CN100480249C - Pyrrolopyridine-2-carboxylic acid amide inhibitors of glycogen phoshorylase - Google Patents

Abstract

Compounds represented by Formula (I): or pharmaceutically acceptable salts thereof, are inhibitors of glycogen phosphorylase and are useful in the prophylactic or therapeutic treatment of diabetes, hyperglycemia, hypercholesterolemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis or tissue ischemia e.g. myocardial ischemia, and as cardioprotectants.

Description

Pyrrolopyridine-2-benzoic acid amides as glycogen phosphorylase inhibitors

Technical field

The present invention relates to pyrrolopyridine-2-methane amide.Particularly, the present invention relates to pyrrolopyridine-2-methane amide as glycogen phosphorylase inhibitors.

Background technology

Although acceptable clinically treatment plan comprises diet, exercise, hypoglycemic drug, and can utilize Regular Insulin, insulin-dependent type i diabetes and non-insulin-dependent type ii diabetes are difficult to treatment.Treatment is that the patient is dependent, thereby still needs new hypoglycemic drug, especially has the medicine of tolerance preferably and less side effect.

Thereby liver and some other organ are by the decomposition glycogen or by producing glucose by small molecules precursor synthesis of glucose---improve glucose level.The decomposition of glycogen is subjected to the catalysis of glycogen phosphorylase.Therefore, suppress glycogen phosphorylase (" GP ") and just can reduce the glucose level that raises among the diabetic subject.

Similarly, hypertension and related pathologies thereof for example atherosclerosis, lipidemia (lipidemia), hyperlipidemia and hypercholesterolemia are all relevant with the insulin level (hyperinsulinemia) that raises, and it can cause glucose level unusual.And, can cause myocardial ischemia (myocardial ischemia).This disease can comprise the compounds for treating that suppresses glycogen phosphorylase with hypoglycemic drug.Also once put down in writing glycogen phosphorylase inhibitors behind reperfusion injury for example, have cardioprotection (referring to; as Ross etc., American Journal of Physiology.Heart and Circulatory Physiology, Mar 2004; 286 (3), H1177-84).Therefore, think suppress glycogen phosphorylase (referring to, as U.S. Patent No. 6,297,269) compound can be used for treating diabetes, hyperglycemia, hypercholesterolemia, hyperinsulinemia, hyperlipidemia, atherosclerosis or myocardial ischemia.Yet it is favourable obtaining other new compound that suppresses glycogen phosphorylase.

R.Kurukulasuriya, J.T.Link, etc., Current Medicinal Chem., 10: 99-121 (2003) has put down in writing " Prospects for Pharmacologic Inhibition of Hepatic GlucoseProduction ".R.Kurukulasuriya, J.T.Link etc., Current Medicinal Chem., 10: 123-153 (2003) has put down in writing " Potential Drug Targets and Progress TowardsPharmacologic Inhibition of Hepatic Glucose Production ".

U.S. Patent No. 6,297,269 and european patent application No.EP 0832066 put down in writing N-(indole-2-carbonyl) acid amides and derivative as the replacement of glycogen phosphorylase inhibitors.U.S. Patent No. 6,107,329 and 6,277,877 have put down in writing N-(indole-2-carbonyl) G-NH2 and the derivative as the replacement of glycogen phosphorylase inhibitors.U.S. Patent No. 6,399,601 have put down in writing the bicyclic pyrrole acid amides as glycogen phosphorylase inhibitors.European patent application No.EP 0978276 and EP 1136071 have put down in writing human glycogen phosphorylase inhibitors and application thereof.The open No.WO 01/68055 of international monopoly has put down in writing glycogen phosphorylase inhibitors.U.S. Patent No. 5,952,322 have put down in writing the method for utilizing glycogen phosphorylase inhibitors to reduce non-heart ischemia sex organization's damage (non-cardiac ischemial tissue damage).

The open No.WO 01/55146 of international monopoly has put down in writing the aryl amidine.The open No.WO 01/62775 of international monopoly has put down in writing antiarrhythmia peptide.The open No.WO 01/96346 of international monopoly has put down in writing tricyclic compound.The open No.WO 02/16314 of international monopoly has put down in writing the polyamino compound that replaces.The open No.WO 02/20475 of international monopoly has put down in writing the serine protease inhibitor.The open No.WO 02/40469 of international monopoly has put down in writing the bombesin receptor antagonist.The open No.WO 02/46159 of international monopoly has put down in writing guanidine and amidine derivative.The open No.WO00/69815 of international monopoly has put down in writing the Cycloamine derivative that urea groups replaces.

The open No.WO 00/43384 of international monopoly has put down in writing heteroaromatic compound.Open No.WO 02/26697 of international monopoly and WO 00/76970 have put down in writing fragrance derivatives.The open No.WO 01/32622 of international monopoly has put down in writing indoles.European patent application No.EP 1101759 has put down in writing the phenylpyrrole compound.European patent application No.EP 1179341 has put down in writing cyclammonium (cyclicamino) compound.U.S. Patent No. 6,037,325 have put down in writing the heterogeneous ring compound that replaces.U.S. Patent No. 5,672,582 have put down in writing the cyclohexylamine derivant that 4-replaces.European patent application No.EP 1201239 has put down in writing cyclic amine CCR 3 antagonisis.The open No.WO 98/25617 of international monopoly has put down in writing the aryl piperazines that replaces.U.S. Patent No. 5,756,810 have put down in writing preparation 3-nitrobenzoic acid salt compound.

U.S. Patent No. 5,710,153 have put down in writing tetrazole compound.U.S. Patent No. 6,174,887 and 6,420,561 have put down in writing amide compound.S.P.Hiremath etc., Acta Ciencia Indica, XVIII: 397 (1992) put down in writing indyl thiosemicarbazide and Urea,amino-synthetic and biological activity.The open No.WO 96/36595 of international monopoly has put down in writing 3, the dibasic phenyl sulfanilamide (SN) of 4-.U.S. Patent No. 5,618,825 have put down in writing combination amine compound storehouse.European patent application No.EP0810221 has put down in writing oxygen containing Hete rocyclic derivatives.European patent application No.EP 0345990 has put down in writing polypeptide compound.European patent application No.EP 0254545 has put down in writing diamine compound.

The open No.WO 97/31016 of international monopoly has put down in writing the inhibitor of the process of SH2 mediation.U.S. Patent No. 6,034,067 has put down in writing serpin.Open No.WO 97/17985 of international monopoly and U.S. Patent No. 6,107,309 record blood are regulated compound (hemoregulatory compounds).U.S. Patent No. 6,432,921 have put down in writing thrombin inhibitors.UK Patent Application No.GB 2292149 has put down in writing the inhibitor peptides of preceding il-1 'beta ' converting emzyme.U.S. Patent No. 5,821,241 have put down in writing fibrinogen deceptor antagonists.

The open No.WO 01/02424 of international monopoly has put down in writing boronic acid compounds.U.S. Patent No. 6,001,811,5,869,455 and 5,618,792 put down in writing oxadiazole, thiadiazoles and triazole species peptide (peptoid).U.S. Patent No. 5,885,967,6,090,787 and 6,124,277 record zymoplasm inhibitory peptide derivatives.U.S. Patent No. 6,455,529 have put down in writing adhesion receptor antagonists.U.S. Patent No. 6,410,684 have put down in writing the serine stretch protein inhibitor.

The open No.WO 01/94310 of international monopoly has put down in writing two-heterocycle alkaloid.The open No.WO 96/39384 of U.S. Patent Publication No.20030004162A1, european patent application No.EP 0846464 and international monopoly has put down in writing glycogen phosphorylase inhibitors.The open No.WO 97/28798 of international monopoly has put down in writing pyrrolidin derivatives.U.S. Patent No. 5,346,907 have put down in writing amino acid analogue.

Summary of the invention

The compound of general formula (I) representative or its steric isomer or the acceptable salt of pharmacology

Inhibitor for glycogen phosphorylase; and can be used for preventative or therapeutic ground treatment diabetes, hyperglycemia, hypercholesterolemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis or tissue ischemia such as myocardial ischemia, and as heart protective agent.

Embodiment

The present invention relates to compound or its steric isomer or the acceptable salt of its pharmacology of general formula (I):

Wherein:

X ₁, X ₂, X ₃And X ₄One of be necessary for N and other be necessary for C;

R ¹And R ^{1 '}Independent separately is halogen, hydroxyl, cyano group, C _0-4Alkyl, C _1-4Alkoxyl group, fluoro methyl, difluoromethyl, trifluoromethyl, vinyl or ethynyl;

R ²Be C _0-4Alkyl, COOR ⁶, COR ⁶, C _1-4Alkoxy C _1-4Alkyl-, hydroxyl C _1-4Alkyl-, cycloalkyl C _0-4Alkyl-, aryl C _0-4Alkyl-, heteroaryl C _0-4Alkyl-, wherein arbitrary aromatic ring or hetero-aromatic ring are randomly by 1-2 individual independently halogen, cyano group, C _1-4Alkyl, C _1-4Alkoxyl group ,-N (C _0-4Alkyl) (C _0-4Alkyl) ,-SO ₂C _1-4Alkyl ,-SO ₂N (C _0-4Alkyl) (C _0-4Alkyl), hydroxyl, fluoro methyl, difluoromethyl or trifluoromethyl substituent replace;

Y is C _0-2Alkyl or-CH (OH)-;

Z is CH ₂,-C (O)-,-O-, N (C _0-4Alkyl), N (C 〉 _3-6Cycloalkyl) or not exist; But when Y be-CH (OH)-time, Z or R ³Must be connected on the Y by the C-C key;

R ³For hydrogen ,-COOC _0-4Alkyl, C _1-4Alkoxyl group, C _1-4Alkyl, aryl C _1-4Alkylthio-,-C _0-4Alkylaryl ,-C _0-4Miscellaneous alkyl aryl ,-C _0-4Alkyl-cycloalkyl or-C _0-4Alkyl heterocyclic, wherein ring is randomly replaced by 1-3 following independent substituent arbitrarily: halogen, cyano group, C _1-4Alkyl, fluoro methyl, difluoromethyl, trifluoromethyl ,-C _0-4Alkyl NHC (O) O (C _1-4Alkyl) ,-C _0-4Alkyl NR ⁷R ⁸,-C (O) R ⁹, C _1-4Alkoxy C _0-4Alkyl-,-COOC _0-4Alkyl ,-C _0-4Alkyl NHC (O) R ⁹,-C _0-4Alkyl C (O) N (R ¹⁰) ₂,-C _1-4Alkoxy C _1-4Alkoxyl group, hydroxyl C _0-4Alkyl-,-NHSO ₂R ¹⁰,-SO ₂(C _1-4Alkyl) ,-SO ₂NR ¹¹R ¹², 5-to 6-member's heterocyclic radical, phenyl C _0-2Alkoxyl group or phenyl C _0-2Alkyl, wherein phenyl is randomly by 1-2 individual independently halogen, cyano group, C _1-4Alkyl, C _1-4Alkoxyl group ,-N (C _0-4Alkyl) (C _0-4Alkyl) ,-SO ₂C _1-4Alkyl ,-SO ₂N (C _0-4Alkyl) (C _0-4Alkyl), hydroxyl, fluoro methyl, difluoromethyl or trifluoromethyl substituent replace, the perhaps (=O) substituting group of two key option ground formation oxygen bases on the heterocyclic ring carbon;

Perhaps R ³For-NR ⁴(C _0-4Alkyl R ⁵);

R ⁴Be C _0-3Alkyl ,-C _2-3Alkyl-NR ⁷R ⁸, randomly by hydroxyl C _0-4Alkyl-replacement and the C that can randomly further be replaced by hydroxyl _3-6Cycloalkyl, C _1-2Alkoxy C _2-4Alkyl-or C _1-2Alkyl-S (O) _n-C _2-3Alkyl-;

N is 0,1 or 2;

R ⁵Be hydrogen, hydroxyl C _2-3Alkyl-, C _1-2Alkoxy C _0-4Alkyl-or aryl, heteroaryl (hetaryl) or heterocyclic radical;

The R of heterocyclic nitrogen containing wherein ⁵Ring is encircling on the nitrogen randomly by C _1-4Alkyl, benzyl, benzoyl, C _1-4Alkyl-C (O)-,-SO ₂C _1-4Alkyl ,-SO ₂N (C _0-4Alkyl) (C _0-4Alkyl), C _1-4Alkoxy carbonyl or aryl (C _1-4Alkoxyl group) the carbonyl list replaces; And if wherein do not comprise quaternised (quaternised) nitrogen, then R ⁵Ring is encircling on the carbon randomly by halogen, cyano group, C _1-4Alkyl-C (O)-, C _1-4Alkyl-SO ₂-, C _1-4Alkyl, C _1-4Alkoxyl group, hydroxyl ,-N (C _0-4Alkyl) (C _0-4Alkyl), hydroxyl C _0-4Alkyl-or C _0-4Alkylcarbamoyl group-list replaces; Perhaps two keys on the heterocyclic ring carbon can randomly form oxygen base (=O) substituting group;

R ⁶Be C _1-4Alkyl, aryl or heteroaryl;

R ⁷And R ⁸Independent separately is C _0-4Alkyl, C _3-6Cycloalkyl or CO (C _1-4Alkyl);

R ⁹Be C _1-4Alkyl or C _3-6Cycloalkyl;

R ¹⁰Be C _0-4Alkyl or C _3-6Cycloalkyl;

R ¹¹And R ¹²Independent separately is C _0-4Alkyl or the nitrogen that connects on it with them form 4 to 6 Yuans heterocycle; And

Wherein do not exist-Y-Z-R ³Interconnective nitrogen-the oxygen of three parts, nitrogen-nitrogen, nitrogen-halogen bond.

The molecular weight of general formula (I) compound is preferably and is lower than 800, more preferably is lower than 600.

In first aspect, the present invention relates to compound or its steric isomer or the acceptable salt of pharmacology, the wherein X of general formula (I) representative ₁Be N, and the definition of other variable such as above-mentioned mutual-through type (I).

In a specific embodiments of first aspect, the present invention relates to compound or its steric isomer or the acceptable salt of pharmacology, the wherein X of general formula (I) representative ₁Be N, Y is C _0-2Alkyl, and Z be-C (O)-, and the definition of other variable such as above-mentioned mutual-through type (I).

In another specific embodiments of first aspect, the present invention relates to compound or its steric isomer or the acceptable salt of pharmacology, the wherein X of general formula (I) representative ₁Be N, Y is C _0-2Alkyl, and Z is-O-, and the definition of other variable such as above-mentioned mutual-through type (I).

In another specific embodiments of first aspect, the present invention relates to compound or its steric isomer or the acceptable salt of pharmacology, the wherein X of general formula (I) representative ₁Be N, Y is C _0-2Alkyl, and Z is〉N (C _0-4And the definition of other variable such as above-mentioned mutual-through type (I) alkyl).

In second aspect, the present invention relates to the compound of general formula (I) representative or its steric isomer, the acceptable salt of its pharmacology, wherein X ₂Be N, and the definition of other variable such as above-mentioned mutual-through type (I).

In a specific embodiments of second aspect, the present invention relates to compound or its steric isomer or the acceptable salt of pharmacology, the wherein X of general formula (I) representative ₂Be N, Y is C _0-2Alkyl, and Z be-C (O)-, and the definition of other variable such as above-mentioned mutual-through type (I).

In the third aspect, the present invention relates to compound or its steric isomer or the acceptable salt of pharmacology, the wherein X of general formula (I) representative ₃Be N, and the definition of other variable such as above-mentioned mutual-through type (I).

In a specific embodiments of the third aspect, the present invention relates to compound or its steric isomer or the acceptable salt of pharmacology, the wherein X of general formula (I) representative ₃Be N, Y is C _0-2Alkyl, and Z be-C (O)-, and the definition of other variable such as above-mentioned mutual-through type (I).

In another specific embodiments of the third aspect, the present invention relates to compound or its steric isomer or the acceptable salt of pharmacology, the wherein X of general formula (I) representative ₃Be N, Y is-CH (OH)-, and Z be-C (O)-, and the definition of other variable such as above-mentioned mutual-through type (I).

In another specific embodiments of the third aspect, the present invention relates to compound or its steric isomer or the acceptable salt of pharmacology, the wherein X of general formula (I) representative ₃Be N, Y is C _0-2Alkyl, and Z is-O-, and the definition of other variable such as above-mentioned mutual-through type (I).

In another specific embodiments of the third aspect, the present invention relates to compound or its steric isomer or the acceptable salt of pharmacology, the wherein X of general formula (I) representative ₃Be N, Y is C _0-2Alkyl, and Z do not exist, and the definition of other variable such as above-mentioned mutual-through type (I).

In another specific embodiments of the third aspect, the present invention relates to compound or its steric isomer or the acceptable salt of pharmacology, the wherein X of general formula (I) representative ₃Be N, Y is C _0-2Alkyl, and Z is〉N (C _0-4And the definition of other variable such as above-mentioned mutual-through type (I) alkyl).

In fourth aspect, the present invention relates to compound or its steric isomer or the acceptable salt of pharmacology, the wherein X of general formula (I) representative ₄Be N, and the definition of other variable such as above-mentioned mutual-through type (I).

In a specific embodiments of fourth aspect, the present invention relates to compound or its steric isomer or the acceptable salt of pharmacology, the wherein X of general formula (I) representative ₄Be N, Y is-CH (OH)-, and Z be-C (O)-, and the definition of other variable such as above-mentioned mutual-through type (I).

When Y be direct key then Z be not preferably for-O-, N (C _0-4Alkyl) or N (C _3-6Cycloalkyl).

X ₃Be preferably N.

Preferably, R ¹And R ^{1 '}Be halogen, cyano group, hydrogen, methyl, methoxyl group or ethynyl independently of one another.R more preferably ¹And R ^{1 '}Be halogen, cyano group or hydrogen independently of one another.

R at least preferably ¹And R ^{1 '}One of be hydrogen.R more preferably ¹And R ^{1 '}One of be hydrogen.

Preferred one group of compound is those wherein X ₃Be N, R ¹And R ^{1 '}One of another is the compound of 5-halogen or 5-cyano group for hydrogen.

Preferably, Y is C _0-2Alkyl, more preferably Y is direct key.

Preferably Z be-C (O)-.

Preferred one group of compound be those wherein:

X ₃Be N;

Y is C _0-2Alkyl; And

Z is-C (O)-compound.

Preferably, R ²Be C _0-4Alkyl or aryl C _0-4Alkyl-, wherein this aromatic ring is randomly by 1-2 individual independently halogen, cyano group, C _1-4Alkyl, C _1-4Alkoxyl group ,-N (C _0-4Alkyl) (C _0-4Alkyl) ,-SO ₂C _1-4Alkyl ,-SO ₂N (C _0-4Alkyl) (C _0-4Alkyl), hydroxyl, fluoro methyl, difluoromethyl or trifluoromethyl substituent replace.More preferably, R ²Be the benzyl that is randomly replaced by 1-2 halogenic substituent.A noteworthy concrete R ²Substituting group is-(S)-(4-luorobenzyl).

R preferably ³For randomly by the following independent substituent of 1-3 replace-C _0-4Alkyl heterocycle: halogen, cyano group, C _1-4Alkyl, fluoro methyl, difluoromethyl, trifluoromethyl ,-C _0-4Alkyl NHC (O) O (C _1-4Alkyl) ,-C _0-4Alkyl NR ⁷R ⁸,-C (O) R ⁹, C _1-4Alkoxy C _0-4Alkyl-,-COOC _0-4Alkyl ,-C _0-4Alkyl NHC (O) R ⁹,-C _0-4Alkyl C (O) N (R ¹⁰) ₂,-C _1-4Alkoxy C _1-4Alkoxyl group, hydroxyl C _0-4Alkyl-,-NHSO ₂R ¹⁰,-SO ₂(C _1-4Alkyl) ,-SO ₂NR ¹¹R ¹², the heterocycle of 5-to 6-unit, phenyl C _0-2Alkoxyl group or phenyl C _0-2Alkyl, wherein phenyl can be randomly by 1-2 individual independently halogen, cyano group, C _1-4Alkyl, C _1-4Alkoxyl group ,-N (C _0-4Alkyl) (C _0-4Alkyl) ,-SO ₂C _1-4Alkyl ,-SO ₂N (C _0-4Alkyl) (C _0-4Alkyl), hydroxyl, fluoro methyl, difluoromethyl or trifluoromethyl substituent replace, perhaps two keys on the heterocyclic ring carbon can randomly form oxygen base (=O) substituting group; Perhaps R ³For-NR ⁴(C _0-4Alkyl R ⁵).

More preferably, R ³Be the nitrogen heterocyclic ring group, especially be connected to 4 on the Z to 8 yuan nitrogen heterocyclic ring group by theheterocyclic nitrogen atom, it can randomly be replaced by 1-3 following independent substituent: halogen, cyano group, C _1-4Alkyl, fluoro methyl, difluoromethyl, trifluoromethyl ,-C _0-4Alkyl NHC (O) O (C _1-4Alkyl) ,-C _0-4Alkyl NR ⁷R ⁸,-C (O) R ⁹, C _1-4Alkoxy C _0-4Alkyl-,-COOC _0-4Alkyl ,-C _0-4Alkyl NHC (O) R ⁹,-C _0-4Alkyl C (O) N (R ¹⁰) ₂,-C _1-4Alkoxy C _1-4Alkoxyl group, hydroxyl C _0-4Alkyl-,-NHSO ₂R ¹⁰,-SO ₂(C _1-4Alkyl) ,-SO ₂NR ¹¹R ¹², the heterocycle of 5-to 6-unit, phenyl C _0-2Alkoxyl group or phenyl C _0-2Alkyl, wherein phenyl is randomly by 1-2 individual independently halogen, cyano group, C _1-4Alkyl, C _1-4Alkoxyl group ,-N (C _0-4Alkyl) (C _0-4Alkyl) ,-SO ₂C _1-4Alkyl ,-SO ₂N (C _0-4Alkyl) (C _0-4Alkyl), hydroxyl, fluoro methyl, difluoromethyl or trifluoromethyl substituent replace, perhaps two keys on the heterocyclic ring carbon can randomly form oxygen base (=O) substituting group; Perhaps R ³For-NR ⁴(C _0-4Alkyl R ⁵).

R wherein ³The example of the nitrogen heterocyclic ring group that can represent comprises azetidine-1-base, tetramethyleneimine-1-base, piperidines-1-base, 1,4-Diazesuberane (diazapan)-1-base, piperazine-1-base, morpholine-4-base, thiomorpholine-4-base, 1,1-dioxy-thiomorpholine-4-base or thiazolidine-3-base; Wherein each group can randomly be substituted as mentioned above.

For R ³Preferred substituted comprises-C _1-4Alkoxyl group, hydroxyl and oxygen base.

R ³Even the tetramethyleneimine that is more preferably randomly replaced by hydroxyl-1-base or piperidines-1-base, as 4-hydroxy piperidine-1-base and 3-(S)-hydroxyl pyrrolidine-1-base.

The specific compound that the present invention mentions is those included compounds among the embodiment, particularly 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)-(4-luorobenzyl)-2-(4-hydroxy piperidine-1-yl)-2-oxygen ethyl] acid amides and 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)-(4-luorobenzyl)-2-(3-(S)-hydroxyl pyrrolidine-1-yl)-2-oxygen ethyl] acid amides.

One group of concrete compound may mentioning is those compounds or its steric isomer or the acceptable salt of pharmacology of general formula (IA) representative,

Wherein:

X ₁, X ₂, X ₃And X ₄One of be necessary for N and other is necessary for C;

R ¹And R ²Independent separately is halogen, hydroxyl, cyano group, C _0-4Alkyl, C _1-4Alkoxyl group, fluoro methyl, difluoromethyl, trifluoromethyl, vinyl or ethynyl;

R ²Be C _0-4Alkyl, aryl C _0-4Alkyl-, heteroaryl C _0-4Alkyl-, wherein any aromatic ring or hetero-aromatic ring can be by 1-2 individual independently halogen, cyano group, C _1-4Alkyl, C _1-4Alkoxyl group ,-N (C _0-4Alkyl) (C _0-4Alkyl) ,-SO ₂C _1-4Alkyl ,-SO ₂N (C _0-4Alkyl) (C _0-4Alkyl), hydroxyl, fluoro methyl, difluoromethyl or trifluoromethyl substituent randomly replace;

Y is C _0-2Alkyl or-CH (OH)-;

Z is CH ₂,-C (O)-,-O-, N (C _0-4Alkyl), N (C 〉 _3-6Cycloalkyl) or not exist; But when Y be-CH (OH)-time, Z or R ³Must be incorporated on the Y by C-C bond;

R ³For hydrogen ,-COOC _0-4Alkyl, C _1-4Alkoxyl group, aryl C _1-4Alkylthio-,-C _0-4Alkylaryl ,-C _0-4Miscellaneous alkyl aryl or-C _0-4Alkyl heterocyclic, wherein any ring can be by 1-3 individual independently halogen, cyano group, C _1-4Alkyl, fluoro methyl, difluoromethyl, trifluoromethyl ,-C _0-4Alkyl N (C _0-4Alkyl) (C _0-4Alkyl) ,-C (O) (C _0-4Alkyl), C _1-4Alkoxy C _0-4Alkyl-,-COOC _0-4Alkyl, C _0-4Alkylcarbamoyl group-,-C _1-4Alkoxyl group methoxy base, hydroxyl C _0-4Alkyl-,-SO ₂(C _1-4Alkyl) or phenyl C _0-2Alkyl substituent randomly replaces, and perhaps two bond energys on the heterocyclic ring carbon randomly form oxygen base (=O) substituting group;

Perhaps R ³For-NR ⁴(C _0-4Alkyl R ⁵);

R ⁴Be C _0-3Alkyl ,-C _2-3Alkyl-N (C _1-3Alkyl) (C _1-3Alkyl), C _3-6Cycloalkyl, hydroxyl C _2-3Alkyl-, C _1-2Alkoxy C _2-4Alkyl-or C _1-2Alkyl-S (O) _n-C _2-3Alkyl-;

N is 0,1 or 2;

R ⁵Be hydrogen, hydroxyl C _2-3Alkyl-, C _1-2Alkoxy C _2-4Alkyl or aryl, heteroaryl or heterocyclic radical;

The R of heterocyclic nitrogen containing wherein ⁵Ring can randomly encircle on the nitrogen by C _1-4Alkyl, benzyl, benzoyl, C _1-4Alkyl-C (O)-,-SO ₂C _1-4Alkyl ,-SO ₂N (C _0-4Alkyl) (C _0-4Alkyl) or C _1-4Alkoxy carbonyl aryl (C _1-4Alkoxyl group) the carbonyl list replaces; And if do not comprise quaternised nitrogen, wherein R ⁵Ring can be randomly by halogen, cyano group, C on ring carbon _1-4Alkyl-C (O)-, C _1-4Alkyl-SO ₂-, C _1-4Alkyl, C _1-4Alkoxyl group ,-N (C _0-4Alkyl) (C _0-4Alkyl), hydroxyl C _0-4Alkyl-or C _0-4Alkylcarbamoyl group-list replaces; And

Wherein do not exist-Y-Z-R ³Interconnective nitrogen-the oxygen of this three part, nitrogen-nitrogen or nitrogen-halogen bond.

Although the preferred group for each variable is listed separately at each variable usually in the above, the preferred compound of the present invention comprises that several or each variable in those general formulas (I) is selected from each variable to preferred, preferred, most preferred, especially or the compound of the group of listing especially.Therefore, the present invention is intended to comprise preferred, preferred, most preferred, especially or all combinations of the group of listing especially.

When being used for herein, unless otherwise prescribed, " alkyl " and other group that contains prefix " alk " are meant carbochain or its combination of straight or branched as alkoxyl group, alkyl, thiazolinyl, alkynyl etc.The example of alkyl comprises methyl, ethyl, propyl group, sec.-propyl, butyl, the second month in a season and the tertiary butyl, amyl group, hexyl, heptyl etc." thiazolinyl ", " alkynyl " and other similar terms comprise the carbochain that contains at least one unsaturated carbon-carbon bond.

When being used for herein, for example, " C _0-4Alkyl " be meant and contain 0-4 carbon atom that promptly 0,1,2,3 or 4 carbon atom adopts the alkyl of straight or branched structure.When alkyl was end group, carbon-free alkyl was hydrogen.When alkyl was bridging (connection) base, carbon-free alkyl was direct key.

Term " cycloalkyl " and " carbocyclic ring " (carbocyclic ring) be meant and do not contain heteroatomic carbocyclic ring, and comprise single, double and three ring filling carbocyclic rings, and condensed ring and bridge ring systems.This condensed ring system can comprise a partially or completely undersaturated ring, as phenyl ring, to form the condensed ring system, as benzene condensed carbocyclic ring.Cycloalkyl comprises the condensed ring system such as the spiro-condensed loop systems.Cycloalkyl and isocyclic example comprise C _3-10Cycloalkyl, especially C _3-8Cycloalkyl is as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, naphthalane, diamantane, 2,3-indanyl, 1,2,3,4-naphthane etc.

Term " halogen " comprises fluorine, chlorine, bromine and iodine atom.

Term " carbamyl " unless stated otherwise, otherwise be meant-C (O)-NH-or-NH-C (O)-.

Term " aryl " is known by the chemist.Preferred aryl groups is phenyl and naphthyl, more preferably phenyl.

Term " heteroaryl " is known by the chemist.This term comprises that containing 1-4 is selected from oxygen, sulphur, and nitrogen, oxygen and sulphur non-conterminous heteroatomic 5 or 6 yuan of heterocycles mutually wherein.The example of this hetero-aromatic ring is furyl, thienyl, pyrryl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazole base (oxadiazolyl), thiadiazolyl group (thiadiazolyl), tetrazyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl and triazinyl.Term " heteroaryl " comprises and contains the partially or completely undersaturated hetero-aromatic ring that condenses carbon-loop system such as phenyl ring, to form benzene condensed heteroaryl.For example, benzoglyoxaline, benzoxazole, benzothiazole, cumarone, quinoline, isoquinoline 99.9, quinoxaline etc.

Except as otherwise noted, term " heterocycle (heterocyclic ring) ", " heterocyclic radical (heterocyclyl) " and " heterocycle (heterocycle) " are equal to, and comprise containing the 4-10 unit that one or two is selected from the heteroatomic saturated or fractional saturation of oxygen, sulphur and nitrogen, as 4-8 unit ring.This sulphur and oxygen heteroatom directly do not interconnect.Any nitrogen heteroatom on the ring can be randomly by C _1-4Alkyl replaces.The heterocyclic example comprises azetidine, trimethylene oxide, tetrahydrofuran (THF), tetrahydropyrans, epoxy hexane (oxepane), epoxy heptane (oxocane), epithio propane (thietane), thiazolidine oxazolidine, the oxaza butane, pyrazolidine isoxazole alkyl, isothiazolidine, tetramethylene sulfide, tetrahydric thiapyran, epithio hexane (thiepane), epithio heptane (thiocane), azetidine, tetramethyleneimine, piperidines, the N-methyl piperidine, azepan (azepane), 1,4-Diazesuberane (diazapane), Azacyclooctane (azocane), [1,3] dioxane oxazolidine, piperazine, high piperazine, morpholine, thiomorpholine, 1,2,3,6-tetrahydropyridine etc.Other example of heterocyclic comprises the oxidised form of sulfur-bearing ring.Thereby, tetramethylene sulfide-1-oxide compound, tetramethylene sulfide-1,1-dioxide, thiomorpholine-1-oxide compound, thiomorpholine-1,1-dioxide, tetrahydric thiapyran-1-oxide compound, tetrahydric thiapyran-1,1-dioxide, thiazolidine-1-oxide compound and thiazolidine-1, the 1-dioxide also is considered to heterocycle.Term " heterocyclic " also comprises the condensed ring system and can comprise partially or completely undersaturated carbocyclic ring, as phenyl ring, to form the benzene condensed heterocycle.For example, 3,4-dihydro-1,4-Ben Bing dioxine, tetrahydroquinoline, tetrahydroisoquinoline etc.

Compound described herein can comprise one or more asymmetric center and therefore produce diastereomer and optical isomer.The present invention includes all these possible diastereomers and their racemic mixture, the enantiomorph of their pure substantially fractionations, all possible geometrical isomer and the acceptable salt of pharmacology thereof.Above-mentioned general formula (I) does not demonstrate definite stereochemistry in some position.The present invention includes all steric isomers and the acceptable salt of pharmacology thereof of general formula (I).In addition, in stereoisomer mixture and isolating particular stereoisomer are also included within.During being used to prepare the building-up process of this compound, perhaps in using racemization well-known to those skilled in the art or epimerization process, the product of this process can be the mixture of steric isomer.

When there is tautomer in the compound of general formula (I), unless indicate especially or stipulate, the present invention includes any possible tautomer and the acceptable salt of pharmacology thereof, and their mixture.

When the compound of general formula (I) and the acceptable salt of pharmacology thereof exist with the form of solvate or polymorphic form, the present invention includes any possible solvate and polymorphic form form.A kind solvent that forms solvate then there is no particular restriction so long as pharmacology is acceptable.For example, can make water, ethanol, propyl alcohol, acetone etc.

The compound that comprises general formula (I) or the pharmaceutical composition of acceptable salt of its pharmacology and pharmacology acceptable carrier are also contained in the present invention.

Preferably, said composition comprises the compound or the acceptable salt of its pharmacology of the general formula (I) of pharmacology acceptable carrier and nontoxic treatment significant quantity.

And, in this preferred specific embodiments, a kind of compound of the general formula (I) that comprises pharmacology acceptable carrier and nontoxic treatment significant quantity or the pharmaceutical composition that is used for the treatment of disease of the acceptable salt of its pharmacology are contained in the present invention, this pharmaceutical composition is by the inhibition glycogen phosphorylase, thus preventative or therapeutic ground treatment diabetes, hyperglycemia, hypercholesterolemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis or tissue ischemia such as myocardial ischemia.

Term " the acceptable salt of pharmacology " is meant by the acceptable nontoxic alkali of pharmacology or the salt of acid preparation.When compound of the present invention when being acid, its corresponding salt can be easily from the acceptable non-toxic bases of pharmacology, comprise that mineral alkali and organic bases prepare.The salt that is derived from this mineral alkali comprises salt such as aluminium, ammonium, calcium, copper (copper and cuprous), iron, ferrous, lithium, magnesium, potassium, sodium, zinc.Be preferably ammonium, calcium, magnesium, potassium and sodium salt especially.The salt that the salt that is derived from the acceptable organic non-toxic bases of pharmacology comprises primary, secondary, tertiary amine and cyclammonium and replacement amine such as natural existence and synthetic replace amine.Can by the salifiable other medicines of shape learn acceptable organic non-toxic bases and comprise arginine, trimethyl-glycine, caffeine, choline, N ' N '-dibenzyl-ethylenediamin, diethylamine, the 2-DEAE diethylaminoethanol, the 2-dimethylaminoethanol, thanomin, quadrol, N-ethylmorpholine, N-ethylpiperidine, glycosamine, glucosamine, Histidine, breathe out amine (hydrabamine), Isopropylamine, Methionin, methylglucosamine, morpholine, piperazine, piperidines, versamid 900, PROCAINE HCL, PHARMA GRADE, purine, Theobromine, triethylamine, Trimethylamine 99, tripropyl amine, Trometamol etc.

When The compounds of this invention is when alkalescence, its corresponding salt can be easily from the acceptable non-toxicity acid of pharmacology, comprise inorganic and organic acid prepares.This acid comprises, for example, acetate, Phenylsulfonic acid, M-nitro benzoic acid, camphorsulfonic acid, citric acid, ethyl sulfonic acid, FUMARIC ACID TECH GRADE, gluconic acid, L-glutamic acid, Hydrogen bromide, hydrochloric acid, isethionic acid, lactic acid, toxilic acid, oxysuccinic acid, amygdalic acid, methylsulfonic acid, glactaric acid, nitric acid, two hydrogen naphthoic acid, pantothenic acid, phosphoric acid, succsinic acid, sulfuric acid, tartrate, tosic acid etc.Be preferably citric acid, Hydrogen bromide, hydrochloric acid, toxilic acid, phosphoric acid, sulfuric acid and tartrate especially.

