CN101529254A - Organic compounds - Google Patents

Abstract

A method to predict which patients will respond to an IAP inhibiting compound comprising: a) administering an IAP inhibitor compound to a patient, and b) measuring TNF-a or IL-8 levels.

Description

Organic compound

Background of invention

Tumor necrosis factor (TNF-α) is the cell factor that is mainly discharged by inflammation and mononuclear macrophage in response to immunostimulant.TNF-α can promote the most cells process, such as break up, raise, proliferation function and protein degradation effect.When low-level, TNF-α resists the protection of infective agent, tumour and tissue damage.But TNF-α also has effect in numerous disease.When being applied to mammal such as the mankind, TNF-α causes or aggravates inflammation, fever, cardiovascular effect, hemorrhage, blood coagulation and the similar acute stage response of finding during acute infection and shock state.The TNF-α that improves or raise generates and has involved numerous disease and medical conditions, and for example, cancer is such as solid tumor and the tumour of coming autoblood; Heart disease, such as congestive heart failure; With virus, heredity, inflammatory, allergy and autoimmune disease.

Found to as the compound of single-activity agent (suppressing Smac albumen combines with IAP) (hereinafter " IAP inhibitor compound ") extremely sensitive (IC₅₀In＜500nM) the tumor cell line, antitumor activity comes from the release of the short apoptosis autocrine TNF-alpha signal loop of blocking-up.The coordination result who discharges this blocking-up is increase and the alpha mediated apoptotic promotion of TNF-that TNF-α generates.Proliferative diseases in the scope of the invention is that TNF-alpha signal composing type is opened those diseases of (constitutively on).

At present not understanding the IAP inhibitor compound is how to regulate and control the TNF-alpha levels.But because cell factor IL-B generates in response to TNF-α, the cytokine levels in circulation blood (being IL-B) can influence the therapeutic action of IAP inhibitor compound and therefore can be used as biomarker.

The present invention also relates to prediction and suffers from the method for the patient of TNF-α response disease to the response of IAP inhibitor compound.Especially, the present invention relates to by measuring patient's response of TNF-alpha levels prediction IAP inhibitor compound, mensuration may be before treatment and after the treatment.

Summary of the invention

The present invention, as this paper the following stated by provide mensuration with composing type TNF-alpha signal conduction be the individuality of disease of feature in response to the method for IAP inhibitor compound, overcome in IAP inhibitor compound defective in use.

In another embodiment, the present invention relates to suppress compound that Smac protein combines with IAP (" IAP inhibitor "), to be used for the conduction of composing type TNF-alpha signal be the purposes of the disease treatment of feature, being used for the treatment of with composing type TNF-alpha signal conduction with preparation is the method for medicine of the disease of feature, and be used for the treatment of warm-blooded animal, comprise human methods of treatment, wherein the IAP inhibitor is applied to that to suffer from composing type TNF-alpha signal conduction be the disease of feature, particularly be subjected to the proliferative diseases that cell factor generates to be influenced, such as cancer, arthritis, pyemia, the cachexia that cancer is relevant, the warm-blooded animal of Crohn disease and other inflammatory disorder.

Description of drawings

Fig. 1 show (a) in a series of tumor cell lines to the correlativity between Compound I I and the horizontal sensitivity of TNF mRNA.(b), the tumor cell line of IAP inhibitor compound sensitivity induced improve TNF mRNA level as their part of response.

Fig. 2 is presented in the SKOV-3 cell, the rising in dosage dependence mode of the TNF α mRNA relevant with III with Compound I I.

Detailed Description Of The Invention

One embodiment of the invention provide the prediction patient that the method for response will be arranged the IAP inhibitor compound, and wherein the patient suffers from the disease take the conduction of composing type TNF-alpha signal as feature, and Forecasting Methodology comprises:

A) to the patient use the IAP inhibitor compound and

B) TNF-α and/or the IL-8 level among the described patient of mensuration.

If the TNF-alpha levels among the patient suppresses using of compound along with IAP and raises, this is this compound indication just in action.

In another embodiment, the present invention relates to suppress the purposes of medicine that compound treatment that Smac protein combines with IAP (" IAP inhibitor ") is the disease of feature with the conduction of composing type TNF-alpha signal.

The inhibition compound combined I AP inhibitor for treating that the present invention also relates to by using the other medicines combination of conducting with TNF-α, interferon-alpha, IFN-or adjusting TNF-alpha signal is the method for the disease of feature with the conduction of composing type TNF-alpha signal.

The example of the IAP inhibitor of Shi Yonging comprises formula I compound or the acceptable salt of its medicine in the present invention:

Wherein:

R₁Be H, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl or C₃-C₁₀Naphthenic base, wherein R₁Can be not and to replace or replace;

R₂Be H, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₃-C₁₀Naphthenic base, wherein R₂Can be not and to replace or replace;

R₃Be H, CF₃, C₂F₅, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, CH₂-Z or R₂And R₃The nitrogen-atoms that is connected with them lumps together the formation heterocycle, and wherein alkyl, alkenyl, alkynyl or het ring can be not replace or replace;

Z is H, OH, F, Cl, CH₃, CH₂Cl, CH₂F or CH₂OH;

R₄Be C₀-C₁₀Alkyl, C₃-C₁₀Naphthenic base, wherein C₀-C₁₀Alkyl or group of naphthene base are not replace or replace;

A is het, and it can be replacement or unsubstituted;

D is C₁-C₇Alkylidene, C₂-C₉Alkylene group, C (O), O, NR₇, S (O) r, C (O)-C₁-C₁₀Alkyl, O-C₁-C₁₀Alkyl, S (O) r-C₁-C₁₀Alkyl, C (O) C₀-C₁₀Aryl alkyl OC₀-C₁₀Aryl alkyl or S (O) rC₀-C₁₀Aryl alkyl, wherein alkyl and aromatic yl group can be not and to replace or replace;

R is 0,1 or 2;

A₁Be aryl that replaces or the het that does not replace or replace, the substituting group on its aryl and the het is halogen, lower alkoxy, NR₅R₆, CN, NO₂Or SR₅

Each Q is H, C independently₁-C₁₀Alkyl, C₁-C₁₀Alkoxy, aryl C₁-C₁₀Alkoxy, OH, O-C₁-C₁₀Alkyl, (CH₂)_0-6-C₃-C₇Naphthenic base, aryl, aryl C₁-C₁₀Alkyl, O-(CH₂)_0-6-aryl, (CH₂)_1-6-het, het, O-(CH₂)_1-6Het ,-OR₁₁, C (O) R₁₁,-C (O) N (R₁₁) (R₁₂), N (R₁₁) (R₁₂), SR₁₁, S (O) R₁₁, S (O)₂R₁₁, S (O)₂N (R₁₁) (R₁₂) or NR₁₁-S (O)₂-(R₁₂), wherein alkyl, naphthenic base and aryl are not replace or replace;

