TWI299039B - Pyrrolindine compounds - Google Patents

Description

1299039 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD The present invention relates to a pharmaceutical composition, and more particularly to a method and a pharmaceutical composition suitable for inhibiting dipeptidase IV. 5 [Prior Art] Glucagon-like peptide (GLP-1) is a small intestinal hormone, which is produced by intestinal endocrine L-cell after digesting nutrients. GLP-1 inhibits the secretion of glycoside, and the stimulating 10 is dependent on the secretion of insulin from the membrane. Studies have shown that providing GLP-1 in patients with type 2 diabetes can significantly reduce blood glucose levels (Zander M, et al. Lancet 2002). However, regardless of endogenous or exogenously provided GLP-1, its lifespan is shortened by rapid degradation (Kieffer T.J., et al. 15 Endocrinology 136: 3585-3596, 1995; & Mentlein R, etal.

Eur. J. Biochem. 214: 829-839, 1993), and this degradation results from the catalysis of dipeptide > peptidase IV, DPP-IV), a prolyl peptidase. Recent clinical data show that inhibition of DPP-IV increases insulin secretion, lowers plasma glucose concentrations, and enhances the function of pancreatic β-2〇 cells (Pederson RA·, et al. Diabetes 47:1253-1258, 1998; and Ahren B, Et al Diabetes Care 25: 869-875, 2002), therefore, DPP-IV inhibitors as potential drugs for type 2 diabetes will have their potential. 1299039 Dipeptidyl peptidase VIII (DPP-VIII) is another amidoxime-based peptide, which has the highest homology with DPP-IV. Current studies have shown that among the effects of various DPP-IV, there is one Part is the activity derived from DPP-VIII (Rosenblum JS, et al. Current Opinion in 5 Chemical Biology, 7: 496-504, 2003). SUMMARY OF THE INVENTION The present inventors have discovered that a novel group of pyrrolopridinium compounds can inhibit DPP-IV, one of which is related to a compound of the formula:

In the above formula, R1 is hydrogen or cyano; each ",", ^, and to each are hydrogen, _, nitro, cyano, amine, hydrogen, alkyl, alkyl halide, alkoxy Alkyl, alkoxy, aralkyl, cyclic, heterocyclic, aryl or heteroaryl; m is 〇, 1, 2, 3, 4 or 5; each η and p are 〇, U2, 3, respectively Or 4; χ is CR R,NR,〇 or S; wherein Ra and Ra are respectively hydrogen, halogen, alkyl, or aryl; Y is NRb, 0, S or CRb (NRb'Rb,,); wherein Rb , Rb, and Rb are each hydrogen, alkyl or aryl; A is 〇

II RCN, S\ , /S\, RC|STS,

1299039 alkyl, cyclo, heterocyclyl, aryl, aralkyl or heteroaryl; and z is NR7R8, wherein each R7 and R8 are independently hydrogen, alkyl, alkoxyalkyl, haloalkyl, A cycloalkyl, heterocyclyl, aryl, aralkyl or heteroaryl group, or NR7R8 is a 3-8 membered ring having 1 or 2 heteroatoms, optionally halogen, 5 CN, N02,- ORe, alkyl, aryl, heteroaryl, alkyl halide, -ORe, -C(0)Rc, -SRC, _S(0)Rc, _S(0)2Rc, -NRCRC',_C(0)0Rc , -C(0)NRcRc,, -0C(0)Rc, -NRcC(0)Rc', -NRcC(0)0Rc or -NReC(0)NRe'Re'', or a selective ring One of a group, a heterocyclic group, an aryl group and a heteroaryl group is fused; wherein each of Re, Re' and Re'' is 10, hydrogen, a group or an aryl group. In the above structural formula, another group of compounds is characterized in that R1 is CN and X is CH2; in one of the compounds, each R5 and R6 may be hydrogen, Y may be CRb(NRb'Rb'') and Z may Is NR7R8 wherein R7 is hydrogen and R8 is alkyl, aralkyl, cyclo, heterocyclyl, aryl or heteroaryl, or NR7R8 15 is a 3-8 membered ring having 1 or 2 heteroatoms. In other compounds, each of R5 and R6 may be hydrogen, Y may be NH and Z may be NR7R8, wherein R7 is hydrogen or alkyl, and R8 is alkyl, aralkyl, cyclic, heterocyclic, An aryl or heteroaryl group, or NR7R8 is a 3-8 membered ring having 1 or 2 heteroatoms. The subgroup of the other compound is characterized in that Z is NR7R8, wherein R7 is hydrogen 20 or alkyl, and R8 is alkyl, aralkyl, cyclo, heterocyclyl, aryl or heteroaryl; among these compounds , Y can be CH(NH2) or NH. The subgroup of the other compound is characterized by Z being NR7R8 wherein NR7R8 is a 3-8 membered ring having 1 or 2 heteroatoms; in these compounds, Y can be CH(NH2) or NH. 1299039 The following structural formulas are examples of compounds:

Compound 1

OMe

OMe

Compound 10

CN

OMe

OMe

Compound 11 OMe

Compound 3

Compound 6 OMe

1299039

Compound 16 compound 17 compound 18

Compound 21 compound 23 compound 24 1299039

Compound 25

Compound 26

Compound 27

Compound 28

Compound 30

Compound 34 compound 35 compound 36 10 1299039

trN? H O CN

Compound 38

Compound 37

Compound 40 compound 41 compound 42

Compound 46 Compound 47 Compound 48 11 1299039 The term "aralkyl" means an alkyl group substituted by an aryl group. The term "ring group" refers to a saturated and partially unsaturated cyclic hydrocarbon chain containing 3 to 12 carbons. Examples of ring groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentene. Base, cyclohexyl, cyclohexenyl, cycloheptyl 5 and cyclooctyl. The term "heteroaryl" means a 5- to 8-membered monocyclic ring, an 8- to 12-membered bicyclic ring, or an 11- to 14-membered tricyclic ring containing one or more heteroatoms (such as N, hydrazine or S); heteroaryl examples Including pyridyl, furyl, imidazolyl, benzimidaz〇lyl, pyrimidinyl 10, thiophenyl or thienyl, quinine Quinolinyl, 吲哚yl, and thiazolyl. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group. The term "heterocyclyl" means a 5- to 8-membered monocyclic ring, an 8- to 12-membered bicyclic ring, or a 1 to 14-membered tricyclic ring containing one or more heteroatoms (such as N, 〇15 or S); Examples of bases include, but are not limited to, piperazinyl, pyrrolidinyl, dioxanan, morpholinyl, and tetrahydrofuranyl. The above alkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, aralkyl 2 decyl 'heteroalkyl" alkoxy and aryloxy groups include saturated and unsaturated groups; examples of substituents include Not limited to the element, hydroxyl, amine, cyano, nitro, mercapto 'alkoxycarbonyl, amido, carboxy, alkanesulfonyl , alkylcarbonyl, carbamate 13 1299039 (carbamido), carbamel, carboxyl, thioureido, thiocyanato, decylamine Sulfonamido, an alkyl group, an alkenyl group, an alkynyl group, an alkoxy group, an aryl group, a heteroaryl group, a cyclic group, a heterocyclic group; wherein an alkyl group, an alkene group, an alkynyl group, The oxy, aryl, heteroaryl, cyclo and heterocyclic groups are more optionally alkyl, aryl, heteroaryl, arginyl, hydroxy, amine, thiol, cyano or nitro Replace it. The above compounds include pharmaceutically acceptable salts thereof and applicable Lu precursors. Such salts can be formed between a negatively charged 10 subgroup (e.g., a carbonate group) of a pyrroline pyridine compound and a positively charged counter ion (e.g., sodium, potassium, calcium or magnesium ions). Similarly, a positively charged ionic group (e.g., an ammonium group) of a pyrroline pyridine compound can also form a salt with a negatively charged opposite ion (e.g., chlorine, bromine or iodide). Examples of prodrugs include esters and other pharmaceutically acceptable compounds, including those which provide the above pyrroline 15 pyridine compounds, depending on the mode of administration. The compound of the present invention can inhibit DPP-iv; therefore, another aspect of the compound of the present invention is to use the above pyrroline pyridine compound as an inhibitor of DPP-IV; a method for inhibiting DPP-IV, that is, to administer a receptor a method for obtaining an effective dose of a pyrroline pyridine compound; and a method for producing a DPP_IV inhibitor by using a pyrroline pyridine 20 compound; since the inhibition of DPP-IV can lower the blood glucose concentration and increase insulin secretion, the present invention The compound can also be used for the treatment of type 2 diabetes. Thus, another aspect of the compound of the present invention is the above-mentioned pyrroline pyridine compound as a method for treating a second type diabetes drug; a method for treating type 2 diabetes of 1299039 A method of administering an effective dose of π to a dose of a compound to a receptor; and a method of using a quinololidine compound to produce a medicament for treating a second type of diabetes. The compound of the present invention can be used to inhibit the diaplase vih (dpp-viii); another aspect of the compound of the present invention is the above-mentioned porphyrin pyridine compound as an inhibitor of DPP-VIII; a method for inhibiting Dpp-VIII , a method of administering an effective dose of a pyrroline pyridine compound to a receptor; and a method of producing a DPP-VIII-inhibiting agent using a pyrroline pyridine compound. The invention is also related to a composition comprising the above porphyrin pyridine compound, and a pharmaceutically acceptable carrier. Details of various embodiments of the invention are disclosed below. Other features, objects, and advantages of the invention will be apparent from the description and appended claims. [Embodiment] # The pyrrolopridinium compound of the present invention can be prepared by the following two methods. A method of preparing a compound is shown in Scheme i. In the present synthetic route, the compound is an amine-substituted dicarboxylic acid (I) 'where one of the amine group and the acid group is protected, and the compound is substituted with 2-substituted η bicin sedative hydrochloride ( 2-substituted pyrrolidine hydoixhloride salt) (II) - reacts to form an intermediate product - monoamide (III); and 2-substituted indolylate hydrochloride (Π)

