TW200906392A - Protease inhibitors - Google Patents

Abstract

Compounds of the formula II: wherein R2 is the side chain of leucine, isoleucine, cyclohexylglycine, O-methyl threonine, 4-fluoroleucine or 3-methoxyvaline; R3 is H, methyl or fluoro; R4 is C1-C6 alkyl; E is a bond or thiazolyl, optionally substituted with methyl or fluoro; n is 0 or 1; or a pharmaceutically acceptable salt, N-oxide or hydrate thereof; have utility in the treatment of disorders characterized by inappropriate expression or activation of cathepsin K, such as osteoporosis, osteoarthritis, rheumatoid arthritis or bone metastases.

Description

200906392 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to inhibitors of cysteine protein 醢%, especially papain, which are inhibitors of the steroid family. The present invention is useful for the prevention or treatment of physiological protein heads, such as those derived from cathepsin. Novelization of disorders in which leanase is unbalanced [Prior Art] The papain of the cysteine protease is a widely distributed genus of mammals, invertebrates, protozoa, scorpions and bacteria. Among the various species. Many mammalian cathepsins including cathepsins B, F, h'K, t ^ ^ KL, 〇 and § have been assigned to this superfamily & leeches and their inappropriate regulation of activity has been implicated in including arthritis, muscle atrophy Disease, inflammation, spheroid nephritis and a variety of metabolic disorders of tumor invasion. Pathogenic cathepsin-like enzymes include B. gingivalis, malaria, sputum, m, etc., and from Pneumocystis carinii, Trypanosoma cruzi, and Trypanosoma brucei (7> (10), the genus C. cerevisiae (CWr/n. Shan·/(4)·(3), schistosomiasis (Sc/nWoioma spp) cysteine protease. Improper regulation of cathepsin K has been implicated in including osteoporosis, Among the various diseases such as gum disease and periodontitis, Paget, s disease, malignant hypercalcemia and metabolic bone disease, in view of its destruction in the chondrocytes of the synovium of osteoarthritis At higher levels, cathepsin K is involved in diseases characterized by excessive degradation of cartilage or matrix, such as osteoarthritis and rheumatoid arthritis. 129860.doc 200906392 Will often "Soul osteophytes and cartilage disorders A population of patients who may be at or near the aging stage will be administered a tissue protein inhibitor for the rest of their lives. This situation is an unreasonable requirement for the simplicity of the suspiciousness of such a condition, and an attempt is made to Current osteoporosis The dosage range of the drug is extended to a weekly or longer dosing range to aid compliance. However, even if the administration is improved, other side effects of the bisphosphonate are still present. The bisphosphonate blocks the bone turnover. It does not attenuate skeletal transformation like a cathepsin inhibitor. The important line for healthy bones maintains the re-formation of bisphosphonate blockade. In addition, bisphosphonates have extremely long half-lives in bone, so If bone necrosis such as granules occur, it is impossible to remove the double scale H from the bone network and the phase & 'the cathepsin κ inhibitor usually has a faster start = stop rate senile mode, which means if the identification If there is a problem, the administration can be stopped and the inhibitor will not accumulate in the bone matrix. Therefore, alternative osteoporosis and osteoarthritis drugs with excellent pharmacokinetic and/or pharmacodynamic properties are required. International Patent Application Compound No. WO 02/〇57270 discloses a compound of formula I:

VIII VWXγ roughly corresponds to p3 and P2 of a peptide cysteine protease inhibitor (the expressions are explained below), z is especially 〇's, methylene or -NR-, R', is an alkyl group. , alkyl aryl group, etc. and Pi & Q each especially Aachen 129860.doc 200906392 soil although ",,,,,,,,,,,,,,,,,,,,,,,,,,,,, ^曰4& 祀圆仁无-- has been embodied or exemplified and does not provide a guide for -σ. In fact, the separate synthetic recommendations provided at w〇 g2/g572 do not allow Pi4q to take t(d) compounds at all, and are particularly useful for treating protozoal infections such as trypanosomes. In particular, the International Patent Application No. W〇 2〇〇5/〇66丨8〇 discloses a compound of the formula:

Wherein "end group" defines an inhibitor of the activity of a different class of proteinase K, modified to produce a cyclic structure relating to pharmacokinetics. These compounds are tissues but as further shown below, further and/or pharmacodynamic improvements of the structure. : The sputum technique still requires a potent inhibitor of cathepsin κ. The cathepsin κ::: is particularly beneficial for tissue transfer to a selectivity other than that of other cathepsins (eg, proteinaceous or cathepsin selective). Effective inhibitors of cathepsin scales that exhibit properties such as high permeability and/or favorable metabolic profiles are of great value. In the red bed configuration, the invention provides a compound according to the invention of the invention: 129860.doc 200906392

among them:

R2 is a side chain of leucine, 4 leucine, cyclohexylglycine, 〇-methyl sulphonic acid, 4-fluoroleucine or 3- methoxy valine; R3 is hydrazine, methyl Or a fluoro group; R4 is a cvc6 alkyl group; E is a bond or a thiazolyl group optionally substituted with a fluorenyl group or a fluoro group; η is hydrazine or 1; or a pharmaceutically acceptable salt thereof, ice oxide or hydrate ( These are collectively referred to herein as compounds of the invention). It will be appreciated that the compounds of the invention may exist in the form of hydrates such as the following formula:

And the invention extends to all such alternatives. In one embodiment of the invention, R2 represents a side chain of leucine. In the first embodiment of the present month, R2 represents a side chain of isoleucine. In the second embodiment of the present invention, 129860.doc -10- 200906392, r2 represents a side chain of cyclohexylglycine. In a fourth embodiment of the invention, R2 represents the side chain of 〇-methylthreonine. In a fifth embodiment of the invention, R2 represents a side chain of 4-fluoroleucine. In a sixth embodiment of the invention, R2 represents a side chain of 3-methoxyproline. The preferred values of R's field order j include their values represented by the following partial structures:

And especially the preferred group of R parts is the part represented by the following partial structure

Another preferred group of R2 is a side chain of methoxy valine. • Methyl sulphate 4 fluoro leucine and 3 曱 are of particular interest in one embodiment of the invention. η represents 〇 wherein η represents a compound of 1 r3 suitably represents a methyl group or a fluoro group, and when 11 represents 1, R3 is as follows, particularly a fluoro group. Appropriately positioned as shown by the structure:

R3 129860.doc

200906392 The definition of the 6-alkyl group is meant to include a total of six and six branches between the anatomical and unbranched bases. Examples of R4 groups are methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, second butyl and second butyl), pentyl (positive) Mercapto, isopentyl, etc.) and hexyl (n-hexyl, etc.). Suitably 'R4 represents an alkyl group (such as c丨alkyl group is of particular interest) - the group 4 is a group S. The second R4 group of interest is especially a propyl group (especially n-propyl). In some embodiments, E is a bond. Preferred compounds in this embodiment include: Tian Gang

Wherein R and R3 are as defined above. Representative examples in this example include: N-[1-(6-azido_3_sideoxy-hexahydro-σøranyl)-3-methyl-butyl]_4_(4_ Propyl-piperazine-丨-yl)-peptidylamine; Ν·Ι>(6-azido-3-oxo-hexahydro-furo[3,2-b]pyrrole_4_yl)- 1-cyclohexyl-2-oxo-ethyl]-4-(4-propyl-p-methyl-l-yl)-benzylamine; 1^[1-(6-azido-3- Side oxy-hexahydro-benzoic acid [3,24]«1 pyrrole_4_yl)-2-methyl-butyl]_4_(4-propyl-piperazine-indenyl)-benzyl Indoleamine; 129860.doc 12 200906392 N-[l-(6-azepine_3-o-oxy-hexahydro-ββ-rano[3,2_b]indol-4-carbonyl)-2-oxo -propyl]_4_(4_propyl_slightly 嗓_丨_yl)-benzylamine; N-[l-(6-azido-oxyl_hexahydro-furo[3,2_b]pyrrole _4•carbonyl)_2_methoxy-propyl]-4-(4-propyl-l-azine-i-yl)-benzylamine; and pharmaceutically acceptable salts, hydrates and ... oxidation Things. In other embodiments, E is a thiazolyl group optionally substituted with a methyl or fluoro group. Preferred compounds in this embodiment include those of the formula:

Wherein R2 and the optional substituent R3 are as defined above and are R, thiol or a gas group. Representative examples in this embodiment include:

N-[l-(6-azido-3-oxo-hexahydro-indolyl)-[5,2-b]pyrrole-4-carbonyl)-3-indolyl-butyl]-4 -[2-(4-indolyl-d-chen0, y, oxazin-1-yl)-thiazol-4-yl]-benzamide; N-[l-(6-azido-3- Side oxy-hexamethylene. Soil +,,, furan [3,2_b]pyrrole_4_yl)-1-cyclohexyl_2-sideoxy-ethyl]J methyl-piperazinyl)-thiazole- 4-yl]-nodal amine; N-[1-(6-azido-3-oxo-hexahydro, lactofo[3,2-b]pyrrole-4-carbonyl-yl)- Thiazol-4-yl]-benzyl)-2-indolyl-butyl]-4-[2-(4-mercapto-piperidamine; 129860.doc -13- 200906392 N-[l-(6 - alkalyl-3-flank-six-snake-suffol[3,2-1>]σΛρ-4--4-diyl)-2-methoxy-propyl]-4-[2- (4-Methyl-piperazin-1-yl)-thiazol-4-yl]-benzylamine; N-[l_(6-Fungyl-3-oxo-hexa-nitro-chito[3] ,2-Ϊ3]σpyr-4-yl)-2-methoxy-2-methyl-propyl]-4-[2-(4.methyl-piperazin-1-ylthiazole-4 -yl]-benzylamine; Ν-[1·(6-Humbufen-3-lateral oxy-hexaza-bita-[3,2-1>]° ratio of -4-··) 3-mercapto-butyl]-4-[5.methyl-2-(4-indolyl-pyridin-1-yl)-嗟σ sitting-4 _ benzyl]-benzylamine; N-[l-(6-streprise-3-yloxy-hexaza-σ-pentanyl-4-yl)-1-cyclohexyl-2-oxo -ethyl]-4-[5-mercapto-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide; N-[l-(6-beneficial Benzyl-3-saltyl-hexanitro-s-pentanose [3,2-b]. ratio p--4-mercapto)-2-methyl-butyl]_4-[5-methyl-2 -(4-mercapto-piperazin-1-ylthiazol-4-yl)-benzylguanamine; N-[l-(6-azepine-3-oxo-hexanitro-σfolmo[ 3,2-13]1^17 each _4-amino group-2-oxo-propyl]-4-[5-methyl- 2-(4-methyl-σ嘻嘻-1_yl - σ 嗤 嗤 -4-yl]-benzyl hydrazide; N-[l-(6-azepine-3 - flavonyl-six-mice- sigma-[3,2-b] fluorene- 4-mercapto)-2-oxo-2-indenyl-propyl]-4-[5-indolyl-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl ]-benzylamine; N-[l-(6-azepine-3-oxo-hexanitro-s-pentanthrace[3,2-13]indol-4-weiyl)-3-indole Alkyl-butyl]-4-[5-gas-2-(4-methyl-tour-1-yl)-° plug. -4-yl]-benzylamine; 129860.doc -14- 200906392 N-[ 1-(6-azido-3-oxo hexahydro-furo[3,2-b]pyrrole-4- ))-1-cyclohexyl-2-yloxy-ethyl]-4-[5-fluoro-2-(4-methyl-piperazine-l-yl)-σsec-4-yl]- Amylamine; N-[l-(6-azido-3-oxo-hexahydro-furo[3,2-b]pyrrole-4-carbonyl)_2-indolyl-butyl]-4 -[5-fluoro-2-(4-methyl-〇底°qin-1-yl)-〇塞σ sitting_4_yl]-benzylamine;

N-[l-(6-azido-3-oxo-hexahydro-furo[3,2-b]pyrrole-4-carbonyl)-2-methoxy-propyl]-4-[ 5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzylguanamine; N-[1-(6-azido-oxy-hexahydro-furan) And [3,2_b]pyrrole-4-carbonyl)-2-methoxy-2-methyl-propyl]_4-[5-fluoro-2-(4-indolyl-piperazin-1-yl)-嗟嗤-4-yl]"•tuberamine; and its pharmaceutically acceptable salts, N-oxides and hydrates. In one embodiment of the invention, £ represents an unsubstituted thiazolyl group. The thiazolyl group substituted in the examples of the examples which are particularly unfavourable by the fluorenyl or fluoro group, especially by fluorine E, are unsubstituted or substituted by a methyl group. Or thiazolyl. The combination of the thiazolyl groups shown in the formula wherein E represents the position of the following part of the structure is of particular interest: where R5 is an optional substitution

The position (ie, R5 represents H, methyl or fluoro). 129860.doc •15- 200906392

Treatment of conditions mediated by cathepsin kappa such as: the use of the above-mentioned compounds in the manufacture of a medicament for the use of such osteoporosis, gum disease (such as gingivitis and periodontitis), Paget's disease , malignant bureaurous hyperemia, metabolic bone disease, soft moon or excessive degradation of the matrix characterized by diseases (such as osteoarthritis and rheumatoid arthritis), including neoplastic bone cancer, pain (especially chronic pain). Additionally provided is a method of treating or preventing a condition mediated by cathepsin kappa comprising administering a safe and effective amount of a compound of the invention for the treatment or prevention of the condition mediated by cathepsin kappa. Also provided is a compound of the invention for use in the treatment or prevention of a condition mediated by cathepsin kappa. Additionally, as an aspect of the invention, novel intermediates (as described herein) useful in the preparation of the compounds of the invention are provided. Specifically, the compound of the following formula is provided: 129860.doc -16- 200906392

). The invention also provides a protected derivative thereof (for example or an N-protected derivative thereof (for example, B〇c protects the corresponding 1,3-dioxolane-protected analog and N such as Boc protection). Providing a compound of the formula:

Wherein R4 represents a core 6 alkyl group (such as a methyl group); * a salt thereof or a lower carbon group (e.g., a C-6 alkyl group) ester such as an oxime ester or an HCl salt. In certain embodiments, the present invention does not include the subject matter described in International Patent Application No. 2008/007107. For example, the compounds of the present invention do not comprise the compounds described on column 37, column 8 to page 38, column 6 of WO 2008/007107: (8) - (3 & 8, 611, 6 & 8)- 6-azido-3-oxooxydihydro-2-p-furfuro[3,2-b].pyrrole-4(5H,6H,6aH)-yl)-4-methylindolyl _2•yl)_ 4-(2-(4-methylpyridin-1-yl)indole. Sodium-4-yl)benzylate N-(S)-l-((3aS,6R,6aS) -6 -azido-3-oxo-dihydro-2-indole-pf-[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-4,4-dimethyl -1·Sideoxypenta-2-(yl)-4-(2-(4-methyl-0- σ 秦-qin-1-yl)° 嗤-4-yl) tanning amine N-(S)-l -((3aS,6R,6aS)-6-streprise-3-yloxydihydro-2h_ufu. Nanhe [3,2-b] ° ratio 11-4(5H,6H,6aH) - Base)-3,3-dimethyl-1-oxo-butyl 129860.doc -17- 200906392 2-based)-4-(2-(4-methyl-0-°-qin-1-yl)° ° sit-4-yl) nodal amine 1^-((28,38)-1-((338,611,638)-6-azido_3_sideoxydihydro-2-furo[3] ,2-b]»比比_4(5H,6H,6aH)-yl)_3_methyl-small-oxypentan-2-yl)-4-(2-(4-methyl°辰°秦- 1-base) 嗟° sit-4-base) N-(S)-2-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H ,6aH)-yl)-1-cyclopentyl-2-oxoethylethyl 4-(2-(4-methyl- s- -1-yl)thiazol-4-yl)benzamide N- (S)-2-((3aS,6R,6aS)-6-azido-3-oxo-dihydro-2-indole-β-folme[3,2-bppyr-4(5H,6H, 6aH)-yl)small cyclohexyl-2-ylideneoxyethyl 4-(2-(4-methyl-branches-heptan-1-yl). s-β--4-yl) decylamine N-(S )-l-((3aS,6R,6aS)_6-azido_3_sideoxyhexahydro-2Η-furo[3,2-b]° ratio ρ-4-carbonyl)cyclohexyl)- 4-(2-(4-methylπ-piperazine-I)-thiazol-4-yl)peptidylamine N-(S)-l-((3aS,6R,6aS)-6-azido- 3-sided oxydihydro-2H-indolo[3,2-1>]11 is more than -4 (5^1,61^,6&11)-yl)-4-methyl_1_ Phenyloxypenta-2-yl) 4-(2-(4-(2-methoxyethyl)piperazin-1-yl)thiazole-4(yl)peptidylamine N-(S)-l -((3aS,6R,6aS)-6_ azido_3_ pendant oxydihydro-2H_furo[3,2-bp than s--4(5H,6H,6aH)-yl)-4,4- Dimethyl small-oxypentapenta-2-yl)-4-(2-(4-(2-methoxyethyl)piperazine-indenyl) thiophene The oxazolidine 4 does not include its pharmaceutically acceptable salts, N-oxides or hydrates. In certain embodiments, the invention is not included in the subject matter described in International Patent Application No. 2008/0071. For example, the compounds of the present invention do not comprise the compounds described on page 70, column 6 to page 77, column 8 of WO 2〇〇8/007114: 129860.doc -18- 200906392 N-((S)-l -((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-4 ,4-dimethyl-1-oxoethoxypentyl-2-yl)-4-(4-methylpiperazin-1-yl)nodecylamine N-((S)-l-((3aS,6R) ,6aS)-6-azido-3-oxooxydihydro-2H_^D Nanto[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-4,4-dimethyl -1-la-oxypentyl-2-yl)-4-(4-ethylpiperazin-1-yl)nodecylamine N-((S)-l-((3aS,6R,6aS)-6 -azido-3-oxooxydialdehyde_2H_吱 and [3,2-b]pyrrole-4(5H,6H,6aH)-yl)-4,4·dimethyl-1- N-(()-l-((3aS,6R,6aS)-6-azido 3-Oxyloxydihydro-2H-indolo[3,2-b] ° ratio B-4(5H,6H,6aH)-yl)-4,4-dimethyl-1- side Oxypenta-2-yl)-4-(4-isopropylpiperazin-1-yl)nodecylamine N-((S)-l-((3aS,6R,6aS)-6-azido -3-sided oxydihydrof-b-s-[3,2-b]0 ratio σ--4 (5H,6H,6aH -yl)-4,4-dimethyl-l_ oxooxime-2-yl)-4-(4-(2-methoxyethyl)fluorenoid-1-yl) nodal amine N -((S)-l-((3aS,6R,6aS)-6 - alkoxy-3-oxo-dihydro-2-indole-π-f-[3,2-b]° ratio -4 ( 5H,6H,6aH)-yl)-4,4-dimercapto-1_p-oxyindole-2-yl)-4-(4-cyclopropylpiperazin-1-yl)nodecylamine N- ((S)-l-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H_〇〇南和[3,2-b]fl 比咯-4(5H ,6H,6 aH)-yl)-4,4-dimercapto-i_ oxopurin-2-yl)-4-(4-cyclobutylpiperazin-1-yl)benzylamine N-(( S)-l-((3aS,6R,6aS)-6-azido-3-oxooxydihydrofuran[3,2-b] ° ratio σ-4(5H,6H,6aH) -yl)-4,4-dimethyl-1_oxoxime-2-yl)-4-(1-propylpiperidin-4-yl) decylamine 129860.doc -19- 200906392 N-( (S)-l-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-buttering 弁[3,2-b]n ratio slightly-4(5H,6H , 6aH)-yl)-4,4-dimercapto-1-yloxypenta-2-yl)-4-(1-isopropyl-based s-butyr-4-yl)nodal amine N-(( S)-l-((3aS,6R,6aS)-6-azido-3-oxo-dihydro-2-indole_bito[3,2-b]pyrrole-4(5H,6H,6aH ) -yl)-4,4-dimercapto-1-yloxypent-2-yl)-4-(1-(2-anthoxyethyl)anthracene. Ding-4-yl) basal amine ((8)-1-((3&8,6-foot,6&3)-6-azido-3-oxooxydihydro-2]^_吱M-[3,2-b]pyrrole-4 (5 611,6&1^)-yl)-4,4-dimethyl-1-oxoethoxypentyl. 2-yl)-4-(1 -cyclopropylpiperidin-4-yl)peptidomamine N-((S)-l-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-garnet Nanhe [3,2-b]0 to 11-4(5H,6H,6aH)-yl)-4,4-dimercapto-1-yloxyindole-2-yl)-4-(1) - ί butyl ketone-4-yl) tanning amine N-((S)-l-((3aS,6R,6aS)-6-azido-3-oxo-dihydro-2-indole-β Furano[3,2-b]0 to 11 -4(5H,6H,6aH)-yl)-4-methyl-1-oxoethoxypentan-2-yl) 4-(4-A Nipperazine-1-yl)peptidylamine N-((S)-l-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-indole[3 ,2-b].Bisole-4(5H,6H,6aH)-yl)-4-mercapto-1-yloxypenta-2-yl)-4-(4-ethylpiperazine-1- N-((S)-l-((3aS,6R,6aS)-6-azido-3-oxo-dihydro-2Η_β-folme[3,2-b]° ratio 4-(5H,6H,6aH)-yl)-4-methyl-1-oxoethoxypent-2-yl)-4-(4-propylpiperazin-1-yl)peptidylamine]^-( (8)-1-((338,6 11,638)-6-azido-3-oxooxydihydro_21^-.f 〇^ and [3,2-b]. 比略-4(5H,6H,6aH)-yl)- 4-mercapto-1-oneoxypenta-2-yl) 4-(4-isopropylpiperazin-1-yl)benzylamine 129860.doc •20- 200906392 N-((S)-l -((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2h-c-c-[3,2-b].pyr-4(5H,6H,6aH)-yl )-4-mercapto-i_sideoxypentanyl) 4-(4-(2-methoxyethyl)piperazin-1-yl)benzylamine N-((S)-l -((3aS,6R,6aS)-6-azido-3-oxooxydichloride_2h_biting and [3,2-1?]0 to 11-4 (511,611,6311) -yl)-4-methyl-1-oxoethoxypent-2-yl)-4-(4-cyclopropylpiperazin-1-yl)benzylamine N-((S) -1 -(( 3aS,6R,6aS)-6-azido-3-oxooxydihydro-2n_π-f-[3,2-b]0 is compared with 17--4(5H,6H,6aH)-yl)-4 -methyl-1-flavorylpenta-2-yl) 4-(4-cyclobutylpiperazin-1-yl)benzylamine N-((S)-l-((3aS,6R,6aS) -6-azido-3-oxo-dihydro-2-indole-π-f-[3,2-b]0 is Β--4(5H,6H,6aH)-yl)-4-methyl- 1-Phenyloxypenta-2-yl)-4-(1-propylpiperidin-4-yl)nodecylamine N-((S)-l-((3aS,6R,6a) S)-6-azido-3-oxo-dihydro-2h_u-fu[3,2-b]0-pyrrol-4(5H,6H,6aH)-yl)-4-methyl-1 -Sideoxypenta-2-yl) 4-(1-cyclopropylpiperidin-4-yl)benzylamine 1^-((3)-1-((338,611,6")-6-azido 3-O-oxydihydro-211_11-f-[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-4-methyl-1-pentyloxypenta-2- 4-(1-cyclobutylpiperidin-4-yl)nodecylamine 1((23,38)-1-((3&8,611,638)-6-azido-3-side oxygen Dichloro-_21^furo[3,2-b]. Bilota-4(5H,6H,6aH)-yl)-3-indolyl-^-oxypentyl-2-yl)-4-(4-methylpiperazin-1-yl)benzylamine N- ((2S,3S)-l-((3aS,6R,6aS)-6-azido-3-epoxydifurfuro[3,2-b]pyrrole-4(5H,6H,6aH) -yl)-3-indolyl-h-side oxime 戍-2-yl)-4-(4-ethyl bucky-1-yl) nodal amine 129860.doc -21 - 200906392 ]^-((28 , 33)-1-((3&8,611,638)-6-azido-3-oxooxydihydro-2]^0fu0南和[3,2-b]0 ratio σ each - 4(5H ,6H,6aH)-yl)-3-mercapto-1-yloxypentyl-2-yl)-4-(4-propylpiperazin-1-yl)benzylamine N-((2S,3S) )-l-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H_furo[3,2-b]0 to 11-4(5H,6H,6aH) -yl)-3-mercapto-1-oneoxypenta-2-yl)-4-(4-isopropylpiperazin-1-yl)nodecylamine 1 ((28,38)-1-( (3&8,611,6&8)-6-azido-3-oxooxydihydro-211_furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-fluorenyl -1-Sideoxypenta-2-yl)-4-(4-(2-decyloxyethyl)piperazin-1-yl)peptidylamine ((28,3 8)-1-((3&amp ;8,611,6&8)-6-azido-3-oxo-dihydro-_211_ °fu-[3,2-1)]° ratio -4 (511,6 ^1,631-1)-yl)-3-mercapto-1-indolylpentyl-2-yl)-4-(4-cyclopropylpiperazin-1-yl)dodecylamine 1^-( (28,38)-1-((338,611,6)-6-azido-3-oxooxydihydro-211_furo[3,2-b]0 than ha-4 (5H,6H, 6aH)-yl)-3-indolyl-1-yloxypenta-2-yl)-4-(4-cyclobutylpiperazin-1-yl)peptidylamine N-((2S,3S)- L-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H_furo[3,2-13]pyrrole-4(511,611,6311)-yl)-3 -mercapto-1-oxooxypent-2-yl)-4-(1-methylpiperidin-4-yl)nodecylamine 1^-((28,3 8)-1-((3& 8,611,6-)-6-azido-3-oxooxydihydro-211_furo[3,2-13]0 pyrol-4 (51^61^63-yl)-3-fluorenyl -1-Sideoxypenta-2-yl)-4-(1-ethylpiperidin-4-yl)dodecylamine^[-((28,38)-1-((3&8,611,638)) -6-azido-3-oxooxydihydro-211_furo[3,2-b]. Bilota-4(5H,6H,6aH)-yl)-3-methyl-1-oxoethoxypent-2-yl)-4-(1-propylpiperidin-4-yl)nodecylamine 129860 .doc •22- 200906392 ^1-((25,38)-1-((3,611,6&3)-6-azido-3-oxo-oxydichloride_211_furan[3, 2-b]"Big-But-4(5H,6H,6aH)-yl)-3-methyl-oxo-pentyl-2-yl)-4-(1-isopropylpiperidin-4-yl) Benzylamine oxime ((28,38)-1-((3&8,611,6&8)-6-azido-3-oxodiazepine-2^furo[3,2_b]pyrrole-4 (5H,6H,6aH)-yl)-3-indolyl-1β-side oxygen a certain 戍 2 -yl)-4-(1-(2-anoxyethyl) oxime-decyl-4-yl) Amylose ((28,38)-1-((3&8,6-foot,6&8)-6-azido-3-oxooxy 2 gas-2 sfuran[3,2- b]pyrrole-4(5H,6H,6aH)-yl)-3-indolyloxy pentyl-2-yl)-4-(1-cyclopropylpiperidin-4-yl)peptidylamine 1^ ((28,38)-1-((3&8,6-foot,6&8)-6-azido-3-indolyl dioxin_讯_furo[3,2-b]pyrrole- 4(5H,6H,6aH)-yl)-3_indolyl small-side oxime-2-yl)-4-(1-cyclobutylpiperidin-4-yl)nodecylamine N-((S )-l-((3aS,6R,6aS)-6-Laminated 3-oxo-oxydichloride. Fu. Nanhe [3,2- b] fluorene-4(5H,6H,6aH)-yl)-3,3-dimethylacetoacetoxy-2-yl)-4-(4-methylpiperazin-1-yl)fruce Amine N-((S)-l-((3aS,6R,6aS)-6-la-l-yl-3-yloxydi-n-n-n-[3,2-b]pyrrole-4 (5H, 6H,6aH)-yl)-3,3-dimethyl-small oxybutyrate-2-yl)-4-(4-ethyl0-decyl-1-yl)nodal amine N-((S) -l-((3aS,6R,6aS)-6·azido_3-o-oxydihydrocarbamate[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-3 ,3-dimercapto-small-oxybutyryl-2-yl)-4-(4-propylpiperazin-1-yl)nodecylamine N-((S)-l-((3aS,6R,6aS) - 6 - azido-3-oxo-oxydichloromethane nans [3,2-b]pyrrole-4(5H,6H,6aH)-yl)-3,3-dimethyl small side oxygen Chitin 2-yl)-4-(4-isopropylpi-α-methyl-1-yl) nodal amine 129860.doc 23- 200906392 N-((S)-l-((3aS,6R,6aS)_6 -azido-_3_ pendant oxydihydro 2 Η η 夫 喃 [3,2-b] «Big- 4 (5H,6H,6aH)-yl)-3,3-dimercapto-l_ side Oxybutyryl-2-yl)-4-(4-(2-milylethyl)-p-beta-heptan-1-yl)thranylamine N-((S)-l-((3aS,6R,6aS) - 6 - azide-3-oxooxydihydro 2 Η-β-furan-弁[3,2-b]0 to 11 each-4(5H,6H ,6aH)-yl)-3,3-dimethyl-1-oxobutylbut-2-yl)-4-(4-cyclopropylpiperazin-1-yl)dodecylamine>1-( (8)-1-((3&8,611,638)-6-azido-3-oxooxydihydro-211-. Furano[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-3,3-dimercapto-1-yloxybutane f ' 2 -yl)-4-(4 -cyclobutyl-N-B-yl-1-yl)thranylamine N-((S)-l-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furan And [3,2-b]pyrrole-4(5H,6H,6aH)-yl)-3,3-dimercapto-1-yloxybut-2-yl)-4-(1-propenyl)基旅.定-4-基)Carboxamine N-((S)-l-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2Η-furo[3 ,2-b]pyrrole-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(1-cyclopropyl brigade 17 -4-yl)tubonic amine / ·, N-((S)-l-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3, 2-b]pyrrole-4(5H,6H,6aH)-yl)-3,3-dimethyl_1_pentoxybutan-2-yl)-4-(1-cyclobutylpiperidine-4 -yl) decylamine • N-((S)-2-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furan' and [3,2-b .rho-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-yloxyethyl)-4-(4-methylpiperazin-1-yl)benzylamine N -((S)-2-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]pyrrole-4 (5H,6H, 6aH)-yl)-1-cyclopentyl-2-side Oxyethyl)-4-(4-ethyl 嗓·ιι) benzyl hydrazine 129860.doc -24- 200906392 N-((S)-2-((3aS,6R,6aS)-6- Azido-3-oxooxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-1-cyclopentyl_2_sideoxy B 4-(4-propyl-s-.q.-l-yl)-tertiary amine N-((S)-2-((3aS,6R,6aS)-6-azido-3-oxooxy Dihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-iso Propyl piperazin-1-yl)benzylguanamine N-((S)-2-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2-indole-β-propanol^ And [3,2-b]c is more than -4(5H,6H,6aH)-yl)-1.cyclopentyloxyethyl)-4-(4-(2-methoxyethyl) Piperazin-1-yl)benzylamine N-((S)-2-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-°fol[3 , 2-1)] fluoren-4-(5H,6H,6aH)-yl)-1-cyclopentyloxyethyl) 4-(4-cyclopropylpiperazin-1-yl)benzylhydrazine Amine>1-((8)-2-((3&8,611,638)-6-azido-3-oxo-dihydro-211-furo[3,2-b] ° ratio _ 4(5H,6H,6aH)-yl)-1 -cyclopentyl-2-oxoethyl)-4-(4-cyclobutylpiperazine-1- Benzoylamine I N-((S)-2-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]° Bile-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(1-propylpiperidin-4-yl)benzylamine•]^ -((8)-2-((3 38,611,638)-6-azido-3-oxo-dihydro-211-furo[3,2-b]° ratio of 4-(5H,6H, 6aH)-yl)-1-cyclopentyl-2-oxoethylethyl> 4-(1-cyclopropylpiperidin-4-yl)benzylamine N-((S)-2-(( 3aS,6R,6aS)-6-azido-3-oxo-dihydro-2Η-β-f-[3,2-b]n-pyr-4(5H,6H,6aH)-yl) Cyclopentyl-2-oxoethyl) 4-(1-cyclobutylpiperidin-4-yl)benzylamine 129860.doc •25- 200906392 1((8)-2-((3&8,611,6-)-6-azido-3-oxo-dihydro-21" 1-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-1-cyclo Hexyl-2-oxoethyl)-4-(4-methylpiperazin-1-yl)nodecylamine N-((S)-2-((3aS,6R,6aS)-6-azide 3-Oxo-dihydro-2H-furo[3,2-b]. Bile-4(5H,6H,6aH)-yl)-1-cyclohexyl_2_sideoxyethyl)-4-(4-ethylpiperazin-1-yl)peptidylamine]^-( (8)-2-((3&8,611,638)-6-azido-3-oxo-dihydro-211-furo[3,2-b]pyrrole-4(5H,6H,6aH) -yl)-1-cyclohexyl-2·sideoxyethyl)-4-(4-propylpiperazin-1-yl)benzylamine N-((S)-2-((3aS,6R, 6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-1-cyclohexyl-2- Oxyoxyethyl)-4-(4-isopropylpiperazin-1-yl)benzylamine N-((S)-2-((3aS,6R,6aS)-6-azido-3 -Phenoxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-bucyclohexyl-2-yloxyethyl)-4-(4 -(2-methoxyethyl)piperazin-1-yl)benzylamine N-((S)-2-((3aS,6R,6aS)-6-azido-3-oxirane II Hydrogen-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-yloxyethyl)-4-(4-cyclopropylpiperidine Zin-1-yl) decylamine N-((S)-2-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2- b]pyrrole-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-yloxyethyl)-4-(4-cyclobutylpiperazin-1-yl) Indoleamine N-((S)-2-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-bp ratior-4(5H) ,6H,6aH)-yl)-1-cyclohexyl-2-yloxyethyl)-4-(1-methylpiperidin-4-yl)benzylamine 129860.doc -26- 200906392 5) -2-((3&8,611,6&8)-6-azido-3-oxo-dihydro-211-furo[3,2-b]"bibromo-4(5H, 6H,6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(1-ethylpiperidin-4-yl)nodecylamine N-((S)-2-(( 3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-1-cyclohexyl -2-Sideoxyethyl)-4-(1-propylpiperidin-4-yl)nodecylamine N-((S)-2-((3aS,6R,6aS)-6-azido -3-Silyl dichloro-2Η-β-f-[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-bucyclohexyl-2-yloxyethyl)-4 -(1-isopropylpiperidin-4-yl)benzylguanamine N-((S)-2-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H -furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)small cyclohexyl-2-yloxyethyl)-4-(1-(2-decyloxyethyl) Piperidin-4-yl)benzylguanamine N-((S)-2-((3aS,6R,6aS)-6-azido-3-side Dihydro-2H-furo[3,2-b]° ratio of 4-(5H,6H,6aH)-yl)-1-cyclohexyloxyethyl) 4-(1-cyclopropyl Piperidin-4-yl)peptidylamine N-((S)-2-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2 -1)]吼--4(51^,61^6311)-yl)-1-cyclohexyl_2-sideoxyethyl)-4-(1-cyclobutylbenza-4-yl)benzyl Indoleamine also does not include its pharmaceutically acceptable salts, N-oxides or hydrates. The compounds of the invention may form salts which form additional aspects of the invention. Suitable pharmaceutically acceptable salts of the compounds of formula II include: salts of organic acids, especially carboxylic acids, including but not limited to acetates, trifluoroacetates, lactates, gluconates, citrates, Tartrate 'maleate, malate, pantothenate, hydroxyethyl sulfide, adipate, alginate, 129860.doc -27· 200906392 Aspartate, citrate Butyrate, digluconate, cyclopentanoate, glucoheptanoate, glycerol phosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinic acid, Pamoate, pectate, 3-phenylpropionate, picrate, pivaiate, propionate, tartrate, lactobate, pivalate , camphoric acid 'undecanoate and succinate; salts of organic sulfonic acids, such as decane sulfonate, ethane sulfonate, 2-hydroxyethane sulfonate, camphor sulfonate, 2-

Naphthalene sulfonate, besylate, p-chlorobenzenesulfonate and p-toluenesulfonate; and salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, 4 « Acid hydrogen salt, hemisulfate, thiocyanate, persulfate; acid and acid salt. The compounds of the invention may be separated into hydrates in some cases. Hydrate is prepared by recrystallization from an aqueous/organic solvent mixture using an organic solvent such as dioxin, tetrahydrofuran or methanol. Hydrates can also be produced in situ by administering the corresponding ketone to the patient. "N-oxides of the monthly compound can be prepared by a method known to those skilled in the art. For example, the N_oxide can be used as an oxidizing agent in a suitable inert organic solvent (for example, a hydrogenated hydrocarbon '° (for example, difluoro W π decane) - diacetic acid, peroxybutyric acid Prepared by treating the form with perbenzoic acid, peracetic acid, 1 hydrazine, or the like. Or the oxidizing gas of the poor sulphate or the yttrium oxide of the compound of the present invention. The material can be self-property, the bismuth-oxide of the present invention, and the like. Included in the following part structure 129860.doc •28· 200906392 R4

Ο

Ο R4,

... (a) ... π early.精 隹υ χ χ 下 下 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在 在, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium nitride, two wrapped ^ (Bu_

And (iv), tribromide or the like) are prepared by treating the N-oxide of the corresponding compound of the present invention. The position of the group on any molecular moiety used in the ideology can be any position on the moiety as long as it is chemically stable. Unless otherwise stated, the radicals used in the definition of such variables include all possible isomers. For example, the thiazolyl group includes a 4-substituted thiazol-2-yl group, a 2-substituted thiazole-4-yl group, a 2-substituted thiazole _5- group, etc. (especially, a 4-substituted thiazole-2) a _ group or a 2-substituted thiazole _4 group wherein the optional substituent is at the 5-position). Preferred is thiazole-4-yl, wherein piperazine is substituted at the 2-position and the optional methyl or fluoro substituent is at the 5-position. Similarly, butyl includes tert-butyl, isobutyl, n-butyl, and the like. Each definition is independent when any variable occurs more than one time in any component. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses a mixture of all possible stereochemically isomeric forms that the compound may have. The mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of the compound. 129860.doc of the compound of the invention in pure form or in a mixture with each other • 29-200906392 All stereochemically isomeric forms are intended to be within the scope of the invention. A compound as referred to herein is defined as a pure stereoisomer on the sorghum and other enantiomeric forms of the same basic molecular structure of the 3# compound or intermediate. Isomerism of enantiomeric forms: Lv, term |, stereoisomerically pure "Tea 疋 疋 / 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有 具有Over-the-counter, acre..../ steroids and other potentially isomers of 10% more.) Compounds or intermediates of stereoisomeric excess (ie, (10)% of __: other isomers) More specifically, it has a stereoisomeric excess of 9: even 100% of the stereoscopic 埚蔷B k in the case of the shirt, and the soil structure is over and specifically 97% up to 100% Excess compound or + intermediate. The terms "enantiomerically pure" and "quote diastereomerically pure" should be resolved analogously from θ human ♦ but separately considering the enantiomeric excess and diastereomeric of the desired complex. Excessive structure. The compounds of the present invention can be formed by reacting a racemic mixture of a fish optically active resolving agent to form a diastereomeric compound, separating the diastereomers and recovering the optically pure enantiomer. Prepared as its individual stereoisomers. Although resolution of the enantiomers can be carried out using the diastereomeric derivatives of the formula (10) to form a ', separable complex, which is preferred (e.g., cation-positive diastereomeric salt). Diastereomers have different physical properties (e.g., melting points, sites, solubility, reactivity, etc.) and can be readily separated by utilizing 4 different iso points. Diastereomers can be separated by, for example, HPLC chromatography or preferably by separation/resolution techniques based on solubility differences. The optically pure enantiomer is then recovered along with the resolving agent by any practical method that does not cause racemization. A more detailed description of the technique for the resolution of stereoisomers of compounds from compound races 129860.doc • 30-200906392 isomers can be found in Jean Jacques Andre Collet, Samuel H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981). It will be appreciated that the invention extends to drugs, solvates, complexes and other forms prior to the release of the compounds of the invention in vivo. While the active agent may be administered alone, it is preferably provided as part of a pharmaceutical formulation. The formulation will comprise an active agent as defined above together with one or more acceptable carriers/excipients and, where appropriate, other therapeutic carriers which must be compatible with the other ingredients of the formulation and which are not deleterious to the recipient. It is acceptable in the right way. Formulations include those suitable for rectal, nasal, topical (including and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous, and intradermal) administration, but the formulation is more Preferably, the formulation is orally administered as a unit of a lozenge and a sustained release capsule, which can be prepared by any method well known in the art of pharmacy. One such method comprises the step of associating an active agent as defined above with a carrier. In general, the formulation is prepared by subjecting the active agent to a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product. The invention extends to a method of preparing a pharmaceutical composition comprising a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof in association with or associated with a pharmaceutically acceptable carrier or vehicle. If the manufacture of a pharmaceutical formulation involves the intimate mixing of the excipient with the active ingredient in the form of a salt, it is often preferred to use excipients which are non-testable (i.e., acidic or neutral). 129860.doc -31 - 200906392 = (4) W in the oral administration of the (four) things can be politically early 'such as capsules, cachets or spinners, ... people 2 supply. From the active agent mum, 八 3 have a predetermined amount The solution or suspension liquid is called: aqueous liquid or non-aqueous emulsion and boluse, etc. „ ^ oil-type liquid emulsion or water-in-oil type liquid for oral injection of έ 厶 ,, package m/, (4) and capsules), the term is suitable for loading = (4) such as * see the vehicle of the excipient, such as cement

