CN101247804B - Chemical compounds - Google Patents

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CN101247804B
CN101247804B CN2006800304481A CN200680030448A CN101247804B CN 101247804 B CN101247804 B CN 101247804B CN 2006800304481 A CN2006800304481 A CN 2006800304481A CN 200680030448 A CN200680030448 A CN 200680030448A CN 101247804 B CN101247804 B CN 101247804B
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methyl
indole
piperidyl
methanamide
ethylsulfonyl
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CN101247804A (en
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邓江贺
杰弗里·K·克恩斯
金琦
林国良
林熹晨
迈克尔·林登穆思
克里斯托弗·E·尼普
聂红
索尼娅·M·托马斯
凯瑟琳·L·威多森
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SmithKline Beecham Corp
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Abstract

The invention is directed to novel indole carboxamide derivatives. Specifically, the invention is directed to compounds according to formula I: Formula (I) where R1 , R2, R3, U and V are defined below and to pharmaceutically acceptable salts thereof. The compounds of the invention are inhibitors of IKK2 and can be useful in the treatment of disorders associated with inappropriate IKK2 (also knownas IKKss) activity, such as rheumatoid arthritis, asthma, and COPD (chronic obstructive pulmonary disease). Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting IKK2 activity and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.

Description

Chemical compound
Invention field
The present invention relates to some indole carboxamides chemical compound, it is the inhibitor of kinase activity.More particularly, described chemical compound is the IKK2 inhibitor.These chemical compounds are used for treatment and the active diseases associated of inappropriate IKK2 (also claiming IKK β), comprise inflammatory diseases and tissue repair disease especially for treatment and prevention by the disease that IKK2 mechanism mediates.These diseases comprise rheumatoid arthritis, asthma and COPD (chronic obstructive pulmonary disease).
Background of invention
Important extended familys of enzyme are protein kinase families.At present, 500 kinds of different known protein kinases are arranged approximately.Yet, because the password that the people's gene group of 3-4% is a protein kinase to be formed, thereby in human body, have thousands of different and isolating kinases.Through with ATP-Mg 2+(γ-phosphate) is transferred to described amino acid side chain to the γ-phosphoric acid of complex, and protein kinase is used for the phosphorylation of catalytic amino acid side chain in various albumen.Most signal processing in these enzymes control cells, the reversibility phosphorylation of the hydroxyl through serine, threonine and tyrosine residue in the albumen is arranged cell function, growth, differentiation and destruction (accent is died) thus.Research shows that protein kinase is the crucial moderator of many cell functions, and described cell function comprises signal transduction, transcriptional regulatory, cell mobility and cell division.Some oncogene show the encoding proteins kinases equally, show that kinases plays certain function in tumor generates.These processes are often interosculated approach by altitude mixture control through complex, and wherein every kind of kinases itself is regulated by one or more kinases.Therefore, unusual or inappropriate protein kinase activity possibly promote the rising with these unusual kinase activity disease states associated.Because their physiology's relatedness, multiformity and ubiquity, protein kinase has become a kind of enzyme family of most important and broad research in biochemistry and medical research.
Based on the amino acid residue of their phosphorylations, the protein kinase family of enzyme typically is divided into two kinds of main subfamilies: protein tyrosine kinase and albumen serine/threonine kinase.Serine/threonine kinase (PSTK) comprises ring AMP-and cyclo GMP-dependency (dependent) protein kinase, calcium and phospholipid deopendent protein kinase, and calcium-and calmodulin, CaM-deopendent protein kinase, casein kinase, cell division cycle protein kinases or the like.These kinases are normally cytoplasmic or relevant with the particulate fraction of cell, maybe be by means of anchorin.In a large amount of condition of illness such as rheumatoid arthritis, psoriasis, septic shock, bone loss, many cancers and other proliferative disease, related to or suspected relevant with unusual protein serine/threonine kinase activity.Therefore, serine/threonine kinase and their signal transduction pathway thereof are the important target of drug design to a certain extent.Described EGFR-TK phosphorylated tyrosine residue.EGFR-TK plays a part no less important equally in cell is regulated.These kinases comprise the receptor of some molecules such as somatomedin and hormone, comprise EGF-R ELISA, Insulin receptor INSR, platelet-derived growth factor receptors or the like.Research shows that many EGFR-TKs are transmembrane proteins, and their receptor zone is positioned at extracellular and their kinases zone at cell.Many work have been done in identification to tyrosine kinase modulators equally.
Nuclear factor κ B (NF-κ B) belongs to gang's closely-related dimerization transcription factor complex, and its various combinations by the Rel/NF-κ B family of polypeptide are formed.This family is made up of five kinds of independent mammalian genes products, RelA (p65), NF-κ B1 (p50/p105), NF-κ B2 (p49/p100), c-Rel and RelB, they all can constitute allos or homodimer.These albumen are shared homologous 300 aminoacid of a kind of height " Rel homeodomain ", and it contains DNA and combines territory and dimerization domain.Terminal C-end at the Rel homeodomain is nuclear transposition (translocation) sequence, and it is important in that NF-κ B is transported to the nucleus from Cytoplasm.In addition, p65 and cRel have effective trans-activation domain at their C-end.
The member of the activity of NF-κ B through it and proteic inhibitor I κ B family interacts and regulates.This interaction is the nuclear localization sequence on the block N F-kB protein effectively, stops dimer to migrate to this nuclear thus.Stimulation miscellaneous activates NF-κ B through being likely the multiple signal transduction pathway.That comprise is bacterial product (LPS), some viruses (HIV-1, HTLV-1), inflammatory cytokine (TNF α, IL-1), environmental stress and oxidative stress and DNA damage agent.Yet obviously identical with all stimulations is the phosphorylation of I κ B and degraded subsequently.I κ B on the terminal serines of two N-by I kappa b kinase (IKK-α and the IKK-β) phosphorylation of nearest identification.IKK-β also is called IKK2.Site-directed mutagenesis research shows, these phosphorylations are crucial to the activation of subsequently NF-κ B, because in case by phosphorylation, this albumen is through ubiquitin-proteasome pathway labelling degraded.Discharge from I κ B, this activity NF-κ B complex can be transferred to nuclear, and they combine with preferred gene-specific enhancer sequence in a selective manner there.The gene of being regulated by NF-κ B comprises a large amount of cytokines and chemotactic factor, cell adhesion molecule, acute phase protein, immune modulator, eicosanoid metabolic enzyme (eicosanoid metabolizingenzymes) and anti-apoptotic gene.
Known at present; NF-κ B plays key effect in the regulated expression of a large amount of pro-inflammatory mediators, this pro-inflammatory mediator comprises cytokine for example TNF, IL-1 β, IL-6 and IL-8, cell adhesion molecule; For example ICAM and VCAM, and derivable nitricoxide synthase (iNOS).Known these media play certain function in the leukocyte recruitment of inflammation part, and in the situation of iNOS, in some inflammatory diseasess and autoimmune disease, can cause organ to destroy.
In addition, the importance of NF-κ B in inflammation strengthened through the research of airway inflammation (comprising asthma), shows that wherein NF-κ B is activated.This activation possibly increase the leukocyte infiltration characteristic of cytokine generation and these diseases potentially.In addition, known imbedibility steroidal reduces airway hyperreactivity and suppresses the inflammatory response in the asthma property air flue.According to the up-to-date discovery that suppresses about the glucocorticoid of NF-κ B, people can infer that these effects are regulated through suppressing NF-κ B.
Other evidence that in inflammation, acts on about NF-κ B is from the research to the rheumatoid synovial membrane.Though NF-κ B exists with the form of nonactive Cytoplasm complex usually, up-to-date immunohistochemistry research shows that in the cell that comprises the rheumatoid synovial membrane, NF-κ B is present in the nuclear, and is active therefore.In addition, shown that NF-κ B is activated with stimulating with TNF-α or IL-1 β in people synovial cell.This distribution possibly be the basic mechanism that the eicosanoid of cytokine increase and this tissue produces characteristic.Referring to Roshak, A.K., etc., J.Biol.Chem., 271,31496-31501 (1996).The expression of IKK-β has been presented among the synovial cell of patient with rheumatoid arthritis, and gene transfer research is verified, the irritable inflammation medium aborning important function of IKK-β in these cells.Referring to .J.Immunology2001 such as .J.Immunology 1999.163:427-433 such as Aupperele and Aupperle; 166:2705-11.Recently, the intra-articular administration of wild type IKK-β adenovirus structure causes the swelling of rat pawl, and intra-articular administration dominance-negative IKK β suppresses the rat arthritis that adjuvant brings out.Referring to .Arthritis and Rheumatism 2001 such as Tak, 44:1897-1907.
NF-κ B/Rel and I kB protein also possibly play key effect at neoplastic transformation with in shifting.The family member is with external relevant with the cells in vivo conversion, and this is because the result of overexpression, gene amplification, gene rearrangement or transposition.In addition, in some human lymphoma of 20-25%, can see the rearrangement and/or the amplification of these proteic genes of coding.In addition, NF-κ B is activated by carcinogenic ras, and common deficiency in people's tumor and the activated blocking-up of NF-κ B suppress the cell transformation of ras mediation.In addition, report at present that the effect of NF-κ B in regulating apoptosis strengthened the effect of this transcription factor in the regulate tumor cell hypertrophy.TNF, ionizing radiation and DNA damage agent all show and activate NF-κ B, and said then NF-κ B causes that some anti-apoptotics are proteic is just regulating expression.On the contrary, show at present that in some tumor cell types, the inhibition of NF-κ B has increased the apoptosis that is killed by these reagent.Because this possibly represent a kind of dominant mechanism of the anti-chemotherapy of tumor cell, the activated inhibitor of NF-κ B can be used as the chemotherapeutics of single agents or auxiliary treatment.Latest report shows that NF-κ B is as the amyotrophic regulator (Science such as Guttridge of bone cells differentiation inhibitors and cytokine induction; 2000; 289:2363-2365.) further supported the potential of NF-kB inhibitor as new treatment of cancer.
Some NF-kB inhibitors are described in .J.Clin.Invest.101 such as C.Wahl (5); 1163-1174 (1998) .J.Med.Chem.41 such as R.W.Sullivan, 413-419 (1998); .J.Biol.Chem.272 such as J.W.Pierce are among the 21096-21103 (1997).
The known inhibition of marine natural products hymenialdisine NF-κ 3.Roshak, A., etc., JPET, 283,955-961 (1997) .Breton, J.J and Chabot-Fletcher, M.C., JPET, 282,459-466 (1997).
In addition, submit to about the patent application of the aminothiophene inhibitor of IKK2, referring to WO such as Callahan 2002030353; WO such as Baxter 2001058890, WO such as Faull 2003010158; WO2003010163 such as Griffiths; WO such as Fancelli 200198290; Granetto etc., WO2003037886; The imidazoles inhibitor of IKK2 is referring to WO such as Callahan 200230423; The anilino-phenyl pyrimidine inhibitor of IKK2 is referring to WO such as Kois 2002046171; The B-carboline inhibitor of IKK2, referring to WO such as Ritzeler 2001068648, EP such as Ritzeler 1134221; DE such as Nielsch 19807993; EP such as Ritzeler 1209158; The indole inhibitor of IKK2 is referring to WO such as Ritzeler 2001030774; The benzimidazole inhibitor of IKK2 is referring to DE such as Ritzeler 19928424; WO such as Ritzeler 2001000610; WO such as Ritzeler 2004022553; The aminopyridine inhibitor of IKK2, referring to Lowinger etc., WO 2002024679; Murata etc., WO 2002024693; Murata etc., WO 2002044153; The aminopyrimidine inhibitor of IKK2 is referring to WO2004089913 such as Bollbuck; The pyrazoles inhibitor of IKK2 is referring to WO2003024935 such as Bergmains; WO2003024936 such as Metz; WO2003027075 such as Geng; WO2003035625 such as Stealey; WO200307076 such as Xu; WO2003095430 such as Lennon; The pyrazine ketone inhibitors of IKK2 is referring to WO2005035527 such as Boys; The pyrazolo quinazoline inhibitor of IKK2, referring to Beaulieu etc., WO 2002028860; Burke etc., WO 2002060386, US such as Burke 20030022898; The thiophene tricyclic inhibitors of IKK2 is referring to WO2003084959 such as Belema; The pyrazolo purine inhibitors of IKK2 is referring to WO2004075846 such as Qiu; IKK2 De oxazole and pyridine and thiazole and pyridine inhibitor are referring to WO2004106293 such as Pitts; The quinoline inhibitor of IKK2, Browner etc., WO2002041843, Browner etc.; The pyridyl cyanoguandine inhibitor of US 20020161004 and IKK2, referring to Bjorkling etc., WO 2002094813; Binderup etc., WO 2002094322 and Madsen etc., WO 200294265; The thienopyridine inhibitor of IKK2 is referring to WO2003103661 such as Cywin; WO2005035537 such as Liu; The benzothiophene inhibitors of IKK2 is referring to WO2005012283 such as Chen.Natural product staurosporine, Quercetin, K252a and K252b have shown it is the IKK2 inhibitor, referring to Peet, and G.W. and Li, J.J.Biol.Chem.; 274,32655-32661 (1999) and Wisniewski, D.; Deng, Analytical Biochem.274,220-228 (1999).The synthetic inhibitor of IKK2 has also been described, referring to .J.Biol.Chem. such as Burke, 278,1450-1456 (2003) and Murata etc., Bioorg.Med.Chem.Lett., 13,913-198 (2003), Murata etc., Bioorg.Med.Chem.Lett., 14,4013-4017 (2004) and Murata etc., Bioorg.Med.Chem.Lett., 14,4019-4022 (2004) has described the IKK2 inhibitor.
Therefore, attempting the preparation inhibition active chemical compound of IKK2 and many these chemical compounds discloses in the art.Yet, consider that by the number of the pathologic reaction of IKK2 mediation also need the IKK2 inhibitor, it can be used to treat various diseases.
The inventor has had been found that new indole carboxamides chemical compound, and it is the inhibitor of kinase activity, the active inhibitor of particularly inappropriate IKK2.Therefore; These indole carboxamides derivants can be used for treatment and the active diseases associated of inappropriate kinases, particularly inappropriate IKK2; Especially for treating and preventing by IKK2 mechanism disease states mediated; Comprise inflammatory and tissue repair disease, particularly rheumatoid arthritis, inflammatory bowel, asthma and COPD (chronic obstructive pulmonary disease); Osteoarthritis, osteoporosis and fibrotic conditions; Dermatosis comprises psoriasis, atopic dermatitis and ultraviolet (UV) radiation-induced skin; Autoimmune disease comprises systemic lupus erythematosus (sle), multiple sclerosis, arthritic psoriasis, ankylosing spondylitis, tissue and organ rejection, Alzheimer, apoplexy, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, comprises Hokdkin disease, cachexia, with infect the inflammation relevant with some viral infection, comprise AIDS (AIDS), adult respiratory distress syndrome and ataxia telangiectasia.
Summary of the invention
The present invention relates to new indole carboxamides derivant.Specifically, the present invention relates to the chemical compound and the pharmaceutically acceptable salt thereof of formula (I):
Figure S2006800304481D00061
Wherein R1, R2, R3, U and V are like following definition.
Chemical compound of the present invention is the IKK2 inhibitor, and can be used for treatment and the active diseases associated of inappropriate IKK2 (also claiming IKK β), for example rheumatoid arthritis, asthma and COPD (chronic obstructive pulmonary disease).Therefore, the invention still further relates to the pharmaceutical composition that comprises The compounds of this invention.The present invention further relates to the pharmaceutical composition that uses chemical compound of the present invention or comprise chemical compound of the present invention and suppresses the method that IKK2 is active and treat relevant disease.
Detailed description of the invention
The present invention relates to the chemical compound of formula (I), or its pharmaceutically acceptable salt, solvate or polymorph:
Figure S2006800304481D00062
Wherein R1 is group-XYZ or
Figure S2006800304481D00063
X is phenyl, heteroaryl, 1,2,3,4-tetralyl or 2, and 3-dihydro-1H-indenyl,
Wherein said phenyl, heteroaryl, 1,2,3,4-tetralyl and 2,3-dihydro-1H-indenyl is optional to be selected from following substituent group independently of one another by one or two and to replace:
1) halogen,
2) nitro,
3) cyanic acid,
4)-NR7R8，
5) C 1-C 6-alkyl,
6)CHO，
7) CONH 2And
8)-OR4，
Wherein said C 1-C 6-alkyl is optional to be replaced by one-NR4R5 group;
Y is chemical bond or C 1-C 6Alkylidene,
C wherein 1-C 6Alkylidene is optional to be selected from following substituent group independently of one another by one or two and to replace:
1) optional by a substituted C of OR4 group 1-C 3-alkyl,
2) C 3-C 7-cycloalkyl,
3) methoxyl group,
4) hydroxyl and
5) heteroaryl;
Z is-NR4R5 or Heterocyclylalkyl,
Wherein said Heterocyclylalkyl is optional to be selected from following substituent group independently of one another by one or two and to replace:
1) optional by an OR4 or the substituted C of Heterocyclylalkyl 1-C 6-alkyl,
2) C 3-C 7-cycloalkyl,
3) methoxyl group,
4)-CONH 2，
5) hydroxyl,
6) heteroaryl,
7)CF 3，
8) phenyl,
9) Heterocyclylalkyl and
10)N(CH 3) 2；
R2 is 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 with
2) C 1-C 6-alkyl,
Wherein said C 1-C 6-alkyl is optional to be replaced by a hydroxyl or a methoxyl group;
R5 is selected from
1)H，
2) C 5-C 6-Heterocyclylalkyl,
3)-CO 2Et，
4) C 1-C 6-alkoxyl,
5) C 3-C 7-cycloalkyl,
6) C 1-C 6-alkyl,
7)-SO 2R10 and
8)-C(O)R10，
Wherein said C 3-C 7-cycloalkyl and C 1-C 6-alkyl is optional to be replaced by 1-3 substituent group that is selected from R6;
Each R6 is independently selected from
1)-NR7R8，
2)-SO 2R7，
3)-CONH 2，
4)-CF 3，
5)-CN，
6)-CO 2R7，
7)-OCH 2CH 2OR7，
8)-SR5，
9) C3-C4 alkenyl,
10)OH，
11) C 1-C 6-alkoxyl,
12) heteroaryl,
13) C 3-C 7-cycloalkyl,
14) phenyl,
15) Heterocyclylalkyl and
16) halogen,
Wherein said heteroaryl, cycloalkyl, phenyl and Heterocyclylalkyl are optional to be replaced by 1-2 substituent group that is 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
1) hydroxyl,
2)-OMe，
3) nitro,
4) C 1-C 6-alkyl,
5)NH 2，
6) halogen,
7)CF 3，
8) C 1-C 6-alkoxyl 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) Heterocyclylalkyl,
Wherein said C 1-C 6-alkyl is optional to be selected from C independently of one another by one or two 3-C 7The substituent group of-cycloalkyl and-S-R7 replaces; Wherein said Heterocyclylalkyl is optional to be replaced by one-C (O) R7 group; And wherein said phenyl, heteroaryl and C 1-C 6-heteroaryl is optional to be replaced by 1-2 substituent group that is selected from R11;
Each R11 is independently selected from
1)H，
2) C 1-C 6-alkyl and
3) halogen;
U is chemical bond, C 1-C 6Alkylidene or C 2-C 6Alkenylene;
V is phenyl, 5 or 6 yuan of heteroaryls, 5-7 unit Heterocyclylalkyl, C 5-C 7Cycloalkyl or C 5-C 7Cycloalkenyl group, its each quilt-N (R7) S (O) mR12 ,-S (O) mN (R7) R12 ,-S (O) mR12 or-C (O) R12 replaces;
M is 1 or 2; With
R12 is C 1-C 6-alkyl, C 3-C 7Cycloalkyl, C 1-C 6-alkyl-C 3-C 7Cycloalkyl or C 1-C 6-alkyl-phenyl; Or its pharmaceutically acceptable salt.
A chemical compound that specific embodiments is formula (I) of the present invention:
Wherein R1 is group-XYZ;
X is phenyl or heteroaryl,
Wherein said phenyl and heteroaryl be optional to be selected from following substituent group independently of one another by one or two and to replace:
1) halogen,
2) nitro,
3) cyanic acid,
4)-NR7R8，
5) C 1-C 6-alkyl,
6)CHO，
7) CONH 2And
8)-OR4，
Wherein said C 1-C 6-alkyl is optional to be replaced by one-NR4R5 group;
Y is chemical bond or C 1-C 6Alkylidene,
C wherein 1-C 6Alkylidene is optional to be selected from following substituent group independently of one another by one or two and to replace:
1) optional by a substituted C of OR4 group 1-C 3-alkyl,
2) C 3-C 7-cycloalkyl,
3) methoxyl group,
4) hydroxyl and
5) heteroaryl;
Z is-NR4R5 or Heterocyclylalkyl,
Wherein said Heterocyclylalkyl is optional to be selected from following substituent group independently of one another by one or two and to replace:
1) optional by a substituted C of OR4 group 1-C 6-alkyl,
2) C 3-C 7-cycloalkyl,
3) methoxyl group,
4) hydroxyl and
5) heteroaryl;
R2 is 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 with
2) C 1-C 6-alkyl,
Wherein said C 1-C 6-alkyl is optional to be replaced by a hydroxyl or a methoxyl group;
R5 is selected from
1)H，
2) C 1-C 6-alkoxyl,
3) C 3-C 7-cycloalkyl,
4) C 1-C 6-alkyl,
5)-SO 2R10 and
6)-C(O)R10，
Wherein said C 3-C 7-cycloalkyl and C 1-C 6-alkyl is optional to be replaced by 1-3 substituent group that is selected from R6;
Each R6 is independently selected from
1)-NR7R8，
2)-SO 2R7，
3)OH，
4) methoxyl group,
5) heteroaryl,
6) C 3-C 7-cycloalkyl,
7) phenyl,
8) Heterocyclylalkyl and
9) halogen,
Wherein said heteroaryl, cycloalkyl, phenyl and Heterocyclylalkyl are optional to be replaced by 1-2 substituent group that is selected from R9;
R7 is selected from
1) H with
2) C 1-C 3-alkyl;
R8 is selected from
1) H with
2) C 1-C 3-alkyl;
Each R9 is independently selected from
1) hydroxyl,
2) nitro,
3) C 1-C 6-alkyl,
4)NH 2，
5) halogen,
6)CF 3，
7) C 1-C 6-alkoxyl and
8)CN；
R10 is selected from
1)H，
2) C 1-C 6-alkyl,
3) phenyl,
4) C 3-C 7-cycloalkyl and
5) heteroaryl,
Wherein said C 1-C 6-alkyl is optional to be selected from C independently of one another by one or two 3-C 7The substituent group of-cycloalkyl and-S-R7 replaces; Wherein said Heterocyclylalkyl is optional to be replaced by one-C (O) R7 group; And wherein said phenyl and heteroaryl are optional to be replaced by 1-2 substituent group that is selected from R11;
Each R11 is independently selected from
1)H，
2) C 1-C 6-alkyl and
3) halogen;
U is chemical bond, C 1-C 6Alkylidene or C 2-C 6Alkenylene;
V is phenyl, 5 or 6 yuan of heteroaryls, 5-7 unit Heterocyclylalkyl, C 5-C 7Cycloalkyl or C 5-C 7Cycloalkenyl group, its each quilt-N (R7) S (O) mR12 ,-S (O) mN (R7) R12 ,-S (O) mR12 or-C (O) R12 replaces;
M is 1 or 2; With
R12 is C 1-C 6-alkyl, C 3-C 7Cycloalkyl, C 1-C 6-alkyl-C 3-C 7Cycloalkyl or C 1-C 6-alkyl-phenyl; Or its pharmaceutically acceptable salt.
Another specific embodiments of the present invention is the chemical compound of formula (I):
Wherein R1 is group-XYZ or
Figure S2006800304481D00141
X is phenyl, heteroaryl, 1,2,3,4-tetralyl or 2,3-dihydro-1H-indenyl;
Y is chemical bond or C 1-C 6Alkylidene;
Z is-NR4R5 or Heterocyclylalkyl,
Wherein said Heterocyclylalkyl is optional to be selected from following substituent group independently of one another by one or two and to replace:
1) optional by an OR4 or the substituted C of Heterocyclylalkyl 1-C 6-alkyl,
2) C 3-C 7-cycloalkyl,
3) methoxyl group,
4)-CONH 2，
5) hydroxyl,
6) heteroaryl;
7)CF 3，
8) phenyl,
9) Heterocyclylalkyl and
10)N(CH 3) 2；
R2 is H;
R3 is H;
R4 is selected from
1) H with
2) C 1-C 6-alkyl,
Wherein said C 1-C 6-alkyl is optional to be replaced by a hydroxyl or a methoxyl group;
R5 is selected from
1)H，
2) C 5-C 6-Heterocyclylalkyl,
3)-CO 2Et，
4) C 1-C 6-alkoxyl,
5) C 3-C 7-cycloalkyl,
6) C 1-C 6-alkyl,
7)-SO 2R10 and
8)-C(O)R10，
Wherein said C 3-C 7-cycloalkyl and C 1-C 6-alkyl is optional to be replaced by 1-3 substituent group that is selected from R6;
Each R6 is independently selected from
1)-NR7R8，
2)-SO 2R7，
3)-CONH 2，
4)-CF 3，
5)-CN，
6)-CO 2R7，
7)-OCH 2CH 2OR7，
8)-SR5，
9) C3-C4 alkenyl,
10)OH，
11) C 1-C 6-alkoxyl,
12) heteroaryl,
13) C 3-C 7-cycloalkyl,
14) phenyl,
15) Heterocyclylalkyl and
16) halogen,
Wherein said heteroaryl, cycloalkyl, phenyl and Heterocyclylalkyl are optional to be replaced by 1-2 substituent group that is 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
1) hydroxyl,
2)-OMe
3) nitro,
4) C 1-C 6-alkyl,
5)NH 2，
6) halogen,
7)CF 3，
8) C 1-C 6-alkoxyl 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) Heterocyclylalkyl,
Wherein said C 1-C 6-alkyl is optional to be selected from C independently of one another by one or two 3-C 7The substituent group of-cycloalkyl and-S-R7 replaces; Wherein said Heterocyclylalkyl is optional to be replaced by one-C (O) R7 group; And wherein said phenyl, heteroaryl and C 1-C 6-heteroaryl is optional to be replaced by 1-2 substituent group that is selected from R11;
Each R11 is independently selected from
1)H，
2) C 1-C 6-alkyl and
3) halogen;
U is a chemical bond;
V is quilt-S (O) mThe substituted 5-7 of R12 unit Heterocyclylalkyl;
M is 1 or 2; With
R12 is C 1-C 6-alkyl; Or its pharmaceutically acceptable salt.
Another specific embodiments of the present invention is the chemical compound of formula (I):
Wherein R1 is group-XYZ;
X is phenyl or heteroaryl;
Y is chemical bond or C 1-C 6Alkylidene;
Z is-NR4R5 or Heterocyclylalkyl,
Wherein said Heterocyclylalkyl is optional to be selected from following substituent group independently of one another by one or two and to replace:
1) optional by a substituted C of OR4 group 1-C 6-alkyl,
2) C 3-C 7-cycloalkyl,
3) methoxyl group,
4) hydroxyl and
5) heteroaryl;
R2 is H;
R3 is H;
R4 is selected from
1) H with
2) C 1-C 6-alkyl,
Wherein said C 1-C 6-alkyl is optional to be replaced by a hydroxyl or a methoxyl group;
R5 is selected from
1)H，
2) C 1-C 6-alkoxyl,
3) C 3-C 7-cycloalkyl,
1) C 1-C 6-alkyl,
2)-SO 2R10 and
3)-C(O)R10，
Wherein said C 3-C 7-cycloalkyl and C 1-C 6-alkyl is optional to be replaced by 1-3 substituent group that is selected from R6;
Each R6 is independently selected from
1)NR7R8，
2)SO 2R7，
3)OH，
4) methoxyl group,
5) heteroaryl,
6) C 3-C 7-cycloalkyl,
7) phenyl,
8) Heterocyclylalkyl and
9) halogen,
Wherein said heteroaryl, cycloalkyl, phenyl and Heterocyclylalkyl are optional to be replaced by 1-2 substituent group that is selected from R9;
R7 is selected from
1) H with
2) C 1-C 3-alkyl;
R8 is selected from
1) H with
2) C 1-C 3-alkyl;
Each R9 is independently selected from
1) hydroxyl,
2) nitro,
3) C 1-C 6-alkyl,
4)NH 2，
5) halogen,
6)CF 3，
7) C 1-C 6-alkoxyl and
8)CN；
R10 is selected from
1)H，
2) C 1-C 6-alkyl,
3) phenyl,
4) C 3-C 7-cycloalkyl and
5) heteroaryl,
Wherein said C 1-C 6-alkyl is optional to be selected from C independently of one another by one or two 3-C 7The substituent group of-cycloalkyl and-S-R7 replaces; Wherein said Heterocyclylalkyl is optional to be replaced by one-C (O) R7 group; And wherein said phenyl and heteroaryl are optional to be replaced by 1-2 substituent group that is selected from R11;
Each R11 is independently selected from
1)H，
2) C 1-C 6-alkyl and
3) halogen;
U is a chemical bond;
V is quilt-S (O) mThe substituted 5-7 of R12 unit Heterocyclylalkyl;
M is 1 or 2; With
R12 is C 1-C 6-alkyl; Or its pharmaceutically acceptable salt.
Another specific embodiments of the present invention is formula (I) chemical compound, wherein:
Wherein R1 is group-XYZ;
X is 2-or 3-thienyl;
Y is chemical bond or C 1-C 4Alkylidene;
Z is-NR4R5 or Heterocyclylalkyl,
Wherein said Heterocyclylalkyl is optional to be selected from following substituent group independently of one another by one or two and to replace:
1) optional by an OR4 or the substituted C of Heterocyclylalkyl 1-C 6-alkyl,
2) C 3-C 7-cycloalkyl,
3) methoxyl group,
4)-CONH 2，
5) hydroxyl,
6) heteroaryl;
7)CF 3，
8) phenyl,
9) Heterocyclylalkyl and
10)N(CH 3) 2；
R2 is H;
R3 is H;
R4 is selected from
1) H with
2) C 1-C 6-alkyl,
Wherein said C 1-C 6-alkyl is optional to be replaced by a hydroxyl or a methoxyl group;
R5 is selected from
1) C 3-C 7-cycloalkyl,
2) C 1-C 6-alkyl,
Wherein said C 3-C 7-cycloalkyl and C 1-C 6-alkyl is optional to be replaced by 1-3 substituent group that is selected from R6;
Each R6 is independently selected from
1)-NR7R8，
2)-CONH 2，
3)-CN，
4)-OCH 2CH 2OR7，
5) C3-C4 alkenyl,
6)OH，
7) C 1-C 6-alkoxyl,
8) heteroaryl,
9) C 3-C 7-cycloalkyl,
10) phenyl,
11) Heterocyclylalkyl and
12) halogen,
Wherein said heteroaryl, cycloalkyl, phenyl and Heterocyclylalkyl are optional to be replaced by 1-2 substituent group that is 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
1) C 1-C 6-alkyl;
U is a chemical bond;
V is quilt-S (O) 2The substituted 4-piperidyl of R12; With
R12 is ethyl or isopropyl; Or its pharmaceutically acceptable salt.
Another specific embodiments of the present invention be formula (I) chemical compound wherein group U-V do
Figure S2006800304481D00221
and R12 are ethyl or isopropyl.
Another specific embodiments of the present invention is formula (II) chemical compound
Wherein R13 is-NR14R15 or Heterocyclylalkyl,
Wherein said Heterocyclylalkyl is optional to be selected from following substituent group by one or two and to replace:
1) optional by a substituted C of OR14 group 1-C 6-alkyl,
2) hydroxyl,
3) methoxyl group and
4) heteroaryl;
R14 is selected from
1) H with
2) C 1-C 6-alkyl,
Wherein said C 1-C 6-alkyl is optional to be replaced by a hydroxyl or a methoxyl group;
R15 is selected from
1)H，
2) methoxyl group,
3) C 3-C 7Cycloalkyl and
4) C 1-C 6-alkyl,
Wherein said C 3-C 7Cycloalkyl and C 1-C 6-alkyl is optional to be replaced by 1-3 substituent group that is selected from R16;
Each R16 is independently selected from
1)-NR17R18，
2)-SO 2R17，
3)OH，
4) methoxyl group
5) heteroaryl,
6) C 3-C 7Cycloalkyl,
7) phenyl and
8) Heterocyclylalkyl,
Wherein said heteroaryl, cycloalkyl, phenyl and Heterocyclylalkyl are optional to be replaced by 1-3 substituent group that is selected from R19;
R17 is selected from
1) H with
2) C 1-C 3-alkyl;
R18 is selected from
1) H with
2) C 1-C 3-alkyl;
R19 is selected from
1) hydroxyl,
2) nitro,
3) C 1-C 6-alkyl,
4)NH 2，
5) halogen,
6) CF 3And
7) C 1-C 6-alkoxyl; With
N is 1-3; Or its pharmaceutically acceptable salt.
The instantiation of The compounds of this invention comprises following:
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(piperidino methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(1-piperazinyl methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ methyl [2-(mesyl) ethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-(3-{ [[2-(dimethylamino) ethyl] (methyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(4-{2-[(2-hydroxyethyl) oxygen base] ethyl }-the 1-piperazinyl) methyl] phenyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [3-(hydroxymethyl)-piperidino] methyl } phenyl)-1H-indole-7-Methanamide;
5-[3-({ two [2-(methoxyl group) ethyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{3-[(2,6-dimethyl-4-morpholinyl) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [2-(1,3-thiazoles-2-yl)-1-pyrrolidinyl] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [2-(2-thienyl)-1-pyrrolidinyl] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-hydroxyl-2-phenylethyl) (methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-(3-{ [ethyl (methyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[3-(amino methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{3-[(cyclopenta is amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[3-({ [(3, the 4-dihydroxy phenyl) methyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-thienyl methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-([(2S)-and 2-(hydroxymethyl)-3-methyl butyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-hydroxyl-1-Methylethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(anti--the 4-hydroxy-cyclohexyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[({ [1-(piperidino) cyclohexyl] methyl } amino) methyl] phenyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-([(2S)-and the 2-hydroxypropyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-{3-[(ethylamino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(propyl group is amino) methyl] phenyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(1-Methylethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-(3-{ [(1-ethyl propyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(piperidino methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(piperidino methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(methylamino) methyl] phenyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide;
5-[4-(amino methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide;
5-{3-[(cyclopropyl is amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{3-[(cyclobutyl is amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-(1-{ [3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[4-(piperidino methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(2-methyl-propyl) amino]-2,3-dihydro-1H-indenes-5-yl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{8-[(2-methyl-propyl) amino]-5,6,7,8-tetrahydrochysene-2-naphthyl }-1H-indole-7-Methanamide;
5-(5-{ [(2-cyano ethyl) amino] methyl }-the 2-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-fluoro-5-{ [(2,2, the 2-trifluoroethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(1,2,3,4-tetrahydrochysene-7-isoquinolyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2,2, the 2-trifluoroethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-(3-{ [(2-amino-2-oxoethyl) (methyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-{ [(2,2, the 2-trifluoroethyl) amino] methyl }-1,3-thiazoles-4-yl)-1H-indole-7-Methanamide;
5-(3-cyanic acid-5-{ [(2,2, the 2-trifluoroethyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (1-methyl-4-piperidyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
5-(5-{ [(2-cyano ethyl) (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [(2-amino-2-oxoethyl) (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ methyl [2-(phenyl sulfonyl) ethyl] amino } methyl)-3-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-phenyl-1-pyrrolidinyl) methyl]-3-thienyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [2-(piperidino methyl)-1-pyrrolidinyl] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
5-(5-{ [(2R)-and 2-(amino carbonyl)-1-pyrrolidinyl] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [(2S)-and 2-(dimethylamino)-1-pyrrolidinyl] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(1-{2-[4-(dimethylamino)-piperidino] ethyl }-1H-pyrazoles-4-yl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[3-[(dimethylamino) methyl]-4, two (methoxyl group) phenyl of 5-]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[3, two (methoxyl group)-5-(the 4-morpholinyl methyl) phenyl of 4-]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-{ [(1-Methylethyl) amino] methyl }-4, two (methoxyl group) phenyl of 5-]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-{ [(1-Methylethyl) amino] methyl }-4, two (methoxyl group) phenyl of 5-]-1H-indole-7-Methanamide;
5-[3-{ [(2, the 2-dimethyl propyl) amino] methyl }-4, two (methoxyl group) phenyl of 5-]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-{ [(2-hydroxyethyl) (methyl) amino] methyl }-4, two (methoxyl group) phenyl of 5-]-1H-indole-7-Methanamide;
5-[3, two (methoxyl group)-5-(the 1-pyrrolidinyl methyl) phenyl of 4-]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{4-[(dimethylamino) methyl]-2,3-dihydro-1-benzofuran-6-yl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(1-Methylethyl) amino] methyl }-2,3-dihydro-1-benzofuran-6-yl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(4-morpholinyl methyl)-2,3-dihydro-1-benzofuran-6-yl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ [1-methyl-2-(methoxyl group) ethyl] amino } methyl)-2-thienyl]-1H-indole-7-Methanamide;
5-(5-{ [(2-cyano ethyl) amino] methyl }-the 3-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2,2, the 2-trifluoroethyl) amino] methyl }-the 3-pyridine radicals)-1H-indole-7-Methanamide;
5-{3-[(dimethylamino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [ethyl (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [[2-(diethylamino) ethyl] (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [butyl (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (propyl group) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
5-(5-{ [[2-(dimethylamino) ethyl] (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [[3-(dimethylamino) propyl group] (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [cyclopenta (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (amyl group) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (2-methyl-propyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (phenyl methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-hydroxyethyl) (methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ methyl [2-(2-pyridine radicals) ethyl] amino } methyl)-3-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-furyl methyl) (methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (4-pyridylmethyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(methyl { [1-(1-Methylethyl)-3-pyrrolidinyl] methyl } amino) methyl]-3-thienyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (2-thienyl methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ methyl [1-(2-thienyl) ethyl] amino } methyl)-3-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (3-thienyl methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide; Trifluoroacetate
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (3-pyridylmethyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide; Trifluoroacetate
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (4-Pyrimidylmethyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ methyl [2-(methoxyl group) ethyl] amino } methyl)-3-thienyl]-1H-indole-7-Methanamide;
5-{3-[(dimethylamino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (1-Methylethyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-propyl group-1-pyrrolidinyl) methyl]-3-thienyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [2-(3-pyridine radicals)-1-pyrrolidinyl] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
5-(5-{ [2-(1, the 1-dimethyl ethyl)-1-pyrrolidinyl] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{5-[(2-ethyl-1-pyrrolidinyl) methyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [2-(2-methyl-propyl)-1-pyrrolidinyl] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [2-(1-Methylethyl)-1-pyrrolidinyl] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-((2S)-and 2-[(methoxyl group) methyl]-1-pyrrolidinyl } methyl)-the 3-thienyl]-1H-indole-7-Methanamide;
5-(5-{ [cyclohexyl (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [2-(2-methyl-propyl)-1-pyrrolidinyl] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
5-(5-{ [ethyl (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (propyl group) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-5-(5-{ [methyl (propyl group) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
5-(5-{ [ethyl (methyl) amino] methyl }-the 3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide;
3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-5-[5-({ methyl [2-(methoxyl group) ethyl] amino } methyl)-3-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(methylamino) methyl]-2-thienyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-methyl isophthalic acid-pyrrolidinyl) methyl]-3-thienyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl-propyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(propyl group is amino) methyl]-3-thienyl }-1H-indole-7-Methanamide;
5-{5-[(diethylamino) methyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [(2R, SR)-2,5-dimethyl-1-pyrrolidinyl] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{5-[(cyclopropyl is amino) methyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{5-[(cyclobutyl is amino) methyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{5-[(dimethylamino) methyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [(cyclopentyl-methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[5-({ [(1R)-1,2-dimethyl propyl] amino } methyl)-3-thienyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{5-[(cyclopenta is amino) methyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [(cyclopropyl methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[5-({ [(1S)-1,2-dimethyl propyl] amino } methyl)-3-thienyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [(2, the 2-dimethyl propyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(phenyl methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-([(2S)-and tetrahydrochysene-2-furyl methyl] amino } methyl)-the 3-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
5-{5-[(butyl is amino) methyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-([(2R)-and tetrahydrochysene-2-furyl methyl] amino } methyl)-the 3-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-((2S)-and 2-[(methoxyl group) methyl]-1-pyrrolidinyl } methyl)-the 3-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-((2R)-and 2-[(methoxyl group) methyl]-1-pyrrolidinyl } methyl)-the 3-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-[2-(methylamino) ethyl] phenyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-[2-(propyl group is amino) ethyl] phenyl }-1H-indole-7-Methanamide;
5-{4-[2-(ethylamino) ethyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{4-[({ [1-(1, the 1-dimethyl ethyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] carbonyl } amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(4-pyridine radicals carbonyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-(4-{ [(cyclopentylcarbonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(2-furyl carbonyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-{4-[2-(acetyl-amino) ethyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{2-[(mesyl) amino] ethyl } phenyl)-1H-indole-7-Methanamide;
5-(4-{2-[(cyclobutyl carbonyl) amino] ethyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(4-{2-[(cyclohexyl-carbonyl) amino] ethyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{2-[(mesyl) amino] ethyl } phenyl)-1H-indole-7-Methanamide;
5-(3-{2-[(cyclohexyl-carbonyl) amino] ethyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[6-(1-piperazinyl)-3-pyridine radicals]-1H-indole-7-Methanamide trifluoroacetate;
5-[6-(4-ethyl-1-piperazinyl)-3-pyridine radicals]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(piperidino methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(piperidino methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-[(methylamino) methyl] phenyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(1-Methylethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-[(propyl group is amino) methyl] phenyl }-1H-indole-7-Methanamide;
5-(4-{ [(1-ethyl propyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{4-[(cyclopenta is amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{4-[(cyclobutyl is amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{4-[(ethylamino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{4-[(dimethylamino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{4-[(diethylamino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(1-pyrrolidinyl methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-([(1S)-and 2-hydroxyl-1-Methylethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-([(1R)-and 2-hydroxyl-1-Methylethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-([(2R)-and the 2-hydroxypropyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-({ [2-hydroxyl-1-(hydroxymethyl) ethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(1-methyl butyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-([(1R)-and the 1-methyl-propyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-methyl-propyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-([(1S)-and the 1-methyl-propyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-{4-[(acetyl-amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-[(propiono is amino) methyl] phenyl }-1H-indole-7-Methanamide;
5-(4-{ [(cyclopropyl carbonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(4-{ [(cyclobutyl carbonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(2-thienyl acetyl group) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-[4-({ [(1S)-1,2-dimethyl propyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{4-[(bytyry is amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(2-methylpropionyl) amino] methyl } phenyl)-1H-indole-7-Methanamide
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(3-methylbutyryl base) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(mesyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-[3-({ [(1R)-1,2-dimethyl propyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(4-{ [(ethylsulfonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(4-{ [(butyl sulfonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-({ [(1-Methylethyl) sulfonyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-(6-amino-2-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(1H-pyrazol-1-yl) phenyl]-1H-indole-7-Methanamide;
5-[4-(dimethylamino) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(3-aminophenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-methyl isophthalic acid-pyrrolidinyl) methyl]-2-thienyl }-1H-indole-7-Methanamide;
5-{5-[(ethylamino) methyl]-2-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(1-Methylethyl) amino] methyl }-the 2-thienyl)-1H-indole-7-Methanamide;
5-{5-[(cyclopropyl is amino) methyl]-2-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [(2, the 2-dimethyl propyl) amino] methyl }-the 2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [(cyclopropyl methyl) amino] methyl }-the 2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [(cyclopropyl methyl) amino] methyl }-the 3-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ [2-(methoxyl group) ethyl] amino } methyl)-3-pyridine radicals]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ [3-(methoxyl group) propyl group] amino } methyl)-3-pyridine radicals]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(4-morpholinyl methyl)-3-pyridine radicals]-1H-indole-7-Methanamide;
5-{5-[(ethylamino) methyl]-3-pyridine radicals }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{5-[(dimethylamino) methyl]-3-pyridine radicals }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-methyl isophthalic acid-pyrrolidinyl) methyl]-3-pyridine radicals }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl-propyl) amino] methyl }-the 3-pyridine radicals)-1H-indole-7-Methanamide;
5-(5-{ [(2, the 2-dimethyl propyl) amino] methyl }-the 3-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl butyl) amino] methyl }-the 2-thienyl)-1H-indole-7-Methanamide;
5-[5-({ [(1R)-1,2-dimethyl propyl] amino } methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(amyl group is amino) methyl]-2-thienyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-([(2S)-and the 2-methyl butyl] amino } methyl)-the 2-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(1-methyl butyl) amino] methyl }-the 2-thienyl)-1H-indole-7-Methanamide;
5-{5-[(butyl is amino) methyl]-2-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ [2-(methoxyl group) ethyl] amino } methyl)-2-thienyl]-1H-indole-7-Methanamide;
5-{5-[(cyclopenta is amino) methyl]-2-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(3-methyl butyl) amino] methyl }-the 2-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(1-Methylethyl) amino] methyl }-the 3-pyridine radicals)-1H-indole-7-Methanamide;
5-(5-{ [(2-ethyl-butyl) amino] methyl }-the 2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[5-({ [3-(ethyoxyl) propyl group] amino } methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ [3-(methoxyl group) propyl group] amino } methyl)-2-thienyl]-1H-indole-7-Methanamide;
5-(5-{ [(cyclohexyl methyl) amino] methyl }-the 2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[({ 3-[(1-Methylethyl) oxygen base] propyl group } amino) methyl]-2-thienyl }-1H-indole-7-Methanamide;
5-[5-({ [2-(ethyoxyl) ethyl] amino } methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ [3-(propoxyl group) propyl group] amino } methyl)-2-thienyl]-1H-indole-7-Methanamide;
5-(5-{ [(3, the 3-dimethylbutyl) amino] methyl }-the 2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ [(1S)-1,2,2-trimethyl propyl group] amino } methyl)-2-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(hexyl is amino) methyl]-2-thienyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-[(mesyl) amino] phenyl }-1H-indole-7-Methanamide;
5-[2-(dimethylamino)-4-pyridine radicals]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(1-pyrrolidinyl)-4-pyridine radicals]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(4-morpholinyl)-4-pyridine radicals]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{2-[(2-methyl-propyl) amino]-4-pyridine radicals }-1H-indole-7-Methanamide;
5-{2-[(2, the 2-dimethyl propyl) amino]-4-pyridine radicals }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(propyl group is amino)-4-pyridine radicals]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-[(methylamino) methyl]-2-thienyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(1-pyrrolidinyl methyl)-2-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(2-methyl-propyl) amino] methyl }-the 2-thienyl)-1H-indole-7-Methanamide;
5-{4-[(dimethylamino) methyl]-2-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(1S)-1-(1-pyrrolidinyl) ethyl]-the 3-thienyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(1R)-1-(1-pyrrolidinyl) ethyl]-the 3-thienyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-({ [3-(methoxyl group) propyl group] amino } methyl)-2-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-((2S)-and 2-[(methoxyl group) methyl]-1-pyrrolidinyl } methyl)-the 2-thienyl]-1H-indole-7-Methanamide;
5-(4-{ [(2R, 5R)-2,5-dimethyl-1-pyrrolidinyl] methyl }-the 2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2S)-and 2-methyl isophthalic acid-pyrrolidinyl] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2R)-and 2-methyl isophthalic acid-pyrrolidinyl] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[1-(1-pyrrolidinyl) propyl group]-3-thienyl }-1H-indole-7-Methanamide;
5-{5-[(dimethylamino) methyl]-3-thienyl }-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide;
5-[5-(amino methyl)-3-thienyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{2-[(2-methyl-propyl) amino] ethyl }-the 3-thienyl)-1H-indole-7-Methanamide;
5-{5-[2-(dimethylamino) ethyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[6-(1-pyrrolidinyl)-3-pyridine radicals]-1H-indole-7-Methanamide;
5-{6-[ethyl (methyl) amino]-3-pyridine radicals }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[6-(dimethylamino)-3-pyridine radicals]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[6-(propyl group is amino)-3-pyridine radicals]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{6-[(1-Methylethyl) amino]-3-pyridine radicals }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[6-(4-morpholinyl)-3-pyridine radicals]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(methylamino) methyl]-3-thienyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(1-Methylethyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(1-pyrrolidinyl methyl)-3-thienyl]-1H-indole-7-Methanamide;
5-{5-[(ethylamino) methyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-([(1R)-and 2-hydroxyl-1-Methylethyl] amino } methyl)-the 3-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(piperidino methyl)-3-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(4-morpholinyl methyl)-3-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(methylamino) methyl]-3-furyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[1-(1-pyrrolidinyl) ethyl]-3-thienyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(1-pyrrolidinyl methyl)-2-thienyl]-1H-indole-7-Methanamide;
5-{5-[(dimethylamino) methyl]-2-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(propyl group is amino) methyl]-2-thienyl }-1H-indole-7-Methanamide;
5-{5-[(diethylamino) methyl]-2-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl-propyl) amino] methyl }-the 2-thienyl)-1H-indole-7-Methanamide;
5-(5-{ [(2, the 2-dimethyl propyl) amino] methyl }-the 3-furyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl-propyl) amino] methyl }-the 3-furyl)-1H-indole-7-Methanamide;
5-(5-{ [(cyclopentyl-methyl) amino] methyl }-the 3-furyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(1-pyrrolidinyl methyl)-3-furyl]-1H-indole-7-Methanamide;
5-{5-[(diethylamino) methyl]-3-furyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(1-pyrrolidinyl methyl)-1,3-thiazoles-2-yl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[2-methyl isophthalic acid-(1-pyrrolidinyl) propyl group]-3-thienyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(1-pyrrolidinyl methyl)-1,3-thiazoles-2-yl]-1H-indole-7-Methanamide;
5-{1-[2-(dimethylamino) ethyl]-1H-pyrazoles-4-yl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{1-[2-(1-pyrrolidinyl) ethyl]-1H-pyrazoles-4-yl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{1-[2-(4-morpholinyl) ethyl]-1H-pyrazoles-4-yl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(1-{2-[(2-hydroxyethyl) amino] ethyl }-1H-pyrazoles-4-yl)-1H-indole-7-Methanamide;
5-{1-[2-(butyl is amino) ethyl]-1H-pyrazoles-4-yl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{1-[2-(cyclobutyl is amino) ethyl]-1H-pyrazoles-4-yl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[1-(2-{ [2-(diethylamino) ethyl] amino } ethyl)-1H-pyrazoles-4-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(1-{2-[(1-Methylethyl) amino] ethyl }-1H-pyrazoles-4-yl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(1-{2-[(2-methyl-propyl) amino] ethyl }-1H-pyrazoles-4-yl)-1H-indole-7-Methanamide;
5-(1-{2-[(cyclopentyl-methyl) amino] ethyl }-1H-pyrazoles-4-yl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(methoxyl group)-3-(1-pyrrolidinyl methyl) phenyl]-1H-indole-7-Methanamide;
5-[3-[(dimethylamino) methyl]-4-(methoxyl group) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(methoxyl group)-3-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-{ [(1-Methylethyl) amino] methyl }-4-(methoxyl group) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-[(methylamino) methyl]-4-(methoxyl group) phenyl]-1H-indole-7-Methanamide;
5-[3-{ [(2, the 2-dimethyl propyl) amino] methyl }-4-(methoxyl group) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(1-{2-[(2-hydroxyethyl) (methyl) amino] ethyl }-1H-pyrazoles-4-yl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-fluoro-3-[(methylamino) methyl] phenyl }-1H-indole-7-Methanamide;
5-{3, two [(methylamino) methyl] phenyl of 5-}-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{3-[(ethylamino) methyl]-4-fluorophenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-fluoro-3-({ [2-hydroxyl-1-(hydroxymethyl) ethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-fluoro-3-([(1S)-and 2-hydroxyl-1-Methylethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-{3-[(cyclopropyl is amino) methyl]-4-fluorophenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{3-[(cyclobutyl is amino) methyl]-4-fluorophenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(1-pyrrolidinyl methyl) phenyl]-1H-indole-7-Methanamide;
5-{3, two [(ethylamino) methyl] phenyl of 5-}-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{3, two [(dimethylamino) methyl] phenyl of 5-}-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(2-piperidyl) phenyl]-1H-indole-7-Methanamide;
5-{3-[1-(ethylamino) ethyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{3-[1-(dimethylamino) ethyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-fluoro-5-[(methylamino) methyl] phenyl }-1H-indole-7-Methanamide;
5-{3-[(ethylamino) methyl]-5-fluorophenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-fluoro-5-[(propyl group is amino) methyl] phenyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-{ [(1-Methylethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-{ [(2-methyl-propyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-{3-[(cyclobutyl is amino) methyl]-5-fluorophenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{3-[(dimethylamino) methyl]-5-fluorophenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-(1-pyrrolidinyl methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-(piperidino methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[1-(methylamino) ethyl] phenyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{1-[(1-Methylethyl) amino] ethyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{1-[(2-methyl-propyl) amino] ethyl } phenyl)-1H-indole-7-Methanamide;
5-{3-[1-(cyclobutyl is amino) ethyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[1-(1-pyrrolidinyl) ethyl] phenyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(3-thio-morpholinyl (thiomorpholinyl)) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(2-piperazinyl)-2-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(2-piperazinyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(2-piperazinyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[6-(4-morpholinyl)-3-pyridazinyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[6-(1-pyrrolidinyl)-3-pyridazinyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{2-[(methylamino) methyl] phenyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-thienyl methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ [(5-methyl-2-furyl) methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-([(2R)-and tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-([(2S)-and tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-(3-{ [(2, the 2-dimethyl propyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-methyl butyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-([(2S)-and the 2-methyl butyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ [(1R)-1,2,2-trimethyl propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-([(2S)-and tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-([(2R)-and tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-[3-({ [(1S)-1,2-dimethyl propyl] amino } methyl)-5-fluorophenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[3-({ [(1R)-1,2-dimethyl propyl] amino } methyl)-5-fluorophenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-{ [(1-methyl-propyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(1S)-1,2,2-trimethyl propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-([(2S)-and the 2-methyl butyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-{ [(2-methyl butyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(1R)-1,2,2-trimethyl propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-(3-{ [(2, the 2-dimethyl propyl) amino] methyl }-the 5-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(3-{ [(cyclopropyl methyl) amino] methyl }-the 5-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(3-{ [(cyclopentyl-methyl) amino] methyl }-the 5-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-{ [(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-{ [(2-thienyl methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [2-(methoxyl group) ethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [3-(methoxyl group) propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-{ [(2-furyl methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-{ [(3-methyl butyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(5-methyl-2-furyl) methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-methyl-propyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(2-pyrrolidinyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{2-fluoro-5-[(methylamino) methyl] phenyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{2-fluoro-5-[(propyl group is amino) methyl] phenyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-fluoro-5-{ [(2-methyl-propyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-(5-{ [(2, the 2-dimethyl propyl) amino] methyl }-the 2-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[5-({ [(1S)-1,2-dimethyl propyl] amino } methyl)-2-fluorophenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[5-({ [(1R)-1,2-dimethyl propyl] amino } methyl)-2-fluorophenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [(cyclopropyl methyl) amino] methyl }-the 2-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-fluoro-5-(1-pyrrolidinyl methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-fluoro-5-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-fluoro-5-({ [2-(methoxyl group) ethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-fluoro-5-({ [3-(methoxyl group) propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(1-methyl-2-pyrrolidinyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{2-[(2-methyl-propyl) amino] ethyl } phenyl)-1H-indole-7-Methanamide;
5-{3-[2-(ethylamino) ethyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[2-(propyl group is amino) ethyl] phenyl }-1H-indole-7-Methanamide;
5-{3-[2-(dimethylamino) ethyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{3-[2-(dipropyl is amino) ethyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[3-({ [2-(3,5-dimethyl-1H-pyrazol-1-yl) ethyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(4-morpholinyl methyl)-1,3-thiazoles-4-yl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-{ [(2-methyl-propyl) amino] methyl }-1,3-thiazoles-4-yl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(1-pyrrolidinyl methyl)-1,3-thiazoles-4-yl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(piperidino methyl)-1,3-thiazoles-4-yl]-1H-indole-7-Methanamide;
5-{2-[(dimethylamino) methyl]-1,3-thiazoles-4-yl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(2-{ [ethyl (methyl) amino] methyl }-1,3-thiazoles-4-yl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(3-cyanic acid-5-{ [(2-methyl-propyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{3-cyanic acid-5-[(dimethylamino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(mesyl) amino] phenyl }-1H-indole-7-Methanamide;
5-[4-(acetyl-amino) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[3-(acetyl-amino) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide;
5-{3-[(acetyl-amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(mesyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-{3-[(bytyry is amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ [(4-fluorophenyl) carbonyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-methylpropionyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-furyl carbonyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-(3-{ [(cyclopentylcarbonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(valeryl is amino) methyl] phenyl }-1H-indole-7-Methanamide;
5-(3-{ [(2-ethyl bytyry) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(3-{ [(1-benzothiophene-2-base carbonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[3-({ [(1-acetyl group-4-piperidyl) carbonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ [(1-methyl isophthalic acid H-pyrroles-2-yl) carbonyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(3-methyl-2-butene acyl group (butenoyl)) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(heptanoyl group is amino) methyl] phenyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(caprylyl is amino) methyl] phenyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-methylpent acyl group) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(3-methylbutyryl base) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-thienyl acetyl group) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(caproyl is amino) methyl] phenyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-methylbutyryl base) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-(3-{ [(cyclobutyl carbonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(3-{ [(cyclopropyl carbonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(propiono is amino) methyl] phenyl }-1H-indole-7-Methanamide;
5-(3-{ [(cyclopenta acetyl group) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ [3-(methyl mercapto) propiono] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ [(1-Methylethyl) sulfonyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-(3-{ [(cyclopropyl sulfonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[3-({ [(2, the 5-Dichlorobenzene base) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[3-({ [(4-bromophenyl) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[3-({ [(4-chlorphenyl) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ [(3-fluorophenyl) sulfonyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-[3-({ [(2-chlorphenyl) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[3-({ [(2,5-two chloro-3-thienyls) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[3-({ [(2-chloro-6-aminomethyl phenyl) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ [(5-fluoro-2-aminomethyl phenyl) sulfonyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-[3-({ [(1,2-dimethyl-1H-imidazol-4 yl) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(sulfonyl propyl base) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-(3-{ [(butyl sulfonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(phenyl sulfonyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ [(4-fluorophenyl) sulfonyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-[3-({ [(4-bromo-2-ethylphenyl) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(3-{ [(1-benzothiophene-3-base sulfonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-{3-[({ [4-(1, the 1-dimethyl ethyl) phenyl] sulfonyl } amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[3-({ [(3, the 4-difluorophenyl) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(3-{ [(ethylsulfonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(3-{ [(2,1,3-benzo _ diazole-4-base sulfonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(tetrahydrochysene-3-furyl carbonyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-{4-[(cyclopenta sulfonyl) amino] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(4-methyl-2-oxo-1-piperazinyl) phenyl]-1H-indole-7-Methanamide;
5-[6-(4-acetyl group-1-piperazinyl)-3-pyridine radicals]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(methoxyl group) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(methoxyl group) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [4-(1-pyrrolidinyl)-piperidino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2S)-and 2-(trifluoromethyl)-1-pyrrolidinyl] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
5-(5-{ [(2R)-and 2-(hydroxymethyl)-1-pyrrolidinyl] methyl }-the 3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide;
5-(5-{ [(3S)-and 3-hydroxyl-1-pyrrolidinyl] methyl }-the 3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide;
5-(5-{ [cyclopenta (methyl) amino] methyl }-the 3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide;
5-(5-{ [(2-hydroxyethyl) (methyl) amino] methyl }-the 3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide;
5-(5-{ [(2-amino-2-oxoethyl) (methyl) amino] methyl }-the 3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (2-propylene-1-yl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
5-(5-{ [[(3,5-dimethyl-1H-pyrazoles-4-yl) methyl] (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [(cyano methyl) (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (1-methyl-propyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
5-(5-{ [[2-(ethyoxyl) ethyl] (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [cyclobutyl (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ 2-[(methoxyl group) methyl]-1-pyrrolidinyl } methyl)-3-thienyl]-1H-indole-7-Methanamide;
5-(5-{ [(1, the 1-dimethyl ethyl) (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [3-(trifluoromethyl)-piperidino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[(1S)-and 2-hydroxyl-1-Methylethyl] (methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
5-(5-{ [(cyclopropyl methyl) (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(5-{ [[2-(acetyl-amino) ethyl] (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[(1R, 2R)-2-hydroxycyclopent base] (methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
5-(5-{ [(1, the 1-dimethyl propyl) (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[(2S)-and the 2-hydroxypropyl] (methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(methyl [(2R)-and tetrahydrochysene-2-furyl methyl] amino } methyl)-the 3-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [{ 2-[(2-hydroxyethyl) oxygen base] ethyl } (methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(1-{ methyl [2-(methoxyl group) ethyl] amino } ethyl)-the 3-thienyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{1-[methyl (propyl group) amino] ethyl }-the 3-thienyl)-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[(1S)-and 2-hydroxyl-1-Methylethyl] (methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide; With
5-(5-{ [(1,1-dioxo tetrahydrochysene-3-thienyl) (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; Or its pharmaceutically acceptable salt.
