TW200416032A - Cathepsin cysteine protease inhibitors - Google Patents

Abstract

This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis.

Description

200416032 (1) Description of the invention: [Technical field to which the invention belongs] The present invention relates to a novel class of cysteine protease inhibitors including, but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful in the treatment of diseases such as osteoporosis which show inhibition of bone resorption. [Prior art] There are human and other mammalian disorders that involve or are associated with abnormal bone resorption. Such conditions include, but are not limited to, osteoporosis, osteoporosis due to glucocorticoids, Paget, s disease: abnormally increased bone turnover, periodontal disease, tooth loss, fractures, Rheumatoid arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignant disease and multiple myeloma One of the most common of these conditions is osteoporosis, which most often occurs in women after menopause. Osteoporosis is a systemic skeletal disease that is characterized by low bone mass and the deterioration of the microstructure of bone tissue, which makes bones more vulnerable and prone to fracture. Osteoporotic fractures are the main cause of morbidity and mortality in the elderly population. Up to 50% of women and one-third of men experience osteoporotic fractures. Yes-Most elderly populations are already at risk of low bone density and high fractures. At present, there is a clear need for lions to treat osteoporosis and other conditions related to bone resorption. Because osteoporosis and many other conditions related to bone loss are often chronic conditions, it is believed that Zhou Dangzhi's therapy also requires long-term treatment. Cathepsin inhibitors such as cathepsins κ, B, L, and S can be used to treat such conditions. 87282 [Summary of the Invention] The present invention relates to a compound capable of treating and / or preventing mammals in need, or a mother-dependent disease or disease state of Qi A. A specific embodiment of the present invention is illustrated by the compound of Formula 1 and its pharmaceutically acceptable salts, stereostructures and N-oxide derivatives:

The following Table II lists the compounds of formula j starting from R1 and R2 together with the carbon atoms to which they are attached, and R4, R5 and R8 are hydrogen:

Stereochemistry in (* c) R2 R6-(D) n-R7 RS Η 1CF3-~ ---- Phenyl RS ——— __—--- Η cf3 4-Bromophenyl RS Η cf3 4'- Hexahydropyrine-1- ---------- ^ ------ --- ^^) diphenyl-4-yl R8 is hydrogen compound of formula τ:

〇 cf

N 87282 200416032 Stereochemistry of (* C, * * Λ 氺 氺 氺 C) R2 R3 R6-(dvr7 S, S, S, methyl 2-methyl-propyl cf3 4 '-methylcontinyl di Phenyl-4-yl S, s, s, 2-methylthioethyl 2-methyl-propylcf3 4'-methylsulfonyldiphenyl-4-yl S, s, s, 2-methyl Containing acid-ethyl 2-methyl-propyl cf3 4'-methylsulfobiphenyl-4- Specific specific embodiments of the basic invention include, but are not limited to: N ^ (l-cyanocyclopropyl) -4-fluoroyl-N2-{(lS) -2,2,2-trifluoroyl-1- [4,-(methylsulfonyldiphenyl-4-yl) ethylbenzene L-leucine Amidoamine; cyanomethyl) -N2- (2,2,2-trifluoro-1-phenylethyl) _L_leukoamine; N-(cyanomethyl) -N2- [2,2,2 -Trifluorofluoromethylphenyl) ethyl] _L-leukinamine; N (cyanomethyl) -N-[(lR) -2,2,2-trifluoro group small (4_ outer dagger) Ytylphenyl) ethyl] -L-leukoamine;

Nl- (cyanomethyl) _n2 _ [(1S) _2,2,2-triyl] _L_leukinamine; Fluoro-1- (4-pyridin-3-ylphenyl) ethyl It covers pharmaceutical compounds including the above-mentioned compounds and medicines ":::. The present invention also encompasses the combination of "carriers and any particular disclosure of this patent application 87282 200416032 pharmaceutical composition." These and other aspects of the invention are clear from the teachings contained herein. The compound of the present invention is an inhibitor of cathepsin, and thus can be used for treating or: anti-mammalian, and preferably cathepsin dependent diseases or conditions of human beings. In particular, the compounds of the present invention are inhibitors of cathepsin κ, and can be used to treat or prevent mammals, as well as human tissue proteinase K-dependent diseases or conditions. "Cathepsin-dependent diseases or conditions are for pathological conditions that depend on protease activity." Cathepsin K-dependent or conditions' are for pathological conditions that depend on cathepsin κ activity. Diseases related to disk cathepsin include osteoporosis, glucocorticoid-induced osteoporosis, domain osteitis, abnormally increased bone turnover, periodontal disease, tooth loss, fractures, rheumatoid arthritis , Bone joints *, osteolysis around components, osteogenesis imperfecta, metastatic osteopathy, cardiac hypercalcemia and multiple myeloma. When using the patent application to treat such conditions, the required drug dose is equal to 70 according to the specific disease, and it is easy for those skilled in the art to determine. In spite of this, people are suffering from the target field.

> Oral cavity and prevention; However, treating these conditions is a better use. I One embodiment of the present invention is a method for inhibiting the * r protease activity of a mammal in need thereof, which comprises administering a mammalian therapy, and weaving any compound or any pharmaceutical composition. ≪ The above-mentioned one specific embodiment is a method in which the activity of the tissue enzyme K is active. Tissue protein 87282 -10- 200416032 Another specific embodiment of the present invention is a method for treating or preventing a mammalian cathepsin-dependent condition, which comprises administering to a mammal a therapeutically effective amount of any of the above compounds or any pharmaceutical composition . One specific embodiment is a method in which the cathepsin activity is the activity of a cathepsin. Another embodiment of the present invention is a method for inhibiting mammalian bone loss in need thereof, comprising administering to a mammal a therapeutically effective amount of any of the above compounds or any pharmaceutical composition. Another embodiment of the present invention is a method for reducing mammal bone loss in need thereof, comprising administering to a mammal a therapeutically effective amount of any of the above compounds or any pharmaceutical composition. The use of cathepsin K inhibitors to inhibit bone resorption is well known in the literature, please refer to Stroup, G.B., Lark, M.W., Veber, DF., Bhattacharrya, A., Blake, S., Dare L. C., Erhard, K. F., Hoffman, S. J., James, I. E., Marquis, R. W., Ru, Y, Vasko-Moser, J. A., Smith, B. R., Tomaszek, T. and Gowen, M. Potent and selective inhibition of human cathepsin K leads to inhibition of bone resorption in vivo in a non-human primate. J. Bone Miner. Res., 16: 1739-1746 2001; with Votta, B.J., Levy, M.A., Badger, A., Dodds, R. A., James, I. E., Thompson, S., Bossard, M. J., Carr , T ·, Connor, J. R ·, Tomaszek, TA, Szewczuk, L ·, Drake, FH, Veber, D ·, and Gowen, M. Peptide aldehyde inhibitors of cathepsin K inhibit bone resorption both in vivo and in vitro. J. Bone Miner. Res., 12: 1396-1406; 1997. Another specific embodiment of the present invention is a method for treating or preventing mammalian bone in need thereof 87282-11-200416032 osteoporosis, comprising administering a therapeutically effective amount of any of the above compounds or any pharmaceutical composition to mammals. The use of histone protease kappa inhibitors to inhibit osteoporosis is well known in the literature. Please refer to Saftig, P., Hunziker, E., Wehmeyer, 0., Jones, S., Boyde, A., Rommerskirch, W. Moritz, J. D., Schu, P., and Vonfigura, K. Impaired osteoclast bone resorption leads to osteoporosis in cathepsin K-deficient mice. Proc. Natl. Acad. Sci. USA 95: 13453-13458; 1998. Another embodiment of the present invention is a method for treating or preventing a condition of mammalian rheumatoid arthritis in need thereof, which comprises administering to a mammal an effective amount of any of the above compounds or any pharmaceutical composition. Known in the literature is the main factor that causes continuous joint destruction of the skeletal rheumatoid arthritis (RA) patients around the joints with poor joint function and disability. Please refer to Goldring SR, "Pathogenesis of bone erosions in rheumatoid arthritis". Curr. Opin. Rheumatol. 2002; 14: 406-10. Analysis of joint tissues in RA patients provides evidence of cathepsin K positive osteoclast line mediators and cellular patterns of focal bone resorption in rheumatoid synovial injury. Please refer to Hou, WS, Li, W , Keyszer, G, Weber, E, Levy, R, Klein, MJ, Gravallese, EM, Goldring, SR, Bromme, D, "Comparison of Cathepsin K and S expression within the Rheumatoid and Osteoarthritic Synovium", Arthritis

Rheumatism 2002; 46: 663-74. In addition, systemic bone loss is the main cause of morbidity associated with severe RA. The frequency of hip and spine fractures has increased substantially in patients with chronic RA, see Gould A, Sambrook, P, 87282 -12- 200416032

Devlin J et al., "Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis" · J. Rheumatol. 1998; 25: 1282-9 〇 cathepsin K inhibitors in the sub-articular bone and normal bone The treatment or prevention of lost reabsorption represents a reasonable method of pharmacological intervention in rheumatoid arthritis. Another embodiment of the present invention is a method of treating or preventing the progression of mammalian osteoarthritis in need thereof, comprising administering to a mammal a therapeutically effective amount of any of the above compounds or any pharmaceutical composition. It is known in the literature that osteoarthritis (OA) is accompanied by changes in the well-defined joints, including erosion of the articular cartilage surface, ossification / osteophyte formation in the articular cartilage and subchondral sclerosis and cyst formation. , Abendroth, K, "Osteoarthritis and

bone: osteologic types of osteoarthritis of the hip ", Skeletal Radiol. 1989; 18: 165-74. Recently, the potential contribution of subchondral bone sclerosis to the initiation and progression of OA has been mentioned. When joints respond to the burden of repetitive impulses At the same time, the rigid subchondral bone is less able to reduce and distribute the force through the joint, causing it to bear greater mechanical pressure on the joint cartilage surface. This in turn will accelerate cartilage wear and fibrosis. Please refer to Radin, EL and Rose RM, uRole of subchondral bone in the initiation and progression of cartilage damage ", Clin Orthop · 1986; 213: 34-40. The use of anti-resorption agents, such as cathepsin K inhibitors, to inhibit excessive bone resorption in the joints will cause inhibition of subchondral bone turnover; therefore, it may have a beneficial effect on the progression of OA. In addition to the above hypotheses, cathepsin K 87282 has been identified recently in synovial fibroblasts, giant cell-like cells, synovial-derived chondrocytes, and articular cartilage specimens derived from OA patients. 200416032 Protein performance, please refer to Hou, W_S, Li, W, Keyszei ·, G, Weber, E, Levy, R, Klein, MJ, Gravallese, EM, Goldring SR, Bromme, D, "Comparison of Cathepsin K and S expression within the Rheumatoid and Osteoarthritic Synovium ", Arthritis Rheumatism 2002; 46: 663-74 and Dodd, RA, Connor, JR, Drake, FH5 Gowen, M," Expression of Cathepsin K messenger RNA in giant cells and their precursors in human osteoarthritic synovial tissues ". Arthritis Rheumatism 1999; 42: 1588-93; and Konttinen, YT, Mandelin, J, Li, TF, Salo, J, Lassus, J, etc." Acidic cysteine endoproteinase cathepsin K in the degeneration of the superficial articular hyaline cartilage in osteoarthritis ", Artritrit Rheumatism 2002; 46: 953-60. These recent studies therefore suggest the role of cathepsin K in the destruction of articular cartilage collagen type 2 that is involved in the progression of osteoarthritis. According to the present invention, cathepsin K is used to treat or prevent osteoarthritis, and therefore includes two different mechanisms. One is to inhibit osteoclast-driven subchondral bone conversion, and the second is to directly inhibit OA patients. Synovial and cartilage collagen type II degradation. A specific embodiment of the present invention is a method for treating mammalian cancer in need thereof, which comprises administering a therapeutically effective amount of any of the above compounds or any pharmaceutical composition to a mammal. It is known in the literature that cathepsin K is expressed in human breast cancer. Please refer to Littlewood-Evans AJ, Bilbe G, Bowler WB, Farley D, Wlodarski B, Kokubo T, Inaoka T, Sloane J, Evans DB, Gallagher JA, " The osteoclast-associated protease 87282 -14- 200416032 cathepsin K is expressed in human breast carcinoma. Cancer Res December 1, 1997; 57 (23): 53 86-90. The invention is exemplified by using any of the above compounds in the preparation A medicine for treating and preventing osteoporosis in mammals in need thereof. The present invention further exemplifies the use of any of the above compounds in the preparation of treatment and or prevention: bone loss, bone resorption, fracture, metastatic bone, and various diseases and And / or disorders related to cathepsin function. The compounds of the present invention can be administered to mammals, and are preferably human. According to standard pharmaceutical practice, if not alone, it is preferred to be a pharmaceutically acceptable carrier or diluent, and Optionally, a known adjuvant such as alum is added to the pharmaceutical composition. The compound can be administered orally or parenterally, including Intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and topical routes. In the case of oral lozenges, commonly used carriers include lactose and corn starch, and lubricants such as magnesium stearate are commonly added. For capsules for oral administration, the diluents used include lactose and dried corn starch. In the case of the therapeutic compounds according to the present invention for oral administration, the selected compounds may be in the form of, for example, tablets or capsules, or aqueous solutions or Suspension type administration. In the form of tablets or capsules for oral administration, the active pharmaceutical ingredients can be mixed orally, non-toxic, and pharmaceutically acceptable inert carriers such as lactose, starch, sucrose, glucose, methyl cellulose, stearin Magnesium acid, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like; in the liquid form for oral administration, the oral pharmaceutical ingredients can be mixed with any oral, non-toxic, pharmaceutically acceptable inert carrier such as Ethanol, glycerol, water, and the like. Even when desired or necessary, suitable adhesives 87282 -15- 200416 032, emollient, disintegrating agent and coloring agent are incorporated into the mixture. Suitable adhesives include winch, gelatin, natural sugars such as glucose or / 5-lactose, corn sweets such as acacia, tragacanth and natural With synthetic gum or sodium alginate 'methylcellulose, polyethylene: alcohol, sacrifice and the like. Moisturizing scrapers used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzate , Acetylamidine, sodium chloride and the like. Decomposing agents include, but are not limited to, dianfen, methyl, truncated, quasi-synthetic, compound clay, sanxian gum, and the like. When the aqueous suspension / night system is intended for oral administration, the active ingredient is mixed with an emulsifier and a suspending agent / if necessary, and then certain sweeteners and / or flavor enhancers can be added. When administered intramuscularly, subperitoneally, or intravenously, the pH of the active ingredient should be adjusted to provide sterile active ingredients and the pH of the fluid should be appropriately adjusted and buffered. For intravenous administration, the total concentration of ' valley is tethered to make the preparation isotonic. The present hairy compound can also be applied in the form of small monolayer capsules, large monolayer capsules, and multilayer capsules (liposome delivery system). Liposomes can be formed from a variety of phospholipids, such as cholesterol, amine stearate, or phospholipids. Second: Ming compounds can also be delivered using the :::: body of a single antibody coupled to the compound. The compound of the present invention can also be used as a soluble polymer for directing < wood carrier. Such polymers can include poly G ~ pyrrolidone, piperan copolymerization ~, ~ ~ Yongzhao propyl methacrylamide-phenol 7yl ethyl aspartamine amine-phenol or pectin Alkane-polyionine. In addition, it is possible to couple the compounds of the present invention to a class that can be used to achieve controlled release of drugs. 47 "Biodegradable polymers such as polybismuth, polyglycolic acid, polylactic acid, etc. # 木 内舻 ,, copolymer of glacial glycolic acid, poly (ε-caproic acid), poly (hydroxybutyric acid, poly-n-ester), 87282 ice + acetal, polydihydropiran, polycyanide-16-200416032 Cross-linked or bipolar block copolymer with hydrated gum. The compound can also be used in combination with osteoporosis, glucocorticoid-induced osteoporosis, glucocorticoid-induced osteoporosis, teratogenic osteitis, abnormally increased bone turnover, periodontal Disease, tooth loss, fractures, rheumatoid arthritis, osteoarthritis, osteolysis around components, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignant disease and multiple myeloma. The present invention discloses the combination of a compound with other agents for use in the oral treatment or prevention of osteoporosis or other skeletal disorders that fall within the scope of the present invention. Based on the particular characteristics of the drug and the disease involved, a person skilled in the art will be able to identify which combination of drugs is useful. Such agents include the following: organic bisphosphonates, estrogen receptor modulators, androgen receptor modulators, osteoclast proton ATPase inhibitors, HMg_C () A reductase inhibitors, integrin receptor antagonists Agents, osteoblast assimilating agents such as PTH, and pharmaceutically acceptable salts and mixtures thereof. A preferred combination is a compound of the invention and an organic bisphosphonate. Another preferred combination is a compound of the invention with an estrogen receptor modulator. Another preferred combination is a compound of this invention and an androgen receptor modulator. Another preferred combination is a compound of the present invention with an osteoblast assimilating agent. "Organic bisphosphonates" include, but are not limited to, compounds of the formula: p〇 ^ h2 ·

A- (CH2) n-C-X

I p〇3h2 where n is an integer from 0 to 7, and where A and X can only be independently selected by each of the following 87282 -17- 200416032: Η, OH, halogen, NH2, SH, phenyl, C1- C30 alkyl, C3-C30 branched or cyclic alkyl, bicyclic structure containing 2 or 3 N, C1-C30 substituted alkyl, NH substituted with C1-C10 alkyl, or C3-C10 branched or Cycloalkyl-substituted NH2, C1-C10 dialkyl-substituted NH2, C1-C10 oxooxy, thio substituted with C1-C10 alkyl, thiophenyl, phenylbenzyl, C1- C10 alkyl substituted phenyl, pyridyl, furyl, pyrrolidinyl

, Mitotyl, mitoxedronium, and nodyl; so when η is 0, both a and X are selected from Η or OH; or A and X together form a C3- with the carbon atom to which they are attached C10 ring. In the foregoing chemical formula, as long as the atoms selected for the chemical formula are sufficient, the alkyl group may be linear, branched, or cyclic. The C1-C30 substituted alkyl group may include various substituents, and non-limiting conditions include one selected from the following: phenyl, pyridyl, furyl, pyrrolidinyl, imidazolyl, NA, ci_CW alkyl, or dialkyl Substituted NΗζ, OH, 811 and (: 1 _ (:: 10alkoxy). The foregoing chemical formula is also intended to cover the carbocyclic, aromatic and heteroatom structures of the complex for A and / or X substituents, which are not limited Examples include naphthyl, perylene =, isoquinolinyl, adamantyl, and chlorophenylthio. In this context, bisphosphonates can also be used in a pharmaceutically acceptable manner .... Non-limiting examples include those that can only be selected from the following: metal, earth metal, ammonium salts and ammonium salts substituted with-, di, tri, or tetra. Preferred salts are those that can only be selected from the following. Cantonese, Ma, Magnesium and Ammonium salts. The best ones are sodium salts. The nature of the derivatives includes: those that can only be selected by the following. Lu Su, $ 贝 1 岸,, main voice, too, 6 types, Hydrates and donkey amines | You / Wang Siben also used, 'bisphosphonates, and ,, bisphosphonates, and, 87282 -18-. "In the month of the month, the oral medicine will cover all bis (di) phosphonates, bis (ampl) tetanic acid and bis (W), non-special) bismuth, as well as salts and derivatives of these materials. Except g 丨L ten pairs of specific names of bisulfate salts or double pentanoate salts ^ ^ to limit the material of the present invention. Because the current-as familiar as the current use of this name ", so unless otherwise specified; otherwise, Mao Yue The specific weight or percentage is based on the active weight of the acid. For example, according to the wording, the active weight of alendronic acid = the only basis that can be used to cut fumarate, which is medically Acceptable salts and their mixtures yield <about 5 grams of bone resorption inhibitory bitenate, meaning that the amount of bitenate compound selected is based on 5 mg of alendronate. Non-limiting examples of bisphosphonates that can also be used include the following: alendronate salt (also known as alendronate, sodium alendronate, or monobasic salt of alendronate dihydrate), 4 -Amine-Q-protecting-butylene ", monobendonic acid mono-residual salt trihydrate. Alendronate is described in the following: Patent No. 4,922,007 was publicly issued to Kieczykowski et al. On May 1, 1990, and U.S. Patent No. 5,019,651 was issued to May 28, 1991—Laye Ye et al. ”, U.S. Patent No. 5,51〇, 517 It was published on April 23, 1996 and 1) Catch et al., US Patent No. 5,648,491 was published to Dauer et al. On July 1, 1997; all of which are incorporated herein by reference in their entirety. Cycloheptylaminomethylene-ι, fluorene-bisphosphonic acid, YM175, Yamanochi (S incadronate, formerly known as cimadronicate) as U.S. Patent No. The 4,970,335 clarifier was published to Isomura et al. On November 13, 1990, the entire text of which is incorporated herein by reference. 1,1-monochloromethylene-1,1-bisphosphonic acid (clodronic acid ((^ 1〇 (^ 〇11 丨 (: 状 丨 (^)) and 87282 -19- 200416032 disodium salt ( Clodronate, Procter &amp; Gamble) is described in Belgian Patent Nos. 675,205 (1966) and J.org Chem 32, 4111 (1967), both of which are incorporated herein by reference in their entirety. 1-Hydroxy- 3- (1-pyrrolidinyl) -propylidene-fluorene, fluorene-bisphosphonic acid (Eb-1053), 1 to diethylidene-1,1-bisphosphonic acid (etidronic acid )), 1-Ethyl-3- (N-methyl-N-pentylamino) -propylene-i, i-bisphosphonic acid is also named BM-210955, Boehringer-Mannheim Salt (ibandronate), published in U.S. Patent No. 4,927,814, May 22, 1990, the entire contents of which are incorporated herein by reference. 1-Ethyl-2-imidyl- (1,24 &gt; Hiyodo-3-Kiya Ethyl-1,1-bisphosphonic acid (minodronate), 6-amino-1_hydroxyhexylene_ι, fluorene-bisphosphonic acid (neridronate), 3- (dimethylamino) -1-hydroxypropylidene-fluorene, i-bisphosphonic acid (olpadronate), 3-amino-1-hydroxypropylidene-i, i_ Phosphonic acid (pamidronate), [2- (2-elide) -ethylene] -i, i-bisphosphonic acid (piridronate), in the US patent It is described in No. 4,761,406, which is incorporated herein by reference in its entirety. 1-Ethyl-2- (3-pyridinylethylenebisphosphonic acid (risedronate)), (4-chloro Phenyl) thiomethane-1,1-bisphosphonic acid (tiiudronate) 'published on October 24, 1989 as 87282-20-200416032 as described in US Patent No. 4,876,248