Acacia gum, gelatin, sorbose syrup, cyanine t-vinylpyrrolidone (polyvinylpyrrolidone), methylcellulose ethylcellulose, methine cellulose, propylmethylcellulose, Yan sugar and temple Powder; fillers and carriers, such as corn granules, sundial, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, sulphate, sodium chloride and alginic acid; and lubricants, such as hard Magnesium citrate, stearic acid steel and other metal stearates, glyceryl stearate stearate n talc m, oils and gels. It is also possible to use a fragrance of Zhushi Yuejiao 4, wintergreen oil, cherry flavor or the like. Colorants may need to be added to make the dosage form readily identifiable. Tablets can also be coated by methods well known in the art. Tablets may optionally be prepared by compression or molding using one or more accessory ingredients. Compressed tablets may be compressed in a suitable machine by mixing the active agent, such as a powder or granules, in a readily flowable form, as appropriate with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. preparation. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The lozenge may optionally be coated or scored and may be formulated to provide a slow or controlled release of the active agent. 129860.doc •32·200906392 Release. Other formulations suitable for oral administration include buccal agents containing the active agent in the flavoring base (usually sucrose and arabic or scutellaria); in inert primary agents such as gelatin and glycerin or sucrose and gum arabic A tablet comprising an active agent; and a mouthwash comprising the active agent in a suitable liquid carrier. Suitable dosages of the compounds or formulations of the invention will vary depending on the indication and the patient and are readily determined by conventional animal testing. It is generally advantageous and achievable to provide a dose of about 0.01-1 00 μΜ, more preferably 〇μ〇, such as 〇丨_25, which is used in cells (for inhibiting the physiological protease of the papain superfamily) concentration. . The compounds of the invention are prepared by a variety of solutions and solid phase chemistry. The compound is usually prepared as a basic component of the Ρ丨, Ρ2 and Ρ3 knives reflecting the final product inhibitor. Without wishing to be bound by theory in any way, or assuming that the binding mode is attributed to a particular variable, the symbolic concepts ρι, ρ2, and Ρ3 as used herein are provided for convenience only and generally have their well-known Schlect^ & Berger meaning and Saskatchewan fills the s丨, §2, and S3 sub-site inhibitors of the enzyme, respectively, where s丨 is adjacent to the cleavage site and S3 is remote from the cleavage site. Compounds defined by the formula are intended to be within the scope of the invention, without regard to the mode of association. In summary, the basic component of Ρ 1 will have the following formula: 129860.doc -33- 200906392 r

among them:

Or ss PG·

a

The Re group SS is N3 or ύα - ^ 3 Λ /, σ group 兀, such as two rim groups protected by a conventional OH or Ο; protecting group, defining a 铋 πφβ π 曱 曱 _ ketal Or together define a cyclic ketal such as 1,3-dioxolane; and Re is a trans-protecting group, and the age of 戎 & & amp amp amp & Η Η Η Η Η Η Η Η Η Η Η Η Η Η Η The base component, when extended, represents the ketone functional group of the final product inhibitor. The above P1 basic component, WO 05/066 180 describes the preparation of the intermediate to include:

Prior to coupling with P2, the s component of azide, the earthworm, is usually treated, for example, by treating an aqueous solution of P1 dissolved in a solvent such as a foot with an azide salt (for example, an alkali metal salt such as an aqueous solution of NaN3). The component is converted to azide. P2 is usually N. protected amine money 1 such as arginine, acid, hydrazine methyl _L-threonine, L_3_hydroxylamine _ ^ ^ ^ guanamine owe, 4-rolled leucine or L_ Glycosylglycine, the deletion usually comprises a capping group, such as a benzoic acid derivative having a N-alkyl-piperazinyl-E moiety or a synthetic component thereof introduced in the para position 129860.doc -34-200906392 . The individual basic components suitably protected may be prepared first and then preferably coupled together in the following order to minimize racemization at P2: P2+P1-P2-P1' followed by N-alkyl Piperazinyl-E-benzoic acid*+P2-Pl-N-alkylpiperazinyl-E-benzoate_P2_P1, wherein * represents the activated form. Coupling between two amino acids, amino acids and peptides or two peptide fragments can be carried out using standard coupling procedures, such as the azide method, mixed carbonate-deoxyanhydride (isobutyl methacrylate) method, carbonization Method of diimine (dicyclohexylcarbodiimide, diisopropylcarbodiimide or water-soluble carbodiimide), active ester (p-nitrophenyl ester, N-hydroxysuccinic acid imino group) Ester) method, Woodward reagent K-method, carbonyl diimidazole method, phosphorus reagent or redox method. Some of these methods (especially carbodiimide methods) can be enhanced by the addition of 1-hydroxybenzotriazole or 4-DMAP. These coupling reactions can be carried out in solution (liquid phase) or in a solid phase. More specifically, the coupling step involves the dehydration coupling of the free carboxyl group of one reactant in the presence of a coupling agent with the free amine group of the other reactant to form a linkage guanamine linkage. A description of such coupling agents can be found in general textbooks on peptide chemistry, for example, M. Bodanszky, "Peptide Chemistry", Second Revision, Springer-Verlag, Berlin, Germany, (1993) (hereinafter referred to as

Bodanszky) '' its contents are incorporated herein by reference. An example of a suitable coupling agent is N,N'-dicyclohexylcarbodiimide, in the presence of N,N,-dicyclohexylcarbodiimide, 1-pyridylbenzotrifluoride or ethylidene 129860. Doc -35- 200906392 Amino)propyl]carbodiimide. A practical and suitable coupling agent is a commercially available hexafluorophosphoric acid (benzotriazole-hydrazinyloxy) ginsyl-(dimethylamino) scale, either alone or in 1-hydroxybenzotriazole or 4- In the presence of DMAP. Another practical and suitable coupling agent is commercially available tetrafluoroborate 2-(1H-benzotriazolyl)_N,N,N',N'-tetraindole. Another useful and suitable coupling agent is the commercially available hexafluorophosphoric acid (7) s-azabenzotriazole- 丨-kib team ^^^-four.

The coupling reaction is carried out in an inert solvent such as dichlorosilane, acetonitrile or dimethylformamide. An excess of the tertiary amine (e.g., diisopropylethylamine, N-decylmorpholine, N-methylpyrrolidine or 4_DMAp) is added to maintain the reaction mixture at a pH of about 8. The reaction temperature is usually in the hydrazine. 〇 with 5 〇. (within the range between and the reaction time is usually in the range of 15 minutes and 24 hours. It is usually necessary to protect the functional group of the unnatural amino acid component during the coupling reaction to avoid formation of an improper bond. Listed in Protective Groups in Organic Chemistry", John Wiley & Sons, New York (1981) and "The The peptides: heart sputum, plus sputum,

Biology, Vol. 3, Academic Press, New Y〇rk (1981) (hereafter referred to as Greene), the disclosure of which is hereby incorporated by reference herein in its entirety, the <RTIgt; Protection, the ester can be cleaved to produce a carboxylic acid. Protecting groups which may be used include 1} alkyl esters such as methyl, trimethyldecyl and tert-butyl, 2) aralkyl esters such as benzyl and substituted benzyl, or 3) It is a weak base or a mild reduction method, such as trichloroethyl ester and benzoquinone methyl ester. It is usually necessary to protect the ?-amino group of each amino acid to be coupled. Any protecting group known in the art can be used 129860.doc -36- 200906392. Examples of such groups include: u-acid groups such as fluorenyl, trifluoroethenyl, phthalyl and fluorenyl, and 2) aromatic urethane groups, such as Benzyloxycarbonyl (hydrazine or z) and substituted benzyloxycarbonyl, and 9-fluorenyloxycarbonyl* (Fm〇c); 3) lipoamine phthalate group, such as third butoxide a carbonyl group (B〇c), an ethoxylated carbon group, a diisopropylmethoxy-carbonyl group and an allyloxycarbonyl group; 4) a cyclic alkylaminocarbamic acid brewing group such as a cyclopentyloxycarbonyl group and Adamantyloxycarbonyl;

5) an alkyl group such as a triphenylsulfonyl group and a benzyl group; 6) a trialkyl decyl group such as a trimethyl decyl group; and 7) a thiol group such as a phenylthiocarbonyl group and a thia group Ding Erji. A preferred cardioprotective group is or a pawl (10). A wide variety of amino acid derivatives which have been suitably protected for peptide synthesis are commercially available. The ex-amino protecting group is typically cleaved prior to the next coupling step. When the Boc group is used, the method selected is carried out without using a solvent or using trifluoroacetamidine in a gas-fired gas, or using HQ in dioxane or ethyl acetate to carry out the obtained ammonium salt before coupling. Or in situ, neutralization using a tertiary amine such as an aqueous buffer, or trichloromethane or acetonitrile or dimethylformamide. When using? The base is selected (4), and the selected reagent is carried out in dimethylformamide, but any secondary amine can also be used. The removal of the protecting group is carried out at a temperature between room temperature and room temperature (usually 20-22 ° C). Once the inhibitor sequence is completed, it is not known to any operator. 'There are any remaining protecting groups that are removed by the choice. These procedures are familiar with the technique 129860.doc -37. 200906392 〇The invention of the invention compound (such as the compound of the general formula π) P white & pass to prepare the functionalized P1 basic component in solution state .

12 13 14 i·Dess-Martin! IX Dess-Martin Periodinane, DCM,

2 hours, room temperature; ii. Trimethyl orthoformate, pTs〇H, Me〇H, 8 hours, 60〇C; iii. Pd(OH)2, H2, MeOH, 48 hours, room temperature; iv. Boc20 , 10% Na2C03, 16 hours, 〇 ° C to room temperature; v. 曱 burning 醯 chlorine, DIPEA, DCM, 2 hours, 〇. 〇 ; vi. NaN3, DMF, 2 x 1 hour, 130 ° C in the microwave P1 basic component 14 was prepared as described above and described in Example 1 or 9. Compound 10 was prepared as described in W005/066180 and the alcohol functional group was oxidized by Dess-Martin Gauze to provide -9. Treatment of the ketone 9 under the conditions described provides a dimethyl ketal intermediate 10'. Hydrogenolysis of compound 10* removes Cbz and a benzyl protecting group to provide intermediate 12 for the Boc protection of the amine functional group of amine 11.11. The fluorite 13 is provided by treating the C-6 alcohol of Compound 12 with methanesulfonate and a base. Substitution of 13 C-6 for acid with sodium azide in DMF 129860.doc -38· 200906392 The salt provides the desired C-6 azide P14. Typically to obtain the final compound, intermediate 14 is treated with acetonitrile in methanol to remove the N-Boc protecting group. (In some cases, the azide treatment at high temperatures directly results in the removal of the Boc group, so the deprotection step can be omitted.) By the subsequent free amine, P2 is used using standard coupling conditions such as HATU in DMF, DIPEA. The residue was introduced via BocP2-OH. The end Boc was further removed by acetamidine in methanol and the p3 residue was introduced via p3_〇H using standard coupling conditions such as HATU in DMF, DIPEA. Finally, the monomethyl ketal protection is removed with TFA to provide the desired final compound. Elongation is usually carried out in the presence of a hydroxybenzotriazole (HOBT) and a base such as hydrazine, hydrazine-diisopropylethylamine, triethylamine, N_f-based morpholine and the like. In the presence of a suitable coupling agent: hexafluorophosphoric acid oxadiazole-1·yloxy cis-pyrrolidine scale (PyBOP), hexafluorophosphate 〇 benzophenanone 1-yl-N,N,N', N'-tetradecyl-indole (HBTU), bismuth hexafluorophosphate-(7-azabenzobisazolyl)-1,1,3,3-tetradecyl-indole (HATU), 1-( 3-Dimethylj-aminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) or hydrazine, 3-dicyclohexylcarbodiimide (DCC). The reaction is usually carried out at 20 to 3 (TC, preferably at about 25 C, and takes 2 to 24 hours to complete. A suitable reaction solvent is an inert organic solvent such as an organic solvent (for example, a gas-burning, chloroform). And "analogs", acetonitrile, N,N-dimethylguanamine, ether solvents (such as tetrahydrofur. South, - oxoxime and the like). Or the above elongation coupling step can be achieved by first Ρ3 The basic component is converted to an active acid derivative such as butyl sulphate and then reacted with guanamine. The reaction usually takes 2 to 3 hours to complete. 129860.doc -39-200906392 The condition depends on the nature of the active acid derivative. For example, if it is an acid organism, the reaction is carried out in the presence of a suitable test (for example, triethylamine, diisopropyl ratio bite and the like). a polar organic solvent such as acetonitrile, hydrazine, hydrazine dimethyl ketone: '', or any suitable mixture thereof. ..., methylene chloride _ protected L. amino acid form Ρ 2 basic component is easy to structure Having, for example, can be constructed with many protecting group variants (such as coffee) Such as ... L_ leucine, L_isoleucine, cyclohexylglycine, methyl sulphonic acid and others. Other variants of R2 are readily prepared from commercially available starting materials: eg ' The compound wherein R2 is -c(CH3)2〇ch3 can be obtained by CBz-protected (S)-(+)_2-amino-3-hydroxy-3-methylbutyric acid with 3,3_2 The methoxy-hexahydro-furo(3,2b)pyrrole is reacted to form the desired ρ2_ρι unit. The P2 side chain alcohol can now be methylated using methyl iodide under conventional sodium hydride, imidazole, and thf conditions. The desired oxime 2 is obtained without substantially ablation of the a-center. This Ρ2-Ρ1 moiety can now be synthesized as described herein, i.e., CBz removal and coupling.

WO 05/565299 describes the preparation of the basic component of gamma-fluoroleucine P2. An alternative synthetic line of the basic components of Fmoc and N-Boc-γ fluoroleucine is shown in

Truong et al. Syn. Lett. 2005 No. 8 1278-1280. The preparation of the P3 basic component wherein E is a bond, a thiazolyl group or a substituted thiazolyl group and/or a benzoic acid moiety substituted with R3 is described in WO 05/066180 or is readily prepared by a similar method. For example, Scheme E below shows the preparation of the P3 basic component wherein e is a fluorozolyl substituted thiazolyl group: 129860.doc -40· 200906392

i. HOAc, Br2, room temperature, 2 hours, 55% yield; specific lamp, 18_crown-6, CH3CN, 90 ° C, 16 hours, 31% yield; (1), h〇Ac, Br2, 45 °C , 4 hours, 100% yield; W. 4-methylpiperazine small thiocarbamine, ethanol, 70 Torr, 2 hours, 74% yield, v, Li〇H, thf, H20, room temperature, 16 Hour, 79°/〇 yield.

Scheme E 4-[5-Fluoro-2-(4-indolyl-Brigade. Qin-1-yl)-oxime. Synthesis of _4_yl]-benzoic acid The starting material 4-ethylmercaptobenzoic acid was commercially available. The position of the heart of the heart, / stinky is achieved by the acetic acid, / odor to provide the desired 4_(2_演_乙醯基)_benzoic acid brewing. Subsequent treatment with potassium fluoride in the presence of 18-crown-6 at 90 ° C in the presence of 18-crown-6 (2 - oxa-ethyl fluorenyl) - methyl formate is provided after column chromatography to provide 4_(2_ fluoro-acetamidine) Base)-methyl benzoate. Repeated bromination of the alpha-position of the ketone is achieved by bromine in acetic acid to provide the desired methyl 4-(2-bromo-2-fluoro-ethinyl)-benzoate. The formation of thiazole is usually carried out by heating methyl 4-(2-bromo-2-fluoro-ethenyl)-benzoate at 701: with 4-methyl-methyl hydrazine-1-thiocarbenium. Hours to come. After cooling, the desired 4-[5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazin-4-yl]-benzoic acid decyl ester was precipitated. The deprotection of the methyl ester is carried out using a hydrazine hydroxide solution and the desired acid 4-[5-fluoro-2-(4-methyl-pyrazin-1-yl)-oxime-4-yl]-benzene Formic acid is usually obtained in good yield in the form of the dihydrochloride salt after treatment with hydrochloric acid. 129860.doc -41 - 200906392 The term "N-protecting group, as used herein, or "Ν·protected" refers to protecting the amine end of an amino acid or peptide or protecting the amine during the synthetic procedure. Bases are free of these groups that are improperly reacted. The commonly used oxime-protecting system is disclosed in Greene, "Protective Groups in Organic Synthesis" (John Wiley & Sons, New York, 1981), which is incorporated herein by reference. Ν·protecting group includes sulfhydryl group, such as fluorenyl, acetyl, propyl, trimethyl acetyl, tert-butyl acetyl, 2-chloroethyl, 2 bromoethyl, three Fluorinyl, trichloroethylene, phthalic acid, o-butylphenoxyethyl, α-chlorobutyridinyl, benzindenyl, 4-chloroindenyl, 4-nodolinyl , 4-nitrobenzyl fluorenyl and the like; sulfonyl, such as bentonin, fluorenyl, p-toluenesulfonyl and the like, a carbamate-forming group such as benzyloxycarbonyl, p-Chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-methoxy Benzyloxycarbonyl, 2-nitro-4,5-dimethoxyoxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, iota(p-biphenyl)-1-methylethoxycarbonyl , α,α-dimercapto-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, tert-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropoxycarbonyl 'Ethoxycarbonyl, methoxycarbonyl, allyloxy Ik, 2,2,2-trisethoxycarbonyl , phenoxycarbonyl, 4-nitrophenoxycarbonyl, -9-nonyloxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and Analogs; alkyl groups such as mercapto, triphenylmethyl, benzyloxymethyl and the like; and anthracenyl groups such as dimethylalkylalkyl and the like. Advantageous N_protecting groups include indolyl, ethyl hydrazino, benzhydrazinyl, trimethylethenyl, tert-butyl hydrazine 129860.doc -42-200906392, benzenesulfonyl, benzyl (bz ), a third butoxycarbonyl group (B〇c) and a benzyloxycarbonyl group (Cbz). The thiol and/or thiol protecting groups are also broadly described in the above Greene and include ethers such as methyl ether, substituted methyl ethers such as decyloxy thiol, methylthiomethyl An ether of a benzyloxymethyl group, a benzyloxymethyl group, a 2-methoxyethoxymethyl group, and the like, a decyl ether such as trimethyl decyl (TMS), a third An ether of butyl dimethyl fluorenyl (TBDMS), tribenzyl decyl, triphenyl decyl, tert-butyldiphenyl decyl, triisopropyl decyl, and the like, substituted Ethers such as 1-ethoxymethyl, 1-indenyl-1-methoxyethyl, second butyl, propyl, benzyl, p-nonoxyl, diphenylmethyl An ether of triphenylsulfonyl and its analogs, an aralkyl group such as trityl and pixyl (9-hydroxy-9-phenyldibenzopyran derivative, especially a vapor). The ester hydroxy protecting group includes esters such as phthalate, benzyl phthalate, gas acetate, methoxy acetate, phenoxy acetate, trimethyl acetate, and diamond powder. Acid esters, mesitoates, benzoates and the like. The carbonate hydroxy group 5 mercapto group includes a mercapto group, a propyl group, a cinnamyl group, a fluorenyl group and the like. [Embodiment] Various embodiments of the present invention will now be described by way of example only with reference to the following examples. Example 1 P1 basic component (3aS, 6aS)-6R-azido-3,3-dimethoxy-hexa-argon-furo[3,2-b]pyrrole-4-carboxylic acid tert-butyl ester 14 Preparation 129860.doc • 43· 200906392

Preparation of (3as,6aS)-6R-co-oxyl_3-o-oxy-hexahydro-furo[3,2-b]pyrrole_4_decanoic acid benzyl ester 9

0 9 Dissolve Dess-Martin reagent (12.5 g, 30 mmol) in DCM (250 ml). Compound 10 (7.4 g, 20 mmol) from WO 05/066180 in DCM (50 ml) was added to a stirred solution of oxidant at room temperature under nitrogen for 45 min. After stirring for a further 90 minutes, the reaction was monitored by tlC (50:50 ethyl acetate: hexanes). Once the reaction was judged to be complete by TLC, a 1% </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; </ RTI> solution (200 mL) was added and the mixture was stirred for a further 5 minutes at room temperature. The two phase system was transferred to a separatory funnel and extracted twice with Et〇Ac (200 mL and 100 ml, respectively). The combined organic phases were washed once with saturated aq. NaH (aq. EtOAc) (aq.) and brine (1 mL), dried over Na.sub.2, filtered and evaporated in vacuo. Crude product 9 (7 69 g); ESI+, m/z: 368 (M+ +1).