Term and definition
" alkyl " is meant the saturated hydrocarbon chain with mandatory member's atom number.For example, C 1-C 6Alkyl is meant the alkyl with 1-6 member's atom.Alkyl can choose wantonly by as replace in these defined one or more substituent groups.Alkyl can be straight chain or side chain.Representational branched alkyl has one, two or three side chains.Alkyl comprises methyl, ethyl, propyl group (n-pro-pyl and isopropyl), butyl (normal-butyl, isobutyl group and the tert-butyl group), amyl group (n-pentyl, isopentyl and neopentyl) and hexyl.
" alkylidene " is independent or forming other group (like C 1-C 6Alkylidene-heteroaryl, C 1-C 6Alkylidenyl-heterocyclic alkyl, C 1-C 6Alkylidene-C 4-C 7Cycloalkyl and C 1-C 6Alkylidene-C 5-C 7When using cycloalkenyl group), be meant saturated bivalent hydrocarbon chain with mandatory member's atom number.For example, C 1-C 6Alkylidene is meant the alkylidene with 1-6 member's atom.Alkylidene can choose wantonly by as replace in these defined one or more substituent groups.Alkylidene can be straight chain or side chain.Representational branched alkylidene has one, two or three side chains.Alkylidene comprises methylene, ethylidene, propylidene (inferior n-pro-pyl and isopropylidene), butylidene (inferior normal-butyl, isobutylene and the inferior tert-butyl group), pentylidene (inferior n-pentyl, isopentylidene and inferior neopentyl) and hexylidene.
" alkenyl " is meant the aliphatic unsaturated hydrocarbon that has mandatory member's atom number and in chain, have one or more carbon-to-carbon double bonds.For example, C 2-C 6Alkenyl is meant the alkenyl with 2-6 member's atom.In certain embodiments, alkenyl has a carbon-to-carbon double bond in chain.In other embodiments, alkenyl has a more than carbon-to-carbon double bond in chain.Alkenyl can choose wantonly by as replace in these defined one or more substituent groups.Alkenyl can be straight chain or side chain.Representational branched alkenyl has one, two or three side chains.Alkenyl comprises vinyl, acrylic, cyclobutenyl, pentenyl and hexenyl.
" alkenylene " is meant the unsaturated bivalent hydrocarbon chain that has mandatory member's atom number and in chain, have one or more carbon-to-carbon double bonds.For example, C 2-C 6Alkenylene is meant the alkenylene with 2-6 member's atom.In certain embodiments, alkenylene has a carbon-to-carbon double bond in chain.In other embodiments, alkenylene has a more than carbon-to-carbon double bond in chain.Alkenylene can choose wantonly by as replace in these defined one or more substituent groups.Alkenylene can be straight chain or side chain.Representational side chain alkenylene has one, two or three side chains.Alkenylene comprises ethenylidene, allylidene, butenylidene, inferior pentenyl and inferior hexenyl.
" alkynylene " is meant the unsaturated bivalent hydrocarbon chain that has mandatory member's atom number and in chain, have one or more carbon-to-carbon triple bonds.For example, C 2-C 6Alkynylene is meant the alkynylene with 2-6 member's atom.In certain embodiments, alkynylene has a carbon-to-carbon triple bond in chain.In other embodiments, alkynylene has a more than carbon-to-carbon triple bond in chain.For the sake of clarity, the unsaturated bivalent hydrocarbon chain that in chain, has one or more carbon-to-carbon triple bonds and in chain, have one or more carbon-to-carbon double bonds is an alkynylene.Alkynylene can choose wantonly by as replace in these defined one or more substituent groups.Alkynylene can be straight chain or side chain.Representational side chain alkynylene has one, two or three side chains.Alkynylene comprises ethynylene, inferior propinyl, butynelene, inferior pentynyl and inferior hexyn.
" aryl " is meant the aromatic hydrocarbon ring.Aryl is monocycle system or bicyclic system.Monocyclic aromatic rings is meant phenyl.The dicyclo aromatic ring be meant naphthyl and wherein phenyl with have the cycloalkyl or the condensed ring of cyclenes basic ring of 5,6 or 7 member's atoms.Aryl can choose wantonly by as replace in these defined one or more substituent groups.
" cycloalkyl " is meant the saturated hydrocarbons ring with mandatory member's atom number.Cycloalkyl is the monocycle system.For example, C 3-C 6Cycloalkyl is meant the cycloalkyl with 3-6 member's atom.Cycloalkyl can choose wantonly by as replace in these defined one or more substituent groups.Cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.
" cycloalkenyl group " is meant the unsaturated hydrocarbons ring that has mandatory member's atom number and in ring, have carbon-to-carbon double bond.For example, C 3-C 6Cycloalkenyl group is meant the cycloalkenyl group with 3-6 member's atom.In certain embodiments, cycloalkenyl group has a carbon-to-carbon double bond in ring.In other embodiments, cycloalkenyl group has a more than carbon-to-carbon double bond in ring.But the cyclenes basic ring is not an armaticity.Cycloalkenyl group is the monocycle system.Cycloalkenyl group can choose wantonly by as replace in these defined one or more substituent groups.Cycloalkenyl group comprises cyclopropanyl, cyclobutane base, cyclopentenyl and cyclohexenyl group.
" (the enantiomerically enriched) of enantiomer enrichment " is meant that enantiomer is excessive in 0 product.For example, the enantiomer enrichment be meant that enantiomer is excessive in 50%ee, greater than 75%ee and greater than the product of 90%ee.
What " enantiomeric excess (enantiomeric excess) " or " ee " were a kind of enantiomers with respect to another kind of enantiomer is excessive, representes with percentage ratio.Therefore, because two kinds of enantiomers exist with equivalent in racemic mixture, therefore, the enantiomer of racemic mixture is excessive to be 0 (0%ee).Yet if make it account for 95% of product a kind of enantiomer enrichment, so described enantiomer is excessive will to be 90%ee (quantity of the enantiomer of enrichment, 95%, deduct the quantity of another kind of enantiomer, 5%).
" optical voidness (enantimerically pure) " is meant that enantiomer is excessive in 99%ee or bigger product.
" half-life " (or " half-life ") is meant that the material of half quantity in external or body is converted into the another kind of chemically different required time of material.
" halogen " is meant the halogen group that is selected from fluorine, chlorine, bromine or iodine.
" haloalkyl " is meant alkyl, and wherein at least one hydrogen atom that is connected on member's atom in the alkyl replaces with halogen.Haloalkyl comprises trifluoromethyl.
" heteroaryl " is meant and in ring, contains the aromatic ring of 1-4 hetero atom as member's atom.Contain a more than heteroatomic heteroaryl and can contain different hetero atoms.Heteroaryl can choose wantonly by as replace in these defined one or more substituent groups.Heteroaryl be the monocycle system or condense, volution or bridging bicyclic system.The bicyclic heteroaryl ring has 5 or 6 member's atoms.The bicyclic heteroaryl ring has 7-11 member's atom.The bicyclic heteroaryl ring comprises those rings; Wherein phenyl and monocyclic heterocycles alkyl ring be connected to form condense, volution or bridging bicyclic system, and those encircle wherein bicyclic heteroaryl ring and monocyclic cycloalkyl, cycloalkenyl group, Heterocyclylalkyl or heteroaryl ring be connected to form condense, volution or bridging bicyclic system.Heteroaryl comprises pyrrole radicals; Pyrazolyl; Imidazole radicals; _ azoles base; Different _ the azoles base; Thiazolyl; Isothiazolyl; Furyl; The furazan base; Thienyl; Triazolyl; Pyridine radicals; Pyrimidine radicals; Pyridazinyl; Pyrazinyl; Triazine radical; The tetrazine base; Indyl; Isoindolyl; The indolizine base; Indazolyl; Purine radicals; Quinolyl; Isoquinolyl; Quinoxalinyl; Quinazolyl; Pteridyl; The cinnolines base; Benzimidazolyl; Benzopyranyl; Benzo _ azoles base; Benzofuranyl; Isobenzofuran-base; Benzothiazolyl; Benzothienyl; Furo pyridine radicals and naphthyridinyl.
" hetero atom " is meant nitrogen, sulfur or oxygen atom.
" Heterocyclylalkyl " is meant and in ring, contains the saturated or unsaturated ring of 1-4 hetero atom as member's atom.But heterocycloalkyl ring is not an armaticity.Contain a more than heteroatomic Heterocyclylalkyl and can contain different hetero atoms.Heterocyclylalkyl can choose wantonly by as replace in these defined one or more substituent groups.Heterocyclylalkyl is to have 4-7 member's atom.In certain embodiments, Heterocyclylalkyl is saturated.In other embodiments, Heterocyclylalkyl is undersaturated but is not armaticity.Heterocyclylalkyl comprise pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, pyranose, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro-thienyl, pyrazolidinyl, _ oxazolidinyl, thiazolidinyl, piperidyl, homopiperidinyl, piperazinyl, morpholinyl, thio-morpholinyl, 1; 3-dioxolanyl, 1; 3-two _ alkyl, 1; 4-two _ alkyl, 1; 3-oxathiolane base (oxathiolanyl), 1,3-thioxane base (oxathianyl), 1,3-dithiane base (dithianyl) and azetidinyl.
" member's atom " is meant the one or more atoms that constitute chain or ring.If in chain and ring, have more than member's atom, each member's atom combines with adjacent member's atom covalence in this chain or ring so.On chain or ring, constituting substituent atom is not the member's atom in chain or the ring.
" optional substituted " expression group, for example alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl group, Heterocyclylalkyl or heteroaryl, it can be unsubstituted or by one or more as replace in this defined substituent group." replacement " is meant that the hydrogen atom that group is connected in member's atom is replaced.Be to be understood that; Term " replacement " comprises implied condition; Be that substituted atom and substituent permission quantivalence are abideed by in this replacement, and be somebody's turn to do a kind of stable compound of replacement generation (chemical compound of conversion promptly can for example spontaneously not take place through rearrangement, cyclisation or elimination).In certain embodiments, single atom can be replaced by a more than substituent group, as long as this replacement meets the permission quantivalence of this atom.For each substituted or optional substituted group, suitable substituents this define.
" pharmaceutically acceptable " is meant those chemical compounds, material, compositions and dosage form; It is in the scope of healthy medical judgment; Be fit to contact use, and do not have over-drastic toxicity, zest or other problem or complication, have rationally being benefited/the risk ratio of matching with the tissue of human body and animal.
Those that use in the symbol that in these methods, scheme and embodiment, uses and convention (conventions) and the modern science document are consistent; For example, Journal of the American Chemical Society or Journal of Biological Chemistry.The single letter of standard or three letter abbreviations are generally used for representing amino acid residue, and except as otherwise noted, it is assumed to be the L-configuration.Except as otherwise noted, all parent materials are from commercial and further do not purify and use.Specifically, in embodiment and whole description, can use following abbreviation:
G (gram); Mg (milligram);
L (liter); ML (milliliter);
μ L (microlitre); Psi (pound/square inch);
M (mole); MM (mM);
I.v. (intravenous); Hz (hertz);
MHz (megahertz); Mol (mole);
Mmol (mM); Rt (room temperature);
Min (minute); H (hour);
Mp (fusing point); TLC (thin layer chromatography);
Tr (retention time); RP (anti-phase);
MeOH (methanol); I-PrOH (isopropyl alcohol);
TEA (triethylamine); TFA (trifluoroacetic acid);
TFAA (TFAA); THF (oxolane);
DMSO (dimethyl sulfoxine); AcOEt (ethyl acetate);
DME (1, the 2-dimethoxy-ethane); DCM (dichloromethane);
DCE (dichloroethanes); DMF (N, dinethylformamide);
DMPU (N, N '-dimethylpropylene urea); CDI (1, the 1-carbonyl dimidazoles);
IBCF (isobutyl chlorocarbonate); HOAc (acetic acid);
HOSu (N-hydroxy-succinamide); HOBT (I-hydroxybenzotriazole);
MCPBA (-the chlorine benzylhydroperoxide);
EDC (1-[the 3-dimethylamino) propyl group]-the 3-ethyl-carbodiimide hydrochloride);
BOC (tertbutyloxycarbonyl); FMOC (9-fluorenylmethyloxycarbonyl);
DCC (dicyclohexylcarbodiimide); CBZ (benzyloxycarbonyl group);
Ac (acetyl group); Atm (atmospheric pressure);
TMSE (2-(trimethyl silyl) ethyl); TMS (trimethyl silyl);
TIPS (triisopropyl silicyl); TBS (tert-butyl group dimethyl silane
Base);
DMAP (4-dimethylaminopyridine); BSA (bovine serum albumin);
ATP (ATP); HRP (horseradish peroxidase);
DMEM (the improved Eagle culture medium of Dulbecco);
HPLC (HPLC);
BOP (two (2-oxo-3-_ oxazolidinyl) inferior phosphonic chlorides (phosphinic chloride));
TBAF (tetra-n-butyl ammonium fluoride);
HBTU (O-BTA-1-base-N, N, N ', N '-tetramethylurea _ hexafluorophosphate);
HEPES (4-(2-hydroxyethyl)-1-piperazine ethyl sulfonic acid);
DPPA (diphenyl phosphoryl azide);
FHNO 3(the HNO of being fuming 3);
EDTA (ethylenediaminetetraacetic acid);
TMEDA (N, N, N ', N '-tetramethyl-1);
NBS (N-bromine butanimide);
HATU (O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethylurea _ hexafluorophosphate);
DIPEA (diisopropylethylamine);
Imes (1, two (2,4, the 6-trimethylphenyl) imidazoles _ hydrochlorates of 3-);
Dppf (1,1 '-two (diphenylphosphino) ferrocene);
MDAP (the automatic preparation (Mass Directed AutoPrep) of mass spectrum monitoring);
CH 3CN (acetonitrile);
EtOAc (ethyl acetate); With
NIS (N-iodine butanimide)
All refer to that the place of ether all is meant ether, and saline is meant saturated NaCl aqueous solution.
Chemical compound according to formula I-II can contain one or more asymmetric centers (being also referred to as chiral centre), and therefore, it can exist with the form of independent enantiomer, diastereomer or other stereoisomeric forms in any ratio or its mixture.Chiral centre such as chiral carbon atom can also be present in substituent group such as the alkyl.When the spatial chemistry of chiral centre is present in formula I-II or any chemical constitution shown here, though do not have specific pointing out, described structure should comprise any stereoisomer with and all mixture.Therefore, the formula I-II chemical compound that contains one or more chiral centres can use with the form of each stereoisomer of the mixture of racemic mixture, enantiomer enrichment or enantiomer-pure.
Each stereoisomer that contains the formula I-II chemical compound of one or more asymmetric centers can known by one of skill in the art method split.For example, this fractionation can be carried out (1) as follows through forming diastereomeric salt, complex or other derivant; (2) through reacting, for example through oxydasis or reduction reaction with stereoisomer specificity reagent selectivity; Or (3) gas liquid chromatography or liquid chromatograph through under chiral environment, said environment for example, on chiral support such as silicon dioxide with bonded chiral ligand or in the presence of chiral solvent.It will be understood to those of skill in the art that when required stereoisomer is converted into another kind of chemical individual through one of aforesaid separation method, need other step to discharge required form.Perhaps, specific stereoisomer can synthesize through asymmetric synthesis through reagent, substrate, catalyst or the solvent that uses optically active, or through asymmetric conversion a kind of enantiomer is converted into another kind of enantiomer.
Formula I-II chemical compound can also contain two keys or other how much asymmetric centers.When there were how much asymmetric spatial chemistry centers in formula I-II or any chemical constitution shown here, though there be not specific pointing out, described structure should comprise trans (E) geometric isomer, cis (Z) geometric isomer with and all mixture.Equally, all tautomeric forms also will be included in the formula I-II, no matter these tautomers exist with equilibrium form or accounting for main form with a kind of form exists.
It will be understood to those of skill in the art that the pharmaceutically acceptable salt that can make formula I-II chemical compound.Really; In certain embodiments of the invention; The pharmaceutically acceptable salt of formula I-II chemical compound can be preferably be the basis with separately free alkali or free acid, because these salt give bigger stability of molecule or dissolubility, helps thus to be formulated in the dosage form.Therefore, the invention still further relates to the pharmaceutically acceptable salt of formula I-II chemical compound.
Be meant those salt that keep the required BA of motif compound and show extremely low undesirable toxicology effect at this employed term " pharmaceutically acceptable salt ".(in situ) preparation in position during these pharmaceutically acceptable salts can and be purified in the last separation of chemical compound, or prepare through the chemical compound that exists with its free acid or free alkali form after the purification is reacted respectively with suitable alkali or acid individually.
In certain embodiments, formula I-II chemical compound can contain acidic functionality.Suitable pharmaceutically acceptable salt comprises the salt of these acidic functionalities.Representational salt comprises pharmaceutically acceptable slaine such as sodium, potassium, lithium, calcium, magnesium, aluminum and zinc salt; The carbonate of pharmaceutically acceptable metal cation such as sodium, potassium, lithium, calcium, magnesium, aluminum and zinc and bicarbonate; Pharmaceutically acceptable organic primary, second month in a season and tertiary amine comprise aliphatic amine, aromatic amine, aliphatic diamine and hydroxy alkyl amine such as methylamine, ethamine, 2 hydroxy ethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine and cyclohexylamine.
In certain embodiments, formula I-II chemical compound can contain basic functionality, and therefore can be through forming pharmaceutically-acceptable acid addition with suitable acid treatment.Suitable acid comprises pharmaceutically acceptable inorganic acids and pharmaceutically acceptable organic acid.Representational pharmaceutically-acceptable acid addition comprises hydrochlorate; Hydrobromate; Nitrate; Methyl nitrate; Sulfate; Disulfate; Sulfamate; Phosphate; Acetate; Trifluoroacetate; Hydroxyl acetate; Phenylacetate; Propionate; Butyrate; Isobutyrate; Valerate; Maleate; Hydroxymaleic acid salt; Acrylates; Fumarate; Malate; Tartrate; Citrate; Salicylate; Para-aminosalicylic acid salt; Glycollate; Lactate; Enanthate; Phthalate; Oxalates; Succinate; Benzoate; O-acetyl-p-methoxybenzoic acid salt; Chloro benzoate; Ar-Toluic acid salt; Dinitro-benzoate; Hydroxy benzoate; Methoxybenzoic acid salt; Mandelate; Tannate; Formates; Stearate; Ascorbate; Palmitate; Oleate; Pyruvate; Pamoate; Malonate; Laruate; Glutarate; Glutamate, Glu; The propionic ester lauryl sulfate; Mesylate (mesylate); Esilate (esylate); The 2-isethionate; Benzene sulfonate (besylate); Sulfanilate; Tosilate (tosylate) and naphthalene-2-sulfonic acid salt.
Be meant formula I-II chemical compound and pharmaceutically acceptable salt thereof at this employed term " chemical compound of the present invention ".
Chemical compound of the present invention can exist with the form of solid or liquid.In solid-state, chemical compound of the present invention can exist with crystal or non-crystal form, or exists with their form of mixture.For the chemical compound of the present invention that exists with crystal form, it will be understood to those of skill in the art that to form pharmaceutically acceptable solvate that wherein solvent molecule is blended in the lattice during crystallization.Solvate can comprise nonaqueous solvent such as ethanol, isopropyl alcohol, DMSO, acetic acid, ethanolamine and ethyl acetate, and perhaps they can comprise water, and it is as being blended into the solvent in the lattice.Wherein water is that the solvate that is blended into the solvent in the lattice is commonly referred to as " hydrate ".Hydrate comprises stoichiometric hydrate and the compositions that contains variable water gaging.The present invention includes all these solvates.
Those skilled in the art are further understood that the present invention comprises its various solvates with some chemical compound that crystal form exists, and can show polymorphism (performance that the different crystal structure promptly occurs).These crystals with different forms are commonly referred to as " polymorph ".The present invention includes all these polymorphs.Polymorph has identical chemical composition, but different at the solid-state accumulation of crystal, geometry arrangement and other said aspect of performance.Therefore, polymorph can have different physical propertys such as shape, density, hardness, deformability, stability and solubility property.Polymorph generally shows different fusing points, IR spectrum and X-ray powder diffraction pattern, and it can be used to identify.It will be understood to those of skill in the art that different polymorphs for example can be through changing or being adjusted in the preparation chemical compound employed reaction condition or reagent prepares.For example, change temperature, pressure or solvent and can produce polymorph.In addition, under certain conditions, a kind of polymorph can spontaneously be transformed into another kind of polymorph.
Compound
Chemical compound of the present invention can comprise standard chemical process through the several different methods preparation.Except as otherwise noted, any variable of definition before will have defined implication before.Set forth illustrative general synthetic method below, then, particular compound of the present invention will prepare in preparation embodiment.
For example, the chemical compound of formula I and II can prepare according to for example scheme 1,2 and 3 described below:
Scheme 1
Figure S2006800304481D00611
Condition: a) (BOC) 2O, THF; B) s-BuLi, ClCO 2Me, TMEDA, Et 2O; C) N-bromine butanimide, dichloromethane; D) TFA; E) MnO 2, THF; F) LiOH, MeOH, water; G) R1B (OR) 2, Imes-HCl, Pd (OAc) 2, two _ 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) 2O, DMAP, dichloromethane
The general approach of scheme 1 expression preparation formula I and II chemical compound, wherein R2 and R3 are H, F or Cl, U is chemical bond or C 1-C 6Alkylidene or C 2-C 6Alkenylene, and V is C5-C7 cycloalkyl or C5-C7 cycloalkenyl group or Heterocyclylalkyl or heterocycloalkenyl.Scheme 1 is also represented the general approach of preparation formula I and II chemical compound, and wherein U is C 1-C 6Alkylidene or C 2-C 6Alkenylene, and V is aryl or heteroaryl.In scheme 1, only if definition is arranged in addition, R1 as above defines.Described starting material indoline 1 is commercially available.Reaction condition is as above described in the scheme; Yet those skilled in the art will be understood that used reaction condition and/or reagent aspect have some change.
In suitable solvent such as THF or dichloromethane, handle indoline 1, generate the product of required BOC protection with di-tert-butyl dicarbonate (di-tertbutyldicarbonate).Can further be converted into required bromide 2 through following method: use s-butyl lithium in the presence of TMEDA, to carry out lithiumation, and stop, use N-bromine butanimide bromination subsequently with methylchloroformate.Bromide 2 usefulness trifluoroacetic acids are handled, subsequently the indoline that generates is oxidized to indole with manganese dioxide, and then methyl ester is hydrolyzed into acid, obtain required carboxylic acid 3.The coupling reaction that can mediate through the transition metal that uses appropriate catalyst and coupling part is accomplished the access of substituent R 1.As the instance of this conversion, for the situation of the condition " g " of scheme 1, the Suzuki cross-coupling reaction can be at Pd (OAc) 2, Imes-HCl and Cs 2CO 31, in 4-two _ alkane and the water, use borate or acid to accomplish under existing.The preparation of uncle's Methanamide 4 can be accomplished through carboxylic acid and ammonia are reacted.Introducing the conversion by 4 to 5 of group U-V accomplishes through generating U-V with suitable aldehydes or ketones precursors reaction.This conversion can be accomplished under alkalescence or acid condition.For group U-V wherein is saturated situation fully, subsequently midbody product is reduced and generates required product 5.As this reductive instance, for the situation of the condition " j " of scheme 1, at Pd (OH) 2Exist down and accomplish hydrogenation to change into 5.U-V and/or R1 contain in the situation of suitable protection base therein, can be through under appropriate condition, removing protection base, and further be converted into other product and accomplish.Subsequently the amine functional group of group U-V is converted into sulfonamide or the amide of R4, suitable sulfonyl that can be through using R4 or acyl chlorides or anhydride are realized.Those skilled in the art is to be understood that behind sulfonamide that is converted into R4 or amide, the product that is generated possibly further be modified to R4.This can include but not limited to suitable protection and functional group processing and with the reaction of amine/pure R5.
Scheme 2
Condition: a) R1B (OR) 2, Imes-HCl, Pd (OAc) 2, two _ alkane/water; B) HATU, NH 3, DMF; C) N-iodine butanimide, dichloromethane; D) VUB (OR) 2, Pd (PPh 3) 4, Cs 2CO 3, 1,4-two _ alkane, water; E) R 2Cl, TEA, dichloromethane (or) (R 2) 2O, DMAP, dichloromethane
The general approach of scheme 2 expression preparation formula I and II chemical compound, wherein U is that chemical bond and V are aryl or heteroaryl.In scheme 2, only if definition is arranged in addition, R1 as above defines.Described starting material indole-carboxylic acid 3 obtains described in scheme 1.Reaction condition is as above described in the scheme; Yet those skilled in the art will be understood that used reaction condition and/or reagent aspect have some change.
Those skilled in the art will be understood that, if said substituent group is not complementary with said synthetic method, so this substituent group can use suitable, to the protection base protection of stable reaction conditions.In course of reaction, described protection base can be removed in the suitable moment, so that obtain required intermediate or target compound.Suitable protection base and to use the method for protection of these suitable protection bases and deprotection different substituents be well known to a person skilled in the art; The example can be at T.Greene and P. Wuts, Protecting Groups in Chemical Synthesis(the 3rd edition), John Wiley&Sons, NY finds in (1999).In some cases, can specifically select substituent group under employed reaction condition so that be that tool is active.In these cases, described reaction condition changes into another kind of substituent group with selected substituent group, this another kind substituent group as midbody compound or in target compound required substituent group.
Method for using
Chemical compound of the present invention is the IKK2 inhibitor.These chemical compounds can be used for treating wherein said potential condition of illness (at least to a certain extent) and are attributable to the active disease of inappropriate IKK2 (also claiming IKK β), like rheumatoid arthritis, inflammatory bowel, asthma and COPD (chronic obstructive pulmonary disease)." inappropriate IKK2 is active " is meant and in concrete patient, departs from the active any IKK2 activity of desired normal IKK2.Inappropriate IKK2 activity for example can increase for activity unusually, or regularly and or the not normal form of IKK2 activity control.Then, this inappropriate activity can be produced by overexpression that causes for example inappropriate or uncontrolled activated protein kinase or sudden change.Therefore, in another aspect, the present invention relates to treat the method for these diseases.
These diseases comprise inflammatory diseases and tissue repair disease, particularly rheumatoid arthritis, inflammatory bowel, asthma and COPD (chronic obstructive pulmonary disease); Osteoarthritis, osteoporosis and fibrotic conditions; Dermatosis comprises the skin injury of psoriasis, atopic dermatitis and ultraviolet radiation (UV)-bring out; Autoimmune disease comprises systemic lupus erythematosus (sle), multiple sclerosis, arthritic psoriasis, ankylosing spondylitis (alkylosing spondylitis), tissue and organ rejection, Alzheimer, apoplexy, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, comprises Hokdkin disease, cachexia, with infect the inflammation relevant with some viral infection, comprise acquired immunodeficiency syndrome (AIDS), adult's RD syndrome and ataxia telangiectasia.
Therapeutic Method of the present invention comprises the patient safety that needs and formula I-II chemical compound or its pharmaceutically acceptable salt of effective dose.Each embodiment of the present invention comprises the method for treating above-mentioned any disease, and said method is through the patient safety that needs and formula I-II chemical compound or its pharmaceutically acceptable salt of effective dose.
Relevant in this employed " treatment " with disease; Be meant: one or more performances biology of (1) improvement or prevent disease or disease; (2) one or more points of interference (a) cascade biology; It causes disease or causes the reason of disease or (b) one or more performances biology of disease that (3) alleviate one or more symptoms or the influence relevant with disease, or one or more performances biology of the progress or the disease of disease are slowed down in (4).
" treatment " of aforesaid disease comprises the prevention of this disease.Those skilled in the art will be understood that " prevention " is not absolute term.In medical science, " prevention " be understood that to be meant preventative give medicine with remarkable weakening disease or its biology of performance maybe or the order of severity, or postpone the outbreak of this disease or its biology of performance.
Be meant in correct medical judgment scope at this employed " safety and effective dose ", be enough to treat disease of patient but simultaneously enough low to avoid the serious side effects chemical compound quantity of (reasonably benefit/risk compares) about The compounds of this invention or other forms of pharmacologically active agents.The safety of chemical compound and effective dose will be with selected particular compound (for example considering drug effect, effectiveness and the half-life of this chemical compound); Selected route of administration; The disease of being treated; The order of severity of the disease of treating; The patient's age of treating, size, body weight and condition; The patient's that treats medical history; The persistent period of treatment; The character of therapeutic alliance; Factor such as required therapeutic effect and changing, but still can confirm by those skilled in the art usually.
Be meant people or other animal this employed " patient ".
Chemical compound of the present invention can give through any suitable route of administration, comprises general administration and topical.The general administration comprises oral administration, parenteral, percutaneous dosing, rectally and inhalation.Parenteral is meant except that intestinal canal administration, percutaneous dosing or the route of administration the inhalation, and generally passes through injection or transfusion administration.Parenteral comprises intravenous, intramuscular and subcutaneous injection or transfusion.Inhalation is meant oral or passes through the nasal passage inhalation in patient's lung.Topical comprises and is applied to skin and ophthalmic, in ear, intravaginal and intranasal administration.
Chemical compound of the present invention can single administration, or according to dosage regimen, official hour in the cycle with variable interval multiple dosing.For example, can be administered once every day, secondary, three times or four times.Can give dosage, till realizing required curative effect, perhaps administration since die is to keep required curative effect always.The suitable dosage regimen of The compounds of this invention depends on the pharmacokinetic property of this chemical compound, for example absorbs, distribution and half-life, and it can be confirmed by those skilled in the art.In addition; For chemical compound of the present invention; Suitable dosage regimen; The persistent period that comprises these dosage regimens, its will depend on the disease of being treated, the disease of treating the order of severity, the patient's age of treating and condition, the patient's that treats medical history, the character of therapeutic alliance, required factors such as curative effect, these are all in the scope of those skilled in the art's knowledge and technology.Those skilled in the art can further understand, and after the reaction of consideration individual patient to dosage regimen, suitable dosage regimen possibly need adjustment, and perhaps individual patient needs and changes in time.
General daily dose can change with selected concrete route of administration.For oral administration, general daily dose is in the scope of the every kg TBW of 0.001mg-50mg.
In addition, form that can prodrug gives chemical compound of the present invention." prodrug " at this employed The compounds of this invention is this compound functions derivant, and when giving the patient with it, it finally discharges chemical compound of the present invention in vivo.Giving chemical compound of the present invention with the form of prodrug, that those skilled in the art are done is following one or more: (a) change chemical compound beginning in vivo; (b) change chemical compound acting duration in vivo; (c) change chemical compound transportation or distribution in vivo; (d) change chemical compound dissolubility in vivo; And (e) overcome the side effect of chemical compound or other difficult point that chemical compound ran into.The functional deriv that generally is used to prepare prodrug comprises the chemical compound that is modified at chemistry in the body or enzymatic lysis.These are modified, and the preparation that it comprises phosphate ester, amide, ester, monothioester, carbonic ester and carbamate is well known to a person skilled in the art.
The present invention also provides the purposes of chemical compound of the present invention on therapeutic treatment, particularly the purposes in the disease that treatment is mediated by the IKK2 activity.Therefore, on the other hand, the present invention relates to formula I-II chemical compound or its pharmaceutically acceptable salt are used for treating the medicine that is characterized as the active disease of inappropriate IKK2 in preparation purposes.
Be characterised in that the active disease specific of inappropriate IKK2 comprises inflammatory diseases and tissue repair disease, particularly rheumatoid arthritis, inflammatory bowel, asthma and COPD (chronic obstructive pulmonary disease); Osteoarthritis, osteoporosis and fibrotic conditions; Dermatosis comprises the skin injury of psoriasis, atopic dermatitis and ultraviolet radiation (UV)-bring out; Autoimmune disease comprises systemic lupus erythematosus (sle), multiple sclerosis, arthritic psoriasis, ankylosing spondylitis, tissue and organ rejection, Alzheimer, apoplexy, atherosclerosis, restenosis, diabetes, glomerulonephritis, cancer, comprises Hokdkin disease, cachexia, with infect the inflammation relevant with some viral infection; Comprise acquired immunodeficiency syndrome (AIDS), adult's RD syndrome and ataxia telangiectasia, it is the result that protein kinase IKK2 suppresses.
Compositions
Before delivering medicine to the patient, usually with chemical compound of the present invention, but not necessary, be mixed with pharmaceutical composition.Therefore, in another aspect, the present invention relates to comprise the pharmaceutical composition of The compounds of this invention and one or more acceptable accessories.
Pharmaceutical composition of the present invention can wherein can extract the The compounds of this invention of safety and effective dose with prepare and packing in batch, gives the patient with powder or syrupy form then.Perhaps, pharmaceutical composition of the present invention can be with the prepare and the packing of unit dosage forms, and wherein each unit that physically separates contains the The compounds of this invention of safety and effective dose.When preparing with unit dosage forms, pharmaceutical composition of the present invention generally can contain, for example, and 0.5mg-1g, or 1mg-700mg, or the The compounds of this invention of 5mg-100mg.
Pharmaceutical composition of the present invention generally contains a kind of The compounds of this invention.Yet in certain embodiments, pharmaceutical composition of the present invention contains more than a kind of The compounds of this invention.For example, in certain embodiments, pharmaceutical composition of the present invention contains two kinds of chemical compounds of the present invention.In addition, pharmaceutical composition of the present invention can be chosen wantonly and further comprise one or more other pharmaceutically active compound.
Be meant pharmaceutically acceptable material, compositions or carrier in this employed " acceptable accessories ", they are used to produce the shape or the concordance of pharmaceutical composition.When sneaking into, every kind of adjuvant must with other compatible in the pharmaceutical composition, will avoid when delivering medicine to the patient, significantly reducing interaction that The compounds of this invention renders a service and the interaction that causes not being pharmaceutically acceptable pharmaceutical composition like this.In addition, every kind of adjuvant must have sufficiently high purity certainly, so that it is pharmaceutically acceptable.
Generally, The compounds of this invention and pharmaceutically acceptable one or more adjuvants are mixed with dosage form, this dosage form is fit to deliver medicine to the patient through required route of administration.For example, dosage form comprises and is suitable for (1) oral administration for example tablet, capsule, Caplet, pill, lozenge, powder, syrup, elixir, suspension, solution, Emulsion, wafer and cachet; (2) the parenteral powder of sterile solution, suspension and reconstruct (reconstitution) for example; (3) percutaneous dosing transdermal patch for example; (4) rectally suppository for example; (5) for example aerosol, solution and dry powder of inhalation; And those dosage forms of (6) topical example emulsion, unguentum, washing liquid, solution, paste, spray, foam and gel.
Suitable acceptable accessories will change with selected concrete dosage form.In addition, can select suitable acceptable accessories, specific so that they can play a part in compositions.For example, can select some acceptable accessories, these adjuvants can promote to generate uniform dosage form.Can select some acceptable accessories, these adjuvants can promote to generate stable dosage form.Can select some acceptable accessories, in case give the patient, they can promote one or more chemical compound of the present invention to carry or be transported to another part of another organ or health from the part of a kind of organ or health.Can select some acceptable accessories, they can strengthen patient's compliance.
Suitable pharmaceutically acceptable excipient comprises the adjuvant of following type: diluent, filler, binding agent, disintegrating agent, lubricant, fluidizer, granulating agent, coating materials, wetting agent, solvent, cosolvent, suspending agent, emulsifying agent, sweeting agent, flavoring agent, taste masked agent, coloring agent, anti-caking agent, hemectants, chelating agen, plasticizer, viscosifier, antioxidant, antiseptic, stabilizing agent, surfactant and buffer agent.It will be understood to those of skill in the art that some pharmaceutically acceptable excipient can play more than a kind of effect, and other component that exists in what and the preparation according to figuration dosage in the preparation, can play alternative effect.
Those skilled in the art can select suitable pharmaceutically acceptable excipient to be used for the present invention with suitable amount.In addition, those skilled in the art can obtain resource from the place of many description acceptable accessories and can be used for selecting suitable acceptable accessories.Instance comprises Remington ' s Pharmaceutical Sciences(Mack Publishing Company), TheHandbook of Pharmaceutical Additives(Gower Publishing Limited) and TheHandbook of Pharmaceutical Excipients(the American PharmaceuticalAssociation and the Pharmaceutical Press).
Pharmaceutical composition of the present invention uses technology well known by persons skilled in the art and method to prepare.Some universal methods of using in the art are described in Remington ' s PharmaceuticalSciencesIn (Mack Publishing Company).
On the one hand, the present invention relates to solid oral dosage form such as tablet or capsule, it comprises The compounds of this invention and the diluent or the filler of safety and effective dose.Suitable diluent and filler comprise lactose, sucrose, glucose, mannitol, Sorbitol, starch (for example corn starch, potato starch and pregelatinized starch), cellulose and derivant (for example microcrystalline Cellulose), calcium sulfate and calcium hydrogen phosphate.Described oral dosage form can further comprise binding agent.Suitable bonding comprises starch (for example corn starch, potato starch and pregelatinized starch), gelatin, arabic gum, sodium alginate, alginic acid, tragakanta, guar gum, polyvidone and cellulose and derivant (for example microcrystalline Cellulose) thereof.Described oral dosage form can further comprise disintegrating agent.Suitable disintegrants comprises crospovidone, sodium starch glycollate, croscarmellose, alginic acid and sodium carboxymethyl cellulose.Described oral dosage form can further comprise lubricant.Examples of suitable lubricants comprises stearic acid, magnesium stearate, calcium stearate and Pulvis Talci.
If suitable, can carry out micro encapsulation to the dosage unit preparations of oral administration.For example, through with the particulate matter coating or be embedded in polymer, the wax etc., can prolong or keep the release of said composition.
The compounds of this invention can also with the soluble polymer coupling as target medicine carrier.These polymer can comprise polyvidone, pyran co-polymer, gather hydroxypropyl methyl acrylamide-phenol, poly-hydroxyethyl agedoite phenol or by the substituted PEO poly-D-lysine of palmityl residue.In addition; Chemical compound of the present invention can with one type of biodegradable polymer coupling in obtaining controlled release drug, using; For example, polylactic acid, polycaprolactone (polepsilon caprolactone), multi-hydroxybutyrate, poe, polyacetals, gather the crosslinked or amphiphilic block copolymer of dihydropyran, polybutylcyanoacrylate and hydrogel.
In another aspect, the present invention relates to liquid oral dosage form.Liquid oral such as solution, syrup and elixir can make with dosage unit form, contain the The compounds of this invention of scheduled volume in the given like this quantity.Syrup can make through The compounds of this invention is dissolved in the suitably seasoned aqueous solution, and elixir makes through using the avirulence alcohol carrier.Suspension can be prepared through The compounds of this invention is dispersed in the non-toxic carrier.Can also add solubilizing agent and emulsifying agent such as ethoxylation isooctadecanol and polyoxyethylene sorbitol ether, antiseptic, flavouring additive such as Oleum menthae or natural sweetener or glucide or other artificial sweetening agents etc.
In another aspect, the present invention relates to be adapted to pass through the dosage form that suction gives the patient.For example, chemical compound of the present invention can be inhaled in the lung with the form of dry powder, aerosol, suspension or solution.
The dry powder composite that is delivered to lung through suction generally comprises the The compounds of this invention of fine powder form and with one or more acceptable accessories of fine powder form.The acceptable accessories that is particularly suitable in dry powder, using is well known by persons skilled in the art, and comprises lactose, starch, mannitol and monosaccharide, disaccharide and polysaccharide.
Described dry powder can give the patient through the inhaler (RDPI) of storing dry powder, and this inhaler has the storage of (not dosing) medicine that is suitable for storing a plurality of dry powder forms.RDPI generally comprises and from storage, measures the equipment of each drug dose to the administration position.For example, this measuring equipment can comprise jigger, and it can move to the second position from primary importance, and at the primary importance place, jigger can be full of the medicine from storage, and at second position place, the drug dose that measured can be sucked by the patient.
Perhaps, described dry powder may reside in capsule (for example gelatin or plastic), cartridge case or the blister package (blister packs) and uses for multidose dry powder inhaler (MDPI).MDPI is an inhaler, and its Chinese medicine is comprised in the multiple-unit container that contains (or otherwise carrying) a plurality of limiting doses (or its part) medicine.When described dry powder existed with the form of blister package, it comprised a plurality of bubble-caps (blister) that contain the dry powder form medicine.General described bubble-cap is arranged with regular fashion, to make things convenient for from wherein discharging medicine.For example, described bubble-cap can be arranged in the disc blister package with circular, fashion usually, or described bubble-cap can be microsclerly, for example comprises strip or band shape.Each capsule, cartridge case or bubble-cap can for example contain the The compounds of this invention of 20 μ g-10mg.
Aerosol can prepare through chemical compound of the present invention is suspended or is dissolved in the liquefied propellant.Suitable propellant comprises the gas of halogenated hydrocarbons, hydrocarbon and other liquefaction.Representational propellant comprises: Arcton 11 (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetra-fluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1,1-Difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoro-propane (HFA-227a), perfluoropropane, perfluorinated butane, perflenapent, butane, iso-butane and pentane.The aerosol that comprises The compounds of this invention generally gives the patient through metered dose inhaler (MDI).These devices are well known by persons skilled in the art.
Described aerosol can contain adjuvant such as surfactant, lubricant, cosolvent and other adjuvant that other is pharmaceutically acceptable, generally use with MDI, with the physical stability of improving preparation, improve valve performance, improve dissolubility or improve taste.
The suspension and the solution that comprise The compounds of this invention also can give the patient through aerosol apparatus.Solvent that is used to spray or suspending agent can be any pharmaceutically acceptable liquid such as water, saline, alcohol or glycols, for example, and ethanol, isopropyl alcohol, glycerin, propylene glycol, Polyethylene Glycol etc. or its mixture.The salt that does not almost have or do not show pharmacological activity after the saline solution use administration.For this reason, can use the halide salt of inorganic salt such as alkali metal salt or ammonium, for example, sodium chloride, potassium chloride or organic salt, like potassium, sodium and ammonium salt or organic acid, for example, ascorbic acid, citric acid, acetic acid, tartaric acid etc.
Can other acceptable accessories be joined in described suspension or the solution.Chemical compound of the present invention can pass through to add mineral acid, for example, and hydrochloric acid, nitric acid, sulphuric acid and/or phosphoric acid; Organic acid, for example, ascorbic acid, citric acid, acetic acid and tartaric acid etc.; Chelating agent such as EDTA or citric acid and salt thereof; Or antioxidant such as vitamin E or ascorbic acid are stablized.These can use separately or use together stablize chemical compound of the present invention.Can add antiseptic such as benzalkonium chloride or benzoic acid and salt thereof.Can add surfactant especially to improve the physical stability of suspension.These comprise lecithin, dioctyl sulfo-succinic acid disodium, oleic acid and sorbitan ester.
The pharmaceutical composition that is fit to percutaneous dosing can use with isolating patch form, is used for contacting secular a period of time closely with patient's epidermis.For example, can infiltrate release of active ingredients from paster through ion, it is generally described in Pharmaceutical Research, in 3 (6), 318 (1986).
The pharmaceutical composition that is suitable for topical can be mixed with ointment, Emulsion, suspension, washing liquid, powder, solution, paste, gel, spray, aerosol or oil preparation.
For the treatment of eyes or other outside organization, for example oral cavity and skin, described compositions can be used with the form of topical ointment or Emulsion.When being mixed with ointment, chemical compound of the present invention can use with paraffin or with the mixable ointment base of water.Perhaps, chemical compound of the present invention can be mixed with Emulsion with oil-in-water ointment base or Water-In-Oil substrate.
The pharmaceutical composition that is suitable for intranasal administration; Wherein said carrier is a kind of solid; Comprise the for example corase meal in the 20-500 micrometer range of particle diameter, administration in such a way, it sucks through nasal passage from the container that contains powder near nose fast.Suitable compositions, wherein said carrier is a liquid, is used for comprising the aqueous solution or the oil solution of chemical compound of the present invention as the nose spray delivery or as the nasal drop administration.
The pharmaceutical composition that is suitable for parenteral comprises moisture and anhydrous aseptic parenteral solution, and it can contain antioxidant, buffer, antibacterial and solute, and it makes said preparation and specified receiver's blood etc. ooze; And moisture and anhydrous sterile suspensions can comprise suspending agent and thickening agent.Described compositions can for example exist in the ampoule of sealing and the medicine bottle, and can under lyophilizing (lyophilization) condition, store at UD or multi-dose container, and it only needs to add at once before use sterile liquid carrier, for example water for injection.Interim injection solution and suspension can be by sterile powder, granule and preparation tablets.
Embodiment
Following embodiment makes an explanation to the present invention.These embodiment are used to limit scope of the present invention, but instruct those skilled in the art to prepare and use chemical compound of the present invention, compositions and method.Though described specific embodiments of the present invention, it will be understood to those of skill in the art that under the situation that does not break away from the spirit and scope of the present invention, can carry out various changes and improvement.
All refer to that the place of ether all is meant ether; Saline is meant saturated NaCl aqueous solution.Except as otherwise noted, all temperature all use ℃ (degree centigrade) expression.Except as otherwise noted, respond and all in inert atmosphere, at room temperature carry out.
1H NMR spectrum record on Brucker DPX400, Brucker DPX250, Brucker AC400 or Varian Inova 400.Chemical shift is represented (ppm, δ unit) with a few millionths.Splitting merotype has described apparent (apparent) multiplicity and has been called as s (unimodal), d (bimodal), t (triplet), q (quartet), quint (quintet), m (multiplet), br (broad peak).
Low resolution mass spectrum (MS) is record on JOEL JMS-AX505HA, JOEL SX-102 or SCIEX-APIiii spectrometer; LC-MS is record on Waters ZQ or PE Sciex Single QuadrupoleLC/MS API-150 spectrometer.