N is 0,1,2 or 3,4,5,6 or 7;

Het comprises the 5-7 unit monocyclic heterocycles that 1-4 is selected from the heteroatom of N, O and S, or comprises a heterocyclic fused member ring systems of 8-12 unit that contains the 5-7 unit monocyclic heterocycles of 1,2 or 3 heteroatom that is selected from N, O and S, and wherein het is unsubstituted or replaces;

R₁₁And R₁₂Be H, C independently₁-C₁₀Alkyl, (CH₂)_0-6-C₃-C₁₀Naphthenic base, (CH₂)_0-6-(CH)_0-1(aryl)_1-2, C (O)-C₁-C₁₀Alkyl ,-C (O)-(CH₂)_1-6-C₃-C₇Naphthenic base ,-C (O)-O-(CH₂)_0-6-aryl ,-C (O)-(CH₂)_0-6-O-fluorenyl, C (O)-NH-(CH₂)_0-6-aryl, C (O)-(CH₂)_0-6-aryl, C (O)-(CH₂)_1-6-het ,-C (S)-C₁-C₁₀Alkyl ,-C (S)-(CH₂)_1-6-C₃-C₇Naphthenic base ,-C (S)-O-(CH₂)_0-6-aryl ,-C (S)-(CH₂)_0-6-O-fluorenyl, C (S)-NH-(CH₂)_0-6-aryl ,-C (S)-(CH₂)_0-6-aryl or C (S)-(CH₂)_1-6-het, C (O) R₁₁, C (O) NR₁₁R₁₂, C (O) OR₁₁, S (O)_nR₁₁, S (O)_mNR₁₁R₁₂, m=1 or 2, C (S) R₁₁, C (S) NR₁₁R₁₂, C (S) OR₁₁, wherein alkyl, naphthenic base and aryl are not replace or replace; Or R₁₁And R₁₂Be the substituting group that promotes the transhipment of molecule cross-cell membrane, perhaps R₁₁And R₁₂Form het together with nitrogen-atoms;

R wherein₁₁And R₁₂Alkyl substituent can be for unsubstituted, or by one or more C that are selected from₁-C₁₀Alkyl, halogen, OH, O-C₁-C₆Alkyl, S-C₁-C₆Alkyl, CF₃Or NR₁₁R₁₂Substituting group replace;

R₁₁And R₁₂The naphthenic substituent of replacement by one or more C that are selected from₂-C₁₀Alkylidene, C₁-C₆Alkyl, halogen, OH, O-C₁-C₆Alkyl, S-C₁-C₆Alkyl, CF₃, or NR₁₁R₁₂Substituting group replace; And

R₁₁And R₁₂The het of replacement or the aryl of replacement by one or more halogen, hydroxyl, C of being selected from₁-C₄Alkyl, C₁-C₄Alkoxy, nitro, CN, O-C (O)-C₁-C₄Alkyl and C (O)-O-C₁-C₄The substituting group of alkyl replaces;

R₅, R₆And R₇Be hydrogen, low alkyl group, aryl, aromatic yl elementary alkyl, naphthenic base or cycloalkyl low-grade alkyl independently; And

R wherein₁, R₂, R₃, R₄, Q and A and A₁Substituting group on the group is halogen independently; hydroxyl; low alkyl group; low-grade alkenyl; low-grade alkynyl; low-grade alkane acidyl; lower alkoxy; aryl; aromatic yl elementary alkyl; amino; amino low alkyl group; two elementary alkyl amido; low-grade alkane acidyl; amino lower alkoxy; nitro; cyano group; cyano-lower alkyl group; carboxyl; lower alkoxycarbonyl; low-grade alkane acidyl; aroyl; the lower aryl alkanoyl; carbamyl; the N-list-or N, N-two elementary alkyl amido formoxyl; the lower alkyl-ammonium carbamate; amidino groups; guanidine radicals; urea groups; sulfydryl; sulfo group; lower alkylthio; sulfo group amino; sulfonamide; benzene sulfinyl amine; sulfonate; sulfane base low alkyl group; aryl sulfonic acid amides; arylsulphonate or ester that halogen replaces; the low alkyl group sulfinyl; aryl sulfonyl kia; the aryl lower alkyl sulfinyl; the low-grade alkylaryl sulfinyl; the low alkyl group sulfonyl; aryl sulfonyl; the aryl lower alkyl sulfonyl; lower aryl alkyl low-grade alkylaryl sulfonyl; halogen-low alkyl group sulfydryl; halogen-low alkyl group sulfonyl; phosphono (P (=O) (OH)₂), hydroxyl-lower alkoxy phosphoryl or two lower alkoxy phosphoryls, (R₉) NC (O)-NR₁₀R₁₃, lower alkyl-ammonium carbamate or carbamate or-NR₈R₁₄, R wherein₈And R₁₄Can be identical or different, and be H or low alkyl group, perhaps R independently₈And R₁₄Form 3 to 8 yuan of heterocycles that comprise the azacyclo-atom together with the N atom; and can randomly comprise one or two other nitrogen that is selected from; the heteroatom of oxygen and sulphur; its heterocycle can be unsubstituted or is replaced by following group: low alkyl group; halogen; low-grade alkenyl; low-grade alkynyl; hydroxyl; lower alkoxy; nitro; amino; low alkyl group; amino; two elementary alkyl amido; cyano group; carboxyl; lower alkoxycarbonyl; formoxyl; low-grade alkane acidyl; oxo; carbamyl; rudimentary or the N of N-; N-two elementary alkyl amido formoxyl; sulfydryl; or lower alkylthio, and

R₉, R₁₀And R₁₃Be the aryl that replaces of low alkyl group, aryl, aromatic yl elementary alkyl, halogen that hydrogen, low alkyl group, halogen replace, the aromatic yl elementary alkyl that halogen replaces independently.The compound in formula (I) scope and the method for preparation thereof are disclosed in US 60/835,000, are incorporated herein among the application as a reference.Preferred compound is selected from following and pharmaceutically acceptable salt: (S)-N-((S)-1-cyclohexyl-2-{ (S)-2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidine-1-yl }-2-oxo-ethyl)-2-methylamino-propionamide (Compound I I); (S)-N-[(S)-cyclohexyl-(ethyl-(S)-1-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-propyl group } carbamyl)-methyl]-2-methylamino-propionamide (compound III); (S)-N-[(S)-1-cyclohexyl-2-{ (S)-2-[5-(4-fluoro-phenoxy group)-pyridin-3-yl]-pyrrolidine-1-yl }-2-oxo-ethyl)-2-methylamino-propionamide; With N-[1-cyclohexyl-2-(2-{2-[(4-fluorophenyl)-methyl-amino]-pyridin-4-yl } pyrrolidine-1-yl)-2-oxo-ethyl]-2-methylamino-propionamide.

