒與偶合對象進行。以反應圖1中條件“g”為此等轉形法實例之一，該鈴木交叉偶合反應(Suzuki cross-coupling reaction)可使用二羥硼酸酯或酸，於Pd(OAc)₂、Imes-HCl與Cs₂CO₃之存在下，於1,4-二烷與水中進行。一級羧醯胺4之製法可利用羧酸與氨，於HATU之存在下反應完成。由4引進基團U-V形成5之轉化法可利用適當醛或酮前體與U-V反應達成。此轉形反應可於鹼性或酸性條件下進行。若基團U-V為完全飽和時，接續還原中間產物後，產生所需產物5。此等還原法實例為反應圖1條件“j”，其係於Pd(OH)₂之存在下進行氫化反應，完成轉形反應，產生5。若U-V與/或R1包含合適保護基時，可於適當條件下脫除保護基，進一步轉形成其他產物。基團U-V之胺官能基隨後轉形成R4之磺醯胺或醯胺之反應可使用R4之適當磺醯氯或醯基氯或酸酐進行。習此相關技藝之人士咸了解，當轉形成R4之磺醯胺或醯胺時，所得產物可能需要進行操作形成R4。此作法可包括(但不限於)：操作合適之保護基與官能基，並與胺/醇R5反應。 Treatment of the porphyrin 1 with di-tert-butyl dicarbonate in a suitable solvent such as THF or dichloromethane affords the desired product of &lt Further conversion to the desired bromide 2 is carried out by a lithiation reaction using a second butyllithium in the presence of TMEDA and quenching with methyl chloroformate followed by N-bromosuccinimide Bromination reaction. After bromide 2 is treated with trifluoroacetic acid, the resulting porphyrin is oxidized using manganese dioxide to produce hydrazine, and then the methyl ester is hydrolyzed to produce an acid to give the desired carboxylic acid 3 . The method of placing the substituent R1 can be carried out by using the coupling method of the transition metal medium, using a suitable catalyst and a coupling object. One of the examples of the transformation method in the reaction condition "g" in Fig. 1 is that the Suzuki cross-coupling reaction can use a dihydroxyborate or an acid in Pd(OAc) ₂ , Imes- In the presence of HCl and Cs ₂ CO ₃ , in 1,4-two The alkane is carried out in water. The preparation of the primary carboxamide 4 can be carried out by using a carboxylic acid and ammonia in the presence of HATU. 4 is formed by the introduction of a group of 5 UV transformation may be achieved using an appropriate aldehyde or ketone precursor with the UV reactor. This transformation reaction can be carried out under basic or acidic conditions. If the group UV is fully saturated, subsequent reduction of the intermediate product produces the desired product 5 . An example of such a reduction method is the reaction condition "j" of Figure 1, which is subjected to a hydrogenation reaction in the presence of Pd(OH) _{2 to} complete the transformation reaction to produce 5 . If UV and/or R1 comprise a suitable protecting group, the protecting group can be removed under appropriate conditions and further converted to other products. The subsequent reaction of the amine functional group of the group UV to the sulfonamide or decylamine of R4 can be carried out using the appropriate sulfonium chloride or mercapto chloride or anhydride of R4. It will be appreciated by those skilled in the art that when converted to the sulfonamide or guanamine of R4, the resulting product may require manipulation to form R4. This practice can include, but is not limited to, manipulation of a suitable protecting group and functional group, and reaction with an amine/alcohol R5.

條件：a)R1B(OR)₂，Imes-HCl，Pd(OAc)₂，二烷/水；b)HATU，NH₃，DMF；c)N-碘琥珀醯亞胺，二氯甲烷；d)VUB(OR)₂，Pd(PPh₃)₄，Cs₂CO₃，1,4-二烷，水；e)R₂Cl，TEA，二氯甲烷(或)(R₂)₂O，DMAP，二氯甲烷 Conditions: a) R1B(OR) ₂ , Imes-HCl, Pd(OAc) ₂ , II Alkane/water; b) HATU, NH ₃ , DMF; c) N-iodosuccinimide, dichloromethane; d) VUB(OR) ₂ , Pd(PPh ₃ ) ₄ , Cs ₂ CO ₃ , 1, 4 -two Alkane, water; e) R ₂ Cl, TEA, dichloromethane (or) (R ₂ ) ₂ O, DMAP, dichloromethane

反應圖2代表製備根據式I與II中U為一鍵結與V為芳基或雜芳基之化合物之一般反應圖。反應圖2中，R1如上述定義，除非本文中另有說明。作為起始物之吲哚羧酸3係依反應圖1之說明製得。反應條件如上述反應圖之說明；然而，習此相關技藝之人士咸了解，可能在所採用之反應條件與/或試劑上進行某些修飾。 Reaction Scheme 2 represents a general reaction diagram for the preparation of compounds according to formula I and II wherein U is a linkage and V is an aryl or heteroaryl group. In Reaction Scheme 2, R1 is as defined above, unless otherwise stated herein. The ruthenium carboxylic acid 3 as a starting material was prepared as described in the reaction scheme of Fig. 1. The reaction conditions are as described in the above reaction scheme; however, it will be apparent to those skilled in the art that certain modifications may be made to the reaction conditions and/or reagents employed.

習此相關技藝之人士咸了解，若本文所述取代基無法與本文所說明合成法相容時，取代基可能需要使用對反應條件安定之合適保護基保護。保護基可在反應順序中合適時機脫除，產生所需中間物或目標化合物。合適保護基及不同取代基使用此等合適保護基進行保護與脫除保護之方法係習此相關技藝之人士習知者；其實例可參見T.Greene與P.Wuts之有機合成法之保護基(Protecting Groups in Chemical Synthesis)(第3版)，John Wiley & Sons，NY(1999)。有些例子中，可專一性選擇使用對所使用反應條件有反應性之取代基。在此等環境下，反應條件可轉化所選用之取代基形成另一種適用為中間化合物或目標化合物所需取代基之取代基。 It will be appreciated by those skilled in the art that if the substituents described herein are not compatible with the synthetic methods described herein, the substituents may require the use of suitable protecting groups for stability of the reaction conditions. The protecting group can be removed at a suitable time in the reaction sequence to produce the desired intermediate or target compound. Suitable protecting groups and different substituents for the protection and deprotection using such suitable protecting groups are well known to those skilled in the art; examples of which can be found in the protective groups of the organic synthesis of T. Greene and P. Wuts. ( Protected Groups in Chemical Synthesis) (3rd Edition), John Wiley & Sons, NY (1999). In some instances, it is possible to specifically select a substituent that is reactive toward the reaction conditions employed. Under such circumstances, the reaction conditions can convert the substituents selected to form another substituent suitable for use as an intermediate compound or a substituent required for the target compound.

使用方法Instructions

本發明化合物為IKK2之抑制劑。此等化合物適用於治療(至少部份)因IKK2(亦稱為IKKβ)活性不當所造成病變，如：類風濕關節炎、發炎性腸部疾病、氣喘與COPD(慢性阻塞性肺病)。"不當之IKK2活性"係指特定患者之任何IKK2活性偏離正常IKK2活性。不當之IKK2活性可能呈例如：活性異常提高或IKK2活性之時間點與/或控制偏差。此等不當活性可能因例如：蛋白質激酶過度表現或突變，造成活化作用不當或無法控制。因此，本發明另一方面係有關治療此等病變之方法。 The compounds of the invention are inhibitors of IKK2. These compounds are indicated for the treatment (at least in part) of lesions caused by inappropriate activity of IKK2 (also known as IKKβ), such as rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease). "Inappropriate IKK2 activity" means that any IKK2 activity in a particular patient deviates from normal IKK2 activity. Improper IKK2 activity may be, for example, an increase in activity or a time point and/or control bias in the activity of IKK2. Such inappropriate activity may be due to, for example, excessive expression or mutation of the protein kinase, resulting in improper or uncontrolled activation. Accordingly, another aspect of the invention relates to methods of treating such lesions.

此等病變包括發炎與組織修復病變，特定言之類風濕關節炎、發炎性腸部疾病、氣喘與COPD(慢性阻塞性肺病)；骨關節炎、骨質疏鬆症與纖維變性疾病；皮膚病，包括乾癬、異位性皮膚炎與紫外線(UV)所誘發皮膚傷害；自體免疫疾病，包括全身紅斑性狼瘡、多發性硬化、乾癬性關節炎、僵直性脊椎炎、組織與器官排斥、阿茲海默氏症、中風、動脈粥樣硬化、術後再狹窄、糖尿病、腎小球腎炎、癌症，包括霍金氏症、惡病質、與感染及某些病毒感染有關之發炎，包括後天免疫缺乏症候群(AIDS)、成人呼吸窘迫症候群與共濟失調-毛細血管擴張症(Ataxia Telangiestasia)。 These lesions include inflammation and tissue repair lesions, such as rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease); osteoarthritis, osteoporosis and fibrotic diseases; skin diseases, including dry 癣, atopic dermatitis and ultraviolet (UV)-induced skin damage; autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis, dry arthritis, ankylosing spondylitis, tissue and organ rejection, Azhai Mourn's disease, stroke, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, including Hodgkin's disease, cachexia, inflammation associated with infections and certain viral infections, including acquired immunodeficiency syndrome (AIDS) ), adult respiratory distress syndrome and ataxia - telangiectasia (Ataxia Telangiestasia).

本發明治療方法包括對有此需要之患者投與安全且有效量之根據式I-II化合物或其醫藥上可接受之鹽。本發明個別具體實施例包括治療如上述任一種疾病之方法，其包括對有此需要之患者投與安全且有效量之根據式I-II化合物或其醫藥上可接受之鹽。 The method of treatment of the present invention comprises administering to a patient in need thereof a safe and effective amount of a compound according to formula I-II or a pharmaceutically acceptable salt thereof. Specific embodiments of the invention include a method of treating a disease according to any of the above, which comprises administering to a patient in need thereof a safe and effective amount of a compound according to formula I-II or a pharmaceutically acceptable salt thereof.

本文在疾病中所提及"治療"係指：(1)緩和或預防病變或病變之一種或多種生物性表徵，(2)在造成或負責該病變之一連串生物反應中干擾(a)一個或多個點或(b)該病變之一種或多種生物性表徵，(3)減輕與病變有關之一種或多種症狀或效應，或(4)減緩病變或病變之一種或多種生物性表徵之發展。 Reference herein to "treatment" in a disease means: (1) mitigating or preventing one or more biological characterizations of a lesion or lesion, and (2) interfering with (a) one or a series of biological responses that cause or are responsible for the lesion. Multiple points or (b) one or more biological characterizations of the lesion, (3) alleviating one or more symptoms or effects associated with the lesion, or (4) slowing the progression of one or more biological characterizations of the lesion or lesion.

如上述，病變之"治療"包括預防病變。習此相關技藝之人士咸了解，"預防"並非絕對名詞。醫學上咸了解，"預防"係指預防性投與藥物，以實質上消除病變或其生物性表徵之可能性或嚴重性，或延緩此等病變或其生物性表徵發作。 As mentioned above, "treatment" of a lesion includes preventing a lesion. Those who learn this skill know that "prevention" is not an absolute noun. It is medically understood that "prevention" refers to the prophylactic administration of a drug to substantially eliminate the likelihood or severity of a lesion or its biological characterization, or to delay the onset of such lesion or its biological characterization.

本文在本發明化合物或其他醫藥活性劑所採用"安全且有效量"係指在完整之醫學判斷下，該化合物用量足以治療患者之病症，但仍夠低至足以避免嚴重副作用(合理之效益/危險比例)。化合物之安全且有效量將隨所選用特定化合物(例如：考量化合物之效力、有效性與半衰期)；所選用之投藥途徑；待治療之病變；所治療病變之嚴重性；所治療患者之體型、體重、與身體狀況；所治療患者之病史；治療期長短；併行療法之性質；所需之醫療效果；與類似因素變化，但照例仍需由習此相關技藝之人士決定。 As used herein, a "safe and effective amount" of a compound of the invention or other pharmaceutically active agent means that the compound is administered in an amount sufficient to treat the drug under complete medical judgment. The patient's condition, but still low enough to avoid serious side effects (reasonable benefit/risk ratio). A safe and effective amount of the compound will be chosen with the particular compound selected (eg, to determine the potency, effectiveness, and half-life of the compound); the route of administration selected; the condition to be treated; the severity of the condition being treated; the size of the patient being treated, Weight, physical condition; history of the patient being treated; length of treatment; nature of concurrent therapy; medical effects required; and similar factors, but as usual, still need to be determined by those skilled in the art.

本文所採用"患者"係指人類或其他動物。 As used herein, "patient" refers to a human or other animal.

本發明化合物可依任何合適之投藥途徑投藥，包括全身性或局部投藥。全身性投藥法包括經口投藥、非經腸式投藥、穿皮式投藥、經直腸投藥與經吸入投藥。非經腸式投藥法係指除了經腸式、穿皮式或吸入以外之投藥法，典型係經注射或輸液投藥。非經腸式投藥法包括靜脈內、肌內與皮下注射或輸液。吸入法係指不論經口或鼻通道吸入至患者肺部之投藥法。局部投藥法包括施藥至皮膚及眼內、耳部、陰道內與經鼻內投藥。 The compounds of the invention may be administered by any suitable route of administration, including systemic or topical administration. Systemic administration includes oral administration, parenteral administration, transdermal administration, rectal administration, and administration by inhalation. Parenteral administration refers to the administration of drugs other than enteral, transdermal or inhalation, typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injections or infusions. Inhalation is a method of administration that is inhaled into the lungs of a patient, either by the oral or nasal passages. Topical administration includes administration to the skin and eyes, ears, vagina, and intranasal administration.

本發明化合物可投藥一次或依據投藥療程投藥，其中係在不同時間點或一段時間內投與許多劑量。例如：一天可投與1、2、3或4次劑量。劑量可投藥到達到所需醫療效果為止或無限制維持所需醫療效果。本發明化合物之投藥療程依化合物之藥物動力學性質決定，如：吸收性、分佈性與半衰期，其可由習此相關技藝之人士決定。此外，合適之劑量療程，包括此等投藥療程之期限，係依習此相關技藝之人士之知識與經驗範圍內，由所治療之病變、所治療病變之嚴重性、所治療患者之年齡與身體狀況、所治療患者之病史、併行療法之性質、所需醫療效果，等等因素決定。習此相關技藝之人士亦咸了解，合適之投藥療程可能需要針對個別患者對投藥療程之反應或隨時間針對患者之個別需要變化來調整。 The compounds of the invention may be administered once or in accordance with a course of administration wherein a plurality of doses are administered at different time points or for a period of time. For example, one, two, three or four doses can be administered a day. The dose can be administered until the desired medical effect is achieved or the desired medical effect is maintained without limitation. The course of administration of a compound of the invention will depend on the pharmacokinetic properties of the compound, such as absorbency, distribution and half-life, as determined by those skilled in the art. In addition, the appropriate course of treatment, including the duration of such administration, is based on the knowledge and experience of those who follow the relevant skills, and the lesions treated and the lesions treated are severe. Sex, the age and physical condition of the patient being treated, the history of the patient being treated, the nature of the concurrent therapy, the medical effect required, and the like. Those skilled in the art will also appreciate that appropriate medication regimens may need to be tailored to the individual patient's response to the medication regimen or to individual changes in the patient's needs over time.

典型之每日療程可能隨所選用之特定投藥途徑變化。典型之每日口服劑量範圍為每公斤總體重0.001毫克至50毫克。 A typical daily course of treatment may vary depending on the particular route of administration chosen. Typical daily oral doses range from 0.001 mg to 50 mg per kg of total weight.

此外，本發明化合物可呈前藥投藥。本文所採用本發明化合物之"前藥"為化合物之功能衍生物，當投與患者時，最後會於活體內釋出本發明化合物。呈前藥投藥之本發明化合物可為習此相關技藝之人士提供下列一項或多項：(a)修飾化合物於活體內之作用起點；(b)修飾化合物於活體內之作用效期；(c)修飾化合物於活體內之運送與分佈；(d)修飾化合物於活體內之溶解度；與(e)克服化合物之副作用或其他困難。用於製備前藥之典型功能衍生物包括使之可於活體內經化學或酵素裂解之經修飾化合物。此等修飾法包括習此相關技藝之人士習知之磷酸酯、醯胺、酯類、硫酯類、碳酸酯與胺甲酸酯製法。 Furthermore, the compounds of the invention may be administered as prodrugs. As used herein, a "prodrug" of a compound of the invention is a functional derivative of a compound which, when administered to a patient, will eventually release the compound of the invention in vivo. The compound of the present invention administered as a prodrug may provide one or more of the following for those skilled in the art: (a) the starting point of action of the modified compound in vivo; (b) the effect of the modified compound in vivo; (c) Modifying the transport and distribution of the compound in vivo; (d) modifying the solubility of the compound in vivo; and (e) overcoming the side effects or other difficulties of the compound. Typical functional derivatives for the preparation of prodrugs include modified compounds which are capable of being chemically or enzymatically cleaved in vivo. Such modifications include those conventionally known to those skilled in the art of phosphates, guanamines, esters, thioesters, carbonates and urethanes.

本發明亦提供一種用於醫療之本發明化合物，特定言之用於治療由IKK2活性所媒介之病變。因此，本發明另一方面係有關以根據式I-II化合物或其醫藥上可接受之鹽於製備醫藥，供治療出現不當IKK2活性之特性之病變上之用途。 The invention also provides a compound of the invention for use in therapy, in particular for the treatment of a lesion mediated by IKK2 activity. Accordingly, another aspect of the invention relates to the use of a compound according to formula I-II or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a condition characterized by inappropriate IKK2 activity.

出現不當IKK2活性之特性且可抑制其蛋白質激酶IKK2之特定病變包括發炎與組織修復病變，特定言之類風濕關節炎、發炎性腸部疾病、氣喘與COPD(慢性阻塞性肺病)；骨關節炎、骨質疏鬆症與纖維變性疾病；皮膚病，包括乾癬、異位性皮膚炎與紫外線(UV)所誘發皮膚傷害；自體免疫疾病，包括全身紅斑性狼瘡、多發性硬化、乾癬性關節炎、僵直性脊椎炎、組織與器官排斥、阿茲海默氏症、中風、動脈粥樣硬化、術後再狹窄、糖尿病、腎小球腎炎、癌症，包括霍金氏症、惡病質、與感染及某些病毒感染有關之發炎，包括後天免疫缺乏症候群(AIDS)、成人呼吸窘迫症候群與共濟失調-毛細血管擴張症(Ataxia Telangiestasia)。 The presence of inappropriate IKK2 activity and inhibition of its specific protein kinase IKK2 include inflammation and tissue repair lesions, such as rheumatoid arthritis, inflammatory bowel disease, asthma and COPD (chronic obstructive pulmonary disease) Disease); osteoarthritis, osteoporosis and fibrotic diseases; skin diseases, including dry skin, atopic dermatitis and ultraviolet (UV)-induced skin damage; autoimmune diseases, including systemic lupus erythematosus, multiple sclerosis , dry arthritis, ankylosing spondylitis, tissue and organ rejection, Alzheimer's disease, stroke, atherosclerosis, postoperative restenosis, diabetes, glomerulonephritis, cancer, including Hawking's disease, cachexia Inflammation associated with infections and certain viral infections, including acquired immunodeficiency syndrome (AIDS), adult respiratory distress syndrome and ataxia - telangiectasia (Ataxia Telangiestasia).

組合物combination

本發明化合物通常(但不一定)先調配成醫療組合物後才投與患者。因此，本發明另一方面係有關一種包含本發明化合物與一種或多種醫藥上可接受之賦形劑之醫藥組合物。 The compounds of the invention are typically, but not necessarily, formulated into a medical composition prior to administration to a patient. Accordingly, another aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention and one or more pharmaceutically acceptable excipients.

本發明醫藥組合物可呈散裝型式製備及包裝，其中係萃取安全且有效量本發明化合物並使用如：粉末或糖漿投藥給患者。或者，本發明醫藥組合物可呈單位劑型製備及包裝，其中各分離之物理單位包含安全且有效量之本發明化合物。當製備單位劑型時，本發明醫藥組合物可包含例如：0.5毫克至1克，或1毫克至700毫克或5毫克至100毫克本發明化合物。 The pharmaceutical compositions of the present invention can be prepared and packaged in a bulk form wherein the compound of the invention is safely and effectively extracted and administered to a patient using, for example, a powder or syrup. Alternatively, the pharmaceutical compositions of the invention may be prepared and packaged in unit dosage form, wherein each separate physical unit comprises a safe and effective amount of a compound of the invention. When preparing a unit dosage form, the pharmaceutical compositions of the present invention may comprise, for example, from 0.5 mg to 1 gram, or from 1 mg to 700 mg or from 5 mg to 100 mg of the compound of the invention.

本發明醫藥組合物典型地包含一種本發明化合物。然而，某些具體實施例中，本發明醫藥組合物包含一種以上本發明化合物。例如：某些具體實施例中，本發明醫藥組合物包含兩種本發明化合物。此外，本發明醫藥組合物可視需要再包含一種或多種其他醫藥活性化合物。 The pharmaceutical compositions of the invention typically comprise a compound of the invention. However, in certain embodiments, the pharmaceutical compositions of the invention comprise more than one compound of the invention. For example, in certain embodiments, the pharmaceutical compositions of the invention Two compounds of the invention are included. In addition, the pharmaceutical compositions of the present invention may further comprise one or more additional pharmaceutically active compounds as needed.

本文所採用"醫藥上可接受之賦形劑"係指涉及指定之醫藥型式或一致性之醫藥上可接受之材料、組合物或媒劑。當混合時，各賦形劑必需可與醫藥組合物中其他成份相容，以避免本發明化合物投與患者時可能大幅降低效力之交互作用及醫藥上不可接受之醫藥組合物可能產生之交互作用。此外，各賦形劑當然必需具有足夠高純度來達成醫藥上可接受性。 As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, composition or vehicle that relates to a specified pharmaceutical form or consistency. When mixed, the excipients must be compatible with the other ingredients of the pharmaceutical compositions to avoid the potentially significant reduction in potency of the compounds of the invention when administered to a patient and the possible interaction of pharmaceutically unacceptable pharmaceutical compositions. . In addition, each excipient must of course have a sufficiently high purity to achieve pharmaceutically acceptable properties.

本發明化合物與醫藥上可接受之賦形劑(群)典型地係配合患者所需之投藥途徑調配成劑型。例如：劑型包括適合(1)經口投藥之劑型，如：錠劑、膠囊、膜衣錠、丸劑、糖錠、粉劑、糖漿、酏劑、懸浮液、溶液、乳液、藥包與扁囊錠；(2)非經腸式投藥之劑型，如：無菌溶液、懸浮液與供再組成之粉劑；(3)穿皮式投藥之劑型，如：穿皮式貼布；(4)經直腸投藥之劑型，如：栓劑；(5)經吸入投藥之劑型，如：氣霧劑、溶液與乾粉劑；與(6)局部投藥用劑型，如：乳霜、油膏、洗液、溶液、糊劑、噴液、泡沫劑與凝膠。 The compounds of the invention and the pharmaceutically acceptable excipients (groups) are typically formulated into a dosage form in accordance with the desired route of administration for the patient. For example, the dosage form includes a dosage form suitable for (1) oral administration, such as: tablets, capsules, film-coated tablets, pills, syrups, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and sachets. (2) dosage forms for parenteral administration, such as: sterile solutions, suspensions and powders for reconstitution; (3) dosage forms for transdermal administration, such as: wearing a skin patch; (4) transrectal administration Dosage forms, such as: suppositories; (5) dosage forms for administration by inhalation, such as: aerosols, solutions and dry powders; and (6) topical dosage forms, such as: creams, ointments, lotions, solutions, pastes Agents, sprays, foams and gels.

合適之醫藥上可接受之賦形劑將依所選用之特定劑型變化。此外，合適之醫藥上可接受之賦形劑可依其在組合物中之特定功能選擇。例如：某些醫藥上可接受之賦形劑可依據其促進製成均一單位劑型之能力選擇。某些醫藥上可接受之賦形劑可依據其促進製成安定單位劑型之能力選擇。某些醫藥上可接受之賦形劑可依據其一旦經患者服藥後，促進本發明化合物自一種器官或體內一部份攜帶或運送至另一種器官或體內另一部份之能力來選擇。某些醫藥上可接受之賦形劑可依據其加強患者適應性之能力選擇。 Suitable pharmaceutically acceptable excipients will vary depending upon the particular dosage form chosen. In addition, suitable pharmaceutically acceptable excipients can be selected based on their particular function in the composition. For example, certain pharmaceutically acceptable excipients may be selected based on their ability to promote a uniform unit dosage form. Certain pharmaceutically acceptable excipients may be selected based on their ability to facilitate the manufacture of a stable unit dosage form. Certain pharmaceutically acceptable excipients can be used to facilitate the carrying or delivery of a compound of the invention from one organ or part of the body to another organ upon administration by the patient. Or the ability to choose another part of the body. Certain pharmaceutically acceptable excipients can be selected based on their ability to enhance patient fitness.

合適之醫藥上可接受之賦形劑包括下列幾種賦形劑：稀釋劑、填料、結合劑、崩解劑、潤滑劑、滑動劑、製粒劑、包衣劑、濕化劑、溶劑、共溶劑、懸浮劑、乳化劑、甜味劑、調味劑、氣味遮敝劑、著色劑、抗結塊劑、保濕劑、螯合劑、增塑劑、黏度加強劑、抗氧化劑、防腐劑、安定劑、界面活性劑與緩衝劑。習此相關技藝之人士咸了解，某些醫藥上可接受之賦形劑可提供一種以上之功能，且亦可提供其他替代功能，端賴調配物中賦形劑含量及調配物中所包含其他成份而定。 Suitable pharmaceutically acceptable excipients include the following excipients: diluents, fillers, binders, disintegrants, lubricants, slip agents, granulating agents, coating agents, wetting agents, solvents, Cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, odor concealers, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity enhancers, antioxidants, preservatives, stability Agents, surfactants and buffers. It is understood by those skilled in the art that certain pharmaceutically acceptable excipients may provide more than one function and may also provide other alternative functions depending on the amount of excipients in the formulation and other inclusions in the formulation. Depending on the ingredients.

習此相關技藝之人士有知識及能力來選擇適用於本發明之適量之合適之醫藥上可接受之賦形劑。此外，習此相關技藝之人士可以參考許多說明醫藥上可接受之賦形劑且適用於選擇合適醫藥上可接受之賦形劑之資料來源。其實例包括雷氏醫藥學(Remington's Pharmaceutical Sciences)(出版公司：Mack Publishing Company)、醫藥添加物手冊(The Handbook of Pharmaceutical Additives)(出版公司：Gower Publishing Limited)與醫藥賦型劑手冊(The Handbook of Pharmaceutical Excipients)(出版公司：the American Pharmaceutical Association and the Pharmaceutical Press)。 The person skilled in the art has the knowledge and ability to select the appropriate amount of suitable pharmaceutically acceptable excipients suitable for use in the present invention. In addition, those skilled in the art can refer to a number of sources which describe pharmaceutically acceptable excipients and which are suitable for the selection of suitable pharmaceutically acceptable excipients. Examples thereof include Remington's Pharmaceutical Sciences (publishing company: Mack Publishing Company), The Handbook of Pharmaceutical Additives (Publishing Company: Gower Publishing Limited), and Handbook of Pharmaceutical Excipients ( The Handbook of Pharmaceutical Excipients) (publishing company: the American Pharmaceutical Association and the Pharmaceutical Press).

本發明醫藥組合物係採用習此相關技藝之人士習知之技術與方法製備。習此相關技藝之人士習知之有些方法已說明於雷氏醫藥學(Remington's Pharmaceutical Sciences)(出版公司：Mack Publishing Company)。 The pharmaceutical compositions of the present invention are prepared using techniques and methods well known to those skilled in the art. Some methods known to those skilled in the art have been described in Remington's Pharmaceutical Sciences (publishing company: Mack Publishing Company).

本發明一方面係有關一種固態口服劑型，如：包含安全且有效量之本發明化合物與稀釋劑或填料之錠劑或膠囊。合適之稀釋劑與填料包括乳糖、蔗糖、右旋糖、甘露糖醇、山梨糖醇、澱粉(例如：玉米澱粉、馬鈴薯澱粉與預糊化澱粉)、纖維素與其衍生物(例如：微晶纖維素)、硫酸鈣與二鹼價磷酸鈣。固態口服劑型可再包含一種結合劑。合適之結合劑包括澱粉(例如：玉米澱粉、馬鈴薯澱粉與預糊化澱粉)、明膠、金合歡膠、藻酸鈉、藻酸、黃耆膠、關華豆膠、聚乙烯吡咯烷酮及纖維素與其衍生物(例如：微晶纖維素)。固態口服劑型可另包含一種崩解劑。合適之崩解劑包括交聯聚乙烯吡咯烷酮、乙醇酸澱粉鈉、交聯羧甲基纖維素、藻酸與羧甲基纖維素鈉。固態口服劑型可另包含一種潤滑劑。合適之潤滑劑包括硬脂酸、硬脂酸鎂、硬脂酸鈣與滑石。 One aspect of the invention relates to a solid oral dosage form, such as a lozenge or capsule comprising a safe and effective amount of a compound of the invention and a diluent or filler. Suitable diluents and fillers include lactose, sucrose, dextrose, mannitol, sorbitol, starch (eg, corn starch, potato starch and pregelatinized starch), cellulose and its derivatives (eg, microcrystalline fibers) , calcium sulfate and dibasic calcium phosphate. The solid oral dosage form may further comprise a binding agent. Suitable binders include starch (eg, corn starch, potato starch and pregelatinized starch), gelatin, acacia gum, sodium alginate, alginic acid, tragacanth, Guanhua bean gum, polyvinylpyrrolidone and cellulose. Derivatives (for example: microcrystalline cellulose). The solid oral dosage form may additionally comprise a disintegrant. Suitable disintegrants include crosslinked polyvinylpyrrolidone, sodium starch glycolate, croscarmellose, alginic acid and sodium carboxymethylcellulose. The solid oral dosage form may additionally comprise a lubricant. Suitable lubricants include stearic acid, magnesium stearate, calcium stearate and talc.

若適當時，口服用單位劑量調配物可微包埋化。該組合物亦可製成長期或持續釋放，例如：利用聚合物、蠟等等物質包覆或包埋粒狀材料。 Oral dosage formulations for oral administration can be microencapsulated, if appropriate. The composition may also be formulated for prolonged or sustained release, for example by coating or embedding the particulate material with a polymer, wax or the like.

本發明化合物亦可使用可溶性聚合物作為針對標靶之藥物載劑，進行偶合。此等聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羥丙基甲基丙烯醯胺-苯酚、聚羥乙基天冬醯胺二苯酚或經棕櫚醯基取代之聚環氧乙烷聚離胺酸。此外，本發明化合物亦可與一類適用於控制釋放藥物之生物可降解性聚合物偶合，例如：聚乳酸、聚ε-己內酯、聚羥基丁酸、聚原酸酯類、聚縮醛類、聚二氫吡喃類、聚氰基丙烯酸酯類與水凝膠之交聯或兩性嵌段共聚物。 The compounds of the invention may also be coupled using a soluble polymer as the target drug carrier. Such polymers may include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamide diphenol or palmitoyl substituted polyethylene oxide. Acetylic acid. In addition, the compounds of the invention may also be coupled to a class of biodegradable polymers suitable for controlled release drugs, such as polylactic acid, polyε-caprolactone, polyhydroxybutyrate, Crosslinked or amphoteric block copolymers of polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and hydrogels.

本發明另一方面係有關一種液態口服劑型。口服液，如：溶液、糖漿與酏劑可製成單位劑型，使指定量中包含預定量之本發明化合物。糖漿製法可由本發明化合物溶於適當調味之水溶液中，而酏劑則係利用無毒性醇類媒劑製備。懸浮液調配法為使本發明化合物勻散在無毒性媒劑中。亦可添加溶解劑與乳化劑，如：乙氧基化異硬脂基醇類與聚氧乙烯山梨糖醇醚類，防腐劑、調味劑，如：薄荷油或天然甜味劑或糖精或其他人工甜味劑，等等。 Another aspect of the invention relates to a liquid oral dosage form. Oral solutions, such as solutions, syrups, and elixirs, can be presented in unit dosage form, such compositions, in a given amount, containing a predetermined amount of a compound of the invention. The syrup preparation process can be prepared by dissolving the compound of the present invention in a suitably flavored aqueous solution, while the elixirs are prepared using a non-toxic alcoholic vehicle. Suspension formulation is such that the compound of the invention is dispersed in a non-toxic vehicle. Solvents and emulsifiers may also be added, such as: ethoxylated isostearyl alcohols and polyoxyethylene sorbitol ethers, preservatives, flavorings such as peppermint oil or natural sweeteners or saccharin or other Artificial sweeteners, etc.

本發明另一方面係有關一種適合患者吸入投藥之劑型。例如：本發明化合物可呈乾粉劑、氣霧劑、懸浮液或溶液吸入肺部。 Another aspect of the invention relates to a dosage form suitable for inhalation administration to a patient. For example, a compound of the invention may be inhaled into the lungs as a dry powder, aerosol, suspension or solution.

經吸入傳送至肺部之乾粉劑典型地包含呈細粉狀之本發明化合物，及一種或多種細粉狀之醫藥上可接受之賦形劑。特別適合用於乾粉劑中之醫藥上可接受之賦形劑係習此相關技藝之人士習知者，且包括乳糖、澱粉、甘露糖醇、及單醣、雙醣與多醣。 Dry powders for delivery to the lungs by inhalation typically comprise a compound of the invention in the form of a fine powder, and one or more finely divided pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients which are particularly suitable for use in dry powders are well known to those skilled in the art and include lactose, starch, mannitol, and monosaccharides, disaccharides and polysaccharides.

乾粉劑可利用儲積式乾粉吸藥器(RDPI)投與患者，該吸藥器具有適合存放多劑量(未定量)乾粉狀醫藥之儲積槽。RDPI典型地包括自儲積槽量取各藥物劑量送至定點之裝置。例如：該定量裝置包括可自第一個位置取下之定量杯，其中可在杯內填裝自儲積槽送至第二個位置之藥物，在此提供藥物劑量給患者吸入。 Dry powders can be administered to a patient using a stored dry powder inhaler (RDPI) having a reservoir suitable for storing multiple doses (unquantified) of dry powdered medicine. The RDPI typically includes means for taking a dose of each drug from a reservoir to a fixed point. For example, the dosing device includes a dosing cup that can be removed from the first position, wherein the cup can be filled with the drug delivered from the accumulator to the second location where the drug dose is provided for inhalation by the patient.

或者，乾粉劑可呈膠囊型式(例如：明膠囊或塑膠膠囊)、卡管或發泡包，用於多劑量乾粉劑吸藥器(MDPI)。MDPI係一種在含(或攜帶)多重指定劑量(或其部份劑量)之藥物之多劑量包裝中包含藥物之吸藥器。當乾粉劑製成發泡包時，其包括包含粉劑型藥物之多重發泡包。發泡包典型排列成長方形，以方便釋放藥物。例如：發泡包通常可在盤形發泡包包裝上呈圓形排列，或發泡包可呈拉長形例如：包含長條或線帶。各膠囊、卡管或發泡包均可例如：包含20微克-10毫克本發明化合物。 Alternatively, the dry powder may be in the form of a capsule (eg, a gelatin capsule or a plastic capsule), a tube or a foaming pack for use in a multi-dose dry powder inhaler (MDPI). MDPI is an inhaler that contains a drug in a multi-dose package containing (or carrying) multiple specified doses (or portions thereof) of the drug. When the dry powder is made into a foaming pack, it includes a multiple foaming pack containing a powder type medicine. The foaming packs are typically arranged in a rectangular shape to facilitate release of the drug. For example, the foam packs may generally be arranged in a circular shape on the disc-shaped foam pack, or the foam pack may be elongated, for example, comprising a strip or a strip. Each capsule, cartridge or foaming pack may, for example, comprise from 20 micrograms to 10 milligrams of a compound of the invention.

氣霧劑製法可由本發明化合物懸浮或溶解於液化推進劑中。合適之推進劑包括鹵化碳、烴類與其他液化氣體。代表性推進劑包括：三氯氟甲烷(推進劑11)、二氯氟甲烷(推進劑12)、二氯四氟乙烷(推進劑114)、四氟乙烷(HFA-134a)、1,1-二氟乙烷(HFA-152a)、二氟甲烷(HFA-32)、五氟乙烷(HFA-12)、七氟丙烷(HFA-227a)、全氟丙烷、全氟丁烷、全氟戊烷、丁烷、異丁烷與戊烷。包含本發明化合物之氣霧劑典型地係利用定劑量吸藥器(MDI)投與患者。此等裝置係習此相關技藝之人士習知者。 Aerosol formulations can be suspended or dissolved in a liquefied propellant from a compound of the invention. Suitable propellants include halocarbons, hydrocarbons and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1, 1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane Alkanes, butanes, isobutanes and pentanes. Aerosols comprising a compound of the invention are typically administered to a patient using a fixed dose inhaler (MDI). These devices are known to those skilled in the art.

氣霧劑可包含典型用於MDI之其他醫藥上可接受之賦形劑，如：界面活性劑、潤滑劑、共溶劑與其他賦形劑，以改善調配物之物理安定性、改善開關性能、改善溶解性或改善口味。 Aerosols may contain other pharmaceutically acceptable excipients typically used in MDI, such as surfactants, lubricants, cosolvents, and other excipients to improve the physical stability of the formulation, improve switching performance, Improve solubility or improve taste.

包含本發明化合物之懸浮液與溶液亦可利用霧化器投與患者。霧化器所使用之溶劑或懸浮劑可為任何醫藥上可接受之液體，如：水、食鹽水溶液、醇類或二醇類，例如：乙醇、異丙醇、甘油、丙二醇、聚乙二醇，等等或其混合物。食鹽溶液所使用之鹽在投藥後所展現之活性很低或幾乎沒有。此目的可使用有機鹽類，如：鹼金屬或銨鹵素鹽類，例如：氯化鈉、氯化鉀，或有機鹽類，如：有機酸，例如：抗壞血酸、檸檬酸、乙酸、酒石酸，等等之如：鉀、鈉與銨鹽類。 Suspensions and solutions comprising a compound of the invention may also be administered to a patient using a nebulizer. The solvent or suspending agent used in the nebulizer can be any pharmaceutically acceptable liquid A body such as water, an aqueous salt solution, an alcohol or a glycol such as ethanol, isopropanol, glycerol, propylene glycol, polyethylene glycol, or the like or a mixture thereof. The salt used in the salt solution exhibits little or no activity after administration. Organic salts such as alkali metal or ammonium halogen salts such as sodium chloride, potassium chloride or organic salts such as organic acids such as ascorbic acid, citric acid, acetic acid, tartaric acid, etc. may be used for this purpose. Such as: potassium, sodium and ammonium salts.

懸浮液或溶液中可添加其他醫藥上可接受之賦形劑。本發明化合物可因添加無機酸，例如：鹽酸、硝酸、硫酸與/或磷酸；有機酸，例如：抗壞血酸、檸檬酸、乙酸與酒石酸，等等，錯化劑，如：EDTA或檸檬酸與其鹽類；或抗氧化劑，如：維生素E或抗壞血酸而安定化。此等物質可單獨使用或共同用於安定本發明化合物。可添加防腐劑，如：氯苄烷銨或苯甲酸與其鹽類。可特別添加界面活性劑來改善懸浮液之物理安定性。其包括卵磷脂、二辛基磺基琥珀酸二鈉、油酸與山梨糖醇酐酯類。 Other pharmaceutically acceptable excipients may be added to the suspension or solution. The compound of the present invention may be added with a mineral acid such as hydrochloric acid, nitric acid, sulfuric acid and/or phosphoric acid; an organic acid such as ascorbic acid, citric acid, acetic acid and tartaric acid, etc., a modifier such as EDTA or citric acid and its salt Class; or an antioxidant, such as: vitamin E or ascorbic acid to stabilize. These materials may be used alone or together to stabilize the compounds of the invention. Preservatives such as benzalkonium chloride or benzoic acid and its salts may be added. Surfactants may be specially added to improve the physical stability of the suspension. It includes lecithin, disodium dioctylsulfosuccinate, oleic acid and sorbitan esters.

適合穿皮式投藥之醫藥組合物可呈獨立之貼布，以留在患者表皮上長期密切接觸。例如：貼布中之活性成份可利用一般說明於Pharmaceutical Research,3(6),318(1986)之離子電滲透法傳送。 Pharmaceutical compositions suitable for transdermal administration may be presented as separate patches to remain in close contact with the patient's epidermis for prolonged periods of time. For example, the active ingredient in the patch can be delivered by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).

局部投藥用醫藥組合物可調配成油膏、乳霜、懸浮液、洗液、粉劑、溶液、糊劑、凝膠、噴液、氣霧劑或油劑。 The topical pharmaceutical composition can be formulated into an ointment, a cream, a suspension, a lotion, a powder, a solution, a paste, a gel, a spray, an aerosol or an oil.

處理眼睛或其他體外組織，例如：口與皮膚時，組合物可呈局部用油膏或乳霜施用。當調配成油膏時，本發明化合物可使用與石蠟或水相容之油膏基質調配。或者，本發明化合物可使用水包油性或油包水性基質調配成乳霜。 When treating the eye or other in vitro tissue, such as the mouth and skin, the composition can be applied topically with an ointment or cream. When formulated into a grease, the present invention The material can be formulated using a paraffin or water compatible ointment base. Alternatively, the compounds of the invention may be formulated as a cream using an oil-in-water or oil-in-water base.

適合鼻內投藥之醫藥組合物中之載劑為固體，包括粒度範圍在20至500微米之粗粒粉劑，其係由粉劑之容器接近鼻子經由鼻道快速吸入投藥。以液體為載劑形成鼻噴液或鼻滴液投藥之合適組合物包括本發明化合物之水性或油性溶液。 The carrier in a pharmaceutical composition suitable for intranasal administration is a solid, including a coarse granule having a particle size ranging from 20 to 500 microns, which is administered by a container of powder close to the nose via a nasal passage. Suitable compositions for the administration of nasal sprays or nasal drops with a liquid as a carrier include aqueous or oily solutions of the compounds of the invention.

適合非經腸式投藥之醫藥組合物包括水性與非水性注射液，其可包含抗氧化劑、緩衝劑、制菌劑及使調配物與接受投藥者之血液呈等張性之溶質；與水性與非水性無菌懸浮液，其可包括懸浮劑與增稠劑。組合物可製成單位劑量或多重劑量容器，例如：密封安瓶與小瓶，且可保存在冷凍乾燥狀態，僅需在臨用前添加無菌液態載體(例如：注射用水)。臨用前方組成之注射用溶液與懸浮液可由無菌粉劑、粒劑與錠劑製備。 Pharmaceutical compositions suitable for parenteral administration include aqueous and non-aqueous injections, which may contain antioxidants, buffers, bacteriostatic agents, and solutes which render the formulation is isotonic with the blood of the recipient; and aqueous and non-aqueous Sterile suspensions, which may include suspending agents and thickening agents. The composition can be formulated as a unit dose or multiple dose container, for example, a sealed ampoule and vial, and can be stored in a freeze-dried state, with the addition of a sterile liquid carrier (eg, water for injection) just prior to use. The solutions and suspensions for injection which are used in the front may be prepared from sterile powders, granules and lozenges.

實例Instance

下列實例說明本發明。此等實例無意限制本發明範圍，但可指示習此相關技藝之人士製備及使用本發明化合物、組合物之方法。本發明特別具體實施例中，習此相關技藝之人士咸了解，可在不偏離本發明本質與範圍下進行不同變化與修飾。 The following examples illustrate the invention. The examples are not intended to limit the scope of the invention, but may be directed to a person skilled in the art to make and use the compounds and compositions of the invention. In the present invention, it will be apparent to those skilled in the art that various changes and modifications can be made without departing from the spirit and scope of the invention.

所有提及之醚均指乙醚；鹽水係指飽和NaCl水溶液。除非本文中另有說明，否則所有溫度均以℃(攝氏溫度)表示。所有反應均於惰性蒙氣及室溫下進行，除非本文中另有說明。 All ethers referred to are diethyl ether; brine means saturated aqueous NaCl solution. Unless otherwise stated herein, all temperatures are in °C (Celsius) Show. All reactions were carried out under inert atmosphere and at room temperature unless otherwise stated herein.

¹H NMR光譜係於Brucker DPX400、Brucker DPX250、Brucker AC400或Varian Inova 400上記錄。化學遷移係以百萬分之一(ppm，δ單位)表示。以分裂型態說明表觀多峰性，且以s(單峰)、d(雙峰)、t(參峰)、q(四峰)、quint(五峰)、m(多峰)、br(寬峰)表示。 ^{The 1} H NMR spectrum was recorded on a Brucker DPX400, Brucker DPX250, Brucker AC400 or Varian Inova 400. Chemical migration is expressed in parts per million (ppm, δ units). The apparent multimodality is illustrated by the splitting pattern, and is s (single peak), d (double peak), t (parallel peak), q (four peaks), quint (five peaks), m (multiple peaks), br ( Wide peak).

低解析質譜(MS)係於JOEL JMS-AX505HA、JOEL SX-102或SCIEX-APIiii分光計上測定；LC-MS係於Waters ZQ或PE Sciex Single Quadrupole LC/MS API-150分光計上測定。 Low-resolution mass spectrometry (MS) was determined on a JOEL JMS-AX505HA, JOEL SX-102 or SCIEX-APIiii spectrometer; LC-MS was determined on a Waters ZQ or PE Sciex Single Quadrupole LC/MS API-150 spectrometer.

製備性HPLC係指該方法中之材料係利用高效液相層析法，於HPLC ABZ+5μm管柱(10 cm x 21.2 mm i.d.)上，使用0.1%甲酸之水溶液與0.05%之乙腈溶液，利用流速8 ml/min之梯度溶離液純化，並於UV 254nm下檢測。 Preparative HPLC means that the material in the method is utilized by high performance liquid chromatography on HPLC ABZ + 5 μm column (10 cm x 21.2 mm id) using 0.1% formic acid in water and 0.05% acetonitrile solution. The gradient was eluted with a flow rate of 8 ml/min and detected at UV 254 nm.

除非本文中另有說明，否則矽石急驟管柱層析法與組合急驟層析法(Combiflash)係指材料使用Redisep^TM預填充矽石急驟管柱，於ISCO sq16x機器上，使用指定溶劑系統純化。 Herein, unless otherwise indicated, Silica flash column chromatography in combination with flash chromatography (Combiflash) ^(TM) refers to materials prefilled chert flash a Redisep column, on the ISCO sq16x machine, purified using the indicated solvent system .

逆向HPLC方法A係指該方法中之材料係利用高效液相層析法，於HPLC S-5μm管柱(75×30 mm i.d.)上，使用指定溶劑系統進行梯度溶離，並於UV 254 nm下檢測。 Reverse HPLC method A means that the material in the method is subjected to high-performance liquid chromatography on a HPLC S-5 μm column (75 × 30 mm id) using a specified solvent system for gradient elution at UV 254 nm. Detection.

逆向HPLC方法B係指該方法中之材料係利用高效液相層析法，於HPLC Luna C18(2)100A管柱(50x21.2 mm i.d.)上，使用指定溶劑系統進行梯度溶離，並於UV 254 nm下檢測。 Reverse HPLC Method B means that the material in this method is subjected to high performance liquid chromatography on HPLC Luna C18(2) 100A column (50 x 21.2 mm). On i.d.), gradient elution was performed using the indicated solvent system and tested at UV 254 nm.

PE Sciex Single Quadrupole LC/MS API-150之LC-MS實驗條件： LC-MS experimental conditions for PE Sciex Single Quadrupole LC/MS API-150:

液相層析法： Liquid chromatography:

系統：Shimadzu LC系統，使用SCL-10A控制器與雙重UV檢測器 System: Shimadzu LC system with SCL-10A controller and dual UV detector

自動取樣器：具有Valco六孔注射器之Leap CTC Autosampler: Leap CTC with Valco six-hole syringe

管柱：Aquasil/Aquasil(C18 40x1 mm) Column: Aquasil/Aquasil (C18 40x1 mm)

注射體積(微升)：2.0 Injection volume (microliter): 2.0

溶劑A：H2O,0.02% TFA Solvent A: H2O, 0.02% TFA

溶劑B：MeCN,0.018% TFA Solvent B: MeCN, 0.018% TFA

梯度：線性 Gradient: linear

A頻道：UV 214 nm Channel A: UV 214 nm

B頻道：ELS Channel B: ELS

質譜：PE Sciex Single Quadrupole LC/MS API-150 Mass Spectrometry: PE Sciex Single Quadrupole LC/MS API-150

極性：正 Polarity: positive

取得模式：圖形 Get mode: graphics

中間物Intermediate

中間物1：2,3-二氫-1H-吲哚-1-羧酸1,1-二甲基乙基酯Intermediate 1: 1,1-dimethylethyl ester of 2,3-dihydro-1H-indole-1-carboxylic acid

取吲哚啉(10克，84毫莫耳)溶於四氫呋喃(100毫升)，添加碳酸二-第三丁酯(22克，0.1莫耳)。於室溫與惰性氮蒙氣下攪拌混合物16小時。真空排除四氫呋喃，粗產物經真空蒸餾純化，產生標題化合物(15.1克)之透明淺粉紅色油狀物，靜置時即結晶(溫度：160-162℃，壓力1-0.1 mm Hg)。 The porphyrin (10 g, 84 mmol) was dissolved in tetrahydrofuran (100 mL) and di-t-butyl carbonate (22 g, 0.1 mol) was added. The mixture was stirred at room temperature under an inert nitrogen atmosphere for 16 hours. The tetrahydrofuran was removed in vacuo, and the crude material was purified mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj

1H NMR(400 MHz,DMSO-D6)δ ppm 1.50(s,9 H)3.04(t,J=8.7 Hz,2 H)3.89(t,J=8.8 Hz,2 H)6.91(td,J=7.3,0.8 Hz,1 H)7.13(t,J=7.5 Hz,1 H)7.18(d,J=7.3 Hz,1 H)7.5-7.8(bs,1 H)r.t.3.44分鐘。 1H NMR (400 MHz, DMSO-D6) δ ppm 1.50 (s , 9 H) 3.04 (t, J = 8.7 Hz, 2 H) 3.89 (t, J = 8.8 Hz, 2 H) 6.91 (td, J = 7.3 , 0.8 Hz, 1 H) 7.13 (t, J = 7.5 Hz, 1 H) 7.18 (d, J = 7.3 Hz, 1 H) 7.5-7.8 (bs, 1 H) rt 3.44 min.

中間物2：2,3-二氫-1H-吲哚-1,7-二羧酸1-(1,1-二甲基乙基)7-甲基酯Intermediate 2: 2,3-dihydro-1H-indole-1,7-dicarboxylic acid 1-(1,1-dimethylethyl) 7-methyl ester

取2,3-二氫-1H-吲哚-1-羧酸1,1-二甲基乙基酯(5克，22.8毫莫耳)與N,N,N',N'-四甲基-1,2-乙二胺(4.6毫升，30.5毫莫耳)溶於無水乙醚(300毫升)，於乙腈/乾冰浴中冷卻至-78℃。以10分鐘時間滴加第二丁基鋰(1.4M環己烷溶液，17.6毫升，24.6毫莫耳)，於此溫度下攪拌90分鐘。添加氯甲酸甲酯(8.8毫升，10.8克，0.1莫耳)至混合物中，使反應以1小時時間回升至室溫。小心加水至混合物中，分離有機層，再以水洗滌3次。有機層經硫酸鎂脫水，過濾與真空濃縮，產生標題化合物(4.91克)之膠質狀黃色固體。 Take 1,1-dimethylethyl 2,3-dihydro-1H-indole-1-carboxylate (5 g, 22.8 mmol) with N , N , N ', N '-tetramethyl -1,2-Ethylenediamine (4.6 mL, 30.5 mmol) was dissolved in dry diethyl ether (300 mL) and cooled to -78 ° C in acetonitrile / dry ice bath. Dibutyllithium (1.4 M cyclohexane solution, 17.6 ml, 24.6 mmol) was added dropwise over 10 minutes and stirred at this temperature for 90 minutes. Methyl chloroformate (8.8 ml, 10.8 g, 0.1 mol) was added to the mixture and the reaction was allowed to warm to room temperature over 1 hour. Water was carefully added to the mixture, and the organic layer was separated and washed with water three times. The org. <RTI ID=0.0></RTI><RTIID=0.0>

1H NMR(400 MHz,DMSO-D6)δ ppm 1.44(s,9 H)3.06(t,J=8.2 Hz,2 H)3.69(s,3 H)4.02(t,J=8.3 Hz,2 H)7.06(t,J=7.5 Hz,1 H)7.35(d,J=7.5 Hz,1 H)7.39(dd,J=7.4,1.1 Hz,1 H)MS m/z 278(M+1)⁺ r.t.3.18分鐘。 1H NMR (400 MHz, DMSO- D6) δ ppm 1.44 (s, 9 H) 3.06 (t, J = 8.2 Hz, 2 H) 3.69 (s, 3 H) 4.02 (t, J = 8.3 Hz, 2 H) 7.06(t, J = 7.5 Hz, 1 H) 7.35 (d, J = 7.5 Hz, 1 H) 7.39 (dd, J = 7.4, 1.1 Hz, 1 H) MS m/z 278 (M+1) ⁺ rt3 .18 minutes.

中間物3：5-溴-2,3-二氫-1H-吲哚-1,7-二羧酸1-(1,1-二甲基乙基)7-甲基酯Intermediate 3: 5-(1,1-dimethylethyl) 7-methyl ester of 5-bromo-2,3-dihydro-1H-indole-1,7-dicarboxylate

取2,3-二氫-1H-吲哚-1,7-二羧酸1-(1,1-二甲基乙基)7-甲基酯(3.1克，11.2毫莫耳)與N-溴琥珀醯亞胺(2.0克，11.2毫莫耳)溶於無水二氯甲烷(100毫升)，於室溫與氮蒙氣下攪拌16小時。反應分溶於氫氧化鈉溶液(2 M)，分離，再以氫氧化鈉溶液洗滌。有機層經硫酸鎂脫水，與真空濃縮，產生標題化合物之膠質狀紅色固體(3.55克)。 2,3-Dihydro-1H-indole-1,7-dicarboxylic acid 1-(1,1-dimethylethyl) 7-methyl ester (3.1 g, 11.2 mmol) and N- Bromoammonium imine (2.0 g, 11.2 mmol) was dissolved in anhydrous dichloromethane (100 mL) and stirred at room temperature under nitrogen atmosphere for 16 h. The reaction was dissolved in sodium hydroxide solution (2 M), separated, and washed with sodium hydroxide. The organic layer was dried with EtOAc (EtOAc m.

1H NMR(400 MHz,DMSO-D6)δ ppm 1.41(s,9 H)3.09(t,J=8.3 Hz,2 H)3.70(s,3 H)4.02(t,J=8.3 Hz,2 H)7.46(s,1 H)7.60(s,1 H)MS m/z 356/358(1：1比例)(M+1)⁺ r.t.3.52分鐘。 1H NMR (400 MHz, DMSO- D6) δ ppm 1.41 (s, 9 H) 3.09 (t, J = 8.3 Hz, 2 H) 3.70 (s, 3 H) 4.02 (t, J = 8.3 Hz, 2 H) 7.46 (s, 1 H) 7.60 (s, 1 H) MS m/z 356/358 (1:1 ratio) (M+1) ⁺ rt 3.52 min.

中間物4：5-溴-2.3-二氫-1H-吲哚-7-羧酸甲酯Intermediate 4: methyl 5-bromo-2.3-dihydro-1H-indole-7-carboxylate

取5-溴-2,3-二氫-1H-吲哚-1,7-二羧酸1-(1,1-二甲基乙基)7-甲基酯(9克，25毫莫耳)溶於三氟乙酸(6毫升)，於室溫下攪拌16小時。添加二氯甲烷與氫氧化鈉溶液(2M)，有機層經氫氧化鈉溶液洗滌至水層pH>7。有機層經真空濃縮，產生標題化合物之褐色固體(6.5克)。 Take 5-bromo-2,3-dihydro-1H-indole-1,7-dicarboxylic acid 1-(1,1-dimethylethyl) 7-methyl ester (9 g, 25 mmol) Dissolved in trifluoroacetic acid (6 ml) and stirred at room temperature for 16 h. Dichloromethane and sodium hydroxide solution (2M) were added and the organic layer was washed with sodium hydroxide solution until the aqueous layer pH > The organic layer was concentrated in vacuo to give crystallite crystallite

1H NMR(400 MHz,DMSO-D6)δ ppm 2.99(t,J=8.5 Hz,2 H)3.61(t,J=8.4 Hz,2 H)3.78(s,3 H)6.72(s,1 H)7.28(d,J=1 Hz,1 H)7.46(d,J=2 Hz,1 H)MS m/z 256/258(1：1比例)(M+1)⁺ r.t.3.32分鐘。 1H NMR (400 MHz, DMSO-D6) δ ppm 2.99 (t , J = 8.5 Hz, 2 H) 3.61 (t, J = 8.4 Hz, 2 H) 3.78 (s, 3 H) 6.72 (s, 1 H) 7.28 (d, J =1 Hz, 1 H) 7.46 (d, J = 2 Hz, 1 H) MS m/z 256/258 (1:1 ratio) (M+1) ⁺ rt 3.32 min.

中間物5：5-溴-1H-吲哚-7-羧酸甲酯Intermediate 5: methyl 5-bromo-1H-indole-7-carboxylate

取5-溴-2,3-二氫-1H-吲哚-7-羧酸甲酯(6.5克，25毫莫耳)溶於四氫呋喃(100毫升)。添加活化之二氧化錳(粒度5微米，22克，0.25莫耳)。混合物於室溫下攪拌16小時。再加22克活化二氧化錳，攪拌反應96小時。反應經寅氏鹽過濾，與真空濃縮，產生標題化合物(5.1克)之米色固體。 Methyl 5-bromo-2,3-dihydro-1H-indole-7-carboxylate (6.5 g, 25 mmol) was dissolved in tetrahydrofuran (100 mL). Activated manganese dioxide (particle size 5 microns, 22 grams, 0.25 moles) was added. The mixture was stirred at room temperature for 16 hours. An additional 22 grams of activated manganese dioxide was added and the reaction was stirred for 96 hours. The reaction was filtered with EtOAc (EtOAc)EtOAc.

1H NMR(400 MHz,DMSO-D6)δ ppm 3.94(s,3 H)6.58(d,J=3 Hz,1 H)7.48(d,J=3 Hz,1 H)7.8(d,J=2 Hz,1 H)8.07(d,J=1.8 Hz,1 H)11.39(bs,1 H)MS m/z 252/254(1：1比例)(M-1)r.t.3.41分鐘。 1H NMR (400 MHz, DMSO-D6) δ ppm 3.94 (s , 3 H) 6.58 (d, J = 3 Hz, 1 H) 7.48 (d, J = 3 Hz, 1 H) 7.8 (d, J = 2 Hz, 1 H) 8.07 (d, J = 1.8 Hz, 1 H) 11.39 (bs, 1 H) MS m/z 252/254 (1:1 ratio) (M-1) rt 3.41 min.

中間物6：5-溴-1H-吲哚-7-羧酸Intermediate 6: 5-bromo-1H-indole-7-carboxylic acid

取5-溴-1H-吲哚-7-羧酸酯(5克，19.7毫莫耳)溶於甲醇(200毫升)，添加含氫氧化鋰(0.99克，41毫莫耳)之水溶液(10毫升)。混合物回流加熱50小時。真空排除甲醇，殘質經鹽酸水溶液(2M)稀釋。濾出所得沉澱，以加熱之真空槍乾燥，產生標題化合物之米色固體(4.7克)。 5-Bromo-1H-indole-7-carboxylate (5 g, 19.7 mmol) was dissolved in methanol (200 mL), and an aqueous solution containing lithium hydroxide (0.99 g, 41 mmol) was added. ML). The mixture was heated under reflux for 50 hours. Methanol was removed in vacuo and the residue was diluted with aqueous hydrochloric acid (2M). The resulting precipitate was filtered, dried with EtOAc EtOAc EtOAc

1H NMR(400 MHz,DMSO-D6)δ ppm 6.54(dd,J=2.0,3.2 Hz,1 H)7.42(t,J=2.8 Hz,1 H)7.77(d,J=2 Hz,1 H)8.03(d,J=1.8 Hz,1 H)11.27(s,1 H)13.1-13.7(bs,1 H)MS m/z 238/240(1：1比例)(M-1)r.t.3.41分鐘。 1H NMR (400 MHz, DMSO-D6) δ ppm 6.54 (dd , J = 2.0, 3.2 Hz, 1 H) 7.42 (t, J = 2.8 Hz, 1 H) 7.77 (d, J = 2 Hz, 1 H) 8.03 (d, J = 1.8 Hz, 1 H) 11.27 (s, 1 H) 13.1-13.7 (bs, 1 H) MS m/z 238/240 (1:1 ratio) (M-1) rt 3.41 min .

中間物7：5-溴-1H-吲哚-7-羧醯胺Intermediate 7: 5-bromo-1 H -吲哚-7-carboxyguanamine

於室溫下，在含5-溴-1H-吲哚-7-羧酸(10.0克，42毫莫耳)之CH₂Cl₂(100毫升)溶液中添加EDC(9.66克，50.4毫莫耳)、HOBt(6.81克，50.4毫莫耳)與NH₃(2.0M MeOH溶液，84毫升，168毫莫耳)。反應混合物於室溫下攪拌16小時。蒸發溶劑，殘質分溶於乙酸乙酯(100毫升)與水(100毫升)之間。水層經乙酸乙酯(100毫升x2)萃取，合併之有機相經MgSO₄脫水，濃縮，產生粗產物(10克，98%)。此粗產物未再純化即直接用於下一個步驟。 EDC (9.66 g, 50.4 mmol) was added to a solution of 5-bromo-1 H -indole-7-carboxylic acid (10.0 g, 42 mmol) in CH ₂ Cl ₂ (100 mL). ear), HOBt (6.81 g, 50.4 mmol) and NH ₃ (2.0M MeOH solution, 84 ml, 168 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated, and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml). Aqueous layer with ethyl acetate (100 mL x2). The combined organic phases were dried over MgSO ₄ the dehydration, concentrated to yield the crude product (10 g, 98%). This crude product was used directly in the next step without further purification.

LC/MS：m/z 240.0(M+H)，1.95分鐘。 LC/MS: m/z.

中間物8：4-[7-(胺基羰基)-5-溴-1H-吲哚-3-基]-3,6-二氫-1(2H)-吡啶羧酸1,1-二甲基乙基酯Intermediate 8: 4-[7-(Aminocarbonyl)-5-bromo-1 H -indol-3-yl]-3,6-dihydro-1(2 H )-pyridinecarboxylic acid 1,1- Dimethyl ethyl ester

在含5-溴-1H-吲哚-7-羧醯胺(10克，41.84毫莫耳)之甲醇(5毫升)溶液中添加4-氧代-1-哌啶羧酸1,1-二甲基乙基酯(684毫克，3.42毫莫耳)與甲醇鈉(0.5 M THF溶液，13.7毫升，6.84毫莫耳)。反應混合物於回流溫度下攪拌16小時。減壓蒸發所有溶劑。殘質分溶於乙酸乙酯(100毫升)與水(100毫升)之間。合併之有機相經MgSO₄脫水，減壓濃縮，經急驟管柱層析法純化(乙酸乙酯/己烷，1/1)，產生所需產物(7.4克，43%)。 Add 4-oxo-1-piperidinecarboxylic acid 1,1-di in a solution of 5-bromo-1H-indole-7-carboxamide (10 g, 41.84 mmol) in methanol (5 mL) Methyl ethyl ester (684 mg, 3.42 mmol) with sodium methoxide (0.5 M in THF, 13.7 mL, 6.84 mmol). The reaction mixture was stirred at reflux temperature for 16 hours. All solvents were evaporated under reduced pressure. The residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The combined organic phase was anhydrified on MgSO _4, concentrated under reduced pressure, purified by flash column chromatography (ethyl acetate / hexane 1/1) to yield the desired product (7.4 g, 43%).

LC/MS：m/z 420.0(M+H)，2.35分鐘。 LC/MS: m/z 42.

中間物9：4-[7-(胺基羰基)-5-溴-1H-吲哚-3-基]-1-哌啶羧酸1,1-二甲基乙基酯Intermediate 9: 4-[7-(Aminocarbonyl)-5-bromo-1 H -indol-3-yl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester

在含4-[7-(胺基羰基)-5-溴-1H-吲哚-3-基]-3,6-二氫-1(2H)-吡啶羧酸1,1-二甲基乙基酯(7.41克，17.64毫莫耳)之乙醇(600毫升)溶液中添加氧化鉑(200毫克，5%)。反應混合物於H₂蒙氣下氫化16小時。所得混合物經寅氏鹽過濾，濾液濃縮。所得殘質經急驟管柱層析法純化(乙酸乙酯/己烷，1：4至2：1 v/v)，產生所需產物(3.6克，48%)。 In the presence of 4-[7-(aminocarbonyl)-5-bromo-1H-indol-3-yl]-3,6-dihydro-1(2H)-pyridinecarboxylic acid 1,1-dimethylethyl Platinum oxide (200 mg, 5%) was added to a solution of the base ester (7.41 g, 17.64 mmol) in ethanol (600 ml). H ₂ 16 The reaction mixture was hydrogenated gas mask hours. The resulting mixture was filtered over EtOAc (EtOAc). The residue was purified by flash column chromatography (EtOAc / EtOAcjjjjjj

LC-MS：m/z 422.0(M+H)，2.25分鐘。 LC-MS: m/z 4221.

中間物10：5-溴-3-(4-哌啶基)-1H-吲哚-7-羧醯胺Intermediate 10: 5-bromo-3-(4-piperidinyl)-1 H -indole-7-carboxamide

在含4-[7-(胺基羰基)-5-溴-1H-吲哚-3-基]-1-哌啶羧酸1,1-二甲基乙基酯(1.56克，3.7毫莫耳)之甲醇(10毫升)溶液中添加HCl之二烷溶液(4M，35.5毫升)。反應混合物於室溫下攪拌2小時。減壓蒸發溶劑，所得殘質分溶於乙酸乙酯(50毫升)與5%NaOH水溶液(50毫升)之間。水層經乙酸乙酯(2x50毫升)洗滌，合併之有機相經MgSO₄脫水，減壓濃縮，產生所需產物(685毫克，58%)，其未再純化即用於下一個步驟。 1,1-dimethylethyl 4-(7-(aminocarbonyl)-5-bromo-1 H -indol-3-yl]-1-piperidinecarboxylate (1.56 g, 3.7 m) Add HCl to the solution of methanol (10 ml) Alkane solution (4M, 35.5 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated <RTI ID=0.0> Aqueous layer with ethyl acetate (2x50 mL), the combined organic phase was anhydrified on MgSO _4, and concentrated under reduced pressure to yield the desired product (685 mg, 58%), which was used further without purification to the next step.

LC-MS：m/z 322.0(M+H)，1.45分鐘。 LC-MS: m/z 3221.

中間物11：5-溴-3-[1-(乙磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Intermediate 11: 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide

滴加乙磺醯氯(4.5毫升，47.4毫莫耳)至0℃(槽溫)下含5-溴-3-(4-哌啶基)-1H-吲哚-7-羧醯胺鹽酸鹽(8.49克，23.7毫莫耳)與三乙胺(13.2毫升，94.7毫莫耳)之DMF(80毫升)溶液中。反應混合物於0℃下攪拌45分鐘。倒至2：1 EtOAc/H₂O混合物(300毫升)中。濾出所得沉澱，以EtOAc(2 x 50毫升)洗滌，置於一旁。分離EtOAc/H₂O雙層，水層經EtOAc(2 x 100毫升)萃取。合併之有機層經飽和NaCl(1 x 100毫升)洗滌，脫水(MgSO₄)，過濾，減壓濃縮。粗產物與如上述單離之沉澱物合併，以MeOH(1 x 10毫升)洗滌，產生8.19克標題化合物(83%)。 Ethyl sulfonium chloride (4.5 ml, 47.4 mmol) was added dropwise to 5-bromo-3-(4-piperidinyl)-1H-indole-7-carboxamide hydrochloride at 0 ° C (tank temperature) Salt (8.49 g, 23.7 mmol) with triethylamine (13.2 mL, 94.7 mmol) in DMF (80 mL). The reaction mixture was stirred at 0 ° C for 45 minutes. Down to _2: 1 EtOAc / H 2 O mixture (300 ml). The resulting precipitate was filtered, washed with EtOAc (2 <RTI ID=0.0> The EtOAc/H ₂ O. The combined organic layers with saturated NaCl (1 x 100 mL), dehydration (MgSO _4), filtered, and concentrated under reduced pressure. The crude product was combined with EtOAc (EtOAc m.

或者，標題化合物可依下列方法製備： Alternatively, the title compound can be prepared as follows:

於0℃下，在含5-溴-3-(4-哌啶基)-1H-吲哚-7-羧醯胺(900毫克，2.8毫莫耳)之CH₂Cl₂(100毫升)溶液中添加乙磺醯氯(0.8毫克，8.4毫莫耳)與三乙胺(1.6毫升，11.2毫莫耳)。反應混合物於0℃下攪拌30分鐘。然後使混合物分溶於CH₂Cl₂與水之間。水相經CH₂Cl₂(50毫升x2)萃取，合併之有機相經MgSO₄脫水，減壓濃縮。所得殘質經固相萃取法，於500毫克胺基丙基管柱(International Sorbent Technologies)上，使用氯仿(30毫升x 2)與乙酸乙酯(50毫升)溶離純化，產生800毫克標題化合物(69%)。 a solution of CH ₂ Cl ₂ (100 ml) containing 5-bromo-3-(4-piperidinyl)-1H-indole-7-carboxamide (900 mg, 2.8 mmol) at 0 °C Ethyl sulfonium chloride (0.8 mg, 8.4 mmol) was added with triethylamine (1.6 ml, 11.2 mmol). The reaction mixture was stirred at 0 ° C for 30 minutes. And then the mixture was partitioned between CH _₂ Cl ₂ was dissolved in water. The aqueous phase was extracted with CH _₂ Cl ₂ (50 mL X2), the combined organic phase was anhydrified on MgSO _4, and concentrated under reduced pressure. The resulting residue was purified by EtOAc (EtOAc) elut elut elut elut elut elut 69%).

LC/MS：m/z 414.0(M+H)，2.2分鐘。 LC/MS: m/z 414.0 (M+H)

中間物12：3-[1-(乙基磺醯基)-4-哌啶基1-5-[3-(羥基甲基)苯基]-1H-吲哚-7-羧醯胺Intermediate 12: 3-[1-(ethylsulfonyl)-4-piperidinyl1-5-[3-(hydroxymethyl)phenyl]-1 H -indole-7-carboxamide

在含5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(20.0毫克，0.048毫莫耳)、K₃PO₄(21.0毫克，0.096毫莫耳)與[3-(羥基甲基)苯基]二羥硼酸(30.0毫克，0.193毫莫耳)之二烷/H₂O(2毫升/0.7毫升)溶液中通入氬氣5分鐘後，添加Pd(PPh₃)₄(5.0毫克，0.0048毫莫耳)。反應混合物於微波反應器(Smith synthesizer)中，於160℃下加熱20分鐘。蒸發溶劑，殘質分溶於乙酸乙酯與水之間。有機層經鹽水(10毫升)洗滌，脫水(MgSO₄)，濃縮，及經逆向HPLC方法A純化(水/CH₃CN，0.1%TFA10-90%)，產生標題化合物(9.7毫克，46%)。 In the presence of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (20.0 mg, 0.048 mmol), K ₃ PO ₄ (21.0 mg, 0.096 mmol) and [3-(hydroxymethyl)phenyl]dihydroxyboric acid (30.0 mg, 0.193 mmol) After argon gas was introduced into the alkane/H ₂ O (2 ml / 0.7 ml) solution for 5 minutes, Pd(PPh ₃ ) ₄ (5.0 mg, 0.0048 mmol) was added. The reaction mixture was heated in a microwave reactor (Smith synthesizer) at 160 ° C for 20 minutes. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was with brine (10 mL), dehydrated (MgSO _4), concentrated, and purified by reverse HPLC method A (water _{/ CH 3 CN, 0.1% TFA10-90} %), the title compound (9.7 mg, 46%) .

1H NMR(400 MHz,DMSO-D6)δ ppm 1.25(t,J=7.2 Hz,3H),1.65(m,2H),2.02(m,2H),2.99(m,7H),3.71(m,2H),7.16(s,1H),7.42(m,3H),7.77(m,2H),8.02(m,2H),8.22(m,1H),10.91(s,1H)。 1H NMR (400 MHz, DMSO-D6) δ ppm 1.25 (t, J = 7.2 Hz, 3H), 1.65 (m, 2H), 2.02 (m, 2H), 2.99 (m, 7H), 3.71 (m, 2H) ), 7.16 (s, 1H), 7.42 (m, 3H), 7.77 (m, 2H), 8.02 (m, 2H), 8.22 (m, 1H), 10.91 (s, 1H).

LC/MS：m/z 442.4(M+H)，r.t：1.73分鐘。 </RTI> <RTI ID=0.0></RTI></RTI>

中間物13：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺Intermediate 13: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -indole-7-carboxamide

於周溫下，在含3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(羥基甲基)苯基]-1H-吲哚-7-羧醯胺(52.0毫克，0.120毫莫耳)之THF(10毫升)溶液中添加MnO₂(360.0毫克，3.5毫莫耳)。所得懸浮液攪拌一夜，經寅氏鹽過濾，固體經THF(3X10毫升)潤洗。濾液濃縮，產生標題化合物(51.0毫克，98%)，其未再純化即用於下一個步驟。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(hydroxymethyl)phenyl]-1 H -吲哚-7-carboxylate at weekly temperature Amides (52.0 mg, 0.120 mmol) of THF (10 mL) solution was added MnO ₂ (360.0 mg, 3.5 mmol). The resulting suspension was stirred overnight, filtered over EtOAc (EtOAc)EtOAc. The filtrate was concentrated to give the title compound (jjjjjjj

LC/MS：m/z 440.4(M+H)，r.t：1.97分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

中間物14：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(羥基甲基)苯基]-1H-吲哚-7-羧醯胺Intermediate 14: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(hydroxymethyl)phenyl]-1 H -indole-7-carboxamide

在含5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(20.0毫克，0.048毫莫耳)、K₃PO₄(21.0毫克，0.096毫莫耳)與[4-(羥基甲基)苯基]二羥硼酸(30.0毫克，0.193毫莫耳)之二烷/H₂O(2毫升/0.7毫升)溶液中通入氬氣5分鐘後，添加Pd(PPh₃)₄(5.0毫克，0.0048毫莫耳)。反應混合物於微波反應器(Smith synthesizer)中，於160℃下加熱20分鐘。蒸發溶劑，殘質分溶於乙酸乙酯與水之間。有機層經鹽水(10毫升)洗滌，脫水(MgSO₄)，過濾，濃縮，經逆向 HPLC方法A純化(水/CH₃CN，0.1% TFA 10-90%)，產生標題化合物(6.4毫克，30%)。 In the presence of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (20.0 mg, 0.048 mmol), K ₃ PO ₄ (21.0 mg, 0.096 mmol) and [4-(hydroxymethyl)phenyl]dihydroxyboric acid (30.0 mg, 0.193 mmol) After argon gas was introduced into the alkane/H ₂ O (2 ml / 0.7 ml) solution for 5 minutes, Pd(PPh ₃ ) ₄ (5.0 mg, 0.0048 mmol) was added. The reaction mixture was heated in a microwave reactor (Smith synthesizer) at 160 ° C for 20 minutes. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was with brine (10 mL), dehydrated (MgSO _4), filtered, concentrated and purified by reverse HPLC method A (water _{/ CH 3 CN, 0.1% TFA} 10-90%), the title compound (6.4 mg, 30 %).

LC/MS：m/z 442.4(M+H)，r.t：1.78分鐘。 </RTI> <RTI ID=0.0></RTI></RTI>

中間物15：3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺Intermediate 15: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -indole-7-carboxamide

於周溫下，在含3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(羥基甲基)苯基]-1H-吲哚-7-羧醯胺(25毫克，0.058毫莫耳)之THF(5毫升)溶液中添加MnO₂(160.0毫克，1.73毫莫耳)。所得懸浮液攪拌一夜。經寅氏鹽過濾，固體經THF(3X10毫升)潤洗。濾液濃縮，產生標題化合物(15毫克，58%)，其未再純化即用於下一個步驟。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(hydroxymethyl)phenyl]-1 H -吲哚-7-carboxylate at weekly temperature Amides (25 mg, 0.058 mmol) of THF (5 mL) was added a solution of MnO ₂ (160.0 mg, 1.73 mmol). The resulting suspension was stirred overnight. Filter through guanidine salt and rinse the solid with THF (3×10 mL). The filtrate was concentrated to give the title compound (15 mg, 58%).

LC/MS：m/z 440.4(M+H)，r.t：2.02分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

中間物16：3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺Intermediate 16: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-1 H -吲哚-7-carboxyguanamine

取含5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(1.0克，2.42毫莫耳)、雙(四甲基乙二醯)乙硼烷(2.45克，9.66毫莫耳)與碳酸鉀(2.10克，21.8毫莫耳)之DME(15.0毫升)溶液脫氣5分鐘後，添加Pd₂Cl₂(dppf)。混合物於微波爐中，在130℃下加熱11000秒。反應混合物經EtOAc(300毫升)與H₂O(100毫升)稀釋，過濾固體。有機層經H₂O(3 x 80毫升)與鹽水洗滌。有機層經MgSO₄脫水，濃縮。添加DCM(40毫升)，以排除任何副產物，產生2.4克標題化合物。 Take 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (1.0 g, 2.42 mmol), double (four After degassing a solution of methyl ethyl hydrazine) diborane (2.45 g, 9.66 mmol) with potassium carbonate (2.10 g, 21.8 mmol) in DME (15.0 mL) for 5 min, Pd ₂ Cl ₂ (dppf) ). The mixture was heated in a microwave oven at 130 ° C for 11,000 seconds. The reaction mixture was diluted with EtOAc (300 mL) and H ₂ O (100 ml), the solid was filtered. The organic layer was dried over H ₂ O (3 x 80 mL) and washed with brine. The organic layer was anhydrified on MgSO _4, and concentrated. DCM (40 mL) was added to remove any of the sub-products to yield 2.4 g of the title compound.

LC/MS：m/z 462.3(M+H)，r.t：2.03分鐘。 </RTI> <RTI ID=0.0></RTI></RTI>

中間物17：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-2-噻吩基)-1H-吲哚-7-羧醯胺Intermediate 17: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-2-thienyl)-1 H -indole-7-carboxamide

在含5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(200毫克，0.49毫莫耳)之二烷(4.5毫升)與H2O(1.5毫升)溶液中添加[5-(羥基甲基)-2-噻吩基]二羥硼酸(232毫克，1.47毫莫耳)、碳酸鉀(406毫克，2.94毫莫耳)與肆(三苯基膦)鈀(0)(57毫克，0.049毫莫耳)。反應於微波爐中，於150℃下進行20分鐘。以EtOAc/H₂O處理水層後，產生447毫克3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(羥基甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺。 In the presence of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxamide (200 mg, 0.49 mmol) Add [5-(hydroxymethyl)-2-thienyl]dihydroxyboronic acid (232 mg, 1.47 mmol) and potassium carbonate (406 mg, 2.94 mmol) to a solution of alkane (4.5 mL) and H.sub.2 (1.5 mL). Ear) with hydrazine (triphenylphosphine) palladium (0) (57 mg, 0.049 mmol). The reaction was carried out in a microwave oven at 150 ° C for 20 minutes. After in EtOAc / H ₂ O aqueous layer treated to produce 447 mg of 3- [1- (ethyl-sulfo acyl) -4-piperidinyl] -5- [5- (hydroxymethyl) -2-thienyl] -1 H -吲哚-7-carboxyguanamine.