Preparation of 1,4--4-carboxylic acid benzyl ester 10' 129860.doc •44· 200906392

Compound 9 (7.6 g) was dissolved in dry methanol (100 ml). Tridecyl orthoformate (30 ml) and pTsOH (0.2 g) were added under a nitrogen atmosphere at room temperature. The mixture was heated at 60 ° C for 8 hours. The reaction was monitored by TLC (50:50 ethyl acetate: hexanes). The Rf of the ketone was 0.38 and the Rf of the ketal was 0.66. Once it was determined that the reaction had reached completion, it was cooled to room temperature and concentrated in vacuo. The crude product was purified by column chromatography eluting with ethyl acetate-heptane (1:4) eluting to </RTI> </ RTI> </ RTI> as a clear oil, </RTI> m/z: 382 (M+-OMe). Preparation of (3aS,6aS)-3,3-dimethoxy-hexa-argon-furan oxime 3 2_b]pyrrole·611-alcohol 11

OH

A solution of the compound 10' (2.5 g' 6.4 mmol) in methanol (60 ml) and Pd (OH) 2 (0.7 g) was stirred at room temperature for 48 hours. The reaction was monitored by TLC (50:50 ethyl acetate: isohexane) to determine the disappearance of the ket. Once it was judged that the reaction had been completed, the mixture was filtered and concentrated in vacuo to give crude compound 11 (1 15 g) as a brownish oil. 129860.doc •45-200906392 ESI+,m/z: 190 (M+ +1). Preparation of (3aS,6aS)-6R-hydroxy-3,3-dimethoxy-hexa-argon-furo[3,2-b]pyrrole·4-carboxylic acid tert-butyl I2

10 〇 - 12 3,3-methoxy-hexahydro-trinute [3,2-匕]° is dissolved in 75 ml of 嘻-6-alcohol 11 (2.80 g' 14·8 mmol) In a mixture of dioxane/water (2:1). A 10% Na2CO3 solution (25 ml) was added dropwise to a pH of 9-9.5. The mixture was cooled to 〇 ° C in an ice water bath and B 〇 c anhydride (quantity?) was added in one portion. The reaction was stirred overnight at room temperature and if necessary, more 丨〇% Na2CO3 solution was added to maintain the pH of the mixture at 9-9.5. The reaction was monitored by tlC (50:50 ethyl acetate: isohexane). Once completed, the mixture is filtered to remove the salt formed and the solvent is eliminated in a vacuum. The aqueous mixture was extracted with EtOAc (3 mL) EtOAc (EtOAc)EtOAc. The amine amide was obtained from 12 (89%), 94% pure (HPLC), ESI+, m/z: 312 (M++Na). Preparation of (3aS,6aS)-6R-methanesulfonyloxy-3,3-dimethoxyhexahydrofuro[3,2-b]pyrrolecarboxylic acid tert-butyl ester

0 〇 - 13 129860.doc -46- 200906392 Compound 12 (3.15 g, 10.9 mmol) was dissolved in DCM (50 ml) and cooled to EtOAc. Monoisopropylethylamine (3.9 ml, 21.78 mmol), sulfonium sulfonate (1.13 ml ' 14.48 mmol) and DMAP (0.05 g) were added to the solution. The mixture was stirred at 0&lt;0&gt;C for 2 h, diluted with EtOAc (EtOAc (EtOAc) , 30 ml), saturated with NaHCO3 (30 ml) and brine (30 ml). The organic phase was dried with EtOAc (EtOAc m.) ESI +, m/z: 368 (M+ +1). Preparation of (3aS,6aS)-6R-azido-3,3-dimethoxy-hexahydro-trimone and l3,2_b]pyrene ratio _4·carboxylic acid tert-butyl ester 14

An aqueous solution of NaN3 was added to compound 13 (1.1 g, 3 mmol) dissolved in DMF (6 ml) and the mixture was then warmed for 2 x 60 min at 130 ° C in a microwave reactor. The mixture was cooled to rt, saturated with EtOAc (EtOAc)EtOAc. The combined organics were dried with EtOAc (EtOAc m.). M+ +1). Example 2 129860.doc -47- 200906392 P-2 is coupled with L-Ile [l-((3aS,6aS)-6R-azido-3,3-dimethoxy-hexahydro-furan oxime 3, 2_b]°lt-lt--4-yl)]-2-methyl-butyl]-carbamic acid dibutyl S曰7

f %

The product compound 14 of Example 1 was dissolved in DCM (20 mL) and EtOAc EtOAc (EtOAc (EtOAc) Stirring in the presence of 6 mmol) and NMM (0.71 ml, 6.5 mmol) for 16 h, diluted with EtOAc (50 ml), EtOAc (1 EtOAc, 30 ml), sat. NaHCO3 (30 ml) and brine (30 ml) washing. The organic phase was dried over NajCU, filtered and evaporated in vacuo</RTI> <RTI ID=0.0> The crude mixture was separated by column chromatography eluting with ethyl acetate-heptane (1:4) to yield pure 7 (0.406 g). ESI +, m/z: 428 (M+ +1). Example 3 Coupling with P3 functional group Nn-WaSMSH6!^ 4 gas group-3,3·dimethoxyhexahydrocarbamate[3,2_b]indole/4_carbonyl))_2_methyl·butyl 】_4_丨2 (4·methyl-piperazine small group)-thiazole_4-carbobylamine 15 129860.doc -48- 200906392

[1-(6 R-Apilyl-3,3-monodecyloxy-six---fusphet[3,2-b]. Biluo_ &quot; 4_individual)_2_indenyl -Butyl]-carbamic acid tert-butyl ester 7 (0.4 g, 0.94 mmol) &gt; glutathione in anhydrous MeOH (18 ml) and cooled to &lt;RTIgt; Ethylene gas (2 ml) was then added dropwise. The mixture was stirred at room temperature and the reaction was monitored by TLC (50: 50 ethyl acetate: isohexane). When the reaction was completed, the solvent was removed in vacuo and the residue was lyophilized from H 2 〇: ACN (1:1) (1 〇 ml). The obtained amine HCl salt (0.16 g) was obtained as the HBr salt of 4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl}-benzoic acid (0.174 g, 0.37 mmol). HOBt (0.051 g, 0.37 mmol), WSC.HC1 (0.11 g, 0.56 mmol) and NMM (0.082 ml, 0.74 mmol). The mixture was diluted with Et0Ac, then the organic phase was washed once with saturated NaHC.sub.3 and once with 0.5 EtOAc. The organic solution was dried over Na.sub.2SO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub. [81+, 11^: 613(]^++1). Example 4 N-[l-(3aS,6aS)-6R-Laminated-3-oxo-hexahydro-cough and [3,2-b]*pyr-4-carbonyl)-2-indole Benzyl-butyl]-4-[2-(4-methyl-piperazine·1·yl)-thiazol-4-yl]-benzylguanamine 16 129860.doc -49- 200906392

Compound 15 (39 mg) was dissolved in 2 ml of a mixture of TFA/H20 (97.5: 2.5) and stirred at room temperature for 3 hours. Once the reaction was completed by HPLC, the solvent was removed in vacuo, 5 ml of acetonitrile was added and the mixture was neutralized with solid NazCO3, filtered and solvent removed in vacuo. The crude material was purified by semi- preparative HPLC to yield 134 mg (yield: EtOAc) Example 5 N-丨l-((3aS,6aS)-6R-azido-3,3-dimethoxyhexahydrofuro[3,2-b]pyrrole-4-carbonyl)-3-methyl -butyl butyl butyl carbamate

In a similar manner to the last step of Example i and Example 2, the title compound was prepared from the compound &lt;RTI ID=0.0&gt;&gt;&gt; [l-(3aS,6aS)-6R-4 nitrogen-based pendant hexa-hexafluoroterpene and 丨3 is 吼] 吼 -4--4-yl)-3-methyl-butyl]-4 仏 (4) methyl (IV)小基)_叹叹_4· 129860.doc -50. 200906392 base]-benzylamine 18

18, free compound 17 derived amine raw 99% pure (HPLC) ketone 18 (12 in a similar manner to the synthesis of Example 3

HC1 salt to prepare the title compound, X

Yield mg) ° ESI+, m/z: 567 (M+ +1). Example 7 [(3aS,6aS)-6R_4 gas group·3·sideoxy hexa-happa and [^^Bilo_4_yl)]·3-mercaptobutyl 44·(4_propyl sinyl small group )_节敌胺2ΐ

The title compound was prepared in a similar manner to the synthesis of compound 18 to afford the title compound as a compound of the compound </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> to yield 99Q/t^(HpLc)_2i (ii6 mg). ESI+, m/z: 512 (M+ +1). Comparative Example 1 N-[(S)-l-((3aS,6S,6aS)-(6_Fluor_3_sideoxy_hexa-argon bite and [32b]Biro-4-yl)-3·A Base·butyl b 4_(4_propyl·娘 sniffing 醯 129 129860.doc 200906392

Step a) N-[(S)-l-(3aS,6S,6aS)-(6-fluoro-3-indolyl-hexahydro-furan-[3,2-b]pyrrole-4-carbonyl) Benzyl 3-methyl-butyl]carbamate

The title compound (having the described stereochemistry) was prepared using Cbz protection, similar to Example 2 of w〇 05/066180. Step ϊ&gt;)Ν-[(8)-1-(338,68,6β8)-(6-fluoro-3-hydroxy-hexa-argon-furo[3,2_b]pyrrole-4-carbonyl)-3-A Base-butyl]_4_(4-propyl-piperazine q•yl) benzinamide

The c3-3 alcohol of the P2-P1 basic component of step a) is oxidized to a ketone with Dess Martinnoin and the ketone is protected to a dimercapto. The Cbz protecting group is then subjected to standard procedures from the resulting N_[(8) small (3aS,6S,6aS)_(6_gas_3,3.dimethoxy-hexahydro-furo[3,2-b]pyrrole- The 4-carbonyl)-3-methyl-butyl]amino decanoic acid benzyl S oxime was removed and the free amine was coupled to 4-(4-propyl-piperazinyl)benzoic acid. The final step involves the cleavage of dimethyl ketal to obtain the desired 129860.doc -52- 200906392 ketone N-[(S)-l-((3aS,6S,6aS)-(6-fluoro_3_ side oxygen Lithyl-hexahydrofuro[3,2-b]pyrrole-4-carbonyl)-3-methyl-butyl]-4-(4-propyl-p-but-1-yl)-benzylamine. Comparative Example 2 1\-[(8)-1_((338,68,638)-6-azido-3-oxooxy)-hexahydro-furo[3,2-b]pyrrole-4-carbonyl) -3-methyl-butyl]-4-[2-(4-mercapto-piperazin-1-yl)-thiazol-4-yl]benzylamine

S In the preparation of compound 14, the corresponding 6S-azido isomer-(3aSJaS)-6S-azido-3,3-dimethoxy-hexahydro-furo[3,2_b]pyrrole_4 _ Formic acid second butyl vinegar is separated as the main by-product. This isomer was then subjected to the remainder of the synthesis as described in Example 6 to provide N-[(s)_1·((3aS,6aS)_6R-«azin-3-yloxy)_hexahydro_ Furando[3,2_6]pyrrole·4_carbonyl)_3_methyl-butyl]_4-[2-(4-mercapto• kibsyl-pyridylamine) Comparative Example 3 N-[(lS) -l-((3aS,6aR)_3_sideoxy)hexa-argon-flavored and [ή]haha 4-rebase)-3-methyl-butyl]_4·[2 (4 methyl-l-azine Small base) azole-benzylamine 129860.doc -53- 200906392

The P1 basic component was synthesized as shown in WO 02/05720 and coupled to the ruthenium-protected L-leucine and the Ρ3 basic component of Example 8 below, and oxidized as shown in Examples 2 and 3. to make_. Example 8 Alternative Ρ3 basic components Step a) 4-fluoro phenyl propyl mesh

4-bromopropiophenone (5.65 g &gt; 26.4 mmol), Zn(CN) 2 ( 1.80 g, 15.3 mmol) and Pd (as described for the preparation of 4-cyanoacetophenone Commww 1994, 887-890) A mixture of PPh3)4 (2.95 g, 2.6 mmol) was refluxed for 18 hours at 80 ° C in deoxygenated DMF (35 mL, stored on 4 A molecular sieves, bubbed with Ar before use). The mixture was partitioned between toluene (100 mL) and 2N NH4OH (100 mL). The organic phase was extracted with 2N EtOAc (EtOAc)EtOAc. A 1 〇 mmol grade reaction was similarly carried out and the crude products were combined. Flash chromatography (330 g of ruthenium chloride, 6/1 petroleum ether EtOAc) gave a white solid (5.17 g, 89%). !H NMR (CDCI3) δ ppm: 1.22 (t, 3H, J = 7.2 Hz), 3.00 2H, J=7.3 Hz), 7.75 (d, 2H, J=8.8 Hz), 8.03 (d, 2H, J= 8.4 129860.doc -54- 200906392

Hz) 13C NMR (CDC13) δ ppm: 7.8, 32.1, 116.1, 117.9, 128.3, 132.4, 139.7, 199.2 Step b) 4-propenylbenzoic acid

4-cyanopropiophenone (4.67 g, 29.3 mmol) was combined with 2 N NaOH (90 mL '180 mmol) and dioxane (9 〇 mL) at 95. His knees flowed back overnight. The mixture was diluted with water (150 mL) EtOAc (EtOAc)EtOAc. The organic phase was washed with aq. EtOAc EtOAc (EtOAc) !H NMR (CDC13 + CD3OD) δ ppm: 1.18 (t, 3H, J=7.2 Hz), 2.99, (q5 2H, J = 7.1 Hz), 7.95 (d, 2H, J=8.4 Hz), 8.08 (d , 2H, J-8.8 Hz) 13C NMR (CDCI3) δ ppm: 7.9, 32.1, 127.7, 130.0, 134.0, 140.0, 168.0, 200.8 Step c) Methyl 4-propenylbenzoate

DMF (10 mL) t of the above benzoic acid (89 mg, 5 mmol), NaHC.sub.3 (l.sup.26 g, 15 s. The mixture was diluted with aq. aq. EtOAc (5 mL) andEtOAc. The organic phase was washed with water (50 mL) dried EtOAc EtOAc. Flash chromatography (90 g of cerium oxide, 2/1 petroleum ether·Εί〇Α(:) yielded a white solid (744 mg, 77%).]H NMR (CDC13) δ ppm: 1.24 (t, 3H, J= 7 Hz), 3.03 (q, 2H, J=7 Hz), 3.95 (s, 3H), 8.0 and 8.12 (ABq, 4H) Step d) 4-(2-Bromopropionyl)benzoic acid methyl ester

h /)~COOMe

ο, J (methyl 4-propylmercaptobenzoate (744 mg, 3.87 mmol) in THF (38 mL), pyrrolidone hydrobromide (丨, 98 g) and 2-pyrrolidine under nitrogen The ketone (3 80 mg '4.5 mmol) was heated at 50 °C for 3 h. The mixture was cooled, filtered, concentrated and then redissolved in diethyl ether (50 mL). Washed with aqueous solution (20 mL), aq. EtOAc (EtOAc) (EtOAc) (EtOAc) This material contained 91% of the desired bromoketone, 5% of the starting I ketone, and 4% of 4-bromo-1-butanol. ]H NMR (CDCI3) δ ppm: 1.92 (d, 3H, J=7 Hz ), 3.96 (s, • 3H), 5·28 (q, 1H, J=7 Hz), 8.07 and 8_14 (ABq, 4H) Step e) 4-[2-(4-Tertiyloxycarbonylpiperidine) Methyl benzoate _5_methylthiazole _4·yl] benzoate

All of the above α-bromo ketones and 4-thiocarbonylpiperazine-1- 129860.doc -56-200906392 formic acid tert-butyl ester at 70 ° C under A (乂四,., 1998, 5037-5054, 917 mg, 3.73 mmol) was refluxed in 36 mL THF for 2 h. The precipitate was filtered and the mash was evaporated to give a yellow solid. Flash column chromatography (2D, 5/1 petroleum ether-EtOAc) yielded 624 mg of pale yellow solid. Chromatography of the precipitate (ruthenium dioxide &lt;RTI ID=0.0&gt;&gt; The total yield is 44%. NMR (CDC13) δ ppm: 1.46 (s, 9H), 2.43 (s, 3H), 3.42 (m, 4H), 3.54 (m, 4H), 3.90 (s, 3H), 7.68 and 8.04 (ABq, 4H) . Step f) 4-[2_(4_Tertiyloxycarbonyl)isyl-5-5-carbazole-4-yl]benzoic acid

The above mercapto ester (564 mg, 1.35 mmol) was heated with 1.35 mL of 2 N NaOH, 5 mL of THF and 3.65 mL of water at 60 ° C for 4 hours. The reaction mixture was evaporated, poured into 20 mL of saturated aqueous NaCI and 20 mL (: ίί 2 (: 12, and then acidified to pH 3 with 5 〇/0 citric acid in an ice bath. The layers were separated and the organic phase was separately 2x10 mL CHei2 extraction. The organic phases were combined, washed with water (10 mL), dried and evaporated to give pale yellow solid (537 mg, 98%) 〇'Η NMR (CDC13) δ ppm: 1.48 (s, 9H ), 2.47 (s, 3H), 3.47 (m, 4H), 3.57 (m, 4H), 7.74 and 8.12 (ABq, 4H). I3C NMR (CDCI3) § ppm: 12.6, 28.3, 42.8, 48.1, 80.3 129860 .doc -57- 200906392 119·1,127.8,128.2,130.1, 140.5,145.6,154.6, 167.2 171.4. LCMS: (Μ+Η) + 404,(Μ-Η)-402. Step g)4-[5 -methyl-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]benzoic acid

