TWI325783B - Broadspectrum 2-(substituted-amino)-benzothiazole sulfonamide hiv protease inhibitors - Google Patents

Description

丄A7 V. Inventive Note B7 10 15 20 The Ming Department is about 2•(substituted amino group)·stupid and sorrowful, amines, enzymes, as a broad-spectrum HIV protein ==, its preparation method and its The medicinal composition and the diagnostic amine =: r: the reference test in the analysis of the material; the use of the sputum in the present invention, the name of the mi after the immunization insufficiency from ms) of the virus in various social ships η ^ °, Including τ_lymphocytovirus iππ (Ητχν·ιπ) or lymphatic virus (LAV) or side-associated virus (arv) or human: immunity: virus (HIV), so far, two distinct ethnic groups have been identified It is commonly known as γιν_ι and hiv-2, and then it will be used as a critical path (criticai ys) in the life cycle of retroviruses to treat polyproteinase precursor P by aspartic acid protease. Yprotem p_rs〇rs), for example, Ηιν virus to vaccinate the gene of the type of virus) protease, the aspartic acid tart is correct, the polyprotease has a need to collect the smear of the virus Aspartame is a drug in antiviral therapy. On the other hand, HIV protease is a kind of anti-shear compound mTRT, AlDS patients with a serotonin inhibitor (PIS), and #j, such as a complex reversal transcriptase inhibitor non-nucleoside reverse transcriptase inhibitor Class (NNTRIs) or other protease inhibitors, regardless of the fact that these antiretroviruses are extremely useful, this paper scale applies to Chinese specifications (21〇χ297 91170a 1325783 A7 V. Inventions (2) 10 15 Ministry of Economics Intellectual Property Bureau employees' consumption cooperatives print 20 ^ have a common limitation, that is, the hormones that are set as targets in the HIV virus can be mutated to make known drugs become less effective, even for the second to fight against these mutations. The HIV virus, or, in other words, the mv disease, the drug that can be obtained by the mother can produce a more resistant person. The resistance of the anti-retroviral (and especially HIV) anti-inhibitor is the main cause of the failure of the second treatment, for example, Half of the patients who received the anti-Ηΐν age therapy did not respond adequately to the treatment. The virus was mainly used for one or more of the viruses. The virus was also resistant. Individuals who enter the new sense of wood, resulting in the selection and treatment of these newly infected patients are quite affected by the younger brother J', in this art it is necessary to seek new compounds for retroviral therapy, especially for the treatment of AIDS, in the art The need is particularly eager to find a person who is active not only against the wild type ΗIV virus but also the increased resistance HI v virus. The known antiretroviral drugs (antiretrovirais), often administered by mixed therapy, ultimately lead to The aforementioned resistance, which often forces the physician to supplement the plasma value of the active drug so that the antiretroviral drug regains effectiveness against the mutated HIV virus, thus causing a highly unnecessary pill burden. The amount of plasma also leads to an increased risk of unrecognized prescription therapy, so compounds are important not only for the development of a wide range of HIV variants, but also for the activity against mutant strains in a wide range of HIV variants. The difference in activity against the wild-type HIV virus (also defined as fold resistance or FR) should be small or absent, so HIV virus becomes sensitive to the opportunity for the active ingredient to increase in the patient such that the same combination therapy regimen may be applied for a long time. -4- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) β Packing line 1325783 A7 B7 V. Invention description (3) 10 15 If the treatment level is kept to a minimum, due to the pill burden looking for the wild Type and a wide variety of mutants with high potency compounds 乂, and, very importantly, one way to reduce the burden of such pills is to seek antibiotics for the availability of sputum, ie, with a good pharmacokinetic plate = , In addition, the daily _# can be minimized. _ The number of pills is reduced. Another important feature of the anti-HIV compound is that the inhibitory enzyme binding has little or no effect on its efficacy. Plasma egg, there is a great medical need for protease inhibitors, which can be minimally different in multiplex resistance, has good bio-sufficiency and is less affected or not combined with plasma proteases. HIV strains that are affected by the spectrum of efficacy. To date, many protease inhibitors have been sold or developed, and a particular core structure (described below) has been disclosed in many references, for example, WO 95/06030, WO 96/foot 2287 WO 96/28418 'W 96/28463 ' WO 96/28464 'WO 96/28465 and WO 97/18205, the compounds disclosed therein are referred to as reverse transcription protease inhibitors. Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 20

WO 99/67254 discloses reverse transcription which inhibits multiple drug resistance. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) t 41

1325783 A7 B7 V. Description of the invention (〇 Viral proteases 4-substituted-stupyl sulfonamides)

10 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 Surprisingly, the 2-(substituted amino)-benzothiazole sulfonamides of the present invention were found to have quite good pharmacological and pharmacological effects. Profiles that are not only resistant to wild-type HIV but also to a wide range of mutant HIV viruses that are resistant to known protease inhibitors. Although some of the 2-(substituted amino)-benzothiazole sulfonamides of the present invention appear to be included in the general descriptions described in some of the above mentioned patent publications, they are not specifically disclosed as 'implicit or It is advocated that it can stimulate the induction of the artisan to design it as a broad-spectrum protease inhibitor. The present invention relates to a 2-(substituted amino)-benzothiazole protease inhibitor having the chemical formula r2 〇h r4 vtA-, (i) with its N-oxides, salts, stereoisomers, racemic mixtures, The paper scale applies to the Chinese National Standard (CNS) A4 specification (2丨〇χ 297 mm) 1325783 A7 B7 5. Inventions (5) Agents, esters and metabolites, among which

Ri and R·8 are each independently hydrogen, Ck alkyl, C2·6 alkenyl, aryl q 6 alkyl 'C3·7 cycloalkyl, C3.7 cycloalkyl Ci-<5 alkyl, Aryl, Het1, Het1 Ci-6 alkyl, Het2 or Het2 Cm alkyl; 5 R! may also be a group of the formula 10

(Π) ά 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 R9, RlOa and Ri〇b are independently hydrogen, Cm alkoxycarbonyl 'slow base, aminocarbonyl, mono- or di(Cw alkyl) An aminocarbonyl group, a c3.7 cycloalkyl group, a C2-6 alkenyl group, a C'2-6 alkynyl group or a Cw alkyl group, which are optionally substituted by an aryl group, Het1, Het2, C3-7 Cycloalkyl, Ci.4 alkoxy group, fluorenyl, amino group, mono- or di(Cl·4 alkyl)amine-based prison group, amine aryl group, CN4 alkyl group s (o a t, a thiol group, a cyano group, a halogen or an amine group optionally bearing one or two of the following substituents: CN4 alkyl, aryl, aryl Cm alkyl, C3-7 cycloalkyl, C3-7 ring a pyridyl C丨-4 alkyl group, Het1, Het2, Het1 C丨-4 alkyl group and Het2 Cm alkyl group; wherein R9, Ri〇a and a carbon atom bonded thereto can also form a C3-7 cycloalkyl group § L is -0-〇1.6, burning diyl-C(=0)- or -NRs-Ck, burning diyl·C(=0)-, R9 can also be _yl (〇乂〇); Paper scale post + s @家标准(CNS)A4 Specification (210x297 mm) 1325783 A7 B7 V. Description of invention (6)

Rlla is a gas, a C2-6 fine group 'C2-6 block group, a C3.7 cycloalkyl group 'aryl group, an aryl Ci-4 group, optionally a mono- or disubstituted aminocarbonyl group, optionally Mono- or disubstituted amino Cm alkyl-carbonyloxy, C^-4 alkoxy, aryloxy, Het1 oxy, Het2 oxycarbonyl, aryloxycarbonyl C-4 alkyl, An aryl Cm alkoxy group, a Ci_4 alkyl group 'C3-7 cycloalkyl group, a C3-7 cycloalkyl Cm alkoxycarbonyl group, a c3-7 cycloalkylcarbonyloxy group, a carboxy Cm alkylcarbonyloxy group, Cm alkylcarbonyloxy, aryl CN4 alkylcarbonyloxy, arylcarbonyloxy, aryloxycarbonyloxy, Het1 carbonyl, Het1 carbonyloxy, Het1 Cm alkoxycarbonyl, Het2 carbonyloxy, Het2 The Cm alkylcarbonyloxy group, the Het2CM alkoxycarbonyloxy group or the CM alkyl group is optionally substituted with an aryl group, an aryloxy group, a Het2, a hydroxyl group or a hydroxyl group; wherein the substituents on the amine group are independently selected From: Ci-4, aryl, aryl Ci_4, C3-7 cycloalkyl, c3.7 ring-based Cm alkyl, Het1, Het2, He? (pM alkyl and Het (Ι; ι; ·4 burning base; Ministry of Economic Affairs, Intellectual Property Bureau, Consumer Cooperatives, Printing 20

Riib is hydrogen, C3-7 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, C, -6 alkoxycarbonyl, Het1, Het2 or CU4 alkyl, optionally via the following groups Substitution: anion, hydroxy, Cl.4 alkyl S(=〇)t, aryl, C3-7 cycloalkyl, Het1, Het2, an amine group optionally having one or two substituents: C|· 4-alkyl, aryl, aryl C, ·4 alkyl, C3_7 cycloalkyl, c3.7 cycloalkyl q 4 alkyl, Het1, Het2, Hed Cm alkyl and Het2 (: 丨.4 alkyl; Wherein Rllb can be bonded to the remainder of the molecule via a sulfonyl group;

1325783 A7 B7 V. INSTRUCTIONS (7) Each independent t is 〇, 1 or 2; R2 is hydrogen or Ck alkyl; L is -c(=o)-, -〇-C(=〇)-,- Nr8-c(=o)-, -O-Cw alkanediyl-C(=0)-, -NRs-C^ alkanediyl-C(=0)-, -S(=0)2-'0 -5 S(=0)2-, 8-8(=0)2, wherein the C(=0) group or the S(=〇)2 group is attached to the NR2 moiety; and the alkanediyl moiety is selected Disubstituted with aryl, aryl Cw alkyl, (: 3-7 cycloalkyl, c3-7 cycloalkyl cM alkyl, Het1, Het2, Het1 Cm alkyl and Het2 Ci.4 alkyl; R3 is Cy alkyl, Aryl, c3.7 cycloalkyl, C3.7 cycloalkyl Cw alkyl 10 or aryl Cm alkyl; I is hydrogen, cM alkoxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Cw alkyl) An aminocarbonyl group, a C3_7 cycloalkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group or a Cy alkyl group, which is optionally substituted by an aryl group, Het1, Het2, C3_7 cycloalkyl group, Q_4 alkane Oxycarbonyl group, carboxyl group, aminocarbonyl 15 group, mono- or di(Cw alkyl)aminocarbonyl group, aminosulfonyl group, (^_4 alkanes Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing base s (=o ) t 'hydroxy, cyano, halogen or alternatively one or two of the following Substituted amine group: Cw alkyl, aryl, aryl (^-4 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl CM alkyl, Het1, Het2, HedCM alkyl and HefC alkyl 20 A is CN6 alkanediyl, -C(=0)-, _C(=S)_, -S(=0)2-, Cm alkanediyl-C(=〇)-, C〗 _6 alkane Diki-C(=S)- or Cw alkanediyl-S(=0)2-; wherein the junction with the nitrogen atom is the Ci-6 compound diyl group of those containing a Cm alkanediyl group; R5 It is hydrogen, hydroxyl, c, _6 alkyl, HePc^ alkyl, HefCa alkyl, -9- This paper scale applies Chinese National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 B7 V. Invention description (ο The amine group may optionally be an amine Cm thio group having one or two CM alkyl substituents; R6 is a Ci-6 alkoxy group, Het1, Het1 Ο, fjet2, Het2 〇, aryl, aryloxy or amine group; And if -A- is different from cK6-sintered base, then 6 and 5 may be Ci-6 alkyl, Hettw fluorenyl, Heti〇Ci4 alkyl 'Het Cm alkyl, Het2OC丨-4 alkyl, aromatic a base q 4 alkyl group, an aryloxy Cm group or an amine group; wherein each of the amine groups in the definition of & is optionally substituted - a substituent selected from the group consisting of Cm-burning , Cm is fired several yl group 'Cl.4 group burning several group, an aryl group, an aryl group several groups 10, aryloxycarbonyl, Het1, Het2, Off A 0 ^ ^,

, a square CM alkyl group, a HePCM alkyl group or a HefC alkyl group; and R5m. may also form a fine or a nitrogen atom bonded thereto. According to one of the specific examples, the present invention relates to a 2((substituted amino)-benzothiazole protease inhibitor of the formula (1), and i, an emulsifier, a scent, a 15 stereoisomer, a racemic mixture, a former Agents, brewings and metabolites ^ and R8 are independently hydrogen, cU6 alkyl, c,,, fluorene 2-6, lysine, alkyl, C3-7 cycloalkyl, c3_7 naphthenic This is the HetiCl.6 yard base, Het2, Het2Ci 6 alkyl group; the square soil R! can also be a group of the following formula ' 20 tviua v (Π) Χΐ RUb R9 Among them -10- the paper scale applies to the Chinese national standard (cns) A4 specification Q丨π7 public love) 1325783 A7 B7 V. Invention description (9) R9, ulnar and R1 () b are independently hydrogen, Cm alkoxy a carbonyl group, a carboxyl group, an aminocarbonyl group, a mono- or di(Cw alkyl)aminocarbonyl group, a C3-7 cyclohexyl group, a C2-6 group, a C2-6 group or a Ci.4 group, optionally Substituted by the following groups: aryl, Het1, Het2, C3_7 cycloalkane 5, <^_4 alkoxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci_4 alkyl)amino group, amine group continued Brewing base, Ci_4 An alkyl group of (o)t, hydroxy, cyano, halogen or optionally having one or two substituents: CN4 alkyl, aryl, aryl Cm, C3-7 cycloalkyl, C3 -7 cycloalkyl group C1-4, Het1, 10 Het2, Het1 Cm alkyl and Het2 Cm alkyl; wherein R9,

R10A and a carbon atom to which they are bonded may also form a C3_7 cycloalkyl group;

Rlla is murine, C2-6 dilute, C2-6 fast radical, C3-7 bad alkyl, aryl, optionally mono- or disubstituted aminocarbonyl, optionally mono- or disubstituted amine Cm alkylcarbonyloxy, Cw alkoxycarbonyl, 15 aryloxycarbonyl, Het1 oxycarbonyl, Het2. oxycarbonyl, aryl-based carbonyl economic ministry intellectual property staff consumption cooperative printing base C!·4 burning base , aryl CU4, oxyalkyl, Ci.4 alkyl, C3,7 cycloalkylcarbonyl, C3-7 cycloalkyl Cm alkoxycarbonyl, 'CP cycloalkylcarbonyloxy, carboxy CU4 alkane Carbocarbonyloxy, Cm alkylcarbonyloxy, aryl Cw alkylcarbonyloxy, arylcarbonyloxy, 20 aryloxycarbonyloxy, Het1 carbonyl, Het1 carbonyloxy, Het1 CN4

Alkoxycarbonyl, Het2carbonyloxy, Het2 CU4 alkylcarbonyloxy, Het2^4 alkoxycarbonyloxy or Cm alkyl optionally substituted by aryl, aryloxy, Het2 or hydroxy; The substituents on the amine group are independently selected from: CN4 alkyl, aryl, aryl cM -11- This paper scale applies to China National Standard (CNS) A4 specification (2ι〇χ297 public) 1325783 A7 B7 V. (10) an alkyl group, a C3-7 cycloalkyl group, a C3.7 cycloalkyl Cw alkyl group, a Het1, a Het2, a Het1 Cm alkyl group, and a HefCM alkyl group;

