TWI287015B - N-6 substituted 7-deazapurine compounds as adenosine receptor antagonists - Google Patents

Abstract

This invention pertains to compounds which specifically inhibit the adenosine A1 and A3 receptor and the use of these compounds to treat a disease associated with A1 and A3 adenosine receptors in a subject.

Description

1287015 A7

V. INSTRUCTIONS (/) The Intellectual Property Office of the Ministry of Economic Affairs and the Consumers' Cooperatives are printed in the entire application. The authors and the dates refer to various announcements. A full citation of these announcements can be found in the entire application. The whole of these announcements. The disclosure of the present application is hereby incorporated by reference in its entirety to the extent of the disclosure of the disclosure of the present disclosure. BACKGROUND OF THE INVENTION Adenosine is a regulator of many physiological activities that exist everywhere, especially in the cardiovascular and nervous systems. The effects of adenosine appear to be controlled by specific cell surface receptor proteins, and adenosine can regulate different physiological functions including 10 sedation, vasodilation, inhibition of heartbeat and contraction, inhibition of platelet aggregation, stimulation of gluconeogenesis and inhibition of lipolysis, in addition to the effect on adenylate cyclase, adenosine also shows the opening and unloading channels, reducing the transduction Loss of channels, and inhibition or stimulation of phosphoinositide conversion via receptor-induced mechanisms (see eg CE· Muller and B. Stein “Adenosine Receptor 15 Antagonists. Structures and Potential Therapeutic

Applications, Current Pharmaceutical Design, 2:501 (1996) and CE· Muller ArAdenosine Receptor Antagonists, “Mother Opin·Ther· Patents l(5y.4\9 (\997). Adenosine receptors belong to the 嘌呤 receptor superfamily, It is currently subdivided into sputum (adenosine) 20 and P2 (atp, and other nucleoside s complex) receptors, and has now replicated four subtype receptors of nucleoside adenosine from different species including humans, two subtypes. Receptors (4 and AJ show affinity for adenosine in the nanomolar concentration range, while the other two known A% and A; paratypes are low affinity receptors, affinity for adenosine Sexuality in the low micromolar concentration range, A! & A3 adenosine receptor activation can be ~3~ This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) *1^----- ---^--------- (Please read the phonetic transcription on the back? Please fill out this page again) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1287015 A7 ----------- ----B7 _ V. Inventive Note (> ) Lead to inhibition of adenylate cyclase activity, ❿Aj ^ activation causes stimulation of adenylate cyclase. A small number of A! antagonists have been developed for therapeutic cognition Sexually transmitted diseases, renal failure, and irregularities, and the use of antagonists is beneficial to patients with M〇rbus 5 ParkinS〇n (Parkinson's disease), especially in view of the possibility of local delivery, adenosine Body antagonists can be used to treat allergic inflammation and asthma, such as Nyce & Metzger "DNA antisense Therapy for Asthma in an Animal Model 55 Nature (1997) 385: 721-5), in this pathophysiological part , * antagonists can prevent smooth muscle contraction under the epithelium of respiratory tract 10, and A2b or A3 receptor antagonists can prevent the degranulation of mast cells, ease the release of histamine and other inflammatory mediators, and found that A% receptors are distributed in The gastrointestinal tract, especially in the colon and intestinal epithelium, suggests that the A2b receptor triggers a cAMP response (Strohmeier β a C/zem. (1995) 270: 2387-94). 15 Adenosine receptors also appear to exist in different On the retina of mammals, including cattle, pigs, monkeys, voles, guinea pigs, mice, rabbits, and humans (see Blazynski et al) Discrete Distributions of Adenosine Receptors in Mammalian Retina, Journal of Neurochemi Stry, volume 545 pages 648-655 (1991). Woods et al} 20 Characterization of Adenosine A "Receptor Binding Sites in Bovine Retinal Membranes, Experimental Eye Research, volume 53? pages 325-331 (1991) A Braas et aly Endogenous adenosine And adenosine receptors localized to ganglion cells of the retina, Proceeding of the National Academy of Science, this paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -------^---- -----^ ^__w. (Please read the notes on the back and fill out this page) 1287015 A7 V. Invention Description (3 15 20 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Print Volume, pages 3906-3910 ( 1987)), recently, Williams reported the observation of adenosine transport sites in cultured human retinal cell lines (Williams et aly Nucleoside Transport Sites in a Cultured Human Retinal Cell Line Established By SV-40 T Antigen Gene, Current Eye Research, volume 13? pages 109-118 (1994)) 〇 Previously recommended the use of compounds that regulate adenosine uptake as a viable medical agent for therapeutic treatment Membrane and optic nerve head injury, in US Patent 5,780,450 issued to ShadeT, Shade discusses the use of adenosine uptake inhibitors to treat eye diseases, Shade does not disclose the use of specific As receptor inhibitors, the entire contents of U.S. Patent 5,780,450 is incorporated herein by reference. reference. It is of great interest to require other adenosine receptor antagonists as pharmacological agents and as agents for the above mentioned disease states and/or conditions. SUMMARY OF THE INVENTION The present invention is based on the discovery of compounds that are selectively linked to adenosine, a receptor, and thus can be treated in a subject with adenosine receptors after administration of a therapeutically effective amount of the compound to a subject. The condition, the condition being treated is related to cognitive disease, renal failure, arrhythmia, respiratory epithelial disease, transmitter release, sedation, vasoconstriction, bradykinesia, negative myocardial contraction, reflux or ulceration . The present invention is based, at least in part, on the discovery that certain N-6 substituted 7-deazaindole compounds are useful in the treatment of N_6 substituted 7-deazaindole compounds, such states Examples include the activity of increasing adenosine stylistics, such as bronchitis, gastrointestinal disease or asthma, these 4IN ^---------^ 2f read the back of the precautions and then fill out this page] ~5° 1287015 A7 V. INSTRUCTION DESCRIPTION (#) The state is characterized in that adenosine receptor activity can result in inhibition of adenylate cyclase activity, and the compositions and methods of the present invention include pure palmar isomerism or non-palphalinomerism. N-6 substituted 'deazaindole compound, preferably N-6 substituted 7-deazaindole compound, including cyclohexyl group, such as cyclohexyluretyl group, containing acetamide, a 5-amine substituted A compound that is attached to N-6 nitrogen by a wire bond. The present invention relates to a method for regulating adenosine receptors by administering an effective medical amount of a N-6 substituted 7-deazaindole compound to a feeding animal. A suitable glandular genus includes 10 A A or A. In a preferred embodiment, the thoracic substituted 7-deaza compound is an adenosine receptor antagonist. Methods for treating N-6 substituted 7-deazaindole compounds in mammals, such as asthma, bronchitis, allergic rhinitis, sexual obstructive pneumonia, disease, gastrointestinal diseases and eye diseases, will be passed through 15 The therapeutically-replaced 7-deaza compound is administered to a sputum animal to cause treatment of a disease in a mammal, and a suitable sputum-substituted 7-deazapine compound includes the following Compounds Description: 20 Printed by the Intellectual Property Office of the Ministry of Economic Affairs

5 R : ί "Ί.ιΜ—-^1^1i [Β This paper scale applies to China National Standard (CNS) A4 Regulation 4 (21〇X 297 璧)---------- --- -----------------Book---------Line"^ιρ· (Please read the notes on the back and fill out this page) 1287015 A7 B7 V And the pharmaceutically acceptable salts thereof, and Ri and R2 are each independently a hydrogen atom or a substituted or unsubstituted alkyl, aryl or alkylaryl group, or together A substituted or unsubstituted heterocyclic ring is formed, R 3 is a substituted or unsubstituted alkyl group, an aryl group or an alkyl aryl group, and R 4 is a hydrogen atom or a substituted or unsubstituted alkyl group, an aryl group, Or a aryl group, the Rs and the core are each independently a _ atom such as a gas, a gas or a odor, a rat atom or a substituted or unsubstituted alkyl, aryl, or alkylaryl group, or & And / or R5 and the core together form a substituted or unsubstituted heterocyclic ring or carbocyclic ring. In some embodiments, R! and & can each independently be a substituted or unsubstituted cycloalkyl or heteroarylalkyl group. In other embodiments, R3 is a hydrogen atom or substituted Or an unsubstituted heteroaryl group. In still other specific embodiments, Re, the ruler 5 and the core may each independently be a heteroaryl group. In a preferred embodiment, & is a hydrogen atom, & Is cyclohexanol such as trans-cyclohexanol, Rs is phenyl, & is a hydrogen atom, I is a methyl group and !^ is a methyl group. In still other embodiments, R1 is a hydrogen atom, and ^ is a 'orbital

20 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed NHMe Heart is a phenyl group, the heart is a hydrogen atom, and the heart and heart are methyl. The invention also relates to a pharmaceutical composition for treatment in a mammal to replace N-6 The 7-deazaindole compound has a responsive state, such as asthma, bronchitis, allergic rhinitis, chronic obstructive pneumonia, kidney disease, gastrointestinal disease and eye disease, and the pharmaceutical composition contains an effective medical amount of n_6 substituted 7- A deazapine compound and a pharmaceutically acceptable carrier. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm ------- order--------- line (please read the back note first and then fill out this page) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1287015 A7 _______ B7_____ V. INSTRUCTION DESCRIPTION (;) The present invention also relates to a complete pharmaceutical composition for the treatment of N-6 substituted 7-deaza in mammals In the responsive state of the bismuth compound, the complete pharmaceutical composition comprises a container containing at least one N-6 substituted 7-deaza σ gram compound and a N 6 substituted 5 - Use of a deazaindole compound for the treatment of a condition in response to a 7-deazaindole compound substituted with indole-6 in a mammal. The invention also relates to a compound of formula I, wherein: & is hydrogen; a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkyl group, or a heart or a heart together to form a substituted or unsubstituted heterocyclic ring; an unsubstituted or substituted aryl group; R4 is hydrogen;

Rs and R0 are each independently hydrogen or an alkyl group, and a pharmaceutically acceptable salt thereof. The deazaindole compound of this embodiment is suitably a 15-receptor, receptor antagonist, and these compounds are available. In a variety of medical applications, such as the treatment of asthma, renal failure associated with heart failure, and glaucoma, in a particularly preferred embodiment, the deaza compound is a water-soluble prodrug that can be passed, for example, in vivo through an ester. Enzymatically catalyzed hydrolysis is metabolized into an active agent. In another embodiment, the invention features inhibiting adenosine receptors by contacting the cells with a N-6 substituted 7-deazaindole compound (e.g., preferably an adenosine receptor antagonist). (For example, As) activity in cells. On the other hand, the invention is characterized by the effective amount of formula j N_6 〜8'------------- (Please read the notes on the back and fill out this page)

1287015 A7 B7 V. Description of invention (

The substituted 7-deazaindole compound is administered to an animal for treating eye damage of an animal (for example, a human), and the N-6 substituted 7-deazaindole compound is preferably an Adenosine receptor in an animal cell. Antagonist, the injury is in the retina or nerve head and can be polar or chronic, and the injury can be caused, for example, by glaucoma, edema, ischemia, hypoxia or trauma. The invention also discloses a medical composition comprising a N-6 substituted 7-deazaindole compound of the formula I, preferably the pharmaceutical preparation is an ophthalmic formulation (for example, around the eye, after the eyeball or intraocular injection formula, systemic Formula or surgical irrigation solution). In yet another embodiment, the present invention discloses a deaza compound of the formula: m 15

• W (II) II. Lee, 3⁄4 .ft (please read the notes on the back and fill out this page) 20 The Ministry of Intellectual Property of the Ministry of Intellectual Property prints that X is N or CR^RAR2 are each independently chlorine. Or by taking or unsubstituted silk I, silk, silk, or poorly aryl, or - shaped hetero-substituted silk by substitution, under the condition that r J ^ is not hydrogen at the same time; R3 is Substituted or unsubstituted filaments, aryl or aryl; & oxime or substituted or unsubstituted alkyl, L 3 , substituted or unsubstituted alkyl, or R4 and dioxin Replace or not, spine or rhyme; & money, peak generation silk replaced --------- tr--------- climb ^ 9 ~

1287015 V. Description of invention (8) in

An alkyl group, or a halogen group; Q is CH2, hydrazine, S or NR", wherein & is 1 or a substituted or unsubstituted CrC: 6 alkyl group, and W is unsubstituted or substituted Alkyl, cycloalkyl, aryl, arylalkyl, biaryl, heteroaryl, substituted carbonyl, substituted thiocarbonyl or substituted aryl; provided that if R3 is 吼洛In the case of a bite group, R4 is not a methyl group, and the present invention also discloses pharmaceutically acceptable salts and prodrugs of the compounds of the invention. In an advantageous embodiment, the oxime in the compound of formula II is CRe and Q. Is CH2, 〇, S or NR7, which is the same as defined above. In another embodiment of Formula II, X is N. The invention also discloses inhibiting adenosine receptors by contacting a cell with a compound of the invention ( Methods of activity of, for example, A2b adenosine receptors in cells. The invention also discloses treating gastrointestinal disorders (eg, diarrhea) in an animal by administering an effective amount of a compound of the formula (eg, an antagonist of eight) to the animal or For respiratory diseases (such as allergic rhinitis, chronic obstructive pneumonia), this animal is more suitable for humans. The present invention also relates to compounds having the following structures · Ministry of Economic Affairs Intellectual Property Office employees consumer cooperatives printed

-10· 89624A- The paper size is applicable to the t-small standard (CNS)^^丨〇χ297 1287015 at _____ B7 V. Inventive Note (9) -Positive η Μ Ethylaminoethyl or methylaminocarbonylamine Alkyl; wherein & is a substituted or unsubstituted four to six membered ring wherein & is Η, alkyl, substituted alkyl, aryl, aralkyl, amine, substituted aryl Wherein the substituted alkyl group is -c(R7)(R8)XR9, wherein X is oxime, S or NR10, the center and r8 are each independently η or alkyl, wherein R9 and R1G are each independently an alkane a cycloalkyl group, or a R9r1 fluorene and a nitrogen atom, together form a substituted or unsubstituted 4 to 7 membered ring; wherein R6 is H, alkyl, substituted alkyl, cycloalkyl; or pharmaceutically acceptable Accepted salts or prodrug derivatives or biologically active metabolites; provided that when Ri is an ethylaminoethyl group, R3 is not a 4-pyridyl group. The Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed in a specific example of the compound, & phenyl, pyrrole, thiophene, furan, 嗔 、, 味味, 吼 、, 1,2,4-三峻, σ Specific bite, 2 (ih)-bite ketone, 4 (1H)-pyridone, pyridin, pyrimidine, sorghum, isothiazole, isoindole, sputum, tetragon, naphthalene, tetralin, naphthoquinone, benzene And humming, benzophenone, anthracene, 2,3-dihydroanthracene, 1H-indole, anthracene, benzopyrine, 1,3-benzodioxime, benzoxazole, Anthraquinone, coumarin, chromone, porphyrin, tetrahydrotetrazine, isoindole, benzimidazole, oxazolidine, pyrido[2,3-b]indole, acridine[3,4_b]pyridinium Plough, pyridinium [3,2-c], till [3, heart b] pyridine, 1H-pyrazolo[3,4-d]pyrimidine, acridine, 2(111)-4 Novo, 1(2H)-isononolone, 1,4-benzoxanthene, benzothiazole, porphyrin, 喳N_oxide, iso-N-oxide, cerium oxide , oxazolidine oxide, benzopyrene, tillage, alfalfa or the following structures:

This paper scale applies to China National Standard (CNS) A4 specification (210 X297 mm) A7 B7 丨 Amendment i Supplement 1287015 V. Inventive Note (10) where Y is carbon or nitrogen; wherein R2 and Rr are independently Η, substituted Or unsubstituted alkyl, substituted or unsubstituted aryl, dentate 'methoxy, methylamino or methylthio; the invention also relates to compounds having the structure:

Wherein & is aryl, substituted aryl, or heteroaryl; wherein R0 is H, alkyl, substituted alkyl or cycloalkyl; wherein is H, alkyl, substituted alkyl, aromatic a arylalkylamino group, a substituted aryl group, wherein the substituted alkyl group is -c(R7)(R8)NR9Ri〇, wherein R7 and R8 are each an anthracene or an alkyl group, wherein It is an alkyl or cycloalkyl group, or R9, R10 and nitrogen together form a ring system of between 4 and 7 members. Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative The present invention also relates to a method of inhibiting the activity of a 腺 a adenosine receptor in a cell comprising contacting the cell with a compound as described above. DETAILED DESCRIPTION OF THE INVENTION The features and other details of the present invention will now be described more clearly and are indicated in the scope of the claims. It is understood that the specific embodiment of the present invention is 12- the paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 PCT) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1287015 A7 ------------ B7____ V. INSTRUCTIONS (") Illustrated and not as a limitation of the present invention, the present invention The main features can be used in different specific embodiments without departing from the scope of the invention. The present invention relates to a method of treating a condition in a mammal for treatment of a N-6 substituted 7-deazaindole compound in a mammal, the method comprising administering an effective medical amount as described below. The N-6 substituted 7-deazaindole compound is administered to a mammal such that treatment in the mammal is responsive to the N-6 substituted 7-deazaindole compound. ~ The so-called "state of response to N-6 substituted 7-deazaindole compound" is meant to include a disease state or condition characterized by the use of N-6 substituted 7 described below. - the deazapine compound treatment is responsive, for example, the treatment comprises at least one symptom or effect of the apparently disappearing state using the N_6 substituted 7-deazaindole compound of the invention, usually in a state in which the gland is in the host Glycosides increase the association and often cause the host to feel signs of life, including but not limited to release of toxins, inflammation, coma, edema, weight gain or weight loss, pancreatitis, emphysema, rheumatoid arthritis, bone and joint Inflammation, multiple organ failure, respiratory syndrome in infants and adults, allergic rhinitis, chronic obstructive pneumonia, eye disease, gastrointestinal disease, skin tumor enhancement, immunodeficiency and asthma (see eg CE 20 Muller and B. Stein) Adenosine Receptor Antagonists:

Structures and Potential Therapeutic Applications, "Current P/zarmac from fea/Z)(2) as 7, 2:501 (1996) and CE Muller ApAdenosine Receptor Antagonists, uExp. Opin Ther 7(5):419 (1997) and I. Feoktistove, R.Polosa, ST·~13~ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) — — — — — — — — — — — — — — — — — II ^ ·11111111 (Please read the note on the back and fill out this page) 1287015 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Invention Description (/>)

Holgate and Biaggioni “Adenosine A2B receptors: a novel therapeutic target in asthma?” TiPS 19; 148 (1998)), which is usually associated with these syndromes, including but not limited to fever, hypopnea, σ nausea, diarrhea, and weakness. , headache and even death, in a specific embodiment 5, the state of response to the Ν6 substituted 7-deazaindole compound includes that they are triggered by stimulating adenosine receptors such as Α1λ A2a, A2b, Α3, etc. The disease state, such that the regulation of intracellular calcium concentration and/or activation of PLC (10) lipase c), in a preferred embodiment, is in response to a N-6 substituted 7-deazaindole compound. An example of a suitable responsive state that can be treated with a compound of the invention, such as a para-adenosine that elicits a biological effect, associated with an adenosine receptor, such as a 10 N-6 substituted 7-deazaindole compound as an antagonist. Receptors, including central nervous system (CNS) effects, cardiovascular effects, renal effects, respiratory effects, immune effects, gastrointestinal effects, and metabolic effects, the relative amount of adenosine in patients The following effects associated, that is to say 15 to increase the content of adenosine can trigger a physiological response, for example, is not intended to be effect, for example asthma occurs. CNS effects include reduced transmitter release, sedative effects (A 丄 reduced exercise organ activity (A%), anti-shocking, chemical receptor stimulation (heart) and hyperalgesia, and therapeutic uses of the compounds of the invention include treatment of stupid Alzheimer's disease and memory enhancement. Cardiovascular effects include vasodilation (AJ, (A2b) and (A vasoconstriction (A 〇, bradycardia (eight sputum platelet inhibition (eight 丄 丄 negative myocardial contraction) With the use of transduction (A〇, arrhythmia, rapid heartbeat, and angiogenesis, therapeutic uses of the compounds of the invention include, for example, lion ischemia caused by visceral damage and strong ~14, this paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -------- order--------- line (please read the notes on the back and fill out this page) A7

1287015 V. INSTRUCTIONS (/Rule) Heart, protect myocardial tissue and restore heart function. Renal effects include reduction of GFR (A〇, vascular mesangial cell contraction (Al), antidiuretic (A!), and inhibition of renin release (A〇, suitable therapeutic uses of the compounds of the invention include the use of a compound of the invention as a diuretic, Natriuretic diuretic, potassium 5 preservative, kidney protection / prevention of acute renal failure, antihypertensive agents, anti-edema agents and anti-inflammatory agents. Respiratory effects include tracheal dilatation (A2), tracheal contraction (AJ, chronic obstructive pneumonia, Allergic rhinitis, mucosal secretion, and decreased respiratory function (8-2), suitable therapeutic uses for the compounds of the invention include anti-asthmatic use, treatment of lung disease and respiratory diseases after transplantation 10. Immune effects include immunosuppression (A2), neutrophils Chemotaxis (W neutrophil hematopoietic peroxide production (a2j and mast cell degranulation (A^ and AO, therapeutic uses of antagonists include allergies and non-allergic inflammation, such as release of histamine and other inflammatory properties) Media. 15 Gastrointestinal effects include inhibition of gastric acid secretion (Α) therapeutic uses include reflux and ulceration, gastrointestinal effects also include colon, small intestine and diarrhea, such as inflammation of the small intestine Diarrhea (A2b). Eye diseases include retinal and ocular nerve head injuries and disease-related wounds (A;). In a preferred embodiment, the eye disease is glaucoma. 2 Other therapeutic uses of the compounds of the invention include treatment Obesity (fat decomposition properties), hypertension, treatment of depression, sedatives, anti-anxiety agents, as an inducer and as a defecation agent, for example, affecting peristalsis but not causing diarrhea. The term "disease state" means including unwanted Adenosine, adenylate cyclase activity, increased physiological activity associated with abnormal stimulation of adenosine receptors and / 15' This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) - ------------------- Order --------- line (please read the notes on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau staff consumption Cooperatives Printed 1287015 Α7 Β7 V. Invention Description (/〆) The Department of Economic Intelligence's Intellectual Property Office employee consumption cooperative prints or increases the situation caused or related to cAMP. In one embodiment, the disease state is, for example, asthma, chronic obstructive pneumonia. Allergic rhinitis Other examples of bronchitis, kidney disease, gastrointestinal disease or eye disease include chronic bronchitis and cystic fibrosis of the adrenal gland. Suitable examples of inflammatory diseases include 5 non-lymphocytic leukemia, myocardial ischemia, angina pectoris, infarction, and cerebrovascular localization. Ischemia, intermittent claudication, severe limb ischemia, venous hypertension, varicose veins, venous ulcers, and arteriosclerosis, and impaired reperfusion conditions include, for example, any post-operative trauma, such as reconstructive surgery, thrombolysis, or angioplasty 10 The treatment of "the state of response to the 7-deazaindole compound substituted by Ν6" or "the state of response to the 7-deazaindole compound substituted by Ν-6" Means to change the above-mentioned disease state or situation such that the physiological signs in the mammal can be clearly disappeared or alleviated, and also include controlling, preventing or inhibiting the physiological signs or effects associated with the abnormal amount of adenosine. In a preferred embodiment, controlling the disease state or condition, eradicating the disease state or situation, in another preferred embodiment , The selective control making it possible to control the amount of the abnormal activity of adenosine receptor, but does not affect other physiologic systems and parameters. The so-called "Ν-6 substituted 7-deazaindole compound, which is known to the art 20 and refers to the compound comprising formula I: This paper scale is applicable) Α4 specification (binding line ~16~ 1287015 A7 Β7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention description (A)

An N-substituted 7-deazaindole compound, including a pharmaceutically acceptable salt thereof, and in a particular embodiment, also includes a portion of the N-6 substituted indole compound described herein. In some embodiments, the N-6 substituted 7-deazaindole compound is not substituted by N-6 benzyl or N-6 phenylethyl. In other embodiments, R4 is not Substituent or phenylethyl substitution, in a preferred embodiment, R1 and & are not hydrogen atoms, and in still other embodiments, R3 is not a chlorine atom. The so-called "effective therapeutic amount" is The N_6 substituted 7-deazaindole compound described herein refers to an amount of a medical compound that must be or is sufficient to perform its intended function in a mammal, for example, in a mammal, the treatment of 2〇N·6 is substituted. 7_Deaza, the state in which the compound of the ticket compound is responsive or the effective amount of the medical compound of the disease may vary depending on factors such as the amount of the therapeutic agent already present in the mammal, the age, sex and weight of the mammal, and the present Medical compound of the invention The ability of mammals to influence the state of response to N 6 substituted 7-deaza σ 呤 呤 compounds, ~ 17 ' This paper scale applies to China National Standard (CNS) A4 specifications (210 X 297 liters) " — ------ -------------------- Order --------- Line ^_w. (Please read the notes on the back first. Fill in this page) 1287015 A7 B7 V. INSTRUCTIONS (Μ) 15 The Ministry of Economic Affairs, the Intellectual Property Office, the employee consumption cooperative, who is generally familiar with this art, can study the above factors and can make effective doses of medical compounds without repeated experiments. It is contemplated that in vitro or in vivo tests can be used to determine the effective amount of the medical compound described herein, and those skilled in the art will generally select an appropriate amount of the medical compound for use in the above test or as a medical treatment. An effective amount of medical treatment may reduce at least 23% of the symptoms or effects associated with the N-6 substituted 7-deazaindole compound in response to at least about 20% (more preferably at least about 40%, and even more Preferably at least about 60%, and more preferably at least about 80 ° /.) relative to untreated patients, cooked The artist can design a test method to measure the degree of mitigation of such signs and/or effects, and any test method known in the art that can measure this parameter is included and is part of the present invention, for example, if asthma is For the condition to be treated, the volume of gas expelled from the patient's lungs can be measured before and after treatment using techniques known in the art to measure the volume increase, and if inflammation is the condition to be treated, then it can be used. Techniques known in the art measure the area of inflammation before and after treatment to measure the extent of reduction in the area of inflammation. The so-called "cells" include prokaryotic and eukaryotic cells. The so-called "animals" include adenosine receptors. Any organism or any organism that is responsive to the N-6 substituted 7-deazaindole compound, examples of which include yeast, mammals, reptiles and birds, as well as genetically transformed animals. The so-called "mammals" are known to the art and are meant to include animals, more preferably warm-blooded animals, most preferably cows, sheep, pigs, dogs, cats, large voles, mice and humans. N_6 substituted 7_deazaindene wood paper scale is applicable to China National Standard (CNS) A4 specification (21〇x 297 璧 (please read the back of the note first? Please fill in this page again) 0---- --------------- 1287015 A7 V. Description of invention (,7) 15 20 The state of response, such as inflammation, emphysema, asthma, central nervous system or acute respiratory depression The mammals of the group include a part of the invention. In another aspect, the present invention relates to a method for modulating a glandular receptor in a mammal, via a 7-deazapurine substituted with N-6. The compound is administered to a mammal such that regulation of adenosine receptors occurs in a mammal, and suitable adenosine receptors include Al, VIII or VIII, in a preferred and solid G-N-6 Substituting 7·deazaindole compounds for adenosine receptor antagonism as ''regulatory adenosine receptors'' Interaction with adenosine receptors, causing physiologic activity, vasodilation, inhibition of adenosine by __ physiological activity increased, decreased or markedly or from subsequent cascade effectors that regulate adenosine receptor production P-type platelet/recording, thorn impurity regeneration, inhibition of lining decomposition, opening and unloading channels, reducing sodium channel efflux, etc., > what is called "regulation, and,, regulation,", for example, in the treatment method of the present invention Intracirculation refers to the undesired physiological activity that is associated with an abnormal stimulation of the glandular sputum, and in another specific embodiment, the regulation includes an antagonistic effect, such as mitigation from an over-stimulated gland. The activity or production of a glycosidic receptor-derived allergic and allergic inflamed medium, for example, a lunar surface deazapurine compound can act with a glandular receptor to inhibit the activity of, for example, adenylate cyclase. '...What is the case of abnormal adenosine receptor activity characteristics, which refers to diseases, disorders or conditions associated with abnormalities of the glandular genus, in which the recipient's stab line Λ9- the paper scale applies to China National Standard (CNS) A4 Specification (2) (3) π Public Love) 1287015

1287015

V. Description of invention (,?) The Intellectual Property Office of the Ministry of Economic Affairs, the employee consumption cooperative, printed the yuan base: aryl, or dazzling, or formed a substituted or unsubstituted heterocyclic ring 'heart is a hydrogen atom or a substituted or unsubstituted alkyl, aryl, or alkylaryl group; an R4 atom or a substituted or unsubstituted alkyl, aryl, or a calcined aryl; R5 and & A halogen atom such as chlorine, 5 murine, a hydrogen atom or a substituted silk, substituted by a substituted silk, or a aryl group, or R4 and Rs or Rs and & together form a substituted or unsubstituted heterocyclic ring or carbon The ring also includes a pharmaceutically acceptable salt of the N_6 substituted 7-deazaindole compound. In some embodiments, R1 and r2 may each independently be a 10 or unsubstituted cycloalkyl or heteroarylalkyl group. In another embodiment, & is a hydrogen atom. Or a substituted or unsubstituted heteroaryl group, in yet another embodiment, A' & and the core may each independently be a heteroaryl group. In a specific embodiment, Ri is a hydrogen atom, R2 is a substituted or unsubstituted, left-substituted cyclohexyl group, a cyclopentyl group, a cyclobutyl group or a cyclopropyl group, and hydrazine is a substituted or unsubstituted phenyl group. The heart is a hydrogen atom, and the heart is a methyl group. * In another embodiment, the core is cyclohexanol, cyclohexanediol, cyclodecylamine, cyclohexylamine, cyclohexyl, cyclohexene, cyclopentanol or cyclodecanediol, and R3 is Phenyl. In still another embodiment, R1 is a hydrogen atom, R2 is cyclohexanol, and 2 is a substituted or unsubstituted phenyl, vadine, fluorenyl, cyclopentyl or thienyl group, and Re is hydrogen. An atom, a substituted alkyl group, an aryl group or an arylalkyl group, and the oxime and the core are each independently a hydrogen atom, a substituted or unsubstituted alkyl group, an aryl group or an alkyl group. In yet another embodiment, K is a hydrogen atom and R2 is substituted ～21. The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -------- ------- Line ^wl (Please read the notes on the back and fill out this page) 1287015 Α7 Β7 V. Description of the invention (or unsubstituted alkylamine, arylamine, or alkylarylamine) , substituted or unsubstituted alkyl decylamine, aryl decylamine or alkyl aryl decylamine, substituted or unsubstituted alkyl sulfonamide, aryl sulfonamide or alkyl aryl sulfonium sulfonate Amine, substituted or unsubstituted alkyl urea, aryl urea or alkyl aryl urea, substituted or unsubstituted alkyl urethane, aryl urethane or alkyl aryl a urethane, a substituted or unsubstituted alkyl carboxylic acid, an aryl carboxylic acid or an alkyl aryl carboxylic acid, R 3 is a substituted or unsubstituted phenyl group, the heart is a hydrogen atom, and R 5 and 1 is a methyl group. In yet another embodiment, r2 is a fluorenyl group, a modified fluorenyl group, a cyanoguanidinyl group, a thiourea group, a thiol amide group or a fluorenyl group.

>2C

(Please read the note on the back first? Then fill out this page.) 15 20 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed In a specific embodiment, R2 can be: R2a, K2b M, each of which is independently a helium atom Or a saturated or unsaturated alkyl, aryl or alkylaryl group, and R 2d is a hydrogen atom or a saturated or unsaturated alkyl, aryl or alkylaryl group, 1^2#^ or 〇& Wherein RyR% are each independently a hydrogen atom or a saturated or unsaturated alkyl, aryl or alkylaryl group, or together with Ra may form a carbocyclic or heterocyclic ring having a ring size of about 3 to 8 members, such as a ring. Propyl, cyclopentyl, cyclohexyl. In one aspect of the invention, the heart and heart are not simultaneously methyl, preferably one of the cores and the central group is an alkyl group, such as a methyl group, and the other is a hydrogen atom. In another aspect of the invention, when R4 is 1-phenylethyl and the hydrogen atom is present, ^R3 is not phenyl, 2-chlorophenyl, 3-phenylphenyl, 4-chlorophenyl, 3 '4 monochlorobenzyl, 3-methoxyphenyl or 4-methoxyphenyl, or when Γ. Lili people paper size is appropriate (four) off (10), 7 male hair) 1287015

V. INSTRUCTIONS (>/) When R4 and 1^ are 1-phenylethyl, when r3 is not an atom and the heart is a phenyl group, it is not a phenylethyl group 4 as a wind, as in the ttr aspect, when R5 and ^ together form a carbon ring example 5

15 20 When 疋 is opened, then & is not phenylphenyl)ethyl, phenylisopropyl: #R4 is H4-A is a hydrogen atom, then the heart is phenylethyl/di-benylethyl or When the ruler 3 is not = or aliphatic and may have 4 to 12 ^; the base 荨 'better has 5 to 7 carbon atoms, the two base nucleus is, the 仏 and the heart - can form an example ^ base == a group, or a mixture of 4 to 12 carbon atoms, a heteronuclear group, a typical heterocyclic ring or an aliphatic group, a heterocyclic ring substituted by an I® carbon atom, and which may be one or more carbon atoms of an aromatic structure. One or more heteroatom-substituted rings. In another aspect of the invention, examples of R properties include, but are not limited to, a lower heterocyclic ring, which represents a hydrazine group, etc., such as a 4-mercaptohexahydro group such as, for example, a ruthenium group. Hexahydro, m2-starting to form hexahydrogen such as well base soil, 4, base ^ such as base, -23^ paper size suitable for wealth _ Xushun (cns) A4 X 297 mm) 1287015 gR7 can be a hydrogen atom or Substituted or not in the present invention, such as substituted alkyl, aryl or alkyl

R4 and R5 can form a heterocyclic ring. Example 10 15 20 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 3 This impurity 3 is aromatic or aliphatic and can form 'to 12 carbon atoms such as two 'ρ= ί a base, a benzene-hexyl group, etc., and may be an aromatic or aliphatic group, such as a pentyl group, which may also be substituted, including a carbon atom with one or more _ structures, or a combination of a core and a < For example, the following heterocyclic ring. In a specific embodiment of the 4 injury, the Ν6 substituted 7-deazaindole is not a Ν-6 fluorenyl or Ν-6 phenylethyl substitution, and in another embodiment, & is not a benzyl group. Or a phenylethyl group, in a preferred embodiment, both 1 and 2 are not hydrogen atoms. In another preferred embodiment, R3 is not a hydrogen atom. The compounds of the present invention may contain a water-soluble prodrug which can be metabolized in vivo to an active agent, for example, via esterase-catalyzed hydrolysis. Examples of possible prodrugs include deazaindole compounds such as R2 via 〇C(〇)(Z) NH2 substituted cycloalkyl, wherein Z is a side chain of an alpha or /5, r or omega amino acid or dipeptide of a natural or non-naturally occurring amino acid or analog thereof, preferably an amino acid side chain comprising Glycine, alanine, valine, leucine, isoleucine, lysine, α-methylalanine, aminocyclopropyl carboxylic acid, azetidin-2-carboxylic acid, paper The scale applies to China National Standard (CNS) A4 specification (210 X 297 public) (Please read the note on the back and fill out this page) #订---------Line· Ministry of Economic Affairs Intellectual Property Bureau staff consumption Co-operative printing 1287015 A7 ~_______B7______ V. Description of the invention (> multi) - A side of alanine, r-aminobutyric acid, alanine-alanine or glycine-alanine. In another embodiment, the invention recites the deazaindole compound of Formula 1, wherein R is hydrogen; R2 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted An alkyl group, or a combination of a heart and a heart, forms a substituted or unsubstituted aryl group; an unsubstituted or substituted aryl group; the heart is hydrogen; and the heart and the heart are each independently an oxime or an alkyl group, And a pharmaceutically acceptable salt thereof, the deazazepine sigma compound of this embodiment may be a selective Α3 receptor antagonist. In a specific embodiment, R2 is a substituted (e.g., substituted by a base) or unsubstituted cycloalkyl group. In an advantageous sub-embodiment, & and R4 are hydrogen and Rs is a substituted or substituted phenyl group, and each of the ruthenium 5 and & is an alkyl group, preferably R2 is a monohydroxycyclopentyl group or a monohydroxycyclohexyl group, and the core may be substituted by -NH-C(=0)E, wherein E is a substituted or unsubstituted 2Ci_C4 I5 building group (e.g., an alkylamine such as ethylamine).