Because the compound of general formula (I) is intended to be used for the pharmacology purposes, they are preferably the pure substantially form of employing and provide, for example at least 60% purity, be more suitable for being at least 75% purity, especially at least 98% purity (% is based on weight by weight).

Pharmaceutical composition of the present invention comprises the compound of general formula (I) representative or the acceptable salt of its pharmacology as activeconstituents, pharmacology acceptable carrier and optional other therapeutic ingredient or adjuvant.Although only approach will depend on host, character and the seriousness of the disease of activeconstituents institute administration under any given situation, but still comprise that those are suitable for the component of oral, rectum, part and parenteral route (comprising subcutaneous, intramuscular and intravenously) administration.Said composition is preferably and is suitable for oral administration.This pharmaceutical composition can adopt the form of unitary dose expediently and can prepare by any method that pharmacy field is known.

In the practice, according to the conventional medicine hybrid technology, the activeconstituents that the compound of general formula (I) or the acceptable salt of its pharmacology can be used as in the uniform mixture combines with pharmaceutical carrier.The form difference of the preparation of administration as required, this carrier can adopt various ways such as oral or parenteral route (comprising intravenously) administration.Therefore, pharmaceutical composition of the present invention can adopt the discrete unit that is suitable for oral administration capsule, wafer or the tablet as the activeconstituents that contains predetermined amount separately.In addition, said composition can be powder, granule, solution, suspensoid, on-aqueous liquid, oil-in-water emulsion, water-in-oil emulsion in liquid, aqueous.Except that the above-mentioned common dose form of listing, the compound of general formula (I) or the acceptable salt of its pharmacology can also come administration by controlled release method and/or transfer device.Said composition can prepare by any pharmaceutical methods.Usually, this method comprises the step that activeconstituents is combined with carriers of forming one or more kind neccessary compositions.Usually, said composition is by both mix evenly, subtly and prepare with the solid carrier of activeconstituents and liquid vehicle or fine dispersion or its.This product can be configured as required outward appearance expediently.

Thereby pharmaceutical composition of the present invention can comprise the compound or the acceptable salt of its pharmacology of pharmacology acceptable carrier and general formula (I).The compound of general formula (I) or the acceptable salt of its pharmacology also can be planted other therapeutic activity composition with one or more and together is included in the pharmaceutical composition.

Used pharmaceutical carrier can be for example solid, liquid or gas.The example of solid carrier comprises lactose, kaolin, sucrose, talcum, gelatin, agar, pectin, Sudan Gum-arabic, Magnesium Stearate and stearic acid.The example of liquid vehicle is syrup, peanut oil, sweet oil and water.The example of carrier gas comprises carbonic acid gas and nitrogen.

In the composition of preparation oral dosage form, any drug media easily all can be used.For example water, glycol, oil, alcohol, seasonings, sanitas, tinting material etc. can be used for forming oral liquid such as suspensoid, elixir and solution; And carrier such as starch, sugar, Microcrystalline Cellulose, thinner, granulating agent, lubricant, tackiness agent, disintegrating agent etc. can be used for forming oral solid formulation such as powder, capsule and tablet.Because their convenient drug administration, tablet and capsule are preferred oral dosage units when the applying solid pharmaceutical carrier.Randomly, tablet can be by moisture or non-water technology coatings.

The tablet that comprises the present composition can randomly prepare by compression or moulding (molding) with one or more kind supplementary components or adjuvant.Compressed tablet can randomly be compressed preparation with tackiness agent, lubricant, inert diluent, tensio-active agent or dispersant by the activeconstituents with free-flowing form such as powder or granule form in suitable machine.The moulding tablet can prepare by the mixture forming by the powder compounds that inert diluent is wetting in suitable machine.Each tablet is preferably and comprises about 0.05mg to the activeconstituents of about 5g, and each wafer or capsule are preferably and comprise the extremely activeconstituents of about 5g of about 0.05mg.

For example, be used for preparation to human oral administration and can comprise about 0.5mg to the solid support material of about 5g and suitable and convenient dosage blended active medicine mutually, this solid support material can account for about 5% of total composition and not wait to about 95%.Unit dosage form comprises the activeconstituents of about 1mg to about 2g usually, typically is 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000mg.

The present composition that is suitable for parenteral administration can be prepared into solution or the suspensoid of active compound in water.Suitable tensio-active agent can comprise as hydroxypropylcellulose.Dispersion can also prepare in glycerine, liquid macrogol and the mixture in oil thereof.In addition, can comprise sanitas to prevent the obnoxious growth of microorganism.

The pharmaceutical composition of the present invention that is suitable for injecting application comprises aseptic aqueous solution or dispersion.In addition, said composition can adopt the form of sterilized powder to be used for the instant preparation of this sterile injectable solution or dispersion.Under any circumstance, final injection form must be aseptic and must be effectively flowed so that inject.This pharmaceutical composition must be stable under the condition of producing and storing; Thereby, should preferably avoid the contamination of microorganism such as bacterium and fungi and preserve.Carrier can be solvent or for example comprise water, ethanol, polyvalent alcohol (as glycerine, propylene glycol and liquid macrogol), vegetables oil and the dispersion medium of suitable mixture.

Pharmaceutical composition of the present invention can adopt and be suitable for the local form of using, as aerosol, emulsifiable paste, ointment, lotion, face powder etc.In addition, said composition can adopt the form that is applicable to transdermal device.These preparations can utilize the compound of general formula (I) or the acceptable salt of its pharmacology to prepare by conventional treatment method.For example, emulsifiable paste or ointment can prepare by hydrophilic material and water and about 5 weight % are mixed mutually to the compound of about 10 weight %, have the emulsifiable paste or the ointment of required denseness with generation.

Pharmaceutical composition of the present invention can adopt wherein, and carrier is the form that solid is suitable for rectal administration.Preferred this mixture forms the suppository of unitary dose.Appropriate carriers comprises theobroma oil and this area other material commonly used.This suppository can be expediently by and carrier softening or that melt mixes mutually, then cools off in mould and moulding prepares with said composition.

Except that above-mentioned carrier components, the said medicine preparation can comprise one or more in due course and plant extra carrier components such as thinner, buffer reagent, seasonings, tackiness agent, tensio-active agent, thickening material, lubricant, sanitas (comprising antioxidant) etc.In addition, can comprise other adjuvant oozes with blood of keeping said preparation and designated receptor etc.The composition that contains the compound of general formula (I) or the acceptable salt of its pharmacology can be prepared into the form of powder or liquid concentrates.

Usually, to every day 0.01mg/kg to about 150mg/kg body weight or every patient's every day about 0.5mg extremely the similar dosage level of about 7g can be used for treating above-mentioned disease.For example, by with per kilogram of body weight administration every day about 0.01 to 50mg or every day every about 0.5mg of patient's administration can effectively treat diabetes and hyperglycemia to this compound of about 3.5g.Similarly, by with per kilogram of body weight administration every day about 0.01 to 50mg or every day every about 0.5mg of patient's administration can effectively treat hypercholesterolemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis or tissue ischemia such as myocardial ischemia to this compound of about 3.5g.

Yet, should understand for any particular patient, concrete dosage level will depend on various factors such as age, body weight, whole body health situation, sex, diet, administration time, route of administration, excretion rate, drug regimen and the seriousness of the specified disease of receiving treatment.

The compound of general formula (I) and the acceptable salt of pharmacology thereof can be used for treating disease or the morbid state that glycogen phosphorylase wherein works.

Therefore, the present invention also provides a kind of disease that glycogen phosphorylase wherein works or method of morbid state of being used for the treatment of, and it comprises the step to the compound or the acceptable salt of its pharmacology of the general formula (I) of patient's administration effective dose that these needs are arranged.

Wherein the disease that works of glycogen phosphorylase or morbid state comprise diabetes (comprise that I type and II type, glucose tolerance weaken, insulin resistant and diabetic complication such as neuropathy, ephrosis, retinopathy and cataract), hyperglycemia, hypercholesterolemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis, tissue ischemia such as myocardial ischemia.

The present invention also provides a kind of method that is used for the treatment of hyperglycemia or diabetes, and it comprises the step to the compound or the acceptable salt of its pharmacology of the general formula (I) of patient's administration effective dose that these needs are arranged.

The present invention also provides a kind of method that is used to prevent to show the people's that hyperglycemia before the diabetes or glucose tolerance weaken diabetes, and it comprises the step to the compound or the acceptable salt of its pharmacology of the general formula (I) of patient's administration effective dose that these needs are arranged.

The present invention also provides a kind of method that is used for the treatment of hypercholesterolemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis or tissue ischemia, and it comprises the step to the compound or the acceptable salt of its pharmacology of the general formula (I) of patient's administration effective dose that these needs are arranged.

The present invention also provides a kind of method as protection heart behind the reperfusion injury, and it comprises the step to the compound or the acceptable salt of its pharmacology of the general formula (I) of patient's administration effective dose that these needs are arranged.

The present invention also provides the compound or the application of the acceptable salt of its pharmacology in the above-mentioned disease of treatment of general formula (I).

The present invention also provides the compound of general formula (I) or the acceptable salt of its pharmacology to be used for the treatment of application in the medicine of above-mentioned disease in preparation.

Term " treatment " comprises therapeutic treatment and prophylactic treatment in the methods of the invention.

The compound of general formula (I) or the acceptable salt of its pharmacology can be individually dosed or be planted the therapeutical active compound Combined Preparation with one or more.Other therapeutical active compound can be used for the treatment of the identical disease or the morbid state for the treatment of with general formula (I) compound, perhaps different diseases or morbid state.This therapeutical active compound can be simultaneously, successively or individually dosed.

The compound of general formula (I) can be used for the treatment of active compound such as the Regular Insulin and the insulin analog of diabetes with other, sulfonylurea and analogue, biguanides, α 2 agonists, fatty acid oxidation inhibitors, alpha-glucosidase inhibitor, beta-2-agonists, phosphodiesterase inhibitor, fat-reducing medicament, slimming medicine, pancreas opsonin (amylin) antagonist, lipoxidase inhibitor, Somatostatin (somostatin) analogue, glucokinase activators, glucagon antagonist, the insulin signaling agonist, the PTP1B inhibitor, the glyconeogenesis inhibitor, the antilypolitic medicine, the GSK inhibitor, the galanin receptors agonist, anorectic medicaments, the cck receptor agonist, leptin (leptin), the conjugated protein administration together of CRF antagonist or CRF.

The compound of general formula (I) can also be with Protirelin compound, aldose reductase inhibitor, glucocorticoid receptor antagonists, NHE-1 inhibitor or sorbitol dehydrogenase inhibitors administration.

The compound of general formula (I) is compared with known glycogen phosphorylase inhibitors and is shown favorable properties, thereby for example this compound dissolution is improved and has improved absorptivity and bioavailability.In addition, the compound of general formula (I) also shows more, and favorable properties this means that as reducing the inhibition of pair cell cytochrome p 450 enzyme comparing them with known glycogen phosphorylase inhibitors causes that the interactional possibility between disadvantageous medicine-medicine is lower.

All publications include but not limited to that the patent and the patent application of quoting in this specification sheets all incorporate into herein as a reference, just look like concrete and illustrate that respectively each independent publication all incorporates into the same as a reference in full herein.

Embodiment

According to the present invention, the compound of general formula (I) can be according to preparing that following route 1 outlines, wherein R ¹, R ^{1 '}, R ², R ³, X ₁, X ₂, X ₃, X ₄, Y and Z such as above-mentioned mutual-through type (I) definition:

Route 1:

According to route 1, the amine of protected or activatory derivative of pyrrolopyridine-2-formic acid that the compound of general formula (I) can be by making suitable general formula (II) or its and suitable general formula (III) carries out coupling and prepares.The compound of general formula (II) can be by obtaining following route 3 and 5 described synthesizing of route.General formula (III) but compound can buy usually and obtain or pass course 8 and obtaining 9 described synthesizing.

Typically, the protected or activatory derivative of the compound of general formula (II) or its combines with the compound of general formula (III) in the presence of suitable coupling agent.The example of suitable coupling agent is 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride/hydroxybenzotriazole (EDCI/HOBt), 1,1-carbonyl dimidazoles (CDI), dicyclohexylcarbodiimide/hydroxybenzotriazole (DCC/HOBt), O-(1H-benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-Tetrafluoroboric acid urea (R.Knorr etc., Tetrahedron Lett., 1989,30,1927-1930) and carbodiimide-I-hydroxybenzotriazole of supporting of polymkeric substance (typical operation referring to as, Argonaut Technical Note 501, can be available from Argonaut Technologies, Inc., Foster City, California).This coupling is at inert solvent, be preferably in protophobic solvent, in the presence of tertiary amine base such as diisopropyl ethyl amine (DIPEA) or triethylamine, about 0 ℃ to about 45 ℃ of temperature reaction realized in about 1 to 72 hour.The example of solvent comprises acetonitrile, chloroform, methylene dichloride, N, dinethylformamide (DMF) or its mixture.The suitable selection of the use of these coupling agents and solvent and temperature is well known to those skilled in the art or can easily determines according to document.These and other can be used for the coupling carboxylic acid exemplary condition be recorded in Houben-Weyl, Vol XV, part II, E.Wunsch, Ed., G.Thieme Verlag, 1974, Stuttgart and M.Bodansky, Principles of PeptideSynthesis, Springer-Verlag, Berlin, 1984 and The Peptides, Analysis, Synthesis and Biology (Ed., E.Gross and J.Meienhofer), Vols 1-5, AcademicPress NY 1979-1983.

Route 2:

In second step, (wherein Z is C=O and R to the compound of general formula (I) ³For-NR ⁴(C _0-4Alkyl R ⁵)) can (wherein not contain Z and R according to carboxylic acid or its protected or activatory derivative of route 2 by making suitable general formula (I) ³For-CO ₂H) the amine coupling with suitable general formula (IV) prepares.The example of suitable coupling agent and condition are as previously discussed.The compound of general formula (IV) is available commercially or can prepares by known technology at an easy rate.

The compound of general formula (II) can be according to route 3 described preparations.

Route 3:

The compound of general formula (VI) can prepare with the barkite condensation in the presence of alkali such as potassium ethylate or DBU in solvent such as ether by the adjacent methyl nitro-compound that makes logical formula V.The compound of general formula (VII) is prepared under reductive condition such as iron powder and ammonium chloride by the compound of general formula (VI), perhaps utilizes palladium catalyst to prepare by hydrogenization in ethanol.Utilize alkaline solution, the compound of general formula (VII) obtains the pyrrolopyridine-2-formic acid of general formula (II) through the ester hydrolysis.The compound of logical formula V be converted into the further information of the compound of general formula (II) put down in writing in the literature (Kermack, etc., J.Chem, Soc., 1921,119,1602; Cannon etc., J.Med.Chem., 1981,24,238; Julian etc., in Heterocyclic Compounds, Vol 3 (Wiley, NewYork, NY, 1962, R.C.Elderfield, Ed.) p 18.

Perhaps, X wherein ₂For the compound of the general formula (VII) of nitrogen can be according to route 4 described preparations.

Route 4:

In appropriate solvent such as THF, use the compound deprotonation of organolithium such as n-Butyl Lithium, then obtain the compound of general formula (IX) with the methyl iodide cancellation with general formula (VIII).This compound can then be used the oxalic acid diethyl ester cancellation through tert-butyl lithium further deprotonation in appropriate solvent such as THF, the intermediate reflux is obtained the compound of general formula (VII) then in hydrochloric acid.

The compound of general formula (II) can also according to the Heck coupling of route 5 by adjacent iodine aminopyridine (XIV), then under 100 to 150 ℃ of temperature in catalyzer such as acid chloride and alkali such as DABCO cyclisation preparation in solvent such as DMF (referring to Chen etc., J.Org.Chem.1997,62,2676).This neighbour's iodine aminopyridine (XIV) can prepare the direct iodate of suitable aminopyridine (XIII) by utilize iodine in the presence of Sulfuric acid disilver salt under envrionment temperature in solvent such as ethanol.(referring to, Sy, W., Synth.Commun., 1992,22,3215).

Route 5:

Perhaps, the compound of general formula (XIV) can prepare by utilizing hydrochloric acid that N-pivalyl compound (XV) is gone to protect under reflux according to route 6.And this N-pivalyl compound (XV) is compound and organolithium such as tert-butyl lithium by general formula (XVI), deprotonation in appropriate solvent such as THF, then with iodine at low temperatures cancellation prepare.The compound of general formula (XVI) can trimethyl-acetyl chloride and alkali such as triethylamine in solvent such as methylene dichloride, protect commercially available aminopyridine (XIII) to prepare.

Route 6:

Perhaps, the compound of general formula (XIV) can make compound (XVII) deprotection of N-BOC protection prepare by utilizing acid in solvent such as methylene dichloride under envrionment temperature as trifluoroacetic acid according to route 7.And N-BOC compound (XVII) by with organolithium such as n-Butyl Lithium at N, N, N ', N ',-Tetramethyl Ethylene Diamine (TMEDA) exists down, in appropriate solvent such as ether, under temperature approximately-70 ℃ with the compound deprotonation of general formula (XVIII), then under-10 ℃ temperature approximately, add iodine and prepare.This N-BOC aminopyridine (XVIII) usually by commercially available aminopyridine (XIII) utilize two-tertiary butyl-supercarbonate at solvent as 1, prepare by heating in the 4-dioxane.

Route 7:

Protected or the activatory derivative of general formula (II) compound can prepare according to method well-known to those skilled in the art.

The compound of general formula (III) can be according to preparation shown in the route 8.

The compound of general formula (X) is available commercially usually or can obtains at an easy rate by known technology.PG represents protecting group such as tertbutyloxycarbonyl (Boc).The compound of general formula (XI) is by the carboxylic acid utilization of general formula (X) such as the 1 described standard coupling condition preparation of above-mentioned route.

The compound of general formula (III) can be according to route 8 preparations.

Route 8:

The compound of general formula (III) can be removed protecting group as the dichloromethane solution of trifluoroacetic acid and prepares by utilizing under acidic conditions by the compound of the general formula of PG=Boc (XI) wherein under about 25 ℃ temperature.

R wherein ²For H, Y are C ₀Alkyl, Z be-C (O)-and R ³Be C ₀Alkylaryl or C ₀The compound of the general formula of miscellaneous alkyl aryl (III) can be according to route 9 preparations.

Route 9:

The compound of general formula (XXIII) and potassium phthalimide react the compound that generates general formula (XXII) in solvent such as DMF, then it again can with ethylene glycol in the presence of the acid of catalytic amount such as tosic acid in solvent such as toluene reaction remove the compound of water generation general formula (XXI) simultaneously.Afterwards, this phthalic imidine protecting group can utilize hydrazine hydrate by heating pure solution or pass through the compound that heating generates general formula (XX) in solvent such as ethanol.The compound of these amine and general formula (II) carries out coupling under route 1 described standard coupling condition afterwards, and ketal group is removed the compound that generates general formula (I) under reflux temperature in solvent such as acetone in the presence of sour example hydrochloric acid then.

Route 10:

(wherein Z is C=O and R to the compound of general formula (I) ³Be C _1-4Alkoxyl group) can be 10 described according to route, under route 1 described standard coupling condition, combine with the compound of general formula (XII) by compound and to prepare general formula (II).The compound of general formula (XII) can be commercially available usually or can prepare at an easy rate by known technology.

The compound of general formula (I) (does not wherein contain Z and R ³For-CO ₂H) can by utilize alkaline solution, (wherein Z is C=O and R usually to make the compound of general formula (I) under about 25 ℃ temperature ³Be C _1-4Alkoxyl group) prepared in 30 minutes to 20 hours through the ester hydrolysis.

The compound of general formula (I) can prepare separately or as comprising 2 at least, for example 5 to 1,000 compounds and more preferably the compound library of the compound of 10 to 100 general formulas (I) prepare.Compound library can by combination " separate and mix (split and mix) " method prepare or utilize solution or or solid state chemistry use program well-known to those skilled in the art and synthesize by multiple parallel and prepare.

In the synthetic process of the compound of general formula (I), unsettled functional group such as hydroxyl, carboxyl and amino in the midbody compound can be protected.The compound of general formula (II) can be at 1 for example with arylmethyl, acyl group, alkoxy carbonyl, alkylsulfonyl or silyl protection.These protecting groups can remove or can appear in the final compound of general formula (I) in synthetic any stage of the compound of general formula (I).About the various unsettled functional groups that should be protected and about how comprehensive discussion of the method for the derivative fracture of the protection of gained for example is recorded in; Protective Groups in Organic Chemistry; T.W.Greene and P.G.M.Wuts; (1991) Wiley-Interscience; New York, 2 ^NdEdition.

Above-described any new intermediate is also contained in the scope of the invention.

The present invention also provides compound or its C of general formula (IIA) _1-4Alkyl ester or protected derivative,

Wherein:

X ₁, X ₂, X ₃And X ₄One of be necessary for N and other is necessary for C;

R ¹And R ^{1 '}Be halogen, hydroxyl, cyano group, C independently of one another _0-4Alkyl, C _1-4Alkoxyl group, fluoro methyl, difluoromethyl, trifluoromethyl, vinyl or ethynyl or do not exist;

Condition is if X ₁, X ₃Or X ₄During for N, R then ¹And R ^{1 '}Not all be hydrogen.

The preferred compound of general formula (IIA) comprises those X ₃Compound for N.

Preferably, R ¹And R ^{1 '}One of another is halogen or cyano group for hydrogen, especially, work as X ₁, X ₃Or X ₄During for N, be preferably 5-halogen such as 5-chlorine or 5-cyano group.

The particular compound of general formula (IIA) comprising:

5-chloro-1H-pyrrolo-[3,2-b] pyridine-2-formic acid;

5-bromo-1H-pyrrolo-[3,2-b] pyridine-2-formic acid;

5-cyano group-1H-pyrrolo-[3,2-b] pyridine-2-formic acid;

5-methoxyl group-1H-pyrrolo-[3,2-b] pyridine-2-formic acid;

The 1H-pyrrole is also coughed up [3,2-c] pyridine-2-formic acid;

6-chloro-1H-pyrrolo-[3,2-c] pyridine-2-formic acid;

6-cyano group-1H-pyrrolo-[3,2-c] pyridine-2-formic acid;

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid;

5-bromo-1H-pyrrolo-[2,3-c] pyridine-2-formic acid;

5-ethynyl-1H-pyrrolo-[2,3-c] pyridine-2-formic acid;

5-cyano group-1H-pyrrolo-[2,3-c] pyridine-2-formic acid;

5-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-formic acid;

5-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid;

6-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid; And

6-cyano group-1H-pyrrolo-[2,3-b] pyridine-2-formic acid.

The present invention also provides the compound of general formula (XIX):

R wherein ¹, R ^{1 '}, X ₁, X ₂, X ₃And X ₄Such as above-mentioned general formula (I) definition and R ³Be C ₀Alkylaryl or C ₀Miscellaneous alkyl aryl.

The present invention provides also that new compound 4 (S)-(it can prepare according to following experimental section is described for 4-luorobenzyl) oxazolidine-2,5-diketone.

Experiment

Material and method

Column chromatography is at SiO ₂(40-63 order) gone up and implemented.The LCMS data are to use WatersSymmetry 3.5 μ C ₁₈Post (2.1 * 30.0mm, flow velocity=0.8mL/min) with the HCO that contains 0.1% ₂(the 5%MeCN aqueous solution)-MeCN eluant solution 6min of H, and carry out ultraviolet detection at 220nm wavelength place.Gradient information: 0.0-1.2min:100% (the 5%MeCN aqueous solution); 1.2-3.8min: gradient is upgraded to 10% (the 5%MeCN aqueous solution)-90%MeCN; 3.8-4.4min: maintain 10% (the 5%MeCN aqueous solution)-90%MeCN; 4.4-5.5min: gradient is upgraded to 100%MeCN; 5.5-6.0min: return to 100% (the 5%MeCN aqueous solution).Mass spectrum is to use the spraying ionization ion source with (ES just ⁺) the ionic means acquisition.The NMR spectrum is to operate under the 400MHz or operation acquisition under 500MHz on Bruker AMX2 500 spectrometers on VarianMercury 400 spectrometers at 27 ℃.The purifying (mass directed purification) that quality instructs be on Micromass Platform LC with taper hole voltage 30v, use the spraying ionization ion source with (ES just ⁺) ionic means, Waters 996 diode-array detectors (210-390mn), Xterra PrepMS, C18,5 μ, 19 * 50mm post, moving phase is MeCN+0.1% formic acid/H ₂The O+5%MeCN+0.1% formic acid is implemented.

Abbreviation and acronym: BOC: tertbutyloxycarbonyl; DABCO: two ring [2,2,2]-1,4-aza-octane; DBU:1,8-diazabicyclo [5.4.0] 11 carbon-7-alkene; DCM: methylene dichloride; DIPEA:N, the N-diisopropylethylamine; DMAP:4-(N, N-dimethylamino) pyridine; DMF:N, dinethylformamide; DMSO: methyl-sulphoxide; DMTMM:4-(4,6-dimethoxy [1.3.5] triazine-2-yl)-4-methyl chlorination morpholine hydrate; EDCI:1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride; GP: glycogen phosphorylase; HATU:O-(7-azepine benzo triazol-1-yl)-N, N, N ', N '-tetramethyl-phosphofluoric acid urea; The HOBt:1-hydroxybenzotriazole; MDP: the purifying that quality instructs; MgSO ₄: sal epsom; PS: polymkeric substance is supported; Rt: room temperature; RT: retention time; THF: tetrahydrofuran (THF); TBTU:O-(benzotriazole-1-yl) N, N, N ', N '-tetramethyl-Tetrafluoroboric acid urea.

Preparation 1:6-methyl-5-nitro pyridine-2-base amine

This target compound is according to the method for Parker and Shive (J.Am.Chem.Soc., 1947,69,63) preparation, obtains brown ceramic powder.δ _H(d ₆DMSO)：2.6(3H，s)，6.37(1H，d，9.13Hz)，7.31(2H，s)，8.08(1H，d，9.13Hz)；m/z(ES ⁺)＝154.06[M+H] ⁺；RT＝0.57min。

Preparation 2:6-methyl-5-nitro-1H-pyridin-2-ones

This target compound obtains brown ceramic powder according to method (J.Am.Chem.Soc, 1952,74, the 3828) preparation of Baumgarten and Su.δ _H(d ₆DMSO)：2.62(3H，s)，6.28(1H，d，9.94Hz)，8.10(1H，d，9.94Hz)。

Preparation 3:2-chloro-6-methyl-5-nitro pyridine

(phosphoryl chloride 22.9mmol) (20mL) suspension liquid is cooled to room temperature then in 115 ℃ of heating (oil bath temperature) 3h for preparation 2,3.53g with 6-methyl-5-nitro-1H-pyridin-2-ones.Vacuum is removed phosphoryl chloride and resistates is poured in the frozen water (100mL).Add saturated sodium bicarbonate solution and come termination reaction in this mixture, (3 * 100mL) extract mixture aqueous solution with ethyl acetate then.The organic layer that merges is through the salt water washing, dry (MgSO ₄), filter and vacuum concentration obtains the target compound of brown solid shape.δ _H(CDCl ₃)：2.86(3H，s)，7.36(1H，d，8.59Hz)，8.27(1H，d，8.32Hz)。

Preparation 4:3-(2-chloro-5-nitropyridine-6-yl)-ethyl 2-oxopropanoate

(134mg, (218 μ L 1.59mmol) and with gained solution stir 30min to disposable adding oxalic acid diethyl ester under room temperature in ether 1.59mmol) (5mL) and ethanol (1mL) solution to potassium ethylate.((2mL, the anhydrous) suspension liquid of ether 1.45mmol) also continues to stir 17h under room temperature for preparation 3,250mg to add 2-chloro-6-methyl-5-nitro pyridine.Mixture filters, washs with cold diethyl ether through sinter.Being dissolved in the glacial acetic acid precipitation of collecting then, evaporated in vacuo obtains brown ceramic powder shape target compound.δ _H(CDCl ₃)：1.40(3H，t，7.27Hz)，4.38(2H，q，7.25Hz)，7.33(1H，d，8.59Hz)，7.37(1H，s)，8.40(1H，d，8.86Hz)。

Preparation 5:5-chloro-1H-pyrrolo-[3,2-b] pyridine-2-ethyl formate

To 3-(2-chloro-5-nitropyridine-6-yl)-ethyl 2-oxopropanoate (preparation 4,1.53g, the saturated aqueous ammonium chloride solution (30mL) of adding and with suspension liquid vigorous stirring under room temperature in THF 5.6mmol) (65mL) and ethanol (30mL) solution.Gradation adds iron powder, and (1.95g 34.8mmol) and before filtering by plug of celite (celite plug) cools off mixture heating 2h under refluxing, then by warm THF washing.This mixture obtains containing aqueous suspension through concentrating under reduced pressure, and this suspension liquid can filter by sinter, washing.Wet solid is also dry with methanol wash.Be adsorbed in resistates on the silica gel and obtain the target compound of white solid through flash chromatography (flash chromatography) purifying with ethyl acetate/hexane (1: 19) wash-out.δH(CD ₃OD)：1.42(3H，t，7.03Hz)，4.42(2H，q，7.32Hz)，7.15(1H，s)，7.30(1H，d，8.79Hz)，7.89(1H，d，8.35Hz)；m/z(ES ⁺)＝225.03[M+H] ⁺；RT＝3.32min。

Preparation 6:5-chloro-1H-pyrrolo-[3,2-b] pyridine-2-formic acid

((0.35mL 2M) and with this stirred solution heats 2h in 70 ℃ to add sodium hydroxide in ethanol 0.67mmol) (10mL) solution for preparation 5,151mg to 5-chloro-1H-pyrrolo-[3, the 2-b] pyridine-2-ethyl formate that stirs.Then this reaction mixture is cooled to room temperature and places 16h.Adding glacial acetic acid adjusting pH is 4, and solvent removed in vacuo obtains white solid, and this solid can be suspended in the methylene dichloride and can filter by sinter, and other adds washed with dichloromethane.Filter cake washs (3 * 30mL) the also dry target compounds that obtain white solid with ethyl acetate.δ _H(CD ₃OD)：6.97(1H，s)，7.17(1H，d，8.35Hz)，7.83(1H，d，8.35Hz)；m/z(ES ⁺)＝197[M+H] ⁺；RT＝2.82min。

Preparation 7:N-tertbutyloxycarbonyl-(S)-the phenylalanine dimethylformamide

With Dimethylammonium chloride (1.45g, DMF 17.8mmol) (46mL) solution be cooled to-10 ℃ and add triethylamine (2.7mL, 19.4mmol).Add then the N-Boc-L-phenylalanine (4.59g, 17.3mmol, Aldrich) and HOBt (3.49g, 26mmol), (3.33g 17.4mmol) stirs 5min with reaction solution before adding EDCI.This reaction mixture stirs 16h and uses ethyl acetate (400mL) dilution then, uses aqueous sodium hydroxide solution (2M, 2 * 100mL), hydrochloric acid (2N, 2 * 100mL), the dry then (MgSO of salt solution (250mL) washing successively ₄).Vacuum-evaporation obtains the target compound of light yellow oily.δ _H(CDCl ₃)：1.41(9H，s)，2.61，2.85(6H，2s)，2.91-2.99(2H，m)，4.83(1H，m)，5.40(1H，brd)，7.18-7.29(5H，m)。

Preparation 8:2-(S)-amino-N, N-dimethyl-3-Phenylpropionamide hydrochloride

((4N is dissolved in dioxane, 40mL) and this mixture is stirred 3h under room temperature to add hydrochloric acid soln in methyl alcohol 84mmol) (50mL) solution for preparation 7,24.8g to N-tertbutyloxycarbonyl-(S)-phenylalanine dimethylformamide.In gained solution for vacuum concentration water-soluble then (300mL).(3 * 100mL) washing gained solution also concentrate once more with ethyl acetate.(1: 1, mixture continuous recrystallization 200mL) obtained the colourless crystallization target compound with methyl alcohol (200mL) and methyl alcohol and toluene.δ _H(D ₂O)2.75，2.90(6H，2×s)，3.18(2H，m)，4.72(1H，t)，7.28-7.45(5H，m)。

Preparation 9: pyridin-4-yl t-butyl carbamate

It is white crystalline solid that the pyridin-4-yl t-butyl carbamate prepares target compound according to the method for (J.Org.Chem., 1999,64,9430) such as Spivey.δ _H(CDCl ₃)：1.52(9H，s)，7.08(1H，br?s)，7.32(2H，d)，8.43(2H，d)。

Preparation 10:(3-picoline-4-yl) t-butyl carbamate

(3-picoline-4-yl) t-butyl carbamate prepares the target compound of light yellow solid shape according to the method for (Synthesis, 1996,7,877) such as Hands.δ _H(CDCl ₃)：1.55(9H，s)，2.22(3H，s)，6.52(1H，s)，7.97(1H，d)，8.27(1H，s)，8.36(1H，d)。

Preparation 11:1H-pyrrolo-[3,2-c] pyridine-2-ethyl formate

With (3-picoline-4-yl) t-butyl carbamate (preparation 10,1.0g, anhydrous THF (10mL) solution 4.8mmol) be cooled to-40 ℃ and dropwise add tert-butyl lithium (5.9mL, 10.1mmol).Temperature is remained on-40 ℃ of 1h and in mixture, add oxalic acid diethyl ester (0.72mL, THF 5.3mmol) (20mL) solution then.With this reaction temperature to 0 ℃, keep this temperature 2h, rise to room temperature and stir 16h.Add hydrochloric acid (2N, 40mL) and will react reflux 90min, vacuum concentration and with saturated sodium bicarbonate aqueous solution adjusting pH to 8.The mixture ethyl acetate extraction (3 * 100mL), dry organic liquor (MgSO ₄) and vacuum concentration obtain target compound.δ _H(d ₆DMSO)：1.33(3H，t)，4.35(2H，q)，7.27(1H，s)，7.38(1H，d)，8.25(1H，d)，8.95(1H，s)；m/z(ES ⁺)＝191[M+H] ⁺。

Preparation 12:1H-pyrrolo-[3,2-c] pyridine-2-formic acid

With aqueous sodium hydroxide solution (2.4mL, 2M, 4.8mmol) join 1H-pyrrolo-[3,2-c] pyridine-2-ethyl formate (preparation 11,0.76g, in ethanol 4.0mmol) (40mL) solution, and with the mixture heating up 2h that refluxes, cooling and vacuum concentration then.Resistates is dissolved in the minimum water, adds glacial acetic acid (1mL) and also this solution was hidden 3 days in refrigerator and cooled.Filter resulting precipitation of collection and vacuum-drying and obtain cream-colored solid target compound.δ _H(D ₂O)：7.05(1H，s)，7.63(1H，d)，8.08(1H，d)，8.94(1H，s)。

Preparation 13:3-(3-nitropyridine-4-yl)-ethyl 2-oxopropanoate

(3.1g, (4.9mL 36.2mmol), and stirs 30min with reaction solution under room temperature to add oxalic acid diethyl ester in ether 36.2mmol) (70mL) and ethanol (10mL) solution to potassium ethylate under argon atmospher.(5.0g, ether 36.2mmol) (20mL) solution generate the garnet precipitation immediately to add 4-methyl-3-nitro pyridine.This reaction mixture is stirred 72h under room temperature, be cooled to 0 ℃ and filtration then.With being acidified with acetic acid to pH in the solid water-soluble (500mL) is 4, and collecting precipitation and drying obtain red solid shape target compound.δ _H(d ₆DMSO)：1.27(3H，t)，4.25(2H，q)，6.74(1H，s)，8.34(1H，d)，8.43(1H，d)，8.98(1H，s)；m/z(ES ⁺)＝239[M+H] ⁺。

Preparation 14:1H-pyrrolo-[2,3-c] pyridine-2-ethyl formate

To 3-(3-nitropyridine-4-yl)-ethyl 2-oxopropanoate (preparation 13,500mg, add in ethanol 2.1mmol) (20mL) and THF (10mL) solution saturated ammonium chloride solution (10mL) and iron powder (700mg, 12.6mmol).Reaction solution in the heating 1h down that refluxes, then by diatomite filtration, is used hot ethyl acetate (3 * 30mL) washings.The organic moiety that merges is washed through salt solution (20mL), dry (MgSO ₄) and vacuum concentration obtain the target compound of brown solid shape.δ _H(CD ₃OD)：1.44(3H，t)，4.43(2H，q)，7.21(1H，s)，7.69(1H，d)，8.12(1H，d)，8.80(1H，s)。

Preparation 15:1H-pyrrolo-[2,3-c] pyridine-2-formic acid

((1mL 2.0mmol) and with reaction mixture heats 1.5h vacuum concentration then down to the sodium hydroxide solution of adding 2N in ethanol 1.6mmol) (20mL) solution in refluxing for preparation 14,310mg to 1H-pyrrolo-[2,3-c] pyridine-2-ethyl formate.To also obtain brown precipitate immediately in the resistates water-soluble (10mL) with the acetate acidifying.Filter this solid and the dry target compound that obtains light brown solid state.δ _H(D ₂O)：7.11(1H，s)，7.99(1H，d)，8.05(1H，d)，8.85(1H，s)；m/z(ES ⁺)＝163[M+H] ⁺。

Preparation 16:3-(2-chloro-5-nitropyridine-4-yl)-ethyl 2-oxopropanoate

Route A: (1.46g, (2.4mL 17.4mmol) also stirs 0.5h with this mixture under room temperature to add oxalic acid diethyl ester in ether 17.4mmol) (80mL) and ethanol (10mL) solution to potassium ethylate under argon atmospher.(3.0g, ether 17.4mmol) (20mL) solution generate the sap green precipitation to add 2-chloro-4-methyl-5-nitro pyridine.This is reacted under the room temperature stir 15h, be cooled to 0 ℃, filter and obtain the sap green solid with the cold diethyl ether washing.With in this solid water-soluble (200mL) and to be acidified with acetic acid to pH be 4, obtain orange precipitation.Filter this solid of collection and drying and obtain target compound.m/z(ES ⁺)＝273[M+H] ⁺。

Route B: under argon atmospher to 2-chloro-4-methyl-5-nitro pyridine (1.0g, oxalic acid diethyl ester 5.8mmol) (4.23g 29mmol) adds 1 in the solution, 8-diazabicyclo [5.4.0]-11 carbon-7-alkene (0.95mL, 6.4mol).This mixture is stirred 1.5h use t-butyl methyl ether (40mL), water (30mL) and acetate (1ml) dilution then under room temperature.Organic layer is through separation, washing, dry (MgSO ₄) and be evaporated to dried.The wet red solid resistates of gained the most finally under 40-50 ℃ of high vacuum drying obtain target compound.