Dissolving 4-[4-(4-sulfo-phenyl)-5-fluorenyl-sept-2-yl]-t-butyl-1-carboxylic acid tert-butyl ester (0.421 mmol) in 1,4-di 4 M HCl in methane, and stirred at room temperature for 1 hour. The solvent was then removed under vacuum and the residue 4-(5-mercapto-2-piperazin-1-yl-thiazol-4-yl)-benzoic acid was suspended in methanol (10 ml) AcOH/AcONa buffer (pH 5.5, 5 ml) and furfural (0.547 mmol) were treated. The reaction mixture was stirred at room temperature for 1 hour. then was treated with NaCN.sub.2H.sub.3 (0.547 mmol) and was then allowed to stand overnight at room temperature. The solvent was removed under EtOAc (EtOAc m.) MS (ES) m/z 318 (100%, [M+H] + ). Step h) The p3 acid from step g was coupled with the basic component from Example 52P1_P2 and oxidized as shown above. Example 9 Alternative Preparation of P1 Basic Component

129860.doc •58- 200906392 Step a)

Compound 12 from Example 1 (1 55 g, 5.36 mmol), benzoic acid (〇.9〇g, 8 04 mmol) &amp;triphenylphosphine (162 g ' 8.04 mmol) at 0 °C To a stirred solution of tetrahydrofuran (20 ml), a solution of decanoic acid monopropionic acid (1.58 ml ' 8.02 mmol) in tetrahydrofuran (5 ml) was added dropwise. The reaction mixture was allowed to slowly reach room temperature and then stirred overnight. The reaction mixture was then concentrated with EtOAc (EtOAc) EtOAc (EtOAc (EtOAc) Mm〇1, 96%) ° NMR data (400 MHz, 298 K, CDC13): Η, δ 1.40 and 1.49 (2 s 9 Η), 3.27-3.42 (m, 6 Η), 3.44-3.51 (2 d, 1H), 3.69 (m, 3.76-3.89 (m, 1H), 4.01-4.19 (2 d, 1H), 4.52-4.78 (m, 2H), 5.26 (brs, 1H), 7.40-7.46 (m, 2H) , 7.54 - 7.58 (m, 1H), 7 96 (d, 2H). (2:3 mixture of rotamers) Step b)

To a stirred solution of the product (1. The reaction mixture was monitored by TLC (hexane-ethyl acetate 7:3 and 1:1, and observed by ultraviolet light and stained with a 10% aqueous sulfuric acid solution containing ammonium molybdate-barium sulfate). After 2 hours, the reaction mixture was neutralized by Dowex (50WX8-100 'H+-form, pH monitored by pH paper), then filtered and concentrated. The residue was flash chromatographed eluting with EtOAc (EtOAc EtOAc (EtOAc) (1.23 g, 4.27 mmol, 86%). In CDC13 at 25 ° C, NMR showed the product to be present as a mixture of geometric isomers. NMR data (400 MHz, 298 K, CDC13): δ 1.47 (s, 9H), 3.28-3.38 (m, 7 Η), 3.62 (d, 1H), 3.74-3.85 (m, 2H), 4.15 (m, 1 H), 4.45-4.54 (m, 2H). Step c)

The product containing step b (1.50 g, 5.18 mmol) and &quot;bite (1.26 ml, 15.6 mmol) in anhydrous dichloromethane (45 ml) was cooled to EtOAc. Trifluoromethanesulfonic anhydride (丨74 ml, 10.3 mmol) was added dropwise over 1 Torr with stirring. The reaction mixture was stirred for a further 2 hours under EtOAc and then washed with EtOAc EtOAc EtOAc. The aquifer was washed with 129860.doc -60- 200906392 dichlorodecane (2 χ 25 ml). The combined organic layers were dried (Na.sub.s.sub.4), filtered and concentrated in vacuo. The residue was dissolved in Dmf (45 丨) and sodium azide (0.50 g, 7.78 _ 〇 1) was added. The reaction mixture was stirred at room temperature for 1 hr and then concentrated in vacuo. The residue was purified by a silica gel column chromatography (yield gradient of &lt;RTI ID=0.0&gt;&gt; Basic component of ρι protected by N-Boc and dimethyl ketal (〇84 §, 51%). Example 10 Alternative P3 Basic Component 3_Fluoro-4-[2-(4-methylpiperazine_1-yl)-thiazole_4_yl]benzoic acid Hci salt

6M HCI Quantitation CI OH

S 』 F Step a) Methyl 4-bromo-3-fluorobenzoate 4-Bromo-3-fluorobenzoic acid (2.46 g, 11.2 mmol) was dissolved in Me 〇H (9 mL) and toluene (4 mL) And cooled in an ice bath. (Trimethyl oxalate) diazomethane (2_0 Μ, 22 mmol in 11 mL 'hexane) was added dropwise until a yellow color. The solution was stirred at room temperature for 40 minutes and then concentrated in a vacuum 129860.doc •61·200906392. The second batch of carboxylic acid (2.33 g) was treated similarly. The crude product from the two batches was combined and subjected to flash chromatography (c.c., 5/1 pentane - EtOAc) to give the methyl ester as a white solid (4 92 g, %% yield) . Η NMR (400 MHz, CDC13) δ ppm 7.77 (m, 1H), 7.71 (m, 1H), 7.64 (m, 1H), 3.93 (s, 3H). Step b) 4-Ethyloxy_3_fluorobenzoic acid methyl ester under the inert gas 'Addition of propyl chloride (1 〇 5 pL, 1.28 mmol) and TFA (20 pL, 0.26 mmol) to the powder ( 480 mg, 7.34 mmol) and anhydrous &gt; stinky drill (11) (96.6 111, 0.44 111111〇1) in a suspension of 4 1111^). After stirring for 1 minute at room temperature, add aryldiamine from (a) (1.003 g ' 4.30 mmol, dissolved in 5 mL MeCN), followed by acetic anhydride (0.45 mL, 4.79 mmol) and more MeCN (l mL). The mixture was scrambled and stopped at 1 M HC1 (20 mL) and subsequently

Extract with EtOAc (3 x 20 mL). The organic phase was washed with a saturated aqueous solution of NaHC EtOAc (20 mL) and saturated NaCI (2×20 mL), dried (Na2S04) and concentrated. Flash chromatography (2:1 to 4/1 petroleum hydrazine-EtOAc) yielded the recovered bromide (161·1 mg, 16%) and the desired ketone (white solid, 305.5 mg, 36%). NMR (CDC13) δ ppm: 'Η (400 MHz) 7.94-7.86 (m, 2H), 7.80 (dd, 1H, J=11.2, 1.6 Hz), 3.95 (s, 3H), 2.67 (d, 3H, J =4.4 Hz); 19F (376 MHz) -109.2 (m); 13C (100 MHz) 195.4 (d, J=3.7 Hz), 165.1 (d, J=2.2 Hz), 161.6 (d, J=255 Hz) , 135.8 (d, J=8.1 Hz), 130.7 (d, J=2.9 Hz), 129.0 (d, J=14 Hz), 125.2 (d, J = 3.6 Hz), 117.9 (d, J=26 Hz) , 52.7 (s), 31.4 (d, 129860.doc -62- 200906392 J=7.3 Hz). Step c) 4-(2-Bromoethenyloxy)-3-fluorobenzoic acid decyl ester THF (10 mL) and EtOAc. The ketone (91 pL, 1.20 mmol) was added to a mixture of ketone from b) (198 mg, 1.01 mmol) and pyrrolidone hydrogen tribromide (532 mg, 1.07 mmol). After heating at 6 Torr to 65 °C for 2 hours, the mixture was concentrated in vacuo and then partitioned between EtOAc (20 mL) and sat. Na.sub.2. The aqueous phase was extracted with EtOAc (10 mL). The organic phases were combined, washed with sat. NaCI (2×lO mL), dried (Nd. Flash chromatography (2D, 7/1 petroleum-EtOAc) gave a white solid (0.2634 g) of 84% of the desired bromide (as determined by integration of the 19f NMR peak). NMR (CDC13) δ ppm: (400 MHz) 7.93 (m, 1H), 7.88 (m, 1H), 7.79 (dd, 1H, J=11.2, 1.6 Hz), 4.50 (d, 2H, J = 2.4 Hz) , 3.94 (s, 3H); 19F (376 MHz) -108.4 (m). Step (1) 3-Fluoro-4-[2-(4-methyl 嗓 嗓_1_yl)_隹嗤_4_yl] benzamidine methyl ester Add EtOH (5.0 mL) to the above bromoketone (193 mg, 0.70 mm〇i) and 4-mercapto-piperazine-b-thioguanidinium carbonate (113 mg, ο.?! mm〇1) and the mixture was heated at 70 ° C for 2 hours 1 5 minute. The precipitate was transitioned, washed with cold EtOH and dried and characterized under vacuum. Repeat this procedure for a larger grade of 5 g bromoketone (6.3 6 mmol). NMR (1/1 CDC13 -CD3OD) § ppm: ]H (400 MHz) 8 20 (m 1H), 7.86 (dd,1H, J = 8.4, 1·6 Hz), 7.76 (dd,1H,J = ll .4, i.8 Hz), 7.38 (d,1 H,J=2.4 Hz), 4.23 (br,2H),3.95, (s,3H), 3.65 (br, 4H), 3.32 (br, 2H) , 2.98 (s, 3H); 19F (376 MHz) - 129860.doc -63. 200906392 114.0 (m). LCMS [M+H]+=336. The precipitates from the two preparations were combined and suspended in the remainder (5 〇 mL). The mixture was extracted with EtOAc. The organic phase was washed with water, dried (Na2SO4) and evaporated Step: e) 3-fluoro-4-[2-(4-methylpiperazin+yl)- oxazole]-based benzoic acid hci salt will be methyl ester from (d) (1.76 g, 5.25 mm 〇1) ) heated at 8 (rc and 6 M HC1 (40 mL) for 5.5 hours. Add more 6 Μ Ηα (ΐ() 卩 and heat the mixture at 9 (TC for 1 hour and 15 minutes. After cooling, then The mixture was evaporated under vacuum and lyophilized from water to give a final product (yield yield) as a cream solid. NMR (DMSO) δ ppm: (400 MHz) 11.60 (br, 1H), 8.18 (t , 1H, J=8.0 Hz), 7.82 (dd, 1H, J=8.4, 1.6 Hz), 7.72 (dd, 1H, J=12.0, 1.6 Hz), 7.48 (d, 1H, J=2.8 Hz), 4.11 (m, 2H), 3.58 (m, 2H), 3.49 (m, 2H), 3.19 (m, 2H), 2.80 (d, 3H, J=4.4 Hz); , 9F (376 MHz) -113.5 (m) ; , 3C (100 MHz) 168.9, 166.0, 159.0 (d, J=250 Hz), 143.4, 131.4 (d, J=8 Hz), 129.8, 125.8 (d, J=ll Hz), 125.6, 116.6 (d , J=24 Hz), 111.1 (J=15

Hz), 51.1, 45.0, 41.9· LCMS [M+H]+=322. Example 11 N-[2-(6-azido-oxyl_hexahydrofuro[3,21)]pyrrole_4-cyclohexyl-2-yloxy-ethyl b 4_[2_(4_ Methyl _ oxazinyl) thiazole _4_ yl] - sulphonic acid amine 129860.doc -64- 200906392

Step a) [2-(6-integrator-3,3-dimethoxy-hexahydrobite and 丨3,2-b]e pirin-4-yl)-1-cyclohexyl-2 -side gas-ethyl]-tert-butyl methacrylate (na)

6-azido-3,3-dimethoxy-hexahydrofuro[3,2-b]pyrrole-4-carboxylic acid tert-butyl ester (256 mg '0.8 1 mmol) in acidic conditions (sterol) / 醯 )) to protect the crude 6-azido-3,3-dimethoxy-hexahydrofuro[3,2-b]pyrrole hydrochloride' using conventional DMF/DIPEA/HATU Coupling with N-Boc-cyclohexylglycine to give the title compound (315 mg, 85%) ° MS m/z 454·3 (Μ+Η) + ° Step b) N-[2-(6- Nitrogen-3,3-dimethoxy-hexahydrofuro[3,2-b]pyrrol-4-yl)-1-cyclohexyl-2-yloxy-ethyl b-4-[2-( 4-methyl-piperazine-i-yl)-cough olyl]-benzylic amine (lib) [2-(6-azido-3,3-dimethoxy-hexahydrofuran [3, 2-b]pyrrol-4-yl)-1 -cyclohexyl-2-oxo-ethyl]-aminocarboxylic acid tert-butyl ester (3 j 〇mg, 0.68 mmol) under acidic conditions as above The method is deprotected in the same manner as 'and subsequently using the conventional DMF/DIPEA/HATU conditions to convert the crude, specific salt hydrochloride intermediate to 4-[2-(4-methyl-piperazine-bu)thiazole_ Coupling of the HBr salt of the benzoic acid to give the title compound (421 mg, 97%). MS m/z 639.3 (M+H)+. 129860.doc 65· 200906392 iH-NMR (400 MHz, CDC13): 7.90-7.80 (m, 4H), 6 96 (d 1H), 6.88 (s, 1H), 4.90 (m, 1H), 4.78 (d, 1H), 4.68 (t, 1H) 4.32 (m, 1H), 3.95 (d, 1H), 3.73 (d, 1H), 3.70 (m, 1H), 3 6 〇 (m, 4H), 3.47 (s, 3H), 3.45 (t, 1H), 3.26 (s, 3H), 2 58 (m 4H), 2.38 (s, 3H), 1.98-1.65 (m, 6H), 1.36-1, 10 (m, 5H) . 'Step c) N-丨2-(6-azido-3-indolyl-hexahydrofuro[3,2_b]吼嘻·4_yl)-1-cyclohexyl-2-sideoxy-B 4-[2-(4-methyl-benzinyl)-oxazol-4-yl]-benzylguanamine (11c) N-[2-(6-azido-3,3- Dimethoxy-hexahydrofuro[3,2_b]pyrrole-4-yl)-1-cyclohexyl-2-yloxy-ethyl]-4-[2-(4-methyl-pyr-α -1-yl)-thiazol-4-yl]-benzylguanamine (200 mg '0.313 mmol) was hydrolyzed under acidic conditions (TFA/H20) and preparative HPLC chromatography (C8, gradient 10-90% MeCN/HA Producing the pure title product 89 mg (48 ° / 〇), which is the two rotamers of ketone (20 ° / 〇) [MS m / z 593.5 (M + H) +] and hydrate (80%) Mixture 0 [MS m/z 611.6 (Μ+Η20+Η)+] ° Example 12 ]\-[2-(6-Laminated gas-3-lateral gas base_hexahydro cough and 丨3,2- 1)] 咐 1 洛-4- _ yl)-3-methylbutyl]-4-[5-methyl-2-(4-methyl-piperazin-1-yl)-thiazole-4- Benzoylamine

129860.doc -66- 200906392 Step a) [2-(6-azido-3,3·dimethoxy-hexahydrofuran-3,2_b]pyrrole_4-carbonyl)-3-methyl Butyl]-carbamic acid tert-butyl ester (12a) under acidic conditions, the third butyl ester group from 6-azido- 3,3-dimethoxy-hexahydrofuran [3,2 -b]Pyrrol-4-pyruic acid tert-butyl ester (1 〇〇 mg, 0.318 mmol) was removed. The crude 6-azido-3,3-dimethoxy-hexahydrofuro[3,2-b]pyrrole hydrochloride and N-Boc-white were provided using conventional DMF/DIPEA/HATU conditions. Amino acid coupling gave the title compound 〇34 mg, 99%). MS m/z 428.1 (M+H)+. Step b) N-[2-(6-azido-3,3-dimethoxy-hexahydrofuroindole 3,2_b]etb pyrrol-4-carbonyl)-3-methylbutyl b 4 -丨5-methyl-2-(4-methyl-piperazine-l-yl)_thiazol-4-yl]-benzylguanamine (Ub) will be the third under acidic conditions (methanol / ethyl chloroform) Butyl ester group from [2_(6-azido-3,3-dimethoxy-hexahydrofuro[3,2-1?]° ratio '1 each 4-carbonyl)-3-methyl Removed from butyl]-amino decanoic acid tert-butyl ester (134 mg, 0.318 mmol). The crude hydrochloride intermediate provided is then combined with 4-[5-methyl-2-(4-methyl-piperazin-1-yl)-thiazolyl]-benz using conventional DMF/DIPEA/HATU conditions. The HCl of citric acid was coupled to give the title compound (166 mg, 84%). MS m/z 627.3 (M+H)+. 'H-NMR (400 MHz, CDCls): 7.82-7.65 (m, 4H), 6.96 (d, 1H), 4.90 (m, 1H), 5.02 (m, 1H), 4.75 (dd, 1H), 4.68 ( Dt, 1H), 4.40 (dt, 1H), 3.90 (d, 1H), 3.75 (d5 1H), 3.74 (m, 1H), 3.65 (m, 4H), 3.43 (s, 3H), 3.41 (t, 1H), 3.26 (s, 3H), 3.00 (m, 4H), 2.73 (s, 3H), 2.42 (s, 3H), 1.85 (m, 1H), 1.70 (m, 2H), 1.05 (d, 3H) ), 1.00 (d, 3H). 129860.doc •67· 200906392 Step by step c) N-[2-(6-Ethyl-3-oxo-hexahydrobite and [3,2-b]ebi--4-yl) -3-methylbutyl]-4-[5-methyl-2-(4-methyl-branazine)____ 4-yl]-benzylamine (12c) will be N-[2- (6-azido-3,3-dimethoxy-hexahydrofuro[3,2-b]pyrrole-4-lkyl)-3-methylbutyl]_4-[5-methyl- 2-(4-Methyl-u-endazine-1-yl)-oxazol-4-yl]-benzylguanamine (16 mg, 0.255 mmol) was hydrolyzed under acidic conditions (TFA/H20) and preparative hplc Chromatography (C8, gradient 10-90% MeCN / HsO) yielded the crude title product 93 mg (63%) as ketone m/z 581.4 (M+H) + ] and hydrate (8 %) [MS m /z 599.5 (M+H20+H)+] A mixture of two rotamers. Example 13 Ν-[2-(6-φNitro-_3_sideoxy-hexahydrofuro[3,2-b]nb-R--4-carbonyl)- 3-Ga-3-methylbutyl M_ [2_(4-methyl-piperazine-4-yl)thiazole-4-yl]benzylamine

Step a) [2-(6·azido-3,3-dioxaoxy_hexahydrofuran p,2_bjpyrrole-4-yl)-3-fluoro-3-methylbutene]- Tert-butyl carbazate (13a) The tert-butyl ester group from 6-azido's 3-methoxy-hexahydro 11 fumonate under acidic conditions (methanol / acetonitrile) , 2-b]0 than η each 4-carboxylic acid third butyl 129860.doc •68- 200906392