Breliere et al. Are incorporated herein by reference in their entirety. Non-limiting examples of 1-hydroxy-2 · (1Η_imidazolyl) _ethylene "bisphosphonic acid (zoledronate) ° Bisphosphonates include the following: alendronate , Cimetronate, clodronate, etidronate, itidronate, incadronate, minodronate, niridonate, obodonate, barbados Midodronate, bilidronate, leidronate, tirudronate and levodronate 'and their pharmaceutically acceptable salts and cools. Particularly preferred bisphosphonates are alfronate, especially sodium, #, _, magnesium or ammonium salts of alendronate. Exemplary preferred bisphosphonates are the sodium salts of aquinic acid, especially the hydrated sodium salt of aquinic acid. The salt can be hydrated with water with a complete mole number or water with an incomplete mole number. The further exemplified preferred bisphosphonate is the hydrated sodium salt of alentonic acid ', especially when the hydrated salt is adenosine mononaphthalate trihydrate. We understand that two or more bisphosphonates can be used Mixture of salt active ingredients. The exact dose of organic bisphosphonates depends on the dosimetry plan, the specific panic acid salt selected, the age, size, gender and condition of the mammal or human being, the nature and severity of treatment, and other relevant medical and physiological factors. set. Therefore, the exact drug effective amount cannot be specified in advance, but it can be easily determined by the client or doctor. Routine experiments can be used to determine the appropriate amount for clinical studies in animal models. In general, the amount of bisphosphonate used is to achieve the effect of inhibiting bone resorption, that is, the bisphosphonate is used as the inhibitor of bone W absorption. For humans, effective oral coated bisphosphonates are typically from about U to about 嶋 micrograms / kg body weight, preferably from ^ 87282 -21- 200416032 10 to about 2000 micrograms / kg body weight. For alendronate monosodium salt trihydrate, human doses typically administered typically range from about 2 mg / day to about 40 mg / day, preferably about 5 mg / day to about 40 mg / day. In the United States, the current approved alendronate monosodium salt trihydrate dosage is 5 mg / day to prevent osteoporosis, 10 mg / day to treat osteoporosis, and 40 mg / day to treat Berger's disease. In alternative dose courses, bisphosphonates are administered at intervals other than daily, such as once weekly, twice weekly, biweekly, and twice monthly. Alendronate monosodium salt trihydrate is administered at a dose of 35 mg / week or 70 mg / week during the once weekly dose course. "Selective estrogen receptor modulators" target compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of its mechanism. Examples of estrogen receptor modulators include, but are not limited to, estrogen, progesterone, estradiol, droloxifene, raloxifene, lasofoxifene, TSE- 424, tamoxifen, idoxyfene, LY353381, LY117081, toremifene, fulvestrant, 4- [7- (2,2-dimethyl) Methyl-1-oxypropoxy_4-methyl-2 [4- [2- (1_hexahydropyridyl) ethoxy] phenyl] -2H-1-benzopiperan-3-yl) _Phenyl-2,2-dimethylpropionate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl-Yuezong and SH646. "Estrogen receptor / 5 modulators" are compounds that selectively agonize or antagonize estrogen receptor / 3 (ER / 3). Agonist ER / 3 increases the transcription of tryptophan hydroxylase (TPH, the major enzyme of serotonin synthesis) gene through ER cold mediator events. Examples of estrogen receptor cold agonists can be found in PCT International Publications WO 01/82923, 87282 -22- 200416032 November 8, 2001 Publication and WO 02/4183 5, May 20, 2002 Publication 9 of 2 All of them are listed in this article for reference. "Androgen receptor modulators, which target compounds that interfere with or inhibit the binding of androgens to receptors, regardless of their mechanism. Examples of androgen receptor modulators include finasteride and other 5 alpha-reduction Enzyme inhibitors, nilutamide, flutamide, bicalutamide, liarozole and abiraterone acetate. "Bonebreaking Cell proton ATPase inhibitors, inhibitors of proton ATPase, are found on the apical membrane of osteoclasts and have been reported to play an important role in the process of bone resorption. This proton pump represents an attractive target for bone resorption inhibitor designs with potential for use in the treatment and prevention of osteoporosis and related metabolic diseases. Please refer to C. Farina et al. "Selective inhibitors of the osteoclast vacuolar proton ATPase as novel bone antiresorptive agents," DDT, 4: 163-172 (1999), the entire text of which is incorporated herein by reference. "HMG-CoA reductase inhibitor" is an inhibitor of 3-hydroxy-3-methylglutaridine-CoA reductase. Compounds with HMG-CoA reductase inhibitory activity can be easily identified using analysis well known in the art. For example, reference is made to the analysis illustrated or quoted in U.S. Patent No. 4,231,938 (: 01.6 and 0 84/02131, pages 30-33. As used herein, "HMG-CoA reductase inhibitor" and "HMG-CoA "Reductase inhibitors" have the same meaning. Examples of HMG-CoA reductase inhibitors that can be used include, but are not limited to, lovastatin; lovastatin (MEVACOR⑧, please refer to US Patent No. 87282 -23- 200416032) 4,231,938, 4,294,926 and 4,319,039), Simvastatin (ZOCOR®, please refer to US Patent Nos. 4,444,784, 4,820,850 and 4,916,239), Pravastatin (PRAVACHOLAV, please refer to US Patent Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589), Yizhi Ke (^ 1 ^ &amp; 81 &amp; to 11) (1 ^ 3 (3〇1 ^, please refer to US Patent No. 5,354,772, 4,911,165 &gt; 4,929,437 &gt; 5,189,164, 5, 1 18,853, 5,290,946 and 5,356,896), atorvastatinXLIPITOR® (see U.S. Patent Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952) and cerivastatin (Also known as rivastatin and BAYCHOL®, please refer to US Patent No. 5,177,080). For the structural formula of these HMG-CoA reductase inhibitors that can be used with this method, please refer to M.

I

Yalpani, "Cholesterol Lowering Drugs", Chemistry &amp; Industry, pp. 87-87, p. 87, and U.S. Patent Nos. 4,782,084 and 4,885,314. As used herein, the term HMG-CoA reductase inhibitor includes all pharmaceutically acceptable forms of lactones and -acids (that is, the ring of the lactone opens to form a free acid) and those having HMG-CoA reductase inhibitory activity Salt and ester forms of the compounds, and such salts, esters, open acids and lactone forms are all included in the scope of the present invention. A description of the lactone moiety and its corresponding open-acid form is listed below as structures I and II.

87282 -24 200416032 In the presence of open-acid HMG-CoA reductase inhibitors, the salt and ester types are preferably formed from the open-acid; moreover, all such types are used herein as "HMG-CoA reduction The meaning of the term "enzyme inhibitor" is included. Preferably, the HMG-CoA reductase inhibitor is selected from Lofastatin and Merck, and Merck is best. As used herein, "pharmaceutically acceptable salt", relative to HMG-CoA reductase inhibitors, means non-toxic salts of the compounds used in the present invention, which are usually prepared by reacting a free acid with an appropriate organic or inorganic test , Especially formed by cations such as sodium, potassium, Ming, # 5, noodles, osmium, zinc, and tetramethylammonium, and by amines such as ammonia, acetamidine diamine, and N-methylamine deoxysorbate Alcohol, lysine, arginine, ornithine, choline, N, N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenylethylamine, 1 -A salt formed by p-chlorobenzyl-2-pyrrolidin-1'-yl-methylbenzimidazole, diethylamine, hexahydropyrine and ginsyl (hydroxymethyl) aminomethane. Further examples of salt forms of HMG-CoA reductase inhibitors may include, but are not limited to, acetate, benzenesulfonate, benzylate, bicarbonate, sulphate, hydrogen tartrate, borate, bromide , Calcium edetate (EDTA), camphor acid, carbonate, chloride, clavulanate, citrate, hydrogen chloride, edetate, edetate, propyl ester Estolate, ethanesulfonic acid, fumarate, grape heptanoate, gluconate, glutamate, glycolyllarsanilate, 2,4-di Hexyl benzyl, hydrabamine, hydrobromide, hydrochloride, rityl succinate, decomposed salt, 2-hydroxyethanesulfonic acid, lactate, lactate, laurel Acid salt, frequency fruit salt, maleic acid salt, mandelate salt, methane sulfonate salt, mucus 87282 -25- 200416032 ㈣, "acid salt, nitrate, oleate, oxalate, bisacid Salt, brown "hydrochloride" «salt / bisphosphate, lactobionate, salicylate, stearate, hypoacetate, succinate, Tannate, tartrate, teoclate (teoclate), tosylate, triethiodide gallamine (triethiodide) and valerate. The ester derivative of the HMG-CoA reductase inhibitor compound may be used as a prodrug &apos; which, when absorbed into the bloodstream of a warm-blooded animal, will be cut off in a drug release mode and allow the drug to provide improved treatment efficiency. When used above, "integrin receptor antagonists are targeted at compounds that selectively antagonize, inhibit, or reverse the binding of physiological ligands to integrin αv / 5 3, and selectively antagonize, inhibit, or reverse Physiological ligands versus integrin ^ ν cold 5 knot &amp; compounds are compounds that antagonize, inhibit or reverse the binding of physiological ligands to integrin αν / 5 3 and αν / 5 5 and A compound that inhibits or reverses the activity of specific integrin expressed in capillary endothelial cells. Child language also targets αν / 56, avy58, αΐ ^ ι, α2 / 3ι, α5 / 51, α 6/3/1, and α 6 stone 4 integration Antagonists of auxins. This term is also directed at "ν 冷 3 ^ ανβ 5 ^ ανββ ^ ανβ% ^ α \ β Λ &gt; α2β \. Α5β \ ^« 6/5 1 and any combination of α6 /? 4 integrin Antagonist. ην · and colleagues observed in PNAS USA 96: 1591-1596 (1999) that the anti-angiogenesis av integrin antagonist and the tumor-specific antibody cytokinin (interleukin_2) fusion protein are between the eradication of spontaneous tumor metastasis Synergistic effect. The results suggest that this combination has the potential to treat the growth of cancer and metastatic tumors. Integrin receptor antagonists inhibit bone resorption through a new mechanism that is completely different from all currently available drugs. Integrins are heterodiplex transmembrane attachment receptors for intermediary cell 'cells and 87282 -26-200416032 cell-matrix interactions. The "/ 5 integrin" subunit acts as a non-covalent and binds extracellular matrix ligands in a bivalent cation-dependent manner. The largest integrin in osteoclasts is α ν stone 3 (&gt; 107 / osteoclasts), which appears to play a rate-limiting role in the bone and skeletal tissue of cells that are important for cell migration and polarization. The α ν / 5 3 antagonistic effect is selected from the group consisting of inhibition of bone resorption, inhibition of restenosis, inhibition of plaque degeneration, inhibition of arthritis, and inhibition of cancer and metastatic growth. An "osteoblast assimilating agent" is an agent that targets bones such as PTZ. It has been shown that intermittent administration of parathyroid hormone (PTZ) or its amine terminal fragments and the like can prevent, capture, partially reverse bone loss in animals and humans, and stimulate bone formation. For its discussion, please refer to D.W. Dempster et al., "Anabolic actions of parathyroid hormone on bone," Endocr Rev 14.690-709 (1993). Studies have shown the clinical benefits of the parathyroid to stimulate bone formation and thereby increase bone mass and strength. The results are reported in RM Neer et al., New Eng J Med 344 1434-1441 (2001). In addition, parathyroid hormone-related protein fragments or the like such as PTHrP- (l-36) show potent anticalciuria effects [see M_A. Syed et al., "Para thyroid hormone-related protein- (1 -3 6) stimulates renal tubular calcium reabsorption in normal human volunteers: implications for the pathogenesis of humoral hypercalcemia of malignancy, "JCEM 86: 1525-1531 (2001)], and may also be used as an assimilating agent for the treatment of osteoporosis potential. When formulated into a fixed dose, such combined products use the compounds of the invention within the dosage range described below and other active pharmaceutical agents within the approved dosage range of 87282-27-27200416032. When the combined formulation is not appropriate, the compounds of the invention may alternatively be used sequentially with known pharmaceutically acceptable agents. The term "administering" and its variants (e.g., "administering" a compound) when directed to a compound of the present invention means that the compound or compound prodrug is introduced into an animal system in need of treatment. When the compound of the present invention or its prodrug is provided in combination with one or more other active agents (such as cytotoxic agents, etc.), "administration" and its variants are individually understood, and will include simultaneous and sequential introduction of the compound or its prodrug And other medicaments. The invention includes within its scope prodrugs of the compounds of the invention. In general, such prodrugs will be functional derivatives of the compounds of the invention which are readily converted in vivo into the desired compounds. Therefore, in the method of treatment of the present invention, the term "administering" will cover a compound that is specifically disclosed; or a compound that is not specifically disclosed but which can be converted into a specific compound in vivo after being administered to a patient. The different conditions described. Please refer to the usual methods for the selection and preparation of appropriate prodrug derivatives, such as the description of "Designs of Prodrugs," edited by B. Bundgaard, Elsevier, 1985, the entire text of which is incorporated herein by reference. Metabolites of these compounds include the active species produced by introducing the compounds of the present invention into the biological environment. As used herein, the term "composition" is intended to encompass a specific amount of a specific ingredient product, as well as any product that results directly or indirectly from the combination of specific amounts of the specific ingredients. The term "therapeutically effective amount", as used herein, means the amount of active compound or agent in a body tissue, system, animal or human of a researcher, veterinary surgeon, physician or other clinician. The terms "healing" or "treating" of a disease, when used herein, include: Pre-87282 -28- 200416032 Prevention of disease, that is, mammals that have been exposed or susceptible to disease but have not experienced or exhibited symptoms of the disease will not The clinical symptoms of the disease; inhibiting the disease means capturing or reducing the development of the disease or its clinical symptoms; or alleviating the disease, which is causing the deterioration of the disease or its clinical symptoms. This article uses 纟 f negative resorption, the term, for each process of osteoclast degradation of bone. θ: The invention also covers quotients that can be used to treat osteoporosis or other skeletal disorders, and also includes administering a therapeutically effective amount of a compound of the invention, with or without a pharmaceutically acceptable carrier or diluent ^ Suitable compositions of the present invention include aqueous solutions, including the compounds of the present invention and a pharmaceutically acceptable carrier such as a saline solution, in the range of cations such as 7.4. This solution can be introduced into the patient's bloodstream by injecting Shao Zhiju pills. When a compound according to the present invention is administered to a human subject, its daily dose is usually determined by the prescribing physician 'and its dose is usually based on the age, weight and response of the individual patient, and the severity of the patient's symptoms There are different. In one exemplary application, an appropriate amount of a compound is administered to a mammal undergoing cathepsin-dependent treatment. When used for the effects shown, the oral dose of the present invention ranges from about 0.001 mg / kg / day to about 100 mg / kg / day per kilogram of body weight at about 0.01 mg / kg / day. Kg / day to 10 mg / kg / day is preferred, and (U mg / kg / day to 50 mg / kg / day is most preferred. For continued administration, 'the composition is preferably provided in the form of a tablet. Contains o.omo.muinoqomo, 25.0, 50.0, the dosage of the patient. ⑽ and · milligrams of active ingredient, and adjusted according to symptoms. Administration of drugs typically contains from about 0.01 mg to about 500 mg of active 87282 -29- 200416032 'It is preferred to contain from about 1 mg to about 2 mg of the active ingredient. For intravenous administration' the optimal dosage range for perfusion at a verified rate is from ^ to about 10 gram / kg / minute. Advantageously, The compounds of the invention can be administered in a single-daily dose 'or the total daily dose can be divided into two, three, or four administrations per day. Furthermore,' the preferred compounds of the invention can be administered in an intranasal form via a suitable topical carrier ' For topical application; or use a transdermal patch known to the artist Transdermal route of administration. When transdermal delivery mode is to be used, the dosage in the dose therapy is of course continuous rather than intermittent. The compound of the present invention can be used in combination with other drugs used to treat cathepsin-mediated diseases. Individual components of such combinations may be administered separately at different times during the course of treatment, or in separate or single combined forms at the same time. It is understood, therefore, that the present invention encompasses all such simultaneous or alternating treatment therapies; and the terms of administration are also It should be interpreted accordingly. It should be understood that the scope of the combination of the compound of the present invention and other drugs for treating cathepsin-mediated diseases includes, in principle, any pharmaceutical composition for treating diseases related to the performance of estrogen function. Therefore, the scope of the present invention covers the compounds of this patent application, combined with the use of a second agent selected from the group consisting of organic bisphosphonates, estrogen receptor modulators, androgen dimer regulators, osteoclast proton ATp Enzyme inhibitors, HMG-CoA reductase inhibitors, integrin receptor antagonists, such as pTHi osteoblast assimilation agents, And their pharmaceutically acceptable salts and mixtures. These and other aspects of the present invention are clear from the teachings contained herein. Definitions 87282 -30- 200416032 The compounds of the present invention may have asymmetric centers, are palm-like Axis and palmar planes (eg EL Eliel and S. H. Wilen, Stereochemistry of

Carbon Compounds, John Wiley &amp; Sons, New York, 1994, pages 1119-1190)), and racemates, racemic mixtures and individual stereoisomers, plus all possible isomers and mixtures Including optical isomers are also included in the present invention. In addition, the compounds disclosed herein may exist tautomers, and both tautomeric forms are covered by the scope of the present invention, even though only one tautomeric structure is drawn. For example, the scope of any of the following patent applications for Compound A should be understood to include tautomer structure B, and vice versa, and mixtures thereof.