Preparation 17:5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ethyl formate

(preparation 16,3.0g 11.0mmol) is dissolved among ethanol (100mL) and the THF (50mL) with 3-(2-chloro-5-nitropyridine-4-yl)-ethyl 2-oxopropanoate.Add iron powder (3.7g, 66.0mmol) and saturated ammonium chloride solution (50mL) and with this mixture in the heating 2h down that refluxes.This mixture washs for several times by diatomite filtration and with ethyl acetate through cooling.Organic layer is through merging, salt solution (100mL) washing, dry (MgSO ₄) and vacuum concentration obtain the target compound of brown solid shape.δ _H(CD ₃OD)：1.42(3H，t)，4.44(2H，q)，7.15(1H，s)，7.70(1H，s)，8.59(1H，s)；m/z(ES ⁺)＝225[M+H] ⁺。

Preparation 18:5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid

Route A: ((5.2mL, 2M 10.3mmol) and with mixture heat 2h down in refluxing to add sodium hydroxide solution in ethanol 7.9mmol) (70mL) solution for preparation 17,1.78g to 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-ethyl formate.Solvent removed in vacuo and with in the solid water-soluble (150mL) and be acidified with acetic acid to pH and 4 obtain the target compound of brown solid shape, this solid can separate by filtration.δ _H(CD ₃OD)：7.13(1H，s)，7.68(1H，s)，8.58(1H，s)；m/z(ES ⁺)＝197[M+H] ⁺。

Route B: with 6-chloro-4-iodine pyridine-3-base amine (preparation 106,0.33g, 1.30mmol), pyruvic acid (0.27mL, 3.89mmol), DABCO (0.44g, 3.89mmol) and acid chloride (0.015g, dry DMF mixture vigorous stirring 0.07mmol) is also used argon-degassed 15min.This reaction mixture is stirred 5h in 107 ℃.Reaction mixture is through being cooled to room temperature and stirring 16h.Remove volatile matter and resistates is distributed between ethyl acetate (100mL) and water (50mL) under the decompression.Use ethyl acetate (2 * 50mL) aqueous layer extracted after separating each layer.The organic layer that merges NaOH (2M, 3 * 70mL) aqueous solution extractions.It is 4 that careful adding glacial acetic acid is acidified to pH with the water layer extraction liquid that merges, and uses ethyl acetate (3 * 60mL) extractions then.The organic layer that merges is through salt solution (50mL) washing, dry (MgSO ₄), filter and vacuum concentration obtains the target compound of brown solid shape.RT＝2.72min，m/z(ES ⁺)＝197[M+H] ⁺。

Preparation 19:[1-(S)-(4-luorobenzyl)-2-(4-hydroxy piperidine-1-yl)-2-oxoethyl] t-butyl carbamate

To Boc-3-(4-fluorophenyl)-(S)-L-Ala (10.0g that stirs, 35.3mmol), 4-hydroxyl piperidine hydrochloric acid salt (5.1g, 37.1mmol) and HOBt (7.2g, 52.9mmol) DMF (100mL) solution in add DIPEA (12.3mL, 70.6mmol), behind the 5min, add EDCI (7.4g, stirring reaction 16h 38.8mmol) and under room temperature.Solvent removed in vacuo also (is distributed resistates in water (150mL) and ethyl acetate between 2 * 150mL).The organic moiety that merges with sodium hydroxide solution (2M, 50mL), hydrochloric acid (2N, 50mL) washing, dry (MgSO ₄) and vacuum concentration.Product obtains the target compound of white solid with eluent ethyl acetate through silica gel chromatography.m/z(ES ⁺)＝367[M+H] ⁺；RT＝3.28min。

Preparation 20:2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxy piperidine-1-yl) third-1-keto hydrochloride

Route A the: to (preparation 19 of [1 (S)-(4-luorobenzyl)-2-(4-hydroxy piperidine-1-yl)-2-oxoethyl] t-butyl carbamate, 11.6g, 31.7mmol) methyl alcohol (40mL) solution in add the dioxane solution (24mL of hydrochloric acid, 4N 95.0mmol) and with reaction mixture stirs 16h under room temperature.Solvent removed in vacuo and with in the resistates water-soluble (100mL), with ethyl acetate (2 * 50mL) extraction.The water evaporate to dryness is obtained the target compound of white solid.δ _H(D ₂O)：0.52-0.63(0.5H，m)，1.12-1.23(0.5H，m)，1.26-1.38(1H，m)，1.42-1.50(0.5H，m)，1.59-1.69(0.5H，m)，1.72-1.82(1H，m)，2.61-2.71(0.5H，m)，2.91-3.15(4H，m)，3.33-3.47(1H，m)，3.69-3.78(1H，m)，3.88-3.96(1H，m)，4.60-4.72(1H，m)，7.02-7.11(2H，m)，7.14-7.26(2H，m)。

Route B: in (40mg, anhydrous THF (3mL) solution 0.4mmol) drips 4 (S)-(4-luorobenzyl) oxazolidine-2,5-diketone (preparation 117,100mg, THF 0.48mmol) (2mL) solution to the 4-hydroxy piperidine in 15min under the argon atmospher.Before the solvent removed in vacuo gained mixture is being stirred 40h under room temperature.Crude product is through column chromatography (SiO ₂, 9: 1 methylene chloride) and purifying obtains oily matter.Be dissolved in unhindered amina in the methyl alcohol (2mL) and add the dioxane solution (0.3mL) of 4M HCl, continue to stir 15min.Solvent removed in vacuo is also distributed product between ethyl acetate (5mL) and water (5mL).The vacuum concentration water layer obtains target compound.δ _H(CD ₃OD)：7.36-7.29(2H，m)，7.17-7.10(2H，m)，4.70(1H，t)，4.09-4.00(0.5H，m)，3.91-3.74(1.5H，m)，3.64-3.56(0.5H，m)，3.43-3.31(1H，m)，3.26-3.07(3H，m)，2.89-2.80(0.5H，m)，1.87-1.69(1.5H，m)，1.56-1.36(2H，m)，1.09-0.99(0.5H，m)。

Preparation 21:(3S, 2R)-3-amino-2-hydroxy-4-phenyl methyl-butyrate

(3S, 2R)-3-amino-2-hydroxy-4-phenyl methyl-butyrate can be according to A.

Carry out three-step reaction and synthesize from commercially available N-(tertbutyloxycarbonyl)-L-phenylalanine (phenylalaninal) Deng the method for (Tetrahedron Lett., 1998,39,4925).R _f0.29 (methylene chloride: 9/1); δ _H(CDCl ₃): 2.04 (3H, m), 2.73 (1H, dd), 2.92 (1H, dd), 3.36 (1H, ddd), 3.79 (3H, s), 4.08 (1H, d), 7.22-7.33 (5H, m).

Preparation 21A:(3S, 2S)-3-amino-2-hydroxy-4-phenyl methyl-butyrate

(3S, 2S)-3-amino-2-hydroxy-4-phenyl methyl-butyrate is to obtain as the by product of preparation 21.R _f(0.19 methylene chloride: 9./1); δ _H(CDCl ₃): 2.10 (2H, br s), 2.61 (1H, dd), 2.84 (1H, dd), 3.38 (1H, m), 3.78 (3H, s), 4.14 (1H, br s).

Preparation 22: suitable-3,4-dihydroxy pyrrolidine-1-benzyl formate

With perosmic anhydride solution (2.5% t-butanol solution, 5mL) and N-methylmorpholine (6.90g, 59.0mmol) handle benzyl-2,5-dihydro-1H-pyrroles-1-manthanoate (10.0g, (200mL) solution of THF 49.3mmol) and with reaction mixture stirring at room 72h under argon gas.The adding sodium thiosulfate solution (10%, 200mL) and with mixture continue to stir 1h vacuum concentration then.The gained water layer with ethyl acetate (3 * 200mL) extractions and with the organic layer that merges with sodium thiosulfate solution (10%, 300mL) and hydrochloric acid (1N, 300mL) washing.With organic layer drying (MgSO ₄) and vacuum concentration obtain the target compound of pale solid shape.δ _H(CDCl ₃)：2.67(2H，br?s)，3.38-3.45(2H，m)，3.63-3.67(2H，m)，4.22-4.26(2H，m)，5.12(2H，s)，7.30-7.38(5H，m)；m/z(ES ⁺)＝238[M+H] ⁺。

Preparation 23: suitable-3, the 4-dihydroxy pyrrolidine

Palladium carbon (144mg, 10 weight %) is joined suitable-3, (preparation 22,403mg is in ethanol 1.70mmol) (20mL) and hexanaphthene (2mL) solution and with mixture stirring, reflux 6h for 4-dihydroxy pyrrolidine-1-benzyl formate.By (careful behind the diatomite filtration with methyl alcohol repetitive scrubbing catalyzer! ), merge the target compound that filtrate and washings and vacuum concentration obtain colorless oil.δ _H(d ₄MeOH)：2.81(2H，dd)，3.03(2H，m)，4.07(2H，m)。

Preparation 24:2-bromo-4-methyl-5-nitro pyridine

(1g adds phosphorus oxybromide (2.8g, ethylene dichloride 9.7mmol) (10mL) solution in methylene dichloride 6.5mmol) (10mL) suspension liquid to 2-hydroxy-4-methyl-5-nitropyridine.Reaction mixture reflux 4h is cooled to room temperature and water (40mL) termination reaction then.Separate behind each layer water layer with dichloromethane extraction (2 * 30mL).With the organic layer drying (MgSO that merges ₄), vacuum concentration and obtain the target compound of faint yellow solid shape through silica gel column chromatography with the methylene dichloride wash-out.δ _H(CDCl ₃)：2.63(3H，s)，7.52(1H，s)，8.96(1H，s)。

Preparation 25:3-(2-bromo-5-nitropyridine-4-yl)-ethyl 2-oxopropanoate

(2.05g, (3.3mL 24.3mmol) and with reaction solution stirs 15min under room temperature to add oxalic acid diethyl ester in ether 24.3mmol) (70mL) and ethanol (10mL) solution to potassium ethylate under argon atmospher.(ether 22.1mmol) (20mL) solution joins and generates black precipitate in the reaction mixture immediately for preparation 24,4.8g with 2-bromo-4-methyl-5-nitro pyridine.To react under the room temperature and stir 6h, and be cooled to 0 ℃ then, filter and to obtain black solid.With in this solid water-soluble (250mL) and be acidified with acetic acid to pH and 4 generate red precipitates.Collect solid and the dry target compound that obtains the red solid shape.δ _H(d ₆DMSO)：1.16(3H，t)，4.01(2H，q)，6.55(1H，s)，7.92(1H，s)，8.96(1H，s)。

Preparation 26:5-bromo-1H-pyrrolo-[2,3-c] pyridine-2-ethyl formate

Route A the: to (preparation 25 of 3-(2-bromo-5-nitropyridine-4-yl)-ethyl 2-oxopropanoate, 3.38g, 10.7mmol) THF (50mL) and ethanol (100mL) solution in add saturated ammonium chloride solution (50mL) and iron powder (3.57g 64.0mmol) and with this react on the heating 2h down that refluxes.Reaction mixture washs for several times by diatomite filtration and with ethyl acetate.Solvent removed in vacuo also (is distributed resistates in saturated sodium bicarbonate solution (100mL) and ethyl acetate between 3 * 150mL).Organic moiety drying (the MgSO that merges ₄) and vacuum concentration obtain the target compound of brown solid shape.δ _H(CD ₃OD)：1.42(3H，t)，4.43(2H，q)，7.14(1H，s)，7.85(1H，s)，8.58(1H，s)；m/z(ES ⁺)＝269[M+H] ⁺。

Route B: (prepare 24,5.7g adds 1 in oxalic acid diethyl ester 26.3mmol) (17.9mL) solution, and (4.5mL 30.2mmol) obtains the garnet precipitation to 8-diazabicyclo [5,4,0]-11 carbon-7-alkene to 2-bromo-4-methyl-5-nitro pyridine under the argon gas.Reaction mixture stirs 4.5h and vacuum concentration under room temperature.Under argon gas, join acetate (140mL) in the resistates and be heated to 60 ℃.In 1h, repeatedly add on a small quantity iron powder (2.94g, 52.6mmol).Reaction mixture is in 80 ℃ of heating 4h.This reaction mixture is cooled to room temperature, pours water into and obtain light brown precipitation in (300mL).Precipitation separation also washes with water.Be dissolved in the ethyl acetate (700ml) solid that obtains and filtration.Vacuum concentrated filtrate obtains target compound.m/z(ES ⁺)＝269[M+H] ⁺；RT＝3.39min。

Preparation 27:5-bromo-1H-pyrrolo-[2,3-c] pyridine-2-formic acid

(1.1mL, 2M 2.23mmol) join 5-bromo-1H-pyrrolo-[2,3-c] pyridine-2-ethyl formate (preparation 26,500mg with sodium hydroxide solution.1.86mmol) ethanol (20mL) solution in, reaction mixture reflux 1.5h is vacuum concentration then.Generate brown precipitate in the resistates water-soluble (15mL) and with the acetate acidifying.Filter collecting precipitation and the dry target compound that obtains the brown solid shape.δ _H(d ₆DMSO)：7.08(1H，s)，7.97(1H，s)，8.60(1H，s)；m/z(ES ⁺)＝241[M+H] ⁺。

Preparation 28:1H-pyrrolo-[2,3-b] pyridine-2-formic acid

This target compound is according to the method preparation of Romero and Mitchell (WO 91/09849).

Preparation 29:2-methyl-3-nitro pyridine

With 2-chloro-3-nitropyridine (1.00g, 6.30mmol), salt of wormwood (2.62g, 18.90mmol), tetrakis triphenylphosphine palladium (0.73g, 0.63mmol) and trimethylboroxin (0.88mL, 6.30mmol) 1, the mixture heating up to 110 of 4-dioxane (2mL) and water (8mL) solution ℃ (oil bath temperature) 6h is then in stirring at room 16h.This mixture is through Celite pad filtration, THF washing then.With the filtrate vacuum suck on silica gel and obtain the target compound of yellow solid shape with ethyl acetate/hexane (3: 7) wash-out through the flash column chromatography purifying.δ _H(CDCl ₃)：2.86(3H，s)，7.34(1H，dd)，8.26(1H，dd)，8.71(1H，dd)。

Preparation 30:3-(3-nitropyridine-2-yl)-ethyl 2-oxopropanoate

(2.44g, (3.79mL 27.7mmol) obtains yellow suspension liquid to add oxalic acid diethyl ester in ether 27.7mmol) (90mL) and ethanol (8mL) solution to potassium ethylate.(preparation 29,3.40g 24.6mmol) stir 5min with this reaction mixture to disposable adding 2-methyl-3-nitro pyridine before.Under argon gas with the red suspension liquid stirring at room 20h of gained.Filtering mixt, also dry with the ether thorough washing.Red solid is soluble in water, add glacial acetic acid and regulate mixture pH to 4.Filter, collect the gained precipitation, with its be dissolved in the methylene dichloride, through salt water washing, drying (MgSO ₄), filtration and vacuum concentration obtain the target compound of orange solids shape then.δ _H(CDCl ₃)：1.40(3H，t)，4.39(2H，q)，7.34(1H，s)，7.36(1H，dd)，8.43(1H，dd)，8.66(1H，dd)。

Preparation 31:1H-pyrrolo-[3,2-b] pyridine-2-ethyl formate

To (the preparation 30 of 3-(3-nitropyridine-2-yl)-ethyl 2-oxopropanoate, 1.00g, 4.20mmol) ethanol (30mL, anhydrous) (10% on gac to add palladium in the suspension liquid, 447mg is 0.42mmol) also with this reaction mixture vigorous stirring 12h in hydrogen, pressure 20-30psi environment.By this reaction mixture of diatomite filtration, with ethyl acetate washing and vacuum concentration to about 20mL.Add entry (150mL) and mixture is cooled between 0 ℃ to 5 ℃.Filter and collect precipitation and the dry target compound that obtains light brown solid state that generates.δ _H(CDCl ₃)：1.44(3H，t)，4.45(2H，q)，7.25(1H，dd)，7.39(1H，s)，7.75(1H，dd)，8.57(1H，dd)，8.98(1H，s)。

Preparation 32:1H-pyrrolo-[3,2-b] pyridine-2-formic acid

(preparation 31,0.34g is 1.77mmol) at aqueous sodium hydroxide solution (2M, 10mL) the suspension liquid reflux 3h in and gained solution is cooled to room temperature with 1H-pyrrolo-[3,2-b] pyridine-2-ethyl formate.Add glacial acetic acid and regulate pH to 4.Vacuum is removed excessive acetate and the gained suspension liquid is cooled to 0 ℃ of room temperature placement 16h then.Filter and collect light brown precipitation and the dry target compound that obtains light brown solid state that obtains.δ _H(d ₆DMSO)：7.12(1H，s)，7.23(1H，dd)，7.79(1H，d)，8.42(1H，dd)。

Preparation 33:6-methoxyl group-2-methyl-3-nitro pyridine

To the 2-chloro-6-methoxyl group-3-nitropyridine (2.44g that stirs, 12.9mmol) the suspension liquid of the 10%v/v dioxane aqueous solution (25mL) in add tetrakis triphenylphosphine palladium (1.50g, 1.3mmol), mixture is stirred 15min add trimethylboroxin (1.81mL afterwards, 12.9mmol) and salt of wormwood (5.36g, 38.8mmol).Reaction mixture reflux 6h is cooled to room temperature 16h then.Add ethyl acetate (100mL) and with mixture vigorous stirring 1h.Mixture is through diatomite filtration, ethyl acetate washing.Also (3 * 30mL) extractions, the organic layer of merging is through salt solution (50mL) washing, dry (MgSO with ethyl acetate to separate water layer ₄), filter and use silica gel adsorption.Through flash column chromatography (SiO ₂, ethyl acetate/isohexane, 1: 20) and purifying obtains the target compound of light yellow solid shape.δ _H(CDCl ₃)：2.81(3H，s)，4.01(3H，s)，6.65(1H，d)，8.26(1H，d)。

Preparation 34:3-(6-methoxyl group-3-nitropyridine-2-yl)-ethyl 2-oxopropanoate

To the potassium ethylate (0.55g that stirs, 6.55mmol) ether (20mL, anhydrous) and the suspension liquid of ethanol (4mL) in add oxalic acid diethyl ester (894 μ L, 6.55mmol) and reaction mixture stirred 30min, add (the preparation 33 of 6-methoxyl group-2-methyl-3-nitro pyridine then, 1.0g, ether 5.95mmol) (8mL) solution.The red suspension liquid of gained stirring at room 20h under argon gas.Mixture after filtration, solid is through ether thorough washing and dry.Then this red solid is absorbed in hot water and this solution is cooled to 0 ℃.Filtering-depositing, with cold water washing and the dry target compound that obtains light brown solid state.δ _H(CDCl ₃)：1.40(3H，t)，4.07(3H，s)，4.39(2H，q)，6.74(1H，d)，7.57(1H，s)，8.40(1H，d)，13.82(1H，s)。

Preparation 35:5-methoxyl group-1H-pyrrolo-[3,2-b] pyridine-2-ethyl formate

To 3-(6-methoxyl group-3-nitro pyrrole-2-yl)-ethyl 2-oxopropanoate (preparation 34,276mg, disposable adding saturated aqueous ammonium chloride (5mL) and iron powder in THF 1.03mmol) (12mL) and ethanol (5mL) suspension liquid (346mg, 6.18mmol).Reaction mixture reflux 1h filters by plug of celite then while hot, washs with hot ethyl acetate.Cooling filtrate and through salt solution (20mL) washing, dry (MgSO ₄), filter and use the silica gel vacuum suck.Through flash column chromatography (SiO ₂, ethyl acetate/hexane, 1: 9) and purifying obtains the target compound of light brown solid state.δ _H(CDCl ₃)：1.40(3H，t)，3.99(3H，s)，4.41(2H，q)，6.74(1H，d)，7.20(1H，m)，7.62(1H，d)，9.27(1H，s)。

Preparation 36:5-methoxyl group-1H-pyrrolo-[3,2-b] pyridine-2-formic acid

To 5-methoxyl group-1H-pyrrolo-[3,2-b] pyridine-2-ethyl formate (preparation 35,128mg, ethanol (10mL 0.58mmol), anhydrous) (0.35mL 2M) and with mixture is cooled to room temperature then in being heated to 70 ℃ of 3h to add aqueous sodium hydroxide solution in the solution.Adding glacial acetic acid, to regulate pH be 4 and removal of solvent under reduced pressure.In the oily matter of gained, add ethyl acetate (20mL) and mixture is ultrasonic up to generating little suspension liquid (fine suspension).Pour out mother liquor and residual solid is washed with ethyl acetate, vacuum-drying obtains the pulverous target compound of light orange.δ _H(CD ₃OD)：3.92(3H，s)，6.63(1H，d)，6.94(1H，s)，7.72(1H，d)。

Preparation 37:2-[2-(4-p-methoxy-phenyl)-2-oxoethyl] isoindole-1, the 3-diketone

(5.78g, (5.00g 26.99mmol) and with reactant stirs 18h under room temperature to add phthalimide potassium in DMF 25.23mmol) (20mL) solution to 4-methoxyl group benzoyl monobromomethane.Reaction mixture is distributed between methylene dichloride (200mL) and water (100mL).Use methylene dichloride (3 * 50mL) aqueous layer extracted after separating each layer.The organic layer that merges with sodium hydroxide (2M, 50mL), water (50mL) and salt solution (50mL) washing and dry (MgSO4).Filter the concentrated white solid that obtains of final vacuum.Grind then filtration and collect the target compound that obtains white solid with ether.δ _H(CDCl ₃)：3.86(3H，s)，5.15(2H，s)，7.09(2H，d)，7.81-8.01(4H，m)，8.05(2H，d)。

Following compounds is synthesized from phthalimide potassium and suitable α-bromoketone according to preparation 37.

Preparation 41:2-[2-(4-p-methoxy-phenyl)-[1,3] dioxolane-2-ylmethyl] isoindole-1, the 3-diketone

With 2-[2-(4-p-methoxy-phenyl)-2-oxoethyl] isoindole-1, (preparation 37,6.35g 21.5mmol) is suspended in the toluene (50mL) and adds ethylene glycol (12mL) the 3-diketone.Add tosic acid (300mg, 1.58mmol) and with gained mixture heating up backflow 40h, with the Dean-Stark trap except that anhydrating.Reaction mixture is cooled to room temperature to be distributed between ethyl acetate (200mL) and saturated sodium bicarbonate solution (100mL) then.Organic layer is through salt solution (50mL) washing, dry (MgSO ₄), filter and concentrating under reduced pressure obtains the target compound of pale solid shape.δ _H(d ₆DMSO)：3.66(2H，t)，3.72(3H，s)，3.87(4H，m)，6.88(2H，d)，7.32(2H，d)，7.83(4H，m)。

Following compounds is synthesized by ethylene glycol and suitable ketone according to preparation 41.

Preparation 45:[2-(4-p-methoxy-phenyl)-[1,3] dioxolane-2-yl] methylamine

With 2-[2-(4-p-methoxy-phenyl)-[1,3] dioxolane-2-ylmethyl] isoindole-1, the 3-diketone (preparation 41,2.0g, 5.90mmol) and hydrazine hydrate (5mL) mixing.The reaction mixture that stirs is heated 48h down in refluxing be cooled to room temperature then.Add aqueous sodium hydroxide solution (2M, 10-15mL) and water (20mL) and stirring the mixture form until solution.Add ether (20mL) and with two-phase mixture vigorous stirring 16h.Separate behind each layer with extracted with diethyl ether (3 * 20mL), latter incorporated organic extract liquid wash through salt solution (20mL).Ethereal solution by filter paper then evaporated in vacuo obtain the target compound of yellow oily, (on standing) solidified when this oily matter left standstill.δ _H(CDCl ₃)：1.42(2H，br?s)，3.06(2H，s)，3.97(3H，s)，4.00(2H，t)，4.21(2H，t)，7.04(2H，d)，7.53(2H，d)。

Following compounds is synthetic by hydrazine hydrate and corresponding phthalimide according to preparation 45.

Preparation 49:5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(4-p-methoxy-phenyl)-[1,3]-dioxolane-2-ylmethyl] acid amides

To [2-(4-p-methoxy-phenyl)-[1,3] dioxolane-2-yl] methylamine (preparation 45,0.117g, 0.56mmol) methylene dichloride (5mL) solution in add DIPEA (213 μ L, 1.22mmol), 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18,0.100g, 0.51mmol) and HOBT (0.076g, 0.56mmol).Gained solution stirring 2min add then EDCI (0.117g, 0.61mmol) and continue under the room temperature and stir 18h.This reaction mixture is distributed and separates each layer between methylene dichloride (30mL) and water (20mL).(3 * 20mL) extractions merge organic phase and through salt solution (20mL) washing, dry (MgSO to water then with methylene dichloride ₄), filter and vacuum concentration.Obtain the target compound of orange solids shape through the ethanol/methylene recrystallization.δ _H(CDCl ₃)：3.81(3H，s)，3.84-3.91(4H，m)，4.05(2H，m)，6.56(1H，t)，6.76(1H，s)，6.89(2H，d)，7.44(2H，d)，7.57(1H，s)，8.68(1H，s)，9.94(1H，br?s)。

Following compounds is synthesized by 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and suitable amine according to preparation 49.

Preparation 53:(S)-and 2-amino-N, N-dimethyl-3-pyridin-3-yl propionamide hydrochloride

To (S)-2-t-butoxycarbonyl amino-3-pyridin-3-yl propionic acid (500mg, add in DMF 1.88mmol) (10mL) solution Dimethylammonium chloride (153mg, 1.88mmol), DIPEA (1.2mL, 6.57mmol) and TBTU (602mg, 1.88mol).Reaction mixture stirs 16h under room temperature.Solvent removed in vacuo also is dissolved in resistates in the methyl alcohol (20mL).In this reaction solution, add dioxane (20mL) solution of 4M hydrochloric acid and will react under the room temperature and stir 16h.Solvent removed in vacuo also (is distributed resistates in water (100mL) and ethyl acetate between 2 * 100mL).Evaporate to dryness water layer, resistates obtain the target compound of white solid through ethanol/ethoxy ethanol (9: 1) recrystallization.δ _H(CD ₃OD)：2.99(3H，s)，3.06(3H，s)，3.35-3.42(1H，m)，3.45-3.53(1H，m)，4.87-4.94(1H，m)，8.04-8.10(1H，m)，8.48-8.53(1H，m)，8.84-8.90(2H，m)。

Preparation 54:(S)-2-amino-3-pyridin-3-yl-1-tetramethyleneimine-1-base third-1-keto hydrochloride

To tetramethyleneimine (157 μ L, add in DMF 1.88mmol) (10mL) solution DIPEA (817 μ L, 4.69mmol), (S)-2-t-butoxycarbonyl amino-3-pyridin-3-yl propionic acid (500mg, 1.88mmol) and TBTU (663mg, 2.06mmol).This is reacted under the room temperature stir 72h.Solvent removed in vacuo also is dissolved in resistates in the methyl alcohol (15mL).In this reaction solution, add dioxane (20mL) solution of 4M hydrochloric acid and will react under the room temperature and stir 16h.Solvent removed in vacuo also (is distributed resistates in water (100mL) and ethyl acetate between 2 * 100mL).The evaporate to dryness water layer obtains green buttery target compound.δ _H(CD ₃OD)：1.86-2.05(4H，m)，3.20-3.28(2H，m)，3.39-3.58(2H，m)，3.68-3.78(2H，m)，4.63-4.71(1H，m)，8.11-8.17(1H，m)，8.56-8.64(1H，m)，8.85-8.93(2H，m)。

Preparation 55:(S)-and 2-amino-N, N-dimethylamino-3-pyridine-2-base propionamide hydrochloride

To the Dimethylammonium chloride (0.153g that stirs, 1.87mmol) DMF (8mL) solution in add DIPEA (2mL, 6.55mmol), (S)-2-t-butoxycarbonyl amino-3-pyridine-2-base propionic acid (0.50g, 1.87mmol, Acros) and TBTU (0.60g, 1.87mmol).Reaction mixture stirs 16h under room temperature.Solvent removed in vacuo also is dissolved in resistates in the methyl alcohol (15mL).In this reaction solution, add dioxane (20mL) solution of 4M hydrochloric acid and stirring reaction 16h under room temperature.Solvent removed in vacuo also is dissolved in resistates in the methyl alcohol (15mL).In this reaction solution, add dioxane (20mL) solution of 4M hydrochloric acid and stirring reaction 16h under room temperature.Solvent removed in vacuo also (is distributed resistates in water (100mL) and ethyl acetate between 2 * 100mL).The evaporate to dryness water layer obtains solid, and this solid obtains the target compound of light brown solid state from ethyl alcohol recrystallization.m/z(ES ⁺)＝194。

Preparation 56:5-chloro-3-iodine pyridine-2-base amine

With Sulfuric acid disilver salt (3.40g, 10.9mmol) and 2-amino-5-chloropyridine (1g, (2.76g stirs 72h in ethanol 10.9mmol) (50ml) solution and with reaction mixture under room temperature 7.8mmol) to add iodine.This mixture after filtration, methanol wash and vacuum concentrated filtrate.With resistates at saturated Na ₂S ₂O ₃Solution (50ml) and DCM (distribute between 2 * 50ml).Organic layer drying (the MgSO that merges ₄), vacuum concentration and obtain the target compound of light brown solid state through the silica gel chromatography purifying with the DCM wash-out.δ _H(CDCl ₃)：4.95(2H，br?s)，7.84(1H，d)，7.98(1H，d)。

Preparation 57:5-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid

With pyruvic acid (0.43ml, 6.24mmol) join 5-chloro-3-iodine pyridine-2-base amine (preparation 56,500mg, 2.08mmol), palladium (23mg, 0.10mmol) and DABCO (700mg is in dry DMF 6.24mmol) (20ml) solution.With this reaction mixture argon-degassed 20min, be heated to 110 ℃ of 16h then.Solvent removed in vacuo and resistates is suspended in water (10ml) and the acetate (5ml) after filter.Solid is dissolved in EtOAc (50ml), extracts and discard organic layer with 2N NaOH solution (50ml).(2 * 40ml) extract with dense HCl acidified aqueous solution and with EtOAc.With the organic layer drying (MgSO that merges ₄) and vacuum concentration obtain the target compound of light brown solid state.δ _H(CD ₃OD)：7.14(1H，s)，8.14(1H，d)，8.35(1H，d)。

Preparation 58:5-trimethyl silyl acetylene-1H-pyrrolo-[2,3-c] pyridine-2-ethyl formate

Under argon atmospher with PdCl ₂(PPh ₃) ₂(0.026g, 0.037mmol) and Cu (I) I (0.007g, 0.037mmol) join successively 5-bromo-1H-pyrrolo-[2,3-c] pyridine-2-ethyl formate (preparation 26,0.100g, 0.370mmol) in.Add 1,4-dioxane (7mL, anhydrous) adds diisopropylamine then, and (0.063mL 0.45mmol), and feeds argon gas 5min in stirred mixture.(0.064mL, 0.45mmol), the gained mixture stirs 24h under room temperature dropwise to add trimethyl silyl acetylene afterwards.This reaction mixture is distributed and separates each layer between water (50mL) and ethyl acetate (100mL).(3 * 30mL) extract water layer with ethyl acetate.The organic layer that merges is through salt water washing (50mL), dry (MgSO ₄), filter and vacuum concentration.Resistates is dissolved in minimum methylene dichloride and is loaded on the silicagel column.Through flash column chromatography (SiO ₂, methylene dichloride is used 25% ethyl acetate/isohexane then) and purifying obtains light yellow solid.δ _H(CDCl ₃)：0.28(9H，s)，1.43(3H，t)，4.45(2H，q)，7.18(1H，s)，7.83(1H，s)，8.86(1H，s)，9.21(1H，br?s)。

Preparation 59:5-ethynyl-1H-pyrrolo-[2,3-c] pyridine-2-ethyl formate

(preparation 58 adds tetra-n-butyl Neutral ammonium fluoride (the THF solution of 1.0M, the H of 5 weight % in stirred solution 0.123g) to ester ₂O, 0.47mL, 0.47mmol), this solution becomes garnet immediately.Behind the 5min, this is reflected at distribution between ethyl acetate (60mL) and the water (40mL).(2 * 20mL) extract water layer with ethyl acetate after separating each layer.Glacial acetic acid is joined in the organic layer of merging and become yellow from pink up to color.With this solution with water (20mL), salt solution (20mL) washing, dry then (MgSO ₄), filter and vacuum concentration.Resistates is dissolved in methyl alcohol and is adsorbed on the silica gel.Through flash column chromatography (SiO ₂, ethyl acetate: isohexane, 1: 1, v/v) purifying obtained the target compound of yellow powder powder.δ _H(CDCl ₃)：1.44(3H，t)，3.08(1H，s)，4.46(2H，q)，7.20(1H，s)，7.85(1H，s)，8.89(1H，s)，9.33(1H，s)。

