TWI293955B - 8-quinolinxanthine and 8-isoquinolinxanthine derivatives as pde 5 inhibitors - Google Patents

Description

1293955

V. Description of the Invention (The present invention relates to the organic compound & the method of its preparation and its use as a medicine. The invention is punctured on the one hand, A kt, Wang domain or state Formula compound 〇R3

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumers' Cooperatives: R1 is hydrogen or alkyl as required by yours & gal, bis, & alkoxy, or alkyl sulphide, R is a hydroalkyl , ankylosyl, alkylcarbonyloxyalkyl, alkoxyalkyl, alkylsulfanyl, #yl, cycloalkyl, heterocyclyl, aramidyl, aryl can be visually required with 5 - a heterocyclic group fused, or optionally selected via - or more selected from the group consisting of an alkoxy group, an amine group, an alkylamino group, a dialkylamino group, a decylamino group, a halogen I group, an alkyl group, a decyl group a mercapto group, a dialkylamino group substituted with a substituent of the alkyl group 3, an alkylsulfonylamino group or a dialkylamine sulfonylamino group, and R3 is hydrogen or optionally substituted via a hydroxyl group, an alkoxy group, or an alkyl sulfide. The alkyl group, R4 is hydrogen or an alkyl group, and _R is optionally condensed with a 5-membered heterocyclic group, optionally via one or more selected from the group consisting of i-cyano, methoxy, alkyl, and alkyl. Alkoxyalkyl, alkyl thiol-based 'alkoxy, alkyl sulfonate, sulfhydryl, sulfhydryl, alkyl, alkyl, fluorenyl, a -N(R6)R7 group, aryl ( It can be visually accessed via one or more Substituted from a substituent derived from i or alkoxy), or a heteroaryl group (having 5 - 4 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------ -------暾-------_Book---------Line· (Please read the notes on the back and fill out this page)

--T 1293955

a description of the invention (2 or 6 ring atoms via a ring group substituted by a W material) substituted R6^f-lin or ketodihydroisoquinolyl, and the mouth 6 is a monohydrogen or optionally via a hydroxyl group Or alkoxy-substituted alkane II: 戈...7--the species is hydrogen, and the other species is a stilbyl group, or the nitrogen atom to which R6 and R7 are attached to the temple-indicating _ species or 6_member Ring base. The use of <alkyl '' refers to a straight or branched alkyl group, which may be = 'for example, ccc10_alkyl, for example, methyl, ethyl, n-propyl, /, propyl' -butyl, isobutyl, second-butyl, tert-butyl, linear or branched pentyl, straight or branched hexyl, straight or branched bond heptyl, straight or branched octyl , a straight or branched bond thiol or a straight or branched chain thiol. The alkyl group is preferably a CKC8-alkyl group. "Alkoxy" as used herein denotes a straight or branched alkoxy group which may be, for example, a Ci-Cio-alkoxy group, for example, a methoxy group, an ethoxy group, a n-propoxy group. , isopropoxy, n-butoxy, isobutoxy, second-butoxy, second-butoxy, linear or branched pentyloxy, straight or branched hexyloxy, straight Chain or branched chain heptyloxy, straight or branched chain octyloxy, straight or branched chain decyloxy or straight or branched chain decyloxy. The alkoxy group is preferably a cvcv alkoxy group. As used herein, alkylsulfide" may be Ci SC1G-alkylsulfide, for example, methyl & ethylthio, n-propylsulfide, isopropylsulfide, n-butylsulfide, second - Butyl sulphide, isobutyl sulphide, third butyl sulphide, pentyl sulphur, hexyl sulphide, heptyl sulphur, octyl sulphur, sulfhydryl sulphur or sulfhydryl sulphur. Mercapto sulphur is preferably C 1 sulphur As used herein, the term "initial" means a straight or branched chain thiol, which can be used in the paper scale - _ home standard (CNS) A4 size (2) G X 297 mil

-------------------Book---------Line. (Please read the phonetic on the back? Please fill out this page again) 1293955 A7

5. Description of the invention (3) 疋 'for example 'C2 to C丨〇-fluorenyl, for example, ethyl, 1-propenyl, 2 · propenyl, 1-butenyl, isobutenyl, or linear or Branched chain pentenyl, hexyl, heptyl, octyl, nonenyl or nonenyl. The alkenyl group is preferably c2 to c4-indenyl. As used herein, ''ring group') is meant to be via a c 3 to c 8 cycloalkyl group (eg, cyclopropyl, methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, fluorenyl) a cyclohexyl, dimethylcyclohexyl, cycloheptyl or cyclooctyl) substituted group, for example, a C i to C ̄ fe group, such as one of the c 1 to c iQ-alkyl groups described above. The alkyl group is preferably a c3-c6-cycloalkylalkyl group. The M heterocyclic group alkyl group as used herein means a hetero atom having one or more selected from the group consisting of nitrogen, oxygen and sulfur on the ring. 5- or 6-membered heterocyclic group (eg, pyrrolyl, pyrrolidinyl, furyl, pyrenyl, pyridyl, hexachloropyridyl, imidazolyl, imidazolidinyl, pyrazolidinyl, hexahydropyrrole An alkyl group substituted with a hydrazino group, a carbazolyl group, or a furyl group, for example, a substituent, such as one of the above-mentioned groups, preferably a heterocyclic group. a tiger group substituted with one or two nitrogen or oxygen atoms or a nitrogen atom and an oxygen atom of a 5- or 6-membered heterocyclic group. As used herein, the ''aralkyl'' Refers to a C^-ClQ-aryl-Cl-ClQ-alkyl group substituted with a phenyl group, a tolyl group, a dimethylphenyl group or a phenyl group, and may be, for example, one of the CVCio-alkyl groups described above, in particular One of the alkyl groups. The aryl group is preferably a phenyl-C i -C 4 -alkyl group, particularly a ^: group or a 2-phenylethyl group. As used herein, the term ''fluorenyl'' Applicable to one or more self--6 - paper scales applicable to China National Standard (CNS) A4 specifications (210 X 297 gong----- Φ -------------Mm (please first Read the notes on the back and fill out this page. Order---------Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1293955 A7 B7 V. Description of Invention (4) Atom-substituted alkylcarbonyl, for example , Cl-C1 (r alkylcarbonyl group, wherein CK cur alkyl group may be one of the above-mentioned (: 1-〇1()-alkyl group, cycloalkylcarbonyl group, for example, C3_c8-cycloalkylcarbonyl group, Wherein C3_C8_cycloalkyl can be, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or anthranyl; having one or two selected from the group consisting of nitrogen, oxygen and sulfur Heteroatoms <5 - or 6 _ a heterocyclic carbonyl group, for example, a furylcarbonyl group or a pyridylcarbonyl group; an arylcarbonyl group, for example, a C6_C1 (rarylcarbonyl group, for example, a benzylidene group; or an aralkylcarbonyl group, for example, a fluorene to an aryl group) _Ci-C4"alkylcarbonyl", for example, benzylcarbonyl or phenylethylcarbonyl. The fluorenyl group is preferably a Ci_c4-alkylcarbonyl group. As used herein, "alkynyl" means a straight or branched alkynyl group. For example, a C2 to c0-block group, for example, an ethynyl group, a propynyl group, a 2-butynyl group, a pentynyl group or a hexynyl group. The alkynyl group is preferably a c2-c4-alkynyl group. "Aryl" as used herein denotes a monovalent carbocyclic aromatic group, for example, C6-C1 (raryl, for example, phenyl, via one or more (eg, i, 2 or 3) Ci- C4. Alkyl substituted phenyl, or naphthyl. The aryl group is preferably phenyl. As used herein, "heteroaryl having 5 or 6 ring atoms" means having 5 or 6 ring atoms (wherein丨, 2 or 3 monovalent aromatic heterocyclic groups selected from nitrogen, oxygen and sulfur, for example, pyrrolyl, furyl, thienyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl , isoxazolyl, pyrazolyl, isopyrazolyl, dipyrazolyl, trithiazolyl, furazanyl, pyridinyl, pyrimidinyl or tri-negative. In alkylamino, dialkylamino, hydrazine Amino, dialkylaminosulfonylamino, alkylcarbonyl, alkylcarbonyloxy, alkoxycarbonyl, hydroxyalkyl, alkylsulfanyl paper 3 turned -7- (210 X 297 public) - ------------------- Order --------- line (please read the notes on the back and then fill out this page) 1293955 V. Invention Description (5 )

And alkoxyalkyl, if appropriate, the alkyl, mercapto or alkoxy group has the meaning as previously described. J. The 'halogen' as used herein may be fluorine, chlorine, bromine or pyridine; it is preferably fluorine, gas or bromine. 'R5 (for example, porphyrinyl, isoindolyl or ketodihydroisoquinolyl) may be fused to the 5-membered heterocyclic ring as needed, for example, having -&amp; A 5-membered heterocyclic ring of a hetero atom selected from the group consisting of oxygen, nitrogen and sulfur. Examples of such heterocyclic rings include P. Biluo, P. P. Lin, P. Biluo, 吱 ,, 二 气, 'tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, imidazole, imipenem' imidazole , pyrazole, pyrazole, pyrazolidine, dioxin, p-azole, iso-sal, thiazole and isopyrazole. The 5-membered heterocyclic ring is preferably a saturated ring having two hetero atoms (preferably two oxygen or two nitrogen atoms, particularly preferably two oxygen atoms). For example, R5 of quinolyl group may be 2-carbolinyl, 3-carbolinyl, 4-mercapto, 5-tylinyl, 6-junolin, 7-junolin or 8-junolin. Preferably, it is 4 _ 峻 p 林基 ' 5 - p quinionyl or 8-tolan. For example, R5 of iso-p-quineyl may be 1 _isoquinolyl, 3-isoquinolinyl, 4-isoquinolinyl, 5-isoquinolinyl, 6-iso-4-phenyl, 7-isoquinoline Or a 8-isoquinolyl group, preferably a 1-isolinyl group or a 4-iso-4 group. For most of the preferred embodiments of the invention, R5 is a 4-isolinyl group. R5, such as substituted P quinionyl or isotactic TT, is preferably substituted by one, two, three or four of the above substituents (especially one, two or three of these substituents). Preferably, the substituted 4-isoquinolyl group is substituted at the first and/or sixth and/or seventh and/or eighth positions of the isoindoline ring system. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm---I------------- 丨丨 · ί 线! line (please read the back first) Note: Please fill out this page again)

1293955 V. INSTRUCTION DESCRIPTION (6) In a particularly preferred embodiment of the present invention, R5 is a quinolyl group of the formula

R 13 or isoquinolyl

R 12

R 11

, cyano, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, alkylsulfanyl, alkoxy, alkylthio, alkenyl, alkoxycarbonyl, alkynyl, carboxy, fluorenyl, formula - a N(R6)R7 group, an aryl group which may optionally be substituted via one or more substituents selected from halogen or alkoxy groups, or a substituent having a heteroaryl group of 5 or 6 ring atoms, or R11 and R12 together with the carbon atom to which they are attached represents a 5-membered heterocyclic ring having 2 oxygen or nitrogen atoms in the ring, and R0&amp;R7 is as defined above. Preferably, R5, such as oxydihydroisoquinolyl, has the oxy group adjacent to the ring nitrogen atom, preferably at the fluorene position on the rudoquinoline ring system. Preferably, the residue of the molecule of formula I is attached via the ring carbon atom spaced from the ring nitrogen atom (i.e., at the fourth position of the hetero 4 ring system).尤佳的氧二气--------------------- order---------- line (please read the notes on the back first) Fill in this page) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing -9-

R 11 R 12 R1 1293955 V. Description of invention (7)

IIIA wherein R1〇/RU, Rl2 and Rl3 are as defined above, and Ra is hydrogen or a Cl-C4e group.

Fortunately, the compound of formula I in the free state or the salt form is such that R is hydrogen or optionally via a hydroxyl group, Ci_c4-alkoxy or Ci-C4-alkylthio is cvcv alkyl, and R is chloro' CkC8-alkyl group; light base-CVCV yard base; cv (v-based carbonyl group-cvcvfc group; κ4· alkoxy group; Ci-c4·alkyl sulphide CrCVfe group; c2-c4-mercapto group; c3 a -c8-cycloalkyl-CrC4-alkyl group, a hetero-yl group-CVCV alkyl group, wherein the heterocyclic group is 5 or 6 having one or two heteroatoms from the nitrogen and oxygen atoms in the ring. a heterocyclic group; a phenyl-C1-a group wherein the phenyl ring may optionally be selected from one or more selected from the group consisting of Ci-C4_oxy, amine, Cl-c4-alkylamino, and di(Ci-( Substituted by a substituent of a V alkyl)amino group, a Ci_a alkylcarbonylamino group, a halogen, a Cl-Czr alkylsulfonylamino group, or a bis(c-C4- and yl)aminosulfonylamino group, and optionally Condensed with a 5-membered heterocyclic ring having two oxygen or two nitrogen atoms in the ring, R3 is hydrogen or may be substituted via a hydroxyl group, a Cl_C4_alkoxy group or a Ci-Czr alkane 3 sulfur group, R4 is Hydrogen or CVCV alkyl, -10- This paper scale applies to China National Standard (CNS) A4 (210 X 297 mm) -------------------- Order --------- Line i^w. (Please read the notes on the back first. Fill in this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1293955

Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed Agriculture R, as needed, may be fused with a 5-membered heterocyclic group having 2 oxygen or 2 nitrogen atoms on the ring and may optionally be selected from halogen, cyanide via one or more Base, carboxyl group, hydroxyl group, cvcvfe group, hydroxyl group _Ci-c4_alkyl, Ci_C4·alkoxy _ cvcvfe base, cvcv thiol group, cvcv oxime, CrCVfe ruthenium, C2-C4-mercapto group, a substituent of a c2-c4-blockyl group, a CVC4.sodium carbonyl group, a -n(r6)r7 group or a phenyl group which may optionally be substituted via one or more substituents selected from halogen or c! _C4_alkoxy group. Substituted quinolinyl, isoindolyl or oxydihydroisoquinolinyl, and R6 and R7 are each independently hydrogen or CVC4-alkyl which may be substituted via a hydroxy or alkoxy group, or one of R6 and R7 Is hydrogen, and the other is Ci_C4_alkylcarbonyl, or R6 and R7 together with the nitrogen atom to which they are attached represent one or two nitrogen atoms in the ring and, if desired, an oxygen atom 5 - or 6-Bei heterocyclyl. Further preferably, the compound of formula I is such that R is hydrogen or CVC4-alkyl, R2 is hydrogen, CVCV alkyl, light-Ci-Cs-k- or Cf-CVfe-based oxygen-Cn-CV Base, C2-C4-indenyl, c3·C6·cycloalkyl-CVC4-alkyl, heterocyclyl-Cj-C: 4-alkyl (wherein the heterocyclic group has a nitrogen or oxygen on the ring) a 5-membered heterocyclic group of an atom, a phenyl-Cl-Cf alkyl group (wherein the phenyl ring may be selected from one or two selected from the group consisting of Ci_C4-alkoxy, amine, cvc4-alkylcarbonylamino) , chlorine, bromine, Cl_c4-alkyl amide, or a substituent of bis(q-C4-alkyl)aminosulfonylamino, and optionally 5 with two oxygen atoms on the ring _ member heterocyclic ring), R3 is hydrogen or CVC4-alkyl, -11- 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 in this page again) 1293955

The Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative printed R4 as hydrogen or CVCV alkyl, R horse II porphyrin, anisoindolino or a fluorenyl dihydroisoindolyl group, of which R, R, R10 , Ru, Rl2 and r13 are each independently selected from the group consisting of hydrogen, halogen, cyano, carboxyl, hydroxy, CkCV alkyl, hydroxy-Ci_C4_alkyl, Cj-cvfeoxy-Ci-cv alkyl, c-C4-alkyl Sulfur Ci_C44-charged, t c4-alkoxy, cvcv-based sulphur, c2_C4_fluorenyl, C2_C4-blockyl, ^cVk carboxy, _n(r6)r7 group or optionally selected from one or two halogens or Ci-C: a phenyl group substituted with a substituent of a 4-alkoxy group, or a ruthenium 11 and a ruthenium 12 together with the carbon atom to which they are attached may represent a 5-membered heterocyclic ring having two oxygen atoms in the ring. And R6 and R7 are each independently hydrogen or a Cj-cv alkyl group which may be substituted by a hydroxyl group or an alkoxy group, or one of r6 and R7 is hydrogen, and the other is an alkylcarbonyl group, or R6 and R7 are the same The nitrogen atom to which it is attached may together represent a 6-membered heterocyclic group having one or two nitrogen atoms, or a nitrogen atom and an oxygen atom on the five curtains. Among the preferred compounds described above, a preferred compound is generally such that R5 is an isoquinolyl group of the formula III wherein R8 is hydrogen, Ci_C4_alkyl, _ cyano, cyano, -n(r6)r7 ( Wherein r6&amp;r7 is independently c "c4_alkyl or R6&amp;R7 together with the nitrogen atom to which they are attached, means having one or two nitrogen atoms on the ring, or a nitrogen atom and an oxygen atom; a heterocyclic group, or a phenyl group substituted by one or two q-C4-alkoxy groups; R9 and rig are each independently hydrogen, CVCV alkyl or halogen; Rii and each independently hydrogen, halogen, cyano , carboxy, hydroxy, (VCV alkyl, CVC4-alkoxy or c2-c4-alkynyl, or R11 and R12 together with the carbon atom to which they are attached are indicated in the ring-12- Standard (CNS) A4 specification (21Q x 297 public) --------------------- Order --------- line (please read the back first Note: Please fill out this page again} 1293955 A7 B7 V. Inventive Note (1〇) A 5-membered heterocyclic ring having 2 oxygen atoms; and R13 is hydrogen or halogen. More preferred compounds of formula I are These compounds are described in the examples More preferably, it is described in Examples 7, 10, 15, 35, 45, 49 55, 60, 68 and 7 。. The compound of formula I may be in the form of a salt, particularly a pharmaceutically acceptable peak compound I. Acceptable acid addition salts include inorganic acids, such as Z, hydrohalic acids, for example, hydrofluoric acid 'hydrochloric acid, hydrobromic acid or hydromoic acid, nitric acid, phosphoric acid; and organic acids, for example, aliphatic monocarboxylic acids, For example, formic acid, acetic acid, trifluoroacetic acid, propionic acid and butyric acid, aliphatic hydroxy acids such as lactic acid, citric acid, tartaric acid or malic acid, dicarboxylic acids, for example, 7-butanedioic acid or succinic acid, Aromatic tickic acid, for example, benzoic acid, t-butidine-mouse formic acid, diphenylacetic acid or triphenylacetic acid, aromatic hydroxy acid, for example, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxyl Naphthalene-2-carboxylic acid or 3 _A 荇-2- oxo acid, and transacid, for example, methanesulfonic acid or benzoic acid. The pharmaceutically acceptable alkali salt of the compound of formula I wherein Han 3 = hydrogen includes a metal salt, especially for the examination of metal or soil metal salts, for example, steel, unloading, magnesium or __, and having a salt of ammonia, or pharmaceutically acceptable An organic amine or a heterocyclic base such as an acetamidine amine, benzylamine or pyridine. These salts can be prepared from free compounds of the gas I or other salts of the compounds of the formula I via known salt formation procedures. The invention also provides a preparation A person or method in the form of a free state or a salt type, which comprises the following steps: 1) (a) dehydrating a compound of the formula: - Table paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) (Please read the notes on the back and fill out this page) Order---------Line. Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printed Economy Ministry Intellectual Property Bureau Staff Consumer Cooperatives Printed 1293955 A7 B7 -- ----—^. V. Description of invention (11)

R2 wherein Ri, R2, R4 and R5 are as defined above; or (b) in the preparation of a compound of formula I wherein R3 is a free or salt form which may optionally be via a hydroxy, alkoxy or alkylthio-substituted alkyl group. Said to react a compound of the formula I in a free or salt form with a suitable alkylating agent, or (wherein R is prepared wherein R2 is substituted on the aryl ring via an alkylsulfonylamino or a dialkylsulfonylamino group) In the case of a compound of formula J wherein the aralkyl group is in a free or salt form, the compound of formula I wherein R2 is an aralkyl group substituted via an amine group is in the form of a salt of the formula I, respectively, with an alkylsulfonyl or dialkylamine sulfonate. Or hydrating; or (d) hydrating a compound of formula I wherein R 2 is a fluorenyl group for the preparation of a compound of formula I wherein R 2 is a hydroxy substituted alkyl group; or (e) For the preparation of a compound of formula I wherein R 2 is a free or salt form of an alkyl group which may be substituted via an alkylcarbonyloxy group, the esterification reaction of a compound of formula I wherein R 2 is a hydroxy substituted alkyl group; (0) to prepare a free alkyl group in which R2 is substituted via an amine group on the aryl ring Or a salt form of a compound of formula I wherein a compound of formula I wherein R2 is an aralkyl group substituted on the aryl ring via a hydrazino group is hydrolyzed; or (g) wherein R5 is substituted via a hydroxy group For a compound of formula I in which the quinolinyl or isoquinolyl group is in a free or salt form, wherein R5 is respectively applied to the Chinese National Standard (CNS) A4 specification (21 X X 297 mm) on a 14-sheet scale. ---------------------Book --------- C Please read the phonetic transcription on the back? Please fill out this page again} 1293955 A7 B7 V. DESCRIPTION OF THE INVENTION (12) Alkoxy (especially methoxy)-substituted quinolinyl or isoquinolinyl compounds are subjected to dealkylation; or (h) is prepared wherein R5 is quinolinyl substituted via halogen Or a compound of the formula I in which the isoquinolyl group is in a free or salt form, wherein a compound of the formula I wherein R5 is a quinolinyl or isoindolyl group, respectively, having an unsubstituted ring atom suitable for the deuteration reaction, is carried out. a reaction, or (1) in the preparation of a compound of formula I wherein R 2 is a free-sorrow or salt form of a cyclopropyl group which may optionally be substituted via an alkyl group, wherein R 2 is a fluorenyl group The compound of the formula is subjected to a Simmons Smith cyclopropanation reaction; and 2) the product of the formula I formed in a free or salt form is recovered. The process (a) can be carried out by heating or by reaction with an inorganic or organic base. Either in an aqueous solvent or a mixed aqueous/organic solvent. The reaction can be carried out at ambient temperature, or more conveniently, at elevated temperatures: preferably two, for example, as described in the examples below, at elevated temperatures. The alcohol-based agent is treated with an aqueous solution of an alkali metal hydroxide to carry out the reaction. The compound of the formula I v is preferably a compound wherein r5 is a group of the formula η4ΙΠ. The compound of the formula π wn -------- -----m clothing (please read the phonetic on the back first? Matters to fill out this page) Order --------- Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

v (wherein R1 and R2 are as defined above) and the compound of the formula HOOC--CH-R5 R4 -15- 1293955

5. Description of the invention (13) (wherein R4 and R5 are as defined above) or a derivative thereof which forms a guanamine to prepare a compound of formula IV. The method of accomplishing the reaction is to use the formula coupling agent to form an active vinegar or a mixed acid liver on the spot, followed by organic dissolution (for example, a dipolar aprotic organic solvent), or a mixture of water-organic^ For example, a gas hydrocarbon) is treated with the compound of formula v. The treatment method described later can be carried out under the environmental temperature of the human body; at the temperature of the environment or at the south temperature, and it is convenient to carry out the salt-type VI acid at ambient temperature, preferably in the presence of hydroxybenzotriazole and optionally in the presence of a base. Treatment with a guanamine derivative or treatment with a benzotriazole group (three t alkylamino hydroxy scale salts. preferably at ambient temperature in a dipolar aprotic solvent or a mixed chlorocarbon/aqueous solvent) The intermediate formed by the treatment of the V compound can be carried out as described in the following examples. The compound of the formula V can be produced by a reduction reaction of a compound of the formula: 〇, r^n-VN0, human N-R2

VII ------------% (Please read the note on the back? Please fill out this page again)

NK Order --------- Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing R1 and R2 are as defined above. The reaction can be carried out by known procedures, for example, by treating the compound of formula VII with a bluff in an organic or aqueous solvent. The reaction can be carried out at ambient temperature, or more conveniently, at elevated temperatures. Preferred reducing agents are alkali metal dithionite in an aqueous medium or hydrogen in the presence of a noble metal catalyst. More preferably, it is treated with sodium dithionite in an aqueous solution at 80-90 °C. The following formula can be used in organic or aqueous or mixed organic_aqueous solvents. 16 Table paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1293955

V. Description of the invention (14 compound R\

N 〇 O^^N’, Nhl

VIII. Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs (where R1 and R2 are as defined above) and nitrosation with an organic or inorganic nitrosating agent to prepare a compound of the formula νπ. The nitrosation reaction can be carried out using sub-ambients, % ambient temperature or elevated temperature using known procedures, preferably in a mixed alcoholic-aqueous, falling-off agent (eg, an ethanol solution) at sub-ambient or ambient temperature in the acid ( For example, in the presence of acetic acid, nitrosation is preferably carried out using an alkali metal nitrite such as 'sodium nitrite. The compound of the formula VIII is prepared by reacting a compound of the formula: R2-N-C〇-N-C〇-CH2CN IX Η Η (wherein R is as defined) with an inorganic or organic base to complete the cyclization reaction, wherein R1 The alkyl group which is optionally substituted is then reacted with an alkylating agent. A conventional procedure can be used to complete the cyclization reaction. It is conveniently carried out in aqueous, organic or mixed organic-aqueous solvents. The reaction can be carried out in an environment or, more conveniently, at a high temperature. The base is preferably an alkali metal hydroxide, particularly sodium cerium oxide, which is preferably subjected to a reaction at a high temperature (for example, 8 〇 -9 Torr. in a mixed aqueous-alcoholic solvent). Knowing the procedure to perform this selection: the feation step, for example, in the presence of an inorganic or organic base in an aqueous, organic or mixed aqueous-organic solution J. It can be applied to the national standard at sub-ambient temperature or '17-paper scale. (CNS) A4 size (210 X 297 mm) I-----------% (Please read the note on the back and fill out this page) Order---------Line_ 1293955 A7

V. Description of invention (15) The Ministry of Economic Affairs' Intellectual Property Office staff consumption cooperative prints more conveniently, and performs alkylation at ambient temperature or high temperature. A preferred blowing agent is an alkyl iodide or, in particular, a dialkyl sulfate. The preferred base is an aqueous alcohol solvent (especially an aqueous ethanol solution) of an alkali metal gas oxide. The compound of formula I X is prepared by the following compound

R-N-CO-ΝΗ2·X Η 2 is reacted with cyanoacetic acid or a derivative thereof which forms a guanamine (for example, a brew or a halogen thereof, preferably the acid or an ethyl ester thereof). The reaction can be carried out using a known procedure (for example, in an organic solvent, preferably an acid anhydride (for example, acetic anhydride). The reaction temperature can be ambient temperature or, more conveniently, high temperature, for example, 6 5 to 70 〇 C. Compounds of formula X can be prepared using conventional procedures, for example, the reaction of isocyanate R2NCO with gaseous or aqueous ammonia, or the reaction of amine R2NH2 with a metal cyanate as described in the following examples. The alkyl group substituted by a hydroxyl group, an alkoxy group or a pyridyl group, if necessary, and R2, except for the absence of hydrogen, is prepared by subjecting a compound of the formula to a hydrogenolysis reaction, wherein R1 is via a hydroxyl group as needed. Alkoxy or alkylthio substituted alkyl, R2 as defined above (except for the absence of hydrogen), and Ar is applicable to the Chinese National Standard (CNS) A4 specification (210) via one or more -18-paper scales as needed. X 297 mm) --------------------- Order --------- line (please read the note on the back? page)

1293955

5. Description of the invention (π kinds of CrC4_alkoxy (preferably methoxy) substituted phenyl. It is known that the hydrogenolysis reaction is carried out by, for example, hydrogen or a hydrogen source and = (for, platinum or , preferably, palladium catalyst treatment. The reaction can be carried out in: catalyst = the reaction temperature can be ambient temperature or high temperature. As follows == As stated, the decomposing reaction is preferably carried out using palladium black in formic acid. · proceed. 'The compound of formula XI is prepared by the following formula (also N 〇人N〆R2)

XII

CI (wherein R1 and R2 are as defined above for formula XI) is reacted with a compound of the formula ArCH2NH2 (wherein Ar is as defined). The reaction can be carried out using known methods, for example, by carrying out the reaction in an organic solvent (preferably an alcohol such as n-butanol) at ambient or elevated temperature, or by a method similar to that described in the examples below. reaction. The compound of formula XII is prepared by making the compound of the formula - R' ----------------------- order--------- line. Read the phonetic transcription on the back first? Then fill out this page.) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 〇0'

XIII (wherein R1 is as defined in formula XI above) is reacted with a compound of the formula R2X (wherein R2 is as defined above for formula XI, and X is a halogen or a group), and if X is a light group, -19· the paper size is applicable to the Chinese country Standard (CNS) A4 specification (21〇X 297 mm) 1293955 A7 B7 V. Description of the invention (17) The reaction is carried out in an activator (preferably an azodicarboxylate such as azodicarboxylic acid). The third-butyl ester; and is carried out in the presence of a triarylphosphine, for example, diphenylpyridylphosphine. This reaction can be carried out in an organic solvent (preferably an ether such as dioxane). The reaction temperature can be a sub-ambient temperature or, preferably, an ambient temperature or a high temperature. The reaction can be carried out using the procedure of Mitsonobu, Synthesis 1981, or a method similar to that described in the examples below. Compounds of formula XIII are known or can be made via known procedures. The compound of formula VI can be prepared from, for example, (1) from benzoic acid or substituted benzaldehyde using the procedure described by Dyke et al., Tetrahedron 1968, 24, 1467, or (ii) using Dyke et al. in Tetrahedron 1968. , 24, 1467, the process of reacting an optionally substituted N-protected 1,2-dihydroiso-p-quine with 2 -lacyl-acid, and optionally using j. March, Advanced Organic Chemistry, 4th edition, Wiley, New York, 1992, pages 393 and 378, the procedure for converting a carboxylic acid formed into a formazan, followed by conversion to a metal salt, or (iii) using Minter et al. The procedure described in 〇rg. Chem. 198 8, 53, 2653, which allows the porphyrin or isoquinoline to be reacted with a hydride reducing agent and a 2-oxy-carboxylate, if necessary, or Iv) using the procedure described by Janin and Biagani in Tetrahedron 1993, 39, 10305, or the procedure described by Ford et al., J. Med. Chem, 1985, 28, 164, to give a substituent to the acid of formula VI. On the ring. Certain compounds of the formula VI can be prepared by the following reaction scheme: -20-degrees of the medium® (CNS) A4 size (2) 0 x 297 mm) ------------- ( Please read the notes on the back and fill out this page. Order---------Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1293955 A7 B7 V. Invention Description (18) (i) The reaction process As follows: R 13

CHO (8) R 13 R9

XV (b) XIV 13

R R

XVI R 13

(Please read the notes on the back and fill out this page.) Printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs. R4, R9, R10, R11, R12 and R13 are as defined above. Steps (a) to (c) can be carried out using known methods, for example, using the procedure described in Dyke et al., Tetrahedron 1968, 24, 1467, or a method similar to that described in the examples below; -21- The paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) [293955 A7 B7 V. Description of invention (19) (ii) The reaction process is as follows, 12

R 13

COCH FT FV XIX 3 (8)

13 R 13

(g) -------------# (Please read the notes on the back and fill out this page) xx

R

-------Book---------· Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing R4, R9, R10, R11, R12 and R13 are as defined above. Steps (d) through (g) can be carried out using known methods, for example, step (d) using the procedure described by Katayama et al. in Chem. Pharm. Bull, 1980, 28, 2226, step (e) using Dyke et al. The procedure described in Tetrahedron 1968, 24, 1467, and steps (f) and (g) using J. March, Advanced Organic -22- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 PCT) [293955 R 13

R XVII A7 B7 V. Description of invention (20)

Chemistry, 4th edition, Wiley, New York, 1992, pages 393 and 378, or similar to the methods described in the examples below; (iii) the reaction is as follows:

R 13

R

XVIII For example, using the procedure described by Minter et al., J. Org. Chem. 1988, 53, 2653, or a method similar to that described in the examples below, followed by a hydride reducing agent and a 2-oxy-carboxylic acid Ester Treatment of Formula XVIII; (iv) For the preparation of a compound of Formula VI wherein R5 is a 4-isoquinolinyl group substituted at the 1st position, the reaction scheme is as follows: (Read the back of the note first? Please fill out this page again) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed R 13

XXII (h) R 13

XXIII (0 -23- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1293955

V. Description of invention (21)

(j) XXIVR\

XXV 13 N-R7

XXVI Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed R4, R6, R7, R9, Ri〇, Rii, R12 and Rl3 as defined above to perform steps (h) to (k) using known methods, for example, steps ( h) to (j) use the procedure described by Janin and Biagni in Tetrahedron 1993, 3 9, 103 05, and step (k) uses J. March, Advanced Organic Chemistry 4th Edition, New York, 19_92, p. 378 The procedure described in the above, or a method similar to that described in the following examples; (v) For the preparation of a compound of formula VI wherein r5 is an isoquinolinyl group and r8 is a cyano group, the reaction scheme is as follows: 24· This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm). (Please read the note on the back? Please fill out this page again)

1293955 A7 B7 V. INSTRUCTIONS (22) R 13

(I) R 13

R (four)

XXIII

(η) XXVIII XXVII ^13

XXIX wherein R4, R9, R10, R11, R12 and R13 are as defined above. Steps (1) to (n) can be carried out using known methods, for example, steps (1) and (m) using the procedure described by Ford et al., J. Med. Chem, 1985, 28, 164, and step (η) Using J. March, the procedure described on page 378 of the above book; (vi) for the preparation of a compound of formula VI wherein R5 is oxydihydroisoquinoline 4, the reaction scheme is as follows: ----- ---Order---------Line· (Please read the notes on the back and fill out this page). t Fill in the π Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print D 13 .13

- CH0 C〇〇H R4 R XX XXX XXXI -25- The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1293955 A7 B7 R1

Rc order:

XXXIII V. INSTRUCTIONS (23 where R4, R9, R1, r11, R and R are as defined above. Steps can be carried out using known methods (〇) and (P) 'for example' using Holzgrabe, Arch Pharm. (Weinheim , Ger), 1988, 321,767, or a method similar to that described in the examples below; (vii) for the preparation of a compound of formula VI wherein R5 is a quinolinyl group, the reaction is as follows: 13 ♦ -------------— (Please read the notes on the back and fill out this page.) Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Printed R4, R9, R10, R&quot;, R12 And R13 is as defined above. The reaction can be carried out using known methods, for example, using the procedures described in Brown and Curless Tetrahedron Lett., 1986, 27, 6005, or the methods described in the examples, respectively, via a strong base. (preferably an alkali metal alkylguanamine, for example, lithium diisopropyl decylamine) and carbon dioxide treatment. (viii) For the preparation of a compound of formula VI wherein R5 is 4-iso-p-loryl, the reaction scheme is as follows : The Chinese national standard has been applied to the line of the 26-sheet paper. CNS) A4 size (210 X 297 mm) 1293955 A7 B7 V. invention is described in (24) R 10

CHO R XIV (q) R 10

C02CH2CH3 fT XXXIV (")

R

R -------------% (Please read the notes on the back and fill out this page)

XXXV

XXXVI ^10

R (9)

Order ----------Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed XXXVI!