When any variant (such as Rl, R2, Ra, etc.) occurs more than once in any composition, its definition of each occurrence and each occurrence are independent. Moreover, the combination of substituents and variants is only possible if such combination results in a stable compound. The line drawn by the substituent into the ring system shows that the bond shown may be attached to any substitutable ring carbon atom. If the ring is polycyclic, it only wants the bond to be attached to any appropriate near-ring carbon atom. It should be understood that the substituents and substitution types of the compounds of the present invention can be selected by those skilled in the art to provide chemically stable compounds; and, it is convenient to use the techniques well-known in the art and the methods mentioned by them to be easily obtained Synthesis of starting materials. If the substitution base is replaced by more than one base, it should be 87282 -31 · 200416032. As long as a stable structure can be generated, these plural bases can be on the same or different carbons. The term "replaced by-or more substituents" should be equivalent to the term "replaced by at least one substituent, as the case may be," and in this case, the preferred embodiment will have 0 to 3 substituents. When used As used herein, the term "alkyl", unless specifically stated otherwise, is intended to include branched and linear saturated aliphatic hydrocarbon groups having κ10 carbon atoms. For example, in "Cl_ClQ alkyl," is defined as _ 4 6, 7, 8, 9, or 10 linear or branched cyclic carbon atoms. For example, "" Cl_ca group "includes methyl groups , Ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. Alkyl, or "alkyloxy", unless otherwise specified, is defined as alkyl, Among them, the fluorene group is attached via an oxygen bridge.疋 stands for "cycloalkyl" or "carbocycle," unless specifically speaking about the production of 3 to 8 carbons ^ P 疋 思 扣 总 奴 原 丁丁 _ 疋 衣 or any number within its range (also (Cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). # 佳 I, ', ^ Non-aromatic hydrocarbons with a carbon-carbon double bond are preferred. Carbon-carbon double bonds, and carbon-carbon double bonds. Therefore, "cm stands for 4 non-allenyl narrow alkenyl groups. The fluorenyl group includes 6-year-old native soil, which refers to the above-mentioned relative groups having 2 to 6 carbon atoms: relative groups: allyl, butyryl, and cyclohexyl. For example, if a double bond is included, it can be substituted if the straight, branched, or cyclic moiety can be wrapped with a "浐 / 頟 unsubstituted fluorenyl group." X 土 之 用 # Unless otherwise specified, a carbon-carbon double bond It contains at least 87,82% of humans (5F, i.e., propionyl, cyclobutan-32-200416032, fluorenyl, cyclopentanyl, cyclohexenyl, cycloheptyl, or cyclooctyl). ). The term "block group" refers to a straight or branched hydrocarbon group containing from 2 to 10 atoms and having at least one carbon-carbon triple bond unless otherwise specified. There can be up to 3 carbon-carbon triple bonds. Therefore, "CyC: 6 alkynyl" means a block group having 2 to 6 stone antiatoms. Block groups include ethyl block, propyl block, and butyl block. As mentioned above, relative to the alkyl group, the alkynyl group A linear, branched or cyclic moiety may contain a triple bond 'and may be substituted if a substituted block is shown. In certain examples, a substituent may be defined as a carbon atom range including 0, such as (Co-C6 ) Alkyl-aryl. If aryl is phenyl, this definition includes the phenyl itself and -C ^ Ph, -CHAHaPh, CH (CH3) CH2CH (CH3) Ph, etc. 时 As used herein, ^ The radical is intended to mean any stable single or bicyclic ring with up to 12 carbons in an individual ring, at least one of which is aromatic. Examples of this powerful element include phenyl, fluorenyl, and tetralin Group, hydroindenyl, monophenyl, phenanthryl, anthryl or dihydrofluorenyl. In the case where the aryl substituent is a bicyclic ring and one ring is a non-aromatic ring, it is understood that the attachment system is via an aromatic ring. When used in As used herein, "heteroaryl" refers to a single, bicyclic, or tricyclic ring with up to 10 carbons in an individual ring; at least one ring is aromatic. The fragrant group also contains from 1 to 4 heteroatoms which can only be selected by 0, 1 ^ and 8. Heteroaryl groups within this definition include, but are not limited to, benzimidazolyl, benzofuranyl, benzofuryl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzo W-based, W-based, base-based, fluorenyl-based, squeaked 1 ”injective linyl? 丨 wood-based 4 indolazinyl, 4 thiol, isobenzofuranyl, iso-indole Base, isoquinolinyl, isothiazolyl, isoxazolyl, fluorene 87282 -33- 200416032 pyridyl, oxadiazolyl, oxazolyl, oxazoline, isoxazolinyl, piperanyl, pyridine Cultyl, pyrazolyl, daphyl, pyridopyridyl, pyridyl, pyrimidinyl, pyrrolyl, P-chazolinyl, Junlinyl, Junlinyl, tetrazolyl, tetrazole Yodo, p-dioxalyl, p-thiophenyl, p-thiophene, trisyl, dihydrobenzimidyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, dihydrobenzo Oxazolyl, dihydroxolinyl, dihydroquinolinium, methylenedioxybenzene, benzopyrazolyl, benzopyrimyl, quinolinyl, isoquinolinyl, oxazolyl With tetrahydrophospholine. The heteroaryl substituent is bicyclic and When a ring is non-aromatic or does not contain heteroatoms, it should be understood that its attachment system is through an aromatic ring or a ring containing a heteroatom. If the heteroaryl group contains a nitrogen atom, it should know its corresponding ice oxide It is also covered by this definition. As a person familiar with this art understands, when used herein, "halo, or" _ is intended to include chloro, fluoro, bromo, and iodo. "Keto, The term means f base (00). As used herein, the term "alkoxy" means the alkyl portion of an alkyl group as defined above, which is connected to the remainder of the molecule via an oxygen atom. Examples of alkoxy include methoxy, Ethoxy and its analogs. M. The term alkyl, unless specifically stated otherwise, means that it is substituted by the above-mentioned five elements, with one to three preferred radicals. Representative examples include , But not limited to three elephant methyl, dichloroethyl, and the like. The term "Hito_Methoxy" represents that R is as defined above, and it is substituted by 1 to 3 The preferred alkyl group is -0. Representative examples include, but are not limited to, trifluoromethoxy, dichloroethoxy, and the like. The term mewanyl includes an alkyl moiety whose alkyl group is as defined above, 87282 • 34-200416032 and includes an aryl moiety whose aryl group is as defined above. Examples of aralkyl include, but are not limited to, benzyl, fluorobenzyl, chlorobenzyl, phenethyl, phenylpropyl, fluorophenethyl, and chlorophenethyl. Examples of alkaryl include, but are not limited to, tolyl, ethylphenyl, and propylphenyl. As used herein, the term "heteroaralkyl," will be directed to a system that includes a heteroaryl moiety as defined above, and includes an alkyl moiety. Examples of heteroaralkyl include, but not Limited to pyrimidinylmethyl, pyrimidinylethyl, pyrimidinyl, pyridylmethyl, pyridylethyl, and imidazolylmethyl. '' Cycloalkyl, the term includes alkyl groups whose alkyl group is as defined above Part also includes a cycloalkyl moiety whose cycloalkyl group is as defined above. Examples of cycloalkylalkyl include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, and the like Analogs. The term "glycyl" means substituted by 丨 or 2 hydroxy groups, to 6 carbon atoms &lt; straight monovalent hydrocarbon group or branched chain monovalent hydrocarbon group of 3 to 6 carbon atoms; the limitation is that if the two Each hydroxyl group exists, and they are not all located on the same carbon atom. Representative examples include, but are not limited to, methyl, ethyl, propyl, 3-¾propyl, and the like. As used herein, the term "heterocyclic," or "heterocyclyl," unless specifically stated otherwise, is intended to include the inclusion of from 1 to 4 which can only consist of 0, N, s, SO or S02. Selected 5- to 10-ring non-aromatic rings include bicyclic groups. Thus, "heterocyclyl" includes, but is not limited to, the following: hexahydroxyl, hexahydrofluorenyl, halonyl, morpholinyl, thiomorpholinyl, tetrahydrocarbyl, dioxyl Hydropyridyl, tetrahydrothiophenyl, and the like. When a heterocycle contains nitrogen :: Knowing its corresponding N-oxide is also covered by this definition. 87282 -35- 200416032 The present invention also includes N-oxide derivatives and protected derivatives of compounds of formula I. For example, when a compound of formula I contains an oxidizable nitrogen atom, the nitrogen atom can be converted into an N-oxide by methods well known in the art. Furthermore, when the compound of the formula I contains, for example, a hydroxyl group, a carboxyl group, a thiol or any group containing a nitrogen atom, these groups may be protected by a suitable protecting group. A complete listing of suitable protecting groups can be found in TW Greene, Protective Groups in Organic Synthesis, John Wiley &amp; Sons, Inc. 1981, the full disclosure of which is incorporated herein by reference. Protected derivatives of the compound of formula I can be prepared in a manner well known in the art. When the term "alkyl" or "aryl" or the prefix of either appears in the name of a substituent (eg, aryl CG.8 alkyl), it should be construed to include those given above "Alkyl" and "aryl". The specified number of carbon atoms (for example, Cwo) will be independent of the number of carbon atoms in the alkyl or cycloalkyl portion, or the alkyl portion where the alkyl group becomes the larger substituent at the beginning. The pharmaceutically acceptable salts of the compounds of the present invention include non-toxic salts of the compounds of the present invention which are conventionally formed with inorganic or organic acids. For example, commonly used non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like; and those made with organic acids such as acetic acid, Propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, dihydroxylic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, Benzyl acid, salicylic acid, sulfanilic acid, 2-acetoxyoxy-benzic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid, and Its analog. 87282 -36- 200416032 The above mentioned pharmaceutically acceptable salts and other typical pharmaceutically acceptable salts were prepared by Berg et al. "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19 for a more complete explanation, which is incorporated herein by reference. The pharmaceutically acceptable salts of the compounds of the present invention can be synthesized from the compounds of the present invention containing a basic or acidic moiety by conventional chemical methods. Generally, the salts of basic compounds are prepared by ion exchange chromatography or by free base and inorganic or organic acids quantified or in excess to form the desired salt in different combinations of suitable solvents or solvents. Similarly, salts of acid compounds are formed by reaction with appropriate inorganic or organic bases. For the purposes of this patent specification, the following abbreviations have the meaning indicated:

AcOH = acetic acid bf3 = boron trifluoride Boc — second-butoxyzoyl group Boc20 = di-di-di-butanyl dicarbonate BuLi dibutyllithium CC14 tetra-methylene chloride CH2C12 = dichloromethane ch3cn = ethoxylate Paste CHC13 Dichloroform Cs2C03 = Cs retarded acid Cul = Broken cuprous DAST = Diethylaminosulfide digas DIPEA = Diisopropylethylamine DMA = N, N-dimethylethylamine 87282 -37- 200416032

DMAP DMF DMSO DPPA EDCI

Et20

Et3N EtOAc EtOH HATU HOAc k2co3 KHMDS KOBu 'LDA LiOH mCPBA MeOH MeS03H MgS04 Ms 4-(dimethylamino) p-specific N, N-dimethylformamidine dimethylformamidine diphenylphosphine azide Compound 1- (3-dimethylaminopropyl) -3 -ethylcarbonyldiimine hydrochloride ether triethylamine ethyl acetate ethanol 0- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylphosphonium hexafluorophosphate acetate potassium carbonate hexamethyldisilazane potassium third-potassium butoxide diisopropylammonium lithium lithium hydroxide partial chloride Acid-saving methanol methyl succinate acid magnesium sulphate methyl succinate methyl ester = mesyl 87282 -38- 200416032

MsCl NaBH4 NaH Nal NaCNBH3 Na2C03 NaHC03 NaOH Na2S04 NBS NH3 NH4C1 Pd / C PdCl2 PdCl2 (dppf) Pd2 (dba) 3 PG PPh3 (PhO) 3PMeI PPTS iPr2Nli PyBOP Sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium sulfate, N-bromosuccinimide, ammonia, ammonium gasification, saturated palladium (II) dichloride [1,1'_bis (diphenylphosphine) ferrocene] Palladium (II) dichloride (dibenzylideneacetone) dipalladium (II) protecting group triphenylphosphine methyltriphenoxy scale iodide pyridinium p-methanesulfonate diisopropyl acid amination 4 Pyrene benzotrityl-1 -yloxy ginseng (late p-dose) hexafluorophosphate 87282 39- 200416032 Π-room temperature sate aqe = saturated aqueous solution TFA = difluoroacetic acid THF = tetrahydrofuran TiCl4 tic = Titanium (IV) chloride --- Thin layer chromatography TMSC1 = Rat trimethyl hard burn Me Methyl Et ethyl n-Pr = n-propyl i-Pr isopropyl n_Bu = n-butyl i_Bu iso Butyl s'Bu second butyl t'Bu third butyl The novel compounds of the present invention can be prepared according to the following general methods. Made of suitable material, and further based by the following specific examples illustrated. However, the compounds described in the examples should not be construed as forming the only class recognized as the present invention. The following examples further illustrate the details of the preparation of the compounds of the invention. Those skilled in the art will readily understand that the following changes in known conditions and methods can be used to prepare more compounds. Unless otherwise stated, all, w degrees are in Celsius. [Embodiment] Scheme -40- 87282 200416032 The compound of the present invention can be prepared according to the scheme of the following formula. Therefore, the α-amino ester can be added to the i-alkyl ketone to form an amine aldehyde, which can then be dehydrated to an imine in the presence of a dehydrating agent such as TiCi4, MgS04, or isopropyl trifluoroacetate. Reduction of an imine with a reducing agent such as sodium cyanoboronate gas or a native hydrogenated steel can provide an amine. Ester hydrolysis and hydrazine formation using a suitably substituted aminoacetonitrile can provide compounds of the present invention. If the substituent on the D system is a halogen, palladium-catalyzed Suzuki coupling with a suitable boric acid can provide another compound of the present invention. Scheme 1 halogen

1) iPr2EtN, TiCI4, 〇 \ ch2ci2 halo 2) MeOH, NaCNBH3

U〇H, H2〇,

MeOH

Na2C〇3 aqueous solution, DMF, PdCI2 (dppf), Δ

87282 -41-200416032 The compound of the invention can also be made according to Scheme 2 of the following formula. A ketone or acid can be condensed with an amino alcohol to form a cyclic amine aldehyde. Treatment with 3 equivalents of Greiner's reagent or organic clock reagent provides the appropriate alkylated amine alcohol. Oxidation of the alcohol in a chromium system such as 0 plus 3 oxidation or HsIOVCrO3 or an alternative by two-step oxidative oxidation (for example, chlorchloride / DMSO / EtsN, followed by NaC10) can provide equivalent carboxylic acids. Performing the peptide coupling with Suzuki as shown in Figure 1 provides the compound of the present invention. Scheme 2 R5 R6 Y 〇 r4 R3 ^ Y oh Dean-Stark

RwR3 HN ^ \ halo-P) n-MgBr 丨 -L>-R5 oxidation r5r6r4 r3

r5 rV R3 _S \ (d ^ nX ^ 〇h Wn h

PyBOP, DMF,

Et3N R5 R6 r4 r3 h N R7—B (OH) 2 halo γ Na2C03 aqueous solution, DMF, V / n H five R2'R1 PdCI2 (dppf), Δ

87282 -42-200416032 The compound of the present invention can also be prepared by Scheme 3 which is condensed with an amino alcohol to form amidine. Ketones or aldehydes or organolithium reagents can be treated. The Grignard test uses the square and hearty alkylated amine alcohols described in Scheme 2. This alcohol can be converted into a compound of the invention. Schema

R4 〇3 η2νχ ^ οη 〇

MgS04

R5 R6 R4 R3 r7- {

D

, N H

〇

Schema 2 R5R6R4 R3

,: Invention "Compounds can also be made according to Scheme 4 below. Hemiacetals can be condensed with alcohols that have been appropriately protected. Treating the resulting imine with a Grignard reagent or an organolithium reagent provides a suitable alkylated amine alcohol. Then, the alcohol protecting group can be removed, and in the manner shown in Figure 2, or by first performing a Suzuki reaction, and then oxidizing the alcohol with HsKVCrO3, and then coupling the peptide to the compound of the invention. 87282 -43-200416032 Scheme 4 h2n rx ^ 〇pg .OH 〇Me U, nX ^ 〇pg

1) Halo- (D) n-Li 2) Remove PG

Scheme 2 R6 R4 R3 halo

R6 R4 R3

H5106 / Cr03 R7-B (〇H) 2 Na2CO3 aqueous solution, DMF, PdCI2 (dppf), Δ

The compound of the present invention can also be prepared according to Scheme 5 of the following formula. As shown in Figure 丨, 2 or 4, the α-amino acid and ^:-aminoamidine undergo peptide coupling, followed by dehydration of the primary amidine (V () egel].) α-H pure (1996, 79, 1863) can provide the compound of the present invention. 87282 -44- 200416032 Scheme 5

TFAA, p ratio

-R7—b (oh) 2 halo &amp; 2 (: 03 aqueous solution, DMF, PdCI2 (dppf), Δ

The synthesis of certain amino alcohols used at the beginning of schemes 2, 3 and 4 is illustrated in schemes 6-8. For example, the synthesis of R = Mei (2S) _2_amino_4_fluoro_4_methylpentan-1-ol is illustrated in Scheme 6 below. Starting from an appropriately di-protected aspartic acid, the carboxyl group can be reduced to an alcohol using standard literature methods (for example, mixed hydrazone formation followed by NaBH4 reduction). Then, the appropriate version of Grignard or organolithium can be reacted to produce a protected 2-amino-4_methylpentane_1,4-diol (R = Me). Finally, a fluorinated clam such as DAST can be used to convert the hydroxyl moiety to the desired fluoride. The protected or unprotected version of this amino alcohol can then be converted to the compound of the invention according to the scheme, 2, 3, and 4. 87282 -45- 〇

PG reduction scheme 6 〇

'PG 〇

PG ethanol Ό PG, 2 'OH protect PG,

, N H

〇PG RMgBr to protect_

PG.

〇PG

R F

DAST 4,5_dehydroleucine such as 4-air leucohydrin can be synthesized according to Scheme 7 J Scheme 7F is converted into (4S) -4- (2-methylpropan-2-enyl) -1,3-humazolidinone. The intermediate product is then treated with a hydrofluorinating reagent such as HF-pyridine to form (4S) -4- (2-fluoro-2-methylpropyl) -1,3_Yodo-2-one . The hydrolysis (i.e., Ba (OH) 2 or NaOH) then provides (2S) -2-amino-4-fluoro-4-methylpentane-1-ol. Scheme 7 87282

-46- 1. Cbz-Cl, Test 2. Esterification 3. Reduction 4. Base

Hydrofluorination

200416032 The amine alcohol used in the present invention can also be synthesized according to Scheme 8. The protected amine hydrazone is reduced with a reducing agent such as NaBH4, with or without additives such as Licl, such as EtOH or a mixed solvent system such as EtOH and THF. Then, according to the characteristics of the protecting group, the amine protecting group is removed by an appropriate method. Scheme 8

Reduction of R4 R3 Ί〇η Η Deprotection R4 R3 ^^ η2N> 〇η The following examples illustrate the synthesis of the compounds selected by the present invention.

Amine (3 ~ trigas acetophenone (.75 ml, 5.34 mmol) and triisopropylethyl liter, Hopper, Shanghai, 5 37 * Pen ear) was added with L_leucine methyl ester Hydrochloride (975 mg 87282

TiCl ^ mol) in a solution of methyl chloride (30 ml). Gross liters, 5.0¾ mol) of 0.45 ml of dichloromethane were added dropwise, and the mixed -47-200416032 was stirred overnight. Then additional TiCl4 (0.4 ml, 3β6 mmol) was added and the mixture was allowed to stir for 3 hours. A solution of NaCNBH3 (1050 mg, 16 7 mol) in MeOH (20 ml) was added and the mixture was allowed to stir for 2 hours. Pour i-equivalent NaOH and extract with ethyl acetate (2X). The organic phase was washed with i-equivalent NaOH and saline solution, then dehydrated with MgS04 and evaporated. Purified by ISCO column chromatography (30% -90% ethyl acetate / hexanes gradient) to provide methyl N- (2,2,2-trifluoro-1-phenylethyl) -L-leucine salt. One equivalent of LiOH was added to a 2: 1 THF / MeOH solution of methyl N- (2,2,2-trifluoro-phenethylleukin) (150 mg, 0.50 mmol) in room temperature. The mixture was allowed to stir overnight and concentrated. The residue was distinguished between ethyl acetate and phosphate buffered saline pH 3 · 5. The organic phase was washed with saline, dehydrated with MgSCU and concentrated to form N- (2,2 , 2-trifluorophenylethyl) _L_leucine. N- (2,2,2-trifluoro-1-phenylethyl) _L_leucine (149 mg, 0.50 mmol) Ear), acetonitrile hydrochloride (102 mg, 1.1 mmol) and PyBOP (26 mg, 0.50 mmol) were dissolved in DMF (5 ml). Triethylamine (0.3 ml, 2_1) was added Millimoles) and the mixture was stirred overnight, then poured into a phosphate buffered saline at pH 3 and extracted with 3: 1 ether / ethyl acetate. The organic phase was washed with saturated NaHC03 and saline, and MgS04 was dehydrated and evaporated. Purified by isco column chromatography (20% -50% ethyl acetate / hexane gradient) to provide # &lt; cyanomethyl) -N2- (2,2,2-trifluoro- 1-phenethyl) _L-leucine amine is a 1: 1 stereoisomer mixture. MS (+ APCI): 313.9 [M + 1]. Example 2 N-(oxymethyl) -N2- [2 · 2 · 2_trifluoro-W4'-hexa, mouth ratio _-!-Some- ΐ, ι, _ di 87282 -48- 200416032 phenyl di 4-yl) Ethyl 1-L-leucine