Prepare HPLC and be meant such method; Wherein material is gone up at HPLC ABZ+5 μ m post (10cm * 21.2mm i.d.) and is purified with HPLC; Carry out gradient elution with the acetonitrile solution of the aqueous solution of 0.1% formic acid and 0.05% formic acid with the flow velocity of 8mL/min, and carry out UV at the 254nm place and detect.
Except as otherwise noted, silica gel (silica) flash column chromatography and Combiflash are meant that material uses Redisep TMThe quick post of silica gel of filling in advance uses described dicyandiamide solution to purify on ISCO sq 16x appearance.
Reversed-phase HPLC method A is meant such method, and wherein material is gone up through HPLC at HPLC S-5 μ m post (75 * 30mm i.d.) and purified, and uses described dicyandiamide solution to carry out gradient elution and carries out the UV detection at 254nb place.
Reversed-phase HPLC method B is meant such method, and wherein material is gone up through HPLC at HPLC Luna C18 (2) 100A post (50 * 21.2mm i.d.) and purified, and carries out gradient elution and carries out the UV detection at the 254nm place with described dicyandiamide solution.
The LC-MS experiment condition of PE Sciex Single Quadrupole LC/MS API-150:
Chromatograph of liquid:
System: the Shimadzu LC system of band SCL-10A controller and dual UV detector
Automatic sampler: the Leap CTC of band Valco six hole syringes
(C18 40 * 1mm) for post: Aquasil/Aquasil
Volume injected (μ L): 2.0
Solvent orange 2 A: H 2O, 0.02%TFA
Solvent B:MeCN, 0.018%TFA
Gradient: linear
Passage A:UV 214nm
Channel B: ELS
Step time remaining time flow velocity (μ L/min) solvent orange 2 A solvent B
(min) (min)
0 0.00 0.00 300.00 95.00 5.00
1 0.00 0.01 300.00 95.00 5.00
2 0.01 3.20 300.00 10.00 90.00
3 3.21 1.00 300.00 10.00 90.00
4 4.21 0.10 300.00 95.00 5.00
5 4.31 0.40 300.00 95.00 5.00
Mass spectrograph: PE Sciex Single Quadrupole LC/MS API-150
Polarity: cation
Acquisition mode: profile (profile)
Intermediate
Intermediate 1:2,3-dihydro-1H-indole-1-carboxylic acid 1,1-dimethyl ethyl ester
Figure S2006800304481D00721
With indoline (10g 84mmol) is dissolved in the oxolane (100mL), and add the dimethyl dicarbonate butyl ester (22g, 0.1mol).This mixture was at room temperature stirred 16 hours in inert nitrogen atmosphere.Remove oxolane in a vacuum, crude product is purified with vacuum distilling, obtains the title compound (15.1g) of clarifying pale pink color oil form, crystallization when it leaves standstill (temperature: 160-162 ℃, pressure 1-0.1mm Hg).
1H?NMR(400MHz，DMSO-D6)δppm?1.50(s，9H)3.04(t，J＝8.7Hz，2H)3.89(t，J＝8.8Hz，2H)6.91(td，J＝7.3，0.8Hz，1H)7.13(t，J＝7.5Hz，1H)7.18(d，J＝7.3Hz，1H)7.5-7.8(bs，1H)r.t.3.44min。
Intermediate 2:1-(1, the 1-dimethyl ethyl) 7-methyl 2,3-dihydro-1H-indole-1,7-dicarboxylic ester
With 2,3-dihydro-1H-indole-1-carboxylic acid 1,1-dimethyl ethyl ester (5g, 22.8mmol) and N, N, N ', (4.6mL 30.5mmol) is dissolved in the dry ether (300mL) N '-tetramethyl-1, and in acetone/the dry ice bath, is cooled to-78 ℃.(cyclohexane solution of 1.4M, 17.6mL 24.6mmol), then stir reactant mixture 90 minutes under this temperature in 10 minutes, to drip s-butyl lithium.With methylchloroformate (8.8mL, 10.8g 0.1mol) join in this mixture, then with reactant mixture 1 little, the time in be warmed to room temperature.In this mixture, add water carefully, separate organic layer, and with more water washing 3 times.Organic layer filters through dried over mgso, and concentrates in a vacuum, obtains the title compound (4.91g) of gluey yellow solid.
1H?NMR(400MHz，DMSO-D6)δppm?1.44(s，9H)3.06(t，J＝8.2Hz，2H)3.69(s，3H)4.02(t，J＝8.3Hz，2H)7.06(t，J＝7.5Hz，1H)7.35(d，J＝7.5Hz，1H)7.39(dd，J＝7.4，1.1Hz，1H)MS?m/z?278(M+1) +r.t.3.18min。
Intermediate 3:1-(1, the 1-dimethyl ethyl) 7-methyl 5-bromo-2,3-dihydro-1H-indole-1,7-dicarboxylic ester
Figure S2006800304481D00731
With 1-(1, the 1-dimethyl ethyl) 7-methyl 2,3-dihydro-1H-indole-1; 7-dicarboxylic ester (3.1g; 11.2mmol) and N-bromine butanimide (2.0g 11.2mmol) is dissolved in the dry methylene chloride (100mL), then in blanket of nitrogen, at room temperature stirs 16 hours.This reactant mixture distributes with sodium hydroxide solution (2M), separates and washs with more sodium hydroxide solution.Organic layer through dried over mgso, and is concentrated in a vacuum, obtain the title compound (3.55g) of gluey red solid.
(400MHz, DMSO-D6) (s, 9H) 3.09 (2H) 3.70 (s, 3H) 4.02 (2H) 7.46 (s, 1H) 7.60 (s, 1H) MS m/z 356/358 (1: 1 ratio) (M+1) for t, J=8.3Hz for t, J=8.3Hz for δ ppm 1.41 for 1H NMR +R.t.3.52min.
Intermediate 4:5-bromo-2,3-dihydro-1H-indole-7-carboxylic acid methyl ester
Figure S2006800304481D00732
With 1-(1, the 1-dimethyl ethyl) 7-methyl 5-bromo-2,3-dihydro-1H-indole-1, (9g 25mmol) is dissolved in the trifluoroacetic acid (6mL) the 7-dicarboxylic ester, then at room temperature stirs 16 hours.Add dichloromethane and sodium hydroxide solution (2M), then organic layer is used the sodium hydroxide solution washed twice, till water layer pH＞7.Then, organic layer is concentrated in a vacuum, obtain the title compound (6.5g) of brown solid.
(400MHz, DMSO-D6) (2H) 3.61 (2H) 3.78 (s, 3H) 6.72 (s, 1H) 7.28 (1H) 7.46 (1H) MS m/z 256/258 (1: 1 ratio) (M+1) for d, J=2Hz for d, J=1Hz for t, J=8.4Hz for t, J=8.5Hz for δ ppm 2.99 for 1H NMR +R.t.3.32min.
Intermediate 5:5-bromo-1H-indole-7-carboxylic acid methyl ester
Figure S2006800304481D00741
With 5-bromo-2, (6.5g 25mmol) is dissolved in the oxolane (100mL) 3-dihydro-1H-indole-7-carboxylic acid methyl ester.(5 μ m particle diameters, 22g 0.25mol), then at room temperature stirred this mixture 16 hours to add activatory manganese dioxide.Add the activatory manganese dioxide of 22g again, then will react and stir 96 hours.Then, will react, then concentrate in a vacuum, obtain the solid title compound of ecru (5.1g) through diatomite filtration.
1H NMR (400MHz, DMSO-D6) δ ppm 3.94 (s, 3H) 6.58 (d, J=3Hz; 1H) 7.48 (d, J=3Hz, 1H) 7.8 (d, J=2Hz; 1H) 8.07 (d, J=1.8Hz, 1H) 11.39 (bs, 1H) (M-1) r.t.3.41min of MS m/z 252/254 (1: 1 ratio).
Intermediate 6:5-bromo-1H-indole-7-carboxylic acid
Figure S2006800304481D00742
(5g 19.7mmol) is dissolved in the methanol (200mL), then adds Lithium hydrate (0.99g, 41mmol) solution in water (10mL) with 5-bromo-1H-indole-7-carboxylic acid methyl ester.Mixture was heated 50 hours under refluxing.Under vacuum, remove methanol, residue dilutes with aqueous hydrochloric acid solution (2M).The gained deposition is leached, then, obtain the solid title compound of ecru (4.7g) with vacuum spray gun (the heated vacuum pistol) drying of heating.
1H NMR (400MHz, DMSO-D6) δ ppm 6.54 (dd, J=2.0,3.2Hz, 1H) 7.42 (t; J=2.8Hz, 1H) 7.77 (d, J=2Hz, 1H) 8.03 (d; J=1.8Hz, 1H) 11.27 (s, 1H) 13.1-13.7 (bs, 1H) (M-1) r.t.3.41min of MS m/z 238/240 (1: 1 ratio).
Intermediate 7:5-bromo-1H-indole-7-Methanamide
Figure S2006800304481D00743
At room temperature, to 5-bromo-1H-indole-7-carboxylic acid (10.0g, CH 42mmol) 2Cl 2(100mL) add in the solution EDC (9.66g, 50.4mmol), HOBt (6.81g, 50.4mmol) and NH 3(the MeOH solution of 2.0M, 84mL, 168mmol).Reactant mixture was at room temperature stirred 16 hours.Evaporating solvent, and residue distributed between ethyl acetate (100mL) and water (100mL).With water layer with ethyl acetate (100mL * 2) extraction, and with the organic facies that merges through MgSO 4Drying, and concentrate, crude product (10g, 98%) obtained.This crude product is not further purified and just directly is used for next step.
LC/MS：m/z?240.0(M+H)，1.95min。
Intermediate 8:4-[7-(amino carbonyl)-5-bromo-1H-indol-3-yl]-3,6-dihydro-1 (2H)-picolinic acid 1,1-dimethyl ethyl ester
Figure S2006800304481D00751
To 5-bromo-1H-indole-7-Methanamide (10g adds 4-oxo-1-piperidine carboxylic acid 1 in methanol 41.84mmol) (5mL) solution, 1-dimethyl ethyl ester (684mg, 3.42mmol) and Feldalat NM (the THF solution of 0.5M, 13.7mL, 6.84mmol).Reactant mixture was stirred 16 hours under reflux temperature.All solvents of reduction vaporization.Residue is distributed between ethyl acetate (100mL) and water (100mL).With the organic facies that merges through MgSO 4Drying, and concentrating under reduced pressure, and, generate required product (7.4g, 43%) through flash column chromatography (ethyl acetate/hexane, 1/1) purification.
LC/MS：m/z?420.0(M+H)，2.35min。
Intermediate 9:4-[7-(amino carbonyl)-5-bromo-1H-indol-3-yl]-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester
Figure S2006800304481D00761
To 4-[7-(amino carbonyl)-5-bromo-1H-indol-3-yl]-3,6-dihydro-1 (2H)-picolinic acid 1, (7.41g 17.64mmol) adds platinum oxide (200mg, 5%) to 1-dimethyl ethyl ester in the solution in ethanol (600mL).With reactant mixture at H 2Hydrogenation is 16 hours in the atmosphere.Through diatomite filtration gained mixture, then will filtrate concentrates.The gained residue is with flash column chromatography (ethyl acetate/hexane, 1: 4-2: 1v/v) purify, obtain required product (3.6g, 48%).
LC-MS：m/z?422.0(M+H)，2.25min。
Intermediate 10:5-bromo-3-(4-piperidyl)-1H-indole-7-Methanamide
Figure S2006800304481D00762
To 4-[7-(amino carbonyl)-5-bromo-1H-indol-3-yl]-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester (1.56g, 3.7mmol) add in the solution in methanol (10mL) HCl two _ alkane solution (4M, 35.5mL).Reactant mixture at room temperature stirred 2 hours.Vapourisation under reduced pressure solvent, gained residue distribute between the NaOH aqueous solution (50mL) of ethyl acetate (50mL) and 5%.(2 * 50mL) washings are used MgSO with the organic facies that merges to water layer with ethyl acetate 4Dry and under reduced pressure concentrated, obtain required product (685mg, 58%), it does not have further purification just to be used for next step.
LC-MS：m/z?322.0(M+H)，1.45min。
Intermediate 11:5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D00771
0 ℃ (bathing temperature); With ethyl sulfonic chloride (4.5mL; 47.4mmol) be added drop-wise to 5-bromo-3-(4-piperidyl)-1H-indole-7-carboxamide hydrochloride (8.49g, 23.7mmol) and triethylamine (13.2mL is 94.7mmol) in the solution in DMF (80mL); Reactant mixture is stirred 45min down at 0 ℃, and be poured into 2: 1 EtOAc/H then 2In the O mixture (300mL).Leach the deposition of generation, (2 * 50mL) wash, and leave standstill with EtOAc.Separate EtOAc/H 2O is double-deck, and (2 * 100mL) extract with EtOAc with water layer.(1 * 100mL) washes, dry (MgSO with saturated NaCl with the organic layer that merges 4), filter, and concentrating under reduced pressure.With crude product with above isolating precipitate merge, and (1 * 10mL) washes, and obtains the title compound (83%) of 8.19g with MeOH.
Perhaps, title compound can be according to being prepared as follows:
Under 0 ℃, to 5-bromo-3-(4-piperidyl)-1H-indole-7-Methanamide (900mg, CH 2.8mmol) 2Cl 2(100mL) add in the solution ethyl sulfonic chloride (0.8mg, 8.4mmol) and triethylamine (1.6mL, 11.2mmol).Reactant mixture is stirred down 30min at 0 ℃, subsequently with mixture at CH 2Cl 2And distribute between the water.Water is used CH 2Cl 2(50mL * 2) extraction, and with the organic facies that merges through MgSO 4Drying, and concentrating under reduced pressure.The residue that generates is gone up through the SPE purification at 500mg aminopropyl post (International Sorbent Technologies),, obtained the title compound (69%) of 800mg with chloroform (30mL * 2) and ethyl acetate (50mL) eluting.
LC/MS：m/z?414.0(M+H)，2.2min。
Intermediate 12:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(hydroxymethyl) phenyl]-1H-indole-7-Methanamide
Figure S2006800304481D00781
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (20.0mg, 0.048mmol), K 3PO 4(21.0mg, 0.096mmol) (30.0mg is 0.193mmol) at two _ alkane/H with [3-(hydroxymethyl) phenyl] boric acid (boronicacid) 2Blast argon 5 minutes in the solution among the O (2mL/0.7mL), add Pd (PPh subsequently 3) 4(5.0mg, 0.0048mmol).Reactant mixture was being heated 20 minutes in microwave reactor (Smith synthesizer) under 160 ℃.Evaporating solvent, and residue distributed between ethyl acetate and water.Organic layer is washed with saline (10mL), through MgSO 4Drying concentrates, and through reversed-phase HPLC method A (water/CH 3CN, 0.1%TFA 10-90%) purification, obtain title compound (9.7mg, 46%).
1H?NMR(400MHz，DMSO-D6)δppm?1.25(t，J＝7.2Hz，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：1.73min。
Intermediate 13:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide
Figure S2006800304481D00782
At ambient temperature, to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(hydroxymethyl) phenyl]-(52.0mg 0.120mmol) adds MnO in the solution in THF (10mL) to 1H-indole-7-Methanamide 2(360.0mg, 3.5mmol).With the suspension stirred overnight that generates, through diatomite filtration, and with solid (3 * 10mL) wash with THF.Concentrated filtrate obtains title compound (51.0mg, 98%), does not need purification to be used for next step it.
LC/MS：m/z?440.4(M+H)，r.t：1.97min。
Intermediate 14:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(hydroxymethyl) phenyl]-1H-indole-7-Methanamide
Figure S2006800304481D00791
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (20.0mg, 0.048mmol), K 3PO 4(21.0mg, 0.096mmol) (30.0mg is 0.193mmol) at two _ alkane/H with [4-(hydroxymethyl) phenyl] boric acid 2Blast argon 5 minutes in the solution among the O (2mL/0.7mL), add Pd (PPh subsequently 3) 4(5.0mg, 0.0048mmol).Reactant mixture was being heated 20 minutes in microwave reactor (Smith synthesizer) under 160 ℃.Evaporating solvent, and residue distributed between ethyl acetate and water.Organic layer is washed with saline (10mL), through MgSO 4Drying is filtered, concentrates, and through reversed-phase HPLC method A (water/CH 3CN, 0.1%TFA 10-90%) purification, obtain title compound (6.4mg, 30%).
LC/MS：m/z?442.4(M+H)，r.t：1.78min。
Intermediate 15:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide
Figure S2006800304481D00792
At ambient temperature, to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(hydroxymethyl) phenyl]-(25mg 0.058mmol) adds MnO in the solution in THF (5mL) to 1H-indole-7-Methanamide 2(160.0ng, 1.73mmol).With the suspension stirred overnight that generates, through diatomite filtration, and with solid (3 * 10mL) wash with THF.Concentrated filtrate obtains title compound (15mg, 58%), does not need purification to be used for next step it.
LC/MS：m/z?440.4(M+H)，r.t：2.02min。
Intermediate 16:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-1H-indole-7-Methanamide
Figure S2006800304481D00801
5min after the degassing, the 5 - bromo-3 - [1 - (ethylsulfonyl) -4 - piperidinyl]-1H-indole-7 - carboxamide (1.0g, 2.42mmol), United borate knit the brows pinacol ester (bis (pinacolato) diboron) (2.45g, 9.66mmol) and potassium carbonate (2.10g, 21.8mmol) in DME (15.0mL) was added a solution of Pd 2 Cl 2 (dppf).Then mixture was heated 11000 seconds down at 130 ℃ in microwave.Then with reactant mixture with EtOAc (300mL) and H 2O (100mL) dilution, and filter this solid.Then organic layer is used H 2O (3 * 80mL) with salt washing.With organic layer through MgSO 4Dry and concentrated.Add DCM (40mL) then to remove any by-product, obtain the title compound of 2.4g.
LC/MS：m/z?462.3(M+H)，r.t：2.03min。
Intermediate 17:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-2-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D00811
(200mg is 0.49mmol) at two _ alkane (4.5mL) and H to 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide 2Add in the solution among the O (1.5mL) [5-(hydroxymethyl)-2-thienyl] boric acid (232mg, 1.47mmol), potassium carbonate (406mg, 2.94mmol) with four (triphenylphosphines) close palladium (0) (57mg, 0.049mmol).Be reflected at and under 150 ℃, carry out 20min in the microwave.Use EtOAc/H 2O treating water solution obtains 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(hydroxymethyl)-2-thienyl]-1H-indole-7-Methanamide of 447mg.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-(200mg 0.46mmol) adds MnO in the solution in THF (5.0mL) to 5-[5-(hydroxymethyl)-2-thienyl]-1H-indole-7-Methanamide 2(1.21g, 13.9mmol).Mixture is at room temperature stirred 3h.Through the diatomite filtration reactant mixture, obtain the title compound (48.8%) of 100mg
LC/MS：m/z?446.2(M+H)，r.t：2.27min。
Intermediate 18:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl-2-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D00812
Under 0 ℃, to the 3-thiophenecarboxaldehyde (3.0g, 26.8mmol) add in the solution in DCM (54mL) aluminum chloride (8.37g, 63mmol).To react reflux then, and dripping bromine (1.6mL, 30.28mmol).After the adding, reaction mixture refluxed is stirred 4h.After being cooled to room temperature, add cold H 2O (100mL), and with DCM (2 * 100mL) extractions.The organic layer that merges is used NaHCO 3Wash and drying.It through purified by flash chromatography, is obtained the 5-bromo-3-thiophenecarboxaldehyde (71%) of 3.62g.
(250mg is 1.29mmol) at two _ alkane (4.5mL) and H to 5-bromo-3-thiophenecarboxaldehyde 2Add 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5 in the solution among the O (1.5mL); 5-tetramethyl-1; 3,2-dioxa bora ring penta-2-yl)-and 1H-indole-7-Methanamide (200mg, 0.43mmol), potassium carbonate (250mg; 2.58mmol) and four (triphenylphosphines) close palladium (0) (56mg, 0.049mmol).This is reflected at and under 150 ℃, carries out 20min in the microwave.Then with it with EtOAc and H 2O handles, and obtains crude product.Then it is handled with MeOH (10mL), and, obtain the required title compound of 310mg solid filtering and collection.
LC/MS：m/z?446.4(M+H)，r.t：1.94min。
Intermediate 19:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D00821
Of 4 - bromo-2 - thiophene formaldehyde (1.0g, 4.48mmol) in DME (16mL) was added a solution which knit the brows United borate ester (1.48g, 5.82mmol), KOAc (1.14g, 5.11mmol) and Pd 2 Cl 2 (dppf) (106mg, 0.448mmol).This is reflected at and under 150 ℃, carries out 20min in the microwave.Concentrated solvent, and use EtOAc and H 2O carries out aqueous solution to be handled.Chemical compound through using the purified by flash chromatography of hexane and EtOAc, is obtained 4-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-2 thiophene carboxaldehyde of 1.8g.
(909mg is 2.2mmol) at two _ alkane (7.5mL) and H to 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide 2Add in the solution among the O (2.5mL) 4-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-2 thiophene carboxaldehyde (1.57g, 6.6mmol), potassium carbonate (1.82g, 13.2mmol) with four (triphenylphosphines) close palladium (0) (30mg, 0.22mmol).This is reflected in the microwave in 150 ℃ of heating 20min.Then mixture is concentrated into dried.EtOAc (50mL) is joined in the residue, and wash with salt.The sedimentation and filtration that will between water and organic layer, form, and collect, be brown solid, obtain the title compound (89%) of 874mg.
LC/MS：m/z?446.4(M+H)，r.t：1.93min。
Intermediate 20:5-bromine xylylenimine (isoindoline)
Figure S2006800304481D00831
Be equipped with charging hopper and CaCl 2Place 2.0g (13.6mmol) phthalimide in the exsiccant 50mL two neck round-bottomed flasks of drying tube.Then this flask is cooled to 0 ℃ in salt and ice bath.Under constantly stirring, add ice-cold concentrated sulphuric acid of 8mL and fuming nitric aicd (1: mixture 1v/v) gradually.Under 0 ℃, mixture is stirred 30min then, and in stirring 1h, slowly be warmed to room temperature.Then reactant mixture is poured in the ice.Filter the solid product and the drying that generate, obtain 5-nitro-1H-iso-indoles-1,3 (2H)-diketone of 1.6g (61.3%), be yellow solid.
To 5-nitro-1H-iso-indoles-1,3 (2H)-diketone (1.0g, 5.2mmol) Pd/C (0.2g) of adding 10% in the solution in exsiccant THF (15mL).With mixture hydrogenation 17h under 30-40psi.Filter this catalyst, and the vacuum evaporation of will filtrating, obtain 5-amino-1H-iso-indoles-1,3 (2H)-diketone of 0.5g (59.3%), be yellow solid.
Under 0 ℃, to vitriolization solution (the dense H of 2mL 2SO 4H at 7.5mL 2Among the O) in 5-amino-1H-iso-indoles-1,3 (2H)-diketone (1.0g, (0.8g is at the H of 2mL to drip ice-cold sodium nitrite solution in agitating solution 6.2mmol) 2Among the O).0 ℃ down stir 45min after, adding CuBr under uniform temp (3.4g, 23.7mmol) and HBr [48%] (13.6mL, 4vol.w.r.t.CuBr).The mixture of this generation is stirred 8h down at 80 ℃, be poured in the trash ice then.Filter this solid, wash, and intensive drying, obtain 5-bromo-1H-iso-indoles-1,3 (2H)-diketone of 0.6g (43.0%), be brown solid with icy water.
In the exsiccant 500mL that is equipped with reflux condenser and charging hopper three neck round-bottomed flasks, BH is housed 3-THF (160mL) solution and exsiccant THF (50mL).Mixture is cooled to 0 ℃.In this cooling solution, add 5-bromo-1H-iso-indoles-1,3 (2H)-diketone (8.0g, exsiccant THF (100mL) solution 35.4mmol), and be warmed to room temperature gradually.At room temperature behind the 10min, with the mixture 16h that refluxes.Then reactant mixture is cooled to 0 ℃, and stops (noting: violent foaming will take place) with methanol.The HCL that adds the 2N of 20-30mL, and with the mixture 1h that refluxes.Cool off this mixture, and with the alkalization of NaOH solution, and use ethyl acetate extraction.The organic extract liquid water that merges, saturated NaCl solution are washed, through Na 2SO 4Dry also vacuum concentration.In the MeOH of crude product solution (150mL), add Et 3(13.8g 63.23mmol), and at room temperature stirs 16h for N (12mL) and di-tert-butyl dicarbonate.Then with the reactant mixture vacuum concentration.Crude product is used CH 2Cl 2(200mL) dilution, water, saturated NaCl solution are washed, and through Na 2SO 4Dry.Through the column chromatography purification, the hexane solution that uses 20% ethyl acetate obtains colorless solid as eluent with crude product.At room temperature to wherein adding two _ alkane-HCl, and stir 10min, filter the solid that obtains and dry then, obtain the 5-bromine xylylenimine hydrochlorate of 3.0g (42.8%), be gray solid.
Intermediate 21:5-bromo-3-(4-piperidyl)-1H-indole-7-carboxamide hydrochloride
Figure S2006800304481D00841
Two _ alkane solution (194mL) of the HCl of 4M is joined 4-[7-(amino carbonyl)-5-bromo-1H-indol-3-yl]-1-piperidine carboxylic acid 1, and (10g is in methanol 23.7mmol) (50mL) solution for 1-dimethyl ethyl ester.Reactant mixture is at room temperature stirred 4 hours, and solvent evaporated under reduced pressure, obtain title compound (9.5g), do not need purification to be used for next step it.
LC-MS：m/z?322.4(M+H)，1.40min。
Intermediate 22:5-bromo-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide
Figure S2006800304481D00851
Under 0 ℃, (2.6mL 18.7mmol) joins in DMF (15mL) solution of 5-bromo-3-(4-piperidyl)-1H-indole-7-carboxamide hydrochloride with triethylamine.Mixture is at room temperature stirred 10min, and adding 2-third sulfonic acid chloride (1.04mL, 9.32mmol).Continue again to stir 30min, and with the EtOAc/H of reactant mixture with 1: 1 2O (200mL) dilution.Separate each layer, and (2 * 50mL) extract with EtOAc with water layer.(1 * 100mL) washes, dry (MgSO with saturated NaCl with the organic layer that merges 4), and concentrating under reduced pressure.(2 * 10mL) Xian obtain title compound (1.5g, 75%) with MeOH with crude product.
LC/MS：m/z?427.8(M+H)，1.98min。
Intermediate 23:5-(5-formoxyl-3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide
Prepared by the method according to the following six separate batch for the preparation of such a boronic acid ester of the title compound: of 4 - bromo-2 - thiophene formaldehyde (1.0g, 4.48mmol) in DME (20mL) was added a solution of boric acid Union two knit the brows pinacol ester (1.48g, 5.82mmol), KOAc (1.14g, 5.11mmol) and? Pd 2 Cl 2 (dppf) (106mg, 0.448mmol).This is reflected in the Smith microwave and carries out 20min in 150 ℃.Mix 6 reactants, and concentrating under reduced pressure.Residue is dissolved in EtOAc (200mL) and H 2Among the O (50mL).Separate each layer, (1 * 50mL) washes, dry (Na with saturated NaCl with organic layer 2SO 4), and concentrating under reduced pressure.Crude product through purified by flash chromatography, with hexane/EtOAc eluting, is obtained 4-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-2 thiophene carboxaldehyde (5g, 78%).
With 5-bromo-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide (428mg, 1mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-2 thiophene carboxaldehyde (960mg, 4mmol), Cs 2CO 3(800mg, 2.46mmol) and Pd (PPh 3) 4(100mg, solution 0.0865mmol) heat 20min down in 160 ℃ in the Smith microwave.Filter reaction mixture, and concentrating under reduced pressure.(1 * 5mL) washes, and obtains title compound (395mg, 86%) with MeOH with crude product.
LC/MS：m/z?460.4(M+H)，1.98min。
Embodiment
Embodiment 1:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(piperidino methyl) phenyl]-1H-indole-7-Methanamide
Figure S2006800304481D00861
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (15.0mg, 0.034mmol) add in the solution in DCM (2mL) piperidines (4.0ul, 0.04mmol).Reaction solution is stirred 1hr at ambient temperature, add NaBH (OAc) subsequently 3(23.0mg, 0.109mmol).With the mixture that generates stirred overnight, removal of solvent under reduced pressure subsequently at ambient temperature.The residue that generates is dissolved among the DMSO of 1.2mL, and leaches all insoluble solids.The DMSO solution of this crude product is passed through reversed-phase HPLC (H 2O/CH 3CN, 0.1%TFA 10-90%) purification, obtain title compound (8.8mg, 50.5%).
LC/MS：m/z?509.4(M+H)，r.t：1.87min。
Embodiment 2:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(1-piperazinyl methyl) phenyl]-1H-indole-7-Methanamide
Figure S2006800304481D00871
According to the conventional method of embodiment 1, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (15.0mg, 0.034mmol), piperazine (3.5mg, 0.04mmol) and NaBH (OAc) 3(23.0mg, 0.102mmol) reaction obtains title compound (3.4mg, 19.7%).
LC/MS：m/z?510.2(M+H)，r.t：1.43min。
Embodiment 3:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide
According to the conventional method of embodiment 1, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (15.0mg, 0.034mmol), morpholine (3.5ul, 0.04mmol) and NaBH (OAc) 3(23.0mg, 0.102mmol) reaction obtains title compound (7.5mg, 43%).
LC/MS：m/z?511.2(M+H)，r.t：1.58min。
Perhaps, embodiment 3 can be according to being prepared as follows:
(20mg, (0.070mL is 0.276mmol) with 1 acetic acid 0.046mmol) to add morpholine in the solution in dichloromethane (1.5mL) and methanol (1.5mL) to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide.This mixture is at room temperature stirred 2h, and add then sodium borohydride (11mg, 0.276mmol).Behind the 30min, mixture is poured on the SCX post (5.0g), and uses EtOAc (10.0mL) and MeOH (10.0mL) to wash this post.Use the NH of 2M 3This product of/MeOH solution (10.0mL) eluting, and concentrate then.Residue is dissolved in the dimethyl sulfoxine (1.0mL), and prepares the HPLC purification, obtain title compound (17.6mg, 75%) through Gilson.
Embodiment 4:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ methyl [2-(mesyl) ethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide
Figure S2006800304481D00881
According to the conventional method of embodiment 1, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (42.0mg, 0.096mmol), N-methyl-2-(mesyl) ethamine (12.0mg, 0.087mmol) and NaBH (OAc) 3(58.0mg, 0.261mmol) reaction obtains title compound (15.1mg, 28.0%).
LC/MS：m/z?561.2(M+H)，r.t：1.58min。
Embodiment 5:5-(3-{ [[2-(dimethylamino) ethyl] (methyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (45.0mg 0.101mmol) adds N in the solution in DCM (2mL), N, N '-trimethyl-1 (116ul, 0.90mmol).Reaction solution was stirred 1 hour at ambient temperature, add NaBH (OAc) subsequently 3(69mg, 0.326mmol).With the mixture that generates stirred overnight at ambient temperature, and add other NaBH (OAc) 3(128mg, 0.606mmol).Should react restir 2h, removal of solvent under reduced pressure subsequently.Crude product is passed through reversed-phase HPLC (water/CH 3CN, 0.1%TFA 10-90%) purification, obtain title compound (16.0mg, 29.6%).
LC/MS：m/z?526.8(M+H)，r.t：1.28min。
Embodiment 6:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(4-{2-[(2-hydroxyethyl) oxygen base] ethyl }-the 1-piperazinyl) methyl] phenyl }-1H-indole-7-Methanamide
Figure S2006800304481D00891
Conventional method according to embodiment 1; Make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50.0mg; 0.112mmol), 2-{ [2-(1-piperazinyl) ethyl] oxygen base ethanol (150mg, 0.87mmol) and NaBH (OAc) 3(58.0mg, 0.303mmol) reaction obtains title compound (16.7mg, 25%).
LC/MS：m/z?598.4(M+H)，r.t：1.48min。
Embodiment 7:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [3-(hydroxymethyl)-piperidino] methyl } phenyl)-1H-indole-7-Methanamide
Figure S2006800304481D00892
According to the conventional method of embodiment 1, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50.0mg, 0.112mmol), 3-piperidyl methanol (98.9mg, 0.86mmol) and NaBH (OAc) 3(58.0mg, 0.303mmol) reaction obtains title compound (10.2mg, 17%).
LC/MS：m/z?539.4(M+H)，r.t：1.52min。
Embodiment 8:5-[3-({ two [2-(methoxyl group) ethyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D00901
Conventional method according to embodiment 1; Make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50.0mg; 0.112mmol), 2-(methoxyl group)-N-[2-(methoxyl group) ethyl] ethamine (114.3mg, 0.86mmol) and NaBH (OAc) 3(58.0mg, 0.303mmol) reaction obtains title compound (10.5mg, 16%).
LC/MS：m/z?557.6(M+H)，r.t：1.62min。
Embodiment 9:5-{3-[(2,6-dimethyl-4-morpholinyl) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D00902
According to the conventional method of embodiment 1, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50.0mg, 0.112mmol), 2, the 6-thebaine (98.9mg, 0.86mmol) and NaBH (OAc) 3(58.0mg, 0.303mmol) reaction obtains title compound (19.6mg, 32%).
LC/MS：m/z?539.2(M+H)，r.t：1.75min。
Embodiment 10:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [2-(1,3-thiazoles-2-yl)-1-pyrrolidinyl] methyl } phenyl)-1H-indole-7-Methanamide
Figure S2006800304481D00911
According to the conventional method of embodiment 1, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50.0mg, 0.112mmol), 2-(2-pyrrolidinyl)-1,3-thiazoles (132.4mg, 0.86mmol) and NaBH (OAc) 3(58.0mg, 0.303mmol) reaction obtains title compound (20.0mg, 30.4%).
LC/MS：m/z?578.6(M+H)，r.t：1.57min。
Embodiment 11:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [2-(2-thienyl)-1-pyrrolidinyl] methyl } phenyl)-1H-indole-7-Methanamide
Figure S2006800304481D00912
According to the conventional method of embodiment 1, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50.0mg, 0.112mmol), 2-(2-thienyl) pyrrolidine (132.4mg, 0.86mmol) and NaBH (OAc) 3(58.0mg, 0.303mmol) reaction obtains title compound (20.0mg, 30.4%).
LC/MS：m/z?577.4(M+H)，r.t：1.78min。
Embodiment 12:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-hydroxyl-2-phenylethyl)-(methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide
Figure S2006800304481D00921
According to the conventional method of embodiment 1, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50.0mg, 0.112mmol), 2-(methylamino)-1-phenylethanol (129.9mg, 0.86mmol) and NaBH (OAc) 3(58.0mg, 0.303mmol) reaction obtains title compound (22.1mg, 36.6%).
LC/MS：m/z?575.4(M+H)，r.t：1.66min。
Embodiment 13:5-(3-{ [ethyl (methyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D00922
According to the conventional method of embodiment 1, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50.0mg, 0.112mmol), the N-methyl ethyl-amine (50.7mg, 0.86mmol) and NaBH (OAc) 3(58.0mg, 0.303mmol) reaction obtains title compound (11.5mg, 21%).
LC/MS：m/z?483.4(M+H)，r.t：1.57min。
Embodiment 14:5-[3-(amino methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D00931
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (30.0mg, 0.072mmol), Cs 2CO 3(95mg, 0.290mmol) and 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] (82mg is 0.350mmol) at two _ alkane/H for methylamine 2Blast argon 5 minutes in the solution among the O (2mL/0.7mL), add Pd (PPh subsequently 3) 4(7.5mg, 0.0072mmol).Reactant mixture was heated 20 minutes in 160 ℃ in microwave reactor (Smith synthesizer).Evaporating solvent, and residue distributed between ethyl acetate and water.Organic layer is washed with saline (10mL), through MgSO 4Drying is filtered, concentrates, and through reversed-phase HPLC method A (water/CH 3CN, 0.1%TFA 10-90%) purification, obtain title compound (2.7mg, 8.5%).
LC/MS：m/z?441.4(M+H)，r.t：1.54min。
Embodiment 15:5-{3-[(cyclopenta is amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D00932
According to the conventional method of embodiment 5, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (45mg, 0.101mmol), Aminocyclopentane (90uL, 0.090mmol) and NaBH (OAc) 3(197mg, 0.93mmol) reaction obtains title compound (33.0mg, 64%).
LC/MS：m/z?509.4(M+H)，r.t：1.64min。
Embodiment 16:5-[3-({ [(3, the 4-dihydroxy phenyl) methyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D00941
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50mg 0.114mmol) adds 4-(amino methyl)-1 in the solution in dichloroethanes (2mL), the 2-Benzodiazepines (12.1mg, 0.087mmol).Reaction solution is stirred 10min at ambient temperature, add NaBH (OAc) subsequently 3(58mg, 0.261mmol).With the mixture that generates shaken overnight, removal of solvent under reduced pressure subsequently at ambient temperature.Crude product is passed through reversed-phase HPLC (water/CH 3CN, 0.1%TFA 10-90%) purification, obtain title compound (7.4mg, 12%).
LC/MS：m/z?563.2(M+H)，r.t：1.67min。
Embodiment 17:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(3-thienyl methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide
According to the conventional method of embodiment 16, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol), 1-(3-thienyl) methylamine (9.83mg, 0.087mmol) and NaBH (OAc) 3(58mg, 0.261mmol) reaction obtains title compound (4.7mg, 7.8%).
LC/MS：m/z?537.2(M+H)，r.t：1.62min。
Embodiment 18:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-([(1R)-and 1-(hydroxymethyl)-2-methyl-propyl] amino } methyl) phenyl]-1H-indole-7-Methanamide
According to the conventional method of embodiment 16, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol), (2R)-2-amino-3-methyl isophthalic acid-butanols (10.2mg, 0.087mmol) and NaBH (OAc) 3(58mg, 0.261mmol) reaction obtains title compound (14.9mg, 25%).
LC/MS：m/z?527.6(M+H)，r.t：1.48min。
Embodiment 19:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [2-hydroxyl-1-Methylethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide:
Figure S2006800304481D00952
According to the conventional method of embodiment 16, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol), 2-amino-1-propanol (6.5mg, 0.087mmol) and NaBH (OAc) 3(58mg, 0.261mmol) reaction obtains title compound (3.4mg, 6.0%).
LC/MS：m/z?499.6(M+H)，r.t：1.46min。
Embodiment 20:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(anti--the 4-hydroxy-cyclohexyl) amino] methyl } phenyl)-1H-indole-7-Methanamide
According to the conventional method of embodiment 16, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol), anti--the 4-aminocyclohexanol (10mg, 0.087mmol) and NaBH (OAc) 3(58mg, 0.261mmol) reaction obtains title compound (6.0mg, 9.8%).
LC/MS：m/z?539.2(M+H)，r.t：1.54min。
Embodiment 21:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[({ [1-(piperidino) cyclohexyl] methyl } amino) methyl] phenyl }-1H-indole-7-Methanamide
Figure S2006800304481D00962
According to the conventional method of embodiment 16, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol), 1-[1-(piperidino) cyclohexyl] methylamine (17mg, 0.087mmol) and NaBH (OAc) 3(58mg, 0.261mmol) reaction obtains title compound (18.7mg, 27%).
LC/MS：m/z?620.6(M+H)，r.t：1.6min。
Embodiment 22:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-([(2S)-and the 2-hydroxypropyl] amino } methyl) phenyl]-1H-indole-7-Methanamide
Figure S2006800304481D00971
According to the conventional method of embodiment 16, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol), (2S)-1-amino-2-propanol (6.5mg, 0.087mmol) and NaBH (OAc) 3(58mg, 0.261mmol) reaction obtains title compound (13.1mg, 23%).
LC/MS：m/z?499.6(M+H)，r.t：1.46min。
Embodiment 23:5-{3-[(ethylamino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D00972
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (20mg, 0.045mmol) add in the solution in dichloromethane (0.5mL) and methanol (0.5mL) ethamine (130uL, 0.27mmol).This mixture is at room temperature stirred 1h, and add then sodium borohydride (10mg, 0.27mmol).This is reacted stirred overnight at ambient temperature, and removal of solvent under reduced pressure.Crude product is passed through reversed-phase HPLC (water/CH 3CN, 0.1%TFA 10-90%) purification, obtain title compound (13.2mg, 63%).
LC/MS：m/z?469.4(M+H)，r.t：1.54min。
Embodiment 24:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(propyl group is amino) methyl] phenyl }-1H-indole-7-Methanamide
Figure S2006800304481D00981
(20mg, (22uL is 0.27mmol) with 1 acetic acid 0.046mmol) to add propylamine in the solution in dichloromethane (0.7mL) and methanol (0.7mL) to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide.This mixture is at room temperature stirred 1h, and add then sodium borohydride (10mg, 0.27mmol).To react stirred overnight at ambient temperature, and removal of solvent under reduced pressure.Crude product is passed through reversed-phase HPLC (water/CH 3CN, 0.1%TFA 10-90%) purification, obtain title compound (22.1mg, 99%).
LC/MS：m/z?483.2(M+H)，r.t：1.58min。
Embodiment 25:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(1-Methylethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide:
According to the conventional method of embodiment 24, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (20mg, 0.045mmol), 2-aminopropane. (23uL, 0.27mmol) and NaBH 4(10mg, 0.27mmol) reaction obtains title compound (11.5mg, 53%).
LC/MS：m/z?483.2(M+H)，r.t：1.52min。
Embodiment 26:5-(3-{ [(1-ethyl propyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D00991
According to the conventional method of embodiment 1, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (20mg, 0.045mmol), the 3-amylamine (32uL, 0.27mmol) and NaBH 4(10mg, 0.27mmol) reaction obtains title compound (18.5mg, 80%).
LC/MS：m/z?511.4(M+H)，r.t：1.66min。
Embodiment 27:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(piperidino methyl) phenyl]-1H-indole-7-Methanamide:
Figure S2006800304481D00992
According to the conventional method of embodiment 1, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (40mg, 0.09mmol), piperidines (0.009mL, 0.09mmol) and NaBH (OAc) 3(58mg, 0.27mmol) reaction obtains title compound (8mg, 17.5%).
LC/MS：m/z?509.4(M+H)，r.t：1.71min。
Embodiment 28:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(methylamino) methyl] phenyl }-1H-indole-7-Methanamide
Figure S2006800304481D01001
According to the conventional method of embodiment 24, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (20mg, 0.045mmol), methylamine (130uL, 0.27mmol) and NaBH 4(10mg, 0.27mmol) reaction obtains title compound (17.0mg, 83%).
LC/MS：m/z?455.2(M+H)，r.t：1.48min。
Embodiment 29:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide
Figure S2006800304481D01002
According to the conventional method of embodiment 1, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol), morpholine (18uL, 0.206mmol) and NaBH (OAc) 3(290mg, 1.37mmol) reaction obtains title compound (2.1mg, 13%).
LC/MS：m/z?511.4(M+H)，r.t：1.63min。
Embodiment 30:5-[4-(amino methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01011
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (30.0mg, 0.072mmol), Cs 2CO 3(95mg is 0.290mmol) with [(55mg is 0.290mmol) at two _ alkane/H for 4-(amino methyl) phenylboric acid 2Blast argon 5 minutes in the solution among the O (1.5mL/0.5mL), add Pd (PPh subsequently 3) 4(7.5mg, 0.0072mmol).Reactant mixture was heated 20 minutes in microwave reactor (Smith synthesizer) at 160 ℃.Evaporating solvent, and residue distributed between ethyl acetate and water.Organic layer is washed with saline (10mL), through MgSO 4Drying is filtered, concentrates, and through reversed-phase HPLC (water/CH 3CN, 0.1%TFA 10-90%) purification, obtain title compound (9.8mg, 31%).
LC/MS：m/z?424.4(M-NH2)，r.t：1.48min。
Embodiment 31:5-{3-[(cyclopropyl is amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01012
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.113mmol) add in the solution in DCM (2mL) cyclopropylamine (19.3mg, 0.339mmol).Reaction solution is stirred 30min at ambient temperature, add HOAc (1) and NaBH (OAc) subsequently 3(75mg, 0.545mmol).With the mixture that generates stirred overnight, removal of solvent under reduced pressure subsequently at ambient temperature.Crude product is passed through reversed-phase HPLC (water/CH 3CN, 0.1%TFA 10-90%) purification, obtain title compound (18.2mg, 34%).
LC/MS：m/z?481.2(M+H)，r.t：1.52min。
Embodiment 32:5-{3-[(cyclobutyl is amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01021
According to the conventional method of embodiment 31, make 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.113mmol), the ring butylamine (24.1mg, 0.339mmol) and NaBH (OAc) 3(75mg, 0.545mmol) reaction obtains title compound (19.3mg, 35%).
LC/MS：m/z?495.6(M+H)，r.t：1.55min。
Embodiment 33:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(2-methyl-propyl) amino]-2,3-dihydro-1H-indenes-5-yl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01022
In microwave tube, (4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-(200mg is 0.434mmol) at two _ alkane (3.0mL) and H for 1H-indole-7-Methanamide to 3-[1-(ethylsulfonyl)-4-piperidyl]-5- 2Add 6-bromo-2 in the solution among the O (1.0mL), 3-dihydro-1H-1-Indanone (274mg, 1.30mmol) and potassium carbonate (360mg, 2.60mmol).With reactant mixture degasification 5min, add subsequently four (triphenylphosphines) close palladium (0) (50mg, 0.043mmol).Then this is reflected in the microwave in 160 ℃ of heating 30min.Filter then and should react, and solid is dissolved in EtOAc and H 2Among the O.Separate organic layer and concentrated.Thick residue is prepared the HPLC purification through Gilson, obtain 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-oxo-2,3-dihydro-1H-indenes-5-yl)-1H-indole-7-Methanamide.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-oxo-2; 3-dihydro-1H-indenes-5-yl)-1H-indole-7-Methanamide (45mg; 0.097mmol) add 2-methyl isophthalic acid-propylamine (170 μ L in the solution in EtOH (2mL) and acetic acid (200 μ L); 1.93mmol) and sodium cyanoborohydride (20mg, 0.291mmol).The mixture that generates is reacted 40min in 150 ℃ in the CEM microwave tube.Then it is prepared the HPLC purification through Gilson, obtain the title compound (8.9%) of 4.5mg.
LC/MS=m/z 523.4 [M+H] retention time: 1.72
Embodiment 34:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{8-[(2-methyl-propyl) amino]-5,6,7,8-tetrahydrochysene-2-naphthyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01031
In microwave tube, (4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-(200mg is 0.434mmol) at two _ alkane (3.0mL) and H for 1H-indole-7-Methanamide to 3-[1-(ethylsulfonyl)-4-piperidyl]-5- 2Add 7-bromo-3 in the solution among the O (1.0mL), 4-dihydro-1 (2H)-naphthalenone (292mg, 1.30mmol) and potassium carbonate (360mg, 2.60mmol).With reactant mixture degasification 5min, add subsequently four (triphenylphosphines) close palladium (0) (50mg, 0.043mmol).Then this is reflected in the microwave in 160 ℃ of heating 30min.Filter then and should react, and solid is dissolved in EtOAc and H 2Among the O.Separate organic layer and concentrated.Thick residue is prepared the HPLC purification through Gilson, obtain 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(8-oxo-5,6,7,8-tetrahydrochysene-2-naphthyl)-1H-indole-7-Methanamide.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(8-oxo-5; 6; 7,8-tetrahydrochysene-2-naphthyl)-(40mg 0.08mmol) adds 2-methyl isophthalic acid-propylamine (140 μ L to 1H-indole-7-Methanamide in the solution in EtOH (2mL) and acetic acid (0.2mL); 1.6mmol) and sodium cyanoborohydride (15mg, 0.24mmol).The mixture that generates is reacted 40min in 150 ℃ in the CEM microwave tube.Then it is prepared the HPLC purification through Gilson, obtain the title compound (7.5%) of 3.2mg.
LC/MS=m/z 537.4 [M+H] retention time: 1.71
Embodiment 35:5-(5-{ [(2-cyano ethyl) amino] methyl }-the 2-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
In microwave tube, (4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-(200mg is 0.434mmol) at two _ alkane (3.0mL) and H for 1H-indole-7-Methanamide to 3-[1-(ethylsulfonyl)-4-piperidyl]-5- 2Add in the solution among the O (1.0mL) 3-bromo-4-fluorobenzaldehyde (264mg, 1.30mmol) and K 2CO 3(360mg, 2.60mmol).With reactant mixture degasification 5min, add subsequently four (triphenylphosphines) close palladium (0) (48mg, 0.043mmol).This is reflected in the microwave in 160 ℃ of heating 30min.Separate organic layer and concentrated.Residue is dissolved among the MeOH, comes out, obtain 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-fluoro-5-formoxyl phenyl)-1H-indole-7-Methanamide until solid precipitation.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-fluoro-5-formoxyl phenyl)-1H-indole-7-Methanamide (40mg; 0.087mmol) (53 μ L are 0.524mmol) with 1 acetic acid to add the 3-aminopropionitrile in the solution in dichloromethane (2mL) and methanol (1mL).Reactant mixture is at room temperature stirred 48h.(20mg 0.524mmol), and at room temperature reacts 30min to add sodium borohydride then.Prepare the HPLC purification through Gilson, obtain the title compound (32.4%) of 14.4mg.
LC/MS=m/z 512.2 [M+H] retention time: 1.45
Embodiment 36:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-fluoro-5-{ [(2,2, the 2-trifluoroethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01051
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-fluoro-5-formoxyl phenyl)-1H-indole-7-Methanamide (20mg; 0.04mmol) add 2 acetic acid and 2 in the solution in dichloromethane (4mL) and methanol (2mL); 2, and 2-trifluoro ethamine (23 μ L, 0.26mmol).With the mixture stirred overnight that generates.Evaporate all solvents, and be dissolved in the dimethyl sulfoxine (1mL).Prepare the HPLC purification through Gilson, obtain the title compound (24.0%) of 5.2mg.
LC/MS=m/z 541.4 [M+H] retention time 1.67
Embodiment 37:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(1,2,3,4-tetrahydrochysene-7-isoquinolyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01052
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-1H-indole-7-Methanamide (60mg; 0.13mmol) add 7-bromo-1,2,3 in the solution in two _ alkane (2mL) and water (1mL); The 4-tetrahydroisoquinoline (97mg, 0.39mmol) and potassium carbonate (108mg, 0.78mmol).With this mixture degasification 5min, add subsequently four (triphenylphosphines) close palladium (0) (15mg, 0.013mmol).The mixture that generates is reacted 30min in 160 ℃ in the CEM microwave tube.Separate organic layer and concentrated.The residue that generates is dissolved in the dimethyl sulfoxine (1mL), and prepares the HPLC purification, obtain the title compound (5.7%) of 3.5mg through Gilson.
LC/MS=m/z 467.2 [M+H] retention time 1.48
Embodiment 38:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2,2, the 2-trifluoroethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01061
In microwave tube, (200mg is 0.483mmol) at two _ alkane (3.0mL) and H to 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide 2Add in the solution among the O (1.0mL) (3-formoxyl phenyl) boric acid (317mg, 1.93mmol) and Cs 2CO 3(315mg, 0.97mmol).With reactant mixture degasification 5min, add subsequently four (triphenylphosphines) close palladium (0) (48mg, 0.043mmol).This is reflected in the microwave in 160 ℃ of heating 30min.Separate organic layer and concentrated.Residue is dissolved among the MeOH, comes out, obtain 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide until solid precipitation.
(40mg, 0.09mmol) with 2,2, (78 μ L 0.55mmol) add 2 acetic acid to 2-trifluoro ethamine in the solution in dichloromethane (2mL) and methanol (1mL) to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide.Then with the mixture stirred overnight.(20.8mg 0.55mmol), and stirs 30min with mixture to add sodium borohydride then.Concentrate the mixture that generates, and be dissolved in the dimethyl sulfoxine, prepare the HPLC purification through Gilson subsequently, obtain the title compound (62.5%) of 29.4mg.
LC/MS=m/z 523.2 [M+H] retention time 1.66
Embodiment 39:5-(3-{ [(2-amino-2-oxoethyl) (methyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01071
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (44mg, 0.1mmol) and N 2(76mg 0.6mmol) adds 3 acetic acid to-methyl Aminoacetamide in the solution in dichloromethane (3mL) and methanol (1.5mL).With this mixture stirred overnight.Add then sodium triacetoxy borohydride (134mg, 0.6mmol), and stirred overnight.The reactant that generates is stopped with sodium bicarbonate (2mL) and saline (2mL).Collected organic layer also concentrates then.Then the residue that generates is prepared the HPLC purification through Gilson, obtain the title compound (25.4%) of 13mg.
LC/MS=m/z 512.6 [M+H] retention time 1.20
Embodiment 40:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-{ [(2,2, the 2-trifluoroethyl) amino] methyl }-1,3-thiazoles-4-yl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01072
To 4-bromo-1,3-thiazoles-2-formaldehyde (192mg 1.0mmol) adds acetic acid (3) and 2,2 in the solution in DCM (4.0mL), 2-trifluoro ethamine (120 μ L, 1.5mmol).Should react stirred overnight.(335mg 1.5mmol), and should react and stir 6h to add sodium triacetoxy borohydride then.Then it is stopped with sodium bicarbonate, obtain 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-1H-indole-7-Methanamide.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-1H-indole-7-Methanamide (46mg; 0.1mmol) add N-[(4-bromo-1,3-thiazoles-2-yl) methyl]-2,2 in the solution in two _ alkane (2mL) and water (0.7mL); 2-trifluoro ethamine (30mg, 0.11mmol) and potassium carbonate (83mg, 0.6mmol).With the mixture degasification 5min that generates, add subsequently four (triphenylphosphines) close palladium (0) (11mg, 0.01mmol).Mixture is reacted 20min in 160 ℃ in the CEM microwave tube.Separate organic layer and concentrated.The residue that generates is prepared the HPLC purification through Gilson, obtain the title compound (47.2%) of 25mg.