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(羥基甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺(200毫克，0.46毫莫耳)之THF(5.0毫升)溶液中添加MnO₂(1.21克，13.9毫莫耳)。混合物於室溫下攪拌3小時。經寅氏鹽過濾反應混合物，產生100毫克標題化合物(48.8%) Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(hydroxymethyl)-2-thienyl]-1 H -indole-7-carboxamide MnO ₂ (1.21 g, 13.9 mmol) was added to a solution of (200 mg, 0.46 mmol) in THF (5.0 mL). The mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered <RTI ID=0.0>

LC/MS：m/z 446.2(M+H)，r.t：2.27分鐘。 </RTI> <RTI ID=0.0></RTI></RTI>

中間物18：3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基-2-噻吩基)-1H-吲哚-7-羧醯胺Intermediate 18: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylindol-2-thienyl)-1 H -indole-7-carboxamide

於0℃下，在含3-噻吩甲醛(3.0克，26.8毫莫耳)之DCM(54毫升)溶液中添加三氯化鋁(8.37克，63毫莫耳)。加熱反應至回流，滴加溴(1.6毫升，30.28毫莫耳)。添加後，於回流下攪拌反應混合物4小時。冷卻至至室溫後，添加冷H₂O(100毫升)，以DCM(2 x 100毫升)萃取。合併之有機層經NaHCO3洗滌及乾燥。經急驟層析法純化，產生3.62克5-溴-3-噻吩甲醛(71%)。 Aluminum trichloride (8.37 g, 63 mmol) was added to a solution of 3-thiophenecarboxaldehyde (3.0 g, 26.8 mmol) in DCM (EtOAc). The reaction was heated to reflux and bromo (1.6 mL, 30.28 m.). After the addition, the reaction mixture was stirred under reflux for 4 hours. To cool to room temperature, was added cold H ₂ O (100 mL), (2 x 100 mL), extracted with DCM. The combined organic layers were washed and dried over NaHCO3. Purification by flash chromatography gave 3.62 g of 5-bromo-3-thiophenecarbaldehyde (71%).

在含5-溴-3-噻吩甲醛(250毫克，1.29毫莫耳)之二烷(4.5毫升)與H₂O(1.5毫升)溶液中添加3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(200毫克，0.43毫莫耳)、碳酸鉀(250毫克，2.58毫莫耳)與肆(三苯基膦)鈀(0)(56毫克，0.049毫莫耳)。反應於微波爐中，於150℃下進行20分鐘。然後以EtOAc與H₂O處理，得到粗產物。以MeOH(10毫升)處理，過濾固體，並收集，產生310毫克所需之標題化合物。 In the presence of 5-bromo-3-thiophenecarboxaldehyde (250 mg, 1.29 mmol) Add 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl) to a solution of alkane (4.5 mL) and H ₂ O (1.5 mL) -1,3,2-dioxaborolan-2-yl)-1 H -indole-7-carboxamide (200 mg, 0.43 mmol), potassium carbonate (250 mg, 2.58 mmol) With hydrazine (triphenylphosphine) palladium (0) (56 mg, 0.049 mmol). The reaction was carried out in a microwave oven at 150 ° C for 20 minutes. Then EtOAc and H ₂ O to give the crude product. Treated with MeOH (10 mL).

LC/MS：m/z 446.4(M+H)，r.t：1.94分鐘。 </RTI> <RTI ID=0.0></RTI>

中間物19：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺Intermediate 19: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide

在含4-溴-2-噻吩甲醛(1.0克，4.48毫莫耳)之DME(16毫升)溶液中添加雙(四甲基乙二醯)乙硼烷(1.48克，5.82毫莫耳)、KOAc(1.14克，5.11毫莫耳)與Pd₂Cl₂(dppf)(106毫克，.448毫莫耳)。反應於微波爐中，於150℃下進行20分鐘。濃縮溶劑，使用EtOAc與H₂O處理水相。化合物經急驟層析法，使用己烷與EtOAc純化，產生1.8克4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-2-噻吩甲醛。 Add bis(tetramethylglyoxime) diborane (1.48 g, 5.82 mmol) to a solution of 4-bromo-2-thiophenecarboxaldehyde (1.0 g, 4.48 mmol) in DME (16 mL). KOAc (1.14 g, 5.11 mmol) and Pd ₂ Cl ₂ (dppf) (106 mg, .448 mmol). The reaction was carried out in a microwave oven at 150 ° C for 20 minutes. The solvent was concentrated, using EtOAc and treated with H ₂ O water. The compound was purified by flash chromatography using hexanes eluting with EtOAc to yield <RTI ID=0.> - Thiophenecarboxaldehyde.

在含5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(909毫克，2.2毫莫耳)之二烷(7.5毫升)與H₂O(2.5毫升)溶液中添加4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-2-噻吩甲醛(1.57克，6.6毫莫耳)、碳酸鉀(1.82克，13.2毫莫耳)與肆(三苯基膦)鈀(0)(30毫克，.22毫莫耳)。反應於微波爐中，於150℃下加熱20分鐘。混合物濃縮至乾。添加EtOAc(50毫升)至殘質中，以鹽水洗滌。過濾並收集水與有機層之間所形成沉澱之褐色固體，產生874毫克標題化合物(89%)。 In the presence of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxamide (909 mg, 2.2 mmol) Add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- to a solution of alkane (7.5 mL) and H ₂ O (2.5 mL) Thiophenecarboxaldehyde (1.57 g, 6.6 mmol), potassium carbonate (1.82 g, 13.2 mmol) and hydrazine (triphenylphosphine) palladium (0) (30 mg, .22 mmol). The reaction was heated in a microwave oven at 150 ° C for 20 minutes. The mixture was concentrated to dryness. EtOAc (50 mL) was added to a residue and washed with brine. The brown solid which precipitated between the water and the organic layer was filtered and collected to give 874 mg of the title compound (89%).

LC/MS：m/z 446.4(M+H)，r.t：1.93分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

中間物20：5-溴異吲哚啉Intermediate 20: 5-bromoisoporphyrin

在加裝添加漏斗及CaCl₂乾燥管之乾燥之50毫升雙頸圓底燒瓶中添加2.0克(13.6毫莫耳)酞醯亞胺。燒瓶於鹽/冰浴中冷卻至0℃。在持續攪拌下慢慢添加含濃硫酸與發煙硝酸之冰冷混合物(1：1 v/v，8毫升)。混合物於0℃下攪拌30分鐘，攪拌1小時使之慢慢回升至室溫。反應混合物倒至冰中。所得固體產物過濾及乾燥，產生1.6克(61.3%)5-硝基-1H-異吲哚-1,3(2H)-二酮之黃色固體。 2.0 g (13.6 mmol) of the imine was added to a dry 50 ml two-necked round bottom flask equipped with a addition funnel and a CaCl ₂ drying tube. The flask was cooled to 0 ° C in a salt / ice bath. An ice-cold mixture (1:1 v/v, 8 ml) containing concentrated sulfuric acid and fuming nitric acid was slowly added with continuous stirring. The mixture was stirred at 0 ° C for 30 minutes and stirred for 1 hour to slowly warm to room temperature. The reaction mixture was poured into ice. The solid product obtained was filtered and dried to give 1.6 g (yield: 61.3%) of 5-nitro- 1H -isoindole-1,3( 2H )-dione as a yellow solid.

在含5-硝基-1H-異吲哚-1,3(2H)-二酮(1.0克，5.2毫莫耳)之無水THF(15毫升)溶液中添加10% Pd/C(0.2克)。混合物於30-40psi下氫化17小時。濾出觸媒，濾液真空蒸發，產生0.5克(59.3%)5-胺基-1H-異吲哚-1,3(2H)-二酮之黃色固體。 Add 10% Pd/C (0.2) to a solution of 5-nitro-1 H -isoindole-1,3( 2H )-dione (1.0 g, 5.2 mmol) in dry THF (15 mL) Gram). The mixture was hydrogenated at 30-40 psi for 17 hours. Catalyst was filtered off, filtrate was evaporated, yielding 0.5 g (59.3%) of 5-amino -1 H - isoindole -1,3 (2 H) - dione of yellow solid.

於0℃下，在攪拌之含5-胺基-1H-異吲哚-1,3(2H)-二酮(1.0克，6.2毫莫耳)之硫酸溶液(2毫升濃H₂SO₄含於7.5毫升H₂O)中滴加冰冷之亞硝酸鈉溶液(0.8克含於2毫升H₂O中)。於0℃下攪拌45分鐘後，於相同溫度下添加CuBr(3.4克，23.7毫莫耳)與HBr[48%](13.6毫升，4vol.w.r.t.CuBr)。所得混合物於80℃下攪拌8小時後，倒至碎冰中。過濾固體，以冰冷水洗滌，徹底乾燥，產生0.6克(43.0%)5-溴-1H-異吲哚-1,3(2H)-二酮之褐色固體。 A solution of 5-amino-1 H -isoindole-1,3( 2H )-dione (1.0 g, 6.2 mmol) in sulfuric acid at 0 ° C (2 mL of concentrated H ₂ SO) _{4 An} ice-cold sodium nitrite solution (0.8 g in 2 ml of H ₂ O) was added dropwise to 7.5 ml of H ₂ O). After stirring at 0 ° C for 45 minutes, CuBr (3.4 g, 23.7 mmol) and HBr [48%] (13.6 mL, 4 vol. wrt CuBr) were added at the same temperature. The resulting mixture was stirred at 80 ° C for 8 hours and then poured into crushed ice. The solid was filtered, washed with ice cold water and dried thoroughly to give < RTI ID=0.0&gt ;>

在加裝回流冷凝器與添加漏斗之乾燥之500毫升三頸燒瓶中添加含BH₃-THF(160毫升)之無水THF(50毫升)溶液。混合物冷卻至0℃。在此冷卻溶液中慢慢添加含5-溴-1H-異吲哚-1,3(2H)-二酮(8.0克，35.4毫莫耳)之無水THF(100毫升)溶液，使之回升至室溫。於室溫下10分鐘後，混合物回流16小時。反應混合物冷卻至0℃，以甲醇中止反應(注意：會出現激烈冒泡)。添加20-30毫升2N HCL並回流混合物1小時。冷卻混合物，以NaOH溶液鹼化，以乙酸乙酯萃取。合併之有機萃液經水、飽和NaCl溶液洗滌，經Na₂SO₄脫水與真空濃縮。在含粗產物之MeOH(150毫升)中添加Et₃N(12毫升)與二碳酸二-第三丁酯(13.8克，63.23毫莫耳)，於室溫下攪拌16小時。反應混合物真空濃縮。粗產物經CH₂Cl₂(200毫升)稀釋，以水、飽和NaCl溶液洗滌，及經Na₂SO₄脫水。粗產物經管柱層析法，使用20%乙酸乙酯之己烷溶液為溶離液純化，產生無色固體。於室溫下添加二烷-HCl，攪拌10分鐘，過濾所得固體與乾燥，產生3.0克(42.8%)5-溴異吲哚啉鹽酸鹽之灰色固體。 Containing added BH ₃ -THF (160 ml) in dry THF (50 ml) and add 500 ml three-necked flask and dried in the funnel of the installation of a reflux condenser. The mixture was cooled to 0 °C. A solution of 5-bromo-1 H -isoindole-1,3( 2H )-dione (8.0 g, 35.4 mmol) in anhydrous THF (100 ml) was slowly added to the cooled solution. Rise back to room temperature. After 10 minutes at room temperature, the mixture was refluxed for 16 hours. The reaction mixture was cooled to 0 ° C and quenched with methanol (Note: intense bubbling occurred). 20-30 ml of 2N HCL was added and the mixture was refluxed for 1 hour. The mixture was cooled, basified with NaOH solution and extracted with ethyl acetate. The combined organic extracts was washed with water, saturated NaCl solution, dehydrated over Na ₂ SO ₄ and concentrated in vacuo. Et ₃ N (12 ml) and di-tert-butyl dicarbonate (13.8 g, 63.23 mmol) were added to MeOH (150 mL). The reaction mixture was concentrated in vacuo. The crude product was diluted with CH _₂ Cl ₂ (200 mL), washed with water, saturated NaCl solution, and dehydrated over Na ₂ SO _4. The crude product was purified by column chromatography eluting with 20%EtOAcEtOAc Add two at room temperature The alkane-HCl was stirred for 10 min and the resulting solid was filtered and dried to give <RTI ID=0.0>>

中間物21：5-溴-3-(4-哌啶基)-1H-吲哚-7-羧醯胺鹽酸鹽Intermediate 21: 5-bromo-3-(4-piperidinyl)-1 H -indole-7-carboxamide hydrochloride

添加4M HCl之二烷溶液(194毫升)至含4-[7-(胺基羰基)-5-溴-1H-吲哚-3-基]-1-哌啶羧酸1,1-二甲基乙基酯(10 克，23.7毫莫耳)之甲醇(50毫升)溶液中。反應混合物於室溫下攪拌4小時，減壓蒸發溶劑，產生標題化合物(9.5克)，其未再純化即用於下一個步驟。 Add 4M HCl II Alkane solution (194 ml) to 1,1-dimethylethyl 4-(7-(aminocarbonyl)-5-bromo-1 H -indol-3-yl]-1-piperidinecarboxylate (10 g, 23.7 mmol) in methanol (50 mL). The reaction mixture was stirred with EtOAc EtOAc m.

LC-MS：m/z 322.4(M+H)，1.40分鐘。 LC-MS: m/z 3221.

中間物22：5-溴-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺Intermediate 22: 5-bromo-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1 H -indole-7-carboxamide

於0℃下添加三乙胺(2.6毫升，18.7毫莫耳)至含5-溴-3-(4-哌啶基)-1H-吲哚-7-羧醯胺鹽酸鹽之DMF(15毫升)溶液中。混合物於室溫下攪拌10分鐘，添加2-丙磺醯氯(1.04毫升，9.32毫莫耳)。續攪拌30分鐘，反應混合物經1：1 EtOAc/H₂O(200毫升)稀釋。分層，水層經EtOAc(2 x 50毫升)萃取。合併之有機層經飽和NaCl(1 x 100毫升)洗滌，脫水(MgSO₄)，減壓濃縮。粗產物經MeOH(2 x 10毫升)洗滌，產生標題化合物(1.5克，75%)。 Add triethylamine (2.6 ml, 18.7 mmol) to DMF containing 5-bromo-3-(4-piperidinyl)-1 H -indole-7-carboxamide hydrochloride at 0 ° C ( 15 ml) in solution. The mixture was stirred at room temperature for 10 minutes and 2-propanesulfonium chloride (1.04 mL, 9.32 mmol). Stirring was continued for 30 minutes, the reaction mixture was _{1: 1 EtOAc / H 2 O (} 200 mL). The layers were separated and the aqueous extracted with EtOAc EtOAc. The combined organic layers with saturated NaCl (1 x 100 mL), dehydration (MgSO _4), concentrated under reduced pressure. The crude product was purified with EtOAc EtOAc EtOAc

LC/MS：m/z 427.8(M+H)，1.98分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

中間物23：5-(5-甲醯基-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺Intermediate 23: 5-(5-Mercapto-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1 H -indole -7-carboxyguanamine

用於製備標題化合物之二羥硼酸酯係依據下列製程，分成6等份製備：在含4-溴-2-噻吩甲醛(1.0克，4.48毫莫耳)之DME(20毫升)溶液中添加雙(四甲基乙二醯)乙硼烷(1.48克，5.82毫莫耳)、KOAc(1.14克，5.11毫莫耳)與Pd₂Cl₂(dppf)(106毫克，0.448毫莫耳)。反應於Smith微波爐中，於150℃下進行20分鐘。集合6次反應，減壓濃縮。殘質溶於EtOAc(200毫升)與H₂O(50毫升)。分層，有機層經飽和NaCl(1 x 50毫升)洗滌，脫水(Na₂SO₄)，與減壓濃縮。粗產物經急驟層析法，使用己烷/EtOAc溶離純化，產生4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-2-噻吩甲醛(5克，78%)。 The dihydroxyborate used to prepare the title compound was prepared in 6 aliquots according to the following procedure: in a solution of 4-bromo-2-thiophenecarboxaldehyde (1.0 g, 4.48 mmol) in DME (20 mL) Bis(tetramethylglyoxime) diborane (1.48 g, 5.82 mmol), KOAc (1.14 g, 5.11 mmol) and Pd ₂ Cl ₂ (dppf) (106 mg, 0.448 mmol). The reaction was carried out in a Smith microwave oven at 150 ° C for 20 minutes. The reaction was concentrated 6 times and concentrated under reduced pressure. The residue was dissolved in EtOAc (200 mL) and H ₂ O (50 mL). The layers were separated organic layer with saturated NaCl (1 x 50 mL), dehydration (Na ₂ SO _4), and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with hexane /EtOAc to afford 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2 - Thiophenecarboxaldehyde (5 g, 78%).

取含5-溴-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺(428毫克，1毫莫耳)、4-(4,4,5,5-四甲基-1,3,2- 二氧硼戊環-2-基)-2-噻吩甲醛(960毫克，4毫莫耳)、Cs₂CO₃(800毫克，2.46毫莫耳)與Pd(PPh₃)₄(100毫克，0.0865毫莫耳)之溶液於Smith微波爐中，於160℃下加熱20分鐘。反應混合物過濾與減壓濃縮。粗產物經MeOH(1 x 5毫升)洗滌，產生標題化合物(395毫克，86%)。 Take 5-bromo-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1 H -indole-7-carboxamide (428 mg, 1 mmol) Ear), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-thiophenecarboxaldehyde (960 mg, 4 mmol), Cs ₂ CO ₃ (800 mg, 2.46 mmol) and Pd(PPh ₃ ) ₄ (100 mg, 0.0865 mmol) solution were heated in a Smith microwave oven at 160 ° C for 20 minutes. The reaction mixture was filtered and concentrated under reduced pressure. The crude product was purified with EtOAc EtOAc EtOAc

LC/MS：m/z 460.4(M+H)，1.98分鐘。 LC/MS: m/z 460.4 (M+H)

實例Instance

實例1：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(1-哌啶基甲基)苯基]-1H-吲哚-7-羧醯胺Example 1: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperidinylmethyl)phenyl]-1 H -indole-7-carboxylate Guanamine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(15.0毫克，0.034毫莫耳)之DCM(2毫升)溶液中添加哌啶(4.0微升，0.04毫莫耳)。於周溫下攪拌反應溶液1小時後，添加NaBH(OAc)₃(23.0毫克，0.109毫莫耳)。所得混合物於周溫下攪拌一夜後，減壓排除溶劑。所得殘質溶於1.2毫升DMSO，濾出所有未溶解之固體。此含粗產物之DMSO溶液經逆向HPLC純化(H₂O/CH₃CN，0.1% TFA 10-90%)，產生標題化合物(8.8毫克，50.5%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -indole-7-carboxamide (15.0 mg, 0.034 Piperidine (4.0 microliters, 0.04 millimolar) was added to a solution of millimolar DCM (2 mL). After stirring the reaction solution at ambient temperature for 1 hour, NaBH(OAc) ₃ (23.0 mg, 0.109 mmol) was added. After the resulting mixture was stirred at ambient temperature overnight, solvent was evaporated under reduced pressure. The resulting residue was dissolved in 1.2 mL of DMSO and filtered to dissolve all undissolved solids. This DMSO solution containing the crude product was purified by the reverse _{_{HPLC (H 2 O / CH 3}} CN, 0.1% TFA 10-90%), the title compound (8.8 mg, 50.5%).

LC/MS：m/z 509.4(M+H)，r.t：1.87分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

實例2：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(1-哌 基甲基)苯基]-1H-吲哚-7-羧醯胺 Example 2: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperazine Methyl)phenyl]-1 H -indole-7-carboxyguanamine

依據實例1之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(15.0毫克，0.034毫莫耳)、哌(3.5毫克，0.04毫莫耳)與NaBH(OAc)₃(23.0毫克，0.102毫莫耳)進行反應，產生標題化合物(3.4毫克，19.7%)。 According to the general procedure of Example 1 , 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole Amine (15.0 mg, 0.034 mmol), piper (3.5 mg, 0.04 mmol) and NaBH (OAc) ₃ (23.0 mg, 0.102 mmol) was reacted to give the title compound (3.4 mg, 19.7%).

LC/MS：m/z 510.2(M+H)，r.t：1.43分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

實例3：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(4-嗎啉基甲基)苯基]-1H-吲哚-7-羧醯胺Example 3: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinylmethyl)phenyl]-1 H -indole-7-carboxylate Guanamine

依據實例1之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(15.0毫克，0.034毫莫耳)、嗎啉(3.5微升，0.04毫莫耳)與NaBH(OAc)₃(23.0毫克，0.102毫莫耳)進行反應，產生標題化合物(7.5毫克，43%)。 According to the general procedure of Example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole The amine (15.0 mg, 0.034 mmol), morpholine (3.5 mL, 0.04 mmol) was reacted with NaBH (OAc) ₃ (23.0 mg, 0.102 mmol) to give the title compound (7.5 mg, 43%) ).

LC/MS：m/z 511.2(M+H)，r.t：1.58分鐘。 </RTI> <RTI ID=0.0></RTI></RTI>

或者，實例3亦可依據下列方法製備： Alternatively, Example 3 can also be prepared according to the following method:

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(20毫克，0.046毫莫耳)之二氯甲烷(1.5毫升)與甲醇(1.5毫升)溶液中添加嗎啉(0.070毫升，0.276毫莫耳)與1滴乙酸。於室溫下攪拌此混合物2小時後，添加氫硼化鈉(11毫克，0.276毫莫耳)。30分鐘後，混合物倒至SCX卡管(5.0克)上，使用EtOAc(10.0毫升)與MeOH(10.0毫升)沖刷卡管。使用2 M NH₃/MeOH溶液(10.0毫升)溶離產物後，濃縮。殘質溶於二甲亞碸(1.0毫升)，經Gilson製備性HPLC純化，產生標題化合物(17.6毫克，75%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -indole-7-carboxamide (20 mg, 0.046 To a solution of dichloromethane (1.5 ml) and methanol (1.5 ml) was added morpholine (0.070 mL, 0.276 mmol) and 1 drop of acetic acid. After the mixture was stirred at room temperature for 2 hours, sodium borohydride (11 mg, 0.276 mmol) was added. After 30 minutes, the mixture was poured onto EtOAc (EtOAc) (EtOAc) Using 2 M NH ₃ / MeOH solution (10.0 ml), the product from the solution and concentrated. The residue was dissolved in EtOAc (1 mL,EtOAc)

實例4：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({甲基[2-(甲基磺醯基)乙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺Example 4: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-({methyl[2-(methylsulfonyl)ethyl]amino}methyl) Phenyl]-1 H -吲哚-7-carboxyguanamine

依據實例1之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(42.0毫克，0.096毫莫耳)、N-甲基-2-(甲基磺醯基)乙胺(12.0毫克，0.087毫莫耳)與NaBH(OAc)₃(58.0毫克，0.261毫莫耳)進行反應，產生標題化合物(15.1毫克，28.0%)。 According to the general procedure of Example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole Amine (42.0 mg, 0.096 mmol), N -methyl-2-(methylsulfonyl)ethylamine (12.0 mg, 0.087 mmol) and NaBH(OAc) ₃ (58.0 mg, 0.261 mmol) The reaction was carried to give the title compound (15.1 mg, 28.0%).

LC/MS：m/z 561.2(M+H)，r.t：1.58分鐘。 LC/MS: m/z.

實例5：5-(3-{[[2-(二甲基胺基)乙基](甲基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 5: 5-(3-{[[2-(Dimethylamino)ethyl](methyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)- 4-piperidinyl]-1 H -吲哚-7-carboxyguanamine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(45.0毫克，0.101毫莫耳)之DCM(2毫升)溶液中添加N,N,N'-三甲基-1,2-乙二胺(116微升，0.90毫莫耳)。反應溶液於周溫下攪拌1小時後，添加NaBH(OAc)₃(69毫克，0.326毫莫耳)。於周溫下攪拌所得混合物一夜，再加NaBH(OAc)₃(128毫克，0.606毫莫耳)。再攪拌反應2小時後，減壓排除溶劑。粗產物經逆向HPLC純化(水/CH₃CN，0.1% TFA 10-90%)，產生標題化合物(16.0毫克，29.6%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxamide (45.0 mg, 0.101) N , N , N '-trimethyl-1,2-ethanediamine (116 μL, 0.90 mmol) was added to a solution of MeOH (2 mL). After the reaction solution was stirred at ambient temperature for 1 hour, NaBH(OAc) ₃ (69 mg, 0.326 mmol) was added. The resulting mixture was stirred overnight at ambient temperature, then NaBH(OAc) ₃ (128 mg, 0.606 m. After further stirring the reaction for 2 hours, the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (water _{/ CH 3 CN, 0.1% TFA} 10-90%), the title compound (16.0 mg, 29.6%).

LC/MS：m/z 526.8(M+H)，r.t：1.28分鐘。 LC/MS: m/z 526.8 (M+H).

實例6：3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(4-{2-[(2-羥基乙基)氧]乙基}-1-哌 基)甲基]苯基}-1H-吲哚-7-羧醯胺 Example 6: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(4-{2-[(2-hydroxyethyl)oxy]ethyl}-1 -piper Methyl]phenyl}-1 H -吲哚-7-carboxyguanamine

依據實例1之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50.0毫克，0.112毫莫耳)、2-{[2-(1-哌基)乙基]氧}乙醇(150毫克，0.87毫莫耳)與NaBH(OAc)₃(58.0毫克，0.303毫莫耳)進行反應，產生標題化合物(16.7毫克，25%)。 According to the general procedure of Example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole Amine (50.0 mg, 0.112 mmol), 2-{[2-(1-pipera) Yl) ethyl] oxy} ethanol (150 mg, 0.87 mmol) and NaBH (OAc) ₃ (58.0 mg, 0.303 mmol) was reacted to give the title compound (16.7 mg, 25%).

LC/MS：m/z 598.4(M+H)，r.t：1.48分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

實例7：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[3-(羥基甲基)-1-哌啶基]甲基}苯基)-1H-吲哚-7-羧醯胺Example 7: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-{[3-(hydroxymethyl)-1-piperidinyl]methyl}phenyl) -1 H -吲哚-7-carboxyguanamine

依據實例1之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50.0毫克，0.112毫莫耳)、3-哌啶基甲醇(98.9毫克，0.86毫莫耳)與NaBH(OAc)₃(58.0毫克，0.303毫莫耳)進行反應，產生標題化合物(10.2毫克，17%)。 According to the general procedure of Example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole Amine (50.0 mg, 0.112 mmol), 3-piperidinylmethanol (98.9 mg, 0.86 mmol) was reacted with NaBH(OAc) ₃ (58.0 mg, 0.303 mmol) to give the title compound (10.2 mg , 17%).

LC/MS：m/z 539.4(M+H)，r.t：1.52分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

實例8：5-[3-({雙[2-(甲基氧)乙基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 8: 5-[3-({bis[2-(methyloxy)ethyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl ]-1 H -吲哚-7-carboxyguanamine

依據實例1之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50.0毫克，0.112毫莫耳)、2-(甲基氧)-N-[2-(甲基氧)乙基]乙胺(114.3毫克， 0.86毫莫耳)與NaBH(OAc)₃(58.0毫克，0.303毫莫耳)進行反應，產生標題化合物(10.5毫克，16%)。 According to the general procedure of Example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole amine (50.0 mg, 0.112 mmol), 2- (oxo-methyl) - N - [2- (methyl) ethyl] ethanamine (114.3 mg, 0.86 mmol) and NaBH (OAc) ₃ ( Reaction was carried out to give the title compound (10.5 mg, 16%).

LC/MS：m/z 557.6(M+H)，r.t：1.62分鐘。 LC/MS: m/z 557.6 (M+H).

實例9：5-{3-[(2,6-二甲基-4-嗎啉基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 9: 5-{3-[(2,6-Dimethyl-4-morpholinyl)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl] -1 H -吲哚-7-carboxyguanamine

依據實例1之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50.0毫克，0.112毫莫耳)、2,6-二甲基嗎啉(98.9毫克，0.86毫莫耳)與NaBH(OAc)₃(58.0毫克，0.303毫莫耳)進行反應，產生標題化合物(19.6毫克，32%)。 According to the general procedure of Example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole The amine (50.0 mg, 0.112 mmol), 2,6-dimethylmorpholine (98.9 mg, 0.86 mmol) was reacted with NaBH(OAc) ₃ (58.0 mg, 0.303 mmol) to give the title compound (19.6 mg, 32%).

LC/MS：m/z 539.2(M+H)，r.t：1.75分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

實例10：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[2-(1,3-噻唑-2-基)-1-吡咯啶基]甲基}苯基)-1H-吲哚-7-羧醯胺Example 10: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-{[2-(1,3-thiazol-2-yl)-1-pyrrolidinyl] Methyl}phenyl)-1 H -吲哚-7-carboxyguanamine

依據實例1之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50.0毫克，0.112毫莫耳)、2-(2-吡咯啶基)-1,3-噻唑(132.4毫克，0.86毫莫耳)與NaBH(OAc)₃(58.0毫克，0.303毫莫耳)進行反應，產生標題化合物(20.0毫克，30.4%)。 According to the general procedure of Example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole Amine (50.0 mg, 0.112 mmol), 2-(2-pyrrolidinyl)-1,3-thiazole (132.4 mg, 0.86 mmol) and NaBH(OAc) ₃ (58.0 mg, 0.303 mmol) Reaction was carried out to give the title compound (20.0 mg, 30.4%).

LC/MS：m/z 578.6(M+H)，r.t：1.57分鐘。 </RTI> <RTI ID=0.0></RTI></RTI>

實例11：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[2-(2-噻吩基)-1-吡咯啶基]甲基}苯基)-1H-吲哚-7-羧醯胺Example 11: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-{[2-(2-thienyl)-1-pyrrolidinyl]methyl}phenyl )-1 H -吲哚-7-carboxyguanamine

依據實例1之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50.0毫克，0.112 毫莫耳)、2-(2-噻吩基)吡咯啶(132.4毫克，0.86毫莫耳)與NaBH(OAc)₃(58.0毫克，0.303毫莫耳)進行反應，產生標題化合物(20.0毫克，30.4%)。 According to the general procedure of Example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole The amine (50.0 mg, 0.112 mmol), 2-(2-thienyl)pyrrolidine (132.4 mg, 0.86 mmol) was reacted with NaBH(OAc) ₃ (58.0 mg, 0.303 mmol) to give the title Compound (20.0 mg, 30.4%).

LC/MS：m/z 577.4(M+H)，r.t：1.78分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

實例12：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-羥基-2-苯基乙基)-(甲基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺Example 12: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-hydroxy-2-phenylethyl)-(methyl)amino] Methyl}phenyl)-1 H -吲哚-7-carboxyguanamine

依據實例1之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50.0毫克，0.112毫莫耳)、2-(甲基胺基)-1-苯基乙醇(129.9毫克，0.86毫莫耳)與NaBH(OAc)₃(58.0毫克，0.303毫莫耳)進行反應，產生標題化合物(22.1毫克，36.6%)。 According to the general procedure of Example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole Amine (50.0 mg, 0.112 mmol), 2-(methylamino)-1-phenylethanol (129.9 mg, 0.86 mmol) and NaBH(OAc) ₃ (58.0 mg, 0.303 mmol) Reaction gave the title compound (22.1 mg, 36.6%).

LC/MS：m/z 575.4(M+H)，r.t：1.66分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

實例13：5-(3-{[乙基(甲基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 13: 5-(3-{[Ethyl(methyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole哚-7-carboxyguanamine

依據實例1之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50.0毫克，0.112毫莫耳)、N-甲基乙胺(50.7毫克，0.86毫莫耳)與NaBH(OAc)₃(58.0毫克，0.303毫莫耳)進行反應，產生標題化合物(11.5毫克，21%)。 According to the general procedure of Example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole The amine (50.0 mg, 0.112 mmol), N -methylethylamine (50.7 mg, 0.86 mmol) was reacted with NaBH(OAc) ₃ (58.0 mg, 0.303 mmol) to give the title compound (11.5 mg) ,twenty one%).

LC/MS：m/z 483.4(M+H)，r.t：1.57分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

實例14：5-[3-(胺基甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 14: 5-[3-(Aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide

在含5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(30.0毫克，0.072毫莫耳)、Cs₂CO₃(95毫克，0.290毫莫耳)與1-[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基] 甲胺(82毫克，0.350毫莫耳)之二烷/H₂O(2毫升/0.7毫升)溶液中通入氬氣5分鐘後，添加Pd(PPh₃)₄(7.5毫克，0.0072毫莫耳)。反應混合物於微波反應器(Smith synthesizer)中，於160℃下加熱20分鐘。蒸發溶劑，殘質分溶於乙酸乙酯與水之間。有機層經鹽水(10毫升)洗滌，經MgSO₄脫水，過濾，濃縮，經逆向HPLC方法A純化(水/CH₃CN，0.1% TFA 10-90%)，產生標題化合物(2.7毫克，8.5%)。 In the presence of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (30.0 mg, 0.072 mmol), Cs ₂ CO ₃ (95 mg, 0.290 mmol) and 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylamine (82 mg, 0.350 millimoles) After argon gas was bubbled through the alkane/H ₂ O (2 ml / 0.7 ml) solution for 5 min, Pd(PPh ₃ ) ₄ (7.5 mg, 0.0072 mmol) was added. The reaction mixture was heated in a microwave reactor (Smith synthesizer) at 160 ° C for 20 minutes. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was with brine (10 mL), dried MgSO ₄ dried, filtered, concentrated and purified by reverse HPLC method A (water _{/ CH 3 CN, 0.1% TFA} 10-90%), the title compound (2.7 mg, 8.5% ).

LC/MS：m/z 441.4(M+H)，r.t：1.54分鐘。 </RTI> <RTI ID=0.0></RTI></RTI>

實例15：5-{3-[(環戊基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 15: 5-{3-[(Cyclopentylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7 -carboxamide

依據實例5之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(45毫克，0.101毫莫耳)、環戊基胺(90微升，0.090毫莫耳)與NaBH(OAc)₃(197毫克，0.93毫莫耳)進行反應，產生標題化合物(33.0毫克，64%)。 According to the general procedure of Example 5 , 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole amine (45 mg, 0.101 mmol), cyclopentylamine (90 [mu] l, 0.090 mmol) and NaBH (OAc) ₃ (197 mg, 0.93 mmol) was reacted to give the title compound (33.0 mg, 64%).

LC/MS：m/z 509.4(M+H)，r.t：1.64分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

實例16：5-[3-({[(3,4-二羥苯基)甲基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 16: 5-[3-({[(3,4-Dihydroxyphenyl)methyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-1 H -吲哚-7-carboxyguanamine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)之二氯乙烷(2毫升)溶液中添加4-(胺基甲基)-1,2-苯二醇(12.1毫克，0.087毫莫耳)。反應溶液於周溫下攪拌10分鐘後，添加NaBH(OAc)₃(58毫克，0.261毫莫耳)。所得混合物於周溫下振盪一夜後，減壓排除溶劑。粗產物經逆向HPLC純化(水/CH₃CN，0.1% TFA 10-90%)，產生標題化合物(7.4毫克，12%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxamide (50 mg, 0.114 To a solution of methylene chloride (2 ml) was added 4-(aminomethyl)-1,2-benzenediol (12.1 mg, 0.087 mmol). After the reaction solution was stirred at ambient temperature for 10 minutes, NaBH(OAc) ₃ (58 mg, 0.261 mmol) was added. After the resulting mixture was shaken overnight at ambient temperature, the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (water _{/ CH 3 CN, 0.1% TFA} 10-90%), the title compound (7.4 mg, 12%).

LC/MS：m/z 563.2(M+H)，r.t：1.67分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

實例17：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(3-噻吩基甲基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺Example 17: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-{[(3-thienylmethyl)amino]methyl}phenyl)-1H-吲哚-7-carboxyguanamine

依據實例16之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)、1-(3-噻吩基)甲胺(9.83毫克，0.087毫莫耳)與NaBH(OAc)₃(58毫克，0.261毫莫耳)進行反應，產生標題化合物(4.7毫克，7.8%)。 According to the general procedure of Example 16 , 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole The amine (50 mg, 0.114 mmol), 1-(3-thienyl)methylamine (9.83 mg, 0.087 mmol) was reacted with NaBH(OAc) ₃ (58 mg, 0.261 mmol) to give title Compound (4.7 mg, 7.8%).

LC/MS：m/z 537.2(M+H)，r.t：1.62分鐘。 </RTI> </RTI> </RTI> <RTI ID=0.0></RTI>

實例18：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(1R)-1-(羥基甲基)-2-甲基丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺Example 18: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1 R )-1-(hydroxymethyl)-2-methylpropyl) Amino}methyl)phenyl]-1 H -indole-7-carboxamide

依據實例16之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)、(2R)-2-胺基-3-甲基-1-丁醇(10.2毫克，0.087毫莫耳) 與NaBH(OAc)₃(58毫克，0.261毫莫耳)進行反應，產生標題化合物(14.9毫克，25%)。 According to the general procedure of Example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole Amine (50 mg, 0.114 mmol), ( 2R )-2-amino-3-methyl-1-butanol (10.2 mg, 0.087 mmol) and NaBH(OAc) ₃ (58 mg, 0.261) Reaction was carried out to give the title compound (14.9 mg, 25%).

LC/MS：m/z 527.6(M+H)，r.t：1.48分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

實例19：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-羥基-1-甲基乙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺：Example 19: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-hydroxy-1-methylethyl)amino]methyl}phenyl )-1 H -吲哚-7-carboxyguanamine:

依據實例16之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)、2-胺基-1-丙醇(6.5毫克，0.087毫莫耳)與NaBH(OAc)₃(58毫克，0.261毫莫耳)進行反應，產生標題化合物(3.4毫克，6.0%)。 According to the general procedure of Example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole The amine (50 mg, 0.114 mmol), 2-amino-1-propanol (6.5 mg, 0.087 mmol) was reacted with NaBH(OAc) ₃ (58 mg, 0.261 mmol) to give the title compound (3.4 mg, 6.0%).

LC/MS：m/z 499.6(M+H)，r.t：1.46分鐘。 </RTI> <RTI ID=0.0></RTI>

實例20：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(反式-4-羥基環己基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺Example 20: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-{[(trans-4-hydroxycyclohexyl)amino]methyl}phenyl)- 1 H -吲哚-7-carboxyguanamine

依據實例16之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)、反式-4-胺基環己醇(10毫克，0.087毫莫耳)與NaBH(OAc)₃(58毫克，0.261毫莫耳)進行反應，產生標題化合物(6.0毫克，9.8%)。 According to the general procedure of Example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole The amine (50 mg, 0.114 mmol), trans-4-aminocyclohexanol (10 mg, 0.087 mmol) was reacted with NaBH(OAc) ₃ (58 mg, 0.261 mmol) to give the title Compound (6.0 mg, 9.8%).

LC/MS：m/z 539.2(M+H)，r.t：1.54分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

實例21：3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[({[1-(1-哌啶基)環己基]甲基}胺基)甲基]苯基}-1H-吲哚-7-羧醯胺Example 21: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[({[1-(1-piperidinyl)cyclohexyl]methyl}amine) Methyl]phenyl}-1 H -吲哚-7-carboxyguanamine

依據實例16之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)、1-[1-(1-哌啶基)環己基]甲胺(17毫克，0.087毫莫耳) 與NaBH(OAc)₃(58毫克，0.261毫莫耳)進行反應，產生標題化合物(18.7毫克，27%)。 According to the general procedure of Example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole Amine (50 mg, 0.114 mmol), 1-[1-(1-piperidinyl)cyclohexyl]methylamine (17 mg, 0.087 mmol) with NaBH(OAc) ₃ (58 mg, 0.261 mmol) The reaction was carried out to give the title compound (18.7 mg, 27%).

LC/MS：m/z 620.6(M+H)，r.t：1.6分鐘。 LC/MS: m/z 620.6 (M+H).

實例22：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(2S)-2-羥基丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺Example 22: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-({[( 2S )-2-hydroxypropyl]amino}methyl)phenyl) ]-1 H -吲哚-7-carboxyguanamine

依據實例16之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)、(2S)-1-胺基-2-丙醇(6.5毫克，0.087毫莫耳)與NaBH(OAc)₃(58毫克，0.261毫莫耳)進行反應，產生標題化合物(13.1毫克，23%)。 According to the general procedure of Example 16, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole Amine (50 mg, 0.114 mmol), ( 2S )-1-amino-2-propanol (6.5 mg, 0.087 mmol) and NaBH(OAc) ₃ (58 mg, 0.261 mmol) Reaction gave the title compound (13.1 mg, 23%).

LC/MS：m/z 499.6(M+H)，r.t：1.46分鐘。 </RTI> <RTI ID=0.0></RTI>

實例23：5-{3-[(乙基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 23: 5-{3-[(Ethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7- Carboxylamidine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(20毫克，0.045毫莫耳)之二氯甲烷(0.5毫升)與甲醇(0.5毫升)溶液中添加乙基胺(130微升，0.27毫莫耳)。於室溫下攪拌此混合物1小時後，添加氫硼化鈉(10毫克，0.27毫莫耳)。反應於周溫下攪拌一夜，減壓排除溶劑。粗產物經逆向HPLC純化(水/CH₃CN，0.1% TFA 10-90%)，產生標題化合物(13.2毫克，63%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxamide (20 mg, 0.045 Ethylamine (130 μL, 0.27 mmol) was added to a solution of dichloromethane (0.5 mL) and methanol (0.5 mL). After the mixture was stirred at room temperature for 1 hour, sodium borohydride (10 mg, 0.27 mmol) was added. The reaction was stirred overnight at ambient temperature and the solvent was removed under reduced pressure. The crude product was purified by reverse phase HPLC (water _{/ CH 3 CN, 0.1% TFA} 10-90%), the title compound (13.2 mg, 63%).

LC/MS：m/z 469.4(M+H)，r.t：1.54分鐘。 </RTI> <RTI ID=0.0></RTI></RTI>

實例24：3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(丙基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺Example 24: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{3-[(propylamino)methyl]phenyl}-1 H -吲哚-7- Carboxylamidine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(20毫克，0.046毫莫耳)之二氯甲烷(0.7毫升)與甲醇(0.7毫升)溶液中添加丙基胺(22微升，0.27毫莫耳)與1滴乙酸。於室溫下攪拌此混合物1小時後，添加氫硼化鈉(10毫克，0.27毫莫耳)。於周溫下攪拌反應一夜，減壓排除溶劑。粗產物經逆向HPLC純化(水/CH₃CN，0.1% TFA 10-90%)，產生標題化合物(22.1毫克，99%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -indole-7-carboxamide (20 mg, 0.046 To a solution of dichloromethane (0.7 mL) and methanol (0.7 mL) was added propylamine (22 [mu]L, 0.27 mmol) and 1 drop of acetic acid. After the mixture was stirred at room temperature for 1 hour, sodium borohydride (10 mg, 0.27 mmol) was added. The reaction was stirred overnight at ambient temperature and the solvent was evaporated under reduced pressure. The crude product was purified by reverse phase HPLC (water _{/ CH 3 CN, 0.1% TFA} 10-90%), the title compound (22.1 mg, 99%).

LC/MS：m/z 483.2(M+H)，r.t：1.58分鐘。 LC/MS: m/z 483.2 (M+H).

實例25：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(1-甲基乙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺：Example 25: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-{[(1-methylethyl)amino]methyl}phenyl)-1 H -吲哚-7-carboxyguanamine:

依據實例24之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(20毫克，0.045毫莫耳)、異丙基胺(23微升，0.27毫莫耳)與NaBH₄(10毫克，0.27毫莫耳)進行反應，產生標題化合物(11.5毫克，53%)。 According to the general procedure of Example 24 , 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole amine (20 mg, 0.045 mmol), isopropylamine (23 [mu] l, 0.27 mmol) and NaBH ₄ (10 mg, 0.27 mmol) was reacted to give the title compound (11.5 mg, 53%) .

LC/MS：m/z 483.2(M+H)，r.t：1.52分鐘。 </RTI> <RTI ID=0.0></RTI></RTI>

實例26：5-(3-{[(1-乙基丙基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 26: 5-(3-{[(1-Ethylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxyguanamine

依據實例1之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(20毫克，0.045毫莫耳)、3-戊胺(32微升，0.27毫莫耳)與NaBH₄(10毫克，0.27毫莫耳)進行反應，產生標題化合物(18.5毫克，80%)。 According to the general procedure of Example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole The amine (20 mg, 0.045 mmol), 3-pentylamine (32 mL, 0.27 mmol) was reacted with NaBH ₄ (10 mg, 0.27 mmol) to give the title compound (18.5 mg, 80%) .

LC/MS：m/z 511.4(M+H)，r.t：1.66分鐘。 </RTI> <RTI ID=0.0></RTI></RTI>

實例27：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(1-哌啶基甲基)苯基]-1H-吲哚-7-羧醯胺：Example 27: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[4-(1-piperidinylmethyl)phenyl]-1 H -indole-7-carboxylate Guanamine:

依據實例1之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(40毫克，0.09毫莫耳)、哌啶(0.009毫升，0.09毫莫耳)與NaBH(OAc)₃(58毫克，0.27毫莫耳)進行反應，產生標題化合物(8毫克，17.5%)。 According to the general procedure of Example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole amine (40 mg, 0.09 mmol), piperidine (0.009 ml, 0.09 mmol) and NaBH (OAc) ₃ (58 mg, 0.27 mmol) was reacted to give the title compound (8 mg, 17.5%) .

LC/MS：m/z 509.4(M+H)，r.t：1.71分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

實例28：3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺Example 28: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{3-[(methylamino)methyl]phenyl}-1 H -indole-7- Carboxylamidine

依據實例24之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(20毫克，0.045毫莫耳)、甲基胺(130微升，0.27毫莫耳)與NaBH₄(10毫克，0.27毫莫耳)進行反應，產生標題化合物(17.0毫克，83%)。 According to the general procedure of Example 24, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole amine (20 mg, 0.045 mmol), methylamine (130 [mu] l, 0.27 mmol) and NaBH ₄ (10 mg, 0.27 mmol) was reacted to give the title compound (17.0 mg, 83%).

LC/MS：m/z 455.2(M+H)，r.t：1.48分鐘。 </RTI> </RTI> </RTI> <RTI ID=0.0></RTI>

實例29：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(4-嗎啉基甲基)苯基]-1H-吲哚-7-羧醯胺Example 29: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[4-(4-morpholinylmethyl)phenyl]-1 H -indole-7-carboxylate Guanamine

依據實例1之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)、嗎啉(18微升，0.206毫莫耳)與NaBH(OAc)₃(290毫克，1.37毫莫耳)進行反應，產生標題化合物(2.1毫克，13%)。 According to the general procedure of Example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -吲哚-7-carboxyindole The amine (50 mg, 0.114 mmol), morpholine (18 μL, 0.206 mmol) was reacted with NaBH(OAc) ₃ (290 mg, 1.37 mmol) to give the title compound (2.1 mg, 13%) ).

LC/MS：m/z 511.4(M+H)，r.t：1.63分鐘。 </RTI> <RTI ID=0.0></RTI></RTI>

實例30：5-[4-(胺基甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 30: 5-[4-(Aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide

在含5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(30.0毫克，0.072毫莫耳)、Cs₂CO₃(95毫克，0.290毫莫耳)與[4-(胺基甲基)苯基二羥硼酸(55毫克，0.290毫莫耳)之二烷/H₂O(1.5毫升/0.5毫升)溶液中通入氬氣5分鐘後，添加Pd(PPh₃)₄(7.5毫克，0.0072毫莫耳)。反應混合物於微波反應器(Smith synthesizer)中，在160℃下加熱20分鐘。蒸發溶劑，殘質分溶於乙酸乙酯與水之間。有機層經鹽水(10毫升)洗滌，經MgSO₄脫水，過濾，濃縮，經逆向HPLC純化(水/CH₃CN，0.1%TFA10-90%)，產生標題化合物(9.8毫克，31%)。 In the presence of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (30.0 mg, 0.072 mmol), Cs ₂ CO ₃ (95 mg, 0.290 mmol) and [4-(aminomethyl)phenyldihydroxyboronic acid (55 mg, 0.290 mmol) After argon gas was bubbled through a solution of alkane/H ₂ O (1.5 ml / 0.5 ml) for 5 min, Pd(PPh ₃ ) ₄ (7.5 mg, 0.0072 mmol) was added. The reaction mixture was heated in a microwave reactor (Smith synthesizer) at 160 ° C for 20 minutes. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was with brine (10 mL), dried MgSO ₄ dried, filtered, concentrated and purified by reverse phase HPLC (water _{/ CH 3 CN, 0.1% TFA10-90} %), the title compound (9.8 mg, 31%).

LC/MS：m/z 424.4(M-NH2),r.t：1.48分鐘。 </RTI> <RTI ID=0.0></RTI></RTI>

實例31：5-{3-[(環丙基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 31: 5-{3-[(Cyclopropylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7 -carboxamide

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.113毫莫耳)之DCM(2毫升)溶液中添加環丙胺(19.3毫克，0.339毫莫耳)。反應溶液於周溫下攪拌30分鐘後，添加HOAc(1滴)與NaBH(OAc)₃(75毫克，0.545毫莫耳)。所得混合物於周溫下攪拌一夜後，減壓排除溶劑。粗產物經逆向HPLC純化(水/CH₃CN，0.1%TFA10-90%)，產生標題化合物(18.2毫克，34%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxamide (50 mg, 0.113 To a solution of millimolar DCM (2 mL) was added cyclopropylamine (19.3 mg, 0.339 mmol). After the reaction solution was stirred at ambient temperature for 30 minutes, HOAc (1 drop) and NaBH(OAc) ₃ (75 mg, 0.545 mmol) were added. After the resulting mixture was stirred at ambient temperature overnight, solvent was evaporated under reduced pressure. The crude product was purified by reverse phase HPLC (water _{/ CH 3 CN, 0.1% TFA10-90} %), the title compound (18.2 mg, 34%).

LC/MS：m/z 481.2(M+H)，r.t：1.52分鐘。 </RTI> </RTI> <RTI ID=0.0></RTI>

實例32：5-{3-[(環丁基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 32: 5-{3-[(Cyclobutylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7 -carboxamide

依據實例31之一般製程，由3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.113毫莫耳)、環丁胺(24.1毫克，0.339毫莫耳)與NaBH(OAc)₃(75毫克，0.545毫莫耳)進行反應，產生標題化合物(19.3毫克，35%)。 According to the general procedure of Example 31 , 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxyindole The amine (50 mg, 0.113 mmol), cyclobutylamine (24.1 mg, 0.339 mmol) was reacted with NaBH(OAc) ₃ (75 mg, 0.545 mmol) to give the title compound (19.3 mg, 35%) ).

LC/MS：m/z 495.6(M+H)，r.t：1.55分鐘。 LC/MS: m/z 495.6 (M+H).

實例33：3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(2-甲基丙基)胺基]-2,3-二氫-1H-茚-5-基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 33: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{3-[(2-methylpropyl)amino]-2,3-dihydro-1 H -茚-5-yl}-1 H-吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(200毫克，0.434毫莫耳)之二烷(3.0毫升)與H₂O(1.0毫升)溶液之微波反應管中添加6-溴-2,3-二氫-1H-茚-1-酮(274毫克，1.30毫莫耳)與碳酸鉀(360毫克，2.60毫莫耳)。反應混合物脫氣5分鐘後，添加肆(三苯基膦)鈀(0)(50毫克，0.043毫莫耳)。反應於微波爐中，在160℃下加熱30分鐘。反應過濾，固體溶於EtOAc與H₂O中。分離有機層與濃縮。粗產物殘質經Gilson製備性HPLC純化，產生3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氧代-2,3-二氫-1H-茚-5-基)-1H-吲哚-7-羧醯胺。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (200 mg, 0.434 mmol) 6-Bromo-2,3-dihydro-1 H -indol-1-one (274 mg, 1.30 mmol) and carbonic acid in a microwave reaction tube of a solution of alkane (3.0 mL) and H ₂ O (1.0 mL) Potassium (360 mg, 2.60 mmol). After the reaction mixture was degassed for 5 minutes, hydrazine (triphenylphosphine)palladium(0) (50 mg, 0.043 mmol) was added. The reaction was heated in a microwave oven at 160 ° C for 30 minutes. The reaction was filtered, the solid was dissolved in EtOAc and H ₂ O. The organic layer was separated and concentrated. The crude residue was purified by Gilson preparative HPLC to give 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-oxo-2,3-dihydro-1 H -茚-5-yl)-1 H -吲哚-7-carboxyguanamine.

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氧代-2,3-二氫-1H-茚-5-基)-1H-吲哚-7-羧醯胺(45毫克，0.097毫莫耳)之EtOH(2毫升)與乙酸(200微升)溶液中添加2-甲基-1-丙胺(170微升，1.93毫莫耳)與氰基氫硼化鈉(20毫克，0.291毫莫耳)。所得混合物於CEM微波管中，於150℃下反應40分鐘。然後經Gilson製備性HPLC純化，產生4.5毫克標題化合物(8.9%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-oxo-2,3-dihydro-1 H -indol-5-yl)-1 H - Add 2-methyl-1-propylamine (170 μl, 1.93 mmol) to a solution of 吲哚-7-carboxamide (45 mg, 0.097 mmol) in EtOH (2 mL) and acetic acid (200 μL) ) with sodium cyanoborohydride (20 mg, 0.291 mmol). The resulting mixture was reacted in a CEM microwave tube at 150 ° C for 40 minutes. Purification by Gilson preparative HPLC gave 4.5 mg of the title compound (8.9%).

LC/MS=m/z 523.4[M+H]滯留時間：1.72 LC/MS=m/z 523.4 [M+H] retention time: 1.72

實例34：3-[1-(乙基磺醯基)-4-哌啶基]-5-{8-[(2-甲基丙基)胺基]-5,6,7,8-四氫-2-萘基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 34: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{8-[(2-methylpropyl)amino]-5,6,7,8-tetra Hydrogen-2-naphthyl}-1H-indole-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(200毫克，0.434毫莫耳)之二烷(3.0毫升)與H₂O(1.0毫升)溶液之微波管中添加7-溴-3,4-二氫-1(2H)-萘酮(292毫克，1.30毫莫耳)與碳酸鉀(360毫克，2.60毫莫耳)。反應混合物脫氣5分鐘後，添加肆(三苯基膦)鈀(0)(50毫克，0.043毫莫耳)。反應於微波爐中，於160℃下加熱30分鐘。反應過濾，固體溶於EtOAc與H₂O中。分離有機層與濃縮。粗產物殘質經Gilson製備性HPLC純化，產生3-[1-(乙基磺醯基)-4-哌啶基]-5-(8-氧代-5,6,7,8-四氫-2-萘基)-1H-吲哚-7-羧醯胺。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (200 mg, 0.434 mmol) Add 7-bromo-3,4-dihydro-1( 2H )-naphthalenone (292 mg, 1.30 mmol) to potassium carbonate in a microwave tube of a solution of alkane (3.0 mL) and H ₂ O (1.0 mL) (360 mg, 2.60 mmol). After the reaction mixture was degassed for 5 minutes, hydrazine (triphenylphosphine)palladium(0) (50 mg, 0.043 mmol) was added. The reaction was heated in a microwave oven at 160 ° C for 30 minutes. The reaction was filtered, the solid was dissolved in EtOAc and H ₂ O. The organic layer was separated and concentrated. The crude residue was purified by Gilson preparative HPLC to give 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(8-oxo-5,6,7,8-tetrahydro -2-Naphthyl)-1 H -indole-7-carboxamide.

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(8-氧代-5,6,7,8-四氫-2-萘基)-1H-吲哚-7-羧醯胺(40毫克，0.08毫莫耳)之EtOH(2毫升)與乙酸(0.2毫升)溶液中添加2-甲基-1-丙胺(140微升，1.6毫莫耳)與氰基氫硼化鈉(15毫克，0.24毫莫耳)。所得混合物於CEM微波管中，於150℃下反應40分鐘。經Gilson製備性HPLC純化，產生3.2毫克標題化合物(7.5%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(8-oxo-5,6,7,8-tetrahydro-2-naphthyl)-1 H - Add 2-methyl-1-propylamine (140 μL, 1.6 mmol) to a solution of 吲哚-7-carboxamide (40 mg, 0.08 mmol) in EtOH (2 mL) and acetic acid (0.2 mL) With sodium cyanoborohydride (15 mg, 0.24 mmol). The resulting mixture was reacted in a CEM microwave tube at 150 ° C for 40 minutes. Purification by Gilson preparative HPLC gave 3.2 mg of the title compound (7.5%).

LC/MS=m/z 537.4[M+H]滯留時間：1.71 LC/MS=m/z 537.4 [M+H] retention time: 1.71

實例35：5-(5-{[(2-氰基乙基)胺基]甲基}-2-氟苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 35: 5-(5-{[(2-Cyanoethyl)amino]methyl}-2-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl ]-1H-吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(200毫克，0.434毫莫耳)之二烷(3.0毫升)與H₂O(1.0毫升)溶液之微波管中添加3-溴-4-氟苯甲醛(264毫克，1.30毫莫耳)與K₂CO₃(360毫克，2.60毫莫耳)。反應混合物脫氣5分鐘後，添加肆(三苯基膦)鈀(0)(48毫克，0.043毫莫耳)。反應於微波爐中，於160℃下加熱30分鐘。分離有機層與濃縮。殘質溶於MeOH中，直到固體沉澱為止，產生3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-氟-5-甲醯基苯基)-1H-吲哚-7-羧醯胺。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (200 mg, 0.434 mmol) Add 3-bromo-4-fluorobenzaldehyde (264 mg, 1.30 mmol) to K ₂ CO ₃ (360 mg, 2.60 mmol) in a microwave tube of a solution of alkane (3.0 mL) and H ₂ O (1.0 mL) ). After the reaction mixture was degassed for 5 minutes, hydrazine (triphenylphosphine)palladium(0) (48 mg, 0.043 mmol) was added. The reaction was heated in a microwave oven at 160 ° C for 30 minutes. The organic layer was separated and concentrated. The residue was dissolved in MeOH until solid precipitated to give 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-methylphenylphenyl)-1 H-吲哚-7-carboxyguanamine.

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-氟-5-甲醯基苯基)-1H-吲哚-7-羧醯胺(40毫克，0.087毫莫耳)之二氯甲烷(2毫升)與甲醇(1毫升)溶液中添加3-胺基丙腈(53微升，0.524毫莫耳)與1滴乙酸。反應混合物於室溫下攪拌48小時。添加氫硼化鈉(20毫克，0.524毫莫耳)，於室溫下反應30分鐘。經Gilson製備性HPLC純化，產生14.4毫克標題化合物(32.4%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-methylindenylphenyl)-1 H -indole-7-carboxamide Add 40-aminopropionitrile (53 μL, 0.524 mmol) and 1 drop of acetic acid to a solution of 40 mg, 0.087 mmol of dichloromethane (2 mL) and methanol (1 mL). The reaction mixture was stirred at room temperature for 48 hours. Sodium borohydride (20 mg, 0.524 mmol) was added and allowed to react at room temperature for 30 minutes. Purification by Gilson preparative HPLC gave 14.4 mg of the title compound (32.4%).

LC/MS=m/z 512.2[M+H]滯留時間：1.45 LC/MS=m/z 512.2 [M+H] retention time: 1.45

實例36：3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-氟-5-{[(2,2,2-三氟乙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 36: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-{[(2,2,2-trifluoroethyl)amino]- }}phenyl)-1H-indole-7-carboxamide guanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-氟-5-甲醯基苯基)-1H-吲哚-7-羧醯胺(20毫克，0.04毫莫耳)之二氯甲烷(4毫升)與甲醇(2毫升)溶液中添加2滴乙酸與2,2,2-三氟乙胺(23微升，0.26毫莫耳)。所得混合物攪拌一夜。蒸發所有溶劑，溶於二甲亞碸(1毫升)。經Gilson製備性HPLC純化，產生5.2毫克標題化合物(24.0%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-methylindenylphenyl)-1 H -indole-7-carboxamide 2 mg of acetic acid and 2,2,2-trifluoroethylamine (23 μL, 0.26 mmol) were added to a solution of 20 mg, 0.04 mmol of dichloromethane (4 mL) and methanol (2 mL). The resulting mixture was stirred overnight. All solvents were evaporated and dissolved in dimethyl hydrazine (1 mL). Purification by Gilson preparative HPLC gave 5.2 mg of the title compound (24.0%).

LC/MS=m/z 541.4[M+H]滯留時間：1.67 LC/MS=m/z 541.4 [M+H] retention time: 1.67

實例37：3-[1-(乙基磺醯基)-4-哌啶基]-5-(1,2,3,4-四氫-7-異喹啉基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 37: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(1,2,3,4-tetrahydro-7-isoquinolinyl)-1H-indole- 7-Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(60毫克，0.13毫莫耳)之二烷(2毫升)與水(1毫升)溶液中添加7-溴-1,2,3,4-四氫異喹啉(97毫克，0.39毫莫耳)與碳酸鉀(108毫克，0.78毫莫耳)。此混合物脫氣5分鐘後，添加肆(三苯基膦)鈀(0)(15毫克，0.013毫莫耳)。所得混合物於CEM微波管中，於160℃下反應30分鐘。分離有機層與濃縮。所得殘質溶於二甲亞碸(1毫升)，經Gilson製備性HPLC純化，產生3.5毫克標題化合物(5.7%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (60 mg, 0.13 mmol) Add 7-bromo-1,2,3,4-tetrahydroisoquinoline (97 mg, 0.39 mmol) to potassium carbonate (108 mg, 0.78 mmol) in a solution of alkane (2 mL) and water (1 mL) ear). After the mixture was degassed for 5 minutes, hydrazine (triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) was added. The resulting mixture was reacted in a CEM microwave tube at 160 ° C for 30 minutes. The organic layer was separated and concentrated. The resulting residue was dissolved in EtOAc (EtOAc) elute

LC/MS=m/z 467.2[M+H]滯留時間：1.48 LC/MS=m/z 467.2 [M+H] retention time: 1.48

實例38：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2,2,2-三氟乙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 38: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl )-1H-吲哚-7-carboxyguanamine trifluoroacetate

在含5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(200毫克，0.483毫莫耳)之二烷(3.0毫升)與H₂O(1.0毫升)溶液之微波管中添加(3-甲醯基苯基)二羥硼酸(317毫克，1.93毫莫耳)與Cs₂CO₃(315毫克，0.97毫莫耳)。反應混合物脫氣5分鐘後，添加肆(三苯基膦)鈀(0)(48毫克，0.043毫莫耳)。反應於微波爐中，於160℃下加熱30分鐘。分離有機層與濃縮。殘質溶於MeOH中，至固體沉澱為止，產生3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺。 In the presence of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (200 mg, 0.483 mmol) (3-Methylphenyl) dihydroxyboric acid (317 mg, 1.93 mmol) with Cs ₂ CO ₃ (315 mg, 0.97) in a microwave tube of a solution of alkane (3.0 mL) and H ₂ O (1.0 mL) Millions of ears). After the reaction mixture was degassed for 5 minutes, hydrazine (triphenylphosphine)palladium(0) (48 mg, 0.043 mmol) was added. The reaction was heated in a microwave oven at 160 ° C for 30 minutes. The organic layer was separated and concentrated. The residue is dissolved in MeOH until a solid precipitates to give 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-carbamidophenyl)-1 H -indole -7-Carboxyguanamine.

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(40毫克，0.09毫莫耳)與2,2,2-三氟乙基胺(78微升，0.55毫莫耳)之二氯甲烷(2毫升)與甲醇(1毫升)溶液中添加2滴乙酸。攪拌混合物一夜。添加氫硼化鈉(20.8毫克，0.55毫莫耳)。攪拌混合物30分鐘。所得混合物濃縮，溶於二甲亞碸中後，經Gilson製備性HPLC純化，產生29.4毫克標題化合物(62.5%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxamide (40 mg, 0.09 2 ml of acetic acid was added to a solution of 2,2,2-trifluoroethylamine (78 μL, 0.55 mmol) in dichloromethane (2 mL) and methanol (1 mL). The mixture was stirred overnight. Sodium borohydride (20.8 mg, 0.55 mmol) was added. The mixture was stirred for 30 minutes. The resulting mixture was concentrated, purified EtOAc EtOAcjjjjjj

LC/MS=m/z 523.2[M+H]滯留時間：1.66 LC/MS=m/z 523.2 [M+H] retention time: 1.66

實例39：5-(3-{[(2-胺基-2-氧代乙基)(甲基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 39: 5-(3-{[(2-Amino-2-oxoethyl)(methyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)- 4-piperidinyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(44毫克，0.1毫莫耳)與N ²-甲基甘胺醯胺(76毫克，0.6毫莫耳)之二氯甲烷(3毫升)與甲醇(1.5毫升)溶液中添加3滴乙酸。攪拌混合物一夜。添加三乙醯氧基氫硼化鈉(134毫克，0.6毫莫耳)，攪拌一夜。所得反應經碳酸氫鈉(2毫升)與鹽水(2毫升)中止反應。收集有機層與濃縮。所得殘質經Gilson製備性HPLC純化，產生13毫克標題化合物(25.4%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -indole-7-carboxamide (44 mg, 0.1 To a solution of N ² -methylglycinamide (76 mg, 0.6 mmol) in dichloromethane (3 mL) and methanol (1. The mixture was stirred overnight. Sodium triethoxy hydride hydride (134 mg, 0.6 mmol) was added and stirred overnight. The reaction was quenched with sodium bicarbonate (2 mL) and brine (2 mL). The organic layer was collected and concentrated. The residue obtained was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 512.6[M+H]滯留時間：1.20 LC/MS=m/z 512.6 [M+H] retention time: 1.20

實例40：3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-{[(2,2,2-三氟乙基)胺基]甲基}-1,3-噻唑-4-基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 40: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2,2,2-trifluoroethyl)amino]methyl}-1 , 3-thiazol-4-yl)-1H-indole-7-carboxamide guanamine trifluoroacetate

在含4-溴-1,3-噻唑-2-甲醛(192毫克，1.0毫莫耳)之DCM(4.0毫升)溶液中添加乙酸(3滴)與2,2,2-三氟乙胺(120微升，1.5毫莫耳)。攪拌反應一夜。添加三乙醯氧基氫硼化鈉(335毫克，1.5毫莫耳)，攪拌反應6小時。以碳酸氫鈉中止反應，產生3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺。 Add acetic acid (3 drops) and 2,2,2-trifluoroethylamine to a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 mL) 120 microliters, 1.5 millimoles). Stir the reaction overnight. Sodium triethoxy hydride hydride (335 mg, 1.5 mmol) was added and the reaction was stirred for 6 hours. The reaction was quenched with sodium bicarbonate to give 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-di Oxoborolan-2-yl)-1 H -indole-7-carboxamide.

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(46毫克，0.1毫莫耳)之二烷(2毫升)與水(0.7毫升)溶液中添加N-[(4-溴-1,3-噻唑-2-基)甲基]-2,2,2-三氟乙胺(30毫克，0.11毫莫耳)與碳酸鉀(83毫克，0.6毫莫耳)。所得混合物脫氣5分鐘後，添加肆(三苯基膦)鈀(0)(11毫克，0.01毫莫耳)。混合物於CEM微波管中，於160℃下反應20分鐘。分離有機層，與濃縮。所得殘質經Gilson製備性HPLC純化，產生25毫克標題化合物(47.2%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -吲哚-7-carboxyguanamine (46 mg, 0.1 mmol) Add N-[(4-bromo-1,3-thiazol-2-yl)methyl]-2,2,2-trifluoroethylamine (30 mg, in a solution of hexane (2 mL) and water (0.7 mL) 0.11 mM) with potassium carbonate (83 mg, 0.6 mmol). After the resulting mixture was degassed for 5 minutes, hydrazine (triphenylphosphine)palladium(0) (11 mg, 0.01 mmol) was added. The mixture was reacted in a CEM microwave tube at 160 ° C for 20 minutes. The organic layer was separated and concentrated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc)

LC/MS=m/z 530.2[M+H]滯留時間：1.94 LC/MS=m/z 530.2 [M+H] retention time: 1.94

實例41：5-(3-氰基-5-{[(2,2,2-三氟乙基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 41: 5-(3-Cyano-5-{[(2,2,2-trifluoroethyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)- 4-piperidinyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(46毫克，0.1毫莫耳)之二烷(2.0毫升，0.7毫升)溶液之微波管中添加3-溴-5-甲醯基苯基氰(68毫克，0.3毫莫耳)與K₂CO₃(83毫克，0.6毫莫耳)。反應混合物脫氣5分鐘後，添加肆(三苯基膦)鈀(0)(11毫克，0.01毫莫耳)。反應於微波爐中，於160℃下反應20分鐘。經Gilson製備性HPLC純化，產生5-(3-氰基-5-甲醯基苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -吲哚-7-carboxyguanamine (46 mg, 0.1 mmol) To a microwave tube of a solution of alkane (2.0 mL, 0.7 mL) was added 3-bromo-5-mercaptophenyl cyanide (68 mg, 0.3 mmol) with K ₂ CO ₃ (83 mg, 0.6 mmol). After the reaction mixture was degassed for 5 minutes, hydrazine (triphenylphosphine)palladium(0) (11 mg, 0.01 mmol) was added. The reaction was carried out in a microwave oven and reacted at 160 ° C for 20 minutes. Purified by Gilson preparative HPLC to give 5-(3-cyano-5-methylindenylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole -7-Carboxyguanamine.

在含5-(3-氰基-5-甲醯基苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(52毫克，0.11毫莫耳)之二氯甲烷(3毫升)與甲醇(1毫升)溶液中添加20滴乙酸與2,2,2-三氟乙胺(53微升，0.66毫莫耳)。攪拌混合物48小時後，添加三乙醯氧基氫硼化鈉(140毫克，0.66毫莫耳)。攪拌混合物48小時。所得反應經碳酸氫鈉中止反應，添加鹽水。分離有機層，經Gilson製備性HPLC純化，產生3.6毫克標題化合物(6.0%)。 In the presence of 5-(3-cyano-5-methylindenylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (52 mg, 0.11 mmol) of dichloromethane (3 ml) and methanol (1 ml) were added 20 drops of acetic acid and 2,2,2-trifluoroethylamine (53 μl, 0.66 mmol) . After the mixture was stirred for 48 hours, sodium triethoxysulfonium borohydride (140 mg, 0.66 mmol) was added. The mixture was stirred for 48 hours. The resulting reaction was quenched with sodium bicarbonate and brine was added. The organic layer was separated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 548.2[M+H]滯留時間：1.88 LC/MS=m/z 548.2 [M+H] retention time: 1.88

實例42：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(1-甲基-4-哌啶基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 42: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methyl-4-piperidyl)amino]methyl} -3-thienyl)-1 H -indole-7-carboxamide fluorotrifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)之二甲亞碸(2毫升)溶液中添加N,1-二甲基-4-哌啶胺(128.22毫克，1.0毫莫耳)、2滴乙酸，反應一夜。添加三乙醯氧基氫硼化鈉(212毫克，1毫莫耳)，於室溫下反應一夜。經Gilson製備性HPLC純化，產生8毫克標題化合物(13.0%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (50 N ,1-dimethyl-4-piperidinamine (128.22 mg, 1.0 mmol), 2 drops of acetic acid were added to a solution of dimethylidene (2 ml) in MeOH (0.11 mmol). Sodium triethoxy hydride hydride (212 mg, 1 mmol) was added and allowed to react at room temperature overnight. Purification by Gilson preparative HPLC gave 8 mg of the title compound (13.0%).

LC/MS=m/z 558.4[M+H]滯留時間：1.32分鐘 LC/MS=m/z 558.4 [M+H] retention time: 1.32 minutes

實例43：5-(5-{[(2-氰基乙基)(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 43: 5-(5-{[(2-Cyanoethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4- Piperidinyl]-1 H -吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(1-甲基-4-哌啶基)胺基]甲基}-3-噻吩基)-1H-吲哚-7- 羧醯胺三氟乙酸鹽之一般製程，但改用3-(甲基胺基)丙腈(84.12毫克，1.0毫莫耳)替代N,1-二甲基-4-哌啶胺製備，產生24毫克標題化合物(42.5%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methyl-4-piperidinyl)amino]methyl }-3-Thienyl)-1 H -吲哚-7- Carboxylamidine trifluoroacetate, but replaced with 3-(methylamino)propionitrile (84.12 mg, 1.0 mmol) Preparation of N ,1-dimethyl-4-piperidinamine gave 24 mg of the title compound (42.5%).

LC/MS=m/z 514.4[M+H]滯留時間：1.55分鐘 LC/MS = m / z 514.4 [M + H] retention time: 1.55 minutes

實例44：5-(5-{[(2-胺基-2-氧代乙基)(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 44: 5-(5-{[(2-Amino-2-oxoethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonate) Base)-4-piperidinyl]-1 H -indole-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(1-甲基-4-哌啶基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用N ²-甲基甘胺醯胺(88.11毫克，1.0毫莫耳)替代N,1-二甲基-4-哌啶胺製備，產生19毫克標題化合物(33.3%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methyl-4-piperidinyl)amino]methyl }-3-Thienyl)-1 H -吲哚-7-carboxamide guanamine trifluoroacetate, but with N ² -methylglycine decylamine (88.11 mg, 1.0 mM) instead of N Preparation of 1-dimethyl-4-piperidinamine gave 19 mg of the title compound (33.3%).

LC/MS=m/z 518.2[M+H]滯留時間：1.43分鐘 LC/MS = m / z 518.2 [M + H] retention time: 1.43 minutes

實例45：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({甲基[2-(苯基磺醯基)乙基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 45: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[2-(phenylsulfonyl)ethyl]amino}methyl) )-3-thienyl]-1 H -indole-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(1-甲基-4-哌啶基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用N-甲基-2-(苯基磺醯基)乙胺(199.27毫克，1.0毫莫耳)替代N,1-二甲基-4-哌啶胺製備，產生30毫克標題化合物(47.3%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methyl-4-piperidinyl)amino]methyl }-3-Thienyl)-1 H -indole-7-carboxamide guanamine trifluoroacetate, but using N-methyl-2-(phenylsulfonyl)ethylamine (199.27 mg, Preparation of 1.0 mmoles of N ,1-dimethyl-4-piperidinamine gave 30 mg of the title compound (47.3%).

LC/MS=m/z 629.4[M+H]滯留時間：1.57分鐘 LC/MS = m / z 629.4 [M + H] retention time: 1.57 minutes

實例46：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-苯基-1-吡咯啶基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺Example 46: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-thienyl} -1 H -吲哚-7-carboxyguanamine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)之DMSO(2.0毫升)溶液中添加2-苯基吡咯啶(147毫克，1.0毫莫耳)。反應混合物於微波爐中，於120℃下反應10分鐘。添加三乙醯氧基氫硼化鈉(220毫克，1.0毫莫耳)，於室溫下反應一夜。經Gilson製備性HPLC純化，產生14.0毫克標題化合物(22%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (50 To a solution of milligrams (0.11 mmol) in DMSO (2.0 mL) was added 2-phenylpyrrolidine (147 mg, 1.0 mmol). The reaction mixture was reacted in a microwave oven at 120 ° C for 10 minutes. Sodium triethoxy hydride hydride (220 mg, 1.0 mmol) was added and allowed to react at room temperature overnight. Purification by Gilson preparative HPLC gave 14.0 mg of the title compound (22%).

LC/MS=m/z 577.2[M+H]滯留時間：1.65分鐘。 LC/MS = m/z 577.2 [M+H].

實例47：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[2-(1-哌啶基甲基)-1-吡咯啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺Example 47: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(1-piperidinylmethyl)-1-pyrrolidinyl]methyl }-3-Thienyl)-1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-苯基-1-吡咯啶基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺之一般製程，但改用1-(2-吡咯啶基甲基)哌啶(168.3毫克，1.0毫莫耳)替代2-苯基吡咯啶製備，產生21毫克標題化合物(32%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-thienyl }-1 H -吲哚-7-carboxyguanamine general procedure, but instead of 1-(2-pyrrolidylmethyl)piperidine (168.3 mg, 1.0 mmol) instead of 2-phenylpyrrolidine Yield 21 mg of the title compound (32%).

LC/MS=m/z 598.4[M+H]滯留時間：1.34 LC/MS=m/z 598.4 [M+H] retention time: 1.34

實例48：5-(5-{[(2R)-2-(胺基羰基)-1-吡咯啶基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 48: 5-(5-{[(2 R )-2-(Aminocarbonyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-苯基-1-吡咯啶基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺之一般製程，但改用D-脯胺醯胺(114毫克，1.0毫莫耳)替代2-苯基吡咯啶製備，產生14毫克標題化合物(23%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-thienyl }-1 H -吲哚-7-carboxyguanamine general procedure, but instead of D-guanamine amine (114 mg, 1.0 mmol) instead of 2-phenylpyrrolidine, yielded 14 mg of the title compound ( twenty three%).

LC/MS=m/z 544.2[M+H]滯留時間：1.39 LC/MS=m/z 544.2 [M+H] retention time: 1.39

實例49：5-(5-{[(3S)-3-(二甲基胺基)-1-吡咯啶基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 49: 5- (5 - {[ (3 S) -3- ( dimethylamino) -1-pyrrolidinyl] methyl} -3-thienyl) -3- [1- (ethanesulfonamide Mercapto)-4-piperidinyl]-1 H -indole-7-carboxamide

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-苯基-1-吡咯啶基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺之一般製程，但改用(2R)-N,N-二甲基-2-吡咯啶胺(114毫克， 1.0毫莫耳)替代2-苯基吡咯啶製備，產生11毫克標題化合物(18%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-phenyl-1-pyrrolidinyl)methyl]-3-thienyl }-1 H -吲哚-7-carboxyguanamine general procedure, but instead of ( 2R ) -N , N -dimethyl-2-pyrrolidine (114 mg, 1.0 mmol) instead of 2- Preparation of phenylpyrrolidine gave 11 mg of the title compound (18%).

LC/MS=m/z 544.2[M+H]滯留時間：1.36 LC/MS=m/z 544.2 [M+H] retention time: 1.36

實例50：5-(1-{2-[4-(二甲基胺基)-1-哌啶基]乙基}-1H-吡唑-4-基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 50: 5-(1-{2-[4-(Dimethylamino)-1-piperidinyl]ethyl}-1H-pyrazol-4-yl)-3-[1-(ethyl Sulfomethyl)-4-piperidinyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(40毫克，0.090毫莫耳)之二烷(750微升)與H₂O(250微升)溶液中添加碳酸鈉(53毫克，0.50毫莫耳)與4-溴-1-(2-氯乙基)-1H-吡唑(26毫克，0.126毫莫耳)。反應混合物經氬氣沖刷10分鐘後，添加肆(三苯基膦)鈀(0)(5毫克，0.004毫莫耳)。反應於微波爐中，於120℃下加熱20分鐘。以EtOAc(10毫升)稀釋，經寅氏鹽過濾後，操作水相。化合物經Gilson製備性HPLC純化，產生10毫克5-[1-(2-氯乙基)-1H-吡唑-4-基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(24%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -吲哚-7-carboxamide (40 mg, 0.090 mmol) Add sodium carbonate (53 mg, 0.50 mmol) and 4 -bromo-1-(2-chloroethyl)-1 H -pyrazole to a solution of alkane (750 μl) and H ₂ O (250 μL). 26 mg, 0.126 mmol. After the reaction mixture was flushed with argon for 10 minutes, bis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) was added. The reaction was heated in a microwave oven at 120 ° C for 20 minutes. Diluted with EtOAc (10 mL) and filtered over EtOAc. The compound was purified by Gilson preparative HPLC to give 10 mg of 5-[1-(2-chloroethyl)-1 H -pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4- Piperidinyl]-1 H -indole-7-carboxamide (24%).

在含5-[1-(2-氯乙基)-1H-吡唑-4-基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(33毫克，0.071毫莫耳)之四氫呋喃(500微升)溶液中添加N,N-二甲基-4-哌啶胺(100微升，0.71毫莫耳)與碘化鈉(5毫克，0.018毫莫耳)。所得混合物於微波管中，於130℃下反應2小時。以EtOAc與水洗滌水相，分離有機層，排除所有溶劑。經Gilson製備性HPLC純化，產生7.0毫克標題化合物(14.7%)。 In the presence of 5-[1-(2-chloroethyl)-1 H -pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲Add N , N -dimethyl-4-piperidinamine (100 μl, 0.71 mmol) to a solution of 哚-7-carboxamide (33 mg, 0.071 mmol) in tetrahydrofuran (500 μL) Sodium iodide (5 mg, 0.018 mmol). The resulting mixture was reacted in a microwave tube at 130 ° C for 2 hours. The aqueous phase was washed with EtOAc and water and organic layer was separated and evaporated. Purification by Gilson preparative HPLC gave 7.0 mg of the title compound (14.7%).

LC/MS=m/z 556[M+H]滯留時間：1.23分鐘。 LC/MS = m/z 556 [M+H] retention: 1.23 min.