Preparation 60:5-ethynyl-1H-pyrrolo-[2,3-c] pyridine-2-formic acid

((the 2M aqueous solution, 1.5mL 3.0mmol) and with mixture stir 3h in 50 ℃ to add sodium hydroxide in ethanol 0.30mmol) (6mL) suspension liquid for preparation 59,0.065g to ester.Mixture is cooled to room temperature and adds glacial acetic acid, produces the white solid precipitation.Collect solid after filtration, water (20mL) is used ether (20mL) washing then.This solid is through the air-dry target compound that obtains white powder.m/z(ES ⁺)＝187[M+H] ⁺；RT＝1.85min。

Preparation 61:5-cyano group-1H-pyrrolo-[2,3-c] pyridine-2-ethyl formate

((anhydrous, (0.041g 0.35mmol), adds tetra-triphenylphosphine palladium (0) to DMF 0.590mmol) then 5mL) to add zinc cyanide (II) in the solution for preparation 26,0.160g to 5-bromo-1H-pyrrolo-[2,3-c] pyridine-2-ethyl formate.This reaction mixture is fed Argon Bubble degassing 10min.This reaction mixture is heated to reflux temperature 4.5h is cooled to room temperature then.Add entry (30mL) and use ethyl acetate (2 * 50mL) extraction mixtures.The organic layer that merges is through salt solution (30mL) washing, dry (MgSO ₄), filter and vacuum concentration.Resistates is dissolved in the ethyl acetate is adsorbed on the silica gel then.Through flash column chromatography (SiO ₂, ethyl acetate: isohexane, 1: 3, v/v) purifying obtained the target compound of white solid.δ _H(CDCl ₃)：1.45(3H，t)，4.49(2H，q)，7.31(1H，s)，8.09(1H，s)，8.97(1H，s)，9.60(1H，br?s)；m/z(ES ⁺)＝216[M+H] ⁺；RT＝3.03min。

Preparation 62:5-cyano group-1H-pyrrolo-[2,3-c] pyridine-2-formic acid

To ester (preparation 61,0.266g, 1.24mmol) in the stirring suspension liquid of ethanol (6mL) and water (0.6mL), add sodium hydroxide (0.108g, 2.72mmol).This reaction mixture in 50 ℃ of stirring 24h, is cooled to room temperature then.Reaction mixture is collected after filtration and is washed with ether with ether (30mL) dilution.(wash with ether then by 2 * 50mL) washings with acetic acid aqueous solution for this solid.This solid is through the air-dry target compound that obtains white solid.δ _H(d ₆DMSO)：7.22(1H，s)，8.37(1H，s)，8.88(1H，s)，12.88(1H，s)。

Preparation 63:2,4-dimethyl-5-nitropyridine

To 2-chloro-4-methyl-5-nitro pyridine (9.419g, 54.6mmol) in the stirring suspension liquid of dioxane (110mL), add tetrakis triphenylphosphine palladium (6.330g, 5.46mmol), this mixture is stirred 15min, add trimethylboroxin (7.68mL afterwards, 54.6mmol) and salt of wormwood (22.64g, 164.0mmol).Reaction mixture reflux 6h is cooled to room temperature 16h then.Add ethyl acetate (200mL) and with mixture vigorous stirring 1h.Mixture through diatomite filtration, ethyl acetate/THF (1: 1, v/v) washing.Add salt solution (100mL), separate each layer and obtain dense milk sap.After removing the volatile matter of gained, add ethyl acetate (300mL), filtering mixt generation two-phase mixture.Separate each layer, (3 * 100mL) extract water with ethyl acetate.The organic layer that merges is through salt solution (100mL) washing, dry (MgSO ₄), filter and vacuum concentration.Gained oily matter is dissolved in the methylene dichloride, then through flash column chromatography (SiO ₂, ethyl acetate/isohexane, 3: 7, v/v) purifying obtained orange buttery target compound.δ _H(CDCl ₃)：2.59(3H，s)，2.60(3H，s)，7.12(1H，s)，9.07(1H，s)。

Preparation 64:3-(2-methyl-5-nitro pyridin-4-yl)-ethyl 2-oxopropanoate

(0.262g, (0.404mL 2.96mmol) and with gained solution stirs 10min to disposable adding oxalic acid diethyl ester under room temperature in ether 2.96mmol) (10mL) and ethanol (1mL) solution to potassium ethylate.Add 2,4-dimethyl-5-nitropyridine (preparation 63,0.400g, 2.63mmol) suspension liquid in ether (1mL)/ethanol (1.5mL) and under room temperature, continue to stir 16h.This mixture after filtration, cold diethyl ether washing.The precipitation of collecting is soluble in water and add glacial acetic acid to regulate pH be 4.The collection, air-dry after filtration of gained precipitation.This solid is distributed and separates each layer between ethyl acetate (150mL) and water (50mL).Water layer with ethyl acetate (3 * 20mL) extractions and with the organic layer that merges through salt solution (50mL) washing, dry (MgSO ₄), filter and concentrating under reduced pressure obtains the target compound that the red solid shape need not to be further purified.δ _H(CDCl ₃)：1.40(3H，t)，4.40(2H，q)，4.52(2H，s)，7.11(1H，s)，9.25(1H，s)。

Preparation 65:5-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-ethyl formate

(preparation 64,0.749g add saturated aqueous ammonium chloride (15mL) also with this suspension liquid vigorous stirring under room temperature in THF 2.97mmol) (30mL) and ethanol (15mL) solution to pyruvate.Gradation add iron powder (1.38g, 24.64mmol) and with mixture heating up reflux 2h then after cooling by plug of celite filtration, warm methanol wash.Mixture is through concentrating under reduced pressure, and resistates distributes and separate each layer between ethyl acetate (250mL) and water (250mL).(the latter incorporated organic layer of 3 * 50mL) extractions is through salt solution (100mL) washing, dry (MgSO with ethyl acetate for water layer ₄), filter and vacuum concentration.Be adsorbed in resistates on the silica gel and through flash chromatography (SiO ₂, ethyl acetate) and purifying obtains the target compound of light orange solid state.δ _H(CDCl ₃)：1.42(3H，t)，2.63(3H，s)，4.43(2H，q)，7.10(1H，s)，7.40(1H，s)，8.81(1H，s)，9.08(1H，br?s)。

Preparation 66:5-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-formic acid

To the ester that stirs (preparation 65,117mg, 0.574mmol) in the solution of ethanol (10mL), add aqueous sodium hydroxide solution (2M, 0.43mL, 0.861mmol).Gained solution is heated to 55 ℃ of 4h and is cooled to room temperature then and stirs 17h.Adding excessive glacial acetic acid reduces pressure then and removes all volatile matters.The resistates water grinds and filters the solid of collecting gained, and is air-dry then through water washing.Separate the target compound that obtains the light yellow solid shape.m/z(ES ⁺)＝177[M+H] ⁺；RT＝1.60min。

Preparation 67:4-methoxyl group piperidines-1-t-butyl formate

To the 4-of vigorous stirring hydroxy piperidine-1-t-butyl formate (2.07g, add in DMF 10.3mmol) (25mL) solution 60% sodium hydride mineral oil dispersion (500mg, 12.5mmol).After stirring 20min, (0.9mL 14.5mmol) and with gained mixture stirring 48h joins in the mixture of water and salt solution (250mL, 1: 1) afterwards to add methyl iodide.(4 * 50mL) extractions, the extraction liquid of merging is through salt solution (100mL) washing and dry (MgSO with ethyl acetate ₄), the resistates that obtains after concentrating obtains the target compound of colorless oil through flash chromatography (silica gel, ethyl acetate/hexane, 1: 1) purifying.δ _H(CDCl ₃): 1.50 (9H, s), 1.52,1.88 (4H, 2m) 3.12 (2H, ddd), 3.18 (1H, m), 3.19 (3H, s), 3.77 (2H, m); R _f(0.33 ethyl acetate/hexane, 1: 1).

Preparation 68:4-methoxyl group piperidine hydrochlorate

(preparation 67,1.58g add 1 of hydrochloric acid in methyl alcohol 7.34mmol) (20mL) solution, 4-dioxane (4M, 10mL) solution and mixture stirred 3h under room temperature to 4-methoxyl group piperidines-1-t-butyl formate.Vacuum concentration obtains oily matter, in its water-soluble again (100mL).(2 * 30mL) wash and the concentrated colorless solid that obtains water layer with ethyl acetate.δ _H(D ₂O)：1.80，2.14(4H，2m)，3.13(2H，m)，3.38(2H，m)，3.40(3H，s)，3.68(m，1H)。

Preparation 69:(R)-3-methoxyl group tetramethyleneimine-1-t-butyl formate

Adopt and prepare 67 similar modes and use 60% sodium hydride dispersion (267mg, 6.68mmol) and methyl iodide (0.5mL, 8.06mmol) DMF (15ml) solution (1.04g 5.55mmol) methylates and purifying with (R)-3-hydroxyl pyrrolidine-1-t-butyl formate (Sigma-Aldrich).δ _H(CDCl ₃): 1.50 (9H, s), 1.94-2.02 (2H, m), 3.37 (3H, s), 3.38-3.58 (4H, m), 3.95 (1H, m); R _f0.47 (ethyl acetate/hexane: 1/1).

Preparation 70:(R)-3-methoxyl group pyrrolidine hydrochloride

Adopt the mode similar with preparation 68 to use 1 of methyl alcohol (10mL) and hydrochloric acid, (4M, 5.0mL) (840mg 4.17mmol) removes to protect also purifying to solution to the 4-dioxane with (R)-3-methoxyl group tetramethyleneimine-1-t-butyl formate.δ _H(D ₂O)：2.12(2H，m)，3.10-3.56(8H，m)，4.20(1H，m)。

Preparation 71:(S)-3-methoxyl group tetramethyleneimine-1-t-butyl formate

Adopt and prepare 67 similar modes and use 60% sodium hydride dispersion (260mg, 6.50mmol) and methyl iodide (0.5mL, 8.06mmol) DMF (15ml) solution (950mg 5.55mmol) methylates and purifying with (S)-3-hydroxyl pyrrolidine-1-t-butyl formate (Omega chemical company). ¹HNMR and R _fConsistent with (R)-enantiomorph.

Preparation 72:(S)-3-methoxyl group pyrrolidine hydrochloride

Adopt the mode similar with preparation 68 to use 1 of methyl alcohol (10mL) and hydrochloric acid, (4M, 5.0mL) (720mg 3.58mmol) removes to protect also purifying to solution to the 4-dioxane with (S)-3-methoxyl group tetramethyleneimine-1-t-butyl formate. ¹H NMR and R _fConsistent with (R)-enantiomorph.

Preparation 73:4-(2-oil of mirbane sulfuryl amino) piperidines-1-t-butyl formate

(400mg, (340 μ L 2.4mmol) also cool off this solution in ice bath to add triethylamine in anhydrous methylene chloride 200mmol) (14mL) solution to 4-amino piperidine-1-t-butyl formate under argon gas.Add the 2-nitrobenzene sulfonyl chloride (443mg, 2.0mmol) and will react under the room temperature and stir 16h.Thick solution with water (solvent removed in vacuo after 2 * 30mL) washings.Crude product obtains the target compound of pale powder shape as the elutriant purifying through chromatographic grade ethyl acetate/petroleum ether (30-60%).δ _H(d ₆DMSO)：8.43(2H，m)，8.17(1H，s)，8.09(2H，m)，3.80-3.69(2H，m)，3.31-3.23(1H，m)，2.86-2.69(2H，m)，1.63-1.51(2H，m)，1.39(9H，s)，1.29-1.17(2H，m)。

Preparation 74:4-[methyl-(2-oil of mirbane alkylsulfonyl) amino] piperidines-1-t-butyl formate

(400mg, (507mg 1.56mmol) and with mixture stirs 40min under room temperature to add cesium carbonate in DMF 1.04mmol) (10mL) solution to 4-(2-oil of mirbane sulfuryl amino) piperidines-1-t-butyl formate (preparation 73).(323 μ L 5.19mmol) and with mixture stir 16h to add methyl iodide.Solvent removed in vacuo is also distributed thick resistates between ethyl acetate (20mL) and water (20mL).Separate organic layer and with 1M HC1 (2 * 20mL), water (20mL) salt solution (2 * 20mL) washings, dry afterwards (MgSO then ₄).Solvent removed in vacuo obtains the target compound of yellow powder shape.δ _H(d ₆DMSO)：8.43(2H，m)，8.01(2H，m)，4.00-3.89(3H，m)，2.83-2.67(5H，m)，1.54-1.43(2H，m)，1.39(9H，s)，1.34-1.24(2H，m)。

Preparation 75:N-methyl-2-nitro-N-piperidin-4-yl benzsulfamide

According to embodiment 182 by 4-[methyl (2-oil of mirbane alkylsulfonyl) amino] piperidines-1-t-butyl formate (preparation 74) preparation.δ _H(d ₆-DMSO)：8.44(2H，m)，8.13(2H，m)，4.20-7.07(1H，m)，3.29-3.17(2H，m)，3.03-2.90(2H，m)，2.77(3H，s)，2.00-1.84(2H，m)，1.51-1.43(2H，m)。

Preparation 76:5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1-(S)-(4-luorobenzyl)-2-{4-[methyl (2-oil of mirbane alkylsulfonyl) amino] piperidines-1-yl }-the 2-oxoethyl) acid amides

Prepare by 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid (embodiment 230) and N-methyl-2-nitro-N-piperidin-4-yl benzsulfamide hydrochloride (preparation 75) according to embodiment 231.m/z(ES ⁺)＝643.36[M+H] ⁺。

Preparation 77: thiomorpholine 1,1-dioxide

(1.0g, (30%w/v 4mL) also is heated to 100 ℃ of 16h with this reaction to add aqueous hydrogen peroxide solution in acetate 9.69mmol) (11.5mL) solution to the thiomorpholine that is cooled to 0 ℃ (ice bath).With this mixture cooling and solvent removed in vacuo, obtain white precipitate with the methyl alcohol grinding residues then.Filter this solid and obtain the target compound of pale powder shape with methanol wash.m/z(ES ⁺)＝136.06[M+H] ⁺。

Preparation 78: piperidines-4-methyl-formiate hydrochloride

(7.1mL is 0.1mol) also with this solution stirring 75min to add Acetyl Chloride 98Min. to refrigerative anhydrous methanol (100mL) solution.(150mg 1.16mmol) is dissolved in the preparation solution (10mL) and stirring reaction 16h with piperidines-4-formic acid.Solvent removed in vacuo obtains the target compound of hydrochloride form.m/z(ES ⁺)＝144.12[M+H] ⁺。

Preparation 79:2-(S)-formamyl-piperidines-1-t-butyl formate

To the N-Boc-L-2-nipecotic acid (200mg, add in DMF 0.87mmol) (3.5mL) solution TBTU (336mg, 1.05mmol), (93mg, (182 μ L 1.05mmol) and with reaction solution stir 16h to ammonium chloride 1.74mmol) to add DIPEA then.With mixture ethyl acetate (2 * 30mL) and water (30mL) between distribute, merge after the organic layer with 1M sodium hydroxide (3 * 30mL) and salt solution (3 * 30mL) washings.Organic solution drying (MgSO ₄) and solvent removed in vacuo obtain the target compound of white solid.δ _H(d ₆-DMSO)：7.23(1H，s)，6.97(1H，s)，4.56-4.39(1H，br?m)，3.43-3.74(1H，d)，3.14-2.90(1H，br?m)，2.09-2.00(1H，d)，1.63-1.47(3H，m)，1.30-1.17(2H，m)。

Preparation 80:(S)-piperidines-2-carboxamide hydrochloride

Piperidines-2-methane amide according to Johnson etc. (J.Med.Chem., 1986,29, method preparation 2100-2104) obtains the target compound of white solid.δ _H(CD ₃OD)：3.87-3.75(1H，m)，3.43-3.34(1H，m)，3.09-2.96(1H，br?m)，2.31-2.16(1H，m)，1.97-1.81(2H，br?m)，1.77-1.57(3H，br?m)。

Preparation 81:4-(2-methoxy ethoxy) piperidines-1-t-butyl formate

To tertiary butyl-4-hydroxy-1-piperidine carboxylic acid ester (300mg, 1.49mmol) DMF (2mL) solution in add 1-bromo-2-methyl ethyl ether (168 μ L, 1.79mmol), then add potassiumiodide (25mg, 0.15mmol) and sodium hydride (83.5mg, 2.09mmol), and will react under the room temperature and stir 16h.Solvent removed in vacuo is also distributed thick resistates between ethyl acetate (10mL) and water (10mL).Organic layer is with 1M HCl (10mL), 1M NaOH (10mL) and salt solution (2 * 10mL) washings, dry (MgSO then ₄) and solvent removed in vacuo.Obtain the target compound of yellow oily as elutriant with methylene chloride (97: 3) through chromatogram purification.δ _H(CDCl ₃)：3.89-3.77(2H，m)，3.66(2H，m)，2.57(2H，m)，3.54-3.46(1H，m)，3.43(3H，s)，3.11-3.03(2H，m)，1.93-1.83(2H，m)，1.60-1.46(11H，m)。

Preparation 82:4-(2-methoxy ethoxy) piperidine hydrochlorate

(preparation 81,114mg add dioxane (550 μ L, 2.20mmol) solution and reaction solution stirred 16h under room temperature of 4M HCl in methyl alcohol 0.44mmol) (3mL) solution to 4-(2-methoxy ethoxy) piperidines-1-t-butyl formate.Solvent removed in vacuo is also with in the thick resistates water-soluble (10mL).(2 * 10mL) wash vacuum concentration then to the aqueous solution with ethyl acetate.Grind the target compound that purifying obtains hydrochloride form with ethyl acetate.δ _H(CD ₃OD)：3.74-3.67(1H，m)，3.64(2H，m)，3.56(2H，m)，3.40-2.39(7H，m)，2.11-1.96(2H，m)，1.93-1.83(2H，m)。

Preparation 83:[1-(R)-(4-luorobenzyl)-2-(4-hydroxy piperidine-1-yl)-2-oxoethyl] t-butyl carbamate

This target compound is according to embodiment 231 but be to use the preparation of Boc-3-(4-fluorophenyl)-(R)-L-Ala and 4-hydroxy piperidine.m/z(ES ⁺)＝367.34[M+H] ⁺。

Preparation 84:2-(R)-amino-3-(4-fluorophenyl)-1-(4-hydroxy piperidine-1-yl) third-1-keto hydrochloride

This target compound is by [1-(R)-(4-luorobenzyl)-2-(4-hydroxy piperidine-1-yl)-2-oxoethyl] t-butyl carbamate (preparation 83) preparation according to preparation 20.m/z(ES ⁺)＝267.20[M+H] ⁺。

Preparation 85:4-(N-benzyl-N-methylamino) piperidines-1-t-butyl formate

To N-benzyl methylamine (648 μ L, 5.02mmol) and 1-tertbutyloxycarbonyl-4-piperidone (500mg, 2.51mmol) THF (8mL) solution in add sodium triacetoxy borohydride (798mg, 3.76mmol) (144 μ L react under the room temperature 2.51mmol) and with this and to stir 40h then to add acetate.Solvent removed in vacuo is also distributed resistates between ethyl acetate (15mL) and water (15mL).(2 * 15mL) then with salt solution (2 * 20mL) washings, dry (MgSO with sodium bicarbonate for organic layer ₄) and solvent removed in vacuo.Crude product obtains the target compound of yellow oily as elutriant with ethyl acetate/petroleum ether (2: 1) through chromatogram purification.m/z(ES ⁺)＝305.32[M+H] ⁺。

Preparation 86:4-methylamino piperidines-1-t-butyl formate

This target compound is by 4-(benzyl methylamino) piperidines-1-t-butyl formate (preparation 85) preparation according to preparation 23.δ _H(CD ₃OD)：4.13-4.03(2H，m)，2.90-2.76(2H，br?m)，2.63-2.53(1H，m)，2.40(3H，s)，2.97-1.87(2H，m)，1.49(9H，s)，1.27-1.16(2H，m)。

Preparation 87: benzyl methyl (tetrahydropyran-4-base) amine

This target compound is by N-benzyl methylamine and tetrahydrochysene-4H-pyrans-4-ketone preparation according to preparation 85.Crude product uses methylene chloride (98: 2) to obtain the target compound of yellow oily as elutriant through chromatogram purification.δ _H(CD ₃OD)：7.50-7.40(5H，m)，4.08(2H，m)，4.06-(2H，s)，3.49-3.40(2H，ddd)，3.23-3.14(1H，m)，2.51(3H，s)，2.03-1.97(2H，m)，1.89-1.76(2H，m)。

Preparation 88: methyl (tetrahydropyran-4-base) amine hydrochlorate

This target compound is by benzyl methyl (tetrahydropyran-4-base) amine (preparation 87) preparation according to preparation 23.Be dissolved in coarse raw materials in the methyl alcohol and drip the diethyl ether solution of 1M HCl and generate precipitation.Product after filtration, ether washing obtains the target compound of hydrochloride form, is white crystalline solid.δ _H(CD ₃OD)：4.11-4.00(2H，m)，3.53-3.43(2H，m)，3.37-3.27(1H，m)，2.74(3H，s)，2.11-2.03(2H，m)，1.74-1.60(2H，m)。

Preparation 89:1-benzyl piepridine-4-base-dimethyl amine

Under 0 ℃ to 4-amino-1-benzyl piepridine (536 μ L, add in formic acid 2.63mmol) (8.5mL) solution formaldehyde solution (37%, 5.5mL) and with the mixture heating up 6h that refluxes.Solvent removed in vacuo is also distributed thick resistates between ethyl acetate (20mL) and water (20mL).Separate water layer, regulating pH with 2M NaOH solution is with ethyl acetate (2 * 20mL) extractions after 12.Organic moiety is through salt solution (30mL) washing, dry (MgSO ₄) afterwards solvent removed in vacuo obtain the target compound of yellow oily.m/z(ES ⁺)＝219.25[M+H] ⁺。

Preparation 90: lupetidine-4-base amine

This target compound is by 1-benzyl piepridine-4-base-dimethyl amine (preparation 89) preparation according to preparation 23.δ _H(CD ₃OD)：3.17-3.09(2H，m)，2.66-2.54(2H，m)，2.30(6H，s)，2.26(1H，m)，1.94-1.86(2H，m)，1.49-1.29(2H，m)。

Preparation 91:4-methylsulfonyl amino-piperadine-1-t-butyl formate

To 4-amino-1-Boc-piperidines (300mg, 1.50mmol) methylene dichloride (2.0mL) solution in add methylsulfonyl chloride (348 μ L, 4.49mmol) methylene dichloride (1mL) solution, (485 μ L, methylene dichloride 5.99mmol) (1mL) solution also react on this under room temperature and stir 16h then to add piperidines.Add entry (10mL), separating mixture and with organic layer with the washing of 1M HCl (10mL), sodium hydrogen carbonate solution (10mL), then through salt solution (2 * 10mL) washings.With this solution drying (MgSO ₄) and solvent removed in vacuo.Crude product uses methylene chloride (95: 5) to obtain the target compound of pale powder shape as elutriant through chromatogram purification.δ _H(CD ₃OD)：4.46-4.40(1H，m)，4.09-3.97(2H，m)，3.53-3.40(1H，m)，3.0(3H，s)，2.93-2.81(2H，m)，2.01-1.93(2H，m)，1.50-1.37(2H，m)。

Preparation 92:N-piperidin-4-yl Toluidrin

This target compound is to be prepared by 4-methylsulfonyl amino-piperadine-1-t-butyl formate (preparation 91) according to preparation 82, is pale powder.δ _H(CD ₃OD)：3.67-3.57(1H，m)，3.47-3.40(2H，m)，3.19-3.10(2H，m)，3.03(3H，s)，2.26-2.17(2H，m)，1.87-1.76(2H，m)。

Preparation 93:2-(S)-amino-3-pyridin-4-yl methyl propionate hydrochloride

This target compound is to use Boc-3-(4-pyridyl)-L-L-Ala to prepare as starting acid according to preparation 78.δ _H(CD ₃OD)：8.90(2H，br?s)，8.16(2H，br?s)，4.73-4.60(1H，m)，3.84(3H，s)，3.73-3.50(2H，m)。

Preparation 94:1,4-two oxa-s-7-azepine-spiral shell [4.5] decane

To 1-Boc-3-piperidone (700mg, 3.51mmol) toluene (20mL) solution in add ethylene glycol (588 μ L 10.54mmol), then add tosic acid hydrate (1.0g, 5.27mmol), and use the Dean-Stark device will react reflux 7h.In this mixture, add NaHCO ₃Solution is also removed organic layer.The evaporate to dryness water, the gained resistates is dissolved in THF.Obtain the desired product of light brown oily by diatomite filtration and solvent removed in vacuo.δ _H(CD ₃OD)：3.99(2H，s)，3.73-3.57(2H，m)，3.63(4H，m)，2.77(1H，m)，2.73(1H，m)，1.76(2H，m)。

Preparation 95:2-phenyl-1-(S)-(2-phenyl-[1,3] dioxolane-2-yl) ethamine

To commercially available 2-(S)-(N-tertbutyloxycarbonyl)-amino-1,3-phenylbenzene-1-acetone (250mg, add in toluene 0.768mmol) (100mL) solution ethylene glycol (1.0mL, 17.9mmol) and the tosic acid monohydrate (262mg, 1.38mmol).This mixture uses the Dean-Stark trap to remove and anhydrates through reflux 48h.After being cooled to room temperature, this mixture is with ethyl acetate (200mL) dilution and successively with the sodium hydroxide solution of dilution (1M, 2 * 50mL), salt solution (50mL) washing.With this solution drying (MgSO ₄) and simmer down to oily matter, (elutriant: ethyl acetate) purifying obtains the target compound of colorless oil to this oily matter by fast silica gel chromatogram.δ _H(CDCl ₃)：2.07(2H，br?s)，2.37(1H，dd)，2.92(1H，dd)，3.36(1H，m)，3.85-4.35(4H，3m)，7.14-7.59(10H，m)；m/z(ES ⁺)＝270.20[M+H] ⁺；RT＝2.63min。

Preparation 96:5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-phenyl-1-(S)-(2-phenyl-[1,3] dioxolane-2-yl) ethyl] acid amides

To 5-chloro-1H-pyrrolo-[2,3-c] (the preparation 18 of pyridine-2-formic acid, 88mg, 0.403mmol) and 2-phenyl-1-(S)-(2-phenyl-[1,3] dioxolane-2-yl) ethamine (preparation 95,104mg, 0.386mmol) DMF (5mL) solution in add HOBt (65mg, 0.424mmol), DIPEA (0.155mL, 0.890mmol) and EDCI (90mg, 0.469mmol).After stirring 12h under the room temperature, mixture is joined in the weak brine (100mL, water/salt solution: 1: 1).With ethyl acetate (4 * 25mL) extractions, the organic extract liquid of merging with dilute hydrochloric acid (1M, 30ml), dilute sodium hydroxide aqueous solution (1M, 30ml) and the then dry (MgSO of salt solution (50mL) washing ₄), obtain resistates after concentrating, through fast silica gel chromatogram (elutriant: hexane/ethyl acetate: 50/50) purifying.Obtain the target compound of colorless oil.δ _H(CDCl ₃)：2.73(1H，dd)，3.10(1H，dd)，3.84-4.22(4H，4m)，5.01(1H，ddd)，6.37(1H，d)，6.72(1H，s)，7.05-7.62(11H，3m)，8.64(1H，s)，10.48(1H，s)；m/z(ES ⁺)＝448.24[M+H] ⁺；RT＝3.64min。

Preparation 97:2-(2-oxo-2-pyridin-3-yl-ethyl) isoindole-1, the 3-diketone

With bromo methyl cycloheptapyridine-(4.55g, 16.2mmol) (6.0g, DMF 32.4mmol) (50mL) solution stirred under room temperature 3 days 3-base ketone, added weak brine (500ml, 1: 1) afterwards with phthalimide potassium.This solution is used ethyl acetate (2 * 100ml) washings afterwards with dilute hydrochloric acid (1M) acidifying (pH2).Water layer is used sodium hydroxide solution (2M) alkalization (pH12) again and is used DCM (4 * 200ml) extractions then.Combining extraction liquid and dry (MgSO ₄), vacuum concentration afterwards.Remove the crystal phthalimide from methyl alcohol (2 *) recrystallization, thereby be rich in target compound in the mother liquor.This crude product is used to prepare 98 without being further purified.δ _H(d ₆DMSO)：5.33(2H，s)，7.64(1H，dd)，7.92，7.97(4H，2m)，8.43(1H，m)，8.88(1H，m)，9.28(1H，s)；m/z(ES ⁺)＝308.13[M+MeCN+H] ⁺；RT＝2.39min。

Preparation 98:2-amino-1-pyridin-3-yl ethanol

To thick 2-(2-oxo-2-pyridin-3-yl ethyl) isoindole-1, the 3-diketone (preparation 97,5.0g ,～19.0mmol) isopropanol water solution (add at twice among the 210ml, water/IPA:1/6) sodium borohydride (10.2g, 270mmol).This mixture is used dilute hydrochloric acid (1M) acidifying carefully (pH2) stir 12h under room temperature after.Except that pouring into resistates in the distilled water (100mL) after desolvating and passing through ion exchange resin column (Amberlite IR 120, H ⁺-form, 300g, elutriant: 500mL water is the 2M ammonia soln of 1L afterwards).Concentrated alkali lye partly obtains the target compound of yellow oily.δ _H(d ₆DMSO)：2.74，2.85(2H，2m)，4.66(1H，m)，5.15(3H，br?s)，7.36(1H，dd)，7.75(1H，m)，8.46(1H，m)，8.56(1H，m)；m/z(ES ⁺)＝139.11[M+H] ⁺；RT＝0.21min。

Preparation 99:2-(S)-amino-3-(t-butyldimethylsilyl oxygen)-1-(S)-phenyl third-1-alcohol

To (1S, 2S)-2-amino-1-phenyl-1, ammediol (2.07g, add in DMF 12.4mmol) (10mL) solution imidazoles (1.0g, 14.7mmol) and tert-butyldimethylsilyl chloride (2.30g, 15.3mmol).Behind stirring at room 12h, this mixture joined weak brine (150mL, water/salt solution: 1/1).(4 * 30mL) extractions, the extraction liquid of merging is through salt solution (30mL) washing and dry (MgSO with ethyl acetate ₄), obtaining resistates after concentrating, this resistates is through fast silica gel chromatogram (elutriant: ethyl acetate) purifying.Obtain the target compound of colorless oil.δ _H(CDCl ₃)：0.24，0.26(6H，2s)，1.12(9H，s)，2.50-2.78(3H，br?s)，3.16(1H，d?dd)，3.78(1H，dd)，3.85(1H，dd)，4.84(1H，d)，7.49-7.55(5H，m)；m/z(ES ⁺)＝282.32[M+H] ⁺；RT＝2.87min。

Preparation 100:5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)-(t-butyldimethylsilyl oxygen methyl)-2-(S)-hydroxyl-2-phenylethyl] acid amides

To 5-chloro-1H-pyrrolo-[2,3-c] (the preparation 18 of pyridine-2-formic acid, 520mg, 2.65mmol) and (preparation 99 of 2-(S)-amino-3-(t-butyldimethylsilyl oxygen)-1-phenyl third-1-alcohol, 780mg, add in DMF 2.77mmol) (15mL) solution HOBt (411mg, 2.68mmol), DIPEA (0.96mL, 5.51mmol) and EDCI (589mg, 3.07mmol).After stirring 12h under the room temperature, this mixture is joined weak brine (150mL, water/salt solution: 1/1).With ethyl acetate (4 * 50mL) extractions, with dilute hydrochloric acid (1M, 50ml), dilute sodium hydroxide aqueous solution (1M, 50ml) and the extraction liquid that merges of salt solution (50mL) washing, then dry (MgSO ₄), obtaining resistates after concentrating, this resistates is through fast silica gel chromatogram (elutriant: hexane/ethyl acetate: 50: 50) purifying.Obtain the target compound of colorless oil.δ _H(CD ₃OD)：0.00，0.01(6H，2s)，0.84(9H，s)，3.60(1H，dd)，3.84(1H，dd)，4.33(1H，ddd)，4.98(1H，d)，7.05(1H，s)，7.12-7.37(5H，3m)，7.60(1H，s)，8.49(1H，s)；m/z(ES ⁺)＝460.36[M+H] ⁺；RT＝4.16min。

Preparation 101:5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)-(t-butyldimethylsilyl oxygen methyl)-2-oxo-2-phenylethyl] acid amides

To 5-chloro-1H-pyrrolo-[2,3-c] (the preparation 100 of pyridine-2-formic acid [1-(S)-(t-butyldimethylsilyl oxygen methyl)-2-(S)-hydroxyl-2-phenylethyl] acid amides, 304mg, 0.661mmol) anhydrous DCM (10mL) solution in add Dess-Martin cross iodine alkane (periodinane) (342mg, 0.806mmol).After stirring 3h under the room temperature, add alkaline hypo solution (5.4g Na ₂SO ₃Be dissolved in the saturated NaHCO of 20mL ₃In the solution), and with this milk sap vigorous stirring 30min again.Add ethyl acetate (150ml) and remove water layer.Organic layer is through salt solution (50ml) washing, dry (MgSO ₄), concentrate and to obtain resistates, this resistates obtains the target compound of colorless solid shape through fast silica gel chromatogram (elutriant: hexane/ethyl acetate: 50: 50) purifying.m/z(ES ⁺)＝458.34[M+H] ⁺；RT＝4.32min。

Preparation 102:[1-(S)-(4-luorobenzyl)-2-(3-(S)-hydroxyl pyrrolidine-1-yl)-2-oxoethyl] t-butyl carbamate

To (the S)-N-Boc-4-fluorophenylalanine that stirs (5.08g, 17.9mmol) and (S)-the 3-hydroxyl pyrrolidine (1.05mL, add in dry DMF 19.7mmol) (200mL) solution DIPEA (6.87mL, 39.5mmol) and HOBt.H ₂O (3.02g, 19.7mmol).This mixture stirs 10min and adds EDCI then (4.13g 21.5mmol), and stirs 20h with gained solution under room temperature under room temperature.Vacuum is removed volatile matter and then resistates is distributed between water (200mL) and ethyl acetate (200mL).(3 * 50mL) extract with ethyl acetate with water layer after separating each layer.The organic layer that merges is with aqueous sodium hydroxide solution (2M, 3 * 50mL), salt solution (100mL) washing, dry (MgSO ₄), filter and vacuum concentration.The oily resistates is through flash chromatography (SiO ₂, ethanol/methylene, 1: 19, v/v) purifying obtained the target compound of colorless oil, and it becomes white solid when placing.m/z(ES ⁺)＝353[M+H] ⁺；RT＝3.17min。

Preparation 103:2-(S)-amino-3-(4-fluorophenyl)-1-(3-(S)-hydroxyl pyrrolidine-1-yl) third-1-keto hydrochloride