Ri and R2 may also together form a substituted or unsubstituted heterocyclic ring which may be substituted with an amine group or an acetamino group. In another aspect, R2 can be -A-NHC(=〇)B, wherein A is an unsubstituted CrC4 alkyl group (e.g., ethyl, propyl, butyl), and b is substituted or 20 unsubstituted CrQ alkyl (for example, methyl, aminoalkyl such as aminomethyl or aminoethyl, alkylamino such as methylamino, ethylamino), preferably Ri and R4 are hydrogen, R3 is not The substituted or substituted phenyl group, and & each is an alkyl group, and B may be a substituted or unsubstituted cycloalkyl group such as a cyclopropyl group or a 1-aminocyclopropyl group. ~2 5, This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------Mwi--------- (Please read the note on the back? Please fill out this page again) 1287015

V. Description of the invention (w) Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperatives - In another embodiment, the unsubstituted or substituted phenyl group is preferably an alkyl group. More preferably & may contain one or more substituents (e.g., o-, m- or p-chlorophenyl, o-, m- or p-fluorophenyl). Suitably R3 may be a substituted or unsubstituted heteroaryl group, preferably a care center and a heart group, and examples of heteroaryl groups include. ratio. Stationary, n-dimethyl sulfhydryl, tower well, pyridyl, pyrrolyl, triazolyl, thiazolyl, oxazolyl, oxadiazolyl, fluorenyl, methylenedioxyphenyl and thiophenyl, More preferably, Han 3 is 2-pyridyl, 3-indenyl, 4-pyridyl, 2-pyrimidinyl or 3-pyrimidinyl. Preferably, in one embodiment, the heart and heart are each hydrogen, and in another embodiment 10, the heart and heart are each a methyl group. In a particularly preferred embodiment, the deazaindole compound of the present invention is a water-soluble prodrug which can be metabolized into an active agent in vivo, for example, by esterase-catalyzed hydrolysis, preferably R2 of the previous drug-containing drug is a cycloalkyl group substituted by -oc(o)(z)nh2, wherein Z is a side chain of an amino acid which is naturally or unnaturally produced 15 or an analogue thereof, α, /3, 7 or amidinoic acid or a dipeptide Preferred examples of side chains include glycine, alanine, lysine, leucine, isoleucine, lysine, α-methylalanine, aminocyclopropyl carboxylic acid, and ketone. a side chain of quinone-2-carboxylic acid,/5-alanine, y-aminobutyric acid, alanine-alanine or glycine-alanine. 2 In a particularly preferred embodiment, the hydrazine is a side chain of glycine, R2 is a cyclohexyl group, R3 is a phenyl group, and R5 and R6 are methyl groups. In another embodiment, the deazaindole compound is 4-(cis-3-ylcyclopentyl)amino-5,6-dimercapto-2-phenylpyrazine [2,3d] . Melidine. 2 6~ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------- order---------^ IAWI (please read the notes on the back first) Fill in this page again) A7 1287015 B7 ----------- V. INSTRUCTION DESCRIPTION (>/) In another embodiment, the deazaindole compound is 4-7-3-(2) -Aminoethyl methoxy)cyclopentyl)amino-5,6-dimethyl-2-phenyl, 7h^xo[2,3d]pyrimidine trifluoroacetate. In another embodiment, the deazaindole compound is 5 acetylamino) hexahydro σ than butyl-5,6-dimethyl-2-phenyl-7H-咐^ and [2,3dj Pyrimidine. In another embodiment, the deazaindole compound is methylurea propyl)amino-5,6-dimercapto-2-phenyl-7H-^b 弁[2,3(i] n 密口定. 10 In another embodiment, the deazaindole compound is acetamidobutyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2, 3d] Continued to set. In another embodiment, the deazaindole compound is methylurea butyl)amino group 5,6-dimercapto-2.phenyl-7H-pyrrolo[2,3d], 1500. In another embodiment, the deazaindole compound is an aminocyclopropylethylaminoethyl)amino-2-phenyl-7H-pyrrolo[2,3d] continuation of 0 in another In a particular embodiment, the deazaindole compound is 4-(trans, 4, 20 hydroxycyclohexyl)amino-2-(3-chlorophenyl)-7H-pyrrolo[2,3d]pyrimidine. In another specific embodiment, the deazaindole compound is 4-(indolylcyclohexyl)amino-2-(3-fluorophenyl)-7H-pyrrolo[2,3d]pyrimidine. In another embodiment, the deazaindole compound is 4-(trans, 4, cyclohexyl)amino-2-(4-indenyl)-7Η-σ ratio 17 and [2, 3d ] mouth biting. ~27~ This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------------1------- Order ------ ---Line one ^" (Please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1287015 A7 B7 V. Invention Description (4) 5 15 20 In another embodiment In the present invention, the present invention describes a method for inhibiting the intracellular activity of an adenosine receptor (for example, A, AM, A2b or preferably As) by passing a cell with a N-6 substituted 7-deazaindole compound (for example, preferably ^Adenosine receptor inhibitor) contact. In another aspect, the invention features a method of treating eye damage in an animal (e.g., a human) by administering an effective amount of a N-6 substituted 7-deazaindole compound to the animal, preferably a ^6 substituted The 7-deaza is the a3 adenosine receptor in the animal cell. The anti-1 read "can be caused by the nerve head and can be acute or chronic. The damage can be, for example, glaucoma, edema, ischemia, hypoxia. Or a result of a wound. In a preferred embodiment, the invention recites a compound of formula π above, wherein: χ Ν or CR6; RI and R2 are each independently, 虱, or substituted or unsubstituted Alkoxy, amine alkyl, alkyl, aryl, or alkyl aryl, or together form a substituted or unsubstituted comon, provided that & and hydrazine are not hydrogen at the same time; R3 is Substituted or unsubstituted, substituted alkyl, aryl silk or silk; R4 money or recorded or not taken riCrC: 6 leucoyl 'L 4 hydrogen, substituted or unsubstituted syllabary deuterated or not taken The % of the Wei ring is hydrogen, hydrazine substituted or unsubstituted silk, or CH2, hydrazine, s or NR" where & is hydrogen or substituted Without the 匚 _ Syrian silk, Guan, silk: = Fang,: the United States: ❹ two soils, two heteroaryl groups, substituted groups, substituted thio ί ί ί ^ ^ base condition, if 1 " 3 is suppressed Set the base, then set - 28, the scale of the application of the Chinese National Standard (CNS) A4 regulations x 10 x 297 public) a 1287015 Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed Β 7 Β 7 5, invention description (θ) In a specific embodiment of the compound II, X is ^ and Q is CH2, 〇, s or ΝΗ, and in another embodiment, χ is Ν. In another specific embodiment of the compound of Formula II, w is substituted or unsubstituted aryl, 5- or 6-membered heteroaryl or biaryl, and the term may be substituted by one or more than five substituents. Examples of the substituent include: a group, a hydroxyl group, an alkoxy group, an amine group, an aminoalkyl group, an aminocarboxy carboxy guanamine group, CN, CF3, c〇2Rg, C0NHR8, c〇NR8R9, sor8, so2r8 or 8〇. 2 serving 81^, which

Rs and R9 are each independently hydrogen, substituted or unsubstituted alkyl, cycloalkyl, aryl or arylalkyl, preferably W substituted or unsubstituted, such as methylene Dioxyphenyl, W may also be a substituted or unsubstituted 5-membered heteroaryl ring such as pirolo, pyrenyl, hydrazine. Sitylene, imidazolyl, triazolyl, tetrazolyl, furyl, thienyl, thiazolyl and oxadiazolyl, preferably a 6-membered heteroaryl ring such as pyridyl, pyrimidinyl, hydrazine, Pyridinyl and thiophenyl, in a preferred embodiment, W is 2-pyridyl, 3-15 guanidine, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl or 5-pyrimidinyl . In an advantageous embodiment of the compound of formula II, hydrazine is _ and W is a 3-pyrrolo ring which is unsubstituted or substituted or unsubstituted alkyl, cycloalkyl, aryl or aryl Alkyl hydrazine-substituted. In another specific embodiment of the compound of Formula II, q is oxygen and w is a 20 oxathiazole ring which is unsubstituted or substituted or unsubstituted alkyl, cyclodecyl, aryl or aryl Alkyl substitution. In another specific embodiment of the compound of Formula II, w is a substituted or unsubstituted alkyl group, a cycloalkyl group such as a cyclopentyl group or an arylalkyl group, and examples of the substituent include a halogen group, a hydroxyl group, a substituted group or Unsubstituted alkyl, naphthenic ~29' This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) C Please read the back of the note first and then fill out this page) _ ---- ----^---------. 1287015 A7 B7 V. Inventions (>) 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printing Base, Aryl, Arylalkyl or NHR1G, Wherein Riq is hydrogen, or a substituted or unsubstituted alkyl, cycloalkyl, aryl or arylalkyl group. In still another embodiment, the invention recites a deazaindole compound of the formula π, wherein W is -(CH2)aC(=〇)Y or -(CH2)aC(=S)Y, and a is An integer from 0 to 3, Y is aryl, alkyl, arylalkyl, cycloalkyl, heteroaryl, alkynyl, NHRnR12, or the condition is q is nh, 〇Ri3, wherein Ru, "^ and !^ Each of which is independently hydrogen, or an unsubstituted or substituted alkyl, aryl, arylalkyl or cycloalkyl group, is preferably a 5- or 6-membered heteroaryl ring. Further, W may be -(CH2)bS(=〇)jY, wherein j is i or 2, b is 〇, 1, 2 or 3, and Y is an aryl group, an alkyl group, an aryl group, a cycloalkyl group, Block-heteroaryl, NHR^Rm, provided that when b is 1, Q is CH2, and wherein R14, R15 and Ri6 are each independently hydrogen, or unsubstituted or substituted alkyl, aryl, aryl Alkyl or cycloalkyl. In another specific embodiment, & is selected from the group consisting of substituted or unsubstituted phenyl, pyridyl, pyrimidinyl, hydrazine, pyridinyl, fluorenyltriazolyl, thiazolyl, hydrazine An azole group, an oxadiazolyl group, a pyrazolyl group, a guanidinium, a methylenedioxyphenyl group, and a thiophenyl group. When Rs is a phenyl group, it may be, for example, a benzyloxy group (for example, a methoxy group). , alkyl (such as tolyl) and dentate (such as ^ wide, m- or p-fluorophenyl or o-, m- or p-chlorophenyl) substitution, suitable for Han 2-, 3- or 4-pyridine Or a 2- or 3-pyrimidinyl group. 3... The present invention also relates to a deazaindene compound having a gas alkyl group at its center, and more preferably R6 is hydrogen. F 3 The present invention also includes a deazaindene compound whose center is gas and R is a paper scale applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------------- -------Book---------Line (please read the note on the back and fill out this page) 1287015 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 5, Invention Description (α Substituted or unsubstituted alkyl or alkoxy group, substituted or unsubstituted azide group, arylamino group or alkylarylamino group, substituted or unsubstituted amino group, amine group Aryl or amine alkyl aryl, substituted or unsubstituted decyl decylamine, aryl decylamine or alkyl aryl decylamine, substituted or unsubstituted 5 ketone amine, square a substituted amine or a aryl aryl amine, a substituted hydrazine unsubstituted carbazyl, an aryl sulfonyl or an alkyl aryl urea, a substituted or unsubstituted alkyl urethane, a aryl Alkyl decanoate or alkylaryl carbazate, substituted or unsubstituted decyl decanoic acid, aryl carboxylic acid or alkyl aryl carboxylic acid, preferably & Substituted naphthenic _ Such as mono- or dihydroxy-substituted 1〇 the cyclohexyl or cyclopentyl (more appropriate monohydroxy-substituted cyclohexyl group or the mono-substituted by the group of cyclopentyl).

Wherein Α is a CrC6 alkyl group, a C3-C7i^ group, a bond of 1 to 7 atoms, or a ring of 3 to 7 atoms, optionally via a crC6 alkyl group, a hydroxy group, a hydroxy group, a thio group or an amine group. Substitution; B is methyl, N(Me)2, N(Et)2, NHMe, 20 NHEt, (CH2)rNH3' NH(CH2)rCH3, (CH2XNH2, (CH2)rCHCH3NH2, (CH2)rNHMe, (CH2 rOH, CH2CN, (CH2)mC02H, CHR18R19 or CHMeOH, where r is an integer from 0 to 2, m is 1 or 2, R18 is alkyl, ri9 is νη3+ or CO2H or R18 and Rl9 is from ~31 The scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------------#--------tT--------- (please Read the note on the back first? Then fill out this page. 1287015 A7 B7

V. Inventive Note (V) F. r, I. :;;vj 13⁄4 15 a 20 •CH-NH- \ / (CH2)p where p is 2 or 3; and R17 is CrC6 alkyl, 〇:3- (: 7 cycloalkyl, a chain of 1 to 7 atoms, or a ring of 3 to 7 atoms, optionally substituted by a crC6 alkyl group, a halogen group, a trans group, a thiol group, a thio group or an amine group. Unsubstituted or substituted 2CrC6 alkyl, B may be unsubstituted or substituted CrC6 alkyl. In a preferred embodiment, & is a formula -A-NHC(=〇)b, in a particular In a suitable embodiment, A is -CH2CH2- and B is methyl. The compounds of the invention may contain a water-soluble prodrug which can be metabolized in vivo to an active agent, for example, via esterase-catalyzed hydrolysis, examples of possible prodrugs include A deazaindole compound such as R2 is a soil alkyl group substituted with -OC(0)(Z)NH2, wherein z is a natural or non-naturally occurring amino acid or analog thereof cold, r or omega amino acid or two The side chain of the peptide, preferably the amino acid side chain includes glycine, alanine, valine, leucine, isoleucine, lysine, alpha-methyl alanine, aminocyclopropyl Wei acid, ϋ丁ϋ定-2-rebel , the side bond of no-alanine, T-aminobutyric acid, alanine-alanine or glycine-alanine. In another embodiment, 1^ and 112 are: ----- ---Order---------Line (please read the phonetic on the back? Please fill out this page again) Printed by the Intellectual Property Office of the Ministry of Economic Affairs

N erren's paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 V. Invention description (present / 5 10 15 20 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed η 1 or 2, and wherein the ring may be optionally substituted by one or more hydroxyl, amine, thio, carboxy, halo, CH2OH, ch2nhc(=o)alkyl or CH2NHC(=〇)NH alkyl, preferably η Is 1 or 2 and the ring is substituted with -NHC(=0)alkyl. In another suitable embodiment, Ri is hydrogen, a substituted or unsubstituted CrC6 alkyl group, and the heart is substituted Or unsubstituted phenyl, & is hydrogen, L is hydrogen or substituted or unsubstituted alkyl, q is hydrazine, S or NR7, wherein R? is hydrogen or substituted or unsubstituted alkyl And W is a substituted or unsubstituted aryl group, preferably -A-NHC(=0)B, wherein A and B are each independently an unsubstituted or substituted crc4 alkyl group, for example A may be Ch2CH2, B may be, for example, an alkyl group (e.g., a methyl group), or an amine group (e.g., an aminomethyl group), preferably & is an unsubstituted phenyl group and the L domain, & Or a better domain, Preferably, q is 0, S or NR7, wherein & is hydrogen or substituted or unsubstituted (w is unsubstituted or substituted phenyl (for example, 6 methoxy benzene iw keering base, or 4^BH job masks fortune, listen to (four) 吟 compound trace 6 Yunna 2 media ^ for 4 Cong (four) specific Wei, listen to the compound ah (4_ acetylaminoethyl) amine. 7Η-pyrrolo[(3)] blasting. I presently based on a particularly preferred embodiment of the present invention, the deaza compound is applied to the Chinese national standard x 297 PCT) -------------------- Order --------- line (please read the notes on the back and fill out this page) 1287015 Ministry of Economics Property Bureau employee consumption cooperative printed A7 V. Invention description u>) 4-(2-Ethylaminoethyl)amino _6_(4-chlorophenoxy)methyl_2_phenyl_7H_ ^ 嘻 and Od] ♦ 定. In a particularly preferred embodiment, the deazaindole compound, 4-(2-acetamidoethyl)amino-6-(4-methoxyphenoxy)methyl-2-5benzene The base-7Η_σ is more than [2,3d] pyrimidine. In a particularly preferred embodiment, the deazaindole compound is 4-(2-diethylaminoethyl)amino-6-(2-pyridyloxy)methyl-2-phenyl-7H- t each [2, quinopyrimidine. In a particularly preferred embodiment, the deazaindole compound 10 is 4-(2-ethylaminoethyl)amino-6-(N-phenylamino)methyl-2-phenyl- 7H-pyrrolo[2,3d]pyrimidine. In a particularly preferred embodiment, the deazaindole compound is 4·(2-ethylaminomethyl)amino-6-(N-fluorenyl-N-phenylamino)fluorenyl -2-phenyl-7H-pyrrolo[2,3d]pyrimidine. In a particularly preferred embodiment, the deazaindole compound is 4-(2-N'-methylureidoethyl)amino-phenoxymethyl-2-phenyl-7-lepirozolo[ 2,3d]pyrimidine. The present invention also relates to a method of inhibiting the intracellular activity of an adenosine receptor (e.g., A2b adenosine receptor) by contacting a cell with a compound of the present invention. Preferably, the compound is an adenosine receptor inhibitor. The invention also relates to a method of treating a gastrointestinal disorder (e.g., abdomen) in an animal by administering an effective amount of a compound of the invention (e.g., an anti-inflammatory agent to the animal), preferably the animal is a human. . In another embodiment, the present invention relates to a pharmaceutical combination of ~34~ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------------ f--------Book---------Line· (Please read the phonetic on the back? Please fill out this page again) 1287015 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. DESCRIPTION OF THE INVENTION (w) Penta, which contains the N-6 substituted 7-deaza compound of the present invention and a pharmaceutically acceptable carrier. The present invention also relates to a therapeutic pair in an animal which is substituted A method in which the 7-deazaindole compound has a responsive state, by administering a therapeutically effective amount of the deazaindole compound of the present invention to an animal, so that treatment in the animal is performed on 7-deaza The heterozygous compound has a responsive state, and the disease state is suitable for a disease caused by adenosine. Examples of preferred disease states include central nervous system diseases, gastrointestinal diseases, eye diseases, and respiratory diseases. , alkyl, including linear alkyl, branched alkane 10, cyclized (alicyclic) a pyridyl-substituted cycloalkyl group and a cycloalkyl-substituted alkyl group, the so-called alkyl group further comprising an alkyl group, which may further comprise an oxygen, nitrogen, sulfur or phosphorus atom in place of one or more carbon chains such as oxygen, a nitrogen, sulfur or phosphorus atom, in a preferred embodiment, the linear or branched alkyl group contains 3 or less carbon atoms in its main chain (for example, a straight chain of CrC3G, a branch of crC3G), More preferably, it contains 15 20 or less carbon atoms. Similarly, a preferred cycloalkyl group has 4 to 10 carbon atoms in its ring structure, and more preferably 5, 6 or 7 in its ring structure. Further, the term "alkyl" as used throughout the specification and claims is intended to include "unsubstituted alkyl" and, substituted alkyl, and the latter 20 refers to alkyl in the hydrocarbon chain. The hydrogen on one or more carbons is substituted with a substituent, which may include, for example, a halo group, a hydroxyl group, an alkylcarbonyloxy group, an arylcarbonyloxy group, an alkoxycarbonyloxy group, an aryloxycarbonyloxy group, Carboxylic acid ester group, alkylcarbonyl group, alkoxycarbonyl group, aminocarbonyl group, alkylthiocarbonyl group, alkoxy group, phosphate group, phosphonic acid group, phosphinic acid , cyano, amine (including alkyl amine, dialkylamine ~ 35' This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ----------- ----------Book---------Line (please read the note on the back? Please fill out this page again) 1287015 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed Β7 Β7 5 , Description of the invention (¥), arylamino, diarylamine and alkylarylamine), mercaptoamine (including alkylcarbonylamino, arylcarbonylamino, aminocarbamyl) And ureido), fluorenyl, imido, thiol, alkylthio, arylthio, thiocarboxylate, sulfate, contiguous, amine thiol, hydrazine, nitro , trifluoromethyl, 5-carbon, azo, hetero-based, alkyl aryl or aromatic or heteroaromatic groups, those skilled in the art can know that the basic body substituted on the main chain can be Substituted, a cycloalkyl group may be substituted with, for example, the above-mentioned substituents, "alkylaryl", which means an alkyl group substituted with an aryl group (for example, phenylmethyl (benzyl)), said, alkyl group, Also includes similar alkyl lengths and possible Instead unsaturated aliphatic groups, each containing at least 10 but a double or triple bond. As used herein, "aryl" refers to an aryl group containing 5- and 6-membered monocyclic aromatic groups which may contain from 0 to 4 heteroatoms such as benzene, pyroline, furan, thiophene, saliva, benzo. Anthracene, benzopyrene, triterpenoid, tetrazolium, σ, 口, 比, 吼, 嘧啶, and pyrimidine, etc., aryl also includes polycyclic fused aromatics such as naphthyl, anthracene An aryl group containing a hetero atom in a ring structure may also be referred to as an "aryl heterocycle, ',,, a heteroaryl, or a heteroaromatic group, an aromatic ring It may be substituted at one or more ring positions by the above substituents, for example, a halogen group, a hydroxyl group, an alkoxy group, an alkylcarbonyloxy group, an arylcarbonyloxy group, an alkoxycarbonyloxy group, an aryloxycarbonyloxy group, Carboxylic acid ester group, alkylcarbonyl group, alkoxycarbonyl group, amine 20-based carbonyl group, alkylthiocarbonyl group, phosphate group, phosphonic acid group, phosphinic acid group, cyano group, amine group (including alkylamino group, two Alkylamino, arylamino, diarylamino and alkylarylamino), mercaptoamine (including alkylcarbonylamino, arylcarbonylamino, aminomethylguanidino and ureido) ), lung base, imine , thiol group, thiol group, arylthio group, thiocarboxylate group, sulfate group, sulfo group, amine stone yellow paper size applicable to China National Standard (CNS) A4 specification (210 X 297 mm) - -------------------- Order --------- Line IAWI (please read the note on the back? Please fill out this page again) V. Invention Description (y) fluorenyl, amide, nitro, trifluoromethyl, cyano, azo, alkyl or aromatic or heteroaromatic, aryl and alicyclic = aromatic The heterocyclic ring is fused to form a polycyclic ring (e.g., tetralin). 4 + The so-called "dilute group," and ", fast radical," means a long-term and possibly substituted unsaturated similar to the above-described alkyl group. Month|Family base, but each contains at least one ^ key or a key. For example, the cyano and allyl groups contemplated by the present invention. And unless the number of carbon, the core, the low-carbon alkyl group of the above-mentioned alkyl group, but contains i to 10 carbon atoms, more preferably in the primary bond structure; containing 1 to 6 carbon atoms, and more preferably in the main chain structure It contains 43 carbon atoms, and similarly, 'lower alkenyl, and, lower alkynyl, has a similar bond length. The term "alkoxyalkyl", ", polyaminoalkyl", and, thioalkoxyalkyl" refers to the above alkyl group, and additionally includes an oxygen, nitrogen or sulfur atom in place of its main chain. One or more carbon atoms, such as an oxygen, nitrogen or sulfur atom. 15 As used herein, a polycyclic ring, or a polycyclic ring, refers to a ring containing two or more rings (eg, cycloalkyl, cycloalkenyl) a group of a cycloalkynyl, aryl and/or heterocyclic ring wherein two or more carbons are shared by two adjacent rings, such as a ring, a fused, a ring, which is attached via a non-adjacent atom The ring, the bridged, the ring, and the polycyclic ring may be substituted by the above substituents, for example, a halogen group, a hydroxyl group, an alkoxy group, an alkylcarbonyloxy group, an arylcarbonyloxy group, an alkoxycarbonyloxy group. , aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthiocarbonyl, phosphate, phosphonic acid, phosphinic acid, cyano, amine Including alkylamino, dialkylamino, arylamino, diarylamine and alkylarylamine), mercaptoamine (including alkylcarbonylamino, arylcarbonylamino, amine) Methyl acyl group and off), county, imino, sulfhydryl, alkylthio, arylthio, this paper carbothioic applicable China National Standard Scale (CNS) A4 size (210 X 297 Kimiyoshi) 1287015

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, printing acid ester, sulfate, sulfo, sulfonamide, sulfonamide, nitro, trifluoromethyl, cyano, azo, miscellaneous, silk Silk or aromatic or heteroaromatic groups. The hetero atom '' as used herein refers to a raw material other than carbon or hydrogen, and preferred heteroatoms are nitrogen, oxygen, sulfur and phosphorus. The so-called 'amino acids, including natural and non-naturally occurring amino acids in proteins, such as glycine, alanine, _ acid, hemi-amic acid, x valine, isoleucine Acid, serine, threonine, methionine, valine, aspartic acid, glutamine, aspartame, lysine, arginine, brinic acid, histidine , phenylalanine, tyrosine, and tryptophan, amino acid analogs including amino acids that lengthen or shorten side chains or different side chains with appropriate functional groups, when the structure of the amino acid allows stereoisomeric forms The amino acid also includes the D and L stereoisomers of the amino acid, so-called, dipeptides, including two or more amino acids linked together, and the preferred dipeptide is two amine groups. The acid is linked via a peptide I5 linkage, and particularly preferred dipeptides include, for example, alanine-alanine and acid-alanine. It can be noted that some of the compounds of the present invention contain asymmetric carbon atoms, whereby it is known that the isomers resulting from such asymmetry (for example, all of the pair of palmar isomers and non-palphaliomers) are included in Within the scope of the invention, unless otherwise stated, these isomers can be obtained in substantially pure form via conventional separation techniques and stereochemical synthesis. The present invention also relates to pharmaceutical compositions for treating a condition in a mammal that responds to a N-6 substituted 7-deazaindole compound, such as a respiratory disease (eg, asthma, bronchitis, chronic obstructive pulmonary disease, and allergy). ~38

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public )

1287015 A7 V. INSTRUCTION DESCRIPTION (3; 7) Sexual rhinitis), kidney disease, gastrointestinal disease, and eye disease, the pharmaceutical composition containing the above-mentioned Ν-6 substituted 7-deazaindole compound and a pharmaceutically effective amount thereof Acceptable carriers, it must be understood that all of the above deazaindole compounds are included in the medical treatment, it is also understood that the deazaindole compounds of the present invention may be used alone or in combination with other deazaindole compounds of the present invention or Used in combination with other medical compounds such as antibiotics, anti-inflammatory agents or anticancer agents. The term "antibiotic" is art-recognized and refers to a substance made by culturing a microorganism and synthesizing a derivative thereof, which can eliminate or inhibit the growth of a pathogen and selectively toxic to the disease, but to the infection. Host patients produce little or no exacerbation effects, and suitable examples of antibiotics include, but are not limited to, major classes of aminoglycans, cephalosporins, amminemycin, fusidic acid, macrolides, penicillins, polymyxins. , tetracycline and streptomycin. 15 20 The term 'anti-inflammatory agent' is known to the art and refers to hair buds that act on the body but do not directly antagonize inflammation, such as glucocorticoids, aspirin, ibuprofen. Acid, NSAIDS, etc. The so-called 'anticancer agent' is known to the art and refers to agents including reduction, root = or prevention of cancer cell growth and preferably not adversely affecting other physiological functions, representative examples Including chloramphenicol and phosphoniumamine. When the compound of the present invention is administered as a medicament to humans and mammals, it can be administered by itself or in a pharmaceutical composition containing, for example, 〇·i to 99·more preferably 0.5 to 90%. As used herein, a pharmaceutically acceptable carrier means a substance, composition or vehicle that is acceptable, such as a liquid or solid filled formulation, excipient, solvent or Encapsulation material, and carrying or transporting the paper size of the thorn towel off & fresh (CNS) A4 specifications (2) 〇: 297 mm)

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

#· (Please read the note on the back? Please fill out this page.) 1287015 The compound of the invention is related to the patient so that it can carry out the desired function. The compound can be carried or transported from the body to the other organ. Or location, all sides must be, acceptable, other ingredients are compatible and do not harm the patient, and some examples of substances that are pharmaceutically acceptable carriers include: sugars such as lactose grape sugar; Temple powders such as corn starch and horse mash potato powder; cellulose and organisms such as county methyl cellulose sodium, ethyl cellulose and cellulose acetate vinegar; powdered scutellaria; malt; gelatin; talc; Forming agents such as cocoa butter and suppository ants; oils such as peanut oil, cottonseed oil, flowers, H) sesame oil, eucalyptus oil, corn oil and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbose Alcohol, mannitol and polyethylene glycol; vinegars are known as oleic acid ethyl vinegar and lauric acid B; agar; buffers such as magnesium hydroxide and hydroxide; alginic acid; pyrogen-free water; isotonic saline ;Curry solution ; ethanol; phosphate buffer solution; and other non-toxic compatible substances used in _ modulation. As indicated above, some embodiments of the compounds of the invention may contain a basic functional group, such as an amine or alkylamine group, and thus form a pharmaceutically acceptable salt with a pharmaceutically acceptable acid, As used herein, a pharmaceutically acceptable salt refers to a substantially non-toxic, non-organic, organic acid addition salt of the compounds of the invention which can be isolated and purified at the end of the compound of the invention. Prepared on the spot, or the purified compound of the invention is separately reacted with a suitable organic or inorganic acid in its free form, and the salts thus formed, representative salts include hydrobromide, hydrogen Chlorate, Sulfate, Sulfite, Phosphate, Nitrate, Acetate, Valerate, ~40- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) --- ----Book---------Line· 1287015

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 5, Inventions (V) Oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, Thionate, maleate, fumarate, succinate, tartrate, naphthate, methanesulfonate, glucoheptonate, lactanoate and lauryl sulfonate (see For example, Bergevetal 5 (1977) "Pharmaveutical Salts,,, />/ 隐 隐 5W. 66:1-19). In other cases, the compounds of the invention may contain one or more acidic functional groups, and thus may be pharmaceutically The acceptable base forms a pharmaceutically acceptable salt, and in these instances, a pharmaceutically acceptable salt, refers to a relatively non-toxic inorganic and organic base addition salt of the compound of the invention. These salts 10 can likewise be prepared in situ when the compound of the invention is finally isolated and purified, or the purified compound of the invention can be reacted separately with a suitable base in its free acid form, for example with a pharmaceutically acceptable metal. Cationic hydroxide, carbonate or carbon Acid hydrogen salt, with ammonia or with pharmaceutically acceptable organic primary, secondary or tertiary amines, representative alkali metal or alkaline earth metal salts 15 including clock, sodium, potassium, calcium, magnesium and aluminum salts Representative organic amines which can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, hexahydropyrrole, etc. The so-called "pharmaceutically acceptable esters" , means a relatively non-toxic esterification product of the compounds of the invention which may be prepared in situ upon final isolation and purification of the compounds of the invention, or the purification of the compound of the invention in its free acid form or hydroxy group and suitable The esterification agent is separately reacted, the carboxylic acid can be converted to an ester via the use of an alcohol in the presence of a catalyst, and the hydroxyl group-containing derivative can be converted to an ester by treatment with an esterifying agent such as an alkane-based toothing. Includes low-carbon hydrocarbon groups that can be solvated under physiological conditions, such as alkyl esters, methyl groups, ~41. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) -------- ^--------- (Please read the phonetic on the back first? Refill this page) 1287015 A7 B7 V. INSTRUCTIONS (Iron and propyl S) (see, for example, Bergeia/.). The present invention also encompasses the use of prodrugs which can be converted in vivo. Invented medical compound (see for example RB Silverman, 199Hhe

Organic Chemistry of Drug Design and Drug Action" 5 Academic Press, Chp. 8), previously used to alter the biodistribution of a medical compound (eg, to allow a compound to enter a protease reaction site that is generally unreachable) or pharmacokinetics, such as carboxy The acid group can be esterified with, for example, methyl or ethyl to form an ester. When the ester is administered to a patient, the ester is dissociated by an enzyme or a non-enzyme, reducing or hydrolyzing to release an anionic group, and the anionic group can be separated from the cleavable group. Rather, the group of the intermediate compound is acetated (for example, methoxyoxymethyl g), which is subsequently decomposed to give the active compound. In another embodiment, the prodrug is a reduction of sulfate or rhein. a form, such as a thiol, which can be oxidized in vivo to a medical compound, and the anionic group can be converted into a base that can be actively transported in vivo, or it can be selectively taken up by a target organ, and the ester can be selected. The treatment site is specifically labeled to a specific reaction site, as described below in the carrier base. Wetting agents, emulsifiers and lubricants may also be present in the compositions, for example Such as sodium lauryl sulfate and magnesium stearate, as well as dyes, release agents, coating agents, sweeteners, flavors and fragrances, preservatives and antioxidants. 20 Examples of pharmaceutically acceptable antioxidants include: water soluble Sexual Antioxidant Economics Department Intellectual Property Bureau employees consumption cooperative printing preparations such as ascorbic acid, cysteamine hydrochloride, sodium hydrogen sulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyl Anisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl citrate, alpha-tocopherol, etc.; and metal chelating agents such as citric acid, ethane-2 42' This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm) 1287015

The Intellectual Property Office of the Ministry of Economic Affairs, the employee consumption cooperative, printed amine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. The compositions of the present invention include compositions for oral, nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration, which are conveniently presented in unit dosage form and It can be prepared by any of the methods known in the art of pharmacy, and the amount of active ingredient which can be combined with the carrier to produce a single dosage form is usually the amount of the compound which produces a medical effect, usually containing from 1% to about 99% The active ingredient is preferably from about 5% to about 70%, most preferably from about 10% to about 30%. A method of preparing such a composition or composition, the method comprising the step of mixing a compound of the present invention with a carrier and optionally one or more accessory ingredients, usually by preparing a compound of the invention and a liquid carrier Or the solid carrier of the micro-segmented particles or both are uniformly and intimately mixed, and then the product is shaped if necessary. The compositions of the present invention suitable for oral administration may be capsules, sachets, 15 $, tablets, lozenges (using flavored bases, usually sucrose and acacia or tragacanth), powders, granules, Or a liquid or suspension in an aqueous or non-aqueous liquid, or as a liquid emulsion of oil in water or water in oil, or as an elixir or syrup, or as an additive (using an inert matrix such as gelatin And glycerin, or sucrose and gum arabic, and/or mouthwash, each containing a predetermined amount of the compound of the present invention as an active ingredient, and the compound of the present invention may also be administered as a bolus, elixirs or paste. The solid dosage form of the present invention for oral administration (capsules, tablets, pills, sugar-coated pills, powders, granules, etc.), the active ingredient is a raincoat or a mixture of various pharmaceutically acceptable carriers, such as sodium citrate Or dicalcium phosphate, ~43~ This paper scale applies _ National Standard (CNS) A4 specification (210 X 297 mm)

--------Book --------- Line · (Please read the note on the back and fill out this page) # 1287015 A7 B7 V. Invention Description (θ) and / or any of the following substances : fillers or extenders, such as starch, lactose, sugar, glucose, mannitol, and/or citric acid; adhesives such as carboxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, cane and / or Arab cockroach; sizing agents such as glycerin; decomposers such as agar, calcium carbonate, horse mash 5 or tapioca starch, alginic acid, partial citrates and sodium carbonate; solution retarders such as rocky soil; absorption acceleration Agents such as quaternary ammonium compounds; wetting agents such as whale base alcohol and glyceryl monostearate; absorbents such as kaolin and scented clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene a diol, sodium lauryl sulfate, and a mixture thereof; and a coloring agent, in the case of a capsule, a tablet, and a pill, the pharmaceutical composition of the present invention may also contain a buffering agent, and a solid composition of a similar form may also be used. Used as a filler in soft and hard-filled gelatin capsules, using lactose Or milk sugar as well as high molecular weight polyethylene glycol or the like as an excipient. Tablets may be made by extrusion or molding, and optionally one or more of 15 auxiliary ingredients may be used, and the extruded tablets may be coated with an adhesive (for example, gelatin or hydroxypropylmethylcellulose), a lubricant, or an inert diluent. Prepared with a preservative, preservative, decomposing agent (such as sodium starch glycolate or crosslinked sodium carboxymethylcellulose), a surfactant or a dispersing agent. The molded tablet can be molded by inerting in a suitable machine. Prepared by mixing a liquid diluent with a moistened powdered compound. 20 Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills, and granules, may optionally be scored or coated with a coating or shell preparation, such as are known in the form of edible coatings and pharmaceutical arts. Other coatings, which can also be formulated to provide active ingredients slowly or controlledly in the body using, for example, varying proportions of hydroxypropyl methylcellulose to provide the desired release. 44. The paper size applies to the Chinese National Standard (CNS). A4 size (21〇x 297 mm) (Please read the note on the back and fill out this page) - Ordering. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1287015 V. Invention description (^^) 5 15 20 Economy The Ministry of Intellectual Property's employee consumption cooperatives prints the shape of the body, which can be combined with the amyl group and/or the small ball. It can also be used to kill the bacteria, or to mix the fungicide into a substance. Money • Water that can be dissolved in money or other ''', can be; main shot (four) medium towel, this compound can also be used as a turbid agent, and can also be released only in or better in certain parts of the gastrointestinal tract a composition of active ingredients, And, if desired, in a delayed manner, the burial composition that can be used comprises the polymer f and the ant, and the active ingredient may also be in a microencapsulated form, optionally containing one or more of the above-mentioned excipients. The compound of the present invention is for oral administration, and includes a pharmaceutically acceptable emulsion, a microemulsion, a solution, a suspension, a syrup, and a granule. In addition to the active ingredient, a liquid dosage form may be included in the art. Inert diluents often used in the process, such as water or other solvents, solvents and emulsifiers such as ethanol, isopropanol, ethylene carbonate, acetic acid (10), + alcohol, benzoic acid, propylene glycol, H-butanediol, Oils (especially cotton stalks, peanuts, corn, germ, eucalyptus, ramie and sesame oil), glycerol, tetra-n-ol, polyethylene glycol and sorbitan fatty acid esters, and mixtures thereof. Besides the inert diluent, the oral compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, pigments, flavors and preservatives. In addition to the active compound, the suspension may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, Agar and tragacanth, and mixtures thereof. The composition of the pharmaceutical composition of the present invention for rectal or vaginal administration may be present in the paper size. The Chinese National Standard (CNS) A4 specification (21〇X 297 mm) is applicable. 1287015 A7 5. The invention description (inhibition) is a suppository. It may be prepared by mixing one or more compounds of the invention with one or more excipients or carriers which are non-irritating, including, for example, cocoa butter, ethyl alcohol, suppository or salicylate, It is a solid at room temperature, but liquid at body temperature, so it will melt in the rectum or vaginal cavity and release a living compound. Blends of the invention suitable for vaginal administration also include pessaries, stoppers, creams, gels, pastes, foams or spray formulations, and include suitable carriers known in the art. The dosage form of the compound of the present invention for topical or subcutaneous administration includes powder 10, spray, ointment, paste, cream, lotion, gel, solution, patch and inhalant, and the sterile compound can be sterilized and pharmaceutically The carrier can be accepted, mixed with any preservatives, buffers, or propellants that may be required. In addition to the active compound of the present invention, ointments, pastes, creams and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin films, starches, 15 tragacanth, cellulose derivatives, polyethylidene Glycols, anthrones, bentonites, sulphur, talc, and oxidized words, and mixtures thereof. In addition to the compound of the present invention, the powders and sprays may contain excipients such as lactose, talc, citric acid, aluminum hydroxide, citric acid and polyamidamine powder, or a mixture of these substances, and the spray may additionally contain conventional Propellants such as gas 20 fluorocarbons and volatile unsubstituted hydrocarbons such as butadiene and propane. Another advantage of a transdermal patch is to provide a controlled delivery of a compound of the invention to the body. The dosage form can be prepared by dissolving or dispersing the compound in a suitable medium, or an absorption enhancer can be used to increase the rate of passage of the compound through the skin. Can be provided by rate-control film or dispersion of active compound ~46' This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the back note before filling this page) ---- ----订---------Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1287015 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 V. Invention Description (ο in polymer matrix Controls, ophthalmic blends, eye ointments, powders, solutions and the like are also included in the scope of the invention, and the pharmaceutical preparations are preferably ophthalmic preparations (for example, around the eyes, after the eye or intraocular injection formula, systemic formula or surgery). Rinsing solution) 5 The ophthalmic composition of the present invention may contain one or more deazaindole compounds and a pharmaceutically acceptable vehicle, and various forms of vehicles may be used. The agent is usually of an aqueous nature, usually in the form of an aqueous solution, in the case of a blend, and the convenience of the patient by dripping one to two drops of the solution into the infected eye, but the deazapine of the present invention The phthalate composition may also be readily incorporated into compositions of other forms, such as suspensions, viscous or semi-viscous colloids or other forms of solid or semi-solid compositions, and the ophthalmic compositions of the present invention may also contain different Other ingredients such as buffers, preservatives, auxiliary solvents and tackifiers. Add appropriate buffer systems (eg sodium sulphate, sodium acetate or 15% acid) to prevent pH changes during storage. Usually packaged in multiple doses, so preservatives are needed to avoid microbial contamination during use. Suitable preservatives include: gasified benzalkonium chloride, thimerosal, oxybutanol, methylparaben, p-hydroxybenzene Propyl propylate, phenylethyl alcohol, edetate disodium salt, sorbic acid, poly boast 20 or other agents known to the art, usually these preservatives are used in an amount of 0.001 to 10% by weight/volume ("% by weight/volume,") When using the deaza compound of the present invention during intraocular surgery, for example, via the eyeball or around the eye and intraocular perfusion or injection, optimum Use a balanced salt rinse solution as a vehicle, BSS@ Sterile ~47' -------- order --------- line (please read the phonetic on the back? Please fill out this page again)

1287015 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

15 20 V. Description of invention (β)

Irrigating Solution and BSS Plus® Sterile Intraocular Irrigating Solution (Alcon Laboratories, Inc., Fort Worth, TX. USA) are examples of physiologically balanced intraocular irrigation solutions, the latter forms of which are disclosed in U.S. Patent 4,550,022 (Garabedian, β α/ The entire contents are incorporated herein by reference, and are incorporated by reference to the art and are disclosed in various publications, such as Ophthalmic Surgery Principles: of Practice, Ed.? GL Spaeth. WB Sanders Co. 5 Philadelphia, Pa., USA, pp. 85-87 (1990). As described above, the use of a deazazenium compound to prevent or reduce damage to the retina and intracellular optic nerve head tissue is a particularly important aspect of particular embodiments of the invention, and treatable eye conditions include, but are not limited to, retinopathy, macular degeneration, Eye ischemia, glaucoma, and injuries associated with eye tissue damage, such as ischemia reperfusion injury, photochemical damage, and eye surgery-related injuries, especially retinal or optic nerve head injuries after exposure to light or surgical instruments, The compound of the present invention can also be used as an additional agent in eye surgery, such as ocular glass or subconjunctival injection after eye surgery, and the compound of the present invention can be used as an acute treatment for a short-term situation, or a chronic drug, especially in the case of a change. The inventive compounds are also prophylactic, especially before eye surgery or non-invasive ocular procedures or other forms of surgery. A pharmaceutical composition of the invention suitable for parenteral administration comprising one or more compounds of the invention in combination with a surface-acceptable sterile isotonic aqueous or non-aqueous solution, dispersion, suspension or emulsion, or prior to use Sterile injectable solution or dispersion of sterile powder, which can be - anti-oxidant scraping, buffer, bactericide, make the mixture and patient blood have special ------------- -----Order---------Line (please read the note on the back? Please fill out this page again) Paper size (4) Country (2); X 297 mm) 1287015 A7 V. Invention Description (P7) A substance, suspension or thickener that is permeable. I. In the present invention, the combination of suitable aqueous and non-aqueous carrier I includes water, ethanol, polyol (for example, glycerin, propylene glycol, polyethylene glycol, etc.) and a mixture thereof, vegetable oil such as lye oil. And an organic vinegar such as oleic acid vinegar which can be injected with hydrazine can maintain proper fluidity by using a coating material such as _ lipid, maintaining a desired particle size in the case of a dispersion, and using a surfactant. Some compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents, and the action of P-stopping microorganisms may be through the use of different fungicides and 10 fungicides, for example, p-benzene phthalate, gas Butanol, sorbic acid, etc., which may also require isotonic agents such as sugars, sodium chloride, etc. to be added to the composition, and, in addition, delayed addition of substances such as monostearic acid and gelatin may be added to delay Ingested pharmaceutical form for injection. In order to prolong the effect of the drug, it is necessary to slowly absorb the drug I5 from 2 or intramuscular injection, which may be through the use of a poorly water-soluble, oral or non-small substance. The liquid suspension is achieved, so that the absorption of the drug depends on its dissolution rate, and the dissolution rate is determined by the crystal size and the crystalline form, or the parenteral drug can be delayed by dissolving or suspending the agent in the oily vehicle. The absorption of the pharmacy. 20 Preparation of a deposited form for injection can be carried out by forming a microencapsulated material in a bioavailable, a polymer, such as a polyglycolic acid glycoside, depending on the ratio of the agent to the polymer, and the particular The nature of the compound can control the release rate of the drug. Other examples of biodegradable polymers include poly(o- vinegar) and poly(anhydride). The preparation of the depositional formulation for injection can also be processed through a 49-