XXXIX (w)

XXXVIII

Xxxx ,27- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) [293955 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed A7 B7 V. Invention description (25) where R8 ' R10 ' R11 'R12 and R13 are as defined above. Steps (q) to (w) may be carried out using known methods; for example, step (q) is carried out in an organic solvent (preferably ether or smoke, preferably toluene) at sub-ambient temperature, high temperature or 'better environmental degree' a mesogenic ethyltriaryl acetylation scale (preferably a carboxyethyltriphenyl block scale); step (r) at sub-ambient temperature, ambient temperature or, preferably, elevated temperature (eg, 60-80) At ° C), in the presence of an inorganic base or, preferably, an amine base, especially tetramethyl hydrazine, for example, in the presence of a solvent or, preferably, in the absence of a solvent, by nitromethane; Reducing agent at a sub-ambient temperature, ambient temperature or, preferably, at a temperature (for example, under reflux) in water or, preferably, in an organic falling agent (preferably an alcohol such as ethanol) Preferably, the tin (π) salt is treated with tin (π) chloride hydrate; the step (1) is at a high temperature or, preferably, at a sub-ambient or ambient temperature (for example, ϋ ° C to ambient temperature) Aqueous or, preferably, in an organic solvent (especially a chlorinated solvent, such as 'dichloromethane), good fortune is good (especially An amine, for example, triethylamine), under the acid or the acid liver (preferably the chlorinated chlorine) of the acid r8cooh: v (8) car is better than the environment or, especially, at high temperatures (for example, In the case of the fine I), the car is better in the organic falling agent (for example, hydrocarbon or nitrile, especially acetonitrile); i = compound ★ ^ by (preferably pentachlorinated, or phosphorus oxychloride) at n (7) # : better at high temperatures (for example, in a reflux solvent (especially a hydrocarbon, for example, ^ ^ 敉 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在Better than sub-ambient temperature, high temperature or, preferably, ring 2): in: machine, water-based or mixed organic treatment of 225 (which is oxychloride (preferably oxychloride (4) or chlorooxidation (1), 仃 step. 咏The specific methods of (4) to (8) are as follows: Paper size -28- x 297) (Please read the notes on the back and fill out this page)

1293955 A7 B7 V. INSTRUCTIONS (26) (ix) The reaction flow is as follows: R 13

R9 (X) R 13

FT (y)

XXXXIII (2) R 13

XXXXIV iza) (Please read the note on the back? Please fill out this page again), 13 R·

Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed xxxxv where R9, R&quot;, R12 and R13 are as defined above, Ac is a sulfhydryl group, and Y is a halogen. Steps (χ) to (za) can be carried out using known methods, for example, 'Step (X), for example, as described in J. March, supra, pp. 53 1 , via a halogenating agent (for example, bromine or N) - Halo-succinimide, preferably N-chlorosuccinimide) is reacted; step (y), for example, as Katayama et al. in the above-mentioned book - 9 - This paper scale applies the Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1 Employees Printed! 293955 V. Inventive Note (27) As described in A7 B7, in the presence of a sulphurizing agent, the disk shield is 丨 / yt 卜 M your original agent (for example, metal hydride The reaction is carried out; step (b), for example, as described by Dyke et al. in Tetrahedron 1968 24, 1467, in the presence of mineral acid, with "homologous acid (preferably acetic acid); and step (iv), for example , as described in et al., page 566, treated with a reducing agent; or treated as described in the examples below. Certain compounds of formula V are novel compounds, including as described below Mo. Certain compounds of formula VI are novel compounds which include an intermediate as described herein. 4 8. The method variant (8) can be carried out by a known method, for example, by making the formula "the substance (wherein R3 is hydrogen) and a suitable burning agent (preferably a hydrazine or a sulphuric acid, for example, the formula R31 or The (R3) state, in which R3 is a Cl-c4-mercapto group, can be reacted in the presence of an inorganic or organic test, such as aqueous, organic or t-aqueous organic money. The firing reaction can be carried out at sub-ambient temperature t: more volatility at ambient temperature or elevated temperature. A preferred base is an alkali gold (tetra) salt. A preferred solvent is an organic dipolar aprotic dimethylformamide. Second, the hydrazine:: deuteration reaction procedure, in the presence of, for example, an organic or inorganic organic test, such as "specific oxime", the process change (4). The reaction temperature can be sub-ambient temperature. The preferred procedure is as follows in each example. H. The degree of H or preferably, the method variant (4) can be carried out by a known procedure, for example, treatment of a compound of the formula I (wherein r2 is a sulfhydryl group) with boron ammonia, followed by an oxygen monthly treatment. Under the sub-ambient temperature or, or convenient, ^ combined high-tech ring (___ -30- ^ paper scale 赖 country standard ^^^2iQx297 public hair) _ middle and lower two burning mixed N-

(Please read the note on the back? Please fill out this page again) --------Book --------- Line 1293955

V. Description of the invention (28 at ambient temperature or high temperature. The preferred borohydride agent is the second boron boron pit (example)

For example, 9-borobicyclo[2.2.0]nonane), which is preferably subjected to a reaction under reflux, is preferably subjected to an oxidation treatment using hydrogen peroxide and an alkali metal hydroxide (preferably hydrogen peroxide). The processing temperature is preferably 4 (K6〇t. I) The method variant can be carried out using a conventional esterification reaction procedure (for example, at sub-ambient temperature or preferably at ambient temperature or elevated temperature (for example, (9).c) The compound of the formula j (wherein r2 is a fluorene) is reacted with citric acid or a ruthenium compound thereof (preferably fluorenyl group) in the presence of an organic or inorganic base. Preferably, the base is an organic second test 'for example, P is determined by TT. The method variant (f) can be carried out by a known procedure for converting a mercaptoamine group into an amine group, for example, by treatment with a sulfonic acid (for example, sulfuric acid or, preferably, hydrochloric acid). It is carried out in a mixed aqueous-organic solvent (for example, aqueous ethanol). The reaction temperature is conveniently at ambient temperature or, preferably, high temperature, and particularly preferably at reflux temperature. Method variants can be carried out using known dealkylation reaction methods (§ ), for example, as described in the following examples, Preferably, it is reacted with HBr or HI by heating with a cyclic hydrobromic acid. The method variant (h) can be carried out using a known halogenation reaction procedure, for example, by reacting with bromine or chlorine in a solvent (for example, acetic acid). The reaction is conveniently carried out at ambient temperature as described in the examples. The known procedure for the Simmons Smith reaction can be used (for example, by reacting with diethylzinc and chlorine (iodomethane) to process variant (i). The reaction is usually carried out in an organic solvent, preferably a hydrocarbon. For example, as described in the examples below, the reaction is suitably carried out at ambient temperature. -31- This paper scale applies to the Chinese National Standard (CNS) A4 specification. (210 x 297 mm) ------------- ft clothing (please read the phonetic transcription on the back? Please fill out this page again) Order---------Line · Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1293955

V. INSTRUCTIONS (29 (Please read the phonetic on the back first and then fill out this page) You can use the conventional method to convert the compound in the free form! into a salt form, and vice versa. It can be hydrated or crystallized. The compound of the formula used in the form of a free or salt form can be used to recover the compound of the formula I in a free or salt form using conventional methods. Conventional methods can be used (for example, via segmentation). Crystallization) Separation of the mixture of isomers into individual isomers, for example, mirror image isomers. A compound of formula j (hereinafter may be referred to as an agent of the invention) in a free or pharmaceutically acceptable salt form can be used as a medicament. Specifically, it is an inhibitor of cyclic black scorpion 甞-3,5'-monophosphate phosphodiesterase (cGMp pDEs), particularly PDE 5. The agent of the present invention is a selective pDE5 inhibitor; In particular, it has a good selectivity against the inhibition of PDE5 with respect to the inhibition of other phosphodiesterases (especially PDE1 and PDE6). Moreover, the agent of the present invention has a suitable period of action, and in many cases, the action can be quickly carried out. The inhibitory properties of the agent of the present invention can be proved by the following test procedures: PDE5 knife printing by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative - The dms 〇 solution of the 1 〇耄 molar concentration test compound was diluted 1 〇〇 times with 20% v/v DMSO aqueous solution to obtain a 1 〇〇 micromolar stock solution, which was further passed through 20% v/v. Dilute with DMSO in water to know 10 solutions with a concentration of 1 〇 micromolar to 〇〇〇〇5 丨 micromolar. Transfer 10 μl of each of these solutions to a 95-well ptiplate microtiter plate ( Ex Packard) in the intended well. To determine total binding, add 1 〇 microliter of 20% v/v DMSO in water to other selected wells. To determine non-specific binding, make 100% DMSO of 10% molar concentration of silkenafil Solution-32- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1293955 A7 B7 V. Description of invention (3〇) diluted 20 times with 20% Wv DMSO aqueous solution, then add 1 〇 microliter The institute A solution was added to the other selected wells of the Optiplate plate. 8 μL of the analytical mixture was added (by mixing PDE assay buffer (2 mL) with 5 mg BSA/ml bovine serum albumin (BSA) in water (2 ml) ), 75 micromolar concentration of cGMP steel salt solution (〇·2 ml), 3H-cGMP (ex Amersham, 10 μL) and distilled water (丨丨·8 ml) to all wells containing test compound solution (The PDE assay buffer was prepared by dissolving Bu Xiaozhen (7.56 g) in water (800 ml), adding 1 molar concentration of MgClyX solution (10.325 ml) and 〇·5 molar concentration EDTA (4.25 ml). , with 1 zhongli; Chendu salt fel adjust the p Η to 7 · 5 ' and add water to 1 liter). Self-human platelets (11 μl, which contains 〇.〇丨7 units of pDE5 per ml, which is at 3 7 C at pH 7 · 5 per minute in 1 unit to make 1 · 〇 micromole 3 ',5'_cyclic GMP hydrolyzed to 5,-GMP) partially purified human PDE5i2 〇 millimolar concentration Hepes, pH 7.4, 100 millimolar concentration sodium chloride, 1〇0/〇v/v glycerol, 1 A milliliter concentration 芊脒 and a 2 mM concentration of dithiothreitol solution via an enzyme buffer (the preparation method is an aqueous solution of 〇. 5 molar concentration EDTA (2 ml) to Tris-base (1.21 g) (800 ml), the pH was adjusted to 7.5 with 1 equivalent of Hci, and added with water to the soar) diluted 2 times. The PDE5 dilution (10 microliters) was added to all wells containing the test compound, dms(R) or Sildenafil aqueous solution. The plate was incubated for 1 hour at room temperature. Add 500 gram PDE Shi Xi! 50 μL of green liquid from acetic acid SPA pellets (ex Amersham) in 28 ml of water to each well, and the plate was incubated for another 2 minutes, then sealed with Top Seal-S (ex Packard) according to the manufacturer's instructions. . Use Canberra Packard Top Count (one minute per well) to calculate the location (please read the note on the back and then fill out this page) Order---------Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing _ 33· Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed 1293955

&gt; A number of flicker is used as a method for determining the binding of the simple 5 to the particle. The concentration of the test compound (IC5〇) which was inhibited by the method of f from the concentration_suppressing curve_definite 5 and the knot of the granule was suppressed by 5%. The compounds of each of the following examples have lca in the order of micromolar to 10 micromolar in the above analysis. For example, in the above analysis, the ICw値 of the examples...0,15,35'4 5,49,5 5,60,6 8 and 70•^ compounds are respectively 0.007 micromolar concentration, 〇〇1 micromolar concentration , 0.006 micromolar concentration, 〇〇1〇 micromolar concentration, 〇〇〇2 micromolar concentration f, 0.0037 micromolar concentration, 〇·〇〇 55 micromolar concentration, 〇〇〇28 micromolar; Chen Degree ' 0.007 micromolar concentration and 〇〇〇 9 micromolar concentration. Regarding its inhibition of PDE5, the agents of the invention may be used to treat conditions mediated by PDE5. The treatment according to the invention may be symptomatic or prophylactic. Too long, the agents of the invention may be used to treat sexual dysfunction (including male erectile dysfunction and female sexual dysfunction), premature birth, dysmenorrhea, benign prostatic gland proliferation, bladder outlet obstruction, incontinence, stability, restlessness and difference ( Prinzmetal) angina, hypertension, high blood pressure in the pulmonary circulation, congestive heart failure, atherosclerosis, reduced vascular opening (eg, from percutaneous transluminal coronary angioplasty), peripheral vascular disease, bronchitis, Qi%, allergic rhinitis, glaucoma, tinnitus, intestinal motility disorders (eg, irritable bowel syndrome), eclampsia aura, Kawasaki syndrome, nitric acid tolerance, multiple sclerosis, peripheral neuropathy, Stroke, Alzheimer's disease, acute respiratory failure, psoriasis, and necrosis, cancer, metastases, hair loss, nutcracker esophagus, anal fissures and tight blood vessels

(Please read the phonetic on the back first? Then fill in this page) --------Book --------- Line 1

This paper scale applicable standard (CNS) A4 specification curry tearing, especially male boss, Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing 1293955

The agents of the invention are particularly useful for treating dysfunction as a dysfunction. According to the foregoing, the present invention also provides a therapeutic method (for example, the above-mentioned and 踝J &lt; dysfunction dysfunction, positive, L, sexual dysfunction, especially for the dysfunction) . It includes the application of an effective amount of free energy to the mouth of the person (Yuba, person) to vote for you, resentment or the main medical form of acceptable salt type; [Chemical and Ming Ming on the other hand, ^ ^ The disease of the vector / η J is used to cure the treatment of the drug via PDE5 r, the above mentioned conditions, especially sexual dysfunction, erectile dysfunction (4); A compound of the formula I can be administered in a salt form. The agent of the invention can be administered in any combination, for example, in the form of a capsule, a solution or a suspension, or a parenteral injection, such as an intravenous injection. Intra-injection, intramuscular injection or Piwang shot; #内内', for example, in the form of a mist-like inhalation or aqueous dispersion, and for therapeutic use, for example, a mist inhaler, an atomized aqueous dispersion or... Water U's buccal or sublingual administration, for example, in the form of a lozenge or tablet: f is applied to the skin, for example, in the form of an emulsion or ointment; or in the form of a rectum, for example, in the form of a suppository. In another aspect, providing a salt-containing form in a free form or in a pharmaceutical form, and There is a need for a pharmaceutical composition in which a pharmaceutically acceptable diluent or carrier thereof is used as an active ingredient. Such compositions can be prepared using conventional excipients and techniques known in the art of galenic. Thus, oral dosage forms can include lozenges and Capsule. The composition for inhalation may include a mist