To ester (preparation 102,5.25g, methyl alcohol 14.9mmol) (anhydrous, 30mL) add dioxane (7.64mL, 30.6mmol) solution and gained solution stirred 18h solvent removed in vacuo then under room temperature of 4M HCl in the solution.Resistates is distributed between ethyl acetate (150mL) and water (100mL).Separate each layer, (2 * 50mL) extractions of organic layer water.The water extract that merges with ethyl acetate (30mL) washing once obtains the organic extract liquid evaporated under reduced pressure that merges the target compound of white foam shape then.δ _H(CD ₃OD)：1.47-1.62(0.5H，m)，1.67-1.80(1H，m)，1.83-1.96(0.5H，m)，2.72-2.87(1H，m)，2.96-3.12(2H，m)，3.19-3.29(1H，m)，3.30-3.62(2H，m)，4.14-4.39(2H，m)，6.91-7.08(2H，m)，7.22(2H，dd)。

Preparation 104:(6-chloropyridine-3-yl) t-butyl carbamate

The method preparation that this target compound is described according to (US 2002/0022624 A1) such as Dinnell.δ _H(CD ₃OD)：1.52(9H，s)，6.52(1H，s)，7.26(1H，d)，7.97(1H，d)，8.23(1H，d)。

Preparation 105:(6-chloro-4-iodine pyridine-3-yl) t-butyl carbamate

This target compound is the method described according to (US 2002/0022624 A1) such as the Dinnell compound by preparation 104.δ _H(CDCl ₃)：1.54(9H，s)，6.62(1H，s)，7.72(1H，s)，8.93(1H，s)。

Preparation 106:6-chloro-4-iodine pyridine-3-base amine

This target compound is the method described according to (US 2002/0022624 A1) such as the Dinnell compound by preparation 105.δ _H(CDCl ₃)：4.12(2H，br?s)，7.60(1H，s)，7.79(1H，s)。

Preparation 107:N-(6-chloropyridine-2-yl)-2,2-dimethyl propylene acid amides

(3.0g, (4.10mL 29.2mmol) and with reaction solution is cooled to 0 ℃ (ice bath) to add triethylamine in methylene dichloride 23.3mmol) (45mL) solution to 2-amino-6-chloropyridine under the argon gas.In 20min, dropwise add trimethyl-acetyl chloride and (stir 30min down in 0 ℃ after the 3.16mL, methylene dichloride 25.7mmol) (10mL) solution.Reaction solution is risen to room temperature and restir 5h, add entry (30mL) then.Organic layer is through separation and use Na ₂CO ₃(2 * 50mL) solution washings, drying (MgSO ₄), solvent removed in vacuo.Through column chromatography (SiO ₂, CH ₂Cl ₂) purifying obtains target compound.m/z(ES ⁺)＝213.04[M+H] ⁺。

Preparation 108:N-(6-chloro-3-iodine pyridine-2-yl)-2,2-dimethyl propylene acid amides

In 40min to the N-(6-chloropyridine-2-yl)-2 that is cooled to-78 ℃, 2-dimethyl propylene acid amides (preparation 107,8.0g, dropwise add in THF 37.6mmol) (120mL) anhydrous solution tert-butyl lithium pentane solution (1.7M, 48.7mL, 82.8mmol).Drip iodine (11.46g, THF 45.1mmol) (40mL) solution after reacting on-78 ℃ of stirring 3h.This mixture is risen to room temperature and stirs 16h.Add 2M HCl (30mL) in reaction, the 20min final vacuum removes and desolvates.Crude product is distributed between ethyl acetate (200mL) and water (150mL).(4 * 100mL) use NaHCO to organic layer then through separation and with 10% hypo solution ₃Solution (2 * 100mL) washings, dry (MgSO ₄), solvent removed in vacuo.Resistates is through column chromatography (SiO ₂, CH ₂Cl ₂) purifying obtains target compound.m/z(ES ⁺)＝338.93[M+H] ⁺。

Preparation 109:6-chloro-3-iodine pyridine-2-base amine

With N-(6-chloro-3-iodine pyridine-2-yl)-2,2-dimethyl propylene acid amides (preparation 108,5.0g, the suspension liquid reflux 4.5h of 1M HCl 14.8mmol).Reaction is cooled to room temperature uses ether (2 * 50mL) extractions then.Organic layer Na ₂CO ₃Solution (dry (MgSO after 2 * 50mL) washings ₄) and solvent removed in vacuo.Through column chromatography (SiO ₂, CH ₂Cl ₂) purifying obtains target compound.δ _H(CDCl ₃)：7.76(1H，d)，6.46(1H，d)，5.43-5.20(2H，br?s)。

Preparation 110:6-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid

(prepare 109 to 6-chloro-3-iodo-pyridine-2-base amine under the argon gas, 2.80g, 11.0mmol) DMF (80mL) anhydrous solution in add pyruvic acid (2.29mL, 33.0munol), DABCO (3.70g, 33.0mmol) add then palladium (II) (124mg, 0.55mmol) and with mixture with purification for argon (purge) 20min.Reaction is heated to 105 ℃ of (bathing temperature) 3h, is cooled to room temperature afterwards.Solvent removed in vacuo is distributed crude product then between ethyl acetate (100mL) and water (75mL).((2 * 75mL) extract organic layer with 2M NaOH after 2 * 75mL) washings through separation, water.It is 3 that water layer is acidified to pH with 2M HCl, and with ethyl acetate extraction (2 * 100mL).Merge organic layer, dry (MgSO ₄) and vacuum concentration.Resistates is suspended in water, remove filtrate and obtain target compound.m/z(ES ⁺)＝196.91[M+H] ⁺，RT＝3.07min。

Preparation 111:[1-(S)-(4-luorobenzyl)-2-oxo-2-(5-oxo-[1,4] Diazesuberane-1-yl) ethyl] t-butyl carbamate

With DIPEA (2.08mL, 11.95mmol), the acid of BOC-L-phenylpropylamine (1.128g, 3.98mmol) and HOBt (592mg 4.38mmol) joins [1,4]-(500mg stirs 5min in DMF 4.38mmol) (10mL) solution and with mixture to Diazesuberane-5-ketone.(992mg 5.18mmol) also will react stirring 16h solvent removed in vacuo afterwards to add EDCI.Through column chromatography (SiO ₂, 9: 1CH ₂Cl ₂/ MeOH) purifying obtains target compound.m/z(ES ⁺)＝380.00[M+H] ⁺。

Preparation 112:1-(S)-[2-amino-3-(4-fluorophenyl) propionyl] [1,4]-Diazesuberane-5-ketone

To [1-(S)-(4-luorobenzyl)-2-oxo-2-(5-oxo-[1,4]-and Diazesuberane-1-yl) ethyl] t-butyl carbamate (preparation 111,1.23g, 3.24mmol) methyl alcohol (15mL) solution in add dioxane (6.48mL, 25.9mmol) solution and will react stirring 3.5h of 4M HCl.Solvent removed in vacuo places crude product water (20mL) then.With ethyl acetate (15mL) aqueous layer extracted, vacuum is removed to anhydrate and is obtained the target compound of hydrochloride form then.m/z(ES ⁺)＝279.95[M+H] ⁺。

Preparation 113:2-(S)-t-butoxycarbonyl amino-3-(4-fluorophenyl) propionic acid tert-butyl ester

(S)-N-Boc-4-fluorophenyl Beta Alanine under stirring (2.83g, 10.0mmol), DMAP (0.12g, DCM 1.0mmol) (20mL) and 2-methyl-2-propyl alcohol (1.05mL, add in solution 11.0mmol) DCC (2.27g, 11.0mmol).This reaction mixture is stirred 16h under room temperature.Filter reaction mixture also washs several times with DCM.Filtrate is through vacuum concentration and carry out the silica gel chromatography ethyl acetate: isohexane (1: 4) wash-out obtains target compound.δ _H(CDCl ₃)：1.39(9H，s)，1.41(9H，s)，3.01(2H，m)，4.41(1H，m)，4.98(1H，m)，6.95(2H，m)，7.12(2H，m)。

Preparation 114:2-(S)-amino-3-(4-fluorophenyl) propionic acid tert-butyl ester hydrochloride

(0.60mL, solution 14.7mmol) are cooled to 0 ℃ for ethyl acetate (10mL) under will stirring under the argon atmospher and methyl alcohol.(1.05mL 14.7mmol) and with solution rises to room temperature and stirs 30min to drip Acetyl Chloride 98Min..(preparation 113,1g 2.95mmol) and with reaction mixture stirs 4h under room temperature to add 2-(S)-t-butoxycarbonyl amino-3-(4-fluorophenyl) propionic acid tert-butyl ester.Reaction mixture washs several times with ether after filtration, and vacuum-drying obtains target compound.δ _H(DMSO)：1.30(9H，s)，3.01(1H，dd)，3.20(1H，dd)，4.08(1H，m)，7.15(2H，m)，7.32(2H，m)，8.64(3H，br?s)。

Preparation 115:2-chloro-5-iodine pyridine-4-base amine

(7.1g, 22.8mmol) (4.06g, (5.65g also stirs 72h with this reaction mixture in ethanol 22.3mmol) (100mL) solution under room temperature 31.6mmol) to join iodine with 4-amino-2-chloropyridine with Sulfuric acid disilver salt.Filter the glassy yellow suspension liquid, with methanol wash and vacuum concentrated filtrate.Resistates is at saturated Na ₂CO ₃Distribute between solution (200mL) and the ethyl acetate (200ml).Organic layer is through Na after separating each layer ₂S ₂O ₃Solution (50mL, 25%) and salt solution (50mL) washing, dry (MgSO ₄), vacuum concentration and obtain target compound with isohexane/ethyl acetate (3: 1 to 2.5: 1) wash-out through the silica gel chromatography purifying.δ _H(CDCl ₃)：4.81(2H，br?s)，6.63(1H，s)，8.38(1H，s)；m/z(ES ⁺)＝254.86[M+H] ⁺；RT＝2.51min。

Preparation 116:6-chloro-1H-pyrrolo-[3,2-c] pyridine-2-formic acid

With pyruvic acid (0.86ml, 12.4mmol) join 2-chloro-5-iodine pyridine-4-base amine (preparation 115,1.05mg, 4.13mmol), palladium (56mg, 0.25mmol) and DABCO (1.39g is in the dry DMF of 12.4mmol (30ml).With reaction mixture argon-degassed 20min, be heated to 145 ℃ of 2h then.Solvent removed in vacuo is also handled resistates water (200mL).Suspension liquid is with dilute NaOH solution (1M) alkalization (pH9-10) and through diatomite filtration.With transferring pH with rare HCl solution (1M) behind ethyl acetate (50mL) and ether (50mL) wash filtrate is 3.With ethyl acetate (5 * 50mL) extractions, dry (MgSO ₄) extraction liquid that merges and concentrate and obtain target compound.δ _H(d ₆DMSO)：7.24(1H，s)，7.42(1H，s)，8.80(1H，s)；m/z(ES ^-)＝195.02[M-H] ^-；RT＝2.36min。

Preparation 117:4 (S)-(4-luorobenzyl) oxazolidine-2,5-diketone

Under argon atmospher to 2 (S)-t-butoxycarbonyl amino-3-(4-fluorophenyl) propionic acid (1.5g, add in the ethyl acetate of 5.29mmol (100mL) solution triphosgene (628mg, 2.12mmol).(0.8mL 5.76mmol), and reacts on this under room temperature and to stir 72h to add triethylamine in the 1min in this solution.This reaction mixture after filtration and vacuum concentrated filtrate obtain the oily resistates.Crude product crystallization in methylene dichloride and sherwood oil obtains target compound.δ _H(CD ₃OD)：7.20(2H，m)，7.10(2H，m)，5.86(1H，s，(NH))，4.58(1H，s)，3.33-3.23(2H，m)，3.11-3.00(1H，m)。

Embodiment:

Embodiment 1

5-chloro-1H-pyrrolo-[3,2-b] pyridine-2-formic acid (1-formyl-dimethylamino-2-(S)-styroyl) acyl Amine

To 5-chloro-1H-pyrrolo-[3,2-b] (the preparation 6 of pyridine-2-formic acid, 36mg, 0.18mmol) DMF (4mL, anhydrous) solution in add 2-(S)-amino-N successively, N-dimethyl-3-Phenylpropionamide hydrochloride (preparation 8,46mg, 0.20mmol), DIPEA (105 μ L, 6.05mmol) and HOBt (25mg, 0.18mmol).Disposable adding EDCI after this solution stirring 5min (42mg, 0.22mmol).Gained solution stirs 16h under room temperature.This reaction mixture is distributed between ethyl acetate (50mL) and salt solution (20mL).Separate behind each layer water with ethyl acetate extraction (3 * 20mL), then with the organic layer water that merges (3 * 10mL) and salt solution (10mL) wash.With organic phase drying (MgSO ₄), filtration, vacuum concentration.Obtain orange through the flash column chromatography purifying with ethanol/methylene (1: 19) wash-out, grind the target compound that obtains the orange solids shape with ether/hexane.δ _H(CDCl ₃)：2.71(3H，s)，2.93(3H，s)，3.05-3.21(2H，m)，5.28-5.39(1H，m)，7.00(1H，s)，7.17-7.36(6H，m)，7.69(1H，d，9.23Hz)，9.27(1H，s)；m/z(ES ⁺)＝371.15[M+H] ⁺；RT＝3.28min。

Embodiment 2

1H-pyrrolo-[3,2-c] pyridine-2-formic acid (1-formyl-dimethylamino-2 (S)-styroyl) acid amides

To 1H-pyrrolo-[3,2-c] (the preparation 12 of pyridine-2-formic acid, 100mg, 0.62mmol) DMF (15mL) solution in add 2-(S)-amino-N, N-dimethyl-3-Phenylpropionamide hydrochloride (preparation 8,141mg, 0.62mmol), HOBt (83mg, 0.62mmol) and DIPEA (0.21mL, 1.23mmol).(154mg 0.80mmol) also stirs 72h with this mixture under room temperature to add EDCI behind the 30min.Solvent removed in vacuo also (is distributed this solid at water (50mL) and ethyl acetate between 3 * 50mL).With the organic layer drying (MgSO that merges ₄), vacuum concentration and obtain the target compound of light brown solid state through the silica gel chromatography purifying with ethanol/methylene (6: 94) wash-out.δ _H(CD ₃OD)：3.06-3.19(2H，m)，4.83(6H，s)，5.27(1H，t)，7.20-7.32(5H，m)，7.34(1H，s)，7.45(1H，d)，8.20(1H，d)，8.87(1H，s)；m/z(ES ⁺)＝337[M+H] ⁺。

Embodiment 3

1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1-formyl-dimethylamino-2 (S)-styroyl) acid amides

To 1H-pyrrolo-[2,3-c] (the preparation 15 of pyridine-2-formic acid, 100mg, 0.62mmol) DMF (15mL) solution in add 2-(S)-amino-N, N-dimethyl-3-Phenylpropionamide hydrochloride (preparation 8,141mg, 0.62mmol), HOBt (83mg, 0.62mmol) and DIPEA (0.21mL, 1.23mmol).This reaction solution is stirred 0.5h under room temperature, then add EDCI (154mg, 0.80mmol).Mixture (distributes between 3 * 50mL) at water (50mL) and ethyl acetate then in stirring 72h under the room temperature.Organic moiety drying (the MgSO that merges ₄), vacuum concentration and obtain the target compound of yellow solid shape through the silica gel chromatography purifying with ethanol/methylene (1: 19) wash-out.δ _H(CD ₃OD)：2.88(6H，s)，3.07-3.20(2H，m)，5.28(1H，t)，7.20(1H，s)，7.22-7.31(5H，m)，7.65(1H，d)，8.10(1H，d)，8.76(1H，s)；m/z(ES ⁺)＝337[M+H] ⁺。

Embodiment 4

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1-formyl-dimethylamino-2-(S)-styroyl) acyl Amine

To 5-chloro-1H-pyrrolo-[2,3-c] (the preparation 18 of pyridine-2-formic acid, 100mg, 0.51mmol) DMF (15mL) solution in add 2-(5)-amino-N, N-dimethyl-3-Phenylpropionamide hydrochloride (preparation 8,116mg, 0.51mmol), HOBt (69mg, 0.51mmol) and DIPEA (0.18mL, 1.02mmol).(127mg 0.66mmol) also stirs 15h with this mixture under room temperature to add EDCI behind the 15min.Solvent removed in vacuo also (is distributed this solid at water (50mL) and ethyl acetate between 3 * 50mL).Organic phase drying (the MgSO that merges ₄), vacuum concentration and obtain the target compound of light brown solid state through the silica gel chromatography purifying with ethanol/methylene (1: 19) wash-out.δ _H(CD ₃OD)：2.89(6H，s)，3.05-3.19(2H，m)，5.27(1H，t)，7.16(1H，s)，7.20-7.32(5H，m)，7.67(1H，s)，8.56(1H，s)；m/z(ES ⁺)＝371[M+H] ⁺。

Embodiment 5

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)-(4-luorobenzyl)-2-(4-hydroxy piperidine-1- Base)-and the 2-oxoethyl] acid amides

Route A: to 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-(embodiment 228 for 3-(4-fluorophenyl) propionic acid, 1.4g (1.77g 4.64mmol) and with this reaction solution stirs 10min to add HATU in DMF 3.87mmol) (35mL) solution.(0.43g, 4.26mmol), (0.8mL 4.64mmol) also stirs 16h with this reaction solution under room temperature then to add DIPEA to add the 4-hydroxy piperidine.Solvent removed in vacuo is also distributed crude product between ethyl acetate (50mL) and water (50mL).Organic layer is with sodium bicarbonate (2 * 30mL) and salt solution (2 * 30mL) washings, dry (MgSO ₄) and under vacuum, remove and desolvate.Through column chromatography (SiO ₂, 96: 4 methylene chloride) and purifying obtains target compound.m/z(ES ⁺)＝445.15[M+H] ⁺；RT＝3.24min。

Route B: this target compound is described from 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and 2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxy piperidine-1-yl) third-1-keto hydrochloride (preparation 20) preparation according to embodiment 1.Product obtains the target compound of light yellow solid shape with ethanol/methylene (1: 19) wash-out by the silica gel chromatography purifying.δ _H(CD ₃OD)：1.08-1.19(0.5H，m)，1.29-1.51(1.5H，m)，1.54-1.62(0.5H，m)，1.73-1.84(1.5H，m)，3.06-3.36(4H，m)，3.67-3.95(2.5H，m)，4.03-4.10(0.5H，m)，5.32(1H，t)，6.97-7.04(2H，m)，7.14(1H，s)，7.26-7.33(2H，m)，7.66(1H，s)，8.55(1H，s)；m/z(ES ⁺)＝445[M+H] ⁺；RT＝3.27min。

Embodiment 6

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)-benzyl-3-(suitable-3,4-dihydroxy pyrrolidine-1- Base)-2 (R)-hydroxyl-3-oxopropyl] acid amides

To (S)-3-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-(embodiment 44 for 2-(R)-hydroxy-4-phenyl butyric acid, 50mg, 0.13mmol), suitable-3, the 4-dihydroxy pyrrolidine (preparation 23,15mg, 0.15mmol) and HOBt (27mg, 0.20mmol) DMF (5mL) solution in add DIPEA (47 μ L, 0.27mmol).After stirring 5min, (28mg 0.15mmol) also stirs 72h with this reaction solution under room temperature to add EDCI.Solvent removed in vacuo also (is distributed resistates in water (30mL) and ethyl acetate between 3 * 30mL).The organic moiety that merges is carried out drying (MgSO ₄), vacuum concentration, resistates obtains the target compound of white solid with ethanol/methylene (1: 9) wash-out through the silica gel chromatography purifying.m/z(ES ⁺)＝459[M+H] ⁺，RT＝3.07min。

Embodiment 7

5-bromo-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1-formyl-dimethylamino-2-(S)-styroyl) acyl Amine

To 5-bromo-1H-pyrrolo-[2,3-c] (the preparation 27 of pyridine-2-formic acid, 50mg, 0.21mmol) DMF (5mL) solution in add 2-(S)-amino-N, N-dimethyl-3-Phenylpropionamide hydrochloride (preparation 8,52mg, 0.23mmol), HOBt (31mg, 0.23mmol) and DIPEA (72 μ L, 0.41mmol).(44mg 0.23mmol) also stirs 16h with this reaction solution under room temperature to add EDCI behind the 5min.Solvent removed in vacuo also (is distributed resistates in water (30mL) and ethyl acetate between 3 * 30mL).Organic moiety drying (the MgSO that merges ₄), vacuum concentration and resistates is obtained the target compound of pale solid shape through the silica gel chromatography purifying with ethanol/methylene (3: 97) wash-out.δ _H(CD ₃OD)：2.88(6H，s)，3.06-3.18(2H，m)，5.27(1H，t)，7.13(1H，s)，7.19-7.29(5H，m)，7.80(1H，s)，8.53(1H，s)；m/z(ES ⁺)＝415[M+H] ⁺。

Embodiment 8

1H-pyrrolo-[2,3-b] pyridine-2-formic acid (1-formyl-dimethylamino-2-(S)-styroyl) acid amides

(82 μ L 0.59mmol) join 2-(S)-amino-N, and (preparation 8,117mg is in DCM 0.51mmol) (5mL) solution for N-dimethyl-3-Phenylpropionamide hydrochloride with triethylamine in the ar gas environment under room temperature.With mixture be cooled to 0 ℃ and add 1H-pyrrolo-[2,3-b] pyridine-2-formic acid (preparation 28,75mg, 0.51mmol) then add HOBt (102mg, 0.765mmol), add then EDCI (98mg, 0.51mmol).Afterwards reaction mixture is risen to room temperature and stirred 4 days, use ethyl acetate (25mL) dilution then, with aqueous sodium hydroxide solution (2M, 2 * 25mL), aqueous hydrochloric acid (2N, 2 * 25mL) washings and dry (MgSO ₄).This organic solution obtains light brown foam through vacuum concentration, obtains the target compound of white solid with ethanol/methylene (2: 98) wash-out through the column chromatography purifying.δ _H(CDCl ₃)：2.74(3H，s)，2.95(3H，s)，3.17(2H，m)，5.41(1H，dd)，6.90(1H，s)，7.08-7.48(7H，m)，7.98(1H，d)，8.55(1H，d)；m/z(ES ⁺)＝337.2[M+H] ⁺，RT＝1.38min。

Embodiment 9

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (2-benzene oxygen ethyl) acid amides

This target compound is described by 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and the preparation of 2-phenoxy ethylamine according to embodiment 1.This product obtains the target compound of yellow solid shape with ethanol/methylene (1: 19) wash-out by the silica gel chromatography purifying.δ _H(CD ₃OD)：3.79(2H，t)，4.17(2H，t)，6.88-6.97(3H，m)，7.08(1H，s)，7.16(2H，t)，7.67(1H，s)，8.58(1H，s)；m/z(ES ⁺)＝316[M+H] ⁺。

Embodiment 10

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (2-morpholine-4-base ethyl) acid amides

This target compound is described by 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and 2-morpholine-4-base ethamine preparation according to embodiment 1.This product obtains the target compound of yellow solid shape with ethanol/methylene (1: 19) wash-out by the silica gel chromatography purifying.δ _H(CD ₃OD)：2.54-2.60(4H，m)，2.64(2H，t)，3.58(2H，t)，3.69-3.73(4H，m)，7.05(1H，s)，7.66(1H，s)，8.58(1H，s)；m/z(ES ⁺)＝309[M+H] ⁺。

Embodiment 11

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [(2-(4-methoxyl group phenoxy group) ethyl)] acid amides

This target compound is described by 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and the preparation of 2-(4-methoxyl group phenoxy group) ethamine according to embodiment 1.This product obtains the target compound of yellow solid shape with ethanol/methylene (3: 97) wash-out by the silica gel chromatography purifying.δ _H(CD ₃OD)：3.71(3H，s)，3.77(2H，t)，4.12(2H，t)，6.81-6.91(4H，m)，7.09(1H，s)，7.67(1H，s)，8.58(1H，s)；m/z(ES ⁺)＝346[M+H] ⁺。

Embodiment 12

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (2-thiophene-2-base ethyl) acid amides

This target compound is described by 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and 2-thiophene-2-base ethamine preparation according to embodiment 1.This product obtains the target compound of yellow solid shape with ethanol/methylene (3: 97) wash-out by the silica gel chromatography purifying.δ _H(CD ₃OD)：3.16(2H，t)，3.65(2H，t)，6.89-6.94(2H，m)，7.03(1H，s)，7.20(1H，d)，7.66(1H，s)，8.57(1H，s)；m/z(ES ⁺)＝306[M+H] ⁺。

Embodiment 13

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(2-p-methoxy-phenyl) ethyl] acid amides

This target compound is described by 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and the preparation of 2-(2-p-methoxy-phenyl) ethamine according to embodiment 1.This product obtains the target compound of yellow solid shape with ethanol/methylene (3: 97) wash-out by the silica gel chromatography purifying.δ _H(CD ₃OD)：2.94(2H，t)，3.59(2H，t)，3.78(3H，s)，6.84(1H，t)，6.89(1H，d)，6.97(1H，s)，7.12-7.18(2H，m)，7.60(1H，s)，8.55(1H，s)；m/z(ES ⁺)＝330[M+H] ⁺。

Embodiment 14

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (2-oxo-2-styroyl) acid amides

This target compound is described by 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and 2-oxo-2-phenylethylamine preparation according to embodiment 1.The purifying that this product instructs by quality obtains the target compound of orange solids shape.m/z(ES ⁺)＝314[M+H] ⁺；RT＝3.30min。

Embodiment 15

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1H-benzimidazolyl-2 radicals-ylmethyl) acid amides

This target compound is described by 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and 2-oxo-2-phenylethylamine preparation according to embodiment 1.The purifying that this product instructs by quality obtains the target compound of yellow solid shape.m/z(ES ⁺)＝326[M+H] ⁺；RT＝2.66min。

Embodiment 16

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid styroyl acid amides

This target compound is described by 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and phenylethylamine preparation according to embodiment 1.The purifying that this product instructs by quality obtains the target compound of orange solids shape.δ _H(CD ₃OD)：2.94(2H，t)，3.63(2H，t)，7.00(1H，s)，7.15-7.30(5H，m)，7.64(1H，s)，8.57(1H，s)；m/z(ES ⁺)＝300[M+H] ⁺。

Embodiment 17

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(4-fluorophenyl) ethyl] acid amides

This target compound is described by 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and the preparation of 4-fluorophenethylamine according to embodiment 1.The purifying that this product instructs by quality obtains the target compound of orange solids shape.δ _H(CD ₃OD)：2.93(2H，t)，3.60(2H，t)，6.97-7.04(3H，m)，7.24-7.30(2H，m)，7.65(1H，s)，8.56(1H，s)；m/z(ES ⁺)＝318[M+H] ⁺。

Embodiment 18

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(2-chloro-6-luorobenzyl sulfane base) ethyl] acid amides

This target compound is described by 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and the preparation of 2-(2-chloro-6-luorobenzyl sulfane base) ethamine according to embodiment 1.The purifying that this product instructs by quality obtains the target compound of yellow solid shape.δ _H(CD ₃OD)：2.82(2H，t)，3.64(2H，t)，3.95(2H，s)，7.04-7.09(2H，m)，7.20-7.25(2H，m)，7.67(1H，s)，8.58(1H，s)；m/z(ES ⁺)＝398[M+H] ⁺。

Embodiment 19

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (2,3-dihydrobenzo [1,4] dioxy

-2-ylmethyl) acyl Amine

This target compound is described by 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and 2,3-dihydrobenzo [1,4] dioxy according to embodiment 1

The preparation of-2-ylmethyl amine.The purifying that this product instructs by quality obtains the target compound of yellow solid shape.δ _H(CD ₃OD)：3.69-3.73(2H，m)，3.97-4.03(1H，m)，4.32-4.42(2H，m)，6.77-6.88(4H，m)，7.10(1H，s)，7.67(1H，s)，8.58(1H，s)；m/z(ES ⁺)＝344[M+H] ⁺。

Embodiment 20

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(naphthalene-1-base is amino) ethyl] acid amides

This target compound is described by 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and 2-(naphthalene-1-base is amino) ethamine preparation according to embodiment 1.The purifying that this product instructs by quality obtains the target compound of brown solid shape.δ _H(CD ₃OD)：3.55(2H，t)，3.80(2H，t)，6.68(1H，d)，7.04(1H，s)，7.14(1H，d)，7.28(1H，t)，7.36-7.42(2H，m)，7.65(1H，s)，7.70-7.74(1H，m)，7.98-8.02(1H，m)，8.58(1H，s)；m/z(ES ⁺)＝365[M+H] ⁺。

Embodiment 21

1H-pyrrolo-[2,3-c] pyridine-2-formic acid (2-phenyl amino ethyl) acid amides

This target compound is described by 1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 15) and the preparation of 2-phenyl amino ethamine according to embodiment 1, obtains the target compound of light yellow solid shape.δ _H(CD ₃OD)：3.37(2H，t)，3.63(2H，t)，6.61(1H，t)，6.69(2H，d)，7.08-7.13(2H，m)，7.64(1H，d)，8.10(1H，d)，8.78(1H，s)；m/z(ES ⁺)＝281[M+H] ⁺。

Embodiment 22

1H-pyrrolo-[2,3-c] pyridine-2-formic acid (2-benzene oxygen ethyl) acid amides

This target compound is described by 1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 15) and the preparation of 2-phenoxyethylamine according to embodiment 1, obtains the target compound of light yellow solid shape.δ _H(CD ₃OD)：3.81(2H，t)，4.18(2H，t)，6.89-6.97(3H，m)，7.14(1H，s)，7.26(2H，t)，7.65(1H，d)，8.10(1H，d)，8.78(1H，s)；m/z(ES ⁺)＝282[M+H] ⁺。

Embodiment 23

5-methoxyl group-1H-pyrrolo-[3,2-b] pyridine-2-formic acid (1- Dimethylamino formyl radical-2-(S)-styroyl) acid amides

To 5-methoxyl group-1H-pyrrolo-[3,2-b] pyridine-2-formic acid (preparation 36,50mg, add successively in DMF 0.26mmol) (3mL) solution DIPEA (100 μ L, 0.57mmol), HOBt (35mg, 0.26mmol) and EDCI (60mg, 0.31mmol).Disposable adding 2-(S)-amino-N after this solution stirring 5min, and N-dimethyl-3-Phenylpropionamide hydrochloride (preparation 8,65mg, 0.29mmol).This mixture stirs 21h and adds entry (15mL) and methylene dichloride (30ml) then under room temperature.Separate each layer behind the mixture vigorous stirring 10min.(organic layer of 3 * 15mL) extractions and merging is through salt solution (30mL) washing, dry (MgSO with methylene dichloride for water ₄), filtration, vacuum concentration.Through flash column chromatography purifying (SiO ₂, ethyl acetate/isohexane, 1: 1) and obtain yellow oil.Water grinding after-filtration, drying obtain the target compound of white solid.δ _H(CD ₃OD)：2.88(6H，2×s)，3.12(2H，m)，3.94(3H，s)，5.26(1H，dd)，6.71(1H，d)，7.13(1H，s)，7.25(5H，m)，7.74(1H，d)；m/z(ES ⁺)＝367[M+H] ⁺；RT＝3.20min。

Embodiment 24

1H-pyrrolo-[3,2-b] pyridine-2-formic acid (1-dimethylamino formyl radical-2-(S)-styroyl) acid amides

Described according to embodiment 1 by 1H-pyrrolo-[3,2-b] pyridine-2-formic acid (preparation 32) and 2-(S)-amino-N, N-dimethyl-3-Phenylpropionamide hydrochloride (preparation 8,78mg, 0.34mmol) preparation.This target compound is through being separated into white solid.δ _H(d ₆DMSO)：2.82(3H，s)，2.98(3H，s)，3.03(2H，m)，5.12(1H，m)，7.16(2H，m)，7.24(2H，m)，7.32(2H，m)，7.40(1H，d)，7.74(1H，d)，8.37(1H，dd)，8.93(1H，d)；m/z(ES ⁺)＝337[M+H] ⁺；RT＝3.10min。

Embodiment 25

1H-pyrrolo-[3,2-b] pyridine-2-formic acid (2-benzene oxygen ethyl) acid amides

To 1H-pyrrolo-[3,2-b] pyridine-2-formic acid (preparation 32,50mg, add successively in DMF 0.31mmol) (5mL) solution 2-phenoxyethylamine (44 μ L, 0.34mmol), DIPEA (118 μ L, 0.68mmol) and HOBt (42mg, 0.31mmol).Disposable adding EDCI behind this reaction mixture stirring 5min (42mg, 0.22mmol).Gained solution is in stirring 20h under the room temperature and distributing between ethyl acetate (50mL) and water (20mL).Separate behind each layer water with ethyl acetate extraction (2 * 30mL).The organic moiety that merges is through salt solution (20mL) washing, dry (MgSO ₄), filtration, vacuum concentration obtain oily matter.Grind, filter the target compound of collecting, obtaining cream-colored solid state after air-dry with ether/isohexane.δ _H(d ₆DMSO)：3.48(2H，m)，4.14(2H，t)，6.94(3H，m)，7.17(1H，dd)，7.28(3H，m)，7.77(1H，d)，8.37(1H，dd)，8.86(1H，t)；m/z(ES ⁺)＝282[M+H] ⁺；RT＝2.60min。

Embodiment 26

1H-pyrrolo-[3,2-b] pyridine-2-formic acid (2-phenyl amino ethyl) acid amides

This target compound is according to embodiment 25 is described but (44 μ L 0.34mmol) replace the preparation of 2-phenoxyethylamine with the N-phenylethylenediamine.This target compound is through being separated into cream-colored solid.δ _H(d ₆DMSO)：3.23(2H，m)，3.37(2H，m)，5.70(1H，t)，6.52(1H，t)，6.63(2H，dd)，7.07(2H，dd)，7.17(1H，dd)，7.22(1H，s)，7.77(1H，d)，8.37(1H，dd)，8.73(1H，t)；m/z(ES ⁺)＝281[M+H] ⁺；RT＝2.36min。

Embodiment 27

5-chloro-1H-pyrrolo-[3,2-b] pyridine-2-formic acid (2-phenoxy group ethyl) acid amides

This target compound is described by 5-chloro-1H-pyrrolo-[3,2-b] pyridine-2-formic acid (preparation 6) and the preparation of 2-phenoxyethylamine according to embodiment 1.After reacting completely, this mixture is gone up at hydrophobic glaze (frit) and is distributed between water and methylene dichloride, uses washed with dichloromethane.Organic filtrate concentrates then under vacuum and grinds the target compound that obtains cream-colored solid state with methylene chloride/ethyl acetate.δ _H(d ₆DMSO)：3.68(2H，m)，4.13(2H，m)，6.94(3H，m)，7.25(4H，m)，7.83(1H，d)，8.95(1H，t)，12.09(1H，s).m/z(ES ⁺)＝316[M+H] ⁺；RT＝3.45min。

Embodiment 28

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(4-benzyl diethylenediamine-1-yl) ethyl] acid amides

This target compound is described by 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and 4-benzyl diethylenediamine-1-base ethamine preparation according to embodiment 1.The purifying that this product instructs by quality obtains the target compound of orange solids shape.m/z(ES ⁺)＝398[M+H] ⁺；RT＝2.75min。

Embodiment 29

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (2-benzylamino ethyl) acid amides

This target compound is described by 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and the preparation of 2-benzylamino ethamine according to embodiment 1.The purifying that this product instructs by quality obtains the target compound of pale solid shape.m/z(ES ⁺)＝329[M+H] ⁺；RT＝2.75min。

Embodiment 30

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid phenyl amino formyl radical methyl nitrosourea

(embodiment 40,30mg for acetate to [(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino], 0.12mmol) DMF (2mL) solution in add aniline (12 μ L, 0.13mmol), HOBt (16mg, 0.12mmol) and DIPEA (41 μ L, 0.24mmol).(29mg 0.15mmol) also stirs 16h with this reaction solution under room temperature to add EDCI behind the 5min.Solvent removed in vacuo also (is distributed this solid at water (20mL) and ethyl acetate between 3 * 20mL).Organic moiety drying (the MgSO that merges ₄), vacuum concentration, resistates obtains the target compound of yellow solid shape with ethanol/methylene (1: 19) wash-out through silica gel purification.m/z(ES ⁺)＝329[M+H] ⁺；RT＝3.17min。

