TWI310036B - Novel thieno 2,3-d pyrimidinediones, processes for their preparation,and pharmaceutical compositions containing them - Google Patents

Description

1310036

.ΪΓ:: There are Γ 吩 吩 [ [2,3. 二网, its method of production, including its disease. It plays an important role in the regulation of autoimmune diseases in τ, but in autoimmune diseases: 'Ding cells will be inappropriately activated and enhanced for specific tissues, such as: arthritis Inflammation. Inhibition of τ·cell proliferation will be beneficial to disease = disease = disease. The present invention relates to (four) regulation of autoimmunity. Known compounds of WO 2_/125 14 and w〇 2〇〇1/〇38489 are suitable for use in modulating immune responses. These claims include compounds having a serotonin-C-N_ at the % position of the 4 (4) cut. These compounds exhibit an interactive conversion rate, a slow geometric isomer' because it rotates around the amide-based c_N chain and rotates slowly around the bond from the guanamine-based carbonyl to the phenanthro-pyrimidine core. And by using HpLC to separate isomers based on these cross-switching speeds. These evasive rotations cause significant problems in the development of pharmaceutical compounds: the equilibrium time is so long that, if the synthesis method is changed - the final geometrical mixture may be produced, resulting in analytical purity and crudeness. Solid drug reproducibility issues. In addition, life expectancy is equivalent to biological half-life < geometric isomers should be treated by different metabolic processes, resulting in metabolites with dissimilar structures, and must be fully studied and documented for biosafety. We have now found a compound having a stilbene-CN- group at the 5 position of the ρ-phenantrimidine ring system, which has advantageous potency and does not exhibit a separate geometrical difference in the indoor conditions. The problem of the structure. According to the present invention, a compound of the formula (1) is provided: The paper scale is applicable to the Chinese National Standard (cns) A4 specification 1310036

Description of the invention

R (1) wherein alkylene M alone represents Cl.6 alkyl, C3_6 alkenyl, anthracene; 3·5 cycloalkyl C Bu 3 疋. [Environmental basis; each of which may be substituted by ι_3 1 atom; a oxo-oxazolyl-2 carbonyl or a tetrahydroisoindole-2-ylcarbonyl, wherein each % may be substituted with a hydroxy group; ΟΛ co or -c(r4)(r5)_ (wherein r4 is a hydrogen atom or a group, and r5 is a halogen atom or a hydroxyl group); 'June=· to 1〇_member aromatic ring system, wherein up to 4 ring atoms can be For the 7th day of the seventh day, "heteroatoms: nitrogen, oxygen and sulfur", the ring system can be replaced by: a substituent independently selected from the following: c " alkyl (which: depending on T1, 2 or 3 Base phantom, C "decyloxy, cyclin, (10);, c I base, tridecyl, Cl · 4 alkoxy C-alkyl, Cl to sulfur: its oxime is carbonyl, C2.4_, oxygen Substituent, thio, decyl, di-subordinate = and -(CH2)PN(R8)R9, a few groups, C"垸定临基, I卜d元亚% fe; base, amine-like, Γ .μ* i π, makeup Τ I violent C|-4k amide group, two... pit base) amine mercapto group, carboxyl group or containing up to 4 separate independent selection ^

<heteroatom<5 or 6 member aromatic ring: nitrogen, oxygen and sulfur; lJ p is 1 to 4; R6 and R7 independently represent a hydrogen atom, a Ci group or a C thiol group, or the paper size is applicable to China. National Standards (CNS) A4 specifications (2ΐ〇χ 297 public) 1310036 V. Description of the invention (combined with the nitrogen atom attached to the 8 to form a 5 to 7-membered saturated heterocyclic ring; R a R knife alone represents hydrogen An atom, a Cw alkanoyl group or a ci 4 alkyl group, or a nitrogen atom attached thereto, together form a 5- to 7-membered saturated heterocyclic ring; or a pharmaceutically acceptable salt or prodrug thereof. Further, the present invention relates to a compound of the formula (1) as defined above, or a pharmaceutically acceptable salt thereof. The salt of the compound of the formula U) or a salt thereof within the scope of the present invention may exhibit a tautomerization phenomenon, and The chemical formulas shown in the specification represent only one of the mutual and/or configuration' and it is understood that the specification encompasses any tautomeric form, and is not limited to any one of the tautomeric forms shown herein. The chemical formula represents only one of the possible tautomeric forms, and it is understood that this specification encompasses the compounds shown herein. Illustrative of all possible tautomeric forms 0 - The present invention relates to a compound of the formula (1) as defined above, and a salt thereof. The salt used in the pharmaceutical composition is a pharmaceutically acceptable salt, but other salts may be suitable. To produce a compound of the formula (1) and a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt of the present invention may include, for example, an acid addition of a compound of the formula (1) as defined above, which is basic enough to form a salt. Salts. These acid addition salts include, for example, salts with inorganic or organic acids which provide pharmaceutically acceptable anions, such as: with hydrogen 13⁄4 (especially hydrochloric acid and hydrobromic acid, especially with hydrochloric acid). Good) or with sulfuric acid or phosphoric acid' or with trifluoroacetic acid, citric acid or malay salt. Suitable salts include hydrochloride, hydrobromide, sulphate, salt, hard acid hydrogen, Pit base acid salt, aryl acid salt, acetate, benzoate, citrate, maleate, fumarate, succinate, lactic acid This paper scale applies to Chinese national standards (CNSIA4 specifications ( 210X297 mm) 1310036 A7 B7 V. Description of invention (salt And tartrate. In addition, an outer, if the formula (1) compounds having a sufficiently acidic

Including, for example, an alkali metal salt such as a sodium or potassium salt, a caustic or organic base to form an organic base to form a salt of a soil test metal salt such as calcium or magnesium salt or an ammonium salt or, for example, with methylamine or dimethylamine a salt formed by trimethylamine, biting, morpholine or cis-(2-hydroxyethyl)amine. Preferred salts include acid addition salts such as: hydrochloride, hydrobromide, sulphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methane An acid salt or p-toluenesulfonate, or an alkali metal salt such as a sodium salt or a clock salt. A variety of different forms of prior art are known to those skilled in the art. For example, such prodrug derivatives can be found in: a) Η· Bundgaard, edited by "Design of Prodrugs" (Elsevier, 1985) and edited by K. Widder et al. "Methods in Enzymology1', Vol. 42, p. 309-396 (Academic Press, 1985); b) MA Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5, H. Bundgaard "Design and Application of Prodrugs " p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews. 8., 1-3 8 (1992); d) H. Bundgaard et al. Journal of Pharmaceutical Sciences., ZL 285 (1 988); And e) N.Kakeya et al., Chem. Pharm. Bull., 692 (1984). Examples of such prodrugs that can be used are in vivo cleavable compounds of formula (1) - 8 - This paper scale applies to China National Standard (CNS) A4 Specification (210 X 297 mm) A7 B7 1310036 V. Description of the Invention (Acid. The in vivo cleavable ester of the compound of formula (1) containing a hydroxyl group is, for example, a commercially acceptable ester. It can be hydrolyzed into an alcohol precursor in the human or animal body. 4 Nouns include inorganic esters such as Phosphate esters with α-醯 oxyalkyl ethers and related compounds which can hydrolyze esters in vivo to form hydroxy precursors. Examples of α _ 醯 oxyalkyl ethers include ethoxylated methoxy and 2,2-dimethylpropane oxy Methoxy group. Hydrolyzable ester-forming groups which can be used for hydroxyl groups include alkanoyl, benzamyl, phenylethyl and substituted benzamidine and phenethyl, alkoxycarbonyl (Formation of alkyl carbonate), dialkylamine methyl sulfonyl and decyl dialkylamine ethyl) ketone amine carbaryl (formation of urethane), dialkylamine acetamyl and acetophenone It is also known that certain compounds of formula (1) may be solvated and unsolvated, for example, hydrated. It is also understood that the present invention encompasses all solvated forms suitable for therapy, in particular. For medical purposes as described below. In the present specification, the alkyl, alkenyl or alkynyl group or the alkyl, alkenyl or alkynyl moiety in the substituent may be straight-chain or branched, unless otherwise stated.

Ar may be bonded to the _c〇_ or group using a ring carbon or a ring nitrogen, but the limitation is that the quaternization cannot be caused. It is understood that, in the -C(R4)(R5)Ar group, R5 can represent a hydroxyl group only when Ar utilizes a carbon atom instead of a hetero atom to bond a /(RW) group. Further, 'it should be understood that' -C(0)Ar, the Ar system is bonded to a part of the group _c(〇) by a carbon atom instead of a hetero atom. (4) The base may contain more than one (four), but the "(iv) base is preferred. For the avoidance of doubt, when red is substituted with an oxo or thio group, the dihydrogen type of the aromatic ring system should be included. For example: it includes. Retazolyl and & dihydropyrimidin (when the latter is substituted with an oxo or thio group). Similarly, ^ package

1310036 A7 B7 V. INSTRUCTIONS (6) include, for example, 2,3-dihydrobenzoxazolyl, 2,3-dihydrobenzothiazolyl, 2,3-dihydropyridinyl and 2,3-di Hydrobenzimidazolyl (when such groups are substituted with an oxo or thio group).

Ar is a 5- to 10-membered aromatic ring system, wherein up to 4 ring atoms may be heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, which may be i, 2, 3 or 4, respectively, as desired. Substituted independently of the following substituents: ci 4 alkyl (which may optionally be substituted by 1, 2 or 3 trans) (eg methyl, ethyl, n-propyl, n-butyl, hydroxymethyl) Base, 2-hydroxyethyl, 1-hydroxyethyl or 3-hydroxypropyl), Cm alkoxy (eg methoxy, ethoxy, n-propoxy or n-butoxy), halogen # (eg: fluorine, chlorine, bromine or iodine), haloalkyl (eg fluoromethyl, methoxymethyl, bromomethyl, 2-fluoroethyl, 2-fluoropropyl or 3-fluoropropyl), Dimethyl group (for example: difluoromethyl, di-methyl, fluoromethyl, dibromomethyl, 2,2-fluoroethyl, 2,2-difluoropropyl or 2,3-di Fluoropropyl), trihaloalkyl (eg trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 2,2,2-trifluoropropyl or 2,2,3- Trifluoropropyl), Cw alkoxy CU4 alkyl (eg methoxymethyl, ethoxymethyl, 2-methoxyethyl, 2-methoxypropyl or 3-methoxypropyl), C丨alkyl Base (for example: methylthio, ethylthio, n-propylthio or n-butylthio) 'C, _4 alkoxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropyl Oxycarbonyl or n-butoxycarbonyl), Cw alkanoyl (eg, ethyl or propyl), oxo, thio, nitro, cyano, _n(r6)r7 (eg amino group) , methylamino, and -ethylamino, di-N,N-methylamino or N-ethyl-fluorenyl-methylamino), -(CH2)i)N(R8)R9 [eg: -CH2N (R8) R9, -ch2ch2n(r8)r9 or -CH2CH2CH2N(R8)R9], hydroxy, c"4 alkanesulfonyl (for example: methylsulfonyl, ethylsulfonyl or propylsulfonyl), cU4 alkane Enzyme.__- 10 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) !31〇〇36 Α7

DESCRIPTION OF THE INVENTION Base (methylsulfinyl, ethanesulfinyl or propylsulfinyl), amine methyl sulfhydryl, cμ alkylamine sulfhydryl (eg methylamine methyl sulfonyl, ethylamine methyl hydrazide) And propylamine-methyl hydrazino), bis-Cl_4 alkylamine fluorenyl (for example: diterpene, hydrazine methylamine, N-ethyl-N-methylaminemethanyl or di-N , N-ethylamine-methyl fluorenyl), a group and a 5- or 6-membered aromatic ring containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur (eg phenyl, pyrimidinyl, porphin) Base and furanyl). The aromatic ring system may be monocyclic or polycyclic (for example, bicyclic), and examples thereof include a strepto group, a naphthyl group, a porphyrin group, a pyrazolyl group, a p-senyl group, a carbazolyl group, an imidazolyl group, and a pyridyl group. , pyrha[2,3-b]pyridyl, benzimidazolyl, oxazolyl, benzopyrazole, 2,3-dihydrobenzoxazolyl, benzoxazolyl-pyrazolyl , 2,3-Dihydropyrazolyl, 2,3-dihydrobenzimidazolyl, 2,3-dihydrobenzo-15, oxazolo[5,4-b]pyridyl and benzo Triazolyl. ^ Further definitions of the substituents are as follows. Any such definition may be employed, where appropriate, in the context of the < patent application or particular embodiments. On the one hand, 'Ar is a single ring of 5 or 6 members. On the other hand, Ar is a double ring of 8, 9 or 1 employee. On the other hand, Ar is a 9 or 1 employee double ring. The broad-side aspect is a compound of the formula: wherein Ar is a compound containing up to 4 selected from the group consisting of nitrogen, oxygen and sulfur, and 5 to 1 〇 ^ ^ is a condition in which at least one ring nitrogen is contained therein. Replace as above. These compounds have been found to be advantageous compounds. Righteousness, I., second, on the other hand.

Ar is 1 or 2 ring argon and may optionally contain a ring 1310036 A7 B7 5. Inventive Note (8) Stone or oxygen or 5 ring nitrogen atoms 5 _ to 1 〇 _ aromatic ring The ring may be replaced as desired by the above definition. On the other hand, 'Ar is a 5- to 10-membered aromatic ring system containing i or 2 ring nitrogens and optionally containing a ring of atoms, which ring may be substituted as defined above. On the other hand, Ar is a 5- to 10-membered aromatic ring system containing 2 ring nitrogens. The ring may be substituted as defined above. On the other hand 'Ar is selected from the group consisting of: imidazolyl, blowing group, ρ, carbyl, isoxazolyl, phenyl, porphyrinyl, fluorenyl, benzimidazolyl, oxazolyl, benzotriazole , 2,3-Dihydroalrazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[丨,]^]pyridyl, imidazo[4 ,5-b]pyridyl, 2,3-dihydrotetrazolo[5,4_b^t-pyridyl, 2,3-dihydropyrrolidinyl, 2,3-dihydrobenzene-pyrimidazolyl and 2 , 3-dihydrobenzimidazolyl. On the other hand, 'Ar is selected from the group consisting of: Mi", the base of p, the base of p, the ratio of ρ, 洛基, 》, 喳 喳, 喳 、, benzoimidazolyl, carbazolyl, benzo Triazolyl, 2,3-dihydrocarbazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[l,2-a]pyridyl , imidazo[4,5-b]pyridyl, 2,3-dihydropyrazolo[5,4-b]pyridyl, 2,3-dihydropyrrino, 2,3-dihydrobenzo Pyridoxine 2,3 - 2 mad 1 benzo-flavor σ sitting. On the other hand, 'Ar is selected from the group consisting of: taste base, ρ-wow group, stupid taste β-based, ρ 丨嗤 、, benzotriazolyl, 2,3-dihydro benzoxazolyl, pyrrole [2,3-b] oxaridinyl, imidazo[l,2-a]acridinyl, imidazo[4,54^pyridyl, 2,3-dihydrocarbazo[5,4-b Pyridyl, 2,3-dihydropyrrino and 2,3-dihydrobenzimid. _ 12 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1310036 A7 _____B7 V. Description of invention (9) More specific 'f' from: Mickey, Jun, Lin, ^丨Mercapto, benzimidazolyl, oxazolyl, pyrazolyl, benzotriazolyl, 2,3-dihydropyrrazolyl, 2,3-dihydrobenzindole olynyl, ρ ratio ρ [2,3-b]<» than bite base, <» sedative [5,4-b]pyridyl, 2,3-dihydrobenzopyrazole and 2,3-dihydrobenzo Imidazolyl. On the other hand, 'Ar is selected from: Mi. Sitting group, p ratio σ sitting group, u ratio base, iso-p- oxime, phenyl and 2,3-dihydropyrrole. Ar, on the other hand, is selected from the group consisting of quinolyl, fluorenyl, benzimidazolyl, oxazolyl, benzotriazolyl, 2,3-dihydrothiazolyl, 2,3-dihydrobenzoxazole The base and the mouth are more than [2,3-b]·7 than the bite group, the oxime and [i,2-a]p are more than the thiol group, the mers are [4,5-b]pyridyl, 2, 3-Dihydrobenzopyrazolo[5,4-b]pyridyl, 2,3-dihydrobenzoxazolyl and 2,3-dihydrobenzimidazolyl. On the other hand, when on Ar When the substituent is a 5- or 6-membered aromatic ring, the substituent on Ar contains up to two heteroatoms independently selected from nitrogen, oxygen and sulfur. On the one hand, it is selected from furyl, porphinyl, Stupid and pyrimidinyl. On the other hand, it is selected from pyrimidinyl and phenyl. On the other hand, it is a phenyl group. An example of a ring formed by R6 and R7 and the nitrogen atom to which they are attached并 基 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , P is a thiol group, and a ring is formed by a combination of R8 and R9 and the nitrogen atom to which they are attached. , shouting and merging, merging, yelling, and 、 并 并 基 基 号 号 号 号 号 号 号 号 号 号 号 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 Dicylene, succinyl or morphine. R1 and R2 independently represent Cm alkyl, such as: Cl 5 alkyl (for example: methyl----- 13 - This paper size is suitable for China Standard (CNS) A4 size (21〇X 297 mm) 1310036 Five invention instructions 10 A7 B7

2,2_di-n-propyl, propylmethylethyl, n-butyl, 2-methylpropyl, 抡["^methylpropyl, n-pentyl or n-hexyl), fluorenyl, :C3 ~ group (for example, . ^3'4 c - yielding κ acryl, 丨-butyl fluorenyl, 1-pentenyl or 1-hexenyl), bis 2 'yl C|" fluorenyl (cyclopropyl) A fluorenyl group, a cyclobutylmethyl group, a cyclopentylmethyl-(3⁄43⁄4yl)ethyl group, a 2-(cyclobutyl)ethyl group or a 2/(cyclopentyl)ethyl) group or a hexyl group. C"cycloalkyl (cyclopropyl, cyclobutyl, cyclodecyl or ring, each of which may optionally be substituted with 3 halogen atoms (for example: trifluoromethyl, -trifluoroethyl, 2- Chloroethyl, 2-apropyl or 3,3,3-trifluoropropyl). Fu, 20,000 Å, R^R2 independently represent Cm alkyl or cycloalkyl sulphate. 1-3 halogen atoms are substituted. In another aspect, R1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl, cyclopropyl a group, a trifluoromethyl group, a 2,2,2-trifluoroethyl group, a 2-gas ethyl group, a 2-chloropropyl group or a 3,3,3·trifluoropropyl group. In addition, r1 is an ethyl group. N-propyl, isopropyl or 2_ Further, Ri is 2-methylpropyl. In another aspect, 'R2 is methyl or trifluoromethyl. -_ Further, R2 is methyl. On the other hand, 'R3 is a hydroxyl group. 》 唑 啶 _2 _ _ _ _ 羰 羰 四 四 或 或 或 或 或 或 或 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 另一方面 。 。 。 。 。 另一方面 。 另一方面 。 。 。 Tetrahydroisoindole-2-ylcarbonyl. On the other hand, R3 is hydroxyisoazazin-2-ylcarbonyl. On the other hand, R3 is 4-iso-iso- sigma-2-yl. On the one hand, R3 is 4S-hydroxyisoxazolidine-2-yl. -14 - This paper scale applies to Chinese National Standard (CNS) Α4 size (210X 297 mm) !310036

In another aspect, R and R are each independently hydrogen or methyl. On the other hand, Q is -CO - or _ch2·. In one aspect, Q is -CO-. On the other hand, 'Q is -CH2-. In another aspect, Ar is unsubstituted or substituted with i, 2 or 3 substituents. On the other hand, 'Ar is unsubstituted or substituted with 1 or 2 substituents. On the other hand, the substituent of Ar includes a c14 alkyl group (which may optionally be substituted by a hydroxyl group), a Cm alkoxy group, a halogen, a tris-alkyl group, a c14 alkylthio group, a CM alkyl alcohol group, an oxo group, a thio group. a cyano group, wherein p is 1 or 2), a hydroxy group, a Cm alkanesulfonyl group, an amine carbaryl group, a Cm alkylamine carbhydryl group, a mono-(C!-4 alkyl)amine fluorenyl group, a few Or a 5 or 6 membered aromatic ring system containing up to 4 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In a specific aspect, the substituent of Ar is selected from: .Cl_4 alkyl, _, c2_4 alkyl, trifluoromethyl, oxo, thio, hydroxy c14 alkyl, amine, Cm alkylamino And (:|.4 alkylthio group. On the other hand, the substituent of Ar includes methyl, ethyl, n-propyl, isopropyl, t-butyl, 1-methylethyl, trifluoromethyl , gas, fluorine, bromine, methyl, ethyl sulfonyl, sulfonylthio, amine, methylamino, furyl, thiophene, p-density, phenyl, cyano, thio and oxo On the other hand, the substituent of Ar includes methyl, propyl, isopropyl, 1,4-butyl, 1-methyl'ethyl, trifluoromethyl, chlorine, gas, desert, methylthio, amine. a group, a methylamino group, a phenyl group, a pyrimidinyl group, a cyano group, a thio group and an oxo group. On the other hand, the specific substituent of Ar is selected from the group consisting of methyl, ethyl, propyl, tert-butyl, 1- Methyl ethyl, gas, fluorine, bromine, hydroxymethyl, ethyl ketone, methyl-15

This paper scale applies to China National Standard (CNS) A4 specification (210x 297 metric tons) 1310036 A7 B7 V. Description of invention (12) Sulfur, amine, methylamino, thio and oxo groups. On the other hand, the specific substituent of 'Ar is selected from the group consisting of methyl, ethyl, propyl, tert-butyl, fluorine, chlorine, oxo, thio, hydroxymethyl, amine, methylamine and methyl sulfide base. In another aspect, the specific substituent of Ar is selected from the group consisting of methyl, propyl, tert-butyl, fluorenyl-methylethyl, gas, fluorine, methylthio, amine, methylamino, thio and oxo. i.

Special meanings for Ar include 4,5-mono-2-methyl-zemonyl, 45-dichloro-2-hydroxymethylimidazol-1-yl, 2,4,5-tris-2-methylimidazole _丨_yl, 4,5•diazol-2-yl, 2-bromo-4,5-diimidazol-2-yl, 2-methylthio-imidazole 丨····, 3,5--峨wow-4-yl, 1,3,5-trimethyl p-t-but-4-yl, 3 5-dimethyl-yttrium-4-yl, 3-tert-butyl-5-methyl Pyrazol-4-yl, 3,5-dimethyl? Bisazo-1-yl, 5-methyl-3-phenylpyrazol-4-yl, 5-methyl-3-(trifluoromethyl)pyrazole-4-yl, 5-methyl-3- (prop-2-yl)pyrazol-4-yl, 3,5-methyl-i-yl, phenylpyrazol-4-yl, 5-dioxa-2,3-dihydro-2-oxo Pyrazol-3-yl, 4-chloro-2,3-dihydro-2-oxo psec-3-yl, 3,5-dimethylisoindole-4-yl, 2,4-di Methyl-1-(propan-2-yl)ρbilo-3-yl, 2-trifluorophenyl, 2,3-dihydro-6-mercapto-3-oxo-p-r n林-4 -基,Β查11林-5-yl, 6-qikui alin·4 -yl, 8 _ ρ ρ trocarto-4-yl, 2-methyl morpholin-4-yl, 2 -methylindol-3-yl, 7-methyl<indol-3-yl, 5-cyanothion-1-yl, 2-methylbenzimidazole-indoleyl, 2-ethylbenzene Imidazolyl-1 -yl, 2-propylbenzimidazole-1-yl, 2-methylthiobenzimidazol-1-yl, 2-hydroxymethylbenzimidazol-1-yl, 2-methylamino Benzimidazole 丨 丨 基, 2-amino benzo benzophenone-1-yl, u ratio p and [2,3-b]! 7 ratio bite 3-yl, 2-methylpyrrolo[2 ,3-b]pyridin-1-yl, 2-methylpyrrolo[2,3-b]pyridin-3-yl, -16 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 PCT) A7 B7

1310036 V. Description of the invention: [i,2-[a]pyridin-3-yl, 2,(methylthio)imidazo[4,5-b] ton, yl, 2-(methylthio)imidazo[4 , 5_b]pyridine-3-yl, alum, '1-oxazol-bry, 2,oxo-2,3-dihydrobenzopyrazol-3-yl, 2-thio-3, teach three stupid and &quot ; stopper °-3_ base, 2-oxo-2,3-dihydrobenzoxazole-1-yl, 1~ gas 2,3-dihydrobenzimidazole-3-yl, 2_oxygen代·2,3·Dihydrobenzimido _ 1 · 5,6-difluoro 2′ oxo-2,3-dihydrobenzimidazol-1-yl and 2-oxo_2 3 : Dibenzothiazolo[5,4-b]pyridin-3-yl. ~wind

Other specific definitions of Ar include 4,5-dichloro-2-methylimidazolium-indenyl, 2,4,5-di-2-methylimidazol-1-yl, 4,5-diimidazole-2 a ratio of -3,5-dimethylpyridin-4-yl, 1,3,5-trimethyl p to quaternary-4-yl, 3,5-dimethyl p. _4-yl, 3-t-butyl-5-methylpyrazol-4-yl, 5-dichloro-2,3-dihydro-2-oxopyrazole-3-yl, 4-chloro -2,3-dihydro-2-oxo-3-yl, phenyl-4-yl, +4-5-yl, .6-fluoroporphyrin-4-yl, 8-fluoroindole- 4-yl, 2-mercaptoquinolin-4-yl, 2-methylindol-3-yl, 7-methylβ哚-3-yl, 5-cyanoindole_yl-yl, 2- Methyl benzimidazole '1-yl, 2-ethylbenzimidazol-1-yl, 2-propylbenzene I imidazol-1-yl, 2-methylthiobenzimidazol-1-yl, 2-hydroxyl Methyl benzimidazol-1-yl '2-methylaminobenzimidium oxime, 2-aminobenzimidazole-indole-based, p-pyrolo[2,3-b]acridine 3-yl, 2-methylpyrrolo[2,3-b]pyridine_1-yl, 2-methyl-17, succinyl[2,3-b]oxa-3-yl, 1H-1, 2,3-benzotriazol-1_yl, 2-oxo-2,3-dihydrobenzotetrazole-3-yl, 2-thio-2,3-dihydrobenzoxazole-3 -yl, 2-oxo-2,3-dihydroindole 吟α-l-yl, 6-methyl-3-oxo-2,3-dihydro-3 ratio ρ well-2-yl and 2 -oxo_ι,3·thiazolon [5,4-b]pyridin-3-yl. In one aspect, R6 and R7 independently represent a hydrogen atom, a CU4 alkanoyl group (e.g., a methylidene group, an ethyl thiol group or a propyl group) or a C. .4 alkyl group (for example, methyl group, B group).

________- 17 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1310036 A7 B7 V. Description of invention (14) Base, n-propyl or n-butyl), or attached thereto The nitrogen atoms together form a 5- to 7-membered saturated heterocyclic ring. On the other hand, 'R6 and R7 each independently represent a hydrogen atom or an alkyl group. In one aspect, R8 and R9 each independently represent a hydrogen atom, a Cm alkano group (eg, a decyl group, an ethyl fluorenyl group or a propyl group) or a ci 4 alkyl group (eg, a methyl group, an ethyl group, a n-propyl group). Or n-butyl), or a nitrogen atom attached thereto, to form a 5- to 7-membered saturated heterocyclic ring. On the other hand, R8 and R9 each independently represent a hydrogen atom or a C14 alkyl group. - A specific compound is a compound of the formula (1), wherein: a tiger group or a C; 5-6 cycloalkylmethyl group; R 2 is a C 1 _5 alkyl group; and R 3 is a heterotopic thiophene-2-ylcarbonyl group or a tetrahydroiso a quinone-2-ylcarbonyl group, wherein each ring may be optionally substituted with a light group; Q is -CO- or -CH2. (wherein R4 is a hydrogen atom or a c14 alkyl group and the rule 5 is a hydrogen atom or a hydroxyl group);

Ar is a 5- to 10-membered aromatic ring system, wherein up to 4 ring atoms may be heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, respectively, which may be independently 1, 2 or 3, respectively. Substituted by a substituent selected from the group consisting of Ci 4 alkyl (which may optionally be substituted with 2' or 3 hydroxyl groups), Cw alkoxy, halogen, ! S,,,,,,,,,,,,,,,,,,,,,, a group, a cyano group, a -N(R6)r7 and a _ch2nr8r9; R6 and R7 each independently represent a hydrogen atom or a C?_4 alkyl group, or a nitrogen atom attached thereto to form a 5- to 7-membered saturated heterocyclic ring; -18 - This paper size applies to China National Standard (CNS) A4 specification (21GX 297 public) 1310036

R R independently represents a hydrogen atom or an alkyl group to form a 5- to 7-member saturated heterocyclic ring; 〜', attached thereto or a pharmaceutically acceptable salt or prodrug thereof. Another compound is a compound of formula (1) wherein: R is C!-5-based or c3_6 cycloalkylmethyl; R2 is Cm alkyl; R3 is hydroxyisoindole__2-ylcarbonyl, thiol iso-iso-sigma No. 2 - fluorenyl; Q is -CO- or -CH2-: Ar is a 5- to 10-membered aromatic ring system, which is selected from the following ring heteroatoms: Nitrogen-Iso-2-yl-based It/comprising up to 4 can be individually, oxygen and sulfur, but the limiting conditions cover, and S has at least one ring nitrogen'. The ring may be replaced by one or more substituents each selected from the following: C Knife U and Ll·4 alkyl (which may be replaced by 1 or 3 searches), Cu4 alkoxy, _ _, _ phenyl, geminary, trifunctional, c 丨 oxy red · Aged, Ci-thio, c" alkanocarbyl, cw-filled, oxo, thio, nitro, aryl, -N(R6)R7 and -(CH2)pN(r8 )r9, county, Ci material base, c ^ sulfinyl group, amine methyl sulfonyl group, Ci_4 alkyl amine methyl sulfonyl group, dialkyl) amine methyl sulfonyl group, carboxyl group, and containing up to 4 separately selected 5 or 6 member aromatic rings from the atom of the earth: nitrogen, oxygen and sulfur: R6 and R7 stand independently An atom or a Ci 4 alkyl group, or a nitrogen atom to which it is attached, together form a 5- to 7-membered saturated heterocyclic ring; R8 and R9 are divided into (four) an alternating 4 hydrogen atom or c "4 alkane"; or attached thereto The nitrogen atoms together form a 5- to 7-membered saturated heterocyclic ring; -19 -

A7 B7 1310036 V. Description of the invention (16) or a pharmaceutically acceptable salt thereof. Another compound is a compound of formula (1) wherein: R1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-methyl-propyl, cyclopropyl Methyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2-oxoethyl, 2-chloropropyl or 3,3,3-trifluoropropyl; R2 is methyl; R3 is hydroxy Tetrahydroisoindol-2-ylcarbonyl, tetrahydroisoindol-2-ylcarbonyl or transtetrahydroisophthalene-2-ylcarbonyl; Q is -CO- or -CH2-;

Ar is a 5- to 10-membered aromatic ring system comprising up to four heterocyclic atoms which may be independently selected from the group consisting of nitrogen, oxygen and sulfur, but with the proviso that at least one ring nitrogen is present therein, the ring being visible It is desired to be substituted by one or more substituents each independently selected from the group consisting of Cm alkyl (which may optionally be substituted with 1, 2 or 3 hydroxyl groups), Cl4 alkoxy, _, haloalkyl, dihaloalkyl , trihaloalkyl, C丨-4 alkoxy Cl-4 alkyl, Cw alkylthio, C 4 alkoxycarbonyl, C2-4 alkanoyl, oxo, thio...nitro, cyanide , -N(R6)R7 and -(CH2)PN(R8)R9, hydroxy, CU4 alkanesulfonyl, Ci-4 alkylsulfinyl, amine methyl sulfhydryl, Cl 4 alkylamine fluorenyl, -(C,-4 alkyl)aminecarbamyl, carboxyl, and 5 or 6 membered aromatic rings containing up to 4 heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; R6 and R7 each independently represent hydrogen An atom or a Cl 4 alkyl group, or a nitrogen atom to which it is attached, forms a 5- to 7-membered saturated heterocyclic ring; R and R 9 each independently represent a hydrogen atom or a C! 4 aryl group, or are attached thereto (a nitrogen atom Forming a 5- to 7-membered saturated heterocyclic ring; National Standard for Paper Scales _ A7 B7 1310036 V. Description of Invention (17) or a pharmaceutically acceptable salt thereof. Another compound is a compound of formula (1) wherein: R1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl or cyclopropylmethyl; R2 is methyl; R3 is hydroxytetrahydroisoxazolidine-2-ylcarbonyl, Tetrahydroisoindole-2-ylcarbonyl or hydroxytetrahydroisoindole-2-ylcarbonyl; Q is -CH2-;

Ar is a 5- to 10-membered aromatic ring system comprising up to 4 ring heteroatoms independently separable from nitrogen, oxygen and sulfur, but with the proviso that at least one ring nitrogen is present therein, which may optionally Substituted by 1 or 2 substituents each independently selected from the group consisting of CU4 alkyl (which may optionally be substituted with 1, 2 or 3 hydrazine hydroxy), C^4 alkoxy, halogen, tris-alkyl, Cw alkane Thio group, C2_4 alkyl fluorenyl group, oxo group, thio group, cyano group and -(CH2)pN(R8)R9 (wherein p is 1 or 2), hydroxyl group, Cw alkanesulfonyl group, amine carbenyl group, Cm alkylamine methyl sulfonyl, bis-(C, alkyl) amine methyl sulfonyl, carboxyl, and 5 or 6 member aromatic rings containing up to 4' each independently selected from the following heteroatoms: nitrogen, oxygen and Sulfur: or a pharmaceutically acceptable salt thereof. Another compound is a compound of formula (1) wherein: R1 is ethyl, n-propyl, 1-methylethyl, 2-methylpropyl, 2,2-dimercaptopropyl or cyclopropyl R2 is methyl; R3 is 4-hydroxytetrahydroisoindole-2-ylcarbonyl or tetrahydroisoindole-2-ylcarbonyl_- 21 - This paper scale applies to China National Standard (CNS) A4 specification ( 210X 297 mm) 131〇〇36 A7

B7 base; Q is -ch2-;

Ar is selected from the group consisting of: imidazolyl, pyrazolyl, pyrrolyl, isoxazolyl, phenyl, ° lin, 4-mercapto, benzimidazolyl, oxazolyl, benzotriazolyl, 2'3 -dihydrotetrazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl-Zhuteng [l,2-a]p is more than a decyl group [4,5-b]p ratio decyl, 2,3-hydrothiazolo[5,4-b]pyridyl, 2,3-dihydropyrryl, 2,3-dihydrobenzo &quot ; thiol and 2,3-dihydrobenzimidazolyl, the ring may be substituted by 1 or 2 substituents each independently selected from the group consisting of methyl, ethyl, n-propyl, isopropyl , tert-butyl, hydrazine-methylethyl, trifluoromethyl, chloro, fluoro, bromo, hydroxymethyl, ethyl thiol, methylthio, amine, methylamino, flunan, ° a pyrimidyl group, a phenyl group, a cyano group, a thio group and an oxo group; or a pharmaceutically acceptable salt thereof. Another aspect - the present invention relates to a compound of the formula (1)

Wherein: R1 and R2 independently represent a Cl_6 alkyl group, a C3.6 alkyl group, a CM cycloalkyl Cu group or a C3.6 cycloalkyl group; each of which may be substituted with 1 to 3 halogen atoms; R3 is an isoindole Azolidin-2-ylcarbonyl or tetrahydroisoindole-2-ylcarbonyl, wherein each _____- 22 - this paper scale is applicable to China National Standard (CNS) A4 specification (210X297 public Chu) 1310036 A7 B7 V. Description of invention (19) The ring may be optionally substituted with a hydroxyl group; Q is -CO- or -C(R4)(R5)- (wherein R4 is a hydrogen atom or a Ci_4 alkyl group, and R5 is a hydrogen atom or a via group);

Ar is a 5- to 10-membered aromatic ring system, wherein up to 4 ring atoms may be independently selected from the following heteroatoms: nitrogen, oxygen and sulfur, and the ring system may be independently selected by one or more separately as needed. Substituted from the following substituents: Cm alkyl (which may optionally be substituted with 1, 2 or 3 hydroxy groups), Cm alkoxy, halogen, haloalkyl, di-alkyl, tri-alkyl, Ci 4 alkoxy Alkyl 4 alkyl, d. 4 alkylthio, Cm alkoxycarbonyl, Cm alkanoyl, oxo, thio, nitro, cyano, -n(r6)r7 and _(CH2)pN ( R8) r9, hydroxy, Ci j sulfonyl, Cm alkyl sulfinyl, amine carbaryl, Ci. 4 alkyl fluorenyl, bis-methionylamino group, several groups; P is 1 to 4 ;

Ci-4^g| group or cN4 alkyl group, or i 7-membered saturated heterocyclic ring; C1 block * enzyme group or C 4 alkyl group, or R6 and R7 independently represent a hydrogen atom, Cu and its attached nitrogen The atoms together form 5 to 7 R8 and R9 each independently represent a hydrogen atom, and C, together with the nitrogen atom to which they are attached, form a 5-7 to 7-membered saturated heterocyclic ring; or a pharmaceutically acceptable salt or prodrug thereof. A specific compound is a compound of the formula (丨) wherein: R1 is Cm alkyl or c3-6 cycloalkylmethyl; R ' is C | . 5 pit; R3 is isoxazolidine-2-ylcarbonyl or tetrahydroiso a gas carbonyl-based group in which each ring may be substituted with a hydroxyl group as needed;

1310036 A7 _______ B7 a ___ V. Description of the invention (2〇) A hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, which may be substituted by 1, 2 or 3 substituents independently selected from the following: C! -4 alkyl (which may be substituted by 1, 2 or 3 radicals), C1 - 4 -oxy, halo, haloalkyl, dihaloalkyl, trihaloalkyl, CN4 alkoxy · 4 alkyl, C, _4 alkylthio, cU4 alkoxycarbonyl, c2-4 alkanoyl, oxo, nitro, cyano '-N(R6)R7 and _CH2NR8R9; R0 and R7 independently represent A hydrogen atom or a Cl 4 alkyl group, or a nitrogen atom attached thereto, forms a 5- to 7-membered saturated heterocyclic ring; R 8 and R 9 each independently represent a hydrogen atom or a C μ alkyl group, or a nitrogen atom attached thereto Forming a 5- to 7-membered saturated heterocyclic ring; or a pharmaceutically acceptable salt or prodrug thereof. Another compound is a compound of formula (1) wherein:

WgCus alkyl or c3-6 cycloalkylmethyl; R is C 1.5 pit; R3 is hydroxytetrahydroisoindole-2-ylcarbonyl or hydroxytetrahydroiso 11 " well-2-yl Base; Q is -CO- or -CH2-;

Ar is a 5- to 10-membered aromatic ring system, wherein up to 4 ring atoms may be heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, which may be independently selected by 1, 2 or 3, respectively. Substituted from the following substituents: Cl. 4 alkyl (which may optionally be substituted with 1, 2 or 3 hydroxy groups), Cm alkoxy, _ s, haloalkyl, di-alkyl, trihaloalkyl, Cw Alkoxy Cl·4 alkyl, Cufe thio, CU4 垸 oxycarbonyl, C2-4 alkyl fluorenyl, oxo, $ 肖基, cyano, N(R6)R7 and -CH2NR8R9 ; ____ - 24 - Ben The paper scale applies to the Chinese National Standard (CNS) A* specification (21〇χ297 mm) 1310036

R and R each independently represent a hydrogen atom or a Cw alkyl group, or a nitrogen atom bonded thereto to form a 5·7-7-membered saturated heterocyclic ring; 'R and R each independently represent a hydrogen atom or a C|·4 alkyl group, Or together with the nitrogen atom to which it is attached, form a 5- to 7-membered saturated heterocyclic ring; or a pharmaceutically acceptable salt thereof. Another compound is a compound of formula (1) wherein: R1 is Ci-5 alkyl or c3-6 cycloalkylmethyl; R2 is methyl; R3 is hydroxyisoxazolidin-2-ylcarbonyl or hydroxytetrahydro Isobarosin_2_ylcarbonyl: _Q is -CO- or -CH2-;

Ar is a 5- to 10-membered aromatic ring system, wherein up to 4 ring atoms may be heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, which may be independently selected by 1, 2 or 3, respectively. Substituted from the following substituents: Cm alkyl (which may optionally be substituted with 1, 2 or 3 hydroxy groups), Cl 4 alkoxy, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, Cl.4 alkane Oxy Cw alkyl, Cw alkylthio, Cm alkoxycarbonyl, c2_4 alkylthio, oxo, nitro, cyano, -N(R6)R7 and -CH2NR8R9; R6 and R7 each independently represent a hydrogen atom or a Cw alkyl group, or a nitrogen atom to which it is attached, together form a 5- to 7-membered saturated heterocyclic ring; and R9 independently represent a hydrogen atom or a Cw alkyl group, respectively, or a nitrogen atom attached thereto to form a 5- to a 7-membered saturated heterocyclic ring; or a pharmaceutically acceptable salt thereof. Another compound is a compound of formula (1), where: -25 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)

Binding

1310036

R is ethyl, n-propyl, hydrazine, methylethyl, 2-methylpropyl, 2,2 dimethylpropyl or cyclopropylmethyl; R2 is methyl; Α R is fluorenyl Isoxazolidin-2-ylcarbonyl or hydroxytetraisoxan-2-ylcarbonyl; 'Q is -CO- or _〇η2-;

Ar is a 5- to 丨〇-membered aromatic ring system, wherein up to 4 ring atoms may be heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur, respectively, which may be independently 1, 2 or 3, respectively. Substituted by a substituent selected from C, -4 alkyl (which may optionally be substituted with hydrazine, 2 or 3 hydroxy groups), Ci-4 alkoxy, halogen, ketyl, dialkyl, trihaloalkyl, C14 alkoxy Cm alkyl, C|'4 pit thio, ci-4 alkoxycarbonyl, C2.4 alkyl fluorenyl, oxo, nitro, cyano, n(r6)r7 and -CH2NR8R9; R7 and R9 independently represent a hydrogen atom or a C4 alkyl group, respectively The attached nitrogen atoms together form a 5-7 to 7-membered saturated heterocyclic ring; or a pharmaceutically acceptable salt thereof. Another specific compound is a compound of formula (i) wherein: R1 is ethyl, n-propyl, hydrazine-methylethyl, 2-methylpropyl, 2,2-dimethylpropyl or cyclopropyl Methyl; R2 is methyl; R3 is hydroxyisodinyl-2-ylcarbonyl; Q is -CO- or -CH2-; _ - 26 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X) 297 public) 1310036 invention description 23 A7 B7