Rllb is hydrogen, C3.7 cycloalkyl, C2_6 alkenyl, C2_6 alkynyl, aryl, Het1, Het2 or C-4 alkyl, which is optionally substituted for 5 generations by halogen, hydroxyl, Cm Alkyl S(=0)t, aryl, C3_7 cycloalkyl, Het1, Het2, an amine group optionally having one or two substituents: C丨-4 alkyl, aryl, aryl Cm alkyl , C3.7 cycloalkyl, C3-7 cycloalkyl Cw alkyl, Het1, Het2, Het1 Cm alkyl and Het2 Cw alkyl; - 10 wherein Rnb can be bonded to the remainder of the molecule via a sulfonyl group; Each independent t is 0, 1 or 2; R_2 is nitrogen or Ci_6 alkyl; L is -C(=0)-, -0-C(=0)_, -NRg-CpO)-.-,.. -0-01.6 Burning two. Base ~ 0 (= = 0) -, -NRs_Ci.6 Burning two base - C (=0) -, -S (=0) 2 ·, -0_ 15 s (= o) 2 -, -nr8-s(=o)2, where ..c(=o) or ~.s(=o_)2 is attached to the NR2 moiety; R3 is C^6 alkyl, aryl, c3. 7-cycloalkyl, c3_7 cycloalkyl cN4 alkyl or aryl Ci.4 alkyl; Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative printed R4 is hydrogen, CU4 alkoxycarbonyl, carboxyl, aminocarbonyl, mono- or Bis(Cl 4 2〇alkyl)aminocarbonyl, C3.7 cycloalkyl 'C2_6 alkenyl, c2_6 alkyne a group or a Q.6 alkyl group which is optionally substituted by an aryl group, Het1, Het2, C3-7 cycloalkyl 'Cm alkoxycarbonyl group, a carboxyl group, an aminocarbonyl group, a mono- or a di- (Cm) Alkyl)aminocarbonyl, aminosulfonyl, Cm alkyl s(=o)t, thiol, cyano, halogen or alternatively one or -12- this paper scale applies to Chinese National Standard (CNS) A4 Specification (210x297 public) 1325783 Α7 Β7 V. Description of the invention (11) Amino group substituted by two substituents: C1-4 alkyl, aryl, aryl Cw alkyl, C3_7 cycloalkyl, C3_7 cycloalkyl Cm alkyl, Het1, Het2, HedCM alkyl and HefCM alkyl; A is Cw alkanediyl, -C(=0)-, -C(=S)-, -S(=0)2-, C, -6 alkanedi-5yl-C(=0)-, CN6 alkanediyl-(:(=8)- or Cu alkanediyl-S(=0)2-; wherein the contact with the nitrogen atom is those Cw alkylene group of Cw alkanediyl group; R5 is hydrogen, hydroxy, Ci_6 alkyl, HePCw alkyl, hWCk alkyl, amine group Cm 10 alkane whose amine group may optionally have one or two alkyl substituents R6 is Cw alkoxy, Het1, Het1 oxy, Het2, Het2 oxy, aryl, aryloxy or amine; and if -A- is different In the case of CN6 alkanediyl, then R6 may also be CN6 alkyl, HedC^alkyl, HePOC^alkyl, HefC^alkyl, HefOCM alkyl, aryl Cm alkyl, aryl15 oxy CV4 alkyl or amine a Cm alkyl group; wherein the Ministry of Economic Affairs Intellectual Property Office employee consumption cooperative in the definition of R6: is optionally substituted with one or more substituents selected from the group consisting of: Cw alkyl, Cw alkyl Carbonyl, Cw alkoxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1, Het2, aryl CN4 alkyl, HetCw alkyl or Het2Ci_4, and 20 Rs together with -A-R6 Its nitrogen atom can also form Het1 or Het2. The present invention also contemplates the quaternization of the nitrogen atom of the present compound. The basic nitrogen can be quaternized using any reagent known to those skilled in the art, for example, using lower alkyl halides, dialkyl groups. Sulfates, long chain halides and aralkyl functionals. -13- t _ Specifications (Do not χ 297 public Chu) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1325783 A7 B7 V. Description of invention (12) For the definition of the term "substitution" in the compound of formula (I) It is meant that one or more hydrogen atoms on the atom shown are selected to be replaced by the indicated group, as long as the normal valence of the atom shown is not exceeded and a chemically stable compound is produced after the substitution, it is obtained from the mixture. Free of isolated pure substances, and 5 can be formulated into therapeutic agents. The term "halo" or "halogen" as used in a group or group refers to what is commonly referred to as fluorine, gas, bromine or iodine, etc. "(^_4 alkyl) refers to having 1 to a linear or branched saturated hydrocarbon group of 4 carbon atoms, such as a methyl group, an ethyl group, a propyl group, a butyl group, a 2-mercapto-propyl 10 group, etc. "C^alkyl group" means having 1 a linear or branched saturated hydrocarbon group of up to 6 carbon atoms, such as a group under the definition of a CN4 alkyl group, a pentyl group, a hexyl group, a 2-methylbutyl group, a 3-decylpentyl group, etc. "Cm alkanediyl group" "" refers to a divalent straight chain or a 15 branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as a methylene group, a group, an ethyl group, a 1,2-a group, a ... -diyl, propyl-1,2-diyl, butane-1,4-diyl, indole-1,5-diyl, hex-1,6-diyl, 2-mercaptobutyl-1,4- Diyl, 3-mercapto-1,5-diyl, etc. "C2_6 alkenyl" refers to a straight or branched hydrocarbon group having from 2 to 6 carbon atoms containing at least one double bond, such as ethylene. a base 'propenyl, butenyl 20, pentenyl, hexenyl, etc. "C2_6 alkynyl" means 2 to 6 having at least one triple bond a linear or branched hydrocarbon group of an atom, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. "C3_7 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclo Pentyl, cyclohexyl-14-

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 B7 V. Description of invention (13) or the general name of cycloheptyl. "Aryl" means a group comprising a phenyl group and a naphthyl group, both of which are optionally substituted with one or more substituents each independently selected from the group consisting of C丨-6 alkyl, cU6 alkoxy, A dentate, a hydroxyl group, optionally a mono- or disubstituted amine 5 group, a nitro group, a cyano group, a halogen C, a -6 alkyl group, a carboxyl group, an alkoxycarbonyl group, a c3_7 cycloalkyl group, Het1, optionally Or a disubstituted aminocarbonyl group, optionally a mono- or disubstituted amino group CN6 alkyl group, an anthracene group, a methylsulfonyl group, and optionally substituted with one or more substituents selected from the group consisting of Phenyl group: Cw alkyl group, cN6 alkoxy group, dentate, hydroxyl group, optionally mono- or di-substituted amine group, nitro group, cyano group, dentate Cm alkyl group, carboxyl group 'Cw alkoxycarbonyl group, C3.7 cycloalkyl, Het1, optionally mono- or disubstituted aminocarbonyl, sulfonylthio and methylsulfonyl; wherein the amine functionally selected substituents are independently selected from Ci_6 alkyl, Ck alkylcarbonyl, Ci-6 alkoxy-A-, Heti-A-, Het1 Ci-6 alkyl, HePCu alkyl-A-15, Het1 oxygen-A-, Het丨 oxygen Ci_4 alkane phenyl-A-phenyl-A-, stupid-oxygen A_ Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed, this oxy Cm alkyl-A-, phenyl C!_6 alkyl-A-, Ci-6 alkoxyamino-A-, amine- A-, an amino Cm alkyl group and an amine group CN6 alkyl group _A_, wherein each amine group is optionally substituted with one or possibly a CM alkyl group and wherein A is as defined above. 20 "Halogen Ci.6 alkyl", meaning that a Cw alkyl group as defined is substituted with one or more halogen atoms, preferably a gas or fluorine atom, more preferably a fluorine atom, preferably a dentate C, The _6 alkyl group includes, for example, a trifluoromethyl group and a difluoromethyl group. The term "Het1" means having 3 to 14 ring atoms (preferably having from 10 to 10 ring atoms, and more preferably having 5 to 8) Saturated or -15- of this ring atom is applicable to China National Standard (CNS) A4 specification (210 X 297 public) 丄 y/83 A7 V. Invention description (14) Partially unsaturated single ring a bicyclic or tricyclic heterocyclic ring having a ring atom containing one or more heteroatoms selected from nitrogen, oxygen or sulfur and optionally having the following substituents on one or more carbon atoms: cN6 alkyl , cN6 alkoxy, dentate, hydroxy, keto, optionally mono- or disubstituted amine, nitrate 5 A, cyano 'n-c-C alkyl -6 alkyl, carboxyl, c -6 Alkoxycarbonyl, C3 7 per alkyl, optionally mono- or disubstituted aminocarbonyl, optionally mono- or disubstituted amine C1-6 alkyl, methylthio, methylsulfonyl, aryl Base and a saturated or partially unsaturated monocyclic, double or tricyclic heterocyclic ring having from 3 to 14 ring atoms containing one or more heteroatom atoms selected from nitrogen, oxygen or sulfur and at any of the amine groups The substituents selected on the functional group are each independently selected from the group consisting of Cw alkyl, Cw alkylcarbonyl, Cl-6 alkoxy-8, Het2-A-Het2 Cyalkyl, HefCw alkyl- A-, Het2 oxygen-A_,

Het oxy-Cm-alkyl-A-, aryl-A-, aryloxy-oxime, aryloxy (^14-burning group Ci·6-based-A-, Ci·6 alkoxyamino group Amino- 15 A-, amino Cw alkyl and amino Cw alkyl-A-, wherein each amine group may be selected; or may be disubstituted with Ci·4 alkyl and wherein a is as defined above 0 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed

The term "Het2" refers to a bicyclic or tricyclic heterocyclic ring having from 3 to 14 ring atoms (preferably having from 5 to 10% by atom, and more preferably from 5 to 10 ring atoms) of an aromatic monocyclic ring. a ring having ring atoms containing one or more heteroatoms selected from nitrogen, oxygen or sulfur and optionally having the following substituents on one or more carbon atoms: Cw alkyl, Ci0 alkoxy, halogen, hydroxy Optionally, mono- or di-substituted amine group, nitro 'cyano group, dentate Ci6 alkyl group, carboxyl group, ci-6 alkoxycarbonyl group, C3·7 cycloalkyl group' ___ -16- ΐ paper scale suitable for wealth Uj standard cns) a4 specifications (2) tear public Chu -- 1325783 A7 B7 five, invention description (alternative aminocarbonyl, selective mono- or disubstituted amine c丨-6 alkyl, methylthio, methylsulfonyl, aryl, Het1 and an aromatic monocyclic, bicyclic or tricyclic heterocyclic ring having 3 to 14 ring atoms; selected on any of the amine functional groups The substituents are each independently selected from the group consisting of: Cl.6 alkyl, 5 C -6 carbonylcarbonyl, Ci.6 methoxy-A-, HeP-A-, HePCu alkyl,

HedCw Alkyl-A-, Het1 Oxygen-A-, Het1 Oxygen C "4 alkyl-A-, aryl-A-, aryloxy-A-, aryloxy CK4 alkyl _A_, aryl Cl 6 alkyl-A-, Cu alkoxycarbonylamino-A-, amino-A-, amino cN6 alkyl and amine Ci6 alkyl-A-, wherein each amine group is optionally subjected to one or It may be disubstituted with 10 Cw alkyl and wherein hydrazine is as defined above. In the present specification, (=0) represents a moiety which combines with a carbon atom to form a carbonyl group. As described in the specification: one or more "covers all The possibility of a C-atom that can be utilized, if appropriate, is replaced by two or three. 15 When any variable (such as halogen or CN4 alkyl) is present in more than one component of any composition, the definitions are independent. Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives Printed in this manual, "pre-agents" represent pharmaceutically acceptable derivatives, such as esters, guanamines and phosphates, which are biotransformed in vivo. Derived as an active drug defining a compound of formula (1), by G. Dman and 2 〇 Gilman (The Pharmacological Basis of Therapeutics, 8 ed, McGraw-Hill, Int, Ed. 1992, "Biotransformation of Drugs", The prodrugs described in p 13-15) are generally incorporated by reference, and the prodrugs of the present invention are prepared by modifying the functional groups present in the compound such that the modifications are carried out under normal routine operations or in vivo. Is broken into the original compound, the pre-agent -17- This paper scale applies to the national standard (CNS) M specification (10) x 297 public Chu) 1325783 A7 B7 V. Description of the invention (including the hydroxyl group of the compound of the present invention (for example, The hydroxy group or the amine group on the asymmetric carbon atom is bonded to any of the groups, and when the current agent is applied to the patient, it will break apart to form a free hydroxyl group or an amine group, respectively.

Examples of typical tanning agents are disclosed, for example, in WO 99/33795, WO 5 99/33815, WO 99/33793 and WO 99/33792, all of which are incorporated herein by reference. Prodrugs are characterized by excellent water solubility, increased bioavailability, and the ability to metabolize into active inhibitors in vivo. For therapeutic use, the salt of the compound of formula (1) is pharmaceutically acceptable or physiologically acceptable, however, salts which are not pharmaceutically acceptable may also be used, for example, for the preparation or purification of pharmaceutically acceptable formulas. (1) In the case of a compound, all salts, whether pharmaceutically acceptable or not, are encompassed within the claims of the present invention. The Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives can produce pharmaceutically acceptable or physiologically acceptable 15 added salt forms which can be formed by the compounds of the present invention. It can be conveniently prepared using suitable acids, for example, using inorganic acids such as hydrohalic acids. (such as hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, acid and other acids; or use organic acids such as acetic acid, propionic acid, transacetic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, acid , cis-succinic acid, fumaric acid, malic acid 'tartaric acid, citric acid, methyl 2-sulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-methylsulfonic acid, sulfonic acid, salicylic acid An acid such as p-amino-salicylic acid or pamoic acid. Conversely, the acid addition salt form can be converted to a free salt ground state by treatment with a suitable base. Compounds of formula (I) containing acidic protons, via appropriate organic or inorganic bases - 18 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 B7 V. Description of invention (17) After treatment, it can also be converted into its non-toxic metal or amine addition salt form. Suitable salt types include, for example, salt, metal and soil metal salts such as lithium, sodium, potassium and magnesium. Calcium salts and the like, and salts formed with organic bases, such as benzathine, N-methyl '-D-glucosamine, hydrabamine salts, and amino acids ( For example, salts formed by arginine, lysine, and the like. Conversely, the base addition salt form can also be converted to the free acid form by treatment with a suitable acid. The term "salt" also encompasses hydrates and 10 solvates which the compounds of the invention can form, such examples including, for example, hydrates, alcoholates, etc. The N-oxide form of the compounds of the invention is meant to include formula (1). The one or several nitrogen atoms in the compound are oxidized to the so-called N-oxide. The compounds of the invention may also exist in the form of their racemic mixture, which is not indicated in the above chemical formula, but still It is encompassed within the scope of the present invention. The stereoisomeric form of the compound of the present invention referred to in the text of the present invention is that the compound of the present invention may be secretly different from the same atom by the same sequence. All possible compounds of the second-order spatial structure, at or after the K, include all possible isoforms of the compound that may be present, and the mixture may contain all of the compounds Non-mirror and/or mirror phase of the knive structure, the inventions of the invention are all ===: type 'in a pure state or are mutually fused 5, the purity of the compounds and intermediates mentioned in the oxime Stereoisomeric (210x 297 mm) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed 20 1325783 A7 B7 V. INSTRUCTIONS (is 10 15 20 (4) means that these isomers do not contain substantially the same properties as the compounds or intermediates. The mirror image or diastereomeric form of the basic molecular structure, in particular, "stereoisomerically pure, with respect to having at least 80% of a certain stereoisomer (ie, at least 9G% of which is heterogeneous) More preferably, only up to 10% of the other possible isomers are present, or more than the compound or intermediate of the competent (ie, 100% of the isomers and no other isomers), more preferably, The compound or intermediate is from more than 9% to up to (10) ❶乂, or more preferably, the stereoisomer exceeds 94% up to, and optimally has more than 97% up to 丨(9)% , 'Samely, the so-called "environmental pure state, and, and the diastereomeric pure state, that is, the "enantiomers," and "diastereomers", respectively, are dominant. To the extent that the compound of the present invention is pure and stereoscopic with the intermediate The construct can be prepared by a known procedure, for example, the enantiomer can be obtained by selectively crystallizing the diastereomeric salt formed by the optically active acid, or the enantiomer can be made using an asymmetric EJ. The chromatographic technique of the phase is isolated, and as long as the reaction can occur stereospecifically, the pure stereoisomer of the stereochemistry can also be derived from a suitable starting material of the pure stereoisomer, preferably, such as There is a need for: stereoisomers, which will be synthesized by stereospecific preparation, so that these methods will be carried out in the form of a homogenous starting material. The diastereomeric racemic isomer of formula (1) can be used. It is prepared by a conventional method, and a suitable physical separation method for breaking application is, for example, selective crystallization disk chromatography, that is, column chromatography. 〃 It is apparent to those skilled in the art that the compound of the formula (1) is contained. At least one asymmetric center and therefore its existence of different stereoisomers, this asymmetry in the loading. Line I___ -20- This paper ruler @家标 rI325783 A7 B7 V, invention description (I9) In the following figure

The absolute configuration of the asymmetric centers that may exist in the compound of formula (I) is not labeled as the R and S configurations. The labeling of R and s is based on the disclosure of the Ministry of Economic Affairs' Intellectual Property Office employee consumption cooperative. Rule: Pure APP1_Chem. 1976, 45, 11-30, and, *,, the labeled carbonogen 10 preferably has an R configuration. The present invention also encompasses the presence of isotopic atoms in the compounds of the present invention. The isotopes include those having the same atomic order but different mass numbers, and are generally used in the general case of non-P艮, and the gas isotopes include gas and gas. Broken isotopes include C-13 and C-14. After that, the compound of the formula (1), or the betate of the invention or the like, is intended to include a compound of the formula (I), an N-oxide, a salt, a stereoisomer, a racemic mixture, an anionic agent. , esters and metabolites, as well as their quaternary nitrogen homologues. Particularly preferred compounds are those of formula (I) wherein one or more of the following are subject to the following specifications: cardio, Het1, Het2, aryl, Heti Cl_6 alkyl, Het2 Cl_6 alkyl, aryl L-filament, More preferably Ri, a saturated or partially unsaturated monocyclic or bicyclic heterocyclic ring having 5 to 8 ring atoms, which contains one or more heteroatoms selected from the group consisting of nitrogen, oxygen or sulfur and which are selected地-21- This paper scales the appropriate financial standard (CNS) A4 specifications (2丨Q χ 297 public love---------- invention description (20) A7 B7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing An aromatic single earth having one or more groups, optionally having 5 to 6 ring atoms, or one or more selected from nitrogen, oxygen or each having - or (d) carbon Field filament recording = selectively in a ring atom U ring _ take shape = one or more carbon atom field has a substituent; a hetero atom and optionally in R 丨 la is a hydrazine, a pyroxy group; Rnb is a Cm alkyl group optionally substituted with an aryl group; 10 R2 is hydrogen; L is -C (which, ·〇_〇: (, _, ·6 6 nc (which code _ -6-6-yl-C-C) (Which, better, L is _c(=〇)_, -o-ch2-c (= each of the c<=〇) of the 〇k is attached to the % moiety; R3 is an aryl group "4 alkyl, especially an arylmethyl group, more preferably a phenylmethyl group;仏 is a selectively substituted Cl.6, especially a Cw group substituted with an aryl group, Hetl, Het2, c3 7 cycloalkyl or alternatively substituted with one or two of the following groups Amino group: C14 alkyl group, aryl group, Het1 and Het2; A is C -6 alkanediyl group, -(:(=〇)_ or Q-6 alkanediyl-c(=〇)_, in particular , A is methylene, 1,2-ethanediyl, iota, 3-propanediyl, _c(=〇)_ or _CH2-C(=0)-; R5 is hydrogen, Cm alkyl, HedCy alkane The base 'amino C,.6 alkyl, wherein the amine group is optionally substituted by one or two CN4 alkyl groups; 5 6 15 20 -22- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 public) PCT) 1325783 A7 B7 V. INSTRUCTION DESCRIPTION (21) R6 is Ci-6 alkoxy, Hetl, aryl, amine; and if -A- is different from CN6, R6 may also be Ci. 6 alkyl, HetiCw, aryloxy Cm thio or amino-based Ci-4 ray; wherein each amine group is optionally substituted; or 5 115 and - 八-116 - Hetl can also be formed with a nitrogen atom bonded thereto. A more specific compound is a compound of the formula (1), wherein Ri is Het1, aryl, Het2 Ci-6 炫; rule 2 is hydrogen; L is -C(=〇)_ , -〇-C(=0)-, -〇_ch2-c(=o)-, wherein each c(=0) group is attached to the NR2 moiety; R3 is a phenylmethyl group; and R4 is Ci- 6 yard base. 10 is also a particularly preferred compound of the formula (1) wherein A is (^.6 alkyldiyl or -C(=0)-; R5 is hydrogen, methyl, Hettw alkyl, amino Ck alkyl, Wherein the amine group is optionally substituted with one or two CV4 alkyl groups; R6 is a Cu6 alkoxy group, Het1, an amine group; and if -A- is a CN6 alkanediyl group, then R6 may also be a CN6 alkane. Base, He^C^alkyl or amine Cw alkyl; 15 wherein each of the amine groups is optionally substituted... A group of compounds of the formula (I) that are printed by the Ministry of Economic Intelligence's employee property cooperatives. Wherein -A- is carbonyl and r6 is aryl, HedC^alkyl, aryloxy CN4 alkyl or amine CM alkyl, wherein the amine group is optionally substituted; or -A- is a carbonyl group, CM alkyl and R·5 are Hett!·6 alkyl or amine Cu6 alkyl, wherein the amine group may be substituted with one or two alkyl groups. Other preferred group of compounds are compounds of formula (I). Wherein -A- is Ci.6-based and R.6 is an amine group and Het1; wherein the amine group is optionally substituted with one or two CU4 alkyl groups. Other preferred group of compounds are formula (1) a compound in which the cockroach is - 23- This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 public). 5. Inventive Note ( , , > alkyl, C2.6 alkenyl, aryl Ci 6 wire, C3 7 ring alkyl a 3-7-based Cl 6 filament, an aryl group, a g6 county, a w, a group, wherein Heti is a saturated saturated monocyclic heterocyclic ring having 5 to 6 ring atoms, which contains one or more selected from a hetero atom in nitrogen, an oxygen atom, and optionally a substituent on one or more carbon atoms. Other advantageous group of compounds are those compounds of formula (1) wherein L is -O-Ck alkanediyl _ c(=〇)_. 10 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 Other beneficial group of compounds are those of formula (1), where A is CK6 alkanediyl, -(:(=〇) _ or c "6-alkylenediyl-c(=〇)_; wherein the point to the nitrogen atom is the Ck-sintering group at those sites containing the group;