Embodiment 31

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [(THP trtrahydropyranyl-4-base carbamyl) methyl] acid amides

This target compound is according to the step of embodiment 30 but replaces the aniline preparation with the 4-amino tetrahydro pyran.Behind the 16h, this reaction mixture is poured in the water, left standstill 16h again.Cross filter solid and the dry target compound that obtains the white crystalline solid shape.m/z(ES ⁺)＝337[M+H] ⁺；RT＝2.72min。

Embodiment 32

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid { [(thiophene-2-ylmethyl) formamyl] methyl } acyl Amine

This target compound is according to embodiment 30 but replace the aniline preparation with 2-amino methyl thiophene.After stirring 16h, reaction mixture is poured in the water into the also dry after filtration target compound that obtains white solid of precipitation.m/z(ES ⁺)＝349[M+H] ⁺；RT＝3.07min。

Embodiment 33

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [(4-p-methoxy-phenyl formamyl) methyl] acyl Amine

This target compound is according to embodiment 30 but replace the aniline preparation with P-nethoxyaniline (p-anisidine).After stirring 16h, reaction mixture is poured in the water into the also dry after filtration target compound that obtains light brown solid state of precipitation.m/z(ES ⁺)＝359[M+H] ⁺；RT＝3.22min。

Embodiment 34

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1-(S)-benzyl-2- Oxo-2-tetramethyleneimine-1-base ethyl) acid amides

To 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-(embodiment 42,50mg for the 3-phenylpropionic acid, 0.15mmol) DMF (3mL) solution in add tetramethyleneimine (13 μ L, 0.16mmol), HOBt (20mg, 0.15mmol) and DIPEA (51 μ L, 0.29mmol).(36mg 0.19mmol) also stirs 16h with this reaction solution under room temperature to add EDCI behind the 5min.Solvent removed in vacuo is also ground the solid water, filter and the dry target compound that obtains light brown solid state.m/z(ES ⁺)＝397[M+H] ⁺；RT＝3.38min。

Embodiment 35

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)- Benzyl-2-(3-(S)-hydroxyl pyrrolidine-1-yl)-2-oxoethyl] acid amides

To 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-(embodiment 42 for the 3-phenylpropionic acid, 50mg, 0.15mmol) DMF (3mL) solution in add 3-(S)-hydroxyl pyrrolidine (13.9mg, 0.16mmol), HOBt (20mg, 0.15mmol) and DIPEA (51 μ L, 0.29mmol).(36mg 0.19mmol) and with reaction solution stirs 16h under room temperature to add EDCI behind the 5min.Solvent removed in vacuo and with resistates water (20mL) and ethyl acetate (distribute between 3 * 20mL), dry (MgSO ₄), vacuum concentration.Obtain the target compound of white solid with ethanol/methylene (4: 96) wash-out through the silica gel chromatography purifying.m/z(ES ⁺)＝413[M+H] ⁺；RT＝3.20min。

Embodiment 36

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)- Benzyl-2-(3,4-dihydroxy pyrrolidine-1-yl)-2-oxo-ethyl] acid amides

This target compound is according to embodiment 35 is described but with suitable-3, the 4-dihydroxy pyrrolidine replaces 3-(S)-hydroxyl pyrrolidine preparation.Obtain the target compound of white solid through silica gel chromatography with ethanol/methylene gradient (4: 96 to 1: 9) wash-out.m/z(ES ⁺)＝429[M+H] ⁺；RT＝3.12min。

Embodiment 37

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1-(S)-benzyl-2- Oxo-2-thiomorpholine-4-base ethyl) acid amides

This target compound is according to the step that is used for embodiment 35 but replaces 3-(S)-hydroxyl pyrrolidine preparation with thiomorpholine.Carry out the target compound that wash-out obtains white solid through the silica gel chromatography purifying with ethanol/methylene (3: 97).m/z(ES ⁺)＝429[M+H] ⁺；RT＝3.54min。

Embodiment 38

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-phenyl-1- (S)-(tetrahydropyran-4-base formamyl) ethyl] acid amides

This target compound is according to embodiment 35 but replaces 3-(S)-hydroxyl pyrrolidine preparation with the 4-amino tetrahydro pyran.This product obtains the target compound of white solid from ethanol/methylene (3: 97) recrystallization.m/z(ES ⁺)＝427[M+H] ⁺；RT＝3.23min。

Embodiment 39

[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino] ethyl acetate

To 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18,800mg, 4.1mmol) DMF (40mL) solution in add ethyl aminoacetate hydrochloride (625mg, 4.5mmol), HOBt (0.55g, 4.1mmol) and DIPEA (2.13mL, 12.2mmol).(1.01mg 5.3mmol) and with reaction solution stirs 16h under room temperature to add EDCI behind the 5min.Solvent removed in vacuo also (is distributed this solid at water (100mL) and ethyl acetate between 3 * 80mL).Organic moiety drying (the MgSO that merges ₄), vacuum concentration and obtain the target compound of yellow solid shape through the silica gel chromatography purifying with ethanol/methylene (4: 96) wash-out.δ _H(CD ₃OD)：1.28(3H，t)，4.14(2H，s)，4.23(2H，q)，7.10(1H，s)，7.68(1H，s)，8.59(1H，s)；m/z(ES ⁺)＝282[M+H] ⁺。

Embodiment 40

[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino] acetate

To [(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino] ethyl acetate (embodiment 39,500mg, (1.8ml, 2M 3.6mmol) and with reaction solution stir 4h under room temperature to add sodium hydroxide solution in THF 1.8mmol) (30ml) solution.Solvent removed in vacuo and with solid hydrochloric acid (1M, 100mL) and ethyl acetate (distribute between 2 * 100mL).The water layer vacuum concentration also is suspended in solid residue in the water (10ml), filters and the dry target compound that obtains the pale solid shape.δ _H(d ₆DMSO)：3.97(2H，d)，7.18(1H，s)，7.76(1H，s)，8.57(1H，s)，9.17(1H，t)，12.32(1H，s)；m/z(ES ⁺)＝254[M+H] ⁺。

Embodiment 41

2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-phenylpropionic acid ethyl ester

To 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18,2.00mg, 10.2mmol) DMF (50mL) solution in add L-phenylalanine ethyl ester hydrochloride (2.45g, 10.7mmol), HOBt (1.37g, 10.2mmol) and DIPEA (5.3mL, 30.5mmol).(2.54g 13.2mmol) and with reaction mixture stirs 16h under room temperature to add EDCI behind the 5min.Solvent removed in vacuo also is dissolved in solid in the ethyl acetate (150mL), water (200ml) washing.With organic phase drying (MgSO ₄), vacuum concentration and obtain the target compound of light yellow solid shape through the silica gel chromatography purifying with ethanol/methylene (3: 97) wash-out.δ _H(CD ₃OD)：1.21(3H，t)，3.13(1H，dd)，3.28(1H，dd)，4.17(2H，q)，4.86(1H，m)，7.09(1H，s)，7.16-7.26(5H，m)，7.65(1H，s)，8.55(1H，s)；m/z(ES ⁺)＝372[M+H] ⁺。

Embodiment 42

2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-phenylpropionic acid

With sodium hydroxide solution (2.5ml, 2M 5.1mmol) joins that 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-(embodiment 41 for 3-phenylpropionic acid ethyl ester, 940mg also stirs 16h with this reaction mixture in THF 2.5mmol) (30ml) solution under room temperature.Solvent removed in vacuo and with this solid hydrochloric acid (2M, 40mL) and ethyl acetate (between 3 * 40mL) distribution.Organic moiety drying (the MgSO that merges ₄), vacuum concentration obtains the target compound of yellow solid shape.m/z(ES ⁺)＝344[M+H] ⁺；RT＝3.29min。

Embodiment 43

(S)-and 3-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]- (R)-2-hydroxy-4-phenyl methyl-butyrate

To 5-chloro-1H-pyrrolo-[2,3-c] (the preparation 18 of pyridine-2-formic acid, 165mg, 0.84mmol) and (3S, 2R)-3-amino-2-hydroxy-4-phenyl methyl-butyrate (preparation 21,175mg, 0.84mmol) DMF (10mL) solution in add HOBt (125mg, 0.92mmol), DIPEA (0.29mL, 1.68mmol) and EDCI (177mg, 0.92mmol) and this reaction solution is stirred 72h under room temperature.Solvent removed in vacuo also (is distributed resistates in water (40ml) and ethyl acetate between 3 * 40mL).Organic moiety drying (the MgSO that merges ₄), vacuum concentration, resistates obtain the target compound of yellow solid shape with ethanol/methylene (3: 97) wash-out through the silica gel chromatography purifying.δ _H(CD ₃OD)：2.97-3.12(2H，m)，3.67(1H，s)，4.25(1H，d)，4.70-4.75(1H，m)，7.08(1H，s)，7.15-7.21(1H，m)，7.25-7.34(4H，m)，7.65(1H，s)，8.55(1H，s)；m/z(ES ⁺)＝388[M+H] ⁺。

Embodiment 44

(S)-and 3-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-(R)-2-hydroxy-4-phenyl butyric acid

With sodium hydroxide solution (0.24ml, 2M, 0.48mmol) join (S)-3-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-(R)-(embodiment 43 for 2-hydroxy-4-phenyl methyl-butyrate, 170mg also stirs 24h with this reaction solution in methyl alcohol 0.44mmol) (5ml) solution under room temperature.Solvent removed in vacuo and with resistates hydrochloric acid (1N, 30mL) and ethyl acetate (distribute between 3 * 30mL).Organic moiety drying (the MgSO that merges ₄), vacuum concentration obtains the target compound of yellow solid shape.δ _H(DMSO)：2.71(1H，dd)，2.91(1H，dd)，3.56(1H，d)，4.38-4.46(1H，m)，4.77(1H，s)，6.76(1H，s)，7.11-7.16(1H，m)，7.19-7.27(4H，m)，7.45(1H，s)，8.44-8.52(2H，m)；m/z(ES ⁺)＝374[M+H] ⁺。

Embodiment 45

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(4-p-methoxy-phenyl)-2-oxoethyl] acyl Amine

(2.1mL, (preparation 49,160mg is in acetone 0.41mmol) (20ml) solution 2M) to join 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(4-p-methoxy-phenyl) [1,3] dioxolane-2-ylmethyl] acid amides with aqueous hydrochloric acid.90min is cooled to room temperature then with this mixture heating up backflow.This suspension liquid filtered and with washing with acetone, the air-dry target compound that obtains the light yellow solid shape.δ _H(d ₆DMSO)：3.86(3H，s)，4.79(2H，d)，7.08(2H，d)，7.23(1H，s)，7.77(1H，s)，8.03(2H，d)，8.58(1H，s)，9.14(1H，t)，12.31(1H，br?s).m/z(ES ⁺)＝344[M+H] ⁺；RT＝3.34min。

Following compounds uses suitable ketal and aqueous hydrochloric acid to synthesize according to the method for embodiment 45.

Embodiment 49

Z 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(4-fluorophenyl)-2-hydroxyethyl] acid amides

To the 5-chloro-1H-pyrrolo-[2 that stirs, 3-c] (embodiment 48 for acid amides for pyridine-2-formic acid [2-(4-fluorophenyl)-2-oxoethyl], 0.05g, ethanol (5ml 151mmol), anhydrous) add the hydroborate (2.5mmol/g that polymkeric substance is supported in the suspension liquid, 0.09g 226mmol), this mixture is through ultrasonic and leniently heat up and dissolve until ketone.This reaction mixture is stirred 2 days after-filtration under room temperature, use methanol wash.With filtrate vacuum-evaporation to the dried colorless oil that obtains.Through flash column chromatography (SiO ₂, ethyl acetate: isohexane, 1: 1, v/v) purifying obtained the target compound of white solid.m/z(ES ⁺)＝334[M+H] ⁺；RT＝2.93min。

Embodiment 50

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1- Formyl-dimethylamino-2-(S)-pyridin-3-yl-ethyl] acid amides

To (S)-2-amino-N, (the preparation 53 of N-dimethyl-3-pyridin-3-yl propionamide hydrochloride, 170mg, 0.74mmol) DMF (5mL) solution in add DIPEA (0.45mL, 2.58mmol), 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18,145mg, 0.74mmol) and TBTU (262mg, 0.82mmol).This reaction mixture is stirred 16h under room temperature.Solvent removed in vacuo also obtains resistates the target compound of pale solid shape by preparation HPLC purifying.δ _H(CD ₃OD)：2.95(3H，s)，3.08(3H，s)，3.11-3.18(1H，m)，3.22-3.28(1H，m)，5.31-5.37(1H，m)，7.12(1H，s)，7.34-7.38(1H，m)，7.65(1H，s)，7.79-7.84(1H，m)，8.37-8.41(1H，m)，8.45-8.51(1H，m)，8.54(1H，s)；m/z(ES ⁺)＝372[M+H] ⁺。

Embodiment 51

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (2-oxo-1- (S)-and pyridin-3-yl methyl-2-tetramethyleneimine-1-base-ethyl] acid amides

To (the preparation 54 of (S)-2-amino-3-pyridin-3-yl-1-tetramethyleneimine-1-base third-1-keto hydrochloride, 239mg, 0.94mmol) DMF (5mL) solution in add DIPEA (0.60mL, 3.28mmol), 5-chloro-1H-pyrrolo-[2,3-c] (the preparation 18 of pyridine-2-formic acid, 184mg, 0.94mmol) and TBTU (330mg, 1.03mmol).Reaction mixture stirs 16h under room temperature.Solvent removed in vacuo and with resistates (2 * 100mL distributes between 1N) at ethyl acetate (100ml) and sodium hydroxide solution.Organic phase drying (MgSO ₄), evaporate to dryness obtains the target compound of brown solid shape.δ _H(CD ₃OD)：1.74-1.94(4H，m)，3.12-3.39(4H，m)，3.41-3.48(1H，m)，3.69-3.75(1H，m)，5.07-5.12(1H，m)，7.16(1H，s)，7.34-7.39(1H，m)，7.67(1H，s)，7.79-7.83(1H，m)，8.37-8.42(1H，m)，8.45-8.51(1H，m)，8.56(1H，s)；m/z(ES ⁺)＝398[M+H] ⁺。

Embodiment 52

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1- Formyl-dimethylamino-2-(S)-pyridine-2-base-ethyl] acid amides

To 2-(S)-amino-N, N-dimethylamino-3-pyridine-2-base propionamide hydrochloride (preparation 53,0.15g, 0.66mmol) DMF (5mL) solution in add DIPEA (0.4mL, 2.31mmol), TBTU (0.212g, 0.66mmol) and 5-chloro-1H-indole-2-carboxylic acid (preparation 18,0.130mg, 0.66mmol).This reaction mixture is stirred 16h concentrating under reduced pressure then under room temperature.Resistates is dissolved in the ethyl acetate (200ml) also with sodium hydroxide solution (100ml, 1N) washing.Organic extract liquid drying and vacuum concentration.Obtain the target compound of white solid by preparation HPLC purifying.m/z(ES ⁺)＝372[M+H] ⁺；RT＝2.47min。

Embodiment 53

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-(3-(S)-hydroxyl pyrrolidine-1-yl)-2-oxoethyl] acid amides

To formic acid (embodiment 18,2.66mg, DMF 13.6mmol) (anhydrous, 120mL) add in the solution amine hydrochloride (preparation 103,4.30g, 14.9mmol), DIPEA (7.79mL, 44.7mmol) and HOBt.H ₂O (2.280g, 14.9mmol).Gained solution is added EDCI after stirring 10min under the room temperature (3.12g 16.3mmol), stirs 17h with reaction mixture then under room temperature.Vacuum is removed volatile matter and then resistates is distributed between ethyl acetate (200mL) and water (200mL).Water with ethyl acetate extraction (3 * 50mL), latter incorporated organic layer through sodium hydroxide solution (2M, 3 * 50mL), hydrochloric acid (2M, 2 * 50mL), salt solution (100ml) washing, dry (MgSO ₄), filter and vacuum concentration.With isolating solid be dissolved in ethanol/methylene (15: 185, v/v), then through flash chromatography (SiO ₂, be dissolved in ethanol/methylene, 15: 185, v/v) purifying obtained the target compound of yellow powder powder.δ _H(CD ₃OD)：1.72-2.02(2H，m)，3.01-3.13(1H，m)，3.13-3.26(2H，m)，3.35-3.52(1.5H，m)，3.55-3.65(0.5H，m)，3.71-3.81(0.5H，m)，3.84(0.5H，dd)，4.23-4.33(0.5H，m)，4.37-4.45(0.5H，m)，4.99(0.5H，t)，5.07(0.5H，t)，6.90-7.07(2H，m)，7.13(1H，d)，7.31(2H，dd)，7.66(1H，s)，8.54(1H，d)；m/z(ES ⁺)＝431[M+H] ⁺；RT＝3.17min。

Embodiment 54

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(S)- (4-fluorophenyl)-1-sec.-propyl formamyl ethyl] acid amides

To 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid (30mg, add in DMF 0.08mmol) (3mL) solution DIPEA (17.3 μ L, 0.10mmol) and HATU (37.8mg, 0.10mmol).Add behind the 15min isopropylamine (7.1 μ L, 0.08mmol).This reaction mixture is stirred 24h concentrating under reduced pressure (genevac) then under room temperature.Obtain the target compound of yellow solid shape by the purifying of quality guidance.m/z(ES ⁺)＝403[M+H] ⁺；RT＝3.39min。

Embodiment 55-98

Following compounds according to the method for embodiment 54 by 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid and suitable amine preparation.

Embodiment 99

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1- Cyclopropyl formamyl-2-(S)-(4-fluorophenyl) ethyl] acid amides

To 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid (100mg, add in DMF 0.28mmol) (5mL) solution cyclopropylamine (19.2 μ L, 0.28mmol), HOBt (37mg, 0.28mmol) and DIPEA (96 μ L, 0.55mmol).(69mg 0.36mmol) also stirs 16h with this reaction mixture under room temperature to add EDCI behind the 5min.Solvent removed in vacuo and with the resistates water grind, through silica gel chromatography methyl alcohol: methylene dichloride (1: 24) wash-out obtains the target compound of pale solid shape.m/z(ES ⁺)＝401[M+H] ⁺；RT＝3.22min。

Embodiment 100-106

Following compounds according to the method for embodiment 99 by 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid and suitable amine preparation.All compounds through the silica gel chromatography purifying with above-mentioned solvent systems wash-out.

Embodiment 107

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-(3-hydroxy azetidine-1-yl)-2-oxoethyl] acid amides

With 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid (100mg, 0.28mmol), 3-hydroxy azetidine hydrochloride (Heterocycles, 2002,56 (1-2), 433-442; 30mg; 0.28mmol) and HOBt (37mg, 0.28mmol) be dissolved in DMF (5ml) and DIPEA (0.14ml, 0.83mmol) in.(69mg 0.36mmol) and with reaction mixture at room temperature stirs 16h to add EDCI behind the 5min.Solvent removed in vacuo is also ground the resistates water.Through silica gel chromatography purifying methyl alcohol: methylene dichloride (1: 49 to 3: 97) wash-out obtains the target compound of yellow solid shape.δ _H(CD ₃OD)：3.08-3.21(2H，m)，3.58-3.63(0.5H，m)，3.84-3.91(0.5H，m)，4.03-4.09(0.5H，m)，4.25-4.32(0.5H，m)，4.38-4.94(4H，m)，7.03-7.12(2H，m)，7.15-7.19(1H，m)，7.30-7.38(2H，m)，7.68(1H，s)，8.59(1H，s)；RT＝3.32min。

Embodiment 108

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)- Benzyl-2-(3-hydroxy azetidine-1-yl)-2-oxoethyl] acid amides

With 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-phenylpropionic acid (100mg, 0.29mmol), 3-hydroxy azetidine hydrochloride (32mg, 0.29mmol) and HOBt (39mg, 0.29mmol) be dissolved in DMF (5ml) and DIPEA (0.15ml, 0.87mmol) in.(72mg 0.38mmol) also stirs 16h with this reaction mixture under room temperature to add EDCI behind the 5min.Solvent removed in vacuo is also ground the resistates water.Through silica gel chromatography purifying methyl alcohol: methylene dichloride (1: 49 to 3: 97) wash-out obtains the target compound of pale solid shape.δ _H(CD ₃OD)：3.12-3.20(2H，m)，3.45-3.51(0.5H，m)，3.83-3.90(0.5H，m)，4.00-4.13(1H，m)，4.35-4.52(2H，m)，4.57-4.94(2H，m)，7.18-7.22(1H，m)，7.27-7.40(5H，m)，7.68(1H，s)，8.59(1H，s)；RT＝3.27min。

Embodiment 109

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(3- Hydroxy azetidine-1-yl)-and the 2-oxoethyl] acid amides

With [(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino] acetate (30mg, 0.12mmol), 3-hydroxy azetidine hydrochloride (13mg, 0.12mmol) and HOBt (16mg, 0.12mmol) be dissolved in DMF (3ml) and DIPEA (43 μ l, 0.25mmol).(30mg 0.15mmol) also stirs 16h with this reaction mixture under room temperature to add EDCI behind the 5min.Solvent removed in vacuo also (is distributed resistates at water (20ml) and DCM between 3 * 20ml).Organic layer drying (the MgSO that merges ₄), vacuum concentration and with resistates through silica gel chromatography purifying methyl alcohol: methylene dichloride (1: 24) wash-out obtains the target compound of white solid.δ _H(CD ₃OD)：4.06-4.15(3H，m)，4.40-4.46(1H，m)，4.55-4.63(1H，m)，4.77-4.94(2H，m)，7.14(1H，s)，7.71(1H，s)，8.62(1H，s)；RT＝2.82min。

Embodiment 110-111

Following compounds according to the method for embodiment 109 by [(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino] acetate and suitable amine preparation.All compounds adopt above-mentioned solvent systems wash-out purifying through silica gel chromatography.

Embodiment 112

2-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-oxo-3-phenylpropionic acid ethyl ester

With 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (100mg, 0.51mmol) and 4-(4,6-dimethoxy [1.3.5] triazine-2-yl)-(183mg 0.66mmol) is dissolved among the THF (20ml) 4-methylmorpholine muriate (DMTMM).Add 2-amino-3-oxo-3-phenylpropionic acid carbethoxy hydrochloride (Tetrahedron Lett., 1993,34 (2), 211-214 behind the 5min; 124mg, 0.51mmol) (56 μ l 0.51mmol) and with reaction mixture stir 72h under room temperature with the 4-methylmorpholine.Solvent removed in vacuo also (is distributed resistates at water (40ml) and EtOAc between 3 * 30ml).Organic layer drying (the MgSO that merges ₄), vacuum concentration and with resistates through silica gel chromatography purifying methyl alcohol: methylene dichloride (1: 19) wash-out.This material is further used methyl alcohol: ether (1: 19) grinds the target compound that obtains the light yellow solid shape.m/z(ES ⁺)＝386[M+H] ⁺；RT＝3.56min。

Embodiment 113

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2- (S)-and (4-fluorophenyl)-1-(methoxymethyl formamyl) ethyl] acid amides

With 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid (80mg, 0.22mmol) and N, O-dimethyl hydroxylamine hydrochloride (24mg, 0.24mmol) be dissolved in ethanol (10ml) and 4-methylmorpholine (27 μ l, 0.24mmol) in.(67mg 0.24mmol) also stirs 16h with this reaction mixture under room temperature to add DMTMM in this solution.In addition, add N, the O-dimethyl hydroxylamine hydrochloride (12mg, 0.12mmol), the 4-methylmorpholine (14 μ l, 0.12mmol) and DMTMM (34mg 0.12mmol) also stirs 96h with this reaction mixture under room temperature.Solvent removed in vacuo also (is distributed resistates at water (40ml) and EtOAc between 2 * 40ml).Organic layer drying (the MgSO that merges ₄), vacuum concentration and through silica gel chromatography purifying methyl alcohol: methylene dichloride (1: 19) wash-out obtains the target compound of white solid.m/z(ES ⁺)＝405[M+H] ⁺；RT＝3.36min。

Embodiment 114

5-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-(4-hydroxy piperidine-1-yl)-2-oxoethyl] acid amides

With 5-chloro-1H-pyrrolo-[2,3-b] (the preparation 57 of pyridine-2-formic acid, 50mg, 0.25mmol), 2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxy piperidine-1-yl) third-1-keto hydrochloride (85mg, 0.25mmol) and DMTMM (85mg, 0.31mmol) be dissolved in ethanol (5ml) and 4-methylmorpholine (31 μ l, 0.28mmol) in.This reaction mixture is stirred 16h under room temperature.Solvent removed in vacuo also (is distributed resistates at water (30ml) and EtOAc between 3 * 25ml).Organic layer drying (the MgSO that merges ₄), vacuum concentration and through silica gel chromatography purifying methyl alcohol: methylene dichloride (1: 19) wash-out obtains the target compound of light brown solid state.m/z(ES ⁺)＝445[M+H] ⁺；RT＝3.31min。

Embodiment 115

5-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid (1- Formyl-dimethylamino-2-(S)-phenylethyl] acid amides

With 5-chloro-1H-pyrrolo-[2,3-b] (the preparation 57 of pyridine-2-formic acid, 55mg, 0.28mmol), 2-(S)-amino-N, N-dimethyl-3-Phenylpropionamide hydrochloride (70mg, 0.31mmol) and DMTMM (93mg, 0.34mmol) be dissolved in ethanol (5ml) and 4-methylmorpholine (34 μ l, 0.31mmol) in.This reaction mixture is stirred 24h under room temperature.Solvent removed in vacuo also (is distributed resistates at water (40ml) and EtOAc between 2 * 40ml).The organic layer that merges is through 2N NaOH solution (40ml), salt solution (40ml) washing, dry (MgSO ₄), vacuum concentration and through silica gel chromatography purifying methyl alcohol: methylene dichloride (3: 97) wash-out obtains the target compound of yellow solid shape.m/z(ES ⁺)＝371[M+H] ⁺；RT＝3.49min。

Embodiment 116

5-ethynyl-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1- (S)-and formyl-dimethylamino-2-styroyl) acid amides

To 2-(S)-amino-N, N-dimethyl-3-Phenylpropionamide hydrochloride (preparation 8,0.0135g, 0.059mmol) DMF (anhydrous, 3ml) add in the solution DIPEA (0.031mL, 0.177mmol), add then formic acid (preparation 60,0.010g, 0.054mmol).In the solution that stirs, add HOBt.H ₂O (0.008g, 0.059mmol), add behind the 10min then EDCI (0.012g, 0.065mmol).This reaction mixture is stirred 18h, and vacuum is removed all volatile matters then.Resistates is distributed between ethyl acetate (30mL) and water (20mL).Separate behind each layer water layer with ethyl acetate extraction (3 * 20mL).The organic layer that merges salt solution (30mL) washing, dry (MgSO ₄), filter and vacuum concentration.Resistates is dissolved in methyl alcohol uses silica gel adsorption then.Through flash column chromatography (SiO ₂, CH ₂Cl ₂: MeOH, 19: 1, v/v) purifying obtained the target compound of pale solid shape.δ _H(CD ₃OD)：2.88(3H，s)，2.89(3H，s)，3.00-3.23(2H，m)，3.50(1H，s)，5.27(1H，t)，7.10-7.37(6H，m)，7.86(1H，s)，8.70(1H，s).m/z(ES ⁺)＝361[M+H] ⁺；RT＝2.65min。

Embodiment 117

5-cyano group-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1-(S)- Formyl-dimethylamino-2-styroyl) acid amides

To 2-(S)-amino-N, N-dimethyl-3-Phenylpropionamide hydrochloride (preparation 8,0.023g, 0.100mmol) DMF (anhydrous, 4ml) add in the solution DIPEA (0.052mL, 0.300mmol), add then formic acid (preparation 62,0.017g, 0.091mmol).In the solution that stirs, add HOBt.H ₂O (0.0135g, 0.100mmol), add behind the 10min then EDCI (0.021g, 0.109mmol).With this reaction mixture stir 18h then vacuum remove all volatile matters.Resistates is distributed between ethyl acetate (30mL) and water (20mL).Separate behind each layer water layer with ethyl acetate extraction (3 * 20mL).The organic layer that merges is through salt solution (30mL) washing, dry (MgSO ₄), filter and vacuum concentration.Resistates is dissolved in ethyl acetate uses silica gel adsorption then.Through flash column chromatography (SiO ₂, ethyl acetate: isohexane, 1: 1, v/v) purifying obtained the target compound of light brown solid state.δ _H(CDCl ₃)：2.77(3H，s)，2.96(3H，s)，3.08-8.20(2H，m)，5.23-5.41(1H，m)，6.99(1H，s)，7.14-7.36(5H，m)，7.65(1H，d)，8.01(1H，s)，8.87(1H，s)，.10.01(1H，s)；m/z(ES ⁺)＝362[M+H] ⁺；RT＝3.11min。

Embodiment 118

5-cyano group-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1- (S)-and (4-luorobenzyl)-2-(4-hydroxy piperidine-1-yl)-2-oxoethyl] acid amides

(DMF 0.118mmol) is (anhydrous for preparation 20,0.036g to 2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxy piperidine-1-yl) third-1-keto hydrochloride, (0.061mL 0.353mmol), adds formic acid (preparation 62 then 5ml) to add DIPEA in the solution, 0.020g, 0.107mmol).In the solution that stirs, add HOBt.H ₂O (0.016g, 0.107mmol), add behind the 10min then EDCI (0.025g, 0.128mmol).This reaction mixture is stirred 18h, and vacuum is removed all volatile matters then.With resistates at CH ₂Cl ₂(30mL) and between the water (20mL) distribute.Separate water layer CH behind each layer ₂Cl ₂Extraction (2 * 30mL).The organic layer that merges is through salt solution (50mL) washing, dry (MgSO ₄), filter and vacuum concentration.Resistates is dissolved in methyl alcohol uses silica gel adsorption then.Through flash column chromatography (SiO ₂, methyl alcohol: methylene dichloride, 7: 93, v/v) purifying obtained the target compound of white solid.δ _H(d ₆DMSO)：1.05-1.32(2H，m)，1.49-1.72(2H，m)，2.86-3.42(4H，m)，3.53-3.87(2.5H，m)，3.93-4.05(0.5H，m)，4.69(1H，d)，5.07-5.21(1H，m)，6.97-7.12(2H，m)，7.26-7.39(2H，m)，7.47(1H，s)，8.41(1H，s)，8.81(1H，s)，9.01-9.41(1H，m)，12.64(1H，s)；m/z(ES ⁺)＝436[M+H] ⁺；RT＝1.51min。

Embodiment 119

5-methyl isophthalic acid H-pyrrolo-[23-c] pyridine-2-formic acid (1- Formyl-dimethylamino-2-(S)-styroyl) acid amides

To 2-(S)-amino-N, N-dimethyl-3-Phenylpropionamide hydrochloride (preparation 8,0.0286g, 0.125mmol) DMF (anhydrous, 5ml) add in the solution DIPEA (0.071mL, 0.409mmol), add then formic acid (preparation 66,0.020g, 0.114mmol).In the solution that stirs, add HOBt.H ₂O (0.017g, 0.125mmol), add behind the 10min then EDCI (0.026g, 0.136mmol).This reaction mixture is stirred 16h under room temperature, vacuum is removed all volatile matters then.With resistates at CH ₂Cl ₂(50mL) and between the water (50mL) distribute.Separate water layer CH behind each layer ₂Cl ₂Extraction (3 * 20mL).The organic layer that merges is through salt solution (30mL) washing, dry (MgSO ₄), filter and vacuum concentration.Resistates is dissolved in CH ₂Cl ₂Then through flash column chromatography (SiO ₂, CH ₂Cl ₂Methyl alcohol: CH then ₂Cl ₂, 1: 19, v/v) purifying obtained the target compound of light yellow solid shape.δ _H(CDCl ₃)：2.63(3H，s)，2.77(3H，s)，2.97(3H，s)，3.11-3.25(2H，m)，5.34-5.44(1H，m)，6.85(1H，s)，7.20-7.33(6H，m)，7.34(1H，s)，7.83(1H，d)，8.78(1H，s)；m/z(ES ⁺)＝351[M+H] ⁺；RT＝2.36min。

Embodiment 120

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-(4-methoxyl group piperidines-1-yl)-2-oxoethyl] acid amides

To 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-(embodiment 42 for the 3-phenylpropionic acid, 150mg, 0.42mmol) and (preparation 68 of 4-methoxyl group piperidine hydrochlorate, 86mg, add in DMF 0.57mmol) (5ml) solution HOBt (66mg, 0.43mmol), DIPEA (0.23mL, 1.34mmol) and EDCI (102mg, 0.53mmol).After stirring 12h under the room temperature this mixture is joined (100mL, water/salt solution: 1/1) in the weak brine.(4 * 25mL), the extraction liquid of merging washs with salt solution (50mL) and dry (MgSO with ethyl acetate extraction ₄), the resistates after concentrating obtains the target compound of colorless solid shape from recrystallizing methanol.m/z(ES ⁺)＝459.38[M+H] ⁺；RT＝3.40min。

Embodiment 121

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-(3-(R)-methoxyl group tetramethyleneimine-1-yl)-2-oxoethyl] acid amides

To 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-(embodiment 42 for the 3-phenylpropionic acid, 104mg, 0.29mmol) and (R)-(preparation 70 of 3-methoxyl group pyrrolidine hydrochloride, 40mg, add in DMF 0.29mmol) (5ml) solution HOBt (44mg, 0.29mmol), DIPEA (0.15mL, 0.88mmol) and EDCl (66mg, 0.344mmol).After stirring 12h under the room temperature mixture is joined (100mL, water/salt solution: 1/1) in the weak brine.(4 * 25mL), the extraction liquid usefulness salt water washing (50mL) of merging is drying (MgSO also with ethyl acetate extraction ₄), the resistates after concentrating obtains the target compound of colorless solid shape from the acetonitrile recrystallization.m/z(ES ⁺)＝445.31[M+H] ⁺；RT＝3.36min。

Embodiment 122

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-(3-(S)-methoxyl group tetramethyleneimine-1-yl)-2-oxoethyl] acid amides

To 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-(embodiment 42 for the 3-phenylpropionic acid, 53mg, 0.15mmol) and (S)-(preparation 72 of 3-methoxyl group pyrrolidine hydrochloride, 20mg, add in DMF 0.15mmol) (5ml) solution HOBt (25mg, 0.16mmol), DIPEA (76 μ L, 0.44mmol) and EDC1 (34mg, 0.18mmol).After stirring 12h under the room temperature this mixture is joined (100mL, water/salt solution: 1/1) in the weak brine.(4 * 25mL), the extraction liquid of merging washs with salt solution (50mL) and dry (MgSO with ethyl acetate extraction ₄), the resistates after concentrating obtains the target compound of colorless solid shape through flash chromatography (silica gel, methylene chloride, 95: 5) purifying.m/z(ES ⁺)＝445.34[M+H] ⁺；RT＝3.34min。

Embodiment 123

3-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2- Carbonyl) amino]-2-(S)-hydroxy-4-phenyl methyl-butyrate

Under the condition similar, use HOBt (142mg to embodiment 43,0.93mmol), EDCI (200mg, 1.04mmol), DIPEA (0.32mL, 1.87mmol) DMF (10mL) solution make 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18,170mg, 0.86mmol) and (3S, 2S)-3-amino-2-hydroxy-4-phenyl methyl-butyrate (preparation 21A, 174mg, 0.83mmol) coupling.Thick product obtains the target compound of colorless oil with hexane/ethyl acetate (25: 75) wash-out through the silica gel chromatography purifying.δ _H(CD ₃Cl ₃)：3.04(4H，2dd)，3.74(3H，s)，4.36(1H，br?s)，4.63(1H，m)，4.98(1H，ddd)，6.66(1H，s)，6.96(1H，d)，7.18-7.35(5H，m)，7.48(1H，s)，8.63(1H，s)。

Embodiment 124

3-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-2-(S)-hydroxy-4-phenyl butyric acid

To use sodium hydroxide (0.44ml with embodiment 44 similar methods, 1N, 0.44mmol) methyl alcohol (10mL) solution make that 3-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-(152mg's 2-(S)-hydroxy-4-phenyl methyl-butyrate 0.39mmol) is hydrolyzed.δ _H(d ₆DMSO)：2.83，2.95(2H，2dd)，4.19(1H，d)，4.52(1H，m)，5.75(1H，br?s)，7.10-7.33(6H，2m)，7.68(1H，s)，8.54(1H，s)，8.72(1H，d)。

Embodiment 125

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1-(S)- Benzyl-2-formyl-dimethylamino-2-(S)-hydroxyethyl) acid amides

With dimethylamine hydrochloride (7mg, 0.085mmol) join 3-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-(embodiment 124 for 2-(S)-hydroxy-4-phenyl butyric acid, 30mg, 0.080mmol), HOBt (14mg, 0.091mmol), DIPEA (31 μ L, 0.18mmol) and EDCI (18mg is in DMF 0.094mmol) (3mL) solution.Add DIPEA (14mL, 0.080mmol) after, mixture is stirred 12h adds weak brine (100mL, water/salt solution: 1/1) then.(4 * 25mL), the extraction liquid of merging washs with salt solution (50mL) and dry (MgSO with ethyl acetate extraction ₄), the resistates after concentrating obtains the target compound of colorless solid shape through preparation LCMS purifying.m/z(ES ⁺)＝401.28[M+H] ⁺；RT＝3.06min。

Embodiment 126

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1-(S)- Benzyl-2-(S)-hydroxyl-3-oxo-3-tetramethyleneimine-1-base-propyl group) acid amides

With tetramethyleneimine (7 μ g, 0-084mmol) join 3-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-(embodiment 124 for 2-(S)-hydroxy-4-phenyl butyric acid, 30mg, 0.080mmol), HOBt (14mg, 0.091mmol), DIPEA (31 μ L, 0.18mmol) and EDCI (18mg is in DMF 0.094mmol) (3mL) solution.After stirring 12h mixture is joined weak brine (100mL, water/salt solution: 1/1).(4 * 25mL), the extraction liquid of merging washs with salt solution (50mL) and dry (MgSO with ethyl acetate extraction ₄), the resistates after concentrating obtains the target compound of colorless solid shape through preparation LCMS purifying.m/z(ES ⁺)＝427.31[M+H] ⁺；RT＝3.27min。

Embodiment 127

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)-benzyl-3-(3,4- Dihydroxy pyrrolidine-1-yl)-and 2-(S)-hydroxyl-3-oxopropyl) acid amides

With suitable-3, (the preparation 23 of 4-dihydroxy pyrrolidine, 9mg, 0.087mmol) join that 3-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-(embodiment 124,30mg for 2-(S)-hydroxy-4-phenyl butyric acid, 0.080mmol), HOBt (14mg, 0.091mmol), DIPEA (31 μ L, 0.18mmol) and EDCI (18mg is in DMF 0.094mmol) (3mL) solution.After stirring 12h mixture is joined weak brine (100mL, water/salt solution: 1/1).(4 * 25mL), the extraction liquid of merging washs with salt solution (50mL) and dry (MgSO with ethyl acetate extraction ₄), the resistates after concentrating obtains the target compound of colorless solid shape through preparation LCMS purifying.m/z(ES ⁺)＝459.29[M+H] ⁺；RT＝2.87min。

Embodiment 128

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1-(S)- Benzyl-2-(R)-hydroxyl-2-propyl group formamyl ethyl) acid amides

With Tri N-Propyl Amine (16 μ L, 0.19mmol) join 3-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-(embodiment 44 for 2-(R)-hydroxy-4-phenyl butyric acid, 40mg, 0.11mmol), HOBt (16.4mg, 0.11mmol), DIPEA (41 μ L, 0.24mmol) and EDCI (25mg is in DMF 0.13mmol) (3mL) solution.Remove in stirring at room 72h final vacuum and to desolvate, and resistates is obtained the target compound of colorless solid shape through preparation LCMS purifying.m/z(ES ⁺)＝415.34[M+H] ⁺；RT＝3.10min。

Embodiment 129-147

Following compounds according to the method for embodiment 128 from 3-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-2-(R)-hydroxy-4-phenyl butyric acid and suitable amine preparation.

