CN101262906A - JNK inhibitors for the treatment of endometreosis - Google Patents
JNK inhibitors for the treatment of endometreosis Download PDFInfo
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- CN101262906A CN101262906A CNA2006800335920A CN200680033592A CN101262906A CN 101262906 A CN101262906 A CN 101262906A CN A2006800335920 A CNA2006800335920 A CN A2006800335920A CN 200680033592 A CN200680033592 A CN 200680033592A CN 101262906 A CN101262906 A CN 101262906A
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Abstract
This invention relates to a method of treating and/or preventing endometriosis comprising administering a JNK inhibitor. The JNK inhibitor can also be administered combined with a hormonal suppressor. The invention further relates to the treatment of endometriosis-related infertility.
Description
The background of invention
Endometriosis is women 's fertility modal disease in the stage.It is characterized by cavity of uterus external memory membrane tissue in uterus, comprise the histologic characteristics of a body of gland and a matter.The most normal region of anatomy of getting involved is ovary, utero-sacral ligament, pelvic peritoneum, recto-vaginal septum, cervix uteri, vagina, fallopian tube and pudendum.
Endometriosis is considered to benign disease, and still, the endometriosis damage also can worsen once in a while.Similar to the malignant tumor of other types, the development of the vegetation that endometriosis causes (neoplasm) is because concurrent incident comprises the change (Kyama e al.2003) of somatomedin and/or oncogene regulation and control.In addition, endometriosis is considered to the main cause (Giudice et al.2004) of infertility.
The current treatment of endometriosis comprises hormonotherapy and/or operation.Hormonotherapy comprises high dose progestogen, ethisterone, oral contraceptive (estrogen and ethisterone share), danazol (the short male derivant of ethisterone), and gonadotropin releasing hormone (GnRH) agonist is arranged again recently.These hormonotherapies are effective to pelycalgia, and can cause objective damage recovery, but some restrictions are arranged.Estrogen can stimulate and cause endometriotic tissue propagation, because it may not react to ethisterone (Dawood et al, 1993).Progestational agents can promote irregular bleeding and depression, weight increase and body fluid storage to stay.Danazol can improve the symptom of about 66-100% pain patients, but relapse rate is about 40%-50% after 4 years.Other shortcoming of danazol therapy is weight increase and short masculine side effect.The GnRH analog is stronger than natural GnRH effect, long action time, by removing the estrogen stimulation of all estrogen sensitive organization growths is worked.The side effect of GnRH analog is secondary to mainly that extremely (profound) blood estrogen is low excessively, reduce as bone density, its after 5 years relapse rate can reach 50% (Waller et al., 1993).The treatment that makes situation become more complicated is to find that the damage of a lot of patients' endometriosis has toleration or the toleration that become (Bulun et al.2006) to the effect of progesterone and/or ethisterone.
Surgical operation can be conservative (fertility if desired), maybe can hysterectomize, fallopian tube and ovary (under the situation of serious disease).In either case, in addition limited surgical intervention all can cause the obvious reduction of fertility.
Although the inner membrance dystopy has been represented the maximum a kind of disease of research in the gynecology, current understanding to this disease pathophysiology remains unintelligible.According to a more received theory, because of leaving its original position (may be retrograde menstruation due to), the normal position cell implants distal site, and invade its tissue of living away from home and propagation therein then, thereby produce the endometriosis damage.In addition, seemingly a kind of aggressive of endometriosis and animal migration disease.Though the endometriosis cell is bred to a certain extent, they do not resemble typical being seen vegetation in cancer.Clearly, become old and feeble, apoptosis and necrosis of endometriosis cell.Damaged structure causes or the inflammatory response followed finally causes fibre modification and cicatrization.
Whether inferred that tumor or nm-23 (as the E-cadherin) are associated with endometriosis.The E-cadherin is a kind of metastasis inhibition molecule, and its downward modulation or functionally inactive are the prerequisite (Frixen etc., 1991) of invasion and attack and migration.Zeitvogel etc. (2001) prove, the E-cadherin lacks and has a N-cadherin in the endometriosis cell.Someone proposes, and the N-cadherin is a kind of molecule of exploring the way, and it makes cell invasion and migration in normal development and pathological process.
Recently, D ' Hooghe etc. (2001) proves in the endometriosis experimental model that in uterus recombined human conjugated protein (rh-TBP-1) reduces the scope and the degree of endometrial impairment effectively.These results have proved that first the anti-inflammatory molecular (rh-TBP-1) of targeting TNF path provides effective medical treatment to the endometriosis patient and do not suppress ovulation.
Yoshino etc. (2004) prove, some effect of signal conductive protein basic element of cell division activated protein kinase (MAPKs) mediation proinflammatory cytokine performance in the cell.Yoshino etc. have also proved the existence of MAPKs in the endometriosis cell (as ERK, JNK and p38) and at IL-1 β, TNF α and H
2O
2Phosphorylation under the inflammatory stimulus.MAPKs is a serine/threonine kinase, and they are activated because of the diphosphate on threonine and the tyrosine residue.Have at least three kinds to separate and parallel approach sends the information that extracellular stimulus produces to MAPKs in the mammalian cell.Described approach comprises and causes the activated kinase cascade of ERKs (extracellular regulate kinases), JNKs (the terminal kinases of c-Jun N-) and p38/CSBP kinases (Dent etc. 2003).
C-Jun is a kind of protein, and it forms homodimer and heterodimer (with for example c-Fos), produces the complex AP-1 of Transactivation, and the latter is that a lot of genes (as the matrix metalloproteinase) activation that relates in the inflammatory response is needed.
Invention disclosed herein has clearly been described by jnk inhibitor and has been suppressed the beyond thought result that JNK reduces endometriosis in rat and the nude mouse experimental model-sample focus.Rat model has proved that also the cytokine by suppressing the active of natural killer cell that this disease follows and reducing some rising that sees endometriosis reaches such effect.Barcz etc. (2000) propose, and these cytokines and II-6, II-8 play a part crucial.Jnk inhibitor recovery endometrial cell that this description is described and damage are to the sensitivity of ethisterone.In addition, the jnk inhibitor of this description description and SPRM or ethisterone share and can prevent endometriotic answer.Reduce the endometriosis damage with jnk inhibitor and also can improve fertility rate, because the normalization of genital structure has positive effect to implantation rate.
Some micromolecule are proposed as JNK approach adjusting control agent.
(WO 00/35909 for general formula (A); WO 00/35906; WO 00/35920) and general formula (B) (WO00/64872) separately shown in aryl-oxindole derivatives be developed and be used for the treatment of neurodegenerative disease, inflammation and solid tumor (general formula (A)) and therapeutic domain disease widely, comprise neurodegenerative disease, inflammation and autoimmune disease, cardiovascular and skeletal diseases (general formula (B)).
The pyrazole anthrone derivant be it was reported and can be suppressed JNK shown in the formula (C), is used for the treatment of neurodegenerative disease, inflammation and autoimmune disease, and cardiovascular pathologies (WO 01/12609).
Tetrahydropyrimidinederivatives derivatives it was reported it is jnk inhibitor shown in the formula (D), is used for the treatment of disease widely, comprises neurodegenerative disease, inflammation and autoimmune disease, heart and destructive skeleton condition of illness (WO00/75118).
Someone proposes, other heterocyclic compound Profilin kinases shown in the formula (E), particularly the terminal kinases (WO 01/12621) of c-un-N-is used for the treatment of " disease of JNK-mediation ", comprises proliferative disease, neurodegenerative disease, inflammation and autoimmune disease.
Indole (benzazole) derivant (WO 01/47920) suc as formula (F) representative has been described to the regulator of JNK path, can be used for treating neuronal disease, autoimmune disease, cancer and cardiovascular disease.
Developed also that sulfohydrazide derivant (WO01/23382) suppresses JNKs shown in sulfuryl amino acid derivative (WO 01/23379) shown in some sulfamide derivatives (WO 01/23378) shown in the formula (G), the formula (H) and the formula (J), be used for the treatment of neurodegenerative disease, autoimmune disease, cancer and cardiovascular disease.
Summary of the invention
The present invention relates to treat and/or prevent the method for individual endometriosis, comprise the jnk inhibitor for the treatment of effective dose.
The invention still further relates to the method that hormone inhibitors (as GnRH antagonist, GnRH agonist, aromatase inhibitor, progesterone receptor adjusting control agent, estrogen receptor adjusting control agent) and jnk inhibitor therapeutic alliance are used for the treatment of and/or prevent endometriosis.
The invention still further relates to the method for the treatment female infertility relevant, comprise separately or and share, treat the jnk inhibitor of effective dose with other fertility drug with endometriosis.
At last, the invention still further relates to the pharmaceutical composition that comprises jnk inhibitor (a kind of hormone inhibitors) and pharmaceutically acceptable excipient.
The simple declaration of accompanying drawing
Fig. 1: the expression of N-cadherin and cytokeratin in the endometriosis cell (12Z).The cell fixation that to handle with jnk inhibitor is done the dyeing of N-cadherin and cytokeratin in paraformaldehyde.Observation of cell under fluorescence microscope (differing and fluoroscopic image).Handle the expression that cell has reduced the N-cadherin with jnk inhibitor.The expression of handling the back cytokeratin with jnk inhibitor does not become.
Fig. 2: jnk inhibitor is to the influence of endometrial-like focus growth in the rat experiment inductivity endometriosis.When dosage is 10mg/kg, the effect of jnk inhibitor and excipient indifference.30mg/kg and 60mg/kg dosage show that the endometriosis damage of having established has tangible recovery.
Fig. 3: jnk inhibitor is to the influence of cytokine in the endometrial-like focus of rat endometrium dystopy model.Jnk inhibitor reduces the level of struvite cytokine, IL-12, INF-, IL-10 and MCP-1 in the endometriosis focus.
Fig. 4: jnk inhibitor is to the influence of rat experiment inductivity endometriosis to cytokine in the side angle (contralateralhorn).Observe the expression of the jnk inhibitor pair cell factor and do not have influence.
Fig. 5: jnk inhibitor is to the influence of NK cytoactive in the rat endometrium dystopy model.Compare with vehicle-treated group, jnk inhibitor strengthens the NK cell activity.
Detailed Description Of The Invention
Following paragraph provides the definition that consists of the various chemical groups of the compounds of this invention, its objective is unified application the in specification and claim, unless the definition of statement has provided wider restriction separately.
“C
1-C
6-alkyl " refer to have the alkyl group of 1-6 carbon atom. This term can illustrate with groups such as methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, normal-butyl, n-pentyl, n-hexyls.
The unsaturated aromatic carbon ring group of 6-14 the carbon atom of " aryl " refer to have monocycle (such as phenyl) or many condensed ring (such as naphthyl). Preferred aryl comprises phenyl, naphthyl, phenanthryl etc.
“C
1-C
6-alkylaryl " refer to have the C of aryl substituent1-C
6-alkyl group comprises benzyl, phenethyl etc.
" heteroaryl " refers to monocycle heteroaromatic or dicyclo or three ring condensed ring heteroaromatic group.The object lesson of heteroaryl comprises the pyridine radicals that randomly replaces, pyrrole radicals, furyl, thienyl, imidazole radicals oxazolyl isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base, 1,3,4-oxadiazole base, 1,3, the 4-triazine radical, 1,2, the 3-triazine radical, benzofuranyl, [2, the 3-dihydro] benzofuranyl, isobenzofuran-base, benzothienyl, the benzotriazole base, isobenzo-thienyl, indyl, isoindolyl, the 3H-indyl, benzimidazolyl, imidazo [1,2-a] pyridine radicals, benzothiazolyl benzoxazolyl, quinolizinyl, quinazolyl, 2, the 3-phthalazinyl, quinoxalinyl, the cinnolines base, the naphthyridine base, pyrido [3,4-b] pyridine radicals, pyrido [3,2-b] pyridine radicals, pyrido [4,3-b] pyridine radicals, quinolyl, isoquinolyl, tetrazole radical, 5,6,7, the 8-tetrahydric quinoline group, 5,6,7, the 8-tetrahydro isoquinolyl, purine radicals, pteridine radicals, carbazyl, xanthyl or benzoquinoline base.
" C
1-C
6-miscellaneous alkyl aryl " refer to have the substituent C of heteroaryl
1-C
6-alkyl group comprises 2-furyl methyl, 2-thienyl methyl, 2-(1H-indol-3-yl) ethyl etc.
" C
2-C
6-thiazolinyl " alkenyl group that refers to preferably have 2-6 carbon atom and have at least 1 or 2 thiazolinyl unsaturated bond.Preferred thiazolinyl comprises vinyl (CH=CH
2), n-2-acrylic (pi-allyl ,-CH
2CH=CH
2) etc.
" C
2-C
6-alkenyl aryl " refer to have the C of aryl substituent
2-C
6-alkenyl group comprises 2-phenyl vinyl etc.
" C
2-C
6-thiazolinyl heteroaryl " refer to have the substituent C of heteroaryl
2-C
6-alkenyl group comprises 2-(3-pyridine radicals) vinyl etc.
" C
2-C
6-alkynyl " refer to preferably have 2-6 carbon atom and have the alkynyl group of 1-2 alkynyl unsaturated bond at least.Preferred alkynyl group comprises acetenyl (CH ≡ CH), propinyl (CH
2C ≡ CH) etc.
" C
2-C
6-alkynyl aryl " refer to have the C of aryl substituent
2-C
6-alkynyl group comprises phenylacetylene base etc.
" C
2-C
6-alkynyl heteroaryl " refer to have the substituent C of heteroaryl
2-C
6-alkynyl group comprises 2-thienyl acetenyl etc.
" C
3-C
8-cycloalkyl " the saturated carbon ring group of 3-8 carbon atom of refer to have monocycle (as cyclohexyl) or many condensed ring (as norborny).Preferred cycloalkyl comprises cyclopenta, cyclohexyl, norborny etc.
" C
1-C
6-alkyl-cycloalkyl " refer to have the C of naphthenic substituent
1-C
6-alkyl group comprises cyclohexyl methyl, cyclopenta propyl group etc.
" Heterocyclylalkyl " refers to the C of above-mentioned definition
3-C
8-group of naphthene base, wherein 1-3 carbon atom hetero atom of being selected from O, S, NR substitutes, and R is defined as hydrogen or C
1-C
6Alkyl.Preferred Heterocyclylalkyl comprises pyrrolidine, piperidines, piperazine, 1-methyl piperazine, morpholine etc.
" C
1-C
6-alkyl heterocycle alkyl " refer to have the substituent C of Heterocyclylalkyl
1-C
6-alkyl group comprises 2-(1-pyrrolidinyl) ethyl, 4-morpholinyl methyl, (1-methyl-4-piperidyl) methyl etc.
" carboxyl " refers to group-C (O) OH.
" C
1-C
6-alkyl carboxyl " refer to have the C of carboxyl substituent
1-C
6-alkyl group comprises 2-carboxy ethyl etc.
" acyl group " refers to group-C (O) R, and wherein R comprises H, " C
1-C
6-alkyl ", " C
2-C
6-thiazolinyl ", " C
2-C
6-alkynyl ", " C
3-C
8-cycloalkyl ", " Heterocyclylalkyl ", " aryl ", " heteroaryl ", " C
1-C
6-alkylaryl " or " C
1-C
6-miscellaneous alkyl aryl ", " C
2-C
6-alkenyl aryl ", " C
2-C
6-thiazolinyl heteroaryl ", " C
2-C
6-alkynyl aryl ", " C
2-C
6-alkynyl heteroaryl ", " C
1-C
6-alkyl-cycloalkyl ", " C
1-C
6-alkyl heterocycle alkyl ".
" C
1-C
6-alkyl acyl " refer to have the C of acyl substituent
1-C
6-alkyl group comprises 2-acetyl group ethyl etc.
" acyloxy " refers to group-OC (O) R, and wherein R comprises H, " C
1-C
6-alkyl ", " C
2-C
6-thiazolinyl ", " C
2-C
6-alkynyl ", " C
3-C
8-cycloalkyl ", " Heterocyclylalkyl ", " aryl ", " heteroaryl ", " C
1-C
6-alkylaryl " or " C
1-C
6-miscellaneous alkyl aryl ", " C
2-C
6-alkenyl aryl ", " C
2-C
6-thiazolinyl heteroaryl ", " C
2-C
6-alkynyl aryl ", " C
2-C
6-alkynyl heteroaryl ", " C
1-C
6-alkyl-cycloalkyl ", " C
1-C
6-alkyl heterocycle alkyl ".
" C
1-C
6-alkyl acyloxy " refer to have the substituent C of acyloxy
1-C
6-alkyl group comprises 2-(acetoxyl group) ethyl etc.
" alkoxyl " refers to group-O-R, and wherein R comprises " C
1-C
6-alkyl ", " C
2-C
6-thiazolinyl ", " C
2-C
6-alkynyl ", " C
3-C
8-cycloalkyl ", " Heterocyclylalkyl ", " aryl ", " heteroaryl ", " C
1-C
6-alkylaryl " or " C
1-C
6-miscellaneous alkyl aryl ", " C
2-C
6-alkenyl aryl ", " C
2-C
6-thiazolinyl heteroaryl ", " C
2-C
6-alkynyl aryl ", " C
2-C
6-alkynyl heteroaryl ", " C
1-C
6-alkyl-cycloalkyl ", " C
1-C
6-alkyl heterocycle alkyl ".
" C
1-C
6-alkyl alkoxy " refer to have the C of alkoxy substituent
1-C
6-alkyl group comprises 2-ethoxyethyl group etc.
" alkoxy carbonyl " refers to group-C (O) OR, and wherein R comprises " C
1-C
6-alkyl ", " C
2-C
6-thiazolinyl ", " C
2-C
6-alkynyl ", " C
3-C
8-cycloalkyl ", " Heterocyclylalkyl ", " aryl ", " heteroaryl ", " C
1-C
6-alkylaryl " or " C
1-C
6-miscellaneous alkyl aryl ", " C
2-C
6-alkenyl aryl ", " C
2-C
6-thiazolinyl heteroaryl ", " C
2-C
6-alkynyl aryl ", " C
2-C
6-alkynyl heteroaryl ", " C
1-C
6-alkyl-cycloalkyl ", " C
1-C
6-alkyl heterocycle alkyl ".
" C
1-C
6-alkyl alkoxy carbonyl " refer to have the substituent C of alkoxy carbonyl
1-C
6-alkyl group comprises 2-(benzyloxycarbonyl) ethyl etc.
" amino carbonyl " refers to group-C (O) NRR ', and wherein R, R ' comprise hydrogen, " C independently
1-C
6-alkyl ", " C
2-C
6-thiazolinyl ", " C
2-C
6-alkynyl ", " C
3-C
8-cycloalkyl ", " Heterocyclylalkyl ", " aryl ", " heteroaryl ", " C
1-C
6-alkylaryl " or " C
1-C
6-miscellaneous alkyl aryl ", " C
2-C
6-alkenyl aryl ", " C
2-C
6-thiazolinyl heteroaryl ", " C
2-C
6-alkynyl aryl ", " C
2-C
6-alkynyl heteroaryl ", " C
1-C
6-alkyl-cycloalkyl ", " C
1-C
6-alkyl heterocycle alkyl ".