The example of other IAP inhibitor comprises disclosed compound among the WO 05/097791 that published on October 20th, 2005, and it is introduced among the application as a reference.In formula (I) scope preferred compound be N-[1-cyclohexyl-2-oxo-2-(6-phenethyl-octahydro-pyrrolo-[2,3-c] pyridine-1-base-ethyl]-2-methylamino-propionamide, hereinafter be called Compound I I.

Other IAP inhibitor comprises the compound that is disclosed among WO04/005284, PCT/US2006/013984, the PCT/US2006/021850, the application quote wherein whole compounds as a reference.

Other IAP inhibitor compounds that use among the application comprise the compound that is disclosed in WO 06/069063, WO05/069888, US2006/0014700, WO04/007529, US2006/0025347, WO06/010118, WO05/069894, WO06/017295, WO04/007529, WO05/094818.

Under the situation of the patented claim that on any quoting, provides, introduce the application as a reference about the theme of compound is whole.Equally also comprise wherein disclosed their pharmaceutically acceptable salt, corresponding raceme, diastereo-isomerism, enantiomter, dynamic isomer, and (if existence) above disclosed compound corresponding crystal modified outcome, for example, solvate, hydrate and polymorphic.The compound that is used as activating agent in combination of the present invention can be prepared and use according to the method for describing in institute's reference document respectively.The combination that surpasses 2 kinds of above-mentioned independent active components in addition within the scope of the present invention, that is, drug regimen within the scope of the present invention can comprise three kinds or more kinds of active component.

Term " treatment " (treatment) or " treatment " (therapy) (particularly tyrosine protein kinase dependence disease or obstacle) be meant the preventative or preferred therapeutic treatment (including but not limited to mitigation, healing, symptom-alleviation, symptom-alleviate, kinase regulatory and/or kinases-inhibition) of described disease, particularly following disease.

Warm-blooded animal (or patient) is preferably mammal, and is particularly human.

Mention that hereinafter or above term " purposes " (as verb or noun) (purposes that relates to the IAP inhibitor) locates, this (if be not indicated as being difference or prompt for difference in context) comprises the embodiment (except as otherwise noted) below any or multiple the present invention respectively: the purposes in disease (particularly alpha mediated by excessive TNF-or the disease that increases the weight of or be the disease of feature with the conduction of composing type TNF-alpha signal) treatment, be used to prepare treatment or the disease that increase the weight of alpha mediated or be the purposes of pharmaceutical composition of the disease of feature with the conduction of composing type TNF-alpha signal by excessive TNF-, it in or the disease that increase the weight of alpha mediated or with the conduction of composing type TNF-alpha signal the using method of one or more IAP inhibitor in the disease treatment of feature by excessive TNF-, comprise and be used for or the disease that increase the weight of alpha mediated or be the pharmaceutical preparation of one or more IAP inhibitor of the described disease treatment of feature with the conduction of composing type TNF-alpha signal by excessive TNF-, and in or the disease that increase the weight of alpha mediated or to constitute one or more IAP inhibitor in the described disease treatment that the conduction of TNF-alpha signal is a feature by excessive TNF-, with suitable and advantageous forms, unless otherwise stated.Especially, the disease that will treat and therefore be selected from alpha mediated or the disease that increases the weight of or be the disease of feature with the conduction of composing type TNF-alpha signal by excessive TNF-to the preferred disease of IAP inhibitor " purposes ".

The purposes of the IAP inhibitor of the treatment (comprising prevention) of proliferative disorder (being feature particularly) preferably with composing type TNF-alpha signal conduction, described proliferative disorder is selected from tumour or Cancerous disease, especially preferably resist benign tumour or particularly malignant tumour or Cancerous disease, more preferably solid tumor, brain for example, kidney, liver, adrenal gland, bladder, breast, stomach (particularly tumor stomach), ovary, colon, rectum, prostate, pancreas, lung (for example, cellule or maxicell lung cancer), vagina, thyroid gland, sarcoma, glioblastoma, Huppert's disease (MM) or human primary gastrointestinal cancers, particularly colon cancer or the knot adenomas, or head and tumor colli, for example the head and carcinoma of neck, comprise neoformation, epithelial character particularly, for example, the situation of breast cancer; Hyperproliferative epidermal (but not cancer), particularly psoriasis; Hypertrophy of the prostate; Or leukaemia, particularly acute myeloblastic leukemia (AML) and chronic myelocytic leukemia (CML).

The exact dose of employed IAP inhibitor compound depends on several factors, the attribute of the illness of comprise the host, being treated and seriousness, mode of administration.The IAP inhibitor compound can be used by any approach, comprises oral, parenteral, for example in the peritonaeum, in vein, muscle, subcutaneous, the tumour or any approach in rectum or the intestines.Preferred IAP inhibitor compound is Orally administered, preferred every day dosage 1-300mg/kg body weight, or, for the bigger primate of great majority, every day dosage 50-5000,500-3000mg preferably.Preferred every day, oral dose was the 1-75mg/kg body weight, or for the bigger primate of great majority, every day dosage 10-2000mg, with single dose or be divided into a plurality of dosage, such as twice administration every day.

Usually, initially use, and dosage increases the optimal dose until the host of determined treatment gradually with low dose.The dosage upper limit is the dosage that spinoff is arranged, and can pass through the host's that treated test and determine.

Dosage must progressively be determined at patient's concrete indication, age, body weight and overall physical qualification and required response, but general dosage is from about 10 to about 500mg/ days, on demand once-a-day administration or repeatedly.Usually, the initial therapy scheme can be duplicated and get the therapeutic scheme that disturbs the effective The compounds of this invention of TNF-alpha active to be used for the alpha mediated morbid state of other TNF-by known.The mensuration that the individuality of being treated will be checked T cell number and T4/T8 ratio and/or viremia virusemia regularly such as the level that reverses transcriptase or virus protein and/or be used for and progress such as the disease of the cell factor-mediation of cachexia or muscle degeneration variation relevant issues.If onset is not rapid after the general treatment scheme, increase the amount of the cytokine activity interferon activity agent of using so, for example weekly 50 percent.

IAP suppresses compound and can and choose any one kind of them or multiple other conventional medicine assistant agent combinations with one or more medicine acceptable carriers, and use in the intestines, for example oral, form with tablet, capsule, caplets etc., or parenteral, for example, the interior or intravenous of peritonaeum is with the form of sterile injectable solution or suspension.Can prepare by conventional method with parenteral composition in the intestines.