I line paper size is based on the precautions (fNS) A4 specifications (2) X 297 mm) 1287015 V. Invention description U(P) 15 20 Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives are printed by the main agent Somatically compatible liposomes or microemulsions. The preparation of the present invention can be administered orally, parenterally, topically or rectally, and is of course supplied in a form suitable for each administration, for example, in the form of a tablet or a gel; a solution, an inhalation solution, Eye drops, ointments, examinations, etc. are administered by injection, perfusion or inhalation; topical administration via lotion or ointment, and rectal administration via suppository, preferably by oral administration. As used herein, parenteral administration, and/or medication, which is parenteral, refers to a mode of administration that is different from ingestion and topical administration, usually via injection, including but not limited to intravenous, intramuscular, and arterial. Internal, intra-, intra-, intravascular, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, intraspinal and intrasternal injections and perfusion. , as referred to herein, systemic medication,,,, medication, systemic,, "peripheral medication" and "drug terminal," refers to the drug used in the direct use of the book nervous system, compounds, _ and other substances that cause it to enter the patient's body and thus undergo metabolic and other similar processes, such as subcutaneous administration. These compounds can be administered to humans and other animals via any suitable means of administration, including oral, nasal, for example via Spray, rectal, intravaginal, parenteral, intracellular and topical, and via powder, soft palate or drops, including buccal and sublingual administration. Month / regardless of the route of administration, the compounds of the invention may be suitable The hydrated form and/or the pharmaceutical composition tau of the present invention is used in the form of a pharmaceutically acceptable pharmaceutical form prepared by the conventional methods known in the art. # In the pharmaceutical composition of the present invention, the actual active ingredient The dosage is variable, so that the amount of the active ingredient can be effectively targeted to a specific patient, composition and use ------ 丨丨tr------- ά φ (please read the notes on the back and refill This page) 丨.50~ This paper scale thorn + National Standard (CNS) A4 specification (210 X 297 public) 1287015 A7 -----^_____ V. Invention description (¥f) Medicine mode to get the required medical treatment Responsive and non-toxic to the patient. The dosage chosen will depend on a number of factors, including the particular compound of the invention, its ester, salt or guanamine activity, the route of administration, the time of administration, the frequency of excretion when a particular compound is used, Other agents, compounds and/or substances used with the specific conjugate during treatment, age, sex, weight, condition, physical condition and prior medical history of the patient being treated, and similar factors known in medical skills A physician or veterinarian having this general skill can readily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian 10 begins to use a pharmaceutical composition that is less than the desired medical effect. The desired amount of the compound of the invention is then gradually increased in dosage until the desired effect is achieved. Typically, a suitable daily dose of the compound of the invention will be The lowest dose effective to produce a medical effect, which is usually determined by the above 15 factors. Generally, the intravenous and subcutaneous doses of the compound of the present invention to a patient range from about 00001 to about 2 (8) mg when used for the analgesic effect described above. Each kilogram of body weight per day is more preferably from about 0.01 to about 150 milligrams per kilogram of body weight, and more preferably from about 0.2 to about 140 milligrams per kilogram of body weight per day. If desired, the effective daily dose of active compound can be on the day. At a suitable interval of 20, the second dose is divided into two, three, four, five, six or more sub-doses, and the drug is administered in unit dosage form as needed. Although the compound of the present invention can be administered alone, it is preferred to use a pharmaceutical combination. The invention also relates to a complete set of pharmaceutical compositions for treatment in mammals~51~ The paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) --------- ----Sale (please read the phonetic on the back first? Matters fill out this page) Order---------Line. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1287015 at _ B7 V. Invention description (50) - one one - one η # 气朴年ί 补充 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Heteroquinone compounds and instructions for use in the treatment of deazaindole compounds in a mammal using a deaza compound. The deazaindole compound of the present invention can be prepared by a standard method of organic synthesis, and the deazaindole compound can be purified by reverse phase HPLC, chromatography, recrystallization, etc., and its structure can be analyzed by mass spectrometry, elemental analysis, and/or Or confirmed by NMR spectroscopy. In general, the synthesis of the intermediates of the present invention and the deazaindole compound is carried out in solution, and it is also a typical practice to add and remove one or more protecting groups, and it is known to be skilled in the art to prepare the deazaindole of the present invention. A typical synthetic scheme for a compound intermediate is set forth in Scheme I below. The invention also provides a compound having the structure (IV): printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Bayer Consumer Cooperative

Wherein Ri is trans-4-hydroxycyclohexyl, 2-methylaminocarbonylaminocyclohexyl, acetamidoethyl or methylaminocarbonylaminoethyl; wherein R3 is substituted or unsubstituted four to six Ring, phenyl, pyrrole, thiophene, furan, thiazole, imidazole, pyrazole, 1,2,4-triazole, bite, -52- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 A7 (51) 1287015 Description of the invention. This R is called 2 (1H)-pyridone, 4 (1H) _ 咁 匕 ― ― —— —— ― ― ― —— —— —— 咄 咄 咄 咄 咄 咄 咄 咄 咄 咄 咄 咄 咄 咄 咄 咄嗒耕,异嗤, 圬, Π, 唾, 啥, 奈, nep, naphthyridine, benzofuran, stupid thiophene, anthracene, 2,3_dihydroindole.Μ ¥,, Leading wood, 1Η-吲哚, porphyrin, benzopyrazole, 1,3-opening bismuth, stupid and 1.7嗤, showing %, coumarin, color _, 唉 弁 ; La; Porphyrin, stupid imidazole, oxazolidine, pyridinium[2>b] ;!' ^#[3,.b] X is more than saliva [3, heart bites, bites, 2 (1H)- Ketone, 1 is isoindrone, 1,4_benzoiso-n-tower ^ ^ . t Xing 5 Kai, Benzothiazole, Porphyrin, 喳咁-N_ Telluride, Allocall咐-N-oxide, smear oxide, (iv) sputum oxide, benzo, 酞, ah or the following structure:

R^%>C

Jl2f wherein Y is carbon or nitrogen; wherein R 2 and Rr are independently H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, yl, methoxy, methylamine or Sulfhydryl; the center of the amine is H, an alkyl group, a substituted alkyl group, an aryl group, an aromatic alkyl group, a printed base of the Ministry of Economic Affairs, and a substituted aryl group, wherein the substituted alkane The group is C(R7)(R8)XR9, wherein X is oxime, s or NRi〇, wherein 仏 and ^ are each independently fluorenyl or alkyl, wherein R9 and rig are each independently alkyl or cycloalkyl, or NR9R1G is a substituted or unsubstituted 4 to 7 membered ring; the center of which is H, alkyl, substituted alkyl, cycloalkyl; or a pharmaceutically acceptable salt or precursor derivative thereof or biological activity Metabolite; condition is that when Ri is an ethylaminoethyl group, r3 is not a 4-pyridyl group. -53· This paper scale applies to Chinese National Standard (CNS) A4 specification U10X297 public) 1287015 Α7 Β7 V. Inventive Note (52) Amendment I Supplement η In a specific embodiment of the structure IV compound, NR9R1G is substituted or not Substituted 4 to 7 membered rings and selected from the group consisting of: Ό m N. where m is 0, 1 or 2,

Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed η is 0, 1, 2 or 3; where R8 is hydrogen,-011, -CH2OH, -C(=O)NR9R10, NHRn; where Rn is -C(= 0) CH3 or -S02Me or

• NR , Ν. -54- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1287015 V. Invention description (53) .i 多* 丄I:, Λ , I Supplement Wherein R is H, alkyl or aryl in another embodiment of the compound of structure IV, having the structure: wherein hydrazine is carbon or nitrogen; wherein hydrazine is hydrazine, or halo, - hydrazine-alkyl, amine Or a thio group; wherein Rs is hydrazine, alkyl, substituted alkyl, aryl, aralkyl, amine, substituted aryl, wherein the substituted alkyl is -C(R7)(R8) NR9R10, wherein the center and r8 are each independently η or alkyl, wherein R5 and Re are each independently alkyl or cycloalkyl, or R9, Ri〇 and the nitrogen atom are taken together to form substituted or unsubstituted 4 to 7 Member ring. In another embodiment of the compound, gamma is carbon. In another specific embodiment of the compound, r2 is hydrogen. In another specific embodiment of the compound, R6 is hydrogen. In another specific embodiment of the compound, Rs is hydrogen. In another embodiment of the compound, & and ^ are each methyl. In another specific embodiment of the compound printed by the Ministry of Economic Affairs, the Intellectual Property Officer X Consumer Cooperative, r5 is _ C(R7)(R8)NR9R1(), where ~ and ~ are each independently _ 院 院 s where R9 and R1 The oxime is independently a ruthenium or a ring-based base, or R9, Ri, and a gas atom are taken together to form a substituted or unsubstituted 4 to 7 membered ring. In another embodiment of the compound, the core is a yl group. In another embodiment of the compound, γ is nitrogen. In still another embodiment of the compound, R2 is hydrogen. 55-

In still another embodiment of the compound, R^5LR6 is each hydrogen. The invention also provides a compound having the structure (V):

HX

-Rs · wherein & is aryl, substituted aryl or heteroaryl; wherein R6 is H, alkyl, substituted alkyl or cycloalkyl; wherein is H, alkyl, substituted alkane a aryl group, an arylalkyl group, an arylalkyl group, a substituted aryl group, wherein the substituted alkyl group is -C(R7)(R8)NR9R10, wherein each of the monomers 7 and R8 is an anthracene or an alkyl group, wherein % and Each of RlG is an alkyl or cycloalkyl group or R9, Rio and nitrogen together form a ring system of between 4 and 7 members. In a specific embodiment of the structure V compound, each of the scales 7 and R8 is Η, wherein R9 is Η and Ri〇 S_Ri2C(=〇)R13. In a specific embodiment of the compound of structure V, each of r8 and r8 is deuterium; wherein the ring system is ruthenium, thiofenofyl, N-4-substituted hexahydro 11 to 17 well, 2-substituted Hexahydroquinone; a hydrazine base, or r8, substituted u, a fluorenyl group, a hexahydropyridyl group, wherein R8 is Η, OH, CH2〇H, -C(=0)NR9Ri〇, NRu, wherein R11 Is -C(=〇)CH3, -S〇2Me. In another embodiment of the compound, the compound has the following knot -56- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) η

••I Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1287015 A7 B7 V. Invention description (Π)

HCV

rHN

-ch3 kp,tT Ten females two: In,1 丨,.vAt In another specific embodiment of the compound, the compound has the following structure: 15

-ch3 it In another specific embodiment of the compound, the compound has the following structure: ------------ MW-------- order--------- line # (Please read the notes on the back and fill out this page) 20 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed ~5 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 Five Invention description (β)

rNH

•Η ΝΗ

• Η Η〇Κ it .π 1 10 (compound 1318-a) _ In another specific embodiment of the compound, the compound has the structure: _ h〇ap 15 20 (compound 131 §-b) in another compound In a specific embodiment, the compound has the following structure: The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------------------ ------- Line (please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1287015 A7 B7 V. Invention Description (r7)

OH (Please read the note on the back and fill out this page) 10 (Compound 1319) In another specific embodiment of the compound, the compound has the following structure:

0H Γί Μ .f B \ 15 20 Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperative (Compound 1320) In another specific embodiment of the compound, the compound has the following characteristics. 59- This paper scale applies to the Chinese National Standard (CNS) A4 size (210 X 297 mm) 1287015 A7 B7 V. Invention description (58) j Supplement

·, "ΙΙ〇Η (Compound 1321) A compound with the following structure ch3 Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

Wherein R3 is a 5-6 membered aromatic ring; wherein R5 and R6 are independently hydrazine or alkyl. In another specific embodiment of the compound, the compound has the following structure: -60- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). Line III « 1287015 A7 B7 V. Description of invention (r 〇

(Compound 1500) In another specific embodiment of the compound, the compound has the following structure

CH 15

I HN

3

.〇

20 Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

In another specific embodiment of the compound, the compound has the following structure: · This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) --------------- -----Order---------Line (please read the notes on the back and fill out this page) 1287015 A7 B7 V. Invention Description

CH3 knows a..>! ..-rl In another specific embodiment of the compound, the compound has the following knot

(Please read the notes on the back and fill out this page.) 15 In another specific embodiment of the compound, the compound has the following structure: 20 Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative

Rf- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1287015 V. Inventive Note (61) The present invention also provides a compound having the following structure

Wherein R3 is a 5-6 membered aromatic ring; wherein R5 and R6 are independently hydrazine or alkyl; provided that R3 is not 4-pyridyl. In a specific embodiment of the compound, the compound has the following structure:

NH

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives (Compound 1501) The present invention also provides a compound having the following structure -63. The paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 1287015 at B7 V. Description of the Invention (62) Amendment 丨 Supplement

VIII Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

Cl wherein R3 is a substituted 5-6 membered aromatic ring; wherein 115 and R6 are independently hydrazine or alkyl. In a specific embodiment of the compound, the compound has the following structure: - ΝΗ

ΝΗ-CH3 (Compound 1520) The present invention also provides a compound having the following structure: -64- The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm) 1287015 V. Description of the invention (63) A7 B7

HCV 丨 尤

IX wherein R3 is a 5-6 membered aromatic ring; wherein X is oxygen or sulfur. In a specific embodiment of the compound, the compound has the structure

HCV

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperative (Compound 1503) The present invention also provides a compound HO having the following structure,

X This paper scale applies to China National Standard (CNS) A4 specification (210 X297 mm) 1287015 at B7 V. Invention description (64)

Amendment Supplement bVf / wherein R3 is a 5-6 membered aromatic ring; wherein X is oxygen or sulfur. In one embodiment of the compound, the compound has the structure: X).

X

NH

Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative (Compound 1504) The present invention also provides a method for treating a condition associated with Α a adenosine receptor in a subject, including a therapeutically effective amount of Formula IV, V, VI A compound of VII, VIII, IX or X is administered to the subject. In a specific embodiment of the method, the subject is a mammal, and in another embodiment of the method, the subject is a human. In another embodiment of the method, the Α a adenosine receptor is for cognitive disease, renal failure, arrhythmia, respiratory epithelial disease, transmitter release, sedation, vasoconstriction, bradycardia, negative myocardial Contraction, reflux, or ulceration. The present invention also provides a mixed treatment for asthma comprising Compounds IV and V, and a steroid, a β2 stimulating agent, a glucocorticoid, a progesterone antagonist, or an anticholinergic stimulant, and adenosine A! A2a, A2b and receptor-associated disorders are revealed in WO 99/06053 and WO-09822465 Αι

66- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1287015 A7 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed B7 V. Invention Notes (K) WO-09705138, WO_09511681, WO-09733879, JP -09291089, PCT/US98/16053, and U.S. Patent No. 5,516,894, the entire contents of each of which are incorporated herein by reference. The present invention also provides a water-soluble precursor drug having a compound of the structure IV, V, VI, VII, VIII, IX or 5 X, wherein the water-soluble precursor drug is metabolized into an active agent in vivo to selectively inhibit A1 adenosine Receptor. In a specific embodiment of the prodrug, the prodrug is metabolized in vivo via esterase catalyzed hydrolysis. The invention also provides a pharmaceutical composition comprising a prodrug and a pharmaceutically acceptable carrier. The invention also provides a method for inhibiting the activity of a4 adenosine receptor in a cell comprising contacting the cell with a compound having structure IV, V, VI, VII VIII, IX or X. In a specific embodiment of the method, the compound is a scavenger of the adenosine I5 receptor. The invention also provides a method for treating a gastrointestinal disorder in a subject, comprising administering a compound having a structure IV, V, νι, νπ, νπι, IX or X in an effective amount. In a specific embodiment of the method, the condition is diarrhea. In another embodiment of the method, the subject is a human. In another embodiment of this method, the compound is an antagonist of the octaadenosine receptor. 1 The present invention also provides a method for treating a respiratory disorder in a subject, which comprises administering an effective amount of structure IV, V, VI, ～67'. The paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ^---------^ (Please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1287015 A7 --------B7 Five , Description of the Invention (To) Compounds of IX or X are administered to a subject. In a specific embodiment of the method, the condition is asthma, chronic obstructive pulmonary disease, allergic rhinitis or an upper respiratory condition. In another embodiment of this method, the subject is a human. 5 In another embodiment of this method, the compound is an antagonist of the 'adenosine receptor. The invention also provides a method for treating an eye injury in a subject comprising administering an effective amount of a compound having structure IV, V, VI, VII, VIII, IX or X to the subject. In a specific embodiment of the method, the injury comprises retinal and optic nerve head injuries. In another embodiment of the method, the injury is acute or chronic. In another embodiment of the method wherein the injury is caused by glaucoma I5, edema, ischemia, hypoxia or trauma. In another embodiment of this method, the subject is a human. In another embodiment of this method, the compound is the eight! An antagonist of adenosine receptors. The invention also provides a pharmaceutical composition comprising a compound having an effective medical amount of 20 structures IV, V, VI, VII, VIII, IX or X and a pharmaceutically acceptable carrier. In another embodiment of the pharmaceutical composition, the effective medical amount is effective to treat a respiratory condition or a gastrointestinal condition. In another specific embodiment of the pharmaceutical composition, the gastrointestinal condition of the paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) -------- --- Line ^11 (Please read the phonetic on the back? Please fill out this page again) 1287015

Is diarrhea In another specific embodiment of the pharmaceutical composition, the respiratory condition is asthma, allergic rhinitis or chronic obstructive pulmonary disease. In another embodiment of the pharmaceutical composition, the pharmaceutical composition is an ophthalmic preparation. In another specific embodiment of the pharmaceutical composition, the pharmaceutical composition is a periocular, post-ocular or intraocular injection preparation. In another embodiment of the pharmaceutical composition, the pharmaceutical composition is a systemic modulator. In another specific embodiment of the pharmaceutical composition, the pharmaceutical composition is a solution for surgical irrigation. The invention also provides a packaged pharmaceutical composition for treating a condition associated with an Ai adenosine receptor in a subject, comprising: (1) a container containing an effective, therapeutic amount of adenosine A! specific compound; 2) Instructions for treating the condition in a subject using the compound. When the compound is 'selective to Αι, it means that the compound 2 is at least ten times higher than the adenosine receptor than the adenosine A A2b or A3. The present invention also provides a structure for preparing a compound 1 The method and the steps include: CN ^ a), the Ministry of Economic Affairs, the Intellectual Property Bureau, the employee consumption cooperative, printed

Where P is a removable release base; and , and the ruler is obtained. • 69. This paper scale applies to the Chinese National Standard (CNS) A4 specification (21〇 χ297 mm) 1287015

1287015

A7 B7 1287015 V. Description of invention (70)

Treating the chlorination product of step C) to obtain α

Wherein R 3 is aryl, substituted aryl, heteroaryl; wherein R 6 is H, alkyl, substituted alkyl or cycloalkyl; wherein hydrazine is H, alkyl, substituted alkyl, aryl An aralkyl group, an amine group, a substituted aryl group, wherein the substituted alkyl group is -C(R7)(R8)NR9R10, wherein R7 and R8 are each an anthracene or an alkyl group, wherein each of R9 and R1G is an alkane The base or cycloalkyl group, or NR9R10 is a ring system of between 4 and 7 members. The compounds represented by the formulae VI, VII and VIII can be synthesized by any of the methods shown by the formula ι-νπι, and the compounds represented by the formula IX and X can be produced via the κ shown. The invention is further illustrated by the following examples, but it is not to be construed as limiting the invention, all of the references listed in the present application, the pending patents, and the specifics of the claims, including in the background section. Participate in the literature on the consumption of the Intellectual Property Office of the Ministry of Economic Affairs, and for reference in this article, 0 must know that the mode used in the whole instance is an acceptable mode, and the efficacy described in these modes is the predicted value of the human body's efficacy. . The details of the present invention will be better understood from the following (four) examination details. However, the specific method and results of the discussion will be more fully disclosed in the following claims. -72- 1287015 A7 B7 V. INSTRUCTION DESCRIPTION (7〇Explanation 纟gf The deazaindole compound of the present invention can be prepared by a standard method of organic synthesis, and the deazaindole compound can be subjected to reverse phase HPLC, chromatography, recrystallization. Purification, and its structure can be confirmed by mass spectrometry, elemental analysis, IR 5 and/or NMR spectroscopy. ^ Generally, the synthesis of the intermediate of the present invention and the deazaindole compound is carried out in the heart liquid, adding and removing one or more A protecting group is also a typical practice and is known to be familiar with the art. A typical synthetic pattern of a nitrogen (tetra) quinone compound intermediate is illustrated in the following Scheme I. 10 ----------- ----------Book---------Line (please read the note on the back of the page and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed this paper scale itffl T ® National Fresh (CNS) A4 Specification (210) 297 mm) 1287015 A7 B7

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives, where R3, :^, and !^ are the same as defined above. Typically, the protected 2-amino-3-cyano-sigma ratio α can be treated with a mercapto halide to form a carboxy guanylaminocyanopyrrole which can be treated with an acid sterol to form a ring closure into a ruthenium [ 2,3d]pyrimidine_4(3H)_ig (Muller, CE et al. J. Med. Chem. 40:4396 (1997)), removing pyrrole and protecting groups, followed by treatment with a gasifying agent such as phosphonium chloride, resulting in Substituted or unsubstituted 4 chloro-7H-indolo[2,3d] ♦, treated with amines to determine chlorhexidine to give 7_deaza~74' This paper scale applies to Chinese national standards (cns) ^^721() x 297 公董)--- 1287015 A7 V. INSTRUCTIONS (: 今今) 嘌呤 compound. Life =, as shown in Figure 1, N_(l_dl-phenylethyl)-2-amino-3-cyanodi-di-anthracene, 1, chlorine 7-burning, brewing, treatment, the obtained native soil benzene The carboxy-carboxyammonium _3_cyanopyrrole was treated with methanol/wide, 10.1 mouth to carry out ring closure, and the ratio of u_(bu benzene = ethene) was obtained: each [2'3d]pyrimidine _4 (called ketone) Using polyphosphonic acid (ppA) and subsequent #^理疋,* to remove the phenylethyl group to obtain the key intermediate 4- 4 (3H) low using the different amines in Table 1 below, 虱7H And [2,3d]対_4(3H>_, get the formula (1) ------------------- order--------- line ^ !^· (Please read the precautions on the back and fill out this page) and (11) Compounds. Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed Moderately I-shaped, One Paper, 97 2 X 10 2 One Grid A4 S N (C Standards 1287015 A7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed R Μ* + Η RM* - H 343.2 ο Ly 1 351.27 ' y 343.18 430.35 ΟΗ ΟΗ人 337.21 OH 359.44 364.19 ;~仏404.32 330.18 330.45 347.22 OK 339.47 CK_: Ding 350.28 〇353.41 沁, (Please read the notes on the back first) Complete this page) This paper scale applicable Chinese National Standard (CNS) A4 size (210 X 297 mm) 1287015 Α7 Β7 V. description of the invention (λΟ Ministry of Economic Affairs Intellectual Property Office employees consumer cooperatives printed

-11- (Please read the note on the back and fill out this page.) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm). 1287015 A7 B7 V. Invention Description (〆) Ministry of Economic Affairs Intellectual Property Bureau Printed by employee consumption cooperatives

(Please read the notes on the back and fill out this page) --------Book·-------. This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) ) 287015 A7 B7 V. Description of invention (π )

Figure II 15

(Please read the notes on the back and fill out this page) 20

Order ---------Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed its center to 115 is the same as the above definition. Ester transfer and alkylation of ethyl cyanoacetate with α-functional ketone to give ketoxime ester, protect ketone and then use ruthenium (for example, alkyl, aryl or alkyl aryl paper scale applicable to Chinese national standard (CNS) )A4 size (210 X 297 mm) 1287015

V. Description of the invention (pair) The ketal obtained by the hydrochloride treatment is protected. The protecting group is removed, followed by cyclization and treatment with phosphorus chlorinated chlorine to obtain the intermediate of the listener. After the replacement of Mi, it is possible to achieve the alkylation of pyrrole nitrogen in the case of this technology*. 5 (The general treatment method of the 经B replaced by the figure is stated in the following figure. Figure III

NC ΝΗ2·

NC

R6

+人 Λ

/R6

N H (Please read the note on the back and fill out this page) 15 20 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed

OH

Where ^ is the same as the above definition and R is the removable protection -------- order ---------. i! ) #^ Private r»a-,--- ... Must be '师Α1' in this paper size specification (2) Q X 297 gongdong 7----- 1287015 Patent application No. 89125535 ROC Patent Appln. No.89125535 Chinese manual revision I replacement this--attachment (2) R7 Amended Page of The Chinese Specification - Fnrl (τη V. Illustrated by the invention (Amended & Submitted on April 24, 20') 7) Condensation of malononitrile with excess ketone The reaction is followed by bromination of the product to give a mixture of the starting material, monobrominated and dibrominated product, which is treated with an alkylamine, an arylamine or an alkylarylamine. The resulting amine product is a mercaptochloromethyl group. The monothiolated pyrrole is cyclized in the presence of an acid to give a corresponding pyrimidine. 5 The pyrrole protecting group is removed with polyphosphonic acid and treated with oxygenated phosphorus to obtain a gasified product, and the chlorinated pyrrole is subsequently available. Amine treatment with an amine 5-substituted valproate allows alkylation of pyrrole nitrogen to be achieved in the art. Figure IV and V. A method of preparing the deazaindole compounds 1 and 2 of the present invention.

Read the back of the note first

I : Installation Page I Economics Department of Finance and Welfare Bureau Beigong Consumer Co., Ltd. Printed in which & and heart are the same as above, such as CH3. The specific reaction of 6-methylpyrrolopyrimidine (1) [R5=CH3] is the main reaction of cyclization of cyanoacetate with benzamidine to pyrimidine, salty cyanoacetic acid The cyclization of oxime ester with benzamidine to pyrimidine is higher than that of the corresponding ethyl ester. Therefore, the transesterification and alkylation reaction of ethyl cyanoacetate in the presence of NaOMe and excess α-haloacetyl group such as chloroacetone , the desired methyl ester (3) is obtained in 79% yield (Fig. ~ 81

1287015 A7 Description of the invention (I) The yield is reduced to (4), the new cyclization method using hydrochloric acid two == salt and 2 equivalents to reach the shot (5), the yield of % islands Obtaining 5, this method improves the use of the 2〇/° yield in the case of the announcement, wherein NaOMe is used in the cyclization with the vein, and cyclization to pyridine is achieved in the yield by the protection of the silk in the 5 HCl aqueous solution. Pyrimidine (6), (6) and phosphonium chloride are reacted under reflux to obtain the corresponding gas derivative (7), (7) coupled with trans-4_aminocyanohexanol in dimethyl sulphur at 135 ° C, at 57% Obtaining (1) in the yield, the skilled artisan will understand that the choice of reagent has great flexibility in selecting the desired substituent core. (Please read the note on the back and then fill out this page) Order---------Line# Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed This paper scale applies China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 V. Invention description (Chuan A7 B7

Schema IV

Nc 〇

NC

HO meter Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

NH

Χχ Specific preparation of 5-methylpyrrolopyrimidine: Knoevengel condensation reaction of malononitrile with an excess of a ketone such as acetone in refluxing benzene, after distillation to obtain 8 in 50% yield, using N-bromosuccinimide Bromination in the presence of benzoquinone in the gas, 8 is obtained after distillation. • 83. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1287015 A7 V. Invention Description (》&gt ; ) a mixture of starting materials, mono-(9) and dibrominated products (5/90/5) (70%), making the mixture with α-methylalkylamine or methylarylamine such as methyl node The amine is reacted to give the aminopyrrole (10). After passing through a short oxime column, the partially purified amine (31% yield) is thiolated with mercapto chloride such as benzhydryl chloride to give mono-(11). And dithiolated (12) pyrrolidine, which is separated by flash chromatography and acid-hydrolyzed by disubstituted pyrrole (12) to obtain a mercaptopyrrole (11) with a mixed yield of 29%, in concentrated sulfuric acid and DMF. In the presence of lower cyclization, (丨3) (23%) is obtained, which is removed and protected by polyphosphonic acid to form (14), and (14) is reacted with hydrazine chloride under reflux to obtain the corresponding 4-chloro derivative. (15), and The transazacyclohexanol is coupled in a dimethyl sulphide wind at 135 C, and (2) [ι^<:Η3] is obtained from (η) at 30% (see Figure V), a dark artist It will be appreciated that the choice of reagent is highly flexible for the selection of the desired substituent 116. (Please read the note on the back? Please fill out this page again) f Order---------Line · Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed This paper scale applies China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 V. Description of invention (打打)

Schema V

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1287015 A7 B7 V. INSTRUCTIONS (an alternative synthetic route for substituted pyrrole such as 5-methylpyridylpyrimidine: IV substituted This alternative synthetic route for pyrrole, such as 5-methylpyrrolopyrimidine, involves the transfer and alkylation of ethyl cyanoacetate to (16) (FIG. VI) using (2) DBU to make (16) The pyrimidine (17) is obtained by condensation of benzamidine hydrochloride, and the cyclization to pyrrole-pyrimidine (14) can be achieved by removing the acetal from the aqueous solution of HC1, and the corresponding reaction of (14) with phosphonium chloride under reflux is obtained. The 4-chloro derivative (15) is coupled with trans-4-aminocyclohexanol in 135 C dimethyl sulfoxide to give (2). The reaction number of the synthesized standard compound (2) is from 9 Reduced to 4 steps, and the yield is greatly improved. Again, those skilled in the art will understand that the choice of reagents is very flexible for the choice of the desired substituent Re. (Please read the notes on the back and fill out this page) -·Line·· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1287015 A7 B7 V. Invention Description (K )

Schema VI

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 V. Invention Description (#)

The following scheme illustrates the general synthesis of demethylpyrrole. Figure VII

. =^10 - NC, NH2 15

Ο-Et _ ό, — 5 Miscellaneous (Please read the note on the back and fill out this page) Order---------Line· 20 Printed by the Intellectual Property Office of the Ministry of Economic Affairs

Where 1^ to 113 are the same as defined above. Alkylation of alkyl cyanoacetate with diethyl acetal in the presence of a base This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 t A7 B7 Ministry of Economic Affairs Intellectual Property Office staff consumption Co-operative printing 5, invention description (57) to obtain cyanodiethyl acetal, which is treated with hydrazine salt to obtain methylpyrrolopyrimidine precursor, chlorinating the precursor and treating with amine to form the above-mentioned demethylation Pyrrolizidine bite.

~89~ This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) Order ·-------Line·· 1287015 A7 B7 V. INSTRUCTION DESCRIPTION (Yarn) Commercially available methyl cyanoacetate is obtained by alkylation of bromoacetic acid diethyl acetal in the presence of potassium carbonate and Nal (19), which is achieved in two steps. Conversion to pyrimidine (20), initially reacting (19) with simvastatin hydrochloride with 2 equivalents of DBU to form a pyrimidine-acetal, and removing the resulting pyrimidine-acetal with 1 equivalent of HCl without purification, The obtained aldehyde is cyclized to pyrrolopyrimidine (20), which is purified by filtration, and (2〇) and phosphonium chloride are reacted under reflux to obtain a corresponding 4-chloro derivative (21), and Compound (18) is obtained from compound (21) after coupling of 4-aminocyclohexanol in DMSO at 135 °C. Schemes II-VIII illustrate that the pyrrolopyrimidine ring and the 6-position can be functionalized, and can be used in formulas (I) and (II) by using different starting reagents and slightly modifying the above reaction scheme. Different functional groups are added to the 5_ and 6-positions, and Table 2 illustrates some examples. Table 2. List of 5- and 6-substituted pyrrolopyrimidines (please read the notes on the back and fill out this page) Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative 15 20 Starting reagent R5 R6 cr Η Η a~y W>R3 Η Substituted Ar Ο Ο Η CH2C(0)0CH3 0 Ο Cl C(0)OCH3 CH3 0 ο — 6, Η C(0)NHCH3 CH3

遂 遂 gA 订--------- Line · This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 mm) 1287015 A7 --------__ V. Description of invention (矜) Those skilled in the art will appreciate that the metabolic effects of the compounds disclosed herein produce a biologically active metabolite that acts as a pharmaceutical agent in a therapeutic practitioner. The invention is further illustrated by the following examples, which are not to be construed as limiting the invention, all of the references listed in the present application, the patent application of claim 5, and the patent application filed in the For reference, and for reference herein, it is necessary to know that the modes used throughout the examples are acceptable modes, and the efficacy described in these modes is a predictor of efficacy in the human body. Example 10 Preparation 1: Using a modified alkylation method of Seela and Lupke, slowly added to a solution of ethyl cyanoacetate (6.58 g, 58.1 mmol) in MeOH (20 mL) in ice cold (EtOAc) NaOMe solution (25% w/v, 58.1 mmol), after 10 min, slowly add acetone (5 mL, 62 8 mmol 15 s). After 4 s, solvent was removed and EtOAc (100 mL) The brown oil was diluted and washed with H20 (1 mL). The organic layer was dried, filtered, and concentrated to a brown oil (7.79 g, 79%), this oil (3) (Form IV) was methyl/ Mixture of ethyl ester product (9/1), used without further purification, iHNMR (200 MHz? CDC13) δ 4.24 (q5 J=7.2 Hz, OCH2), 3.91 (dd5 1H5 20 J=7.2, 7.0 Hz, CH), 3.62 (s, 3H, OCH3), 3.42 (dd, 1H, J = 15.0, 7.1 Hz, 1xCH2), 3.02 (dd, 1H, J = 15.0, 7.0 Hz, 1xCH2), 2.44 (s, 3H, CH3), 1.26 (t, J = 7.1 Hz, ester _CH3). 1 Seela, F·; Lupke, U. Chem. Ber· 1977, 110, 1462-1469. Preparation 2: ~91~ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

A ------------- Feng -! (Please read the phonetic on the back first? Then fill out this page) Order---------Line - Ministry of Economic Affairs Intellectual Property Bureau employees Consumer Cooperatives Printed 1287015 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed A7 B7 V. Invention Description (%) Using Method 1 of Seela and Lupke, according to which ethylene glycol (4 ml, 64·4 mmol) Protection of the ketone (3) in the presence of TsOH (100 mg) (Figure IV; 5.0 g, 32·2 mmol) by flash chromatography (si〇2; 3/7 Et 〇Ac/hexane, RA35) After the oil of (4) (Figure IV; 5.2 g, 81.0 mmol), still containing ~5% ethyl ester: iHNMR (200 MHz, CDCl3) 54.24 (q, J = 7.2)

Hz, OCH2), 3.98 (s, 4H, 2x acetal-CH2), 3.79 (s, 3H, OCH3), 3.62 (dd, 1H, J=7.2, 7.0 Hz, CH), 2.48 (dd, 1H, J =15.0, 7.1 Hz, 1xCH2), 2·32 (dd, 1H, J=15·0, 7.0 Hz, 1xCH2), 1.35 (s, 3H, CH3), 1·26 (t, J=7.1 Hz, vinegar -CH3); MS (ES): 200.1 (M++1). 10 1 Seela, F·; Lupke, U. Chem. Ber. 1977, 110, 1462-1469. Preparation 3: Acetal (4) (Formula IV; 1 g, 5.02 mmol), benzamidine (786) Mg, 5·02 house Moule) and DBU (1.5 ml, 1 〇·〇 4 mmol) solution in anhydrous DMF (I5 house liter) heated at 85 c for 15 hours with CHC13 15 (30 The mixture was diluted with EtOAc (1 mL) EtOAc (EtOAc)EtOAc. Rf0·35), but the material crystallized on the column, the gel was washed with MeOH, and the fractions containing the product (5) (fig. iv) were concentrated and used without further purification (783 mg, 543%): 20 咁NMR (200 MHz, CDC13) 6 8.24 (m, 2H, Ar-H), 7.45 (m, 3H, ar-H), 5.24 (br s, 2H, NH2), 3.98 (s, 4H, 2x acetal - CH2), 3.60-3.15 (m, 2H, CH2), 1.38 (s, 3H, CH3); MS (ES): 288.1 (M++l) 〇Preparation of compound (20) (Figure VIII): (19) (4.43g, 20.6~92~ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------- order--------- line ( Matters to read the back of the note and then fill in this page) 1287015 A7

V. Description of the invention () printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative, Moer), benzamidine hydrochloride (3.22 g, 20.6 mmol) and DBU (6.15 soar, 41.23⁄4 mol) in anhydrous DMF The solution in (20 ml) was at 85. Heat the underarm for 15 hours, dilute the mixture with 1 mL of chC13 and wash with h2 〇 (2 X 503⁄4 L). Dry the organic layer, filter and concentrate to a dark brown oil. HC1 (1 mL) was mixed for 2 hours at room temperature, and the obtained thick slurry was filtered to give a brown solid (3.60 g, 70.6%) of the HCl salt (20): iHNMR (200 MHz DMSad6). (s, 1H)5 8.05 (m5 2H, Ar-H)? 7.45 (m5 3H? Ar-H)? 7.05 (s? 1H, pyrrole _H); MS (ES): 212·1 (M++1 ). 10 Preparation 4: A solution of the hydrazine (5) (700 mg, 2.44 mmol) in 1 eq. 1 1 (40 mL) was stirred at room temperature for 2 hr. Salt 2-Phenyl-6-methyl-7H-pyrido[2,3d] oxime-4(3H)-one as a brown solid (498 mg, 78.0%): NMR (200 15 MHz, DMSO- D6) 5 11.78 (s, 1H), 8.05 (m, 2H, Ar-Η), 7·45 (m, 3H, Ar-H), 6.17 (s, 1H, pyrrole-H), 2.25 (s) , 3H, CH3); MS (ES): 226.1 (M++1). Preparation 5: Using cyclization Method 1 of modified Chen et al, chilled (0 ° in bromine (9) (Figure V; 20 20.0 g, 108 mmol; 901 purity) in isopropanol (60 mL) C) In the solution, slowly add α-methylbenzylamine (1.25 ml, 97.3 mmol), warm the mixture to rt and stir for 1.5 h, dilute mixture with EtOAc (200 mL) Wash with NaOH (50 ml), dry the organic layer, filter, and concentrate to black tar (19.2 g, '93~ This paper size applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) (please read first) Note on the back side of this page) --------Book --------- Line 1 1287015 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (f>) 94%), the residue was subjected to flash chromatography (9) 〇 2; 4/96 Me 〇 H/CH 2 Cl 2 ,