Ar is 5- to i〇_g divided into mussel non-fragrance ring system, wherein at most 4 ring atoms may be independently selected from the following, _ heteroatoms: nitrogen, oxygen and sulfur, the ring system may be subjected to 1 2, every 2 gamma 8 & j 1U knife is independently selected from the following substituents: Cl_4 alkyl (which can be replaced by I's two, two or three radicals), C1,4 alkoxy , halogen ketone, di-alkyl, trihaloalkyl, Ci.4 alkoxy C 4 alkyl, Cufk thio, Ci-4 alkoxycarbonyl, c 2 4 alkyl thiol, oxo, nitro, 6 Aromatic group, 'N(R6)R7 and -CH2NR8R9; 77爿] the sole work represents a hydrogen atom or a C_t-4 alkyl group, or a nitrogen atom bonded thereto to form a 5- to 7-membered saturated heterocyclic ring; And R9 independently represent a hydrogen atom or a C 4 alkyl group, or a nitrogen atom to which it is attached, to form a 5- to 7-membered saturated heterocyclic ring; or a pharmaceutically acceptable salt thereof. Another compound is a compound of formula (1) wherein: R1 is ethyl, n-propyl, b methylethyl, 2 mercaptopropyl, 2,2-dimercaptopropyl or cyclopropyl R2 is methyl; R3 is hydroxyisoxazolidin-2-ylcarbonyl; Q is -CO- or -CH2-:

Ar is selected from the group consisting of: imidazolyl, pyrazolyl, 2,3-dihydrocarbazolyl, porphyrinyl, (9) mercapto, benzimidazolyl, tetrazolyl, pyrrolo[2,3_b0tidine, 1H-1 , 2,3 - stupid and succinyl, 2,3, dihydrobenzo oxothyl, 2 3-dibenzophenidyl, 2,3-dihydro cumin $ thiol and 1,3 - Thiazolo[5,4_b]p is a aryl group which may be substituted by 2 or 3 substituents each independently selected from the group consisting of Cm alkyl (which may be substituted by 1, 2 or 3 hydroxyl groups as desired) ) -27 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public 1310036)

V. Description of the invention (24), oxy group, halogen, haloalkyl, dihaloalkyl, trihaloalkyl, Ci-4 alkoxy Ci-4 alkyl, Cw alkylthio, Ci.4 alkoxy Carbonyl group, C2_4 alkyl group, oxo group, nitro group, cyano group, N(R6)R7 and _CH2NR8R9; R and R7 each independently represent a hydrogen atom or a C|_4 alkyl group, or a nitrogen atom attached thereto Forming a 5- to 7-membered saturated heterocyclic ring; R and V each independently represent a hydrogen atom or a C U4 alkyl group, or a nitrogen atom attached thereto to form a 5- to 7-membered saturated heterocyclic ring; or a pharmaceutically acceptable Accept the salt. Another compound is a compound of formula (1) wherein: R1 is n-propyl, 1-methylethyl or 2-methylpropyl; R2 is methyl; R3 is 4-hydroxyisoxazolidine-2- Carbocarbonyl; Q is -co- or -ch2-;

Ar is selected from the group consisting of imidazolyl, pyrazolyl, 2,3-dihydrocarbazolyl, quinolyl, decyl, benzoxazolyl, pyrrolo[2,3-b]pyridinyl, 1H-1, 2,3-benzodiazepine, 2,3-di-substrate benzo-p-sigma. base, 2,3 - one y1 and 1 guanyl and 1,3-4 oxazolo[5,4- b] pyridyl group, which may be substituted by 1, 2 or 3 substituents each independently selected from the group consisting of methyl, ethyl, propyl, tert-butyl, chloro, fluoro, thio, hydroxy Methyl, methylthio, amine, methylamino and oxo; or a pharmaceutically acceptable salt thereof. Specific compounds of the present invention include: (S)-5-[4-superyliso 11 spit-2-ylcarbonyl-yl]-3-methyl-1-(2-methylpropyl)-6- (4-4 phenylmethyl) "deseno[2,3-d]pyrimidine-2,4(1Η,3Η)-:_; -28 - 1310036 A7 B7 V. Description of invention (25) (艮) 5-[4-Hydroxyisoxazolidine-2-ylcarbonyl]_3_methyl_1_(2-methylpropyl)_6_(4-. quinolinylmethyl) benzophenan [2,3_d]pyrimidine _2,4(1h,3h)-dione; (S) 6-[4,5-Dichloro-2-methyl-1H-imidazol-1-ylmethyl]-5-[4-hydroxy-2 -isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)sulfono[2,3_d]pyrimidine-2,4(1H,3H)-dione; (S) 5 -[4-hydroxyisoxazolidine-2-ylcarbonyl]_3_indolyl_丨_(2-methylpropyl)_6_(4-4 phenylcarbonyl)thieno[2,3-ci]pyrimidine- 2,4(1Η,3Η)-:_; (S) 5-[4-Hydroxyisoxazolidine-2-ylcarbonyl]_3·methyl_6_[(2•methyl·1Η-啕哚-3 -yl)methyl]-1-(2-mercaptopropyl)sulfono[2,3_d]pyrimidine·2,4(1Η,3Η)_dione; (S) 5-[4-hydroxyisoindole Azolidinyl-2-ylcarbonyl]_3_indolyl-^^-methylpropyl)_6_ [(1 Η _ ρ 毕洛和[2,3 - b ] ρ比症-3 _基)methyl]ρ Sepheno[2,3 , d ] α -2,4(1Η,3Η)-dione; (S) 5-[4-starting co-dissolving _2-ylcarbonyl]·3·methyl_6-[(2-methyl- ΐΗ-哚 哚-3-yl)carbonyl]-1-(2-methylpropyl)thieno[2,3-d]pyrimidine_2,4(丨Η,3Η)-dione; (S) 5-[ 4-hydroxyisoxazolidinyl-2-ylcarbonyl]_3_mercapto_; u(1•methylethyl)_6_ (1 Η - ϊ ratio β and [2,3 - b ] ρ ratio bite _ 3 -ylmethyl)p-senteno[2,3 _d]»dense-2,4(1H,3H)-dione; (S) 5 -[4-mouryliso-4-pyridin-2-yl Carbonyl]_3 -methyl_ι_propyl_6_(exit_yellow p and [2,3-b]p is more than -3-ylmethyl)t>seno[2,3-d] . Bite 2,4(lH,3H)-dione; (S) 6-[4,5-monochloro-2-oxo-3 (2H)-p succinylmethyl]_5_[4_ υ υ 唆 -2- -2- 基 ] ] ] ] ] ] ] ] ] ] -3 -3 -3 -3 -3 -3 -3 -3 -3 - - - - - - - - - - - - - - - - - Household Standard (CNS) Α4 Specification (210X 297 mm) 1310036 A7 B7 V. Description of Invention (26) ~ -2,4(1H,3H)-Dione; (S) 6-[(3,5-dimethyl -1H-pyrazol-4-yl)methyl]·5_{4-hydroxyisoxazolidine-2-ylcarbonyl}-1-isobutyl-3-methyl-4-pheno[2,3-d Pyrimidine-2,4(1 Η,3Η)-dione; (S) 5-{4-initial. Sedative-2-ylcarbonyl 丨_ι_isobutyl _3_methyl _6_ [1,3,5-trimethyl-1 Η-pyrazole-4-ylmethyl] 喽 并 [2, 3 - d ] pyrimidine-2,4(1H,3H)-dione: (R) 6-[(4,5-di-gas-2-methyl-1H-imidazolyl)methyl]_5·[4- Benzyl-isoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)P-seceno[2,3-d]pyrimidine-2,4(1H,3H) -dione; (S) 5-[4-carbazyloxazolidin-2-ylcarbonyl]-3-methyl-6-[(2-methyl-111-benzimid-1-yl) Methyl]-1-(2-methylpropyl)p-seceno[2,3-d] p-biti-2,4(1H,3H)-dione; (S) 6-[(2- Ethyl-1H-benzimidazol-1-yl)methyl]·5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)indole Sepheno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-indolyl-1 -(2-methylpropyl)-6-[(2-propyl-1H-benzimidazol-1-yl)methyl]sulfono[2,3-d]pyrimidine-2,4(1H, 3H)-dione; (S) 5-[4-carbazyl- thiophene-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6- [2- ( Methylthio)-1 -benzimidazol-1-ylmethyl]indeno[2,3 - d ]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4- hydroxyl Isooxazolidine-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1Η-benzid-1-ylmethyl]-3-methyl-1-(2-methylpropane) Benzo[2,3-d]p-dense-30 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) A7 B7 1310036 V. Invention description (27) -2,4 ( 1H,3H)-dione; (S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1H-benzimidazole -1-ylmethyl]-1-(2-methylpropyl)sulfono[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4- Hydroxyisoxazolidine-2-ylcarbonyl]-3-methyl-6-[2·amino-1H·benzimidazol-1-ylmethyl]-1-(2-methylpropyl)sulfonate And [2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1- (2-methylpropyl)-6-[(2,4,5-dichloro-1H-sodium-1-ylmethyl)-p-indeno[2,3-d]11-bite-2, 4(1H,3H)-dione; (S) 5-[4-Hydroxyisoxazin-2-ylcarbonyl]-3-methyl-1-(2-mercaptopropyl)-6-[2 -thio-3(2H)-benzo-alphazolyl T-yl]4-[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4 -hydroxyisoxazolidine-2-ylindenyl]-3-methyl-1-(2-methylpropyl)-6-[4- -2-oxo-3(2^1)-1> plug" sityl sulfhydryl] 11 phenophene [2,3-<1]'1 bite-2,4(1H,3H)- Ketone; - (S) 5-indole 4-hydroxyisoxazolin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-oxo-1,3 -benzoxazole-3(2)-ylmethyl]thieno[2,3-(1]pyrimidine-2,4(1H,3H)-dione: (S) 5-{4-hydroxyiso Oxazolidine-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl: l·6-[(2-oxo[丨,3]pyrazolo[5,4-b]] Pyridin-1-(2H)-yl)methyl]P-seceno[2,3-(1]pyrimidine-2,4(1,31^)-dione: (S) 5-[4-异异》号吐虎-2-ylcarbonyl]-3 -mercapto-1-(2-methylpropyl)-6-(1H-1,2,3-benzotris-1-ylmethyl σ 塞 并 [2,3-d].密-31 - This paper size is applicable @国标准(CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (28) -2,4(1H,3H)-dione; S) 5-[4-Hydroxyisoxazolidine-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)_6_ (1 Η-pyrrolo[2,3 - b]pyridine- 1-methyl-)P-seceno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazolin-2-ylcarbonyl] -3-methyl-l-(2-f-propyl)-6-[2-indolyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl-seceno[2,3- d] oxaridin-2,4(1H,3H)-dione; (S) 1-[1,2,3,4-tetrahydro-5-[4-hydroxyisoxazolidine-2-ylcarbonyl] -3-methyl-1-(2-methylpropyl)-2,4-oxo- 1» tomb-[2,3-(1]1^-Bite-6-ylmethyl)-111 - 1嗓-5-nitrile; (S) 5-{4-hydroxyisoxazolidine-2-ylcarbonyl-3-methyl-1-(2-methylpropyl)-6-[2-oxo --1,3-benzoxazole-3 (2H)-ylmethyl]P-seceno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (R) 5- [4-Hydroxyisoxazin-2-ylcarbonyl]-3-fyl-6-[2-methyl-1H-indol-3-ylmethyl]-1-(2-methylpropyl) Pyrimido[2,3-d]pyrimidine-2,4(1H,3H)-dione; - (R) 5-[4-hydroxyl Oxazolidine-2-ylcarbonyl]-3-methyl-6-[2-methyl-1H-4indol-3-ylmethyl]-1-(2-methylpropyl)indole[2] , 3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]·3-methyl-6-[2-( Mercaptoamino)-3Η-imidazo[4,5-b]pyridin-3-ylmethyl]·ι_propyl-seceno[2,3-d]pyrimidine-2,4(1H,3H) - diketone; (S) 6-[4,5-dioxa-2-methyl-1H-imidazol-1-ylmethyl]_5-[4-hydroxy-2·isosalitonyl carbonyl]-3 -Methyl-1-propyl-p-amino-[2,3-d]*1---- This paper scale applies to Chinese Painter Standard (CNS) A4 size (210 X 297 mm) 1310036 A7 B7 , invention description (29) -2,4(1H,3H)-dione; (3) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6-[2-( Methylamino)) 1H-benzimidazol-1-ylmethyl]-1-(1-methylethyl) thieno[2,3 gnache-2,4(1Η,3Η)-dione; (S) 6-[4,5-di-gas-2-methyl-1 fluorene-imiton-1-ylmethyl]-5-[4-superyl·2-isoxazolidinylcarbonyl]-3- Methyl-1-(1-methylethyl)thieno[2,3-d]pyrimidine-5-carboxamide; (S) 6·[3,5-diethyl-1 Η-ρ ratio spit -4-ylmethyl]-5-{4-pyro-g-snose · 2-ylcarbonyl}-3-A 1-(2-methylpropyl-deseno[2,3-d]n-dense-2,4(1H,3H)-dione; (3)6-[3-(1,1- Dimethylethyl)-5-methyl-1^1-pyrazol-4-ylindenyl]-5-{4-hydroxyisoxazolidine-2-ylcarbonyl-3-methyl-1-( 2-methylpropyl)sulfonio[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazolin-2-ylcarbonyl] -3-methyl-1-(2-methylpropyl)-6-[2-methyl-4-indolyl fluorenyl]thieno[2,3-d]pyrimidine-2,4(1H, 3H)-dione; (S) 6-[6-fluoro-4-quinolinylmethyl]-5-{4-hydroxyisoxazolidine-2-ylcarbonyl}- 3-methyl-1-( 2-methylpropyl>deseno[2,3-d]pyrimidine-2,4(1 H,3H)-dione; (S) 6-[8-emulsion-4-t7cha 1#•曱基基]-5-{4-基基基崎11坐坐-2-基谈基}- 3-methyl-1-(2-methylpropyl) sulfonio[2,3-d] Pyrimidine-2,4(1H,3H)-dione; (S) 5-indole 4-hydroxyisoxazolidine-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)- 6-(5-4 phenylmethyl) 4 benzo[2,3-d]pyrimidine-2,4(1 H,3H)-dione; (S) 5-{4-hydroxyisoxazole pyridine- 2-ylcarbonyl-3-ethyl-1-propyl-6-(porphyrin-4-ylmethyl)4 benzo[2,3-d]pyrimidine-2,4(1H,3H)-dione (S) 5-{4-hydroxyisoxazolidine-2-ylcarbonyl } -3-methyl-1- (1-methylethyl) ---33-- scale applies the solid sheet according to the present national standards (CMS) A4 size (210X 297 mm)

Binding

A7 B7 !310036 V. Description of the invention (30) 6-(4-〇 quinolinylmethyl)sulfono[2,3-d]pyrimidine-2,4(1 H,3H)-dione; (S 5-[4-Hydroxyisoxazin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2, 3-b]pyridin-3-yl)methyl]sulfeno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (R) 5-[4-hydroxyisoxazole -2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-6-[(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)- ,]]-[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)-5-[4-hydroxyisoxazolidine-2-ylcarbonyl]-3- Methyl-1-(isobutyl)-6-[2,3-dihydro-6-methyl-3-oxo-pyrrol-2-ylmethyl]-thieno[2,3-d] Pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazolidine-2-ylcarbonyl]-3-methyl_6-[(2-methyl)- 1Η-pyrrolo[2,3-b]pyridin-3-yl)methyl]-1-propylseceno[2,3-d]pyrimidine-2,4(1H,3H)-dione; 5 -[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1Η-benzimidazole-1-ylmethyl]-3-methyl-1 -propyl·Mimipheno[2,3 - d ]pyrimidine-2,4(1ϋ,3Γί)-dione; 5-[(4S)-4-hydroxyisoazolidine-2-ylcarbonyl ]-3-Methyl-1-propyl-6-[2-amino-1Η-benzoimidazol-1-ylmethyl]cepheno[2,3-d]pyrimidine-2,4(1Η, 3Η)-dione; (S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-6-[2-(hydroxyindenyl)-1Η-benzimidazole-[-ylmethyl] -3 -Methyl-1 -(isopropyl), tomb-[2,3-d]pyrimidine, 2,4(1H,3H)-dione; (S)-5-[4-hydroxyisoindole Azolidin-2-ylcarbonyl]-3-methyl-1-(isopropyl)_6_[2_amino-1^1- benzopyr-1-ylmethyl]0 pheno[2,3 - (1) shouting -34 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1310036 Δ7 Α7 _Β7 V. Invention description (31) -2,4(1H,3H)- Ketone; propyl)-6-[2-pheno[2,3-d]pyrimidine-1-(isopropyl)-6-[2-pheno[2,3-d]pyrimidine(S)-5 -[4-基基°°号吐苯-2-ylcarbonyl]-3-methyl. Mercapto-1 Η - ρ ratio 11 and [2,3 · b ]»pyridin-1 -ylmethyl Mouth-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methylmethyl· 1 Η-pyrrolo[2, 3-B]pyridin-3-ylmethyl]indole-2,4(1H,3H)-dione; (S)-6-[4,5-dichloro-2-mylmethyl)-lH- Mimi oxime methyl group -基基基]-3-methyl small (isobutyl)"cepheno[2,3_d]^-2,4(1H,3H)-dione; (5)-6-[3,5-dimethyl --m-峨峻-丨-基曱基]_5_[4嘈基异崎喷盐_2 基基基]-3-Methyl-1-(isobutyl) Sophora[2,3_d]pyrimidine (S)-6-[2,3-dihydro-2-oxo-1H-benzopyrimidinylmethyl]-5·[4 provinces -methyl-1-(isobutyl)"cepheno[2,3-small pyridine-2,4(1H,3H)-dione; (S) 6-[3,5-dimethyl- 1H-pyrazol-4-ylmethyl]_5_[4-hydroxyisoxazolidine-2-ylcarbonyl]-3-mercapto-1-propyl, pheno[2,3-d]pyrimidine_2, 4(1H 3H)-dione; (s) 6-[3,5-dimethyl-m-pyrazol-4-ylmethyl]·5_[4-hydroxyisoxazole pyridine-2-phenyl] 1-isopropyl-3-methyl P-seceno[2,3_d]pyrimidine·2,4(1H,3H)^ 酉; (S)-6-[3,5-dimethyllocene吐-4-ylmethyl]-5_[4• via 里 里 oxazolidinyl-2-yl post-group] small (isobutyl)-3-methyl, pheno[2,3_d]pyrimidine_2, 4(1H,3H)_ -35 - This paper size is applicable to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 1310036 V. Invention description (32) 6-[4,5- 二气-2-甲--111-imidol-1-ylindenyl]-1-ethyl_5_[(43)- 4-Lightyl-2-iso-3 thiolcarbonyl]-3-methyl-p-benzo[2,3-d]indole-2,4(lH,3H)-dione; 1-B Base - 5-[(4S)-4. thiophene-2-iso-17 squid carbonyl]_3·methyl _6-(1Η-ρ ratio ρ and [2,3-d]p ratio bite- 3-ylmethyl)-3⁄4 benzo[2,3-d]"·dense-2,4(lH,3H)-dione; 1-ethyl-5-[(4S)-4- -2--2-iso·^# 瓦 淀 carbonyl]_3·methyl_6·[2_propyl-1 Η-benzopyrimidin-1-ylmethyl]-Β 吩 并. [2,3 -d]. Bite 2,4(1Η,3Η)-dione; ^ * 1-ethyl-5-[(4S)-4-alkyl-2-iso-11-dipylcarbonyl]_3-methyl·6 -[2-oxo-3(2Η)-benzo-hydrazinomethyl]-oxime-[2,3-d]«►-biti-2,4(1Η,3Η)-dione; 1-ethyl-5-[(4S)-4-||yl-2-isophonic stimulating base]_3-methyl-6-[2-methyl-1 Η-ρ ratio [2 ,3-b]pyridin-3-ylmethyl]4-pheno[2,3-d]pyrimidine-2,4(1H,3H)-dione; 1-ethyl-5-[(4S)-4 -hydroxy-2-isoxazolidinylcarbonyl]_3.methyl-6-[5-cyano-1H-MI哚-U-methyl]-pyrimido[2,3-d]pyrimidine-2, 4(1H,3H)-dione; 5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-6-[1-isopropyl-3, 5-dimethyl-1 H-pyrazol-4-ylmethyl]-3-methylsulfonio[2,3-d]pyrimidine-2,4(iH,3H)-dione; 5-[ (4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6-[5-methyl-3-phenyl-1-indole-pyrazole- 4-ylmethyl] benzopheno[2,3-d]pyrimidine-2,4(1H,3H)-dione; 5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl] -I-isobutyl-3-methyl-6-[5- -36 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm)

Binding

A7 B7 1310036 V. INSTRUCTIONS (33) Methyl-3-(trifluoromethyl)-1Η-ρ-pyrazol-4-ylmethyl] Sophora[2,3_d]n-dense-2,4 ( 1H,3H)-dione; 5-[(4S)-4-carbazide-2-carbyl]-1-isobutyl-6-[3-isopropyl^^-methyl-lH -p than ol-4-ylmethyl]-3-methyl p-seceno-2,4(iH,3H)-dione: 6-[3,5-dimethyl-1-phenyl-1H -pyrazol-4-ylmethyl]-5-[(4S)-4-methylidyloxazolidin-2-ylcarbonyl]-1-isobutyl-3-methylsulfono[2,3_d N-dense-2,4(1H,3H)-dione; 6-[3,5-dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl]-5-[(4S -4-superylisoxazolidine-2-ylcarbonyl]-3-methyl-dipropyl sulfonyl[2,3-d] π-dense-2,4(1Η,3Η)-dione; 6 -(1^1-1,2,3-benzotriazin-1-ylmethyl)-5-[(45)-4-exiyl 11th biting carbonyl]-3-methyl-1 -(isopropyl)-, pheno[2,3-d]pyrimidine-2,4(1Η,3Η>dione; 5-[(4S)-4-hydroxyisoxazolidinylcarbonyl]-3 -methyl-1-(isopropyl)_6_[(2•oxothiazolo[5,4-b]pyridine-1(2H)-yl)methyl]sulfonyl-[2,3_d]ij This-2,4(IH,3H)-dione; 6-[2,3-dihydro-2-oxo-1-benzimidazol-1-ylmethyl ]-5-[(43)-4-Phase and 11-biting this group] 3-methyl-1-(isopropyl)-p-tomb-[2,3-d] 〇·密Bite-2,4(1H,3H)-dione; 6-[5,6-one gas-2,3-digas-2-milo-111-benzo-flavor 11-l-yl-methyl]_5 · [(4S)-4-Hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl)-, pheno[2,3-d]pyrimidine-2,4 ( 1H,3H)-dione; 5-[(4S)-4-ylidyl 11-denyl-2-ylcarbonyl]-6-(imixo[i,2_a]p ratio _3_ _ - 37 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) A7 B7 1310036 V. Description of invention (34) Methyl)-1-isobutyl-3-methylthieno[2,3-d Pyrimidine-2,4(1H,3H)-dioxime; 3-methyl-6-[2-methylindol-3-ylmethyl]-1-(isobutyl)-5-(four Hydrogen isoindole-2-ylcarbonyl)-pyrimido[2,3-d]pyrimidine-2,4(1Η,3Η)-:_; 6-[2->odor-4,5-dichloro -1H-Sensyl-1-ylmethyl]-5-[(4S)-4-Lightyliso 11 σ-s-ylcarbonyl]-3-methyl-1-(isobutyl)<» Benzo[2,3-d]pyrimidine-2,4(1Η,3Η)-dione; 5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1 -(isobutyl)·6_(;2-(methylthio)-1 Η-miproxil[4,5-b]ρ Reading · 1 -ylmethyl]-ρ-seceno[2,3-d]pyrimidine-2,4(1H,3H)-dione; 5-[(4S)-4-radioisoindyl Carbonyl]-3-methyl-1-(isobutyl)_6_[2-(methylthio)-3H-imipo[4,5-b]indol-3-ylmethyl] benzo[ 2,3-d]»Midine-2,4(1H,3H)-dione; 6-[3,5-S-methyl-1H-indol-4-ylmethyl]-3-ethyl- 5-[(S)-4-Imino-2-iso-sigma carbonyl]]i-(isopropyl)·ρ-seno[2,3_d]n bite ·2,4(ιη,3Η ) · diketone; - 5-[(4S)-4-^yl-2-isomeric decylcarbonyl]-3-methyl-ΐ-(isobutyl)_6_[2_(trifluoromethyl)benzene Methyl]-sulfonio[2,3-d]pyrimidine-2,4(1H,3H)-dione; 5-[(43)-4-hydroxy-2-isoxazolidinylcarbonyl]- 3-methyl-1-(isobutyl)_6_[2_(methylthio)-1H-miso-s-yl-1-ylmethyl]-II-senteno[2,3-d]n-bit 2 4(ih 3H)·dione: and (S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-indenyl small (isobutyl)_6_ [2,3-di Hydrogen-6-methyl-3-oxo-pyroxy-2-ylmethyl]-indeno[2,3_d]pyrimidine-2,4(1H,3H)-dione; -38 - paper scale Applicable to China National Standard (CNS) A4 specification (21〇x 297 mm) 1310036 A7

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1310036 V. Description of the invention (36 hydrogenation reaction. Or 'trialkyl decyl or aryl dialkyl decyl group (such as: * * butyl 〒 夕 或 base or monomethyl phenyl sulphate removal method available For example: use peripheric acid (such as: hydrochloric acid, sulfuric acid, squaric acid or trioxane, or use metal or fluoride (such as: with or specifically tetrabutyl morphine treatment. Or, burn) The base removal method can be treated, for example, by examining metal (1) 4C) 'reverse sulfide (such as sodium thioacetate) or by using a metal diaryl sulphide (such as diphenyl squamization). Or for example: using a deletion or a second treatment by a compound (such as: three; boron odor). Alternatively, (1_4 〇 oxymethyl or tetrapyranyl group can be removed by using, for example, using a suitable acid (such as: Treatment with hydrochloric acid or trifluoroacetic acid. Alternatively, a suitable protecting group via a base is, for example, a stabilizing group, for example: (2_4c) a flammable base (especially an ethyl aryl group) or an aryl fluorenyl group (especially a benzoyl group). The conditions for removal of the above protecting groups must vary with the protecting group selected. Therefore, for example, a brewing group (eg: burning Si-based or The removal of the brewing base can be carried out, for example, by using a suitable test such as: alkali metal hydroxide such as sodium hydroxide or lithium hydrolysis. Suitable protecting groups for the amine, imine or alkylamine group are, for example, mercapto groups. For example: (2-4C) pit base (especially ethyl ketone), (1_4 oxime oxycarbonyl (many nail $ carbonyl, ethoxycarbonyl or tert-butoxycarbonyl), aryl methoxycarbonyl ( In particular, methoxycarbonyl or aryl sulfhydryl (especially benzylidene). The conditions for removal of the above protecting groups must vary with the protecting group chosen. For this reason, for example: The removal method of a group, an alkoxycarbonyl group or an aryl fluorenyl group can be carried out, for example, using a suitable base such as an alkali metal hydroxide such as sodium hydroxide or lithium.) Alternatively, a mercapto group (e.g., a third butoxycarbonyl group) The removal method can be used, for example, fat: treated with a suitable acid (such as hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid), aryl-40 - paper size gg gg (CNS) A4 specification (2 cut 297 Gong love) Gutter 1310036 A7 B7 V. Description of invention (37 methoxy group (such as benzoyloxycarbonyl) removal method The hydrogenation reaction is carried out using, for example, a catalyst (e.g., Pd/C). The functional group protection and removal protection methods are fully described in LW F. Mc〇mie's 'Protective Groups in Organic Chemistry' published by Plenum (1973) And TW Greene and PG, M. Wuts, the second edition is like _ Groups in Organic Phase, Wiley_Interscience (i99l). At least one of the compounds of formula (1) or formula (1) is protected. The compound can be prepared by one of the following methods: a) From the compound of formula (0): co2h η

R1 Q-Ar (10) reacts with isoindole or tetrahydroiso(4), each of which may be substituted by a trans group. b) When Q is a methylene group, a compound of formula (π) 〇 R3

CH7L R1 (11) reacts with compound of formula Ar; -41 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1310036 V. Description of invention (38 c) when Q is methylene When reducing the compound of formula (12) · R3

R1 (12) CH(〇H)-Ar d) is subjected to primary ring synthesis reaction by formula (11) or (13) to form Ar-R3

R1 CH, (13) e) Reaction of a compound of formula (14) with Ri-L2: Λ R3

, Q' 'Ar Η (14) where L and L2 are debonded, and R1, R2, R3, Q# Ar are as defined above, and may be followed by a), b), c) or d) (1) The compound forms a further compound of the formula (1) and/or forms a pharmaceutically acceptable salt or solvate thereof. -42 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (39

The reaction between the compound of the formula (10) and isoxazolidine or tetrahydroisoindole (which may optionally be substituted with a few groups) is preferably carried out under the conditions of the indole bond formation reaction. For example, it is carried out in the presence of a coupling agent such as dicyclohexylcarbodiimide or i-ethyl-3-(3-dimethylaminopropyl)ethylcarbodiimide. The specific organic base such as triethylamine can be used as needed. A suitable solvent is usually an aprotic solvent such as dimethylformamide or a chlorinated solvent such as dichloromethane or dichloromethane. Further, a compound which catalyzes the formation of such a guanamine bond, such as hydrazine-hydroxybenzotriazole, can also be used. The temperature is usually in the range of from about _3 to about 60 ° C, specifically at or near ambient temperature. The reaction between the compound of the formula (丨丨) and Ar is usually carried out in the presence of a strong base such as sodium hydride. Suitable exfoliation groups include ··· groups, specifically bromine. The reaction is carried out in an inert solvent (e.g., tetrahydrofuran), specifically at ambient temperature or near ambient temperature. Sometimes, for example, when a ring nitrogen atom which does not require removal of a proton is contained, a milder base such as sodium hydrogencarbonate can be used. This reaction is a compound prepared by the preparation of a ring-to-ring nitrogen atom chain. However, this method can be used to prepare a compound in which Ar is bonded by a ring carbon atom. This reaction can be carried out using a strong base and a zinc salt (e.g., zinc chloride) and optionally using sodium iodide as a catalyst. The compound of formula (12) can be reduced to the corresponding methylene compound using standard conditions known in the art for hydroxyl groups. For example, it can be protonated by acid trifluoroacetic acid and reduced with trialkylnonane. Alternatively, the hydroxy group can be converted to a stronger cleavage group, such as mesylate and tosylate, and the resulting material is used in a non-hyperradical solvent, specifically tetrahydrofuran, using a catalyst (: • Pd/C)' Within the temperature range, specifically for the weekly temperature - 7 paper size ίϊ with the Chinese national standard grid - 43 - '297 mm)

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1310036 A7 B7 V. Inventive Note (40), and hydrogenation at 1-5 bar pressure. The -Q-Ar group on the compound of the formula (1I) or (13) is preferably formed by a primary ring synthesis method. This reaction can be found in the literature: E.C_ Taylor and A. Weissberger 1 The Chemistry of Heterocyclic Compound s' (published by John Wiley and Sons) and AR Katritzky and C. W Rees' 'Comprehensive Heterocyclic Chemistry' (Pergamon Press (Pergamon Press ( Elsevier))). For example, when preparing a compound of the formula (1) wherein Ar is a 3,5-dimethylpyrazol-4-yl group or an I,3,5-trimethylpyrazole-4-yl group, refer to the examples in the clear examples. 11 and 12. The compound of the formula (14) can be reacted with a compound of the formula rL12 in the presence of a mild test (e.g., potassium carbonate) in an aprotic bipolar solvent (e.g., DMF) at a temperature ranging from about 30 °C. The preparation of the compound of the formula (1) can be carried out by another chemical modification of the compound of the formula (1). For example, a compound of the formula (1) wherein Q is a methylene group can be oxidized to a compound of the formula (1) wherein Q is a carbonyl group. Preferably, the oxidizing agent is 2,3-dioxa-5'6-dicyano-1,4-benzoxanthene pDQp contained in an organic solvent (e.g., tetrahydrofuran), sometimes exposed to air by a methylene compound. Oxidation is carried out. The intermediate of formula (1〇) can be formed from the compound of formula (15): C〇2R20

A7 B7 1310036 V. Description of the invention (41 wherein R is a Cu alkyl group, for example: methyl or ethyl, and rZ1 is (wherein L is as defined above) or -CH(〇H)Ar. In the formula (15), R21 is The compound of -cha can be reacted with a condition similar to the above method b). * When Ar is bonded by a ring carbon atom, the compound of formula (15) wherein r2! is _CH(〇H)Ar_^ can be reduced by a condition similar to the above method c). In the formula (12) or (15), the compound of the formula _ch(0H)Ai^ is prepared from the compound of the formula (16):

("R-2 in the case of R3 or 〇〇2κ20 when appropriate") and the formula Ar-CHO, in the presence of a strong test (eg, dialkyl. amination, for example: lithium diisopropylamide) 'Reaction in an inert organic solvent (eg tetrahydrofuran), preceded by low temperature (eg _78 ° C), and then brought back to the ambient temperature. Intermediates are generally prepared from compounds of formula (17):

R1 07) -45 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm)

1310036 A7B7 V. Description of the invention (42) wherein R23 is hydrogen or methyl. When R21 is -CH(OH)Ar, R23 is hydrogen, and the compound of the formula (16) can be reacted with Ar-CHO by the reaction of the above formula (15). When ^ is -CH2L, 'P is a methyl group, which can be converted to -CH2L by, for example, a painting reaction. When L is, when odorous, the methyl group can be subjected to a bromination reaction under standard conditions using a standard alkalizing agent (e.g., N-brook amber imine). In the formula (17), the compound wherein R23 is hydrogen may be prepared from the compound of the formula (18):

With alkyl bromopyruvate (such as: ethyl bromopyruvate), in the presence of a mild base (such as: test metal carbonate 'for example: carbonic acid unloading), in polar solvents such as: listen), on behalf of the 赃The temperature is reacted, and then the resulting person is subjected to Lewis acid (specifically, the gasification enthalpy) in an inert solvent (for example: dimethane) at a temperature between -20 t and 50 t (specifically, Q ( :

Between) processing. L, 乂Π) in the 'R, methyl compound can be prepared by the formula (10) compound m2-milobutyric acid alkyl vinegar (such as: 3_O-oxobutanoic acid hydrazine and the presence of the test (such as: test Metal tetrate 1 (such as sodium acetate), in a polar solvent (for example: DMF, or specifically water), to 50 forces; reaction between temperatures, and then the resulting adduct via Lewis acid (specifically Four: -46 -

1310036 A7 B7

5. Description of the invention (43) Titanium), treated in an inert solvent (eg dichloromethane) between _2 〇 t and 5 (between rc (specifically 〇 ° C to 25 ° C) The compound of the formula (17) can be produced from the compound of the formula (19):

(19) (wherein R24 is C|_4: t-based, for example: ethyl) and ethoxylated, in an inert solvent (for example: toluene), up to 5 Torr. The reaction between the oxime and the oxime solution is then carried out in the presence of a compound of the formula r2_li (where L is in the range of 〇 ° C to 30 ° C) Deviation from the base 'example. Such as: monument ion) reaction. The compound of the formula (19) is produced by reacting a compound of the formula (20), r1-n=s, with a Witt compound (wittig compound), for example, a compound of the formula (21):

(wherein R' is phenyl or substituted phenyl, such as fluorenylphenyl) which is in an inert solvent such as THF at 20. (: to the temperature of 80 ° C, 'the obtained adduct is then reacted in situ with the compound of formula (22) at a temperature of -78 ° C to 60 ° C: This paper scale applies to the Chinese national standard (CNS) A4 size (210 X 297 mm) 1310036 A7 B7 V. Description of invention (44)

/R20 The compound of the formula (18) is produced by the compound of the formula (23): 〇

R1 (23)

It is charged with a metal (for example, a mercaptan) and reacted in a polar solvent (e.g., an alcohol such as ethanol) at a temperature of 10 to 50 °C. The compound of formula (23) can be prepared from a compound of formula (24):

Η (24) is reacted with a compound of the formula R1 - L2 under the conditions described in the above method e). The compound of the above formula (1) can be converted into a pharmaceutically acceptable salt or solvate thereof. Some of the compounds of formula (1) may be stereoisomeric. It is understood that all geometric and optical isomers of the compound of the formula (1) and mixtures thereof, including racemic -48 - the paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)

'Line 1310036 V. DESCRIPTION OF THE INVENTION (45. These compounds also form the isomer of the present invention, which can be used in various forms. Segmental Crystal S. Pairs of Yingtian ##Unfolding or Separating' For example: chromatography or sub-compounds Other compounds are known to separate racemic compounds or (HPLC). Or, +, ^ ( j Ρ • for palm-shaped high-performance liquid chromatography active starting materials, not = learning, the method of production can be by appropriate light • • use high carbon to palm acid 2:&quot The conditions of the τ reaction, or, for example, enantiomeric derivatives:; = c, = Xiguang separation non-preferential starting materials and preparation of the palmitic reagents are all included in the scope of the present invention. W has an isomer, and the compound can be isolated from the reaction mixture by conventional techniques. Sexuality, so that it can be used as a medical activity in the body of the animal. Immunity, inflammation, hyperplasia and hyperproliferative diseases, and: from diseases, including transplant organs or tissue rejection and: Tianji = AIDS syndrome. (Respiratory) respiratory diseases, including chronic obstructive pulmonary disease (1) 〇... Asthma: such as: a trachea, allergic, endogenous, exogenous and dusty: %, especially s full or intractable asthma (eg : late onset respiratory tract hyperactivity); bronchitis; acute, slow , atrophy 3 inflammation and chronic rhinitis 'including dry rhinitis, hypertrophic rhinitis rhinitis, dry rhinitis and drug rhinitis; membranous rhinitis including secondary rhinitis, fibrotic and pseudomembranous rhinitis and adenoma sinus IW cloth, sputum nose 49 - This paper scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) 1310036 V. Invention description (46) A7 B7

Inflammation includes sacral rhinitis (hay fever) and vasomotor neuropathic rhinitis: lang disease, farmer's lung and related diseases 'pulmonary fibrosis pneumonia; ^ (2) (bone and joint) rheumatoid arthritis Serum-negative spondyloarthropathy (including adhesional spondylitis, dry arthritis and RAMS disease, Behcet (s) (10), Sjogren's syndrome and Systemic sclerosis; (3) (skin) dryness, atopic dermatitis, contact with dermatitis and other moist dermatitis' sebum dermatitis, lichen planus, pemphigus, bullous blisters, big bubbles Sexual epidermis, urticaria, dry skin disease, vasculitis, skin erythema, cutaneous eosinophilia, Portuguese*, clustered hair and spring conjunctivitis; (4) (gastrointestinal) colon disease, straight Enteritis, eosinophilic gastroenteritis, mast cell germination, Crohn's disease, ulcerative enteritis, food-related allergic reactions caused by leftovers, such as migraine, _ nose 1 and eczema ; —, (5) (Other organizations And systemic diseases) multiple sclerosis, arteriosclerosis, acquired immunodeficiency syndrome (AIDS), lupus erythematosus, systemic lupus, erythema, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, renal syndrome, eosinophils Membrane inflammation, excessive IgE syndrome, leprosy nodular leprosy, sezary syndrome and idiopathic thrombocytopenic purpura; (6) (allograft rejection) following transplantation such as: kidney, heart, liver, bone marrow, Acute and chronic rejection after skin and cornea; and chronic graft versus ___- 50 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm)