LC/MS=m/z 530.2 [M+H] retention time 1.94
Embodiment 41:5-(3-cyanic acid-5-{ [(2,2, the 2-trifluoroethyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01081
In microwave tube, to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4; 5,5-tetramethyl-1,3; 2-dioxa bora ring penta-2-yl)-1H-indole-7-Methanamide (46mg; 0.1mmol) two _ alkane (2.0mL, add in the solution in 0.7mL) 3-bromo-5-formoxyl benzonitrile (68mg, 0.3mmol) and K 2CO 3(83mg, 0.6mmol).With reactant mixture degasification 5min, add subsequently four (triphenylphosphines) close palladium (0) (11mg, 0.01mmol).This is reflected in the microwave in 160 ℃ of heating 20min.Then it is prepared the HPLC purification through Gilson, obtain 5-(3-cyanic acid-5-formoxyl phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide.
To 5-(3-cyanic acid-5-formoxyl phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (52mg; 0.11mmol) add 20 acetic acid and 2 in the solution in dichloromethane (3mL) and methanol (1mL); 2, and 2-trifluoro ethamine (53 μ L, 0.66mmol).Mixture is stirred 48h, add subsequently sodium triacetoxy borohydride (140mg, 0.66mmol).Then mixture is stirred 48h.The reactant that generates is stopped with sodium bicarbonate, and add saline.Separate organic layer, and prepare the HPLC purification, obtain the title compound (6.0%) of 3.6mg through Gilson.
LC/MS=m/z 548.2 [M+H] retention time 1.88
Embodiment 42:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (1-methyl-4-piperidyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01091
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.11mmol) add N in the solution in dimethyl sulfoxine (2mL); 1-dimethyl-4-piperidine amine (128.22mg, 1.0mmol), 2 acetic acid, and spend the night by reaction.(212mg, 1mmol), and at room temperature reaction is spent the night to add sodium triacetoxy borohydride then.Then it is prepared the HPLC purification through Gilson, obtain the title compound (13.0%) of 8mg.
LC/MS=m/z 558.4 [M+H] retention time: 1.32min
Embodiment 43:5-(5-{ [(2-cyano ethyl) (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01092
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (1-methyl-4-piperidyl) amino] methyl }-3-thienyl)-1H-indole-7-Methanamide trifluoroacetate; With 3-(methylamino) propionitrile (84.12mg; 1.0mmol) replacement N; 1-dimethyl-4-piperidine amine prepares, and obtains the title compound (42.5%) of 24mg.
LC/MS=m/z 514.4 [M+H] retention time: 1.55min
Embodiment 44:5-(5-{ [(2-amino-2-oxoethyl) (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01101
Title compound is according to the conventional method of preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (1-methyl-4-piperidyl) amino] methyl }-3-thienyl)-1H-indole-7-Methanamide trifluoroacetate, uses N 2(88.11mg 1.0mmol) replaces N to-methyl Aminoacetamide, and 1-dimethyl-4-piperidine amine prepares, and obtains the title compound (33.3%) of 19mg.
LC/MS=m/z 518.2 [M+H] retention time: 1.43min
Embodiment 45:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ methyl [2-(phenyl sulfonyl) ethyl] amino } methyl)-3-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01102
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (1-methyl-4-piperidyl) amino] methyl }-3-thienyl)-1H-indole-7-Methanamide trifluoroacetate; With N-methyl-2-(phenyl sulfonyl) ethamine (199.27mg; 1.0mmol) replacement N; 1-dimethyl-4-piperidine amine prepares, and obtains the title compound (47.3%) of 30mg.
LC/MS=m/z 629.4 [M+H] retention time: 1.57min
Embodiment 46:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-phenyl-1-pyrrolidinyl) methyl]-3-thienyl }-1H-indole-7-Methanamide
Figure S2006800304481D01111
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg, 0.11mmol) add in the solution in DMSO (2.0mL) the 2-Phenylpyrrolidine (147mg, 1.0mmol).Then reactant mixture is reacted 10min down in 120 ℃ in microwave.(220mg 1.0mmol), and will react reaction at room temperature and spend the night to add sodium triacetoxy borohydride then.Then it is prepared the HPLC purification through Gilson, obtain the title compound (22%) of 14.0mg.
LC/MS=m/z 577.2 [M+H] retention time: 1.65min.
Embodiment 47:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [2-(piperidino methyl)-1-pyrrolidinyl] methyl }-the 3-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D01112
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-phenyl-1-pyrrolidinyl) methyl]-3-thienyl }-conventional method of 1H-indole-7-Methanamide; With 1-(2-pyrrolidinyl methyl) piperidines (168.3mg; 1.0mmol) replace the 2-Phenylpyrrolidine to prepare, obtain the title compound (32%) of 21mg.
LC/MS=m/z 598.4 [M+H] retention time: 1.34
Embodiment 48:5-(5-{ [(2R)-and 2-(amino carbonyl)-1-pyrrolidinyl] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01121
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-phenyl-1-pyrrolidinyl) methyl]-3-thienyl }-conventional method of 1H-indole-7-Methanamide; With D-prolineamide (114mg; 1.0mmol) replace the 2-Phenylpyrrolidine to prepare, obtain the title compound (23%) of 14mg.
LC/MS=m/z 544.2 [M+H] retention time: 1.39
Embodiment 49:5-(5-{ [(3S)-and 3-(dimethylamino)-1-pyrrolidinyl] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01122
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-phenyl-1-pyrrolidinyl) methyl]-3-thienyl }-conventional method of 1H-indole-7-Methanamide; With (2R)-N; N-dimethyl-2-pyrroles's alkanamine (114mg; 1.0mmol) replace the 2-Phenylpyrrolidine to prepare, obtain the title compound (18%) of 11mg.
LC/MS=m/z 544.2 [M+H] retention time: 1.36
Embodiment 50:5-(1-{2-[4-(dimethylamino)-piperidino] ethyl }-1H-pyrazoles-4-yl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01131
(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-(40mg is 0.090mmol) at two _ alkane (750 μ L) and H for 1H-indole-7-Methanamide to 3-[1-(ethylsulfonyl)-4-piperidyl]-5- 2Add in the solution among the O (250 μ L) sodium carbonate (53mg, 0.50mmol) with 4-bromo-1-(2-chloroethyl)-1H-pyrazoles (26mg, 0.126mmol).Reactant mixture is washed 10min under argon, add subsequently four (triphenylphosphines) close palladium (0) (5mg, 0.004mmol).This is reflected in the microwave in 120 ℃ of heating 20min.Then it is diluted with EtOAc (10mL),, handle with rear solution through diatomite filtration.This chemical compound is prepared the HPLC purification through Gilson, obtain 5-[1-(2-chloroethyl)-1H-pyrazoles-4-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (24%) of 10mg.
To 5-[1-(2-chloroethyl)-1H-pyrazoles-4-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (33mg; 0.071mmol) add N in the solution in oxolane (500uL); N-dimethyl-4-piperidine amine (100 μ L; 0.71mmol) and sodium iodide (5mg, 0.018mmol).The mixture that generates is reacted 2h in 130 ℃ in microwave tube.Wash with EtOAc and water, separate organic layer, and remove all solvents.Then it is prepared the HPLC purification through Gilson, obtain the title compound (14.7%) of 7.0mg.
LC/MS=m/z 556 [M+H] retention time: 1.23min.
Embodiment 51:5-[3-[(dimethylamino) methyl]-4, two (methoxyl group) phenyl of 5-]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01141
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-1H-indole-7-Methanamide (500mg, 1.09mmo]) at two _ alkane (9.0mL) and H 2Add in the solution among the O (3.0mL) sodium carbonate (690mg, 6.51mmol) with 5-bromo-2, two (methoxyl group) benzaldehydes of 3-(7.95mg, 3.25mmol).Reactant mixture is washed 10min under argon, add subsequently four (triphenylphosphines) close palladium (0) (63mg, 0.054mmol).Then this is reflected in the microwave in 120 ℃ of heating 30min.Concentrate all solvents then, and with EtOAc and H 2O washes.Precipitate required chemical compound then, and filter, obtain 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-formoxyl-4, two (methoxyl group) phenyl of 5-]-1H-indole-7-Methanamide (59%) of 322mg.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-formoxyl-4; Two (methoxyl group) phenyl of 5-]-1H-indole-7-Methanamide (30mg; 0.06mmol) add zinc chloride (5mg in the solution in methanol (2mL); 0.03mmol), sodium cyanoborohydride (5mg, 0.06mmol) and DMA (100 μ L, 0.30mmol).Mixture is at room temperature stirred 2h, in microwave, react 30min then in 100 ℃.The mixture that generates is prepared the HPLC purification through Gilson, obtain the title compound (34.7%) of 11mg.
LC/MS=m/z 529 [M+H] retention time: 1.67min.
Embodiment 52:5-[3, two (methoxyl group)-5-(the 4-morpholinyl methyl) phenyl of 4-]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01142
Title compound is according to preparation 5-[3-[(dimethylamino) methyl]-4; Two (methoxyl group) phenyl of 5-]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With morpholine (20 μ L; 0.30mmol) replace DMA to prepare, obtain the title compound (23.4%) of 8.0mg.
LC/MS=m/z 571 [M+H] retention time: 1.59min.
Embodiment 53:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-{ [(1-Methylethyl) amino] methyl }-4, two (methoxyl group) phenyl of 5-]-1H-indole-7-Methanamide
Figure S2006800304481D01151
Title compound is according to preparation 5-[3-[(dimethylamino) methyl]-4; Two (methoxyl group) phenyl of 5-]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 2-propylamine (20 μ L; 0.30mmol) replace DMA to prepare, obtain the title compound (46.1%) of 15mg.
LC/MS=m/z 543 [M+H] retention time: 1.59min.
Embodiment 54:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-{ [(1-Methylethyl) amino] methyl }-4, two (methoxyl group) phenyl of 5-]-1H-indole-7-Methanamide
Figure S2006800304481D01152
Title compound is according to preparation 5-[3-[(dimethylamino) methyl]-4; Two (methoxyl group) phenyl of 5-]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 40wt.% methylamine (50 μ L; 0.30mmol) replace DMA to prepare, obtain the title compound (19.4%) of 6mg.
LC/MS=m/z 515 [M+H] retention time: 1.46min.
Embodiment 55:5-[3-{ [(2, the 2-dimethyl propyl) amino] methyl }-4, two (methoxyl group) phenyl of 5-]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01161
Title compound is according to preparation 5-[3-[(dimethylamino) methyl]-4; Two (methoxyl group) phenyl of 5-]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With (2; The 2-dimethyl propyl) (20 μ L 0.30mmol) replace DMA to prepare to amine, obtain the title compound (29.2%) of 10mg.
LC/MS=m/z 571 [M+H] retention time: 1.75min.
Embodiment 56:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-{ [(2-hydroxyethyl) (methyl) amino] methyl }-4, two (methoxyl group) phenyl of 5-]-1H-indole-7-Methanamide
Title compound is according to preparation 5-[3-[(dimethylamino) methyl]-4; Two (methoxyl group) phenyl of 5-]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 2-(methylamino) ethanol (20 μ L; 0.30mmol) replace DMA to prepare, obtain the title compound (29.8%) of 10mg.
LC/MS=m/z 559 [M+H] retention time: 1.54min.
Embodiment 57:5-[3, two (methoxyl group)-5-(the 1-pyrrolidinyl methyl) phenyl of 4-]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01171
Title compound is according to preparation 5-[3-[(dimethylamino) methyl]-4; Two (methoxyl group) phenyl of 5-]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With pyrrolidine (50 μ L; 0.30mmol) replace DMA to prepare, obtain the title compound (39.1%) of 13mg.
LC/MS=m/z 555 [M+H] retention time: 1.61min.
Embodiment 58:5-{4-[(dimethylamino) methyl]-2,3-dihydro-1-benzofuran-6-yl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01172
(113mg is 0.274mmol) at two _ alkane (9.0mL) and H to 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide 2Add in the solution among the O (3.0mL) sodium carbonate (174mg, 1.64mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-2,3-dihydro-1-benzofuran-4-formaldehyde (150mg, 0.547mmol).Reactant mixture is washed 10min under argon, add subsequently four (triphenylphosphines) close palladium (0) (16mg, 0.014mmol).This is reflected in the microwave in 120 ℃ of heating 30min.Concentrate all solvents then, and, obtain 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl-2,3-dihydro-1-benzofuran-6-yl)-1H-indole-7-Methanamide (91%) of 120mg through using the purified by flash chromatography of DCM and MeOH.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl-2; 3-dihydro-1-benzofuran-6-yl)-1H-indole-7-Methanamide (20mg; 0.042mmol) add DMA (3 μ L in the solution in methanol (2mL); 0.050mmol), zinc chloride (3mg, 0.021mmol) and sodium cyanoborohydride (4mg, 0.062mmol).With this mixture in microwave in 100 ℃ of reaction 1h, and remove all solvents then.With residue with EtOAc and washing.Remove all solvents, and prepare the HPLC purification, obtain the title compound (19.6%) of 6.0mg through Gilson.
LC/MS=m/z 525 [M+H] retention time: 1.56min.
Embodiment 59:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(1-Methylethyl) amino] methyl-2,3-dihydro-1-benzofuran-6-yl)-1H-indole-7-Methanamide
Figure S2006800304481D01181
Title compound is according to preparation 5-{4-[(dimethylamino) methyl]-2; 3-dihydro-1-benzofuran-6-yl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 2-propylamine (3mg; 0.050mmol) replace DMA to prepare, obtain the title compound (28.6%) of 9.0mg.
LC/MS=m/z 511 [M+H] retention time: 1.58min.
Embodiment 60:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(4-morpholinyl methyl)-2,3-dihydro-1-benzofuran-6-yl]-1H-indole-7-Methanamide
Figure S2006800304481D01182
Title compound is according to preparation 5-{4-[(dimethylamino) methyl]-2; 3-dihydro-1-benzofuran-6-yl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 2; (4mg 0.050mmol) replaces DMA to prepare to 2-dimethyl-1-propylamine, obtains the title compound (24.1%) of 8.0mg.
LC/MS=m/z 554 [M+H] retention time: 1.71min.
Embodiment 61:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ [1-methyl-2-(methoxyl group) ethyl] amino } methyl)-2-thienyl]-1H-indole-7-Methanamide
Figure S2006800304481D01191
(60mg 0.262mmol) transfers in the CEM microwave tube with [5-({ [1-methyl-2-(methoxyl group) ethyl] amino } methyl)-2-thienyl] boric acid with methanol.At N 2Air-flow is this methanol of evaporation down.To wherein add 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (80mg, 0.19mmol), potassium carbonate (160mg, 1.16mmol), four (triphenylphosphines) close palladium (0) (5mg, 0.004mmol), two _ alkane (1.5mL) and water (0.5mL).Seal this bottle, and in the CEM microwave, react 30min in 150 ℃.This solution is loaded to on the pretreated 2g SCX of the 3mL methanol SPE post.Then with the NH of this post water successively (3mL), methanol (9mL) and 2M 3MeOH solution (6mL) eluting.At N 2Descend dry NH at 40 ℃ under the air-flow 3The MeOH fraction.Crude product is dissolved in the dimethyl sulfoxine (1mL), and on Agilent MDAP purification, detect with UV (230nm) and MS.Required fraction is passed through two successive 500mg Pharmasil CHQAX posts with 1mL methanol and 1mL water pretreatment.At N 2In 60 ℃ of these solvents of evaporation, obtain the title compound (34%) of 34.7mg under the air-flow.
LC/MS=m/z 430 [M+H] retention time: 1.32min.
Embodiment 62:5-(5-{ [(2-cyano ethyl) amino] methyl }-the 3-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (30mg, ({ [5-(4,4 to add 3-in 0.072mmol); 5,5-tetramethyl-1,3; 2-dioxa bora ring penta-2-yl)-and the 3-pyridine radicals] methyl } amino) propionitrile (24.8mg, 0.086mmol).In this mixture, add two _ alkane (0.75mL), add subsequently potassium carbonate (60mg, (0.25mL) solution of water 0.434mmol) and SK-CC02-A (4.4mg, 0.007mmol).Seal this bottle, and in the CEM microwave, react 30min in 150 ℃.Reactant is loaded to on the pretreated 2g SCX of the 3mL methanol SPE post.Then with the NH of this post water successively (3mL), methanol (9mL) and 2M 3MeOH solution (6mL) eluting.With NH 3The MeOH fraction at N 2Under the air-flow in 40 ℃ of dryings.With crude product purification on Agilent MDAP, detect with UV (230nm) and MS.Required fraction is passed through the 5gCHQAX post with 4mL methanol and 4mL water pretreatment.At N 2Under 65 ℃, evaporate this solvent under the air-flow, obtain the title compound (17.4%) of 6.2mg.
LC/MS=m/z 495 [M+H] retention time: 1.29min.
Embodiment 63:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2,2, the 2-trifluoroethyl) amino] methyl }-the 3-pyridine radicals)-1H-indole-7-Methanamide
Figure S2006800304481D01202
Title compound is that with 2,2, [5-(4 for 2-three fluoro-N-{ according to the conventional method of preparation 5-(5-{ [(2-cyano ethyl) amino] methyl }-3-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; 4,5,5-tetramethyl-1; 3,2-dioxa bora ring penta-2-yl)-the 3-pyridine radicals] methyl } ethamine (24.3mg, ({ [5-(4 0.077mmol) to replace 3-; 4,5,5-tetramethyl-1; 3,2-dioxa bora ring penta-2-yl)-and the 3-pyridine radicals] methyl } amino) propionitrile prepares, and obtains the title compound (22.0 %) of 8.3mg.
LC/MS=m/z 524 [M+H] retention time: 1.55min.
Embodiment 64:5-{3-[(dimethylamino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01211
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (45mg, 0.10mmol) add in the solution in DMSO (2mL) the 2M DMA THF solution (500 μ L, 1.0mmol).Reactant mixture is at room temperature stirred 5h, add subsequently sodium triacetoxy borohydride (220mg, 1.04mmol).Should react stirred overnight then.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (19.2%) of 9.0mg.
LC/MS=m/z 469 [M+H] retention time: 1.55min
Embodiment 65:5-(5-{ [ethyl (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01212
(50mg, (59.1mg, 1.0mmol), 2 acetic acid, and reaction is spent the night 0.11mmol) to add the N-methyl ethyl-amine in the solution in dimethyl sulfoxine (2mL) to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide.(212 mg, 1mmol), and at room temperature reaction is spent the night to add sodium triacetoxy borohydride then.Then it is prepared the HPLC purification through Gilson, obtain the title compound (33.2%) of 20.0mg.
LC/MS=m/z 489 [M+H] retention time: 1.50min
Embodiment 66:5-(5-{ [[2-(diethylamino) ethyl] (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01221
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; Use N; N-diethyl-N '-methyl isophthalic acid; (130mg 1.0mmol) replaces the N-methyl ethyl-amine to prepare to the 2-ethylenediamine, obtains the title compound (44.5%) of 30.0mg.
LC/MS=m/z 560 [M+H] retention time: 1.41min.
Embodiment 67:5-(5-{ [butyl (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01222
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With butyl (methyl) amine (87mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (15.8%) of 10mg.
LC/MS=m/z 517 [M+H] retention time: 1.61min.
Embodiment 68:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (propyl group) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01231
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With methyl (propyl group) amine (73mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (32.4%) of 20.0mg.
LC/MS=m/z 503 [M+H] retention time: 1.54min.
Embodiment 69:5-(5-{ [[2-(dimethylamino) ethyl] (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01232
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With [2-(dimethylamino) ethyl] methylamine (102mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (40.3%) of 26.0mg.
LC/MS=m/z 532 [M+H] retention time: 1.48min.
Embodiment 70:5-(5-{ [[3-(dimethylamino) propyl group] (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With [3-(dimethylamino) propyl group] methylamine (116mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (31.8%) of 21.0mg.
LC/MS=m/z 546 [M+H] retention time: 1.49min.
Embodiment 71:5-(5-{ [cyclopenta (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01242
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With cyclopenta (methyl) amine (99mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (7.78%) of 5.0mg.
LC/MS=m/z 529 [M+H] retention time: 1.65min.
Embodiment 72:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (amyl group) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01251
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With methyl (amyl group) amine (101mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (29.5%) of 19.0mg.
LC/MS=m/z 531 [M+H] retention time: 161min.
Embodiment 73:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (2-methyl-propyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01252
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With methyl (2-methyl-propyl) amine (87mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (4.8%) of 3.0mg.
LC/MS=m/z 517 [M+H] retention time: 1.61min.
Embodiment 74:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (phenyl methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01261
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With methyl (phenyl methyl) amine (121mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (22.6%) of 15mg.
LC/MS=m/z 551 [M+H] retention time: 1.67min.
Embodiment 75:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-hydroxyethyl) (methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01262
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With 2-(methylamino) ethanol (75mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (43.6%) of 27.0mg.
LC/MS=m/z 505 [M+H] retention time: 1.46min.
Embodiment 76:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ methyl [2-(2-pyridine radicals) ethyl] amino } methyl)-3-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01271
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With methyl [2-(2-pyridine radicals) ethyl] amine (75mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (7.36%) of 5.0mg.
LC/MS=m/z 566 [M+H] retention time: 1.59min.
Embodiment 77:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-furyl methyl) (methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01272
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With 1-(2-furyl)-N-methyl methylamine (111mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (29.0%) of 19.0mg.
LC/MS=m/z 541 [M+H] retention time: 1.59min.
Embodiment 78:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (4-pyridylmethyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01281
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With methyl (4-pyridylmethyl) amine (122mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (46.6%) of 31.0mg.
LC/MS=m/z 552 [M+H] retention time: 1.37min.
Embodiment 79:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(methyl { [1-(1-Methylethyl)-3-pyrrolidinyl] methyl } amino) methyl]-3-thienyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01282
Title compound is according to preparation 5-(5-{ [ethyl (methyl) amino] methyl)-3-thienyl)-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With methyl { [1-(1-Methylethyl)-3-pyrrolidinyl] methyl } amine (156mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (30.0%) of 21.0mg.
LC/MS=m/z 586 [M+H] retention time: 1.43min.
Embodiment 80:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (2-thienyl methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01291
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With methyl (2-thienyl methyl) amine (127mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (38.8%) of 26.0mg.
LC/MS=m/z 557 [M+H] retention time: 1.72min.
Embodiment 81:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ methyl [1-(2-thienyl) ethyl] amino } methyl)-3-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01292
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With methyl [1-(2-thienyl) ethyl] amine (141mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (8.76%) of 6.0mg.
LC/MS=m/z 571 [M+H] retention time: 1.78min.
Embodiment 82:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (3-thienyl methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01301
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With methyl (3-thienyl methyl) amine (127mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (10.4%) of 7.0mg.
LC/MS=m/z 557 [M+H] retention time: 1.78min.
Embodiment 83:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With methyl (tetrahydrochysene-2H-pyrans-4-ylmethyl) amine (129mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (16.4%) of 11.0mg.
LC/MS=m/z 559 [M+H] retention time: 1.63min.
Embodiment 84:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (3-pyridylmethyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01311
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With methyl (3-pyridylmethyl) amine (122mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (14.3%) of 9.5mg.
LC/MS=m/z 552 [M+H] retention time: 1.56min.
Embodiment 85:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (4-Pyrimidylmethyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01312
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With methyl (4-Pyrimidylmethyl) amine (123mg; 1.0mmol) replace the N-methyl ethyl-amine to prepare, obtain the title compound (6.0%) of 4.0mg.
LC/MS=m/z 555 [M+H] retention time: 1.65min.
Embodiment 86:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ methyl [2-(methoxyl group) ethyl] amino } methyl)-3-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01321
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (884mg; 1.98mmol) add methyl [2-(methoxyl group) ethyl] amine (1.86g in the solution in dimethyl sulfoxine (5mL); 21mmol) and HOAc (2mL, 35mmol).To react stirred overnight at room temperature, and the adding sodium triacetoxy borohydride (212mg, 1mmol).Continue to stir 1 hour, and add CHCl 3(50mL).Filtering mixt, concentrating under reduced pressure CHCl 3, and crude product/dmso solution prepared the HPLC purification through Gilson, obtain title compound (590mg, 47%).
LC/MS=m/z 519 [M+H] retention time: 1.50min.
Embodiment 87:5-{3-[(dimethylamino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01322
(45mg, (500 μ L 1.0mmol), and at room temperature stir 5h 0.1mmol) to add the THF solution of 2M methylamine in the solution in DMSO (2mL) to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide.In this mixture, add then sodium triacetoxy borohydride (220mg, 1.0mmol), and stirred overnight.Then it is prepared the HPLC purification through Gilson, obtain the title compound (15.4%) of 9.0mg.
LC/MS=m/z 469 [M+H] retention time: 1.55min.
Embodiment 88:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (1-Methylethyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01331
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (46.0mg, 0.1mmol) add in the solution in DMSO (2.0mL) N-methyl-2-propylamine (73.1mg, 1.0mmol).Then reactant mixture is reacted 10min down in 160 ℃ in microwave.(220mg 1.0mmol), and will react reaction at room temperature and spend the night to add sodium triacetoxy borohydride then.Then it is prepared the HPLC purification through Gilson, obtain the title compound (44.2%) of 24.0mg.
LC/MS=m/z 543 [M+H] retention time: 1.70min.
Embodiment 89:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-propyl group-1-pyrrolidinyl) methyl]-3-thienyl }-1H-indole-7-Methanamide
Figure S2006800304481D01332
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg, 0.11mmol) add in the solution in DMSO (2.0mL) 2-propyl pyrrole alkane (113mg, 1.0mmol).Then reactant mixture is reacted 10min down in 120 ℃ in microwave.(220mg 1.0mmol), and will react reaction at room temperature and spend the night to add sodium triacetoxy borohydride then.Then it is prepared the HPLC purification through Gilson, obtain the title compound (38.7%) of 21.0mg.
LC/MS=m/z 543 [M+H] retention time: 1.70min.
Embodiment 90:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [2-(3-pyridine radicals)-1-pyrrolidinyl] methyl }-the 3-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D01341
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-propyl group-1-pyrrolidinyl) methyl]-3-thienyl }-conventional method of 1H-indole-7-Methanamide; With 3-(2-pyrrolidinyl) pyridine (148mg; 1.0mmol) replace 2-propyl pyrrole alkane to prepare, obtain the title compound (22.5%) of 13.0mg.
LC/MS=m/z 578 [M+H] retention time: 1.52min.
Embodiment 91:5-(5-{ [2-(1, the 1-dimethyl ethyl)-1-pyrrolidinyl] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01342
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-propyl group-1-pyrrolidinyl) methyl]-3-thienyl }-conventional method of 1H-indole-7-Methanamide; With 2-(1; The 1-dimethyl ethyl) pyrrolidine (127mg; 1.0mmol) replace 2-propyl pyrrole alkane to prepare, obtain the title compound (16.4%) of 11.0mg.
LC/MS=m/z 557 [M+H] retention time: 1.65min.
Embodiment 92:5-{5-[(2-ethyl-1-pyrrolidinyl) methyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-propyl group-1-pyrrolidinyl) methyl]-3-thienyl }-conventional method of 1H-indole-7-Methanamide; With 2-ethyl pyrrolidine (99.0mg; 1.0mmol) replace 2-propyl pyrrole alkane to prepare, obtain the title compound (28.4%) of 15.0mg.
LC/MS=m/z 529 [M+H] retention time: 1.66min.
Embodiment 93:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [2-(2-methyl-propyl)-1-pyrrolidinyl] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01352
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-propyl group-1-pyrrolidinyl) methyl]-3-thienyl }-conventional method of 1H-indole-7-Methanamide; With 2-(2-methyl-propyl) pyrrolidine (127mg; 1.0mmol) replace 2-propyl pyrrole alkane to prepare, obtain the title compound (10.4%) of 7.0mg.
LC/MS=m/z 557 [M+H] retention time: 1.74min.
Embodiment 94:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [2-(1-Methylethyl)-1-pyrrolidinyl] methyl }-the 3-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D01361
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-propyl group-1-pyrrolidinyl) methyl]-3-thienyl }-conventional method of 1H-indole-7-Methanamide; With 2-(1-Methylethyl) pyrrolidine (113mg; 1.0mmol) replace 2-propyl pyrrole alkane to prepare, obtain the title compound (29.5%) of 16.0mg.
LC/MS=m/z 543 [M+H] retention time: 1.61min.
Embodiment 95:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-((2S)-and 2-[(methoxyl group) methyl]-1-pyrrolidinyl } methyl)-the 3-thienyl]-1H-indole-7-Methanamide
Figure S2006800304481D01362
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-propyl group-1-pyrrolidinyl) methyl]-3-thienyl }-conventional method of 1H-indole-7-Methanamide; With (2S)-2-[(methoxyl group) methyl] pyrrolidine (115mg; 1.0mmol) replace 2-propyl pyrrole alkane to prepare, obtain the title compound (40.4%) of 22.0mg.
LC/MS=m/z 544 [M+H] retention time: 1.44min.
Embodiment 96:5-(5-{ [cyclohexyl (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01371
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-propyl group-1-pyrrolidinyl) methyl]-3-thienyl }-conventional method of 1H-indole-7-Methanamide; With cyclohexyl (methyl) amine (113mg; 1.0mmol) replace 2-propyl pyrrole alkane to prepare, obtain the title compound (27.6%) of 15.0mg.
LC/MS=m/z 543 [M+H] retention time: 1.64min.
Embodiment 97:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [2-(2-methyl-propyl)-1-pyrrolidinyl] methyl }-the 3-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D01372
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-propyl group-1-pyrrolidinyl) methyl]-3-thienyl }-conventional method of 1H-indole-7-Methanamide; With 2-(2-methyl-propyl) pyrrolidine (127mg; 1.0mmol) replace 2-propyl pyrrole alkane to prepare, obtain the title compound (21.6%) of 12.0mg.
LC/MS=m/z 557 [M+H] retention time: 1.74min.
Embodiment 98:5-(5-{ [ethyl (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01381
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.11mmol) add 2 acetic acid, ethyl (methyl) amine (59mg in the solution in DMSO (2.0mL); 1.0mmol), and at room temperature stir 5h.(212mg, 1.0mmol), and reaction is spent the night to wherein adding sodium triacetoxy borohydride then.Then it is prepared the HPLC purification through Gilson, obtain the title compound (61.4%) of 30.0mg.
LC/MS=m/z 489 [M+H] retention time: 1.50min.
Embodiment 99:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (propyl group) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D01382
Title compound is the conventional method according to preparation 5-(5-{ [ethyl (methyl) amino] methyl }-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With methyl (propyl group) amine (73mg; 1.0mmol) replace 2-propyl pyrrole alkane to prepare, obtain the title compound (63.7%) of 32.0mg.
LC/MS=m/z 503 [M+H] retention time: 1.54min.
Embodiment 100:3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-5-(5-{ [methyl (propyl group) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01391
To 5-(5-formoxyl-3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide (46mg; 0.10mmol) add 2 acetic acid, methyl (propyl group) amine (73mg in the solution in DMSO (2.0mL); 1.0mmol), and at room temperature stir 5h.(212mg, 1.0mmol), and reaction is spent the night to wherein adding sodium triacetoxy borohydride.Then it is prepared the HPLC purification through Gilson, obtain the title compound (39.6%) of 25.0mg.
LC/MS=m/z 517 [M+H] retention time: 1.61min.
Embodiment 101:5-(5-{ [ethyl (methyl) amino] methyl }-the 3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide
Figure S2006800304481D01392
Title compound is according to preparation 3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-conventional method of 5-(5-{ [methyl (propyl group) amino] methyl }-3-thienyl)-1H-indole-7-Methanamide trifluoroacetate; With ethyl (methyl) amine (59mg; 1.0mmol) replace methyl (propyl group) amine to prepare, obtain the title compound (15.9%) of 8.0mg.
LC/MS=m/z 503 [M+H] retention time: 1.59min.
Embodiment 102:3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-5-[5-({ methyl [2-(methoxyl group) ethyl] amino } methyl)-3-thienyl]-1H-indole-7-Methanamide
Figure S2006800304481D01401
Title compound is according to preparation 3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-conventional method of 5-(5-{ [methyl (propyl group) amino] methyl }-3-thienyl)-1H-indole-7-Methanamide trifluoroacetate; With methyl [2-(methoxyl group) ethyl] amine (89mg; 1.0mmol) replace methyl (propyl group) amine to prepare, obtain the title compound (69.4%) of 37.0mg.
LC/MS=m/z 533 [M+H] retention time: 1.58min.
Embodiment 103:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(methylamino) methyl]-2-thienyl }-1H-indole-7-Methanamide
Figure S2006800304481D01402
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-2-thienyl)-1H-indole-7-Methanamide (35mg; 0.078mmol) add the THF solution (0.24mL of acetic acid (3), 2M methylamine in the solution in DMSO (1.0mL); 0.471mmol), and reaction 3h.(100mg 0.471mmol), and will react stirred overnight to add sodium triacetoxy borohydride then.Vacuum is removed all solvents, and prepares the HPLC purification through Gilson.With impure required fraction concentrating under reduced pressure, and load to on the pretreated 500mg SCX of the 10mL methanol SPE post.Then this post is used successively the NH of 2M 3MeOH (10mL * 2) eluting.Concentrate NH 3The MeOH fraction, obtain the title compound (20%) of 7.3mg.
LC/MS=m/z 459.6 [M+H] retention time: 1.25min.
Embodiment 104:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-methyl isophthalic acid-pyrrolidinyl) methyl]-3-thienyl }-1H-indole-7-Methanamide trifluoroacetate
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-2-thienyl)-1H-indole-7-Methanamide (50mg; 0.112mmol) add acetic acid (3), 2-crassitude (0.12mL in the solution in DMSO (3.0mL); 1.12mmol), and reaction 4h.(238mg 1.12mmol), and should react stirred overnight to add sodium triacetoxy borohydride then.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (30%) of 17mg.
LCMS：515.4(M+H)，Rt?1.60min
Embodiment 105:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl-propyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01412
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.112mmol) add acetic acid (4) in the solution in DMSO (2.0mL); Make (2-methyl-propyl) amine (0.17mL; 1.68mmol) and sodium triacetoxy borohydride (356mg, 1.68mmol) reaction.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (27%) of 15mg.
LCMS：503.4(M+H)，Rt?1.60min
Embodiment 106:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(propyl group is amino) methyl]-3-thienyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01421
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.112mmol) add acetic acid (3) in the solution in DMSO (2.0mL); Make (2-methyl-propyl) amine (0.17mL; 1.68mmol) and sodium triacetoxy borohydride (356mg, 1.68mmol) reaction.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (27%) of 15mg.
LCMS：489(M+H)，Rt?1.61min
Embodiment 107:5-{5-[(diethylamino) methyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01422
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.11mmol) add acetic acid (3), diethylamine (0.12mL in the solution in DMSO (2.0mL); 1.12mmol), and at room temperature stir 4h.(238mg 1.12mmol), and should react stirred overnight to add sodium triacetoxy borohydride then.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (13%) of 7.0mg.
LCMS：501.4(M+H)，Rt1.51min
Embodiment 108:5-(5-{ [(2R, 5R)-2,5-dimethyl-1-pyrrolidinyl] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01431
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.112mmol) add in the solution in DMSO (2.0mL) acetic acid (3), (2R, 5R)-2,5-dimethyl pyrrolidine (151mg; 1.123mmol), and reaction 4h.Add then sodium triacetoxy borohydride (238mg, 1.123mmol).Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (46%) of 27mg.
LCMS：529.4(M+H)，Rt?1.64min
Embodiment 109:5-{5-[(cyclopropyl is amino) methyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01441
(50mg, (0.12mL 1.68mmol), and reacts 6h 0.11mmol) to add acetic acid (5) and cyclopropylamine in the solution in DMSO (2.0mL) to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide.(356mg 1.68mmol), and should react stirred overnight to add sodium triacetoxy borohydride then.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (10%) of 8.0mg.
LCMS:487.2 (M+H), Rt 1.64min and 1.68min
Embodiment 110:5-{5-[(cyclobutyl is amino) methyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01442
(50mg, (0.15mL 1.68mmol), and reacts 4h 0.11mmol) to add acetic acid (4) and ring butylamine in the solution in DMSO (2.0mL) to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide.(356mg 1.68mmol), and should react stirred overnight to add sodium triacetoxy borohydride then.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (10%) of 5.0mg.
LCMS：501.4(M+H)，Rt?1.51min
Embodiment 111:5-{5-[(dimethylamino) methyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01451
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl-2-thienyl)-1H-indole-7-Methanamide (300mg, 0.67mmol) add in the solution in DMSO (4mL) the 2M DMA THF solution (3.36mL, 6.7mmol).Should react and at room temperature stir 7h, and the adding sodium triacetoxy borohydride (1.42g, 6.7mmol).At room temperature continue stirred overnight.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain title compound (205mg, 64%).
LCMS：475.2(M+H)，Rt?1.51min
Embodiment 112:5-(5-{ [(cyclopentyl-methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01452
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.112mmol) add acetic acid (3), (cyclopentyl-methyl) amine (112mg in the solution in DMSO (2.0mL); 1.123mmol), and reaction 4h.(238mg 1.123mmol), and should react stirred overnight to add sodium triacetoxy borohydride then.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (14%) of 8.0mg.
LCMS:529.4 (M+H), Rt 1.61min and 1.64min
Embodiment 113:5-[5-({ [(1R)-1,2-dimethyl propyl] amino } methyl)-3-thienyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.112mmol) add acetic acid (3), (2R)-3-methyl-2-butylamine (98mg in the solution in DMSO (2.0mL); 1.123mmol), and reaction 4h.(238mg 1.123mmol), and should react stirred overnight to add sodium triacetoxy borohydride then.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (10%) of 5.0mg.
LCMS：517.2(M+H)，Rt?1.65min
Embodiment 114:5-{5-[(cyclopenta is amino) methyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01471
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg, 0.112mmol) add in the solution in DMSO (2.0mL) acetic acid (3), Aminocyclopentane (0.11mL, 1.123mmol), and reaction 4h.(238mg 1.123mmol), and spends the night this reaction response to add sodium triacetoxy borohydride then.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (6.0%) of 5.0mg.
LCMS：515.6(M+H)，Rt?1.38min
Embodiment 115:5-(5-{ [(cyclopropyl methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01472
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.112mmol) add acetic acid (3), 1-cyclopropyl-methylamine (0.10mL in the solution in DMSO (2.0mL); 1.123mmol), and reaction 6h.(238mg 1.123mmol), and should react stirred overnight to add sodium triacetoxy borohydride then.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (10%) of 5.0mg.
LCMS：501.4(M+H)，Rt?1.53min
Embodiment 116:5-[5-({ [(1S)-1,2-dimethyl propyl] amino } methyl)-3-thienyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01481
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.112mmol) add acetic acid (3), (2S)-3-methyl-2-butylamine (98mg in the solution in DMSO (2.0mL); 1.123mmol), and reaction 6h.(238mg 1.123mmol), and should react stirred overnight to add sodium triacetoxy borohydride then.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (15%) of 8.0mg.
LCMS：517.2(M+H)，Rt?1.65min
Embodiment 117:5-(5-{ [(2, the 2-dimethyl propyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01482
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.112mmol) add acetic acid (3), (2 in the solution in DMSO (2.0mL); The 2-dimethyl propyl) (0.13mL 1.123mmol), and reacts 6h to amine.Add then sodium triacetoxy borohydride (238mg, 1.123mmol), and stirred overnight.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (7%) of 4.0mg.
LCMS:517.2 (M+H), Rt 1.68min and 1.71min
Embodiment 118:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(phenyl methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.112mmol) add acetic acid (5), (phenyl methyl) amine (0.14mL in the solution in DMSO (2.0mL); 1.123mmol), and reaction 6h.Add then sodium triacetoxy borohydride (238mg, 1.123mmol), and stirred overnight.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (8%) of 5.0mg.
LCMS：537.2(M+H)，Rt?1.68min
Embodiment 119:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-([(2S)-and tetrahydrochysene-2-furyl methyl] amino } methyl)-the 3-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01501
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.112mmol) add acetic acid (5), 1-[(2S)-tetrahydrochysene-2-furyl] methylamine (0.12mL in the solution in dichloromethane (3.0mL) and methanol (1.5mL); 1.123mmol), and reaction 6h.Add then sodium triacetoxy borohydride (238mg, 1.123mmol), and with reactant mixture stirred overnight at room temperature.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (8%) of 23mg.
LCMS：531.4(M+H)，Rt?1.58min
Embodiment 120:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01502
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.112mmol) add acetic acid (5) and (tetrahydrochysene-2H-pyrans-4-ylmethyl) amine (130mg in the solution in DMSO (2.0mL); 1.123mmol), and reaction 6h.(238mg 1.123mmol), and should react stirred overnight to add sodium triacetoxy borohydride then.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (11%) of 7.0mg.
LCMS：545.4(M+H)，Rt?1.52min
Embodiment 121:5-{5-[(butyl is amino) methyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01511
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.112mmol) add 5 acetic acid, butylamine (0.11mL in the solution in dichloromethane (3.0mL) and methanol (1.5mL); 1.123mmol), and reaction 6h.Add then sodium borohydride (43mg, 1.123mmol), and stirred overnight at room temperature.Vacuum is removed all solvents, and is dissolved among the DMSO (1.0mL).Then it is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (10%) of 5.0mg.
LCMS：503.4(M+H)，Rt?1.63min
Embodiment 122:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-([(2R)-and tetrahydrochysene-2-furyl methyl] amino } methyl)-the 3-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01512
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.112mmol) add acetic acid (5), 1-[(2R)-tetrahydrochysene-2-furyl] methylamine (130mg in the solution in DMSO (2.0mL); 1.123mmol), and reactant mixture reacted 6h.(238mg 1.123mmol), and should react stirred overnight to add sodium triacetoxy borohydride then.(130mg 1.123mmol), adds sodium triacetoxy borohydride to methylamine subsequently behind the 6h to add other 1-[(2R)-tetrahydrochysene-2-furyl] then.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (8.0%) of 5.0mg.
LCMS：531.4(M+H)，Rt?1.50min
Embodiment 123:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-((2S)-and 2-[(methoxyl group) methyl]-1-pyrrolidinyl } methyl)-the 3-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01521
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.112mmol) add 5 acetic acid, (2S)-2-[(methoxyl group) methyl] pyrrolidine (129mg in the solution in dichloromethane (3.0mL) and methanol (1.5mL); 1.123mmol), and at room temperature react 6h.(43mg 1.123mmol), and reacts this to stirred overnight at room temperature to add sodium borohydride then.Reactant mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (13%) of 8.0mg.
LCMS:545.2 (M+H), Rt 1.62min and 1.66min.
Embodiment 124:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-((2R)-and 2-[(methoxyl group) methyl]-1-pyrrolidinyl } methyl)-the 3-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01531
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.112mmol) add acetic acid (5), (2R)-2-[(methoxyl group) methyl] pyrrolidine (129mg in the solution in dichloromethane (3.0mL) and methanol (1.5mL); 1.123mmol), and at room temperature stir 6h.(43mg 1.123mmol), and reacts this to stirred overnight at room temperature to add sodium borohydride then.Mixture is prepared the HPLC purification through anti-phase Gilson, obtain the title compound (13%) of 5.0mg.
LCMS:545.2 (M+H), Rt 1.62min and 1.66min.
Embodiment 125:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-[2-(methylamino) ethyl] phenyl }-1H-indole-7-Methanamide
Figure S2006800304481D01532
(200mg is 0.48mmol) at two _ alkane and H to 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide 2Add in the solution among the O [4-(cyano methyl) phenyl] boric acid (232mg, 0.144mmol), potassium carbonate (400mg, 2.88mmol) with four (triphenylphosphines) close palladium (0) (30mg, 0.048mmol).Stir this solution, and in microwave, heat 40min in 160 ℃.With reactant with EtOAc and H 2The O dilution is also filtered, and obtains the required product of yellow crystal.With this solution with saline and H 2O washes, and concentrates EtOAc then.In this residue, add MEOH, be settled out required product, and and then wash with MeOH, obtain 5-[4-(cyano methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide.
Under 0 ℃, to 5-[4-(cyano methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (78mg, add in DCM solution 0.173mmol) the 1.5M diisobutylaluminium hydride toluene solution (240mL, 0.346mmol).This is reflected at 0 ℃ stirs 20min down.To react then with saturated KNa tartrate solution and stop.Filtration should bilayer, and solid is required product.In addition, concentrate this organic layer, obtain required chemical compound 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(2-oxoethyl) phenyl]-1H-indole-7-Methanamide, it need be further purified use.
At room temperature; To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(2-oxoethyl) phenyl]-1H-indole-7-Methanamide (50mg; 0.11mmol) add the tetrahydrofuran solution (0.4mL) of 2M methylamine in the solution in methanol (5mL) and dichloromethane (5mL), add 1 acetic acid subsequently.Should react and at room temperature stir 2h, add subsequently sodium triacetoxy borohydride (200mg, 0.94mmol).Should react stirred overnight.Then it is passed through purified by flash chromatography, obtain the title compound (19.4%) of 10mg.
LC/MS=m/z 469.4 [M+H] retention time: 1.63min.
Embodiment 126:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-[2-(propyl group is amino) ethyl] phenyl }-1H-indole-7-Methanamide
Figure S2006800304481D01541
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-[2-(methylamino) ethyl] phenyl }-conventional method of 1H-indole-7-Methanamide; Tetrahydrofuran solution (0.4mL) with the 2M propylamine replaces methylamine to prepare, and obtains the title compound (27.5%) of 15mg.
LC/MS=m/z 497.6 [M+H] retention time: 1.63min.
Embodiment 127:5-{4-[2-(ethylamino) ethyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01551
At room temperature; To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(2-oxoethyl) phenyl]-1H-indole-7-Methanamide (50mg; 0.11mmol) add the tetrahydrofuran solution (0.4mL) of 2M ethamine in the solution in methanol (5mL) and dichloromethane (5mL), add 1 acetic acid subsequently.Should react and at room temperature stir 2h, add subsequently sodium triacetoxy borohydride (200mg, 0.94mmol).Should react stirred overnight.Then it is passed through purified by flash chromatography, obtain the title compound (28.3%) of 15mg.
LC/MS=m/z 483.2 [M+H] retention time: 1.57min.
Embodiment 128:5-{4-[({ [1-(1, the 1-dimethyl ethyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] carbonyl } amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01552
To [4-(amino methyl) phenyl] boric acid (145mg, 0.966mmol) add in the solution in DMF (2mL) 1-(1, the 1-dimethyl ethyl)-3-methyl isophthalic acid H-pyrazoles-5-phosgene (290mg, 1.45mmol) and triethylamine (403 μ L, 2.90mmol).Should react and stir 2h.Then with this reaction terminating, and at EtOAc and H 2Distribute between the O, and concentrate this organic layer, obtain { 4-[({ [1-(1, the 1-dimethyl ethyl)-3-methyl isophthalic acid H-pyrazoles-5-yl] carbonyl } amino) methyl] phenyl } boric acid.
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (50mg; 0.120mmol) add potassium carbonate (74mg in the solution in two _ alkane (1mL) and water (0.4mL); 0.484mmol) and { [({ [1-(1 for 4-; The 1-dimethyl ethyl)-and 3-methyl isophthalic acid H-pyrazoles-5-yl] carbonyl } amino) methyl] phenyl } boric acid (153mg, 0.483mmol).Stir this reactant mixture, and blast argon 5min, add subsequently chlorination (two-2-norborny (norbomyl) phosphino-) (2-dimethylaminomethyl ferrocene-1-yl) close palladium (II) (7mg, 0.012mmol).Should react and stir 10min, be heated to 150 ℃ then.With this reactive evaporation, and prepare the HPLC purification, obtain the title compound (5.8%) of 5mg through Gilson.
LC/MS=m/z 605.4 [M+H] retention time: 2.14min.
Embodiment 129:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(4-pyridine radicals carbonyl) amino] methyl } phenyl)-1H-indole-7-Methanamide
Title compound is that [({ [1-(1 according to preparation 5-{4-; The 1-dimethyl ethyl)-and 3-methyl isophthalic acid H-pyrazoles-5-yl] carbonyl } amino) methyl] phenyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With (4-{ [(4-pyridine radicals carbonyl) amino] methyl } phenyl) boric acid (124mg; 0.480mmol) { [({ [1-(1 for 4-in replacement; The 1-dimethyl ethyl)-and 3-methyl isophthalic acid H-pyrazoles-5-yl] carbonyl } amino) methyl] phenyl } boric acid prepares, and obtains the title compound (45.8%) of 30mg.
LC/MS=m/z 537 [M+H] retention time: 2.04min.
Embodiment 130:5-(4-{ [(cyclopentylcarbonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01571
Title compound is that [({ [1-(1 according to preparation 5-{4-; The 1-dimethyl ethyl)-and 3-methyl isophthalic acid H-pyrazoles-5-yl] carbonyl } amino) methyl] phenyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With (4-{ [(cyclopentylcarbonyl) amino] methyl } phenyl) boric acid (119mg; 0.480mmol) { [({ [1-(1 for 4-in replacement; The 1-dimethyl ethyl)-and 3-methyl isophthalic acid H-pyrazoles-5-yl] carbonyl } amino) methyl] phenyl } boric acid prepares, and obtains the title compound (47%) of 30mg.
LC/MS=m/z 537 [M+H] retention time: 2.04min.
Embodiment 131:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(2-furyl carbonyl) amino] methyl } phenyl)-1H-indole-7-Methanamide
Figure S2006800304481D01572
Title compound is that [({ [1-(1 according to preparation 5-{4-; The 1-dimethyl ethyl)-and 3-methyl isophthalic acid H-pyrazoles-5-yl] carbonyl } amino) methyl] phenyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With (4-{ [(2-furyl carbonyl) amino] methyl } phenyl) boric acid (118mg; 0.480mmol) { [({ [1-(1 for 4-in replacement; The 1-dimethyl ethyl)-and 3-methyl isophthalic acid H-pyrazoles-5-yl] carbonyl } amino) methyl] phenyl } boric acid prepares, and obtains the title compound (25%) of 16mg.
LC/MS=m/z 535.5 [M+H] retention time: 1.99min.
Embodiment 132:5-(4-{2-[(cyclobutyl carbonyl) amino] ethyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01581
Title compound is according to preparation 5-{4-[2-(acetyl-amino) ethyl] phenyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; (100mg 0.324mmol) replaces N-[2-(4-bromophenyl) ethyl] acetamide to prepare with N-[2-(4-bromophenyl) ethyl] Tetramethylene. Methanamide.Through purified by flash chromatography, obtain the title compound (48.3%) of 28mg.
LC/MS=m/z 537.2 [M+H] retention time: 1.99min.
Embodiment 133:5-(4-{2-[(cyclohexyl-carbonyl) amino] ethyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01582
Title compound is according to preparation 5-{4-[2-(acetyl-amino) ethyl] phenyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; (100mg 0.324mmol) replaces N-[2-(4-bromophenyl) ethyl] acetamide to prepare with N-[2-(4-bromophenyl) ethyl] cyclohexane carboxamide.Through purified by flash chromatography, obtain the title compound (52.5%) of 32mg.
LC/MS=m/z 565.4 [M+H] retention time: 2.14min.
Embodiment 134:5-(3-{2-[(cyclohexyl-carbonyl) amino] ethyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01591
Title compound is according to preparation 5-{4-[2-(acetyl-amino) ethyl] phenyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; (100mg 0.324mmol) replaces N-[2-(4-bromophenyl) ethyl] acetamide to prepare with N-[2-(3-bromophenyl) ethyl] cyclohexane carboxamide.Spissated reactant mixture is prepared the HPLC purification through Gilson, pass through flash chromatography purification once more subsequently, obtain title compound.
LC/MS=m/z 565.2 [M+H] retention time: 2.16min.
Embodiment 135:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[6-(1-piperazinyl)-3-pyridine radicals]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01592
(100mg is 0.241mmol) at two _ alkane (1.0mL) and H to 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide 2Add in the solution among the O (0.8mL) cesium carbonate (314mg, 0.964mmol) with [6-(4-{ [(1, the 1-dimethyl ethyl) oxygen base] carbonyl }-1-piperazinyl)-3-pyridine radicals] boric acid (297mg, 0.964mmol).Stir this reactant mixture, add subsequently four (triphenylphosphines) close palladium (0) (28mg, 0.024mmol).This is reflected in the microwave in 160 ℃ of heating 20min.Mixture is concentrated, and be dissolved in EtOAc (10mL) and H 2Among the O (5.0mL).Chemical compound is prepared the HPLC purification through Gilson; Obtain 4-(5-{7-(amino carbonyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-5-yl }-2-pyridine radicals)-1-piperazine carboxylic acid 1 of 129mg, 1-dimethyl ethyl ester and 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[6-(1-piperazinyl)-3-pyridine radicals]-1H-indole-7-Methanamide (44%).
To 4-(5-{7-(amino carbonyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-5-yl }-2-pyridine radicals)-1-piperazine carboxylic acid 1; 1-dimethyl ethyl ester (130mg, 0.218mmol) two _ alkane solution (0.3mL) of the HCl of adding 4M in the solution in methanol (0.3mL).This is reflected at 50 ℃ of heating down, and stirs 3h.Reactant mixture is concentrated, and using CH 2Cl 2, subsequently with neutralizing on the pretreated SCX post of MeOH, and collect with the MeOH solution of ammonia.Concentrate the required fraction of 20mg, and use the MDAPHPLC purification, obtain the title compound (7%) of 9.4mg.