15 1299039 can be prepared by methods known in the art; for example, the 2-substituted pyrroline pyridinium hydrochloride (II) can be prepared by reference to the description of Bi〇〇rg Med·Chem. Lett. 1996, 6, 1163, and the middle is removed. a protecting group on the acid group of the product to form a monoamine compound (IV), followed by bonding with an amine group to form a diamine compound (V), which can be formed after deprotection of the bisamine compound (ν) The desired amine substituted bisamine compound (VI). Flow chart 1

II

10 The second method for preparing a pyrroline pyridine compound is as shown in Scheme 2. In the present synthetic route, the compound is a slow acid (VII) which is substituted by a protective amine group which is bonded to an amine group (VIII) to form a guanamine compound (IX). The indoleamine compound (IX) is deprotected to form an amine compound (X), which is then reacted with 1-(2-bromo-ethenyl) 1299039 pyrrolopridinium compound (XI) to form the desired compound (XII). The 1-(2-bromo-ethinyl)pyrroline pyridine compound (XI) can be produced by a method known in the art; for example, it can be prepared as described in J. Med. Chem. 2003, 46, 2774. 1-(2-bromo-acetamidine)pyrrolidinium-2-indolecarbonitrile (IX). 5 Flowchart 2

XII XI The chemical used in the above synthetic route may include, for example, a solvent, a drug, a catalyst, and a protecting group and a deprotecting agent; the above method may further include an additional step before or after the specific step , Add or • 10 Remove the appropriate protecting group to synthesize the pyrroline pyridine compound. In addition, the synthesis of the desired compounds can be carried out in different synthetic steps. The synthetic chemical transformation and protecting group methodology (protection and deprotection) which can be used to synthesize pyrroline pyridine compounds is well known in the art. See: R. Larock, (9) hve Organic Transformations^ VCH Publishers (1989); TW 15 Greene and PGM Wuts5 Protective Groups in Organic Synthesis, 3rd Ed.5 John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., 17 1299039

Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent versions. Another method for synthesizing the present invention is to use a method known in the art. Please refer to the synthetic routes of the four main compounds shown in Schemes 3 to 6. Flow chart 3

In the above flow chart, the N-protected 2-amino-2-methyl-propane-sulfanoic 10 acid (l) is first Sulfuryl chloride is reacted and reacted with 2,3-dihydroisoindole to form sulfonyl amide (4), followed by deprotection. Amine compound (5); this amine compound is bonded to β-bromo amide (6) to form the desired compound (7) of the present invention. 15 Flowchart 4

18 1299039 CCNH \Λα + H2N^V0^^ o 3 8

9 6 10 Referring to Scheme 4, thionyl chloride is continuously and 2,3-f dihydroxyisoindole (3) and (2-amino-1,1 dimethyl-ethyl)-amino The benzyl formate (8) is reacted, and the product-protected amine compound 5 (not shown) is deprotected to form a free amine compound (9), which is further reacted with β-ammonium bromide. (6) Coupling to form a pyrroline pyridine compound (1〇), which is another compound of the present invention. Similarly, the other two compounds of the present invention, Compounds (14) and (), can be synthesized by a procedure similar to the above Schemes 3 and 4. 10 Flowchart 5

15 Flowchart 6 19 1299039

The chemicals used in the above synthetic routes are commercially available (eg, Compound 1)' or have been previously disclosed in synthetic methods (eg, Compounds 5 12 and 16); multiple steps in the synthetic pathway may The different sequences are carried out to synthesize the desired compound. The use of chemical transformation and protecting group theory (protection and deprotection) to synthesize pyrroline pyridine compounds is well known in the art. References to the following documents: R. Larock, Comprehensive Organic

Transformations, VCH Publishers (1989); TW Greene and 10 PGM Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser ^ and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed.5 Encyclopedia of Reagents /br Oga/n'c Do John Wiley and Sons (1995) and its follow-up 15 publications. The above prepared σ piroxime biting compound can be purified by column chromatography, high performance liquid chromatography or crystallization. The indole compound of the present invention may comprise a non-aromatic double bond and one or more asymmetric centers. Therefore, this compound can be a racemic acid salt, a single 20 1299039 mirror image isomer, an individual non-image isomer, a non-image mixture, and an isomer of the cis/trans- or E-/Z-double bond form. Form exists. All similar forms of isomers are taken into account. The scope of the present invention includes a method of inhibiting DPP_IV, which comprises administering 5 of the above-mentioned 0-bilelin sigma compound of the present invention in an amount effective to inhibit the body of DPIMV. The invention further comprises a method of treating a second type of diabetes which comprises administering to a subject in need thereof an effective amount of the above pyrroline pyridine 1 compound of the invention and a pharmaceutically acceptable carrier therefor. The term "treatment" refers to the application or supply of a composition comprising a pyridoxine 疋 compound to a type 2 diabetes, a second type of diabetes, or a predisposition to type 2 diabetes. The ontology, the possible cure, healing, alleviation, alleviation, change, healing, improvement, enhancement, or type 2 diabetes, the symptoms of type 2 diabetes, and the tendency to have type 2 diabetes affect 15 effect. "An effective dose" means that the dose of the pyrroline pyridine compound can have a therapeutic effect on the individual to be administered; as is known to those skilled in the art, the effective agent t Ϊ may also depend on the type of disease to be treated, the route of administration, the subject's The utilization rate is changed with the active substance used in combination with other treatments. Further, in the scope of the present invention, a method of inhibiting DPP-VIII is further included, which comprises administering an effective amount of the above pyrrolopridinium compound to a receptor which is required to inhibit DpP-VIII. The invention further comprises a pharmaceutical composition comprising at least one effective amount of the above η-pyrroline pyridine compound and a pharmaceutically acceptable carrier. For carrying out the method of the present invention, a composition comprising one or more of the above-mentioned t! ratio 21 1299039 lindane compounds can be administered intravenously, orally, nasally, orally or sublingually. "Intravenous administration" refers to subcutaneous abdominal cavity, intravenous injection, intramuscular injection, intra-articular injection, aortic injection, intra-liquid injection, intrathoracic injection, intraspinal injection, and the main part of the disease department. Intra-injection, or other suitable drug delivery techniques. The sterile injectable composition can be a solution or suspended in a non-toxic intravenous diluent or solvent such as hydrazine, 3-butanediol. Acceptable Lu load, or the solvent can be mannitol or water. In addition, solid oils are generally used in solvents or suspension media (for example, synthetic single or one-dimensional diglycerin). Fatty acids, such as Oleic Acid and its glycerol vinegar derivative, can be used as an injectable and acceptable pharmaceutical for natural medicine, such as withdrawal: oil or sesame oil, especially its polyoxyethylation. Type. These oil solutions or suspensions may contain long-chain alcohol diluents or dispersants, cytotoxic or similar dispersants. Other commonly used surfactants, such as 15 or SpanS or other similar emulsifiers, are used in the pharmaceutical industry for solid, liquid or other dosage forms that are acceptable for formulation purposes. The composition for oral administration is any orally acceptable dosage form comprising a capsule, a tablet, an emulsifier and a liquid suspension, a dispersing agent 20 and a solvent. In the case of tablets, the carrier generally used is lactose or corn, powder; a lubricant such as magnesium stearate is a basic additive. In the form of oral capsule administration, effective diluents include lactose and dried corn starch. When the liquid suspension or emulsifier is administered by π, the active substance may be suspended or dissolved in an oily interface in combination with an emulsifier or a suspending agent. If necessary, add 22 1299039 with a mild amount of sweetener, flavor or color. Nasal gasifying sprays or inhalant compositions can be prepared according to known pharmaceutical dosage form techniques. For example, the composition can be prepared in physiological saline using stupid alcohol or other suitable preservatives to enhance bioavailability, fluorocarbons or other known well-utilizable dissolvable dispersants. Compositions comprising one or more active pyrrolopridinium compounds can also be administered in the form of a suppository for rectal administration. The carrier must be "acceptable" in the pharmaceutical grade composition, i.e., it must be compatible with the active principal component of the composition (more preferably, it has the function of stabilizing the active primary component) and cannot be The receptor causes damage. One or more of the dissolutions 7 can be used as a pharmaceutical ingredient for delivering the active ingredient of the pyrroline pyridine compound, and other carriers include, for example, cerium oxide gum, magnesium stearate, cellulose, sodium laurate sulfate, and D&C Yellow #10. 15 The pyrrolopridinium compound of the present invention can be preliminarily tested for its activity of inhibition = ρΡ-ιν and DPP_VIII by in vitro inhibition analysis, and the compound having high activity after preliminary screening can be further tested by a living body. Analyze it; the effect of oral therapy type 1 diabetes. For example, a test compound can be administered to an animal having type 2 diabetes (e.g., in a mouse mode; 0 ψ ) ) and then evaluated for its therapeutic effect. Based on these results, the range of appropriate doses and route of administration can be assessed. The following specific examples are merely illustrative, and the remainder of the disclosure is limited by any means. The form, details, modifications, derogations, and modifications of the formulations of the present invention can be carried out by those skilled in the art without departing from the spirit of the invention. Will be cited in this article