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Line 1310036

The disease of the Lord; and (7) cancer. „Therefore, the present invention proposes a compound of the formula (1) as defined above or a therapeutic salt of the medicinal compound for use in medicine. ^ Wan® 'The present invention proposes a compound of the formula (1) as defined above or Sauce: an acceptable salt for inhibiting T cell proliferation. Another 1: Φ * The invention proposes a compound of formula (1) as defined above or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting tau cell proliferation The use of the above. In this month, the term "medical law" also includes "prevention law", unless otherwise stated, so the terms 'medical" and "medicality" should be explained. The precautionary approach should be particularly relevant to the treatment of individuals who have suffered from this particular disease or who are at increased risk of developing this particular condition. Individuals who develop this particular disease or secret risk usually include those with a family history, and they have passed the gene: testing or screening to demonstrate that it is particularly easy to develop the disease or condition. The present invention further provides a method for suppressing immunity. (eg, for cardiac therapy: species transplant rejection) 'which includes administering to the patient a medically effective amount, such as: a compound of formula (1) or a pharmaceutically acceptable salt thereof. The invention also provides a method of treating or reducing the risk of the disease in a patient suffering from or likely to suffer; aspiration, asthma or COPD, which comprises administering to the patient a medically effective amount of a formula as defined above, or A pharmaceutically acceptable salt. ^ Compounding The dosage of the above medical uses will of course depend on the compound used, the method of administration, the method of treatment, and the condition to be treated. However, the effective dose of the compound of formula (1) is usually 〇1 mg/kg, specifically 0.3 mg/kg, more specifically 55 mg/kg, and more specifically ^ mg /kg, up to 冋 and including 3〇mg/kg. For the treatment of respiratory diseases, the daily dose of the compound of formula (1) is usually from 0.001 mg/kg to 3 mg/kg. The compound of the formula (1) and its pharmaceutically acceptable salt can be used in its own form, but it is usually administered in the form of a pharmaceutical composition. The compound of the formula (1) / = / compound (active ingredient) is pharmaceutically acceptable. Accepted adjuvant, diluent or carrier combination. Depending on the mode of administration, the particular pharmaceutical composition will comprise from 〇5 to "% by weight of active ingredient, more specifically below 80% by weight: for example 曰1() to 7()% by weight, or even more Specifically, it is 5 (% by weight or less), and all weight percentages are based on the total amount of the composition. M Thus, the present invention also provides a pharmaceutical composition comprising, as defined above, a compound of formula (1) or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable cola, diluent or carrier. The present invention also provides a method of preparing a pharmaceutical composition of the present invention = a compound of the formula (1) as defined above, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier. And :::: Γ乐 composition can be a solution, suspension, sevoflurane aerosol, the first two: "" form of Shao Shao and (for example: cast to the lungs and / or breathing = = skin); or In the form of a drug bond, capsule, syrup, powder or granules, the whole body is not: intestines, orally administered or in the form of a solution or suspension or by transdermal administration. Sub-11 form of rectal administration, -52 paper Zhang Jiqi Caiguoguo National Standard (CNg) A4 Specification (2l0X297i^7 Binding. Line 1310036 A7 B7 Description of the Invention (49) The ability of this compound to inhibit the peripheral proliferation induced by PMA/ionomycin can be used, for example, as explained below. The method of analyzing the PBM〇f activity stimulated by A./Ionomycin-like g Μ . A./Ionomycin can be carried out on the flat: microtiter plate. In the dimethyl hydrazine, the preservation solution. Make a 50-fold dilution in the surface, and then prepare the dilution solution from the solution. Take the Η) μ1 observation dilution solution or its solution into the hole*, and analyze The initial concentration of the method is 9·5 μΜ 'and then gradually decreasing. Add 1^__ in each well (from the human body of a single blood donor) Blood preparation) (RPMI 1640 medium, supplemented with (10) human serum, 2 Fushou" and Qingxu/streptavidin. In the medium containing such cells (such as i), add force to the mouth肖肖豆豆蓝酸醋acetic acid vinegar (pMA) (final concentration 0.5 ng / ml) and ionomycin (final concentration 5 (9) ng / mi), so that the final analysis volume is 0.. 2 m cells in 37t of moisture In the last 6 hours of culture, the % chest answer was added (〇5 (4). The radioactivity absorbed in the cells was measured as the measured value of the twin effect. In the above experiment, the example was found. The iAs of the compound has a value of 丄X ι〇-6 M. In the following obvious example, the 丨50 value of l7 〇 ι〇·ιο M 'Example 20 in the above test is 57 〇 ι〇·ιο M 'Example 20 The IA50 value of Example 20 is 5 xl 〇-9Kl. The invention will be described 'unless otherwise stated: (1) The evaporation process is carried out using a vacuum rotary evaporator and the operation is carried out after filtration to remove residual solids (eg dehydrating agent): (ii) at ambient temperature, ie丨8_25ΐ之园 and inert gas binding line -53 - 1310036 A7 B7 5. Description of the invention (50) Under the gas, such as: operation under argon or nitrogen; (iii) The amount of the product is only for the description 'not necessarily the maximum value; (IV) the structural formula of the final product of formula (1) The nuclear (usually proton) magnetic resonance (NMR) and mass-induced techniques are forbearance; the mass spectral chemical migration values are expressed in δ scales. 'Multimodality is represented by the following codes: s, singlet; d, double φ ; t, ginseng; m, multimodal; br, broad; q, four peaks; qUin, five peaks. (v) intermediates are not fully discriminated, the purity is by thin layer chromatography (butyl lC), high performance liquid phase Analysis by Chromatography (HPLC), Mass Spectrometry (MS), Infrared (IR) or NMR Analysis: Abbreviation

2,3-·- disorder-5,6-dimercapto-1,4-benzoin from Kunming DDQ

Dimethylformamide DMF

M-benzoic acid mCPBA

Tetrahydrofuran. , THF Example 1 Isoazolidine-2-anthracepin 1-3 methyl-1-(iso-butyl)-6-(4-4-morpholinylmethyl) remnant and "2.3- Dl-pyrimidine-2.4ΠΗ.3Η)-dione

OH

a) (S)2-"4-Hydroxyisoxazolidine-2-one methyl benzobenzoate added with triethylamine (0.28 ml) to nitrogen, containing N-hydroxy quinone imine (5.00 -54 - This paper scale applies to the Chinese National Standard (CMS) A4 specification (210X 297 mm)

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Line 1310036 A7 B7 V. INSTRUCTIONS (51) g) In a solution of (R)-(+)-epichlorohydrin (2.40 ml) in anhydrous dioxane (10 Å). The mixture was stirred at 50 ° C for 48 hours, and (R)-(+)-epidol (〇 24 ml) and triethylamine (0.28 ml) were added, and the mixture was stirred at 50 ° C for 24 hours. Methanol (10 ml) and triethylamine (4.27 ml) were added and the mixture was stirred at 50 ° C for 2 hours. The mixture was evaporated under reduced pressure. EtOAc (EtOAc m. The combined organic extracts were dehydrated with anhydrous sulfuric acid steel and filtered. Residue was recrystallized from ethyl acetate to give the subtitle compound (3.4 g). MS (ESI) 252 [M+H]+. δ , , , nCDci3 -3.66 (1H, d, br), 3.79 (1H, d, br), 3.89-3.99 (IH, m), 3 99 4 1〇(1H, m), 4.74-4.81 (1H, m), 7.46 (1H, d), 7.49 (lH t) 7 62 (1H, t), 7_99 (1H, d). b) (S)-4-isog and other succinyl alcohol hydrochloride Hydrochloric acid (4M, 15 ml) was added to the product of step a) (1.87 g), and the mixture was heated under reflux for 3 hours. The mixture was cooled to room temperature, filtered and evaporated under reduced pressure. The residue was recrystallized from propan-2-ol to give a white powder of the subtitle compound (〇78 g) ° δ 'Hdmso 3.35 (1H, d), 3.47 (1H, dd), 4.03 (1H, dd) , 4.07 (1H, d), 4.78-4.81 (1H, m). ¢) 1,2,3,4-tetraqi-3-methyl-1-i-isobutyl)-2.4-di It generation 4 slightly and "2.3_dl pyrimidine-5-decanoic acid ethyl ester to take 6-hydrogen sulfur Base-3·methyl-1-(isobutyl)-pyrimidine-2,4(1H,3H)-dione (49.5 g) was dissolved in anhydrous DMF (900 ml), and ethyl bromopyruvate was added (30) Anhydrous potassium carbonate (1.95 g) was added with stirring. The mixture was stirred at room temperature for 5 hours and then poured into water (5 L). The aqueous solution was acidified with dilute hydrochloric acid and extracted with ethyl acetate. Dehydration (MgS04) under high vacuum

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__ - 55 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Invention description (S2) j Hot hair leaves a semi-solid substance. A portion of this hydrazine solid (24 g) was dissolved in dichloromethane (5 mL) and cooled in an ice bath under nitrogen. Titanium tetrachloride (13.5 ml) was slowly added with sufficient stirring. The reaction mixture was stirred in an ice bath for 1 hour and then stirred at room temperature for 3 hr. The reaction mixture was slowly poured into ice water (1.5 L) under vigorous agitation. The resulting suspension was extracted with a second gas. After dehydration, the organic solvent was removed in vacuo, and residue chromatography (Si </ RTI> </ RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; t), 2.31-2.45 (1H, m), 3·4 (3H' s), 3·8 (2H, d), 4 4 (2H, q), 7 28 (1H, s). Magic tetrahydro -6-[~ with base (4-4·» 林基, methyl 1-3-甲某: 丁某L分和"2_3-dl-pyrimidine-5-acid ethyl ester in 1 hour Add a solution of diisopropyl amination (5.52 g) in anhydrous THF (80 ml) to -78. (3 with nitrogen, containing step c) product (8.02 g) and 4-»奎普林叛基(8..12 g) in anhydrous THF (80 ml). Mix the mixture at -78 °C for 1 day, then add glacial acetic acid (丨〇ml) to stop the reaction, then bring it back to the room. - diluted with saturated sodium bicarbonate solution (1 mL), extracted with ethyl acetate (2 X 1 〇〇mi). The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo. Purified by <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; (3H,d), 1.43 (3H, t), 2.10-2.16 (1H, m), 3.38 (3H, s), 3.49 (1H, dd), 3.61 (1H, s, br), 3.71 (1H, dd ), 4.48 (2H, quartet), 6.78 (1H, s), 7.52 (1H, t), 7.72 (1H, t), 7.83 (1H, d), 7.90 (1H, d), 8.17 (1H, d) , 9.02 (1H,d). -56 - This paper Applicable to China National Standard (CNS) A4 specification (210 x 297 public love:) 1310036 A7 B7 V. Invention description (53 ^1^~2^^^1^ base-1-(isobutyl)-2.4-two笥 -6-6-(4-崦呲其密pyridine-5-decanoic acid ethyl ester was added with dioxoacetic acid (3.33 ml) to room temperature under nitrogen with step d) product (7.34 g) and diethylamine ( 6.56 ml) in anhydrous THF (150 ml), stir the mixture for 15 minutes, add 1 〇% pd/c (5 〇〇 claw magic, the mixture is chlorinated under the bar for 20 hours. Filtered by 寅 salt) The organic layer was extracted with ethyl acetate (50 ml), and the combined extracts were dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography eluting with 1:1:1 ethyl acetate/isohexane to give the title compound as a solid (5·9 illusion. MS (ESi) 452 [Μ + Η]+ 〇δ 'Hcdcs 0.90 (6H, d), 1.37 (3H, t), 2.10-2.16 (1H, m), 3.39 (3H, s), 3.64 (2H, d), 4.45 (2H, q), 4.61 ( 2H, s), 7.29 (1H, d), 7.60 (1H, t), 7.75 (1H, t), 8.11 (1H, d), 8.16 (1H, d), 8.89 (lH, d). 'tetrahydro-?2^_1: (Wu Ding)-2,4二^代_6_(4_ _Methylphene~ and "2,3-dl-pyrimidin-5-decanoic acid - take step e The product (5.89 g) in THF (15 ml) and methanol (23 ml) was degassed under repeated argon and nitrogen flushing under argon. Add 1 M sodium hydroxide (18 ml). The resulting precipitated solid was collected by EtOAc (EtOAc m.jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (1H, m), 3.20 (3H, s), 3.56 (2H, d), 4.56 (2H, s)[ 7.52 (1H, dd), 7.57 (1H, td), 7.74 (1H, td), 8. 〇〇(iH, dd),8.83 (1H,d). , ,· __ - 57 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm)

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:Line 1— __ !31〇〇36 A7 B7 V. Description of the invention (54 hydroxyisoxazolidine-2-carbonylation 1-3 methyl-14 isobutyl)-6-(4-side A-based The base V is cold and "2.3-cH pyrimidine-2.4ΠΗ.3Η)-dione.

To a suspension of the product of step f) (157 mg) in dichloromethane (5 ml) was added &lt;RTI ID=0.0&gt;&gt; 1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (135 mg) was added and stirring was continued for 1 hour. The reaction mixture of (S)-4-isoxazolidine hydrochloride (Example 1, item b)) (69 mg) and triethylamine (147 μM) was stirred for 18 hr. The residue was purified by column chromatography eluting with EtOAc EtOAc (EtOAc: MS (APCI) 495 [M + H]+. δ 士(10) such as 0.80-0.90 (6H, m), 2.03-2.17 (1H, m), 3.21 (1.8H, s), 3.22 (1.2H, s), 3.55-3.68 (3H, m), 3.70-4.13 (3H, m), 4.52-4.68 (2.4H, m), 4.78-4.81 (0.6H, m), 5.50 (0.4H, d), 5.54 (0.6H, d), 7.42 (0.4H, d), 7.46 (0.6H, d), 7.63 (1H, t), 7-.78 (1H, t), 8.05 (1H, d), 8.24 (0.4H, d), 8.28 (0.6H, d), 8.86 ( 1H, d) = instance 2 -, one - 〆

LR) 5-"4-Hydroxyisoxazin-2-ylindole 1-3-methyl-1-(isobutyl V6-(4-porphyrin methyl V-secret and 2.3-dl pyrimidine- 2.4 (lH.3m-dione.

OH

g)..(R)2-丨4-Hydroxyisoxazolidine-2-ylindole-1 Molybdenum-methyl-58 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) ) 1310036

According to the method of the example i a), it was prepared from neoprene and (8) (+) epichlorohydrin. MS (ESI) 252 [Μ+ΗΓ. s lHc_ 3 66 (iH,d,(iv) 3- 79 (1H, d, br), 3.89-3.99 (1H, m), 3.99-4.10 〇Η, m), 4.74- 4.81 (1H, m), 7.46 ( 1H, d), 7.49 (1H, t), , 7.62 (1H, 〇, 7.99 (1 H, d). kLLR)· 4-isoxazole 咗 drunk salt g sacrifice according to the method of Example 1 b), Prepared from the product of step a). δ IHdms〇3 35 (1H, d), 3.47 (1H, dd), 4.03 (1H, dd), 4.07 (1H, d), 4.78-4.81 (1H, m) ° Sniff bite -2-1 1 ·3·Methyl _ 邕 I I, A base V phenophene and l~2.3-dl pyrimidine-2 4r〗 H.3fn-dioxin stirred in dichloromethane containing the product of Example 1 f) (200 mg) Hydroxybenzotriazole (9〇Claw and 丨_ethyl·3_(3,-dimethylaminopropyl) carbodiimide hydrochloride (128 mg) was added sequentially to the suspension (8 ml). After 15 minutes, (R)_4-iso-(anthracene hydrochloride) (84 mg) and triethylamine (0.093 ml) were added and stirred for 18 hours. The mixture was purified by silica gel column chromatography. The product was dissolved in ether to give the title compound as a white powder (92 mg). MS (APCI) 495 [Μ+Η]+. δ 咕 〇〇 〇〇 8 〇〇9〇(6H, m), 2.03-2.17 (1H, m), 3.21 (1.8H, s), 3.22 (1.2H, s), 3- 55-3.68 (3H, m), 3.70-4.13 ( 3H, m), 4.52-4.68 (2.4H, m), 4- 78-4.81 (0.6H.m), 5.50 (0.4H, d), 5.54 (0.6H, d), 7.42 (0.4H, d) , 7.46 (0.6H, d), 7.63 (1H, t), 7.78 (1H, t), 8.05 (1H, d), 8.24 (0.4H, d), 8.28 (0.6H, d), 8.86 ( 1H, d) Example 3 -59 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7B7 V. Invention description (56) (S) 6-丨4,5-two gas -2 dimethyl lH-imidazole-1-one a certain l-5_"4-hydroxy-2-吴°°°ϋ..ylcarbonyl.1二3 某-1 -(isobutylene phenanthrene and f 2 ,3 - d 1 pyrimidine-2.4( 1H.3H)-dione

Packed with 5·)__1,2,3,4-four winds-3} mutual ^A _ι_(isobutyl)-2,4-digaso-disc and 2,3-(11-pyrimidine- 5-carboxylic acid methyl ^

Take 6-hydrothio-3-methyl-1-(isobutyl)-pyrimidine_2,4( 1H,3H)-dione (50 g) dissolved in water containing sodium acetate (95.6 g) (1.5 In the solution of L), methyl 3-bromo-2-oxo-butyrate (44.6 g) was added dropwise with stirring. After stirring at room temperature for 1 hour, the mixture was extracted with ethyl acetate. The organic solution was washed with brine, dehydrated (MgS04), and evaporated to leave a mixture. This oil (75.1 g) was dissolved in dichloromethane (800 ml) and was cooled in a cold bath. Titanium tetrachloride (43.3 ml) was slowly added dropwise with thorough stirring. The reaction mixture was stirred in an ice bath for 1 hour and then stirred at room temperature for 3 hr. The reaction mixture was slowly poured into ice water (2 L) with vigorous stirring. The resulting suspension was extracted with dioxane. After dehydration, the organic solvent was evaporated in vacuo to give crystals eluted eluted elut elut elut elut elut elut It was ground with isohexane to give a white powder. δ 'Hcdcu 0.98 (6H, d), 2.23 - 2.41 (1H, m), 2.46 (3H, s), 3.4 (3H, s), 3.75 (2H, d), 3.96 (3H, s). -60 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (57) rb) 6-(Bromomethyl)-1,2,3,4^ Tetramethyl _3-methyl-14 isobutyl)-2.4-di-argon-p-phene-pyrene|&quot;2,3-dl-p-[alpha]--5-翱醢y brewing product containing step a) (1〇§) and N_bromosuccinimide (5.74 g) in chloroform (350 ml) were refluxed for 4 hours under a tungsten lamp. The solution was washed sequentially with water, saturated sodium bicarbonate solution, and brine. The organic layer is dehydrated by magnesium sulfate.

Filter and vacuum to concentrate. The residue was purified by EtOAc (EtOAc) elute MS (APCI) 390/39 1 [M + H]+. δ 'HcDcnl.OO (6H,d), 2.31 (1H, septet), 3.39 (3H, s), 3.76 (2H, dd), 3.99 (3H, s), 4.66 (2H, s). c) 6-"4,5-Dichloro-2-methyl-1H-carbazolylhydrazide 1-1.2.4.3-tetraki-3-methyl-1-(isobutyl-yl)-2,4 - Dihydrogen 4 pheno-[~2.3-dl-pyrimidine-5-cyanate methyl ester dropwise addition of 4,5-di-2-methylimidazole (1.3 g) in anhydrous tetrahydrofuran (20 ml) solution to room temperature Under a nitrogen atmosphere, a solution of sodium hydride (0.34 g, 60%) in anhydrous tetrahydrofuran (20 ml). After 15 minutes, a solution of the product of step b) (3.35 g) in anhydrous tetrahydrofuran (20 ml) was added dropwise. Stir at room temperature for 3 hours.: The solution is poured into -water. The mixture is extracted with ethyl acetate. The combined extracts are taken from &lt;RTI ID=0.0&gt; 5 0-1 00% ethyl acetate in hexanes to give the title compound as a white solid (2.28 g). MS (APCI) 459/460 [M + H] + δ 'Hcdcij 0.97 (6Η, d) , 2.26 (1H, septet), 2.38 (3H, s), 3.39 (3H, s), 3.73 (2H, d), 3.99 (3H, s), 5.26 (2H, s) d) 64 (4, 5 -dichloro-2-methyl-1H-imidazol-1-yl)methyl M.2.3.4. tetra-i--3-methyl-1-(isobutyl)-2.4-dioxoindole "2.3-dl-pyrimidine-5-carboxylic acid. Add sodium hydroxide (7.3 ml 1 Μ aqueous solution) and methanol (4 ml) to step-61 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) 1310036 A7 B7 V. Invention description (58 r) The product (2.28 g) in tetrahydrofuran (50 ml) was stirred at room temperature for 3 hr. The solution was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. Desiccated with magnesium sulphate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting eluting elut elut ) 445/447 [M + H]+.δ hcDc&quot; 0.96 (6H,d), 2.22 (1H, septet), 2.37 (3H, s), 3.51 (3H, s), 3.78 (2H, d), 5.78 (2H, s), 15.51 (1 H, br_s) 0 e) 64(4,5-Dichloro-2-methyl-1H-imidazol-1-yl) A certain l-5-"4-(SV衮a certain 2-isoxazole carbonyl group 1 - 3 -methyl-1 - isopropyl isobutyl V is exemplified by "2.3 - d 1 pyrimidine-2, 4 ΠΗ, 3 Η)-dione according to the example 1 g) The title compound was prepared by the method. MS (APCI) 516/518 [M + H]+. δ 'Hcdch 0.98 (6H, dd); 2.29 (1H, septet); 2.39 (3H, s); 3.38 (3H, s); 3.54 (1H, dd); 3.66-3.70 (1H, m); 3.80-3.87 (1H, m); 4.04-4.10 (2H, m); 4.56 (1H, d); 4.70-4.75: (1H, m); 4:92 (1H, d); 5.13-5.30 (2H, m). - Example 4 (S) 5-"4-Hydroxyisoxazin-2-ylcarbonyl1-3-methyl-1-(isobutyl)-6-(4-purinylcarbonylcarbonyl V-pheno[ 2,3-dl pyrimidine-2,4(1H,3H)-dione

This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (59): According to the method of Example 1 g), the product of Example 1 b) (115 mg And the product of Example 1 (342 mg) was prepared and then the product was exposed to air for 18 hours. The crude product was purified by reverse-phase preparative HpLC eluting with EtOAc EtOAc (EtOAc: EtOAc) *δ 1_(130.〇) 0.97 (6H,d), 2.23-2.33 ( 1 H, m), 2.68-2.95 (2H, m), 3.23 (3H, s), 3.60 (1H, dd), 3.65- 3.75 (1H, m); 3.81 (2H, d), 4.50 (1H, s, br), 7.56 (1H, d), 7.61 (1H, d), 7,73-7.82 (2H, m), 8.10 ( 1H, d), 8.97 (1 H, d) ° (*NB material is a mixture of geometric isomers, so the NMR measured at room temperature is complex, but simplified under heating). Example 5 (S) 5-[4-Alkylisoylcarbonyl]μ3-甲某_6_"(2-甲某_m•(4)哚-3-yl)methyl1-1-(isopyrimidine) 2,3_di-pyrimidine_2 4Πη,3Η)-dione

a) 1,2,3,4-tetrahydro-3-methyl _-6-"(2-methyl-1H-W -3-) 1-1 1-1-(isobutyl)-2 , 4-dioxoindole "2.3-dl-pyrimidine-5-cyanium methyl ester was obtained by gas-like imitation of the product of Example 3 a) (7 g) and N-bromosuccinimide (4.42 g) 140 ml) The solution was refluxed for 2 hours under irradiation with a tungsten lamp. The solution was cooled to room temperature. A mixture of saturated aqueous sodium hydrogencarbonate (14 mL) and 2-methyl 4-indole (5.92 g) was stirred rapidly for 48 hours. Layered, the aqueous phase is methylene chloride (1 〇〇ml). This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Invention description (6 〇 取. Combined The organic extract was dehydrated with anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/isohexane (1:3). Solid (6 68 g). MS (ESI) 440 [Μ + Η] ° δ lHcD (3) 0.87 (6H,d), 2.11-2.21 (1H,m), 2.42 (3H, s), 3.38 (3H, s), 3.61 (2H, d), 3.99 (3H, s), 4.22 (2H, s), 7.08 (1H, t), 7.15 (1H, t), 7.31 (1H, d), 7.46 (1H, d), 7.91 (1H, s, br) M374'一^^基-6-"(2-甲一-1H-叫丨哚-V) A certain l-1-f isoform. base)-2,4-di_ to _^ "23_€11_pyrimidine-&lt;;_platinum base added sodium hydroxide solution (1M, 13 6 ml) and methanol (25 m 丨) to the product containing step a) (4 g) of tetrahydrofuran (H) 〇 (7)丨) Stir the solution. After 28 hours, concentrate the solution under reduced pressure to a volume of 20 ml, dilute with water (2 〇〇ml), and draw with ether (2 χ 1 〇〇ml) / 4" enriched salt § cultural water phase To pH 2, extracted with ethyl acetate / methanol (19.1 '2 X 200 mi). The organic extract was dehydrated with anhydrous magnesium sulfate, and filtered to give a white solid (4 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> m), 2.37 (3H, s), 3.18 (3H, s), 3.59 (2H, d), 4.32 (2H, s), 6.91 (1H, t), 7.00 (1H, t), 7_26 (1H, d ), 10.96 (1H, s), 14.05 〇 H, s, br).基-6-U2-甲一-1H- 企皇土基)甲^密咬_2.4n Η·3Η, _ 二铜 according to the method of formula 1 g), from item b) and (s)_4_ Isoxazole alkoxide I. [Bee Example 1 b) member] I prepared a solid which gave the title compound. (Ap(3) 497 [M + H]+.δ G.8(M).83 (6H,m),丨 98_2 G8 (ih, called -64 -

1310036 A7 B7

2.37 (1H, s), 3.19 (1.5H, s), 3.21 (1.5H, s), 3.50-3.65 (3H, m), 3.70-3.93 (2H, m), 4.00-4.18 (3H, m), 4.62-4.83 (1H, m), 5.5〇(0.5H, d, br), 5.54 (0.5H, d), 6.90 (IH, t), 6.98 (1H, t), 7.25 UH, d), 7· 39 (0.5H, d), 7.43 (0.5H, d), 10.91 (1H, s). Example 6 Hydroxy Wu-oxazolidine-2·A certain carbonyl group 1-3-Methyl-1 - (Tomb, LliiL-j, carbazide-3-, methyl 1 sulfenoindole 2 $ -2,4ΠΗ .31·η-diketone

Ajj,2,3,4-^_l-i- formazan-1 (isobutyl)-2,4-dioxo-6_『ηΗ jj jj2,3-bn遂-_η)methyl]sulfenophene T2,3-dl-pyrimidine-5_衮醢甲船方; 10C and gas, in a solution containing 7-argon (〇.78g) in anhydrous THF (3〇ml) i drip 2.5 M-butyl group (2_6 ml), the mixture was mixed! 5 minutes. Add 1 _0M zinc chloride ether solution (6·61 ^1), bring the mixture back to i temperature, and mix for 2 hours. The solvent was removed under reduced pressure. The residue was diluted with anhydrous toluene (2 〇 mi). A solution containing the product of Example 3 b) (3.14 g) in anhydrous toluene (1 mL) and a mixture of sodium iodide in a solvent amount was added sequentially under stirring for 72 hours under nitrogen. The solvent was decanted, the solid residue was distributed between 2N hydrochloric acid and ethyl acetate; the organic phase was alkalized with sodium bicarbonate, extracted with ethyl acetate (2×1〇〇mi), and the combined paper size of the Chinese genus was used. Home 搮 (CNS) Α 4 specifications (210X 297 public) 1310036 A7 ______B7 V. Description of invention (62) r The extract is dehydrated by magnesium sulfate 'filtered and concentrated in vacuo. The residue was purified by column chromatography eluting with isohexane/ethyl acetate (20-75 〇 / 〇 gradient). The subtitle compound was obtained as a yellow solid (1.37 g). MS (APCI) 427 [M+H]+. δ Hdmso 0.83 (6H, d), 2.09 (1H, heptet), 3.20 (3H, s), 3.61 (2H, d), 3.86 (3H, S), 4.22 (2H, s), 7.02-7.05 (1H, m), 7.43 (1H, m), 7.88 (1H, d), 8.20 (1H, d), 11.56 (1H, s, br). Emperor-3-methyl-1 (isobutyl)-2.4-dioxane-6-"(丨+彼墓基)methyl 1 喽 并 "2.3-dl pyrimidine-5-跆 依 according to the example 3 steps d) Method for the preparation of the subtitle compound from the product of step a) MS (ESI) 413 [M + H] + (S) oxazolidine · 2 · ι _ _ _ _ _ _ _ _ _ _ _ _ 3-base) A certain slightly p 忒々-2,4 ΠΗ·3 Η, - two lion according to the method of step 1) g), from step b) product Π 50 mg), and (s) _4_ hydroxy ° ° acridine The title compound (55 mg) was obtained. MS (Apci) 484 _ [M + H]. S^omso 0.82-0.85 (6H,m), 2,03-2.13 (1H, m), a 3-20-3.21 ( 3H, m), 3.53-3.68 (3H, m), 3.75-3.90 (2H, m), 4.00-4.18 (3H, m), 4.60-4.80 (1H, m), 5.50-5.55 (1H, m), 6.99-7.02 (1H, m), 7.41-7.44 (1H, m), 7.90-7.97 (1H, m), 8.18-8.20 (1H, m), 11.53 (1H, s, br) 〇 Example 7 111_^11 - 啥 p -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- -2- β β β β β β β β β β β β β β β β β |心1^1^-二狮. -66 - This paper scale applies to Chinese national standards (CNS> A4 specification (21〇x 297 mm) 1310036 A7 B7 V. Invention description (63)

OH

Add 2,3-dichloro-5,6-dicyano-1,4-benzoxanthene (48 mg) to tetrahydrofuran/water (9:1,1 ml) containing the product of Example 5 c) (48 mg) ) Stir the solution. After 1 hour, the solution was evaporated under reduced pressure. EtOAc m. MS (APCI) 511 [M + H]+. δ 0.90 (6H, d), 2.13-2.23 (1H, m), 2.46 (3H, s), 3.23 (0.4H, s), 3.24 (0.6H, s), 3.18-3.25 (0.6H, m), 3.63.-3.93 (5H, m), 4.05-4.12 (0.4H, m), 4.56-4.62 (0.6H, m), 4.70-4.76 (0.4H, m), 5.46 (1H, s, br), 7.07 (1H, t), 7.15 (IH, t), 7.39 (1H, d), 7.46-7.53 (1H, m), 12.01 (1H, s). Example 8 ''-(5)5-"4-Hydroxyisoxazolidine-2-one sulfhydryl 1-3-A certain-1-(1-A certain ethyl)-6-f (1 Η - mouth倍比和"2,3 - b 1pyridine-3 - a certain methyl sulfonate "2.3 - dl pyrimidine - 2,4 ΠΗ · 3 Η)-dione a) 2-methyl-5- (Ν, Ν- Methylethylamine, a phenanthrene-3.4-dicarboxymethyl ester ethyl ester, was taken as a solution of ethane, methylenetriphenylphosphorane (33.8 g) in anhydrous THF (200 ml) at 65 ° C with nitrogen. After treatment with isopropyl isothiocyanate (10.1 g) for 16 hours, the mixture was cooled to -78 ° C, and methyl 3-bromo-2-oxo-butyrate was added. The reaction was allowed to slowly rise to room temperature. After 24 hours at room temperature, add 3_ -67 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Invention description (04) Bromo-2-oxobutyl Methyl ester (2.8 g), the mixture was warmed to 60 ° C for 16 hours. The reaction was cooled to water (1.5 L) and extracted with ether. After dehydration and evaporation, the oil was purified by chromatography (SiO2) /10: 1 isohexane-ethyl acetate, then 5:1 isohexane ethyl acetate) to give the subtitle compound (23.5 g). δ 1HCDC13^23-1.35 (9H, m), 2.26 (3H, s), 3.46 (1H, m), 3.82 (3H, s), 4.2 (2H,q), 7.42 (1H,br.s). Four iu-dimethyl-Ml-methylethyl)-2.4- Diterpene-嗓1 pyrimidine-5-嵩S§ methyl ester was obtained by suspending silver cyanide (13.5 g) in anhydrous toluene (90 ml), and adding B-St gas (5.34 ml) under nitrogen to stir vigorously. 30 minutes. Add a solution of the product of step a) (23 g) in anhydrous toluene (5 ml), and the mixture was stirred for 72 hours. Add the mixture (3 60 ml), filter out insolubles, wash with a small amount of ether. The solution was washed with saturated sodium bicarbonate solution, dehydrated and evaporated. The residue was treated with methanolic sodium methoxide (25% by weight, 64 ml) at room temperature for 72 hours. The reaction was cooled in ice to trimethylsulfonyl (50.8). Ml) treatment, stirring at room temperature for one night. A vacuum is used to remove all volatiles, and the residue is distributed between water and ethyl acetate. After dehydration and evaporation of the organic solution, the residue is chromatographed (si〇2/ 2 : i isohexane-ethyl acetate, then 3: 2 isohexane-ethyl acetate), separated from the main component (12.2 g). This material was combined with potassium carbonate (6.95 g) and methyl iodide (7.1 g). Dissolved in anhydrous DMF ( 1 50 ml) was carried out at room temperature for 72 hours. The mixture was poured into water (2 L) and acidified and extracted with ether. Wash with brine, dehydrate and evaporate the resulting solid in a solution of ethyl acetate (3 ml) in isohexane (2 mL). 'Collecting a pale yellow solid' upon drying to give the title compound (1 〇.5 g)

. δ士士(3)(3) 1.6 (6H,d), 2.44 (3H, s),3.37 (3H,s),3.95 (3H -68 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm)

Binding

Line 1310036 A7 B7 V. Description of invention (65 s), 4.66 (1H, br). MS (APCI) (M++ H) 297 gL-(bromomethyl)-oxime, 2,3.4-tetraki-3-methyl-l-(l-methylζ^l·2.4-diode) Methyl 2,3-dlpyrimidine-5-carboxylate was prepared according to the procedure of Example 3 b), starting from the product of b) to give the subtitle compound. δ 士(3) is called 1.62-1.64 (6H, m), 3.37 (3H ,s), 3 99 (3H,s), 4.60-4.70 (3H,m) ,' 3丄.丨,2,3,4-tetrahydro-3-methyl-1-(1-methyl a)-2.4-two 1_^11_&amp; drink: and [2,3-bl^-l shy methyl), sputum and "2,3-cn pyrimidine τ products according to the method of example 6 a), by c The product was prepared to give the subtitle compound. MS (ESI) 413 [M+H] + g)-..m4-tetramethylmethyl·m^tdi-6-πΗ-pyridyl-3-yl The base of the p-Pentene and the "2.3_h1p" is used in the preparation of the product of the item d) to produce the subtitle compound. MS (ESI) 399 [M+H] + filg)5-[ [4- post-production Wusong rabbit pyridine 碁 1 carbonyl a certain B 2_, 3 two bi. Pi Li: 3- base ·: -2,4 ΠΗ · 3 Η, - two lions according to the example 3 magic method, by e) The product is prepared to produce a titled character. MS (APCI) 470 [Μ + ΗΓ.δ, (10)丄(6) 42 (6h :) 3.17-3.19 (3H,m),3·32-3· 42 (7H,m),4Kb (〇5h is 4.78-4.82 (0_·5Η,m), 5.50-5.55 (1H,m),7 〇〇_7 〇3 (mm)' 7.43-7.44 UH, m),7_95-7.99 ( 1 H,m),8 l9_82i (iH,蚧. 11.54 (1 H, s, br) Example 9 -69 -

Binding

This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) 1310036 A7 B7 V. Description of invention (66) / (S) 544-Hydroxyl Ioxazolidine-2-&amp; V-A-丨-Bing-6-ΠΗ-pyrrole-and f2,3-b~|g-pyridin-3-ylmethyl)&gt;Sports #Midine-2.4Π H,3H)-dione _ a) 6-lactosyl-3-methyl-1-propanyl-P---2.4 ilH.3H)-diterpenoid containing 6-chloro-3-methyl-1-propyl-pyrimidine-2 A mixture of 4(1H,3H)-dione (3.76 g), sodium sulphate hydrate (6 g) and ethanol (1 mL) was stirred at room temperature for 48 hr. The residue was dissolved in water (500 ml) and washed with ethyl acetate (2×1 〇〇 ml). The aqueous phase was acidified with dilute aqueous EtOAc (EtOAc)EtOAc. The combined organic phases were dehydrated (MgS04), evaporated, and the pale yellow solid was taken directly to the next step. 1)) 1,2,3_14-tetraqi-3.6-dimethyl-2.4-di- gas-1-propyl 4-pheno-"2.3-(11 pyrimidine-5-# S# methyl ester according to Example 3 a) The preparation method of the item is prepared from the product of item a). δ 1.00 (3H, t), 1.81 (2H, sextet), 2.46 (3H, s), 3.39 (3H, s), 3.87- 3.90 (2H, m), 3.96 (3H, s). c) 6-(Lianjia Shame&gt;1,2,3,4-Tetraquinone.-3-A.2.4.2-Dioxo-K-propyl thiophene: and "2,3-dH-pyridine-5- Carboxymethyl methacrylate - prepared according to the procedure of Example 3 b), starting from product b), yielding the subtitle compound. δ 1 HeDC: l; i 1.02 (3H, t), 1.82 (2H, sextet), 3.39 (3H , s), 3.91 (2H, t), 4.00 (3H, s), 4.68 (2H, s) d) Hydrogen-3-methyl-2,4-dioxopyrano[2,3-b Said pyridine-3-ylmethyl benzo-"2.3-cll-pyrimidine _5_ 淼 酉 酉 酉 依 依 依 依 依 实例 实例 实例 实例 实例 实例 实例 实例 实例 ' ' ' ' ' ' ' ' ' ' ' MS MS MS MS MS MS MS ) 413 [M + H] + e) 1,2,3,4-tetra-di-2-methyl-2,4-oxo-substituted 2-propanyl·6·Πη_pyrrolo-- 70 - Ben Paper scale applies to China National Standard (CNS) Α4 specification (210 X 297 mm) Binding

A7 B7 1310036 V. Description of the invention (67) "2, 3-31 pyridin-3-ylmethyl) sulfeno[2,3-€11 pyrimidine-5-carboxylic acid according to the method of Example 3 d), Preparation of the product of d), the title compound is obtained. MS (ESI) 399 [M + H] + Π (S) 5 - "" 4-hydroxyisoxazole pyridine-2-one carbonyl 1-3-A- 1-propyl-6-indole-pyrrolo and "2,3-bl&lt; pyridine-3-methyl-4- oxo" 2,3-dl pyrimidine-2.4 ilH.3 HV di-solids example 3 e) Prepared by the product of item e) to give the title compound: MS (APCI) 470 [Μ+Η]+ ° δ 'Hcocn 0.81-0.85 (3H, m), I. 55- 1.63 (2H, m), 3.20-3.21 (3H, m), 3.54-4.23 (8H, m), 4.60-4.70 (0.42H, m), 4.77-4.83 (0.58H, m), 6.99-7.03 (1H, m), 7.41.7.44 (ih, m), 7.93-7.97 (1H, m), 8.19-8.20 (1H, m), II. 53 (1H, s, br) Example 10 (S) 6-"4,5-two gas-2 - gaso-(2H)-pyrazol-3-methyl-1-5-"4-hydroxyl isoxazolidine-2-ylcarbonyl-3-methyl-1-(isobutyl) And "2.3-dl pyrimidine-2.4ΠΗ: 3Η&gt;-dione

a) 1.2, 3.4-tetrahydro-3,6-dimethyl-1-(isobutyl) V2,4-di-pyrimidine-l~2,3-d&quot;l-density-5.-tour Acid __- 71 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 ___ _ B7 V. Description of invention (68) According to the method of step 3) of Example 3, by example 3 Step a) Product Preparation of the subtitle compound. MS (ESI) 297 [M+H]+. δ ^dmso 0.93 (6H,d), 2.21 (1H,non),2.53 (3H,s), 3.27 (3H,s),3.75 (2H,d),14.04 (ih, s) ° tLXg_)5-" 4-hydroxyisoxazin-2-ylcarbonyl a 1-3.6-dimethyl butyl sulfonate, and a "2.3-H1 pyridinium-2.4HH.3 HV diketone according to Example 1 step g) Step a) Product Preparation of the subtitle compound MS (APCI) 368 [Μ+Η]+. δ WcDcn 1.00 (6H, m), 2.25-2.37 (1H, m), 2.46 (3H, s), 3.39 (3H, s), 3.53-4.09 (5H, m), 4.61 (1H, d), 4.71 (1H, dt), 5.05 (1H, d) c) Dimethyl) dimethyl dimethyl sulfonate忒 Early carbonyl 1-3.6-dimethyl-1-(isobutyl)sulfono-[2.3-(11-pyrimidine-2.4 (11_3卩,. dione. In step b) product (1.2 g) with imidazole ( 0.24 g) of di-methane (20 ml) was added with tributyldimethyl dimethyl chloride (0.54 g). After stirring at ambient temperature for 16 hours, the mixture was washed with water and the organic phase was poured onto a biotage column. </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; 0.99 (6H, d), 2.3 0 (1H, non), 2.44 (3H, s), 3.36 (3H, s), 3.54 (1H, dd), 3.64 (1H, dd), 3.75 (1H, d), 3.84 (1H, dd), 3.98 (1H, dd), 4.47 (1H, dd), 4.89 (1H, dd) d) (S)6-(bromomethyl)-5-"44 (1,1-dimethylh-ethyl) dimethyl矽 alkoxy 1 Isoxazolidine-2-ylcarbonyl 1-3·甲一-1-(冀丁某)-4 pheno[2,3-arseny-2,4ΠΗ,3Η)-dione-72 - This paper size applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) Binding

*Line 1310036 A7 |______ B7 V. Inventive Description (69 T ' According to the procedure of Example 3, step b), the subtitle compound was prepared from the product of step c). 5 lHcDCI3 〇·09 (3H, s), 0.12 (3H, s), 0.98 (9H, s), 1.00 (6H, d), 2.3l (1H, non), 3.36 (3H, s), 3.63 (1H , dd), 3.68 (1H, dd), 3.81 (1H' d), 3·87 (lH, dd), 4_00 (1H, dd), 4.37 (1H, dd), 4.64 (1H, d), 4.69 ( 1H, d), 4, 87_4 92 (1H, m). KS)6-[(4,5-digas^_oxo-3 oxazole, A certain 1-5_"4_"n"_ylethyl)dioxy]isoxazolidinyl w isoindole)-pi phenanthroline P-pyridine 4 (1Η·3Η)-dione according to the procedure of Example 3, step c), from step d) product and 4,5-dichloro-2-oxo-3 (2H) - Sorbone Preparation of the subtitle compound. δ iHcdci3 〇11 (3H, s), 0.12 (3H, s), 0.91 (9H, s), 0.98 (6H, d), 2.28 (1H, non), 3.36 (3H, s), 3.57 (1H, dd ), 3.66 (1H, dd), 3.79 (1H, d), 3.85 (1H, dd), '3.99 (IH, dd), 4.40 (1H, dd), 4.88 (1H, dd), 5.11 (1H, d ), 5.20 (1H, d). Fl—(S)6-“(4,5-diqi-2-Chrysanthemum, generation _3 f2H)-pyrazole)) A certain l-5-"4-hydroxym 畧g No.: bite: 2-茱Carbonyl 1-3-A _ (isobutyl, 3⁄4 pheno-"2.3-dl ulanium-2,4HH.3HV diketone under nitrogen atmosphere, in step e) product (180 mg) Add glacial acetic acid (〇.1〇ml) and 1N tetrabutylammonium fluoride in THF (0.5 ml) in THF (5 ml). After 16 hours at weekly temperature, in saturated sodium bicarbonate solution. And the mixture was extracted with ethyl acetate. EtOAc EtOAc (EtOAc). , d), 2.18 (1H, non), 3.20 (3H, s), 3.43-4.11 (6H, m), 4.60-4.76 (1H, m), -73 - ft 1Λ A 'Λ id -1« rn rxn Ei&gt; 1Λ -Ut / y^a τ τ\. * λ Xh ί ζ\Λ C\ ^ 007^&gt;S· Jm ) 1310036 A7 B7 V. Description of invention (7〇) 5.04-5.11 (2H, m) , 5.51 (1H, s). f Example 丨丨 @1~^11(3,&amp;two _^_^-11^1:.喳'4-base) methyl 1-5-丨4-诲Isoxazolidine-yl ί--diphenyl-3 T-sh-P-Pentenopyrene|~2,3-dl Pyrimidine-2 .4ΠΗ.3Η)-

二味-4_基)甲某[_〗_里丁某_3_ _ _24· Hydrogen·»塞苯和"2 3-dl-pyrimidine-s_逄 to add potassium carbonate (3.55 g) and two gas Bis(trisylphosphine)cobalt („)(〇)g) to a nitrogen-containing gas containing the product of Example 3 a) (1 g) and 2,4-nonanedione (2.64 ml) of dichloromethane ( 30 ml) Stir the solution. After 48 hours, an aqueous solution of hydrazine (35% ' 2.33 ml) was added, and the mixture was vigorously stirred. The mixture was diluted with water (3 ml) and extracted with ethyl acetate (2×60 ml). The organic extract was dried over anhydrous magnesium sulfate and filtered and evaporated. The residue was purified by vermiculite column chromatography and dissolved in acetic acid. The product was dissolved in tetrahydrofuran (2??) and methanol (3 ml). After 3 days, the mixture was evaporated to dryness EtOAc (EtOAc) The aqueous phase was acidified with EtOAc (EtOAc) (3.times. The organic extract was dried over anhydrous MgSO.sub. MS (ES [) 391 [M+H]+. δ lHDMS0 0.85 (6H,d), this paper size applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) A7 B7

1310036 V. INSTRUCTIONS (71) 2.05-2.18 (1H, m), 2.08 (6H, s), 3.17 (3H, s), 3.62 (2H d) 3.71 (2H, s). ' ' b) (S) 6.-.[(3,5-1 曱-lHw azole-4-, a certain thiophene-2-yl 1 carbonyl- 1 - 1 -isobutyl-3 - A-g is exemplified and "? · ϋ 令 | _ _ _ _ _ Π Η Η Η Η - - - 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例_4_#5 Its isoxazolidine hydrochloride {Example 1 b)} Preparation, the title compound (98 mg) was obtained. MS (ESI) 462 [M+H]+. δ towel 50 0.87 (10), Magic 2.05-2.20 ( 1 H,m), 3.19 (2H,s), 3.21 (1H,s), 3.48 (0.67H d)' 3.47-3.85 (6H,m),3.90-4.05 (0.67H, m) , 4·1〇·(〇v^.o/hi, dd), 4.57-4.78 (1H, m), 5.51 (1H,d), 12.08 (1H, s, br). Example 1 2 Pack (S) 5-M-hydroxyiso-g-oxazolidine-2-one carbonyl ΚΙ n "1,3,5-trimethyl-11~1-11 than 吐-4- a huahua: 1 daring: ^ -2.4 ΠΗ.3Η)-dione

OH

Order

Total a) (S) 6-(bromomethyl)-5-indole 4-hydroxyl isoxazolidine-2-y^(isobutyl) dish 吩"2.3-dl pyrimidine-2·4ΠΗ.3Ην二^ Prepared from the product of Example 10 b) according to the method of Example 3 b).