LC/MS=m/z 497.2 [M+H] retention time: 1.45min
Embodiment 136:5-[6-(4-ethyl-1-piperazinyl)-3-pyridine radicals]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01601
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[6-(1-piperazinyl)-3-pyridine radicals]-1H-indole-7-Methanamide (40mg; 0.081mmol) add acetaldehyde (7mg in the solution in dichloromethane; 0.162mmol) and sodium triacetoxy borohydride (100mg, 0.472mmol).To react stirred overnight at room temperature.Then reactant mixture is concentrated, and be dissolved in EtOAc and H 2Among the O.Filter this salt, and concentrate this organic layer, and prepare the HPLC purification, obtain the title compound (92%) of 39mg through Gilson.
LC/MS=m/z 525.6 [M+H] retention time: 1.44min
Embodiment 137:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(piperidino methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01611
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (40mg, 0.09mmol) add in the solution in dichloromethane piperidines (9 μ L, 0.09mmol).Should react and stir 1h, add subsequently sodium triacetoxy borohydride (58mg, 0.27mmol).With reactant mixture stirred overnight at room temperature.Then mixture is concentrated, and prepare the HPLC purification, obtain the title compound (14%) of 8.0mg through Gilson.
LC/MS=m/z 509.4 [M+H] retention time: 1.71min
Embodiment 138:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(piperidino methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01612
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol) add in the solution in dichloromethane (2mL) and acetic acid (1) piperidines (46 μ L, 0.456mmol).Should react and at room temperature stir 2h, add subsequently sodium triacetoxy borohydride (75mg, 0.342mmol).Should react restir 3h then.Then mixture is prepared the HPLC purification through Gilson, obtain the title compound (61%) of 36mg.
LC/MS=m/z 509.4 [M+H] retention time: 1.80min
Embodiment 139:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-[(methylamino) methyl] phenyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01621
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (20mg, 0.045mmol) add in the solution in dichloromethane (12mL), methanol (2mL) and acetic acid methylamine THF solution (20 μ L, 0.54mmol).Reactant mixture is at room temperature stirred 2h, add subsequently sodium triacetoxy borohydride (10.3mg, 0.270mmol).With mixture restir 3h, subsequently mixture is concentrated then, and prepare the HPLC purification, obtain the title compound (10%) of 6mg through Gilson.
LC/MS=m/z 454.6 [M+H] retention time: 1.23min
Embodiment 140:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(1-Methylethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide
Figure S2006800304481D01622
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (40mg, 0.09mmol) add in the solution in DMSO (900 μ L) and acetic acid (2) the 2-propylamine (93 μ L, 1.08mmol).Behind the 2h, and the adding sodium triacetoxy borohydride (172mg, 0.81mmol).With the reactant mixture stirred overnight.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (69%) of 30mg.
LC/MS=m/z 483.2 [M+H] retention time: 1.56min
Embodiment 141:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-[(propyl group is amino) methyl] phenyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01631
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (20mg, 0.045mmol) add in the solution in DMSO (900 μ L) and acetic acid (2) propylamine (45 μ L, 1.08mmol).Behind the 2h, and the adding sodium triacetoxy borohydride (172mg, 0.81mmol).With the reactant mixture stirred overnight.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (74%) of 21.1mg.
LC/MS=m/z 483.2 [M+H] retention time: 1.54min.
Embodiment 142:5-(4-{ [(1-ethyl propyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01632
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (40mg, 0.09mmol) add in the solution in DMSO (900 μ L) and acetic acid (2) the 3-amylamine (108 μ L, 1.08mmol).Behind the 2h, and the adding sodium triacetoxy borohydride (172mg, 0.81mmol).With the reactant mixture stirred overnight.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (74%) of 34.5mg.
LC/MS=m/z 511.4 [M+H] retention time: 1.69min
Embodiment 143:5-{4-[(cyclopenta is amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01641
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (40mg, 0.09mmol) add in the solution in DMSO (900 μ L) and acetic acid (2) Aminocyclopentane (108 μ L, 1.08mmol).Behind the 2h, and the adding sodium triacetoxy borohydride (172mg, 0.81mmol).With the reactant mixture stirred overnight.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (20%) of 11.1mg.
LC/MS=m/z 509.4 [M+H] retention time: 1.66min.
Embodiment 144:5-{4-[(cyclobutyl is amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01642
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (40 mg, 0.091mmol) add in the solution in DMSO (900 μ L) and acetic acid (2) the ring butylamine (94 μ L, 1.08mmol).Behind the 2h, and the adding sodium triacetoxy borohydride (120mg, 1.10mmol).With the reactant mixture stirred overnight.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (59%) of 26.3mg.
LC/MS=m/z 495.4 [M+H] retention time: 1.37min
Embodiment 145:5-{4-[(ethylamino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01651
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (20mg, 0.046mmol) add in the solution in DMSO and acetic acid ethamine (32 μ L, 0.547mmol).Behind the 2h, and the adding sodium triacetoxy borohydride (120mg, 1.10mmol).With the reactant mixture stirred overnight.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (55%) of 11.5mg.
LC/MS=m/z 469.4 [M+H] retention time: 1.52min.
Embodiment 146:5-{4-[(dimethylamino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol) add in the solution in DMSO (3mL) and acetic acid TMSDMA N dimethylamine (170 μ L, 0.342mmol).Behind the 2h, and the adding sodium triacetoxy borohydride (290mg, 1.36mmol).With the reactant mixture stirred overnight.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (54%) of 28.9mg.
LC/MS=m/z 469.4 [M+H] retention time: 1.52min.
Embodiment 147:5-{4-[(diethylamino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01662
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol) add in the solution in DMSO (3mL) and acetic acid diethylamine (36 μ L, 0.342mmol).Behind the 2h, and the adding sodium triacetoxy borohydride (290mg, 1.36mmol).With the reactant mixture stirred overnight.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (67%) of 37.6mg.
LC/MS=m/z 497.6 [M+H] retention time: 1.52min.
Embodiment 148:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide
Figure S2006800304481D01671
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol) add in the solution in DMSO (3mL) and acetic acid morpholine (30 μ L, 0.342mmol).Behind the 2h, and the adding sodium triacetoxy borohydride (290mg, 1.36mmol).With the reactant mixture stirred overnight.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (70%) of 40.3mg.
LC/MS=m/z 511.4 [M+H] retention time: 1.53min
Embodiment 149:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(1-pyrrolidinyl methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01672
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol) add in the solution in DMSO (3mL) and acetic acid Aminocyclopentane (28 μ L, 0.342mmol).Behind the 2h, and the adding sodium triacetoxy borohydride (290mg, 1.36mmol).With the reactant mixture stirred overnight.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (36%) of 20.1mg.
LC/MS=m/z 495.4 [M+H] retention time: 1.58min
Embodiment 150:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-([(1S)-and 2-hydroxyl-1-Methylethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01681
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol) add in the solution in DMSO (3mL) and acetic acid (2S)-2-amino-1-propanol (56 μ L, 0.745mmol).Behind the 2h, and the adding sodium triacetoxy borohydride (290mg, 1.36mmol).With the reactant mixture stirred overnight.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (15%) of 25.9mg.
LC/MS=m/z 499.6 [M+H] retention time: 1.54min
Embodiment 151:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-([(1R)-and 2-hydroxyl-1-Methylethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01682
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (50 mg, 0.114mmol) add in the solution in DMSO (3mL) and acetic acid (2R)-2-amino-1-propanol (56 μ L, 0.745mmol).Behind the 2h, and the adding sodium triacetoxy borohydride (290mg, 1.36mmol).With the reactant mixture stirred overnight.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (53%) of 29.6mg.
LC/MS=m/z 499.6 [M+H] retention time: 1.47min
Embodiment 152:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-([(2R)-and the 2-hydroxypropyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01691
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol) add in the solution in DMSO (3mL) and acetic acid (2R)-1-amino-2-propanol (56 μ L, 0.745mmol).Behind the 2h, and the adding sodium triacetoxy borohydride (290mg, 1.36mmol).With the reactant mixture stirred overnight.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (26%) of 14.7mg.
LC/MS=m/z 499.6 [M+H] retention time: 1.46min.
Embodiment 153:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-({ [2-hydroxyl-1-(hydroxymethyl) ethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01701
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (40mg, it is amino-1 0.091mmol) to add 2-in the solution in DMSO, ammediol (50mg, 0.55mmol) and acetic acid (1).Behind the 2h, and the adding sodium triacetoxy borohydride (232mg, 1.10mmol).With the reactant mixture stirred overnight.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (28%) of 15.9mg.
LC/MS=m/z 515.4 [M+H] retention time: 1.45min.
Embodiment 154:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(1-methyl butyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01702
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol) add in the solution in DMSO (3.0mL) the 2-amylamine (324 μ L, 2.74mmoL) and acetic acid (1).Behind the 2h, and the adding sodium triacetoxy borohydride (290mg, 1.10mmol).With the reactant mixture stirred overnight.Then chemical compound is filtered and concentrates.Then it is prepared the HPLC purification through Gilson, obtain the title compound (13%) of 9.5mg.
LC/MS=m/z 511.4 [M+H] retention time: 1.66min
Embodiment 155:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-([(1R)-and the 1-methyl-propyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01711
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol) add in the solution in DMSO (2.0mL) (2R)-2-butylamine (69 μ L, 0.684mmol) and acetic acid (1).Behind the 2h, and the adding sodium triacetoxy borohydride (0.435mg, 2.05mmol).With the reactant mixture stirred overnight.Then chemical compound is filtered and concentrates.Then it is prepared the HPLC purification through Gilson, obtain the title compound (33%) of 18.6mg.
LC/MS=m/z 497.6 [M+H] retention time: 1.70min
Embodiment 156:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-methyl-propyl) amino] methyl } phenyl)-1H-indole-7-Methanamide
Figure S2006800304481D01712
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50mg; 0.114mmol) add 2-methyl isophthalic acid-propylamine (137 μ L in the solution in DCM (1.5mL), MeOH (1.5mL) and acetic acid (4); 1.37mmol), and at room temperature stir.Behind the 2h, add sodium borohydride (23mg, 0.684mmol), and with reactant mixture through the SCX column purification, obtain the title compound (85%) of 47.8mg.
LC/MS=m/z 497.2 [M+H] retention time: 1.69min
Embodiment 157:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-([(1S)-and the 1-methyl-propyl] amino } methyl) phenyl]-1H-indole-7-Methanamide acetate
Figure S2006800304481D01721
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-methyl-propyl) amino] methyl } phenyl)-1H-indole-7-Methanamide; With (2S)-2-butylamine (138 μ L; 1.37mmol) replace 2-methyl isophthalic acid-propylamine to prepare, obtain the title compound (76%) of 43.2mg.
LC/MS=m/z 497.4 [M+H] retention time: 1.84min
Embodiment 158:5-(4-{ [(cyclopropyl carbonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01722
Title compound is according to preparation 5-{4-[(acetyl-amino) methyl] phenyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide, prepare with cyclopropane phosgene (14 μ L, 1.37 mmol) replacing acetyl chloride.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (28%) of 19.1mg.
LC/MS=m/z 509.2 [M+H] retention time: 1.86min
Embodiment 159:5-(4-{ [(cyclobutyl carbonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Title compound is according to preparation 5-{4-[(acetyl-amino) methyl] phenyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide, (17 μ L, 1.37mmol) replacing acetyl chloride prepares with the Tetramethylene. phosgene.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (28%) of 20.2mg.
LC/MS=m/z 523.2 [M+H] retention time: 1.94min
Embodiment 160:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(2-thienyl acetyl group) amino] methyl } phenyl)-1H-indole-7-Methanamide
Figure S2006800304481D01732
Title compound is according to preparation 5-{4-[(acetyl-amino) methyl] phenyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With (3Z)-3-(methyl mercapto)-3; (18 μ L, 1.37mmol) replacing acetyl chloride prepares 5-hexadiene acyl chlorides.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (18%) of 13.5mg.
LC/MS=m/z 565.2 [M+H] retention time: 1.98min
Embodiment 161:5-[4-({ [(1S)-1,2-dimethyl propyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01741
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (40mg; 0.091mmol) add (2S)-3-methyl-2-butylamine (128 μ L in the solution in DCM (1.5mL), MeOH (1.5mL) and acetic acid; 1.10mmol), and at room temperature stir 2h.(19mg 0.546mmol), and stirs 48h to add sodium borohydride then.Then this chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (12%) of 5.8mg.
LC/MS=m/z 511.2 [M+H] retention time: 1.76min
(50mg is 0.121mmol) at two _ alkane (1mL) and H to 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide 2Add in the solution among the O (0.4mL) potassium carbonate (74mg, 0.484mmol) with (4{ [(mesyl) amino] methyl } phenyl) boric acid (110mg, 0.50mmol).Stir this reactant mixture, and blast argon 5min, add subsequently chlorination (two-2-norborny phosphino-) (2-dimethylaminomethyl ferrocene-1-yl) close palladium (II) (7mg, 0.012mmol).Should react stirring then, and in microwave, heat 10min in 160 ℃.Mixture is concentrated, and prepare the HPLC purification, obtain the title compound (55%) of 34.3mg through Gilson.
LC/MS=m/z 519.4 [M+H] retention time: 1.77min
Embodiment 162:5-[3-({ [(1R)-1,2-dimethyl propyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D01751
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50mg; 0.114mmol) add (2R)-3-methyl-2-butylamine (160 μ L in the solution in DCM (1.5mL), MeOH (1.5mL) and acetic acid; 1.37mmol), and at room temperature stir 2h.(19mg 0.546mmol), and stirs 48h to add sodium borohydride then.Then chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (86%) of 50mg.
LC/MS=m/z 511.4 [M+H] retention time: 1.65min
Embodiment 163:5-(6-amino-2-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1; 3,2-dioxa bora ring penta-2-yl)-(83mg 0.18mmol) adds 6-bromo-2-pyridine amine (93mg to 1H-indole-7-Methanamide in the solution in two _ alkane (5mL); 0.54mmol), potassium carbonate (149mg, H 1.08mmol) 2O (1.5mL) solution and chlorination (two-2-norborny phosphino-) (2-dimethylaminomethyl ferrocene-1-yl) close palladium (II) (19mg, 0.031mmol).This is reflected in the microwave in 150 ℃ of heating 20min.Then reactant mixture is concentrated, and carry out the water extraction.Then organic layer is concentrated, and on Mass Directed AutoPrep HPLC purification, obtain the title compound (29%) of 22.3mg.
LC/MS=m/z 428.6 [M+H] retention time: 1.34min
Embodiment 164:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(1H-pyrazol-1-yl) phenyl]-1H-indole-7-Methanamide
Figure S2006800304481D01761
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (20mg, add in 0.048mmol) [3-(1H-pyrazol-1-yl) phenyl] boric acid (36mg, 0.193mmol), water (1.2mL) solution of two _ alkane (2.8mL) and potassium carbonate (20mg).In this mixture, add chloro-2-(dimethylaminomethyl)-ferrocene-1-base-(two norborny phosphino-s) close palladium (II) (3mg, 0.005mmol).With the mixture that generates in the CEM microwave in 160 ℃ of reaction 10min, under nitrogen current, concentrate (greenhouses) then in 80 ℃.With crude product at water (2mL) and CH 2CL 2Distribute (2mL).Separate each layer with the Hydrophobic glass material, and water layer is used CH 2CL 2(2 * 2mL) extractions.Mix organic layer, and under nitrogen current, concentrate in 80 ℃.(0.8mL) joins in the residue with dimethyl sulfoxine, with its supersound process 10 seconds, filters through tampon, and filters through 0.2 μ m filter then.Crude product is used Zorbax Eclipse XDB 61021.2 * 50mm column purification on Agilent MDAP, obtain the title compound (10%) of 2.3mg.
LC/MS=m/z 478.2 [M+H] retention time: 2.05min.
Embodiment 165:5-[4-(dimethylamino) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01762
In the CEM microwave tube, add 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (40mg, 0.097mmol), two _ alkane (2.8mL) and potassium carbonate (40mg, water 0.289mmol) (1.2mL) solution.In this mixture, add [4-(dimethylamino) phenyl] boric acid (65mg, 0.386mmol) with chloro-2-(dimethylaminomethyl)-ferrocene-1-base-(two norborny phosphino-s) close palladium (II) (1mg, 0.002mmol).Seal this bottle, and this is reflected in the CEM microwave in 160 ℃ of reaction 10min.Be reflected under the nitrogen current this concentrated in 80 ℃.Crude product is dissolved in the dimethyl sulfoxine (1mL), and through 1g silicon dioxide SPE column purification, with dimethyl sulfoxine (4mL) eluting.In Genevac,, and residue regenerate in dimethyl sulfoxine (1mL), and pass through the acrodisc filtration in 65 ℃ of following concentrated dimethyl sulfoxine 3h.Then the solution of crude product is gone up purification at Agilent MDAP (UV 214 selects).The product of purification is passed through polymer-bonded carbonate SPE post, obtain the title compound (6.2%) of 2.7mg.
LC/MS=m/z 455.2 [M+H] retention time: 1.71min.
Embodiment 166:5-(3-aminophenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01771
In the CEM microwave tube, add 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (40mg, 0.0965mmol), potassium carbonate (80mg, 0.578mmol) with (3-aminophenyl) boric acid sulfate (145mg, 0.386mmol).In mixture water-soluble (1.2mL) and two _ alkane (2.8mL), and add chloro-2-(dimethylaminomethyl)-ferrocene-1-base-(two norborny phosphino-s) close palladium (II) (1mg, 0.002mmol).Then mixture is reacted 10min in 150 ℃ in the CEM microwave.Add ethyl acetate (2mL), and separate each layer.(1 * 2mL) washes with ethyl acetate with water layer.Mix organic layer, under nitrogen current, concentrate, and be dissolved in dimethyl sulfoxine (0.89mL) and the trifluoroacetic acid (0.15mL).With solution purification on Agilent MDAP of this crude product, use 30%CH 3CN/H 2O (0.1%TFA) is to 70%CH 3CN/H 2The linear gradient of O (0.1%TFA) is with 20mL/min eluting 9min.In the HPLC fraction that contains product, add saturated K 2CO 3The sodium hydroxide solution (1mL) of solution (1mL), 1M and ethyl acetate (2mL).Separate each layer, and (2 * 2mL) extract with ethyl acetate with water layer.Mix organic layer, filter, and under nitrogen current, concentrate, obtain the title compound (36%) of 14.9mg through the magnesium sulfate filler.
LC/MS=m/z 427.2 [M+H] retention time: 1.39min.
Embodiment 167:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-methyl isophthalic acid-pyrrolidinyl) methyl]-2-thienyl }-1H-indole-7-Methanamide
Figure S2006800304481D01781
Be used to prepare 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-methyl isophthalic acid-pyrrolidinyl) methyl]-2-thienyl }-{ 5-[(2-methyl isophthalic acid-pyrrolidinyl) methyl]-2-thienyl } boric acid of 1H-indole-7-Methanamide is to use step as follows to divide other three batches to prepare:
First: in 2-dram bottle, with NaBH (OAc) 3(271mg, 1.28mmol), (0.043mL 0.42mmol) joins (5-formoxyl-2-thienyl) boric acid (100mg, CH 0.64mmol) for HOAc (0.07mL) and 2-crassitude 2Cl 2(4mL) in the solution.Seal this bottle, and should react and at room temperature stir 15h.Reactant mixture is directly loaded on the 2g SCX post (using the MeOH balance in advance), use the NH of MeOH (12mL) and 2M successively 3/ MeOH solution (8mL) eluting.The fraction that will contain this boric acid crude product is at N 2Air-flow concentrates down, and dry under fine vacuum, obtains the crude product of 45mg.Crude product is dissolved in saturated NaHCO 3(2mL), and with EtOAc (3 * 2mL) extractions obtain bullion { 5-[(2-methyl isophthalic acid-pyrrolidinyl) the methyl]-2-thienyl } boric acid of 6.6mg.
Second batch: in 2-dram bottle, with NaBH (OAc) 3(271mg, 1.28mmol), (0.043mL, (100mg is 0.64mmol) at 1: 1 CH 0.42mmol) to join (5-formoxyl-2-thienyl) boric acid for HOAc (0.07mL) and 2-crassitude 2Cl 2In the solution among the/MeOH (4mL).Seal this bottle, and should react and at room temperature stir 15h.Reactant mixture is directly loaded on the 2g SCX post (using the MeOH balance in advance), use the NH of MeOH (12mL) and 2M successively 3/ MeOH solution (8mL) eluting.The fraction that will contain this boric acid crude product is at N 2Air-flow concentrates down, and dry under fine vacuum, obtains the crude product of 45mg.Crude product is dissolved in saturated NaHCO 3(2mL), and with EtOAc (3 * 2mL) extractions obtain bullion { 5-[(2-methyl isophthalic acid-pyrrolidinyl) the methyl]-2-thienyl } boric acid of 5mg.
The 3rd batch: in 2-dram bottle, (0.033mL, (50mg is in MeOH 0.32mmol) (1mL) solution 0.32mmol) to join (5-formoxyl-2-thienyl) boric acid with the 2-crassitude.Seal this bottle, and should react and at room temperature stir 2h.Add NaCNBH 3(40mg 0.64mol), and continues to stir 19h.Reactant mixture is directly loaded on the 2g SCX post (using the MeOH balance in advance), use the NH of MeOH (12mL) and 2M successively 3/ MeOH solution (9mL) eluting.The fraction that will contain this boric acid crude product is at N 2Air-flow concentrates down, and dry under fine vacuum, obtains the crude product of 45mg.Crude product is dissolved in saturated NaHCO 3(2mL), and with EtOAc (3 * 2mL) extractions obtain bullion { 5-[(2-methyl isophthalic acid-pyrrolidinyl) the methyl]-2-thienyl } boric acid of 7.8mg.The thick boric acid of above-mentioned three reactions is mixed, and be used for preparing 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-methyl isophthalic acid-pyrrolidinyl) methyl]-2-thienyl-1H-indole-7-Methanamide (is 19mg with three batches of { 5-[(2-methyl isophthalic acid-pyrrolidinyl) methyl]-2-thienyl } mixed final weights of boric acid).
With 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (36mg; 0.0862mmol), { 5-[(2-methyl isophthalic acid-pyrrolidinyl) methyl]-2-thienyl } boric acid (19mg; 0.0862mmol) and potassium carbonate (71mg, solution 0.517mmol) mixes in the CEM microwave tube.In this mixture, add entry (0.25mL), two _ alkane (0.75mL) and four (triphenylphosphines) close palladium (0) (10mg, 0.009mmol).Seal this bottle, and in the CEM microwave, react 20min in 150 ℃.In this reaction, add four (triphenylphosphines) close palladium (0) (10mg, 0.009mmol), and in microwave in 150 ℃ the reaction 20min.Adding four other (triphenylphosphines) closes palladium (0) (10mg 0.009mmol), and is reflected in the CEM microwave this in 150 ℃ of other 20min of heating.(use 3mL H through 2g SCX post 2The O pre-balance) filter reaction mixture, the NH of water (3mL), MeOH (9mL) and 2M successively 3/ MeOH solution (9mL) eluting.The fraction that will contain crude product in solution concentrates under nitrogen current, and residue is dissolved among the DMSO (3mL).(zorbax Eclipse XDB-C18 post: 21.2 * 50mm) go up and carry out purification with three other injections of branch (each injects 1mL), use 10%CH with 20mL/min at Agilent MDAP with the DMSO solution of this crude product 3CN/H 2O (0.1%TFA) eluting 1min uses 10%CH then 3CN/H 2O (0.1%TFA) is to 95%CH 3CN/H 2The linear gradient elution 8min of O (0.1%TFA), and under ultimate density, kept 30 seconds.Through the 500mg Pharmasil CHQAX post (ammonium hydroxide that polymer combines; United Chemical Technologies) filters two fraction containing product removing TFA (2 posts that each fraction is used), and under nitrogen current, concentrate in 40 ℃, obtain the title compound (29.3%) of 13mg.
LC/MS=m/z 515.6 [M+H] retention time: 1.62min.
Embodiment 168:5-{5-[(ethylamino) methyl]-2-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01801
Be used for preparing 5-{5-[(ethylamino) methyl]-2-thienyl }-{ 5-[(ethylamino) methyl]-2-thienyl } boric acid of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide is according to being prepared as follows: at 2-dram bottle; THF solution (0.16mL with 2M ethamine; 0.32mmol) (50mg is in MeOH 0.32mmol) (1mL) solution to join (5-formoxyl-2-thienyl) boric acid.Seal this bottle, and should react and at room temperature stir 2h.Add NaCNBH 3(40mg 0.64mmol), and continues to stir 17h.Through 2g SCX post (with the MeOH pre-balance of 3mL) filter reaction mixture, use the NH of MeOH (6mL) and 2M successively 3/ MeOH solution (9mL) eluting.With NH 3/ MeOH fraction concentrates under nitrogen current, obtains bullion { 5-[(ethylamino) the methyl]-2-thienyl } boric acid of 47mg.
To containing { 5-[(ethylamino) methyl]-2-thienyl } boric acid (47mg; 0.254mmol) the CEM microwave tube in add 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (80mg; 0.193mmol), potassium carbonate (160mg, 1.16mmol), two _ alkane (1.5mL), H 2O (0.5mL) and four (triphenylphosphines) close palladium (0) (5mg, 0.004mmol).This is reflected in the CEM microwave in 150 ℃ of heating 30min.(this operation stops before 30min owing to accumulated over-drastic pressure).Through 2gSCX post (with 3mL MeOH pre-balance) filter reaction mixture, use H successively 2The NH of O (3mL), MeOH (9mL) and 2M 3/ MeOH solution (6mL) eluting.With NH 3/ MeOH fraction is dry under 40 ℃ under nitrogen current, and crude product is dissolved in the dimethyl sulfoxine (1mL), and (Zorbax Eclipse XDB-C18 post: 21.2 * 50mm) go up purification, use 10%CH with 20mL/min at AgilentMDAP 3CN/H 2O (0.1%TFA) eluting 1min uses 10%CH then 3CN/H 2O (0.1%TFA) is to 95%CH 3CN/H 2The linear gradient elution 8min of O (0.1%TFA), and under ultimate density, kept 30 seconds.Through the 500mg Pharmasil CHQAX post (ammonium hydroxide that polymer combines; UnitedChemical Technologies) filters the fraction contain product removing TFA (2 posts that each fraction is used), and under nitrogen current, concentrate in 60 ℃, obtain the title compound (10%) of 8.8mg.
LC/MS=m/z 429.8 [M+H] retention time: 1.25min.
Embodiment 169:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(1-Methylethyl) amino] methyl }-the 2-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D01811
According to preparation 5-{5-[(ethylamino) methyl]-2-thienyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), 2-aminopropane. (0.027mL, 0.32mmol) and NaCNBH 3(40mg, 0.64mmol) reaction obtain bullion (5-{ [(1-Methylethyl) amino] methyl }-2-thienyl) boric acid of 41mg.Make bullion (5-{ [(1-Methylethyl) amino] methyl }-2-thienyl) boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (80mg then; 0.193mmol), potassium carbonate (160mg; 1.16mmol) and four (triphenylphosphines) close palladium (0) (5mg; 0.004mmol) react, obtain the title compound (37%) of 74mg.
LC/MS=m/z 430.2 [M+H] retention time: 1.29min.
Embodiment 170:5-{5-[(cyclopropyl is amino) methyl]-2-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01812
According to preparation 5-{5-[(ethylamino) methyl]-2-thienyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), cyclopropylamine (0.022mL, 0.32mmol) and NaCNBH 3(40mg 0.64mmol) reacts, and obtains bullion { 5-[(cyclopropyl is amino) the methyl]-2-thienyl } boric acid of 63mg.Make bullion { 5-[(cyclopropyl is amino) methyl]-2-thienyl } boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (80mg then; 0.193mmol), potassium carbonate (160mg; 1.16mmol) and four (triphenylphosphines) close palladium (0) (5mg; 0.004mmol) reaction, obtain impure title compound.The title compound that this is impure is used Agilent MDAP purification once more, and separates into the form of free alkali according to the method shown in the embodiment 5, obtains the title compound (7.2%) of 6.8mg.
LC/MS=m/z 430.2 [M+H] retention time: 1.62min.
Embodiment 171:5-(5-{ [(2, the 2-dimethyl propyl) amino] methyl }-the 2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01821
According to preparation 5-{5-[(ethylamino) methyl]-2-thienyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), (2, the 2-dimethyl propyl) amine (0.037mL, 0.32mmol) and NaCNBH 3(40mg, 0.64mmol) reaction obtain bullion (5-{ [(2, the 2-dimethyl propyl) amino] methyl }-2-thienyl) boric acid of 73mg.(5-{ [(2 to make bullion then; The 2-dimethyl propyl) amino] methyl }-the 2-thienyl) boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (80mg; 0.193mmol), potassium carbonate (160mg; 1.16mmol) and four (triphenylphosphines) close palladium (0), and (5mg 0.004mmol) reacts, and obtains the title compound (21%) of 21mg.
LC/MS=m/z 430.2 [M+H] retention time: 1.45min.
Embodiment 172:5-(5-{ [(cyclopropyl methyl) amino] methyl }-the 2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01822
According to preparation 5-{5-[(ethylamino) methyl]-2-thienyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), (cyclopropyl methyl) amine (0.027mL, 0.32mmol) and NaCNBH 3(40mg, 0.64mmol) reaction obtain bullion (5-{ [(cyclopropyl methyl) amino] methyl }-2-thienyl) boric acid of 73mg.Make bullion (5-{ [(cyclopropyl methyl) amino] methyl }-2-thienyl) boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (80mg then; 0.193mmol), potassium carbonate (160mg; 1.16mmol) and four (triphenylphosphines) close palladium (0) (5mg; 0.004mmol) react, obtain the title compound (20%) of 19.1mg.
LC/MS=m/z 430.2 [M+H] retention time: 1.33min.
Embodiment 173:5-(5-{ [(cyclopropyl methyl) amino] methyl }-the 3-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01831
{ [5-(4,4,5 to be used to prepare (the cyclopropyl methyl) of 5-(5-{ [(cyclopropyl methyl) amino] methyl }-3-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-and the 3-pyridine radicals] methyl } amine is according to being prepared as follows: in 2-dram bottle; (0.011mL 0.129mmol) joins 5-(4,4 with (cyclopropyl methyl) amine; 5,5-tetramethyl-1,3; 2-dioxa bora ring penta-2-yl)-(30mg is in MeOH 0.129mmol) (1mL) solution for the 3-pyridine carboxaldehyde.Seal this bottle, and should react and at room temperature stir 17h.Add NaCNBH 3(16mg 0.258mmol), and continues to stir 30h.Through 2g SCX post (with the MeOH pre-balance of 3mL) filter reaction mixture, use the NH of MeOH (6mL) and 2M successively 3/ MeOH solution (9mL) eluting.With NH 3/ MeOH fraction concentrates under nitrogen current, obtains bullion (cyclopropyl methyl) { [5-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-3-pyridine radicals] methyl } amine of 21mg.
{ [5-(4,4,5 to containing (cyclopropyl methyl); 5-tetramethyl-1; 3,2-dioxa bora ring penta-2-yl)-the 3-pyridine radicals] methyl } (21mg adds 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (30mg to amine in CEM microwave tube 0.0725mmol); 0.0723mmol), two _ alkane (0.75mL), potassium carbonate (60mg, H 0.434mmol) 2O (0.25mL) solution and chloro-2-(dimethylaminomethyl)-ferrocene-1-base-(two norborny phosphino-s) close palladium (II) (4.4mg, 0.00723mmol).This is reflected in the CEM microwave in 150 ℃ of heating 30min.Through 2g SCX post (with the MeOH pre-balance of 3mL) filter reaction mixture, use H successively 2The NH of O (3mL), MeOH (6mL) and 2M 3/ MeOH solution (9mL) eluting.With NH 3/ MeOH fraction under nitrogen current in 40 ℃ of dryings, and at Agilent MDAP (Zorbax Eclipse XDB-C18 post: 21.2 * 50mm) go up purification, use 10%CH with 20mL/min 3CN/H 2O (0.1%TFA) eluting 1min uses 10%CH then 3CN/H 2O (0.1%TFA) is to 95%CH 3CN/H 2The linear gradient elution 8min of O (0.1%TFA), and under ultimate density, kept 30 seconds.Through the 2g Pharmasil CHQAX post (ammonium hydroxide that polymer combines; United Chemical Technologies) filter contain product fraction to remove TFA; And under nitrogen current, concentrate in 65 ℃; Obtain impure title compound, with its on Agilent MDAP according to as above purification once more, obtain the title compound (70%) of 25mg.
LC/MS=m/z 496.6 [M+H] retention time: 1.35min.
Embodiment 174:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ [2-(methoxyl group) ethyl] amino } methyl)-3-pyridine radicals]-1H-indole-7-Methanamide
Figure S2006800304481D01841
Conventional method according to preparation 5-(5-{ [(cyclopropyl methyl) amino] methyl }-3-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide makes 5-(4,4; 5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-3-pyridine carboxaldehyde (30mg; 0.129mmol), [2-(methoxyl group) ethyl] amine (0.011mL, 0.129mmol) and NaCNBH 3(16mg 0.258mmol) reacts, and obtains bullion [2-(methoxyl group) ethyl] { [5-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-3-pyridine radicals] methyl } amine of 19mg.{ [5-(4,4,5 to make bullion [2-(methoxyl group) ethyl] then; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-the 3-pyridine radicals] methyl } amine and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (30mg; 0.0723mmol), potassium carbonate (60mg; 0.434mmol) and chloro-2-(dimethylaminomethyl)-ferrocene-1-base-(two norborny phosphino-s) closes palladium (II), and (4.4mg 0.00723mmol) reacts, and obtains the title compound (46%) of 15mg.
LC/MS=m/z 500.6 [M+H] retention time: 1.52min.
Embodiment 175:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ [3-(methoxyl group) propyl group] amino } methyl)-3-pyridine radicals]-1H-indole-7-Methanamide
Figure S2006800304481D01851
Conventional method according to preparation 5-(5-{ [(cyclopropyl methyl) amino] methyl }-3-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide makes 5-(4,4; 5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-3-pyridine carboxaldehyde (30mg; 0.129mmol), [3-(methoxyl group) propyl group] amine (0.013mL, 0.129mmol) and NaCNBH 3(16mg 0.258mmol) reacts, and obtains bullion [3-(methoxyl group) propyl group] { [5-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-3-pyridine radicals] methyl } amine of 22mg.{ [5-(4,4,5 to make bullion [3-(methoxyl group) propyl group] then; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-the 3-pyridine radicals] methyl } amine and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (30mg; 0.0723mmol), potassium carbonate (60mg; 0.434mmol) and chloro-2-(dimethylaminomethyl)-ferrocene-1-base-(two norborny phosphino-s) closes palladium (II), and (4.4mg 0.00723mmol) reacts, and obtains the title compound (83%) of 31mg.
LC/MS=m/z 514.4 [M+H] retention time: 1.46min.
Embodiment 176:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(4-morpholinyl methyl)-3-pyridine radicals]-1H-indole-7-Methanamide
Figure S2006800304481D01852
Conventional method according to preparation 5-(5-{ [(cyclopropyl methyl) amino] methyl }-3-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide makes 5-(4,4; 5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-3-pyridine carboxaldehyde (30mg; 0.129mmol), morpholine (0.011mL, 0.129mmol) and NaCNBH 3(16mg 0.258mmol) reacts, and obtains bullion 4-{ [5-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-3-pyridine radicals] methyl of 28mg } morpholine.[5-(4,4,5 to make bullion 4-{ then; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-the 3-pyridine radicals] methyl } morpholine and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (30mg; 0.0723mmol), potassium carbonate (60mg; 0.434mmol) and chloro-2-(dimethylaminomethyl)-ferrocene-1-base-(two norborny phosphino-s) closes palladium (II), and (4.4mg 0.00723mmol) reacts, and obtains the title compound (43%) of 15.8mg.
LC/MS=m/z 512.2 [M+H] retention time: 1.38min.
Embodiment 177:5-{5-[(ethylamino) methyl]-3-pyridine radicals }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Conventional method according to preparation 5-(5-{ [(cyclopropyl methyl) amino] methyl }-3-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide makes 5-(4,4; 5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-3-pyridine carboxaldehyde (30mg; 0.129mmol), the THF solution of 2M ethamine (0.065mL, 0.129mmol) and NaCNBH 3(16mg 0.258mmol) reacts, and obtains bullion ethyl { [5-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-3-pyridine radicals] methyl } amine of 19mg.{ [5-(4,4,5 to make the bullion ethyl then; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-the 3-pyridine radicals] methyl } amine and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (30mg; 0.0723mmol), potassium carbonate (60mg; 0.434mmol) and chloro-2-(dimethylaminomethyl)-ferrocene-1-base-(two norborny phosphino-s) closes palladium (II), and (4.4mg 0.00723mmol) reacts, and obtains the title compound (36%) of 12.3mg.
LC/MS=m/z 470.4 [M+H] retention time: 1.44min.
Embodiment 178:5-{5-[(dimethylamino) methyl]-3-pyridine radicals }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Conventional method according to preparation 5-(5-{ [(cyclopropyl methyl) amino] methyl }-3-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide makes 5-(4,4; 5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-3-pyridine carboxaldehyde (30mg; 0.129mmol), the THF solution of 2M DMA (0.065mL, 0.129mmol) and NaCNBH 3(16mg 0.258mmol) reacts, and obtains bullion dimethyl { [5-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-3-pyridine radicals] methyl } amine of 23mg.{ [5-(4,4,5 to make the bullion dimethyl then; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-the 3-pyridine radicals] methyl } amine and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (30mg; 0.0723mmol), potassium carbonate (60mg; 0.434mmol) and chloro-2-(dimethylaminomethyl)-ferrocene-1-base-(two norborny phosphino-s) closes palladium (II), and (4.4mg 0.00723mmol) reacts, and obtains the title compound (16%) of 5.4mg.
LC/MS=m/z 470.6 [M+H] retention time: 1.35min.
Embodiment 179:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(2-methyl isophthalic acid-pyrrolidinyl) methyl]-3-pyridine radicals }-1H-indole-7-Methanamide
Figure S2006800304481D01871
Conventional method according to preparation 5-(5-{ [(cyclopropyl methyl) amino] methyl }-3-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide makes 5-(4,4; 5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-3-pyridine carboxaldehyde (30mg; 0.129mmol), the 2-crassitude (0.013mL, 0.129mmol) and NaCNBH 3(16mg 0.258mmol) reacts, and obtains bullion 3-[(2-methyl isophthalic acid-pyrrolidinyl) methyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) pyridine of 25mg.Make bullion 3-[(2-methyl isophthalic acid-pyrrolidinyl) methyl]-5-(4,4,5 then; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) pyridine and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (30mg; 0.0723mmol), potassium carbonate (60mg; 0.434mmol) and chloro-2-(dimethylaminomethyl)-ferrocene-1-base-(two norborny phosphino-s) closes palladium (II), and (4.4mg 0.00723mmol) reacts, and obtains the title compound (16%) of 6mg.
LC/MS=m/z 512.6 [M+H] retention time: 1.67min.
Embodiment 180:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl-propyl) amino] methyl }-the 3-pyridine radicals)-1H-indole-7-Methanamide
Figure S2006800304481D01881
Conventional method according to preparation 5-(5-{ [(cyclopropyl methyl) amino] methyl }-3-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide makes 5-(4,4; 5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-3-pyridine carboxaldehyde (30mg; 0.129mmol), isobutyl amine (0.013mL, 0.129mmol) and NaCNBH 3(16mg 0.258mmol) reacts, and obtains bullion (2-methyl-propyl) { [5-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-3-pyridine radicals] methyl } amine of 21mg.{ [5-(4,4,5 to make bullion (2-methyl-propyl) then; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-the 3-pyridine radicals] methyl } amine and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (30mg; 0.0723mmol), potassium carbonate (60mg; 0.434mmol) and chloro-2-(dimethylaminomethyl)-ferrocene-1-base-(two norborny phosphino-s) closes palladium (II), and (4.4mg 0.00723mmol) reacts, and obtains the title compound (35%) of 12.5mg.
LC/MS=m/z 498.2 [M+H] retention time: 1.38min.
Embodiment 181:5-(5-{ [(2, the 2-dimethyl propyl) amino] methyl }-the 3-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01882
Conventional method according to preparation 5-(5-{ [(cyclopropyl methyl) amino] methyl }-3-pyridine radicals)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide makes 5-(4,4; 5,5-tetramethyl-1,3; 2-dioxa bora ring penta-2-yl)-3-pyridine carboxaldehyde (30mg; 0.129mmol), (2, the 2-dimethyl propyl) amine (0.015mL, 0.129mmol) and NaCNBH 3(16mg 0.258mmol) reacts, and obtains bullion (2, the 2-dimethyl propyl) { [5-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-3-pyridine radicals] methyl } amine of 25mg.{ [5-(4,4 to make bullion (2, the 2-dimethyl propyl) then; 5,5-tetramethyl-1,3; 2-dioxa bora ring penta-2-yl)-and the 3-pyridine radicals] methyl } amine and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (30mg, 0.0723mmol), (60mg 0.434mmol) closes palladium (II) (4.4mg with chloro-2-(dimethylaminomethyl)-ferrocene-1-base-(two norborny phosphino-s) to potassium carbonate; 0.00723mmol) react, obtain the title compound (34%) of 12.7mg.
LC/MS=m/z 512.4 [M+H] retention time: 1.51min.
Embodiment 182:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl butyl) amino] methyl }-the 2-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D01891
{ 5-[(ethylamino) the methyl]-2-thienyl } boric acid that is used for preparing 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl butyl) amino] methyl }-2-thienyl)-1H-indole-7-Methanamide is according to being prepared as follows: at 2-dram bottle; With (5-formoxyl-2-thienyl) boric acid (50mg, (0.5mL) solution of MeOH 0.32mmol) and NaCNBH 3(40mg, MeOH 0.64mmol) (0.5mL) solution join (2-methyl butyl) amine (28mg, 0.32mmol) in.Seal this bottle, and should react and at room temperature stir 20h.Through 2g SCX post (with 3mL MeOH pre-balance) filter reaction mixture, use the NH of MeOH (6mL) and 2M successively 3/ MeOH solution (9mL) eluting.With NH 3/ MeOH fraction concentrates under nitrogen current, obtains bullion (5-{ [(2-methyl butyl) amino] methyl }-2-thienyl) boric acid of 43mg.
To contain bullion (5-{ [(2-methyl butyl) amino] methyl }-2-thienyl) boric acid (43mg, add in CEM microwave tube 0.188mmol) 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg, 0.942mmol), two _ alkane (1.5mL), H 2O (0.5mL) and four (triphenylphosphines) close palladium (0) (4mg, 0.003mmol).This is reflected in the CEM microwave in 150 ℃ of heating 30min.Through 2g SCX post (with the MeOH pre-balance of 3mL) filter reaction mixture, use H successively 2The NH of O (3mL), MeOH (9mL) and 2M 3/ MeOH solution (6mL) eluting.With NH 3/ MeOH fraction is dry under 40 ℃ under nitrogen current, and crude product is dissolved in the dimethyl sulfoxine (1mL), and (Zorbax Eclipse XDB-C18 post: 21.2 * 50mm) go up purification, use 10%CH with 20mL/min at Agilent MDAP 3CN/H 2O (0.1%TFA) eluting 1min uses 10%CH then 3CN/H 2O (0.1%TFA) is to 95%CH 3CN/H 2The linear gradient elution 8min of O (0.1%TFA), and under ultimate density, kept 30 seconds.Through the 2g Pharmasil CHQAX post (ammonium hydroxide that polymer combines; United Chemical Technologies) filters the fraction contain product removing TFA, and under nitrogen current, concentrate in 50 ℃, obtain the title compound (17%) of 16.2mg.
LC/MS=m/z 430.4 [M+H] retention time: 1.75min.
Embodiment 183:5-[5-({ [(1R)-1,2-dimethyl propyl] amino } methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01901
Conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl butyl) amino] methyl }-2-thienyl)-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), [(1R)-1; The 2-dimethyl propyl] and amine (28mg, 0.32mmol) and NaCNBH 3(40mg 0.64mmol) reacts, and obtains bullion [5-({ [(1R)-1,2-dimethyl propyl] amino } the methyl)-2-thienyl] boric acid of 30mg.Make then bullion [5-({ [(1R)-1, the 2-dimethyl propyl] amino } methyl)-2-thienyl] boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg, (4mg 0.003mmol) reacts, and obtains the title compound (30%) of 20.5mg 0.942mmol) to close palladium (0) with four (triphenylphosphines).
LC/MS=m/z 430.4 [M+H] retention time: 1.75min.
Embodiment 184:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(amyl group is amino) methyl]-2-thienyl }-1H-indole-7-Methanamide
Figure S2006800304481D01911
Conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl butyl) amino] methyl }-2-thienyl)-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), amylamine (29mg, 0.32mmol) and NaCNBH 3(40mg 0.64mmol) reacts, and obtains bullion { 5-[(amyl group is amino) the methyl]-2-thienyl } boric acid of 45mg.Make then bullion { 5-[(amyl group amino) methyl]-2-thienyl } boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg, (4mg 0.003mmol) reacts, and obtains the title compound (20%) of 20.7mg 0.942mmol) to close palladium (0) with four (triphenylphosphines).
LC/MS=m/z 430.6 [M+H] retention time: 1.75min.
Embodiment 185:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-([(2S)-and the 2-methyl butyl] amino } methyl)-the 2-thienyl]-1H-indole-7-Methanamide
Figure S2006800304481D01912
Conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl butyl) amino] methyl }-2-thienyl)-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), [(2S)-2-methyl butyl] amine (28mg, 0.32mmol) and NaCNBH 3(40mg, 0.64mmol) reaction obtain bullion [5-({ [(2S)-2-methyl butyl] amino } the methyl)-2-thienyl] boric acid of 43mg.Make then bullion [5-({ [(2S)-2-methyl butyl] amino } methyl)-2-thienyl] boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg, (4mg 0.003mmol) reacts, and obtains the title compound (39%) of 37.6mg 0.942mmol) to close palladium (0) with four (triphenylphosphines).
LC/MS=m/z 430 [M+H] retention time: 1.67min.
Embodiment 186:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(1-methyl butyl) amino] methyl }-the 2-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D01921
Conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl butyl) amino] methyl }-2-thienyl)-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), (1-methyl butyl) amine (29mg, 0.32mmol) and NaCNBH 3(40mg, 0.64mmol) reaction obtain bullion (5-{ [(1-methyl butyl) amino] methyl }-2-thienyl) boric acid of 43mg.Make then bullion (5-{ [(1-methyl butyl) amino] methyl }-2-thienyl) boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg, (4mg 0.003mmol) reacts, and obtains the title compound (60%) of 35.2mg 0.942mmol) to close palladium (0) with four (triphenylphosphines).
LC/MS=m/z 430 [M+H] retention time: 1.62min.
Embodiment 187:5-{5-[(butyl is amino) methyl]-2-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01922
Conventional method according to preparation 3-[1-(ethylsulfonyl)-4-second piperidyl]-5-(5-{ [(2-methyl butyl) amino] methyl }-2-thienyl)-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), butylamine (24mg, 0.32mmol) and NaCNBH 3(40mg 0.64mmol) reacts, and obtains bullion { 5-[(butyl is amino) the methyl]-2-thienyl } boric acid of 49mg.Make then bullion { 5-[(butyl amino) methyl]-2-thienyl } boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg, (4mg 0.003mmol) reacts, and obtains the title compound (24%) of 27.2mg 0.942mmol) to close palladium (0) with four (triphenylphosphines).
LC/MS=m/z 430 [M+H] retention time: 1.56min.
Embodiment 188:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ [2-(methoxyl group) ethyl] amino } methyl)-2-thienyl]-1H-indole-7-Methanamide
Figure S2006800304481D01931
Conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl butyl) amino] methyl }-2-thienyl)-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), [2-(methoxyl group) ethyl] amine (24mg, 0.32mmol) and NaCNBH 3(40mg 0.64mmol) reacts, and obtains bullion [5-({ [2-(methoxyl group) ethyl] amino } the methyl)-2-thienyl] boric acid of 42mg.Make then bullion [5-({ [2-(methoxyl group) ethyl] amino } methyl)-2-thienyl] boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg, (4mg, 0.003mmol) reaction obtains impure title compound 0.942mmol) to close palladium (0) with four (triphenylphosphines).Title compound that this is impure uses HPLC and handles at the ammonium hydroxide SPE shown in preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl butyl) amino] methyl }-2-thienyl)-1H-indole-7-Methanamide and carries out purification once more, obtains the title compound (15%) of 15mg.
LC/MS=m/z 430.2 [M+H] retention time: 1.33min.
Embodiment 189:5-{5-[(cyclopenta is amino) methyl]-2-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01932
Conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl butyl) amino] methyl }-2-thienyl)-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), Aminocyclopentane (28mg, 0.32mmol) and NaCNBH 3(40mg 0.64mmol) reacts, and obtains bullion { 5-[(cyclopenta is amino) the methyl]-2-thienyl } boric acid of 48mg.Make then bullion { 5-[(cyclopenta amino) methyl]-2-thienyl } boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg, (4mg 0.003mmol) reacts, and obtains the title compound (85%) of 93.5mg 0.942mmol) to close palladium (0) with four (triphenylphosphines).
LC/MS=m/z 430.4 [M+H] retention time: 1.64min.
Embodiment 190:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(3-methyl butyl) amino] methyl }-the 2-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D01941
Conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl butyl) amino] methyl }-2-thienyl)-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), (3-methyl butyl) amine (28mg, 0.32mmol) and NaCNBH 3(40mg, 0.64mmol) reaction obtain bullion (5-{ [(3-methyl butyl) amino] methyl }-2-thienyl) boric acid of 46mg.Make then bullion (5-{ [(3-methyl butyl) amino] methyl }-2-thienyl) boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg, (4mg 0.003mmol) reacts, and obtains the title compound (37%) of 38.3mg 0.942mmol) to close palladium (0) with four (triphenylphosphines).
LC/MS=m/z 430.4 [M+H] retention time: 1.75min.
Embodiment 191:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(1-Methylethyl) amino] methyl }-the 3-pyridine radicals)-1H-indole-7-Methanamide
{ [5-(4,4,5 to be used to prepare (the cyclopropyl methyl) of 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(1-Methylethyl) amino] methyl }-3-pyridine radicals)-1H-indole-7-Methanamide; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-and the 3-pyridine radicals] methyl } amine is according to being prepared as follows: in 2-dram bottle; (0.011mL 0.129mmol) joins 5-(4,4 with 2-aminopropane.; 5,5-tetramethyl-1,3; 2-dioxa bora ring penta-2-yl)-(30mg is in MeOH 0.129mmol) (1mL) solution for the 3-pyridine carboxaldehyde.Add NaCNBH then 3(16mg 0.258mmol), seals this bottle, and should react and at room temperature stir 24h.Through 2g SCX post (with the MeOH pre-balance of 3mL) filter reaction mixture, use the NH of MeOH (6mL) and 2M successively 3/ MeOH solution (9mL) eluting.With NH 3/ MeOH fraction concentrates under nitrogen current, obtains bullion (1-Methylethyl) { [5-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-3-pyridine radicals] methyl } amine of 22mg.
{ [5-(4 to containing (1-Methylethyl); 4,5,5-tetramethyl-1; 3; 2-dioxa bora ring penta-2-yl)-the 3-pyridine radicals] methyl amine (22mg, add in CEM microwave tube 0.080mmol) 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (50mg, 0.121mmol), K 2CO 3(100mg, 0.724mmol), two _ alkane (1.5mL), H 2O (0.5mL) and chloro-2-(dimethylaminomethyl)-ferrocene-1-base-(two norborny phosphino-s) close palladium (II) (7.3mg, 0.012mmol).This is reflected in the CEM microwave in 150 ℃ of heating 30min.Through 2g SCX post (with 3mL MeOH pre-balance) filter reaction mixture, use H successively 2The NH of O (3mL), MeOH (6mL) and 2M 3/ MeOH solution (9mL) eluting.With NH 3/ MeOH fraction under nitrogen current in 50 ℃ of dryings, and at Agilent MDAP (Zorbax Eclipse XDB-C18 post: 21.2 * 100mm) go up purification, use 10%CH with 20mL/min 3CN/H 2O (0.1%TFA) eluting 1min uses 10%CH then 3CN/H 2O (0.1%TFA) is to 95%CH 3CN/H 2The linear gradient elution 8min of O (0.1%TFA), and under ultimate density, kept 30 seconds.Through the 2g Pharmasil CHQAX post (ammonium hydroxide that polymer combines; United ChemicalTechnologies) filters the fraction contain product removing TFA, and under nitrogen current, concentrate in 50 ℃, obtain the title compound (70%) of 27.2mg.
LC/MS=m/z 484 [M+H] retention time: 1.25min.
Embodiment 192:5-(5-{ [(2-ethyl-butyl) amino] methyl }-the 2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
{ 5-[(ethylamino) the methyl]-2-thienyl } boric acid that is used for preparing 5-(5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide is according to being prepared as follows: at 2-dram bottle; With (5-formoxyl-2-thienyl) boric acid (50mg, (0.5mL) solution of MeOH 0.32mmol) and NaCNBH 3(40mg, MeOH 0.64mmol) (0.5mL) solution join (2-ethyl-butyl) amine (32mg, 0.32mmol) in.Seal this bottle, and should react and at room temperature stir 20h.Through 2g SCX post (with the MeOH pre-balance of 3mL) filter reaction mixture, use the NH of MeOH (6mL) and 2M successively 3/ MeOH solution (9mL) eluting.With NH 3/ MeOH fraction concentrates under nitrogen current, obtains bullion (5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl) boric acid of 48mg.