Partially purified to a black solid (6·38 g, 3(8) compound like phenylethyl)-2-amino-3-cyano-4-methylpyrrol: MS (ES): 226.1 (M++1) 〇5 Chen, YL, Mansbach, RS; Winter, SM; Brooks, E.; Collins, J.; Corman? ML; Dunaiskis, AR; Faraci, WS; Gallaschun? RJ; Schmidt, A. Schulz, DWJ Med Chem. 1997, 40, 1749-1754. Preparation 6 : 10 in ΑΗ1·phenylethyl)-2-amino-3-cyano-4,5-dimethylpyrrole 1 (14.9 g , 62.5 mmol, and pyridinium (1 ml) in a solution of methylene chloride (wo ml) at 0 ° C to add benzamidine chloride (9 · 37 g, 66 · 7 mmol) After stirring at 0 ° C for 1 hour, add hexane (1 〇〇 ml) to help the product precipitate, remove the solvent under vacuum, and then solidify 15 crystals from Et〇H/H2〇 to obtain 13· 9 g (65%) of small (1-phenylethyl)-2-phenylcarbonylamino group cyano-4,5-dimethylpyrrole, melting point 2i8-221 ° C, ^NMROZOO MHz? CDC13 δ 1.72 (s, 3H), 1.76 (d? J=7.3 Hz? 3H)5 1.98 (s5 3H), 5.52 (q, J=7.3 Hz, 1H), 7.14-7.54 (m, 9H), 7.68- 7.72 (dd, J=1.4 Hz, 6·9 Hz, 2H ), 10.73 (s, 1H); MS (ES): 344.4 (M++1). 20 1 Liebigs Ann. Chem. 1986, 1485-1505. The following compounds were obtained in a similar manner: Preparation 6A: Heart 1_(1_phenylethylpeak...pyridyl)carbonylamino-3_cyano_4 , 5_Dimethyl~94' This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) • -------- --------- Line · A7 1287015 ____Β7_ V. Invention description (P) 3Η), 2·02 (s, 3Η), 2.12 (s, 3Η), 5.50 (q, J=6.8 Ηζ, 1Η ), 7.14-7.42 (m, 5H), 8.08 (m, 2H), 8.75 (m, 3H); MS (ES): 345·2 (M++1). Dl-1 -(1-Phenylethyl)-2-(2-carbyl)monoylamino-3-nitro-4,5-dimethyl-5*^b&,1H NMR (200MHz, CDCl3) (51.84 ((U=7.4Hz, 3H), 1.92 (s, 3H), 2.09 (s, 3H), 5.49 (q, J=7.4 Hz, 1H), 6.54 (dd, J=1.8 Hz, 3·6 Hz,1H),7.12-7.47 (m,7H); MS (ES): 334.2 (M++1), 230J. dl-l_(l-phenylethyl)_2_(3-indolyl) Amino-3-cyano-4,5-dimethyl-10-pyrrole, 1H NMR (200 MHz, CDC13) 51 · 80 (d, J = 7 Hz, 3H), 1·89 (s, 3H), 2 ·05 (s,3H),5_48 (q,J=7 Hz,1H), 6.59 (s,1H), 7·12_7·40 (m,6H),7_93 (s,1H); MS (ES): 334.1 (M++1), 230.0. dl-l-(l-phenylethyl)-2-cyclopentylcarbonylamino-3-cyano-4,5-dimethylpyrrole 15 ;^(200]^,〇0:13)31.82(4]=7.4, 311), 1.88 (s, 3H), 2.05 (s,3H),1·63_1.85 (m,8H), 2.63 ( m,1H), 5.43 (q, J=7.4 Hz, 1H), 6.52 (s, 1H), 7.05-7.20 (m, 5H); MS (ES): 336·3 (M++1). L-(l-Phenylethyl)-2-(2-σ-sepenyl)-andylamino-3-nitro-4,5-diindole-20-pyrrole, also Lili 11(20〇]^1112 , €0 (:13) 51.82 (〇1,1=6.8 , 3H),1·96 (s,3H),2.09 (s,3H),5.49 (q,J=6.8 Hz,1H), 7.05-7.55 (m,8H); MS (ES): 350.1 (M+ +1), 246.0. dl_l-(l-phenylethyl)·2_(3-thienyl)carbonylamino-3-cyano-4,5-dimethylpyrrole, 屯1^\4!1 ( 200 round 2, €0 (: 13) 51.83 ((1, > 7.0 out, ~95) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------- ---------Line ml (please read the note on the back and fill in this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1287015 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 5, invention Description (f〆) 3H), 1.99 (s, 3H), 2·12 (s, 3H), 5.49 (q, J=7.0 Hz, 1H), 6.90 (m, 1H), 7.18-7.36 (m, 6H ), 7·79 (m, 1H); MS (ES): 350.2 (M++1), 246. (11-1-(1-phenylethyl)-2-(4-phenylphenyl) Alkylamino-3-3-carbyl-4,5-dimethyl-5*<,,1H NMR (200MHz, CDCl3) 51.83 (d, J=7.4Hz, 3H), 1_96 (s, 3H), 2·08 (s, 3H), 5.51 (q, J = 7.4 Hz, 1H), 7.16-7.55 (m, 9H); MS (ES): 362.2 (M++1), 258·b dl-l-(l- Phenylethyl)-2-(3-fluoro Carbonyl)aminocarbonyl-3-cyano-4,5-dimercaptopyrrole, 1H NMR (200MHz, CDC13) 61.83 (d, JK7.4Hz, 10 3H), 1·97 (s, 3H), 2·10 (s, 3H), 5·50 (q, J = 7.4 Hz, 1H), 7.05-7.38 (m, 7H), 7.67-7.74 (m, 2H); MS (ES): 362.2 (M++1) 258. dl-l-(l-phenylethyl)_2-(2-fluorophenyl)carbonylamino-3-cyano-4,5-dimethylpyrrole, 1H NMR (200MHz, CDCl3) Π·85 (d, J=7.2Hz, 15 3H), 1.94 (s, 3H), 2.11 (s, 3H), 5·50 (q, J=7.2 Hz, 1H), 7.12-7.35 (m , 6H), 7.53 (m, 1H), 7_77 (m, 1H); MS (ES): 362.2 (M++1), 258.0. Dl-l-(l-phenylethyl)_2-isopropylcarbonylamino-3-cyano-4,5-dimethylpyrrole, 咁>^]^111 (2001^, 〇〇(: 13) (51.19((1,1=7.0112,611), 20 1.82 (d,J=7.2 Hz,3H),1.88 (s,3H),2·06 (s,3H),2.46 (m, 1Η) , 5.39 (m, J = 7.2 Ηζ, 1 Η), 6·64 (s, 1 Η), 7·11-7.36 (m, 5H); MS (ES): 310.2 (M++1), 206.1. In the case of phenylethyl) 2 -amino-3-cyano-4-methylpyrrole, mono-decylated dl-l-(l-phenylethyl)-2-phenylhydrazine is obtained. ~96' This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) -------------------- Order ------- --Line (please read the note on the back and fill out this page) 1287015 A7 B7 V. INSTRUCTIONS (y) Aminoamino-3-cyano-4-dimethyl 17 ratio slightly di-decylated dl -l-(l-phenylethyl)-2·diphenylhydrazinyl-3-cyanoindolemethylpyrrole, monothiolated pyrrole: 屯NMR (200 MHz, CDC13) (5 7.69 ( d, 2H, J = 7.8 Hz, Ar-H), 7·58-7·12 (m, 8H, Ar_H), 6.18 (s, 1H, pyrrole-H), 5.52 (q, 5 1H, JK7.2 Hz, C^-CH3), 2.05 (s, 3H, pyrrole-C H3), 1.85 (d, 3H, J = 7.2 Hz, CH-CH3); MS (ES): 330.2 (M++1); dimerization of the mouth ratio: NMR (200 MHz, CDC13) 5 7.85 (d, 2H, J = 7.7 Hz, Ar-H), 7.74 (d, 2H, J = 7.8 Hz, Ar-H), 7.52-7.20 (m, 9H, Ar-H), 7.04 (m , 2H, Ar-H), 6.21 (s, 1H, pyrrole _H), 5.52 (q, 1H, J = 7.2 10 Hz, CH-CH3), 1.77 (d? 3H, J = 7.2 Hz? CH-CH3 5 1.74 (s5 3H5 pyrrole-CH3); MS (ES): 434.1 (M++1) Preparation 7: in dl-l-(l-phenylethyl)_2-phenyl sulfhydryl amide _Cyano- 4,5-dimercaptopyr (1.0 g, 2.92 mmol) in a solution of methanol (M.M.) in concentrated sulphuric acid (1.0 mL) at 〇 ° C. The mixture was refluxed for 15 hours, cooled to room temperature, and the precipitate was filtered to give y-48 g (48%) of dl-5,6-dimethylphenyl-7. ,3d]pyrimidine_4(3h)_ ketone, 屮_[11(200_^, €0(:13)62.02(〇1,]=7.4他,311) 2.04 (s,3H),2.41 (s,3H ), 6.25 (q, J = 7.4 Hz, 1H), 7.22-7.50 20 (m, 9H), 8.07-8.12 (dd, J = 3.4 Hz, 6.8 Hz, 2H), 10.51 (s, 1H) · Ministry of Economic Affairs Intellectual Property Bureau staff consumption Social printed MS (ES): 344.2 (M ++ 1). ' ' The following compounds are obtained from a method similar to that of Preparation 7: dl-5,6-dimethyl-2-(3-pyridyl)-7-7--7-(1-phenylethyl)pyrrolo[2,3d ] Pyridoxine-4(3H)-_, NMR (200 MHz, CDC13) 5 2.03 (d 2 ~ 97~ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) "-- ---- A7 1287015 __B7_ V. Description of invention (%)

Hz, 3H), 2.08 (s, 3H), 2.42 (s, 3H), 6.24 (q, J = 7.2 Hz, 1H), 7.09-7.42 (m, 5H), 8.48 (m, 2H), 8.70 (m , 3H); MS (ES): 345.1 (M++1). Dl-5,6·Dimethyl-2-(2-furyl)-7Η-7-(1·phenylethyl)pyrrolo[2,3d] 5 pyrimidine-4(3H)-one, 1H NMR (200 MHz, CDC13) 5 1.98 (d, J=7.8

Hz, 3H), 1·99 (s, 3H), 2.37 (s, 3H), 6.12 (q, J = 7.8 Hz, 1H), 6.48 (dd, J = 1.8 Hz, 3·6 Hz, 1H), 7.17-7.55 (m, 7H), 9.6 (s, 1H); MS (ES): 334.2 (M++1). Dl-5,6-Dimethyl-2-(3-furyl)-7Η_7-(1·phenylethyl)pyrrolo[2,3d] 10 pyrimidine-4(311)-one, 111]^^ 11(200]\4^,€〇(:13)(51.99(山>7

Hz,3H),2.02 (s,3H),2.42 (s,3H),6.24 (q,J=7 Hz,1H),7.09 (s,1H),7.18-7.32 (m,5H),7·48 (s, 1H), 8.51 (s, 1H); MS (ES): 334.2 (M++1). Dl-5,6-Dimethyl-2-cyclopentyl-7H_7-(1•phenylethyl)11bilorin[2,3d].密15 pyridine-4(311)-ketone, 1^[>^11 (200 paintings 2,000:13) 51.95 ((1,]=7.4

Hz, 3H), 2·00 (s, 3H), 2·33 (s, 3H), 1.68-1.88 (m, 8H), 2.97 (m, 1H), 6.10 (q, J = 7.4 Hz, 1H) , 7.16-7.30 (m, 5H), 9.29 (s, 1H); MS (ES): 336.3 (M++1). Dl-5,6-Dimethyl-2-(2-thienyl)-7H-7-(l-phenylethyl)pyrrolo[2,3d] 20 pyrimidine-4(3H)-one, 1H NMR (200 MHz, CDC13) (5 2·02 (d, J=7.2 Hz, 3H), 2.06 (s, 3H), 2.41 (s, 3H), 6.13 (q, J = 7.2 Hz, 1H), 7.12 ( Dd, J = 4.8, 2.8 Hz, 1H), 7.26-7.32 (m, 5H), 7.44 (d, J = 4.8 Hz, 1H), 8.01 (d, J = 2.8 Hz, 1H), 11.25 (s, 1H) ); MS (ES)·· 350.2 (M++1). 9 8~ -------------------- Order --------- Line (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumer Cooperatives Printed 1 Paper Standard Applicable to China National Standard (CNS) A4 Specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Office Staff Consumption Co-operative printing 1287015 A7 B7 V. Description of the invention (dl-5,6-dimethyl-2-(3-thienyl)_7H_7-(1-phenylethyl)pyrrolo[2,3d] cancer bite-4 (3H)-嗣,1H NMR (200 MHz, CDCI3) δ 2.00 (d, J=7.4 Hz, 3H), 2_05 (s, 3H), 2.43 (s, 3H), 6.24 (q, J = 7.4 Hz, 1H), 7.24-7.33 (m,5H),7.33-7.39 (m,1H),7_85 (m,1H),8.47 (m, 5 1H),12.01 (s,1H); MS (ES): 350.2 ( M++1). dl-5,6-two Methyl-2-(4-fluorophenyl)_7Η·7-(1-phenylethyl)σ ratio σ each [2,3d]pyrimidine-4(3H)·one, 1H NMR (200 MHz, CDC13 5 2.01 (d, J=6.8 Hz, 3H), 2.05 (s, 3H), 2.42 (s, 3H), 6.26 (q, J = 6.8 Hz, 1H), 7.12- 7.36 (m5 7H)? 8.23- 8.30 (m? 2H)? 11.82 (s? 1H); MS (ES): 10 362.3 (M++1). dl-5,6-dimethyl-2-(3-fluorophenyl)-7H- 7-( 1 ·Phenylethyl)吼σ each [2,3d] pyrimidine, 4(3H)-one, 1H NMR (200 MHz, CDC13) 5 2.02 (d, J = 7.4 Hz, 3H), 2.06 (s, 3H), 2.44 (s, 3H), 6.29 (q, J = 7.4 Hz, 1H), 7.13- 7.51 (m, 7H), 8.00-8.04 (m, 2H), 11.72 (s, 1H); MS (ES): 15 362-2 (M++1). Dl-5,6-Dimethyl-2-(2-fluorophenyl)-7H-7-(l-phenylethyl)π is a slightly [2,3d]pyrimidin-4(3H)-one, 1H NMR (200 MHz, CDC13) 5 2.00 (d, J = 7.2 Hz, 3H), 2.05 (s, 3H), 2.38 (s, 3H), 6.24 (q5) = 7·2 Hz, ih), 7.18- 7.45 (m,8H), 8.21 (m,1H), 9.54 (s,1H); MS (ES): 362.2 20 (M++1)0 dl-5,6-dimethyl-2-isopropyl -7H-7-(l-phenylethyl)σ ratio p and [2,3d]^

Hz, 3H), 1.32 (d, J = 7.0 Hz, 3H), 2_01 (s, 3H), 2·34 (s, 3H), 2.90 (m, 1H), 6.13 (m, 1H), 7.17-7.34 (m,5H),10.16 (s,1H); 99' This paper scales the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ---------------- ---Order---------Line (please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1287015 A7 -------____ V. Invention Description (poor) MS (ES): 310.2 (M++1). Preparation 8 : dl-l-(l-phenylethyl)-2- benzoic acid amine cyano ice dimethylpyrrole (785 house gram, Z38 耄 Moer) and concentrated Η ^ 〇 4 (1 The solution of ML 5 (丨 3 ml) was stirred at 130 ° C for 48 hours. The black solution was diluted with CHCl 3 (10 mL) and washed with 1N NaOH (30 mL) and brine (30 mL). Dry, filter, and purified by flash chromatography (EtOAc EtOAc EtOAc (EtOAc) 7-(1-Phenylethyl)indole, each [2,3d] hydrazin 10 -4(3H)-one: 咁NMR (200 MHz, CDCl3) 5 8 18 (m, 2H,

Ar-H), 7.62-7.44 (m, 3H, Ar_H), 7.40_7.18 (m, 5H, Ar-H), 6.48 (s, 1H, 吼-H), 6.28 (q, 1H, J =7.2 Hz, Cg-CH3), 2.18 (s, 3H, ♦ each -CHS), 2.07 (d, 3H, J=7·2 Hz, CH-C); MS (ES): 330.2 (M++ 1) ° 15 Preparation 9: dl-l-(l-phenylethyl)_2-amino-3-cyano-4,5-dimethylpyrrole (9.60 g, 40.0 mmol) with formic acid ( 5 〇. 〇ml, 98%) of the mixture was refluxed for 5 hours, after cooling to room temperature, the side wall of the flask was scraped to form a lot of precipitate and filtered, and the substance was washed with water until the cleaning solution appeared neutral, resulting in dl-5,6- 2 〇 dimethyl phenyl ethyl ratio [2, 3d] spray π ding · 4 (3 Η) - _ : also NMR (200 MHz? CDC13) δ 1.96 (d5 J = 7.4 Hz, 3H)? 2.00 ( s? 3H), 2.38 (s, 3H), 6.21 (q, J = 7.4 Hz, 1H ), 7.11 - 7.35 (m, 5H), 7.81 (s, 1H), 11.71 (s, 1H); MS (ES 》268.2 (M++1). Preparation 10: ~100~ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------- order------- --Line (please read the notes on the back and fill out this page) 1287015 A7 B7 V. Invention Description ( 15 20 Ministry of Economic Affairs Employees' consumption cooperatives printed dl-5,6-dimethyl-butylphenyl-7H_7-(1-phenylethyl: Kb-[2,3d]pyrimidine-4(3H)-one (1 · 0 g, 2.91 mmol) suspended in polyphosphonic acid (30.0 house liter), the mixture was heated at 10 ° C for 4 hours, the hot suspension was poured into ice water, and the suspension was dispersed with vigorous stirring. , alkalized to pH 6 with solid K0H, and the obtained solid was filtered and collected to give 49 g (69%) of 5,6-dimercapto-2-phenyl-7-pyridinium [2,3d]. Bite _4(3Η)-ketone: also Lili 11 (200 MHz? DMSO-d6) 5 2.17 (s5 3H)? 2.22 (s5 3H), 7.45 (br5 3H), 8·〇7 (br,; 2H ), 11·49 (s, 1H), 11·82 (s, 1H); MS (ES): 344.2 (M++1) 〇 The following compounds are obtained from a method similar to the preparation of 1-oxime. -Phenyl-7H-t each [2,3d] ♦ -4 (3H)-_; MS (ES): 226·0 (M++1). 5,6-Dimethyl-2-(3·Ca丁基)_7Η-吼 并[2, kunpyrimidinone; MS (ES): 241.1 (Μ++1). 5,6-Dimethyl_2_(2_吱-ylHH-indole[heart]pyrimidine; 1HNMR(200MHz5DMSOA), 2.13 (, 3H)? 2,8 (s? 3H)5 6.39 (dd,J =1.8, 3·6 Hz, 1H), 6.65 (dd, >18, 3 6 out m 7.85 (dd, J=1.8, 3.6Hz, 1H), 11 45 “ 1rj, ' ' (ES): 230.1 ( M++1), 5.6-dimethyl-2-(3-indolyl)-7Ηπ than Hayangq open d] η密咬-4(3 m-ketone; lHNMR(2〇〇MHz, DMSO -d6) such as % 疋h 6.66(s,1H), 7.78(s,1Η), 835(Μη)^13"η/1;4(, 1H); MS (ES): 230.1 (M++l) 〇U 1 5 5.6- Dimercapto-2-cyclopentyl-7H- 并[2,3d]^4(3_; This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) ~----------Set---------Line (please read the notes on the back and fill in this page) Α7 Β7

1287015 V. INSTRUCTIONS (/^0) NMR (200 MHz, DMSO-d6) (5 1.57-1.91 (m 8H) 2 12 (s 3Η)? 2,6 (,3Η) 52.99^1Η)?11.24(Μη ^ MS (ES): 232.2 (M++1). 5.6- Dimercapto-2-(2 temples HH-♦ each and like imidadine _4 (Talk about 5 1H NMR (200MHz? DMSO-d6) ^2.14 (s5 3«)5 2 19 (s 3H) 7.14 (dd, J=3.0, 5·2 HzJH), 7.70 (d, J=5.2 Hz, m) 8S'10 (d J=3.0 Hz, 1H ), 11.50 (s, 1H); MS (ES): 246.1 (Μ++υ. ' 5.6- Dimethyl_2_(3 Temples are divided into groups and [2, 3 intimate bites _4 (聊嗣· 1H NMR (200MHz5DMSO-d6) ^2.17 (Sj 3H)5 2 21 (s 3H)? 10 7·66 (m,1H), 7.75 (m,1H ),8·43 (m,1H ),1 i 47 ( s 1H) 11.69 (s,1H); MS (ES): 246.1 (M++1). ' '5,6-Dimethyl·2_(4_fluorophenyl)-7H-oral ratio (10) Pyrimidine _4(SH)_嗣; 屯NMR (200 MHz, DMSO-d6) (5 2.17 (s, 3H) 5 2 21 (s, 3H), 7.31 (m, 2H), 8·12 (m, 2H), 11.47 (s, 1H); MS (ES): 258.2 15 (M++1) 〇5.6--Methyl-2-(3-fluorobenzyl)-7Η-σpiro[2,3d ] n n n _4 (3h) ketone; ]H NMR (200 MHz? DMSO-d6) 5 2.18 (s5 3H)? 2 2l (s? 3H)? 7.33 (m, 1H), 7.52 (m, 1H), 7.85 -7.95 (m, 2H) 11 56 (s 1H) 11.80 (s, 1H); MS (ES): 258.1 (M++1). 20 5,6-Dimethyl-2_(2_fluorobenzine) "7Η_σ ratio slightly [2,3 outer dense. 定_4(criminal)·ketone; NMR (200 MHz, DMSO-d6) (52.18 (s5 3H) 2 22 (s 3H) 7.27-7.37 (m, 2H ), 7.53 (m, 1H), 7.68 (m, 1H), !i 54 (s, m), 11.78 (s, 1H); MS (ES): 258.1 (M++1). '5.6-Dimethyl-2-isopropyllo[2,3d].定_4(犯)_ketone; 1η ~102' This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------- order--------line (Please read the phonetic transcription on the back? Please fill out this page again) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1287015

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 5, Invention Description (γ/Ο NMR (200 MHz, DMSO_d6) 3U7 (d, Γ=6·6 κζ, 6H), 2·11 (s, 3H), 2.15 (s5 3HX 2.81 (m, 1Ηχ iL2〇(s> m% 1L39 (s? 1H); MS (ES): 206.1 (M++1). 5,6 1-methyl 7m slightly [2,3d]♦ _4(3h)__; 1hnmr(2〇〇5 MHz, DMSO-d6) ^.13 (s53H)5 2.17 (Sj3H)5 7.65 MS (ES): 164.0 (M++1) Preparation 11 : 5,6-=methyl_2_phenyl κ 洛 [ [2,3d] ♦ _4 (L. ketone (1·〇克, 4_2 mmol) in phosphorus chlorochloride (10) ml) solution reflux 6 After 10 hours, it is condensed to dryness under vacuum, and the water is added to the residue to initiate crystallization. Then, the obtained +_ body is filtered and collected to obtain _g ((4) of 1 gas_5,6_monomethyl-2-benzene -7H-pyrrolo[2,3d]pyrimidine: ΐρΐΝΜΚ(200ΜΗζ, DMSO-d6) 5 2·33 (s,3Η), 2.33 (s,3Η), 7.46-7.49 (m,3Η), 8.30-8.35 (m, 2H), 12·20 (s, 1H); MS (ES)·· 258.1 (M++1). 15 The following compound is obtained from a method similar to Preparation 11: 4-A-5-methyl -2-phenyl|pyrido[2,3 outer bite; Ms (ES): 244 〇(M++l) 〇4-chloro-6_methyl_2_phenyl_7 Η-pyrrolo[2,3d]♦; Ms (ES): 244 〇(M++l) 〇2〇4-gas-2-phenyl_7Η-pyrrolo[2,3d]pyrimidine; iHNMRQOOMHz , DMSO-d6) 5 8.35 (s,2H),7·63 (br s,1H),7·45 (m,3H),647 (br s,1H ); MS (ES)·· 230.0 (M+ +1) 4-chloro-5,6-dimethyl-2-(3-pyridyl)-7H-pyrrolo[2,3d]pyrimidine; MS (ES): 259.0 (M++1). This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) -------------------- Order -------- line (Please read the precautions on the back and fill out this page) 1287015 A7 B7 V. Inventions 15 20 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Print 4-Chloro_5,6-Dimethyl-2-(2-吱喃基)_7 such as the ratio of each mouth [2,3 (|] POS (200MHz, DMSOd6) 52.35 (s, 3H), 2.35 (s 3H 6.68 (dd, J = 1.8, 3.6 Hz, 1H), 7.34 (dd, J=1.8, 3.6 fH)) 7.89 (dd, J=1.8, 32_6 Hz, 1H); MS (ES): 248.0. '4·Chloro_5,6-dimethyl-2-(3-furyl)_7H_pyrrolo[2, Kun Ruding·1h NMR (200 MHz, DMSO-d6) (5 2.31 (s, 3H), 2·31 (S々3H) 6.62 (s, 1H), 7.78 (s, 1H), 8.18 (s, 1H), 12.02 (s, 1% MS(ES): 248.1 (M++1). ' . 4-gas-5,6-dimethyl-n-cyclopentyl-7H-pyrrolo[2,3d]pyrimidine; lHNMR (200 MHz, DMSO-d6) (5 1.61-1.96 (m, 8H), 2.27 | s 3H) 2·27 (s, 3H), 3.22 (m, 1H), 11.97 (s, 1H); MS (ES): i5ai' (M++1). · 4_gas_5,6·2曱基_2_(2-σ塞基基基[2,3 唆 唆 · ipj NMR (200 MHz, DMSO-d6) 5 2·29 (s, 3Η) 5 2·31 (s, 3H), 7.14 (dd, J=3.1, 4·0 Hz, 1H), 7.33 (d, J=4.9 Hz, 1H), 7·82 (d, J=3.1 Hz, 1H), 12.19 (s, 1H); MS (ES): 264.1 (]yr+1). 4_Gas_5,6-Dimethyl-2-(3_0Septenyl-Indole- 吼17-[2,3d]n-Bite·ih NMR ( 200 MHz, DMSO-d6) 5 2.32 (s, 3H), 2·32 (s, 3H), 7.62 (dd, J=3.0, 5.2 Hz, 1H), 7.75 (d, J = 5.2 Hz, 1H), 8.20 (d, J=3.0 Hz, 1H); MS (ES): 264.0 (M++1) 〇4-qi_5,6-dimercapto-2-(4-fluorophenyl)[2,3d喷u定; 1h NMR (200 MHz, D MSO-d6) 5 2·33 (s,3H), 2.33 (s,3H), 7.30 (m,2H),8_34 (m,2H),12·11 (s,1H); MS (ES)·· 276.1 (M++l) 〇This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------------------- Order -- ------- Line (please read the phonetic on the back? Please fill out this page again) 1287015 A7

V. Description of the invention (<Η) The Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs printed 4_chloro_5,6_dimethyl-2_(3-fluorophenyl y7H-pyrrole['''' 200 MHz, DMSO-d6) 5 2.31 (s, 3Η), 2.33 (s= 7.29 (m, 1H), 7.52 (m, 1H), 7.96 (m, 1H), 8·14 (m, out 3^ 57 (s, 1H); MS (ES): 276·1 (M++1). ' ' · 5 4_gas_5,6-dimethyl-2·(2-fluorophenyl)J7H-pyrrole [w]*定·屯NMR (200 MHz, DMSO-d6) 5 2·34 (s, 3H), 2·34 (s, 3H)

7·33 (m, 2H), 7.44 (m, 1H), 7.99 (m, 1H), 12·23 (s, 1H); MS (ES): 276.1 (M++1). ' '4-Ga-5,6-dimethyl-2-isopropyl-7-pyrrolidino[2,3(1]pyrimidine; 11_1 Gu 11 10 (200MHz, DMSO-d6) accounted for 1.24 (d, J = 6.6 Hz, 6H), 2.28 (s 3H) 2.28 (s, 3H), 3.08 (q, J = 6.6 Hz, 1H), 11.95 (s, 1H); MS (ES): 224.0 (M++1 ' 4- 4--5,6-dimercapto-7H-indolo[2,3d]pyrimidine; ^NMR (200 MHz,

DMSO-d6) (5 2·31 (s, 3H), 2·32 (s, 3H), 8·40 (s, ih); MS 15 (ES): 182.0 (M++1). ' dl- Each chloro-5,b dimethyl-2-phenylene (1_phenylethyl) quinolo[(10)] is administered. Preparation 12: In DL-1,2-diaminopropane (1· 48 g, 2 〇〇 mmol, and sodium carbonate 2 〇 (2·73 g, 22.0 house Moule) in a solution of No. 2 (100 〇 ml) and water _ 〇亳) at room temperature The second carbonate was dibutyl carbonate, 220 mM, and the resulting mixture was stirred for 14 hours and removed under vacuum. Condensate, the precipitate was filtered and the filtrate was concentrated to dryness in vacuo. residue was taken and purified using eToaC, filtered, and concentrated to dryness under vacuum, ~105 ----------- ---------Book --------- line (please read the phonetic on the back? Please fill out this page again)

1287015 Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

(Please read the back of the note 咅g and then fill out this page) A7 V. Invention description (γθ, DL-1-amine base, 1-dimethylethoxy)-silyl-based propane, which is used in 佘The chromatography was not separable and the mixture was used in the reaction of Example 8. Preparation 13 : in Fmoc-P-Ala_OH (l. gram, 3 · 2 〗 2 mmol) and grass 醯 5 (0. 428 g, 〇 · 29 ml, 3 373 mmol) in dichloro A few drops of ν, Ν-dimethylformamide were added to the solution (2 〇〇 ml) at 0 ° C, and the mixture was stirred at room temperature for 1 hour, followed by the addition of cyclopropylmethylamine (〇). · 229 g, 0.28 liters, 3.212 mmol, and triethylamine (0 65 g, 〇 9 〇 ml, 6424 mp). After 10 minutes, add i molar concentration of hydrogen chloride 10 acid to the mixture. (10·0 ml), the aqueous mixture was extracted with dichloromethane (3×30.0 ml), and the organic solution was concentrated to dryness in vacuo, and the residue was used in 20% of hexane, dimethylformamide Hydrogen pyridine (2 〇. 〇 ml) was treated for 5 hours, and after removing the solvent under vacuum, the residue was treated with 1 molar concentration of hydrochloric acid (20·0 ml) and ethyl acetate (20.03⁄4 liter). The mixture was separated, and the aqueous layer was acidified to pH = 8 with a solid hydroxide of 15 </ RTI>, filtered, and the precipitate was removed. The aqueous solution was filled in an ion exchange tube and dissolved in 20% pyridine to obtain 262262 g (57 %) Ν _ cyclopropyl methyl β 丙 丙 丙, iH nmr (2〇〇5 〇·22 (m, 2Η), 0.49 (m, 2Η), 0.96 (m, 2Η), 2.40 (t, 2Η), 2.92 (t, 2H), 3.05 (d, 2H) MS (ES): 143.1 (M++1). 20 Preparation 14: N-t-butoxycarbonyl-trans 4,4-cyclohexyldiamine anti-_1,4-cyclohexyldiamine (6.08 g) , 53.2 millimolar) dissolved in dioxane (100 ml), via a catheter was added a solution of di-tert-butyl dibutylate (2-32 g, 10.65 mmol in 40 ml of di-methane) 2〇小时~106' This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm). Order line j 1287015 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (/β) The reaction was distributed in CHC13 and water. The liquid layer was separated and the aqueous layer was extracted three times with CHC13. The combined organic layer was dried over EtOAc, filtered and concentrated to give 1.20 g of white solid (53%), iHnmr (200MHz, CDC13) .0-1.3 (m5 4H), 1·44 (s,9H),1.8-2.1 (m,4H),2.62 5 (brm,1Η),3·40 (brs,1Η),4·37 (brs, 1H); MS (ES): 215.2 (M++1) 〇4-(N-ethylidyl)_N-t-butoxycarbonyl- _i,4_ ring Hexyldiamine Dissolve N-tert-butoxycarbonyl-trans-1,4·cyclohexyldiamine (530 mg, 2.47 耄mol) in di-methane (2 mL) and add acetic anhydride (25 逐 dropwise) After 10 hours, the reaction was diluted with water &amp; CHC1s. The layers were separated and the aqueous layer was extracted three times with CH.sub.3, and the combined organic layer was dried over MgSO4, filtered and concentrated from (Et 〇H/H2〇) After recrystallization, 19 mg of white crystals (30%) were obtained, ^NMRpOOMH^CDCy 5 0.9-1.30 (m,4H), 1.43 (s,9H), 1.96-2.10 (m,7H) , 3.40 (brs, 15 1H), 3·70 (brs, 1H), 4·4〇 (brs, 1H), 4.40 (brs, 1H); MS (ES): 257.2 (M++1), 242.1 ( M+_5), 201.1 (M+_56). '(4-trans-acetamidocyclohexyl)amino _5,6-dimethyl-2-phenyl----phenylethyl)pyrrolo[2,3d]pyrimidine 4-(N -Ethyl)-N-Tertiyloxycarbonyl-trans-κcyclohexyldiamine 2 〇 (^9 〇 mg, 0·74 mmol) dissolved in dichloromethane (5 mL) and used TFA (6 mL) Diluted, after 16 hours, the reaction was concentrated, crude solid, DMS (2 mL), NaHC03 (200 mg, 2·2 mmol) and winter chloro-5,6-didecyl- 2 Base_7H_pyrrolo[2,3d]pyrazine (35 mg, 0.14 mmol) was mixed in a flask and heated to 130 ° C. After 4.5 hours, the reaction was cooled to chamber 107'. (10) x 297 Gongdong) -------- order --------- line (please read the note on the back and fill in this page) 1287015 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 five The invention was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted three times with CH.sub.3, and the combined organic layer was dried over MgSO4, filtered and concentrated and chromatographed. Obtained 0.3 mg of a brown solid (1% yield), MS (ES): 378.2 (M++1). 5 4_(N_Methanesulfonyl)_N-t-butoxycarbonyl-trans-1,4-cyclohexyldiamine Dissolve trans-1,4-cyclohexyldiamine (530 mg, 2.47 mmol) Dichloromethane (20 ml) was diluted with pyridine (233 mg, 3.0 mmol), methanesulfonyl chloride (3 mg, 2.60 mmol) was added dropwise, and after 16 h, diluted with water and CHCI3 The liquid layer was separated and the aqueous layer was extracted three times with CH.sub.3, and the combined organic layer was dried over MgSO 4 , filtered and concentrated, and then recrystallized (Et0H/H20) to give 206 mg of white crystals (29%). CDC13) 5 1.10-1.40 (m, 4H), 1.45 (s, 9H), 2.00-2.20 (m, 4H), 2.98 (s, 3H), 3.20-3.50 (brs, 2H), 4.37 (brs, 1H) MS (ES)·· 293.1 (M++1), 278.1 (MM5), 237.1 (M+_56). L5 4-(4_trans-methylsulfonylcyclohexyl)amine _5, bis-dimethyl-2-phenyl-m-(1-phenylethyl)pyrrolo[2,3d]pyrimidine 4- (N-Methanesulfonyl-tert-butoxycarbonyl-trans-1,4-cyclohexyldiamine (206 mg, 0-71 mmol) was dissolved in dichloromethane (5 mL) and diluted with TFA (6 mL) After 16 hours, the reaction was concentrated to give a crude solid, D.sub.2 (2 liters), NaHCO/100 mg (L1 mM) and chloro as dimethyl-2-phenyl-7H-pyridinium. [2,3d]. Mix in a flask and heat to 130C. After 15 hours, the reaction is cooled to room temperature and diluted with Et〇Ac and water. The liquid layer is separated from the aqueous extract layer of CHC13 three times. Drying through MgS〇4, hydrazine and concentration, chromatography (Shixi gum preparation board; 2〇: ι ~108) This paper scale applies to China National Standard (CNS) A4 specification (210x297 public shame ------- ------------Book --------- Line · (Please read the notes on the back and fill out this page) 1287015

V. Illustrative =_) After obtaining 2.6 mg of brown solid (5% 414.2 (M++l) 〇v Example 1: 4_,_5,6-dimethyl-2-phenylene , 3 substances (〇·5〇5g, 1.94mmol) and 4-trans-cyclohexylamine (2.23g, -mole) in dimethyl slate (10.0ml) The solution was heated at n (rc for 5 hours, cooled to warmness, water (1 mL) was added and the obtained aqueous solution was extracted with Et.sub. j and filtered, the filtrate was concentrated to dryness under vacuum, and the residue was chromatographed on silica gel to give 0.49 g (75%) of 4-(4-di-hydroxycyclohexyl)amine _5,6-dimethyl Benzyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine, melting point 197-199 ° C, ^NMR (200 MHz, CDC13) 6 1·25·1·59 (m,8H), 2_08 ( s, 3H), 2.29 (s, 3H), 3.68-3.79 (m, 1H), 4.32-4.38 (m, 1H), 4·88 (d, J=8 Hz, 1H), 7.26-7.49 (m, 3H), 8.40-8.44 (dd, J=2.2, 8 Hz, 2H), 10.60 15 (s, 1H); MS (ES): 337.2 (M++1). The following compounds are obtained from analogous examples. Method: 4-(4-Re-hydroxycyclohexyl)amino-6-methyl-2-benzene -7H-pyrrolo[2,3d]pyrimidine, ^NMRGOOMH^CDCIJ 511.37 (s,lH,pyrrole-NH),8.45 (m,2H,Ar-H),7.55 (m,3H,Ar-H),6.17 (s, 1H, 20 咯 _H), 4.90 (br d, 1H, NH), 4.18 (m, 1H, CH-O), 3.69 (m, 13⁄4 CH-N), 2.40-2.20 (m, 2H ), 2.19-1.98 (m, 2H), 2.25 (s, 3H, CH3), 1.68-1.20 (m, 4H); MS (ES): 323.2 (M++1). 4-(4-trans-hydroxyl Cyclohexyl)amino-5-methyl-2-phenyl-7H-pyrrolop,3d]pyrimidine, ^NMRQOOMH^CDCD 511.37 (s,lH,pyrrole 109~ This paper scale applies to Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) ------------19 (Please read the notes on the back and fill out this page) Order---------Line·- Ministry of Economics Property Bureau Staff Consumer Cooperative Printed 1287015 A7 B7

V. Description of invention (pG 15 20 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed - NH), 8.40 (m, 2H, Ar-H), 7.45 (m, 3H, Ar-H), 5.96 (s, 1H, Pyrrole _H), 4.90 (br d,1H,NH), 4.18 (m,1H,CH-O), 3.69 (m, 1H,CH-N), 2.38-2.20 (m,2H), 2.18-1.98 ( m, 2H), 2.00 (s, 3H, CH3), 1.68-1.20 (m, 4H); MS (ES): 323.2 (M++1) 〇 4-(4-trans-hydroxycyclohexyl)amino- 2-Phenyl-7H-pyrrolo[2,3d]pyrimidine, m.p. 245.5-246.5 ° C, iHNMRpOOMH^CDsOD) 5 8.33 (m, 2H, Ar-H), 7.42 (m, 3H, Ar-H), 7.02 (d, 1H, J = 3.6 Hz, pyrrole-H), 6.53 (d, 1H, J = 3.6 Hz, pyrrole-H), 4·26 (m, 1H, CH-O), 3.62 (m, 1H) ,CH-N), 2.30-2.12 (m, 2H), 2.12-1.96 (m, 2H), 1.64-1.34 (m, 4H); MS M+l=309.3; elemental analysis (Ci8h2()N4〇) c , H,N. '4-(4-Re-hydroxycyclohexyl)amino-5,6-dimethyl-2-(3-pyridyl)-7 Η-^ oxo[2,3d]pyrimidine, WNMR (200 MHz, CDC13) δ i.2i_154 (m 8Η), 2·28 (s, 3Η), 2·33 (s, 3Η), 3·70 (m, 1Η), 4·31 (m, 1Η), ' 4.89 (d, 1Η), 7·40 (m, 1Η), 8.61 (m 2Η), 9.64 (m, 1H); MS (ES): 338.2 (M ++ 1). 4&quot;*(4·反-cyclohexyl)amine _5,6-dimethyl-2_(2_σ-fumanyl oxime)[2,3d]pyrimidine, ^NMR (200 MHz, CDC13) (5 1.26 -1.64 (m, 8H), 2·22 (s, 3H), 2.30 (s, 3H), 3.72 (m, 1H), 4.23 (m, iH), ' 4·85 (d, 1H), 6_52 ( m,1H), 7.12 (m,1H), 7.53 (m,iH),9 28 (s, 1H); MS (ES): 327.2 (M++1) 4-(4-trans-hydroxycyclohexyl Amino-5,6-dimethyl-2-(3-furyl)-7H_indolo[2,3d]pyrimidine, NMR (200 MHz, CDC13) (5 1.25-1.63 (m 8 Η), 2·11 (s, 3Η), 2·27 (s, 3Η), 3·Ή (m, 1Η), 4·2〇 (m, 1H), 5 (Please read the notes on the back and fill out this page. ) ------- order --------- line i 410- 1287015 A7 _B7__ five, invention description (/β) 4·84 (d, 1H), 7_03 (m, 1H), 7 ·45 (m,1H), 8.13 (m,1H), 10.38 (s,1H); MS (ES): 327.2 (M++1). (Please read the note on the back and fill out this page) 4- (4-trans-hydroxycyclohexyl)amino-5,6-dimethyl-2-cyclopentyl-7H-pyrrolo[2,3d]pyrimidine, MNMR (200 MHz, CDC13) 51.26-2.04 (m, 5 16H), 2-26 (s, 3H), 2.27 (s, 3H), 3.15 (m, 1H), 3.70 (m,1H), 4.12 (m,1H), 4.75 (d,1H); MS (ES): 329.2 (M++1) 4-(4-trans-hydroxycyclohexyl)amino-5,6 - dimethyl-2-(2-thienyl)-7H-pyrrolo[2,3d]pyrimidine, iHNMRpOOMH^CDCls) 51·28-1·59(ιη, 8Η), 2.19 (s, 3Η), 2.29 (s, 3Η), 3.74 (m, 1Η), 4.19 (m, 1Η), 10 4.84 (d, 1H), 7.09 (m, 1H), 7·34 (m, 1H), 7.85 (m, 1H) , 9.02 (s, 1H); MS (ES): 343.2 (M++1). 4_(4-trans-yl----------吩))7Η-σpyrho[2,3d]pyrimidine, ^NMRGOOMH^CDCy 51.21-1.60(m, 8H),1·98 (s,3H), 2.23 (s,3H),3.66 (m,1H) ), 4.22 (m, 1H),

15 7.27 (m, 1H), 7.86 (m, 1H), 8.09 (m, 1H), 11.23 (s, 1H); MS (ES): 343.2 (M++1). 4-(4-trans-carbamic acid hexyl)amino-5,6-dimethyl-2-(4-carbophenylpyrolo[2,3d]pyrimidine, ^NMR (200 MHz, CDC13) 6 1·26-1·66 (m, 8Η), 1.94 (s, 3Η), 2.28 (s, 3Η), 3.73 (m, 1Η), 4·33 (m, 1Η),