35·

Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1293955 A7 ----------- —__Β7 V. Invention description (33) ~—Inhalation or other atomizable formulation or dry powder formulation. A composition suitable for use in the skin sector may include an emulsion, ointment or gel. • The monthly agent may also be combined with other (iv) 5 inhibitors or other therapeutic agents suitable for therapeutic dysfunction (especially male erectile dysfunction), for example, “adrenergic receptor antagonists, for example, fentanyl methyl a sulfonate; a dopa feD2 agonist, for example, apomorphine; or a no-body, for example, l-arginine. The agent of the invention may be mixed with an adjuvant in a pharmaceutical composition 7 or may be treated with bismuth The agents are administered separately, simultaneously or thereafter. The invention is illustrated by the following examples. The intermediate of formula V is prepared as follows: Intermediate 1_ Add methyl allysamine (211 g, 2_97 mol) to concentrated hydrochloric acid (25 ml) Water (1 · 9 liters) solution, then add cyanate _ (240 g, 2.97 mol) one by one. Then heat the reaction for 2 hours at 8 Torr, then cool and yTT, wool, Produce (2_methyl-lessbupro)-month urine (244.5 g), dissolve point ιΐ4_115 ° C. Add the urea (268 g, 2.35 mol) to cyanoacetic acid (22 g, 2.59 mol) a solution of acetic anhydride (536 ml) and heat the reaction for 1 hour at 7 (rc) Cool to hydrazine and dilute with ether. Collect the solid formed by filtration, wash with ether, suspend in water (2.2 liters), and heat to 75 C. Then add 2 mM in 30 minutes. The ear concentration is 氲 aqueous sodium hydroxide solution to maintain the pH between 8 and 9.5. The reaction is cooled to room temperature, treated with acetic acid (12 mL), cooled to hydrazine, and the solid formed is collected by filtration. Washed with cold water and dried to give 6-amino-methyl-mercaptopropyl)-1Η-pyrimidine-2,4-dione, melting point 267-269 ° C. Adding uracil-36- This paper size is applicable to China Standard (CNS) A4 specification (210 X 297 mm) ------1----------------- line (please read the notes on the back and fill in the form) Page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1293955

5. Description of the invention (34) (253 g ' 1.40 mol) to a solution of sodium hydroxide (123 g, 3.07 mol) in water (25 liters) and allowed to exotherm, then cooled to 2 〇 °C. Take! Dimethyl sulfate (196 ml, 2 · 06 mol) was added portion by hour. After standing overnight, the reaction was cooled to 5 Torr, and the solid was collected by filtration to give 6-amino-3-methyl-1-(2-methyl-propyl propylidene-2,4 - Copper, melting point 162-163 ° C. The methyl uracil (165 g, 〇·85 mol) was suspended in water (1.55 liters) and concentrated hydrochloric acid (72 ml), then added dropwise in 30 minutes. A solution of sodium nitrate (58.4 g, 0.85 mol) in water (in ml) was stirred for 3 h at 20 C. The solid was collected by filtration and washed sequentially with water, methanol and ether to give 6-amine. -3·methyl-1-(2-methyl- propyl)-5-nitroso-1H-pyrimidine·2,4-dione, melting point 213 ° C (decomposition). Pyrimidine (190 g, 0.85 mol) was suspended in water (950 ml), heated to 85 ° C, and sodium dithionite (85 〇 / 〇, 347.2 g, 1.69 mol) was added portion by portion. After standing to room temperature, the solid was collected by filtration to give 5,6-diamino-3-methyl-1-(2-methyl-allyl)-lH-pyrimidine-2,4-dione, melting point 152-153 ° C. Intermediate 2 using the general procedure for preparing intermediate 1 to make (3 - nitrate Indole)-urea [J. Med. Chem. 1996, 3 9, 1924] is converted to 6-amino-3-methyl-1·(3-nitro-benzyl)-1Η-pyrimidine-2,4- Diketone, [Μ-ΗΓ 275. A suspension of this compound (4·88 g, 17.7 mmol) and 1% Pd/C (0.484 g) in ethanol (200 ml) was hydrogenated at 1 atmosphere for 1.5 hours. The reaction mixture was filtered through celite, and evaporated to give 6-amino-1-(3-amino-indenyl)-3-methyl-1H-pyrimidine-2,4-di Ketone acetate [Μ-ΗΓ 245. Add acetic acid-37- 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)

1293955 Α7 Β7 V. Description of the invention (35) Anhydride (1.85 ml, 19.57 mmol) to 6-amino-1_(3-aminoindolyl)_3-methyl-1H-pyrimidine-2,4-di Ketone acetate (5.01 g, 16.35 mmol) of leaf acridine (50 ml) in a cold (0 °C) suspension. The reaction mixture was allowed to warm to room temperature, stirred for 6 hours and then evaporated. The residue was triturated with water and the solid was collected by filtration then dried to give N-[3-(6-amino-3-methyl-2,4-dioxy-3,4-dihydro-2H -Pyridine-1-ylmethyl)-phenyl]acetamide, 1H NMR (400 Mhz, DMSO) j 2.00 (s 3H), 3.09 (s 3H), 4·72 (s 1H), 5.02 (s 2H) , 6.75 (s 2H), 6.88 (d J 6 1H), 7.25 (t J 6 1H), 7.30 (s 1H), 7.55 (d «7 6 1H). The compound was converted to N-[3-(5,6-diamino-3methyl- 2,4-dioxy-3,4-dihydro-2H- using the general procedure for the preparation of intermediate i). Pyrimidine-1-ylmethyl)-phenyl]-acetamide [MH]+ 304. Intermediate 3 using the general procedure for the preparation of intermediate 1 to give (4-nitro-indenyl)-urea [j

Med_Chem. 1996, 3 9, 1924] converted to 6-amino-3-methyl-1-(4-nitro-benzyl)-1 fluorene-pyrimidine-2,4-dione, [MH]+ 277 . Add a solution of calcium chloride (4.94 g, 45 mmol) in water (100 ml) to 6-amino-3-methyl-1-(4-nitro-benzyl)-1 Η-pyrimidine-2,4 Diacetone (19.08 g, 69.0 mmol) of acetic acid (300 ml) was dropped. Then add zinc powder ($$ · $g, 900 mmol) one by one and perform external cooling. The reaction was stirred at room temperature for 1.5 hours and filtered through a plug of Celite, and washed successively with ethanol and acetic acid. Evaporating the combined filtrate and washing solution to obtain 6-amino-[丨-(4-nitro-benzyl)-3-methyl-1H.pyrimidine-2,4-dione acetate, [Μ- 3ΗΓ 243. Add acetic anhydride (7.2 ml, 76.0 mmol) to 6-amino-indole_('nitro-benzyl-38- this paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 public)) -----------% (Please read the note on the back? Please fill out this page again) Order---------Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1293955 Α7 Β7 V. Description of invention (36) yl)-3-methyl-1H-pyrimidine_2,4-dione acetate (1·7 g, 69 〇 mmol) P. pyridin (260 ml) cold (( Rc) in the suspension. The reaction mixture was allowed to warm to a temperate temperature and stirred for 6 hours, then the solvent was evaporated. The residue was triturated with water and the solid was collected by filtration and then dried to give N-[4_(6-amine _ 3-Methyl-2,4-dioxy·3, dihydrogen-2H-pyrimidinylmethyl)-phenyl]•acetamidine, [MH]+ 289. General use of preparation intermediate i Procedure for converting the compound to N-[4-(5,6-diamino-3-methyl-2,4-dioxy-3,4-dihydro-2H-pyrimidin-1-ylmethyl) ) phenyl phenyl acetamide, [MH] + 304. Intermediate 4 first added 2-pyridyldiphenylphosphine (3·6 gram, 13·7 mmol) and cyclopentane k methanol (1.33⁄4 liters, 13.8 moles) to 6-chloromercaptouracil (2. gram, 12 millimoles) of THF/dioxane (ι: 1,16 ml) cold (〇τ) In the slurry, followed by the addition of di-tertiary-butyl azodicarboxylate (3.15 g, 13.7 mmol). The reaction was stirred overnight at ambient temperature and passed through a 4 mM concentration of HC1 4 k (1 5 liters) of treatment, and evaporation. The residue was extracted in dichloromethane, washed with EtOAc EtOAc (EtOAc), dried over magnesium sulfate and evaporated. Purification of the crude product by methane·methanol elution afforded 6-chloro-1-cyclobutylmethyl-3-methyl-1H-pyrimidine-2,4-dione, 1H NMR (400 MHz, CDCl3)d 1.70-2.0 (m 6H), 2.60 (m 1H), 3.20 (s 3H), 4.00 (d / 7 2H), 5.78 (s 1H), dissolved in n-butanol (50 ml). Rusamine (4 liters, 26.5 mmol), and the reaction was heated to reflux for 16 hours. The solvent was evaporated and the residue was taken in dichloromethane and washed with 1 mM aqueous HCl. Article, -------------3⁄4 (Please read the notes on the back and then fill in Page) 11111 line. Economic Intellectual Property Office employee consumer cooperative printed -39- 1293955 A7 B7 V. invention is described in (37 Intellectual Property Office employee Economic Co-op printed over magnesium sulfate and evaporated. The crude product was purified by a flash chromatography (50:1 methylene chloride-methanol elution) to afford 1- </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; 4-Dihydrogen, 1H NMR (400MHz, CDC13) d 1.60-1.80 (m 4Η), 1.80-2.00 (m 2Η), 2.50 (m 1H)? 3.21 (s 3H)5 3.80 (s 6H)5 3.85 ( d J 7 2H)? 4.11 (d J 5 1H)5 4.25 (m 1H)5 4.84 (s 1H)? 6.74 (s 1H)? 6.80 (s 2H) 'Make it dissolved in formic acid (5 〇 ml), And add pd black (〇26 grams). At 40. (:, when the reaction is heated to a temperature of 2 ', filtered through Celite, evaporated and purified by preparative HPLC to give 6-aminosuccinylmethyl-3-methyl-1H-pyrimidine-2,4 -Dione, M+ 209, converted to 5,6-diamino-indole-cyclobutylmethyl-3-methyl-1H-Shuangdong-2 +dione using a general procedure for the preparation of Intermediate 1, HPLC retention Time 〇·ΐ 7 minutes (30-95% acetonitrile water gradient in 4 minutes) Intermediate 5 Use the general procedure for preparing intermediate 1 from (tetrahydrofuranylmethylurea (Collect. Czech. Chem. Commun) 1972, 37, 2786) Preparation of 5,6-monoamino-3-methyl-i-(tetrahydrofuran-2-ylmethyl)_m-pyrimidine-2,4·di, the same, melting point 1 15-116° C. Intermediate 6^ Preparation of 5,6-diamino-3-methyl-d-(2-methyl-butyl)-1 -pyrimidine-2,4-dione using the general procedure for the preparation of intermediate 1 Melting point 163-165. (: Intermediate Ί - General procedure for the preparation of intermediate 1, from 6-amino-indole-hexyl-1H-pyrimidine-2,4-dione Med chem· 1993, 36, 1465 ) Preparation of 5,6-diamine-1- -40- This paper ruler Wei + National Standard (CNS) A4 specification (210 X 297 mm) {Please Notes on the back read and re-fill of this page) 11- · • and

I 1293955 A7 B7 V. INSTRUCTIONS (38) Hexyl-3-methyl-1H-pyrimidine-2,4·dione, HPLC retention time (0-95% acetonitrile water gradient in 8 minutes) ° Intermediate 8 5,6 was prepared from (3,4-dimethoxy-yl-yl)-urea (?&amp;〇1^〇, £(1.8(^.1977,32,813) using the general procedure for the preparation of intermediate 1 -diamino]1-(3,4-dimethoxy-indenyl)-3-methyl-indole-p-dense 2,4-dione, [MH]' 305 0 Intermediate 9 Preparation General procedure for intermediate 1, preparation of 5,6-diamino-indole-benzoquinone [1,3]dioxy-indolyl-5-ylmethyl-3-indenyl-Up-dense _2,4-di Ketone, melting point 183_186〇C 〇Intermediate 1 0 Preparation of 5,6-diamino-M2, 'dichloro-yl-yl)-3-methyl-1H-salt-2 using the general procedure for the preparation of intermediate 1 , 4-dione, 1H nmr (400MHz DMS〇-d6M 3.16 (s 3H), 5.05 (s 2H), 6 18 (s 2h), 6 82 (dj 9 1H), 7.38 (d J 9 1H), 7.62 (s 1H) 制备Other intermediates can be prepared according to the literature references as described below. (Please read the note on the back? Please fill out this page again) --------Book----- ----Line j Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing - 41- 1293955 A7 -____ _B7__ V. INSTRUCTIONS (39) No. R1 R2 Reference 11 12 13 14 15 16 17 CH3 Η CH3 ch3 ch3 (ch3)2chch2 ch3 (CH3)2CHCH2 ch3 ch2=chch2 —CH2 (CH3) 3CCH2 (CH3)2CHCH2

CH. (1)(2)(3)(1)(1)(l)(l) 18 19 H CH3 ch3ch2ch2 ch3o

(2) (4) -------------% (Please read the notes on the back and fill out this page) References: (1) Eur. J. Med. Chem. 1990, 25, 653 (2) J. Med·Chem· 1996, 39, 2 (3) FR 2 53 1 085 (4) Eur. J. Med. Chem. -Chim. Ther. 1974,9,313 Intermediate of formula VI The preparation method is as follows: Intermediate 2 0 Ethyl 3-(3,4-dimethoxy-phenyl)-5-nitro-pentanoate [j· Med·Chem, 1989, 32, 1450] (0.50 A mixture of gram (1.68 mmol) and tin (II) chloride dihydrate (1.90 g of '8.4 mil) in ethanol (1 mL) was heated to reflux for 2 hrs, cooled to ambient temperature and evaporated. The crude product was extracted in dichloromethane (1 cc), cooled to 〇 ° C and added triethylamine (5 ml) and ordered ------------- Department of Economic Affairs Intellectual Property Bureau employee consumption cooperative Printing -42· 1293955 A7 --------B7__—____ V. Description of the invention (4〇) 3,5-Dimethoxybenzhydrazide chloride (0.404 g, 2.02 mmol). The reaction was stirred at ambient temperature overnight, then evaporated and evaporated with ethyl acetate. Evaporation and purification by flash column chromatography (i^hexane-ethyl acetate elution) to give 4-(3,5-dimethoxy-benzylamino)-3-(3,4 -Dimethoxy-phenyl)-butyric acid ethyl ester, [mh] + 432. The intermediate was extracted in acetonitrile (8 mL) (〇························ . After the solvent was evaporated, the residue was extracted with ethyl acetate and washed with a saturated aqueous solution of &lt;RTI ID=0.0&gt;;;;;;;;;;; -6,7-Dimethoxy-3,4-dihydro-iso-p-quineline__4-yl]-ethyl acetate, [MH]+414. The intermediate (0.50 g, 11.21 mmol) was dissolved in decahydroquinone (10 mL) and 1 〇〇 / 0 pd / C (5 gram) was added. The reaction was heated at 190 °C for 2.5 hours, then cooled to ambient temperature and diluted with dichloromethane. After filtration through Celite, the combined filtrate and washings are evaporated to obtain [丨-^% dimethoxy-phenyl)-6,7_monomethoxy-iso-quinoline-4 -Methyl acetate, 4 NMR (400MHz, CDC13) d 1.18 (t J 7 3H), 3.78 (s 6H)5 3.80 (s 3H)? 3.90 (s 2H), 3.99 (s 3H), 4.10 ( qJ7 2H), 6.50 (d, JO. 5, 1H), 6.75 (d, 0.5 2H), 7.20 (s 1H), 7.36 (s 1H), 8.40 (s, 1H). The intermediate (〇·30 g, 〇·73 mmol) was dissolved in methanol (10 mL), and the mixture was stirred and stirred at ambient temperature. The reaction was overnight. After the methanol was evaporated, the pH of the remaining solution was adjusted to 7 using a 1 molar aqueous solution of HCl, and the formed solid was collected by filtration, followed by drying to give [1-(3,5-dimethoxy-phenyl). _6,7_Dimethoxy-43- 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 j Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Ministry of Printing Economy Intellectual Property Bureau Consumer Cooperatives Printed 1293955 A7 ————_ B7___ V. Description of Invention (41) -Isoquinolin-4-ylbu-acetate. Earth, things 2 1