To containing bullion (5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl) boric acid (48mg; 0.199mmol) the CEM microwave tube in add 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, two _ alkane 0.157mmol) (1.75mL) solution, K 2CO 3(130mg, H 0.942mmol) 2O (0.25mL) solution and four (triphenylphosphines) close palladium (0) (9mg, 0.0079mmol).This is reflected in the CEM microwave in 150 ℃ of heating 30min.Through 2g SCX post (with 3mL MeOH pre-balance) filter reaction mixture, use the NH of MeOH (3mL) and 2M successively 3/ MeOH solution (9mL) eluting.With NH 3/ MeOH fraction in 50 ℃ of dryings, and is dissolved in crude product in the dimethyl sulfoxine (1.1mL) under nitrogen current, and (Zorbax Eclipse XDB-C18 post: 21.2 * 100mm) go up purification, use 10%CH with 20mL/min at Agilent MDAP 3CN/H 2O (0.1%TFA) eluting 1min uses 10%CH then 3CN/H 2O (0.1%TFA) is to 95%CH 3CN/H 2The linear gradient elution 8min of O (0.1%TFA), and under ultimate density, kept 30 seconds.Through the 2g Pharmasil CHQAX post (ammonium hydroxide that polymer combines; United Chemical Technologies) filters the fraction contain product removing TFA, and under nitrogen current, concentrate in 50 ℃, obtain impure title compound.According to as implied above this impure title compound is also carried out purification once more with the ammonium hydroxide post of free alkali on Agilent MDAP, obtain the title compound (10%) of 8.5mg.
LC/MS=m/z 430 [M+H] retention time: 1.72min.
Embodiment 193:5-[5-({ [3-(ethyoxyl) propyl group] amino } methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01971
Conventional method according to preparation 5-(5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), [3-(ethyoxyl) propyl group] amine (34mg, 0.32mmol) and NaCNBH 3(40mg 0.64mmol) reacts, and obtains bullion [5-({ [3-(ethyoxyl) propyl group] amino } the methyl)-2-thienyl] boric acid of 30mg.Make then bullion [5-({ [3-(ethyoxyl) propyl group] amino } methyl)-2-thienyl] boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg, (9mg 0.0079mmol) reacts, and obtains the title compound (10%) of 8.1mg 0.942mmol) to close palladium (0) with four (triphenylphosphines).
LC/MS=m/z 430 [M+H] retention time: 1.62min.
Embodiment 194:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ [3-(methoxyl group) propyl group] amino } methyl)-2-thienyl]-1H-indole-7-Methanamide
Conventional method according to preparation 5-(5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), [3-(methoxyl group) propyl group] amine (29mg, 0.32mmol) and NaCNBH 3(40mg 0.64mmol) reacts, and obtains bullion [5-({ [3-(methoxyl group) propyl group] amino } the methyl)-2-thienyl] boric acid of 30mg.Make then bullion [5-({ [3-(methoxyl group) propyl group] amino } methyl)-2-thienyl] boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg 0.942mmol) closes palladium (0) (9mg, 0.0079mmol) reaction with four (triphenylphosphines).Crude product used prepare the method purification shown in 5-(5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide once on Agilent MDAP, obtain the title compound (9%) of 7.6mg.
LC/MS=m/z 430 [M+H] retention time: 1.50min.
Embodiment 195:5-(5-{ [(cyclohexyl methyl) amino] methyl }-the 2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Conventional method according to preparation 5-(5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), (cyclohexyl methyl) amine (37mg, 0.32mmol) and NaCNBH 3(40mg, 0.64mmol) reaction obtain bullion (5-{ [(cyclohexyl methyl) amino] methyl }-2-thienyl) boric acid of 30mg.Make then bullion (5-{ [(cyclohexyl methyl) amino] methyl }-2-thienyl) boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg 0.942mmol) closes palladium (0) (9mng, 0.0079mmol) reaction with four (triphenylphosphines).Crude product used on AgilentMDAP prepare the method purification shown in 5-(5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide once.The product of purification is washed with hexane/EtOAc/MeOH mixture (2.5mL) of 20: 4: 1, be dissolved among the EtOAc (2mL), and with saturated K 2CO 3(1mL) wash.Concentrate this organic layer, obtain the title compound (6%) of 4.7mg.
LC/MS=m/z 430 [M+H] retention time: 1.82min.
Embodiment 196:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[({ 3-[(1-Methylethyl) oxygen base] propyl group } amino) methyl]-2-thienyl }-1H-indole-7-Methanamide
Figure S2006800304481D01991
Conventional method according to preparation 5-(5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), { 3-[(1-Methylethyl) oxygen base] propyl group } amine (38mg, 0.32mmol) and NaCNBH 3(40mg 0.64mmol) reacts, and obtains bullion { 5-[({ 3-[(1-Methylethyl) oxygen base] propyl group } amino) the methyl]-2-thienyl } boric acid of 30mg.Make then bullion { 5-[({ 3-[(1-Methylethyl) oxygen base] propyl group } amino) methyl]-2-thienyl } boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg 0.942mmol) closes palladium (0) (9mg, 0.0079mmol) reaction with four (triphenylphosphines).According to shown in preparation 5-(5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide behind twice of purification on the Agilent MDAP; Impure title compound is washed with hexane/EtOAc/MeOH mixture (2.5mL) of 20: 4: 1, obtained the title compound (9%) of 7.6mg.
LC/MS=m/z 430 [M+H] retention time: 1.62min.
Embodiment 197:5-[5-({ [2-(ethyoxyl) ethyl] amino } methyl)-2-thienyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D01992
Conventional method according to preparation 5-(5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), [2-(ethyoxyl) ethyl] amine (30mg, 0.32mmol) and NaCNBH 3(40mg 0.64mmol) reacts, and obtains bullion [5-({ [2-(ethyoxyl) ethyl] amino } the methyl)-2-thienyl] boric acid of 30mg.Make then bullion [5-({ [2-(ethyoxyl) ethyl] amino } methyl)-2-thienyl] boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg 0.942mmol) closes palladium (0) (9mg, 0.0079mmol) reaction with four (triphenylphosphines).Crude product used prepare the method purification on Agilent MDAP shown in 5-(5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide and once obtain the title compound (7%) of 6mg.
LC/MS=m/z 430 [M+H] retention time: 1.66min.
Embodiment 198:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ [3-(propoxyl group) propyl group] amino } methyl)-2-thienyl]-1H-indole-7-Methanamide
Figure S2006800304481D02001
Conventional method according to preparation 5-(5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol); [3-(propoxyl group) propyl group] amine (38mg, 0.32mmol) and NaCNBH 3(40mg 0.64mmol) reacts, and obtains bullion [5-({ [3-(propoxyl group) propyl group] amino } the methyl)-2-thienyl] boric acid of 30mg.Make then bullion [5-({ [3-(propoxyl group) propyl group] amino } methyl)-2-thienyl] boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg 0.942mmol) closes palladium (0) (9mg, 0.0079mmol) reaction with four (triphenylphosphines).Crude product used prepare twice of the purification on Agilent MDAP of the method shown in 5-(5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide.The product of purification is washed with hexane/EtOAc/MeOH mixture (2.5mL) of 20: 4: 1, be dissolved among the EtOAc (2mL), and with saturated K 2CO 3(1mL) wash.Concentrate this organic layer, obtain the title compound (2%) of 1.4mg.
LC/MS=m/z 430 [M+H] retention time: 1.66min.
Embodiment 199:5-(5-{ [(3, the 3-dimethylbutyl) amino] methyl }-the 2-thienyl)-3 acyl groups)-the 4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D02011
Conventional method according to preparation 5-(5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), (3; The 3-dimethylbutyl) amine (32mg, 0.32mmol) and NaCNBH 3(40mg, 0.64mmol) reaction obtain bullion (5-{ [(3, the 3-dimethylbutyl) amino] methyl }-2-thienyl) boric acid of 30mg.Make then bullion (5-{ [(3, the 3-dimethylbutyl) amino] methyl }-2-thienyl) boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg, (9mg 0.0079mmol) reacts, and obtains the title compound (5%) of 4.5mg 0.942mmol) to close palladium (0) with four (triphenylphosphines).
LC/MS=m/z 430 [M+H] retention time: 1.79min.
Embodiment 200:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ [(1S)-12,2-trimethyl propyl group] amino } methyl)-2-thienyl]-1H-indole-7-Methanamide
Figure S2006800304481D02012
Conventional method according to preparation 5-(5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), [(1S)-1; 2,2-trimethyl propyl group] and amine (32mg, 0.32mmol) and NaCNBH 3(40mg 0.64mmol) reacts, and obtains bullion [5-({ [(1S)-1,2,2-trimethyl propyl group] amino } the methyl)-2-thienyl] boric acid of 30mg.Make then bullion [5-({ [(1S)-1,2,2-trimethyl propyl group] amino } methyl)-2-thienyl] boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg, (9mg 0.0079mmol) reacts, and obtains the title compound (12%) of 10.3mg 0.942mmol) to close palladium (0) with four (triphenylphosphines).
LC/MS=m/z 430 [M+H] retention time: 1.62min.
Embodiment 201:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(hexyl is amino) methyl]-2-thienyl }-1H-indole-7-Methanamide
Figure S2006800304481D02021
Conventional method according to preparation 5-(5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; Make (5-formoxyl-2-thienyl) boric acid (50mg; 0.32mmol), hexylamine (33mg, 0.32mmol) and NaCNBH 3(40mg 0.64mmol) reacts, and obtains bullion { 5-[(hexyl is amino) the methyl]-2-thienyl } boric acid of 30mg.Make then bullion { 5-[(hexyl amino) methyl]-2-thienyl } boric acid and 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (65mg, 0.157mmol), K 2CO 3(130mg 0.942mmol) closes palladium (0) (9mg, 0.0079mmol) reaction with four (triphenylphosphines).Crude product used prepare the method purification shown in 5-(5-{ [(2-ethyl-butyl) amino] methyl }-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide once on Agilent MDAP, obtain the title compound (16%) of 13mg.
LC/MS=m/z 430.6 [M+H] retention time: 1.92min.
Embodiment 202:5-[2-(dimethylamino)-4-pyridine radicals]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02022
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-fluoro-4-pyridine radicals)-1H-indole-7-Methanamide (40mg, add in 0.093mmol) DMA (1mL, 0.015mmol) and DMF (0.3mL).The mixture that generates is reacted 1h in 180 ℃ in microwave.Evaporate all solvents, and then mixture is prepared the HPLC purification through Gilson, obtain the title compound (34.4%) of 18.2mg.
LC/MS=m/z 456.2 [M+H] retention time: 1.54min.
Embodiment 203:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(1-pyrrolidinyl)-4-pyridine radicals]-1H-indole-7-Methanamide trifluoroacetate
Title compound is the conventional method according to preparation 5-[2-(dimethylamino)-4-pyridine radicals]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; Replace DMA to prepare with pyrrolidine (1mL), obtain the title compound (27.1%) of 48.9mg.
LC/MS=m/z 482.2 [M+H] retention time: 1.62min.
Embodiment 204:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(4-morpholinyl)-4-pyridine radicals]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02032
Title compound is the conventional method according to preparation 5-[2-(dimethylamino)-4-pyridine radicals]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; Replace DMA to prepare with morpholine (1mL), obtain the title compound (21.1%) of 12mg.
LC/MS=m/z 498.6 [M+H] retention time: 1.47min.
Embodiment 205:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{2-[(2-methyl-propyl) amino]-4-pyridine radicals }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02041
Title compound is the conventional method according to preparation 5-[2-(dimethylamino)-4-pyridine radicals]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; Replace DMA to prepare with 2-methyl isophthalic acid-propylamine (1mL), obtain the title compound (20%) of 11.1mg.
LC/MS=m/z 484.2 [M+H] retention time: 1.68min.
Embodiment 206:5-{2-[(2, the 2-dimethyl propyl) amino]-4-pyridine radicals }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02042
Title compound is the conventional method according to preparation 5-[2-(dimethylamino)-4-pyridine radicals]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With 2; 2-dimethyl-1-propylamine (1mL) replaces DMA to prepare, and obtains the title compound (15.8%) of 9mg.
LC/MS=m/z 498.6 [M+H] retention time: 1.75min.
Embodiment 207:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(propyl group is amino)-4-pyridine radicals]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02051
Title compound is the conventional method according to preparation 5-[2-(dimethylamino)-4-pyridine radicals]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; Replace DMA to prepare with propylamine (1mL), obtain the title compound (33.5%) of 18.2mg.
LC/MS=m/z 470.4 [M+H] retention time: 1.57min.
Embodiment 208:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-[(methylamino) methyl]-2-thienyl }-1H-indole-7-Methanamide trifluoroacetate
(45mg 0.1mmol) adds 2M methylamine (0.5mL) in the solution in dichloromethane (2mL) and methanol (1mL) to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl-2-thienyl)-1H-indole-7-Methanamide.Reactant mixture is at room temperature stirred 5h, add subsequently Sodium Borohydride (37.83mg, 1mmol).With the mixture that generates stirred overnight at room temperature.Concentrated solvent, and use Gilson to prepare the HPLC purification, obtain the title compound (29.2%) of 16.8mg.
LC/MS=m/z 461.6 [M+H] retention time: 1.40min.
Embodiment 209:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(1-pyrrolidinyl methyl)-2-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02061
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-[(methylamino) methyl]-2-thienyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; Replace the 2M methylamine to prepare with pyrrolidine (0.083mL), obtain the title compound (24.1%) of 14.8mg.
LC/MS=m/z 470.4 [M+H] retention time: 1.57min.
Embodiment 210:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(2-methyl-propyl) amino] methyl }-the 2-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02062
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-[(methylamino) methyl]-2-thienyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; Replace the 2M methylamine to prepare with 2-methyl isophthalic acid-propylamine (0.1mL), obtain the title compound (25%) of 15.4mg.
LC/MS=m/z 503.2 [M+H] retention time: 1.42min.
Embodiment 211:5-{4-[(dimethylamino) methyl]-2-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02071
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-[(methylamino) methyl]-2-thienyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; Replace the 2M methylamine to prepare with DMA (0.5mL), obtain the title compound (15.3%) of 9mg.
LC/MS=m/z 475.2 [M+H] retention time: 1.27min.
Embodiment 212:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(1S)-1-(1-pyrrolidinyl) ethyl]-the 3-thienyl }-1H-indole-7-Methanamide
Figure S2006800304481D02072
To 5-(5-acetyl group-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (10mg, add in 0.02mmol) sodium cyanoborohydride (7.5mg, 0.12mmol) and pyrrolidine (0.03mL, 0.30mmol).The mixture that generates is reacted 40min in 150 ℃ in microwave.Evaporate all solvents, and crude product is distributed between ethyl acetate (1.5mL) and 1M sodium hydroxide (0.2mL).Should react through the SFC purification, obtain the title compound of 100% chiral purity.
LC/MS=m/z 515.4 [M+H] retention time: 1.54min.
Embodiment 213:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(1R)-1-(1-pyrrolidinyl) ethyl]-the 3-thienyl }-1H-indole-7-Methanamide
To 5-(5-acetyl group-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (10mg, add in 0.02mmol) sodium cyanoborohydride (7.5mg, 0.12mmol) and pyrrolidine (0.03mL, 0.30mmol).The mixture that generates is reacted 40min in 150 ℃ in microwave.Evaporate all solvents, and crude product is distributed between ethyl acetate (1.5mL) and 1M sodium hydroxide (0.2mL).Should react through the SFC purification, obtain the title compound of 100% chiral purity.
LC/MS=m/z 515.4 [M+H] retention time: 1.54min.
Embodiment 214:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-({ [3-(methoxyl group) propyl group] amino } methyl)-2-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02082
To 5-[(1Z)-1-(vinyl sulfenyl)-4-oxo-1-butylene-1-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (45mg; 0.1mmol) add in the solution in dichloromethane (2mL) and methanol (1mL) 3 acetic acid and 3-(methoxyl group)-1-propylamine (89.14mg, 1mmol).The mixture of this generation is stirred 6h, add subsequently sodium borohydride (37.83mg, 1mmol).This is reacted stirred overnight at room temperature.Evaporating solvent, and then mixture is prepared the HPLC purification through Gilson, obtain the title compound (37.5%) of 23.7mg.
LC/MS=m/z 519.4 [M+H] retention time: 1.69min.
Embodiment 215:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-((2S)-and 2-[(methoxyl group) methyl]-1-pyrrolidinyl } methyl)-the 2-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02091
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-({ [3-(methoxyl group) propyl group] amino } methyl)-2-thienyl]-1H-indole-7-Methanamide trifluoroacetate; With (2S)-2-[(methoxyl group) methyl] pyrrolidine (115.18mg; 1mmol) replace 3-(methoxyl group)-1-propylamine to prepare, obtain the title compound (4.6%) of 3mg.
LC/MS=m/z 545.2 [M+H] retention time: 1.78min.
Embodiment 216:5-(4-{ [(2R, 5R)-2,5-dimethyl-1-pyrrolidinyl] methyl }-the 2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02092
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-({ [3-(methoxyl group) propyl group] amino } methyl)-2-thienyl]-1H-indole-7-Methanamide trifluoroacetate; With (2R; 5R)-2; (64.3mg 1mmol) replaces 3-(methoxyl group)-1-propylamine to prepare to the 5-dimethyl pyrrolidine, obtains the title compound (10%) of 6.4mg.
LC/MS=m/z 529.4 [M+H] retention time: 1.69min.
Embodiment 217:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2S)-and 2-methyl isophthalic acid-pyrrolidinyl] methyl }-the 3-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D02101
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (600mg; 1.348mmol) add in the solution in dimethyl sulfoxine (10mL) 20 acetic acid with (2S)-1; The 2-dimethyl pyrrolidine (1.37mL, 13.483mmol).The mixture of this generation is at room temperature stirred 6h, add subsequently sodium triacetoxy borohydride (2.858g, 13.483mmol).This is reacted stirred overnight at room temperature, then through the SFC purification.This chemical compound is left through RTP CASS component.The level of enantiomer #1 is divided into 99.7% chiral purity, obtains the title compound (17.3%) of 119.9mg.
LC/MS=m/z 515.4 [M+H] retention time: 1.56min.
Embodiment 218:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2R)-and 2-methyl isophthalic acid-pyrrolidinyl] methyl }-the 3-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D02102
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (600mg, 1.35mmol) add in the solution in dimethyl sulfoxine (10mL) 20 acetic acid and 2-crassitude (1.37mL, 13.5mmol).The mixture of this generation is at room temperature stirred 6h, add subsequently sodium triacetoxy borohydride (2.86g, 13.5mmol).This is reacted stirred overnight at room temperature, prepare the HPLC purification through Gilson then.Separate this chemical compound then, obtain the title compound of 98.6% chiral purity.
LC/MS=m/z 515.4 [M+H] retention time: 1.56min.
Embodiment 219:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[1-(1-pyrrolidinyl) propyl group]-3-thienyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02111
(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-(250mg is 0.541mmol) at two _ alkane (4.5mL) and H for 1H-indole-7-Methanamide to 3-[1-(ethylsulfonyl)-4-piperidyl]-5- 2Add in the solution among the O (1.5mL) 1-(4-bromo-2-thienyl)-1-acetone (356mg, 1.62mmol), potassium carbonate (447mg, 3.24mmol) with four (triphenylphosphines) close palladium (0) (64mg, 0.055mmol).This is reflected under 150 ℃, carries out 20min in the microwave.Use EtOAc and H 2O carries out aqueous solution to be handled, and adds MeOH (20mL) subsequently to crude product.Required product is precipitated out, and filters, and obtains 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-propiono-3-thienyl)-1H-indole-7-Methanamide (43%) of 110mg.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-propiono-3-thienyl)-1H-indole-7-Methanamide (60mg; 0.13mmol) the middle sodium cyanoborohydride (49.2mg that adds; 0.78mmol), pyrrolidine (0.2mL, 1.95mmol), ethanol (3mL) and acetic acid (0.4mL).The mixture that generates is reacted 30min in 150 ℃ in microwave.Evaporate all solvents, and then mixture is prepared the HPLC purification through Gilson, obtain the title compound (14.4%) of 12mg.
LC/MS=m/z 529.4 [M+H] retention time: 1.65min.
Embodiment 220:5-{5-[(dimethylamino) methyl]-3-thienyl }-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02121
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg, 0.11mmol) add in the solution in dimethyl sulfoxine (2mL) 3 acetic acid and trimethylamine (0.55mL, 1.1mmol).The mixture of this generation is at room temperature stirred 6h, add subsequently sodium triacetoxy borohydride (233mg, 1mmol).With its stirred overnight at room temperature, prepare the HPLC purification through Gilson then then, obtain the title compound (44.3%) of 29.4mg.
LC/MS=m/z 489.4 [M+H] retention time: 1.32min.
Embodiment 221:5-[5-(amino methyl)-3-thienyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.11mmol) add ammonium acetate (84.7mg in the solution in dichloromethane (2mL) and methanol (1mL); 1.1mmol) and sodium cyanoborohydride (4.84mg, 0.077mmol).With the mixture that generates stirred overnight at room temperature.Evaporate all solvents, and then mixture is prepared the HPLC purification through Gilson, obtain the title compound (2.9%) of 1.8mg.
LC/MS=m/z 447.2 [M+H] retention time: 1.53min.
Embodiment 222:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{2-[(2-methyl-propyl) amino] ethyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02131
To [2-(4-bromo-2-thienyl) ethyl] amine (100mg, 0.48mmol) add in the solution in DCM (2.0mL) and MeOH (1.0mL) acetic acid (3) and 2 methyl propanal (105mg, 1.44mmol).To react stirred overnight at room temperature, add subsequently sodium borohydride (53.3mg, 1.44mmol).1h is carried out in this reaction, and use EtOAc and saline treatment then.Dry then organic layer also concentrates, and obtains [2-(4-bromo-2-thienyl) ethyl] (1-Methylethyl) amine (64%) of 80mg.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-1H-indole-7-Methanamide (139mg; 0.3mmol) add [2-(4-bromo-2-thienyl) ethyl] (1-Methylethyl) amine (50mg in the solution in two _ alkane (3mL) and water (1mL); 0.2mmol), potassium carbonate (82.8mg, 0.6mmol) with four (triphenylphosphines) close palladium (0) (22mg, 0.019mmol).The mixture that generates is reacted 20min in 150 ℃ in microwave.Evaporate all solvents, and then mixture is prepared the HPLC purification through Gilson, obtain the title compound (9.5%) of 18mg.
LC/MS=m/z 517.2 [M+H] retention time: 1.68min.
Embodiment 223:5-{5-[2-(dimethylamino) ethyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02141
(100mg 0.48mmol) adds the H of acetic acid (3) and 37% formaldehyde in the solution in DCM (2.0mL) and MeOH (1.0mL) to [2-(4-bromo-2-thienyl) ethyl] amine 2O solution (105mg, 1.44mmol).To react stirred overnight at room temperature, add subsequently sodium borohydride (53.3mg, 1.44mmol).1h is carried out in this reaction, and use EtOAc and saline treatment then.Dry then organic layer also concentrates, and obtains 2-(4-bromo-2-thienyl)-N of 50mg, N-dimethyl amine (44%).
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-1H-indole-7-Methanamide (139mg; 0.345mmol) add 2-(4-bromo-2-thienyl)-N in the solution in two _ alkane (3mL) and water (1mL), and the N-dimethyl amine (50mg, 0.23mmol), potassium carbonate (82.8mg; 0.69mmol) and four (triphenylphosphines) close palladium (0) (22mg, 0.019mmol).The mixture that generates is reacted 20min in 150 ℃ in microwave.Evaporate all solvents, and then mixture is prepared the HPLC purification through Gilson, obtain the title compound (5.8%) of 12mg.
LC/MS=m/z 489.2 [M+H] retention time: 1.54min.
Embodiment 224:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[6-(1-pyrrolidinyl)-3-pyridine radicals]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02142
(110mg is 0.27mmol) at two _ alkane (2.0mL) and H to 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide 2Add in the solution among the O (0.7mL) (6-fluoro-3-pyridine radicals) boric acid (151mg, 1.08mmol), potassium carbonate (298mg, 2.16mmol) with four (triphenylphosphines) close palladium (0) (31mg, 0.026mmol).This is reflected in the microwave carries out 20min in 150 ℃.Should react then, and, obtain 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(6-fluoro-3-pyridine radicals)-1H-indole-7-Methanamide (43%) of 50mg through purified by flash chromatography with EtOAc and saline treatment.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(6-fluoro-3-pyridine radicals)-1H-indole-7-Methanamide (25mg, 0.058mmol) the middle pyrrolidine (3mL) that adds.The mixture that generates is reacted 30min in 100 ℃ in microwave.Evaporate all extra pyrrolidines, and then it is prepared the HPLC purification through Gilson, obtain the title compound (72.4%) of 25mg.
LC/MS=m/z 482.2 [M+H] retention time: 1.67min.
Embodiment 225:5-{6-[ethyl (methyl) amino]-3-pyridine radicals }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02151
(110mg is 0.27mmol) at two _ alkane (2.0mL) and H to 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide 2Add in the solution among the O (0.7mL) (6-fluoro-3-pyridine radicals) boric acid (151mg, 1.08mmol), potassium carbonate (298mg, 2.16mmol) with four (triphenylphosphines) close palladium (0) (31mg, 0.026mmol).This is reflected in the microwave carries out 20min in 150 ℃.Should react then with EtOAc and saline treatment,, obtain 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(6-fluoro-3-pyridine radicals)-1H-indole-7-Methanamide (43%) of 50mg through purified by flash chromatography.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(6-fluoro-3-pyridine radicals)-1H-indole-7-Methanamide (40mg, 0.093mmol) middle DMA (1mL) and the DMF (0.3mL) of adding.The mixture that generates is reacted 1h in 200 ℃ in microwave.The mixture that generates is used washing.Add ethyl acetate, and evaporate organic layer, and prepare the HPLC purification, obtain the title compound (63.4%) of 34.4mg through Gilson.
LC/MS=m/z 470 [M+H] retention time: 1.50min.
Embodiment 226:5-[6-(dimethylamino)-3-pyridine radicals]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02161
(110mg is 0.27mmol) at two _ alkane (2.0mL) and H to 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide 2Add in the solution among the O (0.7mL) (6-fluoro-3-pyridine radicals) boric acid (151mg, 1.08mmol), potassium carbonate (298mg, 2.16mmol) with four (triphenylphosphines) close palladium (0) (31mg, 0.026mmol).This is reflected in the microwave carries out 20min in 150 ℃.Should react then with EtOAc and saline treatment,, obtain 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(6-fluoro-3-pyridine radicals)-1H-indole-7-Methanamide (43%) of 50mg through purified by flash chromatography.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(6-fluoro-3-pyridine radicals)-1H-indole-7-Methanamide (50mg, 0.116mmol) middle DMA (1mL) and the DMF (0.3mL) of adding.With the mixture that generates in microwave in 200 ℃ of reaction 1h, prepare the HPLC purification through Gilson then, obtain the title compound (12.7%) of 8.4mg.
LC/MS=m/z 456.2 [M+H] retention time: 1.39min.
Embodiment 227:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[6-(propyl group is amino)-3-pyridine radicals]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02171
(110mg is 0.27mmol) at two _ alkane (2.0mL) and H to 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide 2Add in the solution among the O (0.7mL) (6-fluoro-3-pyridine radicals) boric acid (151mg, 1.08mmol), potassium carbonate (298mg, 2.16mmol) with four (triphenylphosphines) close palladium (0) (31mg, 0.026mmol).This is reflected in the microwave carries out 20min in 150 ℃.Should react then, and, obtain 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(6-fluoro-3-pyridine radicals)-1H-indole-7-Methanamide (43%) of 50mg through purified by flash chromatography with EtOAc and saline treatment.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(6-fluoro-3-pyridine radicals)-1H-indole-7-Methanamide (50mg, 0.116mmol) middle propylamine (1mL) and the DMF (0.3mL) of adding.With the mixture that generates in microwave in 200 ℃ of reaction 5h, prepare the HPLC purification through Gilson, obtain the title compound (36.2%) of 24.5mg.
LC/MS=m/z 470.2 [M+H] retention time: 1.49min.
Embodiment 228:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{6-[(1-Methylethyl) amino]-3-pyridine radicals }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02172
Title compound is according to preparation 5-{6-[ethyl (methyl) amino]-3-pyridine radicals }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With 2-propylamine (64.3mg; 1mmol) replace DMA to prepare, obtain the title compound (14.5%) of 9.8mg.
LC/MS=m/z 470.4 [M+H] retention time: 1.52min.
Embodiment 229:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[6-(4-morpholinyl)-3-pyridine radicals]-1H-indole-7-Methanamide
Title compound is according to preparation 5-{6-[ethyl (methyl) amino]-3-pyridine radicals }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; Replace DMA to prepare with morpholine (1mL), obtain the title compound (69.5%) of 40.1mg.
LC/MS=m/z 498.6 [M+H] retention time: 1.44min.
Embodiment 230:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5 [(methylamino) methyl]-3-thienyl }-1H-indole-7-Methanamide trifluoroacetate
(20mg 0.045mmol) adds methylamine (0.13mL) in the solution in methanol (1.5mL) and dichloromethane (1.5mL) to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide.The mixture of this generation is at room temperature stirred 2h, add subsequently Sodium Borohydride (9.18mg, 0.27mmol).It is at room temperature stirred 1h.Evaporate all solvents, and then it is prepared the HPLC purification through Gilson, obtain the title compound (48%) of 12.4mg.
LC/MS=m/z 461.4 [M+H] retention time: 1.48min.
Embodiment 231:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(1-Methylethyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02191
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (30mg, 0.067mmol) add in the solution in methanol (0.5mL) and dichloromethane (1mL) the 2-propylamine (23.8mg, 0.402mmol).The mixture of this generation is stirred 2.5h, add subsequently Sodium Borohydride (15.2mg, 0.402mmol).Should react and at room temperature stir 1h.Evaporate all solvents, and then it is prepared the HPLC purification through Gilson, obtain the title compound (48.3%) of 19.5mg.
LC/MS=m/z 489.2 [M+H] retention time: 1.54min.
Embodiment 232:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(1-pyrrolidinyl methyl)-3-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02192
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (30mg, 0.067mmol) add in the solution in methanol (0.5mL) and dichloromethane (1mL) pyrrolidine (85mg, 1.195mmol).The mixture of this generation is stirred 1.5h, add subsequently sodium triacetoxy borohydride (85mg, 0.402mmol).Should react and at room temperature stir 2h.Evaporate all solvents, and then it is prepared the HPLC purification through Gilson, obtain the title compound (54.6%) of 22.5mg.
LC/MS=m/z 501.4 [M+H] retention time: 1.52min.
Embodiment 233:5-{5-[(ethylamino) methyl]-3-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (30mg, 0.067mmol) add in the solution in methanol (3mL) and dichloromethane (3mL) ethamine (0.2mL, 0.402mmol).Behind the 2h, (27mg 0.402mmol), and leaves standstill 1h with mixture to add Sodium Borohydride.Evaporate all solvents, and then it is prepared the HPLC purification through Gilson, obtain the title compound (38%) of 15mg.
LC/MS=m/z 475.4 [M+H] retention time: 1.52min.
Embodiment 234:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-([(1R)-and 2-hydroxyl-1-Methylethyl] amino } methyl)-the 3-thienyl]-1H-indole-7-Methanamide trifluoroacetate (salt)
Figure S2006800304481D02202
Title compound is according to preparation 5-{5-[(ethylamino) methyl]-3-thienyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With (2R)-2-amino-1-propanol (0.031mL; 0.402mmol) replace ethamine to prepare, obtain the title compound (39.1%) of 16.2mg.
LC/MS=m/z 505.4 [M+H] retention time: 1.42min.
Embodiment 235:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(piperidino methyl)-3-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02211
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (30mg, 0.067mmol) add in the solution in dimethyl sulfoxine (2mL) piperidines (70mg, 0.670mmol).The mixture that generates is left standstill 2h, add then sodium triacetoxy borohydride (142mg, 0.670mmol).With this mixture stirred overnight at room temperature, prepare the HPLC purification through Gilson then, obtain the title compound (38.5%) of 16.2mg.
LC/MS=m/z 514.8 [M+H] retention time: 1.37min.
Embodiment 236:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(4-morpholinyl methyl)-3-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02212
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(1-pyrrolidinyl methyl)-3-thienyl]-1H-indole-7-Methanamide trifluoroacetate; With morpholine (70mg; 0.670mmol) replace piperidines to prepare, obtain the title compound (14.9%) of 6.3mg.
LC/MS=m/z 517 [M+H] retention time: 1.54min.
Embodiment 237:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(methylamino) methyl]-3-furyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02221
(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-(50mg is 0.11mmol) at two _ alkane (3.0mL) and H for 1H-indole-7-Methanamide to 3-[1-(ethylsulfonyl)-4-piperidyl]-5- 2Add in the solution among the O (1.0mL) 4-bromo-2 furan carboxyaldehyde (58mg, 0.33mmol), potassium carbonate (89.8mg, 0.66mmol) with four (triphenylphosphines) close palladium (0) (14mg, 0.012mmol).This is reflected in the microwave in 150 ℃ of heating 20min, obtains 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-furyl)-1H-indole-7-Methanamide of 58mg.
(20.6mg 0.05mmol) adds methylamine (0.24mL, 2M tetrahydrofuran solution 0.5mmol) in the solution in DMSO (0.5mL) to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-furyl)-1H-indole-7-Methanamide.Mixture reaction 6h with generating adds sodium triacetoxy borohydride subsequently.Then it is prepared the HPLC purification through Gilson, obtain the title compound (32.8%) of 5.5mg.
LC/MS=m/z 459.4 [M+H] retention time: 1.42min.
Embodiment 238:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[1-(1-pyrrolidinyl) ethyl]-3-thienyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02222
(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-(300mg is 0.65mmol) at two _ alkane (9mL) and H for 1H-indole-7-Methanamide to 3-[1-(ethylsulfonyl)-4-piperidyl]-5- 2Add in the solution among the O (3mL) 1-(4-bromo-2-thienyl) ethyl ketone (400mg, 1.95mmol), potassium carbonate (538mg, 3.90mmol) with four (triphenylphosphines) close palladium (0) (70mg, 0.060mmol).This is reflected under 150 ℃, carries out 20min in the microwave.Use EtOAc and H 2O carries out aqueous solution to be handled, and adds MeOH (3mL) subsequently to crude product.Required product is precipitated out, and filters, and obtains 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-propiono-3-thienyl)-1H-indole-7-Methanamide (77%) of 230mg.
To 5-(5-acetyl group-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (50mg; 0.11mmol) add pyrrolidine (30.92mg in the solution in DMF (0.8mL) and acetic acid (0.2mL); 0.44mmol) and N, and dinethylformamide (30mg, 0.44mmol).Reactant mixture is reacted 20min in 150 ℃ in microwave.Then product is prepared HPLC purification twice through Gilson, obtain the title compound (5.3%) of 3.7mg.
LC/MS=m/z 515.4 [M+H] retention time: 1.62min.
Embodiment 239:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(1-pyrrolidinyl methyl)-2-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02231
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-2-thienyl)-1H-indole-7-Methanamide (40mg, add in dimethyl sulfoxine 0.09mmol) (0.5mL) solution 2M pyrrolidine (0.074mL, 0.90mmol).The mixture that generates is left standstill 6h, add subsequently sodium triacetoxy borohydride (233mg, 9.90mmol).Then it is left standstill 2h, prepare the HPLC purification through Gilson then, obtain the title compound (11.7%) of 6.5mg.
LC/MS=m/z 515.4 [M+H] retention time: 1.62min.
Embodiment 240:5-{5-[(dimethylamino) methyl]-2-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02241
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-2-thienyl)-1H-indole-7-Methanamide (35mg, add in dimethyl sulfoxine 0.09mmol) (0.5mL) solution 2M DMA (0.4mL, 0.90mmol).The mixture that generates is left standstill 6h, add subsequently sodium triacetoxy borohydride (233mg, 9.90mmol).Then it is left standstill 2h, prepare the HPLC purification through Gilson then, obtain the title compound (33.6%) of 17.8mg.
LC/MS=m/z 475.2 [M+H] retention time: 1.53min.
Embodiment 241:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(propyl group is amino) methyl]-2-thienyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02242
Title compound is according to preparation 5-{5-[(dimethylamino) methyl]-2-thienyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With propylamine (0.064mL; 0.90mmol) replace the 2M DMA to prepare, obtain the title compound (16.4%) of 8.9mg.
LC/MS=m/z 487.2 [M+H] retention time: 1.80min.
Embodiment 242:5-{5-[(diethylamino) methyl]-2-thienyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Title compound is according to preparation 5-{5-[(dimethylamino) methyl]-2-thienyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With diethylamine (0.081mL; 0.90mmol) replace the 2M DMA to prepare, obtain the title compound (29.9%) of 16.6mg.
LC/MS=m/z 502.0 [M+H] retention time: 1.71min.
Embodiment 243:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl-propyl) amino] methyl }-the 2-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02252
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-2-thienyl)-1H-indole-7-Methanamide (30mg, add in dimethyl sulfoxine 0.09mmol) (0.5mL) solution 2-methyl isophthalic acid-propylamine (0.068mL, 0.90mmol).The mixture that generates is left standstill 6h, add subsequently sodium triacetoxy borohydride (233mg, 9.90mmol).Then it is left standstill 2h, prepare the HPLC purification through Gilson then, obtain the title compound (4.9%) of 2.7mg.
LC/MS=m/z 501.4 [M+H] retention time: 1.79min.
Embodiment 244:5-(5-{ [(2, the 2-dimethyl propyl) amino] methyl }-the 3-furyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02261
(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-(50mg is 0.11mmol) at two _ alkane (3.0mL) and H for 1H-indole-7-Methanamide to 3-[1-(ethylsulfonyl)-4-piperidyl]-5- 2Add in the solution among the O (1.0mL) 4-bromo-2 furan carboxyaldehyde (58mg, 0.33mmol), potassium carbonate (89.8mg, 0.66mmol) with four (triphenylphosphines) close palladium (0) (14mg, 0.012mmol).This is reflected in the microwave in 150 ℃ of heating 20min, obtains 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-furyl)-1H-indole-7-Methanamide of 58mg.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-furyl)-1H-indole-7-Methanamide (60ng; 0.14mmol) middle adding 2; (60mg, dimethyl sulfoxine 0.14mmol) (0.5mL) solution add 2 to 2-dimethyl-1-propylamine; 2-dimethyl-1-propylamine (122mg, 1.40mmol).The mixture that generates is left standstill 6h, add subsequently sodium triacetoxy borohydride (233mg, 9.90mmol).Then it is left standstill 2h, prepare the HPLC purification through Gilson then, obtain the title compound (27.7%) of 23.8mg.
LC/MS=m/z 501.1 [M+H] retention time: 1.67min.
Embodiment 245:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2-methyl-propyl) amino] methyl }-the 3-furyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02262
Title compound is that (5-{ [(2 according to preparation 5-; The 2-dimethyl propyl) amino] methyl }-the 3-furyl)-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With 2-methyl isophthalic acid-propylamine (102.4mg; 1.4mmol) replacing 2,2-dimethyl-1-propylamine prepares, and obtains the title compound (37.7%) of 31.7mg.
LC/MS=m/z 487.2 [M+H] retention time: 1.44min.
Embodiment 246:5-(5-{ [(cyclopentyl-methyl) amino] methyl }-the 3-furyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02271
Title compound is that (5-{ [(2 according to preparation 5-; The 2-dimethyl propyl) amino] methyl }-the 3-furyl)-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With 1-cyclopenta methylamine (137mg; 1.4mmol) replacing 2,2-dimethyl-1-propylamine prepares, and obtains the title compound (25.1%) of 22mg.
LC/MS=m/z 513.4 [M+H] retention time: 1.59min.
Embodiment 247:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(1-pyrrolidinyl methyl)-3-furyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02272
Title compound is that (5-{ [(2 according to preparation 5-; The 2-dimethyl propyl) amino] methyl }-the 3-furyl)-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With pyrrolidine (99.6mg; 1.4mmol) replacing 2,2-dimethyl-1-propylamine prepares, and obtains the title compound (7.2%) of 6mg.
LC/MS=m/z 485.2 [M+H] retention time: 1.50min.
Embodiment 248:5-{5-[(diethylamino) methyl]-3-furyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02281
Title compound is that (5-{ [(2 according to preparation 5-; The 2-dimethyl propyl) amino] methyl }-the 3-furyl)-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With 2M diethylamine (102.4mg; 1.4mmol) replacing 2,2-dimethyl-1-propylamine prepares, and obtains the title compound (12%) of 10.1mg.
LC/MS=m/z 487.4 [M+H] retention time: 1.50min.
Embodiment 249:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(1-pyrrolidinyl methyl)-1,3-thiazoles-2-yl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02282
(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-(500mg is 1.1mmol) at two _ alkane (12mL) and H for 1H-indole-7-Methanamide to 3-[1-(ethylsulfonyl)-4-piperidyl]-5- 2Add in the solution among the O (4mL) 2-bromo-1,3-thiazoles-5-formaldehyde (634mg, 3.3mmol), potassium carbonate (898mg, 8.8mmol) with four (triphenylphosphines) close palladium (0) (210mg, 0.181mmol).Be reflected at and under 150 ℃, carry out 20min in the microwave.Carry out aqueous solution and handle, obtain crude product.This is reflected in the microwave in 150 ℃ repeats 30min, obtain 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-1,3-thiazoles-2-yl)-1H-indole-7-Methanamide.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-1,3-thiazoles-2-yl)-1H-indole-7-Methanamide (25mg, 0.06mmol) add in the solution in dimethyl sulfoxine (1mL) pyrrolidine (0.05mL, 0.60mmol).The mixture of this generation is at room temperature stirred 6h, add subsequently sodium triacetoxy borohydride (160mg, 0.60mmol).Mixture stirred overnight with generating prepares the HPLC purification through Gilson then, obtains the title compound (17.1%) of 6.3mg.
LC/MS=m/z 502.2 [M+H] retention time: 1.35min.
Embodiment 250:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[2-methyl isophthalic acid-(1-pyrrolidinyl) propyl group]-3-thienyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02291
(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-(50mg is 0.11mmol) at two _ alkane (3mL) and H for 1H-indole-7-Methanamide to 3-[1-(ethylsulfonyl)-4-piperidyl]-5- 2Add in the solution among the O (1mL) potassium carbonate (89.8mg, 0.66mmol), 1-(4-bromo-2-thienyl)-2-methyl isophthalic acid-acetone (87mg, 0.33mmol) with four (triphenylphosphines) close palladium (0) (14mg, 0.012mmol).This is reflected in the microwave in 150 ℃ carries out 20min, use ethyl acetate and H subsequently 2O carries out aqueous solution to be handled.Should react concentrated then, and handle, and extract with EtOAc with the NaOH of 1N.Chemical compound through using the purified by flash chromatography of DCM and MeOH, is obtained 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(2-methylpropionyl)-3-thienyl]-1H-indole-7-Methanamide.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(2-methylpropionyl)-3-thienyl]-1H-indole-7-Methanamide (40mg; 0.02mmol) add sodium cyanoborohydride (7.5mg in the solution in EtOH (1.5mL) and acetic acid (0.2mL); 0.12mmol) and pyrrolidine (0.03mL, 0.3mmol).The mixture that generates is reacted 40min in 150 ℃ in microwave.Evaporate all solvents then, and in sodium hydroxide, alkalize, and use ethyl acetate extraction.Then it is prepared the HPLC purification through Gilson, obtain the title compound of 13mg.
LC/MS=m/z 543.4 [M+H] retention time: 1.71min.
Embodiment 251:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(1-pyrrolidinyl methyl)-1,3-thiazoles-2-yl]-1H-indole-7-Methanamide trifluoroacetate
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-formoxyl-1,3-thiazoles-4-yl)-1H-indole-7-Methanamide (42mg, 0.094mmol) add in the solution in DMSO (2mL) pyrrolidine (0.08mL, 0.940mmol).The mixture of this generation is at room temperature stirred 6h, add sodium triacetoxy borohydride subsequently.With this mixture stirred overnight at room temperature, prepare the HPLC purification through Gilson then, obtain the title compound (26.1%) of 15.1mg.
LC/MS=m/z 502.4 [M+H] retention time: 1.54min.
Embodiment 252:5-{1-[2-(dimethylamino) ethyl]-1H-pyrazoles-4-yl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D02311
With 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1; 3,2-dioxa bora ring penta-2-yl)-and 1H-indole-7-Methanamide (40mg, 0.084mmol), [2-(4-bromo-1H-pyrazol-1-yl) ethyl] DMA (27mg; 0.126mmol) and sodium carbonate (53mg, solution 0.5mmol) are suspended in two _ alkane (750 μ L) and the water (250 μ L).Then it is fed argon 10min, add subsequently four (triphenylphosphines) close palladium (0) (5mg, 0.004mmol).With the mixture that generates in microwave in 120 ℃ of reaction 20min, use EtOAc (10mL) dilution then.Through the diatomite filtration mixture, and carry out water washing.Then it is prepared the HPLC purification through Gilson, obtain the title compound (15%) of 6mg.
LC/MS=m/z 473.4 [M+H] retention time: 1.48min.
Embodiment 253:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{1-[2-(1-pyrrolidinyl) ethyl]-1H-pyrazoles-4-yl }-1H-indole-7-Methanamide trifluoroacetate
(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-(40mg is 0.090mmol) at two _ alkane (750 μ L) and H for 1H-indole-7-Methanamide to 3-[1-(ethylsulfonyl)-4-piperidyl]-5- 2Add in the solution among the O (250 μ L) sodium carbonate (53mg, 0.50mmol) with 4-bromo-1-(2-chloroethyl)-1H-pyrazoles (26mg, 0.126mmol).In reactant mixture, feed argon 10min, add subsequently four (triphenylphosphines) close palladium (0) (5mg, 0.004mmol).This is reflected in the microwave in 120 ℃ of following heating 20min.Then it is diluted with EtOAc (10mL),, carry out aqueous solution subsequently and handle through diatomite filtration.This chemical compound is prepared the HPLC purification through Gilson, obtain 5-[1-(2-chloroethyl)-1H-pyrazoles-4-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (24%) of 10mg.
To 5-[1-(2-chloroethyl)-1H-pyrazoles-4-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (33mg; 0.071mmol), pyrrolidine (60 μ L; 0.710mmol) and sodium iodide (5mg 0.018mmol) adds oxolane (500 μ L) in the solution.With this mixture in microwave in 130 ℃ of reaction 2h, and wash with EtOAc and water.Then organic layer is separated, and remove all solvents.Then it is prepared the HPLC purification through Gilson, obtain the title compound (25%) of 11mg.
LC/MS=m/z 499.6 [M+H] retention time: 1.34min.
Embodiment 254:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{1-[2-(4-morpholinyl) ethyl]-1H-pyrazoles-4-yl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02321
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{1-[2-(1-pyrrolidinyl) ethyl]-1H-pyrazoles-4-yl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With morpholine (70 μ L; 0.71mmol) replace pyrrolidine to prepare, obtain the title compound (34%) of 15mg.
LC/MS=m/z 515.4 [M+H] retention time: 1.46min.
Embodiment 255:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(1-{2-[(hydroxyethyl) amino] ethyl }-1H-pyrazoles-4-yl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02331
(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-(40mg is 0.090mmol) at two _ alkane (750 μ L) and H for 1H-indole-7-Methanamide to 3-[1-(ethylsulfonyl)-4-piperidyl]-5- 2Add in the solution among the O (250 μ L) sodium carbonate (53mg, 0.50mmol) with 4-bromo-1-(2-chloroethyl)-1H-pyrazoles (26mg, 0.126mmol).In reactant mixture, feed argon 10min, add subsequently four (triphenylphosphines) close palladium (0) (5mg, 0.004mmol).This is reflected in the microwave in 120 ℃ of heating 20min.Then it is diluted with EtOAc (10mL),, carry out aqueous solution subsequently and handle through diatomite filtration.This chemical compound is prepared the HPLC purification through Gilson, obtain 5-[1-(2-chloroethyl)-1H-pyrazoles-4-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (24%) of 10mg.
With 5-[1-(2-chloroethyl)-1H-pyrazoles-4-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (20mg; 0.043mmol), 2-ethylaminoethanol (26mg; 0.43mmol) and sodium iodide (5mg, 0.022mmol) solution in oxolane (1mL) in microwave in 130 ℃ the reaction 2h.Remove oxolane then, and mixture is washed with EtOAc and water.Separate organic layer then, and remove all solvents.Then mixture is prepared the HPLC purification through Gilson, obtain the title compound (31%) of 8mg.
LC/MS=m/z 489.2 [M+H] retention time: 1.40min.
Embodiment 256:5-{1-[2-(butyl is amino) ethyl]-1H-pyrazoles-4-yl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(1-{2-[(2-hydroxyethyl) amino] ethyl }-1H-pyrazoles-4-yl)-1H-indole-7-Methanamide trifluoroacetate; With 1-butylamine (31mg; 0.43mmol) replace the 2-ethylaminoethanol to prepare, obtain the title compound (26%) of 7mg.
LC/MS=m/z 499.4 [M+H] retention time: 1.39min.
Embodiment 257:5-{1-[2-(cyclobutyl is amino) ethyl]-1H-pyrazoles-4-yl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02342
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(1-{2-[(2-hydroxyethyl) amino] ethyl }-1H-pyrazoles-4-yl)-1H-indole-7-Methanamide trifluoroacetate; With ring butylamine (31mg; 0.43mmol) replace the 2-ethylaminoethanol to prepare, obtain the title compound (38%) of 10mg.
LC/MS=m/z 501.4 [M [+H] retention time: 1.48min.
Embodiment 258:5-[1-(2-{ [2-(diethylamino) ethyl] amino } ethyl)-1H-pyrazoles-4-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02351
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(1-{2-[(2-hydroxyethyl) amino] ethyl }-1H-pyrazoles-4-yl)-1H-indole-7-Methanamide trifluoroacetate; Use N; N-diethyl-1; (50mg 0.43mmol) replaces the 2-ethylaminoethanol to prepare to the 2-ethylenediamine, obtains the title compound (42%) of 12mg.
LC/MS=m/z 545.2 [M+H] retention time: 1.25min.
Embodiment 259:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(1-{2-[(1-Methylethyl) amino] ethyl }-1H-pyrazoles-4-yl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02352
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(conventional method of 1-(2-[(2-hydroxyethyl) amino] ethyl }-1H-pyrazoles-4-yl)-1H-indole-7-Methanamide trifluoroacetate; With 2-propylamine (25mg; 0.43mmol) replace the 2-ethylaminoethanol to prepare, obtain the title compound (35%) of 9mg.
LC/MS=m/z 487.2 [M+H] retention time: 1.47min.
Embodiment 260:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(1-{2-[(2-methyl-propyl) amino] ethyl }-1H-pyrazoles-4-yl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02361
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(1-{2-[(2-hydroxyethyl) amino] ethyl }-1H-pyrazoles-4-yl)-1H-indole-7-Methanamide trifluoroacetate; With 2-methyl isophthalic acid-propylamine (31mg; 0.43mmol) replace the 2-ethylaminoethanol to prepare, obtain the title compound (30%) of 8mg.
LC/MS=m/z 501.2 [M+H] retention time: 1.45min.
Embodiment 261:5-(1-{2-[(cyclopentyl-methyl) amino] ethyl }-1H-pyrazoles-4-yl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02362
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(1-{2-[(2-hydroxyethyl) amino] ethyl }-1H-pyrazoles-4-yl)-1H-indole-7-Methanamide trifluoroacetate; With Aminocyclopentane (37mg; 0.43mmol) replace the 2-ethylaminoethanol to prepare, obtain the title compound (40%) of 11mg.
LC/MS=m/z 513.4 [M+H] retention time: 1.47min.
Embodiment 262:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(methoxyl group)-3-(1-pyrrolidinyl methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02371
(610mg is 2.33mmol) at two _ alkane (19mL) and H for benzaldehyde to 2-(methoxyl group)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) 2Add in the solution among the O (6.3mL) 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (963mg, 2.33mmol) and sodium carbonate (1.48g, 13.9mmol).After feeding argon 10min, add four (triphenylphosphines) close palladium (0) (134mg, 0.166mmol).This is reflected in the microwave in 120 ℃ of heating 120min.This chemical compound through using the purified by flash chromatography of DCM and MeOH, is obtained 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-formoxyl-4-(methoxyl group) phenyl]-1H-indole-7-Methanamide (58%) of 632mg.
With 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-formoxyl-4-(methoxyl group) phenyl]-1H-indole-7-Methanamide (50mg; 0.107mmol), pyrrolidine (45 μ L; 0.214mmol), zinc chloride (10mg; 0.054mmol) and sodium cyanoborohydride (7mg, 0.107mmol) solution in methanol (5mL) at room temperature stirs 2h.Water (2mL) solution that in this mixture, adds 0.1 normal sodium hydroxide.Evaporate methanol then.Water is extracted three times with EtOAc (5mL).Then organic facies is washed twice with saline (5mL).Remove all solvents then.Mixture is prepared the HPLC purification through Gilson, obtain the title compound (13%) of 9mg.
LC/MS=m/z 525.6 [M+H] retention time: 1.67min.