The preparation of TNF-α and IAP inhibitor compound can use anti-TNF-Alpha antibodies to measure easily.For example, handled 12 to 14 hours with purified rabbit anti-TNF-Alpha antibodies of 5 μ g/mL in 4 ℃ of lower plates (Nunc Immunoplates, Roskilde, Denmark).Plate was blocked 2 hours with the PBS/0.05% tween that comprises 5mg/mL BSA down at 25 ℃ then.After the cleaning, use unknown material and the contrast of 100 μ L, and plate was hatched under 4 ℃ 12 to 14 hours.Clean described plate and measure, be used in the o-phenylenediamine formation color that comprises 0.012% hydrogen peroxide in phosphate-citrate buffer and at the 492nm reading with the bond of peroxidase (horseradish) and mouse-anti-TNF-alpha monoclonal antibodies.

Following examples provide in the mode of explanation, and are not in order to limit the scope of the invention.

Embodiment 1

N-[1-cyclohexyl-2-(2-{2-[(4-fluorophenyl)-methyl-amino]-pyridin-4-yl } pyrrolidine-1-yl)-2-oxo-ethyl]-2-methylamino-propionamide, hereinafter be referred to as Compound I I, in many clones as shown in fig. 1, test.Each of shown tumor cell line handled 18 hours with the Compound I I of 1uM.Use Qiagen ' s TurboCapture mRNA separating kit results mRNA.Use the synthetic cDNA of BioRad iScript cDNA synthetic agent box.

To the special primer of cDNA coding TNF-α, be used to the TNF cDNA of pcr amplification then from each sample, use Applied Biosystems TaqMan Universal PCR MasterMix.Data are normalized to B-actin (Actin) mRNA and are expressed as the level relatively of TNF mRNA.

Fig. 1 shows sensitive cell line, and (72 hours IC50＜1uM) express the TNFmRNA of higher baseline values, and the expression by improving TNF mRNA is in response to the processing of Compound I I.What these test findings hinted is that the TNF level can be used for predicting the susceptibility to the Smac simulated compound, and the evaluation of rising TNF level may have the potentiality that are used to supervise the therapeutic response policy.

Fig. 2 shows that Compound I I and III induce TNF α mRNA in the SKOV-3 cell as dose dependent mode how.TNF α induces and requires the proteosome activity, because it is suppressed by MG132 (PI).TNF α induces and does not require caspase activity (not blocked by ZVAD) but require autocrine TNF alpha signal conduction, because it is blocked by soluble TNF α acceptor (STR).

Describe to comprise that by the figure of the TNF inducing action of Compound I I the multiple with respect to untreated cell TNF increases by nine relevant rod figure.From left to right read the untreated cell of first rod figure expression (about 0-1 doubly).The Compound I I (about 120-130 doubly increases) of second rod figure expression 1000nM.The Compound I I (about 50 times of increases) of the 3rd rod figure expression 100nM.The 4th rod figure expression 1000nM Compound I I+PI (about 25-30 doubly increases).The Compound I I+PI (about 15-20 doubly increases) of the 5th rod figure expression 100nM.The Compound I I+ZVAD (about 125-130 doubly increases) of the 6th rod figure expression 1000nM.The Compound I I+ZVAD (about 95-100 doubly increases) of the 7th rod figure expression 100nM.The Compound I I+sTNFR (about 0-5 doubly increases) of the 8th rod figure expression 1000nM.The Compound I I+sTNFR (about 0-1 doubly increases) of the 9th rod figure expression 100nM.

The figure that describes the TNF inducing action by compound III comprises and increases by nine relevant rods with respect to the TNF multiple of untreated cell and schemes.From left to right read the untreated cell of first rod figure expression (about 0-1 doubly).The compound III (about 105-115 doubly increases) of second rod figure expression 1000nM.The compound III (about 85-95 doubly increases) of the 3rd rod figure expression 100nM.The 4th rod figure expression 1000nM compound III+PI (about 30-40 doubly increases).Compound III+PI (about 15-20 doubly increases) of the 5th rod figure expression 100nM.Compound III+ZVAD (about 75-80 doubly increases) of the 6th rod figure expression 1000nM.Compound III+ZVAD (about 85-95 doubly increases) of the 7th rod figure expression 100nM.Compound III+sTNFR (about 0-1 doubly increases) of the 8th rod figure expression 1000nM.Compound III+sTNFR (about 0-31 doubly increases) of the 9th rod figure expression 100nM.

To those skilled in the art, variant as herein described, change will take place, reach other enforcement, and not depart from the spirit and the fundamental characteristics of the present invention's instruction.Scope correspondingly of the present invention is not subjected to the restriction of front illustrative explanation, and limited by following claim, and whole variations that can bring in the implication of the equivalence of claim and scope are intended to be comprised in claims.

Claims (16)

1. the prediction patient will have the method for response to IAP inhibition compound, comprise:

A) to the patient use the IAP inhibitor compound and

B) measure TNF-α and/or IL-8 level.

2. according to the method for claim 1, it comprises additional step:

D) if related coefficient is lower than----determines that described patient is not for there being the response patient.

3. the process of claim 1 wherein that described IAP inhibition compound has the structure of formula I:

Or the acceptable salt of its pharmacy, wherein:

R₁Be H, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl or C₃-C₁₀Naphthenic base, wherein R₁Can be not and to replace or replace;

R₂Be H, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₃-C₁₀Naphthenic base, wherein R₂Can be not and to replace or replace;

R₃Be H, CF₃, C₂F₅, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, CH₂-Z or R₂And R₃The nitrogen-atoms that is connected with them lumps together the formation heterocycle, and wherein alkyl, alkenyl, alkynyl or het ring can be not replace or replace;

Z is H, OH, F, Cl, CH₃, CH₂Cl, CH₂F or CH₂OH;

R₄Be C₀-C₁₀Alkyl, C₃-C₁₀Naphthenic base, wherein C₀-C₁₀Alkyl or group of naphthene base are not replace or replace;

A is het, and it can be replacement or unsubstituted;

D is C₁-C₇Alkylidene, C₂-C₉Alkylene group, C (O), O, NR₇, S (O) r, C (O)-C₁-C₁₀Alkyl, O-C₁-C₁₀Alkyl, S (O) r-C₁-C₁₀Alkyl, C (O) C₀-C₁₀Aryl alkyl OC₀-C₁₀Aryl alkyl or S (O) rC₀-C₁₀Aryl alkyl, wherein alkyl and aromatic yl group can be not and to replace or replace;

R is 0,1 or 2;

A₁Be aryl that replaces or the het that does not replace or replace, the substituting group on its aryl and the het is halogen, lower alkoxy, NR₅R₆, CN, NO₂Or SR₅

Each Q is H, C independently₁-C₁₀Alkyl, C₁-C₁₀Alkoxy, aryl C₁-C₁₀Alkoxy, OH, O-C₁-C₁₀Alkyl, (CH₂)_0-6-C₃-C₇Naphthenic base, aryl, aryl C₁-C₁₀Alkyl, O-(CH₂)_0-6-aryl, (CH₂)_1-6-het, het, O-(CH₂)_1-6Het ,-OR₁₁, C (O) R₁₁,-C (O) N (R₁₁) (R₁₂), N (R₁₁) (R₁₂), SR₁₁, S (O) R₁₁, S (O)₂R₁₁, S (O)₂N (R₁₁) (R₁₂) or NR₁₁-S (O)₂-(R₁₂), wherein alkyl, naphthenic base and aryl are not replace or replace;