Rs is hydrogen, Cw alkyl, HePCu alkyl, Het2CV6 alkyl, amine

a Cue alkyl group, wherein the amine group is optionally substituted with one or two ci 4 alkyl groups; and if Α· is -C(=0)_, then r6 is a Ci 6 alkoxy group, Hetl, Hetl oxygen Or Het2oxy, aryl, HettM alkyl, Het1 oxy Cm alkyl, Hett.4 alkyl, Het2 oxy CM alkyl, aryl Cw alkyl, ^oxy Ci-4 alkyl or amine Ci- 4-alkyl; and if -A- is a Cl.6 dibasic group, then Re is an amine group, a cN6 alkoxy group, a Het1, a Het1oxy group or a Het2oxy group; and if -A- is a C.6 alkane When diyl-C(=0)-, then r6 is Cm alkoxy, Het1, Het1 oxy or Het2 oxy, aryl, Cl-6 alkyl, HetiCi 4 alkyl, Het1 oxy Cm alkyl, Het2CV4 Alkyl, Het2 oxy Cm alkyl, aryl Cm alkyl, aryloxy Cw alkyl or amine cM alkyl; • 24--paper scale applicable to China National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 B7 V. Inventive Note (23) wherein each of the amine groups defined in R6 is optionally substituted with one or more substituents selected from the group consisting of Cm alkyl, Cm alkylcarbonyl, Q_4 alkoxycarbonyl, aromatic Base, arylcarbonyl, aryloxycarbonyl, Het1, Het2, aryl Cm alkyl, HettM alkyl Or HefCM alkyl; and 5 R5 together with -A-R6 and the nitrogen atom to which it is bonded may also form Het1, wherein Het1 may be substituted by at least one oxo group, and the preferred compound is wherein L is - Ο-Ck alkanediyl-C(=0)- or -NR8-C1-6 succinyl _C(=0)- and Ri is a group of the formula

Among them, 15 R9 is a ketone group, printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative.

Ri〇a and Ri〇b, each independently, hydrogen or C, _4 alkyl optionally substituted by aryl, Het1, Het2, Cm alkoxycarbonyl, carboxy, aminocarbonyl, hydroxy; In the case of an amine group optionally substituted by one or two Cm alkyl groups, 20 Rlla is an aryl CN4 alkyl group, or a Ci_4 alkyl group optionally substituted by an aryl group or a halogen, and R11b is a nitrogen or a Ci-6 alkoxy group. Rebel. Also preferred are those wherein L is -O-Cualkyldiyl-C(=0)- or -NRs-Ck-alkanediyl-(:(=0)- and R is a group of the formula -25- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 B7 V. Description of invention (24)

5 wherein R9 is a ketone group,

RlOa and RlOb are hydrogen,

Rlla is an aryl Q_4 alkyl group in which the aryl group is substituted by dentate and R11b is hydrogen or a Ci_6 alkoxy group. 10 Other preferred compounds are those wherein L is -O-Cualkyldiyl-C(=0)- or -NRs-Cw-alkyldiyl-0:(=〇)- and R! is a group of the formula

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the Consumer Cooperatives, where R_9 is a sulfhydryl group, Ri〇a and RlOb are hydrogen, Rlla is m-fluorobenzyl and Rllb is hydrogen or a Ci_6 alkoxy group. Other preferred compounds are those wherein L is -O-Cw alkanediyl-C(=0)- or -NRs-Ckalkanediyl-(:(=0)- and the enthalpy is a group of the formula

-26- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 B7 V. Description of invention (Μ R9 is a ketone group, Rl〇a and RlOb are hydrogen, and R丨U is inter- Fluoroquinone and Rl 1 b are gas. Other preferred compounds are those in which L is _〇_Cl 6 alkanediyl NRs-C丨·6 alkyldiyl h is a group of the formula R|〇a, .R-1

(H) Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative 10 where ^ is _ group, Rioa and R1〇b are hydrogen, Rlla is m-fluorobenzyl and R丨丨b is a third butoxycarbonyl. Possibly, the compound of the present invention may comprise a chemically reactive site capable of forming a covalent bond at a confined position such that the compound has increased tissue retention and half-life, and the chemically reactive group means that a total A chemical group of a valence bond. A reactive group is usually a ruthenium in an aqueous environment and is usually a sulfhydryl group, a sulfhydryl group, or a convenient sulfhydryl group, present as a vinegar or a mixed anhydride, or a hydrazine. An amine ester, or a maleine quinone ester, and a monthly bond b forms a covalent bond with a functional group (eg, an amine group, a hydroxyl group, or a thiol group) at a target site (eg, a blood component). When required, the compound is capable of forming a covalent bond (e.g., interacting with a blood component) at a confined position such that the compound of the invention can have increased tissue retention and half-life, typically, the covalent bond formed should Can be maintained during the life of the blood component, unless it is in the released position, the main advantage of this new compound is that only a small amount can be used 15 20 to install the line -27- 1325783

Providing an effective effect, there is a reason for the subsistence to be set by the delivery target, a high-yield reaction between the reacted entity γ and the reacting functional group and an irreversible essential bond after the reaction, and further, the compound of the present invention Once it is bound to the membrane or on the tissue, it is not easily affected by the liver, the kidney is saturated and excreted, and even protected from the active decomposition of the protease (except peptidase), which leads to the elimination of bribes and acceleration. The “blood component” printed by the Ministry of Economic Affairs’ Intellectual Property Office employee consumption cooperative refers to a fixed or mobile money component. The fixed blood component is a non-moving blood component including tissue, membrane receptor, interstitial protein, Fibrin, collagen, platelets, endothelial cells, cells of the epidermis and their associated membranes and membrane receptors, somatic cells, bone and smooth muscle cells, nerve components, bone cells and surname bone cells and all body tissues, Especially those associated with the circulation and lymphatic system; the moving blood component is a blood component that does not stay in a fixed position for any extended period of time (usually no more than 5 minutes, more often no more than one minute). 15, these blood components are present in the blood for an extended period of time - but not associated with the membrane and present at a minimum concentration of at least !·! μg/ml, the moving blood components include serum albumin, Iron transfer proteins, ferritin and immunoglobulins, such as IgM and IgG, have a half-life of the mobile blood component of at least about 12 hours. 20 Compounds of formula (1) can generally be used in a manner similar to that disclosed below.

Preparation: WO 95/06030, WO 96/22287, wo 96/28418, WO 96/28463, WO 96/28464, WO 96/28465 and WO 97/18205. The specific reaction procedure for the preparation of the compounds of the invention is described -28- This paper scale applies to the Chinese National Standard (CNS) A4 specification (2i〇x297 mm) 1325783 A7 B7 V. Description of the invention (27 below, if necessary, The reaction product may be isolated from the medium and further purified by methods generally known in the art, such as extraction, crystallization, mashing, chromatography, and the like.

Chart A

,so> Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative

(a-8)

丨丨"々一NH

'N 2-Ethylamino-6-oxasulfonylbenzothiazole (intermediate a-2) was prepared according to the method described in EP-A-0,445,926, and the preparation of intermediate a-4 was -29- This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 _______B7_ V. Description of invention (28) Intermediate a-3 [Established in the method of w〇97/182〇5 and is also described In the diagram F] and the intermediate a_2, in the reaction_inert solvent (for example, methylene chloride), and in the presence of a test (such as triethylamine) and at low temperature (for example, the next reaction, intermediate a_3 The Boc group is a protected third-butoxycarbonyl group which is conveniently replaced by other suitable protecting groups (for example, quinone or phenoxycarbonyl); starting with the intermediate a_4 The material, the deprotection of the intermediate a-5 is carried out in an appropriate solvent (for example, di-methane) using an acid (for example, trifluoroacetic acid), and the resulting intermediate may further be combined with the formula RrL-(release group). Intermediate, with 10 selected 1-(3-methylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) in the presence of a base such as triethylamine or In the presence of an alcohol (for example, a second butanol), and reacting in a suitable solvent (for example, dichloromethylmethanone); thus forming an intermediate core 6, in particular, an intermediate of the formula Ri_c (=〇)_〇h is suitable Further reacting with the intermediate a_5. Alternatively, the intermediate a-4 can be deprotected with a strong acid (for example, hydrochloric acid in isopropanol) 15 in a suitable solvent (for example, a mixture of ethanol and dioxane). The middle of the a-7, the intermediate a_8 can be prepared according to the procedure similar to the description of the preparation of the intermediate a-6. The Ministry of Economic Affairs, the Intellectual Property Bureau, the employee consumption cooperative, printed with a moderate ruler paper) A- s) (CN Standard home

1325783 A7 B7 V. Description of invention (29)

Chart B

Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Employees' Consumption Co., Ltd. 20 Intermediate b-5 can be prepared according to the method described in Figure A. The aminobenzothiazole derivative b-5 can be deaminated, for example, using sodium nitrite in combination with phosphoric acid. Treatment, and treatment with copper sulphate and sodium sulphate, thus obtaining the intermediate b-6, then the intermediate b-6 can be combined with the intermediate of the formula RrL- (release) in a base (such as triethylamine ) and optionally existing EDC or alcohol (for example, the third -31- paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1325783 A7 B7 V. Description of invention (3〇)

Butanol), and reacting in a suitable solvent (eg dichloromethane) to form intermediate b-8, intermediate b-8 may further be combined with an amine of formula H2N-A-R-6 in a suitable solvent (eg acetonitrile) The intermediate b-9 is obtained, or the intermediate b-6 can be reacted with H^NA-Rg first, and then with the formula Ri-L-5 (release group), as shown in the diagram B, the intermediate B-9 may be finally reacted with R5C0C1 or its functional equivalent in the presence of a base such as triethylamine in a suitable solvent such as dioxane, conveniently in an inert atmosphere get on. Chart C

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 B7 V. INSTRUCTIONS (31) Another method for preparing the compound of formula (I) is exemplified in Figure C, intermediate c-1 ( Prepared by the method described in US 6,140,505), reacted with thiocarbonyldimethine in an inert solvent such as tetrahydrofuran, and the resulting intermediate is further reacted with an amine such as dimethylethylamine. Thus, thiourea derivative 5 bioc-2 is produced, and this intermediate c-2 is cyclized with bromine in the presence of an acid such as acetic acid, thereby producing a benzothiazole derivative c-3, the following two in the chart C The procedure is similar to those in the preparation of the intermediate a-5 and the intermediate a-6 in the diagram A, if necessary, the intermediate c-5 can be N-oxidized, for example using m-chloroperbenzoic acid in dichloromethane. get on. A special method for the preparation of acetamide substituted benzothiazoles is described in Figure D.

Chart D

Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, Print Intermediate dl (prepared according to the method described in Figure A), in a solvent such as 1,3-dioxane in the presence of a base such as triethylamine , and Qi B-33- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 B7 V. Description of invention (32) 醯 base gas, or its functional equivalent, to produce The d-guanamine can be further reacted with an amine of the formula NRaRb wherein Ra and Rb are possible substituents on the amine group in the variable R6. Other special preparations of acetamide substituted benzothiazoles are described in Figure E.

Chart E

Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, Printing 20 Intermediates e-2 Preparation Intermediates el (prepared according to the method described in Figure A) with an alkali (eg sodium carbonate) in an aqueous medium (eg water and dioxins) The procedure described in Scheme E to obtain intermediate e-6 is a reaction procedure all similar to the above synthetic chart. Many of the intermediates and starting materials used in the above preparations are -34- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 B7 V. Description of the invention (33 known compounds, Others can be prepared according to methods known in the literature for preparing such or analogous compounds.

Chart F

, R4 (XBu sMe 15 (gi) (g-2) Intermediate f-2, with respect to the intermediate a-3 of the chart A, may be added by adding H2N in a suitable solvent (for example, isopropanol) -A4 of the amine to the intermediate 10 f-Ι derived.

Compounds of the invention can also be prepared by the methods described in Scheme G. Chart G

NH ^ · PG'^rrw- (g^) PG. vV r2 oh /)—S〇2Me PG. '1 R2 oh R4 S(0)Me Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 20, R5 2) Deprotection (gi) tVrO:> , AR^ (g-7) R2 OH ^ AR^ -35- (g-8) This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 B7 5. Description of the invention (34) The benzothiazole derivative gl can be reacted with gas sulfonic acid and then treated with thioindole to produce an intermediate g-2, which can be further reacted with an intermediate The g-3 reaction produces the intermediate g-4, wherein PG represents an appropriate 'release group, such as Boc, and the reaction can be carried out in a suitable solvent (for example, a 5-pyrene) and selected in an appropriate assay (eg, three The intermediate g-4 can be carried out in the presence of ethylamine) and then can be combined with a suitable reagent [eg, meta-gas-peracid (mCPB A) or monoperoxy magnesium citrate hexahydrate (MMPP)] in a suitable solvent ( For example, it is reacted in 2-mercaptotetrahydrofuran in ethanol to prepare intermediates g_s and g-6. 10 The intermediates g-5 and g-6 may further react with the compound tf of the formula HN(R5)A-R6, and after deprotection, the intermediate g-7 is produced, and the intermediate g-7 may be further alkali ( An intermediate with a linear RrL_ (release group) in the presence of, for example, triethylamine) and optionally EDC or an alcohol (eg, third butanol) in a suitable solvent (eg, dioxane) The reaction is then carried out to obtain a compound of the formula 15 (I) of the compound g-8. Another particular method for preparing some of the compounds of the present invention is described in the Table Η. Chart Η Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 20

-36- Specifications (210x297 mm) Paper Size 1325783 A7 B7 V. Description of Invention (35)