實例51：5-[3-[(二甲基胺基)甲基]-4,5-雙(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 51: 5-[3-[(Dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperider Pyridyl]-1H-indole-7-carboxamide

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(500毫克，1.09毫莫耳)之二烷(9.0毫升)與H₂O(3.0毫升)溶液中添加碳酸鈉(690毫克，6.51毫莫耳)與5-溴-2,3-雙(甲基氧)苯甲醛(7.95毫克，3.25毫莫耳)。反應混合物經氬氣沖刷10分鐘後，添加肆(三苯基膦)鈀(0)(63毫克，0.054毫莫耳)。反應於微波爐中，於120℃下加熱30分鐘。濃縮所有溶劑，以EtOAc與H₂O洗滌水相。使所需化合物沉澱，過濾，產生322毫克3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-甲醯基-4,5-雙(甲基氧)苯基]-1H-吲哚-7-羧醯胺(59%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (500 mg, 1.09 mmol) Dioxane (9.0 mL) and H ₂ O (3.0 mL) was added a solution of sodium carbonate (690 mg, 6.51 mmol) and 5-bromo-2,3-bis (meth oxy) benzaldehyde (7.95 mg, 3.25 mmol Moore). After the reaction mixture was flushed with argon for 10 minutes, hydrazine(triphenylphosphine)palladium(0) (63 mg, 0.054 mmol) was added. The reaction was heated in a microwave oven at 120 ° C for 30 minutes. All solvent was concentrated, EtOAc and H ₂ O in the aqueous phase is washed. The desired compound is precipitated and filtered to give 322 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-carbazin-4,5-bis(methyloxy) Phenyl]-1 H -indole-7-carboxamide (59%).

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-甲醯基-4,5-雙(甲基氧)苯基]-1H-吲哚-7-羧醯胺(30毫克，0.06毫莫耳)之甲醇(2毫升)溶液中添加氯化鋅(5毫克，0.03毫莫耳)、氰基氫硼化鈉(5毫克，0.06毫莫耳)與二甲基胺(100微升，0.30毫莫耳)。混合物於室溫下攪拌2小時後，於微波爐中，於100℃下反應30分鐘。所得混合物經Gilson製備性HPLC純化，產生11毫克標題化合物(34.7%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-methylindolyl-4,5-bis(methyloxy)phenyl]-1 H -吲哚Add zinc chloride (5 mg, 0.03 mmol) to sodium cyanoborohydride (5 mg, 0.06 mmol) in a solution of -7-carboxyguanamine (30 mg, 0.06 mmol) in methanol (2 mL) Ear) with dimethylamine (100 μl, 0.30 mmol). After the mixture was stirred at room temperature for 2 hours, it was reacted in a microwave oven at 100 ° C for 30 minutes. The resulting mixture was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 529[M+H]滯留時間：1.67分鐘。 LC/MS = m/z 529 [M+H].

實例52：5-[3,4-雙(甲基氧)-5-(4-嗎啉基甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 52: 5-[3,4-Bis(methyloxy)-5-(4-morpholinylmethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl ]-1H-吲哚-7-carboxyguanamine

標題化合物係依據5-[3-[(二甲基胺基)甲基]-4,5-雙(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用嗎啉(20微升，0.30毫莫耳)替代二甲基胺製備，產生8.0毫克標題化合物(23.4%)。 The title compound is based on 5-[3-[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4- Piperidinyl]-1H-indole-7-carboxyguanamine The general procedure, but instead of morpholine (20 microliters, 0.30 millimoles) instead of dimethylamine, yielded 8.0 mg of the title compound (23.4%).

LC/MS=m/z 571[M+H]滯留時間：1.59分鐘。 LC/MS = m/z 571 [M+H].

實例53：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-{[(1-甲基乙基)胺基]甲基}-4,5-雙(甲基氧)苯基]-1H-吲哚-7-羧醯胺Example 53: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-{[(1-methylethyl)amino]methyl}-4,5-bis (methyloxy)phenyl]-1H-indole-7-carboxyguanamine

標題化合物係依據5-[3-[(二甲基胺基)甲基]-4,5-雙(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用2-丙胺(20微升，0.30毫莫耳)替代二甲基胺製備，產生15毫克標題化合物(46.1%)。 The title compound is based on 5-[3-[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4- General procedure for piperidinyl]-1H-indole-7-carboxamide, but using 2-propylamine (20 μL, 0.30 mmol) instead of dimethylamine to give 15 mg of the title compound (46.1% ).

LC/MS=m/z 543[M+H]滯留時間：1.59分鐘。 LC/MS = m/z 543 [M+H].

實例54：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-{[(1-甲基乙基)胺基]甲基}-4,5-雙(甲基氧)苯基]-1H-吲哚-7-羧醯胺Example 54: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-{[(1-methylethyl)amino]methyl}-4,5-bis (methyloxy)phenyl]-1H-indole-7-carboxyguanamine

標題化合物係依據5-[3-[(二甲基胺基)甲基]-4,5-雙(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用40 wt.%甲基胺(50微升，0.30毫莫耳)替代二甲基胺製備，產生6毫克標題化合物(19.4%)。 The title compound is based on 5-[3-[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4- General procedure for piperidinyl]-1H-indole-7-carboxamide. Instead, use 40 wt.% methylamine (50 μL, 0.30 mmol) instead of dimethylamine to give a 6 mg heading. Compound (19.4%).

LC/MS=m/z 515[M+H]滯留時間：1.46分鐘。 LC/MS = m/z 515 [M+H].

實例55：5-[3-{[(2,2-二甲基丙基)胺基]甲基}-4,5-雙(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 55: 5-[3-{[(2,2-Dimethylpropyl)amino]methyl}-4,5-bis(methyloxy)phenyl]-3-[1-(ethyl Sulfomethyl)-4-piperidinyl]-1H-indole-7-carboxamide

標題化合物係依據5-[3-[(二甲基胺基)甲基]-4,5-雙(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之製程，但改用(2,2-二甲基丙基)胺(20微升，0.30毫莫耳)替代二甲基胺製備，產生10毫克標題化合物(29.2%)。 The title compound is based on 5-[3-[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4- Process for piperidinyl]-1H-indole-7-carboxamide, but instead using (2,2-dimethylpropyl)amine (20 μL, 0.30 mmol) instead of dimethylamine, Yield 10 mg of the title compound (29.2%).

LC/MS=m/z 571[M+H]滯留時間：1.75分鐘。 LC/MS = m/z 571 [M + H].

實例56：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-{[(2-羥基乙基)(甲基)胺基]甲基}-4,5-雙(甲基氧)苯基]-1H-吲哚-7-羧醯胺Example 56: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-{[(2-hydroxyethyl)(methyl)amino]methyl}-4, 5-bis(methyloxy)phenyl]-1H-indole-7-carboxamide

標題化合物係依據5-[3-[(二甲基胺基)甲基]-4,5-雙(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用2-(甲基胺基)乙醇(20微升，0.30毫莫耳)替代二甲基胺製備，產生10毫克標題化合物(29.8%)。 The title compound is based on 5-[3-[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4- General procedure for piperidinyl]-1H-indole-7-carboxamide, but instead of 2-(methylamino)ethanol (20 μL, 0.30 mmol) instead of dimethylamine, yield 10 Mg title compound (29.8%).

LC/MS=m/z 559[M+H]滯留時間：1.54分鐘。 LC/MS = m/z 559 [M+H].

實例57：5-[3,4-雙(甲基氧)-5-(1-吡咯啶基甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 57: 5-[3,4-Bis(methyloxy)-5-(1-pyrrolidinylmethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl ]-1H-吲哚-7-carboxyguanamine

標題化合物係依據5-[3-[(二甲基胺基)甲基]-4,5-雙(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用吡咯啶(50微升，0.30毫莫耳)替代二甲基胺製備，產生13毫克標題化合物(39.1%)。 The title compound is based on 5-[3-[(dimethylamino)methyl]-4,5-bis(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4- General procedure for piperidinyl]-1H-indole-7-carboxamide, but using pyrrolidine (50 μL, 0.30 mmol) instead of dimethylamine to give 13 mg of the title compound (39.1%) .

LC/MS=m/z 555[M+H]滯留時間：1.61分鐘。 LC/MS = m/z 555 [M+H] retention: 1.61 min.

實例58：5-{4-[(二甲基胺基)甲基]-2,3-二氫-1-苯并呋喃-6-基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 58: 5-{4-[(Dimethylamino)methyl]-2,3-dihydro-1-benzofuran-6-yl}-3-[1-(ethylsulfonyl) 4-piperidinyl]-1H-indole-7-carboxamide

在含5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(113毫克，0.274毫莫耳)之二烷(9.0毫升)與H₂O(3.0毫升)溶液中添加碳酸鈉(174毫克，1.64毫莫耳)與6-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-2,3-二氫-1-苯并呋喃-4-甲醛(150毫克，0.547毫莫耳)。反應混合物經氬氣沖刷10分鐘後，添加肆(三苯基膦)鈀(0)(16毫克，0.014毫莫耳)。反應於微波爐中，於120℃下反應30分鐘。濃縮所有溶劑，經急驟層析法，使用DCM與MeOH純化，產生120毫克3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基-2,3-二氫-1-苯并呋喃-6-基)-1H-吲哚-7-羧醯胺(91%)。 In the presence of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxamide (113 mg, 0.274 mmol) Add sodium carbonate (174 mg, 1.64 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-di) to a solution of alkane (9.0 mL) and H ₂ O (3.0 mL) Oxoborolan-2-yl)-2,3-dihydro-1-benzofuran-4-carbaldehyde (150 mg, 0.547 mmol). After the reaction mixture was flushed with argon for 10 minutes, hydrazine(triphenylphosphine)palladium(0) (16 mg, 0.014 mmol) was added. The reaction was carried out in a microwave oven and reacted at 120 ° C for 30 minutes. All solvents were concentrated and purified by flash chromatography using EtOAc EtOAc EtOAc EtOAc 3-Dihydro-1-benzofuran-6-yl)-1 H -indole-7-carboxamide (91%).

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基-2,3-二氫-1-苯并呋喃-6-基)-1H-吲哚-7-羧醯胺(20毫克，0.042毫莫耳)之甲醇(2毫升)溶液中添加二甲基胺(3微升，0.050毫莫耳)、氯化鋅(3毫克，0.021毫莫耳)與氰基氫硼化鈉(4毫克，0.062毫莫耳)。此混合物於微波爐中，於100℃下反應1小時後，排除所有溶劑。殘質經EtOAc與水洗滌。排除所有溶劑，經Gilson製備性HPLC純化，產生6.0毫克標題化合物(19.6%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-carbamimido-2,3-dihydro-1-benzofuran-6-yl)-1 Add dimethylamine (3 μL, 0.050 mmol) to zinc chloride (3 mg, in a solution of H -indole-7-carboxamide (20 mg, 0.042 mmol) in methanol (2 mL) 0.021 mmoles with sodium cyanoborohydride (4 mg, 0.062 mmol). This mixture was subjected to a reaction in a microwave oven at 100 ° C for 1 hour to remove all solvents. The residue was washed with EtOAc and water. All solvents were removed and purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 525[M+H]滯留時間：1.56分鐘。 LC/MS = m/z 525 [M+H].

實例59：3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(1-甲基乙基)胺基]甲基}-2,3-二氫-1-苯并呋喃-6-基)-1H-吲哚-7-羧醯胺Example 59: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(4-{[(1-methylethyl)amino]methyl}-2,3-di Hydrogen-1-benzofuran-6-yl)-1H-indole-7-carboxamide

標題化合物係依據5-{4-[(二甲基胺基)甲基]-2,3-二氫-1-苯并呋喃-6-基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用2-丙胺(3毫克，0.050毫莫耳)替代二甲基胺製備，產生9.0毫克標題化合物(28.6%)。 The title compound is based on 5-{4-[(dimethylamino)methyl]-2,3-dihydro-1-benzofuran-6-yl}-3-[1-(ethylsulfonyl) a general procedure for the preparation of 4-piperidinyl]-1H-indole-7-carboxamide, but using 2-propylamine (3 mg, 0.050 mmol) instead of dimethylamine to give 9.0 mg of the title compound (28.6%).

LC/MS=m/z 511[M+H]滯留時間：1.58分鐘。 LC/MS = m/z 511 [M+H].

實例60：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(4-嗎啉基甲基)-2,3-二氫-1-苯并呋喃-6-基]-1H-吲哚-7-羧醯胺Example 60: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[4-(4-morpholinylmethyl)-2,3-dihydro-1-benzofuran -6-yl]-1H-indole-7-carboxyguanamine

標題化合物係依據5-{4-[(二甲基胺基)甲基]-2,3-二氫-1-苯并呋喃-6-基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用2,2-二甲基-1-丙胺(4毫克，0.050毫莫耳)替代二甲基胺製備，產生8.0毫克標題化合物(24.1%)。 The title compound is based on 5-{4-[(dimethylamino)methyl]-2,3-dihydro-1-benzofuran-6-yl}-3-[1-(ethylsulfonyl) a general procedure for 4-piperidinyl]-1H-indole-7-carboxamide, but instead of 2,2-dimethyl-1-propylamine (4 mg, 0.050 mmol) instead of dimethyl The amine was prepared to give 8.0 mg of the title compound (24.1%).

LC/MS=m/z 554[M+H]滯留時間：1.71分鐘。 LC/MS = m/z 554 [M+H].

實例61：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[1-甲基-2-(甲基氧)乙基]胺基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺Example 61: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({[1-methyl-2-(methyloxy)ethyl]amino}} 2-thiophenyl]-1 H -indole-7-carboxyguanamine

使用甲醇轉移[5-({[1-甲基-2-(甲基氧)乙基]胺基}甲基)-2-噻吩基]二羥硼酸(60毫克，0.262毫莫耳)至CEM微波管中。於氮氣流下蒸發甲醇。添加5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(80毫克，0.19毫莫耳)、碳酸鉀(160毫克，1.16毫莫耳)、肆(三苯基膦)鈀(0)(5毫克，0.004毫莫耳)、二烷(1.5毫升)與水(0.5毫升)。反應瓶加蓋，於CEM微波爐中，於150℃下反應30分鐘。添加此溶液至先添加3毫升甲醇之2克SCX SPE卡管中。卡管依序經水(3毫升)、甲醇(9毫升)與2M NH₃之MeOH溶液(6毫升)溶離。取NH₃之MeOH溶液部份於氮氣流與40℃下乾燥。粗產物溶於二甲亞碸(1毫升)，經Agilent MDAP純化，使用UV(230 nm)與MS檢測。取所需溶離份連續通過兩個先添加1毫升甲醇與1毫升水之500毫克Pharmasil CHQAX卡管。於氮氣流與60℃下蒸發排除溶劑，產生34.7毫克標題化合物(34%)。 Transfer of [5-({[1-methyl-2-(methyloxy)ethyl]amino}methyl)-2-thienyl]dihydroxyboronic acid (60 mg, 0.262 mmol) to CEM using methanol In the microwave tube. The methanol was evaporated under a stream of nitrogen. Add 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (80 mg, 0.19 mmol), potassium carbonate (160) Mg, 1.16 mmol, 肆 (triphenylphosphine) palladium (0) (5 mg, 0.004 mmol), II Alkane (1.5 ml) with water (0.5 ml). The reaction flask was capped and reacted in a CEM microwave oven at 150 ° C for 30 minutes. This solution was added to a 2 g SCX SPE cartridge with 3 ml of methanol added first. Stuck pipe sequentially with water (3 mL), methanol (9 mL) and of 2M NH ₃ in MeOH (6 ml) fractions. The NH ₃ MeOH solution portion was dried under a nitrogen stream at 40 ° C. The crude product was dissolved in dimethyl hydrazine (1 mL), purified by Agilent <RTIgt; The desired fraction was taken continuously through two 500 mg Pharmasil CHQAX cartridges with 1 ml of methanol and 1 ml of water. The solvent was evaporated under a nitrogen stream at 60 ° C to yield 34.7 mg of the title compound (34%).

LC/MS=m/z 430[M+H]滯留時間：1.32分鐘。 LC/MS = m/z 430 [M+H] retention time: 1.32 min.

實例62：5-(5-{[(2-氰基乙基)胺基]甲基}-3-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 62: 5-(5-{[(2-Cyanoethyl)amino]methyl}-3-pyridyl)-3-[1-(ethylsulfonyl)-4-piperidinyl] -1 H -吲哚-7-carboxyguanamine

在5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(30毫克，0.072毫莫耳)中添加3-({[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺基)丙腈(24.8毫克，0.086毫莫耳)。在此混合物中添加二烷(0.75毫升)後，添加含碳酸鉀(60毫克，0.434毫莫耳)之水溶液(0.25毫升)與SK-CC02-A(4.4毫克，0.007毫莫耳)。反應瓶加蓋，於CEM微波爐中，於150℃下反應30分鐘。添加此溶液至先添加3毫升甲醇之2克SCX SPE卡管中。卡管依序經水(3毫升)、甲醇(9毫升)與2M NH₃之MeOH溶液(6毫升)溶離。取NH₃之MeOH溶液部份於氮氣流與40℃下乾燥。粗產物經Agilent MDAP純化，使用UV(230 nm)與MS檢測。取所需溶離份通過先添加4毫升甲醇與4毫升水之5克CHQAX卡管。於氮氣流與65℃下蒸發排除溶劑，產生6.2毫克標題化合物(17.4%)。 Add 3-(5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxamide (30 mg, 0.072 mmol) {[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]methyl}amino)propanenitrile (24.8 mg , 0.086 millimoles). Add two to this mixture After the alkane (0.75 ml), aqueous solution (0.25 mL) and potassium carbonate (60 mg, 0.434 m. The reaction flask was capped and reacted in a CEM microwave oven at 150 ° C for 30 minutes. This solution was added to a 2 g SCX SPE cartridge with 3 ml of methanol added first. Stuck pipe sequentially with water (3 mL), methanol (9 mL) and of 2M NH ₃ in MeOH (6 ml) fractions. The NH ₃ MeOH solution portion was dried under a nitrogen stream at 40 ° C. The crude product was purified by Agilent MDAP using UV (230 nm) and MS. The desired fraction was taken by first adding 5 ml of CHQAX cartridge with 4 ml of methanol and 4 ml of water. The solvent was evaporated under a nitrogen stream at 65 ° C to give 6.2 mg of the title compound (17.4%).

LC/MS=m/z 495[M+H]滯留時間：1.29分鐘。 LC/MS = m/z 495 [M+H].

實例63：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2,2,2-三氟乙基)胺基]甲基}-3-吡啶基)-1H-吲哚-7-羧醯胺Example 63: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2,2,2-trifluoroethyl)amino]methyl}-3 -pyridyl)-1 H -吲哚-7-carboxyguanamine

標題化合物係依據5-(5-{[(2-氰基乙基)胺基]甲基}-3-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用2,2,2-三氟-N-{[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}乙胺(24.3毫克，0.077毫莫耳)替代3-({[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺基)丙腈製備，產生8.3毫克標題化合物(22.0%)。 The title compound is based on 5-(5-{[(2-cyanoethyl)amino]methyl}-3-pyridyl)-3-[1-(ethylsulfonyl)-4-piperidinyl ]-1 H -吲哚-7-carboxyguanamine general process, but switched to 2,2,2-trifluoro- N -{[5-(4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)-3-pyridyl]methyl}ethylamine (24.3 mg, 0.077 mmol) instead of 3-({[5-(4,4,5,5) Preparation of tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]methyl}amino)propanenitrile gave 8.3 mg of the title compound (22.0%).

LC/MS=m/z 524[M+H]滯留時間：1.55分鐘。 LC/MS = m/z 524 [M+H].

實例64：5-{3-[(二甲基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 64: 5-{3-[(Dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7 -carboxamide

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(45毫克，0.10毫莫耳)之DMSO(2毫升)溶液中添加2 M二甲基胺之THF溶液(500微升，1.0毫莫耳)。反應混合物於室溫下攪拌5小時後，添加三乙醯氧基氫硼化鈉(220毫克，1.04毫莫耳)。攪拌反應一夜。化合物經Gilson製備性HPLC純化，產生9.0毫克標題化合物(19.2%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxamide (45 mg, 0.10) A solution of 2 M dimethylamine in THF (500 μL, 1.0 mmol) was added to a solution of MeOH (2 mL). After the reaction mixture was stirred at room temperature for 5 hours, sodium triethyl sulfoxide (220 mg, 1.04 mmol) was added. Stir the reaction overnight. The compound was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 469[M+H]滯留時間：1.55分鐘 LC/MS=m/z 469 [M+H] retention time: 1.55 minutes

實例65：5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 65: 5-(5-{[Ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)之二甲亞碸(2毫升)溶液中添加N-甲基乙胺(59.1毫克，1.0毫莫耳)、2滴乙酸，並反應一夜。添加三乙醯氧基氫硼化鈉(212毫克，1毫莫耳)，於室溫下反應一夜。然後經Gilson製備性HPLC純化，產生20.0毫克標題化合物(33.2%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (50 To a solution of dimethylidene (2 ml) in milligrams (0.11 mmol) was added N -methylethylamine (59.1 mg, 1.0 mmol), and two portions of acetic acid, and reacted overnight. Sodium triethoxy hydride hydride (212 mg, 1 mmol) was added and allowed to react at room temperature overnight. Purification by Gilson preparative HPLC gave 20.0 mg of the title compound (33.2%).

LC/MS=m/z 489[M+H]滯留時間：1.50分鐘 LC/MS=m/z 489 [M+H] retention time: 1.50 minutes

實例66：5-(5-{[[2-(二乙基胺基)乙基](甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 66: 5-(5-{[[2-(Diethylamino)ethyl](methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonate) Base)-4-piperidinyl]-1 H -indole-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用N,N-二乙基-N'-甲基-1,2-乙二胺(130毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生30.0毫克標題化合物(44.5%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxamide guanamine trifluoroacetate, but using N , N -diethyl- N '-methyl-1,2-ethanediamine (130 mg, 1.0 mmol) The preparation of the title compound (44.5%) was obtained by substituting N -methylethylamine.

LC/MS=m/z 560[M+H]滯留時間：1.41分鐘。 LC/MS = m/z 560 [M+H].

實例67：5-(5-{[丁基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 67: 5-(5-{[butyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用丁基(甲基)胺(87毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生10毫克標題化合物(15.8%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxamide guanamine trifluoroacetate, but using butyl (methyl)amine (87 mg, 1.0 mmol) instead of N -methylethylamine to give 10 mg The title compound (15.8%).

LC/MS=m/z 517[M+H]滯留時間：1.61分鐘。 LC/MS = m/z 517 [M+H] retention: 1.61 min.

實例68：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 68: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(propyl)amino]methyl}-3-thienyl)-1 H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用甲基(丙基)胺(73毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生20.0毫克標題化合物(32.4%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxamide guanamine trifluoroacetate, but using methyl (propyl)amine (73 mg, 1.0 mmol) instead of N -methylethylamine to give 20.0 mg The title compound (32.4%).

LC/MS=m/z 503[M+H]滯留時間：1.54分鐘。 LC/MS = m/z 503 [M+H].

實例69：5-(5-{[[2-(二甲基胺基)乙基](甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 69: 5-(5-{[[2-(Dimethylamino)ethyl](methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonate) Base)-4-piperidinyl]-1 H -indole-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用[2-(二甲基胺基)乙基]甲基胺(102毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生26.0毫克標題化合物(40.3%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxyguanamine trifluoroacetate, but using [2-(dimethylamino)ethyl]methylamine (102 mg, 1.0 mmol) instead of N- Preparation of methylethylamine gave 26.0 mg of the title compound (40.3%).

LC/MS=m/z 532[M+H]滯留時間：1.48分鐘。 LC/MS = m/z 532 [M+H] retention time: 1.48 min.

實例70：5-(5-{[[3-(二甲基胺基)丙基](甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 70: 5-(5-{[[3-(Dimethylamino)propyl](methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonate) Base)-4-piperidinyl]-1 H -indole-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用[3-(二甲基胺基)丙基]甲基胺(116毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生21.0毫克標題化合物(31.8%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxyguanamine trifluoroacetate, but using [3-(dimethylamino)propyl]methylamine (116 mg, 1.0 mmol) instead of N- Methylethylamine was prepared to give 21.0 mg of the title compound (31.8%).

LC/MS=m/z 546[M+H]滯留時間：1.49分鐘。 LC/MS = m/z 546 [M+H].

實例71：5-(5-{[環戊基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 71: 5-(5-{[Cyclopentyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用環戊基(甲基)胺(99毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生5.0毫克標題化合物(7.78%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxamide guanamine trifluoroacetate, but using cyclopentyl (methyl)amine (99 mg, 1.0 mmol) instead of N -methylethylamine to produce 5.0 Mg title compound (7.78%).

LC/MS=m/z 529[M+H]滯留時間：1.65分鐘。 LC/MS = m/z 529 [M+H].

實例72：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(戊基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 72: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(pentyl)amino]methyl}-3-thienyl)-1 H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用甲基(戊基)胺(101毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生19.0毫克標題化合物(29.5%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxamide guanamine trifluoroacetate, but using methyl (pentyl)amine (101 mg, 1.0 mmol) instead of N -methylethylamine to give 19.0 mg The title compound (29.5%).

LC/MS=m/z 531[M+H]滯留時間：161分鐘。 LC/MS = m/z 531 [M+H]: 161 min.

實例73：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(2-甲基丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 73: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(2-methylpropyl)amino]methyl}-3-thiophene -1 H -吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用甲基(2-甲基丙基)胺(87毫克， 1.0毫莫耳)替代N-甲基乙胺製備，產生3.0毫克標題化合物(4.8%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxyguanamine trifluoroacetate, but using methyl (2-methylpropyl)amine (87 mg, 1.0 mmol) instead of N -methylethylamine Yield 3.0 mg of the title compound (4.8%).

實例74：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(苯基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 74: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(phenylmethyl)amino]methyl}-3-thienyl) -1 H -吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用甲基(苯基甲基)胺(121毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生15毫克標題化合物(22.6%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxamide guanamine trifluoroacetate, but using methyl (phenylmethyl)amine (121 mg, 1.0 mmol) instead of N -methylethylamine to produce 15 mg of the title compound (22.6%).

LC/MS=m/z 551[M+H]滯留時間：1.67分鐘。 LC/MS = m/z 551 [M+H] retention time: 1.67 min.

實例75：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-羥基乙基)(甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 75: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-hydroxyethyl)(methyl)amino]methyl}-3- Thienyl)-1 H -吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-(甲基胺基)乙醇(75毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生27.0毫克標題化合物(43.6%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxamide guanamine trifluoroacetate, but using 2-(methylamino)ethanol (75 mg, 1.0 mmol) instead of N -methylethylamine to produce 27.0 mg of the title compound (43.6%).

LC/MS=m/z 505[M+H]滯留時間：1.46分鐘。 LC/MS = m/z 505 [M+H].

實例76：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({甲基[2-(2-吡啶基)乙基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 76: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[2-(2-pyridyl)ethyl]amino}methyl) -3-thienyl]-1 H -吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用甲基[2-(2-吡啶基)乙基]胺(75毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生5.0毫克標題化合物(7.36%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxamide guanamine trifluoroacetate, but replaced with methyl [2-(2-pyridyl)ethyl]amine (75 mg, 1.0 mmol) instead of N -A The ethylamine was prepared to give 5.0 mg of the title compound (7.36%).

LC/MS=m/z 566[M+H]滯留時間：1.59分鐘。 LC/MS = m/z 566 [M+H].

實例77：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-呋喃基甲基)(甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 77: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-furylmethyl)(methyl)amino]methyl}-3 -thienyl)-1 H -indole-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用1-(2-呋喃基)-N-甲基甲胺(111毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生19.0毫克標題化合物(29.0%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxamide guanamine trifluoroacetate, but instead of 1-(2-furyl) -N -methylmethylamine (111 mg, 1.0 mmol) instead of N -A The ethylamine was prepared to give 19.0 mg of the title compound (29.0%).

LC/MS=m/z 541[M+H]滯留時間：1.59分鐘。 LC/MS = m/z 541 [M+H].

實例78：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(4-吡啶基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 78: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(4-pyridylmethyl)amino]methyl}-3-thiophene -1 H -吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用甲基(4-吡啶基甲基)胺(122毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生31.0毫克標題化合物(46.6%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- Preparation of 1 H -吲哚-7-carboxamide fluorotrifluoroacetate, but using methyl (4-pyridylmethyl)amine (122 mg, 1.0 mmol) instead of N -methylethylamine Yield 31.0 mg of the title compound (46.6%).

LC/MS=m/z 552[M+H]滯留時間：1.37分鐘。 LC/MS = m/z 552 [M+H].

實例79：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(甲基{[1-(1-甲基乙基)-3-吡咯啶基]甲基}胺基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 79: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[(methyl{[1-(1-methylethyl)-3-pyrrolidinyl) Methyl}amino)methyl]-3-thienyl}-1 H -indole-7-carboxamide fluorotrifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用甲基{[1-(1-甲基乙基)-3-吡咯啶基]甲基}胺(156毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生21.0毫克標題化合物(30.0%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxamide guanamine trifluoroacetate, but with methyl {[1-(1-methylethyl)-3-pyrrolidinyl]methyl}amine (156 mg) Prepared by substituting N -methylethylamine to give 21.0 mg of the title compound (30.0%).

LC/MS=m/z 586[M+H]滯留時間：1.43分鐘。 LC/MS = m/z 586 [M+H].

實例80：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(2-噻吩基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 80: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(2-thienylmethyl)amino]methyl}-3-thiophene -1 H -吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用甲基(2-噻吩基甲基)胺(127毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生26.0毫克標題化合物(38.8%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- General procedure for 1 H -吲哚-7-carboxyguanamine trifluoroacetate, but instead of methyl (2-thienylmethyl)amine (127 mg, 1.0 mmol) instead of N -methylethylamine Yield 26.0 mg of the title compound (38.8%).

LC/MS=m/z 557[M+H]滯留時間：1.72分鐘。 LC/MS = m/z 557 [M+H].

實例81：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({甲基[1-(2-噻吩基)乙基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 81: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[1-(2-thienyl)ethyl]amino}methyl) -3-thienyl]-1 H -吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用甲基[1-(2-噻吩基)乙基]胺(141毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生6.0毫克標題化合物(8.76%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- General procedure for 1H-indole-7-carboxyguanamine trifluoroacetate, but instead of methyl [1-(2-thienyl)ethyl]amine (141 mg, 1.0 mmol) instead of N -methyl Ethylamine was prepared to give 6.0 mg of the title compound (8.76%).

LC/MS=m/z 571[M+H]滯留時間：1.78分鐘。 LC/MS = m/z 571 [M+H].

實例82：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(3-噻吩基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 82: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(3-thienylmethyl)amino]methyl}-3-thiophene -1 H -吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用甲基(3-噻吩基甲基)胺(127毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生7.0毫克標題化合物(10.4%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxyguanamine trifluoroacetate, but using methyl (3-thienylmethyl)amine (127 mg, 1.0 mmol) instead of N-methylethylamine , yielded 7.0 mg of the title compound (10.4%).

LC/MS=m/z 557[M+H]滯留時間：1.78分鐘。 LC/MS = m/z 557 [M+H].

實例83：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(四氫-2H-吡喃-4-基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 83: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(tetrahydro-2 H -pyran-4-ylmethyl)amino) ]methyl}-3-thienyl)-1 H -indole-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用甲基(四氫-2H-吡喃-4-基甲基)胺(129毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生11.0毫克標題化合物(16.4%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- General procedure for 1 H -吲哚-7-carboxamide fluorotrifluoroacetate, but with methyl (tetrahydro-2 H -pyran-4-ylmethyl)amine (129 mg, 1.0 mmol) Substitution of N-methylethylamine gave 11.0 mg of the title compound (16.4%).

LC/MS=m/z 559[M+H]滯留時間：1.63分鐘。 LC/MS = m/z 559 [M+H] retention time: 1.63 min.

實例84：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(3-吡啶基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 84: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(3-pyridylmethyl)amino]methyl}-3-thiophene -1 H -吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用甲基(3-吡啶基甲基)胺(122毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生9.5毫克標題化合物(14.3%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- General procedure for 1 H -indole-7-carboxime trifluoroacetate, but using methyl (3-pyridylmethyl)amine (122 mg, 1.0 mmol) instead of N-methylethylamine Yield 9.5 mg of the title compound (14.3%).

LC/MS=m/z 552[M+H]滯留時間：1.56分鐘。 LC/MS = m/z 552 [M+H].

實例85：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(4-嘧啶基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 85: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(4-pyrimidylmethyl)amino]methyl}-3-thiophene -1 H -吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用甲基(4-嘧啶基甲基)胺(123毫克，1.0毫莫耳)替代N-甲基乙胺製備，產生4.0毫克標題化合物(6.0%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxyguanamine trifluoroacetate, but using methyl (4-pyrimidinylmethyl)amine (123 mg, 1.0 mmol) instead of N-methylethylamine Yield 4.0 mg of the title compound (6.0%).

LC/MS=m/z 555[M+H]滯留時間：1.65分鐘。 LC/MS = m/z 555 [M+H] retention time: 1.65 min.

實例86：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({甲基[2-(甲基氧)乙基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 86: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[2-(methyloxy)ethyl]amino}methyl)- 3-thienyl]-1 H -indole-7-carboxamide fluorotrifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(884毫克，1.98毫莫耳)之二甲亞碸(5毫升)溶液中添加甲基[2-(甲基氧)乙基]胺(1.86克，21毫莫耳)與HOAc(2毫升，35毫莫耳)。於室溫下攪拌反應一夜，添加三乙醯氧基氫硼化鈉(212毫克，1毫莫耳)。續攪拌1小時，添加CHCl₃(50毫升)。混合物過濾，減壓濃縮CHCl₃，粗產物/DMSO溶液經Gilson製備性HPLC純化，產生標題化合物(590毫克，47%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (884 Add millimethyl [2-(methyloxy)ethyl]amine (1.86 g, 21 mmol) to HOAc (2 mL, 35 mM) in MeOH (1.98 mmol). Moore). The reaction was stirred overnight at room temperature and sodium triethyloxy borohydride (212 mg, 1 mmol) was added. Stirring was continued for 1 h, CHCl ₃ (50 mL). The mixture was filtered, concentrated CHCl _3, the crude product was purified by preparative HPLC / DMSO solution by Gilson reduced pressure to give the title compound (590 mg, 47%).

LC/MS=m/z 519[M+H]滯留時間：1.50分鐘。 LC/MS = m/z 519 [M+H].

實例87：5-{3-[(二甲基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 87: 5-{3-[(Dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7 -Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(45毫克，0.1毫莫耳)之DMSO(2毫升)溶液中添加2 M甲基胺之THF溶液(500微升，1.0毫莫耳)，於室溫下攪拌5小時。在混合物中添加三乙醯氧基氫硼化鈉(220毫克，1.0毫莫耳)，攪拌一夜。經Gilson製備性HPLC純化，產生9.0毫克標題化合物(15.4%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxamide (45 mg, 0.1 A solution of 2 M methylamine in THF (500 μL, 1.0 mmol) was added to a solution of MeOH (2 mL) and stirred at room temperature for 5 hr. Sodium triethoxysulfonium borohydride (220 mg, 1.0 mmol) was added to the mixture and stirred overnight. Purification by Gilson preparative HPLC gave 9.0 mg of the title compound (15.4%).

LC/MS=m/z 469[M+H]滯留時間：1.55分鐘。 LC/MS = m/z 469 [M+H].

實例88：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(1-甲基乙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 88: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylethyl)amino]methyl}-3-thiophene -1 H -吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(46.0毫克，0.1毫莫耳)之DMSO(2.0毫升)溶液中添加N-甲基-2-丙胺(73.1毫克，1.0毫莫耳)。反應混合物於微波爐中，於160℃下反應10分鐘。添加三乙醯氧基氫硼化鈉(220毫克，1.0毫莫耳)，於室溫下反應一夜。經Gilson製備性HPLC純化，產生24.0毫克標題化合物(44.2%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (46.0 N-methyl-2-propylamine (73.1 mg, 1.0 mmol) was added to a solution of mM (0.1 mL) in DMSO (2.0 mL). The reaction mixture was reacted in a microwave oven at 160 ° C for 10 minutes. Sodium triethoxy hydride hydride (220 mg, 1.0 mmol) was added and allowed to react at room temperature overnight. Purification by Gilson preparative HPLC gave 24.0 mg of the title compound (44.2%).

LC/MS=m/z 543[M+H]滯留時間：1.70分鐘。 LC/MS = m/z 543 [M+H].

實例89：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-丙基-1-吡咯啶基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺Example 89: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl} -1 H -吲哚-7-carboxyguanamine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)之DMSO(2.0毫升)溶液中添加2-丙基吡咯啶(113毫克，1.0毫莫耳)。反應混合物於微波爐中，於120℃下反應10分鐘。添加三乙醯氧基氫硼化鈉(220毫克，1.0毫莫耳)，於室溫下反應一夜。經Gilson製備性HPLC純化，產生21.0毫克標題化合物(38.7%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (50 To a solution of milligrams (0.11 mmol) in DMSO (2.0 mL) was added 2-propylpyrrolidine (113 mg, 1.0 mmol). The reaction mixture was reacted in a microwave oven at 120 ° C for 10 minutes. Sodium triethoxy hydride hydride (220 mg, 1.0 mmol) was added and allowed to react at room temperature overnight. Purification by Gilson preparative HPLC gave 21.0 mg of the title compound (38.7%).

LC/MS=m/z 543[M+H]滯留時間：1.70分鐘。 LC/MS = m/z 543 [M+H].

實例90：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[2-(3-吡啶基)-1-吡咯啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺Example 90: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(3-pyridyl)-1-pyrrolidinyl]methyl}-3 -thienyl)-1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-丙基-1-吡咯啶基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺之一般製程，但改用3-(2-吡咯啶基)吡啶(148毫克，1.0毫莫耳)替代2-丙基吡咯啶製備，產生13.0毫克標題化合物(22.5%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl }-1 H -吲哚-7-carboxyguanamine general procedure, but instead of 3-(2-pyrrolidinyl)pyridine (148 mg, 1.0 mmol) instead of 2-propylpyrrolidine, yielding 13.0 Mg title compound (22.5%).

LC/MS=m/z 578[M+H]滯留時間：1.52分鐘。 LC/MS = m/z 578 [M+H].

實例91：5-(5-{[2-(1,1-二甲基乙基)-1-吡咯啶基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 91: 5-(5-{[2-(1,1-Dimethylethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-[1-(ethylsulfonate) Base)-4-piperidinyl]-1 H -indole-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-丙基-1-吡咯啶基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺之一般製程，但改用2-(1,1-二甲基乙基)吡咯啶(127毫克，1.0毫莫耳)替代2-丙基吡咯啶製備，產生11.0毫克標題化合物(16.4%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl }-1 H -吲哚-7-carboxyguanamine general process, but instead of 2-(1,1-dimethylethyl)pyrrolidine (127 mg, 1.0 mmol) instead of 2-propylpyrrole Preparation of the pyridine gave 11.0 mg of the title compound (16.4%).

LC/MS=m/z 557[M+H]滯留時間：1.65分鐘。 LC/MS = m/z 557 [M+H].

實例92：5-{5-[(2-乙基-1-吡咯啶基)甲基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 92: 5-{5-[(2-Ethyl-1-pyrrolidinyl)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl] -1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-丙基-1-吡咯啶基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺之一般製程，但改用2-乙基吡咯啶(99.0毫克，1.0毫莫耳)替代2-丙基吡咯啶製備，產生15.0毫克標題化合物(28.4%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl }-1 H-吲哚-7-carboxyguanamine general procedure, but using 2-ethylpyrrolidine (99.0 mg, 1.0 mmol) instead of 2-propylpyrrolidine to give 15.0 mg of the title compound ( 28.4%).

LC/MS=m/z 529[M+H]滯留時間：1.66分鐘。 LC/MS = m/z 529 [M+H].

實例93：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[2-(2-甲基丙基)-1-吡咯啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 93: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(2-methylpropyl)-1-pyrrolidinyl]methyl} -3-thienyl)-1 H -indole-7-carboxamide fluorotrifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-丙基-1-吡咯啶基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺之一般製程，但改用2-(2-甲基丙基)吡咯啶(127毫克，1.0毫莫耳)替代2-丙基吡咯啶製備，產生7.0毫克標題化合物(10.4%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl }-1 H -吲哚-7-carboxyguanamine general process, but replaced with 2-(2-methylpropyl)pyrrolidine (127 mg, 1.0 mmol) instead of 2-propylpyrrolidine, Yield 7.0 mg of the title compound (10.4%).

LC/MS=m/z 557[M+H]滯留時間：1.74分鐘。 LC/MS = m/z 557 [M+H].

實例94：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[2-(1-甲基乙基)-1-吡咯啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺Example 94: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(1-methylethyl)-1-pyrrolidinyl]methyl} -3-thienyl)-1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-丙基-1-吡咯啶基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺之一般製程，但改用2-(1-甲基乙基)吡咯啶(113毫克，1.0毫莫耳)替代2-丙基吡咯啶製備，產生16.0毫克標題化合物(29.5%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl }-1 H-吲哚-7-carboxyguanamine general process, but instead of 2-(1-methylethyl)pyrrolidine (113 mg, 1.0 mmol) instead of 2-propylpyrrolidine, 16.0 mg of the title compound (29.5%) was obtained.

LC/MS=m/z 543[M+H]滯留時間：1.61分鐘。 LC/MS = m/z 543 [M+H].

實例95：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({(2S)-2-[(甲基氧)甲基]-1-吡咯啶基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺Example 95: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({( 2S )-2-[(methyloxy)methyl]-1-pyrrole Pyridyl}methyl)-3-thienyl]-1 H -indole-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-丙基-1-吡咯啶基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺之一般製程，但改用(2S)-2-[(甲基氧)甲基]吡咯啶(115毫克，1.0毫莫耳)替代2-丙基吡咯啶製備，產生22.0毫克標題化合物(40.4%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl }-1 H -吲哚-7-carboxyguanamine general process, but instead of (2 S )-2-[(methyloxy)methyl]pyrrolidine (115 mg, 1.0 mmol) instead of 2- Preparation of propyl pyrrolidine gave 22.0 mg of the title compound (40.4%).

LC/MS=m/z 544[M+H]滯留時間：1.44分鐘。 LC/MS = m/z 544 [M+H].

實例96：5-(5-{[環己基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 96: 5-(5-{[Cyclohexyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-丙基-1-吡咯啶基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺之一般製程，但改用環己基(甲基)胺(113毫克，1.0毫莫耳)替代2-丙基吡咯啶製備，產生15.0毫克標題化合物(27.6%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl }-1 H -吲哚-7-carboxyguanamine general procedure, but instead of cyclohexyl (methyl)amine (113 mg, 1.0 mmol) instead of 2-propylpyrrolidine, yielding 15.0 mg of the title compound (27.6%).

LC/MS=m/z 543[M+H]滯留時間：1.64分鐘。 LC/MS = m/z 543 [M+H].

實例97：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[2-(2-甲基丙基)-1-吡咯啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺Example 97: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[2-(2-methylpropyl)-1-pyrrolidinyl]methyl} -3-thienyl)-1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-丙基-1-吡咯啶基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺之一般製程，但改用2-(2-甲基丙基)吡咯啶(127毫克，1.0毫莫耳)替代2-丙基吡咯啶製備，產生12.0毫克標題化合物(21.6%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-propyl-1-pyrrolidinyl)methyl]-3-thienyl }-1 H -吲哚-7-carboxyguanamine general process, but replaced with 2-(2-methylpropyl)pyrrolidine (127 mg, 1.0 mmol) instead of 2-propylpyrrolidine, 12.0 mg of the title compound (21.6%) was obtained.

LC/MS=m/z 557[M+H]滯留時間：1.74分鐘。 LC/MS = m/z 557 [M+H].

實例98：5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 98: 5-(5-{[Ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-吲哚-7-carboxyguanamine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)之DMSO(2.0毫升)溶液中添加2滴乙酸、乙基(甲基)胺(59毫克，1.0毫莫耳)，於室溫下攪拌5小時。然後添加三乙醯氧基氫硼化鈉(212毫克，1.0毫莫耳)並反應一夜。經Gilson製備性HPLC純化，產生30.0毫克標題化合物(61.4%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (50 To a solution of DMSO (0.11 mmol) in DMSO (2.0 mL) was added 2 portions of acetic acid, ethyl (ethyl)amine (59 mg, 1.0 mmol), and stirred at room temperature for 5 hours. Sodium triethoxy borohydride (212 mg, 1.0 mmol) was then added and allowed to react overnight. Purification by Gilson preparative HPLC gave 30.0 mg of the title compound (61.4%).

LC/MS=m/z 489[M+H]滯留時間：1.50分鐘。 LC/MS = m/z 489 [M+H].

實例99：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺Example 99: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(propyl)amino]methyl}-3-thienyl)-1 H-吲哚-7-carboxyguanamine

標題化合物係依據5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用甲基(丙基)胺(73毫克，1.0毫莫耳)替代2-丙基吡咯啶製備，產生32.0毫克標題化合物(63.7%)。 The title compound is based on 5-(5-{[ethyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxyguanamine general procedure, but instead of methyl (propyl)amine (73 mg, 1.0 mmol) instead of 2-propylpyrrolidine, yielded 32.0 mg of the title compound (63.7 %).

LC/MS=m/z 503[M+H]滯留時間：1.54分鐘。 LC/MS = m/z 503 [M+H].

實例100：3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-5-(5-{[甲基(丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 100: 3-{1-[(1-Methylethyl)sulfonyl]-4-piperidinyl}-5-(5-{[methyl(propyl)amino]methyl}-3 -thienyl)-1 H -indole-7-carboxyguanamine trifluoroacetate

在含5-(5-甲醯基-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺(46毫克，0.10毫莫耳)之DMSO(2.0毫升)溶液中添加2滴乙酸、甲基(丙基)胺(73毫克，1.0毫莫耳)，於室溫下攪拌5小時。添加三乙醯氧基氫硼化鈉(212毫克，1.0毫莫耳)，並反應一夜。經Gilson製備性HPLC純化，產生25.0毫克標題化合物(39.6%)。 In the presence of 5-(5-methylindolyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1 H -吲哚-7 - 2 drops of acetic acid, methyl (propyl) amine (73 mg, 1.0 mmol) in a solution of carboxyguanamine (46 mg, 0.10 mmol) in DMSO (2.0 mL), stirring at room temperature for 5 hours . Sodium triethoxy hydride hydride (212 mg, 1.0 mmol) was added and reacted overnight. Purification by Gilson preparative HPLC gave 25.0 mg of the title compound (39.6%).

實例101：5-(5-{[乙基(甲基)胺基]甲基}-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺Example 101: 5-(5-{[Ethyl(methyl)amino]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4- Piperidinyl}-1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}5-(5-{[甲基(丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用乙基(甲基)胺(59毫克，1.0毫莫耳)替代甲基(丙基)胺製備，產生8.0毫克標題化合物(15.9%)。 The title compound is based on 3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}5-(5-{[methyl(propyl)amino]methyl}-3 -Thienyl)-1 H -indole-7-carboxamide amine trifluoroacetate, but with ethyl (methyl)amine (59 mg, 1.0 mmol) instead of methyl (propyl) The amine was prepared to give 8.0 mg of the title compound (15.9%).

LC/MS=m/z 503[M+H]滯留時間：1.59分鐘。 LC/MS = m/z 503 [M+H].

實例102：3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-5-[5-({甲基[2-(甲基氧)乙基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺Example 102: 3-{1-[(1-Methylethyl)sulfonyl]-4-piperidinyl}-5-[5-({methyl[2-(methyloxy)ethyl]amine }]methyl)-3-thienyl]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-5-(5-{[甲基(丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用甲基[2-(甲基氧)乙基]胺(89毫克，1.0毫莫耳)替代甲基(丙基)胺製備，產生37.0毫克標題化合物(69.4%)。 The title compound is based on 3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-5-(5-{[methyl(propyl)amino]methyl}- General procedure for 3-thienyl)-1 H -indole-7-carboxamide fluorotrifluoroacetate, but with methyl [2-(methyloxy)ethyl]amine (89 mg, 1.0 mmol) Prepared instead of methyl (propyl)amine to give 37.0 mg of the title compound (69.4%).

LC/MS=m/z 533[M+H]滯留時間：1.58分鐘。 LC/MS = m/z 533 [M + H].

實例103：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(甲基胺基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺Example 103: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-2-thienyl}-1 H -indole -7-carboxyguanamine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-2-噻吩基)-1H-吲哚-7-羧醯胺(35毫克，0.078毫莫耳)之DMSO(1.0毫升)溶液中添加乙酸(3滴)、2 M甲基胺之THF溶液(0.24毫升，0.471毫莫耳)，反應3小時。添加三乙醯氧基氫硼化鈉(100毫克，0.471毫莫耳)，攪拌反應一夜。真空排除所有溶劑，經Gilson製備性HPLC純化。取不純之所需溶離份減壓濃縮，加至先添加10毫升甲醇之500毫克SCX SPE卡管上。卡管經2M NH₃之MeOH溶液(10毫升x 2)溶離。取NH₃之MeOH溶液溶離份濃縮，產生7.3毫克標題化合物(20%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-2-thienyl)-1 H -indole-7-carboxamide (35 A solution of acetic acid (3 drops), 2 M methylamine in THF (0.24 mL, 0.471 mmol) was added to a solution of MeOH (1.0 mL). Sodium triethoxy hydride hydride (100 mg, 0.471 mmol) was added and the reaction was stirred overnight. All solvents were removed in vacuo and purified by Gilson preparative HPLC. The desired fractions of the impure fraction were concentrated under reduced pressure and added to a 500 mg SCX SPE cartridge which was first added with 10 ml of methanol. Card through the tube of 2M NH ₃ in MeOH (10 mL x 2) fractions. NH MeOH solution was taken from the solution of ₃ parts concentrated to yield 7.3 mg of the title compound (20%).

LC/MS=m/z 459.6[M+H]滯留時間：1.25分鐘。 LC/MS = m/z 459.6 [M+H]: 1.25 min.

實例104：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-甲基-1-吡咯啶基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 104: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-3-thienyl} -1 H -吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-2-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之DMSO(3.0毫升)溶液中添加乙酸(3滴)、2-甲基吡咯啶(0.12毫升，1.12毫莫耳)，反應4小時。添加三乙醯氧基氫硼化鈉(238毫克，1.12毫莫耳)，攪拌反應一夜。反應混合物經逆向Gilson製備性HPLC純化，產生17毫克標題化合物(30%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-2-thienyl)-1 H -indole-7-carboxamide (50 Acetic acid (3 drops), 2-methylpyrrolidine (0.12 ml, 1.12 mmol) were added to a solution of mM (0.112 mmol) in DMSO (3.0 mL). Sodium triethoxy hydride hydride (238 mg, 1.12 mmol) was added and the reaction was stirred overnight. The reaction mixture was purified by reverse EtOAc EtOAc (EtOAc)

LCMS：515.4(M+H)，Rt 1.60分鐘 LCMS: 515.4 (M+H), Rt 1.60 min

實例105：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 105: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-3-thienyl) -1 H -吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之DMSO(2.0毫升)溶液中添加乙酸(4滴)、(2-甲基丙基)胺(0.17毫升，1.68毫莫耳)，與三乙醯氧基氫硼化鈉(356毫克，1.68毫莫耳)進行反應。反應混合物經逆向Gilson製備性HPLC純化，產生15毫克標題化合物(27%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (50 Add milliacetic acid (4 drops), (2-methylpropyl)amine (0.17 ml, 1.68 mmol) to a solution of milligrams (0.112 mmol) in DMSO (2.0 mL). Sodium (356 mg, 1.68 mmol) was reacted. The reaction mixture was purified by reverse EtOAc EtOAc (EtOAc)

LCMS：503.4(M+H)，Rt 1.60分鐘 LCMS: 503.4 (M+H), Rt 1.60 min

實例106：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(丙基胺基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 106: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[(propylamino)methyl]-3-thienyl}-1 H -indole -7-Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之DMSO(2.0毫升)溶液中添加乙酸(3滴)、(2-甲基丙基)胺(0.17毫升，1.68毫莫耳)，與三乙醯氧基氫硼化鈉(356毫克，1.68毫莫耳)進行反應。反應混合物經逆向Gilson製備性HPLC純化，產生15毫克標題化合物(27%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (50 Add milliacetic acid (3 drops), (2-methylpropyl)amine (0.17 mL, 1.68 mmol) to a solution of milligrams (0.112 mmol) in DMSO (2.0 mL). Sodium (356 mg, 1.68 mmol) was reacted. The reaction mixture was purified by reverse EtOAc EtOAc (EtOAc)

LCMS：489(M+H)，Rt 1.61分鐘 LCMS: 489 (M+H), Rt 1.61 min

實例107：5-{5-[(二乙基胺基)甲基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 107: 5-{5-[(Diethylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)之DMSO(2.0毫升)溶液中添加乙酸(3滴)、二乙基胺(0.12毫升，1.12毫莫耳)，於室溫下攪拌4小時。添加三乙醯氧基氫硼化鈉(238毫克，1.12毫莫耳)，攪拌反應一夜。反應混合物經逆向Gilson製備性HPLC純化，產生7.0毫克標題化合物(13%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (50 Acetic acid (3 drops), diethylamine (0.12 ml, 1.12 mmol) were added to a solution of MeOH (0.11 mmol) in DMSO (2.0 mL) and stirred at room temperature for 4 hr. Sodium triethoxy hydride hydride (238 mg, 1.12 mmol) was added and the reaction was stirred overnight. The reaction mixture was purified by reverse EtOAc EtOAc (EtOAc)

LCMS：501.4(M+H)，Rt 1.51分鐘 LCMS: 501.4 (M+H), Rt 1.51 min

實例108：5-(5-{[(2R,5R)-2,5-二甲基-1-吡咯啶基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 108: 5-(5-{[(2 R ,5 R )-2,5-Dimethyl-1-pyrrolidinyl]methyl}-3-thienyl)-3-[1-(ethyl Sulfomethyl)-4-piperidinyl]-1 H -indole-7-carboxamide fluorotrifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之DMSO(2.0毫升)溶液中添加乙酸(3滴)、(2R,5R)-2,5-二甲基吡咯啶(151毫克，1.123毫莫耳)，反應4小時。添加三乙醯氧基氫硼化鈉(238毫克，1.123毫莫耳)。反應混合物經逆向Gilson製備性HPLC純化，產生27毫克標題化合物(46%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1H-indole-7-carboxamide (50 mg , 0.112 mmol of DMSO (2.0 ml) was added with acetic acid (3 drops), (2 R , 5 R )-2,5-dimethylpyrrolidine (151 mg, 1.123 mmol), reaction 4 hour. Sodium triethoxy hydride hydride (238 mg, 1.123 mmol) was added. The reaction mixture was purified by reverse EtOAc EtOAc (EtOAc)

LCMS：529.4(M+H)，Rt 1.64分鐘 LCMS: 529.4 (M+H), Rt 1.64 min

實例109：5-{5-[(環丙基胺基)甲基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 109: 5-{5-[(cyclopropylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)之DMSO(2.0毫升)溶液中添加乙酸(5滴)，與環丙基胺(0.12毫升，1.68毫莫耳)反應6小時。添加三乙醯氧基氫硼化鈉(356毫克，1.68毫莫耳)，攪拌反應一夜。反應混合物經逆向Gilson製備性HPLC純化，產生8.0毫克標題化合物(10%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1H-indole-7-carboxamide (50 mg Acetic acid (5 drops) was added to a solution of 0.11 mmol of DMSO (2.0 mL) and reacted with cyclopropylamine (0.12 mL, 1.68 mmol) for 6 hours. Sodium triethoxy hydride hydride (356 mg, 1.68 mmol) was added and the reaction was stirred overnight. The reaction mixture was purified by reverse EtOAc EtOAc (EtOAc)

LCMS：487.2(M+H)，Rt 1.64分鐘與1.68分鐘 LCMS: 487.2 (M+H), Rt 1.64 min and 1.68 min.

實例110：5-{5-[(環丁基胺基)甲基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 110: 5-{5-[(Cyclobutylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)之DMSO(2.0毫升)溶液中添加乙酸(4滴)，與環丁基胺(0.15毫升，1.68毫莫耳)反應4小時。添加三乙醯氧基氫硼化鈉(356毫克，1.68毫莫耳)，攪拌反應一夜。反應混合物經逆向Gilson製備性HPLC純化，產生5.0毫克標題化合物(10%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1H-indole-7-carboxamide (50 mg Acetic acid (4 drops) was added to a solution of 0.11 mmol of DMSO (2.0 mL) and reacted with cyclobutylamine (0.15 mL, 1.68 mmol) for 4 hours. Sodium triethoxy hydride hydride (356 mg, 1.68 mmol) was added and the reaction was stirred overnight. The reaction mixture was purified by reverse EtOAc EtOAc (EtOAc)

LCMS：501.4(M+H)，Rt 1.51分鐘 LCMS: 501.4 (M+H), Rt 1.51 min

實例111：5-{5-[(二甲基胺基)甲基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 111: 5-{5-[(Dimethylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基-2-噻吩基)-1H-吲哚-7-羧醯胺(300毫克，0.67毫莫耳)之DMSO(4毫升)溶液中添加2 M二甲基胺之THF溶液(3.36毫升，6.7毫莫耳)。反應於室溫下攪拌7小時，添加三乙醯氧基氫硼化鈉(1.42克，6.7毫莫耳)。續於室溫下攪拌一夜。反應混合物經逆向Gilson製備性HPLC，產生標題化合物(205毫克，64%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylindolyl-2-thienyl)-1 H -indole-7-carboxamide (300 A solution of 2 M dimethylamine in THF (3.36 mL, 6.7 mmol) was added to a solution of MeOH (4 mL). The reaction was stirred at room temperature for 7 hours and sodium triacetoxyborohydride (1.42 g, 6.7 mmol) was added. Stir at room temperature overnight. The reaction mixture was purified by EtOAc EtOAc EtOAc EtOAc

LCMS：475.2(M+H)，Rt 1.51分鐘 LCMS: 475.2 (M+H), Rt 1.51 min

實例112：5-(5-{[(環戊基甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 112: 5-(5-{[(Cyclopentylmethyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之DMSO(2.0毫升)溶液中，與乙酸(3滴)、(環戊基甲基)胺(112毫克，1.123毫莫耳)反應4小時。添加三乙醯氧基氫硼化鈉(238毫克，1.123毫莫耳)，攪拌反應一夜。反應混合物經逆向Gilson製備性HPLC純化，產生8.0毫克標題化合物(14%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1H-indole-7-carboxamide (50 mg In a solution of 0.112 mmol of DMSO (2.0 mL), was reacted with acetic acid (3 drops) and (cyclopentylmethyl)amine (112 mg, 1.123 mmol) for 4 hours. Sodium triethoxy hydride hydride (238 mg, 1.123 mmol) was added and the reaction was stirred overnight. The reaction mixture was purified by EtOAc EtOAc (EtOAc)

LCMS：529.4(M+H)，Rt 1.61分鐘與1.64分鐘 LCMS: 529.4 (M+H), Rt 1.61 min and 1.64 min.

實例113：5-[5-({[(1R)-1,2-二甲基丙基]胺基}甲基)-3-噻吩基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 113: 5-[5-({[(1 R )-1,2-dimethylpropyl]amino}methyl)-3-thienyl]-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1 H -indole-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之DMSO(2.0毫升)溶液中添加乙酸(3滴)、(2R)-3-甲基-2-丁胺(98毫克，1.123毫莫耳)，反應4小時。添加三乙醯氧基氫硼化鈉(238毫克，1.123毫莫耳)，攪拌反應一夜。反應混合物經逆向Gilson製備性HPLC純化，產生5.0毫克標題化合物(10%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1H-indole-7-carboxamide (50 mg Acetic acid (3 drops), ( 2R )-3-methyl-2-butylamine (98 mg, 1.123 mmol) was added to a solution of 0.112 mmol of DMSO (2.0 mL) for 4 hours. Sodium triethoxy hydride hydride (238 mg, 1.123 mmol) was added and the reaction was stirred overnight. The reaction mixture was purified by reverse EtOAc EtOAc (EtOAc)

LCMS：517.2(M+H)，Rt 1.65分鐘 LCMS: 517.2 (M+H), Rt 1.65 min

實例114：5-{5-[(環戊基胺基)甲基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 114: 5-{5-[(Cyclopentylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之DMSO(2.0毫升)溶液中添加乙酸(3滴)、環戊胺(0.11毫升，1.123毫莫耳)，反應4小時。添加三乙醯氧基氫硼化鈉(238毫克， 1.123毫莫耳)，反應一夜。反應混合物經逆向Gilson製備性HPLC純化，產生5.0毫克標題化合物(6.0%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1H-indole-7-carboxamide (50 mg Acetic acid (3 drops), cyclopentylamine (0.11 ml, 1.123 mmol) were added to a solution of 0.112 mmol of DMSO (2.0 mL) for 4 hours. Add sodium triethoxy hydride hydride (238 mg, 1.123 millimoles), reacted overnight. The reaction mixture was purified by reverse EtOAc EtOAc (EtOAc)

LCMS：515.6(M+H)，Rt 1.38分鐘 LCMS: 515.6 (M+H), Rt 1.38 min

實例115：5-(5-{[(環丙基甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 115: 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之DMSO(2.0毫升)溶液中，與乙酸(3滴)、1-環丙基甲胺(0.10毫升，1.123毫莫耳)反應6小時。添加三乙醯氧基氫硼化鈉(238毫克，1.123毫莫耳)，反應一夜。反應混合物經逆向Gilson製備性HPLC純化，產生5.0毫克標題化合物(10%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1H-indole-7-carboxamide (50 mg A solution of 0.112 mmol of DMSO (2.0 mL) was reacted with acetic acid (3 drops) and 1-cyclopropylmethylamine (0.10 mL, 1.123 mmol) for 6 hours. Sodium triethoxy hydride hydride (238 mg, 1.123 mmol) was added and the reaction was carried out overnight. The reaction mixture was purified by reverse EtOAc EtOAc (EtOAc)

LCMS：501.4(M+H)，Rt 1.53分鐘 LCMS: 501.4 (M+H), Rt 1.53 min

實例116：5-[5-({[(1S)-1,2-二甲基丙基]胺基}甲基)-3-噻吩基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 116: 5-[5-({[(1 S )-1,2-Dimethylpropyl]amino}methyl)-3-thienyl]-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1 H -indole-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之DMSO(2.0毫升)溶液中，與乙酸(3滴)、(2S)-3-甲基-2-丁胺(98毫克，1.123毫莫耳)反應6小時。添加三乙醯氧基氫硼化鈉(238毫克，1.123毫莫耳)，攪拌反應一夜。反應混合物經逆向Gilson製備性HPLC純化，產生8.0毫克標題化合物(15%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1H-indole-7-carboxamide (50 mg A solution of 0.112 mmol (DMSO) (2.0 mL) was reacted with acetic acid (3 drops) and ( 2S )-3-methyl-2-butylamine (98 mg, 1.123 mmol) for 6 hours. Sodium triethoxy hydride hydride (238 mg, 1.123 mmol) was added and the reaction was stirred overnight. The reaction mixture was purified by EtOAc EtOAc (EtOAc)

LCMS：517.2(M+H)，Rt 1.65分鐘 LCMS: 517.2 (M+H), Rt 1.65 min

實例117：5-(5-{[(2,2-二甲基丙基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 117: 5-(5-{[(2,2-Dimethylpropyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-1 H -吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之DMSO(2.0毫升)溶液中添加乙酸(3滴)、(2,2-二甲基丙基)胺(0.13毫升，1.123毫莫耳)，反應6小時。添加三乙醯氧基氫硼化鈉(238毫克，1.123毫莫耳)，攪拌一夜。反應混合物經逆向Gilson製備性HPLC純化，產生4.0毫克標題化合物(7%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1H-indole-7-carboxamide (50 mg Acetic acid (3 drops), (2,2-dimethylpropyl)amine (0.13 ml, 1.123 mmol) was added to a solution of 0.112 mmol of DMSO (2.0 mL) for 6 hours. Sodium triethoxy hydride hydride (238 mg, 1.123 mmol) was added and stirred overnight. The reaction mixture was purified by reverse EtOAc EtOAc (EtOAc)

LCMS：517.2(M+H)，Rt 1.68分鐘與1.71分鐘 LCMS: 517.2 (M+H), Rt 1.68 min and 1.71 min.

實例118：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(苯基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 118: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[(phenylmethyl)amino]methyl}-3-thienyl)-1 H-吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之DMSO(2.0毫升)溶液中添加乙酸(5滴)、(苯基甲基)胺(0.14毫升，1.123毫莫耳)，反應6小時。添加三乙醯氧基氫硼化鈉(238毫克，1.123毫莫耳)，攪拌一夜。反應混合物經逆向Gilson製備性HPLC純化，產生5.0毫克標題化合物(8%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1H-indole-7-carboxamide (50 mg Acetic acid (5 drops), (phenylmethyl)amine (0.14 ml, 1.123 mmol) was added to a solution of 0.112 mmol of DMSO (2.0 mL) for 6 hours. Sodium triethoxy hydride hydride (238 mg, 1.123 mmol) was added and stirred overnight. The reaction mixture was purified by reverse EtOAc EtOAc (EtOAc)

LCMS：537.2(M+H)，Rt 1.68分鐘 LCMS: 537.2 (M+H), Rt 1.68 min

實例119：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 119: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({[(2 S )-tetrahydro-2-furanylmethyl]amino} A 3-thiophenyl]-1 H -indole-7-carboxamide fluorotrifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之二氯甲烷(3.0毫升)與甲醇(1.5毫升)溶液中添加乙酸(5滴)、1-[(2S)-四氫-2-呋喃基]甲胺(0.12毫升，1.123毫莫耳)，反應6小時。添加三乙醯氧基氫硼化鈉(238毫克，1.123毫莫耳)，於室溫下攪拌反應混合物一夜。反應混合物經逆向Gilson製備性HPLC純化，產生23毫克標題化合物(8%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1H-indole-7-carboxamide (50 mg Acetic acid (5 drops), 1-[( 2S )-tetrahydro-2-furanyl]methylamine (0.12 ml), methylene chloride (3.0 ml) and methanol (1.5 ml) , 1.123 millimoles), reacted for 6 hours. Sodium triethoxysulfonium borohydride (238 mg, 1.123 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was purified by reverse EtOAc EtOAc (EtOAc)

LCMS：531.4(M+H)，Rt 1.58分鐘 LCMS: 531.4 (M+H), Rt 1.58 min

實例120：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(四氫-2H-吡喃-4-基甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 120: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[(tetrahydro-2 H -pyran-4-ylmethyl)amino]- }}-3-thienyl)-1 H -indole-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之DMSO(2.0毫升)溶液中，與乙酸(5滴)及(四氫-2H-吡喃-4-基甲基)胺(130毫克，1.123毫莫耳)反應6小時。添加三乙醯氧基氫硼化鈉(238毫克，1.123毫莫耳)，攪拌反應一夜。反應混合物經逆向Gilson製備性HPLC純化，產生7.0毫克標題化合物(11%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1H-indole-7-carboxamide (50 mg , 0.112 mmol) in DMSO (2.0 mL), reacted with acetic acid (5 drops) and (tetrahydro-2H-pyran-4-ylmethyl)amine (130 mg, 1.123 mmol) for 6 hours. . Sodium triethoxy hydride hydride (238 mg, 1.123 mmol) was added and the reaction was stirred overnight. The reaction mixture was purified by EtOAc EtOAc (EtOAc)

LCMS：545.4(M+H)，Rt 1.52分鐘 LCMS: 545.4 (M+H), Rt 1.52 min

實例121：5-{5-[(丁基胺基)甲基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 121: 5-{5-[(butylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole -7-Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之二氯甲烷(3.0毫升)與甲醇(1.5毫升)溶液中添加5滴乙酸、丁基胺(0.11毫升，1.123毫莫耳)，反應6小時。添加氫硼化鈉(43毫克，1.123毫莫耳)，於室溫下攪拌一夜。真空排除所有溶劑，溶於DMSO(1.0毫升)。經逆向Gilson製備性HPLC純化，產生5.0毫克標題化合物(10%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1H-indole-7-carboxamide (50 mg To a solution of 0.112 mmol of dichloromethane (3.0 ml) and methanol (1.5 ml), 5 portions of acetic acid and butylamine (0.11 ml, 1.123 mmol) were added and reacted for 6 hours. Sodium borohydride (43 mg, 1.123 mmol) was added and stirred at room temperature overnight. All solvents were removed in vacuo and dissolved in DMSO (1.0 mL). Purification by reverse Gilson preparative HPLC gave 5.0 mg of the title compound (10%).

LCMS：503.4(M+H)，Rt 1.63分鐘 LCMS: 503.4 (M+H), Rt 1.63 min

實例122：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[(2R)-四氫-2-呋喃基甲基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 122: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({[(2 R )-tetrahydro-2-furanylmethyl]amino} 3-thiophenyl]-1 H -indole-7-carboxamide fluorotrifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之DMSO(2.0毫升)溶液中添加乙酸(5滴)、1-[(2R)-四氫-2-呋喃基]甲胺(130毫克，1.123毫莫耳)，反應混合物反應6小時。添加三乙醯氧基氫硼化鈉(238毫克，1.123毫莫耳)，攪拌反應一夜。再加1-[(2R)-四氫-2-呋喃基]甲胺(130毫克，1.123毫莫耳)，6小時後，添加三乙醯氧基氫硼化鈉。反應混合物經逆向Gilson製備性HPLC純化，產生5.0毫克標題化合物(8.0%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1H-indole-7-carboxamide (50 mg , 0.112 mmol (DMSO) (2.0 ml) was added with acetic acid (5 drops), 1-[( 2R )-tetrahydro-2-furanyl]methylamine (130 mg, 1.123 mmol), reaction The mixture was reacted for 6 hours. Sodium triethoxy hydride hydride (238 mg, 1.123 mmol) was added and the reaction was stirred overnight. Further, 1-[( 2R )-tetrahydro-2-furanyl]methanamine (130 mg, 1.123 mmol) was added, and after 6 hours, sodium triethoxysulfonium hydride was added. The reaction mixture was purified by reverse EtOAc EtOAc (EtOAc)

LCMS：531.4(M+H)，Rt 1.50分鐘 LCMS: 531.4 (M+H), Rt 1.50 min

實例123：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({(2S)-2-[(甲基氧)甲基]-1-吡咯啶基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 123: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({( 2S )-2-[(methyloxy)methyl]-1-pyrrole Pyridyl}methyl)-3-thienyl]-1 H -indole-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之二氯甲烷(3.0毫升)與甲醇(1.5毫升)溶液中添加5滴乙酸、(2S)-2-[(甲基氧)甲基]吡咯啶(129毫克，1.123毫莫耳)，於室溫下反應6小時。添加氫硼化鈉(43毫克，1.123毫莫耳)，於室溫下攪拌反應一夜。反應混合物經逆向Gilson製備性HPLC純化，產生8.0毫克標題化合物the(13%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1H-indole-7-carboxamide (50 mg , 0.112 mmol of dichloromethane (3.0 ml) and methanol (1.5 ml) were added 5 drops of acetic acid, ( 2S )-2-[(methyloxy)methyl]pyrrolidine (129 mg, 1.123) Milligram), reacted at room temperature for 6 hours. Sodium borohydride (43 mg, 1.123 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was purified by reverse Gilson preparative HPLC to yield </RTI><RTIgt;

LCMS：545.2(M+H)，Rt 1.62分鐘與1.66分鐘。 LCMS: 545.2 (M+H).

實例124：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({(2R)-2-[(甲基氧)甲基]-1-吡咯啶基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 124: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({( 2R )-2-[(methyloxy)methyl]-1-pyrrole Pyridyl}methyl)-3-thienyl]-1 H -indole-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之二氯甲烷(3.0毫升)與甲醇(1.5毫升)溶液中添加乙酸(5滴)、(2R)-2-[(甲基氧)甲基]吡咯啶(129毫克，1.123毫莫耳)，於室溫下攪拌6小時。添加氫硼化鈉(43毫克，1.123毫莫耳)，於室溫下攪拌反應一夜。混合物經逆向Gilson製備性HPLC純化，產生5.0毫克標題化合物(13%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1H-indole-7-carboxamide (50 mg , 0.112 mmol) of dichloromethane (3.0 ml) and methanol (1.5 ml) were added with acetic acid (5 drops), ( 2R )-2-[(methyloxy)methyl]pyrrolidine (129 mg) , 1.123 mmol, stirred at room temperature for 6 hours. Sodium borohydride (43 mg, 1.123 mmol) was added and the reaction was stirred at room temperature overnight. The mixture was purified by reverse EtOAc EtOAc (EtOAc)

LCMS：545.2(M+H)，Rt 1.62分鐘與1.66分鐘。 LCMS: 545.2 (M+H).

實例125：3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-[2-(甲基胺基)乙基]苯基}-1H-吲哚-7-羧醯胺Example 125: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{4-[2-(methylamino)ethyl]phenyl}-1H-indole-7 -carboxamide

在含5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(200毫克，0.48毫莫耳)之二烷與H₂O之溶液中添加[4-(氰基甲基)苯基]二羥硼酸(232毫克，0.144毫莫耳)、碳酸鉀(400毫克，2.88毫莫耳)，與肆(三苯基膦)鈀(0)(30毫克，0.048毫莫耳)。攪拌溶液，於微波爐中，於160℃下加熱40分鐘。反應經EtOAc與H₂O稀釋，過濾得到黃色晶體之所需產物。溶液經鹽水與H₂O洗滌後，以EtOAc洗滌，濃縮。在殘質中添加MEOH，使所需產物沉澱後，再以MeOH洗滌一次，產生5-[4-(氰基甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺。 In the presence of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxamide (200 mg, 0.48 mmol) [4-(Cyanomethyl)phenyl]dihydroxyboronic acid (232 mg, 0.144 mmol), potassium carbonate (400 mg, 2.88 mmol), and hydrazine (three) were added to the solution of the alkane and H ₂ O. Phenylphosphine) palladium (0) (30 mg, 0.048 mmol). The solution was stirred and heated in a microwave oven at 160 ° C for 40 minutes. The reaction was diluted with EtOAc and H ₂ O and filtered to give the desired product as yellow crystals. The solution was washed with brine and H ₂ O, in EtOAc, washed and concentrated. Add MEOH to the residue, precipitate the desired product, and wash once with MeOH to give 5-[4-(cyanomethyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl]-1 H -indole-7-carboxamide.

於0℃下，在含5-[4-(氰基甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(78毫克，0.173毫莫耳)之DCM中添加1.5 M二異丁基氫化鋁之甲苯溶液(240毫升，0.346毫莫耳)。反應於0℃下攪拌20分鐘。以飽和酒石酸鉀鈉溶液中止反應。過濾雙層，固體為所需產物。此外，有機層濃縮，產生所需化合物：3-[1-(乙基磺醯基)-4-哌啶基]- 5-[4-(2-氧代乙基)苯基]-1H-吲哚-7-羧醯胺，其未再純化即使用。 Containing 5-[4-(cyanomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7- at 0 ° C A solution of 1.5 M diisobutylaluminum hydride in toluene (240 ml, 0.346 mmol) was added to DCM of carbamide (78 mg, 0.173 mmol). The reaction was stirred at 0 ° C for 20 minutes. The reaction was stopped with a saturated sodium potassium tartrate solution. The bilayer was filtered and the solid was the desired product. In addition, the organic layer is concentrated to give the desired compound: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(2-oxoethyl)phenyl]-1 H - 吲哚-7-carboxamide, which was used without further purification.

於室溫下，在含3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(2-氧代乙基)苯基]-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)之甲醇(5毫升)與二氯甲烷(5毫升)溶液中添加2 M甲基胺之四氫呋喃溶液(0.4毫升)後，添加1滴乙酸。反應於室溫下攪拌2小時後，添加三乙醯氧基氫硼化鈉(200毫克，0.94毫莫耳)。攪拌此反應一夜。經急驟層析法純化，產生10毫克標題化合物(19.4%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(2-oxoethyl)phenyl]-1 H -吲哚 at room temperature After a solution of 7 M methylamine in tetrahydrofuran (0.4 ml) was added to a solution of 7-carboxamide (50 mg, 0.11 mmol) in methanol (5 ml) and dichloromethane (5 ml). After the reaction was stirred at room temperature for 2 hours, sodium triacetoxyborohydride (200 mg, 0.94 mmol) was added. The reaction was stirred overnight. Purification by flash chromatography gave 10 mg of the title compound (19.4%).

LC/MS=m/z 469.4[M+H]滯留時間：1.63分鐘。 LC/MS = m/z 469.4 [M+H].

實例126：3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-[2-(丙基胺基)乙基]苯基}-1H-吲哚-7-羧醯胺Example 126: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{4-[2-(propylamino)ethyl]phenyl}-1H-indole-7 -carboxamide

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-[2-(甲基胺基)乙基]苯基}-1H-吲哚-7-羧醯胺之一般製程，但改用2 M丙基胺之四氫呋喃溶液(0.4毫升)替代甲基胺製備，產生15毫克標題化合物(27.5%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[2-(methylamino)ethyl]phenyl}-1H-indole- General procedure for 7-carboxyguanamine, but Prepared by replacing the methylamine with a solution of 2M propylamine in THF (0.4 mL).

LC/MS=m/z 497.6[M+H]滯留時間：1.63分鐘。 LC/MS = m/z 497.6 [M+H].

實例127：5-{4-[2-(乙基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 127: 5-{4-[2-(ethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7 -carboxamide

於室溫下，在含3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(2-氧代乙基)苯基]-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)之甲醇(5毫升)與二氯甲烷(5毫升)溶液中添加2 M乙基胺之四氫呋喃溶液(0.4毫升)後，添加1滴乙酸。反應於室溫下攪拌2小時後，添加三乙醯氧基氫硼化鈉(200毫克，0.94毫莫耳)。攪拌此反應一夜。經急驟層析法純化，產生15毫克標題化合物(28.3%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(2-oxoethyl)phenyl]-1 H -吲哚 at room temperature After adding a solution of 7 M ethylamine in tetrahydrofuran (0.4 ml), a solution of 7-carboxamide (50 mg, 0.11 mmol) in methanol (5 ml) and dichloromethane (5 ml), After the reaction was stirred at room temperature for 2 hours, sodium triacetoxyborohydride (200 mg, 0.94 mmol) was added. The reaction was stirred overnight. Purification by flash chromatography gave 15 mg of the title compound (28.3%).

LC/MS=m/z 483.2[M+H]滯留時間：1.57分鐘。 LC/MS = m/z 483.2 [M+H].

實例128：5-{4-[({[1-(1,1-二甲基乙基)-3-甲基-1H-吡唑-5-基]羰基}胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 128: 5-{4-[({[1-(1,1-Dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl }-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide fluorotrifluoroacetate

在含[4-(胺基甲基)苯基]二羥硼酸(145毫克，0.966毫莫耳)之DMF(2毫升)溶液中添加1-(1,1-二甲基乙基)-3-甲基-1H-吡唑-5-羰基氯(290毫克，1.45毫莫耳)與三乙胺(403微升，2.90毫莫耳)。攪拌反應2小時。然後中止反應，分溶於EtOAc與H₂O之間，有機層濃縮，產生{4-[({[1-(1,1-二甲基乙基)-3-甲基-1H-吡唑-5-基]羰基}胺基)甲基]苯基}二羥硼酸。 Add 1-(1,1-dimethylethyl)-3 to a solution of [4-(aminomethyl)phenyl]dihydroxyboronic acid (145 mg, 0.966 mmol) in DMF (2 mL) Methyl-1 H -pyrazole-5-carbonyl chloride (290 mg, 1.45 mmol) with triethylamine (403 μL, 2.90 mmol). The reaction was stirred for 2 hours. The reaction was then quenched divided between EtOAc and dissolved in H ₂ O, the organic layer was concentrated to yield {4 - [({[1- (1,1-dimethylethyl) -3-methyl -1 H - pyrazol Zyrid-5-yl]carbonyl}amino)methyl]phenyl}dihydroxyboronic acid.

在含5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(50毫克，0.120毫莫耳)之二烷(1毫升)與水(0.4毫升)溶液中添加碳酸鉀(74毫克，0.484毫莫耳)與{4-[({[1-(1,1-二甲基乙基)-3-甲基-1H-吡唑-5-基]羰基}胺基)甲基]苯基}二羥硼酸(153毫克，0.483毫莫耳)。攪拌反應混合物，通入氬氣5分鐘後，添加氯(二-2-原冰片基膦基)(2-二甲基胺基甲基二茂絡鐵-1-基)鈀(II)(7毫克，0.012毫莫耳)。攪拌反應10分鐘後，加熱至150℃。反應蒸發，經Gilson製備性HPLC純化，產生5毫克標題化合物(5.8%)。 In the presence of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (50 mg, 0.120 mmol) Add potassium carbonate (74 mg, 0.484 mmol) and {4-[({[1-(1,1-dimethylethyl))-3-) to a solution of alkane (1 ml) and water (0.4 ml) Base-1 H -pyrazol-5-yl]carbonyl}amino)methyl]phenyl}dihydroxyboronic acid (153 mg, 0.483 mmol). The reaction mixture was stirred, and after argon gas was added for 5 minutes, chlorine (di-2-norbornylphosphino)(2-dimethylaminomethyldithioferron-1-yl)palladium(II) (7) was added. Mg, 0.012 millimoles). After stirring for 10 minutes, it was heated to 150 °C. The reaction was evaporated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 605.4[M+H]滯留時間：2.14分鐘。 LC/MS = m/z 605.4 [M+H].