20 4.92 (d,1H),7.13 (m,2H),8.41 (m,2H),11_14 (s,1H); MS Ministry of Economic Affairs Intellectual Property Office Staff Cooperatives Printed (ES): 355.2 (M++1 ). 4-(4-trans-hydroxycyclohexyl)amino- 5,6-dimethyl-2-(3-fluorophenyl)-7H-pyrrolo[2,3d]pyrimidine, WNMRGOOMH^CDCIJ (Π.26 -1.71 (m, 8H), 2.06 (s, 3H), 2.30 (s, 3H), 3.72 (m, 1H), 4.30 (m, 1H), 111 This paper size applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) 1287015 A7 _B7_ V. Description of invention (&quot;Ο 4.90 (d,1Η),7·09 (m,1Η), 7.39 (m,1Η),8·05 (m,1Η), 8.20 (m, 1H), 10.04 (s, 1H); MS (ES): 355.2 (M++1). (Please read the note on the back and fill out this page) 4-(4-Re-hydroxycyclohexyl) Amino-5,6-dimethyl-2-(2-fluorophenyl)-7H-pyrrolo[2,3d]pyrimidine, iHNMRpOOMH^CDCy 51.3 (M.64 (m, 5 8H), 2.17 (s ,3H),2·31 (s,3H),3·73 (m,1H), 4.24 (m,1H), 4.82 (d,1H), 7.28 (m,2H), 8.18 (m,1H), 9.02 (m, 1H), 12.20 (s, 1H); MS (ES): 355.3 (M++1) 4-(4-trans-hydroxycyclohexyl)amino-5,6-dimethyl-2 -isopropyl-7H-pyrrolo[2,3d]pyrimidine, β NMR (200 MHz, CDC13) (Π·31 (d, J=7.0 Hz, 10 6H), 1.30-1.65 (m, 8H), 2.27 (s, 3H), 2.28 (s, 3H), 3. 01 (m, J=7.0 Hz, 1H), 3.71 (m, 1H), 4.14 (m, 1H), 4.78 (d, 1H); MS (ES): 303.2 (M++1). dl-4- (2-trans-hydroxycyclohexyl)amino-5,6-dimethyl, 2-isopropyl-7H-pyrrolo[2,3d]pyrimidine, iHNMRGOOMH^CDCls) 51.31-1.42 (br 15 4H), 1.75-1.82 (br,4H),2.02 (s,3H), 2.29 (s,3H),3.53 (m, 1H), 4.02 (m,1H),5·08 (d,1H),7·41· 7·48 (m,3H), 8.30 (m, 2H), 10.08 (s,1H); MS (ES): 337.2 (M++1). 4_(3,4_反-二经基ί Amino-5,6-dimethyl-2-phenyl-7H-11 biro[2,3d]pyrimidine, MS (ES): 353. 2 (M++1). 20 4-(3,4-cis-dihydroxycyclohexyl)amino-5,6-dimethyl-2-phenyl-7-pyrrole Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed and [2,3d] Pyrimidine, MS (ES): 353.2 (Μ++1). 4-(2-Ethylaminoethyl)amino-5,6-dimethyl-2·phenyl-7H-pyrrolo[2,3d]pyrimidine, mp 196-199 ° C, NMRpOO CDC13) 5 1.72 (s, 3H), 1.97 (s, 3H), 2.31 (s, 3H), 3.59 (m, 2H), 3.96 (m, 112' This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) 1287015 A7 B7_ V. Description of invention (&quot;/) 2H), 5.63 (br,1H), 7.44-7.47 (m,3H), 8.36-8.43 (dd,J=1 Hz, (please Read the notes on the back and fill out this page. 7 Hz, 2H), 10.76 (s, 1H); MS (ES): 324·5 (M++1). Dl-4-(2-trans-radioyl pentyl)amino-5,6-dimethyl-2-phenyl-7H-17 piroxime [2,3d]pyrimidine\eNMRpOOMK^CDCy (51.62 (m, 2H), 5 1.79 (br, 4H), 1_92 (s, 3H), 2.29 (s, 3H), 4·11 (m, 1H), 4.23 (m, 1H), 5.28 (d, 1H) , 7.41-7.49 (m, 3H), 8.22 (m, 2H), 10.51 (s, 1H); MS (ES): 323.2 (M++1). Preparation of 2- 2- hydroxy-cyclopentylamine, See PCT 9417090. dl-4-(3-trans-trans-p-pentyl)amino-5,6-dimethyl-2-phenyl·7Η-σpyrazine 10 1H NMR (200MHz?CDC13) 5 1.58 -1.90 (br? 6H), 2.05 (s, 3H), 2·29 (s, 3H), 4.48-4.57 (m, 1H), 4.91-5.01 (m, 2H), 7.35-7.46 (m, 3H) , 8.42 - 8.47 (m, 2H), 10.11 (s, 1H); MS (ES): 323.2 (M++1). 1 Preparation of 3-trans-hydroxycyclopentylamine, see EP-A-322242. 15 dl_4-(3-cis-Rhosinyl)-amino-5,6-dimethyl-2.phenyl-7H-11bipirin[2,3d]pyrimidine\^NMR (200 MHz , CDC13) 5 1.82-2.28 (br, 6H), 2·02 (s, 3H), 2.30 (s, 3H), 4.53-4.60 (m, 1H), 4.95-5.08 (m, 1H), 5.85 -5·93 (d,1H),7.35-7.47 (m,3H),8.42-8.46 (m, 2H),10.05 (s,1H); MS (E S): 323.2 (M++1). 20 1 Preparation of 3-cis-hydroxycyclopentylamine, see EP-A-322242. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 4-(3,4-reverse -dihydroxycyclopentyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine\^NMRGOOMH^CDCy (H_92-1.99(br, 2H), 2.14 ( s, 3H), 2.20 (br, 2H), 2.30 (s, 3H), 2.41-2.52 (br, 2H), 4.35 (m, 2H), 4_98 (m, 2H), 7.38-7.47 (m, 3H) , 8.38-8.42 113 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (//&gt;) (m, 2H), 9.53 (s, 1H); MS (ES): 339.2 (M++1). For the preparation of 1 3,4-trans-dihydroxycyclopentylamine, see PCT 9417090. 4-(3-Amino-3-oxopropyl)amino-5,6-dimethyl-2-phenyl-7H-atb ox[2,3d]pyrimidine, ^NMR (200 MHz, CDC13) (52.02 (s,3H), 2.29 5 (s,3H), 2.71 (t,2H), 4.18 (m,2H),5·75-5_95 (m,3H), 7.38-7.48 (m,3H), 8.37-8.41 (m, 2H), 10.42 (s, 1H); MS (ES): 310.1 (M++1) 4-(3-N-cyclopropylmethylamino-3-oxypropyl) Amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine, ^NMRGOOMHaCDsOD) 50.51 10 (q,2H),0·40 (q,2H),1·79_1 · 95 (br, 1H), 2.36 (s, 3H), 2·40 (s, 3H), 2.72 (t, 2H), 2.99 (d, 2H), 4.04 (t, 2H), 7.58-7.62 (m , 3H), 8.22-8.29 (m, 2H); MS (ES): 364.2 (M++1). 4-(2-Amino-2-oxoethyl)amino-5,6-diamidino-2-phenyl-7H-pyrrolo[2,3d]pyrimidine, iHNMRQOOMH^CDpD) 62.31(s,3H ),

15 2·38 (s, 3H), 4.26 (s, 2H), 7·36 (m, 3H), 8.33 (m, 2H); MS (ES): 396.1 (M++1). 4-(2-N-Methylamino-3-oxoethyl)amino-5,6-dimethylbutenyl-7H-pyrrolo[2,3d]pyrimidine, iHNMR (200MHz, CDC13) Δ1.99〇,3Η), 2.17 (s,3Η),2_82 (d,3Η),4·39 (d,2Η),5·76 (t,1Η),6.71 (br, 20 Qiu,7·41 ·7·48 (m,3H), 8.40 (m,2H), 10.66 (s,1H); MS (ES): 310.1 (M++1) 〇4_(3_Tertibutoxy-3-oxo Propyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine, iHNMR (200MHz, CDC13) 5l.45(s,9H), L96 (Sj 3H&gt;;^ 2·29 (s5 3H)? 2.71 (t5 2H)? 4.01 (q5 2H)5 5.78 (t5 114~ This paper size _ towel _ home (10) x29w -------- order --------- --- Line (please read the note on the back and fill out this page) 1287015 A7 B7 V. Invention Description (&quot;Μ 15 20 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1H), 7.41-7.48 (m, 3H ), 8.22-8.29 (m, 2H); MS (ES): 367.2 (M++1) 4-(2-hydroxyethyl)amino-5,6-dimethyl-2-phenyl-7H -pyrrolo[2,3d] continued pyridine, 屯]^]\411 (200 legs 2, € 〇 (: 13) (51.92 (8, 311), 2.29 (3, 3) 3- 81-3.98 (br, 4H ), 5.59 (t, 1H), 7.39-7.48 (m, 3H), 8.37 (m? 2H), 10·72 (s, 1H); MS (ES): 283.1 (M++1) 4-(3-hydroxypropyl)amino- 5,6-dimethyl-2-phenyl- 7H-pyrrolo[2,3d^ pyridine, 1H NMR (200 MHz, CDC13) 5 1.84 (m,2H), 1.99 (s,3H) 2.32 (s,3H),3·62 (t,2H),3 · 96 (m, 2H), 3.35 (t, 1H), 7·39·7·48 (m, 3H), 8.36 (m, 2H), 10.27 (s, 1H); MS (ES): 297.2 4-(4-hydroxybutyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3〇1] contigyl, 1H NMR (200 MHZ, CDC13) 5 1.71-1.82 ( m, 4H), 1.99 (s 3H), 2.31 (s5 3H), 3.68-3.80 (m, 4H), 5·20 (t, 1H), 7·41-7·49 ' (m? 3HX 8.41 (m 2H), 10.37 (s5 1H); MS (ES): 311.2 (M++1)o 4-(4•trans-acetamidocyclohexyl)amino-5,6-dimethyl-2 Phenyl-7JJi-[2,3d]pyrimidine. 4_(4_trans-methylsulfonylaminocyclohexyl)amino _5,6-dimethyl-2-phenyl, pyrrolo[2,3d]pyrimidine. 4-(2-Ethylaminoethyl)amino-5,6-dimethyl-2-phenyl-7H_7-(1) phenylethylpyrrolo[2,3d]pyrimidine. 4-(4•trans·perylcyclohexyl)amino group _5,6-dimethylindole phenyl-7 Η7·(1-phenylideneethyl)pyrrolo[2,3d]pyrimidine. Soil 4-(3·吼 基 methyl)amino _5,6-dimethyl-2- phenyl _ 7 phenyl phenyl pyri[2,3d] pyrimidine. 415^ -------------------- Order --------- line (please read the note on the back and fill in this page) This paper Standards for national standards (CNS$i^_lG χ 297 gongdong) Ministry of Economic Affairs Intellectual Property Bureau employees consumption cooperatives printed 1287015 A7 ______________ V. Invention Description (&quot;〆) 4-(2-methylpropyl)amino- 5,6·Dimethyl winter phenyl _ _7_(1_phenylethyl)pyrrolo[2,3d]pyrimidine. Example 2: In triphenylphosphine (0.047 g, 〇·ΐ 79 mmol) and benzoic acid (0·〇22 5 g, 0·179 mmol) in THF (1. 〇 ml) and cooled to stirring In the suspension, 4·(4-trans-ylcyclohexyl)amino group _5,6-dimethyl-2-indolyl-7Η-吼洛[2,3d]n is added at 0 °C. σ定(〇·〇5g, 〇149mmol), then add diethyl diazodicarboxylate (0.028ml, 0179mmol) for 10 minutes, then warm the reaction to room temperature, TLC After the completion of the reaction, the reaction was quenched with EtOAc EtOAc EtOAc EtOAc (EtOAc) Diethyl ether (2 liters) and hexane (5.0 liters) were added to the residue, and the triphenylphosphine oxide was removed by filtration. The filtrate was concentrated and the viscous oil was passed through column chromatography (hexane·acetic acid Ester di 4 : 1) Purification, yielding 15 to 5.0 mg (7.6%) of 4-(4-cis-benzylidenecyclohexyl)amino- 5,6-dimethyl-2-phenyl _7Ή-pyrrolo[2,3d]pyrimidine, MS (ES): 441.3 (M++1), the reaction also prepared 50.0 mg (84%) of 4-(3-cyclo) Yl) amino-2-phenyl -7H_ _5,6- two port pyrrole [2,3d] pyrimidine pyrimidine bite, MS (ES): 319.2 (M ++ 1). Example 3: 20 in cis-benzylideneoxycyclohexyl)amino-5,6-dimethyl-2-indolyl-7H's pyrrolo[W]pyrimidine (10) mg, 〇〇1丨4 To a solution of ethanol (1.0 ml), 1 liter of 2 molar sodium hydroxide was added, and after 1 hour, the reaction mixture was extracted with ethyl acetate (3×5.0 mL) and the organic layer was dried. Filter and concentrate to dryness under vacuum, and carry the residue to the column layer ~116' This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------- Order --- ------Line (please read the notes on the back and fill out this page) 1287015

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 5, Inventions (&quot;Γ) Analysis (hexane: ethyl acetate = 4:1), 3.6 mg (94%) of 4-(4-cis-hydroxyl ring) Hexyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine, MS (ES): 337.2 (M++1). The following compounds were obtained in a similar manner to Example 3: 5 4 -(3_N,N-dimethyl-3-oxopropyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[ 2,3d]pyrimidine, W NMR (200 MHz, CDC13) 5 2.01 (s, 3H), 2·31 (s, 3H), 2.73 (t, 2H), 2.97 (s, 6H), 4.08 (m, 2H) ),6·〇9 (t, 1H), 7·41_7·48 (m, 3H), 8.43 (m, 2H), 10.46 (s, 1H); MS (ES): 338.2 (M++1) 〇 10 4_(2-carbamidoethyl)amino _5, cardiodimethyl 2-phenyl-7-pyrido[2,3d]pyrimidine, iHNMR (200 MHz, CDC13) 62.26 (s, 3H ), 2.37 (s, 3H), 3·59_3·78 (m, 2H), 3·88_4_01 (m, 2H), 5·48-5·60 (m, out), 7.38-7.57 (m, 3H) , 8.09 (s, 1H), 8.30-8.45 (m, 2H), 8.82 (s, 1H); MS (ES) 310.1 (M++1). 15 4_(3·Ethylaminopropyl)amine _5,6-Dimethyl-2-phenyl-7H-indolo[2,3d]pyrimidine; MS (ES): 338.2 (M++1). Example 4: Will '(3-third Butoxy _3_ oxypropyl)amino group 5, 孓 dimethyl 2 _ phenyl pyrrolo[2,3d] • (mg, 〇. (9) millimolar) dissolved in trifluoro 2 〇 Acetate · 'dichloromethane (1:1, 5 〇 ml), the resulting solution at room temperature The mixture was stirred for 1 hour, then refluxed for 2 hours, cooled to room temperature, and then dried in a straight space, and the residue was subjected to preparative thin layer chromatography (c: c: hexane (68%). 4_(3 shop title propyl group ~ methyl-2-phenyl · 7 Η - σ ratio slightly [2, 3 things, 1hnmr (fine ~ 117 ~ [Please read the back of the phonetic? Please fill out this page again) --------Book --------- Line a paper ruler money m (CNs) A4 m^ (2i〇m: 297 mm)

1287015 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (/^) MHz, CD3OD) 6 2.32 (s, 3H), 2.38 (s, 3H), 2·81 (t, 2H), 4.01 (t, 2H), 7·55 (m, 3H), 8·24 (m, 2H); MS (ES): 311.1 (M++1). The following compounds were obtained from a method similar to that of Example 4: 4-(3-Aminopropyl)amino- 5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine Sigma; MS (ES): 296.1 (M++1), 279.1 (M+-NH3). Example 5: 4_(3-Hydroxy-3-oxopropyl)amino- 5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine (50.0 mg, 0.161 mmol) Dissolved in a mixture of N,N-dimethylamine (0.50 ml), dioxane (〇·5 mL) and water (〇·25 ml), and the resulting solution was stirred at room temperature 1 Hour, then reflux for 2 hours, adding methylamine (〇.〇2 ml, 40% in water, 0.242 mmol), triethylamine (0.085 ml) and hydrazine, hydrazine, Ν', Ν' _Tetramethylurea tetrafluoro side acid salt (61.2 mg, 0.203 mmol), after stirring at room temperature for 1 min, the solution was concentrated and the residue was subjected to preparative thin layer chromatography (EtOAc) to give 15 35.0 Mg (67%) of 4-(3-N-methyl-3-ethoxypropyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine, 屯NMR (200 MHZ, CDC13) 5 1.92 (s, 3H), 2·30 (s, 3H), 2.65 (t, 2H), 4.08 (t, 2H), 5·90 (t, 1H), 6.12 (m, 1H), 7.45 (m, 3H), 8.41 (m, 2H), 10.68 (s, 1H); MS (ES): 311.1 (M++1). 2〇 The following compound was obtained from a method similar to Example 5···················· , 3d] pyrimidine; MS (ES): 350.2 (M++1). 4-(2-Isobutylguanidinoethyl)amino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine. MS; ES (ES): 352.2 (M++1). ~118~ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------- order--------- line (please read the note on the back first) Fill in this page) 1287015 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed A7 B7 V. Invention Description (&quot;N-(3-propionylaminopropyl)amine _5,6-dimethyl-2 -Phenyl-7H-pyrrolo[2,3d]pyrimidine, iH nmr (200 MHz, CDC13) 5 1.00-1.08 (t,3H), 1.71-2.03 (m,4H),2.08 (s,3H), 2.37 (s, 3H), 3.26-3.40 (m, 2H), 3.79_3·96 (m, 2H), 5.53-5.62 (m, 1H), 6.17-6.33 (m, 1H), 5 7.33-7.57 (m , 3H), 8.31-8.39 (m, 2H), 9.69 (s, 1H); MS (ES): 352.2 (M++1) 〇 4-(2-methyl sulphate aminoethyl) amide 5,6-Dimethyl-2-phenyl-711-pyrrolo[2,3d]pyrimidine, ^NMRGOOMH^CDCy 62.18(s,3H), 2.27 (s,3H),2·92 (s,3H) , 3.39-3.53 (m, 2H), 3·71_3·88 (m, 10 2Η), 5·31-5·39 (m, 1Η), 6.17-6.33 (m, 1Η), 7·36-7· 43 (m, 3Η), 8.20-8.25 (m, 2H), 9·52 (s, 1H); MS (ES): 360.2 (M++1). Example 6: 4_gas_5,6- Dimethyl-2-benzene -7H·pyrolo[2,3d&gt; dense oxime (0.70 g, 2.72 mmol) and 1,2-diaminoethane (ι〇·〇 ml, 15 〇 mmol) 15 under inert gas pressure After refluxing for 6 hours, excess amine was removed under vacuum, and the residue was washed successively with diethyl ether and hexane to give y·75 mg (98%) of 4-(2-aminoethyl)amine _5,6- Methyl-2_phenyl-7H-port ratios are each [2,3d]; MS (ES): 282.2 (M++1), 265·1 (Μ+-ΝΗ3). Example 7: 20 In 4-(2-aminoethyl)amino- 5,6-dimethyl-2-phenyl-pro-pyrolo[2,3d]pyrimidine (70·0 mg, ο, mmol) and Triethylamine (5 〇·4 mg, 0.498 mM) was added to a solution of methylene chloride (2 mM) in chloroform (25.6 mg, 0.024 mL, 0.274 mmol). After 1 hour, the mixture was concentrated under vacuum, and the residue was subjected to a preparative thin layer~119~ ------------------------- ---- Line (please read the phonetic on the back first? Please fill out this page again)

1287015 A7

V. Inventive Note (&quot;A Chromatography (EtOAc) to give 22·〇 mg (26%) of 4 points of propylamine amino) Amine _5,6-dimethyl-2·phenyl_7Η _ 并 口 ] ] ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms ms 6_Dimethyl_2_phenyl-7h_吼洛和[2,3d]^^, 1HNMR(200MHz, CDC13) ^2.13 (s, 3H), 2.32 (s, 3Η), 3.53 (d, 3Η) ), 3.55 (m, 2H), 3.88 (m, 2H), 4.29 (m, 1H), 5- 68 (t, 1H), 5.84 (m, 1H), 7.42 (m, 3H), 8.36 (dd, 2H), 9.52 (s 1H); MS (ES): 339.3 (M++1). '4-(2·Ν'-Ethylureaethyl)amine-based dimethyl iphenyl-indolyl [2,3d] pyridinium; MS (ES): 353_2 (Μ++1). Example 8: In 1 minute dimethylaminopropyl peak ethylcarbamate hydrochloride (4)" 15 20 = gram, 0.215 mmol), ethylamine (24 mg, 嶋 millimol) And the solution of pyruvic acid (18.9 mg, 〇. 〇 15 ml 〇: : burning, liter) is added as aminoethyl: : 2-benyl-τη-pyrrole [2,3d] ♦ (55 〇 mM, 〇··············································································

If MU W[2,3dm; MS (ES): Example 9: Γ2 3^4_(2_Aminoethyl)amine·5,6^methylphenyl-7Η·pyrrole and '3· 〇.〇 Mg, 〇.213 mmol) in dichloromethane (10) ml) ~120, paper size μ 财 @ g^i^7CNS) A4 size (21〇· x 297 mm) 1287015 Ministry of Economic Affairs Intellectual Property Office staff Consumer Cooperatives Print A7 --------------- -B7_____ V. Inventive Note (&quot;f) Adding isocyanate N-trimethyl sulphate to the solution 3 mg, 〇〇51 ml, 0^320 mmol), the mixture was allowed to stir at room temperature for 3 hours, then an aqueous solution of sodium hydrogencarbonate was added, and after a small amount of Shiqi gum transition, the transition liquid was concentrated under vacuum. To dryness, 9·8 mg (Μ%) of 4 galydoladylethyl)amine _5,6-5 dimethyl-2-phenyl-7-pyrrolo[2,3d]pyrimidine; MS (ES) ): 325.2 (M++l) 〇 The following compound is obtained from a method similar to that of Example 9: icy (2-ethylhydrazinopropylpropyl)amine _5,6-dimethyl-2-phenyl _7Η-pyrolo[2,3d]pyrazine, iHNMR (200MHz, CDC13) (5 1.28-1.32(d, 1〇J~8^3H)? 1.66 (s, 3H)? 1.96 (s? 3H) 2.30 (s? 3H)? 3.76-3.83 (m, 2H), 4.10-4.30 (m, 1H), 5.60-5.66 (t, J=6 Hz, 1H), 7·40_7·51 (m, 3H), 8.36-8.43 (m, 2H), 10.83 (s, 1H); MS (ES ): 338.2 (M++l) 〇(RM-(2-Ethylaminopropyl)amino}5,6-dimethyl-2_phenyl oxime 15 and [2,3d]pyrimidine , ^NMRGOOMHz'CDCy (51.31(d,3H), i.66 (s5 3H), 1.99 (s,3H), 2_31 (s,3H), 3.78-3.83 (m,2H), 4·17_4·22 ( m,1H), 5.67 (t,1H), 7.38-7.5 (m,3H), 8.39 (m, 2H), 10.81 (s,ih); MS (ES): 338.2 (M++1). )-4-(ι-methyl_2_Ethylaminoethyl)amino-5,6-dimethylbutenyl 20 _71^pyrho[2,3(1]pyrimidine, 111&gt; ^^2〇〇]^/[]9[2,(:1:)(::13) 141 (d,3H), 1.68 (s,3H), 2.21 (s,3H), 2.34 (s, 3H), 3.46-3.52 (br, m, 2H), 4.73 (m, 1H), 5.22 (d, 1H), 7·41-7·46 (m, 3H), 8·36-8·4〇 ( m, 2H), 8.93 (s, 1H); MS (ES): 338.2 (M++1). (8)-4-(2-Ethylaminopropyl)amino-5,6-dimethyl-t-phenylphenyl-7H_pyrrole 121~ This paper size is applicable to the Chinese National Standard (CNS) A4. (10) X Moves to the public) -------- Order --------- Line (please read the notes on the back and fill in this page) 1287015 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. INSTRUCTIONS (/°^) and [2,3d]pyrimidine, WNMRpOOMHz'CDCU) (H.31(d,3H), 1.66 (s,3H), 2.26 (s,3H), 2.35 (s ,3H),3·78_3·83 (m,2H), 4.17-4.22 (m,1H),5·67 (t,1H),7.38-7.5 (m,3H),8.39 (m, 2H),8 · 67 (s, 1H); MS (ES): 338.2 (M++1). 5(5) fluorenyl 4 acetylaminoethyl)amino-5,6-dimethyl-2-phenyl-7H ·. More than [2,3d] pyrimidine bite,! HNMR (200MHz, CDC13) 51.41 (d, 3H), 1.68 (s, 3H), 2.05 (s, 3H), 2.32 (s, 3H), 3.46-3.52 (m, 2H), 4.73 (m, 1H) ), 5.22 (d, 1H), 7.41-7.46 (m, 3H), 8.36-8.40 (m, 2H), 10.13 (s, iH); (ES): 338.2 (M++1). 10 Example 10: Similar to the method of Example 1, 4-chloro-5,6-dimethyl-2-phenyl-7H-&quot;bilo[2,3d]pyrimidine and dl-indole-amino group- A mixture of 2-(1,1-dimethylethoxy)carbonylaminopropane and dl-2-aminomethylethoxy-decylaminopropane is reacted to obtain dl_4_(i_methyl- 2-(1,1-dimethylethoxy) 15carbonylamino)ethylamino-5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine with dl-4_ a mixture of (2-methylmethylethoxy)carbonylamino)ethylamino-5,6-dimethyl-2-phenyl-711-pyrrolo[2,3&lt;1]pyrimidine via a column layer Separation by HPLC (EtOAc: hexane = 1:3), the first fraction is dl (1-methyl-2-(1,1 dimethylethoxy)carbonylamino)ethylamine _5 , bis(2-methyl)-2-phenyl]20-7H-pyrrolo[2,3d]pyrimidine: 咁NMR (200 MHz, CDC13) occupies 1.29-1.38 (m,12H),1·95 (s,3H), 2·31 (s,3H),3.34-3.43 (m, 2H), 4.62-4.70 (m,1H),5·36_5·40 (d,J=8 Hz,1H),5.53 (br, 1H), 7.37-7.49 (m,3H), 8.37-8.44 (m,2H), 10.75 (s,1H); MS (ES): 396.3 (M++1); the second dissolved fraction is dl-4-(2) -methyl-2-(l,l-two~122' This paper scale applies to China National Standard (CNS) A4 regulations (210 X 297 mm) -------------------- Order --------- Line (please read the phonetic on the back? Please fill out this page again) A7 1287015 _______B7__ V. INSTRUCTIONS (/&gt;/) Methyl ethoxy)carbonylamino)ethylamino-5,6-dimethyl- 2-phenyl-7H-pyrrolo[2,3d]pyrimidine: iHNMR (200 MHz, CDC13) δ 1.26-1.40 (m, 12H), 2.00 (s5 3H)? 2.31 (s5 3H), 3.60-3.90 (m5 2H)5 3.95-4.10 (m,1H),5·41_5·44 (d,J=6.0 Hz,1H), 5.65 (br,1H), 7.40-7.46 5 (m,3H),8·37-8 · 44 (m, 2H), 10.89 (s, 1H); MS (ES): 396.2 (M++l) 〇 The following compounds are obtained from a method similar to that of Example 10 (S, S)-4_(2 -Ethylaminocyclohexyl)amino _5,6-dimethyl-2-phenyl hydrazine H_ pheno[2,3d]pyrimidine, iHNMRGOOMH^CDClJ 51.43 (m, 10 4 Η), 1· 6〇(s,3H),1.83 (m,2H),2·18 (s,3H),2·30 (m,2H), 2.32 (s,3Η),3·73 (br,1Η),4 · 25 (br, 1Η), 5·29 (d, 1Η), 7·43-7_48 (m, 3H), 8.35-8.40 (m, 2H), 9.05 (s, 1H). 4-(2•Methyl-2-ethenylaminopropyl)amino _5,6-dimethyl-2-phenylphenyl H-port ratio [2,3d]pyrimidine, iHNMR (200MHz, CDCl3) 51.51(s, 15 6H), 156 (s, 3H), 2.07 (s, 3H), 2_36 (s, 3H), 3·76 (d, 2H), 5.78 (t, 1H), 7.41-7.48 (m, 3H), 7_93 (s, 1H), 8.39 (m, 2H), 10.07 (s, 1H); MS (ES): 352·3 (M++1). Example 11: dl+(i-methyl·2-(1,;^methylethoxy)carbonylamino)ethylamino 20 j,6-dimethyl 1phenyl-7H-pyrrolo[2, 3d]·定(60.6 mg, 0.153 mmol) was treated with trifluoroacetic acid (〇. 5 ml) in di-methane (2 mL) for 14 hours, and the organic solvent was removed to dryness under vacuum. The solution was dissolved in N,N-methylcarbamide (2.0 ml) and triethylamine (2.0 ml), and acetic anhydride (172 mg, 〇169 mmol) was added to the solution at 〇 °c. The resulting ~123~L paper size applies to China National Standard (CNS) A4 specification (210 X Ngonggong) ----- ------------------ --Book --------- Line (please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1287015 A7 B7 V. Invention Description (/&gt;Λ) Economy The printed mixture of the Ministry of Intellectual Property's staff and consumer cooperatives was mixed for 48 hours at room temperature, then concentrated to dryness under vacuum, and the residue was subjected to a preparative thin layer of toAC) to obtain 2.7 mg (p2%) of dl. Ice (1-methylethyl decylamino)amino _5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d] Pyridine, iHNMR (200MHz, CDCy 5:38-1.42 (d, J=8 Hz, 3H), 1.69 (s, 3H), 2·01 (s, 3H), 2.32 (s, 3H), 3.38-3.60 ( m, 2H), 4.65-4.80 (m, 1H), 5.23-5.26 (d, J=6 Hz, 1H), 7.40-7.51 (m, 3H), 8.37_8·43 (m, 2H), 10.44 ( s,1H); MS (ES): 338.2 (]Vr+l). ' ' Example 12 : 10 A method similar to Example 1 from 4-chloro-5,6-dimethyl-2-phenyl-7H - 吼[2,3d]pyrimidine (〇·ΐ5g, 583·583mmol) and (10) Zhenfen prepared with diaminocyclohexane (0.63g, 5.517mmol) only _4_( 2-aminocyclohexyl)amino-5,6-dimethyl-2-phenyl-7-pyrrolo[2,3d]pyrimidine with diethylamine (0.726 g, 7.175 mmol) and acetic anhydride ( 325·325 g, 3.18 I5 millimolar) in hydrazine, hydrazine-dimethylformamide (ι〇·〇 ml) and at room temperature for 2 hours, after removing the solvent under vacuum, ethyl acetate (1 ml) and water (10.0 ml) were added to the residue, the mixture was separated and the aqueous layer was extracted with ethyl acetate (2×10.0 ml), and the combined ethyl acetate solution was dried (MgSCg and filtered, under vacuum) Concentrate the filtrate to dryness and leave the residue Column 20 was subjected to column chromatography (EtOAc: hexane = 1:1) to afford 57.0 mg (26%) of (R, R) -4- (2- ethylaminocyclohexyl) amide. 6_Dimethylbutyl-7H_indole[2,3d]pyrimidine, iHNMRpOOMH^CDCls) (51.43 (m, 4H)? 1.60 (s5 3H)5 1.84 (m5 2H)5 2.22 (s? 3H)? 2.30 (m? 2H)5 2.33 (s,3H), 3.72 (br,1H), 4.24 (bi·,1H),5·29 (d,1H), ~124' This paper scale applies to China Standard (CNS) A4 specification (21〇X 297 mm) (Please read the note on the back and fill out this page) - Order---------Line - 1287015 A7 B7, Invention Description (/VjJ) 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 7.43-7.48 (m5 3H)5 8.35-8.39 (m5 2H)5 8.83 (s, 1H) ; MS (ES): 378.3 (M++1) 〇'Example 13 : in 4_(2-hydroxyethyl)amino _5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]. dense. Dilute (4 〇.〇mg, 〇"41 mmol) in a solution of pyridine (1 〇 ml) at 0 ° with acetic acid needle (〇.1 〇 8 g, 1.06 mmol), the mixture junction temperature The lion was removed for 4 hours, the solvent was removed under vacuum, and the residue was subjected to preparative thin chromatography (EtOAc··············乙乳乳ethyl)amine _5,6-dimethyl-2-phenyl]_7H-cyclopyrrolo[2,3d]pyrimidine, 1H NMR (200MHZ, CDC13) 3m 2-08 (s, 3H ), 231 (S, 3H), 4.05 4.45 (t52H); 5^m' 1H), 7.41_7.49 (m, 3H), 8.42 (m, 2H), 11.23 (s 1H). Example 14: Ρηκχ-β_Α1α_ΟΗ (97·4 mg, (4) 3 mmol) and grass 醯 chlorine (39.7 house gram, 27.3 μL, 〇313 mM) in the dichlorocarbyl (four) millilitre and 1 drop, The solution of hydrazine dimethylformamide is stirred for 丨t under 〇t, then 4_(2·aminoethyl)amine _5,6-dimethyl-2-phenylene is added at o°c. H_ pyrrolo[2,3d]pyrimidine (80.0 mg, 0.285 mmol) mg, % microliter, (d) millimolar), after 3 hours, mixed, concentrated to dryness, residue used in N, Treatment of =/, hydroquinone (2.0 ml) in N-dimethylolacine for 0.5 hours, after removing the solvent under vacuum, the residue was treated with diethyl ether: hexane (1:5) to give 30 mg. Aminosyl-3-3-aza-4-oxoethyl)amino- 5,6-dimethyl-2-phenyl-7 Η 11 each [2,3d] pyrimidine; MS (ES): 353.2 ( Μ++1). ^125- Wood paper scale suitable for wealth and customs specifications (21〇x 297 public meals-------I ---------^ AW (please read the notes on the back and fill out this page) -Pylon 1287015 A7 B7 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed V. Invention Description (/W) Example 15: 4_(2·Aminoethyl)amino _5,6-dimethyl-2-benzene Base-711_pyrrolo[2,3d]. (70.0 mg, 0.249 mmol) and succinic anhydride (27 mg, 0.274 mmol) in dichloromethane (4.0 mL) and j The solution of the base 5 amine was stirred at room temperature for 4 hours, and the reaction mixture was extracted with 20% sodium hydroxide (3 χ 5 · 〇 ml), and the aqueous solution was acidified to pH Η = 7.0 with acetic acid at 3 m. Ethyl acetate (3 χ 10 mL) was extracted and the combined organics were dried (MgSOjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 3-aza- 4,7-dioxoheptylamino)-5,6-dimethyl-2-phenyl-7 Η_πί: slightly and [2,3d] caffeine; MS (ES): 382.2 ( M++1). Example 16: In a solution of 10 ml of dimethylformamide (DMF), at room temperature, 700 克 4- (cis-3-ylcyclopentanyl) Amino-2-phenyl- 5,6-dimethyl-7H-purine each 15 and [2,3d] mouth bite and 455 mg N-Boc glycine, 20 mg N,N-dimethyl Aminoguanidine (DMAP), 293 mg of benzotriazide (hobt) and 622 keke 1-(3-dimethylaminopropyl)-3-ethylphosphoric acid imide hydrochloride (EDCI) The reaction mixture was stirred overnight, the hydrazine was removed under reduced pressure, the reaction mixture was distributed in 20 ml of ethyl acetate and 5 ml of water, and then the aqueous layer was extracted with 2×20 ml of ethyl acetate. It is washed with brine, dried over sodium sulfate, filtered and concentrated, and then purified and purified with ethyl acetate/hexane to give 410 mg of the desired product: 4 _ -3- -3- 3-butoxycarbonyl _ 2_Aminoethyloxy)cyclopentyl)amino-2-phenyl]5,6-dimethyl-7H-pyrrolo[2,3d]pyrimidine, MS(ES)(M++1) =480.2, then ~126' This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------- order--------- line (please read the back first) Note: Please fill out this page again. 1287015 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Invention Description (/&lt;) After 5 The ester was treated with 2% trifluoroacetic acid in di-methane methane at room temperature. After standing overnight, it was concentrated and triturated with ethyl acetate to give 3 mg of sm. Cyclopentyl)amino- 5,6-dimethylbutyryl-7H-pyrrolo[2,3d]pyrimidine trifluoroacetate, mS(ES) 5 (Μ++1)=380·1. Those skilled in the art will appreciate that the following compounds can be synthesized by the above procedure: cis_3_hydroxycyclopentyl)amino-5,6-dimethyl-2-phenyl-7-pyrrolo[2,3d]pyrimidine, Ms(ES)(M++1)=323J. 4_(cis-3&lt;2_aminoethyloxy)cyclopentyl)amino-5,6-dimethyl-2-ylphenyl 10 fluoren[2,3d]pyrimidine trifluoroacetate, MS (ES) (M++l) = 380.1. 4-(3_Acetylamino)hexahydropyridyl-5,6-dimethyl-tungylphenyl-7Hpyrroloy[2,3d]pyrimidine, MS (ES) (Μ++1)=364· 2. 4 (2-Ν-methyl-urea propyl)amino _5,6-dimethyl- 2 phenyl _7η_π υ υ [2,3d] pyrimidine, MS (ES) (M++1 ) = 353.4. 15 4_(2-acetamidobutyl)amino-5,6-dimethyl-2-phenyl-7H·pyrrolo[2,3d]pyrimidine, MS(ES)(M++1)= 352.4. 4·(2-Ν'-methylureabutyl)amino- 5,6-dimethyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine, MS(ES)(M++1 ) = 367.5. Aminocyclopropylacetamidoethyl)amino-2.phenyl-7H-pyrrolo 20 [2,3 pyrimidine, MS (ES) (M++1) = 309.1. 4_(trans+hydroxycyclohexyl)amine-based winter (3-chlorophenyl)-7H-pyrrolo[2,3d] pyridine, MS (ES) (Μ++1)=342·8. 4_(Reverse hydroxycyclohexyl)amino-m-(3-fluorophenyl)-7-pyrrolo[2,3d] shout, MS (ES) (M++1) = 327.2. ~127~ This paper size applies to China National Standard (CNS) A4 specification (21〇X 297 mm) (Please read the note on the back and fill out this page) --------Book----- ---- 1287015 A7

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives, (7) Pyrrole nitrogen (Figure IX) is protected with di-tert-butyl dicarbonate in an alkaline condition to obtain the corresponding amino decanoate (22). Stereoselectively performing the radical bromination reaction of (22) to obtain the bromide (23). Usually, the compound (23) is used as a main electrophilic intermediate for various nucleophilic couplings, using a dihydrated dihydrate. Substituting the alkyl group to give the compound (24), followed by substituting the aryl bromide in the same step and removing the third butyl carbamic acid protecting group to give the desired compound (25). ~128~ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 1287015 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (, &gt;;) Compound (22)- (25) Detailed synthesis according to Figure IX

Adding dibutyl succinate (5.37 g, 24.6 mmol) and diethylamine 10 pyridine (1.13 g, 9.2 mmol) to (7) (1.50 g, 6.15 mmol) After a solution of pyridine (30 ml), the reaction was concentrated and the residue was partitioned between CH2C12 and water, and the CH2C12 layer was separated, dried, filtered and concentrated to give a black solid. (Si〇2; l/9 EtOAc / hexanes, RfO.40) gave 1.70 g (80%) of white 15 solid (22), NMR (200 MHz, CDC13) 5 8.50 (m, 2H, Ar-H ), 7·45 (m, 3H, Ar-H), 6.39 (s, 1H, pyrha-H), 2.66 (s, 3H, pyrrole-CH3), 1.76 (s, 9H, carbamate - MS, M+1 = 344.1; m.p. 175-177.

Cl

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------- order--------- line (please read the notes on the back and fill out this page) ) 1287015 A7

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Cooperatives. V. Invention instructions: N-bromosuccinimide (5〇8 mg, 2.86 mmol) and aibn (112 mg, 〇·68 mmol) Add to a solution containing (2 magic (935 mg, 2 71 mmol) and CCI4 (503⁄4 liter), heat the solution to reflux, and after 2 hours, allow the solution to cool to room temperature and concentrate under vacuum to give white Solid 5, fast chromatography (Si〇2; CHA/hexane, Rf 0.30) gave 960 mg (84%) of white solid (23), lHNMRpoOMHiCDCy 3 8.52 (m, 2H, Ar_H), 7·48 ( m, 3H, Ar-H), 6.76 (s, 1H, pyrrole _h), 4·93 (s, 2H, fluorenyl-CH2Br), I·79 (s, 9H, carbazate _Ch3) MS, M+1 = 423.9; m.p.