mCPBA, DCM

(h-5) (h-6) using a method known in the art (for example, when PG is a Boc group, using hydrogenated hydrogen in isopropanol), the protective group of iLJL_ is removed, and then free The reaction of an amine with a carboxylic acid is carried out in an organic solvent (for example, di-methane) in the presence of a coupling agent (for example, EDC and HOBt) to obtain h-2 〇10. A preferred embodiment of the carboxylic acid It is Boc-protected L-third-leucine. Further deprotection according to the above method and reacting with chloroacetic acid in the presence of EDC and HOBt in dichlorosilane to prepare intermediate h_3, and then in an organic solvent [for example, dimethyl decylamine (DMF) In the case of heating, in a heated state, it is substituted with a primary amine in 15 steps, and then sufficiently protected with a protecting group such as Boc to obtain an intermediate h-4. The intermediate & is reacted with m-p-peroxybenzoic acid in di-methane to produce a sub-hardness] and then heated in an organic solvent (such as acetonitrile), and then printed into the Ministry of Economic Affairs, the Intellectual Property Bureau, and the Consumer Cooperatives. After the amine substitution of the formula NHRsR4, the last compound h-6 can be obtained after removing the protecting group in the above manner. The compound of formula (1) can also be converted to the related N-oxide form by conversion of trivalent nitrogen to its N-oxide according to methods known in the art, as in the intermediate e_6 of Figure C, oxidation reaction It is usually obtained by reacting the starting material of formula (I) with a suitable organic or inorganic peroxide. -37- This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 B7 V. DESCRIPTION OF THE INVENTION (36) Suitable inorganic peroxides include, for example, hydrogen peroxide, metal or soil-measuring metal peroxides such as sodium peroxide, potassium peroxide; suitable organic peroxides may include peroxygen An acid such as phenylcarbonyl peroxyacid or a halogen-substituted phenylcarbonyl peroxyacid such as 3-chloro-phenylcarbonyl peroxyacid or peroxy5 alkanoic acid such as peroxyacetic acid or alkyl hydroperoxide, for example, Tributyl hydroperoxide, suitable solvents are, for example, water, lower alkanols such as ethanol, etc., hydrocarbons such as toluene, ketones such as 2-butanone, halogenated hydrocarbons such as dioxane Methane, and a mixture of such solvents. Advantageous groups of the intermediate are the formula a-8, b-9 or d-oxime, wherein -A-R6 10 is hydrogen, and these intermediates may also have pharmaceutical properties similar to those of the compound of formula (I). . The compound of the present invention can thus be used in animals, preferably in mammals, and especially in humans, as a pharmaceutical, in a mixture with another agent or in a pharmaceutical preparation. In addition, the present invention relates to a pharmaceutical preparation comprising at least one formula (I) as an effective dose of an active ingredient in addition to a non-hazardous excipient and an adjuvant printed by a pharmacist's consumer cooperative of the Ministry of Pharmacy and Economics The compound, the pharmaceutical preparation usually contains 0.1 to 90% by weight of the compound of the formula (I), and the pharmaceutical preparation can be prepared by a method known to those skilled in the art to prepare at least one compound of the formula (I). 20 is used in combination with one or more solid or liquid pharmaceutical excipients and/or adjuvants, if necessary, with other pharmaceutically active compounds, together with appropriate application or dosage forms, which are then used as humans. Or veterinary medicine. Pharmaceutical products containing the compounds of the present invention can be applied to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) via oral, non-gastrointestinal-38-paper scales. 1325783 A7 V. Inventions 10 15 Ministry of Economics Intellectual Property Bureau staff light fee cooperatives printed 20 intestinal _ heart static _ 'rectal, inhalation, or local) application, the preferred parental use of oil body conditions, cases (4) treatment of disease (four) special course of disease, oral or better By. Based on the knowledge of the skilled person, it is known which adjuvant is used for the desired pharmaceutical formulation. In addition to the solvent, a knee forming agent, a suppository base, a key adjuvant and other active compound carriers can also be used. Oxide, dispersant, emulsifier, suds suppressor, flavoring agent, preservative, cosolvent, deposition effect agent, buffer substance or colorant. Due to its good pharmaceutical properties, in particular its mv protease enzymes against multi-drug resistance, the compounds of the invention are useful in the treatment of individuals receiving the infection and for the prevention of these health benefits, the compounds of the invention are useful for treatment A disease-preserving or treating condition, in particular a condition associated with HIV and other pathogenic retroviruses, including AIDS, AIDS-related, by a warm-blooded animal infected by a virus present in the egg (iv) enzyme medium Complex symptoms (ARC), progressive systemic lymphadenopathy (PGL); and chronic CNS diseases caused by retroviruses, such as HIV-mediated cancer and multiple sclerosis. The compound of the present invention or any sub-grown compound thereof can thus be used as a pharmaceutical against the above-mentioned conditions, and the use or treatment method as a medicament includes systemically administering an effective amount to an HIV-infected patient. The drug is against conditions associated with HIV and other pathogenic retroviruses (especially HIV1), and therefore, the compounds of the present invention can be used to manufacture pharmaceuticals for treating conditions associated with HIV and other pathogenic retroviruses. In particular, it is used to manufacture HIV-infected patients with multi-drug-resistant HIV infection. This paper scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm). Line (10) 783 Α 7 Invention Description (38) Patient's Pharmacy . In a preferred embodiment, the present invention relates to the use of a compound of formula (1) or any of its sub-compounds for the manufacture of a medicament for the treatment or combating of mammals «or with anti-retroviral attenuation. The invention also relates to HIV-1 infected persons, and the present invention also relates to a method for treating a retrovirus or a disease associated with a retrovirus-infected retrovirus, including a method of applying time-effects to those in need. (I) a compound or a subgroup thereof. 10 15 Ministry of Economic Affairs Intellectual Property Office Employees Consumption Cooperative Printed 20 In another preferred embodiment, the present invention relates to the use of a compound of formula (1) or, any known physiochemical substance for the manufacture of a medicament for inhibiting infection with a retrovirus. A multi-, mammalian, retroviral protease, particularly an HIV-1 retrovirus. In another preferred embodiment, the invention relates to the use of a compound of formula (I)

It ^ ^ subfamily compounds are used in the manufacture of pharmaceuticals for inhibiting the replication of multi-drug antiviral viruses, particularly HIV-1. The compounds are also produced in an ex vivo-containing (ex viv°) sample containing HIV or the like, and therefore, the compounds of the present invention, tanning, are present in HIV containing or suspected of being contained or exposed to a sample of a body fluid. The present invention is also related to the inclusion of (4) the agent of the present invention for the simultaneous anti-retroviral compound of the present invention, As a mixed sense of sensation, special "Tian, or successive use in the treatment of retroviruses..., in the transformation of multi-drug resistant retroviruses -40 - Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives 1325783 A7 B7 V. INSTRUCTIONS (39) Infection, therefore, to combat or treat HIV infection, or infections and diseases associated with HIV infection, such as acquired immunodeficiency (AIDS) or AIDS-related symptoms (ARC), the present invention The compounds can be administered in combination, for example, in combination with inhibitors such as dextran sulfate, suramine, polyanions, soluble CDs; fusion inhibitors such as T20, T1249, SHC-C, PR0542; co-receptor binding inhibitors, such as AMD 3100 (Bicyclams), TAK 779; RT inhibitors, for example, foscarnet and prodrug, MIV-310; nucleoside RTIs, such as AZT, 3TC , DDC, DDI, D4T, Abacavir, FTC, 10 DAPD, Dote; nucleotide RTIs, such as PMEA, PMPA, tenofovir; NNRTIS, such as nevirapine, delavirdine, Efavirenz, 8 and 9-C1 TIBO (tivirapine), Luo Weide (10^14(^), Ding 1^〇125, Ding]^(:-120, MKC-442, UC 781 Capravirine, DPC 15 961 ' DPC963 ' DPC082 ' DPC083 ' calanolide A ' SJ-3366, RTSAO, 4"-deaminated TSAO; RNAse H inhibitors such as SP1093V, PD126338; TAT inhibitors For example, RO-5-3335, K37; nucleic acid-binding enzymes such as l 708906, L 731988; protease inhibitors such as amprenavir, ritonavir, and na. (nelflnavir), saquinavir, indinavir, i〇pinavir, BMS 232632, BMS 186316 'DPC 681, DPC 684, tipranavir, AG1776 , DMP 450, L 756425, PDI178390, PNU 140135; saccharification inhibitors, such as Castan 〇Spermine, -41- Zhang scale applicable Chinese National Standard (CNS) A4 size (210x297 male Chu)

1325783 A7 B7 V. INSTRUCTIONS (40) Deoxynomycin (eg 0 parent > 010) 丨 1* 丨 111 > ^ 116). Mixed use may provide a benign synergistic effect (potentiating effect) in which the infectivity of the virus and its associated symptoms can be prevented, substantially attenuated, or completely eliminated. 5 The compounds of the invention may also be combined with immunomodulators [e.g., bropirimine, anti-human interferon alpha antibody, IL-2, arginine enkephalin, interferon alpha, and naltrexone (naltrexone). )], antibiotics [such as pentamidine isothiorate], vaccines or hormones (such as growth hormone) are used to improve, combat, or eliminate HIV infection and its symptoms. The Ministry of Economic Affairs, the Intellectual Property Office, the Staff Consumer Cooperative, prints the dosage form for oral administration, and the compound of the present invention is mixed into a suitable additive such as an excipient, a stabilizer or an inert diluent, and is suitably formed by a conventional method. Application forms, such as lozenges, coated lozenges, hard capsules, aqueous, alcoholic or oily solutions, suitable inert carriers are Allah 15 gum, magnesium oxide, magnesium carbonate, potassium phosphate, lactose, glucose, or starch , especially corn starch, in which case dry and wet agglomerates can be used. Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil, solvents for suitable aqueous or alcoholic solutions. For water, ethanol, sugar solutions, or mixtures thereof, polyethylene glycol and poly 20 propylene glycol are also useful adjuvants for other application forms. For subcutaneous or intravenous administration, if necessary, the active compound may be combined with other conventional substances, such as co-solvents, emulsifiers or other adjuvants, as a solution, suspension, or emulsion, and the compound of formula (1) may also be used. It is cooled and dried and used as a lyophilized product, for example, as an injection or -42- This paper scale is applicable to National Standard (CNS) A4 (210x297 mm) 1325783 A7 B7 V. Description of invention (41) Perfusion preparation Suitable solvents are, for example, water, physiological salines or alcohols, such as ethanol, propanol, glycerol, and also sugar solutions, such as glucose or glacial sugar solutions, or mixtures of various solvents mentioned. Suitable pharmaceutical formulations for administration to an aerosol or spray are, for example, a compound of formula (1) 5 or a physiologically acceptable salt thereof in a pharmaceutically acceptable solvent such as ethanol or water or a mixture of such solvents. Solutions, suspensions or emulsions, if necessary, may additionally contain other pharmaceutical adjuvants, such as surfactants, emulsifiers and stabilizers, and propellants, such preparations customarily contain The concentration of the active compound is from about 10 to 50%, especially from about 0.3 to 3% by weight. To enhance the solubility and/or ampoules of the compound of formula (I) in a pharmaceutical composition, alpha-, /3- or gamma-cyclodextrin or a derivative thereof may be advantageously employed, in addition, a co-solvent, For example, an alcohol can improve the solubility and/or stability of the compound of the formula (1) in a pharmaceutical composition, and when the aqueous composition is prepared, it is obviously more suitable for being added because the addition salt of the compound 15 has greater water solubility. application. The Department of Intellectual Property of the Ministry of Finance and Intellectual Property, the Consumer Cooperatives, prints appropriate cyclodextrin as α-, cold- or 7*-cyclodextrin (CDs) or ethers mixed with ethers, one or more of which are ring-shaped. The hydroxy group of the anhydroglucose unit of dextrin is substituted with a Cu alkyl group, especially a decyl group, an ethyl group or an isopropyl group, such as a randomly methylated /3-CD; a hydroxy cN6 alkyl group, especially a hydroxy 20-ethyl group. , hydroxypropyl or hydroxybutyl; carboxy Ck alkyl, especially carboxy fluorenyl or carboxyethyl; Cm alkylcarbonyl, especially ethyl hydrazide; Cu alkoxy ridyl Cy alkyl or carboxy C alkoxy Cl_6 alkyl, especially carboxy methoxy propyl or carboxy ethoxy propyl; CN6 alkyl decyloxy (^-6 alkyl, especially 疋 2-ethyl propyl propyl), particularly worthy of being a composite agent / or cosolvent -43- This paper scale is applicable to China National Standard (CNS) A4 specification (2丨Ox297 mm) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1325783 A7 V. Invention description (42) is /3- CD, random methylated call-CD '2,6-dimethyl-0-CD, 2-mercaptoethyl-stone-CD, 2-hydroxyethyl _ γ _cj), 2-hydroxypropyl _ γ _c d with (2-carboxymethoxy)propyl-/5-CD, and especially 2-hydroxyl CD (2-HP- 0 -CD). The term "mixed ether" refers to a cyclodextrin derivative in which at least two cyclic dextrin hydroxyl groups are etherified with different groups (e.g., hydroxy-propyl and hydroxyethyl). An advantageous method of mixing a formulation of a compound of the invention with a cyclodextrin or a derivative thereof is disclosed in EP-A-721,331, although the formulation described therein has an antifungal active ingredient, they are still advantageous. Formulation of a compound of the present invention, wherein the formulation is particularly suitable for oral administration and comprises as an active ingredient an antifungal ingredient, a cyclodextrin or a derivative thereof as a cosolvent, an aqueous acidic medium as a total liquid carrier The agent is formulated with an alcoholic co-solvent which greatly simplifies the formulation of the composition which can be made more palatable by the addition of a pharmaceutically acceptable sweetener and/or aroma. Other convenient methods for increasing the solubility of the compounds of the invention in pharmaceutical compositions are disclosed in WO 〇 94/〇 5263, PCT Application Serial No. PCT/EP98/01773, EP-A-499, 299 and W0 97/44014 All materials are incorporated herein by reference. More particularly, the compounds of the invention may be formulated in a pharmaceutical composition comprising a therapeutically effective amount of particles consisting of a solid dispersion comprising (a) a compound of formula (I), (b) one or more pharmaceutically acceptable polymers which are soluble in water. The term "solid dispersion," means solid (relative to liquid or gaseous) -44- This paper scale is timely S @家标准(CNS:)A4

1325783

A7 5. A system of invention (43) comprising at least two components, one of which is more or less a component is dispersed evenly among the other component(s) Such a dispersion of the various components results in a system that is chemically and physically homogeneous or homogeneous or thermodynamically one-phase, such a solid dispersion 5 is classified as a "solid solution," A preferred physical system is that the components within it are generally readily bioavailable by the subject being administered. The term "solid dispersion" also encompasses dispersions that are not completely homogeneous with respect to the solid solution. The dispersion is not completely identical in terms of chemical and physical uniformity 10 or it contains more than one phase. The polymer in which the particles are soluble in water is when it is formulated into a 2% aqueous solution at 2 〇〇c. It has an apparent viscosity of 1 to 100 mPa.s. The polymer that is soluble in water is hydroxypropylmethylcellulose 戋15 HPMC, which has a methoxy substitution degree of about 〇· 8 to about 2.5 and propyl group ^ HPMC having an degree of substitution of from about 0.05 to about 3.0 is generally soluble, and the degree of substitution of the methoxy group is methyl (tetra) in the dehydrated glucose unit present in the cellulose molecule, Propyl Mo = generation is the average number of moles of propylene oxide that has been reacted with each of the anhydrous glucose monohydrates 20 on the cellulose molecule. The preparation of the particles defined above, first of all, to prepare the solids of each component, And then selectively pulverizing or grinding the dispersion. The existing various techniques for preparing the solid dispersion include melting (four) t prepared usion), spray-drying and solution evaporation, and the method of melting and extruding the paper scale is applicable to the Chinese national standard ( CNS) A4 Specification (210: -45- 1325783 A7 B7 V. INSTRUCTION DESCRIPTION (44) It is preferable to more conveniently formulate a compound of the present invention in a nanoplate type having a surface modification adsorbed on its surface, thus maintaining The effective average particle size is less than 1000 nm, and useful surface modifiers are cut into packages which include those which are physically affixed to the antiretroviral agent but are not chemically bound to the anti-retroviral agent. Suitable for transcription of viral agents. Suitable surface modifying agents are preferably selected from known organic and inorganic pharmaceutical excipients, including various polymers, low molecular weight polymerizers, natural materials and surfactants. Preferred surface modifiers include non-10 ionic and anionic surfactants. Another advantageous method of formulating the compounds of the invention. Including a pharmaceutical composition in which the present compound is incorporated into a hydrophilic polymer. And this mixture is applied by coating a plurality of small beads with a coating film, thus producing a composition having good bioavailability, which can be conveniently manufactured and which is suitable for the preparation of a pharmaceutical dosage form for oral administration. The beads comprise (a) a central, round or spherical core, (b) a coated film of a hydrophilic polymer and an anti-retroviral agent ((〇 seal-coated polymer) Floor. Printed by the Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperatives 20 Materials suitable for use in the core of the bead can be varied, as long as the material is pharmaceutically acceptable and has the appropriate size and firmness. Examples of such materials They are polymers, inorganic substances, organic substances, and polysaccharides and their derivatives. Another object of the present invention relates to a kit or container comprising an effective amount of a standard or test reagent or an analytical assay having the potential -46- specification (210 x 297 mm) 1325783 Α7 _ Β7 5. Invention A compound of formula (I) illustrating the ability of a pharmaceutical product (45) to inhibit HIV protease, HIV growth, or both, and the use of this compound is applied to a pharmaceutical research program. The compounds of the invention can be used in high throughput target-analyte assays, such as those for determining the efficacy of the compounds in the treatment of ΗIV. 5 The compounds of the invention can be used in phenotypic resistance monitoring assays, such as known recombinant assays, in the clinical management of developed disease (eg, HIV) resistance, a particularly useful resistance monitoring system. For recombinant analysis known as AntivirogramTM, this AntivirogramTM is a highly automated, high throughput, second generation heavy 10 assay that can determine the susceptibility to the compounds of the invention. (Hertogs K, de Bethune MP, Miller V et al. Antimicrob C/zewo Aer, 1998; 42(2): 269-276, incorporated by reference). The dosage of the compound of the present invention or its physiologically acceptable salt to be printed by the Intellectual Property Office of the Intellectual Property Office of the Ministry of Economic Affairs shall be 15 depending on the individual circumstances, and it is customary to adjust to the most appropriate effect according to the individual, so Need to, of course, the frequency of administration and the potential and duration of action of the compound used, for treatment or prevention, etc., also depends on the nature and severity of the infection and the symptoms, and the sex, age, and weight of the human or animal being treated. Responding to the individual, and the treatment is acute or prophylactic. It is customary for 20 patients with a body weight of about 75 kg. The amount of the compound of formula (I) is from 1 mg to 1 g, preferably from 3 mg to 0. 5 grams, the dose may be administered in a single dose or divided into several doses (eg, two, three or four times) in separate doses. EXPERIMENTAL -47- This paper scale applies to Chinese National Standard (CNS) A4 specification (210x297 mm) 1325783 Α7 Β7 V. Description of invention (46) Preparation of compound of formula (1) and its intermediates Paste 1: Preparation of compound 29

At 〇 ° C, stir in 1.5 ml of methylene chloride from 1.56 g of intermediate a-3 (R2 = H and R4 = -CH2-CH2-NH-(2-pyridyl)) and 0.59 g of triethyl A mixture of the amine groups was then added, and then 1.25 g of 2-ethylhydrazinoamino)-10 6-benzothiazolesulfonyl sulfhydryl gas was added, and the reaction mixture was stirred at room temperature overnight, and after washing with water, the organic layer was separated. After drying, the solvent was evaporated, and the obtained brown solid was redissolved in methanol at 70 ° C. After cooling, it was filtered to obtain 1.9 g (75%) of intermediate a_4 (R2=H, R4=-CH2-CH2- NH-(2-pyridyl) and -A-R6=H). Ministry of Economic Affairs, Intellectual Property Officer, Consumer Cooperative, printed 15 pairs of 6 g of intermediate a-4 in 50 ml of dioxane (R2=H, R4=-CH2-CH2-NH-(2-acridinyl) And -A-R6=H) mixture, adding 7.3 ml of trifluoroacetic acid, stirring the reaction mixture for 6 hours at room temperature, adding an additional gas chamber and washing with sodium bicarbonate solution, drying the organic layer and The solvent was evaporated under reduced pressure to give 4.1 g (yield: s), </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> . From 0.60 g of intermediate a_5 (R2 = H, R4 = _ch2-CH2-NH-(2_ hexidyl) and -A-RfH), 0.29 g of l-[[[3S,3aR,6aS]+ ( 3R,3aS, 6aR)-hexahydrofuro[2,3_b]furan-3-yloxy]carbonyl]oxy]_2,5-pyrrolidone (prepared analogously to the method disclosed in W09967417) and hydrazine 33克-48- Scale China National Standard (CNS) A4 Specification (21〇χ 297 mm) Printed by the Intellectual Property Office of the Ministry of Economic Affairs