Hcdci3 -75 -

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (72 1.01 (6H, d), 2.27-2.36 (1H, m), 3.39 (3H, s) , 3.58 (1H, dd) „ 3.69-3.76 (2H, m), 3.88 (1H, dd), 4.01 (iH, d), 4.13 (1H, dd), 4.59 (1H, d), 4.60 (IH,d ), 4.72 (1H, d), 4·89 (1H, d). 6) (S) 5-Alumina ^isoxazole oxime-2-some 淼I methyl isobutylene V6_ [(1,3 : 5 - yl-1 Η - pyrazole-4 - one, formazan 1 side, and f 2.3 - d 1 pyrimidine-2,4( 1 H,3H)-diming, potassium tert-butoxide solution (1 Μ tetrahydrofuran) Solution, 2.99 ml) to a stirred solution of the product containing a) (100 g) and 2,4-pentanedione (0.31 ml) in tetrahydrofuran (20 ml) at room temperature under nitrogen. 8 ml of this solution was taken and treated with methyl hydrazine (64 μl). After 24 hours, the mixture was evaporated under reduced pressure. The residue was purified by reverse phase preparative HPLC, eluted with aqueous ammonium acetate / acetonitrile gradient. Column chromatography on silica gel, eluting with ethyl acetate/methanol (24:1) to give the title compound as a solid (24 mg). MS (ESI) 476 [Μ+Η]+.δ旧(10)吕. 0.88 (6H, d) , 2.02 (3H, s), 2.08-2.18 (4H, m), 3.19 (2H, s), 3.21 (1H, s), 3.47 (0.67H, d), 3.62 (3H, s), 3.55-4.03 ( 6.67H, m)' 4.10 (〇; 67H, dd), 4.58-4.78 (1H, m), 5.52 (1H, d). Example 13Π (_R) 6-K4,5-dif-2-A- 1H-imidazole-1-oxime)-methylpyrazine-5-[4-淼 some ιΑ pyridine-2-ylcarbonyl one 1 -3 · A certain _ 1 - (isodin phenanthrene f 2 1 _ d 1 p The title compound was prepared from the product of Example 3 d) and the product of Example 2 b). MS (APCI) 516/518. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; [M+H]+.δ 1HCdci3 0.98 (6H, dd) ; 2.29 (1H, septet) ; 2.39 (3H, s) ; 3.38 (3H, s) ; 3.54(1H, dd); 3.66-3.70 (IH, m) ; 3.80-3.87 (1 H, m); -76 - This paper size applies to the Chinese Gull National Standard (CNS) A4 specification (210x 297 mm)

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1310036 A7 B7 V. INSTRUCTIONS (73) 4.04-4.10 (2H, m) ; 4.56 (1H, d) ; 4.70-4.75 (1H, m) ; 4.92 (1H, d) ; 5.13-5.30 (2H, m) . Example 13ii) _(S) 5-"4-Hydroxyl-oxazolidine-2-ylcarbonyl 1-3-methyl-6-oxime 2-A-1H-Bao Longmi ^_L·基) A certain 1 -1-(isobutyl Vi phen # f2.3-dl pyrimidine-2.4ΠΗ.3Η)- gentry

According to the method of Example 3 c), the product of Example 3 b) and 2-methylbenzimid a)J, 2t3,4-tetradec-3-methyl-6-f (2-methyl- Ih_Stupid and squatting on Xiaomou) A certain 1 - (isobutyl) 2,4 · dioxoindolyl "2,3_-d~l·Nym-5- 醢 醢 HC HC HCdci3 0.9 ( 6H, d), 2.09-s), 3.62 (2H, d), 4.01

Preparation of azole. MS (API) 440 [M+H]+. δ !ί· 2.12 (1Η, rh), 2.63 (3H, s), 3.39 (3H (3H' s)' 5.49 (2H,S), 7.23-7.35 (3H,m),7·7·7 75 ( 1H, called

c) (S) 5-174-Hydroxyisoxazolidine-2- 1 H- to _-imidazolyl-1 -yl)methyl 1-1 -(iso-2.4(lH.3m-diketone c)(3) 5-J~A-6-!72·Kaki--77-A7 B7 1310036 V. INSTRUCTIONS (74) According to the preparation method of Example 3 e), the title compound is prepared from the product of item b). MS (APC1) 498 [M + H]+. δ 'Hcdcu 〇.87_〇93 (6H, m), 2 〇2_ 2.17 (1H, m), 2.66 (3H, s), 3.24 (3H, s), 3.38 (3H, s), 3.52-3.58 ( 2H, m), 3.71-3.δ (1H,m), 4.01-4.07 (2h,m),4 59 (1H, d), 4.71-4.75 (1H m), 4.94 (1H, d), 5.3- 5.54 (2H, m), 7.22- 7.28 (2H, m), 7.39-7.42 (1H, m), 7.69-7.71 (1H, m). Example 13ΠΠ(S) 6-『(2-乙一-1H-笨和米°坐-1-_盖)甲一基羟 Someisoindole _ 2- Some 1-3-methyl-1 _(isobutyl phenanthrene-2.4ΠΗ.3Η,-dione

a) 6-ΙΎ2-B. A-1 H-stupid and 0-diyl)methyl 1-1 j i'4-tetra g.-3-methyl--isobutyl dioxolan Quote! The preparation of 2,3-dl-pyrimidine-s-indole according to Example 3 c) was prepared from the product of Example 3 b) and 2-ethylbenzimidazole, and purified by flash verach chromatography. After dissolving from 30% to 70% of ethyl acetate in the isotactic solution, the title compound is produced. MS (ESI) 455 [M + H] + 0 δ !Hcdci3 0.86-0.88 (6Η, d), 1.44-1.50 (3Η, t),2-2.1 (1H, m), 2.89-3 (2H, q), 3.39 (3H, s), 3.59-3.62 ( 2H, d), 4 (3H, s), 5.50 (2H, s) , 7.2-7.34 (3H, m), 7.60-7.78 (1H, m) 0 b) 6-"(2-B--1H- Stupid A certain 1-丨.2^ 4 shoulder gas-3-A -78 - This paper is available in China National Standard (CNS) A4 size (210X297 mm)

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A7 B7 1310036 V. INSTRUCTIONS (75) The preparation method of the 12.4-di-gas oxime and the 2,3-dl-pyrimidine example 3 d) is prepared from the product of item a) to produce the subtitle compound. .]^(£31)441[\1 + 1&quot;1]+.8 4 means 5〇0.79-0.81(6^1,(1),1.30- 1.35 (3H, t), 2 -2.1 (1H, m), 2.88-2.95 (2H, q), 3.25 (3H, s), 3.58-3.61 ( 2H, d), 5.80 (2H, s), 7.2-7.23 (2H, m), 7.57-7.63 (2H, m). c) (S) 6-"(2-Ethyl-1H-benzopyrazine-1-) A certain U_"4_ with a certain squid ° °定定-2-基录一1-3 -Methyl-1-(isobutyl)&lt;&quot;&quot;&quot;&quot;2.3-(11啼11-?,4(111,311)-dione according to Example 3 e), prepared from product b) The title compound was purified by flash chromatography eluting with EtOAc EtOAc EtOAc EtOAc EtOAc 'Hdmso 0.80-0.83 (6H, m), 1.29 -1.34 (3H, t), 2 -2.1 (1H, m), 2.88-2.96 (2H, q), 3.20 (3H, s), 3.55-3.71 ( 3H , m),3.81-3.91 (2H, m), 4-4.1 (1H, m), 4.55-4.81 (1H, 2m), 5.51-5.57 (3H, m)', 7:15-7.20 (2H, m ), 7.55-7.58 (1H, m), 7.62-7.6 5 (1H, ~ m). Example 13iv) (S) 5-"4-Isoisoxazole-2-ylcarbonyl 1-3 - A certain -1- Γ 丁)-6-ΙΪ2- Propyl-1Η-indolozolidine-1-yl)methyl 1-4 aryl r2.3-dl pyrimidine-2.4ΠΗ.3Η)-I with &amp;) 1,2,3,4-tetrahydro-3 -Methyl-1-(isobutyl)-2.4-dioxane-6-"(2-propanyl-. 1 H-stupidimidol-bu-ki)methyl-supplemental jj "2.3-dl pyrimidine- 5-# acid methyl ester according to the method of Example 3 c), from the product of example 3 b) and 2-n-propyl benzo _____- 79 - the paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1310036 V. INSTRUCTION DESCRIPTION (76) Imidazole preparation, which was purified by flash chromatography, eluted with isohexane:ethyl acetate (1:1) to give the subtitle compound. MS (APCI) 469 [M + H]. δ Womso 0.81-0.83 (6H, d), 0.94-0.99 (3H, t), 1.72-1.82 (2H, sextet), 2.01-2.08 (1H, m), 2.80-2.85 (2H, t), 3.19 (3H , s) , 3.59-3.61 (2H, d), 3.78 (3H, s), 5.65 (2H, s), 7.15-7.23 (2H, m), 7.53-7.59 (2H, m) 匕, 丨-2.3. 4-tetrahydro-3-methyl-1-(isobutyl)-2.4-di-deutero-6-[~(2-propyl- 1H-package odor-1-yl)methyl V phenan And "2,3-dl pain-cooling _ according to the method of the preparation of the example 1" from the product of item a) preparation of the subtitle compound. MS (APCI) 455 [M + H]. δ (10) such as 0.78-0.85 (6H, d), 0.94-1 (3H, t), 1.74-1.86 (2H, sextet), 2-2.07 (1H, rn), 2.87-2.92 (2H, t), 3.25 (3H, s), 3.58-3.6 (2H, d), 5.82 (2H, s), 7.21-7.27 (2H, m), 7.58-7.65 (2H, m). ι·(2·丙棊-mji咪峻-i-棊) A method for the preparation of a 2,3 dl-pyrimidine-2.4nHT3m-dione according to Example 3 e), which is lightly produced by b) and (s)_4_ Preparation of the title compound II ms (Apci) 526.2 [Μ + Η]+ ° δ 0.80-0.84 (6H, m), 〇954 (3H, t ), 1.76-1.83 (2H, sextet), 2-2.1 (1H, m), 2.86-2 90 (2H m) 3 2 (wind S), 3.5:61 (3H,m), 3_7_3.92 (2_5H, m),·... m), 4.5-4.6 (0.4H, m), 4.8 (0.6H, m), 5.52-5.57 (3H, m), 7.16-7.19 (2H,m), 7.55-7.65 (2H, 2m). Example 13v) -80 -

1310036 A7 _____B7 V. Inventive Note (77) to 5-"4-Bay oxazolidine bis 2 - carbonyl 1-3 - formazan - 丨彳 丁 χ χ _ "2 "甲盈. 基) - 1Η-Benzimidazol-1-ylmethyl 1 soul is exemplified by "2丄10_啶_2.4(1Η 3Η)_dione 4!_,2,3,4-tetraindole-3-methylindole-jj · Butyl)·6_[2_(甲结其,_1Η_笨咮咮1-1-ylmethyl I-2,4·一乳代,»襄” and 2,3-dlp hetero-g^-5 - Preparation of the subtitle compound by the method of the example 3 b) and the 2-methylthiobenzoate bite by the method of the acid methyl hydrazide. MS (APCI) 474 [M+H] +. LL 1,2,3,4·tetrakilyl 1-(isobutyl)_6-Γ2-ί methylthio, η-benzofur beer-1-ylmethyl 1-2Α·Ά.oxo 4 </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; ) 5-[4-hydroxyisoxazosin-2-one 1-31-3-A curtain_ι_(Iso-L2-(·methylthio)-1 Η-stupid imidazole-1-yl-methyl 1 - 4 orders "2.3 - d 1 pyrimidine - 2, 4 ΠΗ. 3 Η, - diketone according to the example 3 e), from the b) product and (S)-4-isoxazol Hydrochloric acid salt preparation, the title compound was obtained. MS (APCI + ) 530 [M + H]+. -δ 'Hcdcij 0.Β7 (3Η, s), 0.81 (3H, s), 1.98-2.19 (2H, m), 2.8 (3H, s), 3.21 (3H, m), 3.58-4.17 (6H, m), 4.6-4.8 (1H, m), 5.43-5.58 (2H, m), 7.15-7.19 (2H, m), 7.54-7.6 (2H, m). Example 13 v Π - hydroxy tongs p poxazin-2-yl hydrazine l-6-"2-(with methyl V1H-benzofurazol-1- 1-3-Methyl-1-(isobutyl)-pyrimidopurine 2.3-dl-pyrimidine-2.4ΠΗ.3Η)-'dione _ - 81 - The paper scale applies to China National Standard (CNS) A4 Specifications (210X 297 mm) 1310036 A7 B7 V. Description of invention (78)

a) 1,2.3.4-four j. -642-(hydroxymethyl)-1Η-stupid and squirting-1-a certain 1-3-methyl-1-(isobutyl)-2,4 -dioxosole benzophene "2.3-dl pyrimidine-5-# S#甲西肖

The product of Example 3 b) (0.6 g) was dissolved in DMF (5 mL). 2-Hydroxymethyl- phenylidene i (0.28 g) and anhydrous potassium carbonate (0.6 g) were added to the solution and mixed for 16 hours. The reaction mixture was filtered and evaporated to give white crystals (j. MS (APCI) 457 [M + H]+. S lHCDCi3 0.87 (3H, s), 0.9 (3H, s), 2.1-2.2 (m, 1H), 3.38 (s, 3H), 3.57-3.64 (m, 3H), 3.96 (s, 3H), 4.97 ( s, 2H), 5.64 (s, 2H), 7.26-7.38 (m, 2H), 7.22-7.3 (m, 1H) and 7.74-7.8 (m, 1H). Order

b) 1,2,3.4-four, -6-"2-(#f methyl Ί-1Η-stupid and imi- il A-i-3_ methyl-1-(isobutyl)-2, 4-(2-oxo-p-phenothi-f2.3-d~| s, y-5-by acid, according to the method of Example 3 d), prepared from the product of item a), yielding the subtitle compound. MS (APCI) 443 [M + H]+. c) (S) 5-"4-Hydroxyisophthylpyridin-2-one carbonyl some 淼A 丨Η- Stupid and imi- -1-ylmethyl 1-3 - A The title compound is prepared from the product of item b). The title compound is prepared from the product of item b). (MS-APCI) 474 /475 [M + H]+ 〇δ 'Hdms〇0.83 (3Η, s), 0.85 (3H, s), 2.06-2.18 (1H, m), 3.22 (3H, s), 3.42-3.98 (6H, m ), 4.7-4.8 -82 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (79 (1H, _'4.82(2H, s), 5.25 (1h, s), 5 49 (1h, s), 5 62 (2h, s), 7.16-7.19 (2H, m) and 7.57-7.6 (2H, m). Example 13 vii) LW-"4- Substituted (10) m 丕 imidazole imidazole-1-methylpyrazine i2,3-dl^2,4(10) sindione

CT

丄11^4 Ditetrahydro-3-methyl-6-"2-(methylamine L V1H-茇反1^1二(isobutyl)-2,4-dioxo-pyridyl dj"2.3- The dl-pyrimidine was added in portions to a solution of sodium hydride (0.24 g, 60% in mineral oil) to a stirred solution of 2-(methylamino)benzimidazole (0.93 g) in DMF (50 ml). After 30 minutes of warming, Dmf (10 ml) solution containing the product of Example 3 b) (2.16 §) was added dropwise. The reaction was stirred at room temperature for 16 hours. The solution was poured into water and extracted with ethyl acetate. Dehydration over magnesium sulfate, over-expansion and concentration, and re-crystallized from ethyl acetate to give the title compound as a dichrome solid ' 1.5 g. MS (ESI) 456 [Μ+Η]+.δ 咕_〇 〇83^8 white (6Η, d), 2.05 (1H, m), 2.94-2.95 (3H, d), 3.19 〇Η Λ §5

3.63 (2H, d), 3.84 (3H, s), 5.39 (2H, s), 6.83-6.87 r〇tT in) 6.90-6,99 (1H,t),7.08-7.11 (1H,d), 7 -20-7.22 (1H, d). _1,2,3,4-tetradec-3-methyl-6-"2-(methylamino V1H-茇# 呻H. , ^ 83 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 public) 1310036 A7 ___ B7 V. Description of invention (80) Base 1.-.!-(Different::! Diyl)-2·4·Di-arsonopyrenoyl r2.3-dl-pyrimidine-5 -# 酩 例 Example 3 d) The preparation method of the product of item a) produces the subtitle compound. MS (APCI) 442 [M + H]+. c) C_§_L 5 - "4 - pp峻峻症-2 -基凝基1 - 3 -甲某-ή -丨2 -(甲领其布1Η-笨笨和咮azole-1-ylmethylι_ι_(异丁某) soul phenophene; ^ -2 , 4( 1H,3H)-di-copper addition (S), 4-#f_yl-iso-salt ylide hydrochloride (example 1, item b)) (0.08 g) and triethylamine (0.09 ml) to In a solution of the product of b) (0.13 g) in dichloromethane (5 ml), 1-hydroxybenzotriazole (0.09 g) and 1-ethyl-3-(3,-dimethylaminopropyl) - carbodiimide hydrochloride (0.12 g). The reaction mixture was stirred at room temperature for 12 hours. The solution was concentrated under reduced pressure. The residue was purified by flash chromatography eluting with EtOAc Ethyl acetate solution was dissolved in a gradient. The obtained product was obtained from acetic acid B. Recrystallization from /hexane/methanol to give the title compound as a white solid (0.07 g). MS (APCI) 513.2 [M+H]+ δ 'Hdwo 〇.82_〇86 (6Ή, m), 2-2.1 (1H, m), 2.9 (3H, m), 3.2 (3H, s), 3.6-3.68 (3H, m), 3.78-3.84 (1H, m), 3.9-3.94 (1H, m), 4-4.12 (1H, m), 4.6-4.8 (1H, 2m), 5.2-5.61 (3H, m), 6.86-6.99 (3H, m), 7.19-7.27 (2H, m). Example 1 3 vii Π LU 5- F4-hydroxyisoxazolidin-2-ylcarbonyl-3-1-3-methyl-1H-indenyloxazolyl-1-yl T-indole-(isobutyl) porphin oxime 2,3-ying^ 2_4ΠΗ 3Η)_2 1 I with

OH

This paper scale applies to Chinese National Standard (CMS) A4 specification (210X297 mm) 1310036 A7 B7 V. Description of invention (81 red 6 and carbazole small base) A certain 1 2 3 4-tetrahydro _ 1 - (岂Dingqi, 〇/1 Hydrogenimidophene 2,3-dl pyrimidine-5-comonate methyl carbamide 13VU 3), by example 3 b) product (0.4 g) and 2-amine The benzimidazole (0.16 g) was prepared to give the subtitle compound. MS (ESI) 442 [M + H]+. Imidazole-_ι_--yl)methyl M-2-34-m is a product of the preparation of Example 3 d), and the product of a) Prepared to give the subtitle compound. MS (ESI) 428 [M+H]+.哼 皇 皇 」 」 H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H H The title compound is prepared from the product of item b). MS (ESI) 499 [M+H] + δ 'Hcocn 0.93 (6Η, d), 2.16-2.28 (1Η, m), 3.3^34 (5H m) 3.62-4,37 (6H' m)' 4.59 ( 1H, d), 4.78 and 4 9 (1H, t, geometric isomers ' 2.25 (2H, AB q) and 7.16-7.4 (4H, m). Example 13 ix) (3.) 5-『4-light哼 哼 啶 基 ^ ^ U U U U U U U U U U U U U U U U U U U U U U U U U U U U U U

This paper scale applies to China National Standard (CNS) A4 specification (210X 297 dongdong) 1310036 A7B7 V. Invention description (82) &amp;) 1.2.3,4-four windows.-3-methyl-1-(different Ding Mou)-2.4-digas-6-"2,4,5-trif-1H-imidazole-1-one a certain pheno-"2.3-dl pyrimidine-5-carboxylic acid methyl ester according to Example 3 c) The title compound was prepared from 2,4,5-trichloro-imidazole and the product of Example 3 b) and purified by chromatography (SiO 2 / 20% - 50% ethyl acetate - isohexane). APCI) 479/481/483 [M+H]+.δ WcDcn 0.97 (6H, d), 2.25 (1H, septet), 3.39 (3H, s), 3.74 (2H, d), 3·99 (3H, s), 5.37 (2H, s). 13) 1,2,3, raw-_tetrahydro-3-methyl-1-(isobutyl)-2.4-di-argon-6-|~2,4.5 -Three gas-1 H-imidate-1 -ylmethyl 1 sulfonyl "2.3-d~|pyrimidine-5-43⁄4 age a) product (I 70 mg) containing lithium hydroxide monohydrate (3 1 mg) of water (0.75 ml), methanol (0_75 ml) and THF (2.25 ml) were treated at room temperature for 4 hours. The reaction was acidified with glacial acetic acid and evaporated to dryness. Extraction with dichloromethane, dehydration and evaporation to give the subtitle compound (U0 mg). MS (APCI) 465/ 467/469 [M+H]+. Benzyl-2-isoxazole decyl carbonyl 某^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Preparation of the title compound from the product of step b) MS (APCI) 536/538/540 [Μ + Η1+ 〇δ 'η c〇ci3 0.98 (6Η, dd); 2.26 (1H, septet); 3.40 (3H&lt; , s); 3.47 (1H ήή\ , dd); 3.66-3.70 ( 1H, m); 3.80-3.87 (1H, m); 4.04-4.20 (2H m)· 4 }, 4 55 (1H, d); 4.70- 4.75 (IH,m); 4.90 (1H,d); 5_25 (1H,d); 5.40 (lH d Example 13x), d). (S) 5-"4-Hydroxyisoxazole pyridine-2 -Based on a l_3_甲-86 - This paper scale applies to the Chinese standard of Chinese painting (CNS> A4 specification (210X 297 mm) _ 1310036 A7 B7 V. Invention description (83) Thio-3 (2H)-Stup # 4 CT Xiaoqitian _ poor η. Gong..., #, , - 指 j [U, cH pyrimidine·2,4ΠΗ.3ΗΙ 二酉同

OH

Di-argon·(3) -l(2jj)-i and 4 棊 棊 _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The solution of 〇mg) diethylene glycol dimethyl ether (3 ml) was heated to (10) t by microwave irradiation (6 〇〇w). (10) After the clock, 'vacuum steaming hall to eliminate the dissolution of the sword, (4) purified by gradient chromatography, dissolved in dichloromethane to 5% methanol in a gas-burning solution, resulting in a white solid of the subtitle compound (10) called bu ~ ah (four) (10)... 2.22 (1H, _), 3.38 (3H, s), 3.71 (2H, d), 4 〇〇 (3H, s) 4 8 〇 (2H, S), 7_33 (lH, dt), 7.45 (1H, dt ), 7.77 (iH, dd), 7 d) ° -丄(2_Η)-benzopyrimidinyl) A certain 1 喽 并, 3, tetrahydro-3-methyl ΐ · (Iso · ".... Carboxylic acid according to the method of Example 3 d), from the product of a), for the preparation of the sub-title compound MS (APCI) 461 [M + H] +. lHDMS0 0.86 (6H heart * (four), d) , 2.1G (1H, _), 3.25 (3H, s), 3.70 (2H, d), 5.00 (2H ^ , , ,, 7.39 (1H t) 7 52 (1H, t), 7.93 (iH, d) , 8.02 (1H,d). ' ' c) (S) 544-hydroxyisoxazolidine-2-ylcarbonyl a certain field 1- (isobutyl)-6- -87 - This paper scale applies to Chinese countries搮Quasi-(CNS) Α4 size (210x 297 mm) 1310036 A7 _____ B7 V. Inventive Note (84) Generation-3(2H)-t-based carbazole oxime and "23_di pyrimidine-2,4 (lH.3m-dione According to the method of the method of item 3 e), the product is prepared from the product of item b) Compounds.ms (APCI) 533 [M + H]+.δ 丨HDMS.0.81-0.88 (6H,m), 21〇(1H, non), 3.19 (3H, s), 4.14-4.45 (6H, m ), 4.65 ΠΗ 4 77 Γ2Η a 5. Clear m), 7.40 (iH, (4) 8.04 (1H, d). Example 1 3 xi) (S) · 5-丨 4-hydroxyisoindolyl 棊 3 3 2 ^ ^·丨异丁农6_r4_代-3..(2Η)-4·1ϋ_ylpheno-pyrimidine_2 4MH 3m-dione

a) 4-Gas-2-oxazolone The tetramethylene-containing 2_ suspension containing 2,4-diH(5 §) and fluorinated fresh (5 g) was heated at 130 t for 6 hours. Add fluorination (5 g) and heat the mixture for 16 days. The reaction mixture was evaporated in vacuo to give a crystallite. δ UH, d). b) 4-t.-2(3H)-°serazolidone, taking water containing step a) (1.7 g) and potassium hydroxide (122 g) (25 volts and -88 - this paper size is suitable for 囲National Standard (CNS) A4 Specification (210x 297 mm) 1310036 A7 B7 V. INSTRUCTIONS (85) The acetonitrile (5 m丨) mixture is stirred at ambient temperature for 6 hours. The mixture is distributed between water and dichloromethane. The aqueous layer was collected, dried with EtOAc EtOAc (EtOAc) (EtOAc) ,s), 9.47 (1H, s). MS (ESI) 135/137 [M + H] + gas-2-oxo-3(2Η)-4_^^ 曱 1-1.2.3.4-tetrazine- 3-methyl- 丄 丄 丄 棊 ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) ) -2 -2 -2 -2 -2 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- 3- Subtitle compound. δ 'Hcocn 0.97 (6H, d), 2.29 (1H, non), 3.39 (3H, S), 3.76 (2H, d), 3.99 (3H, s), 5.17 (2H, s), 6.08 (1H, s) d) 6-(~4-Gas-2-oxo-3(2Η)-&quot;Bite base A certain 1-2·3 -4_Four arrows·3_甲华_ 1 bis (.isobutyl)-2,4-digas The preparation of the sub-detailed f2,3-d~|p Naijun-5-# aging according to the method of Example 3 d) was prepared from the product of item c) to give the subtitle compound MS (ESI) 430/432 [M+ H]+.δ 0.90 (6H,d) , 2.15 (1H, non), 3.25 (3H, s) ' 3.73 (2H,d), 5.25 (2H, s), 6.79 (1H, s). e) ( S) 6-"4-Gas-2-Gas-3(2H)- 口宸唆一甲~|-5-"4-转某异》号 P Sitting ρ定-2-基carbonyl 1-3 · A certain -1- (isobutyl thiophene 2,3-d Ip cleavage-2,4 ΠΗ·3 Η)-dione according to the preparation method of item 3 e), prepared from the product of item d), producing the title Compound. MS (APC1) 501/503 [M + H]+. 'Hdms. 0.82-0.92 (6H, m), 2.15-2.20 (1H, m), 3.20 (3H, s), 3.40-3.60 (6H, m), 4.60-4.80 (1H, m), 5.04 (2H, s), 5.50 (1H's), 6.72 (1H, s). -89 - This paper size applies to National Standard (CNS) A4 (210 x 297 mm) 1310036 A7 B7

Iso Ding 1-6-『? .-ί 2.3 - d 1 ^ ^ Example 13 xih

(SHH-hydroxymethane sputum alkaloids 2-yl carbonyl oxo-1,3 -苽# 〇 oxazolium-3 ( 2 Η )- a certain 2,4 ( 1 HJHU 2 SH aiJ-U / 2 _H3·Methyl·1-(Isobutyl)_2 4_ - - ^ ~~~~::::^~1戈-6-ΙΎ2- U.- (2Η)-基)甲-基游Ageing A is prepared according to the procedure of Example 3 c), from the product of Example 3, and the product of benzoxazole, 2(3H)-one to give the subtitle compound. δ ιΗ nc〇ci3 0.95 (6H, d), 2.25 (out, septet), 3.39 (3H, d), 3·73 (2H, sentence, 4 〇 4 (3h, s), 5_18 (2H, s), 7.18 (4H,m). I f base-..丨丄--butyl on 1^^代-6-r2-氪夜, 1^^^3(2Η)-基.甲Hi指^^唉^ The method for the preparation of the article 3 d) of the method of the preparation of the product of the example 3 a) produces the subtitle compound. MS (ESI) 430.1 (M++H) c) (S) 5-indole-hydroxyisoxazolidine-2-ylindole Ki 1 ^ benzoxazole-3 (..2Η).-based f- ^^ and F^3_dl pyridinium-2,4ΠΗ·3Η,-dione is prepared according to the method of item 3 e), which is prepared from the product of item b) to give the subtitle compound. δ lHCDCI3 0.89 (6H,d), 2.15 (1H,m),3·20 (3H,d),3 2 (6H, m), 4.68 (1H, m), 5.13 (2H, m), 5.50 (1H , m), 7.18 (2H dd), 7.38 (2H, m). MS (APCI) 50 1 · 1 (M++H).

Example 13 xiiiV (S) 5-M-hydroxyisoxazolidine-2-ylcarbonylbu 3-methylas-g, butyl s-n "p-generation 丨, 3 卜塞峻和"5,4-blpyridine-1 (2H)-基)甲甚~|g stoppered p,3_di shouting pyridine-2,4ΠΗ.3Η)-dione-90 - This paper scale applies to China S standard (CNS) Α4 specification (21〇x 297 public I)

Binding

1310036 A7 B7 V. Description of invention (87)

a) 3 -nitro ρ than bite · 2 - thiopurine? - NaS(R) (6.41 g) was added to a solution of 3-nitro-2-chloropyridine (9.07 g) in ethanol (12 mL), and the mixture was stirred for 30 min then concentrated in vacuo. Water was added to the residue &apos;acidified with dilute HC1&apos; with ethyl acetate (x5). The organic phase is washed with water, 'dehydrated' and vacuum concentrated to produce a light color of the subtitle compound.

Solid (9.08 g). δ 'HcDcn 7.19 (dd, J=2.7, 4.2 Hz, 1H); 8.44 (m, 2H). MS (ESI) 154.9 b) 3-amine pyridine-2-thiol was added to a solution of the product a) (0.50 g) in glacial acetic acid (5 ml), which was cooled in a water bath, and reduced iron powder (0.50 g). Mix for 45 minutes at room temperature. Additional acetic acid (5 ml) was added and stirring was continued for 20 minutes. The reaction mixture was added dropwise to a sodium hydrogen hydride solution and extracted with ethyl acetate (EtOAc). The organic phase was dried <RTI ID=0.0> δ tHcDcn 4.95 (s, 2H); 6.68 (t, J=6.8 Hz, 1H); 6.80 (d, J=7.7 Hz, 1H); 7.14 (dj= 5.6 Hz, 1H); 12.75 (s, 1H). £) "1,314 oxazo"5.4-bl pyridine-2ΠΗ)-one is added to a solution of the product b) (280 mg) in toluene (300 ml) with hydrazine + number base dimi (3 9 2 mg) , heated to reflux for 16 hours. The reaction mixture is true -91 - This paper scale is applicable to China National Standard (CNS) A4 specification (210X297 mm)

Line A7 B7 1310036 V. Inventive Note (., Concentrated 'Residual Slots Normal Phase Chromatography Purification, Dissolve in a mixture of isohexane·ethyl acetate (3:2). The combined organic phases are partially concentrated in vacuo to produce Subtitle compound "off-white solid (214 mg). δ iHcocu 7.23 (dd, J = 7.9 ' 7. 3 δ (dd, J = 8.1, 1.4 Hz, 1H); 8.31 (dd, J = 4.9 h5 HZ, 1H); 9.5〇(s, 1H).MS (ESI) 150.9 [M + H] + 4) A-isobutyl)_2 4_二代代£1^1嗔pyridine-1(2^1)-)) Base 1 sulfono-r2.3_d]p 5-hydroxy acid methyl ester ^ According to the procedure of Example 3 C), the product of Example 3 b) and the product of item c) were prepared. δ Hcdci3 0.95 (dj j=6.5 Hz, 6H); 2.25 (septet, J=6.9 Hz, 1H); 3.38 (s,3H); 3.73 (d; J=7.9 Hz, 2H); 4.04 (s, 3H) , 5.30 (dd, J=0.3, 2.6 Hz, 2H); 7.26 (t, J- 8.8 Hz, 1H); 7.74 (dd, 8.4' L2 Hz, 1H); 8.31 (dd, J=5.0, 1.3 Hz , ΪΗ). MS (ESI) 460.9 [M + H] + g·) 1,2,3.,4-Eg^ methyl-w isobutyl diindole, substituted 丄^_4-blp than pyridine-U2-based Methyl MU is exemplified by "2 夂..., 々". The carboxylic acid is prepared from the product of item d) according to the method of Example 3 d). δ icDm 0.96 (q, J=3.3 Hz, 6H); 2.26 (septet, J= 7.7 Hz, 1H); 3.51 (s, 3H); 3.81 (d, J=2l.i Hz, 2H); 6.06 (s , 2H); 7.25 (m, 1H); 7.62 (dd, J=8.1, 1.3 Hz, 1H); 8.32 (m, 1H) » MS (ESI) 447 [M + H] + Π (S) 5_:14 - hydroxy-isoxazolidine-2-ylindolyl-3-methyl even $-butyl p_6_ [2-oxo ί 1,3~|ρ窠 also 5.4-blg than lake-1 (2HV methyl group 1 Peak and 丨2.3-dl This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) Binding. Line 1310036 A7 B7 V. Invention description (89) Pyrimidine-2.4ΠΗ.3Η)- The ketone is prepared from the product of item e) according to the procedure of Example 3 e) to give the title compound. δ 1 HDMS 0 〇. 89 (q, J=6.5 Hz, 6H); 2.15 (septet, J=7.8 Hz, 1H); 3.20 (d, J=4.0 Hz, 3H); 3.76 (m, 6H); 4.68 (m, 1H); 5.26 (m, 1H); 7.41 (dd, J=8.2, 4.9 Hz, 1H); 7.80 (d, J= 8.3 Hz, 1H), 8.31 (d, J=4_8Hz, 1H). MS (APCI) 518.0 Example 13 xiv) (S) 5-"4-Hydroxyisoxazole pyridine-2-one carbonyl some 1-3-A-M-di-butyl"-6-ΠΗ-l,2,3 - stupid and triazole-l-ylmethyl)-pyrimido "2,3-dl pyrimidine-2,4(lH,3H)-dii with a) 6-Π Η-1.2,3-stupid three Imidazole-1-methyl)-1,2,3,4-tetramethyl-3-methyl-1-[isobutyl)-2,4-dioxo-"2.3-dl-pyrimidine-5- The methyl carboxylate was prepared according to the procedure of Example 3 c) from the product of Example 3 b) and benzotriazole to give the subtitle compound. MS [ESI] 3 〇 9 [M-benzotriazole] + δ ' Hcocn 0.9 (3H, s), 0.98 (3H, s), 2.18-2.24 (1H, m), 2.48 (3H, s), 3.38 (3H, s), 3.62 (2H, d), 4.11 (3H, s ), 6.03 (2H, s), 7.41 (1H, t), 7.49 (1H, t), 7.71 (1H, d), and 8.09 (1H, d). 13) 6-(1st-1, 2, 3-Strepto-triazol-1-ylmethyl)-1,2,3,4-tetrazol-3-methyl-1-(isobutyl)-2,4-difluoro 4"2.3" The dl-pyrimidine-5-carboxylic acid is prepared according to the procedure of Example 3 d), which is obtained from the product of item a) to give the subtitle compound. MS (ESJ) 414 [M + H] + δ iHowso 0.87 (3H, s), 0.91 (3H, s), 2.01-2.19 (1H, m), 3.2 (3H, s), 3.7 (2H, d), 6.3 (2H, s), 7.46 (1 H, t), 7. 6 (1H, t). c) (S) 5-"4-Hydroxyisoxazin-2-ylcarbonyl1-3-methyl-1-(isobutyl)-6--93 - Paper size Applicable to China National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1310036 V. Description of invention (90)

Prepared by the product of item b) according to the procedure of Example 1 g) to give the subtitle compound. MS (ESI) 486 [M + H]. δ H〇ms〇0.87 (3H, s) ' 0.89 (3H, s) &gt; 2.01-2.19 (1H, m), 3-08-3.22 (3H, m), 3.62-4.17 (6H, m), 4.6 2 - 4.8 2 (1 H,m),5 · 6 - 5 · 8 (1H,m),6 · 〇7 - 6 · 12 (2 H m) 7 4 2 (1H,t),7.6 (1H, q), 7.93 (1H, m) and 8.04 (1H, d). Example 1 3 xv) (S)-5-f4-hydroxyisoxazolidin-2-ylcarbonyl 1-3-methylpyridinium 17 each than p and "2,3-b~|p ratio-1 -ylmethyl V thiophene and "2,3-c^]Ip dense _2·4(lH.3H~)-

a) 1,2,3,4 -four n. -3 -Methyl-1-(isobutyl)-2,4-digastone - 6- (1Η-口比吃# [2,3-1 The 10 prince-1-ylmethyl V dish is exemplified by the method of Example 3 c), and the product of Example 3 b) is prepared with 7-azaindole to give the subtitle compound. MS (APCI) 427 [M+H]+. δ 'Hcdch 0.85 (3H, s)., 0.92 (3H, s), 2.15-2.25 (1H, m), 3.38 (3H, s), 3.66 (3H, d), 4.03 (3H, s), 4.97 ( s,2H), 5.61 (2H, s), 6.49-6.91 (1H, d), 7.06-7.14 (1H, m), 7·38 (1H, d), 7.91-7.95 (1H, m) and 8.3 1 -8.37 (l H, m). This paper scale applies to Chinese Standards (CNS). A4 size (21〇x 297 mm) A7 B7 1310036 V. Description of invention (91) b) 1,2,3,4-tetrazole-3-methyl -1-(isobutyl)-2,4-dioxo-6-indole-pyrrolof2.3-blpyridine-I-ylmethyl)-disc[2.3-dl-pyrimidine-5-carboxylic acid The preparation of Example 3, d), was prepared from the product of item a) to give the subtitle compound. MS (APCI) 412 [M + H] + c) (S)-5-"4-Hydroxyisoxazolidine-2-ylcarbonyl 1-3-曱一-1-(isobutyl V6-(1 Η -pyrrolof 2,3 - b 1 pyridin-1-ylmethyl V-secret and "2,3 - d 1 pyrimidine-2,4( 1 H,3H)-dione according to Example 3 e) Prepared from product b) to give the subtitle compound. MS (ESI) 484 [M + H] + δ 'Hdmso 1.82- 1.93 (6H, m), 1.16-1.22 (1H, m), 2.02-2.09 ( 1H, m), 3.20 (3H, s), 3.42-3.98 (4H, m), 4.03-4.18 (1H, m), 4.9-4.81 (1H, m), 5.39-5.61 (3H, m), 6.52 ( 1H, d), 7.06-7.18 (1H, m), 7.43-7.57 (1H, m), 7.99 (lH, d) and 8.28-8.33 (1H, m). Example 13 χνΠ (S)-5-"4 -hydroxyisoxazolidine-2-carbonyl 1-3-methyl-1-(isobutyl V6-"2-methyl-1H-pyrrolo-l-2,3-blpyridin-1-ylmethyl 1 thiophene "2.3-dl pyrimidine-2,4( 1H.3H)-dione

-95 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1310036 A7 ______B7 V. Invention description (92) — ~&quot; methyl 1-2,4-dioxo 4 phenanthrene [2,3-dl-pyrimidine-5-hydroxy acid methyl g was prepared according to the procedure of Example 3 c) from the product of Example 3 b) and 2-methyl-7-aza. Ms (ESI) 441 [m+h]+. δ 'HCdci3 0.87 (3H, s), 0.90 (3H, s), 2.04-2.21 (1H, m), 2.48 (3H, s), 3.38 (3H, s), 3.62 (2H, d), 3.9 (s ,3H), 4.21 (2H, s), 7.01- 7.06 (1H,m), 7.76 (1H,d),8.22 (1H,d), and 8.8 (1H,(br) s) ° base-M A-1H-pyrrolomethyl 1-2,4-1 oxo "2 3_dl pyridinium ss- decanoic acid according to the method of Example 3 d), prepared from the product of item a), to give the subtitle compound. MS (ESI) 427 [M + H] + carbazole € 棊 turtle base tomb _6- each and "2,3-_&lt;lgt" and "2 3-dl „ pyridine-2,4ΠΗ.3ΡΠ- Diketone The subtitle compound was prepared from the product of item b) according to the procedure of Example 3 e). MS 498 [M+H]H(1) 0.88(3h,s),〇9i(3h,s), 1.2- 1.4 (3H,m),2.13-2.22 (1H,m),3.3δ (5) 359 (2H' m) '3H8(1H'm), 4.28_4.4(4H,m), 4 62-4 8 (2H, m), 5.〇7-5,18(1H,m),6.91-7.04(1H , m) 7 84 (iH d) 822 (1 H, m) and 9. present 1 (1 H, m). Example 13xvii) 幽-[4-基基异异啥后暴小(isoxinxin-6_[5- -96 - This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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1310036 V. Description of invention (A7 B7 93 ) ^ 0