Phenol sodium trihydrate (173 mg, L〇2 mmol) was added in one portion to bromide (23) (410 mg, 〇·97 mmol) dissolved in Ch2C12 (5 mL) and DMF (10 mL) After 2 hours, the reaction solution was distributed in 03⁄4⁄4 and water, and the aqueous layer was extracted with CH2a2. The combined cH2Cl2 layer was washed with 20 water, dried over MgSO4, filtered and concentrated to give a yellow solid. Chromatography (SiCy l/6 EtOAc / hexanes, EtOAc) afforded 210 mg (50%) of white solid (24), iHNMR pOOMH^CDClJ 58.53 (m, 2H, Ar-H), 7-48 (m, 3H, Ar- H), 7·34 (m, 2H, Ar-H), 7.03 (m, 3H, Ar-H), 6.83 (s, 1H, pyrrole-H), 5·45 (s, 2H, ArCH20), ~ 130~ This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) I I-----------Book--------- (Please read the back Please fill out this page again) 1287015

A7 B7 V. Description of the invention (/a L76(s, 9H, urethane _CH3); MS, M+1 = 436.2. V' 10 will contain (24) (85 mg, 0.20 mmol), A solution of N-ethinyl ethylenediamine (201 mg, 1.95 mmol) and DMSO (3 ml) was heated to 10 ° C. After 1 hour, the temperature was raised to 130 ° C for 3 hours. The reaction was then cooled to rt and EtOAc (EtOAc)EtOAc (EtOAc)EtOAc. Obtained 73 mg (93%) of a white foamy solid (25), NMR (200 MHz, DMSO-d6) 511.81 (br s, 1H, NH), 8.39 (m, 2H,Ar-H), 8.03 (br t,1H,NH), 7.57 (br t,1H,NH), 7.20-7.50 (m,5H,Ar-H), 6.89-7.09 (m,3H,Ar- H), 6.59 (s, 1H, pyrrole-H), 5.12 (s, 2H, 20 ArCH20), 3.61 (m, 2H, NCH2), 3.36 (m, 2H, NCH2), 1.79 (s, 3H, COCH3), MS, M+1 = 402.6. The following compound is obtained from a method analogous to Example 17: 4-(2-ethylaminoethyl)amino -6-phenoxymethyl 4-phenyl _711 _pyrrolo[2 , 3d] pyrimidine, melting point 196-197 ° C, MS (ES): 401.6 (M + 1). ~ 131 This paper scale applies to China National Standard (CNS) A4 specifications (210 x 297 mm) --- -----------------Book---------Line (please read the notes on the back and then fill in this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative 1287015 A7 V. INSTRUCTION DESCRIPTION B7 10 15 4 acetoxyaminoethyl)amino-6-(4fluorophenoxy)methyl_2_phenyl_7H-port ratios [2,3d ]♦, MS (ES): 420.1 (M++1). 4 parts of ethylaminoethyl)amino-6-(4-chlorophenoxy)methyl-tert-phenyl-7H-♦ each [2,3d] pyrimidine, MS (ES) · · 436.1 ( M++1). 4 must be ethylaminoethyl)amino _6_(4-methoxyphenoxy)methyl_2_stupylpyrazine [2,3d] pyrimidine, MS (ES) · · 432.1 ( M++1). 4_(2_Ethylaminoethyl)amino-6-(N-pyridine-2__)methyl_2_phenyl-7H-indolo[2,3d]pyrimidine, MS (ES): 403.1 (M++1). 4-(2-Ethylaminoethyl)amino)-phenylphenylamino)methyl-2-phenyl-7H-pyrrolo[2,3d]pyrimidine, MS (ES): 400.9 ( M++1). 4&lt;2-Ethylaminoethyl)amino-6- and methylphenylamino)methyl-2_phenyl-7H-pyrrolo[2,3d]pyrimidine, MS (ES): 414.8 (M++1). 4_(2-N'-methylureaethyl)amino _6•phenoxymethyl-2_phenyl_7Η-pyrrolo[2,3d]pyrimidine, MS (ES): 416.9 (Μ+ +1). Example 18: Synthesis of adenosine\antagonist Compound 1319 and compound 1320 (Table 13 below) can be synthesized via one of the steps herein. m 20 C1

N Η Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

Η〇/α 一〆xtyN

— II------I----订------11 (Please read the notes on the back and fill out this page) Compound 26 X=F Compound 27 X=C1 Compound 1319 Compound 1320 432- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 Α7 Β7 V. Invention description (〇/) Compound 1319 (81°/〇) ^-NMR (d6_DMSO) 51.37 (m, 4Η) , 1.93 (m, 2H), 2.01 (m, 2H), 4·11 (brs, 1H), 4.61 (d, 1H, J = 4.4 Hz), 6.59 (m, 1H), 7.09 (m, 1H), 7.21 (m, 2H), 7.49 (dd, 1H, J=8 Hz, 14 Hz), 8.03 (m, 1H), 8.18 (d, 1H, J = 8 Hz), 11.55 (brs, 1H), MS ( ES): 327.0 (M++1). Compound 1320 (31%), MS (ESI): 343.1 (M++1). Example 19: Synthesis of adenosine antagonists Compound 1321 (Table 13 below) can be synthesized via the general procedures herein. 10

MeO

OEt

29

30 15 20 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Compound 1321 Compound 28 (10.93 g, 50.76 mmol) was dissolved in DMF (67 mL), and 4-mercaptopyridine hydrochloride (8.0 g, 50.76 mmol) and DBU (15.4 g, 101.5 mmol) and the reaction was heated to 85 ° C. After 22 hours, the reaction was cooled to room temperature and DMF was removed in vacuo. The molar concentration of HC1 (80 ml) was diluted. After the reaction was allowed to stand for 2 hours, the solution was cooled to 10 ° C and filtered, and the solid was washed with cold water and dried to give 7.40 g of a yellow solid, Compound 29 (69%), iH -NMR (200 MHz, d6_DMSO) 5 6.58 (s, 1H), 7.27 (s, 1H), 8.53 (d, 2H, J = 5.6 Ηζ), 9.00 (d, 2 Η, J = 5.2 Ηζ), 12.35 (brs, 1Η), MS (ES):

433. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 V. INSTRUCTION DESCRIPTION GY) 212.8 (M++1) 化合物Compound 29 (7.4 g, 29·8 mmol) Diluted with P〇Cl3 and heated to 105 C. After 18 h, the reaction was cooled to rt and EtOAc (EtOAc) was evaporated. EtOAc. Diluted, the amorphous red solid was filtered and washed with diethyl ether to give 3. <RTI ID=0.0; ). Compound 1321 (15%) W-NMR (200 MHz, d6-DMSO) 5 1.38 (m, 4H), 1.92 (brs, 2H), 2.02 (brs, 2H), 3·44 (brsvlH), 10 4.14 (brs ,1H), 4.56 (d,1H,J=4 Hz),6·63 (m,1H),7·15 (m, 1H), 7.32 (d,1H,J=6.2 Hz), 8.20 (d, 2H, J = 4.4 Hz), 8.65 (d, 2H, J = 4.4 Hz), 11.67 (brs, 1H), MS (ES): 310.2 (M++1). Compound 1501 (Table 15 below) (70%), ^NMR (200 MHz, CD3OD) 1.84 (s? 3H), 3.52 (t5 23⁄4 J=6.0 Hz), 3.83 (t, 2H, 15 J=6.0 Hz), 6.51 (d, 1H, J = 3.4 Hz), 7.06 (d, 1H, J = 3.8 Hz), 7.42 (m, 3H), 8.36 (m, 2H), MS (ES): 296.0 (M++1) . Compound 1502 (Table 15 below), MS (ES): 345.0 (M++1). Compound 1500 (Table 15 below) iH-NMR (200 MHz, CDC13) 5 1.40-1.80 (m, 6H), 1.85-2.10 (m, 2H), 2·18 (s, 3H), 2·33 (s, 20 3H), 2.50 (d, 3H), 3.90-4.10 (m, 2H), 4.76 (m, 1H), 5·50 (d, 1H), 6.03 (m, 1H), 7.40 (m, 3H), 8.37 (m, 2H), 9.15 (brs, 1H), MS (ES): 393.3 (M++1). Example 20: Synthesis of adenosine\antagonist Compound 1504 (Table 15 below) can be synthesized via the following general procedure. ~134~ This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 mm) (Please read the note on the back and fill out this page) Order---------Line·Ministry of Economics Intellectual Property Bureau employee consumption cooperative printed 1287015 A7 B7 V. Invention description (/$)

Η〇/α 15 20 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Compound 1504 Compound 31 (200 mg, 0 Λ 7 mmol) was dissolved in j) CM (4 mL), followed by the addition of triethylamine (51 mg, 0.5 mM) and thiofolf (52 mg, 0.5 mmol), the solution was mixed for a few minutes and then allowed to stand for 1 hour. The reaction was diluted with DCM and H.sub.2 and the layers were separated. The aqueous layer was extracted with DCM. The combined DCM layer was dried with EtOAc EtOAc (EtOAc m.j.jjjjjjjj (s,9H), 2·66 (brs,2H),2·79 (brs,2H),3·86 (s,2H),7.46 (m,3H),8·50 (m? 2H) Compound 32 was mixed with EtOAc (3 mL) and EtOAc (EtOAc (EtOAc) The layers were separated and the aqueous extracted with EtOAc EtOAc (EtOAc)EtOAc. The oil was added to diethyl ether and the obtained solid was filtered to give 5 mg of white solid (9%) of OSICM48265: e-NMRQOOMHz, CD3〇D) 1.44 (brm, 4H), 2·03 (brm, 2H), 2.21 (bmi , 2H),

435^ This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1287015 A7 B7 V. Invention description (/Kun) 2·7〇(brm,8H),3_63 (m,4H),3.92 (m, 1H), 4.26 (brs, 1H), 6.42 (s, 1H), 7.42 (m, 3H), 8.33 (m, 2H). Example 21: Synthesis of adenosine\antagonist Compound 1503 (Table 15 below) can be synthesized via the following general procedure.

III Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 10 Compound 1503 Dissolve bromide compound 31 (220 mg, 0.47 mmol) in 1:1 DMF: dichloromethane (5 mL), add k2C03 (71 mg, 〇 · 52 mM) and oxime (0.047 ml, 0.47 mmol), stir the mixture at room temperature for 15 overnight, remove the solvent under vacuum and distribute the residue in Η20 and methylene chloride. The organic layer was dried with EtOAc EtOAc (EtOAc m.jjjjjjjjj , 9H), 2.54 〇, 4Η), 3_65 (s, 4Η), 3.85 (s, 1Η), 6.59 (s, 1Η), 7.45 (m, 3Η), 8.52〇 (m, 2H). Compound 33 (50 mg, o. ii millimolar) and trans-cyclohexanol (105 mg, 0.91 mmol) were dissolved in DMSO (2 mL) and the resulting solution was spouted with N2 in an oil bath Heat it to 100 and stir overnight. Pour the crude reaction mixture into water and extract twice with ethyl acetate (5 mL). Apply 436- paper size to Chinese National Standard (CNS) A4 specification (210 X 297 public) ) Order 1287015 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 V. Invention Description (0Γ) The combined organic layers were washed with H20, dried and filtered through MgS〇4, and the organic layer was concentrated under vacuum to give an orange. Solid, Chromatography (Shixi gum, 1% CH3OH in CH2C12) gave 15 mg (33%), iH-NMRGOO MHz, CDC13) 51.24-1.62 (m,4H),1·85 (m,2H) ,2·10 (m,2H), 5 2.26 (m,4H), 3·53 (m,4H), 4.22 (m,1H),4·73 (m,1H),5·85 (d,1H) ),6·15 (s,1H), 7.25 (m,3H), 8.42 (m,2H),10.0 (s,1H), MS (ES)·· 408 (M++l) 〇Preparation of compound 1500, 1501 and 1502 can be prepared using a preparation procedure similar to that of Example 20 Substituted amine compound 32 treatment. 10 Human adenosine A and A2a receptor yeast y?-galactosidase reporter gene test method: use human adenosine A! (AIR, CADUS species CY12660) or human A2a (A2a; CADUS species CY8362) and add lacz (y?-galactosidase) The reporter gene is transformed into a yeast species (Saccharomyces cerevisiae) as a functional reading. The complete description of the transformation is listed below (see Yeast species), and there are 15 pairs of receptors and receptors. NEC A (5,-N-ethylformamide adenosine), a similar adenosine receptor stimulating agent, was used as a ligand for all assays at 8 concentrations (0·1-10,000 nanomolar) The test compound inhibits the ability of the point-galactosidase activity of CY12660 or CY8362 induced by the test compound. The farmer's mother-in-law 锗涝赛赛 swirling the representative yeast strains CY1266〇 and 20 CY8362 into the LT agar culture dish and cultured at 3〇t: until the colonies are observed, from these Yeast was added to the LT solution (Yang 68) and grown overnight at 3 ° C, and then each yeast was diluted to a photometer ces X). . =1 〇2 : (° about 2χ 1〇7 cells/ml), for each 6 ml of yeast liquid culture solution, add 4~137' This paper scale applies to China National Standard (CNS) A4 specification (210 X 297厘 (Please read the notes on the back and fill out this page) Order---------Line 1 1287015 A7 B7 15 20 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 40% Glycerin (1:1.5) Volume: volume) ("Yeast/glycerol stock solution"), from this yeast/glycerol stock solution, prepare 10 1 ml portions and store them at _8〇t until the test is required. 擘母和为,游试法· Glass bottles containing CY8362 and CY12660 yeast/glycerol stock solutions were thawed and used to grow Supplemented LT liquid medium pH 6·8 (92 ml LT liquid, which was added: 5 ml 40% glucose, 0.45 ml 1 molar concentration 2.5 and 2.5 ml Pipes , pH 6.8), the liquid culture was grown at 30 ° C for 16-18 hours (overnight), then the overnight culture was partially diluted in LT medium containing 4 U / ml adenosine deaminase (from the cattle intestine Mucosal type VI or VII, Sigma), obtained CY CY8362 (A2aR) 〇 D_ = 0.15 (1 · 5 χ 106 cells / ml), CY12660 ('R) 〇D6〇〇=〇_50 (5x 106 cells/ml). Test with a final volume of 100 μl in a 96-well microtiter dish to achieve a final concentration of 2% DMSO in all tanks. For primary screening, use 1-2 test compounds (1 〇 micromolar concentration, 1 micromolar concentration), for the summary of compounds, test 8 concentrations (10000, 1 〇〇〇, 5〇〇, 100, 50, 10, 1 and (U nanomolar concentration), in each microtiter dish, 10 μl of 20% DMSO was added to the “control group, and,, the whole group, the trough, Add 1 μl of the test compound (in 20% DMSO), unknown group, and then add 10 μl of NECA (A1R with 5 micromolar concentration, 'π with 丫 micro ear concentration) to the whole Group "and" unknown group" slot, add 1 〇 microliter pBs to the "rhyme group," slot, in the final addition, add 8G microliters of yeast strain CY8362 or CY12660 in all, then briefly stir all Petri dish (LabLine orbital shaker 2_3 minutes), make it dry in 3〇t^C. Please read the notes on the back before filling in this page) -1------Book ------ ---line 438- 1287015 A7

V. Description of the invention (~ is cultured for 4 hours. Calling _galactose-enzyme activity can be done with a colorimeter (such as 〇NpG CPRG), a luminometer (such as Galacton-Star) or a fluorescent object (such as FDG, ReS〇rufln) Quantitative, at present, based on good signal · noise ratio, interference 5 relative freedom and low cost, fluorescent detection is better, a fluorescent galactosidase activator fluorescein Glycosides (FDG, M〇lecular Probes or Marker Gene Technologies) were added to all tanks at 20 μl/well (final concentration = 80 micromolar concentration) and the dish was shaken for 5-6 seconds (LabLine) , then incubated at 37 ° C for 90 minutes (95% 10 〇 2 / 5% C 〇 2 incubator), after the end of the 90-minute incubation period, use 2 〇 microliter / tank of 1 molar concentration of Na2C03 and shake all The petri dish was stopped for 5-6 seconds, and then the culture was stopped for 6 seconds and the relative fluorescence intensity was measured with a fluorometer (Tecan Spectrafluor; excitation = 485 nm, emission = 535 nm). The relative fluorescence value of the "control" slot is considered as the background value and from, the overall group "and" unknown group Value deduction compound analysis via logarithmic conversion. (X-axis: compound concentration) and the one-side anastomosis to calculate the competition curves IC5 values (GraphPad Prism) °

Yeast species · Development Saccharomyces cerevisiae CY12660[far]*1442tbtl-l fUs 20 l-fflS3 canl stel4::trp 1::LYS2 ste3*1156 gpal(41&gt;Ga 13 lys2 ura3 leu2 trpl:his3; LEU2 PGKp-Mfa lLeader-hAIR-PH05term 2mu-orig REP3 Ampr] and CY8362 [gpalp_fG a sE10Kfarl*1442tbtM fusl-fflS3 canl ste 14::trp 1:LYS2 ste3*l 156 lys2 ura3 leu2 trpl his3; LEU2 PGKp-hA2aR ~139~ this paper The scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) --------Book --------- Line' Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1287015 A7 _____ B7 V. Invention Description (/release) 2mu-〇ri REP3 Ampr] Lamp Divided · LT (Leu_Trp Supplement) Medium is made up of 1 gram DIFCO yeast nitrogen Matrix composition, and supplemented with the following substances: 1.0 g of proline, 1.0 g of aspartic acid, 〇 · 75 g of phenylalanine, 0.9 g of lysine, 〇 · 45 g of tyrosine, 5 〇 · 45 Leucine, 0.3 g of methionine, 0.6 g of adenine, 0.4 g of uracil, 0.3 g of serine, 0.3 g of valine, 0.3 g of cysteine, 0.3 g, fine Acid 0.9 g of histidine and 1.0 g of sulphate. Establishment of yeast species releasing human scorpion adenosine receptors In this example, the establishment of a human scorpion glucoside receptor functionally 10 synthetic yeast pheromones Yeast species of the system channel. L-establishing expression vector In order to establish a human 'adenosine receptor expression vector, primers designed according to the sequence of human\adenosine receptors and standard techniques, reverse transcriptase PCR via human hippocampal mRNA The adenosine receptor cDNA was obtained, and the 15 PCR product was replicated into yeast to express the plastid pMP15; the ΡΜΡ15 plastid was created from pLPXt according to the following method: J51 of the JiM site (Broach, JR· et al (1983),, Vectors for high-level, inducible expression of cloned genes in yeast55 p. 83-117 in M. 20 Inouye (ed.)? Experimental Manipukation of Gene Expression. Academic Press, New York) The tail is filled and then crusted to produce Yep51NcoDXba, the other part is in the caricature and the cartilage is digested, the tail is filled, and the link (NewEngland Biolabs, #1081) is ligated, fear (31 digestion and This paper ligation to produce ~140~ scale applicable Chinese National Standard (CNS) A4 size (210 X 297 male f) (Please read the back of the phonetic? Matters fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs

1287015 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 _______Β7____ V. Invention description (/7) YEP5UViraXt, digested with Esp31 and Ncol, and ligated into Leu2 and PGK fragments produced by PCR, using containing households 31 and The plastid of the /π site, via the potentiation from YEP51Nco, produces a 2kbLeu2 PCR product via a fortification from PPGK as (Kang, γ.-s. et al, (199〇), 5 Mo1 CdL Bi〇l. 10 :2582-2590), using PCR plastids containing Bg/II and Ncol sites, yielding 660 sets of PGKpPCR products, the resulting plastid is called pLPXt, and the coding portion of the a-factor pre-guide is inserted into the 〇1 site. While the pLPXt is modified, the pre-insertion body maintains the Ncol replication site at the 3' end of the leader, but does not regenerate at the 5th end. In this manner, the receptor can be replicated by digesting the plastid using 10 and d. The resulting plastid is called pMP15 °. The ρΜΡ15 plastid inserted into the human octa Adenosine receptor cDNA is called P5095. In this vector, the receptor cDNA is fused to the 3 terminus of the yeast a-factor pre-director, and the protein is matured. During the propeptide sequence dissociation yields a full length of 15 matures Receptor, which occurs during the processing of the receptor through the yeast secretory pathway, which is maintained by Leu selection (ie, grown on a medium lacking leucine), the sequence of the replicated coding site is determined and found to be The literature is equal (GenBank accession numbers S45235 and S56143). Π· Establishing yeast species 20 In order to produce yeast species that express human adenosine receptors, the yeast strain CY7967 is used as the starting yeast species, and the genotype of CY7967 is as follows:

MaTagpaD1163 gpal(41)Gai3 farlD1442 tbt-1 FUS1-HIS3 canl ste 14::trpl::LYS 2 ste3Dl 156 lys2 ura3 leu2 trpl his3 ~141 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public shame )

--------^--------- (Please read the notes on the back and fill out this page) 1287015 A7 B7 V. Invention Description (/θ) The gene labeling review is as follows:

MaTa............... a type mating gene. (Please read the notes on the back and fill out this page) gpalD1163... GPA1 removes endogenous yeast G-protein. Gpal(41)Gai3...gpal(41)-Gai3 is integrated into the yeast genome, which is composed of the first 41 amino acids of the endogenous yeast Ga subunit GPA1 of the g protein Gai3 fused to mammals. The related N-terminal amino acid is removed. farlD1442......... The FAR1 gene (which is responsible for cell cycle capture) is removed (thus preventing pheromone response channels from being activated during cell cycle capture). ................. A strain with high conversion rate during electronic processing. The FUS1-HIS3.........FUS1 promoter is fused to the HIS3 coding region (thereby generating a pheromone-evokable gene). Canl................. arginine/canavanate permease. Stel4 "trpl::LYS STE14 gene distribution, a c_farnesylmethyl 2·transferase (thus reducing the baseline signal in the pheromone channel). ste3D1156.........endogenous yeast STR,a Factor pheromone receptor (§τε3) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed and destroyed. ^s2............... Defects in 2-aminoadipate reduction Enzyme, yeast into... Long need lysine. ura3.................. Defect in orotidine nucleoside-5,-phosphate decarboxylase, yeast paper scale Applicable to China National Standard (CNS) A4 Specification (210 X 297 public) 1287015 A7 B7 V. Invention Description (/¥/) 10 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 15 Female growth requires uracil. .... ......... Defects in isopropyl malate detoxification, yeast growth requires leucine. ........... Defect in phosphoribosamine anisoate, yeast growth Need to... Tryptophan acid. hls3.................. Defects in imidazole glycerol phosphate, yeast growth requires histidine. Electronic processing converts two plastids into CY7967: plastid p5〇95 (the above decoded human A1 adenosine receptor And plastid pl584, which is the FUS1-/3-galactosidase reporter gene plastid, and the plastid pl584 is derived from the plastid pRS426 (Christianson, TU α/. (1992) Gene welcome: 119_1122), The body pRS426 contains a multi-linker in nucleotides 2004-2016, the fusion insertion of FUS1 promoter and galactosidase, and the formation of plastid P1584 in the initial part of the melon, and the plastid ρ1584 is maintained via Trp selection (that is, Growth in a medium lacking leucine.) The resulting strain has ρ5095 and ρ1584, called CY12660, which express the human Α1 adenosine receptor. In order to grow this strain in a liquid or slow-limt culture dish, the lack of leucine is used. And the minimum amount of medium of tryptophan, the growth test method of the culture dish (test 7^757-7/75^), the culture dish is in Yang 6 8 and contains 0.5-2.5 house mole concentration of 3-amino-1 2,4-trisodium and lacking leucine, tryptophan and histidine, as indicated by the comparison, included in all experiments with one of the seven transmembrane receptor screens of one or more other yeast matrices. The yeast species of the human A2a adenosine receptor, in this example, demonstrates the establishment of a human a2a adenosine receptor Energy leu2 trpl 443^ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) Order---------Line 1 1287015 A7

: ί 办 整合 整合 整合 整合 整合 整合 整合 酵母 酵母 酵母 酵母 酵母 酵母 酵母 酵母 酵母 酵母 酵母 酵母 酵母 酵母 酵母 酵母 酵母 酵母 酵母 酵母 为了 为了 为了 为了 为了 为了 为了 为了 为了 为了 为了

Phil Murphy (NIH) obtained the human AZa receptor cDNA. After receiving this replica, the receptor was inserted into the sequence and found to be identical to the published sequence (GenBank accession #S46950). The receptor cDNA was removed from the VENT polymerase by PCR. The plastid is excised and replicated to the plastid pLPBX, which produces receptor expression via the structural phosphoglycerol kinase (PGK) promoter in yeast, re-serializing the entire inserted sequence and finding the same sequence as the announcement, but via use The nature of the replication strategy is that three amino acids are attached to the carboxy terminus of the receptor, GlySerVal. II. Establishment of yeast species In order to produce yeast species that express human A2a adenosine receptors, the yeast strain CY8342 was used as the starting yeast species. The genotype of CY78342 is as follows: Printed by the Intellectual Property Office of the Ministry of Economic Affairs

MaTa farlD1442 tbt-1 lys2 ura3 leu2 trpl his3 fusl-HIS3 canl ste3D1156 gpaD1163 stel4::trpl::LYS 2 gpajp-rGasE10K (or gpalp-rGasD229S or gpalp-rGasE10K+D229S) In addition to the G-protein change, the gene is labeled the same as As described above, for human A2a receptor expression, yeast strains are used in which the endogenous yeast G protein GPA1 is removed and replaced with mammalian Gas, and three large voles Gas mutants are used, and these variables contain one or two mutations, Converted into a protein that is operably coupled to yeast ySr, which has been identified as GasE10K (where the proline is replaced by lysine at the 10 position), GasD229S (where -144- this paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1287015 A7 ____-----------___ V. Invention Description (^{^) Aspartic acid silk at position 229 Amine acid substitution) and GasEl〇K+D229s (including two point mutations). The strain CY8342 (three mutant hamster proteins with one of them) was ligated with the parental vector pLPBX (receptor) or PLPBX-A2a (receptor +), 5 and the FUS1 promoter was fused to galactosidase. The plastid of the coding sequence (described above) is used to assess the degree of activation of the pheromone response channel. Functional Testing Using Yeast Species Expressing Human Pro-adenosine Receptor In this example, a functional screening assay was developed in yeast as a human VIII receptor. 10 I· Ligand used in the test method This test was developed using the receptor's natural stimulant adenosine and two other artificial stimulants, using EC5() in an affiliated experiment reported to be approximately 75 耄 micromoles The concentration of adenosine and affinity was reported as (a) _N6_(2_phenylisopropyl)-adenosine (PIA) at a concentration of about 5 〇 nanomolar, and 5'-N- was used in all growth test methods 15 Ethyl-mercapto-adenosine (NECA) was added to adenosine deaminase (4 U/ml) in all tests in order to avoid signalling due to adenosine present in the growth medium. II. Biological Response in Yeast The Ar adenosine receptor was assessed in a heterogeneous yeast system by adding a \receptor expression vector (p5〇95 above) to a series of yeast species exhibiting different 20 G protein subunits. The ability to functionally couple, most of these variants are expressed as Gai or G% subtypes of Ga subunits, and Ga proteins are also tested for identification of promiscuous receptor _Ga protein couplings, among different species, STE18 or The chimeric STE18_Gr2 structure is integrated into the yeast genome, ~145 This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public). (Please read the back note and fill out this page) ----- ---^---------$411 1287015 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 ~----- B7 V. Invention description (仏〆)^ —— Yeast species hidden defect HIS3 gene and FUS1-HIS3 integrated replica, so you can choose 3-amino-containing 1,2,4-triazole and lack of histidine selectivity* (in 0.2, 〇·5 and ΐ·〇 莫Ear concentration test), separation of transformants, containing 3-amino-purine, 2,4-tris-sal, 4U/ml adenosine deaminase and deficiency A single layer is prepared in a medium containing no histidine 5, and 5 μl of different concentrations of ligand (for example, five microliters of different concentrations of ligands at concentrations of 〇, 0·Κ 1.0, and 10 millimolar) are added to monitor growth 2 In this way, ligand-related growth responses were tested in different yeast species under this method. The results are summarized in the table below. Symbols (a) indicate that no ligand activity associated with the ligand was detected, and (1) indicates that the ligand was associated. In response, 10 "LIRMA" refers to receptor-initiated activation independent of ligand. 146~ This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) (Please read the note on the back and fill out this page)

1287015 A7 B7 77 Description of invention (/A〇

Table 3 15 20 1 ·-Λ Yeast species Listening unit Gy Secondary position: i kind variable 'Result CY1316 GPAi STE18 - GPA41-G, 1: GPA41-Ga.: + GPA41-G3i3 Ten GPA41-Gai:-Ga0B LIRMA GPA41-GaSri〇K - GPA41 -GaSD229S - CY7S€1 integrated · STE18 ++10 CY2120 GPA: STE18 SSt2A + GPA41-Gail + GPA41-G3i: + _ GPA41-G3l3 + GPA41-Gai;-GQ05 LIRMA GPA41-GaSE1 〇K - GPA41-GaSD: 29s - CY9438 GPAi STE18-GY2 - GPA41-Gai: •f GPA41-Gai: + GPA41-Gai3 + GPA41-Gai:-G3〇B LIRMA GPA4 1 -G3SE10k - GPA41 -G3SD:29s - ~CY10560 GPAr integrated STElvB-Gy2 sst2A + + IIIIII As shown in Table 3, the strongest signal was found to be present in the yeast species expressing the GpA1(41)_Ga13 chimera. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Ruler Paper IIL/nsALacZ Test Method In order to more fully identify the activation of the pheromone response channel, the measurement response thorn A7 B7 f 1287015 V. Invention Description (146) Repair: c G Arsenic Year The synthesis of y5_galactosidase stimulated by the agonist, in order to carry out the galactosidase test, an increasing concentration of the ligand is added to the human A1 adenosine of the Stel8-Gr2 conjugate and the GPAwGai3 which are expressed in the yeast species. In the body culture solution, the deformed body was separated and grown overnight in the presence of histamine and 4 U/ml adenosine deaminase, and cultured with 4 U/ml adenosine deaminase and ligand for 5 hours, using CPRG as a call-half The matrix of lactosides measures the inducibility of galactosidase, using 5 x 105 cells per test. The results obtained by NECA stimulation showed that the neca of 1 〇·8 molar concentration caused about 2 times stimulation of the point-galactosidase activity, and about 1 〇 of the stimulation was observed at NECA of ίο·5 molar concentration. Extend the use of this test to confirm the activity of the antagonist on this species, and test two known adenosine antagonists XAC and DPCPX to compete with NECA (5 molar concentration) in the yS-galactosidase assay. In terms of activity, in these tests, FDG was used as a matrix and the inducibility of galactosidase was measured using 1.6 cells per test. Printed by the Intellectual Property Cooperative of the Ministry of Economics In order to determine whether this inhibitory effect specifically targets the Ai subtype, a series of auxiliary experiments using the yeast receptor Ah receptor test method, the results obtained from the Aia yeast matrix test method show that XAC is a kind of A fairly potent A2a receptor antagonist is consistent with the reported report. Conversely, DPCPX is quite inert at this receptor, as expected by the reported report. IV. Radioligand binding

The A! glandular receptor assay was further identified by measuring the radioligand binding parameters of the receptor, and several adenosine receptor reference compounds XAC, DPCPX were analyzed using a membrane prepared from yeast expressing human VIII! adenosine receptor. And CGS-148· 1287015 A7 V. Inventive Note (/^) [3H]CPX substitution binding, the results obtained with the yeast membrane expressing human Αι adenosine receptors showed the human A2a oblique redness _ job performance human A3 gland Comparison of the results of glycosidic yeast: to determine the specificity of the combination, in order to carry out this test method, the concentration of adenosine receptor ligand was increased by 毫·4 nanomolar concentration [3H]cpx and 5 Milligram of membrane at 50 mM Tns-HCl, pH 7.4, 1 mM EDTA, 1 mM molar concentration of MgCL, 0.25% BSA and 2 U/ml adenosine deaminase and presence in protease inhibitors After incubation for 60 minutes at room temperature, 10 binding was terminated via the addition of ice-cold 5 Torr milliliters of Tris-HCl, pH 7.4 and 10 mM molar concentration of MgCl2, followed by pre-soaking of 0.5% polyethyleneimine GF. /B filter paper is quickly filtered and used with Packard 96-tank collector, using PrismZ01 soft body The nonlinear least square curve method is used to analyze the data. The IC50 values obtained in this experiment are summarized in Table 4 below (please read the note on the back sheet and then fill in the page). Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed Table 4 IC5〇[home micromolar concentration] Compound hA,R hA,R XAC 6.6 11.7 53.1 DPCPX 8.5 326.4 1307.0 CGS-15943 13.1 15.8 55.5 NECA 215.5 294.9 34.9 R-PIA 67.6 678.1 23.6 IB-MECA 727.7 859.4 3.1 Alloxozine 1072.0 1934.0 8216.0 15 These data show the affinity of the reference compound and one of the 149~ reported in the literature. The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). Order--------- Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1287015 A7 ----------^------- V. Invention description (for (f), data migration display yeast-based test The method is sensitive enough to distinguish the specificity of the receptor's paratype. Using a functional test that expresses the human yeast into the yeast species In this example, a functional screening test was developed in yeast as a human A2a gland. Glycoside receptor I. The ligands used in the test method use the natural ligand adenosine and other well-studied and commercially available ligands to study the human Ah receptor functionally expressed in yeast, in establishing this test method. Three ligands were used, including: Ligand-reported K. Functional adenosine 500 nanomolar concentration _ stimulant _ 5'-N-ethyl methionine adenosine (NECA) 10-15 micromolar stimulation Agent (I)-N6-(2-phenylisopropyl)-adenosine (PIA) 100-125 nanomolar _$:_ stimulant In order to avoid the signal generated by adenosine present in the growth medium, in all Adenosine deaminase (4 U/ml) was added to the test. II. Biological response test in yeast Ala receptor stimulator is transformed with A2a receptor which expresses plastid and expresses one of Gas E丨〇κ, GasD229S or GasE10K+D229S, 15 stimulates pheromone receptor in yeast The ability of the channel, the ability of the ligand to stimulate the pheromone receptor channel in a receptor-associated manner is indicated by a change in yeast phenotype, which improves the phenotype from histamine auxotrophy to histamine auxotrophy. Activate), separate three independent variants and apply the Chinese National Standard (CNS) A4 specification (210 X 297 mm) at ~150~. (Please read the phonetic on the back? Please fill out this page) --- ------_ 1287015 A7 B7 V. Invention Description (#/),,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, 5 μl of each deformed body is placed on a non-selective medium (containing histamine) or a selective medium (tetragen concentration TA) without or with 4 U/home lift deaminase, and cultured under _ After the hour, in the presence of histamine, both the receptor W) and the receptor _ (R·) species can grow. In the absence of histamine, only r+ cells grow, because there are two possible explanations for the addition of ligands in the two sigma dishes. One possible explanation is due to receptors not associated with ligands. Initiation of activation (LIRMA) gives birth to a green material, or yeast can synthesize ligand gland 4," distinguishes two kinds of enzymes, and adds the enzyme of adenosine deaminase (ADA) to growth. In the presence of yeast and petri dishes, R+ cells cannot grow without histamine in the presence of mechanical pradamine, indicating that the yeast is indeed a synthetic ligand. 15 20 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Print This explanation is confirmed by the A _ a growth test in liquids. In this experiment, R+ yeast (GasE10K strain expression receptor) is at three densities (ΐχ 1〇6 Cells/ml, 3x 1〇5 cells/ml or ix 105 cells/ml) and cultured in the presence or absence of adenosine deaminase (4U/ml), the perceptibility of this test is increased by concentration (〇 Enhanced by 3-amino-1,2,4-triazole (AT) at a concentration of 0.1, 0.2 or 0.4 millimoles, which is a competitive antagonist of the imidazole glycerol-p dehydratase of the protein product of the HIS3 gene In the presence of adenosine deaminase and 3-amino-1,2,4-triazole, yeast growth is less intense, but in the absence of 3-amino-1,2,4-triazole, adenosine The effect of deaminase is small, so adenosine deaminase itself has no direct effect on the pheromone receptor channel. Another way to measure growth and minimize high-throughput screening A2a ~15l· This paper scale applies to China National Standard (CNS) A4 specification (21〇χ 297 mm) 1287015 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print A7 B7 V. INSTRUCTIONS (/0) Receptor ligand point test method, showing A〗A receptor (Ά+) or lack of receptor (R〇's GasE10K strain in histamine and 4U/ml adenosine deaminase In the presence of growth, wash the cells to remove histamine and dilute to 5 x 1 6 cells/ml, disperse \ X 106 cells to 4 U/ml adenosine deaminase and 〇 5 or 1 〇 5 molar concentration 3 - Amino-1,2,4-triazole (AT) in a petri dish and allowed to dry for 1 hour, 5 microliters of each of the following reagents were applied to the monolayer: 1 〇 millimolar adenosine , 38.7 millimolar concentration of histamine, diazepam (dms〇), 10 millimolar concentration PIA or 10 millimolar concentration neca, allowing cells to grow under conditions such as C for 24 hours, the results showed that cells without receptors only It can grow under the medium of tissue 10 amine addition. Conversely, R+ cells can only grow in the region of the receptor ligands PIA and NECA. The culture dish contains adenosine deaminase, which is adenosine but does not grow, confirming the activity of adenosine deaminase. IILyii^-LacZ test method To quantify the activation of the yeast mating channel, measure the cold-half milk via 丄acZ 15 Glycosidase synthesis, transforming the yeast species expressing GasE1〇K, asD229S or Gas E10K+D229S with a plastid that decodes the human A2a receptor (R+) or lacks the receptor (R-), and separates the deformed body and Incubate overnight in the presence of histamine and 4 U/ml adenosine deaminase, dilute 1χ1〇7 cells to lx1〇6 cells/ml and expose to increasing concentrations of _(:: into the 4 hours, 20 subsequent The activity of gal-galactosidase in the cells was measured, and it was found that no gal-galactosidase activity was detected in the permeate of the R-bacteria, but when the CA/Chen degree was increased, the performance of GasE10K, G« was exhibited. sD229S or G% E10K+D229S R+ strain detected an increase in the gamma-galactosidase activity, indicating that the detected unit of galactosidase increased the response to the increase of ~152' The Financial Secretary Standard (CNS) A4 specification (210 X 297 public) (please read the precautions on the back and fill in This page) —------ order--------- line · A7 B7 1287015 V. Invention description (m) ---------_. |#j£ vj There was a dose-related correlation between the concentration of the ligand and the concentration of the ligand, and the dose correlation was only observed in the cells of the 4|J A2a receptor of the Shenming Province, and the most effective Gas structure of the A2a receptor was GasE10K, G«sD229S. The structure is the second most effective G «s structure of the A2a receptor, and the Gas E10K+D229S structure is the least effective structure among the three G«s structures tested. It is easy to stimulate even if the G«s E10K+D229S structure can be stimulated. The amount of CAM-galactosidase activity that can be detected. For a more detailed description of the test method, see U.S. Patent Publication No. US-2002-0015967_Al, entitled "Functional Expression of Adenosine Receptors in Yeast", published February 7, 2002. for reference. Pharmacological identification materials and method materials for human adenosine receptors: [3H]_DPCPX [cyclopentyl-1,3-dipropylxanthine, 8-[dipropyl]-2,3-3H(N )] (120.0 ritual / millimolar); [3H]_CGS 21680 [rebel ethyl 3Η (Ν)] (3〇居礼/毫莫耳) and [125I]-AB-MECA ([125I]- 4-Aminobenzyl-5'-N-methylguanidino adenosine) (2,200 rit/mole) was purchased from England Nuclear (Boston, MA), XAC (xanthine-like compound) ), NECA (5, · Ν-ethylmethionine adenosine) and IB-MECAv from Reaearch Biochemicals Interbational (RBI, Natick, MA), GEM Department of Intellectual Property, Staff Consumer Cooperative, printing glycosidase and The entire protease inhibitor mixed tablet was purchased from Boehring Mannheim Corp. (Indianapolis, IN) and stably released human adenosine 2a [RB-HA2a], adenosine 2b [RB-HA2b] from the membrane of HEK-293 cells. Or the genotype 3 [RB-HA3] receptor subtypes were purchased from Receptor Biology (Beltsville, MD), and the Cell culture reagents were from Life Technologies -153- This paper scale was applied to the Chinese National Standard (CNS) A4 specification (210 x 297). Public love) 1287015 A7 B7 five Description invention (/ 0) (Grand Island, NY), but serum from Hyclone (Logan, UT). Aunt Grinding · According to the above development Saccharomyces cerevisiae CY12660[far]*1442 tbtl-1 fus 1-HIS3 canl stel4::trp 1::LYS2 ste3*1156 gpal (41)- G a i3 lys2 ura3 leu2 trpl : His3; LEU2 PGKp-Mf a 5 ILeader· hAlR-PH05term 2mu_orig REP3 Ampr] and CY8362 [gpalp-rGasE10Kfarl*1442 tbtl-1 fusl-fflS3 canl ste 14::trp 1:LYS2 ste3*l 156 lys2 ura3 leu2 trpl his3; LEU2 PGKp-hA2aR 2mu- ori REP3 Ampr] o 肄承培赛旋: Deformed yeast growth in the Leu-Trp 10 [LT] medium (pH 5.4) supplemented with 2% glucose, 250 ml LT medium when preparing the membrane 3 〇 ml of the overnight culture medium of l-2 x 106 cells/ml of the fermentation broth was inoculated and cultured under a continuous oxygenation at 30 ° C. After 16 hours of growth, the cells were collected by centrifugation and prepared as follows. membrane. The ridge is Weng #气鳞 Each play ··Stable release of human adenosine 2a receptor subtype 15 HEK-293 cells (Cadus clonal line #5) in supplement 10% burdock serum and IX penicillin / streptomycin Dulbeco's minimal essential medium (DMEM) was grown under selective pressure at 500 mg/ml G4l8 antibiotic at 37 ° C humidified 5% CO 2 gas pressure. Ministry of Economic Affairs, Intellectual Property Office, Staff and Consumers Cooperative, Printed Momo, sensitized and depleted: Centrifuge at 2, 〇〇〇20 X g in a Sorvall RT6000 centrifuge, collect 250 ml of culture medium after overnight culture, use ice water Wash the cells, centrifuge at 4 C and resuspend the pellets in 1 ml of ice-cold lysing buffer [5 millimolar Tris-HCl, supplemented with a protease inhibitor mixed tablet (1 tablet per 25 ml). In pH 7.5, 5 millimolar concentration EDTA and 5 millimolar concentration EGTA], the glass is added to the suspension ^ 1515 Φ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1287015 A7 ____-____B7 V. Inventive Note (/^) (17 g, 400-600 mesh, Sigma), break the cells by vigorous stirring for 5 minutes under 4 art, add 30 ml of lysing buffer containing protease inhibitor The homogenate was diluted and centrifuged at 3,_x g for 5 minutes, then the membrane was granulated (Sorvall RC5B, SS34 rotor) at 36, 嶋X g for 45 minutes, and the 5 membrane pellets were resuspended in the supplemental protease inhibitor. Mixing tablets (1 tablet per '50 ml buffer) membrane buffer [50 m Ear concentration Tris_HC1, 7 · 5,0.6 mmol EDTA concentration and the concentration of 5 mmol MgCy pH and stored at -80 ° C for other experiments. Breast-feeding cell membrane preparations····················· Collect, pellet the cells in a Sorvall RT6000 centrifuge at 4 °c 2 〇〇 xg, and resuspend the pellets in 5 ml / 4 °C lysing buffer [5 millimolar concentration Tris-HC1, PH7 .5, 5 millimolar concentration EDTA, 5 millimolar concentration EGTA, αι 15 millimolar concentration phenylmethylphosphonium fluoride, 10 mg/ml pepsin A and 1 〇家克/宅升抑Enzyme] and homogenized in the D〇unce homogenizer, printed by the Ministry of Economic Affairs, the Intellectual Property Office, and then the cell lysate was centrifuged at 36,000xg (Sorvall RC5B, SS34 rotor) for 45 minutes, and the pellets were re-applied. Suspended in 5 ml of membrane buffer [50 millimolar Tris-HCl, pH 7.5, 0.6 millimolar concentration 20 EDTA, 5 millimolar concentration MgCl2, 0_1 millimolar concentration phenyl methyl sulfone, 10 MG/ml pepsin A and 10 mg/ml aprotinin] and stored at _80 °C for other For experimental use. Bio-Rad protein test method based on Bradford staining-binding procedure (Bradford, M.: Anal. Biochem 72:248 (1976)) ~155 This paper scale applies to Chinese National Standard (CNS) A4 specifications. (210 X 297 public) 1287015 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 ------R7____ V. Invention Description (/Jri〇 reagent group for determination of total protein concentration in yeast and mammalian membranes. Adenosine 1 receptor subtype saturation and competitive radioligand binding using antagonist [3h] dpcpx as a radioactive ligand, saturation and competitive binding on the membrane of yeast cells modified with human A1 receptor paraform, 5 in binding buffer Liquid [50 millimolar concentration Tris-HC1, pH 7.4, containing 10 millimolar concentration MgCl2, 1.0 millimolar concentration EDTA, 〇.25% BSA, 2U/ml adenosine deaminase and 1 protease inhibitor Mix the tablets / 5 〇 ml] to dilute the membrane to a concentration of 1.0 mg / ml, in saturated combination, with increasing concentration of [3H]DPCPX (0.05-25 nanomolar concentration) in a final volume of 100 10 micro In the binding buffer, no or 10 micromolar concentration is not indicated Incubate for 1 hour in a 96-well microplate at 25 ° C in the presence of XAC. In competitive binding, use [3H]DPCPX (1.0 mM molar concentration) in a final volume of 100 μl of binding buffer. Membrane (5 μg/well) was cultured in a 96-well microplate at 25 ° C in the absence or presence of XAC at a concentration of 1 micromolar or at a concentration of 15 increasing competitive compounds. i hours. The adenosine 2a receptor paratype competes with the radioligand in combination with the stimulant [3H] CGS-21680 as a radioactive ligand for competitive binding on a membrane that stably displays the human A2a receptor paraform, in combination with a buffer of 20 [ 50 millimolar concentration Tris-HCl, pH 7.4, containing 10 millimolar concentration MgCL 1·0 millimolar concentration EDTA, 0.25% BSA, 2U/ml adenosine deaminase and 1 protease inhibitor mixed tablet /50 ml] the membrane was diluted to a concentration of 0.2 mg/ml, using [3h] CGS-21680 (100 nanomolar concentration) in a final volume of 1 〇〇 microliter of binding buffer, in the absence or presence ~156' This paper size applies to China National Standard (CNS) A4 specification (210 X 297 public). (Please read the phonetic on the back? Please fill out this page again) ^------------ --------------------- A7 1287015 B7 V. INSTRUCTIONS (/ Ο 50 micromolar concentration unlabeled NECA, or in the presence of competitive compounds At a concentration, the membrane (1 μg/well) was incubated for 1 hour in a 96-well microplate at 25 ° C. Adenosine 3 receptor competes for radioligand binding 5 Using stimulant [125I] AB-MECA as radiation Active ligand, in Stable binding on membranes stably expressing human A3 receptor subtypes in binding buffer [50 millimolar Tris-HCl, pH 7.4, containing 10 millimolar concentration MgCl2, 1.0 millimolar concentration EDTA, 0.25% BSA, 2 U/ml adenosine deaminase and 1 protease inhibitor mixed tablet / 50 ml] medium diluted membrane to a concentration of 0.2 mg / ml, using [125I] AB-MECA (0.75 nanomolar concentration In a final volume of 100 microliters of binding buffer, 96-well micros at 25 ° C in the absence or presence of unlabeled IB-MECA at 10 micromolar concentrations, or at increasing concentrations of competing compounds The membrane (10 μg/well) was incubated for 1 hour in the culture dish. 15 After the completion of the culture, the A was terminated by adding an ice-cold 50 mM Tris-HCl (pH 7.4) buffer supplemented with 10 mL of MgCl 2 . And A3 receptor accessory radioligand binding assay, followed by rapid filtration (96-well GF/C UniFilters, Packard) via a 0.5% polyethyleneimine glass fiber filter paper soaked in a Filtermate 196 tank collector (Packard). Dry the 20 filter plate and apply 50 μL/well of the flash liquid (MicroScint-20,