-49- 1325783 A7 B7 V. Inventive Note (47) Triethylamine was co-disposed into a mixture of 15 ml of dichloromethane, stirred at room temperature for 24 hours, and the solvent was evaporated to remove the solid. Dissolved in decyl alcohol at 70 ° C, cooled and filtered to give 0.53 g (69%) of compound 329, MS: m/z = 711 (M+H) 5 Example 2: Preparation of compound 31

Placed in 5 ml of di-gas methane from 540 mg of intermediate a-5 (R2=H, R4=-CH2-(2-pyridyl) and -A-R6=H), 135 mg of third A mixture of alcohol, 192 mg of EDC and 101 mg of triethylamine was stirred at room temperature overnight. The reaction mixture was washed with sodium carbonate solution and brine, and then the organic layer was separated. The residue was purified by preparative-HPLC to yield 184 mg (26%) of Compound 31. Mass Spectrometry Data: m/z = 702 (M+H) Example Compound 33 20 This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm)

1325783 A7 B7 V. INSTRUCTIONS (48) 54 mg of intermediates a_ 5 (1^=1^114=-(:-(2-pyridyl)) and placed in 5 ml of di-methane八-1164), 271 mg of 1-[[[[33,3成六沾]+(311,3&amp;8 plus 1〇-hexahydrofuro[2,3-13]furan-3-yl]oxy a mixture of alkoxy]-2,5-pyrrolidonedione and 1 〇1 mg of triethylamine, stirred at room temperature for 24 hours, and the reaction mixture was washed with sodium carbonate solution and brine. The organic layer was separated, dried and evaporated, mjjjjjjjjjjjjjjjjjjjjjjjjj

10 compound 2

15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 0.3 g of the racemic intermediate a_ 8 (R2=H, R4=isobutyl, -A-R6=H and placed in anhydrous dioxane) a mixture of -LR丨=[[hexahydrofuro[2,3-b] oxa-3-yl]oxy]alkyl) and 〇·g of triethylamine is added in 0.18 g of bismuth citrate The ester was heated to 60 C overnight, and 10 ml of water and 0-4 g of potassium carbonate were added to the mixture, followed by stirring for two hours, and the dioxane was removed under vacuum, and the aqueous phase was extracted by two-dimensional appearance. After concentrating the organic layer, the residue was purified by chromatography to yield 0.23 g (68%) of Compound 2

(210x297 mm) Printed by the Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative 1325783 A7 B7 V. Description of Invention (49)

5 (d) 19.66 g of [2R_carbyl_3-[(2-mercaptopropyl)amine-based HS·(stylmethyl)propyl]carbamic acid ' U-dimercaptoethyl ester ( The mixture formed in (10)7/deleted 5) and 17.76 g of triethylamine was placed in a gas-burning furnace of 2 liters of home, in an inert gas, 0. (: under the stirring for 20 minutes, a small amount of 18 · 72 grams of 2_(ethyl arylamino) _·6· benzoic acid continued to be ground 10 gas, then mixed at room temperature for 2 hours, washed with 5% hydrochloric acid solution, saturated sodium bicarbonate solution and brine After the sulphate, the organic layer was separated, and after drying, the solvent was evaporated under reduced pressure, and the hydrazine product was placed on the zea gum to be purified by the methanol mashing in the gas chamber of the state, and 3 G.82 g was obtained. , _ b_4 (R2 = H and R4 = isobutyl). 15 will be placed in 130 ml of ethanol / two chews: 1) of the intermediate material b 4 (R2 Η and ruler 4 = different a mixture of butyl), adding 65 ml of HCl (5 to 6 N in isopropanol)' The mixture was stirred at 5 ° C for 22 hours, and after concentration, the salt was treated with the remaining sodium bicarbonate solution and Extraction of the second gas, the organic layer is separated, and after drying, the solvent is evaporated, and the residue is in the Shiji gum. Purified 20, washed with 3% methanol in dioxin, and obtained a% gram (72%) of intermediate b_s ((R2=H and R4=isobutyl). 'President at -ίοc Next, a solution of 181 g of sodium sulfoxide dissolved in 10 ml of water was added over a period of 40 minutes to an intermediate b_s of 9.8 g of 85% phosphoric acid in 18 ml of water ((R2=H and k different) -51- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm)-----

Iszy/^3 A7

After 1.5 hours of mixing, the mixture was added to a solution of 80 ml of water-gathered cup-acid steel pentahydrate and UP g of gasified sodium under stirring at TC, and the mixture was mixed for 15 hours. Let it warm to room temperature, and then adjust the viscosity (pH=8) with ammonium nitrite solution under cooling. The solution obtained in 5 is extracted with ethyl acetate, dried and evaporated to remove the solvent. 7.59 g (74%) of intermediate b_6 (R yields H and R4 = isobutyl). 1.63 g of intermediate b_6 ((R2=H and &amp; isobutyl ▲), 〇8 gram of i-[ a mixture of [[[(3s)--hydro-3- fluorenyl]oxy] yloxy] oxalate and 0.53 g of diethylamine is placed in 1 Torr at room temperature After _5 hours, the obtained crude product was purified on Shishijiao, and washed with 3% methanol dissolved in the second gas chamber to obtain 0.58 g (29%) of intermediate b_8. (R2=H,~=isobutyl, R丨-L-=[[(3S)-tetrahydro-3_fluorenyl]oxy]carbonyl). Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed on dissolution Intermediate b_8 in 30 ml of acetonitrile (R2 = H, R4 = iso-l-butyl, RrL-=[[(3S)·tetrahydro-3-indolyl]oxy] The solution was added with 2 g of N,N-dimercaptoethylenediamine in 8 Torr. The mixture was stirred for 4 hours under ankle, and the acetonitrile was evaporated under reduced pressure. The mixture was washed with 2% sterol in dichloromethane, and 12 g (5%) of compound 56 was obtained. Mass spectral data: m/z = 634 (M+H) 20 Example 6: Preparation of compound 44

-52- This paper scale applies to Chinese national standard (〇sjS) A4 specification (210 X 297 mm) 1325783 A7 B7 V. Invention description (5 !) Add 0.88 g of n,N-didecylethylenediamine to Dissolved in a solution of 0. 90 g of intermediate b-6 (R2 = Ha R4 = isobutyl) in 2 mL of acetonitrile at 80. After the acetonitrile was evaporated under reduced pressure, the product was washed with 2% sodium carbonate and extracted with ethyl acetate. The organic layer was dried over 5 EtOAc. Using a 1〇/〇 ammonia flow eluted in a two-gas form, 0.57 g (58〇/〇) of intermediate b_7 was obtained (R2=H, R4=isobutyl and -A-R6=CH2CH2N(CH3) 2) 0.65 g of (earth trans)·4·(dimethylamino)tetraar _3_B-fusanol (synthesized by the method disclosed in US 3,265'711) '3.78 g of No. 2 Ria 1 A mixture of guanamine-based carbonic acid and 0g of triethylamine was placed in 3 〇ml = dimethylformamidine at room temperature for 24 hours, after the solution was washed with saturated sodium bicarbonate. The organic layer was dried and evaporated to remove the solvent under reduced pressure to give hexane (52%) (yield: s), s, s, s. ] - a few bases] oxygen] 2,5_B than the two bite. 15 0·25 grams of intermediate b-7 (R) = H, R2 = CH2CH2N (Me) 2), 0.13 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed gram (± trans) · 1-[[[ [4-(Dimethylamino)-tetrahydro-furan-3-yl]oxy]•carbonyl]oxy]·2,5-pyrrolidinedione and 0.07 g of triethylamine It was placed in 15 ml of dioxane, stirred at room temperature for 24 hours, and evaporated under reduced pressure. After the dioxane was evaporated, the crude product was purified on silica gel to 4% of 20 in methane. Ammonia flow washing, yielding 0.14 g (43 〇 / 〇) of compound 44, mass spectral data: m / z = 677 (M + H). Example 7: _ preparation of compound - 53 - the paper scale applies to national standards of t countries (CNS) A4 specification (2丨〇χ 297 public Chu) i02y/^0 V. Invention description (52)

5 10 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 ^ solution of 〇83 g of intermediate b-6 (R2=H and butyl) in 20 ml of acetonitrile plus 〇. 40 g of N- (2-Amino-based group)_°°°° bite, (4)^The solution was dropped for 4 hours, and after evaporation of acetonitrile under reduced pressure, 2% sodium sulphate was washed with ethyl acetate. Extraction, the organic layer was dried 4' under reduced pressure, and the crude product was placed on Shishijiao, and 1% of the ammonia was purged in a gas mixture of dioxane, and 47 g (49%) was obtained. Intermediate b_7 (R2 = H, Rf isobutyl and - fluorene-fluorenyl). 0.47 g of intermediate b_7 (R2 = H, heart = isobutyl and (1 - ca), 0.24 g of H, R, 3aS, 6aR) - hexahydroindole. Nanhe [2, 3 -b]furan-3-yl]oxy]carbonyl]oxy]_2,5-pyrrole. The mixture of di- and 〇1 gram of triethylamine is placed in 20 ml of di-methane. After stirring for 24 hours under a shirt, the dichloromethane was evaporated under reduced pressure, and the crude product was purified on a silica gel and washed with 2% ammonia in di-methane to yield 0.54 g (88%). Intermediate b-9 (R2=H, R4=isobutyl, A_pyrrolidinyl) and -LR 丨=[[(3R,3aS,6aR)-hexahydropyrano[2,3-b] Furan-3-yl]oxy]carbonyl). 0.54 g of intermediate b_9 (R2=H, R4=isobutyl, -A-R6=CH2CH2-(1-pyrrole) dissolved in 40 ml of di-methane Pyridyl) and _L· Ri=[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]alkyl) and -54- table paper scale applicable + National Standard (CNS) A4 specification (2丨〇X 297 mm) Loading line 1325783 A7 B7 V. Description of invention (53 0.16 g of diethylamine solution, added to an inert atmosphere of 〇.22 g of B Base gas at room temperature After stirring for 2 hours, washed with water works, the organic layer was concentrated under reduced drying treatment can be obtained 0.50 g (87%) of compound 19. Mass spectrometry data: m / z = 744 (M + H) 5 Example 8: Preparation of Compound 1610

Compound 16

, L 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative printed 20 pairs of 4.11 g of [(1S,2R)-3-[[(4-aminophenyl)sulfonyl] dissolved in 40 ml of anhydrous tetrahydrofuran] (2-Methylpropyl)-amino]_2-hydroxy_1_(phenylindenyl)propyl]aminocarboxylic acid, 1,1-di-methylethyl vinegar (Exposed in US 6, HO, 5 The solution prepared by the method of 〇5 was added with 8 g of 1,1'-thiocarbonyldiimidazole, and the solution was heated under reflux for 4 hours, cooled to 25 ° C, and 0.88 g of N,N-dimethyl was added. The ethylamine was heated to reflux for 16 hours. After cooling at 25 ° C, the tetrahydrofuran was evaporated under reduced pressure, dioxane was added, washed with water, and the organic layer was dried and concentrated. The product was purified on silica gel and washed with 5% methanol in di-methane to yield 3.8 g (yield: 62%) of intermediates C-2 (R.sup.2, H, R.sup.4 = isobutyl). Mass spectral data: m/z = 622 (M+H), 566, 532. To a solution of 2.5 g of intermediate C 2 = H, r 4 =: isobutyl) dissolved in 10 ml of acetic acid, a solution of 64 g of bromine dissolved in 10 ml of acetic acid was added, and after 2 hours, the crude product was concentrated. Add dichlorosilane to saturated carbonic acid-55- This paper scale is applicable to China National Standard (CNS) A4 specification (210x297 public). Line 1325783 A7 B7 V. Invention description (54) Potassium solution washing organic layer, organic layer After drying over magnesium sulfate, it was filtered and concentrated to give intermediate m.sup.3 (H.sup.2, H, R4 = isobutyl). Mass spectral data: m/z = 620 (M+H), 564, 520, 261. Intermediate c-3 (R2=H, R4=isobutyl) was slightly released with 5 ml of intermediate c-3 (R2=H, R4=isobutyl) in 20 ml of dichloromethane. Difluoroacetic acid, the solution was stirred for 1 hour, concentrated, and the residue was evaporated with a solution of potassium carbonate, and then extracted with methylene chloride. The crude product was purified on silica gel and washed with 5% methanol in dichloromethane. 1.5 g (72%) of intermediate C-4 (R2 = H, R4 = isobutyl) was obtained. 10 1.5 g of intermediate c-4 (R2 = H, R4 = isobutyl), 0.81 g of 1-[[[[(3R,3aS,6aR)-hexahydrofuro[2,3_b]furan-3 a mixture of _yloxy]carbonyl]oxy]- 2,5-pyrrolidone and 0.67 g of triethylamine was placed in 5 ml of di-methane and stirred at room temperature for 4 hours. The product was directly purified on silica gel and washed with 5% MeOH in dichloromethane to yield 15 0.80 g (39%) of Compound 16. Example 9: Preparation of compounds? 7 Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperative, printing

To 34 g of compound 16 dissolved in 5 ml of di-methane, 〇·〇 8 g of sodium bicarbonate and 15.15 g of (75%) of methane formic acid were added, and the solution was aged at room temperature. 2 hours, add water and burn with two gas -56- Ministry of Economic Affairs Intellectual Property Bureau, Consumer Cooperatives Printed 1325783 A7 B7 V. Inventions (55) Residues, the organic layer is dried over magnesium sulfate, filtered and concentrated. The crude product was purified on silica gel and washed with 5% decyl alcohol in dichloromethane to yield 0.09 g (26%) of compound 27, mass spectral data: m/z = 692 (M+H) 5 Example 10: Preparation of Compound 11

10 pairs of 2-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-oxime) placed in methylene chloride a mixture of propyl sulfonamide and 1.0 g of triethylamine, adding 1.47 g of i-^^RjaS/aR)-hexahydrofuro[2,3_b]pyran-3-yl Oxy]carbonyl]oxy]_2,5-pyrrolidinedione, after stirring overnight, the reaction mixture was washed with saturated sodium bicarbonate solution, dried over 15 magnesium sulfate, filtered and then evaporated. Purification by layer chromatography (dioxane: sterol 95:5) gave 2.76 g of intermediate dl (R2=H, ^4=isobutyl, -A-R6=H and ·L- RdfGRjaSjaR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl) (88%). Opposite to dry 1,4-dioxane by intermediate r4 = isobutyl 20, -A-R6 = H and 心 = [[(31^, 3 into 6 &amp; 11)-hexahydrofuran And [2,3-b]pyran-3-yl]oxy]carbonyl) (2, gram; 3.3 mmol) and a mixture of triethylamine (1.16 g; II. 5 mmol), added Gas-based gas (429 mg; 3 8 mmol), the mixture was stirred at room temperature for 3 hours, and another wound of ethylene-based gas (180 mg; 1.5 mmol) was added. Continue to mix for 3 hours, -57-^ for Chinese National Standard (CNS) A4 specification (2i〇x297 mm)&quot;

1325783 A7 B7 56 V. INSTRUCTIONS (After evaporation of the solvent, the residue is purified by column chromatography (di-methane: decyl alcohol 98:2) to give i 57 g (7 %) of intermediate d 2 ( R2=H, R4=isobutyl, -A-R6=h and _l_R丨=[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy] Carbonyl) (88./0) Mass spectral data: (ES+): 681/683 (M+H) 40% arfuran 10 pairs of intermediates d-2 dissolved in tetrahydrofuran (R2 = H, R4 = Isobutyl, -A-R6=H and -L-RdipiUaSAaR)-hexahydrofuro[2,3-b]pyranyloxy]oxy]number) (0.45 g; 〇·66 mmol) solution After adding 4.6 milligrams of weight to the aqueous solution of dimethylhydrazine, after stirring for 2 hours, the tetrad was evaporated and the aqueous layer was extracted with dioxane. The combined organic layer was dried over magnesium sulfate and concentrated in vacuo. Obtained 0.42 g (92 ° /.) of the drug. Mass spectral data: (ES+): 690 (Μ+Η), 560. ΑΑ1Ι: Preparation of compound 12 15

Compound 12 .SO,

vLO Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 pairs of intermediates d-2 dissolved in di-methane (R2=H, isodecyl, A-R6=H and -LR丨=[[3R,3aS , 6aR)-hexahydrofuro[2,3-b]pyranyl 3-yloxy]carbonyl), 1.5 equivalents of pyrrolidine and sodium carbonate base were added, stirred at room temperature overnight, and evaporated to remove solvent in vacuo Purification by residue nickel column chromatography (di-methane:methanol) gave 76% of compound 12. Mass Spectrometry (ES+): 715(M+H) •58- This paper scale applies to China National Standard (CNS) A4 specification (210x297 public Chu) 1325783 A7 ------15, invention description (π) Lending compound 43

The mixture of 6.13 g of the intermediate el (R2=H R4=isobutyl and -A-RfH) and 10 g of sodium sulphate in water/dioxane (1/2) was heated to 8 〇. The C group was removed for 48 hours, and the dioxane was removed under vacuum. The obtained aqueous phase was extracted twice with ethyl acetate, dried over magnesium sulfate, and filtered, and the combined organic layer was concentrated to obtain 5.08 g of intermediate e. -2 (R_2=H and R4=isobutyl and -A-R6=H). Mass spectral data (ES+): 549 (M+H), 449. The intermediate e-2 (R2=H, Rf isobutyl and -A-R6=H) and 1.1 g of 3.0 g of 2-aminobenzoindole in dry 1,4-dioxane The mixture of triethylamine was added to 0.77 g of chloroethionyl chloride, and the mixture was stirred overnight. After the solvent was removed by evaporation, the residue was purified by column chromatography (dichloromethane: methanol 98:2). 2-7 g (78%) of intermediate e-3 (R2 = H, R4 = isobutyl and _A-RfH). Mass spectral data (ES+): 625/627 (M+H). The Ministry of Economic Affairs, Intellectual Property Office, Staff Consumer Cooperative, printed a solution of 0.8 g of intermediate e-3 (R2=H, R4=isobutyl and -A-R6=H) dissolved in tetrahydrofuran, and added to a 40 ml weight of 8 ml. After stirring for 3 hours, the aqueous solution of dimercaptoamine was evaporated to remove the tetrahydrofuran. The aqueous layer was extracted with methylene chloride. The combined organic layer was dried over magnesium sulfate and concentrated in vacuo to give 0.58 g (85%). Interstitial e-4 (R2=H, R4=isobutyl A-R6=H and Ra=Rb=CH3), mass spectral data (ES+): 634 (M+H), 534. For the intermediate e-4 dissolved in methylene chloride (R2=H, R4=isobutyl, -A- -59- This paper scale applies the Chinese National Standard (CNS) A4 specification (210x297 mm) 1325783 V. DESCRIPTION OF THE INVENTION (π 10 6 Η and Ra Rb CHA gluten, force 1Q equivalent of trifluoroacetic acid, after 2 nights of application, the organic layer is washed with saturated sodium bicarbonate solution and salt solution, after being dried by the acid , transition and preconcentration, the intermediate e_5 can be obtained (R2=H, 仏=isobutyl, -A-R6=H and Ra=Rb=Cii3). 4 g of G35g dissolved in trichloromethane In a solution of benzoyl benzoic acid, add 〇.09 g of 1· mercaptobenzotriene with (U3 g of C,, 'Λ 1.5 small 4 stirring, let the temperature rise to room temperature and continue After the addition of the intermediate e_5 (R2=H, R4=isobutyl, _ar6=h and Ra=Rb=CH3), the reaction mixture was mixed for two days at room temperature and then removed under vacuum. Solvent, the residue obtained was purified by column chromatography of &lt;&quot;&gt;&gt; methanol 97:3) to give a compound of &lt;RTI ID=0.0&gt; 15

Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Consumer Cooperatives 20 Place 25 g of 2-pyridylmethylamine in 400 ml of isopropanol, stir to reflux, and then add dropwise to 200 ml of isopropanol. 21 g of 2S, 3S-1,2-epoxy winter (t-butoxycarbonylamino)_4_ phenyl butyl hydride solution, the solution was stirred under reflux overnight, and the solvent was removed by evaporation to make a residue Re-dissolved in di-methane and washed four times with water, the organic layer was dried and concentrated, and the residue obtained was purified by chromatography (two gas-fired, -60- 1325783 A7 B7. 5. Description of invention (59) 7N NH3, 98:2) in decyl alcohol gives 24 g (84%) of intermediate f-2 (R2 = H and R4 = -CH2-(2-pyridyl)). Example 14: Preparation of Compound 20 Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative

5 Compound 20 can also be prepared according to the method depicted in Figure G. This particular method is illustrated in Figure I below. Chart I

20 At 10 ° C, stir the chlorosulfonic acid (0.193 kg; 1.65 mol) in a nitrogen blanket, carefully add i-丨, and stir the reaction mixture at 90 ° C. 3 -61- This paper scale applies. China National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 B7 V. Description of invention (6〇) Hours, stop heating, slowly add sulfur gas (0 079 kg; 0 66 mo;), then at 90 The reaction mixture was further stirred for 1 hour under C. After cooling to 35 ° C, 200 ml of ethyl acetate was slowly added. When the product began to precipitate, another 200 ml of ethyl acetate was quickly added, and the precipitate was filtered and taken to 200 ml. Wash 5 ethyl acetate twice and wash twice with 1000 ml of cold water, then stir the precipitate into sodium bicarbonate solution until pH = 7, filter the mixture, and place the white solid i-2 in a vacuum oven at 50 ° C. Dry in the middle. (0.123 kg, 80%). (LC/MS MW+; 280,282) 0.120 kg (0.36 mol of intermediate i-3 and 0.073 kg (0.72 mol 10 mil) of diethylamine mixture, placed in 2-methyltetrafuran (1.150 In kg), stir at 35 ° C until the reactants are dissolved, then add 1 〇〇 kg (0.36 mol) of intermediate i_2, and stir the reaction mixture for 5 hours at 55 ° t, water (0.500 kg) After washing the succulent, the organic layer was separated and washed with 1.5 N HCl of 1.5 〇〇 kg, and the organic layer was separated, dried and concentrated to obtain a blatt 15 4; 0.208 kg (1 〇〇〇 / 0). /MS MW+; 480,481,482) Mix 0.208 kg (0.36 mol) of intermediate i_4 into 4 (TC, 1 kg of 2-methyltetrahydrofuran, 〇_〇 printed by the Ministry of Economic Affairs, Intellectual Property Office Staff Cooperatives Mix a mixture of 6 kg of water and 丨〇 kg of ethanol until all the reactants have dissolved, then add 0.200 kg (0.4 mol) of magnesium monoperoxynate hexahydrate, stir the mixture and 20 at 60 ° C. Heated for 15 minutes, the reaction mixture became alkaline with pH=10 with 0.400 kg of sodium carbonate, intermediates i-5 and i-6 (about 70% i-5) With 30% i-6) (LC/MS MW+ i-5; 496, 497, 498 MW+ i-6; 511, 513), 0.050 kg (〇·43 mol) of hydrazine was added to the reaction mixture at 60 ° C. (2-Aminoethylpyrazole, the mixture was mixed at 70 ° C for 2 hours, -62- This paper scale applies to China National Standard (CNS) A4 specification (2丨0 X 297 mm) 1325783 A7 B7 V. Description of the invention (Μ) The concentrated slurry is cooled to 40 ° C and concentrated hydrochloric acid (πν) is added dropwise until ρη = 7.8, a precipitate is obtained, the organic layer is separated, and after concentration, it is placed at 5 (rCT Drying in a vacuum box gives Boc N-protected 丨_7; 0.217 kg (93 〇/〇). (LC/MS MW+; 66,647,648) 5 0.217 kg (0.36 mol) of intermediate at 50 ° C Boc's 1-7 was dissolved in 1.4 kg of isopropanol and then at 7 Torr. The mixture was heated and stirred for 2.5 hours, and the hot solution was added dropwise to 〇5 kg of cold (0 C - 15 C) In isopropanol, the sedimentation chamber was filtered and washed with diisopropyl riddle. The slightly brown solid was dispersed in DIPE/A stupid (5Ό/50), then filtered, and 10 placed at 5 °C. The vacuum oven is dried to obtain ο.πο kg (76%) Ν7 HC1 salt. (LC/MS MW+; 546, 547, 548) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed 1.3 grams of intermediates i-7, 〇.774 grams of l-[[[[3R,3aR,6aS ) + (3R, 3aS, 6 &amp; ruler) - hexahydropyrene and [2,3_b] blowing _3_yl]oxy]alkyl]oxy]·2,5-pyrrolidone (similar to w Prepared by the method disclosed in 〇9967417) 15 and a mixture of 0.33 g of triethylamine, placed in a milliliter of a gas chamber, and then stirred at room temperature for 24 hours, the crude product was washed with sodium bicarbonate solution. The organic layer was dried <RTI ID=0.0></RTI> to <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; 20 Example 15: Preparation of Compound 85 and its intermediate (R = = isobutyl)

-63- This paper scale applies to China National Standard (CNS) A4 specification (210x297 public) 1325783 A7 B7 V. Invention description (62 10 15 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 20 This compound is described in the chart Preparation by hydrazine method 11 g of intermediate 11 1 (PG = B 〇 C, R 丨 = isobutyl) [(1S, 2R) 2 hydroxy-3-[(2-methylpropyl) [[2-( Mercaptothio)-benzothiazole-6-yl]sulfonyl]amino]-1-(phenylindenyl)propyl]aminocarboxylic acid, dimethylethyl ester is dissolved in 300 ml The propylene alcohol HCl was stirred with 1 mM of the two gas at room temperature overnight, and then the reaction mixture was concentrated and treated with a mixture of two gas and a sodium hydroxide dissolved in water, and the organic layer was dried over magnesium sulfate. Thereafter, 8.8 g (97%) of the deprotected intermediate n_[(2r,3S)_3_amino-2-carbyl-4-phenylbutyl]-N-(2-mercaptopropyl) was obtained. [2_(methylsulfo)_ benzopyrazine-6-yl]sulfonamide, which is a free salt base, mass spectrometry data: m/z:=48〇(M+H) 〇4·15 grams of the aforementioned middle 2 g of Boc-L-third leucine, 1 17 g of HOBt and 1.66 g of EDC, dissolved in 150 ml The gas was calcined and stirred at room temperature overnight, then washed successively with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and evaporated to give 6 g (1%) of intermediate llzl [(lS)-H [[(lS,2R)-2-carbyl-3·[(2-methylpropyl)[(2-mercaptopropyl)[(2-(methylthio)-benzoquinone-6- Alkyl]_ι_(phenylmethyl)propyl]amino]-carbonyl]-2,2-dimethylpropyl]amino decanoic acid,-dimercaptoethyl vinegar, mass spectrometry Data: m/z = 693 (M+H). 6 g of intermediate h 2 was dissolved in 1 mL of hydrochloric acid dissolved in isopropyl alcohol, stirred at room temperature for 2 hours, then the reaction mixture was concentrated and The mixture was treated with a mixture of di-methane and sodium carbonate in water. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to give 3.9 g (76%) of the deprotected intermediate in the free salt. m/z=593 (M+H). -64- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm). Loading line 1325783 A7 B7 V. Description of invention (63) 3.9 g of the aforementioned intermediate , 0.69 of gas acetic acid, 0.98 grams of HOBt and 1.38 grams of EDC, Dissolved in 100 ml of dichloromethane and stirred at room temperature overnight, then washed with brine, dried over magnesium sulfate and concentrated by evaporation. The crude product was purified on silica gel and placed in di-methane from 0 to 5%. The 5 methanol was washed to obtain 3_72 g (85%) of the desired intermediate i i 2-[(gas vinyl)amino]-3,3-dimethyl-N-[(lS,2R)-2 -Hydroxy-3-[(2-methylpropyl)[[2-(methylthio)-benzothiazide. -6-yl]sulfonyl]amino]-1-(phenylindenyl)propyl]-(2S)-butanamine, mass spectral data: m/z = 669 (M+H). 3.72 g of the intermediate 1111_ with 1.27 ml of meta-fluorophenylhydrazinamine was dissolved in DMF at 10 and stirred at 60 ° C for 2 hours, then the reaction mixture was concentrated and dioxane with carbonic acid in water The mixture was treated with a sodium solution, and the organic layer was dried over magnesium sulfate and evaporated to give &lt;RTI ID=0.0&gt;&gt;&gt; , 2R)-2-hydroxy-3-[(2-mercaptopropyl)[[2_(methylsulfanyl)benzo"sodium-6-yl]]]]]]]]]] Base) propyl)_3·methyl-L-decylamine amide, mass spectral data: m/z = 758 (M+H). The Intellectual Property Intelligence Bureau staff consumption cooperative printed 4.2 grams of the aforementioned intermediate, 1.2 grams of BoczO and 0_77 ml of triethylamine dissolved in 50 ml of di-methane, stirred at room temperature overnight and added 1.2 g. After 5 hours, the reaction mixture was washed successively with sodium carbonate solution dissolved in 20 water, brine, dried over magnesium sulfate, and concentrated by evaporation. The crude product was purified on silica gel and placed in 2 to 5%. The methanol in the stream was washed to obtain 3.2 g (67%) of the desired intermediate u ι_didecylethoxy)carbonyl]_N,_[(3-fluorophenyl)methyl]glycidyl-n_ [ (1S, 2R> 2-hydroxy_3-[(2-methylpropyl)[[2-(indolylthio) benzothiazol-6-yl] -65- This paper scale applies to China National Standard (CNS) A4 Specification (210x297 mm) 1325783 Α7 _ Β7 V. Description of invention (64) Sulfhydryl]amino H-(phenylindenyl)propyl]-3-methyl-L-nonylamine decylamine, mass spectrometry data: m/z = 858 (M+H). 3.2 g of the intermediate h-4 Μ 0.92 g of m-chloroperoxy benzoic acid (mCPBA) was placed in 100 ml of di-methane and reacted at room temperature. One and a half hours, then with carbon in the water After washing the sodium azide reaction mixture, it is dried with magnesium sulfate and concentrated to give 3.45 g (100%) of the desired intermediate 1 Ν, -[(1,1:methylethoxy) ethylphenyl) Glycosyl]glycine-based N-[(lS,2R)-2-hydroxy-3-[(2-mercaptopropyl)[[2-(methylsulfinyl)benzothiazole-6_ ]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]]] Let 0.5 g of the intermediate and 16.16 ml of n-(2-aminoethyl) 0 each bite in 10 liters of acetonitrile, react at 6 ° C for 1.5 hours, then concentrate the reaction mixture and place it in silicone. Purification, using 5 to 1% of methanol in a gas purge of dioxane, to obtain 24 g (46%) of the desired intermediate κ-ΐ5 [(1'1 monomethylethoxy) Alkyl]-N,-[(3-lphenyl)methyl]glycine hydrazino _ Ν_[( 1 S'2R)-2-hydroxy-3-[(2-methylpropyl)[[2 -[2-(pyrrolidinyl)ethylamino] benzothiazol-6-yl]amino]amino]]-(phenylmethyl)propyl]·3_methyl-L-decylamine Indoleamine, mass spectral data: m/z = 924 (M+H). Printed by the Department of Intellectual Property of the Ministry of Land and Economy, Employees' Consumption Co., Ltd. 0.15 g of the above intermediate was dissolved in 5 ml of HCl dissolved in isopropanol 20, stirred at room temperature for 2 hours, and then evaporated to prepare the crude compound. Purification by HPLC, 60 mg of the desired final compound 妓N,-[(3-fluorophenyl)methyl]glycine hydrazino-7-[(18,2 phantom-2-hydroxy-3-[(2_) Methylpropyl)[[2_[2_(pyrrolidinyl)-yl)ethylamino]benzothiazol-6-yl]sulfonyl]amino]-indole (phenylmethyl)propyl]_3 ς丄- -66-

1325783 A7 B7 V. INSTRUCTIONS (65) Amidoxime, bis-trifluoroacetate, in the form of a TFA salt, mass spectrometry data · m/z = 824 (M+H). Example _16: _ Preparation of compound 86 (R, = tomb, •. P9^吖

10 15 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed 20 〇·5g of Intermediate &amp; 016ml of 3_(Dimethylamino)propylamine in 10ml of acetonitrile at 60〇c After 2 hours, the reaction mixture was concentrated to give 0.54 g (100%) of desired intermediate ν'-[(1,1·didecylethoxy)carbonyl]-indole,-[(3-fluorophenyl) Methyl]glycine-yl-indole-[(1 S,2R)-2-hydroxy-3-[[[(2-[3-(dimethylamino)propylamino)] benzothiophene- 6-yl) 醯 ]]] (2-methylpropyl)amino] small (phenylmethyl) propyl]_3 methyl-L-rope amine, mass spectrometry data: m / z = 912 (Μ +Η). The above intermediate of 54 g was dissolved in 1 ml of HCl dissolved in isopropanol, stirred at room temperature for 2 hours, and then evaporated, and the crude compound was purified by preparative HPLC to give 83 mg. The last compound of the desired compound Zhao N'-[(3-fluorophenyl)indolyl]glyoximeyl_n_[(is,2R)-2-hydroxy·3_ [[[(2-[3-(methylamino) Propylamino]benzothiazole-6-yl)sulfonyl](2methylpropyl)amino]-1-(phenylindenyl)propyl]_3_methylguanamine amide _ Difluoroacetate, in the form of TFA salt, mass spectrometry data: ηι / ζ = 812 (Μ + Η). U1J7: Preparation of compound 87 (R, = isobutyl) -67- 1325783 A7 B7 V. Description of invention (66)

5 〇·5g of intermediate 1111_ with 0.18 mg of methyl, #-(2-?-4-ylethyl)amine in 10 ml of acetonitrile, reacted at 60 ° C overnight, then add 0.9 g The thiol group is added to the reaction mixture, and after two days of stirring, the reaction mixture is concentrated and placed in a silica gel to be placed in a methane methane. The % methanol is washed, and the desired intermediate ν, _[(ι,ι_dimethylethoxy)carbonyl]-Ν'-[(3- Fluorophenyl) fluorenyl]glycine 醯*_N_[(1S,2R)_2_hydroxy_3_ [[[(2-[沁methyl,#-(2_morpholin-4-yl)ethyl) ] stupid thiazole _6 base) succinyl] methyl propyl) amino] -1- (stupyl fluorenyl) propyl]-3-methyl-L-green amine sulphate, mass spectrometry data: m / z=954 (M+H). Printed by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumers Co., Ltd. 15 Dissolve 6 g of the above intermediate in 100 ml of HC1 dissolved in isopropanol, stir at room temperature for 2 hours, then evaporate and digest. The mixture is treated with a mixture of methane and sodium carbonate in water, and then the organic layer is dried over magnesium sulfate. The crude compound is purified by preparative Hplc to yield 424 mg (60%) of the desired compound. 3_fluorophenyl)methyl 2 fluorenyl]glycine fluorenyl-N-[(1S,2R)-2-ylamino-3_[[[(2曱曱基尽(2_?咐_4_基乙乙) Amino]benzothiazole_6-yl) continue fluorenyl](2·mercaptopropyl)amino]_ 1 (benylmethyl)propyl]-3-indenyl-L-sentamine Amine, bis-trifluoroacetate, in the form of a TFA salt, mass spectral data: m/z = 854 (M+H). The compound (1) listed below is in accordance with one of the above reaction charts -68- This paper scale applies to the Chinese National Standard (CNS) A4 specification (2丨〇X 297 public) 1325783 A7 B7 V. Description of invention (67 ) Prepared. Table 1

Printed by the Ministry of Economic Affairs, the Ministry of Finance and Industry