Removed (63 mg ’ 0·20 mmol). The crude 6-azido-3,3-dimethoxy-hexahydrofuro[3,2-b]indole hydrochloride and N_Boc_y_fluoro white are provided using conventional DMF/DIPEA/HATU conditions. Aminic acid (prepared in Trinng et al. Syn Lett. 20, 5, 8th) was coupled to give the title compound (84 mg '94%). MS m/z 446.2 (M+H)+. Step b) N-[2-(6-azido-3,3-dimethoxy-hexahydro-pyrano- 3,2_b]-la--4-carbonyl)-3-fluoro-3·A Butyl]-4-[2-(4-methyl-Nantazinyl)-thiazol-4-yl]-benzylamine (13b) The tertiary butyl ester group from acidic conditions [2_ (6_azido-3,3-dimethoxy-hexahydrofuro[3,2-b]pyrrole-4-carbonyl)-3-fluoro-3-indolyl butyl]-aminocarboxylic acid Removed from dibutyl (84 mg, 0·1 88 mmol). The crude hydrochloride intermediate provided is then combined with 4-[2-(4-indolyl-bistazin-1-yl)- using conventional DMF/DIPEA/HATU conditions. Plug. The title compound (110 mg, 93%) was obtained from the <RTIgt; MS m/z 6312 (M+H)+. • H-NMR (400 MHz, CDC13): 7.90-7.78 (m, 4H), 6.96 (d, 1H), 6.90 (s, 1H), 5.06 (m, 1H), 4.76 (d, 1H), 4.70 ( m, 1H), 4.52 (dt, 1H), 3.90 (d, 1H), 3.80 (m, 1H), 3.75 (d, 1H), 3.62 (m, 4H), 3.42 (s, 3H), 3.42 (t , 1H), 3.25 (s, 3H), 2.65 (m, 4H), 2.45 (s, 3H), 2.15 (m, 1H), 1.52 (d, 3H), 1.48 (d, 3H). Step c) N-[2-(6-azido-3_sideoxy·hexahydrofuro[3,2_b]pyrrole_4·carbonyl)-3-fluoro-3-methylbutyl]-4 -[2-(4-methyl-旅嗓-ΐ_基)_sniff _4_ base]· benzamide (13c) 129860.doc •69· 200906392 Will 1^-[2-(6- stacked gas -3,3-dimethoxy-hexahydro! 1 futino[3,2-13]° ratio 11 -4 -alkyl)-3 -fluoro-3-indolyl butyl]-4- [2-(4-曱 base 嗓-1-yl)_^ plug. Sodium 4-yl]-benzylamine (105 mg, 0.166 mmol) was hydrolyzed under acidic conditions (TFA/H2). The residue was purified by preparative EtOAc EtOAc (EtOAc (EtOAc) A mixture of two rotamers of (M+H)+] and hydrate (80%) [MS m/z 603.6 (M+H20+H)+]. Example 14 N-[2_(6·azido-3-oxo-hexahydrofuro[3,2-b]"tbola-4-carbonyl)-3-methylbutyl]-3-fluoro -4-[2-(4-methyl-piperazin-1-yl)-thiazole-4·yl]-benzylamine

Step a) [2-(6-azido-3,3-dimethoxy-hexahydrofuro[3,2-b]pyrrole-4-carbonyl)-3-methylbutyl]-amino Tert-butyl formate (14a) The third butyl ester group from 6-azido-3,3-dimethoxy-hexahydrofuran [3, under acidic conditions (MeOH/acetonitrile). 2-b]pyrrole-4-decanoic acid tert-butyl ester (63 mg, 0.20 mmol) was removed. The crude 6-azido-3,3-dimethoxy-hexahydroamino[3,2-b]pyrrole hydrochloride and N-Boc- provided are provided using conventional DMF/DIPEA/HATU conditions. The leucine was coupled to give the title compound 129860.doc-70-200906392 (83 mg, 97%). MS m/z 428.1 (M+H)+. Step b) N_[2-(6-azido-3,3-dimethoxy-hexahydrofurfuro[3,2 b]indol-4-pyridyl)-3-methylbutyl 3-fluoro-4-[2-(4-methyl bromo_ι_yl)- olazole-4-yl]-benzylamine (14b) tert-butyl ester group under acidic conditions Group from [2-(6-azido-3,3-dimethoxy-hexahydrofuro[3,2-b]pyrrole-4-carbonyl)-3-mercaptobutyl]-amino Removed from tert-butyl citrate (83 mg, 0.194 mmol). The crude hydrochloride intermediates provided are then provided using conventional DMF/DIPEA/HATU conditions | 3-r ', fluoro-4-[2-(4-methyl-pyrene-1-yl-pyrazole-4- Coupling of the HC1 salt of the benzoic acid to give the title compound (110 mg, 93%). MS m/z 63 1.2 (M+H) + .H-NMR (400 MHz, CDCls): 8.18 (t, 1H) ), 7.52 (m, 2H), 7.20 (s, 1H), 7.08 (d, 1H), 4.98 (m, 1H), 4.78 (d, 1H), 4.70 (m, 1H), 4.40 (dt, 1H) , 3.90 (d, 1H), 3.85 (d, 1H), 3.85 (m, 1H), 3.65 (m, 4H), 3.43 (s, 3H), 3.42 (t, 1H), 3.26 (s, 3H), ^ 2.80 (m, 4H), 2.58 (s, 3H), 1.83 (m, 1H), 1.70 (m, 2H), 1.05 (d, 3H), 1.00 (d, 3H). Step by step c)N -丨2-(6-3⁄4-yl-3-oxo-hexa-nitrozabite and 丨3,2-b]® lt- 4_ carbonyl)-3-methylbutyl]-3-fluoro-4·[ 2-(4-Methyl-piperazin-1-yl)-thiazol-4-yl]-benzylguanamine (14c) N-[2-(6-azido-3,3-didecyloxy) -hexahydrofuro[3,2-b]pyrrole-4-carbonyl)-3-mercaptobutyl]-3-fluoro-4-[2-(4-methyl-piperazin-1-yl)- Thiazol-4-yl]-nodalamine (105 mg, 0.166 mmol) was hydrolyzed under acidic conditions (TFA/H20) and preparative HPLC chromatography (C8, gradient 10-90% MeCN/H20) 129 860.doc 200906392 yielded the pure title product 72 mg (74%) as a ketone (28%) [MS m/z 585.5 (M+H)] and hydrate (72%) [MS m/z 603.5 (Μ+ Η20+Η)+] A mixture of two rotamers. Example 15

Azide group _3_sideoxy-hexa-argon-吱 丨 丨 3,2_b] 吼 _ 4 yl) 3 methyl-butyl] _4 · [5-fluoro-2-(4-methyl-旅嗓-1-基)-嗟嗤_4_ base]-benzyl ugly amine

Step 3) [2-(6-azido-3,3-dimethoxy-hexahydrofuro[3,2-1)]pyrrole-4-carbonyl)-3-indolylbutyl]-amine Third butyl carboxylic acid (15a) The third butyl ester group was removed from compound 14 (63 mg, 0.20 mmol) under acidic conditions (methanol / acetonitrile). The crude 6-azido-3,3-dimethoxy-hexahydro-n-[3,2-b]° ratio of the slightly hydrochloride and N- provided is provided using conventional DMF/DIPEA/HATU conditions. Coupling of Boc-leucine gave the title compound (81 mg '95%). MS m/z 428.3 (M+H)+. Step by step b) N-[2-(6-azido-3,3-dimethoxy-hexahydropyrano[3,2-b]0 piroxi-4-base)-3·A Benzyl]-4-[5-fluoro-2-(4-methyl-pickyo)-- oxazol-4-yl]-benzylguanamine (15b) under acidic conditions (methanol / acetamidine) The third butyl ester group was removed from the compound 129860.doc-72-200906392 15a (81 mg, 0.189 mmol) under chloro). Coupling the provided crude hydrochloride intermediate with the HC1 salt of 4_[5_fluoro_2_(4-mercaptopiperazin-1-yl)-epizozol-4-yl]-benzoic acid using conventional HATU conditions The title compound (105 mg, 88%) was obtained. MS m/z 631.2 (M+H)+. ^-NMR (400 MHz, CDC13): 7.92 (d, 2H), 7.82 (d, 2H), 6.84 (d, 1H), 5.03 (m, 1H), 4.75 (d, 1H), 4.70 (m, 1H) ), 4.42 (dt, 1H), 3.90 (d, 1H), 3.75 (d, 1H), 3.74 (m, 1H), 3.47 (m, 4H), 3.43 (s, 3H), 3.42 (t, 1H) , 3.25 (s, 3H), 2.55 (m, 4H), 2.37 (s, 3H), 1.84 (m, 1H), 1.70 (m, 2H), 1.05 (d, 3H), l.〇〇(d, 3H). Step c) N-[l-(6-azido-3-oxo-hexahydro-furo[3,2-b]pyrrol-4-yl)-3-methyl-butyl]- 4-[5-Fluoro-2-(4-methyl-Becken-1-yl)-sniff _ 4-yl]-benzylamine (15c) The ketal of compound 16b (100 mg, 0.159 mmol) Hydrolysis under acidic conditions (TFA/H20), followed by preparative HPLC chromatography (C8, gradient 10-90% MeCN/H20) to yield the title compound 35.1 mg (38%) as ketone (26%) A mixture of two kinds of rotamers of [MS m/z 585.2 (M+H)+] and hydrate (74°/〇) [MS m/z 6〇3.2 (M+H20+H)+]. Example 16 Ν-[1-(6·azido-3-oxo-hexa-ar-furo[3,2-b]pyrrole_4·carbonyl)_3_gas-3-methyl-butyl] 3-fluoro-4-indol-2-(4-methyl-Bellyl)-oxime-4-yl]-pheneamine step a) [l-(6-azido-3,3-di曱oxy-hexa-argon-furo[3,2-b]pyrrole-4-carbonyl)-3-fluoro-3-methyl-butyl-aminoglycolic acid tert-butyl ester (16a) 129860.doc - 73 · 200906392

To a solution of Compound 14 (Example 1 Step f) (69 mg, 0.22 1 mmol) in methanol (4 mL), EtOAc (EtOAc) The reaction mixture was stirred at room temperature overnight and then concentrated. The residue was redissolved twice in dry DMF (5 mL) and concentrated to dryness and then taken to DMF (3 mL). γ-Fluorine_BOC_Leu_OH (5 〇 mg, 〇2〇1 on demand and DIEA (133 μιη, 0.802 mmol) was added to the solution, which was then cooled to 0 ° C and HATU (80 mg, 0.211 mmol) was added. The reaction was stirred at room temperature for 3 h, then the solvent was removed by rotary evaporation. The crude mixture was dissolved in EtOAc (20 mL) EtOAc EtOAc Washed with 〇3 (aq. sat.) (10 mL). EtOAc (EtOAc m. 69 mg, 77. /.) 446 = step, -[H azido-3,3_dimethoxy_hexaza cough and [321)] fluoren-4-carbonyl)-3-fluoro -3-mercapto-butyl]_3_fluoro_4_丨2 (4methylpiperazine-yl)-oxazol-4-yl]-benzylamine (i6b)

129860.doc • 74- 200906392 Acetyl chloride (0.4 mL) was added dropwise to a solution of compound 16a (69 mg, 0·154 mmol) in MeOH. The reaction mixture was stirred overnight to &lt;1&gt; and then concentrated. The residue was dissolved in hydrazine, 4-di 11 smolder (5 ml) and lyophilized overnight. The solid was dissolved in dmf (4 mL). 3-Fluoro-4-[2-(4-methyl-piperazin-1-yl)-thiazole-4-yl]-benzoic acid x HC1 (63 mg, 0.177 mmol) and DIEA (1 () 2吣, 〇 617 〇 〇 1) Add to the bath 'after cooling it to 〇 it and add HATU (62 mg, 〇 · 162 mmol). The reaction mixture was stirred at room temperature for 3 hours, after which time the solvent was removed by evaporation. The crude mixture was dissolved in Et EtOAc (2 mL) and washed with 2×15 mL NaHC EtOAc. The organic phase was dried over NazSCU, filtered and evaporated. The crude product was purified by flash chromatography (ethyl acetate: EtOAc: EtOAc: EtOAc) [m+H]+=649. The crude compound was used in the next step without further purification. Step c) N-[1-(6-azido-3-oxo-hexa-ar-furan-3,2-b]pyrrole-4-carbonyl)-3-fluoro-3-methyl-butyl] -3-fluoro-4-[2-(4-methyl-piperazine-Iι_yl)·隹 基 ]]·benzyl benzamide (10c)

Compound 16b (123 mg crude, 0.154 mm 〇i) was dissolved in 2 〇 mL 丁 2 〇 2 〇 (97.5: 2.5) and stirred for 2 hours. The solvent was removed and the crude 129860.doc -75 - 200906392 product was dissolved in ethyl acetate and washed with 2 x 10 mL NaHC03 (saturated aqueous). The organic phase was dried over Na 2 SO 4 filtered and evaporated. The crude product was started on 40-5% B on a Sunfire C18 column with mobile phase A (90:10 H20.·acetonitrile, 10 mM NH4Ac) and hydrazine (10··90 Η2〇: acetonitrile, 10 mM NH4Ac). Purified by semi-preparative HPLC. The purification was repeated four times (second time: 40-60% B, third time: 4〇45〇/〇b, fourth time: 3〇_45〇/〇B) to give the title compound as an off-white solid ( 14 mg, 15%). [M+H]+= 603. Example 17 Azido side oxy-hexahydro-furo[3,2-b]pyrrol-4-yl)-3-fluoro-4-[2_(4•methyl-4-oxy-piperazine- 1-yl)-thiazole-4-yl]-benzylguanamine Step a) 3-Fluoro-4_[2_(4-methyl-4-oxy-piperazine-I-based thiazole-4-ylbenzoic acid Methyl ester (17a) 〇' 〇

l 〇d (154 mg, 0.46 mmol) in dichloromethane (1 mL), and the mixture was stirred overnight. The mixture was diluted with di-methane (5 mL) and the organic phase was washed with saturated aqueous sodium hydrogen carbonate and then extracted with dichloromethane. The combined organic phases were washed with citric acid and brine, dried over sodium sulfate, filtered and evaporated. The obtained N_oxide was further used without additional purification. Yield 89% (143 mg) LC/MS [M+1] 129860.doc -76- 200906392 Step b) 3-Fluoro-4-[2-(4-methyl-4-ethoxy-piperazine) )_thiazole_4_yl]_benzoic acid (17b)

LiOH (1 Μ ' 2 ml) was added to a solution of vinegar i7a (143 mg, 0.41 mmol) in THF-water (2:1). After stirring at room temperature for 4 hours, the solution was acidified to pH 4 by the addition of 1 M HCl. The combined organic layers were combined, dried over sodium sulfate, filtered and evaporated. The residue was triturated with EtOAc (EtOAc)EtOAc. Yield 58 mg, 0.17 mmol, 41%, LC/MS [M+1] 339. Step by step ~)~-(6-Fed-hydrogen-3,3-dimethyll-hexa-nitro-f-butan[3,2-15]|1 ratio slightly 4-yl)-3-gas-4 -[2-(4.Methyl-4-oxy-Behind-1-yl)- sulphend-4-yl]-nodal amine (17c)

To a cooled solution (〇 ° C) of compound 17 (49 mg, 0.17 mmol) in methanol (5 ml) was added dropwise. The temperature of the reaction mixture was raised until 22 ° C and the mixing was continued for 6 129 860.doc • 77- 200906392 hours. The reaction mixture was concentrated and the residue was dissolved in EtOAc EtOAc EtOAc. The obtained salt was dissolved in DMF (7 mL). Water (0.6 ml), compound 17b (0.17 mmol) and 0.55 ml of diisopropylethylamine were added and the mixture was cooled to 0 ° C, then HATU (55 mg) was added. The reaction mixture was stirred for 2 hrs to evaporate to a volume of 1 mL and purified by preparative HPLC (NH4OAc buffer, 30:80 system (MeCN-water) to give the title compound (19 mg, 18%) LC/ MS [M+1] 647. Step d) N-(6-azido-3-oxo-hexa-ar-furo[3,2-b]pyrrole-4-yl)-3-fluoro-4- [2-(4-Methyl-4-oxy-Behind-1-yl)_嗟峻_4_基]-Benzylamine (17d)

Compound 17c (19 mg) was dissolved in a solution of TFA97 5D / (wJc 2 5% (2 ml) and water. After 2 hours, the solution was concentrated and the residue was dissolved in acetonitrile (7 ml) Stirring with solid sodium bicarbonate for 1 hour. The solid formed was filtered off < EtOAc (EtOAc) eluted eluted eluted Mg '86%). LC/MS [M+1] 6〇1 and [M+i9] 619 (Hydrate Comparative Example 4 Azido_3·Sideoxy_hexa-argon_吱-[nb]pyrrole 4-carbonyl)-3-methyl-butyl]_3_fluoro_4丨2 (4methylpiperazine j-based thiazole heart 129860.doc -78- 200906392 base]-benzylic amine step a[l-(6 -azido-3,3-dimethoxy-hexahydrofuran-3,2-b]pyrrole_carbonyl)_3_methyl-butyl]-carbamic acid tert-butyl ester (19a)

19a Dissolve 6-azido-3,3-dimethoxy-hexahydrofuran [3,2-b]pyrrole-4-carboxylic acid tert-butyl ester (〇·3 mmol) in methanol (5 ml) The solution was cooled to 〇 ° C and acetonitrile (0.5 ml) was added dropwise over 10 minutes. The temperature of the reaction mixture was raised until 2 2 . 〇, after which the mixture was mixed for 6 hours. The solvent was evaporated and the residue was dissolved in EtOAc (EtOAc m.). The obtained salt was dissolved in DMF (3 ml), and Boc-Leu-purs H (0.3 mmol) and diisopropylethylamine (0.6 ml) were added. The mixture was cooled to 〇 C and then HATU (145 mg) was added. The reaction mixture was stirred for 2 hours, the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed once more with water, then dried over brine and sodium sulfate, dried and evaporated. The residue was purified by EtOAc EtOAcjjjjjjjj Step b) N-[l-(6-azido-3-oxo-hexahydro-furo[3,2-b]«tb-lo--4-carbonyl)-3-indolyl-butyl] ·3_Fluoryl_4_丨2-(4-methyl-piperazine-yl)·嗔 sniffing_ 4-yl]·benzyl benzamide (19b) 129860.doc -79· 200906392

Acetyl chloride (0.5 ml) was added dropwise to a cooled solution of the compound 19a (53 mg, 83.l83 mmol) in methanol (5 ml) over a period of 10 min. The mixture was stirred for 6 hours to 22 ° C. The solvent was evaporated and the residue was dissolved in EtOAc EtOAc EtOAc (EtOAc) e (0,183 mmol) and diisopropylethylamine (〇6) and the mixture was cooled to 0 C ', then HATU (60 mg) was added. After stirring for 2 hours, the solvent was hot and the residue was Distribute between ethyl acetate and water. Wash the organic phase with water once again. Then dry with brine and sodium sulfate, filter and concentrate. The residue was purified by flash chromatography (5 〇/〇Me〇H in CHCl3) , with 0·1〇/〇NEt3) purification 'produces the title compound (87, 75%) LC/Ms [M+i] 631 ° Comparative Example 5 N [M6-azido-3-sideoxy_six Hydrogen_furo[3 2 b]pyrrole_4_carbonyldecylbutyl]_4-[5-gas-2-(4-methyl-Broadcast_ι_基)-嗟吐_4_ base]- Indoleamine (20)

〇 20 129860.doc 200906392 Ethylene gas (0.5 ml) was added dropwise to a cooled solution (0 ° C) of compound 19a (42 mg, 0.146 mmol) in methanol (5 ml) over 10 min. The temperature of the reaction mixture was raised to 22 °C. After stirring for 6 hours, the reaction mixture was concentrated and the residue was dissolved in 1,4- dioxane and lyophilized overnight. The obtained salt was dissolved in DMF (3 ml), and 4-[5-fluoro-2(-4-methylpiperazin-1-yl)-thiazol-4-yl]-benzoic acid (0.146 mmol) was added. And diisopropylethylamine (0.5 ml). The mixture was cooled to 〇 ° C and then HATU (48 mg) was added. After stirring for 2 hours, the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed once more with water then dried over brine and sodium sulfate filtered and concentrated. The residue was purified by EtOAc EtOAc EtOAc. Biological Examples Determination of Cathepsin K Proteolytic Catalytic Activity A convenient assay for cathepsin K was performed using a human recombinant enzyme such as that described in PDB. ID BC016058 standard; mRNA; HUM; 1699 BP. DE Homologin cathepsin K (compact bone development disorder), mRNA (cDNA pure line MGC: 23107 RX MEDLINE; RX PUBMED; 12477932. DR RZPD; IRALp962G1234. DR SWISS-PROT; P43235; recombinant cathepsin K can be expressed in including Escherichia coli Pichia pastoris and 129860.doc 200906392 A variety of commercially available expression systems for baculovirus systems. Purified enzymes are activated by removal of the prosequences by conventional methods.