Embodiment 148-174

Following compounds according to following step from 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and suitable amine preparation.

To 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (0.12mmol, 1.5eq.) 1: add in 1.2DMF/DCM (2ml) solution HOBT (0.16mmol, 2eq.), then add the PS-carbodiimide (0.16mmol, 2eq).Reaction mixture jolting 15min is added amine (0.08mmol, DCM 1eq) (0.5ml) solution then.The reaction mixture jolting is spent the night.(0.36mmol 4.5eq) extracts with MP-Trisamine for HOBT and the acid of unreacted starting raw material.MP-Tutofusin tris (Trisamine) is joined in the reaction mixture also with this mixture jolting 5h.With the resin elimination and with 1: 1 DMF/DCM (2 * 4ml) solution washings.Filtrate concentrating obtained the product acid amides.

Embodiment 175

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(4- Benzyl oxygen phenylpiperidines-1-yl)-and 1-(S)-(4-luorobenzyl)-2-oxoethyl] acid amides

Under argon gas to 5-chloro-1H-pyrrolo-[2,3-c] (embodiment 5 for acid amides for pyridine-2-formic acid [1-(S)-(4-luorobenzyl)-2-(4-hydroxy piperidine-1-yl)-2-oxoethyl], 50mg, 0.11mmol) dry DMF (3mL) solution in add bromotoluene (16 μ l, 0.13mmol), (6.3mg 0.16mmol) and with this reaction solution stirs 16h then to add sodium hydride.Solvent removed in vacuo and with resistates ethyl acetate (2 * 20mL) and water (20mL) between distribute.Organic moiety 1MHCl (20mL), NaHCO ₃(2 * 20mL) and salt solution (2 * 20mL) washings, dry (MgSO4) also remove under vacuum and desolvate.Crude product obtains the target compound of pale powder shape with methylene chloride (9: 1) wash-out through the silica gel chromatography purifying.m/z(ES ⁺)＝535.33[M+H] ⁺；RT＝3.44min。

Embodiment 176

1-[2-(S)-[5-chloro-1H-pyrrolo-[2,3-c] pyridine-2- Carbonyl) amino]-3-(4-fluorophenyl) propionyl] piperidines-4-formic acid

To 1-[2-(S)-[5-chloro-1H-pyrrolo-[2; 3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionyl] (embodiment 239 for piperidines-4-methyl-formiate; 48mg; 0.1mmol) THF (2.0mL) solution in add 1M sodium hydroxide solution (0.11mL; 0.11mmol), and reaction solution stirred 3h under room temperature.Solvent removed in vacuo also (is distributed crude product at ether (20mL) and water between 2 * 20mL).Combining water layer also is acidified to pH2 with HCl, and organic layer is with ethyl acetate (2 * 20mL) extractions.Merge organic layer and use salt solution (2 * 15mL) washings, dry (MgSO ₄) and under vacuum, remove and desolvate.Crude product is obtained the target compound of white powder from recrystallization from ethyl acetate/petroleum ether.m/z(ES ⁺)＝473.30[M+H] ⁺；RT＝3.20min。

Embodiment 177 and 178 is to synthesize with embodiment 176 similar modes.

Embodiment 179

Acetate 1-[2-(S)-[5-chloro-1H-pyrrolo-[2,3-c] pyridine-2- Carbonyl) amino]-3-(4-fluorophenyl) propionyl] the piperidin-4-yl ester

This target compound prepares from 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)-(4-luorobenzyl)-2-(4-hydroxy piperidine-1-yl)-2-oxoethyl] acid amides (embodiment 5).(50mg adds diacetyl oxide (1mL) in anhydrous pyridine 0.14mmol) (2mL) solution, and reactant is stirred 4h under room temperature to initial acid amides under argon gas.Solvent removed in vacuo also is dissolved in crude product in the ethyl acetate (30mL).Organic layer with 1M HCl (2 * 15mL), water (15mL) and salt solution (2 * 15mL) washings, dry (MgSO ₄) and under vacuum, remove and desolvate.Resistates obtains the target product of white powder through chromatographic grade methylene chloride (99: 1) wash-out.m/z(ES ⁺)＝487.26[M+H] ⁺；RT＝3.38min。

Embodiment 180

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(4- Amino piperidine-1-yl)-and 1-(S)-(4-luorobenzyl)-2-oxoethyl] acid amides

To { 1-[2-(S)-[(5-chloro-1H-pyrrolo-[2; 3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionyl] piperidin-4-yl } (embodiment 230 for t-butyl carbamate; 500mg; 0.92mmol) methyl alcohol (12mL) suspension liquid in add dioxane (0.69mL, 2.76mmol) solution and reaction solution stirred 48h of 4M HCl.Wash the yellow powder powder target compound that obtains hydrochloride form with the sedimentation and filtration of gained and with ethyl acetate.m/z(ES ⁺)＝444.16[M+H] ⁺；RT＝2.65min。This product is dissolved in the saturated sodium hydrogen carbonate solution.Solvent removed in vacuo also is dissolved in crude product among the THF (30mL).This solution is obtained the target compound of yellow powder shape by diatomite filtration and solvent removed in vacuo.m/z(ES ⁺)＝444.32[M+H] ⁺；RT＝2.59min。

Embodiment 181-189 is according to the amine preparation of embodiment 180 by suitable Boc-protection.

Embodiment 190

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(4- Diacetyl amino piperidine-1-yl)-and 1-(S)-(4-luorobenzyl)-2-oxoethyl] acid amides

Prepare from 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(4-amino piperidine-1-yl)-1-(S)-(4-luorobenzyl)-2-oxoethyl] acid amides (embodiment 180).This compound synthesizes and obtains through preparation HPLC purifying the target compound of white powder according to embodiment 179.m/z(ES ⁺)＝486.28[M-CH ₃CO ₂H+NH ₄] ⁺；RT＝3.18min。

Embodiment 191

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-(4-methylamino piperidines-1-yl)-2-oxoethyl] acid amides

To 5-chloro-1H-pyrrolo-[2; 3-c] pyridine-2-formic acid (1-(S)-(4-luorobenzyl)-2-{4-[methyl-(2-oil of mirbane alkylsulfonyl) amino] piperidines-1-yl }-the 2-oxoethyl) acid amides (preparation 76; 82mg; 0.13mmol) acetonitrile (6mL) solution in add phenyl mercaptan (145 μ L; 1.4mmol); (230mg 1.66mmol) and with reaction solution is heated to 50 ℃ of 24h then to add salt of wormwood.In this mixture, add ether (10mL) and 1M HCl (15mL) and stir 5min.Separate organic layer, with combining water layer after 1M HCl (15mL) washing.Use solid carbonic acid potashization to pH9 this solution, and (2 * 20mL) extract with ethyl acetate.Organic layer is through merging, salt solution (2 * 20mL) washings, dry (MgSO ₄).The product that solvent removed in vacuo obtains expecting is a pale powder.m/z(ES ⁺)＝458.40[M+H] ⁺；RT＝2.67min。Small portion product (10mg) is dissolved in the middle 1M of adding of methyl alcohol (2mL) HCl makes its pH to 1-2.After stirring 20min, solvent removed in vacuo obtains the target compound of the yellow powder shape of hydrochloride form.m/z(ES ⁺)＝458.38[M+H] ⁺；RT＝2.64min。

Embodiment 192

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-(4-methylamino methyl piperidine-1-yl)-2-oxoethyl] acid amides

According to embodiment 191 from 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1-(S)-(4-luorobenzyl)-2-{4-[methyl-(2-oil of mirbane alkylsulfonyl) amino] methyl } piperidines-1-yl)-2-oxoethyl] acid amides (73-76 is a starting raw material with 4-amino methyl piperidines-1-t-butyl formate according to preparation) preparation.M/z (ES ⁺) free alkali=472.33[M+H] ⁺RT=2.80min.M/z (ES ⁺) HCl salt=430.43[M+H] ⁺RT=2.72min.

Embodiment 193

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)- Benzyl-2-(3-(R)-hydroxyl pyrrolidine-1-yl)-2-oxoethyl] acid amides

According to embodiment 35, use 3-(R)-hydroxyl pyrrolidine to replace 3-(S)-hydroxyl pyrrolidine preparation.Obtain the target compound of pale powder shape by chromatographic grade methylene chloride (95: 5) wash-out purifying.m/z(ES ⁺)＝413.22[M+H] ⁺；RT＝3.13min。

Embodiment 194

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-oxo-2-(4-trifluoromethyl piperidines-1-yl) ethyl] acid amides

To 4-trifluoromethyl piperidines (17mg, 0.11mmol) middle 2-(S)-[(the 5-chloro-1H-pyrrolo-[2 that adds, 3-c] pyridine-2-carbonyl) amino]-(embodiment 228 for 3-(4-fluorophenyl) propionic acid, 40mg, 0.11mmol) DMF (400 μ L) solution, then add HATU (50mg, DMF 0.13mmol) (400 μ L) solution, add DIPEA (23 μ L, DMF 0.13mmol) (200 μ L) solution at last.The mixture of gained is stirred 96h under room temperature, then solvent removed in vacuo.The crystallization from the THF/ sherwood oil of this crude product is obtained the target compound of yellow powder shape.(ES ⁺)＝497.23[M+H] ⁺；RT＝3.50min。

Embodiment 195-225 is with the method preparation identical with embodiment 194.

Embodiment 226

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-oxo-2-piperazine-1-base ethyl] acid amides

According to embodiment 180 by 4-[2-(S)-[5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionyl] piperazine-1-t-butyl formate (according to embodiment 222 preparations) preparation.Purifying obtains yellow powder shape target compound.m/z(ES ⁺)＝430.34[M+H] ⁺；RT＝2.56min。

Embodiment 227

2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2- Carbonyl) amino]-3-(4-fluorophenyl) ethyl propionate

Use p-fluoro-L-phenylalanine ethyl ester hydrochloride to replace L-phenylalanine ethyl ester hydrochloride synthetic according to embodiment 41.Obtain the target compound of yellow powder shape through chromatogram purification.m/z(ES ⁺)＝390.27[M+H] ⁺；RT＝3.71min。

Embodiment 228

2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid

This target compound uses 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) ethyl propionate (embodiment 227) preparation according to embodiment 42.Solvent removed in vacuo also places water with resistates.It is 2 that water layer is acidified to pH with 2M HCl then with ethyl acetate (3 *) washing.Filtering-depositing and water thorough washing obtain cream-colored pulverous target compound.(ES ⁺)＝362.24[M+H] ⁺；RT＝3.21min。

Embodiment 229

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(1,4- Two oxa-s-8-azaspiro [4.5] last of the ten Heavenly stems-8-yl)-and 1-(S)-(4-luorobenzyl)-2-oxoethyl] acid amides

To 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid (embodiment 228,40mg, add in DMF 0.11mmol) (4mL) solution HATU (50mg, 0.13mmol) and stirring reaction liquid 10min.(19mg, 0.13mmol), (23 μ L 0.13mmol), and stir 16h with reaction solution under room temperature then to add DIPEA to add 4-piperidone condensed ethandiol.Solvent removed in vacuo is also distributed crude product between ethyl acetate (15mL) and water (15mL).Organic layer with 1M HCl solution (15mL), sodium hydrogen carbonate solution (2 * 20mL), use salt solution (2 * 20mL) washings, dry (MgSO then ₄) and solvent removed in vacuo.Obtain the target compound of yellow powder powder with methylene chloride (9: 1) wash-out through chromatogram purification.(ES ⁺)＝487.30[M+H] ⁺；RT＝3.28min。

Embodiment 230-237 is to prepare with embodiment 229 similar methods.

Embodiment 238

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(1,1- Dioxo-1,6-thiomorpholine-4-yl)-1-(S)-(4-luorobenzyl)-2-oxoethyl] acid amides

By 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid (embodiment 228) and thiomorpholine-1,1-dioxide (preparation 77) prepares according to embodiment 229.Grind purifying with methyl alcohol and obtain yellow powder powder target compound.(ES ⁺)＝479.24[M+H] ⁺；RT＝3.17min。

Embodiment 239

1-[2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2- Carbonyl) amino]-3-(4-fluorophenyl) propionyl] piperidines-4-methyl-formiate

Prepare by 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid (embodiment 228) and piperidines-4-methyl-formiate hydrochloride (preparation 78) according to embodiment 229.Obtain yellow powder powder target compound by chromatogram purification with ethyl acetate/petroleum ether (70: 30) wash-out.(ES ⁺)＝487.32[M+H] ⁺；RT＝3.44min。

Embodiment 240 prepares in the mode similar to embodiment 239.

m/z(ES ⁺)＝487.35[M+H] ⁺；RT＝3.88min。

Embodiment 241

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)- Benzyl-2-(4-hydroxy piperidine-1-yl)-2-oxoethyl] acid amides

This target compound uses 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-phenylpropionic acid (embodiment 42) and the preparation of 4-hydroxy piperidine according to embodiment 229.Obtain orange powder shape target compound through chromatogram purification with methylene chloride (9: 1) wash-out.m/z(ES ⁺)＝427.35[M+H] ⁺；RT＝2.99min。

Embodiment 242

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(2- Carbamyl phenylpiperidines-1-yl)-and 1-(S)-(4-luorobenzyl)-2-oxoethyl] acid amides

To (the preparation 80 of piperidines-2-benzoic acid amides hydrochloride, 24mg, 0.17mmol) DMF (3mL) solution in add 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid (embodiment 230,52mg, 0.14mmol), then add HATU (65.6mg, 0.17mmol) and DIPEA (63 μ L 0.36mmol), and stir 16h with this reaction solution under room temperature.Solvent removed in vacuo, obtain pale powder shape target compound through preparation HPLC purifying.m/z(ES ⁺)＝472.31[M+H] ⁺；RT＝3.19min。

Embodiment 243

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid 1-(S)- (4-luorobenzyl)-2-[4-(2-methoxy ethoxy) piperidines-1-yl]-the 2-oxoethyl } acid amides

This target compound is by 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid (embodiment 228) and 4-(2-methoxy ethoxy) piperidine hydrochlorate (preparation 82) preparation according to embodiment 229.Obtain pale powder shape target compound through chromatogram purification with methylene chloride (95: 5) wash-out.m/z(ES ⁺)＝503.26[M+H] ⁺；RT＝3.31min。

Embodiment 244

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid 1-(S)- (4-luorobenzyl)-2-[4-(3-methoxy propoxy) piperidines-1-yl]-the 2-oxoethyl } acid amides

This target compound is to use from the preparation of suitable starting raw material (preparation 81 and 82) synthetic 4-(3-methoxy propoxy) piperidine hydrochlorate according to embodiment 229.Obtain pale powder shape target compound through chromatogram purification with methylene chloride (9: 1) wash-out.m/z(ES ⁺)＝517.36[M+H] ⁺；RT＝3.41min。

Embodiment 245

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(4- Kharophen piperidines-1-yl)-and 1-(S)-(4-luorobenzyl)-2-oxoethyl } acid amides

To acetate (7.5 μ L, 0.13mmol) DMF (5mL) solution in add EDCl (33mg, 0.17mmol), HOBt (19.5mg, 0.14mmol), 5-chloro-1H-pyrrolo-[2,3-c] (embodiment 180 for ammonia for pyridine-2-formic acid [2-(4-amino piperidine-1-yl)-1-(S)-(4-luorobenzyl)-2-oxoethyl], 70mg, 0.16mmol) and DIPEA (57 μ L, 0.33mmol) and this reaction solution is stirred 16h under room temperature.Solvent removed in vacuo is distributed crude product then between ethyl acetate (15mL) and water (15mL).Organic layer is through NaHCO ₃(2 * 20mL) and salt solution (2 * 30mL) washings, dry (MgSO ₄) and solvent removed in vacuo.Obtain pale powder shape target compound through chromatogram purification with methylene chloride (95: 5) wash-out.m/z(ES ⁺)＝486.27[M+H] ⁺；RT＝3.16min。

Embodiment 246

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(4- Acetylamino methyl) piperidines-1-yl]-1-(S)-(4-luorobenzyl)-2-oxoethyl] acid amides

This target compound is from 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(4-amino methyl piperidines-1-yl)-1-(S)-(4-luorobenzyl)-2-oxoethyl] acid amides (embodiment 229 then 180, from the suitable piperidin-4-yl methyl carbamic acid tert-butyl ester) preparation.Obtain the white powder target compound through preparation HPLC purifying.m/z(ES ⁺)＝500.38[M+H] ⁺；RT＝3.14min。

Embodiment 247

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(R)-(4- Luorobenzyl)-and 2-(4-hydroxy piperidine-1-yl)-2-oxoethyl] acid amides

This target compound is by 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (preparation 18) and 2-(R)-amino-3-(4-fluorophenyl)-1-(4-hydroxy piperidine-1-yl) third-1-keto hydrochloride (preparation 84) preparation according to embodiment 1.Obtain yellow powder powder target compound with methylene chloride (92: 8) as elutriant through chromatogram purification.m/z(ES ⁺)＝445.34[M+H] ⁺；RT＝3.10min。

Embodiment 248

4-{[2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2- Carbonyl) amino]-3-(4-fluorophenyl) propionyl] methylamino } piperidines-1-t-butyl formate

This target compound is by 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid (embodiment 228) and 4-methylamino piperidines-1-t-butyl formate (preparation 86) preparation according to embodiment 229.Obtain yellow powder powder target compound with methylene chloride (95: 5) as elutriant through chromatogram purification.m/z(ES ⁺)＝558.48[M+H] ⁺；RT＝3.82min。

Embodiment 249

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(S)- (4-fluorophenyl)-1-(methyl piperidine-4-base formamyl) ethyl] acid amides

This target compound is by 4-{[2-(S)-[(5-chloro-1H-pyrrolo-[2 according to preparation 82; 3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionyl] methylamino } piperidines-1-t-butyl formate (embodiment 248) preparation, obtaining target compound is yellow crystal shape solid salt hydrochlorate.m/z(ES ⁺)＝458.30[M+H] ⁺；RT＝2.86min。This product is dissolved in the saturated sodium bicarbonate solution, and uses ethyl acetate extraction.It is the free alkali of yellow powder shape that vacuum is removed the target compound that organic solvent obtains.m/z(ES ⁺)＝458.33[M+H] ⁺；RT＝2.82min。

Embodiment 250

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid 2-(S)- (4-fluorophenyl)-1-[methyl (tetrahydropyran-4-base) formamyl] ethyl } acid amides

This target compound is by 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid (embodiment 228) and methyl (tetrahydropyran-4-base) amine hydrochlorate (preparation 88) preparation according to embodiment 229.m/z(ES ⁺)＝459.27[M+H] ⁺；RT＝3.41min。

Embodiment 251

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2- (4-dimethylamino piperidine-1-yl)-1-(S)-(4-luorobenzyl)-2-oxoethyl] acid amides

This target compound is by 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid (embodiment 228) and lupetidine-4-base amine (preparation 90) preparation according to embodiment 35.Obtain yellow crystal shape solid target product through preparation HPLC purifying.m/z(ES ⁺)＝472.34[M+H] ⁺；RT＝2.64min。

Embodiment 252

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-(4-methylsulfonyl amino piperidine-1-yl)-2-oxoethyl] acid amides

This target compound is by 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid (embodiment 228) and N-piperidin-4-yl Toluidrin hydrochloride (preparation 92) preparation according to embodiment 229.It is pale powder that purifying obtains target product.m/z(ES ⁺)＝522.30[M+H] ⁺；RT＝3.29min。

Embodiment 253

2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2- Carbonyl)-amino]-3-piperidin-4-yl methyl propionate

To 5-chloro-1H-pyrrolo-[2,3-c] (the preparation 18 of pyridine-2-formic acid, 185mg, 0.94mmol) DMF (7mL) solution in add 2-(S)-amino-3-pyridin-4-yl methyl propionate hydrochloride (preparation 93,204mg, 0.94mmol), then add TBTU (333mg, 1.04mmol) and DIPEA (740 μ L 4.24mmol), and stir 16h with this reaction solution under room temperature.Solvent removed in vacuo is also distributed resistates between ethyl acetate (30mL) and water (30mL).The organic layer water (2 * 30mL), NaHCO ₃Solution (3 * 40mL), use salt solution (3 * 50mL) washings, dry (MgSO then ₄) and solvent removed in vacuo.Through chromatogram (SiO ₂, EtOAc) purifying obtains pink powder shape target compound.m/z(ES ⁺)＝359.11[M+H] ⁺；RT＝2.42min。

Embodiment 254

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1- Formyl-dimethylamino-2-(S)-pyridin-4-yl-ethyl) acid amides

This target compound prepares from 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-pyridin-4-yl-propionic acid (embodiment 259) and dimethylamine hydrochloride according to embodiment 253.Obtain pale powder shape target compound through preparation HPLC purifying.m/z(ES ⁺)＝372.13[M+H] ⁺；RT＝2.31min。

Embodiment 255 prepares in the mode similar to embodiment 254.

m/z(ES ⁺)＝398.15[M+H] ⁺；RT＝2.53min。

Embodiment 256

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(1,4-two oxa-s- 7-azaspiro [4.5] last of the ten Heavenly stems-7-yl)-and 1-(S)-(4-luorobenzyl)-2-oxoethyl] acid amides

To 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-(embodiment 228, and 80mg adds DMTMM (78mg in ethanol 0.22mmol) (6mL) suspension liquid for 3-(4-fluorophenyl) propionic acid, 0.27mmol), and reaction solution stirred 5min.Add 1 in this mixture, (preparation 94,35mg 0.24mmol), and continue to stir 16h to 4-two oxa-s-7-azaspiro [4.5] decane.Solvent removed in vacuo is also distributed crude product between ethyl acetate and water.Organic layer NaHCO ₃(2 * 20mL) use salt solution (2 * 20mL) washings, dry (MgSO to solution then ₄) and solvent removed in vacuo.Obtain yellow powder powder target compound with methylene chloride (95: 5) as elutriant through chromatogram purification.m/z(ES ⁺)＝487.21[M+H] ⁺；RT＝3.50min。

Embodiment 257

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(3R, 4R)- Dihydroxy pyrrolidine-1-base-1-(S)-(4-luorobenzyl)-2-oxoethyl] acid amides

This target compound according to embodiment 229 use (3R, 4R)-dihydroxy pyrrolidine (according to the benzyl derivative preparation of preparation 23) preparation from buying.Obtain the colourless crystallization target compound from methanol crystallization again.m/z(ES ⁺)＝447.33[M+H] ⁺；RT＝2.99min。

Embodiment 258

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-(3-(S)-4-(S)- Dihydroxy pyrrolidine-1-yl)-and 1-(S)-(4-luorobenzyl)-2-oxoethyl] acid amides

This target compound uses 3-(S)-4-(S)-dihydroxy pyrrolidine (according to preparation 23 preparations) preparation according to embodiment 229.Obtain the colourless crystallization target compound from methanol crystallization again.m/z(ES ⁺)＝447.33[M+H] ⁺；RT＝3.07min。

Embodiment 259

2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-pyridin-4-yl-propionic acid

This target compound prepares from 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-pyridin-4-yl-methyl propionate (embodiment 253) according to embodiment 42.m/z(ES ⁺)＝345.09[M+H] ⁺。

Embodiment 260

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1-(S)-benzyl-2-oxo-2-phenylethyl) acid amides

To 5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [2-phenyl-1-(S)-(2-phenyl-[1,3] dioxolane-2-yl) ethyl] acid amides (preparation 96,47mg, add in acetone 0.105mmol) (20mL) solution aqueous hydrochloric acid (1mL, 1M).Stir 3 days final vacuums down except that desolvating in refluxing.Resistates is distributed between ethyl acetate (100mL) and saturated sodium carbonate solution (50mL).After the separation with organic layer with salt solution (50ml) washing, dry (MgSO ₄) and concentrate, (elutriant: hexane/ethyl acetate: 50/50) purifying obtains the colorless solid target compound to the resistates that obtains through fast silica gel chromatogram.m/z(ES ⁺)＝404.21[M+H] ⁺；RT＝3.58min。

Embodiment 261

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (2-hydroxyl-2-pyridin-3-yl-ethyl) acid amides

To 5-chloro-1H-pyrrolo-[2,3-c] (the preparation 18 of pyridine-2-formic acid, 296mg, 1.51mmol) and (preparation 98 of 2-amino-1-pyridin-3-yl ethanol, 214mg, add in DMF 1.55mmol) (10mL) solution HOBt (225mg, 1.47mmol), DIPEA (0.55mL, 3.16mmol) and EDCI (340mg, 1.77mmol).Under room temperature, stir the 12h final vacuum and remove and desolvate with THF (150mL) absorption of residual excess, and with diluted sodium hydroxide solution (1M, 50mL), (2 * 50mL) wash salt solution.With this solution drying (MgSO ₄), be concentrated into oily matter, (elutriant: DCM/ methyl alcohol: the 90/10+0.5% triethylamine) purifying obtains the target compound of pale solid shape to this oily matter through fast silica gel chromatogram.δ _H(d ₆DMSO)：3.53(2H，m)，4.85(1H，m)，5.75(1H，d)，7.15(1H，s)，7.37(1H，dd)，7.75(2H，m)，8.47(1H，m)，8.57(1H，s)，8.89(1H，appt)，12.24(1H，s)；m/z(ES ⁺)＝317.17[M+H] ⁺；RT＝2.71min。

Embodiment 262

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (2-(S)- Hydroxyl-1-(S)-methoxymethyl-2-phenylethyl) acid amides

To 5-chloro-1H-pyrrolo-[2,3-c] (the preparation 18 of pyridine-2-formic acid, 223mg, 1.13mmol) and (1S that can buy, 2S)-(+)-2-amino-3-methoxyl group-1-phenyl-1-propyl alcohol (200mg, add in DMF 1.10mmol) (5mL) solution HOBt (173mg, 1.13mmol), DIPEA (0.42mL, 2.41mmol) and EDCI (260mg, 1.36mmol).After stirring 12h under the room temperature, mixture is joined weak brine (100mL, water/salt solution: 1/1).With ethyl acetate (4 * 25mL) extractions, with the extraction liquid that merges with dilute hydrochloric acid (1M, 30ml), dilute sodium hydroxide aqueous solution (1M, 30ml) and salt solution (30mL) washing, then use dried over mgso, the resistates that obtains after concentrating is through fast silica gel chromatogram (elutriant: ethyl acetate) purifying.Obtain the colorless solid target compound.δ _H(CD ₃OD)：3.37(3H，s)，3.34(1H，dd)，3.66(1H，dd)，4.53(1H，ddd)，5.03(1H，d)，7.15(1H，s)，7.25-7.45(5H，3m)，7.68(1H，s)，8.58(1H，s)；m/z(ES ⁺)＝360.22[M+H] ⁺；RT＝3.12min。

Embodiment 263

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1-(S)-methylol-2-oxo-2-phenylethyl) acid amides

Under room temperature to 5-chloro-1H-pyrrolo-[2,3-c] (the preparation 101 of pyridine-2-formic acid [1-(S)-(tertiary butyl dimethylsilyl oxygen ylmethyl)-2-oxo-2-phenylethyl] acid amides, 220mg, 0.48mmol) THF (10mL) solution in add acetate (60 μ L) and tetrabutyl ammonium fluoride solution (1ml, the THF solution of 1M).After stirring 3h this reaction mixture is distributed between ethyl acetate (100mL) and water (30mL).Separate organic layer, use salt solution (50ml) washing, dry (MgSO then ₄) and the concentrated solid residue that obtains.Recrystallization obtains this target compound from THF.m/z(ES ⁺)＝344.21[M+H] ⁺；RT＝3.02min。

Embodiment 264:

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (1-(S)- Methoxymethyl-2-oxo-2-phenylethyl) acid amides

With 5-chloro-1H-pyrrolo-[2,3-c] (embodiment 262 for acid amides for pyridine-2-formic acid (2-(S)-hydroxyl-1-(S)-methoxymethyl-2-phenylethyl), 101mg, 0.281mmol) oxidation and use and prepare 101 similar modes and use Dess-Martin to cross iodine alkane (240mg, DCM 0.566mmol) (10mL) solution separating.Crude product recrystallization from methyl alcohol obtains target compound.m/z(ES ⁺)＝358.24[M+H] ⁺；RT＝3.18min。

Embodiment 265

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (2-oxo-2-pyridin-3-yl ethyl) acid amides

To racemic 5-chloro-1H-pyrrolo-[2,3-c] (embodiment 261 for acid amides for pyridine-2-formic acid (2-hydroxyl-2-pyridin-3-yl-ethyl), 80mg, add in anhydrous THF (20mL) solution 0.253mmol) Dess-Martin cross iodine alkane (307mg, 0.724mmol).After stirring 4h under the room temperature, add alkaline sodium thiosulfate solution (with 5.4g Na ₂SO ₃Be dissolved in the saturated NaHCO of 20mL ₃Solution), this emulsion of vigorous stirring 30min adds entry (～150mL) dilution then.With THF extraction (4 * 50mL), with saturated sodium bicarbonate (50mL) and salt solution (50mL) washing and combining extraction liquid, with the solution that obtains at dry (MgSO ₄) concentrate afterwards.(elutriant: DCM/ methyl alcohol: 90/10) the purifying resistates obtains the white solid target compound through fast silica gel chromatogram.m/z(ES ⁺)＝315.19[M+H] ⁺；RT＝2.65min。

Embodiment 266

6-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid (1- Formyl-dimethylamino-2-(S)-styroyl) acid amides

With DIPEA (155 μ L, 0.89mmol), HOBt (43mg, 0.28mmol) and 6-chloro-1H-pyrrolo-[2,3-b] (the preparation 110 of pyridine-2-formic acid, 50mg 0.25mmol) joins 2-(S)-amino-N of stirring, (the preparation 8 of N-dimethyl-3-Phenylpropionamide hydrochloride, 61mg is in DMF 0.27mmol) (4mL) solution.(63mg 0.33mmol) and with this reaction solution stirs 22h to add EDCI behind the 5min.Through column chromatography (SiO ₂, 95: 5CH ₂Cl ₂/ MeOH) purifying obtains target compound.m/z(ES ⁺)＝370.93[M+H] ⁺；RT＝3.62min。

Embodiment 267

6-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-(3-(S)-hydroxyl pyrrolidine-1-yl)-2-oxoethyl] acid amides

This target compound is according to embodiment 266 but use 2-(S)-amino-3-(4-fluorophenyl)-1-(3-(S)-hydroxyl pyrrolidine-1-yl)-third-1-keto hydrochloride (preparation 103) to replace 2-(S)-amino-N, N-dimethyl-3-Phenylpropionamide hydrochloride preparation.m/z(ES ⁺)＝430.94[M+H] ⁺；RT＝4.31min。

Embodiment 268

6-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-(4-hydroxy piperidine-1-yl)-2-oxoethyl] acid amides

This target compound is according to embodiment 266 but use 2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxy piperidine-1-yl)-third-1-keto hydrochloride (preparation 20) to replace 2-(S)-amino-N, N-dimethyl-3-Phenylpropionamide hydrochloride preparation.Through column chromatography (SiO ₂, 9: 1CH ₂Cl ₂/ MeOH) purifying obtains target compound.m/z(ES ⁺)＝444.91[M+H] ⁺；RT＝3.55min。

Embodiment 269

6-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-oxo-2-(5-oxo-[1,4] Diazesuberane-1-yl) ethyl] acid amides

This target compound according to embodiment 266 but be to use 1-[2-(S)-amino-3-(4-fluorophenyl) propionyl]-[1,4] Diazesuberane-5-keto hydrochloride (preparation 112) replaces 2-(S)-amino-N, N-dimethyl-3-Phenylpropionamide hydrochloride preparation.Through column chromatography (SiO ₂, 94: 6CH ₂Cl ₂/ MeOH) purifying obtains target compound.m/z(ES ⁺)＝457.91[M+H] ⁺；RT＝3.74min。

Embodiment 270

6-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid (2-oxo-2-styroyl) acid amides

To 6-chloro-1H-pyrrolo-[2,3-b] (the preparation 110 of pyridine-2-formic acid, 60mg, 0.31mmol) ethanol (5mL) solution in add 2-glycyl benzene hydrochloride (58mg, 0.34mmol), N-methylmorpholine (74 μ L, 0.67mmol) and DMTMM (198mg 0.67mmol), and stirs 16h with reaction solution under room temperature.Solvent removed in vacuo is also distributed the gained resistates between ethyl acetate (20mL) and water (20mL).With 1M HCl (20mL), water (20mL), NaHCO ₃Solution (2 * 20mL), use dry (MgSO after salt solution (20mL) the washing organic layer then ₄), and vacuum boils off solvent.Through column chromatography (SiO ₂, 2: 1Pet. ether/EtOAc is 97 then: 3CH ₂Cl ₂/ MeOH) purifying obtains target compound.

Embodiment 271

2-(S)-[(6-chloro-1H-pyrrolo-[2,3-b] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) ethyl propionate

To 6-chloro-1H pyrrolo-[2,3-b] (the preparation 110 of pyridine-2-formic acid, 450mg, 2.29mmol) DMF (20mL) solution in add 4-fluorophenylalanine carbethoxy hydrochloride (624mg, 2.52mmol), DIPEA (1.40mL, 8.01mmol) and HOBt (386mg, 2.52mmol) and stir this reaction solution.(570mg 2.98mmol) also continues to stir 16hr to add EDCI behind the 5min.Solvent removed in vacuo is also distributed crude product between ethyl acetate (75mL) and water (50mL).Organic layer NaHCO ₃Solution (3 * 50mL), use salt solution (2 * 50mL) washings, dry (MgSO then ₄) and solvent removed in vacuo obtain target compound.m/z(ES ⁺)＝389.90[M+H] ⁺；RT＝3.79min。

Embodiment 272

2-(S)-[(6-chloro-1H-pyrrolo-[2,3-b] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid

To 2-[(6-chloro-1H-pyrrolo-[2,3-b] pyridine-2-carbonyl) amino]-(embodiment 271, and 780mg adds 2M NaOH (2mL in methyl alcohol 2.0mmol) (15mL) solution for 3-(4-fluorophenyl) ethyl propionate, 4.0mmol), and with this reaction solution stirring 16hr.Solvent removed in vacuo and with in the thick resistates water-soluble (20mL).(2 * 20mL) washing waters are acidified to pH3 with 2M HCl then with ethyl acetate.With organic layer with ethyl acetate extraction (2 * 30mL), dry then (MgSO ₄), the vacuum concentration solvent obtains target compound afterwards.m/z(ES ⁺)＝361.88[M+H] ⁺。

Embodiment 273

6-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-oxo-2-tetramethyleneimine-1-base-ethyl] acid amides

To tetramethyleneimine (11.5mg, 0.14mmol) middle DIPEA (the 60 μ L that add, 0.35mmol) DMF (500 μ L) solution, then add 2-(S)-[(6-chloro-1H-pyrrolo-[2,3-b] pyridine-2-carbonyl) amino]-(embodiment 272,50mg, DMF 0.14mmol) (500 μ L) solution and HOBt (23mg for 3-(4-fluorophenyl) propionic acid, 0.15mmol) DMF (500 μ L) solution, and stir this mixture.Add EDCI (34.5mg, DMF 0.18mmol) (500 μ L) solution, and stirring reaction liquid 16hr behind the 5min.Solvent removed in vacuo obtains target compound with crude product through the purifying that quality instructs then.m/z(ES ⁺)＝414.93[M+H] ⁺；RT＝3.77min。

Embodiment 274-276 prepares in a like fashion.

Embodiment 277-280 prepares in a like fashion, but carries out purifying by grinding from methyl alcohol.

Embodiment 281

2-(S)-[(5-chloro-1H-pyrrolo-[2,3-b] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid tert-butyl ester

To 5-chloro-1H-pyrrolo-[2,3-b] (the preparation 57 of pyridine-2-formic acid, 500mg, 2.54mmol) DMF (20mL) solution in add 2 (S)-amino-3-(4-fluorophenyl) propionic acid tert-butyl ester hydrochloride (preparation 114,701mg, 2.54mmol), HOBt (344mg, 2.54mmol) and DIPEA (1.4mL, 7.88mmol).(634mg 3.31mmol), and stirs 72h with reaction mixture under room temperature to add EDCI behind the 5min.Solvent removed in vacuo also (is distributed solid in water (50mL) and ethyl acetate between 3 * 40mL).The organic phase that merges salt solution (20mL) washing, dry (MgSO ₄), vacuum concentration and through silica gel chromatography purifying methyl alcohol: methylene dichloride (1: 99) wash-out obtains target compound.δ _H(CD ₃OD)：1.42(9H，s)，3.09(1H，dd)，3.22(1H，dd)，4.76(1H，m)，6.98(2H，m)，7.07(1H，s)，7.27(2H，m)，8.06(1H，d)，8.28(1H，d)；m/z(ES ⁺)＝418[M+H] ⁺。

Embodiment 282

2-(S)-[(5-chloro-1H-pyrrolo-[2,3-b] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid

With trifluoroacetic acid (1.9mL, 24.3mmol) join 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-b] pyridine-2-carbonyl) amino]-(embodiment 281 for 3-(4-fluorophenyl) the propionic acid tert-butyl ester, 507mg, 1.21mmol) DMF (25mL) solution in, and this reaction mixture stirred 16h under room temperature.Add trifluoroacetic acid (2mL) again and this reaction solution is stirred 48h under room temperature.Solvent removed in vacuo also (is distributed solid at the hydrochloric acid (50mL) of 1N and ethyl acetate between 3 * 30mL).The organic moiety that merges salt solution (20mL) washing, dry (MgSO ₄), vacuum concentration obtains target compound.δ _H(CD ₃OD)：3.11(1H，dd)，3.33(1H，dd)，4.88(1H，m)，6.97(2H，m)，7.06(1H，s)，7.28(2H，m)，8.08(1H，d)，8.29(1H，d)；m/z(ES ⁺)＝362[M+H] ⁺；RT＝3.67min。

Embodiment 283

5-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-(3-hydroxyl-tetramethyleneimine-1-yl)-2-oxo-ethyl]-acid amides

To 5-chloro-1H-pyrrolo-[2,3-b] (the preparation 57 of pyridine-2-formic acid, 34mg, 0.17mmol) DMF (5mL) solution in add 2-(S)-amino-3-(4-fluorophenyl)-1-(3-(S)-hydroxyl pyrrolidine-1-yl) third-1-keto hydrochloride (preparation 103,50mg, 0.17mmol), HOBt (23mg, 0.17mmol) and DIPEA (94 μ L, 0.54mmol).Add behind the 5min EDCI (43mg, 0.23mmol), and under room temperature stirring reaction liquid 16h.Solvent removed in vacuo also (is distributed resistates in water (25mL) and ethyl acetate between 3 * 20mL).The organic layer that merges with the 2N sodium hydroxide solution (2 * 10mL), salt solution (10mL) washing, dry (MgSO ₄), vacuum concentration.Through silica gel chromatography purifying methyl alcohol: methylene dichloride (7: 93) wash-out obtains target compound.m/z(ES ⁺)＝431[M+H] ⁺；RT＝3.49min。

Embodiment 284

5-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid (2-oxo-2-styroyl] acid amides

With 5-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid (preparation 57,50mg, 0.25mmol), 2-glycyl benzene hydrochloride (48mg, 0.28mmol) and DMTMM (85mg, 0.31mmol) be dissolved in THF (5mL) and 4-methylmorpholine (31 μ L, 0.28mmol) in.This reaction mixture is stirred 16h under room temperature.Solvent removed in vacuo also (is distributed resistates at water (20mL) and EtOAc between 3 * 20mL).With the organic layer drying (MgSO that merges ₄), vacuum concentration and through silica gel chromatography purifying methyl alcohol: methylene dichloride (1: 19) wash-out obtains target compound.m/z(ES ⁺)＝314[M+H] ⁺；RT＝3.47min。

Embodiment 285

5-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid [2-(S)- (4-fluorophenyl)-1-(methoxymethyl formamyl) ethyl] acid amides

With 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-b] pyridine-2-carbonyl) amino]-(embodiment 282,300mg for 3-(4-fluorophenyl) propionic acid, 0.08mmol) and N, the O-dimethyl hydroxylamine hydrochloride (8mg, 0.08mmol) be dissolved in THF (5mL) and 4-methylmorpholine (9 μ L, 0.08mmol) in.(28mg 0.10mmol), and stirs 16h with reaction mixture under room temperature to wherein adding DMTMM.Solvent removed in vacuo also (is distributed resistates at water (30mL) and EtOAc between 3 * 30mL).With the organic layer that merges with the 2N aqueous sodium hydroxide solution (2 * 20ml), salt solution (20ml) washing, dry (MgSO ₄) and vacuum concentration.With thick resistates through silica gel chromatography purifying methyl alcohol: methylene dichloride (1: 24) wash-out obtains target compound.m/z(ES ⁺)＝405[M+H] ⁺；RT＝3.69min。

Embodiment 286

5-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-(3-hydroxyl-tetramethyleneimine-1-yl)-2-oxo-ethyl] acid amides

To 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-b] pyridine-2-carbonyl) amino]-(embodiment 286 for 3-(4-fluorophenyl) propionic acid, 30mg, 0.08mmol) DMF (3mL) solution in add (R)-(+)-3-hydroxyl pyrrolidine (7.2mg, 0.08mmol), HOBt (11.2mg, 0.08mmol) and DIPEA (30.3 μ L, 0.11mmol).(20.7mg 0.11mmol), and stirs 16h with reaction solution under room temperature to add EDCI behind the 5min.Solvent removed in vacuo also (is distributed resistates in water (20mL) and ethyl acetate between 3 * 20mL).The organic moiety that merges 2N sodium hydroxide solution (20mL), salt solution (20mL) washing, dry (MgSO ₄), vacuum concentration.Crude product grinds from methyl alcohol and obtains target compound.m/z(ES ⁺)＝431[M+H] ⁺；RT＝3.44min。

Embodiment 287-294:

Following compounds according to the method for embodiment 286 from 2-(S)-[(5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(4-fluorophenyl) propionic acid (embodiment 282) and suitable amine preparation, but all compounds carry out purifying by the purifying that quality instructs.

Embodiment 295

6-chloro-1H-pyrrolo-[3,2-c] pyridine-2-formic acid (1- Formyl-dimethylamino-2-(S)-styroyl) acid amides

To 6-chloro-1H-pyrrolo-[3,2-c] (the preparation 116 of pyridine-2-formic acid, 47mg, 0.24mmol) DMF (5mL, anhydrous) solution in add 2-(S)-amino-N successively, N-dimethyl-3-Phenylpropionamide hydrochloride (preparation 8,56mg, 0.25mmol), DIPEA (131 μ L, 0.75mmol) and HOBt (40mg, 0.26mmol).With solution stirring 5min, and disposable then adding EDCI (55mg, 0.29mmol).The solution of gained is stirred 12h under room temperature.Reaction mixture is distributed between ethyl acetate (50mL) and water/salt solution (150mL, 1: 1).Separate behind each layer with water with ethyl acetate extraction (3 * 50mL), then with the organic layer that merges with rare HCl solution (1M, 50mL), dilute NaOH solution (1M, 50mL) and salt solution (50mL) wash.With organic phase drying (MgSO ₄), filter and vacuum concentration.Obtain target compound through the flash column chromatography purifying with toluene/acetone (3: 1) wash-out.δ _H(CDCl ₃)：2.88，3.05(6H，2s)，3.18，3.28(2H，2dd)，5.41(2H，m)，7.02(1H，s)，7.28-7.34(6H，m)，8.17(1H，d)，8.68(1H，s)，10.58(1H，br?s)；m/z(ES ⁺)＝371.13[M+H] ⁺；RT＝3.28min。

Embodiment 296

6-chloro-1H-pyrrolo-[3,2-c] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-(4-hydroxy piperidine-1-yl)-2-oxoethyl] acid amides

This target compound is described from 6-chloro-1H-pyrrolo-[3,2-c] pyridine-2-formic acid (preparation 116) and 2-(S)-amino-3-(4-fluorophenyl)-1-(4-hydroxy piperidine-1-yl) third-1-keto hydrochloride (preparation 20) preparation according to embodiment 295.This product obtains target compound through the silica gel chromatography purifying with ethanol/methylene (1: 19) wash-out.δ _H(CD ₃OD)：1.16-1.88(4H，3m)，3.04-3.19(4H，m)，3.69-4.16(3H，2m)，5.31(1H，m)，7.00(2H，m)，7.29(3H，m)，7.42(1H，s)，8.67(1H，s)；m/z(ES ⁺)＝444.89[M+H] ⁺；RT＝3.27min。

Embodiment 297

6-chloro-1H-pyrrolo-[3,2-c] pyridine-2-formic acid [1-(S)- (4-luorobenzyl)-2-(3-(S)-hydroxyl pyrrolidine-1-yl)-2-oxoethyl] acid amides

This target compound is described from 6-chloro-1H-pyrrolo-[3,2-c] pyridine-2-formic acid (preparation 116) and 2-(S)-amino-3-(4-fluorophenyl)-1-(3-(S)-hydroxyl pyrrolidine-1-yl) third-1-keto hydrochloride (preparation 103) preparation according to embodiment 295.Crude product obtains target compound from re-crystallizing in ethyl acetate.δ _H(CD ₃OD)：1.77-1.98(2H，m)，3.08-3.88(6H，6m)，4.30，4.42(1H，2m)，5.07，5.09(1H，2m)，7.00(2H，m)，7.30(3H，m)，7.43(1H，m)，8.67(1H，s)；m/z(ES ⁺)＝430.90[M+H] ⁺；RT＝3.29min。

Embodiment 298

5-cyano group-1H-pyrrolo-[2,3-c] pyridine-2-formic acid (2-oxo-2-styroyl) acid amides

Under argon gas to 5-cyano group-1H-pyrrolo-[2,3-c] (the preparation 62 of pyridine-2-formic acid, 0.035g, 0.19mmol) THF (15mL) solution in add 2-glycyl benzene hydrochloride (0.036g, 0.21mmol), N-methylmorpholine (25 μ M, 0.23mmol) and DMTMM (0.072g, 0.27mmol).This reaction mixture stirs 16h under room temperature.Be concentrated into this reaction mixture dried under the vacuum.Resistates is distributed between ethyl acetate (100mL) and water (50mL).Separate organic phase and water is further used ethyl acetate (100mL) extraction.The organic extract liquid that merges 1N NaOH (40mL), saturated sodium-chloride (40mL) washing, dry (MgSO ₄), filter and vacuum concentration.Crude product obtains target compound through chromatographic grade hexane/ethyl acetate (1: 2) purifying and from recrystallizing methanol.m/z(ES ⁺)＝304[M+H] ⁺；RT＝4.37。

Embodiment 299

2-[(5-cyano group-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3 (S)-(4-fluorophenyl) ethyl propionate

To 2-amino-3-(S)-(4-fluorophenyl) ethyl propionate hydrochloride (0.530g, 2.14mmol) DMF (15mL) solution in add DIPEA (1.3mL, 7.49mmol), HOBt (0.290g, 2.14mmol), 5-cyano group-1H-pyrrolo-[2,3-c] (the preparation 62 of pyridine-2-formic acid, 0.400g, 2.14mmol) and EDCI (0.492g, 2.57mmol).This reaction mixture is stirred 16h under room temperature.Under the vacuum this reaction mixture is concentrated, and resistates is distributed between water (150mL) and ethyl acetate (200mL).Separate organic phase and water is further used ethyl acetate (200mL) extraction.With the saturated NaHCO of organic extract liquid that merges ₃(75mL), saturated sodium-chloride (100mL) washing, dry (MgSO ₄), filter and vacuum concentration obtains target compound.m/z(ES ⁺)＝381[M+H] ⁺；RT＝4.79min。

Embodiment 300

2-[(5-cyano group-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3 (S)-(4-fluorophenyl) propionic acid

To 2-[(5-cyano group-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3 (S)-(embodiment 299 for (4-fluorophenyl) ethyl propionate, 0.800g (4.2mL 4.2mmol) and under room temperature stirs 16h to add 1N NaOH in methanol 2.1mmol) (2: the 1) solution.With reaction mixture concentrated methyl alcohol of removing under vacuum.Water (150mL) is joined in the resistates also with ethyl acetate (2 * 75ml) washings.Water is cooled off in ice bath and be acidified to pH4 with 2N HCl.Precipitation that separation generates and water and ether washing obtain target compound.m/z(ES ⁺)＝353[M+H] ⁺；RT＝3.27min。

Embodiment 301

5-cyano group-1H-pyrrolo-[2,3-c] pyridine-2-formic acid [1- Formyl-dimethylamino-2-(S)-(4-fluorophenyl) ethyl] acid amides

To N dimethylamine hydrochloride (0.006g, 0.07mmol) DMF (6mL) solution in add DIPEA (37 μ L, 0.21mmol), HOBt (0.009g, 0.07mmol), 2-[(5-cyano group-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(S)-(embodiment 300 for (4-fluorophenyl) propionic acid, 0.025g, 0.07mmol) and EDCI (0.016g, 0.084mmol).This reaction mixture is stirred 16h and vacuum concentration under room temperature, resistates is distributed between water (50mL) and ethyl acetate (100mL).Separate organic phase and water is further used ethyl acetate (100mL) extraction.The saturated NaHCO of organic extract liquid that merges ₃(50mL), saturated sodium-chloride (75mL) washing, dry (MgSO ₄), filter and vacuum concentration obtains target compound.m/z(ES ⁺)＝380；RT＝3.45。

Embodiment 302-307:

Following compounds according to the method for embodiment 301 by 2-[(5-cyano group-1H-pyrrolo-[2,3-c] pyridine-2-carbonyl) amino]-3-(S)-(4-fluorophenyl) propionic acid (embodiment 300) and suitable amine preparation.

External GP activity

Material

Alpha-D-glucose-1-phosphoric acid salt (disodium salt), glycogen, D-glucose, Victoria Green WPB hydrochloride, Ammonium Molybdate Tetrahydrate, BSA, HEPES and rabbit muscle Starch phosphorylase (P1261) are bought from Sigma.Other all reagent are analytical pure.

Method

External glycogen phosphorylase analysis:

Glycogen phosphorylase is active oppositely to be analyzed based on Engers etc., Can.J.Biochem., 1970,48,746-754] described method carries out.Rabbit muscle glycogen phosphorylase α (Sigma) is reconstructed into the concentration of 100 μ g/mL in 25mMTris/HCl.The final volume that contains 50mMHepes pH7.2,7.5mM glucose, 0.5mM Cori ester salt and 1mg/mL glycogen that is determined on 96 orifice plates is the pH of 100 μ L.Behind 30 ℃ of following incubation 30min, by adding be used in ammonium molybdate, the 15mL0.045% Victoria Green WPB of 5mL 4.2% among the 4NHC1,150 μ L Victoria Green WPBs/molybdate of 50 μ L polysorbas20s preparation is measured the inorganic phosphate that discharges from Cori ester salt.Behind incubation 30min under the room temperature, measure light absorption ratio at the 620nm place.The DMSO solution of the compound (100 μ M to 0.004 μ M) of 10 μ L serial dilutions is added in each bipartite reaction, and in the reaction that does not suppress in contrast, add isocyatic DMSO, thereby measure IC ₅₀Pass through then to suppress % log ₁₀The compound concentration mapping obtains dose response curve.IC ₅₀Be defined as the compound concentrations when under described analysis condition, obtaining 50% inhibiting rate.

IC among each embodiment ₅₀＜1mM.As, embodiment 1-20,22,27 and the measured IC of 30-48 ₅₀Value proves effectively in 62.8-0.07 μ M scope.Embodiment 21,23-26,28 and 29 IC that obtain ₅₀Be 100 μ M or higher.The IC that records ₅₀Favourable during less than 100 μ M.IC ₅₀More favourable less than 50 μ M.IC ₅₀More favourable less than 5 μ M.And IC ₅₀More favourable less than 0.5 μ M.

Claims (31)

1, the compound of general formula (I) or its steric isomer or the acceptable salt of pharmacology:

Wherein:

X ₁, X ₂, X ₃And X ₄One of be necessary for N and other be necessary for C;

R ¹And R ^{1 '}Independent separately is hydrogen, halogen, hydroxyl, cyano group, C _1-4Alkyl, C _1-4Alkoxyl group, fluoro methyl, difluoromethyl, trifluoromethyl, vinyl or ethynyl;

R ²Be hydrogen, C _1-4Alkyl, COOR ⁶, COR ⁶, C _1-4Alkoxy C _1-4Alkyl-, hydroxyl C _1-4Alkyl-, cycloalkyl, cycloalkyl C _1-4Alkyl-, aryl, aryl C _1-4Alkyl-, heteroaryl, heteroaryl C _1-4Alkyl-, wherein arbitrary aromatic ring or hetero-aromatic ring are randomly by 1-2 individual independently halogen, cyano group, C _1-4Alkyl, C _1-4Alkoxyl group ,-NR ¹³R ¹⁴,-SO ₂C _1-4Alkyl ,-SO ₂N R ¹³R ¹⁴, hydroxyl, fluoro methyl, difluoromethyl or trifluoromethyl substituent replace;

Y is direct key, C _1-2Alkyl or-CH (OH)-;

Z is CH ₂,-C (O)-,-O-, N, N (C _1-4Alkyl), N (C 〉 _3-6Cycloalkyl) or not exist; But when Y be-CH (OH)-time, Z or R ³Must be connected on the Y by the C-C key;

R ³For hydrogen ,-COOH ,-COOC _1-4Alkyl, C _1-4Alkoxyl group, C _1-4Alkyl, aryl C _1-4Alkylthio-, aryl ,-C _1-4Alkylaryl, heteroaryl ,-C _1-4Miscellaneous alkyl aryl, cycloalkyl ,-C _1-4Alkyl-cycloalkyl, heterocyclic radical or-C _1-4Alkyl heterocyclic, wherein ring can randomly be replaced by 1-3 following independent substituent arbitrarily: halogen, cyano group, C _1-4Alkyl, fluoro methyl, difluoromethyl, trifluoromethyl ,-NHC (O) O (C _1-4Alkyl) ,-C _1-4Alkyl NHC (O) O (C _1-4Alkyl), NR ⁷R ⁸,-C _1-4Alkyl NR ⁷R ⁸,-C (O) R ⁹, C _1-4Alkoxyl group, C _1-4Alkoxy C _1-4Alkyl-,-COOH ,-COOC _1-4Alkyl, NHC (O) R ⁹,-C _1-4Alkyl NHC (O) R ⁹, C (O) N (R ¹⁰) ₂,-C _1-4Alkyl C (O) N (R ¹⁰) ₂,-C _1-4Alkoxy C _1-4Alkoxyl group, hydroxyl, hydroxyl C _1-4Alkyl-,-NHSO ₂R ¹⁰,-SO ₂(C _1-4Alkyl) ,-SO ₂NR ¹¹R ¹², 5-to 6-unit heterocyclic radical, phenyl, phenyl C _1-2Alkoxyl group or phenyl C _1-2Alkyl, wherein phenyl is randomly by 1-2 individual independently halogen, cyano group, C _1-4Alkyl, C _1-4Alkoxyl group ,-NR ¹³R ¹⁴,-SO ₂C _1-4Alkyl ,-SO ₂N R ¹³R ¹⁴, hydroxyl, fluoro methyl, difluoromethyl or trifluoromethyl substituent replace, perhaps two keys on the heterocyclic ring carbon can randomly form oxygen base (=O) substituting group;

Perhaps R ³For-NR ⁴R ⁵Or-NR ⁴(C _1-4Alkyl R ⁵);

R ⁴Be hydrogen, C _1-3Alkyl ,-C _2-3Alkyl-NR ⁷R ⁸, randomly by hydroxyl, hydroxyl C _1-4Alkyl-replacement and the C that can randomly further be replaced by hydroxyl _3-6Cycloalkyl, C _1-2Alkoxy C _2-4Alkyl-or C _1-2Alkyl-S (O) _n-C _2-3Alkyl-;

N is 0,1 or 2;

R ⁵Be hydrogen, hydroxyl C _2-3Alkyl-, C _1-2Alkoxyl group, C _1-2Alkoxy C _1-4Alkyl-or aryl, heteroaryl or heterocyclic radical;

The R of heterocyclic nitrogen containing wherein ⁵Ring is encircling on the nitrogen randomly by C _1-4Alkyl, benzyl, benzoyl, C _1-4Alkyl-C (O)-,-SO ₂C _1-4Alkyl ,-SO ₂NR ¹³R ¹⁴, C _1-4Alkoxy carbonyl or aryl (C _1-4Alkoxyl group) the carbonyl list replaces; And if wherein do not comprise quaternised nitrogen, then R ⁵Ring is encircling on the carbon randomly by halogen, cyano group, C _1-4Alkyl-C (O)-, C _1-4Alkyl-SO ₂-, C _1-4Alkyl, C _1-4Alkoxyl group, hydroxyl ,-N R ¹³R ¹⁴, hydroxyl, hydroxyl C _1-4Alkyl-, carbamyl or C _1-4Alkylcarbamoyl group-list replaces; Perhaps two keys on the heterocyclic ring carbon can randomly form oxygen base (=O) substituting group;

R ⁶Be C _1-4Alkyl, aryl or heteroaryl;

R ⁷And R ⁸Independent separately is hydrogen, C _1-4Alkyl, C _3-6Cycloalkyl or CO (C _1-4Alkyl);

R ⁹Be C _1-4Alkyl or C _3-6Cycloalkyl;

R ¹⁰Be hydrogen, C _1-4Alkyl or C _3-6Cycloalkyl;

R ¹¹And R ¹²Independent separately is hydrogen, C _1-4Alkyl or the nitrogen that connects thereon with them form 4 to 6 yuan heterocycle;

R ¹³And R ¹⁴Be hydrogen or C _1-4Alkyl; And

Wherein do not exist-Y-Z-R ³Interconnective nitrogen-the oxygen of this three part, nitrogen-nitrogen or nitrogen-halogen bond;

Condition is that described compound is not 2R, 4S, 5S-6-cyclohexyl-5-(6 '-azaindole-2 '-Ji carbonylamino)-2-(2 '-methyl-propyl)-γ-Ji Neizhi.

2, compound as claimed in claim 1 or its steric isomer or the acceptable salt of pharmacology, wherein X ₃Be N.

3, compound as claimed in claim 1 or its steric isomer or the acceptable salt of pharmacology, wherein X ₁Be N.

4, compound as claimed in claim 1 or its steric isomer or the acceptable salt of pharmacology, wherein X ₂Be N.

5, compound as claimed in claim 1 or its steric isomer or the acceptable salt of pharmacology, wherein X ₄Be N.

6, compound as claimed in claim 1 or its steric isomer or the acceptable salt of pharmacology, wherein R ¹And R ^{1 '}Independent separately is halogen, cyano group or hydrogen.

7, compound as claimed in claim 6 or its steric isomer or the acceptable salt of pharmacology, wherein R ¹And R ^{1 '}One of another is 5-halogen or 5-cyano group for hydrogen.

8, compound as claimed in claim 1 or its steric isomer or the acceptable salt of pharmacology, wherein Y is direct key or C _1-2Alkyl.

9, compound as claimed in claim 1, wherein Z be-C (O)-.

10, as any one described compound or its steric isomer in the claim 1,2 or 6 to 9 or the acceptable salt of pharmacology, wherein:

X ₃Be N;

Y is direct key or C _1-2Alkyl; And

Z is-C (O)-.

11, as any one described compound or its steric isomer among the claim 1-9 or the acceptable salt of pharmacology, wherein Y is direct key.

12, as any one described compound or its steric isomer among the claim 1-9 or the acceptable salt of pharmacology, wherein R ²Be hydrogen, C _1-4Alkyl, aryl or aryl C _1-4Alkyl-, wherein this aromatic ring is randomly by 1-2 individual independently halogen, cyano group, C _1-4Alkyl, C _1-4Alkoxyl group ,-NR ¹³R ¹⁴,-SO ₂C _1-4Alkyl ,-SO ₂NR ¹³R ¹⁴, hydroxyl, fluoro methyl, difluoromethyl or trifluoromethyl substituent replace.

13, compound as claimed in claim 12 or its steric isomer or the acceptable salt of pharmacology, wherein R ²Be the benzyl that is randomly replaced by 1-2 halogenic substituent.

14, as any one described compound or its steric isomer among the claim 1-9 or the acceptable salt of pharmacology, wherein R ³For the heterocyclic radical that randomly replaced by the following independent substituent of 1-3 or-C _1-4Alkyl heterocyclic: halogen, cyano group, C _1-4Alkyl, fluoro methyl, difluoromethyl, trifluoromethyl, NHC (O) O (C _1-4Alkyl) ,-C _1-4Alkyl NHC (O) O (C _1-4Alkyl), NR ⁷R ⁸,-C _1-4Alkyl NR ⁷R ⁸,-C (O) R ⁹, C _1-4Alkoxyl group, C _1-4Alkoxy C _1-4Alkyl-,-COOH ,-COOC _1-4Alkyl, NHC (O) R ⁹,-C _1-4Alkyl NHC (O) R ⁹, C (O) N (R ¹⁰) ₂,-C _1-4Alkyl C (O) N (R ¹⁰) ₂,-C _1-4Alkoxy C _1-4Alkoxyl group, hydroxyl, hydroxyl C _1-4Alkyl-,-NHSO ₂R ¹⁰,-SO ₂(C _1-4Alkyl) ,-SO ₂NR ¹¹R ¹², 5-to 6-unit heterocycle, phenyl, phenyl C _1-2Alkoxyl group or phenyl C _1-2Alkyl substituent, wherein phenyl is randomly by 1-2 individual independently halogen, cyano group, C _1-4Alkyl, C _1-4Alkoxyl group ,-NR ¹³R ¹⁴,-SO ₂C _1-4Alkyl ,-SO ₂NR ¹³R ¹⁴, hydroxyl, fluoro methyl, difluoromethyl or trifluoromethyl substituent replace, the perhaps (=O) substituting group of two key option ground formation oxygen bases on the heterocyclic ring carbon; Perhaps R ³For-NR ⁴R ⁵,-NR ⁴(C _1-4Alkyl R ⁵).

15, compound as claimed in claim 14, wherein R ³For be connected to the randomly substituted nitrogen heterocyclic ring group on the Z, perhaps R by theheterocyclic nitrogen atom ³For-NR ⁴R ⁵,-NR ⁴(C _1-4Alkyl R ⁵).

16, compound as claimed in claim 15, wherein R ³Be the nitrogen heterocyclic ring group of substituted 4-8 unit randomly.

17, compound as claimed in claim 16 or its steric isomer or the acceptable salt of pharmacology, wherein R ³Be tetramethyleneimine-1-base or the piperidines-1-base that is randomly replaced by hydroxyl.

18, following compound or the acceptable salt of its pharmacology of being selected from as claimed in claim 1:

19, following compound or the acceptable salt of its pharmacology of being selected from as claimed in claim 1:

20, following compound or the acceptable salt of its pharmacology of being selected from as claimed in claim 1:

21, following compound or the acceptable salt of its pharmacology of being selected from as claimed in claim 1:

22, following compound or the acceptable salt of its pharmacology:

23, a kind of composition, it comprises as any one described compound or its steric isomer in the claim 1 to 22 or the acceptable salt of pharmacology, and the pharmacology acceptable carrier.

24, be used for the application of the medicine of preventative or therapeutic treatment hyperglycemia or diabetes in preparation as any one described compound or its steric isomer in the claim 1 to 22 or the acceptable salt of pharmacology.

25, as any one described compound or its steric isomer in the claim 1 to 22 or the acceptable salt of the pharmacology hyperglycemia before preparation is used for preventing to show diabetes or the application of the medicine of the patient's that weakens of glucose tolerance diabetes.

26, be used for the application of the medicine of preventative or therapeutic treatment hypercholesterolemia, hyperinsulinemia, hyperlipidemia, atherosclerosis or myocardial ischemia in preparation as any one described compound or its steric isomer in the claim 1 to 22 or the acceptable salt of pharmacology.

27, preparing as the application in the medicine of heart protective agent as any one described compound or its steric isomer in the claim 1 to 22 or the acceptable salt of pharmacology.

28, the method for the compound of a kind of preparation general formula as claimed in claim 1 (I): it comprises:

Make pyrrolopyridine-2-formic acid or its amine coupling protected or activatory derivative and general formula (III) of general formula (II); Perhaps

For Z wherein is C=O and R ³For-NR ⁴R ⁵,-NR ⁴(C _1-4Alkyl R ⁵) the compound of general formula (I), wherein Z does not exist and R ³For-CO ₂The carboxylic acid of the general formula of H (I) or its amine coupling protected or activatory derivative and general formula (IV); Perhaps

For R wherein ²For H, Y are that H, Z are-C (O) and R ³For-aryl or-compound of the general formula (III) of heteroaryl, generate the compound of general formula (XIX) with the compound of general formula (XX) or with compound coupling under the standard coupling condition of general formula (II), then in the presence of acid, remove ketal group; Perhaps

For Z wherein is C=O and R ³Be C _1-4The compound of the general formula of alkoxyl group (I) is with compound or its compound coupling protected or activatory derivative and general formula (XII) of general formula (II); Perhaps

E) do not exist and R for Z wherein ³For-CO ₂The compound of the general formula of H (I), making wherein, Z is C=O and R ³Be C _1-4The compound ester hydrolysis of the general formula of alkoxyl group (I).

29, be selected from one of any C in following compound or they _1-4Alkyl ester:

5-chloro-1H-pyrrolo-[3,2-b] pyridine-2-formic acid;

5-bromo-1H-pyrrolo-[3,2-b] pyridine-2-formic acid;

5-cyano group-1H-pyrrolo-[3,2-b] pyridine-2-formic acid;

1H-pyrrolo-[3,2-c] pyridine-2-formic acid;

6-chloro-1H-pyrrolo-[3,2-c] pyridine-2-formic acid;

6-cyano group-1H-pyrrolo-[3,2-c] pyridine-2-formic acid;

5-chloro-1H-pyrrolo-[2,3-c] pyridine-2-formic acid;

5-bromo-1H-pyrrolo-[2,3-c] pyridine-2-formic acid;

5-ethynyl-1H-pyrrolo-[2,3-c] pyridine-2-formic acid;

5-cyano group-1H-pyrrolo-[2,3-c] pyridine-2-formic acid;

5-methyl isophthalic acid H-pyrrolo-[2,3-c] pyridine-2-formic acid;

5-chloro-1H-pyrrolo-[2,3-b] pyridine-2-formic acid; And

6-cyano group-1H-pyrrolo-[2,3-b] pyridine-2-formic acid.

30, the compound of general formula (XIX):

R wherein ¹, R ^{1 '}, X ₁, X ₂, X ₃And X ₄As defined in claim 1 and R ³For-aryl or-heteroaryl.

31,4 (S)-(4-luorobenzyl) oxazolidine-2,5-diketone.