2 mol sodium carbonate aqueous solution (0.9 ml, 18 mmol) was added to bromophenyl under nitrogen) 2,2,2-trifluoroethyl] hepta-1_ (cyanomethyl) fluorene_leucine Si &amp; amine (242¾ g, 0.60¾ mole) and 4- [4- (third-butoxyfluorenyl) · hexahydropyridyl] phenylboronic acid (220 mg, 0.72 mmol) iDME (3 ml ) To the solution, the catalyst PdCl2 (dppf) (63 mg, 0.077 mmol) was added. The reaction was heated to 85X: over 18 hours. Water was added and the product was extracted with EtOAc. The organic layer was dried over NajO4 and concentrated in vacuo. The crude product was purified by hexane chromatography using E t Ο A c to provide the third-butyl (4 '-{1-[((18) -1-{[(cyanomethyl) amino] carbonyl) [3-Methylbutyl) amino] -2,2,2-trifluoroethyl} -1,1, -diphenyl-4-yl) hexahydropyridylcarboxylate. MeS〇3H (125 microliters, 1.9 mmol) was added dropwise to the third-butyl (4,-{1-[((18) -1-{[(cyanide (Methyl) amino] carbonyl} -3 -methylbutyl) amino] _2,2,2-trifluoroethyl 1,1, -diphenyl-4-yl) -1-hexahydropyridyl A solution of carboxylic acid ester (275 mg, 0.47 mmol) in anhydrous THF (1 ml) and the reaction was allowed to continue for 18 hours. The reaction mixture was separated between EtOAc and water + saturated NaHC03 to adjust the pH to 7.5. The organic phase was dehydrated over Na 2 SO 4 and concentrated in vacuo. The crude product was purified by chromatographic separation of 87282 -49- 200416032 using silica gel with NH4OH / MeOH / CH2Cl2 (l / 10/89) to provide N1 ^ cyanomethyl) -N2_ [2,2,2-three A light yellow foam of fluoro-l- (4, _hexahydropyrine-1-yl-1,1'-diphenyl-4_yl) ethyl] -L_leucine and amine. MS (+ ESI): 488.3 [M + 1], Example 3 Cyanomethyl VN2-("4 '-(A certain green Bi some dimo some -4- some 1" 4 彳 _ sulfo sulfonyl) Of 1-methyl-1-L-leukoamine

I o = s = o

A}-L-leucine acid decree (4-bromophenyl) [4- (methylsulfonyl) phenyl] methanone (202 mg, 0.59 mmol), methyl L-leucine A toluene solution of the hydrochloride (3 28 mg, 2.0 mmol) and camphorsulfonic acid (52 mg, 0.22 mmol) was heated under reflux in a Dean-Stark elbow for 18 hours. The solvent was removed in vacuo and the resulting residue was purified by chromatography using EtOAc and hexane as eluents to give the title compound as a 1: 1 mixture with the starting (4-bromophenyl) [4- (methyl Sulfo) phenyl] methanone. Steps ·· _methyl_yl N-K4-bromosulfonium) "4- (methylsulfonyl, fluorenyl) &quot; [甲某 丨 -L- glutamate makes methyl N- {from step 1 (4-bromophenyl) [4- (methylsulfonyl) phenyl] 87282 -50- 200416032 methylene} leucine and (4-bromophenyl) [4_ (methylsulfonyl) Phenyl] methanone in a 1: 1 mixture (185 mg, ~ 0.2 mmol) in acetic acid / methanol (1: 3, 4 ml) solution, added via a solid addition funnel, and added in batches every 30 minutes For 2 days (addition stopped at night) sodium borohydride was added. The reaction mixture was separated between EtOAc and water, the organic layer was dehydrated with Na2SO4 and concentrated. The resulting mixture was lysed with Et0Ac and hexane. Chromatographic purification. The methyl N-{(4-bromophenyl) [4- (methylsulfonyl) phenyl] methylbuthyl L-leukobismuthate and white solid ( 4-bromophenyl) [4- (methylsulfonyl) phenyl] methanol. Phenyl H4- (Methosulfamyl Ammonium), 1 Methylamino acid, 1 equivalent concentration LiOH (0.3 ml, 0.3 mmol Ear) Add methyl N-{(4-bromophenyl) [4- (methylsulfonyl) phenyl] formyl from step 2 } _L-leucine (81 mg, 0.17 mmol) in THF (1 ml) and MeOH (05 ml). The resulting mixture was stirred at room temperature for 18 hours, then SEt 〇Ac was distinguished from water + 1 mile; Chendu HC1 (0.5 liter). The organic layer was dehydrated with Na2s〇4, filtered, and concentrated in vacuo to give the title compound as a colorless gum.

Nlr.K4-bromophenylamidine) "4- (formamidine a certain || formamidine_methyl) -L-leucine ai neck N, N-diisopropylethylamine (0.3 ml, 0.75 mmol) N-{(4-bromophenyl) ['(methylsulfonyl) phenyl] methyl} -1 ^ white amine cooled from step 3 to -10 ° C was added Acid (76 mg, 0.17 mmol), HATU (146 mg, 0.38 mmol), amine acetonitrile hydrochloride (52 mg, 0.56 mmol) in DMF (1.1 halo). Make the reaction It was carried out at room temperature for 18 hours, and distinguished between acetic acid and water 87282-51-200416032. The organic layer was dehydrated with Na2s04, filtered, and concentrated in vacuo. The crude product was subjected to EtOAc and hexane as eluent. Chromatographic purification to produce the title compound as a colorless gum. Step i: Over! ΤίΑ 甲某 VN2- {| ~ 4-r 甲某 碏 醯 某) Momou 1 "4, Dou Jia I ΜΑ · Μ, Γ_ 二茇 A-4-A, 1A, and 1 L-leucine Amine will be N2-{(4-bromophenyl) [4- (methylsulfonyl) phenyl] methyl 1- (Cyanomethyl) _L-leukoamine (72 mg, 015 mmol), 4- (methylthio) phenylboronic acid (37 mg, 0.22 mmol) Ear) of a heterogeneous mixture of ethylene glycol dimethyl ether (1 ml) and a 2 mol sodium carbonate aqueous solution was degassed in vacuum and purged with nitrogen. [1,1, _bis (diphenylphosphine) di Ferrocene] palladium (II) dichloride dichloromethane complex (19 mg, 0023 mmol) was added to this mixture, followed by degassing 'and purging with nitrogen. The reaction was heated at 85 for 16 hours and was effective Stir. Separate the reaction mixture between Et0Ac and NH4OAc 25% w / v aqueous solution. Let the organic layer dehydrate with Na2S04, filter, and concentrate in vacuo. Purify the crude product by chromatography using EtOAc and hexane as eluents to produce The title compound of the color-supplying gel. Müller 6 ·· Cyme, M, M, M, M, and M VI.,-Dimom, M-4-, 1-4- (M, M, M, S, M), 1, M, ___ Leucinamine Add 30% w / v aqueous hydrogen peroxide solution (100 μl, 0.9 mmol) to N1- (cyanomethyl) -N2-{[4- (methylsulfonyl ) Phenyl] [4,-(methylthio) -1, Γ-diphenyl-4-yl] methyl} -L-leukoamidamine (63 mg, 0.12 mmol), sodium tungstate Dihydrate (2 mg, 〇_〇 〇6mmol), tetrabutylammonium hydrogen sulfate (4¾g, 0.01 mmol), and the resulting mixture was stirred at direct temperature for 10 minutes. Make the reaction mixture in EtOAc and water + 1 equiv. 87282 -52- 200416032

NaHS〇3 (~ 3: 1). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography using EtOAc and hexane as eluents to give the title compound as a colorless gum. MS (+ ESI): 568.2 [M + 1], Example 4 &gt; ^ 二 (1 „甲. 基„ 1- 丑 2 一-. ((13) -2,2,2-trifluoro ^^ 1_ 「 Synthesis of 4,4 methyl hydrazone, _ dibenzyl-4-yl 1 ethyl phenyl L_leucoamine

Step 1 ··· (2S) -l-{"The preparation of the third butyl (dimethyl form) stone oxane 1 璧 4_methyl 莘 Cheng Yue -2- amine Preparation of triethylamine (11 Φ liter ), Dmap (oi grams) and tertiary butyl dimethylsilyl chloride (8.5 grams) add dichloromethane (100 ml) at room temperature with L-leucohol (6.0 grams) The solution. The mixture was allowed to stir at room temperature for 2 hours, and then water was added. The organic layer was separated and the aqueous layer was further extracted with a rodent. The combined organic layers were washed with saline, dehydrated with magnesium sulfate, and the solvent was removed in vacuo. To generate the title compound for use in the residual stream for the next reaction.! H NMR (CD3COCD3) δ 3.48 (m, 2Η), 3.32 (m, 1Η), 2.76 (m, 1H), 1.78 (m, 1H) 1.22-1 · 〇2 (ιη, 2H), 0.88 (m, 15H), 0.06 (s, 6H) 08872 -53- 200416032 step m · (.2 $)-1- {[弟 X ^ _L 二甲 篡 、 石》 Check a 1 氲 一 卜 4_ 甲 t -N-[(iE) m .- ^ j ^ ethyl 1 戍 Yu's preparation order comes from step 1 ( 2S) -1 _ {[Third-butyl (dimethyl) silyl] oxy} -4-methylpentane-2-amine (50 g) and trifluoroacetaldehyde methyl hemiacetal (3 5 Ml) of toluene (300 milliliters L) The solution was heated under reflux for 16 hours, at which time water was collected in a Dean-Stark elbow. The solvent was evaporated in vacuo and the residue was purified by SiO2 using hexane and ethyl acetate (9: 1) as eluent. To produce the title compound: lH NMR (CD3COCD3) δ 7.88 (m, 1H)? 3.76-3.45 (m? 3H)? 1.60-1.25 (m, 3H), 0.88 (m, 15H), 0.06 (s, 3H), 0.04 (s, 3H). Step 3: (2SJ-2- {f (lS) _l_ (4-bromobenzene) -2 · 2.2 · 2-trifluoroethane}} 4-methyl-1 —Alcohol preparation and n-BuLi (2.5 moles; Chendu's own pit '42 ¾ liters) was added to a solution of 1,4-monoalized (25.8 g) in THF (400 ml) at -70 ° C, and The mixture was stirred for 25 minutes. Then (2S) -l-{[third-butyl (dimethyl) silyl] oxyb 4-methyl-N-[(1Ε) -2,2, A solution of 2-trifluoroethylene] pentane-2-amine (31 g) in THF (30 ml), and the mixture was stirred for 5 hours. Then it was slowly poured into ethyl acetate (500 ml), water (2 liters), ice (300 g) and a mixture of ammonium chloride (100 g), and stirred vigorously. The organic layer was separated, and ethyl acetate (2 X 500 L) aqueous layer was further extracted. The organic layers were combined to make a salt solution, dried over magnesium sulfate, and the solvent was removed in vacuo and check to generate directly the residual). The residue was dissolved in THF (250 ml) and the solution was cooled to 0 ° C. A 1 mol solution of tertiary-butylammonium fluoride in THF (110 ml) was added dropwise, and the mixture was allowed to react for 4 hours. Pour it into ethyl acetate 87282-54-200416032 (300 ml), water (2 liters) and ammonium chloride (100 g) and stir vigorously. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate (2 × 100 ml). The combined organic layers were washed with a saline solution, dehydrated with magnesium sulfate, and the solvent was removed under vacuum to generate a residue. The residue was subjected to a dissolution solution using ethyl acetate and a hexane calcination gradient (i: 5 to 1: 4). SiO2 was purified to give the title compound. NMR (CD3COCD3) δ 7.6 (2H, d) 5 7.45 (2H? D) 9 4.55 (1H? M) 9 3.65-3 „7 (lH, m), 3e5-3.55 (lH, m), 3.25-3.35 ( lH, m), 2.6-2 · 7 (1Η, m), 2.25-2 · 35 (1Η, m), 1.65-1 · 75 (1Η, m), 1.3-1 · 4 (1Η, m), 1 · 2-1 · 3 (1Η, m), 0 · 75-0 · 9 (6Η, dd). (2S) _4-methyl even-2- (KlSV2,2,2-trichloro _ "4, stilbene is very basic-1,1 '-dibenzyl-4 _yl 1 ethyl} amine group" Cheng Yue -1 _ alcohol pan prepared by passing a nitrogen stream through the bromine from step 3 (27.7 g ), 4- (methylthio) phenylboronic acid (15.7 g), a suspension of 2 mol Na2C03 (100 ml) and n-propanol (500 ml) for 15 minutes. Then a 1: 3 mixture of Pd (〇Ac) 2 and PPh3 was added, and the mixture was heated to 7 (TC, and stirred under nitrogen for 8 hours. The mixture was cooled to room temperature, and ethyl acetate (500 ml) was used. Dilute and pour onto water (2 L) and ice (500 g). Separate the ethyl acetate layer and further extract the aqueous layer with ethyl acetate (200 mL). Allow the combined ethyl acetate extracts to _5 equivalent concentration NaOH (2X 200 ml), Nh4C1 aqueous solution, salt solution, washed and diluted with osmium sulfate. Residue was removed from the solvent, and the residue was subjected to a gradient of ethyl acetate and hexane (1: 4 to 1: 3). ) Is the eluent, and it is purified again by SiO2 chromatography, which is eluent with acetone and toluene U: 10). The residue was dissolved in hot hexane (200 ml) and the solution was allowed to cool to agitation. The resulting solid was filtered and dried to yield 87282-55-200416032 and the title compound. lH NMR (CD3COCD3) δ 7.7 (2H, d)? 7.65 (2H5 d) 5 7.6 (2H? d)? 7e35 (2H5 d), 4.5_4 · 6 (1Η, m), 3.7 (1H (0H), m ), 3_5-3 · 6 (1Η, m), 3.3-3 · 4 (1Η, m), 2.7 (1H, m), 2.5 (3H, s), 2.3 · 2 · 4 (1Η (ΝΗ), m ), 1.65_1,75 (1Η, m), 1.2 · 1.4 (3Η, m), 0.8-0 · 9 (6Η, dd). Step 5: (2S _) _- 4-A Mou-2-anSV2.2.2-Sangai-1--1-4,-(A Mouchi · Menyl) -1,1 Dibenzyl-4-yl 1 B A certain amine, a) oxane-1- 醢 of _ Preparation Na2W04 · 2Η20 (0 · 16 g) and Bh4NHSO4 (0.81 g) were added to 0 ° C toluene (400 g) from the sulfide of step 4 (19 g) Ml) solution. Then, 30% hydrogen peroxide (12.2 ml) was slowly added, and the mixture was stirred at room temperature for 4.5 hours. The mixture was slowly poured into a mixture of ice, dilute aqueous sodium thiosulfate and ethyl acetate. The organic layer was separated, and the aqueous layer was further extracted with ethyl acetate (2 X 100 mL). The combined organic layers were washed with saline solution, dehydrated with magnesium sulfate, and the solvent was removed under vacuum to produce residues. The residues were purified by SiO2 using ethyl ethyl ester and hexane (1: 1) as eluent. To produce products. NMR (CD3COCD3) δ 8.05 (2H5 d) 5 8.0 (2Η, d)? 7.85 (2Η? D)? 7 · 7 (2Η, d), 4 · 6-4 · 7 (1Η, m), 3.75 (1Η, m), 36 (m, m), 3 35_3.45 (1Η, m), 3.2 (3Η, s), 2.7_2 · 8 (1Η, m), 2 35_2 45 °, ⑷, 1 · 7_1 · 8 (1Η, m), 1 · 2_1 · 5 (2η, m), 〇8_〇95 (roaring. Step 6 ·· Preparation of amino acid HsICVCrCM529 ml of 044 mol concentration The ch3cn solution (see note below) is cooled to 0. . And dropwise add the ch3CN solution (230 ml) of the alcohol (20 g) from Step 5 of 87282 * 56-200416032. Allow the mixture to stir at 0-5 ° C for 3.5 hours. It was poured into vigorously stirred Na2HP04 (1.5 liters) at pH 4 and the mixture was extracted with ether (3 x 250 ml). The combined ether extracts were washed with water and saline (1: 1), diluted NaHS03 aqueous solution and saline. The organic extract was dehydrated over Na2S04, filtered, and evaporated to dryness to produce a residue that was divided into two batches for subsequent purification. The crude acid obtained above was dissolved (10 g) in isopropyl acetate (250 ml) and extracted into cold 0.1 equivalent NaOH (3 x 250 ml). The combined extracts were washed with diethyl ether (250 ml) and then slowly acidified to pH 4 with 6 equivalents of HC1. The carboxylic acid was extracted with isopropyl acetate (2 x 250 ml), and the isopropyl acetate layer was dehydrated and concentrated to produce a product of sufficient purity to be used directly in the next step. Precautions ·· Oxidant (H5I06 / Cr03) such as Tetrahedron Letters

39 (1998) 5323-5326, but using HPLC grade CH3CN (containing 0.5% water) without adding water. lU NMR (CD3COCD3) δ 8.05 (2H, d)? 7.95 (2H, d) 5 7.8 (2H? d)? 7.65 (2H, d), 4.45-4 · 55 (1Η, m), 3.55 -3.6 (1Η, m), 3.2 (3H, s), 2.8-3.0 (width m, ΝΗ / ΟΗ) 1.95 · 2 · 05 (1Η, m), 1.55-1 · 6 (2Η , M), 0.9-1.0 (6H, m). ± M1: K1] Cyanomethoxine, 氤, -1 · Γ4,-(methyl hydration § truncated group) _1,1 a radical -4- curtain 1 ethyl 丨 -L-Leucamine donkey amine Benzotriazol-1-yloxy ginseng (dimethylamino) scale-hexafluorophosphate (11. 6 g), aminoacetonitrile hydrochloride (3.94 g) add the acid from step 7 (9 G) of DMF (200 ml) and the mixture was allowed to cool to 0 ° C. Add 87282 -57- 200416032 dropwise and add triethylamine (9.9 ml) and allow the mixture to warm to room temperature and stir for 16 hours. It was poured into ice and saturated aqueous sodium bicarbonate solution and extracted with ether (3 × 100 ml). The combined extracts were washed with a saline solution, dehydrated with magnesium sulfate and the solvent was removed in vacuo. The residue was purified by SiO2 chromatography using ethyl acetate and hexane G: 1) as eluent. Then, the title compound was stirred in diethyl ether for 6 hours, filtered, and dehydrated (melting point 14.0.5.0. 1U NMR (CD3COCD3) δ 8.02 (2H? D)? 7.95 (2H? D)? 7.8 (2H? D ) 5 7 · 65 (2Η, d), 4.35-4 · 45 (1Η, m), 4.1-4 · 2 (2Η, m), 3.45-3 · 55 (1Η, m), 3.15 (3H, s), 2.65-2.7 (lH, m), 1.85-1.95 (lH, m), l.'1.6 (2m, m), 0.85-0 · 95 (6Η, m). Example 5 N 4 ′-(Aminosulfonyl Vl, l, _ Di Pingmou_4_miao_2 · 2 · 2_trit Ethylcyanomethyl VL-leukomamine

