CN101060842A - Chemical compounds - Google Patents
Chemical compounds Download PDFInfo
- Publication number
- CN101060842A CN101060842A CNA2005800397636A CN200580039763A CN101060842A CN 101060842 A CN101060842 A CN 101060842A CN A2005800397636 A CNA2005800397636 A CN A2005800397636A CN 200580039763 A CN200580039763 A CN 200580039763A CN 101060842 A CN101060842 A CN 101060842A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- indole
- sulfonyl
- piperidyl
- methanamide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention is directed to novel indole carboxamide derivatives. Specifically, the invention is directed to compounds according to formula (1): 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 known as 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
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 the treatment of the active diseases associated with 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.By with ATP-Mg
2+γ-the phosphate ester of complex is transferred to described amino acid side chain, 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, by serine, threonine and tyrosine residue in the albumen
*The reversibility phosphorylation of hydroxyl is arranged cell function, growth, differentiation and destruction (programmed cell death) thus.Studies show that protein kinase is the crucial moderator of many cell functions, described cell function comprises signal transduction, transcriptional regulatory, cell mobility and cell division.Some oncogene show the encoding proteins kinases equally, and it is certain to show that kinases plays a part in tumor generates.These processes are often interosculated approach by altitude mixture control by complex, and wherein every kind of kinases itself is regulated by one or more kinases.Therefore, unusual or inappropriate protein kinase activity may 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, may 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 activity of serine/threonine kinases.Therefore, serine/threonine kinase and their signal transduction pathway thereof are the important target of drug design to a certain extent.Described tyrosine kinase phosphorylated tyrosine residue.Tyrosine kinase 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.Studies show that many tyrosine kinase are transmembrane proteins, 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 in conjunction with 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 active region at their C-end.
The member of the activity of NF-κ B by it and proteic inhibitor I κ B family interacts and regulates.The nuclear localization sequence on the NF-kB protein is blocked in this interaction effectively, stops dimer to migrate to this nuclear thus.Stimulation miscellaneous activates NF-κ B by 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 the I kappa b kinase (IKK-α and IKK-β) of nearest identification by phosphorylation.IKK-β also is called IKK2.Site-directed mutagenesis studies show that, these phosphorylations are crucial to the activation of subsequently NF-κ B, because in case by phosphorylation, this albumen is by ubiquitin-proteasome pathway labelling degraded.Do not have 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.
Now known, 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 inducible nitric oxide synthase (iNOS).Known these media play a part certain in the leukocyte recruitment of inflammation part, and in the situation of iNOS, can cause organ to destroy in some diseases associated with inflammation and autoimmune disease.
In addition, the importance of NF-κ B in inflammation strengthened by the research of airway inflammation (comprising asthma), shows that wherein NF-κ B is activated.This activation may increase the leukocyte infiltration feature of cytokine generation and these diseases potentially.In addition, known imbedibility steroidal reduces airway hyperreactivity and suppresses inflammatory response in the asthma air flue.According to the up-to-date discovery that suppresses about the glucocorticoid of NF-κ B, people may infer that these effects are regulated by suppressing NF-κ B.
Other evidence that acts in inflammation 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 studies show that NF-κ B is present in the nuclear, and is active therefore, in the cell that comprises the rheumatoid synovial membrane.In addition, shown that NF-κ B is activated with stimulating with TNF-α or IL-1 β in people synovial cell.This distribution may be the basic mechanism that the eicosanoid of cytokine increase and this tissue produces feature.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 may 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 now that the effect of NF-κ B in regulating apoptosis strengthened the effect of this transcription factor in regulate tumor cell propagation.TNF, ionizing radiation and DNA damage agent all show and activate NF-κ B, and it causes conversely, and some anti-apoptotics are proteic is just regulating expression.On the contrary, show now that in some tumor cell types, the inhibition of NF-κ B has increased the apoptosis that is killed by these reagent.Because this may 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 B.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; 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; The aminopyridine inhibitor of IKK2, referring to Lowinger etc., WO 2002024679; Murata etc., WO 2002024693; Murata etc., WO 2002044153; The pyrazolo quinazoline inhibitor of IKK2, referring to Beaulieu etc., WO 2002028860; Burke etc., WO 2002060386, US such as Burke 20030022898; 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.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) has described the IKK2 inhibitor.
Therefore, attempt preparation and suppress the active chemical compound of IKK2, many these chemical compounds disclose 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 struvite 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 acquired immune deficiency syndrome (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):
Wherein R1, R2, R3, U and V are as 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:
Wherein:
R1 is H, halogen or group-YZ;
R2 is H, fluorine or chlorine;
R3 is H, fluorine or chlorine;
Y is chemical bond, C
1-C
6Alkylidene, C
2-C
6Alkenylene or C
2-C
6Alkynylene;
Z is optional aryl that replaces or the optional heteroaryl that replaces,
Wherein said aryl and heteroaryl are optional to be replaced by one to three substituent group, and described substituent group is independently selected from: halo ,-CN ,-N (Rb) SO
2Re ,-N (Rb) C (O) Ra ,-C (O) NRaRb ,-C (O) NRfRg ,-C (O) H ,-SO
2Ri ,-NRaRb ,-SO
2NRaRb ,-SO
2NRfRg ,-ORc ,-N (Rb) C (O) NRaRb ,-N (Rb) C (O) NRfRg ,-N (Rb) C (O) ORd, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by 1-3
1-C
6Alkyl :-NRaRb, C
3-C
6Cycloalkyl, phenyl ,-ORc, Heterocyclylalkyl and by OH ,-C (O) NH
2Perhaps one or two C
1-C
6The Heterocyclylalkyl that alkyl replaces; C
1-C
6Haloalkyl is independently selected from the following C that substituent group replaced by 1-3
1-C
6Haloalkyl :-NRaRb, C
3-C
6Cycloalkyl, phenyl, Heterocyclylalkyl and by one or two C
1-C
6The Heterocyclylalkyl that alkyl replaces; Heterocyclylalkyl and by one or two C
1-C
6The Heterocyclylalkyl that alkyl replaces;
U is chemical bond, C
1-C
6Alkylidene or C
2-C
6Alkenylene;
V is phenyl, 5 or 6 Yuans heteroaryls, 5-7 element heterocycle alkyl, C
5-C
7Cycloalkyl or C
5-C
7Cycloalkenyl group, its each quilt-N (Rb) S (O)
mR4 ,-S (O)
mN (Rb) R4 or-S (O)
mR4 replaces;
M is 1 or 2;
R4 is group-X-R5;
X is chemical bond, C
1-C
6Alkylidene, C
2-C
6Alkenylene, C
2-C
6Alkynylene, aryl, C
1-C
6Alkylidene-aryl, heteroaryl, C
1-C
6Alkylidene-heteroaryl, Heterocyclylalkyl, C
1-C
6Alkylidenyl-heterocyclic alkyl, C
4-C
7Cycloalkyl, C
1-C
6Alkylidene-C
4-C
7Cycloalkyl, C
5-C
7Cycloalkenyl group or C
1-C
6Alkylidene-C
5-C
7Cycloalkenyl group;
R5 is-NRaRb ,-ORj, the optional Heterocyclylalkyl that replaces or the optional heteroaryl that replaces,
The Heterocyclylalkyl of wherein said optional replacement and the optional heteroaryl that replaces be optional to be independently selected from following substituent group by one to three and to replace: halo, heteroaryl, oxo base ,-CN ,-C (O) Ra ,-N (Rb) SO
2Re ,-N (Rb) C (O) Ra ,-NRaRb ,-C (O) NRaRb ,-C (O) NRfRg ,-SO
2NRaRb ,-SO
2NRfRg ,-ORc ,-C (O) ORc ,-N (Rb) C (O) NRaRb ,-N (Rb) C (O) NRfRg ,-N (Rb) C (O) ORd, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl :-NRaRb ,-ORc ,-C (O) NRaRb ,-C (O) Rc, C
3-C
6Cycloalkyl, Heterocyclylalkyl and phenyl; C
1-C
6Haloalkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Haloalkyl :-NRaRb ,-ORc ,-C (O) NRaRb, C
3-C
6Cycloalkyl, Heterocyclylalkyl and phenyl; Heterocyclylalkyl is independently selected from the following Heterocyclylalkyl that substituent group replaced: C by one to three
1-C
6Alkyl, halo ,-ORc, haloalkyl, CN and-SO
2Ri; Phenyl, and be independently selected from the following phenyl that substituent group replaced by one to three: halo ,-ORc, haloalkyl ,-CN and-SO
2Ri;
Each Ra is independently selected from: H ,-ORh, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl: halo ,-CN ,-C (O) NH
2,-NRkRk ,-SO
2Ri ,-N (Rb) SO
2Re ,-C (O) ORb ,-N (Rb) C (O) Rb ,-ORc ,-SRc, C
3-C
7Cycloalkyl, C
1-C
6Haloalkyl, Heterocyclylalkyl, phenyl, phenylol (phenolyl) and heteroaryl; Phenyl is independently selected from the following phenyl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl ,-ORc and-NRfRg; Heteroaryl is independently selected from the following heteroaryl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl ,-ORc and-NRfRg; C
3-C
7Cycloalkyl is independently selected from the following C that substituent group replaced by one to three
3-C
7Cycloalkyl: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl ,-ORc and-NRfRg; Heterocyclylalkyl, and be independently selected from the following Heterocyclylalkyl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl ,-CH
2C (O) Rb, C
1-C
6Haloalkyl ,-C (O) ORb, NH
2, heteroaryl ,-ORc and NRfRg;
Each Rb is independently selected from: H, C
1-C
6Alkyl is by one-C that ORc replaced
1-C
6Alkyl, and C
3-C
7Cycloalkyl;
Each Rc is independently selected from: H, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl: OH, C
3-C
6Cycloalkyl, phenyl, Heterocyclylalkyl and heteroaryl; C
1-C
6Haloalkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Haloalkyl: OH, C
3-C
6Cycloalkyl, phenyl, Heterocyclylalkyl and heteroaryl; C
3-C
7Cycloalkyl is by one to three C
1-C
3The C that alkyl replaced
3-C
7Cycloalkyl; Heterocyclylalkyl is by one to three C
1-C
3The Heterocyclylalkyl that alkyl replaced; Aryl is independently selected from the following aryl that substituent group replaced by one to three: halo, C
1-C
3Alkyl, C
1-C
3Haloalkyl and OH; Heteroaryl, and be independently selected from the following heteroaryl that substituent group replaced by one to three: halo, C
1-C
3Alkyl, C
1-C
3Haloalkyl and OH;
Each Rd is the optional C that replaces independently
1-C
3Alkyl, wherein said C
1-C
3Alkyl is optional to be selected from following substituent group by one to three and to replace: C
3-C
6Cycloalkyl, Heterocyclylalkyl, the optional phenyl that replaces and the optional heteroaryl that replaces; Wherein said phenyl and heteroaryl be optional to be selected from following substituent group by one to three and to replace: halo, C
1-C
6Alkyl and C
3-C
6Cycloalkyl;
Each Re is independently selected from: C
1-C
6Alkyl is selected from the following C that substituent group replaced by one
1-C
6Alkyl: phenyl, heteroaryl, Heterocyclylalkyl and NRaRb; Phenyl is selected from the following phenyl that substituent group replaced by one to three: halo, CN, C
1-C
6Alkyl, C
1-C
6Haloalkyl and ORh; Heteroaryl is selected from the following heteroaryl that substituent group replaced by one to three: halo, CN, C
1-C
6Alkyl, C
1-C
6Haloalkyl and-ORh; C
5-C
7Cycloalkyl is selected from the following C that substituent group replaced by one to three
5-C
7Cycloalkyl: halo, C
1-C
6Alkyl and C
3-C
6Cycloalkyl; Heterocyclylalkyl, and be selected from the following Heterocyclylalkyl that substituent group replaced by one to three: halo, C
1-C
6Alkyl and C
3-C
6Cycloalkyl;
Rf forms the ring with 5-7 member's atom with the nitrogen-atoms that Rg links to each other with them, wherein said ring is optional to contain other a hetero atom as member's atom, described ring is saturated or undersaturated but is not aromatic, and described ring is optional by one or two C
1-C
3Alkyl substituent replaces;
Each Rh is independently selected from: H, C
1-C
6Alkyl and C
1-C
6Haloalkyl;
Each Ri is independently selected from: C
1-C
3Alkyl and phenyl;
Rj is selected from H, the optional C that replaces
1-C
6Alkyl, C
1-C
6Haloalkyl, heteroaryl and the optional phenyl that replaces,
The C of wherein said optional replacement
1-C
6Alkyl is optional to be replaced by one or two substituent group, and each substituent group is independently selected from following: hydroxyl, C
1-C
6Alkoxyl ,-OCH
2CH
2N (CH
3)
2, methyl mercapto, C
3-C
6Cycloalkyl is by a C
1-C
3The C that alkyl replaced
3-C
6Cycloalkyl; Heterocyclylalkyl is by a C
1-C
3Alkyl, an oxo base or the Heterocyclylalkyl that the 4-luorobenzyl is replaced;-NRkRk, heteroaryl ,-NHC (O) CH
3With-S (O)
2Ri;
Wherein said phenyl is optional to be replaced by one to three substituent group, and each substituent group is independently selected from following: C
1-C
3Alkoxyl ,-NHC (O) CH
3,-C (O) NH
2, halo, CF
3,-S (O)
2Ri ,-S (O)
2NHRi, hydroxyl ,-C
1-C
3-alkyl-NRkRk ,-NRkRk, C
1-C
3Alkyl, Heterocyclylalkyl, and by one-C (O) CH
3The Heterocyclylalkyl that group replaced; With
Each Rk is independently selected from: H, C
1-C
6Alkyl is by the C that one or two hydroxyl replaced
1-C
6Alkyl; Phenyl, and by a C
1-C
3The phenyl that alkyl replaced.
In one embodiment of the invention:
Z is optional aryl that replaces or the optional heteroaryl that replaces,
Wherein said aryl and heteroaryl be optional to be independently selected from following substituent group by one to three and to replace: halo ,-CN ,-N (Rb) SO
2Re ,-N (Rb) C (O) Ra ,-C (O) NRaRb ,-C (O) NRfRg ,-C (O) H ,-SO
2Ri ,-NRaRb ,-SO
2NRaRb ,-SO
2NRfRg ,-ORc ,-N (Rb) C (O) NRaRb ,-N (Rb) C (O) NRfRg ,-N (Rb) C (O) ORd, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl :-NRaRb, C
3-C
6Cycloalkyl, phenyl ,-ORc, Heterocyclylalkyl and by one or two C
1-C
6The Heterocyclylalkyl that alkyl replaced; C
1-C
6Haloalkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Haloalkyl :-NRaRb, C
3-C
6Cycloalkyl, phenyl, Heterocyclylalkyl and by one or two C
1-C
6The Heterocyclylalkyl that alkyl replaced; Heterocyclylalkyl and by one or two C
1-C
6The Heterocyclylalkyl that alkyl replaced;
Each Ra is independently selected from: H, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl: halo ,-CN ,-C (O) NH
2,-NRkRk ,-SO
2Ri ,-N (Rb) SO
2Re ,-C (O) ORb ,-N (Rb) C (O) Rb ,-ORc ,-SRc, C
3-C
7Cycloalkyl, C
1-C
6Haloalkyl, Heterocyclylalkyl, phenyl, phenylol and heteroaryl; Phenyl is independently selected from the following phenyl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl ,-ORc and-NRfRg; Heteroaryl is independently selected from the following heteroaryl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl ,-ORc and-NRfRg; C
3-C
7Cycloalkyl is independently selected from the following C that substituent group replaced by one to three
3-C
7Cycloalkyl: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl ,-ORc and-NRfRg; Heterocyclylalkyl, and be independently selected from the following Heterocyclylalkyl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl ,-CH
2C (O) Rb, C
1-C
6Haloalkyl ,-C (O) ORb, NH
2, heteroaryl ,-ORc and NRfRg; With
Rj is selected from H, the optional C that replaces
1-C
6Alkyl, C
1-C
6Haloalkyl, heteroaryl and the optional phenyl that replaces,
The C of wherein said optional replacement
1-C
6Alkyl is optional to be replaced by one or two substituent group, and each substituent group is independently selected from following: hydroxyl, methyl mercapto, C
3-C
6Cycloalkyl is by a C
1-C
3The C that alkyl replaced
3-C
6Cycloalkyl; Heterocyclylalkyl is by a C
1-C
3Alkyl, an oxo base or the Heterocyclylalkyl that the 4-luorobenzyl is replaced;-NRkRk, heteroaryl ,-NHC (O) CH
3With-S (O)
2Ri;
Wherein said phenyl is optional to be replaced by one to three substituent group, and each substituent group is independently selected from following: C
1-C
3Alkoxyl ,-NHC (O) CH
3,-C (O) NH
2, halo, CF
3,-S (O)
2Ri ,-S (O)
2NHRi, hydroxyl ,-C
1-C
3-alkyl-NRkRk ,-NRkRk, C
1-C
3Alkyl, Heterocyclylalkyl, and by one-C (O) CH
3The Heterocyclylalkyl that group replaced;
Or its pharmaceutically acceptable salt, solvate or polymorph.
Another embodiment of the invention is the chemical compound according to formula I, or its pharmaceutically acceptable salt, solvate or polymorph, wherein:
R1 is group-YZ;
Y is a chemical bond;
Z is optional phenyl that replaces or the optional heteroaryl that replaces,
Wherein said phenyl and heteroaryl be optional to be selected from following substituent group by one or two and to replace: halo, cyano group ,-N (Rb) SO
2Re ,-N (Rb) C (O) Ra, C
1-C
6Alkyl, and be selected from the following C that substituent group replaced by one
1-C
6Alkyl :-NRaRb ,-ORc, Heterocyclylalkyl and by a C
1-C
3The Heterocyclylalkyl that alkyl replaced;
R2 is H;
R3 is H;
U is a chemical bond;
V is phenyl or 5 or 6 Yuans heteroaryls, its each quilt-N (Rb) S (O)
mR4 ,-S (O)
mN (Rb) R4 or-S (O)
mR4 replaces;
M is 1 or 2;
R4 is radicals X-R5;
X is chemical bond, C
1-C
6Alkylidene, heteroaryl or C
1-C
6The alkylidenyl-heterocyclic alkyl;
R5 is NRaRb, ORj, the optional Heterocyclylalkyl that replaces or the optional heteroaryl that replaces,
Wherein said Heterocyclylalkyl and heteroaryl be optional to be independently selected from following substituent group by one to three and to replace: halo, and-C (O) Ra ,-NRaRb, Heterocyclylalkyl is by a C
1-C
6The Heterocyclylalkyl that alkyl replaced; Phenyl, C
1-C
6Alkyl is selected from the following C that substituent group replaced by one or two
1-C
6Alkyl :-ORc ,-C (O) Rc ,-C (O) NRaRb and phenyl; Heteroaryl, the oxo base, N (Rb) C (O) Ra ,-ORc ,-C (O) NRaRb and-C (O) ORc;
Each Ra is independently selected from: H, Heterocyclylalkyl, the Heterocyclylalkyl that is replaced by one-C (O) ORb group; C
2-C
6Alkynyl, the optional C that replaces
1-C
6Alkyl, C
3-C
6Cycloalkyl, the C that is replaced by one-ORc group
3-C
7Cycloalkyl, and phenyl, the C of wherein said optional replacement
1-C
6Alkyl is optional to be selected from following substituent group by one to three and to replace: halo, heteroaryl, Heterocyclylalkyl ,-ORc, N (Rb) SO
2Re ,-N (Rk)
2, C
3-C
7Cycloalkyl, phenyl and phenylol;
Each Rb is independently selected from: H, C
1-C
6Alkyl, the C that is replaced by one-ORc group
1-C
6Alkyl;
Each Rc is independently selected from: H, C
1-C
6Alkyl, Heterocyclylalkyl and aryl;
Each Re is independently selected from: C
1-C
6Alkyl, phenyl, and by a C
1-C
6The phenyl that alkyl replaced;
Each Ri is independently selected from: C
1-C
3Alkyl and phenyl;
Rj is selected from H, the optional C that replaces
1-C
6Alkyl, C
1-C
6Haloalkyl, heteroaryl and the optional phenyl that replaces,
The C of wherein said optional replacement
1-C
6Alkyl is optional to be replaced by one or two substituent group, and each substituent group is independently selected from following: hydroxyl, methyl mercapto, C
3-C
6Cycloalkyl is by a C
1-C
3The C that alkyl replaced
3-C
6Cycloalkyl; Heterocyclylalkyl is by a C
1-C
3Alkyl, an oxo base or the Heterocyclylalkyl that the 4-luorobenzyl is replaced;-NRkRk, heteroaryl ,-NHC (O) CH
3With-S (O)
2Ri;
Wherein said phenyl is optional to be replaced by one to three substituent group, and each substituent group is independently selected from following: C
1-C
3Alkoxyl ,-NHC (O) CH
3,-C (O) NH
2, halo, CF
3,-S (O)
2Ri ,-S (O)
2NHRi, hydroxyl ,-C
1-C
3-alkyl-NRkRk ,-NRkRk, C
1-C
3Alkyl, Heterocyclylalkyl, and by one-C (O) CH
3The Heterocyclylalkyl that group replaced; With
Each Rk is independently selected from H, C
1-C
6Alkyl.
Another embodiment of the invention is the chemical compound according to formula I, or its pharmaceutically acceptable salt, solvate or polymorph, wherein:
R1 is group-YZ;
Y is a chemical bond;
Z is optional phenyl that replaces or the optional heteroaryl that replaces,
Wherein said phenyl and heteroaryl be optional to be selected from following substituent group by one or two and to replace: halo, cyano group ,-N (Rb) SO
2Re ,-N (Rb) C (O) Ra, C
1-C
6Alkyl, and be selected from the following C that substituent group replaced by one
1-C
6Alkyl :-NRaRb ,-ORc, Heterocyclylalkyl and by an OH ,-C (O) NH
2Or C
1-C
3The Heterocyclylalkyl that alkyl replaced;
R2 is H;
R3 is H;
U is a chemical bond;
V is
M is 2;
R4 is group-X-R5;
X is chemical bond or C
1-C
6Alkylidene;
R5 is-NRaRb, the optional Heterocyclylalkyl that replaces or the optional heteroaryl that replaces,
Wherein said Heterocyclylalkyl and heteroaryl be optional to be independently selected from following substituent group by one to three and to replace: halo, and-C (O) Ra ,-NRaRb, Heterocyclylalkyl is by a C
1-C
6The Heterocyclylalkyl that alkyl replaced; Phenyl, C
1-C
6Alkyl is selected from the following C that substituent group replaced by one or two
1-C
6Alkyl :-ORc ,-C (O) Rc ,-C (O) NRaRb and phenyl; Heteroaryl, the oxo base, N (Rb) C (O) Ra ,-ORc ,-C (O) NRaRb and-C (O) ORc;
Each Ra is independently selected from: H ,-ORh, Heterocyclylalkyl, the Heterocyclylalkyl that is replaced by one-C (O) ORb group; C
2-C
6Alkynyl, the optional C that replaces
1-C
6Alkyl, C
3-C
6Cycloalkyl, the C that is replaced by one-ORc group
3-C
7Cycloalkyl, and phenyl, the C of wherein said optional replacement
1-C
6Alkyl is optional to be selected from following substituent group by one to three and to replace: halo, heteroaryl, Heterocyclylalkyl ,-ORc, N (Rb) SO
2Re ,-N (Rk)
2, C
3-C
7Cycloalkyl, phenyl and phenylol;
Each Rb is independently selected from: H, C
1-C
6Alkyl, the C that is replaced by one-ORc group
1-C
6Alkyl;
Each Rc is independently selected from: H, C
1-C
6Alkyl, Heterocyclylalkyl and aryl;
Each Re is independently selected from: C
1-C
6Alkyl, phenyl and by a C
1-C
6The phenyl that alkyl replaced;
Each Rh is independently selected from: H, C
1-C
6Alkyl and C
1-C
6Haloalkyl; And
Each Rk is independently selected from H, C
1-C
6Alkyl.
Another embodiment of the invention is the chemical compound according to formula I, or its pharmaceutically acceptable salt, solvate or polymorph, wherein:
R1 is group-YZ;
Y is a chemical bond;
Z is optional phenyl that replaces or the optional heteroaryl that replaces,
Wherein said phenyl and heteroaryl be optional to be selected from following substituent group by one or two and to replace: halo, cyano group ,-N (Rb) SO
2Re ,-N (Rb) C (O) Ra, C
1-C
6Alkyl, and be selected from the following C that substituent group replaced by one
1-C
6Alkyl :-NRaRb ,-ORc, Heterocyclylalkyl and by a C
1-C
3The Heterocyclylalkyl that alkyl replaced;
R2 is H;
R3 is H;
U is a chemical bond;
V is
M is 2;
R4 is group-X-R5;
X is chemical bond or C
1-C
6Alkylidene;
R5 is-NRaRb, the optional Heterocyclylalkyl that replaces or the optional heteroaryl that replaces,
Wherein said Heterocyclylalkyl and heteroaryl be optional to be independently selected from following substituent group by one to three and to replace: halo, and-C (O) Ra ,-NRaRb, Heterocyclylalkyl is by a C
1-C
6The Heterocyclylalkyl that alkyl replaced; Phenyl, C
1-C
6Alkyl is selected from the following C that substituent group replaced by one or two
1-C
6Alkyl :-ORc ,-C (O) Rc ,-C (O) NRaRb and phenyl; Heteroaryl, the oxo base, N (Rb) C (O) Ra ,-ORc ,-C (O) NRaRb and-C (O) ORc;
Each Ra is independently selected from: H, Heterocyclylalkyl, the Heterocyclylalkyl that is replaced by one-C (O) ORb group; C
2-C
6Alkynyl, the optional C that replaces
1-C
6Alkyl, C
3-C
6Cycloalkyl, the C that is replaced by one-ORc group
3-C
7Cycloalkyl, and phenyl, the C of wherein said optional replacement
1-C
6Alkyl is optional to be selected from following substituent group by one to three and to replace: halo, heteroaryl, Heterocyclylalkyl ,-ORc, N (Rb) SO
2Re ,-N (Rk)
2, C
3-C
7Cycloalkyl, phenyl and phenylol;
Each Rb is independently selected from: H, C
1-C
6Alkyl, the C that is replaced by one-ORc group
1-C
6Alkyl;
Each Rc is independently selected from: H, C
1-C
6Alkyl, Heterocyclylalkyl and aryl;
Each Re is independently selected from: C
1-C
6Alkyl, phenyl and by a C
1-C
6The phenyl that alkyl replaced;
Each Rh is independently selected from: H, C
1-C
6Alkyl and C
1-C
6Haloalkyl; With
Each Rk is independently selected from H, C
1-C
6Alkyl.
Another embodiment of the invention is the chemical compound according to formula I, or its pharmaceutically acceptable salt, solvate or polymorph, wherein:
R1 is group-YZ;
Y is a chemical bond;
Z is a phenyl;
R2 is H;
R3 is H;
U is a chemical bond;
V is
M is 2;
R4 is radicals X-R5;
X is chemical bond or C
1-C
6Alkylidene;
R5 is-ORj;
Each Ri is independently selected from: C
1-C
3Alkyl and phenyl;
Rj is selected from H, the optional C that replaces
1-C
6Alkyl, C
1-C
6Haloalkyl, heteroaryl and the optional phenyl that replaces,
The C of wherein said optional replacement
1-C
6Alkyl is optional to be replaced by one or two substituent group, and each substituent group is independently selected from following: hydroxyl, C
1-C
6Alkoxyl ,-OCH
2CH
2N (CH
3)
2, methyl mercapto, C
3-C
6Cycloalkyl is by a C
1-C
3The C that alkyl replaced
3-C
6Cycloalkyl; Heterocyclylalkyl is by a C
1-C
3Alkyl, an oxo base or the Heterocyclylalkyl that the 4-luorobenzyl is replaced;-NRkRk, heteroaryl ,-NHC (O) CH
3With-S (O)
2Ri;
Wherein said phenyl is optional to be replaced by one to three substituent group, and each substituent group is independently selected from following: C
1-C
3Alkoxyl ,-NHC (O) CH
3,-C (O) NH
2, halo, CF
3,-S (O)
2Ri ,-S (O)
2NHRi, hydroxyl ,-C
1-C
3-alkyl-NRkRk ,-NRkRk, C
1-C
3Alkyl, Heterocyclylalkyl and by one-C (O) CH
3The Heterocyclylalkyl that group replaced; With
Each Rk is independently selected from: H, C
1-C
6Alkyl is by the C that one or two hydroxyl replaced
1-C
6Alkyl; Phenyl, and by a C
1-C
3The phenyl that alkyl replaced.