The method for preparing methyl 1-1,2.3.4-tetra-iG-methyl- 丨-r 畧-cephene and "2-3-dl pyrimidine-5-fluorenylmethyl ester according to Example 3 c) Example 3 b) The product was prepared with 5-cyanohydrazide to give the subtitle compound, which was purified by flash chromatography, eluted with 4% EtOAc EtOAc (EtOAc) [M+H]+.δ HDMSO 0.84-0.86 (6Η,d),2-2.1 (1Η,m),3.2 (3Η,s), 3.6-3.63 (2H, d), 4.85 (3H, s), 5.68 (2H, s), 6.67-6.68 (1H, d), 7.53-7.56 (1H, dd), 7.62-7.63 (1H, d), 7-7l-7.74 (1H, d), 8.12 (1H, s ) -i-棊甲羞羞四箭m小e.工基)-2,4-di-i-imido-"2.3_di-pyrene-md-md) method, prepared from product a) produces a subtitle Compound. MS(ESl) 437 [_r4iHDMsc)() 8i_〇83(6H,d),2.2"UH,m),3.19(3H,s),3.57_3.59(2H,d) 5 52 ( 2H, s), 5.59-5.6 7.42-7.45 (lH, d), 7.8l.7 82 (iH) 58(iH)S); 8.15-8.18 (1_H, d) ϋ-f4- 棊呉 吨 症-2-Volume^^Methyl small^ Butyl^ Substituted 棊f-based H-pheno-pyrimidine_2 4nH1HV diketone-97 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) A7 B7

1310036 V. INSTRUCTIONS (94) According to the method of Example 3 e), the product of b) is prepared by γ I, and purified by a flash vermiculite method, with 0-2% methanol in ethyl acetate solution, % Fen After that, the title compound is produced. MS (APCI) 508 [M + H]+. δ H^ms〇0.82-0.86 (6H, m) 2-2.1 (1H, m), 3.2 (3H, s), 3.58-3.7 (3h , m), 3.8-3.9 (2H, m) 4-4.1 ( 1H, m), 4.6-4.8 (lH, 2m), 5.5-5 6 , • 0 (3H, m), 6.66-6.67 (1H, d), 7.49-7.53 (1 H, m), 7.62-7.65 ( lH m, 7 .

m), 7.81-7,84 (1H d), 8.il (1H, s) ' Example 13xvii 2,4 (lH.3m-dione (s··) 5-H-hydroxyisoindole-2 - 棊 棊 ^ ^ 篡 篡 篡 _ 丁 丁 i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i i

a) 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-2.4-diox-6-"2-gas-3(2H)-iso-g-based The preparation of the product of the example 3 b) and the preparation of the benzoxazolone by the method of the method of the example 3 b) according to the method of the example 3 c) , produces the subtitle compound. MS (APCI) 460 [M + H] + 0 δ 1Hd6-dmso 0.88 (6H, d)_, 2.13 (1H, non), 3.19 (3H, s), 3.67 (2H, d) , 3.84 (3H, s), 5.32 (2H, s), 7.23-7.70 (4H, m). b) 1,2.3.4-tetra-H-3-methyl-1-(isobutyl)-2.4- Dioxo-642-gas-3(2H)-benzene·1έ oxazolylmethyl 1 sulfonyl “2.3-dl pyrimidine-5-cyanic acid-98 - This paper scale applies to China National Standard (CNS) A4 size (210X 297 mm)

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1310036 A7 B7 V. INSTRUCTIONS INSTRUCTION (Q5) Depending on the method of preparation of item 3 d), the product of item a) is prepared to produce a subtitle compound. MS (APCI) 468 [M+H]+. δ 巾 06_隐0 0.86 (6H,d), 2.13 (1H, non), 3.19 (3H, s), 3.64 (2H, d), 5.20 (2H, s), 7.18 (1H, dt), 7.28 ( 1H, dt), 7.63 (1H, dt), 8.18 (1H, d). P-I(S) 5-[4 diisoxazole pyridine_2_a carbonyl group μ3_methodamine U_-oxo-xacarbazole dam-yl group a pheno-"2 々-2,4 ( 1Η, 3Η) - 二西同

• Line The title compound was prepared from product b) according to the procedure of Example 丨g). Ms (ES ) 517 [M+H]+. δ iHc^-DMso (90〇C) 0.88 (6H,d),2.11 (1H, non), 3.20 (3H, s), 3.70 (5H, m), 4.09 (iH) dt), 4.58-4.82 (1H , m), 5.21 (2H, m), 5.54 (1H, dd), 7.22 (iH, m), 7.40 (2H, m), 7·69 (1 H, d) 〇Example-1 3 xix (_S) 5-|~4_#至基异g号吐唉-2_基凝基i_3_甲某二]二(isobutyl dioxin-6-甲..基-3-礼.代_g ratio p well _ 2 - 基甲一1 ~ Commanded "2.3 _ d 1 p dense bite-2,4ΠΗ.3Η)-二西同

N Η §丄1'2,,3,4-Four-6-|~2,3-Dihydro-6-methyl-3-free. Generation_;:|?1; Bu 1 and _2 _Methyl 1_ This paper scale applies to China National Standard (CNS) Α4 specification (210X297 mm) 1310036 A7 B7 V. Description of invention (96) 3-methyl-1-(isobutyl)-2,4-di Oxygen exemplified by "2.3-dl, pyridine-5-decanoic acid methyl ester according to the method of Example 3 c) 'from the product of Example 3 b) and 2,3-dihydro-6-methyl-3 The oxo-p ratio p well was used to prepare the subtitle compound. The crude product was purified by chromatography (Si02/EtOAc). MS (APCI) 419 [M+H]+. δ soil (3)(3) 0.97 (6H, d), 2.23-2.33 (1 H, m), 2.29 (3H, s), 3.38 (3H, s), 3.75 (2H, d), 4.03 (3H, s), 5_39 ( 2H, s), 6.85 (1H, d), 7.07 (1H, d). b) 1,2,3,4-tetrahydro-6-"2,3-dihydro-6-methyl-3-hydrogen-leafyl 1-3-mercapto-1-(isobutyl) - 2,4 - di-milo-p-pheno[2,3-dlp-dense p^.-5-borrowing acid according to the method of Example 1 f) was prepared from the product of step a). The crude product was dried in vacuo. It was used directly in the next step without further identification. c) (S)-5-[4-Hydroxyisoxazin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[ 2,3-Di-argon-6-methyl-3-oxo-pyroxy-2-ylmethyl]-sulfonio[2,3-d]pyrimidine-2,4(1H,3H)-dione The crude product from step b) was reacted with (S)-4-#t-iso-s-s-s-s------------ (75% aqueous ammonium acetate / 25% acetonitrile to 100 〇 / 〇 月). MS (APCI) 476 [Μ + Η] + δ 咕 (3) (3) (complex mass spectrometry due to geometric isomers) 1.0 ( 6H,d),2.3 (3H,s),2.5 (1H,m),3 4

(3H, s), 3.5-3.7 (~2H, m), 3.8-4.0 (~2H, m), 4.0-4.2 (~2H πί), 4_ 6-5.0 (~ 2Η, m), 5 · 3- 5 ·6 (~2H, dd), 6·9 (1 H, m) 7 1 (I Η, m). _ X Μ 14 i)

LgJ 5-"4-Hydroxylisoazolidine-2-ylcarbonyl1-3-methyl-6-JJ-A, methyl-l-U (isobutyl V) and 2.3-dl pyrimidine -2,4(111.:^^;^^ -100 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Invention description (97) a) l, 2 , 3"i ditetrahydro-3-methyl-6-indole 7-methyl-1K哚-3-, a certain 1-1-1 (isobutyl)-2,4-difluoro 4-[ 2.3-dl Pyrimidine-5-oxime-methyl ester The subtitle compound was prepared from the product of Example 3 b) and 7-methylindole according to the procedure of Example 5 a). MS (APCI) 440 [M+H]+. δ lHCDC丨3 0.85-0.89 (6H, d), 2.1-2.2 (1H, m), 2.5 (3H, s), 3.39 (3H, s), 3.62-3.65 (2H, d), 3.98 (3H, s ), 4.28 (2H, s), 7.01-7.07 (2H, m), 7.13-7.14 (1H, d), 7.41-7.43 (1H, d), 8 (1H, (br)s) 1))1, 2,3,4-tetra-1.-3-methyl-6-"7-methyl-111-indole-3-m-methyl-1-(isobutyl)-2,4-dioxo The preparation of the p dish "2.3-dlp_Jun-5-Lyin according to Example 1 c) is prepared from the product of item a) to produce a subtitle compound *〇MS(APCI) 426 [M + H]+«51Hdmso 〇.8〇_0.83(6h,(1),2-2.1 (1H, m), 2.44 (3H, s), 3.25 (3H, s), 3.6-3.62 (2H, d), 4.37 (2H, s ), 6.84-6.89 (2H, m), 7.27-7.31 (2H, m), 11 (lH, bs), 14 (1H, (bs), s) c) (S) hydroxyisoxazole pyridine-; 2-yl 1 carbonyl li-methyl-β-"7_甲幕H- P^1 % -3-ylmethyl1-1-(isobutyl V-pheno- and 2,3-d~[p_ Reading j/fiHJH)-dione according to the method of the example 1 g), the product of step b) is reacted with (s)-4-pyridylisosyl. pyridine hydrochloride [example 1 b] Purified by stone chromatography, dissolved in ethyl acetate solution of 3% methanol, and recrystallized from ethyl acetate: isohexyl (9: i) _, produces the title compound. MS (APCI) 497.1 [M + H]. δ 'Hdms〇0.81-0.84 (6H, m), 2-2.1 (1H, m), 2.44 (3H s) 3 2 (3H, s ), 3.5-3.9 (6H, 3m), 4.1-4.2 (2H, m), 4.7-4.8 (1H, 2m), 5.5 (1H, d), 6.82-6.87 (2H, m), 7.28-7.38 (2H , m)&gt; 10.95 (1H, -101 This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1310036 A7 B7

Bs). Example 14ii) (R) 棊J· oxazolidine-2-^ 3 -3-·yl H isobutyl) 4 ha a) 1,2,3,4-tetra 1 2 3-A-6 - "2-methyl-methyl-ή-ρ-甲一- lH-gH ^-^12^-cn pyrimidine-2 4(Ί H.3H)-二ϋ Qiao 1哚-3-一甲一1- 1-(iso- pyridine-5-跆 甲 甲 依 依 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 员 员 员 员 员 员 员 员 员 员 员 员

d), 7.91 (1H, s, br) 〇

JL-based H4.-dioxetane is produced by the product of item a). MS (£§1) 426 [M + Hb δ HDMS〇 0.80 (6H, d),! 99 2 〇9 (1H, (4), 2 37 (3H, s), 3.18 (3H, s), 3.59 (2H, d), 4.32 (2H, s), 6.91 (1H, t), 7.00 (1H, t ), 7.26 (1H, d), 10.96 (1H, s), M.05 (1H, s, br). 21. (Min) · 盐基炭甲甲____?_甲甲"h_ _jl .N. _. 农 〒 〒 丄丄 丄丄 丄丄 皋吟 皋吟 皋吟 皋吟 皋吟 皋吟 皋吟 口 例 例 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Preparation of salt [Case 2 b]. MS (APCI) 497 [M+H]+. δ丨知抑. 0.80-0.83 (6H, m), i.98-2.08 ( 1H, m), 2.37 (1H , s), 3.19 (1.5H, s), 3.21 (1.5H, s), 3.50-3.65 (3H, m), 3.70-3.93 (2H, _____- 102 - This paper scale applies to China National Standard (CNS) A.4 specification (210 X 297 dongdong) 1310036 A7 B7 V. Description of invention (99) m), 4.00-4.18 (3H, m), 4.62-4.83 (1H, m), 5.50 (0.5H, d, br ), 5.54 (0.5H, d), 6.90 (1H, t), 6.98 (1H, t), 7.25 (1H, d), 7.39 (0.5H, d), 7.43 (0_5H, d), 10.91 (1H, s). Example 14 iii) (S) 5-"4-Hydroxyisoxazolidine-2-carbonyl 1-3-methyl-6-oxime-2-methyl)-lH-pyrrolo-"2.3-b 1 pyridine -3 - A certain 1 - 1 -propyl 4 of the base A and "2,3 - d 1 Piperidine -2,4ΠΗ, 3Η) - dione

£〇3-methyl-64(2-methyl-1Η-pyrrolo[2,3-blpyridin-3-yl)methyl1-2.4-dioxo-1-propyl-1.2.3,4 - a method for the preparation of tetramethylpyrimidine "2.3-dl pyrimidine-5-carboxylate according to Example 6 b), from the product of Example 9c and 2-methyl-1H-pyrrolo[2,3-b] The title compound was prepared by pyridine. MS (ESI) 427 [M + H] + δ 1 Hd^-dmso 0.82 (6 Η, t), 1.59 (2H, sextet), 2.38 (3H, s), 3.19 (3H, s) , 3.72 (2H, t), 3.83 (3H, s), 4.17 (2H, s), 6.98 (1H, dd), 7.75 (1H, d), 8.10 (1H, dd), 11.48 (1H, s). b) 3-methyl-6-"(2-methyl-1H-pyrrolo-i2.3-blpyridin-3-yl)methyl-1-2.4-di- gaso-1-propyl-1.2.3.4- Tetramethyl thiophene "2,3-dl pyrimidine-5-decanoate-103 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 According to Example 1 f) The method of preparation, from the product of a product, 』田a., 座1, subtitle compound. MS (ESI) 413 [M + H] + δ 'Hd2〇0.77 (3Η, t), 1.55 ΠΗ sextet^ ί λ ·^ (in, sextet), 2.43 〇H, s), 3.34 (3Η, s), 3.63 (2H,t), 4.16 (2Η, s),7.08(lH, dd), 7.89 (1 Η, d) , 8.06 (1Η, d). O. (s) 5 -μ- via base cover ·6_γγ2_甲) _ih_ -2,4(1H,3H)-dione according to the method of the example 1 g), from the product of step b) and (8) oxazolidine hydrochloride The salt [Example 1 b) was prepared to give the title compound as a solid. MS (APCI) 484 [M+H]+ and δ 'HD6.DMS 〇 0.84 (3H, d), 1.64 (2H, d), 2.38 ( 3H, s), 3.22 (3H, s), 3.41 (1H, d), 3.75 (3H, m), 3.93 (2H, S), 4.10 (2H, m), 4.70 (1H, s), 5.00 (1H , s), 6.91 (1H, s), 7.76 (1H, d), 8.06 (1H, s) 10.92 (1H, s). ' 'Example 15i) (SL·Bu 4-hydroxyisocarbonyl>3-methyl·6_“f2_甲”^ 圭和[4i5_b1 ton li-propyl-2.4ΠΗ.3Η)-dione red 1,213, 4-四气-1^_^6_丨(21-amino)_3simidazole^11^^ Feeding methyl-oxo-oxo-propionium-disc and "2.3-dl peak methyl ester" by example 13xii a) Method for the preparation of small standards, compounds from the product of Example 9 c). &quot; MS (ESI) 456 [M + H] + ____- 104 -

This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 public) 1310036 A7 B7 V. Invention description (101) δ 1 H〇mso 0.83 (3H, s), 0.85 (3H, s), 2.04- 2.11 (1H, m) 2 94 (2H, d), 3.19 (3H, s), 3.6 (2H, d), 3.85 (3H, s), 5.4 (2H s) 6.83-6.9 (2H, m), 6.97 (1H, t), 7.22 (1H, d). b) 1,2,3,4-tetrahydro-3-methyl-6〇(methylaminoxanthene# p 5_bK 噱-3-violet methyl b 2,4 di^-oxo-1 diamyl The preparation method of "2 pyridinium-5-teaching acid according to the example 3 d) is prepared from the product of item a) to produce the subtitle compound 0 MS (APCI) 428 [M + H] + m)· 5-[4 - hydroxy acesulfame oxime oxime) Mimi &lt; Κ 5 · 卟 密 密 - 2, 4 ( 1H. 3H) - dione according to the method of Example 3 e), from the product of b) preparation of clothing 1 Severe, resulting in a subtitle. MS (APCI) 499 [M + H], δ lHDMS0 0.81 (3H, m), 0.86 (2H, mu 58"6l (3H s) 2 (5) 'S)' 3.2 (3H, s),3·6"·2 (6H, ,, 5 ΐδ_5 62 (10), γ 6.88-6.99 (3H, m), 7.2-7.3 (2H, m); Example 15 m

装

Μ

LS_)-5-f4-mercapto-2-isoxazole pyridine 藕 丄 T, 立 1 二丙-6-f4.5-. 盖-2 · methyl-1 Η -味 g生-1 -ylmethyl~|g dish ordered r 2 -&gt; ,,. 1 = pyrimidine-2 4n h._3H dimorphic _

1310036 A7 B7 V. INSTRUCTIONS (102) a) β-[4,5-Dimethyl-2-methyl-1H-imidazolylmethyltetrayl-2,4-dioxo-_1-propyl-yl-indole The preparation of the product 2,3-(11-pyrimidine-^^^^7@ according to Example 3 c) was prepared from the product of Example 9 c), yielding a subtitle compound. MS (APCI) 445/447 [ M + H] + δ 'HCdcl3 〇·99 (3H, t), 1.76 (2H, sextet), 2.38 (3H s) 3 39 (3H, s), 3.85 (2H, td), 3.99 (3H, s) , 5.26 (2H, s).

Mpt. 155-1 56〇C b) 6-『4,5-disorder-2-methyl-1! 1-imi-1-ylmethyl-1-17&gt;3.4_tetraqi_3_methyl - 2,4-di-lactyl-1-propyl-&gt; thiophene and 2,3-dlp screaming -5 - ergon salt according to the method of Example 3 d) 'Preparation of product of example a) , producing a subtitle compound. MS (APCI) 43 1/433 [M+H] + δ 1ΗDMso-D6 〇·87 (3Η, t), 1.67 (2Η, sextet), 2.38 (3Η, s), 3.19 (3H, s), 3.78 ( 2H, t), 5.23 (2H, s). c) (S)-5-"4-Hydroxy-2-isoxazole pyridine a carbonyl 1-3-methyl-1-propanol- ή-μ s. one gas-2-methyl-1H - taste ° The preparation of -1-ylmethyl 1-13⁄4 phenanthrene is resistant to "2,3-dlp mil-2,4(1H.3H)-dione according to Example 3 e), and is prepared from the product of example b). Subtitle compound MS (APCI) 502/504 [M + H] + δ 丨HcdCI3 Γ.01 (3H, t), 1.79 (2H, sextet), 2.39 (3H, s), 3.35 + 3.38 (3H, 2xs Proportion 1: 4), 3.47-3.57 (1H, m), 3.81-3.96 (2H, m), 4.01-4.10 (2H, m), 4.57 (1H, d), 4.58-4.75 (1H, m), 4.93 (1H, d), 5.19-5.27 (2H, m) -106 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1310036 A7 B7 V. Invention description (103) Example 15iii 5-" (4S)-4-hydroxyisoxazolidine-2-ylcarbonyl1-6-"2-(hydroxymethyl)-1Η-stupidimidazol-1-ylmethyl1-3-methyl-1-propane Base-violent pyrimidine-2,4ΠΗ,3Η)-

a) 1,2,3,4-tetramethylolmethyl)-1Η-benzimidazol-1-ylmethyl 1-3-methyl-2,4-dihydro-1-propylphene ~2,3-dl-pyrimidine-5-decanoic acid methyl ester was added with sodium hydride (60 mg, 60% suspension) to 0 ° C under nitrogen with 2-benzimidazole methanol (2 10 mg) In anhydrous DMF solution. After 10 minutes, a solution of the product of Example 9c (500 mg) was applied dropwise, and the mixture was stirred at room temperature for 3 hours. Water was added and the resulting residue was purified eluting elut elut elut elut elut elut elut elut elut The filtrate was extracted twice with dioxane. The organic phase was dried with EtOAc (EtOAc)EtOAc. MS (ES) 443 [M + H] + *δ !Hdmso 0.79-0.84 (3H, t), 1.52-1.62 (2H, q), 3.19 (3H, s), 3.69-3.74 (2H, t), 3.85 (3H, s), 4.77-4.79 (2H, d), 5.71 (2H, s), 5.84-5.88 ( 1 H, t), 7.17-7.26 (2H, m), 7.51-7.54 (1H, d), 7.61- -107 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

- Line 1310036 A7 B7 V. INSTRUCTIONS (104) 7.63 (1H, d). W_l,2,3,4-tetrahydroxymethyl-indoloimidazole-N-methyl-methyl-2,4-dioxo-1dipropyl^"2 3-d·!pyrimidine_5_ Sodium decanoate was prepared according to the procedure of Example 1f) from EtOAc (m.

Prepared from the product of Example 15iii b) according to the procedure of Example 13vii c). The crude product was purified by EtOAc EtOAc EtOAc. MS (ES) 500.1 583 [M + H] + 5 'HDMs〇0.79-0.84 (3H, t), 1.54-1.59 (2H, m), 3.2 (3H, s), 3.6-4.2 (6H, m range ), 4.6-4.8 (3H, 2m), 5.4-5.9 (4H, m), 7.18-7.20 (2H, m), 7.6-7.66 (2H, m). Example 15iv g..: "(4S)-4-. Light-based isoxazolidine-2-ylcarbonyl carbonyl i_3_methylpropan _6_Γ2_ neck base-1 Η-benzopyr-1-yl group A 1-4 NB rndl pyrimidine-2 4r] hh)-dione

OH

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 __B7 V. Description of invention (105) a) 6-f2-Amino-1H-Benzo-indole 臬-1-臬甲Ig_ι·2.3,4 -tetraki-3-carboindole_2.4-dioxo-1 -propyl-&gt;ceramone"2.3-d~|p dimethyl-5-decanoate methyl ester added sodium hydride ( 60 mg '60% suspension) to a solution of 2-aminobenzimidazole (200 mg) in anhydrous DMF under nitrogen. After 1 min, an anhydrous DMF solution containing the product of Example 9c (500 mg) was added dropwise. The reaction mixture was stirred at room temperature for 3 hr. EtOAc (EtOAc) EtOAc. + δ 'Hdms〇0.81-0.86 (3H, t), 1.54-1.66 (2H, q), 3.19 (3H, s), 3.72-3.76 (2H, t), 3.88 (3H, s), 5.4 (2H, s), 6.6 (2H, s), 6.84-6.89 (1H, t), 6.93-6.98 (1H, t), 7-7.15 (2H, m) ° b) 6-丨2-amino-1H-benzene And imidazole-i-a certain 甲·μ i 2 3 4•tetrachloro_3_甲某_ 2.4- dioxo-1-propyl-soul tactics P., 3-dl pyrimidine-5- Example 1 Method f) is produced by example 15iv a) Preparation (22 mg), yielding 4 compound as a pale yellow solid (190 mg). MS (ES) 414 [M + H] + 丨4 (S)-hydroxyisoindole. -3-A certain-1-propan-6-l~2-amine benzo benzopyrene ° sitting 1- -1- A 1-4 commanded f2,3-dl pyridinium-2.4ΠΗ.3Η)-two The ketone was prepared according to the procedure of Example 13vii c), which was obtained from the product i iv b) (190 mg). The crude product was purified by reverse phase preparative HPLC eluting with 5% to 95% acetonitrile in 0.1% acetic acid. It is then triturated with methanol and filtered to give the title compound as a white solid (19 mg). MS (ES) 485.1 63 1 [M + H] + -- -109 - The paper size applies to the Chinese National Standard (CNS) A4 specification _( 21〇X 297 公)) 1310036 A7 B7 V. INSTRUCTIONS (106) δ 'Hdmso 0.82-0.86 (3H, t), 1.57-1.62 (2H, q), 3.19 (3H, s), 3.65-4.15 (6H , range of m), 4.65-4.80 (1H, m), 5.26-5.60 (3H, m), 6.63-6.69 (2H, bm), 6.84-6.87 (1H, t), 6.93-6.97 (1H, t) , 7.12-7.14 (1H, d), 7.20-7.27 (1H, 2d). Example 16 i) (3) 5-f4-hydroxyisoxazole pyridine-2-carbonyl 1-3-methyl-6-f2-(methylamino)-1Η-

1^(isopropyl)-2,4-digastrix 3 exemplified "2,3-dl-pyrim-5-volum acid methyl ester according to Example 13vii) Method a) [Example 8 c) The product was prepared with 2-methylamine benzimidazole, which was triturated with ethyl acetate and filtered to give a small fraction of compound. MS (ESI) 442 [M + H] + δ 'Hdmsq 1.40-1.42 (6Η, d) , 2.94-2.96 (3H, d), 3.16 (3H, s) 3.85 (3H, s), 4.3 (lH, bs), 5.39 (2H, s), 6.84-6.99 (3H, m) 7. 1 1- 7.14 (1Ή, d), 7.20-7.22 (1H,d). ",3,4-tetrahydro-1^6-"(2_methylamino)^苽^furfuryl 1^1-yl_kl -(isopropylidene)-substituted 4-phenothi-pyrimidine_% platinum is prepared according to the method of item 3 d), which is prepared from the product of item a) to produce a subtitle

1310036 A7 B7 V. Description of invention (107). MS (ESI) 428 [M + H] + C) (sm. 4-hydroxyisoxazole-2-one carbonyl 1-3-methylamine)-1 Η-benzimidazole-1_-yl Base 1 - 1 -(isopropyl)gf is exemplified by "2.3 - d 1 pyridin-2.4ΠΗ.3Η)-dione via flash meteorite followed by the method of example 1 3vii c), by item b) Preparation of the product, purification by chromatography <RTI ID=0.0></RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; , 2.94-2.95 (3H, d), 3 1? 3.55-3.66 (1H, 2d), 3.81-3.84 (1H, m), 3.89-4 riR , ' S)' ' m), 】 (1H, m) , 4.1-4.2 (1H, m), 4.6-4.75 (1H, 2m), 5.i7 · •26 (13⁄4 m), 5.37-5.44 (1H, 2m), 5.52-5.61 (1H, 2m), 6.89. 6 99 ' m)' 7.19-7.30 (2H, m). (3'H,

Example 16 ii) (S)-5-f4-hydroxyl-2-isoxazole pyridine a carbonyl group l-6-f4,5-dichloromethylid d-ylmethyl-3-methyl-1-(iso Propyl pheno- and "2,3_-d] double

Diazol-2-methyl-1H-imidazole-buylmethyl"-3 d -1 -ϊ*-^--- 3 _mercapto-1-(isopropyl _ _ - 111 -

This paper scale is applicable to China National Standard (CNS) Α4 specification (210X 297 mm) 1310036 A7 B7 V. Inventive Note (108) -- According to the method of Example 3 c), it is prepared from the product of Example 8 c), resulting in small Title compound. . MS (APCI) 445/446 [M + H] + δ 'HcDcn 1.56-1.61 (6H, m), 2.37-2.38 (3H, m), 3.37 (3H, S), 3.98 (3H, s), 4.40- 4.50 (1H, br.s), 5.25 (2H, s). Ϋ-『4,5·:· 二气-2-甲棊-1_H-imidazol-1-yl-methyl -4-mu-methyl hydrazine-1-(iso-bone-based)-2,4-dioxo-4 And [2.3-(11-Sulphate_5-Lecool) Example 3 d) process was prepared from the product of item a) to give the subtitle compound. MS (APCI) 43 1/433 [M + H] + δ 1.53 (6H,d), 2.39 (3H,S),3.31 (3H,s,),3.54-3.69 (IH,m),5.32 (2H, s). Gl (§..)-5-".4-丧基-2-iso-p 吐 carboxy group 1·6-Γ4,5-two.-2-methyl-1H- fans__a sit two L a method for the preparation of a compound of the formula (b), which is prepared from the product of item b) to give the title compound MS (APCI) 502/504 [M + H] δ 'Hcocn 1.55-1.61 (6Η, m), 2.39 (3H, s), 3.33 (3H, s), 3.51 (1H, dd), 4.01-4.09 ( 2H, m), 4.40-4.55 (lH, br.s), 4.57 (1H, d); 4.68-4.75 (1H, m); 4.95 (1H, d); 5.15-5.28 (2H, m). 6 iii (S)-5-"4-Hydroxyindisoxazin-2-ylcarbonyl1-6-丨?-(Baijia)-1 H-Bumimidazole-Bulkyl 1-3- Methyl-1-(isopropyl V-seceno[2.3-dl-pyrimidine-2.4UH.3H)-dione-112 - This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) 1310036 A7 B7 V. Description of invention (109)

OH

^~1,2'3'4 -四空甲甲)-1Η -Cage · # 咪口坐-1-Methyl 1-3 -Methyl-1-(呉巧一基)-2,4- Dioxophenophene T2.3-dl pyrimidine-5-comonate methyl ester was added sodium hydride (79 mg, 60% suspension) to hydrazine. (: with a solution of 2-benzimidazole in methanol (280 mg) in anhydrous DMF under nitrogen. After 10 min, a solution containing the product of Example 8b (660 mg) was added dropwise and the mixture was stirred at room temperature. The resulting precipitate was filtered with EtOAc (EtOAc) elute elute elute elute elut elut elut elut elut , d), 3.18 (3H, s), 3.85 (3H, s), 4 32 (1H, bs), 4.78-4.80 (2H, s), 5.71 (2H, s), 5.86 (1H, bs), 7.23 (2H,m), 7.55-7.57 ( 1 H,d), 7.61-7.64 (1H, d) b) 1,2,3,4-tetrahydro-6-"2-(hydroxymethyl)-1 H-benzoxazole-1-somemethyl]^^yl-1 isopropyl...yl)-2,4-dioxosindol [2,3-dl^唉-5-acid surface Preparation of the title compound as a white solid (340 mg) from EtOAc (EtOAc)

c) (S) _5-[4-hydroxyisoxazolidine-2-carbonyl-1-6-"2-f-hydroxymethyl-imidazoledi-l-ylmethyl-1-methyl-1-(isopropyl) Base) pyrimine μ = -2·4(1Η.3Η)-dione

-113 - This sheet is applicable to the Standard® (CNS) Α4 specification (210Χ 297 mm) 1310036 A7 B7 5. Inventive Note (110) According to the example 丨3vu c), by example 16iii b) Preparation of the product. The crude product was purified by reverse phase preparative HPLC with 25% to 95% acetonitrile. /. The aqueous solution of ammonium acetate was dissolved to give the title compound (11 mg). MS (ES) 500.1610 [m+H] + δ [Ho' 1.37-1.40 (6H, m), 3.18 (3H, s), 3.5-4.4 (5H, range of m), 4.6-4.8 (3H, 2m) , 5.5-6.9 (4H, m), 7.17-7.21 (2H, m), 7.59-7.68 (2H, m). ' ' Example 16iv (s)-5-Li-_. Hydroxy Wu A certain isopropyl ή _ "?_ Amino- 丨ίίϋ M ^ 2 - Τ Τ 唓 唓 2 points and "2.3-dl pyrimidine-2.4 ΠΗ.Ή·Π- 二酉同ΟΗ

a) 6-[2-基基-1Η·遂·_和米吨_丨_基甲华ρ 2 3 4•四氦_3-甲某”' (isopropyl A)- 2 soil.—代〇 Methyl b2,3-dl-pyrimidin-5-l-acid

Prepared from the product of Example 8 b) (66 〇 mg) and I.*-benzimidazole (250 mg) according to the procedure of Example 13vii a). The crude product was purified by flash chromatography eluting with 50% ethyl acetate in hexanes</RTI> and then eluted with EtOAc EtOAc EtOAc (360 mg). MS (ES) 428 [M + H] + _____- 114 - This paper is used again. (4) Alignment (CNS) A4 specification (21QX 297 DON) ----- 1310036 A7

Dmso 1.40-1.42 (6Η, d), 3.17 (3H, s), 3.88 (3H, Η (lH, bs), 5.42 (2H, S), 6.62 (2H, s), 6.87-6.90 (1H, t) 6g 3 6.98 (1H,t), 7.U-7.丨5 (2H,m). ' '3~ m2-Amino-1H2^Methyl M 2 fly 4_四-I Bu (opening C The phenanthroline f2.3-dl-pyrimidine-5-indole was subjected to the title compound (m. MS (ES) 414 [M + H] + £l(s) carbonyl hydrazine 夂 夂 某 ^ ^^ U diaminomethyl 1-p thiophene # "2 λ_Ηϋ^ -2,4 (ΊΗ · 3ΗΠ-dione ~ according to the method of s Example 13νπ c), prepared by the product of i6iv (9) (i.9). The crude product was purified by reverse phase preparative HPLC with 25% to 95% acetonitrile and 1% ammonium acetate. The aqueous solution was dissolved in EtOAc (3 mL, EtOAc, m. 3H,m), 3.6_4.4 (5H, range of m), 4.6-4.8 (1H, m), 5·2-5.6 (3H, m), 6 7_6 8 (2H, (4), 6 86_ 6.90 (1H , t), 6.95-6.98 (1H, t), 7.13-7.15 (1H, d), 7.2-7.3 (lH, 2d). Example 1 6 v) _ hydroxyisoxazole pyridine-2- 粦 1-3-A 甚 丨 昱 昱 昱 昱 v v v v v v v v 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2卜 甲 甲 芊吟 芊吟 「 υ υ υ 口 口 口 -2 -2 -2 -2 -2 -2 , -2 -2 , -2 -2 , -2 , , , -2 -2 -2 -2 -2 -2 -2 -2 -2 , -2 , , , , , , , , , 本 本 本

Binding

1310036 A7 B7 112 V. INSTRUCTIONS (

OH

幻一 i^li·^ Hydrogen '3- T-based-1-(iso-methyl-1H-A skin: 3⁄4 basal kL4-sulphur) 1^, and "2.3-dl pyrimidine-5_跆醢A solution of 2-methylazepine (25 g) in THF (5 ml) was added dropwise to a stirred mixture of THF (5 mL). After stirring for 5 minutes, the mixture was cooled to EtOAc. Extracted with dichloromethane, the organic extract was dehydrated with anhydrous magnesium sulfate. 'Filtered and evaporated under reduced pressure. Residue was purified by column chromatography. Ethyl acetate/isohexane (hexane: oxime) and ethyl acetate/acetic acid § Hand (9:1) is dissolved in sequence to give the title compound as a solid (〇〇6. MS (ESI) 413 [M + H] + δ 'Hdmso 1.36 (6Η, d), 3.17 (3H, s), 4.20 (1H, s, br), 5.73 (2H, s), 6.32 (1H, s), 7.09-7.12 (1H, s), 7.88-7.90 (iH, m), 8.20-8.2 1 (1 H, m )

[[4-hydroxylisoxazolidine-2-ylcarbonyl 1-3-methyl-1-pyranyl iso-I pyrrole and "2.3-bl-pyridine-1-methylphenan #吟立-2,4 (1H.3m-dione according to s1g) The method of 'products' and (S) - 4 - is 11 also bite alkoxide ______- 116 - This paper scale applies to Chinese national standards (CNS A4 size (210X297 mm). 1310036 A7 B7 V. Description of the invention (acid salt [Example 1 b] prepared to give the title compound as a solid. MS (APCI) 484 [M + H] dec δ 1 Hdmso 1 8- 1.40 (6Η, m), 2.41 (3H, m), 3.16-3.19 (3H, m), 3.54-4.25 (5H, m), 4.60-4.73 (1H, m), 5.42-5.58 (3H, m), 6.29 (1H, s), 7.09-7.13 (1H, m), 7.88 (1H, dd), 8.22-8.26 (1H, m) Example 17i) (S)-5 44-Hydroxyisoxazole pyridine-2-耩一1-3-甲一-1-(昙JI.基)-6-f3,5-diethyl-1H-pyrazole-4-A certain 1-4 phenanthrene "2.3-dl pyrimidine- 2,4(1H,3H)-

Binding

a) 643,5-diethyl-1H-pyrazole-4-a certain 1-3-methyl-1-(isobutyl)-2.4-dioxane-1,2,3,4-tetraindole Preparation of the pyrimidopurine 2,3-(11-pyrimidin-5-# acid according to Example 12 a) from the product of Example 3 c) (1 g) and 3,5-heptanedione to give the subtitle compound Solid (0.37 g). MS (ESI) 419 [M+H] + δ 'Hdmsq 0.86 (6Η, d), 1.10 (6H, t), 2.05-2.15 (1H, m), 2.49 (4H, q), 3.26 (3H, s) , 3.66 (2H, d), 4.06 (2H, s).

b) (S) 5-"4-Hydroxyisoxazole pyridine-2-someone 1-3-甲一-1-(isobutyl oxime-ή-"3,5-diethyl-1 Η- ρ-Bistazole·4·Ketyl-1-pyrimido[2,3-dl-pyrimidine-2.4 (1 H diketone 117 - The original Zhang scale applies to China's 8 standards (CNS) Α4 specification (210X297 mm) 1310036 A7 B7 V. Description of the invention (114) Prepared according to the procedure of Example 3 e), starting from product a) and (S)-4-hydroxyisoxazolidinium hydrochloride [Example lb], yielding the title compound as a solid (145mg) MS (ESI) 490 [M + H] + 5 'Hdmso 〇·86 (6Η, d), 1.09 (6Η, t), 2.03-2.19 (ΊΗ, m), 2.49-2.52 (4Η, m ), 3.19 (2H, s), 3.21 (1H, s), 3.50 (0.67H, d), 3.35-3.63 (1H, m), 3.70 (1H, dd), 3.75-3.80 (3H, m), 3.84 (0.67H, dd), 3.90-4.05 (1H, m), 4.09 (0.67H, dd), 4.58-4.80 (1H, m), 5.51 (1H, d), 12.18 (1H, s, br). 17ii) (S) 5-"4-Hydroxyisoxazole-2-one carbonyl 1-3-methyl-1-(isobutyl)-6-"3-Π.1-dimethylethyl) -5-Methyl-1H-pyrazol-4-ylmethyl 1-sulfono-[2,3-dl pyrimidine-2.4ΠΗ.3Η)-dione

Prepared from the product of Example 12 a), 5,5-dimethylhexane-2,4-dione, and 35% hydrazide to give the title compound as a solid. MS (ESI) 50_4 [M + H] + δ 'HdmsoO.85 (6H, d), 1.23 (9H, s), 1.99-2.06 (4H, m), 3.19 (2.25H, s), 3.2 1 (0.7525 H, s), 3.50-3.60 (2H, m), 3.64-3.72 (1H, m) 3.79 (1H, m), 3.83-3.96 (3H, m), 3.98-4.05 (0.25H, this paper size applies to China National Standard (CNS) A4 Specification (210 X 297 mm)

M * 1310036 A7 B7 V. INSTRUCTIONS (115) m), 4.07 (0.75H, dd), 4.58-4.78 (1H, m), 5.51 (1H, d), 12.08 (1 H, s, br). Example 18i) G). 5-"4. hydroxy-screen 哼 哼 S S S S S S S l -1- -1- -1- -1- -1- -1- 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 642 And "2,3-dl shouts θ-2.4ΠΗ, 3Η)-dione

a) Ν-methoxy-oxime, 2-dimethyl-4-ρ set of Leopard 1 in dmF (1 drop) containing 2-methyl-4-porphyrincarboxylic acid (8.2 g) Add early hurricane ^4.5 ml) to the di-methane (10 0 m 1) bath. The mixture was heated under reflux for 1 hour. After concentrating in vacuo to dryness, the residue was redissolved in di-methane (5 mL), and then triethylamine (17 ml) and hydrazine, dimethyl-hydroxylamine (8.2 g) were added to the reaction at ambient temperature. Stir for 16 hours. The reaction mixture was washed with water (2×100 ml) and evaporated. MS (ESI) 231 [M + H] + δ 'Hcdcij 2.77 (3Η, s), 3.24/3.40 (3H, s), 3.47/3.74 (3H, s), 7.26 (IHa s), 7.52 (1H, t ), 7.71 (1H, t), 7.8 〇 (IH, d), 8.06 (1H, d). b) 2-Mercapto-4-Phenanthroline added 2.5N diisobutylaluminum hydride in toluene solution (5.6 mi) to _78 This paper scale applies to China National Standard (CNS) Α4 specification (210 297 gong) PCT)

Μ 1310036 A7 B7 V. Inventive Note (116) The product containing the product of step a) (1.6 g) in anhydrous toluene (4 〇 ml). After 2 hours, a solution of sodium potassium tartrate (5 g) in water (25 ml) was added to quench the reaction and allowed to warm to room temperature. The organic phase was collected, washed with water, dried over magnesium sulfate and evaporated. The residue was purified by EtOAc (EtOAc) elute 3 HCDcn 2. 87 (3H, s), 7.26 (1H, s), 7.67 (1H, ddd), 7.69 (1H, s), 7.78 (1H, ddd), 8_12 (1H, d), 8.96 (1H, d), 10.49 (1H, s). -3-_Methyl-1-(isobutyl, ·2·4_dioxophene) "2.3-Bite-5-carboxylic acid 1,1 ·Dimethyl l ester in the case of Example 1 c) To the solution of product (2.0 g) containing DMF (1 drop) in dichloromethane (12 ml), add chlorophyll chloride (1 · 〇^1). Mix the mixture at room temperature for 丨 hours. The residue was redissolved in dichloromethane (8 ml), and then diethylamine (4 ml) and 2-methylpropan-2-ol (8.0 ml) were added to the mixture, and the mixture was stirred at ambient temperature for 4 hours. Washing the reaction mixture with water (2 X 1 〇〇mi), dehydration and evaporation of the organic phase. The residue was purified by chromatography eluting with hexane/ethyl acetate (5:,) to give the title compound as an orange oil. (丨6g) δ ^00013〇-99 (6Η, d), 1.61 (9H, s), 2.31 (ΙΗ,ηοη), 3.42 (3Η s), 3.80 (2Η, d), 7.26 (1Η, s ''L2,3,4-tetrahydro-6-[mono-yl-(2-methyl^quinolinyl w))-2,4-dihydro-deutero[~2, Pyrimidine-5-oxyl 1·] Amethyst was prepared according to the procedure of Example 1, step d), subtitle compound was prepared from the product of step and b). MS (ESI) 510 [M + H] +