Health: Motrifluoro 1-N1- (number of 1-based VL-leukoamidamine) _ let H5ICVcr〇3 (1925 i: 0.44 Molar concentration of CH3CN solution, see shell example 4 Note for step 6) The suspension was cooled to zero, and -58- 87282 200416032 was added dropwise from (28) -2 _ {[(18) -1- (4-bromophenyl)) from step 4 of Example 4. -2,2,2-trifluoroethyl] amino} -4-methylpentane-1-ol (60 g) in a solution of CH3CN (1500 ml). The mixture was stirred at 0-5 ° C for 3 · 5 hours. Pour it into vigorously stirred Na2HP04 (2.5 liters) at pH 4 and extract the mixture with ether (3 x 500 ml). Let the combined ether extracts pass through water and brine (丨: 丨) , Dilute NaHS〇3 aqueous solution and salt solution. The organic extract was dehydrated with Na2S04, filtered and evaporated to dryness, resulting in N-[(lS) -l- (4-bromo Phenyl) -2,2,2-trifluoroethyl] leucine. Benzotriazol-1-yloxyginsine (dimethylamino) squamyl-hexafluorophosphate (71 · 5 g) , Aminoacetonitrile hydrochloride (25.4 g) was added to a solution of crude acid (46 g) in DMF (1500 ml), and the mixture was allowed to To 0 ° C. Triethylamine (60.8 ml) was added dropwise, and the mixture was allowed to warm to room temperature and stirred for 16 hours. Pour it into ice and saturated aqueous sodium bicarbonate solution, and diethyl ether (3 X 3 00 Ml) extraction. The combined extracts were washed with brine, dehydrated with magnesium sulfate and the solvent was removed in vacuo. The residue was passed through Si02 using a gradient of ethyl acetate and hexane (1: 3 to 1: 2) as the eluent. Purified by chromatography to produce the title compound with sufficient purity to be used directly in the next step. {H NMR (CD3COCD3) δ 7.95-8.05 (bs? NH), 7.6 (2H5 d) 5 7.45 (2H, d), 4.4 (lH , M), 4.1-4.2 (2H, m), 3.4-3.5 (lH, m), 2.6-2 · 7 (1Η, m), 1.8 ~ 1.95 (1Η, m), 1.4-1 · 6 (2Η, m), 0 · 85-0 · 95 (6Η, m) o Step 2: A certain VN2-K1SV2,2,2-Sanqi some-1- "4_Μ.4ίΊ Tetramethyl-based-1, 3 · 2-Digas heteroborane. 0) 〇rolanV2-even) Grasshopper] Ethylhydrazone-L-leukoamine. Preparation of 87282 -59-200416032 Pass nitrogen gas through N2 from step 1 [(1S ) -l- (4-bromophenyl) -2,2,2-trifluoroethyl] -N1- (cyanomethyl) leucine (28.5 g), bis (binaclad) diboron (bis (pinacolato) dibor 〇n) (23 g) and potassium acetate (24 g) in DMF (700 ml) suspension for 15 minutes, followed by the addition of [1, 丨, _bis (diphenylphosphine) ferrocene] dichloride Complex (1: 1) of palladium (II) and dichloromethane (2.9 g). The mixture was heated to 65 ° C and stirred under nitrogen for 2.5 hours. Allow the mixture to cool to Huang'an, dilute it with Ji Fei Ji and Ji Ji (1: 1, 300 ml), and pour onto water (2 liters) and ice (500 g). The organic layer was separated, and the aqueous layer was further extracted with ethyl acetate and hexane (1: 1, 3 x 200 mL). The combined extracts were washed with brine and dehydrated over magnesium sulfate. The solvent was removed to leave a residue, and the residue was purified by SiO2 chromatography using ethyl acetate and hexane (1: 2) as eluent to produce a salt. H NMR (CD3COCD3) δ 7.95-8.05 (bs, NΗ), 7.7-7 · 8 (2Η, d), 7.45-7.55 (2H, d), 4.3-4.4 (lH, m), 4.05-4.15 ( 2H, m), 3.4-3 · 5 (1Η, m), 2.55-2 · 65 (1Η, m), 1.85 · 1 · 95 (1Η, m), 1.45_ 1.5 · 2 (2Η , M), 1.15-1 · 4 (12Η, m; some tetramethylethylene glycol also appears as a pollutant), 0.85-0.95 (6H, m). Children's silver 3_ · N-amino base si, diphenyl, trifluoroethyl} -NV carbamate, etc. Preparation of nitrogen flow through borate (4 g), 4-bromobenzenesulfonate from step 2 A suspension of amine (33 g), 2 moles NaKO3 (20 ml) and n-propanol (100 ml) was made for 15 minutes. A 1: 3 mixture of Pd (OAc) 2 and PPh (0.25 g) was then added, and the reaction was heated to 85 ° C and stirred under nitrogen for 3 hours. 87282 -60- 200416032 Allow the mixture to cool to room temperature, dilute with ethyl acetate (100 ml), and pour onto water (500 ml) and ice (100 g). The ethyl acetate layer was separated, and the aqueous layer was further extracted with ethyl acetate (100 ml). The combined ethyl acetate extracts were washed with dilute NaHC03 aqueous solution, brine, and dried over magnesium sulfate. The solvent was removed and the residue was left. The residue was purified by O2 chromatography using a gradient of ethyl acetate, hexane, and dichloromethane (2: 3: 0.1 to 1: 1: 0_1) as the eluent. The product was then stirred in ether for 16 hours, filtered and dried to give the title compound. H NMR (CD3COCD3) δ 8-8 · 1 (3Η, m), 7-9 (2H, d), 7.8 (2H, d) 7 · 65 (2Η, d), 6 · 6-6 · 7 (2Η, m ), 4 · 4 (1Η, m), 4.1-4.2 (2H, m), 3.5 · (1Η, m), 2 · 6-2 · 7 (1Η, m), 1 · 9 (1Η, m) , 1.45_1 · 6 (2Η, m), 1.4-1 · 6 (4Η, m), 0.9-1.0 (6H, m). Example 6

: JXlS) -2,2,3,3,3-Wu Gujian-1 leaf h p containing -4-¾ 芣 莘)

Ethyl VL3- 咩 岫 dissolves pentafluoropropionaldehyde methyl hemiacetal (9 g, 82.8 mmol) and leukosol (9.7 g, 82.8 mmol) in 100%. Milliliters of benzene were heated under reflux overnight in the apparatus Dean_Stark 'Examiner &lt; Alum. The resulting solution was cooled and concentrated to provide the title compound as an oil, which was used directly in the next step. 87282 -61-200416032 4-methylpentane-i-pyridine. Add n-BuLi (16.5 ^: hexane solution with a concentration of 2.5 mol, 41.2 mmol) to -78 ° C bis A solution of benzene bromide (9.95 g, 41.8 mmol) in 100 ml of THF gave a thick suspension. After stirring for 10 minutes, a solution of (4S) -4_isobutyl-2- (pentafluoroethyl) -i, 3-oxazolidine (3.3 g, 13 mmol) in THF was added to give a dark brown solution. . The solution was allowed to warm to room temperature, then poured into a saturated aqueous ammonium chloride solution and extracted with ether. Purification by silica gel chromatography (10% to 40% ethyl acetate / hexanes gradient) gave the title compound as a single stereoisomer. ^ 1 ^ · 3 ·· ^ = 1 (18) -1: (4-bromobenzene) -2,2,3 · 3 · 3-pentaoxine N1- (cyano! VL-leucine) Preparation of amines Using the method in Steps 4 and 6 of Example 4, (28) -2 _ {[(18) _1- (4-bromophenyl) -2,2,3,3,3_pentafluoropropyl] A total sample of amino} -4-methylpentan-1-ol (1.6 g, 4.0 mmol) was converted to the title compound. Silica gel chromatography (15 ° / 0 to 80% ethyl acetate / hexane gradient ) Purified to provide the title compound as a solid. NMR (CD3COCD3, 500 ΜΗζ) δ 7 · 8 (1Η, br), 7.55 (2Η, m), 7.40 (2Η, m), 4 · 4_4 · 5 (1Η, m), 3.95 (2Η, m), 3.33 (1Η, m), 2.75 (1Η, m), 1.82 (1Η, m), 1-5 (1Η, m), 1.38 (1Η, m), 0.88 (6Η, dd) ON1 · (cyanomethyl D-N2-"(lS) -2,2.3-3.3- 5 cyanopyrimidinedi-4-ylbenzyl) propyl 1 -L-leukoamine Preparation of 2 molar Na2CO3 (0.25 ml) to N2-[(lS) -l- (4-bromophenyl) 2,2,3,3,3-pentapropyl ] -N-(Gasmethyl) -L-leucine amine (82 gram '.18 mmol), 4-pyridine boronic acid (30 mg, 0.24 mmol) and 87282 -62- 200416032

PdCl2 (dppf) (14 mg, 0.02 mmol) in 2.5 ml of DMF. The mixture was heated to 95 ° C for 2.5 hours, then cooled and distinguished between Na2CO3 and ether. The aqueous phase was washed with saline and dehydrated with MgSCU. Purification by silica gel chromatography (65% to 95% ethyl acetate / hexane gradient) provided the title compound. ! Η NMR (CD3COCD3, 500 ΜΗζ) δ 8.66 (2H, m), 7.85 (1Η, br), 7.81 (2Η, m), 7β70 (2Η, m), 7.62 (2Η, m) , 4.5-4 · 6 (1Η, m), 3,95 (2Η, m), 3.4 · 1 (1Η, m), 2.81 (1Η, m), 1.88 (1Η, m), 1 · 55 (1Η, m), 1.42 (1Η, m), 0.92 (6Η, dd). Example 7 Synthesis of Να-Π-aminocyclopropyl V4-chloro-N2-U1SV2.2.2-three gas ---

Step _ Step 1 · Preparation of benzyl (3S) _34 (篥 tri-butane 羱) amine 1-4 蕤 酩 酩 酩 酩 酩 N- (third-butoxycarbonyl) -L-asparagus The 4-benzyl amino acid (30 g) was dissolved in dimethoxyethane (90 ml) and the solution was cooled to -5 ° C. Add N-methylmorpholine (10.32 ml), followed by slowly adding isobutyl chloroformate (12.66 ml), keeping the reaction temperature below -10 ° C. The reaction was aged for 0.5 hours. The solid was quickly filtered off and washed with dimethoxyethane (90 ml). The filtrate was cooled 87282 -63- 200416032 to 0 ° C ′ and a solution of sodium borohydride (4.4 g) in water (45 ml) was slowly added, and the reaction temperature was maintained between -30 and -15 ° C. Then, water (500 ml) was added to keep the temperature of the reaction mixture below -15 ° C. The suspension was filtered, the solid was washed with water (400 ml) and dried to give benzyl (3S) _3 _ [(third-butoxycarbonyl) amino] -4-hydroxybutyrate. ! H NMR (CD3COCD3) δ 7.3-7 · 45 (5Η, m), 5.85-5 · 95 (1Η, NH), 5.15 (2Η, s), 3.95-4 · 1 (2Η, m), 3 · 5-3 · 7 (2Η, m), 2.55-2.75 (2Η, m), 1.4 · 9 (Η, s) 〇 Step 2 * Main group fY4S) -2-hydrogen-1 · 3_ 崎 峻 症 -4-yl 1 ethyl vinegar · rabbitum Tonidine (625 ml) was added to the dichloroethane (925 ml) solution of the alcohol (95.7 g) from step 丨 and the mixture was allowed to cool To 〇_5 seven. Anhydrous p-toluenesulfonic anhydride (1.05 g) was added, and the mixture was warmed to room temperature and stirred for 1 hour, and then heated to 90 ° C for 2 hours. The mixture was cooled, diluted with dichloromethane (1000 ml) and washed with 1 equivalent of HC1 (3 X 600 ml). The organic layer was washed with brine, dried over sodium sulfate and the solvent was removed in vacuo. Let the residue be purified by SiO2 chromatography using ethyl acetate and hexane in a ratio of 1: 1 followed by the eluent of ethyl acetate to produce benzyl [(4S) -2-oxy-1,3 -Oxazolyl] acetate. lU NMR (CD3SOCD3) δ 7.8 (1Η? ΝΗ) 5 7.3-7.45 (5Η5 m) 5 5.05 ^ 5 · 15 (2Η, m), 4.4-4 · 5 (1Η, m), 4.1 · 4.2 (1Η , M), 4.0-4.05 (1Ηm) 3.6 ~ 3 · 8 (2Η, m). Step 3: Prepare) 4- (2-Hydroxy-2-methylpropanone). Prepare methyl magnesium bromide (227 ml of a 3 molar solution in diethyl ether) to 87282 -64- 200416032 -20 ° C. Toluene (340 ml) and a mixture of THF (340 ml). Then, a warm THF solution (170 ml) of the ester (40 g) from Step 2 was added dropwise while maintaining the temperature at -10 ° C. The mixture was aged for 2 hours, then slowly added to a mixture of water (1000 ml) and acetic acid (200 ml), and the resulting mixture was stirred at room temperature for 2 hours. The aqueous layer was separated and the organic layer was subjected to water ( 2 X 200 ml) extraction. The product was extracted from the combined aqueous layers using dichloromethane and a continuous extractor. The heptane was used as a co-solvent and the acetic acid was azeotroped to evaporate the methylene chloride extract. Purified by SiO2 chromatography using ethanol and dichloromethane (1: 3〇) as eluent to produce (4S) -4- (2-hydroxy-2-methylpropyl) -1,3-4 halide- 2- 嗣. NMR (CD3COCD3) δ 6.1-6.4 (1Η5 ΝΗ)? 4.45-4.55 (1Η? M) 5 4 · 1-4 · 2 (1Η, m), 3.95 · 4 · 05 (1Η, m ), 3 · 7 (1Η, s), 1.65-1 · 85 (2 , M), 1.25 (6Η, m) 〇 Step 4 · (4S) -4- (2-chaosyl-2-methylpropyl) -1,3-? The same preparation Add a solution of the alcohol (47.8 g) in digas methane (100 ml) from step 3 to -70 ° C (diethylamino) sulfur trifluoride (4 8.5 g) in dichloromethane (500 ml) of the solution. The mixture was allowed to warm to room temperature and stirred for 1 hour. Then, the mixture was carefully added to a saturated aqueous solution of NaHC0 (800 ml) at 0 ° C. The organic layer was separated It was washed with a saturated aqueous solution of NaHC03. The aqueous layer was further extracted with dichloromethane (100 ml), and the combined dichloromethane layers were dehydrated and concentrated. The residue was subjected to ethyl acetate and hexane (1: 5). ), Followed by SiO2 chromatography followed by ethyl acetate as eluent to produce (4S) -4- (2-fluoro-2-methylpropyl) -1,3-yinjundian-2 -Ketone. 87282 -65- 200416032 H NMR (CD3SOCD3) δ 7.6 (1Η, ΝΗ), 4.4-4.5 (1Η5 m) 9 3.95-4 · 05 (1Η, m), 3.9-3 · 95 (1Η , M), 1.8-1.95 (2Η, m), 1.25-1 · 4 (6Η, 2s). (2SV2-Amine-4-Ga-1-4-Methyl-1midine-1- Preparation of JI Potassium hydroxide (21.9 g) was added 90% aqueous ethanol from the step 4 of mule-fluoro derivative (21.0 g) (216 mL). The mixture was heated at reflux for 4 hours and cooled to room temperature. The mixture was then concentrated and azeotroped with toluene (3 X 300 mL). The residue was dissolved in dichloromethane (500 ml) and stirred for 0.5 hours. The suspension was filtered through celite and the celite was washed with dichloromethane (3 x 100 ml). The filtrate was concentrated to dryness to give (2S) -2-amino-4-fluoro-4-Tylpentan-1-ol. ! H NMR (CD3OD) δ 3.4-3.5 (1H5 m)? 3.2-3.3 (1H? M)? 3.0-3.1 (1H, m), 1.5-1.7 (2H, m), 1.35 (3H, s) , 1.3 (3H, s). (2_S) -1-U Tertiary Ding dimethyl dimethyl succinyl silicon comb 1 _ 4 _ 4_ Huaqi methyl pentane-2-amine production will be from the amine alcohol of step 5 (21 0 g) was dissolved in dichloromethane (300 ml), and the solution was cooled to 0 ° C. Add 4- (dimethylamino) pyridine (0.051 g) and tertiary-butyldimethylsilyl chloride (21 g), followed by triethylamine (25 ml). The mixture was allowed to stir overnight at room temperature. The reaction mixture was slowly poured into a saturated aqueous ammonium chloride solution at 0 ° C and extracted with dichloromethane (3 X 300 ml). The organic layer was washed with a saline solution, dehydrated with sodium sulfate, and the solvent was removed in vacuo to produce (2S) -l-{[third-butyl (dimethyl) silyl] oxyfluoro-4-methylpentane -2-amine. lR NMR (CD3OD) δ 3.6-3.65 (1H? m)? 3.4-3.5 (1Η5 m) 5 3.1-3.2 (1Η, m), 1.6 ~ 1.8 (2Η, m), 1.35-1.45 (6Η , M), 0.93 (9Η, s), 0.0087282-66- 200416032 (6H, s). Step: (2S) _— 1 di {[Third-butyl (dimethyl) silicone curtain [Oxygen m [Base di 4-methyl_sam,> 1_ | ~ (1 £) -2,2.2 _Preparation of trifluoroethylene sulfonium-2-amine. Trifluoroacetaldehyde methyl hemiacetal (21.6 ml) was added to a solution of amine (3 1 · 5 g) in benzene (126 ml) from Step 6. . The solution was heated at reflux overnight and moisture was collected using a Dean-Star * k elbow. The reaction mixture was allowed to cool to room temperature and concentrated to dryness. The residue was purified by SiO2 using 4% ethyl acetate in hexane as eluent to produce (2S) _1-{[Third-butyl (dimethyl) silyl] oxyl-4_denyl-4 -Methylpentan-2-amine. ! H NMR (CD3COCD3) δ 7.9-7.95 (1Η, m) 5 3.75-3.85 (1H? M)? 3.7-3.75 (1H, m), 3.53-3.6 (1H, m), 1 · 9-2 · 0 (2H, m), 1.3-1.4 (6H, m), 0.9 (9H, s), 0.1 (3H, s), 0.05 (3H, s). Step 8 · (_2S) -2- {KlSVl- (4 -Xi Benmou V2.2J-trisylhexyl] amino group 4-Gu, a 4-a certain 戍 忮 -1__ of the farmer will be- BuLi (0_42 ml of a 2.5 molar solution in hexane) was added to a solution of -75 ° C M-dibromobenzene (0.26 g) in THF (4 ml) and the mixture was aged for 20 minutes THF (2 ml) of imine (0.329 g) from Step 7 was added and the mixture was aged for 2 hours. Then, the mixture was added with water (50 ml), NH4C1 (1 g) and In a mixture of crushed ice. Extract with ethyl acetate (2 X 25 ml) and dehydrate and evaporate the combined ethyl acetate layers. Use 1,4-dibromobenzene (1 · 2 g), n-BuLi (1-84 ml) and imine (38 g) were re-scaled on a larger scale and the reaction mixture was treated as described above. 87282 -67- 200416032 The combined residues from the two preparations were dissolved in THF (10 ml) and cooled to 0 ° C. Add n-tetrabutylammonium fluoride (6 ml of a 1 molar solution in THF) and allow the mixture to stir at + 5 ° C for 16 hours. The mixture was poured into a mixture of water (50 ml), Nuclei g) and crushed ice, and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate (2 X 15 ml), and the combined organic layers were dehydrated and concentrated. The residue was purified by SiO2 using ethyl acetate and hexane (1: 5) as eluent to produce (2S) -2-{[(lS) -1-('bromophenyl) _2,2,2- Trifluoroethyl] amino} -4-fluoro-4-methylpentane-1-ol. 'H NMR (CD3COCD3) 6 7.65 (2H5 m) 5 7.5 (2H5 m)? 4.5-4.6 (1H, m), 3 · 8 (1H, m), 3.6 (1H, m), 3.3-3.4 (1H, m), 2.85-2.0 (1H, m), 2.55 (1H, m), 1.7-1.9 (2H, s), 1.3-1_4 (6H, m). Step 9: N-2-2-rnSVW4_Bromo-m)) · 2.2 · 2-Third version of B-l-NUlU ^ -V4-fluoroleukoamine, H5I〇6 / Cr〇3 ( 66 ml of 0.44 molar CH3CN solution, precautions) The suspension is cooled to 0 ° C, and the (^ 3〇 ^ solution (5 ml) of the alcohol (1.55 g) from step 8 is added dropwise. Let this Mix the mixture at 0-5. (3 remove 3.5 hours. Pour it into vigorously stirred Na2HP04 (200 ml) at pH 4 and extract the mixture with ether (3 x 50 ml). Let the combined ether extracts first After washing with water and saline solution (1: 1), followed by dilute aqueous NaHS solution and saline solution, the mixture was dehydrated with sodium sulfate, filtered, and the solvent was evaporated to produce N- which was directly used in the next step. [(lS) _l- (4-bromophenyl) -2,2,2-trifluoroethyl] -4-fluoroleucine. Notes and oxidants (H5I〇6 / Cr03) are, for example, Tetrahedron Letters