All of the published documents are hereby incorporated by reference. Chemical Synthesis Example 1. Synthesis of 1-[2-amino-4(3,4-bis-l-nitro-isoindole-1-yl)-4-oxo-5-butyl]-pyrroline Pyridine-2-carbonitrile trifluoroacetic acid (Compound 1) Scheme 3 shows the synthetic route of Compound 1. (1) Preparation of 3-tert-butoxymethylamino-4-(2-cyano-indole 11-lin-l-yl)-4-oxo-butyric acid benzyl ester (C) • tert-Butoxycarbonyl (BOC)-L-glutamic acid 5-benzyl ester (A) (0.65 g, 10 2 mmol) and N-carbamic acid succinic acid succinimide (HOSu, 0.23 g, 2 mmol) 6 ml of di-methane/1,4-epoxyhexane (2/1) was cooled in an ice bath, followed by the addition of dicyclohexylcarbodimide (DCC, 0.45 g, 2.2 mmol) with stirring. The reaction mixture was stirred at room temperature for one hour. Then, 11 pirolin-2-meronitrile hydrochloride (B) (0.27 g, 2 mmol) was added to 15 and triethylamine (Et3N, 0.22 g). , 2.2mmol); after treatment at room temperature for 4 hours, remove DCC by filtration and wash with dioxane; combine the filtrate with the cleaning solution, and use 10% citric acid solution and saturated sodium bicarbonate solution Washed, dried over MgSO.sub.sub.sub.subsubsubsubsubsubsubsubsubsubsubsubsubsubsubsubsubsub (80%) 〇(2) Preparation of Nt-BOC protected 1-[2-amino-4-(3,4-bishydroxy-1 hydrogen-isoquinolin-2-yl)-4-oxy·butyl The compound (C) (0.40 g, 1 mmol) and 5% Pd/C (20 mg) were dissolved in ethyl acetate (6 mL) and decyl alcohol (250 μM, And stirred under a hydrogen atmosphere for 7 25 hours and filtered, and the filtrate was concentrated under vacuum to form a white solidified

24 1299039 Compound (D), this compound (D) can be used directly without further purification. Compound (D) and HOSu (0.12 g, 1 mmol) were dissolved in a solution of 3 ml of dichloromethane / 1,4-hexanehexane (2/1) and cooled in an ice bath. After stirring, DCC (0.23 g, 1.1 mmol) was added for 1 hour, then 1,2,3,4-tetrahydroisoquinoline (0.20 g, 1.5 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Next, DCC was removed by filtration and washed with dichloromethane; the filtrate was combined with the washing solution, washed with 10% citric acid solution and saturated sodium bicarbonate solution, dried over magnesium sulfate, and concentrated under vacuum. Purified by flash column chromatography (extracted with n-hexane/dichloromethane/ethyl acetate = 3/6/1) to give a foamy 10-[2-amine 4-(3,4-bishydroxy-1 hydrogen-isoquinolin-2-yl)-4-yloxy-butyl]-nonporphyrin pyridine-2-indene nitrile (85%). (3) Preparation of 1-[2-amino-4-(3,4-bishydroxy-1 hydrogen·isoquinolin-2-yl)-4-oxy-butanyl]-pyrroline pyridine-2- Indole trifluoroacetic acid - 1-[2-amino-4-(3,4-bishydroxy-1 hydrogen-isoquinoline 15 -2-yl)-4-oxy group protected by Ν-ί-BOC Butyl]-pyrroline pyridine-2-indenecarbonitrile (0.43 g, 1 mmol) was dissolved in EtOAc (EtOAc) A pale yellow semi-solid. MS (ES+) m/z. 327.1 (M+H)+? 349.1 (M+Na)+. 20 Flowchart 3

25 1299039

Example 2-18

C

OH C

D The preparation of each of the compounds 2-18 was carried out in a manner similar to that described in Example 1. Example 2 6-{4_[3-Amino-4-(2-disyl-based pi-Lolinine-1 -yl)-4-butyryl]-benzin-1-yl-nicotinyl nitrile group, (3) -dimethoxy-3,4-bishydroxy-1hydro-isoquinolin-2-yl)-4-butoxy]-2-cyano-oxime S)-indolopyridinium, trifluoroacetic acid ( Compound 3) MS (ES+) m/z. 387.1 (M+H)+, 409.1 (M+Na)+. Example 4: 15 1-[2-Amino- 4·(4·Benzene 曱 嘻-1 -yl)-4-oxy-butyl]-2-ranyl-($)- 26 1299039

10 15

20 σ piroxime bite, trifluoroacetic acid (compound 4) MS (ES+) m/z. 384.1 (M+H)+, 406.1 (M+Na)+. Example 5: l-{2-Amino- 4.·[1-(2-Hydroxyethyl)-6,7-dimethoxy-3,4-bishydroxy-1 hydrogen, iso-p-yl-2-yl]-4·butoxycarbonyl]-2 - cyanopyrene ϋ ϋ ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' ' The preparation process was carried out in a manner similar to that described in Example 1. 1_[2_Amino-4-(3,4-bishydroxy-1hydro-isoquinolin-2-yl)-4. Butoxyb%Halolinidine-2-carbonitrile trifluoroacetic acid (Compound 6 MS (ES+) m/z. 313.4 (M+H) + Example 7: l-[2-amino-4-(1-isopropyl-6,7-dimethoxy-3,4- Dihydroxy-1 hydrogen-isoquinolin-2-yl)-4-butoxyindolyl]-2-cyano-indenyl S)-per porphyrin pyridine, trifluoroacetic acid (compound 7) MS (ES+) m/ Z.429.5 (M+H)+, 451.5 (M+Na)+. Example 8: l-[2-amino-4-(1-phenylmethyl-6,7-dimethoxy-3, 4-bishydroxy-1 hydrogen-isoquinolin-2-yl)-4-butoxy]-2.cyano-indole S> porphyrin pyridine, trifluoroacetic acid (compound 8) MS (ES+) m/ Z.477.5 (M+H)+? 499.5 (M+Na)+. Example 9: l-[2-Amino-4-(1·t-butyl-6,7-dimethoxy-3 , 4_bishydroxy-1 hydrogen-isoquine 25 oxalin-2-yl)_4.butoxy]-2-cyano-(5>pyrrolidine,trifluoroacetic acid (compound 27 1299039 9) MS (ES+) m/z. 443.2 (M+H)+5 465.2 (M+Na)+. Example 10: 3-amino-4-(2-cyano-(aS)-11 pirolene-1. )_N-[2-(3,4-dioxalyl-phenyl)-ethyl]-4-oxetamine, trifluoroacetic acid (Compound 10) lR NMR (CD3OD) δ 2.09-2.31 (m, 4H5)5 2.69-2.88

(m,4H,), 3.29-3.43 (m, 2H,), 3.60-3.73 (m, 2H,), 3.78 (s, 3H, OCH3), 3·81 (s, 3H, OCH3), 4.47-4.52 (dd, = 7.7, 4.5 Hz, 1H,), 4.78-4.82 (dd, /= 7.8, 5.4 Hz, 1H, C//CN), 6.73-6.86 (m, 3H,); MS (ES+) m/ Z.375.4(M+H)+, 397.4 (M+Na)+· Example 11: Preparation of Compound 11 was carried out in a manner similar to that described in Example 1 15 1-P-Amino-4-(3) -hydroxymethyl-3,4-bishydroxy-1hydro-isoquinolin-2-yl)-4, gas <butane]Biharine bite-2-carbonitrile (Compound 11) MS (ES+) m /z.357.4 (M+H)+ Example 12:

3-aminobenzylmethyl_4_(2-cyano-(5>pyrrolidine-1-ylbutyl,trifluoroacetic acid (compound 12) 20 MS (ES+) m/z.301.4 (M+H) +, 323.4 (M+Na)+. Example 13: 3-amino-4-(2-lacyl-bilorinine-1 -yl)-4-oxo-stupylyl)butanyl; Fluoroacetic acid (Compound 13) MS (ES+) m/z. 329.2 (M+H) + 5 35 1.2 (M+Na)+. Example 14: 25 3-amino-4-(2·milyl-(夕)-11 piroxicam -1-1 _yl 1 -mercapto-1 笨 乂 乂 28 1299039 ))-4-butoxycarbonyl, trifluoroacetic acid (compound 14) ]H NMR (CD3OD) (3 To 1 mixture of trans/cis amide rotomers) (5 1.60 to 1.75 (m, 3H, CH3), 2.05 to 2.38 (m, 4H), 2.40 to 2.65 (m, 2H), 3.40 (m, 1/4H), 3.46~3.65 (m,lH), 5 3.65~3.78(m,3/4H), 3.96~4.05(m,lH).3.65~3.78(m, 3/4H),5.05 (d, / = 7.5,1.8 Hz, 1/4H), 7.08~7.40 (m, 5H, ArH); MS (ES+) m/z.329.2 (M+H)+, 351.2 (M+Na) + · Example 15: Preparation of Compound 15 The method was completed in a manner similar to that described in Example 1.