實例129：3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(4-吡啶基羰基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺Example 129: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(4-{[(4-pyridylcarbonyl)amino]methyl}phenyl)-1H-indole哚-7-carboxyguanamine

標題化合物係依據5-{4-[({[1-(1,1-二甲基乙基)-3-甲基-1H-吡唑-5-基]羰基}胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(4-{[(4-吡啶基羰基)胺基]甲基}苯基)二羥硼酸(124毫克，.480毫莫耳)替代{4-[({[1-(1,1-二甲基乙基)-3-甲基-1H-吡唑-5-基]羰基}胺基)甲基]苯基}二羥硼酸製備，產生30毫克標題化合物(45.8%)。 The title compound is based on 5-{4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]benzene General procedure for the radical -3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide fluorotrifluoroacetate, but instead (4-{[( 4-pyridylcarbonyl)amino]methyl}phenyl)dihydroxyboronic acid (124 mg, .480 mmol) instead of {4-[({[1-(1,1-dimethylethyl))- Preparation of 3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}dihydroxyboronic acid gave 30 mg of the title compound (45.8%).

LC/MS=m/z 537[M+H]滯留時間：2.04分鐘。 LC/MS = m/z 537 [M+H].

實例130：5-(4-{[(環戊基羰基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 130: 5-(4-{[(Cyclopentylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole -7-carboxyguanamine

標題化合物係依據5-{4-[({[1-(1,1-二甲基乙基)-3-甲基-1H-吡唑-5-基]羰基}胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(4-{[(環戊基羰基)胺基]甲基}苯基)二羥硼酸(119毫克，0.480毫莫耳)替代{4-[({[1-(1,1-二甲基乙基)-3-甲基-1H-吡唑-5-基]羰基}胺基)甲基]苯基}二羥硼酸製備，產生30毫克標題化合物(47%)。 The title compound is based on 5-{4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]benzene General procedure for the radical -3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide fluorotrifluoroacetate, but instead (4-{[( Cyclopentylcarbonyl)amino]methyl}phenyl)dihydroxyboronic acid (119 mg, 0.480 mmol) instead of {4-[({[1-(1,1-dimethylethyl))-3-) Preparation of methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}dihydroxyboronic acid gave 30 mg of the title compound (47%).

LC/MS=m/z 537[M+H]滯留時間：2.04分鐘。 LC/MS = m/z 537 [M+H].

實例131：3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(2-呋喃基羰基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺Example 131: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-furylcarbonyl)amino]methyl}phenyl)-1H-indole哚-7-carboxyguanamine

標題化合物係依據5-{4-[({[1-(1,1-二甲基乙基)-3-甲基-1H-吡唑-5-基]羰基}胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(4-{[(2-呋喃基羰基)胺基]甲基}苯基)二羥硼酸(118毫克，0.480毫莫耳)替代{4-[({[1-(1,1-二甲基乙基)-3-甲基-1H-吡唑-5-基]羰基}胺基)甲基]苯基}二羥硼酸製備，產生16毫克標題化合物(25%)。 The title compound is based on 5-{4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]benzene General procedure for the radical -3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide fluorotrifluoroacetate, but instead (4-{[( 2-furoylcarbonyl)amino]methyl}phenyl)dihydroxyboronic acid (118 mg, 0.480 mmol) instead of {4-[({[1-(1,1-dimethylethyl))-3) Preparation of -methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}dihydroxyboronic acid gave 16 mg of the title compound (25%).

LC/MS=m/z 535.5[M+H]滯留時間：1.99分鐘。 LC/MS = m/z 535.5 [M+H].

實例132：5-(4-{2-[(環丁基羰基)胺基]乙基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 132: 5-(4-{2-[(Cyclobutylcarbonyl)amino]ethyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-吲哚-7-carboxyguanamine

標題化合物係依據5-{4-[2-(乙醯基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用N-[2-(4-溴苯基)乙基]環丁烷羧醯胺(100毫克，0.324毫莫耳)替代N-[2-(4-溴苯基)乙基]乙醯胺製備。經急驟層析法純化，產生28毫克標題化合物(48.3%)。 The title compound is based on 5-{4-[2-(ethylhydrazino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole General procedure for -7-carboxyguanamine, but instead of N- [2-(2-(4-bromophenyl)ethyl]cyclobutanecarboxime (100 mg, 0.324 mmol) instead of N- [2-( Preparation of 4-bromophenyl)ethyl]acetamide. Purification by flash chromatography gave 28 mg of the title compound (48.3%).

LC/MS=m/z 537.2[M+H]滯留時間：1.99分鐘。 LC/MS = m/z 537.2 [M+H].

實例133：5-(4-{2-[(環己基羰基)胺基]乙基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 133: 5-(4-{2-[(cyclohexylcarbonyl)amino]ethyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole哚-7-carboxyguanamine

標題化合物係依據5-{4-[2-(乙醯基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用N-[2-(4-溴苯基)乙基]環己烷羧醯胺(100毫克，0.324毫莫耳)替代N-[2-(4-溴苯基)乙基]乙醯胺製備。經急驟層析法純化，產生32毫克標題化合物(52.5%)。 The title compound is based on 5-{4-[2-(ethylhydrazino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole General procedure for -7-carboxyguanamine, but instead of N- [2-(2-(4-bromophenyl)ethyl]cyclohexanecarboxamide (100 mg, 0.324 mmol) instead of N- [2-( Preparation of 4-bromophenyl)ethyl]acetamide. Purification by flash chromatography gave 32 mg of the title compound (52.5%).

LC/MS=m/z 565.4[M+H]滯留時間：2.14分鐘。 LC/MS = m/z 565.4 [M+H].

實例134：5-(3-{2-[(環己基羰基)胺基]乙基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 134: 5-(3-{2-[(Cyclohexylcarbonyl)amino]ethyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole哚-7-carboxyguanamine

標題化合物係依據5-{4-[2-(乙醯基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用N-[2-(3-溴苯基)乙基]環己烷羧醯胺(100毫克，0.324毫莫耳)替代N-[2-(4-溴苯基)乙基]乙醯胺製備。濃縮之反應混合物經Gilson製備性HPLC純化後，再經急驟層析法純化，產生標題化合物。 The title compound is based on 5-{4-[2-(ethylhydrazino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole General procedure for -7-carboxyguanamine, but instead of N- [2-(2-(3-bromophenyl)ethyl]cyclohexanecarboxamide (100 mg, 0.324 mmol) instead of N- [2-( Preparation of 4-bromophenyl)ethyl]acetamide. The concentrated reaction mixture was purified by EtOAc EtOAc EtOAc.

LC/MS=m/z 565.2[M+H]滯留時間：2.16分鐘。 LC/MS = m/z 565.2 [M+H].

實例135：3-[1-(乙基磺醯基)-4-哌啶基]-5-[6-(1-哌 基)-3-吡啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽 Example 135: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-piperazine Benzyl-3-pyridyl]-1 H -indole-7-carboxamide fluorotrifluoroacetate

在含5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(100毫克，0.241毫莫耳)之二烷(1.0毫升)與H₂O(0.8毫升)之溶液中添加碳酸銫(314毫克，0.964毫莫耳)與[6-(4-{[(1,1-二甲基乙基)氧]羰基}-1-哌基)-3-吡啶基]二羥硼酸(297毫克，0.964毫莫耳)。攪拌反應混合物後，添加肆(三苯基膦)鈀(0)(28毫克，0.024毫莫耳)。反應於微波爐中，於160℃下加熱20分鐘。混合物濃縮，溶於EtOAc(10毫升)與H₂O(5.0毫升)中。化合物經Gilson製備性HPLC純化，產生129毫克4-(5-{7-(胺基羰基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-5-基}-2-吡啶基)-1-哌羧酸1,1-二甲基乙基酯與3-[1-(乙基磺醯基)-4-哌啶基]-5-[6-(1-哌基)-3-吡啶基]-1H-吲哚-7-羧醯胺(44%)。 In the presence of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxamide (100 mg, 0.241 mmol) Dioxane (1.0 mL) was added cesium carbonate and H ₂ O (0.8 ml) solution of (314 mg, 0.964 mmol) and [6- (4 - {[(1,1-dimethylethyl) oxy] Carbonyl}-1-piper Base)-3-pyridyl]dihydroxyboronic acid (297 mg, 0.964 mmol). After the reaction mixture was stirred, hydrazine (triphenylphosphine)palladium(0) (28 mg, 0.024 mmol) was added. The reaction was heated in a microwave oven at 160 ° C for 20 minutes. The mixture was concentrated, dissolved in EtOAc (10 mL) and H ₂ O (5.0 mL). The compound was purified by Gilson preparative HPLC to give 129 mg of 4-(5-{7-(aminocarbonyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole. -5-yl}-2-pyridyl)-1-piper 1,1-dimethylethyl carboxylate and 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-pipeper Benzyl-3-pyridyl]-1 H -indole-7-carboxamide (44%).

在含4-(5-{7-(胺基羰基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-5-基}-2-吡啶基)-1-哌羧酸1,1-二甲基乙基酯(130毫克，0.218毫莫耳)之甲醇(0.3毫升)溶液中添加4 M HCl之二烷溶液(0.3毫升)。反應於50℃下加熱及攪拌3小時。反應混合物濃縮，於先後添加CH₂Cl₂與MeOH之SCX卡管上中和，使用氨之MeOH溶液收集。取20毫克所需溶離份濃縮，使用MDAP HPLC純化，產生9.4毫克標題化合物(7%)。 In the presence of 4-(5-{7-(aminocarbonyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indol-5-yl}-2-pyridine Base-1-phenyl Add 4 M HCl to a solution of 1,1-dimethylethyl carboxylate (130 mg, 0.218 mmol) in methanol (0.3 mL) Alkane solution (0.3 ml). The reaction was heated and stirred at 50 ° C for 3 hours. The reaction mixture was concentrated, added successively to the CH _₂ Cl ₂ and MeOH and the SCX card tube, using MeOH ammonia solution was collected. 20 mg of the desired fractions were concentrated and purified using EtOAc EtOAc (EtOAc)

LC/MS=m/z 497.2[M+H]滯留時間：1.45分鐘 LC/MS = m / z 497.2 [M + H] retention time: 1.45 minutes

實例136：5-[6-(4-乙基-1-哌 基)-3-吡啶基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽 Example 136: 5-[6-(4-ethyl-1-piperidin Benzyl-3-pyridyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide fluorotrifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-[6-(1-哌基)-3-吡啶基]-1H-吲哚-7-羧醯胺(40毫克，0.081毫莫耳)之二氯甲烷溶液中添加乙醛(7毫克，0.162毫莫耳)與三乙醯氧基氫硼化鈉(100毫克，0.472毫莫耳)。於室溫下攪拌反應一夜。反應混合物濃縮，溶於EtOAc與H₂O中。濾出鹽，有機層濃縮與經Gilson製備性HPLC純化，產生39毫克標題化合物(92%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-piperidin Addition of acetaldehyde (7 mg, 0.162 mmol) and triethyl to a solution of benzylidene-3-pyridyl]-1 H -indole-7-carboxamide (40 mg, 0.081 mmol) in dichloromethane Sodium decyloxyborohydride (100 mg, 0.472 mmol). The reaction was stirred overnight at room temperature. The reaction mixture was concentrated, dissolved in EtOAc and H ₂ O. The salt was filtered, EtOAcqqqqqqqqq

LC/MS=m/z 525.6[M+H]滯留時間：1.44分鐘 LC/MS=m/z 525.6 [M+H] retention time: 1.44 minutes

實例137：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(1-哌啶基甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 137: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[4-(1-piperidinylmethyl)phenyl]-1 H -indole-7-carboxylate Guanidine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(40毫克，0.09毫莫耳)之二氯甲烷溶液中添加哌啶(9微升，0.09毫莫耳)。攪拌反應1小時後，添加三乙醯氧基氫硼化鈉(58毫克，0.27毫莫耳)。於室溫下攪拌反應混合物一夜。混合物濃縮後，經Gilson製備性HPLC純化，產生8.0毫克標題化合物(14%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -吲哚-7-carboxamide (40 mg, 0.09 Piperidine (9 μL, 0.09 mmol) was added to the methylene chloride solution. After stirring the reaction for 1 hour, sodium triethoxysulfonium borohydride (58 mg, 0.27 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was concentrated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 509.4[M+H]滯留時間：1.71分鐘 LC/MS = m / z 509.4 [M + H] retention time: 1.71 minutes

實例138：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(1-哌啶基甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 138: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-(1-piperidinylmethyl)phenyl]-1 H -indole-7-carboxylate Guanidine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)之二氯甲烷(2毫升)與乙酸(1滴)溶液中添加哌啶(46微升，0.456毫莫耳)。於室溫下攪拌反應2小時後，添加三乙醯氧基氫硼化鈉(75毫克，0.342毫莫耳)。再攪拌反應3小時。混合物經Gilson製備性HPLC純化，產生36毫克標題化合物(61%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxamide (50 mg, 0.114 Piperidine (46 μL, 0.456 mmol) was added to a solution of dichloromethane (2 mL) and acetic acid (1 drop). After stirring the reaction for 2 hours at room temperature, sodium triethoxysulfonium borohydride (75 mg, 0.342 mmol) was added. The reaction was stirred for another 3 hours. The mixture was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 509.4[M+H]滯留時間：1.80分鐘 LC/MS = m / z 509.4 [M + H] retention time: 1.80 minutes

實例139：3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 139: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]phenyl}-1 H -indole-7- Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(20毫克，0.045毫莫耳)之二氯甲烷(12毫升)、甲醇(2毫升)與乙酸溶液中添加甲基胺之THF溶液(20微升，0.54毫莫耳)。反應混合物於室溫下攪拌2小時後，添加三乙醯氧基氫硼化鈉(10.3毫克，0.270毫莫耳)。混合物再攪拌3小時後，混合物濃縮後，經Gilson製備性HPLC純化，產生6毫克標題化合物(10%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -吲哚-7-carboxamide (20 mg, 0.045 A solution of methylamine in THF (20 μL, 0.54 mmol) was added to dichloromethane (12 mL), methanol (2 mL) and acetic acid. After the reaction mixture was stirred at room temperature for 2 hr, sodium triethyloxy borohydride (10.3 mg, 0.270 mmol) was added. After the mixture was stirred for additional 3 hours, the mixture was concentrated and purified mjjjjjjj

LC/MS=m/z 454.6[M+H]滯留時間：1.23分鐘 LC/MS=m/z 454.6 [M+H] retention time: 1.23 minutes

實例140：3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(1-甲基乙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺Example 140: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(4-{[(1-methylethyl)amino]methyl}phenyl)-1 H -吲哚-7-carboxyguanamine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(40毫克，0.09毫莫耳)之DMSO(900微升)與乙酸(2滴)溶液中添加2-丙胺(93微升，1.08毫莫耳)。2小時後，添加三乙醯氧基氫硼化鈉(172毫克，0.81毫莫耳)。攪拌反應混合物一夜。化合物經Gilson製備性HPLC純化，產生30毫克標題化合物(69%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -吲哚-7-carboxamide (40 mg, 0.09 To a solution of DMSO (900 microliters) and acetic acid (2 drops), 2-propylamine (93 microliters, 1.08 millimoles) was added. After 2 hours, sodium triethoxysulfonium borohydride (172 mg, 0.81 mmol) was added. The reaction mixture was stirred overnight. The compound was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 483.2[M+H]滯留時間：1.56分鐘 LC/MS=m/z 483.2 [M+H] retention time: 1.56 min

實例141：3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-[(丙基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 141: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{4-[(propylamino)methyl]phenyl}-1 H -indole-7- Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(20毫克，0.045毫莫耳)之DMSO(900微升)與乙酸(2滴)溶液中添加丙基胺(45微升，1.08毫莫耳)。2小時後，添加三乙醯氧基氫硼化鈉(172毫克，0.81毫莫耳)。攪拌反應混合物一夜。化合物經Gilson製備性HPLC純化，產生21.1毫克標題化合物(74%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -吲哚-7-carboxamide (20 mg, 0.045 To the solution of DMSO (900 μl) and acetic acid (2 drops), propylamine (45 μL, 1.08 mmol) was added. After 2 hours, sodium triethoxysulfonium borohydride (172 mg, 0.81 mmol) was added. The reaction mixture was stirred overnight. The compound was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 483.2[M+H]滯留時間：1.54分鐘。 LC/MS = m/z 483.2 [M+H].

實例142：5-(4-{[(1-乙基丙基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 142: 5-(4-{[(1-Ethylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxyguanamine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(40毫克，0.09毫莫耳)之DMSO(900微升)與乙酸(2滴)溶液中添加3-戊胺(108微升，1.08毫莫耳)。2小時後，添加三乙醯氧基氫硼化鈉(172毫克，0.81毫莫耳)。攪拌反應混合物一夜。化合物經Gilson製備性HPLC純化，產生34.5毫克標題化合物(74%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -吲哚-7-carboxamide (40 mg, 0.09 To a solution of DMSO (900 microliters) and acetic acid (2 drops), 3-pentylamine (108 microliters, 1.08 millimolar) was added. After 2 hours, sodium triethoxysulfonium borohydride (172 mg, 0.81 mmol) was added. The reaction mixture was stirred overnight. The compound was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 511.4[M+H]滯留時間：1.69分鐘 LC/MS=m/z 511.4 [M+H] retention time: 1.69 minutes

實例143：5-{4-[(環戊基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 143: 5-{4-[(Cyclopentylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7 -Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(40毫克，0.09毫莫耳)之DMSO(900微升)與乙酸(2滴)溶液中添加環戊基胺(108微升，1.08毫莫耳)。2小時後，添加三乙醯氧基氫硼化鈉(172毫克，0.81毫莫耳)。攪拌反應混合物一夜。化合物經Gilson製備性HPLC純化，產生11.1毫克標題化合物(20%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -吲哚-7-carboxamide (40 mg, 0.09 To the solution of DMSO (900 μl) and acetic acid (2 drops), cyclopentylamine (108 μl, 1.08 mmol) was added. After 2 hours, sodium triethoxysulfonium borohydride (172 mg, 0.81 mmol) was added. The reaction mixture was stirred overnight. The compound was purified by Gilson preparative HPLC to yield 11.1 mg of the title compound (20%).

LC/MS=m/z 509.4[M+H]滯留時間：1.66分鐘。 LC/MS = m/z 509.4 [M+H].

實例144：5-{4-[(環丁基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 144: 5-{4-[(Cyclobutylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7 -carboxamide

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(40毫克，0.091毫莫耳)之DMSO(900微升)與乙酸(2滴)溶液中添加環丁基胺(94微升，1.08毫莫耳)。2小時後，添加三乙醯氧基氫硼化鈉(120毫克，1.10毫莫耳)。攪拌反應混合物一夜。化合物經Gilson製備性HPLC純化，產生26.3毫克標題化合物(59%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -吲哚-7-carboxamide (40 mg, 0.091 To a solution of DMSO (900 μl) and acetic acid (2 drops) was added cyclobutylamine (94 μL, 1.08 mmol). After 2 hours, sodium triethoxysulfonium borohydride (120 mg, 1.10 mmol) was added. The reaction mixture was stirred overnight. The compound was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 495.4[M+H]滯留時間：1.37分鐘 LC/MS=m/z 495.4 [M+H] retention time: 1.37 minutes

實例145：5-{4-[(乙基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 145: 5-{4-[(Ethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7- Carboxylamidine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(20毫克，0.046毫莫耳)之DMSO與乙酸溶液中添加乙基胺(32微升，0.547毫莫耳)。2小時後，添加三乙醯氧基氫硼化鈉(120毫克，1.10毫莫耳)。攪拌反應混合物一夜。化合物經Gilson製備性HPLC純化，產生11.5毫克標題化合物(55%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -吲哚-7-carboxamide (20 mg, 0.046 To the DMSO and acetic acid solution of millimolar) ethylamine (32 microliters, 0.547 millimolar) was added. After 2 hours, sodium triethoxysulfonium borohydride (120 mg, 1.10 mmol) was added. The reaction mixture was stirred overnight. The compound was purified by Gilson preparative HPLC to yield 11.5 mg of the title compound (55%).

LC/MS=m/z 469.4[M+H]滯留時間：1.52分鐘。 LC/MS = m/z 469.4 [M+H].

實例146：5-{4-[(二甲基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 146: 5-{4-[(Dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7 -carboxamide

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)之DMSO(3毫升)與乙酸溶液中添加N-二甲基胺(170微升，0.342毫莫耳)。2小時後，添加三乙醯氧基氫硼化鈉(290毫克，1.36毫莫耳)。攪拌反應混合物一夜。化合物經Gilson製備性HPLC純化，產生28.9毫克標題化合物(54%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -indole-7-carboxamide (50 mg, 0.114 To a solution of mM DMSO (3 mL) and acetic acid was added N -dimethylamine (170 μL, 0.342 mmol). After 2 hours, sodium triethoxysulfonium borohydride (290 mg, 1.36 mmol) was added. The reaction mixture was stirred overnight. The compound was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 469.4[M+H]滯留時間：1.52分鐘。 LC/MS = m/z 469.4 [M+H].

實例147：5-{4-[(二乙基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 147: 5-{4-[(Diethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7 -carboxamide

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)之DMSO(3毫升)與乙酸溶液中添加二乙基胺(36微升，0.342毫莫耳)。2小時後，添加三乙醯氧基氫硼化鈉(290毫克，1.36毫莫耳)。攪拌反應混合物一夜。化合物經Gilson製備性HPLC純化，產生37.6毫克標題化合物(67%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -indole-7-carboxamide (50 mg, 0.114 Monoethylamine (36 microliters, 0.342 millimolar) was added to the DMSO (3 ml) and acetic acid solution. After 2 hours, sodium triethoxysulfonium borohydride (290 mg, 1.36 mmol) was added. The reaction mixture was stirred overnight. The compound was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 497.6[M+H]滯留時間：1.52分鐘。 LC/MS = m/z 497.6 [M+H].

實例148：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(4-嗎啉基甲基)苯基]-1H-吲哚-7-羧醯胺Example 148: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[4-(4-morpholinylmethyl)phenyl]-1 H -indole-7-carboxylate Guanamine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)之DMSO(3毫升)與乙酸溶液中添加嗎啉(30微升，0.342毫莫耳)。2小時後，添加三乙醯氧基氫硼化鈉(290毫克，1.36毫莫耳)。攪拌反應混合物一夜。化合物經Gilson製備性HPLC純化，產生40.3毫克標題化合物(70%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -indole-7-carboxamide (50 mg, 0.114 Morpholine (30 μL, 0.342 mmol) was added to the DMSO (3 mL) and acetic acid solution. After 2 hours, sodium triethoxysulfonium borohydride (290 mg, 1.36 mmol) was added. The reaction mixture was stirred overnight. The compound was purified by Gilson preparative HPLC to yield 40.3 <RTIgt;

LC/MS=m/z 511.4[M+H]滯留時間：1.53分鐘 LC/MS = m / z 511.4 [M + H] retention time: 1.53 minutes

實例149：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(1-吡咯啶基甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 149: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[4-(1-pyrrolidylmethyl)phenyl]-1 H -indole-7-carboxylate Guanidine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)之DMSO(3毫升)與乙酸溶液中添加環戊基胺(28微升，0.342毫莫耳)。2小時後，添加三乙醯氧基氫硼化鈉(290毫克，1.36毫莫耳)。攪拌反應混合物一夜。化合物經Gilson製備性HPLC純化，產生20.1毫克標題化合物(36%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -indole-7-carboxamide (50 mg, 0.114 Milliol) DMSO (3 ml) was added to the acetic acid solution with cyclopentylamine (28 μL, 0.342 mmol). After 2 hours, sodium triethoxysulfonium borohydride (290 mg, 1.36 mmol) was added. The reaction mixture was stirred overnight. The compound was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 495.4[M+H]滯留時間：1.58分鐘 LC/MS=m/z 495.4 [M+H] retention time: 1.58 min

實例150：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-({[(1S)-2-羥基-1-甲基乙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 150: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[4-({[(1 S )-2-hydroxy-1-methylethyl]amino} Methyl)phenyl]-1 H -indole-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)之DMSO(3毫升)與乙酸之溶液中添加(2S)-2-胺基-1-丙醇(56微升，0.745毫莫耳)。2小時後，添加三乙醯氧基氫硼化鈉(290毫克，1.36毫莫耳)。攪拌反應混合物一夜。化合物經Gilson製備性HPLC純化，產生25.9毫克標題化合物(15%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -indole-7-carboxamide (50 mg, 0.114 ( 2S )-2-Amino-1-propanol (56 μL, 0.745 mmol) was added to a solution of DMSO (3 mL) and acetic acid. After 2 hours, sodium triethoxysulfonium borohydride (290 mg, 1.36 mmol) was added. The reaction mixture was stirred overnight. The compound was purified by Gilson preparative HPLC to yield 25.9 <RTIgt;

LC/MS=m/z 499.6[M+H]滯留時間：1.54分鐘 LC/MS = m / z 499.6 [M + H] retention time: 1.54 minutes

實例151：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-({[(1R)-2-羥基-1-甲基乙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 151: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[(1 R )-2-hydroxy-1-methylethyl]amino} Methyl)phenyl]-1 H -indole-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)之DMSO(3毫升)與乙酸之溶液中添加(2R)-2-胺基-1-丙醇(56微升，0.745毫莫耳)。2小時後，添加三乙醯氧基氫硼化鈉(290毫克，1.36毫莫耳)。攪拌反應混合物一夜。化合物經Gilson製備性HPLC純化，產生29.6毫克標題化合物(53%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -indole-7-carboxamide (50 mg, 0.114 ( 2R )-2-Amino-1-propanol (56 μL, 0.745 mmol) was added to a solution of DMSO (3 mL) and acetic acid. After 2 hours, sodium triethoxysulfonium borohydride (290 mg, 1.36 mmol) was added. The reaction mixture was stirred overnight. The compound was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 499.6[M+H]滯留時間：1.47分鐘 LC/MS = m / z 499.6 [M + H] retention time: 1.47 minutes

實例152：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-({[(2R)-2-羥基丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 152: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[4-({[(2 R )-2-hydroxypropyl]amino}methyl)phenyl ]-1 H -吲哚-7-Carboguanamine Trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)之DMSO(3毫升)與乙酸之溶液中添加(2R)-1-胺基-2-丙醇(56微升，0.745毫莫耳)。2小時後，添加三乙醯氧基氫硼化鈉(290毫克，1.36毫莫耳)。攪拌反應混合物一夜。化合物經Gilson製備性HPLC純化，產生14.7毫克標題化合物(26%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -indole-7-carboxamide (50 mg, 0.114 ( 2R )-1-Amino-2-propanol (56 μL, 0.745 mmol) was added to a solution of DMSO (3 mL) and acetic acid. After 2 hours, sodium triethoxysulfonium borohydride (290 mg, 1.36 mmol) was added. The reaction mixture was stirred overnight. The compound was purified by Gilson preparative HPLC to give 14.7 mg of the title compound (26%).

LC/MS=m/z 499.6[M+H]滯留時間：1.46分鐘。 LC/MS = m/z 499.6 [M+H].

實例153：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-({[2-羥基-1-(羥基甲基)乙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 153: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[2-hydroxy-1-(hydroxymethyl)ethyl]amino}methyl) Phenyl]-1 H -吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(40毫克，0.091毫莫耳)之DMSO溶液中添加2-胺基-1,3-丙二醇(50毫克，0.55毫莫耳)與乙酸(1滴)。2小時後，添加三乙醯氧基氫硼化鈉(232毫克，1.10 毫莫耳)。攪拌反應混合物一夜。化合物經Gilson製備性HPLC純化，產生15.9毫克標題化合物(28%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-carbamidophenyl)-1H-indole-7-carboxamide (40 mg, 0.091 m 2-Amino-1,3-propanediol (50 mg, 0.55 mmol) and acetic acid (1 drop) were added to the DMSO solution. After 2 hours, sodium triethoxy hydride hydride (232 mg, 1.10) was added. Millions of ears). The reaction mixture was stirred overnight. The compound was purified by Gilson preparative HPLC to yield 15.9 mg of the title compound (28%).

LC/MS=m/z 515.4[M+H]滯留時間：1.45分鐘。 LC/MS = m/z 515.4 [M+H].

實例154：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(1-甲基丁基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 154: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(1-methylbutyl)amino]methyl}phenyl)-1 H -吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)之DMSO(3.0毫升)溶液中添加1-2-戊胺(324微升，2.74毫莫耳)與乙酸(1滴)。2小時後，添加三乙醯氧基氫硼化鈉(290毫克，1.10毫莫耳)。攪拌反應混合物一夜。化合物過濾與濃縮。然後經Gilson製備性HPLC純化，產生9.5毫克標題化合物(13%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxamide (50 mg, 0.114 To a solution of millimolar DMSO (3.0 mL) was added 1-2-pentylamine (324 μL, 2.74 mmol) and acetic acid (1 drop). After 2 hours, sodium triethoxysulfonium borohydride (290 mg, 1.10 mmol) was added. The reaction mixture was stirred overnight. The compound was filtered and concentrated. Purification by Gilson preparative HPLC gave 9.5 mg of the title compound (13%).

LC/MS=m/z 511.4[M+H]滯留時間：1.66分鐘 LC/MS = m / z 511.4 [M + H] retention time: 1.66 minutes

實例155：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(1R)-1-甲基丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 155: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1 R )-1-methylpropyl]amino}methyl)benzene ]]-1 H -吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)之DMSO(2.0毫升)溶液中添加(2R)-2-丁胺(69微升，0.684毫莫耳)與乙酸(1滴)。2小時後，添加三乙醯氧基氫硼化鈉(0.435毫克，2.05毫莫耳)。攪拌反應混合物一夜。化合物過濾與濃縮。然後經Gilson製備性HPLC純化，產生18.6毫克標題化合物(33%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxamide (50 mg, 0.114 To a solution of millimolar DMSO (2.0 mL) was added ( 2R )-2-butylamine (69 μL, 0.684 mmol) and acetic acid (1 drop). After 2 hours, sodium triethoxysulfonium borohydride (0.435 mg, 2.05 mmol) was added. The reaction mixture was stirred overnight. The compound was filtered and concentrated. Purification by Gilson preparative HPLC gave 18.6 mg of the title compound (33%).

LC/MS=m/z 497.6[M+H]滯留時間：1.70分鐘 LC/MS=m/z 497.6 [M+H] retention time: 1.70 min

實例156：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-甲基丙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺Example 156: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylpropyl)amino]methyl}phenyl)-1 H -吲哚-7-carboxyguanamine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)之DCM(1.5毫升)、MeOH(1.5毫升)與乙酸(4滴)溶液中添加2-甲基-1-丙胺(137微升，1.37毫莫耳)，於室溫下攪拌。2小時後，添加氫硼化鈉(23毫克，0.684毫莫耳)。反應混合物經SCX卡管純化，產生47.8毫克標題化合物(85%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxamide (50 mg, 0.114 2-Methyl-1-propylamine (137 μL, 1.37 mmol) was added to a solution of DCM (1.5 mL), MeOH ( 1.5 mL) and acetic acid (4 drops) and stirred at room temperature. After 2 hours, sodium borohydride (23 mg, 0.684 mmol) was added. The reaction mixture was purified with EtOAc EtOAc (EtOAc)

LC/MS=m/z 497.2[M+H]滯留時間：1.69分鐘 LC/MS = m / z 497.2 [M + H] retention time: 1.69 minutes

實例157：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(1S)-1-甲基丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺乙酸鹽Example 157: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1 S )-1-methylpropyl]amino}methyl)benzene Base]-1 H-吲哚-7-carboxyguanamine acetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-甲基丙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺之一般製程，但改用(2S)-2-丁胺(138微升，1.37毫莫耳)替代2-甲基-1-丙胺製備，產生43.2毫克標題化合物(76%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylpropyl)amino]methyl}phenyl)-1 General procedure for H-吲哚-7-carboxyguanamine, but replaced with ( 2S )-2-butylamine (138 μl, 1.37 mmol) instead of 2-methyl-1-propylamine to give 43.2 mg The title compound (76%).

LC/MS=m/z 497.4[M+H]滯留時間：1.84分鐘 LC/MS = m / z 497.4 [M + H] retention time: 1.84 minutes

實例158：5-(4-{[(環丙基羰基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 158: 5-(4-{[(cyclopropylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole哚-7-carboxyguanamine

標題化合物係依據5-{4-[(乙醯基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用環丙烷羰基氯(14微升，1.37毫莫耳)替代乙醯氯製備。化合物經Gilson製備性HPLC純化，產生19.1毫克標題化合物(28%)。 The title compound is based on 5-{4-[(ethinylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole- The general procedure for 7-carboxyguanamine was prepared by replacing cyclopropane carbonyl chloride (14 μL, 1.37 mmol) with ethyl chloroform. The compound was purified by Gilson preparative HPLC to yield 19.1 mg of the title compound (28%).

LC/MS=m/z 509.2[M+H]滯留時間：1.86分鐘 LC/MS = m / z 509.2 [M + H] retention time: 1.86 minutes

實例159：5-(4-{[(環丁基羰基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 159: 5-(4-{[(Cyclobutylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole哚-7-carboxyguanamine

標題化合物係依據5-{4-[(乙醯基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用環丁烷羰基氯(17微升，1.37毫莫耳)替代乙醯氯製備。化合物經Gilson製備性HPLC純化，產生20.2毫克標題化合物(28%)。 The title compound is based on 5-{4-[(ethinylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole- The general procedure for 7-carboxamide was prepared using cyclobutanecarbonyl chloride (17 μl, 1.37 mmol) instead of ethyl chloroform. The compound was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 523.2[M+H]滯留時間：1.94分鐘 LC/MS=m/z 523.2 [M+H] retention time: 1.94 minutes

實例160：3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(2-噻吩基乙醯基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺Example 160: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-thienylethyl)amino]methyl}phenyl)-1 H-吲哚-7-carboxyguanamine

標題化合物係依據5-{4-[(乙醯基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用(3Z)-3-(甲基硫)-3,5-己二烯醯氯(18微升，1.37毫莫耳)替代乙醯氯製備。化合物經Gilson製備性HPLC純化，產生13.5毫克標題化合物(18%)。 The title compound is based on 5-{4-[(ethinylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole- The general procedure for 7-carboxamide was used instead of ( 3Z )-3-(methylsulfo)-3,5-hexadienium chloride (18 μL, 1.37 mmol) instead of ethyl chloroform. The compound was purified by Gilson preparative HPLC to yield 13.5 mg of the title compound (18%).

LC/MS=m/z 565.2[M+H]滯留時間：1.98分鐘 LC/MS=m/z 565.2 [M+H] retention time: 1.98 minutes

實例161：5-[4-({[(1S)-1,2-二甲基丙基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 161: 5-[4-({[(1 S )-1,2-dimethylpropyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl]-1 H -吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(40毫克，0.091毫莫耳)之DCM(1.5毫升)、MeOH(1.5毫升)與乙酸溶液中添加(2S)-3-甲基-2-丁胺(128微升，1.10毫莫耳)，於室溫下攪拌2小時。添加氫硼化鈉(19毫克，0.546毫莫耳)，攪拌48小時。化合物經Gilson製備性HPLC純化，產生5.8毫克標題化合物(12%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -indole-7-carboxamide (40 mg, 0.091 ( 2S )-3-methyl-2-butylamine (128 μl, 1.10 mmol) at room temperature in DCM (1.5 mL), MeOH (1.5 mL) and acetic acid. Stir for 2 hours. Sodium borohydride (19 mg, 0.546 mmol) was added and stirred for 48 hours. The compound was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 511.2[M+H]滯留時間：1.76分鐘 LC/MS = m / z 511.2 [M + H] retention time: 1.76 minutes

在含5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(50毫克，0.121毫莫耳)之二烷(1毫升)與H₂O(0.4毫升)溶液中添加碳酸鉀(74毫克，0.484毫莫耳)與(4{[(甲基磺醯基)胺基]甲基}苯基)二羥硼酸(110毫克，0.50毫莫耳)。攪拌反應混合物，通入氬氣5分鐘後，添加氯(二-2-原冰片基膦基)(2-二甲基胺基甲基二茂絡鐵-1-基)鈀(II)(7毫克，0.012毫莫耳)。攪拌反應，於微波爐中，於160℃下加熱10分鐘。混合物濃縮後，經Gilson製備性HPLC純化，產生34.3毫克標題化合物(55%)。 In the presence of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (50 mg, 0.121 mmol) Dioxane (1 mL) and H ₂ O (0.4 mL) was added potassium carbonate (74 mg, 0.484 mmol) and (4 {[(acyl sulfo methyl) amino] methyl} phenyl) glyoxylic Boric acid (110 mg, 0.50 mmol). The reaction mixture was stirred, and after argon gas was added for 5 minutes, chlorine (di-2-norbornylphosphino)(2-dimethylaminomethyldithioferron-1-yl)palladium(II) (7) was added. Mg, 0.012 millimoles). The reaction was stirred and heated in a microwave oven at 160 ° C for 10 minutes. The mixture was concentrated and purified by EtOAc EtOAc EtOAc EtOAc

LC/MS=m/z 519.4[M+H]滯留時間：1.77分鐘 LC/MS = m / z 519.4 [M + H] retention time: 1.77 minutes

實例162：5-[3-({[(1R)-1,2-二甲基丙基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 162: 5-[3-({[(1 R )-1,2-dimethylpropyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl]-1 H -吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)之DCM(1.5毫升)、MeOH(1.5毫升)與乙酸溶液中添加(2R)-3-甲基-2-丁胺 (160微升，1.37毫莫耳)，於室溫下攪拌2小時。添加氫硼化鈉(19毫克，0.546毫莫耳)。攪拌48小時。化合物經Gilson製備性HPLC純化，產生50毫克標題化合物(86%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxamide (50 mg, 0.114 (2 R )-3-methyl-2-butylamine (160 μL, 1.37 mmol) at room temperature in DCM (1.5 mL), MeOH (1.5 mL) and acetic acid. Stir for 2 hours. Sodium borohydride (19 mg, 0.546 mmol) was added. Stir for 48 hours. The compound was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 511.4[M+H]滯留時間：1.65分鐘 LC/MS=m/z 511.4 [M+H] retention time: 1.65 minutes

實例163：5-(6-胺基-2-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 163: 5-(6-Amino-2-pyridyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide fluorotrifluoroacetic acid salt

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(83毫克，0.18毫莫耳)之二烷(5毫升)溶液中添加6-溴-2-吡啶胺(93毫克，0.54毫莫耳)、碳酸鉀(149毫克，1.08毫莫耳)之H₂O(1.5毫升)溶液與氯(二-2-原冰片基膦基)(2-二甲基胺基甲基二茂絡鐵-1-基)鈀(II)(19毫克，0.031毫莫耳)。反應於微波爐中，於150℃下加熱20分鐘。反應混合物濃縮，進行水性萃取。有機層濃縮，經質量導向式自動製備性HPLC(Mass Directed Auto Prep HPLC)純化，產生22.3毫克標題化合物(29%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (83 mg, 0.18 mmol) A solution of 6-bromo-2-pyridinamine (93 mg, 0.54 mmol), potassium carbonate (149 mg, 1.08 mmol) in H ₂ O (1.5 mL) -2-Oryopyrylphosphino)(2-dimethylaminomethyldithioferron-1-yl)palladium(II) (19 mg, 0.031 mmol). The reaction was heated in a microwave oven at 150 ° C for 20 minutes. The reaction mixture was concentrated and subjected to aqueous extraction. The organic layer was concentrated and purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 428.6[M+H]滯留時間：1.34分鐘 LC/MS = m / z 428.6 [M + H] retention time: 1.34 minutes

實例164：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(1H-吡唑-1-基)苯基]-1H-吲哚-7-羧醯胺Example 164: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-(1H-pyrazol-1-yl)phenyl]-1H-indole-7-carboxylate Guanamine

在5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(20毫克，0.048毫莫耳)中添加[3-(1H-吡唑-1-基)苯基]二羥硼酸(36毫克，0.193毫莫耳)、二烷(2.8毫升)與碳酸鉀(20毫克)之水溶液(1.2毫升)。在此混合物中添加氯-2-(二甲基胺基甲基)-二茂絡鐵-1-基-(二原冰片基膦基)鈀(II)(3毫克，0.005毫莫耳)。所得混合物於CEM微波爐中，於160℃下反應10分鐘後，於氮氣流(溫室)與80℃下濃縮。粗產物分溶於水(2毫升)與CH₂Cl₂(2毫升)之間。經疏水性玻璃料分層，水層經CH₂Cl₂(2 x 2毫升)萃取。收集有機層，於氮氣流與80℃下濃縮。添加二甲亞碸(0.8毫升)至殘質中，經音波處理10秒，經棉墊過濾，然後經0.2微米濾料過濾。粗產物經Agilent MDAP，使用Zorbax Eclipse XDB 610 21.2 x 50 mm管柱純化，產生2.3毫克標題化合物(10%)。 Add [3-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxamide (20 mg, 0.048 mmol) (1 H -pyrazol-1-yl)phenyl]dihydroxyboronic acid (36 mg, 0.193 mmol), An aqueous solution (1.2 ml) of alkane (2.8 mL) and potassium carbonate (20 mg). To the mixture was added chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(di-norbornylphosphino)palladium(II) (3 mg, 0.005 mmol). The resulting mixture was reacted in a CEM microwave oven at 160 ° C for 10 minutes, and then concentrated under a nitrogen stream (greenhouse) at 80 ° C. The crude product was dissolved in water divided between CH _₂ Cl _{2 (2} mL) (2 mL). The layers were separated by a hydrophobic frit and the aqueous layer was extracted with CH ₂ Cl ₂ (2×2 mL). The organic layer was collected and concentrated under a nitrogen stream at 80 °C. Dimethyl hydrazine (0.8 ml) was added to the residue, sonicated for 10 seconds, filtered through a pad of cotton, and then filtered through a 0.2 micron filter. The crude product was purified with a pad of EtOAc EtOAc EtOAc EtOAc.

LC/MS=m/z 478.2[M+H]滯留時間：2.05分鐘。 LC/MS = m/z 478.2 [M+H].

實例165：5-[4-(二甲基胺基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 165: 5-[4-(Dimethylamino)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide

在CEM微波管中添加5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(40毫克，0.097毫莫耳)、二烷(2.8毫升)與碳酸鉀(40毫克，0.289毫莫耳)之水溶液(1.2毫升)。在此混合物中添加[4-(二甲基胺基)苯基]二羥硼酸(65毫克，0.386毫莫耳)與氯-2-(二甲基胺基甲基)-二茂絡鐵-1-基-(二原冰片基膦基)鈀(II)(1毫克，0.002毫莫耳)。反應瓶加蓋，於CEM微波爐中，於160℃下反應10分鐘。反應於氮氣流與80℃下濃縮。粗產物溶於二甲亞碸(1毫升)，經1克矽石SPE卡管，以二甲亞碸(4毫升)溶離純化。二甲亞碸於Genevac中，於65℃下濃縮3小時，殘質於二甲亞碸(1毫升)中再組成，經acrodisc過濾。粗產物溶液經Agilent MDAP(選擇UV 214)純化。純化產物通過與聚合物結合之碳酸鹽SPE卡管，產生2.7毫克標題化合物(6.2%)。 Add 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (40 mg, 0.097 mmol) to a CEM microwave tube. ,two An aqueous solution (1.2 ml) of alkane (2.8 ml) and potassium carbonate (40 mg, 0.289 mmol). To this mixture was added [4-(dimethylamino)phenyl]dihydroxyboronic acid (65 mg, 0.386 mmol) and chloro-2-(dimethylaminomethyl)-diferrocene- 1-yl-(di-norbornylphosphino)palladium(II) (1 mg, 0.002 mmol). The reaction flask was capped and reacted in a CEM microwave oven at 160 ° C for 10 minutes. The reaction was concentrated under a stream of nitrogen at 80 °C. The crude product was dissolved in dimethyl hydrazine (1 mL). Dimethyl hydrazine was concentrated in Genevac at 65 ° C for 3 hours, and the residue was reconstituted in dimethyl hydrazine (1 ml) and filtered through acrodisc. The crude product solution was purified by Agilent MDAP (UV 214). The purified product was passed through a carbonated SPE cartridge to give 2.7 mg of the title compound (6.2%).

LC/MS=m/z 455.2[M+H]滯留時間：1.71分鐘。 LC/MS = m/z 455.2 [M+H].

實例166：5-(3-胺基苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 166: 5-(3-Aminophenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide

在CEM微波管中添加5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(40毫克，0.0965毫莫耳)、碳酸鉀(80毫克，0.578毫莫耳)與(3-胺基苯基)二羥硼酸硫酸鹽(145毫克，0.386毫莫耳)。混合物溶於水(1.2毫升)與二烷(2.8毫升)中，添加氯-2-(二甲基胺基甲基)-二茂絡鐵-1-基-(二原冰片基膦基)鈀(II)(1毫克，0.002毫莫耳)。混合物於CEM微波爐中，於150℃下反應10分鐘。添加乙酸乙酯(2毫升)，分層。水層經乙酸乙酯(1 x 2毫升)洗滌。集合有機層，於氮氣流下濃縮，溶於二甲亞碸(0.89毫升)與三氟乙酸(0.15毫升)中。此粗產物溶液經Agilent MDAP，以9分鐘之線性梯度30%CH₃CN/H₂O(0.1%TFA)至70%CH₃CN/H₂O(0.1%TFA)，20毫升/分鐘溶離純化。在含產物之HPLC溶離份中添加飽和K₂CO₃溶液(1毫升)、1 M氫氧化鈉溶液(1毫升)與乙酸乙酯(2毫升)。分層，水層經乙酸乙酯(2 x 2毫升)萃取。集合有機層，經硫酸鎂填料過濾，於氮氣流下濃縮，產生14.9毫克標題化合物(36%)。 Add 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (40 mg, 0.0965 mmol) to a CEM microwave tube. Potassium carbonate (80 mg, 0.578 mmol) and (3-aminophenyl) dihydroborate sulfate (145 mg, 0.386 mmol). The mixture is soluble in water (1.2 ml) with two In alkane (2.8 ml), add chloro-2-(dimethylaminomethyl)-dilocomoferrin-1-yl-(di-norbornylphosphino)palladium(II) (1 mg, 0.002 mmol) ear). The mixture was reacted in a CEM microwave oven at 150 ° C for 10 minutes. Ethyl acetate (2 mL) was added and the layers were separated. The aqueous layer was washed with ethyl acetate (1×2 mL). The organic layer was combined, concentrated under EtOAc EtOAc (EtOAc) This crude product solution was purified by Agilent MDAP with a linear gradient of 30% CH ₃ CN/H ₂ O (0.1% TFA) to 70% CH ₃ CN/H ₂ O (0.1% TFA) in 20 mL/min. . A saturated K ₂ CO ₃ solution (1 mL), 1 M sodium hydroxide solution (1 mL) and ethyl acetate (2 mL). The layers were separated and the aqueous extracted with EtOAc EtOAc. The organic layer was combined, filtered with EtOAc EtOAc EtOAc EtOAc

LC/MS=m/z 427.2[M+H]滯留時間：1.39分鐘。 LC/MS = m/z 427.2 [M+H].

實例167：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-甲基-1-吡咯啶基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺Example 167: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl} -1H-吲哚-7-carboxyguanamine

用於製備3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-甲基-1-吡咯啶基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺之{5-[(2-甲基-1-吡咯啶基)甲基]-2-噻吩基}二羥硼酸係採用下列製程，分三批製備： For the preparation of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-2-thienyl} {5-[(2-Methyl-1-pyrrolidinyl)methyl]-2-thienyl}-dihydroxyboronic acid of -1H-indole-7-carboxyguanamine was prepared in three batches using the following process:

第1批：添加NaBH(OAc)₃(271毫克，1.28毫莫耳)、HOAc(0.07毫升)與2-甲基吡咯啶(0.043毫升，0.42毫莫耳)至2達蘭(dram)小瓶中含(5-甲醯基-2-噻吩基)二羥硼酸(100毫克，0.64毫莫耳)之CH₂Cl₂(4毫升)溶液中。小瓶加蓋，反應於室溫下攪拌15小時。反應混合物直接加至2克SCX卡管(先經MeOH平衡)上，依序以MeOH(12毫升)與2M NH₃/MeOH溶液(8毫升)溶離。取含二羥硼酸粗產物之溶離份於氮氣流下濃縮，於高度真空下乾燥，產生45毫克粗產物。粗產物溶於飽和NaHCO₃(2毫升)，以EtOAc(3 x 2毫升)萃取，產生6.6毫克粗產物{5-[(2-甲基-1-吡咯啶基)甲基]-2-噻吩基}二羥硼酸。 Batch 1: Add NaBH(OAc) ₃ (271 mg, 1.28 mmol), HOAc (0.07 mL) and 2-methylpyrrolidine (0.043 mL, 0.42 mmol) to 2 dram vials containing (5-acyl-2-thienyl) glyoxylic acid (100 mg, 0.64 mmol) of CH _₂ Cl ₂ (4 mL). The vial was capped and the reaction was stirred at room temperature for 15 hours. The reaction mixture was added directly to a 2 g SCX card tube (first balance by MeOH) on to successively MeOH (12 is mL) and 2M NH ₃ / MeOH solution (8 ml) fractions. The fractions containing the crude product of dihydroxyboric acid were concentrated under a stream of nitrogen and dried under high vacuum to yield 45 mg of crude material. The crude product was dissolved in saturated NaHCO ₃ (2 mL), EtOAc (3 x 2 ml) to produce 6.6 mg of crude product {5 - [(2-methyl-1-pyrrolidinyl) methyl] -2-thienyl Base} dihydroxyboric acid.

第2批：添加NaBH(OAc)₃(271毫克，1.28毫莫耳)、HOAc(0.07毫升)與2-甲基吡咯啶(0.043毫升，0.42毫莫耳)至2達蘭(dram)小瓶中含(5-甲醯基-2-噻吩基)二羥硼酸(100毫克，0.64毫莫耳)之CH₂Cl₂/MeOH溶液(4毫升)中。小瓶加蓋，反應於室溫下攪拌15小時。反應混合物直接加至2克SCX卡管(先經MeOH平衡)上，依序以MeOH(12毫升)與2M NH₃/MeOH溶液(8毫升)溶離。取含二羥硼酸粗產物之溶離份於氮氣流下濃縮，於高度真空下乾燥，產生45毫克粗產物。粗產物溶於飽和NaHCO₃(2毫升)，以EtOAc(3 x 2毫升)萃取，產生5毫克粗產物{5-[(2-甲基-1-吡咯啶基)甲基]-2-噻吩基}二羥硼酸。 Batch 2: Add NaBH(OAc) ₃ (271 mg, 1.28 mmol), HOAc (0.07 mL) and 2-methylpyrrolidine (0.043 mL, 0.42 mmol) to 2 dram vials (5-Methylmethyl-2-thienyl) dihydroxyboronic acid (100 mg, 0.64 mmol) in CH ₂ Cl ₂ /MeOH (4 mL). The vial was capped and the reaction was stirred at room temperature for 15 hours. The reaction mixture was added directly to a 2 g SCX card tube (first balance by MeOH) on to successively MeOH (12 is mL) and 2M NH ₃ / MeOH solution (8 ml) fractions. The fractions containing the crude product of dihydroxyboric acid were concentrated under a stream of nitrogen and dried under high vacuum to yield 45 mg of crude material. The crude product was dissolved in saturated NaHCO ₃ (2 mL), EtOAc (3 x 2 ml) to produce 5 mg of crude product {5 - [(2-methyl-1-pyrrolidinyl) methyl] -2-thienyl Base} dihydroxyboric acid.

第3批：添加2-甲基吡咯啶(0.033毫升，0.32毫莫耳)至2達蘭(dram)小瓶中含(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)之MeOH溶液(1毫升)中。小瓶加蓋，反應於室溫下攪拌2小時。添加NaCNBH₃(40毫克，0.64莫耳)，續攪拌19小時。反應混合物直接加至2克SCX卡管(先經MeOH平衡)上，依序以MeOH(12毫升)與2M NH₃/MeOH溶液(9毫升)溶離。取含二羥硼酸粗產物之溶離份於氮氣流下濃縮，於高度真空下乾燥，產生45毫克粗產物。粗產物溶於飽和NaHCO₃(2毫升)，以EtOAc(3 x 2毫升)萃取，產生7.8毫克粗產物{5-[(2-甲基-1-吡咯啶基)甲基]-2-噻吩基}二羥硼酸。收集如上述三批反應之二羥硼酸粗產物，用於製備3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-甲基-1-吡咯啶基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺(三批終產物{5-[(2-甲基-1-吡咯啶基)甲基]-2-噻吩基}二羥硼酸總重19毫克)。 Batch 3: Add 2-methylpyrrolidine (0.033 ml, 0.32 mmol) to 2 (dram) vials containing (5-methylnonyl-2-thienyl) dihydroxyboronic acid (50 mg, 0.32) Milliol) in MeOH (1 mL). The vial was capped and the reaction was stirred at room temperature for 2 hours. NaCNBH ₃ (40 mg, 0.64 mol) was added and stirring was continued for 19 hours. The reaction mixture was added directly to a 2 g SCX card tube (first balance by MeOH) on to successively MeOH (12 is mL) and 2M NH ₃ / MeOH solution (9 ml) fractions. The fractions containing the crude product of dihydroxyboric acid were concentrated under a stream of nitrogen and dried under high vacuum to yield 45 mg of crude material. The crude product was dissolved in saturated NaHCO ₃ (2 mL), EtOAc (3 x 2 ml) to produce 7.8 mg of crude product {5 - [(2-methyl-1-pyrrolidinyl) methyl] -2-thienyl Base} dihydroxyboric acid. The crude product of dihydroborate as the above three batches of the reaction was collected for the preparation of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-) Pyrrolidinyl)methyl]-2-thienyl}-1H-indole-7-carboxamide (three batches of final product {5-[(2-methyl-1-pyrrolidinyl)methyl]-2) -Thienyl} diboric acid total weight 19 mg).

取含5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(36毫克，0.0862毫莫耳)、{5-[(2-甲基-1-吡咯啶基)甲基]-2-噻吩基}二羥硼酸(19毫克，0.0862毫莫耳)與碳酸鉀(71毫克，0.517毫莫耳)之溶液於CEM微波管中合併。在此混合物中加水(0.25毫升)、二烷(0.75毫升)與肆(三苯基膦)鈀(0)(10毫克，0.009毫莫耳)。小瓶加蓋，於CEM微波爐中，於150℃下反應20分鐘。在此反應中添加肆(三苯基膦)鈀(0)(10毫克，0.009毫莫耳)，於微波爐中，於150℃下反應20分鐘。再加肆(三苯基膦)鈀(0)(10毫克，0.009毫莫耳)，反應於CEM微波爐中，再於150℃下反應20分鐘。反應混合物經2克SCX卡管(先經3毫升H₂O平衡)過濾，依序以水(3毫升)、MeOH(9毫升)與2M NH₃/MeOH溶液(9毫升)溶離。含粗產物溶液之溶離份於氮氣流下濃縮，殘質溶於DMSO(3毫升)。此粗產物之DMSO溶液分三批注射(各1毫升)，於Agilent MDAP(Zorbax Eclipse XDB-C18管柱：21.2 x 50 mm)上，以每分鐘20毫升，使用10%CH₃CN/H₂O(0.1% TFA)溶離1分鐘後，依線性梯度10% CH₃CN/H₂O(0.1%TFA)至95% CH₃CN/H₂O(0.1% TFA)溶離8分鐘，最後保持終濃度30秒。取含產物之兩個溶離份經500毫克Pharmasil CHQAX管柱(與氫氧化銨結合之聚合物；United Chemical Technologies)過濾，排除TFA(每份溶離份使用2支管柱)，於氮氣流及40℃下濃縮，產生13毫克標題化合物(29.3%)。 Take 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxamide (36 mg, 0.0862 mmol), {5- [(2-Methyl-1-pyrrolidinyl)methyl]-2-thienyl}dihydroxyboronic acid (19 mg, 0.0862 mmol) and potassium carbonate (71 mg, 0.517 mmol) in CEM Merged in the microwave tube. Add water (0.25 ml) to the mixture, two Alkane (0.75 ml) with hydrazine (triphenylphosphine) palladium (0) (10 mg, 0.009 mmol). The vial was capped and reacted in a CEM microwave oven at 150 ° C for 20 minutes. To the reaction was added hydrazine(triphenylphosphine)palladium(0) (10 mg, 0.009 mmol), which was reacted in a microwave oven at 150 ° C for 20 minutes. Further, ruthenium (triphenylphosphine)palladium(0) (10 mg, 0.009 mmol) was reacted in a CEM microwave oven and reacted at 150 ° C for 20 minutes. The reaction mixture was 2 g SCX card tube (first by 3 ml H ₂ O balance) was filtered, washed sequentially with water (3 mL), MeOH (9 mL) and 2M NH ₃ / MeOH solution (9 ml) fractions. The fractions containing the crude product were concentrated under a stream of nitrogen and the residue was dissolved in EtOAc (3 mL). This crude DMSO solution was injected in three batches (1 mL each) on Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2 x 50 mm) at 20 mL per minute using 10% CH ₃ CN/H ₂ O (0.1% TFA) was dissolved for 1 minute, and eluted according to a linear gradient of 10% CH ₃ CN/H ₂ O (0.1% TFA) to 95% CH ₃ CN/H ₂ O (0.1% TFA) for 8 minutes. The concentration is 30 seconds. The two fractions containing the product were filtered through a 500 mg Pharmasil CHQAX column (polymer bound to ammonium hydroxide; United Chemical Technologies) to remove TFA (2 columns per fraction), under nitrogen flow and 40 °C. Concentration gave 13 mg of the title compound (29.3%).

LC/MS=m/z 515.6[M+H]滯留時間：1.62分鐘。 LC/MS = m/z 515.6 [M+H].

實例168：5-{5-[(乙基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 168: 5-{5-[(Ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole- 7-carboxyguanamine

用於製備5-{5-[(乙基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之{5-[(乙基胺基)甲基]-2-噻吩基}二羥硼酸之製法如下：添加2M乙基胺之THF溶液(0.16毫升，0.32毫莫耳)至2達蘭瓶中含(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)之MeOH(1毫升)溶液中。小瓶加蓋，反應於室溫下攪拌2小時。添加NaCNBH₃(40毫克，0.64毫莫耳)，續攪拌17小時。反應混合物經2克SCX卡管(先經3毫升MeOH平衡)過濾，依序以MeOH(6毫升)與2 M NH₃/MeOH溶液(9毫升)溶離。取NH₃/MeOH溶離份於氮氣流下濃縮，產生47毫克粗產物{5-[(乙基胺基)甲基]-2-噻吩基}二羥硼酸。 For the preparation of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole- 7-Carboxylamidine {5-[(ethylamino)methyl]-2-thienyl} dihydroxyboronic acid was prepared as follows: 2M ethylamine in THF (0.16 mL, 0.32 mmol) was added 2 A solution of (5-methylindolyl-2-thienyl) dihydroxyboronic acid (50 mg, 0.32 mmol) in MeOH (1 mL). The vial was capped and the reaction was stirred at room temperature for 2 hours. Was added NaCNBH ₃ (40 mg, 0.64 mmol), stirring was continued for 17 hours. The reaction mixture was 2 g SCX card tube (to balance over 3 mL of MeOH) was filtered, washed successively with MeOH (. 6 mL) and 2 M NH ₃ / MeOH solution (9 ml) fractions. The NH ₃ /MeOH fraction was concentrated under a stream of nitrogen to give 47 mg of crude product (5-[(ethylamino)methyl]-2-thienyl}).

在含{5-[(乙基胺基)甲基]-2-噻吩基}二羥硼酸(47毫克，0.254毫莫耳)之CEM微波管中添加5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(80毫克，0.193毫莫耳)、碳酸鉀(160毫克，1.16毫莫耳)、二烷(1.5毫升)、H₂O(0.5毫升)與肆(三苯基膦)鈀(0)(5毫克，0.004毫莫耳)。反應於CEM微波爐中，於150℃下反應30分鐘。(此次操作前30分鐘因產生過高壓力而取消)。反應混合物經2克SCX卡管(先經3毫升MeOH平衡)，依序以H₂O(3毫升)、MeOH(9毫升)與2M NH₃/MeOH(6毫升)溶離。取NH₃/MeOH溶離份於氮氣流與40℃下乾燥，粗產物溶於二甲亞碸(1毫升)，經Agilent MDAP(Zorbax Eclipse XDB-C18管柱：21.2 x 50 mm)，依每分鐘20毫升，以1分鐘使用10% CH₃CN/H₂O(0.1%TFA)後，以8分鐘使用線性梯度10%CH₃CN/H₂O(0.1%TFA)至95% CH₃CN/H₂O(0.1% TFA)，保持終濃度30秒進行溶離純化。取含產物之溶離份經500毫克Pharmasil CHQAX管柱(與氫氧化銨結合之聚合物；United Chemical Technologies)過濾，排除TFA(每個溶離份使用2支管柱)，於氮氣流與60℃下濃縮，產生8.8毫克標題化合物(10%)。 Add 5-bromo-3-[1-(B) to a CEM microwave tube containing {5-[(ethylamino)methyl]-2-thienyl} dihydroxyboric acid (47 mg, 0.254 mmol) Sulfosyl)-4-piperidinyl]-1 H -indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), Alkane (1.5 ml), H ₂ O (0.5 ml) and hydrazine (triphenylphosphine) palladium (0) (5 mg, 0.004 mmol). The reaction was carried out in a CEM microwave oven and reacted at 150 ° C for 30 minutes. (Cancelled 30 minutes before the operation due to excessive pressure). The reaction mixture was 2 g SCX card tube (to balance over 3 mL of MeOH), washed sequentially with H ₂ O (3 mL), MeOH (. 9 mL) and 2M NH ₃ / MeOH (6 mL) fractions. The NH ₃ /MeOH fractions were dried in a stream of nitrogen at 40 ° C. The crude product was dissolved in dimethyl hydrazine (1 mL) and then applied to Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2 x 50 mm). 20 ml, using 10% CH ₃ CN/H ₂ O (0.1% TFA) in 1 minute, using a linear gradient of 10% CH ₃ CN/H ₂ O (0.1% TFA) to 95% CH ₃ CN/ in 8 minutes. H ₂ O (0.1% TFA) was subjected to dissolution purification at a final concentration of 30 seconds. The product-containing fractions were filtered through a 500 mg Pharmasil CHQAX column (polymer bound to ammonium hydroxide; United Chemical Technologies), TFA was removed (two columns per fraction), and concentrated under nitrogen flow at 60 °C. , yielding 8.8 mg of the title compound (10%).

LC/MS=m/z 429.8[M+H]滯留時間：1.25分鐘。 LC/MS = m/z 429.8 [M+H]: 1.25 min.

實例169：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(1-甲基乙基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺Example 169: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-2-thienyl) -1H-吲哚-7-carboxyguanamine

依據5-{5-[(乙基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、異丙基胺(0.027毫升，0.32毫莫耳)與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生41毫克粗產物(5-{[(1-甲基乙基)胺基]甲基}-2-噻吩基)二羥硼酸。由粗產物(5-{[(1-甲基乙基)胺基]甲基}-2-噻吩基)二羥硼酸與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(80毫克，0.193毫莫耳)、碳酸鉀(160毫克，1.16毫莫耳)，與肆(三苯基膦)鈀(0)(5毫克，0.004毫莫耳)反應，產生74毫克標題化合物(37%)。 According to 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7- The general procedure for carboxamide is from (5-methylindenyl-2-thienyl) dihydroboronic acid (50 mg, 0.32 mmol), isopropylamine (0.027 mL, 0.32 mmol) and NaCNBH ₃ ( The reaction was carried out to give 41 mg of crude (5-{[(1-methylethyl)amino]methyl}-2-thienyl)dihydroxyboronic acid as a crude product (40 mg, 0.64 mmol). From the crude product (5-{[(1-methylethyl)amino]methyl}-2-thienyl) dihydroborate and 5-bromo-3-[1-(ethylsulfonyl)-4 -piperidinyl]-1 H -indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and hydrazine (triphenylphosphine) palladium (0 (5 mg, 0.004 mmol) gave 74 mg of the title compound (37%).

LC/MS=m/z 430.2[M+H]滯留時間：1.29分鐘。 LC/MS = m/z 430.2 [M+H].

實例170：5-{5-[(環丙基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 170: 5-{5-[(Cyclopropylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole -7-carboxyguanamine

依據5-{5-[(乙基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、環丙基胺(0.022毫升，0.32毫莫耳)與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生63毫克粗產物{5-[(環丙基胺基)甲基]-2-噻吩基}二羥硼酸。粗產物{5-[(環丙基胺基)甲基]-2-噻吩基}二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(80毫克，0.193毫莫耳)、碳酸鉀(160毫克，1.16毫莫耳)及肆(三苯基膦)鈀(0)(5毫克，0.004毫莫耳)反應，產生不純之標題化合物。不純之標題化合物再經Agilent MDAP純化，依據實例5之製程單離出游離鹼，產生6.8毫克標題化合物(7.2%)。 According to 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7- The general procedure for carboxamide is from (5-methylindenyl-2-thienyl) dihydroboronic acid (50 mg, 0.32 mmol), cyclopropylamine (0.022 mL, 0.32 mmol) and NaCNBH ₃ ( The reaction was carried out in 40 mg of 0.64 mmol, yielding 63 mg of crude product {5-[(cyclopropylamino)methyl]-2-thienyl} dihydroxyboronic acid. The crude product {5-[(cyclopropylamino)methyl]-2-thienyl}dihydroxyboronic acid is further combined with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl] -1 H -吲哚-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol) and hydrazine (triphenylphosphine) palladium (0) (5 mg, 0.004 Reaction in millimolar yields the title compound which is impure. The impure title compound was purified by Agilent <RTI ID=0.0>>

LC/MS=m/z 430.2[M+H]滯留時間：1.62分鐘。 LC/MS = m/z 430.2 [M+H].

實例171：5-(5-{[(2,2-二甲基丙基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 171: 5-(5-{[(2,2-Dimethylpropyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-1H-indole-7-carboxamide

依據5-{5-[(乙基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基- 2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、(2,2-二甲基丙基)胺(0.037毫升，0.32毫莫耳)與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生73毫克粗產物(5-{[(2,2-二甲基丙基)胺基]甲基}-2-噻吩基)二羥硼酸。粗產物(5-{[(2,2-二甲基丙基)胺基]甲基}-2-噻吩基)二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(80毫克，0.193毫莫耳)、碳酸鉀(160毫克，1.16毫莫耳)與肆(三苯基膦)鈀(0)(5毫克，0.004毫莫耳)反應，產生21毫克標題化合物(21%)。 According to 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7- The general procedure for carboxamide is from (5-methyl-nonyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), (2,2-dimethylpropyl)amine (0.037 ml, 0.32). Reaction with NaCNBH ₃ (40 mg, 0.64 mmol) yielded 73 mg of crude (5-{[(2,2-dimethylpropyl)amino]methyl}-2-thiophene Base) dihydroxyboric acid. The crude product (5-{[(2,2-dimethylpropyl)amino]methyl}-2-thienyl)dihydroxyboronic acid is further combined with 5-bromo-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1 H -indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol) and hydrazine (triphenylphosphine) palladium (0) (5 mg, 0.004 mmol) gave 21 mg of the title compound (21%).

LC/MS=m/z 430.2[M+H]滯留時間：1.45分鐘。 LC/MS = m/z 430.2 [M+H].

實例172：5-(5-{[(環丙基甲基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 172: 5-(5-{[(Cyclopropylmethyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1H-吲哚-7-carboxyguanamine

依據5-{5-[(乙基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、(環丙基甲基)胺(0.027毫升，0.32毫莫耳)與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生73毫克粗產物(5-{[(環丙基甲基)胺基]甲基}-2-噻吩基)二羥硼酸。粗產物(5-{[(環丙基甲基)胺基]甲基}-2-噻吩基)二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(80毫克，0.193毫莫耳)、碳酸鉀(160毫克，1.16毫莫耳)及肆(三苯基膦)鈀(0)(5毫克，0.004毫莫耳)反應，產生19.1毫克標題化合物(20%)。 According to 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7- The general procedure for carboxamide is from (5-methylindenyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), (cyclopropylmethyl)amine (0.027 mL, 0.32 mmol). and NaCNBH ₃ (40 mg, 0.64 mmol) reacted to produce 73 mg of crude product (5 - {[(cyclopropylmethyl) amino] methyl} -2-thienyl) glyoxylic acid. The crude product (5-{[(cyclopropylmethyl)amino]methyl}-2-thienyl)dihydroxyboronic acid is further combined with 5-bromo-3-[1-(ethylsulfonyl)-4- Piperidinyl]-1 H -indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol) and hydrazine (triphenylphosphine) palladium (0) ( Reaction of 5 mg, 0.004 mmol, yielding 19.1 mg of the title compound (20%).

LC/MS=m/z 430.2[M+H]滯留時間：1.33分鐘。 LC/MS = m/z 430.2 [M+H].

實例173：5-(5-{[(環丙基甲基)胺基]甲基}-3-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 173: 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1H-吲哚-7-carboxyguanamine

用於製備5-(5-{[(環丙基甲基)胺基]甲基}-3-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之(環丙基甲基){[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺之製法如下：添加(環丙基甲基)胺(0.011毫升，0.129毫莫耳)至2達蘭小瓶中含5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶甲醛(30毫克，0.129毫莫耳)之MeOH(1毫升)溶液中。小瓶加蓋，於室溫下攪拌反應17小時。添加NaCNBH₃(16毫克，0.258毫莫耳)，續攪拌30小時。反應混合物經2克SCX卡管(先經3毫升MeOH平衡)過濾，依序以MeOH(6毫升)與2M NH₃/MeOH溶液(9毫升)溶離。取NH₃/MeOH溶離份於氮氣流下濃縮，產生21毫克粗產物(環丙基甲基){[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺。 For the preparation of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1H-吲哚-7-carboxyguanamine (cyclopropylmethyl) {[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -3-pyridyl]methyl}amine is prepared by adding (cyclopropylmethyl)amine (0.011 ml, 0.129 mmol) to 2 dallan vials containing 5-(4,4,5,5 A solution of tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarboxaldehyde (30 mg, 0.129 mmol) in MeOH (1 mL). The vial was capped and the reaction was stirred at room temperature for 17 hours. NaCNBH ₃ (16 mg, 0.258 mmol) was added and stirring was continued for 30 hours. The reaction mixture was 2 g SCX card tube (to balance over 3 mL of MeOH) was filtered, washed successively with MeOH (. 6 mL) and 2M NH ₃ / MeOH solution (9 ml) fractions. The NH ₃ /MeOH fraction was concentrated under a stream of nitrogen to give 21 mg of crude product (cyclopropylmethyl) {[5-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Pentocyclo-2-yl)-3-pyridyl]methyl}amine.

在含(環丙基甲基){[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺(21毫克，0.0725毫莫耳)之CEM微波管中添加5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(30毫克，0.0723毫莫耳)、二烷(0.75毫升)、碳酸鉀(60毫克，0.434毫莫耳)之H₂O(0.25毫升)溶液與氯-2-(二甲基胺基甲基)-二茂絡鐵-1-基-(二原冰片基膦基)鈀(II)(4.4毫克，0.00723毫莫耳)。反應於CEM微波爐中，於150℃下加熱30分鐘。反應混合物經2克SCX卡管(先經3毫升MeOH平衡)過濾，依序以H₂O(3毫升)、MeOH(6毫升)與2M NH₃/MeOH溶液(9毫升)溶離。取NH₃/MeOH溶離份於氮氣流及40℃下乾燥，經Agilent MDAP(Zorbax Eclipse XDB-C18管柱：21.2 x 50 mm)，依每分鐘20毫升，以1分鐘使用10%CH₃CN/H₂O(0.1%TFA)後，以8分鐘使用線性梯度10% CH₃CN/H₂O(0.1%TFA)至95% CH₃CN/H₂O(0.1%TFA)，及保持終濃度30秒進行溶離純化。取含產物溶離份經2克Pharmasil CHQAX管柱(與氫氧化銨結合之聚合物；United Chemical Technologies)，以排除TFA，於氮氣流與65℃下濃縮，產生不純之標題化合物，其再如上述經Agilent MDAP純化，產生25毫克標題化合物(70%)。 Containing (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]methyl Add 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxylate to a CEM microwave tube of amine (21 mg, 0.0725 mmol) Guanamine (30 mg, 0.0723 mmol), two Dioxane (0.75 ml), potassium carbonate (60 mg, 0.434 mmol) of H ₂ O (0.25 ml) and chloro-2- (dimethylamino-methyl) - ferrocene-1-yl - (Di-originyl phosphinyl) palladium (II) (4.4 mg, 0.00723 mmol). The reaction was heated in a CEM microwave oven and heated at 150 ° C for 30 minutes. The reaction mixture was 2 g SCX card tube (to balance over 3 mL of MeOH) was filtered, washed sequentially with H ₂ O (3 mL), MeOH (. 6 mL) and 2M NH ₃ / MeOH solution (9 ml) fractions. The NH ₃ /MeOH fraction was dried in a stream of nitrogen and dried at 40 ° C, using Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2 x 50 mm), 20 ml per minute, using 10% CH ₃ CN/ for 1 minute. After H ₂ O (0.1% TFA), a linear gradient of 10% CH ₃ CN/H ₂ O (0.1% TFA) to 95% CH ₃ CN/H ₂ O (0.1% TFA) was used over 8 minutes, and the final concentration was maintained. The dissolution purification was carried out for 30 seconds. The product-containing fraction was taken over 2 g of a Pharmasil CHQAX column (polymer combined with ammonium hydroxide; United Chemical Technologies) to remove the TFA and concentrated under a nitrogen stream at 65 ° C to give the title compound as imp. Purification by Agilent MDAP gave 25 mg of the title compound (70%).

LC/MS=m/z 496.6[M+H]滯留時間：1.35分鐘。 LC/MS = m/z 496.6 [M+H].

實例174：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[2-(甲基氧)乙基]胺基}甲基)-3-吡啶基]-1H-吲哚-7-羧醯胺Example 174: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[2-(methyloxy)ethyl]amino}methyl)-3- Pyridyl]-1H-indole-7-carboxyguanamine

依據5-(5-{[(環丙基甲基)胺基]甲基}-3-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶甲醛(30毫克，0.129毫莫耳)、[2-(甲基氧)乙基]胺(0.011毫升，0.129毫莫耳)與NaCNBH₃(16毫克，0.258毫莫耳)進行反應，產生19毫克粗產物[2-(甲基氧)乙基]{[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺。粗產物[2-(甲基氧)乙基]{[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(30毫克，0.0723毫莫耳)、碳酸鉀(60毫克，0.434毫莫耳)及氯-2-(二甲基胺基甲基)-二茂絡鐵-1-基-(二原冰片基膦基)鈀(II)(4.4毫克，0.00723毫莫耳)反應，產生15毫克標題化合物(46%)。 According to 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H- The general process of 吲哚-7-carboxyguanamine is composed of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarboxaldehyde ( 30 mg, 0.129 mmol), [2- (methylamino) ethyl] amine (0.011 mL, 0.129 mmol) and NaCNBH ₃ (16 mg, 0.258 mmol) is reacted to produce 19 mg of the crude product [2-(Methyloxy)ethyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl] Methyl}amine. Crude product [2-(methyloxy)ethyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridine Methyl}amine followed by 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (30 mg, 0.0723 mmol) Ear), potassium carbonate (60 mg, 0.434 mmol) and chloro-2-(dimethylaminomethyl)-ferrocen-l-yl-(di-norbornylphosphino)palladium(II) (4.4 mg, 0.00723 mmol) gave 15 mg of the title compound (46%).

LC/MS=m/z 500.6[M+H]滯留時間：1.52分鐘。 LC/MS = m/z 500.6 [M+H].

實例175：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[3-(甲基氧)丙基]胺基}甲基)-3-吡啶基]-1H-吲哚-7-羧醯胺Example 175: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[3-(methyloxy)propyl]amino}methyl)-3- Pyridyl]-1H-indole-7-carboxyguanamine

依據5-(5-{[(環丙基甲基)胺基]甲基}-3-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶甲醛(30毫克，0.129毫莫耳)、[3-(甲基氧)丙基]胺(0.013毫升，0.129毫莫耳)，與NaCNBH₃(16毫克，0.258毫莫耳)進行反應，產生22毫克粗產物[3-(甲基氧)丙基]{[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺。粗產物[3-(甲基氧)丙基]{[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(30毫克，0.0723毫莫耳)、碳酸鉀(60毫克，0.434毫莫耳)及氯-2-(二甲基胺基甲基)-二茂絡鐵-1-基-(二原冰片基膦基)鈀(II)(4.4毫克，0.00723毫莫耳)反應，產生31毫克標題化合物(83%)。 According to 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H- The general process of 吲哚-7-carboxyguanamine is composed of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarboxaldehyde ( 30 mg, 0.129 mmol), [3- (methylthio) propyl] amine (0.013 mL, 0.129 mmol), reaction with NaCNBH ₃ (16 mg, 0.258 mmol) to give 22 mg of crude Product [3-(Methyloxy)propyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl ]methyl}amine. Crude product [3-(methyloxy)propyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridine Methyl}amine followed by 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (30 mg, 0.0723 mmol) Ear), potassium carbonate (60 mg, 0.434 mmol) and chloro-2-(dimethylaminomethyl)-ferrocen-l-yl-(di-norbornylphosphino)palladium(II) (4.4 mg, 0.00723 mmol) gave 31 mg of the title compound (83%).

LC/MS=m/z 514.4[M+H]滯留時間：1.46分鐘。 LC/MS = m/z 514.4 [M+H].

實例176：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(4-嗎啉基甲基)-3-吡啶基]-1H-吲哚-7-羧醯胺Example 176: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-(4-morpholinylmethyl)-3-pyridyl]-1H-indole-7 -carboxamide

依據5-(5-{[(環丙基甲基)胺基]甲基}-3-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶甲醛(30毫克，0.129毫莫耳)、嗎啉(0.011毫升，0.129毫莫耳)，與NaCNBH₃(16毫克，0.258毫莫耳)進行反應，產生28毫克粗產物4-{[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}嗎啉。粗產物4-{[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}嗎啉再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(30毫克，0.0723毫莫耳)、碳酸鉀(60毫克，0.434毫莫耳)及氯-2-(二甲基胺基甲基)-二茂絡鐵-1-基-(二原冰片基膦基)鈀(II)(4.4毫克，0.00723毫莫耳)反應，產生15.8毫克標題化合物(43%)。 According to 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H- The general process of 吲哚-7-carboxyguanamine is composed of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarboxaldehyde ( 30 mg, 0.129 mmol), morpholine (0.011 mL, 0.129 mmol), and NaCNBH ₃ (16 mg, 0.258 mmol) is reacted to produce 28 mg of a crude product of 4 - {[5- (4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]methyl}morpholine. The crude product 4-{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]methyl}morpholine 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg) , 0.434 mmol, and chloro-2-(dimethylaminomethyl)-ferrocen-l-yl-(di-norbornylphosphino)palladium(II) (4.4 mg, 0.00723 mmol) The reaction gave 15.8 mg of the title compound (43%).

LC/MS=m/z 512.2[M+H]滯留時間：1.38分鐘。 LC/MS = m/z 512.2 [M+H].

實例177：5-{5-[(乙基胺基)甲基]-3-吡啶基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 177: 5-{5-[(Ethylamino)methyl]-3-pyridyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole- 7-carboxyguanamine

依據5-(5-{[(環丙基甲基)胺基]甲基}-3-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶甲醛(30毫克，0.129毫莫耳)、2 M乙基胺之THF溶液(0.065毫升，0.129毫莫耳)及NaCNBH₃(16毫克，0.258毫莫耳)進行反應，產生19毫克粗產物乙基{[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺。粗產物乙基{[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(30毫克，0.0723毫莫耳)、碳酸鉀(60毫克，0.434毫莫耳)及氯-2-(二甲基胺基甲基)-二茂絡鐵-1-基-(二原冰片基膦基)鈀(II)(4.4毫克，0.00723毫莫耳)反應，產生12.3毫克標題化合物(36%)。 According to 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H- The general process of 吲哚-7-carboxyguanamine is composed of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarboxaldehyde ( 30 mg, 0.129 mmol, 2 M ethylamine in THF (0.065 mL, 0.129 mmol) and NaCNBH ₃ (16 mg, 0.258 mmol) afforded 19 mg of crude ethyl. 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]methyl}amine. The crude product ethyl {[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]methyl}amine is further combined with 5 -Bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 millimolar) and chloro-2-(dimethylaminomethyl)-diferrocen-1-yl-(di-norbornylphosphino)palladium(II) (4.4 mg, 0.00723 mmol) Reaction gave 12.3 mg of the title compound (36%).