Another embodiment of the invention is the chemical compound according to formula I, or its pharmaceutically acceptable salt, solvate or polymorph, wherein:
R1 is group-YZ;
Y is a chemical bond;
Z is a phenyl;
R2 is H;
R3 is H;
U is a chemical bond;
V is
M is 2;
R4 is radicals X-R5;
X is chemical bond or C
1-C
6Alkylidene;
R5 is-ORj;
Each Ri is independently selected from: C
1-C
3Alkyl and phenyl;
Rj is selected from H, the optional C that replaces
1-C
6Alkyl, C
1-C
6Haloalkyl, heteroaryl and the optional phenyl that replaces,
The C of wherein said optional replacement
1-C
6Alkyl is optional to be replaced by one or two substituent group, and each substituent group is independently selected from following: hydroxyl, methyl mercapto, C
3-C
6Cycloalkyl is by a C
1-C
3The C that alkyl replaced
3-C
6Cycloalkyl; Heterocyclylalkyl is by a C
1-C
3Alkyl, an oxo base or the Heterocyclylalkyl that the 4-luorobenzyl is replaced;-NRkRk, heteroaryl ,-NHC (O) CH
3With-S (O)
2Ri;
Wherein said phenyl is optional to be replaced by one to three substituent group, and each substituent group is independently selected from following: C
1-C
3Alkoxyl ,-NHC (O) CH
3,-C (O) NH
2, halo, CF
3,-S (O)
2Ri ,-S (O)
2NHRi, hydroxyl ,-C
1-C
3-alkyl-NRkRk ,-NRkRk, C
1-C
3Alkyl, Heterocyclylalkyl and by one-C (O) CH
3The Heterocyclylalkyl that group replaced; With
Each Rk is independently selected from: H, C
1-C
6Alkyl is by the C that one or two hydroxyl replaced
1-C
6Alkyl; Phenyl, and by a C
1-C
3The phenyl that alkyl replaced.
Another embodiment of the invention is to be selected from following chemical compound:
The 3-{1-[(2-amino-ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(dimethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-methyl isophthalic acid-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[3-(piperidino) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(2-methyl isophthalic acid-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-hydroxyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(cyclopenta amino) ethyl] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(1-pyrrolidinyl) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(dimethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(cyclopenta amino) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(4-hydroxyl-piperidino) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
The 3-{1-[(2-hydroxyethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
5-(5-chloro-2-thienyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[2-(methylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[2-(piperidino) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[2-(4-methyl isophthalic acid-piperazinyl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[[2-(dimethylamino) ethyl] and (methyl) amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(4-morpholinyl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[3-(2-hydroxyethyl)-1-piperazinyl] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(cyclopenta amino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(cyclobutyl amino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-[1-(the 2-[(phenyl methyl) and amino] ethyl } sulfonyl)-the 4-piperidyl]-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[2-(1-pyrrolidinyl) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[2-(4-hydroxyl-piperidino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[[3-(dimethylamino) propyl group] and (methyl) amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(1,4 '-Lian piperidines-1 '-yl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(diethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[2-(2-phenyl-1-pyrrolidinyl) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[2-(six hydrogen-1H-azepine -1-yl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(cyclohexyl methyl) and amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-hydroxyl-1-(hydroxymethyl) ethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(ethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[ethyl (methyl) amino] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(2-hydroxyethyl) and amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[(2S)-and the 2-hydroxypropyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[(1S)-and 2-hydroxyl-1-Methylethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[(1R)-and 2-hydroxyl-1-Methylethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[4-(amino carbonyl)-piperidino] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[4-(4-morpholinyl)-piperidino] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(dimethylamino) ethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(the 4-methyl isophthalic acid, 4 '-Lian piperidines-1 '-yl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[4-(4-methyl isophthalic acid-piperazinyl)-piperidino] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(methoxyl group) ethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[3-(4-morpholinyl) propyl group] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(4-acetyl group-1-piperazinyl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[4-(2-hydroxyethyl)-1-piperazinyl] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[3-(hydroxymethyl)-piperidino] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(2-{[(4-aminomethyl phenyl) and sulfonyl] amino } ethyl) amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(4-morpholinyl) ethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{ methyl [2-(methylamino) ethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{4-[2-oxo-2-(1-pyrrolidinyl) ethyl]-the 1-piperazinyl } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
The 3-{1-[(2-{2-[(dimethylamino) carbonyl]-the 1-pyrrolidinyl } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[(2S)-2-(amino carbonyl)-1-pyrrolidinyl] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-[5-(hydroxymethyl)-2-thienyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[5-(1-pyrrolidinyl methyl)-2-thienyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-{5-[(methylamino) methyl]-the 2-thienyl }-3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-{5-[(ethylamino) methyl]-the 2-thienyl }-3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-[1-(two (1-Methylethyl) amino of 3-[] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(methoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2S, 5S)-2,5-dimethyl-1-pyrrolidinyl] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-methyl isophthalic acid-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-hydroxyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-methyl isophthalic acid-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
5-(4-fluorophenyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-(hydroxymethyl) phenyl]-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[4-(hydroxymethyl) phenyl]-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(4-aminomethyl phenyl)-1H-indole-7-Methanamide;
5-[4-(acetyl-amino) phenyl]-3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-the 5-{4-[(mesyl) amino] phenyl }-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(1H-pyrazoles-4-yl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-(mesyl) phenyl]-1H-indole-7-Methanamide;
5-[3-(hydroxymethyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(4-aminomethyl phenyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[4-(acetyl-amino) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-{4-[(mesyl) amino] phenyl }-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(1H-pyrazoles-4-yl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-(mesyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[4-(hydroxymethyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-{3-[(ethylamino) methyl] phenyl }-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-{3-[(methylamino) methyl] phenyl }-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(1-Methylethyl) amino] methyl } phenyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-([(2S)-and the 2-hydroxypropyl] amino } methyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-{3-[(cyclopenta amino) methyl] phenyl }-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-([(1S)-and 2-hydroxyl-1-Methylethyl] amino } methyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-the 5-{3-[(ethylamino) methyl] phenyl }-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-([(1S)-and 2-hydroxyl-1-Methylethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-([(2S)-and the 2-hydroxypropyl] amino } methyl) phenyl]-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-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[4-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[4-(1-pyrrolidinyl methyl) phenyl]-1H-indole-7-Methanamide;
3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-(hydroxymethyl) phenyl]-1H-indole-7-Methanamide;
3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-(4-aminomethyl phenyl)-1H-indole-7-Methanamide;
3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3, the 4-difluorophenyl)-1H-indole-7-Methanamide;
5-(3-chlorphenyl)-3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-(4-ethylphenyl)-1H-indole-7-Methanamide;
3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-[4-(dimethylamino) phenyl]-1H-indole-7-Methanamide;
4-{[3-(4-[7-(amino carbonyl)-5-phenyl-1H-indol-3-yl]-piperidino } sulfonyl) propyl group] amino }-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester;
5-phenyl-3-(1-{[3-(4-piperidyl amino) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-phenyl-3-{1-[(3-{[(2R)-tetrahydrochysene-2-furyl methyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[[3-(dimethylamino) propyl group] and (methyl) amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[4-(amino carbonyl)-piperidino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-hydroxyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(1,4 '-Lian piperidines-1 '-yl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-[1-(3-[4-(phenyl methyl)-piperidino] and propyl group } sulfonyl)-the 4-piperidyl]-1H-indole-7-Methanamide;
3-(1-{[3-(octahydro-1 (2H)-quinolyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(six hydrogen-1H-azepine -1-yl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-{2-[(1-Methylethyl) amino]-the 2-oxoethyl }-the 1-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(2-ethyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(2-methyl isophthalic acid-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-[1-(3-[2-(2-thienyl)-1-pyrrolidinyl] and propyl group } sulfonyl)-the 4-piperidyl]-1H-indole-7-Methanamide;
3-(1-{[3-(3-hydroxyl-1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-hydroxy-4-phenyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(3-hydroxyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2R)-2-(amino carbonyl)-1-pyrrolidinyl] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-hydroxyethyl) and (1-Methylethyl) amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[methyl (2-propine-1-yl) amino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[3-(1,3-thiazoles alkane-3-yl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-phenyl-3-[1-(3-[2-(1,3-thiazoles-2-yl)-1-pyrrolidinyl] and propyl group } sulfonyl)-the 4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-furyl methyl) and (methyl) amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(2-methyl isophthalic acid-aziridine base) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[ethyl (1-Methylethyl) amino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{ ethyl [2-(methoxyl group) ethyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(diethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[[2-hydroxyl-2-(4-hydroxy phenyl) ethyl] and (methyl) amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(3-amino-1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[ethyl (methyl) amino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
Two [2-(methoxyl group) ethyl] amino of 3-{1-[(3-{ } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(2,6-dimethyl-4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[2-(hydroxymethyl)-piperidino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[3-(hydroxymethyl)-piperidino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{ (2S)-2-[(methoxyl group) methyl]-the 1-pyrrolidinyl } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[methyl (1-Methylethyl) amino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[(1S)-and 1-(hydroxymethyl)-2-methyl-propyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2-hydroxyl-1-Methylethyl) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-(dimethylamino) ethyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-({ 3-[(trans-4-hydroxy-cyclohexyl) amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-hydroxypropyl) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[1-methyl-2-(methoxyl group) ethyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-hydroxyethyl) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-hydroxybutyl) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-(4-morpholinyl) ethyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[(2R)-and the 2-hydroxypropyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[(1R)-and 1-(hydroxymethyl)-2-methyl-propyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[(1S)-and 1-(hydroxymethyl) propyl group] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(cyclohexyl amino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(4-aminomethyl phenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[3-(phenoxy group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(3-{[2-(trifluoromethyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-[1-(the 3-[(4-hydroxybutyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(cyclopropyl methyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2-hydroxyl-1-methyl-propyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(cyclobutylmethyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-[1-(3-[(tetrahydrochysene-3-furyl methyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-1H-indole-7-Methanamide;
3-{1-[(3-{[4-(acetyl-amino) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[4-(methoxyl group) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-(methoxyl group) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(4-fluorophenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(3-{[3-(trifluoromethyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-{1-[(3-{[3-(methoxyl group) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
The 3-{1-[(3-hydroxypropyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(ethyoxyl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(ethyoxyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-the 5-{3-[(methylamino) methyl] phenyl }-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(2-{[2-(piperidino) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-(1-{[2-([(2S)-and 1-methyl-2-pyrrolidinyl] methyl } the oxygen base) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(2-OXo-1-pyrrolidine base) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(two (1-Methylethyl) amino of 2-[] and ethyl } the oxygen base) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(4-morpholinyl) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(six hydrogen-1H-azepine -1-yl) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(diethylamino) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(2-{4-[(4-fluorophenyl) methyl]-the 1-piperazinyl } ethyl) the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(2-[ethyl (3-aminomethyl phenyl) amino] and ethyl } the oxygen base) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(two (2-hydroxypropyl) amino of 2-[] and ethyl } the oxygen base) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(acetyl-amino) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(the 2-[(1-Methylethyl) and the oxygen base] ethyl } the oxygen base) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(2-furyl methyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(3-furyl methyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(methyl mercapto) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(2-{[2-(3-thienyl) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-{1-[(2-{[(2-methyl cyclopropyl) methyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(ethyoxyl) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[(2,2,3,3,3-five fluoropropyls) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(2-methyl-propyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[2-(propoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-phenyl-3-[1-(2-[(2,2,2-trifluoroethyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-1H-indole-7-Methanamide;
5-phenyl-3-[1-(2-[(tetrahydrochysene-3-furyl methyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(mesyl) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-([(2S)-and 5-oxo-2-pyrrolidinyl] methyl } the oxygen base) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[3-(dimethylamino) propyl group] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[(cyclopropyl methyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(cyclopentyl-methyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(1-Methylethyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[(2-{[2-(dimethylamino) ethyl] and the oxygen base } ethyl) the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[(1S, 3S)-3-hydroxyl-1-methyl butyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(4-hydroxybutyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[(1R, 3R)-3-hydroxyl-1-methyl butyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[(2-hydroxyl-1-methyl-propyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(2-{[2-(2-thienyl) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(2-{[2-(1-pyrrolidinyl) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[(1-Methylethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(the 2-[(methoxyl group) and amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[hydroxyl (methyl) amino] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[methyl (methoxyl group) amino] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(ethyoxyl) and amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(methoxyl group) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[hydroxyl (methyl) amino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[methyl (methoxyl group) amino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(ethyoxyl) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
The 5-{3-[(methylamino) methyl] phenyl }-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-{3-[(ethylamino) methyl] phenyl }-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(1-Methylethyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-{3-[(propyl group amino) methyl] phenyl }-1H-indole-7-Methanamide;
5-[3-([(2R)-and the 2-hydroxypropyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-([(2S)-and the 2-hydroxypropyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(cyclopropyl methyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [2-(methoxyl group) ethyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-([(2R)-and the 2-methyl butyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(2,2-dimethyl propyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [3-(methoxyl group) propyl group] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [2-(ethyoxyl) ethyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[(tetrahydrochysene-2-furyl methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-([(2R)-and tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-[3-({ [(1S)-1,2-dimethyl propyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [1-methyl-2-(methoxyl group) ethyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-({ [(1S)-1,2,2-trimethyl propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide;
The 5-{3-[({1-[(methoxyl group) methyl] propyl group } amino) methyl] phenyl }-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [(5-methyl-2-furyl) methyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(2-hydroxyl-1-Methylethyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(1,1-dimethyl propyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(4-hydroxybutyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[(4-pyridylmethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[(2-pyridylmethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-[3-({ [3-(1H-imidazoles-1-yl) propyl group] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-({ [3-(1-pyrrolidinyl) propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-({ [2-(piperidino) ethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-({ [3-(4-morpholinyl) propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-[3-([(1S)-and 1-cyclohexyl ethyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[methyl (2-propylene-1-yl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-(3-{[(3R)-3-hydroxyl-1-pyrrolidinyl] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(2-hydroxyethyl) (propyl group) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-{3-[(2-propyl group-1-pyrrolidinyl) methyl] phenyl }-1H-indole-7-Methanamide;
5-(3-{[2-(1-Methylethyl)-1-pyrrolidinyl] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-{3-[(3,5-dimethyl-piperidino) methyl] phenyl }-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(2S)-2-(amino carbonyl)-1-pyrrolidinyl] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(1,1-dimethyl ethyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-{3-[(methylamino) methyl] phenyl }-3-(1-{[2-(methoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(1,1-dimethyl propyl) amino] methyl } phenyl)-3-(1-{[2-(methoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(ethyoxyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(ethyoxyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
The 3-{1-[(3-hydroxypropyl) sulfonyl]-the 4-piperidyl }-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-{1-[(1-methyl isophthalic acid H-imidazol-4 yl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-[1-(2-thienyl sulphonyl base)-4-piperidyl]-1H-indole-7-Methanamide;
3-{1-[(5-chloro-2-thienyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[5-(the different azoles of 3-base)-3-thienyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(5-{[(phenyl methyl) amino] methyl }-the 2-thienyl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-(1-{[2-(acetyl-amino)-4-methyl isophthalic acid, 3-thiazole-5-yl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(5-chloro-1,3-dimethyl-1H-pyrazoles-4-yl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(4-chloro-2,1,3-benzo diazole-5-yl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(1,2-dimethyl-1H-imidazol-4 yl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(1,3,5-trimethyl-1H-pyrazoles-4-yl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-{1-[(3, the different azoles of 5-dimethyl-4-base) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2,4-dimethyl-1,3-thiazoles-5-yl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(1,2-dimethyl-1H-imidazoles-5-yl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(1-methyl isophthalic acid H-imidazol-4 yl) sulfonyl]-the 4-piperidyl }-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-[5-(1-pyrrolidinyl methyl)-3-thienyl]-1H-indole-7-Methanamide;
5-(5-{[(2,2-dimethyl propyl) amino] methyl }-the 3-thienyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-[1-(the 3-[(3-ethylphenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(3-aminomethyl phenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[4-(ethyoxyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[4-(amino carbonyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-(acetyl-amino)-5-aminomethyl phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-fluoro-6-(methoxyl group) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-fluoro-3-(trifluoromethyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(the 2-[(dimethylamino) and methyl] phenyl } the oxygen base) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(3-fluorophenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[3-(acetyl-amino) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-fluorophenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[3-(dimethylamino) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2,6-difluorophenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-(acetyl-amino) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[3-(diethylamino) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(1,3-benzodioxole-5-base oxygen base) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[3-(the 3-[(phenyl amino) and sulfonyl] phenyl } the oxygen base) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-{1-[(3-{[4-(4-acetyl group-1-piperazinyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(4-hydroxy phenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-(acetyl-amino)-4-aminomethyl phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-(mesyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(3-{[3-(piperidino) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-hydroxy phenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(3-hydroxy phenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(3-{[4-(trifluoromethyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
5-[3-(1-pyrrolidinyl methyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-(4-morpholinyl methyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-(piperidino methyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-phenyl-3-[1-(3-thienyl sulphonyl base)-4-piperidyl]-1H-indole-7-Methanamide;
3-{1-[(4-methyl-2-thienyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(5-methyl-2-thienyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(1-benzothiophene-3-base sulfonyl)-4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-(4-[7-(amino carbonyl)-5-phenyl-1H-indol-3-yl]-piperidino } sulfonyl)-1-methyl isophthalic acid H-pyrroles-2-carboxylate methyl ester; Or
5-(4-[7-(amino carbonyl)-5-phenyl-1H-indol-3-yl]-piperidino } sulfonyl)-2-methyl-3-furancarboxylic acid methyl ester;
Or its pharmaceutically acceptable salt.
Another embodiment of the invention is to be selected from following chemical compound:
The 3-{1-[(2-amino-ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(dimethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(2-methyl isophthalic acid-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-hydroxyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(cyclopenta amino) ethyl] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(1-pyrrolidinyl) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(dimethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(cyclopenta amino) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(4-hydroxyl-piperidino) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
The 3-{1-[(2-hydroxyethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
5-(5-chloro-2-thienyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[2-(methylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[2-(piperidino) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[2-(4-methyl isophthalic acid-piperazinyl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(4-morpholinyl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[2-(1-pyrrolidinyl) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[2-(4-hydroxyl-piperidino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[[3-(dimethylamino) propyl group] and (methyl) amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(1,4 '-Lian piperidines-1 '-yl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(diethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(six hydrogen-1H-azepine -1-yl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(ethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[ethyl (methyl) amino] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(2-hydroxyethyl) and amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[(2S)-and the 2-hydroxypropyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[(1S)-and 2-hydroxyl-1-Methylethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(4-acetyl group-1-piperazinyl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[4-(2-hydroxyethyl)-1-piperazinyl] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{ methyl [2-(methylamino) ethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{4-[2-oxo-2-(1-pyrrolidinyl) ethyl]-the 1-piperazinyl } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
The 3-{1-[(2-{2-[(dimethylamino) carbonyl]-the 1-pyrrolidinyl } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[(2S)-2-(amino carbonyl)-1-pyrrolidinyl] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-[5-(hydroxymethyl)-2-thienyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[5-(1-pyrrolidinyl methyl)-2-thienyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-[1-(two (1-Methylethyl) amino of 3-[] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(methoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2S, 5S)-2,5-dimethyl-1-pyrrolidinyl] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-methyl isophthalic acid-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-hydroxyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-methyl isophthalic acid-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
5-(4-fluorophenyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(1H-pyrazoles-4-yl)-1H-indole-7-Methanamide;
5-[3-(hydroxymethyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(4-aminomethyl phenyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-[1-(3-[[3-(dimethylamino) propyl group] and (methyl) amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(1,4 '-Lian piperidines-1 '-yl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(six hydrogen-1H-azepine -1-yl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-{2-[(1-Methylethyl) amino]-the 2-oxoethyl }-the 1-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(3-hydroxyl-1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(diethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[[2-hydroxyl-2-(4-hydroxy phenyl) ethyl] and (methyl) amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[2-(hydroxymethyl)-piperidino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[(1S)-and 1-(hydroxymethyl)-2-methyl-propyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2-hydroxyl-1-Methylethyl) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-(dimethylamino) ethyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-({ 3-[(trans-4-hydroxy-cyclohexyl) amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-hydroxypropyl) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[1-methyl-2-(methoxyl group) ethyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-hydroxybutyl) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[(2R)-and the 2-hydroxypropyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[(1R)-and 1-(hydroxymethyl)-2-methyl-propyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[(1S)-and 1-(hydroxymethyl) propyl group] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(cyclohexyl amino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
The 3-{1-[(3-hydroxypropyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(ethyoxyl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(ethyoxyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(4-hydroxybutyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(2-{[2-(1-pyrrolidinyl) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
The 5-{3-[(methylamino) methyl] phenyl }-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-{3-[(ethylamino) methyl] phenyl }-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(1-Methylethyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-{3-[(propyl group amino) methyl] phenyl }-1H-indole-7-Methanamide;
5-[3-([(2S)-and the 2-hydroxypropyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(cyclopropyl methyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [2-(methoxyl group) ethyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(2,2-dimethyl propyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [3-(methoxyl group) propyl group] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [2-(ethyoxyl) ethyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[(tetrahydrochysene-2-furyl methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-([(2R)-and tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-[3-({ [(1S)-1,2-dimethyl propyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [1-methyl-2-(methoxyl group) ethyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-({ [(1S)-1,2,2-trimethyl propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-[3-({ [(5-methyl-2-furyl) methyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(4-hydroxybutyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[(4-pyridylmethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[(2-pyridylmethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[methyl (2-propylene-1-yl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-(3-{[(3R)-3-hydroxyl-1-pyrrolidinyl] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(ethyoxyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide; Or
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
Or its pharmaceutically acceptable salt.
Another embodiment of the invention is to be selected from following chemical compound:
The 3-{1-[(2-amino-ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(dimethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[2-(1-pyrrolidinyl) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[2-(methoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2S, 5S)-2,5-dimethyl-1-pyrrolidinyl] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(diethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-(3-{[(2,2-dimethyl propyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide; Or
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
Or its pharmaceutically acceptable salt.
Another embodiment of the invention is the chemical compound according to formula Ia, or its pharmaceutically acceptable salt, solvate or polymorph, wherein:
R wherein
1Be H, halogen or group-YZ;
Y is chemical bond, C
1-C
6Alkylidene, C
2-C
6Alkenylene or C
2-C
6Alkynylene;
Z is optional aryl that replaces or the optional heteroaryl that replaces,
Wherein said aryl and heteroaryl be optional to be independently selected from following substituent group by one to three and to replace: halo, CN, N (Rb) SO
2Re, N (Rb) C (O) Ra, C (O) NRaRb, C (O) NRfRg, SO
2NRaRb, SO
2NRfRg, ORc, N (Rb) C (O) NRaRb, N (Rb) C (O) NRfRg, N (Rb) C (O) ORd, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl: NRaRb, C
3-C
6Cycloalkyl, phenyl, Heterocyclylalkyl and by one or two C
1-C
6The Heterocyclylalkyl that alkyl replaced; C
1-C
6Haloalkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Haloalkyl: NRaRb, C
3-C
6Cycloalkyl, phenyl, Heterocyclylalkyl and by one or two C
1-C
6The Heterocyclylalkyl that alkyl replaced; Heterocyclylalkyl, and by one or two C
1-C
6The Heterocyclylalkyl that alkyl replaced;
U is chemical bond, C
1-C
6Alkylidene or C
2-C
6Alkenylene;
V is phenyl, 5 or 6 Yuans heteroaryls, 5-7 element heterocycle alkyl, C
5-C
7Cycloalkyl or C
5-C
7Cycloalkenyl group, its each by N (Rb) S (O)
mR
2Replace; Perhaps V is N (Rb) S (O)
mR
2,
M is 1 or 2;
R
2Be radicals X-R
3
X is chemical bond, C
1-C
6Alkylidene, C
2-C
6Alkenylene, C
2-C
6Alkynylene, aryl, C
1-C
6Alkylidene-aryl, heteroaryl, C
1-C
6Alkylidene-heteroaryl, Heterocyclylalkyl, C
1-C
6Alkylidenyl-heterocyclic alkyl, C
4-C
7Cycloalkyl, C
1-C
6Alkylidene-C
4-C
7Cycloalkyl, C
5-C
7Cycloalkenyl group or C
1-C
6Alkylidene-C
5-C
7Cycloalkenyl group;
R
3Be NRaRb, the optional Heterocyclylalkyl that replaces or the optional heteroaryl that replaces;
Wherein said Heterocyclylalkyl and heteroaryl be optional to be independently selected from following substituent group by one to three and to replace: halo, Heterocyclylalkyl, oxo base, CN, C (O) Ra, N (Rb) SO
2Re, N (Rb) C (O) Ra, NRaRb, C (O) NRaRb, C (O) NRfRg, SO
2NRaRb, SO
2NRfRg, ORc, C (O) ORc, N (Rb) C (O) NRaRb, N (Rb) C (O) NRfRg, N (Rb) C (O) ORd, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl: NRaRb, ORc, C (O) NRaRb, C
3-C
6Cycloalkyl, Heterocyclylalkyl and phenyl; C
1-C
6Haloalkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Haloalkyl: NRaRb, ORc, C (O) NRaRb, C
3-C
6Cycloalkyl, Heterocyclylalkyl and phenyl; Heterocyclylalkyl is independently selected from the following Heterocyclylalkyl that substituent group replaced by one to three: halo, ORc, haloalkyl, CN and SO
2Ri; Phenyl, and be independently selected from the following phenyl that substituent group replaced by one to three: halo, ORc, haloalkyl, CN and SO
2Ri;
Each Ra is independently selected from: H, C
2-C
6Alkenyl, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl: halo, CN, C (O) NH
2, N (CH
3)
2, SO
2Ri, C (O) ORb, N (Rb) C (O) Rb, ORc, SRc, C
3-C
7Cycloalkyl, C
1-C
6Haloalkyl, Heterocyclylalkyl, phenyl and heteroaryl; Phenyl is independently selected from the following phenyl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl, ORc and NRfRg; Heteroaryl is independently selected from the following heteroaryl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl, ORc and NRfRg; C
3-C
7Cycloalkyl is independently selected from the following C that substituent group replaced by one to three
3-C
7Cycloalkyl: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl, ORc and NRfRg; Heterocyclylalkyl, and be independently selected from the following Heterocyclylalkyl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl, ORc and NRfRg;
Each Rb is independently selected from: H, C
1-C
3Alkyl and C
3-C
7Cycloalkyl;
Each Rc is independently selected from: H, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl: OH, C
3-C
6Cycloalkyl, phenyl, Heterocyclylalkyl and heteroaryl; C
1-C
6Haloalkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Haloalkyl: OH, C
3-C
6Cycloalkyl, phenyl, Heterocyclylalkyl and heteroaryl; C
3-C
7Cycloalkyl is by one to three C
1-C
3The C that alkyl replaced
3-C
7Cycloalkyl; Heterocyclylalkyl is by one to three C
1-C
3The Heterocyclylalkyl that alkyl replaced; Aryl is independently selected from the following aryl that substituent group replaced by one to three: halo, C
1-C
3Alkyl, C
1-C
3Haloalkyl and OH; Heteroaryl, and be independently selected from the following heteroaryl that substituent group replaced by one to three: halo, C
1-C
3Alkyl, C
1-C
3Haloalkyl and OH;
Each Rd is the optional C that replaces independently
1-C
3Alkyl, wherein said C
1-C
3Alkyl is optional to be selected from following substituent group by one to three and to replace: C
3-C
6Cycloalkyl, the optional phenyl that replaces, and the optional heteroaryl that replaces; Wherein said phenyl and heteroaryl be optional to be selected from following substituent group by one to three and to replace: halo, C
1-C
6Alkyl and C
3-C
6Cycloalkyl;
Each Re is independently selected from: C
1-C
6Alkyl is selected from the following C that substituent group replaced by one
1-C
6Alkyl: phenyl, heteroaryl, Heterocyclylalkyl and NRaRb; Phenyl is selected from the following phenyl that substituent group replaced by one to three: halo, CN, C
1-C
6Alkyl, C
1-C
6Haloalkyl and ORh; Heteroaryl is selected from the following heteroaryl that substituent group replaced by one to three: halo, CN, C
1-C
6Alkyl, C
1-C
6Haloalkyl and ORh; C
5-C
7Cycloalkyl is selected from the following C that substituent group replaced by one to three
5-C
7Cycloalkyl: halo, C
1-C
6Alkyl and C
3-C
6Cycloalkyl; Heterocyclylalkyl, and be selected from the following Heterocyclylalkyl that substituent group replaced by one to three: halo, C
1-C
6Alkyl and C
3-C
6Cycloalkyl;
Rf forms the ring with 5-7 member's atom with the nitrogen-atoms that Rg links to each other with them, wherein said ring is optional to contain other a hetero atom as member's atom, described ring is saturated or undersaturated but is not aromatic, and described ring is optional by one or two C
1-C
3Alkyl substituent replaces;
Each Rh is independently selected from: H, C
1-C
6Alkyl and C
1-C
6Haloalkyl; With
Each Ri is independently selected from: C
1-C
3Alkyl and OH.
Another embodiment of the invention is the chemical compound according to formula Ia, or its pharmaceutically acceptable salt, solvate or polymorph, wherein:
R1 is group-YZ;
Y is a chemical bond;
Z is a heteroaryl, phenyl or be selected from the following phenyl that substituent group replaced by: halo, N (Rb) SO
2Re, SO
2NRaRb, C
1-C
6Alkyl and be selected from the following C that substituent group replaced by one
1-C
6Alkyl: NRaRb, Heterocyclylalkyl and by a C
1-C
3The Heterocyclylalkyl that alkyl replaced;
U is a chemical bond;
V is
M is 2;
R
2Be radicals X-R
3
X is chemical bond or C
1-C
6Alkylidene;
R
3Be NRaRb, the optional Heterocyclylalkyl that replaces or the optional heteroaryl that replaces;
Wherein said Heterocyclylalkyl and heteroaryl be optional to be independently selected from following substituent group by one to three and to replace: halo, the optional C that replaces
1-C
6Alkyl, heteroaryl, oxo base, N (Rb) C (O) Ra, ORc and C (O) ORc; Wherein said C
1-C
6Alkyl is optional to be replaced by a NRaRb group;
Each Ra is independently selected from: H, the optional C that replaces
1-C
3Alkyl and phenyl, wherein said C
1-C
3Alkyl is optional to be replaced by one to three substituent group that is selected from halo and phenyl:;
Each Rb is independently selected from: H and C
1-C
3Alkyl;
Each Rc is independently selected from: H, C
1-C
6Alkyl and aryl; With
Each Re is independently selected from: C
1-C
6Alkyl and phenyl.
Another embodiment of the invention is to be selected from following chemical compound:
3-(1-{[2-(1,3-dioxo-1,3-dihydro-2H-iso-indoles-2-yl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
The 3-{1-[(2-amino-ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(dimethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-methyl isophthalic acid-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[3-(piperidino) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide; Or
5-phenyl-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 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 be chosen wantonly by one or more substituent groups replacements as defined in this.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.
Separately or forming other group (as 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
7Cycloalkenyl group) used " alkylidene " is meant the saturated bivalent hydrocarbon chain with mandatory member's atom number in.For example, C
1-C
6Alkylidene is meant the alkylidene with 1-6 member's atom.Alkylidene can be chosen wantonly by one or more substituent groups replacements as defined in this.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 have one or more carbon-to-carbon double bonds in chain.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 be chosen wantonly by one or more substituent groups replacements as defined in this.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 have one or more carbon-to-carbon double bonds in chain.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 be chosen wantonly by one or more substituent groups replacements as defined in this.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 have one or more carbon-to-carbon triple bonds in chain.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 has one or more carbon-to-carbon triple bonds and have one or more carbon-to-carbon double bonds in chain in chain is an alkynylene.Alkynylene can be chosen wantonly by one or more substituent groups replacements as defined in this.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 hexin base.
" 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 be chosen wantonly by one or more substituent groups replacements as defined in this.
" 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 be chosen wantonly by one or more substituent groups replacements as defined in this.Cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl.
" cycloalkenyl group " is meant the unsaturated hydrocarbons ring that has mandatory member's atom number and have carbon-to-carbon double bond in ring.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 be chosen wantonly by one or more substituent groups replacements as defined in this.Cycloalkenyl group comprises cyclopropanyl, cyclobutane base, cyclopentenyl and cyclohexenyl group.
" the 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 " enantiomer is excessive " or " ee " was a kind of enantiomer with respect to another kind of enantiomer is excessive, represents 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%).
" enantiomeric 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.
" halo " 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 contains the aromatic ring of 1-4 hetero atom as member's atom in ring.Contain a more than heteroatomic heteroaryl and can contain different hetero atoms.Heteroaryl can be chosen wantonly by one or more substituent groups replacements as defined in this.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 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, the benzoxazol base, benzofuranyl, isobenzofuran-base, benzothiazolyl, benzothienyl, furo pyridine radicals and naphthyridinyl.
" hetero atom " is meant nitrogen, sulfur or oxygen atom.
" Heterocyclylalkyl " is meant and contains the saturated or unsaturated ring of 1-4 hetero atom as member's atom in ring.But heterocycloalkyl ring is not an armaticity.Contain a more than heteroatomic Heterocyclylalkyl and can contain different hetero atoms.Heterocyclylalkyl can be chosen wantonly by one or more substituent groups replacements as defined in this.Heterocyclylalkyl is that monocycle system or Heterocyclylalkyl with 4-7 member's atom can be the bicyclic system Decahydroisoquinolinpreparation.In certain embodiments, Heterocyclylalkyl is saturated.In other embodiments, Heterocyclylalkyl is undersaturated but is not armaticity.Heterocyclylalkyl comprises pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, pyranose, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro-thienyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidyl, homopiperidinyl, piperazinyl, morpholinyl, tetrahydro-1,4-thiazine base, 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 have more than member's atom in chain and ring, each member's atom combines with adjacent member's atom covalence in this chain or ring so.The substituent atom of formation is not the member's atom in chain or the ring on chain or ring.
" the optional replacement " expression group, for example alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl group, Heterocyclylalkyl or heteroaryl, it can be unsubstituted or be replaced by one or more substituent groups as defined in this." replacement " is meant group, and the hydrogen atom that wherein is connected in member's atom is replaced by group.Be to be understood that, " replacement " comprises implicit regulation to term, 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 by 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 the group that replaces each replacement or optional, suitable substituents defines at this.
" 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 with the animal body tissue, and do not have over-drastic toxicity, zest or other problem or complication, have rationally being benefited/the risk ratio of matching with human body.
Those that use in the symbol that uses in these methods, scheme and embodiment and convention (conventions) and the modern science document are consistent, for example, the Journal ofthe American Chemical Society or the 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 (trifluoroacetic anhydride); THF (oxolane);
DMSO (dimethyl sulfoxine); AcOEt (ethyl acetate);
DME (1, the 2-dimethoxy-ethane); DCM (dichloromethane);
DCE (dichloroethanes); DMF (N, dinethylformamide);
DMPU (N, N '-DMPU (propyleneurea)); 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-[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 (t-butyldimethylsilyl);
DMAP (4-dimethylaminopyridine); BSA (bovine serum albumin);
ATP (adenosine triphosphate); HRP (horseradish peroxidase);
DMEM (Dulbecco ' the improved Eagle culture medium of s);
HPLC (high pressure liquid chromatography);
BOP (two (2-oxo-3- oxazolidinyl) phosphonic chloride (phosphinic chloride));
TBAF (tetra-n-butyl ammonium fluoride);
HBTU (O-benzotriazole-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) the imidazoles hydrochlorates of 3-);
Dppf (1,1 '-two (diphenylphosphino) ferrocene);
CLR (controlled laboratory reaction device (Controlled Laboratory Reactor)); 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 and Ia 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 and Ia or any chemical constitution shown here, though do not have specific pointing out, described structure should comprise any stereoisomer with and all mixture.Therefore, containing the formula I of one or more chiral centres and Ia chemical compound can use with the form of each stereoisomer of the mixture of racemic mixture, enantiomer enrichment or enantiomer-pure.
Containing the formula I of one or more asymmetric centers and each stereoisomer of Ia chemical compound can split by the procedure known to those skilled in the art.For example, this fractionation can followingly be carried out (1) by forming diastereomeric salt, complex or other derivant; (2) by reacting, for example by oxydasis or reduction reaction with stereoisomer specificity reagent selectivity; Or (3) gas liquid chromatography or liquid chromatograph by under chiral environment, for example, on chiral support such as silicon dioxide with bonded chiral ligand or in the presence of chiral solvent.Those skilled in the art will be understood that, when required stereoisomer is converted into another kind of chemical individual by one of aforesaid separation method, need other step to discharge required form.Perhaps, specific stereoisomer can synthesize by asymmetric synthesis by reagent, substrate, catalyst or the solvent that uses optically-active, or by asymmetric conversion a kind of enantiomer is converted into another kind of enantiomer.
Formula I and Ia chemical compound can also contain two keys or other how much asymmetric centers.When there are how much asymmetric spatial chemistry centers in formula I and Ia or any chemical constitution shown here, though there be not specific pointing out, but described structure should comprise described trans (E) geometric isomer, described cis (Z) geometric isomer with and all mixture.Equally, all tautomeric forms also will be included in formula I and the Ia, no matter these tautomers exist with equilibrium form or accounting for main form with a kind of form exists.
Those skilled in the art will be understood that, can make the pharmaceutically acceptable salt of formula I and Ia chemical compound.Really, in certain embodiments of the invention, the pharmaceutically acceptable salt of formula I and Ia chemical compound can be preferably separately free alkali or free acid because these salt give bigger stability of molecule or dissolubility, help thus to be formulated in the dosage form.Therefore, the invention still further relates to the pharmaceutically acceptable salt of formula I and Ia chemical compound.
Be meant those salt that keep the required biologic activity 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 be prepared by 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 and Ia 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 and Ia chemical compound can contain basic functionality, and therefore can be by 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, 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, embonate, 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 and Ia 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, those skilled in the art will be understood that, can form pharmaceutically acceptable solvate, and 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 the solvent that is blended in the lattice.Wherein water is that the solvate that is blended into the solvent in the lattice is typically referred to as " hydrate ".Hydrate comprises stoichiometric hydrate and contains the compositions of 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 different crystal forms typically are called 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 described aspect of performance.Therefore, polymorph can have different physical propertys such as shape, density, hardness, deformability, stability and solubility property.The polymorph typical earth surface reveals different fusing points, IR spectrum and X-ray powder diffraction pattern, and it can be used to identify.Those skilled in the art will be understood that, different polymorphs for example can be by changing or being adjusted in the preparation chemical compound employed reaction condition or reagent is prepared.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 prepare by several different methods, comprises standard chemical process.Except as otherwise noted, any variable of definition before will have implication defined previously.Set forth illustrative general synthetic method below, then, particular compound of the present invention will be prepared in preparation embodiment.
For example, the chemical compound of formula I and Ia can be prepared according to for example scheme 1,2 and 3 described below:
Scheme 1
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) ZYB (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 I 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 I compound, and wherein U is C
1-C
6Alkylidene or C
2-C
6Alkenylene, and V is NH, aryl or heteroaryl.In scheme 1, unless otherwise defined, Y and Z are as defined above.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 Bis(tert-butoxycarbonyl)oxide.Can further be converted into required bromide 2 by 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 by the transition metal that uses appropriate catalyst and coupling part is finished the access of substituent group YZ.As the example 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 finish under existing.The preparation of uncle's Methanamide 4 can be finished by carboxylic acid and ammonia are reacted.Introduce finishing by generating U-V of group U-V with suitable aldehydes or ketones precursors reaction by 4 to 5 conversion.This conversion can be finished 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 example, for the situation of the condition " j " of scheme 1, at Pd (OH)
2Finish hydrogenation to change into 5 under existing.U-V and/or YZ contain in the situation of suitable protecting group therein, can be by under appropriate condition, removing protecting group, and further be converted into other product and finish.Subsequently the amine functional group of group U-V is converted into sulfonamide or the amide of R4, suitable sulfonyl that can be by using R4 or acid chloride 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 may need further to 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) sodium nitrite, HOAc; B) sodium dithionite; C) R4Cl, TEA, dichloromethane (or) (R4)
2O, DMAP, dichloromethane
Scheme 2 expressions prepare wherein, and U is that chemical bond and V are the general approach of the formula I chemical compound of NH.In scheme 2, unless otherwise defined, Y and Z are as defined above.Described starting material indole carboxamides 4 is according to the acquisition described in the 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.
The preparation of C3 amino indole can be finished by nitration reaction and reduction reaction subsequently.Conversion by 4 to 7 is finished by handling with sodium nitrite in the presence of acetic acid.With the C3 nitroreduction is that amino can be finished by using sodium dithionite.Subsequently amine functional group is converted into sulfonamide or the amide of R4, suitable sulfonyl that can be by using R4 or acid chloride 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 may need further to 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 3
Condition: a) N-iodine butanimide, CH
2Cl
2B) VUB (OR)
2, Pd (PPh
3)
4, Cs
2CO
3, 1,4-two alkane, water; C) R4Cl, TEA, dichloromethane (or) (R4)
2O, DMAP, dichloromethane
Scheme 3 expressions prepare wherein, and U is that chemical bond and V are the general approach of the formula I chemical compound of aryl or heteroaryl.In scheme 2, unless otherwise defined, Y and Z are as defined above.Described starting material indole carboxamides 4 is according to the acquisition described in the 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.
The preparation of the chemical compound of structure 12 can be finished by at first starting material indole carboxamides 4 being converted into C3 halogenide 10.As halid example, and be used for purpose of explanation, the C3 iodide have been shown in the scheme 3.The coupling reaction that can mediate by the transition metal that uses appropriate catalyst and coupling part is finished the access of substituent group U-V.As the example of this conversion, for the situation of the condition " b " of scheme 3, the Suzuki cross-coupling reaction can be at Pd (OAc)
2And Cs
2CO
31, in 4-two alkane and the water, use borate or acid to finish under existing.Subsequently amine functional group is converted into sulfonamide or the amide of R4, suitable sulfonyl that can be by using R4 or acid chloride 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 may need further to 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.
Those skilled in the art will be understood that, if substituent group described herein is not complementary with synthetic method described herein, so this substituent group can with suitable, to the protecting group protection of stable reaction conditions.In reaction process, described protecting group can be removed in the suitable moment, so that obtain required intermediate or target compound.Suitable protecting group and to use protection of these suitable protecting groups and the various substituent methods of deprotection be that those skilled in the art are known; The example can be at T.Greene and P.Wuts,
Protecting Groups in Chemical Synthesis(3rd ed.), John Wiley ﹠amp; Sons, NY finds in (1999).In some cases, can specifically select substituent group so that under employed reaction condition, be active.In these cases, described reaction condition changes into another kind of substituent group with selected substituent group, and this another kind substituent group is useful as midbody compound or is a kind of required substituent group in target compound.
Using method
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), as rheumatoid arthritis, inflammatory bowel, asthma and COPD (chronic obstructive pulmonary disease)." inappropriate IKK2 activity " is meant in concrete patient and departs from the active any IKK2 activity of desired normal IKK2.Inappropriate IKK2 activity for example can be taked active unusual increase, timing and/or the not normal form of IKK2 activity control.Then, this inappropriate activity for example can be produced by overexpression that causes 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 and Ia chemical compound or its pharmaceutically acceptable salt of effective dose.Each embodiment of the present invention comprises the method for the treatment of above-mentioned any disease, and described method comprises the patient safety that needs and formula I and Ia chemical compound or its pharmaceutically acceptable salt of effective dose.
Employed " treatment is " relevant with disease at this, 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 (biological cascade), it causes disease or causes the reason of disease or (b) one or more performances biology of disease, (3) alleviate one or more symptoms or the influence relevant, or (4) slow down one or more performances biology of the progress or the disease of disease with disease.
Aforesaid disease " treatment " 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 to mean preventative give medicine with the performance of remarkable weakening disease or its biology may or the order of severity, or postpone the morbidity 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 for the treatment of; The patient's age for the treatment of, 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 determine by those skilled in the art usually.
Be meant people or other animal this employed " patient ".
Chemical compound of the present invention can give by 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 the route of administration except that intestinal canal administration, percutaneous dosing or inhalation, and typically by injection or transfusion administration.Parenteral comprises intravenous, intramuscular and subcutaneous injection or transfusion.Inhalation is meant by the oral cavity 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 be administered once, or according to dosage regimen, in official hour 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 determined 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, to depend on the disease of being treated, the disease for the treatment of the order of severity, the patient's age for the treatment of and condition, the patient's that treats medical history, the character of therapeutic alliance (concurrent therapy), 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, suitable dosage regimen may need to adjust, and perhaps needs in time to change.
Typical daily dose can change with selected concrete route of administration.For oral administration, typical 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 typical functions derivant that 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 that those skilled in the art are known.
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 and Ia chemical compound or its pharmaceutically acceptable salt and be used for the treatment of purposes in the medicine that is characterized as the active disease of inappropriate IKK2 in preparation.
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 pharmaceutically acceptable excipient.
Pharmaceutical composition of the present invention can wherein can extract the The compounds of this invention of safety and effective dose with preparation of form in batch and packing, gives the patient with powder or syrupy form then.Perhaps, pharmaceutical composition of the present invention can be with the form preparation 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 typically 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 typically 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 excipient at this employed " pharmaceutically acceptable excipient ", they are used to produce the shape or the concordance of pharmaceutical composition.When sneaking into, every kind of excipient must with other component compatibility 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 excipient must have sufficiently high purity certainly, so that it is pharmaceutically acceptable.
Typically, The compounds of this invention and pharmaceutically acceptable one or more excipient are mixed with a kind of dosage form, this dosage form is fit to deliver medicine to described patient by 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 pharmaceutically acceptable excipient will change with selected concrete dosage form.In addition, can select suitable pharmaceutically acceptable excipient, specific so that they can play a part in compositions.For example, can select some pharmaceutically acceptable excipient, these excipient can promote to generate uniform dosage form.Can select some pharmaceutically acceptable excipient, these excipient can promote to generate stable dosage form.Can select some pharmaceutically acceptable excipient, 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 pharmaceutically acceptable excipient, they can strengthen patient's compliance.
Suitable pharmaceutically acceptable excipient comprises the excipient 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.Those skilled in the art will be understood 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 the pharmaceutically acceptable excipient of many descriptions and can be used for selecting suitable pharmaceutically acceptable excipient.Example comprises
Remington ' s Pharmaceutical Sciences(Mack Publishing Company),
The Handbook of Pharmaceutical Additives(Gower Publishing Limited) and
The Handbook of Pharmaceutical Excipients(the American PharmaceuticalAssociation and the Pharmaceutical Press).
Pharmaceutical composition of the present invention uses known technology of those skilled in the art and method to be prepared.Some universal methods of Shi Yonging are described in the art
Remington ' s Pharmaceutical SciencesIn (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 glycolate, 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, by 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, poly-hydroxypropyl methyl acrylamide-phenol, poly-hydroxyethyl agedoite phenol or the polyethylene glycol oxide poly-D-lysine that is replaced by the palmityl residue.In addition, chemical compound of the present invention can with the biodegradable polymer coupling of in obtaining the sustained release medicine, using of a class, for example, the crosslinked or amphiphilic block copolymer of polylactic acid, polycaprolactone (polepsilon caprolactone), multi-hydroxybutyrate, poe, polyacetals, poly-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 by The compounds of this invention is dissolved in the suitably seasoned aqueous solution, and elixir makes by using avirulence alcohol excipient.Suspension can be prepared by The compounds of this invention is dispersed in the avirulence excipient.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 sweetenings etc.
In another aspect, the present invention relates to a kind of being adapted to pass through and suck the dosage form that 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 by suction typically comprises the The compounds of this invention of fine powder form and with one or more pharmaceutically acceptable excipient of fine powder form.The pharmaceutically acceptable excipient that is particularly suitable for using in dry powder is that those skilled in the art are known, and comprises lactose, starch, mannitol and monosaccharide, disaccharide and polysaccharide.
Described dry powder can give the patient by 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 comprises that typically each drug dose of metering is to the equipment of administration position from storage.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 pack (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 pack, it comprised a plurality of bubble-caps (blister) that contain the dry powder form medicine.Typically, 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 collar plate shape 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 be prepared by 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 typically (MDI) gives the patient by quantitative pressure inhaler (metered dosed inhaler).These devices are that those skilled in the art are known.
Described aerosol can contain other excipient such as surfactant, lubricant, cosolvent and other excipient pharmaceutically acceptable, that typically 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 by 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, glycerol, 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 organic salt such as alkali metal salt or ammonium halide salt, for example, sodium chloride, potassium chloride or organic salt, as potassium, sodium and ammonium salt or organic acid, for example, ascorbic acid, citric acid, acetic acid, tartaric acid etc.
Other pharmaceutically acceptable excipient can 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 by 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 for example corase meal in the 20-500 micrometer range of particle diameter, administration in such a way, it is by sucking fast by nasal passage in the dust container of holding near nose.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 described 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 Mi Feng ampoule and the medicine bottle at unit-dosage or multi-dose container, and can store under lyophilizing (lyophilization) condition, and it only needs to add immediately 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
The following examples make an explanation to the present invention.These embodiment are used to limit the scope of the 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, those skilled in the art will be understood that, under the situation that does not break away from the spirit and scope of the present invention, can carry out various changes and improvements.
Except as otherwise noted, all raw materials are from commercial and be not further purified and use.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.For reversed-phase HPLC purification (except as otherwise noted), use 50 * 20mmI.D.Luna C18,5 μ posts, use acetonitrile that contains 0.1%TFA and the water that contains 0.1%TFA, and carry out the UV detection at 215nM and 254nM place.
Nuclear magnetic resoance spectrum uses Bruker AC 400 spectrometer records under 400MHz.CDCl
3Be deuterochloroform, DMSO-d
6Be six deuterated dimethyl sulfoxides, and CD
3OD is four deuterated methanols.Chemical shift is with a few millionths (δ) record of the downfield of the interior mark tetramethylsilane of distance.The abbreviation of NMR data is as follows: s=is unimodal, and d=is bimodal, the t=triplet, and the q=quartet, the m=multiplet, the dd=double doublet, the two triplets of dt=, app=is tangible, the br=broad peak.J represents the NMR coupling constant with hertz mensuration.Mass spectrum uses electrojet (ES) ioning method record on PE Sciex Single Quadrupole LC/MS API-150.Use Perkin-Elmer 240C elemental analyzer to obtain elementary analysis.
Use Analtech Sillca Gel GF and E.Merck Silica Gel 60F-254 lamellae to carry out thin layer chromatography.Flash chromatography and gravity chromatography carry out on E.Merck Kieselgel 60 (230-400 order) silica gel.
Intermediate
(1) 1,1-dimethyl ethyl-2,3-dihydro-1H-indole-1-carboxylate
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 under vacuum, crude product is purified by vacuum distilling, obtains the buttery title compound of clarifying baby pink (15.1g), 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)。
Another kind of alternative synthetic:
Under 0 ℃, to the indoline that stirs (250g, 2.1mol) and triethylamine (28.9mL, 0.21mol) add in the solution in dichloromethane (2.5L) in batches two dimethyl dicarbonate butyl esters (458g, 2.1mol).Mixture is stirred 5h down at 0 ℃, be warmed to room temperature then, and stir and spend the night.Mixture is washed with 1N citric acid (1L), saturated sodium bicarbonate (1L) and saline (1L).Dry organic facies (MgSO
4), filter, and removal of solvent under reduced pressure, obtaining grease, it leaves standstill crystallization.With thick chemical compound by distillation (bp110 ℃/0.3mmHg) purification obtains indoline-1-carboxylic acid tert-butyl ester of 392g (85%).
(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 is cooled to-78 ℃ in acetone/the dry ice bath.(cyclohexane solution of 1.4M, 17.6mL 24.6mmol), then stir reactant mixture 90 minutes under this temperature to drip s-butyl lithium in 10 minutes.(8.8mL, 10.8g 0.1mol) join in this mixture, then reactant mixture are warmed to room temperature in 1 hour with methylchloroformate.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.
LCMS?m/z?278(M+H)。
(3) 1-(1, the 1-dimethyl ethyl) 7-methyl-5-bromo-2,3-dihydro-1H-indole-1,7-dicarboxylic ester
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 at room temperature stirs in blanket of nitrogen 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.
LCMS?m/z?356/358(M+H)。
(4) the 5-bromo-2,3-dihydro-1H-indole-7-carboxylic acid methyl ester
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 with organic layer 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.
LCMS?m/z?256/258(M+H)
(5) 5-bromo-1H-indole-7-carboxylic acid methyl ester
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 by celite and filter, then concentrate in a vacuum, obtain the solid title compound of ecru (5.1g).
LCMS?m/z?252/254(M+H)。
(6) 5-bromo-1H-indole-7-carboxylic acid
(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.Remove methanol under vacuum, residue dilutes with aqueous hydrochloric acid solution (2M).The gained precipitation is leached, then, obtain the solid title compound of ecru (4.7g) with vacuum spray gun (the heated vacuum pistol) drying of heating.
LCMS?m/z?238/240(M+H)。
(7) 5-phenyl-1H-indole-7-carboxylic acid
To 5-bromo-1H-indole-7-carboxylic acid (10g, 41.8mmol) add phenylboric acid (19.5g in the solution in two alkane (150mL) and water (50mL), 159.9mmol), cesium carbonate (26.0g, 79.8mmol), 1, two (2,4, the 6-trimethylphenyl) imidazoles (imidazolium) hydrochlorate (2.8g of 3-, 8.2mmol) and acid chloride (0.9g, 4.01mmol).Reactant mixture is stirred 15min at ambient temperature, and refluxed 15 hours down at 80 ℃ then.Organic solvent is removed in decompression, and water layer is adjusted to pH=1-2 with 6M hydrochloric acid, subsequently to wherein adding ethyl acetate (350mL).(100mLx3) washes with the organic layer water, and drying also is condensed into heavy-gravity grease (approximately remaining 40mL solvent) under 45 ℃, be cooled to-20 ℃, and filter.Solid is washed with cold ethyl acetate (10mLx3), and collected.Filtrate is condensed into heavy-gravity grease under 45 ℃, is cooled to-20 ℃ then, obtain pale solid.Filter this suspension, and wash with cold ethyl acetate (5mLx3).Remove filtrate after aforesaid operations repeated 3 times.
LCMS?m/z?238(M+H)。
(8) 5-phenyl-1H-indole-7-Methanamide
At ambient temperature, to 5-phenyl-1H-indole-7-carboxylic acid (1.25g, 5.25mmol) and O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethylurea hexafluorophosphate (HATU) (3.25g, 8.55mmol) methanol solution (the 2.0M solution of 8.5mL) of adding ammonia in the solution in DMF (15mL).After 3 hours, solution is diluted with ethyl acetate, and with 4%HCl (1 * 50mL), water (1 * 50mL), (1 * 50mL) extraction is through dried over mgso and filter for saline.Removal of solvent under reduced pressure obtains yellow solid (1.33g).
LCMS?m/z?237(M+H)。
Another kind of alternative synthetic I:
At room temperature, (10.0g is 42.0mmol) at CH to 5-phenyl-1H-indole-7-carboxylic acid
2Cl
2(100mL) and add N-(3-dimethylaminopropyl)-N '-ethyl-carbodiimide hydrochloride (9.66g in the solution in the mixture of THF (100mL), 50.4mmol), I-hydroxybenzotriazole hydrate (6.81g, 50.4mmol) and ammonia (methanol solution of 2.M, 168mmol, 84mL).Reactant mixture was at room temperature stirred 24 hours.Evaporate all solvents, and reactant mixture is distributed between ethyl acetate (200mL) and water (200mL).Separate organic layer, and with ethyl acetate (x2) aqueous layer extracted.The organic facies that merges is washed with salt, through Mg
2SO
4Drying, and concentrate, obtaining product, it is for following reaction enough pure (10g, 100%).
LC-MS?m/z?237.2(M+H)，1.94min。
Another kind of alternative synthetic II:
In the 5L three-neck flask, pack into 5-bromo-1H-indole-7-Methanamide (60g, 0.251mole, 1eq).Add subsequently phenylboric acid (91.88g, 0.753mole, 3eq) and tripotassium phosphate (106g, 0.502mole, 2eq).To in 4-two alkane (1.2L, 20vol wrt 12) this flask of packing into, add entry (1.2L, 20vol wrt 12) subsequently with 1 of nitrogen purge then.Add 2 then '-(dimethylamino)-2-xenyl-Palladous chloride. (II) two norcamphane base phosphine (dinorbornylphosphine) complex (7.03g, 0.0126mole, 0.05eq), and with reactant mixture reflux 3 hours.Reactant mixture is cooled to room temperature, and filters by celite then.Then filtrate is distributed between ethyl acetate and saline.Separate each layer, and the vacuum concentration organic layer.Under heating, residue is dissolved in the acetonitrile/water (550mL/50mL, 10vol wrt 12) then.Then with solution water (1.5L, 30vol wrt 12) processing under agitation.The solid by filtration that forms is collected, and with water/acetonitrile of 3: 1, use hot water wash subsequently, then with it at 40 ℃ of following vacuum dryings, generate required product (57.69g).
MS：(M+H)：237
(9) 5-phenyl-3-[1-(phenyl methyl)-1,2,3,6-tetrahydrochysene-4-pyridine radicals]-1H-indole-7-Methanamide
(3.11g, (7.4g 36mmol), adds the NaOMe (the MeOH solution of 0.5M) of 156mL subsequently to add benzyl piepridine ketone in methanol 12mmol) (100mL) solution to 5-phenyl-1H-indole-7-Methanamide.Then with reactant mixture 80 ℃ of following heated overnight.Solution is cooled to ambient temperature, and removal of solvent under reduced pressure, and the residue that generates is dissolved in ethyl acetate and 5% sodium hydroxide solution two-layer again.Organic facies is washed with salt, through the potassium carbonate drying, and removal of solvent under reduced pressure.Residue is passed through silica gel chromatography (CH
2Cl
2: MeOH: NH
4OH=96: 3: 1) purification obtains required product (2.66g, 51%).
LCMS?m/z?408(M+H)。
Another kind of alternative synthetic:
In the 5L three-neck flask, pack into 85%wt phosphoric acid (423mL, 6.16moles, 25eq), benzyl piepridine ketone (142mL, 0.733mole, 3eq) and glacial acetic acid (400mL).With the mixture heated to 90 that generates ℃.Add 5-phenyl-1H-indole-7-Methanamide (57.69g, 0.244mole, glacial acetic acid 1eq) (755mL) solution then in batches.To be reflected at 90 ℃ then keeps down spending the night.Reactant mixture is cooled to room temperature.Be divided into two equal portions then, and in the mixture with every part of ice/0.88 ammonia (1L/1L) that joins independent stirring at leisure.Also use dry ice/acetone batch to control heat release.Under agitation ethyl acetate (600mL) is joined in the mixture then.Wash well with ethyl acetate then with its filtration, and with solid.Separating filtrate then, and water layer extracted once more with ethyl acetate.Then with organic layer through dried over mgso, and filter, merge two batches subsequently, and reduction vaporization.Then residue is dissolved in DCM (300mL) solution of 3% (methanol solution of 3.5M ammonia).Filter then and collect this solid sediment, vacuum drying generates required product (42.25g) then.MS：(M+H)：408。
(10) 5-phenyl-3-(4-piperidyl)-1H-indole-7-Methanamide
At ambient temperature, to 5-phenyl-3-[1-(phenyl methyl)-1,2,3,6-tetrahydrochysene-4-pyridine radicals]-(2.66g 6.5mmol) adds Pd (OH) in the solution in ethanol (150mL) and acetic acid (3mL) to 1H-indole-7-Methanamide
2(20 weight % are on carbon) (0.8g).Solution was stirred 2 days under the hydrogen of 1atm.Then reactant mixture is filtered by Celite,, and use ethyl acetate extraction with the neutralization of 5% sodium hydroxide solution.Removal of solvent under reduced pressure generates required product (1.45g, 70%).