I 10 Example 16: 3-Amino-4-(2-ranyl-pylinyl-1-yl)_7V»(2·methyl-1-phenylpropyl)·4·butanyl, trifluoroacetic acid (Compound 16) MS (ES+) m/z. 343.2 (M+H) + 5 365.1 (M+Na)+. Example 17: 15 3-amino _4_(2· cyano-(5)-° Bilolin biting -1_yl)-(1_methoxymethyl-2-phenylethyl)-4-butenyl, trifluoroacetic acid (compound 17) lH NMR (CD3OD) 5 2.09-2.31 (m , 4H5)5 2.62-2.90 _ (m,4H,), 3.25-3.39 (m,5H, overlapped with single at 3.32, 0CH3 and others), 3.56-3.69 (m,2H,), 4.18-4.23 (m, 2H,), 2〇4.34-4.48 (dd5 J = 7.8, 5.4 Hz, 1H)5 4.78-4.82 (dd, J = 7.85 4·5 Hz, 1H, C//CN), 7.15-7, 29 (m , 5H,ArH)); MS (ES+) m/z. 349.1 (M+H)+, 381.1 (M+Na)+. Example 18: 3-amino-4. σ定-1-yl)_(2,2-dimethyl-1-phenyl-25-propyl)-4-butoxycarbonyl, trifluoroacetic acid (compound 18) MS (ES+) m/z.357.2 (M+H)+, 379.2 (M+Na)+. 29 1299039 Example 19: Synthesis of 1-{2-[3-(3,4·bis-l-hydrogen-isoindolene-2)- 3-oxy-propylamino]-acetamidine}-pyrroline pyridine-2-indole (compound) 19) Scheme 4 illustrates the synthetic steps of compound 19. 5 (1) Preparation of [3-(3,4-bishydroxy-1hydro-isoquinolin-2-yl)-3-oxy-propyl]-carbamic acid tert-butyl ester (G) BOC-β- Alanine (1.89 g, 10 mmol) and HOSu (1.15 g, 10 mmol) were dissolved in 20 mL of dichloromethane/1,4-epoxyhexane (2/1), placed in an ice bath, cooled, and stirred. DCC (2.3 g, 11 mmol), stirred at room temperature for 10 hours, and then added 1,2,3,4-tetrahydro-isoform (2.0 g, 15 mmol), and reacted at room temperature for 4 hours. The DCC was removed by filtration and washed with dichloromethane; the filtrate was combined with the washing solution, washed with 10% citric acid solution and saturated sodium hydrogencarbonate solution, dried over magnesium sulfate, and concentrated under vacuum. Purification by flash column chromatography (dichloromethane / ethyl acetate = 9 / 1) yielded a foamy compound (G) (88%). (2) Preparation of the title compound. The compound (G) (0.30 g, 1 mmol) was dissolved in EtOAc. The material was dissolved in dichloromethane and cooled in an ice bath. Et3N 20 (0.3 g, 3 mmol) was added to the solution, and a solution of the bromine-containing compound (I) in methylene chloride (O.llg, 〇. 5 mmol) was added dropwise, and the resulting mixture was stirred overnight at room temperature. . The mixture was diluted with methylene chloride and washed with EtOAc EtOAc EtOAc EtOAc. 4 extraction), yielding a pale yellow 30 1299039 color oily compound (19, 45%). 4 NMR (CD3OD) δ 2.16-2.28 (m,4H), 2.87 (t,1H, /=6.0 Hz), 2.94-2.98 (m,3H),3·41 (t,2H,j = 5.9 Hz), 3.46-3.51 (m, 2H), 3.63-3.68 (m, 1H), 3.73 (t, lh, 6·〇Hz), 5 3.81 (t, 1H, J = 6.0 Hz), 4.11·4·13 (m , 2H), 4.70 (d, 2H, = 9.9 Hz, ArC//2N), 4.81 (dd, 1H, 9.9 and 5.1 Hz, Ci/CN), 7.18-7.19 (m, 4H); HRMS (El) m /z calcd f〇r c19H24N4〇2 340.1899, found 340.1899.

Examples 20-48: Example 20 15 was prepared in a manner similar to that described in Example 18 for each compound 20-48. 1-[3_[2-[2-cyano-[ 1β-ethoxyethoxyamino]-1,oxypropyl]-4-[bis-(4-fluorophenyl)indolyl]piperazine (Compound 2〇) ^ 31 1299039 NMR (CDC13) 5; 2.62~ 2·18 (m,10H), 2.91 (m,2H), 3.20~3·80 (m,8H), 4.22 (s,1H),4·75 (br d,6·0Ηζ, 3/4H), 4.82 (br d, /= 6·3Ηζ, 1/4H), 6.95 (d,8·4Ηζ,2H),6·98 (d, J = 8.4Hz5 2H)5 7.31 (d5 J = 8.4Hz, 2H) , 7.34 (d5 J = 8.4 Hz 5 5 2H); MS (ES+) m/z. 496.3 (M+H)+. Example 21 1- [3-[2-cyano-(phantom/pyrroline pyridine)- 1-yl]-2-ethoxyamino]-1-oxypropyl]-4-[2-methoxyphenyl]piperazine (Compound 21) ^ MS (ES+) m/z. 400.2 ( M+H)+5 422.2 (M+Na)+. W10 Example 22 2- [3-[2-[2-Cyano-〇S)·吼- oxalin-1-yl]-2-ethoxy Amino]-1-oxypropyl]-1-(2-hydroxyethyl)-6,7-dimethoxy-1,2,3,4-bishydroxyisoquinoline (combination; 22 MS (ES+) m/z. 445.2 (M+H)+, 467.3 (M+Na) + _ '15 Example 23 2-[3-[2-[2 - 乱基·($) - ° ratio Lorraine biting -1-yl]-2-ethoxyethylamino]·1-oxypropyl]·6,7-dimethoxy-1,2,3,4-tetrahydroisoquineline (Compound 23) • lH NMR (CDC13) (9 to 1 mixture of trans/cis amide fotomers) δ 2.16-2.28 (m5 4H), 2.68 (t, 2H, /=6.0 Hz), 2.77 (t, 20 1H, /= 6.0 Hz) ), 2.83 (t, 1H5 7 = 6.0 Hz), 3.04 (t5 2H? J= 6.3

Hz), 3.41-3.62 (m, 4H, overlapped singlet at 3.51), 3.67 (t3 1H, /=6.0 Hz), 3.79-3.87 (m, 7H, overlapped singlet OC//3 at 3.87), 4.56 (s, 0.9H, ArCi/2N), 4.65 (s, 1·1Η, ArCi/2N), 4.73-4.74 (m, 0.9H, Ci/CN), 4·83 (d, 0·1Η, = 6.0 Hz, 25 Ci/CN), 6.60-6.63 (m, 2H); HRMS (El) m/z calcd for C21H28N404 400.2111, found 400.2112

32 1299039 Example 24 1-[3-[2-[2-Cyano-(5>)-° ratio 11 lin 11 -1-yl]-2-oxoethylamino]-1-oxo Propyl]-4-[3-phenylphenyl]piperazine (Compound 24) lH NMR (CDCI3) (4 to 1 mixture of trans/cis amide 5 rotomers) δ 2.05-2.33 (m, 4H), 2.61 ( t? 2H? J = 6.6 Hz)? 2.92-3.03 (m, 2H), 3.14 - 3.21 (m, 4H), 3.38-3.46 (m, 3H, overlapped singlet at 3.46), 3.55-3.65 (m5 3H), 3.77 (t5 2H, J = 5.4 Hz), 3.74 - 3.78 (m, 4/5H, Ci/CN), 4·83 (dd, 1/5H, J = 7.5 and 1.8 Hz, Ci/CN), 6.77- 6.89 (m, 3H), 7.19 (t, 1H, J = ^10 7.8 Hz); MS (ESI) m/z 404.2 (M+H)+. Example 25 l-[3-[2-[2- Cyano-hydrazine S)-nonyl-pyridin-1-yl]-2-oxyethylamino]-1-oxypropyl]-4-benzopyridazine (Compound 25) MS (ES+) m/z. 398.3 (M+H)+5 420.2 (M+Na)+. 15 Example 26 1-[3-[2-[2-carbyl-(*9)-11 pirole bite-1 -yloxy-2-aminoethylamino]-1-oxypropyl]-4-[3,5·dioxabenzhydrazide]piperazine (Compound 26) | !H NMR (CDCI3) δ 2.10 -2.20 (m, 2H), 2.21-2.30 (m, 2H), 2.60 (bs, 2H), 2.85-2.95 (bm, 2H), 3.36-3.55 (m, 3H), 20 3. 56-3.88 (m, 9H), 4.77-4.80 (m, 1H, CifCN), 6.88-6.96 (m, 3H); HRMS (El) m/z calcd for C21H25F2N503 433.1925, found 433.1922. Example 27 2·[ 3-[2_[2-cyano-indenyl)-indoloxalin-1-yl]-2-oxoethylamino]-1_oxy-25-propyl]-1,3-dihydroxyiso吲哚 (Compound 27). lU NMR (CDCI3) δ 2.05-2.31 (m5 4H)5 2.62-2.66 (m5 33 1299039 2H), 3.04-3.08 (m, 2H), 3.43-3.50 (m, 3H, overlapped singlet At 3.50, ArCi/2NCi/2, CifCN), 3.59-3.65 (m, 1H), 4.75-4.83 (m, 5H, two overlapped singlet at 4.79 and 4.83), 7.28-7.30 (m, 4H); HRMS (El m/z calcd for C18H22N402 326-1743, 5 found 326.1744. Example 28 1-[3-[2·[2-乱基-ϋ比洛琳σ定-1 _基]-2-ethoxyethyl Amino]-1 -oxypropyl]-4-[4-[1-oxyethylamino]phenylsulfonyl]piperazine (Compound 28) 10 !H NMR (CD3OD) δ 2.11-2.23 (m? 7H5 overlapped singlet -NHC(0)C//3 at 2.13), 2.57 (t, 2H, /= 6.6 Hz)5 2.88 (t5 2H, J = 6.6 Hz), 2.96 (bt5 2H, J = 4.8 Hz), 3.01 (bt? 2H, J = 4.8 Hz), 3.41-3.67 (m, 8H, overlapped doublet at 3.49 / = 6.0 Hz), 4.71 (t, 1H, / = 5.4 Hz), 7.69-7.73 (m, 2H), 15 7.79-7.83 (m, 2H); MS (ES+) m/z. 491.4 (M+H +, 513.3 (M+Na)+. Example 29 l-[3-[2-[2-Cyano-oxime S)·吼 啉 啉 -1-1-yl]-2-ethoxyethylamino ]-1-Oxygen> propyl] 4-[5-cyano-2-acridine]piperazine (Compound 29) 20 MS (ES+) m/z. 396.3 (M+H)+. Example 30 3_[2-(2-Alkyl-($)-n-Biro--------------------------------------- Compound 30) 1H NMR (CDCl3) 32.50~1.80 (m, 6H), 3.00~2.60 (m, 25 4H), 3.70~3·10 (m, 6H), 4.63 (br s, 2H), 7.25~6.88 (m , 5H), 7.58 (br s5 1H); MS (ES+) m/z. 341.1 (M+H)+.