3-Isopropoxy-4-methoxy-benzaldehyde (3.9 g, 20 mmol) and (ethoxycarbonylmethylene)triphenylphosphane (6.96 g, 20 mmol) under reflux The toluene (100 ml) mixture of the ear was heated for 2 hours, cooled to ambient temperature and evaporated. The crude product was extracted in dichloromethane and eluted with yttrium oxide pad to afford ethyl (E)-3-(3-isopropoxy-4-methoxyphenyl)-propionate, TLC Rf 0·70 (1:1 hexane-ethyl acetate). The intermediate was dissolved in nitromethane (10 mL), 1,1,3,3-tetramethylhydrazine (5 ml) was added, and the reaction was heated at 70 ° C for 36 hours. . The solvent was evaporated, and the residue was extracted with ethyl acetate, and washed with 2? After drying over sodium sulphate and evaporation, the crude product was purified by flash column chromatography (4:1 hexanes-ethyl acetate elution) to give 3-(3-isopropoxy-4-methoxy -Phenyl)-4-nitro-butyric acid ethyl acetate, 1h NMR (400MHz, CDCl3) cn.20 (t /7 3H), 1.38 (d J7 6H), 2.75 (d J 6 2H), 3.90 (mlH ), 4.10 (m2H), 4.48-4.78 (m3H), 6.75- 6.86 (m 3H). The intermediate was converted to [1-(3,5-diisopropoxy-phenyl)-6-isopropoxy-7-methoxy-iso-hydroxyquinoline using the general procedure for the preparation of intermediate 20. Base] acetic acid. This ethyl ester [MH] + 496 is characterized. Intermediate 2 2 Add a solution of 3-ethoxy-4-methoxybenzoic acid (3.6 g, 20 mmol) in ethanol (15 mL) to 2,2-dimethoxyethylamine (21 mmol) The mixture was heated under reflux for 2 hours. After cooling to room temperature, sodium borohydride (0.794 g, 21 mmol) was added and stirred at room temperature overnight. By -44- This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back and fill out this page) ϋ n ·ϋ n ϋ I ϋ^OJa .^1 ϋ ϋ ί 1293955 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Clothing A7 B7 V. INSTRUCTIONS (42) Evaporate to remove ethanol, add water, and then extract with acetic acid. The organic extract is combined, washed with water, brine, dried over magnesium sulfate and evaporated to give (2,2-dimethoxy-ethyl)-(3-ethoxy-4-methoxy-indenyl) )-Amine, [MH]+ 270. The intermediate (2.70 g, 1 〇 mmol) was suspended in 6 equivalents of HCl (50 mL), acetic acid (〇·88 g, 12 mmol) was added, and the mixture was heated at 100 C. 1 hour. After cooling to room temperature, methanol (30 mL) was added, and the mixture was filtered, which was characterized by the methyl ester. The filtrate and the filtrate were treated with ammoxidation clock (1 Torr) in THF-methanol-water for one night. After the solvent was evaporated, the crude product was partitioned between water and a mouse. The aqueous phase is washed with dimethyl ketone and evaporated to dryness to give (7-ethoxy-6-methoxy-iso-p- cylin-4-yl)- ruthenium acetate salt without further characterization. Can be used to form a yellow U ticket. Intermediate 2 3 chloroform (20 ml) of (6,7-dimethoxy-isoindol-4-yl)-acetate (Tetrahedron 1973, 29, 3881) (1.668 g, 6.07 mmol) The solution was treated with m-chloroperoxybenzoic acid (1.153 g, 6.67 mmol) in one portion for 5 hours. The reaction mixture was washed with saturated sodium bicarbonate and brine, dried over EtOAc EtOAc EtOAc EtOAc 96%). All the product was dissolved in chloroform (30 mL), taken to EtOAc (3 mL, 32.3 m After evaporation, dichloromethane and ice water were added, and the mixture was basified with aqueous ammonia. The aqueous phase was further extracted with dichloromethane, and the combined organic phase was washed with brine, dried over magnesium sulfate, and evaporated to give (1 - gas-6,7-methoxy-iso- 4-lin-4-yl) - Acetic acid B. Make this chlorine g-45- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public) (please read the phonetic on the back? Please fill out this page)

1293955

V. INSTRUCTIONS (43) The organism (〇·50 g, 1.6 mmol) was suspended in 2 molar concentrations of sodium hydroxide (dm). Ethanol (5 ml) was added and the solution was stirred at room temperature for 2 hours, and the solvent was evaporated. The 1) 11 to 2 is adjusted with concentrated hydrochloric acid to give a solid which can be collected by filtration and dried to give (?-chloro-6,7-dimethoxy-isoquinolin-4-yl)-acetic acid. iH NMR (4〇〇MHz, DMS〇d6) j : 3 % (s 3H), 3.96 (s 3H), 4.02 (s 2H), 7·31 (s 1Η), 7·44 (s 1H), 8 · 04 (s 1H). Intermediate 2 4 (2,2-Dimethoxy-ethyl)-(3.methoxy+yl)-amine (Tetrahedron 1973, 29, 3) treated with pyruvic acid according to the general procedure for the preparation of intermediate 2 2 881) 'Get 2-(7-methoxy-isoindoline-4-yl)-propionic acid hydrochloride, m.p. 174-176. Treatment with HCl in ethanol to give the corresponding ethyl ester hydrochloride, m.p. 190-192 ° C, and then, as in the preparation of the intermediates of intermediates 2, to be continuous with m-chloroperoxybenzoic acid and oxygen. The hydrazine chloride reaction gave 2-(1-chloro-7-methoxy-isoquinolinyl)-propionic acid ethyl ester, m.p. The intermediate (47 g, 0.16 mol) was dissolved in ethanol (4 mL) and 2 equivalents of sodium hydroxide (50 mL) was added, then the mixture was heated at 6 °C. After an hour, the solvent was evaporated. The crystallization reaction from acetone is carried out to 2-(1-chloro-7-methoxy-iso-p-quinolin-4-yl)-propionic acid, melting point 167-168. . . Intermediate 2 5 Add dimethyl sulfate (12.7 ml, 〇.1 〇 mol) to 2_(7-methoxy-2-hydroxy-isoindol-4-yl)-propionic acid ethyl ester. (28 g, 〇.1〇莫耳), and exothermed to 100 °C. Maintain the reaction at this temperature for 2 hours, cool 46- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------------% (please read first Precautions on the back side Fill in this page) Order---------Line· Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1293955 A7 __________B7________ V. Invention Description (44) To warm and soluble in water ( 50 ml). A solution of sodium cyanide (i 5 g, 0.31 mol) in water (90 ml) was added over 3 minutes, and externally cooled, then the reaction was stirred at room temperature for 3 hours. The crude product was extracted with EtOAc (EtOAc)EtOAc. The crystallization reaction was carried out from 3 equivalents of an ethanol-based HCl-ether to give ethyl 2-yt-cyano-7-methoxy-isoquinolin-4-yl)-propionic acid hydrochloride, m.p.: 89-98. The compound is hydrolyzed to the acid as described in the general procedure for the preparation of intermediate 22, and the crude product is used directly to form xanthine. Intermediate 2 6 Add sodium triethylborohydride solution (丨 molar concentration THF, 12 7 liters, 12.7 mmol) to isoquinoline (1.64 g, 12.7 mmol) 1^17 (25 ML) solution. The reaction was stirred at room temperature for 1 hour, and then a solution of ethyl glyoxylate (丨.43 g, 13.9 mmol) of toluene which had been previously heated at 110 ° C for 1 β for 5 hours was added dropwise. After 4 hours at room temperature, the reaction was cooled to 0 C, and then sodium hydroxide (aqueous solution of 〇·5 mol concentration, 25.4 ml) and hydrogen peroxide (3 〇% aqueous solution, 127 ml) were added. Then mix for 2 hours. The reaction was acidified with 1 equivalent of HCl and washed three times with ethyl acetate. The volume of the aqueous phase was reduced by evaporation and cooled overnight. The precipitate formed was collected by filtration and dried to give isoquinoline-4-yl-acetic acid salt, MH.s. Intermediate 2 7 Add excess morpholine to (1_chloro-6,7-dimethoxy-isoquinolin-4-yl)-ethyl acetate (0.200 g, 〇·65 mmol) toluene (1 The suspension is allowed to warm up and the mixture is heated to reflux until the starting material is consumed. Evaporation-47- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) -------------· (Please read the note on the back and fill out this page) Order ---------Line· Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed 1293955 Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperative Printed A7 B7 V. Invention Description (45) After 'Distributing the residue The organic phase was dried over magnesium sulfate between water and dichloromethane, and evaporated to give (6,7-dimethoxy-4-4-yl-iso-hydroxypyran-4-yl)-ethyl acetate [ ΜΗ]+ 361. The crude ester (24 g, 〇 66 mmol) was dissolved in ethanol (2 mL) and treated with EtOAc (3 mL). After adjusting to ρΗ 1 with concentrated hydrochloric acid, the solvent was evaporated, and the crude acid was directly used to form the xanthine derivative. Intermediate 2 8

Repeat the procedure for preparing the intermediate 27, using an excess of Ν-methylhexahydropyrene to replace the morpholine to obtain [6,7-dimethoxy-1-(4-methyl-hexahydropyrazine) -^ base)-iso-p-quino-p-cyl- 4·yl]-acetate-ethyl acetate (〇·1% gram, 38%) NMR (DMSO-d6) cM.19 (tJ7 3H), 2.30 (s3H), 2.61 ( m4H), 3.10- 3.30 (m 4H)? 3.92 (s 6H)? 3.97 (s 2H)? 4.10 (q J 7 2H)? 7.19 (31 deduction, 7.37〇1 deduction, 7.91〇111). The ester (0.186 g, 〇.5 〇 mmol) was dissolved in ethanol (20 mL) and treated with EtOAc (3 mL) and then stirred at room temperature; After adjusting to pH 1 with concentrated hydrochloric acid, the solvent was evaporated, and the crude acid was directly used to form the xanthine derivative. 0 Intermediate 2 9 N-chloroammonium imine (0.347 g, 2.60 mmol) To a solution of 6-methoxyiso-hydroxypyrazine (Synth. Commun. 1999, 29, 1617) (0.207 ^, ΐ·3〇 mmol) in acetic acid (9 ml). The reaction was heated at 50 °C for 3 hours &lt;cooling to a soil temperature&apos; to evaporate and partition between &lt;RTI ID=0.0&gt;&gt; Wash the organic phase with water and brine, and apply the Chinese National Standard (CNS) A4 specification (210 X 297 mm) on the sulfur-48-paper scale -1———------------ -Book--------- (Please read the phonetic on the back? Please fill out this page again) 1293955

5. Description of the invention (46) The magnesium silicate is dried and evaporated to give 5 _ chloro-6-methoxyisoquinoline, [MH] + . The intermediate (0.175 g, 0.90 mmol) in THF (4.5 mL) and acetic anhydride (EtOAc············· The solution was stirred and the reaction was stirred at ambient temperature for 2 hours. The solvent was evaporated, and the residue was extracted with ethyl acetate (yield), then washed with a 0.5 mM aqueous hydrochloric acid and brine, and dried over magnesium sulfate. Evaporation to give 1-(5-chloro-6-methoxy-1H-isoindole-2-yl)-B-, m.p. 78-80 (m.). , 0.60 mmol, and a suspension of glyoxylic acid (76 mg, 0.80 mmol) in 6 molar aqueous hydrochloric acid (2.8 mL) was heated for 3 hours. After cooling to ambient temperature, it was collected by filtration. Solid (5-chloro-6-methoxy-isoindoline-4-yl)-acetic acid, [MH]+ 252. The intermediate was treated with 10% Pd / C (0.730 g) (0.970 g ' 3.383⁄4 Mohr) and ammonium formate (Ig 5 g, 16.9 mmol) of 1:1 acetic acid, water (25 ml) suspension, and stir-fry for 6 hours at ambient temperature. After filtration of the soil (Celite@), the combined filtrate and washings were evaporated and purified by Soxhlet extraction using acetone to give (6-methoxy-isoquinolinyl)-acetic acid [MH] + 218. Reduction of (5-chlorojmethoxy-isoquinoline-4-yl)-acetic acid to give (6-methoxy-isoindoline-4-yl)-acetic acid in the step of stirring (5_ Chloro-6-methoxy-isoindoline-4-yl)-acetic acid (20 g, 69.4 mmol) )! Suspension of sodium hydroxide solution (400 ml) for 20 minutes, the salt formed is filtered off, and then treated with hydrogen under normal pressure in the presence of 10% Pd/C (1.4 g). The suspension formed by the filtration of the diatomaceous earth was washed with water (15 liters), then the solution was cooled in a water bath and slowly neutralized (3 〇 minutes), then 鲈49- the paper size was applied to the Chinese country. Standard (CNS) A4 specifications (210 X 297 public ------------------------ order--------- line (please read the back of the note first) Matters fill out this page) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1293955 A7

V. Description of the invention (47) 5 molar hydrochloric acid (80 ml) acidified. A suspension was formed and allowed to stand at 5 Torr for 20 hours to accelerate the crystallization reaction. The formed crystals were removed by filtration and washed with ice-cold ethanol (25 ml) to dryness under reduced ink to give (6-methoxy-isoquinolin-4-yl)-acetic acid. _ Intermediate 3 0 Add acetic acid (1_37 g ' 9.284: Molar) to 1-(6-gas _1 | ^ 峻 淋 ― - 2- base) · Ethyl ketone [J. Org. Chem·, 1980, 45,1950] (1_44 g, 5 90 mmol) 6 equivalents of HC1 (24 ml) in a mixture. The reaction was heated at 100 ° C for 3 hours, cooled to R T, washed with ether and evaporated to EtOAc. After freezing overnight, the solid was collected by filtration and dried to give (6-chloro-iso-p-pylin-4-yl)-acetic acid hydrochloride. 4 NMR (400MHz, DMS0)d: 4.45 (s 2H), 8.18 (d J 9 1H)? 8.52 (s 1H), 8.70 (d J 8 1H)5 8.83 (s 1H), 9.96 (s 1H). Intermediate 3 1 Add sodium borohydride (1·12 g, 29.6 mmol) to 6-bromoiso-juntoin [J Chem Soc Perkin Trans 2, 1998, 437] (1.544 g, 7.42 m) A solution of acetic acid (10 ml) and acetic anhydride (3 ml) in cold (〇 ° C). After heating at 60 ° C for 4 hours, the mixture was cooled, evaporated and diluted with water. After adjusting to pH 10 with potassium carbonate, the organic phase was washed twice with ethyl acetate and brine, and then dried over sodium sulfate. Evaporation gave 1-(6-bromo-1H-isoindoline-2-yl)-ethanone, MH+ 253. Adding 6 equivalents of glyoxylic acid (0.812 g, 8.80 mmol) to b (6-溪-1Η·isostone-2_yl)-ethanone (1.50 g, 5.90 mmol) 11 &lt; ::1 (20 ml) in the mixture. Heat the reaction at 100 ° C for 2 hours 'cooling to -50 - 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) - --I----订---------Line j Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1293955 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed A7 B7 V. Invention Description (48) RT And washed with ethyl acetate. After evaporation, the residue was taken in MeOH (2 mL), concentrated EtOAc (EtOAc) After the solvent was partially evaporated, the solid formed was collected by filtration, washed with methanol and dried to give (6-bromo-isoindol-4-yl)-methyl acetate hydrochloride, MH. Add hydrazine hydroxide hydrate (8.5 mg, 0.20 mmol) to (6-bromo-isoindol-4-yl)-methyl acetate (50 mg, 0.18 mmol) in 3:1 THF-water ( 3 ml) cold (in TC) solution. After 1 hour, evaporate the solvent to obtain (6-bromo-isoindole_4-yl)•lithium acetate, ΜΗ+266° intermediate 3 2 Methyl methacrylate block (0.17 liters, 1.23 mmol) and copper iodide (I) (40 mg, 0.20 mmol) with (Ph3P)2PdCl2 (73 mg, 〇·1 mmol) (6-Bromo-isoquinolin-4-yl)-acetic acid methyl ester (0.325 g, 1·〇3 mmol) in DMF (1.75 mL) and triethylamine (1 mL) suspension. The reaction was heated at 5 ° C for 40 minutes, cooled to ambient temperature and diluted with ethyl acetate. After washing with water and brine, the organic phase was dried over sulphuric acid, evaporated and passed through a column or analysis (1: Purification by 1 ethyl acetate-hexane elution to obtain (6-trimethylphosphonyl ethynyl-isoindolyl acetate methyl ester. [MH] + 298. The intermediate (〇_221 g) , 〇·74 mmol) dissolved in methanol (7.5 m升中), and treated with potassium carbonate (75 g, 0.54 mmol). The reaction was stirred at ambient temperature for 30 minutes, evaporated and subjected to a flash chromatography (5:1 dichloromethane-methanol elution) Purification to give (6-ethynyl-isoquinolin-4-yl)-acetic acid, [MH]+ 212. Intermediate 3 3 -51- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297) PCT) (Please read the notes on the back and fill out this page)

1293955 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed A7 B7 V. Description of Invention (49) Add bromine (0.211 ml, 6.28 mol) of dichloromethane (1 ml) to 6-methoxyisoindole 4 wood [Synth· Commun. 1999, 29, 1617] The solution was stirred in a cold (〇 ° C) solution at ambient temperature for 2 hrs. After injecting into a 1 molar aqueous solution of sodium hydroxide, the organic phase was washed with brine, dried over magnesium sulfate and evaporated. The crude product was purified via a flash column chromatography (2:1 dichloromethane-methanol elution) to afford 5-bromo-6-methoxyisophthalline, [MH]+ 240. This material was then converted to (5-bromo-6-methoxy-isoquinolin-4-yl)-acetic acid [MH] + 298 according to the procedure for the preparation of Intermediate 29. Intermediate 3 4