LCMS?m/z?320(M+H)
(11) sulfonyl 3-{1-[(3-chloropropyl)]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide
Under 0 ℃, to 5-phenyl-3-(4-piperidyl)-1H-indole-7-Methanamide (404mg, CH 1.26mmol)
2Cl
2Add in the solution triethylamine (0.7mL, 5.04mmol) and 3-chlorine third sulfonic acid chloride (0.23mL, 1.89mmol).Reactant mixture is stirred 30min down at 0 ℃.With reactant mixture at CH
2Cl
2(100mL) and between the water (50mL) distribute.Separate organic layer, and with water layer CH
2Cl
2(2 * 100mL) extractions.The organic facies that merges is washed with saline (50mL), through dried over mgso and filtration.Removal of solvent under reduced pressure, and by SPE post (Cartridge) (aminopropyl NH
2, 500mg/6mL), obtain title compound (370mg, 64%) through filtering purification.
LCMS?m/z?460.0(M+H)。
(12) 5-bromo-1H-indole-7-Methanamide
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 (100mLx2) extraction, and with the organic facies that merges through MgSO
4Drying, and concentrate, crude product (10g, 98%) obtained.There is not further purification just to be directly used in next step this crude product.
LC/MS：m/z?240.0(M+H)，1.95min。
(13) 1,1-dimethyl ethyl-4-[7-(amino carbonyl)-5-bromo-1H-indol-3-yl]-3,6-dihydro-1 (2H)-picolinic acid ester
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%) by flash column chromatography (ethyl acetate/hexane, 1/1) purification.
LC/MS：m/z?420.0(M+H)，Rt?2.35min。
Another kind of alternative synthetic:
Adding Boc-piperidones in 10L CLR (270g, 1.356moles, 3eq).Add subsequently 85%wt phosphoric acid (782mL, 11.42moles, 25eq) and glacial acetic acid (2160mL, 20vol wrt 12).With the mixture heated to 90 that generates ℃, (108g, 0.452mole 1eq), join it among CLR then to add 5-bromo-1H-indole-7-Methanamide subsequently.Then mixture is kept down spending the night at 90 ℃.Then reactant mixture is cooled to room temperature, and from reactor, discharges.Then 0.88 ammonia (3.5L) is joined in the reactor, and it is cooled to 0 ℃.Then reactant mixture is added back in the reactor at leisure.In the process that adds, add ice and be lower than 50 ℃ to keep temperature.Then precipitate is discharged from reactor, and filter.Then solid residue is added back in the reactor, and with water (7L) vigorous stirring.Then solid is filtered once more, and dry under suction then.Then crude product is ground in methanol (216ml, 2vol.wrt 12).Solid filtering is collected, and washed well with methanol.Then with solid at 40 ℃ of following vacuum dryings, obtain the condensation compound that 95g does not have Boc protection.There is not further purification just to be used for next step this chemical compound.
In 10L CLR, add condensation compound (100g, 0.3125moles, 1eq).Add subsequently dry DMF (1000mL, 10vol.).((81.84g, 0.375mole 1.2eq) handle to use the boc-acid anhydride 2eq), subsequently for 87mL, 0.627mole with triethylamine with the mixture that generates then.Then the mixture that generates was stirred 2 hours under blanket of nitrogen.Then mixture is discharged to from reactor in the water (7.5L).Then mixture is transferred in the 20L liquor separator, and between ethyl acetate and 10%LiCl, distributed.Separate each layer, and water layer is extracted once more with ethyl acetate.Then with the organic layer that merges with 10%LiCl solution, salt washing, then through dried over mgso, filter then and evaporate.Then orange residue is suspended in water, filter, generate required product (113g) then at 40 ℃ of following vacuum dryings.
MS：(M+H)：420.422.
(14) 1,1-dimethyl ethyl-4-[7-(amino carbonyl)-5-bromo-1H-indol-3-yl]-1-piperidine carboxylic acid ester
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 of balloon.Filter the gained mixture by Celite, then filtrate is concentrated.(ethyl acetate/hexane, 1: 4-2: 1v/v) purification obtains required product (3.6g, 48%) to the gained residue with flash column chromatography.
LC/MS：m/z?422.0(M+H)，Rt?2.25min。
(15) 5-bromo-3-(4-piperidyl)-1H-indole-7-Methanamide
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.Steaming under reduced pressure desolventizes, and the gained residue distributes between ethyl acetate (50mL) and 5%NaOH aqueous solution (50mL).(2 * 50mL) washings also under reduced pressure concentrate the organic facies drying that merges water layer, obtain required product (685mg, 58%), and it does not have further purification just to be used for next step with ethyl acetate.
LC/MS：m/z?322.0(M+H)，Rt?1.45min。
(16) 1,1-dimethyl ethyl-4-[7-(amino carbonyl)-5-(2-thienyl)-1H-indol-3-yls]-1-piperidine carboxylic acid ester
To 4-[7-(amino carbonyl)-5-bromo-1H-indol-3-yl]-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester (95mg, 0.23mmol) add in the solution in two alkane (1.5mL) and water (0.5mL) 2-thienyl boric acid (115.2mg, 0.92mmol), Pd (PPh
3)
4(26.6mg, 10%) and potassium carbonate (254mg, 1.84mmol).Reactant mixture is heated 20min at 150 ℃ in Smith synthesizer microwave.Under reduced pressure steam and remove all solvents.Residue distributes between ethyl acetate (10ml) and water (10mL).Organic facies is through MgSO
4Drying under reduced pressure concentrates, and purifies with flash column chromatography (ethyl acetate/hexane, 1/1), obtains required product (90mg, 95%).
LC/MS：m/z?426.0(M+H)，Rt?2.47min。
(17) 3-(4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide
To 4-[7-(amino carbonyl)-5-(2-thienyl)-1H-indol-3-yl]-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester (90mg, 0.22mmol) add in the solution in MeOH (3mL) HCl (the two alkane solution of 4.0M, 2.06mL).Reactant mixture was stirred 2 hours at ambient temperature, under reduced pressure remove then and desolvate, the gained residue distributes between ethyl acetate (10mL) and 10% sodium hydroxide (10mL).Water layer extracts with ethyl acetate (10mLx2), and the organic facies of merging is through MgSO
4Drying concentrates, and obtains crude product (53mg, 77%).There is not further purification just to be directly used in next step it.
LC/MS：m/z?326.0(M+H)，Rt?1.49min。
(18) 1,1-dimethyl ethyl-4-[7-(amino carbonyl)-5-(3-thienyl)-1H-indol-3-yls]-1-piperidine carboxylic acid ester
This title compound is prepared according to the conventional method of intermediate 16.Therefore, will be at the 4-[7-(amino carbonyl) in two alkane (1.5mL) and the water (0.5mL)-5-bromo-1H-indol-3-yl]-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester (500mg, 1.18mmol), 3-thienyl boric acid (606mg, 4.72mmol), Pd (PPh
3)
4(651mg, 4.72mmol) reaction generates required product, and it is purified with flash column chromatography (ethyl acetate/hexane, 1/1), obtains required product (460mg, 92%) for (136mg, 10%) and the potassium carbonate in two alkane (3.0mL) and water (1.0mL).
LC/MS：m/z?426.0(M+H)，Rt?2.45min。
(19) 3-(4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide
This title compound is prepared according to the conventional method of intermediate 17.Therefore, with 4-[7-(amino carbonyl)-5-(3-thienyl)-1H-indol-3-yl]-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester (460mg, 1.08mmol) and the HCl in MeOH (5mL) (4.0M is in two alkane, 10mL) reaction, generate the required product (260mg, 74%) of further not purifying.
LC/MS：m/z?326.0(M+H)，Rt?1.60min。
(20) 3-(1-{[2-(1,3-dioxo-1,3-dihydro-2H-iso-indoles-2-yl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide
Under 0 ℃, to 5-phenyl-3-(4-piperidyl)-1H-indole-7-Methanamide (84.8mg, CH 0.265mmol)
2Cl
2Add in the solution triethylamine (0.15mL, 1.06mmol) and 2-(1,3-dioxo-1,3-dihydro-2H-iso-indoles-2-yl) ethyl sulfonic chloride (87.03mg, 0.32mmol).Reactant mixture is stirred 30min down at 0 ℃.With reactant mixture at CH
2Cl
2And distribute between the water.Separate organic layer, and with water layer CH
2Cl
2(2x) extraction.The organic facies that merges is washed with salt, through dried over mgso and filtration.Removal of solvent under reduced pressure obtains crude product (90mg, 61%).
LC/MS?m/z?557.2(M+H)。
(21) sulfonyl 3-{1-[(2-chloroethyl)]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide
Under 0 ℃, to 5-phenyl-3-(4-piperidyl)-1H-indole-7-Methanamide (65mg, CH 0.2mmol)
2Cl
2(5mL) add in the solution triethylamine (0.11mL, 0.8mmol) and the 2-chloro-ethane-sulfonyl chloride (0.042mL, 0.4mmol).0 ℃ down stir 30min after, with reactant mixture at CH
2Cl
2And distribute between the water.Separate organic layer, and with water layer CH
2Cl
2(2x) extraction.With the organic facies that merges through dried over mgso, and removal of solvent under reduced pressure.The residue that generates is passed through SPE post (aminopropyl NH
2, 500mg/6mL) filter purification, obtain required product (26mg, 32%).
LC/MS?m/z?445.0(M+H)。
(22) sulfonyl 3-{1-[(3-chloropropyl)]-the 4-piperidyl }-5-(3-thienyl)-1H-indole-7-Methanamide
This title compound is prepared according to the conventional method of intermediate 11.(220mg, 0.67mmol) (0.4mL, 2.68mmol) (0.12mL, 1.01mmol) reaction obtains title compound (117mg, 37%) with 3-chloropropyl sulfonic acid chloride with triethylamine with 3-(4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide.
LC/MS：m/z?466.0(M+H)，Rt?2.18min。
(23) sulfonyl 3-{1-[(3-chloropropyl)]-the 4-piperidyl }-5-(2-thienyl)-1H-indole-7-Methanamide
This title compound is prepared according to the conventional method of intermediate 11.(275mg, 0.84mmol) (0.35mL, 2.52mmol) (0.4mL, 1.68mmol) reaction obtains title compound (250mg, 64%) with 3-chloropropyl sulfonic acid chloride with triethylamine with 3-(4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide.
LC/MS：m/z?466.2(M+H)，Rt?2.22min。
(24) sulfonyl 5-bromo-3-{1-[(3-chloropropyl)]-the 4-piperidyl }-1H-indole-7-Methanamide
This title compound is prepared according to the conventional method of intermediate 11.(875mg, 2.72mmol) (2.27mL, 16.32mmol) (0.64mL, 5.44mmol) reaction obtains title compound (656mg, 52%) with 3-chloropropyl sulfonic acid chloride with triethylamine with 5-bromo-3-(4-piperidyl)-1H-indole-7-Methanamide.
LC/MS：m/z?462.0(M+H)，Rt?2.15min。
(25) 5-bromo-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
According to described in the embodiment 2 preparation sulfamide conventional method, make 5-bromo-3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-1H-indole-Methanamide (656mg, 1.41mmol) and pyrrolidine (505mg is 7.05mmol) at K
2CO
3(2.82mmol) there is reaction down in 389.16mg.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (600mg, 87%).
LC/MS：m/z?497.4(M+H)，Rt?1.57min。
(26) 3-[1-(vinylsulfonyl)-4-piperidyl]-5-phenyl-1H-indole-7-Methanamide
Under 0 ℃, to 5-phenyl-3-(4-piperidyl)-1H-indole-7-Methanamide (260mg, CH 0.8mmol)
2Cl
2Add in the solution triethylamine (0.44mL, 3.2mmol) and the 2-chloro-ethane-sulfonyl chloride (0.168mL, 1.6mmol).Reactant mixture is stirred 30min down at 0 ℃.With reactant mixture at CH
2Cl
2(100mL) and between the water (50mL) distribute.Separate organic layer, and with water layer CH
2Cl
2(2 * 100mL) extractions.The organic facies that merges is washed with saline (50mL), through dried over mgso and filtration.Removal of solvent under reduced pressure, and by SPE post (aminopropyl NH
2, 500mg/6mL) filter purification, obtain title compound (245mg, 75%).
LCMS?m/z?410(M+H)。
(27) 5-(5-formoxyl-2-thienyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
To 5-[5-(hydroxymethyl)-2-thienyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-(14.4mg adds MnO in THF 0.027mmol) (5mL) solution to 1H-indole-7-Methanamide
2(71.7mg, 0.81mmol).Reactant mixture at room temperature stirred spend the night, filter by celite filler (pad) subsequently.Collect filtrate, and concentrating under reduced pressure, obtaining crude product (8.3mg, 58%), it does not have further purification just to be used for next step.
LC/MS：m/z?529.4(M+H)，Rt?1.67min。
(28) 5-bromo-3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
Conventional method according to the sulfamide of preparation described in the embodiment 2 makes 5-bromo-3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-(0.8mL is 9.05mmol) at K for 1H-indole-Methanamide (1.81mmol) and morpholine
2CO
3(3.62mmol) there is reaction down in 500mg.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (426mg, 51%).
LC/MS：m/z?462.2(M+H)，Rt?2.14min
(29) 5-[5-(hydroxymethyl)-2-thienyl]-3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
This title compound is prepared according to the conventional method of intermediate 16.Therefore; will the 5-bromo-3-in two alkane (3mL) and the water (1mL) (1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide (400mg; 0.78mmol), [5-(hydroxymethyl)-2-thienyl] boric acid (493mg, 3.12mmol), Pd (PPh
3)
4(861mg, 6.24mmol) reaction generates required product, and it is purified with flash column chromatography (ethyl acetate/hexane, 1/1), obtains required product (83mg, 20%) for (90mg, 10%) and potassium carbonate.
LC/MS：m/z?547.4(M+H)，Rt?1.38min。
(30) 5-(5-formoxyl-2-thienyl)-3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
To 5-[5-(hydroxymethyl)-2-thienyl]-3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-(82.5mg adds MnO in THF 0.015mmol) (10mL) solution to 1H-indole-7-Methanamide
2(391mg, 4.5mmol).Reactant mixture at room temperature stirred spend the night, filter by the celite filler subsequently.Collect filtrate, and concentrating under reduced pressure, obtaining crude product (60mg, 73%), it does not have further purification just to be used for next step.
LC/MS：m/z?545.0(M+H)，Rt?1.62min。
(31) 4-[7-(amino carbonyl)-5-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester
This title compound is prepared according to the conventional method of intermediate 16.Therefore, will be in two alkane (3mL) and water (1mL) 1,1-dimethyl ethyl-4-[7-(amino carbonyl)-5-bromo-1H-indol-3-yl]-1-piperidine carboxylic acid ester (100mg, 0.24mmol), (4-fluorophenyl) boric acid (134mg, 0.98mmol), Pd (PPh
3)
4(265mg, 1.92mmol) reaction generates required product, and it is purified with flash column chromatography (ethyl acetate/hexane, 1/1), obtains required product (92.8mg, 90%) for (28mg, 10%) and potassium carbonate.
LC/MS：m/z?339.4(M+H)，Rt?2.92min。
(32) 5-(4-fluorophenyl)-3-(4-piperidyl)-1H-indole-7-Methanamide
To 4-[7-(amino carbonyl)-5-(4-fluorophenyl)-1H-indol-3-yl]-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester (92.9g, be added in methanol 0.205mmol) (10mL) solution HCl in the two alkane (4M, 2.01mL).Reactant mixture at room temperature stirred 2 hours.Steaming under reduced pressure desolventizes, and the gained residue distributes between ethyl acetate (50mL) and 5%NaOH aqueous solution (50mL).(2 * 50mL) washings also under reduced pressure concentrate the organic facies drying that merges water layer, obtain required product (55.9mg, 78%), and it does not have further purification just to be used for next step with ethyl acetate.
LC/MS：m/z?338.6(M+H)，Rt?1.53min。
(33) 5-bromo-3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
Conventional method according to the sulfamide of preparation described in the embodiment 2 makes 5-bromo-3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-1H-indole-Methanamide (434mg, 0.93mmol) and the THF solution of 2M dimethyl amine (7mL is 14mmol) at K
2CO
3(650mg 4.7mmol) and under NaI (10mg) existence reacts.With the reactant mixture concentrating under reduced pressure.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (220mg, 50%).
LC/MS：m/z?471.4(M+H)，Rt?1.39min。
(34) 5-(3-formoxyl phenyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
To 5-[3-(hydroxymethyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-(250mg adds MnO in THF 0.477mmol) (60mL) solution to 1H-indole-7-Methanamide
2(1.3g, 14.30mmol).Reactant mixture at room temperature stirred spend the night, filter by the celite filler subsequently.Collect filtrate, and concentrating under reduced pressure, obtaining crude product (150mg, 60%), it does not have further purification just to be used for next step.
LC/MS：m/z?525.6(M+H)，Rt?1.50min。
(35) 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide
To 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-(hydroxymethyl) phenyl]-(230mg adds MnO in THF 0.47mmol) (60mL) solution to 1H-indole-7-Methanamide
2(1.3g, 14.05mmol).Reactant mixture at room temperature stirred spend the night, filter by the celite filler subsequently.Collect filtrate, and concentrating under reduced pressure, obtaining crude product (150mg, 65%), it does not have further purification just to be used for next step.
LC/MS：m/z?499.6(M+H)，Rt?1.55min。
(36) 5-bromo-3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
Conventional method according to the sulfamide of preparation described in the embodiment 2 makes 5-bromo-3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-(2.00g, 4.320mmol) (2.73mL is 21.6mmol) at K with cyclopenta amine for 1H-indole-Methanamide
2CO
3(2.4g, 17.3mmol) and NaI (0.433mmol) there is reaction down in 80mg.With the reactant mixture concentrating under reduced pressure.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (176mg, 8%).
LC/MS：m/z?513.2(M+H)，Rt?1.54min。
(37) 5-bromo-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
With 5-bromo-3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide (23mg, 0.050mmol), the mixture of 0.1M NaOMe (1ml) in methanol (1mL) reflux and to spend the night.Reactant mixture is concentrated, and by reversed-phase HPLC (water/CH
3CN, 0.1%TFA 10-90%) purification, obtain title compound (18.0mg, 78%).
LC/MS：458.2?r.t：2.13min。
(38) 5-(3-formoxyl phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
To 5-bromo-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide (420mg; 0.9mmol) add in the solution in two alkane (6.0mL) and water (2.0ml) (3-formoxyl phenyl) boric acid (750.0mg, 5.0mmol), Pd (PPh
3)
4(100.0mg, 10%) and cesium carbonate (800mg, 1.8mmol).Reactant mixture is heated 20min at 160 ℃ in Smith synthesizer microwave.Under reduced pressure steam and remove all solvents.Residue by flash column chromatography (ethyl acetate/hexane, 1/1) purification, is generated required product (300.0mg, 70%).
LC/MS：m/z?484.2(M+H)，Rt?2.06min。
(39) 5-bromo-3-[1-(vinylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide
At room temperature, to 5-bromo-3-(4-piperidyl)-1H-indole-7-Methanamide (500mg, add in dichloromethane solution 1.3mmol) triethylamine (0.44mL, 3.2mmol) and the 2-chloro-ethane-sulfonyl chloride (0.168mL, 1.6mmol).Reactant mixture is stirred 30min.Remove and desolvate, residue by the combiflash purification, is obtained title compound (150mg, 75%).
LCMS?m/z?413.8(M+H)，1.96min。
(40) 5-bromo-3-(1-{[2-(methoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
With 5-bromo-3-[1-(vinylsulfonyl)-4-piperidyl]-1H-indole-7-Methanamide (150mg, 0.36mmol), the methanol solution of Feldalat NM (25%, 1.0mL) and the mixture of methanol (2.0mL) stirred 1 hour in 80 ℃.Subsequently with the reactant mixture concentrating under reduced pressure.Residue by the combiflash purification, is obtained title compound (100.0mg, 63%).
LC/MS：444.4?r.t：1.90min。
(41) 5-(3-formoxyl phenyl)-3-(1-{[2-(methoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
To 5-bromo-3-(1-{[2-(methoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide (100mg; 0.22mmol) add in the solution in two alkane (3.0mL) and water (1.0ml) (3-formoxyl phenyl) boric acid (186mg, 1.25mmol), Pd (PPh
3)
4(25.0mg, 10%) and cesium carbonate (200mg, 0.45mmol).Reactant mixture is heated 20min at 160 ℃ in Smith synthesizer microwave.Under reduced pressure steam and remove all solvents.Residue by flash column chromatography (ethyl acetate/hexane, 1/1) purification, is generated required product (50.0mg, 48%).
LC/MS：m/z?470.4(M+H)，Rt?1.95min。
(42) 4-(4,4,5,5-tetramethyl-1,3,2-dioxo bora penta ring (dioxaborolan)-2-yl)-2 thiophene carboxaldehyde
To 4-bromo-2 thiophene carboxaldehyde (500mg, add in DME 2.61mmol) (18mL) solution connection boric acid two pinacol esters (bis (pinacolato) diboron) (865mg, 3.403mmol), potassium acetate (667mg, 6.81mmol) and PdCl
2(dppf) (96mg, 0.131mmol).Reactant mixture was passed through microwave heating 20 minutes in 150 ℃.Evaporate all solvents then.Residue is distributed between ethyl acetate (100mL) and water (100mL).(2 * 100mL) extract with ethyl acetate with water layer.The organic facies that merges is washed with saline (100mL), and use Mg
2SO
4Drying, and concentrate.(20min.) purification obtains title compound (550mg, 88%) for hexane/ethyl acetate, 1%-30% ethyl acetate by Combiflash with crude product.
LC/MS：m/z，238.2(M+H)，1.88min。
(43) 5-(5-formoxyl-3-thienyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
To the 5-bromo-3-in the mixture of two alkane (4.5mL) and water (1.5mL) (1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide (170mg; 0.37mmol) adding 4-(4; 4; 5; 5-tetramethyl-1,3,2-dioxo bora penta ring-2-yl)-2 thiophene carboxaldehyde (265.2mg; 1.11mmol), potassium carbonate (309mg, 2.22mmol) and Pd (PPh
3)
4(44.2mg, 0.04mmol).Reactant mixture was passed through microwave heating 20 minutes in 150 ℃.Evaporate all solvents then.Residue is distributed between ethyl acetate (50mL) and water (50mL).(2 * 50mL) extract with ethyl acetate with water layer.The organic facies that merges is washed with saline (50mL), and use Mg
2SO
4Drying, and concentrate.(25min.) purification obtains title compound (110mg, 61%) for methylene chloride, 1%-40% methanol by Combiflash with crude product.
LC/MS：m/z，490.2(M+H)，2.00min。
Embodiment
(1) sulfonyl 3-{1-[(2-amino-ethyl)]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide
At room temperature, to 3-(1-{[2-(1,3-dioxo-1,3-dihydro-2H-iso-indoles-2-yl) ethyl] sulfonyl }-the 4-piperidyl)-(70mg adds hydrazine (0.3mL) in EtOH 0.13mmol) (2mL) solution to 5-phenyl-1H-indole-7-Methanamide.Reactant mixture was at room temperature stirred 2 hours.Removal of solvent under reduced pressure, and with the residue that generates by the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (26.9mg, 50%).
LC/MS?m/z?427.0(M+H)。
(2) 3-(1-{[2-(dimethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide
To the 3-{1-[(2-chloroethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide (26mg, CH 0.063mmol)
3Add in CN (5mL) solution dimethyl amine (0.16mL, 0.315mmol), K
2CO
3(35mg, 0.252mmol) and NaI (catalyst, 0.5mg).Reactant mixture was stirred 16 hours in 80 ℃.Removal of solvent under reduced pressure is distributed residue between ethyl acetate and water.Organic facies through dried over mgso, is filtered, and removal of solvent under reduced pressure.The residue that generates is passed through reversed-phase HPLC (CH
3CN/ water, 0.1%TFA) purification obtains title compound (14mg, 48%).
LC/MS?m/z?455.2(M+H)。
(3) 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide
Conventional method according to the sulfamide of preparation described in the embodiment 2; make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide (47mg; 0.1mmol) and dimethyl amine (the THF solution of 2.0M, 0.5mL is 0.5mmol) at K
2CO
3(55.2mg, 0.4mmol) and NaI (1.51mg) there is reaction down in catalyst.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (8.7mg, 19%).
LC/MS?m/z?469.0(M+H)。
(4) 3-(1-{[3-(4-methyl isophthalic acid-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide
Conventional method according to the sulfamide of preparation described in the embodiment 2 makes the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-(65mg, 0.14mmol) (70.5mg is 0.7mmol) at K with the 1-methyl piperazine for 5-phenyl-1H-indole-7-Methanamide
2CO
3(77.3mg, 0.56mmol) and NaI (2.13mg) there is reaction down in catalyst.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (52.7mg, 71%).
LC/MS?m/z?524.2(M+H)。
(5) 5-phenyl-3-(1-{[3-(piperidino) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
According to described in the embodiment 2 preparation sulfamide conventional method, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (62mg, 0.13mmol) and piperidines (55.25mg is 0.65mmol) at K
2CO
3(72mg, 0.56mmol) and NaI (2.0mg) there is reaction down in catalyst.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (31.5mg, 46%).
LC/MS?m/z?509.2(M+H)。
(6) 3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide
According to described in the embodiment 2 preparation sulfamide conventional method, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (60mg, 0.13mmol) and morpholine (56.63mg is 0.65mmol) at K
2CO
3(77mg, 0.56mmol) and NaI (2.13mg) there is reaction down in catalyst.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (20mg, 30%).
LC/MS?m/z?511.0(M+H)。
(7) 5-phenyl-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
According to described in the embodiment 2 preparation sulfamide conventional method, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (60mg, 0.13mmol) and pyrrolidine (46.2mg is 0.65mmol) at K
2CO
3(77mg, 0.56mmol) and NaI (2.13mg) there is reaction down in catalyst.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (27mg, 42%).
LC/MS?m/z?495.4(M+H)。
(8) 3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide
According to described in the embodiment 2 preparation sulfamide conventional method, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-(3-thienyl)-1H-indole-7-Methanamide (55mg, 0.12mmol) and pyrrolidine (42.6mg is 0.60mmol) at K
2CO
3(84.6mg, 0.24mmol) and NaI (5mg) there is reaction down in catalyst.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (23.2mg, 39%).
LC/MS：m/z?501.4(M+H)Rt?1.66min。
(9) 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide
Conventional method according to the sulfamide of preparation described in the embodiment 2; make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-(3-thienyl)-1H-indole-7-Methanamide (50mg; 0.12mmol) and the THF solution of 2M dimethyl amine (0.3mL is 0.60mmol) at K
2CO
3(84.6mg, 0.24mmol) and NaI (5mg) there is reaction down in catalyst.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (17.1mg, 30%).
LC/MS：m/z?475.4(M+H)Rt?1.64min。
(10) 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide
Conventional method according to the sulfamide of preparation described in the embodiment 2; make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-(2-thienyl)-1H-indole-7-Methanamide (50mg; 0.12mmol) and the THF solution of 2M dimethyl amine (0.3mL is 0.60mmol) at K
2CO
3(74mg, 0.55mmol) and NaI (catalyst 5mg) exists down in 80 ℃ of reactions.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (35mg, 61%).
LC/MS：m/z?475.4(M+H)Rt?1.55min。
(11) 3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide
According to described in the embodiment 2 preparation sulfamide conventional method, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-(2-thienyl)-1H-indole-7-Methanamide (50mg, 0.12mmol) and pyrrolidine (45uL is 0.60mmol) at K
2CO
3(74mg, 0.55mmol) and NaI (catalyst 5mg) exists down in 80 ℃ of reactions.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (41.2mg, 68%).
LC/MS：m/z?501.4(M+H)Rt?1.57min。
(12) 3-(1-{[3-(2-methyl isophthalic acid-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide
Conventional method according to the sulfamide of preparation described in the embodiment 2 makes the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-(50mg, 0.12mmol) (56uL is 0.60mmol) at K with the 2-crassitude for 5-(2-thienyl)-1H-indole-7-Methanamide
2CO
3(74mg, 0.55mmol) and NaI (catalyst 5mg) exists down in 80 ℃ of reactions.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (36.5mg, 59%).
LC/MS：m/z?515.4(M+H)Rt?1.60min。
(13) 3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide
According to described in the embodiment 2 preparation sulfamide conventional method, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-(2-thienyl)-1H-indole-7-Methanamide (50mg, 0.12mmol) and Aminocyclopentane (54uL is 0.60mmol) at K
2CO
3(74mg, 0.55mmol) and NaI (catalyst 5mg) exists down in DMF in 120 ℃ of reactions.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (27.2mg, 44%).
LC/MS：m/z?515.4(M+H)Rt?1.60min。
(14) 3-(1-{[3-(4-hydroxyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide
Conventional method according to the sulfamide of preparation described in the embodiment 2; make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-(2-thienyl)-1H-indole-7-Methanamide (50mg; 0.12mmol) and 4-piperidines alcohol (piperidinol) (55.6mg is 0.60mmol) at K
2CO
3(74mg, 0.55mmol) and NaI (catalyst 5mg) exists down in DMF in 120 ℃ of reactions.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (32.3mg, 51%).