34 1299039 Example 31 1-[3·[2-[2-Cyano-indoleS)-indolyl-1-yl]-2-oxoethylamino]-1-oxypropyl] -4·(3,5-Dimethoxy-benzimidyl)piperazine (Compound SUMS (ES+) m/z. 458.3 (M+H)+, 480.1 (M+Na)+· 5 Example 32 L-{2-[3-(3,4-Dihydroxy-1hydro-isoquinolin-2-yl)-1-(1hydro-indol-3-ylmethyl)-3-oxy-propyl胺 ] 醯 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- 2- ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( 10 Example 33 2-[3-[2-[2-Cyanoindolopyridin-1-yl]-2-oxoethylamino]-4-methyl-1-oxypentyl] -1,2,3,4-tetrahydroxyisoquinoline (Compound 33) lU NMR (CDC13) δ 0.93-0.99 (m, 5H)? 1.90-2.00 (m5 1H), 2.01-2.27 (m, 4H), 2.40-2.52 (m, 2H), 2.86-3.07 (m, 3H, 15 three overlapped multiplets), 3.25-3.89 (m5 6H)5 4.49-4.86 (m, 3H), 7.14-7.18 (m, 4H); HRMS (El) m/z calcd for C22H30N4O2 382.2369, found 382.2369. > Example 34 The procedure for the preparation of compound 34 is similar to that described in Example 18. 20 1-{2-[3-(3-benzamide- Imidazolin-1-yl)·3-oxy-propylamino]-醯-}-pyrroline pyridine-2-carbonitrile (Compound 34) MS (ES+) m/z. 384.4 (M+H)+ Example 35 benzyl-3-[2-(2-cyano-indole) S)-Indolylpyridin-1-yl)-2-oxoethylamine 25-yl]-propanamide (Compound 35) 35 1299039 lU NMR (CDCI3) (4 to 1 mixture of trans/cis amide rotomers) δ 2.05-2.32 (m, 4H), 2.45 (t, 2H, J= 6.0 Hz)? 2.95 (t, 2H, "/= 6.0 Hz), 3.31-3.57 (m, 4H, overlapped doublet at 3.38, 3.3 Hz ), 4.45 (d, 2H, 5.7 Hz), 4.64 (dd, 1/5H, J = 5 7.5 and 1.5 Hz, C//CN), 4.70-4.73 (m, 4/5H, C//CN), 7.22-7.36 (m,5H), 7.56 (br s, 1/5H, ArCH2N/〇, 7.74 (bs, 4/5H, ArCH2Ni/); HRMS (El) m/z calcd for C17H22N402 314.1743, found 314.1741. Example 36 ® 10 , Benzyl-3-[2-(2-cyano-indole S> oxalyl-1-yl)-2-oxoethylamino]-TV-methylpropanamide (Compound 36) MS (ES+) m/z. 329.1 (M+H) +. Example 37 " 1-[3-[2-[2.Cyano-indole-S)-- ]-2-oxyethylamino] -15 -1 -oxypropyl]-4-[benzothiazol-2-yl]piperazine (Compound 37) !H NMR (CDCI3) δ 2.09-2.36 ( M5 4H), 2.62 (t 2H, J = 6·3 Hz), 2·97·3·04 (m, 2H), 3.37-3.52 (m, 3H, overlapped win singlet at 3.47), 3.53-3.81 (m, 9H), 4.74 4.78 (m,1H), 7.09-7.14 (m,1H), 7.29-7.35 (m,1H),7.56-7.64 (m,2H); 20 HRMS (El) m/z calcd for C21H26N602S 426.1838,found 426.1841. Example 38 3-[>(2-Cyano-indole S> oxopiperidinium-fluorenyl)-2-oxoethylamino]-7V-[2-(4-nitrophenyl) Ethyl]propanamide (Compound 38) 25 lU NMR (CDCI3) 52.55^1.85 (m5 6H), 2.83 (m5 2H)? 2.97 (m5 2H), 3.75~3.10 (m, 6H), 4.65 (d, 7.6 Hz, 1/4H), 4.72 (m, 36 1299039 3/4 H), 7.39 (d, ·== 8.4 Hz, 2H), 7·86 (m, 1Η), 8·12 (d, J = 8.1 Hz, 2H); MS (ES+) m/z. 374.2 (M+H)+. Example 39 3-[2-(2-cyanoindolinoxadin-1-yl)-2-oxyethyl Amino]-(4-nitro-5-benzylmethyl)propanamide (4 chelate 39) ]H NMR (CDC13) (4 to 1 mixture of trans/cis amide rotomers) δ 2.05-2.35 (m, 4H), 2.50 (t, 2H, ·/= 6.0 Hz), 3.00 (t, 2H? J = 6.0 Hz), 3.30-3.70 (m5 4H, overlapped doublet at 3.44, J = 7.5 Hz), 4.44 - 4.60 ( m, 2 H+1/5H, overlapped 10 doublet at 4.54, J = 7.5 Hz, 2H ArC/f2N and 1/5H C/iCN), 4.68-4.76 (m, 4/5H, C//CN), 7.50 (d, 2H, "/= 12.0 Hz), 8.16 (d, 2H, / = 12.0 Hz), 8.28 (bt, 1/5H, ArCH2N/i), 8.40 (bt, 4/5H, ArCH2N//); HRMS (El) m/z calcd for C17H21N504 359.1594, found 359.1594· 15 Example 40 3-[2-(2•lacyl-(iS)-11-pirolene-l-yl)-2-ethoxyethylamino Benzylpropionamide (Compound 40) !H NMR (CDCI3) (4 to 1 mixture of trans/cis amide rotomers) δ 2.05-2.35 (m, 6H5 overlapped triplet at 2.31, J = 6.0 Hz), 20 2.75 -2.83 (m5 4H), 3.17-3.35 (m, 3H, overlapped doublet at 3.23, J = 3.0 Hz), 3.42-3.51 (m, 3H), 4.60 (dd, 1/5H, J = 7.5 and 1.8 Hz, Ci/CN), 4.69-4.73 (m, 4/5H, Ci/CN), 7.16-7.27 (m, 5H), 7.29 (bs, 1/5H, ArCH2CH2N//), 7.52 (bs, 4/5H, ArCH2CH2N/〇; HRMS (El) m/z calcd for C18H24N402 25 328.1899, found 328.1904. Example 41 2-[3-[2-[2-Cyanoindolopyridin-1-yl]-2-oxyl Ethylamine 37 1299039 yl]-1-oxypropyl]-l-isopropyl-1,2,3,4-dihydroxyisoquine (Compound 41). MS (ES+) m/z. 383.3 (M+H)+, 405.2 (M+Na)+ Example 42 3-[2-(2---------) ^ -1 -yl)-2-oxoethylamino]1 _ 5 phenylpropyl)propanamide (Compound 42) ιΐί NMR (CDC13) (9 to 1 mixture of trans/cis amide rotomers) δ 0.88 ( t,3H,= 7·5 Hz),1·74_1·90 (m,2H), 2.02-2.31 (bm,4H), 2.37-2.49 (m,2H),2.86-3.01 (m,2H), I 3.32-3.62 (m? 4H), 4.62 (d3 1/10H, J = 7.5 Hz, C//CN) 10 4.73-4.77 (m, 9/10H, Ci/CN), 4.89 (q, 1H, = 7.5) Hz), 7.22-7.40 (m, 5H), 7.81 (bt, 1H); HRMS (El) m/z calcd for C19H26N4O2 342.2056, found 342.2060. Example 43 2-[3-[2-[2-] _(*S)-σ 嘻 嘻 -1--1-yl]-2-oxoethylamino]-1 -oxy-15 propyl]-1-isopropyl-7-fluoro-1,2, 3,4-Dihydroxyisoquinoline (Compound 43)· MS (ES+) m/z. 401.2 (M+H)+ Example 44 j 2-[3·[2-[2-Cyanobilorin唆-1-yl]-2-ethoxyethylamino]_1-oxypropyl]_1-hydroindolyl-1,2,3,4-bishydroxyisoquinoline (Compound 44). 20 MS (ES+ m/z. 371.2 (M+H)+, 393.1 (M+Na)+. Example 45 2-[3-[2_[(2-N-yl-nt) t洛琳°-1-yl)-2-oxoethylamino]-1-oxypropyl]-indole-butyl-7-fluoro-1,2,3,4-tetrahydroxyisoquine Phenanthine (Compound 45). 25 MS (ES+) m/z. 415.3 (M+H)+5 438.3 (M+Na)+. Example 46 38 1299039 3 -[2-(2 -Nymyl-(aS) · 11 Bilene beta-1,4-yl)-2-oxyethylamino]-iV"(1-methyl-1-phenylpropylethyl)propanamide (Compound 46) !H NMR (CDCI3 (9 to 1 mixture of trans/cis amide rotomers) δ 1.68 (s, 6H), 2.05-2.31 (m, 4H), 2.38-2.46 (m, 5 2H), 2.92-2.98 (m, 2H), 3.31 -3.44 (m,1H), 3.45-3.65 (m,3H, overlapped singlet at 3.48), 4.67 (dd, 1/10H, J = 7.5 Hz and 2.·1, Ci/CN) 4.73-4.75 (m,9 /10H, Ci/CN), 7.17-7.45 (m, 6H); HRMS (El) m/z calcd for C19H26N402 342.2056, found 342.2057. • 10 Example 47 2·[3·[[2·[2-Cyanide 〇-〇S)-吼 吼 啶 啶 · · · · · · -2- 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物 化合物47)