LC/MS=m/z 470.4[M+H]滯留時間：1.44分鐘。 LC/MS = m/z 470.4 [M+H].

實例178：5-{5-[(二甲基胺基)甲基]-3-吡啶基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 178: 5-{5-[(Dimethylamino)methyl]-3-pyridyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole -7-carboxyguanamine

依據5-(5-{[(環丙基甲基)胺基]甲基}-3-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶甲醛(30毫克，0.129毫莫耳)、2M二甲基胺之THF溶液(0.065毫升，0.129毫莫耳)，與NaCNBH₃(16毫克，0.258毫莫耳)進行反應，產生23毫克粗產物二甲基{[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺。粗產物二甲基{[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(30毫克，0.0723毫莫耳)、碳酸鉀(60毫克，0.434毫莫耳)及氯-2-(二甲基胺基甲基)-二茂絡鐵-1-基-(二原冰片基膦基)鈀(II)(4.4毫克，0.00723毫莫耳)反應，產生5.4毫克標題化合物(16%)。 According to 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H- The general process of 吲哚-7-carboxyguanamine is composed of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarboxaldehyde ( 30 mg, 0.129 mmol), 2M THF solution of dimethylamine (0.065 mL, 0.129 mmol), and NaCNBH ₃ (16 mg, 0.258 mmol) is reacted to produce 23 mg of crude product dimethyl {[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]methyl}amine. The crude product dimethyl {[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]methyl}amine 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg) , 0.434 mmol, and chloro-2-(dimethylaminomethyl)-ferrocen-l-yl-(di-norbornylphosphino)palladium(II) (4.4 mg, 0.00723 mmol) The reaction gave 5.4 mg of the title compound (16%).

LC/MS=m/z 470.6[M+H]滯留時間：1.35分鐘。 LC/MS = m/z 470.6 [M+H].

實例179：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(2-甲基-1-吡咯啶基)甲基]-3-吡啶基}-1H-吲哚-7-羧醯胺Example 179: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[(2-methyl-1-pyrrolidinyl)methyl]-3-pyridyl} -1H-吲哚-7-carboxyguanamine

依據5-(5-{[(環丙基甲基)胺基]甲基}-3-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶甲醛(30毫克，0.129毫莫耳)、2-甲基吡咯啶(0.013毫升，0.129毫莫耳)與NaCNBH₃(16毫克，0.258毫莫耳)進行反應，產生25毫克粗產物3-[(2-甲基-1-吡咯啶基)甲基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)吡啶。粗產物3-[(2-甲基-1-吡咯啶基)甲基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)吡啶再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(30毫克，0.0723毫莫耳)、碳酸鉀(60毫克，0.434毫莫耳)，與氯-2-(二甲基胺基甲基)-二茂絡鐵-1-基-(二原冰片基膦基)鈀(II)(4.4毫克，0.00723毫莫耳)反應，產生6毫克標題化合物(16%)。 According to 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H- The general process of 吲哚-7-carboxyguanamine is composed of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarboxaldehyde ( 30 mg, 0.129 mmol), 2-methyl pyrrolidine (0.013 mL, 0.129 mmol) and NaCNBH ₃ (16 mg, 0.258 mmol) is reacted to produce 25 mg of the crude product 3 - [(2 Methyl-1-pyrrolidyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. The crude product 3-[(2-methyl-1-pyrrolidinyl)methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Pyridine and then 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (30 mg, 0.0723 mmol), Potassium carbonate (60 mg, 0.434 mmol), with chloro-2-(dimethylaminomethyl)-diferrocen-1-yl-(di-norbornylphosphino)palladium(II) (4.4 Reaction in milligrams, 0.00723 mmol, yielding 6 mg of the title compound (16%).

LC/MS=m/z 512.6[M+H]滯留時間：1.67分鐘。 LC/MS = m/z 512.6 [M+H] retention time: 1.67 min.

實例180：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丙基)胺基]甲基}-3-吡啶基)-1H-吲哚-7-羧醯胺Example 180: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-3-pyridyl) -1H-吲哚-7-carboxyguanamine

依據5-(5-{[(環丙基甲基)胺基]甲基}-3-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶甲醛(30毫克，0.129毫莫耳)、異丁基胺(0.013毫升，0.129毫莫耳)與NaCNBH₃(16毫克，0.258毫莫耳)進行反應，產生21毫克粗產物(2-甲基丙基){[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺。粗產物(2-甲基丙基){[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(30毫克，0.0723毫莫耳)、碳酸鉀(60毫克，0.434毫莫耳)，與氯-2-(二甲基胺基甲基)-二茂絡鐵-1-基-(二原冰片基膦基)鈀(II)(4.4毫克，0.00723毫莫耳)反應，產生12.5毫克標題化合物(35%)。 According to 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H- The general process of 吲哚-7-carboxyguanamine is composed of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarboxaldehyde ( 30 mg, 0.129 mmol), isobutylamine (0.013 mL, 0.129 mmol) and NaCNBH ₃ (16 mg, 0.258 mmol) is reacted to produce 21 mg of the crude product (2-methylpropyl) {[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]methyl}amine. Crude product (2-methylpropyl) {[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]- And amine 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (30 mg, 0.0723 mmol), Potassium carbonate (60 mg, 0.434 mmol), with chloro-2-(dimethylaminomethyl)-diferrocen-1-yl-(di-norbornylphosphino)palladium(II) (4.4 Reaction in milligrams, 0.00723 mmol, yielding 12.5 mg of the title compound (35%).

LC/MS=m/z 498.2[M+H]滯留時間：1.38分鐘。 LC/MS = m/z 498.2 [M+H].

實例181：5-(5-{[(2,2-二甲基丙基)胺基]甲基}-3-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 181: 5-(5-{[(2,2-Dimethylpropyl)amino]methyl}-3-pyridyl)-3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-1H-indole-7-carboxamide

依據5-(5-{[(環丙基甲基)胺基]甲基}-3-吡啶基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶甲醛(30毫克，0.129毫莫耳)、(2,2-二甲基丙基)胺(0.015毫升，0.129毫莫耳)與NaCNBH₃(16毫克，0.258毫莫耳)進行反應，產生25毫克粗產物(2,2-二甲基丙基){[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺。粗產物(2,2-二甲基丙基){[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(30毫克，0.0723毫莫耳)、碳酸鉀(60毫克，0.434毫莫耳)與氯-2-(二甲基胺基甲基)-二茂絡鐵-1-基-(二原冰片基膦基)鈀(II)(4.4毫克，0.00723毫莫耳)反應，產生12.7毫克標題化合物(34%)。 According to 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H- The general process of 吲哚-7-carboxyguanamine is composed of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarboxaldehyde ( 30 mg, 0.129 mmol), (2,2-dimethylpropyl) amine (0.015 mL, 0.129 mmol) and NaCNBH ₃ (16 mg, 0.258 mmol) is reacted to produce 25 mg of the crude product (2,2-dimethylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl] Methyl}amine. Crude product (2,2-dimethylpropyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridine Methyl}amine followed by 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (30 mg, 0.0723 mmol) Ear), potassium carbonate (60 mg, 0.434 mmol) and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(di-originylphosphino)palladium(II) (4.4 mg, 0.00723 mmol) gave 12.7 mg of the title compound (34%).

LC/MS=m/z 512.4[M+H]滯留時間：1.51分鐘。 LC/MS = m/z 512.4 [M+H].

實例182：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丁基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺Example 182: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl) -1H-吲哚-7-carboxyguanamine

用於製備3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丁基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺之{5-[(乙基胺基)甲基]-2-噻吩基}二羥硼酸之製法如下：添加含(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)之MeOH(0.5毫升)溶液與含NaCNBH₃(40毫克，0.64毫莫耳)之MeOH(0.5毫升)溶液至2達蘭瓶中之(2-甲基丁基)胺(28毫克，0.32毫莫耳)中。小瓶加蓋，於室溫下攪拌反應20小時。反應混合物經2克SCX卡管(先經3毫升MeOH平衡)，依序以MeOH(6毫升)與2M NH₃/MeOH溶液(9毫升)溶離。取NH₃/MeOH溶離份於氮氣流下濃縮，產生43毫克粗產物(5-{[(2-甲基丁基)胺基]甲基}-2-噻吩基)二羥硼酸。 For the preparation of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl) {5-[(Ethylamino)methyl]-2-thienyl}-dihydroxyboronic acid of -1H-indole-7-carboxamide is prepared as follows: (5-methylindenyl-2-thiophene is added) yl) glyoxylic acid (50 mg, 0.32 mmol) of MeOH (0.5 mL) containing NaCNBH ₃ (40 mg, 0.64 mmol) of MeOH (0.5 mL) to a 2 dram vial of (2 Methyl butyl)amine (28 mg, 0.32 mmol). The vial was capped and the reaction was stirred at room temperature for 20 hours. The reaction mixture was 2 g SCX card tube (to balance over 3 mL of MeOH), washed successively with MeOH (. 6 mL) and 2M NH ₃ / MeOH solution (9 ml) fractions. The NH ₃ /MeOH fraction was concentrated under a stream of nitrogen to give 43 mg of crude (5-{[(2-methylbutyl)amino]methyl}-2-thienyl)dihydroxyboronic acid.

在含粗產物(5-{[(2-甲基丁基)胺基]甲基}-2-噻吩基)二羥硼酸(43毫克，0.188毫莫耳)之CEM微波管中添加5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、K₂CO₃(130毫克，0.942毫莫耳)、二烷(1.5毫升)、H₂O(0.5毫升)與肆(三苯基膦)鈀(0)(4毫克，0.003毫莫耳)。反應於CEM微波爐中，於150℃下加熱30分鐘。反應混合物經2克SCX卡管(先經3毫升MeOH平衡)過濾，依序以H₂O(3毫升)、MeOH(9毫升)與2M NH₃/MeOH溶液(6毫升)溶離。取NH₃/MeOH溶離份於氮氣流與40℃下乾燥，粗產物溶於二甲亞碸(1毫升)，經Agilent MDAP(Zorbax Eclipse XDB-C18管柱：21.2 x 50 mm)，依每分鐘20毫升，以1分鐘使用10%CH₃CN/H₂O(0.1% TFA)後，以8分鐘使用線性梯度10%CH₃CN/H₂O(0.1%TFA)至 95%CH₃CN/H₂O(0.1% TFA)，及保持終濃度30秒，進行溶離純化。取含產物之溶離份經2克Pharmasil CHQAX管柱(與氫氧化銨結合之聚合物；United Chemical Technologies)過濾排除TFA，於氮氣流與50℃下濃縮，產生16.2毫克標題化合物(17%)。 Add 5-bromine to a CEM microwave tube containing the crude product (5-{[(2-methylbutyl)amino]methyl}-2-thienyl) dihydroborate (43 mg, 0.188 mmol) -3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 millimoles), two Alkane (1.5 ml), H ₂ O (0.5 ml) and hydrazine (triphenylphosphine) palladium (0) (4 mg, 0.003 mmol). The reaction was heated in a CEM microwave oven and heated at 150 ° C for 30 minutes. The reaction mixture was 2 g SCX card pipe (3 ml MeOH was first balanced) filtered, washed sequentially with H ₂ O (3 mL), MeOH (. 9 mL) and 2M NH ₃ / MeOH solution (6 ml) fractions. The NH ₃ /MeOH fractions were dried in a stream of nitrogen at 40 ° C. The crude product was dissolved in dimethyl hydrazine (1 mL) and then applied to Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2 x 50 mm). 20 ml, using 10% CH ₃ CN/H ₂ O (0.1% TFA) in 1 minute, using a linear gradient of 10% CH ₃ CN/H ₂ O (0.1% TFA) to 95% CH ₃ CN/ in 8 minutes. H ₂ O (0.1% TFA), and maintaining a final concentration for 30 seconds, was subjected to elution purification. The product-containing fractions were taken through 2 g of Pharmasil CHQAX column (polymers combined with ammonium hydroxide; United Chemical Technologies) to remove TFA, and concentrated under a nitrogen stream at 50 ° C to give 16.2 mg of the title compound (17%).

LC/MS=m/z 430.4[M+H]滯留時間：1.75分鐘。 LC/MS = m/z 430.4 [M+H].

實例183：5-[5-({[(1R)-1,2-二甲基丙基]胺基}甲基)-2-噻吩基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 183: 5-[5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]-3-[1-(ethylsulfonyl) 4-piperidinyl]-1H-indole-7-carboxamide

依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丁基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、[(1R)-1,2-二甲基丙基]胺(28毫克，0.32毫莫耳)與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生30毫克粗產物[5-({[(1R)-1,2-二甲基丙基]胺基}甲基)-2-噻吩基]二羥硼酸。粗產物[5-({[(1R)-1,2-二甲基丙基]胺基}甲基)-2-噻吩基]二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、K₂CO₃(130毫克，0.942毫莫耳)，與肆(三苯基膦)鈀(0)(4毫克，0.003毫莫耳)反應，產生20.5毫克標題化合物(30%)。 According to 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H - 吲哚-7-carboxyguanamine general process from (5-methyl-nonyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), [(1R)-1,2-dimethyl The reaction of propyl propylamine (28 mg, 0.32 mmol) with NaCNBH ₃ (40 mg, 0.64 mmol) yielded 30 mg of crude product [5-({[(1R)-1,2-dimethyl) Propyl]amino}methyl)-2-thienyl]dihydroxyboronic acid. The crude product [5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]dihydroxyboronic acid is further combined with 5-bromo-3-[1-(B Sulfosyl)-4-piperidinyl]-1 H -indole-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 mmol), with hydrazine Reaction of (triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) gave 20.5 mg of the title compound (30%).

LC/MS=m/z 430.4[M+H]滯留時間：1.75分鐘。 LC/MS = m/z 430.4 [M+H].

實例184：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(戊基胺基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺Example 184: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[(pentylamino)methyl]-2-thienyl}-1H-indole- 7-carboxyguanamine

依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丁基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、戊基胺(29毫克，0.32毫莫耳)與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生45毫克粗產物{5-[(戊基胺基)甲基]-2-噻吩基}二羥硼酸。粗產物{5-[(戊基胺基)甲基]-2-噻吩基}二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、K₂CO₃(130毫克，0.942毫莫耳)及肆(三苯基膦)鈀(0)(4毫克，0.003毫莫耳)反應，產生20.7毫克標題化合物(20%)。 According to 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H - General procedure for 吲哚-7-carboxyguanamine, from (5-methylindenyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), pentylamine (29 mg, 0.32 mmol) Reaction with NaCNBH ₃ (40 mg, 0.64 mmol) gave 45 mg of crude product {5-[(pentylamino)methyl]-2-thienyl}dihydroxyboronic acid. The crude product {5-[(pentylamino)methyl]-2-thienyl}dihydroxyboronic acid is further combined with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 mmol) and hydrazine (triphenylphosphine) palladium (0) (4 mg, Reaction (0.003 mmol) gave 20.7 mg of the title compound (20%).

LC/MS=m/z 430.6[M+H]滯留時間：1.75分鐘。 LC/MS = m/z 430.6 [M+H].

實例185：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[(2S)-2-甲基丁基]胺基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺Example 185: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({[(2S)-2-methylbutyl]amino}methyl)-2 -thienyl]-1H-indole-7-carboxyguanamine

依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丁基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、[(2S)-2-甲基丁基]胺(28毫克，0.32毫莫耳)，與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生43毫克粗產物[5-({[(2S)-2-甲基丁基]胺基}甲基)-2-噻吩基]二羥硼酸。粗產物[5-({[(2S)-2-甲基丁基]胺基}甲基)-2-噻吩基]二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、K₂CO₃(130毫克，0.942毫莫耳)及肆(三苯基膦)鈀(0)(4毫克，0.003毫莫耳)反應，產生37.6毫克標題化合物(39%)。 According to 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H - General procedure for 吲哚-7-carboxyguanamine, from (5-methylindenyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), [(2S)-2-methylbutyl ] amine (28 mg, 0.32 mmol), and NaCNBH ₃ (40 mg, 0.64 mmol) reacted to produce 43 mg of the crude product [5 - ({[(2S ) -2- methylbutyl] amine Methyl}methyl)-2-thienyl] dihydroxyboric acid. The crude product [5-({[(2S)-2-methylbutyl]amino}methyl)-2-thienyl]dihydroxyboronic acid is further combined with 5-bromo-3-[1-(ethylsulfonate) 4-piperidinyl]-1 H -indole-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 mmol) and hydrazine (triphenyl) Reaction of palladium (0) (4 mg, 0.003 mmol) gave 37.6 mg of the title compound (39%).

LC/MS=m/z 430[M+H]滯留時間：1.67分鐘。 LC/MS = m/z 430 [M+H] retention time: 1.67 min.

實例186：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(1-甲基丁基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺Example 186: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylbutyl)amino]methyl}-2-thienyl) -1H-吲哚-7-carboxyguanamine

依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丁基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、(1-甲基丁基)胺(29毫克，0.32毫莫耳)與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生43毫克粗產物(5-{[(1-甲基丁基)胺基]甲基}-2-噻吩基)二羥硼酸。粗產物(5-{[(1-甲基丁基)胺基]甲基}-2-噻吩基)二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、K₂CO₃(130毫克，0.942毫莫耳)及肆(三苯基膦)鈀(0)(4毫克，0.003毫莫耳)反應，產生35.2毫克標題化合物(60%)。 According to 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H - General procedure for 吲哚-7-carboxyguanamine, from (5-methylindenyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), (1-methylbutyl)amine (29 Milligrams, 0.32 mmol, reacted with NaCNBH ₃ (40 mg, 0.64 mmol) to give 43 mg of crude (5-{[(1-methylbutyl)amino]methyl}-2-thiophene Base) dihydroxyboric acid. The crude product (5-{[(1-methylbutyl)amino]methyl}-2-thienyl)dihydroxyboronic acid is further combined with 5-bromo-3-[1-(ethylsulfonyl)-4 -piperidinyl]-1 H -indole-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 mmol) and hydrazine (triphenylphosphine) palladium ( 0) (4 mg, 0.003 mmol) gave 35.2 mg of the title compound (60%).

LC/MS=m/z 430[M+H]滯留時間：1.62分鐘。 LC/MS = m/z 430 [M+H] retention: 1.62 min.

實例187：5-{5-[(丁基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 187: 5-{5-[(butylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole- 7-carboxyguanamine

依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丁基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、丁基胺(24毫克，0.32毫莫耳)與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生49毫克粗產物{5-[(丁基胺基)甲基]-2-噻吩基}二羥硼酸。粗產物{5-[(丁基胺基)甲基]-2-噻吩基}二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、K₂CO₃(130毫克，0.942毫莫耳)及肆(三苯基膦)鈀(0)(4毫克，0.003毫莫耳)反應，產生27.2毫克標題化合物(24%)。 According to 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H - General procedure for 吲哚-7-carboxyguanamine, from (5-methylindenyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), butylamine (24 mg, 0.32 mmol) Reaction with NaCNBH ₃ (40 mg, 0.64 mmol) gave 49 mg of crude product {5-[(butylamino)methyl]-2-thienyl} dihydroxyboronic acid. The crude product {5-[(butylamino)methyl]-2-thienyl}dihydroxyboronic acid is further combined with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 mmol) and hydrazine (triphenylphosphine) palladium (0) (4 mg, The reaction was carried out to give the title compound (24%).

LC/MS=m/z 430[M+H]滯留時間：1.56分鐘。 LC/MS = m/z 430 [M+H].

實例188：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[2-(甲基氧)乙基]胺基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺Example 188: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-({[2-(methyloxy)ethyl]amino}methyl)-2- Thienyl]-1H-indole-7-carboxyguanamine

依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丁基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、[2-(甲基氧)乙基]胺(24毫克，0.32毫莫耳)與NaCNBH₃(40毫克， 0.64毫莫耳)進行反應，產生42毫克粗產物[5-({[2-(甲基氧)乙基]胺基}甲基)-2-噻吩基]二羥硼酸。粗產物[5-({[2-(甲基氧)乙基]胺基}甲基)-2-噻吩基]二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、K₂CO₃(130毫克，0.942毫莫耳)及肆(三苯基膦)鈀(0)(4毫克，0.003毫莫耳)反應，產生不純之標題化合物。該不純之標題化合物再依3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丁基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺製法所示HPLC與氫氧化銨SPE操作法純化，產生15毫克標題化合物(15%)。 According to 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H - General procedure for 吲哚-7-carboxyguanamine, from (5-methylindenyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), [2-(methyloxy)ethyl] amine (24 mg, 0.32 mmol) and NaCNBH ₃ (40 mg, 0.64 mmol) reacted to produce 42 mg of crude product [5 - ({[2- (methylamino) ethyl] amino} methyl Base)-2-thienyl] dihydroxyboric acid. The crude product [5-({[2-(methyloxy)ethyl]amino}methyl)-2-thienyl]dihydroxyboronic acid is further combined with 5-bromo-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1 H -indole-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 mmol) and hydrazine (triphenylphosphine) Reaction of palladium (0) (4 mg, 0.003 mmol) afforded the title compound. The impure title compound is again 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2 -Thienyl)-1H-indole-7-carboxamide compound was purified by HPLC and ammonium hydroxide SPE to give 15 mg of the title compound (15%).

LC/MS=m/z 430.2[M+H]滯留時間：1.33分鐘。 LC/MS = m/z 430.2 [M+H].

實例189：5-{5-[(環戊基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 189: 5-{5-[(Cyclopentylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole -7-carboxyguanamine

依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丁基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、環戊基胺(28毫克，0.32毫莫耳)與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生48毫克粗產物{5-[(環戊基胺基)甲基]-2-噻吩基}二羥硼酸。粗產物{5-[(環戊基胺基)甲基]-2-噻吩基}二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、K₂CO₃(130毫克，0.942毫莫耳)與肆(三苯基膦)鈀(0)(4毫克，0.003毫莫耳)反應，產生93.5毫克標題化合物(85%)。 According to 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H - General procedure for 吲哚-7-carboxyguanamine, from (5-methylindenyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), cyclopentylamine (28 mg, 0.32 mmol) ear) and NaCNBH ₃ (40 mg, 0.64 mmol) reacted to produce 48 mg of crude product {5 - [(cyclopentyl) methyl] -2-thienyl} glyoxylic acid. The crude product {5-[(cyclopentylamino)methyl]-2-thienyl}dihydroxyboronic acid is further combined with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl] -1 H -吲哚-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 mmol) and hydrazine (triphenylphosphine) palladium (0) (4 mg , 0.003 mmol), yielding 93.5 mg of the title compound (85%).

LC/MS=m/z 430.4[M+H]滯留時間：1.64分鐘。 LC/MS = m/z 430.4 [M+H].

實例190：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(3-甲基丁基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺Example 190: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[(3-methylbutyl)amino]methyl}-2-thienyl) -1H-吲哚-7-carboxyguanamine

依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丁基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、(3-甲基丁基)胺(28毫克，0.32毫莫耳)，與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生46毫克粗產物(5-{[(3-甲基丁基)胺基]甲基}-2-噻吩基)二羥硼酸。粗產物(5-{[(3-甲基丁基)胺基]甲基}-2-噻吩基)二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、 K₂CO₃(130毫克，0.942毫莫耳)及肆(三苯基膦)鈀(0)(4毫克，0.003毫莫耳)反應，產生38.3毫克標題化合物(37%)。 According to 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H - General procedure for 吲哚-7-carboxyguanamine, from (5-methylindenyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), (3-methylbutyl)amine (28 Milligram, 0.32 mmol, reacted with NaCNBH ₃ (40 mg, 0.64 mmol) to give 46 mg of crude (5-{[(3-methylbutyl)amino]methyl}-2- Thienyl) dihydroxyboric acid. The crude product (5-{[(3-methylbutyl)amino]methyl}-2-thienyl)dihydroxyboronic acid is further combined with 5-bromo-3-[1-(ethylsulfonyl)-4 -piperidinyl]-1 H -indole-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 mmol) and hydrazine (triphenylphosphine) palladium ( 0) (4 mg, 0.003 mmol) gave 38.3 mg of the title compound (37%).

LC/MS=m/z 430.4[M+H]滯留時間：1.75分鐘。 LC/MS = m/z 430.4 [M+H].

實例191：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(1-甲基乙基)胺基]甲基}-3-吡啶基)-1H-吲哚-7-羧醯胺Example 191: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-3-pyridyl) -1H-吲哚-7-carboxyguanamine

用於製備3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(1-甲基乙基)胺基]甲基}-3-吡啶基)-1H-吲哚-7-羧醯胺之(環丙基甲基){[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺之製法如下：添加異丙基胺(0.011毫升，0.129毫莫耳)至2達蘭瓶中含5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶甲醛(30毫克，0.129毫莫耳)之MeOH(1毫升)溶液中。添加NaCNBH₃(16毫克，0.258毫莫耳)，小瓶加蓋，於室溫下攪拌反應24小時。反應混合物經2克SCX卡管(先經3毫升MeOH平衡)過濾，依序以MeOH(6毫升)與2M NH₃/MeOH溶液(9毫升)溶離。取NH₃/MeOH溶離份於氮氣流下濃縮，產生22毫克粗產物(1-甲基乙基){[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺。 For the preparation of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-3-pyridyl) -1H-吲哚-7-carboxyguanamine (cyclopropylmethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- The benzyl-3-pyridyl]methyl}amine is prepared by adding isopropylamine (0.011 ml, 0.129 mmol) to 2 (4,4,5,5-tetramethyl) A solution of benzyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarboxaldehyde (30 mg, 0.129 mmol) in MeOH (1 mL). NaCNBH ₃ (16 mg, 0.258 mmol) was added, the vial was capped and the reaction was stirred at room temperature for 24 hours. The reaction mixture was 2 g SCX card tube (to balance over 3 mL of MeOH) was filtered, washed successively with MeOH (. 6 mL) and 2M NH ₃ / MeOH solution (9 ml) fractions. The NH ₃ /MeOH fraction was concentrated under a stream of nitrogen to give 22 mg of crude (1-methylethyl){[5-(4,4,5,5-tetramethyl-1,3,2-diox Borapenta-2-yl)-3-pyridyl]methyl}amine.

在含(1-甲基乙基){[5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-3-吡啶基]甲基}胺(22毫克，0.080毫莫耳)之CEM微波管中添加5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(50毫克，0.121毫莫耳)、K₂CO₃(100毫克，0.724毫莫耳)、二烷(1.5毫升)、H₂O(0.5毫升)與氯-2-(二甲基胺基甲基)-二茂絡鐵-1-基-(二原冰片基膦基)鈀(II)(7.3毫克，0.012毫莫耳)。反應於CEM微波爐中，於150℃下加熱30分鐘。反應混合物經2克SCX卡管(先經3毫升MeOH平衡)過濾，依序以H₂O(3毫升)、MeOH(6毫升)與2M NH₃/MeOH溶液(9毫升)溶離。取NH₃/MeOH溶離份於氮氣流與50℃下乾燥，經Agilent MDAP(Zorbax Eclipse XDB-C18管柱：21.2 x 100 mm)，依每分鐘20毫升，以1分鐘使用10%CH₃CN/H₂O(0.1%TFA)後，以8分鐘使用線性梯度10%CH₃CN/H₂O(0.1%TFA)至95%CH₃CN/H₂O(0.1%TFA)，保持終濃度30秒，進行溶離純化。取含產物之溶離份經2克Pharmasil CHQAX管柱(與氫氧化銨結合之聚合物；United Chemical Technologies)過濾排除TFA，於氮氣流與50℃下濃縮，產生27.2毫克標題化合物(70%)。 In the presence of (1-methylethyl){[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridyl]- Add 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7- to the CEM microwave tube of the amine (22 mg, 0.080 mmol) Carboxylamamine (50 mg, 0.121 mmol), K ₂ CO ₃ (100 mg, 0.724 mmol), two Alkane (1.5 ml), H ₂ O (0.5 ml) and chloro-2-(dimethylaminomethyl)-diferrocen-1-yl-(di-norbornylphosphino)palladium(II) ( 7.3 mg, 0.012 mmol. The reaction was heated in a CEM microwave oven and heated at 150 ° C for 30 minutes. The reaction mixture was 2 g SCX card tube (to balance over 3 mL of MeOH) was filtered, washed sequentially with H ₂ O (3 mL), MeOH (. 6 mL) and 2M NH ₃ / MeOH solution (9 ml) fractions. The NH ₃ /MeOH fractions were dried in a stream of nitrogen at 50 ° C, then passed through Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2 x 100 mm) at 20 mL per minute, using 10% CH ₃ CN/ in 1 min. After H ₂ O (0.1% TFA), a linear gradient of 10% CH ₃ CN/H ₂ O (0.1% TFA) to 95% CH ₃ CN/H ₂ O (0.1% TFA) was used over 8 minutes maintaining a final concentration of 30 Separate purification was carried out in seconds. The product-containing fractions were taken up on a 2 g Pharmasil CHQAX column (polymers in combination with ammonium hydroxide; United Chemical Technologies) to remove TFA and concentrated under a nitrogen stream at 50 ° C to yield 27.2 mg of the title compound (70%).

LC/MS=m/z 484[M+H]滯留時間：1.25分鐘。 LC/MS = m/z 484 [M+H]: 1.25 min.

實例192：5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 192: 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl] -1H-吲哚-7-carboxyguanamine

用於製備5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之{5-[(乙基胺基)甲基]-2-噻吩基}二羥硼酸之製法如下：添加含(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)之MeOH(0.5毫升)溶液與含NaCNBH₃(40毫克，0.64毫莫耳)之MeOH(0.5毫升)溶液至含在2達蘭瓶中之(2-乙基丁基)胺(32毫克，0.32毫莫耳)中。小瓶加蓋，於室溫下攪拌反應20小時。反應混合物經2克SCX卡管(先經3毫升MeOH平衡)過濾，依序以MeOH(6毫升)與2M NH₃/MeOH溶液(9毫升)溶離。取NH₃/MeOH溶離份於氮氣流下濃縮，產生48毫克粗產物(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)二羥硼酸。 For the preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl] {5-[(Ethylamino)methyl]-2-thienyl}-dihydroxyboronic acid of -1H-indole-7-carboxamide is prepared as follows: (5-methylindenyl-2-thiophene is added) yl) glyoxylic acid (50 mg, 0.32 mmol) of MeOH (0.5 mL) containing NaCNBH ₃ (40 mg, 0.64 mmol) of MeOH (0.5 mL) contained in a 2 dram vial to the (2-ethylbutyl)amine (32 mg, 0.32 mmol). The vial was capped and the reaction was stirred at room temperature for 20 hours. The reaction mixture was 2 g SCX card tube (to balance over 3 mL of MeOH) was filtered, washed successively with MeOH (. 6 mL) and 2M NH ₃ / MeOH solution (9 ml) fractions. The NH ₃ /MeOH fraction was concentrated under a nitrogen stream to yield 48 mg of crude material (5-{[(2-ethylbutyl)amino]methyl}-2-thienyl) dihydroboronic acid.

在含粗產物(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)二羥硼酸(48毫克，0.199毫莫耳)之CEM微波管中添加含5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)之二烷(1.75毫升)溶液、含K₂CO₃(130毫克，0.942毫莫耳)之H₂O(0.25毫升)溶液與肆(三苯基膦)鈀(0)(9毫克，0.0079毫莫耳)。反應於CEM微波爐中，於150℃下加熱30分鐘。反應混合物經2克SCX卡管(先經3毫升MeOH平衡)過濾，依序以MeOH(3毫升)與2M NH₃/MeOH溶液(9毫升)溶離。取NH₃/MeOH溶離份於氮氣流與50℃下乾燥，粗產物溶於二甲亞碸(1.1毫升)，經Agilent MDAP(Zorbax Eclipse XDB-C18管柱：21.2 x 100 mm)，依每分鐘20毫升，以1分鐘使用10%CH₃CN/H₂O(0.1%TFA)後，以8分鐘使用線性梯度10%CH₃CN/H₂O(0.1%TFA)至95%CH₃CN/H₂O(0.1%TFA)，保持終濃度30秒，進行溶離純化。取含產物之溶離份經2克Pharmasil CHQAX管柱(與氫氧化銨結合之聚合物；United Chemical Technologies)過濾排除TFA，於氮氣流與50℃下濃縮，產生不純之標題化合物。該不純之標題化合物再如上述經Agilent MDAP純化及經氫氧化銨管柱釋出游離鹼，產生8.5毫克標題化合物(10%)。 Add 5-5 to the CEM microwave tube containing the crude product (5-{[(2-ethylbutyl)amino]methyl}-2-thienyl) dihydroxyboric acid (48 mg, 0.199 mmol) Bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (65 mg, 0.157 mmol) Alkane (1.75 ml) solution, H ₂ O (0.25 mL) solution containing K ₂ CO ₃ (130 mg, 0.942 mmol) and bis(triphenylphosphine) palladium (0) (9 mg, 0.0079 mmol) ). The reaction was heated in a CEM microwave oven and heated at 150 ° C for 30 minutes. The reaction mixture was 2 g SCX card tube (to balance over 3 mL of MeOH) was filtered, washed successively with MeOH (3 mL) and 2M NH ₃ / MeOH solution (9 ml) fractions. The NH ₃ /MeOH fraction was dried in a stream of nitrogen at 50 ° C. The crude product was dissolved in dimethyl hydrazine (1.1 mL) and then applied to Agilent MDAP (Zorbax Eclipse XDB-C18 column: 21.2 x 100 mm). 20 ml, using 10% CH ₃ CN/H ₂ O (0.1% TFA) in 1 minute, using a linear gradient of 10% CH ₃ CN/H ₂ O (0.1% TFA) to 95% CH ₃ CN/ in 8 minutes. H ₂ O (0.1% TFA) was maintained at a final concentration for 30 seconds and purified by elution. The product-containing fractions were taken from a 2 g Pharmasil CHQAX column (polymer combined with ammonium hydroxide; United Chemicals) to remove TFA and concentrated under a nitrogen stream at 50 ° C to give the title compound. The impure title compound was purified by Agilent <RTI ID=0.0>>

LC/MS=m/z 430[M+H]滯留時間：1.72分鐘。 LC/MS = m/z 430 [M+H].

實例193：5-[5-({[3-(乙基氧)丙基]胺基}甲基)-2-噻吩基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 193: 5-[5-({[3-(Ethyloxy)propyl]amino}methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-1H-indole-7-carboxamide

依據5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由 (5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、[3-(乙基氧)丙基]胺(34毫克，0.32毫莫耳)與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生30毫克粗產物[5-({[3-(乙基氧)丙基]胺基}甲基)-2-噻吩基]二羥硼酸。粗產物[5-({[3-(乙基氧)丙基]胺基}甲基)-2-噻吩基]二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、K₂CO₃(130毫克，0.942毫莫耳)及肆(三苯基膦)鈀(0)(9毫克，0.0079毫莫耳)反應，產生8.1毫克標題化合物(10%)。 According to 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H - General procedure for 吲哚-7-carboxyguanamine, from (5-methylindenyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), [3-(ethyloxy)propyl] amine (34 mg, 0.32 mmol) and NaCNBH ₃ (40 mg, 0.64 mmol) reacted to produce 30 mg of crude product [5 - ({[3- (ethyl) propyl] amino} methyl Base)-2-thienyl] dihydroxyboric acid. The crude product [5-({[3-(ethyloxy)propyl)amino}methyl)-2-thienyl]dihydroxyboronic acid is further combined with 5-bromo-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1 H -indole-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 mmol) and hydrazine (triphenylphosphine) Palladium (0) (9 mg, 0.0079 mmol) gave 8.1 mg of the title compound (10%).

實例194：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[3-(甲基氧)丙基]胺基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺Example 194: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({[3-(methyloxy)propyl]amino}methyl)-2- Thienyl]-1H-indole-7-carboxyguanamine

依據5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、[3-(甲基氧)丙基]胺(29毫克，0.32毫莫耳)，與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生30毫克粗產物[5-({[3-(甲基氧)丙基]胺基}甲基)-2-噻吩基]二羥硼酸。粗產物[5- ({[3-(甲基氧)丙基]胺基}甲基)-2-噻吩基]二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、K₂CO₃(130毫克，0.942毫莫耳)及肆(三苯基膦)鈀(0)(9毫克，0.0079毫莫耳)反應。粗產物依5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之製法所示，經Agilent MDAP純化一次，產生7.6毫克標題化合物(9%)。 According to 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H - General procedure for 吲哚-7-carboxyguanamine, from (5-methylindenyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), [3-(methyloxy)propyl] amine (29 mg, 0.32 mmol), and NaCNBH ₃ (40 mg, 0.64 mmol) reacted to produce 30 mg of crude product [5 - ({[3- (methylthio) propyl] amino} Methyl)-2-thienyl] dihydroxyboric acid. The crude product [5-({[3-(methyloxy)propyl]amino}methyl)-2-thienyl]dihydroxyboronic acid is further combined with 5-bromo-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1 H -indole-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 mmol) and hydrazine (triphenylphosphine) Palladium (0) (9 mg, 0.0079 mmol) was reacted. The crude product is 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl] -1H-indole-7-carboxamide was purified by Agilent MDAP to give 7.6 mg of the title compound (9%).

LC/MS=m/z 430[M+H]滯留時間：1.50分鐘。 LC/MS = m/z 430 [M+H].

實例195：5-(5-{[(環己基甲基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 195: 5-(5-{[(cyclohexylmethyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H -吲哚-7-carboxyguanamine

依據5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、(環己基甲基)胺(37毫克，0.32毫莫耳)與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生30毫克粗產物(5-{[(環己基甲基)胺基]甲基}-2-噻吩基)二羥硼酸。粗產物(5-{[(環己基甲基)胺基]甲基}-2-噻吩基)二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、K₂CO₃(130毫克，0.942毫莫耳)及肆(三苯基膦)鈀(0)(9毫克，0.0079毫莫耳)反應。粗產物依5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之製法所示，經Agilent MDAP純化一次。純化產物使用己烷/EtOAc/MeOH之20：4：1混合物(2.5毫升)洗滌，溶於EtOAc(2毫升)，以飽和K₂CO₃(1毫升)洗滌。有機層濃縮，產生4.7毫克標題化合物(6%)。 According to 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H - 吲哚-7-carboxyguanamine general process from (5-methyl-nonyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), (cyclohexylmethyl)amine (37 mg, 0.32 mmoles was reacted with NaCNBH ₃ (40 mg, 0.64 mmol) to give 30 mg of crude product (5-{[(cyclohexylmethyl)amino]methyl}-2-thienyl)dihydroxy Boric acid. The crude product (5-{[(cyclohexylmethyl)amino]methyl}-2-thienyl)dihydroxyboronic acid is further combined with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-1 H -吲哚-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 mmol) and hydrazine (triphenylphosphine) palladium (0) (9 mg, 0.0079 mmol) reaction. The crude product is 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl] -1H-indole-7-carboxamide was purified once by Agilent MDAP. The product was purified using hexane / EtOAc / MeOH of 20: 4: 1 mixture (2.5 ml), was dissolved in EtOAc (2 mL), saturated K ₂ CO ₃ (1 mL). The organic layer was concentrated to give 4.7 mg of the title compound ( 6%).

LC/MS=m/z 430[M+H]滯留時間：1.82分鐘。 LC/MS = m/z 430 [M+H].

實例196：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[({3-[(1-甲基乙基)氧]丙基}胺基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺Example 196: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[({3-[(1-methylethyl)oxy)propyl}amino) Methyl]-2-thienyl}-1H-indole-7-carboxamide

依據5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、{3-[(1-甲基乙基)氧]丙基}胺(38毫克，0.32毫莫耳)，與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生30毫克粗產物{5-[({3-[(1-甲基乙基)氧]丙基}胺基)甲基]-2-噻吩基}二羥硼酸。粗產物{5-[({3-[(1-甲基乙基)氧]丙基}胺基)甲基]-2-噻吩基}二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、K₂CO₃(130毫克，0.942毫莫耳)及肆(三苯基膦)鈀(0)(9毫克，0.0079毫莫耳)反應。依5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之製法所示，經Agilent MDAP純化二次。不純之標題化合物經己烷/EtOAc/MeOH之20：4：1混合物(2.5毫升)洗滌，產生7.6毫克標題化合物(9%)。 According to 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H - General procedure for 吲哚-7-carboxyguanamine, from (5-methylindenyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), {3-[(1-methylethyl) ) oxy] propyl} amine (38 mg, 0.32 mmol), and NaCNBH ₃ (40 mg, 0.64 mmol) reacted to produce 30 mg of crude product {5 - [({3 - [(1-methyl Ethylethyl)oxy]propyl}amino)methyl]-2-thienyl}dihydroxyboronic acid. The crude product {5-[({3-[(1-methylethyl)oxy)propyl)amino)methyl]-2-thienyl}dihydroxyboronic acid is further combined with 5-bromo-3-[1- (ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 mmol) and The reaction of hydrazine (triphenylphosphine) palladium (0) (9 mg, 0.0079 mmol). 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H - 吲哚-7-carboxyguanamine was prepared and purified twice by Agilent MDAP. The title compound was washed with EtOAc / EtOAc / EtOAc EtOAc.

實例197：5-[5-({[2-(乙基氧)乙基]胺基}甲基)-2-噻吩基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 197: 5-[5-({[2-(Ethyloxy)ethyl]amino}methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-1H-indole-7-carboxamide

依據5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、[2-(乙基氧)乙基]胺(30毫克，0.32毫莫耳)，與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生30毫克粗產物[5-({[2-(乙基氧)乙基]胺基}甲基)-2-噻吩基]二羥硼酸。粗產物[5- ({[2-(乙基氧)乙基]胺基}甲基)-2-噻吩基]二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、K₂CO₃(130毫克，0.942毫莫耳)及肆(三苯基膦)鈀(0)(9毫克，0.0079毫莫耳)反應。粗產物依5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之製法所示，經Agilent MDAP純化一次，產生6毫克標題化合物(7%)。 According to 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H - General procedure for 吲哚-7-carboxyguanamine, from (5-methylindenyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), [2-(ethyloxy)ethyl] amine (30 mg, 0.32 mmol), and NaCNBH ₃ (40 mg, 0.64 mmol) reacted to produce 30 mg of crude product [5 - ({[2- (ethyl) ethyl] amino} Methyl)-2-thienyl] dihydroxyboric acid. The crude product [5-({[2-(ethyloxy)ethyl]amino}methyl)-2-thienyl]dihydroxyboronic acid is further combined with 5-bromo-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1 H -indole-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 mmol) and hydrazine (triphenylphosphine) Palladium (0) (9 mg, 0.0079 mmol) was reacted. The crude product is 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl] -1H-indole-7-carboxamide was purified by Agilent MDAP to give 6 mg of the title compound (7%).

LC/MS=m/z 430[M+H]滯留時間：1.66分鐘。 LC/MS = m/z 430 [M+H] retention time: 1.66 min.

實例198：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[3-(丙基氧)丙基]胺基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺Example 198: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({[3-(propyloxy)propyl]amino}methyl)-2- Thienyl]-1H-indole-7-carboxyguanamine

依據5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、[3-(丙基氧)丙基]胺(38毫克，0.32毫莫耳)，與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生30毫克粗產物[5-({[3-(丙基氧)丙基]胺基}甲基)-2-噻吩基]二羥硼酸。粗產物[5-({[3-(丙基氧)丙基]胺基}甲基)-2-噻吩基]二羥硼酸再與5-溴- 3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、K₂CO₃(130毫克，0.942毫莫耳)及肆(三苯基膦)鈀(0)(9毫克，0.0079毫莫耳)反應。粗產物依5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之製法所示，經Agilent MDAP純化二次。純化產物經己烷/EtOAc/MeOH之20：4：1混合物(2.5毫升)洗滌，溶於EtOAc(2毫升)，以飽和K₂CO₃(1毫升)洗滌。有機層濃縮，產生1.4毫克標題化合物(2%)。 According to 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H - General procedure for 吲哚-7-carboxyguanamine, from (5-methylindenyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), [3-(propyloxy)propyl] amine (38 mg, 0.32 mmol), and NaCNBH ₃ (40 mg, 0.64 mmol) reacted to produce 30 mg of crude product [5 - ({[3- (propyloxy) propyl] amino} Methyl)-2-thienyl] dihydroxyboric acid. The crude product [5-({[3-(propyloxy)propyl)amino}methyl)-2-thienyl]dihydroxyboronic acid is further combined with 5-bromo-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1 H -indole-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 mmol) and hydrazine (triphenylphosphine) Palladium (0) (9 mg, 0.0079 mmol) was reacted. The crude product is 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl] -1H-吲哚-7-carboxyguanamine was prepared and purified twice by Agilent MDAP. The product was purified with hexane / EtOAc / MeOH of 20: 4: 1 mixture (2.5 ml), was dissolved in EtOAc (2 mL), saturated K ₂ CO ₃ (1 mL). The organic layer was concentrated to give the title compound (2%).

實例199：5-(5-{[(3,3-二甲基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 199: 5-(5-{[(3,3-Dimethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-1H-indole-7-carboxamide

依據5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、(3,3-二甲基丁基)胺(32毫克，0.32毫莫耳)，與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生30毫克粗產物(5-{[(3,3-二甲基丁基)胺基]甲基}-2-噻吩基)二羥硼酸。粗產物(5-{[(3,3-二甲基丁基) 胺基]甲基}-2-噻吩基)二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、K₂CO₃(130毫克，0.942毫莫耳)及肆(三苯基膦)鈀(0)(9毫克，0.0079毫莫耳)反應，產生4.5毫克標題化合物(5%)。 According to 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H - General procedure for 吲哚-7-carboxyguanamine, from (5-methylindenyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), (3,3-dimethylbutyl) amine (32 mg, 0.32 mmol), and NaCNBH ₃ (40 mg, 0.64 mmol) reacted to produce 30 mg of crude product (5 - {[(3,3-dimethylbutyl) amino] Methyl}-2-thienyl) dihydroxyboric acid. The crude product (5-{[(3,3-dimethylbutyl)amino]methyl}-2-thienyl)dihydroxyboronic acid is further combined with 5-bromo-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1 H -indole-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 mmol) and hydrazine (triphenylphosphine) Palladium (0) (9 mg, 0.0079 mmol) gave 4.5 mg of the title compound (5%).

LC/MS=m/z 430[M+H]滯留時間：1.79分鐘。 LC/MS = m/z 430 [M+H].

實例200：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[(1S)-1,2,2-三甲基丙基]胺基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺Example 200: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({[(1S)-1,2,2-trimethylpropyl]amino} Methyl)-2-thienyl]-1H-indole-7-carboxamide

依據5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、[(1S)-1,2,2-三甲基丙基]胺(32毫克，0.32毫莫耳)，與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生30毫克粗產物[5-({[(1S)-1,2,2-三甲基丙基]胺基}甲基)-2-噻吩基]二羥硼酸。粗產物[5-({[(1S)-1,2,2-三甲基丙基]胺基}甲基)-2-噻吩基]二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、K₂CO₃(130毫克，0.942毫莫耳)及肆(三苯基膦)鈀(0)(9毫克，0.0079毫莫耳)反應，產生10.3毫克標題化合物(12%)。 According to 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H - General procedure for 吲哚-7-carboxyguanamine, from (5-methylindenyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), [(1S)-1,2,2- trimethylpropyl] amine (32 mg, 0.32 mmol), and NaCNBH ₃ (40 mg, 0.64 mmol) reacted to produce 30 mg of the crude product [5 - ({[(1S ) -1,2 , 2-trimethylpropyl]amino}methyl)-2-thienyl]dihydroxyboronic acid. The crude product [5-({[(1S)-1,2,2-trimethylpropyl]amino}methyl)-2-thienyl]dihydroxyboronic acid is further combined with 5-bromo-3-[1- (ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 mmol) and Reaction of hydrazine (triphenylphosphine) palladium (0) (9 mg, 0.0079 mmol) gave 10.3 mg of the title compound (12%).

實例201：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(己基胺基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺Example 201: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[(hexylamino)methyl]-2-thienyl}-1H-indole-7 -carboxamide

依據5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，由(5-甲醯基-2-噻吩基)二羥硼酸(50毫克，0.32毫莫耳)、己基胺(33毫克，0.32毫莫耳)，與NaCNBH₃(40毫克，0.64毫莫耳)進行反應，產生30毫克粗產物{5-[(己基胺基)甲基]-2-噻吩基}二羥硼酸。粗產物{5-[(己基胺基)甲基]-2-噻吩基}二羥硼酸再與5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(65毫克，0.157毫莫耳)、K₂CO₃(130毫克，0.942毫莫耳)及肆(三苯基膦)鈀(0)(9毫克，0.0079毫莫耳)反應。粗產物依5-(5-{[(2-乙基丁基)胺基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之製法所示，經Agilent MDAP純化一次，產生13毫克標題化合物(16%)。 According to 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H - General procedure for 吲哚-7-carboxyguanamine, from (5-methylindenyl-2-thienyl) dihydroxyboric acid (50 mg, 0.32 mmol), hexylamine (33 mg, 0.32 mmol) Reaction with NaCNBH ₃ (40 mg, 0.64 mmol) gave 30 mg of crude product {5-[(hexylamino)methyl]-2-thienyl}dihydroxyboronic acid. The crude product {5-[(hexylamino)methyl]-2-thienyl}dihydroxyboronic acid is further combined with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H-吲哚-7-carboxamide (65 mg, 0.157 mmol), K ₂ CO ₃ (130 mg, 0.942 mmol) and hydrazine (triphenylphosphine) palladium (0) (9 mg, 0.0079) Millions of reactions. The crude product is 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl] -1H-indole-7-carboxamide was purified by Agilent MDAP to give 13 mg of the title compound (16%).

LC/MS=m/z 430.6[M+H]滯留時間：1.92分鐘。 LC/MS = m/z 430.6 [M+H].

實例202：5-[2-(二甲基胺基)-4-吡啶基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 202: 5-[2-(Dimethylamino)-4-pyridyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxylate Guanidine trifluoroacetate

在3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-氟-4-吡啶基)-1H-吲哚-7-羧醯胺(40毫克，0.093毫莫耳)中添加二甲基胺(1毫升，0.015毫莫耳)與DMF(0.3毫升)。所得混合物於微波爐中，於180℃下反應1小時。蒸發所有溶劑。混合物經Gilson製備性HPLC純化，產生18.2毫克標題化合物(34.4%)。 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-4-pyridinyl)-1 H -indole-7-carboxamide (40 mg, 0.093 Methylamine (1 ml, 0.015 mmol) and DMF (0.3 mL) were added. The resulting mixture was reacted in a microwave oven at 180 ° C for 1 hour. Evaporate all solvents. The mixture was purified by Gilson preparative HPLC to yield 18.2 mg of the title compound (34.4%).

LC/MS=m/z 456.2[M+H]滯留時間：1.54分鐘。 LC/MS = m/z 456.2 [M+H].

實例203：5-{6-[乙基(甲基)胺基]-3-吡啶基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 203: 5-{6-[Ethyl(methyl)amino]-3-pyridyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole- 7-Carboguanamine trifluoroacetate

標題化合物係依據5-[2-(二甲基胺基)-4-吡啶基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用吡咯啶(1毫升)替代二甲基胺製備，產生48.9毫克標題化合物(27.1%)。 The title compound is based on 5-[2-(dimethylamino)-4-pyridyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7- The general procedure for carboxamide trifluoroacetate, but using pyrrolidine (1 ml) instead of dimethylamine afforded 48.9 mg of the title compound (27.1%).

LC/MS=m/z 482.2[M+H]滯留時間：1.62分鐘。 LC/MS = m/z 482.2 [M+H].

實例204：3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(4-嗎啉基)-4-吡啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 204: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[2-(4-morpholinyl)-4-pyridyl]-1H-indole-7-carboxylate Guanidine trifluoroacetate

標題化合物係依據5-[2-(二甲基胺基)-4-吡啶基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用嗎啉(1毫升)替代二甲基胺製備，產生12毫克標題化合物(21.1%)。 The title compound is based on 5-[2-(dimethylamino)-4-pyridyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7- One of carboguanamine trifluoroacetate The procedure was followed, but morpholine (1 mL) was used instead of dimethylamine to give 12 mg of the title compound (21.1%).

LC/MS=m/z 498.6[M+H]滯留時間：1.47分鐘。 LC/MS = m/z 498.6 [M+H].

實例205：3-[1-(乙基磺醯基)-4-哌啶基]-5-{2-[(2-甲基丙基)胺基]-4-吡啶基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 205: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{2-[(2-methylpropyl)amino]-4-pyridyl}-1H-indole哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-[2-(二甲基胺基)-4-吡啶基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-甲基-1-丙胺(1毫升)替代二甲基胺製備，產生11.1毫克標題化合物(20%)。 The title compound is based on 5-[2-(dimethylamino)-4-pyridyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7- The general procedure for the carboxamide trifluoroacetate was prepared using 2-methyl-1-propylamine (1 mL) instead of dimethylamine to give 11.1 mg of the title compound (20%).

LC/MS=m/z 484.2[M+H]滯留時間：1.68分鐘。 LC/MS = m/z 484.2 [M+H].

實例206：5-{2-[(2,2-二甲基丙基)胺基]-4-吡啶基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 206: 5-{2-[(2,2-Dimethylpropyl)amino]-4-pyridyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-[2-(二甲基胺基)-4-吡啶基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2,2-二甲基-1-丙胺(1毫升)替代二甲基胺製備，產生9毫克標題化合物(15.8%)。 The title compound is based on 5-[2-(dimethylamino)-4-pyridyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7- The general procedure for carboxamide trifluoroacetate, but using 2,2-dimethyl-1-propylamine (1 mL) instead of dimethylamine afforded 9 mg of the title compound (15.8%).

LC/MS=m/z 498.6[M+H]滯留時間：1.75分鐘。 LC/MS = m/z 498.6 [M+H].

實例207：3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(丙基胺基)-4-吡啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 207: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[2-(propylamino)-4-pyridyl]-1H-indole-7-carboxyindole Amine trifluoroacetate

標題化合物係依據5-[2-(二甲基胺基)-4-吡啶基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用丙基胺(1毫升)替代二甲基胺製備，產生18.2毫克標題化合物(33.5%)。 The title compound is based on 5-[2-(dimethylamino)-4-pyridyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7- One of carboguanamine trifluoroacetate The procedure was followed, but propylamine (1 mL) was used instead of dimethylamine to afford 18.2 mg of the title compound (33.5%).

LC/MS=m/z 470.4[M+H]滯留時間：1.57分鐘。 LC/MS = m/z 470.4 [M+H].

實例208：3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-[(甲基胺基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 208: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1H-indole- 7-Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基-2-噻吩基)-1H-吲哚-7-羧醯胺(45毫克，0.1毫莫耳)之二氯甲烷(2毫升)與甲醇(1毫升)溶液中添加2 M甲基胺(0.5毫升)。反應混合物於室溫下攪拌5小時後，添加四氫硼酸鈉(37.83毫克，1毫莫耳)。於室溫下攪拌所得混合物一夜。濃縮溶劑，經Gilson製備性HPLC純化，產生16.8毫克標題化合物(29.2%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylindolyl-2-thienyl)-1 H -indole-7-carboxamide (45 2 mg of methylamine (0.5 ml) was added to a solution of methylene chloride (2 ml) and methanol (1 ml). After the reaction mixture was stirred at room temperature for 5 hours, sodium tetrahydroborate (37.83 mg, 1 mmol) was added. The resulting mixture was stirred at room temperature overnight. The solvent was concentrated and purified by EtOAc EtOAc EtOAc.

LC/MS=m/z 461.6[M+H]滯留時間：1.40分鐘。 LC/MS = m/z 461.6 [M+H].

實例209：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(1-吡咯啶基甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 209: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[4-(1-pyrrolidinylmethyl)-2-thienyl]-1H-indole-7 -Carboguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-[(甲基胺基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用吡咯啶(0.083毫升)替代2 M甲基胺製備，產生14.8毫克標題化合物(24.1%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1H-indole The general procedure for -7-carboxyguanamine trifluoroacetate, but using pyrrolidine (0.083 mL) instead of 2M methylamine afforded 14.8 mg of the title compound (24.1%).

LC/MS=m/z 470.4[M+H]滯留時間：1.57分鐘。 LC/MS = m/z 470.4 [M+H].

實例210：3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(2-甲基丙基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 210: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(4-{[(2-methylpropyl)amino]methyl}-2-thienyl) -1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-[(甲基胺基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-甲基-1-丙胺(0.1毫升)替代2 M甲基胺製備，產生15.4毫克標題化合物(25%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1H-indole -7-Carboguanamine trifluoroacetate The general procedure was followed by 2-methyl-1-propylamine (0.1 mL) instead of 2M methylamine to give 15.4 mg of the title compound (25%).

LC/MS=m/z 503.2[M+H]滯留時間：1.42分鐘。 LC/MS = m/z 503.2 [M+H].

實例211：5-{4-[(二甲基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 211: 5-{4-[(Dimethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole -7-Carboguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-[(甲基胺基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用二甲基胺(0.5毫升)替代2 M甲基胺製備，產生9毫克標題化合物(15.3%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{4-[(methylamino)methyl]-2-thienyl}-1H-indole The general procedure for -7-carboxyguanamine trifluoroacetate was prepared using dimethylamine (0.5 mL) instead of 2M methylamine to give 9 mg of the title compound (15.3%).

LC/MS=m/z 475.2[M+H]滯留時間：1.27分鐘。 LC/MS = m/z 475.2 [M+H].

實例212：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(1S)-1-(1-吡咯啶基)乙基]-3-噻吩基}-1H-吲哚-7-羧醯胺Example 212: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[(1S)-1-(1-pyrrolidinyl)ethyl]-3-thienyl }-1H-吲哚-7-carboxyguanamine

在5-(5-乙醯基-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(10毫克，0.02毫莫耳)中添加氰基氫硼化鈉(7.5毫克，0.12毫莫耳)與吡咯啶(0.03毫升，0.30毫莫耳)。所得混合物於微波爐中，於150℃下反應40分鐘。蒸發所有溶劑，粗產物分溶於乙酸乙酯(1.5毫升)與1M氫氧化鈉(0.2毫升)之間。反應經SFC純化，產生標題化合物，對掌性純度100%。 5-(5-Ethyl-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (10 mg Add 0.02 mg of sodium cyanoborohydride (7.5 mg, 0.12 mmol) to pyrrolidine (0.03 mL, 0.30 mmol). The resulting mixture was reacted in a microwave oven at 150 ° C for 40 minutes. All solvents were evaporated and the crude material was crystalljjjjjjjjjj The reaction was purified by SFC to give the title compound.

LC/MS=m/z 515.4[M+H]滯留時間：1.54分鐘。 LC/MS = m/z 515.4 [M+H].

實例213：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(1R)-1-(1-吡咯啶基)乙基]-3-噻吩基}-1H-吲哚-7-羧醯胺Example 213: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[(1R)-1-(1-pyrrolidinyl)ethyl]-3-thienyl }-1H-吲哚-7-carboxyguanamine

LC/MS=m/z 515.4[M+H]滯留時間：1.54分鐘。 LC/MS = m/z 515.4 [M+H].

實例214：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-({[3-(甲基氧)丙基]胺基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 214: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[3-(methyloxy)propyl]amino}methyl)-2- Thienyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

在含5-[(1Z)-1-(乙烯基硫)-4-氧代-1-丁烯-1-基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(45毫克，0.1毫莫耳)之二氯甲烷(2毫升)與甲醇(1毫升)中添加3滴乙酸與3-(甲基氧)-1-丙胺(89.14毫克，1毫莫耳)。所得混合物攪拌6小時後，添加氫硼化鈉(37.83毫克，1毫莫耳)。於室溫下攪拌反應一夜。蒸發溶劑。混合物經Gilson製備性HPLC純化，產生23.7毫克標題化合物(37.5%)。 In the presence of 5-[(1 Z )-1-(vinylthio)-4-oxo-1-buten-1-yl]-3-[1-(ethylsulfonyl)-4-piperidine Add 3 drops of acetic acid and 3-(methyloxy) to methylene chloride (2 ml) and methanol (1 ml) with H -indole-7-carboxamide (45 mg, 0.1 mmol) -1-propylamine (89.14 mg, 1 mmol). After the resulting mixture was stirred for 6 hours, sodium borohydride (37.83 mg, 1 mmol) was added. The reaction was stirred overnight at room temperature. Evaporate the solvent. The mixture was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 519.4[M+H]滯留時間：1.69分鐘。 LC/MS = m/z 519.4 [M+H].

實例215：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-({(2S)-2-[(甲基氧)甲基]-1-吡咯啶基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 215: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[4-({(2S)-2-[(methyloxy)methyl]-1-pyrrolidine) }]methyl)-2-thienyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-({[3-(甲基氧)丙基]胺基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(2S)-2-[(甲基氧)甲基]吡咯啶(115.18毫克，1毫莫耳)替代3-(甲基氧)-1-丙胺製備，產生3毫克標題化合物(4.6%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[3-(methyloxy)propyl]amino}methyl)-2 -Thienyl]-1H-indole-7-carboxamide guanamine trifluoroacetate, but using ( 2S )-2-[(methyloxy)methyl]pyrrolidine (115.18 mg, 1 mM) Mol) was prepared in place of 3-(methyloxy)-1-propanamine to give 3 mg of the title compound (4.6%).

LC/MS=m/z 545.2[M+H]滯留時間：1.78分鐘。 LC/MS = m/z 545.2 [M+H].

實例216：5-(4-{[(2R,5R)-2,5-二甲基-1-吡咯啶基]甲基}-2-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 216: 5-(4-{[(2R,5R)-2,5-Dimethyl-1-pyrrolidinyl]methyl}-2-thienyl)-3-[1-(ethylsulfonate) Base)-4-piperidinyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-({[3-(甲基氧)丙基]胺基}甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程， The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-({[3-(methyloxy)propyl]amino}methyl)-2 -Thienyl]-1H-indole-7-carboxyguanamine trifluoroacetate, the general process,

(64.3毫克，1毫莫耳)替代3-(甲基氧)-1-丙胺製備，產生6.4毫克標題化合物(10%)。 (64.3 mg, 1 mmol) for 3- (methyl oxy) -1-propanamine, to produce 6.4 mg of the title compound (10%).

LC/MS=m/z 529.4[M+H]滯留時間：1.69分鐘。 LC/MS = m/z 529.4 [M+H].

實例217：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2S)-2-甲基-1-吡咯啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺Example 217: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2S)-2-methyl-1-pyrrolidinyl]methyl}-3 -thienyl)-1H-indole-7-carboxamide

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(600毫克，1.348毫莫耳)之二甲亞碸 (10毫升)溶液中添加20滴乙酸與(2S)-1,2-二甲基吡咯啶(1.37毫升，13.483毫莫耳)。所得混合物於室溫下攪拌6小時後，添加三乙醯氧基氫硼化鈉(2.858克，13.483毫莫耳)。於室溫下攪拌反應一夜後，經SFC純化。此化合物經RTP CASS Group分離。含對映異構物#1之溶離份對掌性純度為99.7%，產生119.9毫克標題化合物(17.3%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (600 To a solution of dimethylidene (10 ml) in milligrams (1.348 mmol) was added 20 drops of acetic acid and ( 2S )-1,2-dimethylpyrrolidine (1.37 mL, 13.48 mmol). After the resulting mixture was stirred at room temperature for 6 hr, sodium triethyl oxy hydride hydride (2.858 g, 13.48. After stirring at room temperature for one night, it was purified by SFC. This compound was isolated by RTP CASS Group. The fractions containing enantiomer #1 had a palmity purity of 99.7%, yielding 119.9 mg of the title compound (17.3%).

LC/MS=m/z 515.4[M+H]滯留時間：1.56分鐘。 LC/MS = m/z 515.4 [M+H].

實例218：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2R)-2-甲基-1-吡咯啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺Example 218: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2R)-2-methyl-1-pyrrolidinyl]methyl}-3 -thienyl)-1H-indole-7-carboxamide

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(600毫克，1.35毫莫耳)之二甲亞碸(10毫升)溶液中添加20滴乙酸與2-甲基吡咯啶(1.37毫升，13.5毫莫耳)。所得混合物於室溫下攪拌6小時後，添加三乙醯氧基氫硼化鈉(2.86克，13.5毫莫耳)。於室溫下攪拌反應一夜後，經Gilson製備性HPLC純化。分離此化合物，產生標題化合物，對掌性純度98.6%。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (600 To a solution of milligrams, 1.35 millimoles of dimethyl hydrazine (10 ml) was added 20 drops of acetic acid and 2-methylpyrrolidine ( 1.37 ml, 13.5 mmol). After the resulting mixture was stirred at room temperature for 6 hr, sodium triethyloxy borohydride (2.86 g, 13.5 m. After stirring at room temperature for one night, it was purified by Gilson preparative HPLC. This compound was isolated to give the title compound, which was 98.6%.

LC/MS=m/z 515.4[M+H]滯留時間：1.56分鐘。 LC/MS = m/z 515.4 [M+H].

實例219：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[1-(1-吡咯啶基)丙基]-3-噻吩基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 219: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[1-(1-pyrrolidinyl)propyl]-3-thienyl}-1H-吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(250毫克，0.541毫莫耳)之二烷(4.5毫升)與H₂O(1.5毫升)溶液中添加1-(4-溴-2-噻吩基)-1-丙酮(356毫克，1.62毫莫耳)、碳酸鉀(447毫克，3.24毫莫耳)與肆(三苯基膦)鈀(0)(64毫克，0.055毫莫耳)。反應於微波爐中，150℃下反應20分鐘。使用EtOAc與H₂O操作水相後，添加MeOH(20毫升)至粗產物中。所需產物沉澱並過濾，產生110毫克3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-丙醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(43%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (250 mg, 0.541 mmol) Dioxane (4.5 mL) and H ₂ O (1.5 mL) was added a solution of 1- (4-bromo-2-thienyl) -1-propanone (356 mg, 1.62 mmol), potassium carbonate (447 mg, 3.24 mmol Mohr) with hydrazine (triphenylphosphine) palladium (0) (64 mg, 0.055 mmol). The reaction was carried out in a microwave oven at 150 ° C for 20 minutes. After using EtOAc and H ₂ O operations aqueous phase was added MeOH (20 mL) to the crude product. The desired product was precipitated and filtered to give <RTI ID=0.0 > > -7-Carboxyguanamine (43%).

在3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-丙醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(60毫克，0.13毫莫耳)中添加氰基氫硼化鈉(49.2毫克，0.78毫莫耳)、吡咯啶(0.2毫升，1.95毫莫耳)、乙醇(3毫升)與乙酸(0.4毫升)。所得混合物於微波爐中，於150℃下反應30分鐘。蒸發所有溶劑。混合物經Gilson製備性HPLC純化，產生12毫克標題化合物(14.4%)。 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-propionyl-3-thienyl)-1 H -indole-7-carboxamide (60 mg Sodium cyanoborohydride (49.2 mg, 0.78 mmol), pyrrolidine (0.2 mL, 1.95 mmol), ethanol (3 mL) and acetic acid (0.4 mL) were added. The resulting mixture was reacted in a microwave oven at 150 ° C for 30 minutes. Evaporate all solvents. The mixture was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 529.4[M+H]滯留時間：1.65分鐘。 LC/MS = m/z 529.4 [M+H].

實例220：5-{5-[(二甲基胺基)甲基]-3-噻吩基}-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 220: 5-{5-[(Dimethylamino)methyl]-3-thienyl}-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl }-1H-吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)之二甲亞碸(2毫升)溶液中添加3滴乙酸與三甲基胺(0.55毫升，1.1毫莫耳)。所得混合物於室溫下攪拌6小時後，添加三乙醯氧基氫硼化鈉(233毫克，1毫莫耳)。於室溫下攪拌一夜後，經Gilson製備性HPLC純化，產生29.4毫克標題化合物(44.3%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (50 To a solution of milligrams (0.11 mmol) of dimethyl hydrazine (2 ml) was added 3 drops of acetic acid and trimethylamine (0.55 mL, 1.1 mmol). After the resulting mixture was stirred at room temperature for 6 hours, sodium triethyloxy borohydride (233 mg, 1 mmol) was added. After stirring overnight at rt, EtOAc (EtOAc)

LC/MS=m/z 489.4[M+H]滯留時間：1.32分鐘。 LC/MS = m/z 489.4 [M+H].

實例221：5-[5-(胺基甲基)-3-噻吩基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 221: 5-[5-(Aminomethyl)-3-thienyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxyindole Amine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)之二氯甲烷(2毫升)與甲醇(1毫升)溶液中添加乙酸銨(84.7毫克，1.1毫莫耳)與氰基氫硼化鈉(4.84毫克，0.077毫莫耳)。於室溫下攪拌所得混合物一夜。蒸發所有溶劑。混合物經Gilson製備性HPLC純化，產生1.8毫克標題化合物(2.9%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (50 Add milliamyl acetate (84.7 mg, 1.1 mmol) to sodium cyanoborohydride (4.84 mg, 0.077 mmol) in milligrams (0.11 mmol) in dichloromethane (2 mL) and methanol (1 mL) ). The resulting mixture was stirred at room temperature overnight. Evaporate all solvents. The mixture was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 447.2[M+H]滯留時間：1.53分鐘。 LC/MS = m/z 447.2 [M+H].

實例222：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{2-[(2-甲基丙基)胺基]乙基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 222: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{2-[(2-methylpropyl)amino]ethyl}-3-thiophene -1H-indole-7-carboxyguanamine trifluoroacetate

在含[2-(4-溴-2-噻吩基)乙基]胺(100毫克，0.48毫莫耳)之DCM(2.0毫升)與MeOH(1.0毫升)溶液中添加乙酸(3滴)與2-甲基丙醛(105毫克，1.44毫莫耳)。於室溫下攪拌反應一夜後，添加氫硼化鈉(53.3毫克，1.44毫莫耳)。反應1小時後，以EtOAc與鹽水處理。有機層脫水與濃縮，產生80毫克[2-(4-溴-2-噻吩基)乙基](1-甲基乙基)胺(64%)。 Add acetic acid (3 drops) and 2 in a solution of [2-(4-bromo-2-thienyl)ethyl]amine (100 mg, 0.48 mmol) in DCM (2.0 mL) - Methylpropanal (105 mg, 1.44 mmol). After stirring the reaction overnight at room temperature, sodium borohydride (53.3 mg, 1.44 mmol) was added. After 1 hour of reaction, it was treated with EtOAc and brine. The organic layer was dried and concentrated to give <RTI ID=0.0>>>

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(139毫克，0.3毫莫耳)之二烷(3毫升)與水(1毫升)溶液中添加[2-(4-溴-2-噻吩基)乙基](1-甲基乙基)胺(50毫克，0.2毫莫耳)、碳酸鉀(82.8毫克，0.6毫莫耳)與肆(三苯基膦)鈀(0)(22毫克，0.019毫莫耳)。所得混合物於微波爐中，於150℃下反應20分鐘。蒸發所有溶劑。混合物經Gilson製備性HPLC純化，產生18毫克標題化合物(9.5%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (139 mg, 0.3 mmol) Add [2-(4-bromo-2-thienyl)ethyl](1-methylethyl)amine (50 mg, 0.2 mmol) to a solution of alkane (3 mL) and water (1 mL). Potassium (82.8 mg, 0.6 mmol) with hydrazine (triphenylphosphine) palladium (0) (22 mg, 0.019 mmol ). The resulting mixture was reacted in a microwave oven at 150 ° C for 20 minutes. Evaporate all solvents. The mixture was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 517.2[M+H]滯留時間：1.68分鐘。 LC/MS = m/z 517.2 [M+H] retention time: 1.68 min.

實例223：5-{5-[2-(二甲基胺基)乙基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 223: 5-{5-[2-(Dimethylamino)ethyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-吲哚-7-carboxyguanamine trifluoroacetate

在含[2-(4-溴-2-噻吩基)乙基]胺(100毫克，0.48毫莫耳)之DCM(2.0毫升)與MeOH(1.0毫升)溶液中添加乙酸(3滴)與甲醛37%之水溶液(105毫克，1.44毫莫耳)。於室溫下攪拌反應一夜後，添加氫硼化鈉(53.3毫克，1.44毫莫耳)。反應1小時後，以EtOAc與鹽水處理。有機層脫水與濃縮，產生50毫克2-(4-溴-2-噻吩基)-N,N-二甲基乙胺(44%)。 Add acetic acid (3 drops) and formaldehyde to a solution of [2-(4-bromo-2-thienyl)ethyl]amine (100 mg, 0.48 mmol) in DCM (2.0 mL) 37% aqueous solution (105 mg, 1.44 mmol). After stirring the reaction overnight at room temperature, sodium borohydride (53.3 mg, 1.44 mmol) was added. After 1 hour of reaction, it was treated with EtOAc and brine. The organic layer was dried and concentrated to give 50 mg of 2-(4-bromo-2-thienyl) -N , N -dimethylethylamine (44%).

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(139毫克，0.345毫莫耳)之二烷(3毫升)與水(1毫升)溶液中添加2-(4-溴-2-噻吩基)-N,N-二甲基乙胺(50毫克，0.23毫莫耳)、碳酸鉀(82.8毫克，0.69毫莫耳)與肆(三苯基膦)鈀(0)(22毫克，0.019毫莫耳)。所得混合物於微波爐中，於150℃下反應20分鐘。蒸發所有溶劑。混合物經Gilson製備性HPLC純化，產生12毫克標題化合物(5.8%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -吲哚-7-carboxyguanamine (139 mg, 0.345 mmol) Add 2-(4-bromo-2-thienyl) -N , N -dimethylethylamine (50 mg, 0.23 mmol), potassium carbonate (82.8) to a solution of aq. (3 mL) and water (1 mL) Mg, 0.69 mmoles with hydrazine (triphenylphosphine) palladium (0) (22 mg, 0.019 mmol). The resulting mixture was reacted in a microwave oven at 150 ° C for 20 minutes. Evaporate all solvents. The mixture was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 489.2[M+H]滯留時間：1.54分鐘。 LC/MS = m/z 489.2 [M+H].

實例224：3-[1-(乙基磺醯基)-4-哌啶基]-5-[6-(1-吡咯啶基)-3-吡啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 224: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[6-(1-pyrrolidinyl)-3-pyridyl]-1H-indole-7-carboxylate Guanidine trifluoroacetate

在含5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(110毫克，0.27毫莫耳)之二烷(2.0毫升)與H₂O(0.7毫升)溶液中添加(6-氟-3-吡啶基)二羥硼酸(151毫克，1.08毫莫耳)、碳酸鉀(298毫克，2.16毫莫耳)與肆(三苯基膦)鈀(0)(31毫克，0.026毫莫耳)。於微波爐中，於150℃下反應20分鐘。以EtOAc與鹽水處理反應，經急驟層析法純化，產生50毫克3-[1-(乙基磺醯基)-4-哌啶基]-5-(6-氟-3-吡啶基)-1H-吲哚-7-羧醯胺(43%)。 In the presence of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxamide (110 mg, 0.27 mmol) Dioxane (2.0 mL) and H ₂ O (0.7 mL) was added (6-fluoro-3-pyridyl) solution of glyoxylic acid (151 mg, 1.08 mmol), potassium carbonate (298 mg, 2.16 mmol) With hydrazine (triphenylphosphine) palladium (0) (31 mg, 0.026 mmol). The reaction was carried out in a microwave oven at 150 ° C for 20 minutes. The reaction was quenched with EtOAc (EtOAc) elut 1 H -吲哚-7-carboxyguanamine (43%).

在3-[1-(乙基磺醯基)-4-哌啶基]-5-(6-氟-3-吡啶基)-1H-吲哚-7-羧醯胺(25毫克，0.058毫莫耳)中添加吡咯啶(3毫升)。所得混合物於微波爐中，於100℃下反應30分鐘。蒸發所有過量吡咯啶後，經Gilson製備性HPLC純化，產生25毫克標題化合物(72.4%)。 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1 H -indole-7-carboxamide (25 mg, 0.058 Pyrrolidine (3 ml) was added to the millimolar. The resulting mixture was reacted in a microwave oven at 100 ° C for 30 minutes. After purging all the excess pyrrolidine, it was purified by Gilson preparative HPLC to yield 25 mg of the title compound (72.4%).

LC/MS=m/z 482.2[M+H]滯留時間：1.67分鐘。 LC/MS = m/z 482.2 [M+H].

實例225：5-{6-[乙基(甲基)胺基]-3-吡啶基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 225: 5-{6-[Ethyl(methyl)amino]-3-pyridyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole- 7-Carboguanamine trifluoroacetate

在含5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(110毫克，0.27毫莫耳)之二烷(2.0毫升)與H₂O(0.7毫升)溶液中添加(6-氟-3-吡啶基)二羥硼酸(151毫克，1.08毫莫耳)、碳酸鉀(298毫克，2.16毫莫耳)與肆(三苯基膦)鈀(0)(31毫克，0.026毫莫耳)。於微波爐中，於150℃下反應20分鐘。反應經EtOAc與鹽水處理，經急驟層析法純化，產生50毫克3-[1-(乙基磺醯基)-4-哌啶基]-5-(6-氟-3-吡啶基)-1H-吲哚-7-羧醯胺(43%)。 In the presence of 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxamide (110 mg, 0.27 mmol) Dioxane (2.0 mL) and H ₂ O (0.7 mL) was added (6-fluoro-3-pyridyl) solution of glyoxylic acid (151 mg, 1.08 mmol), potassium carbonate (298 mg, 2.16 mmol) With hydrazine (triphenylphosphine) palladium (0) (31 mg, 0.026 mmol). The reaction was carried out in a microwave oven at 150 ° C for 20 minutes. The reaction was treated with EtOAc and EtOAc (EtOAc) 1 H -吲哚-7-carboxyguanamine (43%).

在3-[1-(乙基磺醯基)-4-哌啶基]-5-(6-氟-3-吡啶基)-1H-吲哚-7-羧醯胺(40毫克，0.093毫莫耳)中添加二甲基胺(1毫升)與DMF(0.3毫升)。所得混合物於微波爐中，於200℃下反應1小時。所得混合物經水洗滌。添加乙酸乙酯，蒸發有機層，經Gilson製備性HPLC純化，產生34.4毫克標題化合物(63.4%)。 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1 H -indole-7-carboxamide (40 mg, 0.093 To the millimolar) was added dimethylamine (1 mL) and DMF (0.3 mL). The resulting mixture was reacted in a microwave oven at 200 ° C for 1 hour. The resulting mixture was washed with water. Ethyl acetate was added and the organic layer was evaporated,jjjjjjjj

LC/MS=m/z 470[M+H]滯留時間：1.50分鐘。 LC/MS = m/z 470 [M+H].

實例226：5-[6-(二甲基胺基)-3-吡啶基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 226: 5-[6-(Dimethylamino)-3-pyridyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxylate Guanidine trifluoroacetate

在3-[1-(乙基磺醯基)-4-哌啶基]-5-(6-氟-3-吡啶基)-1H-吲哚-7-羧醯胺(50毫克，0.116毫莫耳)中添加二甲基胺(1毫升)與DMF(0.3毫升)。所得混合物於微波爐中，於200℃下反應1小時後，經Gilson製備性HPLC純化，產生8.4毫克標題化合物(12.7%)。 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1 H -indole-7-carboxamide (50 mg, 0.116 To the millimolar) was added dimethylamine (1 mL) and DMF (0.3 mL). The resulting mixture was reacted in a microwave oven for 1 hour at 200 ° C and purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 456.2[M+H]滯留時間：1.39分鐘。 LC/MS = m/z 456.2 [M+H].

實例227：3-[1-(乙基磺醯基)-4-哌啶基]-5-[6-(丙基胺基)-3-吡啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 227: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[6-(propylamino)-3-pyridyl]-1H-indole-7-carboxyindole Amine trifluoroacetate

在3-[1-(乙基磺醯基)-4-哌啶基]-5-(6-氟-3-吡啶基)-1H-吲哚-7-羧醯胺(50毫克，0.116毫莫耳)中添加丙基胺(1毫升)與DMF(0.3毫升)。所得混合物於微波爐中，於200℃下反應5小時後，經Gilson製備性HPLC純化，產生24.5毫克標題化合物(36.2%)。 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(6-fluoro-3-pyridinyl)-1 H -indole-7-carboxamide (50 mg, 0.116 To the millimolar), propylamine (1 ml) and DMF (0.3 ml) were added. The resulting mixture was reacted in a microwave oven at 200 ° C for 5 hours and then purified by EtOAc EtOAc.

LC/MS=m/z 470.2[M+H]滯留時間：1.49分鐘。 LC/MS = m/z 470.2 [M+H].

實例228：3-[1-(乙基磺醯基)-4-哌啶基]-5-{6-[(1-甲基乙基)胺基]-3-吡啶基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 228: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{6-[(1-methylethyl)amino]-3-pyridyl}-1H-indole哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-{6-[乙基(甲基)胺基]-3-吡啶基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-丙胺(64.3毫克，1毫莫耳)替代二甲基胺製備，產生9.8毫克標題化合物(14.5%)。 The title compound is based on 5-{6-[ethyl(methyl)amino]-3-pyridyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole The general procedure for -7-carboxylamidine trifluoroacetate, but using 2-propylamine (64.3 mg, 1 mmol) instead of dimethylamine afforded 9.8 mg of the title compound (14.5%).