Packard) was counted on TopCount (Packard) and repeated three times. In the A#, A2aR and A3R binding assays, the non-specific combinations were 5.6 ± 0.5%, 10.8 ± 1.4%, and 15.1 ± 2.6, respectively. %. Adenosine 2b Receptor Subtype Competing Radioligand Binding 157~ This paper scale is in the ®® Family Standard (CNS) A4 specification (210 297 297 metric f) (Please read the back of the note? Please fill out this page)

-------- Order --------- Line II Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1287015 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing Α 7 Β 7 5, invention description (/ eve /) Using the receptor antagonist [3h]dpcpx as a radioactive ligand for competitive binding on a membrane that stably exhibits the human A2b receptor paratype, in binding buffer [10 millimolar concentration Hepes-KOH, pH 7. 4, containing 1.0 mM concentration of EDTA, 0.1 mmol concentration of benzamidine and 2 U / ml adenosine deaminase] 5 to dilute the membrane to a concentration of 0.3 mg / ml, with [3H]DPCPX (15 nanomolar Ear concentration) 96- at 25 ° C in binding buffer with a final volume of 1 μL in the absence or presence of unlabeled XAC at 10 μmol concentration, or at increasing concentrations of competing compounds The membrane (15 μg/well) was incubated for 1 hour in a trough microplate. After the end of the culture, the test was terminated by adding ice-cold 10 mM molar concentration of Hepes_KOH (pH 7.4) buffer, followed by soaking in the Filtermate 196 tank. Rapid filtration of 0.5% polyethyleneimine glass fiber filter paper in a packer (96-well GF/C UniFilters, Packard), the filter plates were dry coated with 50 μl/well scintillation liquid (MicroScint-20, Packard) and counted on TopCount (Packard), 15 repeated tests three times, non-specific combination for total binding of 14.3 soil 2.3%. The specificity of [3H] DPCPX, [3H] CGS-21680 and [125I] AB-MECA is defined as the difference between the total binding and the non-specific binding, and the percentage of inhibition of the total binding compound is calculated using GraphPad Prizm software, via 20 The competition data was analyzed from the inverse curve of the single-position mode, and the K! value was calculated from the IC5G value ((: 1^ and Prusof, Biochem· Pharmacol. 22, 3099_3109, 1973). The main function of the partial cell surface receptor is Identify the appropriate receptor, according to ~158' This paper size is applicable to the _ home standard (CNSjA4 specification (2) Q χ 公 公 ) ) (Please read the phonetic on the back? Please fill out this page) - ϋ sOJ I ϋ 1_1 · 1_ — ϋ 1 I Βϋ ϋ ^1 ϋ ^1 ^1 ^1 ^1 ϋ ·ϋ 1 ϋ n ϋ ^1 ^1 ϋ I ^1 ^1 ϋ ϋ 1287015 Five Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 , invention description (/ qi,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Brewing_mother preparation_,_k"4g±αι9 nanomolar concentration of Yangqing grasping special-saturated combination, 5 Values were calculated from saturated isotherms and the Scatchard transformation of the data showed a single, class of binding site&apos; density of the glandular binding site in the yeast membrane formulation estimated to be 716·8 ± 43.4 fmol/mg membrane protein.

Sub-type selective adenosine receptors (XAC, Dpcpx, CGS_15943 CDS-嶋42, CD please 6123, neCA, (R)_piA, IB MECA 10 and Alloxazine) were used to study the recombination of human and receptor accessory variants. The pharmacological subtype characteristics of yeast cells, which can be compared with the expected order of Dpcpx, the substitution curves of these compounds show typical and unreasonable with all ligands, and the data of each ligand can be modeled by one-sided coordination. The apparent dissociation constants for each compound estimated from the curve (Table 5) are consistent with the published values for Receptor 15 from other sources. Table 5: The value of the yeast cell membrane of the winter type A receptor receptor subtype XAC 5.5 CPCPX 7.1 CGS-1594 10.8 NECA 179.6 (R)-PIA 56.3 IB-MECA 606.5 ~159~ This paper scale applies to China Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 V. Description of invention (/^)

Alloxazine CDS-046142 CDS-046123 894.1 13.9 9.8 Tables 6 to 12 illustrate the efficacy and structural activity of the deazaindole compounds of the present invention, and Tables 13 and 14 illustrate that human adenosine receptors can be achieved by adjusting the functional groups of the deazaindole compound. The selectivity of the moieties, Table 14 also illustrates the surprising discovery that the compounds described herein have sub-nanomolar activity and are more selective for A% receptors than the compounds of Table 13. (Please read the precautions on the back and fill in the purchase) --------Book---------Line' Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed Wood Paper Scale Applicable to Chinese National Standards (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 V. Description of invention (/θ)

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives--wm- Bu--. A1 Compound R Binding Ki ίηΜ) Yeast / IC50 _ 600 ...··OH 13.9 97.2 601 KD^〇h 1 1423 ! &gt;10.000 ^ 602 , OH 〉-OH 1 1 ! 483.5 ! &gt;10.000 603 OH / 196.6 4442.0 ◦ ◦ 0H 60A , —HO ! ◦ ◦ 10! ! &gt;10.000 ί i 1 &gt;10000 605 _ HO h("....· N :&gt;10000 1 1 I 1 &gt;10000 606 Bu,—/ A 0—:297.9 &gt;10000 ～161~ -----------it-------丨-------- Line (please read the note on the back and then fill out this page) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 Β7 V. Invention description (/ β) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 607 3097 丨&gt;10_ 1 ii 608 ···“OH 29.1 m 609 193.9 &quot;- * 610 411.5 I 611 K&gt;YPh 785.6 &gt;10000 612 X 1 •rans (S ic ;.S) 1 64.8 613 TL· rans (F iC LR) 6726.0 \ 61 AH〇··.. X o (dl) 32.1 ~162~ (Please read the notes on the back and fill out this page) Paper scale applies to China National Standard (CNS) A4 Specification (210 X 297 mm) 1287015 A7 B7 V. Invention Description (//, /)

Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed V A1 Compound R Binding Ki (nM) Yeast IC50 (nM) 700 1 604.5 1 &gt;10000 701 0&quot; 157.7 763.1 463^ 615 X) x (dl) I 816.9 2577.0 616 1 ^2^···&quot;〇h V0H 34.3 —m~- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 Α7 Β7 V. Invention description (Μ &gt;) 702 198.5 2782.5 703 443.6 &gt;10000 70A 0&quot; 61.1 297.0 705 30.1 194.7 706 19.9

(Please read the notes on the back and fill out this page.) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 707 ί 62.8 708 &gt;+ 2145 709 F u 48.7 li mi- k ::Yes |$Α 〜164~ This paper The scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 V. Description of invention (/厶) Table 8 (effect of ft#_lipyrrole ring substituent

Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A1 Compound RR·R·, R&quot;, Combined with Ki(nM) Yeast IG50 (nM) 800 Me Me Me 3311 &gt;10000 801 Η I 1 Me &gt; 1 H 22.3 148.3 802 Η H Me 8.9 803 0&quot; Me Me 2210 &gt;10000 804 m^~d Me Me 863.1 805 1 X —, i Me m/- _/ ! 1 1 ' Me 4512 465. --------------------Book --------- Line &quot;^1&quot; (Please read the notes on the back and fill out this page) Paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 V. Invention description (乂0

Table 9

Precautions on the back page Fill in this page Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed A1 Compound R Binding Ki (nM) Yeast IC50 (nM) 900 863.1 ν· 901 4512 902 X^/NKAc 8451 903 35.3 166~ Grain IIII ▲ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) 1287015 A7 B7 V. Invention description (///)

Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A1 Compound R Binding Ki(nM) Yeast IC50 (πΜ) 1000 \ - 1789 &gt;10000 1001 Η 54.4 1865 1002 ν Η 9.8 82.8 1003 0 26.7 195.7 1004 C Plant 32.8 545.8 ~167 ' This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------ fee-------book--------- Line (please read the notes on the back and fill out this page) 1287015 A7 B7 V. Invention Description (/) The Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative prints 1005 1 \ II 〇 147.5 ; 3972 i 1 1 1 I 1006 0 Ν-^ΝΗ^\ 〇151.7 2918 1007 〇II ' NH-S-Me V II ' 〇692.5 &gt;10000 1008 ΝΤνΝΗγ^/^ο〇Η 93.1 3217 1009 Υ^ΝΗγ/^ΝΗ: 475.3 I &gt;10000 1010 N^^^NHAc 674.9 9376.0 1011 \^^^〇Ac 121.9 2067.5 1012 〇, II ί 1 233.9 3462 1013 0 . II 270.1 3009.5 1014 χ-^/0Η 384.9 2005 1015 179.3 3712 1016 j 176.1 J 5054 1 1 Feeding Generation 1 ::-'-y Person 1~168~ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------------ -- --------- #-line (Read precautions to fill out the back of the page) 1287015 Α7 Β7 V. invention is described in (/ β) Table 11 n6- group of substituent effects

NHR

ΝΙΗ

Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A1 Compound R Binding: Ki (nM) Yeast IC50(nM) 1100 〇9.8 115.4 1101 NH .NH, r -0 53.9 551.0 1102 \^^ NH /NHMc 0 10.3 101.3 1103 v — NH /NHEi 0 71.1 3217 1104 丫CH: Me 〇(I ) 6.5 58.7 1105 H ; i 1 • _ 1 Me 0 C 2) 105.4 472.1 ~169~ This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) -------------------- Order --------- Line AW. (Please read the notes on the back and fill in the form. Page 1287015 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Invention Description (/) 1106 Me Η 0 (2) 27.8 162.4 1107 Me Η (2) 126.5 1297.0 1108 |x^^NHAc 2.3 1109 9.0 1110 17.3 1111 |^^NHAc :R 2.5 1112 213 ~170~ -------------------- Order --------- Line (Please read the back first Note: Please fill out this page again) piftAj This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 V. Invention Description (/#) Table 12 'Re-Amidamine' analogue

Me _ Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1 A1 1 Compound. R |Combined Ki (nM) Yeast IC50(nM) 1200 〇1丨i 16.5 189.4 1201 〇7.4 45.7 1202 9 i — ! Η V , 95.8 i 3345.0 1203 〇 1 1 ;529.1 | 4040.0 ! 1204 〇1 1060.0 aii , 1 1 1 &gt;10000 47l · This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------- -----0W--------Book---------Line, (Please read the note on the back and fill in this page) 1287015 A7 B7 V. Invention Description 1205 〇ΐί 1272 : &gt;10000 1 * 1 ! 1206 , II 〇 50.8 i 4028 1207 〇 48.5 701.5 X:: V' sonar ', ί. Table 13 Overview of Selective Adenosine Antagonists Printed by the Intellectual Property Office of the Ministry of Economic Affairs

Refill % Page /R HN 1 Me Ph6H Binding Ki(nM) Compound | R Ai Aza A10 Aj 1300 V^^NHAc 9.8· 25.1 18.0- 48.6 \ 80.3 ! 513.0 1301 1 1 Me /NHAc 1 27.8 50.7 84.6 429.8 1302 _ ! HV^N^NHMc ! ° 20.2 75.6 20.1 4.3 IIIIII Book II 472- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 V. Invention description (G/) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed i 〇' | 1303 1 丨 1 | NHMe 1 丨I17·4 I111·3 i : 1 · , i 1 120.6 . 44.0 1 1 1304 i :&gt;0^&quot; ·,.ΟΗ i ]丨ΐ3·9· 1 ί 30.9 ! 933.7 ί 1 1 I i 1 1 138.0 1:1.5 1 II 1 1305- ...·〇Η 46.6 730.9 30% 9.9 :306: 丨^\ &gt ;c^ 16.4 766.3 1 168.3 71.7 1307 1 ,···ΟΗ ! .. I (dl) ! 1 29.1 190.6 1143.0 3.1 1308 κχ)Η 180 230 670 L0 m rfcr:_ jij ~173~ (Please read the back of the note first) Matters fill in this page) ---------Book --------- Line -

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 V. Invention Description (/household) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

~174~ This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------------------- Order------- -- Line (please read the notes on the back and fill out this page) 1287015 A7 B7 V. Invention Description (/9 is S. Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 25 15 20 1315 i .r4 〇> ( Ch2)3^nA^-Nh3· 1 H 75.000 1 II » :720.000 ! 3.400 507 1 1 : 9 1316 〇Υ(〇Η2)3\^Λ^ΝΗ3· 1 H 710.000 i 710.000 ! 97 I 1317 1 710.000 710.000 720.000 1 1 i 369 1 1 1318- ·,··〇Η 3·7±0·5 630± 56.4 2307: 926 1 1 1 630±76 1319-1 &gt;c •..,·〇Η 1.8 206 802 270 1320^' i •.·, 8.0 8.0 531 530 419 13214*' V XT , 〇H 8.0 131 1031 54%* 4 thiophene-2-yl; 2CrH ; 3 water soluble; 4R5 and heart are hydrogen; 5R3 is 3 -fluorophenyl; 6R3 is 3-chlorophenyl; 7R3 is 4-oxinyl; 8% active%@10 micromolar concentration 475- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) )

IIIIII Standard IIIIIIII 1287015 Compound XRj r2 Binding data &amp; (nano molar concentration) Αι A〗 a A2B A3 1400 -O-Ph Me 41.7 21 10.3 14.6 1401 -0-Ph(p)F Me 33 58 8.8 18 1402 - 0-Ph(p)Cl Me 825 591 22 60 1403 -N-pyridin-2-one Me 60 41 18 48 1404 -NH-Ph Me 49 31 4.6 57 A7 B7_ V. Description of invention (/?/) Table 14 Selection Overview of sexual A2b antagonists -------------------- Order --------- line (please read the notes on the back and fill out this page) Economy Ministry of Intellectual Property Bureau employee consumption cooperative printed ~176~ This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 V. Invention Description (/?0 Table 15 adenosine\receptor selection Sex compounds* are at least 10 times more selective than other three sub-types of Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives

(Please read the notes on the back and fill out this page.) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm). Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1287015 A7 _B7 V. Invention Description ( /λΟ 1500 CC people σ1^, ★ 1321 OH P ★ 1501 ΝΗ ★ 1502 ο J Η,, \ ΗΝ-/ ΝΗ — ο ★ ι鹤|:·, ϋ ～178~ ---------- ---------Book---------Line (please read the note on the back and fill in this page first) This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 PCT) 1287015 A7 B7 V. Description of invention (〇;0 Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative

(Please read the notes on the back and fill out this page.) The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1287015 Α7 Β7 5. Inventive Note (/π) The present invention provides compounds of the following structures 15 20 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

'师j · i D :.! Ά 萏 本 The present invention also provides compounds of the following structure:

The invention also provides a compound of the following structure: ^180- I---------- loaded--------order--------- line (please read the back of the note first) Please fill out this page again. This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm). 1287015 A7 B7 V. Invention Description (e?)

I Λ J * t&gt; 1} + C 1 Ώ.. Μ The present invention also provides compounds of the following structures:

15 The present invention also provides compounds of the following structure: CONH2 0 j

% I ί ''v ", light iifA ----------- loading -------- order --------- line (please read the notes on the back first) Fill in this page) 20 The present invention also provides compounds of the following structure: Ministry of Economic Affairs, Intellectual Property Office, employee consumption cooperative, printing

1619 -3⁄4) Lee ~181~ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 V. Inventive Note ((10)) The present invention also provides compounds of the following structures

The invention also provides compounds of the following structure:

Η 1623 persons 15 The present invention also provides compounds of the following structures: ΟΗ 20 Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative

1624 The present invention also provides compounds of the following structure: 482- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) m ψMft II ·ΐί -----------41^ --------Book --------- (Please read the notes on the back and fill out this page) 1287015 A7 B7 V. Invention Description (Λί7)

OH

HN

1625

The present invention also provides a compound of the following structure OH

-〇H (Please read the notes on the back and fill out this page) 15 1626

HN

〇-

The present invention also provides compounds of the following structure: 0H

m ^ ' Ί I 31 Choice i?f;A Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

HN

1627 The present invention also provides compounds of the following structure: 围专||寒邓丨.:.车理 _ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 V. Invention Description (/ (Ρβ

〇 Η 1628 〇 . 'Teach 41 The present invention also provides compounds of the following structure: 1v:.

, 〇〇Η 1629 (Please read the note on the back and then fill out this page) 15 The present invention also provides the following compounds: ΟΗ Flip: Pet-Ί' '1肊-----:----- --------· 20 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

V HN

〇 1630 NH2 ·:*^Γi fts The present invention also provides compounds of the following structure 484- The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 V. Invention Description (/#)

1702 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed In another embodiment, the present invention provides a method for treating a condition associated with Ai adenosine receptors in a subject, comprising a therapeutically effective amount of a compound 1601, 1602, 1605, 1606, 1611, 1614, 1619, 1〇1621, 1623, 1624, 1625, 1626, 1627, 1628, 1629 or 1630 are administered to the subject. In another embodiment, the invention provides the above method wherein the subject is a mammal. In another embodiment, the invention provides the above method, wherein the mammalian animal is a human. In another embodiment, the present invention provides the above method, wherein the 4 adenosine receptor is associated with cognitive diseases, renal failure, arrhythmia, respiratory epithelial disease, transmitter release, sedation, vasoconstriction, heartbeat Sudden, negative myocardial contraction, reflux or ulceration. 2 In another embodiment, the present invention provides a water soluble prodrug of compound 1601, 1602, 1605, 1606, 1611, 1614, 1619, 1621, 1623, 1624 1625, 1626, 1627, 1628, 1629 or 1630, wherein The water-soluble prodrug is metabolized in vivo to an active agent which selectively inhibits the Ai adenosine receptor. ~185 This paper size is applicable to China National Standard (CNS) A4 specification (2丨〇X297 mm) (Please read the note on the back and fill out this page)

, tT 罇· 1287015 A7 B7 V. Description of Invention (丨?¢) 5 15 Ministry of Economic Affairs Intellectual Property Office Employees Consumption Cooperative Printed in another specific example provided by you + praise, wherein the precursor drug is via the enzyme Catalytic hydrolysis is metabolized in vivo. In another embodiment, the present invention provides a pharmaceutical composition comprising the above-described sorbent drug and a pharmaceutically acceptable carrier. In another embodiment, the present invention provides a method for inhibiting the activity of a4 adenosine receptor in a cell comprising: stimulating cells with compounds 1601, 1602, 1605, 1606, 1611, 1614, 1619, 1621, 1623, 1624, 1625, 1626, 1627, 1628, 1629 or 1630 contact. In another embodiment, the invention provides the above method for inhibiting the activity of an adenosine receptor in a cell, wherein the compound is an antagonist of & adenosine receptor. In another embodiment, the invention provides the above method for inhibiting the activity of an octa-adenosine receptor in a cell, wherein the cell is a human cell. "In another embodiment, the present invention provides the above method for inhibiting the activity of an adenosine receptor in humans, cells, and the compound is an antagonist of the adenine receptor. 'This invention is another specific A method is provided in an embodiment for treating a condition associated with an adenosine receptor in a subject, wherein the condition is asthma, chronic obstructive pulmonary disease, allergic rhinitis or an upper respiratory condition. 'The invention is another specific In an embodiment, a method is provided for treating a condition associated with Al adenosine receptors in a subject, wherein the condition is asthma, chronic obstructive pulmonary disease, allergic rhinitis or upper beer suction disease and wherein the party treatment is Human. ', the invention is provided in another specific implementation of the radiation-species green treatment 486- This paper scale is applicable to the Chinese Standard (CNS) A4 g_(_21G x 297 public) 丨丨丨丨丨____丨丨• 丨 丨 丨丨丨 丨丨丨 - - - 线 请 请 ( ( ( ( ( ( ( A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A A 4 antagonist of adenosine receptor. The invention is in another A combination therapy for asthma comprising a compound 1601, 1602, 1605, 1606, 1611, 1614, 1619, 1621, 1623, 1624, 1625, 1626, 1627, 1628, 1629 5 or 1630, and Steroid, gluten 2 stimulating agent, glucocorticoid, progesterone triene antagonist, or anticholinergic stimulating agent. In another embodiment, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of compound 1601. 1602, 1605, 1606, 1611, 1614, 1619, 1621, 1623, 1624, 1625, 1626, 1627, 1628, 10 1629 or 1630, and a pharmaceutically acceptable carrier. The invention is provided in another embodiment A use of a compound 1601, 1602, 1605, 1606, 1611, 1614, 1619, 1621, 1623, 1624, 1625, 1626, 1627, 1628, 1629 or 1630 for the treatment of a respiratory condition, wherein the respiratory condition is asthma, allergy Rhinitis or 15 chronic obstructive pulmonary disease. In another embodiment, the present invention provides the above pharmaceutical composition, wherein the pharmaceutical composition is around the eye, behind the eyeball or in the eye. The present invention provides, in another embodiment, the above pharmaceutical composition, wherein the pharmaceutical composition is a systemic preparation. 20 The present invention provides, in another embodiment, the above pharmaceutical composition, wherein the pharmaceutical composition Is a surgical rinsing solution. The present invention provides, in another embodiment, the above pharmaceutical composition, wherein the medicinal composition is a packaged pharmaceutical composition for treating a condition associated with adenine receptor in a subject, It includes: 187~ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------------------- Order----- ----Line Ί (Please read the note on the back and then fill out this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1287015 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention Description (/W) (1) a container containing a therapeutically effective amount of a compound 1601, 1602, 1605, 1606, 1611, 1614, 1619, 1621, 1623, 1624, 1625, 1626, 1627, 1628, 1629 or 1630; and (2) using the compound Treating the condition in the subject Instructions. 5 A3 By-Usage Use In another embodiment, the present invention provides a method for inhibiting the activity of an adenosine receptor in a cell comprising contacting a cell with a compound 17A. In another embodiment, the present invention provides the above method for inhibiting the activity of an octa3 adenosine receptor in a fine cell, wherein the compound is an antagonist of an A3 adenosine receptor. In another embodiment, the invention provides the above method for inhibiting the activity of an adenosine receptor in a cell, wherein the cell is a human cell. In another embodiment, the invention provides the above method for inhibiting the activity of an A3 adenosine receptor in a human 15 cell, wherein the compound is an antagonist of the A3 adenosine receptor. In another embodiment, the invention provides a method for treating eye damage in a parental treatment comprising administering a composition comprising a therapeutically effective amount of a compound 丨7〇2 to a subject. In another embodiment, the invention provides the above method, wherein the injury comprises retinal or optic nerve head injury. In another embodiment, the present invention provides a therapy for glaucoma comprising administering a therapeutically effective amount of a compound 1702 to a subject 0 to 188~ This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210 χ 297 mm) -------------------- Order --------- line (please read the notes on the back and fill out this page) 1287015 A7 B7 V. INSTRUCTIONS (/i7) 5 15 20 Ministry of Intellectual Property, Ministry of Intellectual Property, Printed by Cooperatives, The present invention provides, in another embodiment, a therapy for glaucoma comprising one or more adenosine receptor antagonists Preferably, it contains a glandular receptor A antagonist (preferably N-6 substituted 7-deazaindole, most preferably [2_(3h_imisyl)-ethyl; K2_phenyl_7H _pyrrolo[2,3_d]pyrimidinyl)amine. In another embodiment, the present invention provides a combination medical treatment for glaucoma comprising an adenosine receptor octa3 antagonist (preferably substituted, deazaindole, most preferably [2_(3H-imidazole-4) -yl)-ethyl]-(2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine) and one or more other compounds selected from the group consisting of /3 adrenergic receptors Antagonist (also known as serotonin receptor antagonist or 6-blocker) (eg σ 塞 心 心 马 马 、 倍 倍 倍 倍 倍 倍 、 、 、 、 、 、 、 、 左 左 左 左 左 左 左 左Benxin, L_653328 (acetate of l_652698), /5-1 adrenergic receptor antagonist), alpha-2 adrenergic receptor stimulator (eg alpha clonidine, brim〇nidine, AGN) -195795, AGN-190837 (homolog of Bay-a-6781)), carbonated enzyme inhibitor (brinzdamide, torzolamide, MK_927 (human carbonic anhydrase) Inhibitors), human carbonic anhydrase IV isoenzyme inhibitors, cholinergic stimulators (eg choline choline stimulants, carbachol, pilocarpine HC1, pilocarpine nitrate, pilocarpine , pilocarpine prodrug (eg DD-22A)), prostaglandins and prostaglandin receptor stimulators (eg latanoprost, isopropyl unoprostone (un〇pr〇st〇ne is〇) Pr〇pyi), PGF2a stimulant, prostate selective stimulator, pG stimulator such as hypotensive propetamine angiotensin converting enzyme (ACE) inhibitor (eg spirapril) , Silk Bishop Ί 89^ This paper scale applies to China National Standard (CNS) A4^7H&quot; 〇χ 297 public ^ I-------------- order 丨 --- (please first Read the notes on the back and fill out this page) 1287015

V. INSTRUCTIONS (/^) (Please read the note on the back and fill out this page) (spiraprilat), AMPA receptor antagonist, 5_HT stimulant (eg selective 5-HT 1A receptor stimulator such as MKC- 242 (5_3-[((2S)_l,4_benzodiamidylmethyl)amino]propoxy-1,3-benzodioxan HC1), an angiogenesis inhibitor (eg steroid Anec Tefu (anec〇rtave)),

NMDA 5 antagonists (eg HU·211, memantine, marijuana NMDA-stereostimulator D-cannabinol, D-cannabinol prodrugs and homologues 'NR2B-selective antagonists (eg Yilip (SL_82〇715)), renin inhibitors (eg CGP-38560, SR-43845), cannabinoid receptor stimulants (eg tetrahydrocannabinol (THC) and THC homologs, selective CB2 cannabinoid 10 Receptor stimulators (eg, L-768242, L-759787), compounds that bind to both brain-specific CB1 and peripheral CB2 receptors, such as anandamide, angiotensin receptor antagonists (eg, blood vessels) Angiotensin π stylistic antagonists (eg CS-088), selective angiotensin n AT_j receptor antagonists such as rostan potassium (l〇sartan p〇tassium), hydrogen σ serazine 15 (HCTZ), growth inhibition Stimulating agents (eg non-peptide somatostatin stimulator NNC-26-9100), glucocorticoid antagonists, mast cell degranulation inhibitors (eg ned〇Cr〇mii), α _ Adrenergic receptor blockers (eg dapipraz〇le, alpha 2 adrenergic receptor antagonists, alpha ΐ kidneys) Receptor antagonists (eg, bunaZ〇sin), an adrenergic receptor antagonist, a thromboxane 2 mimetic, a protein kinase inhibitor (eg H7), prostaglandin derivatives (eg S_1〇33), prostaglandin antagonists (eg PhXA-34), dopamine D1 and 5 HT2 stimulators (fendodpam), tartaric acid Oxide release agent (such as NCX-9〇4 or NCX_905, 嗔 心 之 石 石 氧化 氧化 氧化 氧化 @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ 12 870 870 870 870 870 870 870 870 870 870 870 870 870 870 870

Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperation, Duban drug release agent), 5_ΗΤ2 antagonist (such as sapreg (grpGgrdate)), NMDA antagonist (such as dextro-cannabinol prodrug and homologous adrenergic neo-antagonism) Agents (such as bunamycin), testosterone inhibitors (such as diclofenac or non-steroidal compounds nepafenac), inosine, dopamine receptors and alpha 2 adrenergic receptor stimulators (eg, talipexole), dopamine D1 receptor antagonists and D2 receptor stimulators (eg SDZ_GLC_756), vasopressin receptor antagonists (eg vasopressin V2 receptor antagonists (eg SR_121463) ), endothelin antagonists (eg, TBC_2576), 1-(3-hydroxy-2-phosphonomethoxy 10 propyl) cytosine (^MPC) and related homologs and prodrugs, thyroid hormone ligands ( For example, KB-130015), M1 stimulator, NMDA-receptor antagonist (eg, cannabinoid NMDA-receptor antagonist D-cannabinol), PG stimulator such as hypotensive lipid, stilbenamide (pr 〇stamide), nanochannel blocker, NMDA antagonist, mixed ion channel Hysteresis, 15 no adrenergic receptor antagonists and PGF2a stimulant compositions (eg, latanoprost and timolol), guanylate cyclase activators (eg atrial natriuretic peptide) (ANP) or non-peptide mimetic), ANP neutral endopeptidase inhibitor, nitro A tube dilator (eg nitroglycerin, sputum peptidazine, nitroprus), endothelin receptor modulator (eg ET -1 or non-peptide mimetic, sarafoyoxin-S6c), diuretic acid, other phenoxyacetic acid homologs (eg indacrinone, chlorpheniric acid), actin destruction Agents (eg, latnmculin), homogeneous channel blockers (eg, verapamil, scutane benzoate, vinorelbine, nivaldipine) and neuroprotective agents. 191~ Ben Paper scales _ home standard (CNS) A4 specifications (10) X 297 public f ----------- order --------- line (please read the back of the note before you fill out this Page) 1287015

, invention description (Intellectual Intelligence Department Intellectual Property Bureau employee consumption cooperative printed a combination medical treatment for glaucoma, which contains compound 1702, and one or more compounds selected from the group consisting of no adrenergic receptor antagonist, alpha-2 adrenal gland A stimulatory receptor stimulating agent, a carbonic anhydrase inhibitor, a biliary stimulating agent, and a prostaglandin receptor stimulating agent. 5 In another embodiment, the present invention provides a pharmaceutical composition comprising an effective medical amount of a compound 1702 And a pharmaceutically acceptable carrier. In another embodiment, the invention provides a packaged pharmaceutical composition for treating a condition associated with a Α3 adenosine receptor in a subject, comprising: 10 (1) A container containing a therapeutically effective amount of Compound 1702; and (2) instructions for treating the condition in a subject using the compound. In another embodiment, the present invention provides a method of making a composition comprising Compound 1702, the method This includes mixing the compound wo? with a suitable carrier. 15 In another embodiment, the invention provides compounds 1601, 1602, 1605, 1606, 1611. A pharmaceutically acceptable salt of 1614, 1619, 1621, 1623, 1624, 1625, 1626, 1627, 1628, 1629 or 1630. In another embodiment, the present invention provides a pharmaceutically acceptable salt of the above Wherein the pharmaceutically acceptable salt of compound 1611, 1619, 1625, 1628 or 1629 comprises a cation selected from the group consisting of sodium, calcium and potassium. The invention provides pharmaceutically acceptable compound 1702 in another embodiment. a salt, wherein the pharmaceutically acceptable salt is selected from the group consisting of maleate, fumarate, tartrate, acetate, phosphate and methyl hydrazine~192~ This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) I-----------i ------Book---------Line&lt;Please read the notes on the back and fill out this page) 1287015 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Description of invention (/f/) Acid anion. In another embodiment, the invention provides a method for treating a condition associated with an adenosine receptor in a subject, wherein the A! adenosine receptor is for congestive heart failure. 5 Example 21 · Synthesis of 1-[6-(4-hydroxy-4.phenyl-hexa-pyridylpyridylmethyl)- 2-phenyl-7H-indole[2,3_d] The synthesis of each of the carboxylic acid decylamine (1601) Compound 1601 was obtained in a manner similar to that of Example 17 using the synthesis of 10 Figure TX with L-proline decylamine and 4-phenyl-hexahydropyridin-4-ol:

1601 iH-NMR (d6_DMSO) 5 1.53 (s,1H),1·60 (s,1H) ! 84_2 3〇(m,6H),2.66 (m,2H), 3.60 (s,2H),3.88 (m ,1H),,4 〇2 (m 2〇1H),4·66 (d,1H,J=6·8 Hz),4·73 (s,1H),Μ(s,' ih),= , 1H), 7·12-7·50 (m, 10H), 8.35 (m, 2H), 11.6 (brs ih) · (ES): 305.1 (M++1); melting point = 234-235 ° C . Example 22: Synthesis of hydrazine (2-phenyl-7H-pyrrolo[2,34 blister _4 decyl decylamine (1602) 疋-- soil) (&gt; 193 This paper scale applies to Chinese national standards (CNS) )A4 size (210 X 297 mm) ------------f------- — order--------- line (please read the notes on the back first) Fill in this page again) 1287015 Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative

Cl CI

A7 B7 V. INSTRUCTION DESCRIPTION The synthesis of compound 1602 is carried out using the synthetic formula VII with L. valine amide.

^-NMR (DMSO-d6) δ 2.05 (m? 4Η)? 3.85 (m? 1Η)? 4.05 (m? 10 1H), 4.70 (d, 1H, J=8.0 Hz), 6.58 (brs, 1H), 6.95 (brs,1H), 7.15 (d,1H,J=3.4 Hz), 7.40 (m,3H), 7.50 (brs,1H), 8.40 (m, 2H),11_6 (brs,1H); MS (ES ): 308.3 (M++1); m.p. = 236-238 °C. Example 23: Synthesis of [N-(2-phenyl-6-methoxymethyl-7H4b-[2,3-d]15-pyrimidin-4-yl)-(L)-proline decylamine (1605) The synthesis of compound 1605 is obtained using the compound of the formula IX before the synthesis of compound 23: ~ 194~ This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) --------- -------- Order --------- Line AW. (Please read the back note and then fill out this page) 1287015 Will aryl chloride 4 (2.448 grams, 6.55 millimoles ), DMSO (15 ml), A7 B7 5, inventive (/^) ml) and DCM (120 ml) and treated with Ag02CCF3 for 1 hour at ν2 and room temperature, the solid was removed by filtration and used DCM (2×20 mL) Washing, concentrating the filtrate under vacuum, re-dissolving the residue in DCM (8 mL), then washing the solution with saturated NaHC03 solution and brine 5, drying, filtering and concentrating 3_71g (4,99%) of a gray solid, 1H-NMR (CDC13) 5 1.75 (s, 9H), 3.51 (s, 3H), 4.83 (s, 2H), 6.70 (s, 1H), 7.47 ( m, 3H), 8.52 (m, 2H).