lU NMR (CDCI3) δ 1.20 (d5 3H, / = 8.4 Hz), 2.07-2.32 ^ (m, 4H), 2.41-2.49 (m, 1H), 2.59-2.68 (m, 1H), 2.85 (t, 1H) , J 15 = 6.0 Hz) 5 2.92 (t, 1H? J = 6.0 Hz), 3.24-3.31 (m5 1H), 3.36-3.58 (m, 4H), 3.61-3.73 (m, 1H), 3.75-3.86 ( m,1H), 4.65-4.77 (m5 3H, overlapped doublet at 4.65, J = 3.9 Hz and a singlet at 4.74, ArC//2N and C//CN), 7·10·7·23 (m, 4H) ® HRMS (El) m/z calcd for C20H26N4O2 354.2056, found 20 354.2057. Example 48 2_[3·[[2_[2 -Cyano-($)-11 Bilene bite_1·yl]-2 -oxyethyl]amino]-3-methyl-1-oxybutyl]-1,2,3,4-tetrahydroxyisoquinoline (Compound 48) !H NMR (CDCI3) (4 to 1 Mixture of trans/cis amide 25 rotomers) δ 1.23 (s, 3H), 1.25 (s, 3H), 2·05_2·33 (m, 4H), 2.53 (s, 2H), 2.85 (t, lH, /= 6.0 Hz), 2.91 (t, 1H, /= 6.0 Hz), 39 1299039 3.38-3.48 (m5 3H, overlapped doublet at 3.39, J = 7.5 Hz), 3.53-3.64 (m3 1H) 3.73 (t, 1H5 J = 6.0 Hz), 3.83 (t5 1H5 J = 6.0 Hz), 4.66-4.76 (m, 2.8H, two overlapped singlets at 4.67 and 4.73, 2H ArC7/2 N and 0.8HC/iCN), 5.10 (d, 0.2H, = 5 7.5 Hz5 Ci/CN), 7.09-7.22 (m, 4H); HRMS (El) m/z calcd for C21H28N4O2 368.2212, found 368.2215. 49 Benzyl-3-(2-(2-carbo-(aS)·ϋ 洛 洛 琳 琳 · 1 -yl)-2-oxyethylamino]·3_methylbutanamine (compound) 49) • 10 MS (ES+) m/z. 343.4 (M+H)+. Example 50 3_[2·(2-Cyano-indolyl)-indoloxalin-1-yl)-2-oxo Benzyl-ethylamino]-3-methylindole phenylbutaamine (Compound 50) MS (ES+) m/z. 329.4 (M+H)+.吼 ! ! 基 基 基 基 基 基 基 基 ( ( ( ( ( ( ( ( ( H H H (CDC13)5 1.08(s5 6H)5 2.31-2.2.15(m? 7H), 2.98(t,2H,J=6.6Hz), 3.27(s,2H),3.55-3.36(m,2H),3.64 (dd, 20 2H, 6.0, 6·6Ηζ), 4.76-4.73 (m, 1H), 7.11 (dd, 1H, "/= 7.5, 7.8 Ηζ), 7.17 (d, 1H, 7.8 Hz), 7.58 ( Dd,1H,7.5, 7.8Hz), 8.41(s5 1H)? 8.47( d, 1H, J = 7.5Hz). MS (ES+) m/z. 358.4(M+H)+,480.4 (M+Na) +. Example 52 25 l-{2-[3-(3,4-Bis-l-Chloro-isoindol-2-yl)-l,l-di 3-thioxo - propan-ylamino] - acetyl yl} - pyrroline -2-piperidine-carbonitrile (Compound 52) according to the following system

Claims (2)