LC/MS=m/z 470.4[M+H]滯留時間：1.52分鐘。 LC/MS = m/z 470.4 [M+H].

實例229：3-[1-(乙基磺醯基)-4-哌啶基]-5-[6-(4-嗎啉基)-3-吡啶基]-1H-吲哚-7-羧醯胺Example 229: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[6-(4-morpholinyl)-3-pyridyl]-1H-indole-7-carboxylate Guanamine

標題化合物係依據5-{6-[乙基(甲基)胺基]-3-吡啶基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用嗎啉(1毫升)替代二甲基胺製備，產生40.1毫克標題化合物(69.5%)。 The title compound is based on 5-{6-[ethyl(methyl)amino]-3-pyridyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole The general procedure for -7-carboxyguanamine trifluoroacetate, but morpholine (1 mL) was used instead of dimethylamine to afford 40.1 mg of the title compound (69.5%).

LC/MS=m/z 498.6[M+H]滯留時間：1.44分鐘。 LC/MS = m/z 498.6 [M+H].

實例230：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(甲基胺基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 230: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-3-thienyl}-1H-indole- 7-Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(20毫克，0.045毫莫耳)之甲醇(1.5毫升)與二氯甲烷(1.5毫升)溶液中添加甲基胺(0.13毫升)。所得混合物於室溫下攪拌2小時後，添加四氫硼酸鈉(9.18毫克，0.27毫莫耳)。於室溫下攪拌1小時。蒸發所有溶劑後，經Gilson製備性HPLC純化，產生12.4毫克標題化合物(48%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (20 Methylamine (0.13 ml) was added to a solution of MeOH (EtOAc) (EtOAc) After the resulting mixture was stirred at room temperature for 2 hours, sodium tetrahydroborate (9.18 mg, 0.27 mmol) was added. Stir at room temperature for 1 hour. After evaporation of all solvents, purified by EtOAc EtOAc.

LC/MS=m/z 461.4[M+H]滯留時間：1.48分鐘。 LC/MS = m/z 461.4 [M+H].

實例231：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(1-甲基乙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 231: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[(1-methylethyl)amino]methyl}-3-thienyl) -1H-吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(30毫克，0.067毫莫耳)之甲醇(0.5毫升)與二氯甲烷(1毫升)溶液中添加2-丙胺(23.8毫克，0.402毫莫耳)。攪拌所得混合物2.5小時後，添加四氫硼酸鈉(15.2毫克，0.402毫莫耳)。於室溫下攪拌反應1小時。蒸發所有溶劑後，經Gilson製備性HPLC純化，產生19.5毫克標題化合物(48.3%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (30 To a solution of methanol (0.5 ml) in methanol (0.5 mL) and dichloromethane (1 mL) was added 2-propanamine (23.8 mg, 0.402 mmol). After stirring the resulting mixture for 2.5 hours, sodium tetrahydroborate (15.2 mg, 0.402 mmol) was added. The reaction was stirred at room temperature for 1 hour. After evaporation of all solvents, purified by EtOAc EtOAc.

LC/MS=m/z 489.2[M+H]滯留時間：1.54分鐘。 LC/MS = m/z 489.2 [M+H].

實例232：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(1-吡咯啶基甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 232: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-3-thienyl]-1H-indole-7 -Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(30毫克，0.067毫莫耳)之甲醇(0.5毫升)與二氯甲烷(1毫升)溶液中添加吡咯啶(85毫克，1.195毫莫耳)。攪拌所得混合物1.5小時後，添加三乙醯氧基氫硼化鈉(85毫克，0.402毫莫耳)。於室溫下攪拌反應2小時。蒸發所有溶劑後，經Gilson製備性HPLC純化，產生22.5毫克標題化合物(54.6%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (30 Add pyrrolidine (85 mg, 1.195 mmol) to a solution of methanol (0.5 mL) in methanol (0.5 mL) and dichloromethane (1 mL). After the resulting mixture was stirred for 1.5 hours, sodium triacetoxyborohydride (85 mg, 0.402 mmol) was added. The reaction was stirred at room temperature for 2 hours. After evaporation of all solvents, purified by EtOAc EtOAc.

LC/MS=m/z 501.4[M+H]滯留時間：1.52分鐘。 LC/MS = m/z 501.4 [M+H].

實例233：5-{5-[(乙基胺基)甲基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 233: 5-{5-[(Ethylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole- 7-Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(30毫克，0.067毫莫耳)之甲醇(3毫升)、二氯甲烷(3毫升)溶液中添加乙基胺(0.2毫升，0.402毫莫耳)。2小時後，添加四氫硼酸鈉(27毫克，0.402毫莫耳)。混合物靜置1小時。蒸發所有溶劑後，經Gilson製備性HPLC純化，產生15毫克標題化合物(38%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (30 Methylamine (0.2 ml, 0.402 mmol) was added to a solution of MeOH (3 mL), m. After 2 hours, sodium tetrahydroborate (27 mg, 0.402 mmol) was added. The mixture was allowed to stand for 1 hour. After evaporation of all solvents, EtOAc (EtOAc)

LC/MS=m/z 475.4[M+H]滯留時間：1.52分鐘。 LC/MS = m/z 475.4 [M+H].

實例234：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({[(1R)-2-羥基-1-甲基乙基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 234: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({[(1R)-2-hydroxy-1-methylethyl]amino} 3-thiophenyl]-1H-indole-7-carboxamide fluorotrifluoroacetate

標題化合物係依據5-{5-[(乙基胺基)甲基]-3-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(2R)-2-胺基-1-丙醇(0.031毫升，0.402毫莫耳)替代乙基胺製備，產生16.2毫克標題化合物(39.1%)。 The title compound is based on 5-{5-[(ethylamino)methyl]-3-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole General procedure for -7-carboxyguanamine trifluoroacetate, but instead of (2R)-2-amino-1-propanol (0.031 ml, 0.402 mmol) instead of ethylamine, yielding 16.2 mg of the title compound (39.1%).

LC/MS=m/z 505.4[M+H]滯留時間：1.42分鐘。 LC/MS = m/z 505.4 [M+H].

實例235：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(1-哌啶基甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 235: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-(1-piperidinylmethyl)-3-thienyl]-1H-indole-7 -Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(30毫克，0.067毫莫耳)之二甲亞碸(2毫升)溶液中添加哌啶(70毫克，0.670毫莫耳)。所得混合物靜置2小時後，添加三乙醯氧基氫硼化鈉(142毫克，0.670毫莫耳)。於室溫下攪拌此混合物一夜後，經Gilson製備性HPLC純化，產生16.2毫克標題化合物(38.5%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (30 Piperidine (70 mg, 0.670 mmol) was added to a solution of dimethylidene (2 ml) in milligrams, 0.067 mmol. After the resulting mixture was allowed to stand for 2 hours, sodium triacetoxyborohydride (142 mg, 0.670 mmol) was added. After the mixture was stirred at room temperature overnight, purified by EtOAc EtOAc.

LC/MS=m/z 514.8[M+H]滯留時間：1.37分鐘。 LC/MS = m/z 514.8 [M+H].

實例236：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(4-嗎啉基甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 236: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-(4-morpholinylmethyl)-3-thienyl]-1H-indole-7 -Carboguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(1-吡咯啶基甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用嗎啉(70毫克，0.670毫莫耳)替代哌啶製備，產生6.3毫克標題化合物(14.9%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-3-thienyl]-1H-indole- The general procedure for 7-carboxyguanamine trifluoroacetate, but morpholine (70 mg, 0.670 mmol) was used instead of piperidine to give 6.3 mg of the title compound (14.9%).

LC/MS=m/z 517[M+H]滯留時間：1.54分鐘。 LC/MS = m/z 517 [M+H].

實例237：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(甲基胺基)甲基]-3-呋喃基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 237: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-3-furanyl}-1H-indole- 7-Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)之二烷(3.0毫升)與H₂O(1.0毫升)溶液中添加4-溴-2-呋喃甲醛(58毫克，0.33毫莫耳)、碳酸鉀(89.8毫克，0.66毫莫耳)與肆(三苯基膦)鈀(0)(14毫克，0.012毫莫耳)。反應於微波爐中，於150℃下加熱20分鐘，產生58毫克3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-呋喃基)-1H-吲哚-7-羧醯胺。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (50 mg, 0.11 mmol) Add 4-bromo-2-furaldehyde (58 mg, 0.33 mmol), potassium carbonate (89.8 mg, 0.66 mmol) and hydrazine (triphenyl) to a solution of alkane (3.0 mL) and H ₂ O (1.0 mL). Phenylphosphine) palladium (0) (14 mg, 0.012 mmol). The reaction was heated in a microwave oven at 150 ° C for 20 minutes to yield 58 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindol-3-furanyl) -1 H -吲哚-7-carboxyguanamine.

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-呋喃基)-1H-吲哚-7-羧醯胺(20.6毫克，0.05毫莫耳)之DMSO(0.5毫升)溶液中添加甲基胺(0.24毫升，0.5毫莫耳)之2 M四氫呋喃溶液。所得混合物反應6小時後，添加三乙醯氧基氫硼化鈉，經Gilson製備性HPLC純化，產生5.5毫克標題化合物(32.8%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-furanyl)-1 H -indole-7-carboxamide (20.6 A solution of methylamine (0.24 mL, 0.5 mmol) in 2 M tetrahydrofuran was added to a solution of MeOH (0.5 mL). After the reaction mixture was reacted for 6 hours, sodium triethyl sulfonium hydride hydride was added and purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 459.4[M+H]滯留時間：1.42分鐘。 LC/MS = m/z 459.4 [M+H].

實例238：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[1-(1-吡咯啶基)乙基]-3-噻吩基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 238: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[1-(1-pyrrolidinyl)ethyl]-3-thienyl}-1H-吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(300毫克，0.65毫莫耳)之二烷(9毫升)與H₂O(3毫升)溶液中添加1-(4-溴-2-噻吩基)乙酮(400毫克，1.95毫莫耳)、碳酸鉀(538毫克，3.90毫莫耳)與肆(三苯基膦)鈀(0)(70毫克，0.060毫莫耳)。於微波爐中，於150℃下反應20分鐘。使用EtOAc與H₂O操作水相後，添加MeOH(3毫升)至粗產物中。所需產物沉澱並過濾，產生230毫克3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-丙醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(77%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -吲哚-7-carboxyguanamine (300 mg, 0.65 mmol) Dioxane (9 mL) and H ₂ O (3 mL) was added a solution of 1- (4-bromo-2-thienyl) ethanone (400 mg, 1.95 mmol), potassium carbonate (538 mg, 3.90 mmol ) with hydrazine (triphenylphosphine) palladium (0) (70 mg, 0.060 mmol). The reaction was carried out in a microwave oven at 150 ° C for 20 minutes. After using EtOAc and H ₂ O operations aqueous phase was added MeOH (3 mL) to the crude product. The desired product is precipitated and filtered to give 230 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-propenyl-3-thienyl)-1 H -indole. -7-Carboxyguanamine (77%).

在含5-(5-乙醯基-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)之DMF(0.8毫升)與乙酸(0.2毫升)溶液中添加吡咯啶(30.92毫克，0.44毫莫耳)與N,N-二甲基甲醯胺(30毫克，0.44毫莫耳)。反應混合物於微波爐中，於150℃下反應20分鐘。經Gilson製備性HPLC純化2次，產生3.7毫克標題化合物(5.3%)。 In the presence of 5-(5-ethylindolyl-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (50 Add pyridine (30.92 mg, 0.44 mmol) to N,N-dimethylformamide (30 mg, 0.44 m) in milligrams (0.11 mmol) of DMF (0.8 mL) and acetic acid (0.2 mL) Moore). The reaction mixture was reacted in a microwave oven at 150 ° C for 20 minutes. Purification twice by Gilson preparative HPLC gave 3.7 mg of the title compound (5.3%).

LC/MS=m/z 515.4[M+H]滯留時間：1.62分鐘。 LC/MS = m/z 515.4 [M+H].

實例239：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(1-吡咯啶基甲基)-2-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 239: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-2-thienyl]-1H-indole-7 -Carboguanamine trifluoroacetate

在3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-2-噻吩基)-1H-吲哚-7-羧醯胺(40毫克，0.09毫莫耳)之二甲亞碸(0.5毫升)溶液中添加2M吡咯啶(0.074毫升，0.90毫莫耳)。所得混合物靜置6小時後，添加三乙醯氧基氫硼化鈉(233毫克，9.90毫莫耳)。再靜置2小時後，經Gilson製備性HPLC純化，產生6.5毫克標題化合物(11.7%)。 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-2-thienyl)-1 H -indole-7-carboxamide (40 mg 2M pyrrolidine (0.074 ml, 0.90 mmol) was added to a solution of dimethyl hydrazine (0.5 mL). After the resulting mixture was allowed to stand for 6 hours, sodium triacetoxyborohydride (233 mg, 9.90 mmol) was added. After standing for an additional 2 hours, it was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 515.4[M+H]滯留時間：1.62分鐘。 LC/MS = m/z 515.4 [M+H].

實例240：5-{5-[(二甲基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 240: 5-{5-[(Dimethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole -7-Carboguanamine trifluoroacetate

在3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-2-噻吩基)-1H-吲哚-7-羧醯胺(35毫克，0.09毫莫耳)之二甲亞碸(0.5毫升)溶液中添加2M二甲基胺(0.4毫升，0.90毫莫耳)。所得混合物靜置6小時後，添加三乙醯氧基氫硼化鈉(233毫克，9.90毫莫耳)。再靜置2小時後，經Gilson製備性HPLC純化，產生17.8毫克標題化合物(33.6%)。 In 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-2-thienyl)-1 H -indole-7-carboxamide (35 mg 2M dimethylamine (0.4 ml, 0.90 mmol) was added to a solution of dimethyl hydrazine (0.5 mL). After the resulting mixture was allowed to stand for 6 hours, sodium triacetoxyborohydride (233 mg, 9.90 mmol) was added. After standing for an additional 2 hours, it was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 475.2[M+H]滯留時間：1.53分鐘。 LC/MS = m/z 475.2 [M+H].

實例241：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(丙基胺基)甲基]-2-噻吩基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 241: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[(propylamino)methyl]-2-thienyl}-1H-indole- 7-Carboguanamine trifluoroacetate

標題化合物係依據5-{5-[(二甲基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用丙基胺(0.064毫升，0.90毫莫耳)替代2M二甲基胺製備，產生8.9毫克標題化合物(16.4%)。 The title compound is based on 5-{5-[(dimethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole The general procedure for hydrazine-7-carboxamide fluorotrifluoroacetate was prepared using propylamine (0.064 mL, 0.90 mmol) instead of 2M dimethylamine to afford 8.9 mg of the title compound (16.4%).

LC/MS=m/z 487.2[M+H]滯留時間：1.80分鐘。 LC/MS = m/z 487.2 [M+H].

實例242：5-{5-[(二乙基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 242: 5-{5-[(Diethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole -7-Carboguanamine trifluoroacetate

標題化合物係依據5-{5-[(二甲基胺基)甲基]-2-噻吩基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用二乙基胺(0.081毫升，0.90毫莫耳)替代2M二甲基胺製備，產生16.6毫克標題化合物(29.9%)。 The title compound is based on 5-{5-[(dimethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole The general procedure for 哚-7-carboxylamidine trifluoroacetate, but instead of diethylamine (0.081 mL, 0.90 mmol), was used instead of 2M dimethylamine to afford 16.6 mg of the title compound (29.9%).

LC/MS=m/z 502.0[M+H]滯留時間：1.71分鐘。 LC/MS = m/z 502.0 [M+H].

實例243：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丙基)胺基]甲基}-2-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 243: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-2-thienyl) -1H-吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-2-噻吩基)-1H-吲哚-7-羧醯胺(30毫克，0.09毫莫耳)之二甲亞碸(0.5毫升)溶液中添加2-甲基-1-丙胺(0.068毫升，0.90毫莫耳)。所得混合物靜置6小時後，添加三乙醯氧基氫硼化鈉(233毫克，9.90毫莫耳)。再靜置2小時後，經Gilson製備性HPLC純化，產生2.7毫克標題化合物(4.9%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-2-thienyl)-1 H -indole-7-carboxamide (30 To a solution of dimethylidene (0.5 ml) in MeOH (0.09 mmol) was added 2-methyl-1-propylamine (0.068 mL, 0.90 mmol). After the resulting mixture was allowed to stand for 6 hours, sodium triacetoxyborohydride (233 mg, 9.90 mmol) was added. After standing for an additional 2 hours, it was purified by EtOAc EtOAc.

LC/MS=m/z 501.4[M+H]滯留時間：1.79分鐘。 LC/MS = m/z 501.4 [M+H].

實例244：5-(5-{[(2,2-二甲基丙基)胺基]甲基}-3-呋喃基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 244: 5-(5-{[(2,2-Dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-1H-indole-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)之二烷(3.0毫升)與H₂O(1.0毫升)溶液中添加4-溴-2-呋喃甲醛(58毫克，0.33毫莫耳)、碳酸鉀(89.8毫克，0.66毫莫耳)與肆(三苯基膦)鈀(0)(14毫克，0.012毫莫耳)。反應於微波爐中，於150℃下加熱20分鐘，產生58毫克3-[1- (乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-呋喃基)-1H-吲哚-7-羧醯胺。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (50 mg, 0.11 mmol) Add 4-bromo-2-furaldehyde (58 mg, 0.33 mmol), potassium carbonate (89.8 mg, 0.66 mmol) and hydrazine (triphenyl) to a solution of alkane (3.0 mL) and H ₂ O (1.0 mL). Phenylphosphine) palladium (0) (14 mg, 0.012 mmol). The reaction was heated in a microwave oven at 150 ° C for 20 minutes to yield 58 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindol-3-furanyl) -1 H -吲哚-7-carboxyguanamine.

在3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-呋喃基)-1H-吲哚-7-羧醯胺(60毫克，0.14毫莫耳)中添加含2,2-二甲基-1-丙胺(60毫克，0.14毫莫耳)之二甲亞碸(0.5毫升)，添加2,2-二甲基-1-丙胺(122毫克，1.40毫莫耳)。所得混合物靜置6小時後，添加三乙醯氧基氫硼化鈉(233毫克，9.90毫莫耳)。再靜置2小時後，經Gilson製備性HPLC純化，產生23.8毫克標題化合物(27.7%)。 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-furanyl)-1 H -indole-7-carboxamide (60 mg 2,2-dimethyl-1-propylamine (60 mg, 0.14 mmol) of dimethyl hydrazine (0.5 ml) was added to 0.14 mmol, and 2,2-dimethyl-1- Propylamine (122 mg, 1.40 mmol). After the resulting mixture was allowed to stand for 6 hours, sodium triacetoxyborohydride (233 mg, 9.90 mmol) was added. After standing for an additional 2 hours, it was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 501.1[M+H]滯留時間：1.67分鐘。 LC/MS = m/z 501.1 [M+H].

實例245：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2-甲基丙基)胺基]甲基}-3-呋喃基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 245: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylpropyl)amino]methyl}-3-furanyl) -1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[(2,2-二甲基丙基)胺基]甲基}-3-呋喃基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-甲基-1-丙胺(102.4毫克，1.4毫莫耳)替代2,2-二甲基-1-丙胺製備，產生31.7毫克標題化合物(37.7%)。 The title compound is based on 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4- General procedure for piperidinyl]-1H-indole-7-carboxamide guanamine trifluoroacetate, but with 2-methyl-1-propylamine (102.4 m) Preparation of the compound (37.7%).

LC/MS=m/z 487.2[M+H]滯留時間：1.44分鐘。 LC/MS = m/z 487.2 [M+H].

實例246：5-(5-{[(環戊基甲基)胺基]甲基}-3-呋喃基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 246: 5-(5-{[(Cyclopentylmethyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(5-{[(2,2-二甲基丙基)胺基]甲基}-3-呋喃基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用1-環戊基甲胺(137毫克，1.4毫莫耳)替代2,2-二甲基-1-丙胺製備，產生22毫克標題化合物(25.1%)。 The title compound is based on 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4- General procedure for piperidinyl]-1H-indole-7-carboxamide amine trifluoroacetate, but instead of 2-cyclopentylmethylamine (137 mg, 1.4 mmol) instead of 2,2-dimethyl Preparation of 1-propylamine gave 22 mg of the title compound (25.1%).

LC/MS=m/z 513.4[M+H]滯留時間：1.59分鐘。 LC/MS = m/z 513.4 [M+H].

實例247：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(1-吡咯啶基甲基)-3-呋喃基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 247: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-3-furanyl]-1H-indole-7 -Carboguanamine trifluoroacetate

標題化合物係依據5-(5-{[(2,2-二甲基丙基)胺基]甲基}-3-呋喃基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用吡咯啶(99.6毫克，1.4毫莫耳)替代2,2-二甲基-1-丙胺製備，產生6毫克標題化合物(7.2%)。 The title compound is based on 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4- General procedure for piperidinyl]-1H-indole-7-carboxamide amine trifluoroacetate, but instead of pyrrolidine (99.6 mg, 1.4 mmol) instead of 2,2-dimethyl-1-propylamine , yield 6 mg of the title compound (7.2%).

LC/MS=m/z 485.2[M+H]滯留時間：1.50分鐘。 LC/MS = m/z 485.2 [M+H].

實例248：5-{5-[(二乙基胺基)甲基]-3-呋喃基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 248: 5-{5-[(Diethylamino)methyl]-3-furanyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole -7-Carboguanamine trifluoroacetate

標題化合物係依據5-(5-{[(2,2-二甲基丙基)胺基]甲基}-3-呋喃基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2M二乙基胺(102.4毫克，1.4毫莫耳)替代2,2-二甲基-1-丙胺製備，產生10.1毫克標題化合物(12%)。 The title compound is based on 5-(5-{[(2,2-dimethylpropyl)amino]methyl}-3-furanyl)-3-[1-(ethylsulfonyl)-4- General procedure for piperidinyl]-1H-indole-7-carboxamide amine trifluoroacetate, but instead of 2M diethylamine (102.4 mg, 1.4 mmol) instead of 2,2-dimethyl-1 -Propamine preparation gave 10.1 mg of the title compound (12%).

LC/MS=m/z 487.4[M+H]滯留時間：1.50分鐘。 LC/MS = m/z 487.4 [M+H].

實例249：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(1-吡咯啶基甲基)-1,3-噻唑-2-基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 249: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-1,3-thiazol-2-yl]-1H -吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(500毫克，1.1毫莫耳)之二烷(12毫升)與H₂O(4毫升)溶液中添加2-溴-1,3-噻唑-5-甲醛(634毫克，3.3毫莫耳)、碳酸鉀(898毫克，8.8毫莫耳)與肆(三苯基膦)鈀(0)(210毫克，0.181毫莫耳)。於微波爐中，於150℃下反應20分鐘。操作水相，產生粗產物。反應再於微波爐中，於150℃下重覆反應30分鐘，產生3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-1,3-噻唑-2-基)-1H-吲哚-7-羧醯胺. In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -吲哚-7-carboxyguanamine (500 mg, 1.1 mmol) Dioxane (12 mL) and H ₂ O (4 mL) was added 2-bromo-1,3-thiazole-5-carbaldehyde (634 mg, 3.3 mmol), potassium carbonate (898 mg, 8.8 mmol) was With palladium (triphenylphosphine) palladium (0) (210 mg, 0.181 mmol). The reaction was carried out in a microwave oven at 150 ° C for 20 minutes. The aqueous phase is manipulated to produce a crude product. The reaction was further repeated in a microwave oven at 150 ° C for 30 minutes to give 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindenyl-1,3- Thiazol-2-yl)-1 H -吲哚-7-carboxyguanamine.

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-1,3-噻唑-2-基)-1H-吲哚-7-羧醯胺(25毫克，0.06毫莫耳)之二甲亞碸(1毫升)溶液中添加吡咯啶(0.05毫升，0.60毫莫耳)。所得混合物於室溫下攪拌6小時後，添加三乙醯氧基氫硼化鈉(160毫克，0.60毫莫耳)。攪拌所得混合物一夜後，經Gilson製備性HPLC純化，產生6.3毫克標題化合物(17.1%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-1,3-thiazol-2-yl)-1 H -吲哚-7- Pyrrolidine (0.05 ml, 0.60 mmol) was added to a solution of carbamazepine (25 mg, 0.06 mmol) in dimethyl hydrazine (1 ml). After the resulting mixture was stirred at room temperature for 6 hours, sodium triethyloxy borohydride (160 mg, 0.60 mmol) was added. The resulting mixture was stirred overnight and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 502.2[M+H]滯留時間：1.35分鐘。 LC/MS = m/z 502.2 [M+H].

實例250：3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[2-甲基-1-(1-吡咯啶基)丙基]-3-噻吩基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 250: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{5-[2-methyl-1-(1-pyrrolidinyl)propyl]-3-thiophene }}-1H-吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)之二烷(3毫升)與H₂O(1毫升)溶液中添加碳酸鉀(89.8毫克，0.66毫莫耳)、1-(4-溴-2-噻吩基)-2-甲基-1-丙酮(87毫克，0.33毫莫耳)與肆(三苯基膦)鈀(0)(14毫克，0.012 毫莫耳)。於微波爐中，於150℃下反應20分鐘後，以EtOAd與H₂O操作水相。反應濃縮，以1 N NaOH處理，以EtOAc萃取。化合物經急驟層析法，使用DCM與MeOH純化，產生3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(2-甲基丙醯基)-3-噻吩基]-1H-吲哚-7-羧醯胺。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (50 mg, 0.11 mmol) Dioxane (3 mL) and H ₂ O (1 mL) was added a solution of potassium carbonate (89.8 mg, 0.66 mmol), 1- (4-bromo-2-thienyl) -2-methyl-1-propanone ( 87 mg, 0.33 mmol) with hydrazine (triphenylphosphine) palladium (0) (14 mg, 0.012 mmol). After reacting at 150 ° C for 20 minutes in a microwave oven, the aqueous phase was operated with EtOAd and H ₂ O. The reaction was concentrated, taken up in 1 N EtOAc EtOAc. The compound was purified by flash chromatography using EtOAc (EtOAc) toield -Thienyl]-1 H -吲哚-7-carboxyguanamine.

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(2-甲基丙醯基)-3-噻吩基]-1H-吲哚-7-羧醯胺(40毫克，0.02毫莫耳)之EtOH(1.5毫升)與乙酸(0.2毫升)溶液中添加氰基氫硼化鈉(7.5毫克，0.12毫莫耳)與吡咯啶(0.03毫升，0.3毫莫耳)。所得混合物於微波爐中，於150℃下反應40分鐘。蒸發所有溶劑，經氫氧化鈉鹼化，以乙酸乙酯萃取。然後經Gilson製備性HPLC純化，產生13毫克標題化合物。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(2-methylpropenyl)-3-thienyl]-1 H -吲哚-7 Add cyanoguanidine hydride (7.5 mg, 0.12 mmol) to pyrrolidine (0.03 mL) in a solution of carboxyguanamine (40 mg, 0.02 mmol) in EtOH (1.5 mL) and acetic acid (0.2 mL). 0.3 millimoles). The resulting mixture was reacted in a microwave oven at 150 ° C for 40 minutes. All solvents were evaporated, basified with sodium hydroxide and extracted with ethyl acetate. Purification by Gilson preparative HPLC gave 13 mg of the title compound.

LC/MS=m/z 543.4[M+H]滯留時間：1.71分鐘。 LC/MS = m/z 543.4 [M+H].

實例251：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(1-吡咯啶基甲基)-1,3-噻唑-2-基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 251: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[4-(1-pyrrolidinylmethyl)-1,3-thiazol-2-yl]-1H -吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-甲醯基-1,3-噻唑-4-基)-1H-吲哚-7-羧醯胺(42毫克，0.094毫莫耳)之DMSO(2毫升)溶液中添加吡咯啶(0.08毫升，0.940毫莫耳)。所得混合物於室溫下攪拌6小時後，添加三乙醯氧基氫硼化鈉。於室溫下攪拌此混合物一夜後，經Gilson製備性HPLC純化，產生15.1毫克標題化合物(26.1%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-carbamimido-1,3-thiazol-4-yl)-1 H -吲哚-7- Pyrrolidine (0.08 mL, 0.940 mmol) was added to a solution of carbamide (42 mg, 0.094 mmol) in DMSO (2 mL). After the resulting mixture was stirred at room temperature for 6 hours, sodium triacetoxyborohydride was added. After the mixture was stirred at room temperature overnight, purified by EtOAc EtOAc.

LC/MS=m/z 502.4[M+H]滯留時間：1.54分鐘。 LC/MS = m/z 502.4 [M+H].

實例252：5-{1-[2-(二甲基胺基)乙基]-1H-吡唑-4-基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 252: 5-{1-[2-(Dimethylamino)ethyl]-1H-pyrazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl ]-1H-吲哚-7-carboxyguanamine

取3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(40毫克，0.084毫莫耳)、[2-(4-溴-1H-吡唑-1-基)乙基]二甲基胺(27毫克，0.126毫莫耳)與碳酸鈉(53毫克，0.5毫莫耳)懸浮於二烷(750微升)與水(250微升)。以氬氣沖刷10分鐘後，添加肆(三苯基膦)鈀(0)(5毫克，0.004毫莫耳)。所得混合物於微波爐中，於120℃下反應20分鐘後，以EtOAc(10毫升)稀釋。混合物經寅氏鹽過濾，洗滌水相。經Gilson製備性HPLC純化，產生6毫克標題化合物(15%)。 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- -1 H -吲哚-7-carboxamide (40 mg, 0.084 mmol), [2-(4-bromo-1H-pyrazol-1-yl)ethyl]dimethylamine (27 Mg, 0.126 mmol, suspended in sodium with sodium carbonate (53 mg, 0.5 mmol) Alkane (750 microliters) with water (250 microliters). After flushing with argon for 10 minutes, hydrazine (triphenylphosphine) palladium (0) (5 mg, 0.004 mmol) was added. The resulting mixture was reacted in a microwave oven at 120 ° C for 20 min then diluted with EtOAc (10 mL). The mixture was filtered through strontium salt and the aqueous phase was washed. Purification by Gilson preparative HPLC gave 6 mg of the title compound (15%).

LC/MS=m/z 473.4[M+H]滯留時間：1.48分鐘。 LC/MS = m/z 473.4 [M+H].

實例253：3-[1-(乙基磺醯基)-4-哌啶基]-5-{1-[2-(1-吡咯啶基)乙基]-1H-吡唑-4-基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 253: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{1-[2-(1-pyrrolidinyl)ethyl]-1H-pyrazol-4-yl }-1H-吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(40毫克，0.090毫莫耳)之二烷(750微升)與H₂O(250微升)溶液中添加碳酸鈉(53毫克，0.50毫莫耳)與4-溴-1-(2-氯乙基)-1H-吡唑(26毫克，0.126毫莫耳)。反應混合物經氬氣沖刷10分鐘後，添加肆(三苯基膦)鈀(0)(5毫克，0.004毫莫耳)。反應於微波爐中，於120℃下加熱20分鐘。以EtOAc(10毫升)稀釋，經寅氏鹽過濾，然後操作水相。化合物經Gilson製備性HPLC純化，產生10毫克5-[1-(2-氯乙基)-1H-吡唑-4-基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(24%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -吲哚-7-carboxamide (40 mg, 0.090 mmol) Add sodium carbonate (53 mg, 0.50 mmol) and 4-bromo-1-(2-chloroethyl)-1 H -pyrazole to a solution of alkane (750 μl) and H ₂ O (250 μL) 26 mg, 0.126 mmol. After the reaction mixture was flushed with argon for 10 minutes, bis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) was added. The reaction was heated in a microwave oven at 120 ° C for 20 minutes. Diluted with EtOAc (10 mL) filtered over EtOAc then EtOAc. The compound was purified by Gilson preparative HPLC to give 10 mg of 5-[1-(2-chloroethyl)-1 H -pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4- Piperidinyl]-1 H -indole-7-carboxamide (24%).

在含5-[1-(2-氯乙基)-1H-吡唑-4-基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(33毫克，0.071毫莫耳)、吡咯啶(60微升，0.710毫莫耳)與碘化鈉(5毫克，0.018毫莫耳)溶液中添加四氫呋喃(500微升)。此混合物於微波爐中，於130℃下反應2小時，以EtOAc與水洗滌水相。單離有機層，排除所有溶劑。經Gilson製備性HPLC純化，產生11毫克標題化合物(25%)。 In the presence of 5-[1-(2-chloroethyl)-1 H -pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲Add tetrahydrofuran (500 μl) to a solution of 哚-7-carboxyguanamine (33 mg, 0.071 mmol), pyrrolidine (60 μl, 0.710 mmol) and sodium iodide (5 mg, 0.018 mmol) ). This mixture was reacted in a microwave oven at 130 ° C for 2 hours, and the aqueous phase was washed with EtOAc and water. Separate the organic layer and remove all solvents. Purification by Gilson preparative HPLC gave 11 mg of the title compound (25%).

LC/MS=m/z 499.6[M+H]滯留時間：1.34分鐘。 LC/MS = m/z 499.6 [M+H].

實例254：3-[1-(乙基磺醯基)-4-哌啶基]-5-{1-[2-(4-嗎啉基)乙基]-1H-吡唑-4-基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 254: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{1-[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-yl }-1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{1-[2-(1-吡咯啶基)乙基]-1H-吡唑-4-基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用嗎啉(70微升，0.71毫莫耳)替代吡咯啶製備，產生15毫克標題化合物(34%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{1-[2-(1-pyrrolidinyl)ethyl]-1H-pyrazole-4- General procedure for the formation of the title compound (34%) with morpholine (70 μl, 0.71 mmol) instead of pyrrolidine. .

LC/MS=m/z 515.4[M+H]滯留時間：1.46分鐘。 LC/MS = m/z 515.4 [M+H].

實例255：3-[1-(乙基磺醯基)-4-哌啶基]-5-(1-{2-[(2-羥基乙基)胺基]乙基}-1H-吡唑-4-基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 255: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyrazole -4-yl)-1H-indole-7-carboxamide guanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(40毫克，0.090毫莫耳)之二烷(750微升)與H₂O(250微升)溶液中添加碳酸鈉(53毫克，0.50毫莫耳)與4-溴-1-(2-氯乙基)-1H-吡唑(26毫克，0.126毫莫耳)。反應混合物經氬氣沖刷10分鐘後，添加肆(三苯基膦)鈀(0)(5毫克，0.004毫莫耳)。反應於微波爐中，於120℃下加熱20分鐘。以EtOAc(10毫升)稀釋，經寅氏鹽過濾後，操作水相。化合物經Gilson製備性HPLC純化，產生10毫克5-[1-(2-氯乙基)-1H-吡唑-4-基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(24%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -吲哚-7-carboxamide (40 mg, 0.090 mmol) Add sodium carbonate (53 mg, 0.50 mmol) and 4-bromo-1-(2-chloroethyl)-1 H -pyrazole to a solution of alkane (750 μl) and H ₂ O (250 μL) 26 mg, 0.126 mmol. After the reaction mixture was flushed with argon for 10 minutes, bis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) was added. The reaction was heated in a microwave oven at 120 ° C for 20 minutes. Diluted with EtOAc (10 mL) and filtered over EtOAc. The compound was purified by Gilson preparative HPLC to give 10 mg of 5-[1-(2-chloroethyl)-1 H -pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4- Piperidinyl]-1 H -indole-7-carboxamide (24%).

取含5-[1-(2-氯乙基)-1H-吡唑-4-基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(20毫克，0.043毫莫耳)、 2-胺基乙醇(26毫克，0.43毫莫耳)與碘化鈉(5毫克，0.022毫莫耳)之四氫呋喃(1毫升)溶液於微波爐中，於130℃下反應2小時。排除四氫呋喃，以EtOAc與水處理混合物，產生水相。分離有機層，排除所有溶劑。混合物經Gilson製備性HPLC純化，產生8毫克標題化合物(31%)。 Containing 5-[1-(2-chloroethyl)-1 H -pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxamide (20 mg, 0.043 mmol), 2-aminoethanol (26 mg, 0.43 mmol) and sodium iodide (5 mg, 0.022 mmol) in tetrahydrofuran (1 mL) The solution was reacted in a microwave oven at 130 ° C for 2 hours. The tetrahydrofuran was removed and the mixture was treated with EtOAc and water to give an aqueous phase. The organic layer was separated and all solvents were removed. The mixture was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 489.2[M+H]滯留時間：1.40分鐘。 LC/MS = m/z 489.2 [M+H].

實例256：5-{1-[2-(丁基胺基)乙基]-1H-吡唑-4-基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 256: 5-{1-[2-(butylamino)ethyl]-1H-pyrazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl] -1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(1-{2-[(2-羥基乙基)胺基]乙基}-1H-吡唑-4-基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用1-丁胺(31毫克，0.43毫莫耳)替代2-胺基乙醇製備，產生7毫克標題化合物(26%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyridyl General procedure for oxazol-4-yl)-1H-indole-7-carboxamide guanamine trifluoroacetate, but instead of 1-butylamine (31 mg, 0.43 mmol) instead of 2-aminoethanol, produced 7 mg of the title compound (26%).

LC/MS=m/z 499.4[M+H]滯留時間：1.39分鐘。 LC/MS = m/z 499.4 [M+H].

實例257：5-{1-[2-(環丁基胺基)乙基]-1H-吡唑-4-基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 257: 5-{1-[2-(Cyclobutylamino)ethyl]-1H-pyrazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl ]-1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(1-{2-[(2-羥基乙基)胺基]乙基}-1H-吡唑-4-基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用環丁胺(31毫克，0.43毫莫耳)替代2-胺基乙醇製備，產生10毫克標題化合物(38%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyridyl General procedure for oxazol-4-yl)-1H-indole-7-carboxamide guanamine trifluoroacetate, but instead of cycloamine (31 mg, 0.43 mmol) instead of 2-aminoethanol, yield 10 Mg title compound (38%).

LC/MS=m/z 501.4[M+H]滯留時間：1.48分鐘。 LC/MS = m/z 501.4 [M+H].

實例258：5-[1-(2-{[2-(二乙基胺基)乙基]胺基}乙基)-1H-吡唑-4-基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 258: 5-[1-(2-{[2-(Diethylamino)ethyl]amino}ethyl)-1H-pyrazol-4-yl]-3-[1-(ethyl Sulfomethyl)-4-piperidinyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(1-{2-[(2-羥基乙基)胺基]乙基}-1H-吡唑-4-基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用N,N-二乙基-1,2-乙二胺(50毫克，0.43毫莫耳)替代2-胺基乙醇製備，產生12毫克標題化合物(42%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyridyl General procedure for oxazol-4-yl)-1H-indole-7-carboxamide guanamine trifluoroacetate, but with N,N-diethyl-1,2-ethanediamine (50 mg, 0.43 mmol) Preparation of 2-aminoethanol in place of 12 mg of the title compound (42%).

LC/MS=m/z 545.2[M+H]滯留時間：1.25分鐘。 LC/MS = m/z 545.2 [M+H]: 1.25 min.

實例259：3-[1-(乙基磺醯基)-4-哌啶基]-5-(1-{2-[(1-甲基乙基)胺基]乙基}-1H-吡唑-4-基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 259: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(1-methylethyl)amino]ethyl}-1H-pyridyl Zin-4-yl)-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(1-{2-[(2-羥基乙基)胺基]乙基}-1H-吡唑-4-基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-丙胺(25毫克，0.43毫莫耳)替代2-胺基乙醇製備，產生9毫克標題化合物(35%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyridyl General procedure for oxazol-4-yl)-1H-indole-7-carboxamide guanamine trifluoroacetate, but prepared by replacing 2-aminoethanol with 2-propylamine (25 mg, 0.43 mmol). Mg title compound (35%).

LC/MS=m/z 487.2[M+H]滯留時間：1.47分鐘。 LC/MS = m/z 487.2 [M+H].

實例260：3-[1-(乙基磺醯基)-4-哌啶基]-5-(1-{2-[(2-甲基丙基)胺基]乙基}-1H-吡唑-4-基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 260: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-methylpropyl)amino]ethyl}-1H-pyridyl Zin-4-yl)-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(1-{2-[(2-羥基乙基)胺基]乙基}-1H-吡唑-4-基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-甲基-1-丙胺(31毫克，0.43毫莫耳)替代2-胺基乙醇製備，產生8毫克標題化合物(30%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyridyl General procedure for oxazol-4-yl)-1H-indole-7-carboxamide guanamine trifluoroacetate, but with 2-methyl-1-propylamine (31 mg, 0.43 mmol) instead of 2-amino Ethanol was prepared to give 8 mg of the title compound (30%).

LC/MS=m/z 501.2[M+H]滯留時間：1.45分鐘 LC/MS=m/z 501.2 [M+H] retention time: 1.45 minutes

實例261：5-(1-{2-[(環戊基甲基)胺基]乙基}-1H-吡唑-4-基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 261: 5-(1-{2-[(Cyclopentylmethyl)amino]ethyl}-1H-pyrazol-4-yl)-3-[1-(ethylsulfonyl)-4 -piperidinyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(1-{2-[(2-羥基乙基)胺基]乙基}-1H-吡唑-4-基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用環戊胺(37毫克，0.43毫莫耳)替代2-胺基乙醇製備，產生11毫克標題化合物(40%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)amino]ethyl}-1H-pyridyl The general procedure for the oxazol-4-yl)-1H-indole-7-carboxamide amine trifluoroacetate, but instead of cyclopentylamine (37 mg, 0.43 mmol) instead of 2-aminoethanol, yields 11 Mg title compound (40%).

LC/MS=m/z 513.4[M+H]滯留時間：1.47分鐘。 LC/MS = m/z 513.4 [M+H].

實例262：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(甲基氧)-3-(1-吡咯啶基甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 262: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[4-(methyloxy)-3-(1-pyrrolidinylmethyl)phenyl]-1H -吲哚-7-carboxyguanamine trifluoroacetate

在含2-(甲基氧)-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯甲醛(610毫克，2.33毫莫耳)之二烷(19毫升)與H2O(6.3毫升)溶液中添加5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(963毫克，2.33毫莫耳)與碳酸鈉(1.48克，13.9毫莫耳)。以氬氣沖刷10分鐘後，添加肆(三苯基膦)鈀(0)(134毫克，0.166毫莫耳)。反應於微波爐中，於120℃下加熱120分鐘。化合物經急驟層析法，使用DCM與MeOH純化，產生632毫克3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-甲醯基-4-(甲基氧)苯基]-1H-吲哚-7-羧醯胺(58%)。 In the presence of 2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (610 mg, 2.33 mmol) Ear) Add 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide to a solution of alkane (19 mL) and H.sub.2 (6.3 mL). 963 mg, 2.33 mmoles with sodium carbonate (1.48 g, 13.9 mmol). After flushing with argon for 10 minutes, hydrazine (triphenylphosphine) palladium (0) (134 mg, 0.166 mmol) was added. The reaction was heated in a microwave oven at 120 ° C for 120 minutes. The compound was purified by flash chromatography using EtOAc EtOAc EtOAc EtOAc Oxy)phenyl]-1 H -indole-7-carboxamide (58%).

取含3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-甲醯基-4-(甲基氧)苯基]-1H-吲哚-7-羧醯胺(50毫克，0.107毫莫耳)、吡咯啶(45微升，0.214毫莫耳)、氯化鋅(10毫克，0.054毫莫耳)與氰基氫硼化鈉(7毫克，0.107毫莫耳)之甲醇(5毫升)溶液於室溫下攪拌2小時。在此混合物中添加0.1當量濃度之氫氧化鈉水溶液(2毫升)。蒸發甲醇。以EtOAc(5毫升)萃取水相3次。有機相經鹽水(5毫升)洗滌2次。排除所有溶劑。混合物經Gilson製備性HPLC純化，產生9毫克標題化合物(13%)。 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-methylindol-4-(methyloxy)phenyl]-1 H -吲哚-7- Carboxylamamine (50 mg, 0.107 mmol), pyrrolidine (45 μL, 0.214 mmol), zinc chloride ( 10 mg, 0.054 mmol) and sodium cyanoborohydride (7 mg, 0.107) A solution of methanol (5 ml) was stirred at room temperature for 2 h. A 0.1 equivalent aqueous sodium hydroxide solution (2 ml) was added to the mixture. Evaporate methanol. The aqueous phase was extracted 3 times with EtOAc (5 mL). The organic phase was washed twice with brine (5 mL). Exclude all solvents. The mixture was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 525.6[M+H]滯留時間：1.67分鐘。 LC/MS = m/z 525.6 [M+H] retention time: 1.67 min.

實例263：5-[3-[(二甲基胺基)甲基]-4-(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 263: 5-[3-[(Dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl] -1H-吲哚-7-carboxyguanamine trifluoroacetate

取含3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-甲醯基-4-(甲基氧)苯基]-1H-吲哚-7-羧醯胺(50毫克，0.214毫莫耳)、二甲基胺(107微升，0.214毫莫耳)、氯化鋅(10毫克，0.054毫莫耳)與氰基氫硼化鈉(7毫克，0.107毫莫耳)之甲醇(5毫升)溶液於室溫下攪拌2小時。在此混合物中添加0.1當量濃度氫氧化鈉水溶液(2毫升)。蒸發甲醇。以EtOAc(5毫升)萃取水相3次。有機相經鹽水(5毫升)洗滌2次。排除所有溶劑。混合物經Gilson製備性HPLC純化，產生4毫克標題化合物(6.1%)。 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-methylindol-4-(methyloxy)phenyl]-1 H -吲哚-7- Carboxylamamine (50 mg, 0.214 mmol), dimethylamine (107 μl, 0.214 mmol), zinc chloride (10 mg, 0.054 mmol) and sodium cyanoborohydride (7 mg) A solution of 0.107 mmol of methanol (5 ml) was stirred at room temperature for 2 hr. To this mixture was added 0.1 equivalent of aqueous sodium hydroxide solution (2 ml). Evaporate methanol. The aqueous phase was extracted 3 times with EtOAc (5 mL). The organic phase was washed twice with brine (5 mL). Exclude all solvents. The mixture was purified by Gilson preparative HPLC to yield 4 mg of the title compound (6.1%).

LC/MS=m/z 499.4[M+H]滯留時間：1.56分鐘。 LC/MS = m/z 499.4 [M+H].

實例264：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(甲基氧)-3-(4-嗎啉基甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 264: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[4-(methyloxy)-3-(4-morpholinylmethyl)phenyl]-1H -吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-[3-[(二甲基胺基)甲基]-4-(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用嗎啉(20微升，0.214毫莫耳)替代二甲基胺製備，產生12毫克標題化合物(17%)。 The title compound is based on 5-[3-[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl The general procedure for -1H-indole-7-carboxamide fluorotrifluoroacetate, but instead of morpholine (20 μl, 0.214 mmol) instead of dimethylamine, yielded 12 mg of the title compound (17%) ).

LC/MS=m/z 541.6[M+H]滯留時間：1.69分鐘。 LC/MS = m/z 541.6 [M+H].

實例265：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-{[(1-甲基乙基)胺基]甲基}-4-(甲基氧)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 265: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-{[(1-methylethyl)amino]methyl}-4-(methyl Oxy)phenyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據5-[3-[(二甲基胺基)甲基]-4-(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-丙胺(15微升，0.214毫莫耳)替代二甲基胺製備，產生16毫克標題化合物(24%)。 The title compound is based on 5-[3-[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl General procedure for -1H-indole-7-carboxamide fluorotrifluoroacetate, but using 2-propylamine ( 15 μL, 0.214 mmol) instead of dimethylamine to give 16 mg of the title compound (24) %).

LC/MS=m/z 513.2[M+H]滯留時間：1.62分鐘。 LC/MS = m/z 513.2 [M+H].

實例266：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-[(甲基胺基)甲基]-4-(甲基氧)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 266: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-[(methylamino)methyl]-4-(methyloxy)phenyl]- 1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-[3-[(二甲基胺基)甲基]-4-(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用甲基胺(50微升，0.214毫莫耳)替代二甲基胺製備，產生10毫克標題化合物(16%)。 The title compound is based on 5-[3-[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl General procedure for -1H-indole-7-carboxamide fluorotrifluoroacetate, but using methylamine (50 μL, 0.214 mmol) instead of dimethylamine to give 10 mg of the title compound (16) %).

LC/MS=m/z 485.2[M+H]滯留時間：1.57分鐘。 LC/MS = m/z 485.2 [M+H].

實例267：5-[3-{[(2,2-二甲基丙基)胺基]甲基}-4-(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 267: 5-[3-{[(2,2-Dimethylpropyl)amino]methyl}-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據5-[3-[(二甲基胺基)甲基]-4-(甲基氧)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2,2-二甲基-1-丙胺(20微升，0.214毫莫耳)替代二甲基胺製備，產生11毫克標題化合物(16%)。 The title compound is based on 5-[3-[(dimethylamino)methyl]-4-(methyloxy)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl General procedure for -1H-indole-7-carboxamide guanamine trifluoroacetate, but instead of 2,2-dimethyl-1-propylamine (20 μL, 0.214 mmol) instead of dimethylamine Yield 11 mg of the title compound (16%).

LC/MS=m/z 541.2[M+H]滯留時間：1.77分鐘。 LC/MS = m/z 541.2 [M+H].

實例268：3-[1-(乙基磺醯基)-4-哌啶基]-5-(1-{2-[(2-羥基乙基)(甲基)胺基]乙基}-1H-吡唑-4-基)-1H-吲哚-7-羧醯胺Example 268: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(1-{2-[(2-hydroxyethyl)(methyl)amino]ethyl}- 1H-pyrazol-4-yl)-1H-indole-7-carboxamide

取含5-[1-(2-氯乙基)-1H -吡唑-4-基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(30毫克，0.065毫莫耳)、2-(甲基胺基)乙醇(500微升，6.5毫莫耳)與碘化鈉(3毫克，0.016毫莫耳)之四氫呋喃(1毫升)溶液於微波爐中，於130℃下反應2小時。操作所得混合物之水相。經Gilson製備性HPLC純化，產生9毫克標題化合物(17%)。 Containing 5-[1-(2-chloroethyl) -1 H -pyrazol-4-yl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-Carboxyguanamine (30 mg, 0.065 mmol), 2-(methylamino)ethanol (500 μl, 6.5 mmol) and sodium iodide (3 mg, 0.016 mmol) A tetrahydrofuran (1 ml) solution was reacted in a microwave oven at 130 ° C for 2 hours. The aqueous phase of the resulting mixture was operated. Purification by Gilson preparative HPLC gave 9 mg of the title compound (17%).

LC/MS=m/z 503.2[M+H]滯留時間：1.40分鐘。 LC/MS = m/z 503.2 [M+H].

實例269：3-[1-(乙基磺醯基)-4-哌啶基]-5-{4-氟-3-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 269: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{4-fluoro-3-[(methylamino)methyl]phenyl}-1H-indole -7-Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-氟-3-甲醯基苯基)-1H-吲哚-7-羧醯胺(16.0毫克，0.035毫莫耳)之二氯甲烷(1毫升)與甲醇(1毫升)溶液中添加2M甲基胺之THF溶液(105微升，0.21毫莫耳)與1滴乙酸。攪拌此混合物3小時。添加四氫硼酸鈉(8.4毫克，0.21毫莫耳)。攪拌混合物1小時。所得混合物濃縮，溶於二甲亞碸(1.5毫升)。經Gilson製備性HPLC純化，產生6.4毫克標題化合物(31.2%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-fluoro-3-carboxyphenyl)-1 H -indole-7-carboxamide A solution of 1 M methylamine in THF (105 μL, 0.21 mmol) and 1 drop of acetic acid was added to a solution of 16.0 mg (0.03 mmol) of dichloromethane (1 mL) and methanol (1 mL). This mixture was stirred for 3 hours. Sodium tetrahydroborate (8.4 mg, 0.21 mmol) was added. The mixture was stirred for 1 hour. The mixture was concentrated and dissolved in dimethyl hydrazine (1.5 mL). Purification by Gilson preparative HPLC gave 6.4 mg of the title compound (31.2%).

LC/MS=m/z 473.4[M+H]滯留時間：1.50分鐘。 LC/MS = m/z 473.4 [M+H].

實例270：5-{3,5-雙[(甲基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 270: 5-{3,5-bis[(methylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole- 7-Carboguanamine trifluoroacetate

在含5-(3,5-二甲醯基苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(10毫克，0.2毫莫耳)之二氯甲烷(1毫升)與甲醇(1毫升)溶液中添加甲基胺(64微升，0.128毫莫耳)與1滴乙酸。於室溫下攪拌所得混合物3小時，添加四氫硼酸鈉(5.1毫克，0.128毫莫耳)。攪拌1小時後，濃縮，經 Gilson製備性HPLC純化，產生3毫克標題化合物(23.4%)。 Containing 5-(3,5-dimethylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (10 Methylamine (64 μL, 0.128 mmol) and 1 drop of acetic acid were added to a solution of methylene chloride (1 mL) and methanol (1 mL). The resulting mixture was stirred at room temperature for 3 hours, and sodium tetrahydroborate (5.1 mg, 0.128 mmol) was added. After stirring for 1 h, it was concentrated and purified with EtOAc EtOAc EtOAc

LC/MS=m/z 498.6[M+H]滯留時間：1.17分鐘。 LC/MS = m/z 498.6 [M+H].

實例271：5-{3-[(乙基胺基)甲基]-4-氟苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 271: 5-{3-[(Ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole -7-Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-氟-3-甲醯基苯基)-1H-吲哚-7-羧醯胺(35毫克，0.076毫莫耳)之二氯甲烷(1毫升)與甲醇(1毫升)溶液中添加2 M乙基胺(230微升，0.46毫莫耳)與1滴乙酸。於室溫下攪拌混合物1小時後，添加四氫呋喃(1毫升)。攪拌混合物30分鐘後，添加四氫硼酸鈉(17.5毫克，0.46毫莫耳)。再攪拌所得混合物1小時，濃縮，經Gilson製備性HPLC純化，產生20毫克標題化合物(43.8%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-fluoro-3-carboxyphenyl)-1 H -indole-7-carboxamide Add 2 M ethylamine (230 μL, 0.46 mmol) and 1 drop of acetic acid to a solution of 35 mg, 0.076 mmol of dichloromethane (1 mL) and methanol (1 mL). After the mixture was stirred at room temperature for 1 hour, tetrahydrofuran (1 ml) was added. After the mixture was stirred for 30 minutes, sodium tetrahydroborate (17.5 mg, 0.46 mmol) was added. The resulting mixture was stirred for additional 1 hr.

LC/MS=m/z 487.4[M+H]滯留時間：1.46分鐘。 LC/MS = m/z 487.4 [M+H].

實例272：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-氟-3-({[2-羥基-1-(羥基甲基)乙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 272: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[4-fluoro-3-({[2-hydroxy-1-(hydroxymethyl)ethyl]amine) Methyl)phenyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據5-{3-[(乙基胺基)甲基]-4-氟苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-胺基-1,3-丙二醇(42毫克，0.46毫莫耳)替代乙基胺製備，產生21毫克標題化合物(42.7%)。 The title compound is based on 5-{3-[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole The general procedure for 哚-7-carboxyguanamine trifluoroacetate, but using 2-amino-1,3-propanediol (42 mg, 0.46 mmol) instead of ethylamine afforded 21 mg of the title compound (42.7 %).

LC/MS=m/z 533.2[M+H]滯留時間：1.39分鐘。 LC/MS = m/z 533.2 [M+H].

實例273：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-氟-3-({[(1S)-2-羥基-1-甲基乙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 273: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[4-fluoro-3-({[(1S)-2-hydroxy-1-methylethyl] Amino}methyl)phenyl]-1H-indole-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-{3-[(乙基胺基)甲基]-4-氟苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(2S)-2-胺基-1-丙醇(37毫克，0.46毫莫耳)替代乙基胺製備，產生26毫克標題化合物(54.2%)。 The title compound is based on 5-{3-[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole General procedure for 哚-7-carboxyguanamine trifluoroacetate, but instead of ( 2S )-2-amino-1-propanol (37 mg, 0.46 mmol) instead of ethylamine, yield 26 mg The title compound (54.2%).

LC/MS=m/z 517.2[M+H]滯留時間：1.44 LC/MS=m/z 517.2 [M+H] retention time: 1.44

實例274：5-{3-[(環丙基胺基)甲基]-4-氟苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 274: 5-{3-[(Cyclopropylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-{3-[(乙基胺基)甲基]-4-氟苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用環丙基胺(32毫克，0.46毫莫耳)替代乙基胺製備，產生23毫克標題化合物(49.4%)。 The title compound is based on 5-{3-[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole The general procedure for the hydrazine-7-carboxylidene trifluoroacetate salt was prepared using propylamine (32 mg, 0.46 mmol) instead of ethylamine to afford the title compound (49.4%).

LC/MS=m/z 499.6[M+H]滯留時間：1.75分鐘。 LC/MS = m/z 499.6 [M+H].

實例275：5-{3-[(環丁基胺基)甲基]-4-氟苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 275: 5-{3-[(Cyclobutylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-{3-[(乙基胺基)甲基]-4-氟苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用環丁胺(39毫克，0.46毫莫耳)替代乙基胺製備，產生20毫克標題化合物(42%)。 The title compound is based on 5- {3-[(ethylamino)methyl]-4-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole The general procedure for the hydrazine-7-carboxamide amide trifluoroacetate was prepared using succinamine (39 mg, 0.46 mmol) instead of ethylamine to afford 20 mg of the title compound (42%).

LC/MS=m/z 513.2[M+H]滯留時間：1.58分鐘。 LC/MS = m/z 513.2 [M+H].

實例276：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(1-吡咯啶基甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 276: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-(1-pyrrolidylmethyl)phenyl]-1H-indole-7-carboxyindole Amine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(33毫克，0.74毫莫耳)之二氯甲烷(0.5毫升)與甲醇(0.5毫升)溶液中添加吡咯啶(32毫克，0.444毫莫耳)與1滴乙酸。攪拌混合物2分鐘後，添加四氫硼酸鈉(17.8毫克，0.444毫莫耳)。攪拌一夜後，濃縮，與經Gilson製備性HPLC純化，產生9.7毫克標題化合物(21.5%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxamide (33 mg, 0.74 Pyrrolidine (32 mg, 0.444 mmol) and 1 drop of acetic acid were added to a solution of dichloromethane (0.5 mL) and methanol (0.5 mL). After the mixture was stirred for 2 minutes, sodium tetrahydroborate (17.8 mg, 0.444 mmol) was added. After stirring overnight, it was concentrated and purified with EtOAc EtOAc.

LC/MS=m/z 495.4[M+H]滯留時間：1.67分鐘。 LC/MS = m/z 495.4 [M+H] retention: 1.67 min.

實例277：5-{3,5-雙[(乙基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 277: 5-{3,5-bis[(ethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole- 7-Carboguanamine trifluoroacetate

在含5-(3,5-二甲醯基苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(27毫克，0.058毫莫耳)之二氯甲烷(1.5毫升)與甲醇(1.5毫升)溶液中添加乙基胺(31.4毫克，0.696毫莫耳)與1滴乙酸。攪拌所得混合物2小時後，添加四氫硼酸鈉(13.2毫克，0.348毫莫耳)。再攪拌50分鐘後，經Gilson製備性HPLC純化，產生20毫克標題化合物(53.9%)。 In the presence of 5-(3,5-dimethylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (27 Add milliethylamine (31.4 mg, 0.696 mmol) to 1 drop of acetic acid in milligrams, 0.058 mmol of dichloromethane (1.5 mL) and methanol (1.5 mL). After the resulting mixture was stirred for 2 hours, sodium tetrahydroborate (13.2 mg, 0.348 mmol) was added. After stirring for an additional 50 minutes, it was purified by EtOAc EtOAc.

LC/MS=m/z 526.6[M+H]滯留時間：1.41分鐘。 LC/MS = m/z 526.6 [M+H].

實例278：5-{3,5-雙[(二甲基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 278: 5-{3,5-bis[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole -7-Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基-5-氫硫基苯基)-1H-吲哚-7-羧醯胺(34毫克，0.058毫莫耳)之二氯甲烷(1.5毫升)與甲醇(1.5毫升)溶液中添加二甲基胺(31.4毫克，0.696毫莫耳)與一滴乙酸。所得混合物於室溫下攪拌2小時後，添加四氫硼酸鈉(13.2毫克，0.348毫莫耳)。再攪拌30分鐘後，經Gilson製備性HPLC純化，產生11毫克標題化合物(29.6%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylindolyl-5-hydroxythiophenyl)-1 H -indole-7-carboxyindole A solution of the amine (34 mg, 0.058 mmol) in dichloromethane (1.5 mL) and methanol ( 1.5 mL) was then taken from dimethylamine (31.4 mg, 0.696 m. After the resulting mixture was stirred at room temperature for 2 hours, sodium tetrahydroborate (13.2 mg, 0.348 mmol) was added. After stirring for an additional 30 minutes, it was purified by EtOAc EtOAc.

LC/MS=m/z 526.6[M+H]滯留時間：1.27分鐘。 LC/MS = m/z 526.6 [M+H].

實例279：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(2-哌啶基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 279: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperidinyl)phenyl]-1H-indole-7-carboxyguanamine III Fluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(46毫克，0.1毫莫耳)之二烷(2毫升)與H₂O(0.7毫升)溶液中添加2-(3-氯苯基)哌啶(46毫克，0.2毫莫耳)。添加碳酸鉀(55毫克，0.4毫莫耳)，脫氣5分鐘後，添加肆(三苯基膦)鈀(0)(5毫克，0.5毫莫耳)。所得混合物於300W CEM微波爐中，於160℃下反應30分鐘，然後濾出固體。蒸發溶劑，溶液經Gilson製備性HPLC純化，產生13.2毫克標題化合物(21.7%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -吲哚-7-carboxyguanamine (46 mg, 0.1 mmol) Dioxane (2 mL) and H ₂ O (0.7 mL) was added 2- (3-chlorophenyl) solution of piperidine (46 mg, 0.2 mmol). Potassium carbonate (55 mg, 0.4 mmol) was added, and after degassing for 5 minutes, hydrazine (triphenylphosphine) palladium (0) (5 mg, 0.5 mmol) was added. The resulting mixture was reacted in a 300 W CEM microwave oven at 160 ° C for 30 minutes, and then the solid was filtered off. The solvent was evaporated and the solution was purified mjjjjjjjj

LC/MS=m/z 495.4[M+H]滯留時間：1.76 LC/MS=m/z 495.4 [M+H] retention time: 1.76

實例280：5-{3-[1-(乙基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 280: 5-{3-[1-(Ethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7 -Carboguanamine trifluoroacetate

取含5-(3-乙醯基苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)、乙基胺(19.9毫克，0.441毫莫耳)與氰基氫硼化鈉(30毫克，0.441毫莫耳)之N,N-二甲基甲醯胺(0.8毫升)與乙酸(0.2毫升)溶液於微波爐中，於150℃下反應20分鐘。反應經Gilson製備性HPLC純化，產生20.6毫克標題化合物(39%)。 5-(3-Ethylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (50 mg, 0.11) M, ethylamine (19.9 mg, 0.441 mmol) and sodium cyanoborohydride (30 mg, 0.441 mmol) of N,N-dimethylformamide (0.8 mL) and acetic acid The solution (0.2 ml) was reacted in a microwave oven at 150 ° C for 20 minutes. The reaction was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 483.2[M+H]滯留時間：1.67 LC/MS=m/z 483.2 [M+H] retention time: 1.67

實例281：5-{3-[1-(二甲基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 281: 5-{3-[1-(Dimethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole- 7-Carboguanamine trifluoroacetate

取5-(3-乙醯基苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)、二甲基胺(220微升，0.44毫莫耳)與氰基氫硼化鈉(30毫克，0.44毫莫耳)溶於N,N-二甲基甲醯胺(400微升)與乙酸(100微升)。所得混合物於Smith 150 W微波爐中，於150℃下反應20分鐘。反應經Gilson製備性HPLC純化，產生14.6毫克標題化合物(22.2%)。 5-(3-Ethylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (50 mg, 0.11 mM) Mole), dimethylamine (220 μl, 0.44 mmol) and sodium cyanoborohydride (30 mg, 0.44 mmol) dissolved in N,N-dimethylformamide (400 μl) ) with acetic acid (100 μl). The resulting mixture was reacted in a Smith 150 W microwave oven at 150 ° C for 20 minutes. The reaction was purified by Gilson preparative HPLC to yield 14.4 mg of the title compound (22.2%).

LC/MS=m/z 483.2[M+H]滯留時間：1.63 LC/MS=m/z 483.2 [M+H] retention time: 1.63

實例282：3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 282: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole -7-Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-甲醯基苯基)-1H-吲哚-7-羧醯胺(32毫克，0.07毫莫耳)之二氯甲烷(1.5毫升)與甲醇(1.5毫升)溶液中添加2 M甲基胺之THF溶液(210微升，0.42毫莫耳)與1滴乙酸。所得混合物於室溫下攪拌3小時後，添加四氫硼酸鈉(15毫克，0.42毫莫耳)。攪拌此混合物1小時後，濃縮，經Gilson製備性HPLC純化，產生30毫克標題化合物(73.1%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-methylindenylphenyl)-1 H -indole-7-carboxamide A solution of 2 M methylamine in THF (210 μL, 0.42 mmol) and 1 drop of acetic acid was added to a solution of dichloromethane (1.5 mL) and methanol (1.5 mL). After the resulting mixture was stirred at room temperature for 3 hours, sodium tetrahydroborate (15 mg, 0.42 mmol) was added. After stirring the mixture for 1 hour, it was concentrated and purified mjjjjjjj

LC/MS=m/z 473.6[M+H]滯留時間：1.73分鐘。 LC/MS = m/z 473.6 [M+H].

實例283：5-{3-[(乙基胺基)甲基]-5-氟苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 283: 5-{3-[(Ethylamino)methyl]-5-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole -7-Carboguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2 M乙胺之THF溶液(210微升，0.42毫莫耳)替代甲胺製備，產生6.5毫克標題化合物(15.5%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole The general procedure for 哚-7-carboxylidene trifluoroacetate, but instead of 2M ethylamine in THF (210 [mu]L, 0.42 m.m.), was taken to yield 6.5 mg of the title compound (15.5%).

LC/MS=m/z 487.4[M+H]滯留時間：1.64分鐘。 LC/MS = m/z 487.4 [M+H].

實例284：3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-氟-5-[(丙基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 284: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(propylamino)methyl]phenyl}-1H-indole -7-Carboguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用丙基胺(21毫克，0.42毫莫耳)替代甲胺製備，產生31毫克標題化合物(72%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole The general procedure for 哚-7-carboxylamidine trifluoroacetate, but propylamine (21 mg, 0.42 mmol) was used instead of methylamine to afford 31 mg of the title compound (72%).

LC/MS=m/z 501.4[M+H]滯留時間：1.54 LC/MS=m/z 501.4 [M+H] retention time: 1.54

實例285：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-{[(1-甲基乙基)胺基1甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 285: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(1-methylethyl)amino 1methyl}phenyl )-1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-丙胺(21毫克，0.42毫莫耳)替代甲胺製備，產生28.5毫克標題化合物(66.2%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole The general procedure for the hydrazine-7-carboxamide amine trifluoroacetate, but using 2-propylamine (21 mg, 0.42 mmol) instead of methylamine afforded 28.5 mg of the title compound (66.2%).

LC/MS=m/z 501.4[M+H]滯留時間：1.53分鐘。 LC/MS = m/z 501.4 [M+H].

實例286：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-{[(2-甲基丙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 286: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-methylpropyl)amino]methyl}phenyl )-1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-甲基-1-丙胺(21毫克，0.42毫莫耳)替代甲胺製備，產生10毫克標題化合物(22.7%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole The general procedure for the hydrazine-7-carboxamide amine trifluoroacetate, but using 2-methyl-1-propylamine (21 mg, 0.42 mmol) instead of methylamine afforded 10 mg of the title compound (22.7%).

LC/MS=m/z 515.4[M+H]滯留時間：1.72分鐘。 LC/MS = m/z 515.4 [M+H].

實例287：5-{3-[(環丁基胺基)甲基]-5-氟苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 287: 5-{3-[(Cyclobutylamino)methyl]-5-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用環丁基胺(21.5毫克，0.42毫莫耳)替代甲胺製備，產生33毫克標題化合物(75.2%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole The general procedure for the hydrazine-7-carboxamide amine trifluoroacetate, but instead of cyclobutylamine (21.5 mg, 0.42 mmol), was used instead of methylamine to afford the title compound (75.2%).

LC/MS=m/z 513.2[M+H]滯留時間：1.50分鐘。 LC/MS = m/z 513.2 [M+H].

實例288：5-{3-[(二甲基胺基)甲基]-5-氟苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 288: 5-{3-[(Dimethylamino)methyl]-5-fluorophenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2M二甲基胺之THF溶液(210微升，0.42毫莫耳)替代甲胺製備，產生33.7毫克標題化合物(80.2%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole General procedure for 哚-7-carboxyguanamine trifluoroacetate, but instead of 2M dimethylamine in THF (210 μL, 0.42 mmol) instead of methylamine to give 33.7 mg of the title compound (80.2%) .

LC/MS=m/z 487.2[M+H]滯留時間：1.43分鐘。 LC/MS = m/z 487.2 [M+H].

實例289：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-(1-吡咯啶基甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 289: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-(1-pyrrolidinylmethyl)phenyl]-1H-indole- 7-Carboguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用吡咯啶(20.4毫克，0.42毫莫耳)替代甲胺製備，產生18毫克標題化合物(41%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole The general procedure for 哚-7-carboxyguanamine trifluoroacetate, but using pyrrolidine (20.4 mg, 0.42 mmol) instead of methylamine afforded 18 mg of the title compound (41%).

LC/MS=m/z 513.4[M+H]滯留時間：1.63分鐘。 LC/MS = m/z 513.4 [M+H] retention time: 1.63 min.

實例290：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-(4-嗎啉基甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 290: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-(4-morpholinylmethyl)phenyl]-1H-indole- 7-Carboguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用嗎啉(22毫克，0.42毫莫耳)替代甲胺製備，產生22.9毫克標題化合物(50.9%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole The general procedure for 哚-7-carboxyguanamine trifluoroacetate, but morpholine (22 mg, 0.42 mmol) was used instead of methylamine to give 22.9 mg of the title compound (50.9%).

LC/MS=m/z 529.4[M+H]滯留時間：1.47分鐘。 LC/MS = m/z 529.4 [M+H].

實例291：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-(1-哌啶基甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 291: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-(1-piperidinylmethyl)phenyl]-1H-indole- 7-Carboguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用哌啶(22毫克，0.42毫莫耳)替代甲胺製備，產生13.4毫克標題化合物(29.9%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole The general procedure for 哚-7-carboxylamidine trifluoroacetate, but using piperidine (22 mg, 0.42 mmol) instead of methylamine afforded 13.4 mg of the title compound (29.9%).

LC/MS=m/z 527.6[M+H]滯留時間：1.62 LC/MS=m/z 527.6 [M+H] retention time: 1.62

實例292：3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[1-(甲基胺基)乙基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 292: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{3-[1-(methylamino)ethyl]phenyl}-1H-indole-7 -Carboguanamine trifluoroacetate

在含5-(3-乙醯基苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(20毫克，0.044毫莫耳)之乙醇溶液中添加甲基胺鹽酸鹽與1滴濃鹽酸。混合物於CEM微波爐中，於100℃下反應10分鐘後，添加四氫硼酸鈉。所得混合物於CEM微波爐中，於50℃下反應5分鐘後，蒸發所有溶劑。再溶於二甲亞碸後，經Gilson製備性HPLC純化，產生16.5毫克標題化合物(64.4%)。 5-(3-Ethylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (20 mg, 0.044) To the ethanol solution of millimolar), methylamine hydrochloride and 1 drop of concentrated hydrochloric acid were added. The mixture was reacted in a CEM microwave oven at 100 ° C for 10 minutes, and then sodium tetrahydroborate was added. The resulting mixture was reacted in a CEM microwave oven at 50 ° C for 5 minutes, and then all the solvent was evaporated. Re-dissolved in dimethyl hydrazine and purified by Gilson preparative HPLC to yield 16.5 mg of the title compound (64.4%).

LC/MS=m/z 469.4[M+H]滯留時間：1.45分鐘。 LC/MS = m/z 469.4 [M+H].

實例293：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{1-[(1-甲基乙基)胺基]乙基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 293: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(1-methylethyl)amino]ethyl}phenyl)- 1H-吲哚-7-carboxyguanamine trifluoroacetate

在含5-(3-乙醯基苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(20毫克，0.044毫莫耳)之N,N-二甲基甲醯胺(0.8毫升)與乙酸(0.2毫升)溶液中添加2-丙胺(75微升，0.88毫莫耳)與氰基氫硼化鈉(6毫克，0.09毫莫耳)。所得混合物於Smith微波爐中，於70℃下反應1小時。濾出固體後，經Gilson製備性HPLC純化，產生19.4毫克標題化合物(72.2%)。 5-(3-Ethylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (20 mg, 0.044) To a solution of N,N-dimethylformamide (0.8 ml) and acetic acid (0.2 ml), 2-propylamine (75 μL, 0.88 mmol) and sodium cyanoborohydride (6) Mg, 0.09 millimoles). The resulting mixture was reacted in a Smith microwave oven at 70 ° C for 1 hour. After the solid was filtered, purified by EtOAc EtOAc EtOAc.

LC/MS=m/z 497.4[M+H]滯留時間：1.44分鐘。 LC/MS = m/z 497.4 [M+H].

實例294：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{1-[(2-甲基丙基)胺基]乙基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 294: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(2-methylpropyl)amino]ethyl}phenyl)- 1H-吲哚-7-carboxyguanamine trifluoroacetate

在含5-(3-乙醯基苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(30毫克，0.066毫莫耳)之乙醇(1.2毫升)與乙酸(0.3毫升)溶液中添加(2-甲基丙基)胺(101毫克，1.98毫莫耳)與氰基氫硼化鈉(13.5毫克，0.198毫莫耳)。所得混合物於Smith微波爐中，於70℃下反應1小時。蒸發所有溶劑。使用二甲亞碸溶解固體。然後經Gilson製備性HPLC純化，產生22.7毫克標題化合物(55.1%)。 5-(3-Ethylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (30 mg, 0.066) (2-Methylpropyl)amine (101 mg, 1.98 mmol) and sodium cyanoborohydride (13.5 mg, 0.198 m) were added to a solution of ethanol (1.2 mL) and acetic acid (0.3 mL). Moore). The resulting mixture was reacted in a Smith microwave oven at 70 ° C for 1 hour. Evaporate all solvents. The solid was dissolved using dimethyl hydrazine. Purification by Gilson preparative HPLC gave 22.7 mg of the title compound (55.1%).

LC/MS=m/z 511.2[M+H]滯留時間：1.52分鐘。 LC/MS = m/z 511.2 [M+H].

實例295：5-{3-[1-(環丁基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 295: 5-{3-[1-(Cyclobutylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole- 7-Carboguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{1-[(2-甲基丙基)胺基]乙基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用環丁基胺(101毫克，1.98毫莫耳)替代(2-甲基丙基)胺製備，產生29.1毫克標題化合物(70.8%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(2-methylpropyl)amino]ethyl}phenyl) -1H-吲哚-7-carboxamide guanamine trifluoroacetate, but using cyclobutylamine (101 mg, 1.98 mmol) instead of (2-methylpropyl)amine, yielding 29.1 mg The title compound (70.8%).

LC/MS=m/z 509.4[M+H]滯留時間：1.52分鐘。 LC/MS = m/z 509.4 [M+H].

實例296：3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[1-(1-吡咯啶基)乙基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 296: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{3-[1-(1-pyrrolidinyl)ethyl]phenyl}-1H-indole- 7-Carboguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{1-[(2-甲基丙基)胺基]乙基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用吡咯啶(101毫克，1.98毫莫耳)替代(2-甲基丙基)胺製備，產生29.2毫克標題化合物(71%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{1-[(2-methylpropyl)amino]ethyl}phenyl) -1H-indole-7-carboxamide amine trifluoroacetate, but using pyrrolidine (101 mg, 1.98 mmol) instead of (2-methylpropyl)amine to give 29.2 mg of the title compound (71%).

LC/MS=m/z 509.4[M+H]滯留時間：1.49分鐘。 LC/MS = m/z 509.4 [M+H].

實例297：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(3-硫嗎啉基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 297: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-(3-thiomorpholinyl)phenyl]-1H-indole-7-carboxamide Trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(60毫克，0.13毫莫耳)之二烷(1.5毫升)與水(0.5毫升)溶液中添加3-(3-氯苯基)硫嗎啉(84毫克，0.39毫莫耳)與碳酸鉀(107.6毫克，0.78毫莫耳)。此混合物脫氣5分鐘後，添加肆(三苯基膦)鈀(0)(14.0毫克，0.013毫莫耳)。所得混合物於微波爐中，於160℃下反應30分鐘。濾出固體，蒸發所有溶劑。所得溶液再溶於二氯甲烷，使用分離器排除水。混合物濃縮，產生有機溶劑後，經Gilson製備性HPLC純化，產生7.4毫克標題化合物(11%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (60 mg, 0.13 mmol) 3-(3-Chlorophenyl)thiomorpholine (84 mg, 0.39 mmol) and potassium carbonate (107.6 mg, 0.78 mmol) were added to a solution of hexane (1.5 mL) and water (0.5 mL). After the mixture was degassed for 5 minutes, hydrazine (triphenylphosphine)palladium(0) (14.0 mg, 0.013 mmol) was added. The resulting mixture was reacted in a microwave oven at 160 ° C for 30 minutes. The solid was filtered off and all solvents were evaporated. The resulting solution was redissolved in dichloromethane and the separator was used to remove water. The mixture was concentrated to give EtOAc (EtOAc):

LC/MS=m/z 513.4[M+H]滯留時間：1.54 LC/MS=m/z 513.4 [M+H] retention time: 1.54

實例298：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(2-哌 基)-2-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽 Example 298: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(2-piperidin Benzyl-2-thiophenyl]-1H-indole-7-carboxamide fluorotrifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(60毫克，0.13毫莫耳)之二烷(1.5毫升)與水(0.5毫升)溶液中添加2-(5-溴-2-噻吩基)哌(102毫克，0.39毫莫耳)與碳酸鉀(108毫克，0.78毫莫耳)。此混合物脫氣5分鐘後，添加肆(三苯基膦)鈀(0)(15.0毫克，0.013毫莫耳)。所得混合物於微波爐中，於160℃下反應30分鐘。濾出固體，排除所有溶劑。所得溶液再溶於二氯甲烷，使用分離器排除水。混合物濃縮，產生有機溶劑後，經Gilson製備性HPLC純化，產生29.1毫克標題化合物(36.4%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (60 mg, 0.13 mmol) Add 2-(5-bromo-2-thienyl)peridine to a solution of alkane (1.5 ml) and water (0.5 ml) (102 mg, 0.39 mmol) with potassium carbonate (108 mg, 0.78 mmol). After the mixture was degassed for 5 minutes, hydrazine (triphenylphosphine)palladium(0) (15.0 mg, 0.013 mmol) was added. The resulting mixture was reacted in a microwave oven at 160 ° C for 30 minutes. The solid was filtered off and all solvents were removed. The resulting solution was redissolved in dichloromethane and the separator was used to remove water. The mixture was concentrated to give EtOAc (EtOAc).

LC/MS=m/z 502.4[M+H]滯留時間：1.31 LC/MS=m/z 502.4 [M+H] retention time: 1.31

實例299：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(2-哌 基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽 Example 299: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(2-piperidin Phenyl]-1H-indole-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(2-哌基)-2-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-(4-溴苯基)哌(94毫克，0.39毫莫耳)替代 2-(5-溴-2-噻吩基)哌製備，產生20.5毫克標題化合物(25.9%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(2-piperidin) General procedure for the formation of 2-(4-phenylphenyl)-1H-indole-7-carboxamideamine trifluoroacetate, but with 2-(4-bromophenyl)per (94 mg, 0.39 mmol) instead of 2-(5-bromo-2-thienyl)per Prepared to give 20.5 mg of the title compound (25.9%).