" C
1-C
6-alkyl amino-carbonyl " refer to have the substituent C of amino carbonyl
1-C
6-alkyl group comprises 2-(dimethylamino carbonyl) ethyl etc.
" acyl amino " refers to group-NRC (O) R ', and wherein each R, R ' are hydrogen, " C independently
1-C
6-alkyl ", " C
2-C
6-thiazolinyl ", " C
2-C
6-alkynyl ", " C
3-C
8-cycloalkyl ", " Heterocyclylalkyl ", " aryl ", " heteroaryl ", " C
1-C
6-alkylaryl " or " C
1-C
6-miscellaneous alkyl aryl ", " C
2-C
6-alkenyl aryl ", " C
2-C
6-thiazolinyl heteroaryl ", " C
2-C
6-alkynyl aryl ", " C
2-C
6-alkynyl heteroaryl ", " C
1-C
6-alkyl-cycloalkyl ", " C
1-C
6-alkyl heterocycle alkyl ".
" C
1-C
6-alkyl acyl amino " refer to have the substituent C of acyl amino
1-C
6-alkyl group comprises 2-(propiono amino) ethyl etc.
" urea groups " refers to group-NRC (O) NR ' R ", wherein each R, R ', R " be hydrogen, " C independently
1-C
6-alkyl ", " C
2-C
6-thiazolinyl ", " C
2-C
6-alkynyl ", " C
3-C
8-cycloalkyl ", " Heterocyclylalkyl ", " aryl ", " heteroaryl ", " C
1-C
6-alkylaryl " or " C
1-C
6-miscellaneous alkyl aryl ", " C
2-C
6-alkenyl aryl ", " C
2-C
6-thiazolinyl heteroaryl ", " C
2-C
6-alkynyl aryl ", " C
2-C
6-alkynyl heteroaryl ", " C
1-C
6-alkyl-cycloalkyl ", " C
1-C
6-alkyl heterocycle alkyl ", and wherein R ' and R " nitrogen-atoms that is connected with them can randomly form 3-8 unit heterocycloalkyl ring.
" C
1-C
6-alkyl urea groups " refer to have the substituent C of urea groups
1-C
6-alkyl group comprises 2-(N '-methyl urea groups) ethyl etc.
" amino " refers to group-NRR ', and wherein each R, R ' are hydrogen, " C independently
1-C
6-alkyl ", " C
2-C
6-thiazolinyl ", " C
2-C
6-alkynyl ", " C
3-C
8-cycloalkyl ", " Heterocyclylalkyl ", " aryl ", " heteroaryl ", " C
1-C
6-alkylaryl " or " C
1-C
6-miscellaneous alkyl aryl ", " C
2-C
6-alkenyl aryl ", " C
2-C
6-thiazolinyl heteroaryl ", " C
2-C
6-alkynyl aryl ", " C
2-C
6-alkynyl heteroaryl ", " C
1-C
6-alkyl-cycloalkyl ", " C
1-C
6-alkyl heterocycle alkyl ", and wherein R can randomly form 3-8 unit heterocycloalkyl ring with the nitrogen-atoms that R ' is connected with them.
" C
1-C
6-alkyl amino " refer to have amino substituent C
1-C
6-alkyl group comprises 2-(1-pyrrolidinyl) ethyl etc.
" ring is amino " refers to piperazinyl, piperidyl, imidazolidinyl, imidazolinyl, imidazole radicals, indolinyl, iso-dihydro-indole-group, pyrazolidinyl, pyrrolidinyl." acyclic amino " refers to group-NRR ', and wherein each R, R ' are hydrogen or " C independently
1-C
6-alkyl " or " aryl " or " heteroaryl " or " C
1-C
6-alkylaryl " or " C
1-C
6-miscellaneous alkyl aryl " or " cycloalkyl " or " Heterocyclylalkyl ", also refer to ammonium group-N as defining later
+RR ' R ".
" ammonium " electric charge group-N that makes a comment or criticism
+RR ' R ", wherein each R, R ', R " be " C independently
1-C
6-alkyl ", " C
2-C
6-thiazolinyl ", " C
2-C
6-alkynyl ", " C
3-C
8-cycloalkyl ", " Heterocyclylalkyl ", " C
1-C
6-alkylaryl " or " C
1-C
6-miscellaneous alkyl aryl ", " C
2-C
6-alkenyl aryl ", " C
2-C
6-thiazolinyl heteroaryl ", " C
2-C
6-alkynyl aryl ", " C
2-C
6-alkynyl heteroaryl ", " C
1-C
6-alkyl-cycloalkyl ", " C
1-C
6-alkyl heterocycle alkyl ", and wherein R can randomly form 3-8 unit heterocycloalkyl ring with the nitrogen-atoms that R ' is connected with them.
" C
1-C
6-alkylammonium " refer to have the substituent C of ammonium
1-C
6-alkyl group comprises 2-(1-pyrrolidinyl) ethyl etc.
" halogen " refers to fluorine, chlorine, bromine and iodine atom.
" sulfonyloxy " refers to group-OSO
2-R, wherein R is selected from H, " C
1-C
6-alkyl ", " C that replaced by halogen
1-C
6-alkyl ", as-OSO
2-CF
3Group, " C
2-C
6-thiazolinyl ", " C
2-C
6-alkynyl ", " C
3-C
8-cycloalkyl ", " Heterocyclylalkyl ", " aryl ", " heteroaryl ", " C
1-C
6-alkylaryl " or " C
1-C
6-miscellaneous alkyl aryl ", " C
2-C
6-alkenyl aryl ", " C
2-C
6-thiazolinyl heteroaryl ", " C
2-C
6-alkynyl aryl ", " C
2-C
6-alkynyl heteroaryl ", " C
1-C
6-alkyl-cycloalkyl ", " C
1-C
6-alkyl heterocycle alkyl ".
" C
1-C
6-alkylsulfonyloxy " refer to have the substituent C of sulfonyloxy
1-C
6-alkyl group comprises 2-(sulfonyloxy methyl oxygen base) ethyl etc.
" sulfonyl " refers to group " SO
2-R ", wherein R is selected from H, " aryl ", " heteroaryl ", " C
1-C
6-alkyl ", " C that replaced by halogen
1-C
6-alkyl ", as-SO
2-CF
3Group, " C
2-C
6-thiazolinyl ", " C
2-C
6-alkynyl ", " C
3-C
8-cycloalkyl ", " Heterocyclylalkyl ", " aryl ", " heteroaryl ", " C
1-C
6-alkylaryl " or " C
1-C
6-miscellaneous alkyl aryl ", " C
2-C
6-alkenyl aryl ", " C
2-C
6-thiazolinyl heteroaryl ", " C
2-C
6-alkynyl aryl ", " C
2-C
6-alkynyl heteroaryl ", " C
1-C
6-alkyl-cycloalkyl ", " C
1-C
6-alkyl heterocycle alkyl ".
" C
1-C
6-alkyl sulphonyl " refer to have the substituent C of sulfonyl
1-C
6-alkyl group comprises 2-(methyl sulphonyl) ethyl etc.
" sulfinyl " refers to group " S (O) R ", and wherein R is selected from H, " C
1-C
6-alkyl ", " C that replaced by halogen
1-C
6-alkyl ", as-SO-CF
3Group, " C
2-C
6-thiazolinyl ", " C
2-C
6-alkynyl ", " C
3-C
8-cycloalkyl ", " Heterocyclylalkyl ", " aryl ", " heteroaryl ", " C
1-C
6-alkylaryl " or " C
1-C
6-miscellaneous alkyl aryl ", " C
2-C
6-alkenyl aryl ", " C
2-C
6-thiazolinyl heteroaryl ", " C
2-C
6-alkynyl aryl ", " C
2-C
6-alkynyl heteroaryl ", " C
1-C
6-alkyl-cycloalkyl ", " C
1-C
6-alkyl heterocycle alkyl ".
" C
1-C
6-alkyl sulphinyl " refer to have the substituent C of sulfinyl
1-C
6-alkyl group comprises 2-(methylsulfinyl) ethyl etc.
" sulfane base " refers to group-S-R, and wherein R comprises H, " C
1-C
6-alkyl ", " C that replaced by halogen
1-C
6-alkyl ", as-SO-CF
3Group, " C
2-C
6-thiazolinyl ", " C
2-C
6-alkynyl ", " C
3-C
8-cycloalkyl ", " Heterocyclylalkyl ", " aryl ", " heteroaryl ", " C
1-C
6-alkylaryl " or " C
1-C
6-miscellaneous alkyl aryl ", " C
2-C
6-alkenyl aryl ", " C
2-C
6-thiazolinyl heteroaryl ", " C
2-C
6-alkynyl aryl ", " C
2-C
6-alkynyl heteroaryl ", " C
1-C
6-alkyl-cycloalkyl ", " C
1-C
6-alkyl heterocycle alkyl ".Preferred sulfane base comprises methyl sulfane base, ethyl sulfane base etc.
" C
1-C
6-alkyl alkylthio base " refer to have the substituent C of sulfane base
1-C
6-alkyl group comprises 2-(ethyl sulfane base) ethyl etc.
" sulfuryl amino " refers to group-NRSO
2-R ', wherein each R, R ' independently comprise hydrogen, " C
1-C
6-alkyl ", " C
2-C
6-thiazolinyl ", " C
2-C
6-alkynyl ", " C
3-C
8-cycloalkyl ", " Heterocyclylalkyl ", " aryl ", " heteroaryl ", " C
1-C
6-alkylaryl " or " C
1-C
6-miscellaneous alkyl aryl ", " C
2-C
6-alkenyl aryl ", " C
2-C
6-thiazolinyl heteroaryl ", " C
2-C
6-alkynyl aryl ", " C
2-C
6-alkynyl heteroaryl ", " C
1-C
6-alkyl-cycloalkyl ", " C
1-C
6-alkyl heterocycle alkyl ".
" C
1-C
6-alkyl sulfonyl-amino " refer to have the substituent C of sulfuryl amino
1-C
6-alkyl group comprises 2-(ethylsulfonyl amino) ethyl etc.
" amino-sulfonyl " refers to group-SO
2-NRR ', wherein each R, R ' independently comprise hydrogen, " C
1-C
6-alkyl ", " C
2-C
6-thiazolinyl ", " C
2-C
6-alkynyl ", " C
3-C
8-cycloalkyl ", " Heterocyclylalkyl ", " aryl ", " heteroaryl ", " C
1-C
6-alkylaryl " or " C
1-C
6-miscellaneous alkyl aryl ", " C
2-C
6-alkenyl aryl ", " C
2-C
6-thiazolinyl heteroaryl ", " C
2-C
6-alkynyl aryl ", " C
2-C
6-alkynyl heteroaryl ", " C
1-C
6-alkyl-cycloalkyl ", " C
1-C
6-alkyl heterocycle alkyl ".
" C
1-C
6-alkyl amino sulfonyl " refer to have the substituent C of amino-sulfonyl
1-C
6-alkyl group comprises 2-(cyclohexyl amino-sulfonyl) ethyl etc.
" replacement or unsubstituted ": unless limit separately with each substituent definition, group recited above can randomly be replaced by 1-5 substituent group that is selected from following group as " alkyl ", " thiazolinyl ", " alkynyl ", " aryl " and groups such as " heteroaryls ": " C
1-C
6-alkyl ", " C
2-C
6-thiazolinyl ", " C
2-C
6-alkynyl ", " cycloalkyl ", " Heterocyclylalkyl ", " C
1-C
6-alkylaryl ", " C
1-C
6-miscellaneous alkyl aryl ", " C
1-C
6-alkyl-cycloalkyl ", " C
1-C
6-alkyl heterocycle alkyl ", " amino ", " ammonium ", " acyl group ", " acyloxy ", " acyl amino ", " amino carbonyl ", " alkoxy carbonyl ", " urea groups ", " aryl ", " heteroaryl ", " sulfinyl ", " sulfonyl ", " alkoxyl ", " sulfane base ", " halogen ", " carboxyl ", trihalomethyl, cyano group, hydroxyl, sulfydryl, nitro etc.Perhaps; described " replacement " comprises that also adjacent substituent group carries out the situation of cyclization; when especially relating to adjacent functional substituent group, form for example lactams, lactone, cyclic acid anhydride, but also comprise for example in order to obtain protecting group forms acetal, mercaptal, aminal by cyclization situation.
" pharmaceutically acceptable salt or complex " refers to that they have kept required biologic activity as the salt or the complex of formula (I) chemical compound of giving a definition, and only presents slight or do not present undesirable toxicity.The example of these salt includes but not limited to the acid-addition salts with mineral acid (example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid etc.) formation; Acid-addition salts with organic acid (as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, fumaric acid, maleic acid, ascorbic acid, benzoic acid, tannin, pamoic acid, alginic acid, polyglutamic acid, LOMAR PWA EINECS 246-676-2, naphthalenedisulfonic acid and polygalacturonic acid) formation.Described chemical compound also can those skilled in the art oneself pharmaceutically acceptable quaternary salt administration of knowing, particularly including formula-NR, R ', R "
+Z
-Shown in quaternary ammonium salt, wherein R, R ', R " be hydrogen, alkyl or benzyl independently; Z is counter ion counterionsl gegenions, comprise chloride ion, bromide ion, iodide ion ,-O-alkyl ion, toluenesulfonic acid ion, pyrovinic acid ion, azochlorosulfonate acid ion, phosphate ion or carboxylic acid ion (as benzoic acid, succinic acid, acetic acid, glycolic, maleic acid, malic acid, fumaric acid, citric acid, tartaric acid, ascorbic acid, cinnamic acid, mandelic acid and diphenyl acetic acid ion).
" pharmaceutical active derivant " refers to any chemical compound, the activity that can provide this description to disclose when they are given the receiver directly or indirectly.
" tautomer " of chemical compound shown in the formula I is those wherein R
2And/or R
0Be hydrogen and have formula (Ia) and chemical compound (Ib).
" enantiomeric excess " (ee) refers to (promptly relate to the synthetic of non--raceme initiation material and/or reagent by asymmetric synthesis, perhaps contain at least one mapping and select the synthetic of step) product that obtains, wherein a kind of excess quantity of enantiomer is at least at about 52%ee.
The medicine that " aromatase inhibitor " refers to suppress aromatase and reduce estradiol level thus.Preferred aromatase inhibitor comprises for example Anastrozole, letrozole, vorozole and exemestane.
" estrogen receptor adjusting control agent (SERM) " refers to by occupying the medicine of the estrogen receptor blocking-up estrogen action on the cell.SERMS also comprises estrogen receptor beta antagonists and estrogen receptor beta-agonists.Preferred SERMs comprises for example tamoxifen, raloxifene.
" GnRH antagonist " refers to synthetic GnRH analog, and they are medicines of competitive blocking-up hypophysis cerebri GnRH receptor (being positioned at the plasma membrane of gonadotroph), but induces the quick retroactive inhibition of gonadotrophin secretion.Preferred GnRH antagonist comprises for example cetrorelix, ganirelix.
" GnRH agonist " refers to the decapetide trim of natural hormone GnRH, they are the medicines that make the pituitary gland GnRH receptor desensitization that continues to be exposed to wherein (can stimulate hypophysis-hypothalamic pituitary ovarium axis earlier, reduce circulation priatin concentration then and suppress ovarian function).Preferred GnRH agonist comprises for example buserelin acetate, nafarelin, leuprorelin, triptorelin, goserelin.
" JNK " refers to by the albumen of JNK 1, JNK 2 or JNK 3 gene expressions or its isoform (isoform) (Gupta etc., 1996).
" JNK-inhibitor " is meant chemical compound, peptide or the albumen of c-jun amino terminal kinases (JNK) phosphorylation of the transcription factor that suppresses the JNK targeting.The JNK-inhibitor is a kind ofly can suppress the active medicine of JNK in external or body.This inhibition activity can be determined by detection method well known in the art or animal model.
" progesterone receptor adjusting control agent (SPRMs) ": progesterone receptor is the nuclear receptor superfamily member, is the receptor of the progesterone that plays a crucial role in female/women (female) reproduction.Selectivity progesterone receptor adjusting control agent refers to can have agonist, antagonist or the active medicine of part (mixing) agonist/antagonist according to action site.Preferred SPRM comprises for example asoprisnil.
A specific embodiment of the present invention is that a kind of method that treats and/or prevents endometriosis in the individuality will be provided, and comprises the jnk inhibitor for the treatment of effective dose.
Another specific embodiment of the present invention relates to a kind of method that treats and/or prevents endometriosis, and this method is meant with hormone inhibitors (as GnRH antagonist, GnRH agonist, aromatase inhibitor, progesterone receptor adjusting control agent, estrogen receptor adjusting control agent) and jnk inhibitor in succession or therapeutic alliance.
For the second time or the dosage of treatment effective dose administration subsequently can equal, less than or greater than giving individual dosage for the first time or before.For the second time or during endometriosis or the related symptoms recurrence in uterus of administration subsequently or carry out before.The definition of term " recurrence " or " sending out again " comprises the appearance of one or more endometriosis symptoms.
In another specific embodiment, the present invention relates to a kind of method for the treatment of the infertility of female/women's endometriosis-relevant, comprise the jnk inhibitor for the treatment of effective dose, separately medication or share with other fertility drug.
In another specific embodiment, subsequently or combined treatment make disease reduce to the lightest by suppressing endocrine-dependent cell.
Another specific embodiment of the present invention is the pharmaceutical composition that comprises jnk inhibitor, hormone inhibitors (as GnRH antagonist, GnRH agonist, aromatase inhibitor, progesterone receptor adjusting control agent, estrogen receptor adjusting control agent) and pharmaceutically acceptable excipient.
Another specific embodiment of the present invention is the application of jnk inhibitor in the medicine of production for treating and/or prevention endometriosis.
Term used herein " prevention " is construed as partially or completely one or more symptoms or the cause of disease of preventing, suppress, alleviate or reverse endometriosis.
A model indication that is proposed to be used in endometriotic disease, infringement starts from endocrine is got involved the optimum inflammatory lesion of reacting, to the partly or completely not reactive infringement of hormone, this infringement also relates to the survival path of rise except that relating to the inflammatory path.
Therefore, in the specific embodiment, jnk inhibitor can disturb endometriotic survival path.
Another specific embodiment of the present invention relates to jnk inhibitor and hormone inhibitors (as GnRH antagonist, GnRH agonist, aromatase inhibitor, progesterone receptor adjusting control agent, estrogen receptor adjusting control agent) and the application of pharmaceutically acceptable carrier in the medicine of production for treating and/or prevention endometriosis.
The use of jnk inhibitor and hormone inhibitors (as GnRH antagonist, GnRH agonist, aromatase inhibitor, progesterone receptor adjusting control agent, estrogen receptor adjusting control agent) can be that jnk inhibitor and hormone inhibitors use in succession or unite use.