N is 0,1,2 or 3,4,5,6 or 7;

Het comprises the 5-7 unit monocyclic heterocycles that 1-4 is selected from the heteroatom of N, O and S, or comprises a 8-12 unit fused rings system that contains the 5-7 unit monocyclic heterocycles of 1,2 or 3 heteroatom that is selected from N, O and S, and wherein het is unsubstituted or replaces;

R₁₁And R₁₂Be H, C independently₁-C₁₀Alkyl, (CH₂)_0-6-C₃-C₁₀Naphthenic base, (CH₂)_0-6-(CH)_0-1(aryl)_1-2, C (O)-C₁-C₁₀Alkyl ,-C (O)-(CH₂)_1-6-C₃-C₇Naphthenic base ,-C (O)-O-(CH₂)_0-6-aryl ,-C (O)-(CH₂)_0-6-O-fluorenyl, C (O)-NH-(CH₂)_0-6-aryl, C (O)-(CH₂)_0-6-aryl, C (O)-(CH₂)_1-6-het ,-C (S)-C₁-C₁₀Alkyl ,-C (S)-(CH₂)_1-6-C₃-C₇Naphthenic base ,-C (S)-O-(CH₂)_0-6-aryl ,-C (S)-(CH₂)_0-6-O-fluorenyl, C (S)-NH-(CH₂)_0-6-aryl ,-C (S)-(CH₂)_0-6-aryl or C (S)-(CH₂)_1-6-het, C (O) R₁₁, C (O) NR₁₁R₁₂, C (O) OR₁₁, S (O)_nR₁₁, S (O)_mNR₁₁R₁₂, m=1 or 2, C (S) R₁₁, C (S) NR₁₁R₁₂, C (S) OR₁₁, wherein alkyl, naphthenic base and aryl are not replace or replace; Or R₁₁And R₁₂Be the substituting group that promotes the transhipment of molecule cross-cell membrane, perhaps R₁₁And R₁₂Form het together with nitrogen-atoms;

R wherein₁₁And R₁₂Alkyl substituent can be for unsubstituted, or by one or more C that are selected from₁-C₁₀Alkyl, halogen, OH, O-C₁-C₆Alkyl ,-S-C₁-C₆Alkyl, CF₃Or NR₁₁R₁₂Substituting group replace;

R₁₁And R₁₂The naphthenic substituent of replacement by one or more C that are selected from₂-C₁₀Alkylidene, C₁-C₆Alkyl, halogen, OH, O-C₁-C₆Alkyl, S-C₁-C₆Alkyl, CF₃, or NR₁₁R₁₂Substituting group replace; And

R₁₁And R₁₂The het of replacement or the aryl of replacement by one or more halogen, hydroxyl, C of being selected from₁-C₄Alkyl, C₁-C₄Alkoxy, nitro, CN, O-C (O)-C₁-C₄Alkyl and C (O)-O-C₁-C₄The substituting group of alkyl replaces;

R₅, R₆And R₇Be hydrogen, low alkyl group, aryl, aromatic yl elementary alkyl, naphthenic base or cycloalkyl low-grade alkyl independently; And

R wherein₁, R₂, R₃, R₄, Q and A and A₁Substituting group on the group is halogen independently; hydroxyl; low alkyl group; low-grade alkenyl; low-grade alkynyl; low-grade alkane acidyl; lower alkoxy; aryl; aromatic yl elementary alkyl; amino; amino low alkyl group; two elementary alkyl amido; low-grade alkane acidyl; amino lower alkoxy; nitro; cyano group; cyano-lower alkyl group; carboxyl; lower alkoxycarbonyl; low-grade alkane acidyl; aroyl; the lower aryl alkanoyl; carbamyl; the N-list-or N, N-two elementary alkyl amido formoxyl; the lower alkyl-ammonium carbamate; amidino groups; guanidine radicals; urea groups; sulfydryl; sulfo group; lower alkylthio; sulfo group amino; sulfonamide; benzene sulfinyl amine; sulfonate; sulfane base low alkyl group; aryl sulfonic acid amides; arylsulphonate or ester that halogen replaces; the low alkyl group sulfinyl; aryl sulfonyl kia; the aryl lower alkyl sulfinyl; the low-grade alkylaryl sulfinyl; the low alkyl group sulfonyl; aryl sulfonyl; the aryl lower alkyl sulfonyl; lower aryl alkyl low-grade alkylaryl sulfonyl; halogen-low alkyl group sulfydryl; halogen-low alkyl group sulfonyl; phosphono (P (=O) (OH)₂), hydroxyl-lower alkoxy phosphoryl or two lower alkoxy phosphoryls, (R₉) NC (O)-NR₁₀R₁₃, lower alkyl-ammonium carbamate or carbamate or-NR₈R₁₄, R wherein₈And R₁₄Can be identical or different, and be H or low alkyl group, perhaps R independently₈And R₁₄Form 3 to 8 yuan of heterocycles that comprise the azacyclo-atom together with the N atom; and can randomly comprise one or two other nitrogen that is selected from; the heteroatom of oxygen and sulphur; its heterocycle can be unsubstituted or is replaced by following group: low alkyl group; halogen; low-grade alkenyl; low-grade alkynyl; hydroxyl; lower alkoxy; nitro; amino; low alkyl group; amino; two elementary alkyl amido; cyano group; carboxyl; lower alkoxycarbonyl; formoxyl; low-grade alkane acidyl; oxo; carbamyl; rudimentary or the N of N-; N-two elementary alkyl amido formoxyl; sulfydryl; or lower alkylthio, and

R₉, R₁₀And R₁₃Be the aryl that replaces of low alkyl group, aryl, aromatic yl elementary alkyl, halogen that hydrogen, low alkyl group, halogen replace, the aromatic yl elementary alkyl that halogen replaces independently.

4. determine to suffer from the conduction of composing type TNF-alpha signal be the individuality of disease of feature to method with the response of IAP inhibition compounds for treating, comprising:

A) to the patient use the IAP inhibitor compound and

B) measure TNF-α or IL-8 level.

5. treatment is the method for the disease of feature with the conduction of composing type TNF-alpha signal, comprises

A) use the IAP inhibitor compound and

B) measure the TNF-alpha levels.