LC/MS=m/z 496.4[M+H]滯留時間：1.25 LC/MS=m/z 496.4 [M+H] retention time: 1.25

實例300：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(2-哌 基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽 Example 300: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperidin Phenyl]-1H-indole-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(60毫克，0.13毫莫耳)之二烷(1.5毫升)與水(0.5毫升)溶液中添加2-(3-氯苯基)哌(63.7毫克，0.325毫莫耳)與碳酸鉀(90毫克，0.650毫莫耳)。此混合物脫氣5分鐘後，添加肆(三苯基膦)鈀(0)(12毫克，0.011毫莫耳)。所得混合物於微波爐中，於160℃下反應30分鐘。濾出固體，排除所有溶劑。所得溶液再溶於二氯甲烷，使用分離器排除水。混合物濃縮，產生有機溶劑後，經Gilson製備性HPLC純化，產生21.7毫克標題化合物(27.4%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (60 mg, 0.13 mmol) Add 2-(3-chlorophenyl)peridine to a solution of alkane (1.5 ml) and water (0.5 ml) (63.7 mg, 0.325 mmol) with potassium carbonate (90 mg, 0.650 mmol). After the mixture was degassed for 5 minutes, hydrazine (triphenylphosphine)palladium(0) (12 mg, 0.011 mmol) was added. The resulting mixture was reacted in a microwave oven at 160 ° C for 30 minutes. The solid was filtered off and all solvents were removed. The resulting solution was redissolved in dichloromethane and the separator was used to remove water. The mixture was concentrated to give EtOAc (EtOAc).

LC/MS=m/z 496.4[M+H]滯留時間：1.28分鐘。 LC/MS = m/z 496.4 [M+H].

實例301：3-[1-(乙基磺醯基)-4-哌啶基]-5-[6-(4-嗎啉基)-3-嗒 基]-1H-吲哚-7-羧醯胺三氟乙酸鹽 Example 301: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[6-(4-morpholinyl)-3-indole ]]-1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(2-哌基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用4-(6-氯-3-嗒基)嗎啉(65毫克，0.325毫莫耳)替代2-(3-氯苯基)哌製備，產生3.1毫克標題化合物(3.9%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperidin) General procedure for the phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but with 4-(6-chloro-3-indole) Substituted morpholine (65 mg, 0.325 mmol) instead of 2-(3-chlorophenyl)per Prepared to give 3.1 mg of the title compound (3.9%).

LC/MS=m/z 499.6[M+H]滯留時間：1.57分鐘。 LC/MS = m/z 499.6 [M+H].

實例302：3-[1-(乙基磺醯基)-4-哌啶基]-5-[6-(1-吡咯啶基)-3-嗒 基]-1H-吲哚-7-羧醯胺三氟乙酸鹽 Example 302: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[6-(1-pyrrolidinyl)-3-indole ]]-1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(2-哌基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用3-氯-6-(1-吡咯啶基)嗒(60毫克，0.325毫莫耳)替代2-(3-氯苯基)哌製備，產生4.1毫克標題化合物(5.3%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperidin) The general procedure for the phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but the use of 3-chloro-6-(1-pyrrolidinyl) hydrazine (60 mg, 0.325 mmol) instead of 2-(3-chlorophenyl)per Prepared to give 4.1 mg of the title compound (5.3%).

LC/MS=m/z 483.2[M+H]滯留時間：1.44分鐘。 LC/MS = m/z 483.2 [M+H].

實例303：3-[1-(乙基磺醯基)-4-哌啶基]-5-{2-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 303: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{2-[(methylamino)methyl]phenyl}-1H-indole-7-carboxylate Guanidine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(2-哌基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用1-(2-溴苯基)-N-甲基甲胺(65毫克，0.325毫莫耳)替代2-(3-氯苯基)哌製備，產生14.6毫克標題化合物(19.8%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-piperidin) The general procedure for the phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but using 1-(2-bromophenyl) -N -methylmethylamine (65 mg, 0.325 mmol) Ear) replacing 2-(3-chlorophenyl)per Prepared to give 14.6 mg of the title compound (19.8%).

LC/MS=m/z 455.0[M+H]滯留時間：1.57分鐘。 LC/MS = m/z 455.0 [M+H].

實例304：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-噻吩基甲基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 304: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-1H-吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(44毫克，0.1毫莫耳)之二氯甲烷(2毫升)與甲醇(2毫升)溶液中添加1-(2-噻吩基)甲胺(33.6毫克，0.6毫莫耳)與1滴乙酸。攪拌此混合物2小時後，添加四氫硼酸鈉(22.8毫克，0.6毫莫耳)。所得混合物攪拌1小時後，濃縮，再溶於二甲亞碸(3毫升)。然後經Gilson製備性HPLC純化，產生41.7毫克標題化合物(74.5%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -indole-7-carboxamide (44 mg, 0.1 To a solution of dichloromethane (2 ml) and methanol (2 ml) was added 1-(2-thienyl)methylamine (33.6 mg, 0.6 mmol) with 1 drop of acetic acid. After stirring the mixture for 2 hours, sodium tetrahydroborate (22.8 mg, 0.6 mmol) was added. The mixture was stirred for 1 hour, then concentrated and evaporated over EtOAc EtOAc. Purification by Gilson preparative HPLC gave 41.7 mg of the title compound (74.5%).

LC/MS=m/z 537.2[M+H]滯留時間：1.81分鐘。 LC/MS = m/z 537.2 [M+H].

實例305：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(5-甲基-2-呋喃基)甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 305: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(5-methyl-2-furyl)methyl]amino}methyl) Phenyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-噻吩基甲基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用1-(5-甲基-2-呋喃基)甲胺(32毫克，0.6毫莫耳)替代1-(2-噻吩基)甲胺製備，產生29.3毫克標題化合物(54.7%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-1H -General procedure for 吲哚-7-carboxamide guanamine trifluoroacetate, but instead of 1-(5-methyl-2-furyl)methylamine (32 mg, 0.6 mM) instead of 1-(2- Preparation of thienyl)methylamine gave 29.3 mg of the title compound (54.7%).

LC/MS=m/z 535.2[M+H]滯留時間：1.74分鐘。 LC/MS = m/z 535.2 [M+H].

實例306：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(2R)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 306: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2R)-tetrahydro-2-furanylmethyl]amino}methyl) Phenyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-噻吩基甲基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用1-[(2R)-四氫-2-呋喃基]甲胺(31.5毫克，0.6毫莫耳)替代1-(2-噻吩基)甲胺製備，產生36.9毫克標題化合物(70.3%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-1H - General procedure for 吲哚-7-carboxyguanamine trifluoroacetate, but instead of 1-[(2R)-tetrahydro-2-furanyl]methylamine (31.5 mg, 0.6 mmol) instead of 1-( Preparation of 2-thienyl)methylamine gave 36.9 mg of the title compound (70.3%).

LC/MS=m/z 525.6[M+H]滯留時間：1.63分鐘。 LC/MS = m/z 525.6 [M+H].

實例307：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 307: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl) Phenyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-噻吩基甲基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用1-[(2S)-四氫-2-呋喃基]甲胺(31.5毫克，0.6毫莫耳)替代1-(2-噻吩基)甲胺製備，產生39.2毫克標題化合物(74.7%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-1H - General procedure for 吲哚-7-carboxyguanamine trifluoroacetate, but instead of 1-[(2S)-tetrahydro-2-furanyl]methylamine (31.5 mg, 0.6 mmol) instead of 1-( Preparation of 2-thienyl)methylamine gave 39.2 mg of the title compound (74.7%).

LC/MS=m/z 525.6[M+H]滯留時間：1.61分鐘。 LC/MS = m/z 525.6 [M+H] retention: 1.61 min.

實例308：5-(3-{[(2,2-二甲基丙基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 308: 5-(3-{[(2,2-Dimethylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl] -1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-噻吩基甲基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2,2-二甲基-1-丙胺(30.6毫克，0.6毫莫耳)替代1-(2-噻吩基)甲胺製備，產生30.4毫克標題化合物(59.5%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylmethyl)amino]methyl}phenyl)-1H -General procedure for 吲哚-7-carboxamide guanamine trifluoroacetate, but instead of 2,2-dimethyl-1-propylamine (30.6 mg, 0.6 mM) instead of 1-(2-thienyl) The amine was prepared to give 30.4 mg of the title compound (59.5%).

LC/MS=m/z 511.4[M+H]滯留時間：1.69分鐘。 LC/MS = m/z 511.4 [M+H].

實例309：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-甲基丁基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺Example 309: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylbutyl)amino]methyl}phenyl)-1H-吲哚-7-carboxyguanamine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(44毫克，0.1毫莫耳)之二氯甲烷(2毫升)與甲醇(1毫升)溶液中添加2-甲基-1-丁胺(52毫克，0.6毫莫耳)與1滴乙酸。攪拌此混合物2小時後，添加四氫硼酸鈉(22.8毫克，0.6毫莫耳)。所得混合物攪拌1小時後，濃縮，再溶於二甲亞碸(3毫升)。然後經Gilson製備性HPLC純化，產生28.4毫克標題化合物(55.6%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -indole-7-carboxamide (44 mg, 0.1 To a solution of dichloromethane (2 mL) and methanol (1 mL) was added 2-methyl-1-butylamine (52 mg, 0.6 mmol) and 1 drop of acetic acid. After stirring the mixture for 2 hours, sodium tetrahydroborate (22.8 mg, 0.6 mmol) was added. The mixture was stirred for 1 hour, then concentrated and evaporated over EtOAc EtOAc. Purification by Gilson preparative HPLC gave 28.4 mg of the title compound (55.6%).

LC/MS=m/z 511.4[M+H]滯留時間：1.71 LC/MS=m/z 511.4 [M+H] retention time: 1.71

實例310：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(2S)-2-甲基丁基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺Example 310: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-({[(2S)-2-methylbutyl]amino}methyl)phenyl) ]-1H-吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-甲基丁基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺之一般製程，但改用(2S)-2-甲基-1-丁胺(52毫克，0.6毫莫耳)替代2-甲基-1-丁胺製備，產生30毫克標題化合物(58.7%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylbutyl)amino]methyl}phenyl)-1H -吲哚-7-carboxyguanamine general system This was prepared by substituting (2S)-2-methyl-1-butylamine (52 mg, 0.6 mmol) for 2-methyl-1-butylamine to give 30 mg of the title compound (58.7%).

LC/MS=m/z 511.4[M+H]滯留時間：1.68 LC/MS=m/z 511.4 [M+H] retention time: 1.68

實例311：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(1R)-1,2,2-三甲基丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺Example 311: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1R)-1,2,2-trimethylpropyl]amino} Methyl)phenyl]-1H-indole-7-carboxamide

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-甲基丁基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺之一般製程，但改用(2R)-3,3-二甲基-2-丁胺(60毫克，0.6毫莫耳)替代2-甲基-1-丁胺製備，產生24.5毫克標題化合物(46.7%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylbutyl)amino]methyl}phenyl)-1H - 吲哚-7-carboxyguanamine general process, but instead (2R)-3,3-dimethyl-2-butylamine (60 mg, 0.6 mmol) instead of 2-methyl-1-butyl The amine was prepared to give 24.5 mg of the title compound (46.7%).

LC/MS=m/z 525.6[M+H]滯留時間：1.67 LC/MS=m/z 525.6 [M+H] retention time: 1.67

實例312：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 312: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amine) Methyl)phenyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-甲醯基苯基)-1H-吲哚-7-羧醯胺(40毫克，0.087毫莫耳)之二氯甲烷(2毫升)與甲烷(1毫升)溶液中添加1-[(2S)-四氫-2-呋喃基]甲胺(53毫克，0.525毫莫耳)與2滴乙酸。於室溫下攪拌所得混合物2小時後，添加四氫硼酸鈉(20毫克，0.525毫莫耳)。攪拌此混合物30分鐘後，濃縮與經Gilson製備性HPLC純化，產生26.6毫克標題化合物(46.6%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-methylindenylphenyl)-1 H -indole-7-carboxamide Add 1-[(2S)-tetrahydro-2-furanyl]methylamine (53 mg, 0.525 mmol) to a solution of 40 mg (0.07 mmol) of dichloromethane (2 mL) and methane (1 mL) ) with 2 drops of acetic acid. After the resulting mixture was stirred at room temperature for 2 hours, sodium tetrahydroborate (20 mg, 0.525 mmol) was added. After stirring the mixture for 30 minutes, it was concentrated and purified with EtOAc EtOAc.

LC/MS=m/z 543.4[M+H]滯留時間：1.60分鐘。 LC/MS = m/z 543.4 [M+H]: s.

實例313：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2R)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 313: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2R)-tetrahydro-2-furanylmethyl]amine) Methyl)phenyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用1-[(2R)-四氫-2-呋喃基]甲胺(53毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生27.1毫克標題化合物(47.4%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] General procedure for amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but with 1-[(2R)-tetrahydro-2-furanyl]methylamine (53) Preparation of the compound of the title compound (47.4%).

LC/MS=m/z 543.4[M+H]滯留時間：1.58分鐘。 LC/MS = m/z 543.4 [M+H].

實例314：5-[3-({[(1S)-1,2-二甲基丙基]胺基}甲基)-5-氟苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 314: 5-[3-({[(1S)-1,2-dimethylpropyl]amino}methyl)-5-fluorophenyl]-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1H-indole-7-carboxamide

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(2S)-3-甲基-2-丁胺(45毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生19.3毫克標題化合物(42%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] The general procedure for the amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but with (2S)-3-methyl-2-butylamine (45 mg, 0.525 m) Preparation of 1 -[(2S)-tetrahydro-2-furanyl]methylamine afforded 19.3 mg of the title compound (42%).

LC/MS=m/z 529.6[M+H]滯留時間：1.65 LC/MS=m/z 529.6 [M+H] retention time: 1.65

實例315：5-[3-({[(1R)-1,2-二甲基丙基]胺基}甲基)-5-氟苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 315: 5-[3-({[(1R)-1,2-dimethylpropyl]amino}methyl)-5-fluorophenyl]-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(2R)-3-甲基-2-丁胺(45毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生19.5毫克標題化合物(34.9%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] The general procedure for the amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but with (2R)-3-methyl-2-butylamine (45 mg, 0.525 m) The preparation of the title compound (34.9%) was obtained by substituting 1-[(2S)-tetrahydro-2-furanyl]methylamine.

LC/MS=m/z 529.4[M+H]滯留時間：1.82分鐘。 LC/MS = m/z 529.4 [M+H].

實例316：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-{[(1-甲基丙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 316: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(1-methylpropyl)amino]methyl}phenyl )-1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-丁胺(37毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生27.7毫克標題化合物(50.6%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] The general procedure for the amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but instead of 2-butamine (37 mg, 0.525 mmol) instead of 1-[(2S) Preparation of -tetrahydro-2-furanyl]methylamine gave 27.7 mg of the title compound (50.6%).

LC/MS=m/z 515.4[M+H]滯留時間：1.63分鐘。 LC/MS = m/z 515.4 [M+H].

實例317：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(1S)-1,2,2-三甲基丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 317: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(1S)-1,2,2-trimethylpropyl) Amino}methyl)phenyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(2S)-3,3-二甲基-2-丁胺(52毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生19.8毫克標題化合物(34.7%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] General procedure for amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but with (2S)-3,3-dimethyl-2-butylamine (52 mg) , 0.525 mmol, instead of 1-[(2S)-tetrahydro-2-furanyl]methylamine, yielded 19.8 mg of the title compound (34.7%).

LC/MS=m/z 543.4[M+H]滯留時間：1.78分鐘。 LC/MS = m/z 543.4 [M+H].

實例318：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-2-甲基丁基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 318: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-2-methylbutyl]amino}} Phenyl]-1H-indole-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(2S)-2-甲基-1-丁胺(45毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生23.3毫克標題化合物(41.7%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] General procedure for amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but switched to (2S)-2-methyl-1-butylamine (45 mg, 0.525 m) Preparation of 1 -[(2S)-tetrahydro-2-furanyl]methylamine afforded 23.3 mg of the title compound (41.7%).

LC/MS=m/z 529.4[M+H]滯留時間：1.62分鐘。 LC/MS = m/z 529.4 [M+H].

實例319：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-{[(2-甲基丁基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 319: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-methylbutyl)amino]methyl}phenyl )-1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-甲基-1-丁胺(45毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生30.5毫克標題化合物(54.5%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] A general procedure for the amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but replaced with 2-methyl-1-butylamine (45 mg, 0.525 mmol) Preparation of 1-[(2S)-tetrahydro-2-furanyl]methylamine gave 30.5 mg of the title compound (54.5%).

LC/MS=m/z 529.4[M+H]滯留時間：1.73分鐘。 LC/MS = m/z 529.4 [M+H].

實例320：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(1R)-1,2,2-三甲基丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 320: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(1R)-1,2,2-trimethylpropyl) Amino}methyl)phenyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(2R)-3,3-二甲基-2-丁胺(52毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生24.9毫克標題化合物(43.6%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] General procedure for amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but with (2R)-3,3-dimethyl-2-butylamine (52 mg) Prepared by substituting 1-[(2S)-tetrahydro-2-furanyl]methylamine to give 24.9 mg of the title compound (43.6%).

LC/MS=m/z 543.4[M+H]滯留時間：1.73分鐘。 LC/MS = m/z 543.4 [M+H].

實例321：5-(3-{[(2,2-二甲基丙基)胺基]甲基}-5-氟苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 321: 5-(3-{[(2,2-Dimethylpropyl)amino]methyl}-5-fluorophenyl)-3-[1-(ethylsulfonyl)-4- Piperidinyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2,2-二甲基-1-丙胺(45毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生14毫克標題化合物(25%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] General procedure for amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but with 2,2-dimethyl-1-propylamine (45 mg, 0.525 mmol) Substitution of 1-[(2S)-tetrahydro-2-furanyl]methylamine afforded 14 mg of the title compound (25%).

LC/MS=m/z 529.4[M+H]滯留時間：1.79分鐘。 LC/MS = m/z 529.4 [M+H].

實例322：5-(3-{[(環丙基甲基)胺基]甲基}-5-氟苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 322: 5-(3-{[(Cyclopropylmethyl)amino]methyl}-5-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl] -1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用1-環丙基甲胺(37毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生21.1毫克標題化合物(38.7%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] The general procedure for the amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but instead of 1-cyclopropylmethylamine (37 mg, 0.525 mmol) instead of 1- Preparation of [(2S)-tetrahydro-2-furanyl]methylamine gave 21.1 mg of the title compound (38.7%).

LC/MS=m/z 513.4[M+H]滯留時間：1.69分鐘。 LC/MS = m/z 513.4 [M+H].

實例323：5-(3-{[(環戊基甲基)胺基]甲基}-5-氟苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 323: 5-(3-{[(Cyclopentylmethyl)amino]methyl}-5-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl] -1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用1-環戊基甲胺(52毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生21.6毫克標題化合物(37.9%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] The general procedure for the amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but instead of 1-cyclopentylmethylamine (52 mg, 0.525 mmol) instead of 1- Preparation of [(2S)-tetrahydro-2-furanyl]methylamine gave 21.6 mg of the title compound (37.9%).

LC/MS=m/z 541.4[M+H]滯留時間：1.82分鐘。 LC/MS = m/z 541.4 [M+H].

實例324：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-{[(四氫-2H-吡喃-4-基甲基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 324: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(tetrahydro-2H-pyran-4-ylmethyl)amine Methyl}phenyl)-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用1-(四氫-2H-吡喃- 4-基)甲胺(60毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生40.1毫克標題化合物(68.7%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] The general procedure for the amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but using 1-(tetrahydro-2H-pyran- Preparation of 4-[chi])methylamine (60 mg, 0.525 mmol) eluted from 1-[(2S)-tetrahydro-2-furanylmethylamine afforded 40.1 mg of the title compound (68.7%).

LC/MS=m/z 557.4[M+H]滯留時間：1.54分鐘。 LC/MS = m/z 557.4 [M+H].

實例325：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-{[(2-噻吩基甲基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 325: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-thienylmethyl)amino]methyl}phenyl )-1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用1-(2-噻吩基)甲胺(59毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生24.4毫克標題化合物(41.9%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] General procedure for amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but with 1-(2-thienyl)methylamine (59 mg, 0.525 mmol) Substituting 1-[(2S)-tetrahydro-2-furanyl]methylamine afforded 24.4 mg of the title compound (41.9%).

LC/MS=m/z 555.4[M+H]滯留時間：1.67分鐘。 LC/MS = m/z 555.4 [M+H].

實例326：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[2-(甲基氧)乙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 326: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[2-(methyloxy)ethyl]amino}methyl) Phenyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-(甲基氧)乙胺(39毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生31毫克標題化合物(56.5%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] A general procedure for the amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but replaced with 2-(methyloxy)ethylamine (39 mg, 0.525 mmol) Preparation of 1-[(2S)-tetrahydro-2-furanyl]methylamine gave 31 mg of the title compound (56.5%).

LC/MS=m/z 517.2[M+H]滯留時間：1.52分鐘。 LC/MS = m/z 517.2 [M+H].

實例327：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[3-(甲基氧)丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 327: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[3-(methyloxy)propyl]amino}methyl) Phenyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用3-(甲基氧)-1-丙胺 (46毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生27.3毫克標題化合物(48.7%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] General procedure for amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but with 3-(methyloxy)-1-propylamine (46 mg, 0.525 mmol) was taken in the title compound (1.sub.2).

LC/MS=m/z 531.4[M+H]滯留時間：1.54分鐘。 LC/MS = m/z 531.4 [M+H].

實例328：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-{[(2-呋喃基甲基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 328: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(2-furylmethyl)amino]methyl}phenyl )-1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用1-(2-呋喃基)甲胺(50毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生24.8毫克標題化合物(43.7%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] The general procedure for the amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but using 1-(2-furyl)methylamine (50 mg, 0.525 mmol) Instead of 1-[(2S)-tetrahydro-2-furanyl]methylamine, 24.8 mg of the title compound (43.7%).

LC/MS=m/z 539.4[M+H]滯留時間：1.63分鐘。 LC/MS = m/z 539.4 [M+H].

實例329：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-氟-5-{[(3-甲基丁基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 329: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-fluoro-5-{[(3-methylbutyl)amino]methyl}phenyl )-1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用3-甲基-1-丁胺(45毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生27.6毫克標題化合物(49.4%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] The general procedure for the amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but replaced with 3-methyl-1-butylamine (45 mg, 0.525 mmol) Preparation of 1-[(2S)-tetrahydro-2-furanyl]methylamine gave 27.6 mg of the title compound (49.4%).

LC/MS=m/z 529.4[M+H]滯留時間：1.67分鐘。 LC/MS = m/z 529.4 [M+H].

實例330：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(5-甲基-2-呋喃基)甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 330: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(5-methyl-2-furyl)methyl]amine) Methyl)phenyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-氟-5-({[(2S)-四氫-2-呋喃基甲基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用1-(5-甲基-2-呋喃基)甲胺(58毫克，0.525毫莫耳)替代1-[(2S)-四氫-2-呋喃基]甲胺製備，產生28.3毫克標題化合物(48.8%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]] General procedure for amino}methyl)phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but with 1-(5-methyl-2-furan) Preparation of methylamine (58 mg, 0.525 mmol) instead of 1-[(2S)-tetrahydro-2-furanylmethylamine afforded 28.3 mg of the title compound (48.8%).

LC/MS=m/z 553.6[M+H]滯留時間：1.78分鐘。 LC/MS = m/z 553.6 [M+H].

實例331：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-甲基丙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 331: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-methylpropyl)amino]methyl}phenyl)-1H-吲哚-7-carboxyguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)之二氯甲烷(2毫升)與甲醇(1毫升)溶液中添加2-甲基-1-丙胺(70微升，0.683毫莫耳)與2滴乙酸。於室溫下攪拌此混合物2小時後，添加四氫硼酸鈉(26毫克，0.683毫莫耳)。30分鐘後，混合物濃縮，溶於二甲亞碸(2毫升)，經Gilson製備性HPLC純化，產生19.8毫克標題化合物(61%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxamide (50 mg, 0.114 To a solution of methylene chloride (2 mL) and methanol (1 mL) was added 2-methyl-1-propylamine (70 μL, 0.683 mmol) and 2 drops of acetic acid. After the mixture was stirred at room temperature for 2 hours, sodium tetrahydroborate (26 mg, 0.683 mmol) was added. After 30 minutes, the mixture was evaporated EtOAcjjjjjjjjjjjj

LC/MS=m/z 497.4[M+H]滯留時間：1.57 LC/MS=m/z 497.4 [M+H] retention time: 1.57

實例332：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(2-吡咯啶基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 332: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-(2-pyrrolidinyl)phenyl]-1H-indole-7-carboxamide Fluoroacetate

取含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(70毫克，0.151毫莫耳)、2-(3-碘苯基)吡咯啶(70毫克，0.456毫莫耳)與碳酸鉀(126毫克，0.910毫莫耳)之二烷(2毫升)與水(1毫升)溶液脫氣5分鐘，添加肆(三苯基膦)鈀(0)(17毫克，0.015毫莫耳)。混合物於CEM微波爐中，於160℃下反應20分鐘。分離有機層後，濃縮。然後溶於二甲亞碸(1毫升)，經Gilson製備性HPLC純化，產生48毫克標題化合物(59.5%)。 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (70 mg, 0.151 mmol), 2-(3-iodophenyl)pyrrolidine (70 mg, 0.456 mmol) and potassium carbonate (126) Mg, 0.910 millimoles) A solution of the alkane (2 mL) and water (1 mL) was degassed for 5 min and then added <RTIgt;(triphenylphosphine)palladium(0) (17 mg, 0.015 mmol). The mixture was reacted in a CEM microwave oven at 160 ° C for 20 minutes. After separating the organic layer, it was concentrated. It was then dissolved in dimethyl hydrazine (1 mL).

LC/MS=m/z 481.0[M+H]滯留時間：1.47 LC/MS=m/z 481.0 [M+H] retention time: 1.47

實例333：3-[1-(乙基磺醯基)-4-哌啶基]-5-{2-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 333: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole -7-Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-氟-5-甲醯基苯基)-1H-吲哚-7-羧醯胺(40毫克，0.087毫莫耳)之二氯甲烷(2毫升)與甲醇(1毫升)溶液中添加甲胺(262微升，0.524毫莫耳)與1滴乙酸。於室溫下攪拌2小時後，添加四氫硼酸鈉(20毫克，0.524毫莫耳)，靜置30分鐘。混合物經Gilson製備性HPLC純化，產生12.3毫克標題化合物(58.6%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-methylindenylphenyl)-1 H -indole-7-carboxamide Methylamine (262 μL, 0.524 mmol) and 1 drop of acetic acid were added to a solution of 40 mg, 0.087 mmol of dichloromethane (2 mL) and methanol (1 mL). After stirring at room temperature for 2 hours, sodium tetrahydroborate (20 mg, 0.524 mmol) was added and allowed to stand for 30 minutes. The mixture was purified by Gilson preparative HPLC to yield 12.3 mg of the title compound (58.6%).

LC/MS=m/z 473.4[M+H]滯留時間：1.55. LC/MS = m / z 473.4 [M + H] retention time: 1.55.

實例334：3-[1-(乙基磺醯基)-4-哌啶基]-5-{2-氟-5-[(丙基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 334: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(propylamino)methyl]phenyl}-1H-indole -7-Carboguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{2-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用丙基胺(44微升，0.524毫莫耳)替代甲胺製備，產生15.4毫克標題化合物(61.5%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole The general procedure for 哚-7-carboxyguanamine trifluoroacetate was prepared using propylamine (44 dl, 0.524 mmol) instead of methylamine to yield 15.4 mg of the title compound (61.5%).

LC/MS=m/z 501.4[M+H]滯留時間：1.55 LC/MS=m/z 501.4 [M+H] retention time: 1.55

實例335：3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-氟-5-{[(2-甲基丙基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 335: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-{[(2-methylpropyl)amino]methyl}phenyl )-1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{2-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-甲基-1-丙胺(53微升，0.524毫莫耳)替代甲胺製備，產生15毫克標題化合物(62.9%) The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole The general procedure for 哚-7-carboxyguanamine trifluoroacetate, but using 2-methyl-1-propylamine (53 μL, 0.524 mmol) instead of methylamine to give 15 mg of the title compound (62.9%)

LC/MS=m/z 515.4[M+H]滯留時間：1.55 LC/MS=m/z 515.4 [M+H] retention time: 1.55

實例336：5-(5-{[(2,2-二甲基丙基)胺基]甲基}-2-氟苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 336: 5-(5-{[(2,2-Dimethylpropyl)amino]methyl}-2-fluorophenyl)-3-[1-(ethylsulfonyl)-4- Piperidinyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{2-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2,2-二甲基-1-丙胺(46微升，0.524毫莫耳)替代甲胺製備，產生14.3毫克標題化合物(64.3%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole The general procedure for 哚-7-carboxyguanamine trifluoroacetate, but instead of 2,2-dimethyl-1-propylamine (46 μL, 0.524 mmol) instead of methylamine, yielded 14.3 mg of the title compound ( 64.3%).

LC/MS=m/z 530.2[M+H]滯留時間：1.59 LC/MS=m/z 530.2 [M+H] retention time: 1.59

實例337：5-[5-({[(1S)-1,2-二甲基丙基]胺基}甲基)-2-氟苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 337: 5-[5-({[(1S)-1,2-dimethylpropyl]amino}methyl)-2-fluorophenyl]-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{2-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(2S)-3-甲基-2-丁胺(46微升，0.524毫莫耳)替代甲胺製備，產生17.3毫克標題化合物(64.3%) The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole General procedure for 哚-7-carboxyguanamine trifluoroacetate, but instead of (2S)-3-methyl-2-butylamine (46 μL, 0.524 mmol) instead of methylamine, yielding 17.3 mg of title Compound (64.3%)

LC/MS=m/z 529.4[M+H]滯留時間：1.69 LC/MS=m/z 529.4 [M+H] retention time: 1.69

實例338：5-[5-({[(1R)-1,2-二甲基丙基]胺基}甲基)-2-氟苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 338: 5-[5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-fluorophenyl]-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{2-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(2R)-3-甲基-2-丁胺(46微升，0.524毫莫耳)替代甲胺製備，產生15毫克標題化合物(64.3%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole General procedure for 哚-7-carboxyguanamine trifluoroacetate, but instead using (2R)-3-methyl-2-butylamine (46 μL, 0.524 mmol) instead of methylamine, yielding a 15 mg heading Compound (64.3%).

LC/MS=m/z 529.4[M+H]滯留時間：1.70 LC/MS=m/z 529.4 [M+H] retention time: 1.70

實例339：5-(5-{[(環丙基甲基)胺基]甲基}-2-氟苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 339: 5-(5-{[(cyclopropylmethyl)amino]methyl}-2-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl] -1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{2-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-甲基-1-丁胺(38微升，0.524毫莫耳)替代甲胺製備，產生16.2毫克標題化合物(62.7%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole The general procedure for 哚-7-carboxyguanamine trifluoroacetate, but using 2-methyl-1-butylamine (38 μL, 0.524 mmol) instead of methylamine to give 16.2 mg of the title compound (62.7%) ).

LC/MS=m/z 513.4[M+H]滯留時間：1.57 LC/MS=m/z 513.4 [M+H] retention time: 1.57

實例340：3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-氟-5-(1-吡咯啶基甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 340: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-(1-pyrrolidinylmethyl)phenyl]-1H-indole- 7-Carboguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{2-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用吡咯啶(44微升，0.524毫莫耳)替代甲胺製備，產生10毫克標題化合物(62.7%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole The general procedure for 哚-7-carboxyguanamine trifluoroacetate was prepared using pyrrolidine (44 μL, 0.524 mmol) instead of methylamine to give 10 mg of the title compound (62.7%).

LC/MS=m/z 513.4[M+H]滯留時間：1.62 LC/MS=m/z 513.4 [M+H] retention time: 1.62

實例341：3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-氟-5-(4-嗎啉基甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 341: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-(4-morpholinylmethyl)phenyl]-1H-indole- 7-Carboguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{2-氟-5-[(甲基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用嗎啉(45微升，0.524毫莫耳)替代甲胺製備，產生15毫克標題化合物(64.3%) The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{2-fluoro-5-[(methylamino)methyl]phenyl}-1H-indole General procedure for 哚-7-carboxyguanamine trifluoroacetate, but instead of morpholine (45 μl, 0.524 mmol) instead of methylamine, yield 15 mg of the title compound (64.3%)

LC/MS=m/z 529.4[M+H]滯留時間：1.52 LC/MS=m/z 529.4 [M+H] retention time: 1.52

實例342：3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-氟-5-({[2-(甲基氧)乙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 342: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-({[2-(methyloxy)ethyl]amino}methyl) Phenyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-氟-5-甲醯基苯基)-1H-吲哚-7-羧醯胺(40毫克，0.087毫莫耳)之二氯甲烷(2毫升)與甲醇(1毫升)溶液中添加2-(甲基氧)乙胺(54微升， 0.524毫莫耳)與1滴乙酸。於室溫下攪拌一個週末後，添加四氫硼酸鈉(20毫克，0.524毫莫耳)，靜置30分鐘。混合物經Gilson製備性HPLC純化，產生11.4毫克標題化合物(63%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluoro-5-methylindenylphenyl)-1 H -indole-7-carboxamide To a solution of 40 mg, 0.087 mmol of dichloromethane (2 mL) and methanol (1 mL) was added 2-(methyloxy)ethylamine (54 μL, 0.524 mmol) with 1 drop of acetic acid. After stirring at room temperature for one weekend, sodium tetrahydroborate (20 mg, 0.524 mmol) was added and allowed to stand for 30 minutes. The mixture was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 517.2[M+H]滯留時間：1.57 LC/MS=m/z 517.2 [M+H] retention time: 1.57

實例343：3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-氟-5-({[3-(甲基氧)丙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 343: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-({[3-(methyloxy)propyl]amino}methyl) Phenyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-氟-5-({[2-(甲基氧)乙基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用3-(甲基氧)-1-丙胺(53微升，0.524毫莫耳)替代2-(甲基氧)乙胺製備，產生15毫克標題化合物(64.5%) The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-fluoro-5-({[2-(methyloxy)ethyl]amino}} The general procedure for the phenyl]-1H-indole-7-carboxamide amine trifluoroacetate, but instead of 3-(methyloxy)-1-propanamine (53 microliters, 0.524 millimoles) instead of 2 -(Methyloxy)ethylamine to give 15 mg of the title compound (64.5%)

LC/MS=m/z 531.4[M+H]滯留時間：1.60 LC/MS=m/z 531.4 [M+H] retention time: 1.60

實例344：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(1-甲基-2-吡咯啶基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 344: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-(1-methyl-2-pyrrolidinyl)phenyl]-1H-indole-7 -Carboguanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(2-吡咯啶基)苯基]-1H-吲哚-7-羧醯胺(20毫克，0.04毫莫耳)、甲醛(9.5毫升，0.125毫莫耳)與三乙醯氧基氫硼化鈉之二氯甲烷(2毫升)溶液中添加2滴乙酸。所得混合物於室溫下攪拌一夜。蒸發所有溶劑。所得殘質再溶於二甲亞碸(1毫升)。混合物經Gilson製備性HPLC分離2次，產生8.9毫克標題化合物(60.9%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-(2-pyrrolidinyl)phenyl]-1 H -indole-7-carboxamide ( 2 mg of acetic acid were added to a solution of 20 mg, 0.04 mmol, formaldehyde (9.5 ml, 0.125 mmol) and sodium triethoxy hydride hydride in dichloromethane (2 mL). The resulting mixture was stirred at room temperature overnight. Evaporate all solvents. The resulting residue was redissolved in dimethyl hydrazine (1 mL). The mixture was separated twice by Gilson preparative HPLC to yield 8.9 mg of the title compound (60.9%).

LC/MS=m/z 495.4[M+H]滯留時間：1.54 LC/MS=m/z 495.4[M+H] retention time: 1.54

實例345：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{2-[(2-甲基丙基)胺基]乙基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 345: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-{2-[(2-methylpropyl)amino]ethyl}phenyl)- 1H-吲哚-7-carboxyguanamine trifluoroacetate

取含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(60毫克，0.13毫莫耳)、[2-(3-溴苯基)乙基](2-甲基丙基)胺(100毫克，0.39毫莫耳)與碳酸鉀(108毫克，0.780毫莫耳)之二烷(2毫升)與水(0.7毫升)溶液。所得混合物脫氣5分鐘後，添加肆(三苯基膦)鈀(0)(14毫克，0.013毫莫耳)。於CEM微波爐中，於160℃下反應20分鐘。反應使用Gilson製備性HPLC純化，產生44毫克標題化合物(62.5%)。 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (60 mg, 0.13 mmol), [2-(3-bromophenyl)ethyl](2-methylpropyl)amine (100 mg , 0.39 millimoles) with potassium carbonate (108 mg, 0.780 mmol) A solution of alkane (2 mL) and water (0.7 mL). After the resulting mixture was degassed for 5 minutes, hydrazine (triphenylphosphine)palladium(0) (14 mg, 0.013 mmol) was added. The reaction was carried out at 160 ° C for 20 minutes in a CEM microwave oven. The reaction was purified using EtOAc EtOAc (EtOAc)

LC/MS=m/z 511.2[M+H]滯留時間：1.79 LC/MS=m/z 511.2 [M+H] retention time: 1.79

實例346：5-{3-[2-(乙基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 346: 5-{3-[2-(ethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7 -Carboguanamine trifluoroacetate

取含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(40.4毫克，0.09毫莫耳)、2-(3-溴苯基)-N-乙基乙胺(60毫克，0.263毫莫耳)與碳酸鉀(72毫克，0.526毫莫耳)之二烷(2毫升)與水(0.7毫升)溶液脫氣5分鐘。添加肆(三苯基膦)鈀(0)(11毫克， 0.009毫莫耳)。所得混合物於CEM微波爐中，於160℃下反應20分鐘。反應使用Gilson製備性HPLC純化，產生38.6毫克標題化合物(59.7%)。 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (40.4 mg, 0.09 mmol), 2-(3-bromophenyl)-N-ethylethylamine (60 mg, 0.263 mmol) With potassium carbonate (72 mg, 0.526 mmol) The alkane (2 mL) was degassed with water (0.7 mL) for 5 min. Add ruthenium (triphenylphosphine) palladium (0) (11 mg, 0.009 mmol). The resulting mixture was reacted in a CEM microwave oven at 160 ° C for 20 minutes. The reaction was purified using Gilson preparative HPLC to yield 38.6 <RTIgt;

LC/MS=m/z 482.8[M+H]滯留時間：1.54 LC/MS=m/z 482.8 [M+H] retention time: 1.54

實例347：3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[2-(丙基胺基)乙基]苯基}-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 347: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-{3-[2-(propylamino)ethyl]phenyl}-1H-indole-7 -Carboguanamine trifluoroacetate

取含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(25毫克，0.055毫莫耳)、碳酸鉀(46毫克，0.33毫莫耳)與[2-(3-溴苯基)乙基]丙基胺(40毫克，0.165毫莫耳)之二烷(2毫升)與水(0.7毫升)溶液脫氣5分鐘後，添加肆(三苯基膦)鈀(0)(7毫克，0.006毫莫耳)。所得混合物於CEM微波爐中，於160℃下反應20分鐘。反應使用Gilson製備性HPLC分離，產生17.6毫克標題化合物(61%)。 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (25 mg, 0.055 mmol), potassium carbonate (46 mg, 0.33 mmol) and [2-(3-bromophenyl)ethyl] Propylamine (40 mg, 0.165 mmol) After degassing the alkane (2 mL) and water (0.7 mL) solution for 5 min, EtOAc (triphenylphosphine) palladium (0) (7 mg, 0.006 m. The resulting mixture was reacted in a CEM microwave oven at 160 ° C for 20 minutes. The reaction was isolated using Gilson preparative HPLC to yield 17.6 mg of the title compound (61%).

LC/MS=m/z 497.4[M+H]滯留時間：1.97 LC/MS=m/z 497.4 [M+H] retention time: 1.97

實例348：5-{3-[2-(二甲基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 348: 5-{3-[2-(Dimethylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole- 7-Carboguanamine trifluoroacetate

取含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(60毫克，0.13毫莫耳)、碳酸鉀(108毫克，0.78毫莫耳)與2-(3-溴苯基)-N,N-二甲基乙胺(90毫克，0.39毫莫耳)之二烷(2毫升)與水(0.7毫升)溶液脫氣5分鐘後，添加肆(三苯基膦)鈀(0)(15毫克，0.013毫莫耳)。所得混合物於CEM微波爐中，於160℃下反應20分鐘。反應使用Gilson製備性HPLC分離，產生30毫克標題化合物(59.7%)。 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (60 mg, 0.13 mmol), potassium carbonate (108 mg, 0.78 mmol) and 2-(3-bromophenyl)-N,N - dimethylethylamine (90 mg, 0.39 mmol) After deaeration of the alkane (2 mL) and water (0.7 mL) solution for 5 min, EtOAc (triphenylphosphine) palladium (0) (15 mg, 0.013 mmol) was added. The resulting mixture was reacted in a CEM microwave oven at 160 ° C for 20 minutes. The reaction was isolated using Gilson preparative HPLC to yield 30 mg of the title compound (59.7%).

LC/MS=m/z 483.2[M+H]滯留時間：1.60 LC/MS=m/z 483.2 [M+H] retention time: 1.60

實例349：5-{3-[2-(二丙基胺基)乙基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 349: 5-{3-[2-(Dipropylamino)ethyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole- 7-Carboguanamine trifluoroacetate

取含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(66毫克，0.14毫莫耳)、碳酸鉀(120毫克，0.86毫莫耳)與(2-苯基乙基)二丙基胺(120毫克，0.43毫莫耳)之二烷(2毫升)與水(0.7毫升)溶液脫氣5分鐘後，添加肆(三苯基膦)鈀(0)(15毫克，0.014毫莫耳)。所得混合物於CEM微波爐中，於160℃下反應20分鐘。反應使用Gilson製備性HPLC分離，產生9毫克標題化合物(65.3%)。 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (66 mg, 0.14 mmol), potassium carbonate (120 mg, 0.86 mmol) and (2-phenylethyl)dipropylamine ( 120 mg, 0.43 millimoles) After degassing of the alkane (2 mL) and water (0.7 mL) solution for 5 min, s(triphenylphosphine)palladium(0) (15 mg, 0.014 mmol) was added. The resulting mixture was reacted in a CEM microwave oven at 160 ° C for 20 minutes. The reaction was isolated using Gilson preparative HPLC to yield 9 mg of the title compound (65.3%).

LC/MS=m/z 455.0[M+H]滯留時間：1.55 LC/MS=m/z 455.0 [M+H] retention time: 1.55

實例350：5-[3-({[2-(3,5-二甲基-1H-吡唑-1-基)乙基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 350: 5-[3-({[2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl]amino}methyl)phenyl]-3-[1-( Ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(44毫克，0.1毫莫耳)、2-(3,5-二甲基-1H-吡唑-1-基)乙胺(105毫克，0.6毫莫耳)之二氯甲烷(3毫升)與甲醇(1.5毫升)溶液中添加3滴乙酸。所得混合物攪拌一夜後，添加三乙醯氧基氫硼化鈉(134毫克，0.6毫莫耳)。攪拌此混合物一夜。所得混合物經碳酸氫鈉(2毫升)與鹽水(2毫升)中止反應，收集有機層與濃縮。反應使用Gilson製備性HPLC分離，產生26毫克標題化合物(67.7%) Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -indole-7-carboxamide (44 mg, 0.1 Milliol, 2-(3,5-dimethyl-1H-pyrazol-1-yl)ethylamine (105 mg, 0.6 mmol) in dichloromethane (3 mL) and methanol (1.5 mL) Three drops of acetic acid were added to the solution. After the resulting mixture was stirred overnight, sodium triacetoxyborohydride (134 mg, 0.6 mmol) was added. The mixture was stirred overnight. The mixture was quenched with sodium bicarbonate (2 mL) and brine (2 mL). The reaction was isolated using Gilson preparative HPLC to give 26 mg of the title compound (67.7%)

LC/MS=m/z 563.2[M+H]滯留時間：1.51 LC/MS=m/z 563.2 [M+H] retention time: 1.51

實例351：3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(4-嗎啉基甲基)-1,3-噻唑-4-基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 351: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(4-morpholinylmethyl)-1,3-thiazol-4-yl]-1H -吲哚-7-carboxyguanamine trifluoroacetate

在含4-溴-1,3-噻唑-2-甲醛(192毫克，1.0毫莫耳)之DCM(4.0毫升)溶液中添加嗎啉(130微升，1.5毫莫耳)與3滴AcOH。攪拌混合物12小時後，添加Na(OAc)3BH(0.335克，1.5毫莫耳)。6小時後，混合物經飽和NaHCO3(4.0毫升)與鹽水(3.0毫升)中止反應。分離有機層與濃縮，產生200毫克4-[(4-溴-1,3-噻唑-2-基)甲基]嗎啉(76%)。 To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 mL), morpholine (130 <RTIgt; After stirring the mixture for 12 hours, Na(OAc)3BH (0.335 g, 1.5 mmol) was added. After 6 hours, the mixture was quenched with saturated NaHCO3 (EtOAc) The organic layer was separated and concentrated to give <RTI ID=0.0>>

取含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(46毫克，0.1毫莫耳)、4-[(4-溴-1,3-噻唑-2-基)甲基]嗎啉(79毫克，0.3毫莫耳)與碳酸鉀(83毫克，0.6毫莫耳)之二烷(2毫升)與水(0.7毫升)溶液脫氣5分鐘後，添加三乙醯氧基氫硼化物(11毫克，0.1毫莫耳)。此混合物於CEM微波爐中，於160℃下反應20分鐘。收集有機層與濃縮。殘質再溶於二甲亞碸(1毫升)後，使用Gilson製備性HPLC純化，產生26.6毫克標題化合物(63.2%) 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (46 mg, 0.1 mmol), 4-[(4-bromo-1,3-thiazol-2-yl)methyl]morpholine (79 Mg, 0.3 mmol, and potassium carbonate (83 mg, 0.6 mmol) After degassing the alkane (2 mL) and water (0.7 mL) solution for 5 min, triethyloxy hydride hydride (11 mg, 0.1 mmol). This mixture was reacted in a CEM microwave oven at 160 ° C for 20 minutes. The organic layer was collected and concentrated. The residue was re-dissolved in dimethyl hydrazine (1 mL).

LC/MS=m/z 518.2[M+H]滯留時間：1.49 LC/MS=m/z 518.2 [M+H] retention time: 1.49

實例352：3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-{[(2-甲基丙基)胺基]甲基}-1,3-噻唑-4-基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 352: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2-methylpropyl)amino]methyl}-1,3-thiazole -4-yl)-1H-indole-7-carboxamide guanamine trifluoroacetate

在含4-溴-1,3-噻唑-2-甲醛(192毫克，1.0毫莫耳)之DCM(4.0毫升)溶液中添加異丙基胺(152微升，1.5毫莫耳)與3滴AcOH。攪拌混合物12小時後，添加Na(OAc)3BH(0.335克，1.5毫莫耳)。6小時後，混合物經飽和NaHCO3(4.0毫升)與鹽水(3.0毫升)中止反應。分離有機層與濃縮，產生145毫克標題化合物(58%)。 Add isopropylamine (152 μl, 1.5 mmol) and 3 drops to a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 mL) AcOH. After stirring the mixture for 12 hours, Na(OAc)3BH (0.335 g, 1.5 mmol) was added. After 6 hours, the mixture was Saturated NaHCO3 (4.0 mL) was quenched with brine (3.0 mL). The organic layer was separated and concentrated to give 145 g of the title compound (58%).

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-甲醛(46毫克，0.1毫莫耳)、2-甲基-1-丙胺(70毫克，0.3毫莫耳)與碳酸鉀(83毫克，0.6毫莫耳)之二烷(2毫升)與水(0.7毫升)溶液中添加三乙醯氧基氫硼化物(11毫克，0.01毫莫耳)。此溶液脫氣5分鐘後，於CEM微波爐中，於160℃下反應20分鐘。分離有機層與濃縮。然後使用Gilson製備性HPLC純化，產生24毫克標題化合物(61.8%) In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1H-indole-7-formaldehyde (46 mg, 0.1 mmol), 2-methyl-1-propylamine (70 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) )of two To the solution of the alkane (2 ml) and water (0.7 ml) was added triethyloxy borohydride (11 mg, 0.01 mmol). After the solution was degassed for 5 minutes, it was reacted in a CEM microwave oven at 160 ° C for 20 minutes. The organic layer was separated and concentrated. Purified using Gilson preparative HPLC to give 24 mg of the title compound (61.8%)

LC/MS=m/z 504.2[M+H]滯留時間：1.43 LC/MS=m/z 504.2 [M+H] retention time: 1.43

實例353：3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(1-吡咯啶基甲基)-1,3-噻唑-4-基]-1H-吲哚-7-羧醯胺Example 353: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[2-(1-pyrrolidinylmethyl)-1,3-thiazol-4-yl]-1H -吲哚-7-carboxyguanamine

在含4-溴-1,3-噻唑-2-甲醛(192毫克，1.0毫莫耳)之DCM(4.0毫升)溶液中添加吡咯啶(124微升，1.5毫莫耳)與3滴AcOH。攪拌混合物12小時，添加Na(OAc)3BH(0.335 克，1.5毫莫耳)。6小時後，混合物經飽和NaHCO3(4.0毫升)與鹽水(3.0毫升)中止反應。分離有機層與濃縮，產生200毫克標題化合物(82%)。 Pyrrolidine (124 μL, 1.5 mmol) and 3 drops of AcOH were added to a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 mL). The mixture was stirred for 12 hours and Na(OAc)3BH (0.335) was added. G, 1.5 millimoles). After 6 hours, the mixture was quenched with saturated NaHCO3 (EtOAc) The organic layer was separated and concentrated to give the title compound <RTIgt;

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-{[(2-甲基丙基)胺基]甲基}-1,3-噻唑-4-基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用吡咯啶(74毫克，0.3毫莫耳)替代2-甲基-1-丙胺製備，產生6.3毫克標題化合物(50%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2-methylpropyl)amino]methyl}-1,3- The general procedure for the addition of thiazol-4-yl)-1H-indole-7-carboxamide to trifluoroacetate, but using pyrrolidine (74 mg, 0.3 mmol) instead of 2-methyl-1-propylamine. Yield 6.3 mg of the title compound (50%).

LC/MS=m/z 500.4[M+H]滯留時間：1.22 LC/MS=m/z 500.4 [M+H] retention time: 1.22

實例354：3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(1-哌啶基甲基)-1,3-噻唑-4-基]-1H-吲哚-7-羧醯胺Example 354: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[2-(1-piperidinylmethyl)-1,3-thiazol-4-yl]-1H -吲哚-7-carboxyguanamine

在含4-溴-1,3-噻唑-2-甲醛(192毫克，1.0毫莫耳)之DCM(4.0毫升)溶液中添加哌啶(150微升，1.5毫莫耳)與3滴AcOH。攪拌混合物12小時，添加Na(OAc)3BH(0.335克，1.5毫莫耳)。6小時後，混合物經飽和NaHCO3(4.0毫升)與鹽水(3.0毫升)中止反應。分離有機層與濃縮，產生166毫克標題化合物(64%)。 Piperidine (150 μL, 1.5 mmol) and 3 drops of AcOH were added to a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 mL). The mixture was stirred for 12 hours and Na(OAc)3BH (0.335 g, 1.5 m. After 6 hours, the mixture was quenched with saturated NaHCO3 (EtOAc) The organic layer was separated and concentrated to give 166 g of the title compound (64%).

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-{[(2-甲基丙基)胺基]甲基}-1,3-噻唑-4-基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用哌啶(78毫克，0.3毫莫耳)替代2-甲基-1-丙胺製備，產生15.5毫克標題化合物(51.6%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-{[(2-methylpropyl)amino]methyl}-1,3- The general procedure for the addition of thiazol-4-yl)-1H-indole-7-carboxamide to trifluoroacetate, but using piperidine (78 mg, 0.3 mmol) instead of 2-methyl-1-propylamine. Yield 15.5 mg of the title compound (51.6%).

LC/MS=m/z 517.4[M+H]滯留時間：1.29 LC/MS=m/z 517.4 [M+H] retention time: 1.29

實例355：5-{2-[(二甲基胺基)甲基]-1,3-噻唑-4-基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 355: 5-{2-[(Dimethylamino)methyl]-1,3-thiazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl] -1H-吲哚-7-carboxyguanamine trifluoroacetate

在含4-溴-1,3-噻唑-2-甲醛(192毫克，1.0毫莫耳)之DCM(4.0毫升)溶液中添加二甲基胺(2.0M，3.0毫升)與3滴AcOH。攪拌混合物48小時後，添加Na(OAc)3BH(1.33克，6.0毫莫耳)。12小時後，混合物經飽和NaHCO3(4.0毫升)與鹽水(3.0毫升)中止反應，使用分離器得到DCM有機層。有機層濃縮，產生90毫克所需產物(40%)。 To a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in EtOAc (EtOAc) After stirring the mixture for 48 hours, Na(OAc)3BH (1.33 g, 6.0 mmol) was added. After 12 hours, the mixture was quenched with saturated NaHCO3 (4.0 mL) and brine (3.0 mL). The organic layer was concentrated to give 90 mg of desired material (40%).

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(46毫克，0.1毫莫耳)、二甲基胺(69毫克，0.3毫莫耳)與碳酸鉀(83毫克，0.6毫莫耳)之二烷(2毫升)與水(0.7毫升)溶液中添加三乙醯氧基氫硼化物(12毫克，0.01毫莫耳)。此混合物脫氣5分鐘。混合物於微波爐中，於160℃下反應20分鐘。分離有機層與濃縮。然後使用Gilson製備性HPLC純化，產生23毫克標題化合物(59%) In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (46 mg, 0.1 mmol), dimethylamine (69 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol) of two To the solution of the alkane (2 ml) and water (0.7 ml) was added triethyloxy borohydride (12 mg, 0.01 mmol). This mixture was degassed for 5 minutes. The mixture was reacted in a microwave oven at 160 ° C for 20 minutes. The organic layer was separated and concentrated. Purified by Gilson preparative HPLC to give 23 mg of the title compound (59%)

LC/MS=m/z 474.4[M+H]滯留時間：1.20 LC/MS=m/z 474.4 [M+H] retention time: 1.20

實例356：5-(2-{[乙基(甲基)胺基]甲基}-1,3-噻唑-4-基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 356: 5-(2-{[Ethyl(methyl)amino]methyl}-1,3-thiazol-4-yl)-3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-1H-indole-7-carboxyguanamine trifluoroacetate

在含4-溴-1,3-噻唑-2-甲醛(192毫克，1.0毫莫耳)之DCM(4.0毫升)溶液中添加N-甲基乙胺(470ul,6.0毫莫耳)與3滴AcOH。攪拌混合物48小時。添加Na(OAc)3BH(1.33克，6.0毫莫耳)。12小時後，混合物經飽和NaHCO3(4.0毫升)與鹽水(3.0毫升)中止反應，使用分離器得到DCM有機層。有機層濃縮，產生160毫克標題化合物(68%)。 Add N -methylethylamine (470 ul, 6.0 mmol) and 3 drops to a solution of 4-bromo-1,3-thiazole-2-carbaldehyde (192 mg, 1.0 mmol) in DCM (4.0 mL) AcOH. The mixture was stirred for 48 hours. Na(OAc)3BH (1.33 g, 6.0 mmol) was added. After 12 hours, the mixture was quenched with saturated NaHCO3 (4.0 mL) and brine (3.0 mL). The organic layer was concentrated to give 160 mg (yield: 68%).

標題化合物係依據5-{2-[(二甲基胺基)甲基]-1,3-噻唑-4-基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用乙基(甲基)胺(73毫克，0.3毫莫耳)替代二甲基胺製備，產生25毫克標題化合物(60.4%)。 The title compound is based on 5-{2-[(dimethylamino)methyl]-1,3-thiazol-4-yl}-3-[1-(ethylsulfonyl)-4-piperidinyl General procedure for -1H-indole-7-carboxamide guanamine trifluoroacetate, but using ethyl (methyl)amine (73 mg, 0.3 mmol) instead of dimethylamine to give a 25 mg title Compound (60.4%).

LC/MS=m/z 490.4[M+H]滯留時間：1.25 LC/MS=m/z 490.4 [M+H] retention time: 1.25

實例357：5-(3-氰基-5-{[(2-甲基丙基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 357: 5-(3-Cyano-5-{[(2-methylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidine ]]-1H-吲哚-7-carboxyguanamine trifluoroacetate

於0℃與氬蒙氣下，在含3-甲醯基苯基氰(1.0克，7.6毫莫耳)之TFA(4.0毫升)溶液中滴加濃縮H₂SO₄(6.0毫升)後，分少量添加NBS。混合物慢慢回升至室溫後，於氬蒙氣下攪拌12小時。反應完成時，混合物倒至冰-H₂O(80毫升)、PdCl₂(117毫克，0.658毫莫耳)中，收集固體，真空乾燥一夜，產生1.50克3-溴-5-甲醯基苯醯胺(86%)。 After concentration of H ₂ SO ₄ (6.0 ml) was added dropwise to a solution of 3-methylmercaptophenyl cyanide (1.0 g, 7.6 mmol) in TFA (4.0 mL). Add a small amount of NBS. The mixture was slowly warmed to room temperature and stirred under argon atmosphere for 12 hours. Upon completion of the reaction, the mixture was poured into ice--H ₂ O (80 mL), PdCl ₂ (117 mg, 0.658 mmol), the solid was collected and dried under vacuum overnight to produce 1.50 g of 3-bromo-5-acyl-benzene Indoleamine (86%).

LC/MS=m/z 228.2[M+H]滯留時間：1.37 LC/MS=m/z 228.2 [M+H] retention time: 1.37

在含3-溴-5-甲醯基苯醯胺(1.5克，6.58毫莫耳)之H₂O(50.0毫升)與MeCN(50.0毫升)溶液中添加PdCl₂(117毫克，0.658毫莫耳)。混合物於室溫下攪拌72小時，再加一份H₂O(100毫升)與MeCN(100毫升)後，添加PdCl₂(100毫克，0.56莫耳)。再攪拌混合物12小時，與濃縮。殘質溶於EtOAc(200毫升)，以鹽水(3 X 50.0毫升)洗滌，經Na2SO4脫水，與濃縮，然後經層析法純化(10%EtOAc之己烷溶液)，產生550毫克3-溴-5-甲醯基苯基氰(40%)。 Add PdCl ₂ (117 mg, 0.658 mmol) to a solution of 3-bromo-5-mercaptobenzamide (1.5 g, 6.58 mmol) in H ₂ O (50.0 mL) and MeCN (50.0 mL) ). The mixture was stirred at room temperature for 72 hours together with a H ₂ O (100 mL) and after MeCN (100 mL) was added PdCl ₂ (100 mg, 0.56 mole). The mixture was stirred for a further 12 hours and concentrated. The residue was dissolved in EtOAc (EtOAc (EtOAc) (EtOAcjHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH 5-Methylphenylphenyl cyanide (40%).

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(46毫克，0.1毫莫耳)之二烷(2.0毫升)與H₂O(0.7毫升)溶液中添加3-溴-5-甲醯基苯基氰(68毫克，0.3毫莫耳)與碳酸鉀(83毫克，0.6毫莫耳)。混合物脫氣5分鐘後，添加肆(三苯基膦)鈀(0)(12毫克，0.01毫莫耳)。混合物於微波爐中，於160℃下反應20分鐘。化合物經Gilson製備性HPLC純化，產生5-(3-氰基-5-甲醯基苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -吲哚-7-carboxyguanamine (46 mg, 0.1 mmol) Dioxane (2.0 mL) and H ₂ O (0.7 mL) was added a solution of 3-bromo-5-acyl benzonitrile (68 mg, 0.3 mmol) and potassium carbonate (83 mg, 0.6 mmol). After the mixture was degassed for 5 minutes, hydrazine (triphenylphosphine) palladium (0) (12 mg, 0.01 mmol) was added. The mixture was reacted in a microwave oven at 160 ° C for 20 minutes. The compound was purified by Gilson preparative HPLC to give 5-(3-cyano-5-carbamidophenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole哚-7-carboxyquinone.

在含5-(3-氰基-5-甲醯基苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(47毫克，0.1毫莫耳)之二氯甲烷(3毫升)與甲醇(1毫升)溶液中添加幾滴乙酸與甲基(2-甲基丙基)胺(64微升，0.6毫莫耳)。攪拌此混合物一夜後，添加20滴乙酸與三乙醯氧基氫硼化鈉(0.6毫莫耳)。混合反應4小時後，添加甲基(2-甲基丙基)胺(64微升，0.6毫莫耳)與三乙醯氧基氫硼化鈉(0.6毫莫耳)。攪拌混合物一夜後，以碳酸氫鈉與鹽水中止反應。經SOX卡管分離有機層，濃縮。然後使用Gilson製備性HPLC分離，產生10.3毫克標題化合物(63.6%)。 In the presence of 5-(3-cyano-5-methylindenylphenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide Add a few drops of acetic acid and methyl (2-methylpropyl)amine (64 μL, 0.6 mmol) to a solution of (47 mg, 0.1 mmol) in dichloromethane (3 mL) and methanol (1 mL) ). After stirring the mixture overnight, 20 drops of acetic acid and sodium triethoxypropoxyborohydride (0.6 mmol) were added. After 4 hours of the mixed reaction, methyl (2-methylpropyl)amine (64 μL, 0.6 mmol) and sodium triethoxypropoxyborohydride (0.6 mmol) were added. After the mixture was stirred overnight, the reaction was quenched with sodium bicarbonate and brine. The organic layer was separated through a SOX cartridge and concentrated. It was then isolated using Gilson preparative HPLC to give 10.3 mg of the title compound (63.6%).

LC/MS=m/z 522.4[M+H]滯留時間：1.65 LC/MS=m/z 522.4[M+H] retention time: 1.65

實例358：5-{3-氰基-5-[(二甲基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 358: 5-{3-Cyano-5-[(dimethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-(3-氰基-5-{[(2-甲基丙基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用三甲基胺(300微升，0.3毫莫耳)替代甲基(2-甲基丙基)胺，產生10.5毫克標題化合物(61%)。 The title compound is based on 5-(3-cyano-5-{[(2-methylpropyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidin General procedure for pyridyl]-1H-indole-7-carboxamide amine trifluoroacetate, but instead of trimethylamine (300 μL, 0.3 mmol) instead of methyl (2-methylpropyl) The amine gave 10.5 mg of the title compound (61%).

LC/MS=m/z 494.4[M+H]滯留時間：1.48 LC/MS=m/z 494.4 [M+H] retention time: 1.48

實例359：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-(4-嗎啉基甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 359: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-(4-morpholinylmethyl)phenyl]-1 H -indole-7-carboxylate Guanidine trifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(80毫克，0.181毫莫耳)之DCM溶液中添加嗎啉(50微升，0.545毫莫耳)。反應於室溫下攪拌30分鐘後，添加三乙醯氧基氫硼化鈉(120毫克，0.545毫莫耳)。反應於室溫下進行一夜，濃縮。化合物經Gilson製備性HPLC純化，產生28.6毫克標題化合物(25%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxamide (80 mg, 0.181) Morpholine (50 microliters, 0.545 millimolar) was added to the milliliter solution of DCM. After the reaction was stirred at room temperature for 30 minutes, sodium triacetoxyborohydride (120 mg, 0.545 mmol) was added. The reaction was carried out overnight at room temperature and concentrated. The compound was purified by Gilson preparative HPLC to yield 28.6 mg of the title compound (25%).

LC/MS=m/z 511.4[M+H]滯留時間：1.48分鐘 LC/MS=m/z 511.4 [M+H] retention time: 1.48 minutes

實例360：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(4-氟苯基)羰基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 360: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(4-fluorophenyl)carbonyl]amino}methyl)phenyl]- 1 H -吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-{3-[(乙醯基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用4-氟-N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}苯醯胺(125毫克，0352毫莫耳)替代N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}乙醯胺製備。化合物經Gilson製備性HPLC純化，產生18.3毫克標題化合物(27%)。 The title compound is based on 5-{3-[(ethoxymethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole- General procedure for 7-carboxyguanamine, but with 4-fluoro- N -{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) Phenyl]methyl}benzamide (125 mg, 0352 mmol) instead of N -{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan) Preparation of 2-yl)phenyl]methyl}acetamide. The compound was purified by Gilson preparative HPLC to yield 18.3 mg of the title compound (27%).

LC/MS=m/z 563.1[M+H]滯留時間：2.07分鐘 LC/MS=m/z 563.1 [M+H] retention time: 2.07 minutes

實例361：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-呋喃基羰基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 361: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-furylcarbonyl)amino]methyl}phenyl)-1 H -吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-{3-[(乙醯基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}-2-呋喃羧醯胺(115毫克，0.352毫莫耳)替代N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}乙醯胺製備。化合物經Gilson製備性HPLC純化，產生8.1毫克標題化合物(12%)。 The title compound is based on 5-{3-[(ethoxymethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole- General procedure for 7-carboxyguanamine, but with N -{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] Methyl}-2-furan carboxamide (115 mg, 0.352 mmol) instead of N -{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan) Preparation of 2-yl)phenyl]methyl}acetamide. The compound was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 535[M+H]滯留時間：1.89分鐘 LC/MS=m/z 535 [M+H] retention time: 1.89 minutes

實例362：5-(3-{[(環戊基羰基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 362: 5-(3-{[(Cyclopentylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據5-{3-[(乙醯基胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}環戊烷羧醯胺(116毫克，0.352毫莫耳)替代N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}乙醯胺製備。化合物經Gilson製備性HPLC純化，產生9.2毫克標題化合物(14%)。 The title compound is based on 5-{3-[(ethoxymethylamino)methyl]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole- General procedure for 7-carboxyguanamine, but with N -{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] Methyl}cyclopentane carboxamide (116 mg, 0.352 mmol) instead of N -{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane- Preparation of 2-yl)phenyl]methyl}acetamide. The compound was purified by EtOAc EtOAc (EtOAc)

實例363：5-(3-{[(1-苯并噻吩-2-基羰基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 363: 5-(3-{[(1-benzothiophen-2-ylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl ]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(戊醯基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺之一般製程，但改用N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}-1-苯并噻吩-2-羧醯胺(57毫克，0.144毫莫耳)替代N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}戊醯胺製備。化合物經Gilson製備性HPLC純化，產生標題化合物。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentamnessylamino)methyl]phenyl}-1 H -吲哚- General procedure for 7-carboxyguanamine, but with N -{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] Methyl}-1-benzothiophene-2-carboxamide (57 mg, 0.144 mmol) instead of N -{[3-(4,4,5,5-tetramethyl-1,3,2- Preparation of dioxaborolan-2-yl)phenyl]methyl}pentanylamine. The compound was purified by Gilson preparative HPLC to give the title compound.

LC/MS=m/z 601.2[M+H]滯留時間：2.18分鐘 LC/MS=m/z 601.2 [M+H] retention time: 2.18 minutes

實例364：5-[3-({[(1-乙醯基-4-哌啶基)羰基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 364: 5-[3-({[(1-Ethyl-4-piperidyl)carbonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(戊醯基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺之一般製程，但改用1-乙醯基-N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}-4-哌啶羧醯胺(56毫克，0.144毫莫耳)替代N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}戊醯胺製備。化合物經Gilson製備性HPLC純化，產生標題化合物。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentamnessylamino)methyl]phenyl}-1 H -吲哚- General procedure for 7-carboxyguanamine, but use 1-ethylindenyl- N -{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2) -yl)phenyl]methyl}-4-piperidinecarboxamide (56 mg, 0.144 mmol) instead of N -{[3-(4,4,5,5-tetramethyl-1,3, Preparation of 2-dioxaborolan-2-yl)phenyl]methyl}pentanylamine. The compound was purified by Gilson preparative HPLC to give the title compound.

LC/MS=m/z 594.4[M+H]滯留時間：1.87分鐘 LC/MS=m/z 594.4 [M+H] retention time: 1.87 minutes

實例365：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(1-甲基-1H-吡咯-2-基)羰基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺Example 365: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-({[(1-methyl-1 H -pyrrol-2-yl)carbonyl]amino) }methyl)phenyl]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(戊醯基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺之一般製程，但改用1-甲基-N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}-1H-吡咯-2-羧醯胺(49毫克，0.144毫莫耳)替代N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}戊醯胺製備。化合物經Gilson製備性HPLC純化，產生標題化合物。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentamnessylamino)methyl]phenyl}-1 H -吲哚- General procedure for 7-carboxamide, but switch to 1-methyl- N -{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- Phenyl]methyl}methyl}-1 H -pyrrole-2-carboxamide (49 mg, 0.144 mmol) instead of N -{[3-(4,4,5,5-tetramethyl-1, Preparation of 3,2-dioxaborolan-2-yl)phenyl]methyl}pentanylamine. The compound was purified by Gilson preparative HPLC to give the title compound.

LC/MS=m/z 548.4[M+H]滯留時間：2.02分鐘 LC/MS=m/z 548.4 [M+H] retention time: 2.02 min

實例366：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(2-噻吩基乙醯基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺Example 366: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-{[(2-thienylethyl)amino]methyl}phenyl)-1 H-吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(戊醯基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺之一般製程，但改用N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}-2-(2-噻吩基)乙醯胺(51毫克，0.144毫莫耳)替代N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}戊醯胺製備。化合物經質量導向式自動製備性HPLC純化，產生10.3毫克標題化合物(18.2%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentamnessylamino)methyl]phenyl}-1 H -吲哚- General procedure for 7-carboxyguanamine, but with N -{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] Methyl}-2-(2-thienyl)acetamide (51 mg, 0.144 mmol) instead of N -{[3-(4,4,5,5-tetramethyl-1,3,2- Preparation of dioxaborolan-2-yl)phenyl]methyl}pentanylamine. The compound was purified by mass-directed automated preparative HPLC to yield 10.3 mg of the title compound (18.2%).

LC/MS=m/z 565.2[M+H]滯留時間：1.95分鐘 LC/MS=m/z 565.2 [M+H] retention time: 1.95 minutes

實例367：5-(3-{[(環丁基羰基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 367: 5-(3-{[(Cyclobutylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(戊醯基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺之一般製程，但改用N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}環丁烷羧醯胺(45毫克，0.144毫莫耳)替代N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}戊醯胺製備。化合物經質量導向式自動製備性HPLC純化，產生4.3毫克標題化合物(8%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentamnessylamino)methyl]phenyl}-1H-indole-7 - General procedure for carboxamide, but with N-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]- Substituting N -{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2) as a cyclobutane carboxamide (45 mg, 0.144 mmol) Preparation of -yl)phenyl]methyl}pentanylamine. The compound was purified by mass-directed automated preparative HPLC to yielded title compound:

LC/MS=m/z 523.4[M+H]滯留時間：1.90分鐘 LC/MS = m / z 523.4 [M + H] retention time: 1.90 minutes

實例368：5-(3-{[(環丙基羰基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 368: 5-(3-{[(Cyclopropylcarbonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-{3-[(戊醯基胺基)甲基]苯基}-1H-吲哚-7-羧醯胺之一般製程，但改用N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}環丙烷羧醯胺(43毫克，0.144毫莫耳)替代N-{[3-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]甲基}戊醯胺製備。化合物經質量導向式自動製備性HPLC純化，產生5.5毫克標題化合物(11%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{3-[(pentamnessylamino)methyl]phenyl}-1 H -吲哚- General procedure for 7-carboxyguanamine, but with N -{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl] Methyl}cyclopropanecarboxamide (43 mg, 0.144 mmol) instead of N -{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 Preparation of -yl)phenyl]methyl}pentanylamine. The compound was purified by mass-directed automated preparative HPLC to yield 5.5 mg of the title compound (11%).

LC/MS=m/z 509.2[M+H]滯留時間：1.85分鐘 LC/MS = m / z 509.2 [M + H] retention time: 1.85 minutes

實例369：5-(3-{[(環丙基磺醯基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 369: 5-(3-{[(cyclopropylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxyguanamine

在含5-[3-(胺基甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(35毫克，0.079毫莫耳)之DMF(1.0毫升)與DCM(1.0毫升)溶液中添加環丙烷磺醯氯(11毫克，0.079毫莫耳)與DIEA(14微升，0.079毫莫耳)。反應於室溫下攪拌一夜。化合物經Gilson製備性HPLC純化，產生7.2毫克標題化合物(17%)。 In the presence of 5-[3-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (35 Add Cyclopropane sulfonium chloride (11 mg, 0.079 mmol) to DIEA (14 μL, 0.079 mmol) in a solution of DMF (1.0 mL) and DCM (1.0 mL). The reaction was stirred at room temperature overnight. The compound was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 545.4[M+H]滯留時間：1.94分鐘 LC/MS = m / z 545.4 [M + H] retention time: 1.94 minutes

實例370：5-[3-({[(2,5-二氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H吲哚-7-羧醯胺Example 370: 5-[3-({[(2,5-Dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4- Piperidinyl]-1 H吲哚-7-carboxyguanamine

在含5-[3-(胺基甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(40毫克，0.096毫莫耳)之DMF(1.0毫升)與DCM(1.0毫升)溶液中添加2,5-二氯苯磺醯氯(86毫克，0.352毫莫耳)與DIEA(62微升，0.352毫莫耳)。反應於室溫下攪拌6小時。反應混合物濃縮後，經Gilson製備性HPLC純化，產生6.6毫克標題化合物(11%)。 In the presence of 5-[3-(aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (40 Add 2,5-dichlorobenzenesulfonyl chloride (86 mg, 0.352 mmol) to DIEA (62 μL, 0.352 mM) in DMF (1.0 mL) and DCM (1.0 mL). Moore). The reaction was stirred at room temperature for 6 hours. The reaction mixture was concentrated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 649.2[M+H]滯留時間：2.25分鐘 LC/MS=m/z 649.2 [M+H] retention time: 2.25 minutes

實例371：5-[3-({[(4-溴苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 371: 5-[3-({[(4-Bromophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl ]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據5-[3-({[(2,5-二氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用4-溴苯磺醯氯(90毫克，0.352毫莫耳)替代2,5-二氯苯磺醯氯製備。反應混合物濃縮後，經Gilson製備性HPLC純化，產生19.4毫克標題化合物(31%)。 The title compound is based on 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl- 1H -indole-7-carboxamide in the general process, but replaced with 4-bromobenzenesulfonyl chloride (90 mg, 0.352 mmol) instead of 2,5-dichlorobenzenesulfonate Chlorine preparation. The reaction mixture was concentrated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 659.4[M+H]滯留時間：2.20分鐘 LC/MS=m/z 659.4 [M+H] retention time: 2.20 minutes

實例372：5-[3-({[(4-氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 372: 5-[3-({[(4-Chlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl ]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據5-[3-({[(2,5-二氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用(2E,4E)-5-氯-2,4,6-庚三烯-2-磺醯氯(80毫克，0.352毫莫耳)替代2,5-二氯苯磺醯氯製備。反應混合物濃縮後，經Gilson製備性HPLC純化，產生7.5毫克標題化合物(13%)。 The title compound is based on 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl- 1H -indole-7-carboxamide as a general procedure, but with (2 E , 4 E )-5-chloro-2,4,6-heptatriene-2-sulfonate Chlorine (80 mg, 0.352 mmol) was prepared instead of 2,5-dichlorobenzenesulfonyl chloride. The reaction mixture was concentrated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 615.2[M]滯留時間：2.19分鐘 LC/MS=m/z 615.2 [M] retention time: 2.19 minutes

實例373：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(3-氟苯基)磺醯基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺Example 373: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[3-({[(3-fluorophenyl)sulfonyl]amino}methyl)phenyl) ]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據5-[3-({[(2,5-二氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用3-氟苯磺醯氯(69毫克，0.352毫莫耳)替代2,5-二氯苯磺醯氯製備。反應混合物濃縮後，經Gilson製備性HPLC純化，產生7.3毫克標題化合物(13%)。 The title compound is based on 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl- 1H -indole-7-carboxamide in the general process, but replaced with 3-fluorobenzenesulfonyl chloride (69 mg, 0.352 mmol) instead of 2,5-dichlorobenzenesulfonate Chlorine preparation. The reaction mixture was concentrated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 599.2[M+H]滯留時間：2.15分鐘 LC/MS=m/z 599.2 [M+H] retention time: 2.15 minutes

實例374：5-[3-({[(2-氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 374: 5-[3-({[(2-Chlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl ]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據5-[3-({[(2,5-二氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用2-氯苯磺醯氯(74毫克，0.352毫莫耳)替代2,5-二氯苯磺醯氯製備。反應混合物濃縮後，經Gilson製備性HPLC純化，產生17.3毫克標題化合物(29%)。 The title compound is based on 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl- 1H -indole-7-carboxamide in the general process, but switched to 2-chlorobenzenesulfonium chloride (74 mg, 0.352 mmol) instead of 2,5-dichlorobenzenesulfonate Chlorine preparation. The reaction mixture was concentrated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 615.2[M]滯留時間：2.15分鐘 LC/MS=m/z 615.2 [M] retention time: 2.15 minutes

實例375：5-[3-({[(2,5-二氯-3-噻吩基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 375: 5-[3-({[(2,5-Dichloro-3-thienyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl) 4-piperidinyl]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據5-[3-({[(2,5-二氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用2,5-二氯-3-噻吩磺醯氯(86毫克，0.352毫莫耳)替代2,5-二氯苯磺醯氯製備。反應混合物濃縮後，經Gilson製備性HPLC純化，產生16.7毫克標題化合物(27%)。 The title compound is based on 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl- 1H -indole-7-carboxamide in the general process, but replaced with 2,5-dichloro-3-thiophenesulfonium chloride (86 mg, 0.352 mmol) instead of 2,5 - Preparation of dichlorobenzenesulfonium chloride. The reaction mixture was concentrated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 655.2[M]滯留時間：2.24分鐘 LC/MS=m/z 655.2 [M] retention time: 2.24 minutes

實例376：5-[3-({[(2-氯-6-甲基苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 376: 5-[3-({[(2-chloro-6-methylphenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)- 4-piperidinyl]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據5-[3-({[(2,5-二氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用2-氯-6-甲基苯磺醯氯(86毫克，0.352毫莫耳)替代2,5-二氯苯磺醯氯製備。反應混合物濃縮後，經Gilson製備性HPLC純化，產生17.9毫克標題化合物(30%)。 The title compound is based on 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl- 1H -indole-7-carboxamide in the general process, but replaced with 2-chloro-6-methylbenzenesulfonyl chloride (86 mg, 0.352 mmol) instead of 2,5- Preparation of dichlorobenzenesulfonyl chloride. The reaction mixture was concentrated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 629.4[M]滯留時間：2.19分鐘 LC/MS=m/z 629.4 [M] retention time: 2.19 minutes

實例377：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(5-氟-2-甲基苯基)磺醯基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺Example 377: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(5-fluoro-2-methylphenyl)sulfonyl]amino} Methyl)phenyl]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據5-[3-({[(2,5-二氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用5-氟-2-甲基苯磺醯氯(86毫克，0.352毫莫耳)替代2,5-二氯苯磺醯氯製備。反應混合物濃縮後，經Gilson製備性HPLC純化，產生標題化合物。 The title compound is based on 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl- 1H -indole-7-carboxamide in the general process, but instead of 5-fluoro-2-methylbenzenesulfonyl chloride (86 mg, 0.352 mmol) instead of 2,5- Preparation of dichlorobenzenesulfonyl chloride. The reaction mixture was concentrated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 613.2[M+H]滯留時間：2.18分鐘 LC/MS = m / z 613.2 [M + H] retention time: 2.18 minutes

實例378：5-[3-({[(1,2-二甲基-1H-咪唑-4-基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 378: 5-[3-({[(1,2-Dimethyl- 1H -imidazol-4-yl)sulfonyl]amino}methyl)phenyl]-3-[1-(B Sulfosyl)-4-piperidinyl]-1 H -indole-7-carboxamide

標題化合物係依據5-[3-({[(2,5-二氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用1,2-二甲基-1H-咪唑-4-磺醯氯(69毫克，0.352毫莫耳)替代2,5-二氯苯磺醯氯製備。反應混合物濃縮後，經Gilson製備性HPLC純化，產生1.9毫克標題化合物(3.3%)。 The title compound is based on 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl- 1H -indole-7-carboxamide in the general process, but with 1,2-dimethyl- 1H -imidazole-4-sulfonium chloride (69 mg, 0.352 mmol) Prepare instead of 2,5-dichlorobenzenesulfonyl chloride. The reaction mixture was concentrated and purified with EtOAc EtOAc EtOAc

LC/MS=m/z 599.2[M+H]滯留時間：1.76分鐘 LC/MS=m/z 599.2 [M+H] retention time: 1.76 min

實例379：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(苯基磺醯基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺Example 379: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-{[(phenylsulfonyl)amino]methyl}phenyl)-1 H -吲哚-7-carboxyguanamine

標題化合物係依據5-[3-({[(2,5-二氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用苯磺醯氯(62毫克，0.352毫莫耳)替代2,5-二氯苯磺醯氯製備。反應混合物濃縮後，經Gilson製備性HPLC純化，產生13.4毫克標題化合物(24%)。 The title compound is based on 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 The general procedure for -piperidinyl- 1H -indole-7-carboxamide is prepared by replacing phenylsulfonium chloride (62 mg, 0.352 mmol) with 2,5-dichlorobenzenesulfonyl chloride. The reaction mixture was concentrated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 581.6[M+H]滯留時間：2.10分鐘 LC/MS=m/z 581.6 [M+H] retention time: 2.10 minutes

實例380：3-[1-(乙基磺醯基)-4-哌啶基]-5-[3-({[(4-氟苯基)磺醯基]胺基}甲基)苯基]-1H-吲哚-7-羧醯胺Example 380: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-({[(4-fluorophenyl)sulfonyl]amino}methyl)phenyl) ]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據5-[3-({[(2,5-二氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用4-氟苯磺醯氯(69毫克，0.352毫莫耳)替代2,5-二氯苯磺醯氯製備。反應混合物濃縮後，經Gilson製備性HPLC純化，產生11.5毫克標題化合物(20%)。 The title compound is based on 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl- 1H -indole-7-carboxamide in the general process, but replaced with 4-fluorobenzenesulfonyl chloride (69 mg, 0.352 mmol) instead of 2,5-dichlorobenzenesulfonate Chlorine preparation. The reaction mixture was concentrated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 599.2[M+H]滯留時間：2.10分鐘 LC/MS=m/z 599.2 [M+H] retention time: 2.10 min

實例381：5-[3-({[(4-溴-2-乙基苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 381: 5-[3-({[(4-Bromo-2-ethylphenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)- 4-piperidinyl]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據5-[3-({[(2,5-二氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用4-溴-2-乙基苯磺醯氯(100毫克，0.352毫莫耳)替代2,5-二氯苯磺醯氯製備。反應混合物濃縮後，經Gilson製備性HPLC純化，產生2.7毫克標題化合物(4%)。 The title compound is based on 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl- 1H -indole-7-carboxamide in the general process, but replaced with 4-bromo-2-ethylbenzenesulfonyl chloride (100 mg, 0.352 mmol) instead of 2,5- Preparation of dichlorobenzenesulfonyl chloride. The reaction mixture was concentrated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 687.6[M]滯留時間：2.38分鐘 LC/MS=m/z 687.6 [M] retention time: 2.38 minutes

實例382：5-(3-{[(1-苯并噻吩-3-基磺醯基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 382: 5-(3-{[(1-benzothiophen-3-ylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據5-[3-({[(2,5-二氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用1-苯并噻吩-3-磺醯氯(82毫克，0.352毫莫耳)替代2,5-二氯苯磺醯氯製備。反應混合物濃縮後，經Gilson製備性HPLC純化，產生3.9毫克標題化合物(6%)。 The title compound is based on 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl- 1H -indole-7-carboxamide in the general process, but instead of 1-benzothiophene-3-sulfonyl chloride (82 mg, 0.352 mmol) instead of 2,5-di Preparation of chlorobenzenesulfonyl chloride. The reaction mixture was concentrated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 637.4[M+H]滯留時間：2.19分鐘 LC/MS=m/z 637.4 [M+H] retention time: 2.19 minutes

實例383：5-{3-[({[4-(1,1-二甲基乙基)苯基]磺醯基}胺基)甲基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 383: 5-{3-[({[4-(1,1-Dimethylethyl)phenyl]sulfonyl}amino)methyl]phenyl}-3-[1-(ethyl Sulfomethyl)-4-piperidinyl]-1 H -indole-7-carboxyguanamine

標題化合物係依據5-[3-({[(2,5-二氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用4-(1,1-二甲基乙基)苯磺醯氯(82毫克，0.352毫莫耳)替代2,5-二氯苯磺醯氯製備。反應混合物濃縮後，經Gilson製備性HPLC純化，產生15.6毫克標題化合物(26%)。 The title compound is based on 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl- 1H -indole-7-carboxamide in the general procedure, but using 4-(1,1-dimethylethyl)benzenesulfonyl chloride (82 mg, 0.352 mmol) Instead of 2,5-dichlorobenzenesulfonyl chloride. The reaction mixture was concentrated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 637.4[M+H]滯留時間：2.35分鐘 LC/MS=m/z 637.4 [M+H] retention time: 2.35 minutes

實例384：5-[3-({[(3,4-二氟苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 384: 5-[3-({[(3,4-Difluorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4- Piperidinyl]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據5-[3-({[(2,5-二氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用3,4-二氟苯磺醯氯(75毫克，0.352毫莫耳)替代2,5-二氯苯磺醯氯製備。反應混合物濃縮後，經Gilson製備性HPLC純化，產生標題化合物。 The title compound is based on 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl- 1H -indole-7-carboxamide in the general process, but replaced with 3,4-difluorobenzenesulfonyl chloride (75 mg, 0.352 mmol) instead of 2,5-dichloro Preparation of benzenesulfonyl chloride. The reaction mixture was concentrated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 617.2[M+H]滯留時間：2.16分鐘 LC/MS = m / z 617.2 [M + H] retention time: 2.16 minutes

實例385：5-(3-{[(2,1,3-苯并二 唑-4-基磺醯基)胺基]甲基}苯基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺 Example 385: 5-(3-{[(2,1,3-Benzene) Azyl-4-ylsulfonyl)amino]methyl}phenyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide

標題化合物係依據5-[3-({[(2,5-二氯苯基)磺醯基]胺基}甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用2,1,3-苯并二唑-4-磺醯氯(77毫克，0.352毫莫耳)替代2,5-二氯苯磺醯氯製備。反應混合物濃縮後，經Gilson製備性HPLC純化，產生標題化合物。 The title compound is based on 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4 -piperidinyl]-1 H -吲哚-7-carboxyguanamine general process, but switched to 2,1,3-benzoic acid Oxazole-4-sulfonium chloride (77 mg, 0.352 mmol) was prepared instead of 2,5-dichlorobenzenesulfonyl chloride. The reaction mixture was concentrated and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 623.4[M+H]滯留時間：2.10分鐘 LC/MS=m/z 623.4 [M+H] retention time: 2.10 minutes

實例386：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(四氫-3-呋喃基羰基)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺Example 386: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(tetrahydro-3-furanylcarbonyl)amino]methyl}phenyl)- 1 H -吲哚-7-carboxyguanamine

在含四氫-3-呋喃羧酸(17毫克，0.144毫莫耳)之DCM(2.0毫升)溶液中添加吡啶(3滴)與草醯氯(18毫克，0.144毫莫耳)。於室溫下攪拌反應混合物一夜。在混合物中添加含5-[3-(胺基甲基)苯基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(40毫克，0.096毫莫耳)之DMF(1.0毫升)與DIEA(33微升，0.192毫莫耳)。於室溫下攪拌反應混合物一夜。反應混合物於氮蒙氣下濃縮，經Gilson製備性HPLC純化，產生5.3毫克標題化合物(10%)。 Pyridine (3 drops) and grass chlorohydrate (18 mg, 0.144 mmol) were added to a solution of tetrahydro-3-furancarboxylic acid (17 mg, 0.144 mmol) in DCM (2.0 mL). The reaction mixture was stirred at room temperature overnight. Add 5-[3-(Aminomethyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxyindole to the mixture Amine (40 mg, 0.096 mmol) of DMF (1.0 mL) and DIEA (33 </ RTI></RTI><RTIgt; The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated with EtOAc EtOAc EtOAc.

LC/MS=m/z 539.2[M+H]滯留時間：1.80分鐘 LC/MS = m / z 539.2 [M + H] retention time: 1.80 minutes

實例387：5-{4-[(環戊基磺醯基)胺基]苯基}-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 387: 5-{4-[(Cyclopentylsulfonyl)amino]phenyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole- 7-Carboguanamine trifluoroacetate

在5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(20毫克，0.048毫莫耳)中添加含氯(二-2-原冰片基膦基)(2-二甲基胺基甲基二茂絡鐵-1-基)鈀(II)(10毫克，0.016毫莫耳)、碳酸鉀(13.4毫克，0.097毫莫耳)與N-[4-(4,4,5,5- 四甲基-1,3,2-二氧硼戊環-2-基)苯基]環戊烷磺醯胺(34毫克，0.097毫莫耳)之二烷(3毫升)與H₂O(1毫升)。反應混合物於微波爐中，於160℃下反應10分鐘。反應混合物於氮蒙氣下濃縮，經Gilson製備性HPLC純化，產生8.6毫克標題化合物(32%)。 Adding chlorine to 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚-7-carboxamide (20 mg, 0.048 mmol) Di-2-orthobornylphosphino)(2-dimethylaminomethyldithioferron-1-yl)palladium(II) (10 mg, 0.016 mmol), potassium carbonate (13.4 mg, 0.097) Millol) with N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopentanesulfonamide (34 Mg, 0.097 millimoles) Alkane (3 ml) with H ₂ O (1 mL). The reaction mixture was reacted in a microwave oven at 160 ° C for 10 minutes. The reaction mixture was concentrated with EtOAc EtOAc EtOAc.

LC/MS=m/z 559.2[M+H]滯留時間：2.00分鐘 LC/MS=m/z 559.2 [M+H] retention time: 2.00 min

實例388：3-[1-(乙基磺醯基)-4-哌啶基]-5-[4-(4-甲基-2-氧代-1-哌 基)苯基]-1H-吲哚-7-羧醯胺 Example 388: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[4-(4-methyl-2-oxo-1-piperidin Phenyl]-1 H -吲哚-7-carboxyguanamine

在5-溴-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(20毫克，0.048毫莫耳)中添加含4-甲基-1-[4-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)苯基]-2-哌酮(31毫克，0.097毫莫耳)之二烷(3.0毫升)與H₂O(1.0毫升)、碳酸鉀(13毫克，0.097毫莫耳)與氯(二-2-原冰片基膦基)(2-二甲基胺基甲基二茂絡鐵-1-基)鈀(II)(10毫克，0.016毫莫耳)。反應混合物於微波爐中，於160℃下反應10分鐘。反應混合物於微波爐中，於160℃下加熱10分鐘。反應混合物於氮蒙氣下濃縮，經Gilson製備性HPLC純化。所需溶離份於CH₃CN與H₂O中，經飽和碳酸鉀處理成中性鹽後，濃縮，產生1.9毫克標題化合物(8%)。 Add 4- in 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (20 mg, 0.048 mmol) Methyl-1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-piperidin Ketone (31 mg, 0.097 mmol) Alkane (3.0 ml) with H ₂ O (1.0 ml), potassium carbonate (13 mg, 0.097 mmol) and chlorine (di-2-norbornylphosphino) (2-dimethylaminomethyl dimethyl Complex iron-1-yl)palladium(II) (10 mg, 0.016 mmol). The reaction mixture was reacted in a microwave oven at 160 ° C for 10 minutes. The reaction mixture was heated in a microwave oven at 160 ° C for 10 minutes. The reaction mixture was concentrated under nitrogen and purified by EtOAc EtOAc. The desired fractions from parts in CH ₃ CN and H ₂ O, the post-treatment in a neutral salt with saturated potassium carbonate and concentrated to yield 1.9 mg of the title compound (8%).

LC/MS=m/z 524.6[M+H]滯留時間：1.49分鐘 LC/MS=m/z 524.6 [M+H] retention time: 1.49 minutes

實例389：5-[6-(4-乙醯基-1-哌 基)-3-吡啶基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽 Example 389: 5-[6-(4-Ethyl-1-cylepine) Benzyl-3-pyridyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide fluorotrifluoroacetate

於0℃下，在含3-[1-(乙基磺醯基)-4-哌啶基]-5-[6-(1-哌基)-3-吡啶基]-1H-吲哚-7-羧醯胺(40毫克，0.080毫莫耳)之二氯甲烷溶液中添加乙醯氯(7微升，0.096毫莫耳)與DIEA(11.6微升，0.12毫莫耳)。反應混合物於0℃至室溫之間反應0.5小時後，以H₂O中止反應。化合物經MDAP HPLC純化，產生7毫克標題化合物(40%)。 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[6-(1-piperidin) at 0 ° C Add ethyl ruthenium chloride (7 μL, 0.096 mmol) to a solution of benzylidene-3-pyridyl]-1 H -indole-7-carboxamide (40 mg, 0.080 mmol) in dichloromethane DIEA (11.6 μl, 0.12 mmol). After the reaction mixture was reacted between 0 ° C and room temperature for 0.5 hour, the reaction was quenched with H ₂ O. The compound was purified by MDAP to give 7 mg of the title compound (40%).

LC/MS=m/z 539.4[M+H]滯留時間：1.27分鐘 LC/MS=m/z 539.4 [M+H] retention time: 1.27 minutes

實例390：3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(甲基氧)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺Example 390: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(4-{[(methyloxy)amino]methyl}phenyl)-1 H -indole -7-carboxyguanamine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)之DCM(1.5毫升)與MeOH(1.5毫升)溶液中添加O-甲基羥基胺(114毫克，1.71毫莫耳)。攪拌反應一夜。濃縮溶劑，經Gilson製備性HPLC純化，產生38毫克3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(甲基氧)亞胺基]甲基}苯基)-1H-吲哚-7-羧醯胺(76%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-methylnonylphenyl)-1 H -indole-7-carboxamide (50 mg, 0.114 O -methylhydroxylamine (114 mg, 1.71 mmol) was added to a solution of EtOAc (1 mL). Stir the reaction overnight. The solvent was concentrated and purified by Gilson preparative HPLC to yield 38 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(methyloxy)imido] Base phenyl)-1 H -indole-7-carboxamide (76%).

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4-{[(甲基氧)亞胺基]甲基}苯基)-1H-吲哚-7-羧醯胺(21.5毫克，0.046毫莫耳)之DCM(3.0毫升)與MeOH(3.0毫升)溶液中滴加HCl之1,4-二烷溶液，於0℃下維持pH=4。添加氰基氫硼化鈉(29毫克，0.46毫莫耳)後，於室溫下攪拌一夜。除了添加氰基氫硼化鈉(45毫克，0.72毫莫耳)外，再加HCl之1,4-二烷溶液，維持pH=4。攪拌反應混合物48小時。再於0℃下添加HCl之1,4-二烷溶液，以維持pH=4，並攪拌至回升室溫。混合物經H₂O中止反應。添加DCM操作水相，混合物濃縮。殘質溶於DCM，經SCX SPE卡管純化，產生15.2毫克標題化合物(70%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-{[(methyloxy)imino]methyl}phenyl)-1 H -吲哚Add HCl to 1,4-diethyl -7-carboxyguanamine (21.5 mg, 0.046 mmol) in DCM (3.0 mL) and MeOH (3.0 mL) The alkane solution was maintained at pH = 4 at 0 °C. After adding sodium cyanoborohydride (29 mg, 0.46 mmol), it was stirred at room temperature overnight. In addition to the addition of sodium cyanoborohydride (45 mg, 0.72 mmol), plus HCl 1,4-two Alkane solution, maintaining pH=4. The reaction mixture was stirred for 48 hours. Add HCl 1,4- two at 0 ° C The alkane solution was maintained at pH = 4 and stirred until it was allowed to rise to room temperature. The mixture was quenched with H ₂ O. The aqueous phase was treated with DCM and the mixture was concentrated. The residue was dissolved in DCM and purified eluting with EtOAc EtOAc

LC/MS=m/z 471.6[M+H]滯留時間：1.67分鐘 LC/MS=m/z 471.6 [M+H] retention time: 1.67 minutes

實例391：3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(甲基氧)胺基]甲基}苯基)-1H-吲哚-7-羧醯胺Example 391: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(3-{[(methyloxy)amino]methyl}phenyl)-1 H -indole -7-carboxyguanamine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-甲醯基苯基)-1H-吲哚-7-羧醯胺(50毫克，0.114毫莫耳)之DMSO(3.0毫升)溶液中添加O-甲基羥基胺(57毫克，0.684毫莫耳)。攪拌反應一夜。再加O-甲基羥基胺(0.342毫莫耳)至其反應混合物中，攪拌48小時。濃縮溶劑後，經Gilson製備性HPLC純化，產生29.8毫克3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(甲基氧)亞胺基]甲基}苯基)-1H-吲哚-7-羧醯胺(56%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-methylnonylphenyl)-1 H -吲哚-7-carboxamide (50 mg, 0.114 O -methylhydroxylamine (57 mg, 0.684 mmol) was added to a solution of MeOH (3.0 mL). Stir the reaction overnight. O -Methylhydroxylamine (0.342 mmol) was added to the reaction mixture and stirred for 48 hours. After concentrating the solvent, it was purified by Gilson preparative HPLC to give 29.8 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(methyloxy)imido] Methyl}phenyl)-1 H -indole-7-carboxamide (56%).

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(3-{[(甲基氧)亞胺基]甲基}苯基)-1H-吲哚-7-羧醯胺(58毫克，0.123毫莫耳)之 DCM(3.0毫升)與MeOH(3.0毫升)溶液中添加HCl之1,4-二烷溶液，以維持pH=4。添加氰基氫硼化鈉(176毫克，3.69毫莫耳)後，攪拌一夜48小時。化合物經Gilson製備性HPLC純化，產生20.0毫克標題化合物(89%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-{[(methyloxy)imino]methyl}phenyl)-1 H -吲哚Add HCl to 1,4-bis to a solution of -7-carboxyguanamine (58 mg, 0.123 mmol) in DCM (3.0 mL) and MeOH (3.0 mL) Alkane solution to maintain pH = 4. After adding sodium cyanoborohydride (176 mg, 3.69 mmol), it was stirred overnight for 48 hours. The compound was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 471.6[M+H]滯留時間：1.75分鐘 LC/MS = m / z 471.6 [M + H] retention time: 1.75 minutes

實例392：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[4-(1-吡咯啶基)-1-哌啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 392: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[4-(1-pyrrolidinyl)-1-piperidinyl]methyl}- 3-thienyl)-1 H -indole-7-carboxamide fluorotrifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之DMSO(2.0毫升)溶液中添加4-(1-吡咯啶基)哌啶(173毫克，1.12毫莫耳)與乙酸(5滴)。6小時後，添加三乙醯氧基氫硼化鈉(238毫克，1.12毫莫耳)，攪拌反應一夜。反應混合物經Gilson製備性HPLC純化，產生17.0毫克標題化合物(26%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (50 To a solution of milligrams (0.112 mmol) in DMSO (2.0 mL) was added 4-(1-pyrrolidinyl)piperidine (173 mg, 1.12 mmol) and acetic acid (5 drops). After 6 hours, sodium triethoxysulfonium borohydride (238 mg, 1.12 mmol) was added and the reaction was stirred overnight. The reaction mixture was purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 584.4[M+H]滯留時間：1.38分鐘 LC/MS=m/z 584.4 [M+H] retention time: 1.38 min

實例393：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[(2S)-2-(三氟甲基)-1-吡咯啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 393: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[( 2S )-2-(trifluoromethyl)-1-pyrrolidinyl] Methyl}-3-thienyl)-1 H -indole-7-carboxamide fluorotrifluoroacetate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(50毫克，0.112毫莫耳)之DCM(3.0毫升)與MeOH(1.5毫升)溶液中添加(2S)-2-(三氟甲基)吡咯啶(156毫克，1.12毫莫耳)與乙酸(5滴)。於室溫下攪拌6小時後，添加氫硼化鈉(43毫克，1.12毫莫耳)，攪拌反應一夜。反應混合物經Gilson製備性HPLC純化，產生5.0毫克標題化合物(8%)。 Containing 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (50 ( 2S )-2-(Trifluoromethyl)pyrrolidine (156 mg, 1.12 mmol) and acetic acid (5 mg) in MeOH (0.1 mL). drop). After stirring at room temperature for 6 hours, sodium borohydride (43 mg, 1.12 mmol) was added and the mixture was stirred overnight. The reaction mixture was purified by EtOAc EtOAc EtOAc.

LC/MS=m/z 569.4[M+H]滯留時間：2.37分鐘 LC/MS=m/z 569.4 [M+H] retention time: 2.37 minutes

實例394：5-(5-{[(2R)-2-(羥基甲基)-1-吡咯啶基]甲基}-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-醯醯胺Example 394: 5-(5-{[(2R)-2-(Hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methyl-ethyl) Sulfhydryl]-4-piperidinyl}-1H-indole-7-decylamine

在含5-(5-甲醯基-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺(25毫克，0.054毫莫耳)之DMSO(2毫升)溶液中添加(2R)-2-吡咯啶基甲醇(101.15毫克，1毫莫耳)與2滴乙酸。所得混合物於室溫下攪拌4小時後，添加三乙醯氧基氫硼化鈉(212毫克，0.54毫莫耳)。混合物反應一夜後，經Gilson製備性HPLC純化，產生20.5毫克標題化合物(69.7%)。 In the presence of 5-(5-methylindolyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1 H -吲哚-7 To a solution of carboxyguanamine (25 mg, 0.054 mmol) in DMSO (2 mL) was added (2R)-2-pyrrolidinyl methanol (101.15 mg, 1 mmol) with 2 drops of acetic acid. After the resulting mixture was stirred at room temperature for 4 hr, sodium triethyloxy hydride hydride (212 mg, 0.54 m. The mixture was reacted overnight and purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 546[M+H]滯留時間：1.47分鐘。 LC/MS = m/z 546 [M+H].

實例395：5-(5-{[(3S)-3-羥基-1-吡咯啶基]甲基}-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺Example 395: 5-(5-{[(3S)-3-Hydroxy-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonate 4--4-piperidinyl}-1H-indole-7-carboxamide

標題化合物係依據5-(5-{[(2R)-2-(羥基甲基)-1-吡咯啶基]甲基}-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺之一般製程，但改用(3S)-3-吡咯啶醇(90.13毫克，1.20毫莫耳)替代(2R)-2-吡咯啶基甲醇製備，產生12.8毫克標題化合物(53.1%)。 The title compound is based on 5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methyl) ethyl) sulfo acyl] -4-piperidinyl} -1H- indole-7-carboxamide Amides of the general process, but using (3 S) -3- piperidinol pyrrole (90.13 mg, 1.20 mmol Substitution of (2R)-2-pyrrolidinylmethanol to give 12.8 mg of the title compound (53.1%).

LC/MS=m/z 532[M+H]滯留時間：1.45分鐘。 LC/MS = m/z 532 [M+H] retention: 1.45 min.

實例396：5-(5-{[環戊基(甲基)胺基]甲基}-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺Example 396: 5-(5-{[cyclopentyl(methyl)amino]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4 -piperidinyl}-1H-indole-7-carboxamide

標題化合物係依據5-(5-{[(2R)-2-(羥基甲基)-1-吡咯啶基]甲基}-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺之一般製程，但改用N-甲基環戊烷胺(90.13毫克，1.20毫莫耳)替代(2R)-2-吡咯啶基甲醇製備，產生10毫克標題化合物(54.3%) The title compound is based on 5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methyl) The general procedure for ethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide is replaced by N-methylcyclopentanamine (90.13 mg, 1.20 mmol) Preparation of (2R)-2-pyrrolidinylmethanol to give 10 mg of the title compound (54.3%)

LC/MS=m/z 544.2[M+H]滯留時間：1.65分鐘。 LC/MS = m/z 544.2 [M+H].

實例397：5-(5-{[(2-羥基乙基)(甲基)胺基]甲基}-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺Example 397: 5-(5-{[(2-Hydroxyethyl)(methyl)amino]methyl}-3-thienyl)-3-{1-[(1-methylethyl)sulfonate 4--4-piperidinyl}-1H-indole-7-carboxamide

標題化合物係依據5-(5-{[(2R)-2-(羥基甲基)-1-吡咯啶基]甲基}-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺之一般製程，但改用2-(甲基胺基)乙醇(90.13毫克，1.20毫莫耳)替代(2R)-2-吡咯啶基甲醇製備，產生8毫克標題化合物(51.9%)。 The title compound is based on 5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methyl) The general procedure for ethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide is switched to 2-(methylamino)ethanol (90.13 mg, 1.20 mmol) Substitution of (2R)-2-pyrrolidinylmethanol to give 8 mg of the title compound (51.9%).

LC/MS=m/z 520[M+H]滯留時間：1.44分鐘。 LC/MS = m/z 520 [M+H].

實例398：5-(5-{[(2-胺基-2-氧代乙基)(甲基)胺基]甲基}-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺Example 398: 5-(5-{[(2-Amino-2-oxoethyl)(methyl)amino]methyl}-3-thienyl)-3-{1-[(1-A) Benzyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide

標題化合物係依據5-(5-{[(2R)-2-(羥基甲基)-1-吡咯啶基]甲基}-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺之一般製程，但改用N2-甲基甘胺醯胺(90.13毫克，1.200毫莫耳)替代(2R)-2-吡咯啶基甲醇製備，產生15毫克標題化合物(53.2%)。 The title compound is based on 5-(5-{[(2R)-2-(hydroxymethyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methyl) The general procedure for ethyl)sulfonyl]-4-piperidinyl}-1H-indole-7-carboxamide is replaced by N2-methylglycinamide (90.13 mg, 1.200 mmol) Preparation of (2R)-2-pyrrolidinylmethanol gave 15 mg of the title compound (53.2%).

LC/MS=m/z 520[M+H]滯留時間：1.44分鐘。 LC/MS = m/z 520 [M+H].

實例399：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(2-丙烯-1-基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺Example 399: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(2-propen-1-yl)amino]methyl}-3- Thienyl)-1 H -吲哚-7-carboxyguanamine

添加烯丙基胺(0.034毫升，0.449毫莫耳)與HOAc(0.026毫升，0.449毫莫耳)至1達蘭小瓶中，含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(20毫克，0.0449毫莫耳)之DMSO(0.5毫升)溶液中。添加NaBH(OAc)₃(95毫克，0.449毫莫耳)後，小瓶加蓋，反應於室溫下攪拌15小時。添加NaCNBH₃(28毫克，0.449毫莫耳)與MeOH，再攪拌反應4小時。添加37 wt%甲醛水溶液(0.069毫升，0.898毫莫耳)，再攪拌反應1小時。反應混合物經2克SCX卡管(先經3毫升MeOH平衡) 過濾，依序以MeOH(3毫升)與2M NH₃/MeOH溶液(9毫升)溶離。NH₃/MeOH溶離份於氮氣流與50℃下濃縮，殘質溶於DMSO(1毫升)，經Gilson HPLC(Xbridge Prep C18管柱：19 x 100 mm)，依每分鐘20毫升，以15分鐘，使用線性梯度10%CH₃CN/H₂O(0.1% NH₄OH)至70%CH₃CN/H₂O(0.1%NH₄OH)溶離純化。取含標題化合物之溶離份於氮氣流與50℃下濃縮，產生5.2毫克標題化合物(23%)。 Add allylamine (0.034 ml, 0.449 mmol) and HOAc (0.026 mL, 0.449 mmol) to a 1 Dalan vial containing 3-[1-(ethylsulfonyl)-4-piperidine A solution of 5-(5-methylindolyl-3-thienyl)-1H-indole-7-carboxamide (20 mg, 0.0449 mmol) in DMSO (0.5 mL). After adding NaBH(OAc) ₃ (95 mg, 0.449 mmol), the vial was capped and the reaction was stirred at room temperature for 15 hours. NaCNBH ₃ (28 mg, 0.449 mmol) was added with MeOH and the mixture was stirred for further 4 hr. A 37 wt% aqueous formaldehyde solution (0.069 ml, 0.898 mmol) was added, and the reaction was further stirred for 1 hour. The reaction mixture was 2 g SCX card tube (to balance over 3 mL of MeOH) was filtered, washed successively with MeOH (3 mL) and 2M NH ₃ / MeOH solution (9 ml) fractions. The NH ₃ /MeOH fractions were concentrated in a stream of nitrogen and 50 ° C. The residue was dissolved in DMSO (1 mL), and then applied to Gilson HPLC (Xbridge Prep C18 column: 19 x 100 mm) at 20 ml per minute for 15 minutes using a linear gradient of _{10% CH 3 CN / / H} 2 O (0.1% NH 4 OH) eluting purified _{_{H 2 O (0.1% NH 4}} OH) to 70% CH ₃ CN. The fractions containing the title compound were taken from EtOAc (EtOAc)

LC/MS=m/z 501.4[M+H]滯留時間：1.48分鐘。 LC/MS = m/z 501.4 [M+H].

實例400：5-(5-{[[(3,5-二甲基-1H-吡唑-4-基)甲基](甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 400: 5-(5-{[[(3,5-Dimethyl-1H-pyrazol-4-yl)methyl](methyl)amino]methyl}-3-thienyl)-3 -[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(45毫克，100微莫耳)之二甲亞碸(1.0毫升)溶液中添加1-(3,5-二甲基-1H-吡唑-4-基)-N-甲基甲胺(320微莫耳)與2至3滴冰醋酸。所得混合物攪拌一夜。18 小時後，添加三乙醯氧基氫硼化鈉(200毫克，1000微莫耳)。攪拌此混合物1.5小時後，經Gilson製備性HPLC純化，產生6.24毫克標題化合物(11.0%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (45 Add 1-(3,5-dimethyl-1H-pyrazol-4-yl)-N-methylmethylamine (320 μM) to a solution of dimethylidene (1.0 ml) in milligrams (100 μmol) Ear) with 2 to 3 drops of glacial acetic acid. The resulting mixture was stirred overnight. After 18 hours, sodium triethoxysulfonium borohydride (200 mg, 1000 micromoles) was added. The mixture was stirred for 1.5 h then purified by EtOAc EtOAc EtOAc

LC/MS=m/z 569.3[M+H]滯留時間：1.42分鐘。 LC/MS = m/z 569.3 [M+H].

實例401：5-(5-{[(氰基甲基)(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 401: 5-(5-{[(Cyanomethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidine ]]-1H-吲哚-7-carboxyguanamine

標題化合物係依據5-(5-{[[(3,5-二甲基-1H-吡唑-4-基)甲基](甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺之一般製程，但改用(甲基胺基)乙腈(320微莫耳)替代1-(3,5-二甲基-1H-吡唑-4-基)-N-甲基甲胺製備，產生6.36毫克標題化合物(12.7%)。 The title compound is based on 5-(5-{[[(3,5-dimethyl-1H-pyrazol-4-yl)methyl](methyl)amino]methyl}-3-thienyl)- General procedure for 3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, but with (methylamino)acetonitrile (320 micromoles) Preparation of 1-(3,5-dimethyl-1H-pyrazol-4-yl)-N-methylmethylamine gave 6.36 mg of the title compound (12.7%).

LC/MS=m/z 430[M+H]滯留時間：1.70分鐘。 LC/MS = m/z 430 [M+H].

實例402：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(1-甲基丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺Example 402: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3-thiophene -1H-吲哚-7-carboxyguanamine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(45毫克，0.1毫莫耳)之二甲亞碸(1毫升)溶液中添加2-丁胺(1毫莫耳)、1至2滴乙酸與三乙醯氧基氫硼化鈉(211毫克，1毫莫耳)。所得混合物加蓋攪拌18小時後，添加氰基氫硼化鈉(62毫克，1毫莫耳)之甲醇(0.5毫升)溶液。攪拌3小時後，添加甲醛37%水溶液(1.5毫升)。經SCX(2克)卡管，依序以甲醇及NH₃之甲醇溶液溶離純化。再經Gilson製備性HPLC純化。經XBridge C18管柱(P/N 186002978)，使用梯度10%乙腈至70%乙腈之水溶液(含0.1% NH₄OH)，產生14.4毫克標題化合物(27.9%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (45 Add 2 -butylamine (1 mmol), 1 to 2 drops of acetic acid and sodium triethoxy hydride hydride (211 mg, 1 in milligrams, 0.1 mmol) in dimethyl hydrazine (1 ml). Millions of ears). After the mixture was stirred for 18 hours, a solution of sodium cyanoborohydride (62 mg, 1 mmol) in methanol (0.5 ml) was added. After stirring for 3 hours, a 37% aqueous solution of formaldehyde (1.5 ml) was added. It was purified by LCX and NH ₃ in methanol via SCX (2 g) tube. It was purified by Gilson preparative HPLC. By XBridge C18 column (P / N 186002978), using a gradient of 10% aqueous acetonitrile to 70% acetonitrile (containing 0.1% NH ₄ OH), to produce 14.4 mg of the title compound (27.9%).

LC/MS=m/z 517.3[M+H]滯留時間：1.58分鐘。 LC/MS = m/z 517.3 [M+H].

實例403：5-(5-{[[2-(乙基氧)乙基](甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 403: 5-(5-{[[2-(Ethyloxy)ethyl](methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl) 4-piperidinyl]-1H-indole-7-carboxamide

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(1-甲基丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺之一般製程，但改用2-(乙基氧)乙胺(1毫莫耳)替代添加之2-丁胺製備，產生6.1毫克標題化合物(11.5%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3- General procedure for the thiophenyl)-1H-indole-7-carboxamide, but using 2-(ethyloxy)ethylamine (1 mmol) instead of the added 2-butylamine to give 6.1 mg of the title compound (11.5%).

LC/MS=m/z 533.2[M+H]滯留時間：1.57分鐘。 LC/MS = m/z 533.2 [M+H].

實例404：5-(5-{[環丁基(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 404: 5-(5-{[Cyclobutyl(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1H-吲哚-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(1-甲基丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺之一般製程，但改用環丁基胺(1毫莫耳)替代添加之2-丁胺製備，產生3.7毫克標題化合物(5.9%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3- Thienyl)-1H-indole-7-carboxyguanamine The general procedure, but instead of cyclobutylamine (1 mmol) instead of the added 2-butylamine, yielded 3.7 mg of the title compound (5.9%).

LC/MS=m/z 515.3[M+H]滯留時間：1.64分鐘。 LC/MS = m/z 515.3 [M+H] retention time: 1.64 min.

實例405：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({2-[(甲基氧)甲基]-1-吡咯啶基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 405: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({2-[(methyloxy)methyl)-1-pyrrolidinyl}methyl )-3-thienyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(1-甲基丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺之一般製程，但改用2-[(甲基氧)甲基]吡咯啶(1毫莫耳)替代添加之2-丁胺製備，產生5毫克標題化合物(7.6%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3- General procedure for thienyl)-1H-indole-7-carboxamide, but instead of 2-[(methyloxy)methyl]pyrrolidine (1 mmol) instead of 2-butylamine added, 5 mg of the title compound (7.6%).

LC/MS=m/z 545.3[M+H]滯留時間：1.65分鐘。 LC/MS = m/z 545.3 [M+H].

實例406：5-(5-{[(1,1-二甲基乙基)(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 406: 5-(5-{[(1,1-Dimethylethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl) 4-piperidinyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(1-甲基丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺之一般製程，但改用2-甲基-2-丙胺(1毫莫耳)替代添加之2-丁胺製備，產生10.9毫克標題化合物(17.3%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3- General procedure for thienyl)-1H-indole-7-carboxamide, but using 2-methyl-2-propylamine (1 mmol) instead of the added 2-butylamine to give 10.9 mg of the title compound 17.3%).

LC/MS=m/z 517.3[M+H]滯留時間：1.61分鐘。 LC/MS = m/z 517.3 [M+H].

實例407：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[3-(三氟甲基)-1-哌啶基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 407: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[3-(trifluoromethyl)-1-piperidinyl]methyl}-3 -thienyl)-1H-indole-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[甲基(1-甲基丙基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺之一般製程，但改用3-(三氟甲基)哌啶(1毫莫耳)替代添加之2-丁胺製備，產生5.4毫克標題化合物(7.8%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3- General procedure for thienyl)-1H-indole-7-carboxamide, but using 3-(trifluoromethyl)piperidine (1 mmol) instead of 2-butylamine added to give 5.4 mg of title Compound (7.8%).

LC/MS=m/z 583.3[M+H]滯留時間：1.73分鐘。 LC/MS = m/z 583.3 [M+H].

實例408：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[(1S)-2-羥基-1-甲基乙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 408: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl) Amino]methyl}-3-thienyl)-1H-indole-7-carboxamide guanamine trifluoroacetate

在含(2R)-2-胺基-1-丙醇(90.13毫克，1.2毫莫耳)之小瓶中添加含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(30毫克，0067毫莫耳)之DMSO(300微升)與乙酸(50微升)溶液。所得混合物振盪5分鐘後，添加三乙醯氧基氫硼化鈉(250毫克，1.20毫莫耳)之DMSO(800微升)溶液。混合物振盪一夜。添加含氰基氫硼化鈉(79毫克，1.20毫莫耳)之甲醇(300微升)後，攪拌48小時。然後添加甲醛(100微升)。攪拌反應1小時後，經2克SCX粗產物卡管分離。濾出固體後，溶液濃縮，再經5克SCX卡管，以氨之MeOH溶液溶離純化。收集氨之MeOH溶液溶離份，濃縮，使用Gilson製備性HPLC分離，產生18.6毫克標題化合物(43.9%)。 Add 3-[1-(ethylsulfonyl)-4-piperidinyl]- in a vial containing ( 2R )-2-amino-1-propanol (90.13 mg, 1.2 mmol) 5-(5-Mercapto-3-thienyl)-1 H -indole-7-carboxamide (30 mg, 0067 mmol) in DMSO (300 μL) and acetic acid (50 μL) . After the resulting mixture was shaken for 5 minutes, a solution of sodium triacetoxyborohydride (250 mg, 1.20 mmol) in DMSO (800 μL) was added. The mixture oscillated overnight. After adding sodium cyanoborohydride (79 mg, 1.20 mmol) of methanol (300 μL), it was stirred for 48 hours. Then add formaldehyde (100 microliters). After stirring for 1 hour, it was separated by 2 g of SCX crude product cartridge. After the solid was filtered off, the solution was concentrated and purified by dissolving with EtOAc EtOAc over EtOAc. A solution of the ammonia in MeOH was taken, concentrated and purified using EtOAc EtOAc EtOAc.

LC/MS=m/z 519.3[M+H]滯留時間：1.49分鐘。 LC/MS = m/z 519.3 [M+H].

實例409：5-(5-{[(環丙基甲基)(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 409: 5-(5-{[(cyclopropylmethyl)(methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidin Pyridyl]-1H-indole-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[(1S)-2-羥基-1-甲基乙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(環丙基甲基)胺(1.20毫莫耳)替代(2R)-2-胺基-1-丙醇製備，產生6.2毫克標題化合物(14.7%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl) a general procedure for the amino]methyl}-3-thienyl)-1H-indole-7-carboxamide amine trifluoroacetate, but replaced with (cyclopropylmethyl)amine (1.20 mmol) instead Preparation of ( 2R )-2-amino-1-propanol gave 6.2 mg of the title compound (14.7%).

LC/MS=m/z 515.3[M+H]滯留時間：1.61分鐘。 LC/MS = m/z 515.3 [M+H].

實例410：5-(5-{[[2-(乙醯基胺基)乙基](甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 410: 5-(5-{[[2-(Ethylamino)ethyl](methyl)amino]methyl}-3-thienyl)-3-[1-(ethylsulfonate) Base)-4-piperidinyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[(1S)-2-羥基-1-甲基乙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用N-(2-胺基乙基)乙醯胺(1.20毫莫耳)替代(2R)-2-胺基-1-丙醇製備，產生13.6毫克標題化合物(30.8%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl) The general procedure for the amino]methyl}-3-thienyl)-1H-indole-7-carboxamide guanamine trifluoroacetate, but with N- (2-aminoethyl)acetamidine (1.20) Preparation of ( 2R )-2-amino-1-propanol afforded 13.6 mg of the title compound (30.8%).

LC/MS=m/z 546.2[M+H]滯留時間：1.47分鐘。 LC/MS = m/z 546.2 [M+H].

實例411：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[(1R,2R)-2-羥基環戊基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 411: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1R,2R)-2-hydroxycyclopentyl](methyl)amine ]methyl}-3-thienyl)-1H-indole-7-carboxamide fluorotrifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[(1S)-2-羥基-1-甲基乙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(1R,2R)-2-胺基環戊醇(1.20毫莫耳)替代(2R)-2-胺基-1-丙醇製備，產生9.6毫克標題化合物(21.8%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl) General procedure for amino]methyl}-3-thienyl)-1H-indole-7-carboxamide amine trifluoroacetate, but with (1 R , 2 R )-2-aminocyclopentanol (1.20 mmol) was prepared as a substitute for ( 2R )-2-amino-1-propanol to give 9.6 mg of the title compound (21.8%).

LC/MS=m/z 545.3[M+H]滯留時間：1.54分鐘。 LC/MS = m/z 545.3 [M+H].

實例412：5-(5-{[(1,1-二甲基丙基)(甲基)胺基]甲基-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 412: 5-(5-{[(1,1-Dimethylpropyl)(methyl)amino]methyl-3-thienyl)-3-[1-(ethylsulfonyl)- 4-piperidinyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[(1S)-2-羥基-1-甲基乙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(1,1-二甲基丙基)胺(1.20毫莫耳)替代(2R)-2-胺基-1-丙醇製備，產生13.1毫克標題化合物(30.3%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl) a general procedure for the amino]methyl}-3-thienyl)-1H-indole-7-carboxamide amine trifluoroacetate, but using (1,1-dimethylpropyl)amine (1.20 m) Preparation of ( 2R )-2-amino-1-propanol afforded 13.1 mg of the title compound (30.3%).

LC/MS=m/z 531.3[M+H]滯留時間：1.65分鐘。 LC/MS = m/z 531.3 [M+H].

實例413：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[(2S)-2-羥基丙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 413: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(2S)-2-hydroxypropyl](methyl)amino]methyl }-3-Thienyl)-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[(1S)-2-羥基-1-甲基乙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(2S)-1-胺基-2-丙醇(1.20毫莫耳)替代(2R)-2-胺基-1-丙醇製備，產生15.3毫克標題化合物(36.1%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl) The general procedure for the amino]methyl}-3-thienyl)-1H-indole-7-carboxamide amine trifluoroacetate, but using (2S)-1-amino-2-propanol (1.20) Preparation of ( 2R )-2-amino-1-propanol afforded 15.3 mg of the title compound (36.1%).

LC/MS=m/z 519.3[M+H]滯留時間：1.49分鐘。 LC/MS = m/z 519.3 [M+H].

實例414：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-({甲基[(2R)-四氫-2-呋喃基甲基]胺基}甲基)-3-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 414: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-({methyl[(2R)-tetrahydro-2-furanylmethyl]amino} Methyl)-3-thienyl]-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[(1S)-2-羥基-1-甲基乙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用[(2R)-四氫-2-呋喃基甲基]胺(1.20毫莫耳)替代(2R)-2-胺基-1-丙醇製備，產生15.5毫克標題化合物(35.1%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl) a general procedure for the amino]methyl}-3-thienyl)-1H-indole-7-carboxamide amine trifluoroacetate, but using [(2R)-tetrahydro-2-furanylmethyl] instead Preparation of the amine (1.20 mmol) in place of ( 2R )-2-amino-1-propanol yielded 15.5 mg of the title compound (35.1%).

LC/MS=m/z 545.3[M+H]滯留時間：1.58分鐘。 LC/MS = m/z 545.3 [M+H].

實例415：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[{2-[(2-羥基乙基)氧]乙基}(甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 415: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[{2-[(2-hydroxyethyl)oxy)ethyl}(methyl) Amino]methyl}-3-thienyl)-1H-indole-7-carboxamide guanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[(1S)-2-羥基-1-甲基乙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用2-[(2-胺基乙基)氧]乙醇(1.20毫莫耳)替代(2R)-2-胺基-1-丙醇製備，產生17.2毫克標題化合物(38.7%)。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl) a general procedure for the amino]methyl}-3-thienyl)-1H-indole-7-carboxamide amine trifluoroacetate, but using 2-[(2-aminoethyl)oxy]ethanol ( 1.20 mmoles was prepared in place of ( 2R )-2-amino-1-propanol to give 17.2 mg of the title compound (38.7%).

LC/MS=m/z 549.5[M+H]滯留時間：1.48分鐘。 LC/MS = m/z 549.5 [M+H].

實例416：3-[1-(乙基磺醯基)-4-哌啶基]-5-[5-(1-{甲基[2-(甲基氧)乙基]胺基}乙基)-3-噻吩基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 416: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[5-(1-{methyl[2-(methyloxy)ethyl]amino}ethyl )-3-thienyl]-1 H -indole-7-carboxyguanamine trifluoroacetate

在含5-(5-乙醯基-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(46毫克，0.1毫莫耳)之EtOH(2.0毫升)與AcOH(0.2毫升)溶液中添加甲基[2-(甲基氧)乙基]胺(200微升，2.0毫莫耳)與氰基氫硼化鈉(50毫克，0.8毫莫耳)。混合物於微波爐中，於120℃下反應2小時。再加甲基[2-(甲基氧)乙基]胺(100微升，1.0毫莫耳)與氰基氫硼化鈉(25毫克，0.4毫莫耳)，再反應3小時，於微波爐中，於120℃下反應2小時。然後再加甲基[2-(甲基氧)乙基]胺(100微升，2.0毫莫耳)與氰基氫硼化鈉(25毫克，0.4毫莫耳)，再反應3小時，於微波爐中，於120℃下反應2小時。濃縮所有溶劑，經Gilson製備性HPLC純化，產生20毫克標題化合物(38%)。 In the presence of 5-(5-ethylindolyl-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (46 Add millimethyl [2-(methyloxy)ethyl]amine (200 μL, 2.0 mmol) to cyanohydrogen in milligrams, 0.1 mmol of EtOH (2.0 mL) and AcOH (0.2 mL) Sodium boride (50 mg, 0.8 mmol). The mixture was reacted in a microwave oven at 120 ° C for 2 hours. Add methyl [2-(methyloxy)ethyl]amine (100 μL, 1.0 mmol) with sodium cyanoborohydride (25 mg, 0.4 mmol) for another 3 hours in a microwave oven The reaction was carried out at 120 ° C for 2 hours. Then add methyl [2-(methyloxy)ethyl]amine (100 μL, 2.0 mmol) with sodium cyanoborohydride (25 mg, 0.4 mmol) for another 3 hours. The reaction was carried out at 120 ° C for 2 hours in a microwave oven. All solvents were concentrated and purified by EtOAc EtOAc EtOAc.

LC/MS=m/z 533.2[M+H]滯留時間：1.46分鐘。 LC/MS = m/z 533.2 [M+H].

實例417：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{1-[甲基(丙基)胺基]乙基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 417: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{1-[methyl(propyl)amino]ethyl}-3-thienyl) -1 H -吲哚-7-carboxyguanamine trifluoroacetate

在含5-(5-乙醯基-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(46毫克，0.1毫莫耳)之EtOH(2.0毫升)與AcOH(0.2毫升)溶液中添加N-甲基-1-丙胺(200微升，2.0毫莫耳)與氰基氫硼化鈉(50毫克，0.8毫莫耳)。混合物於微波爐中，於120℃下反應120分鐘。再加N-甲基-1-丙胺(100微升，1.0毫莫耳)與氰基氫硼化鈉(25毫克，0.4毫莫耳)，再反應3小時，微波爐中，於120℃下反應120分鐘。濃縮所有溶劑，溶於DMSO，濾出固體。然後經Gilson製備性HPLC純化，產生18毫克標題化合物(35%)。 In the presence of 5-(5-ethylindolyl-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxamide (46 Add N -methyl-1-propylamine (200 μL, 2.0 mmol) to sodium cyanoborohydride (50 mg in milligrams, 0.1 mmol) in EtOH (2.0 mL) and AcOH (0.2 mL) , 0.8 millimoles). The mixture was reacted in a microwave oven at 120 ° C for 120 minutes. Add N -methyl-1-propylamine (100 μl, 1.0 mmol) with sodium cyanoborohydride (25 mg, 0.4 mmol), react for another 3 hours, and react at 120 ° C in a microwave oven. 120 minutes. All solvents were concentrated, dissolved in DMSO and the solid was filtered. Purification by Gilson preparative HPLC gave 18 mg of the title compound (35%).

LC/MS=m/z 517.2[M+H]滯留時間：1.52分鐘。 LC/MS = m/z 517.2 [M+H].

實例418：5-(2,3-二氫-1H-異吲哚-5-基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 418: 5-(2,3-Dihydro-1 H -isoindol-5-yl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indole -7-carboxyguanamine

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(4,4,5,5-四甲基-1,3,2-二氧硼戊環-2-基)-1H-吲哚-7-羧醯胺(150毫克，0.325毫莫耳)之二烷(0.75毫升)與水(0.25毫升)溶液中添加5-溴-2,3-二氫-1H-異吲哚鹽酸鹽(130毫克，0.651毫莫耳)與碳酸銫(636毫克，1.952毫莫耳)。反應混合物保持在氬氣下10分鐘後，添加肆(三苯基膦)鈀(0)(19毫克，0.016毫莫耳)。所得混合物於微波爐中，於150℃下加熱20分鐘。混合物經HPLC純化，產生11毫克標題化合物。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 -yl)-1 H -indole-7-carboxamide (150 mg, 0.325 mmol) Add 5-bromo-2,3-dihydro-1 H -isoindole hydrochloride (130 mg, 0.651 mmol) to cesium carbonate (636 mg, a solution of alkane (0.75 mL) and water (0.25 mL). 1.952 millimoles). After the reaction mixture was kept under argon for 10 minutes, hydrazine (triphenylphosphine)palladium(0) (19 mg, 0.016 mmol) was added. The resulting mixture was heated in a microwave oven at 150 ° C for 20 minutes. The mixture was purified by HPLC to yield 11 mg of the title compound.

LC/MS=m/z 453[M+H]滯留時間：1.33分鐘。 LC/MS = m/z 453 [M+H].

實例419：5-(2-乙基-2,3-二氫-1H-異吲哚-5-基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 419: 5-(2-Ethyl-2,3-dihydro-1 H -isoindol-5-yl)-3-[1-(ethylsulfonyl)-4-piperidinyl]- 1 H -吲哚-7-carboxyguanamine

在含5-(2,3-二氫-1H-異吲哚-5-基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(20毫克，0.044毫莫耳)之MeOH(1毫升)溶液中添加乙醛(6毫克，0.133毫莫耳)、氰基氫硼化鈉(6毫克，0.088毫莫耳)與氯化鋅(6毫克，0.044毫莫耳)。所得混合物於微波爐中，於100℃下加熱30分鐘。混合物濃縮，過濾與經Gilson製備性HPLC純化，產生8.2毫克標題化合物。 In the presence of 5-(2,3-dihydro-1 H -isoindol-5-yl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚- Add acetaldehyde (6 mg, 0.133 mmol), sodium cyanoborohydride (6 mg, 0.088 mmol) to a solution of 7-carboxamide (20 mg, 0.044 mmol) in MeOH (1 mL) With zinc chloride (6 mg, 0.044 mmol). The resulting mixture was heated in a microwave oven at 100 ° C for 30 minutes. The mixture was concentrated, filtered and purified with EtOAc EtOAc EtOAc

LC/MS=m/z 481[M+H]滯留時間：1.40分鐘。 LC/MS = m/z 481 [M+H].

實例420：3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(1-甲基乙基)-2,3-二氫-1H-異吲哚-5-基]-1H-吲哚-7-羧醯胺Example 420: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1 H -isoindole -5-yl]-1 H -吲哚-7-carboxyguanamine

在含5-(2,3-二氫-1H-異吲哚-5-基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(30毫克，0.066毫莫耳)之MeOH(0.5毫升)溶液中添加2-丙酮(12毫克，0.198毫莫耳)、氰基氫硼化鈉(8毫克，0.133毫莫耳)與氯化鋅(9毫克，0.066毫莫耳)。所得混合物於微波爐中，於100℃下加熱30分鐘。混合物濃縮，過濾與經Gilson製備性HPLC純化，產生0.8毫克標題化合物。 In the presence of 5-(2,3-dihydro-1 H -isoindol-5-yl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚- Add 2-acetone (12 mg, 0.198 mmol) to sodium cyanoborohydride (8 mg, 0.133 mmol) in a solution of 7-carboxamide (30 mg, 0.066 mmol) in MeOH (0.5 mL) ) with zinc chloride (9 mg, 0.066 mmol). The resulting mixture was heated in a microwave oven at 100 ° C for 30 minutes. The mixture was concentrated, filtered and purified with EtOAc EtOAc EtOAc

LC/MS=m/z 495.5[M+H]滯留時間：1.56分鐘。 LC/MS = m/z 495.5 [M+H].

實例421：5-[2-(1.2-二甲基丙基)-2,3-二氫-1H-異吲哚-5-基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 421: 5-[2-(1.2-Dimethylpropyl)-2,3-dihydro-1 H -isoindol-5-yl]-3-[1-(ethylsulfonyl)- 4-piperidinyl]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(1-甲基乙基)-2,3-二氫-1H-異吲哚-5-基]-1H-吲哚-7-羧醯胺之一般製程，但改用3-甲基-2-丁酮(17毫克，0.198毫莫耳)替代2-丙酮製備，產生14.6毫克標題化合物。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1 H -isoindole.哚-5-yl]-1 H-吲哚-7-carboxyguanamine general process, but replaced with 3-methyl-2-butanone (17 mg, 0.198 mmol) instead of 2-propanone, produced 14.6 mg of the title compound.

LC/MS=m/z 523[M+H]滯留時間：1.55分鐘。 LC/MS = m/z 523 [M+H].

實例422：3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(1-甲基丙基)-2,3-二氫-1H-異吲哚-5-基]-1H-吲哚-7-羧醯胺Example 422: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylpropyl)-2,3-dihydro-1 H -isoindole -5-yl]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(1-甲基乙基)-2,3-二氫-1H-異吲哚-5-基]-1H-吲哚-7-羧醯胺之一般製程，但改用2-丁酮(14毫克，0.198毫莫耳)替代2-丙酮製備，產生14.6毫克標題化合物。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1 H -isoindole. The general procedure for 哚-5-yl]-1 H -indole-7-carboxamide was used instead of 2-butanone (14 mg, 0.198 mmol) instead of 2-propanone to yield 14.6 mg of the title compound.

LC/MS=m/z 509[M+H]滯留時間：1.48分鐘。 LC/MS = m/z 509 [M+H].

實例423：5-[2-(1-乙基丙基)-2,3-二氫-1H-異吲哚-5-基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 423: 5-[2-(1-Ethylpropyl)-2,3-dihydro-1 H -isoindol-5-yl]-3-[1-(ethylsulfonyl)-4 -piperidinyl]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(1-甲基乙基)-2,3-二氫-1H-異吲哚-5-基]-1H-吲哚-7-羧醯胺之一般製程，但改用3-戊酮(17毫克，0.198毫莫耳)替代2-丙酮製備，產生13.8毫克標題化合物。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1 H -isoindole. The general procedure for 哚-5-yl]-1 H -indole-7-carboxamide was used instead of 3-pentanone (17 mg, 0.198 mmol) instead of 2-propanone to yield 13.8 mg of the title compound.

LC/MS=m/z 523[M+H]滯留時間：1.58分鐘。 LC/MS = m/z 564 [M+H].

實例424：5-(2-環戊基-2,3-二氫-1H-異吲哚-5-基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 424: 5-(2-Cyclopentyl-2,3-dihydro-1 H -isoindol-5-yl)-3-[1-(ethylsulfonyl)-4-piperidinyl] -1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(1-甲基乙基)-2,3-二氫-1H-異吲哚-5-基]-1H-吲哚-7-羧醯胺之一般製程，但改用環戊酮(17毫克，0.198毫莫耳)替代2-丙酮製備，產生4.8毫克標題化合物。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1 H -isoindole. The general procedure for 哚-5-yl]-1 H -indole-7-carboxamide was prepared using cyclopentanone (17 mg, 0.198 mmol) instead of 2-propanone to give 4.8 mg of the title compound.

LC/MS=m/z 521[M+H]滯留時間：1.54分鐘。 LC/MS = m/z 521 [M+H].

實例425：5-[2-(環丙基甲基)-2,3-二氫-1H-異吲哚-5-基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 425: 5-[2-(Cyclopropylmethyl)-2,3-dihydro-1 H -isoindol-5-yl]-3-[1-(ethylsulfonyl)-4- Piperidinyl]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(1-甲基乙基)-2,3-二氫-1H-異吲哚-5-基]-1H-吲哚-7-羧醯胺之一般製程，但改用環丙烷甲醛(14毫克，0.198毫莫耳)替代2-丙酮製備，產生10.8毫克標題化合物。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1 H -isoindole. The general procedure for 哚-5-yl]-1 H -indole-7-carboxamide was prepared using cyclopropanecarboxaldehyde (14 mg, 0.198 mmol) instead of 2-acetone to yield 10.8 mg of the title compound.

LC/MS=m/z 507[M+H]滯留時間：1.47分鐘。 LC/MS = m/z 507 [M+H].

實例426：5-[2-(2,2-二甲基丙基)-2,3-二氫-1H-異吲哚-5-基]-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺Example 426: 5-[2-(2,2-Dimethylpropyl)-2,3-dihydro-1 H -isoindol-5-yl]-3-[1-(ethylsulfonyl) )-4-piperidinyl]-1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(1-甲基乙基)-2,3-二氫-1H-異吲哚-5-基]-1H-吲哚-7-羧醯胺之一般製程，但改用2,2-二甲基丙醛(17毫克，0.198毫莫耳)替代2-丙酮製備，產生12.7毫克標題化合物。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1 H -isoindole.一般-5-yl]-1 H-吲哚-7-carboxyguanamine general process, but replaced with 2,2-dimethylpropanal (17 mg, 0.198 mmol) instead of 2-propanone, produced 12.7 mg of the title compound.

LC/MS=m/z 523[M+H]滯留時間：1.60分鐘。 LC/MS = m/z 523 [M+H].

實例427：3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-甲基-2,3-二氫-1H-異吲哚-5-基)-1H-吲哚-7-羧醯胺Example 427: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(2-methyl-2,3-dihydro-1 H -isoindol-5-yl)- 1 H -吲哚-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-[2-(1-甲基乙基)-2,3-二氫-1H-異吲哚-5-基]-1H-吲哚-7-羧醯胺之一般製程，但改用甲醛(6毫克，0.198毫莫耳)替代2-丙酮製備，產生1.2毫克標題化合物。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1 H -isoindole. The general procedure for 哚-5-yl]-1 H -indole-7-carboxamide was prepared by substituting formaldehyde (6 mg, 0.198 mmol) instead of 2-propanone to yield 1.2 mg of the title compound.

LC/MS=m/z 467[M+H]滯留時間：1.37分鐘。 LC/MS = m/z 467 [M+H].

實例428：3-[1-(乙基磺醯基)-4-哌啶基]-5-(2-{[(苯基磺醯基)胺基]羰基}-2,3-二氫-1H-異吲哚-5-基)-1H-吲哚-7-羧醯胺Example 428: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(2-{[(phenylsulfonyl)amino]carbonyl}-2,3-dihydro- 1 H -isoindol-5-yl)-1 H -indol-7-carboxyguanamine

在含5-(2,3-二氫-1H-異吲哚-5-基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺(30毫克，0.066毫莫耳)之DMSO(1.0毫升)溶液中添加異氰酸苯磺醯基酯(15毫克，0.079毫莫耳)。所得混合物於室溫下攪拌一夜。混合物經Gilson製備性HPLC純化，產生15.5毫克標題化合物。 In the presence of 5-(2,3-dihydro-1 H -isoindol-5-yl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -吲哚- To a solution of 7-carboxamide (30 mg, 0.066 mmol) in DMSO (1.0 mL) was added acesulfonyl isocyanate (15 mg, 0.079 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was purified by Gilson preparative HPLC to yield 15.5 mg of the title compound.

LC/MS=m/z 637[M+H]滯留時間：1.94分鐘。 LC/MS = m/z 637 [M+H].

實例429：5-(5-{[(2R)-2-(胺基羰基)-1-吡咯啶基]甲基}-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺Example 429: 5-(5-{[(2 R )-2-(Aminocarbonyl)-1-pyrrolidinyl]methyl}-3-thienyl)-3-{1-[(1-methyl) Ethyl)sulfonyl]-4-piperidinyl}-1 H -indole-7-carboxamide

在含5-(5-甲醯基-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺(25毫克，0.054毫莫耳)之DMSO(2毫升)溶液中添加D-脯胺醯胺(114毫克，1毫莫耳)與2滴乙酸。所得混合物於室溫下攪拌4小時後，添加三乙醯氧基氫硼化鈉(212毫克，1.0毫莫耳)。混合物反應一夜。然後經Gilson製備性HPLC純化，產生20.4毫克標題化合物。 In the presence of 5-(5-methylindolyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1 H -吲哚-7 To a solution of carboxamide (25 mg, 0.054 mmol) in DMSO (2 mL) was added D-decylamine (114 mg, 1 mmol) and 2 drops of acetic acid. After the resulting mixture was stirred at room temperature for 4 hr, sodium triethyloxy borohydride (212 mg, 1.0 mmol) was added. The mixture reacted overnight. Purification by Gilson preparative HPLC gave 20.4 mg of the title compound.

LC/MS=m/z 557[M+H]滯留時間：1.56分鐘。 LC/MS = m/z 557 [M+H].

實例430：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[2-(乙基硫)乙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺Example 430: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[[2-(ethylthio)ethyl](methyl)amino]methyl }-3-Thienyl)-1 H -吲哚-7-carboxyguanamine

在含5-(5-甲醯基-3-噻吩基)-3-{1-[(1-甲基乙基)磺醯基]-4-哌啶基}-1H-吲哚-7-羧醯胺(40毫克，0.09毫莫耳)之DMSO(2毫升)溶液中添加[2-(乙基硫)乙基]胺(105毫克，1毫莫耳)、乙酸(50微升)與三乙醯氧基氫硼化鈉(212毫克，1.0毫莫耳)。攪拌所得混合物一夜。在混合物中添加氰基氫硼化鈉(80毫克，1.2毫莫耳)，攪拌一夜後，添加甲醛(100微升，1.2毫莫耳)。混合物再攪拌3小時後，經Gilson製備性HPLC純化，產生7.0毫克標題化合物。 In the presence of 5-(5-methylindolyl-3-thienyl)-3-{1-[(1-methylethyl)sulfonyl]-4-piperidinyl}-1 H -吲哚-7 Add 2-[(Ethylthio)ethyl]amine (105 mg, 1 mmol), acetic acid (50 μl) to a solution of carboxamide (40 mg, 0.09 mmol) in DMSO (2 mL) Sodium triethoxy hydride hydride (212 mg, 1.0 mmol). The resulting mixture was stirred overnight. Sodium cyanoborohydride (80 mg, 1.2 mmol) was added to the mixture, and after stirring overnight, formaldehyde (100 μL, 1.2 mmol) was added. The mixture was stirred for a further 3 hours and purified by EtOAc EtOAc EtOAc

LC/MS=m/z 550[M+H]滯留時間：1.68分鐘。 LC/MS = m/z 550 [M+H] retention time: 1.68 min.

實例431：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[{2-[(2-羥基乙基)硫]乙基}(甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺Example 431: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[{2-[(2-hydroxyethyl)sulfanyl]ethyl}(methyl) Amino]methyl}-3-thienyl)-1 H -indole-7-carboxyguanamine

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[2-(乙基硫)乙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺之一般製程，但改用2-[(2-胺基乙基)硫]乙醇(121毫克，1.0毫莫耳)替代[2-(乙基硫)乙基]胺製備，產生16.0毫克標題化合物。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[2-(ethylthio)ethyl](methyl)amino]] General procedure for the radical -3-thienyl- 1H -indole-7-carboxamide, but with 2-[(2-aminoethyl)sulfide]ethanol (121 mg, 1.0 mmol) Prepared instead of [2-(ethylthio)ethyl]amine gave 16.0 mg of the title compound.

LC/MS=m/z 566[M+H]滯留時間：1.52分鐘。 LC/MS = m/z 566 [M+H].

實例432：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[2-羥基-1-(羥基甲基)乙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺Example 432: 3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-(5-{[[2-hydroxy-1-(hydroxymethyl)ethyl](methyl)amine Methyl}-3-thienyl)-1 H -indole-7-carboxamide

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[2-(乙基硫)乙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺之一般製程，但改用2-胺基-1,3-丙二醇(91毫克，1.0毫莫耳)替代[2-(乙基硫)乙基]胺製備，產生15.0毫克標題化合物。 The title compound is based on 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[2-(ethylthio)ethyl](methyl)amino]] General procedure for the radical -3-thienyl- 1H -indole-7-carboxamide, but replaced with 2-amino-1,3-propanediol (91 mg, 1.0 mmol) instead of [2- (Ethylthio)ethyl]amine was prepared to give 15.0 mg of the title compound.

LC/MS=m/z 535[M+H]滯留時間：1.44分鐘。 LC/MS = m/z 535 [M+H].

實例433：[(4-{7-(胺基羰基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-5-基}-2-噻吩基)甲基]甲基胺甲酸乙酯Example 433: [(4-{7-(Aminocarbonyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indol-5-yl}-2-thiophene Methyl]methylamine methyl formate

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-{5-[(甲基胺基)甲基]-3-噻吩基}-1H-吲哚-7-羧醯胺(50毫克，0.11毫莫耳)之DMF(1.0毫升)溶液中，於0℃下添加三乙胺(0.06毫升，0.44毫莫耳)與氯碳酸乙酯(0.021毫升，0.22毫莫耳)。所得混合物反應30分鐘後，經Gilson製備性HLPC純化，產生31.4毫克標題化合物(53.5%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-{5-[(methylamino)methyl]-3-thienyl}-1 H -吲哚- To a solution of 7-carboxyguanamine (50 mg, 0.11 mmol) in DMF (1.0 mL), EtOAc (EtOAc (EtOAc) Millions of ears). The resulting mixture was reacted for 30 min and purified by EtOAc EtOAc (EtOAc)

LC/MS=m/z 533.2[M+H]滯留時間：2.06分鐘。 LC/MS = m/z 533.2 [M+H].

實例434：N-[(4-{7-(胺基羰基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-5-基}-2-噻吩基)甲基]-N-甲基甘胺酸乙酯Example 434: N -[(4-{7-(Aminocarbonyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1 H -indol-5-yl}-2 -thienyl)methyl] -N -methylglycine ethyl ester

在含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(45毫克，100微莫耳)之二甲亞碸(1.0 毫升)溶液中添加N-甲基甘胺酸乙酯(320微莫耳)與2至3滴冰醋酸。所得混合物攪拌一夜。18小時後，添加三乙醯氧基氫硼化鈉(200毫克，1000微莫耳)。攪拌此混合物1.5小時後，經Gilson製備性HPLC純化，產生16.5毫克標題化合物(30.0%)。 In the presence of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-methylindolyl-3-thienyl)-1 H -indole-7-carboxamide (45 mg, 100 [mu] mole) of dimethyl sulfoxide (1.0 ml) was added N - methylglycine ethyl amine (320 micromolar) and 2 to 3 drops of glacial acetic acid. The resulting mixture was stirred overnight. After 18 hours, sodium triethoxysulfonium borohydride (200 mg, 1000 micromoles) was added. After the mixture was stirred for 1.5 hours, it was purified by EtOAc EtOAc.

LC/MS=m/z 547.1[M+H]滯留時間：1.55分鐘。 LC/MS = m/z 547.1 [M+H].

實例435：3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[(1S)-2-羥基-1-甲基乙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 435: 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1 S )-2-hydroxy-1-methylethyl](methyl Amino]methyl}-3-thienyl)-1 H -indole-7-carboxyguanamine trifluoroacetate

在含(2S)-2-胺基-1-丙醇(91毫克，1.2毫莫耳)之小瓶中添加含3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-甲醯基-3-噻吩基)-1H-吲哚-7-羧醯胺(30毫克，0.067毫莫耳)之DMSO(300微升)與乙酸(50微升)溶液。所得混合物振盪5分鐘後，添加三乙醯氧基氫硼化鈉(250毫克，1.20毫莫耳)之DMSO(800微升)溶液。混合物振盪一夜。添加氰基氫硼化鈉(79毫克，1.20毫莫耳)之甲醇(300微升)溶液後，攪拌48小時。然後添加甲醛(100微升)。攪拌反應1小時後，經2克SCX卡管分離。濾出固體，溶液濃縮，再經5克SCX卡管，以氨之MeOH溶液溶離純化。收集氨之MeOH溶液溶離份，濃縮，使用Gilson製備性HPLC分離，產生18.7毫克標題化合物。 Add 3-[1-(ethylsulfonyl)-4-piperidinyl]- in a vial containing ( 2S )-2-amino-1-propanol (91 mg, 1.2 mmol) 5-(5-Methylmercapto-3-thienyl)-1 H -indole-7-carboxamide (30 mg, 0.067 mmol) in DMSO (300 μL) and acetic acid (50 μL) . After the resulting mixture was shaken for 5 minutes, a solution of sodium triacetoxyborohydride (250 mg, 1.20 mmol) in DMSO (800 μL) was added. The mixture oscillated overnight. After adding a solution of sodium cyanoborohydride (79 mg, 1.20 mmol) in methanol (300 μL), it was stirred for 48 hours. Then add formaldehyde (100 microliters). After stirring for 1 hour, it was separated by 2 g of SCX tube. The solid was filtered off, the solution was concentrated, and then purified by EtOAc EtOAc EtOAc A solution of the ammonia in MeOH was taken, concentrated and purified using EtOAc EtOAc.

LC/MS=m/z 519.3[M+H]滯留時間：1.49分鐘。 LC/MS = m/z 519.3 [M+H].

實例436：5-(5-{[(1,1-二氧撐基四氫-3-噻吩基)(甲基)胺基]甲基}-3-噻吩基)-3-[1-(乙基磺醯基)-4-哌啶基]-1H-吲哚-7-羧醯胺三氟乙酸鹽Example 436: 5-(5-{[(1,1-Dioxytetrahydro-3-thienyl)(methyl)amino]methyl}-3-thienyl)-3-[1-( Ethylsulfonyl)-4-piperidinyl]-1 H -indole-7-carboxyguanamine trifluoroacetate

標題化合物係依據3-[1-(乙基磺醯基)-4-哌啶基]-5-(5-{[[(1S)-2-羥基-1-甲基乙基](甲基)胺基]甲基}-3-噻吩基)-1H-吲哚-7-羧醯胺三氟乙酸鹽之一般製程，但改用(1,1-二氧撐基四氫-3-噻吩基)胺(1.20毫莫耳)替代(2S)-2-胺基-1-丙醇製備，產生9.3毫克標題化合物。 The title compound is based on 3- [1- (ethyl-sulfo acyl) -4-piperidinyl] -5- (5 - {[[ (1 S) -2- hydroxy-1-methylethyl] (A yl) amino] methyl} -3-thienyl) -1 H - indole-7-carboxamide trifluoroacetate Amides of the general process, but using (1,1-dioxo-tetrahydro-3 alkylene group -Thienyl)amine (1.20 mmol) was replaced by ( 2S )-2-amino-1-propanol to give 9.3 mg of the title compound.

LC/MS=m/z 579[M+H]滯留時間：1.54分鐘。 LC/MS = m/z 579 [M+H].

生物數據Biological data

IKK2分析法IKK2 analysis

於桿狀病毒中，以C-末端標記GST之融合蛋白質表現重組人體IKK(殘基1-737)，並採用隨時間解析之螢光共振能量轉移(TR-FRET)分析法分析其活性。簡言之，取IKK2(終濃度0.5 nM-5nM)於分析緩衝液(50 mM HEPES、10 mM MgCl₂、1 mM CHAPS pH 7.4，含1 mM DTT與0.01% w/v BSA)中稀釋，加至含不同濃度化合物或DMSO媒劑(終濃度1.7%)之孔中。添加GST-IB受質(終濃度25 nM)/ATP(終濃度1 μM)啟動反應，總體積為6微升。反應於室溫下培養15分鐘後，添加3微升含檢測試劑之含50mM EDTA之緩衝液(100 mM HEPES pH 7.4、150 mM NaCl、50mM EDTA與0.01% w/v BSA)中止反應，其中包含標記W-1024銪螯合劑(芬蘭Turku市Wallac OY藥廠)之抗磷酸絲胺酸-IB-32/36單株抗體12C2(美國麻州Beverly市Cell Signalling Technology藥廠)，並添加標記APC之抗GST抗體(美國加州San Leandro市Prozyme藥廠)，反應再於室溫下培養60分鐘。採用BMG Rubystar分析板讀數機(BMG Labtech,Aylesbury,UK)測定GST-IB之磷酸化程度，以特定665nm能量轉移訊號對參考物銪620nm訊號比例表示。 In baculovirus, the fusion protein labeled with C-terminal GST expresses recombinant human IKK (residue 1-737) and its activity is analyzed by time-resolved fluorescence resonance energy transfer (TR-FRET) analysis. Briefly, IKK2 (final concentration 0.5 nM-5 nM) was diluted in assay buffer (50 mM HEPES, 10 mM MgCl ₂ , 1 mM CHAPS pH 7.4, containing 1 mM DTT and 0.01% w/v BSA), plus To wells containing different concentrations of compound or DMSO vehicle (final concentration 1.7%). The GST-IB substrate (final concentration 25 nM)/ATP (final concentration 1 μM) was added to initiate the reaction in a total volume of 6 μL. After the reaction was incubated at room temperature for 15 minutes, 3 μl of a buffer containing 50 mM EDTA (100 mM HEPES pH 7.4, 150 mM NaCl, 50 mM EDTA and 0.01% w/v BSA) containing the detection reagent was added to terminate the reaction, which contained Labeled W-1024 chelating agent (Wallac OY, Turku, Finland) anti-phospho-serine-IB-32/36 monoclonal antibody 12C2 (Cell Signalling Technology, Beverly, MA) with the addition of labeled APC Anti-GST antibody (Prozyme Pharmaceuticals, San Leandro, California, USA), the reaction was incubated for 60 minutes at room temperature. The degree of phosphorylation of GST-IB was determined using a BMG Rubystar assay plate reader (BMG Labtech, Aylesbury, UK), expressed as a reference 620 nm signal ratio for a specific 665 nm energy transfer signal.

結果result

測試實例1-31、33、35-51、53-58、60-97、100-116、118-121、123-137、139-163、165-172、174-197、199-220、222-242、244-276、279-330、332-358、360-385、387-402、404-419、421-426，與428-436化合物對抗IKK2之活性，且發現此等實例為IKK2之抑制劑。此等化合物之pIC₅₀為5.0或以上。亦測試實例277與278對抗IKK2之活性且發現這兩種化合物之pIC₅₀均小於5.0。 Test Examples 1-31, 33, 35-51, 53-58, 60-97, 100-116, 118-121, 123-137, 139-163, 165-172, 174-197, 199-220, 222- 242, 244-276, 279-330, 332-358, 360-385, 387-402, 404-419, 421-426, and 428-436 compounds against IKK2 activity, and found that these examples are inhibitors of IKK2 . These compounds have a pIC ₅₀ of 5.0 or more. Example 277 was also tested with the 278 active against IKK2 and these two compounds was found pIC ₅₀ of less than 5.0.

單核細胞分析法Monocyte assay

依下列方法分析IKK-β抑制人體單核細胞所刺激細胞素產生之效應：自經肝素處理之全血中，利用Ficoll梯度單離單核細胞，然後採用MACS磁性細胞分離小珠純化CD14+細胞。單離之單核細胞附著在96孔培養板上2小時，每毫升RPMI 1640 10% FBS(JRH Biosciences,Lenexa KS)含1 x 10⁶個細胞。添加試驗化合物至孔中30分鐘後，使用最終媒劑濃度0.1%DMSO刺激反應。添加200毫微克/毫升內毒素(LPS；大腸桿菌(E.coli)血清型026：B6)(Sigma藥廠，St.Louis,MO.)活化單核細胞，於37℃下培養24小時。採用ELISA或針對TNF-α採用Alphascreen分析法分析無細胞上澄液。ELISA係採用Pharmingen配對Abs進行，及Alphascreen係採用來自Perkin Elmer之Alphascreen受體與供體小珠與來自R&D Systems之抗人體TNF與生物素基化之抗人體TNF Abs進行。利用10%錐藍排除法測定細胞活力。 The effect of IKK-β on the inhibition of cytokine production by human monocytes was analyzed by the following method: From heparin-treated whole blood, mononuclear cells were isolated by Ficoll gradient, and then CD14+ cells were purified by MACS magnetic cell separation beads. The isolated monocytes were attached to a 96-well culture plate for 2 hours, and 1 x 10 ⁶ cells per ml of RPMI 1640 10% FBS (JRH Biosciences, Lenexa KS). After the test compound was added to the well for 30 minutes, the reaction was stimulated with a final vehicle concentration of 0.1% DMSO. Mononuclear cells were activated by adding 200 ng/ml endotoxin (LPS; E. coli serotype 026: B6) (Sigma Pharmaceuticals, St. Louis, MO.) and cultured at 37 ° C for 24 hours. Cell-free supernatants were analyzed by ELISA or by TNF-α using Alphascreen assay. ELISA was performed using Pharmingen paired Abs, and the Alphascreen line was performed using Perpha Elmer's Alphascreen receptor and donor beads with anti-human TNF and biotinylated anti-human TNF Abs from R&D Systems. Cell viability was determined using a 10% cone blue exclusion method.

結果result

於此單核細胞分析法中測試某些本發明實例。於本分析法中發現實例1-3、5-13、16-23、25-31、33、37、42-44、61、65-69、71-73、75-78、83、86-89、92、96、100-117、119-121、123-127、129-131、139、141、144、151、154-157、160-164、166-167、169-172、182、191、208-214、216-220、222、223、227、230-248、250、251、269、271、273-276、279-83、285-90、292-296、298、304-327、329、332-337、342、343、346、348、353、356-358、361、366-368、370-373、376、380、382、391、394-397、399-404、406、408、409、412、417-419、432、434，與435之IC₅₀<2μM。 Some examples of the invention were tested in this monocyte assay. Examples 1-3, 5-13, 16-23, 25-31, 33, 37, 42-44, 61, 65-69, 71-73, 75-78, 83, 86-89 were found in this assay. , 92, 96, 100-117, 1191-121, 123-127, 129-131, 139, 141, 144, 151, 154-157, 160-164, 166-167, 169-172, 182, 191, 208 -214, 216-220, 222, 223, 227, 230-248, 250, 251, 269, 271, 273-276, 279-83, 285-90, 292-296, 298, 304-327, 329, 332 -337, 342, 343, 346, 348, 353, 356-358, 361, 366-368, 370-373, 376, 380, 382, 391, 394-397, 399-404, 406, 408, 409, 412 , 417-419, 432, 434, and 435 IC ₅₀ < 2 μM.

實例4、15、24、34-36、50、70、118、128、132-134、136、137、140、143、146-148、153、158、159、165、168、192-194、196、197、200-207、224、249、253-262、270、272、299-303、330、338-341、360、362、363、365、374、375、377-379、381、383、385、388-390、392，與393在1μM(最高試驗劑量)下之抑制作用不超過65%。 Examples 4, 15, 24, 34-36, 50, 70, 118, 128, 132-134, 136, 137, 140, 143, 146-148, 153, 158, 159, 165, 168, 192-194, 196 , 197, 200-207, 224, 249, 253-262, 270, 272, 299-303, 330, 338-341, 360, 362, 363, 365, 374, 375, 377-379, 381, 383, 385 The inhibition of 388-390, 392, and 393 at 1 μM (the highest test dose) did not exceed 65%.

實例39、40、45-49、58-60、62、63、74、79-81、84、85、90、91、94、95、97、173-181、184-190、195、 198、328、345、347、349-353、345、355、429-431、433，與436在300 nM下之抑制作用<60%。 Examples 39, 40, 45-49, 58-60, 62, 63, 74, 79-81, 84, 85, 90, 91, 94, 95, 97, 173-181, 184-190, 195, The inhibition of 198, 328, 345, 347, 349-353, 345, 355, 429-431, 433, and 436 at 300 nM was <60%.

實例38、64、82、215、297、344、364與369之單核細胞分析法得到可變之結果。 The monocyte assays of Examples 38, 64, 82, 215, 297, 344, 364, and 369 gave variable results.

Claims

3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1 H- Isoindole-5-yl]-1 H -indole-7-carboxamide, Or a pharmaceutically acceptable salt thereof.

3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1 H- Isoindole-5-yl]-1 H -indole-7-carboxamide,

A pharmaceutical composition comprising 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1 H -isoindol-5-yl]-1 H -indole-7-carboxamide, or a pharmaceutically acceptable salt thereof, in association with one or more pharmaceutically acceptable excipients.

The pharmaceutical composition according to item 3 of the patent application further comprises one or more additional pharmaceutically active compounds.

3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1 H - for medical therapy Isoindole-5-yl]-1 H -indole-7-carboxamide or a pharmaceutically acceptable salt thereof.

3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2, for the treatment of asthma or chronic obstructive pulmonary disease (COPD), 3-Dihydro-1 H -isoindol-5-yl]-1 H -indol-7-carboxamide or a pharmaceutically acceptable salt thereof.

3-[1-(Ethylsulfonyl)-4-piperidinyl]-5-[2-(1-methylethyl)-2,3-dihydro-1 H -isoindole-5 - yl] -1 H - acceptable -7- 2carboxamide the indole or a pharmaceutically salt thereof in the manufacture of pharmaceuticals, pharmaceuticals for the treatment of asthma or chronic obstructive pulmonary disease (COPD).