Preparation of [1_(3,5-diisopropoxy- sylyl)-6,7-dimethoxy-iso-p-quinolin-4-yl]-acetic acid using a general procedure for the preparation of intermediate 20, NMR (400 MHz) , CDCl3)d 1.25 (dJ6 12H), 3.78 (s 3H), 3.86 (s 2H) 3.92 (s 3H)5 6.46 (d J 0.5 1H)? 6.65 (d J 0.5 2H), 7.20 (s 2H)? 8 · 30 (s 1H) 〇 The following materials were prepared in a similar manner to the preparation of intermediate 2 1 : Soil 3 1-(3,5-dimethoxy-phenyl)-6-isopropoxy-7- Oxy-isoquinolin-4-yl]-acetic acid, [MH]+ 412. Sister 3·^ (b-tert-butylisopropoxy-7-methoxyisoisoporphyrin-4-ylacetic acid, NMR (4〇〇MHz, CDCl3) (M 32 (d 6h), 1.52 (s 9H), 3.80 (s 2H), 3.90 (s 3H), 4.75 (seven peak j 7 1H), 7·28 (s 1H), 7.66 (s 1H), 8·08 (s 1H). 6-Isopropoxy-1·isopropyl-7-methoxy-isoindoline_4_yl)-acetic acid, [MH]+ 318. The following were prepared in a similar manner to the preparation of intermediate 20: Read the phonetic transcription on the back first? Then fill out this page. Order---------Line j -52- 1293955 A7 B7 V. Invention description (so) 3 8 ; (6,7------- -1-Methyl-iso-p-quine-4-yl)-acetic acid, [MH]+ 262 0 (Please read the notes on the back and fill out this page) -±~M_3_9_L_ (Di-Butyl-Button_6 ,7-dimethoxy-isoquinoline_4_yl)-acetic acid, iH NMR (400MHz, CDC13) d 1.75 (s 9H), 3.95 (s 6H), 4.04 (s 2H), 7.28 (s 1H) , 7.75 (s 1H), 8.66 (s 1H). : (Isopropyl-6J_dimethoxy-isoporphyrin-4_pyrene vinegar) is characterized by the 1H NMR (400MHz5 CDC13) d 1.25 (t J 7 3H), 1.45 (d J 7 3H), 3.82 (seven peak j 7 ih), 3.90 (s 2H), 3.08 (s 2H), 4.15 (q / 7 2H), 7.28 (s 1H), 7.48 (s 1H), 8.30 (s 1H) oxime 4 1 ; 2-(7-methoxy) according to the procedure for preparation of intermediate 27 _ 1-Molin-4-yl-iso-p-lin-4-yl)-propionic acid, melting point 225-227 ° C. The following were prepared in a similar manner to the preparation of intermediate 2 2: Preparation of (3-benzyloxy-4-methoxy-benzyl)-(2,2-dimethoxy-ethyl)-amine [ΜΗ]+ 332 (7-hydroxy-6-methoxy-iso Quinoline-4-yl)-lithium acetate. (6J-Dimethoxy-3-methyl-isoindolyl phenylacetic acid, H NMR (400 MHz, DMSO) (i: 2.50 (s 3H), 3 91 ( s 3H) 3 93 (s 3H), 4.02 (s 2H), 7.30 (s 1H), 7.43 (s 1H), 8.30 (s 1H). Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed soil F曰' 4 hurried 4 4 · (6-ethoxy-7-methoxy-isoindole p-linyl)-acetic acid, 3 M+ 261. The following materials were prepared by a method similar to the preparation of the intermediate 2 2 using pyruvic acid instead of glyoxylic acid: soil_interstitial 4 5 : 2_(6-ethoxy 7-oxy-isoindoline_4_yl) Lithium Propionate-53- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1293955

Salt, which is characterized by the methyl ester, M+ 290. Soil 2-(7-ethoxy-6-methoxy-isoquinoline-4+ propionic acid lithium salt, which is represented by the methyl ester, M+ 290. 2_(6,7-dimethoxy-isoquine Phytyl)-propionic acid, which is characterized by the formation of M+ 276. According to the procedure for preparing the intermediate 31, 8-fluoro-6-methoxy-isoindoline-4-yl)-acetic acid is prepared. The methyl ester, [MH] + 25 〇 represents the property. .....: (6,7-dimethoxy-iso-p-quinionyl)-acetic acid, and intermediate 50' [1,3] as described by Dyke et al., Tetrahedron 1968, 24, 1467. Dioxinyl [4,5-.g.] sulphate-8-yl-acetic acid. Interstitial 5 1 : (7-methoxy-isoquinoline-4-yl) was prepared according to the method described by Dyke et al., Tetrahedron, 1973, 29, 388 1 . Add 2,2-dimethoxyethylamine (13.85 ml, 〇13 mol) to 3 -fluoro-4·methoxybenzaldehyde (2 g, 〇·ΐ 3 mol) toluene (2〇 〇ml) solution. The resulting solution was flushed with nitrogen and then heated in a Dean_Stark apparatus overnight under reflux. The solvent was then removed under reduced pressure to give (2,2-dimethoxy-ethyl)-[i-(3-fluoro-4-methoxy-phenyl)-methylene]-amine. This intermediate (31 g, 0.13 mol) was dissolved in ethyl acetate, and acetic anhydride (13·1 g, 〇·13 mol) was added. Platinum oxide (0.3 g) was then added under a nitrogen blanket, and the resulting mixture was stirred under a hydrogen atmosphere until the absorption was complete. After hydrazine, it was washed with saturated aqueous NaHCO3 (3×100 mL), brine and water, dried over EtOAc and evaporated to give N-(2,2-dimethoxy-ethyl)-N-(3-fluoro- 4-methoxy-benzyl)-acetamide. -54- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the note on the back? Please fill out this page again)

Order ---------Line I Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printing Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printed 1293955 A7 ____B7 V. Invention Description (52) The Intermediate (38·9 g , about 0.13 moles, dissolved in anhydrous CH2C12, then slowly added to a stirred mixture of A1C13 (90 g) and CH2C12 under a nitrogen atmosphere over 20 minutes. The mixture was stirred for an additional 1 minute at room temperature and then cooled in an ice bath while adding 40% aqueous NaOH. The mixture was diluted with water (250 mL), filtered over EtOAc (EtOAc)EtOAc. Drying on MgS04 and evaporating under reduced pressure gave a crude oil which was purified by a layered gravel analysis (washing solution: 1% methanol in CH2C12) to give one of the products 1-(7-fluoro- 6-Methoxy-1H-isoquinolin-2-yl)-ethanone. The intermediate (0.60 g, 2.7 mmol) was mixed with glyoxylic acid (〇·325 g, 3.5 mmol) and water (10 mL), and the mixture was stirred at room temperature. in. Then k salt was added (1 〇 升) and the mixture was heated to reflux for 1 hour. Concentration and purification by preparative HPLC gave (7-fluoro-6-methoxy-isoquinolin-4-yl)-acetic acid, [MH]+ 236. The following were prepared in a similar manner to the preparation of intermediate 20: (1-methyl-6-methoxy-isoquinolin-4-yl)-acetic acid. -^^-54 :-(6·Isopropoxy-1-methyl-isoquinolin-4-yl)-acetic acid. 5 5 . (6-Ethoxy-1-methyl·isojunlin·4_yl)-acetic acid. Adding a solution of (6-bromo-isoquinoline _4_ benzyl acetate (52 mg, 0.19 mmol) (as prepared by the preparation of intermediate 3 i) to DMF (3 ml) under nitrogen atmosphere To zinc dicyanide (26 mg, 〇·22 mmol). Add u, bis(diphenylphosphino)ferrocene (15 mg) and tris(dibenzylidene=ketone)dipalladium (0) (8 mg) to the resulting mixture, and the resulting mixture was stirred for 22 hours at 12 ° C. The solution was cooled and chloroform (3 liters) (please read the back note before filling out this page) )

--------Book --------- Line I

Rrnm^m (cns)a4 (210 χ 297 mm) Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative 1293955

% release, then washed by water (2 χ 20 ml) and brine (2 ο ml): chloroform (40 ml) was added and the solution was dried over MgS 〇 4, filtered and condensed. Repeated layered vermiculite column analysis (washing solution 4: i cH2Ci2: methanol, then 50:1 CH/l2: methanol) gave (6-cyano-isoindolyl)-methyl acetate [MH]+ 227 . The intermediate was saponified by treatment with Li〇H in 3:1 THF/water. The resulting mixture was partially evaporated to remove the thf, diluted with water to 1 mL, and then washed with ethyl acetate. The aqueous phase (to pH 4-5) was then neutralized with i molar concentration of hydrochloric acid and extracted thoroughly with ethyl acetate. in

The organic phase was dried over MgSO.sub.4, filtered and concentrated to afford &lt;RTIgt;(&lt;/RTI&gt; Soil (5-chloromethoxy-iso-P-Pylinyl)-acetic acid was prepared as in the procedure for the preparation of intermediate 29. Add K2C〇3 (72 mg) to (6-trimethyldecyloxyethynylisoquinolin-4-yl)-acetic acid decyl ester (019 g, 〇·64 mmol) as prepared intermediate The solution of 3 2 was dissolved in anhydrous methanol (7 ml) and the mixture was stirred for 1 hour. Then add an additional Κ^〇3 (11 mg) and continue to mix for 30 minutes. The mixture was then neutralized with glacial acetic acid and concentrated. The intermediate layer was subjected to a column chromatography (ethyl acetate/hexane hexane: U to give (6-ethynyl-isoindol-4-yl)-methyl acetate m+ 225. (79 mg, 〇·35 mmol) was dissolved in methanol, and 1% by weight of Pd (79 g) was added. The resulting suspension was vigorously stirred under a gaseous hydrogen atmosphere. After 90 minutes, it was filtered. Wash with methanol and concentrate to give (6-ethyl-isoquinolin-4-yl)-acetic acid methyl ester!^+ 229. Add 1^011 (12.5 g) to the intermediate (6 8 mg, 〇 ·3〇mmol) of THF/methanol/water (3:1:1, -56- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the notes on the back first) Fill in this page again&gt;

1293955 A7 --- _B7___ V. Inventive Note (54) 3. 5 ml) The solution was stirred at room temperature for 20 hours. Concentration under reduced pressure gave (6-ethyl-isoquinolin-4-yl)-lithium acetate Μ + 221 . Soil J 5 9 : A solution of Intermediate 29 (0.5 g, 2.3 mmol) was suspended in 48% aqueous HBr (10 mL) and then heated at 100 ° C for 48 hours. Then, a 48% aqueous solution of HBr (10 ml) was added and heating was continued for another 4 hours at 10 °C. The reaction mixture was allowed to cool to 5 °C for 4 hours and the solid formed was separated by filtration. After washing with water and drying with vacancy at 50 X:, (6-carbazyl-iso-4-lin-4-yl)-hydrobromide bromide [MH]+ 204.4. The intermediate (0.15 g, 0.53 mmol) was suspended in DMF (2 mL) and then k2C03 (0.22 g, 1.58 m) and ethyl iodide (0.085 ml, 1.00 mM) The resulting mixture was then stirred at room temperature for 2 hours. Concentration and purification by flash column chromatography (washing liquid: CH2C12 / methanol 1 : 1) to give (6-ethoxy-isoindolin-4-yl)-ethyl acetate [MH]+ 260 . The intermediate (25 mg, 0.11 mmol) was dissolved in water (1 mL) and LiOH (5 g, 0.11 mmol) was added. The resulting mixture was stirred at room temperature for 30 minutes. Acidified with at least 6 equivalents of HCl and concentrated to give crude (6-ethoxy-isoquinolin-4-yl)-acetic acid. EXAMPLE 1 - 7 0 A compound of formula I, also in the form of a free or salt form, of the formula R8

-57- This paper size is applicable to China National Standard (CNS) A4 specification (21〇X 297 mm) ------------«Installation (please read the phonetic on the back? ) ------------- Line Thai Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1293955 A7 B7 V. Invention Description (55) (where R1 to R4 and R8 to R13 are as defined above) And its preparation method is shown in the following table, which is described below. Except for the example No. 4 (where R3 is CH3), the R3 of the all-salmon case is η. Except for the example of No. 25.27 (where R4 is CH3), R4 of the full enthalpy example is η. Except for the example No. 29 (where R9 is ctl3), R9 of all the examples is Η. R1 0 of all the examples is η except for the example of No. 57 (where R1g is Br) and the example of No. 75 (where R10 is C 1). R13 is Η for all examples except for the example No. 5 (where R13 is F) and the examples of No. 6 5 and No. 6 (where R13 is B r ). ------------_装(Please read the notes on the back and fill out this page) Order---------Line Thai Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print 8 5 The paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1293955 A7 B7 V. Invention description (56) 0\ N&gt; S3 S3 S3 S3 S3 S3 S3 S3 R One (ΟΗ3)20ΜαΗ2 (CH3 )oHCH2 oH3)oHCH2 oH3)2CHCH2 oH3)2CHCH2 oH3)2CHCH2 oH3)2sc:H2 S3

I oh3)3c ΟΗΊΟ

CF

CHK o C-H, T- Tox.

«0 CH

-〇 OH/ ^vorox. ΟΧΙΟ

CH, (Please read the note on the back and fill out this page) 〇ch3 〇choh3)2 osoh3)2 OCHoH3)2 oci)2 OCH3 OCH3 〇ch3 〇ch3 O0H3 〇ch3 OCH3 〇CH3 OCH3

IT

Order ---------line I 437 (Mi 508 588 6t 616 560 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

A

A

A

A

A

A

A m/N MH+ ΜΗ- 11 + 306 11 + 37 11 + 36 11 + 35 11 +:21 11 + 34 11 + 20 This paper size applies to the Chinese National Standard (CNS) A4_ specification (210 x 297 mm) - 59- 1293955 A7 B7 V. INSTRUCTIONS INSTRUCTIONS (57 Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

• 60- (Please read the phonetic notes on the back first and then fill out this page) Order --------- Line · This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1293955 A7 B7 V. Invention Description (58) κ&gt; On Or, Μ N&gt; 〇J N&gt; b〇to 00 Ο PC OJ 0 1 〇J 〇〇3: wo 〇J o u&gt; o re c〇Ο I OJ η X CO X 3: 〇Π: to s u&gt; so work N&gt; X w name X 0 1 to s U) so K&gt; o O h? Work: c Ul o XX Oc? C? O cy? ο X bJ II π ο π: S 9 Ο ozo I re • Work 3: X Ρ: Work 3: XA^/° oo X u&gt; oo 3: u&gt; 〇o re 〇J 〇 O CO ο ο X OJ 〇ο X OJ 〇n 〇 0 1 U) 〇o X u&gt; 〇o X 〇O Π: u&gt; 〇o re u&gt; 〇〇〇J 〇ο D: OJ Ο ο 厶0 〇o〇N&gt; CO v〇〇on O V.'' oooo ο ο — + 〇Ί — + r〇ii—^ + Cn Η-λ — — + o〇+ OO + On + + + νέ 1—^ + -61- (Please read the notes on the back and fill out this page)

Order ---------Line I This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1293955 A7 B7 V. Invention Description (59) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative CO to OJ to OO to 〇re o X &lt;Λ&gt; 〇X cu 〇re u» ο X CO 〇X u&gt; 〇Π: LO 〇n: u&gt; 〇1 -ο -cF oon (xy oo 〇σ Ο P: OJ X to Co s u&gt; $ so re o Π: U) o D: oa: to so 3: X 3: re PC n: 3: r\ O 2 aw 〇ο X o 0 1 OJ 〇 〇X OJ 〇Π 3: Ul 〇O re 〇〇X u&gt; 〇〇re U) 3: 〇Ο D: w 〇o X w 〇OX OJ 〇〇re u&gt; 〇o re OJ 〇O re w 〇3 : 〇o 3: OJ OO {〇OO 〇Ί t〇bo ώ OO bs HA o \〇OJ 4 aof σ oo σ ϋ 〇v〇+ + VD + OO + + H-^ + 6 b-^ + — + — -62- (Please read the phonetic on the back first? Please fill out this page again)

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1293955 A7 B7 V. Invention description (6〇) Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