, August 1996 revision page I 7; t|^ "JTJ β year π月崎修{more) replacement page X. Patent application scope: 1. A compound containing the following structural formula: Wherein R1 is hydrogen or cyano; each R2, R3, R4, R5 and R6 are independently hydrogen, halogen, nitro, cyano, amine, hydroxy, alkyl, ilalkyl, alkoxy, aryl Oxy, aralkyl, cyclic, heterocyclic, aryl or heteroaryl; m is 0, 1, 2, 3, 4 or 5; 10 each η and p are 0, 1, 2, 3, respectively Or 4; 'X is CRaRa' or S; wherein Ra and Ra' are respectively hydrogen, halogen, alkyl or aryl; Y is NRb or CRb (NRb'Rb''); wherein Rb, Rb' and Rb'' Respectively hydrogen, alkyl or aryl; • 15 A is ΠΝ RCN Ξ 丄 〇II s, 丨IJj N · or RCN ′′ , wherein Re is hydrogen, alkyl or aryl; and Z is hydrogen, amine, alkyl, cyclo, heterocyclyl, aryl, aralkyl or hetero Aryl; 49 1299039 \ΐί: Η for: and Ζ is NR7R8, wherein each R7 and R8 are independently hydrogen, alkyl, alkoxy, alkyl, haloalkyl, cyclo, heterocyclyl, aryl , aralkyl or heteroaryl; or NR7R8 is a 3-8 membered ring having 1 or 2 heteroatoms, optionally a halogen 5 'CN 'N〇2, -〇RC 'alkyl, aryl ,heteroaryl,halogenated alkyl, •〇Rc,-C(0)Rc,-SRC,-S(0)Rc,-S(0)2Rc,_NRCRC,,_c(〇)〇RC, •C( 0) NRcRc', -〇C(0)Rc, -NRcC(〇)Rc,, -NRcC(0)〇RC' or -NReC(0)NReRc substituted, or optionally with a cyclic group, a heterocyclic group a combination of one of an aryl group and a heteroaryl group; wherein each RC, RC, and RC, 10 is hydrogen, alkyl or aryl, respectively, wherein 'alkyl is a straight or branched carbon a hydrogen chain containing one carbon atom; an alkoxy group means an alkyl group having an oxygen; a halogenated alkyl group means one or more An alkyl group substituted with a aryl group; a aryl group means a monocyclic ring having 6 carbon atoms, a bicyclic ring of 10 carbon atoms, or a tricyclic aromatic ring system of 14 carbon atoms; and 15 aryloxy means an oxyaryl group An aralkyl group means an alkyl group substituted by an aryl group; a cyclic group means a saturated and partially unsaturated cyclic carbon-chloride chain having 3 to 12 carbons; and a heteroaryl group means one or more N, Ο Or a 5 to 8 membered monocyclic ring of an S hetero atom, a 8 to 12 membered bicyclic ring, or a 11 to 14 membered tricyclic ring; and a heterocyclic group means a 5 to 8 membered single containing one or more hydrazine, hydrazine or S heteroatoms. Ring, 8 to 12 yuan double ring, or u 2 〇 to 14 yuan three ring. 〆 2. The compound of claim 1, wherein Z is chloro, benzyl, alkyl, cyclo, heterocyclyl, aryl, aralkyl or heteroaryl. 3 · For example, the compound described in the first paragraph of the Shenqing patent scope, where a is 50 1299039 for the younger month, 4 days (more) is replacing the page RCN \,rcn*^- , RCN The compound of claim 1, wherein R1 is CN. 5. The compound of claim 4, wherein X is (: 112 or 6) a compound as described in claim 5, wherein 111 is hydrazine. 7. The compound of claim 6, wherein γ is CRb(NRb, Rb"). 8. The compound of claim 7, wherein each Rb, Rb' and Rb' The compound of claim 8, wherein n is oxime and p! 〇. The compound of claim 9, wherein 5 is hydrogen and R6 is hydrogen. The compound of claim 9, wherein 2 is NR7R8, R7 is hydrogen and R8 is alkyl, aralkyl, cyclic, heterocyclic, aryl or heteroaryl. The compound of claim 11 wherein Or CH2CH2OCH3; Re, and r is 0, 1, 2, 3, 4 or 5. 'wherein R is hydrogen, CH2OH, is hydrogen, alkyl or alkoxy; q is 〇1 q is 0, 1, 2 or 3; 13. The compound of claim 12, wherein R 51 1299039 is Or the year of the shirt P month today (more} is the replacement page: 〇CH3 H2CH2C~OCH3 14 · The compound of claim 9 wherein z is NR7R8 ' and NR7r8 is one or two heteroatoms 3-8 member of the ring. 15. The compound of claim 14, wherein z is 10 wherein R is hydrogen, halogen, amine, cyano, nitro, alkyl, alkoxy, aryl or heteroaryl; Rf' is hydrogen, alkyl, aryl, heteroaryl, _ or aryl Alkyl; Rf'' is Rg, C(〇)Rg, s(〇2)Rg; and each is oxime, I 2, 3 or 4; wherein Rg is hydrogen, alkyl, aryl or heteroaryl. 16. The compound of claim 15 wherein z is Wherein Rf is hydrogen, alkyl, aralkyl, hydroxyalkyl or alkoxyalkyl; and Rr is acridinyl, arylcarbonyl, alkylcarbonyl, aryl or heteroaryl. 17. The compound of claim 16, wherein z is 52 15 1299039 Factory—~一一一— The following year, the replacement of 唯•r, 斤^===3⁄43⁄43^4 and R is hydrogen, ch2oh, CH2CH2OH, CH(CH3)2, C(CH3)3 or The compound of claim 6, wherein γ is NRb 〇19. The compound of claim 18, wherein Rb is hydrogen. 20. The compound of claim 19, wherein n is 1, R3 is hydrogen and R4 is hydrogen. The compound of claim 20, wherein ρ is 2, R5 is hydrogen and R6 is hydrogen. A compound according to claim 21, wherein hydrazine is NR7R8, R7 is hydrogen or an alkyl group, and R8 is an alkyl group, an aralkyl group, a cyclic group, a heterocyclic group, an aryl group or a heteroaryl group. 23. The compound of claim 22, wherein R7 15 is hydrazine or methyl, and r8 is CH(R)(CH2)q Or a ring group, where Re is Ni, CH2CH3, CH2OH 'CH2CH2OH or CH2CH2OCH3; Re, chlorine, alkyl, N02 or 〇CH3; q is 0, 1, 2 or 3; and r is 0, 1, 2, 3, 4, or 5. 24. The compound of claim 23, wherein R8 20 is h2c H2CH2C O' N〇2 HC, CH2CH3 Or CO. 25. A compound as described in claim 21, wherein z is 53 1299039 i more) positive replacement page: nr7r8, 26. And NR7R8 is a 3-8 element having 丨 or 2 hetero atoms. Such as the compound described in claim 25, 2 of which are Rr Rf, II -NN , R (t, CMX(Rf)t ' or ' Rf is hydrogen, halogen, amine, cyano, nitro, alkyl, alkoxy, aryl or heteroaryl Rf' is hydrogen, alkyl, aryl, heteroaryl, halogen or aralkyl; Rf" is Rg, C(0)Rg, S(〇2)Rg; and each of 8 and 1 is 〇, ^ And 3 or 4; wherein Rg is hydrogen, alkyl, aryl or heteroaryl. 27. A compound according to claim 26, wherein z 10 Wherein Rf is hydrogen, ch2oh, CH2CH2OH, CH(CH3)2 or C(CH3)3. 28. The compound of claim 26, wherein z is 15 -4n; ~, N-Rf, ^, wherein Rf'' is 29. The compound of claim 2, wherein p is 54 1299039 2 ; each R5 is hydrogen or a burnt group; and R6 is hydrogen and the other R6 is Rh; and Rh is a fen-group, a aryl group or a heteroaryl group. 3. A compound as claimed in claim 29, wherein Rh Is /-propyl or Η. The compound of claim 1, wherein hydrazine is NR7R8 and R7 is hydrogen; and R8 is alkyl, aralkyl, cyclic, heterocyclic, aryl or heteroaryl. 32_A compound as claimed in claim n, wherein R8 is CH(Re)(CH2) ( Re is hydrogen, CH2OH, CH2CH2OH or '10 CH2CH2〇CH3; Re is hydrogen, alkyl or 〇CH3; q is 〇, 1, 2 or 3 and r is 0,1,2,3,4 or 5〇33. A compound according to claim 32, wherein γ is CH(NH2), n is hydrazine, p is 1, r5 is hydrogen and r6 is hydrogen. 34. The compound of claim 32, wherein γ is spring 15 NH, n is 1 and p is 2. 35. The compound of claim 1, wherein ζ is R R ' and NR 7 R 8 is a 3-8 membered ring having 1 or 2 heteroatoms. 36. The compound of claim 35, wherein z is 20 wherein Rf is hydrogen, halogen, amine, cyano, nitro, alkyl, alkoxy, 55 * 1299039 - 7 - -1 No. 94107143, revised June 1997, page f? year / month / / Japanese repair (more) the original round - enjoy the machine 'aryl or heteroaryl; Rf' is hydrogen, alkyl, aryl, heteroaryl, _ or aralkyl; Rf" for Rg, C (0 Rg, S(02)Rg; and each of 8 and 1 is 〇, lj2 3 or 4; wherein Rg is argon, alkyl, aryl or heteroaryl. 37. as described in claim 36 a compound wherein γ is 5 CH(NH 2 ) ' η is 0, p is 1 and each R 5 and R 6 are hydrogen. 38. The compound of claim 36, wherein γ is ΝΗ and η is 1 and ρ is 2. 39. A compound used to inhibit Type η diabetes 2 ® pharmaceutical remedies, including an effective dose of a compound of the formula: Wherein R1 is hydrogen or cyano; each R2, R3, R4, R5 and R6 are independently hydrogen, halogen, nitro, cyano, hydroxy, alkyl, dentate alkyl, alkoxy, aryloxy Alkyl, arylalkyl, 15 cyclyl, heterocyclyl, aryl or heteroaryl; m is 0, 1, 2, 3, 4 or 5; each η and ρ are 〇, 1, 2, 3 or 4 ; X is CRaRa' or S; wherein Ra and Ra' are hydrogen, respectively; W 'alkyl or aromatic 56 1299039 $月正换换页 9/· 1 1 饫 ___ V. RCNX // RCN S 丄〇II R°N 〇II NXN nxn . or RCN 』 , wherein Re is hydrogen, alkyl or aryl; and Z is hydrogen, amine, alkyl, cyclo, heterocyclyl, aryl, Aralkyl or heteroaryl; and • 5 Z is NR7R8, wherein each R7 and R8 are independently hydrogen, alkyl, alkoxyalkyl, lialkyl, cyclo, heterocyclyl, aryl, Aralkyl or heteroaryl; or NR7R8 is a 3-8 membered ring having 1 or 2 heteroatoms, optionally halogen, CN, N02, -ORc, alkyl, aryl, heteroaryl, halogenated Alkyl, • -ORc, -C(0)Rc, -SRC, -S(0)Rc, -S(0)2Rc,_NReRc',_C(0)0Rc, 10 -C(0)NRcRc',- 0C(0)Rc, -NRcC(0)Rc', -NRcC(0)0Rc' or -NReC(0)NRe'Re'' substituted, or optionally with a cyclic group, a heterocyclic group, an aryl group, And one of the heteroaryl groups; wherein each of Re, Re', and Re" φ is hydrogen, alkyl or aryl, respectively, wherein alkyl refers to a straight or branched hydrocarbon chain, which contains 1-10 15 carbon atoms; alkoxy means an alkyl group having oxygen; _ alkyl group means substituted by one or more i elements An alkyl group; an aryl group means a monocyclic ring having 6 carbon atoms, a bicyclic ring of 10 carbon atoms, or a tricyclic aromatic ring system of 14 carbon atoms; an aryloxy group means an oxyaryl group; an aralkyl group Means an alkyl group substituted by an aryl group; a cyclic group means a saturated hydrocarbon chain having 3 to 12 carbons partially saturated and partially unsaturated; and a heteroaryl group containing one or more ruthenium, osmium or S Heteroatoms 5 to 8 yuan single 57 1299039 -10 15 Ban Yi--------- ring, 8 to 12-membered bicyclic ring, or 丨丨 to ^-membered tri-ring; and heterocyclic group means 5 to 8 containing one or more Ν, 〇 or S heteroatoms Yuan single ring, 8 to 12 yuan double ring, or even 14 yuan three ring. 40. The pharmaceutical composition according to claim 39, wherein hydrazine is hydrogen, amine, alkyl, cyclic, heterocyclic, aryl, aralkyl or heteroaryl. The pharmaceutical composition according to the item 39, wherein Α Ο Ον η 0 yO Q KI.CN is human, > t. RcX, RCN1, RCN, or X. 42. The pharmaceutical composition of claim 39, wherein R1 is CN, m or 〇 and X is ch2 or S. 43. The pharmaceutical composition according to claim 42, wherein γ is CH(NH2) 〇44. The pharmaceutical composition according to claim 43, wherein η is 〇' Ρ is 1 and R5 Is hydrogen and R6 is hydrogen. The pharmaceutical composition according to claim 44, wherein ζ is NR7R8 and the uldent 7 is hydrogen; and r8 is an alkyl group, an aralkyl group, a cyclic group, a heterocyclic group, an aryl group or a heteroaryl group. 