The standard assay conditions for determining the kinetic constants are based on the fluoropeptide receptor, usually H-D-Ala-Leu-Lys-AMC, and are contained! mM £1) 1 and 1 mM 2-mercaptoethanol in 100 mM Mes/Tris (pH 7 〇) or 1 mM NaOH, imM EDTA' 0.1% PEG 4000 (pH 6.5) or 5 mM EDTA and The measurement was carried out in 20 mM cysteine 100 sodium acetate (pH 5.5), in each case using 1 M DTT as a stabilizer. The enzyme used was at a concentration of 5 η Μ. A 1 mM stock solution was prepared in DMSO. Screening was performed at a fixed substrate concentration of 6 〇 μΜ and detailed kinetic studies were performed with a double dilution from 25 。. The total DMSO concentration in the assay was kept below 3 / ί». All inspections were performed at ambient temperature. Product fluorescence was monitored with a Labsystems Fluoroskan Ascent plate reader (excitation at 39 Torr, emission at 460 nm). After the AMC product was produced, a product progression curve was produced over 15 minutes. The cathepsin S Ki assay detects human cathepsin S using baculovirus expression and the boc-Val-Leu-Lys-AMC fluorescent receptor available from Bachem in a 384-well plate format, in which it contains known cathepsins A positive control of the S inhibitor comparator tested seven test compounds in parallel. Dilute

280 μl/well of 12.5% DMSO was added to column B-H of two rows of 96 deep well polypropylene sheets. A 70 microliter/well substrate was added to column A. 2x250 μl/well assay buffer (1 mM NaOH, 100 mM 129860.doc • 82 - 200906392)

NaCl 'pH 6.5) was added to column a, mixed and double diluted to the column along the plate. Inhibitor Dilution Add 100 μl/well of assay buffer to rows 2-5 and rows 7-12 of column 4 of a 96-well V-shaped bottom polypropylene plate. Add 200 μl/well of assay buffer to rows 1 and 6. The first test compound to be prepared in DMSO is typically added to row 1 of the top column at a volume of from 1 to 3 times the initial Ki of the initial measurement. The approximate Κι is calculated from the initial operation, in which 1 boo VLK-AMC (1 / 10 dilution of l mM stock diluted in dms 检 in assay buffer) of 1 μL/well is assigned to Columns B through H and 2 〇 microliters/well were dispensed into column A of a 96-well MlCr® flu〇rTM plate. Add 2 μM of each 10 mM test compound to a separate well on column A 'row 1_1〇. To each well of column B_H, 90 μM of assay buffer containing 1 mM DTT and 2 nM cathepsin s was added and 1 80 μl was added to column A. Column A was mixed using a multichannel pipette and double diluted to column G. Column H is mixed and read in a fluorescence spectrophotometer. The reading is the Pdsm data fitted to the competitive inhibition equation with S = l 〇〇 μΜ and ΚΜ = 100 μΜ to obtain an estimate of &amp; The second test compound is added to row 6 of the top column, third row to row 1 of the second column, and the like. A 丨μ1 comparator was added to row 6 of the bottom row. Mix the lines and double dilute to line 5. Mix line 6 and double dilution to line. The 丨〇 microliter/well pattern was distributed to a 384-well assay plate using an 8-channel multi-step pipette set to 5 X 1 0 μΐ. The first row of the substrate is distributed to 129860.doc -83 - 200906392 starting from all rows of the column of column A. The tip spacing of the multichannel pipette will correctly skip the spacer column. The second line is distributed to start with all rows in the column. Dispense 1 μL/well of inhibitor to the 384-well assay plate using a 12-channel multi-step pipette set at 4x10 μΐ. The first column of the inhibitor dilution plate is distributed to the spacer column of the assay plate starting at A1. The tip spacing of the multichannel pipette will correctly skip the interval line. Similarly, the second, third, and fourth columns are respectively distributed to the spaced columns and rows starting at A2, B1, and B2. Mix 20 ml of assay buffer with 20 μl ! M DTT. Sufficient tissue protease S was added to produce a final concentration of 2 nM. Using a distributor such as Multidrop 384, add 3 〇 microliters/well to all wells of the assay plate and read in a spectrophotometer such as Ascent. Despite the presence of inhibitors, the linear rate fit for each well reflects the fluorescence reading of the degree of enzymatic cleavage of the fluorescent material (set with the bandpass filter&apos; excitation and emission wavelengths of 390 nm and 460 nm, respectively). The fitting rate of all wells of each inhibitor was fitted to the competitive inhibition equation using Siginapi(R) 2000 to determine V, Km and Ki values. Cathepsin L Ki The above procedure with the following modifications was used to determine the Ki of cathepsin L. Conversion to commercially available human cathepsin L (eg, Calbiochem). The substrate is H-D-Val-Leu-Lys-AMC which can be constructed from Bahcem. The assay buffer was 100 mM sodium acetate 1 mM EDTA (pH 5.5). The DMSO stock (1 mM in 100% DMSO) was diluted to 1 〇0/〇 in assay buffer. The enzyme at a concentration of 5 129860.doc -84 - 200906392 nM was prepared in assay buffer plus 1 mM dithiothreitol only before use. One 〇 ηιΜ inhibitor prepared in 2 μL of 100% DMSO was dispensed in column A. 50 μΜ of 10 μΐ of the substrate (= 1/200 dilution of 10 mM stock in DMSO diluted in assay buffer) Inhibition study The potential inhibitors were screened with different concentrations of test compounds using the above assay. The reaction is initiated by adding an enzyme to the buffer solution of the substrate and the inhibitor. The Ki value is calculated according to Equation 1.

1 + — + s (1) $ is the equivalent of the Michaelis constant

V J where v0 is the reaction rate, j/ is the maximum velocity, the concentration of the acceptor is 'and/ is the concentration of the inhibitor. The results are provided as follows: A is less than 50 nanomoles B 5〇_5〇〇Nemo C 501-1000 Naimo D 100 Bu 5000 Naimo E 5001-10 〇〇〇Nemo F over 10 〇〇 〇奈莫耳表1

129860.doc -85- 200906392 14 AE c 15 AF ----------- D 16 AD ______ c The compound of formula II is therefore a potent inhibitor of cathepsin κ and still has more than closely related cathepsin S and L selectivity. Metabolic Stability The compounds of the invention were tested in a conventional cytosolic assay and indicated to the metabolic stability of the comparative examples, wherein the compounds were subjected to standardized extraction of metabolic enzymes&apos; and the disappearance of the compounds was monitored by HPLC or MS. Briefly, test compounds (2 μΜ) were incubated at 37 t in pooled human liver cytosol (Xynotech LLC Lenexa US, 1 mg/mL protein 'pH 7.4 in 1 μ disc acid buffer buffer) An hour. The incubation was initiated by the addition of 1 mM NADPH cofactor. Timed subsamples were taken at 〇, 2〇, 4〇, and 6〇 minutes and "pulverized by precipitation" by adding 3 volumes of ice-cold acetonitrile. The sample was centrifuged under cooling and the supernatant was separated and analyzed by LC·MS-MS. Comparative Example 1 employed the F P1 unit under WO 〇5/06018〇. Comparative Example 2 The lower isomer of C6 in the unit of 丨 is used. Comparative Example 3 employed preferred P1 and P2 units of 0*2/057270 and iP3 units within the scope of the patent application (which is outside the scope of W〇 02/057270). Comparative Example * The lower isomer of C6 of the example l4iP1 unit was used. Comparative Example 5 employed the lower isomer of C6 in the Pi unit of Example 15. 129860.doc • 86 - 200906392 Table 2 Example 屯 Minute Example 7 &gt; 300 Comparative Example 1 Wide 0 0 94 Example 6 ί Ν 11 /~\ ° 〇-N^Nf J 210 Comparative Example 2 1 Ν , -λ Ν \ 〇0 30 Comparative example 3 j〇VV^ 72 129860.doc -87- 200906392

The unsubstituted P1 portion favored by 02/05720 is generally more metabolically stable. 129860.doc •88- 200906392 Sex. Further, by comparing Example 6 with Comparative Example 2, Example i4, Comparative Example 4, and Example 15 with Comparative Example 5, it is apparent that the compound having the azido group at this position and otherwise identical is not shown on the present invention. The enhanced stability exhibited by the azido substituent. - Permeability - This experiment measures the transport of inhibitors through human gastrointestinal tract cells. Well-known Caco-2 cells with a number between 40 and 60 were used for the assay. / Top to bottom transport % Normally the parent-compound will be tested in 2 to 4 wells. The bottom and top holes will contain 1,5 mL_4 mL of transport buffer (tb), respectively, and the standard concentration of test substance is Η) μΜ. In addition, all test solutions and buffers will contain 1% DMSO. Prior to the experiment, the transfer plates were pre-coated with medium containing iq% serum for 3 minutes to avoid non-specific binding to the plastic material. After 21 to 28 days of culture on the feeder support, the cells were prepared for permeability experiments.转运 Transfer plate No. 1 contains 3 columns each with 4 holes. Column 1 indicates washing, column 2"30 minutes" and column 3 &quot;6 minutes&quot;. The transfer plate No. 2 contains 3 columns of * holes, which means column 4 &quot;90 minutes,,, column 5"120 minutes&quot; and the remaining columns are not specified. The medium is removed from the top hole and will The insert was transferred to a wash column (No. 1) in a transfer plate (No. 1 plate) in the 2 plates without the insert, which has been in column 1 to 5 with 1.5 mL of transport buffer (HBSS, 25 Prepared by mM HEPES, pH 7.4. In the A-B screen, 1% bovine serum albumin is also contained in the bottom lateral well. 129860.doc -89- 200906392 0.5 11^Transport buffer is 888,25〇1] ^]\^8,1^6.5) was added to the insert and the cell monolayer was equilibrated in a transport buffer system at 37t: for 3G minutes in a P〇lymix shaker. After equilibration relative to the buffer system, The transepithelial electrical resistance (TEER) is measured in each well by the EVOM chopsticks instrument. The TEER value is usually between 4 〇〇 and 1 〇〇〇 Ω per well (depending on the number of passages used). ΤΒ, ρΗ 6.5) removed from the top side and turns the insert

Move to the 30 minute column (No. 2) and add fresh 吣 TB (pH 6.5) including the test substance to the top (donor) well. The plate was incubated at 37 t at a low oscillating speed of about 〇5 〇 to 3 rpm in an (eight) puppies shaker. After incubation for 30 minutes in column 2, the insert was moved every 3 minutes to a new pre-warmed bottom (receiver) well; column 3 (6 minutes), 4 (9 minutes) and 5 (120 minutes) ). The ruthenium sample was taken from the apical solution after about 2 minutes and at the end of the experiment. These sample tables* are from donor samples at the beginning and end of the experiment. Three turns were taken from the bottom outer (receiver) hole at each predetermined time point and the TEER value was measured at the end of the experiment. Acetonitrile was added to all collected samples until 5 was reached in the sample. The final concentration of %. The collected samples were stored at -20 °C until HPLC or LC-MS analysis. Bottom lateral to top transport Each compound will be tested in 2 to 4 wells. The bottom and top holes will contain 1.55 mL and mL.4 mL TB, respectively, and the standard concentration of the test substance μ. In addition, all test solutions and buffers will contain 1 〇 / DMSO DMSO. Prior to the experiment, the transfer plates were pre-coated with medium containing 129860.doc -90-200906392 for 30 minutes to avoid non-specific binding to the plastic material. After 21 to 28 days of culture on the crossover branch, the cells were prepared for permeability experiments. The medium was removed from the apical wells and the insert was transferred to a wash column (No.) in a new plate (transport plate) without inserts.

The transfer plate contains 3 columns with 4 holes.歹丨 means "washing" and column 3 is &quot;experimental column&quot;. The transfer plate has been previously 丨5TB (pH 7.4) in the wash column number and in experiment column No. 3 (donor side) Prepared by including 155 1^丁8 (mouth 117.4) of the test substance. Add 0.5 mL of transport buffer (hBSS, 25 mM MES, ρΗ 6 5) to the insert in column No. 1 and in p〇lymix The cell monolayer was equilibrated in the shaker system for 3 min at 37 t in the shaker. After equilibration relative to the buffer system, the TEER value was measured in each well by an EV〇M chopstick instrument. The liquid (TB, pH 6.5) was removed from the top side and the insert was transferred to column 3 and 400 卟 fresh TB (pH 6 5) was added to the insert. After 3 minutes, from the top (receiver) The wells were extracted 25 〇卟 and replaced with fresh transport buffer. Thereafter, 25 〇吣 samples were taken every 30 minutes and replaced with fresh transport buffer until the end of the experiment at 12 〇 minutes, and finally at the end of the experiment The value after TEER was measured. After about 2 minutes and at the end of the experiment, 25 samples were taken from the bottom outer (donor) compartment. These samples represent the donor samples from the start and end of the experiment. Add acetonitrile to all collected samples until the highest 'ς' agronomy of 5〇0/〇 is reached in the sample. Store the collected samples in Measured by HPLC or LC-M S at -20 ° C. 129860.doc -91 - 200906392 Calculate the cumulative absorption fraction FAcum relative to time. FAcum is calculated by: where CRi is the reception at the end of interval i The body concentration and CDi are the donor concentration at the beginning of the interval i. A linear relationship should be obtained. The permeability coefficient (Papp, cm/s) is determined by the following formula: p _{k-VR) (A-60) where k To define the transport rate (min·1) of the slope obtained from the linear regression of the cumulative absorption fraction (FAeum) as a function of time (minutes), VR is the volume (mL) in the receiver chamber, and A is the filter Area of the device (cm2) Reference compound Absorption type in humans Absorption in humans % Passive transport low (0-20%) Mannitol 16 Methotrexate 20 Moderate (21-75%) Acyclovir 30 high (76-100%) propranolol (Propranolol) 90 coffee Test (the Caffeine) 100 amino acid transporter protein active transport L- phenylalanine 100 active efflux PGP-MDR1 Digoxin (Digoxin) 30

Testing the compounds of the invention using the methods described above indicates that the fluorination of the sulfhydryl ring or the thiazolyl ring generally improves the permeability. For example, a position between a benzyl ring relative to a guanamine bond or a fluoro substituent on a thiazolyl ring can substantially double the cell permeability of the compound relative to a corresponding compound that does not have a fluorine substitution (Example 129860.doc -92- 200906392 I4 vs. Example 6, or Example 15 vs. Example 6). The greater permeability through the gastrointestinal tissue is that it allows a smaller dose to be used to achieve a similar level of exposure to a higher dose of gamma I, yet another less permeable compound. The low dose is introduced to minimize the commercial cost of the sputum dose, which is a key parameter for drugs that are used for a long period of time. Metabolism In addition, the fluorinated compound produces a favorable metabolic profile. In the liver

^ Observed that the metabolism of the fluorinated benzyl ring analog is less metabolic than the unsubstituted analogue. In the hepatocytes, the intrinsic gap of the fluorinated benzyl ring is an unsubstituted analogue. About half of the inherent gap. The complete ketone on each ring of the sulphate is important for the activity against cathepsin K, since this part interacts with the catalytic cysteine of the enzyme. Metabolic processes associated with specific compounds of the invention have been analyzed using Waters Synapt high precision mass spectrometers (HDMs). When the benzyl ring, the fluorinated sigma, is normalized in the liver and/or other in vivo metabolic processes, the resulting metabolite is no longer active because the ketone is reduced. In contrast, compounds having a fluoro group tend to produce a higher proportion of active metabolites, such as the corresponding azine oxime-oxide having an intact ketone on the furopyrazole ring (such as shown in Example 16). Thus, although the metabolism of the compound portion of the compound can help maintain the inhibitory pressure against cathepsin K. abbreviation

DMF TBDMS

Dimethyl decylamine DCM Second butyl dimethyl fluorene rt 129860.doc -93- 200906392 THF Tetrahydrocyanate Ac Ethyl hydrazine TLC Thin layer chromatography DMAP dimethylamine based bite EtOAc ethyl acetate All references (including patents and patent applications) mentioned in this application are hereby incorporated by reference in their entirety to the extent the extent Throughout the specification and the claims below, the word 'comprising' should be understood to include the stated integer, step, integer group or group of steps, rather than excluding any other integer, step, or group of integers, unless the context requires otherwise. Or a group of steps. 129860.doc 94-

Claims (1)