Compound number 圊 Table Ra Salt type / bicyclic stereochemistry 1 A -NH-CO-CH3 free base / (3R, 3aS, 6aR) + (3S, 3aR, 6aS) 2 A -NH-COO-C2H5 free base /(3艮3&amp;8,6〇11)+(38,3〇11 plus 8) 3 D -NH-CO-CH2-N(CH3)2 free base/OR^aSjaig+pSJaR/aS) 4 B -NH-(CH2)2-N(CH3)2 丄0H H free base /(3R,3aS,6aR)+(3S,3aR,6aS) 5 D free base /(3R,3aS,6aR)+( 3S,3aR,6aS) 6 D -NH-CH2-C00CH3 free base /(3R,3aS,6aR)+(3S,3aR,6aS) 7 D 9 ~ free base /QiUaS/aRHpSJaR^aS) 8 DH i r/~ NU-^ V_ HC1(1: lypiUaSAaig+pSJaRAaS) 9 AH -N(CH3)-COCH3 free base /OIUaSjaRHSSJaR^aS) 10 D \ 〇j free base /(3IUaS,6aR)+(3S ,3aR,6aS) 11 DH -NH-CO-CH2-N(CH3)2 free base /(3IUaS,6aR) 12 D π N plant free base /(3R,3aS,6aR) 13 DH 〇Nq Oleate (l:l)/(3R,3aS,6aR)—N—Q~/ \_ H -69- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 B7 , invention description (68) Ministry of Economic Affairs, Intellectual Property Bureau, employee consumption cooperatives, printing and integration No. Chart Ra Salt/Bicyclic Stereochemistry 14 D 〇/~] N-iL^V Η HCl(l:l)/(3R,3aS,6aR) 15 D Μ Ν Η Oxalate (1:1 )/ (3 R,3aS,6aR) 16 17 CD -nh-(ch2)2-n(ch3)2 Ο II Ν ΝΗ _N_J_/ \_/ 游离 Free salt base / (3R, 3aS, 6aR) free base / 3R,3aS,6aR) 18 B —CH3 free salt group/(3R,3aS,6aR) 19 B Η3〇γ° _ν~ο free salt group/(3R,3aS,6aR) 20 B —free salt group/(3R ,3aS,6aR) 〇, ( :h3 21 B νΗ 1~N, CH3( [-ch3 :h3 free base /(3R,3aS,6aR) 22 B -nh-(ch2)3-n(ch3)2 Free base /(3R,3aS,6aR) 23 B -NH-(CH2)2-NH(CH3) free base /(3R,3aS,6aR) 24 B !—N N-CH3 〇free salt base / ( 3R,3aS,6aR) 25 B -N〇Vh3 free base /(3R,3aS,6aR) 26 B r~\ —N Γ^-CH- free base /(3R,3aS,6aR) 27 C 〇A 1 W—Ch 〇 free salt base / (3R, 3aS, 6aR) -70- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) A7 1325783 B7 V. Invention description (69)

Ra Compound No. Chart Ra Salt/Bicyclic Stereochemistry 28 B CH3 Λο-. ch3 Free Salt / (3R, 3aS, 6aR) Table 2 Compound Number 圊 Table Ra Rb Salt / Bicyclic Stereochemistry 29 A &lt;〇ί2 )τΝΗ·&lt;2-0 than Wei) -νη&lt;χκή3 ^0^/(3R3aS,6aR)+&lt;3S3aR,6aS) 5 Table 3

Ministry of Economic Affairs Intellectual Property Bureau Employees Consumption Cooperatives Printed Compound Chart Ra No. Rb Salt/Ra-based Stereochemistry 30 D ϋίζ&quot; --- ch3 O H3C, H, C Free Salt Base /- 31 A CH, φνΧ ch3 -N (CH3)-CO-CH3 free base /- 32 A ch3 ch3 -N(CH3)-CO-CH3 trifluoroacetate (1:1)/- _ -—一_ -71- This paper scale applies + Guanjia Standard (CNS) A^^---% lattice (210x297 mm) 1325783 A7 B7 V. Description of invention (70) Compound number chart Ra Rb Salt/Ra-based stereochemistry 33 A Free salt-N (CH3 )-CO-CH3 /(3R,3aS,6aR)+(3S,3aR,6aS)

Table 4 Printed by the Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm). Line · 1325783 A7 B7 V. Description of invention (71) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Compound No. Table Ra Rb Salt / Ra-based stereochemistry 42 D h2n—into the free base /- 43 D h2N^^_ Xch3 -NH-CO-CH2-N(CH3)2 free base /- 44 B ch3 n-ch3 -NH- (CH2)2-N(CH3)2 free base/±trans 45 B CH3 1~O free base /- 46 B nch3 1~O free base /- 47 B /CH3 1~O trifluoroacetate (1:1)/- 48 B Vyri^ -nh-(ch2)2-n(ch3)2 free base /49 B iTV^0^ free base /50 B 1~O trifluoroacetate ( 1:1)/- 51 B -NH-(CH2)rN(CH3)2 free base / 52 B 6r. / CH -nh-(ch2)3-n(ch3)2 free base /53 B CH -nh-(ch2)3-n(ch3)2 free base /- 54 BV/l 13 CH3 -nh- (ch2)3-n(ch3)2 Free base /- -73- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 B7 V. Invention description (72) Ministry of Economics intellectual property Bureau employee consumption cooperative printing

Compound Number Chart Ra Rb Salt/Ra-based Stereochemistry 55 B Free Salt Group /- Η -Η Ο 56 B -nh-(ch2)2-n(ch3)2 Free Salt Group /3S 57 B ϊτν^°^ _w /v_nQnh Free base / 58 B CH, gossip Η \_J free base / 59 B t_/ 3 -^~ry free base /- 60 B Ι^Ν CH3 ~^ry free base /- 61 D - In. Free salt base /- 62 D η2ν ch3 -Λ~ο Free salt base /- 63 B 〇-〇/ ο —Μ, —Ν\ /N-CH3 free base /3 S 64 B Ο·. / Ο λ^_ ^~\ —^^Ν-0Η3 Trifluoroacetate (1:1)/3S 65 B η2ν ch3 Ο 1 \_/~ is called free base /- 66 BH/J CH3 0 1 VvN_CH3 Fluoroacetate (1:1) / - 67 B £ &gt;. / 1 Vj 盐 盐 / / / / 3S -74- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 B7 V. Description of invention (73) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 I________B7 V. Invention description (74) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed Structure Structure 04 16 90 〇·,λΧ$λ -^ i X (1-stupyl-3-{[2-(2-dimethylamino)ethylamino)-benzothiazole-6-sulfonyl]-isobutyl-amino} -2-hydroxy-propyl)-carbamic acid tetrahydro-n-butyl-3-yl ester (1-phenylhydrazin-3-{[2-(2-didecylamino-ethylamino)-) Benzothiazole-6-sulfonyl]-isobutyl-amino}-2-hydroxy-propyl)-amino decanoic acid hexahydro-furo[2,3-b]furan-3-yl 20 1-Benzyl-2-ylamino-3-{iso 88 93 butyl-[2-(2- η 洛 小 小 --ethylamino)- 笨 and U plug. Sodium-6-ylidene]-aminopropylpropyl)-amino carboxylic acid hexahydro- ol 4 and [2,3-b]吱0^ -3·yl ester (1-benzyl-3-({2) -[(3-dimethylamino-propyl)-methyl-amino]- benzopyrazine-6-sulfonyl}-isobutyl-amino)-2-hydroxy-propyl)- Hexahydro-furo[2&gt;b]furan-3-yl carbazate (1-benzyl-3-({2-[(1-ethyl-pyrrolidin-2-ylindenyl))) ]]-benzoquinone 3 plug. sit-6-continuation base}-isobutyl-amino)·2·hydroxy-propyl)-carbamic acid hexahydro-furo[2,3-b]furan- 3-Based ester __ Compound number 圊 Table Ra Rb salt / Ra based stereochemistry 81 A -N(CH3)-CO-CH3 free base /- 82 A -N(CH3)-CO-CH3 free base / - CH3 83 AA -N(CH3)-CO-CH3 free salt group A* HO CH3 84 A HsCTV^ , N, 〇' . -nh-c〇-ch3 free salt group /- An example of the compound of the present invention is shown Table 5 Table 5 This paper scale applies to China National Standard (CNS) A4 specification (2丨0x297 public Chu) 1325783 A7 B7 V. Description of invention (75) 87 Structure 86 85 Ν''[(3-fluorophenyl) )methyl]glycidyl-N-[(1S,2R)-2-M&amp;-3-[[[2-[N-methyl, N'(2-?咁·4·yl) ) Amine-yl] thiophene and stupid. -6-yl]sulfonyl](2-mercaptopropyl)amino]-l-(phenylmethyl)propyl]-3-indolyl-L-nonylamine decylamine, bis-trifluoro Acetate N'-[(3-IL phenyl)methyl]glycidyl-N-[(1S,2R)-2-hydroxy-3-[[[2-[3-(dimethylamine) Propylamino]benzothiazide "sodium-6-yl]sulfonyl]](2-methylpropyl)amino]-1-(phenylmethyl)propyl]-3-indenyl -L-Amidoxime, bis-trifluoroacetate T 4 does not. Diphenyl)methyl]glycolyl-N-[(lS,2R)-2-hydroxy-3-[(2-methylpropyl)[[2·[2-(pyrrolidin])yl) Ethylamino]benzothiazol-6-yl]sulfonyl]-amino]-1-(phenylindenyl)propyl]-3-indolyl-L-nonylamine decylamine, bis-trifluoro Acetate Table 6 The following compounds were also prepared and evaluated according to the method described below. Column 3 shows the results of pEC50 against wild-type virus (ΠΙΒ), and column 4 shows that pEC50 is resistant to wild-type virus strain f As a result of (R13025), column 5 shows the results of pEC50 against wild-type virus strain S (R13080). Ministry of Economic Affairs, Intellectual Property Bureau, Staff and Consumer Cooperatives, Printed Paper Scale Applicable to China National Standard (CNS) A4 Specification (210x297 mm) 1325783 A7 B7 Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumption Cooperative Printed 5, Invention Description (76) Compound No. Structure HIV-AVE- HIV-AVE-HIV-AVE-MT4-MTT-MT4-MTT-MT4-MTT-IIIB-2-002 R13025-2-002 R13080-2-pEC50 pEC50 002 pEC50 100 8.88 7.36 7.15 101 ~0 6.62 102 7.92 6.88 6.02 103 7.7 6.76 6.28 104 7.18 105 7.33 7.25 6.32 106 . Threat: seven 7.96 7.26 6.66 107 8.7 6.8 6.18 108 7.61 6.54 6.09 109 5.68 5.38 110 8.09 6.17 5.81 111 7.61 6.63 6.18 112 άα.^κ&gt; 8 6.91 6.82 113 8.29 7.61 7.36 -78- This paper scale applies to Chinese national standards (CNS) A4 specification (210x297 mm) 1325783 A7 B7 V. Invention description (77) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Printed Compound No. Structure H1V-AVE- HIV-AVE- HIV-AVE- MT4-MTT- MT4 -MTT- MT4-MTT-IIIB-2-002 R13025-2-002 R13080-2-pEC50 pEC50 002 pEC50 114 7.69 7.47 6.85 115 6.12 5.21 5 116 7.5 7.49 7.36 117 7.32 7.45 6.72 118 6.52 - 119 6.48 120 6.5 121 7.68 5.55 5 122 .0 5.92 123 0, 4 people ¢ / 5.8 124 C' 5.7 -79- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing 1325783 A7 B7 V. INSTRUCTIONS (78) Compound No. Structure HIV-AVE- HIV-AVE-HIV-AVE- MT4-MTT- MT4-MTT- MT4-MTT-IIIB-2-002 R13025-2-002 R13080-2- pEC50 pEC50 002 pEC50 125 8.2 7.57 6.84 126 7.31 5.5 5 127 7.7 8 7.5 6.87 128 8.23 7.72 7.25 129 7.2 130 7.23 131 7.33 6.08 5.98 132 7.19 . 133 〆 〆 7.67 7.47 6.8 134 7.21 135 &amp; fat &gt; ' 7.18 136 6.14 137 5.77 -80- This paper scale applies to Chinese national standards ( CNS) A4 size (210 X 297 mm)

Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1325783 A7 B7 V. Description of Invention (79) Compound No. Structure HI V-AVE- HIV-AVE- HIV-AVE- MT4-MTT- MT4-MTT- MT4-MTT-IIIB- 2-002 R13025-2-002 R13080-2-pEC50 pEC50 002 pEC50 138 0 V 5.84 139 5.68 5.51 5 140 cp, person ^ 8.34 8.12 141 7.83 6.49 6.02 142 5.25 143 e j&gt;, 7.13 5 5 144 f life: 3⁄4 0 145 K 7.9 7.4 6.84 146 8.02 6.52 6 147 647 148 6.43 6.51 6.56 149 7.29 150 7.37 6.79 6.18

-81- This paper size applies to China National Standard (CNS) A4 specification (210x297 mm)

1325783 V. INSTRUCTIONS INSTRUCTIONS (80) Ministry of Economic Affairs Intellectual Property Office Staff Consumption Cooperation Du Printing Compound No. Structure HIV-AVE- HIV-AVE- HIV-AVE- MT4-MTT- MT4-MTT- MT4-MTT-ΙΠΒ-2- 002 R13025-2-002 R13080-2-pEC50 pEC50 002 pEC50 151 6.97 6.09 5.57 152 7.48 6.25 5.76 153 8.13 7.34 6.47 154 ~ This Lu 8.26 7.42 6.43 155 7.37 7.61 7.49 156 8.14 8.27 7.56 157 O^^CO^. 7.54 7.5 . 6.85 158 or’^cc)·^0 8.48 8.1 7.52 159 {r’-^co·人. ’ 8.1 7.78 7.46 160 7.29 6.32 5.61 161 o^. 1-备丨8.04 7.76 7.47 162 7.69 7.33 6.8 163 cr'名丨OOk) 7.94 7.31 6.67 164 cr'-^kx&gt;-k&gt; 8.15 7.47 6.8 -82- This paper scale applies to the Chinese National Standard (CNS) A4 specification ( 210 x 297 public meals) 1325783 A7 B7 V. Description of invention (81) Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperatives Printed Compound No. Structure HIV-AVE- HIV-AVE- HIV-AVE- MT4-MTT- MT4-MTT- MT4 -MTT-IIIB-2-002 R13025-2-002 R13080-2-pEC50 pEC50 002 pEC50 165 Cr-^'CO-^O 7.35 6.91 6.2 166 8.2 7.66 7.13 167 X o 8.31 7.51 6.85 168 7.61 7.5 6.87 169 cT 8.07 8.17 7.45 170 0 8.12 7.76 6.79 171 o 7.29 6.73 6.07 172 p. Boundary 7.37 6.61 6.09 173 8.25 7.52 6.81 174 \-T〇ν· 8.04 6.88 6.18 The paper size applies to the national standard (CNS) A4 specification (210x297 mm) 1325783 A7 B7 V. Description of invention (82) Intellectual property of the Ministry of Economic Affairs Bureau employee consumption cooperative printed compound serial number ΐί constitutive HIV-AVE- HIV-AVE- HIV-AVE- ΜΤ4-ΜΤΤ- ΜΤ4-ΜΤΤ- ΜΤ4-ΜΤΤ-ΙΙΙΒ-2-002 R13025-2-002 R13080-2-pEC50 pEC50 002 pEC50 175 *s 7.3 6.03 5.5 176 8.39 7.2 6.65 177 7.43 8.12 7.31 178 7.76 7.97 7.47 179 8.05 7.24 7.32 180 6.81 6.05 5 181 7.48 6.28 5.74 182 8.32 7.44 - 6.77 183 &lt;r again?^ 8.45 8.77 8.15 184 7.76 8.35 7.57 185 ~' 7.34 7.48 7.46 85 7.24 186 8.21 8.18 7.54 86 I. -84- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1325783 A7 V. Description of invention (83) Compound number structure HIV-AVE- HIV-AVE-HIV-AVE-MT4-MTT-MT4-MTT- MT4-MTT-IIIB-2-002 R13025-2-002 R13080-2· pEC50 PEC50 002 dEC50 187 188 6.7 7.03 6.88 189 7.35 6.99 6.86 Anti-virus Fraction: This issue The compounds of the compounds were examined for their anti-viral activity by cellular assays, and it was demonstrated in the analysis that these compounds exhibited potential HIV strains against the wild-type laboratory (HIV-1 strain LAI). For anti-HIV activity, this cytological assay was performed according to the following procedure. Cytological analysis (Cellular Assav&gt;f test method: HIV: or mock-infected MT4 cells were cultured for five days in the presence of various concentrations of inhibitors, and at the end of the culture period, all of the HIV-infected fine 15 cells were The replicated virus in the control culture without any inhibitor is killed, and the viability of the cells is determined by measuring the concentration of strontium, which is a yellow, water-soluble tetrazolium bracelet dye, which is only in the particles of the surviving cells. In the line body, it will be converted into purple, inzaan which is insoluble in water. After dissolving the formed wax crystals with isopropanol, the absorbance of the solution is monitored at 54 〇ηπι, which is directly related to Upon completion of the five-day incubation, the number of viable cells remaining in the culture was correlated, and the inhibitory activity of the compound was monitored on the virus-infected cells and expressed as EC% and EC9g, respectively -85-x 297 PCT) The paper size i§帛中关家标准(CNS)A4 specification (21^ 1325783 A7 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printed a B7 V. Invention description (84) Representative needs protection 50% and 90% Cell free The cytopathic effect of the δ substance, the toxicity of the compound is determined on the simulated-infected cells and is expressed as CCso, which represents the compoundity of the compound that needs to inhibit 50% of cell growth, selectivity index (SI) ( The ratio of CC5〇/EC5() is a selective indicator of the anti- 5 HIV of the inhibitor. Compounds 1-4, 7, 9-19, 21, 24-26, 28, 33-35, 37-43 45, 46, 49, 50, 56 '61-64, 66, 68, 70, 71, 75, 79-83 and 88-93 all against HIV-1 strain LAI all have EC% values less than 50 nM, these compounds The si range is between about 400 and 10 up to more than 47,000. Compounds 5, 6, 20, 22, 23, 29, 36, 44, 47, 48, 51-55, 58, 59, 69, 72-74, 76- All of 78 and 84 have an EC50 value between 50 nM and 500 nM against the HIV-1 strain, and the SI range of these compounds ranges from about 26 up to over 1900. 15 Compounds 27, 30, 3, 57 with 60 has an EC5G value against the prion strain LAI greater than 5〇〇nM, and the SI range of these compounds ranges from greater than 13 up to over 183. Antiviral 圄20 due to increased production of drug-resistant HIV strains The compounds of the present invention are tested for their potential against a number of variant strains of clinically isolated HIV strains that are associated with resistance to protease inhibitors and which cause the drug to be sold to the drug [eg Safana Saquinavir, ntonavir, nelfinavir, indinavir 'An-86- This paper scale applies to the Chinese National Standard (CNS) A4 specification (2丨〇 x 297 mm)