6 to OJ VO OJ oo U) o〇Q\ U) Co 〇〇I U&gt; ο X UJ 〇D: u&gt; ο 3: U» 〇DC w 〇:c OJ 0 1 OJ o X OJ o u&gt; X OJ S 〇Μ X u&gt; so re K&gt; X ws rr s OJ X o re s tjj s 〇3: s u&gt; X n X s U) sn X to s OJ X o Π: N&gt; XU Sn I Ni 9 U&gt; SOX bJ s u&gt; X n X N&gt; Du XI r~\ O —2 Z — 〇F V_/ o- re X 〇〇〇X 〇J oo re u&gt; 〇o X w 〇 o re u» 〇〇XX UJ 〇〇3: OJ 〇o work to o OX o O 3: XX 〇0 1 OJ I 〇o DC u&gt; 〇o X ijj 〇o K&gt; o X 〇o Π: U) 〇o X Ki o re w 〇〇Π: Ui oo X OJ 〇〇X Co X oo :c u&gt; OJ VO ώ 00 t oo A K&gt; Oi N&gt; i) 00 Co t〇K&gt; o to VO t OO 〇J OO - 4 Dd K&gt; 〇0 1 o O 〇σ o 〇u — + VO + + + ίι t—^ + t〇K) — + N&gt; oo Η-λ + b〇— + + t〇 On t—^ t—k + K&gt; OJ -63- 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) 丨-- ------Set-------- 1293955 A7 B7 V. Description of invention (61) Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives U) K&gt; tO ο 〇ο ο n 〇η Ο η η η rr π: X Π: X UJ IX 3: U* X υ-» X , one 'S—^ η X μ S Π: n X NJ II oo 3: O Υ ο Υ ο X 3: XU·» D ο 2-χ η X NJ η χ —u* * X K&gt; η π: Ν&gt; κ. JX ω Ο X , XXX DC XXX jC 9 η X ο oo Ο Ο ο X o X n η η X u&gt; 3 3 3 3 3 3 3 3 3 3 3 η η ο t—^ t—^ a ha Φν Η-λ — Η-^ Η-λ α\ + + + ten + : + + + + + Ν&gt; N) VD OJ Ο Ν&gt; \ο -64- Ben The paper scale applies 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) 1293955 A7 B7 V. Inventions (62) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed δ On s oo C-Λ Co G\ 〇〇I o 〇J 0 1 u&gt; 〇rc OJ o PC U) 〇X 〇J ί xz 〇=co =〇o' '〇3 «工〇&quot; zo - . X 00 X n X t〇X UJ so D: to IXX n: ο ο ¥ 〇Ο rr u&gt; o 〇i :c Ui oo OJ 〇o P: u&gt; 〇OE 〇o αα 〇ο 〇o Π : OJ oo 1: 〇J oo X 〇o re u&gt; n: Work OJ i 00 oo oa 4x h-^· K&gt; 4 tn T) i •n tn 〇〇« 1 1 1 1 t—^ + OJ oo T—^ + -65- This paper scale applies to China National Standard (CNS) A4 specification (210 297 297 mm) -------- order--------- line win (please read first Note on the back side of this page) #装再填夫1293955 A7 B7 V. Invention description (63) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative print S On 〇〇 ON ON On On ON CO 〇o re U) 〇 Ο η: 〇re wo gong u&gt; o PC Ui o OJ 〇rT Μ 〇oF. 〇o ω Ι X Ο X hJ u&gt; swa: O re N&gt; s u&gt; X z 〇re K&gt; X 〇JX 〇 a: N* X &lt;jU a: o 5: Work X work re 〇o re w Ο Ο re CO 〇ο 3: 3: o 〇3: D: 〇ο u&gt; 〇o Ο Ο DC 〇Ο Re OJ 〇re 〇X 〇X 〇D: t OS N) κ&gt; On OJ v〇G\ OJ \o 4 * r π Η—ί i Η—&lt;工oo 1 1 1 1 1 1 1 \ -66- (Please read the notes on the back and fill out this page) --------Book----- ----- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1293955 A7 B7 V. Invention description (64) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed CN D! 0J 〇Ο Ο Ο Ο Ο ο 〇D: OJ re OJ X OJ ¥ 3: OJ X CO D: u&gt; X OJ JO r^i Cn V a: re X PC S 1 〇ο ο η ο Ο - O _ 3 tsi rc Ni 'XX Ν&gt; X η: Ν&gt; Ρ: XX , XX Ο 〇ο X ο 〇ο ο 〇〇.Ρ: Ο 〇Ο n 〇S OJ ο I Ζ I CU re u&gt; Π: UJ Ρ: XX 2 : Τ3工2: έ 00 OJ νο κ&gt; ο〇00 νο ΟΟ ΟΟ ΐδ κ&gt; U) 4^ Η-^ Ο Ξ 2 ο ω Cd Η-^ — ίο νο — οο — + 〇Ί i, σ\ To Co VO •~* i〇-67- This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) ------------- (Please read the back of the note first) Please fill out this page again) 11111 1293955 A7 B7 V. Description of the invention (65) Printed by the Consumers' Cooperative of the Intellectual Property Office of the Ministry of Economic Affairs

-68- (Please read the notes on the back and fill out this page)

--------Set---------Line I This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1293955 A7

V. Description of invention (66)

Method A (please read the note on the back and fill out this page) Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (〇2〇1 g, 1.30 mmol) Ear) to 5,6-diamino-1-isobutyl-3-methylsulfonate _ 2, one tong (0.223 g ' 1.053⁄4 mol) and (6,7-dimethoxy _1 _Methyl-isoquinolin-4-yl)-acetic acid (0.25 g, 0.96 mmol) in methanol (5 liters) and water (1 mL), and the mixture was stirred at ambient temperature for 16 hours. The methanol was evaporated, and the solid formed was collected by filtration, eluted with methanol (5 ml) and a 5 mM aqueous sodium hydroxide solution (5 ml) was added. The reaction was allowed to heat to reflux for 1 hour, cooled to ambient temperature and evaporated. The residue is dissolved in water and extracted by methylene chloride. The organic extract is dried on sulfuric acid steel and evaporated to give 8-(6,7-dimethoxy-oxime-methyl-iso-p-quine Lin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydrofluorene_2,6-dioxin, M+ 43 7 〇Method B 1 Ministry of Economic Affairs Intellectual Property Office staff The consumer cooperative printed (6-B-phenyl-iso-p-quinolin-4-yl)-acetic acid (58 mg, 〇·28 mmol) dissolved in DMF (1 mL) and added 〇-(7- Aza-benzotriazol-1-yl)_ N,N,N',N'-tetramethylphosphonium hexafluorophosphate (0.125 g, 0.33 mmol) and Hunig's base (0.180 ml) , 1.03 millimolar), followed by the addition of 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (5 8 mg, 〇·28 mmol) DMF (0.7 ml) solution. The reaction was stirred for 2 hours at room temperature. The solvent was evaporated and the residue was purified via flash column chromatography (3: 1 dichloromethane-methanol elution). The intermediate was dissolved in methanol (2 mL) and water (2.75 mL) The reaction was heated at 40 °C for 2 hours, then -69- This paper scale was applied to the Chinese National Standard (CNS) A4 specification (210 x 297 mm). Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1293955

5. Description of the invention (67 °, environment / m degree stirring for 16 hours. Evaporate the solvent and purify the crude product by a flash column analytical method (30:1 dichloromethane-methanol elution) to give 8 -(6-ethynyl-isoquinolinylmethyl)_3_isobutyl_丨_methyl-3,7•dihydroindol-2,6-dione, [MH]+ 388. Method B2 Performance of Hanis base (6·15 liters, 36 millimoles), 〇^7_benzotriazole-1-yl)-N,N,N',Nf-tetramethylphosphonium hexafluorophosphate ( 6.29 g, 16_6 mmol) and 5,diamino+isobutyl-3·methyl-1Η-pyrimidine-2,4-dione (3.22 g, 15.23⁄4 mol) treatment (6_ A suspension of methoxyisoisoporphyrin_4_ kibacetic acid (3. $ g, 13.823⁄4 mol) in acetonitrile (7 mL) while stirring at room temperature. Stirring at ambient temperature After 2 hours, the bubbling agent was evaporated. The residue was triturated with ethyl acetate (5 mL), filtered and washed with ethyl acetate, and then dried under reduced pressure at 5 ° C. In methanol (3 〇 ml) and 4 molar aqueous sodium hydroxide solution (60 liters) The mixture was heated at 8 Torr for 4 5 minutes. The suspension was neutralized with acetic acid and cooled to 〇 Ό 5 Ό overnight. The solid formed was collected by filtration and successively taken from methanol/water 1:9 (3 〇 And methanol (3 liters) washing, drying at 50 ° C with high hollow to give 3 _ isobutyl _8_(6-methoxy-isoquinolinylmethyl hydrazine-methyl · 3,7 -dihydro-indole-2,6-dione, [ΜΗ]+ 394.5 〇

Method C Add 1-(3-dimethylaminopropyl)_3_ethylcarbodiamine hydrochloride (5. 6 molar aqueous solution, 0.33 liters, 1.85 millimoles) to 5,6-two Amino-: 1-isobutyl-3-methyl·1Η-pyrimidine_2,4-dione (0.327 g, 1.54 亳 Mo), (1- (Please read the back of the note first and then fill out this page )

-70- Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1293955 A7 _____B7___ V. Description of invention (68) Chloro-6,7-dimethoxy-isoindol-4-yl)-acetic acid (0.414 g, 1.54 亳) Mole) and 1-hydroxybenzotriazole (0.251 g, 1.85 mmol) in CH2C12 (2 mL) suspension. Water (2 mL) was added, the mixture was shaken and the mixture was stirred for 18 hours, and the solid formed was collected by filtration. The intermediate was suspended in methanol (10 mL), 4 mL aqueous NaOH (5 mL) was added and the mixture was warmed to reflux for 4 hr. After the methanol was evaporated, the residue was acidified to pH 2 with concentrated hydrochloric acid, and the solid formed was collected by filtration, and then purified by preparative HPLC to give 8-(1 -chloro-6,7-dimethoxy-isoquine Phenyl-4-ylmethyl)-3-isobutyl-1-methyl-3,7-diindole-indole-2,6-dione hydrochloride, [MH]+ 458 〇

Wanfa D Add 1-(3-dimethylaminopropyl)_3_ethylcarbodiamine (20.6 ml, 〇11 mol) to 5,6-diamino-1-isobutyl_3 _Methyl-1H-pyrimidine-2,4-dione (20 g '0.094 mol)' (5,6-dimethoxy-iso-quinoline-4-yl)-acetic acid (26.7 g '0.094 Mo Ear), and 1 - benzotriazole (19 2 g, 〇 142 Mo) in a mixture of 1: 1 dichloromethane-water (4 mL). The reaction was stirred at ambient temperature for 4.5 hours and the solid formed was collected via filtration. It is slurried in water (5003⁄4 liters), filtered and washed with water (25 ml), dried, further ground through methanol, and dried to give an intermediate which has a concentration from the methanol. A little low purity shellfish. The intermediate material (16.08 g) was dissolved in water (1 ml) and methanol (1 (8) ml), followed by a 4 mol aqueous sodium hydroxide solution (56 ml), and the solution was placed at 70 C. The solution was formed to heat overnight. After cooling to ambient temperature, the methanol was evaporated and the residue was acidified to 1 with concentrated hydrochloric acid. Passed (please read the notes on the back and fill out this page)

The Chinese and American standards (Cns) A4 specifications (210 X 297 mm)

1293955 V. INSTRUCTIONS (69) 遽 Collect the formed hydrochloride salt and (iv). (d), the pH is reached to U by treatment with an aqueous solution of a steel hydroxide to convert the product into the free base, and washed with water to obtain 3-isobutyl winter (5,6-dimethoxy-iso- 4 _ 4_Methyl)-1-methyl-3J-dihydro-indole_2,6-dione [MH]+ 424.6.

Method E A suspension of 6 equivalents of HU (2.5 mL) and ethanol (1.5 ml) of the product of Example 11 (72 mg, 〇13 mmol) was heated to reflux for 5 hours and then allowed to stand at room temperature. Set a night. The precipitate formed was collected by filtration, washed with water and dried to give 3-(3-amino-benzyl)-8-(6, &lt;RTI ID=0.0&gt; Hydrogen 呤 2,6_dione dihydrochloride W, 1h NMR (400MHz, DMSO) d : 3.20 (s 3H), 3.95 (s 3H), 4.00 (s 3H)5 4.75 (s 2H)? 5.15 (s 2H)? 7.15 (m 2H)? 7.20 (s 1H)? 7.30 (t J 6 1H)5 7.65 (s 1H)9 7.95 (s 1H)? 8.50 (s 1H)? 9.5〇(s 1H)9 13_6 ( Br s 1H). ’

Method F The product of Example 58 (37 mg, 〇·〇 7 mmol) was suspended in pyridine (1.5 mL) and dimethylamine sulfonyl chloride (23 liters, 〇21 mM.) was added. . The reaction was heated at 50 °C for 22 hours and the solvent was evaporated. Developed by water to give a solid which was collected by filtration and dried to give 3-[3-(N,N-dimethylaminesulfonyl)aminobenzyl]|(6,7-dimethoxy Isoindolin-4-ylmethyl)-1-methyl-3J-dihydro-indole_2,6-dione, NMR (400MHz, DMSO) β : 2.64 (s 6H), 3.26 (s 3H) 3 86 (s 3Η), 3.98 (s 3Η), 4·50 (s 2Η), 5.15 (s 2Η), 6·98 (d J 6 1Η) 7·08 (&quot; 6 1H), 7·15 (s 1H),7·22 (t J 6 3H),7.55 (s 1H)' -72- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public H &quot; ' ------- - ------------------Book--------- (Please read the notes on the back and fill out this page) _· Ministry of Economic Affairs Intellectual Property Office staff Consumer Cooperatives Printed 1293955 A7 V. Invention Description (7〇) 7·62 (s 1H), 8.38 (s 1H) 9 lw m)o ), 9·15 (S called, 9.82 (s 1H), 13_6〇 ( s

Method G The product of Example 24 (100 mg, 0.25 moles) was heated at 100 ° C in concentrated bromic acid (5 亳, η ^ liter) for 3 6 hours L, butyl hydrazine, and preparative HPLC The crude product was purified to give 8 (7'-mercapto-s-quinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-diindole-9 A + ^ , 6-diketone, [M+] 379. Method Μ The product of Example 41 (41 mg, 〇〇 9 mmol) was dissolved in acetic acid (4 liters) and treated with bromine in acetic acid (10 mg/ml solution: 1 〇〇 microliter). After 1 hour at the temperature, the solvent was evaporated, the residue was dissolved in hot methanol, filtered and evaporated to give &lt;RTI ID=0.0&gt;&gt; -3_isobutyl_m3,7-dihydro-indole_2,6-dione, M+ 474.

Method I The product of Example 13 was obtained, 3-allyl-8-(6,7-dimethoxy-isoindoline-4-ylmethyl)-1-methyl-3,7-dihydro-indole- 2,6-diketone hydrochloride (0.760 g, 1.873⁄4 mol) '9-Byrobicyclo[2_2.〇]decane (〇.5 molar concentration THF solution ' 18.7 ml, 9.35 mmol) and two A suspension of isopropylethylamine (0. 33 mL, 1. 893⁄4 mol) in THF (9 mL) was warmed to reflux for 2.5 h. Sodium hydroxide (4 molar aqueous solution, 6 liters) and hydrogen peroxide (27.5% '3 ml) were continuously added, and the reaction was heated at 5 ° C for 1.5 hours. After evaporation, the crude product was purified via EtOAc (19: i CH2C12: -MeOH elution) and purified by water to afford &lt;RTI ID=0.0&gt; 73· 'The paper scale applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) ------------ Pack (please read the note on the back? Please fill out this page again) ---------Line| Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printing Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperatives Printing[293955

V. DESCRIPTION OF THE INVENTION (71-based)-3-(3-3⁄4-propylpropyl)-1-methyl^ 'T 丞·3,7-indeno-indole-2,6·dione, [ΜΗ]+ 426 〇3JtJ_ Adding carbonic acid unloading (4 8 mg, 〇^|, π 毛υ υ · 35^莫耳) and methyl iodide (〇〇 18 ml, 0.295 mmol) to the paste 1% of the product; 8-(6,7-Dimethoxy-isoquinolin-4-ylmethyl)-3-isoylmethylmethyl_3,7-dichloro-indole_2,6_dioxin 〇"〇0 g, 0.24 mmol) in DMF (2 mL) solution. The reaction was disturbed overnight and purified by HPLC to give 8-(6,7-dimethoxy-isoporphyrin _ ', '-T-yl-3,7-dihydro-indole-2,6-dione, [ΜΗ]+ 438. Method 使 The product of Example 6 8 at 8 0 C, 8_(6,7-dimethoxyisoindoline_4_ylmethyl)-3-(3-hydroxy-2- Methyl-propyl bromomethyl-3,7-dihydro-indole 2,6-dione (63 mg, 0.14 mmol) and acetonitrile (18 mL, 〇25 mmol) pyridine (1 halo) The suspension was heated for 8 hours. After evaporation, it was purified by a layer chromatography method (19:1 dichloromethane-methanol elution) to give acetic acid 3_[8_(6,7_-methoxy-iso 4 Phenyl-4-ylmethyl)-1-methyl-2,6-dioxy",^^tetrahydro-indol-3-yl]-2-methylpropyl ester, [mh]+ 482.