δ 'HCDC|3 0.85 (6H, d), 1.66 (9H, s), 2.11 (1H, m), 2.82 (3H __- 120 -

This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Inventions (117) s), 3.39 (3H, s), 3.48 (1H, dd), 3.53 (1H, d), 3-71 (1H, dd), 6.72 (1H, d), 7.44 (1H, t), 7.67 (1H, t), 7.72 (1H, s), 7.82 (1H,d), 8.07 (1H , d). e) 1.2, 3.4-tetraqi-3 -methyl-M isobutyl)-64 (2-methyl-4-hydroxylinyl)methyl 1-2,4-di-generation-peak benzo[ 2,3-dl-pyrimidine-5-carboxylic acid 1.1-dimethyl ester was added with methanesulfonate (0.46 ml) to room temperature under nitrogen, containing step d) product (1.42 g) and triethylamine (1.54 ml) The mixture was stirred for 40 minutes in anhydrous THF (30 mL). 10% Pd/C (320 mg) was added and the mixture was hydrogenated at 5 bar for 2 hours. The suspension was filtered through EtOAc (EtOAc) (EtOAc). The organics were concentrated under reduced pressure. EtOAc (EtOAc) MS (ESI) 495 [M + H] + δ 'Hcdcu 0-91 (6Η, d), 1.61 (9H, t), 2.18 (1H, non), 2.74 (3H, s), 3.40 (3H, s) , 3.64 (2H, d), 4.55 (2H, s), 7.18 (1H, s), 7.52 (1H, t), 7.71 (1H, t), 8.05-8.07 (2H, m). Π 1,2,3,4-tetrazine,-3-methyl-M isobutyl)-6-f2-methyl-4-carbolinylmethyl 1-2,4-digas-violet And a solution of the product (0.82 g) in dichloromethane (15 ml) was added with trifluoroacetic acid (3 ml). 】,Time. Add a saturated solution of sodium bicarbonate (1 00 ml), EtOAc (EtOAc)EtOAc. ). δ 'HdmsoO.87 (6H, d), 2.13 (ΙΗ, ηοη), 2.76 (3H, s), 3.51 (3H, s), 3.65 (2H, d), 5.21 (2H, s), 7.21 (1H, s), 7.48 (1H, t), 7.70 -121 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (118) (1H, t), 7.89 (1H, d), 8.06 (1H, d). g) (S) 5-"4-Hydroxypyrene..°#吐t-2-基荪一1-3-甲一-1-f Iso-)-6-"2-Methyl-4- Process for the preparation of the morpholinylf-group 14-pheno-f2.3-dl-pyrimidine-2.4 (1H.3HV dimerization example, step g), starting from product f) and the product of example 1 b)) APCI) 509 [M+H] + δ 'HdmsoO.85 (6H, m), 2.00-2.12 (1H, m), 2.62 (3H, S) 3 (3H, s), 3.55-4.12 (6H, m) , 4.47-4.63 (2H, m), 4.79 (lu ,

s»br)j 5.54 (1H, s,br), 7.31/7.36 (1H, s), 7.54-7.56 (1H , ' ”, 7,71 (IH, t), 7.93 (IH, d), 8.16- 8.23 (1H, m) » Example 18 ii) Packing (S) 646-Gas-4-4: phenyl-methyl-1·5-丨4-荈~isoxazole pyridine-2-(methyl-1-() Isobutyl V stopper and "2.3-dl pyrimidine-2,4(1H,3H)-二西^

OH

a) 6-Γ6-gas-4-carbolinyl (hydroxyl)methyl 1-3-methyl-1-(isobutyl oxo-oxime, 2,3,4-tetrahydro 4 pheno-"2, 3-dl pyrimidine-5-carboxymethyl ester

Order

The product of the example lc) and the 6-fluoro-4~n aldehyde are prepared according to the procedure of Example 1 -d) to give the subtitle compound. MS (ESI) 486 [M + H] + δ 'Hcocn 0.87 (3H, d), 0.90 (3H, d), 1.42 (3H, t), 2.〇7_2 a · z I -122 -

This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1310036 A7 B7 V. Invention description (119) (1H, m), 3.38 (3H, s), 3.51 (1H, dd), 3.63 ( (1H, d) , dd), 8.98 (1H, d). b) 6-"6-Fluoro-4-peakolinylmethyl 1-3-methyl-1-(isobutyl)-2,4-dioxane - 1.2.3.4- tetrai, imipenem f2 , 3-dl pyrimidine-5-decanoic acid ethyl ester was prepared according to the procedure of Example 丨e), which was obtained from the product of item a) to give the subtitle compound MS (ESI) 470 [M + H] δδ 'Hcdcli 0* 91 (6Η, d), 1.38 (3Η, t), 2.13-2.26 (1H, m), 3.40 (3H, s), 3.65 (2H, d), 4.46 (2H, q), 4.53 (2H, s), 7.31 (1H, d), 7.51 (1H, td), 7.75 (1H, dd), 8.16 (1H, dd), 8.85 (1H, d). c) 6-"6-Gas-4-Porphyrinyl 1-3-A-M-butyl-)-2.4-dioxane-1.2.3.4-Four gas. Method for preparing "2.3-dl pyrimidine-5-cyanate salt according to Example 1 f) Prepared from product b) to give the subtitle compound MS (ES) + 442 [M + 2H-Na] + δ 'HDMs 〇 0.81 (6Η, d), 2.02-2.16 (1H, m), 3.20 (3H , s), 3.56 (2H, d), 4.51 (2H, s), 7.59 (1H, d), 7.63 (1H, td), 8.06 (1H, dd), 8.6 1 (1 H, dd), 8_82 ( 1 H, d) d) (S) 646-Fluoroline-methyl 1-5-Γ 4-hydroxyisoxazolidine-2-ylcarbonyl 1-3-A-[-(- 2,3-dl-pyrimidine-2.4ΠΗ.3Η)-dione according to the method of the example lg), from the product of item c) and (S)- Preparation of 4-hydroxyisoxazolidine hydrochloride {Example 113)}, subtitle compound. MS (ESI) 5 13 [M + H] + -123 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)

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1310036 A7 B7 V. Description of invention (12〇

δ* 'HDMS0 0.82-0.85 (6H, m), 2.04-2.17 (IH, m), 3 ' ^ ι (2 H 3·22 (IH, s), 3.55-3.68 (3H, m), 3.75-4.13 (3H, ^ ' S), (2^3H, m), 4.78-4.81 (0.67H, m), 5.50-5.56 (\u : 1 - , rn), 7 4 7.53 (1H, m), 7.69 ( 1H, td), 8.02-8.16 (2H, m), 8. (lH 2' (*n_b. mixture of geometric isomers, excluding minor geometry d) ° peaks 'this mass spectrum is at higher temperatures Simplified. Structure - Example 1 8 jjjl Fluoro-4-indenyl 1-5-R-trans-isoxazole azole-2^^ isobutyl &gt; thiophene and "2.3-dl pyrimidine-2.4" , 3Η)-two

OH

tLliIg-gas-4-porphyrin (蕤) A Μ-A farmer 1^^1,2,3.4-tetrahydro porphin [2.3-(11 pyridin-5-tea ij^JL ^ by example The preparation of the item 1 d), which is prepared from the product of the example lc) and the fluorine _4_Salina acid, yields the subtitle compound. MS (ESI) 486 [M + H]+ ^ δ 'Hcocn 0-85 (3H, d), 0.88 (3H, d), 1.43 (3H, t), 2.〇5 3 74 (1 H, (1H , m), 3.3.8 (3H, s), 3.47 (1H, dd), 3.65 (1H, τ, 7 69 (1H, dd), 4.49 (2H, q), 6.74 (1H, d), 7.38- 7.50 (2H, d), 7.91 (1H, dd), 9.07 (1H, d). ^ b) 648-1 -4-Phosolinyl thiol 1-3-A-B (Different:

This paper scale applies to the Chinese National Standard (CNS) Α4 specification (210X 297 mm)

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Line A7 B7 1310036 V. Inventive Note (121) IJ - Four Peaks Aligned l~2.3-dlp Secret Disease-5-Finic Acid r, according to the method of Example 1 e) [Preparation of product a) Subtitle Compound 0 MS (ESI) 470 [M + H] + δ 'Hcdcl·! 〇·9 丨(6H,d),丨.37 (3H,t),2.13-2.23 (1H,m), 3.39 ( 3H, s), 3.65 (2H, d), 4.45 (2H, q), 4.60 (2H, s), 7.31 (1H, d), 7.73 (1H, d), 7.44 (1H, td), 7.51-7.57 (1H, m), 7.91 (1H, d), and 8.94 (1H, d) ° d 6-"S-gas-4-carbolinylmethyl b 3-methyl-1-(isobutyl guanine) Hydrogen-1 - 7 : 4-tetra- i. sulfonim "2.3-dl-pyrimidine-g-# acid 钿fi according to the procedure of Example 1 f), which was prepared from the product of b) to give the subtitle compound. ) + 442 [M + 2H-Na] + δ 'Hdmso 0.81 (6H, d), 2.03-2.13 (1H, m), 3.20 (3H, s), 3.57 (2H, d), 4.55 (2H, s) , 7.53-7.58 (2H, m), 7.63 (1H, d), 8.45-8.50 (1H, m), 8.88 (1H, d) d) (S)6-"8 - silent-4 - g Lin 〒基l-5-"4 - with (基异〇号. 全^·2 - basophilic 1·3 -methyl-1 -(isobutyl) dish 吟祓r2.3-dlp-melidine-2.4 Π Η.3Η)-dione according to the method of the formula le), from the product of item c) s) 4-Hydroxyisoxazolidine hydrochloride {Example 10) Preparations to give the title compound MS (ESI) 5 L3 [M + H] + * δ 'HDMS 〇 0.83-0.85 (6 Η, m ), 2.04-2.15 (1H, m), 3.21 (2H, s), 3.22 (1H, s), 3.52-3.72 (3H, m), 3.76-4.12 (3H, m), 4.55-4.70 (2.33H, m), 4.78-4.81 (0.67H, m), 5.50-5.57 (1H, m), 7.52 _ - 125 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm)

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1310036 A7 _____ B7 V. Description of invention (1221 (0.33H, d), 7.56 (0.67H, d), 7.58-7.63 (2H, m), 8.05-8.13 (1H, m), 8.92 ( 1 H, d) (* N · B _ geometric isomer 2 : 1 mixture). Example 18 iv iso-iso-arsenic arsenic -2- 篡耩 1-1-3-methyl-1-(isobutyl linyl methyl phene # VH1 pyrimidin-2,4(1Η,3Η)-dione oxime

a) 6-oxime hydroxy (5-4 oxalinium)methyl I 1-3 -methyl-1-(isobutyl)-2.4-di-y-1,2,3,4-tetradecene #"2.3-€11 pyrimidine-5-hydantoic acid ethyl ester according to the method of Example 1 d), from the product of Example 1 c) and 5-porphyrincarboxyaldehyde to produce the subtitle compound. MS (ESI) 468 [ M + H] + δ丨HCDC丨3 0.87 (3H, d), 0.89 (3H, d), 1.33 (3H, t), 2.10-2.22 (1H, m), 3.38 (3H, s), 3.52 (1H , s, br), 3.55 (1H, dd), 3.71 (1H, dd), 4.33-4.41 (2H, m), 6.75 (1H, s), 7.39 (1H, dd), 7.77 (1H, t), 7.90 (1H, d), 8.14 (1H,d), 8.39 (lH,d),8.91 (1H, d) b) 3-methyl-1&gt;(isobutyl)-2.4-diode-6 -(5-4 porphyrin) - L2.3.4-tetrahydrofuranium "2,3-dl-pyrimidin-5- oxime ethyl ester according to the method of item 丨e), prepared from product a) , produces a subtitle compound. -126 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1310036 V. Description of invention (123) MS (ESI) 452 [M + H] + δ HCdci3 0.87 (6Η, d), 1.42 (3H, t), 2.09-2.19 (1H, m), 3.38 (3H, s), 3.60 (2H, d), 4.49 (2H,q), 4.59 (2H, s ), 7.43 (1H, dd), 7.50 (1H , dd), 7.70 (1H, t), 8.1l (ih, d), 8.49 (1H, d), 8.93 (1H, dd). A.-1-(isobutyl)- 2,4- ^^代_6_(5-!?), a certain methyl group, 1,2,3,4-tetrahydro 3⁄4 and "2,3-dlp close bite-5-leic acid sleeps according to example 1 f) Prepared by the product of item b) to give the subtitle compound MS (ESI) 424 [M + 2H-Na] + δ 'Η dms〇0.79 (6Η, d), 2.00-2.10 (1Η, m), 3.19 (3H, s), 3.53 (2H, d), 4.52 (2H, s), 7.46 (1H, dd), 7.64 (1H, d), 7.71 (ih, t), 7.93 (1H, d), 8.85 (1H, dd), 9.14 (iH, d). 4) (S)5-"4_Hydroxyisoxazolidine-2; ^-carbonyl carbonyl methyl iso-butyl keine g-methyl-methyl methyl} mouth pheno- and "2,3 -d 1 ρ 奈 _ 2 · 4(Ί Η, 3 Η)-dione._ Prepared according to the procedure of Example 1 g) 'Products from item c) and the product of Example 1 b) gave the title compound MS (ESI) 495 [M + H] + δ 'Η DMS〇0.80-0.83 (6Η, m), 1.99-2.06 (1Η, m), 3.2〇(2H s) 3.21 (1H, s), 3.50-3.63 (3H, m), 3.77- 4.14 (3H, m), 4·548. 4.70 (2.33H, m), 4.79-4.82 (0.67H, m), 5.50 (0.33H, d), 5 56 (0.67H, d), 7.54 (1H, Dd), 7.59 (0.33H, d), 7.63 (0.67H, d) 7.75 (1H, t), 7.98 (1H, d), 8.60 (0.33H, d), 8.64 (0.67H, d) 8.91 (1H , d). ' -127 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) Binding

1310036 A7 B7 V. INSTRUCTIONS (124) EXAMPLE 1 9 (present) 5-[4-hydroxyisoxazolidine-2-ylindenyl 1-3-methyl-1-propyl-6-(崦A- 4-ylmethyl&gt;&lt;2&gt;&gt;2,3-d~l·Midine-? 4ΠΗ.3Η)-二酉同 a) 6-Ga-3-methyl-1-propylpyrimidine-2 4μη .3Η)-dione is a solution of 6-chloro-3-methylurea (1〇g) and potassium carbonate (10.34 g) in dmF (70 ml), and n-propyl iodide under nitrogen ( 25 4 g) Treatment, heating under reflux for 8 hours. After the reaction was cooled, poured into water (7 mL) andEtOAc. The combined organics were dried <RTI ID=0.0> δ 'Hcdch 0.98 (3H, t), 1.74 (2H, sextet), 3.33 (3H, s), 4.02 (2H, t), 8.02 (1 H, s). 1?"3-Methyl-l-propanyl-6-hydrogen sulphide _2-4(11~1.3]~[)-dione is taken from the ethanol containing step a) (11.43 g) (4〇 〇mi) solution, treated with NaSH (6.3 1 g) under nitrogen. After stirring at room temperature for 48 hours, the solvent was evaporated in vacuo and residue was diluted with water. The aqueous phase was washed with ethyl acetate and then was taken with 2M HCl. After extraction with ethyl acetate, the combined organic phases were dried and evaporatedjjjjjjjjj δ 'Hcdcb 0.97 (3H, t), 1.72 (2H, m), 3.31 (3H, s), 4.29 (2H, s). Cl__3-T-based-2,4-dioxo-indenyl-yl-sulfonyl-[23-dl-pyrimidine-5-acidic acid ethyl ester in the product containing the product (6.95 g) of anhydrous dimethylformamidine Add potassium carbonate (2.4 g) to the amine (1 ml) solution, stir for 丨〇min. Add ethyl bromopyruvate^ ml), stir with argon at room temperature for 2 hours. The reaction is poured into water (iL) Medium, bismuth (2M HCI) 'extracted with ethyl acetate. Organic extract with brine (丨〇〇_ ______- 128 - this paper size applies to China National Standard (CNS) Α 4 specifications (2ι〇X297 public) binding

1310036 A7 B7 V. INSTRUCTIONS (125) Washing strips. Dehydration and evaporation produce an oil. This oil was dissolved in dichlorohydrazine (100 ml) and cooled in ice while stirring. Titanium tetrachloride (7.58 m Torr) was added and the mixture was stirred under nitrogen for 2 hours. The reaction was poured into water (1 L) and extracted with dioxane. The organic phase is dehydrated and evaporated in vacuo. The residue was purified with EtOAc EtOAc (EtOAc:EtOAc: δ 'Hcdch 1.02 (3H, t), 1.83 (2H, sextet), 3.42 (3H, s), 3.95 (2H, t), 4.41 (2H, q), 7.30 (1H, s). MS (APCI) 297.1 (M++H) d) 6-"Hydroxypyridin-4-yl)methyl 1-3-methyl-2,4-di-a-1-1-propyl-1,2 , 3,4-tetrahydrodisc, a method for the preparation of 2,3-(11-pyrimidine-:5-carboxylic acid ethyl ester according to Example 1 d), the title compound is prepared from the product of item c) δ 1 H c DCI 3 0.89 (3Η, t), 1.41 (3H, t), 1.65 (2H, sextet), 3.38 (3H, s), 3.75 (1H, d), 3.64 (1H, m), 3.80 (1H, m), 4.48 (2H, q), 6.78 (1H, d), 7.52 (1H, m), 7.72 (1H, m) 7.84 (1H, m), 7.90 (1H, d), 8.16 (1H, m), 9.02 ( 1H, d) e) 3-methyl-2,4-dioxa-1-propyl-6-h porphyrin-4-ylmethyl)-1,2,3,4-tetrazole And 2,3-dl-pyrimidine-5-decanoic acid ethyl ester was prepared according to the procedure of Example 1 e), and the subtitle compound was obtained from the product of item d) MS (ESI) 437.9 (M + + H) t) 3 - A -2T4-monooxo-1-propyl-6-(mouth -4-methyl)-1,2,3,4-tetrahydro-g-phene and "2,3 _d 1 ρ dense唉 _ 5 _ _ _ 酉 酉 钠 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 依 δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ δ t), 4.55 -129 - This paper scale applies to China National Standard (CNS) A4 specification (210 X297 mm) 1310036 A7 B7 V. INSTRUCTIONS (126) (2H, s), 3.19 (3H, s), 7.53 (2H, d), 7.57 (1H, m) 7.74 (1H, m), 8.01 (1H , d), 8.61 (1H, d), 8.83 (1H, d) ° g) oxazolidine-2-some Wei Ί-3-methyl-丨_丙某_6•卜杏呲- 4-based Ping-based) _嗔^JJ2,3-dl-pyrimidine-2, ΠH, 3HV-dione according to the method of Example 1 g) 'Products from item f) and (s)-isoxazolidine-4-alkoxide Preparation of acid salt. δ 'H DMS0 0.84 (3H, td), 1,60 (2H, septet), 3.21 (3H, d), 3.56 (1H, d), 3.73 (3H, m), 3.81 (1H, d ), 3.90 (1H, m), 4.61 (2H, dd), 4.79 (1H, s), 5.52 (1H, m), 7.46 (1H, dd), 7.63 (1H, m)' 7.79 (lH' m) , 8.05 (1H, d), 8·27 (1H, dd), 8.87 (1H, d). MS (APCI) 1481.1 (M++H) Example 20 (U. 5" 4-hydroxyindolozolidine-2-ylyl}}_3_methyl_b (isopropyl V6-(4-4 phenyl) Mercapto V-expressed (2,3-(11-pyrimidine-2.4ΠΗ,3Η)-dione

a) 2-((isopropyl)amine) 4 phene-3,4-dipic acid diethyl ester containing anhydrous THF containing ethoxy-carbonylmethylenetriphenylphosphorane (33.8 g) (200 The ml solution was treated with isopropyl isothiocyanate (1 〇.丨g) for 16 hours at 65 ° C under nitrogen. The mixture was cooled to -781 and ethyl bromopyruvate (19.5 g) was added. The reaction was allowed to slowly rise to room temperature. After 24 hours at room temperature, add bromoacetone. This paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 mm).

*Line 1310036 A7

The ethyl decanoate diester (3.17 g)&apos; mixture was stirred at room temperature for 16 hours. The reaction was poured into water iS:nL) and taken. Dehydration and evaporation, producing an oily substance, by chromatography 2/5:1 hexahydrate, decyl-acetic acid ethyl) 'produces subtitle compound (21_2g" UHbrd) 1 23&quot;L43 〇2H,^ 3'46 〇H, ^ 4'2&quot;4,35 (4H,m),6'5° 〇H' S)J·52 ^U.2,34- M acid silver (4.5 g) suspended in anhydrous toluene (3 〇 中 ' The mixture was treated with a drop of ethyl acetate (1 - 78 ml) under nitrogen, and stirred vigorously for 3 minutes. A solution of the residue (7.12 g) in anhydrous toluene (5 ml) was added and the mixture was stirred for 24 hours. Ml), insoluble material was filtered off, washed with a small amount of ether. The combined organic 'public hard was washed with saturated sodium bicarbonate solution' dehydration and evaporation. Residues were treated with sodium sate in sodium <ethanol solution (from 95.95 g sodium and 35 Methanol preparation) was treated at room temperature for 24 hours. The reaction was cooled in ice, treated with trimethylsulfanyl (2 〇m) and stirred at room temperature overnight. All volatiles were removed in vacuo. Between ethyl acetate. After dehydration and evaporation of the organic solution, the residue was dissolved in room temperature-free admf (5〇mi) with potassium carbonate (6.W g) and methyl iodide (8·5 g) for 24 hours. Mix the mixture In water (1 L), acidified, extracted with ether, washed with brine, dried and evaporated to give an oil, which was obtained by chromatography (si〇2/3: s. (3.丨g) δ 'HCDC3 1.^9 (3Η, t), 1.6 (6H, d), 3.39 (3H, s), 4.4 (2H, q), 7.25 (1 H, s). MS (APCl) (M + + H) 297 Meridian (4-Porphyrin, Azor, J-Mercapto-1-(iso-aA)_2, 4_Digas ___ - 131 - This paper scale is used in China National Standard (CMS) Α4 Specifications (210 X 297 mm) Binding

-Line 1310036 A7 B7 V. Description of invention (128) 1.2,3,4-Four new.p The procedure for the production of "2.3-dl mouth lake-5-several acid vinegar according to example 1 d", by b) Preparation of the product with 4-quinolinecarboxyl aldehyde to give the subtitle compound. MS (ESI) 454 [M + H] + δ 'HCdci31-41 (3H, t), 1.43 (3H, d), 1.46 (3H, d ), 3.35 (3H, s), 3.66 (1H, d), 4.25-4.45 (1H, m), 4.45-4.51 (2H, m), 6.78 (1H, d), 7.53 (1H, td), 7.72 ( IH, td), 7.83 (1H, d), 7.92 (1H, d), 8.17 (1H, dd), 9.02 (iH, d). cH 3-A-Bu (isopropyl)-2.4-diox -6-M-Phospholine a certain methyl group)-1.2.3.4-tetradecene 4 phenanthrene and r2.3-dl pyrimidine-5-decanoic acid ethyl ester according to the preparation method of the formula 1 c) , produces the subtitle compound MS (ESI) 438 [M + H] + δ 'Hcdch 1.37 (3Η, t), 1.49 (6Η, d), 3.36 (3Η, s), 4.44 (2Η, q), 4.60 ( 2H, s), 4.30-4.60 (1H, m), seven (1H, d), 7.61 (ih, td), 7.76 (1H, td), 8.13 (1H, dd), 8.16 (ih, dd), 8.81 (1H, d) 6) 3-methyl 棊.-1-(isopropyl)-2,4-di-dairy-立:^-峰11林某甲病)_1.2.3,4- four arrows , far g points and f 2,3 -d 1 p close bite-5 - Residual acid salt _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ,3·16 (3H,s), 4 IQ-4 35 (iH m) 4 52 (2H, s), 7.53 (1H, d), 7.58 (1H, t), 7.74 (ih, t), 8.00 ( 1H, d), 8.62 (1H, d), 8.82 (1H, d) -132 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention ( 129 £L(S) 5-|4 di-based isoindole oxidine-2·yl carbonyl 卜3-甲某- l-(昱丙某, j 14_-^117林..棊更基) pyridine And the preparation method of "2.3-(11-pyrimidine_-2, 4 (1幵.3)-二西同依例1g), prepared by MS (ESI) 481 [M + H] + e), Produced the title compound 0 HDMS〇1.40-1.44 3.18 (2H!s)53 i9(iH s) ^ 313.98 (〇.33H,m),3·99.4·05 (〇33h,咕4'), dd),4.22- 4.4 〇 (1H, m), 4.50-4.68 (2.33H, m) 4 79 (〇67H 2, 5.5〇 (0.33H, d), 5.54 (0.67H, d), 7.44 (〇33Hd), 7 48 ( ^", d), 7.64(1H, t), 7.78 (1H, t), 8.05 (lH d)58 26 (〇33H^8_30 (0.67H,d), 8.87 (1H,d). ‘d), does not include minor geometrical differences (* N.B. 2:1 mixture of main geometric isomers). Example 21Π Sodium-2-ylcarbonyl butyl 卟 咬 咬 -3- base ^

-2,4HH,3HV two lions ^L

OH

Base-1-(isobutyl 2,3_bl pyridyl) porphin _ - 133 - This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 by example 6 a) The preparation method of the item was prepared from the product of Example 3 b) and 2-methylazetium. </ RTI> <RTIgt; 4.22 (2H, s), 7.02-7. 〇5 (1H, m), 743 (1H, m), 7.88 (1H, d), 8.20 (1H, d), 11.56 (1H, s, br).丨2,3,4-tetra.i-3-methyl-1-(iso-T-yl)- and "2,3-blpyrid-3-yl-methyl-V-phene-f2,3-dl-pyrimidine#Λ The subtitled chelate (1.22 g) was prepared according to the procedure of Example 3 d) 'Products from item a).

MS (ESI) 413 [M + H] + c) fS) 5- "f4-hydroxylisoxazole pyridine-2-one quinone K2-methyl-1H-pyrrolo[2,3-blpyridine- 3-The pyridine-2,4ΠΗ,3Η)-dione The title compound was prepared according to the procedure of Example 1 g). MS (APCI) 498 [M + H] + δ 1 Hqiviso 0-87- 0.90 (6Η, m), 2.09-2.15 (ih m\ 〇Λ(· m), 2.46 (3H, 叫, (1H,m) 7.00-7.03 ( 1H,m),7.84-7.89 (1H,m), 8 14_815 (10)), 3.25-3.27 (3H, m), 3.58-3.72 (3H, m), 3.81.393 (2H 4.03-4.22 (3H, m), 4.72-4.86 (1H, m), 5 57_5 82 ' Η . 5 1 (1 Η, 幻. Example 21ii) (R) 5-"4-indolylisoxazolidin-2-one carbonyl some j T its thiol-1 Η - g ratio 咯[2,3 - bM pyridine 2 / 134 This paper size applies to Chinese Painter Standard (CNS) A4 size (210X 297 mm) 1310036 A7 B7 V. Description of invention (131 -2,4ΠΗ,3Η)-dione

Prepared according to the procedure of Example i g), the product from step (2), step b), using (R)-4-hydroxyisoxazole pyridine (Example 2 b), yielded the title compound. MS (APCI) 498[M + H] + δ 丨HDMso 0, 81-0.84 (6Η, m), 2.03-2.09 (1Η, m), 2.39 (3H, s), 3.16-3.19 (3H, m), 3.52-3.66 (3H, m), 3.75-3.89 (2H, m), 3.97-4.16 (3H, m), 4.63-4.80 (1H, m), 5.53-5.55 (1H, m), 6.94-6.98 (1H , m), 7.76-7.83 (1H, m), 8.08-8.09 (1H, m), 11.45 (1H, s). Example 22 (S) 544-Hydroxyisoxazole pyridine-2-carbonylation 1-3-methyl-1-(isopropyl)-6-"2-methyl-1 Η-峨" and 2.3- Bl pyridin-3-ylmethyl 1 phenanthrene f2.3-dl pyrimidine-2,4(ΊΗ,3Η)_dione

This paper scale applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of the invention (

132 幻一6-(Bromomethyl 4-tetrachloro-3-methyl-M-isopropyl phage # pyrimidine-5-翔_甲巧取例例8 b) Item (1.6 g), N-Bromopor A solution of hydrazine (1 g) and azoisobutyronitrile (10 mg) in ethyl acetate (25 ml) was refluxed for one hour. The solution was cooled to room temperature &apos; washed sequentially with dilute sodium hydroxide solution and water. The residue was purified by EtOAc EtOAc (EtOAc) δ H c D c I 3 1 . 62 (6H, d), 3.37 (3H, s), 3.99 (3H, s), 3.60-3.70 (3H, m) ° b) 1,2,3,4-four Nitrogen, -3 -mercapto-propyl-methyl- ΙΗ-g than eat # £1,3-13~|〇比峻-3-ylmethyl1-2.4-dioxo-12-cold "2 , 3-(11 by Ha-5-trans-methane vinegar under argon and ambient temperature' in a stirred suspension of 60% sodium hydride (0.23 g) in THF (1 〇mi) was added dropwise with 2-methyl Azepine (0.37 g) in THF (10 ml). After stirring for 5 min, 1 M zinc chloride ether solution (5.6 ml) was added. After stirring for 5 minutes, product a) (0.88 g) was added. The THF (10 ml) was stirred and the mixture was stirred for 3 hr. The mixture was stirred and evaporated with ethyl acetate. Purification, elution with ethyl acetate / hexanes (1 : 1) to give the title compound ( s. 4 g). MS (ESI) 427 [M + H] + δ 1.48 (6H, d) , 2.49 (3H, s), 3.36 (3H, s), 4.11 (2H, s), 4.20 (ΊΗ, s, br), 7.03-7.06 (1H, m), 7.79 (1H, d), 8.23 (1H , 136 - This paper scale applies to Chinese national standards (CNS ) A4 size (210X297 mm)

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‘Line ·· 1310036 A7 B7

Prepared from product b),

V. Description of invention (133)

Two ^^ ,... d), 9.10 (1H, s). c) 1,2,3,4-tetraxin-3-methyl "2,3-bl峨--3- 甲甲 /二依例1 f), the solids of the substance. MS (ESI ) 413 [M + H] +

-2,4 (Limited to 3 out - 2 - according to Example 1 g), prepared from the phantom product and (s)_4_isoxazolidine hydrochloride [Example lb] to produce the title compound solid. MS (APCI) 484 [M+H] + δ Hdms〇1.37-1.40 (6H, m), 2.40 (3H, s), 3.17-3.18 (3H, m) 3.52-4.28 (7H, m), 4.66- 4.79 (1H, m), 5.50-5.55 (1H, m)^ 6-95-6.99 (1H, m), 7.80-7.86 (1H, m), 8.08-8.10 (1H, m)^ 1 1_45 (1H, s). ' ' Example 23 i_S)-6-[4,5-Shibodichloro-2-(holding methyl)-1Η-imidazole-i_华甲某-5_"4-碑早县口可唑哫-2i Carboxyl group 3 - 曱一-1- (literate butyl phenanthrene arsenic 2,4 (1 Η, 3 Η two xitong

1310036 A7 B7 V. INSTRUCTIONS (134) a) 4,5-diox-1H-m-m-methyl-potassium hydroxide (potassium 12 g, 2.14 mmol) in water (4 ml) was added to 4, In a 5-chloropiper pit, the suspension was stirred for 35 minutes. The polymethylmagnesium (0·11 g ' 3.66 mmol) was added portionwise. The reaction mixture was stirred overnight and then diluted with EtOAc EtOAc EtOAc EtOAc δ ' HCdci3 4.36 (2H, s) ^--Chrysanthemum, 2-(transmethylmethyl)-1Η-味g all-1-methylmethyl ι_ι,2·3·4 -tetrahydro-3-fyl -1-[Isobutyl)_2,4·dioxo-indenyl-"2.3-dl-pyrimidine-5-le-methyl ester added potassium carbonate (〇_ 14 g, 3.1 mmol) and a) product (〇 .5 ig, 3.09 mmol) to a DMF solution containing the product of Example 3, the reaction mixture was stirred for 16 h. The precipitated solid formed was filtered and concentrated in vacuo to give an orange solid, 0.6 g, containing DMF. δ 'HCDCI3 0.99 (6Η, m), 2.19-2.31 (1H, m), 3.4 (3H, s), 3.72 (2H,d), 4.0 (3H, s), 4.68 (2H, s), 5.45 (2H, S) ^~ϋ.4'5 - a 1(,-2-(3⁄4 ylmethyl)-1Η - miso _1 - its 〒~[_ι.2.3·4 -tetrahydro-3-methyl- 1 - (Shanggong., base) · 2,4-dioxophosphonium "2.3_dl broken by 5-methyl acid methyl ester according to Example 3 d), prepared from product b). MS (ESI) ) 484 [M + H]+. 4) 6-f4,5-di 1"2-(hydroxymethyl)-1Η·miole 2 丨 芊 芊 s s_p4Sy4- U:· No. 吐 棊 棊 棊 - - - 棊 棊 棊 棊 食 食 食 食 食 食 食 食 食 食 食 -2 -2 , , , , , , , , , , , , , , , , , , , , , , , , , Preparation of the product. Preparation of the product by reverse phase -138 - The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

•Line 鳟 1310036 A7 B7

Purification of H P LC with acetic acid at rr. · 1 The slain has been dissolved (70 · 30) to give the title compound as a white solid. δ soil (3) cl3〇_89(6H,m), 2.06_2.21(1H,m),3 2i(3H,s),3 62_ 4]8 (6H,m),4·44-4.78 (2H,m ), 5.41 (2H, called 5 53 (ih, called with 5.72-5.75 (IH, m). Example 24

Packed with two t-based-iH-tetraqi_3_A small (isobutyl)-2,4-dioxoester as Example 3 b) products (0,4g, _〇1), 2,4_ Dimethyl oxime (0.2 g '2.06 mmol) and dimethyl ethanoamine (about 5 ml) were heated in a microwave oven at 100 ° C for 5 minutes. The reaction mixture was concentrated in vacuo and triturated, 0.34 g (84%). MS (ESI) 40-5 [M + H] + (isobutyl)-2,4-dioxo-sulfonome|~2,3-〇11喩&amp;_5_Teach, acid according to Example 3 d The preparation method of the item is prepared from the product of item a). -139 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm)

Line 1310036 A7 B7 ' V. Description of the invention (136) MS (ESI) 391 [M + H] + c) 6-"3,5-Dimethyl-1H-pyrazole-1-one A-5-" (4S)-4·Hydroxylisoxazole oxazolidine-2-ylaminol 1-3-methyl-1-(isobutyl)-mouth phenanthrene "2,3-dl mouth bite _2.4" </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; MS (ESI) 462 [M + H] + δ 'Hcocn 〇·9 (6Η, m), 2.09-2.19 (1H, m), 2.2 (3H, s), 3.2 (3H, s), 3.52-4.1 ( 6H, m), 4.81-4.77 (1H, m), 5.16-5.23 (2H, m), 5.49-5.57 ( 1 H, m) and 5.82 (1H, s). Example 25 (S)-6-"2 ,3-dioxin-2-oxo-1H-benzimidazol-1-ylmethyll-5-"4-hydroxyisoxazolidine-2-ylcarbonyl-3-methyl-1-(iso) Butyl)-pyrimido "2,3-dl pyrimidine-2,4ΠΗ,3Η)-dione

3-methyl-1-(isobutyl)-2,4-dihydro--"2,3-dl-pyrimidine-5-# acid methyl ester takes the product of example 3 b) (0 · 5 g , 1.2 8 mm ο 1), 2 - benzophenone (0.21 g, 1.37 mmol), potassium carbate (0.36 g, 2.6 mmol) and DMF (10 -140 - this paper scale applies to Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) Binding

1310036 A7 B7 V. INSTRUCTIONS (137) ml) Stir for 1.5 hours. Ethyl acetate and water were added to the reaction mixture. Do not leave the two phases. After the organic layer was dried (MgSO4), EtOAc (EtOAc) δ 4^^0 0.83 and 0.91 (6H, d), 2.1-2.22 (1H, m), 3.38 (3H, s), 3.67 (2H, d), 4_1 (3H, s), 5.58 (2H, s) , 7.26-7.38 (2H, m), 7.41-7.48 (1H, m) and 7.7-7.8 (1H, m). b) 6 - "2,3 - a a - 2 -oxo-1 h - stupid and blow -1 - a certain ii 3-methyl-1-(isobutyl)-2.4-dioxoha "2.3-dl pyrimidine addition step a) product (〇.36g, 0.65 mmol) to a sealed tube containing THF (1 〇ml), water (1 ml) and triethylamine (〇.〇5 ml) at 180 (: heating under 3 days. The reaction mixture was concentrated in vacuo to give title compound (yield: 0.3 g, crude). MS (ESI) 440 [M+H] + c) β-丨2,3 -oxo-1H-benzoxazole-1-methylisoxazolidine-2-ylcarbonyl1-3-methyl-1-(isobutylphenanthene-2·4(1Η,3Η)- The diketone was prepared according to the procedure of Example 3 e), which was obtained from the product of b). The product was purified by reverse phase preparative HPLC, eluted with ammonium acetate: acetonitrile (80: 20), and triturated with diethyl ether to give a pale yellow title compound. δ 1 Hd6-dmso'〇-93 (6H, m), 2.1-2.24 (1H, m), 3. (2H, s), 3 26 (3H, s), 3.52-4.18 (5H, m), 4.62-4.82 (1H, s), 5.02-5.2 (2H s), 6.96-7.03 (2H, m), 7.17-7.19 (1H, m). Example 26 -141 - This paper scale applies to Chinese national standards (CNS) A4 specification (210 X 297 public) 1310036

^^ !~^-=rr ^ base-1 Η-leaf [•口也-4 - it γρ 1 i* r . ~~棊 oxazolidine _2.