Another specific embodiment of the present invention relates to jnk inhibitor, unites the application in the medicine of production for treating endometriosis-dependency infertility separately or with other medicines.
Specifically, in the time will treating or cure endometriosis-dependency infertility, can give biological activity human chorionic gonadotropin (hCG), metakentrin (LH) or the follicle-stimulating hormone (FSH) of highly purified natural or recombinant forms.These molecules and production method thereof are described in European patent application EP 160,699, EP 211,894 and EP 322,438.
Pharmaceutical composition of the present invention can give by number of ways, comprises oral, rectum, transdermal, subcutaneous, intravenous, intramuscular and intranasal.Liquid preparations for oral administration can adopt the form of big liquid solution or suspension, or the form of big powder.But more normally, compositions provides with the form of unit dosage forms, is beneficial to accurate administration.Term " unit dosage forms " refers to physically separated unit, is fit to use as single dose for people or other mammal, and per unit contains calculates the good active substance that can produce the scheduled volume of required therapeutic effect, and suitable drug excipient.Typical unit dosage forms comprises the ampoule or the syringe pre-filled, pre-metering of fluid composition, or the pill of solid composite, tablet, capsule etc.In such compositions, jnk inhibitor is component (about 0.1-50% weight or preferably about 1-40% weight) in a small amount normally, and remaining is various excipient or carrier and the processing aid that helps to form required dosage form.
Be suitable for oral liquid form and can comprise suitable aqueous or non-aqueous excipient, contain buffer agent, suspension and dispersant, colorant, flavoring agent etc.
Solid form can comprise for example any following composition or the chemical compound of similarity: binding agent (as microcrystalline Cellulose, tragacanth or gelatin), excipient (as starch or lactose), disintegrating agent (as alginic acid, Primogel or corn starch), lubricant (as magnesium stearate), fluidizer (as silica sol), sweeting agent (as sucrose or glucide) or flavoring agent (as Herba Menthae, methyl salicylate or the agent of orange flavor).
Injectable composition other injectable carrier that oneself knows based on the injectable saline of sterilization or the saline of phosphate-buffered or this area usually.As mentioned above, jnk inhibitor composition in a small amount normally in such compositions usually is the scope in 0.05-10% weight, and remaining is an injectable carrier etc.
The above-mentioned composition that is used for oral or Injectable composition is representational.Other material and process technology etc. can be referring to " Lei Mingdun pharmaceutical science " (Remington ' s Pharmaceutical Sciences) (the 20th edition, 2000, mark (Marck) publishing company, Easton, Pennsylvania) the 5th part, it is combined in this and draws and be reference.
The form administration that The compounds of this invention also can continue to discharge or from continue discharging the delivery system administration.The narration of representational lasting releasable material also as seen above-mentioned " Lei Mingdun pharmaceutical science ".
The definition of " pharmaceutically acceptable " means and comprises not the biological activity effectiveness of interferon activity composition and any carrier nontoxic to the host who is given.For example, with regard to parenteral, jnk inhibitor can be mixed with the unit dosage forms that is used to inject in the excipient as saline, glucose solution, serum albumin and ringer's solution.
For parenteral (as vein, subcutaneous, intramuscular) administration, jnk inhibitor can be mixed with solution, suspension, Emulsion or freeze dried powder together with the additive that pharmaceutically acceptable parenteral excipient (as water, saline, glucose solution) and keeping etc. oozes (as mannitol) or chemical stability (as antiseptic or buffer agent).This preparation can be sterilized with normally used technology.
The treatment effective dose of jnk inhibitor depends on multiple variable factor, comprises the type, inhibitor of the inhibitor clinical condition to the affinity of JNK, residual toxicity, route of administration or patient that jnk inhibitor presents.
" treatment effective dose " refers to the amount that jnk inhibitor causes the JNK biological activity to suppress when administration.It is different because of multiple factor that single agent or multi-agent give individual dosage, comprises pharmacokinetics character, the route of administration of jnk inhibitor, patient's situation and feature (sex, age, body weight, health status, stature), the degree of symptom, the treatment of carrying out simultaneously, therapeutic frequency and expected effect.Those skilled in the art have the ability to adjust and control the dosage range of having set up, and method in the external and body that definite JNK suppresses on individuality.
Jnk inhibitor can be formula (I) chemical compound
Described chemical compound is disclosed in WO 01/47920 (Applied Research Systems ARS HoldingNV), and the indole derivatives of its Chinese style (A) is described to be particularly suitable for treating neuronal disease, autoimmune disease, cancer and cardiovascular disease.
In the chemical compound shown in the formula (I):
G is the pyrimidine radicals that does not replace or replace.
L is the C that does not replace or replace
1-C
6-alkoxyl, or amino, or the 3-8 unit Heterocyclylalkyl that does not replace or replace, comprise at least one hetero atom that is selected from N, O, S (as piperazine, piperidines, morpholine, pyrrolidine).
R
1Be selected from and comprise or by hydrogen, sulfonyl, amino, the C that do not replace or replace
1-C
6-alkyl, the C that does not replace or replace
2-C
6-thiazolinyl, the C that does not replace or replace
2-C
6-alkynyl or C
1-C
6The group that-alkoxyl, the aryl (as phenyl), halogen, cyano group and the hydroxyl that do not replace or replace are formed.
R
1Preferably H or C
1-C
3Alkyl (as methyl or ethyl).
Formula (I) chemical compound also comprises its tautomer, geometric isomer, its optical activity form, as enantiomer, diastereomer and racemic form, with and pharmaceutically acceptable salt.The salt of formula (I) chemical compound preferred pharmaceutical compositions is the acid-addition salts that forms with pharmaceutically acceptable acid, example hydrochloric acid salt, hydrobromate, sulfate or disulfate, phosphate or hydrophosphate, acetate, benzoate, succinate, fumarate, maleate, lactate, citrate, tartrate, gluconate, mesylate, benzene sulfonate and tosilate.
More particularly, benzothiazole acetonitrile class comprises tautomeric form shown in the formula (I), as following several:
A specific embodiment of the present invention is a benzothiazole acetonitrile class shown in the formula (Ia) of change form, as following several:
R
1Identical with the definition of L with the definition in the formula (I).
According to a specific embodiment, group L is formula-NR
3R
4Amino, R wherein
3And R
4The C that is H independently of each other, does not replace or replace
1-C
6-alkyl, the C that does not replace or replace
2-C
6-thiazolinyl, the C that does not replace or replace
2-C
6-alkynyl, the C that does not replace or replace
1-C
6-alkoxyl, the aryl that does not replace or replace, the heteroaryl that does not replace or replace, the saturated or unsaturated 3-8-unit cycloalkyl that does not replace or replace, the 3-8-unit Heterocyclylalkyl (wherein said cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can again with 1-2 cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl-condensed) that does not replace or replace, do not replace or the C of replacement
1-C
6-alkylaryl, the C that does not replace or replace
1-C
6-miscellaneous alkyl aryl, the C that does not replace or replace
2-C
6-alkenyl aryl, the C that does not replace or replace
2-C
6-thiazolinyl heteroaryl, the C that does not replace or replace
2-C
6-alkynyl aryl, the C that does not replace or replace
2-C
6-alkynyl heteroaryl, the C that does not replace or replace
1-C
6-alkyl-cycloalkyl, the C that does not replace or replace
1-C
6-alkyl heterocycle alkyl, the C that does not replace or replace
2-C
6-thiazolinyl cycloalkyl, the C that does not replace or replace
2-C
6-thiazolinyl Heterocyclylalkyl, the C that does not replace or replace
2-C
6-alkynyl cycloalkyl, the C that does not replace or replace
2-C
6-alkynyl Heterocyclylalkyl.
Perhaps R
3And R
4The nitrogen that can be connected with them is ring formation together.
In the specific embodiment, R
3Be hydrogen or methyl or ethyl or propyl group, and R
4Be selected from (the C that does not replace or replace
1-C
6)-alkyl, the C that does not replace or replace
1-C
6Alkyl-aryl, the C that does not replace or replace
1-C
6-alkyl-heteroaryl, the cycloalkyl that does not replace or replace, the Heterocyclylalkyl that does not replace or replace, the aryl that does not replace or replace or heteroaryl and the saturated or unsaturated cycloalkyl of 4-8 unit that does not replace or replace.
In another specific embodiment, R
3And R
4The nitrogen that is connected with them forms together and replaces or unsubstituted piperazine or piperidines or morpholine or pyrrolidine ring, and wherein said optional substituent group is selected from the C that does not replace or replace
1-C
6-alkyl, the C that does not replace or replace
2-C
6-thiazolinyl, the C that does not replace or replace
2-C
6-alkynyl, the C that does not replace or replace
1-C
6-alkoxyl, the aryl that does not replace or replace, the heteroaryl that does not replace or replace, the saturated or unsaturated 3-8-unit cycloalkyl that does not replace or replace, the 3-8-unit Heterocyclylalkyl (wherein said cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can again with 1-2 cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl-condensed) that does not replace or replace, do not replace or the C of replacement
1-C
6-alkylaryl, the C that does not replace or replace
1-C
6-miscellaneous alkyl aryl, the C that does not replace or replace
2-C
6-alkenyl aryl, the C that does not replace or replace
2-C
6-thiazolinyl heteroaryl, the C that does not replace or replace
2-C
6-alkynyl aryl, the C that does not replace or replace
2-C
6-alkynyl heteroaryl, the C that does not replace or replace
1-C
6-alkyl-cycloalkyl, the C that does not replace or replace
1-C
6-alkyl heterocycle alkyl, the C that does not replace or replace
2-C
6-thiazolinyl cycloalkyl, the C that does not replace or replace
2-C
6-thiazolinyl Heterocyclylalkyl, the C that does not replace or replace
2-C
6-alkynyl cycloalkyl, the C that does not replace or replace
2-C
6-alkynyl Heterocyclylalkyl.
In the specific embodiment, L is selected from:
Wherein n is 1-3, preferred 1 or 2.
R
5And R
5' be selected from H, replacement or unsubstituted C independently of each other
1-C
6Alkyl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl, replacement or unsubstituted C
1-C
6Alkyl-aryl and replacement or unsubstituted C
1-C
6-alkyl-heteroaryl.
Especially preferably wherein L is the chemical compound of group (d).
The object lesson of formula (I) chemical compound comprises following:
1,3-benzothiazole-2-base (2,6-dimethoxy-4 '-pyrimidine radicals) acetonitrile
1,3-benzothiazole-2-base (2-{[2-(1H-imidazoles-5-yl) ethyl] amino }-the 4-pyrimidine radicals) acetonitrile
1,3-benzothiazole-2-base [2-(1-piperazinyl)-4-pyrimidine radicals] acetonitrile
1,3-benzothiazole-2-base [2-(4-benzyl-piperidino)-4-pyrimidine radicals] acetonitrile
1,3-benzothiazole-2-base [2-(4-methyl isophthalic acid-piperazinyl)-4-pyrimidine radicals] acetonitrile
1,3-benzothiazole-2-base [2-(4-morpholinyl)-4-pyrimidine radicals] acetonitrile
1,3-benzothiazole-2-base [2-(methylamino)-4-pyrimidine radicals] acetonitrile
1,3-benzothiazole-2-base (2-{4-[2-(4-morpholinyl) ethyl]-the 1-piperazinyl }-the 4-pyrimidine radicals)-acetonitrile
1,3-benzothiazole-2-base 2-[4-(benzyloxy)-piperidino]-the 4-pyrimidine radicals } acetonitrile
1,3-benzothiazole-2-base [2-(4-hydroxyl-piperidino)-4-pyrimidine radicals] acetonitrile
1,3-benzothiazole-2-base (2-{[2-(dimethylamino) ethyl] amino }-the 4-pyrimidine radicals) acetonitrile
1,3-benzothiazole-2-base [2-(dimethylamino)-4-pyrimidine radicals] acetonitrile
1,3-benzothiazole-2-base the 2-[(2-methoxy ethyl) amino]-the 4-pyrimidine radicals } acetonitrile
1,3-benzothiazole-2-base the 2-[(2-ethoxy) amino]-the 4-pyrimidine radicals } acetonitrile
1,3-benzothiazole-2-base [2-(propyl group amino)-4-pyrimidine radicals] acetonitrile
1,3-benzothiazole-2-base (2-{[3-(1H-imidazoles-1-yl) propyl group] amino }-the 4-pyrimidine radicals) acetonitrile
1,3-benzothiazole-2-base [2-(1-pyrrolidinyl)-4-pyrimidine radicals] acetonitrile
1,3-benzothiazole-2-base the 2-[(2-phenylethyl) amino]-the 4-pyrimidine radicals } acetonitrile
1,3-benzothiazole-2-base (2-{[2-(2-pyridine radicals) ethyl] amino }-the 4-pyrimidine radicals) acetonitrile
1,3-benzothiazole-2-base the 2-[(2-pyridylmethyl) amino]-the 4-pyrimidine radicals } acetonitrile
1,3-benzothiazole-2-base 2-[4-(1H-1,2,3-benzotriazole-1-yl)-piperidino]-the 4-pyrimidine radicals } acetonitrile
1,3-benzothiazole-2-base 2-[4-(2-pyrazinyl)-1-piperazinyl]-the 4-pyrimidine radicals } acetonitrile
1,3-benzothiazole-2-base 2-[4-(2-pyrimidine radicals)-1-piperazinyl]-the 4-pyrimidine radicals } acetonitrile
1,3-benzothiazole-2-base (2-{[2-(3-pyridine radicals) ethyl] amino }-the 4-pyrimidine radicals) acetonitrile
1,3-benzothiazole-2-base (5-bromo-2-{[2-(dimethylamino) ethyl] amino }-the 4-pyrimidine radicals)-acetonitrile
1,3-benzothiazole-2-base 2-[(2-morpholine-4-base ethyl) and amino] pyrimidine-4-yl } acetonitrile
1,3-benzothiazole-2-base [2-(4-{3-[(trifluoromethyl) sulfonyl] anilino-} piperidines-1-yl) pyrimidine-4-yl] acetonitrile
1,3-benzothiazole-2-base (2-{[3-(2-oxygen pyrrolidine-1-yl) propyl group] amino } pyrimidine-4-yl)-acetonitrile
1, and 3-benzothiazole-2-base (2-{ methyl [3-(methylamino) propyl group] amino } pyrimidine-4-yl) acetonitrile
1,3-benzothiazole-2-base (2-{[3-(4-methyl piperazine-1-yl) propyl group] amino } pyrimidine-4-yl)-acetonitrile
1,3-benzothiazole-2-base 2-[(3-morpholine-4-base propyl group) and amino] pyrimidine-4-yl } acetonitrile
1, and 3-benzothiazole-2-base (2-{[2-(1-methyl isophthalic acid H-imidazol-4 yl) ethyl] amino } pyrimidine-4-yl) acetonitrile
1, and 3-benzothiazole-2-base (2-{[2-(1H-indol-3-yl) ethyl] amino } pyrimidine-4-yl) acetonitrile
1, and 3-benzothiazole-2-base (2-{[2-(4-hydroxy phenyl) ethyl] amino } pyrimidine-4-yl) acetonitrile
(4-[1,3-benzothiazole-2-base (cyano group) methyl] and pyrimidine-2-base } amino) tert-butyl acetate
The 2-[(3-aminopropyl) and amino] pyrimidine-4-yl } (1,3-benzothiazole-2-yl) acetonitrile
The 2-[(2-amino-ethyl) and amino] pyrimidine-4-yl } (1,3-benzothiazole-2-yl) acetonitrile
1, and 3-benzothiazole-2-base (2-{[3-(dimethylamino) propyl group] amino } pyrimidine-4-yl) acetonitrile
1,3-benzothiazole-2-base 2-[(2-piperidines-1-base ethyl) and amino] pyrimidine-4-yl } acetonitrile
1, and 3-benzothiazole-2-base (2-{[2-(1-methyl isophthalic acid H-imidazoles-5-yl) ethyl] amino } pyrimidine-4-yl) acetonitrile
1,3-benzothiazole-2-base [2-(benzylamino) pyrimidine-4-yl] acetonitrile
3-(4-[1,3-benzothiazole-2-base (cyano group) methyl] and pyrimidine-2-base } amino) isopropyl propionate