LC/MS：m/z?531.4(M+H)Rt?1.43min。
(15) 3-(1-{[2-(cyclopenta amino) ethyl] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide
Method according to intermediate 11 prepares the 3-{1-[(2-chloroethyl) sulfonyl]-the 4-piperidyl }-5-(2-thienyl)-1H-indole-7-Methanamide.Make 3-(4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide (30mg; 0.09mmol) and triethylamine (0.04mL; 0.27mmol) and 2-chloro-ethane-sulfonyl chloride (0.02mL; 0.18mmol) reaction; obtain the 3-{1-[(2-chloroethyl) sulfonyl]-the 4-piperidyl }-5-(2-thienyl)-1H-indole-7-Methanamide, it does not have further purification just to be used for next step.
Conventional method according to the sulfamide of preparation described in the embodiment 2 makes the 3-{1-[(2-chloroethyl) sulfonyl]-the 4-piperidyl }-(0.04mL is 0.45mmol) at K for 5-(2-thienyl)-1H-indole-7-Methanamide (0.09mmol) and Aminocyclopentane
2CO
3(44mg, 0.45mmol) and NaI (5mg) there is reaction down in catalyst.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (14mg, 39%).
LC/MS：m/z?501.4(M+H)Rt?1.73min。
(16) 3-(1-{[2-(1-pyrrolidinyl) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide
Method according to intermediate 11 prepares the 3-{1-[(2-chloroethyl) sulfonyl]-the 4-piperidyl }-5-(3-thienyl)-1H-indole-7-Methanamide.Make 3-(4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide (30mg; 0.09mmol) and triethylamine (0.025mL; 0.18mmol) and 2-chloro-ethane-sulfonyl chloride (0.012mL; 1.08mmol) reaction; obtain the 3-{1-[(2-chloroethyl) sulfonyl]-the 4-piperidyl }-5-(3-thienyl)-1H-indole-7-Methanamide, it does not have further purification just to be used for next step.
Conventional method according to the sulfamide of preparation described in the embodiment 2 makes the 3-{1-[(2-chloroethyl) sulfonyl]-the 4-piperidyl }-(0.03mL is 0.45mmol) at K for 5-(3-thienyl)-1H-indole-7-Methanamide (0.09mmol) and pyrrolidine
2CO
3(44mg, 0.45mmol) and NaI (5mg) there is reaction down in catalyst.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (12.4mg, 28%).
LC/MS：m/z?487.2(M+H)Rt?1.63min。
(17) 3-(1-{[2-(dimethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide
Method according to intermediate 11 prepares the 3-{1-[(2-chloroethyl) sulfonyl]-the 4-piperidyl }-5-(3-thienyl)-1H-indole-7-Methanamide.Make 3-(4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide (30mg; 0.09mmol) and triethylamine (0.025mL; 0.18mmol) and 2-chloro-ethane-sulfonyl chloride (0.012mL; 1.08mmol) reaction; obtain the 3-{1-[(2-chloroethyl) sulfonyl]-the 4-piperidyl }-5-(3-thienyl)-1H-indole-7-Methanamide, it does not have further purification just to be used for next step.
Conventional method according to the sulfamide of preparation described in the embodiment 2; make the 3-{1-[(2-chloroethyl) sulfonyl]-the 4-piperidyl }-(0.225mL is 0.45mmol) at K for the THF solution of 5-(3-thienyl)-1H-indole-7-Methanamide (0.09mmol) and 2M dimethyl amine
2CO
3(44mg, 0.45mmol) and NaI (5mg) there is reaction down in catalyst.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (5.5mg, 13%).
LC/MS：m/z?461.2(M+H)Rt?1.42min。
(18) 3-(1-{[2-(cyclopenta amino) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide
Method according to intermediate 11 prepares the 3-{1-[(2-chloroethyl) sulfonyl]-the 4-piperidyl }-5-(3-thienyl)-1H-indole-7-Methanamide.Make 3-(4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide (30mg; 0.09mmol) and triethylamine (0.025mL; 0.18mmol) and 2-chloro-ethane-sulfonyl chloride (0.012mL; 1.08mmol) reaction; obtain the 3-{1-[(2-chloroethyl) sulfonyl]-the 4-piperidyl }-5-(3-thienyl)-1H-indole-7-Methanamide, it does not have further purification just to be used for next step.
Conventional method according to the sulfamide of preparation described in the embodiment 2 makes the 3-{1-[(2-chloroethyl) sulfonyl]-the 4-piperidyl }-(0.04mL is 0.45mmol) at K for 5-(3-thienyl)-1H-indole-7-Methanamide (0.09mmol) and Aminocyclopentane
2CO
3(44mg, 0.45mmol) and NaI (5mg) there is reaction down in catalyst.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (7.1mg, 16%).
LC/MS：m/z?501.2(M+H)Rt?1.60min。
(19) 3-[1-({ 2-[(4-hydroxy-cyclohexyl) amino] ethyl } sulfonyl)-the 4-piperidyl]-5-(3-thienyl)-1H-indole-7-Methanamide
Method according to intermediate 11 prepares the 3-{1-[(2-chloroethyl) sulfonyl]-the 4-piperidyl }-5-(3-thienyl)-1H-indole-7-Methanamide.Make 3-(4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide (30mg; 0.09mmol) and triethylamine (0.025mL; 0.18mmol) and 2-chloro-ethane-sulfonyl chloride (0.012mL; 1.08mmol) reaction; obtain the 3-{1-[(2-chloroethyl) sulfonyl]-the 4-piperidyl }-5-(3-thienyl)-1H-indole-7-Methanamide, it does not have further purification just to be used for next step.
Conventional method according to the sulfamide of preparation described in the embodiment 2 makes the 3-{1-[(2-chloroethyl) sulfonyl]-the 4-piperidyl }-(33.4mg is 0.45mmol) at K for 5-(3-thienyl)-1H-indole-7-Methanamide (0.09mmol) and 4-aminocyclohexanol
2CO
3(44mg, 0.45mmol) and NaI (5mg) there is reaction down in catalyst.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (3.6mg, 7.7%).
LC/MS：m/z?517.2(M+H)Rt?1.40min。
(20) sulfonyl 3-{1-[(2-hydroxyethyl)]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide
With 3-[1-(vinylsulfonyl)-4-piperidyl]-5-phenyl-1H-indole-7-Methanamide (26mg, 0.063mmol) and the mixture of 6M NaOH aqueous solution (0.2mL) in DMSO in 80 ℃ of heated overnight.This reactant mixture of subsequent filtration, and by reversed-phase HPLC (water/CH
3CN, 0.1%TFA3-70%) purification obtains title compound (16mg, 59%).
LC/MS：428.2?r.t：1.79min。
(21) 5-(5-chloro-2-thienyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
This title compound is prepared according to the conventional method of intermediate 16.Therefore; will the 5-bromo-3-in two alkane (3mL) and the water (1mL) (1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide (95mg; 0.19mmol), 5-chloro-2-thienyl boric acid (123mg, 0.76mmol), Pd (PPh
3)
4(211mg, 1.52mmol) reaction generates required product, it is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H for (22.2mg, 10%) and the potassium carbonate in two alkane (3mL) and water (1mL)
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (11mg, 11%).
LC/MS：m/z?535.0(M+H)，Rt?1.84min。
(22) 3-(1-{[2-(methylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide
To 3-[1-(vinylsulfonyl)-4-piperidyl]-5-phenyl-1H-indole-7-Methanamide (26mg, CH 0.063mmol)
3Add in CN (1.0mL) solution methylamine (19.5mg, 0.63mmol).With reaction solution in 80 ℃ of heated overnight.Subsequently reactant mixture is passed through reversed-phase HPLC (water/CH
3CN, 0.1%TFA 10-90%) purification, obtain title compound (15mg, 54%).
LC/MS：m/z?414.4.0(M+H)，Rt?1.61min。
According to the conventional method described in the embodiment 22, but replace methylamine, listed chemical compound in the preparation table 1 with suitable amine.
Table 1
(63) 5-[5-(hydroxymethyl)-2-thienyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
This title compound is prepared according to the conventional method of intermediate 16.Therefore; will the 5-bromo-3-in two alkane (3mL) and the water (1mL) (1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide (95mg; 0.19mmol), [5-(hydroxymethyl)-2-thienyl] boric acid (120mg, 0.76mmol), Pd (PPh
3)
4(211mg, 1.52mmol) reaction generates required product, and it by flash column chromatography (ethyl acetate/hexane, 1/1) purification, is generated required product (25mg, 25%) for (22.2mg, 10%) and potassium carbonate.
LC/MS：m/z?531.4(M+H)，Rt?1.44min。
(64) 5-[5-(1-pyrrolidinyl methyl)-2-thienyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
To 5-(5-formoxyl-2-thienyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide (8.3mg, add in dichloromethane 0.016mmol) (5mL) solution pyrrolidine (0.001mL, 0.016mmol).Reactant mixture was at room temperature stirred 1 hour, add NaBH (OAc) subsequently
3(10.2mg, 0.048mmol).Reactant mixture at room temperature stirred spend the night, and evaporate all solvents.Residue is passed through to use Gilson half-preparation HPLC system purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) with the 25mL/min suction, obtains title compound (7mg, 92%).
LC/MS：m/z?484.4(M+H)，Rt?1.40min。
(65) methyl 5-{5-[(methylamino)]-the 2-thienyl }-3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
To 5-(5-formoxyl-2-thienyl)-3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide (20mg, MeOH/CH 0.04mmol)
2Cl
2(1mL/1mL) add in the solution methylamine (0.11mL, 0.24mmol).Reactant mixture was at room temperature stirred 2 hours, add NaBH subsequently
4(10.5mg, 0.24mmol).Reactant mixture at room temperature stirred spend the night, and evaporate all solvents.Residue is passed through to use Gilson half-preparation HPLC system purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) with the 25mL/min suction, obtains title compound (13.4mg, 65%).
LC/MS：m/z?560.4(M+H)，Rt?1.46min。
(66) methyl 5-{5-[(ethylamino)]-the 2-thienyl }-3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
To 5-(5-formoxyl-2-thienyl)-3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide (20mg, MeOH/CH 0.04mmol)
2Cl
2(1mL/1mL) add in the solution ethamine (0.13mL, 0.24mmol).Reactant mixture was at room temperature stirred 2 hours, add NaBH subsequently
4(10.5mg, 0.24mmol).Reactant mixture at room temperature stirred spend the night, and evaporate all solvents.Residue is passed through to use Gilson half-preparation HPLC system purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) with the 25mL/min suction, obtains title compound (11mg, 52%)
LC/MS：m/z?574.2.Rt?1.33min。
(67) 3-[1-({ 3-[two (1-Methylethyl) amino] propyl group } sulfonyl)-4-piperidyl]-5-phenyl-1H-indole-7-Methanamide
Conventional method according to the sulfamide of preparation described in the embodiment 2; make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide (100mg; 0.313mmol) and N-(1-Methylethyl)-2-propylamine (0.22mL is 1.55mmol) at K
2CO
3(1.28mmol) there is reaction down in 172.5mg.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (20.5mg, 13%).
LC/MS：m/z?525.4(M+H)Rt?1.63min。
(68) 3-(1-{[2-(methoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide
With 3-[1-(vinylsulfonyl)-4-piperidyl]-5-phenyl-1H-indole-7-Methanamide (26mg, 0.063mmol), the mixture of the methanol solution (0.1mL) of 0.5M Feldalat NM and methanol (1.0mL) stirred 1 hour down in 60 ℃.Subsequently with the reactant mixture concentrating under reduced pressure.Residue is passed through reversed-phase HPLC (water/CH
3CN, 0.1%TFA 10-90%) purification, obtain title compound (11.0mg, 40%).
LC/MS：442.4?r.t：2.05min。
(69) 3-[1-({ 3-[(2R, 5R)-2,5-dimethyl-1-pyrrolidinyl] propyl group } sulfonyl)-4-piperidyl]-5-phenyl-1H-indole-7-Methanamide
Conventional method according to the sulfamide of preparation described in the embodiment 2; make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (100mg, 0.313mmol) and (2R, 5R)-2; (449mg is 1.56mmol) at K for the 5-dimethyl pyrrolidine
2CO
3(886mg, 0.63mmol) and NaI (1.56mmol) there is reaction down in 251mg.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (60mg, 37%).
LC/MS：m/z?523.6(M+H)?Rt?1.73min。
(70) 3-(1-{[3-(4-methyl isophthalic acid-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide
Conventional method according to the sulfamide of preparation described in the embodiment 2 makes the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-(40mg, 0.13mmol) (0.068mL is 0.65mmol) at K with the 1-methyl piperazine for 5-(2-thienyl)-1H-indole-7-Methanamide
2CO
3(0.65mmol) there is reaction down in 74mg.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (7.0mg, 11%).
LC/MS：m/z?530.0(M+H)?Rt?1.52min。
(71) 3-(1-{[3-(4-hydroxyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide
Conventional method according to the sulfamide of preparation described in the embodiment 2 makes the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-(40mg, 0.13mmol) (0.068mL is 0.65mmol) at K with 4-piperidines alcohol for 5-(3-thienyl)-1H-indole-7-Methanamide
2CO
3(0.65mmol) there is reaction down in 74mg.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (8.2mg, 13%).
LC/MS：m/z?531.0(M+H)?Rt?1.54min。
(72) 3-(1-{[3-(4-methyl isophthalic acid-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide
Conventional method according to the sulfamide of preparation described in the embodiment 2 makes the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-(40mg, 0.13mmol) (0.068mL is 0.65mmol) at K with the 1-methyl piperazine for 5-(3-thienyl)-1H-indole-7-Methanamide
2CO
3(0.65mmol) there is reaction down in 74mg.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (11.2mg, 17.2%).
LC/MS：m/z?530.2(M+H)Rt?1.45min。
(73) 3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide
According to described in the embodiment 2 preparation sulfamide conventional method, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-(2-thienyl)-1H-indole-7-Methanamide (40mg, 0.13mmol) and morpholine (0.069mL is 0.65mmol) at K
2CO
3(0.65mmol) there is reaction down in 74mg.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (37.3mg, 57%).
LC/MS：m/z?517.2(M+H)Rt?1.57min。
(74) 3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide
According to described in the embodiment 2 preparation sulfamide conventional method, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-(3-thienyl)-1H-indole-7-Methanamide (40mg, 0.13mmol) and morpholine (0.069mL is 0.65mmol) at K
2CO
3(0.65mmol) there is reaction down in 74mg.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (33mg, 51%).
LC/MS：m/z?517.2(M+H)Rt?1.50min。
(75) 5-(4-fluorophenyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
Method according to intermediate 11 prepares the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-(4-fluorophenyl)-1H-indole-7-Methanamide.Make 5-(4-fluorophenyl)-3-(4-piperidyl)-1H-indole-7-Methanamide (20mg; 0.059mmol) and triethylamine (0.03mL; 0.236mmol) and 3-chloropropyl sulfonic acid chloride (0.03mL; 0.118mmol) reaction; obtain the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-(4-fluorophenyl)-1H-indole-7-Methanamide, it does not have further purification just to be used for next step.
Conventional method according to the sulfamide of preparation described in the embodiment 2 makes the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-(0.025mL is 0.295mmol) at K for 5-(4-fluorophenyl)-1H-indole-7-Methanamide (0.059mmol) and pyrrolidine
2CO
3(37mg, 0.118mmol) and NaI (2mg) there is reaction down in catalyst.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (6.9mg, 23%).
LC/MS：m/z?513.4(M+H)Rt?1.72min。
(76) 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-(hydroxymethyl) phenyl]-1H-indole-7-Methanamide
This title compound is prepared according to the conventional method of intermediate 16.Therefore, with 5-bromo-3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide (150mg, 0.32mmol), [3-(hydroxymethyl) phenyl] boric acid (195mg, 1.27mmol), Pd (PPh
3)
4(220mg, 0.64mmol) reaction generates required product, it is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H for (31mg, 10%) and cesium carbonate
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) generates required product (230.0mg, 36%).
LC/MS：m/z?499.6(M+H)，Rt?1.45min。
According to the conventional method described in the embodiment 76, but replace [3-(hydroxymethyl) phenyl] boric acid, listed chemical compound in the preparation table 2 with suitable boric acid.
Table 2
| Embodiment | T2 | MS[M] + | ?Rt ?(min) |
(83) 5-[3-(hydroxymethyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
This title compound is prepared according to the conventional method of intermediate 16.Therefore, with 5-bromo-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide (150mg, 0.30mmol), [3-(hydroxymethyl) phenyl] boric acid (188mg, 1.20mmol), Pd (PPh
3)
4(200mg, 0.60mmol) reaction generates required product, it is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H for (30mg, 10%) and cesium carbonate
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) generates required product (280mg, 44%).
LC/MS：m/z?525.6(M+H)，Rt?1.47min。
According to the conventional method described in the embodiment 83, but replace [3-(hydroxymethyl) phenyl] boric acid, listed chemical compound in the preparation table 3 with suitable boric acid.
Table 3
(90) methyl 5-{3-[(ethylamino)] phenyl }-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
To 5-(3-formoxyl phenyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide (25mg, MeOH/CH 0.048mmol)
2Cl
2(1mL/1mL) add in the solution 2M ethamine THF solution (0.144mL, 0.288mmol).Reactant mixture was at room temperature stirred 2 hours, add NaBH subsequently
4(12mg, 0.3mmol).Reactant mixture at room temperature stirred spend the night, and evaporate all solvents.Residue is passed through to use Gilson half-preparation HPLC system purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) with the 25mL/min suction, obtains title compound (11mg, 52%).
LC/MS：m/z?552.8?Rt?1.30min。
According to the conventional method described in the embodiment 90, but replace ethamine, listed chemical compound in the preparation table 4 with suitable amine.
Table 4
| Embodiment | T4 | MS[M] + | Rt (min) |
(96) 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-the 5-{3-[(ethylamino) methyl] phenyl-1H-indole-7-Methanamide
To 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-formoxyl phenyl)-1H-indole-7-Methanamide (25mg, MeOH/CH 0.05mmol)
2Cl
2(1mL/1mL) add in the solution 2M ethamine THF solution (0.15mL, 0.30mmol).Reactant mixture was at room temperature stirred 2 hours, add NaBH subsequently
4(12mg, 0.3mmol).Reactant mixture at room temperature stirred spend the night, and evaporate all solvents.Residue is passed through to use Gilson half-preparation HPLC system purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) with the 25mL/min suction, obtains title compound (11mg, 52%).
LC/MS：m/z?526.8，Rt?1.38min。
According to the conventional method described in the embodiment 96, but replace ethamine, listed chemical compound in the preparation table 5 with suitable amine.
Table 5
(99) 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[4-(piperidino methyl) phenyl]-1H-indole-7-Methanamide
To 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[4-(hydroxymethyl) phenyl]-(230mg adds MnO in THF 0.47mmol) (60mL) solution to 1H-indole-7-Methanamide
2(1.3g, 14.05mmol).Reactant mixture at room temperature stirred spend the night, filter by the celite filler subsequently.Collect filtrate, and concentrating under reduced pressure, obtaining aldehyde (150mg, 65%), it does not have further purification just to be used for next step.
To 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, add in DCM 0.1mmol) (3mL) solution piperidines (8mg, 0.1mmol) and NaBH (OAc)
3(64mg, 0.3mmol).Reactant mixture at room temperature stirred spend the night.Evaporating solvent, and with residue on 1g scx post by Solid-Phase Extraction purification (International SorbentTechnologies), with dichloromethane (6mL), methylene chloride 1: 1 (6mL), methanol (6mL) and ammonia (6mLx3) eluting.Evaporation merges the eluate in the test tube then, and residue is passed through HPLC (water/CH
3CN, 0.1%TFA 10-90%) purification, obtain title compound (8mg, 15%).
LC/MS：m/z?566.2(M+H)，1.34min。
(100) 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[4-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide
According to the method for embodiment (99), make 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.1mmol), morpholine (9mg, 0.1mmol) and NaBH (OAc)
3(64mg, 0.3mmol) reaction obtains title compound (15mg, 30%).
LC/MS：m/z?568.4(M+H)，1.22min。
(101) 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[4-(1-pyrrolidinyl methyl) phenyl]-1H-indole-7-Methanamide
According to the conventional method of embodiment (99), make 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(4-formoxyl phenyl)-1H-indole-7-Methanamide (50mg, 0.1mmol), pyrrolidine (9mg, 0.1mmol) and NaBH (OAc)
3(64mg, 0.3mmol) reaction obtains title compound (20mg, 20%).
LC/MS：m/z?552.6(M+H)，1.29min。
(102) 3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-(hydroxymethyl) phenyl]-1H-indole-7-Methanamide
This title compound is prepared according to the conventional method of intermediate 16.Therefore, with 5-bromo-3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide (46mg, 0.09mmol), [3-(hydroxymethyl) phenyl] boric acid (55mg, 0.36mmol), Pd (PPh
3)
4(10mg, 10%) and cesium carbonate (117mg, 0.36mmol) in microwave in 160 ℃ of heating 40min, generates required product (16.5mg, 34%), it is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid).
LC/MS：m/z?539.4(M+H)，Rt?1.61min。
According to the conventional method described in the embodiment 102, but replace [3-(hydroxymethyl) phenyl] boric acid, listed chemical compound in the preparation table 6 with suitable boric acid.
Table 6
| Embodiment | T6 | MS[M] + | ?Rt ?(min) |
(108) 4-{[3-({ 4-[7-(amino carbonyl)-5-phenyl-1H-indol-3-yl]-piperidino } sulfonyl) propyl group] amino }-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester
Conventional method according to the sulfamide of preparation described in the embodiment 2; make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide (50mg; 0.0.109mmol) and 4-amino-1-piperidine carboxylic acid 1, (108.8mg is 0.543mmol) at K for 1-dimethyl ethyl ester
2CO
3(60mg 0.435mmol) and under sodium iodide (2mg) existence reacts.With the reactant mixture concentrating under reduced pressure.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (17.3mg, 26%).
LC/MS：m/z?624.4(M+H)?Rt?1.86min。
(109) 5-phenyl-3-(1-{[3-(4-piperidyl amino) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
To 4-{[3-({ 4-[7-(amino carbonyl)-5-phenyl-1H-indol-3-yl]-piperidino } sulfonyl) propyl group] amino }-1-piperidine carboxylic acid 1; 1-dimethyl ethyl ester (15.4mg, the aqueous solution (0.1mL) of adding 36%HCl in MeOH 0.025mmol) (3mL) solution.Reactant mixture was stirred 1 hour in 60 ℃, and removal of solvent under reduced pressure subsequently is with the reactant mixture concentrating under reduced pressure.The residue that generates is passed through the reversed-phase HPLC purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (3.2mg, 24%).
LC/MS：m/z?524.4(M+H)?Rt?1.27min。
According to the conventional method described in the embodiment 108, but replace 4-amino-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester, listed chemical compound in the preparation table 7 with suitable amine.
Table 7
(159) 3-[1-({ 3-[(4-aminomethyl phenyl) oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide
To the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (40mg, add in DMSO 0.087mmol) (1.0mL) solution 4-methylphenol (108mg, 0.87mmol), K
2CO
3(35.0mg, 0.35mmol) and sodium iodide (0.5mg).With reaction solution in 80 ℃ of heated overnight.Subsequently with the reactant mixture filtration with by reversed-phase HPLC (water/CH
3CN, 0.1%TFA 10-90%) purification, obtain title compound (6.3mg, 14%).
LC/MS：532.2?r.t.：2.54min。
(160) 3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide
With the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide (46.0mg, 0.1mmol), the mixture of 0.1M NaOMe (4ml) in methanol (2mL) reflux and to spend the night.Reactant mixture is concentrated, and by reversed-phase HPLC (water/CH
3CN, 0.1%TFA 10-90%) purification, obtain title compound (20.0mg, 44%).
LC/MS：456.2?r.t：2.04min。
(161) 5-phenyl-3-(1-{[3-(phenoxy group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
According to the conventional method of embodiment 159, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (40.0mg, 0.087mmol), phenol (94mg, 0.87mmol), K
2CO
3(35.0mg 0.35mmol) and sodium iodide (0.5mg) reaction, obtains title compound (4.2mg, 9.3%).
LC/MS：518.4?r.t：2.45min。
(162) 5-phenyl-3-{1-[(3-{[2-(trifluoromethyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide
According to the conventional method of embodiment 159, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (40.0mg, 0.087mmol), 2-(trifluoromethyl) phenol (162mg, 0.87mmol), K
2CO
3(35.0mg 0.35mmol) and sodium iodide (0.5mg) reaction, obtains title compound (22.9mg, 50%).
LC/MS：586.2?r.t：2.59min。
(163) 3-[1-({ 3-[(4-hydroxybutyl) oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide
According to the conventional method of embodiment 159, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide (40.0mg, 0.087mmol), 1, the 4-butanediol (90mg, 0.87mmol), K
2CO
3(35.0mg 0.35mmol) and sodium iodide (0.5mg) reaction, obtains title compound (9.1mg, 20.4%).
LC/MS：514.1?r.t：1.93min。
(164) 3-[1-({ 3-[(cyclopropyl methyl) oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide
According to the conventional method of embodiment 159, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (40.0mg, 0.087mmol), cyclopropyl-carbinol (72mg, 0.87mmol), K
2CO
3(35.0mg 0.35mmol) and sodium iodide (0.5mg) reaction, obtains title compound (5.2mg, 12%).
LC/MS：496.1?r.t：2.25min。
(165) 3-[1-({ 3-[(2-hydroxyl-1-methyl-propyl) oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide
According to the conventional method of embodiment 159, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide (40.0mg, 0.087mmol), 2, the 3-butanediol (72mg, 0.87mmol), K
2CO
3(35.0mg 0.35mmol) and sodium iodide (0.5mg) reaction, obtains title compound (4.0mg, 8.9%).
LC/MS：514.1?r.t：2.00min。
(166) 3-[1-({ 3-[(cyclobutylmethyl) oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide
According to the conventional method of embodiment 159, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (40.0mg, 0.087mmol), cyclobutanemethanol (86mg, 0.87mmol), K
2CO
3(35.0mg 0.35mmol) and sodium iodide (0.5mg) reaction, obtains title compound (5.6mg, 12.6%).
LC/MS：510.4?r.t：2.46min。
(167) 5-phenyl-3-[1-({ 3-[(tetrahydrochysene-3-furyl methyl) oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-1H-indole-7-Methanamide
According to the conventional method of embodiment 159, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (40.0mg, 0.087mmol), tetrahydrochysene-3-furfuralcohol (102mg, 0.87mmol), K
2CO
3(35.0mg 0.35mmol) and sodium iodide (0.5mg) reaction, obtains title compound (7.0mg, 15.3%).
LC/MS：526.6?r.t：2.14min。
(168) 3-{1-[(3-{[4-(acetyl-amino) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide
According to the conventional method of embodiment 159, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (40.0mg, 0.087mmol), N-(4-hydroxy phenyl) acetamide (151mg, 0.87mmol), K
2CO
3(35.0mg 0.35mmol) and sodium iodide (0.5mg) reaction, obtains title compound (21.0mg, 42%).
LC/MS：575.4?r.t：2.12min。
(169) 3-{1-[(3-{[4-(methoxyl group) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide
According to the conventional method of embodiment 159, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (40.0mg, 0.087mmol), 4-(methoxyl group) phenol (124mg, 0.87mmol), K
2CO
3(35.0mg 0.35mmol) and sodium iodide (0.5mg) reaction, obtains title compound (21.0mg, 44%).
LC/MS：548.4?r.t：2.42min。
(170) 3-{1-[(3-{[2-(methoxyl group) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide
According to the conventional method of embodiment 159, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (40.0mg, 0.087mmol), 2-(methoxyl group) phenol (124mg, 0.87mmol), K
2CO
3(35.0mg 0.35mmol) and sodium iodide (0.5mg) reaction, obtains title compound (23.0mg, 48%).
LC/MS：548.4?r.t：2.35min。
(171) 3-[1-({ 3-[(4-fluorophenyl) oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide
According to the conventional method of embodiment 159, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (40.0mg, 0.087mmol), the 4-fluorophenol (112mg, 0.87mmol), K
2CO
3(35.0mg 0.35mmol) and sodium iodide (0.5mg) reaction, obtains title compound (18.0mg, 39%).
LC/MS：536.2?r.t：2.45min。
(172) 5-phenyl-3-{1-[(3-{[3-(trifluoromethyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide
According to the conventional method of embodiment 159, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (40.0mg, 0.087mmol), the 3-trifloro methyl phenol (162mg, 0.87mmol), K
2CO
3(35.0mg 0.35mmol) and sodium iodide (0.5mg) reaction, obtains title compound (25.0mg, 49%).
LC/MS：586.4?r.t：2.63min。
(173) 3-{1-[(3-{[3-(methoxyl group) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide
According to the conventional method of embodiment 159, make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (40.0mg, 0.087mmol), the 3-methoxyphenol (124mg, 0.87mmol), K
2CO
3(35.0mg 0.35mmol) and sodium iodide (0.5mg) reaction, obtains title compound (20.0mg, 42%).
LC/MS：548.4?r.t：2.45min。
(174) sulfonyl 3-{1-[(3-hydroxypropyl)]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide
Conventional method according to embodiment 159; make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide (23.0mg; 0.050mmol), the aqueous solution (1mL) of 50%NaOH and sodium iodide (5.0mg) reaction, obtain title compound (15.0mg, 68%).
LC/MS：442.4?r.t：1.90min。
(175) 3-(1-{[2-(ethyoxyl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide
With 3-[1-(vinylsulfonyl)-4-piperidyl]-5-phenyl-1H-indole-7-Methanamide (23mg, 0.056mmol), the mixture of NaOEt (10mg) in ethanol (1mL) spend the night in 80 ℃ of backflows.Reactant mixture is concentrated, and by reversed-phase HPLC (water/CH
3CN, 0.1%TFA 10-90%) purification, obtain title compound (15.0mg, 59%).