39 (1998) 5323-5326, but using CH3CN 87282-68-200416032 (containing 0 5% water) of hplC grade without adding water. Diisopropylethylamine (4.2 ml) was added at 0 ° C to the above-obtained acid (15 g), 1-amino-1-carbopropane hydrochloride (1.18 g), 7-Azabenzodi-ton-l-yl) _N, N, N ', N, Tetramethylphosphoniumhexakisphosphate (1.94 g) and dimethylformamide (5 ml) in a suspension , And the mixture was allowed to react at room temperature for 48 hours. Then, it was poured into ice and dilute ammonium chloride. The mixture was extracted with ethyl acetate and diethyl ether (1: 1), and the combined organic layers were washed with dilute Na ^ PCU and saline solution. The solvent was evaporated to dryness and the residue was purified by SiO2 chromatography using ethyl acetate and hexane (1: 2) as eluents to produce N2-[(lS) _l of sufficiently high purity for direct use in the next step. -(4-bromobenzyl) -2,2,2-trifluoroethyl] -N- (l-peptyl) -4-fluoro-leucine amine. NMR (CD3COCD3) δ 8 · 15 (1H, NH), 7.6 (2H, m), 7.45 (2H, m), 4.35-4.45 (1H, m) 5 3.45, 3.55 ( 1H, m), 1.9-2.1 (2H, m), [75-1.85 (1H, NH), 1.35-1.55 (8H, m), 1.1-1.15 (1H, m), 0-95-1.05 (1H, m) °: Ν1-Π-—aminocycline V4_ 氤 某 -N2- {nSV2 ·?,? -Trioxolidine 1 _- "4 '-(methylthiodibenzyl_4_some 1 B-Member L_Blanthamine) A nitrogen stream was passed through the bromide (0.338 g) from step 9, A suspension of 4- (methylthio) phenylboronic acid (0.252 g), 2 molar Na2CO3 (0.8 ml) and DMF (4 ml) was added for 15 minutes. Then, P (JC12 dppf ( 0.1 g), and the reaction was heated to 85 ° C and stirred under nitrogen for 5 hours. The mixture was allowed to cool to room temperature, diluted with ethyl acetate (10 ml), and poured into water (50 liters) With ice. Separate the ethyl acetate layer and further extract the water with ethyl acetate. 87282 • 69- 200416032. Dehydrate the combined ethyl acetate extracts and remove the solvent in vacuo. Ethyl acetate and hexane (1: 2 ) Is a SiO2 chromatography purification residue of the eluent, yielding 1 ^ (1-cyanocyclopropyl) -4-fluoro group "^ 2-{(18) -2,2,2-trifluoro-1- [4, _ (methylthiodiphenyl-4-yl] ethyl} -L-leukoamine. 1U NMR (CD3COCD3) δ 8.15 (1H5 NH) 5 7.1-7.2 (4Η? M)? 7.5 -7.55 (2Η, m), 7.35-7.4 (2Η, m), 4.3-4 · 4 (1Η, m), 3.45-3.55 (1H, m), 2.75-2.8 (1H, NH), 2.5 (3H, s), 1.9-2.05 (2H, m), 1.3-1.5 (8H, m), 1.0-1.1 (1H, m), 0.885-09.5 (1H, m) 〇 Step 11: Preparation of N ^ Π-Cyclocycline V4-Ga-N2-inSV2 ^ r ^ Zao-M4,-(Methylfluorenyldisulfonium-4- its sulfanilamide Add Na2W04 · 2Η20 (0 · 002 g) and n-Bu4NHS04 (0.011 g) to 0 ° C toluene (5 ml) from the sulfide (0.265 g) of step 10 and dichloromethane (5 ml) ) Solution. Then, 30% hydrogen peroxide (0137 liters) was slowly added and the mixture was stirred at room temperature for 3 hours. The mixture was slowly poured into a mixture of ice, dilute sodium thiosulfate aqueous solution and ethyl acetate. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layers were washed with brine, dehydrated with magnesium sulfate, and the solvent was removed in vacuo to produce a residue. The residue was subjected to ethyl acetate and hexane. Purify SiO2 with dichloromethane (1: 1: 〇1) as eluent. Triturate the residue with diethyl ether to give Nl_ (i_cyanocyclopropyl) -4_dunyl-n2 _ {(is) _2,2 , 2-trifluoromethyl- !; 4,-(methylsulfonyldiphenyl-4- Group] ethyl} -L_leukoamidamine. H NMR (CD3COCD3) δ 8.2 (1H, NH), 8.05-8.1 (2H, m), 7.95-8.0 (2H, m), 7.8 (2H, m) , 7.65 (2H, supplement 4 35 4 45'⑽ 87282 -70- 200416032 m), 3.5 · 3.6 · 6 (1H, m), 3.2 · 3 (3H, s), 2.8-2.9 (1H, NH), 1 9-2 · 1 (2¾ m), 1,3-1.5 (8H, m), 1.05-1.15 (1H, m), 0.9-1.0 (1H, m). Example 8

nW cyanomethyl vn2_ {ph4_Nitrogen, some, some, si, some, νι, ι ′: ^ 苽, 4--4-yl, 1, some, and -L-A Synthesis of F

Step 1 ·· LSJ-2- 丨 Preparation of 1-4-methylbenzyl-1-ol of fluorobenzylideneamine—Putting (L) -leukoethanol (3 · g, 9.67 mmol) Ear) and 4-fluorobenzaldehyde (1.20 g, 9.67 mmol) were dissolved in benzene (30 ml) and heated at reflux for 1 hour, and the Dean-Stark device was used to remove moisture. (S) -2-[(4-fluorobenzylidene) -amino] -4-methylpentane-1-ol was isolated by vacuum concentration and used immediately without further purification. Step 2: [2 8) -2- (00-"(4-Bromomonazine)-(4-Pan | phenylhydrazone) -A certain 1 2 1 ^ Some 1-4-methylpentane, burning -1 -醢 夕 _ Prepare n-butyllithium (24.2 ml of a cyclohexane solution with a concentration of 2.0 moles) and add -30C 1,4-di &gt; odorant (4 g , 48.35 millimolar) solution of acetaminophen (120 ml). The reaction mixture was allowed to stir for 45 minutes, at which time (S) 2-[(4-fluorobenzylidene) _amino] methylpentane was added dropwise_ A solution of 1-alcohol (up to 2.16 g, 9.67¾ mol from the previous step) in acetic acid (30 ml). 2 87282 -71-200416032 hours 9 At this point, the reaction mixture is allowed to warm to 0 ° C and water is added (200 mL). The product was extracted with ethyl acetate (150 mL), washed with brine (100 mL), dehydrated with magnesium sulfate, filtered, concentrated in vacuo, and purified on a short silica gel plug (20% ethyl acetate). / Hexane eluent) to form (2S) -2-{(R)-[(4-bromophenylH4-fluorophenyl) -methyl] -aminob 4-methylpentane-1 · ol MS (+ APCI): 3 809 3 82 [M + 1] + 4 NMR (CDC13) δ 0.91 (d, 6H), 1.22 (m, 1H), 1.43 (m, 1H), 1.61 (m, 1H), 2.62 (m, 1H), 3.28 (m, 1H), 3.63 (m, 1H), 4.95 (s, 1H); 7.00 (m, 2H), 7.22 (d, 2H), 7.2 (m, 2H), 7.44 (d , 2H) Step 3 · (2 Preparation of odorous argon-argonous dimethyl-4-methylvaleric acid acetonitrile (periodonic acid and chromium oxide [VI] (50 ml: the preparation is based on

Tetrahedron Letters 39 (1998) ρ 5323-5326. Dissolve 11.4 grams of H5IO06 and 23 mg of CrO3 in 100 ml of CH3CN and stir at room temperature for 2 hours.) The solution is added over a period of 20 minutes. (2S) -2-{(R)-[(4-bromophenyl)-(4-fluorophenyl) -methyl] -aminomethylpentane-1-ol (3.28 g, 8 · 65 millimoles) in water (0.375 ml) of acetonitrile (50 ml). The reaction mixture was allowed to stir overnight while warming to room temperature. Add disodium hydrogen phosphate (1.8 g / 100 ml of water). The reaction mixture was extracted with toluene (150 ml), washed with 1: 1 salt / water (50 ml), freshly prepared sodium bisulfite solution (g / 50 ml water), and saline solution (50 ml). MgS04 is dehydrated, filtered, concentrated in vacuo, and purified by a short stone plug (30% ethyl acetate / hexane is removed to remove non-polar impurities, then 50% ethyl acetate / dichloromethane is dissolved) to produce (28 ) -2-{(feet)-[(4-bromophenylH4-fluorophenylmethyl] -amino} -4-methylvaleric acid. 87282 -72- 200416032 Step 4: (2 8) -2 -{(1〇-『(4-Bromojam)-(4-11 Fumou) Dimethyl Mozhang Bu Miao 4-methylvaleric acid I formamidine Preparation of 4-methylmorpholine ( 315 ml, 2.86 mmol) and isobutyl chloroformate (0.371 ml, 2.86 mmol) were added to (2S) -2-{(R)-[(4-bromo Phenyl)-(4-phenyl) -methyl] -amino} -4-methylvaleric acid (1.17 g '2.86 mmol) in THF (20 ml). The reaction mixture was stirred for 10 minutes , While adding amine acetonitrile hydrochloride (0.3 18 g, 3.43 mmol), followed by 4-methylmorpholine (0.315 ml, 2.86 mmol) The solution was stirred for 90 minutes. Ethyl acetate (30 ml) and an aqueous solution of disodium hydrogen phosphate (30 ml) were added. The organic layer was separated, washed with brine, dehydrated with MgS04 and evaporated to dryness. The product was passed through a short silicone plug ( 10-50% ethyl acetate / hexane gradient elution) purification to generate (2S) -2-{(R) _ [(4_bromophenyl) _ (4 · fluorophenyl) -methyl] -amine } _4_Methylpentanoic acid cyanamide. Free Step 5: N1 &quot; Cyanosulfanyl Gu 1 ·) "4,-(methyl some fluorenyl) -1, Γ-dimolyl-4-yl Methyl} -L-leukoamine Nerve will (23) -2-{(汉)-[(4-Bromophenyl)-(4-fluorophenyl) -methyl] -aminobuxin methyl Cyanomethoxamine valerate (0.27 g, 0.636 mmol), 2- (4-methanesulfonylphenyl) -4,4,5,5_tetramethyl_ [1,3,2] Degassing a mixture of dioxaborolane (0.177 g, 0.626 mmol) and potassium carbonate (0.703 mL of a 2.0 molar solution) in dMF (5 mL). Add [1,1, _double (Diphenylphosphine) ferrocene] Ibarium (II) dichloride, dichloromethane complex (27 mg, 0.0038 mmol). The reaction mixture was placed in a sealed test tube at 80-85 °. C heating for 3 hours Cooled to room temperature. Ethyl acetate (15 mL). The reaction mixture was Order saline (1〇 mL), saturated NaHCCh solution (10 mL), saline (1〇 ml), filtered through -73- 87282200416032

MgSC ^ / DARCO activated carbon / silicone plug, concentrated in vacuo and purified by preparative TLC (Chromatotron® using 5% ethyl acetate / dichloromethane to dissociate) to form N1- (cyanomethyl) -N2-{(S )-(4-Fluorophenyl) [4 '-(methyl-stilbene-diphenyl · 4-yl] methyl} -L-leukoamine. NMR δ (CDC13): 0.777 (d, 3H), 0.9 (d, 3H); 1.38 (m, 1H), 1.57 (m, 1H), 1.71 (m, 1H), 2.01 (br s, 1H), 3 · 09 (s, 3H), 3.09 (m, 1H), 4.07 (m, 2H), 4.89 (1H, s), 7.03 (m, 2H), 7.21 (m, 1H), 7.33 (m , 2H), 7.42 (d, 2H), 7.53 (m, 2H), 7.68 (d, 2H), 7.97 (d, 2H). Example 9 Weep, _- (random methyl)-&gt; ^ 2- { (110-2,2,2-trifluoroyl-1_ 『4 '-(A certain wall 醯) _ LJ'_Di hydrazyl-4- some 1 ethoxyl L-n-valine amine's death

: L4D-4-propyltriamidine, methoxazole, oxazole, and (L) _n-valinol hydrochloride (5.25 g, 37.60 mmol) and trifluoroacetaldehyde methyl hemiacetic acid ( 5 ml, 37.6 mmol) was heated under reflux in benzene (100 ml) containing triethylamine (5.26 ml, 37.6 hamol), and the Dean-Stark device was used to catch the moisture. After 3 hours, the reaction mixture was cooled, diluted with ether (00 ml), filtered and evaporated to dryness to yield (4S) -4-propyl-2-trifluoromethylpyrazolidine, which was used without further purification. . 87282 -74- 200416032 Interest: Preparation of B. m. -1-fluorene, n-butyllithium (41 ml of 2.0 mol concentration cyclohexane solution) was added to -30 ° in 10 minutes A solution of 1,4-dibromobenzyl bromide (19.3 g, 81.89 mmol) in ether (250 ml). After 1 hour, (4s) -4-propyltrifluoromethyloxazolidine (3.00 g, 16.38 mmol) was added to B (50¾ liters) via an addition funnel over a period of 30 minutes. After stirring for 90 minutes, water (1 ml) was added. The organic phase was washed with saline (100 ml), dehydrated with MgSO4, filtered and evaporated to dryness. The residue was purified through a silica plug (10-30% ethyl acetate / hexane). According to the 0.98 ppmCH NMR of n-valamine fei methyldiene), (2S) -2- [1- (4-bromoethenyl) -2,2,2-difluoroethylamine of about 2: 1 can be observed ]]-Pentanyl alcohol 匚 |? 3 stereoisomer mixture. Step 3 :: Linyl): 1,1'-dibenzyl-4-yl-1ethyl-n-valamine g | Neck and N1- (cyanomethyl) -N2_ {Πΐ〇-2 · 2 · 2 -Three hydrants 1- "4,-[methyl stilbene. Bisdiphenyl-4_ylethyl sulfonate KL-n-valamine _ preparation of (2S) -2- [l- (4-bromide And the assimilation of amino) -2,2,2-difluoroethylamino] -valeric acid to amine acetonitrile as additional products using the same N2- [1- (4-bromophenyl)-2.2.2- Trifluoroethyl] -N1- (cyanomethyl) -L-n-valeramine is completed in the same manner as described. The product is treated with N1- (cyanomethyl) -N2-{(lS) -2,2, 2-trifluoro (methylsulfonamido) -1,1'-diphenyl-4-yl] ethyl} -L-n-valamine sulfonamide is coupled in the same manner as described in Suzuki to produce N1- (cyano (Methyl) -N2-{(1S)-2.2.2- Dioxo-1- [4 '-(Methylstilbenzyl) -1,1'-diphenyl-4-yl] ethyl} -87282 -75- 200416032 L_N-valeramine and Ni- (cyanomethyl) _N2-{(1R) -2,2,2_trifluoro group_1- [4, _ (methyl ~ vinyl group) ): 1,1'-diphenyl-4-yl] ethyl} -L-n-eminase amine 2: 1 mixture, which is separated by the method of preparing TLC (Chromatotron®). MS (+ ESI ): 468 [M + 1] + Example 10 A 1- amine into a U-dimethoxy a synthetic acids cyanomethyl of Amides

± M ±: Methyl-3_ (methylbenzylsulfonyloxymethyl), osier i (() xetany), p-toluenesulfonium gas (57.2 g, 300 mmol) is dissolved under nitrogen pressure. To anhydrous pyridine (400 ml). 3-methyl-3- (hydroxymethyl) oselide (20.4 g, 200 mmol) was slowly added, and the solution was stirred for 5 hours. Then, crushed Ice (400 grams) was added to the vigorously stirred mixture and allowed to stir for another 0.5 hours. Then, the white precipitate was collected on Whatman # 1 filter paper and washed with cold water. The product was dehydrated under high vacuum to obtain a white powder. 3 -methyl-3- (toluene-oxymethyl) oxetane (toxidan tosylate) of Sidan Toluene. NMR (CDC13) δ 7.81 (d, 2H ), 7.37 (d, 2H), 4.37 (m, 4H). 4.11 (s, 2H), 2.46 (s, 3H), 1.31 (s, 3H). Steps: (2S) section-2- O'-1 amine, a methyl-amidine__3_formamidine osidan 87282 -76- 200416032 group: methyl ester prepared Cbz-L-leucine (2 g, 75 mmol) and Cs2C03 (1 46 g, 4.5 mmol, 0.6 equivalent) was dissolved in water (20 ml). Then, the water was removed in vacuo, The resulting oil was freeze-dried for 12 hours to form a white solid. To this solid was added 3-methyl-3- (tosylsulfonyl-oxymethyl) oseltan (ossetan tosylate) ( 1.8 g, 4.5 mmoles) and NaI (224 μg, 1.5¾ moles, 0.2 equivalents) dissolved in DMF (35 ml) and allowed to stir under nitrogen for 48 hours. Then, the DMF was removed in vacuo The solid sEtoAc (60 ml) was dissolved and washed with 10% NaHC03 (20 ml) and saturated NaCl (10 ml) and dehydrated with MgSCU. The solvent was removed under reduced pressure to produce a yellow oil, It was subjected to flash column chromatography using 200 cubic centimeters of silica with 3.1 hexane: EtOAc as eluent to give (2S) -2-benzyloxycarbonylamino-4-methyl as a thick yellow oil. -Valeric acid 3-methyl ossetan-3-yl methyl ester (Cbz_Leu-ossetan ester). ^ NMR (CD3SOCD3) δ 7.75 (d, 1H)? 7.26 ^ 7.38 (m5 5H)? 5.05 (s , 2H), 4.0 · 4 · 4 (m, 8H), 1.45-1.7 (m, 3H), 1.25 (s, 3H), 0.85-0.9 (m, 6H). Dipyrene p 9 octyl il-yl V butyl 1-amine methyl benzyl benzyl beer prepared under nitrogen pressure, (2S) -2 -Benzyloxycarbonylamino_4_methyl_valeric acid 3-methylosidan-3-yl methyl ester (Cbz-Leu Osidanyl ester) (2 g, 5.7 mmol) dissolved in anhydrous CH2Cl2 ( 10 ml). BF3.Et2O (40 microliters, 0.3 millimoles, 0.054 equivalents) was diluted with anhydrous CH2C12 (1 mL) and added to the reaction flask. The reaction was allowed to warm to room temperature and stirred for 12 hours. Add triethylamine (335 μl, 3.3 millimoles, 0.58 equivalents), and allow the reaction to stir for another 30 minutes, then concentrate to a thick 87282 -77- 200416032 methyl methyl ester. Prepare Cbz-L -Leucine (2 g, 7.5 mmol) and Cs2C03 (1.46 g, 4.5 mmol, 0.6 equivalent) are dissolved in water (20 ml). Then, water was removed under vacuum, and the resulting oil was freeze-dried for 12 hours to form a white solid. To this solid was added 3-methyl-3- (toluene-oxymethyl) oseltan (Osetan tosylate) (1-8 g, 4.5 mmol) and dissolved in DMF ( 35 ml) of Nal (224 mg, 1.5 mmol, 0.2 eq) and allowed to stir under nitrogen for 48 hours. Then, DMF was removed in vacuo, and the resulting solid was dissolved in EtoAc (60 mL) 'and washed with 10% NaHCO3 (20 mL) and saturated NaCl (10 mL), and dehydrated with MgSO. The solvent was removed under reduced pressure to produce a yellow oil, which was subjected to flash column chromatography using 200 cubic centimeters of silica using 3. · 1 hexane: EtOAc as eluent to produce (2S) -2- Benzyloxycarbonylamino-4-methyl-valeric acid-3-methyl oxedan-3-yl methyl ester (Cbz-Leu-Oxedan Ester). lU NMR (CD3SOCD3) δ 7.75 (d, 1H) 5 7.26-7.38 (m9 5H)? 5.05 (s, 2H), 4.0-4.4 (m, 8H), 1.45-1.7 (m, 3H), 1.25 (s, 3H), 0.85-0.9 (m, 6H). : D-methyl-1- (4-methyl-2,6 · 7- i oxa-difluorene # Γ2 · 2 · 21 octyl 1-butanone 1-aminocarboxylic acid octyl Under nitrogen pressure, (2S) -2-benzyloxycarbonylamino-4-methyl-valeric acid 3-methylosidan-3-yl methyl ester (Cbz-Leu Osidanyl ester) (2 g, 5.7 millimolar) was dissolved in anhydrous CH2C12 (10 mL). BF3 * Et20 (40 microliters, 0.3 millimoles, 0.054 equivalent) was diluted with anhydrous CH2C12 (1 mL) and added to the reaction flask. The reaction was allowed to warm up It was allowed to reach room temperature and stirred for 12 hours. Triethylamine (335 μl, 3.3 mmol, 0.58 equivalent) was added, and the reaction was allowed to stir for another 30 minutes, then concentrated to a thick 87282-77-200416032 oil. The crude product was redissolved in EtOAc (15 mL), washed with 3% NH4C1 (10 mL) and saturated NaCl (10 mL), dehydrated (MgS04) and evaporated to dryness. The reaction produced a colorless thick oil which crystallized upon standing To produce [3-methyl-1_ (4-methyl • 2,6J_trioxa-bicyclo [2 · 2 · 2] oct_1-yl) -butyl] -carbamic acid benzyl ester (Cbz-Leu-OBO ester). H NMR (CD3SOCD3) 5 7.25-7.35 (br m, 5H), 6.88 (d, 1H) 5.05 (s, 2H), 3.80 (s, 6H), 3.7 (m, l H), 1.2-1.6 (m, 3H), 0.75_ 0.85 (m, 6H), 0.70 (s, 3H) 〇3_rmethyl-1- (4-methyl ^ 6_, 7-trimethylbenzene-diphenylene Newsletter Γ9 -1 基)-Ding Yuetuo's injury preparation 10% Pd (320 mg, 10%) of mixed activated carbon was added under nitrogen [3 methyl-1- (4-methyl-2,6 , 7-Trioxabicyclo [2 2 2] octylaminocarbamate (3.2 g, 9.2 mmol) in absolute EtOH (30 ml). The reaction mixture was hydrogenated at 50 psi for 6 hours. The reaction was detected by TLC, and the reaction mixture was filtered through diatomaceous earth. The solvent was removed to obtain 3-methyl-1- (4-methyl-2,6,7-trioxane · bicyclo [ 2 2 2] Sin · 丨 -bibbutamine. ^ NMR (CD3SOCD3) δ 3.80 (S? 6H)? 3.2-3.4 (br s? 3H)? I.75 (m, 1H), 1.0-1.4 (m , 2H), 0.75-0.90 (m, 6H), 0.75 (s, 3H). Step 5 A milky complex — i_3 -methyl-1- (4-methyl even-9. Yl) _but ... : A solution of thiobutamine (1.9 g, 8.8 mmol) and thiazole_2-carboxaldehyde (998 mg, 88 mmol) in benzene was heated under reflux in a Dean-Stark elbow for 3 hours, during which time water was evaporated under reduced pressure Residual crumbs to obtain the orange solid [3-methyl 87282 -78- 200416032 methyl -2,6,7-trioxa-bicyclo [^ "octyl-butyl) · butyl] _pyrimazole_2_ylmethyleneamine. ! H NMR (CD3SOCD3) δ 8.4 (s, 1H), 7.97 (d, 1H), 7.84 (d, 1H), 3.82 (s, 6H), 3.4 (m, 1H), 1.7 (m, 1H), 1.5 (m, iH), 1.3 (m, 1H), (m, 6H), 0.75 (s, 3H). Immuno-'K1 · T-bromo-phenylhydrazone) -4azole-2-some-methyl certain l- 『3 di ^ some 4- (4-methyl certain trioxetane amine · prepared in -30 ° C, 2.5 mol of n-BuLi hexane (1.3 ml, 32 mmol) was added to dibromobenzene (760 mg, 3.2 mmol) of anhydrous ether / spring solution After stirring for 1 hour, [3_methylmethyl_2,6,7_ monooxa-monocyclo [2.2.2] oct-1-yl) _butyl] 4xetylmethylene was slowly added. -A solution of amine (500 ¾ g, 6 mmol) in 5 ml of anhydrous ether. The reaction mixture was allowed to stir at the same temperature for 2 hours. Then, the reaction was stopped by adding water and extracted with ethyl acetate. The organic layer was washed with saturated NaCl and dehydrated with MgS04. Solvent was evaporated in True 2. The crude product was subjected to hexane: EtOAc as eluent &lt; flash column chromatography to obtain [(4_bromo_phenyl) _pyrazol 2-yl · methyl] _ [3 as a pale yellow solid -Methyl- (4 • methyl-2,6,7_trioxa_bicyclo [2 · 2 · 2] oct-1-yl) -butyl] -amine. ln NMR (CD3SOCD3) δ 7.64 (d? 1H)? 7.59 (d5 1H)? 7.5 (d? 2H)? 7 · 28 (d, 2H), 5.68 (s, 1H), 3.82 (s, 6H) , 3.3 (m, 1H), 2.65 (m, 1H), 1,95 (m, 1H), h4 (m, 1H), 1.2 (m, 1H), 0.9 (d, 3H), 0.75 (s, 3H ), 0.7 (d, 3H) 〇Step 7 * stilbene) 莘 -methyl ll-amine usable}-87282 -79- 200416032 Preparation of 4-methyl certain acid formation _ 1 equivalent concentration HC1 (3.5 ml ) Add [(4-bromo-phenyl) -distant-2-yl-methyl]-[3-methyl-1- (4-methyl-2,6,7-trioxa-bicyclo [2.2.2] A solution of oct-1-yl) -butyl l · amine (500 mg, 1.06 mmol) in THF (20 ml) and water (18 ml). The reaction mixture was stirred for 2 hours. After checking whether the starting material disappeared by TLC, Li (OH) .H2O (280.2 mg, 6.3 equivalents) was added and stirred at room temperature for 2 hours. Then, 1 equivalent of HC1 was added to adjust the pH to 4-6, and the product was extracted with EtOAc, and the organic layer was dehydrated with MgS04. The solvent was evaporated to give (2S) -2-{(S)-[(4-bromophenyl) -pyrazol_2-yl_methyl] -amino} -4-methylvaleric acid as a yellow solid. Steps "· (2.S) -2- {Don't take a certain 4 -2-A-a certain will 莘} _ 4-Cyme a cyanomethyl valerate Ning Panning j Prepared with HATU (1 when f) With mono-propyl propylamine (4 equivalents), let (2S) -2-{(SH (4-bromophenyl)-sedazol-2-yl-methylbenzamidine 4-methylvaleric acid and Aminoacetonitrile (2 equivalents' over 1 equivalent) is coupled to form (2S) -2-{(S)-[(4-bromophenyl) -pyrazol-2-yl_methyl]-as a creamy solid Amidob'methyl valerate cyanamide. ^ NMR (CD3SOCD3) δ 8.73 (t? 1H)? 7.66 (d9 1H)? 7.64 (d5 1H), 7.5 (dd, 2H), 7.25 (dd, 2H) ), 4.92 (d, 1H), 4.14 (t 2H) 3.32 (s, 1H), 3.19 (m, 1H), 2.98 (m, 1H), u5 (m, 1H), 146 (m, 1H), 0.9 -0.85 (m, 6H). Example 11