6. claim 4 or 5 method, wherein said IAP inhibition compound has the structure of formula I:

Or its pharmaceutically acceptable salt, wherein:

R₁Be H, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl or C₃-C₁₀Naphthenic base, wherein R₁Can be not and to replace or replace;

R₂Be H, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₃-C₁₀Naphthenic base, wherein R₂Can be not and to replace or replace;

R₃Be H, CF₃, C₂F₅, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, CH₂-Z or R₂And R₃The nitrogen-atoms that is connected with them lumps together the formation heterocycle, and wherein alkyl, alkenyl, alkynyl or het ring can be not replace or replace;

Z is H, OH, F, Cl, CH₃, CH₂Cl, CH₂F or CH₂OH;

R₄Be C₀-C₁₀Alkyl, C₃-C₁₀Naphthenic base, wherein C₀-C₁₀Alkyl or group of naphthene base are not replace or replace;

A is het, and it can be replacement or unsubstituted;

D is C₁-C₇Alkylidene, C₂-C₉Alkylene group, C (O), O, NR₇, S (O) r, C (O)-C₁-C₁₀Alkyl, O-C₁-C₁₀Alkyl, S (O) r-C₁-C₁₀Alkyl, C (O) C₀-C₁₀Aryl alkyl OC₀-C₁₀Aryl alkyl or S (O) rC₀-C₁₀Aryl alkyl, wherein alkyl and aromatic yl group can be not and to replace or replace;

R is 0,1 or 2;

A₁Be aryl that replaces or the het that does not replace or replace, the substituting group on its aryl and the het is halogen, lower alkoxy, NR₅R₆, CN, NO₂Or SR₅

Each Q is H, C independently₁-C₁₀Alkyl, C₁-C₁₀Alkoxy, aryl C₁-C₁₀Alkoxy, OH, O-C₁-C₁₀Alkyl, (CH₂)_0-6-C₃-C₇Naphthenic base, aryl, aryl C₁-C₁₀Alkyl, O-(CH₂)_0-6-aryl, (CH₂)_1-6-het, het, O-(CH₂)_1-6Het ,-OR₁₁, C (O) R₁₁,-C (O) N (R₁₁) (R₁₂), N (R₁₁) (R₁₂), SR₁₁, S (O) R₁₁, S (O)₂R₁₁, S (O)₂N (R₁₁) (R₁₂) or NR₁₁-S (O)₂-(R₁₂), wherein alkyl, naphthenic base and aryl are not replace or replace;

N is 0,1,2 or 3,4,5,6 or 7;

Het comprises the 5-7 unit monocyclic heterocycles that 1-4 is selected from the heteroatom of N, O and S, or comprises a 8-12 unit fused rings system that contains the 5-7 unit monocyclic heterocycles of 1,2 or 3 heteroatom that is selected from N, O and S, and wherein het is unsubstituted or replaces;

R₁₁And R₁₂Be H, C independently₁-C₁₀Alkyl, (CH₂)_0-6-C₃-C₁₀Naphthenic base, (CH₂)_0-6-(CH)_0-1(aryl)_1-2, C (O)-C₁-C₁₀Alkyl ,-C (O)-(CH₂)_1-6-C₃-C₇Naphthenic base ,-C (O)-O-(CH₂)_0-6-aryl ,-C (O)-(CH₂)_0-6-O-fluorenyl, C (O)-NH-(CH₂)_0-6-aryl, C (O)-(CH₂)_0-6-aryl, C (O)-(CH₂)_1-6-het ,-C (S)-C₁-C₁₀Alkyl ,-C (S)-(CH₂)_1-6-C₃-C₇Naphthenic base ,-C (S)-O-(CH₂)_0-6-aryl ,-C (S)-(CH₂)_0-6-O-fluorenyl, C (S)-NH-(CH₂)_0-6-aryl ,-C (S)-(CH₂)_0-6-aryl or C (S)-(CH₂)_1-6-het, C (O) R₁₁, C (O) NR₁₁R₁₂, C (O) OR₁₁, S (O)_nR₁₁, S (O)_mNR₁₁R₁₂, m=1 or 2, C (S) R₁₁, C (S) NR₁₁R₁₂, C (S) OR₁₁, wherein alkyl, naphthenic base and aryl are not replace or replace; Or R₁₁And R₁₂Be the substituting group that promotes the transhipment of molecule cross-cell membrane, perhaps R₁₁And R₁₂Form het together with nitrogen-atoms;

R wherein₁₁And R₁₂Alkyl substituent can be for unsubstituted, or by one or more C that are selected from₁-C₁₀Alkyl, halogen, OH, O-C₁-C₆Alkyl, S-C₁-C₆Alkyl, CF₃Or NR₁₁R₁₂Substituting group replace;

R₁₁And R₁₂The naphthenic substituent of replacement by one or more C that are selected from₂-C₁₀Alkylidene, C₁-C₆Alkyl, halogen, OH, O-C₁-C₆Alkyl, S-C₁-C₆Alkyl, CF₃, or NR₁₁R₁₂Substituting group replace; And

R₁₁And R₁₂The het of replacement or the aryl of replacement by one or more halogen, hydroxyl, C of being selected from₁-C₄Alkyl, C₁-C₄Alkoxy, nitro, CN, O-C (O)-C₁-C₄Alkyl and C (O)-O-C₁-C₄The substituting group of alkyl replaces;

R₅, R₆And R₇Be hydrogen, low alkyl group, aryl, aromatic yl elementary alkyl, naphthenic base or cycloalkyl low-grade alkyl independently; And

R wherein₁, R₂, R₃, R₄, Q and A and A₁Substituting group on the group is halogen independently; hydroxyl; low alkyl group; low-grade alkenyl; low-grade alkynyl; low-grade alkane acidyl; lower alkoxy; aryl; aromatic yl elementary alkyl; amino; amino low alkyl group; two elementary alkyl amido; low-grade alkane acidyl; amino lower alkoxy; nitro; cyano group; cyano-lower alkyl group; carboxyl; lower alkoxycarbonyl; low-grade alkane acidyl; aroyl; the lower aryl alkanoyl; carbamyl; the N-list-or N, N-two elementary alkyl amido formoxyl; the lower alkyl-ammonium carbamate; amidino groups; guanidine radicals; urea groups; sulfydryl; sulfo group; lower alkylthio; sulfo group amino; sulfonamide; benzene sulfinyl amine; sulfonate; sulfane base low alkyl group; aryl sulfonic acid amides; arylsulphonate or ester that halogen replaces; the low alkyl group sulfinyl; aryl sulfonyl kia; the aryl lower alkyl sulfinyl; the low-grade alkylaryl sulfinyl; the low alkyl group sulfonyl; aryl sulfonyl; the aryl lower alkyl sulfonyl; lower aryl alkyl low-grade alkylaryl sulfonyl; halogen-low alkyl group sulfydryl; halogen-low alkyl group sulfonyl; phosphono (P (=O) (OH)₂), hydroxyl-lower alkoxy phosphoryl or two lower alkoxy phosphoryls, (R₉) NC (O)-NR₁₀R₁₃, lower alkyl-ammonium carbamate or carbamate or-NR₈R₁₄, R wherein₈And R₁₄Can be identical or different, and be H or low alkyl group, perhaps R independently₈And R₁₄Form 3 to 8 yuan of heterocycles that comprise the azacyclo-atom together with the N atom; and can randomly comprise one or two other nitrogen that is selected from; the heteroatom of oxygen and sulphur; its heterocycle can be unsubstituted or is replaced by following group: low alkyl group; halogen; low-grade alkenyl; low-grade alkynyl; hydroxyl; lower alkoxy; nitro; amino; low alkyl group; amino; two elementary alkyl amido; cyano group; carboxyl; lower alkoxycarbonyl; formoxyl; low-grade alkane acidyl; oxo; carbamyl; rudimentary or the N of N-; N-two elementary alkyl amido formoxyl; sulfydryl; or lower alkylthio, and