LC/MS：456.2?r.t：2.12min。
(176) 3-(1-{[3-(ethyoxyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide
With the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide (23mg, 0.050mmol), the mixture of NaOEt (10mg) in ethanol (1mL) spend the night in 80 ℃ of backflows.Reactant mixture is concentrated, and by reversed-phase HPLC (water/CH
3CN, 0.1%TFA 10-90%) purification, obtain title compound (15.0mg, 64%).
LC/MS：469.8?r.t：2.14min。
(177) 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-the 5-{3-[(methylamino) methyl] phenyl-1H-indole-7-Methanamide
According to the conventional method described in the embodiment 96; but with methylamine (0.026mL; 0.3mmol) replacement ethamine; generate required product 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-the 5-{3-[(methylamino) methyl] phenyl-1H-indole-7-Methanamide (10.8mg, 40%).
LC/MS：m/z?512.4，Rt?1.36min。
(178) 5-phenyl-3-{1-[(2-{[2-(piperidino) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide
To 3-[1-(vinylsulfonyl)-4-piperidyl]-5-phenyl-1H-indole-7-Methanamide (21mg, 0.05mmol) add in the mixture in DMSO (1.0mL) 2-(piperidino) ethanol (64.6mg, 0.5mmol), K
2CO
3(35.0mg, 0.35mmol) and sodium iodide (0.5mg).With reaction solution in 80 ℃ of heated overnight.Reactant mixture is concentrated, and by reversed-phase HPLC (water/CH
3CN, 0.1%TFA10-90%) purification obtains title compound (12.0mg, 50%).
LC/MS：539.4?r.t：1.80min。
According to the conventional method described in the embodiment 178, but replace 2-(piperidino) ethanol, listed chemical compound in the preparation table 8 with suitable alcohol.
Table 8
(214) 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[(1-Methylethyl) amino] methyl phenyl)-1H-indole-7-Methanamide
According to the conventional method described in the embodiment 96; but with 2-aminopropane. (0.15mL; 0.3mmol) replacement ethamine; generate required product 3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[(1-Methylethyl) amino] methyl phenyl)-1H-indole-7-Methanamide (11mg, 43%).
LC/MS：m/z?540.2，Rt?1.34min。
(215) 3-[1-({ 2-[(methoxyl group) amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide
To 3-[1-(vinylsulfonyl)-4-piperidyl]-5-phenyl-1H-indole-7-Methanamide (41mg, 0.1mmol) add in the mixture in DMSO (2.0mL) O-methyl hydroxy amine hydrochloric acid salt (83.5mg, 1.0mmol), K
2CO
3(70.0mg, 0.70mmol) and sodium iodide (0.5mg).With reaction solution in 80 ℃ of heated overnight.Reactant mixture is concentrated, and by reversed-phase HPLC (water/CH
3CN, 0.1%TFA10-90%) purification obtains title compound (20.7mg, 43%).
LC/MS：457.2?r.t：2.11min。
According to the conventional method described in the foregoing description, but replace O-methyl hydroxy amine hydrochloric acid salt, listed chemical compound in the preparation table 9 with hydroxylamine.
Table 9
(219) 3-[1-({ 3-[(methoxyl group) amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide
To the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (40.0mg, 0.087mmol) add in the mixture in DMSO (2.0mL) O-methyl hydroxy amine hydrochloric acid salt (83.5mg, 1.0mmol), K
2CO
3(35.0mg, 0.35mmol) and sodium iodide (0.5mg).With reaction solution in 80 ℃ of heated overnight.Reactant mixture is concentrated, and by reversed-phase HPLC (water/CH
3CN, 0.1%TFA 10-90%) purification, obtain title compound (20.7mg, 43%).
LC/MS：471.0?r.t：1.91min。
According to the conventional method described in the foregoing description, but replace O-methyl hydroxy amine hydrochloric acid salt, listed chemical compound in the preparation table 10 with hydroxylamine.
Table 10
(223) methyl 5-{3-[(methylamino)] phenyl }-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
To 5-(3-formoxyl phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide (25mg, MeOH/CH 0.055mmol)
2Cl
2(1mL/1mL) add in the solution methylamine (0.15mL, 0.33mmol).Reactant mixture was at room temperature stirred 2 hours, add NaBH subsequently
4(13.2mg, 0.33mmol).Reactant mixture at room temperature stirred spend the night, and evaporate all solvents.Residue is passed through to use Gilson half-preparation HPLC system purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) with the 25mL/min suction, obtains title compound (9.0mg, 36%).
LC/MS：m/z?499.8(M+H)，Rt?1.66min。
According to the conventional method described in the foregoing description, but replace methylamine, listed chemical compound in the preparation table 11 with suitable amine.
Table 11
(260) methyl 5-{3-[(methylamino)] phenyl }-3-(1-{[2-(methoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
To 5-(3-formoxyl phenyl)-3-(1-{[2-(methoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide (25mg, MeOH/CH 0.053mmol)
2Cl
2(1mL/1mL) add in the solution methylamine (0.15mL, 0.33mmol).Reactant mixture was at room temperature stirred 2 hours, add NaBH subsequently
4(13.2mg, 0.33mmol).Reactant mixture at room temperature stirred spend the night, and evaporate all solvents.Residue is passed through to use Gilson half-preparation HPLC system purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) with the 25mL/min suction, obtains title compound (10.0mg, 39%).
LC/MS：m/z?485.2(M+H)，Rt?1.42min。
(261) 5-(3-{[(1,1-dimethyl propyl) amino] methyl } phenyl)-3-(1-{[2-(methoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
According to the conventional method described in the embodiment 260, but replace methylamine, prepare title compound (12.0mg, 42%) with (1, the 1-dimethyl propyl) amine.
LC/MS：m/z?514.4(M+H)，Rt?1.61min。
(262) 3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide
Make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-(2-thienyl)-1H-indole-7-Methanamide (35mg; 0.075mmol) and the Feldalat NM (methanol solution of 0.5M; 1.0mL; 0.488mmol) in the mixture of methanol (4ml) and DMSO (0.5mL), under refluxing, react 16h; form required product; it is passed through the reversed-phase HPLC purification, with 10%B to 70%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (15mg, 43%).
LCMS：462.2(M+H)，Rt?2.04min。
(263) 3-(1-{[3-(ethyoxyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide
Make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-(3-thienyl)-1H-indole-7-Methanamide (60mg; 0.129mmol) and the Sodium ethylate (alcoholic solution of 0.5M; 0.5mL; 0.25mmol) in the mixture of ethanol (5ml) and DMSO (0.2mL), under refluxing, react 16h; form required product; it is passed through the reversed-phase HPLC purification, with 10%B to 70%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (10mg, 17%).
LCMS：476.6(M+H)，Rt?2.10min。
(264) 3-(1-{[3-(ethyoxyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide
Make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-(3-thienyl)-1H-indole-7-Methanamide (80mg; 0.172mmol) and the Sodium ethylate (alcoholic solution of 0.5M; 0.7mL; 0.344mmol) in the mixture of ethanol (6ml) and DMSO (0.2mL), under refluxing, react 16h; form required product; it is passed through the reversed-phase HPLC purification, with 10%B to 70%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (20mg, 25%).
LCMS：476.6(M+H)，Rt?2.10min。
(265) sulfonyl 3-{1-[(3-hydroxypropyl)]-the 4-piperidyl }-5-(2-thienyl)-1H-indole-7-Methanamide
Make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-(3-thienyl)-1H-indole-7-Methanamide (50mg; 0.107mmol) with the sodium iodide (1.6mg of catalytic amount; 0.107mmol) in the mixture of 6N sodium hydroxide (1.3mL) and DMSO (0.7ml), under refluxing, react 16h; form required product; it is passed through the reversed-phase HPLC purification; with 10%B to 70%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (12mg, 25%).
LCMS：448.6(M+H)，Rt?1.90min。
(266) 3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide
Make the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl }-5-(2-thienyl)-1H-indole-7-Methanamide (165mg; 0.355mmol) and the Feldalat NM (methanol solution of 0.5M; 1.5mL; 0.710mmol) in the mixture of methanol (5ml) and DMSO (0.4mL), under refluxing, react 16h; form required product; it is passed through the reversed-phase HPLC purification, with 10%B to 70%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) obtains title compound (25mg, 15%).
LCMS：462.2(M+H)，Rt?2.03min。
(267) sulfonyl 3-{1-[(1-methyl isophthalic acid H-imidazol-4 yl)]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide
Under 0 ℃, to 5-phenyl-3-(4-piperidyl)-1H-indole-7-Methanamide (40mg, add in dichloromethane 0.12mmol) (5mL) solution 1-methyl isophthalic acid H-imidazoles-4-sulfonic acid chloride (27.1mg, 0.14mmol) and triethylamine (0.07mL, 0.50mmol).Reactant mixture is stirred 30min down at 0 ℃.Then reactant mixture is distributed between dichloromethane and water, water layer is extracted with dichloromethane (25mLx2), and with the organic facies Mg that merges
2SO
4Drying, and concentrating under reduced pressure, and by Gilson HPLC (anti-phase, use CH
3CN/ water, 0.1%TFA, 10/90, the v/v eluting is used 15min) purification, obtain title compound (22.5mg, 39%).
LC/MS：m/z，463.4(M+H)，1.72min。
(268) 5-phenyl-3-[1-(2-thienyl sulphonyl base)-4-piperidyl]-1H-indole-7-Methanamide
According to the conventional method among the embodiment 267, make 5-(phenyl)-3-(4-piperidyl)-1H-indole-7-Methanamide (40mg, 0.12mmol), 2-thiophene sulfonic acid chloride (23mg, 0.13mmol) and triethylamine (0.07mL, 0.5mmol) reaction, form required product, it is passed through Gilson HPLC (CH
3CN/ water, 0.1%TFA) purification (30mg, 52%).
LC/MS：m/z?466.2(M+H)，2.23min。
(269) sulfonyl 3-{1-[(5-chloro-2-thienyl)]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide
According to the conventional method among the embodiment 267, make 5-(phenyl)-3-(4-piperidyl)-1H-indole-7-Methanamide (13mg, 0.04mmol), 5-methyl-2-thiophene sulfonic acid chloride (13.2mg, 0.048mmol) and triethylamine (0.02mL, 0.16mmol) reaction, form required product, it is passed through Gilson HPLC (CH
3CN/ water, 0.1%TFA) purification (6.1mg, 30%).
LC/MS：m/z?500.4(M+H)，2.62min。
(270) 3-(1-{[5-(the different azoles of 3-base)-3-thienyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide
According to the conventional method among the embodiment 267, make 5-(phenyl)-3-(4-piperidyl)-1H-indole-7-Methanamide (32mg, 0.1mmol), 5-(the different azoles of 3-base)-3-thiophene sulfonic acid chloride (37.5mg, 0.15mmol) and triethylamine (0.06mL, 0.3mmol) reaction, form required product, it is passed through GilsonHPLC (CH
3CN/ water, 0.1%TFA) purification (11.7mg, 22%).
LC/MS：m/z?533.4(M+H)，2.59min。
(271) amino 5-phenyl-3-{1-[(5-{[(phenyl methyl)] methyl }-the 2-thienyl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide
According to the conventional method among the embodiment 267, make 5-(phenyl)-3-(4-piperidyl)-1H-indole-7-Methanamide (32mg, 0.1mmol), the 5-{[(phenyl methyl) amino] methyl-2-thiophene sulfonic acid chloride (45.3mg, 0.15mmol) and triethylamine (0.06mL, 0.3mmol) reaction, form required product, it is passed through Gilson HPLC (CH
3CN/ water, 0.1%TFA) purification (20mg, 34%).
LC/MS：m/z?599.2(M+H)，2.48min。
(272) 3-(1-{[2-(acetyl-amino)-4-methyl isophthalic acid, 3-thiazole-5-yl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide
According to the conventional method among the embodiment 267; make 5-(phenyl)-3-(4-piperidyl)-1H-indole-7-Methanamide (32mg; 0.1mmol), 2-(acetyl-amino)-4-methyl isophthalic acid; 3-thiazole-5-sulfonic acid chloride (38.2mg; 0.15mmol) and triethylamine (0.06mL; 0.3mmol) reaction, form required product, it is passed through Gilson HPLC (CH
3CN/ water, 0.1%TFA) purification (4.0mg, 7.5%).
LC/MS：m/z?538.2(M+H)，1.96min。
(273) the 3-{1-[(5-chloro-1,3-dimethyl-1H-pyrazoles-4-yl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide
According to the conventional method among the embodiment 267, make 5-(phenyl)-3-(4-piperidyl)-1H-indole-7-Methanamide (32mg, 0.1mmol), 5-chloro-1,3-dimethyl-1H-pyrazoles-4-sulfonic acid chloride (34.5mg, 0.15mmol) and triethylamine (0.06mL, 0.3mmol) reaction, form required product, it is passed through GilsonHPLC (CH
3CN/ water, 0.1%TFA) purification (22mg, 43%).
LC/MS：m/z?511.6，2.12min。
(274) the 3-{1-[(4-chloro-2,1,3-benzo diazole-5-yl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide
According to the conventional method among the embodiment 267, make 5-phenyl-3-(1,2,3,6-tetrahydrochysene-4-pyridine radicals)-1H-indole-7-Methanamide (32mg, 0.1mmol), 4-chloro-2,1,3-benzo diazole-5-sulfonic acid chloride (38mg, 0.15mmol) and triethylamine (0.06mL, 0.3mmol) reaction, form required product, it is passed through Gilson HPLC (CH
3CN/ water, 0.1%TFA) purification (8.0mg, 15%).
LC/MS：m/z?536.0(M+H)，2.44min。
(275) 3-{1-[(1,2-dimethyl-1H-imidazol-4 yl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide
According to the conventional method among the embodiment 267, make 5-phenyl-3-(1,2,3,6-tetrahydrochysene-4-pyridine radicals)-1H-indole-7-Methanamide (32mg, 0.1mmol), 1,2-dimethyl-1H-imidazoles-4-sulfonic acid chloride (22.8mg, 0.15mmol) and triethylamine (0.06mL, 0.3mmol) reaction, form required product, it is passed through Gilson HPLC (CH
3CN/ water, 0.1%TFA) purification (11mg, 23%).
LC/MS：m/z?478.2(M+H)，1.99min。
(276) 5-phenyl-3-{1-[(1,3,5-trimethyl-1H-pyrazoles-4-yl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide
According to the conventional method among the embodiment 267, make 5-phenyl-3-(1,2,3,6-tetrahydrochysene-4-pyridine radicals)-1H-indole-7-Methanamide (32mg, 0.1mmol), 1,3,5-trimethyl-1H-pyrazoles-4-sulfonic acid chloride (24.4mg, 0.15mmol) and triethylamine (0.06mL, 0.3mmol) reaction, form required product, it is passed through Gilson HPLC (CH
3CN/ water, 0.1%TFA) purification (9mg, 18%).
LC/MS：m/z?492.0(M+H)，2.26min。
(277) 3-{1-[(3, the different azoles of 5-dimethyl-4-base) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide
According to the conventional method among the embodiment 267, make 5-phenyl-3-(1,2,3,6-tetrahydrochysene-4-pyridine radicals)-1H-indole-7-Methanamide (32mg, 0.1mmol), 3, the different azoles of 5-dimethyl-4-sulfonic acid chloride (22.9mg, 0.15mmol) and triethylamine (0.06mL, 0.3mmol) reaction, form required product, it is passed through Gilson HPLC (CH
3CN/ water, 0.1%TFA) purification (11mg, 23%).
LC/MS：m/z?479.4(M+H)，2.32min。
(278) 3-{1-[(2,4-dimethyl-1,3-thiazoles-5-yl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide
According to the conventional method among the embodiment 267, make 5-phenyl-3-(4-piperidyl)-1H-indole-7-Methanamide (32mg, 0.1mmol), 2,4-dimethyl-1,3-thiazole-5-sulfonic acid chloride (24.8mg, 0.15mmol) and triethylamine (0.06mL, 0.3mmol) reaction, form required product, it is passed through GilsonHPLC (CH
3CN/ water, 0.1%TFA) purification (12.7mg, 26%).
LC/MS：m/z?495.4(M+H)，2.31min。
(279) 3-{1-[(1,2-dimethyl-1H-imidazoles-5-yl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide
According to the conventional method among the embodiment 267, make 5-(phenyl)-3-(4-piperidyl)-1H-indole-7-Methanamide (72mg, 0.22mmol), 1,2-dimethyl-1H-imidazoles-5-sulfonic acid chloride (64.2mg, 0.33mmol) and triethylamine (0.13mL, 0.66mmol) reaction, form required product, it is passed through GilsonHPLC (CH
3CN/ water, 0.1%TFA) purification (48.3mg, 45%).
LC/MS：m/z?478.0(M+H)，1.65min。
(280) sulfonyl 3-{1-[(1-methyl isophthalic acid H-imidazol-4 yl)]-the 4-piperidyl }-5-(3-thienyl)-1H-indole-7-Methanamide
According to the conventional method among the embodiment 267, make 3-(4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide (40mg, 0.12mmol), 1-methyl isophthalic acid H-imidazoles-4-sulfonic acid chloride (29.7mg, 0.18mmol) and triethylamine (0.05mL, 0.36mmol) reaction, form required product, it is passed through GilsonHPLC (CH
3CN/ water, 0.1%TFA) purification (20mg, 34%).
LC/MS：m/z?470.4(M+H)，1.76min。
(281) 3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-[5-(1-pyrrolidinyl methyl)-3-thienyl]-1H-indole-7-Methanamide
To 5-(5-formoxyl-3-thienyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide (40mg; 0.08mmol) (0.07mL is 0.8mmol) with 2 acetic acid to add pyrrolidine in the mixture of dichloromethane (1.25mL) and methanol (0.5mL).After reactant mixture is at room temperature stirred 6 hours, add NaBH
4(30.26mg, 0.8mmol).Then reactant mixture was at room temperature stirred 30 minutes.Evaporate all solvents, and by Gilson HPLC (CH
3CN/ water, 0.1%TFA) purification obtains title compound (6.5mg, 15%).
LC/MS：m/z?545.2(M+H)，1.65min。
(282) 5-(5-{[(1,1-dimethyl ethyl) amino] methyl }-the 3-thienyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
Conventional method according to embodiment 281; make 5-(5-formoxyl-3-thienyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide (40mg; 0.08mmol), (1, the 1-dimethyl ethyl) amine (70mg, 0.8mmol) and NaBH
4(30.26mg, 0.8mmol) reaction forms required product, and it is passed through Gilson HPLC (CH
3CN/ water, 0.1%TFA) purification (8.4mg, 19%).
LC/MS：m/z?561.2(M+H)，1.65min。
(283) 3-[1-({ 3-[(3-ethylphenyl) oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide
To the 3-{1-[(3-chloropropyl) sulfonyl]-the 4-piperidyl-5-phenyl-1H-indole-7-Methanamide (23.0mg, add in DMSO 0.05mmol) (1.0mL) solution 3-ethyl-phenol (122.0mg, 0.5mmol), K
2CO
3(35.0mg, 0.25mmol) and sodium iodide (1.0mg).With reaction solution in 80 ℃ of heated overnight.This reactant mixture of subsequent filtration, and by reversed-phase HPLC (water/CH
3CN, 0.1%TFA10-90%) purification obtains title compound (5mg, 18%).
LC/MS：546.1?r.t：2.76min。
According to the conventional method described in the foregoing description, but replace the 3-ethyl-phenol, listed chemical compound in the preparation table 12 with suitable alcohol.
Table 12
(308) 5-[3-(1-pyrrolidinyl methyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide
To 5-(3-formoxyl phenyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-add in DCM/MeOH (1.0ml/1.0ml) solution of 1H-indole-7-Methanamide (45.0mg/0.086mmol) pyrrolidine (0.043mL, 0.517mmol) and 1 AcOH.Reactant mixture is at room temperature stirred 2 hours, and add NaBH then
4(17.0mg, 0.086mmol).Reactant mixture is stirred 30min, and concentrate, and be dissolved in once more among the DMSO of 1.5ml.Residue is passed through to use Gilson half-preparation HPLC system purification, with 10%B to 80%B eluting, wherein A=H
2O (0.1% trifluoroacetic acid) and B=CH
3CN (0.1% trifluoroacetic acid) with the 25mL/min suction, obtains title compound (4mg, 8%).
LC/MS：m/z?578.6?Rt?1.40min。
According to the conventional method described in the embodiment 308, but replace pyrrolidine, listed chemical compound in the preparation table 13 with suitable amine.
Table 13
(311) 5-phenyl-3-[1-(3-thienyl sulphonyl base) piperidin-4-yl]-1H-indole-7-Methanamide
CHCl to 5-phenyl-3-(4-piperidyl)-1H-indole-7-Methanamide (31mg/0.067mmol)
3(1.0ml) add diisopropylethylamine (3eq) in the solution.Mixture is cooled to-10 ℃, and joins then in the 3-thiophene sulfonic acid chloride.With this agitation 1.5h.Use aminopropyl post (500mg) to carry out Solid-Phase Extraction (SPE), and use CHCl
3Use eluent ethyl acetate subsequently, obtain title compound (19mg, 61%).LC/MS：m/z?465?Rt?2.29min。
According to the conventional method described in the embodiment 311, but replace 3-thiophene sulfonic acid chloride, listed chemical compound in the preparation table 14 with suitable sulfonic acid chloride.
Table 14
Biological data
The IKK2 test
With the formal representation of the fusion rotein of the terminal GST-labelling of C-, estimate by (resolved) FRET (fluorescence resonance energy transfer) (TR-FRET) test that differentiate its active service time in baculovirus for recombined human IKK β (residue 1-737).Briefly, will be diluted in test buffer (50mM HEPES, 10mMMgCl
2, 1mM CHAPS pH 7.4 contains 1mM DTT and 0.01%w/v BSA) in IKK2 (5nM ultimate density) join in the hole of containing variable concentrations chemical compound or DMSO carrier (3% ultimate density).By adding GST-I κ B α substrate (25nM ultimate density)/ATP (1 μ M ultimate density) to cumulative volume 30 μ l and initiation reaction.Reactant was at room temperature hatched 30 minutes, stopped by the 50mMEDTA that adds 15 μ l then.Be added in and contain useful W-1024 europium chelate (Wallac OY, Turku, Finland) the anti-phosphoserine of labelling-I κ B α-32/36 monoclonal antibody 12C2 (Cell SignallingTechnology, Beverly Massachusetts, USA) buffer (100mM HEPES pH 7.4,150mM NaCl and 0.1%w/v BSA) in detectable (15 μ l) and anti--GST antibody (Prozyme of APC labelling, San Leandro, California, USA), described reactant was at room temperature cultivated 60 minutes again.(Perkin-Elmer Life Sciences, Pangbourne UK), with the ratio of specific 665nm energy delivery signal to reference europium 620nm signal, measure the phosphorylation degree of GST-I κ B α to use Packard Discovery to read the plate instrument.
The result
The anti-IKK2 activity of the chemical compound of test implementation example 1-36,38,40-108,110-173,175-183,185-198,200,202-204,206-210,213-247,259-258,262-280,284-289,291-306 and 308-316, and find it all is the IKK2 inhibitor.These embodiment have 5.0 or bigger plC
50Also tested the anti-IKK2 activity of embodiment 249, and found to have plC less than 4.6
50
The mononuclear cell test
IKK-β estimates according to following the inhibitory action that person monocytic cell's stimulated cells factor generates: by separating in the whole blood of ficoll gradient by heparinization, use MACS magnetic method cell separation pearl that the CD14+ cell is carried out purification subsequently mononuclear cell.Then with the mononuclear cell separated in RPMI 1,640 10% FBS (JRH Biosciences, Lenexa KS) with 1 * 10
6Cell/mL is attached to 96-well culture plate last 2 hour with further enrichment mononuclear cell number.Remove culture medium then, cell is washed once with RPMI 1640, and 0.125mL RPMI 1640 10%FBS are joined in the hole.Stimulated preceding 30 minutes at final carrier concn, test compounds is joined in the hole with 0.1%DMSO.By adding 200ng/mL endotoxin (LPS; E.coli serotype 026:B6) (Sigma, St.Louis MO.) come activated monocyte, and cultivate 24 hours down at 37 ℃.Use the paired Abs of Pharmingen to analyze TNF-α in the acellular supernatant by ELISA.The viability of cell is determined by the repulsion of 10% trypan blue.
The result
The chemical compound of embodiment 1-26,28-76,80-81,83-94,96-116,118-119,122-151,153-165,167-183,186-196,198,200,202-204,206-209,213-226,228-258,262-265,267-280,283,286,290,306-308,310-312 and 314-316 is all carried out the mononuclear cell test.Embodiment 1-26,28-37,39-47,49-55,57-76,81,83-85,91-92,94,96,103,105-106,108-109,110-116,118-119,122-130,132-151,153-158,160,164-165,174-176,178-183,187-192,194-195,200,202-204,206-209,213-226,228-246,251-256,262-265,267-268,271-280,290,310-312 and 314-316 have the IC50 less than 10 μ M.