1325783 A7 B7 V. INSTRUCTIONS (85) The amprenavir exhibits varying degrees of phenotypic interaction-resistance. Results: As for the broad-spectrum activity of the compound of the present invention, it is evaluated as FR (resistance (FR)], which is defined as FR = EC5 〇 (variant strain) / EC5 〇 (HIV-1 strain LAI), Table 7 shows the results of antiviral tests expressed as fold resistance, and as seen in the table, the compounds of the present invention are effective for inhibiting a wide range of mutant strains. Printed by the Intellectual Property Office of the Ministry of Economic Affairs, the consumer cooperatives. This paper scale applies the Chinese National Standard (CNS) A4 specification (210x297 mm). 1325783 A7 B7 Ming Mingfa, 5 Ministry of Economic Affairs Intellectual Property Bureau employee consumption cooperative printing

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Description of invention (88) Divination; τΤ CS vd cs v〇go On 〇CN rvi CN o ° O 〇Os uS vo On SS CN wS &lt;Ν ΓΛ ψ &lt; δ VC VO ΟΝ Ό ΓΊ σ\ m ΟΟ Γ〇οο cs vd CN vq 寸寸卜'ζΤ og vb p 〆v〇vS 卜寸 νο σ\ ο 00 VD \〇ν〇σ\ ο 〇\ ^£&gt; _ &lt; 1 II 1 1 1 1 1 1 1 1 \〇o 1 1 1 1 1 1 1 1 σ 1 II 1 1 1 1 1 1 1 1 m &lt;N 1 1 1 1 1 1 1 1 Ρ-ι 1 1 1 1 1 1 1 1 1 1 1 CS o 1 1 1 1 1 1 Ο Ο Ο CN \S cs o CN 'OO p Γ&lt;ί CS r«S ο &lt;〇^3- οοό r—( » &lt; • &lt ; ζ 1 I 1 1 1 1 1 1 1 1 1 ON 1 1 I 1 ( 1 1 1 1 1 tt 1 1. 1 1 1 1 1 卜 o 1 1 1 1 1 ( I 1 - 1 t 1 1 t 1 1 1 1 1 1 CN 〇1 t 1 1 1 I 1 1 . 1 1 &lt; 1 tt 1 &lt; 1 1 1 1 1 1 1 i I 1 1 CN inch·&lt;N vd cs CO CN m 〇&lt;S 卜vq vo 〇T—^ inch oi S CS 0\ rS ΓΛ rn ρ inch 1—Η r—^ ^rr·^ inch σ\ τ*Η C5 1 tr * rn cn 〇\ CN rn m CN m OO — OO CS rn &inch&lt;N 卜 CS CN CN 〇ΓΊ » 4 &lt;Ν m 〇d κ οο ο vq oov〇v〇vq CN CS uS CS CO 〇\ 〇\ o ΓΛ 卜CN Ον 弍00 〇\ ν〇rS CN CN ο 1 1 1 1 1 1 « 1 1 « 1 1 1 1 « II 1 , ' 1 04 Ο CN VO cn CS VO CS Rm mm CN &lt;S 卜 CS m in tt vq inch · 〇*〇V〇 inch v〇〇\ CN Ο 5 ζΐ vd _ Η 〇\ OO (3⁄4 1 1 1 l 1 » 1 1 1 1 1 Bu 1 1 1 I 1 I 1 ο 1 1 1 1 1 1 1 j 1 1 1 vq 1 1 1 1 1 1 1 1 υ 1 1 1 1 1 I 1 1 1 1 1 vq 1 1 1 1 1 1 1 i » 1 1 1 tti 1 i 1 1 1 1 1 1 1 1 1 1 1 1 &lt;! J 1 1 t 垂 1 t 1 1 1 1 1 1 1 1 1 1 1 1 1 1 ί μ 1 &gt; 4 » _H »— HH — one — one CN «ο m &gt;〇VO OO VO 0\ s 3 CN Ό m Ό s VO v〇OO vo S ο CS ρ jn v〇j Bu called-90- This paper scale applies to China National Standard (CNS) A4 specification (210x297 public) PCT)

1325783 A7 B7 V. INSTRUCTIONS (89 Ministry of Economic Affairs Intellectual Property Office Staff Consumer Cooperative Print δ ί CO Η § rn Ο οο \c κ' VO £ m — *—4 cs Ό 〇 6 inch os οι τΉ CN ρ &lt; ο mm ν〇CS ο CN 〇\ oi 寸 Os ro v〇CN v〇S OO OO CN f &lt; \q cs mg OO vo I 1 1 1 1 1 1 Ο « 1 t 1 1 t 1 Ρ-( I 1 I 1 1 1 1 Ο Ον 〇6 Ξ inch s w-ϊ v〇2: I 1 1 1 1 1 1 s 1 1 1 1 l 1 1 1 I i 1 1 1 1 1 1 1 1 1 1 〇\ &lt;Ν ΟΟ cK ν〇卜' »—η VO 〇\ CS to 2 Ό 〇\ η 0\ fi 〇\ Ον m inch·•^r inch 〆 om κ νο οΐ oi Τ—Η v〇S vo Ti· ο I 1 1 1 1 1 1 1 1 1 1 1 1 1 1 υ II 1 1 1 1 1 C5 1 ( 1 1 1 1 1 i &lt;: 1 1 1 1 1 1 . 1 — — — m &quot;H — Ο U 〇〇〇\ § OO cs OO r〇OO s ^£09 -5ΌΓ47!〇Moo Light Oi iS VCQ pQv Zhang applicable China National Standard Scale (CNS) A4 size (Shu 0x297 mm 2) 1325783 A7 B7 five instructions (90) for the control codes of the invention, the following strains

Variant strains associated with strains A L10I, K20R, Μ36Ι, I54V, A71V, V82T, I84V B L10I, K20R, L24I, Μ36Ι, I54V, L63P, A71V, V82T, I84V C L10I, K20R, Μ36Ι, Μ46Ι, I54V , L63P, A71V, V82T, L90M D L10I, Μ36Ι, I54V, L63P, A71V, G73S, I84V, L90M E L10I, K20R, L24I, Μ36Ι, Μ46Ι, I54V, L63P, A71V, G73S, V82T, I84V, L90M F L10I , Μ46Ι, L63P, A71V, I84V G L10I, L24I, M36V, Μ46Ι, I54V, L63P, A71V, V82T, I84V Η L10I, K20R, Μ36Ι, L63P, A71V, G73S, V77I, I84V, L90M I L10I, Κ20Μ, I54V , L63P, A71V, I84V, L90M J L10I, Μ36Ι, Μ46Ι, L63P, A71V, V77I, I84V, N88D, L90M κ L10I, Μ36Ι, I54V, L63P, A71V, V82T, L90M

Variant strains associated with strains L L10I, L24I, G48V, I54V, V77I, V82T, L90M Μ L10I, L24I, Μ36Ι, I54V, L63P, V82T, L90M Ν L10I, Μ46Ι, I54V, L63P, A71V, V82A, L90M 0 L10I, L24I, Μ36Ι, I54V, L63P, A71V, I84V Ρ L10I, D30N, L63P, V77I, N88D Q L10I, K20R, I54L, L63P, A71V, G73S, L90M R L10I, Μ46Ι, I54V, L63P, Α71Τ, V77I , V82A, L90M S L10F, Μ46Ι, L63P, A71V, I84V Τ V32I, Μ36Ι, Μ46Ι, I47V, I50V, L63P, L90M U L10F, Μ46Ι, I47V, L63P, A71V, I84V Printed by the Intellectual Property Office of the Ministry of Economic Affairs Bioavailability: The bioavailability of the compounds of the present invention is determined in rats, and 20 compounds are administered orally or intraperitoneally. After administration, the mice are sacrificed at different time points to collect whole blood and The standard method of treating serum, the concentration of the compound in the serum is obtained by titrating the anti-HIV activity present in the sample according to the method described above, and the serum concentration is also determined by hplc-ms. -92-This paper scale applies to China National Standard (CNS) A4 specification (210x297 public interest) Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 1325783 A7 B7 V. Description of invention (91) Protease-binding analysis: known, human The combination of a serum protease [such as albumin (HAS) or alpha-1 acid chymotrypsin (AAG)] may result in a decrease in the effectiveness of those compounds 5, in order to determine whether the compounds of the invention will be affected by such binding. The adverse effects were determined by measuring the anti-HIV activity of the compounds in the presence of human serum, thereby assessing the effect of protease inhibitors on the binding of those proteases. 10 Pharmacokinetic data: Rats and dogs were tested for pharmacokinetic properties of compounds 20, 88 and 90. These compounds were evaluated from Iffa Credo, a Whistar rat weighing approximately 350 g, and the animals were banned prior to administration of the drug. After eating overnight (about 12 hours of fasting), the compound was dissolved in DMSO, and the results presented in the table are about 15 results of oral administration of the compound, and the blood is taken at 30_min, 1 hour, 2 hours, Without pre-dose sample down-sampling, the amount of compound in the biological sample was determined using LC-MS. In the table below, "or" represents oral administration and "mpk" represents milligrams per kilogram. The results are shown in Table 8. 20 -93- This paper size applies to national standard (CNS) A4 specification (210x297 mm)

Claims (1)

1325781 A8 B8 C8 D8 Patent Application No. 91108400 ROC Patent Appln. No.91108400 Approved unlined application in the scope of the lyrics Amended Chinese Claims - Encl.fID Annex (II) --imsTUi-six*^卞1 Shen Yiyi 1 Wai (reported on May ^, 2006) 1. A compound of formula (1) The Intellectual Property Office of the Ministry of Economic Affairs and the Consumer Consortium prints its N-oxides, salts, stereoisomers and racemic mixtures, where R is a phenyl CG_6 alkyl group or a hexahydro group which can be substituted by _ or CN6 alkyl. Furando[2,3-b]furanyl or tetrahydrofuranyl which may be substituted with di(Cw alkyl)amino group 10; Κ·2 is nitrogen; L is -C(=0),-0-C(=0 , -NH-Ck alkanediyl-C(=0)-NH-CR'K:&quot;alkanediyl, wherein R' is C〇-8 alkyl; R3 is phenyl Ck alkyl; 15 R4 is Hydrogen, C!_6 alkyl, pyridyl Cualkyl or pyridylamino-based Ci.6 alkyl; A is -C(=0)-, Ci.8 dienyl or -C(=0)-C! .6 alkyl; R5 is hydrogen, Ci-6 alkyl or Cm alkylcarbonyl; and R6 is Ci_6 alkyl, bis(Cl-6 alkyl)amine, σ ratio 11 bite or 20 20 . 2. A compound according to claim 1 wherein R is phenyl C, -6 alkyl, hexahydrofuro[2,3-b]furanyl or may be substituted by dentate or Cu alkyl Di(Ci_6 alkyl)amino substituted tetrahydrofuranyl; and 95- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 91170b-connected 1 1325783 Α8 Β8 R3 is a phenyl CU4 alkyl group. 3. A compound according to claim 1 or 2, wherein 0-C(=〇)-〇4' is a compound according to claim 1 or 2, wherein 5 hexahydro-furo[2] , 3-b]-furanyl. 5. A compound according to claim 1 or 2, wherein the tetrahydrofuranyl group. 6. A compound according to the scope of claim 2 or 2, wherein the phenylhydrazine group. L is, Ri is a compound according to claim 1 or 2, wherein the Ci-6 is a hospital base. 8. According to the compound of the scope of patent application No. 7, wherein the base 0 R4 is printed for the employee consumption cooperative of the Intellectual Property Office of the Ministry of Economic Affairs. 9. According to the compound of the scope of claim 8 of the patent, the κ is the butyl base. 10. A compound according to claim 1 or 2, wherein the nitrogen or Ci-6 yard base. 11. A compound according to claim 10, wherein Rs is hydrogen. 12. A compound according to claim 10, wherein the Han 5 is a methyl or ethyl group. 13. A compound according to claim 12, wherein K is a thiol group. 14. A compound according to claim 1 or 2 wherein A is Ci-6. Κ·5 is 20 -96 This paper scale applies to China National Standard (CNS) A4 specification (2丨〇 297 297 mm) A8 B8 C8 D8 Printed by the Intellectual Property Office of the Ministry of Economic Affairs, Consumers' Cooperatives 1325783 VI. Scope of Application for Patentes 15. According to the compound of Article 14 of the patent application, A is B. 16. According to the compound of claim 1 or 2, 116 is 11 ratio. Each 11 is fixed. The compound according to claim 1 or 2, wherein 116 is an amine group; and each of the amine groups is substituted with two substituents selected from C, -4 alkyl groups. 18. A compound according to claim 17 wherein R6 is a dimethylamino group. 10 19. The compound according to claim 1 of the patent application, which is selected from the group consisting of: (1-benzyl-3-([2-(2-dimethylamino-ethylamino)-benzothiazole) -6-石黄-based]-isobutyl-amino}-2-yl-propyl-propyl)-amino decanoic acid hexaaza-pyrano[2,3-b]pyran-3-ylxi Purpose, (1 - phenylhydrazin-3 -{[2-(2-dimethylamino-ethylamino)-phenylhydrazine. 塞°坐-6_ 15 酿 ]]-isobutyl-amino group }^-2-P-propyl-propyl)-amino phthalic acid tetrazo-Df-amyl-3-yl ester, 1-benzylmethyl-2-carbyl-3-{isobutyl-[2-( 2-π ratio 0 π定-1 -yl-ethylamino)-benzoquinone ° π sitting-6-termyl]-amino}-propyl)-amino citrate hexanitro-D M-[2,3-b]furan-3-yl ester, 20 (1-benzyl-3-({2-[(3-dimethylamino-propyl)-methyl-amino]] -Benzene 弁β塞β坐_6_ 酿 异 异 - - - 胺 -2- -2- 经 - - _ _ 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2喃-3-yl S, (1-benzoinyl-3-({2-[(l-ethyl-π-Binging) 2-amino-2-yl)-amino]-benzothiazole-6 -sulfonyl}-isobutyl-amino)-2-hydroxy-propyl)-carbamic acid-97 - This paper scale applies to China National Standard (CNS) A4 specification (210x297 MM) 1325783 A8 B8 C8 D8 VI. Scope of Patent Application Hexanitrofolphine [2,3-b]nf--3-yl-S. 20. A method for preparing a compound according to the following chart G. According to the method of claim 1 of the patent scope, NH CISO3H R2 OH Ri PG, n^ 'V^, Ν^l! JL &gt;~SMe —^ u X.^ *SMe (g-3) k2 Th \ , N SOv ^—SMe (g-1) (g-2) (g-4) 10 PG, (g-6) , R5 1) hn. AR^ 2) Deprotection (g-5) s〇2^Vs R5 15 R2 〇H 匕(g-7) AR^ xx&gt;Rr^N&quot;^''N&quot;S〇2'V^1-SK hk OH AR^ Ministry of Economics Printed by the Property Bureau Staff Consumer Cooperative (g-8) 20 series includes the following steps: a) reacting the benzothiazole derivative g-1 with gas sulfonic acid, followed by reaction with thiopurine to form intermediate product g-2, b The intermediate product g-2 is reacted with the intermediate g-3 to produce an intermediate g-4, wherein PG is a protecting group, -98 This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm). 10 Ministry of Economic Affairs Intellectual Property Bureau Staff Consumer Cooperative Printed 20 1325783 A8 B8 C8 VI. Application Patent Range c) Let Intermediate G-4 React Intermediates g_5 and g_6, d) reacting intermediates g_5 and g-6 with a compound of formula HN(R5)A-R6 followed by deprotection to produce intermediate g-7, e) which may then be g_7 and formula RrL_ The intermediate (release base) reacts to give compound g-8. 21. According to the method of claim 2, the protection of Boc. The earth is 22. The step (c) according to any one of the 20th or 21st of the patent application is selected from the group consisting of m-chloroperoxybenzoic acid or magnesium monoperoxybenzoate hexahydrate. Proper reagents are used. . - 23. A pharmaceutical composition of a protease that inhibits multiplex-drug-resistant retroviruses in a mammal infected with a retrovirus, comprising an effective amount of any of i-19 of the scope of the patent application a compound and a pharmaceutically acceptable excipient. 15 24· A pharmaceutical composition for treating or combating infections and diseases, which is associated with a multi-drug-resistant retroviral infection of a mammal, comprising an effective amount at least in accordance with claims 1 to 19 A compound of any of the compounds and a pharmaceutically acceptable excipient. 25. A method of inhibiting replication of a multiplex-drug resistant retrovirus in vitro, comprising contacting the retrovirus with an effective amount of a compound according to any one of claims 1 to 19. 26. The pharmaceutical composition according to claim 23 or 24, wherein the retrovirus is a human immunodeficiency virus (Hiv). 27. According to the method of claim 25, the retrovirus 99 - paper scale applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1325783 A8 B8 C8 D8 VI. Patent application scope is a human immunodeficiency virus (HIV). 28. The compound according to claim 1 or 2 of the patent application, which is used as a medical drug. 29. Use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament for the treatment or protection of a disease associated with infection or by a mammalian multi-drug resistant retroviral infection. use. 30. Use of a compound according to any one of claims 1 to 19 for the manufacture of a medicament for inhibiting multiplex-drug resistant retroviruses in mammals infected with the retrovirus 10 Use. 31. Use of a compound according to any one of claims 1 to 19 for the manufacture of an agent for inhibiting replication of a multi-drug resistant retrovirus. The use according to any one of claims 29 to 31, wherein the retrovirus is a human immunodeficiency virus (HIV). 33. The compound according to claim 1 of the patent application, wherein the compound is : Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperative, Printed (1-Benzyl-3-{[2-(2-didecylamino-ethylamino)-benzoquinone), sitting on a -6-20 sulfonate Mercapto]-isobutyl-amino}-2-hydroxy-propyl)-carbamic acid tetrahydro-furan-3-yl vinegar, 1-benzylidene-2-radio-3 - {isobutyl -[2-(2-πΛΒ each D-1,4-yl-ethylamino)-benzo-S-substyl]-amino}-propyl)-carbamic acid hexaaza-D-f- s-[2 ,3-b]furan-3-yl ester, -100 - This paper scale applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1325783 A8 B8 C8 D8 VI. Patent application range (1-benzoquinone) -3-({2-[(3-Didecylamino-propyl)-fluorenyl-amino]-benzoquinone °°°-6-石黄-based}-isobutyl-amino group) -2-light-propyl)-carbamic acid hexamol, β-Nanthene [2,3-b]n. South-3-based vinegar. Ordered by the Ministry of Economic Affairs, Intellectual Property Bureau, Staff Consumer Cooperatives, ο This paper size applies to the Chinese National Standard (CNS) A4 specification (210x297 mm)