R₉, R₁₀And R₁₃Be the aryl that replaces of low alkyl group, aryl, aromatic yl elementary alkyl, halogen that hydrogen, low alkyl group, halogen replace, the aromatic yl elementary alkyl that halogen replaces independently.

7. according to claim 1,4 or 5 method, wherein said IAP inhibitor compound is selected from N-1-cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidine-1-yl }-2-oxo-ethyl)-2-methylamino-propionamide; The N-[cyclohexyl-(ethyl-1-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-propyl group } carbamyl)-methyl]-2-methylamino-propionamide; N-(1-cyclohexyl-2-{2-[5-(4-fluoro-phenoxy group)-pyridin-3-yl]-pyrrolidine-1-yl }-2-oxo-ethyl)-2-methylamino-propionamide; With N-[1-cyclohexyl-2-(2-{2-[(4-fluorophenyl)-methyl-amino]-pyridin-4-yl } pyrrolidine-1-yl)-2-oxo-ethyl]-2-methylamino-propionamide and pharmaceutically acceptable salt thereof.

8.IAP the purposes of inhibitor compound in the treatment of proliferative diseases that with the conduction of composing type TNF-alpha signal is feature.

9. formula I compound or its N oxide or the acceptable salt of the pharmacy purposes in the treatment of diseases that with composing type TNF-alpha signal conduction is feature, wherein said formula I compound has following structure:

Or its pharmaceutically acceptable salt, wherein:

R₁Be H, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl or C₃-C₁₀Naphthenic base, wherein R₁Can be not and to replace or replace;

R₂Be H, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, C₃-C₁₀Naphthenic base, wherein R₂Can be not and to replace or replace;

R₃Be H, CF₃, C₂F₅, C₁-C₄Alkyl, C₂-C₄Alkenyl, C₂-C₄Alkynyl, CH₂-Z or R₂And R₃The nitrogen-atoms that is connected with them lumps together the formation heterocycle, and wherein alkyl, alkenyl, alkynyl or het ring can be not replace or replace;

Z is H, OH, F, Cl, CH₃, CH₂Cl, CH₂F or CH₂OH;

R₄Be C₀-C₁₀Alkyl, C₃-C₁₀Naphthenic base, wherein C₀-C₁₀Alkyl or group of naphthene base are not replace or replace;

A is het, and it can be replacement or unsubstituted;

D is C₁-C₇Alkylidene, C₂-C₉Alkylene group, C (O), O, NR₇, S (O) r, C (O)-C₁-C₁₀Alkyl, O-C₁-C₁₀Alkyl, S (O) r-C₁-C₁₀Alkyl, C (O) C₀-C₁₀Aryl alkyl OC₀-C₁₀Aryl alkyl or S (O) rC₀-C₁₀Aryl alkyl, wherein alkyl and aromatic yl group can be not and to replace or replace;

R is 0,1 or 2;

A₁Be aryl that replaces or the het that does not replace or replace, the substituting group on its aryl and the het is halogen, lower alkoxy, NR₅R₆, CN, NO₂Or SR₅

Each Q is H, C independently₁-C₁₀Alkyl, C₁-C₁₀Alkoxy, aryl C₁-C₁₀Alkoxy, OH, O-C₁-C₁₀Alkyl, (CH₂)_0-6-C₃-C₇Naphthenic base, aryl, aryl C₁-C₁₀Alkyl, O-(CH₂)_0-6-aryl, (CH₂)_1-6-het, het, O-(CH₂)_1-6Het ,-OR₁₁, C (O) R₁₁,-C (O) N (R₁₁) (R₁₂), N (R₁₁) (R₁₂), SR₁₁, S (O) R₁₁, S (O)₂R₁₁, S (O)₂N (R₁₁) (R₁₂) or NR₁₁-S (O)₂-(R₁₂), wherein alkyl, naphthenic base and aryl are not replace or replace;

N is 0,1,2 or 3,4,5,6 or 7;

Het comprises the 5-7 unit monocyclic heterocycles that 1-4 is selected from the heteroatom of N, O and S, or comprises a 8-12 unit fused rings system that contains the 5-7 unit monocyclic heterocycles of 1,2 or 3 heteroatom that is selected from N, O and S, and wherein het is unsubstituted or replaces;

R₁₁And R₁₂Be H, C independently₁-C₁₀Alkyl, (CH₂)_0-6-C₃-C₁₀Naphthenic base, (CH₂)_0-6-(CH)_0-1(aryl)_1-2, C (O)-C₁-C₁₀Alkyl ,-C (O)-(CH₂)_1-6-C₃-C₇Naphthenic base ,-C (O)-O-(CH₂)_0-6-aryl ,-C (O)-(CH₂)_0-6-O-fluorenyl, C (O)-NH-(CH₂)_0-6-aryl, C (O)-(CH₂)_0-6-aryl, C (O)-(CH₂)_1-6-het ,-C (S)-C₁-C₁₀Alkyl ,-C (S)-(CH₂)_1-6-C₃-C₇Naphthenic base ,-C (S)-O-(CH₂)_0-6-aryl ,-C (S)-(CH₂)_0-6-O-fluorenyl, C (S)-NH-(CH₂)_0-6-aryl ,-C (S)-(CH₂)_0-6-aryl or C (S)-(CH₂)_1-6-het, C (O) R₁₁, C (O) NR₁₁R₁₂, C (O) OR₁₁, S (O)_nR₁₁, S (O)_mNR₁₁R₁₂, m=1 or 2, C (S) R₁₁, C (S) NR₁₁R₁₂, C (S) OR₁₁, wherein alkyl, naphthenic base and aryl are not replace or replace; Or R₁₁And R₁₂Be the substituting group that promotes the transhipment of molecule cross-cell membrane, perhaps R₁₁And R₁₂Form het together with nitrogen-atoms;

R wherein₁₁And R₁₂Alkyl substituent can be for unsubstituted, or by one or more C that are selected from₁-C₁₀Alkyl, halogen, OH, O-C₁-C₆Alkyl, S-C₁-C₆Alkyl, CF₃Or NR₁₁R₁₂Substituting group replace;