1,3-benzothiazole-2-base the 2-[(3-hydroxypropyl) and amino] pyrimidine-4-yl } acetonitrile
1,3-benzothiazole-2-base 2-[(pyridin-3-yl methyl) and amino] pyrimidine-4-yl } acetonitrile
1,3-benzothiazole-2-base 2-[(pyridin-4-yl methyl) and amino] pyrimidine-4-yl } acetonitrile
4-[2-(4-[1,3-benzothiazole-2-base (cyano group) methyl] and pyrimidine-2-base } amino)-ethyl] the phenylcarbamic acid tert-butyl ester
(2-{[2-(4-aminophenyl) ethyl] amino } pyrimidine-4-yl) (1,3-benzothiazole-2-yl) acetonitrile
1, and 3-benzothiazole-2-base (2-{[2-(3, the 4-Dimethoxyphenyl) ethyl] amino } pyrimidine-4-yl) acetonitrile
1, and 3-benzothiazole-2-base (2-{[2-(3-methoxyphenyl) ethyl] amino } pyrimidine-4-yl) acetonitrile
1, and 3-benzothiazole-2-base (2-{[2-(2-fluorophenyl) ethyl] amino } pyrimidine-4-yl) acetonitrile
1,3-benzothiazole-2-base [2-(2-[3-(trifluoromethyl) phenyl] and ethyl } amino) pyrimidine-4-yl] acetonitrile
1,3-benzothiazole-2-base 2-[(2-hydroxyl-2-phenylethyl) and amino] pyrimidine-4-yl } acetonitrile
1,3-benzothiazole-2-base 2-[(2-{[3-(trifluoromethyl) pyridine-2-yl] and amino } ethyl) amino]-pyrimidine-4-yl } acetonitrile
1, and 3-benzothiazole-2-base (2-{[2-(3-chlorphenyl) ethyl] amino } pyrimidine-4-yl) acetonitrile
1, and 3-benzothiazole-2-base (2-{[2-(3, the 4-Dichlorobenzene base) ethyl] amino } pyrimidine-4-yl) acetonitrile
1, and 3-benzothiazole-2-base (2-{[2-(4-methoxyphenyl) ethyl] amino } pyrimidine-4-yl) acetonitrile
1, and 3-benzothiazole-2-base (2-{[2-(4-aminomethyl phenyl) ethyl] amino } pyrimidine-4-yl) acetonitrile
1, and 3-benzothiazole-2-base (2-{[2-(3-fluorophenyl) ethyl] amino } pyrimidine-4-yl) acetonitrile
1, and 3-benzothiazole-2-base (2-{[2-(4-Phenoxyphenyl) ethyl] amino } pyrimidine-4-yl) acetonitrile
1, and 3-benzothiazole-2-base (2-{[2-(2-Phenoxyphenyl) ethyl] amino } pyrimidine-4-yl) acetonitrile
1, and 3-benzothiazole-2-base (2-{[2-(4-bromophenyl) ethyl] amino } pyrimidine-4-yl) acetonitrile
1, and 3-benzothiazole-2-base (2-{[2-(4-fluorophenyl) ethyl] amino } pyrimidine-4-yl) acetonitrile
1,3-benzothiazole-2-base 2-[(2-[1,1 '-xenyl]-4-base ethyl) amino] pyrimidine-4-yl } acetonitrile
1,3-benzothiazole-2-base 2-[(2-{4-[hydroxyl (oxygen) amino] and phenyl } ethyl) amino] pyrimidine-4-yl } acetonitrile
1, and 3-benzothiazole-2-base (2-{[2-(1H-1,2,4-triazol-1-yl) ethyl] amino } pyrimidine-4-yl) acetonitrile
1, and 3-benzothiazole-2-base (2-{[3-(1H-pyrazol-1-yl) propyl group] amino } pyrimidine-4-yl) acetonitrile
4-[2-(4-[1,3-benzothiazole-2-base (cyano group) methyl] and pyrimidine-2-base } amino) ethyl] benzsulfamide
2-[(2-pyridin-3-yl ethyl) and amino] pyrimidine-4-yl } [5-(trifluoromethyl)-1,3-benzothiazole-2-yl] acetonitrile
1,3-benzothiazole-2-base 2-[(1H-tetrazolium-5-ylmethyl) and amino] pyrimidine-4-yl } acetonitrile
1,3-benzothiazole-2-base [2-(benzyloxy) pyrimidine-4-yl] acetonitrile
1,3-benzothiazole-2-base 2-[(4-pyridin-3-yl benzyl) and the oxygen base] pyrimidine-4-yl } acetonitrile
1,3-benzothiazole-2-base [2-(pyridin-4-yl methoxyl group) pyrimidine-4-yl] acetonitrile
1,3-benzothiazole-2-base [2-(pyridine-2-ylmethoxy) pyrimidine-4-yl] acetonitrile
1,3-benzothiazole-2-base [2-(3-pyridine-2-base propoxyl group) pyrimidine-4-yl] acetonitrile
1,3-benzothiazole-2-base the 2-[(4-methoxy-benzyl) and the oxygen base] pyrimidine-4-yl } acetonitrile
1,3-benzothiazole-2-base [2-(pyridin-3-yl methoxyl group) pyrimidine-4-yl] acetonitrile
1,3-benzothiazole-2-base 2-[2-(4-methoxyphenyl) ethyoxyl] and pyrimidine-4-yl } acetonitrile
1,3-benzothiazole-2-base [2-([1,1 '-xenyl]-the 3-ylmethoxy) pyrimidine-4-yl] acetonitrile
1,3-benzothiazole-2-base 2-[(3,4,5-trimethoxy benzyl) and the oxygen base] pyrimidine-4-yl } acetonitrile
1,3-benzothiazole-2-base 2-[(3,4-dichloro benzyl) and the oxygen base] pyrimidine-4-yl } acetonitrile
1,3-benzothiazole-2-base [2-(the 3-[(dimethylamino) and methyl] benzyl } the oxygen base) pyrimidine-4-yl] acetonitrile
1,3-benzothiazole-2-base 2-[(1-pyridine oxide-3-yl) and methoxyl group] pyrimidine-4-yl } acetonitrile
1, and 3-benzothiazole-2-base (2-{[4-(morpholine-4-ylmethyl) benzyl] the oxygen base } pyrimidine-4-yl) acetonitrile
1,3-benzothiazole-2-base 2-[(4-pyridine-2-base benzyl) and the oxygen base] pyrimidine-4-yl } acetonitrile
1, and 3-benzothiazole-2-base (2-{[4-(piperidines-1-ylmethyl) benzyl] the oxygen base } pyrimidine-4-yl) acetonitrile
1,3-benzothiazole-2-base [2-(4-methoxyl group phenoxy group) pyrimidine-4-yl] acetonitrile
1,3-benzothiazole-2-base [2-(4-phenoxy butoxy base) pyrimidine-4-yl] acetonitrile
2-[4-(4-acetyl group piperazine-1-yl) phenoxy group] and pyrimidine-4-yl } (1,3-benzothiazole-2-yl) acetonitrile
[2-(4-methoxyl group phenoxy group) pyrimidine-4-yl] [5-(trifluoromethyl)-1,3-benzothiazole-2-yl] acetonitrile
N-[2-(4-[1,3-benzothiazole-2-base (cyano group) methyl] and pyrimidine-2-base } amino) ethyl]-the 4-chlorobenzamide
1,3-benzothiazole-2-base (2-methoxyl group-4-pyrimidine radicals) acetonitrile
1,3-benzothiazole-2-base [2-(4-[(4-methyl piperazine-1-yl) and methyl] benzyl } the oxygen base) pyrimidine-4-yl] acetonitrile
1,3-benzothiazole-2-base [2-(4-[(4-benzyl-piperazine-1-yl) methyl]-benzyl } the oxygen base) pyrimidine-4-yl] acetonitrile
1, and 3-benzothiazole-2-base (2-{[4-(piperazine-1-ylmethyl) benzyl] the oxygen base } pyrimidine-4-yl) acetonitrile
1,3-benzothiazole-2-base [2-(4-[(4-formyl piperazine-1-yl) and methyl] benzyl } the oxygen base) pyrimidine-4-yl] acetonitrile
[2-(4-[(4-acetyl group piperazine-1-yl) and methyl] benzyl } the oxygen base) pyrimidine-4-yl] (1,3-benzothiazole-2-yl) acetonitrile
(3H-benzothiazole-2-subunit)-2-[4-(4-[1,2,4] oxadiazole-3-ylmethyl-piperazine-1-ylmethyl)-benzyloxy]-pyrimidine-4-yl }-acetonitrile
4-(4-{4-[(3H-benzothiazole-2-subunit)-cyano group-methyl]-the pyrimidine-2-yloxy methyl }-benzyl)-piperazine-1-carboxylate methyl ester
2-[4-(4-{4-[(3H-benzothiazole-2-subunit)-cyano group-methyl]-the pyrimidine-2-yloxy methyl }-benzyl)-piperazine-1-yl]-acetamide
(2-{4-[4-(2-amino-acetyl group)-piperazine-1-ylmethyl]-benzyloxy }-pyrimidine-4-yl)-(3H-benzothiazole-2-subunit)-acetonitrile
[4-(4-{4-[(3H-benzothiazole-2-subunit)-cyano group-methyl]-pyrimidine-2-yloxy methyl }-benzyl)-piperazine-1-yl]-methyl acetate
(3H-benzothiazole-2-subunit)-(2-{4-[4-(2-methoxyl group-ethyl)-piperazine-1-ylmethyl]-benzyloxy }-pyrimidine-4-yl)-acetonitrile
4-(4-{4-[(3H-benzothiazole-2-subunit)-cyano group-methyl]-the pyrimidine-2-yloxy methyl }-benzyl)-piperazine-1-carboxylic acid dimethylformamide
(3H-benzothiazole-2-subunit)-2-[4-(4-ethyl-piperazine-1-ylmethyl)-benzyloxy]-pyrimidine-4-yl }-acetonitrile
(3H-benzothiazole-2-subunit)-(2-{4-[4-(2-hydroxyl-ethyl)-piperazine-1-ylmethyl]-benzyloxy }-pyrimidine-4-yl)-acetonitrile.
Formula (I) chemical compound can obtain according to the method for describing among the WO 01/47920.
In another specific embodiment, formula (I) chemical compound is Asia-structure (II) and corresponding tautomer thereof.
R in its Chinese style (II) is selected from and comprises or by hydrogen, replacement or unsubstituted C
1-C
6-alkyl, replacement or unsubstituted C
1-C
6-alkylaryl, replacement or unsubstituted heteroaryl, replacement or unsubstituted C
1-C
6-miscellaneous alkyl aryl, replacement or unsubstituted C
2-C
6-thiazolinyl, replacement or unsubstituted C
2-C
6-alkenyl aryl, replacement or unsubstituted C
2-C
6-thiazolinyl heteroaryl, replacement or unsubstituted C
2-C
6-alkynyl, replacement or unsubstituted C
2-C
6-alkynes aryl, replacement or unsubstituted C
2-C
6-alkynyl heteroaryl, replacement or unsubstituted C
3-C
8-cycloalkyl, replacement or unsubstituted Heterocyclylalkyl, replacement or unsubstituted C
1-C
6-alkyl-cycloalkyl, replacement or unsubstituted C
1-C
6-alkyl heterocycle alkyl, replacement or unsubstituted C
1-C
6-alkyl carboxyl, acyl group, replacement or unsubstituted C
1-C
6-alkyl acyl, acyloxy, replacement or unsubstituted C
1-C
6-alkyl acyl oxygen base, replacement or unsubstituted C
1-C
6-alkyl alkoxy, alkoxy carbonyl, replacement or unsubstituted C
1-C
6-alkyl alkoxy carbonyl, amino carbonyl, replacement or unsubstituted C
1-C
6-alkyl amino-carbonyl, acyl amino, replacement or unsubstituted C
1-C
6-alkyl acyl amino, urea groups, replacement or unsubstituted C
1-C
6-alkyl urea groups, amino, replacement or unsubstituted C
1-C
6-alkyl amino, sulfonyl oxygen base, replacement or unsubstituted C
1-C
6-alkyl sulphonyl oxygen base, sulfonyl, replacement or unsubstituted C
1-C
6-alkyl sulphonyl, sulfinyl, replacement or unsubstituted C
1-C
6-alkyl sulphinyl, sulfane base, replacement or unsubstituted C
1-C
6-alkyl alkylthio base, sulfuryl amino, replacement or unsubstituted C
1-C
6The group that-alkyl sulfonyl-amino is formed.
R
1Be selected from and comprise or by H, halogen, cyano group, nitro, amino, replacement or unsubstituted C
1-C
6-alkyl, particularly C
1-C
3Alkyl, as methyl or ethyl or-CF
3, replacement or unsubstituted C
2-C
6-thiazolinyl, replacement or unsubstituted C
2-C
6-alkynyl, replacement or unsubstituted C
1-C
6-alkyl-aryl, replacement or unsubstituted aryl or replacement or unsubstituted heteroaryl, replacement or unsubstituted C
1-C
6-alkyl-heteroaryl ,-C (O)-OR
2,-C (O)-R
2,-C (O)-NR
2R
2' ,-(SO
2) R
2The group of forming,
R wherein
2And R
2' be independently selected from comprise or by hydrogen, the C that do not replace or replace
1-C
6Alkyl, the C that does not replace or replace
2-C
6Thiazolinyl, the C that does not replace or replace
2-C
6Alkynyl, the aryl that does not replace or replace, the heteroaryl that does not replace or replace, the C that does not replace or replace
1-C
6-alkylaryl, the C that does not replace or replace
1-C
6The group that-miscellaneous alkyl aryl is formed.Preferably, R
1Be H, n is the integer of 0-3, more preferably 1.
Concrete piperazine benzothiazole derivant of the present invention is selected from following:
1,3-benzothiazole-2-base [2-(4-[(4-methyl piperazine-1-yl) and methyl] benzyl } the oxygen base) pyrimidine-4-yl] acetonitrile
1,3-benzothiazole-2-base [2-(4-[(4-benzyl-piperazine-1-yl) methyl]-benzyl } the oxygen base) pyrimidine-4-yl] acetonitrile
1, and 3-benzothiazole-2-base (2-{[4-(piperazine-1-ylmethyl) benzyl] the oxygen base } pyrimidine-4-yl) acetonitrile
1,3-benzothiazole-2-base [2-(4-[(4-formyl piperazine-1-yl) and methyl] benzyl } the oxygen base) pyrimidine-4-yl] acetonitrile
[2-(4-[(4-acetyl group piperazine-1-yl) and methyl] benzyl } the oxygen base) pyrimidine-4-yl] (1,3-benzothiazole-2-yl) acetonitrile
(3H-benzothiazole-2-subunit)-2-[4-(4-[1,2,4] oxadiazole-3-ylmethyl-piperazine-1-ylmethyl)-benzyloxy]-pyrimidine-4-yl }-acetonitrile
4-(4-{4-[(3H-benzothiazole-2-subunit)-cyano group-methyl]-the pyrimidine-2-yloxy methyl }-benzyl)-piperazine-1-carboxylate methyl ester
2-[4-(4-{4-[(3H-benzothiazole-2-subunit)-cyano group-methyl]-the pyrimidine-2-yloxy methyl }-benzyl)-piperazine-1-yl]-acetamide
(2-{4-[4-(2-amino-acetyl group)-piperazine-1-ylmethyl]-benzyloxy }-pyrimidine-4-yl)-(3H-benzothiazole-2-subunit)-acetonitrile
[4-(4-{4-[(3H-benzothiazole-2-subunit)-cyano group-methyl]-pyrimidine-2-yloxy methyl }-benzyl)-piperazine-1-yl]-methyl acetate
(3H-benzothiazole-2-subunit)-(2-{4-[4-(2-methoxyl group-ethyl)-piperazine-1-ylmethyl]-benzyloxy }-pyrimidine-4-yl)-acetonitrile
4-(4-{4-[(3H-benzothiazole-2-subunit)-cyano group-methyl]-the pyrimidine-2-yloxy methyl }-benzyl)-piperazine-1-carboxylic acid dimethylformamide
(3H-benzothiazole-2-subunit)-2-[4-(4-ethyl-piperazine-1-ylmethyl)-benzyloxy]-pyrimidine-4-yl }-acetonitrile
(3H-benzothiazole-2-subunit)-(2-{4-[4-(2-hydroxyl-ethyl)-piperazine-1-ylmethyl]-benzyloxy }-pyrimidine-4-yl)-acetonitrile.
Formula (II) chemical compound can obtain according to the method for describing among the WO 03/091249.
In another specific embodiment, jnk inhibitor can have formula (III):
Y is the 4-12-unit saturated rings or the bicyclic alkyl ring (heterocycle) that contain at least one nitrogen-atoms that does not replace or replace, nitrogen-atoms in the wherein said ring and the sulfonyl Cheng Jian of formula III, generation sulfonamide.
R
1Be selected from and comprise or by hydrogen, the unsubstituted or C that replaces
1-C
6-alkoxyl, the unsubstituted or C that replaces
1-C
6-alkyl, the unsubstituted or C that replaces
2-C
6-thiazolinyl, the unsubstituted or C that replaces
2-C
6-alkynyl, amino, sulfane base, sulfinyl, sulfonyl, sulfonyl oxygen base, sulfonamide, acyl amino, amino carbonyl, the unsubstituted or C that replaces
1-C
6The group that alkoxy carbonyl, the unsubstituted or aryl that replaces, heteroaryl, carboxyl, cyano group, halogen, hydroxyl, nitro, hydrazides unsubstituted or that replace are formed.
More specifically, R
1Be selected from hydrogen, halogen (as chlorine), C
1-C
6Alkyl (as methyl or ethyl) or C
1-C
6The group that alkoxyl (as methoxy or ethoxy) is formed.Most preferably halogen, particularly chlorine.
R
2Be selected from and comprise or by hydrogen, COOR
3,-CONR
3R
3', OH, by OH or the amino C that replaces
1-C
4The group that alkyl, hydrazide group carbonyl, sulfate, sulfonate, amine or ammonium salt are formed, wherein R
3, R
3' be independently selected from H, C
1-C
6-alkyl, C
2-C
6-thiazolinyl, aryl, heteroaryl, aryl-C
1-C
6-alkyl, heteroaryl-C
1-C
6-alkyl.
According to a specific embodiment, cyclammonium Y has one of general formula (a)-(d):
Wherein, L
1And L
2Be selected from C unsubstituted or that replace independently of each other
1-C
6-alkyl, the unsubstituted or C that replaces
2-C
6-thiazolinyl, the unsubstituted or C that replaces
2-C
6-alkynyl, the optional C that contains 1-3 hetero atom and optional and aryl or heteroaryl-condensed unsubstituted or replacement
4-C
8-cycloalkyl.
Perhaps, L
1And L
2Be independently selected from the unsubstituted or aryl that replaces, the unsubstituted or heteroaryl that replaces, unsubstituted or aryl-C of replacing
1-C
6-alkyl, unsubstituted or heteroaryl-C of replacing
1-C
6-alkyl ,-C (O)-OR
3,-C (O)-R
3,-C (O)-NR
3' R
3,-NR
3' R
3,-NR
3' C (O) R
3,-NR
3' C (O) NR
3' R
3The R of ,-(SO)
3,-(SO
2) R
3,-NSO
2R
3,-SO
2NR
3' R
3
Perhaps, L
1And L
2Can form 4-8-unit, unsubstituted or the saturated cyclic alkyls or the assorted alkyl ring that replace together.
R
3, R
3' be independently selected from H, the unsubstituted or C that replaces
1-C
6-alkyl, the unsubstituted or C that replaces
2-C
6-thiazolinyl, the unsubstituted or aryl that replaces, the unsubstituted or heteroaryl that replaces, unsubstituted or aryl-C of replacing
1-C
6-alkyl, unsubstituted or heteroaryl-C of replacing
1-C
6-alkyl.
R
6Be selected from hydrogen, the unsubstituted or C that replaces
1-C
6-alkyl, C
1-C
6-alkoxyl, OH, halogen, nitro, cyano group, sulfonyl, oxygen (=O), and
N ' is the integer of 0-4, preferred 1 or 2.In the specific embodiment, R
6Be hydrogen.
In another specific embodiment, R
6Be H, L
2Be H, L
1Be-NR
3' R
3R wherein
3' and R
3In at least one is not a hydrogen, but a substituent group is selected from straight or branched C
4-C
18-alkyl, aryl-C
1-C
18-alkyl, heteroaryl-C
2-C
18-alkyl, by C
3-C
12-cycloalkyl or-dicyclo or-C that tricyclic alkyl replaces
1-C
14-alkyl, wherein said alkyl chain can contain 1-3 O or S atom.
One more specifically in the embodiment, L
1Be-NHR
3R wherein
3Be straight or branched C
4-C
12-alkyl is preferably by cyclohexyl or the optional C that replaces of benzyl
6-C
12-alkyl.
One more specifically in the embodiment, Y is the piperidines group
L
1Be-NHR
3R wherein
3Be straight or branched C
4-C
12-alkyl, preferred C
8-C
12-alkyl or benzyl.
The object lesson of formula (III) chemical compound comprises following:
4-chloro-N-[5-(piperazine-1-sulfonyl)-thiophene-2-base-methyl]-Benzoylamide
4-chloro-N-{5-[4-(3-trifluoromethane sulfonyl group-phenyl amino)-piperidines-1-sulfonyl]-thiophene-2-ylmethyl }-Benzoylamide
4-chloro-N-(5-[(4-pyridine-2-base piperazine-1-yl) and sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-[(5-{[4-(4-fluoro benzoyl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[4-(trifluoromethyl) phenyl] and piperazine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-({ 5-[(4-{2-nitrobenzophenone } piperazine-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-({ 5-[(4-{4-nitrobenzophenone } piperazine-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-[(5-{[4-(2-furanylcarbonyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(4-hydroxy phenyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(2-oxygen-2-pyrrolidine-1-base ethyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(2-morpholine-4-base-2-oxygen ethyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(pyridin-4-yl methyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(2-thiophene-2-base ethyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(3, the 5-Dimethoxyphenyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(cyclohexyl methyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(2-methoxyphenyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-(5-[(4-benzyl diethylenediamine-1-yl) and sulfonyl] thiophene-2-yl } methyl)-the 4-chlorobenzamide
4-chloro-N-[(5-{[4-(2-phenylethyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(4-luorobenzyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(2-cyano-phenyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[4-chloro-3-(trifluoromethyl) phenyl] and piperazine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-[(5-{[4-(3-piperidines-1-base propyl group) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-({ 5-[(4-{4-chloro-2-nitrobenzophenone } piperazine-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-[(5-{[4-(6-picoline-2-yl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-(5-[(4-hydroxy-4-phenyl piperidine-1-yl) and sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-(5-[(4-benzoyl piperidines-1-yl) and sulfonyl] thiophene-2-yl } methyl)-the 4-chlorobenzamide
4-chloro-N-[(5-{[4-(2-oxygen-2,3-dihydro-1H-benzimidazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-(5-[(4-benzyl piepridine-1-yl) and sulfonyl] thiophene-2-yl } methyl)-the 4-chlorobenzamide
4-chloro-N-(5-[(4-oxygen-1-phenyl-1,3,8-thriazaspiro [4.5] last of the ten Heavenly stems-8-yl) and sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-{[5-(4-[2-(toluidine)-2-oxygen ethyl] and piperazine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(4-[hydroxyl (diphenyl) methyl] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-[(5-{[4-(3-cyanopyrazine-2-yl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-({ 5-[(4-{5-nitropyridine-2-yl } piperazine-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-{[5-(4-[3-chloro-5-(trifluoromethyl) pyridine-2-yl] and piperazine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(4-[5-(trifluoromethyl) pyridine-2-yl] and piperazine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(4-[3-(trifluoromethyl) pyridine-2-yl] and piperazine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-[(5-{[4-(2,4 difluorobenzene formoxyl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
The 5-{4-[(5-{[(4-chlorobenzene formacyl) amino] methyl } thiophene-2-yl) sulfonyl] piperazine-1-yl }-7-(trifluoromethyl) thieno [3,2-b] pyridine-3-carboxylic acid methyl ester
The 2-{4-[(5-{[(4-chlorobenzene formacyl) amino] methyl } thiophene-2-yl) sulfonyl] piperazine-1-yl }-5-cyano group-6-methylnicotinic acid ethyl ester
4-chloro-N-{[5-(4-[5-cyano group-4, two (dimethylamino) pyridines of 6--2-yl] and piperazine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(4-[6-methyl-2-(trifluoromethyl) quinolyl-4] and piperazine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
The 4-[(5-{[(4-chlorobenzene formacyl) amino] methyl } thiophene-2-yl) sulfonyl] piperazine-1-carboxylic acid tert-butyl ester
The 2-{4-[(5-{[(4-chlorobenzene formacyl) amino] methyl } thiophene-2-yl) sulfonyl] piperazine-1-yl }-8-ethyl-5-oxygen-5,8-dihydro pyrido [2,3-d] pyrimidine-6-carboxylic acid
The 7-{4-[(5-{[(4-chlorobenzene formacyl) amino] methyl } thiophene-2-yl) sulfonyl] piperazine-1-yl }-1-ethyl-6-fluoro-4-oxygen-1,4-dihydro [1,8] naphthyridine-3-carboxylic acid
The 7-{4-[(5-{[(4-chlorobenzene formacyl) amino] methyl } thiophene-2-yl) sulfonyl] piperazine-1-yl }-1-ethyl-6-fluoro-4-oxygen-1,4-dihydroquinoline-3-carboxylic acid
4-chloro-N-[(5-{[4-(2,3-dihydro-1,4-Ben Bing dioxine-2-base carbonyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[(2E)-3-phenyl third-2-thiazolinyl] piperazine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-[(5-{[4-(3-phenyl propyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(3,4, the 5-trimethoxyphenyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[4-(4-tert-butyl group benzyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-chlorobenzamide
4-chloro-N-[(5-{[4-(4-fluorophenyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(2-hydroxy phenyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[4-(trifluoromethyl) pyridine-2-yl] and piperazine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-[(5-{[4-(5-cyanopyridine-2-yl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
The 1-[(5-{[(4-chlorobenzene formacyl) amino] methyl } thiophene-2-yl) sulfonyl] the piperidin-4-yl t-butyl carbamate
4-chloro-N-(5-[(4-phenylpiperazine-1-yl) and sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-{[5-(piperidines-1-base sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-[(5-{[4-(1-naphthyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(3, the 4-Dichlorobenzene base) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[3-(trifluoromethyl) phenyl] and piperazine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(3-hydroxyl-4-[3-(trifluoromethyl) phenyl] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-[(5-{[4-(2-aminomethyl phenyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[(1R, 4R)-5-benzyl-2,5-diazabicyclo [2.2.1] heptan-2-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-chlorobenzamide
N-[(5-{[4-(benzyloxy) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-chlorobenzamide
4-chloro-N-[(5-{[4-(the 2-chlorodiphenyl is [b, f] [1,4] oxygen azatropylidene (oxazepin)-11-yl also) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-(4-chlorphenyl)-2-(5-{[4-(2-oxygen-2,3-dihydro-1H-benzimidazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) acetamide
4-chloro-N-(5-[(4-hydroxy piperidine-1-yl) and sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-[(5-{[4-(4-acetylphenyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-chlorobenzamide
4-chloro-N-[(5-{[4-(3,5-dichloropyridine-4-yl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(3-methoxyphenyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-(5-[(4-benzyl-4-hydroxy piperidine-1-yl) and sulfonyl] thiophene-2-yl } methyl)-the 4-chlorobenzamide
N-{[5-(the 4-[(2-tert-butyl group-1H-indole-5-yl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-chlorobenzamide
4-chloro-N-{[5-(the 4-[(phenyl acetyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-[(5-{[4-(oxolane-2-base carbonyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(6-chloropyridine-2-yl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(4-chlorphenyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[4-(2H-1,2,3-benzotriazole-2-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-chlorobenzamide
4-chloro-N-[(5-{[4-(4-chlorobenzene formacyl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-(5-[(4-Phenoxypiperidines-1-yl) and sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-{[5-(4-[benzyl (methyl) amino] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-chlorobenzamide
4-chloro-N-{[5-(4-[3-(2, the 4-Dichlorobenzene base)-1H-pyrazoles-5-yl] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-[(5-{[4-(5-thiophene-2-base-1H-pyrazole-3-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(2,3,4,5,6-pentamethylbenzene formoxyl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(phenyl acetyl)-1,4-diazepine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[5-(4-methoxyphenyl)-1H-pyrazole-3-yl] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-(5-[(4-anilino-piperidines-1-yl) and sulfonyl] thiophene-2-yl } methyl)-the 4-chlorobenzamide
4-chloro-N-[(5-{[4-(3-phenyl-1,2,4-thiadiazoles-5-yl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(2-phenylethyl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-(5-[(4-heptyl piperazine-1-yl) and sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-(5-[(4-octyl group piperazine-1-yl) and sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-[(5-{[4-(1H-1,2,3-benzotriazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-chlorobenzamide
2-(5-{[4-(1H-1,2,3-benzotriazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl)-N-(4-chlorphenyl) acetamide
The 2-{1-[(5-{[(4-chlorobenzene formacyl) amino] methyl } thiophene-2-yl) sulfonyl] piperidin-4-yl }-2H-1,2,3-benzotriazole-5-carboxylic acid
4-chloro-N-[(5-{[4-(5-chloro-1H-1,2,3-benzotriazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
The 1-{1-[(5-{[(4-chlorobenzene formacyl) amino] methyl } thiophene-2-yl) sulfonyl] piperidin-4-yl }-1H-1,2,3-benzotriazole-5-carboxylate methyl ester
The 1-{1-[(5-{[(4-chlorobenzene formacyl) amino] methyl } thiophene-2-yl) sulfonyl] piperidin-4-yl }-1H-1,2,3-benzotriazole-6-carboxylate methyl ester
The 2-{1-[(5-{[(4-chlorobenzene formacyl) amino] methyl } thiophene-2-yl) sulfonyl] piperidin-4-yl }-2H-1,2,3-benzotriazole-5-carboxylate methyl ester
4-chloro-N-[(5-{[4-(6-chloro-1H-1,2,3-benzotriazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[5-(trifluoromethyl)-1H-1,2,3-benzotriazole-1-yl] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-[(5-{[4-(7-azepine-1H-benzimidazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-chlorobenzamide
The 1-{1-[(5-{[(4-chlorobenzene formacyl) amino] methyl } thiophene-2-yl) sulfonyl] piperidin-4-yl }-1H-1,2,3-benzotriazole-5-carboxylic acid
The 1-{1-[(5-{[(4-chlorobenzene formacyl) amino] methyl } thiophene-2-yl) sulfonyl] piperidin-4-yl }-1H-1,2,3-benzotriazole-6-carboxylic acid
N-[(5-{[4-(2-amino-9H-purine-9-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-chlorobenzamide
4-chloro-N-[(5-{[4-(9H-purine-9-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[4-(6-amino-9H-purine-9-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-chlorobenzamide
4-chloro-N-({ 5-[(4-{6-nitro-1H-benzimidazole-1-yl } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-({ 5-[(4-{5-nitro-1H-benzimidazole-1-yl } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-[(5-{[4-(2H-1,2,3-triazole-2-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[4-(1H-benzimidazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-chlorobenzamide
4-chloro-N-{[5-(4-[3-propylbenzene amido] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(4-[3-(trifluoromethyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(4-[3-(dimethylamino) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-(the 1-[(5-{[(4-chlorobenzene formacyl) amino]-methyl } thiophene-2-yl) sulfonyl]-piperidin-4-yl } amino)-essence of Niobe
4-chloro-N-{[5-(4-[3-(methyl sulfane base) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-({ 5-[(4-{3-Nitrobenzol amido } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-[(5-{[4-(2-methoxybenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-(the 1-[(5-{[(4-chlorobenzene formacyl) and amino] methyl } thiophene-2-yl) sulfonyl] piperidin-4-yl } amino) Benzoylamide
4-chloro-N-{[5-(4-[2-(trifluoromethyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-(5-[(4-{2-nitro-4-[(trifluoromethyl) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-[(5-{[4-(4-chloroanilino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[4-(trifluoromethyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-(the 5-[(4-{4-[(trifluoromethyl) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-({ 5-[(4-{2-Nitrobenzol amido } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-{[5-(4-[4-(amino carbonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-chlorobenzamide
4-chloro-N-{[5-(4-[4-(1,3-dithiolane-2-yl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-[(5-{[4-(3-chloroanilino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-nitrobenzamide
4-chloro-N-[(5-{[4-(3-chloroanilino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(3-methoxybenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[3-(methyl sulphonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-(5-[(4-{3-[amino (imido grpup) methyl] and anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 4-chlorobenzamide
4-chloro-N-(the 5-[(4-{3-[(2-ethoxy) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-[(5-{[4-(2-aminobenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-chlorobenzamide
4-chloro-N-[(5-{[4-(2-hydroxy benzenes amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(4-hydroxy benzenes amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-(the 5-[(4-{3-[(trifluoromethyl) and the sulfane base] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-[(5-{[4-(3-toluidino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-(5-[(4-{[3-chloro-5-(trifluoromethyl) pyridine-2-yl] and amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-{[5-(4-[3-(1,3-oxazole-5-yl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-[(5-{[4-(3-tert-butyl benzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-chlorobenzamide
4-chloro-N-[(5-{[4-(2-propylbenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[(2,2-dioxy-1,3-dihydro-2-benzothiophene-5-yl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-[(5-{[4-(2,3-dihydro-1H-indenes-5-base is amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(4-propylbenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-({ 3-nitropyridine-2-yl } amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-{[5-(4-[(3-aminopyridine-2-yl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-chlorobenzamide
N-[(5-{[4-([1,1 '-xenyl]-the 3-base is amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-chlorobenzamide
N-[(5-{[4-(3-benzylaniline base) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-chlorobenzamide
4-chloro-N-[(5-{[4-(pyrimidine-2--amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[4-(morpholine-4-base sulfonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-(5-[(4-{[4-(trifluoromethyl) pyrimidine-2-base] and amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-[(5-{[4-(3-cyclohexyl-4-hydroxy benzenes amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-(5-[(4-{3-[(butyl amino) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 4-chlorobenzamide
4-chloro-N-[(5-{[4-(3-ethylo benzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(5,6,7,8-naphthane-1-base is amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-{[5-(4-[3-(amino-sulfonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-chlorobenzamide
4-chloro-N-[(5-{[4-(quinoline-5-base is amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(quinoline-8-base is amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(3-propyl group phenoxy group) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[(2E)-3-phenyl third-2-enoyl-] piperazine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-({ 5-[(4-{4-nitro benzoyl } piperazine-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-(5-[(4-benzoyl-piperazine-1-yl) and sulfonyl] thiophene-2-yl } methyl)-the 4-chlorobenzamide
4-chloro-N-{[5-(4-[4-(trifluoromethyl) benzoyl] and piperazine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(4-[4-(dimethylamino) benzoyl] and piperazine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-[(5-{[4-(2-fluoro benzoyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(2, the 6-difluoro benzoyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(3-fluoro benzoyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(2-naphthoyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(1-naphthoyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-({ 5-[(4-{2-nitro benzoyl } piperazine-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-[(5-{[4-(pyridin-3-yl carbonyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[4-(2,1,3-Ben Bing oxadiazole-5-base carbonyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-chlorobenzamide
4-chloro-N-[(5-{[4-(2,4 difluorobenzene formoxyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(2,4,6-trifluoromethyl benzonitrile acyl group) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(2,6-dichloro-benzoyl base) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-(5-[(4-heptanoyl group piperazine-1-yl) and sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-[(5-{[4-(quinoline-8-base sulfonyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-nitro-N-(the 5-[(4-{3-[(trifluoromethyl) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-[(5-{[4-(1H-1,2,3-benzotriazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-nitrobenzamide
4-nitro-N-(the 5-[(4-{3-[(trifluoromethyl) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-[(5-{[4-(2,4 difluorobenzene formoxyl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-nitrobenzamide
N-[(5-{[4-(1H-1,2,3-benzotriazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-nitrobenzamide
N-[(5-{[4-(1H-1,2,3-benzotriazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-nitrobenzamide
4-nitro-N-(the 5-[(4-{3-[(trifluoromethyl) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-[(5-{[4-(2,4 difluorobenzene formoxyl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-nitrobenzamide
N-[(5-{[4-(1H-1,2,3-benzotriazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-nitrobenzamide
3-nitro-N-[(5-{[4-(3-methoxybenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-nitro-N-{[5-(4-[3-(trifluoromethyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(4-[3-(dimethylamino) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-nitrobenzamide
3-nitro-N-{[5-(4-[3-(methyl sulphonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-nitro-N-{[5-(4-[3-(methyl sulfane base) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(4-[3-(amino-sulfonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-nitrobenzamide
3-{[1-({ 5-[({3-nitro benzoyl } amino) methyl]-thiophene-2-yl } sulfonyl)-piperidin-4-yl] amino } essence of Niobe
N-{[5-(4-[3-(amino carbonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-nitrobenzamide
3-nitro-N-({ 5-[(4-{3-Nitrobenzol amido } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
3-nitro-N-[(5-{[4-(2-methoxybenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-nitro-N-{[5-(4-[2-(trifluoromethyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-nitro-N-({ 5-[(4-{2-Nitrobenzol amido } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-[(5-{[4-(4-chloroanilino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-nitrobenzamide
3-nitro-N-{[5-(4-[4-(trifluoromethyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-nitro-N-(the 5-[(4-{4-[(trifluoromethyl) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-{[5-(4-[4-(amino carbonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-nitrobenzamide
N-[(5-{[4-(3-propylbenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-nitrobenzamide
N-[(5-{[4-(3-chloroanilino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-nitrobenzamide
4-nitro-N-[(5-{[4-(3-methoxybenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-nitro-N-{[5-(4-[3-(trifluoromethyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(4-[3-(dimethylamino) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-nitrobenzamide
4-nitro-N-[(5-{[4-(3-propylbenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-nitro-N-{[5-(4-[3-(methyl sulphonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-nitro-N-{[5-(4-[3-(methyl sulfane base) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(4-[3-(amino-sulfonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-nitrobenzamide
3-{[1-({ 5-[({4-nitro benzoyl } amino) methyl] thiophene-2-yl } sulfonyl) piperidin-4-yl] amino } Benzoylamide
3-{[1-({ 5-[({4-nitro benzoyl } amino) methyl] thiophene-2-yl } sulfonyl) piperidin-4-yl] amino } Benzoylamide
4-nitro-N-({ 5-[(4-{3-Nitrobenzol amido } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-nitro-N-[(5-{[4-(2-methoxybenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-nitro-N-{[5-(4-[2-(trifluoromethyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-nitro-N-({ 5-[(4-{2-Nitrobenzol amido } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-[(5-{[4-(4-chloroanilino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-nitrobenzamide
4-nitro-N-{[5-(4-[4-(trifluoromethyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-nitro-N-(the 5-[(4-{4-[(trifluoromethyl) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-{[5-(4-[4-(amino carbonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-nitrobenzamide
N-{[5-(4-[4-(1,3-dithiolane-2-yl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-nitrobenzamide
N-(5-[(4-{3-[amino (imido grpup) methyl] and anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-nitrobenzamide
N-(the 5-[(4-{3-[(2-ethoxy) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-nitrobenzamide
N-(5-[(4-anilino-piperidines-1-yl) and sulfonyl] thiophene-2-yl } methyl)-the 3-nitrobenzamide
N-(the 5-[(4-{3-[(2-ethoxy) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 4-nitrobenzamide
N-(5-[(4-anilino-piperidines-1-yl) and sulfonyl] thiophene-2-yl } methyl)-the 4-nitrobenzamide
N-(5-[(4-{3-[amino (imido grpup) methyl] and anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 4-nitrobenzamide
3-nitro-N-(the 5-[(4-{3-[(trifluoromethyl) and the sulfane base] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-nitro-N-(the 5-[(4-{3-[(trifluoromethyl) and the sulfane base] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
3-nitro-N-[(5-{[4-({ 3-nitropyridine-2-yl } amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-{[5-(4-[(2,2-dioxy-1,3-dihydro-2-benzothiophene-5-yl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-nitrobenzamide
N-[(5-{[4-(2,3-dihydro-1H-indenes-5-base is amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-nitrobenzamide
3-nitro-N-[(5-{[4-(2-propylbenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-nitro-N-[(5-{[4-(4-propylbenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[4-(3-tert-butyl benzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-nitrobenzamide
3-nitro-N-{[5-(4-[3-(1,3-oxazole-5-yl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-nitro-N-[(5-{[4-(2-phenylethyl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-(5-[(4-{[3-chloro-5-(trifluoromethyl) pyridine-2-yl] and amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-nitrobenzamide
N-[(5-{[4-([1,1 '-xenyl]-the 3-base is amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-nitrobenzamide
N-[(5-{[4-(3-benzylaniline base) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-nitrobenzamide
3-nitro-N-{[5-(4-[3-(morpholine-4-base sulfonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-nitro-N-[(5-{[4-(3-propyl group phenoxy group) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-nitro-N-[(5-{[4-(pyrimidine-2--amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-{[5-(4-[(3-aminopyridine-2-yl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-nitrobenzamide
4-nitro-N-[(5-{[4-({ 3-nitropyridine-2-yl } amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[4-(2,3-dihydro-1H-indenes-5-base is amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-nitrobenzamide
4-nitro-N-[(5-{[4-(2-propylbenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-nitro-N-[(5-{[4-(4-propylbenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[4-(3-tert-butyl benzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-nitrobenzamide
4-nitro-N-{[5-(4-[3-(1,3-oxazole-5-yl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-nitro-N-[(5-{[4-(2-phenylethyl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-(5-[(4-{[3-chloro-5-(trifluoromethyl) pyridine-2-yl] and amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 4-nitrobenzamide
N-[(5-{[4-([1,1 '-xenyl]-the 3-base is amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-nitrobenzamide
N-[(5-{[4-(3-benzylaniline base) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-nitrobenzamide
4-nitro-N-{[5-(4-[3-(morpholine-4-base sulfonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-[(5-{[4-(2-aminobenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-nitrobenzamide
3-nitro-N-[(5-{[4-(pyrimidine-2--amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-{[5-(4-[(3-aminopyridine-2-yl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-nitrobenzamide
N-(5-[(4-{2-nitro-4-[(trifluoromethyl) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
3-nitro-N-[(5-{[4-(3-phenyl propyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-nitro-N-(5-[(4-{[4-(trifluoromethyl) pyrimidine-2-base] and amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-[(5-{[4-(3-cyclohexyl-4-hydroxy benzenes amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-nitrobenzamide
N-(5-[(4-{3-[(butyl amino) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-nitrobenzamide
N-[(5-{[4-(3-ethylo benzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-nitrobenzamide
3-nitro-N-[(5-{[4-(5,6,7,8-naphthane-1-base is amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-nitro-N-[(5-{[4-(3-propyl group phenoxy group) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[4-(2,4 difluorobenzene formoxyl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-nitrobenzamide
N-[(5-{[4-(2,4 difluorobenzene formoxyl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
The 2-hydroxy-n-(the 5-[(4-{3-[(trifluoromethyl) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-[(5-{[4-(1H-1,2,3-benzotriazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
N-[(5-{[4-(1H-1,2,3-benzotriazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 2-hydroxybenzamide
N-{[5-(4-[4-(1,3-dithiolane-2-yl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-nitrobenzamide
3-methoxyl group-N-[(5-{[4-(3-methoxybenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-methoxyl group-N-{[5-(4-[3-(trifluoromethyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(4-[3-(dimethylamino) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
3-methoxyl group-N-[(5-{[4-(3-propylbenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-methoxyl group-N-{[5-(4-[3-(methyl sulphonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-{[5-(4-[3-(methyl sulfane base) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(4-[3-(amino-sulfonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
3-(the 1-[(5-{[(3-anisoyl) amino]-methyl } thiophene-2-yl) sulfonyl]-piperidin-4-yl } amino)-essence of Niobe
N-{[5-(4-[3-(amino carbonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
3-methoxyl group-N-[(5-{[4-(2-methoxybenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-({ 5-[(4-{3-Nitrobenzol amido } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
3-methoxyl group-N-{[5-(4-[2-(trifluoromethyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-({ 5-[(4-{2-Nitrobenzol amido } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
N-{[5-(4-[4-(amino carbonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-{[5-(4-[4-(1,3-dithiolane-2-yl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-[(5-{[4-(3-chloroanilino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
N-[(5-{[4-(4-chloroanilino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
3-methoxyl group-N-(the 5-[(4-{4-[(trifluoromethyl) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-(5-[(4-{3-[amino (imido grpup) methyl] and anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
N-(the 5-[(4-{3-[(2-ethoxy) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
3-methoxyl group-N-(the 5-[(4-{3-[(trifluoromethyl) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-(5-[(4-anilino-piperidines-1-yl) and sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
3-methoxyl group-N-(the 5-[(4-{3-[(trifluoromethyl) and the sulfane base] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-[(5-{[4-(4-hydroxy benzenes amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
3-nitro-N-(the 5-[(4-{3-[(trifluoromethyl) and the sulfane base] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-nitro-N-(the 5-[(4-{3-[(trifluoromethyl) and the sulfane base] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-[(5-{[4-(2-hydroxy benzenes amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
3-methoxyl group-N-[(5-{[4-(pyrimidine-2--amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-{[5-(4-[(3-aminopyridine-2-yl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-[(5-{[4-({ 3-nitropyridine-2-yl } amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
N-{[5-(4-[(2,2-dioxy-1,3-dihydro-2-benzothiophene-5-yl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-[(5-{[4-(2,3-dihydro-1H-indenes-5-base is amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
3-methoxyl group-N-[(5-{[4-(2-propylbenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-methoxyl group-N-[(5-{[4-(4-propylbenzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[4-(3-tert-butyl benzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
N-(5-[(4-{[3-chloro-5-(trifluoromethyl) pyridine-2-yl] and amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
3-methoxyl group-N-{[5-(4-[3-(1,3-oxazole-5-yl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-[(5-{[4-([1,1 '-xenyl]-the 3-base is amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
3-methoxyl group-N-[(5-{[4-(3-propyl group phenoxy group) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-methoxyl group-N-{[5-(4-[3-(morpholine-4-base sulfonyl) anilino-] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-[(5-{[4-(2-phenylethyl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[4-(3-benzylaniline base) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
3-methoxyl group-N-[(5-{[4-(3-phenyl propyl) piperazine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-methoxyl group-N-(5-[(4-{[4-(trifluoromethyl) pyrimidine-2-base] and amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-[(5-{[4-(3-cyclohexyl-4-hydroxy benzenes amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
N-(5-[(4-{3-[(butyl amino) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
N-[(5-{[4-(3-ethylo benzene amido) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
3-methoxyl group-N-[(5-{[4-(5,6,7,8-naphthane-1-base is amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[4-(1H-1,2,3-benzotriazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-5-nitro-1H-pyrazole-3-formamide
N-[(5-{[4-(1H-1,2,3-benzotriazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-2-oxygen-1,2-dihydropyridine-3-Methanamide
N-[(5-{[4-(1H-1,2,3-benzotriazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-2-sulfo--1,2-dihydropyridine-3-Methanamide
N-[(5-{[4-(1H-1,2,3-benzotriazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-3, the 4-dihydroxy benzoyl amine
N-[(5-{[4-(1H-1,2,3-benzotriazole-1-yl) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] pyridine-2-carboxamide
N-[(5-{[4-(hexyl oxygen base) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
N-(5-[(4-heptanoyl group piperidines-1-yl) and sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
4-chloro-N-[(5-{[4-(3-propylbenzene amido) piperidines-1-yl] sulfonyl }-the 2-furyl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(3-chloroanilino) piperidines-1-yl] sulfonyl }-the 2-furyl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(3-methoxybenzene amido) piperidines-1-yl] sulfonyl }-the 2-furyl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[3-(trifluoromethyl) anilino-] and piperidines-1-yl } sulfonyl)-the 2-furyl] methyl } Benzoylamide
4-chloro-N-{[5-(4-[3-(dimethylamino) anilino-] and piperidines-1-yl } sulfonyl)-the 2-furyl] methyl } Benzoylamide
4-chloro-N-{[5-(4-[3-(methyl sulphonyl) anilino-] and piperidines-1-yl } sulfonyl)-the 2-furyl] methyl } Benzoylamide
4-chloro-N-{[5-(4-[3-(methyl sulfane base) anilino-] and piperidines-1-yl } sulfonyl)-the 2-furyl] methyl } Benzoylamide
N-{[5-(4-[3-(amino-sulfonyl) anilino-] and piperidines-1-yl } sulfonyl)-the 2-furyl] methyl }-the 4-chlorobenzamide
3-(the 1-[(5-{[(4-chlorobenzene formacyl) and amino] methyl }-the 2-furyl) sulfonyl] piperidin-4-yl } amino) essence of Niobe
3-(the 1-[(5-{[(4-chlorobenzene formacyl) and amino] methyl }-the 2-furyl) sulfonyl] piperidin-4-yl } amino) Benzoylamide
4-chloro-N-({ 5-[(4-{3-Nitrobenzol amido } piperidines-1-yl) sulfonyl]-the 2-furyl } methyl) Benzoylamide
4-chloro-N-[(5-{[4-(2-methoxybenzene amido) piperidines-1-yl] sulfonyl }-the 2-furyl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[2-(trifluoromethyl) anilino-] and piperidines-1-yl } sulfonyl)-the 2-furyl] methyl } Benzoylamide
4-chloro-N-({ 5-[(4-{2-Nitrobenzol amido } piperidines-1-yl) sulfonyl]-the 2-furyl } methyl) Benzoylamide
4-chloro-N-[(5-{[4-(4-chloroanilino) piperidines-1-yl] sulfonyl }-the 2-furyl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[4-(trifluoromethyl) anilino-] and piperidines-1-yl } sulfonyl)-the 2-furyl] methyl } Benzoylamide
4-chloro-N-(the 5-[(4-{4-[(trifluoromethyl) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl]-the 2-furyl } methyl) Benzoylamide
N-{[5-(4-[4-(amino carbonyl) anilino-] and piperidines-1-yl } sulfonyl)-the 2-furyl] methyl }-the 4-chlorobenzamide
4-chloro-N-{[5-(4-[4-(1,3-dithiolane-2-yl) anilino-] and piperidines-1-yl } sulfonyl)-the 2-furyl] methyl } Benzoylamide
N-(5-[(4-{3-[amino (imido grpup) methyl] and anilino-} piperidines-1-yl) sulfonyl]-the 2-furyl } methyl)-the 4-chlorobenzamide
4-chloro-N-(the 5-[(4-{3-[(trifluoromethyl) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl]-the 2-furyl } methyl) Benzoylamide
N-(5-[(4-anilino-piperidines-1-yl) sulfonyl]-the 2-furyl } methyl)-the 4-chlorobenzamide
4-nitro-N-(the 5-[(4-{3-[(trifluoromethyl) and the sulfane base] anilino-} piperidines-1-yl) sulfonyl] the 2-furyl } methyl) Benzoylamide
4-chloro-N-(the 5-[(3-{3-[(trifluoromethyl) and sulfonyl] anilino-} pyrrolidine-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-(the 5-[(4-{3-[(trifluoromethyl) and sulfonyl] anilino-} azatropylidene-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
The 5-{[(3-anisoyl) amino] methyl }-the 2-[(4-{3-[(trifluoromethyl) sulfonyl]-anilino-} piperidines-1-yl) sulfonyl] thiophene-3-carboxylic acid
The 5-{[(3-anisoyl) amino] methyl }-2-{[4-(octyl group amino) piperidines-1-yl] sulfonyl } thiophene-3-carboxylic acid
N-(2-ethoxy)-5-{[(3-anisoyl) amino] methyl }-the 2-[(4-{3-[(trifluoromethyl) sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-3-Methanamide
N-(4-(diazanyl carbonyl)-5-[(4-{3-[(trifluoromethyl) and sulfonyl] anilino-}-piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
The 5-{[(3-anisoyl) amino] methyl }-the 2-[(4-{3-[(trifluoromethyl) sulfonyl]-anilino-} piperidines-1-yl) sulfonyl] thiophene-3-Methanamide
N-[2-(dimethylamino) ethyl]-the 5-{[(3-anisoyl) amino] methyl }-the 2-[(4-{3-[(trifluoromethyl) sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-3-Methanamide
N-(4-(hydroxymethyl)-5-[(4-{3-[(trifluoromethyl) and sulfonyl] anilino-} piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
4-chloro-N-[(5-{[4-(hexyl amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-methoxyl group-N-{[5-(the 4-[(4-trifluoromethyl benzyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-[(5-{[4-(1,3-thiazoles-2-base is amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(heptyl amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(amyl group amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(butyl amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(dodecyl amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[(2-cyclohexyl ethyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(the 4-[(cyclohexyl methyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-(5-[(4-{[(1R)-1-cyclohexyl ethyl] amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-{[5-(4-[(1R, 2R, 4S)-dicyclo [2.2.1] heptan-2-base is amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-chlorobenzamide
4-chloro-N-{[5-(4-[(2-propoxyl group ethyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(4-[(1-adamantyl methyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-chlorobenzamide
4-chloro-N-{[5-(4-[(2-pyridine-2-base ethyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(4-[(2-piperidines-1-base ethyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(the 4-[(2-ethylhexyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-(5-[(4-{[3-(1H-imidazoles-1-yl) propyl group] and amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
4-chloro-N-[(5-{[4-(octyl group amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[4-(heptyl amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
3-methoxyl group-N-[(5-{[4-(octyl group amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-methoxyl group-N-[(5-{[4-(amyl group amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[4-(butyl amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
N-[(5-{[4-(dodecyl amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
N-{[5-(4-[(2-cyclohexyl ethyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-(5-[(4-{[(1R)-1-cyclohexyl ethyl] amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
N-{[5-(4-[(1R, 2R, 4S)-dicyclo [2.2.1] heptan-2-base is amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
3-methoxyl group-N-{[5-(4-[(2-propoxyl group ethyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(4-[(1-adamantyl methyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-{[5-(4-[(3,3-diethoxy propyl group) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
3-methoxyl group-N-{[5-(4-[(3-morpholine-4-base propyl group) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-{[5-(4-[(2-pyridine-2-base ethyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-{[5-(4-[(2-piperidines-1-base ethyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(the 4-[(2-ethylhexyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-(5-[(4-{[3-(1H-imidazoles-1-yl) propyl group] and amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
N-[(5-{[4-(hexyl amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
N-[(5-{[4-(heptyl amino) azatropylidene-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
3-methoxyl group-N-[(5-{[4-(octyl group amino) azatropylidene-1-yl] sulfonyl } thiophene-2-yl) methyl] phenyl methylcarbamate amine
3-methoxyl group-N-[(5-{[4-(amyl group amino) azatropylidene-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[4-(butyl amino) azatropylidene-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
N-[(5-{[4-(dodecyl amino) azatropylidene-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
N-{[5-(4-[(2-cyclohexyl ethyl) and amino] azatropylidene-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-(5-[(4-{[(1R)-1-cyclohexyl ethyl] amino } azatropylidene-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
N-{[5-(4-[(1R, 2R, 4S)-dicyclo [2.2.1] heptan-2-base is amino] azatropylidene-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
3-methoxyl group-N-{[5-(4-[(2-propoxyl group ethyl) and amino] azatropylidene-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(the 4-[(cyclohexyl methyl) and amino] azatropylidene-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-{[5-(4-[(1-adamantyl methyl) and amino] azatropylidene-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
3-methoxyl group-N-{[5-(4-[(3-morpholine-4-base propyl group) and amino] azatropylidene-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-{[5-(4-[(2-pyridine-2-base ethyl) and amino] azatropylidene-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-{[5-(4-[(2-piperidines-1-base ethyl) and amino] azatropylidene-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(the 4-[(2-ethylhexyl) and amino] azatropylidene-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-(5-[(4-{[3-(1H-imidazoles-1-yl) propyl group] and amino } azatropylidene-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
4-chloro-N-[(5-{[4-(heptyl amino) azatropylidene-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(octyl group amino) azatropylidene-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(amyl group amino) azatropylidene-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[4-(butyl amino) azatropylidene-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-chlorobenzamide
4-chloro-N-[(5-{[4-(dodecyl amino) azatropylidene-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[(2-cyclohexyl ethyl) and amino] azatropylidene-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(4-[(1R, 2R, 4S)-dicyclo [2.2.1] heptan-2-base is amino] azatropylidene-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-chlorobenzamide
4-chloro-N-{[5-(4-[(2-propoxyl group ethyl) and amino] azatropylidene-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(the 4-[(2-ethylhexyl) and amino] azatropylidene-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-[(5-{[4-(hexyl amino) azatropylidene-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[4-(hexyl amino) azatropylidene-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
3-methoxyl group-N-[(5-{[4-(2-[3-(trifluoromethyl) phenyl] and ethyl } amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-methoxyl group-N-(5-[(4-{[2-(4-aminomethyl phenyl) ethyl] and amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
3-methoxyl group-N-(5-[(4-{[(1S, 2R)-the 2-phenycyclopropyl] amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
3-methoxyl group-N-{[5-(the 4-[(1-naphthyl methyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-{[5-(the 4-[(2-phenyl propyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-(5-[(4-{[2-(4-hydroxy phenyl) ethyl] and amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
3-methoxyl group-N-{[5-(the 4-[(3-phenyl propyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(4-[(2,3-dihydroxypropyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-{[5-(the 4-[(2-ethoxy) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
3-methoxyl group-N-[(5-{[4-(nonyl amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-methoxyl group-N-[(5-{[4-(decyl amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-methoxyl group-N-[(5-{[4-(ethylamino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-{[5-(4-[(2-[1,1 '-xenyl]-4-base ethyl) amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-{[5-(4-[([1,1 '-xenyl]-the 3-ylmethyl) amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
3-methoxyl group-N-{[5-(4-[(2-thiophene-2-base ethyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-[(5-{[4-(the 4-[(trifluoromethyl) and sulfonyl] benzyl } amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-methoxyl group-N-{[5-(4-[(quinolyl-4 methyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(4-[([1,1 '-xenyl]-the 4-ylmethyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl }-the 3-methoxy benzamide
4-chloro-N-{[5-(the 4-[(2-{[(trifluoromethyl) and sulfonyl] amino } ethyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl } Benzoylamide
4-chloro-N-[(5-{[4-(propyl group amino)-piperidino] sulfonyl }-the 2-thienyl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(the 4-[(trifluoromethyl) and sulfonyl] benzyl } amino)-piperidino] sulfonyl }-the 2-thienyl) methyl] Benzoylamide
4-chloro-N-{[5-(4-[(3,4-dihydroxy benzyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl } Benzoylamide
[the 1-[(5-{[(4-chlorobenzene formacyl) and amino] methyl }-the 2-thienyl) sulfonyl]-the 4-piperidyl } (hexyl) amino] methyl acetate
[the 1-[(5-{[(4-chlorobenzene formacyl) and amino] methyl }-the 2-thienyl) sulfonyl]-the 4-piperidyl } (hexyl) amino] tert-butyl acetate
[the 1-[(5-{[(4-chlorobenzene formacyl) and amino] methyl }-the 2-thienyl) sulfonyl]-the 4-piperidyl } (hexyl) amino] acetic acid
N-[(5-{[3-(heptyl amino) pyrrolidine-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
3-methoxyl group-N-[(5-{[3-(octyl group amino) pyrrolidine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-methoxyl group-N-[(5-{[3-(amyl group amino) pyrrolidine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[3-(butyl amino) pyrrolidine-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
N-[(5-{[3-(dodecyl amino) pyrrolidine-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
N-{[5-(3-[(2-cyclohexyl ethyl) and amino] pyrrolidine-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-(5-[(3-{[(1R)-1-cyclohexyl ethyl] amino } pyrrolidine-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
N-{[5-(3-[(1R, 2R, 4S)-dicyclo [2.2.1] heptan-2-base is amino] pyrrolidine-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
3-methoxyl group-N-{[5-(3-[(2-propoxyl group ethyl) and amino] pyrrolidine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(the 3-[(cyclohexyl methyl) and amino] pyrrolidine-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-{[5-(3-[(1-adamantyl methyl) and amino] pyrrolidine-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
3-methoxyl group-N-{[5-(3-[(3-morpholine-4-base propyl group) and amino] pyrrolidine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-{[5-(3-[(2-pyridine-2-base ethyl) and amino] pyrrolidine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-{[5-(3-[(2-piperidines-1-base ethyl) and amino] pyrrolidine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(the 3-[(2-ethylhexyl) and amino] pyrrolidine-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-[(5-{[3-(hexyl amino) pyrrolidine-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide
4-chloro-N-[(5-{[3-(heptyl amino) pyrrolidine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[3-(hexyl amino) pyrrolidine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
4-chloro-N-[(5-{[3-(amyl group amino) pyrrolidine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
N-[(5-{[3-(butyl amino) pyrrolidine-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 4-chlorobenzamide
4-chloro-N-{[5-(3-[(2-cyclohexyl ethyl) and amino] pyrrolidine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(3-[(1R, 2R, 4S)-dicyclo [2.2.1] heptan-2-base is amino] pyrrolidine-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-chlorobenzamide
4-chloro-N-(the 5-[(3-{[(1-hydroxy-cyclohexyl) and methyl] amino } pyrrolidine-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-{[5-(3-[(1-adamantyl methyl) and amino] pyrrolidine-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-chlorobenzamide
4-chloro-N-{[5-(3-[(3-morpholine-4-base propyl group) and amino] pyrrolidine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(3-[(2-pyridine-2-base ethyl) and amino] pyrrolidine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(3-[(2-piperidines-1-base ethyl) and amino] pyrrolidine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(the 3-[(2-ethylhexyl) and amino] pyrrolidine-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-[(5-{[3-(octyl group amino) pyrrolidine-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
(2S)-and the 1-[(5-{[(4-chlorobenzene formacyl) amino] methyl }-the 2-thienyl) sulfonyl]-4-(hexyl amino)-pyrrolidine 2 carboxylic acid methyl ester
3-methoxyl group-N-{[5-(4-[(amyl group amino) and methyl] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(4-[2-(butyl amino) ethyl] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-{[5-(4-[(4-butyl benzene amido) methyl]-piperidino } sulfonyl)-the 2-thienyl] methyl }-the 3-methoxy benzamide
4-chloro-N-{[5-(4-[hexyl (methyl) amino] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(the 4-[(cyclohexyl methyl) and (hexyl) amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(4-[benzyl (hexyl) amino] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-chlorobenzamide
4-chloro-N-{[5-(4-[hexyl (pyridin-3-yl methyl) amino] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(4-[hexyl (pyridin-4-yl methyl) amino] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(4-[hexyl (pyridine-2-ylmethyl) amino] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(4-[butyl (hexyl) amino] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-chlorobenzamide
4-chloro-N-{[5-(4-[hexyl (3-phenyl propyl) amino] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
4-chloro-N-{[5-(4-[hexyl (2-phenylethyl) amino] and piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(4-[[(5-bromo-2-furyl) and methyl] (hexyl) amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 4-chlorobenzamide
3-methoxyl group-N-({ 5-[(4-{ methyl [4-(trifluoromethyl) benzyl] amino }-piperidino) sulfonyl]-the 2-thienyl } methyl) Benzoylamide
4-chloro-N-{[5-(4-[(3-benzyl chloride base) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-(5-[(4-{[4-(trifluoromethyl) benzyl] and amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
3-methoxyl group-N-{[5-(the 4-[(3-methyl-benzyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-{[5-(4-[(4-propyl group benzyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-(5-[(4-{[3-(trifluoromethyl) benzyl] and amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
3-methoxyl group-N-(5-[(4-{[4-(trifluoromethoxy) benzyl] and amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl) Benzoylamide
N-(5-[(4-{[4-(difluoro-methoxy) benzyl] and amino } piperidines-1-yl) sulfonyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
3-methoxyl group-N-{[5-(4-[(2,3,4,5,6-pentamethyl benzyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-{[5-(4-[(4-propoxyl group benzyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(4-[(4-butoxy benzyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
3-methoxyl group-N-{[5-(the 4-[(4-methoxy-benzyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-{[5-(4-[(pyridin-4-yl methyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-{[5-(4-[(pyridine-2-ylmethyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-{[5-(4-[(pyridin-3-yl methyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
N-{[5-(4-[(4-tert-butyl group benzyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-{[5-(the 4-[(3-ethoxy benzyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl }-the 3-methoxy benzamide
3-methoxyl group-N-{[5-(the 4-[(4-phenoxy benzyl) and amino] piperidines-1-yl } sulfonyl) thiophene-2-yl] methyl } Benzoylamide
3-methoxyl group-N-[(5-{[4-(the 4-[(trifluoromethyl) and the sulfane base] benzyl } amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] Benzoylamide
3-methoxyl group-N-(5-[(4-{[4-(methyl sulphonyl) benzyl] amino }-piperidino) sulfonyl]-the 2-thienyl } methyl) Benzoylamide
N-(5-[(4-{[3, two (trifluoromethyl) benzyls of 5-] amino }-piperidino) sulfonyl]-the 2-thienyl } methyl)-the 3-methoxy benzamide
N-(5-[(4-{[2, two (trifluoromethyl) benzyls of 5-] amino }-piperidino) sulfonyl]-the 2-thienyl } methyl)-the 3-methoxy benzamide
N-(5-[(4-{[4-(ethyl sulfane base) benzyl] amino }-piperidino) sulfonyl]-the 2-thienyl } methyl)-the 3-methoxy benzamide
3-methoxyl group-N-[(5-{[4-(the 3-[(trifluoromethyl) and the sulfane base] benzyl } amino)-piperidino] sulfonyl }-the 2-thienyl) methyl] Benzoylamide
N-(5-[(4-{[(2,2-two fluoro-1,3-benzo dioxole-5-yl) and methyl] amino }-piperidino) sulfonyl]-the 2-thienyl } methyl)-the 3-methoxy benzamide
N-{[5-(4-[(4-iodine benzyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl }-the 3-methoxy benzamide
N-(5-[(4-{[4-(benzyloxy) benzyl] amino }-piperidino) sulfonyl]-the 2-thienyl } methyl)-the 3-methoxy benzamide
N-{[5-(4-[(2,4,6-trimethylphenyl methyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl }-the 3-methoxy benzamide
N-{[5-(4-[(4-benzyl chloride base) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl }-the 3-methoxy benzamide
N-{[5-(the 4-[(4-Ethylbenzyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl }-the 3-methoxy benzamide
3-methoxyl group-N-{[5-(4-[(4-amyl group benzyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl } Benzoylamide
3-methoxyl group-N-[(5-{[4-(1-[4-(trifluoromethyl) phenyl] and ethyl } amino)-piperidino] sulfonyl }-the 2-thienyl) methyl] Benzoylamide
3-methoxyl group-N-{[5-(the 4-[(4-methyl-benzyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl } Benzoylamide
N-{[5-(the 4-[(4-butyl benzyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl }-the 3-methoxy benzamide
N-{[5-(the 4-[(4-isopropyl benzyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl }-the 3-methoxy benzamide
N-{[5-(4-[(4-isobutyl group benzyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl }-the 3-methoxy benzamide
N-(5-[(4-{[(1-hydroxyl-1 λ～5～-pyridin-4-yl) methyl] amino }-piperidino) sulfonyl]-the 2-thienyl } methyl)-the 3-methoxy benzamide
N-{[5-(4-[(2,3-dihydro-1,4-Ben Bing dioxine-6-ylmethyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl }-the 3-methoxy benzamide
N-{[5-(4-[(2,3-dihydro-1-benzofuran-5-ylmethyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl }-the 3-methoxy benzamide
4-chloro-N-{[5-(4-[(4-propyl group benzyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl } Benzoylamide
4-chloro-N-(5-[(4-{[4-(trifluoromethoxy) benzyl] amino }-piperidino) sulfonyl]-the 2-thienyl } methyl) Benzoylamide
4-chloro-N-(5-[(4-{[4-(difluoro-methoxy) benzyl] amino }-piperidino) sulfonyl]-the 2-thienyl } methyl) Benzoylamide
4-chloro-N-{[5-(4-[(4-propoxyl group benzyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl } Benzoylamide
N-{[5-(4-[(4-butoxy benzyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl }-the 4-chlorobenzamide
4-chloro-N-{[5-(the 4-[(4-quinolyl methyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl } Benzoylamide
N-{[5-(4-[(4-tert-butyl group benzyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl }-the 4-chlorobenzamide
4-chloro-N-{[5-(the 4-[(4-phenoxy benzyl) amino]-piperidino } sulfonyl)-the 2-thienyl] methyl } Benzoylamide
4-chloro-N-[(5-{[4-(the 4-[(trifluoromethyl) and the sulfane base] benzyl } amino)-piperidino] sulfonyl }-the 2-thienyl) methyl] Benzoylamide
4-chloro-N-(5-[(4-{[4-(trifluoromethyl) benzyl] amino }-piperidino) sulfonyl]-the 2-thienyl } methyl) Benzoylamide
3-methoxyl group-N-(5-[(4-{[2-(trifluoromethyl) benzyl] amino }-piperidino) sulfonyl]-the 2-thienyl } methyl) Benzoylamide
3-methoxyl group-N-[(5-{[4-({ [6-(trifluoromethyl)-3-pyridine radicals] methyl } amino)-piperidino] sulfonyl }-the 2-thienyl) methyl] Benzoylamide
N-[(5-{[4-(benzylamino)-piperidino] sulfonyl }-the 2-thienyl) methyl]-the 3-methoxy benzamide
3-methoxyl group-N-[(5-{[4-(1-[4-(trifluoromethyl) phenyl] and propyl group } amino)-piperidino] sulfonyl }-the 2-thienyl) methyl] Benzoylamide
3-methoxyl group-N-[(5-{[4-({ 1-methyl isophthalic acid-[4-(trifluoromethyl) phenyl] ethyl } amino)-piperidino] sulfonyl }-the 2-thienyl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-(1-[4-(trifluoromethyl) phenyl] and ethyl } amino)-piperidino] sulfonyl }-the 2-thienyl) methyl] Benzoylamide
4-chloro-N-[(5-{[4-({ 1-methyl isophthalic acid-[4-(trifluoromethyl) phenyl] ethyl } amino)-piperidino] sulfonyl }-the 2-thienyl) methyl] Benzoylamide
4-chloro-N-[(5-{[2-({ [4-(trifluoromethyl) benzyl] amino } methyl)-1-pyrrolidinyl] sulfonyl }-the 2-thienyl) methyl] Benzoylamide
4-chloro-N-[(5-{[(3R)-and 3-({ [4-(trifluoromethyl) benzyl] amino } methyl) pyrrolidinyl] sulfonyl }-the 2-thienyl) methyl] Benzoylamide
4-chloro-N-(5-[(3-{[4-(trifluoromethyl) benzyl] amino }-piperidino) sulfonyl]-the 2-thienyl } methyl) Benzoylamide
4-chloro-N-{[5-(3-[(hexyl amino) methyl]-piperidino } sulfonyl)-the 2-thienyl] methyl } Benzoylamide
4-chloro-N-(5-[(3-{[4-(trifluoromethyl) benzyl] amino }-the 1-pyrrolidinyl) sulfonyl]-the 2-thienyl } methyl) Benzoylamide
4-chloro-N-{[5-((3R)-and 3-[(hexyl amino) methyl] pyrrolidinyl } sulfonyl)-the 2-thienyl] methyl } Benzoylamide
4-chloro-N-[(5-{[3-({ [4-(trifluoromethyl) benzyl] amino } methyl)-piperidino] sulfonyl }-the 2-thienyl) methyl] Benzoylamide
2-oxygen-N-(5-[(4-{[4-(trifluoromethyl) benzyl] amino }-piperidino) sulfonyl]-the 2-thienyl } methyl)-1,2-dihydro-3-ascorbyl palmitate
N-[(5-{[4-(hexyl amino)-piperidino] sulfonyl }-the 2-thienyl) methyl]-2-oxygen-1,2-dihydro-3-ascorbyl palmitate
N-[(5-{[4-(hexyl amino)-piperidino] sulfonyl }-the 2-thienyl) methyl]-the 2-hydroxybenzamide
The 2-hydroxy-n-(5-[(4-{[4-(trifluoromethyl) benzyl] amino }-piperidino) sulfonyl]-the 2-thienyl } methyl) Benzoylamide
N-[(5-{[4-(hexyl amino)-piperidino] sulfonyl }-the 2-thienyl) methyl]-2-sulfo--1,2-dihydro-3-ascorbyl palmitate
2-sulfo--N-(5-[(4-{[4-(trifluoromethyl) benzyl] amino }-piperidino) sulfonyl]-the 2-thienyl } methyl)-1,2-dihydro-3-ascorbyl palmitate
N-[(5-{[4-(butyl amino)-piperidino] sulfonyl }-the 2-thienyl) methyl]-2-oxygen-1,2-dihydro-3-ascorbyl palmitate
N-({ 5-[(4-{ ethyl [4-(trifluoromethyl) benzyl] amino }-piperidino) sulfonyl]-the 2-thienyl } methyl)-the 3-methoxy benzamide
4-chloro-N-[(5-{[4-({ imido grpup [4-(trifluoromethyl) phenyl] methyl } amino)-piperidino] sulfonyl }-the 2-thienyl) methyl] Benzoylamide
The 1-[(5-{[(4-chlorobenzene formacyl) amino] methyl }-the 2-thienyl) sulfonyl]-4-(hexyl amino) proline
2-{[4-(hexyl amino) piperidines-1-yl] sulfonyl }-the 5-{[(3-anisoyl) amino] methyl } thiophene-3-carboxylic acid, ethyl ester
N-{[5-{[4-(hexyl amino) piperidines-1-yl] sulfonyl }-4-(trimethyl silicon based) thiophene-2-yl] methyl }-the 3-methoxy benzamide
N-(5-{[4-(hexyl amino) piperidines-1-yl] sulfonyl }-4-[hydroxyl (phenyl) methyl] thiophene-2-yl } methyl)-the 3-methoxy benzamide
5-[(3-methoxyl group-benzoyl-amido)-methyl]-2-[4-(4-trifluoromethyl-benzylamino)-piperidines-1-sulfonyl]-thiophene-3-carboxylic acid, ethyl ester
N-[(4-chloro-5-{[4-(hexyl amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl]-the 3-methoxy benzamide.
Formula (III) chemical compound can obtain according to the method that WO 01/23378, WO 02/28856 and WO 02/26733 describes in any a piece.
In another specific embodiment, jnk inhibitor can be pyrazolo anthracyclinone derivatives shown in the formula (C) (WO 01/12609):
In another specific embodiment, jnk inhibitor can have formula (IV) (WO 03/018022):
Below, the present invention will describe by embodiment, and its purpose is not to limit the present invention by any way.
Embodiment
Embodiment 1: model of endometriosis
The effect of assessment jnk inhibitor on the external and body inner model of endometriosis in uterus.
At two individual inner models ((1) nude mouse model; Rat model) and tested Drug therapy on the in-vitro multiplication organ culture model and suppressed endometriotic effectiveness (2).
Embodiment 1.1:N-cadherin is expressed
For experiment in vitro, adopt people's endometriosis cell (12Z) (Zeitvogel etc. 2001).These cells are invasive and express the N-cadherin, and few its N-cadherin level of cell of aggressive is low.Handle these cells with jnk inhibitor, with cell fixation in paraformaldehyde.With the specific antibody of anti-N-cadherin and cytokeratin, then with being connected the second antibody of Alexafluor (a kind of fluorescent dye) with these fixed cell dyeings.Observation of cell under fluorescence microscope, picked-up differs and fluorescence photo.The expression pattern of Fig. 1 representative cytokeratin and N-cadherin in these cells.Handle the expression (Fig. 1) that cell has reduced the N-cadherin with jnk inhibitor, show that this approach relates to the expression of N-cadherin and the invasion and attack activity of endometriosis.On the other hand, the expression of cytokeratin (epithelial labelling) does not change (Fig. 1) after with compound treatment.This shows, the influence of having only the endometriosis cell handled by jnk inhibitor, and epithelial cell is unaffected.Therefore, blocking-up JNK approach, the invasion and attack character that endometriosis is followed can be suppressed specifically, and this is very useful to the treatment endometriosis.
Embodiment 1.2: the nude mouse model
Give OO nude mouse injection people endometrial tissue to set up disease model (Bruner-Tran etc. 2002).In brief, will be cut into small pieces, in the presence of estradiol, cultivated 24 hours from the endometrium biopsy sample of normal volunteer or endometriosis patient acquisition.With the treated oophorectomize nude mouse subcutaneous or that lumbar injection has gone into to implant estradiol of organizing.In 2-4 days of injection, ectopic endometriosis damage appears in animal.Injection tissue back 10-12 days is with Progesterone or jnk inhibitor treatment.The dosage of chemical compound is each animal 10mg/kg and 30mg/kg, treats 30 days.Adopt the initial stage work of this model to determine the progress of Progesterone treatment preventable disease, therefore used as contrast.After treatment is finished,, measure in the subcutaneous and being seen damage (its size and quantity) in intraperitoneal position by transplanted tissue's development with sacrifice of animal.
Following table 1 shows aforesaid result of study.Compare with the Progesterone treatment, jnk inhibitor (dosage 30mg/kg) is effective to the recovery of establishing disease in 50% animal.Treatment makes the size of average damage location reduce 20%.In another experiment of carrying out with TBP, the number of observing ill animal reduces 60% than positive control Progesterone, but the size of damage location is had no effect.These results are very important because this model measurement the growth/recovery of people's endometrial tissue, therefore the treatment for human diseases has direct dependency.