Claims (25)
1. according to the chemical compound of formula I, or its pharmaceutically acceptable salt, solvate or polymorph:
Wherein:
R1 is H, halogen or group-YZ;
R2 is H, fluorine or chlorine;
R3 is H, fluorine or chlorine;
Y is chemical bond, C
1-C
6Alkylidene, C
2-C
6Alkenylene or C
2-C
6Alkynylene;
Z is optional aryl that replaces or the optional heteroaryl that replaces,
Wherein said aryl and heteroaryl are optional to be replaced by one to three substituent group, and described substituent group is independently selected from: halo ,-CN ,-N (Rb) SO
2Re ,-N (Rb) C (O) Ra ,-C (O) NRaRb ,-C (O) NRfRg ,-C (O) H ,-SO
2Ri ,-NRaRb ,-SO
2NRaRb ,-SO
2NRfRg ,-ORc ,-N (Rb) C (O) NRaRb ,-N (Rb) C (O) NRfRg ,-N (Rb) C (O) ORd, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by 1-3
1-C
6Alkyl :-NRaRb, C
3-C
6Cycloalkyl, phenyl ,-ORc, Heterocyclylalkyl and by OH ,-C (O) NH
2Perhaps one or two C
1-C
6The Heterocyclylalkyl that alkyl replaces; C
1-C
6Haloalkyl is independently selected from the following C that substituent group replaced by 1-3
1-C
6Haloalkyl :-NRaRb, C
3-C
6Cycloalkyl, phenyl, Heterocyclylalkyl and by one or two C
1-C
6The Heterocyclylalkyl that alkyl replaces; Heterocyclylalkyl and by one or two C
1-C
6The Heterocyclylalkyl that alkyl replaces;
U is chemical bond, C
1-C
6Alkylidene or C
2-C
6Alkenylene;
V is phenyl, 5 or 6 Yuans heteroaryls, 5-7 element heterocycle alkyl, C
5-C
7Cycloalkyl or C
5-C
7Cycloalkenyl group, its each quilt-N (Rb) S (O)
mR4 ,-S (O)
mN (Rb) R4 or-S (O)
mR4 replaces;
M is 1 or 2;
R4 is group-X-R5;
X is chemical bond, C
1-C
6Alkylidene, C
2-C
6Alkenylene, C
2-C
6Alkynylene, aryl, C
1-C
6Alkylidene-aryl, heteroaryl, C
1-C
6Alkylidene-heteroaryl, Heterocyclylalkyl, C
1-C
6Alkylidenyl-heterocyclic alkyl, C
4-C
7Cycloalkyl, C
1-C
6Alkylidene-C
4-C
7Cycloalkyl, C
5-C
7Cycloalkenyl group or C
1-C
6Alkylidene-C
5-C
7Cycloalkenyl group;
R5 is-NRaRb ,-ORj, the optional Heterocyclylalkyl that replaces or the optional heteroaryl that replaces,
The Heterocyclylalkyl of wherein said optional replacement and the optional heteroaryl that replaces be optional to be independently selected from following substituent group by one to three and to replace: halo, heteroaryl, oxo base ,-CN ,-C (O) Ra ,-N (Rb) SO
2Re ,-N (Rb) C (O) Ra ,-NRaRb ,-C (O) NRaRb ,-C (O) NRfRg ,-SO
2NRaRb ,-SO
2NRfRg ,-ORc ,-C (O) ORc ,-N (Rb) C (O) NRaRb ,-N (Rb) C (O) NRfRg ,-N (Rb) C (O) ORd, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl :-NRaRb ,-ORc ,-C (O) NRaRb ,-C (O) Rc, C
3-C
6Cycloalkyl, Heterocyclylalkyl and phenyl; C
1-C
6Haloalkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Haloalkyl :-NRaRb ,-ORc ,-C (O) NRaRb, C
3-C
6Cycloalkyl, Heterocyclylalkyl and phenyl; Heterocyclylalkyl is independently selected from the following Heterocyclylalkyl that substituent group replaced: C by one to three
1-C
6Alkyl, halo ,-ORc, haloalkyl, CN and-SO
2Ri; Phenyl, and be independently selected from the following phenyl that substituent group replaced by one to three: halo ,-ORc, haloalkyl ,-CN and-SO
2Ri;
Each Ra is independently selected from: H ,-ORh, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl: halo ,-CN ,-C (O) NH
2,-NRkRk ,-SO
2Ri ,-N (Rb) SO
2Re ,-C (O) ORb ,-N (Rb) C (O) Rb ,-ORc ,-SRc, C
3-C
7Cycloalkyl, C
1-C
6Haloalkyl, Heterocyclylalkyl, phenyl, phenylol and heteroaryl; Phenyl is independently selected from the following phenyl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl ,-ORc and-NRfRg; Heteroaryl is independently selected from the following heteroaryl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl ,-ORc and-NRfRg; C
3-C
7Cycloalkyl is independently selected from the following C that substituent group replaced by one to three
3-C
7Cycloalkyl: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl ,-ORc and-NRfRg; Heterocyclylalkyl, and be independently selected from the following Heterocyclylalkyl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl ,-CH
2C (O) Rb, C
1-C
6Haloalkyl ,-C (O) ORb, NH
2, heteroaryl ,-ORc and NRfRg;
Each Rb is independently selected from: H, C
1-C
6Alkyl is by one-C that ORc replaced
1-C
6Alkyl, and C
3-C
7Cycloalkyl;
Each Rc is independently selected from: H, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl: OH, C
3-C
6Cycloalkyl, phenyl, Heterocyclylalkyl and heteroaryl; C
1-C
6Haloalkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Haloalkyl: OH, C
3-C
6Cycloalkyl, phenyl, Heterocyclylalkyl and heteroaryl; C
3-C
7Cycloalkyl is by one to three C
1-C
3The C that alkyl replaced
3-C
7Cycloalkyl; Heterocyclylalkyl is by one to three C
1-C
3The Heterocyclylalkyl that alkyl replaced; Aryl is independently selected from the following aryl that substituent group replaced by one to three: halo, C
1-C
3Alkyl, C
1-C
3Haloalkyl and OH; Heteroaryl, and be independently selected from the following heteroaryl that substituent group replaced by one to three: halo, C
1-C
3Alkyl, C
1-C
3Haloalkyl and OH;
Each Rd is the optional C that replaces independently
1-C
3Alkyl, wherein said C
1-C
3Alkyl is optional to be selected from following substituent group by one to three and to replace: C
3-C
6Cycloalkyl, Heterocyclylalkyl, the optional phenyl that replaces and the optional heteroaryl that replaces; Wherein said phenyl and heteroaryl be optional to be selected from following substituent group by one to three and to replace: halo, C
1-C
6Alkyl and C
3-C
6Cycloalkyl;
Each Re is independently selected from: C
1-C
6Alkyl is selected from the following C that substituent group replaced by one
1-C
6Alkyl: phenyl, heteroaryl, Heterocyclylalkyl and NRaRb; Phenyl is selected from the following phenyl that substituent group replaced by one to three: halo, CN, C
1-C
6Alkyl, C
1-C
6Haloalkyl and ORh; Heteroaryl is selected from the following heteroaryl that substituent group replaced by one to three: halo, CN, C
1-C
6Alkyl, C
1-C
6Haloalkyl and-ORh; C
5-C
7Cycloalkyl is selected from the following C that substituent group replaced by one to three
5-C
7Cycloalkyl: halo, C
1-C
6Alkyl and C
3-C
6Cycloalkyl; Heterocyclylalkyl, and be selected from the following Heterocyclylalkyl that substituent group replaced by one to three: halo, C
1-C
6Alkyl and C
3-C
6Cycloalkyl;
Rf forms the ring with 5-7 member's atom with the nitrogen-atoms that Rg links to each other with them, wherein said ring is optional to contain other a hetero atom as member's atom, described ring is saturated or undersaturated but is not aromatic, and described ring is optional by one or two C
1-C
3Alkyl substituent replaces;
Each Rh is independently selected from: H, C
1-C
6Alkyl and C
1-C
6Haloalkyl;
Each Ri is independently selected from: C
1-C
3Alkyl and phenyl;
Rj is selected from H, the optional C that replaces
1-C
6Alkyl, C
1-C
6Haloalkyl, heteroaryl and the optional phenyl that replaces,
The C of wherein said optional replacement
1-C
6Alkyl is optional to be replaced by one or two substituent group, and each substituent group is independently selected from following: hydroxyl, C
1-C
6Alkoxyl ,-OCH
2CH
2N (CH
3)
2, methyl mercapto, C
3-C
6Cycloalkyl is by a C
1-C
3The C that alkyl replaced
3-C
6Cycloalkyl; Heterocyclylalkyl is by a C
1-C
3Alkyl, an oxo base or the Heterocyclylalkyl that the 4-luorobenzyl is replaced;-NRkRk, heteroaryl ,-NHC (O) CH
3With-S (O)
2Ri;
Wherein said phenyl is optional to be replaced by one to three substituent group, and each substituent group is independently selected from following: C
1-C
3Alkoxyl ,-NHC (O) CH
3,-C (O) NH
2, halo, CF
3,-S (O)
2Ri ,-S (O)
2NHRi, hydroxyl ,-C
1-C
3-alkyl-NRkRk ,-NRkRk, C
1-C
3Alkyl, Heterocyclylalkyl, and by one-C (O) CH
3The Heterocyclylalkyl that group replaced; With
Each Rk is independently selected from: H, C
1-C
6Alkyl is by the C that one or two hydroxyl replaced
1-C
6Alkyl; Phenyl, and by a C
1-C
3The phenyl that alkyl replaced.
2. according to the chemical compound of claim 1, or its pharmaceutically acceptable salt, solvate or polymorph, wherein:
Z is optional aryl that replaces or the optional heteroaryl that replaces,
Wherein said aryl and heteroaryl be optional to be independently selected from following substituent group by one to three and to replace: halo ,-CN ,-N (Rb) SO
2Re ,-N (Rb) C (O) Ra ,-C (O) NRaRb ,-C (O) NRfRg ,-C (O) H ,-SO
2Ri ,-NRaRb ,-SO
2NRaRb ,-SO
2NRfRg ,-ORc ,-N (Rb) C (O) NRaRb ,-N (Rb) C (O) NRfRg ,-N (Rb) C (O) ORd, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl :-NRaRb, C
3-C
6Cycloalkyl, phenyl ,-ORc, Heterocyclylalkyl and by one or two C
1-C
6The Heterocyclylalkyl that alkyl replaced; C
1-C
6Haloalkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Haloalkyl :-NRaRb, C
3-C
6Cycloalkyl, phenyl, Heterocyclylalkyl and by one or two C
1-C
6The Heterocyclylalkyl that alkyl replaced; Heterocyclylalkyl and by one or two C
1-C
6The Heterocyclylalkyl that alkyl replaced;
Each Ra is independently selected from: H, C
2-C
6Alkenyl, C
2-C
6Alkynyl, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl: halo ,-CN ,-C (O) NH
2,-NRkRk ,-SO
2Ri ,-N (Rb) SO
2Re ,-C (O) ORb ,-N (Rb) C (O) Rb ,-ORc ,-SRc, C
3-C
7Cycloalkyl, C
1-C
6Haloalkyl, Heterocyclylalkyl, phenyl, phenylol and heteroaryl; Phenyl is independently selected from the following phenyl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl ,-ORc and-NRfRg; Heteroaryl is independently selected from the following heteroaryl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl ,-ORc and-NRfRg; C
3-C
7Cycloalkyl is independently selected from the following C that substituent group replaced by one to three
3-C
7Cycloalkyl: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl ,-ORc and-NRfRg; Heterocyclylalkyl, and be independently selected from the following Heterocyclylalkyl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl ,-CH
2C (O) Rb, C
1-C
6Haloalkyl ,-C (O) ORb, NH
2, heteroaryl ,-ORc and NRfRg; With
Rj is selected from H, the optional C that replaces
1-C
6Alkyl, C
1-C
6Haloalkyl, heteroaryl and the optional phenyl that replaces,
The C of wherein said optional replacement
1-C
6Alkyl is optional to be replaced by one or two substituent group, and each substituent group is independently selected from following: hydroxyl, methyl mercapto, C
3-C
6Cycloalkyl is by a C
1-C
3The C that alkyl replaced
3-C
6Cycloalkyl; Heterocyclylalkyl is by a C
1-C
3Alkyl, an oxo base or the Heterocyclylalkyl that the 4-luorobenzyl is replaced;-NRkRk, heteroaryl ,-NHC (O) CH
3With-S (O)
2Ri;
Wherein said phenyl is optional to be replaced by one to three substituent group, and each substituent group is independently selected from following: C
1-C
3Alkoxyl ,-NHC (O) CH
3,-C (O) NH
2, halo, CF
3,-S (O)
2Ri ,-S (O)
2NHRi, hydroxyl ,-C
1-C
3-alkyl-NRkRk ,-NRkRk, C
1-C
3Alkyl, Heterocyclylalkyl, and by one-C (O) CH
3The Heterocyclylalkyl that group replaced.
3. according to the chemical compound of claim 1, or its pharmaceutically acceptable salt, solvate or polymorph, wherein:
R1 is group-YZ;
Y is a chemical bond;
Z is optional phenyl that replaces or the optional heteroaryl that replaces,
Wherein said phenyl and heteroaryl be optional to be selected from following substituent group by one or two and to replace: halo, cyano group ,-N (Rb) SO
2Re ,-N (Rb) C (O) Ra, C
1-C
6Alkyl, and be selected from the following C that substituent group replaced by one
1-C
6Alkyl :-NRaRb ,-ORc, Heterocyclylalkyl and by a C
1-C
3The Heterocyclylalkyl that alkyl replaced;
R2 is H;
R3 is H;
U is a chemical bond;
V is phenyl or 5 or 6 Yuans heteroaryls, its each quilt-N (Rb) S (O)
mR4 ,-S (O)
mN (Rb) R4 or-S (O)
mR4 replaces;
M is 1 or 2;
R4 is radicals X-R5;
X is chemical bond, C
1-C
6Alkylidene, heteroaryl or C
1-C
6The alkylidenyl-heterocyclic alkyl;
R5 is NRaRb, ORj, the optional Heterocyclylalkyl that replaces or the optional heteroaryl that replaces,
Wherein said Heterocyclylalkyl and heteroaryl be optional to be independently selected from following substituent group by one to three and to replace: halo, and-C (O) Ra ,-NRaRb, Heterocyclylalkyl is by a C
1-C
6The Heterocyclylalkyl that alkyl replaced; Phenyl, C
1-C
6Alkyl is selected from the following C that substituent group replaced by one or two
1-C
6Alkyl :-ORc ,-C (O) Rc ,-C (O) NRaRb and phenyl; Heteroaryl, the oxo base, N (Rb) C (O) Ra ,-ORc ,-C (O) NRaRb and-C (O) ORc;
Each Ra is independently selected from: H, Heterocyclylalkyl, the Heterocyclylalkyl that is replaced by one-C (O) ORb group; C
2-C
6Alkynyl, the optional C that replaces
1-C
6Alkyl, C
3-C
6Cycloalkyl, the C that is replaced by one-ORc group
3-C
7Cycloalkyl, and phenyl, the C of wherein said optional replacement
1-C
6Alkyl is optional to be selected from following substituent group by one to three and to replace: halo, heteroaryl, Heterocyclylalkyl ,-ORc, N (Rb) SO
2Re ,-N (Rk)
2, C
3-C
7Cycloalkyl, phenyl and phenylol;
Each Rb is independently selected from: H, C
1-C
6Alkyl, the C that is replaced by one-ORc group
1-C
6Alkyl;
Each Rc is independently selected from: H, C
1-C
6Alkyl, Heterocyclylalkyl and aryl;
Each Re is independently selected from: C
1-C
6Alkyl, phenyl, and by a C
1-C
6The phenyl that alkyl replaced;
Each Ri is independently selected from: C
1-C
3Alkyl and phenyl;
Rj is selected from H, the optional C that replaces
1-C
6Alkyl, C
1-C
6Haloalkyl, heteroaryl and the optional phenyl that replaces,
The C of wherein said optional replacement
1-C
6Alkyl is optional to be replaced by one or two substituent group, and each substituent group is independently selected from following: hydroxyl, methyl mercapto, C
3-C
6Cycloalkyl is by a C
1-C
3The C that alkyl replaced
3-C
6Cycloalkyl; Heterocyclylalkyl is by a C
1-C
3Alkyl, an oxo base or the Heterocyclylalkyl that the 4-luorobenzyl is replaced;-NRkRk, heteroaryl ,-NHC (O) CH
3With-S (O)
2Ri;
Wherein said phenyl is optional to be replaced by one to three substituent group, and each substituent group is independently selected from following: C
1-C
3Alkoxyl ,-NHC (O) CH
3,-C (O) NH
2, halo, CF
3,-S (O)
2Ri ,-S (O)
2NHRi, hydroxyl ,-C
1-C
3-alkyl-NRkRk ,-NRkRk, C
1-C
3Alkyl, Heterocyclylalkyl, and by one-C (O) CH
3The Heterocyclylalkyl that group replaced; With
Each Rk is independently selected from H, C
1-C
6Alkyl.
4. according to the chemical compound of claim 1, or its pharmaceutically acceptable salt, solvate or polymorph, wherein:
R1 is group-YZ;
Y is a chemical bond;
Z is optional phenyl that replaces or the optional heteroaryl that replaces,
Wherein said phenyl and heteroaryl be optional to be selected from following substituent group by one or two and to replace: halo, cyano group ,-N (Rb) SO
2Re ,-N (Rb) C (O) Ra, C
1-C
6Alkyl, and be selected from the following C that substituent group replaced by one
1-C
6Alkyl :-NRaRb ,-ORc, Heterocyclylalkyl and by an OH ,-C (O) NH
2Or C
1-C
3The Heterocyclylalkyl that alkyl replaced;
R2 is H;
R3 is H;
U is a chemical bond;
V is
M is 2;
R4 is group-X-R5;
X is chemical bond or C
1-C
6Alkylidene;
R5 is-NRaRb, the optional Heterocyclylalkyl that replaces or the optional heteroaryl that replaces,
Wherein said Heterocyclylalkyl and heteroaryl be optional to be independently selected from following substituent group by one to three and to replace: halo, and-C (O) Ra ,-NRaRb, Heterocyclylalkyl is by a C
1-C
6The Heterocyclylalkyl that alkyl replaced; Phenyl, C
1-C
6Alkyl is selected from the following C that substituent group replaced by one or two
1-C
6Alkyl :-ORc ,-C (O) Rc ,-C (O) NRaRb and phenyl; Heteroaryl, the oxo base, N (Rb) C (O) Ra ,-ORc ,-C (O) NRaRb and-C (O) ORc;
Each Ra is independently selected from: H ,-ORh, Heterocyclylalkyl, the Heterocyclylalkyl that is replaced by one-C (O) ORb group; C
2-C
6Alkynyl, the optional C that replaces
1-C
6Alkyl, C
3-C
6Cycloalkyl, the C that is replaced by one-ORc group
3-C
7Cycloalkyl, and phenyl, the C of wherein said optional replacement
1-C
6Alkyl is optional to be selected from following substituent group by one to three and to replace: halo, heteroaryl, Heterocyclylalkyl ,-ORc, N (Rb) SO
2Re ,-N (Rk)
2, C
3-C
7Cycloalkyl, phenyl and phenylol;
Each Rb is independently selected from: H, C
1-C
6Alkyl, the C that is replaced by one-ORc group
1-C
6Alkyl;
Each Rc is independently selected from: H, C
1-C
6Alkyl, Heterocyclylalkyl and aryl;
Each Re is independently selected from: C
1-C
6Alkyl, phenyl and by a C
1-C
6The phenyl that alkyl replaced;
Each Rh is independently selected from: H, C
1-C
6Alkyl and C
1-C
6Haloalkyl; And
Each Rk is independently selected from H, C
1-C
6Alkyl.
5. according to the chemical compound of claim 4, or its pharmaceutically acceptable salt, solvate or polymorph, wherein:
Z is optional phenyl that replaces or the optional heteroaryl that replaces,
Wherein said phenyl and heteroaryl be optional to be selected from following substituent group by one or two and to replace: halo, cyano group ,-N (Rb) SO
2Re ,-N (Rb) C (O) Ra, C
1-C
6Alkyl, and be selected from the following C that substituent group replaced by one
1-C
6Alkyl :-NRaRb ,-ORc, Heterocyclylalkyl and by a C
1-C
3The Heterocyclylalkyl that alkyl replaced; With
Each Ra is independently selected from: H, Heterocyclylalkyl, the Heterocyclylalkyl that is replaced by one-C (O) ORb group; C
2-C
6Alkynyl, the optional C that replaces
1-C
6Alkyl, C
3-C
6Cycloalkyl, the C that is replaced by one-ORc group
3-C
7Cycloalkyl, and phenyl, the C of wherein said optional replacement
1-C
6Alkyl is optional to be selected from following substituent group by one to three and to replace: halo, heteroaryl, Heterocyclylalkyl ,-ORc, N (Rb) SO
2Re ,-N (Rk)
2, C
3-C
7Cycloalkyl, phenyl and phenylol.
6. according to the chemical compound of claim 1, or its pharmaceutically acceptable salt, solvate or polymorph, wherein:
R1 is group-YZ;
Y is a chemical bond;
Z is a phenyl;
R2 is H;
R3 is H;
U is a chemical bond;
V is
M is 2;
R4 is radicals X-R5;
X is chemical bond or C
1-C
6Alkylidene;
R5 is-ORj;
Each Ri is independently selected from: C
1-C
3Alkyl and phenyl;
Rj is selected from H, the optional C that replaces
1-C
6Alkyl, C
1-C
6Haloalkyl, heteroaryl and the optional phenyl that replaces,
The C of wherein said optional replacement
1-C
6Alkyl is optional to be replaced by one or two substituent group, and each substituent group is independently selected from following: hydroxyl, C
1-C
6Alkoxyl ,-OCH
2CH
2N (CH
3)
2, methyl mercapto, C
3-C
6Cycloalkyl is by a C
1-C
3The C that alkyl replaced
3-C
6Cycloalkyl; Heterocyclylalkyl is by a C
1-C
3Alkyl, an oxo base or the Heterocyclylalkyl that the 4-luorobenzyl is replaced;-NRkRk, heteroaryl ,-NHC (O) CH
3With-S (O)
2Ri;
Wherein said phenyl is optional to be replaced by one to three substituent group, and each substituent group is independently selected from following: C
1-C
3Alkoxyl ,-NHC (O) CH
3,-C (O) NH
2, halo, CF
3,-S (O)
2Ri ,-S (O)
2NHRi, hydroxyl ,-C
1-C
3-alkyl-NRkRk ,-NRkRk, C
1-C
3Alkyl, Heterocyclylalkyl and by one-C (O) CH
3The Heterocyclylalkyl that group replaced; With
Each Rk is independently selected from: H, C
1-C
6Alkyl is by the C that one or two hydroxyl replaced
1-C
6Alkyl; Phenyl, and by a C
1-C
3The phenyl that alkyl replaced.
7. according to the chemical compound of claim 6, or its pharmaceutically acceptable salt, solvate or polymorph, wherein:
Rj is selected from H, the optional C that replaces
1-C
6Alkyl, C
1-C
6Haloalkyl, heteroaryl and the optional phenyl that replaces,
The C of wherein said optional replacement
1-C
6Alkyl is optional to be replaced by one or two substituent group, and each substituent group is independently selected from following: hydroxyl, methyl mercapto, C
3-C
6Cycloalkyl is by a C
1-C
3The C that alkyl replaced
3-C
6Cycloalkyl; Heterocyclylalkyl is by a C
1-C
3Alkyl, an oxo base or the Heterocyclylalkyl that the 4-luorobenzyl is replaced;-NRkRk, heteroaryl ,-NHC (O) CH
3With-S (O)
2Ri;
Wherein said phenyl is optional to be replaced by one to three substituent group, and each substituent group is independently selected from following: C
1-C
3Alkoxyl ,-NHC (O) CH
3,-C (O) NH
2, halo, CF
3,-S (O)
2Ri ,-S (O)
2NHRi, hydroxyl ,-C
1-C
3-alkyl-NRkRk ,-NRkRk, C
1-C
3Alkyl, Heterocyclylalkyl and by one-C (O) CH
3The Heterocyclylalkyl that group replaced.
8. according to the chemical compound of formula Ia, or its pharmaceutically acceptable salt, solvate or polymorph:
R wherein
1Be H, halogen or group-YZ;
Y is chemical bond, C
1-C
6Alkylidene, C
2-C
6Alkenylene or C
2-C
6Alkynylene;
Z is optional aryl that replaces or the optional heteroaryl that replaces,
Wherein said aryl and heteroaryl be optional to be independently selected from following substituent group by one to three and to replace: halo, CN, N (Rb) SO
2Re, N (Rb) C (O) Ra, C (O) NRaRb, C (O) NRfRg, SO
2NRaRb, SO
2NRfRg, ORc, N (Rb) C (O) NRaRb, N (Rb) C (O) NRfRg, N (Rb) C (O) ORd, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl: NRaRb, C
3-C
6Cycloalkyl, phenyl, Heterocyclylalkyl and by one or two C
1-C
6The Heterocyclylalkyl that alkyl replaced; C
1-C
6Haloalkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Haloalkyl: NRaRb, C
3-C
6Cycloalkyl, phenyl, Heterocyclylalkyl and by one or two C
1-C
6The Heterocyclylalkyl that alkyl replaced; Heterocyclylalkyl, and by one or two C
1-C
6The Heterocyclylalkyl that alkyl replaced;
U is chemical bond, C
1-C
6Alkylidene or C
2-C
6Alkenylene;
V is phenyl, 5 or 6 Yuans heteroaryls, 5-7 element heterocycle alkyl, C
5-C
7Cycloalkyl or C
5-C
7Cycloalkenyl group, its each by N (Rb) S (O)
mR
2Replace; Perhaps V is N (Rb) S (O)
mR
2,
M is 1 or 2;
R
2Be radicals X-R
3
X is chemical bond, C
1-C
6Alkylidene, C
2-C
6Alkenylene, C
2-C
6Alkynylene, aryl, C
1-C
6Alkylidene-aryl, heteroaryl, C
1-C
6Alkylidene-heteroaryl, Heterocyclylalkyl, C
1-C
6Alkylidenyl-heterocyclic alkyl, C
4-C
7Cycloalkyl, C
1-C
6Alkylidene-C
4-C
7Cycloalkyl, C
5-C
7Cycloalkenyl group or C
1-C
6Alkylidene-C
5-C
7Cycloalkenyl group;
R
3Be NRaRb, the optional Heterocyclylalkyl that replaces or the optional heteroaryl that replaces;
Wherein said Heterocyclylalkyl and heteroaryl be optional to be independently selected from following substituent group by one to three and to replace: halo, Heterocyclylalkyl, oxo base, CN, C (O) Ra, N (Rb) SO
2Re, N (Rb) C (O) Ra, NRaRb, C (O) NRaRb, C (O) NRfRg, SO
2NRaRb, SO
2NRfRg, ORc, C (O) ORc, N (Rb) C (O) NRaRb, N (Rb) C (O) NRfRg, N (Rb) C (O) ORd, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl: NRaRb, ORc, C (O) NRaRb, C
3-C
6Cycloalkyl, Heterocyclylalkyl and phenyl; C
1-C
6Haloalkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Haloalkyl: NRaRb, ORc, C (O) NRaRb, C
3-C
6Cycloalkyl, Heterocyclylalkyl and phenyl; Heterocyclylalkyl is independently selected from the following Heterocyclylalkyl that substituent group replaced by one to three: halo, ORc, haloalkyl, CN and SO
2Ri; Phenyl, and be independently selected from the following phenyl that substituent group replaced by one to three: halo, ORc, haloalkyl, CN and SO
2Ri;
Each Ra is independently selected from: H, C
2-C
6Alkenyl, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl: halo, CN, C (O) NH
2, N (CH
3)
2, SO
2Ri, C (O) ORb, N (Rb) C (O) Rb, ORc, SRc, C
3-C
7Cycloalkyl, C
1-C
6Haloalkyl, Heterocyclylalkyl, phenyl and heteroaryl; Phenyl is independently selected from the following phenyl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl, ORc and NRfRg; Heteroaryl is independently selected from the following heteroaryl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl, ORc and NRfRg; C
3-C
7Cycloalkyl is independently selected from the following C that substituent group replaced by one to three
3-C
7Cycloalkyl: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl, ORc and NRfRg; Heterocyclylalkyl, and be independently selected from the following Heterocyclylalkyl that substituent group replaced by one to three: halo, oxo base, C
1-C
6Alkyl, C
1-C
6Haloalkyl, NH
2, heteroaryl, ORc and NRfRg;
Each Rb is independently selected from: H, C
1-C
3Alkyl and C
3-C
7Cycloalkyl;
Each Rc is independently selected from: H, C
1-C
6Alkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Alkyl: OH, C
3-C
6Cycloalkyl, phenyl, Heterocyclylalkyl and heteroaryl; C
1-C
6Haloalkyl is independently selected from the following C that substituent group replaced by one to three
1-C
6Haloalkyl: OH, C
3-C
6Cycloalkyl, phenyl, Heterocyclylalkyl and heteroaryl; C
3-C
7Cycloalkyl is by one to three C
1-C
3The C that alkyl replaced
3-C
7Cycloalkyl; Heterocyclylalkyl is by one to three C
1-C
3The Heterocyclylalkyl that alkyl replaced; Aryl is independently selected from the following aryl that substituent group replaced by one to three: halo, C
1-C
3Alkyl, C
1-C
3Haloalkyl and OH; Heteroaryl, and be independently selected from the following heteroaryl that substituent group replaced by one to three: halo, C
1-C
3Alkyl, C
1-C
3Haloalkyl and OH;
Each Rd is the optional C that replaces independently
1-C
3Alkyl, wherein said C
1-C
3Alkyl is optional to be selected from following substituent group by one to three and to replace: C
3-C
6Cycloalkyl, the optional phenyl that replaces, and the optional heteroaryl that replaces; Wherein said phenyl and heteroaryl be optional to be selected from following substituent group by one to three and to replace: halo, C
1-C
6Alkyl and C
3-C
6Cycloalkyl;
Each Re is independently selected from: C
1-C
6Alkyl is selected from the following C that substituent group replaced by one
1-C
6Alkyl: phenyl, heteroaryl, Heterocyclylalkyl and NRaRb; Phenyl is selected from the following phenyl that substituent group replaced by one to three: halo, CN, C
1-C
6Alkyl, C
1-C
6Haloalkyl and ORh; Heteroaryl is selected from the following heteroaryl that substituent group replaced by one to three: halo, CN, C
1-C
6Alkyl, C
1-C
6Haloalkyl and ORh; C
5-C
7Cycloalkyl is selected from the following C that substituent group replaced by one to three
5-C
7Cycloalkyl: halo, C
1-C
6Alkyl and C
3-C
6Cycloalkyl; Heterocyclylalkyl, and be selected from the following Heterocyclylalkyl that substituent group replaced by one to three: halo, C
1-C
6Alkyl and C
3-C
6Cycloalkyl;
Rf forms the ring with 5-7 member's atom with the nitrogen-atoms that Rg links to each other with them, wherein said ring is optional to contain other a hetero atom as member's atom, described ring is saturated or undersaturated but is not aromatic, and described ring is optional by one or two C
1-C
3Alkyl substituent replaces;
Each Rh is independently selected from: H, C
1-C
6Alkyl and C
1-C
6Haloalkyl; With
Each Ri is independently selected from: C
1-C
3Alkyl and OH.
9. chemical compound according to Claim 8, or its pharmaceutically acceptable salt, solvate or polymorph, wherein:
R1 is group-YZ;
Y is a chemical bond;
Z is a heteroaryl, phenyl or be selected from the following phenyl that substituent group replaced by: halo, N (Rb) SO
2Re, SO
2NRaRb, C
1-C
6Alkyl and be selected from the following C that substituent group replaced by one
1-C
6Alkyl: NRaRb, Heterocyclylalkyl and by a C
1-C
3The Heterocyclylalkyl that alkyl replaced;
U is a chemical bond;
V is
M is 2;
R
2Be radicals X-R
3
X is chemical bond or C
1-C
6Alkylidene;
R
3Be NRaRb, the optional Heterocyclylalkyl that replaces or the optional heteroaryl that replaces;
Wherein said Heterocyclylalkyl and heteroaryl be optional to be independently selected from following substituent group by one to three and to replace: halo, the optional C that replaces
1-C
6Alkyl, heteroaryl, oxo base, N (Rb) C (O) Ra, ORc and C (O) ORc; Wherein said C
1-C
6Alkyl is optional to be replaced by a NRaRb group;
Each Ra is independently selected from: H, the optional C that replaces
1-C
3Alkyl and phenyl, wherein said C
1-C
3Alkyl is optional to be replaced by one to three substituent group that is selected from halo and phenyl:;
Each Rb is independently selected from: H and C
1-C
3Alkyl;
Each Rc is independently selected from: H, C
1-C
6Alkyl and aryl; With
Each Re is independently selected from: C
1-C
6Alkyl and phenyl.