200906392 X. Patent application scope: 1. A compound of formula π: 2. R is a side chain of leucine, isoleucine, cyclohexylglycine, 〇-methyl sulphate, 4-fluoroleucine or 3- methoxy valine; R3 is Η, 曱Or a fluoro group; an alkyl group; E is a bond or optionally substituted with a methyl or fluoro group; η is 0 or 1, or a pharmaceutically acceptable salt thereof, Ν_oxide or hydrated Things. The compound of claim 1 is characterized in that the compound is not: N-((S)-l-((3aS,6R,6aS)-6-azido-3-sideoxydihydro_2η· θ 并[3,2-b] 0 is slightly more than -4 (5H,6H,6aH)-yl)-4-methyl-1-oxo-pentyl-2-yl)-4-(2-(4- Methyl fluorene bottom, Qin-1-yl) 1 plug. Sodium -4-4-mercaptoamine N-((S)-l-((3aS,6R,6aS)-6-azido_3_ side oxygen Dihydrogen 2H_q carboxy[3,2-b] 0 to 0 each - 4(5H,6H,6aH)-yl)·4,4-dimethyl_1_sideoxypentan-2-yl) -4_(2-(4-methyl-α-azin-1-yl)-s-yl) decylamine N-((S)-l-((3aS,6R,6aS)-6-azido_3_ Oxyloxydihydro-2η_〇夫 I29860.doc 200906392 carboxy[3,2-b].pyr-4(5H,6H,6aH)-yl)-3,3-dimethyl-1- side Oxybutan-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)peptidylamine N-((2S,3S)-l-((3aS, 6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-3-methyl-b Oxidylpentyl-2-yl)-4-(2-(4-methylpiperazin-1-yl)thiazol-4-yl)peptidylamine N-((S)-2-((3aS,6R) , 6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]. 4-(5H,6H,6aH)-yl)-1-cyclopentyl-2-yloxyethyl)-4-(2-(4-methylpiperazin-1-yl)thiazole-4- Glutamine amine N-((S)-2-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]. -4-4(5H,6H,6aH)-yl)-1-cyclohexyl-2-yloxyethyl)-4·-(2-(4-methyl-methyl)-yl-1-yl)° ° sit-4-yl) tanning amine N-(l-((3aS,6R,6aS)-6-azido-3-oxo-dihydro-2-indole-pyrano[3,2-b] ° ratio σ -4-alkyl)cyclohexyl)-4·(2-(4-methylpyridin-ΐ-yl) π- oxazol-4-yl) decylamine N-((S)-l -((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2-indole cough[3,2-b] ° than 4-(5H,6H,6aH)-yl) _4-Methyl-1-oxo-pentyl-2-yl)-4-(2-(4-(2-methoxyethyl)piperazine-1-yl)thiazole-4-yl)benzamide N-UW-KPaSjRjaS^-azido-sideoxydihydro-2H_^ ox[3,2-b]pyrrole-4(5H,6H,6aH)-yl)·4,4-dimethyl side oxygen Pentyl-2-yl)-4-(2-(4-(2-methoxyethyl)piperazine-4-yl)thiazole-4-yl)benzamide. 3. The compound of claim 2 or 2, wherein the compound is not: azido-3, pendant oxydihydro^'furan 129860.doc -2-200906392 mer to [3,2-b ]. Bilota-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxoethoxypent-2-yl)-4-(4-methylpiperazin-1-yl) Indoleamine N-((S)-l-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-trinop[3,2-b]pyrrole-4 ( 5H,6H,6aH)-yl)-4,4-dimethyl-1-oxoethoxypentan-2-yl)-4-(4-ethylcarbend-1-yl)dodecylamine 1^- ((8)-1-((333,611,638)-6-azido-3-oxo-dihydro-2仏-[3,2-b]pyrrole-4(5H,6H,6aH)-yl )-4,4-dimercapto-1-yloxypentan-2-yl)-4-(4-propylpiperazin-1-yl)benzylamine N-((S)-l-(( 3aS,6R,6aS)-6-azido-3-oxo-dihydro-2H-°f-[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-4, 4-dimercapto-p-oxypentan-2-yl)-4-(4-isopropylpiperazin-1-yl)peptidylamine N-((S)-l-((3aS,6R, 6aS)-6-azido-3-oxooxydihydro-2H-trinop[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-4,4-dimethyl -Bistyloxypentan-2-yl)-4-(4-(2-decyloxyethyl)piperazin-1-yl)benzylamine 1^-((8)-1-((3&amp;;8,611,6&amp;8)-6-azido-3-oxooxydihydro-2^1-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-4 ,4-dimethyl-1- Oxypentan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)nodecylamine N-((S)-l-((3aS,6R,6aS)-6-azido 3-oxooxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-4,4-dimercapto-1-yloxypentane-2 -yl)-4-(4-cyclobutylpiperazin-1-yl)nodecylamine N-((S)-l-((3aS,6R,6aS)-6-azido-3-side oxygen Dihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxoethoxypentan-2-yl)-4 -(1-propylpiperidin-4-yl)benzylamine]^-((8)-b ((3&8,611,638)-6-azido-3-oxooxydihydro-211- Furfury 129860.doc 200906392 Cyclo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-4-methyl-1-oxoethoxypent-2-yl)-4-(4) -cyclobutylpiperazin-1-yl)benzylguanamine N-((S)_l-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H_ 吱 并[ 3,2-b]pyrrole-4(5H,6H,6aH)-yl)-4-methyl-1-oxoethoxypent-2-yl)-4-(1-propylpiperidin-4-yl ) 醯 醯 & ^ ^ ^ ^ ^ ^ ^ 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 b]pyrrole-4(5H,6H,6aH)-yl)-4-methyl-1-oxoethoxypent-2-yl)-4-(1-cyclopropylpiperidin-4-yl) Indoleamine N-((S)-l-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H_trimethane[3,2-b]&quot; -4(5H,6H,6aH)-yl)-4-mercapto-1-yloxypentyl-2-yl)-4-(1-cyclobutylpiperidin-4-yl)nodecylamine N- ((2S,3S)-l-((3aS,6R,6aS)-6-Fenyl-3-yloxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H ,6aH)-yl)-3-methyl-oxo-pentyl-2-yl)-4-(4-mercaptopiperazin-1-yl)nodecylamine&gt;^-((28,38)-1 -((3&8,611,6&amp;8)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl) -3-indolyl-i•p-oxypentan-2-yl)-4-(4-ethylpiperazin-1-yl)peptidylamine N-((2S,3S)-l-((3aS, 6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-3-indolyl-indole _Side oxindole-2-yl)-4-(4-propyl succinyl-1-yl) nodal amine 1^-((23,38)-1-((338,611,6)-6 -azido-3-oxooxydihydro- 211-0-fusino[3,2-1&gt;]0 to 11 each-4 (511,611,6&14)-yl)-3-indenyl -1_Phenyloxypentan-2-yl)-4-(4-isopropylpiperazin-1-yl)peptidylamine ((28,38)-1-((3, 611, 638)-6-azido-3_sideoxydihydro_129860.doc -4- 200906392 2Η·furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-3 - mercapto-1-yloxypentan-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)benzylamine N-((S)-l-(( 3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]pyrrole_4(5H,6H,6aH)-yl)-4,4- Dimethyl-1-oxopentan-2-yl)-4-(1-isopropylpiperidin-4-yl)benzylamine N-((S)-l-((3aS,6R,6aS) - 6-azido-3-oxooxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-4,4-didecyl- 1-Phenyloxyindol-2-yl)-4-(1-(2-methoxyethylidene-4-yl)nodal amine N-((S)-l-((3aS,6R,6aS) - 6-azido-3-oxo-dihydro-2-indole-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-4,4-dimethyl-1 -Phenyloxypentan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)nodecylamine N-((S)-l-((3aS,6R,6aS)-6-stack Nitro-3-yloxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-4,4-dimethyl-1-oxooxy Indole-2-yl)-4-(1-d-butyl bromide-4-yl)nodal amine N-((S)-l-((3aS,6R,6aS)-6-azido- 3-side oxygen Dihydrogen-2H-furo[3,2-b]. Bilota-4(5H,6H,6aH)-yl)-4-methyl-1-oxoethoxy-2-yl)-4-(4-methylpiperazin-1-yl)peptidylamine N -((S)-l-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-.f-amino[3,2-b]pyrrole-4 (5H, 6H,6aH)-yl)-4-mercapto-1_p-oxypentyl-2-yl)-4-(4-ethylpiperazin-1-yl)nodecylamine N-((S)-l -((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-mouthfu[3,2-1&gt;]&lt;1 to 11-4(51^, 61^,63-decarboxy-yl-4-methyl-1-oxo-pentyl-2-yl)-4-(4-propyl-p-l-l-yl-1-yl)-n-amine N-((S) -l_((3aS,6R,6aS)-6-§ Nitro-3-oxoxy-wind-2H-0 129860.doc 200906392 carboxy[3,2-b]吼4(5H,6H ,6aH)-yl)-4-methyl-1-oxoethoxypentyl-2-yl)-4-(4-isopropyl-4-indol-1-yl)benzylamine N-((S)- L-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-triazino[3,2-b]pyrrole-4(5H,6H,6aH)-yl )-4-mercapto-1-yloxypentyl-2-yl)-4-(4-(2-methoxyethyl)piperazin-1-yl)peptidylamine N-((S)- L-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-indolo[3,2-b]pyrrole-4(5H,6H,6aH)-yl )-4-曱-1-Sideoxypenta-2-yl)-4-(4-cyclopropyl-indol-1-yl)tubanthine&gt;^((28,38)-1-((3&8,611,638 - 6-azido-3-oxo-dihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-3-methyl-b-oxy Pent-2-yl)-4-(4-cyclopropylpiperazin-1-yl)f decylamine 1 ((28,38)-1-((338,611,6)-6-azido-3 -Phenoxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-3-methyl-indole-sideoxypentan-2-yl)-4 -(4-cyclobutylpiperazin-1-yl)peptidylamine]--((28,38)-1-((338,611,6)-6-azido-3-oxooxydihydrol _ 2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-3-methyl-di-oxoindol-2-yl)-4-(1-indenyl) BTS _4_yl) tanning amine N-((2S,3S)-l-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furan[ 3,2-b]pyrrole-4(5H,6H,6aH)-yl)-3-methyl-p-oxypentan-2-yl)-4-(1-ethyl π σ 定 _ _ _ _ base ) (7,33)-1-((3&amp;8,611,6)-6-azido-3-oxo-dihydro-2-indole-furo[3,2-b]pyrrole -4(5H,6H,6aH)-yl)-3-methyl-r-s-oxypentan-2-yl)-4-(1-propylβ- bottom-sigma _4_yl) Amine 1^-((28,38)-1-((338,6-foot,6-)-6-azido-3-oxooxydihydro-129860.doc -6- 200906392 211-furan[ 3, 2-1?]° ratio -4 (514, 61^, 6 and 1 €)-yl)-3-mercapto-1_sideoxypurin-2-yl)-4-(1-iso Propyl group &quot; 1,4-yl) nodal amine N-((2S,3S)-l_((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furan And [3,2-b]pyrrole-4(5H,6H,6aH)-yl)-3-methyl-1-oxomethoxypentan-2-yl)-4-(1-(2-methoxy) Ethyl) 〇 ° 定 -4-yl) knot g leucine N-((2S,3S)-l-((3aS,6R,6aS)-6-azido-3-oxooxydihydro_ 2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-3-methyl-1-oxopentyl-2-yl)-4-(1-cyclopropyl Piperidin-4-yl)peptidylamine 1^-((28,38)-1-((338,6-foot,6-)-6-azido-3-oxooxydihydro-2H-furan And [3,2-b]pyrrole-4(5H,6H,6aH)-yl)-3-methyl-1-oxomethoxypentan-2-yl)-4-(1-cyclobutylpiperidine- 4-yl) decylamine 1 ((8)-1-((3&8,611,638)-6-azido-3-oxooxydihydro-211-furo[3,2-b]. Bilota-4(5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-methylpiperazin-1-yl) Indoleamine N-((S)-l-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]. (5H,6H,6aH)-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-ethylpiperazin-1-yl)peptidylamine]^ -((5)-1-((338,611,638)-6-azido-3-oxo-dihydro-211-furo[3,2-b]&quot;bibromo-4(5H,6H,6aH )-yl)-3,3-dimethyl-1-oxobutan-2-yl)-4-(4-propylpiperazin-1-yl)peptidylamine ((5)-1- ((338, 611, 6 & 8)-6-azido-3-oxo-dihydro-211-furo[3,2-b].pyr-4(5H,6H,6aH)-yl)- 3,3-Dimethyl-1-oxobutan-2-yl)-4-(4-isopropylpiperazin-1-yl)peptidylamine N-((S)-l-((3aS) ,6R,6aS)-6-azido-3-oxooxydihydro-2H-fur 129860.doc 200906392 carboxy[3,2-b]pyrrole-4(5H,6H,6aH)-yl)- 3,3-Dimercapto-1-oxobutan-2-yl)-4-(4-(2-methoxyethyl)piperazine-i-yl)benzylguanamine N_((S)- L-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl )-3,3-dimercapto-1-oxobutan-2-yl)-4-(4-cyclopropylpiperazin-1-yl)-indenylamine &amp;((8)-1-( (338,6 ft,638)-6-azido-3-oxooxydihydro-211-°f-[3,2-b]pyrrole-4(5H,6H,6aH)-yl) -3,3-dimethyl-1-oxobutan-2-yl)-4-(4-cyclobutylpiperazin-1-yl)peptidylamine N-((S)-l-(( 3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-3,3- Dimethyl-1-oxobutan-2-yl)-4-(1-propylpiperidin-4-yl)benzylamine N-((S)-l-((3aS,6R,6aS) -6-azido-3-oxooxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-3,3-dimercapto-1- Oxidylbutan-2-yl)-4-(1-cyclopropylpiperidin-4-yl)nodecylamine N~((S)-l-((3aS,6R,6aS)-6-azide 3-yloxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-3,3-dimercapto-1-yloxybutene- 2-yl)-4-(1-cyclobutylpiperidin-4-yl)nodecylamine 1((8)-2-((3&amp;8,611,6&amp;8)-6-azido-3- Oleoxydihydro-21^furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-yloxyethyl)-4-( 4-methylpiperazine-1- Indoleamine N-((S)-2-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]pyrrole -4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-ethylpiperazin-1-yl)peptidylamine N_((S) -2-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-fur 129860.doc 200906392 carboxy[3,2-b]° piroxi-4 (5H, 6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(4-propylpiperazin-1-yl)peptidylamine N-((S)-2-( (3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-1-cyclo Pentyl-2-yloxyethyl)-4-(4-isopropylpiperazin-1-yl)benzylamine]^-((8)-2-((3&amp;8,611,638)-6-stack Nitro-3-yloxydihydro-21^furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-yloxyethyl) 4-(4-(2-methoxyethyl)piperazin-1-yl) decylamine N-((S)-2-((3aS,6R,6aS)-6-azido-3 -Phenoxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-p-cyclopentyl-2-yloxyethyl)-4-(4 -cyclopropylpiperazin-1-yl)peptidylamine ((3)-8((3&amp;8,611,6&amp;8)-6-azido-3- Oxydihydro-2-zafurfuro[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-yloxyethyl)-4-(4 -cyclobutylpiperazin-1-yl)peptidylamine N-((S)-2-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2Η-η夫M-[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-yloxyethyl)-4-(1-propylpiperidin-4- Benzobenzamine\-((3)-2-((3&amp;8,611,6&amp;8)-6-azido-3-oxooxydihydro-21^furan[3,2-b] Pyrrole-4(5H,6H,6aH)-yl)-1-cyclopentyl-2-oxoethyl)-4-(1-cyclopropylpiperidin-4-yl)peptidylamine N-( (S)-2-((3aS,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]pyrrole-4(5H,6H,6aH )-yl)-1-cyclopentyl-2-oxoethyl)-4-(1-cyclobutylpiperidin-4-yl)nodecylamine N-((S)-2-((3aS) ,6R,6aS)-6-azido-3-oxooxydihydro-2H-fur 129860.doc -9- 200906392 mer to [3,2-b]&quot;birol-4(5H,6H, 6aH)-yl)-1-cyclohexyl-2-oxoethyl)-4-(1-isopropylpiperidin-4-yl)benzylamine N-((S)-2-((3aS) ,6R,6aS)-6-azido-3-oxooxydihydro-2H-furo[3,2-b]° ratio of 4-(5H,6H,6aH)-yl -1-cyclohexyl-2-oxoethyl)-4-(1-(2-methoxyethyl)piperidin-4-yl)benzylamine ((8)-2-((3&amp ;8,611,638)-6-azido-3-oxooxydihydro-211-11-Fando[3,2-b]pyrrole_4(5H,6H,6aH)-yl)-1-cyclo Hexyl-2-sided oxyethyl)-4-(1-cyclopropyl-pept-4-yl)nodal amine N-((S)-2-((3aS,6R,6aS)-6-stack Nitro-3-yloxydihydro-2H-trinop[3,2-b]pyrrole-4(5H,6H,6aH)-yl)-1-cyclohexyloxyethyl)-4- (1-Cyclobutylpiperidine-4-yl)benzamide. The compound of any one of claims 1 to 3, wherein R2 is a side chain of leucine or cyclohexylglycine. The compound according to any one of claims 1 to 3, wherein R2 is a side chain of leucine, cyclohexylglycine or 4·fluoroleucine. The compound according to any one of items 1 to 3, wherein R2 is a side chain of methyl sulphate, gas leucine and 3- methoxy valine. A compound of the formula wherein η represents hydrazine. A compound of 'where η represents i. 7 · As in any of claims 1 to 6. 8. As in any of claims 1 to 6. The compound of claim 8, wherein: R3 129860.doc 10 200906392. The compound according to any one of claims 1 to 9, wherein R3 is a fluoro group or a methyl group. 11. The compound of claim 10, wherein R3 represents a fluoro group. A compound according to any one of claims 1 to 4, wherein E represents an unsubstituted thiazolyl group. 13. A compound according to any one of the preceding claims, wherein e represents a d-synyl sitting group substituted with a methyl or fluoro group. 1 4. The compound of claim 3, wherein Ε represents a thiazolyl group substituted with a fluoro group. The compound of any one of claims 2 to 4, wherein ε is: R5 wherein R5 represents an anthracene, a methyl group or a fluorine group. Lower part structure 1 6. The compound of claim 5, wherein Ε represents the thiazolyl group of the formula: Wherein R5 represents an anthracene, a fluorenyl group or a fluorine group. 17. The compound of claim 15 or 16, wherein R5 is η or CH3. 18. The compound of any one of claims 1 to η, wherein E represents a 〜1. The compound of any one of claims 1 to 8, wherein R4 represents 129860.doc 200906392 20. a compound wherein R4 is a fluorenyl group. 21. The compound of claim 19, wherein R4 is propyl. 22. The compound of claim 1 which is selected from the group consisting of: [1-(3 38,6&amp;8)-611-azido-3-oxo-hexahydro-furo[3,2-b]0 to p--4-indoleyl)-2 -methyl-butyl]-4-[2-(4-methyl-pyrylo-methyl-yl)-thiazol-4-yl]-benzylamine; N S N-[l-(3aS,6aS)-6R-azido-3-oxo-hexahydro-furo[3,2-b]pyrrole-4-carbonyl)-3-indolyl-butyl 4-[2-(4-mercapto-piperazin-1-yl)-thiazol-4-yl]-benzylguanamine; N-[l-(3aS,6aS)-6R-azido-3-oxo-hexahydro-furo[3,2- 129860.doc -12- 200906392 b]α 比略·-4- ))]-3-mercapto-butyl]-4-(4-propyl-birth σ-methyl-1-yl)-nodal amine; N-[2-(6-Fungyl-3-oxo-hexaza-pyridinium [3,2-b]11-pyrol-4-yl)-1-cyclohexyl-2-yloxy -ethyl]-4-[2-(4-mercapto-piperazin-1-yl)-thiazol-4-yl]-peptidylamine; N-[2-(6-azido-3-oxo-hexahydrofuro[3,2-b].pyrol-4-carbonyl)-3-methylbutyl]-4-[5 -mercapto-2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzamide; 129860.doc -13 - 200906392 ί?+ N-[2-(6-Hybrid-3-yloxy-hexaza-β- s-[3,2-b]° ratio p-4-methyl)-3 - -3--3-indole Butyl]-4-[2-(4-methyl-indolyl-1-yl)-indolyl s-yl]-benzylamine; N-[2-(6-strepromoxy-3-ylidene-hexaza-zefroma[3,2-1)]0 pirin-4-rocarbyl)-3-methylbutyl] 3-fluoro-4-[2-(4-methyl-piperazin-1-yl)-thiazol-4-yl]-benzylguanamine; N-[l-(6-azido-3-oxo-hexahydro-furo[3,2-b]. pyrol-4- 129860.doc -14- 200906392 Luo 曱基曱基-丁4-[5-fluoro-2-(4-methyl-piperazin-1-yl)-thiazole-4-yl]-benzylamine; or ί ]^[1,(6-azido-3-oxo-hexahydro-indolyl[3,2-|3].pyr-4-)3-a-3-methyl-butyl Gas_4_[2-(4-methyl-〇辰嗓-1-yl)-°°°~4,yl]-nodalamine; or a pharmaceutically acceptable salt thereof, an oxide or Hydrate 23. The compound of the request item 其 is _ Lapis-3-yloxy·hexahydro-π-fusan[3,2_b]D ratio _4_yl)_fluoro 4 [2-(4-mercapto-4-oxylazine) _sigh. Sit _4_yl]-lumpeneamine or a pharmaceutically acceptable salt or hydrate thereof. 24. A pharmaceutical composition comprising a compound of any one of claims (10) and a pharmaceutically acceptable carrier or diluent thereof. 25. Use of a compound according to any one of claims 1 to 23 for the manufacture or use of a medicament for the treatment or prevention. The system for the condition mediated by 'protease quinone' is used as a drug. 26. A compound according to any one of claims 1 to 23 129860.doc -15- 200906392 2 7. A compound mediated by enzyme K as claimed in claim 26. It is for the treatment or prophylaxis of a protein mediated by cathepsin K. A safe and effective amount of a compound according to any one of the claims is administered to an individual in need thereof. It comprises the items 1 to 23 29. The use, method or compound of the claim 25, 27 or 28 is selected from the group consisting of: the disease osteoporosis, gum disease (such as gingivitis and periodontitis), Paget's Disease (paget, s disease), malignant hypercalcemia, metabolic bone disease, 30. Characterized by excessive degradation of cartilage or matrix Rheumatoid arthritis), including bone cancer of the tumor, pain (especially chronic pain). a compound of the formula: a disease (such as osteoarthritis and Wherein the Rb groups are defined as ^ s von, % 鲷 (such as bis ketal), or together form a quinone ketal (such as _ - ^ and derivatives thereof; Ring), or its N-protected 129860.doc 200906392 31. The compound of claim 30, which is: 32. - Compounds of the following formula: 〇 OH 〆 k alkyl) wherein R 4 represents Cw alkyl, or a salt thereof or a lower alkyl group (for example, C,. 酉. 3 3. The compound of claim 32, which is: 0*γ OH 〇 129860.doc 17 200906392 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: 8. If the case has a chemical formula, please reveal the best display. Chemical formula of the inventive feature: IU N II N 129860.doc