Eiz (l-cyanoj [propyl) -4,4-diargon ^ tri # group "-^, (X · Sulfosulfuryl) di-1,1'-diphenyldifluorene amine compound 87282- 80- 200416032

： Preparation of K3, V3, and alkaloids. Diethylmethane in diethyl ether was added to carbonylbenzyloxy_L_serine (25g, 104 hamol) in ethyl acetate (200ml). ) Solution until light yellow persists. The solvent was evaporated in vacuo. N, N-dimethylformamide (400 ml) and methyldiphenoxyscale iodide (50 g, 0 mmol) were added to the residue. The mixture was stirred for 15 minutes, then methanol (15 ml) was added, and the mixture was poured into 20/0 sodium thiosulfate, and extracted with a 1: 1: 1 ethyl acetate: hexane mixture (^ l). The organic layer was washed with water and saline (3x), dehydrated with magnesium sulfate, filtered, and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate and hexane. The resulting compound was triturated in ether / hexane, filtered and air-dried to provide methyl ((benzyloxy) carbonyl) -3-iodo-L-alanine. Xia Li a) compound) _4_ Qi a -L-normal knot g amino acid blasting soil methyl N _ ((benzyloxy) carbonyl) -3_iodopropionate (1〇 G, 27.5 mmol), zinc-copper coupling (3.3 g) of benzene (110 ml) and Ν, Ν-dimethylacetamide (7.4 ml) were shaken in an ultrasonic bath 2 hours. During this period, 3 parts of gadolinium dibromoethane (0.24 ml) and chlorinated 87282 -81-200416032 dimethylsilane (0.172 liters) were added. Then, bis (triphenylphosphine) palladium chloride (0.595 g, 1.4 mmol) and acetamidine chloride (2.5 ml, 35.2 mmol) were added to the mixture 'and let The mixture was heated at 700c for 2 hours. After cooling to room temperature, the mixture and ethyl acetate were passed over a diatomaceous earth; then, the organic layer was washed with a saturated aqueous ammonium chloride solution and a saline solution (2X), dehydrated with magnesium sulfate, filtered, and dried under vacuum . Let ren feng be purified by chromatography using ethyl acetate and burned stone gelatin to provide methyl N-((benzyloxy) carbonyl) -4-oxy-L-n-valinate. Step-min): 1-based benzyl a) Preparation of V4.4-dioxo-_L-n-valerazine DAST (2.46 ml) was added slowly. 〇 Methyl N-((benzyloxy) carbonyl) -4 • oxy-L-n-valinate (ι_3 g, 4.65 mmol) methylene chloride (200 liters) and methanol (0 · 019 ml) solution. Remove the ice bath and replace it with a hot water bath (57 C). Change the hot water bath 3 times, then let the mixture stir overnight at room temperature. The mixture was slowly poured into cold saturated NaHC03, extracted with ethyl acetate, washed with brine, dehydrated with magnesium sulfate, filtered, and the solvent was evaporated to dryness in vacuo. The residue was purified by silica gel chromatography using ethyl acetate and hexane to provide methyl N-((loweroxy) alkyl) _4,4_diazyl-L-norhexamine. : Preparation of benzyl (1SV3J-difluoro-1- (hydroxymethyl)) butanilamine methyl ester. Lithium chloride (919 mg) was added to methyl &gt; ^-((benzyloxy) carbonyl) _4 A solution of 4-difluoro-L-n-valinate (1.59 g, 5.29 mmol) in ethanol (50 ml), and the mixture was stirred for 10 minutes. Sodium borohydride (820 mg) was slowly added to the solution. The mixture was stirred for 2 hours. Then, another portion of sodium borohydride (100 mg) was added and stirring was continued for 30 minutes. The mixture was diluted with water (20 ml), and 1 equivalent 87282 -82- 200416032 concentration HC1 was slowly Neutralize, then add another-equal parts of water. Extract the mixture (2X) with ethyl acetate, wash with saline, dehydrate with magnesium sulfate, filter, and evaporate the solvent in vacuo to provide the base (18) _3,3 _Difluoro small (#f methyl) butylamino methyl esters. M1, -4.4-Diamyl pentane-2-amine Ning Ning Pd / C (10%, 150 mg) was added to a solution of benzyl (1,3-difluoro small (pentamethyl) butylcarbamate (from step 4) in ethanol (25 ml), and the mixture was placed under H2 pressure. (Balloon stirring) Stir 2 small Add dichloromethane and filter the mixture through diatomaceous earth. Evaporate the solvent in vacuo. Dissolve the residue in methane (15 ml) and add triethylamine (1 ml), n, n-dimethylamine Gyridine (ίο * g) and chloro-tert-butyldimethylsilane (844 mg) stirred the mixture overnight, then added water and saline. The mixture was extracted with ethyl acetate (2 X) ' Wash, dehydrate with magnesium sulfate, filter, and evaporate the solvent in vacuo to provide (2S) -1-((third-butyl (dimethyl) silyl) oxy) &gt; 4,4-difluoropentyl -2-amine. Methyl) silane and even 4-methane-trifluoroethylene. A) pentane-2-amine production order was obtained from step 5 of os). — — ((Third_butyl (Dimethyl) silyl) oxy) -4,4-difluoropentane-2-amine and trifluoroacetaldehyde methyl hemiacetal (808 / 〇, ο ”ml) Winter (20 The solution was refluxed overnight by the Deari Stark device. The effervescent agent was prepared in vacuum and the residue was purified by silica gel chromatography using ethyl acetate and hexane to provide (2S) -l-((third_butyl (di) Methyl) silyl) oxy) -4, 'di -N-((1Ε) -2,2,2-trifluoroethylene) pentane_2-amine. 87282 -83-200416032 ± MJ ~: US) -2r (ai§) -W4-bromobenzene B, humeryl) -4,4-difluoromethane-1, 醅 Xining j. Add 2.5 moles of n-BuLi in hexane solution (0.52 ml) to _78 its Μ -A solution of benzene dibromide (330 mg) in THF (5.2 ml) and aged for 30 minutes. Then, (28) 4-((third-butyl (dimethyl) silyl) oxy) -4,4-difluoro-N-((1Ε) -2,2,2-trifluoro A solution of ethylene) pentaneamine (333 g) in THF (5.2 ml). Let the mixture be at _78. 〇 Mix 45 minutes and then pour it into cold saturated ammonium chloride, extract with ethyl acetate (2X), wash with salt solution, dehydrate with magnesium sulfate, filter, and remove the solvent in vacuo. The residue was cooled in THF (10 ml) in an ice / water bath, and n-tetrabutylammonium fluoride (1 mol THF solution, 1.5 ml) was added. The mixture was stirred at 0 ° C for 1 hour, poured into cold water, extracted with ethyl acetate (2 &gt; &lt;), washed with saline, dehydrated with thiosulfate, filtered and evaporated to dryness the solvent in vacuo to provide (2s) _2 _ ((( ls) -l- (4-bromophenyl ^ 2,2,2-trifluoroethyl) amino) -4,4-difluoropentane-l-ol .: NliLUS) -1- (4-bromo Phenylhydrazone) · hydrazine 2. Tribenzyl. Ethyl I-β-Π-aminopyridine difluoro-L-n-valamine. Preparation of (28) -2-(((( 18) -1- (4-Bromophenyl)-2.2.2-difluoroethyl) amino) -4,4-difluoropentane-1 -ol was converted to the title compound. Step 9: Propyl V4,!: · Dikis-N2_K1SV2.2,2-trisylmethylsulfanyl) 2: U1,-diamidine _4_ 荜 1 Λ L-n-MMM amine M Using the method described in step 15 of Example 15, N2 _ [(1S)-; U (4-bromophenyl) _ 2.2.2-trifluoroethyl]-&gt; ^-(1-cyanocyclopropyl) The 4,4-difluoro-L-n-valamine 醯 87282 -84- 200416032 was converted to the title compound. ± Λ1〇 ^ Cyanocyclo ^ dioxo, the preparation of a certain trioxo-1 bis 1-4'-ί succinyl valeramide using the method described in Example 15 step 骡 11 to Ni- (1_cyano ring (Propyl) _4,4_diamino-N2 _ {(lS) -2,2,2-trifluoroyl-1- [4, _ (methylthio) _u, diphenyl-4_yl] ethyl } -L-N-valeramide is converted to the title compound. As a specific embodiment of the present invention, the medicine group is 100 mg of Nom_ (chloromethyl) _N2- [2,2,2_trifluoroyl-1_ (4'-hexahydrou-biffine_ ι_yl-ΐ, ι'_diphenyl_4_ US) ethyl] -L-leukoamine, formulated with fine enough lactose to provide a total of 58-590 mg to fill No. 0 Hard gelatin capsules. The compounds disclosed in this patent application exhibit activity in the following analysis. In addition, the compounds disclosed in this patent application have enhanced pharmacological conditions relative to previously disclosed compounds. Analysis of cathepsin K A series of dilutions (1/3) of test compounds were prepared from monomethylammonium (DMSO) from a concentration of 500 micromolar to 0.000 micromolar. Then, 2 μl of each diluted DMS 0 was added to 50 μl of analysis buffer (50 millimolar concentration (pH 5.5) ME S, 2.5¾ mole concentration EDTA, 2.5 millimolar concentration). DTT and 10% DMSO) and 25 microliters of human cathepsin K (0.4 nanomolar concentration) dissolved in assay buffer solution. Let the analysis solution mix on the shaker platform for 5-10 seconds and incubate at room temperature for 15 minutes. Z-Leu-Arg-AMC (8 micromolar concentration) dissolved in 25 microliters of analysis buffer was added to the analysis solution. Water 87282 -85-200416032 The coumarin leaving group (AMC) was measured by spectrofluorescence for 10 minutes (Eχ λ = 3 5 5 nm, Em λ = 460 nm). Calculate the percent inhibition using a standard mathematical model that substitutes experimental values into a dose response curve. Analysis of cathepsin L A series of dilutions (1/3) of the test compounds were prepared using dimethylsulfoxide (DMSO) from a concentration of 500 micromolar to 0.0085 micromolar. Then, add 2 μl of each diluted DMSO to 50 μl of analysis buffer (50 millimolar concentration (pH 5.5) MES, 2.5 millimolar concentration of EDTA, 2.5 millimolar concentration of DTT and 10 % DMSO) and 25 microliters of human cathepsin L (0.5 nanomolar concentration) in analysis buffer solution. Let the analysis solution mix on the shaking platform for 5-10 seconds and incubate at room temperature for 15 minutes. Z-Leu-Arg-AMCM (micromolar concentration) dissolved in 25 microliters of analysis buffer was added to the analysis solution. The coumarin leaving group (AMC) was hydrolyzed for 10 minutes after spectrofluorescence measurement (Eχ λ = 3 5 5 nm, Em λ = 460 nm). Calculate the percent inhibition using a standard mathematical model that substitutes experimental values into a dose response curve. Analysis of cathepsin B A series of dilutions (1/3) of the test compounds were prepared using dimethylsulfone (DMSO) from 500 micromolar to 0.0085 micromolar. Then, add 2 μl of each diluted DMSO to 50 μl of analysis buffer (50 millimolar concentration (pH 5 · 5) MES, 2.5 millimolar concentration EDTA, 2.5 millimolar concentration DTT with 10% DMSO) and 25 microliters of human cathepsin B (4.0 nanomolar concentration) dissolved in assay buffer solution. Let the analysis solution mix on the shaking platform for 5-10 seconds and incubate at room temperature for 15 minutes. Z-Leu-Arg-AMC (8 micromolar concentration) dissolved in 25 microliters of analysis buffer was added to the analysis solution. Water 87282 -86 · 200416032 The coumarin leaving group (AMC) was measured by spectrofluorescence for 10 minutes (Eχ λ = 3 5 5 nm, Em λ = 460 nm). Calculate the percent inhibition using a standard mathematical model that substitutes experimental values into a dose response curve. Analysis of cathepsin S A series of dilutions (1/3) of test compounds were prepared using dimethylsulfoxide (DMSO) from a concentration of 500 micromolar to 0.0085 micromolar. Then, add 2 μl of each diluted DMSO to 50 μl of analysis buffer (50 millimolar concentration (pH 5.5) MES, 2.5 millimolar concentration of EDTA, 2.5 millimolar concentration of DTT and 10 % DMSO) and 25 microliters of human cathepsin S (20 nanomolar concentration) in analysis buffer solution. Let the analysis solution mix on the shaking platform for 5-10 seconds and incubate at room temperature for 15 minutes. Z-Leu-Arg-AMC (8 micromolar concentration) dissolved in 25 microliters of analysis buffer was added to the analysis solution. After the hydrolysis of the coumarin leaving group (AMC), a 10-minute spectrofluorescence measurement was performed (Eχ λ = 35 nm, Em λ = 460 nm). Calculate the percentage of inhibition using standard mathematical models that substitute experimental values into dose-response curves. 87282 87-

Claims (1)