Embodiment 263:5-[3-[(dimethylamino) methyl]-4-(methoxyl group) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02381
(610mg is 2.33mmol) at two _ alkane (19mL) and H for benzaldehyde to 2-(methoxyl group)-5-(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) 2Add in the solution among the O (6.3mL) 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (963mg, 2.33mmol) and sodium carbonate (1.48g, 13.9mmol).After feeding argon 10min, add four (triphenylphosphines) close palladium (0) (134mg, 0.166mmol).This is reflected in the microwave in 120 ℃ of heating 120min.This chemical compound through using the purified by flash chromatography of DCM and MeOH, is obtained 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-formoxyl-4-(methoxyl group) phenyl]-1H-indole-7-Methanamide (58%) of 632mg.
With 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-formoxyl-4-(methoxyl group) phenyl]-1H-indole-7-Methanamide (50mg; 0.214mmol), DMA (107 μ L; 0.214mmol), zinc chloride (10mg; 0.054mmol) and sodium cyanoborohydride (7mg, 0.107mmol) solution in methanol (5mL) at room temperature stirs 2h.Water (2mL) solution that in this mixture, adds 0.1 normal sodium hydroxide.Evaporate methanol then.Water is extracted three times with EtOAc (5mL).Then organic facies is washed twice with saline (5mL).Remove all solvents.Mixture is prepared the HPLC purification through Gilson, obtain the title compound (6.1%) of 4mg.
LC/MS=m/z 499.4 [M+H] retention time: 1.56min.
Embodiment 264:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(methoxyl group)-3-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02391
Title compound is the conventional method according to preparation 5-[3-[(dimethylamino) methyl]-4-(methoxyl group) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With morpholine (20 μ L; 0.214mmol) replace DMA to prepare, obtain the title compound (17%) of 12mg.
LC/MS=m/z 541.6 [M+H] retention time: 1.69min.
Embodiment 265:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-{ [(1-Methylethyl) amino] methyl }-4-(methoxyl group) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02392
Title compound is the conventional method according to preparation 5-[3-[(dimethylamino) methyl]-4-(methoxyl group) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With 2-propylamine (15 μ L; 0.214mmol) replace DMA to prepare, obtain the title compound (24%) of 16mg.
LC/MS=m/z 513.2 [M+H] retention time: 1.62min.
Embodiment 266:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-[(methylamino) methyl]-4-(methoxyl group) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02401
Title compound is the conventional method according to preparation 5-[3-[(dimethylamino) methyl]-4-(methoxyl group) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With methylamine (50 μ L; 0.214mmol) replace DMA to prepare, obtain the title compound (16%) of 10mg.
LC/MS=m/z 485.2 [M+H] retention time: 1.57min.
Embodiment 267:5-[3-{ [(2, the 2-dimethyl propyl) amino] methyl }-4-(methoxyl group) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02402
Title compound is the conventional method according to preparation 5-[3-[(dimethylamino) methyl]-4-(methoxyl group) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With 2; 2-dimethyl-1-propylamine (20 μ L; 0.214mmol) replace DMA to prepare, obtain the title compound (16%) of 11mg.
LC/MS=m/z 541.2 [M+H] retention time: 1.77min.
Embodiment 268:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(1-{2-[(2-hydroxyethyl) (methyl) amino] ethyl }-1H-pyrazoles-4-yl)-1H-indole-7-Methanamide
Figure S2006800304481D02411
With 5-[1-(2-chloroethyl)-1H-pyrazoles-4-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (30mg; 0.065mmol), 2-(methylamino) ethanol (500 μ L; 6.5mmol) and sodium iodide (3mg, 0.016mmol) solution in oxolane (1mL) in microwave in 130 ℃ the reaction 2h.The mixture that generates is carried out aqueous solution to be handled.Then it is prepared the HPLC purification through Gilson, obtain the title compound (17%) of 9mg.
LC/MS=m/z 503.2 [M+H] retention time: 1.40min.
Embodiment 269:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{4-fluoro-3-[(methylamino) methyl] phenyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02412
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-fluoro-3-formoxyl phenyl)-1H-indole-7-Methanamide (16.0mg; 0.035mmol) (105 μ L are 0.21mmol) with 1 acetic acid to add the THF solution of 2M methylamine in the solution in dichloromethane (1mL) and methanol (1mL).This mixture is stirred 3h.(8.4mg 0.21mmol), and stirs 1h with mixture to add Sodium Borohydride.Concentrate the mixture that generates, and be dissolved in the dimethyl sulfoxine (1.5mL).Then it is prepared the HPLC purification through Gilson, obtain the title compound (31.2%) of 6.4mg.
LC/MS=m/z 473.4 [M+H] retention time: 1.50min.
Embodiment 270:5-{3, two [(methylamino) methyl] phenyl of 5-}-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
(10mg, (64 μ L are 0.128mmol) with 1 acetic acid 0.2mmol) to add methylamine in the solution in dichloromethane (1mL) and methanol (1mL) to 5-(3,5-diformyl phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide.The mixture of this generation is at room temperature stirred 3h, add then Sodium Borohydride (5.1mg, 0.128mmol).It is stirred 1h, concentrate then, and prepare the HPLC purification, obtain the title compound (23.4%) of 3mg through Gilson.
LC/MS=m/z 498.6 [M+H] retention time: 1.17min.
Embodiment 271:5-{3-[(ethylamino) methyl]-4-fluorophenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02422
(35mg, (230 μ L are 0.46mmol) with 1 acetic acid 0.076mmol) to add 2M ethamine in the solution in dichloromethane (1mL) and methanol (1mL) to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-fluoro-3-formoxyl phenyl)-1H-indole-7-Methanamide.Mixture is at room temperature stirred 1h, add oxolane (1mL) then.Mixture is stirred 30min, add subsequently Sodium Borohydride (17.5mg, 0.46mmol).With the mixture restir 1h of this generation, concentrate, and prepare the HPLC purification through Gilson, obtain the title compound (43.8%) of 20mg.
LC/MS=m/z 487.4 [M+H] retention time: 1.46min.
Embodiment 272:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-fluoro-3-({ [2-hydroxyl-1-(hydroxymethyl) ethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate (salt)
Figure S2006800304481D02431
Title compound is according to preparation 5-{3-[(ethylamino) methyl]-4-fluorophenyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With 2-amino-1; Ammediol (42mg; 0.46mmol) replace ethamine to prepare, obtain the title compound (42.7%) of 21mg.
LC/MS=m/z 533.2 [M+H] retention time: 1.39min.
Embodiment 273:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-fluoro-3-([(1S)-and 2-hydroxyl-1-Methylethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate (salt)
Figure S2006800304481D02432
Title compound is according to preparation 5-{3-[(ethylamino) methyl]-4-fluorophenyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With (2S)-2-amino-1-propanol (37mg; 0.46mmol) replace ethamine to prepare, obtain the title compound (54.2%) of 26mg.
LC/MS=m/z 517.2 [M+H] retention time: 1.44
Embodiment 274:5-{3-[(cyclopropyl is amino) methyl]-4-fluorophenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02441
Title compound is according to preparation 5-{3-[(ethylamino) methyl]-4-fluorophenyl)-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With cyclopropylamine (32mg; 0.46mmol) replace ethamine to prepare, obtain the title compound (49.4%) of 23mg.
LC/MS=m/z 499.6 [M+H] retention time: 1.75min.
Embodiment 275:5-{3-[(cyclobutyl is amino) methyl]-4-fluorophenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02442
Title compound is according to preparation 5-{3-[(ethylamino) methyl]-4-fluorophenyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With ring butylamine (39mg; 0.46mmol) replace ethamine to prepare, obtain the title compound (42%) of 20mg.
LC/MS=m/z 513.2 [M+H] retention time: 1.58min.
Embodiment 276:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(1-pyrrolidinyl methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02443
(32mg is 0.444mmol) with 1 acetic acid in 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl the phenyl)-solution of 1H-indole-7-Methanamide (33 mg 0.74mmol) in dichloromethane (0.5mL) and methanol (0.5mL), to add pyrrolidine.Mixture is stirred 2min, add then Sodium Borohydride (17.8mg, 0.444mmol).Then with its stirred overnight, concentrate then and prepare the HPLC purification through Gilson, obtain the title compound (21.5%) of 9.7mg
LC/MS=m/z 495.4 [M+H] retention time: 1.67min.
Embodiment 277:5-{3, two [(ethylamino) methyl] phenyl of 5-}-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02451
(27mg, (31.4mg is 0.696mmol) with 1 acetic acid 0.058mmol) to add ethamine in the solution in dichloromethane (1.5mL) and methanol (1.5mL) to 5-(3,5-diformyl phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide.The mixture of this generation is stirred 2h, add then Sodium Borohydride (13.2mg, 0.348mmol).With its restir 50min, prepare the HPLC purification through Gilson then, obtain the title compound (53.9%) of 20mg.
LC/MS=m/z 526.6 [M+H] retention time: 1.41min.
Embodiment 278:5-{3, two [(dimethylamino) methyl] phenyl of 5-}-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02452
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl-5-sulfydryl phenyl)-1H-indole-7-Methanamide (34mg; 0.058mmol) (31.4mg is 0.696mmol) with an acetic acid to add DMA in the solution in dichloromethane (1.5mL) and methanol (1.5mL).The mixture of this generation is at room temperature stirred 2h, add then Sodium Borohydride (13.2mg, 0.348mmol).With its restir 30min, prepare the HPLC purification through Gilson then, obtain the title compound (29.6%) of 11mg.
LC/MS=m/z 526.6 [M+H] retention time: 1.27min.
Embodiment 279:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(2-piperidyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02461
(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-(46mg is 0.1mmol) at two _ alkane (2mL) and H for 1H-indole-7-Methanamide to 3-[1-(ethylsulfonyl)-4-piperidyl]-5- 2Add in the solution among the O (0.7mL) 2-(3-chlorphenyl) piperidines (46mg, 0.2mmol).Behind degasification 5min, add potassium carbonate (55mg, 0.4mmol) with four (triphenylphosphines) close palladium (0) (5mg, 0.5mmol).With the mixture that generates in the CEM of 300W microwave in 160 ℃ of reaction 30min, leach solid then.Evaporating solvent, and this solution prepared the HPLC purification through Gilson, obtain the title compound (21.7%) of 13.2mg.
LC/MS=m/z 495.4 [M+H] retention time: 1.76
Embodiment 280:5-{3-[1-(ethylamino) ethyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02462
With 5-(3-acetylphenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (50mg; 0.11mmol), ethamine (19.9mg; 0.441mmol) and sodium cyanoborohydride (30mg; 0.441mmol) at N, the solution in dinethylformamide (0.8mL) and the acetic acid (0.2mL) reacts 20min in 150 ℃ in microwave.Should react and prepared the HPLC purification, obtain the title compound (39%) of 20.6mg through Gilson.
LC/MS=m/z 483.2 [M+H] retention time: 1.67
Embodiment 281:5-{3-[1-(dimethylamino) ethyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
With 5-(3-acetylphenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (50mg; 0.11mmol), DMA (220 μ L; 0.44mmol) and sodium cyanoborohydride (30mg 0.44mmol) is dissolved in N, in dinethylformamide (400 μ L) and the acetic acid (100 μ L).The mixture that generates is reacted 20min in 150 ℃ in Smith 150W microwave.Should react and prepared the HPLC purification, obtain the title compound (22.2%) of 14.6mg through Gilson.
LC/MS=m/z 483.2 [M+H] retention time: 1.63
Embodiment 282:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-fluoro-5-[(methylamino) methyl] phenyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02472
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-formoxyl phenyl)-1H-indole-7-Methanamide (32mg; 0.07mmol) (210 μ l are 0.42mmol) with 1 acetic acid to add the THF solution of 2M methylamine in the solution in dichloromethane (1.5mL) and methanol (1.5mL).The mixture of this generation is at room temperature stirred 3h, add then Sodium Borohydride (15mg, 0.42mmol).This mixture was stirred 1 hour, concentrate then, and prepare the HPLC purification, obtain the title compound (73.1%) of 30mg through Gilson.
LC/MS=m/z 473.6 [M+H] retention time: 1.73min.
Embodiment 283:5-{3-[(ethylamino) methyl]-5-fluorophenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02481
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-fluoro-5-[(methylamino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; THF solution (210ul with 2M ethamine; 0.42mmol) replace methylamine to prepare, obtain the title compound (15.5%) of 6.5mg.
LC/MS=m/z 487.4 [M+H] retention time: 1.64min.
Embodiment 284:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-fluoro-5-[(propyl group is amino) methyl] phenyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02482
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-fluoro-5-[(methylamino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With propylamine (21mg; 0.42mmol) replace methylamine to prepare, obtain the title compound (72%) of 31mg.
LC/MS=m/z 501.4 [M+H] retention time: 1.54
Embodiment 285:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-{ [(1-Methylethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02491
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-fluoro-5-[(methylamino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With 2-propylamine (21mg; 0.42mmol) replace methylamine to prepare, obtain the title compound (66.2%) of 28.5mg.
LC/MS=m/z 501.4 [M+H] retention time: 1.53min.
Embodiment 286:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-{ [(2-methyl-propyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02492
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-fluoro-5-[(methylamino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With 2-methyl isophthalic acid-propylamine (21mg; 0.42mmol) replace methylamine to prepare, obtain the title compound (22.7%) of 10mg.
LC/MS=m/z 515.4 [M+H] retention time: 1.72min.
Embodiment 287:5-{3-[(cyclobutyl is amino) methyl]-5-fluorophenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-fluoro-5-[(methylamino) methyl] phenyl)-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With ring butylamine (21.5mg; 0.42mmol) replace methylamine to prepare, obtain the title compound (75.2%) of 33mg.
LC/MS=m/z 513.2 [M+H] retention time: 1.50min.
Embodiment 288:5-{3-[(dimethylamino) methyl]-5-fluorophenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02501
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-fluoro-5-[(methylamino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; THF solution (210ul with the 2M DMA; 0.42mmol) replace methylamine to prepare, obtain the title compound (80.2%) of 33.7mg.
LC/MS=m/z 487.2 [M+H] retention time: 1.43min.
Embodiment 289:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-(1-pyrrolidinyl methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02502
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-fluoro-5-[(methylamino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With pyrrolidine (20.4mg; 0.42mmol) replace methylamine to prepare, obtain the title compound (41%) of 18mg.
LC/MS=m/z 513.4 [M+H] retention time: 1.63min.
Embodiment 290:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02511
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-fluoro-5-[(methylamino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With morpholine (22mg; 0.42mmol) replace methylamine to prepare, obtain the title compound (50.9%) of 22.9mg.
LC/MS=m/z 529.4 [M+H] retention time: 1.47min.
Embodiment 291:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-(piperidino methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02512
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-fluoro-5-[(methylamino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With piperidines (22mg; 0.42mmol) replace methylamine to prepare, obtain the title compound (29.9%) of 13.4mg.
LC/MS=m/z 527.6 [M+H] retention time: 1.62
Embodiment 292:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[1-(methylamino) ethyl] phenyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02513
(20mg 0.044mmol) adds methylamine hydrochloride and 1 concentrated hydrochloric acid in the solution in ethanol to 5-(3-acetylphenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide.With mixture in the CEM microwave in 100 ℃ the reaction 10min, add Sodium Borohydride then.With the mixture that generates in the CEM microwave in 50 ℃ of reaction 5min, evaporate all solvents then.It is dissolved in the dimethyl sulfoxine once more, prepares the HPLC purification through Gilson then, obtain the title compound (64.4%) of 16.5mg.
LC/MS=m/z 469.4 [M+H] retention time: 1.45min.
Embodiment 293:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{1-[(1-Methylethyl) amino] ethyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
To 5-(3-acetylphenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (20mg; 0.044mmol) at N; Add 2-propylamine (75 μ L in the solution in dinethylformamide (0.8mL) and the acetic acid (0.2mL); 0.88mmol) and sodium cyanoborohydride (6mg, 0.09mmol).The mixture that generates is reacted 1h in 70 ℃ in the Smith microwave.Leach solid, prepare the HPLC purification through Gilson then, obtain the title compound (72.2%) of 19.4mg.
LC/MS=m/z 497.4 [M+H] retention time: 1.44min.
Embodiment 294:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{1-[(2-methyl-propyl) amino] ethyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02522
To 5-(3-acetylphenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (30 mg; 0.066mmol) add (2-methyl-propyl) amine (101mg in the solution in ethanol (1.2mL) and acetic acid (0.3mL); 1.98mmol) and sodium cyanoborohydride (13.5mg, 0.198mmol).The mixture that generates is reacted 1h in 70 ℃ in the Smith microwave.Evaporate all solvents, and use this solid of dimethyl sulfoxine dissolving.Then it is prepared the HPLC purification through Gilson, obtain the title compound (55.1%) of 22.7mg.
LC/MS=m/z 511.2 [M+H] retention time: 1.52min.
Embodiment 295:5-{3-[1-(cyclobutyl is amino) ethyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02531
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{1-[(2-methyl-propyl) amino] ethyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate; With ring butylamine (101mg; 1.98mmol) replace (2-methyl-propyl) amine to prepare, obtain the title compound (70.8%) of 29.1mg.
LC/MS=m/z 509.4 [M+H] retention time: 1.52min.
Embodiment 296:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[1-(1-pyrrolidinyl) ethyl] phenyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02532
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{1-[(2-methyl-propyl) amino] ethyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate; With pyrrolidine (101 mg; 1.98mmol) replace (2-methyl-propyl) amine to prepare, obtain the title compound (71%) of 29.2mg.
LC/MS=m/z 509.4 [M+H] retention time: 1.49min.
Embodiment 297:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(3-thio-morpholinyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02541
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1; 3,2-dioxa bora ring penta-2-yl)-(60mg 0.13mmol) adds 3-(3-chlorphenyl) thiomorpholine (84mg to 1H-indole-7-Methanamide in the solution in two _ alkane (1.5mL) and water (0.5mL); 0.39mmol) and potassium carbonate (107.6mg, 0.78mmol).With this mixture degasification 5min, add then four (triphenylphosphines) close palladium (0) (14.0mg, 0.013mmol).The mixture that generates is reacted 30min in 160 ℃ in microwave.Leach solid, and evaporate all solvents.The solution that generates is dissolved in the dichloromethane again, and uses liquor separator to remove and anhydrate.Mixture is concentrated, obtain organic solvent, prepare the HPLC purification through Gilson then, obtain the title compound (11%) of 7.4mg.
LC/MS=m/z 513.4 [M+H] retention time: 1.54
Embodiment 298:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(2-piperazinyl)-2-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02542
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1; 3,2-dioxa bora ring penta-2-yl)-(60mg 0.13mmol) adds 2-(5-bromo-2-thienyl) piperazine (102mg to 1H-indole-7-Methanamide in the solution in two _ alkane (1.5mL) and water (0.5mL); 0.39mmol) and potassium carbonate (108mg, 0.78mmol).With this mixture degasification 5min, add then four (triphenylphosphines) close palladium (0) (15.0mg, 0.013mmol).The mixture that generates is reacted 30min in 160 ℃ in microwave.Leach solid, and evaporate all solvents.The solution that generates is dissolved in the dichloromethane again, and uses liquor separator to remove and anhydrate.Mixture is concentrated, obtain organic solvent, prepare the HPLC purification through Gilson then, obtain the title compound (36.4%) of 29.1mg.
LC/MS=m/z 502.4 [M+H] retention time: 1.31
Embodiment 299:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(2-piperazinyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02551
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(2-piperazinyl)-2-thienyl]-1H-indole-7-Methanamide trifluoroacetate; With 2-(4-bromophenyl) piperazine (94mg; 0.39mmol) replace 2-(5-bromo-2-thienyl) piperazine to prepare, obtain the title compound (25.9%) of 20.5mg.
LC/MS=m/z 496.4 [M+H] retention time: 1.25
Embodiment 300:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(2-piperazinyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02552
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1; 3,2-dioxa bora ring penta-2-yl)-(60mg 0.13mmol) adds 2-(3-chlorphenyl) piperazine (63.7mg in the solution in two _ alkane (1.5mL) and water (0.5 mL) to 1H-indole-7-Methanamide; 0.325mmol) and potassium carbonate (90mg, 0.650mmol).With this mixture degasification 5min, add then four (triphenylphosphines) close palladium (0) (12mg, 0.011mmol).The mixture that generates is reacted 30min in 160 ℃ in microwave.Leach solid, and evaporate all solvents.The solution that generates is dissolved in the dichloromethane again, and uses liquor separator to remove and anhydrate.Mixture is concentrated, obtain organic solvent, prepare the HPLC purification through Gilson then, obtain the title compound (27.4%) of 21.7mg.
LC/MS=m/z 496.4 [M+H] retention time: 1.28min.
Embodiment 301:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[6-(4-morpholinyl)-3-pyridazinyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02561
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(2-piperazinyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With 4-(6-chloro-3-pyridazinyl) morpholine (65mg; 0.325mmol) replace 2-(3-chlorphenyl) piperazine to prepare, obtain the title compound (3.9%) of 3.1mg.
LC/MS=m/z 499.6 [M+H] retention time: 1.57min.
Embodiment 302:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[6-(1-pyrrolidinyl)-3-pyridazinyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02562
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(2-piperazinyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With 3-chloro-6-(1-pyrrolidinyl) pyridazine (60mg; 0.325mmol) replace 2-(3-chlorphenyl) piperazine to prepare, obtain the title compound (5.3%) of 4.1mg.
LC/MS=m/z 483.2 [M+H] retention time: 1.44min.
Embodiment 303:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{2-[(methylamino) methyl] phenyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02571
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(2-piperazinyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With 1-(2-bromophenyl)-N-methyl methylamine (65mg; 0.325mmol) replace 2-(3-chlorphenyl) piperazine to prepare, obtain the title compound (19.8%) of 14.6mg.
LC/MS=m/z 455.0 [M+H] retention time: 1.57min.
Embodiment 304:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-thienyl methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
(44mg, (33.6mg is 0.6mmol) with 1 acetic acid 0.1mmol) to add 1-(2-thienyl) methylamine in the solution in dichloromethane (2mL) and methanol (2mL) to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide.This mixture is stirred 2h, add then Sodium Borohydride (22.8mg, 0.6mmol).The mixture of this generation is stirred 1h.Then it is concentrated, and be dissolved in once more in the dimethyl sulfoxine (3mL).Then it is prepared the HPLC purification through Gilson, obtain the title compound (74.5%) of 41.7mg.
LC/MS=m/z 537.2 [M+H] retention time: 1.81min.
Embodiment 305:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ [(5-methyl-2-furyl) methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02581
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-thienyl methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate; With 1-(5-methyl-2-furyl) methylamine (32mg; 0.6mmol) replace 1-(2-thienyl) methylamine to prepare, obtain the title compound (54.7%) of 29.3mg.
LC/MS=m/z 535.2 [M+H] retention time: 1.74min.
Embodiment 306:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-([(2R)-and tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02582
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-thienyl methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate; With 1-[(2R)-tetrahydrochysene-2-furyl] methylamine (31.5mg; 0.6mmol) replace 1-(2-thienyl) methylamine to prepare, obtain the title compound (70.3%) of 36.9mg.
LC/MS=m/z 525.6 [M+H] retention time: 1.63min.
Embodiment 307:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-([(2S)-and tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02591
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-thienyl methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate; With 1-[(2S)-tetrahydrochysene-2-furyl] methylamine (31.5mg; 0.6mmol) replace 1-(2-thienyl) methylamine to prepare, obtain the title compound (74.7%) of 39.2mg.
LC/MS=m/z 525.6 [M+H] retention time: 1.61min.
Embodiment 308:5-(3-{ [(2, the 2-dimethyl propyl) amino] methyl } phenyl)-3-[1-(second sulfo group)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02592
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-thienyl methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate; With 2; 2-dimethyl-1-propylamine (30.6mg; 0.6mmol) replace 1-(2-thienyl) methylamine to prepare, obtain the title compound (59.5%) of 30.4mg.
LC/MS=m/z 511.4 [M+H] retention time: 1.69min.
Embodiment 309:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-methyl butyl) amino] methyl } phenyl)-1H-indole-7-Methanamide
Figure S2006800304481D02601
(44mg, (52mg is 0.6mmol) with 1 acetic acid 0.1mmol) to add 2-methyl-1-butene amine in the solution in dichloromethane (2mL) and methanol (1mL) to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide.This mixture is stirred 2h, add then Sodium Borohydride (22.8mg, 0.6mmol).The mixture of this generation is stirred 1h.Then it is concentrated, and be dissolved in once more in the dimethyl sulfoxine (3mL).Then it is prepared the HPLC purification through Gilson, obtain the title compound (55.6%) of 28.4mg.
LC/MS=m/z 511.4 [M+H] retention time: 1.71
Embodiment 310:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-([(2S)-and the 2-methyl butyl] amino } methyl) phenyl]-1H-indole-7-Methanamide
Figure S2006800304481D02602
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-methyl butyl) amino] methyl } phenyl)-1H-indole-7-Methanamide; With (2S)-2-methyl-1-butene amine (52mg; 0.6mmol) replace 2-methyl-1-butene amine to prepare, obtain the title compound (58.7%) of 30mg.
LC/MS=m/z 511.4 [M+H] retention time: 1.68
Embodiment 311:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ [(1R)-1,2,2-trimethyl propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide
Figure S2006800304481D02611
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-methyl butyl) amino] methyl } phenyl)-1H-indole-7-Methanamide; With (2R)-3; 3-dimethyl-2-butylamine (60mg; 0.6mmol) replace 2-methyl-1-butene amine to prepare, obtain the title compound (46.7%) of 24.5mg.
LC/MS=m/z 525.6 [M+H] retention time: 1.67
Embodiment 312:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-([(2S)-and tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02612
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-formoxyl phenyl)-1H-indole-7-Methanamide (40mg; 0.087mmol) (53mg is 0.525mmol) with 2 acetic acid for methylamine to add 1-[(2S)-tetrahydrochysene-2-furyl] in the solution in dichloromethane (2mL) and methanol (1mL).The mixture of this generation is at room temperature stirred 2h, add subsequently Sodium Borohydride (20mg, 0.525mmol).This mixture is stirred 30min, concentrate then, and prepare the HPLC purification, obtain the title compound (46.6%) of 26.6mg through Gilson.
LC/MS=m/z 543.4 [M+H] retention time: 1.60min.
Embodiment 313:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-([(2R)-and tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With 1-[(2R)-tetrahydrochysene-2-furyl] methylamine (53mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (47.4%) of 27.1mg.
LC/MS=m/z 543.4 [M+H] retention time: 1.58min.
Embodiment 314:5-[3-({ [(1S)-1,2-dimethyl propyl] amino } methyl)-5-fluorophenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With (2S)-3-methyl-2-butylamine (45mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (42%) of 19.3mg.
LC/MS=m/z 529.6 [M+H] retention time: 1.65
Embodiment 315:5-[3-({ [(1R)-1,2-dimethyl propyl] amino } methyl)-5-fluorophenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02631
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With (2R)-3-methyl-2-butylamine (45mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (34.9%) of 19.5mg.
LC/MS=m/z 529.4 [M+H] retention time: 1.82min.
Embodiment 316:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-{ [(1-methyl-propyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02632
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With 2-butylamine (37mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (50-6%) of 27-7mg.
LC/MS=m/z 515-4 [M+H] retention time: 1.63min.
Embodiment 317:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(1S)-1,2,2-trimethyl propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02641
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With (2S)-3; 3-dimethyl-2-butylamine (52mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (34.7%) of 19.8mg.
LC/MS=m/z 543.4 [M+H] retention time: 1.78min.
Embodiment 318:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-([(2S)-and the 2-methyl butyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02642
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With (2S)-2-methyl-1-butene amine (45mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (41.7%) of 23.3mg.
LC/MS=m/z 529.4 [M+H] retention time: 1.62min.
Embodiment 319:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-{ [(2-methyl butyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02651
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With 2-methyl-1-butene amine (45mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (54.5%) of 30.5mg.
LC/MS=m/z 529.4 [M+H] retention time: 1.73min.
Embodiment 320:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(1R)-1,2,2-trimethyl propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02652
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With (2R)-3; 3-dimethyl-2-butylamine (52mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (43.6%) of 24.9mg.
LC/MS=m/z 543.4 [M+H] retention time: 1.73min.
Embodiment 321:5-(3-{ [(2, the 2-dimethyl propyl) amino] methyl }-the 5-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With 2; 2-dimethyl-1-propylamine (45mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (25%) of 14mg.
LC/MS=m/z 529.4 [M+H] retention time: 1.79min.
Embodiment 322:5-(3-{ [(cyclopropyl methyl) amino] methyl }-the 5-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02662
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With 1-cyclopropyl-methylamine (37mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (38.7%) of 21.1mg.
LC/MS=m/z 513.4 [M+H] retention time: 1.69min.
Embodiment 323:5-(3-{ [(cyclopentyl-methyl) amino] methyl }-the 5-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02671
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With 1-cyclopenta methylamine (52mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (37.9%) of 21.6mg.
LC/MS=m/z 541.4 [M+H] retention time: 1.82min.
Embodiment 324:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-{ [(tetrahydrochysene-2H-pyrans-4-ylmethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With 1-(tetrahydrochysene-2H-pyrans-4-yl) methylamine (60mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (68.7%) of 40.1mg.
LC/MS=m/z 557.4 [M+H] retention time: 1.54min.
Embodiment 325:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-{ [(2-thienyl methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02681
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With 1-(2-thienyl) methylamine (59mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (41.9%) of 24.4mg.
LC/MS=m/z 555.4 [M+H] retention time: 1.67min.
Embodiment 326:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [2-(methoxyl group) ethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02682
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With 2-(methoxyl group) ethamine (39mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (56.5%) of 31mg.
LC/MS=m/z 517.2 [M+H] retention time: 1.52min.
Embodiment 327:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [3-(methoxyl group) propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02691
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With 3-(methoxyl group)-1-propylamine (46mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (48.7%) of 27.3mg.
LC/MS=m/z 531.4 [M+H] retention time: 1.54min.
Embodiment 328:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-{ [(2-furyl methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With 1-(2-furyl) methylamine (50mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (43.7%) of 24.8mg.
LC/MS=m/z 539.4 [M+H] retention time: 1.63min.
Embodiment 329:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-fluoro-5-{ [(3-methyl butyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02701
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With 3-methyl isophthalic acid-butylamine (45mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (49.4%) of 27.6mg.
LC/MS=m/z 529.4 [M+H] retention time: 1.67min.
Embodiment 330:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(5-methyl-2-furyl) methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02702
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-fluoro-5-({ [(2S)-tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With 1-(5-methyl-2-furyl) methylamine (58mg; 0.525mmol) replace 1-[(2S)-tetrahydrochysene-2-furyl] methylamine to prepare, obtain the title compound (48.8%) of 28.3mg.
LC/MS=m/z 553.6 [M+H] retention time: 1.78min.
Embodiment 331:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-methyl-propyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02711
(50mg, (70 μ L are 0.683mmol) with 2 acetic acid 0.114mmol) to add 2-methyl isophthalic acid-propylamine in the solution in dichloromethane (2mL) and methanol (1mL) to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide.This mixture is at room temperature stirred 2h, and add then Sodium Borohydride (26mg, 0.683mmol).Behind the 30min, mixture is concentrated, and be dissolved in the dimethyl sulfoxine (2mL), and prepare the HPLC purification, obtain the title compound (61%) of 19.8mg through Gilson.
LC/MS=m/z 497.4 [M+H] retention time: 1.57
Embodiment 332:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(2-pyrrolidinyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02712
With 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-1H-indole-7-Methanamide (70mg; 0.151mmol), 2-(3-iodophenyl) pyrrolidine (70mg, 0.456mmol) and potassium carbonate (126mg, 0.910mmol) the solution degasification 5min in two _ alkane (2mL) and water (1mL); And add four (triphenylphosphines) close palladium (0) (17mg, 0.015mmol).Mixture is reacted 20min in 160 ℃ in the CEM microwave.Separate organic layer and concentrated then.Then it is dissolved in the dimethyl sulfoxine (1mL), and prepares the HPLC purification, obtain the title compound (59.5%) of 48mg through Gilson.
LC/MS=m/z 481.0 [M+H] retention time: 1.47
Embodiment 333:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{2-fluoro-5-[(methylamino) methyl] phenyl }-1H-indole-7-Methanamide trifluoroacetate
(40mg, (262 μ L are 0.524mmol) with 1 acetic acid 0.087mmol) to add methylamine in the solution in dichloromethane (2mL) and methanol (1mL) to 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-fluoro-5-formoxyl phenyl)-1H-indole-7-Methanamide.After at room temperature stirring 2h, (20mg 0.524mmol), and leaves standstill 30min to add Sodium Borohydride.Then mixture is prepared the HPLC purification through Gilson, obtain the title compound (58.6%) of 12.3mg.
LC/MS=m/z 473.4 [M+H] retention time: 1.55.
Embodiment 334:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{2-fluoro-5-[(propyl group is amino) methyl] phenyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02722
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{2-fluoro-5-[(methylamino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With propylamine (44 μ L; 0.524mmol) replace methylamine to prepare, obtain the title compound (61.5%) of 15.4mg.
LC/MS=m/z 501.4 [M+H] retention time: 1.55
Embodiment 335:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-fluoro-5-{ [(2-methyl-propyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{2-fluoro-5-[(methylamino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With 2-methyl isophthalic acid-propylamine (53 μ L; 0.524mmol) replace methylamine to prepare, obtain the title compound (62.9%) of 15mg
LC/MS=m/z 515.4 [M+H] retention time: 1.55
Embodiment 336:5-(5-{ [(2, the 2-dimethyl propyl) amino] methyl }-the 2-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02732
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{2-fluoro-5-[(methylamino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With 2; 2-dimethyl-1-propylamine (46 μ L; 0.524mmol) replace methylamine to prepare, obtain the title compound (64.3%) of 14.3mg.
LC/MS=m/z 530.2 [M+H] retention time: 1.59
Embodiment 337:5-[5-({ [(1S)-1,2-dimethyl propyl] amino } methyl)-2-fluorophenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02741
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{2-fluoro-5-[(methylamino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With (2S)-3-methyl-2-butylamine (46 μ L; 0.524mmol) replace methylamine to prepare, obtain the title compound (64.3%) of 17.3mg
LC/MS=m/z 529.4 [M+H] retention time: 1.69
Embodiment 338:5-[5-({ [(1R)-1,2-dimethyl propyl] amino } methyl)-2-fluorophenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02742
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{2-fluoro-5-[(methylamino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With (2R)-3-methyl-2-butylamine (46 μ L; 0.524mmol) replace methylamine to prepare, obtain the title compound (64.3%) of 15mg.
LC/MS=m/z 529.4 [M+H] retention time: 1.70
Embodiment 339:5-(5-{ [(cyclopropyl methyl) amino] methyl }-the 2-fluorophenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02751
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{2-fluoro-5-[(methylamino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With 2-methyl-1-butene amine (38 μ L; 0.524mmol) replace methylamine to prepare, obtain the title compound (62.7%) of 16.2mg.
LC/MS=m/z 513.4 [M+H] retention time: 1.57
Embodiment 340:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-fluoro-5-(1-pyrrolidinyl methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02752
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{2-fluoro-5-[(methylamino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With pyrrolidine (44 μ L; 0.524mmol) replace methylamine to prepare, obtain the title compound (62.7%) of 10mg.
LC/MS=m/z 513.4 [M+H] retention time: 1.62
Embodiment 341:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-fluoro-5-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02761
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{2-fluoro-5-[(methylamino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With morpholine (45 μ L; 0.524mmol) replace methylamine to prepare, obtain the title compound (64.3%) of 15mg
LC/MS=m/z 529.4 [M+H] retention time: 1.52
Embodiment 342:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-fluoro-5-({ [2-(methoxyl group) ethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02762
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-fluoro-5-formoxyl phenyl)-1H-indole-7-Methanamide (40mg; 0.087mmol) (54 μ L are 0.524mmol) with 1 acetic acid to add 2-(methoxyl group) ethamine in the solution in dichloromethane (2mL) and methanol (1mL).It is last at room temperature to stir week, and (20mg 0.524mmol), and leaves standstill 30min to add Sodium Borohydride.Then mixture is prepared the HPLC purification through Gilson, obtain the title compound (63%) of 11.4mg.
LC/MS=m/z 517.2 [M+H] retention time: 1.57
Embodiment 343:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-fluoro-5-({ [3-(methoxyl group) propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02771
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-fluoro-5-({ [2-(methoxyl group) ethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate; With 3-(methoxyl group)-1-propylamine (53 μ L; 0.524mmol) replace 2-(methoxyl group) ethamine to prepare, obtain the title compound (64.5%) of 15mg.
LC/MS=m/z 531.4 [M+H] retention time: 1.60
Embodiment 344:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(1-methyl-2-pyrrolidinyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02772
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(2-pyrrolidinyl) phenyl]-1H-indole-7-Methanamide (20mg; 0.04mmol), (9.5mL 0.125mmol) with in the solution of sodium triacetoxy borohydride in dichloromethane (2mL) adds 2 acetic acid to formaldehyde.With the mixture that generates stirred overnight at room temperature.Evaporate all solvents, and product is dissolved in the dimethyl sulfoxine (1mL) once more.Then mixture is prepared HPLC through Gilson and separate twice, obtain the title compound (60.9%) of 8.9mg.
LC/MS=m/z 495.4 [M+H] retention time: 1.54
Embodiment 345:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{2-[(2-methyl-propyl) amino] ethyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02781
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1; 3,2-dioxa bora ring penta-2-yl)-and 1H-indole-7-Methanamide (60mg, 0.13mmol), [2-(3-bromophenyl) ethyl] (2-methyl-propyl) amine (100mg; 0.39mmol) and potassium carbonate (108mg is 0.780mmol) in the solution in Zai diox (2mL) and the water (0.7mL).With the mixture degasification 5min that generates, add then four (triphenylphosphines) close palladium (0) (14mg, 0.013mmol).It is reacted 20min in 160 ℃ in the CEM microwave.Should react then and use Gilson to prepare the HPLC purification, obtain the title compound (62.5%) of 44mg.
LC/MS=m/z 511.2 [M+H] retention time: 1.79
Embodiment 346:5-{3-[2-(ethylamino) ethyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02782
With 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1; 3,2-dioxa bora ring penta-2-yl)-and 1H-indole-7-Methanamide (40.4mg, 0.09mmol), 2-(3-bromophenyl)-N-ethyl ethamine (60mg; 0.263mmol) and potassium carbonate (72mg, 0.526mmol) the solution degasification 5min in two _ alkane (2mL) and water (0.7mL).To wherein add four (triphenylphosphines) close palladium (0) (11mg, 0.009mmol).The mixture that generates is reacted 20min in 160 ℃ in the CEM microwave.Should react then and use Gilson to prepare the HPLC purification, obtain the title compound (59.7%) of 38.6mg.
LC/MS=m/z 482.8 [M+H] retention time: 1.54
Embodiment 347:3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[2-(propyl group is amino) ethyl] phenyl }-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02791
With 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-1H-indole-7-Methanamide (25mg; 0.055mmol), potassium carbonate (46mg, 0.33mmol) with [2-(3-bromophenyl) ethyl] propylamine (40mg, 0.165mmol) the solution degasification 5min in two _ alkane (2mL) and water (0.7mL); Add then four (triphenylphosphines) close palladium (0) (7mg, 0.006mmol).The mixture that generates is reacted 20min in 160 ℃ in the CEM microwave.Should react then and use Gilson to prepare the HPLC separation, obtain the title compound (61%) of 17.6mg.
LC/MS=m/z 497.4 [M+H] retention time: 1.97
Embodiment 348:5-{3-[2-(dimethylamino) ethyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02801
With 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-1H-indole-7-Methanamide (60mg; 0.13mmol), potassium carbonate (108mg, 0.78mmol) and 2-(3-bromophenyl)-N, N-dimethyl amine (90mg; 0.39mmol) solution degasification 5min in two _ alkane (2mL) and water (0.7mL), add then four (triphenylphosphines) close palladium (0) (15mg, 0.013mmol).The mixture that generates is reacted 20min in 160 ℃ in the CEM microwave.Should react then and use Gilson to prepare the HPLC separation, obtain the title compound (59.7%) of 30mg.
LC/MS=m/z 483.2 [M+H] retention time: 1.60
Embodiment 349:5-{3-[2-(dipropyl is amino) ethyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02802
With 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-1H-indole-7-Methanamide (66mg; 0.14mmol), potassium carbonate (120mg, 0.86mmol) with (2-phenylethyl) di-n-propylamine (120mg, 0.43mmol) the solution degasification 5min in two _ alkane (2mL) and water (0.7mL); Add then four (triphenylphosphines) close palladium (0) (15mg, 0.014mmol).The mixture that generates is reacted 20min in 160 ℃ in the CEM microwave.Should react then and use Gilson to prepare the HPLC separation, obtain the title compound (65.3%) of 9mg.
LC/MS=m/z 455.0 [M+H] retention time: 1.55
Embodiment 350:5-[3-({ [2-(3,5-dimethyl-1H-pyrazol-1-yl) ethyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02811
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (44mg; 0.1mmol), 2-(3; 5-dimethyl-1H-pyrazol-1-yl) (105mg 0.6mmol) adds 3 acetic acid to ethamine in the solution in dichloromethane (3mL) and methanol (1.5mL).With the mixture stirred overnight that generates, add then sodium triacetoxy borohydride (134mg, 0.6mmol).With this mixture stirred overnight.The mixture that generates is stopped with sodium bicarbonate (2mL) and saline (2mL), and collected organic layer, and concentrate.Should react then and use Gilson to prepare the HPLC separation, obtain the title compound (67.7%) of 26mg
LC/MS=m/z 563.2 [M+H] retention time: 1.51
Embodiment 351:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(4-morpholinyl methyl)-1,3-thiazoles-4-yl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02812
(192mg, (130ul is 1.5mmol) with 3 AcOH 1.0mmol) to add morpholine in the solution in DCM (4.0mL) to 4-bromo-1,3-thiazoles-2-formaldehyde.Mixture is stirred 12hr, and add Na then (OAc) 3BH (0.335g, 1.5mmol).Behind the 6hr, with mixture with saturated NaHCO 3(4.0mL) and saline (3.0mL) stop.Separate organic layer and concentrated, obtain 4-[(the 4-bromo-1,3-thiazoles-2-yl) methyl] morpholine (76%) of 200mg.
With 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-1H-indole-7-Methanamide (46mg; 0.1mmol), 4-[(4-bromo-1,3-thiazoles-2-yl) methyl] morpholine (79mg, 0.3mmol) and potassium carbonate (83mg; 0.6mmol) solution degasification 5min in two _ alkane (2mL) and water (0.7mL), add then the triacetoxy boron hydride thing (11mg, 0.1mmol).This mixture is reacted 20min in 160 ℃ in the CEM microwave.Collected organic layer also concentrates.Residue is dissolved in the dimethyl sulfoxine (1mL) again, and uses Gilson to prepare the HPLC purification then, obtain the title compound (63.2%) of 26.6mg
LC/MS=m/z 518.2 [M+H] retention time: 1.49
Embodiment 352:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-{ [(2-methyl-propyl) amino] methyl }-1,3-thiazoles-4-yl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02821
(192mg, (152ul is 1.5mmol) with 3 AcOH 1.0mmol) to add different-propyl group amine in the solution in DCM (4.0mL) to 4-bromo-1,3-thiazoles-2-formaldehyde.Mixture is stirred 12hr, and add Na then (OAc) 3BH (0.335g, 1.5mmol).Behind the 6hr, with mixture with saturated NaHCO 3(4.0mL) and saline (3.0mL) stop.Separate organic layer and concentrated, obtain the title compound (58%) of 145mg.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-1H-indole-7-formaldehyde (46mg; 0.1mmol), 2-methyl isophthalic acid-propylamine (70mg; 0.3mmol) and potassium carbonate (83mg, 0.6mmol) add in the solution in two _ alkane (2mL) and water (0.7mL) the triacetoxy boron hydride thing (11mg, 0.01mmol).With this solution degasification 5min, in the CEM microwave, react 20min then in 160 ℃.Separate organic layer and concentrated.Use Gilson to prepare the HPLC purification it then, obtain the title compound (61.8%) of 24mg.
LC/MS=m/z 504.2 [M+H] retention time: 1.43
Embodiment 353:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(1-pyrrolidinyl methyl)-1,3-thiazoles-4-yl]-1H-indole-7-Methanamide
Figure S2006800304481D02831
(192mg, (124ul is 1.5mmol) with 3 AcOH 1.0mmol) to add pyrrolidine in the solution in DCM (4.0mL) to 4-bromo-1,3-thiazoles-2-formaldehyde.Mixture is stirred 12hr, and add Na then (OAc) 3BH (0.335g, 1.5mmol).Behind the 6hr, with mixture with saturated NaHCO 3(4.0mL) and saline (3.0mL) stop.Separate organic layer and concentrated, obtain the title compound (82%) of 200mg.
Title compound be according to the preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-{ [(2-methyl-propyl) amino] methyl }-1; 3-thiazole-4-yl)-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With pyrrolidine (74mg; 0.3mmol) replace 2-methyl isophthalic acid-propylamine to prepare, obtain the title compound (50%) of 6.3mg.
LC/MS=m/z 500.4 [M+H] retention time: 1.22
Embodiment 354:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(piperidino methyl)-1,3-thiazoles-4-yl]-1H-indole-7-Methanamide
Figure S2006800304481D02841
(192mg, (150ul is 1.5mmol) with 3 AcOH 1.0mmol) to add piperidines in the solution in DCM (4.0mL) to 4-bromo-1,3-thiazoles-2-formaldehyde.Mixture is stirred 12hr, and add Na then (OAc) 3BH (0.335g, 1.5mmol).Behind the 6hr, with mixture with saturated NaHCO 3(4.0mL) and saline (3.0mL) stop.Separate organic layer and concentrated, obtain the title compound (64%) of 166mg.
Title compound be according to the preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-{ [(2-methyl-propyl) amino] methyl }-1; 3-thiazole-4-yl)-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With piperidines (78mg; 0.3mmol) replace 2-methyl isophthalic acid-propylamine to prepare, obtain the title compound (51.6%) of 15.5mg.
LC/MS=m/z 517.4 [M+H] retention time: 1.29
Embodiment 355:5-{2-[(dimethylamino) methyl]-1,3-thiazoles-4-yl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02842
(192mg, (2.0M is 3.0mL) with 3 AcOH 1.0mmol) to add DMA in the solution in DCM (4.0mL) to 4-bromo-1,3-thiazoles-2-formaldehyde.Mixture is stirred 48hr, and add Na then (OAc) 3BH (1.33g, 6.0mmol).Behind the 12hr, with mixture with saturated NaHCO 3(4.0mL) and saline (3.0mL) stop, and use liquor separator to obtain the DCM organic layer.Concentrate this organic layer, obtain the required product (40%) of 90mg.
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-1H-indole-7-Methanamide (46mg; 0.1mmol), DMA (69mg; 0.3mmol) and potassium carbonate (83mg, 0.6mmol) add in the solution in two _ alkane (2mL) and water (0.7mL) the triacetoxy boron hydride thing (12mg, 0.01mmol).With this mixture degasification 5min.Then mixture is reacted 20min in 160 ℃ in microwave.Separate organic layer and concentrated.Use Gilson to prepare the HPLC purification it then, obtain the title compound (59%) of 23mg
LC/MS=m/z 474.4 [M+H] retention time: 1.20
Embodiment 356:5-(2-{ [ethyl (methyl) amino] methyl }-1,3-thiazoles-4-yl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02851
(192mg, (470ul is 6.0mmol) with 3 AcOH 1.0mmol) to add the N-methyl ethyl-amine in the solution in DCM (4.0mL) to 4-bromo-1,3-thiazoles-2-formaldehyde.Mixture is stirred 48hr, and add Na then (OAc) 3BH (1.33g, 6.0mmol).Behind the 12hr, with mixture with saturated NaHCO 3(4.0mL) and saline (3.0mL) stop, and use liquor separator to obtain the DCM organic layer.Concentrate this organic layer, obtain the title compound (68%) of 160mg.
Title compound is according to preparation 5-{2-[(dimethylamino) methyl]-1; 3-thiazole-4-yl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With ethyl (methyl) amine (73mg; 0.3mmol) replace DMA to prepare, obtain the title compound (60.4%) of 25mg.
LC/MS=m/z 490.4 [M+H] retention time: 1.25
Embodiment 357:5-(3-cyanic acid-5-{ [(2-methyl-propyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02861
Under 0 ℃ under argon atmospher, (1.0g 7.6mmol) drips dense H in the solution in TFA (4.0mL) to 3-formoxyl benzonitrile 2SO 4(6.0mL), add NBS with fraction subsequently.Mixture slowly is warmed to room temperature, and under argon, stirs 12h then.When reaction is accomplished, mixture is poured into ice-H 2O (80mL) and PdCl 2(117mg, 0.658mmol) in, and collect this solid, and drying under vacuum overnight, obtain the 3-bromo-5-formoxyl Benzoylamide (86%) of 1.50g.
LC/MS=m/z 228.2 [M+H] retention time: 1.37
(1.5g is 6.58mmol) at H to 3-bromo-5-formoxyl Benzoylamide 2Add PdCl in the solution among O (50.0mL) and the MeCN (50.0mL) 2(117mg, 0.658mmol).Mixture is at room temperature stirred 72h, add the H of another part 2O (100mL) and MeCN (100mL) add PdCl subsequently 2(100mg, 0.56mol).With mixture restir 12hr and concentrated.Residue is dissolved among the EtOAc (200mL), and (3 * 50.0mL) wash, through Na with saline 2SO 4Dry and concentrated, and, obtain the 3-bromo-5-formoxyl benzonitrile (40%) of 550mg then through chromatography (hexane of 10%EtOAc is dissolved in) purification.
(4,4,5,5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-(46mg is 0.1mmol) at two _ alkane (2.0mL) and H for 1H-indole-7-Methanamide to 3-[1-(ethylsulfonyl)-4-piperidyl]-5- 2Add in the solution among the O (0.7mL) 3-bromo-5-formoxyl benzonitrile (68mg, 0.3mmol) and potassium carbonate (83mg, 0.6mmol).With mixture degasification 5min, add subsequently four (triphenylphosphines) close palladium (0) (12mg, 0.01mmol).Mixture is reacted 20min in 160 ℃ in microwave.This chemical compound is prepared the HPLC purification through Gilson, obtain 5-(3-cyanic acid-5-formoxyl phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide.
To 5-(3-cyanic acid-5-formoxyl phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (47mg; 0.1mmol) add in the solution in dichloromethane (3mL) and methanol (1mL) several acetic acid and methyl (2-methyl-propyl) amine (64 μ L, 0.6mmol).With this mixture stirred overnight, add 20 acetic acid and sodium triacetoxy borohydride (0.6mmol) subsequently.Should react and mix 4h, add subsequently methyl (2-methyl-propyl) amine (64 μ L, 0.6mmol) and sodium triacetoxy borohydride (0.6mmol).With this mixture stirred overnight, stop with sodium bicarbonate and saline then.Separate organic layer and concentrated through the SCX post.Using Gilson to prepare HPLC it then separates, obtains the title compound (63.6%) of 10.3mg.
LC/MS=m/z 522.4 [M+H] retention time: 1.65
Embodiment 358:5-{3-cyanic acid-5-[(dimethylamino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02871
Title compound is the conventional method according to preparation 5-(3-cyanic acid-5-{ [(2-methyl-propyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate; With trimethylamine (300 μ L; 0.3mmol) replace methyl (2-methyl-propyl) amine to prepare, obtain the title compound (61%) of 10.5mg.
LC/MS=m/z 494.4 [M+H] retention time: 1.48
Embodiment 359:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02872
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (80mg, 0.181mmol) add in the solution in DCM morpholine (50 μ L, 0.545mmol).Should react and at room temperature stir 30min, add subsequently sodium triacetoxy borohydride (120mg, 0.545mmol).Should react and at room temperature spend the night, and concentrate then.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (25%) of 28.6mg.
LC/MS=m/z 511.4 [M+H] retention time: 1.48min
Embodiment 360:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ [(4-fluorophenyl) carbonyl] amino } methyl) phenyl]-1H-indole-7-Methanamide trifluoroacetate
Title compound is according to preparation 5-{3-[(acetyl-amino) methyl] phenyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide, [3-(4,4,5 with 4-fluoro-N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl } Benzoylamide (125mg; 0.352mmol) [3-(4,4,5 to replace N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl } acetamide prepares.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (27%) of 18.3mg.
LC/MS=m/z 563.1 [M+H] retention time: 2.07min
Embodiment 361:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-furyl carbonyl) amino] methyl } phenyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02891
Title compound is according to preparation 5-{3-[(acetyl-amino) methyl] phenyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide, [3-(4,4,5 with N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl }-2-furoylamide (115mg; 0.352mmol) [3-(4,4,5 to replace N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl } acetamide prepares.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (12%) of 8.1mg.
LC/MS=m/z 535 [M+H] retention time: 1.89min
Embodiment 362:5-(3-{ [(cyclopentylcarbonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D02892
Title compound is according to preparation 5-{3-[(acetyl-amino) methyl] phenyl }-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide, [3-(4,4,5 with N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl } cyclopentane formamide (116mg; 0.352mmol) [3-(4,4,5 to replace N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl } acetamide prepares.Chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (14%) of 9.2mg.
LC/MS=m/z 535 [M+H] retention time: 1.89min
Embodiment 363:5-(3-{ [(1-benzothiophene-2-base carbonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D02901
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(valeryl amino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide, [3-(4,4,5 with N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl }-1-benzothiophene-2-Methanamide (57mg; 0.144mmol) [3-(4,4,5 to replace N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl } pentanamide prepares.Chemical compound is prepared the HPLC purification through Gilson, obtain title compound.