L-proline decylamine (4.0 g, 35.0 mmol) and NaHC03 (2.9 g) were mixed with 15 and heated to 120 ° C under nitrogen pressure. After 4 hours, the reaction was cooled to room temperature and water was used. (60 ml) was diluted, and the obtained thick syrup was extracted with DCM (lOx). The combined organic layer was washed with saturated NaHC03 solution and brine, dried over MgSO4, filtered and concentrated to give Chromatography gave a white solid (1···································· m,1H),3·26 (s,3H),3.92 (m,1H),4.10 (m,1H),4.42 (s,2H),5.08 (d,1H,J=8.2 Hz), 5.49 (tos , 1H), 6·48 (s, 1H), 7.08 (brs, 1H), 7·42 (m, 3H), 8.38 (m, 2H), 9.78 (brs, 1H); MS (ES): 352.2 ( M++1). ~195~ This paper size applies to China National Standard (CNS) A4 specification (210 297 297 mm) I------------------tr--- ------Line# (Please read the notes on the back and fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1287015

A7 B7 V. INSTRUCTIONS (/%0 Example 24: Synthesis of 4-hydroxy-1-(2-phenyl-7H-pyrrolo[2,3-d]pyrimidinyl)-pyrrolidine-2-carboxylic acid hydrazine Amine (1606) The synthesis of compound 1606 was obtained using the synthetic formula VII with cis-hydroxyproline guanamine: 5 10 ^-NMR (d6-DMSO) δ 1.90 (m? 1H)? 3.85 (d, 1H, J =9.2 Hz), 4.08 (m,1H), 4.37 (s,1H), 4.67 (dd,1H,J=8.8, 4.0 Hz), 5.30 (s,1H),6.55 (s,1H),7·15 (s, 2H), 7.37 (m, 3H), 7.64 (s, 1H), 8.37 (m, 2H), 11.65 (brs, 1H); MS (ES): 324.2 (M++1); 268-27l〇C 0 Example 25··Synthesis of 3-[4-((S)-2-aminomethylmercapto-pyrrolidin-1-yl)-2-phenyl-7H-pyrrolo[2,3- d]pyrimidin-6-yl]-propionic acid (1611) The synthesis of compound 1611 is obtained by using compound 23 of the former formula IX: 20 I---------------- ----Book---------Line (please read the notes on the back and fill out this page) Printed by the Intellectual Property Office of the Ministry of Economic Affairs

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 V. Description of invention ( /^) Aryl bromide protected by tert-butyl ester group 23 (4.0 g, 9.5 mmol) Ear), anhydrous DMSO (25 ml), NaH2P〇4 (454 mg, 3.79 mmol) and Na2HP04 (1.62 g, 11.4 mmol) were mixed and heated to 50 C for about 3.5 hours under argon atmosphere, then the mixture was Pour into water (2 mL) and extract with EtOAc (3 mL) EtOAc (EtOAc)EtOAc. Purification afforded L55 g of a pale yellow solid (7), which was purified by flash chromatography eluting with EtOAc EtOAc EtOAc 9H), 7 25 (s, 1H), 7·48 (m, 3H), 8·52 (m, 2H), 10.39 (s, 1H); melting point = 156 °C (decomposition). (Please read the notes on the back and fill out this page) 15

CHO (Ph)3p=CHC02tBi THF, 0°C, lh

20 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Aldehyde 7 (600 mg, 1.7 mmol) dissolved in anhydrous 11117 (2 mL) and cooled to 0 ° C under argon atmosphere. A solution of (second butyl acetoxymethyl) diphenylphosphonium (694 mg, ι·8 mmol) in 10 ml of anhydrous THF was added dropwise, and after 3 hours, the mixture was concentrated and triturated with ethanol. Purification afforded 565 mg (73%) of sd. sd. NMR (CDC13): 1.58 (s? 9H), 1.79 (s5 9H), 6.46 (d? 1H) 6.95 (s, 1H), 7.48 (m, 3H), 8.09 (d, 1H), 8.56 (m, 2H) '. ’

----r---订---------Line. ^ Paper scale applies to China National Standard (CNS) A4 specification (210 x 297 public love 1287015 A7 B7 V. Invention description

A solution of compound 8 (565 mg, 1.2 mmol) in 5 mL of THF was diluted with EtOAc to 100 mL, and 600 mg of catalyst (5 wt/d Pd, 50% H20) was added and flushed with argon. Hydrogenation at atmospheric pressure, after 8 hours, the mixture was filtered, concentrated and purified by flash chromatography (10% EtOAc in hexanes) to isolate 200 mg (35%) of 9 of colorless oil. (s, 9H), 1.75 (s, 9H), 2·65 (t, 2H), 3·32 (t, 2H), 6.41 (s, 1H), 7·45 (m5 3H), 8· 51 (m5 2Η) 〇

Teacher I

15 Source code 丨 20

------------f !卜_丨_订---------线. (Please read the phonetic on the back? Please fill out this page again) Ministry of Economic Affairs Intellectual Property Office staff The consumer cooperative printed and mixed aryl chloride 9 (200 mg, 0.44 mmol), DMSO (10 ml) and L-valine amide (440 mg, 4.4 mmol) and heated under nitrogen pressure. After 14 hours, the mixture was cooled to room temperature and distributed in water and ethyl acetate. The layers were separated and the aqueous layer was extracted with EtOAc (3x). (CNS) A4 size (210 X 297 mm) 1287015 A7 B7 V. Inventive Note (The organic layer is thoroughly washed with water (3 χ) and brine, dried by MgS04, filtered and concentrated to give a yellow film of 10, By flash chromatography (in CH2C 121^ 2.5% MeOH) </RTI> &lt;RTIgt; </RTI> </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt;

HCI, alkane

Return to human 1 15 The ester i〇 (3 mg, mmol) in 5 ml of dioxane was hydrolyzed by the addition of 0.5 ml of concentrated HCl. After 3 hours, the mixture was condensed under vacuum and at EtOH/ Recrystallization from EtOAc afforded EtOAc (EtOAc: EtOAc:EtOAc: Example 26: Synthesis of [N-(2-phenyl-6-aminocarbonylmethoxymethyl-7H-pyrido[2,3-d]pyrimidin-4-yl)-(L)-proline decylamine (The synthesis of 161 compound 1614 is obtained by using the synthetic formula ϊχ precursor compound 23: Please read the back note and then fill in this page II. ▲ Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative

CI

CI

The desert compound 23 (1.27 g, 3 mmol) and molecular sieve (5 g) are applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) in the waterless 499~ Huiren paper scale. 1287015 Α7 Β7 V. Invention Description (β疋) Methyl glycolate (5.8 g, 60 mmol) and DCM (40 ml) were stirred. The solution was treated with AgOTf under &amp; and stirred for 3 hours, and the solid was removed and dried with DCM. 2×20 ml), the filtrate was concentrated under vacuum, and the residue was dissolved again in DCM (80 ml). The obtained solution was washed with water, saturated NaHCO3 solution and brine, dried over MgS 〇4, filtered and concentrated. 1.35 g (99%) of a gray solid (12), H-NMR (CDC13) 5 1.75 (s, 9H), 3.80 (s, 3H), 5.0 (s, 2H), 6.78 (s, 1H), 7· 47 (m, 3H), 8.52 (m, 2H). Read back Φ Note 1

COoCH, L-proline amide, DMSO, 120 ° C, 4 h

C02CH3 15 20 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative printed aryl based gas 12 (177 mg, 0.41 mmol), DMSO (10 ml), L-proline amide (466 mg, 4 mmol) It was mixed with NaHC03 (500 mg) and heated to 12 ° C under nitrogen. After 4 hours, the reaction was cooled to room temperature and diluted with water (60 ml), and the obtained thick slurry was extracted with dcm (5×30 ml) The combined organic layers were washed with EtOAc EtOAc (EtOAc m. H-NMR (CDC13) (5 2.15 (m5 3H), 2.52 (m5 1H)5 3.55 (s? 3H)5 4.58 (s, 2H), 5.08 (s, 1H), 5.85 (brs, 1H), 6.48 ( s, 1H), 7.08 (brs, 1H), 7·42 (m, 3H), 8.40 (m, 2H), 10.58 (brs, 1H); MS (ES): 410.1 (M++1).

▲ -200- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 Α7 Β7 V. Invention Description (πα

C〇2CH3 NH3/HOCH3 rt, 4h

CONH, 15 Dissolve the methyl ester 13 (124 mg, 0_3 mmol) in the shame ^^% house liter), pass the ammonia gas through the solution for 0.5 hours, then stir the anti-mixed character at room temperature. After 3 hours, the solvent was removed to give lu mg white solid (1614, 93%), 1H), 2.80 (m, 1H), 3.10 (m, 1H), 3.63 (dd, 2H, J yield 13.8 Hz, 'J2=19.4 Hz), 3.87 (m, 1H), 4.07 (m, 1H), 4.97 (m, 1H), 5.96 (m, 2H), 6.35 (s, 1H), 6.86 (brs5 1H), 7·11 (brs, 1H), 7.37 (m, 3H), 8·28 (m, 2H), 11.46 (brs, 1H); MS (ES): 394.8 (M++1). Example 27: Synthesis of [4-(2-Aminomethylpyridylpyrrolidin-1-yl)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-6-carboxylic acid] (1619) Compound The synthesis of 1619 is obtained by using the compound 15 of the synthetic formula VII: Item I, I, I, I*, ▲ 20 Printed by the Intellectual Property Office of the Ministry of Economic Affairs

DMF 0-^20 °C, 4h -20l· This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm)

NaH, then PhS02CI --^

[287015 A7 B7 V. INSTRUCTIONS In a suspension of sodium hydride (780 mg of a 60% oil suspension, 19.5 mmol) in anhydrous DMF (20 ml) via ice/water bath, added under nitrogen pressure Pyrrolopyrimidine 15 (2.00 g, 7.52 mmol) in DMF (1 mL) for 5 minutes, after 15 minutes, add benzenesulfonium chloride (1.2 5 halo, 9.40 house mole), then After cooling for 4 hours, the reaction mixture was poured into a mixture of ice and saturated NaHC03 solution, and the precipitated solid was filtered and triturated with acetone (3) and methanol (2) to give 2.37 g of a beige solid. (16) Containing about 10 mol% DMF (based on this, 83% yield) and can be used in the next step, using acetone as a flow wash on silica gel. A pure sample can be obtained by 10 chromatography, 1H-NMR (CDC13) ) (5 6.70 (d, J=4.2)

Hz, 1H), 7.47-7.68 (m, 6H), 7.76 (d, J = 4.2 Hz, 1H), 8.24 - 8.32 (m, 2H), 8.48-8.56 (m, 2H); IR (solid): n =3146 cm-1,1585, 1539, 1506, 1450, 1417, 1386, 1370, 1186, 1176, 1154, 1111, 1015, 919, 726, 683, 616, 607; MS (ES): 372/370 (MH+ ); melt 15 points = 226-227 〇 C.闘 (Please read the note on the back? Please fill out this page again)

Cl

LDA, then C02 THF -78 °C, 1h, then rt

Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed in N-sulfonyl compound 16 (337 mg, 0.911 mmol) in anhydrous THF (34 mL) in dry ice/acetone cooled solution, added LDATHF (1.0 mL, 1.5 Molar concentration in cyclohexane, 1.5 millimolar), -202- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A7 B7 V. Invention description ("/) After 45 minutes Thereafter, the carbon dioxide was bubbled through the solution for 5 minutes, and then the cooling bath was removed. After the solution reached ambient temperature, the solvent was evaporated to obtain 398 mg of salt 17, containing 0.5 equivalent of (ipr) 2NC 2Li yellow solid. This salt is used in the next step without further purification, ^j6_dms〇): 5 = 6.44 (s, Qiu, 7·50-7·75 (m, 6H), 8.33-8.40 (m, 2H), 8· 53 (dd, J=8.0, 1.6Hz, 2H).

fPlease read the phonetic on the back first? Please fill out this page again) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed lithium salt 17 (50 mg) and L-proline amide (122 mg, l〇7 15 mmol) in DMS〇 (l_5 The solution of 5%) was heated to s 〇 °c over 15 hrs, then 4% aqueous acetic acid (1 mL) was added to the cooled solution and the mixture was extracted with EtOAc (5×10 mL). The organic layer was washed with aq. EtOAc EtOAc EtOAc (EtOAc) For the next step, 1H-NMR (CD3OD): 5=1.95-2.36 (m5 4H)5 3.85-3.95 (m5 1H), 3.95-4.17 (m,1H), 4.72 (brs,1H), 7.14 (s , 1H), 7.35-7.45 (m, 3H), 7.45-7.70 (m, 3H), 8.33-8.50 (m, 4H). ~ 203 This paper scale Lai towel® National Standard (CNS) A4 specification (210 X 297 public)! l·!— Order—-!!! Line. 1287015 A7 B7 V. Description of invention

NaOH

MeOH 20 °C, 2h

15 20 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed a solution of sodium hydroxide in methanol (1.5 ml, 5 mol concentration, 7.5 mmol) to pyrrolopyrimidine 18 (4 mg, 〇〇81 Milliol) in decyl alcohol (2 ml), after 2 hours, adjust the pH to 5, evaporate most of the methanol, extract the mixture with EtoAC (5 x liter), and wash the combined organic layer with brine It was dried over Mgso4, filtered and concentrated to give 24 mg of pale-yellow solid, which was taken from toluene to give 15.6 mg (55%) of acid 1619 as a pale yellow solid (CD3OD): 5 = 2.05-2.20 ( m? 4H)? 3.95-4.10 (m5 1H)? 4.15-4.25 (m,1H), 4.85 (brs,1H), 7.14 (s,1H),7·35-7_42 (m,3H), 8.38-8.45 (m, 2H); IR (solid): centimeter -1,2964, 2923, 2877, 1682, 1614, 1567, 1531, 1454, 1374, 1352, 1295, 1262, 1190, 974, 754, 700; MS (ES ): 352 (M++1); melting point = 220 ° C (decomposition). Example 28 ································································································· Compound 1621 is synthesized by the following steps: -204- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) ------------------: ----Book---------Line (please first, read the back of the note and fill out this page) 1287015 A7 B7 V. Invention Description (M3)

15 20 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative printed aryl chloride 20 (3 g, 10.7 mmol), DMSO (50 ml) and (S)-guanidinium amide and heated under argon pressure to After stirring at 85 ° C overnight (14 hours), the mixture was cooled to room temperature and poured into 8 mL of water, which was extracted with three portions of 200 mL of EtOAc. The brine was washed well, dried over EtOAc EtOAc EtOAc EtOAc EtOAc. (Π.8-2.2 (m,4H),2.3 (s,3H),3·8 (m,1H),4.0 (m,1H),1·6 (d, 1H), 6.2 (s,1H) ,6·9 (s,1H),7.2 (m,3H),7·3 (s,1H),8_4 (m, 2H),11.5 (s,1H); MS (ES): 322 (M++ 1) Example 29: Synthesis of 1-[6-(2-hydroxy-ethoxymethyl)_2-phenyl-7H-pyrrolo[2,3-d]pyrimidinyl; μpyrrolidinecarboxylic acid decylamine ( 1623) Compound 1623 was synthesized in a similar manner to the procedure of Example π, using the compound of formula IX with lysamine and hexane-L2-diol: C^NH2 〇Λ MS (ES): 3 82 (Μ++1) 1623 (Please read the notes on the back and fill out this page) Order ---------^»- Ο^ΟΗ

-205- 'The paper size is applicable to China National Standard (CNS) A4 specification (210 297 297 mm) 1287015 A7 B7 V. INSTRUCTION DESCRIPTION Example 30: Synthesis of 40 m salamidinyl methyl group ))-cyclohexanol (1624) soil open [,3-d] compound deletion is a class of the example 17 &lt; yang synthetic formula IX with Ν-nonylcyclohexanol and imidazole to obtain ^ ς 2Η ·

(Please read the note on the back first? Then fill out this page) 15 Example 31: Synthesis of 4-(4-hydroxy-cyclohexylamino)-2-phenyl-7Η-pyrrolo[2,3 _d] -6-Carboxylic Acid (1625) # Compound 1625 was synthesized in a similar manner to that of Example 27, using the synthetic formula IX with N-6 aminocyclohexanol:

OH

丨丨丨卜丨丨丨订丨丨丨丨丨丨丨线»I Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

0 f(s) HN

1625 ^206^ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm). 1287015 Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Co., Ltd. Printed · A7 B7

1287015 A7 B7 V. INSTRUCTIONS (&gt;^) Methyl iodide (0.1 ml, 1.6 min) was stirred at 2 rc under argon for 3 hours, and DMF was evaporated and added to a solution of ammonium sulfate (15 ml) The combined organics were extracted with EtOAc (3 mL EtOAc) (EtOAc) Methyl ester 22.

CI

1. H2N-&lt;^-y ΌΗ DMSO, 80 °C, 5h, then 20 °C, 13.5h 2. NaOH, MeOH, 20 min

16 15 20 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed with methyl vinegar 22 (24.5 house gram, 〇. 〇 57 mM) and 4_ tran-cyclohexanol (66 mg, 0.57 mM) in DMSO The solution (1.5 ml) was heated to 80 ° C for 5 hours under light pressure, then the heating was stopped and stirring was continued for 1 hr at 2 ° C, and 4% aqueous acetic acid (10 ml) was added to the cooled The solution was extracted with EtOAc (3×10 mL). EtOAc (EtOAc m. (ml) and brine (10 ml) were washed and dried over MgSO.sub.sub.sub.sub.sub.sub.sub.sub. A solution of NaOH in MeOH (0.5 mL of a 5 molar solution, 2.5 mM). After 20 min, water and saturated NaHC03 solution (5 mL each) and mixture of EtOAc (4 x 15 mL) Extraction, the combined organic layer is treated with 2 equivalents of NaOH (10 ml) and water (1 〇-208). This paper scale applies to Chinese national standards (CNS). A4 size (210X 297 mm) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1287015 A7 _____B7 V. Invention instructions (Μ;;) liter) and brine (10 ml) washed and dried by MgS04, filtered and concentrated The crude material was purified by chromatography eluting EtOAc EtOAc EtOAc EtOAc ): (5=1.38-1.62 (m5 4H)? 1.95-2.10 (m? 5 2H), 2·10_2·25 (m, 2H), 3·55-3·70 (m, 1H), 3.91 (s, 3H), 4.20-4.35 (m, 1H), 7.32 (s, 1H), 7.35-7.47 (m, 3H), 8.35-8.42 (m, 2H); IR (solid): n = 3352 cm - 1,3064, 2935, 2860, 1701, 1605, 1588, 1574, 1534, 1447, 1386, 1333, 1263, 1206, 1164, 1074, 938, 756, 705; MS (ES): 367 (MH+). 34: Synthesis of [4_Amidinomethylmercapto-pyrrolidinyl)-2-phenyl-7H-indolo[2,3-d]pyrimidin-6-ylmethoxy]acetate (1628) Compound 1628 was synthesized analogously to the method of Example 26 using the precursor compound 12:

Example 35: Synthesis of [4-(2-aminocarbamimido-pyrrolidinyl-1)&gt;2-phenyl-7H-indolo[2,3-d]pyrimidin-6-ylmethoxy]acetic acid ( 1629) Compound 1629 is synthesized analogously to the compound 1628, wherein the methyl ester group is obtained by hydrolysis: ~209~ This paper scale applies to the Chinese National Standard (CNS) A4 specification (2ΐ〇χ297 mm) 0 .ITSW (Please Read the notes on the back and fill out this page. 1287015

Description of the Invention (&gt;β)

〇 1629 〇

Bud hm MS (ES)·· 396 (Μ++1). Example 36 · Synthesis of 4-(4-hydroxy-cyclohexylamino)-2-phenyl-7H-pyrrolo[2,3-d]pyrimidine carboxylic acid decylamine (1630),,, 〇H 15

NH3 MeOH 20 °C, 10d

j heart,: s i V i building search r* _ one two (please read the notes on the back and fill out this page)

Order 20 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed to condense gaseous ammonia to pyrrolopyrimidine 23 (7.8 mg, 0·021 mmol) in methanol (6 mL) via dry ice/acetone cooled solution until the total volume is reached 12 ml, after stirring for 10 days at 20 ° C, the solvent was evaporated, and the residue was purified eluting with EtOAc EtOAc EtOAc 6.5 mg (88%) of decylamine 1630 as a white solid, m.p. 210-220 ° C (decomposition), iH-NMR (CD3OD): 6 = 1.40-1.60 (m, 4H), 2.00-2.15 (m, 2H) 2.15-2.25 (m, 2H), 3·55-3_70 (m, 1H), 4.20-4.35 (m, 1H), 7 16 ί^Α! 4 -210- This paper scale applies to Chinese National Standard (CNS) Α 4 Specification (210Χ297 mm) 1287015 A7 B7 V. Description of invention (&gt;f) (s,1H), 7.35-7.47 (m,3H),8.34-8.40 (m,2H); IR (solid): n=3358 Centimeters ' 3064, 3025, 2964, 2924, 2853, 1652, 1593, 1539, 1493, 1452, 1374, 1326, 1251, 1197, 1113, 1074, 1028, 751, 699; MS (ES): 352 (MH+). Example 37: Synthesis of [2-(3H-imidazol-4-yl)-ethyl]-(2-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (1702) Compound 1702 It is obtained by synthesizing the compound 1 before the synthesis of the formula VII: Μ

P'5_丨 [

{Please read the precautions on the back and fill out this page again. J - Booking · 15 20 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, printed aryl chloride 1 (4 〇〇 mg, 1.5 mM molar), DMSO (10 ml) and histamine were mixed and heated to 120 ° C under nitrogen pressure. After 6.5 hours, the reaction was cooled to room temperature and partitioned between EtOAc and water. The mixture was extracted with EtOAc (3 mL). Gray solid (1702), W-NMR (DMSO-d6) 5 3·〇5 (t, 2H, J=7_0 Hz), 3.94 (t, 2H, J = 7.0 Hz), 6.50 (d, 1H, J =3.5 Hz), 6.88 (brs, 1H), 7.04 (d, 1H, J=3.5 Hz), 7·42 (m, -21 l· This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1287015 Α7 Β7 V. Description of invention (&gt;π) 3Η), 7.57 (s, 1Η), 8·34 (m5 2H); MS (ES): 305 (M++1); melting point = 234-235〇 C. (Please read the notes on the back and fill out this page.) Activity of the compounds According to this document and especially on the pages 152-153 of this manual, 5 pairs of compounds 1601, ! 6〇2, 1605, 1606, 1611, 1614, 1619, 1621, 1623, 1624, 1625, 1626, 1627, 1628, 1629 and 1630 for adenosine i (Ai) receptor paratypic saturation and competitive radioligand binding, The receptor binding affinity of all of the above compounds is equal to or greater than the reference compound 1318 or 10 1319 according to the disclosure herein and especially in Table 13 on page 171 of the specification. The adenosine 3 (A3) receptor competes for radioligand binding according to the description herein and especially on pages 153-154 of the present specification, and the A3 receptor binding affinity of compound 1702 is found to be 10 times greater than that according to the present disclosure. And especially reference compound 1308 in Table 13 on page 169 of the specification. The above compounds listed in Table 16 are expected to be water soluble over reference compound 1318 or 1319 due to their cLogP values, using Cambridge Sofl Corporation, 100 Cambridge Park Drive,

Cambridge, MA 〇214〇 Computer program provided cs chemDraw, ChemDraw Ultra ver. 6.0 ©1999 Calculation. The Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative printed 20 listed compounds with specificity to the Ai receptor in Table 16. The cLogP value is between about 1.5 and about 3.4, which is lower than the reference compound 1318 or 13〇9. The cLogP value of 8, compared with the reference compound, is not expected to be listed in Table % and the cLogP value is lower than the reference compound 13π or 1309. The more polar octa receptor steroid retains the effect and the A! receptor binding selectivity. ~212' This paper size applies to Chinese National Standard (CNS) Α4 specification (210X297 mm) 1287015 A7

And for reference in this article

(Please read the precautions on the back and then fill out this page) -1--Γ---- Dedication ====Materials, Announcement of Patent Application Equivalent Appeals and Other Ministry of Economic Affairs Intellectual Property Office Staff Cooperatives The invention will be able to understand or be able to determine the many intoxications of this embodiment, and these equivalents are included in the following. β ~ 213 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm). Order---------

Claims (1)

128 ir A8 B8 C8 D8 VI. Patent Application No. 89125535 ROC Patent Appln. No. 89125535 Amendment of the dispute 4 Lifan® + text replacement page - Annex (4) Amended Claims in Chinese - Encl.(IV) Submitted on the 1st and 24th. (April 1996, Snhm itfprl A Ο/Ι ΟΠΛ7Λ Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printed in which I is stupid, 吼洛, 嗔, 吱, 嗔, 吐, 嗤^, 2,4-Sanjun, 2(1H)-吼_, 4 Called 吼(四), ^井,射,塔啡, 异嗔嗤,异啊,十坐,四峻, naphthalene, tetralin, naphthalene bite, benzopyrene, stupid and phenophoric, order, Μ dihydro Duo, 1H4" (four) Lin, stupid, 'a slogan, benzoxazole, sputum, fragrant beans boast &amp; this open one and one W, :/:,,: = = than Liu, 4 handsome, 吼Turn [3 2^^ open [3,4-b] Wei, 1H-t sit and [3 4_他定喳诺_, 1(2H)-isoindanone, M 喋定2(1Η)· , 咐 咐 HN_oxide, different D arable, benzopyrene (four) xian-oxide &quot; Kuitian 氡, Ν Ν oxide, 酞 唓 or porphyrin; and its Μ _ ” ° well, base. Mantle or (Cl_C6)婉2. According to the towel, please refer to the compound with the following structure: -214 - ---------- This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 public) 10 pyridine 15 20 89624B-connected 3 1287015 A8 B8 C8 D8 VI. Patent application scope 10 3. Compounds having the following structure according to item 2 of the scope of application: CH3 HN\^° Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Co., Ltd. 20 4. According to the scope of the patent application, the compound with the following structure: -215 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 1287015 A8 B8 C8 D8 VI. Application for patent scope Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives 10 〇 5. Compounds with the following structure according to item 2 of the scope of patent application: ch3 6. Compounds with the following structure according to item 2 of the scope of application: -216 - This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1287015 Α8 Β8 C8 D8 VI. Patent application scope CHU 7. A compound having the following structure: Printed by the Ministry of Economic Affairs, Intellectual Property Office, and the Consumer Cooperatives, where R3 is phenyl, pyroline, porphin, furan, 喧17 sitting, 咪σ sitting, σ ratio 20 azole, 1,2,4-triazole, 2 (1Η) -pyridone, 4(1Η)-pyridone, σ ratio well, 0 dense bite, σ荅口 well, different σ plug mouth, different mouth saliva, slogan σ sitting, four sitting, naphthalene, tetralin, naphthalene Pyridinium, benzofuran, benzothiophene, anthracene, 2,3-dihydroanthracene, 1Η-吲哚, 吲哚咁, benzopyrazole, 1,3-benzodioxime, benzopyrene , 嘌呤, coumarin, chromone, 4σ林, tetrahydro-217 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A8 B8 C8 D8 VI. Patent application scope 喳. Forest, iso-lin, benzimidazole, 4 sputum, 0 sigma and sigma [2,3-bp ratio call, σ ratio ϋ定[[3,4七]° ratio tillage, 吼σ定[3,2 -c] tower σ well, ° ratio ° P, 4-b] pyridine, 1 Η-pyrazolo[3,4-d]pyrimidine, acridine, 2 (1 Η)-nonanone, 1 (2 Η) -isoxanthone, 1,4-benzoxanthene, benzothiazepine, σ 奎崎υ林, n奎奎林-Ν-oxide, iso-quine Ν-oxide, 喳啐咐-N-oxide, oxide, benzopyrene _, hydrazine. Well or hydrazine; and wherein R5 and R6 are independently hydrazine or (CrC6) alkyl. 8. A compound having the following structure according to item 7 of the scope of application: h3c 〇 10 15 , NH 9. A compound with the following structure: Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, 20 p NH-CH3 -218 - This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm). 1287015 Six patent application scope 5 10 where I is phenyl, pyrrole, thiophene, furan, thiazole, imidazole, pyrazole, 1,2,4-three Azole, 2 (called acridone, 4 (1H) ♦ 嗣 嗣, : cultivating dimeridine, morphine, isothiazole, iso-sigma, etc. oxazole, tetrazole, , nep, naphthalene &quot; Benzo[, benzophene, H 2,3-di, 1+, 笨, pyridin, 1,3 benzodioxime, benzo. sit, oxime, coumarin , ketone, ah, tetra quinolin, isoporphyrin, benzimidazole, oxazolidine, pyridinium [2,) _ noisy than morphine, (four) and [3, 4 zhong (four), t ding [3, 2 &lt;;|何, bite and [3,4-b]pyridine, 1H_pyrazolo[3,4_d]pyrimidine, acridine, 2(出)_唼诺_, 1(2H)-isononanone, Benzopyrene, benzothiazepine, 喳4咁, cerium oxide, isoindole | N_oxide, 喳啐啩-N-oxide, oxazoline _N_oxide, stupid and ploughing , 酞耕或唓林, and its Chinese Han 5 and R6 are independently η or (crc6) alkyl. Compounds with the following structure according to item 9 of the scope of application for patents: Printed by the Intellectual Property Office of the Ministry of Economic Affairs, employee consumption cooperatives 15 -219 - This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1287015 VI. Patent application scope Η0κ rNH 10 15 20 wherein R3 is phenyl, oxime, phenophene, oxime, oxime, saliva, carbazole, 1,2,4-triazole, 2(1H)-acridone, 4(1Η)· Acridone, ^ well, «, ten wells, dissimilar materials, different ten sitting, ah, four saliva, naphthalene, tetralin, naphthyridine, benzofuran, benzothiophene, anthracene, 2,3-two ^ bow 1° flower, 1Η-♦朵' 啊林, benzopyrene, u-benzo benzodiazepine, benzoxazole, etc., oxime, coumarin, ketone, oxime, heart ° Kui Lin, Different ° Kui ° Lin, benzo _. Gui &quot; Kui Μ, ^ Ding and [23 · noisy than the well, (four) and [3, 4 zhong (four), "and [3, 2 outer 荅 _, bite and [ 3,4-b] bite, 1 Η 吼 并 and [3 fine] ♦, bite, 2 (ih) _ » quino _, 1 (2H) - ethics _, M_ benzopyrene , benzoxazole, «-Ν_oxide, iso-lin_N_oxide, porphyrin-N-oxide, carbazole-oxide, benzene or decene; and X is oxygen or Sulfur 12. Compounds having the following structure according to item n of the scope of patent application: -220 - 1287015 A8 B8 C8 D8 VI. 13. A compound having the following structure: 10 Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, and the Consumer Cooperatives. R3 is phenyl, oxime, sigh, 吱 喧, 喧 、, miso. Specific to saliva, 1,2,4-triterpene, 2 (111)-° ratio sigma ketone, 4 (1H)-port ratio sigma ketone, 20 ° ratio σ well. Density is determined.荅σ井, 异嗔唾, 异 坐 sitting, σ号 a sitting, four sitting, naphthalene, tetralin, naphthalene bite, benzopyrene, benzoxethen, Θ丨哚, 2,3-two Hydroquinone, 1Η-吲哚, 吲哚咁, benzopyrazole, 1,3-benzodioxan, benzo-4-u, ϋ 呤, coumarin, chromone, 4 σ lin, four Hydroquinone, isoindole, benzimidazole, oxazolidine, pyridinium. Dinghe [2,3- -221 - This paper scale applies Chinese National Standard (CNS) A4 specification (210x297 mm) A8 B8 C8 D8 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1287015 VI. Patent application scope b]吼Well,. Compared with the [3,4-b]^° well, the ϋ ratio is determined by [3,2-c].荅σ well, σ ratio σ and [3,4-b]pyridine, 1Η-pyrazolo[3,4-d]pyrimidine, acridine, 2(1Η)-nonanone, 1(2^〇_ Isonorrone, 1,4-benzopyrene, benzothiazepine, σ奎u, σ, α, 奎, 异, 异, 异, 异, 异, N, N, N, N Ν-oxide, 4 嗤 Ν Ν Ν 氧化物 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ΝΗ 15. A medical composition for treating a condition associated with an Ai adenosine receptor in a subject in need thereof, comprising an effective medical amount according to any one of claims 1, 7, 9, 11 or 13 Compound. 16. The pharmaceutical composition according to item 15 of the patent application, wherein the body 20 is a mammal. 17. The pharmaceutical composition according to item 16 of the patent application, wherein the mammal is a human. 18. The pharmaceutical composition according to claim 15 of the patent application, wherein the condition associated with the A! adenosine receptor is respiratory disease, diuretic, bronchial-222 - the paper size applies to the Chinese National Standard (CNS) A4 specification ( 210 X 297 mm) A8 B8 C8 D8 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1287015 VI. Patent application scope, Alzheimer's disease, heart hypoxia, hypertension, inflammation, sedative effect, bronchoconstriction, bradycardia, negative myocardial Contraction and transduction, reflux, ulceration, cognitive disease, renal failure, arrhythmia, or with respiratory epithelial disease, transmitter release, vasoconstriction, neutrophil chemotaxis, respiratory subepithelial It is related to the contraction of smooth muscle or the degranulation of mast cells. 19. The pharmaceutical composition according to claim 18, wherein the respiratory condition is asthma, chronic obstructive pulmonary disease, allergic rhinitis, or an upper respiratory condition. 10 20. The pharmaceutical composition according to claim 19, wherein the subject is a human. 21. The pharmaceutical composition according to claim 19, wherein the compound is an antagonist of a gossamin receptor. 22. A pharmaceutical composition having an A! adenosine receptor antagonistic activity, comprising a 15 effective dose of a compound according to any one of claims 1, 7, 9, 11 or 13 and pharmaceutically acceptable Accepted carrier. 23. The pharmaceutical composition according to claim 22, wherein the effective medical amount is effective for treating asthma, allergic rhinitis or chronic obstructive pulmonary disease. 20. The pharmaceutical composition according to claim 22, wherein the pharmaceutical composition is a periocular, post-ocular or intraocular injection preparation. 25. The pharmaceutical composition according to claim 22, wherein the pharmaceutical composition is a systemic modulator. 26. According to the pharmaceutical composition of claim 22, the medical standard - 223 - this paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1287015 A8 B8 C8 D8 VI. Scope of Application The drug composition is a surgical rinsing solution. 27. A method of preparing a compound according to any one of claims 1, 7, 9, 11 or 13 comprising the steps of: Ci reacts to obtain 10 wherein P is a removable excipient; b) treating the product of step a) under acidic conditions to obtain 15 -r5 c) Obtained as a product of step b) of oxygenated phosphorus treatment. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative 20 N A CI 57 Η ; and d) treating the chlorination product of step c) with NH2Ri to obtain 224 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 VI. Patent application scope Α8 Β8 C8 D8 The center of the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs printed in the center is 2-(decyl carbonylaminocyclohexyl, ethylaminoethyl, methylaminocarbonylaminoethyl or trans-4-hydroxycyclohexyl Wherein R3 is phenyl, 吼0, phenophene, oxime, 喧α sitting, miso, u-bazole, 1,2,4-triazole, 2(1Η)-pyridone, 4(1Η)- Pyridone, pyridin, pyrimidine, tareng, isothiazole, isoxazole, sirloin, tetrazole, nai, naiman, naphthalene, benzopyrene, benzoxethen, ρ σ σ, 2, 3-dihydroindole, hydrazine, hydrazine, benzopyrazole, ι,3-benzo bis- oxazole, benzoxazole, hydrazine, coumarin, chromone, anthracene, Tetrahydroporphyrin, isoindole, benzopyrene, 喳σ sitting, pyridoxine [2,3_ b]pyridin, pyrido[3,4-b]pyrazine,pyridin[3,2 -c] Tatrica, Pyrido[3,4-b]吼. 定,ΙΗ-吼嗔[3,4-d> 密密,嗓.定,2(1H)-4诺,1,1 2H)-isoxanthone, 1,4-benzoxanthene, benzothiazide. Sit, 喳崎咁, porphyrin_N-oxide, iso- 4σ林_N_oxide, 0 奎σ咐-N-oxide, π 奎嗤η-N-oxidation , benzoxan σ well, σσ well or sputum spray; and its center and 仏6 are independently ruthenium or ruthenium. 28·-a compound with the following structure·· -225 - This paper scale applies to Chinese national standards (CNS) A4 specification (21〇χ 297 mm) 1287015 A8 B8 C8 D8 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1287015 A8 B8 C8 D8 VI. Scope of application for patents 32. — A compound having the following structure: Printed by the Intellectual Property Office of the Ministry of Economic Affairs and the Consumer Cooperatives 35. A compound with the following structure: 20 This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm). 1287015 A8 B8 C8 D8 VI. Patent application scope 36. Compounds with the following structure N 〇^〇H n^n Η ΟΗ 37. A compound having the following structure 10 15 38. A compound having the following structure: ΟΗ Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative, 20 ΗΝ 39. A compound with the following structure: -228 - This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1287015 A8 B8 C8 D8 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1287015 Α8 Β8 C8 D8 VI. Patent application scope 〇 〇 43. A compound having the following structure: 0Η 10 ΗΝ Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative 20 15 44. A compound with the following structure: 45. A pharmaceutical composition for treating a condition associated with adenosine receptor in a subject in need of treatment, comprising an effective medical amount according to the scope of the patent application Nos. 28, 29, 30, 31, 32, 33, 34, 35 , 36, 37, -230 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1287015 5 10 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 20 38, 3, 40, 41, 42 or 43 of the _ item 46. The root shot please special _45 item (4) is a mammal. , dry individuals 47. According to the scope of the patent application, the animal is a human. a medical composition, wherein breastfeeding 48. According to the patent composition of claim 45, the fish related to the disease is related to respiratory diseases, diuretic fistula, Alzheimer's disease, heart Hypoxia, hypertension, anger, sedative, bronchoconstriction, tachycardia, cataract, reflux, _ situation, cognitive disease, exhaustion, arrhythmia or respiratory epithelial disease, transmitter release, It is also related to contraction, neutrophil chemotaxis, thinning of the subcutaneous smooth muscle of the respiratory epithelium, or degranulation of mast cells. 49. The pharmaceutical composition according to claim 48, wherein the respiratory condition is asthma, chronic obstructive pulmonary disease, allergic rhinitis, or upper respiratory disorder. 5. The pharmaceutical composition according to item 49 of the patent application, wherein the individual is a human. 51. The pharmaceutical composition according to claim 50, wherein the compound is an antagonist of a Α1 adenosine receptor. 52. A pharmaceutical composition having an adenine receptor antagonistic activity, comprising an effective medical amount according to the patent application scopes 28, 29, 30, 31 32, 33, 34, 35, 36, 37, 38, 39 A compound of any of 40, 41, 42 or 43 and a pharmaceutically acceptable carrier. -231 - This paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) /, the patent application scope 53. According to the patent application scope 帛 49 items, the beer condition is asthma , allergic rhinitis or chronic obstructive pulmonary disease. 〃 54. According to the pharmaceutical composition of claim 52, the pharmaceutical composition is a periocular, post-ocular or intraocular injection preparation. μ商 5 55. The pharmaceutical composition according to claim 52, wherein the pharmaceutical composition is a systemic modulator. - μ _ 56. The pharmaceutical composition according to claim 52, wherein the medical composition is a surgical rinsing solution. - 57. A pharmaceutical composition for treating an individual's eye damage, which comprises a therapeutically effective amount of a compound according to claim 44 of the patent application. 58. The pharmaceutical composition according to claim 57, wherein the injury comprises retinal or optic nerve head injuries. 59. A pharmaceutical composition for the treatment of glaucoma comprising a compound according to claim 44 in an effective medical treatment, and a carrier. A pharmaceutical composition having an Ai gland receptor antagonistic activity comprising an effective medical amount according to the compound of claim 44 and a pharmaceutically acceptable carrier. 61. A compound according to any one of the 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43 or 44 of the scope of the patent application. A pharmaceutically acceptable salt. 62. The pharmaceutical composition according to claim 15 or 45, wherein the condition associated with the A1 adenosine receptor is congestive heart failure. 63. A pharmaceutical composition for treating a condition associated with a3 glandular receptor in a subject in need of treatment, comprising an effective medical amount according to the patent application No. -232 - Α8 Β8 C8 D8 1287015 A compound wherein the adenosine receptor-associated disorder is associated with bronchoconstriction, asthma, bronchitis, chronic obstructive pulmonary disease, allergic rhinitis, upper respiratory tract disorder, myometrial ischemia, or homotrophic degranulation. 64. A pharmaceutical composition for inducing diuresis in an individual, comprising an effective amount of diuretic according to claims 1, 7, 9, 11, 13, 28, 29, 30, 31, 32, 33, 34, 35, a compound of item 36, 37, 38, 39, 40, 41, 42 or 43, and a carrier. 10 65. A pharmaceutical composition for enhancing memory in an individual, comprising an effective amount according to claims 1, 7, 9, 11, 13, 28, 29, 3, 31, 32, 33, 34, 35 a compound of 36, 37, 38, 39, 40, 〇〇41, 42 or 43 and a carrier 66. a compound having the structure of the formula, Hac 15 .0 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 20 Wherein R3 is unsubstituted guanlo, porphin, gnat, sputum, miso, carbazole, 1,2,4.triazole, 2(1Η)-pyridone, 4(1Η)_pyridine_, Oral well, mouth ϋ定, 塔σ井, 异嗔嗤, 异嗤嗤, 畤嗤 or Sisal-233 - This paper scale applies to China National Standard (CNS) A4 specification (21〇χ 297 mm) 1287015 Α8 Β8 C8 D8 Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Cooperatives. VI. Patent application ring, or 5-6 member aromatic ring; and R5 and R6 are independently hydrazine or alkyl. 67. A pharmaceutical composition for treating a condition associated with a Α3 adenosine receptor in a subject in need thereof, wherein the condition associated with the Α3 adenosine receptor is gas 5 asthma, bronchitis, chronic obstructive pulmonary disease or bronchoconstriction, The composition comprises a valid medical amount of a compound according to item 44 of the patent application. -234 - This paper size applies to China National Standard (CNS) A4 specification (210x297 mm)