46. The pharmaceutical composition according to claim 45, wherein (Re) ^ CH(Re)(CH2)q-ΑΛ R is \=/CH2CH2OCH3; Re is hydrogen, alkyl or 0CH3; q is 0 , 1, 2 or 3 and r is 0, 1, 2, 3, 4 or 5. 47. The pharmaceutical composition according to claim 44, wherein Z 58 20 1299039 ____ 丨................ 丨,| , I||t|, - Preparation. Repair (more) is replacing the purchase.........—一冰一', ___ 11 ........................ . . . is Nr7r8, and NR7R8 is a 3-8 membered ring having 1 or 2 heteroatoms. 48. The pharmaceutical composition according to claim 47, wherein z Wherein Rf is hydrogen, halogen, amine, cyano, nitro, alkyl, alkoxy, 5 10 Aryl or heteroaryl; Rf' is hydrogen, alkyl, aryl, heteroaryl, halogen or aralkyl; Rf" is Rg, C(0)Rg, S(〇2)Rg; and each 3 And 1 is 〇, 12, 3 or 4; wherein Rg is hydrogen, alkyl, aryl or heteroaryl. 49. The pharmaceutical composition according to claim 39, wherein Y is NH〇', 50 The pharmaceutical composition according to claim 49, wherein η is 1, and each: ^ and ^ are hydrogen. 5丨. The pharmaceutical composition according to claim 50, wherein P 2, and each r5 is hydrogen, a R6 is hydrazine, and the remaining R6 is an alkyl group or an aryl group. 52. The pharmaceutical composition according to claim 51, wherein Z is NR7R8, wherein R7 Is a hydrogen or an alkyl group; and is an alkyl group, an aralkyl group, a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group. 53. The pharmaceutical composition according to claim [01], wherein (Re R7 is hydrogen or methyl, and is called hepta or cyclic group, Re is nitrogen, ethyl, CH20H, ch2ch2oh or CH2CH2OCH3; Re is hydrogen, alkyl, nitro or morphoxy; q is 〇, 1,2 Or 3; and r is 0, 1, 2, 3, 4 or 5. 59 The pharmaceutical composition of claim 51, wherein Z is NW, and is a 3-8-membered ring having 1 or 2 heteroatoms. 55. The pharmaceutical composition according to claim 54, wherein Z is Wherein Rf is hydrogen, halogen, amine, cyano, nitro, alkyl, alkoxy, aryl or heteroaryl; Rf' is hydrogen, alkyl, aryl, heteroaryl, halogen or aralkyl ; Rf" is Rg, C(0)Rg, s(〇2)Rg; and each of 3 and 1 is 〇, 1> 2, 3 or 4; wherein Rg is hydrogen, alkyl, aryl or heteroaryl 56. A pharmaceutical composition for inhibiting dipeptidyl peptidase IV comprising an effective amount of a compound of the formula: Wherein R1 is hydrogen or cyano; 15 each ^, ^, ^, and to each are a hydrogen group, a cyano group, a hydroxy group, an alkyl group, an alkyl group, an alkoxy group, an aryloxy group. Alkyl, aralkyl, cyclic, heterocyclic, aryl or heteroaryl; Π1 is 〇, 1, 2, 3, 4 or 5; each η and ρ are 〇, 1, 2, 3 or 4, respectively 20 Χ is CRaRa or S; wherein Ra and Ra' are respectively hydrogen, a hydroxyl group, an alkyl group or an aromatic 60 1299039 base; Y is NRb4CRb(NRb, Rb"); wherein Rb, Rb' and Rb" are each a hydrogen group or an aryl group; V V I I ϊ ϊ / \ . RC!\T,. , RCN-^ . ,s,,RWS,·nxn n^cn Or RCN?, wherein Re is hydrogen, alkyl or aryl; and z is hydrogen, amine, alkyl, heterocyclyl, aryl, aralkyl or heteroaryl; and Z is NR7R8, wherein Each of R7 and R8 is independently hydrogen, alkyl, alkoxy 10 alkyl, halogenated alkyl, cyclic, heterocyclic, aryl, aralkyl or heteroaryl; or NR7R8 is one having 1 or 2 a 3-8 membered ring of a hetero atom, optionally halogen, CN, N02, -ORc, alkyl, aryl, heteroaryl, alkyl halide, -ORc, -C(0)Rc, _SRC,- S(0)Rc, -S(0)2Rc, -NRCRC', -C(0)0Rc, _C(0)NRcRc,,-0C(0)Rc,_NRcC(0)Rc,,-NRcC(0) Substituted by 0Rc' or 15-NReC(0)NRe'Re'', or optionally combined with one of a cyclic group, a heterocyclic group, an aryl group, and a heteroaryl group; each of Re, Re', and Re" is hydrogen 'alkyl or aryl', wherein the alkyl group refers to a hydrocarbon chain of a straight chain or a branched chain, which contains 1 to 10 carbon atoms; and the alkoxy group means an alkyl group having an oxygen; Halogenated alkyl means an alkyl group substituted by 20 halogen or one halogen; aryl means a single 61 1299 having 6 carbon atoms 039 ___________ f month day repair (more) is replacing page ^ ^.Ί^Ίιι_ ^,.. —_一^rr cold,, _" explosion, 』m: a ring of 10 carbon atoms ' or 14 carbon atoms a tricyclic aromatic ring system; - oxygen: a 3-aryl aryl group; an aryl group refers to an alkyl group substituted by an aryl group, a thiol-saturated and partially unsaturated ring containing 3] 2 carbons Carbonaza 7 , heteroaryl group means 5 to 8 membered single 5 soil, 8 to 12 membered bicyclic ring or yttrium tricyclic ring containing one or more N, fluorene or S heteroatoms; and heterocyclic group Means a 5 to 8 membered monocyclic ring, an 8 phantom 2 membered bicyclic ring containing one or more N, hydrazine or S heteroatoms, or a u to 14 membered tricyclic ring. 57. A pharmaceutical combination as described in claim 56 And wherein R is CN, m or 〇 and X is Cfj2 or s. 10 58. The pharmaceutical composition according to claim 57, wherein Y is CH(NH2). The pharmaceutical composition according to the item 58 wherein η is 0, p is 1, R 5 is hydrogen and R 6 is hydrogen. The pharmaceutical composition according to claim 57, wherein 15 Y is NH. 61. The pharmaceutical combination as described in claim 6 And wherein η is 1 and each of R 3 and R 4 is hydrogen. 62. The pharmaceutical composition according to claim 56, wherein the hydrazine is hydrogen, an amine group, an alkyl group, a cyclic group, a heterocyclic group, and an aromatic group. Or a arylalkyl or heteroaryl 20 group. The pharmaceutical composition according to claim 56, wherein 64. — used to inhibit dipeptidase VIII (dipeptidyl peptidase 62 1299039 / /!: η, ~~·...'··., 1....22~.,.~.....~", The pharmaceutical composition of VIII/VIII) comprises a structural formula containing an effective dose as follows: Wherein R1 is hydrogen or cyano; 10 2 feet, 3 feet, 4 feet, 5 feet and each of hydrogen, _, nitro, cyano, amine, hydroxy, alkyl, _ alkyl, alkoxy, aryloxy, aryl Alkyl, %-yl 'heteroyl' or heteroaryl; m is 0, 1, 2, 3, 4 or 5; each η and p are 〇, 1, 2, 3 or 4, respectively; X is CRaRa 'or S; wherein Ra and Ra' are respectively hydrogen, dentate, alkyl or aryl; Y is NRb or CRb (NRb, Rb',); wherein Rb, Rv and Rb, 'respectively hydrogen, alkyl or Aryl; A is Ο 0 II 祖面〆, · RCN, S, · . or RCN 』- , where R ° is hydrogen, alkyl or aryl; and Z is hydrogen, amine, alkyl, cyclic, heterocyclic, aromatic a aryl group or a heteroaryl group; and 63 1299039 s 3, 19, ... Z is NR7R8, wherein each of R7 and R8 is independently hydrogen, alkyl, alkoxyalkyl, _alkyl, ring , heterocyclyl, aryl, aralkyl or heteroaryl; or NR7R8 is a 3-8 membered ring having 1 or 2 heteroatoms, optionally halogen, CN, N02, -ORc, alkyl, Aryl, heteroaryl, halogenated alkyl, 5 -ORc, -C(0)Rc, -SRC, -S(0)Rc, -S(0)2Rc, -NRCRC', -C(0)0Rc, -C(0)NRcRc', -OC( 0) Rc, -NRcC(0)Rc', -NRcC(0)0Rc' or -NReC(0)NRe'Re'' substituted, or optionally with a cyclic group, a heterocyclic group, an aryl group, and a hetero One of the aryl groups is bonded; wherein each Re, Rc', and Re'' are respectively hydrogen, an alkyl group or an aryl group, wherein 10 is an alkyl group which is a straight chain or a branched hydrocarbon chain, which contains 1 -10 carbon atoms; alkoxy means an alkyl group having oxygen; halogenated alkyl means an alkyl group substituted by one or more halogens; aryl means a single ring having 6 carbon atoms, 10 a bicyclic ring of a carbon atom, or a tricyclic aromatic ring system of 14 carbon atoms; an aryloxy group means an oxyaryl group; an aralkyl group means an alkane group 15 substituted by an aryl group; and a ring group means a saturated group Partially unsaturated cyclic hydrocarbon chain containing 3-12 carbons; heteroaryl group means 5 to 8 membered monocyclic ring containing 8 or 12 members of a heterocyclic ring of one or more hydrazine, hydrazine or S, or 11 to a 14-membered tricyclic ring; and a heterocyclic group means a 5- to 8-membered monocyclic ring having 8 or 12 members, or an 11- to 12-membered double ring containing one or more hydrazine, hydrazine or S hetero atoms. 14 yuan three-ring. The pharmaceutical composition according to claim 64, wherein Z is hydrogen, an amine group, an alkyl group, a cyclic group, a heterocyclic group, an aryl group, an aralkyl group or a heteroaryl group. 66. The pharmaceutical composition according to claim 64, wherein 64 T9QQ0^Q • body Q'g曰 repairing) is replacing page A as again, v, Ry, 67. The pharmaceutical composition of claim 64, wherein R1 is CN, m or 〇 and X is ch2 or S. 68. The pharmaceutical composition according to claim 67, wherein 5 -10 Y is ch(nh2) 〇 ', , 69. The pharmaceutical composition according to claim 68, wherein n is 〇, P is 1 and each of R5 and R6 is hydrogen. The pharmaceutical composition according to the invention of claim 67, wherein Y is NH 〇, 71. The pharmaceutical composition as described in claim 70, wherein n is 1, and each - R3 With R4 being hydrogen. 65