Table 1:JNK inhibitor (jnk inhibitor shown in the formula I) and protein immunization regulator
Endometriosis in the nude mouse xenograft models is damaged restorative effect
| Treatment | Damage (% Progesterone) is compared with Progesterone treatment group | The damage location size | |
| Jnk inhibitor 30mg/kg * 30 day | Reduce 50 | Reduce | 20% |
| TBP-1 (contrast) 5mg/kg * 30 days | Reduce 60% | No change |
In the experiment of another nude mouse, obtain people's endometrial tissue from the endometriosis patient, only there is estradiol, cultivating 24 hours under the condition of have estradiol+medroxyprogesterone (MPA) or jnk inhibitor.Then with treated organize subcutaneous or lumbar injection to implanting the oophorectomize nude mouse that estradiol is arranged.In 2-4 days of injection, ectopic endometriosis damage appears in animal.Injection tissue back 10-12 days begins to treat with MPA (separately), jnk inhibitor (separately) or MPA+JNK inhibitor.Jnk inhibitor dosage is each animal 30mg/kg, treats 30 days.After treatment is finished,, measure in the subcutaneous and being seen damage (its size and quantity) in intraperitoneal position by transplanted tissue's development with sacrifice of animal.It is about 50% that the therapeutic alliance of jnk inhibitor shown in MPA and the formula 1 reduces the damage load, and the damage location size reduces about 15-30% (comparing with the damage location size with single damage load for the treatment of mice with estradiol).These results show, jnk inhibitor and ethisterone shown in the formula 1 to share treating and/or preventing on the endometriosis be effective.
Embodiment 1.3: rat model
As described (D ' Antonio et al 2000) in early time, on rat, cause endometriosis.In brief, will be transplanted to the rat abdominal cavity inner face from body cornua uteri fragment.After transplanting for three weeks, measure the size and the viability of engraft tissue.All begin treatments after the affirmation tissue apposition.Matched group is only accepted excipient.Orally give (po) jnk inhibitor, every day dosage 10mg/kg and 30mg/kg.Carried out 9 days with the jnk inhibitor treatment, treat back 2 hours the last time, collect blood sample Animal Anesthesia.Measure the surface area of endometriosis sample focus,, collect offside uterine irrigation liquid simultaneously, be used to measure cytokine with PBS flushing endometriosis sample focus.Extract endometriosis sample focus and spleen, be respectively applied for histology and NK cytoactive and measure.In this model, its effect and excipient indifference when jnk inhibitor dosage is 10mg/kg are obviously restored (Fig. 2) but observe the endometriosis damage of having set up when 30mg/kg and 60mg/kg.Show that with peace peptide (being used for comparison) treatment about 85% restores (data does not show).
Embodiment 1.4: the mensuration of rat model/cytokine levels
The other meaning that shows from these current research is in the endometriosis focus or does not have the cytokine levels change that records in the offside cornua uteri of any damage.In rat model, measure the influence (seeing embodiment 1.3) of jnk inhibitor pair cell factor level.The result proves, with the level (Fig. 3) of jnk inhibitor treatment reduction inflammatory cytokine in the endometriosis focus (IL-12, INF-, IL-10 and MCP-1).Before these cytokine levels improve in ill women's ascites report was arranged.Expression to the side angle jnk inhibitor pair cell factor does not have influence (Fig. 4).In addition, inhibitor is handled than vehicle-treated group NK cytoactive and is improved (Fig. 5).The visible lymphocytic dissolved cell activity of women of suffering from endometriosis reduces.Therefore, these results suggest are treated the increase of the NK cell dissolved cell activity that produces and can be facilitated the endometrial elimination of dystopy because of jnk inhibitor.In addition, about these results suggest of jnk inhibitor, the effect of inhibitor can be treated illing tissue and do not influenced the part of anosis uterus or peritoneal cavity.
The immune system of rat is complete in this model, regulates approach if the main mechanism of prompting molecule only influences host immune, and the effect of this molecule in this model is observed strong on should be than nude mouse.In fact, this molecule of these results suggest that obtains from nude mouse and rat model is directly at the immunocyte group's who keeps endometriotic tissue or the nude mouse important activity.Another key character of rat model is that complete myometrium and endometrial tissue are that excision is implanted laboratory animal.Integrate, relevant with endometriosis from the display target as a result that these two model systems obtain to the inhibitors of kinases of JNK approach, can be effective therapeutic agent of this disease.
Embodiment 1.5: increase nitre organ culture model
Make a definite diagnosis endometriosis women biopsy from donor group (ametria endometrium ectopia history) and operation and obtain normal endometrial tissue before the ovulation.Obtain informed consent before biopsy, the use of tissue obtains the approval of ten thousand Derbilt University College board of review (Vanderbilt University ' s Institutional ReviewBoard) and experimenter protective committee (Committee for the Protection of Human Subjects).
With endometrium biopsy sample morsel (about 1 * 1mm
3), each processed group 8-10 block organization is suspended in tissue culture's insert.The organ culture maintains and contains among the serum DME/F-12, and 37 ℃, totally 72 hours.Organized processing comprises 17 beta estradiols (E), E+ Progesterone (P) or E+ medroxyprogesterone (MPA), has or do not have jnk inhibitor.Culture only maintains among the E 24 hours, begins until experiment condition.The working concentration of jnk inhibitor is 5 or 15 μ M, and the working concentration of MPA is 50,100 or 250 μ M.Collect culture medium from organ cultures, excretory protein is carried out quantitative analysis, 20 μ g total proteins are added on the 10%SDS-PAGE with coomassie+albumen test (Coomassie Plus Protein Assay) (Pierre Si (Pierce)).Albumen is transferred on the PBDF film, in the PBS that contains 10% skimmed milk and 0.05% tween 20, sealed.4 ℃ of overnight incubation in the PBS/ skimmed milk/tween of the first antibody (label of endometrial tissue) that contains identification people MMP-3, washing was cultivated 1 hour with second antibody.Show protein with chemiluminescence (Amersham) and autoradiography.Same speckle is cultivated as negative control under the condition of no first antibody.
The result shows that opposite with the endometrium culture that derives from the endometriosis patient (list can not recover with MPA), normal person's endometrium culture is to the MPA sensitivity.When jnk inhibitor and MPA shown in the formula 1 handle when share, the culture that obtains from the endometriosis patient recovers the sensitivity of MPA, and the culture that obtains from normal volunteer is still kept the sensitivity to MPA.
These results show that endometriotic reconstruction can be treated and prevent to the jnk inhibitor drug combination shown in ethisterone and the formula 1.
List of references
Barcz etc., (2000) Med.Sci.Monit 6,1042-46
Bruner-Tran etc., Ann NY Acad Sci., 955:328-339 (2002)
Bulun etc., Mol.And Cell.Endocrinol., 248:94-103 (2006)
D’Antonio?et?al.，J.Reprod?Immunol.48：81-98(2000)
D ' Hooghe etc., ASRM (2001)
Dawood, M.Y etc., (1993) Int.J.Gynaecol.Obstet.40 (Suppl.), 29-42
Dent etc., (2003) Oncogene, 22,5885-96
Gupta, S. etc., (1996) EMBO is J.15:2760-2770
Frixen etc., J.Cell Biology (1991) 113,173-85
Giudice etc., (2004) Lancet 364,1789-99
Kyama etc., (2003) Reprod Biol Endocrinol.1,123
Waller etc., (1993) Fertil.Steril.59,511-515
Yoshino etc., (2004) Am J Reprod Immunol.52,306-11
Zeitvogel etc., (2001) Am.J Pathol.1591839-52
EP?160,699
EP?211,894
EP?322,438
WO?92/13095
WO?00/35909
WO?00/75118
WO?00/35906
WO?00/35920
WO?00/64872
WO?01/47920
WO?01/12621
WO?01/12609
WO?01/23378
WO?01/23379
WO?01/23382
WO?02/28856
WO?02/26733
WO?03/018022
Claims (23)
1. a method that treats and/or prevents individual endometriosis comprises the jnk inhibitor for the treatment of effective dose.
2. the method for claim 1, wherein described jnk inhibitor and hormone inhibitors administering drug combinations.
3. method as claimed in claim 1 or 2, wherein, described hormone inhibitors is selected from GnRH antagonist, GnRH agonist, aromatase inhibitor, progesterone receptor adjusting control agent and estrogen receptor adjusting control agent.
4. as the described method of one of claim 1-3, wherein, jnk inhibitor is individually dosed or share with other fertility drug of treatment endometriosis dependency infertility.
5. as the described method of one of claim 1-4, wherein, jnk inhibitor is a benzothiazole derivant shown in the formula (I)
And tautomer, its geometric isomer, its optical activity form, as enantiomer, diastereomer and racemic form, with and pharmaceutically acceptable salt, wherein
G is a pyrimidine radicals;
L is C
1-C
6-alkoxyl, or amino, or 3-8 unit Heterocyclylalkyl, comprise the hetero atom that at least one is selected from N, O, S;
R
1Be selected from by hydrogen, sulfonyl, amino, C
1-C
6-alkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl or C
1-C
6The group that-alkoxyl, aryl, halogen, cyano group and hydroxyl are formed.
6. as the described method of one of claim 1-5, wherein, R
1Be H or C
1-C
3Alkyl.
7. as the described method of one of claim 1-6, wherein, jnk inhibitor has formula (Ia), (Ia ') or (Ia "):
Wherein, R
1Be selected from by hydrogen, sulfonyl, amino, C
1-C
6-alkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl or C
1-C
6The group that-alkoxyl, aryl, halogen, cyano group and hydroxyl are formed;
L is formula-NR
3R
4Shown in amino, R wherein
3And R
4Be H, C independently of each other
1-C
6-alkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, C
1-C
6-alkoxyl, aryl, heteroaryl, saturated or unsaturated 3-8-unit cycloalkyl, 3-8-unit Heterocyclylalkyl (wherein said cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can again with 1-2 cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl-condensed), C
1-C
6-alkylaryl, C
1-C
6-miscellaneous alkyl aryl, C
2-C
6-alkenyl aryl, C
2-C
6-thiazolinyl heteroaryl, C
2-C
6-alkynyl aryl, C
2-C
6-alkynyl heteroaryl, C
1-C
6-alkyl-cycloalkyl, C
1-C
6-alkyl heterocycle alkyl, C
2-C
6-thiazolinyl cycloalkyl, C
2-C
6-thiazolinyl Heterocyclylalkyl, C
2-C
6-alkynyl cycloalkyl, C
2-C
6-alkynyl Heterocyclylalkyl, or
R
3And R
4The nitrogen that can be connected with them is ring formation together.
8. as the described method of one of claim 1-7, wherein, R
3Be hydrogen or methyl or ethyl or propyl group,
And R
4Be selected from (C
1-C
6)-alkyl, C
1-C
6Alkyl-aryl, C
1-C
6Saturated or the unsaturated cycloalkyl of-alkyl-heteroaryl, cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl and 4-8 unit.
9. as the described method of one of claim 1-8, wherein, R
3And R
4The nitrogen that is connected with them forms piperazine or piperidines or morpholine or the pyrrolidine ring that can choose replacement wantonly together, and wherein said optional substituent group is selected from C
1-C
6-alkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, C
1-C
6-alkoxyl, aryl, heteroaryl, saturated or unsaturated 3-8-unit cycloalkyl, 3-8-unit Heterocyclylalkyl (wherein said cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl can again with 1-2 cycloalkyl, Heterocyclylalkyl, aryl or heteroaryl-condensed), C
1-C
6-alkylaryl, C
1-C
6-miscellaneous alkyl aryl, C
2-C
6-alkenyl aryl, C
2-C
6-thiazolinyl heteroaryl, C
2-C
6-alkynyl aryl, C
2-C
6-alkynyl heteroaryl, C
1-C
6-alkyl-cycloalkyl, C
1-C
6-alkyl heterocycle alkyl, C
2-C
6-thiazolinyl cycloalkyl, C
2-C
6-thiazolinyl Heterocyclylalkyl, C
2-C
6-alkynyl cycloalkyl, C
2-C
6-alkynyl Heterocyclylalkyl.
10. as the described method of one of claim 1-9, wherein, L is selected from:
Wherein n is 1-10, preferred 1-6;
R
5And R
5' be selected from H, C independently of each other
1-C
6Alkyl, aryl or heteroaryl, C
1-C
6Alkyl-aryl and C
1-C
6-alkyl-heteroaryl.
11. as the described method of one of claim 1-10, wherein, L is selected from:
Wherein n is 1-10, preferred 1-6;
R
5And R
5' be selected from H, C independently of each other
1-C
10Alkyl, aryl or heteroaryl, C
1-C
6Alkyl-aryl and C
1-C
6-alkyl-heteroaryl.
12. as the described method of each claim of front, wherein, jnk inhibitor is:
1, and 3-benzothiazole-2-base (2-{[4-(morpholine-4-ylmethyl) benzyl] oxygen } pyrimidine-4-yl) acetonitrile.
13. as the described method of one of claim 1-3, wherein, jnk inhibitor is formula (III) chemical compound
And geometric isomer, its optical activity form, as enantiomer, diastereomer and racemic form, and pharmaceutically acceptable salt, wherein
Y is 4-12-unit saturated rings or the bicyclic alkyl that contains at least one nitrogen-atoms, nitrogen-atoms in the wherein said ring and sulfonyl Cheng Jian shown in the formula III, generation sulfonamide;
R
1Be selected from by hydrogen, C
1-C
6-alkoxyl, C
1-C
6-alkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, amino, sulfane base, sulfinyl, sulfonyl, sulfonyl oxygen base, sulfonamide, acyl amino, amino carbonyl, C
1-C
6The group that alkoxy carbonyl, aryl, heteroaryl, carboxyl, cyano group, halogen, hydroxyl, nitro and hydrazides are formed;
R
2Be selected from by hydrogen, COOR
3,-CONR
3R
3', OH, by OH or the amino C that replaces
1-C
4The group that alkyl, hydrazide group carbonyl, sulfate, sulfonate, amine or ammonium salt are formed, wherein R
3, R
3' be independently selected from H, C
1-C
6-alkyl, C
2-C
6-thiazolinyl, aryl, heteroaryl, aryl-C
1-C
6-alkyl and heteroaryl-C
1-C
6-alkyl.
14. method as claimed in claim 13, wherein, R
1Be selected from hydrogen, halogen, C
1-C
6Alkyl and C
1-C
6The group that alkoxyl is formed.
15. as claim 13 or 14 described methods, wherein, Y is the cyclammonium with one of general formula (a)-(d):
Wherein, L
1And L
2Be selected from C independently of each other
1-C
6-alkyl, C
2-C
6-thiazolinyl, C
2-C
6-alkynyl, randomly contain 1-3 hetero atom and randomly with aryl or heteroaryl-condensed C
4-C
8-cycloalkyl; Perhaps, L
1And L
2Be independently selected from aryl, heteroaryl, aryl-C
1-C
6-alkyl, heteroaryl-C
1-C
6-alkyl ,-C (O)-OR
3,-C (O)-R
3,-C (O)-NR
3' R
3,-NR
3' R
3,-NR
3' C (O) R
3,-NR
3' C (O) NR
3' R
3The R of ,-(SO)
3,-(SO
2) R
3,-NSO
2R
3With-SO
2NR
3' R
3, R wherein
3, R
3' be independently selected from H, C
1-C
6-alkyl, C
2-C
6-thiazolinyl, aryl, heteroaryl, aryl-C
1-C
6-alkyl and heteroaryl-C
1-C
6-alkyl;
Perhaps, L
1And L
2Can form 4-8-unit's saturated cyclic alkyls or assorted alkyl ring together; And
R
6Be selected from hydrogen, C
1-C
6-alkyl, C
1-C
6-alkoxyl, OH, halogen, nitro, cyano group, sulfonyl, oxygen (=O), and
N ' is the integer of 0-4, preferred 1 or 2.
16. as the described method of one of claim 13-15, wherein, R
6Be H, L
2Be H, L
1Be-NR
3' R
3R wherein
3' and R
3In at least one is not a hydrogen, but a substituent group is selected from straight or branched C
4-C
18-alkyl, aryl-C
1-C
18-alkyl, heteroaryl-C
2-C
18-alkyl, by C
3-C
12-cycloalkyl or-dicyclo or-C that tricyclic alkyl replaces
1-C
14-alkyl, wherein said alkyl chain can contain 1-3 O or S atom.
17. as the described method of one of claim 13-16, wherein, L
1Be-NHR
3R wherein
3Be straight or branched C
4-C
12-alkyl is preferably by cyclohexyl or the optional C that replaces of benzyl
6-C
12-alkyl.
18. as the described method of one of claim 13-17, wherein, Y is the piperidines group
L
1Be-NHR
3R wherein
3Be straight or branched C
4-C
12-alkyl, preferred C
8-C
12-alkyl or benzyl.
19. as the described method of one of claim 13-18, wherein, jnk inhibitor is selected from the group that following chemical compound is formed:
1,3-benzothiazole-2-base (2-{[2-(3-pyridine radicals) ethyl] amino }-the 4-pyrimidine radicals) acetonitrile
4-chloro-N-[(5-{[4-(butyl amino) piperidines-1-yl] sulfonyl } thiophene-2-yl) methyl] the Benzoylamide acetonitrile.
20. comprise the pharmaceutical composition of jnk inhibitor, hormone inhibitors and pharmaceutically acceptable excipient.
21. pharmaceutical composition as claimed in claim 20, wherein, described hormone inhibitors is selected from GnRH antagonist, GnRH agonist, aromatase inhibitor, progesterone receptor adjusting control agent and estrogen receptor adjusting control agent.
22. as claim 20 or 21 described pharmaceutical compositions, wherein, described jnk inhibitor is a benzothiazole derivant shown in the defined formula (I) among the claim 5-12, or chemical compound shown in the defined formula (III) among the claim 13-19.
23. as the described pharmaceutical composition of one of claim 20-22, wherein, described benzothiazole derivant is 1, and 3-benzothiazole-2-base (2-{[4-(morpholine-4-ylmethyl) benzyl] oxygen } pyrimidine-4-yl) acetonitrile.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US69965805P | 2005-07-15 | 2005-07-15 | |
| US60/699,658 | 2005-07-15 | ||
| EP05109447.2 | 2005-10-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101262906A true CN101262906A (en) | 2008-09-10 |
Family
ID=39962917
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800335920A Pending CN101262906A (en) | 2005-07-15 | 2006-07-12 | JNK inhibitors for the treatment of endometreosis |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN101262906A (en) |
| UA (1) | UA89242C2 (en) |
| ZA (1) | ZA200800245B (en) |
-
2006
- 2006-07-12 UA UAA200800235A patent/UA89242C2/en unknown
- 2006-07-12 ZA ZA200800245A patent/ZA200800245B/en unknown
- 2006-07-12 CN CNA2006800335920A patent/CN101262906A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| UA89242C2 (en) | 2010-01-11 |
| ZA200800245B (en) | 2009-08-26 |
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