R₁₁And R₁₂The naphthenic substituent of replacement by one or more C that are selected from₂-C₁₀Alkylidene, C₁-C₆Alkyl, halogen, OH, O-C₁-C₆Alkyl, S-C₁-C₆Alkyl, CF₃, or NR₁₁R₁₂Substituting group replace; And

R₁₁And R₁₂The het of replacement or the aryl of replacement by one or more halogen, hydroxyl, C of being selected from₁-C₄Alkyl, C₁-C₄Alkoxy, nitro, CN, O-C (O)-C₁-C₄Alkyl and C (O)-O-C₁-C₄The substituting group of alkyl replaces;

R₅, R₆And R₇Be hydrogen, low alkyl group, aryl, aromatic yl elementary alkyl, naphthenic base or cycloalkyl low-grade alkyl independently; And

R wherein₁, R₂, R₃, R₄, Q and A and A₁Substituting group on the group is halogen independently; hydroxyl; low alkyl group; low-grade alkenyl; low-grade alkynyl; low-grade alkane acidyl; lower alkoxy; aryl; aromatic yl elementary alkyl; amino; amino low alkyl group; two elementary alkyl amido; low-grade alkane acidyl; amino lower alkoxy; nitro; cyano group; cyano-lower alkyl group; carboxyl; lower alkoxycarbonyl; low-grade alkane acidyl; aroyl; the lower aryl alkanoyl; carbamyl; the N-list-or N, N-two elementary alkyl amido formoxyl; the lower alkyl-ammonium carbamate; amidino groups; guanidine radicals; urea groups; sulfydryl; sulfo group; lower alkylthio; sulfo group amino; sulfonamide; benzene sulfinyl amine; sulfonate; sulfane base low alkyl group; aryl sulfonic acid amides; arylsulphonate or ester that halogen replaces; the low alkyl group sulfinyl; aryl sulfonyl kia; the aryl lower alkyl sulfinyl; the low-grade alkylaryl sulfinyl; the low alkyl group sulfonyl; aryl sulfonyl; the aryl lower alkyl sulfonyl; lower aryl alkyl low-grade alkylaryl sulfonyl; halogen-low alkyl group sulfydryl; halogen-low alkyl group sulfonyl; phosphono (P (=O) (OH)₂), hydroxyl-lower alkoxy phosphoryl or two lower alkoxy phosphoryls, (R₉) NC (O)-NR₁₀R₁₃, lower alkyl-ammonium carbamate or carbamate or-NR₈R₁₄, R wherein₈And R₁₄Can be identical or different, and be H or low alkyl group, perhaps R independently₈And R₁₄Form 3 to 8 yuan of heterocycles that comprise the azacyclo-atom together with the N atom; and can randomly comprise one or two other nitrogen that is selected from; the heteroatom of oxygen and sulphur; its heterocycle can be unsubstituted or is replaced by following group: low alkyl group; halogen; low-grade alkenyl; low-grade alkynyl; hydroxyl; lower alkoxy; nitro; amino; low alkyl group; amino; two elementary alkyl amido; cyano group; carboxyl; lower alkoxycarbonyl; formoxyl; low-grade alkane acidyl; oxo; carbamyl; rudimentary or the N of N-; N-two elementary alkyl amido formoxyl; sulfydryl; or lower alkylthio, and

R₉, R₁₀And R₁₃Be the aryl that replaces of low alkyl group, aryl, aromatic yl elementary alkyl, halogen that hydrogen, low alkyl group, halogen replace, the aromatic yl elementary alkyl that halogen replaces independently.

10. formula I compound or its pharmaceutically acceptable salt according to claim 9 is used to prepare the pharmaceutical composition that is feature is conducted in treatment with composing type TNF-alpha signal purposes.

11. with the conduction of composing type TNF-alpha signal is the treatment of diseases method of feature, comprises formula I compound or its pharmaceutically acceptable salt according to claim 9 to warm-blooded animal, particularly the human administration medicine effective quantity of this class treatment of needs.

12. according to the purposes of claim 9, wherein said formula I compound is selected from N-1-cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidine-1-yl }-2-oxo-ethyl)-2-methylamino-propionamide; The N-[cyclohexyl-(ethyl-1-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-propyl group } carbamyl)-methyl]-2-methylamino-propionamide; N-(1-cyclohexyl-2-{2-[5-(4-fluoro-phenoxy group)-pyridin-3-yl]-pyrrolidine-1-yl }-2-oxo-ethyl)-2-methylamino-propionamide; With N-[1-cyclohexyl-2-(2-{2-[(4-fluorophenyl)-methyl-amino]-pyridin-4-yl } pyrrolidine-1-yl)-2-oxo-ethyl]-2-methylamino-propionamide and pharmaceutically acceptable salt thereof.

13. according to the purposes of claim 10, wherein said formula I compound be selected from N-(1-cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidine-1-yl-2-oxo-ethyl)-2-methylamino-propionamide; The N-[cyclohexyl-(ethyl-1-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-propyl group } carbamyl)-methyl]-2-methylamino-propionamide; N-(1-cyclohexyl-2-{2-[5-(4-fluoro-phenoxy group)-pyridin-3-yl]-pyrrolidine-1-yl }-2-oxo-ethyl)-2-methylamino-propionamide; With N-[1-cyclohexyl-2-(2-{2-[(4-fluorophenyl)-methyl-amino]-pyridin-4-yl } pyrrolidine-1-yl)-2-oxo-ethyl]-2-methylamino-propionamide and pharmaceutically acceptable salt thereof.

14. according to the method for claim 11, wherein said formula I compound be selected from N-(1-cyclohexyl-2-{2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidine-1-yl-2-oxo-ethyl)-2-methylamino-propionamide; The N-[cyclohexyl-(ethyl-1-[5-(4-fluoro-benzoyl)-pyridin-3-yl]-propyl group } carbamyl)-methyl]-2-methylamino-propionamide; N-(1-cyclohexyl-2-{2-[5-(4-fluoro-phenoxy group)-pyridin-3-yl]-pyrrolidine-1-yl }-2-oxo-ethyl)-2-methylamino-propionamide; With N-[1-cyclohexyl-2-(2-{2-[(4-fluorophenyl)-methyl-amino]-pyridin-4-yl } pyrrolidine-1-yl)-2-oxo-ethyl]-2-methylamino-propionamide and pharmaceutically acceptable salt thereof.

15. according to the purposes of claim 9, wherein said disease is a proliferative diseases.

16. according to the purposes of claim 9, wherein said disease is selected from cancer, such as solid tumor and the tumour of coming autoblood; Heart disease, such as congestive heart failure; With virus, heredity, inflammatory, allergy and autoimmune disease.

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