Method L The product of Example 18, 8-(6,7-dimethoxy-isoquinolin-4-ylindenyl)-1_methyl-3-(2-methyl-allyl&gt;3, 7_Dihydro-indole-2,6-dione (1 〇〇 mg '0.243⁄4 mol) was suspended in i,2-dichloroethane (3 〇 ml). Diethylzinc was added successively (1 Mo Ear concentration hexane solution, 1.2 ml, 1 _2 〇 millimolar) and chloroiodomethane (0.174 ml, 0.24 mmol), and stirred at ambient temperature -74- This paper scale applies to Chinese National Standard (CNS) A4 Specifications (210 X 297 public) (Please read the notes on the back and fill out this page)

1293955

V. Description of the invention (72) The reaction was mixed for 1 hour, and then the reaction was stopped by finely fishing with β, and di-saturated NH4C1 aqueous solution. After extraction with chlorine, the organic phase such as J was washed with water, dried on MgS〇4, and evaporated. Purification by preparative HPLC gave 刭β^ to 8,(6,7-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-3-(1-methyl-oxime &amp;amp ; glycine propylmethyl)-3,9-dihydroanthracene 2,6-dione, [ΜΗ]+ 436. Method Μ The product of Example 53 was obtained as '8_(6-bromo-isoquinolinylmethyl) )_3_isobutyl_ \methyl-3,7--hydrogen-^呤_2,6-dione (245 mg, 〇_554 mmol) suspended in ethylamine (0.085 3⁄4 liter, 〇61)亳Moel) and CH2Cl2 (4 ml) in a mixture. Add a solution of di-tert-butoxy carbonate (133 mg, 〇·6 ΐ mM) of CH2C12 (1 liter) to the stirred mixture. 2 hours later, adding triethylamine (〇·170 liters, 1.2 mmol), di-t-butoxy carbonate (130 mg, 0.60 Torr) &amp; DMF (〇 3 ml), The mixture was stirred at room temperature for 2.5 days, concentrated, and partitioned between water and hexane, sonication Filtration, reconcentration, and purification by flash layer column analysis (washing solution 19:1 CH2C12:methanol) affords _(bromo-isoquinolin-4-ylmethyl)-3-isobutyl-1- Methyl-2,6-dioxy_ι, 2,3,6-tetrahydroindol-7-acid second-butyl ester ([MH]+ 543). Add this intermediate (5 8 mg, 〇 · 11 moles to Zn(CN)2 (15 grams, 〇·ΐ 3 millimoles) followed by 1,1-bis(diphenylphosphino)ferrocene (9 mg), three ( Di-n-butyl acetonide) di-sodium (〇) (5 mg) and anhydrous DMF (2.5 ml), and the mixture was stirred at 120 ° C for 18 hours, then stirred at 150 ° C for another 24 hours. Then add Zn(CN)2 (57 mg, 0.49 mmol) and anhydrous DMF (1 ml) and heat at 155 °C for 2 hours, then heat at 145 °C for 1 8 small-75- paper The scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) (please read the note on the back? Please fill out this page again) ---------Book -------- -Line· Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed, 1293955 A7 B7 V. Invention Description (73). Then add 1,1,-bis(diphenylphosphino)ferrocene (9 mg), tris(diphenyl)propanone di-(0) (9 mg), and reheat the reaction at 145 °C 6 hours. Concentrated, developed by water, filtered, washed with 1: 丨 saturated NaHC03/water, then extracted with CH2C12 and 1:1 methanol: CH2C12, and subjected to repeated layered vermiculite column analysis (washing solution 1〇:1 Purification of CH2C12: methanol, then 20:1 CH/h:methanol to afford 4-(3-isobutyl-1-methyl-2,6-dioxy-2,3,6,7-tetrahydro- 1H-嘌呤-8-ylmethyl)-isoquinoline-6-carbonitrile [MH] + 389 °

Method N Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiamine hydrochloride (〇29 g ' 1.93⁄4 mol) to 5,6-monoamino-1-isobutyl 3-methyl-1H-P-dense·* 2,4·dione (0.40 g, 1.9 mmol) and (1-chloro-6,7-dimethoxy-isoindoline-4- The base was dissolved in methanol and aqueous solution of acetic acid (0.39 g, 1.78 mmol), and the mixture was stirred at ambient temperature for 2 hours. The methanol was evaporated and the solid formed by the furnace was collected and then recrystallized from ethyl acetate/methanol. The solid formed was heated in a sealed tube with a 40% aqueous solution of dimethylamine (100 ° C, 8 hours). The mixture was evaporated and extracted with ethyl acetate. The ethyl acetate solution was then washed with water and brine, dried over sulfuric acid steel, filtered and concentrated. Purified by a layered vermiculite column (washing solution: ethyl acetate / methanol) to give 8-(1-dimethylamino-6,7-dimethoxy-isoindoline-4-ylmethyl) -3-isobutylindolyl_3,7-dihydro-indole_2,6-dione, MH+ 467. Method Ο Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiamine hydrochloride (〇29 (please read the notes on the back and fill out this page) ----Book -- ------- Line · Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing Γ · -76- 1293955 A7 B7 V. Invention description (74) ------------•Installation (please Read the phonetic transcription on the back first? Then fill out this page) Order --------- Line 0-g, 1.9 millimoles to 5,6-diamino-isobutyl-3-methyl- 1H-pyrimidine-2,4-dione (0.40 g, 1.9 mmol) and (1-chloro-6,7-dimethoxy-isotetraline-4-yl)-acetic acid (0.39 g, 1.78) The mixture was stirred at ambient temperature for 2 hours in methanol and aqueous solution. The methanol was evaporated and the solid formed was collected via filtration and recrystallized from ethyl acetate / methanol. The solid formed was heated with hexahydropyridine under reflux for 8 hours. The solution was filtered and concentrated. Further purification was carried out by a flash layer column analysis (washing liquid: ethyl acetate / methanol) to yield a solid which was dissolved in 20% 1 eq. NaOH/methanol and heated to reflux for 2 hours. Concentrate, add water, and extract with ethyl acetate. An organic restaurant is obtained, which is washed with water and brine, dried on Na2SO4, filtered and concentrated to give 8-(6,7-dimethoxy-1-7T hydrogen ρ than 1-1-yl-iso 》1 奎(?林-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-indole-2,6-dione, ^111+ 507. NMR of the example Data &quot;Η 400MHz DMSO-d6) Example 1 2 A 3.25 (s 3H), 3.92 (s 3H), 4·02 (s 3H), 4.65 (s 2H), 7·70 (s 1H), 7.88 (s 1H), 8.45 (s 1H), 9.42 (s 1H), 11.1 (s 1H), 13.60 (s 1H) Example 1 3 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Print d 3·20 (s 3H), 4.95 ( s 3H), 4.00 (s 3H), 4.52 (d J 4 2H), 4.70 (s 2H)? 5.04 (d J 18 1H)5 5.09 (d J 10 1H)9 5.88 (m 1H)? 7.60 (s 1H ), 7.88 (s 1H), 8.46 (s 1H), 9.42 (s 1H), 13.7 (s 1H). Example 1 4 ^ 0.20-0.40 (m 4H)? 1.10-1.30 (m 1H)? 3.21 (s 3H)? 3.81 (m -77- This paper scale applies to China National Standard (CNS) A4 specification (21〇x 297厘) * i Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 1293955 A7 _B7___ V. Inventions (75) 2H), 3.98 (s 3H), 4.03 (s 3H), 4.66 (s 2H), 7.65 (s 1H) , 7.85 (s 1H), 8.45 (s 1H), 9.39 (s 1H), 13.70 (s 1H). Example 1 5 0.82 (s 9H)? 3.20 (s 3H)? 3.78 (s 2H)? 3.99 (s 3H)5 4.04 (s 3H), 7_62 (s 1H), 7.90 (s, 1H), 8.45 (s 1H ), 9.44 (s 1H), 13.60 (s 1H). Example 1 6 (ί 0.81 (d J 7 12H)5 1.98 (m 1H)5 2.12 (m 1H)? 3.70 (d J 8 2H), 3.78 (d J 7 2H), 3.99 (s 3H), 4.05 (s 3H), 4.70 (s 2H), 7.65 (s 1H), 7.90 (s 1H), 8_46 (s 1H), 9_45 (s 1H), 13.6 (s 1H). Example 1 7 d 0.80-0.10 (m 6H) , 1.40-1.60 (m 4H), 1.80 (m 1H), 3.15 (s 1H), 3.76 (d J 8 2H), 3.91 (s 3H), 4.02 (s 3H), 4.68 (s 2H), 7.60 (s 1H), 7.88 (s 1H), 8.44 (s 1H), 13.60 (s 1H) 〇 Example 1 8 d 1.69 (s 3H), 3.21 (s 3H), 3.98 (s 3H), 4.01 (s 3H), 4.46 (s 2H), 4.52 (s 1H), 4.68 (s 2H), 4.76 (s 1H), 7.58 (s 1H), 7.84 (s 1H), 8.45 (s 1H), 9.42 (s 1H), 13.60 (s 1H). Example 1 9 d 1.50-1.85 (m 4H)9 3.18 (s 3H)9 3.50-3.85 (m 4H), 3.95 (s 3H), 4.02 (s 3H), 4.10-4.20 (m 1H), 4.70 (s 2H), 7.75 (s 1H), 7.920 (s 1H), 8.50 (s 1H), 9.50 (s 1H), 13.60 (br s 1H). Example 2 0 -78- This paper scale applies to Chinese national standards ( CNS)A4 specification (210 X 297 mm) ------------Package--------Book---------Line · (Please read the back Note: Please fill out this page again) 1293955 A7 B7 Economy Ministry of Intellectual Property Bureau employee consumption cooperative printing 5, invention description (76) d 0.70-0.80 (m5 6H), 0.99-1.10 (m 1H), 1.20-1.25 (m 1H) 1.88-2.00 (m 1H), 3.21 ( s 3H), 3.64-3.80 (m 2H), 3.95 (s 3H)' 4.00 (s 3H)5 4.68 (s 2H)? 7.60 (s 1H)? 7.80 (s 1H)? 8.45 (s? 1H), 9.42 (s 1H), 13.60 (br s 1H). Example 2 1 d 0.83 (t J 8 3H), 1.63 (sextet J 8 2H), 3.83 (t J 8 2H), 3.99 (s 3H), 4.05 (s 3H), 4.69 (s 2H), 7·64 ( s 1H), 7·88 (s iH) 8.44 (s 1H), 9.42 (s 1H), 11.10 (s 1H), 13.60 (s 1H). 'Example 2 3 0.80 (d J 7 6H)? 3.18 (s 3H)5 3.75 (d J 8 2H)? 4.60 (s 2H) 6.32 (s 2H), 7.71 (s 1H), 7.82 (s 1H), 8.50 (s 1H), 9.42 (; 1H), 13.50 (s 1H) 〇 Example 49 ^ 0.12^0.25 (m 4H)? 1.02-1.10 (m 1H)? 3.20 (s 3H)5 3.68 (dj 7 2H)? 4.00 (S 3H)? 4.80 (s 2H)5 7.70 (d J 9 1H)5 8.21 (dj 9 1H), 8.38 (s 1H), 9.20 (s 1H), 13.10 (s 1H). Isobutyl-1-methyl-8-indole 1 di L6-methyl-5-oxy group 〖4,5-.g·]isoquinolinyldiylethyl hydrazine-2,6 _diindole General procedure for the preparation of intermediate 2 2, treatment of phenylhydrazine with pyruvic acid [丨3] Dioxolyl-5-ylmethyl-(2,2-dimethoxyethyl)amine (Tetrahedr〇n 1968) , 24, 1467), 2-[1,3]dioxosyl[4,5_.g.]isoquinoline-8-yl-propionic acid hydrochloride, m.p. 224-226. The corresponding ethyl ester hydrochloride was obtained by treatment with HCl in ethanol to give a melting point of 223 to 225 °C. The standard of China National Standard (CNS) A4 (210 X 297 mm) is applied to the standard of sulfuric acid-79-paper. ------------Installation------ ------· (Please read the notes on the back and fill out this page again) 1293955 Α7 -----Β7__ V. Description of the invention (77) Methyl ester (1.26 g, 10 mmol) to treat the compound ( 2.73 g, 1 〇 mmol) benzene (20 liters) solution, stir at room temperature for 5 hours, and evaporate the solvent. Dissolve the crude oil in water (20 liters), cooling To 〇-5. 〇, and add K3Fe(CN)6 (5.72 g, 17.4 mmol) water (25 ml) and hydroxide steel (2.04 g '5 1 halal) water (丨 5 ml) After 15 hours at $ i, the reaction was adjusted to pH 2 with concentrated hydrochloric acid, and the product was collected by filtration and then crystallized from methanol-dichloromethane to give 2-(6-methyl-5-oxygen -5,6--hydro-[1,3]dioxosyl[4,5-.g.]isoindol-8-yl)-propionic acid, melting point 290 C (decomposition). The general procedure for d is converted to the scutellaria, [MH] + 452. 7 - 8-(6,7-dimethoxy-p-quine _4•methyl)-3-昱Base-1-methyl-3,7-dihydro-p-butyl-2,6-dione at -70 ° C, adding diisopropyl guanamine (2 molar concentration of pentane solution 2.46 halo '4.92 mmol" and third-butyric potassium oxide (〇.552 g, 4.92 mmol) to THF (10 liters) followed by 6,7-dimethoxy-4-methyl-quinoline Porphyrin [J. Org. Chem., 1997, 623, 568] (1.0 g, 4.92 mmol). After 1 hour, the reaction was poured onto excess dry ice and warmed to room temperature overnight. Add pyridine hydrochloride (〇·57 g, 4.92 mmol) and partition the reaction between ether and water. Evaporate the aqueous phase, extract with hot methanol, coke treatment, via Celite The diatomaceous earth was filtered and evaporated to give (6,7-monomethoxy-p-quineline)-acetic acid, hydrazine + 248. Then, according to the general procedure of method c, it was converted to xanthine, melting point &gt; 80. 80- This paper scale applies to China National Standard (CNS) A4 specification (21〇χ 297 mm) (please read the phonetic on the back? Please fill out this page) π装---- Property Bureau employee consumption cooperative printing

Claims (1)

98. 10. 2 4 129 "Longitudinal" patent application No. 489 Neutral application for the scope of the nose to replace the October of this year, six, the scope of the patent application i•-species in the form of free or salt type R2 where: R1 is hydrogen or (VC6 alkyl; alkyl, C2-C6 alkenyl, and c3-c6 cycloalkyl CrC6 alkyl, wherein the alkyl moiety is unsubstituted or substituted with tetrahydrofuran or phenyl, and the phenyl group Unsubstituted or amino group, Ci-C^ alkanoamine or (^-(:6-dialkylsulfonyl); R3 is hydrogen; η R4 is hydrogen; r5 is the following formula III isoquinolinyl R8 R13 Wherein R8 is hydrogen, dentate or heart-fluorenyl; R9 is hydrogen; R10 is hydrogen; RU is &lt;Vc6 alkoxy and R12 is hydrogen or CKC6 alkoxy; or R11 and R12杂4 (CNS) Α4 specifications (coffee X s A8 B8 C8 D8 1293955 s, the scope of application for patents - to form -0-CH2-0, and R13 for hydrogen. 2. According to the scope of claim 1 a compound of the formula I, wherein the alkyl group; 112 is a Ci-CV alkyl group; R8 is hydrogen; an alkoxy group; and R12 is hydrogen. 3. A compound of the formula I according to claim 1 of the patent application, which is in a free form or a salt form. Compound of formula XXXXVI Wherein: (i) R1 is CH3, R2 is (CH3)2CHCH2, R3 and R4 are each Η, R8 is CH3, R9 and R10 are each Η, and R11 and R12 are each OCH3; or (ii) R1 is CH3, R2 is (CH3)2CHCH2, R3, R4, R8, R9 and R10 are each Η, and R11 and R12 are each OCH3; or (iii) R1 is CH3, R2 is (CH3)3CCH2, R3, R4, R8, R9 And R10 are each Η, and R11 and R12 are each OCH3; or the paper @:\§9 turns to 1 祺疣 赢 赢 拜 (CNS) A4 specification (21〇X2-%7-public firefly) 1293955 έ88 C8 _— _ D8 ___ VI. Patent application scope Gv) R1 is CH3, R2 is (CH3)2CHCH2, R3, R4, R9 and R10 are each Η, R8 is C1, and RU&amp;Ri2 are each 〇Ch3; or (v R1 is CH3, R2 is (CH3)2CHCH2, R3, R4, R8, R9 and R10 are each Η, R11 is 〇CH3 and R12 is Η; or (vi) R1 is CH3, and R2 is cyclopropylmethyl. R3, r4, r8, r9, rIO and R12 are each H and R11 is 〇CH3; or (Vli) R1 is CH3, R2 is 1-nonylcyclopropylmethyl, r3, r4, r8, R9 and R1G It is H and R11 and R12 are each 〇ch3. 4. A compound of formula I according to any one of claims i to 3 of the patent application, for use as a medicament for the treatment of a condition mediated by PDE5. A pharmaceutical composition for treating a condition of a PDE 5 vector, which comprises a compound of the formula j according to any one of claims 1 to 3 as an active ingredient, and which may be used in combination as needed Accepted diluent or carrier. 6. A compound of formula I according to any one of claims 1 to 3 for the manufacture of a medicament for the treatment of a condition via a PDE5 vector. 7. A compound of formula I according to any one of claims 1 to 3, which is for use in the manufacture of a medicament for the treatment of sexual dysfunction, particularly male erectile dysfunction. 8. A method of preparing a compound of the formula I according to claim 1 in a free or salt form, which comprises 1) (a) dehydrating a compound of the formula 1293955 A8 B8 C8 D8 Wherein R1, R2, R4 and R5 are as defined in the scope of claim 2; or (b) in the preparation of a formula wherein R8 is a halogen in a free or salt form, wherein R5 is an isoquine of the formula The compound of the formula I wherein the phenyl group (wherein R8 is hydrogen) is subjected to a halogenation reaction, or (C) is prepared as a compound of the formula 1 wherein R2 is a cyclopropyl-alkyl group in a free form or a salt form, wherein R2 is The C-C6 alkenyl group of the formula 1 sigma substance is subjected to Simmons Smith propylene cyanidation reaction; and 2) the recovery is in the form of a swim (four) or a salt type! product. 9_ A compound of the formula IV Rs R4 IV where R] R ′ R and R are as defined in item 1 of the scope of the patent application