10. according to the chemical compound of claim 1, it is:
The 3-{1-[(2-amino-ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(dimethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-methyl isophthalic acid-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[3-(piperidino) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(2-methyl isophthalic acid-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-hydroxyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(cyclopenta amino) ethyl] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(1-pyrrolidinyl) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(dimethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(cyclopenta amino) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(4-hydroxyl-piperidino) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
The 3-{1-[(2-hydroxyethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
5-(5-chloro-2-thienyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[2-(methylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[2-(piperidino) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[2-(4-methyl isophthalic acid-piperazinyl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[[2-(dimethylamino) ethyl] and (methyl) amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(4-morpholinyl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[3-(2-hydroxyethyl)-1-piperazinyl] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(cyclopenta amino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(cyclobutyl amino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-[1-(the 2-[(phenyl methyl) and amino] ethyl } sulfonyl)-the 4-piperidyl]-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[2-(1-pyrrolidinyl) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[2-(4-hydroxyl-piperidino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[[3-(dimethylamino) propyl group] and (methyl) amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(1,4 '-Lian piperidines-1 '-yl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(diethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[2-(2-phenyl-1-pyrrolidinyl) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[2-(six hydrogen-1H-azepine -1-yl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(cyclohexyl methyl) and amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-hydroxyl-1-(hydroxymethyl) ethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(ethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[ethyl (methyl) amino] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(2-hydroxyethyl) and amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[(2S)-and the 2-hydroxypropyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[(1S)-and 2-hydroxyl-1-Methylethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[(1R)-and 2-hydroxyl-1-Methylethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[4-(amino carbonyl)-piperidino] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[4-(4-morpholinyl)-piperidino] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(dimethylamino) ethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(the 4-methyl isophthalic acid, 4 '-Lian piperidines-1 '-yl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[4-(4-methyl isophthalic acid-piperazinyl)-piperidino] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(methoxyl group) ethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[3-(4-morpholinyl) propyl group] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(4-acetyl group-1-piperazinyl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[4-(2-hydroxyethyl)-1-piperazinyl] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[3-(hydroxymethyl)-piperidino] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(2-{[(4-aminomethyl phenyl) and sulfonyl] amino } ethyl) amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(4-morpholinyl) ethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{ methyl [2-(methylamino) ethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{4-[2-oxo-2-(1-pyrrolidinyl) ethyl]-the 1-piperazinyl } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
The 3-{1-[(2-{2-[(dimethylamino) carbonyl]-the 1-pyrrolidinyl } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[(2S)-2-(amino carbonyl)-1-pyrrolidinyl] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-[5-(hydroxymethyl)-2-thienyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[5-(1-pyrrolidinyl methyl)-2-thienyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-{5-[(methylamino) methyl]-the 2-thienyl }-3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-{5-[(ethylamino) methyl]-the 2-thienyl }-3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-[1-(two (1-Methylethyl) amino of 3-[] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(methoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2S, 5S)-2,5-dimethyl-1-pyrrolidinyl] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-methyl isophthalic acid-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-hydroxyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-methyl isophthalic acid-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
5-(4-fluorophenyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-(hydroxymethyl) phenyl]-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[4-(hydroxymethyl) phenyl]-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(4-aminomethyl phenyl)-1H-indole-7-Methanamide;
5-[4-(acetyl-amino) phenyl]-3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-the 5-{4-[(mesyl) amino] phenyl }-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(1H-pyrazoles-4-yl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-(mesyl) phenyl]-1H-indole-7-Methanamide;
5-[3-(hydroxymethyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(4-aminomethyl phenyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[4-(acetyl-amino) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-{4-[(mesyl) amino] phenyl }-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(1H-pyrazoles-4-yl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-(mesyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[4-(hydroxymethyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-{3-[(ethylamino) methyl] phenyl }-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-{3-[(methylamino) methyl] phenyl }-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(1-Methylethyl) amino] methyl } phenyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-([(2S)-and the 2-hydroxypropyl] amino } methyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-{3-[(cyclopenta amino) methyl] phenyl }-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-([(1S)-and 2-hydroxyl-1-Methylethyl] amino } methyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-the 5-{3-[(ethylamino) methyl] phenyl }-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-([(1S)-and 2-hydroxyl-1-Methylethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-([(2S)-and the 2-hydroxypropyl] amino } methyl) phenyl]-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-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[4-(4-morpholinyl methyl) phenyl]-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-[4-(1-pyrrolidinyl methyl) phenyl]-1H-indole-7-Methanamide;
3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-(hydroxymethyl) phenyl]-1H-indole-7-Methanamide;
3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-(4-aminomethyl phenyl)-1H-indole-7-Methanamide;
3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3, the 4-difluorophenyl)-1H-indole-7-Methanamide;
5-(3-chlorphenyl)-3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-(4-ethylphenyl)-1H-indole-7-Methanamide;
3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-[4-(dimethylamino) phenyl]-1H-indole-7-Methanamide;
4-{[3-(4-[7-(amino carbonyl)-5-phenyl-1H-indol-3-yl]-piperidino } sulfonyl) propyl group] amino }-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester;
5-phenyl-3-(1-{[3-(4-piperidyl amino) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-phenyl-3-{1-[(3-{[(2R)-tetrahydrochysene-2-furyl methyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[[3-(dimethylamino) propyl group] and (methyl) amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[4-(amino carbonyl)-piperidino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-hydroxyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(1,4 '-Lian piperidines-1 '-yl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-[1-(3-[4-(phenyl methyl)-piperidino] and propyl group } sulfonyl)-the 4-piperidyl]-1H-indole-7-Methanamide;
3-(1-{[3-(octahydro-1 (2H)-quinolyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(six hydrogen-1H-azepine -1-yl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-{2-[(1-Methylethyl) amino]-the 2-oxoethyl }-the 1-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(2-ethyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(2-methyl isophthalic acid-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-[1-(3-[2-(2-thienyl)-1-pyrrolidinyl] and propyl group } sulfonyl)-the 4-piperidyl]-1H-indole-7-Methanamide;
3-(1-{[3-(3-hydroxyl-1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-hydroxy-4-phenyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(3-hydroxyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2R)-2-(amino carbonyl)-1-pyrrolidinyl] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-hydroxyethyl) and (1-Methylethyl) amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[methyl (2-propine-1-yl) amino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[3-(1,3-thiazoles alkane-3-yl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-phenyl-3-[1-(3-[2-(1,3-thiazoles-2-yl)-1-pyrrolidinyl] and propyl group } sulfonyl)-the 4-piperidyl]-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-furyl methyl) and (methyl) amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(2-methyl isophthalic acid-aziridine base) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[ethyl (1-Methylethyl) amino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{ ethyl [2-(methoxyl group) ethyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(diethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[[2-hydroxyl-2-(4-hydroxy phenyl) ethyl] and (methyl) amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(3-amino-1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[ethyl (methyl) amino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
Two [2-(methoxyl group) ethyl] amino of 3-{1-[(3-{ } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(2,6-dimethyl-4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[2-(hydroxymethyl)-piperidino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[3-(hydroxymethyl)-piperidino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{ (2S)-2-[(methoxyl group) methyl]-the 1-pyrrolidinyl } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[methyl (1-Methylethyl) amino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[(1S)-and 1-(hydroxymethyl)-2-methyl-propyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2-hydroxyl-1-Methylethyl) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-(dimethylamino) ethyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-({ 3-[(trans-4-hydroxy-cyclohexyl) amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-hydroxypropyl) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[1-methyl-2-(methoxyl group) ethyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-hydroxyethyl) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-hydroxybutyl) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-(4-morpholinyl) ethyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[(2R)-and the 2-hydroxypropyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[(1R)-and 1-(hydroxymethyl)-2-methyl-propyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[(1S)-and 1-(hydroxymethyl) propyl group] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(cyclohexyl amino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(4-aminomethyl phenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[3-(phenoxy group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(3-{[2-(trifluoromethyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-[1-(the 3-[(4-hydroxybutyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(cyclopropyl methyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2-hydroxyl-1-methyl-propyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(cyclobutylmethyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-[1-(3-[(tetrahydrochysene-3-furyl methyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-1H-indole-7-Methanamide;
3-{1-[(3-{[4-(acetyl-amino) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[4-(methoxyl group) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-(methoxyl group) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(4-fluorophenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(3-{[3-(trifluoromethyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-{1-[(3-{[3-(methoxyl group) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
The 3-{1-[(3-hydroxypropyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(ethyoxyl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(ethyoxyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-the 5-{3-[(methylamino) methyl] phenyl }-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(2-{[2-(piperidino) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-(1-{[2-([(2S)-and 1-methyl-2-pyrrolidinyl] methyl } the oxygen base) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(2-OXo-1-pyrrolidine base) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(two (1-Methylethyl) amino of 2-[] and ethyl } the oxygen base) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(4-morpholinyl) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(six hydrogen-1H-azepine -1-yl) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(diethylamino) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(2-{4-[(4-fluorophenyl) methyl]-the 1-piperazinyl } ethyl) the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(2-[ethyl (3-aminomethyl phenyl) amino] and ethyl } the oxygen base) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(two (2-hydroxypropyl) amino of 2-[] and ethyl } the oxygen base) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(acetyl-amino) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(the 2-[(1-Methylethyl) and the oxygen base] ethyl } the oxygen base) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(2-furyl methyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(3-furyl methyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(methyl mercapto) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(2-{[2-(3-thienyl) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-{1-[(2-{[(2-methyl cyclopropyl) methyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(ethyoxyl) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[(2,2,3,3,3-five fluoropropyls) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(2-methyl-propyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[2-(propoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-phenyl-3-[1-(2-[(2,2,2-trifluoroethyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-1H-indole-7-Methanamide;
5-phenyl-3-[1-(2-[(tetrahydrochysene-3-furyl methyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-1H-indole-7-Methanamide;
3-{1-[(2-{[2-(mesyl) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-([(2S)-and 5-oxo-2-pyrrolidinyl] methyl } the oxygen base) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[3-(dimethylamino) propyl group] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[(cyclopropyl methyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(cyclopentyl-methyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(1-Methylethyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[(2-{[2-(dimethylamino) ethyl] and the oxygen base } ethyl) the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[(1S, 3S)-3-hydroxyl-1-methyl butyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(4-hydroxybutyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[(1R, 3R)-3-hydroxyl-1-methyl butyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[(2-hydroxyl-1-methyl-propyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(2-{[2-(2-thienyl) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(2-{[2-(1-pyrrolidinyl) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[(1-Methylethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-[1-(the 2-[(methoxyl group) and amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[hydroxyl (methyl) amino] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[methyl (methoxyl group) amino] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(ethyoxyl) and amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(methoxyl group) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[hydroxyl (methyl) amino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[methyl (methoxyl group) amino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(ethyoxyl) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
The 5-{3-[(methylamino) methyl] phenyl }-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-{3-[(ethylamino) methyl] phenyl }-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(1-Methylethyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-{3-[(propyl group amino) methyl] phenyl }-1H-indole-7-Methanamide;
5-[3-([(2R)-and the 2-hydroxypropyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-([(2S)-and the 2-hydroxypropyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(cyclopropyl methyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [2-(methoxyl group) ethyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-([(2R)-and the 2-methyl butyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(2,2-dimethyl propyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [3-(methoxyl group) propyl group] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [2-(ethyoxyl) ethyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[(tetrahydrochysene-2-furyl methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-([(2R)-and tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-[3-({ [(1S)-1,2-dimethyl propyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [1-methyl-2-(methoxyl group) ethyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-({ [(1S)-1,2,2-trimethyl propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide;
The 5-{3-[({1-[(methoxyl group) methyl] propyl group } amino) methyl] phenyl }-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [(5-methyl-2-furyl) methyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(2-hydroxyl-1-Methylethyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(1,1-dimethyl propyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(4-hydroxybutyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[(4-pyridylmethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[(2-pyridylmethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-[3-({ [3-(1H-imidazoles-1-yl) propyl group] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-({ [3-(1-pyrrolidinyl) propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-({ [2-(piperidino) ethyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-({ [3-(4-morpholinyl) propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-[3-([(1S)-and 1-cyclohexyl ethyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[methyl (2-propylene-1-yl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-(3-{[(3R)-3-hydroxyl-1-pyrrolidinyl] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(2-hydroxyethyl) (propyl group) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-{3-[(2-propyl group-1-pyrrolidinyl) methyl] phenyl }-1H-indole-7-Methanamide;
5-(3-{[2-(1-Methylethyl)-1-pyrrolidinyl] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-{3-[(3,5-dimethyl-piperidino) methyl] phenyl }-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(2S)-2-(amino carbonyl)-1-pyrrolidinyl] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(1,1-dimethyl ethyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-{3-[(methylamino) methyl] phenyl }-3-(1-{[2-(methoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(1,1-dimethyl propyl) amino] methyl } phenyl)-3-(1-{[2-(methoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(ethyoxyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(ethyoxyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
The 3-{1-[(3-hydroxypropyl) sulfonyl]-the 4-piperidyl }-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-{1-[(1-methyl isophthalic acid H-imidazol-4 yl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-[1-(2-thienyl sulphonyl base)-4-piperidyl]-1H-indole-7-Methanamide;
3-{1-[(5-chloro-2-thienyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[5-(the different azoles of 3-base)-3-thienyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(5-{[(phenyl methyl) amino] methyl }-the 2-thienyl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-(1-{[2-(acetyl-amino)-4-methyl isophthalic acid, 3-thiazole-5-yl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(5-chloro-1,3-dimethyl-1H-pyrazoles-4-yl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(4-chloro-2,1,3-benzo diazole-5-yl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(1,2-dimethyl-1H-imidazol-4 yl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(1,3,5-trimethyl-1H-pyrazoles-4-yl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-{1-[(3, the different azoles of 5-dimethyl-4-base) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2,4-dimethyl-1,3-thiazoles-5-yl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(1,2-dimethyl-1H-imidazoles-5-yl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(1-methyl isophthalic acid H-imidazol-4 yl) sulfonyl]-the 4-piperidyl }-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-[5-(1-pyrrolidinyl methyl)-3-thienyl]-1H-indole-7-Methanamide;
5-(5-{[(2,2-dimethyl propyl) amino] methyl }-the 3-thienyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-[1-(the 3-[(3-ethylphenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(3-aminomethyl phenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[4-(ethyoxyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[4-(amino carbonyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-(acetyl-amino)-5-aminomethyl phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-fluoro-6-(methoxyl group) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-fluoro-3-(trifluoromethyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(the 2-[(dimethylamino) and methyl] phenyl } the oxygen base) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(3-fluorophenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[3-(acetyl-amino) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-fluorophenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[3-(dimethylamino) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2,6-difluorophenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-(acetyl-amino) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[3-(diethylamino) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(1,3-benzodioxole-5-base oxygen base) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[3-(the 3-[(phenyl amino) and sulfonyl] phenyl } the oxygen base) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-{1-[(3-{[4-(4-acetyl group-1-piperazinyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(4-hydroxy phenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-(acetyl-amino)-4-aminomethyl phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-(mesyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(3-{[3-(piperidino) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-hydroxy phenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(3-hydroxy phenyl) and the oxygen base] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(3-{[4-(trifluoromethyl) phenyl] the oxygen base } propyl group) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
5-[3-(1-pyrrolidinyl methyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-(4-morpholinyl methyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-(piperidino methyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-phenyl-3-[1-(3-thienyl sulphonyl base)-4-piperidyl]-1H-indole-7-Methanamide;
3-{1-[(4-methyl-2-thienyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(5-methyl-2-thienyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(1-benzothiophene-3-base sulfonyl)-4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-(4-[7-(amino carbonyl)-5-phenyl-1H-indol-3-yl]-piperidino } sulfonyl)-1-methyl isophthalic acid H-pyrroles-2-carboxylate methyl ester; Or
5-(4-[7-(amino carbonyl)-5-phenyl-1H-indol-3-yl]-piperidino } sulfonyl)-2-methyl-3-furancarboxylic acid methyl ester;
Or its pharmaceutically acceptable salt, solvate or polymorph.
11. according to the chemical compound of claim 1, it is:
The 3-{1-[(2-amino-ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(dimethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(2-methyl isophthalic acid-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(cyclopenta amino) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-hydroxyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(cyclopenta amino) ethyl] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(1-pyrrolidinyl) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(dimethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(cyclopenta amino) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[2-(4-hydroxyl-piperidino) ethyl] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
The 3-{1-[(2-hydroxyethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
5-(5-chloro-2-thienyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[2-(methylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[2-(piperidino) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[2-(4-methyl isophthalic acid-piperazinyl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(4-morpholinyl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[2-(1-pyrrolidinyl) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[2-(4-hydroxyl-piperidino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[[3-(dimethylamino) propyl group] and (methyl) amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(1,4 '-Lian piperidines-1 '-yl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(diethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(six hydrogen-1H-azepine -1-yl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(ethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[ethyl (methyl) amino] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(2-hydroxyethyl) and amino] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[(2S)-and the 2-hydroxypropyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{[(1S)-and 2-hydroxyl-1-Methylethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(4-acetyl group-1-piperazinyl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[4-(2-hydroxyethyl)-1-piperazinyl] and ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{ methyl [2-(methylamino) ethyl] amino } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(2-{4-[2-oxo-2-(1-pyrrolidinyl) ethyl]-the 1-piperazinyl } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
The 3-{1-[(2-{2-[(dimethylamino) carbonyl]-the 1-pyrrolidinyl } ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(2-[(2S)-2-(amino carbonyl)-1-pyrrolidinyl] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-[5-(hydroxymethyl)-2-thienyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[5-(1-pyrrolidinyl methyl)-2-thienyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-[1-(two (1-Methylethyl) amino of 3-[] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(methoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2S, 5S)-2,5-dimethyl-1-pyrrolidinyl] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-methyl isophthalic acid-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-hydroxyl-piperidino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-methyl isophthalic acid-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
5-(4-fluorophenyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(1H-pyrazoles-4-yl)-1H-indole-7-Methanamide;
5-[3-(hydroxymethyl) phenyl]-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(4-aminomethyl phenyl)-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-[1-(3-[[3-(dimethylamino) propyl group] and (methyl) amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(1,4 '-Lian piperidines-1 '-yl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(six hydrogen-1H-azepine -1-yl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-{2-[(1-Methylethyl) amino]-the 2-oxoethyl }-the 1-piperazinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(3-hydroxyl-1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(diethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[[2-hydroxyl-2-(4-hydroxy phenyl) ethyl] and (methyl) amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[2-(hydroxymethyl)-piperidino] and propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[(1S)-and 1-(hydroxymethyl)-2-methyl-propyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2-hydroxyl-1-Methylethyl) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[2-(dimethylamino) ethyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-({ 3-[(trans-4-hydroxy-cyclohexyl) amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-hydroxypropyl) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[1-methyl-2-(methoxyl group) ethyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 3-[(2-hydroxybutyl) and amino] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[(2R)-and the 2-hydroxypropyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[(1R)-and 1-(hydroxymethyl)-2-methyl-propyl] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-{1-[(3-{[(1S)-and 1-(hydroxymethyl) propyl group] amino } propyl group) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(cyclohexyl amino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
The 3-{1-[(3-hydroxypropyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(ethyoxyl) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(ethyoxyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(the 2-[(4-hydroxybutyl) and the oxygen base] ethyl } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-{1-[(2-{[2-(1-pyrrolidinyl) ethyl] the oxygen base } ethyl) sulfonyl]-the 4-piperidyl }-1H-indole-7-Methanamide;
The 5-{3-[(methylamino) methyl] phenyl }-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
The 5-{3-[(ethylamino) methyl] phenyl }-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(1-Methylethyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-{3-[(propyl group amino) methyl] phenyl }-1H-indole-7-Methanamide;
5-[3-([(2S)-and the 2-hydroxypropyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(cyclopropyl methyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [2-(methoxyl group) ethyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(2,2-dimethyl propyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [3-(methoxyl group) propyl group] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [2-(ethyoxyl) ethyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[(tetrahydrochysene-2-furyl methyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-([(2R)-and tetrahydrochysene-2-furyl methyl] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-[3-({ [(1S)-1,2-dimethyl propyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-[3-({ [1-methyl-2-(methoxyl group) ethyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-[3-({ [(1S)-1,2,2-trimethyl propyl group] amino } methyl) phenyl]-1H-indole-7-Methanamide;
5-[3-({ [(5-methyl-2-furyl) methyl] amino } methyl) phenyl]-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
5-(3-{[(4-hydroxybutyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[(4-pyridylmethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[(2-pyridylmethyl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-{[methyl (2-propylene-1-yl) amino] methyl } phenyl)-1H-indole-7-Methanamide;
5-(3-{[(3R)-3-hydroxyl-1-pyrrolidinyl] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(ethyoxyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide; Or
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
Or its pharmaceutically acceptable salt, solvate or polymorph.
12. according to the chemical compound of claim 1, it is:
The 3-{1-[(2-amino-ethyl) sulfonyl]-the 4-piperidyl }-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[2-(dimethylamino) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[3-(1-pyrrolidinyl) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[3-(dimethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
5-phenyl-3-(1-{[2-(1-pyrrolidinyl) ethyl] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide;
3-(1-{[2-(methoxyl group) ethyl] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-[1-(3-[(2S, 5S)-2,5-dimethyl-1-pyrrolidinyl] propyl group } sulfonyl)-the 4-piperidyl]-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(2-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(4-morpholinyl) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
3-(1-{[3-(diethylamino) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-phenyl-1H-indole-7-Methanamide;
5-(3-{[(2,2-dimethyl propyl) amino] methyl } phenyl)-3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-1H-indole-7-Methanamide; Or
3-(1-{[3-(methoxyl group) propyl group] sulfonyl }-the 4-piperidyl)-5-(3-thienyl)-1H-indole-7-Methanamide;
Or its pharmaceutically acceptable salt, solvate or polymorph.
13. comprise according to the chemical compound of claim 1 and the pharmaceutical composition of one or more pharmaceutically acceptable excipient.
14. treat the method for the disease that is mediated by inappropriate IKK2 activity, described method comprises the patient safety of administration needs and the chemical compound according to claim 1 of effective dose.
15. method according to claim 14, wherein the disease that is mediated by inappropriate IKK2 activity is selected from: rheumatoid arthritis, inflammatory bowel, asthma, COPD (chronic obstructive pulmonary disease), osteoarthritis, osteoporosis, psoriasis, atopic dermatitis, the skin injury of ultraviolet radiation (UV)-bring out, systemic lupus erythematosus (sle), multiple sclerosis, arthritic psoriasis, ankylosing spondylitis, organ rejection episodes, organ rejection, Alzheimer, apoplexy, atherosclerosis, restenosis, diabetes, glomerulonephritis, Hokdkin disease, cachexia, the inflammation relevant with some viral infection with infection comprises acquired immunodeficiency syndrome (AIDS), adult's RD syndrome and ataxia telangiectasia.
16. according to the method for claim 14, wherein the disease that is mediated by inappropriate IKK2 activity is inflammatory diseases or tissue repair disease.
17. according to the method for claim 14, wherein the disease that is mediated by inappropriate IKK2 activity is rheumatoid arthritis, asthma or COPD.
18. according to the method for claim 14, wherein the disease that is mediated by inappropriate IKK2 activity is a rheumatoid arthritis.
19. according to the method for claim 14, wherein the disease that is mediated by inappropriate IKK2 activity is an asthma.
20. according to the method for claim 14, wherein the disease that is mediated by inappropriate IKK2 activity is COPD.
21. according to the method for claim 14, wherein the disease that is mediated by inappropriate IKK2 activity is selected from: Alzheimer, apoplexy, atherosclerosis, restenosis, diabetes, glomerulonephritis, osteoarthritis, osteoporosis and ataxia telangiectasia.
22. according to the method for claim 14, wherein the disease that is mediated by inappropriate IKK2 activity is an autoimmune disease.
23. according to the method for claim 22, wherein autoimmune disease is systemic lupus erythematosus (sle), multiple sclerosis, arthritic psoriasis or ankylosing spondylitis.
24. according to the method for claim 14, wherein the disease that is mediated by inappropriate IKK2 activity is cancer or cachexia.
25. according to the method for claim 24, wherein said cancer is a Hokdkin disease.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US61176104P | 2004-09-21 | 2004-09-21 | |
| US60/611,761 | 2004-09-21 | ||
| US60/695,454 | 2005-06-30 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101060842A true CN101060842A (en) | 2007-10-24 |
Family
ID=38866595
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2005800397636A Pending CN101060842A (en) | 2004-09-21 | 2005-09-21 | Chemical compounds |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN101060842A (en) |
| ZA (1) | ZA200702035B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101247804B (en) * | 2005-06-30 | 2012-09-26 | 史密丝克莱恩比彻姆公司 | Chemical compounds |
| CN104341388A (en) * | 2013-10-16 | 2015-02-11 | 上海润诺生物科技有限公司 | Aromatic amide derivative as well as preparation method and medicinal application thereof |
| CN107108583A (en) * | 2014-10-24 | 2017-08-29 | 百时美施贵宝公司 | It can be used as the indole carboxamides compound of kinase inhibitor |
-
2005
- 2005-09-21 CN CNA2005800397636A patent/CN101060842A/en active Pending
-
2007
- 2007-03-08 ZA ZA200702035A patent/ZA200702035B/en unknown
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101247804B (en) * | 2005-06-30 | 2012-09-26 | 史密丝克莱恩比彻姆公司 | Chemical compounds |
| US11345695B2 (en) | 2013-09-30 | 2022-05-31 | Guangzhou Innocare Pharma Tech Co., Ltd. | Substituted nicotinimide inhibitors of BTK and their preparation and use in the treatment of cancer, inflammation and autoimmune disease |
| US11840513B2 (en) | 2013-09-30 | 2023-12-12 | Guangzhou Innocare Pharma Tech Co., Ltd | Substituted nicotinimide inhibitors of BTK for treating cancer |
| US9951056B2 (en) | 2013-09-30 | 2018-04-24 | Beijing Innocare Pharma Tech Co., Ltd. | Substituted nicotinamide inhibitors of BTK and their preparation and use in the treatment of cancer, inflammation and autoimmune disease |
| US10301297B2 (en) | 2013-09-30 | 2019-05-28 | Guangzhou Innocare Pharma Tech Co., Ltd. | Substituted nicotinimide inhibitors of BTK and their preparation and use in the treatment of cancer, inflammation and autoimmune disease |
| CN104341388A (en) * | 2013-10-16 | 2015-02-11 | 上海润诺生物科技有限公司 | Aromatic amide derivative as well as preparation method and medicinal application thereof |
| CN104341388B (en) * | 2013-10-16 | 2017-03-22 | 北京诺诚健华医药科技有限公司 | Aromatic amide derivative as well as preparation method and medicinal application thereof |
| CN110511209A (en) * | 2014-10-24 | 2019-11-29 | 百时美施贵宝公司 | It can be used as the indole carboxamides compound of kinase inhibitor |
| TWI743401B (en) * | 2014-10-24 | 2021-10-21 | 美商必治妥美雅史谷比公司 | Indole carboxamide compounds |
| TWI744218B (en) * | 2014-10-24 | 2021-11-01 | 美商必治妥美雅史谷比公司 | Indole carboxamide compounds |
| CN107108583B (en) * | 2014-10-24 | 2020-11-13 | 百时美施贵宝公司 | Indole carboxamide compounds useful as kinase inhibitors |
| CN110511209B (en) * | 2014-10-24 | 2022-07-05 | 百时美施贵宝公司 | Indole carboxamide compounds useful as kinase inhibitors |
| CN107108583A (en) * | 2014-10-24 | 2017-08-29 | 百时美施贵宝公司 | It can be used as the indole carboxamides compound of kinase inhibitor |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200702035B (en) | 2008-11-26 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN1933830A (en) | Indole derivatives and use thereof as kinase inhibitors in particular ik. k.2 inhibitors | |
| CN1230434C (en) | Indazolyl-substituted pyrroline compounds as kinase inhibitor | |
| CN1324022C (en) | Inhibitors of tyrosine kinases | |
| CN1293057C (en) | Ethylenediamine derivatives | |
| CN100345847C (en) | Novel biarylcarboxamides | |
| CN1575284A (en) | Substituted triazole diamine derivatives as kinase inhibitors | |
| CN1802357A (en) | Aminopyrimidine derivatives and their medical use | |
| CN1960975A (en) | Substituted pyridones as inhibitors of poly(ADP-ribose) polymerase (PARP) | |
| CN101031559A (en) | Novel cyclic urea derivatives, preparation thereof and pharmaceutical use thereof as kinase inhibitors | |
| CN1867560A (en) | 4-pyrimidone derivatives and their use as peptidyl peptidase inhibitors | |
| CN1514833A (en) | Novel tyrosine kinase inhibitors | |
| CN1764650A (en) | 2, 3, 6-trisubstituted-4-pyrimidone derivatives | |
| CN1278793A (en) | Sulfonyl derivatives | |
| CN1553899A (en) | Quinoline derivative and quinazoline derivative inhibiting self-phosphorylation of hepatocytus proliferator receptor and medicinal composition containing the same | |
| CN1489581A (en) | Quinazolinone derivatives | |
| CN1173867A (en) | Indolyl neuropeptide Y receptor antagonists | |
| CN1684964A (en) | Use of and some novel imidazopyridines | |
| CN1351602A (en) | New pharmaceutically active compounds | |
| CN1946725A (en) | Novel pyrazolopyrimidines as cyclin dependent kinase inhibitors | |
| CN1863779A (en) | Novel indazole derivative | |
| CN1531527A (en) | Carbazole derivatives and their use as neuropeptide Y5 receptor ligands | |
| CN1636996A (en) | Diazabicyclic derivatives as nicotinic acetylcholine receptor ligands | |
| CN1653047A (en) | Monocyclic aroylpyridinones as antiinflammatory agents | |
| CN101048406A (en) | Novel substituted imidazole derivatives | |
| CN1551869A (en) | Novel compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| ASS | Succession or assignment of patent right |
Owner name: SMITHKLINE BEECHAM CORP. Free format text: FORMER OWNER: GLAXO GROUP LTD. Effective date: 20071214 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20071214 Address after: American Pennsylvania Applicant after: Smithkline Beechan Corp. Address before: British Meader Sykes Applicant before: Glaxo Group Ltd. |
|
| AD01 | Patent right deemed abandoned |
Effective date of abandoning: 20071024 |
|
| C20 | Patent right or utility model deemed to be abandoned or is abandoned |