-2,4_m (0.56 w = acid) (〇.405 g) to the example 9 Ο 产 • • 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 T is suspended ~ then reflowed for 15 minutes: 5 minutes of mixing + = saturated / human acid gas solution 〇〇 ml), the mixture is excited '? Stupid.. Li, filtered, with a methane (2 x 25 Ml) extraction. There are books in the merger:: Set, Saki solution (35% '0.26_ treatment, stirring for 16 hours... Dehydration' filtration, 'decompression under reduced pressure. Residue dissolved in tetrahydroanthene (15 ml = Azhi (3.1 m丨) After the middle and the next 'sodium hydroxide solution (iM, 2 μg of the mixture was stirred for 18 hours. The resulting precipitate was collected by filtration, washed with THF (vacuum drying) to give the subtitle compound (〇42 MS (ESI) 377 [M + 2H -Na] + δ 'Hdmso 0.^5 (3H, t), 1.63 (2H, sextet), 2.08 (6H, s), 3.1 (3H, s), 3.74 (4H, m). b)_Cg.) -6-"L5-Dimethyl quaternary-4-a hyperthyroidism 摹荈 啐 -2- -2- 基 基 基 基 1-3 1-3 1-3 1-3 1-3 1-3 1-3 | | | | | | ~ ~ ~ ~ ~ ~ ~ ~ -d~U_pyridine_2.4ΠΗ,3Η)- -142 - f paper scale applicable to Chinese National Standard (CNS) Α4 specification (210 X 297 mm)

Binding

'ψ 1310036 A7 B7 V. INSTRUCTIONS (139) Ketone

Prepared according to the procedure of Example I g), which was obtained from the product of item a) and (3)____________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________________ MS (APCI) 440 [M + H] +δ 'HDMs〇(90°C*) 0.88 (3H, t), 1.68 (1H, sex), 2.08 (6H, s), 3.21 (3H, s), 3.46 (1H, d), 3.67-4.14 (7H, m), 4.63-4.77 (1H, m), 5.23 (1H, s, br), 11.86 (1H, s, br). (* N.B. The material is a mixture of geometric isomers, so the NMR complex measured at room temperature is 'simplified by heating'). Example 26Π Ο 6-[3'5-dimethyl-ΙΗ-pth»Sitting -4-&amp;A and a certain ton ton-2-shiji-3-a certain g-sent and "2.3-dl Pyrimidine-2.4ΠΗ.3Η)-dione OH Λ

Binding

Line g) 6-丨3,5-dimethyl-1Η-pyrazole-4-ylmethyl]-1-isopropyl-3-methyl-2.4-di-daily-1,2,3, The 4-tetrahydrogen peak is exemplified by f2,3-dlp by y--5-sodium salt. The product of Example 26 a) is prepared from the product of Example 8 b) to give the subtitle compound as a solid. MS (ESI) 377 [M + 2H-Na] + δ 1 Η D Μ s Ο 1.44 (6Η, d), 2.10 (6Η, s), 3.17 (3Η, s), 3.74 (2H, s), -143 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1310036 A7 B7 V. Invention description (14〇) -- 4·34 (1H, s, br), 12.01 (1H, s, Br). KLLS) 6-R5-Dimethylpyrazole _4_碁T 上上基基咩 咩 咗 咗 咗 : : : : : : : : : : : : : : : : : : : : : : : : : : : : J J J J J Prepared by the procedure of Example 1 g), starting from the product of item (1) and (s) _4_isoxazolidinol hydrochloride [Example lb], gave the title compound as a solid. MS (APCI) 448 [M+H] + δ 'Hdms〇1.43- 1.46 (6H, m), 2.09 (6H, s, br), (1.87H, s), 3.18 (1.13H, s), 3.47 ( 0.62H, d), 3.58 (0.38H, d), 3.70-3.79 (3H m), 3.80-3.86 (IH, m), 3.88-4.04 (0.38H, m), 4.10 (0.62H, dd), 4.37 (1H, s, br), 4.58-4.78 (1H, s, br), 5.50 (1H, d), 12.11 (1H, s). Example 27 (S)-6-|~3,5-Dimethyl epoxide bit -4- a certain l-5-"4- with a certain succinyl read -2-ylcarbonyl 1-1- (different Butyl)-3-methyl·»Tomb""2.3-dl mouth pyridine-2,4(1H.3H)-dione

OH

a) 6-丨3,5-dimethylisoxazol-4-yl-methyl 1-1-(isobutyl)_3_methyl-2.4-diox-U2,3,4-tetrazed [2,3-dl-pyrimidin-5-methyl ester-144 - This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm)

Binding

.线1310036

Adding a mixture of bis(ethyl acetate) zinc (〇 〇 幻 含 to example 3 b) to the product (20 ml), the resulting suspension was stirred under reflux for 3 knives. Main temperature. Saturated sodium bicarbonate solution (20 ml) was added, and the mixture was stirred vigorously for 5 min. 'filtered, extracted with dichloromethane (2×2 。. The organic extract was dehydrated with anhydrous sulphuric acid) and evaporated under reduced pressure. Add hydroxyamine hydrochloride (〇·54 g) and pyridine (〇.62), and stir the mixture for 16 hours. Add hydrochloric acid (2M, 5) and stir for 24 hours. Evaporate the mixture at least. After volumetric addition, add to saturated sodium bicarbonate solution (25 _ medium 'extracted with ethyl acetate (2 x 25 ml). The organic extract is dehydrated with anhydrous magnesium sulfate' (4) and evaporated under reduced pressure. Purified by EtOAc/EtOAc (EtOAc: EtOAc: EtOAc (EtOAc) 2.18 (3H, s), 2.18-2.30 (1H, m), 3.39 (3H' s), 3.70 (2H, d), 3.85 (2H, s), 3.95 (3H, s). ' ' T嗤-4-A certain ^2·4_ SAi^d, 2,3,4-tetra-i-imido[2,3-(11 shouting _5-Lering according to Example 3d), by a The product was prepared to give the title compound as a solid. MS (ESI) 392 [M+H] + δ 'Hdmso 0.89 (6Η, d), 2.09 (3H, s), 2.09-2.20 (1H, m), 2.34 (3H, s), 3.22 (3H, s), 3.70 (2H, d), 4.04 ( 2H, s). 'Dimethylisoindole ol-4-ylmethyl group ^(4S V4-鼗 a _ 2-yl-monoyl 1-..1.:.(isobutyl)-3- Methyl hydrazine _D,3-cn pyrimidine-145 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1310036 A7 B7 V. Description of invention (142) Diketone example The preparation of 1 g) is prepared from the product of b) and (S)-4-isoxazolidine hydrochloride [Example lb] to give the title compound as a foam. MS (APCI) 463 [M + H] + δ 丨HDMS0 0. 89 (6H, d), 2.10 (3H, s), 2.13-2.24 (1H, m), 2.30 (3H, s), 3.22 (3H, s), 3.44 (1H, d , br), 3.65-3.78 (3H, m), 3.82 (2H, s), 3.85-4.10 (2H, m), 4.70 (1H, s, br), 5.18 (1H, d). Example 28 6-"4,5-diqi-2-methyl-11--weijun-1-ylmethyl-1-1-1--5-"(~4!;^-4-海基- 2-isoindole-based group 1-3-methyl-g-phene-[2,3-dlp 唉-2.4ΠΗ.3Η,. diketone

a) 1-ethyl-3,6-dimethyl-2.4ΠΗ.3Η)pyrimidinedione at room temperature 'in the presence of 3,6-dimethyl-2,4 (1仏3-pyrimidinedione) Potassium carbonate (2.1 g) was added to the DMF (1 5 ml) suspension of 2.0 §). After stirring the mixture for 5 minutes, ethyl iodine (丨. 2 ml) was added and the mixture was stirred for 3 days. The reaction mixture was distributed in water. (5 Ό 0 ml) and ethyl acetate (3 X 100 ml). The combined organic phase was dried (MgSO4) and evaporated to give the title compound as a colorless oil (2.0 g). Ear % DMF) δ 'Hcd(1) 1.32 (3H, t), 3.33 (3H, s), 4.15 (2H, q), 5.92 (1H, s) -146 - This paper scale applies to Chinese National Standard (CNS) A4 size (210X297 mm)

1310036 A7 B7 V. INSTRUCTIONS (143) -- b) J..-Ethyl-6-hydroxythio-3-U^, 4 nH.3m According to the procedure of Example 5, step a), the product from step a) preparation. δ 1.28 (3H, t), 3, 32 (3H, s), 4.14 (2H, s), 4 48 (2H).必.仙, 4-四^^^代"Div dl pyrimidine-5-cyanate methyl ester. According to the procedure of Example 3, step a), the product was prepared from the product of step b). MS (ESI) 283 [M + H] + d) 6-(Bromoformin)-1-By-丄^_4_Four gas leather 2,4_diodes and f2,3-dl pyrimidine- The 5-carboxylic acid was prepared according to the procedure of Example 22, step a), from the product of step c). 4-6-"4,5-digas-2-carboindole-1^.imidazole·丨-基甲其乙某-123 4_师乱..:3-methyl-2,4-_diox产物-哗 并 "2.3-dipyrimidine methyl ester containing step d) product (0.25 g), sodium bicarbonate (〇·29 g) and 4,5-dichloro-2-methyl-1H-imidazole (〇. 115 phantom acetonitrile (1 〇 ml) mixture was heated under reflux for 18 hours. The cooled mixture was distributed between water (5 〇ml) and dichloromethane (3 χ 5 〇ml). The combined organic phase was dehydrated (Mgs04 And evaporating to give the oil of the subtitle compound' directly to the next step. MS (ESI) 429/431/433 [MH] + dichloro-2-methyl-l-indole-imidazole-1-one Ϊ́1-ΐ·匕美-1,2.3〆-^ .Hydromethyl- 2,4·----------------------------------------------------------------------- Preparation of the product of step 1) of Example 1 was carried out from the product of step e) MS (ESI) 417 / 419 / 421 [M + H]+.

S) 6-|~4,5-diqi-2-methyl-1H-imidazole-1-a certain 1-1-[a-5-IY4SH __- 147 - this paper scale is used in China (CNS) A4 size (210X 297 mm) _ 1310036 A7 B7 V. Description of invention (144) Zilkyz-2 -iso-di-f-pyridylcarbonyl bromide 3 - J-based, 吩 亦 r r 2,3 - cM Pyrimidine-2,4(1Η,3Η)-dione was prepared according to the procedure of Example 1, step g), from the product of step f) and the amine of step b) of Example 1. MS (ESI) 488/490/492 [M + H] + δ 'Hdms〇(90°C *)1.25 (3H, ΐ), 2.33 (3Η, s), 3.22 (3Η, s), 2.99 (1H, s), 3.34-3.55 ( 1 H, m), 3.70-4.14 (5H, m), 4.63-4.87 (1H, m), 5.27 (2H, m). (* N _ B · The substance is a mixture of geometric isomers, so the N M R measured at room temperature is complex, but simplified under heating). Example 28Π 1-Ethyl-5-"(4S)-4-hydroxy-2-isog-oxazolidinyl 1-3-methyl-6-indole-pyrrole JJ2,3-blpyrid-3-yl Methyl V stopper and "2.3-dl pyrimidine-2,4ΠΗ,3Η)-dione r\

Η gj 1-ethyl-1,2,3,4-tetrazol-3-methyl-2.4-diode f2,3-b~|p is more than -3-methylmethyl V篆吟[~ 2,3-dlp secret disease-5-, according to the method of Example 22 b), the φ subtitle servate was prepared from the product of Example 28 d). ~ children s),

Hcdcu 1_26 (3Η,t), 3.49 (3Η, s), 3.87 (2H,q),4 (3 -148 - Paper size applies to Chinese National Standard (CNS) A4 size (210X 297 mm) 1310036 A7 B7 V. INSTRUCTIONS (145) 4.28 (2H, s), 7.085 (lH, t), 7.93 (lH, d), 8.32 (1H, d), and 8.89 (1H, s) 〇 ethyl 2, 2, 3,4-tetrahydro-3-methyl- _..4_di-g- _6-(-------[2,.3^1|1 ratio-^1-..ylmethyl)pyrimidine The title compound was prepared by the procedure of the title compound [[2-(1-(4-pyrimidine-5-# acid))). MS (ESI) 386 [M + H] + U-ethyl-di-U; (4S)-4 - 奇基-2-isoxazole 咗莘粦 卜3-甲病-6-ΠΗ~ 啶-3-基甲, 忒 :: 3⁄4 [2·3-ηι崎 &amp; preparation. Product reverse phase Preparation of '3 〇) </ RTI> </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; -4.22 (6H, m), 4.62-^7.03 (1H, m), 7.45 4.75 (1H, s), 4.8 (1H, s),: (1H, m), 7.95-8 (1H, m), 8 Example 28ii

δ Hdmso 1.12 (3H, m), 3.31 (3H, s), 3·58_4 22 (6H 4.75 (1H, s), 4.8 (1H, s), 5.5 (1H, s), 6.9.7 〇3 〇H (1H,m), 7.95-8 (1H,m), 8.19 (1H,d),U 53 (1H s)

This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (146) a) 1-Ethyl-1,2,3,4-tetrahydro-3-methyl Benzyl-2,4-dioxo-6-"2-early early" H-membered imidazolium-1-ylmethyl&gt; phenanthrene and 2.3-dl pyrimidine-5-carboxylic acid methyl ester according to Example 13iv step a The process was prepared from the product of Example 28, step d). MS (ESI) 441 [M + H]+. b) 1-Ethyl-1,2,3,4-tetrahydro-3-methyl-2.4-dialdehyde-6-f2-propyl-iH_y-imidazol-1-ylmethylthiophene "2.3 -dl-pyrimidine-5-斿g# 铷 依 依 依 依 依 依 依 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS "(4S)-4-Light Farming-2 - Different 17 Loss Jun This is a certain number of 1-3 - A propyl -1H - Benzene Mi attack -l-基甲一塞p分#f2,3-d ~[p·奈克定- 2,4ΠΗ,3Η)-diketone MS (ESI) 498 [M + H] + δ 'Hdmso 0.99 (3Η, t), 1.12 (3H, t), 1.80 (2H, sextet ), 2.88 (2H, t), 3.20 and 3.21 (3H, s), 3.58 (1H, d), 3.70-4.15 (5H, m), 4.63 and 4_81 (1H, t), 5.46-5.70 (3H, m ), 7.15-7.22 (2H, m), 7.54-7.69 (2H, m). Example 28iii Ethyl 5-[(45)-fluorenyl-2-isog-oxazolidine carbonyl-methyl-6- "2_气代-3 (2H) - exemplified p-based thiomethylthiophene and f2.3-dl Pain-2,4(1H,3H)·dione

This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 _B7 V. Invention description (M7) 冱) 1-^-1,2,3,4-tetrahydro-3-methyl -2^4-二|;伏.6_"2-&amp; generation-3 (2 out-stupid and 4-oxazolylmethyl 1 喽 [ [2,3-dl acetylpyrazine-teaching, acid vinegar vinegar Example 13xviii, step a), was prepared from the product of step 28, step d) MS (ESI) 432 [M+H] + b) 1-ethyl-1 乂3,4:tetrahydro-3-methyl Generation-6-"2-free generation · 3Γ2Η, _ benzo-andylmethyl V phenanthrene and "2,3-dl ° strip cold -5 - acid #j salt according to the method of step 1 of step 1) Step a) Preparation of the product MS (ESI) 418 [M + H] + (free acid) c) 1-ethyl-5-"(4S)-4-carbyl-2-iso- oxone carbonyl group Base_6-"2-gaso-3(2H)-stupid and biting methyl 1 far and f2,3-d~| shout cold _9,,4(~1H,3H)- = The product from step b) was prepared according to the procedure of Example 1 step g) using m of Example 1 Step b) MS (ESI) 489 [M+H] + 3丨1^〇|^〇1_19(31'1,〇 , 3.19 and 3.20 (311, 5), 3.52-4.00 (6^1, 111), 4.56-4.82 (1H, m), 5.09-5.40 (3H, m), 7.19.7, 25 (1H, m), 7.33- 7.48 (2H,m), 7.67-7.72 (1H, m) 0 Example 28iv 1-Ethyl-5-"(4S)-4-hydroxy-2-isoindolyl 1 1-3. A _6_"2_methyl-1 Η - pyridine And "2,3 - b eats ~ and -2 - 3 - dh dense -2,4 (1Η,3Η)-dione

This paper scale is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1310036 A7 B7 V. Invention description (148) Resistance) 1-B-1.2,3,4-tetrahydro-3. A- 6-[2-甲某-11^-1#, Blowing and [~2.3-Bu 1 p is more than p-3-1, a certain 1-2, 4-dioxo 4 丨 丨 2.3-dlp shouting Methyl 5-5-lacate was prepared from the product of Example 28 d) according to the procedure of Example 14 iii a). MS (ESI) 399 [M + H] + b) 1-By-1,2,3,4 -tetra Jl-3 -methyl-6-[~2 -methyl- lH-g ratio p [2U~| Pyridine-3-methyl 1-2,4-difluoropyrimidopurine 2,3-dl pyrimidine-5-# 铷 salt according to the method of Example 1 f), from product a) preparation. Used directly in the next step. c) 1-By-5-"(4S)-4-hydroxy-2-isoxazolidinylcarbonyl1-3-methyl--6-indole-2-methyl-1H-pyrrolo"2,3-bl Pyridine-3-methyl~l·cephene and 2.3-dl-pyrimidine 2,4(1Η·3Η)-dione according to the method of step 1) of Example 1, using step b) product using example 1 step b) Preparation of the amine. MS (ESI) 470 [M+H] + δ 'Hdmso 1.10-1.16 (3H, m), 2.40 (3H, s), 3.19-3.20 (3H, m), 3.50-4.83 (l〇H , m), 6.94-6.99 (1H, m), 7.78-7.86 (1H, m), 8.09 UH, dd), 1 1.46 (1H, s). Example 28v) 1-B-5-"(4S) -4-You -2-isoxazolidinylcarbonyl 1-3-methyl-yl-ΙΗ-β 哚-1-yl-methyl 1 sulfonium "2.3-dl pyrimidine-2.4 ΠΗ, 3 Η)-: _Ι1

This paper size applies to the National Standard for Sleepy (CNS) Α4 Specification (210 X 297 mm) 1310036 A7 B7 V. Description of Invention (149) a) Cyanide-1-Vemethym μι_ Ethyl-1,2,3, The product was prepared from the product of Example 28 d) by the method of the procedure of Example 1 3xvii a). MS (ESI) 42 1 [M + H] ^~卜丄丨-ethyl-1,2,3,4 -tetraqi_5-(~(4S)-4-superbase bite a county base 1-3 -Methyl-2,4-dioxo 4## [2-3_d~|pyrimidine-6-yl-methyl 1-1 Η·呻呻5-nitrile according to the example 13xvii b) and c) Prepared from product a) to give the title compound. δ 'Hdmso 1.10-1.23 (3H, m), 3.2 (3H, s), 3.8-4.12 (6H, m), 4.62-4.81 (1H, m), 5.5-5.64 (3H, m), 6.68 (1H, d), 7.5-7.9 (1H, m)' 7.6-7.65 (1H, m), 7.77-7.84 (1H, m) and 8.1 (1H, s). Example 29i 5-f(4S)-4-hydroxyisoxazolidine 蒺一·μ1-(isobutyl)_6-F1_isopropyl·2,5-dimethyl-1H-pyrazole-4- A certain 1-3-methyl g 窠 并 [~2_3-dl pyrimidine-2, 4 ΠΗ · 3 Η, - two a

OH is added 2-iodopropane (0.1 ml) and potassium carbonate (1 〇〇mg) to 6-[(3,5-dimercapto-oxime H-purpur-4-yl)methyl]-5-[( 4S)-4-Hydroxyisoxazole-2-ylcarbonyl]- ___- 153 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) Binding

Line A7 B7 1310036 V. Description of invention (150)

Line 1 -(isobutyl)-3-methylsulfonio[2,3-d]pyrimidine-2,4(1H,3H)-dione (Example 1 1 '100 mg) of dimethylformamidine In a solution of the amine (1 ml), the mixture was stirred at i 〇〇 °c. After 2 hours, additional 2-propane propane (〇·2 ml) and potassium carbonate (200 mg) were added. After a further 16 hours, the mixture was cooled to room temperature and diluted with water (2 mL). The combined organic extracts were treated with pyrrolidine (1 ml), dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by EtOAc (EtOAc) elut elut MS (APCI) 504 [M+H] + δ 'Hdmso 0.87 (6H, d), 1.31 (6H, d), 1.99-2.14 (7H, m), 3.19-3.21 (3H, m), 3.45-4.13 ( 8H, m), 4.40 (1H, sept), 4.56-4.79 (1H, m), 5.48-5.55 (1H, m).实何29ii 5-"(4S)-4-蕤A certain isoxazolidine-2-one end 1-1-(isobutyl)-3-methyl-methyl-3 stupyl-1 Η-pyrazole -4 - A waste A 1 phenotype F 2.3 - d 1 忒-2,4(1H,3H)-dione

a) 1-isobutyl-3-methyl-6-"5-methyl-3-methyl-1H-pyrazole-4-methylpyr 2,4-dioxo-1,2,3 , 4-four j,-discriminate "2.3-dl pyrimidine-5-decanoate methyl ester-154 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 _____B7 V. Invention Description (151) Adding zinc acetate (11) (88 mg) to a mixture containing 6-(bromomethyl)-indole isobutyl-3-f-yl-2.4-oxo-1,2,3,4-tetrahydro- The pyrimido[2,3-d]pyrimidine-5-carboxylic acid oxime ester (185 mg) was stirred with a 1-p-methylpyrrolidone (丨54 mg) in a solution (1), and the mixture was refluxed. After heating for 1 hour, it was cooled to room temperature. A saturated aqueous solution of sodium hydrogencarbonate (20 ml) was added, and the mixture was stirred for 30 min, then filtered, and the layers were separated. The aqueous phase was extracted with dichloromethane (10 ml). The hydrazine hydrate (0.046 ml) was treated with methanol. After 20 hours, the solution was dried over anhydrous magnesium sulfate. Base-1H-pyrazole impurity MS (ESI) 467 [M + H] + δ 'HCDci3 0.90 (6Η, d), 2.17 (1H, non), 2.27 (3H, s), 3.38 (3H, s), 3.65 (2H, d), 3.94 (3H, s), 4.10 (2H, s), 7.35 (1H, t), 7.40 (2H, t), 7·46 (2H, d) b) 1-isotin -3-methyl-6-f5-methyl-3-pyrene-1H-pyrazole-4-methyl-1-2.4-dioxo-1.2,3,4-tetradecyl-pyridinium 2.3-dl pyrimidine-5-carboxylic acid was added to a stirred solution of tetrahydrofuran (10 ml) and methanol (1 ml) containing the product of step a) (300 mg). Diluted with water (20 ml), EtOAc (2 mL)EtOAc. , filtered, and evaporated under reduced pressure to give titled compound ( s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s , 3.25 (3H, s), 3.62 (2H, d), 4.23 (2H, s), 7.32 (1H, t), 7.39 (2H, t), 7.49 __- 155 - This paper scale applies to Chinese national standards ( CNS) A4 specification (210 X 297 public I) A7 B7 1310036 V. Description of invention (152 ) (2H,d) 〇c) 5-"(4S)-4-hydroxyisoxazolin-2-ylcarbonyl 1- 1-(昱丁)-645-methyl-3-phenyl-1H-pyrazol-4-yl Methyl 1·»cephene; ϋ|~2,3-dl-pyrimidine-2,4ΠΗ,3Η)-dione added diethyl chlorophosphate (0.076 ml) to product containing b) (200 mg), 1- Hydroxybenzotriazole hydrate (81 mg) was stirred with triethylamine (0.215 ml) in acetonitrile (2 ml). After 1 minute, (S)-4-isoxazolidine hydrochloride [Example 1, item b) '61 mg] was added. After a further 24 hours, the mixture was diluted with EtOAc EtOAc. The organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) MS (APCI) 524 [M+H] + δ 'Hqmso 0.82 (6H, d), 2.04 (1H, non), 2.20 (3H, s, br), 3.3q (3H, s), 3.45-4.15 (8H , m), 4.57-4.80 (1H, m), 5.35-5.55 (iH? m), 7.33 (1H, s, br), 7.40 (2H, s, br), 7.54 (2H, s, br), U .73 (0.5H, s, br) 12.86 (0.5H, s, br). Example 29iii 5-丨(4S)-4-hydroxylisoxazosin-2-one M-isobutyl-3-methylmethyl-3-(trif.methyl)-1Η-pyrazole -4-A certain 1 soul is ordered and "2,3-dln^^ _2,4 (1H.3HV two production

OH

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 ϋ 1310036 A7 B7 5. Inventions (153) - Ml: _methyl H-pyrazole _ 4- A 1 ^ ^ 1 ^ 1, 2,3;4_:4. Hydrogen-taste 丄1^^^^ acid 甲 酉 according to the method of Example 29 (ii) a), from 6 · (Methyl) 丨 异 isobutyl _ 3_Methyl-2,4-dioxo-丨'^xin-printed hydrogen-p-phene and screams ^•carboxylic acid oxime ester (3〇〇mg) and 1,1,丨-trifluoroethenyl Preparation of acetonic acid esters. The crude product was purified by flash chromatography eluting elut elut elut elut elut elut elut elut MS (ESI) 459 [M+H] + δ 'Hdmso 0.94 (6Η, d), 2.22 (1H, non), 2.26 (3H, s), 3.39 (3H s), 3.69 (2H, d), 3.96 ( 3H, s), 4.08 (2H, s), 1〇.29〇H s br) 〇? 基-Η5.Methyl small (Sanqi Zhiji..1-2,4-dioxo-1,2 , 3,4-Propylidine-5-anthracene according to the procedure of Example 29ii b), which was prepared from the product of item a) to give the title compound as a solid. $ MS (ESI) 445 [M+H] + δ 'Hdms〇〇·86 (6Η, d), 2.09 (1Η, non), 2 21 , •丄1 (3H,s), 3.26 (3H, s) , 3.67 (2H, ¢1), 4.20 (2H, s), 13.43 (1H, s), U 9n Mu , α.ζυ (1H, s, br). c) 5-[(4S)-4-hydroxyisoxazolidine-2-one 蕤-丄 计 ^ ^ -ή- 『5-methyl-3-(trifluoromethyl)-1Η-pyrazole -4-A certain Wang]*, ϋ Γ2.3-dlp·% pyridine-2,4ΠΗ,3Η)-dione according to the method of Example 29ii c), from the product of b) for the preparation of the title compound Solid. MS (APCI) 5 16 [M + H] + δ 'HdmsoO.87 (6H, d), 2.11 (IH, non), 2.18 nu λ Λ δ V3H, S), 3.20 (3H, 157) National Standard for Bacteria (CNS> A4 Specification (210 X 297 mm) A7 B7 1310036 V. Description of Invention (154) S), 3.50-4.10 (8H, m), 4.55-4.78 (1H, m). Example 29iv "( 4 S) - 4 - 瘫 异 异 寄 -2 -2 - 2 - carbonyl _J · 1 -1 - County II ^ _ 6 _ Xian two early

I_2, 4 (1H.3HV two _

__1-兴~butyl-6-"3-isopropyl-5-methyl-1^1-?pyridyl-4-ylmethyl 1_3-methyl- 2,4-diox-1,2 , 3,4-tetra-» 吩 并 and f2,3-d~|P from θ - 5- 醢 实例 according to the method of Example 29 (iii) a), from 6-(bromomethyl)_ι_ isobutyl _3-methyl-2,4-dioxo-1,2,3,4-tetrahydroseceno[2,3-d] lyl-5-carboxylate (450 mg) After the preparation of 5-methylhexane-2,4-dione, the ester was hydrolyzed according to the procedure of Example 29 (ii) b) to give the subtitle compound (285 mg) as a solid. MS (ESI) 419 [M + H] + δ 'Hdmsq 0.85 (6Η, d), 1.13 (6H, d), 2.07 (3H, s), 2.09 (1H, non.), 2.88 (1H, sept.) , 3.26 (3H, s), 3.66 (2H, d), 4.04 (2H, s). 1^5-[(4 5)-4-hydroxylisoxazolidine-2-ylindoleyl 1-isobutyl-6-"3-isopropyl-5-methyl-1H-pyrazole- 4-ylmethyl1-3-A, a certain singular, 2,3-dl-pyrimidine-2.4(1H,3H)-dione-158 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 public) Dong) 1310036 A7 B7 V. Description of the invention (155 according to Example 2911 C), prepared from product a) (281 mg). The crude product was purified by reverse-phase HPLC eluting with EtOAc EtOAc EtOAc (EtOAc) (APCI) 490 [M + H] + δ 'Hdmso 0.86 (6H, d), 1.08-1.18 (6H, m), 2.02-2.17 (4H) m), 2.80-2.98 ( 1 H, m), 3.19- 3.21 (3H, m), 3.48-4.12 (8H, m), 4.58-4.78 (1H, m), 5.51 (1H, d), 12.15 (1H, s, br). Example 29 (v) U3,5-dimethylpyrazole-4-one A certain 昱 -2--2-yl penylmethyl 4 is densely attached at -2,4ΠΗ·3Ι~η-二醐 ΟΗ

Al 6-『3,5-_-methyl-1-蹇_盖二j_H-pyrazole_4_一甲一一+丁丁某_3_methyl^1^_二_ Oxo acid methyl ester According to the method of Example 26 a), 6_(bromomethyl)-丨-isobutyl·3_methylbis-2,4·dioxo-1,2,3,4·tetrahydro-4 is exemplified. [2,3-dH pyridine·5-carboxylic acid oxime ester (5 〇〇 mg) 'Acetyl acetophenone zinc hydrate hydrate and stupid base. The crude product was purified by vermiculite column chromatography and eluted with ethyl acetate/isohexane (2:3). ======================================================================================= 297 mm) ----- A7 B7

1310036 Subtitle compound (555 mg) as a solid. MS (ESI) 481 [M + H] + δ 'Η dmso 〇·95 (6Η, d), 2.24 (3Η, s') 〇

8.27 (3Η, s), 2.2〇_2 3〇(1Η,m), 3.39 (3Η,s),3.71 (2Η,d),3 Qw,u ... U .95 (3H,s),3.96 ( 2H y 7.36-7.50 (5H,m)., ' ”, b) 6-f3,5-dimercapto-1-yl-lH-p ratio - according to the method of item 1 f), by item a) The product was prepared as a solid. MS (ESI) 467 [M + H-Na] + -2,4"diodes-1,2,3,4-fourths.---^ m subtitle compound Η 0.87 (6H, d), 2.17 (3H, s), 2_i〇_2 22 (1H, m), 2 17 (3H, s), 3.20 (3H, s), 3.65 (2H, d), 3 84 Oh , · δ4 (2H, S), 7.34-7.39 (lH, m), 7.46-7.51 (4H, m). O 6-D,5-dimethyl-1--stupyl--2,4ΠΗ,3Η)-dione

DMSO was prepared according to the procedure of Example 29(ii), c), from the product of item b), to give the title compound as a solid. τ MS (APCI) 538 [M + H] + δ 'HdmsoO.89 (6H, d), 0.21-0.22 (4H, m), 2.25 (3H s) 3 2〇3.22 (3H, m), 3.45-4.15 (8H, m), 4.55-4.80 (]u , 'r ' υ m), 5.35-5.55 (1H, m), 7.37-7.40 (1 H, m), 7.44-7.54 (4H, m). Example 29 (vi) 643 4-Dimethyl-i-Li Yiji-1Η-, 唆-4-棊〒^鼗 Very -160 - This paper scale uses Chinese National Standard (CNS) A4 specification (210X 297 mm) 1310036 A7 __B7 V. Invention Description (157) &quot;°#°Sit-2 - Base Year Cover 1 - 3 - Hyperthyroidism-1 - Bingyi g-g report "2,3 _ d 1 pyrimidine -2-4(1Η,3Η)-dione

OH

Take 6-(bromomethyl)-3-methyl-1-propyl-2,4-dioxo-1,2,3,4-tetrahydro-4 benzo[2,3-d] A solution of 5-carboxylic acid (500 mg) and zinc acetoxyacetate hydrate (389 mg) in chloroform (10 ml) was stirred under reflux for a few hours and then cooled to room temperature. Water (10 ml) and phenylhydrazine (0·27 ml) were added, and the mixture was stirred for 3 days and layered. The aqueous phase was extracted with dichloromethane (2×1 mL). The organic extract was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was dissolved in EtOAc (5 mL). &lt;RTI ID=0.0&gt;&gt;&gt;&gt; After the mixture was stirred for 1 hour, (s)_4_isoxoxazolidine hydrochloride [Example 1 'b), 173 mg] was added. After a further 24 hours, the mixture was evaporated under reduced pressure. The residue was purified by reverse phase HPLC eluting with 0.1% aqueous ammonium acetate / EtOAc. The product was purified by EtOAc EtOAc EtOAc (EtOAc) MS (APCI) 524 [M + H] 十δ 'Η dmso 〇·89 (3Η, t), 1.67 (2Η, sex), 2.16 (3Η, s), 2.26 (3H, ___- 161 - This paper size applies China National Standard (CNS) A4 Specification (21〇X 297 mm) 1310036 A7 B7 V. Description of Invention (158) s), 3.20 -3.22 (3H, m), 3.45-3.60 (1H, m), 3.71-4.15 (7H, m), 4.57-4.80 (1H, m), 5.46-5.57 (1H, m), 7.37-7.40 (1H, m), 7.44-7.54 (4H, m). Example 30 ^_-(1.11,2,3-Benzatriazole-fluorenylmethyl)-5_"(4sv-decahydroisoxazole carbonyl-3-ylene-1-(isopropyl) F2,3-dl pyrimidine-2,4(1 Η,3Η)-dione

§1.6-(111,213-Benzene)|Triazol-1-ylmethyl)-1丄34_tetra|[_3_甲某_1彳昱基基)-2,4-dioxothiophene# "2.3_dl pyrimidine-5-indole base methyl ester was added with sodium hydride (〇·〇6 g '60°/. suspension) to a solution of stupid and tris(s.19 g) in anhydrous tetrahydrofuran under nitrogen. After 10 minutes, a solution of the product of Example 8 c) (0.6 g) in anhydrous tetrahydrofuran was added dropwise. The reaction mixture was stirred overnight at room temperature. Water was added and the reaction mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate The residue was purified by EtOAc (EtOAc) eluting eluting ^ H CDCI3 1-50-1.52 (6Η, d), 3.35 (3H, s), 4.05 (3H, s), 4.6 (1H, bs), 6.01 (2H, s), 7.4 (1H, m), 7.51 (1H, m), 7.75 (1H, m), 8.07 (IH, m). Package]6-(1?{-1,2,3-stup#::1^_1_a some early)-112,3,4-tetrahydro-3-methylindole-1-(qi._- ΙΟ B · This paper scale is suitable for 8 B standard (CNS) Α 4 · (21〇x297 DON) 1310036

AT _____B7 _ 5, invention description (159) propylene oxo dish j and "2.3-dl pyrimidine-5-teaching acid added sodium hydroxide solution (丨. 5 ml, 1M) to nitrogen, containing example 30 a) product To a solution of tetrahydrofuran. A solution of the title compound was obtained. The title compound was obtained from EtOAc (EtOAc). 6-(111-丄2,3-benzotriazole-1_a certain methyl, _5_|743)-4-hydroxylisoindolyl.U-methyl-1-(isopropyl U尽##""2.3-dl-pyrimidine-2.4(1Η.3Η)-dioxin-added hydroxybenzotriazole (0.23 g), (4S)-4-hydroxyisoxazolinidine hydrochloride (described in Example 1) b)) (0.16 g) and triethylamine (0.22 ml) under nitrogen, containing the product of Example 30 b) in dioxane methane. After 1 min, add EDCI (0.29 g). The mixture was stirred overnight. Water was added and the mixture was extracted with methylene chloride. The organic phase was washed with brine, dried over magnesium sulfate and evaporated. Work up to give the title compound as a white foam. MS (APCI) (M++H) 471.1450 δ 1 HDMS 〇1,4 1 -1 · 45 (6H,m), 3.17 (3H,s), 3.36-4.13 (4H, range of m), 4.4 (lH, bs), 4.8 (1H, 2m), 5.5 (1H, m), 6.02-6.15 (2H, m), 7.4-7.44 (1H, m), 7.54-7.59 (1H, m), 7.91-7.95 (1H, m), 8.05-8.07 (1 H, d). Example 3 1 5- "(4SV4- and some isoxazole a carbonyl 1-3-A: -1-Γ冀丙)-6-f (2-oxo-pyrazole and 5,4-1?1 pyridine-1 (21~〇-yl) A 14 phenanthene #『2.3-£11 pyrimidine- 2,4ΠΗ.3Η)-Dione-163 - This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1310036

Isopropyl]]^^========================================================================================== [5,4_b]pyridine-2(ih)-ketone (0.24 g) [depicted in Example 13xiii c)] and Example 8 c) product (〇6 g). The residue is triturated with ether and filtered to give the subtitle compound. δ 'H CDCI3 1.57-1.59 (6Η, d), 3.36 (3H, s), 4 (3H, s), 4.5 (1H, bs), 5.3 (2H, s), 7.24-7.28 (1H, m), 7.73-7.76 (1H, d), 8.30-8.32 (1H, d). ^1丄2,3,4: Tetra Argon-3-丄-(Wu Bingguo)-2,4-二g.代-6-"2-Pneumatic mouth plugs sit and "5,4-b~Kfc bite -1(2H)-ylmethylanthene# "2,3-d~l·Mimi-5-teaching acid added sodium hydroxide solution (0.78 ml, 1 M) to nitrogen, containing example 3 1 a) product The title compound (〇18 g) was obtained by the addition of 1 ml of methanol, and then the mixture was dissolved. The mixture was stirred at room temperature for 48 hr. MS (ES) (M++H) 433 c) 5-『(4S)-4-海某异崎佐 pyridine carboxycarbonyl 1-3-甲一-1-(isopropyl oxo-oxazolyl and f5 .4-blpyridine-1(2H)-ylindenyl 14-"2.3-dl-pyrene 2,4(1Η·3Η)-dione-164 - This paper scale applies to Chinese National Standard (CNS) Α4 specification ( 210 X 297 gong #) A7 B7 1310036 V. Inventive Note (161) Addition of benzotriazole (〇· 12 g) to a suspension of tetrahydrofuran containing the product of Example 3 1 b) under nitrogen. 1 min Add EDCI (0.1 5 g), and after 40 minutes, add (4S)-4-hydroxyisoxazolidine hydrochloride (〇〇6 g) and triethylamine (0.07 ml). Stir at room temperature overnight. Add water and extract the mixture with di-methane. The organic phase is washed with brine, dehydrated with magnesium sulfate, and concentrated. The residue is purified by Shi Xishi chromatography and 5% carbonitrile. The solution was dissolved to give the title compound as a white foam. MS (APCI) (M + + H) 504.0914 δ H D6 DMSO 1.45-1.48 (6 Η, m), 3.16 (3 Η, s), 3.52-4.1 (4H, m Range), 4_4 (1H, bs), 4.6-4.8 (1H, range of m), 5.^-5,57 (3H, m), 7.4-7.47 (1H, m), 7.79-7.81 (1H, d ), 8.30-8.31 (1H, d). Example 32 4_·"2:3-Dihydro-2-gaso-1H-stupid bite-1-yl-A certain car, etc., oxazolidinylcarbonyl 1-3 -Methyl-1-(isopropyl hydrazine [2,3_dl-pyridinium 2,4ΠΗ.3Η)-dione

CL_L_2,3,4-tetraqi-3-methyl-1-(isopropyl)-6-"2-(A stupid ~-1-ylmethyl 1-2, 4-dilac-1 »菜吩和|~2,3-(11;&gt; 密叫-5-勒|甲甲醋 according to Example 3 c) The method of 'Example 8 c) and 2-methylhydrosulfanyl Prepared by imidazole, purified by vermiculite chromatography, and coated with isohexane/acetic acid (1 ______- 165 - This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) A7 B7 1310036 V. Invention Description (162): 〖After dissolving, the title compound is obtained as a pale yellow solid. MS (ES) (M + + H) 459 δ 1 H D6 DMSO 1.40-1.42 (6Η, d), 2.73 (3Η, s), 3.16 (3H, s), 3.80 (3H, s), 4.3 (1H, bs), 5.56 (2H, s), 7.15-7.23 (2H.m), 7.54-7_58 (2H, m). 13) 1.2.3.4 -tetrahydro-3-methyl-1-(isopropyl hydrazide)-6-"2-(methyl hydrazine||)-1 - stupid imidazol-1-ylmethyl 1-2,4-di Generation-g is exemplified by the addition of mCPBA (1.2 g) to the product of Example 3 1 a) (0.64 g) in dichloromethane. The reaction mixture is at room temperature. Stir for 2 hours. With 10% sodium metabisulfite (40 ml), sodium bicarbonate and brine The reaction mixture was washed with EtOAc (3HHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHHH - stupid #imidazole-1-some a certain u?丄4-tetrazole_3-methyl-1-(isopropyl)-2,4_dioxo,-sulfimenoxadol 2·3-η~ Pyrimidine-5_淼醢 Add sodium bicarbonate (0.55 g) to an aqueous suspension containing the product of Example 32 b) (0.54 g). The reaction mixture was heated under reflux for 17 hours. The reaction mixture was washed with ethyl acetate. Freeze-drying to give the subtitle compound (〇.7 g) MS (ES) (M++H) 415 d) Soap - "^J-士. Hydrobenzimidazole-1- Some A 1-5_"r4S )_4_ hydroxy oxime 5-oxazolidinyl hydrazine-丨_(isopropyl) p 吩 吩 拍 [2 3_di pyrimidine-2,4 ( 1 H, 3HV: according to r 3 I c) member of the method, by Example 32 Preparation of product c), purified by gravel analysis, sequentially dissolved in 0% and 1% methanol acetic acid solution. The paper size is applicable to the aa standard ((: 3⁄4 A4 specification (21Q χ 2971 2)------——- A7 B7 1310036 V. Inventive Note (163), purified by reverse phase HPLC, with 〇·1% aqueous ammonium acetate: acetonitrile (95: 5 to 5: 95) Dissolution to give the title compound. MS (APCI)(M + + H) (486.1469) 5 1 HD 6 D Μ S Ο 300 Mhz 1.44-1.45 (6H, m), 3.16 (3H, s), 3.5-4.5 (5H, range of m), 4.6-5.2 (3H, range of m), 5.5-5.57 (1H, 2m), 6·99 (3H, s), 7.2 (1H, m). Example 33 "(4S)-4-Hydroxy-2-isoxazole pyridine a carbonyl 1-3-methyl- isopropyl isopropyl thiophene and "2.3-dl^^-2.4nH,3H)-: _

a) 5,6 -二漱.-2 - gas stone tiger base 笨 味 味 Φ Take 3,4-difluoro-6-nitroaniline (2 g) and 5% Pd/C (100 mg) The stirred suspension of ethanol (30 ml) was stirred at 5 bar for 24 hours. The mixture was filtered over EtOAc (EtOAc). The solution was stirred at ambient temperature for 5 hours. The solution was poured into water. The mixture was extracted with ethyl acetate (x3). The combined organic extracts were dehydrated (MgSO.sub.4). δ 1 H D6 DMSO 7.6-7.62 (2Η, m), 8.3 (1H, s, br), 13 (s, 1Η). b) 5,6 - 2漱_-2-(methylthio) curtain also. Wei ton This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm)

Line A7 B7 164 1310036 V. Description of the invention (According to a stirred suspension of 5,6-difluoro-2-hydrothiobenzimidazole (2.4 g) and potassium carbonate (1.78 g), via methyl iodide ( Treatment with 0.8 ml), stirring for 2 hours. The reaction was evaporated to dryness and the residue was suspended in water (300 ml). The mixture was extracted with ethyl acetate (?3). The combined organic extracts were dehydrated (MgS04) and evaporated. Chromatography (SiO 2 / EtOAc: EtOAc (EtOAc): EtOAc (EtOAc) Argon-2,3-dioxin-1H-benzofurazan-1-methyl ill "(4S)-4-hydroxyisoxazolidine-2-ylcarbonyl 1-Misopropanol)- 3-methyl propyl i 2,3-dl pyrimidine-2,4( 1H.3H)-dione was added to mCPB A to di-methane, and the reaction mixture was stirred for 1 hour. The reaction mixture was poured to 丨0% meta-sulfuric acid. The mixture was washed with a solution of sodium bicarbonate and brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow foam, water (5 ml), THF (5 ml) The foam was treated with sodium bicarbonate (0.37 g). The reaction mixture was stirred at reflux for 48 hours. The precipitate formed was filtered and washed with water to give a white solid. EtOAc (EtOAc) (EtOAc) (ml) with (S)-hydroxyisoxazole pyridine.HC1 (0_18 g). The reaction mixture was stirred under reflux for 2 days. The residue was chromatographed (Si 〇 2/98 · · 2 ethyl acetate-methanol). Yellow solid. Recrystallized from methanol to give the title compound as white crystals (0.18 g). δ 'Η d6dmso 0.84 (6Η, m), 2.02-2.19 (1H, m), 3.19 (1H, s), 3.74- 4.17 (5H, m), 4.6-4.81 (1H, m), 4.97-5.18 (2H, m), 5.7-5.61 (1H, m), 7.02-7.17 (m, lH) and 7.35-7.41 (m'lH -16B ~ This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm)

Binding

Line 1310036 A7 B7 V. Inventive Note (165) Example 34 5-f(4S)-4-hydroxy disk, soil this: -2-grab ^^mazole #"^咗咗J· 棊methyl)-1 - and X.&quot;基二3"f棊噚"2,3-(〇^啶_2 4ΠΗ 3Η)-dione oxime

a) 6-(imidazolium "l,2-alpyridine-3-one A certain VI-Riding _3_甲某_2 4_dioxo-1,2,3,4-tetrahydro phenanthrene And "2.3-dl ° secrets - 5-# armor brewing example 3 b) product (1 g), imidazo[i,2_a]pyridine (〇4 ml) 'potassium carbonate (0.3 5 g) and THF (20 ml) was stirred under nitrogen for 1 hour. Water was added until the reaction was extracted with ethyl acetate (X 2 ). The combined organic extracts were dehydrated (MgS 〇 4) and concentrated in vacuo. /9:1 ethyl acetate-hexanes, and ethyl acetate) to give the title compound as a colorless oil. LCMS (ESI) 4275 [M + H] + b) 6 Al pyridine-3-methyl meth)-1-isobutyl-3-methyl-2,4-dioxo-1,2,3,4-tetrahydro-p-pyrene and 2.3-dl pyrimidine-5 - The product of item a) was treated with sodium hydroxide (0.75 ml), THF (5 ml) and methanol (0.05 ml). The resulting solution was stirred under nitrogen for 2 hours. The reaction mixture was washed with ethyl acetate. Concentration in vacuo gave the subtitle compound (0.13 g). </RTI> </RTI> 5-((4S)-4-hydroxyisoxazole pyridine-2- carbonyl 1-6-(oxazoloindole. 2-a pyridine) 3-methylmethyl)-1-isobutyl-3-methylpyrimidine And f2,3-dl pyrimidine-2,4ΠΗ,3Η)-dione__- 169 - This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X 297 mm) 1310036 A7 B7 V. Invention Description (166 The product of step b) (0.13 g) was dissolved in THF (3 ml). H〇BT (0.09 g) and EDCI (0.12 g) were added sequentially. After stirring for 1 min, triethylamine (0.05 ml) was added. (S)-Hydroxyisoxazole pyridine hydrochloride (〇. 〇 8 g), the reaction mixture was stirred for 16 hours. Water (10 ml) and ethyl acetate (1 〇mi) were added. The ethyl ester was extracted and the combined organic extracts were dried (EtOAc mjjjjjjjjjjjjjj M + H] + Example 3 5 3 -Methyl-642-A 吲哚-3-A A certain 1-1 彳 丁 ))-5-(四氤异呤