LC/MS=m/z 601.2 [M+H] retention time: 2.18min
Embodiment 364:5-[3-({ [(1-acetyl group-4-piperidyl) carbonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(valeryl amino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide, [3-(4,4,5 with 1-acetyl group-N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl }-4-piperidine formamide (56mg; 0.144mmol) [3-(4,4,5 to replace N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl } pentanamide prepares.Chemical compound is prepared the HPLC purification through Gilson, obtain title compound.
LC/MS=m/z 594.4 [M+H] retention time: 1.87min
Embodiment 365:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ [(1-methyl isophthalic acid H-pyrroles-2-yl) carbonyl] amino } methyl) phenyl]-1H-indole-7-Methanamide
Figure S2006800304481D02911
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(valeryl amino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide, [3-(4,4,5 with 1-methyl-N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl }-1H-pyrroles-2-Methanamide (49mg; 0.144mmol) [3-(4,4,5 to replace N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl } pentanamide prepares.Chemical compound is prepared the HPLC purification through Gilson, obtain title compound.
LC/MS=m/z 548.4 [M+H] retention time: 2.02min
Embodiment 366:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(2-thienyl acetyl group) amino] methyl } phenyl)-1H-indole-7-Methanamide
Figure S2006800304481D02921
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(valeryl amino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide, [3-(4,4,5 with N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl }-2-(2-thienyl) acetamide (51mg; 0.144mmol) [3-(4,4,5 to replace N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl } pentanamide prepares.This chemical compound through Mass Directed Auto Prep HPLC purification, is obtained the title compound (18.2%) of 10.3mg.
LC/MS=m/z 565.2 [M+H] retention time: 1.95min
Embodiment 367:5-(3-{ [(cyclobutyl carbonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D02922
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(valeryl amino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide, [3-(4,4,5 with N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl } Tetramethylene. Methanamide (45mg; 0.144mmol) [3-(4,4,5 to replace N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl } pentanamide prepares.This chemical compound through Mass Directed Auto Prep HPLC purification, is obtained the title compound (8%) of 4.3mg.
LC/MS=m/z 523.4 [M+H] retention time: 1.90min
Embodiment 368:5-(3-{ [(cyclopropyl carbonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D02931
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{3-[(valeryl amino) methyl] phenyl }-conventional method of 1H-indole-7-Methanamide, [3-(4,4,5 with N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl } cyclopropane carboxamide (43mg; 0.144mmol) [3-(4,4,5 to replace N-{; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl) phenyl] methyl } pentanamide prepares.This chemical compound through Mass Directed Auto Prep HPLC purification, is obtained the title compound (11%) of 5.5mg.
LC/MS=m/z 509.2 [M+H] retention time: 1.85min
Embodiment 369:5-(3-{ [(cyclopropyl sulfonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D02932
To 5-[3-(amino methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (35mg; 0-079mmol) add cyclopropane sulfonic acid chloride (11mg in the solution in DMF (1.0mL) and DCM (1.0mL); 0.079mmol) and DIEA (14 μ L, 0.079mmol).This is reacted stirred overnight at room temperature.Chemical compound is prepared the HPLC purification through Gilson, obtain 7.2mg title compound (17%).
.LC/MS=m/z 545.4 [M+H] retention time: 1.94min
Embodiment 370:5-[3-({ [(2, the 5-Dichlorobenzene base) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D02941
To 5-[3-(amino methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (40mg; 0.096mmol) add 2 in the solution in DMF (1.0mL) and DCM (1.0mL); The 5-two chloro phenylsulfonyl chloride (86mg, 0.352mmol) and DIEA (62 μ L, 0.352mmol).Should react and at room temperature stir 6h.Then reactant mixture is concentrated, and prepare the HPLC purification, obtain 6.6mg title compound (11%) through Gilson.
.LC/MS=m/z 649.2 [M+H] retention time: 2.25min
Embodiment 371:5-[3-({ [(4-bromophenyl) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D02951
Title compound is that [3-({ [(2 according to preparation 5-; The 5-Dichlorobenzene base) sulfonyl] amino } methyl) phenyl]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 4-bromobenzene sulfonyl chloride (90mg; 0.352mmol) replacing 2, the 5-two chloro phenylsulfonyl chloride prepares.Then reactant mixture is concentrated, and prepare the HPLC purification, obtain 19.4mg title compound (31%) through Gilson.
LC/MS=m/z 659.4 [M+H] retention time: 2.20min
Embodiment 372:5-[3-({ [(4-chlorphenyl) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D02952
Title compound is that [3-({ [(2 according to preparation 5-; The 5-Dichlorobenzene base) sulfonyl] amino } methyl) phenyl]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide, with (2E, 4E)-5-chloro-2; 4; (80mg 0.352mmol) replaces 2 to 6-heptantriene-2-sulfonic acid chloride, and the 5-two chloro phenylsulfonyl chloride prepares.Then reactant mixture is concentrated, and prepare the HPLC purification, obtain 7.5mg title compound (13%) through Gilson.
LC/MS=m/z 615.2 [M] retention time: 2.19min
Embodiment 373:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ [(3-fluorophenyl) sulfonyl] amino } methyl) phenyl]-1H-indole-7-Methanamide
Figure S2006800304481D02961
Title compound is that [3-({ [(2 according to preparation 5-; The 5-Dichlorobenzene base) sulfonyl] amino } methyl) phenyl]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 3-fluorobenzene sulfonic acid chloride (69mg; 0.352mmol) replacing 2, the 5-two chloro phenylsulfonyl chloride prepares.Then reactant mixture is concentrated, and prepare the HPLC purification, obtain 7.3mg title compound (13%) through Gilson.
LC/MS=m/z 599.2 [M+H] retention time: 2.15min
Embodiment 374:5-[3-({ [(2-chlorphenyl) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D02962
Title compound is that [3-({ [(2 according to preparation 5-; The 5-Dichlorobenzene base) sulfonyl] amino } methyl) phenyl]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 2-chlorobenzene sulfonyl chloride (74mg; 0.352mmol) replacing 2, the 5-two chloro phenylsulfonyl chloride prepares.Then reactant mixture is concentrated, and prepare the HPLC purification, obtain 17.3mg title compound (29%) through Gilson.
LC/MS=m/z 615.2 [M] retention time: 2.15min
Embodiment 375:5-[3-({ [(2,5-two chloro-3-thienyls) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D02971
Title compound is that [3-({ [(2 according to preparation 5-; The 5-Dichlorobenzene base) sulfonyl] amino } methyl) phenyl]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 2; (86mg 0.352mmol) replaces 2 to 5-two chloro-3-thiophene sulfonic acid chlorides, and the 5-two chloro phenylsulfonyl chloride prepares.Then reactant mixture is concentrated, and prepare the HPLC purification, obtain 16.7mg title compound (27%) through Gilson.
LC/MS=m/z 655.2 [M] retention time: 2.24min
Embodiment 376:5-[3-({ [(2-chloro-6-aminomethyl phenyl) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D02972
Title compound is that [3-({ [(2 according to preparation 5-; The 5-Dichlorobenzene base) sulfonyl] amino } methyl) phenyl]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 2-chloro-6-Methyl benzenesulfonyl chlorine (86mg; 0.352mmol) replacing 2, the 5-two chloro phenylsulfonyl chloride prepares.Then reactant mixture is concentrated, and prepare the HPLC purification, obtain 17.9mg title compound (30%) through Gilson.
LC/MS=m/z 629.4 [M] retention time: 2.19min
Embodiment 377:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ [(5-fluoro-2-aminomethyl phenyl) sulfonyl] amino } methyl) phenyl]-1H-indole-7-Methanamide
Figure S2006800304481D02981
Title compound is that [3-({ [(2 according to preparation 5-; The 5-Dichlorobenzene base) sulfonyl] amino } methyl) phenyl]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 5-fluoro-2-Methyl benzenesulfonyl chlorine (86mg; 0.352mmol) replacing 2, the 5-two chloro phenylsulfonyl chloride prepares.Then reactant mixture is concentrated, and prepare the HPLC purification, obtain title compound through Gilson.
LC/MS=m/z 613.2 [M+H] retention time: 2.18min
Embodiment 378:5-[3-({ [(1,2-dimethyl-1H-imidazol-4 yl) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D02991
Title compound is that [3-({ [(2 according to preparation 5-; The 5-Dichlorobenzene base) sulfonyl] amino } methyl) phenyl]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 1; (69mg 0.352mmol) replaces 2 to 2-dimethyl-1H-imidazoles-4-sulfonic acid chloride, and the 5-two chloro phenylsulfonyl chloride prepares.Then reactant mixture is concentrated, and prepare the HPLC purification, obtain 1.9mg title compound (3.3%) through Gilson.
LC/MS=m/z 599.2 [M+H] retention time: 1.76min
Embodiment 379:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(phenyl sulfonyl) amino] methyl } phenyl)-1H-indole-7-Methanamide
Figure S2006800304481D02992
Title compound is that [3-({ [(2 according to preparation 5-; The 5-Dichlorobenzene base) sulfonyl] amino } methyl) phenyl]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; (62mg 0.352mmol) replaces 2, and the 5-two chloro phenylsulfonyl chloride prepares with benzene sulfonyl chloride.Then reactant mixture is concentrated, and prepare the HPLC purification, obtain 13.4mg title compound (24%) through Gilson.
LC/MS=m/z 581.6 [M+H] retention time: 2.10min
Embodiment 380:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[3-({ [(4-fluorophenyl) sulfonyl] amino } methyl) phenyl]-1H-indole-7-Methanamide
Figure S2006800304481D03001
Title compound is that [3-({ [(2 according to preparation 5-; The 5-Dichlorobenzene base) sulfonyl] amino } methyl) phenyl]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 4-fluorobenzene sulfonic acid chloride (69mg; 0.352mmol) replacing 2, the 5-two chloro phenylsulfonyl chloride prepares.Then reactant mixture is concentrated, and prepare the HPLC purification, obtain 11.5mg title compound (20%) through Gilson.
LC/MS=m/z 599.2 [M+H] retention time: 2.10min
Embodiment 381:5-[3-({ [(4-bromo-2-ethylphenyl) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D03011
Title compound is that [3-({ [(2 according to preparation 5-; The 5-Dichlorobenzene base) sulfonyl] amino } methyl) phenyl]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 4-bromo-2-ethylo benzene sulfonic acid chloride (100mg; 0.352mmol) replacing 2, the 5-two chloro phenylsulfonyl chloride prepares.Then reactant mixture is concentrated, and prepare the HPLC purification, obtain 2.7mg title compound (4%) through Gilson.
LC/MS=m/z 687.6 [M] retention time: 2.38min
Embodiment 382:5-(3-{ [(1-benzothiophene-3-base sulfonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D03012
Title compound is that [3-({ [(2 according to preparation 5-; The 5-Dichlorobenzene base) sulfonyl] amino } methyl) phenyl]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 1-benzothiophene-3-sulfonic acid chloride (82mg; 0.352mmol) replacing 2, the 5-two chloro phenylsulfonyl chloride prepares.Then reactant mixture is concentrated, and prepare the HPLC purification, obtain 3.9mg title compound (6%) through Gilson.
LC/MS=m/z 637.4 [M+H] retention time: 2.19min
Embodiment 383:5-{3-[({ [4-(1, the 1-dimethyl ethyl) phenyl] sulfonyl } amino) methyl] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D03021
Title compound is that [3-({ [(2 according to preparation 5-; The 5-Dichlorobenzene base) sulfonyl] amino } methyl) phenyl]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 4-(1; The 1-dimethyl ethyl) (82mg 0.352mmol) replaces 2 to benzene sulfonyl chloride, and the 5-two chloro phenylsulfonyl chloride prepares.Then reactant mixture is concentrated, and prepare the HPLC purification, obtain 15.6mg title compound (26%) through Gilson.
LC/MS=m/z 637.4 [M+H] retention time: 2.35min
Embodiment 384:5-[3-({ [(3, the 4-difluorophenyl) sulfonyl] amino } methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D03031
Title compound is that [3-({ [(2 according to preparation 5-; The 5-Dichlorobenzene base) sulfonyl] amino } methyl) phenyl]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 3; (75mg 0.352mmol) replaces 2 to the 4-difluoro chloride, and the 5-two chloro phenylsulfonyl chloride prepares.Then reactant mixture is concentrated, and prepare the HPLC purification, obtain title compound through Gilson.
LC/MS=m/z 617.2 [M+H] retention time: 2.16min
Embodiment 385:5-(3-{ [(2,1,3-benzo _ diazole-4-base sulfonyl) amino] methyl } phenyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D03032
Title compound is that [3-({ [(2 according to preparation 5-; The 5-Dichlorobenzene base) sulfonyl] amino } methyl) phenyl]-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; With 2,1,3-benzo _ diazole-4-sulfonic acid chloride (77mg; 0.352mmol) replacing 2, the 5-two chloro phenylsulfonyl chloride prepares.Then reactant mixture is concentrated, and prepare the HPLC purification, obtain title compound through Gilson.
LC/MS=m/z 623.4 [M+H] retention time: 2.10min
Embodiment 386:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(tetrahydrochysene-3-furyl carbonyl) amino] methyl } phenyl)-1H-indole-7-Methanamide
Figure S2006800304481D03041
To tetrahydrochysene-3-furancarboxylic acid (17mg, 0.144mmol) add in the solution in DCM (2.0mL) pyridine (3) and oxalyl chloride (18mg, 0.144mmol).With reactant mixture stirred overnight at room temperature.(40mg is 0.096mmol) at DMF (1.0mL) and DIEA (33 μ L, the solution in 0.192mmol) in mixture, to add 5-[3-(amino methyl) phenyl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide then.With reactant mixture stirred overnight at room temperature.Reactant mixture is concentrated under nitrogen, and prepare the HPLC purification, obtain 5.3mg title compound (10%) through Gilson.
LC/MS=m/z 539.2 [M+H] retention time: 1.80min
Embodiment 387:5-{4-[(cyclopenta sulfonyl) amino] phenyl }-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (20mg, add in 0.048mmol) chlorination (two-2-norborny phosphino-) (2-dimethylaminomethyl ferrocene-1-yl) close palladium (II) (10mg, 0.016mmol), potassium carbonate (13.4mg; 0.097mmol) and N-[4-(4,4,5; 5-tetramethyl-1; 3,2-dioxa bora ring penta-2-yl) phenyl] (34mg is 0.097mmol) at two _ alkane (3mL) and H for the Pentamethylene. sulfonamide 2Solution among the O (1mL).Reactant mixture is heated 10min in 160 ℃ in microwave.Reactant mixture is concentrated under nitrogen, and prepare the HPLC purification, obtain 8.6mg title compound (32%) through Gilson.
LC/MS=m/z 559.2 [M+H] retention time: 2.00min
Embodiment 388:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[4-(4-methyl-2-oxo-1-piperazinyl) phenyl]-1H-indole-7-Methanamide
To 5-bromo-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (20mg, methyl isophthalic acid-[4-(4,4 to add 4-in 0.048mmol); 5,5-tetramethyl-1,3; 2-dioxa bora ring penta-2-yl) phenyl]-(31mg is 0.097mmol) at two _ alkane (3.0mL) and H for 2-piperazine ketone 2Add in the solution among the O (1.0mL) potassium carbonate (13mg, 0.097mmol) and chlorination (two-2-norborny phosphino-) (2-dimethylaminomethyl ferrocene-1-yl) close palladium (II) (10mg, 0.016mmol).Reactant mixture is reacted 10min in 160 ℃ in microwave.Reactant mixture is heated 10min in 160 ℃ in microwave.Reactant mixture is concentrated under nitrogen, and prepare the HPLC purification through Gilson.With required fraction at CH 3CN and H 2Solution among the O is handled this salt of neutralization with saturated potassium carbonate, and concentrates then, obtains 1.9mg title compound (8%).
LC/MS=m/z 524.6 [M+H] retention time: 1.49min
Embodiment 389:5-[6-(4-acetyl group-1-piperazinyl)-3-pyridine radicals]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D03061
Under 0 ℃; To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[6-(1-piperazinyl)-3-pyridine radicals]-1H-indole-7-Methanamide (40mg; 0.080mmol) add in the solution in dichloromethane chloroacetic chloride (7 μ L, 0.096mmol) and DIEA (11.6 μ L, 0.12mmol).With reactant mixture by 0 ℃ to room temperature reaction 0.5h, and use H then 2O stops.Chemical compound through MDAP HPLC purification, is obtained the title compound (40%) of 7mg.
LC/MS=m/z 539.4 [M+H] retention time: 1.27min
Embodiment 390:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(methoxyl group) amino] methyl } phenyl)-1H-indole-7-Methanamide
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol) add in the solution in DCM (1.5mL) and MeOH (1.5mL) O-methyl hydroxylamine (114mg, 1.71mmol).Should react stirred overnight.Concentrate this solvent then, and prepare the HPLC purification, obtain 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(methoxyl group) imido grpup] methyl } phenyl)-1H-indole-7-Methanamide (76%) of 38mg through Gilson.
Under 0 ℃; To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4-{ [(methoxyl group) imido grpup] methyl } phenyl)-1H-indole-7-Methanamide (21.5mg; 0.046mmol) adding 1 of several HCl in the solution in DCM (3.0mL) and MeOH (3.0 mL), 4-two _ alkane solution is to keep pH=4.Add then sodium cyanoborohydride (29mg, 0.46mmol), and stirred overnight at room temperature.Remove sodium cyanoborohydride (45mg, 0.72mmol) outside, adds 1 of other HCl, 4-two _ alkane solution is with maintenance pH=4.Then reactant mixture is stirred 48h.Under 0 ℃, add 1 of other HCl, 4-two _ alkane solution is with maintenance pH=4, and stirring is until room temperature.Mixture is used H 2O stops.Add DCM then and carry out the aqueous solution processing, and mixture is concentrated.Then residue is dissolved among the DCM, and on SCX SPE post purification, obtain the title compound (70%) of 15.2mg.
LC/MS=m/z 471.6 [M+H] retention time: 1.67min
Embodiment 391:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(methoxyl group) amino] methyl } phenyl)-1H-indole-7-Methanamide
Figure S2006800304481D03071
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.114mmol) add in the solution in DMSO (3.0mL) O-methyl hydroxylamine (57mg, 0.684mmol).Should react stirred overnight.In this reactant mixture, add other O-methyl hydroxylamine (0.342mmol), and stir 48h.Concentrate this solvent then, and prepare the HPLC purification, obtain 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(methoxyl group) imido grpup] methyl } phenyl)-1H-indole-7-Methanamide (56%) of 29.8mg through Gilson.
Under 0 ℃; To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(3-{ [(methoxyl group) imido grpup] methyl } phenyl)-1H-indole-7-Methanamide (58mg; 0.123mmol) adding 1 of HCl in the solution in DCM (3.0mL) and MeOH (3.0mL), 4-two _ alkane solution is to keep pH=4.Add then sodium cyanoborohydride (176mg, 3.69mmol), and stirred overnight 48h.This chemical compound is prepared the HPLC purification through Gilson, obtain the title compound (89%) of 20.0mg.
LC/MS=m/z 471.6 [M+H] retention time: 1.75min
Embodiment 392:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [4-(1-pyrrolidinyl)-piperidino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg, 0.112mmol) add in the solution in DMSO (2.0mL) 4-(1-pyrrolidinyl) piperidines (173mg, 1.12mmoL) and acetic acid (5).Behind the 6h, (238mg 1.12mmol), and will react stirred overnight, and reactant mixture is prepared the HPLC purification through Gilson, obtain the title compound (26%) of 17.0mg to add sodium triacetoxy borohydride.
LC/MS=m/z 584.4 [M+H] retention time: 1.38min
Embodiment 393:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [(2S)-and 2-(trifluoromethyl)-1-pyrrolidinyl] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (50mg; 0.112mmol) add in the solution in DCM (3.0mL) and MeOH (1.5mL) (2S)-2-(trifluoromethyl) pyrrolidine (156mg, 1.12mmoL) and acetic acid (5).After at room temperature stirring 6h, (43mg 1.12mmol), and will react stirred overnight at room temperature to add sodium borohydride.Reactant mixture is prepared the HPLC purification through Gilson, obtain the title compound (8%) of 5.0mg.
LC/MS=m/z 569.4 [M+H] retention time: 2.37min
Embodiment 394:5-(5-{ [(2R)-and 2-(hydroxymethyl)-1-pyrrolidinyl] methyl }-the 3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide
Figure S2006800304481D03091
To 5-(5-formoxyl-3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide (25mg; 0.054mmol) (101.15mg is 1mmol) with 2 acetic acid to add (2R)-2-pyrrolidinyl methanol in the solution in DMSO (2mL).The mixture of this generation is at room temperature stirred 4h, add subsequently sodium triacetoxy borohydride (212mg, 0.54mmol).Mixture reaction is spent the night.Then it is prepared the HPLC purification through Gilson, obtain the title compound (69.7%) of 20.5mg.
LC/MS=m/z 546 [M+H] retention time: 1.47min.
Routine 395:5-(5-{ [(3S)-3-hydroxyl-1-pyrrolidinyl] methyl }-3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl is executed in enforcement }-1H-indole-7-Methanamide
Figure S2006800304481D03092
Title compound is according to preparation 5-(5-{ [(2R)-2-(hydroxymethyl)-1-pyrrolidinyl] methyl }-3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-conventional method of 1H-indole-7-Methanamide; With (3S)-3-pyrrolidinol (90.13mg; 1.20mmol) replace (2R)-2-pyrrolidinyl methanol to prepare, obtain the title compound (53.1%) of 12.8mg.
LC/MS=m/z 532 [M+H] retention time: 1.45min.
Embodiment 396:5-(5-{ [cyclopenta (methyl) amino] methyl }-the 3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide
Figure S2006800304481D03101
Title compound is according to preparation 5-(5-{ [(2R)-2-(hydroxymethyl)-1-pyrrolidinyl] methyl }-3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-conventional method of 1H-indole-7-Methanamide; With N-methyl Aminocyclopentane (90.13mg; 1.20mmol} replace (2R)-2-pyrrolidinyl methanol to prepare, obtain the title compound (54.3%) of 10mg
LC/MS=m/z 544.2 [M+H] retention time: 1.65min.
Embodiment 397:5-(5-{ [(2-hydroxyethyl) (methyl) amino] methyl }-the 3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide
Figure S2006800304481D03111
Title compound is according to preparation 5-(5-{ [(2R)-2-(hydroxymethyl)-1-pyrrolidinyl] methyl }-3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-conventional method of 1H-indole-7-Methanamide; With 2-(methylamino) ethanol (90.13mg; 1.20mmol) replace (2R)-2-pyrrolidinyl methanol to prepare, obtain the title compound (51.9%) of 8mg.
LC/MS=m/z 520 [M+H] retention time: 1.44min.
Embodiment 398:5-(5-{ [(2-amino-2-oxoethyl) (methyl) amino] methyl }-the 3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide
Figure S2006800304481D03112
Title compound is according to preparation 5-(5-{ [(2R)-2-(hydroxymethyl)-1-pyrrolidinyl] methyl }-3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-conventional method of 1H-indole-7-Methanamide; With N2-methyl Aminoacetamide (90.13mg; 1.200mmol) replace (2R)-2-pyrrolidinyl methanol to prepare, obtain the title compound (53.2%) of 15mg.
LC/MS=m/z 520 [M+H] retention time: 1.44min.
Embodiment 399:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (2-propylene-1-yl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D03121
In 1-dram bottle; With allyl amine (0.034mL; 0.449mmol) and HOAc (0.026mL, (20mg is 0.0449mmol) in the solution in DMSO (0.5mL) 0.449mmol) to join 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide.Add NaBH (OAc) then 3(95mg 0.449mmol), seals this bottle, and should react and at room temperature stir 15h.Add NaCNBH 3(28mg 0.449mmol) and MeOH, and should react restir 4h.(0.069mL 0.898mmol), and should react restir 1h to the formalin of adding 37wt%.Through 2g SCX post (with the MeOH pre-balance of 3mL) filter reaction mixture, use the NH of MeOH (3mL) and 2M successively 3/ MeOH solution (9mL) eluting.With NH 3/ MeOH fraction concentrates down at 50 ℃ under nitrogen current, and residue is dissolved among the DMSO (1mL), and (XbridgePrep C18 post: 19 * 100mm) go up purification, use by 10%CH with 20mL/min at Gilson HPLC 3CN/H 2O (0.1%NH 4OH) to 70%CH 3CN/H 2O (0.1%NH 4OH) linear gradient elution 15min.Under nitrogen current,, obtain the title compound (23%) of 5.2mg in 50 ℃ of concentrated fraction that contain title compound.
LC/MS=m/z 501.4 [M+H] retention time: 1.48min.
Embodiment 400:5-(5-{ [[(3,5-dimethyl-1H-pyrazoles-4-yl) methyl] (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (45mg; 100 μ mol) add 1-(3,5-dimethyl-1H-pyrazoles-4-yl)-N-methyl methylamine (320 μ mol) and 2 to 3 glacial acetic acid in the solution in dimethyl sulfoxine (1.0mL).With the mixture shaken over night that generates.Behind the 18h, add sodium triacetoxy borohydride (200mg, 1000 μ mol).This mixture is shaken 1.5h, prepare the HPLC purification through Gilson subsequently, obtain the title compound (11.0%) of 6.24mg.
LC/MS=m/z 569.3 [M+H] retention time: 1.42min.
Embodiment 401:5-(5-{ [(cyano methyl) (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D03131
Title compound is that (5-{ [[(3 according to preparation 5-; 5-dimethyl-1H-pyrazoles-4-yl) methyl] (methyl) amino] methyl }-the 3-thienyl)-conventional method of 3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; Replace 1-(3 with (methylamino) acetonitrile (320 μ mol); 5-dimethyl-1H-pyrazoles-4-yl)-N-methyl methylamine prepares, and obtains the title compound (12.7%) of 6.36mg.
LC/MS=m/z 430 [M+H] retention time: 1.70min.
Embodiment 402:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (1-methyl-propyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D03132
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (45mg; 0.1mmol) add in the solution in dimethyl sulfoxine (1mL) 2-butylamine (1mmol), 1 to 2 acetic acid and sodium triacetoxy borohydride (211mg, 1mmol).With the mixture cover lid that generates and stir 18h, add sodium cyanoborohydride (62mg, methanol 1mmol) (0.5mL) solution subsequently.It is stirred 3h, add the aqueous solution (1.5mL) of 37% formaldehyde subsequently.It through SCX (2g) column purification, is used NH with methanol subsequently 3The methanol solution eluting.Preparing HPLC through Gilson is further purified.Use contains 0.1%NH 4The gradient of the aqueous solution of 10% acetonitrile to 70% acetonitrile of OH obtains the title compound (27.9%) of 14.4mg through XBridge C18 post (P/N 186002978).
LC/MS=m/z 517.3 [M+H] retention time: 1.58min.
Embodiment 403:5-(5-{ [[2-(ethyoxyl) ethyl] (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D03141
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (1-methyl-propyl) amino] methyl }-3-thienyl)-1H-indole-7-Methanamide; Replace the 2-butylamine of adding to prepare with 2-(ethyoxyl) ethamine (1mmol), obtain the title compound (11.5%) of 6.1mg.
LC/MS=m/z 533.2 [M+H] retention time: 1.57min.
Embodiment 404:5-(5-{ [cyclobutyl (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D03151
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (1-methyl-propyl) amino] methyl }-3-thienyl)-1H-indole-7-Methanamide; Replace the 2-butylamine of adding to prepare with ring butylamine (1mmol), obtain the title compound (5.9%) of 3.7mg.
LC/MS=m/z 515.3 [M+H] retention time: 1.64min.
Embodiment 405:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-({ 2-[(methoxyl group) methyl]-1-pyrrolidinyl } methyl)-3-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D03152
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (1-methyl-propyl) amino] methyl }-3-thienyl)-1H-indole-7-Methanamide; Replace the 2-butylamine of adding to prepare with 2-[(methoxyl group) methyl] pyrrolidine (1mmol), obtain the title compound (7.6%) of 5mg.
LC/MS=m/z 545.3 [M+H] retention time: 1.65min.
Embodiment 406:5-(5-{ [(1, the 1-dimethyl ethyl) (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D03161
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (1-methyl-propyl) amino] methyl }-3-thienyl)-1H-indole-7-Methanamide; Replace the 2-butylamine of adding to prepare with 2-methyl-2-propylamine (1mmol), obtain the title compound (17.3%) of 10.9mg.
LC/MS=m/z 517.3 [M+H] retention time: 1.61min.
Embodiment 407:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [3-(trifluoromethyl)-piperidino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D03162
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [methyl (1-methyl-propyl) amino] methyl }-3-thienyl)-1H-indole-7-Methanamide; Replace the 2-butylamine of adding to prepare with 3-(trifluoromethyl) piperidines (1mmol), obtain the title compound (7.8%) of 5.4mg.
LC/MS=m/z 583.3 [M+H] retention time: 1.73min.
Embodiment 408:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[(1S)-and 2-hydroxyl-1-Methylethyl] (methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D03171
To containing (2R)-2-amino-1-propanol (90.13mg; 1.2mmol) the bottle in add 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (30mg, 0.067mmol) solution in DMSO (300 μ L) and acetic acid (50 μ L).Mixture vibration 5min with generating adds sodium triacetoxy borohydride (250mg, DMSO 1.20mmol) (800 μ L) solution subsequently.With the mixture shaken overnight.Add sodium cyanoborohydride (79mg, methanol 1.20mmol) (300 μ L) solution, and stirring 48h then.Subsequently to wherein adding formaldehyde (100 μ L).Should react then and stir 1h, separate through the original post of 2g SCX subsequently.Leach solid then, concentrated solution, and on 5g SCX post, repeat purification, with the MeOH eluant solution of ammonia.The MeOH fraction of the ammonia of collecting is concentrated, and use Gilson to prepare HPLC and separate, obtain the title compound (43.9%) of 18.6mg.
LC/MS=m/z 519.3 [M+H] retention time: 1.49min.
Embodiment 400:5-(5-{ [(cyclopropyl methyl) (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D03172
Title compound be according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[(1S)-2-hydroxyl-1-Methylethyl] (methyl) amino] methyl }-the 3-thienyl)-conventional method of 1H-indole-7-Methanamide trifluoroacetate (salt); Replace (2R)-2-amino-1-propanol to prepare with (cyclopropyl methyl) amine (1.20mmol), obtain the title compound (14.7%) of 6.2mg.
LC/MS=m/z 515.3 [M+H] retention time: 1.61min.
Embodiment 410:5-(5-{ [[2-(acetyl-amino) ethyl] (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D03181
Title compound be according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[(1S)-2-hydroxyl-1-Methylethyl] (methyl) amino] methyl }-the 3-thienyl)-conventional method of 1H-indole-7-Methanamide trifluoroacetate (salt); Replace (2R)-2-amino-1-propanol to prepare with N-(2-amino-ethyl) acetamide (1.20mmol), obtain the title compound (30.8%) of 13.6mg.
LC/MS=m/z 546.2 [M+H] retention time: 1.47min.
Embodiment 411:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[(1R, 2R)-2-hydroxycyclopent base] (methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D03182
Title compound be according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[(1S)-2-hydroxyl-1-Methylethyl] (methyl) amino] methyl }-the 3-thienyl)-conventional method of 1H-indole-7-Methanamide trifluoroacetate (salt); With (1R; 2R)-2-amino cyclopentyl alcohol (1.20mmol) replaces (2R)-2-amino-1-propanol to prepare, obtains the title compound (21.8%) of 9.6mg.
LC/MS=m/z 545.3 [M+H] retention time: 1.54min.
Embodiment 412:5-(5-{ [(1, the 1-dimethyl propyl) (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D03191
Title compound be according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[(1S)-2-hydroxyl-1-Methylethyl] (methyl) amino] methyl }-the 3-thienyl)-conventional method of 1H-indole-7-Methanamide trifluoroacetate (salt); With (1; The 1-dimethyl propyl) amine (1.20mmol) replaces (2R)-2-amino-1-propanol to prepare, and obtains the title compound (30.3%) of 13.1mg.
LC/MS=m/z 531.3 [M+H] retention time: 1.65min.
Embodiment 413:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[(2S)-and the 2-hydroxypropyl] (methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D03192
Title compound be according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[(1S)-2-hydroxyl-1-Methylethyl] (methyl) amino] methyl }-the 3-thienyl)-conventional method of 1H-indole-7-Methanamide trifluoroacetate (salt); Replace (2R)-2-amino-1-propanol to prepare with (2S)-1-amino-2-propanol (1.20mmol), obtain the title compound (36.1%) of 15.3mg
LC/MS=m/z 519.3 [M+H] retention time: 1.49min.
Embodiment 414:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(methyl [(2R)-and tetrahydrochysene-2-furyl methyl] amino } methyl)-the 3-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D03201
Title compound be according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[(1S)-2-hydroxyl-1-Methylethyl] (methyl) amino] methyl }-the 3-thienyl)-conventional method of 1H-indole-7-Methanamide trifluoroacetate (salt); Replace (2R)-2-amino-1-propanol to prepare with [(2R)-tetrahydrochysene-2-furyl methyl] amine (1.20mmol), obtain the title compound (35.1%) of 15.5mg.
LC/MS=m/z 545.3 [M+H] retention time: 1.58min.
Embodiment 415:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [{ 2-[(2-hydroxyethyl) oxygen base] ethyl } (methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Title compound be according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[(1S)-2-hydroxyl-1-Methylethyl] (methyl) amino] methyl }-the 3-thienyl)-conventional method of 1H-indole-7-Methanamide trifluoroacetate (salt); Replace (2R)-2-amino-1-propanol to prepare with 2-[(2-amino-ethyl) oxygen base] ethanol (1.20mmol), obtain the title compound (38.7%) of 17.2mg.
LC/MS=m/z 549.5 [M+H] retention time: 1.48min.
Embodiment 416:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[5-(1-{ methyl [2-(methoxyl group) ethyl] amino } ethyl)-the 3-thienyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D03211
To 5-(5-acetyl group-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (46mg; 0.1mmol) add methyl [2-(methoxyl group) ethyl] amine (200 μ L in the solution in EtOH (2.0mL) and AcOH (0.2mL); 2.0mmol) and sodium cyanoborohydride (50mg, 0.8mmol).Mixture is reacted 2h in 120 ℃ in microwave.Add other methyl [2-(methoxyl group) ethyl] amine (100 μ L, 1.0mmol) and sodium cyanoborohydride (25mg 0.4mmol), and reacts 3h again in microwave, in 120 ℃ the reaction 2h.Then to wherein add again methyl [2-(methoxyl group) ethyl] amine (100 μ L, 2.0mmol) and sodium cyanoborohydride (25mg 0.4mmol), and reacts 3h again in microwave, in 120 ℃ the reaction 2h.Concentrate all solvents, and prepare the HPLC purification, obtain the title compound (38%) of 20mg through Gilson.
LC/MS=m/z 533.2 [M+H] retention time: 1.46min.
Embodiment 417:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{1-[methyl (propyl group) amino] ethyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D03212
To 5-(5-acetyl group-3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (46mg; 0.1mmol) add N-methyl isophthalic acid-propylamine (200 μ L in the solution in EtOH (2.0mL) and AcOH (0.2mL); 2.0mmol) and sodium cyanoborohydride (50mg, 0.8mmol).Mixture is reacted 120min in 120 ℃ in microwave.Add other N-methyl isophthalic acid-propylamine (100 μ L, 1.0mmol) and sodium cyanoborohydride (25mg 0.4mmol), and reacts 120min in 120 ℃ again in microwave.Concentrate all solvents, be dissolved among the DMSO, and solids filtered.Then it is prepared the HPLC purification through Gilson, obtain the title compound (35%) of 18mg.
LC/MS=m/z 517.2 [M+H] retention time: 1.52min.
Embodiment 418:5-(2,3-dihydro-1H-iso-indoles-5-yl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D03221
To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(4,4,5; 5-tetramethyl-1,3,2-dioxa bora ring penta-2-yl)-1H-indole-7-Methanamide (150mg; 0.325mmol) add 5-bromo-2 in the solution in two _ alkane (0.75mL) and water (0.25mL); 3-dihydro-1H-iso-indoles hydrochlorate (130mg, 0.651mmol) and cesium carbonate (636mg, 1.952mmol).Reactant mixture is kept 10min under argon, add subsequently four (triphenylphosphines) close palladium (0) (19mg, 0.016mmol).The mixture that generates is heated 20min in 150 ℃ in microwave.Then mixture is passed through the HPLC purification, obtain the title compound of 11mg.
LC/MS=m/z 453 [M+H] retention time: 1.33min.
Embodiment 419:5-(2-ethyl-2,3-dihydro-1H-iso-indoles-5-yl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D03222
To 5-(2; 3-dihydro-1H-iso-indoles-5-yl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (20mg; 0.044mmol) add acetaldehyde (6mg in the solution in MeOH (1mL); 0.133mmol), sodium cyanoborohydride (6mg, 0.088mmol) and zinc chloride (6mg, 0.044mmol).The mixture that generates is heated 30min in 100 ℃ in microwave.Then mixture is concentrated, filter, and prepare the HPLC purification, obtain the title compound of 8.2mg through Gilson.
LC/MS=m/z 481 [M+H] retention time: 1.40min.
Embodiment 420:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(1-Methylethyl)-2,3-dihydro-1H-iso-indoles-5-yl]-1H-indole-7-Methanamide
To 5-(2; 3-dihydro-1H-iso-indoles-5-yl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (30mg; 0.066mmol) add 2-acetone (12mg in the solution in MeOH (0.5mL); 0.198mmol), sodium cyanoborohydride (8mg, 0.133mmol) and zinc chloride (9mg, 0.066mmol).The mixture that generates is heated 30min in 100 ℃ in microwave.Then mixture is concentrated, filter, and prepare the HPLC purification, obtain the title compound of 0.8mg through Gilson.
LC/MS=m/z 495.5 [M+H] retention time: 1.56min.
Embodiment 421:5-[2-(1, the 2-dimethyl propyl)-2,3-dihydro-1H-iso-indoles-5-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D03241
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(1-Methylethyl)-2; 3-dihydro-1H-iso-indoles-5-yl]-conventional method of 1H-indole-7-Methanamide; With 3-methyl-2-butanone (17mg; 0.198mmol) replace 2-acetone to prepare, obtain the title compound of 14.6mg.
LC/MS=m/z 523 [M+H] retention time: 1.55min.
Embodiment 422:3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(1-methyl-propyl)-2,3-dihydro-1H-iso-indoles-5-yl]-1H-indole-7-Methanamide
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(1-Methylethyl)-2; 3-dihydro-1H-iso-indoles-5-yl]-conventional method of 1H-indole-7-Methanamide; With 2-butanone (14mg; 0.198mmol) replace 2-acetone to prepare, obtain the title compound of 14.6mg.
LC/MS=m/z 509 [M+H] retention time: 1.48min.
Embodiment 423:5-[2-(1-ethyl propyl)-2,3-dihydro-1H-iso-indoles-5-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D03251
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(1-Methylethyl)-2; 3-dihydro-1H-iso-indoles-5-yl]-conventional method of 1H-indole-7-Methanamide; With propione (17mg; 0.198mmol) replace 2-acetone to prepare, obtain the title compound of 13.8mg.
LC/MS=m/z 523 [M+H] retention time: 1.58min.
Embodiment 424:5-(2-cyclopenta-2,3-dihydro-1H-iso-indoles-5-yl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D03252
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(1-Methylethyl)-2; 3-dihydro-1H-iso-indoles-5-yl]-conventional method of 1H-indole-7-Methanamide; With Ketocyclopentane (17mg; 0.198mmol) replace 2-acetone to prepare, obtain the title compound of 4.8mg.
LC/MS=m/z 521 [M+H] retention time: 1.54min.
Embodiment 425:5-[2-(cyclopropyl methyl)-2,3-dihydro-1H-iso-indoles-5-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D03261
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(1-Methylethyl)-2; 3-dihydro-1H-iso-indoles-5-yl]-conventional method of 1H-indole-7-Methanamide; With cyclopanecarboxaldehyde (14mg; 0.198mmol) replace 2-acetone to prepare, obtain the title compound of 10.8mg.
LC/MS=m/z 507 [M+H] retention time: 1.47min.
Embodiment 426:5-[2-(2, the 2-dimethyl propyl)-2,3-dihydro-1H-iso-indoles-5-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
Figure S2006800304481D03262
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(1-Methylethyl)-2; 3-dihydro-1H-iso-indoles-5-yl]-conventional method of 1H-indole-7-Methanamide; With 2; (17mg 0.198mmol) replaces 2-acetone to prepare to 2-dimethyl propionic aldehyde, obtains the title compound of 12.7mg.
LC/MS=m/z 523 [M+H] retention time: 1.60min.
Embodiment 427:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-methyl-2,3-dihydro-1H-iso-indoles-5-yl)-1H-indole-7-Methanamide
Figure S2006800304481D03271
Title compound is according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(1-Methylethyl)-2; 3-dihydro-1H-iso-indoles-5-yl]-conventional method of 1H-indole-7-Methanamide; With formaldehyde (6mg; 0.198mmol) replace 2-acetone to prepare, obtain the title compound of 1.2mg.
LC/MS=m/z 467 [M+H] retention time: 1.37min.
Embodiment 428:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-{ [(phenyl sulfonyl) amino] carbonyl-2,3-dihydro-1H-iso-indoles-5-yl)-1H-indole-7-Methanamide
Figure S2006800304481D03272
To 5-(2,3-dihydro-1H-iso-indoles-5-yl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (30mg, 0.066mmol) add in the solution in DMSO (1.0mL) the benzenesulfonyl isocyanates (15mg, 0.079mmol).With the mixture that generates stirred overnight at room temperature.Mixture is prepared the HPLC purification through Gilson, obtain the title compound of 15.5mg.
LC/MS=m/z 637 [M+H] retention time: 1.94min.
Embodiment 429:5-(5-{ [(2R)-and 2-(amino carbonyl)-1-pyrrolidinyl] methyl }-the 3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide
Figure S2006800304481D03281
To 5-(5-formoxyl-3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-(25mg, (114mg is 1mmol) with 2 acetic acid 0.054mmol) to add the D-prolineamide in the solution in DMSO (2mL) for 1H-indole-7-Methanamide.The mixture of this generation is at room temperature stirred 4h, add subsequently sodium triacetoxy borohydride (212mg, 1.0mmol).Mixture reaction is spent the night.Then it is prepared the HPLC purification through Gilson, obtain the title compound of 20.4mg.
LC/MS=m/z 557 [M+H] retention time: 1.56min.
Embodiment 430:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[2-(ethylmercapto group) ethyl] (methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D03282
To 5-(5-formoxyl-3-thienyl)-3-{1-[(1-Methylethyl) sulfonyl]-4-piperidyl }-1H-indole-7-Methanamide (40mg; 0.09mmol) add [2-(ethylmercapto group) ethyl] amine (105mg in the solution in DMSO (2mL); 1mmol), acetic acid (50 μ L) and sodium triacetoxy borohydride (212mg, 1.0mmol).With the mixture stirred overnight that generates.In mixture, add sodium cyanoborohydride (80mg, 1.2mmol) and stirred overnight, add subsequently formaldehyde (100 μ L, 1.2mmol).Then with mixture restir 3h.Then it is prepared the HPLC purification through Gilson, obtain the title compound of 7.0mg.
LC/MS=m/z 550 [M+H] retention time: 1.68min.
Embodiment 431:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [{ 2-[(2-hydroxyethyl) sulfenyl] ethyl } (methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide
Figure S2006800304481D03291
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[2-(ethylmercapto group) ethyl] (methyl) amino] methyl }-3-thienyl)-1H-indole-7-Methanamide; With 2-[(2-amino-ethyl) sulfenyl] ethanol (121mg; 1.0mmol) replace [2-(ethylmercapto group) ethyl] amine to prepare, obtain the title compound of 16.0mg.
LC/MS=m/z 566 [M+H] retention time: 1.52min.
Embodiment 432:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[2-hydroxyl-1-(hydroxymethyl) ethyl] (methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide
Title compound is the conventional method according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[2-(ethylmercapto group) ethyl] (methyl) amino] methyl }-3-thienyl)-1H-indole-7-Methanamide; With 2-amino-1; 3-propylene glycol (91mg; 1.0mmol) replace [2-(ethylmercapto group) ethyl] amine to prepare, obtain the title compound of 15.0mg.
LC/MS=m/z 535 [M+H] retention time: 1.44min.
Embodiment 433: [(4-{7-(amino carbonyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-5-yl }-the 2-thienyl) methyl] the methyl carbamic acid ethyl ester
Figure S2006800304481D03301
Under 0 ℃; To 3-[1-(ethylsulfonyl)-4-piperidyl]-5-{5-[(methylamino) methyl]-3-thienyl }-1H-indole-7-Methanamide (50mg; 0.11mmol) add triethylamine (0.06mL in the solution in DMF (1.0mL); 0.44mmol) and the chlorine ethyl carbonate (0.021mL, 0.22mmol).With the mixture reaction 30min that generates, purification on Gilson Preparatory HLPC subsequently obtains the title compound (53.5%) of 31.4mg.
LC/MS=m/z 533.2 [M+H] retention time: 2.06min.
Embodiment 434:N-[(4-{7-(amino carbonyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-5-yl }-the 2-thienyl) methyl]-the sarcosine ethyl ester
In 3-[1-(ethylsulfonyl)-4-the piperidyl]-solution of 5-(5-formoxyl-3-thienyl)-lH-indole-7-Methanamide (45mg, 100 μ mol) in dimethyl sulfoxine (1.0mL), add N-methyl aminoacetic acid ethyl ester (320 μ mol) and 2 to 3 glacial acetic acid.With the mixture stirred overnight that generates.Behind the 18h, add sodium triacetoxy borohydride (200mg, 1000 μ mol).This mixture is stirred 1.5h, prepare the HPLC purification through Gilson subsequently, obtain the title compound (30.0%) of 16.5mg.
LC/MS=m/z 547.1 [M+H] retention time: 1.55min.
Embodiment 435:3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[(1S)-and 2-hydroxyl-1-Methylethyl] (methyl) amino] methyl }-the 3-thienyl)-1H-indole-7-Methanamide trifluoroacetate (salt)
Figure S2006800304481D03311
To containing (2S)-2-amino-1-propanol (91mg; 1.2mmol) the bottle in add 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-formoxyl-3-thienyl)-1H-indole-7-Methanamide (30mg, 0.067mmol) solution in DMSO (300 μ L) and acetic acid (50 μ L).Mixture vibration 5min with generating adds sodium triacetoxy borohydride (250mg, DMSO 1.20mmol) (800 μ L) solution subsequently.With the mixture shaken overnight.Add sodium cyanoborohydride (79mg, methanol 1.20mmol) (300 μ L) solution, and stirring 48h then.Subsequently to wherein adding formaldehyde (100 μ L).Should react then and stir 1h, separate through 2g SCX post subsequently.Then this solid is leached, concentrated solution, and on 5g SCX post, repeat purification, with the MeOH eluant solution of ammonia.Concentrate the MeOH fraction of the ammonia of collecting, and use Gilson to prepare HPLC and separate, obtain the title compound of 18.7mg.
LC/MS=m/z 519.3 [M+H] retention time: 1.49min.
Embodiment 436:5-(5-{ [(1,1-dioxo tetrahydrochysene-3-thienyl) (methyl) amino] methyl }-the 3-thienyl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide trifluoroacetate
Figure S2006800304481D03312
Title compound be according to preparation 3-[1-(ethylsulfonyl)-4-piperidyl]-5-(5-{ [[(1S)-2-hydroxyl-1-Methylethyl] (methyl) amino] methyl }-the 3-thienyl)-conventional method of 1H-indole-7-Methanamide trifluoroacetate; With (1; 1-dioxo tetrahydrochysene-3-thienyl) amine (1.20mmol) replaces (2S)-2-amino-1-propanol to prepare, and obtains the title compound of 9.3mg.
LC/MS=m/z 579 [M+H] retention time: 1.54min.
Biological data
The IKK2 test
With the formal representation of the fusion rotein of the terminal GST-labelling of C-, differentiate FRET (TR-FRET) test and estimate by its active service time in baculovirus for recombined human IKK β (residue 1-737).Briefly, will be diluted in test buffer (HEPES of 50mM, the MgCl of 10mM 2, the CHAPS pH 7.4 of 1mM contains DTT and the 0.01%w/v BSA of 1mM) in IKK2 (ultimate density 0.5nM-5nM) join in the hole of containing variable concentrations chemical compound or DMSO carrier (ultimate density 1.7%).The initiation reaction through GST-IB substrate (ultimate density the 25nM)/ATP (1 μ M ultimate density) that adds cumulative volume 6 μ l.Reactant was at room temperature hatched 15 minutes, then buffer (the HEPES pH 7.4 of 100mM, the NaCl of 150mM of the EDTA that contains 50mM through adding 3 μ l; The EDTA of 50mM and 0.01%w/v BSA) in detectable stop, wherein contain useful W-1024 europium chelate (WallacOY, Turku; Finland) the anti-phosphoserine of labelling-IB-32/36 monoclonal antibody 12C2 (CellSignalling Technology, Beverly Massachusetts, USA); And add resisting-GST antibody (Prozyme, San Leandro, California of APC labelling; USA), said reactant was at room temperature hatched 60 minutes again.(BMG Labtech, Aylesbury UK), with the ratio of specific 665nm energy transfer signal to reference europium 620nm signal, measure the phosphorylation degree of GST-IB to use BMG Rubystar plate reader.
The result
The anti-IKK2 of the chemical compound of test implementation example 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 is active, and finds that these embodiment are the IKK2 inhibitor.These chemical compounds have 5.0 or bigger pIC 50The anti-IKK2 that has also tested embodiment 277 and 278 is active, and finds that these two chemical compounds have the pIC less than 5.0 50
The mononuclear cell test
The inhibitory action that IKK-β generates person monocytic cell's stimulated cells factor is according to estimating as follows: by coming out through the Ficoll gradient separations in the whole blood of heparinization, use MACS cell separation magnetic bead that the CD14+ cell is carried out purification subsequently mononuclear cell.Then with the mononuclear cell of separating in RPMI164010%FBS (JRH Biosciences, Lenexa KS) with 1 * 10 6Cell/mL adhere-wall culture 2 hours on the 96-well culture plate.Stimulated preceding 30 minutes at final carrier concn, test compounds is joined in the hole with 0.1%DMSO.Through adding 200ng/mL endotoxin (LPS; E. coli serotype 026:B6) (Sigma, St.Louis MO.) come activated monocyte, and cultivate 24 hours down at 37 ℃.Analyze the TNF-α in the acellular supernatant through ELISA or Alphascreen.Use the pairing Abs of Pharmingen to carry out the ELISA test, and use from the Alphascreen receptor of Perkin Elmer and donor bead and carry out Alphascreen from the Anti-Human TNF of R&D Systems and biotinylated Anti-Human TNF Abs and test.Cell survival rate repels test through 10% trypan blue and measures.
The result
Some embodiments of the present invention are tested with the mononuclear cell test.Discovery is embodiment 1-3 in this test; 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 and 435 chemical compounds have＜IC50 of 2uM.
Embodiment 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 and 393 chemical compounds show down at 1 μ M (the highest proof load) and are no more than＞65% inhibition.
Embodiment 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 and 436 chemical compounds show＜60% inhibition under 300nM.
In the mononuclear cell test of embodiment 38,64,82,215,297,344,364 and 369 chemical compound, obtain different results.

Claims (5)

1. according to the chemical compound of formula (I), or its pharmaceutically acceptable salt:
Figure FSB00000842642300011
Wherein
R1 is
Figure FSB00000842642300012
R2 is H;
R3 is H;
R5 is selected from
1)H，
2) C 3-C 7-cycloalkyl and
3) C 1-C 6-alkyl,
Wherein said C 1-C 6-alkyl is optional to be replaced by 1-3 substituent group that is selected from R6; Each R6 is C 3-C 7-cycloalkyl,
Group U-V is
Figure FSB00000842642300013
and R12 is an ethyl.
2. according to the chemical compound of claim 1, it is:
5-(2,3-dihydro-1H-iso-indoles-5-yl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(2-ethyl-2,3-dihydro-1H-iso-indoles-5-yl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(1-Methylethyl)-2,3-dihydro-1H-iso-indoles-5-yl]-1H-indole-7-Methanamide;
5-[2-(1, the 2-dimethyl propyl)-2,3-dihydro-1H-iso-indoles-5-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(ethylsulfonyl)-4-piperidyl]-5-[2-(1-methyl-propyl)-2,3-dihydro-1H-iso-indoles-5-yl]-1H-indole-7-Methanamide;
5-[2-(1-ethyl propyl)-2,3-dihydro-1H-iso-indoles-5-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-(2-cyclopenta-2,3-dihydro-1H-iso-indoles-5-yl)-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[2-(cyclopropyl methyl)-2,3-dihydro-1H-iso-indoles-5-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide;
5-[2-(2, the 2-dimethyl propyl)-2,3-dihydro-1H-iso-indoles-5-yl]-3-[1-(ethylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide; Or
3-[1-(ethylsulfonyl)-4-piperidyl]-5-(2-methyl-2,3-dihydro-1H-iso-indoles-5-yl)-1H-indole-7-Methanamide;
Or its pharmaceutically acceptable salt.
3. pharmaceutical composition, it comprises according to the chemical compound of claim 1 or 2 or its pharmaceutically acceptable salt and one or more pharmaceutically acceptable excipient.
4. according to the pharmaceutical composition of claim 3, it further comprises one or more other pharmaceutically active compound.
5. chemical compound or its pharmaceutically acceptable salt according to claim 1 or 2 of safety and effective dose are used for treating the purposes by the medicine of the active disease that mediates of inappropriate IKK2 in preparation, and wherein said disease by the active mediation of inappropriate IKK2 is an asthma.
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