Pick up and apply for a patent garden ·· • A compound of the following chemical formula: Wherein R1 is hydrogen, alkyl, or c2-6fluorenyl, and the alkyl and alkenyl are optionally 1-6 halo, (3-6 cycloalkyl, -SR9, -SR12, -SOR9, _S. Rl2, _S〇2R9, _S02R12, -S02CH (R12) (Rn), -OR12, _ϋK9, _N (R'2, aryl, heteroaryl or heterocyclic group, of which 40,000, heteroaryl and Heterocyclyl is optionally substituted with 1 or 2 substituents independently selected from ci_6 ^, _, hydroxy, hydroxy, alkoxy, or keto; R is hydrogen, Cn, or C2_6 , Where the fluorenyl group and fluorenyl group are optionally through 1-6 halo groups, c3-6 ring alkyl groups, -SR9, -SR12, -SOR9, -SOR12 Λ -S〇2R9. _S〇2R12 ^ -S02CH ( R12) (Rh) &gt; ^ OR12. -OR9. _N (R 2) 2, aryl, heteroaryl or heterocyclic group, wherein the aryl, mobile aryl and heterocyclic group are optionally substituted by 1 Or 2 substituted by a substituent independently selected from ci-6 alkynyl, dentyl, hydroxyalkyl, hydroxy, alkoxy, or keto; or R1'R2 may together form a C3-8 ring with the carbon atom to which they are attached Alkyl or cyclyl ring, where the ring system is independently selected from Cr6 alkyl, hydroxyalkyl, Substituted by alkyl or halo substituents; R is hydrogen, Cn alkyl or C2-6 fluorenyl, wherein the alkyl and alkenyl are optionally substituted with C3 cyclocycloalkyl or 1-6 halo R4 is hydrogen, Cn alkyl or a-6 alkenyl, wherein the alkyl and alkenyl are optionally 87282 200416032 substituted by C3-6 cycloalkyl or 1-6 halo; or R3 and R4 may be Together with the carbon atom to which it is attached (: a 3-8 ring alkyl group, a C5-8 ring fluorenyl ring, or a 5-7 ring heterocyclic group, wherein the cycloalkyl, cyclofluorenyl and heterocyclic group are 1 or 2 substituents independently selected from Ca alkyl, halo, hydroxyalkyl, hydroxy, alkoxy, or keto; R5 is selected from hydrogen or alkyl or substituted with 1-6 halo Ci_6 alkyl; R6 is aryl, heteroaryl, haloalkyl, aralkyl, or heteroaralkyl, wherein the aryl, heteroaryl, aralkyl, and heteroaralkyl are, depending on the situation, 1, 2 or 3 independently selected from halo, Cn alkyl, CV6 haloalkyl, C3-6 cycloalkyl, halooxy, -SR9, -SR12, -SOR9, -SOR12, _S02R9 ... S02R12, -S02CH ( R12) (Ru), -OR12, -n (r10) (Ru), cyano or optionally substituted with -S02R12 Substituted by an aryl group; each D is independently (^ -3 alkyl, C2-3 alkenyl, C2-3 amidino, aryl, heteroaryl, C3-8 cycloalkyl or heterocyclic group, where , Which may be a single or bicyclic individual aryl, heteroaryl, cycloalkyl, and heterocyclic group, depending on the case, on the carbon or heteroatom, independently selected from Ca alkyl and haloalkane through 1 to 5 Group, halo, keto, alkoxy, -SR9, -SR12, -OR9, -OR12, N (R12) 2, _S02R9 or -S02R12 substituent; R7 is hydrogen, CV6 alkyl, C2- 6 alkenyl, C2-6 alkynyl, Cn alkoxy, halo, nitro, cyano, aryl, heteroaryl, C3-8 cycloalkyl, heterocyclyl, -C (0) OR1 ( ), C (0) OSi [CH (CH3) 2] 3, -OR9, -OR1. -C (0) R10, R1GC (0) R9, -C (0) R9, -C (0) N (Ra) (Rb), -C (0) N (R12) (R12), surface C (0) N (R1g) (Ru), -C (R1g) (Ru) OH, -SR12, -SR9, -R10SR9 87282 -2- ^ -R9 ^ -C (R9) 3 &gt; -C (R10 ) (Rn) N (R9) 2 ^ -NR10C (O) NR10S (O) 2R9, _S02R12, -SO (R12), _S02R9, -SOmN (Rc) (Rd), -SOmCH (R10) (Rn),- S02N (R1Q) C (0) (R12), -S02 (R1G) C (0) N (R12) 2, -0S02R1G, -N (R1G) (RU), -N (R1G) C (0) N ( R1G) (R9), -N (R10) CO (R9), -N (R1Q) C (0) R1Q, -N (R1 ()) C (0) 0R1 (), -N (R1G) S02 (R10 ) ^ -C (R10) (R11) NR10C (R10) (R11) R9--C (Rl0) (Ru) lSi (R10) R9 &gt; -C (R10) (R11) N (R10) (R11) ^ -C (R10) (R11) SC (R10) (R11) (R9) ^ R10S-, _C (Ra) (Rb) NRaC (Ra) (Rb) (R9), -C (Ra) (Rb) N ( Ra) (Rb), _C (Ra) (Rb) C (Ra) (Rb) N (Ra) (Rb), -C (0) C (Ra) (Rb) N (Ra) (Rb), -C (Ra) (Rb) N (Ra) C (0) R9, -C (0) C (Ra) (Rb) S (Ra), C (Ra) (Rb) C (0) N (Ra) (Rb ), -B (OH) 2, -0CH20- or 4,4,5,5-tetramethyl_1,3,2-dioxaborolan-2-yl, where the group is carbon or On the heteroatom, 1 to 5 groups are selected from the group consisting of a group, a halo group, a keto group, a cyano group, a alkynyl group, a alkynyl group, -OR9, -no2, -nh2, -nhs (o) 2r8, -r9so2r1 2, -so2r12, -SO (R12), -SR12, -SR9, -SOmN (Rc) (Rd), -SOmNCR10) C (0) (R12), C (R10) (Ru) N (R10) ( Rn), -C (R10) (RU) OH, -COOH, -C (Ra) (Rb) C (0) N (Ra) (Rb), -C (0) (Ra) (Rb),- N (R10) C (R1G) (RU) (R9), -N (R1G) CO (R9), -NH (CH2) 2OH, -NHC (0) 0R1 (), Si (CH3) 3, heterocyclic group R8 is hydrogen or Ca alkyl; or R4 and R8 may be together with any atom to which they may be attached or with each other to form a 4-10 ring heterocyclic system, wherein May be a monocyclic or bicyclic 5-ring system ', depending on the case, via 1 or 2 substituents independently selected from Cl_6 alkyl, halo, hydroxyl 200416032 alkyl, hydroxyl, keto, _ORig ... sr1g * _N (RlG) 2 Substituted; R9 can only be selected from the following: hydrogen, aryl, aryl (Cn) alkyl, heteroaryl, heteroaryl (Cl-4) alkyl, a-8cycloalkyl, Cn ring Alkyl (Ci_4) alkyl and heterocyclyl (Cl_4) alkyl, where the group may be optionally substituted with 丨, 2 or 3 substituents independently selected from dentyl, alkoxy or -S〇2Rl2 ; R1 () is hydrogen or CV6 alkyl; R11 is hydrogen or CV6 alkyl; R12 is hydrogen or Cl-6 alkyl substituted with 1, 2 or 3 substituents independently selected from the group consisting of sulfanyl, alkoxy, cyano, -nr1g or -sr1g, as appropriate; Ra is hydrogen, Cn alkyl, (Cl · 6 alkane Group) aryl, (Ci_6alkylfluorenyl, -CKCnfluorenyl), hydroxyl, halo, aryl, heteroaryl, cycloalkyl, heterocyclic group, wherein the alkyl, aryl, heteroaryl, c3-8 cycloalkyl and heterocyclyl may be substituted on carbon or heteroatom with 1, 2 or 3 substituents independently selected from Ci-6 alkyl or halo; Rb is hydrogen, C ^ 6 alkyl (Cn alkyl) aryl, (Cn alkyl) hydroxy, alkoxy, alkyl, halo, aryl, heteroaryl, C ^ 8 cycloalkyl, heterocyclyl, wherein the alkyl, aryl Group, heteroaryl group, C: 3 »8 cycloalkyl group and heterocyclic group may be optionally substituted on fluorene or heteroatom with 1, 2 or 3 substituents independently selected from the group consisting of C 1-6 alkyl or halo ; Or R and Rb together with the carbon atom to which they are attached or each other form a C ^ 8 cycloalkyl ring or (: 3_8 heterocyclyl ring, where the 3_8 ring system may be independently selected by 1 or 2 From C1 graft and halo substituents 87282 200416032 Re; Re is hydrogen or optionally substituted by 2 or 3 substituents independently selected from halo or -OR9 (^ -6 alkyl; Rd is hydrogen or is optionally substituted by 1, 2 or 3 Independently selected from the group consisting of halo or -OR9, and substituted by Ca alkyl; &gt; or Re and Rd can be formed together with the nitrogen atom to which they are attached or between each other, depending on the situation, 1 or 2 independently selected From a C alkyl group, a halo group, a hydroxyalkyl group, a C3_8 cycloalkyl ring substituted by a substituent of a alkoxy group, an alkoxy group, or a keto group; * η is an integer independently selected from 1 to 3; Independently selected from integers from 0 to 2; and pharmaceutically acceptable salts, stereoiso shopping and sense oxide derivatives thereof. 2. The compound according to item 1 of the scope of the patent application, wherein Ri is hydrogen and R2 is hydrogen, or R1 and R2 may together form a C3_8 cycloalkyl ring with the carbon atom to which they are attached, where the ring system is 2 substituents selected from alkyl or halo, and pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof. 3. The compound according to item 2 of the scope of the patent application, in which R3 is an alkyl group substituted by 1 'to 6 halogen groups, and R4 is hydrogen, and its pharmaceutically acceptable salts and jl isomers Compounds and N-oxide derivatives. 4 ·: Compound No. 3 according to the scope of patent application, in which r3 is n-propyl, Xiutyl, 2-fluoro-2-methylpropyl, 2-trimethylpropyl,% ethyl (2-fluoromethyl) propyl, 2,2-difluoroethyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, 2,2-dichloroethyl, and r4 It is hydrogen, and its salts, JL isomers, and oxide derivatives that can be connected to 87282 W0416032 branch in medicine. The compound according to item 3 of the scope of patent application, wherein R5 is hydrogen and R6 is aryl or heteroaryl; wherein, the aryl or heteroaryl is optionally selected from halo or -S through 1, 2 or 3 〇2R12 substituted by the substituent, and its pharmaceutically acceptable salts, jl isomers and N-oxide derivatives. • The compound according to item 3 of the scope of patent application, wherein R5 is hydrogen and R6 is Ci-6 alkyl substituted with 1 to 6 radicals, and pharmaceutically acceptable salts, stereoisomers and N-oxidation thereof物 Derivatives. • The compound according to item 6 of the scope of patent application, wherein R5 is hydrogen and R6 is difluoromethyl or 3,3,3,2,2-pentafluoroethyl, and its pharmaceutically acceptable steric structure Compounds and N-oxide derivatives. The compound according to item 6 of the patent application park, wherein 2, each D is a unique aryl or heteroaryl group, and 5 ^ is _somm (Ri〇XRii) or _Somm (Rc) ( Rd), ^ and ... are each independently hydrogen or alkyl, and pharmaceutically acceptable salts, stereoisomers and N-oxide derivatives thereof. • Compounds according to the formula under item 1 of the patent application park, Among them: 87282 200416032 stereochemistry of (* c, * * c) R3 R6-(D) n-R7 RS, S 2 -methylpropylcf3 4-bromophenyls, s 2-methylpropylcf3 4'-Methylsulfobiphenyl-4-yl s, s 2-methylpropyl 3-methyl-pyrimin-2-yl 4-bromophenyls, s 2-methylpropyl 3- Methyl-fluoren-2-yl 4'-methylsulfonyldiphenyl-4-yl s, s n-propylcf3 4'-methylsulfonyldiphenyl-4 -yl s, s n-propyl Cf3 4-bromophenyls, s 2-methylpropyl farphen-3 -yl 4-bromophenyls, s 2-methylpropyl p-sphen-3 -yl 4'-methylsulfonium Diphenyl-4-yl s, s n-propyl cf3 4, aminosulfobiphenyl-4 -yl s, s 2-methylpropylphenphen-3 -yl 4'-aminosulfonyl Diphenyl-4 -yl s, s n-propyl cf3 4'-methyl multityl-3'-methylcontinyl diphenyl-4-yl 87282 200416032 s, s n-propyl cf3 4- ( 2-T-group p ratio yodo-4-yl) winteryl s, s 3,3,3, -trifluoropropyl cf3 4'-methylsulfonylbiphenyl-4-yl s, s n-propyl cf3 4- (1Η · pyrazol-3-yl) phenyl s, s n-propyl cf3 4 '-(1-hydroxy-1-methylethyl) diphenyl-4-yls, s n-propyl Base cf 3 4- (5-Methylpyridin-2-yl) benzyl s, s n-propylcf3 4'-ethylfluorenylbiphenyl-4-yls, s n-propylcf3 2 ', 4'- Difluorodiphenyl-4-yls, s n-propylcf3 3 ', 4'-difluorodiphenyl-4-yls, s n-propylcf3 3'-chloro-4'-fluoro Diphenyl-4-yl s, s n-propylcf3 4'-methylsulfonamidodiphenyl-4 -yl s, s n-propylcf3 4 '-chlorodiphenyl-4-yl 87282 200416032 s, s n-propylcf3 4'-chloro-3'-methyldiphenyl-4-yls, s n-propylcf3 4'-chloro-2'-methyldiphenyl-4 -Group s, s n-propylcf3 4'-indol-5-ylphenyls, s n-propylcf3 3'-methylsulfonamidodiphenyl-4-yls, s n- Propyl cf3 4'-aminodiphenyl-4_yl s, s n-propyl cf3 4'-fluoro-3methyldiphenyl-4 -yl s, s n-propylcf3 3'-fluoro- 4'-methyldiphenyl-4-yls, s n-propylcf3 4'-trifluoromethoxydiphenyl-4-yls, s n-propylcf3 4'-methyldiphenyl-4 -Group s, s n-propylcf3 4 '-chlorodiphenyl-4-yl s, s n-propylcf3 4'-methoxydiphenyl-4-yl 87282 -9- 20041 6032 s, s n-propylcf3 4- (3,4-methylenedioxy-phenyl) phenyls, s n-propylcf3 4'-methoxycarbonyldiphenyl-4-yls , S 2-methylpropylpyrazol-2-yl 4-bromophenyls, n-propylcf3 4'-trifluoromethyldiphenyl-4-yls, s n-propylcf3 2 ' -Trifluoromethyldiphenyl-4-yl RS, S 2-methylpropyl p-stilbene-2 -yl 2 ', 4'-difluorodiphenyl-4-yl RS, S 2-methylpropyl Stilbene-2-yl 4'-methylsulfonylbiphenyl-4-yl S, S 2-methylpropyl 4-&gt; s-p-phenphen-2-yl 4-bromophenyls, s 2-methylpropyl cf3 4-methylphenyl s, s 2-methylpropyl cf3 4- (1Η- ρ than polo-3-yl) phenyl s, s 2-methylpropyl cf3 4- (2-methyl-1,3-oxazol-4-yl) phenyl 87282 -10- 200416032 s, s 2-methylpropyl cf3 4- (2-methylexo I: Radical) s, s 2-methylpropyl cf3 4- (4-methylpyridin-3-yl) phenyl s, s 2-methylpropyl cf3 3'-ethenyldiphenyl-4- S, s 2-methylpropyl cf3 5- [4- (l-: ¾yl-1_methylethyl) -phenyl] # b-2-yl s, s 2-methylpropyl cf3 4'-methoxy-3-methylcontinyl-diphenyl -4-yl s, s 2-methylpropyl cf3 3, aminosulfonyl-4'-methoxy-dibenz-4-yl s, s 2-methylpropyl cf3 4- (6- Methoxypyridin-3-yl) phenyl s, s 2-methylpropylcf2cf3 4- (5-methylpyridin-2-yl) benzyl s, s 2-methylpropylcf3 4- (5 -Methylsulfonyl p than 2-Yenyl) phenyl 87282 -11-200416032 s, s 2-methylpropyl cf3 4- (5-Methylexo 1: Yodo-2-yl) phenyls , S 2-fluoro-2-methylpropylcf3 4'-methylsulfonyldiphenyl-4-yls, s 2-fluoro-2-methylpropylcf3 2'-methyl-4'- Methylcontinyldiphenyl-4-yls, s 2-methylpropylcf3 5-(Junlin-6-yl) pyridin-2-yls, s 2-methylpropylchf2 4'-formyl Sulfosulfenyldiphenyl-4-yls, s 2-methylpropylcf2cf3 4'-Ethyldiphenyl-4-yls, s 2-methylpropylcf3 6-chlorop -Yl s, s 2-methylpropyl cf3 5- (4-ethylfluorenylphenyl) p ratio -2 -yl s, s 2-methylpropyl cf3 6- (4-acetylphenyl) p-bito-3 -yl s, s 2-methylpropylcf3 5- (3-ethylfluorenylphenyl) p-bito-2 -yl s, s 2-methylpropylcf3 5- [4- (1-hydroxyethyl) phenyl] -2 -yl 87282 -12- 200416032 s, s 2-methylpropylcf3 pyrazol-4-yl) -1,3-pyrazol-4-yl] phenyls, s 2-methylpropylcf3 4- (2 · methyl-1,3-daptoy-4-yl) phenyls, s 2-methylpropylcf3 4- (2-methylpyridin-4-yl) phenyls, s 2 -Methylpropyl cf3 4- (2-methylpyridin-3-yl) phenyls, s 2-fluoro-2-methylpropylcf3 3'-ethanyldiphenyl-4-yls, s 2-fluoro-2-methylpropyl cf3 4- (1Η-πbijun-3-yl) phenyl s, s 2-methylpropyl cf3 5- (4-methylsulfonylphenyl) Dysmen-2-yl s, s 2-methylpropyl cf3 4 '-(1-hydroxy-1-methylethyl) dibenz-4-yl s, s 2S-difluoro-methylpropyl cf3 4'-Methylsulfonyldiqin-4-yl s, s 2 S -diamino-methylpropylcf3 4'-methylthiodiphenyl-4-yl 872 82 -13-&gt; 00416032 s, s 2-methylpropyl cf2cf3 4- (6-methylex1: Yodo-3 -yl) phenyl s, s 2-methylpropylcf3 4- (6-methylex1: Yodo- 3-yl) phenyl s, s 2-methylpropyl cf2cf3 4-(1-Controll-1 -methylethyl) -diphenyl-4-yl s, s 2-methylpropyl cf2cf3 4 ' -Methyl group S preparation base two -4 _S, s 2-methylpropyl cf2cf3 4- (6-methoxypyridin-2-yl) benzyl s, s 2R-diamino-methylpropylcf3 4'-methylsulfonium Diphenyl-4-yl s, s 2-methylpropyl cf3 4- (1,3-pyrazol-2-yl) phenyl s, s 2-methylpropyl cf3 4- (5-methyl -1,3-pyrimidin-2-yl) phenyl s, s 2-methylpropylcf3 4- (4-methyl-1,3-pyrazol_2_yl) phenyl s, s 2- Fluoro-2-methylpropyl cf3 4 '-ethyl continyldiphenyl-4-yl s, s 2-fluoro-2-methylpropyl cf3 4 -p ratio ρfoot-3 -ylphenyl 87282 -14- ^ 416032 s, s 2-fluoro-2-methyl cf3 4'-methoxy-3'-propylmethyl ----- 2_methylpropyl cf3 4 '-(2-hydroxy-2-methylpropyl continued), diphenyl-4-yl s, s 2_methylpropyl cf3 but 1 &lt; χ &gt; 2'-methyl-4'-methylphenyldiphenyl ————_ s, s ------- 2-methylpropyl ------------- ---------_ cf3 ------ -4-yl 4'-ethylsulfonylbiphenyl-4-yl 2-fluoro-2-methyl cf3 4'-aminosulfonyl Propyl ----------- -------- diphenyl-4-yl j -------- ^ food Accepted salts, corpus isomers, and N-oxide derivatives. .Species N-(L cyanocyclopropyl) _4_fluoro_N2 _ {(1S) _2,2,2_trifluoro- (methylsulfonyl) _15l, _diphenylyl} ethylbenzene L _ Leucamide or a pharmaceutically acceptable salt thereof. U · A kind of Nl- (1_cyanocyclopropyl) -4 • fluoro-N2-{(lS) -2,2,2_trifluoro group ^ [4 '《· ((methylsulfinyl)) _ U __Diphenyl-4_yl] ethyl L_leucine scopolamine or a pharmaceutically acceptable salt thereof. N (Scattered Methyl) _N {(lS) -2,2,2-trifluoroyl-1- [4 '-(methylsulfonyl) -1, Γ-diphenyl-4-yl] Ethyl L-leukoamine or a pharmaceutically acceptable salt thereof. 87282 -15- species (aminosulfosulfanyl group, diphenyl group "-2, 2,2,2-trifluoroethyl group Nl (cyanomethyl) heptaamine or its pharmacologically acceptable Accepted salt. 16. 17. A pharmaceutical composition 'is made by combining a compound according to item ^ of the Patent Application and a pharmaceutically acceptable carrier. A method for manufacturing a pharmaceutical composition, which comprises combining a compound according to item 1 of the patent application park with a pharmaceutically acceptable carrier. A pharmaceutical composition for a mammal in need thereof for inhibiting cathepsin activity, comprising a compound in an effective amount according to item i of the claimed patent range. R The pharmaceutical composition according to item 17 of the patent application, wherein the tissue protease activity is cathepsin K activity. 19 .: A composition for the treatment or prevention of mammals in need thereof selected from the group consisting of: osteoporosis, osteoporosis caused by glucocorticoids, aberrant osteitis, abnormally increased bone turnover 'tooth Peripheral disease, tooth loss, fractures, rheumatoid arthritis, osteoarthritis, component periosteal osteolysis, osteogenesis imperfecta, metastatic osteoporosis, malignant hyperhyperemia or multiple myeloma, including effective The amount is based on the number of compounds in the scope of patent application. The pharmaceutical composition according to item 19 of the scope of application, wherein the disease is osteoporosis. 21 · —For mammals in need thereof for the treatment of cathepsin-dependent conditions 87282 -16- 200416032 &lt; A pharmaceutical composition comprising a therapeutically effective amount of a compound according to item 1 of the scope of patent application. 22 · —A pharmaceutical composition comprising a compound according to item 丨 of the scope of the patent application and another agent selected from the group consisting of an organic bisphosphonate, an estrogen receptor · modulator, an estrogen receptor stone modulator, and male Receptor modulators, osteoclasts; osteocyte proton ATPase inhibitors, HMG_coA reductase inhibitors, integrins receptor antagonists, osteoblast assimilating agents and their pharmaceutically acceptable salts and mixtures thereof. 23 · —A pharmaceutical composition for the treatment or prevention of a disease selected from the group of osteoporosis, glucocorticoid-induced osteoporosis, teratogenic osteitis, ~ abnormally increased bone turnover 'periodontal disease, teeth Loss, fracture, rheumatoid arthritis, osteoarthritis, periosteal osteolysis, osteogenesis imperfecta, metastatic bone disease, hypercalcemia of malignant disease or multiple myeloma, including therapeutically effective amounts according to the scope of the patent The compound of item 丨 and another agent selected from the group consisting of organic bisphosphonates, estrogen receptor modulators, androgen receptor modulators, osteoclast proton Ατρ enzyme inhibitors, HMG-CoA reductase Inhibitors, integrin receptor antagonists or osteoblast assimilating agents, and pharmaceutically acceptable salts and mixtures thereof. · 2 medical composition according to item 23 of the scope of patent application, wherein the disease is osteoporosis. 25 · ~ pharmaceutical compositions, including a compound according to item i of the patent application scope and another agent selected from the group consisting of organic bisphosphonates, estrogen receptor modulators, estrogen receptor modulators, androgens Receptor modulators, osteoclast proton ATPase inhibitors, HMG-COA reductase inhibitors, whole 87282 -17- 200416032 synthase receptor antagonists or osteoblast assimilation agents and their pharmaceutically acceptable salts With a mixture. 26. A pharmaceutical composition for inhibiting bone resorption, including a compound according to item 1 of the scope of patent application. 27. A pharmaceutical composition for increasing bone calcium density, comprising a compound according to item 1 of the scope of patent application. 28. A pharmaceutical composition for reducing the risk of fracture, including a compound according to item 1 of the patent application scope. 87282 18- 200416032 (1) Designated representative map: (1) The designated representative map in this case is: (). (2) Brief description of the element representative symbols of this representative figure: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention 'R5R, v, ^ n Λ R8 ο 87282 -6-