Base-6-"2-methylindole-3-methyl-1-(isobutyl Vs-(tetramium succinyl-2-ylcarbonyl)-&gt; sputum" 2.3-dl Preparation of the pyrimidine-2.4 (1 disisi according to Example 1 g) product from the product of Example 5 b) and tetrahydro-1,2-indole hydrochloride gave the title compound. MS (APCI) 495 [M + H] + δ 'Η dmso. 130-c 0.82 (6Η, d); 1.72 (4H, s s); 2.11 (1H, septet); 2.35 (3H, s); 3.25 (3H, s); 3.6 (2H , br d); 3.70 (2H, br s); 3.85 __- 170 - This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 1310036 V. Invention description (167) (2H, br s ); 4.1 (2H, s); 6.9 (1H, t); 6.95 (1H, t); 7.25 (1H, d); 7 · 3 5 (1 H, d); 10 · 4 (1 H, brs) Example 36 Dioxane-1H-taste-1-yl-methyl and its iso-g-isodinyl 1-3-methyl-1-(1 butyl-pyrazine p vdl-pyrimidine-2,4ΠΗ,3Η )- 二酉同

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a) 6: f2-bromo-4,5-dif-1Η-furox-1-one a certain 1-1.2,3,4-tetra-1-3-methyl-1-(isobutyl)-2 , 4-dihydro-sulfono[2.3-...pyrimidine-5-carboxylic acid methyl ester addition example 3 b) product (丨g) to 2-bromo-4,5-dichloroimidazole (0.73 g) and Potassium carbonate (1 g) in anhydrous dimethylformamide solution. After the reaction was stirred at room temperature for 2 days, it was diluted with water and extracted with ethyl acetate (2 times). The organic phase is dehydrated with magnesium sulfate. The residue is purified by flash chromatography eluting with EtOAc EtOAc (EtOAc) MS (APCI) 524.9 [M + H] δ 'Hcdcu 0.96-0.98 (6H,d),2.2-2.3 (1H, m)' 3 39 (3H, s), 3.73-3.75 (2H, d), 4 ( 3H, s), 5.36 (2H, s) kl..6-[2-bromo-4,5-diox-1H-imidazole-1·ylmethyl 1^,3,4_tetrag-yl-1-( Isobutyl)-2,4 -digaso-p dish"2,3-41_ -171 This paper scale applies to Chinese National Standard (CNS) Α4 specification (210Χ 297 mm) 1310036 A7 B7 V. Invention Description (168) Add sodium hydroxide (2 ml 1M aqueous solution) and methanol (〇.5 mi) to a solution containing the product of step a) (0.85 g) in tetrachloropyran (7 ml) at room temperature. ^ hours. After careful treatment, the sinking was formed by washing with a tetrahydrofuran to give a white solid (0.81 g) of the subtitle compound. MS (APCI) 510.8 [M + H] c)—6—-丄?漠咪吐-li A 淼 淼 显 显 显 显 显 显 显 显 : : : : : : : : : : : : 棊Η 棊Η 「 「 「 「 「 「 「 2 2 2 Liao 4ί1Η 3Ην diketone according to the method of g), prepared by the product of example 10 b) and (4S)-4-pyryl sulphate hydrochloride (example lb product), through the emergency vermiculite layer Purification by chromatography, eluting with 2% methanol in dichloromethane to give the subtitle compound. MS (APCI) 581.8 [M+H] δ ^dmso 0.89-0.91 (6Η, d), 2.1-2.2 (1H, m ), 3.2 (3H, s), 3.6-4 (5H, m), 4-4.1 (1H, m), 4.6-4.8 (1H, 2m), 5.34 (2H, s), 5.51-5.53 (1H, d Example 37 5-"(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl 1-3-methyl-1-(anthracene I (methylthio)-chuan-imidazole" 4,5 -!?1 pyridine-1-methyl 1 hip hop and "2.3-(11 pyrimidine-2,4(1Η,3Η)-dione

-172 - This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 297 mm) 1310036 A7 B7 V. Description of invention (169) a) 2-(曱 某)-1 H-imidazolium a Add B Potassium xanthate (4_51 g) to a solution of 2,3-diaminopyridine (2.51 g) in ethanol (25 ml) and water (5 ml). The reaction mixture was refluxed for 24 hours and then cooled. The precipitate formed was filtered and washed with ethanol and ether to give a pale pink solid (3.16 g). Potassium hydroxide (23 ml, 1 M) was added to the solid for 5 minutes, then iodomethane (3 ml) was added. The reaction mixture was taken at room temperature overnight and extracted with ethyl acetate. The aqueous layer was concentrated in vacuo. The residue was ground with methanol and the insoluble solids were filtered. The filtrate was concentrated in vacuo and EtOAc EtOAc m. MS (ES) 166 [M + H] + δ 'Hdmso 2.56 (3H, s), 6.68-6.73 (1H, m), 7.44-7.47 (1H, d), 7.84- 7.86 (1H, d). b) I, 2U-tetrahydro-3-methyl-1-(isobutyl V6-"2-(methylthio)-1Η-furazan _ l~4,5-bl.. bite-1 -Based methyl 1-2,4-diindole, substituted- far-directed "2.3-dl berylic acid methyl ester according to Example 13vii a), by example 3 b) product (815 mg) and 2- (Methylthio)-1 oxime-imidazo[4,5-b]pyridine (Example 37 a)) (342 mg). The crude product was purified by flash chromatography eluting with 50% acetic acid. The title compound (190 mg) and the product of Example 22i a) (40 mg) were obtained eluted from hexanes of hexanes of hexanes of hexanes (MS) s[M+H] + δ 'HCdci3 0.89- 0.90 (6H, d), 2.1-2.2 (1H, m), 2.8 (3H, s), 3 4 (3H, s), 3.6 (2H, d), 4.1 (3H, s), 5.82 (2H, s ), 6.95-7 (1H, t) 7.85- 7.91 (2H, m). _- 173 -_ This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public attack ^ ' &quot;~~~ ----

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Line 1310036 A7 B7 V. Description of invention (170)

Qi-H3,4-tetrazo.-3-methylindole-1-(isomeric)-6-"2, (methylthio, H_g^...Bugan [~4,5-131pyridine-1-) A certain 214-41^---71-[2.3-(11褚蛉-&lt;S sodium-added sodium hydroxide (0.8 ml '1M) to nitrogen, containing the product of example 37 b) (1 To a solution of 90 mg) in THF, EtOAc (m.). [M+H] +d) 5-f(4SV4-ride: base·〇哥吐咬-2-基几一1-3 -甲某-i_(暮丁苹"2-(methylthio)- lH-thiazolidine 丨4,5-blpyridine-3- 甲其其哈哈佩ρ ιΗ·| Pyrimidine-2,4ΠΗ,3ΡΠ-dione according to the method of Example 1 g), from the product of Example 37 c) The crude product was purified by reverse-phase preparative EtOAc (EtOAc/EtOAc) M+H] + δ 'Hdmso 0.88-0.90 (6H, m), 2.1-2.2 (1H, m), 2.70 (3H, s), 3.18 (3H, s), 3.6-3.9 (5H, 3m), 4 -4.1 (1H, m), 4.6-4.8 (1H, 3m ), 5.5-5.9 (3H, m), 7.1 (1H, m), 7.9 (2H, m). Example 37i 5-"(4S)-4- and .isoxazole pyridine a carbonyl 1-3- A certain -1-(isobutyl methionyl)-3H-imidazolium "4,5-bl pyridine-3-methyl thiophene and l~2.3-dl pyridinium-2,4 (1 Η · 3 Η, -Dione 174 - This paper size applies to China National Standard (CNS) A4 specification (210X297 mm)

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1310036 a) 1,2,3,4-tetra-argon-3-methyl-1-(isomethyl sulfide LL.5-bp ratio bite-.3-ylmethyl l-2,4-di shy R2 3-dl pain cold;: acid methyl ester ^ obtained according to the product of example 37b). MS (ES) 474 [M + H] + δ 'HCdci3〇.88-0.90 (6H, d), 2.1-2.2 (1H, m), 2.8 (3H, s), 3 3g (3H, s), 3.66 -3.68 (2H, d), 4 (3H, s), 5.6 (2H, s), 7.19.7 23 (1H, m), 7.90-7.93 (1H, d), 8.28-8.29 (1H, d). W 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl methylthiol f4,5-bl·»pyram-3-ylmethyl1·2;4·dioxo The title compound was obtained from the product of Example 37 i a) (4 mg). MS (ES) 460 [M + H] + g) 5-"(4S)-4-hydroxyisoxazole pyridine, a certain 1-3-methyl-methylthio group)-3H - benzopyrene · 2.4ΠΗ.3Η)-dione according to the preparation of the method of Example 1 g) 'Prepared from the product of Example 37i b). The crude product was purified by flash quenching chromatography and dissolved in 3% methanol in dichloromethane. 175 This paper size applies to the Chinese National Standard (CNS) Α4 specification (210 X 297 mm)

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Μ 1310036 A7 B7 V. Inventive Note (172) 'Polishing with isohexane' yields the title compound as a pale yellow solid ( 丨〇 mg). MS (ES) 53 1.1 583 [M+H] + δ 1Hcdci3 0.91-0.93 (6H, d), 2.17-2.26 (1H, m), 2.78-2.8 (3H, d), 3.36 (3H, s), 3.5 -4.2 (6H, 3m), 4.6-5 (2H, 3d), 5.43-5.74 (2H, m), 7.19-7.26 (1H, m), 7.9-7.93 (1H, d), 8.26-8.28 (1H, d) ° Example 3 8 Dimethyl-1H-pyrazole ~ 4- A certain lw. A -% "(4S)-4-hydroxyl-2-iso-g 唆 carbonyl thio group μ!. (isopropyl Base) Bianling and "^丄... shouting legacy-2, 4ΠΗ, 3Η)-

1,2,3,4-Tetrahydro-6-A. Bu (isopropyl)·2ί4-$-----"2,3- dl-pyrimidine-5-carboxylic acid (丨3.5 g) was suspended in anhydrous toluene (9 mL) and treated with hexanes (5.34 ml) dropwise under argon and stirred vigorously for 3 min.. Anhydrous benzene (15 ^1) solution was stirred and the mixture was stirred for 72 hours. The mystery (3 60 ml) was added, and the insoluble material was filtered and washed with a small amount of ether. The combined organic solution was washed with saturated sodium hydrogen carbonate solution, dehydrated and evaporated. Sodium sterol sodium sterol solution (25% by weight, 64 ml), treated at room temperature for 72 _____- 176 - Paper size is applicable to China National Standard (CNS) A4 specification (21〇χ297 mm) 1310036 A7 B7

Time. The reaction was cooled with ice, EtOAc (EtOAc)EtOAc All volatiles were removed by vacuum and the residue was partitioned between water and ethyl acetate. After dehydration and evaporation of the organic solution, the residue was chromatographed (Si 〇 2/2: 1 iso-hexane-acetic acid ethyl acetate, then 3:2 isohexane-acetic acid ethyl acetate to give the subtitle compound (12.2 g). ES) 283 [M+H] + chaos aj-methyl-1-CJi_aA)_2,4_2 hope and "2,3-dl pyrimidine-5-fluorenylmethyl ester a) product (0.5 g) Potassium carbonate (0.34 g), ethyl iodide (〇n ml), DMF (5 m丨) and acetone (5 ml) were heated at 50 t for 16 hours. The reaction mixture was added with water (5 ml) to terminate the reaction. Ester extraction. Dehydration of organic extracts (MgS 〇 4) 'Concentration in vacuo. Residues were chromatographed (SicV8: 丨:1 hexanes-ethyl acetate-dichloromethane). 5'HCDC131.23(3H,t), 1.59(6H,m),2.4 (3H, s), 3.95 (3H, t), 4.01-4.06 (2H,q), 4.6-4.8 (1H, m) Base-1,2,3,4-tetrahydro)-2.4-dioxin- phenanthrene "2,3-dl pyrimidin-5-decanoate methyl ester according to the method of Example 22 a), by b Preparation of the subtitle compound. MS (ES) 327 [M + OH-Br] + d) β- "3,5-dimethyl-1H-pyrazole-4-one A, π | -1 , 2 3 4_tetra H 4 L晷propyl)-2,4·^oxo-4 Benzo[2,3-dl遑^ methyl ester

According to the method of Example 26 a), the sub-title compound is prepared from the product of item c). MS (ES) 334 [M + H] + e) 6-[3,5-dimethyl-1H-pyrazole-4-yl-methyl-In, discuss c"-177 - This paper scale applies to Chinese national standards ( CNS) A4 size (21〇X 297 mm) 1310036 A7 B7 V. Description of invention (174) 2-Isooxazolidinylcarbonyl A Mf hydrazinyl-2,4 (l^L3Hk II i taken d) The product (0.6 mmol), diethyl chlorophosphate (0.09 ml), 1-pyridyltriazole (0.08 g), triethylamine (0.11 ml) and acetonitrile (6 ml) were stirred for 30 min. The product of Example 1, b) was added, and the mixture was stirred for 16 hours. The reaction was quenched by the addition of potassium carbonate. The reaction mixture was subjected to EtOAc (MeOH:MeOH) eluting with EtOAc:MeOH (98:2). Purification by phase HPLC to give the title compound as a white solid (30 mg). δ 1H 〇mso 1.06-1.18 (3H, m), 1.41-1.53 (6H, m), 2.1 (6H, s), 3.42-4.18 (7H , m), 4.3-4.47 (1H, s), 4.63-4.8 (1H, m) and 5.5 (1 H, m). Example 39 5-((4S)-4- with certain isoxazole carbonyl 1 -3-methyl-1-(isobutyl)-6-Γ2-(-fluoromethyl) 苽甲某”#2.3-dl-pyrimidine-2,4ΠΗ,3Η)-dione

Magic 1,2,3,4-four. -3-A certain-1-(isobutyl)-2,4-diindole-6-"2-(trifluoromethyl) The phenantho-f2,3-dl-pyrimidine-5-carboxylic acid is contained in 5-bromo-3-methyl-1-(isobutyl)-6-[2-(trifluoromethyl)benzyl] phenanthrene [2,3-d]pyrimidine-2,4(1H,3H)-dione (WO 01 83489) in THF (60 ml) __- 178 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1310036 A7 ___B7 ΐ, invention description (175) In solution, add isopropylmagnesium chloride (2M THF solution 'j. 3 5 m丨) under ot and nitrogen. 5 minutes 彳, with carbon monoxide The mixture was treated with a stream of air for 1 minute. The reaction of adding the water to the reaction mixture was acidified with 2N HCl and extracted with ethyl acetate (x3). The combined organic extracts were washed with dilute HC1 and brine, dehydrated (MgS04) and concentrated. Subtitle compound of yellow solid (2.48 g) MS (ES) 441 [M + H] + b) 5-f(4S)-4-|j-iso- 4-pyridyl carbonyl some I·%〒一丁丁A diterpene methyl group) awkward base 1 peak is arbitrarily "2,3-d]p dense p contains -2,4 ΠΗ,3 Η) - bismuth is prepared according to the method of item 1 g), which is prepared from product a) MS (APCI) 512 [M + H] + δ 'Hdmso 0.8 (6H, m), 2.1 (lH, pentent), 3.2 (3H, m), 3.5-3.8 (4H, m), 4.2 (2H, m), 4.6-4.7 (1H, m), 5.5 (1H, m), 7.5 (2H, m), 7.6 (1H, t) and 7.8 (1H, d). Example 40 5-((45)-4-Iperyl-2-iso-ton 1-1-3-methyl-1-(isobutyl)-6-"2-[-methylthio)-1Η-imidazol-1-ylmethyl1-41-4-phenanthrimidine-2,4ΠΗ,3Η) -

This) 1,2,3,4-tetrahydro-3-methyl-1-(isobutyl)-6-"2-f-methylthio"-lH-mpy- ___- 179 - This paper size applies China National Standard (CNS) Α4 Specifications (210 X 297 mm) 1310036 A7 B7

1 - 棊甲棊: L2,4-_^ oxo-deuterated "2,3^1 pyrimidine _s_ 跆醢 酿 依 依 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例Preparation of the thioimidazole to give the subtitle compound MS (ESI) 423 [M + H] +

丨-碁甲棊丄 代-喧 并 "2,3-41 _ _ _ _ _ Β Φ Φ according to the method of Example 3 d), prepared from the product of item a) MS (ESI) 409 [M + H] + c) 5-K4Sk4-Several U-isoxazole 立基几上上}Methyl small 7

Prepared from product b) according to the method of Example 3 e). MS (APCI) 480 δ 屮(10)so 0.89-0.91 (6H,m),2.11-2.18 (1H,m),2.49·2 52 (3H m), 3.2-3.21 (3Η,m),3_52-4·1 ( 6Η,m), 4.62-4 78 (1Η 5.23-5.25 (2H, m), 5.5-5.58 (1H, m), 6.97 (1H,d) and 7 21-7 23 (1H, m) ° ' -180 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) '一--------

Claims (1)

13 0 呑 呑 116735 Patent Application t X in the patent scope replacement (December 95) VI. Application for patent garden 1 · A compound of formula (1): Wherein: R1 and R2 each independently represent a C.6 alkyl group; R3 is an isoxazolidin-2-ylcarbonyl group or a tetrahydroisoindole-2-ylcarbonyl group, wherein each ring may be substituted with a hydroxyl group as needed; Q is - C0- or -C(H2); Ar is selected from the group consisting of imidazolyl, pyrazolyl, pyrrolyl, isoxazolyl, phenyl, P-cylinyl, fluorenyl, benzophenanyl, 4 bite , benzotriazolyl, 2,3-dihydropyrazolyl, 2,3-dihydrobenzoxazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a Pyridyl, imidazo[4,5-b]pyridinyl, 2,3-dihydrooxazolo[5,4-15]pyridinyl, 2,3-dihydropyrrole, 2,3-di The hydrobenzothiazolyl and 2,3-dihydrobenzimidazolyl' rings may be optionally substituted with one or more substituents each independently selected from the group consisting of C.4 alkyl (which may optionally be substituted by a hydroxy group) , halogen, CF3, (^_4 alkylthio, oxo, thio, cyano, -N(R6)R7, or phenyl, pyrimidinyl, pyridyl or thiazolyl; p is from 1 to 4; R6 and R7 independently represent a hydrogen atom or a Cm alkyl group; the paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 public #) 10036 A8 B8 -------- C8 六^----, R8 and R9 each independently represent a hydrogen atom, a Ci 4 alkyl fluorenyl group or a C "alkyl group" or a nitrogen atom attached thereto to form a 5- to 7-membered saturated heterocyclic ring; a pharmaceutically acceptable salt thereof, 2', a compound according to the scope of claim 1, wherein r2 is methyl or ethyl. 3'A compound according to claim 1 or 2 wherein R1 is ethyl, N-propyl, 1-methylethyl, 2-mercaptopropyl or 2,2-dimethylpropyl. 4. According to the compound of claim 1 or 2, Ar in the sputum contains at least - The compound according to claim 1 or 2, wherein the compound contains at least 2 ring nitrogens. 6. The compound according to the first aspect of the patent application, wherein: (S) 5-[4 -hydroxyisoxazolidine-2-ylcarbonyl]_3_methyl_1(2methylpropyl)-6-(4-quinolinylmethyl)indeno[2,3_d]pyrimidine_2,4 (1Η 3Η)dione; (R) 5-[4-hydroxyiso, oxazolidin-2-ylcarbonyl]-3-mercapto-1-(2-methylpropyl)-6·(4-唆Lolinylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 6-[4,5-dichloro-2-methyl-1H-imidazole- 1-ylmethyl]_5-[4-hydroxy -2-isoazinocarbonyl]-3-methyl-1-(2-methylpropyl)sulfono[2,3_d]pyrimidine-2,4(1H,3H)-dione; (S 5-[4-Py-iso-n-n y y y 2 yl carbonyl]-3 -methyl-1-(2-methylpropyl)-6-(4-p quinolylcarbonyl) sulfonimide [2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazolidine-2-ylcarbonyl]_3_mercapto-6-[(2 -Methyl-1Η-〇5丨"-3-yl)indenyl]-1-(2-methylpropyl)p-senteno[2,3-d]p-biti-2,4(1H , 3H)-dione; -2 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) !31〇〇36 A BCD, patent application scope (S) 5-[4-hydroxyisoindole Azolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)-pyrrolo[2,3-b]pyridin-3-yl)methyl]pyrimido[2,3 , d] pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazolidine-2-ylcarbonyl]_3-methyl-6-[(2-methyl- lH-β哚-3-yl)carbonyl]_1_(2-methylpropyl)ίIseceno[2,3_d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4 -hydroxyisoxazolidine-2-ylcarbonyl]_3_methyl-l-(i-methylethyl)-6-(1Η-ρ ratio succinyl[2,3-b]pyridin-3-yl- P)-Penteno[2,3-d]pyrimidine-2,4(1) H,3H)-dione; (S) 5-[4-Hydroxyisoxazolidine-2-ylcarbonyl]-3-mercapto-1-propyl-6-(1Η-pyrrolo[2,3- b]pyridin-3-ylmethyl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 6-[4,5-dichloro-2-oxo -3 (2H)-»soxazolylmethyl]_5-[4-hydroxyisoxazolidine-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl) fluorene [2 , 3-d] pyrimidine-2,4(1H,3H)-dione; (S) 6-[(3,5-dimethyl-1H-pyrid-4-yl)methyl]-5-{ 4-light-isoazazin-2-ylcarbonyl}-1-isobutyl-3-methylsulfono[2,3-d]pyrimidine-2,4(1H,3H)-dione; S) 5-{4-Singapore-specific B-substrate-2-ylcarbonyl}-1-isobutyl-3-methyl[1,3,5-trimethyl-1H-pyrazol-4-yl Methyl] benzopheno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (R) 6-[(4,5-dichloro-2-methyl-1H-mole 11 -1--1-yl)methyl]_5_[4_carbazyl-isoxazolidin-2-ylcarbonyl]-3-methyl-1-(2-methylpropyl)sulfono[2,3_d] Pyrimidine-2,4(1H,3H)-dione; -3 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 8 8 8 8 A BCD 1310036 VI. Application for Patent Park ( S) 5·[4-#至基异号吐咬-2 -yl base]-3 -methyl- 6-[(2-Methyl-1H-benzopyrimidine-i-yl)methyl]_ι_(2-methylpropyl)p-seceno[2,3_d]pyrimidine-2,4(1H,3H )-dione; (S) 6-[(2-ethyl-1H-benzimidazol-1.yl)indolyl]-5-[4-yliso-(indolyl-2-ylcarbonyl)-3 -methyl-1-(2-methylpropyl) benzophenan [2,3_d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazole pyridine- 2-ylcarbonyl]-3-methyl-1-(2-methylpropyl) •6-[(2-propyl-1H-benzimidazol-1-yl)methyl]p-phene-[2 , 3_d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-carbazyl-2-oxacarbonyl]-3-methyl-1-(2-A Propyl)-6-[2-(methylthio)-1-benzimidazol-1-ylmethyl]indeno[2,3-d]pyrimidine-2,4(1H,3H)- Diketone; (S) 5-[4-Hydroxyisoxazin-2-ylcarbonyl]-6-[2-(hydroxymethyl)-1H-benzimidazol-1-ylmethyl]-3-A 1-(2-methylpropyl)sulfono[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazolidine- 2-ylcarbonyl]-3-methyl-6-[2-(methylamino)-1Η-benzoimidazol-1-ylmethyl]-1-(2·methylpropyl) fluoren 2,3-d]pyrimidine-2,4(1Η,3Η)-dione; (S) 5-[4-hydroxyisoazazin-2-ylcarbonyl]-3- -6-[2-Amino-1H-winter-flavor-1-ylmethyl]-1-(2-methylpropyl)p-seceno[2,3-d]ρ-bite-2 , 4(1H,3H)-dione; (S)-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(2-methylpropyl)-6- [(2,4,5-trichloro-1H-miso-1-ylmethyl]oxime-[2,3-d]i&gt;-biti-2,4(1H,3H)-dione; -4 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1310036 as B8 C8 _ D8 VI. Patent scope (S) 5-[4-Hydroxyisoxazin-2-yl Carbonyl]-3-methyl-1-(2-methylpropyl)-6-[2-thioxo-3(211)-benzoxazolylmethyl]pyrene[2,3-( 1]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-Alkylisoxazolidine-2-ylcarbonyl]-3-methyl-1-(2-amidinopropyl) _6-[4-Chloro-2-oxo-3(21^-thiazolylhydrazyl]11-depheno[2,3-(1]pyrimidine-2,4(1H,3H)-dione (S) 5-{4-Hydroxyisoxazolidine-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-oxo-1,3-benzene And, oxazol-3(2H)-ylmethyl]indeno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-{4-hydroxyisoxazole Pyridin-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[(2-oxo[1,3] Pyrazolo[5,4-b]pyridine_1-(2H)-yl)methyl]sulfeno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-Hydroxyiso, oxazolidine-2-ylcarbonyl]_3_methyl_1_(2-methylpropyl)_ 6-(1Η-1,2,3-benzotriazolylmethyl喽-[2,3_d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazolidinyl-2-ylcarbonyl]_3_methyl_ι_(2 -methylpropyl)_ 6-(1Η-pyrido[2,3-b]pyridin-1-ylmethyl)sulfono[2,3-d]pyrimidine _ 2,4(1H,3H) Diketone; (S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl;]_3_methylίαmethylpropyl)_ 6-[2-methyl-1H-pyrrolo[2, 3-b]pyridin-1-ylmethyl)indeno[2,3_d]pyrimidine-2,4(1H,3H)-dione; (S) 1-[1,2,3,4-tetra Hydrogen-5-[4-hydroxyisoxazolidine-2-ylcarbonyl]_3-methyl-1-(2-methylpropyl)-2,4-dioxo (τ 塞 eno[2,3 -d]pyrimidin-6-ylmethyl)-1H-·1 cited p-5-carbonitrile; -5 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 8 8 8 8 A BCD 1310036 々, the scope of application (S) 5-{4-hydroxyisoxazolidine-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl)-6-[2-oxo- 1,3-benzopyrazole-3(2H)-ylmethyl] Benzo[2,3-d]pyrimidine-2,4(1H,3H)-dione; (R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-6- [2-indolyl-indole-indol-3-ylmethyl]-1 -(2-methylpropyl)pyrimido[2,3-d]pyrimidine-2,4(1H,3H)- Ketone; (R) 5-[4-Hydroxyisoxazin-2-ylcarbonyl]-3-methyl-6-[2-indolyl-1H-indol-3-ylindenyl]-1 - ( 2-(mercaptopropyl)p-seceno[2,3-d]pyrimidine-2,4(1Η,3Η)-dione; (S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl ]-3-methyl-6-[2-(decylamino)-3H-flavor p sits and [4,5-b] p is more than -3-ylmercapto]-1-propyl-p Benzo[2,3-(1]pyrimidine-2,4(1^1,311)-dione; (S) 6-[4,5-dichloro-2-indolyl-1H-imidazol-1- Methyl]-5-[4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-propyl-indeno[2,3-d]pyrimidine-2,4(1H, 3H)-dione; (S) 5-[4-Hydroxyisoxazin-2-ylcarbonyl]-3-indolyl-6-[2-(indolylamino)-1Η-benzofuran- 1-yl-1-yl]-1-(1-methylethyl)p-seceno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 6-[4, 5-dithia-2-methyl-1H-flavors-1-1-methylmethyl]-5-[4-trans-yl-2-isoxazolidinylcarbonyl]-3-mercapto-1-(1- Methyl ethyl sulfonate [2,3-d] pyrimidine-5-carboxamide; (S) 6-[3,5-diethyl-1H-pyrazol-4-ylindenyl]-5-{4-hydroxyisoxazole Pyridin-2-ylcarbonyl}-3-methyl-1-(2-mercaptopropyl)sulfonio[2,3-d]pyrimidine-2,4(1H,3H)-dione; -6 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) A BCD 1310036 a, the scope of application (S) 6-[3-(l,l-dimethylethyl)-5 -曱-1H-pyridin-4-ylmethyl]-5-{4-hydroxyisoxazolidine-2-ylcarbonyl}-3-methyl-1-(2-methylpropyl) [2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-trans-iso-p-precipitate-2-ylcarbonyl]-3-methyl-1- (2-methylpropyl)-6-[2-mercapto-4-p-quinazinylmethyl]oxime-[2,3-d] shouting -2,4(1H,3H)- Ketone; (S) 6-[6-fluoro-4-carbolinylmethyl]-5-{4-hydroxyisoxazolidine-2-ylcarbonyl}-3-methyl-1-(2-methyl Propyl)p-seceno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (s) 6-[8-Ga-4-quinolinylmethyl]-5-{ 4-hydroxyisoxazolidin-2-ylcarbonyl} -3 -methyl-1-(2-methylpropyl)sulfono[2,3-d]pyrimidine-2,4(1H,3H)- Diketone; (S) 5-{4-hydroxyisoazazin-2-ylcarbonyl}-3-methyl-1-(2-A Propyl)-6-(5-&lt;4&lt;4&gt;linylmethyl)pyrimido[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-{4- Hydroxyisoxazin-2-ylcarbonyl}-3-methyl-1-propyl-6-0 quinolin-4-ylmethyl)sulfonio[2,3-d]pyrimidine_2,4 ( 1H,3H)-dione; (S) 5-{4-hydroxyisoxazolidine-2-ylcarbonyl}-3- T-yl-1-(1- T-ethylethyl)-6-(4-oxime Lolinylmethyl)sulfono[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3 -methyl-1-(2-methylpropyl)-6-[(2-methyl-lH-p ratio succinyl[2,3-b]p than -3-yl)methyl] ρ Benzo[2,3-d]pyrimidine-2,4(1H,3H)-dione; (R) 5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3·methyl-1- (2-Methylpropyl) The paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 131〇〇36 Patent application '6~[(2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl]thiophene U,3-d]pyrimidine-2,4(1H, 3H)-dione; (S)-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2,3-dihydro- 6-methyl-3-oxo-pyridin-2-ylmethyl]-indeno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 5- [4-Hydroxyisoxazin-2-ylcarbonyl]-3-methyl-6-[(2-methyl)-iH-pyrrolo[2,3-b]pyridin-3-yl)methyl] 1-propyl-sulfonio[2,3-d]pyrimidine-2,4(1H,3H)-dione; 5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl] -6-[2-(hydroxymethyl)-1Η-benzoimidazol-1-ylmethyl]-3-methyl-1-propyl-sulfonio[2,3-d]pyrimidine-2,4 (1H,3H)·dione; 5_[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-propyl-6-[2-月:^基-111 -Benzene-flavor-1-ylmethyl]-1»cereno[2,3-(1] shouting-2,4(1H,3H)-dione; (S)-5-[4- Hydroxyisoxazin-2-ylcarbonyl]-6-[2-(hydroxyindenyl)_1H_benzimidazol-1-ylmethyl]-3-methyl-1-(isopropyl)sulfono[ 2,3-d]P-pyridine-2,4(1H,3H)-dione; (S)-5-[4-hydroxyisoxazolin-2-ylcarbonyl]-3-indolyl_1_( Isopropyl) _6_ [2-Amino-1H-benzimidazol-1-ylindenyl] sulfeno[2,3_d]n-dense-2,4(1H,3H)-dione; (S)-5-[ 4-hydroxyisoxazolidine-2-ylcarbonyl]-3-methyl_1_(isopropyl)_6_[2-methyl-1H-pyrrolo[2,3-b]pyridin-1-ylmethyl Pyrimido[2,3_d]pyrimidine-2,4(1H,3H)-dione; (S) 5-[4-trans-iso-[1]-precipitate-2-yl-based]-3-A Base-1_(isopropyl)_6_ -8 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) A BCD 1310036 VI. Patent application scope [2-methyl-1H-pyrrole[ 2,3-b]pyridin-3-ylmethyl]thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)-6-[4,5-dichloro -2-(hydroxymethyl)-1Η-imidazol-1-ylindenyl]-5-[4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)- Pyrimido[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)-6-[3,5-dimethyl-1H-pyrazol-1-ylmethyl] -5-[4-Hydroxyisoxazin-2-ylcarbonyl]-3-indolyl-1-(isobutyl)indeno[2,3-d]pyrimidine-2,4(1H,3H) -dione; (S)-6-[2,3-dimur- 2- 3⁄4 generation-1H-benzo- 0-yl-1-ylmethyl]-5-[4-Rotorylisoxazole -2-ylcarbonyl]-3-methyl-1-(isobutyl)-sulfonome [2,3-d] pyrimidine-2,4(1H,3H)-dione; (S) 6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-5-[ 4-hydroxyisoxazolidine-2-ylcarbonyl]-3-methyl-1-propylsulfonio[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S) 6-[3,5-Dimethyl-1H-pyrazol-4-ylmethyl]-5-[4-hydroxyisoxazolidine-2-ylcarbonyl]-1-isopropyl-3-indenyl Pyrimido[2,3-d]pyrimidine-2,4(1H,3H)-dione; (S)-6-[3,5-dimethylisoxazol-4-ylmethyl]-5 -[4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methylsulfono[2,3-d]pyrimidine-2,4(1H,3H)-di Ketone; 6-[4,5-dichloro-2-methyl-1H-imidazol-1-ylmethyl]-1-ethyl-5-[(4S)-4-hydroxy-2-isoxazole Alkylcarbonyl]-3-methyl-sulfeno[2,3-d]pyrimidine-2,4(1H,3H)-dione; 1-ethyl-5-[(4S)-4.hydroxy-2 -isoxazolidinylcarbonyl]-3 -methyl-6- -9 - This paper scale applies to China National Standard (CNS) A4 specification (210 x 297 mm) A BCD 1310036 VI. Patent Application Park (1H- Pyrrolo[2,3-d]pyridin-3-ylmethyl)-indeno[2,3-d]pyrimidine-2,4(1H,3H)·dione; 1_ethyl_5-[ (4S)-4 -Phenyl-2-iso-p 11 Sitrate-based group]-3-mercapto-6-[2-propyl-1H -Benzamidin-1_ylmethyl]-p-seceno[2,3-d]〇-Bite-2,4(1Η,3Η)_dione; 1·Ethyl-5-[(4S )-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[2-oxo-3(2H)-benzopyrazolylmethyl]-sulfono[2,3 -d]pyrimidine-2,4(1H,3H)-dione; 1-ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6- [2-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl]indolo[2,3-d]pyrimidine-2,4(1H,3H)-dione; -ethyl-5-[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-6-[5-cyano-1H-indol-1-ylmethyl]- Pyrimido[2,3-d]pyrimidine-2,4(lH,3H)-dione; 5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl) -6-[1-isopropyl-3,5-dimethyl-1H-pyrazol-4-ylindenyl]-3-methylsulfono[2,3-d]pyrimidine-2, 4(1H,3H)-dione; 5-[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-1-(isobutyl)-3-methyl-6_[5-methyl -3-phenyl-1H-pyrazol-4-ylmethyl]indeno[2,3-d]pyrimidine-2,4(1H,3H)-dione; 5-[(4S)-4- Hydroxyisoxazin-2-ylcarbonyl]-1-isobutyl-3-methyl-6-[5-methyl-3-(trifluoromethyl)-1Η-pyrazol-4-ylmethyl ]Mimido[2,3-d]pyrimidine-2,4(1H ,3H)-dione; 5-[(4S)-4-hydroxyisoazazin-2-ylcarbonyl]-1-isobutyl-6-[3-isopropyl-10 - This paper scale applies to China Standard (CNS) A4 size (210 X 297 mm) ABCD 1310036 VI. Patent application base _5 -Methyl-lH-p than 唆-4-ylmethyl]-3 -methyl p-sepeno[2 ,3-d] p-pyridine-2,4(1H,3H)-dione; 6-[3,5-dimercapto-1-phenyl-lH-ppyt-4-ylmethyl]- 5-[(4S)-4-Phase-iso-p- π-salt-densation_2_yl-enyl]-1-isobutyl-3-methyl-p-phene-[2,3-dJp-pyridine-2, 4(1H,3H)-dione; 6-[3,5-dimethyl-1-phenyl- lH-p than oxa-4-ylmethyl]-5-[(4S)-4-yl Iso-p-butyl-2-ylcarbonyl]-3-methyl-1-propyl p-seceno[2,3-d] p-dense-2,4(1H,3H)-dione; 6- (1Η-1,2,3-benzotriazol-1-ylmethyl)-5-[(4S)-4-hydroxyiso, cytidinecarbonyl]-3-methyl-1-(isopropyl ))--pyrimido[2,3-d]-feeding-2,4(1H,3H)-dione; 5-[(4H)-4-trans-iso- 11 dimethyl carbonyl]-3- Methyl-1-(isopropyl)_6_[(2-oxo-p-oxazolo[5,4-b]pyridine-1(2H)-yl)indolyl]P-seno[2,3-d Pyrimidine-2,4(1H,3H)-dione; 6-[2,3-dihydro-2-oxo-1H-benzene Imidazolyl-1-ylmethyl]_5-[(4S)-4-isoyl sigma base]-3 -mercapto-1-(isopropyl)_ρ-seno[2,3-d] U-pyridine-2,4(1H,3H)-dione; 6-[5,6-difluoro-2,3-dihydro-2-oxo-111-benzo-bito-1-ylmethyl ]_5_ [(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-methyl-1-(isobutyl benzo[2,3-d]pyrimidine-2,4(1H,3H Diketone; 5-[(4S)-4-trans-iso- 17-dept-2-yl-yl]-6-(imiphtho[i,2-a]p is more than -3-ylindenyl) )-1-isobutyl-3-indolyl ρ-seceno[2,3-d] p-dense-2,4(1H,3H)-dione; methyl-6-[2-methylindole Indole-3-ylmethyl]-1-(isobutyl)-5- (tetrahydroisomeric paper scale applicable to Chinese National Standard (CNS) A4 specification (210X 297 mm) 8 8 8 8 AB c D 1310036 Patent application: p-morphin-2-ylcarbonyl)-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione; 6-[2-bromo-4,5-dichloro- 1H-imidazol-1-ylmethyl]-5-[(4S)-4-hydroxyisoindolecarbonyl]-3-methyl-1-(isobutyl)sulfono[2,3-d Pyrimidine-2,4(1H,3H)-dione; 5_[(4S)-4-hydroxyisoxazolidin-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6_[ 2-(methylthio)-1Η-imidazo[4,5-b]pyridyl Pyridin-1-ylmethyl]-pyrimido[2,3-&lt;!]pyrimidine-2,4(11^311)-dione; 5-[(4S)-4-hydroxyisoxazolidinyl Carbonyl]-3-methyl-1-(isobutyl)-6-[2-(methylthio)-3H-imidazo[4,5-b]pyridin-3-ylmethyl]cephene [2,3-d]pyrimidine-2,4(1H,3H)-dione; 6-[3,5-dimethyl-1H-pyrazol-4-ylmethyl]-3-ethyl-5 -[(S)-4-hydroxy-2-isoxazolidinylcarbonyl]-1 -(isopropyl)-sulfonio[2,3-d]pyrimidine-2,4(1H,3H)- Ketone; 5_[(4S)-4-hydroxy-2-isoxazolidinylcarbonyl]-3-mercapto-1-(isobutyl)-6-[2-(trifluoromethyl)phenylmethyl ]_, phenothi[2,3-(1]pyrimidine-2,4(1H,3H)-dione; 5-[(4S)-4-hydroxy_2-isoxazolidinylcarbonyl]-3 -mercapto-1((isobutyl)-6_12-(methylthio)-oxime-imidazol-1-ylmethyl]-pyrimido[2,3-d]pyrimidine-2,4(1H, 3H)-dione; or (S)-5-[4-hydroxyisoxazolidinyl-2-ylcarbonyl]-3-methyl-1-(isobutyl)-6-[2,3-di Hydrogen_6_methyl_3.oxo-pyrazine_2_ylmethylsepteno[2,3_d]pyrimidine-2,4(1H,3H)-dione; and pharmaceutically acceptable salt. 7. Preparation of a compound of formula (1) as defined in the scope of claim 1 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 1310036 8 8 8 8 AB c D The patent range method is carried out by one of the following methods: a) From the compound of formula (10): 〇co2h Q-Ar R1 (10) reacts with isoxazolidine or tetrahydroisoindole (each of which may be substituted by a hydroxyl group), b) when Q is a methylene group, the compound of formula (11) η R3 Ch2l R1 (ll) reacts with a compound of formula Ar; c) reduces compound of formula (12) when Q is methylene; 13 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1310036 8 8 8 8 A BCD Patent Application CH(OH)-Ar (12) d) undergoes primary ring synthesis from formula (11) or (13) to form Ar η R3 CH, R1 (13) e) Reaction of a compound of formula (14) with R1-!^: 〇 R3 (14) wherein L and L2 are debonding groups, and R1, R2, R3, Q and Ar are as defined above, and may be converted to (1) compound-14 after a), b), c) or d) as needed. - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) The compound forms a further compound of formula (1) and/or forms a pharmaceutically acceptable ride or solvate thereof. 1 8. The production method according to item 7 of the patent application, further comprising the step of protecting at least one functional group in the compound of the formula (1) and a group from which the functional group is removed. 9. A compound according to item i of the scope of the patent application is used to inhibit proliferation. A pharmaceutical composition for inhibiting T-cell proliferation, which comprises as an active ingredient a compound according to any one of items 1 to 6 of the application, and a pharmaceutically acceptable adjuvant, diluent or carrier. A pharmaceutical composition for suppressing immunity comprising a compound according to any one of claims 1 to 6 as an active ingredient, and a pharmaceutically acceptable adjuvant, diluent or carrier. 12' A pharmaceutical composition for treating a patient suffering from a reversible obstructive airway disease, comprising a compound according to any one of items 6 to 6 of the patent application as an active ingredient, and a pharmaceutically acceptable adjuvant and diluent Or carrier. -15 - This paper size applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm)