Novel cyclosporin derivatives and uses thereof

Abstract

To provide novel cyclosporin derivatives.SOLUTION: Provided is a compound having the following structure or a pharmaceutically acceptable salt thereof. Also provided are a pharmaceutical composition comprising the same, and a method that uses the same for treating or preventing viral infections, inflammation, dry eye, central nervous disorders, cardiovascular diseases, cancer, obesity, diabetes, muscular dystrophy, lung, liver, and kidney diseases, and hair loss.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Related Applications This application is a continuation of U.S. patent application Ser. No. 13 / 840,088, filed March 15, 2013. This application is related to U.S. Provisional Application No. 62 / 337, filed May 17, 2016. 377, U.S. Provisional Application No. 62 / 339,464, filed May 20, 2016, and and claims priority to U.S. Provisional Application No. 62 / 384,822, filed September 8, 2016. The entire contents of these applications are expressly incorporated by reference in their entirety.

[0002] The present invention relates to novel cyclosporin derivatives, pharmaceutical compositions containing them, and methods for preventing viral infection. Infection, inflammation, dry eyes, central nervous system disorders, liver, lung and kidney diseases, cardiovascular diseases, cancer, obesity, The present invention relates to a method for treating or preventing diabetes, muscular dystrophy, hair loss, and the like. [Background technology]

[0003] Natural cyclosporin is a poly-N-methyl cyclic undecapeptide isolated from a fungus. Cyclosporine A has immunosuppressive activity and is used in kidney, heart, and liver transplant recipients. It has been used for about 33 years to prevent rejection in rats. It has anti-inflammatory properties. However, severe rheumatoid arthritis, severe psoriasis, Behcet's uveitis It is used to treat dry eye disease, ulcerative colitis, and other serious conditions such as ulcerative colitis. Enteritis, Crohn's disease, alopecia areata, aplastic anemia, HSV-1 stromal keratitis, systemic chronic It is useful in the treatment of lupus erythematosus and severe lupus nephritis. The inhibitory activity limits its application in many diseases.

[0004] The anti-HIV activity of cyclosporine A was first discovered in 1986 and has continued to be These have been studied (Non-Patent Documents 1 to 3, each of which is incorporated herein by reference). Its non-immunosuppressive derivative, NIM-811, inhibits cyclophilin A and It has been reported that these compounds have potent anti-HIV activity due to their ability to each of which is incorporated herein by reference).

[0005] NIM-811 (N-MeIle-4-cyclosporine), Debio-025, SC Y-635, EDP-494, DEP-546, NIM-258, CPI-431-32 (CRV431), and cyclosporin A and its non-immunosuppressive derivatives such as STG-175 The body binds to and inhibits cyclophilin, subsequently inhibiting HCV RNA replication and As a result, these compounds have effective anti-HCV activity. (Non-Patent Documents 8 to 17; each of which is incorporated herein by reference). -811, Debio-025, and SCY-635 are in Phase II and I trials for HCV. EDP-494 is being evaluated in a Phase II clinical trial and a Phase I trial of EDP-494 is evaluating resistance-associated mutations in HCV. The body is expected to launch in the first quarter of 2016.

[0006] NIM-811 and Debio-025 have a chemical structure similar to cyclosporin A. In addition, they have poor pharmacokinetic profiles and are prone to induce drug interactions. and are metabolized by P450 (Non-Patent Document 18; incorporated herein by reference). ).

[0007] SCY-635 has an improved pharmacokinetic profile and low serum binding. , which has a low potential for drug-drug interactions. In vitro anti-HCV activity of SCY-635 (EC 50 ) was reported to be 0.10 μM (Non-Patent Document 19; see the present invention for reference). However, SCY-635 can be easily converted into its derivative by epimerization. It is not chemically stable because it is converted into diastereoisomers. is expected to have low binding activity to cyclophilin, resulting in its antiviral activity in vivo. The activity of the enzymes may be affected (see, for example, Patent Documents 1 to 3, each of which is incorporated by reference). (which is incorporated herein in its entirety by reference).

[0008] Cyclosporin A and its non-immunosuppressive derivatives also act through the inhibition of cyclophilin. It has been found to have anti-HBV activity (Non-Patent Documents 20-25; each of which is incorporated herein by reference). (Incorporated herein by reference thereto).

[0009] Furthermore, cyclophilin is a key regulator of severe acute respiratory syndrome coronavirus, vaccinia virus, and He has studied the life cycle and pathogenesis of several viruses, including the herpes simplex virus and the flu virus. It has been reported that the effects of hydroxybenzoates on the hydroxybenzoates of hydroxybenzoates are suppressed (Non-Patent Documents 26-31; each of which is incorporated herein by reference). Cyclosporin A and its non-immunosuppressive derivatives are also used as such antivirals. It has antibacterial activity.

[0010] Another non-immunosuppressive cyclosporine derivative, N-MeVal-4-cyclosporine ( SDZ 220-384) has been reported to have similar biological activity to NIM-811. (Non-patent documents 32 and 33).

[0011] Hepatitis C virus (HCV) is a member of the Flaviviridae family A small (55-65 nm in size) enveloped positive strand of HCV is a single-stranded RNA virus with a high replication rate and a very high mutation rate. Approximately 80% of people infected with HCV develop chronic persistent infection. Americans are infected with HCV, and over 200 million people worldwide are chronically infected It is estimated that approximately 35,000 new cases of hepatitis C occur in the United States each year. HCV infection accounts for approximately 50% of all chronic liver disease, 30% of all liver transplants, and 10% of all liver transplants in the United States. It is the cause of 30% of cirrhosis, end-stage liver disease, and liver cancer. Combination therapy with steroids is the standard treatment for chronic hepatitis C, but its effectiveness against HCV infection is low. Recently, the FDA approved the current interferon / ribavirin regimen for treating HCV. Vertex's Incivek (telaprevir) and Mercari's The U.S. government approved Victrelis (boceprevir) for the treatment of HIV-1. Both drugs are designed to prevent its replication. However, the rapid progression of HCV is difficult to predict. Due to the low mutation rate, drug resistance can develop in a short time. There is a need for effective treatments.

[0012] Hepatitis B virus (HBV) is an outer lipoprotein containing the surface antigen (HBsAg). Consists of a 27 nm nucleocapsid core (HBcAg) surrounded by a cytoplasmic envelope It is a 42 nm partially double-stranded DNA virus that infects over 2 billion people. The virus is a chronic carrier of 350 million people. It is causing epidemics in parts of Africa. Chronic hepatitis B is not responsive to current chemotherapy. It causes cirrhosis and liver cancer, fatal diseases that are very unresponsive to vaccination. HBV load and replication can be prevented by current antiviral drugs, e.g., lamivudine. (Epivir), adefovir (Hepsera), tenofovir (Viread), tert- Vivudine (Tyzeka), Entecavir (Baraclude), and two immune system Modulators of interferon alpha-2a and pegylated interferon alpha However, none of the available drugs can reduce the risk of infection. There is no cure for HBV. Effective therapeutic agents are needed to treat HBV infection. Recently, NTCP has been identified as an HBV entry target (Non-patent Documents 34-37). Cyclosporine A and its analogs inhibit HBV entry at the NTCP receptor. Alisporivir (Alis), a cyclosporine analogue (Non-Patent Documents 38 and 39), porivir) and STG-175 also inhibit cyclophilin in hepatocytes, leading to HBV V RNA replication and HBsAg production and secretion (Non-patent Documents 40 and 41 ).

[0013] Non-immunosuppressive cyclosporine derivatives inhibit the function of viral proteins for viral replication. cis- in protein folding and regulation, which is important for processing and maturation Cycloheximide, a family of host proteins that catalyze transpeptidyl-prolyl isomerization HIV and HCV are viruses with high mutation rates. All current antiviral drugs target the virus itself; once the virus mutates, Instead of directly targeting the virus, they target host cofactors (cyclohexyl) Targeting filin slows the development of drug resistance due to a higher genetic barrier (Non-Patent Documents 42-44; each of which is incorporated herein by reference). The sporin derivatives affect a new target, cyclophilin, and thus act against viruses. This demonstrates a new mechanism of action.

[0014] There are 19 cyclophilins in the human genome (Non-patent Document 45). The functions of rhofilin isoforms remain unclear (Non-patent Document 46; see also (The text is incorporated herein by reference.) Cyclophilins A, B, C, D, and other such Different isoforms play important roles in the pathophysiology of many serious diseases, including: and the like, for example, in cancer (Non-Patent Documents 47-61; each of which is incorporated herein by reference). Inflammation (secreted extracellular cyclophilin and CD-147, surface proteins 62-64; each of which is incorporated herein by reference. Incorporated), cardiovascular disease (vascular stenosis, atherosclerosis, abdominal aortic aneurysm, aortic Pulse rupture, cardiac hypertrophy, pulmonary artery hypertension, myocarditis and myocardial fibrosis and ischemic heart disease, liver, kidney and and pulmonary fibrosis, protection and regeneration); Non-Patent Documents 65-79; each of which is incorporated herein by reference. rheumatoid arthritis (Non-Patent Documents 80-87, each of which is incorporated herein by reference); (incorporated herein by reference to the present application), respiratory inflammation (Non-Patent Documents 88-98; each of these (incorporated herein by reference), lupus (Non-Patent Documents 99-103; each of which is psoriasis (Non-Patent Documents 104-106, each of which is incorporated herein by reference); are incorporated herein by reference), atopic dermatitis (Non-Patent Documents 107-110 each of which is incorporated herein by reference), dry eye disease (Non-Patent Document 1 11-114; each of which is incorporated herein by reference), severe Graves' syndrome Ophthalmopathy (Non-Patent Document 115; incorporated herein by reference), endogenous uveitis (non- U.S. Patent No. 5,629,996; incorporated herein by reference), Wegener's granulomatosis (Non-Patent Document 116; incorporated herein by reference), 117; incorporated herein by reference), vernal keratoconjunctivitis atoconjutivitis) (Non-Patent Document 118; incorporated herein by reference). atopic keratoconjutivitis (Non-Patent Document 119; incorporated herein by reference); Ligneous Conjunctivitis (Non-Patent Document 1 20; incorporated herein by reference), conjuctival lichen planus linchen planus) (Non-Patent Document 121; incorporated herein by reference). superior limbic keratoconjunctivitis tivitis) (Non-Patent Document 122; incorporated herein by reference), inflammatory bowel disease Diseases - Crohn's disease and ulcerative colitis (Non-Patent Documents 123-131; each of these is incorporated by reference) , incorporated herein by reference), NSAID-induced enteropathy (Non-Patent Document 132; see also and ischemic brain injury ( diseases) (Non-Patent Document 133; incorporated herein by reference).

[0015] Cyclosporin derivatives also have the following biological activities due to cyclophilin inhibition: Antifungal (Non-Patent Documents 134-138; each of which is incorporated herein by reference). antimalarials (Non-Patent Documents 139-141; each of which is incorporated herein by reference); and antiparasitic drugs (Leishmania donovani) donovani, Cryptosporidium parvum vum), small tapeworm (Hymenolepis nana), Toxoplasma gondii plasma), Trypanosoma cruzi, and and Schistosomes) (Non-Patent Documents 142-153; (Each of which is incorporated herein by reference.) In addition, cyclosporin derivatives have been shown to promote hair growth. (Non-Patent Documents 154-159; each of which is incorporated herein by reference). (Incorporated into

[0016] Studies of Alzheimer's disease have shown that cyclophilin A mediates APOE4-mediated neurovascular damage and The resulting neuronal dysfunction and degeneration are important targets for treating the disease. (Non-Patent Documents 160 and 161; each of which is incorporated herein by reference.) (Can be).

[0017] For the function of extracellular cyclophilin, a cell-impermeable derivative of cyclosporin was used. Specific targets of extracellular cyclophilins secreted by cyclophilins are known to be involved in diseases such as respiratory inflammation and cardiovascular disease. It should be emphasized that it is effective in reducing inflammation in diseases (Non-Patent Documents 162-161). 68; each of which is incorporated herein by reference). To target this, MM284 was discovered and tested for its anti-inflammatory properties (Non-Patent Document 1). 169) Regarding biliary atresia (BA) and other chronic intrahepatic diseases (Non-patent Document 170), Further research into the reduction of myocardial inflammation and cardiac fibrosis (Non-Patent Document 171) has shown that TNF-α A study on the reduction of lufa (Non-Patent Document 172) has been reported.

[0018] Cyclophilin D (CypD) is essential for mitochondrial-related neuronal and cardiovascular functions It is very important because it is an integral part of the mitochondrial permeability transition pore (mPTP) Unregulated opening of mPTP leads to mitochondrial swelling and cell death. Therefore, CypD-mediated mPTP is involved in many neurological and cardiovascular diseases, For example, Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS, aging, heart failure, Traumatic brain injury, spinal cord injury, status epilepticus, stroke, ischemia in the brain, heart, liver, lungs, and kidneys This study is of direct relevance to novel pharmacological treatment strategies for reperfusion injury, particularly in myocardial infarction. ypD-mediated mPTP is also involved in cancer, obesity, diabetes, muscular dystrophy, liver fibrosis, It is related to new therapeutic strategies for liver protection and regeneration (Non-patent Documents 173-212; (Each of which is incorporated herein by reference.) Cyclosporin A and its derivatives Can block CypD to prevent mitochondrial swelling and cell death , and thus for example as neuro- and cardiovascular- and hepatoprotective agents or as novel mitochondrial drugs As such, they may be useful in the treatment of the above-mentioned diseases.

[0019] Unless otherwise defined, all technical and scientific terms used herein are within the meaning of the present invention. has the same meaning as commonly understood by a person skilled in the art to which it pertains. Methods and materials similar or equivalent to those described in the above may be used in the practice or testing of the present invention. Suitable methods and materials are described below. All publications, patent applications, patents, and other references are incorporated by reference in their entirety. Therefore, the materials, methods, and examples are illustrative only and are not intended to be limiting. do not have. [Prior art documents] [Patent documents]

[0020] [Patent Document 1] International Publication No. 2012 / 009715 [Patent Document 2] International Publication No. 2012 / 021796 [Patent Document 3] International Publication No. 2012 / 075494 [Non-patent literature]

[0021] [Non-Patent Document 1] Klatzmann, D., et al., 1986, CR Acad. Sci. III, 303(9):343-8 [Non-patent document 2] Wainberg, MA, et al., 1988, Blood, 72, 1904-10 [Non-patent document 3] Luban, J., et al., 1993, Cell, 73, 1067-1078 [Non-patent document 4] Franke, EK, et al., 1994, Nature, 372, 359-362 [Non-patent document 5] Thali, M., et al., 1994, Nature, 372, 363-365 [Non-patent document 6] Gamble,TR,et al.,1996,Cell,87,1157-1159

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[0022] [Means for solving the problem]

[0023] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: R: [ka]

[0024] During the ceremony: x is 0 or 1; R8 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl aryl, or heteroaryl; wherein R8 is substituted with one or more R1; provided that R8-R1 are not n-butyl or (E)-but-2-enyl; R2 is ethyl, 1-hydroxyethyl, isopropyl, or n-propyl; W is NR1, O, S, or CH2; R3 is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloa alkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heteroaryl aryl or substituted heteroaryl; wherein R3 is optionally substituted with one or more R1. has been replaced; Each R1 is independently H, halogen, aryl or substituted aryl, heteroaryl, aryl or substituted heteroaryl, OR A , S.R. A , N.R. A R B , -NR A (CH2) O OR B , -N((CH2) O OR A )((CH2) O OR B )-C(=O)R A , -C( =O)OR A , -OC(=O)R A , -OC(=O)(C1-C6 alkyl-R H ), - OC(=O)(CH2) o OR A 、-C(=O)NR A R B 、-NR A C(=O)R B 、 -N(C(=O)R A )(C(=O)R B )、-N(C(=O)(C1-C6アルキル- R H ))(C(=O)(C1-C6アルキル-R H ))、-N(C(=O)(C1-C6 アルキル-R H ))2、-NR A C(=O)(CH2) O OR B 、-NR A C(=O)( CH2) O OR B 、-N(C(=O)(CH2) O OR B )2、-NR A C(=O)(C H2) O NR A R B 、-NR A (CH2) O C(=O)OR B 、-N((CH2) O C( =O)OR A )((CH2) O C(=O)OR B )、-NR A (CH2) O C(=O)N R A R B 、-N((CH2) O C(=O)NR A R B )((CH2) O C(=O)NR A R B )、-NR A (CH2) O C(=O)NR A (CH2) O ORB 、-C(=O)N( (CH2) O OR B )2、-N((CH2) O C(=O)NR A (CH2) O OR B )( (CH2) O C(=O)NR A (CH2) O OR B )、-C(=O)NR A (CH2) O OR B 、-C(=O)NR A (CH2) O OR B 、-C(=O)NR A (CH2) O NR A R B 、-N=CR A -NR A R B 、-NR B -C(=NH)-NR A R B 、O(CH2 ) m OR A 、O(CH2) m COOR A 、O(CH2) m CONR A R B 、O(CH2) m CONR A (CH2) m OR A 、O(CH2) m O(CH2) m OR A 、O(CH2) m NR A R B 、O(CH2) m O(CH2) m NR A R B 、NR C (CH2) m NR A R B , N.R. C (CH2) m NR C (CH2) m NR A R B、 [ka] wherein the aryl or heteroaryl is selected from the group consisting of halogen, hydroxy, (C1- C6) alkyl, (CH2) p OR A , (CH2) p NR A R B , (CH2) p C(=O )NR A R B , and (CH2) p C(=O)OR A The same or different selected from the group consisting of optionally substituted with one or more groups which may be R7 is [ka] and; Each R5 is independently H, alkyl or substituted alkyl, alkenyl or substituted alkenyl. alkenyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkenyl alkyl, cycloalkenyl or substituted cycloalkenyl, or aryl or substituted aryl Rule: R A and R B are each independently: hydrogen; one or more groups R, which may be the same or different D optionally substituted with (C1-C 6) alkyl; (C2-C6)alkenyl or (C2-C6)alkynyl; (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl ; Halogen, -O(C1-C6)alkyl, -C(=O)O(C1-C6)alkyl, amino, alkylamino, and dialkylamino, which may be the same or different; phenyl or benzyl optionally substituted by 1 to 5 groups; Alternatively, 5 to 6 ring atoms and the same or different ring atoms selected from nitrogen, sulfur, and oxygen Heterocyclic rings containing 1 to 3 heteroatoms, which may be different, and may be saturated or unsaturated It is a cyclic ring; Alternatively, R A and R B together with the nitrogen atoms to which they are attached, form 3-7 forming a saturated or unsaturated heterocyclic ring containing ring atoms, which ring is free of nitrogen, oxygen, and It may optionally contain another heteroatom selected from the group consisting of sulfur, alkyl, 1 to 3, which may be the same or different, selected from the group consisting of aryl, phenyl, and benzyl; optionally substituted with 4 groups; R C are each independently hydrogen or (C1-C6) alkyl; R D are each independently halogen, hydroxy, O(C1-C4) alkyl, C(= O)(C1-C4)alkyl, C(=O)O(C1-C4)alkyl, or [ka] (wherein Z is CH2, O, S, NH, NCH3, NEt, N-isopropyl, N-isopropyl) N-propyl, N-neopentyl, N-CH2CH2OH, or N-CH2CH2OMe ) and; R G are each independently, R A、OR A 、SR A 、NR A R B 、-(CH2) o R A 、 -(CH2) o C(=O)OR A 、-(CH2) o C(=O)NR A R B 、C(=O)O R A 、OC(=O)R A 、NR A C(=O)R B 、NR A C(=O)(CH2) O OR A 、C(=O)O(CH2) O OR A 、C(=O)OR B 、C(=O)NR A R B 、C(= O)NR A (CH2) O OR B 、C(=O)N((CH2) O OR A )((CH2) O O R B )、C(=O)N((CH2) O C(=O)OR A )((CH2) O C(=O)OR B )、C(=O)N((CH2) O NR A R B )((CH2) O NR A R B )、C(=O )N((CH2) O OC(=O)(CH2) O OR A )((CH2) O OC(=O)(C H2) O OR B )、C(=O)N((CH2) O NRA C(=O)(CH2) O OR B ) ((CH2) O NR A C(=O)(CH2) O OR B ), C(=O)NR A (CH2) O NR A R B , [ka] C(=O)NR A (CH2) O OC(=O)R B , C(=O)NR A (CH2) O C(= O)OR B , C(=O)NR A (CH2) O C(=O)NR A R B , C(=O)NR A ( CH2) O OC(=O)(CH2) O OR B , or [ka] and; R H are each independently a halogen; Z' is independently CH2, O, S, or NR A , N(CH2) o OR A , N(CH 2) o NR A R B , N(CH2) o COOR A , N(CH2) o OC(=O)R A , N( CH2) o CONR A RB , N(CH2) o NR A C(=O)R B , or N(CH2) o OC(=O)(CH2) o OR A and; each o is independently 0, 1, 2, 3, 4, 5, or 6; each p is independently an integer of 0, 1, 2, 3, 4, or 5; and Each m is independently an integer of 1, 2, 3, 4, or 5.

[0025] In certain specific embodiments, the compounds disclosed herein have the formula (II) or ( III) or a pharmaceutically acceptable salt thereof: [ka]

[0026] During the ceremony: x is 0 or 1; Y is H or OR5; where R5 is H or methyl; m' and n' are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; R A’ and R B’ are each independently: hydrogen; one or more groups R, which may be the same or different D optionally substituted with (C1-C 6) alkyl; (C2-C6)alkenyl or (C2-C6)alkynyl; (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl; Halogen, -O(C1-C6)alkyl, -C(=O)O(C1-C6)alkyl, amino, alkylamino, and dialkylamino, which may be the same or different; phenyl or benzyl optionally substituted with 1 to 5 groups; Alternatively, R A’ and R B’ together with the nitrogen atoms to which they are attached, form 3 Form a saturated or unsaturated heterocyclic ring containing up to 7 ring atoms, which ring may contain nitrogen, oxygen, and sulfur, and phenyl, and benzyl, which may be the same or different. optionally substituted with 1 to 4 groups; and R D are each independently halogen, hydroxy, O(C1-C4) alkyl, C(= O)(C1-C4)alkyl, C(=O)O(C1-C4)alkyl, or [ka] wherein Z is CH2, O, S, NH, NCH3, NEt, N-isopropyl, N -isopropyl, N-neopentyl, N-CH2CH2OH, or N-CH2CH2OM e.

[0027] In certain specific embodiments, the compounds disclosed herein have the formula (IV) or (V): It has the structure: [ka]

[0028] wherein x is 0 or 1; Y is H or OR5; where R5 is H or methyl. Yes;R 1’ are each independently H, halogen, aryl or substituted aryl, aryl or substituted heteroaryl, OR A , S.R. A , N.R. A RB 、-NR A (CH 2) O OR B 、-N((CH2) O OR A )((CH2) O OR B )-C(=O)R A 、 -C(=O)OR A 、-OC(=O)R A 、-OC(=O)(C1-C6アルキル-R H )、-OC(=O)(CH2) o OR A 、-C(=O)NR A R B 、-NR A C(=O) R B 、-N(C(=O)R A )(C(=O)R B )、-N(C(=O)(C1-C6アル キル-R H ))(C(=O)(C1-C6アルキル-R H ))、-N(C(=O)(C1 -C6アルキル-R H ))2、-NR A C(=O)(CH2) O OR B 、-NR A C(= O)(CH2) O OR B 、-N(C(=O)(CH2) O OR B )2、-NR A C(=O )(CH2) O NR A R B 、-NR A (CH2) O C(=O)OR B 、-N((CH2) O C(=O)OR A )((CH2) O C(=O)OR B )、-NR A (CH2)O C(= O)NR A R B 、-N((CH2) O C(=O)NR A R B )((CH2) O C(=O) NR A R B )、-NR A (CH2) O C(=O)NR A (CH2) O OR B 、-C(=O )N((CH2) O OR B )2、-N((CH2) O C(=O)NR A (CH2) O OR B )((CH2) O C(=O)NR A (CH2) O OR B )、-C(=O)NR A (CH 2) O OR B 、-C(=O)NR A (CH2) O OR B 、-C(=O)NR A (CH2) O NR A R B 、-N=CR A -NR A R B 、-NR B -C(=NH)-NR A R B 、O( CH2) m OR A 、O(CH2) m COOR A 、O(CH2) m CONR A R B 、O(C H2) m CONR A (CH2) mOR A , O(CH2) m O(CH2) m OR A , O(C H2) m NR A R B , O(CH2) m O(CH2) m NR A R B , N.R. C (CH2) m N R A R B , N.R. C (CH2) m NR C (CH2) m NR A R B , [ka] wherein the aryl or heteroaryl is selected from halogen, hydroxy, (C1- C6) alkyl, (CH2) p OR A , (CH2) p NR A R B , (CH2) p C(=O )NR A R B , and (CH2) p C(=O)OR A The same or different selected from the group consisting of The group is optionally substituted with one or more groups which may be substituted.

[0029] In certain specific embodiments, R1 is -NR A C(=O)R B and R 1’ is OR A R A Non-limiting examples include H, Me, Et, Pr, Bu, and pentyl. R BNon-limiting examples include H, Me, Et, Pr, Bu, and pentyl. In certain specific embodiments, R is —NHC(═O)R B and R 1’ is OH; and Y is OH or H.

[0030] In certain specific embodiments, the compounds disclosed herein have the structure of formula (VI): do: [ka]

[0031] During the ceremony, x is 0 or 1; W is CH, O, or S; Y is H or OR5; where R5 is H or methyl; m' and n' are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 1 0; and Each R1 is independently H, halogen, aryl or substituted aryl, heteroaryl, aryl or substituted heteroaryl, OR A , S.R. A , N.R. A R B , -C(=O)R A ,- C(=O)OR A , -C(=O)NR A R B , -NR A C(=O)R B , -NR A C(= O)(CH2) O R B , -NR A C(=O)(CH2) O OR B , -NR A C(=O)( CH2) O NR A R B , or -C(=O)NRA (CH2) O R B is.

[0032] In yet another aspect, the present invention provides a method for treating a rheumatoid arthritis, comprising administering to a subject a rheumatoid arthritis, a rheumatoid arthritis, or ... and a pharmaceutically acceptable carrier.

[0033] In a further aspect, the present invention provides a method for treating or preventing a viral infection in a mammalian species in need thereof. The present invention provides a method of preventing the disease, which method comprises administering a therapeutically effective amount of a compound as described herein. The method comprises administering at least one compound to a mammalian species.

[0034] In another aspect, the present invention provides a method for treating hepatitis C virus infection in a mammalian species in need thereof. The present invention provides a method for treating or preventing a rheumatoid arthritis, the method comprising administering a therapeutically effective amount of a compound described herein. The method comprises administering to a mammalian species at least one compound such as

[0035] In yet another aspect, the present invention provides a method for inhibiting cyclophilin in a subject in need thereof. The present invention provides a method for the preparation of a cyclophilin-inhibiting compound, comprising administering an effective cyclophilin-inhibiting amount of a compound as described herein to a patient. The method includes administering to the subject at least one compound such as:

[0036] In yet another aspect, the present invention provides a method for treating cyclophilin-mediated leukemia in a mammalian species in need thereof. The present invention provides a method for treating or preventing a disease mediated by a compound of formula (I) or (II), which comprises administering a therapeutically effective amount of a compound described herein. The method comprises administering at least one compound as described to a mammalian species.

[0037] In yet another aspect, the present invention provides a method for treating or preventing a disease in a mammalian species in need thereof. The present invention provides a method for treating a rheumatoid arthritis, the method comprising administering a therapeutically effective amount of at least one compound as described herein. to a mammalian species, wherein the disease is inflammation, respiratory inflammation, joint inflammation, The treatment is selected from rheumatism and dry eye.

[0038] In yet another aspect, the present invention provides a method for treating or preventing a disease in a mammalian species in need thereof. The present invention provides a method for treating a rheumatoid arthritis, the method comprising administering a therapeutically effective amount of at least one compound as described herein. to a mammalian species, wherein the disease is a neurodegenerative disease, e.g., Alzheimer's disease. Immersion disease, Parkinson's disease, Huntington's disease, or ALS; traumatic brain injury; stroke; and ischemia-reperfusion injury in the brain, heart, and kindey.

[0039] In yet another aspect, the present invention provides a method for treating or preventing a disease in a mammalian species in need thereof. The present invention provides a method for treating a rheumatoid arthritis, the method comprising administering a therapeutically effective amount of at least one compound as described herein. to a mammalian species, wherein the disease is cardiovascular disease, vasostenosis, arterial disease, Arteriosclerosis, abdominal aortic aneurysm, cardiac hypertrophy, aortic rupture, pulmonary arterial hypertension, myocarditis and cardiac The disease is selected from muscle fibrosis, and ischemic heart disease.

[0040] In yet another aspect, the present invention provides a method for treating or preventing a disease or condition in a mammalian species in need thereof. The present invention provides a method for preventing a pulmonary embolism, the method comprising administering a therapeutically effective amount of at least one compound as described herein. The method includes administering one or more compounds to a mammalian species, wherein the disease or condition is selected from the group consisting of cancer; obesity; Diabetes; muscular dystrophy; lung, liver and kidney disease and their protection; and hair loss is selected from.

[0041] In yet another aspect, the present invention provides a method for treating or preventing a disease or condition in a mammalian species in need thereof. The present invention provides a method for preventing a pulmonary embolism, the method comprising administering a therapeutically effective amount of at least one compound as described herein. and administering to a mammalian species a compound of the formula (I) or (II), wherein the disease or condition is atopic dermatitis. ulcerative conjunctivitis, atopic and vernal keratoconjunctivitis, atopic keratoconjunctivitis, anterior uveitis, Behçet's disease, blepharitis, chronic ocular surface inflammation caused by viral infection, corneal transplantation Corneal sensitivity due to rejection, damage caused by surgery on the cornea or other surfaces of the eye, meibomian glands Disease, pterygium (ptyregia), ocular manifestations of graft-versus-host disease, ocular allergy, ocular Ocular cicatricial pemphigoid, Steven-Johnson syndrome, vernal keratoconjunctivitis, uveitis, herpes simplex keratitis, Selected from ocular rosacea, and pinguecula. DETAILED DESCRIPTION OF THE INVENTION

[0042] definition The following are definitions of terms used in this specification. The initial definitions given below are used throughout this specification to refer to individual or separate entities unless otherwise indicated. As part of a group, it applies to that group or term.

[0043] The terms "alkyl" and "alk" refer to alkyl groups having 1 to 12 carbon atoms, preferably 1 to 6 refers to a straight or branched chain alkane (hydrocarbon) radical containing carbon atoms. "Alkyl" groups include methyl, ethyl, propyl, isopropyl, n-butyl, t- Butyl, isobutylpentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl pentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl The term "(C1-C4) alkyl" refers to an alkyl group having 1 to 4 carbon atoms. straight or branched chain alkane (hydrocarbon) radicals containing, for example, methyl, ethyl, This refers to butyl, isopropyl, n-butyl, t-butyl, and isobutyl. (C1-C6 The term "alkyl" refers to a straight or branched chain alkane (carbonyl) containing 1 to 6 carbon atoms. (C1-C4) alkyl) radicals, in addition to those exemplified for "(C1-C4) alkyl" , n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, "Substituted alkyl" refers to any alkyl group that is Aryl substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include the following groups: hydrogen, halogen (e.g., single halo), a halogen or halo substituent, in the latter case a group such as CF3 or Substituents that form alkyl groups bearing Cl3), cyano, nitro, oxo (i.e., =O ), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, Heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2 R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(= O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a ,OC(=O) NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O) 2NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P( =O)2R e In particular, the present invention includes, but is not limited to, one or more of the following: a are each unique In particular, hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl , heterocycle, or aryl; R b , R c , and R d are each independently hydrogen, alkane, alkyl, cycloalkyl, heterocycle, aryl, or b and R c are those together with the N to which it is attached, optionally form a heterocyclic ring; and R e are independent of each other. and alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl. In the above exemplary substituents, alkyl, cycloalkyl, aryl, Groups such as alkynyl, cycloalkenyl, heterocycle, and aryl are themselves substituted or unsubstituted. The body may optionally be substituted.

[0044] The term "alkenyl" refers to an alkyl group having 2 to 12 carbon atoms and at least one carbon-carbon bond. refers to a straight or branched chain hydrocarbon radical containing a double bond. Examples of such groups are The term "C2-C6 alkenyl" refers to an alkyl group having 2 to 6 alkyl groups. A straight or branched chain hydrocarbon containing 10 carbon atoms and at least one carbon-carbon double bond. radicals such as ethylenyl, propenyl, 2-propenyl, (E)-but-2-enyl (Z)-but-2-enyl, 2-methyl(E)-but-2-enyl, 2-methyl(Z )-but-2-enyl, 2,3-dimethyl-but-2-enyl, (Z)-pent-2-enyl (E)-pent-1-enyl, (Z)-hex-1-enyl, (E)-penta-2-enyl -enyl, (Z)-hex-2-enyl, (E)-hex-2-enyl, (Z)-hexa -1-enyl, (E)-hex-1-enyl, (Z)-hex-3-enyl, (E)-hex- "Substituted alkenyl" refers to (E)-hexa-3-enyl, and (E)-hexa-1,3-dienyl. is substituted at any available point of attachment with one or more substituents, preferably 1 to 4 substituents. Examples of substituents include the following groups: hydrogen, halogen (e.g., mono-, di ... A halogen substituent or multiple halo substituents, in the latter case e.g. CF3 a group or a substituent forming an alkyl group bearing Cl), cyano, nitro, oxo (i.e. , =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkyl Nyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(= O)2R e , S(=O)2OR e , P(=O)2ORe , N.R. b R c , N.R. b S(=O) 2nd Round e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , O.C.( =O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S( =O)2NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e In particular, the present invention includes, but is not limited to, one or more of the following: a is that Each independently represents hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkyn ... quinyl, heterocycle, or aryl; R b , R c , and R d are each independently hydrogen , alkyl, cycloalkyl, heterocyclic, aryl, or b and R c Ha, so together with the N to which they are attached, optionally form a heterocyclic ring; and R e are respectively Independently, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, poly Exemplary substituents can themselves be optionally substituted.

[0045] The term "alkynyl" refers to an alkynyl group having 2 to 12 carbon atoms and at least one carbon-carbon bond. refers to a straight or branched chain hydrocarbon radical containing a triple bond. Examples of such groups are: The term "C2-C6 alkynyl" refers to an alkynyl group having 2 to 6 carbon atoms. A straight- or branched-chain hydrocarbon radical containing a carbon atom and at least one carbon-carbon triple bond. , for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but- Ter-2-ynyl, pent-1-ynyl, pent-2-ynyl, hex-1-ynyl, hex "Substituted alkynyl" refers to any available alkynyl. refers to an alkynyl group substituted with one or more substituents, preferably 1 to 4 substituents, at the point of attachment. Exemplary substituents include the following: hydrogen, halogen (e.g., single halogen substituents). or multiple halo substituents, in the latter case containing groups such as CF3 or Cl3. (i.e., a substituent forming an alkyl group having a hydroxyl group), cyano, nitro, oxo (i.e., =O), CF3 , OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, a Lille, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O)2R e , S( =O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. bP (=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P(=O)2R e In particular, the present invention includes, but is not limited to, one or more of the following: a are each independently alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c , and R d are each independently hydrogen, alkyl, cyclohexyl or the R b and R c is that they are combined together with the N optionally form a heterocyclic ring; and R e are each independently aryl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl The exemplary substituents can themselves be optionally substituted.

[0046] The term "cycloalkyl" refers to groups containing 1 to 4 rings and 3 to 8 carbons per ring. "C3-C7 cycloalkyl" refers to cyclopropyl, "Substituted cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl." "Chloroalkyl" refers to one or more substituents, preferably 1 to 4, at any available point of attachment. It refers to a cycloalkyl group substituted with a substituent. Exemplary substituents include the following groups: hydrogen , halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case , for example, a group such as CF3 or a substituent forming an alkyl group bearing Cl3), cyano , nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkyl chloroalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S (=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P (=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , O C(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e, N.R. d C(=O) NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C (=O)R a , or NR b P(=O)2R e These may include, but are not limited to, one or more of the following: First, where R a are each independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c , and R d teeth each independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or This R b and R c may optionally form a heterocyclic ring together with the N to which they are attached and R e are each independently alkyl, cycloalkyl, alkenyl, or cycloalkyl. Exemplary substituents are, by themselves, alkynyl, heterocyclic, or aryl. Exemplary substituents also include spiro- or fused cyclic ( cycloalkyl, spiro-linked cycloalkenyl, spiro-linked ... Pyrrolidone-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl , fused heterocycle, or fused aryl, wherein the above-mentioned cycloalkyl, cycloalkane, The heterocyclic, heterocyclic, and aryl substituents may themselves be optionally substituted.

[0047] The term "cycloalkenyl" refers to alkyl groups containing 1 to 4 rings and 3 to 8 carbons per ring. Examples of such groups include cyclobutene. cyclopentenyl, cyclohexenyl, etc. , one or more substituents, preferably 1 to 4 substituents, at any available point of attachment; It refers to a substituted cycloalkenyl group. Exemplary substituents include the following groups: hydrogen, halo, Gen (e.g., a single halogen substituent or multiple halo substituents, in the latter case e.g., (e.g., a group such as CF3 or a substituent forming an alkyl group bearing Cl3), cyano, nitro O, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloa Alkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O )2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , NR b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O )2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , OC(= O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NRb R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O )R a , or NR b P(=O)2R e These include, but are not limited to, one or more of the following: So, R a are each independently hydrogen, alkyl, cycloalkyl, alkenyl, cyclo alkenyl, alkynyl, heterocycle, or aryl; R b , R c , and R d Each are independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c together with the N to which they are attached optionally form a heterocycle; and BiR e are each independently alkyl, cycloalkyl, alkenyl, or cycloalkenyl , alkynyl, heterocycle, or aryl. Exemplary substituents are themselves optionally Exemplary substituents also include spiro- or fused cyclic (cyl) groups. ic) Substituents, in particular spiro-linked cycloalkyl, spiro-linked cycloalkenyl, spiro-linked Heterocyclic rings (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the above-mentioned cycloalkyl, cycloalkenyl The heterocyclic, and aryl substituents may themselves be optionally substituted.

[0048] The term "aryl" refers to a cyclic aromatic hydrocarbon group having 1 to 5 aromatic rings, especially a monocyclic aromatic hydrocarbon group. A cyclic or bicyclic group, such as phenyl, biphenyl, or naphthyl. When containing a ring (e.g., bicyclic), the aromatic rings of the aryl group may be joined at a single point. It may be fused (for example, biphenyl) or fused (for example, naphthyl, phenanthrenyl, etc.) "Substituted aryl" refers to a group having one or more substituents, preferably one to four, at any available point of attachment. It refers to an aryl group substituted with three substituents. Exemplary substituents include the following groups: hydrogen , halogen (e.g., a single halogen substituent or multiple halo substituents, in the latter case , for example, a group such as CF3 or a substituent forming an alkyl group bearing Cl3), cyano , nitro, oxo (i.e., =O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkyl chloroalkenyl, alkynyl, heterocycle, aryl, OR a , S.R. a , S(=O)R e , S (=O)2R e , P(=O)2R e , S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P (=O)2NR b R c , C(=O)OR d , C(=O)R a , C(=O)NR b R c , O C(=O)R a , OC(=O)NR b R c , N.R. b C(=O)OR e , N.R. d C(=O) NR b R c , N.R. d S(=O)NR b R c , N.R. d P(=O)NR b R c , N.R. b C (=O)R a , or NR b P(=O)2R e These may include, but are not limited to, one or more of the following: First, where R a are each independently hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle, or aryl; R b , R c , and R d teeth each independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or This R b and R c may optionally form a heterocyclic ring together with the N to which they are attached and R e are each independently alkyl, cycloalkyl, alkenyl, or cycloalkyl. Exemplary substituents are, by themselves, alkynyl, heterocyclic, or aryl. Exemplary substituents also include fused cyclic groups, particularly fused cycloaliphatic groups. alkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein The cycloalkyl, cycloalkenyl, heterocycle, and aryl substituents may themselves be substituted or unsubstituted, if desired. may be replaced by

[0049] The terms "heterocycle" and "heterocyclic" refer to a heterocycle that is either fully saturated or partially or fully unsaturated. monocyclic (including aromatic (i.e., "heteroaryl")) cyclic groups (e.g., 4- to 7-membered monocyclic , 7-11 membered bicyclic, or 8-16 membered tricyclic ring systems), which refers to at least one Heterocyclic groups containing at least one heteroatom in the carbon atom-containing ring Each ring may contain 1, 2, 3, or 4 atoms selected from nitrogen, oxygen, and / or sulfur atoms. wherein the nitrogen and sulfur heteroatoms are optionally oxidized. and the nitrogen heteroatom may optionally be quaternized. The term "arylium" refers to a compound that has a quaternary nitrogen atom and therefore a positive charge. A heterocyclic group refers to a heteroaryl group having any heteroatom or carbon atom in the ring or ring system. Exemplary monocyclic heterocyclic groups include azetidine, benzophenone ... pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl , imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazo Linyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl aryl, isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl , piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2 -Oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, hexahydrodiazepinyl , 4-piperidonyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl triazolyl, tetrazolyl, tetrahydropyranyl, morpholinyl, thiamorpholinyl thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane, and tetrahydro Exemplary bicyclic heterocyclic groups include: Indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benzoxazolyl Azolyl, benzothienyl, benzo[d][1,3]dioxolyl, 2,3-dihydrobenzoyl Benzo[b][1,4]dioxinyl, quinuclidinyl, quinolinyl, tetrahydroisoxinyl isoquinolinyl, benzimidazolyl, benzopyranyl, indolizinyl, benzimidazole Benzofuryl, benzofurazanyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (e.g., furo[2 ,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl dihydroisoindolyl, dihydroquinazolinyl (e.g., 3,4-dihydro- 4-oxo-quinazolinyl), triazinylazepinyl, tetrahydroquinolinyl, etc. Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl, phenanthroyl, and the like. Examples include thoronyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

[0050] "Substituted heterocycle" and "substituted heterocycle" (e.g., "substituted heteroaryl") are used interchangeably in any application. Heterocyclic or heterocyclic rings substituted with one or more substituents, preferably 1 to 4 substituents, at any available point of attachment. Exemplary substituents include the following groups: hydrogen, halogen (e.g., a single halogen atom), a halogen substituent or multiple halo substituents, in the latter case a group such as CF3 or is a substituent that forms an alkyl group bearing Cl3), cyano, nitro, oxo (i.e., = O), CF3, OCF3, cycloalkyl, alkenyl, cycloalkenyl, alkynyl , heterocycle, aryl, OR a , S.R. a , S(=O)R e , S(=O)2R e , P(=O) 2nd Round e, S(=O)2OR e , P(=O)2OR e , N.R. b R c , N.R. b S(=O)2R e , N.R. b P(=O)2R e , S(=O)2NR b R c , P(=O)2NR b R c , C( =O)OR d , C(=O)R a , C(=O)NR b R c , OC(=O)R a , OC(=O )NR b R c , N.R. b C(=O)OR e , N.R. d C(=O)NR b R c , N.R. d S(=O )2NR b R c , N.R. d P(=O)NR b R c , N.R. b C(=O)R a , or NR b P (=O)2R e In particular, the present invention includes, but is not limited to, one or more of the following: a are respectively Independently, hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl R is a heterocyclic ring or an aryl; b , R c , and R d are each independently hydrogen, alkyl, cycloalkyl, heterocycle, aryl, or b and R c are those together with the N to which it is attached optionally form a heterocyclic ring; and R eare independent and alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, heterocycle. or aryl. Exemplary substitutents are those which themselves are Exemplary substituents also include alkyl groups at any available point of attachment. Spiro-linked or fused cyclic substituents, especially spiro-linked cycloalkyl, ... chloroalkenyl, spiro-linked heterocycle (excluding heteroaryl), fused cycloalkyl, fused cycloalkenyl, fused heterocycle, or fused aryl, wherein the cycloalkenyls mentioned above are fused heterocycles. The alkyl, cycloalkenyl, heterocycle, and aryl substituents are themselves optionally substituted. It can be done.

[0051] The term "alkylamino" refers to a group having the structure -NHR', where R' is As defined herein, hydrogen, alkyl or substituted alkyl, or cycloalkyl Examples of alkylamino groups include methylamino, ethylamino, and substituted cyclobutyl. ethylamino, n-propylamino, isopropylamino, cyclopropylamino, n-butylamino butylamino, tert-butylamino, neopentylamino, n-pentylamino, hexylamino Examples include, but are not limited to, cyclohexylamino, cyclohexylamino, and the like.

[0052] The term "dialkylamino" refers to a group having the structure -NRR', where R and R and R' are each independently alkyl or substituted alkyl, as defined herein. cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cyclo Alkenyl, aryl or substituted aryl, or heterocyclyl or substituted heterocyclyl R and R' may be the same or different in the dialkylamino moiety. Examples of the dialkylamino group include dimethylamino and methylethylamino. , diethylamino, methylpropylamino, di(n-propyl)amino, di(isopropyl)amino di(cyclopropyl)amino, di(n-butyl)amino, di(tert-butyl)amino di(neopentyl)amino, di(n-pentyl)amino, di(hexyl) Examples include, but are not limited to, amino, di(cyclohexyl)amino, and the like. In embodiments, R and R' are linked to form a cyclic structure. The resulting cyclic structure is aromatic. Examples of cyclic diaminoalkyl groups include aziridinyl, Pyrrolidinyl, piperidinyl, morpholinyl, pyrrolyl, imidazolyl, 1,3,4-trimethylsilyl Examples include, but are not limited to, ryanolyl and tetrazolyl.

[0053] The term "halogen" or "halo" refers to chlorine, bromine, fluorine, or iodine.

[0054] Unless otherwise indicated, any heteroatom with insufficient valences may be replaced by hydrogen atoms sufficient to satisfy the valences. Assume you have an atom.

[0055] The compounds of the present invention may form salts, which are also within the scope of the present invention. References to compounds are understood to include references to salts thereof unless otherwise indicated. As used herein, the term "salt" refers to salts formed with inorganic and / or organic acids and bases. In addition, the compounds of the present invention may include, but are not limited to, acid and / or base salts. basic moieties such as lysine or imidazole and acidic moieties such as, but not limited to, carboxylic acids When both moieties are contained, zwitterions ("inner salts") may be formed, and are referred to herein as When used, the term "salt" includes pharmaceutically acceptable (i.e., non-toxic, biocompatible) salts. Although physiologically acceptable salts are preferred, other salts may also be used, for example, in the preparation of isolated or Salts of the compounds of the present invention are useful in purification processes, for example, by dissolving a compound of formula I in a medium. , for example, in a medium in which a salt precipitates, or in an aqueous medium, with a certain amount of acid or base, e.g. For example, it may be formed by reacting equivalent amounts followed by freeze-drying.

[0056] A basic moiety such as, but not limited to, an amine or a pyridine or imidazole ring The compounds of the present invention may form salts with a variety of organic and inorganic acids. Examples include acetate salts (e.g., formed with acetic acid or trihaloacetic acid, e.g., trifluoroacetic acid). (those used in the manufacture of cereals), adipates, alginates, ascorbates, aspartates, Sulfonate, benzenesulfonate, bisulfate, borate, butyrate, citrate, camphor salts, camphorsulfonates, cyclopentanepropionates, digluconates, Decyl sulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate Salt, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide , hydroxyethanesulfonates (e.g., 2-hydroxyethanesulfonates), lactic acid salts, maleates, methanesulfonates, naphthalenesulfonates (e.g., 2-naphthalenesulfonates) Sulfonates, nicotinates, nitrates, oxalates, pectins ate), persulfates, phenylpropionates (e.g., 3-phenylpropionate) , phosphate, picrate, pivalate, propionate, salicylate, succinate, Sulfates (e.g., formed with sulfuric acid), sulfonates, tartrates, thiocyanates salts, toluenesulfonates such as tosylates, undecanoates, and the like.

[0057] Compounds of the present invention that contain an acidic moiety, such as, but not limited to, a carboxylic acid, can be used in a variety of organic and and inorganic bases. Exemplary basic salts include ammonium salts, alkali metal salts, and the like. metal salts, such as sodium, lithium, and potassium salts; alkaline earth metal salts, such as potassium; calcium and magnesium salts, salts with organic bases (e.g. organic amines), e.g. benzathione Dicyclohexylamine, hydrabamine (N,N-bis(dehydroabietyl)ethyl) N-methyl-D-glucamine, N-methyl-D-glucamine Examples include salts with ricamide, t-butylamine, and amino acids such as arginine and lysine. The basic nitrogen-containing group is a lower alkyl halide (e.g., methyl, ethyl, propyl , and butyl chlorides, bromides, and iodides), dialkyl sulfates (e.g., dimethyl sulfate, butyl, diethyl, dibutyl, and diamyl), long chain halides (e.g., decyl, lauryl, aryl, myristyl, and stearyl chlorides, bromides, and iodides), halogenated alkyls They may also be quaternized with agents such as alkyls (e.g., benzyl bromide and phenethyl bromide).

[0058] Prodrugs and solvates of the compounds of the invention are also contemplated herein. As used herein, the term "prodrug" refers to a compound that undergoes metabolic processing when administered to a subject. The compounds of the present invention or salts thereof and / or The compounds that form solvates are shown.Solvates of the compounds of the present invention include, for example, hydrates.

[0059] The compounds of the present invention and their salts or solvates may be used in their tautomeric forms (e.g. All such tautomers may exist as Contemplated herein as part of the present invention.

[0060] All stereoisomers of the compounds, including enantiomeric and diastereomeric forms ( For example, those that may exist due to asymmetric carbon atoms on various substituents are within the scope of the present invention. It is envisaged that individual stereoisomers of the compounds of the invention may be present in various forms, e.g., as compounds with particular activity. as a pure or substantially pure optical isomer having Optionally, for example, as a racemate or mixed with all or selected other stereoisomers. The chiral centers of the present invention may be those defined by the International Union of Pure and Applied Chemistry (IUPAC) 1974 The racemate may have the S or R configuration as defined by the 2000 Recommendation. fractional crystallization, separation or crystallization of diastereomeric derivatives, or chiral column chromatography The individual optical isomers can be separated by chromatographic separation, without limitation. However, any conventional method, including, for example, salt formation with an optically active acid and subsequent crystallization, may be used. It can be obtained from the racemate by suitable methods.

[0061] The compounds of the present invention may be 90% by weight or more, for example 95% by weight or more, 99% by weight or more, after their preparation. To obtain a composition containing an amount of pure ("substantially pure" Compound I) of 100% or more by weight , preferably isolated and purified, which is then used as described herein, or Such "substantially pure" compounds of the present invention are also included as part of the present invention. It is envisaged in the specification.

[0062] All stereoisomers of the compounds of the present invention may be used in admixture or in pure or substantially pure form. The compounds of this invention are contemplated in either the cis (Z) or trans (E) form. It includes both alkene isomers and cis and trans isomers of cyclic hydrocarbons or heterocycles. do.

[0063] Throughout the specification, groups and substituents thereof are chosen to provide stable moieties and compounds. may be selected.

[0064] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this document, chemical elements are listed in the Periodic Table of the Elements, the CAS version, and the Handbook of Chemistry. Identified and specific according to the Science and Physics, 75th Edition, inside cover Functional groups are generally defined as described therein. Further, general principles of organic chemistry, and specific functional moieties and reactivities are described in "Organic Chemistry", Th omas Sorrell,University Science Books,Sa Usalito:1999, the entire contents of which are incorporated herein by reference. It can be enjoyed.

[0065] Certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. It is understood that cis and trans isomers, R- and S-enantiomers are within the scope of the present invention. diastereomers, (D)-isomers, (L)-isomers, racemic mixtures thereof, and All such compounds are contemplated, including other mixtures thereof. , alkyl groups, etc. All such isomers and mixtures thereof. are intended to be included in the present invention.

[0066] Isomeric mixtures containing any of a variety of isomeric ratios may be utilized in accordance with the present invention. For example, when only two isomers are combined, 50:50, 60:40, 70:3 0, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, 99:1, and All mixtures containing an isomer ratio of 100:0 are contemplated by the present invention. It is readily apparent that similar ratios can be expected for more complex isomeric mixtures.

[0067] The present invention also relates to an element in which one or more atoms have an atomic mass or mass number different from that normally found in nature. Apart from the fact that the group is substituted by an atom having a molecular mass or mass number, This includes isotopically labeled compounds that are identical to the disclosed compounds. Examples of isotopes that can be produced include those of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine. Positions, e.g., 2 H, 3 H, 13 C. 11 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 The compounds or enantiomers of the present invention contain Cl. Thiomers, diastereomers, tautomers or pharmaceutically acceptable salts or solutions thereof Solvates that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically labeled compounds of the invention, such as 3 H and 14 Radioactive isotopes such as C The incorporation is useful for drug and / or substrate tissue distribution assays. , i.e. 3 H and carbon-14, i.e. 14 The C isotope is particularly preferred due to its ease of preparation and detection. Furthermore, deuterium, i.e. 2 Substitution with heavier isotopes such as H results in greater metabolic stability and certain therapeutic advantages resulting from, for example, increased in vivo half-life or reduced dose requirements. Isotopically labeled compounds can be used in a variety of applications, including pharmaceuticals, pharmaceuticals, and pharmaceuticals. is generally achieved by replacing readily available isotopically labeled reagents with non-isotopically labeled reagents. and can be prepared by carrying out the procedures disclosed in the following schemes and / or examples. It is possible.

[0068] For example, if a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, Separation of the asteorimeric mixture and cleavage of the auxiliary group to provide the pure desired enantiomer Alternatively, the molecule may contain a basic functional group such as amino or an acidic functional group such as carboxyl. In this case, diastereomeric salts are formed with suitable optically active acids or bases, followed by diastereomeric The rheomers are resolved and thus separated by fractional crystallization or chromatographic means well known in the art. followed by recovery of the pure enantiomer.

[0069] The compounds as described herein may be substituted with any number of substituents or functional moieties. It is understood that the term "substituted" generally refers to the term "optionally." Whether preceded by or not, the substituents contained in the formulae of this invention are hydrogen radicals of a particular structure. It refers to the replacement of a radical with a specific substituent. When a position can be substituted with more than one substituent selected from a specified group, the substituents can be any of As used herein, "substitution" refers to a group consisting of a group of atoms, ... The term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched substituents of organic compounds. Branched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents are included. Therefore, heteroatoms such as nitrogen may be bonded to the organometallic compounds described herein to satisfy the valence of the heteroatoms. The compound may have hydrogen substituents and / or any permissible substituents. It is not intended to be limited in any manner by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably within the scope of the following: For example, this results in the formation of stable compounds useful in the treatment of infectious diseases or proliferative disorders. As used herein, the term "stable" preferably refers to a compound that allows for manufacture. and have sufficient stability for a sufficient period of time to be detected, preferably for the purposes detailed herein. "Polyester" refers to a compound that maintains its integrity for a period of time sufficient to be useful.

[0070] compound The novel cyclosporin derivatives of the present invention are potent inhibitors of cyclophilin and inhibit HC It is useful for inhibiting viruses such as V, HBV, and HIV.

[0071] In one aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: R: [ka]

[0072] During the ceremony: x is 0 or 1; R8 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl aryl, or heteroaryl; wherein R8 is substituted with one or more R1; provided that , R8-R1 are not n-butyl or (E)-but-2-enyl; R2 is ethyl, 1-hydroxyethyl, isopropyl, or n-propyl; W is O, S, or CH; R3 is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkynyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloa alkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heteroaryl aryl or substituted heteroaryl; wherein R3 is optionally substituted with one or more R1. has been replaced; Each R1 is independently H, halogen, aryl or substituted aryl, heteroaryl, aryl or substituted heteroaryl, CN, OR A , S.R. A , N.R. A R B , -NR A (CH 2) O OR B , -N((CH2) O OR A )((CH2) O OR B)-C(=O)R A 、 -C(=O)OR A 、-OC(=O)R A 、-OC(=O)(C1-C6アルキル-R H )、-OC(=O)(CH2) o OR A 、-C(=O)NR A R B 、-NR A C(=O) R B 、-N(C(=O)R A )(C(=O)R B )、-N(C(=O)(C1-C6アル キル-R H ))(C(=O)(C1-C6アルキル-R H ))、-N(C(=O)(C1 -C6アルキル-R H ))2、-NR A C(=O)(CH2) O OR B 、-NR A C(= O)(CH2) O OR B 、-N(C(=O)(CH2) O OR B )2、-NR A C(=O )(CH2) O NR A R B 、-NR A (CH2) O C(=O)OR B 、-N((CH2) O C(=O)OR A )((CH2) O C(=O)OR B )、-NR A (CH2) O C(= O)NR A R B 、-N((CH2) O C(=O)NR A R B )((CH2) O C(=O) NR A R B ) 、 -NR A (CH2) O C(=O)NR A (CH2) O OR B 、-C(=O )N((CH2) O OR B )2、-N((CH2) O C(=O)NR A (CH2) O OR B )((CH2) O C(=O)NR A (CH2) O OR B )、-C(=O)NR A (CH 2) O OR B 、-C(=O)NR A (CH2) O OR B 、-C(=O)NR A (CH2) O NR A R B 、-N=CR A -NR A R B 、-NR B -C(=NH)-NR A R B 、O( CH2) m OR A 、O(CH2) m COOR A 、O(CH2) m CONR A R B 、O(C H2) m CONR A (CH2) m OR A 、O(CH2) m O(CH2) m OR A 、O(C H2) m NR A R B, O(CH2) m O(CH2) m NR A R B、 NR C (CH2) m N R A R B , N.R. C (CH2) m NR C (CH2) m NR A R B、 [ka] wherein the aryl or heteroaryl is selected from halogen, hydroxy, (C1- C6) alkyl, (CH2) p OR A , (CH2) p NR A R B , (CH2) p C(=O )NR A R B , and (CH2) p C(=O)OR A The same or different selected from the group consisting of optionally substituted with one or more groups which may be R7 is [ka] and Each R5 is independently H, alkyl or substituted alkyl, alkenyl or substituted alkenyl. alkynyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl cycloalkenyl or substituted cycloalkenyl, or aryl or substituted aryl It is: R A and R B are each independently: hydrogen; one or more groups R, which may be the same or different D optionally substituted with (C1-C 6) alkyl; (C2-C6)alkenyl or (C2-C6)alkynyl; (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl ; Halogen, -O(C1-C6)alkyl, -C(=O)O(C1-C6)alkyl, amino, alkylamino, and dialkylamino, which may be the same or different; phenyl or benzyl optionally substituted by 1 to 5 groups; Alternatively, 5 or 6 ring atoms and the same or different ring atoms selected from nitrogen, sulfur, and oxygen may be different, and may be saturated or unsaturated, containing 1 to 3 heteroatoms. elementary cyclic ring; Alternatively, R A and R B together with the nitrogen atoms to which they are attached, form 3-7 forming a saturated or unsaturated heterocyclic ring containing ring atoms, which ring is free of nitrogen, oxygen, and It may optionally contain another heteroatom selected from the group consisting of sulfur, alkyl, 1 to 3, which may be the same or different, selected from the group consisting of aryl, phenyl, and benzyl; optionally substituted with 4 groups; R C are each independently hydrogen or (C1-C6) alkyl; R D are each independently halogen, hydroxy, O(C1-C4) alkyl, C( =O)(C1-C4)alkyl, C(=O)O(C1-C4)alkyl, or [ka] (wherein Z is CH2, O, S, NH, NCH3, NEt, N-isopropyl, N-isopropyl) N-propyl, N-neopentyl, N-CH2CH2OH, or N-CH2CH2OMe ) and; R G are each independently, R A , OR A , S.R. A , N.R. A R B , -(CH2) o R A , -(CH2) o C(=O)OR A , -(CH2) o C(=O)NR A R B , C(=O) OR A , OC(=O)R A , N.R. A C(=O)R B , N.R. A C(=O)(CH2) O OR A , C(=O)O(CH2) O OR A , C(=O)OR B , C(=O)NR A R B , C( =O)NR A (CH2) O OR B , C(=O)N((CH2) O OR A )((CH2) O OR B ), C(=O)N((CH2) O C(=O)OR A )((CH2) O C(=O)O R B ), C(=O)N((CH2) O NR A R B )((CH2) O NR A R B ), C(= O)N((CH2) O OC(=O)(CH2) O OR A )((CH2) O OC(=O)( CH2) O OR B ), C(=O)N((CH2) O NR A C(=O)(CH2) O OR B )((CH2) O NR A C(=O)(CH2) O OR B ), C(=O)NR A (CH2) O NR A R B , [ka] C(=O)NR A (CH2) O OC(=O)R B , C(=O)NR A (CH2) O C(= O)OR B , C(=O)NR A (CH2) O C(=O)NR A R B , C(=O)NR A ( CH2) O OC(=O)(CH2) O OR B , or [ka] and; R H are each independently a halogen; Z' is independently CH2, O, S, or NR A , N(CH2) o OR A , N(C H2)o NR A R B , N(CH2) o COOR A , N(CH2) o OC(=O)R A , N (CH2) o CONR A R B , N(CH2) o NR A C(=O)R B , or N(CH2) o OC(=O)(CH2) o OR A and; each o is independently 0, 1, 2, 3, 4, 5, or 6; each p is independently an integer of 0, 1, 2, 3, 4, or 5; and Each m is independently an integer of 1, 2, 3, 4, or 5.

[0073] In some embodiments, x is 0. In other embodiments, x is 1. In one embodiment, R is (C 12 ) alkyl, (C2-C 12 ) alkenyl, ( C2-C 12 ) alkynyl, (C3-C 12 ) cycloalkyl, or phenyl or C H2-phenyl (optionally selected from halogen, hydroxy, (C1-C6) alkyl) In some embodiments, the substituted alkyl group is a substituted alkyl group, which may be the same or different. In the embodiment, R8 is (C1-C 12 ) alkyl. In yet other embodiments, R8 is ( In yet other embodiments, R is a (C-C 12 )straight In yet other embodiments, R8 is a (C4-C6) straight chain alkyl. In still other embodiments, R8 is a (C6-C8) straight chain alkyl. In certain embodiments, R8 is -(CH2) 3-11 - is an alkyl chain.

[0074] In some embodiments, R8 is (C2-C 12 ) alkenyl. In one embodiment, R8 is (C2-C6) straight chain alkenyl. In yet another embodiment, R8 is ( C7-C 12 In yet other embodiments, R8 is a (C4-C6) straight chain alkenyl. In yet other embodiments, R8 is a (C6-C8) straight chain alkenyl. do.

[0075] In some embodiments, R8 is (C2-C 12 ) alkynyl. In one embodiment, R8 is (C2-C6) straight chain alkynyl. In yet another embodiment, R8 is ( C7-C 12 In yet other embodiments, R8 is a (C4-C6) straight chain alkynyl. In yet other embodiments, R8 is (C6-C8) straight chain alkynyl. do.

[0076] In some embodiments, R1 is H. In still other embodiments, R1 is halogen. In yet other embodiments, R is H, OR A , S.R. A , N.R. A R B , -C(=O)R A , -C(=O)OR A , -C(=O)NR A R B , -NR A C(=O)R B , -NR A C(=O)(CH2) O RB , -NR A C(=O)(CH2) O OR B , -NR A C(= O)(CH2) O NR A R B , -C(=O)NR A (CH2) O R B , -C(=O)NR A (CH2) O OR B , and -C(=O)NR A (CH2) O NR A R B From the group consisting of In other embodiments, R1 is selected from O(CH2) m OR A , O(CH2) m O(C H2) m OR A , O(CH2) m NR A R B , O(CH2) m O(CH2) m NR A R B , N.R. C (CH2) m NR A R B , and NR C (CH2) m NR C (CH2) m NR A R B is selected from the group consisting of:

[0077] In certain specific embodiments, the compounds disclosed herein have the formula (II) or (II I) or a pharmaceutically acceptable salt thereof: [ka]

[0078] During the ceremony: x is 0 or 1; Y is H or OR5; where R5 is H or methyl; m' and n' are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; R A’ and R B’ are each independently: hydrogen; one or more groups R, which may be the same or different D optionally substituted with (C1-C 6) alkyl; (C2-C6)alkenyl or (C2-C6)alkynyl; (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl; Halogen, -O(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, and arylamino, alkylamino, and dialkylamino, which may be the same or different. phenyl or benzyl optionally substituted by 1 to 5 radicals; Alternatively, R A’ and R B’ together with the nitrogen atom to which they are attached, form 3 Forming a saturated or unsaturated heterocyclic ring containing seven ring atoms, which ring is not substituted by nitrogen, oxygen, or and sulfur, optionally containing another heteroatom selected from the group consisting of alkyl, phenyl, and 1 to 4 groups, which may be the same or different, selected from the group consisting of aryl, benzoyl, and benzyl. may be optionally substituted; and R D are each independently halogen, hydroxy, O(C1-C4) alkyl, C(= O)(C1-C4)alkyl, C(=O)O(C1-C4)alkyl, or [ka] wherein Z is CH2, O, S, NH, NCH3, NEt, N-isopropyl, N -isopropyl, N-neopentyl, N-CH2CH2OH, or N-CH2CH2OM e.

[0079] In certain specific embodiments, the compounds disclosed herein have the formula (IV) or (V): It has the structure: [ka]

[0080] wherein x is 0 or 1; Y is H or OR5; where R5 is H or methyl. Yes;R 1’ are each independently H, halogen, aryl or substituted aryl, aryl or substituted heteroaryl, OR A , S.R. A , N.R. A R B , -NR A (CH 2) O OR B , -N((CH2) O OR A )((CH2) O OR B )-C(=O)R A , -C(=O)OR A , -OC(=O)R A , -OC(=O)(C1-C6 alkyl-R H ), -OC(=O)(CH2) o OR A , -C(=O)NR A R B , -NR A C(=O) R B , -N(C(=O)R A )(C(=O)R B ), -N(C(=O)(C1-C6 Al Kill-RH ))(C(=O)(C1-C6アルキル-R H ))、-N(C(=O)(C1 -C6アルキル-R H ))2、-NR A C(=O)(CH2) O OR B 、-NR A C(= O)(CH2) O OR B 、-N(C(=O)(CH2) O OR B )2、-NR A C(=O )(CH2) O NR A R B 、-NR A (CH2) O C(=O)OR B 、-N((CH2) O C(=O)OR A )((CH2) O C(=O)OR B )、-NR A (CH2) O C(= O)NR A R B 、-N((CH2) O C(=O)NR A R B )((CH2) O C(=O) NR A R B )、-NR A (CH2) O C(=O)NR A (CH2) O OR B 、-C(=O )N((CH2) O OR B )2、-N((CH2) O C(=O)NR A (CH2) O OR B )((CH2) O C(=O)NR A (CH2) O ORB )、 -C(=O)NR A (CH 2) O OR B 、 -C(=O)NR A (CH2) O OR B 、 -C(=O)NR A (CH2) O [[ID=ID=20]]NR A R B 、 -N=CR A -NR A R B 、 -NR B -C(=NH)-NR A R B 、 O( CH2) m OR A 、 O(CH2) m COOR A 、 O(CH2) m CONR A R B 、 O(C H2) m CONR A (CH2) m OR A 、 O(CH2) m O(CH2) m OR A 、 O(C H2) m NR A R B 、 O(CH2) m O(CH2) m NR A R B ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​wherein the aryl or heteroaryl is selected from halogen, hydroxy, (C1- C6) alkyl, (CH2) p OR A , (CH2) p NR A R B , (CH2) p C(=O )NR A R B , and (CH2) p C(=O)OR A The same or different selected from the group consisting of The group is optionally substituted with one or more groups which may be substituted.

[0081] In certain specific embodiments, R1 is OR A , OCOCH2OR A , S.R. A , NHR A , N(R A )2, or NHCOCH2OR A In certain specific embodiments, R1 ’ is OAc, OCOCH2Cl, OCOCH2CH3, OCOCHMe2, OCOCM e3, OCOCH=CH2, NHCH2CH2OH, NHCH2CH2OMe, N(CH 2CH2OH)2, N(CH2CH2OMe)2, NHCH2CHMe2, NHCH2C Me2, NHAc, NHCH2COOH, NHCH2COOCH3, NMeCH2COO H, NMeCH2COOCH3, NHCH2CONH2, NHCH2CONHMe, NH CH2CONMe2, NHCH2CONHCH2CH2OH, NHCH2CONHCH2 CH2OMe, NMeCH2CONH2, NMeCH2CONHMe, NMeCH2CO NMe2, N(CH2COOH)2, N(CH2CONH2)2, N(CH2CONHM e)2, N(CH2CONMe2)2, N(CH2CONHCH2CH2OH)2, N( CH2CONHCH2CH2OMe)2, NHCOCH2Cl, NHCOCH2CH3, NHCOCHMe2, NHCOCMe3, NHCOCH=CH2, N(COCH2Cl) 2, N(COCH2CH3)2, N(COCHMe2)2, N(COCMe3)2, or N(COCH=CH2)2.

[0082] In certain specific embodiments, R A’ and R B’ are independently H, Me, Et , n-propyl, isopropyl, isobutyl, neopentyl, cyclopentyl, cyclohexyl Xyl, CH2CH2OH, CH2CH2OMe, [ka] wherein Z is CH2, O, S, NH, NCH3, NEt, N-isopropyl, N- Isopropyl, N-neopentyl, N-CH2CH2OH, or N-CH2CH2OMe In certain specific embodiments, R A’ and R B’ are Me respectively. In specific embodiments, R A’ and R B’ are Et, respectively.

[0083] In certain specific embodiments, the compounds disclosed herein have the structure of formula (VI): do: [ka]

[0084] During the ceremony: x is 0 or 1; W is CH, O, or S; Y is H or OR5; where R5 is H or methyl; m' and n' are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 1 0; and Each R1 is independently H, halogen, aryl or substituted aryl, heteroaryl, aryl or substituted heteroaryl, OR A , S.R. A , N.R. A R B , -C(=O)R A ,- C(=O)OR A , -C(=O)NR A R B , -NR A C(=O)R B , -NR A C(= O)(CH2) O R B , -NR A C(=O)(CH2) O OR B , -NR A C(=O)( CH2) O NR A R B , or -C(=O)NR A (CH2) O R B is.

[0085] In certain specific embodiments, R1 is H, OR A , S.R. A , N.R. A R B , -C(=O) R A , -C(=O)OR A , -C(=O)NR A R B , -NR A C(=O)R B , -NR A C(=O)(CH2) O R B , -NR A C(=O)(CH2) O OR B , -NR A C( =O)(CH2) O NR A R B , -C(=O)NR A (CH2) O R B , -C(=O)N R A (CH2) O OR B , and -C(=O)NR A (CH2) O NR A R B A group consisting of are selected.

[0086] In certain specific embodiments, R1 is O(CH2) m OR A , O(CH2) m O(C H2) m OR A , O(CH2) m NR A R B , O(CH2) m O(CH2) m NR A R B , N.R. C (CH2) m NR A R B , and NR C (CH2) m NR C (CH2) m NR A R B is selected from the group consisting of:

[0087] In certain specific embodiments, R1 is OR A , S.R. A , N.R. A R B , -C(=O)R A , -C(=O)OR A , and -C(=O)NR A R B Some of the compounds are selected from the group consisting of In specific embodiments, R1 is OH, OMe, OEt, O-isopropyl, O-isobutyl Tyl, O-neopentyl, O-cyclopentyl, O-cyclohexyl, SH, SMe, S -Isopropyl, S-Isobutyl, S-Neopentyl, S-Cyclopentyl, S-Cyclo hexyl, [ka] In certain specific embodiments, R1 is [ka] wherein Z is CH2, O, S, NH, NCH3, NEt, N-isopropyl, N -isopropyl, N-neopentyl, N-CH2CH2OH, or N-CH2CH2OM In some embodiments, R A and R B are described herein. is R A and R B are H, Me, Et, isopropyl, isobutyl, and cyclopentyl, respectively. In certain embodiments, R1 is hydroxyl. In another embodiment, R is C(=O)OR A is.

[0088] In still other embodiments, R1 is H, OH, OMe, OEt, O-isopropyl, O- Isobutyl, O-neopentyl, O-isopentyl, O-cyclohexyl, OCH2CH 2OH, OCH2CH2OCH3, OCH2COOH, OCH2COOCH3, OCH2 CONH2, OCH2CONHMe, OCH2CONMe2, OCH2CONHCH2C H2OH, OCH2CONHCH2CH2OMe, OAc, OOCCH2Cl, OOCC H2OR A , OOCCH2CH3, OOCCHMe2, OOCCMe3, and OC(=O )CCH=CH2.

[0089] In still other embodiments, R1 is selected from the group consisting of: [ka] TIFF2025037922000027.tif73155

[0090] In still other embodiments, R1 is SH, SMe, SEt, S-isopropyl, S-isobutyl The alkyl group is S-neopentyl, S-neopentyl, O-cyclopentyl, or S-cyclohexyl.

[0091] In still other embodiments, R1 is NH2, NHCH3, NHCH2CH3, NHCH2 CHOH, NHCH2CH2OMe, NMe2, NEt2, NHCH2CHMe2, NH CH2CMe3, NHAc, NHCH2COOH, NHCH2COOCH3, NMeCH 2COOH, NMeCH2COOCH3, NHCH2CONH2, NHCH2CONHM e, NHCH2CONMe2, NHCH2CONHCH2CH2OH, NHCH2CON HCH2CH2OMe, NMeCH2CONH2, NMeCH2CONHMe, NMeC H2CONMe2, N(CH2COOH)2, N(CH2CONH2)2, N(CH2C ONHMe)2, N(CH2CONMe2)2, N(CH2CONHCH2CH2OH) 2, N(CH2CONHCH2CH2OMe)2, NHCOCH2Cl, NHCOCH2 OR A ,NHCOCH2CH3,NHCOCHMe2,NHCOCMe3,NHCOCH =CH2, N(COCH2Cl)2, N(COCH2OR A)2, N(COCH2CH3 )2, N(COCHMe2)2, N(COCMe3)2, and N(COCH=CH2)2 is selected from the group consisting of:

[0092] In yet other embodiments, R1 is [ka] wherein Z is CH2, O, S, NH, NMe, NEt, N-isopropyl, N- Neopentyl, N-CH2CH2OH, NCH2CH2OCH3, NCH2CH2OCH 3, NCH2COOH, NCH2COOMe, N-CH2CONH2, NCH2CONH Me, or NCH2CONMe2.

[0093] In still other embodiments, R1 is selected from the group consisting of: [ka]

[0094] In yet other embodiments, R1 is: [ka] wherein each Z' is independently selected from the group consisting of CH, O, S, NR A , N (CH2) o OR A , N(CH2) o NR A R B , N(CH2) o COOR A , N(CH 2) o OC(=O)R A , N(CH2) o CONR A R B , N(CH2) o NR AC(= O)R B , or N(CH2) o OC(=O)(CH2) o OR A is.

[0095] In still other embodiments, R1 is -COOH, -COOMe, -COOEt, -CONH 2, -CONHMe, -CONMe2, -CONHEt, -CONEt2, -CONHC H2CH2OH, -CONHCH2CH2OMe, -CON(CH2CH2OH)2, - CON(CH2CH2OMe)2, or -CONMe2.

[0096] In still other embodiments, R1 is selected from the group consisting of: , O, S, NH, NCH3, NEt, N-isopropyl, N-isopropyl, N-neopentyl N-butyl, N-CHCHOH, or N-CHCHOMe: [ka] TIFF2025037922000032.tif241170TIFF2025037922000033.tif121170

[0097] In yet other embodiments, R1 is [ka] In some embodiments, R G OH, OMe, OAc, NH2, NHMe, N HAc, NMe2, NEt2, NHCH2CMe3.

[0098] In still other embodiments, R1 is selected from the group consisting of: [ka]

[0099] In yet other embodiments, R1 is OR A , OCOCH2OR A , S.R. A , NHR A , N( R A )2, or NHCOCH2OR A is.

[0100] In still other embodiments, R1 is OAc, OCOCH2Cl, OCOCH2CH3, O COCHMe2, OCOCMe3, OCOCH=CH2, NHCH2CH2OH, NHC H2CH2OMe, N(CH2CH2OH)2, N(CH2CH2OMe)2, NHCH 2CHMe2, NHCH2CMe2, NHAc, NHCH2COOH, NHCH2COO CH3, NMeCH2COOH, NMeCH2COOCH3, NHCH2CONH2, N HCH2CONHMe, NHCH2CONMe2, NHCH2CONHCH2CH2OH , NHCH2CONHCH2CH2OMe, NMeCH2CONH2, NMeCH2CO NHMe, NMeCH2CONMe2, N(CH2COOH)2, N(CH2CONH2 )2, N(CH2CONHMe)2, N(CH2CONMe2)2, N(CH2CONH CH2CH2OH)2, N(CH2CONHCH2CH2OMe)2, NHCOCH2C l, NHCOCH2CH3, NHCOCHMe2, NHCOCMe3, NHCOCH=C H2, N(COCH2Cl)2, N(COCH2CH3)2, N(COCHMe2)2, N(COCMe3)2 or N(COCH=CH2)2.

[0101] In still other embodiments, R1 is halogen, hydroxy, (C1-C6) alkyl, ( C3-C7) cycloalkyl, SR A , (CH2)p OR A , (CH2) p NR A R B , (CH2) p C(=O)R A , (CH2) p C(=O)NR A R B , and (CH2) p C (=O)OR A and optionally one or more substituents, which may be the same or different, selected from substituted aryl or heteroaryl; where p is 0, 1, 2, 3, 4, 5, 6;R A and R B Each of these is defined herein. In the form, R1 is [ka] wherein Rx is H, (C1-C6) alkyl, or (C3-C7) cycloalkyl. Ry is H, (C1-C6) alkyl, (C3-C7) cycloalkyl, OR A , S.R. A , N.R. A R B , -C(=O)R A , -C(=O)OR A , or -C(=O)NR A R B and t is 1, 2, 3, or 4. In some embodiments, Rx is H or Me is -C(=O)OR A or -C(=O)NR A R B Some In specific embodiments, R1 is [ka] wherein Z is CH2, O, S, NH, NCH3, NEt, N-isopropyl, N -isopropyl, N-neopentyl, N-CH2CH2OH, or N-CH2CH2OM e.

[0102] In yet other embodiments, R A and R B are each independently H, Me, Et, or isopropyl Pyr, isobutyl, neopentyl, cyclopentyl, cyclohexyl, CH2CH2OH , CH2CH2OMe, or [ka] wherein Z is CH2, O, S, NH, NCH3, NEt, N-isopropyl, N- Isopropyl, N-neopentyl, N-CH2CH2OH, or N-CH2CH2OMe In some embodiments, R A and R B are independently H, Me, Et, isopropyl, isobutyl, cyclopentyl, or cyclohexyl. In the embodiment, R A and R B are each independently H or (C1-C6) alkyl.

[0103] In some embodiments, R3 is H, (C1-C 12 ) alkyl, (C2-C 12 ) Alkenyl, (C2-C 12 ) alkynyl, (C3-C 12 ) cycloalkyl or phenyl nyl or CH2-phenyl (optionally halogen, hydroxy, (C1-C6) alkyl) and substituted with one or more groups, which may be the same or different, selected from alkyl, In some embodiments, R3 is (C1-C 12) alkyl. In one embodiment, R3 is a (C1-C6) straight chain alkyl. 7-C 12 In yet other embodiments, R3 is a (C4-C6) straight chain alkyl. In yet another embodiment, R3 is (C6-C8) straight chain alkyl. In this embodiment, R3 is (C7-C 10 ) alkyl. In certain other embodiments, R In yet other embodiments, R3 is (C7-C8) alkyl. 10 )straight In yet other embodiments, R3 is a (C7-C8) straight chain alkyl. In some specific embodiments, R3 is -(CH2) 3-11 - is an alkyl chain.

[0104] In some embodiments, R3 is (C2-C 12 ) alkenyl. In one embodiment, R3 is (C2-C6) straight chain alkenyl. In yet another embodiment, R3 is ( C7-C 12 In yet other embodiments, R3 is a (C4-C6) straight chain alkenyl. In yet other embodiments, R3 is a (C6-C8) straight chain alkenyl. do.

[0105] In some embodiments, R3 is (C2-C 12 ) alkynyl. In one embodiment, R3 is (C2-C6) straight chain alkynyl. In yet another embodiment, R3 is ( C7-C 12 In yet other embodiments, R3 is a (C4-C6) straight chain alkynyl. In yet other embodiments, R3 is (C6-C8) straight chain alkynyl. In any of the embodiments described herein, R3 is 4-hydroxybutyl. It's okay to have it.

[0106] In certain embodiments, R2 is ethyl. In certain embodiments, R7 is [ka] In certain embodiments, W is O or S. Certain embodiments described herein In this embodiment, W is S; x=1; and R3 is 4-hydroxybutyl.

[0107] In certain embodiments, the compound of formula I has the structure of formula (II')-(VI'): or a pharmaceutically acceptable salt thereof: [ka]

[0108] During the ceremony: each x is 0 or 1; each W is independently O, S, or CH; R1 independently represents H, halogen, aryl, heteroaryl, OR A , S.R. A , N.R. A R B , -C(=O)R A , -C(=O)OR A , -C(=O)NR A R B , -N R A C(=O)R B , -NR A C(=O)(CH2) O R B , -NR A C(=O)(CH 2) O OR B , -NR A C(=O)(CH2) O NR AR B , -C(=O)NR A (CH 2) O R B , -N=CR A -NR A R B , -NR B -C(=NH)-NR A R B、 -C( =O)NR A (CH2) O OR B , -C(=O)NR A (CH2) O NR A R B , O(C H2) m OR A , O(CH2) m O(CH2) m OR A , O(CH2) m NR A R B , O (CH2) m O(CH2) m NR A R B、 NR C (CH2) m NR A R B , or NR C ( CH2) m NR C (CH2) m NR A R B wherein the aryl or heteroaryl The group is halogen, hydroxy, (C1-C6) alkyl, (CH2) p OR A , (CH2 ) p NR A R B , (CH2) p C(=O)NR A R B , and (CH2) p C(=O)OR Aand optionally substituted with one or more groups, which may be the same or different, selected from Each R3 is independently (C1-C6) alkyl, (C7-C 12 ) alkyl, (C2- C6) alkenyl, (C7-C 12 ) alkenyl, (C2-C6) alkynyl, or (C 7-C 12 ) alkynyl, aryl, or heteroaryl, all of which may be the same or is optionally substituted by one or more groups R1, which may be different; Each R5 independently: H; optionally substituted with one or more groups R6, which may be the same or different (C1-C 6) alkyl; Each of these is halogen, hydroxy, (C1-C6) alkyl, aryl (e.g., phenyl) nil), (CH2) p OR A , (CH2) m OH, (CH2) m O(CH2) m OH, ( CH2) m NR A R B , (CH2) m O(CH2) m NR A R B , (CH2) p NR A R B , (CH2) p NR C (CH2) m NR A R B , (CH2) p NR c (CH2) m NR c (CH2) m NR A R B , (CH2) p C(=O)NR A R B, (CH2) p C(=O ) OR A and optionally substituted with one or more groups, which may be the same or different, selected from (C2-C6)alkenyl; Each of them is selected from halogen, hydroxy, amino, monoalkylamino, and dialkylamino. and optionally substituted with one or more groups, which may be the same or different, selected from (C2-C6)alkynyl; each of which is selected from halogen, hydroxy, amino, monoalkylamino, and dialkyl and optionally substituted with one or more groups, which may be the same or different, selected from the group consisting of: (C3-C7)cycloalkyl, Halogen, hydroxy, (C1-C6) alkyl, (CH2) p OR A , ( CH2) p NR A R B , (CH2) p C(=O)NR A R B , (CH2) p C(=O)O R A and optionally substituted with one or more groups which may be the same or different, selected from phenyl or CH2-phenyl; Each R6 is independently selected from halogen, hydroxy, aryl (e.g., phenyl), S( C1-C6) alkyl, SR A , OR A , O(CH2) m OR A , O(CH2) m O(C H2) m OR A , C(=O)OR A , C(=O)NR A R B , N.R. A R B , O(CH2) m NR A R B、 O(CH2) m O(CH2) m NR A R B、 NR C (CH2) m NR A R B , or NR C (CH2) m NR C (CH2) m NR A R B wherein the aryl or phenyl, each of which is halogen, hydroxy, (C1-C6) alkyl, (CH2 ) p OR A , (CH2) p NR A R B , (CH2) p C(=O)NR A R B , and (CH 2) p C(=O)OR A and Possibly substituted; R A and R B are each independently: hydrogen; one or more groups R, which may be the same or different D optionally substituted with (C1-C 6) alkyl; (C2-C6)alkenyl or (C2-C6)alkynyl; (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl ; Each is halogen, -O(C1-C6) alkyl, -C(=O)O(C1-C6) the same or different selected from alkyl, amino, alkylamino, and dialkylamino; phenyl optionally substituted by 1 to 5 groups; Alternatively, 5 or 6 ring atoms and each of the ring atoms is selected from nitrogen, sulfur, and oxygen. saturated or unsaturated, containing 1 to 3 heteroatoms which may be the same or different; optionally heterocyclic rings; Or R A and R B together with the nitrogen atoms to which they are attached, form 3 to 7 forming a saturated or unsaturated heterocyclic ring containing ring atoms of nitrogen, oxygen, and sulfur; and optionally contain another heteroatom selected from the group consisting of: alkyl, phenyl, and benzyl, which may be the same or different; optionally substituted with 1 to 4 groups; Or R A and R B together with the nitrogen atom to which they are attached, form -N=C H-NR F R F’ , -N=CMe-NR F R F’ , or -NR F C(=NH)NR F R F ’ Forming; R C are each independently hydrogen or (C1-C6) alkyl; R D are each independently halogen, hydroxy, O(C1-C4) alkyl, C(= O)(C1-C4)alkyl, C(=O)O(C1-C4)alkyl; R F and R F’ are each independently hydrogen, (C1-C6) alkyl, phenyl, benzene or R F and R F’ together with the nitrogen atom to which they are attached, form 3 Form a saturated or unsaturated heterocyclic ring containing 7 ring atoms, which ring may contain nitrogen, oxygen, and sulfur, each of which may be the same or different and is selected from the group consisting of alkyl, phenyl, and benzyl; optionally substituted with 1 to 4 groups which may be p is an integer of 0, 1, 2, 3, 4, 5, or 6; m' is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; m is an integer of 1, 2, 3, 4, 5, or 6; and n is an integer of 1, 2, 3, 4, 5, or 6.

[0109] In any of the embodiments described herein, x is 0 or 1. In any of the embodiments described herein, x may be 0. In any of the embodiments, x may be 1. In certain other embodiments, W is O. In still other embodiments, W is S. is CH2.

[0110] In certain embodiments, m' is 1. In certain other embodiments, m' is 2. In yet other embodiments, m' is 3. In yet other embodiments, m' is 4 or 5. In still other embodiments, m' is 6, 7, 8, or 9.

[0111] In certain embodiments, m is 1. In certain other embodiments, m is 2. In some embodiments, m is 3. In other embodiments, m is 4 or 5.

[0112] In certain embodiments, p is 0. In certain other embodiments, p is 1. In some embodiments, m is 2. In other embodiments, m is 3, 4, or 5.

[0113] In certain embodiments, R3 is [ka] In certain embodiments, R3 is H, methyl, ethyl, n-propyl, i-propyl butyl, n-butyl, i-butyl, t-butyl, CH2CMe3, phenyl, CH2-phenyl Lu, [ka] is.

[0114] In certain embodiments, R3 is -(CH2) n NR A R B where n is 2, 3, is an integer of 4, 5, or 6, or an integer of 7, 8, 9, 10, 11, or 12; and where R A and R B are each independently hydrogen; The above group R D (C1-C4 alkyl) optionally substituted with (wherein R D Each independently, halogen, hydroxy, O(C1-C4) alkyl, C(=O)(C1-C 4) alkyl, C(=O)O(C1-C4) alkyl; or R A and R B together with the nitrogen atom to which they are attached, form saturated or is an unsaturated heterocyclic ring, the ring being selected from the group consisting of nitrogen, oxygen, and sulfur. It may contain other heteroatoms, and optionally (C1-C4) alkyl, phenyl and benzyl, It has been replaced.

[0115] In certain embodiments, R3 is -(CH2) n NR A R B where n is 2, 3, is an integer of 4, 5, or 6, or an integer of 7, 8, 9, 10, 11, or 12; and where R A and R B together with the nitrogen atoms to which they are attached, form 3 to 7 A saturated or unsaturated heterocyclic ring containing ring atoms, which ring may optionally include nitrogen, oxygen, and sulfur, and (C1-C4) alkyl 1 to 4 groups, which may be the same or different, selected from aryl, phenyl, and benzyl; It may be optionally substituted.

[0116] In certain embodiments, n is 2. In certain other embodiments, n is 3. In some embodiments, n is 4, 5, or 6. In still other embodiments, n is 7 or 8. In yet other embodiments, n is 9 or 10. In yet other embodiments, n is 11 or is 12.

[0117] In certain embodiments, R3 is -(CH2) n NR A R B where n is 7, 8, 9, 10, 11, or 12; and wherein R A and R B are independent of each other. and hydrogen; one or more groups R, which may be the same or different. D optionally substituted with (C 1-C4 alkyl) (where R Dare each independently halogen, hydroxy, O(C1 -C4) alkyl, C(=O)(C1-C4) alkyl, C(=O)O(C1-C4) alkyl or R A and R B together with the nitrogen atoms to which they are attached. A saturated or unsaturated heterocyclic ring containing 3 to 7 ring atoms, which ring may optionally may contain additional heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. and optionally the same selected from (C1-C4) alkyl, phenyl, and benzyl. Alternatively, it may be substituted with 1 to 4 groups which may be different.

[0118] In certain embodiments, n is 7. In certain other embodiments, n is 8. In this embodiment, n is 9, 10, 11, or 12.

[0119] In certain embodiments, R3 is 2-aminoethyl, 2-aminopropyl, 3-aminopropyl Pyl, 2-monoalkylaminoethyl, 2-monoalkylaminopropyl, 3-monoalkyl 2-dialkylaminopropyl, 2-dialkylaminoethyl, 2-dialkylaminopropyl, or is 3-dialkylaminopropyl, where the alkyl is (C1-C4) alkyl It is.

[0120] In certain embodiments, R3 is 2-aminoethyl, 2-aminopropyl, 3-aminopropyl 2-monoalkylaminoethyl, 2-monoalkylaminopropyl, 3-monoalkylaminoethyl 2-dialkylaminopropyl, 2-dialkylaminoethyl, 2-dialkylaminopropyl, or 3-dialkylaminopropyl, wherein the alkyl is (C1-C4) alkyl. where R3 is dimethylaminoethyl, diethylaminoethyl, methylethyl methyl-iso-butylaminoethyl, ethyl-iso-butylaminoethyl methyl-tert-butylaminoethyl, or ethyl-tert-butylaminoethyl It is.

[0121] In certain embodiments, R3 is [ka] wherein n is an integer of 2, 3, 4, 5, or 6; and m is an integer of 2, 3, or 4. In certain other embodiments, n is 3. In still other embodiments, n is 4, 5, or 6. In certain embodiments, m is 2. In certain other embodiments, m is 3. In certain other embodiments, m is 4. In certain embodiments, n is 7. In certain other embodiments, n is 8. In embodiments, n is 9, 10, 11, or 12.

[0122] In certain embodiments, R5 is H, (C1-C6) alkyl, (C2-C6) alkenyl. phenyl, benzyl, CH2-S-(C1-C6) alkyl, CH2-O-(C1- C6) alkyl, (C2-C6) OR A , (C1-C6)-monoalkylamine, (C1 -C6)-dialkylamine, or (C1-C6)-cyclic amine, Nyl or benzyl is (C1-C4) alkyl, (C1-C4) alkoxy and halogen optionally substituted with 1 to 3 substitutents selected from and R Ais H, (C1-C6) alkyl, phenyl, CH2-phenyl , (C1-C6) alkyl OH, (CH2) p O(CH2) m OH, (CH2) p O(C H2) m O(CH2) m OH, (C1-C6) alkylO(C1-C4) alkyl, (C H2) p O(CH2) m O(C1-C4) alkyl, or (CH2) p O(CH2) m O (CH2) m O(C1-C4) alkyl; p is an integer of 0, 1, 2, 3, 4, or 5. and m is an integer of 1, 2, 3, 4, or 5.

[0123] In certain embodiments, R5 is H. In certain other embodiments, R5 is methyl In yet other embodiments, R5 is CH2-S-(C1-C6)alkyl, e.g., CH2- In yet other embodiments, R5 is CH2-O-(C1-C6)alkyl. , for example, CH2-O-CH2-CH3. In yet other embodiments, R5 is (C2-C 6) alkenyl, e.g., CH2-CH=CH2. In yet other embodiments, R5 is phenyl. In yet another embodiment, R5 is (C2-C6)OH. In the form, R5 is a (C1-C6)-monoalkylamine, e.g., CH2-NH-Me. In yet other embodiments, R5 is a (C1-C6)-dialkylamine, such as CH2 In yet other embodiments, R5 is —CH2—N(Et)2. In yet other embodiments, R5 is —CH2—N(Et)2. amine, for example CH2-CH2-morpholine.

[0124] In certain embodiments, RA and R B are each independently H, (C1-C6) alkyl , phenyl, CH2-phenyl, (C1-C6) alkylOH, (CH2) p O(CH2 ) m OH, or (CH2) p O(CH2) m O(CH2) m OH, (C1-C6) alkyl O(C1-C4) alkyl, (CH2) p O(CH2) m O(C1-C4) alkyl, or (CH2) p O(CH2) m O(CH2) m O(C1-C4) alkyl. In other embodiments, R A and R B together with the nitrogen atoms to which they are attached, [ka] wherein R C is H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH2CMe3, Ph, CH2Ph, CH2CH2OH , or CH2CH2O(C1-C4)alkyl.

[0125] In another aspect, the present invention provides a compound of formula (IIa) to (VIa) or a pharmaceutically acceptable salt thereof. Provide salt to be used: [ka]

[0126] During the ceremony: each x is 0 or 1; each W is independently O, S, or CH; R1 independently represents H, halogen, aryl, heteroaryl, ORA , S.R. A , N.R. A R B , -C(=O)R A , -C(=O)OR A , -C(=O)NR A R B , -N R A C(=O)R B , -NR A C(=O)(CH2) O R B , -NR A C(=O)(CH 2) O OR B , -NR A C(=O)(CH2) O NR A R B , -C(=O)NR A (CH 2) O R B、 -C(=O)NR A (CH2) O OR B , -C(=O)NR A (CH2) O NR A R B , O(CH2) m OR A , O(CH2) m O(CH2) m OR A , O(CH2 ) m NR A R B、 O(CH2) m O(CH2) m NR A R B、 NR C (CH2) m NR A R B , or NR C (CH2) m NR C (CH2) m NR A R B where the arithmetic aryl or heteroaryl are each selected from halogen, hydroxy, (C1-C6) alkyl, ( CH2) p OR A , (CH2) p NR A R B , (CH2) p C(=O)NR A R B , and (CH2) p C(=O)OR A one or more groups, which may be the same or different, selected from optionally substituted with; Each R5 independently: H; optionally substituted with one or more groups R6, which may be the same or different (C1-C 6) alkyl; Each of these is halogen, hydroxy, (C1-C6) alkyl, aryl (e.g., phenyl) nil), (CH2) p OR A , O(CH2) m OH, O(CH2) m O(CH2) m OH , O(CH2) m NR A R B , O(CH2) m O(CH2) m NR A R B , (CH2) p NR A R B , (CH2) p NR C (CH2) m NR A R B , (CH2) p NR c (CH2 ) m NR c (CH2) m NR A R B , (CH2) p C(=O)NRA R B , (CH2) p C(=O)OR A and optionally one or more groups, which may be the same or different, selected from substituted (C2-C6)alkenyl; Each of them is selected from halogen, hydroxy, amino, monoalkylamino, and dialkylamino. and optionally substituted with one or more groups which may be the same or different. (C2-C6)alkynyl; Halogen, hydroxy, amino, monoalkylamino, and dialkylamino, respectively. and optionally substituted with one or more groups, which may be the same or different, selected from (C3-C7)cycloalkyl, Halogen, hydroxy, (C1-C6) alkyl, (CH2) p OR A , ( CH2) p NR A R B , (CH2) p C(=O)NR A R B , (CH2) p C(=O)O R A and optionally substituted with one or more groups which may be the same or different, selected from phenyl or CH2-phenyl; Each R6 is independently selected from halogen, hydroxy, aryl (e.g., phenyl), S( C1-C6) alkyl, SR A , OR A , O(CH2) m OR A , O(CH2) m O(C H2) m OR A , C(=O)OR A , C(=O)NR A R B , N.R. AR B , O(CH2) m NR A R B , O(CH2) m O(CH2) m NR A R B、 NR C (CH2) m NR A R B , or NR C (CH2) m NR C (CH2) m NR A R B wherein the aryl or phenyl may be selected from halogen, hydroxy, (C1-C6) alkyl, (CH2) p OR A , (CH2) p NR A R B , (CH2) p C(=O)NR A R B , and (CH2 ) p C(=O)OR A and the case is formed by one or more groups, which may be the same or different, selected from is replaced by R A and R B are each independently: hydrogen; one or more groups R, which may be the same or different D optionally substituted with (C1-C 6) alkyl; (C2-C6)alkenyl or (C2-C6)alkynyl; (C3-C7)cycloalkyl optionally substituted with (C1-C6)alkyl ; Halogen, -O(C1-C6) alkyl, -C(=O)O(C1-C6) alkyl, respectively. the same or different, selected from alkyl, amino, alkylamino, and dialkylamino; phenyl optionally substituted by 1 to 5 groups; Alternatively, 5 or 6 ring atoms and each of the ring atoms is selected from nitrogen, sulfur, and oxygen. saturated or unsaturated alkyl group containing 1 to 3 heteroatoms which may be the same or different, May also be heterocyclic rings; Or R A and R B together with the nitrogen atoms to which they are attached, form 3 to 7 forming a saturated or unsaturated heterocyclic ring containing ring atoms of nitrogen, oxygen, and sulfur; and optionally contain another heteroatom selected from the group consisting of: alkyl, phenyl, and benzyl, which may be the same or different; optionally substituted with 1 to 4 groups; R C are each independently hydrogen or (C1-C6) alkyl; R D are each independently halogen, hydroxy, O(C1-C4) alkyl, C(= O)(C1-C4)alkyl, C(=O)O(C1-C4)alkyl; each p is independently an integer of 0, 1, 2, 3, 4, or 5; m' is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; each m and n is independently an integer of 1, 2, 3, 4, or 5; and q is an integer of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11.

[0127] In certain embodiments, q is 1. In certain other embodiments, q is 2. In other embodiments, n is independently an integer of 6, 7, 8, 9, 10, or 11.

[0128] In certain embodiments, W is S. In certain other embodiments, W is O.

[0129] In certain embodiments, R is hydrogen. In certain other embodiments, R is (C-C 6) alkyl. In certain embodiments, R3 is (C1-C6) alkyl. In other embodiments, R3 is NR C CH2(CH2) p NR A R B is.

[0130] In certain embodiments, R5 is H, (C1-C6) alkyl, (C2-C6) alkenyl. phenyl, benzyl, CH2-S-(C1-C6) alkyl, CH2-O-(C1- C6) alkyl, (C2-C6) OR A , (C1-C6)-monoalkylamine, (C1 -C6)-dialkylamine, or (C1-C6)-cyclic amine, wherein the phenyl Nyl or benzyl is (C1-C4) alkyl, (C1-C4) alkoxy, and halogen. optionally substituted with 1 to 3 substituents selected from: A teeth, H, (C1-C6) alkyl, phenyl, CH2-phenyl, (C1-C6) alkylO H, (CH2) p O(CH2) m OH, (CH2) p O(CH2) m O(CH2) m OH , (C1-C6) alkylO(C1-C4) alkyl, (CH2) p O(CH2) m O( C1-C4) alkyl, or (CH2) p O(CH2) m O(CH2) m O(C1-C4 ) alkyl; p is an integer of 0, 1, 2, 3, 4, or 5; and m is 1, is an integer of 2, 3, 4, or 5.

[0131] In certain other embodiments, R5 is H, (C1-C4) alkyl, (C2-C4) alkoxy, or phenyl, benzyl, CH2-S-(C1-C4) alkyl, CH2-O-(C 1-C4) alkyl, (CH2)2OH, or (CH2)2O(C1-C4) alkyl In certain embodiments, R5 is H. In certain other embodiments, R5 is methyl. be.

[0132] In certain embodiments, R A and R B are each independently H, (C1-C6) alkyl , phenyl, CH2-phenyl, (C1-C6) alkylOH, (CH2) p O(CH2 ) m OH, or (CH2) p O(CH2) m O(CH2) m OH, (C1-C6) alkyl O(C1-C4) alkyl, (CH2) p O(CH2) m O(C1-C4) alkyl, or (CH2) p O(CH2) m O(CH2) m O(C1-C4) alkyl. In other embodiments, R A and R B are each independently H or (C1-C6) alkyl In yet another embodiment, R A and R B together with the nitrogen atoms to which they are attached. So, [ka] wherein R Cis H, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, CH2CMe3, Ph, CH2Ph, or CH2CH2 OH and CH2CH2OR d is.

[0133] In certain embodiments, the compound is selected from the group consisting of: It is a salt that can be used: [ka] TIFF2025037922000048.tif233154TIFF2025037922000049.tif232159TIFF2025037922000050.tif195167 wherein x is 0 or 1; m is 2, 3, 4, 5, 6, 7, or 8; and Y is H, O H, or OMe; W is O or S; and each R a are independently the parts shown in Table 1 minutes; [Table 1] TIFF2025037922000052.tif255168TIFF2025037922000053.tif254164TIFF2025037922000054.tif254167TIFF20250379220 00055.tif254163TIFF2025037922000056.tif255166TIFF2025037922000057.tif250167TIFF2025037922000058.tif189168

[0134] In another aspect, compounds having the formula or a pharmaceutically acceptable salt thereof are described: [ka] wherein x is 1; m is 2, 3, 4, 5, 6, 7, or 8; and Y is H, OH, or OMe; W is O or S; and each R a teeth [ka] is.

[0135] In another aspect, compounds having the formula or a pharmaceutically acceptable salt thereof are described: [ka] wherein x is 1; m is 2, 3, 4, 5, 6, 7, or 8; and Y is H, OH, or is OMe; W is O or S; and each R a teeth [ka] is.

[0136] In another aspect, compounds having the formula or a pharmaceutically acceptable salt thereof are described: [ka] wherein x is 1; m is 2, 3, 4, 5, 6, 7, or 8; and Y is H, OH, or is OMe; W is O or S; and each R a teeth [ka] is.

[0137] In another aspect, compounds having the formula or a pharmaceutically acceptable salt thereof are described: [ka] wherein x is 1; m is 2, 3, 4, 5, 6, 7, or 8; and Y is H, OH, or OMe; W is O or S; and each R a teeth [ka] is.

[0138] In another aspect, compounds having the formula or a pharmaceutically acceptable salt thereof are described: [ka] wherein x is 1; m is 2, 3, 4, 5, 6, 7, or 8; and Y is H, OH, or is OMe; W is O or S; and each R a teeth [ka] is.

[0139] In another aspect, the present invention provides a method for treating a rheumatoid arthritis, comprising administering to a subject a rheumatoid arthritis, ... and an acceptable carrier or diluent.

[0140] In a further aspect, the present invention provides a method for treating or preventing a viral infection in a mammalian species in need thereof. provides a method of preventing, which method comprises administering a therapeutically effective amount of at least one of the compounds described herein. In certain embodiments, the viral infection comprises administering to the mammalian species a compound selected from the group consisting of: In certain other embodiments, the viral infection is an HBV infection. In one embodiment, the viral infection is HCV infection. Infections include influenza A virus infection, severe acute respiratory syndrome coronavirus infection, and is a vaccinia virus infection.

[0141] In another aspect, the present invention provides a method for treating hepatitis C virus infection in a mammalian species in need thereof. The present invention provides a method for treating or preventing a rheumatoid arthritis, the method comprising administering a therapeutically effective amount of a compound described herein. The method comprises administering at least one compound to a mammalian species.

[0142] In yet another aspect, the present invention provides a method for inhibiting cyclophilin in a subject in need thereof. The present invention provides a method for the preparation of a cyclophilin-inhibiting compound, comprising administering an effective cyclophilin-inhibiting amount of a compound as described herein to a patient. The method includes administering to the subject at least one compound such as:

[0143] In yet another aspect, the present invention provides a method for treating cyclophilin-mediated leukemia in a mammalian species in need thereof. The present invention provides a method for treating or preventing a disease mediated by a compound of formula (I) or (II), which comprises administering a therapeutically effective amount of a compound described herein. The method comprises administering at least one compound as described to a mammalian species.

[0144] In yet another aspect, the present invention provides a method for treating or preventing a disease in a mammalian species in need thereof. The present invention provides a method for treating a rheumatoid arthritis, the method comprising administering a therapeutically effective amount of at least one compound as described herein. to a mammalian species, wherein the disease is inflammation, respiratory inflammation, rheumatoid arthritis, and dry eye.

[0145] In yet another aspect, the present invention provides a method for treating or preventing a disease in a mammalian species in need thereof. The present invention provides a method for treating a rheumatoid arthritis, the method comprising administering a therapeutically effective amount of at least one compound as described herein. to a mammalian species, wherein the disease is a neurodegenerative disease, e.g., Alzheimer's disease. Hymer's disease, Parkinson's disease, Huntington's disease and ALS; traumatic brain injury; stroke; and ischemia-reperfusion injury in the brain, heart, and kidney.

[0146] In yet another aspect, the present invention provides a method for treating or preventing a disease in a mammalian species in need thereof. The present invention provides a method for treating a rheumatoid arthritis, the method comprising administering a therapeutically effective amount of at least one compound as described herein. to a mammalian species, wherein the disease is cardiovascular disease, vasostenosis, arterial disease, Arteriosclerosis, abdominal aortic aneurysm, cardiac hypertrophy, aortic rupture, pulmonary arterial hypertension, myocarditis and cardiac The disease is selected from muscle fibrosis, and ischemic heart disease.

[0147] In yet another aspect, the present invention provides a method for treating or preventing a disease or condition in a mammalian species in need thereof. The present invention provides a method for preventing a pulmonary embolism, the method comprising administering a therapeutically effective amount of at least one compound as described herein. and administering to a mammalian species a compound of the formula (I) or (II), wherein the disease or condition is selected from the group consisting of cancer; obesity; diabetes; muscular dystrophy; lung, liver and kidney diseases and their protection; and Selected from hair.

[0148] In yet another aspect, the present invention provides a method for treating or preventing a disease or condition in a mammalian species in need thereof. The present invention provides a method for preventing a pulmonary embolism, the method comprising administering a therapeutically effective amount of at least one compound as described herein. and administering to a mammalian species one or more of the compounds, wherein the disease or condition is an allergy. conjunctivitis, atopic and vernal keratoconjunctivitis, atopic keratoconjunctivitis, anterior uveitis, bech Eckstein's disease, blepharitis, chronic ocular surface inflammation caused by viral infection, corneal transplant rejection corneal sensitivity due to surgical damage to the cornea or other surfaces of the eye; meibomian gland disease; Ptyregia, ocular manifestations of graft-versus-host disease, ocular allergies, ocular cicatricial Pemphigoid (ocular cicatricial pemphigoid), Bunn-Johnson syndrome, vernal keratoconjunctivitis, uveitis, herpes simplex keratitis, ocular rosacea and pinguecula.

[0149] Preparation method In certain embodiments, the compound of formula (I) is a compound having a modified cyclosporin A at the 1-position of the MeBmt. The synthesis of intermediates 3, 4, and 5 is described in U.S. Pat. No. 9,200,038 B2, which is incorporated herein by reference; and US Patent Application Publication No. 2013 / 0190223A1, which is incorporated herein by reference. A similar method was used as described in (incorporated in [the original text]). Treatment with ClAc2O and DMAP in lysine, followed by OsO4 and Na in dioxane Cleavage of the double bond with IO4 gave the corresponding aldehyde 2, which was then reacted with Wittig olefins. Nitrilation and reduction with NaBH4 to generate amine 4, followed by coupling with AcOH to give amide 5, which is subsequently hydrolyzed to give the free hydroxyl of amide 6. The α-methylene group on the sarcosine at position 3 of cyclosporin is 1194A1 (which is incorporated herein by reference) and U.S. Patent Application Publication No. 2002 / 0022990. No. 013 / 0210704A1, which is incorporated herein by reference. The sulfur nucleophile was introduced by a similar method to that described above, with the key intermediate 7 being methylene When used for the 1,4-Michael addition of the methyl group, the methylene sulfide has the S-configuration. Yellow side chains can be formed on the sarcosine at position 3 for novel cyclosporine derivatives, for example:

[0150] [ka]

[0151] Other compounds disclosed herein can be prepared using methods similar to those disclosed in Scheme 1. and / or prepared by a method including any modification or variant thereof known to those skilled in the art. It can be done.

[0152] Recently, we published a study on STG-175 (Gallay, PA .,et al,2016,PLoS One 11(4):e0152036.doi :10.1371 / journal.pone.0152036, which is based on the reference (Incorporated herein) CH2-S-CH2CH at the 3-position of sarcosine in cyclosporine. The 2CH2CH2OH moiety exhibits high cyclophilin binding (EC5 for cyclophilin A). 0.6nM) and high anti-HCV activity (for many genotypes of HCV GT1a to 4a) EC 50 It has been demonstrated that viral replication is When bouncing, compared to Sofosbuvir, STG-175 still: No rebound of viral replication was observed after cessation of drug treatment, thus clearing cells from HCV. Even if the drug dose is less than 2.5 times that of Sofosbuvir. It has a higher barrier to resistance than other cyclophilin inhibitors or direct antiviral agents (DAAs). This finding suggests that MeBmt is a potent anti-inflammatory drug, and no cross-resistance is observed with DAAs. Modification of position 1 and position 3 of sarcosine in cyclosporin as novel cyclosporin derivatives. The CH2-S-CH2CH2CH2CH2OH side of It is believed that this is possible.

[0153] Pharmaceutical Composition The present invention also provides compounds as described herein or pharmaceutically acceptable salts thereof, or and a pharmaceutically acceptable carrier. do.

[0154] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutical To carry or transport an agent from one organ or part of the body to another organ or part of the body. pharmaceutical agents such as liquid or solid fillers, diluents, excipients, solvents or encapsulating materials involved in the Each carrier means a material, composition, or vehicle that is compatible with the other ingredients of the formulation. It must be "acceptable" in the sense that it is compatible with the patient and is not harmful to the patient. Some examples of materials that can act as acceptable carriers include sugars, e.g., lactose, glucose, cocoa and sucrose; starches, such as cornstarch and potato starch; cereals cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients, e.g. For example, cocoa butter and suppository wax; oils, such as peanut oil, cottonseed oil, safflower oil, gum ai oil, olive oil, corn oil, and soybean oil; glycols, such as butylene glycol polyols, such as glycerin, sorbitol, mannitol, and polyethylene; Glycols; esters, such as ethyl oleate, ethyl laurate, etc.; agar; buffers for example, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free Water; Isotonic saline; Ringer's solution; Ethyl alcohol; Phosphate buffer; and medicines Other non-toxic compatible materials used in the formulation include:

[0155] As noted above, certain embodiments of the pharmaceutical agent are provided in the form of a pharmaceutically acceptable salt. In this respect, the term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt of the compounds of the present invention. The term "relatively non-toxic inorganic and organic acid addition salts" refers to the final monobasic salts of the compounds of the present invention. In situ during isolation and purification, or in the free base form of the present invention. Separately reacting the compound with a suitable organic or inorganic acid and isolating the salt thus formed. Representative examples include hydrobromide, hydrochloride, sulfate, and bisulfate salts. , phosphate, nitrate, acetate, valerate, oleate, palmitate, stearic acid Salt, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate acid salts, fumarates, succinates, tartrates, naphthylates, mesylates, glucoheptone acid salts, lactobionates, and lauryl sulfonates. rge et al., (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).

[0156] Pharmaceutically acceptable salts of the subject compounds include, for example, salts of the compounds from non-toxic organic or inorganic acids. These include conventional non-toxic salts or quaternary ammonium salts. The salts may be prepared from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, and nitric acid. organic acids, such as acetic acid, butionic acid, amber, Acid, glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid , palmitic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, Benzoic acid, salicylic acid, sulfanilic acid, 2-acetoxybenzoic acid, fumaric acid, toluene Prepared from sulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isothiocyanic acid, etc. Examples of such salts include:

[0157] In other cases, the compounds of the present invention may contain one or more acidic functional groups, and thus These compounds can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in the present invention refers to relatively non-toxic inorganic salts of the compounds of the present invention. and organic base addition salts. These salts may also be used during the final isolation and purification of the compounds. The purified compound in situ or in its free acid form is added to a suitable base. For example, a pharmaceutically acceptable hydroxide, carbonate, or bicarbonate of a metal cation and an ammonia or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include lithium salts. , sodium salts, potassium salts, calcium salts, magnesium salts, and aluminum salts. Representative organic amines useful for the formation of base addition salts include ethylamine, diamine, ethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, etc. (See, for example, Berge et al., supra).

[0158] Sodium lauryl sulfate, magnesium stearate, and polyethylene oxide-poly Wetting agents, emulsifiers, and lubricants such as butylene oxide copolymers, as well as colorants, Forming agents, coating agents, sweetening agents, flavoring and perfuming agents, preservatives and antioxidants may also be added to the composition. It can exist.

[0159] The formulations of the present invention may be administered orally, nasally, topically (including buccal and sublingually), rectally, vaginally, and / or non-oral. The formulations may conveniently be presented in unit dosage form, including those suitable for oral administration. The formulation may be prepared by any method known in the art of pharmacy. The amount of active ingredient that can be combined with the body material will vary depending on the host being treated and the particular mode of administration. The active ingredient that can be combined with the carrier material to produce a single dosage form varies depending on the active ingredient. The amount of active ingredient is generally the amount of compound that produces a therapeutic effect. This amount ranges from about 1% to about 99% of the active ingredient, preferably from about 5% to about 70%, most preferably about The range is from 10% to about 30%.

[0160] Methods for preparing these formulations or compositions include incorporating a compound of the invention into a carrier and optionally one or more Generally, the formulations include combining a compound of the present invention with a liquid carrier or microcrystalline cellulose. uniformly and intimately combine the divided solid carrier or both, and then, if necessary, It is prepared by molding.

[0161] Formulations of the present invention suitable for oral administration include capsules, cachets, pills, tablets, lozenges (flavored), and the like. a coated base, usually sucrose and acacia or tragacanth), powder, It may be in the form of granules, or as a solution or suspension in an aqueous or non-aqueous liquid. or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syringe. as a drop or as a lozenge (an inert base such as gelatin and glycerin, or sucrose) and acacia) and / or mouthwash, etc., each containing a predetermined amount The compounds of the present invention may also be administered as boluses, electuaries, or other injectables containing the compounds of the present invention as an active ingredient. may be administered as a paste.

[0162] The solid dosage forms of the present invention for oral administration (capsules, tablets, pills, sugar-coated tablets, powders, granules, etc.) In the present invention, the active ingredient is one or more pharmaceutical compounds such as sodium citrate or dicalcium phosphate. and / or any of the following: fillers or extenders, e.g. starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; Combinations, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone lydon, sucrose, and / or acacia; humectants, such as glycerol; disintegrants, such as Examples include agar, calcium carbonate, potato or tapioca starch, alginic acid, and certain silicas. sodium carbonate and sodium starch glycolate; solution retarders, e.g., paraffin absorption enhancers, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol; glycerol monostearate, and polyethylene oxide-polybutylene oxide copolymers; absorbents, such as kaolin and bentonite clay; lubricants, such as talc, Calcium stearate, magnesium stearate, solid polyethylene glycol, laurate sodium disulfide sulfate, and mixtures thereof; and coloring agents. In some cases, the pharmaceutical composition may also contain a buffer. Solid compositions of a similar type may also contain A soft milk powder is prepared using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. and may be used as a filler in hard gelatin capsules.

[0163] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may contain binders (e.g., gelatin or hydroxybutylmethylcellulose), lubricants, or Lubricants, inert diluents, preservatives, disintegrating agents (e.g., sodium starch glycolate or crosslinking agents) prepared with cross-linked carboxymethylcellulose sodium), surfactants, or dispersants Molded tablets may be made by molding a mixture of the powdered compound moistened with an inert liquid diluent in a suitable machine. It may also be produced by molding.

[0164] Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as dragees, capsules, pills, and The granules may optionally be scored or enteric coated and the pharmaceutical formulation prepared with coatings and shells such as other coatings well known in the art. They may also be used in various ratios to provide the desired release profile. tions), e.g., hydroxybutyl methylcellulose, other polymer matrices The active ingredient in the formulation may be released slowly or controlled using liposomes, liposomes, and / or microspheres. They may be formulated to provide controlled release, e.g., by filtration through a bacteria-retaining filter. It may be sterilized by filtration or by incorporating a sterilizing agent in the form of a sterile solid composition, These compositions can be dissolved in sterile water or some other sterile injectable medium immediately before use. It may also optionally contain opacifying agents, which may be present in certain parts of the gastrointestinal tract. The composition may be one that releases the active ingredient(s) solely or preferentially, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. It can also be in microencapsulated form, if appropriate, with one or more of the above-described excipients.

[0165] Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions. These include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage form may contain an inert diluent commonly used in the art, e.g. water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isobutyl alcohol, alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, Butylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil) Rosaceae oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuran fatty acid esters of furyl alcohol, polyethylene glycol, and sorbitan, and It may also contain mixtures thereof. In addition, cyclodextrins, such as hydroxybutyl -β-cyclodextrin may be used to solubilize the compounds.

[0166] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying agents, and Suspending agents, sweetening agents, flavoring agents, coloring agents, perfuming agents and preservatives may also be included.

[0167] Suspensions may contain, in addition to the active compound, suspending agents, such as ethoxylated isostearyl alcohols. sorbitol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, Aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof It may also contain.

[0168] Formulations of the pharmaceutical compositions of the present invention for rectal or vaginal administration may be presented as suppositories. , which may comprise one or more compounds of the invention in a composition containing, for example, cocoa butter, polyethylene glycol, Mix with one or more suitable non-irritating excipients or carriers, including a suppository wax or salicylate. It may also be prepared by adding 2-methyl-2-propanol, which is solid at room temperature but liquid at body temperature, It melts in the rectum or vaginal cavity and releases the active pharmaceutical agent of the present invention.

[0169] Formulations of the present invention suitable for vaginal administration may also be prepared using methods known in the art. pessaries, tampons, creams containing a carrier such as is known to be Includes gel, paste or foam or spray formulations.

[0170] Dosage forms for topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, and the like. Active compounds include sprays, creams, lotions, gels, solutions, patches, and inhalants. may be prepared under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers, etc. which may be required. Or it can be mixed with butellant.

[0171] Ointments, pastes, creams, and gels may contain, in addition to the active compounds of the invention, excipients, e.g. For example, animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and may contain zinc oxide, or a mixture thereof.

[0172] Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose and talc. , silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or The spray may further contain a mixture of substances such as conventional butanols, e.g. Further containing fluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and butane. It is possible.

[0173] Transdermal patches have the added advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms are made by dissolving or dispersing a pharmaceutical agent in a buffer medium. Absorption enhancers also increase the flux of the pharmaceutical agents of the present invention through the skin. The rate of such flux can be controlled by providing a rate-controlling membrane or can be controlled by dispersing the compound in a polymer matrix or gel. Cut.

[0174] Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention.

[0175] Pharmaceutical compositions of the present invention suitable for parenteral administration may be prepared by dissolving one or more pharmaceutically acceptable sterile isotonic water solutions in water. In combination with aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders, These may be prepared in a sterile injectable solution or dispersion immediately prior to use, containing one or more compounds of the invention. May be reconstituted with antioxidants, buffers, bacteriostats, and the intended recipient's blood and preparations It may contain solutes that render the solution isotonic, or suspending or thickening agents.

[0176] In some cases, the absorption of drugs from subcutaneous or intramuscular injections is required to prolong the drug's effect. This is because the use of a liquid suspension of crystalline or amorphous material with poor water solubility is desirable. In this case, the rate of absorption of the drug depends on its dissolution rate, The dissolution rate of the parenteral drug form may depend on the crystal size and crystalline form. Delayed absorption is accomplished by dissolving or suspending the drug in an oil vehicle. One strategy for this is to use polyethylene terephthalate, such that the vehicle is fluid at room temperature and solidifies at body temperature. This includes the use of polybutylene oxide-polybutylene oxide copolymers.

[0177] Injectable depot forms are made in biodegradable polymers such as polylactide-polyglycolide. They are prepared by forming a microencapsulated matrix of the subject compound. Controlling the rate of drug release depending on the ratio of polymers and the nature of the particular polymer used Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations also include liposomes or microspheres that are compatible with body tissue. These are prepared by entrapment of the drug in an emulsion.

[0178] When the compounds of the present invention are administered to humans and animals as drugs, they may be administered as such or in a pharmaceutically acceptable form. In combination with an acceptable carrier, for example, 0.1% to 99.5% (more preferably 0.5% to 90%) of the active ingredient.

[0179] The compounds and pharmaceutical compositions of the present invention can be used in combination therapy, i.e., The pharmaceutical composition may be administered simultaneously with, before, or after one or more other desired treatments or medical procedures. The specific combination of therapies (treatments or procedures) used in a combination regimen The selection of a therapeutic agent will take into consideration the suitability of the desired treatment and / or procedure and the desired therapeutic effect to be achieved. The treatments used may achieve the desired effect for the same disorder (e.g., The compound may be administered simultaneously with another anti-HCV agent), or may achieve a different effect (e.g., For example, controlling side effects) is also understood.

[0180] The compounds of the present invention can be administered intravenously, intramuscularly, intraperitoneally, subcutaneously, topically, orally, or by any other acceptable route. The compounds may be administered to mammals (i.e., humans, domestic animals, and farm animals) by any suitable means. , birds, lizards, and any other organisms that can tolerate the compound. It may also be used to

[0181] The present invention also provides a pharmaceutical composition comprising one or more containers filled with one or more of the ingredients of the pharmaceutical composition of the present invention. A medicine pack or kit is provided. Optionally, such containers may contain a medicine or Notices in the form prescribed by government agencies regulating the manufacture, use, or sale of biological products The notice may be in the form of a notice indicating the method of manufacture, use, or sale for human administration. This reflects approval by the authority.

[0182] equivalent The following representative examples are intended to help illustrate the invention and are not intended to limit the scope of the invention. It is not intended to limit the scope, nor should it be construed as such. Various modifications and many further embodiments of the invention in addition to those shown and described herein are possible. The present disclosure includes references to the following examples and the scientific and patent literature cited therein. The contents of those cited documents are considered to be indicative of the state of the art. It is further understood that the present invention is incorporated herein by reference to help explain The following examples are provided to illustrate the practice of the present invention in its various embodiments and equivalents thereof. This document contains important additional information, examples, and guidance that can be adapted to your needs. [Example]

[0183] Example 1 [α-Methylene-Sar]-3-cyclosporine [ka]

[0184] [α-Hydroxymethyl-Sar]-3-cyclo[alpha] ... A solution of 246 mg of benzoxazole (0.20 mmol) was added to a solution of 120 mg of sodium hydride (0.20 mmol). in mineral oil (60%, 3 mmol), and diethyl chlorophosphate (412 mg, 2.40 mmol) l) was added. The resulting mixture was stirred at room temperature overnight. After the starting material disappeared, methanol was added. ethanol (10 ml) and potassium tert-butoxide (33 mg, 26.00 mmol) The mixture was stirred at room temperature for 3 hours, and the solvent was removed under reduced pressure. The dichloromethane layer was washed with brine and dissolved in magnesium sulfate. The residue was purified by elution with dichloromethane / methanol. Purification by flash chromatography using HCl gave 205 mg of product [molecular weight: Formula:C 63 H 111 N 11 O 12 ; Exact mass: 1213.84; MS(m / z): 12 14.59(M+1) + HPLC RT: 17.47 min (C8 reverse phase column: 250 mm ; Acetonitrile / water (0.05% trifluoroacetic acid), Operating temperature: 64°C; Detector: 2 10nm)].

[0185] Example 2 [(3R,4R)-3-hydroxy-4-methyl-6-(4-methoxycarbonyl)benzene [(S)-(4-hydroxybutylthio)methyl-N-MeNle]-1-[(S)-(4-hydroxybutylthio)methyl-Sar ]-3-Cyclosporin

[0186] [3-Acetyl-MeBmt]-1-cyclosporine [ka]

[0187] In a dry flask under nitrogen, cyclosporine (12.00 g, 9.98 mmol), N,N-dimethylaminopyridine (0.12 g, 0.10 mmol), anhydrous pyridine (1 To the mixture was added acetic anhydride (54 ml, 0.54 mol) and stirred overnight at room temperature. After that, the mixture was poured into ice water (600 ml) and stirred until the ice melted. 00 ml) was added and the mixture was separated. The ethyl acetate layer was diluted with 1.0 N hydrochloric acid solution (100 ml) l x 2), saturated sodium bicarbonate solution (100 ml), and brine (100 ml). The residue was purified by chromatography (Hexa Purification with ethanol / acetone gave 11.40 g of pure [3-acetyl-MeBmt]-1- Cyclosporin was obtained [molecular formula: C 64 H 113 N 11 O 13 ;Exact mass: 1243. 85; MS (m / z): 1244.53 (M + 1) + , 1266.70(M+Na) + ; HPLC RT: 18.02 min (C8 reverse phase column: 250 mm; acetonitrile / water (0 0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0188] [(3R,4R)-3-acetyloxy-4-methyl-6-oxo-N-MeNle]- 1-Cyclosporin [ka]

[0189] [3-acetyl-MeBmt]-1-cyclosporine () in dioxane (200 ml) A solution of 10.00 g (8.04 mmol) of osmium (VII) oxide was added to 20 ml of water. I) solution (15.74 mM, 51 ml, 0.80 mmol), and sodium metaperiodate Ammonia (6.88 g, 32.16 mmol) was added, and the reaction mixture was stirred at room temperature for 5 hours. Ethyl acetate (100 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was washed with saturated sodium bicarbonate solution, brine, dried over magnesium sulfate, and The residue was purified by chromatography (hexane / acetone) to give 5 0.10 g of pure [(3R,4R)-3-acetyloxy-4-methyl-6-oxo-N -MeNle]-1-cyclosporin [molecular formula: C 62 H 109 N 11 O 14 ;Correct Exact mass: 1231.82;MS(m / z):1232.75(M+1) + , 1254. 77(M+Na) + HPLC RT: 15.74 min (C8 reverse phase column: 250 mm; Acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64°C; Detector: 210 nm)].

[0190] [(3R,4R)-3-acetyloxy-4-methyl-6-(4-methoxycarbonyl) (phenyl)methylene-N-MeNle]-1-cyclosporine [ka]

[0191] (4-Methoxycarbonylbenzene) in anhydrous tetrahydrofuran (120 ml) under nitrogen. To a solution of (phenyl)triphenylphosphonium bromide (4.00 g, 8.14 mmol), Thorium bis(trimethylsilyl)amide (1.0 M in THF, 10 ml, 10.00 m The reaction mixture was stirred at room temperature for 1 hour and cooled to -40°C. [(3R,4R)-3-acetyloxy-4-methyl- 6-oxo-N-MeNle]-1-cyclosporine (5.00 g, 4.05 mmol) The mixture was stirred at -30°C for another 2 hours and then saturated ammonium chloride solution ( The reaction was quenched by adding 20 ml of tetrahydrofuran. Most of the tetrahydrofuran was evaporated under reduced pressure. Ethyl acetate (150 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed. The resulting mixture was purified with dichloromethane / methanol to give 2.00 g of pure [(3R,4R)- 3-acetyloxy-4-methyl-6-(4-methoxycarbonylphenyl)methylene- N-MeNle]-1-cyclosporin [molecular formula: C 71 H 117 N 11 O 15 ; Exact mass: 1363.87;MS(m / z):1364.61(M+1) + , HPLC RT: 17.89 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0192] [(3R,4R)-3-acetyloxy-4-methyl-6-(4-methoxycarbonyl) N-MeNle]-1-cyclosporine [ka]

[0193] [(3R,4R)-3-acetyloxy-4-methyl-6 -(4-Methoxycarbonylphenyl)methylene-N-MeNle]-1-cyclosporin A solution of palladium (10 wt% on carbon, 20 m g) and acetic acid (5 drops) were added. The mixture was stirred under hydrogen at room temperature for 2 hours. Filtration and evaporation of the filtrate under reduced pressure gave crude [(3R,4R)-3-acetyloxy-4-methyl [6-(4-methoxycarbonylbenzyl)-N-MeNle]-1-cyclosporin The molecular formula: C 71 H 119 N 11 O 15 Exact mass: 1365.89; MS(m / z):1366.73(M+1) + HPLC RT: 18.02 min (C8 reverse phase column) : 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64 °C ;Detector: 210 nm)].

[0194] [(3R,4R)-3-hydroxy-4-methyl-6-(4-carboxybenzyl)-N -MeNle]-1-cyclosporine [ka]

[0195] [(3R,4R)-3-acetyloxy-4-methyl-6-(4-methoxycarbonyl benzyl)-N-MeNle]-1-cyclosporine (0.25 g, 0.18 mmol) was dissolved in methanol (4 ml), water (2 ml) and tetramethylammonium hydroxide. The mixture was stirred at room temperature overnight. The alcohol was evaporated. The pH of the mixture was adjusted to 5 with acetic acid. Ethyl acetate (50 ml) and Brine (10 ml) was added and the mixture was separated. The organic layer was dried over magnesium sulfate. The crude product [(3R,4R)-3-hydroxy-4-methyl-6 -(4-carboxybenzyl)-N-MeNle]-1-cyclosporin [molecular formula :C 68 H 115 N 11 O 14 ; Exact mass: 1309.86; MS(m / z): 131 0.61(M+1) + HPLC RT: 14.36 min (C8 reverse phase column: 250 mm; Acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64°C; Detector: 21 0 nm)].

[0196] [(3R,4R)-3-hydroxy-4-methyl-6-(4-carboxybenzyl)-N -MeNle]-1-[α-methylene-Sar]-3-cyclosporine [ka]

[0197] Diisopropylamine (2. A solution of 0.5g, 20.30mmol) of n-butyllithium (2.65M, 7.7ml The reaction mixture was stirred for 1 hour, and then tetrahydrofuran was added. [(3R,4R)-3-hydroxy-4-methyl-6-(4-carbohydrate)] in ethanol (10 ml) [Oxybenzyl]-N-MeNle]-1-cyclosporine (2.40 g, 1.20 mmol) A solution of HCl was added to the reaction mixture. The mixture was stirred at -78°C for 3 hours. Carbon dioxide gas was added to the reaction mixture. After bubbling gas for 15 minutes, the mixture was stirred at -78°C for an additional hour. The mixture was then cooled to room temperature to remove any unreacted carbon dioxide. The mixture was cooled to 78°C and chloromethyl chloroformate (3.00 ml) was added. The mixture was stirred and allowed to warm to room temperature overnight. Brine (5 ml) was added to quench the reaction. Most of the tetrahydrofuran was removed under reduced pressure. Ethyl acetate (80 ml) and brine were added. (50 ml) was added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. Evaporation under reduced pressure gave 1.50 g of crude product [(3R,4R)-3-hydroxy-4-methyl -6-(4-carboxybenzyl)-N-MeNle]-1-[α-methylene-Sar] 3-Cyclosporin [molecular formula: C 69 H 115 N 11 O 14 ;Exact mass: 13 21.86; MS(m / z):1322.55(M+1) + ;HPLC RT:16.1 3 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid) ); operating temperature: 64°C; detector: 210 nm)].

[0198] [(3R,4R)-3-hydroxy-4-methyl-6-(4-methoxycarbonyl)benzene [N-MeNle]-1-[α-methylene-Sar]-3-cyclosporine [ka]

[0199] [(3R,4R)-3-hydroxy- in N,N-dimethylformamide (15 ml) 4-Methyl-6-(4-carboxybenzyl)-N-MeNle]-1-[α-methylene A solution of [-Sar]-3-cyclosporine (1.32 g, 1.00 mmol) was added to potassium carbonate. ammonium (0.38 g, 2.75 mmol) and iodomethane (0.50 g, 3.52 mmol) The mixture was stirred at room temperature for 3 hours. Ethyl acetate (100 ml) and water (5 0 ml) was added and the mixture was separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane / methanol) to give 1. 60g of pure [(3R,4R)-3-hydroxy-4-methyl-6-(4-methoxycarbonyl) [N-(methylbenzyl)-N-MeNle]-1-[α-methylene-Sar]-3-cyclos Porin [molecular formula: C 70 H 117 N 11 O 14 ;Exact mass: 1335.88;M S(m / z):1336.64(M+1) + HPLC RT: 18.03 min (C8 reverse phase Column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64°C; detector: 210 nm)].

[0200] [(3R,4R)-3-hydroxy-4-methyl-6-(4-methoxycarbonyl)benzene [(S)-(4-hydroxybutylthio)methyl-N-MeNle]-1-[(S)-(4-hydroxybutylthio)methyl-Sar ]-3-Cyclosporin [ka]

[0201] [(3R,4R)-3-hydroxy-4-methyl-6-( 4-Methoxycarbonylbenzyl)-N-MeNle]-1-[α-methylene-Sar] A solution of 4-mercapto-1-cyclosporine (0.60 g, 0.45 mmol) was added to the solution. -butanol (0.45 g, 4.25 mmol) and lithium hydroxide (0.10 g, 4. 25 mmol) was added. The reaction mixture was stirred at room temperature overnight. Most of the methanol was removed. Ethyl acetate (60 ml) and brine (30 ml) were added and the mixture was evaporated under reduced pressure. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The pure [(3R,4R)-3- Hydroxy-4-methyl-6-(4-methoxycarbonylbenzyl)-N-MeNle] -1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporine The molecular formula: C 74 H 127 N 11 O 15 S; Exact mass: 1441.92; MS( m / z): 1422.65 (M+1) + HPLC RT: 16.79 min (C8 reverse phase column) Tube: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64 °C; detector: 210 nm)].

[0202] Example 3 [(3R,4R)-3-hydroxy-4-methyl-6-(4-carboxybenzyl)-N -MeNle]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- Cyclosporine [ka]

[0203] [(3R,4R)-3-hydroxy-4-methyl-6-(4 -Methoxycarbonylbenzyl)-N-MeNle]-1-[(S)-(4-hydroxy Butylthio)methyl-Sar]-3-cyclosporine (85 mg, 0.06 mmol) To the solution was added a solution of lithium hydroxide (15 mg) in water (5 ml). The mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. The mixture was mixed with 1.0 N hydrochloric acid. The pH of the mixture was adjusted to 6. Ethyl acetate (60 ml) and brine (10 ml) were added, The mixture was separated, the organic layer was dried over magnesium sulfate and evaporated under reduced pressure. Purified and pure [(3R,4R)-3-hydroxy-4-methyl-6-(4-carboxy benzyl)-N-MeNle]-1-[(S)-(4-hydroxybutylthio)methyl- Sar]-3-cyclosporin [molecular formula: C 73 H 125 N 11 O 15 S; Accurate Mass:1427.91;MS(m / z):1428.63(M+1) + ;HPLC RT : 14.37 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetate) (Fluoroacetic acid); operating temperature: 64°C; detector: 210 nm).

[0204] Example 4 [(3R,4R)-3-hydroxy-4-methyl-6-(3-amino)benzyl-NM eNle]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclohexyl Rosporin

[0205] (3-Nitrobenzyl)triphenylphosphonium bromide [ka]

[0206] 3-Nitrobenzyl bromide (5.00 g, 23.15 mmol) in toluene (60 ml) l) and triphenylphosphine (6.06 g, 23.15 mmol) were added. The mixture was stirred and heated at reflux overnight. After cooling to room temperature, the precipitate was filtered off and dissolved in toluene and hexane. The resulting mixture was washed with water and dried in vacuo to give 10.50 g of product [molecular formula: C 25 H2 1BrNO2P;Accurate mass:477.05;MS(m / z):398.45(M+1) + -Br].

[0207] [(3R,4R)-3-acetyloxy-4-methyl-6-(3-nitrophenylmethyl) N-MeNle]-1-cyclosporine [ka]

[0208] (3-nitrobenzyl)triphenylphosphine in anhydrous tetrahydrofuran (90 ml) under nitrogen. A solution of bis(trifluoromethylphosphonium bromide (2.40 g, 5.03 mmol) was added to the solution of sodium bis(trifluoromethylphosphonium bromide). (trimethylsilyl)amide (1.0 M in THF, 6 ml, 6.00 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and cooled to -40°C. Anhydrous tetrahydrofuran (2 5 ml) in [(3R,4R)-3-acetyloxy-4-methyl-6-oxo-NM A solution of eNle]-l-cyclosporine (3.69 g, 3.00 mmol) was added. The mixture was stirred at -30°C for a further 2 hours. Then saturated ammonium chloride solution (20 ml) was added. The reaction was quenched by the addition of Most of the tetrahydrofuran was evaporated under reduced pressure. Ethyl acetate (150 ml) and brine (50 ml) were added and the mixture was separated. The layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dic The resulting mixture was purified by hexane / methanol to give 1.60 g of pure [(3R,4R)-3- Acetyloxy-4-methyl-6-(3-nitrophenylmethylene)-N-MeNle] -1-cyclosporin was obtained [molecular formula: C 69 H 114 N 12 O 15 ;Exact mass: 13 50.85; MS(m / z):1351.52(M+1) + ].

[0209] [(3R,4R)-3-acetyloxy-4-methyl-6-(3-amino)benzyl-N -methylamino]-1-cyclosporine [ka]

[0210] [(3R,4R)-3-acetyloxy-4-methyl-2-methyl ...2-methyl-4-methyl-2-methyl-2-methyl-2-methyl-2-methyl-2 ethyl-6-(3-nitrophenylmethylene)-N-MeNle]-1-cyclosporine ( To a solution of nickel(II) chloride hexahydrate (0.19 g, 3.00 g, 2.22 mmol), , 0.81 mmol) was added. The reaction mixture was placed in an ice-water bath. The mixture was cooled to 0°C and 1.80 g (47.33 mmol) was added in 4 batches over 2 hours. After stirring for another 2 hours at rt, water (10 ml) was added. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (50 ml) and saturated sodium bicarbonate solution (50 ml) were added. The mixture was separated. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (30 ml). Palladium (10 wt. on carbon) %, 20 mg) and acetic acid (5 drops) were added. The mixture was stirred under hydrogen at room temperature for 2 hours. The mixture was filtered and the filtrate was evaporated under reduced pressure to give crude [(3R,4R)-3-acetyloxy]. [4-methyl-6-(3-amino)benzyl-N-MeNle]-1-cyclosporine The molecular formula: C 69 H 118 N 12 O 13 ; Exact mass: 1322.89; MS( m / z): 1323.73 (M+1) + ].

[0211] [(3R,4R)-3-hydroxy-4-methyl-6-(3-amino)benzyl-NM eNle]-1-cyclosporine [ka]

[0212] [(3R,4R)-3-acetyloxy-4-methyl-6-(3-amino)benzyl- N-MeNle]-1-cyclosporine (2.60 g, 1.56 mmol) in methanol (70 ml) of water (35 ml) and tetramethylammonium hydroxide pentahydrate. (2.00 g, 11.01 mmol) was added, and the mixture was stirred at room temperature for 8 hours. Ethyl acetate (100 ml) and brine (100 ml) was added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane / methanol) to give 1.9 0 g of pure [(3R,4R)-3-hydroxy-4-methyl-6-(3-aminophenyl) [N-methyl-N-MeNle]-1-cyclosporin [molecular formula: C 67 H 116 N 12 O 12 ;Accurate mass: 1280.88;MS(m / z):1281.64(M+1) + ].

[0213] [(3R,4R)-3-hydroxy-4-methyl-6-(3-tert-butoxycarbonyl) (N-(N-methyl)amino)benzyl-N-MeNle)-1-cyclosporine [ka]

[0214] [(3R,4R)-3-hydroxy-4-methyl-6-(3-amino)benzyl-N- MeNle]-1-cyclosporine (0.80 g, 0.62 mmol) was added to tetrahydrofuran Dissolved in 100 ml of di-tert-butyl dicarbonate (0.37 g, 1. 70 mmol) was added. The mixture was stirred at room temperature for 2 days. Most of the tetrahydrofuran was The solvent was evaporated under reduced pressure. Ethyl acetate (30 ml) and brine (30 ml) were added. The mixture was separated, the organic layer was dried over magnesium sulfate and evaporated under reduced pressure. Purification by chromatography gave 750 ml of pure [(3R,4R)-3-hydroxybenzoate]. -4-methyl-6-(3-(tert-butoxycarbonyl)amino)benzyl-NM eNle]-l-cyclosporin [molecular formula: C 72 H 124 N 12 O 14 ;Accurate Mass: 1380.94;MS(m / z):1381.65(M+1) + ].

[0215] [(3R,4R)-3-hydroxy-4-methyl-6-(3-tert-butoxycarbonyl) (N-methyl)amino)benzyl-N-MeNle]-1-[α-methylene-Sar]-3- closporin [ka]

[0216] Diisopropylamine (0.01%) in tetrahydrofuran (50 ml) was dissolved in 100 ml of water at −78° C. under nitrogen. A solution of 0.71 g, 7.15 mmol) of n-butyllithium (2.6.5 M, 2.70 The reaction mixture was stirred for 1 hour, and then tetrahydrofuran was added. [(3R,4R)-3-hydroxy-4-methyl-6-(3-(te rt-Butoxycarbonyl)amino)benzyl-N-MeNle]-1-cyclosporine A solution of (0.90 g, 0.65 mmol) was added. The mixture was stirred at −78° C. for 3 h. Carbon dioxide gas was bubbled through the reaction mixture for 15 minutes, and the mixture was then heated at -78°C for an additional hour. The cooling bath was then removed and the reaction mixture was allowed to warm to room temperature to remove unreacted carbon dioxide. The mixture was cooled to -78°C and chloromethyl chloroformate (1.20 m l) was added. The mixture was stirred and allowed to warm to room temperature overnight. Brine (5 ml) was added. The reaction was quenched with ethyl acetate. Most of the tetrahydrofuran was removed under reduced pressure. (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was extracted with mag sulfate. The mixture was dried over sodium hydroxide and evaporated under reduced pressure. The residue was purified by chromatography (hexane / acetone). The resulting mixture was purified by HPLC (HPLC) to give 0.45 g of pure (3R,4R)-3-hydroxy-4-methyl 6-(3-(tert-butoxycarbonyl)amino)benzyl-N-MeNle] -1-[α-methylene-Sar]-3-cyclosporin [molecular formula: C73 H 124 N 12 O 14 ;Accurate mass: 1392.94;MS(m / z):1393.88(M+1 ) + ].

[0217] [(3R,4R)-3-hydroxy-4-methyl-6-(3-amino)benzyl-NM eNle]-1-[α-methylene-Sar]-3-cyclosporine [ka]

[0218] [(3R,4R)-3-hydroxy-4-methyl-6-(3-tert-butoxycarbonyl) (carbonyl)amino)benzyl-N-MeNle]-1-[α-methylene-Sar]-3- Cyclosporine (0.80 g, 0.57 mmol) was dissolved in dichloromethane (15 ml). The mixture was then placed in an ice-water bath. Trifluoroacetic acid (7 ml) was added. The mixture was stirred at room temperature for 1 hour. Another portion of dichloromethane (50 ml) was added. The mixture was diluted with brine (30 ml) and and saturated sodium bicarbonate solution (30 ml), dried over magnesium sulfate, and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane / methanol). 0.20 g of pure [(3R,4R)-3-hydroxy-4-methyl-6-(3-aminopropyl)-2-(2-methyl-2-propanol] (amino)benzyl-N-MeNle]-1-[α-methylene-Sar]-3-cyclosporin The molecular formula: C 68 H 116 N 12 O 12 ; Exact mass: 1292.88; MS( m / z): 1293.68 (M+1) + ].

[0219] [(3R,4R)-3-hydroxy-4-methyl-6-(3-amino)benzyl-NM eNle]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-cyclos Porin [ka]

[0220] [(3R,4R)-3-hydroxy-4-methyl-6-( 3-amino)benzyl-N-MeNle]-1-[α-methylene-Sar]-3-cyclo A solution of sporin (0.20 g, 0.15 mmol) in 4-mercapto-1-butanol (0.07 g, 0.66 mmol) and lithium hydroxide (19 mg, 0.79 mmol). The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (30 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane). Dichloromethane / methanol) to give pure [(3R,4R)-3-hydroxybenzoate]. -4-methyl-6-(3-amino)benzyl-N-MeNle]-1-[(S)-(4- Hydroxybutylthio)methyl-Sar]-3-cyclosporin was obtained [molecular formula: C 72 H 126 N 12 O 13 S; Exact mass: 1398.93; MS(m / z): 1399.6 2(M+1) + HPLC RT: 11.33 min (C8 reverse phase column: 250 mm; acetone) Nitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm )].

[0221] Example 5 [(3R,4R)-3-hydroxy-4-methyl-6-(3-(N,N-diisopropyl) Amino)carbonyl)benzyl-N-MeNle]-1-[(S)-(4-hydroxybutanol Thiomethyl-Sar]-3-cyclosporine

[0222] (3-Methoxycarbonylbenzyl)triphenylphosphonium bromide [ka]

[0223] Methyl (3-bromomethyl)benzoate (6.00 g, 2 6.20 mmol) and triphenylphosphine (6.86 g, 26.18 mmol) The mixture was stirred and heated at reflux overnight. After cooling to room temperature, the precipitate was filtered off and The product was washed with toluene and hexane and dried in vacuo to give 11.05 g of product [molecular weight Formula:C 27 H 24 BrO2P; Exact mass: 490.07; MS(m / z): 411.2 5(M+1) + -Br].

[0224] [(3R,4R)-3-acetyloxy-4-methyl-6-(3-methoxycarbonyl) (phenyl)methylene-N-MeNle]-1-cyclosporine [ka]

[0225] (3-Methoxycarbonylbenzene) in anhydrous tetrahydrofuran (120 ml) under nitrogen. To a mixture of 1,2-diphenyltriphenylphosphonium bromide (4.00 g, 8.14 mmol), Sodium bis(trimethylsilyl)amide (1.0 M in THF, 10 ml, 10.00 The reaction mixture was stirred at room temperature for 1 hour and cooled to -40°C. [(3R,4R)-3-acetyloxy-4-methyl tetrahydrofuran (25 ml)] -6-oxo-N-MeNle]-1-cyclosporine (5.00 g, 4.05 mmol A solution of ammonium chloride was added. The mixture was stirred at -30°C for an additional 2 hours. The reaction was quenched by the addition of tetrahydrofuran solution (20 ml). Evaporated under reduced pressure. Ethyl acetate (150 ml) and brine (50 ml) were added and mixed. The mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was Purification by chromatography (dichloromethane / methanol) gave 2.00 g of pure [(3 R,4R)-3-acetyloxy-4-methyl-6-(3-methoxycarbonylphenyl ) methylene-N-MeNle]-1-cyclosporine was obtained [molecular formula: C 71 H 117 N 11 O 15 ;Accurate mass: 1363.87;MS(m / z):1364.61(M+1) + ].

[0226] [(3R,4R)-3-acetyloxy-4-methyl-6-(3-methoxycarbonyl) Benzyl-N-MeNle]-1-cyclosporine [ka]

[0227] [(3R,4R)-3-acetyloxy-4-methyl-6 -(3-Methoxycarbonylphenyl)methylene-N-MeNle]-1-cyclosporin A solution of palladium (10 wt% on carbon, 20 m g) and acetic acid (5 drops) were added. The mixture was stirred under hydrogen at room temperature for 2 hours. Filtration and evaporation of the filtrate under reduced pressure gave crude [(3R,4R)-3-acetyloxy-4-methyl- 6-(3-methoxycarbonyl)benzyl-N-MeNle]-1-cyclosporin The molecular formula: C 71 H 119 N 11 O 15 ; Exact mass: 1365.89; MS( m / z): 1366.73 (M+1) + ].

[0228] [(3R,4R)-3-hydroxy-4-methyl-6-(3-carboxy)benzyl-N -MeNle]-1-cyclosporine [ka]

[0229] [(3R,4R)-3-acetyloxy-4-methyl-6-(3-methoxycarbonyl )benzyl-N-MeNle]-1-cyclosporine (0.25 g, 0.18 mmol) was dissolved in methanol (4 ml), water (2 ml) and tetramethylammonium hydroxide. The mixture was stirred at room temperature overnight. The alcohol was evaporated. The pH of the mixture was adjusted to 6 with acetic acid. Ethyl acetate (50 ml) and Brine (10 ml) was added and the mixture was separated. The organic layer was dried over magnesium sulfate. The residue was used in the next step without further purification. [(3R, 4R)-3-Hydroxy-4-methyl-6-(3-carboxy)benzyl-N-MeNl e]-1-cyclosporin [molecular formula: C 68 H 115 N 11 O 14;Exact mass: 130 9.86; MS(m / z):1310.61(M+1) + ].

[0230] [(3R,4R)-3-hydroxy-4-methyl-6-(3-methoxycarbonyl)benzene Di-N-MeNle]-1-cyclosporine [ka]

[0231] [(3R,4R)-3-hydroxy- in N,N-dimethylformamide (25 ml) 4-Methyl-6-(3-carboxy)benzyl-N-MeNle]-1-cyclosporine (1.80 g, 1.37 mmol) in a solution of potassium carbonate (0.38 g, 2.75 mmol) ol) and iodomethane (0.50 g, 3.52 mmol) were added. The mixture was stirred at room temperature. Stirred for 3 hours. Ethyl acetate (100 ml) and water (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed. Purification with dichloromethane / methanol gave 1.60 g of pure [(3R,4R) -3-hydroxy-4-methyl-6-(3-methoxycarbonyl)benzyl-N-MeN le]-1-cyclosporine was obtained [molecular formula: C 69 H 117 N 11 O 14 ;Exact mass : 1323.88; MS (m / z): 1324.64 (M + 1) + ].

[0232] [(3R,4R)-3-hydroxy-4-methyl-6-((3-N,N-diisopropyl Aminocarbonyl))benzyl-N-MeNle]-1-[α-methylene-Sar]-3 -Cyclosporin [ka]

[0233] Diisopropylamine (1. A solution of 37 g, 13.30 mmol) of n-butyllithium (2.65 M, 5 ml, 1 The reaction mixture was stirred for 1 hour, and then tetrahydrofuran ( (3R,4R)-3-hydroxy-4-methyl-6-(3-methoxycarbamate) in 5 ml [N-(methyl)benzyl-N-MeNle]-1-cyclosporine (1.60 g, 1.20 mm A solution of 1,2-dichloromethane (2,4-diol) was added. The mixture was stirred at -78°C for 3 hours. Carbon dioxide was added to the reaction mixture. After bubbling gas for 15 minutes, the mixture was stirred at −78° C. for an additional hour. The mixture was removed and the reaction mixture was allowed to warm to room temperature to expel unreacted carbon dioxide. The mixture was cooled to 8°C and chloromethyl chloroformate (2.00 ml) was added. The mixture was stirred and allowed to warm to room temperature overnight. Brine (5 ml) was added to quench the reaction. A portion of the tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine ( 50 ml) was added and the mixture was separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (hexane / acetone) to give 0.60 g of Pure [(3R,4R)-3-hydroxy-4-methyl-6-(3-(N,N-diisopropyl) (N-(hydroxylamino)carbonyl)benzyl-N-MeNle]-1-[α-methylene-Sar ]-3-cyclosporin [molecular formula: C 75 H 128 N 12 O 13 ;Exact mass: 1 404.97; MS(m / z):1405.67(M+1) + ].

[0234] [(3R,4R)-3-hydroxy-4-methyl-6-(3-(N,N-diisopropyl) Amino)carbonyl)benzyl-N-MeNle]-1-[(S)-(4-hydroxybutanol Thiomethyl-Sar]-3-cyclosporine [ka]

[0235] [(3R,4R)-3-hydroxy-4-methyl-6-( 3-(N,N-diisopropylamino)carbonyl ) Benzyl-N-MeNle]-1-[α-methylene-Sar]-3-cyclosporine (0.60 g, 0.43 mmol) was added to a solution of 4-mercapto-1-butanol (0.4 5g, 4.25mmol) and lithium hydroxide (0.10g, 4.25mmol) were added. The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (60 ml) and brine (30 ml) were added and the mixture was separated. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane). methane / methanol) to give pure [(3R,4R)-3-hydroxy-4- Methyl-6-(3-(N,N-diisopropylamino) ))carbonyl)benzyl-N-MeNle]-1-[(S)-(4-hydroxybutyl Thio)methyl-Sar]-3-cyclosporin was obtained [molecular formula: C 79 H 138 N 12 O 14S;Accurate mass:1511.02;MS(m / z):1511.70(M+1) + ; HPLC RT: 17.00 min (C8 reverse phase column: 250 mm; acetonitrile / water (0 0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0236] Example 6 [(3R,4R)-3-hydroxy-4-methyl-6-(3-carboxy)benzyl-N -MeNle]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- Cyclosporine

[0237] [(3R,4R)-3-hydroxy-4-methyl-6-(3-carboxy)benzyl-N -MeNle]-1-[α-methylene-Sar]-3-cyclosporine [ka]

[0238] Diisopropylamine (2. A solution of 0.5g, 20.30mmol) of n-butyllithium (2.65M, 7.7ml The reaction mixture was stirred for 1 hour, and then tetrahydrofuran was added. [(3R,4R)-3-hydroxy-4-methyl-6-(3-carbohydrate)] in ethanol (10 ml) [Oxy)benzyl-N-MeNle]-1-cyclosporine (2.40 g, 1.20 mmol) A solution of HCl was added to the reaction mixture. The mixture was stirred at -78°C for 3 hours. Carbon dioxide gas was added to the reaction mixture. After bubbling gas for 15 minutes, the mixture was stirred at -78°C for an additional hour. The mixture was evaporated and the reaction mixture was allowed to warm to room temperature to expel unreacted carbon dioxide. The mixture was cooled to °C and chloromethyl chloroformate (3.00 ml) was added. The reaction was quenched by the addition of brine (5 ml). A portion of the tetrahydrofuran was removed under reduced pressure. Ethyl acetate (80 ml) and brine (5 0 ml) was added and the mixture was separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. Evaporation gave 1.50 g of crude product [(3R,4R)-3-hydroxy-4-methyl-6 -(3-carboxy)benzyl-N-MeNle]-1-[α-methylene-Sar]-3 -Cyclosporin was obtained [molecular formula: C 69 H 115 N 11 O 14 ;Exact mass: 1321 .86; MS(m / z): 1322.45(M+1) + ].

[0239] [(3R,4R)-3-hydroxy-4-methyl-6-(3-methoxycarbonyl)benzene Di-N-MeNle]-1-[α-methylene-Sar]-3-cyclosporine [ka]

[0240] [(3R,4R)-3-hydroxy- in N,N-dimethylformamide (15 ml) 4-Methyl-6-(3-carboxy)benzyl-N-MeNle]-1-[α-methylene A solution of [-Sar]-3-cyclosporine (1.32 g, 1.00 mmol) was added to potassium carbonate. ammonium (0.38 g, 2.75 mmol) and iodomethane (0.50 g, 3.52 mmol) The mixture was stirred at room temperature for 3 hours. Ethyl acetate (100 ml) and water (5 0 ml) was added and the mixture was separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane / methanol) to give 1. 60g of pure [(3R,4R)-3-hydroxy-4-methyl-6-(3-methoxycarbonyl) [N-(methylbenzyl)-N-MeNle]-1-[α-methylene-Sar]-3-cyclos Porin [molecular formula: C 70 H 117 N 11 O 14 ;Exact mass: 1335.88;M S(m / z):1336.64(M+1) + ].

[0241] [(3R,4R)-3-hydroxy-4-methyl-6-(3-methoxycarbonyl)benzene Dimethyl-N-MeNle]-1-[(S)-(4-hydroxybutylthio)methyl-Sar ]-3-Cyclosporin [ka]

[0242] [(3R,4R)-3-hydroxy-4-methyl-6-( 3-Methoxycarbonyl)benzyl-N-MeNle]-1-[α-methylene-Sar] A solution of 4-mercapto-1-cyclosporine (0.60 g, 0.45 mmol) was added to the solution. -butanol (0.45 g, 4.25 mmol) and lithium hydroxide (0.10 g, 4. 25 mmol) was added. The reaction mixture was stirred at room temperature overnight. Most of the methanol was removed. Ethyl acetate (60 ml) and brine (30 ml) were added and the mixture was evaporated under reduced pressure. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The pure [(3R,4R)-3- Hydroxy-4-methyl-6-(3-methoxycarbonyl)benzyl-N-MeNle] -1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporine The molecular formula: C 74 H 127 N 11 O 15 S; Exact mass: 1441.92; MS( m / z): 1422.65 (M+1) + ].

[0243] Example 7 [(3R,4R)-3-hydroxy-4-methyl-6-(3-carboxy)benzyl-N -MeNle]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- Cyclosporine [ka]

[0244] [(3R,4R)-3-hydroxy-4-methyl-6-(3 -Methoxycarbonylbenzyl)-N-MeNle]-1-[(S)-(4-hydroxy Butylthio)methyl-Sar]-3-cyclosporine (85 mg, 0.06 mmol) To the solution was added a solution of lithium hydroxide (15 mg) in water (5 ml). The mixture was allowed to stand at room temperature. The mixture was stirred overnight at rt. Most of the methanol was evaporated under reduced pressure. The aqueous mixture was washed with 1.0 N hydrochloric acid. The pH of the mixture was adjusted to 6. Ethyl acetate (60 ml) and brine (10 ml) were added, The mixture was separated, the organic layer was dried over magnesium sulfate and evaporated under reduced pressure. Purified and pure [(3R,4R)-3-hydroxy-4-methyl-6-(3-carboxy )benzyl-N-MeNle]-1-[(S)-(4-hydroxybutylthio)methyl- Sar]-3-cyclosporin [molecular formula: C 73 H 125 N 11 O 15 S; Accurate Mass:1427.91;MS(m / z):1428.63(M+1) + ;HPLC RT : 14.37 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetate) (Fluoroacetic acid); operating temperature: 64°C; detector: 210 nm).

[0245] Example 8 [(3R,4R)-3-hydroxy-4-methyl-6-(2-hydroxyethyl)-N- MeNle]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- closporin

[0246] [(3R,4R)-3-acetyloxy-4-methyl-(6-methoxycarbonylmethyl) N-MeNle]-1-cyclosporine [ka]

[0247] Methoxycarbonylmethylene trichloride in anhydrous tetrahydrofuran (100 ml) under nitrogen A solution of phenylphosphorane (6.20 g, 18.54 mmol) was added to the solution of [(3R,4R)- 3-Acetyloxy-4-methyl-6-oxo-N-MeNle]-1-cyclosporine (4.10 g, 3.33 mmol) was added, and the mixture was stirred and heated to reflux for 6 h. The reaction was then quenched by the addition of saturated ammonium chloride solution (20 ml). of tetrahydrofuran was evaporated under reduced pressure. Ethyl acetate (150 ml) and brine ( 50 ml) was added and the mixture was separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane / methanol) to give 3 0.60 g of pure [(3R,4R)-3-acetyloxy-4-methyl-(6-methoxy)- (carbonylmethylene)-N-MeNle]-1-cyclosporine was obtained [molecular formula: C65 H 113 N 11 O 15 ; Exact mass: 1287.84; MS(m / z): 1288.61 (M+1) + HPLC RT: 16.43 min. (C8 reverse phase column: 250 mm; acetone Nitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm )].

[0248] [(3R,4R)-3-acetyloxy-4-methyl-6-(methoxycarbonylmethyl) )-N-MeNle]-1-cyclosporine [ka]

[0249] [(3R,4R)-3-acetyloxy-4-methyl- in methanol (100 ml) 6-(methoxycarbonylmethylene)-N-MeNle]-1-cyclosporine (3.8 A solution of palladium (10% by weight on carbon, 250 mg) and and acetic acid (5 drops) were added. The mixture was stirred at room temperature under hydrogen for 8 hours. The mixture was filtered. The filtrate was evaporated under reduced pressure to give crude [(3R,4R)-3-acetyloxy-4-methyl-6- (Methoxycarbonylmethyl)-N-MeNle]-1-cyclosporin [molecular formula :C 65 H 115 N 11 O 15 ; Exact mass: 1289.86; MS(m / z): 129 0.59(M+1) + HPLC RT: 16.50 min (C8 reverse phase column: 250 mm; Acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64°C; Detector: 21 0 nm)].

[0250] [(3R,4R)-3-hydroxy-4-methyl-6-(2-hydroxyethyl)-N- MeNle]-1-cyclosporine [ka]

[0251] [(3R,4R)-3-acetyloxy-4-methyl- in methanol (100 ml) 6-(Methoxycarbonylmethyl)-N-MeNle]-1-cyclosporine (3.50 g, 2.71 mmol) was added to a solution of cesium chloride (5.00 g, 29.78 mmol). Then, sodium borohydride (10.00 g, 262.95 mmol) was added. The mixture was stirred at room temperature for a further 8 hours, after which most of the methanol was added in portions over 30 minutes. The mixture was evaporated under reduced pressure. Ethyl acetate (150 ml) and saturated sodium bicarbonate solution (15 0 ml) was added and the mixture was separated. The organic layer was washed with brine and The residue was purified by chromatography (dichloromethane / methanol ) and purified to obtain 2.85 g of [(3R,4R)-3-hydroxy-4-methyl-6-(2- Hydroxyethyl)-N-MeNle]-1-cyclosporine was obtained [molecular formula: C 62 H 113 N 11 O 13 ; Exact mass: 1219.85; MS (m / z): 1220.68 ( M+1) + HPLC RT: 15.80 min (C8 reverse phase column: 250 mm; acetonite ethyl acetate / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)] .

[0252] [(3R,4R)-3-hydroxy-4-methyl-6-(2-hydroxyethyl)-N- MeNle]-1-[α-methylene-Sar]-3-cyclosporine [ka]

[0253] Diisopropylamine (2. A solution of 56 g, 25.30 mmol) of n-butyllithium (2.65 M, 9.60 m The reaction mixture was stirred for 1 hour, and then tetrahydrofuran was added. [(3R,4R)-3-hydroxy-4-methyl-6-(2-hydroxybenzoyl) [N-MeNle]-1-cyclosporine (2.85 g, 2.30 mmol) A solution of HCl was added to the reaction mixture. The mixture was stirred at -78°C for 3 hours. Carbon dioxide gas was added to the reaction mixture. After bubbling gas for 15 minutes, the mixture was stirred at -78°C for an additional hour. The mixture was evaporated and the reaction mixture was allowed to warm to room temperature to expel unreacted carbon dioxide. The mixture was cooled to °C and chloromethyl chloroformate (3.00 ml) was added. The reaction was quenched by the addition of brine (5 ml). A portion of the tetrahydrofuran was removed under reduced pressure. Ethyl acetate (80 ml) and brine (5 0 ml) was added and the mixture was separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane / methanol) to give 1.0 The product [(3R,4R)-3-hydroxy-4-methyl-6-(2-hydroxyethyl) [N-MeNle]-1-[α-methylene-Sar]-3-cyclosporine was obtained. Molecular formula:C 63H 113 N 11 O 13 ;Accurate mass: 1231.85; MS(m / z): 1232.55(M+1) + HPLC RT: 15.14 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector :210nm)].

[0254] [(3R,4R)-3-hydroxy-4-methyl-6-(2-hydroxyethyl)-N- MeNle]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- closporin [ka]

[0255] [(3R,4R)-3-hydroxy-4-methyl-6-( 2-hydroxyethyl)-N-MeNle]-1-[α-methylene-Sar]-3-cyclohexyl A solution of rosporin (0.60 g, 0.45 mmol) was added to 4-mercapto-1-butanol. Lithium hydroxide (0.10 g, 4.25 mmol) and ethanol (0.45 g, 4.25 mmol) l) was added. The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (60 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography. (dichloromethane / methanol) to give pure [(3R,4R)-3-hydro hydroxy-4-methyl-6-(2-hydroxyethyl)-N-MeNle]-1-[(S)- (4-hydroxybutylthio)methyl-Sar]-3-cyclosporin [molecular formula: C 67 H 123 N 11 O 14 S; Exact mass: 1337.90; MS(m / z): 1338 .74(M+1) + HPLC RT: 12.98 min (C8 reverse phase column: 250 mm; Acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64°C; Detector: 210 nm)].

[0256] Example 9 [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(R)- 2-Methoxymethyl-Sar]-3-cyclosporine

[0257] (3-Cyanopropyl)triphenylphosphonium bromide [ka]

[0258] 4-Bromobutyronitrile (10 ml, 0.10 mol) in toluene (200 ml) and triphenylphosphine (36.23 g, 0.10 mol) were added. The mixture was stirred. After cooling to room temperature, the precipitate was filtered off and washed with toluene and hexane. After washing and drying in vacuo, 26.60 g of product was obtained [molecular formula: C 22 H 21 NP + ;Accurate mass:330.14;MS(m / z):330.23(M) + ].

[0259] [8-Cyanomethyl-3-acetyl-MeBmt]-1-cyclosporine [ka]

[0260] In a dry flask, under nitrogen, add (3-cyanopropyl)triphenylphosphonium bromide (7.98 g, 19.50 mmol) and anhydrous tetrahydrofuran (60 ml) were added. The reaction mixture was placed in an ice-water bath and sodium tert-butoxide (2.19 g, 22. The mixture was stirred for 2 hours, and then anhydrous tetrahydrofuran (20 ml) in [(3R,4R)-3-acetyloxy-4-methyl-6-oxo-N-Me A solution of Nle]-1-cyclosporine (4.00 g, 3.25 mmol) was added. The mixture was stirred at 0°C for a further 5 hours. Saturated ammonium chloride solution (20 ml) was then added. The reaction was quenched by adding ethyl acetate. Most of the tetrahydrofuran was evaporated under reduced pressure. Chill (100 ml) and brine (100 ml) were added and the mixture was separated. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane). methane / methanol) to give 2.00 g of pure [8-cyanomethyl-3-(2-methyl-2-propanol]. Cetyl-MeBmt]-1-cyclosporin was obtained [molecular formula: C 66 H 114 N 12 O1 3;Accurate mass: 1282.86;MS(m / z):1283.51(M+1) + , 13 05.73(M+Na) + HPLC RT: 16.50 min (C8 reverse phase column: 250 m m; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0261] [8-Cyanomethyl-MeBmt]-1-cyclosporine [ka]

[0262] [8-cyanomethyl-3-acetyl-MeBmt]-1-cyclosporine (2.00g , 1.56 mmol) was dissolved in methanol (20 ml). Water (10 ml) and hydroxide Tetramethylammonium pentahydrate (0.85 g, 4.68 mmol) was added. The mixture was stirred at room temperature for 2 hours. Most of the methanol was then evaporated. Ethyl acetate (1 Water (100 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was extracted with magnesium sulfate. The mixture was dried over sodium hydroxide and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane / methanol) to give 1.70 g of pure [8-cyanomethyl-MeBmt]- 1-Cyclosporin was obtained [molecular formula: C 64 H 112 N 12 O 12 ;Exact mass: 124 0.85; MS(m / z):1241.54(M+1) + , 1263.73(M+Na) + HPLC RT: 14.80 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0263] [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-1-cyclosporine [ka]

[0264] [8-cyanomethyl-MeBmt]-1-cyclo[ ... A solution of 2.00 g of benzoxazole (1.61 mmol) in 0.01% ethanol was added to a solution of 0.01% ethanol. The reaction mixture was placed in an ice-water bath. Sodium (3.05 g, 80.50 mmol) was added in 4 batches over 2 hours. The mixture was stirred at 0°C for a further 2 hours, after which water (10 ml) was added. Evaporated under reduced pressure. Ethyl acetate (50 ml) and saturated sodium bicarbonate solution (50 ml) The organic layer was washed with brine and dried over magnesium sulfate. The residue was dissolved in methanol (30 ml). Palladium (on carbon 10% by weight, 20 mg) and acetic acid (5 drops) were added. The mixture was heated under hydrogen at room temperature for 2 hours. The mixture was filtered and the filtrate was evaporated under reduced pressure to give crude [8-(2-aminoethyl) -6,7-dihydro-MeBmt]-1-cyclosporin [molecular formula: C 64 H 11 8N 12 O 12 ;Accurate mass: 1246.90;MS(m / z):1247.69(M+ 1) + HPLC RT: 11.13 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0265] [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-M eBmt]-1-cyclosporine [ka]

[0266] [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-1-cyclosporine (crude, 1.61 mmol) was dissolved in tetrahydrofuran (20 ml). sodium solution (20 ml) and di-tert-butyl dicarbonate (0.39 g, 1 The mixture was stirred at room temperature for 2 hours. Most of the tetrahydrofuran was The run was evaporated under reduced pressure. Ethyl acetate (30 ml) and brine (30 ml) were added. The mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. was purified by chromatography (hexane / acetone) to give 2.00 g of pure [8-(2 -(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt] -1-cyclosporin was obtained [molecular formula: C 69 H 126 N 12 O 14 ;Exact mass: 13 46.95; MS(m / z):1347.54(M+1) + , 1369.78(M+Na ) + HPLC RT: 17.08 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0267] [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-M eBmt]-1-[(S)-2-Methoxycarbonyl-Sar]-3-cyclosporine [ka]

[0268] Diisopropylamine (1. 06 ml, 7.42 mmol) of n-butyllithium (2.20 M, 3.38 m The reaction mixture was stirred for 1 hour, and then tetrahydrofuran was added. [8-(2-(tert-butoxycarbonyl)aminoethyl)-6-(2-tert-butoxycarbonyl)aminoethyl] ... ,7-Dihydro-MeBmt]-1-cyclosporine (1.00 g, 0.74 mmol) The solution was added over 10 minutes. The mixture was stirred at -78°C for 2 hours. The reaction mixture was added with diacid After bubbling carbon dioxide gas for 20 minutes, the mixture was stirred at -78°C for an additional hour. The cooling bath was removed and the reaction mixture was allowed to warm slowly to 0°C. Most of the tetrahydrofuran The residue was quenched by the addition of saturated citric acid solution, and the aqueous layer was The H was adjusted to 3-4 with 1N hydrochloric acid, and the precipitated oil was extracted with ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (100 ml x 3). The combined ethyl acetate layers were washed with brine. The mixture was washed, dried over magnesium sulfate, and evaporated under reduced pressure to give 0.50 g of [8-(2-( tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-1 -[(S)-2-carboxy-Sar]-3-cyclosporin [molecular formula: C 70 H 126 N 12 O 16 ; Exact mass: 1390.94; MS (m / z): 1391.60 ( M+1) + HPLC RT: 15.57 min (C8 reverse phase column: 250 mm; acetonite ethyl acetate / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)] .

[0269] [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro- MeBmt]-1-[(S)-2-carboxy-Sar]-3-cyclosporine (0.5 0g, 0.36mmol) was dissolved in acetone (10ml). ml, 0.54 mmol) and potassium carbonate (0.08 g, 0.54 mmol) were added. The mixture was stirred at room temperature for 2 hours. Most of the acetone was evaporated under reduced pressure. Ethyl acetate (40 ml) and water (40 ml) were added and the mixture was separated. Drying over magnesium sulfate and evaporation under reduced pressure gave 0.51 g of crude [8-(2-(te rt-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-1-[ (S)-2-Methoxycarbonyl-Sar]-3-cyclosporin was obtained [molecular formula: C7 1H 128 N 12 O 16 ; Exact mass: 1404.96; MS(m / z): 1405.6 4(M+1) + , 1427.86(M+Na) + ;HPLC RT:16.65min(C8 Reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature temperature: 64°C; detector: 210 nm)].

[0270] [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-M eBmt]-1-[(R)-2-hydroxymethyl-Sar]-3-cyclosporine [ka]

[0271] [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro- MeBmt]-1-[(S)-2-Methoxycarbonyl-Sar]-3-cyclosporine (0.51 g, 0.36 mmol) was dissolved in tetrahydrofuran (10 ml). Sodium borohydride (0.68 g, 18.00 mmol) and cesium chloride (0.49 g The mixture was stirred at room temperature and methanol (10 ml) was added to The mixture was stirred for another 2 hours, and most of the solvent was evaporated under reduced pressure. Ethyl acetate (40 ml) and water (40 ml) were then added and the mixture was separated. The ethyl layer was dried over magnesium sulfate and evaporated under reduced pressure to give 0.50 g of crude [8-( 2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt ]-1-[(R)-2-hydroxymethyl-Sar]-3-cyclosporine was obtained [molecular Formula:C 70 H 128 N 12 O 15 ; Exact mass: 1376.96; MS(m / z): 13 77.71(M+1) + , 1388.85(M+Na) + ;HPLC RT: 16.49 (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid) ; operating temperature: 64°C; detector: 210 nm)].

[0272] [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(R)- 2-Hydroxymethyl-Sar]-3-cyclosporine [ka]

[0273] [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro- MeBmt]-1-[(R)-2-hydroxymethyl-Sar]-3-cyclosporine ( Dissolve 0.50 g (0.36 mmol) in dichloromethane (10 ml) and place in an ice-water bath. Trifluoroacetic acid (5 ml) was added and the mixture was stirred at room temperature for 1 hour. Chloromethane (20 ml) was added. The mixture was diluted with brine (30 ml), saturated sodium bicarbonate The crude product was washed with ammonium hydroxide solution (30 ml), dried over magnesium sulfate and evaporated under reduced pressure. [8-(2-aminoethyl)-6,7-dihydro-MeBmt]1-[(R)-2-hydro [Cyclosporin-3-yl]-3-hydroxymethyl-Sar 65 H 120 N 12 O 13 ;Accurate mass: 1276.91;MS(m / z):1277.75(M+1) + ;H PLC RT: 9.13 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.0 5% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)]. Aminoethyl)-6,7-dihydro-MeBmt]-1-[(R)-2-hydroxymethyl [Il-Sar]-3-cyclosporine was dissolved in dichloromethane (10 ml). 0.12ml, 2.20mmol), HBTU (0.41g, 1.08mmol), 1-Hydroxyethyl Ether hydroxybenzotriazole (0.15 g, 1.08 mmol), and pyridine (0.5 0 ml) was added. The mixture was stirred at room temperature for 2 hours. Then, dichloromethane (30 ml) was added. 1 ml) and brine (50 ml) were added and separated. The dichloromethane layer was diluted with magnesium sulfate. The mixture was dried over ice and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane / methanol). Purification by ethanol gave 27 mg of pure [8-(2-acetamidoethyl)-6,7- Dihydro-MeBmt]-1-[(R)-2-hydroxymethyl-Sar]-3-cyclo The molecular formula: C 67 H 122 N 12 O 14 ;Exact mass: 1318.92; MS(m / z):1319.72(M+1) + , 1341.91(M+Na)+ ;HPL CRT: 14.12 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05 % trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0274] [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(R)- 2-Methoxymethyl-Sar]-3-cyclosporine [ka]

[0275] [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(R) -2-hydroxymethyl-Sar]-3-cyclosporine (0.20 g, 0.15 mmol) Iodomethane (0.21 g, 1.52 mmol) was dissolved in benzene (10 ml). ), tetra-n-butylammonium bromide (0.49 g, 1.52 mmol), hydroxyl Sodium chloride (1.00 g, 2.50 mmol) and water (2 ml) were added to the mixture. The mixture was stirred at room temperature overnight. Then ethyl acetate (50 ml) and brine (50 ml) were added. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. was purified by chromatography (dichloromethane / methanol) to give 60 mg of pure [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(R)- 2-Methoxymethyl-Sar]-3-cyclosporin was obtained [molecular formula: C 68 H 124 N 12 O 14 ;Accurate mass: 1332.94;MS(m / z):1333.69(M+1) + , 1355.86(M+Na) +HPLC RT: 16.18 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0276] Example 10 [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(S)- (4-Hydroxybutylthio)methyl-Sar]-3-cyclosporine

[0277] [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-M eBmt]-1-[α-methylene-Sar]-3-cyclosporine [ka]

[0278] Diisopropylamine (2 mL) in tetrahydrofuran (40 mL) was dissolved under nitrogen at -78°C. A solution of n-butyllithium (2.20 M, 6.75 mL, 14.85 mmol) was added to ml, 14.85 mmol) was added. The reaction mixture was stirred for 1 hour, and then tetrahydrofuran was added. [8-(2-(tert-butoxycarbonyl)aminoethyl) -6,7-dihydro-MeBmt]-1-cyclosporine (2.00 g, 1.48 mmol) The solution of (I) was added over 10 minutes. The mixture was stirred at -78°C for 2 hours. After bubbling carbon dioxide gas for 30 minutes, the mixture was stirred at -78°C for an additional hour. At this point, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature to expel unreacted carbon dioxide. The mixture was cooled to -78°C and chloromethyl chloroformate (1.32 ml, 14.85 m mol) was added. The mixture was stirred and allowed to warm to room temperature overnight. Brine (5 ml) was added. The reaction was quenched by adding ethyl acetate. Most of the tetrahydrofuran was removed under reduced pressure. Chilled water (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was extracted with sulfuric acid. The mixture was dried over magnesium and evaporated under reduced pressure. The residue was purified by chromatography (hexane / aq). Purification with acetone gave 0.60 g of pure [8-(2-(tert-butoxycarbonyl )aminoethyl)-6,7-dihydro-MeBmt]-1-[α-methylene-Sar]- 3-Cyclosporin was obtained [molecular formula: C 70 H 126 N 12 O 14 ;Exact mass: 135 8.95; MS(m / z):1359.59(M+1) + , 1381.81(M+Na) + HPLC RT: 18.44 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0279] [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[α-methyl Ren-Sar]-3-cyclosporine [ka]

[0280] [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro- MeBmt]-1-[α-methylene-Sar]-3-cyclosporine (0.60 g, 0. 44 mmol) was dissolved in dichloromethane (10 ml) and placed in an ice-water bath. Acetic acid (5 ml) was added. The mixture was stirred at room temperature for 1 hour. Another portion of dichloromethane (20 The mixture was diluted with brine (30 ml), saturated sodium bicarbonate solution (30 ml), l), dried over magnesium sulfate and evaporated under reduced pressure to give crude [8-(2-amino (6,7-dihydro-MeBmt)1-[α-methylene-Sar]-3-cyclohexyl Rosporin was obtained [molecular formula: C 65 H 118 N 12 O 12 ;Exact mass: 1258.90 MS (m / z): 1259.77 (M+1) + , 1281.84(M+Na) + HP LC RT: 13.00 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.0 5% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)]. Aminoethyl)-6,7-dihydro-MeBmt]-1-[α-methylene-Sar]-3 -Cyclosporin was dissolved in dichloromethane (10 ml). Acetic acid (0.12 ml, 2. 20 mmol), HBTU (0.50 g, 1.32 mmol), 1-hydroxybenzoxazole Triazole (0.18 g, 1.32 mmol) and pyridine (1 ml) were added. The mixture was stirred at room temperature for 1 hour. Then, dichloromethane (30 ml) and brine (50 The dichloromethane layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane / methanol) to give 0 0.30g of pure [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt] -1-[α-methylene-Sar]-3-cyclosporin [molecular formula: C 67 H 120 N 12 O 13 ;Accurate mass: 1300.91;MS(m / z):1301.66(M+1 ) + , 1323.92(M+Na) +HPLC RT: 17.41 min (C8 reverse phase column) : 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64 °C ;Detector: 210 nm)].

[0281] [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(S)- (4-Hydroxybutylthio)methyl-Sar]-3-cyclosporine [ka]

[0282] [8-(2-acetamidoethyl)-6,7-dihydro- in methanol (10 ml) MeBmt]-1-[α-methylene-Sar]-3-cyclosporine (0.30 g, 0. 23 mmol) was added to a solution of 4-mercapto-1-butanol (0.14 ml, 1.38 m mol) and lithium hydroxide (0.06 g, 2.31 mmol) were added to the reaction mixture. The mixture was stirred at room temperature for 5 hours. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (30 Water (10 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was extracted with magnesium sulfate. The residue was purified by chromatography (hexane / acetone 90%). Purification with ethanol (75 / 25 to 75 / 10) gave 14 mg of pure 8-(2-acetamidoethyl) )-6,7-dihydro-MeBmt]-1-[(S)-(4-hydroxybutylthio)meth [Ci-Sar]-3-cyclosporin was obtained [molecular formula: C 71 H 130 N 12 O 14 S; Exact mass: 1406.95;MS(m / z):1407.70(M+1) + , 1429 .89(M+Na) +HPLC RT: 15.02 min (C8 reverse phase column: 250 mm; Acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64°C; Detector: 21 0 nm)].

[0283] Example 11 [8-(2-hydroxyethyl)-6,7-dihydro-MeBmt]-1-[(S)-( 4-Hydroxybutylthio)methyl-Sar]-3-cyclosporine

[0284] (4-ethoxy-4-oxobutyl)triphenylphosphonium bromide [ka]

[0285] Ethyl 4-bromobutyrate (14.40 ml, 0.10 mol) in toluene (200 ml) and triphenylphosphine (26.29 g, 0.10 mol) were added. The mixture was stirred. The mixture was stirred and heated at reflux for 24 hours. After cooling to room temperature, the mixture was stirred at room temperature over the weekend. The precipitate was filtered off, washed with toluene and hexane, and dried in vacuo to give 20.0 g of The product obtained was [Molecular formula: C 24 H 26 O2 + ; Exact mass: 377.17; MS (m / z): 377.20(M) + ].

[0286] [8-(2-ethoxy-2-oxoethyl)-3-acetyl-MeBmt]-1-cyclo Sporin [ka]

[0287] In a dry flask, under nitrogen, add (4-ethoxy-4-oxobutyl)triphenylphosphonium A mixture of tetrahydrofuran (60 ml), tetrahydrofuran (60 ml), and tetrahydrofuran (60 ml) was added. The reaction mixture was placed in an ice-water bath and sodium tert-butoxide (2.1 l) was added. The mixture was stirred for 2 hours, and then tetrahydrofuran (8 g, 22.74 mmol) was added. [(3R,4R)-3-acetyloxy-4-methyl-6- A solution of oxo-N-MeNle]-1-cyclosporine (4.00 g, 3.25 mmol) The mixture was stirred at 0°C for an additional 5 hours. Most of the tetrahydrofuran was removed under reduced pressure. Dichloromethane (100 ml) and brine (100 ml) were added and the mixture was evaporated under reduced pressure. The mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. was purified by chromatography (dichloromethane / methanol) to give 2.82 g of [8-(2 -ethoxy-2-oxoethyl)-3-acetyl-MeBmt]-1-cyclosporine The obtained molecular formula: C 68 H 119 N 11 O 15 ;2.82g;Exact Mass: 1329.89 MS (m / z): 1330.51 (M+1) + , 1352.69(M+Na) + HP LC RT: 17.72 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.0 5% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0288] [8-(2-hydroxyethyl)-MeBmt]-1-cyclosporine [ka]

[0289] [8-(2-ethoxy-2-oxoethyl)-3-acetyl-MeBmt]-1-cyclohexyl Dissolve rosporin (2.82 g, 2.12 mmol) in tetrahydrofuran (40 ml). Sodium borohydride (8.02 g, 212.04 mmol) and cesium chloride (3.56 g, 21.20 mmol) was added. The mixture was stirred at room temperature and 40 ml) was added dropwise over 2 hours. The mixture was stirred for an additional 3 hours. Most of the solvent was removed under reduced pressure. Ethyl acetate (100 ml) and water (100 ml) were then added and the mixture was The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. Purification by chromatography (dichloromethane / methanol) gave 2.70 g of [8-(2- Hydroxyethyl)-MeBmt]-1-cyclosporine was obtained [molecular formula: C 64 H 11 5N 11 O 13 ;Accurate mass: 1245.87;MS(m / z):1246.56(M+ 1) + , 1413.96(M+Na) + HPLC RT: 14.15 min (C8 reverse phase column) Tube: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64 °C; detector: 210 nm)].

[0290] [8-(2-hydroxyethyl)-6,7-dihydro-MeBmt]-1-cyclosporin hmm [ka]

[0291] [8-(2-hydroxyethyl)-MeBmt]-1-cyclosporine (2.70 g, Palladium (10 wt. on carbon) was dissolved in methanol (50 ml). %, 50 mg) and acetic acid (6 drops) were added. The mixture was stirred at room temperature under hydrogen overnight. The mixture was filtered and the filtrate was evaporated under reduced pressure to give 1.50 g of crude 8-(2-hydroxyethyl) [MeBmt]-1-cyclosporin (molecular formula: C 64 H 117 N 11 O 13 ; Exact mass: 1247.88; MS (m / z): 1248.66 ( M+1) + , 1270.77(M+Na) + HPLC RT: 14.32 min (C8 reverse phase Column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64°C; detector: 210 nm)].

[0292] [8-(2-hydroxyethyl)-6,7-dihydro-MeBmt]-1-[α-methyl [N-Sar]-3-Cyclosporin [ka]

[0293] Diisopropylamine (1%) in tetrahydrofuran (40 ml) was dissolved under nitrogen at −78°C. A solution of n-butyllithium (2.65 M, 5.00 mL, 0.87 mL, 13.23 mmol) was added to ml, 13.23 mmol) was added. The reaction mixture was stirred for 1 hour, and then tetrahydrofuran was added. [8-(2-hydroxyethyl)-6,7-dihydro-MeBm in furan (15 ml) A solution of t]-1-cyclosporine (1.50 g, 1.20 mmol) was added over 10 min. The mixture was stirred at -78°C for 2 hours. Carbon dioxide gas was blown into the reaction mixture for 30 minutes. After addition, the mixture was stirred at -78°C for an additional hour. The cooling bath was then removed and the reaction mixture The mixture was allowed to warm to room temperature to expel unreacted carbon dioxide. The mixture was cooled to -78°C and To the mixture was added methyl chloroformate (1.07 ml, 12.03 mmol). The mixture was stirred and allowed to warm to room temperature overnight. Brine (5 ml) was added to quench the reaction. Most of the tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine were added. (50 ml) was added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane / acetone) to give 0.50 g of pure [8-(2-hydroxyethyl)-6,7-dihydro-MeBmt]-1-[ α-Methylene-Sar]-3-cyclosporin was obtained [molecular formula: C 65 H 117 N 11 O 13 ;Accurate mass: 1259.88;MS(m / z):1260.61(M+1) + , 1 282.78(M+Na) + HPLC RT: 16.09 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector :210nm)].

[0294] [8-(2-hydroxyethyl)-6,7-dihydro-MeBmt]-1-[(S)-( 4-Hydroxybutylthio)methyl-Sar]-3-cyclosporine [ka]

[0295] [8-(2-hydroxyethyl)-6,7-dihydro-M in methanol (10 ml) eBmt]-1-[α-methylene-Sar]-3-cyclosporine (0.50 g, 0.4 0 mmol) was added to a solution of 4-mercapto-1-butanol (0.25 ml, 2.38 mmol). mol) and lithium hydroxide (0.10 g, 4.00 mmol). The mixture was stirred at room temperature for 4 hours. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (30 ml) 1) and brine (30 ml) were added and the mixture was separated. The organic layer was extracted with magnesium sulfate The residue was purified by chromatography (hexane / acetone). and purified to obtain 80 mg of pure [8-(2-hydroxyethyl)-6,7-dihydro-M eBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclohexyl Rosporin was obtained [molecular formula: C 69 H 127 N 11 O 14 S; Exact mass: 1365.9 3; MS (m / z): 1366.64 (M + 1) + , 1388.84(M+Na) + :H PLC RT: 13.94 min (C8 reverse phase column: 250 mm; acetonitrile / water (0. 0.5% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0296] Example 12 [8-(2-(2-ethoxy-2-oxoethyl)amino)ethyl-6,7-dihydro- MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- Closporin (12a) and [8-(2-bis(2-ethoxy-2-oxoethyl)amine] (S)-(4-hydroxybutyl)-6,7-dihydro-MeBmt Thio)methyl-Sar]-3-cyclosporine (12b)

[0297] [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-M eBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclohexyl Rosporin [ka]

[0298] [8-(2-(tert-butoxycarbonyl)amino)- (ethyl)-6,7-dihydro-MeBmt]-1-[α-methylene-Sar]-3-cyclo A solution of sporin (0.25 g, 0.18 mmol) in 4-mercapto-1-butanol (0.12 ml, 1.10 mmol) and lithium hydroxide (0.04 g, 1.84 mmol) l) was added. The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (30 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography. (hexane / acetone 90 / 10 to 75 / 25) to obtain 100 mg of pure [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-M eBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclohexyl Rosporin was obtained [molecular formula: C 74 H 136 N 12 O 15 S; Exact mass: 1465.0 0; MS (m / z): 1465.53 (M + 1) + , 1487.84(M+Na) + :H PLC RT: 16.77 min (C8 reverse phase column: 250 mm; acetonitrile / water (0. 0.5% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0299] [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-1-[(S)-(4- Hydroxybutylthio)methyl-Sar]-3-cyclosporine [ka]

[0300] [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro- MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- Closporin (0.10 g, 0.07 mmol) was dissolved in dichloromethane (8 ml). The mixture was placed in an ice-water bath, trifluoroacetic acid (4 ml) was added, and the mixture was stirred at 0°C for 2 hours. Another portion of dichloromethane (10 ml) was added. The mixture was diluted with brine (30 ml), saturated Wash with sodium bicarbonate solution (30 ml), dry over magnesium sulfate and evaporate under reduced pressure. The crude [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-1-[( S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin was obtained [min Child expression:C 69 H 128 N 12 O 13 S; Exact mass: 1364.94; MS (m / z): 1365.75(M+1) + HPLC RT: 10.57 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector :210nm)].

[0301] [8-(2-(2-ethoxy-2-oxoethyl)amino)ethyl-6,7-dihydro- MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- Closporin (12a) and [8-(2-bis(2-ethoxy-2-oxoethyl)amine] (S)-(4-hydroxybutyl)-6,7-dihydro-MeBmt Thio)methyl-Sar]-3-cyclosporine (12b) [ka]

[0302] Crude [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-1 from the final step -[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporine di Dissolved in chloromethane (10 ml). Ethyl bromoacetate (48 mg, 0.34 mmol) ) and triethylamine (0.50 ml) were added. The mixture was stirred and heated to reflux for 3 hours. Dichloromethane (30 ml) and brine (50 ml) were then added and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. Purification by chromatography (dichloromethane / methanol) gave 10 mg of [8-(2-( (2-ethoxy-2-oxoethyl)amino)ethyl)-6,7-dihydro-MeBmt ]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin The molecular formula: C 73 H 134 N 12 O 15 S; Exact mass: 1450.98; MS (m / z): 1451.70 (M+1) + , 1473.87(M+Na) + ;HPLC RT: 12.23 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64 °C; detector: 210 nm)] and 30 mg of [8-( 2-(bis(2-ethoxy-2-oxoethyl)amino)ethyl)-6,7-dihydro- MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- Crossporin was obtained [molecular formula: C 77 H 140 N 12 O 17 S; Exact mass: 1537. 02; MS (m / z): 1337.70 (M + 1) + , 1559.90(M+Na) + ; HPLC RT: 14.42 min (C8 reverse phase column: 250 mm; acetonitrile / water (0 0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0303] Example 13 [8-(2-(carboxymethyl)amino)ethyl-6,7-dihydro-MeBmt]- 1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporine [ka]

[0304] [8-(2-(2-ethoxy-2-oxoethyl)amino)ethyl-6,7-dihydro -MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- Cyclosporine (10 mg, 6.9 × 10 -3 (mmol) in methanol (3 ml) Lithium hydroxide (2 mg, 0.08 mmol) and water (3 ml) were added. The mixture was stirred at room temperature for 1 hour. Most of the methanol was then evaporated under reduced pressure. Chill (10 ml) and brine (10 ml) are added, followed by hydrochloric acid solution (1.0 N). The pH of the aqueous layer was adjusted to 3. After separation, the ethyl acetate layer was dried over magnesium sulfate. The residue was purified by chromatography to give [8-(2-((calcium carbonate)]. (S)-((carboxymethyl)amino)ethyl)-6,7-dihydro-MeBmt 4-hydroxybutylthio)methyl-Sar]-3-cyclosporin was obtained [molecular formula: C 71 H 130 N 12 O 15 S; Exact mass: 1422.95; MS(m / z): 1423 .59(M+1) + , 1445.84(M+Na) + HPLC RT: 10.41 min ( C8 reversed-phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64°C; detector: 210 nm).

[0305] Example 14 [8-(2-bis(carboxymethyl)amino)ethyl-6,7-dihydro-MeBmt ]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin hmm [ka]

[0306] [8-(2-bis(2-ethoxy-2-oxoethyl)amino)ethyl-6,7-dihydrochloride Doro-MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]- 3-Cyclosporin (30 mg, 0.02 mmol) was dissolved in methanol (3 ml). Lithium hydroxide (6 mg, 0.23 mmol) and water (3 ml) were added. The mixture The mixture was stirred at room temperature for 1 hour, and then most of the methanol was evaporated under reduced pressure. (10 ml) and brine (10 ml), and then add hydrochloric acid solution (1.0 N). The pH of the aqueous layer was adjusted to 3. After separation, the ethyl acetate layer was dried over magnesium sulfate. The residue was purified by chromatography to give [8-(2-(bis(calcium)]. (S)-((carboxymethyl)amino)ethyl)-6,7-dihydro-MeBmt 4-hydroxybutylthio)methyl-Sar]-3-cyclosporin was obtained [molecular formula: C 73 H 132 N 12 O 17 S; Exact mass: 1480.96; MS(m / z): 1481 .70(M+1) + , 1503.87(M+Na) + ;HPLC RT:9.88min(C 8 reverse-phase columns: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operation temperature: 64°C; detector: 210 nm)].

[0307] Example 15 [8-(2-(4-(methoxycarbonyl)benzyl)amino]ethyl-6,7-dihydriodide rho-MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3 -Cyclosporin [ka]

[0308] [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-1-[(S)-(4 -hydroxybutylthio)methyl-Sar]-3-cyclosporine (0.50 g, 0.3 7 mmol) was dissolved in dichloromethane (50 ml). Zoate (0.08 g, 0.46 mmol), tetramethylammonium triacetoxy Borohydride (0.12 g, 0.46 mmol) and acetic acid (5 drops) were added. The mixture was stirred at room temperature for 1 hour. Then, dichloromethane (30 ml) and saturated sodium bicarbonate were added. A solution of 100 ml of ethanol (50 ml) was added and separated. The dichloromethane layer was dried over magnesium sulfate. The residue was purified by chromatography (dichloromethane / methanol). This was further purified to give 140 mg of [8-(2-(4-(methoxycarbonyl)benzyl)amine]. (S)-(4-hydroxybutyl)-6,7-dihydro-MeBmt Thio)methyl-Sar]-3-cyclosporin was obtained [molecular formula: C 78 H 136 N 12 O 15 S;Accurate mass:1513.00;MS(m / z):1513.77(M+1) + , 1535.80(M+Na) + HPLC RT: 13.40 min (C8 reverse phase column: 25 0 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detection instrument: 210nm)].

[0309] Example 16 [8-(2-(4-carboxybenzyl)amino)ethyl)-6,7-dihydro-MeB mt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclos Porin [ka]

[0310] [8-(2-(4-(methoxycarbonyl)benzyl)amino)ethyl-6,7-dihydrochloride Doro-MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]- 3-Cyclosporin (0.14 g, 0.09 mmol) was dissolved in methanol (5 ml). Lithium hydroxide (0.01 g, 0.40 mmol) and water (5 ml) were added. The mixture was stirred at room temperature for 2 hours. Most of the methanol was then evaporated under reduced pressure. Ethyl acetate (10 ml) and brine (10 ml) were added, followed by hydrochloric acid solution (1.00 N). The pH of the aqueous layer was adjusted to 3. After separation, the ethyl acetate layer was diluted with magnesium sulfate. The mixture was dried at 77°C and evaporated under reduced pressure. The residue was purified by chromatography to give [8-(2-(4 -carboxybenzyl)amino)ethyl-6,7-dihydro-MeBmt]-1-[(S )-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin [molecular Formula:C 77 H 134 N 12 O 15 S; Exact mass: 1498.98; MS(m / z): 1 499.62(M+1) + , 1521.77(M+Na) + ;HPLC RT: 11.7 6 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid) ); operating temperature: 64°C; detector: 210 nm)].

[0311] Example 17 [8-(2-(4-(dimethylcarbamoyl))benzyl)amino]ethyl-6,7-di Hydro-MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar] -3-cyclosporine [ka]

[0312] [8-(2-(4-carboxybenzyl)amino)ethyl-6,7-dihydro-MeB mt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclos Porin (0.13 g, 0.09 mmol) was dissolved in dichloromethane (10 ml). Ethylamine hydrochloride (0.04, 0.45 mmol), HBTU (0.10 g, 0.27 mmol), 1-hydroxybenzotriazole (0.04 g, 0.27 mmol), and and triethylamine (0.5 ml) were added, and the mixture was stirred at room temperature for 2 hours. Dichloromethane (30 ml) and brine (50 ml) were added and separated. The methane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed. Purify the compound by HPLC and obtain [8-(2-(4-(dimethylcarbamoyl))benzyl)amino]ethyl -6,7-dihydro-MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl [C1-Sar]-3-cyclosporin [molecular formula: C 79 H 139 N 13 O 14 S;Correct Exact mass: 1526.03;MS(m / z):1526.72(M+1) + , 1548. 84(M+Na) + HPLC RT: 11.90 min (C8 reverse phase column: 250 mm; Acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64°C; Detector: 210 nm)].

[0313] Example 18 [8-(2-bis(4-(methoxycarbonyl)benzyl)amino))ethyl-6,7- Dihydro-MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar ]-3-Cyclosporin [ka]

[0314] [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-1-[(S)-(4 -hydroxybutylthio)methyl-Sar]-3-cyclosporine (0.50 g, 0.3 7 mmol) was dissolved in dichloromethane (50 ml). Zoate (0.30 g, 1.83 mmol), tetramethylammonium triacetoxy Borohydride (0.48 g, 1.83 mmol) and acetic acid (10 drops) were added. The mixture was stirred at room temperature for 1 hour. Then, dichloromethane (30 ml) and saturated sodium bicarbonate were added. A solution of 100 ml of ethanol (50 ml) was added and separated. The dichloromethane layer was dried over magnesium sulfate. The residue was purified by chromatography (dichloromethane / methanol). This was further purified to give 174 mg of [8-(2-bis(4-(methoxycarbonyl)benzyl)] Amino)ethyl-6,7-dihydro-MeBmt]-1-[(S)-(4-hydroxybutanol (Cithylthio)methyl-Sar]-3-cyclosporin was obtained [molecular formula: C 87 H 144 N1 2O 17 S;Accurate mass:1661.05;MS(m / z):1661.66(M+1) + , 1684.06(M+Na) + HPLC RT: 15.32 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0315] Example 19 [8-(2-(bis(4-carboxybenzyl)amino)ethyl)-6,7-dihydro- MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- closporin [ka]

[0316] [8-(2-bis(4-(methoxycarbonyl)benzyl)amino))ethyl-6,7 -dihydro-MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sa r]-3-Cyclosporin (174 mg, 0.10 mmol) in methanol (5 ml) Lithium hydroxide (12 mg, 0.46 mmol) and water (5 ml) were added. The mixture was stirred at room temperature for 2 hours, and then most of the methanol was evaporated under reduced pressure. Ethyl acetate (10 ml) and brine (10 ml) were added, followed by hydrochloric acid solution (1.00 N). The pH of the aqueous layer was adjusted to 3 by adding magnesium sulfate. Drying with HCl and evaporation gave 100 mg of [8-(2-(bis(4-carboxybenzyl) )amino)ethyl)-6,7-dihydro-MeBmt]-1-[(S)-(4-hydroxy (butylthio)methyl-Sar]-3-cyclosporin was obtained [molecular formula: C 85 H 140 N 12 O 17 S;Accurate mass:1633.02;MS(m / z):1633.56(M+ 1) + , 1655.68(M+Na) + HPLC RT: 11.64 min (C8 reverse phase column) Tube: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64 °C; detector: 210 nm)].

[0317] Example 20 [8-(2-bis(4-(dimethylcarbamoyl))benzyl)amino]ethyl-6,7 -dihydro-MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sa r]-3-cyclosporine [ka]

[0318] [8-(2-(bis(4-carboxybenzyl)amino)ethyl)-6,7-dihydro -MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- Dissolve cyclosporine (0.10 g, 0.06 mmol) in dichloromethane (10 ml). Dimethylamine hydrochloride (0.03, 0.37 mmol), HBTU (0.12 g, 0.31mmol), 1-hydroxybenzotriazole (0.04g, 0.31mmol 1), and triethylamine (0.5 ml) were added. The mixture was stirred at room temperature for 2 hours. Then dichloromethane (30 ml) and brine (50 ml) were added and separated. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The compound was purified by chromatography to give [8-(2-(bis(4-(dimethylcarbamoyl))benzyl)a methylamino)ethyl]-6,7-dihydro-MeBmt]-1-[(S)-(4-hydroxybutanol (Cithylthio)methyl-Sar]-3-cyclosporin was obtained [molecular formula: C 89 H 150 N1 4O 15 S;Accurate mass:1687.11;MS(m / z):1687.73(M+1) + , 1709.88(M+Na) + HPLC RT: 12.44 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0319] Example 21 [8-(2-(3-carboxybenzamido)ethyl)-6,7-dihydro-MeBmt ]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin hmm [ka]

[0320] [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-1-[(S)-(4 -hydroxybutylthio)methyl-Sar]-3-cyclosporine (0.19 g, 0.1 4 mmol) was dissolved in dichloromethane (8 ml). Isophthalic acid (0.07 g, 0. 41 mmol), HBTU (0.16 g, 0.41 mmol), 1-hydroxybenzoxazole Triazole (0.06 g, 0.41 mmol), and N-ethyldiisopropylamine ( 0.50 ml) was added. The mixture was stirred at room temperature for 2 hours. Then, dichloromethane ( Addition of hydrochloric acid solution (1.0 N) and brine (50 ml) was performed. The pH of the aqueous layer was adjusted to 4 by adding HCl. After separating the mixture, the dichloromethane layer was diluted with mag- nesium sulfate. The crude 8-(2-(3-carboxybenzamide) 1-[(S)-(4-hydroxybutyromethyl)ethyl]-6,7-dihydro-MeBmt]- ... (C11)methyl-Sar]-3-cyclosporin [molecular formula: C 77 H 132 N 12 O 16 S;Accurate mass:1512.96;MS(m / z):1513.66(M+1) + , 1535.80(M+Na) + HPLC RT: 14.15 min (C8 reverse phase column: 2 50 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; output: 210nm)].

[0321] Crude [8-(2-(3-carboxybenzamido)ethyl)-6,7-dihydro-MeB mt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclos The porin was dissolved in acetone (10 ml). The mixture was stirred at room temperature for 2 hours. The mixture was stirred for 1 hour. Most of the solvent was then evaporated. Ethyl acetate (50 ml) and brine were added. (50 ml) was added and the mixture was separated. The ethyl acetate layer was dried over magnesium sulfate. The residue was purified by column chromatography (hexane / acetone) to give 44 mg of [ 8-(2-(3-(methoxycarbonyl)benzamido)ethyl)-6,7-dihydro- MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- Crossporin was obtained [molecular formula: C 78 H 134 N 12 O 16 S; Exact mass: 1526. 98; MS (m / z): 1527.62 (M + 1) + , 1549.81(M+Na) + ; HPLC RT: 16.08 min (C8 reverse phase column: 250 mm; acetonitrile / water (0 0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0322] Example 22 [8-(2-(3-carboxybenzamido)ethyl)-6,7-dihydro-MeBmt ]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin hmm [ka]

[0323] [8-(2-(3-(methoxycarbonyl)benzamido)ethyl]-6,7-dihydriodide rho-MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3 -Cyclosporin (44 mg, 0.03 mmol) was dissolved in methanol (3 ml). Lithium hydroxide (20 mg, 0.83 mmol) and water (3 ml) were added. The mixture The mixture was stirred at room temperature for 2 hours, and then most of the methanol was evaporated under reduced pressure. (10 ml) and brine (10 ml), and then add hydrochloric acid solution (1.0 N). The pH of the aqueous layer was adjusted to 4. After separating the mixture, the ethyl acetate layer was diluted with magnesium sulfate. The mixture was dried at 77°C and evaporated under reduced pressure. The residue was purified by chromatography (C8 reversed phase column). 16 mg of [8-(2-(3-carboxybenzamido)ethyl]-6,7-dihydrochloride was prepared. Doro-MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar-] 3-Cyclosporin [molecular formula: C 77 H 132 N 12 O 16 S; Exact mass: 1 512.96; MS(m / z):1513.66(M+1) + , 1535.80(M+N a) + HPLC RT: 14.15 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0324] Example 23 [8-(2-(4-(methoxycarbonyl)benzamido)ethyl]-6,7-dihydro -MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- Cyclosporine [ka]

[0325] [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-1-[(S)-(4 [0.60 g, 0.4 4 mmol) was dissolved in dichloromethane (30 ml). 0.24g, 1.32mmol), HBTU (0.52g, 1.32mmol), 1-Hydro hydroxybenzotriazole (0.16 g, 1.32 mmol), and N,N-diisopropyl Pyroethylamine (3.0 ml) was added, and the mixture was stirred at room temperature for 2 hours. Dichloromethane (100 ml) and brine (100 ml) were added and separated. The methane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed. The product was purified by filtration to give 0.34 g of [8-(2-(4-(methoxycarbonyl)benzamido)ethoxy] (S)-(4-hydroxybutylthio)-6,7-dihydro-MeBmt]-1-[(S)-(4-hydroxybutylthio) )methyl-Sar]-3-cyclosporin was obtained [molecular formula: C 78 H 134 N 12 O 16 S;Accurate mass:1526.98;MS(m / z):1527.69(M+1) + , 15 49.95(M+Na) + HPLC RT: 16.08 min (C8 reverse phase column: 250 m m; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0326] Example 24 [8-(2-(4-carboxybenzamido)ethyl)-6,7-dihydro-MeBm t]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin Phosphorus [ka]

[0327] [8-(2-(4-(methoxycarbonyl)benzamido)ethyl]-6,7-dihydriodide rho-MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3 -Cyclosporin (0.34 mg, 0.24 mmol) was dissolved in methanol (5 ml). Lithium hydroxide (20 mg, 0.83 mmol) and water (5 ml) were added. The mixture was stirred at room temperature for 2 hours. Most of the methanol was then evaporated under reduced pressure. Chill (20 ml) and brine (20 ml) were added, followed by the addition of hydrochloric acid solution (1.00 N). The pH of the aqueous layer was adjusted to 3. After separation, the ethyl acetate layer was washed with magnesium sulfate. The mixture was dried and evaporated under reduced pressure. The residue was purified by chromatography (C18 reversed phase column). 0.22 g of [8-(2-(4-carboxybenzamido)ethyl]-6,7- Dihydro-MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar ]-3-cyclosporin [molecular formula: C 77 H 132 N 12 O 16 S; Exact Mass: 1512.96; MS(m / z):1513.66(M+1) + , 1535.80(M+ Na) + HPLC RT: 13.98 min (C8 reverse phase column: 250 mm; acetonitrile ethanol / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0328] Example 25 [8-(2-(4-(dimethylcarbamoyl)benzamido)ethyl]-6,7-dihydriodide rho-MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3 -Cyclosporin [ka]

[0329] [8-(2-(4-carboxybenzamido)ethyl)-6,7-dihydro-MeBm t]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin Phosphorus (0.22 g, 0.15 mmol) was dissolved in dichloromethane (5 ml). methylamine hydrochloride (0.04, 0.49 mmol), HBTU (0.17 g, 0.45 mmol), ol), 1-hydroxybenzotriazole (0.06 g, 0.45 mmol), and Lysine (0.5 ml) was added. The mixture was stirred at room temperature overnight. Then, dichloromethane The solvent was evaporated under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography to give [8-(2-(4-(dimethylcarbamoyl)benzalkonium] [(S)-(4-hydroxybutanol)-1-(methylamino)ethyl]-6,7-dihydro-MeBmt]-1-[ ... (Cithylthio)methyl-Sar]-3-cyclosporin was obtained [molecular formula: C 79 H 137 N1 3O 15 S;Accurate mass:1540.01;MS(m / z):1540.89(M+1) + , 1563.06(M+Na) + HPLC RT: 14.54 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0330] Example 26 [8-(2-(2-hydroxyacetamido)ethyl)-6,7-dihydro-MeBmt ]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin hmm [ka]

[0331] [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-1-[(S)-(4 -hydroxybutylthio)methyl-Sar]-3-cyclosporine (0.26 g, 0.1 9 mmol) was dissolved in dichloromethane (20 ml). 0.53mmol), HBTU (0.22g, 0.58mmol), 1-hydroxybenzo Triazole (0.08 g, 0.58 mmol) and pyridine (1.00 ml) were added. The mixture was stirred at room temperature for 2 hours. Then, dichloromethane (30 ml) and brine were added. The dichloromethane layer was dried over magnesium sulfate and The residue was purified by chromatography (dichloromethane / methanol). The pure [8-(2-(2-hydroxyacetamido)ethyl]-6,7-dihydro- MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- Crossporin was obtained [molecular formula: C 71 H 130 N 12 O 15 S; Exact mass: 1422. 95; MS (m / z): 1423.80 (M + 1) + , 1445.95(M+Na) + ; HPLC RT: 12.73 min (C8 reverse phase column: 250 mm; acetonitrile / water (0 0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0332] Example 27 [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(R)- (4-Acetoxybutoxy)methyl-Sar]-3-cyclosporine (26a) [ka]

[0333] [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(R) -hydroxymethyl-Sar]-3-cyclosporine (0.14 g, 0.11 mmol) was dissolved in benzene (10 ml). 6mmol), tetra-n-butylammonium bromide (0.34g, 1.06mmol l), tetramethylammonium hydroxide pentahydrate (0.19 g, 1.06 mmol), and and sodium hydroxide solution (2.0 ml, 45%) were added. The mixture was stirred at 50° C. overnight. Ethyl acetate (50 ml) and brine (50 ml) were then added and separated. The ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed. Purification by dichloromethane / methanol gave 50 mg of pure [8-(2-acetamide)]. (R)-(4-acetoxy)-6,7-dihydro-MeBmt]-1-[( ... butoxymethyl-Sar]-3-cyclosporin [molecular formula: C 73 H 132 N1 2O 16 ;Accurate mass: 1432.99;MS(m / z):1433.73(M+1) + , 1455.99(M+Na) + HPLC RT: 17.43 min (C8 reverse phase column: 2 50 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; output: 210nm)].

[0334] Example 28 [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(R)- (4-hydroxybutoxy)methyl-Sar]-3-cyclosporine [ka]

[0335] [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(R) -(4-acetoxybutoxy)methyl-Sar]-3-cyclosporine (50 mg, 0. Lithium hydroxide (20 mg, 0.8 mmol) was dissolved in methanol (5 ml). 3 mmol) and water (5 ml) were added. The mixture was stirred at room temperature for 2 hours. A portion of the methanol was evaporated under reduced pressure. Ethyl acetate (20 ml) and brine (30 ml) were added. l) was added, and the pH of the aqueous layer was adjusted to 3 by adding hydrochloric acid solution (1.00 N). After separation, the ethyl acetate layer was dried over magnesium sulfate and evaporated under reduced pressure. Purify by C18 reverse phase chromatography to obtain 15 mg of [8-(2-acetamidoethyl )-6,7-dihydro-MeBmt]-1-[(R)-(4-hydroxybutoxy)methyl [C1-Sar]-3-cyclosporin [molecular formula: C 71 H 130 N 12 O 15 ;accurate Mass: 1390.98; MS(m / z): 1391.80(M+1) + , 1413.9 8(M+Na) + HPLC RT: 15.50 min (C8 reverse phase column: 250 mm; acetone) Trinitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210n m)].

[0336] Example 29 [8-(3-acetamidopropyl)-6,7-dihydro-MeBmt]-1-[(S) -(3-(N-morpholino)propylthio)methyl-Sar]-3-cyclosporine

[0337] (4-Cyanobutyl)triphenylphosphonium bromide [ka]

[0338] 5-Bromovaleronitrile (1.62 g, 10.00 mmol) and triphenylphos Phenol (2.62 g, 10.00 mmol) was added to toluene (20 ml). The mixture was stirred and heated at reflux overnight. After cooling to room temperature, the precipitate was filtered off and The product was washed with water and dried in vacuo to give 3.00 g of product [molecular formula: C 23 H 23 Br NP; Exact mass: 423.08; MS (m / z): 344.28 (M-Br) + ].

[0339] [8-(2-cyanoethyl)-3-acetyl-MeBmt]-1-cyclosporine [ka]

[0340] (4-cyanobutyl)triphenylphosphine in anhydrous tetrahydrofuran (180 ml) under nitrogen. A solution of bis(trifluoromethylphosphonium bromide (6.40 g, 15.08 mmol) was added to sodium bis(trifluoromethylphosphonium bromide). (trimethylsilyl)amide (2.0 M in THF, 11.2 ml, 22.40 mmol) The reaction mixture was stirred at room temperature for 1 hour and cooled to -30°C. [(3R,4R)-3-acetyloxy-4-methyl-6-oxo A solution of [-N-MeNle]-1-cyclosporine (8.20 g, 6.65 mmol) was added. The mixture was stirred at -30°C for an additional 2 hours. Then saturated ammonium chloride solution (2 The reaction was quenched by adding 100 ml of tetrahydrofuran. Most of the tetrahydrofuran was evaporated under reduced pressure. Ethyl acetate (250 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed. Purification with dichloromethane / methanol gave 5.60 g of pure [8-(2-cyano)- (3-methyl-2-phenyl-2-methyl-1,3-diphenyl-2-methyl-1,3-diphenyl-2-methyl-1,3-diphenyl-1,3-diphenyl-2 ... 67 H 116 N 12 O 13 ; Exact mass: 1296.88; MS(m / z): 1297.57 (M+1) + ].

[0341] [8-(2-cyanoethyl)-MeBmt]-1-cyclosporine [ka]

[0342] [8-(2-cyanoethyl)-3-acetyl-MeBmt]-1-cyclosporine (5 0.00g, 3.86mmol) was dissolved in methanol (100ml) and water (50ml). and tetramethylammonium hydroxide pentahydrate (4.40 g, 24.22 mmol) were added. The mixture was stirred at room temperature overnight. Most of the methanol was then evaporated. Ethyl acetate (250 ml) and brine (100 ml) were added and the mixture was separated. The extract was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane). Purification with hexane / methanol gave 3.60 g of pure [8-(2-cyanoethyl)- MeBmt]-1-cyclosporin [molecular formula: C 65 H 114 N 12 O 12 ;accurate Mass:1254.87;MS(m / z):1255.51(M+1) + ;HPLC R T: 14.90 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trimethylsilane) fluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0343] [8-(3-aminopropyl)-6,7-dihydro-MeBmt]-1-cyclosporine [ka]

[0344] [8-(2-cyanoethyl)-MeBmt]- in methanol (120 ml) under nitrogen. A solution of 1-cyclosporine (2.40 g, 1.91 mmol) was diluted with nickel(II) chloride. hydrate (0.38 g, 1.62 mmol) was added. Sodium borohydride (2.0 0 g, 52.63 mmol) was added in 4 batches over 30 minutes. The mixture was stirred for an additional 1 hour. Afterwards, most of the methanol was evaporated under reduced pressure. Sodium citrate solution (50 ml) was added and the mixture was separated. The organic layer was washed with brine. The residue was dissolved in methanol (30 ml) and evaporated under reduced pressure. Palladium (10 wt% on carbon, 150 mg) and acetic acid (5 drops) were added. The mixture was stirred at room temperature under hydrogen for 4 hours, the mixture was filtered and the filtrate was evaporated under reduced pressure to give Crude [8-(3-aminopropyl)-6,7-dihydro-MeBmt]-1-cyclosporin The molecular formula: C 65 H 120 N 12 O 12 ; Exact mass: 1260.90; MS( m / z): 1261.69 (M+1) + HPLC RT: 11.23 min (C8 reverse phase column) Tube: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64 °C; detector: 210 nm)].

[0345] [8-(3-acetamidopropyl)-6,7-dihydro-MeBmt]-1-cyclos Porin [ka]

[0346] [8-(3-aminopropyl)-6,7-dihydro- -MeBmt]-l-cyclosporine (2.40 g, 1.90 mmol) and acetic acid (24 To a solution of diisopropylethylamine (386 mg, 1.99 mmol) The mixture was stirred at room temperature for 2 hours. After stirring, the reaction mixture was washed with saturated sodium bicarbonate solution, brine, and added magnesium sulfate. The residue was purified by chromatography (dichloromethane / methanol ) to obtain 2.00 g of pure [8-(3-acetamidopropyl)-6,7-dihydrochloride]. dro-MeBmt]-1-cyclosporine was obtained [molecular formula: C 67 H 122 N 12 O 13 ;Accurate mass: 1302.93;MS(m / z):1303.63(M+1) + HPL CRT: 13.74 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05 % trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0347] [8-(3-acetamidopropyl)-6,7-dihydro-MeBmt]-1-[α-methyl Tetylene-Sar]-3-cyclosporine [ka]

[0348] Diisopropylamine (3%) in tetrahydrofuran (100 ml) at −78°C under nitrogen. A solution of n-butyllithium (2.65M, 12 ml, 31 The reaction mixture was stirred for 1 hour, after which tetrahydrofuran (1.80 mmol) was added. 5 ml) in [8-(3-acetamidopropyl)-6,7-dihydro-MeBmt]- A solution of 1-cyclosporine (3.80 g, 2.92 mmol) was added over 10 min. The mixture was stirred at -78°C for 3 hours. Carbon dioxide gas was bubbled into the reaction mixture for 30 minutes. After that, the mixture was stirred for another hour at -78°C. The cooling bath was then removed and the reaction mixture was allowed to warm to room temperature. The mixture was cooled to -78°C and the chloromethyl Dichloroformate (3.70 ml) was added and the mixture was stirred and allowed to warm to room temperature overnight. Brine (20 ml) was added to quench the reaction. Most of the tetrahydrofuran was Ethyl acetate (50 ml) and brine (50 ml) were added and mixed. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The product was purified by chromatography (hexane / acetone) to give 1.20 g of pure [8-(3- Acetamidopropyl)-6,7-dihydro-MeBmt]-1-[α-methylene-Sa r]-3-Cyclosporin was obtained [molecular formula: C 68 H 122 N 12 O 13 ;Exact mass: 1314.93; MS(m / z):1315.61(M+1) + ;HPLC RT:16 0.44 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoromethyl methyl acrylate) acetic acid); operating temperature: 64°C; detector: 210 nm)].

[0349] [8-(3-acetamidopropyl)-6,7-dihydro-MeBmt]-1-[(S) -(3-(N-morpholino)propylthio)methyl-Sar]-3-cyclosporine [ka]

[0350] [8-(3-acetamidopropyl)-6,7-dihydro- -MeBmt]-1-[(S)-(α-methylene-Sar)-3-cyclosporine (0. 50 g, 0.38 mmol) was added to a solution of 3-morpholinopropanethiol (0.48 g, 3.00 mmol) and lithium hydroxide (92 mg, 3.83 mmol) were added. The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (80 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was extracted with mag sulfate. The mixture was dried over sodium hydroxide and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane / Methanol) to give 130 mg of pure 8-(3-acetamidopropyl) -6,7-dihydro-MeBmt]-1-[(S)-(3-(N-morpholino)propyl Thio)methyl-Sar]-3-cyclosporin was obtained [molecular formula: C 75 H 137 N 13 O 14 S;Accurate mass:1476.01;MS(m / z):1476.82(M+1) + ; HPLC RT: 12.61 min (C8 reverse phase column: 250 mm; acetonitrile / water (0 0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0351] Example 30 [8-(3-acetamidopropyl)-6,7-dihydro-MeBmt]-1-[(S) -(4-hydroxybutylthio)methyl-Sar]-3-cyclosporine [ka]

[0352] [8-(3-acetamidopropyl)-6,7-dihydro- -MeBmt]-1-[(S)-(α-methylene-Sar)-3-cyclosporine (0. 50 g, 0.38 mmol) was added to a solution of 4-mercapto-1-butanol (0.28 g, 2.64 mmol) and lithium hydroxide (92 mg, 3.83 mmol) were added. The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (80 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was extracted with mag sulfate. The mixture was dried over sodium hydroxide and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane / methanol) to give 115 mg of pure [8-(3-acetamidopropyl) -6,7-dihydro-MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl [C1-Sar]-3-cyclosporin [molecular formula: C 72 H 132 N 12 O 14 S;Correct Exact mass: 1420.97;MS(m / z):1421.80(M+1) + ;HPLC RT: 15.49 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0353] Example 31 [8-(3-(4-carboxybenzamido)propyl)-6,7-dihydro-MeBm t]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin Phosphorus

[0354] [8-(3-(4-methoxycarbonylbenzamido)propyl)-6,7-dihydro- MeBmt]-1-cyclosporine [ka]

[0355] [8-(3-aminopropyl)-6,7-dihydro- -MeBmt]-1-cyclosporine (4.00 g, 3.17 mmol) and methyl hydrogen A solution of diisopropyl ether terephthalate (0.85 g, 4.72 mmol) was added to ethanol (770 mg, 5.96 mmol) and HATU (2.40 g, 6.30 mmol) The reaction mixture was stirred at room temperature for 2 hours, then saturated sodium bicarbonate solution, brine, The residue was washed with ethyl acetate, dried over magnesium sulfate and evaporated under reduced pressure. The resulting mixture was purified with dichloromethane / methanol to give 2.00 g of pure [8-(3-(4- Methoxycarbonylbenzamido)propyl)-6,7-dihydro-MeBmt]-1- Cyclosporin was obtained [molecular formula: C 74 H 126 N 12 O 15 ;Exact mass: 1422. 95; MS (m / z): 1423.70 (M + 1) + HPLC RT: 16.74 min ( C8 reversed-phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64°C; detector: 210 nm).

[0356] [8-(3-(4-carboxybenzamido)propyl)-6,7-dihydro-MeBm t]-1-cyclosporine [ka]

[0357] [8-(3-(4-methoxycarbonyl)

[0043] -1-cyclosporine (

[0044] propyl)-6,7-dihydro-MeBmt)-1-cyclosporine (

[0045] propyl)-6,7-dihydro-MeBmt)-1-cyclosporine ([0046 ... A solution of lithium hydroxide (0.28 g, 11.66 mmol) was added to the solution of 2.40 g, 1.68 mmol). mol) was added. The reaction mixture was stirred at room temperature for 2 hours and evaporated under reduced pressure. Add ethanol (10 ml) and brine (10 ml) and add hydrochloric acid solution (1.00 N). The pH of the aqueous layer was adjusted to 5. After separation, the ethyl acetate layer was dried over magnesium sulfate. Drying and evaporation gave 2.3 g of [8-(3-(4-carboxybenzamido)propyl )-6,7-dihydro-MeBmt]-1-cyclosporin [molecular formula: C 73 H1 24 N 12 O 15 ;Accurate mass: 1408.93;MS(m / z):1409.70(M +1) + HPLC RT: 14.93 min (C8 reverse phase column: 250 mm; acetonitrile ethanol / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0358] [8-(3-(4-carboxybenzamido)propyl)-6,7-dihydro-MeBm t]-1-[α-methylene-Sar]-3-cyclosporine [ka]

[0359] Diisopropylamine (2%) in tetrahydrofuran (120 ml) at −78°C under nitrogen. A solution of 0.02 g, 20.00 mmol) of n-butyllithium (2.65 M, 7.6 m The reaction mixture was stirred for 1 hour, and then tetrahydrofuran was added. [8-(3-(4-carboxybenzamido)propyl]-6,7 in 15 mL -dihydro-MeBmt]-1-cyclosporine (2.10 g, 1.49 mmol) The mixture was stirred at -78°C for 3 hours. Carbon dioxide was added to the reaction mixture. After bubbling nitrogen gas for 30 minutes, the mixture was stirred at -78°C for an additional hour. The mixture was then heated to room temperature to remove the unreacted carbon dioxide. The mixture was cooled to 78°C and chloromethyl chloroformate (2.20 ml) was added. Stirred and allowed to warm to room temperature overnight. Brine (20 ml) was added to quench the reaction. Most of the tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine were added. (50 ml) was added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography to give 1.20 g of pure [8-(3-( 4-Carboxybenzamido)propyl)-6,7-dihydro-MeBmt]-1-[α -methylene-Sar]-3-cyclosporin [molecular formula: C 74 H 124 N 12 O1 5;Accurate mass: 1420.93;MS(m / z):1421.61(M+1) + HP LC RT: 16.56 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.0 5% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0360] [8-(3-(4-carboxybenzamido)propyl)-6,7-dihydro-MeBm t]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin Phosphorus [ka]

[0361] [8-(3-(4-carboxybenzamido)propyl] in methanol (30 ml) -6,7-dihydro-MeBmt]-1-[α-methylene-Sar]-3-cyclosporin A solution of 4-mercapto-1-butanol (0. 28g, 2.64mmol) and lithium hydroxide (92mg, 3.83mmol) were added. The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (80 ml) and brine (30 ml) were added and the mixture was separated. The mixture was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane). methane / methanol) to give 115 mg of pure [8-(3-(4-carboxymethyl)- (S)-(4-(Cibenzamido)propyl)-6,7-dihydro-MeBmt]-1-[(S)-(4- Methylbutylthio)methyl-Sar]-3-cyclosporin was obtained [molecular formula: C 78 H1 34 N 12 O 16 S; Exact mass: 1526.98; MS (m / z): 1527.84 ( M+1) + HPLC RT: 14.80 min (C8 reverse phase column: 250 mm; acetonite ethyl acetate / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)] .

[0362] Example 32 [8-(3-(4-(diethylcarbamoylbenzamido)propyl)-6,7-dihydriodide rho-MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3 -Cyclosporin [ka]

[0363] [8-(3-(4-carboxybenzamido)propyl]propionate in dichloromethane (10 ml) (S)-(4-hydroxybutylthio)-6,7-dihydro-MeBmt Methyl-Sar]-3-cyclosporine (0.10 g, 0.07 mmol) and diethyl A solution of amine (15 mg, 0.21 mmol) was added to diisopropylethylamine (25 m g, 0.19 mmol), HOBT (29 mg, 0.19 mmol), and HBTU (7 After stirring at room temperature for 2 hours, the reaction mixture was diluted with saturated Washed with sodium carbonate solution and brine, dried over magnesium sulfate and evaporated under reduced pressure The residue was purified by chromatography (dichloromethane / methanol) to give 42 mg of pure [8-(3-(4-diethylcarbamoylbenzamido)propyl]-6, 7-Dihydro-MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-S ar]-3-cyclosporin was obtained [molecular formula: C 82 H 143 N 13 O 15 S; Accurate quality Quantity:1582.05;MS(m / z):1582.70(M+1) + HPLC RT: 16.08 min. (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetate) (Fluoroacetic acid); operating temperature: 64°C; detector: 210 nm).

[0364] Example 33 [8-(3-(3-methoxycarbonylbenzamido)propyl)-6,7-dihydro- MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- closporin

[0365] [8-(3-(3-methoxycarbonylbenzamido)propyl)-6,7-dihydro- MeBmt]-1-cyclosporine [ka]

[0366] [8-(3-aminopropyl)-6,7-dihydro- -MeBmt]-1-cyclosporine (4.33 g, 3.43 mmol) and methyl hydrogen A solution of isophthalate (0.92 g, 5.11 mmol) was added to diisopropyl ethyl amine. ethanol (770 mg, 5.96 mmol) and HATU (2.40 g, 6.30 mmol) The reaction mixture was stirred at room temperature for 2 hours, then saturated sodium bicarbonate solution, brine, The residue was washed with ethyl acetate, dried over magnesium sulfate and evaporated under reduced pressure. The resulting mixture was purified with dichloromethane / methanol to give 2.00 g of pure [8-(3-(3- Methoxycarbonylbenzamido)propyl)-6,7-dihydro-MeBmt]-1- Cyclosporin was obtained [molecular formula: C 74 H 126 N 12 O 15 ;Exact mass: 1422. 95; MS (m / z): 1423.70 (M + 1) + HPLC RT: 16.82 min ( C8 reversed-phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64°C; detector: 210 nm).

[0367] [8-(3-(3-carboxybenzamido)propyl)-6,7-dihydro-MeBm t]-1-cyclosporine [ka]

[0368] [8-(3-(3-methoxycarbonylbenzamide)propanol] in methanol (80 ml) [4,5-Dihydro-MeBmt]-1-cyclosporine (2.50 g, 1.7 A solution of 0.6 mmol of lithium hydroxide (0.28 g, 11.66 mmol) in water (20 ml) ol) was added. The reaction mixture was stirred at room temperature for 2 hours and evaporated under reduced pressure. Ethyl acetate (10 ml) and brine (10 ml) were added, followed by the addition of hydrochloric acid solution (1.00 N). The pH of the aqueous layer was adjusted to 5. After separation, the ethyl acetate layer was dried over magnesium sulfate. and evaporated to give 2.1 g of [8-(3-(3-carboxybenzamido)propyl] -6,7-dihydro-MeBmt]-1-cyclosporin [molecular formula: C 73 H 12 4N 12 O 15 ;Accurate mass: 1408.93;MS(m / z):1409.70(M+ 1)+. HPLC RT: 15.11 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0369] [8-(3-(3-methoxycarbonylbenzamido)propyl)-6,7-dihydro- MeBmt]-1-[α-methylene-Sar]-3-cyclosporine [ka]

[0370] Diisopropylamine (2%) in tetrahydrofuran (120 ml) was dissolved in 2% ethanol at -78°C under nitrogen. A solution of 0.12 g, 21.00 mmol) of n-butyllithium (2.65 M, 7.9 ml The reaction mixture was stirred for 1 hour, and then tetrahydrofuran was added. [8-(3-(3-carboxybenzamido)propyl]-6,7- Solution of dihydro-MeBmt]-1-cyclosporine (2.10 g, 1.49 mmol) was added over 10 minutes. The mixture was stirred at -78°C for 3 hours. Carbon dioxide was added to the reaction mixture. After bubbling gas for 30 minutes, the mixture was stirred at -78°C for an additional hour. The mixture was removed and the reaction mixture was allowed to warm to room temperature to expel unreacted carbon dioxide. The mixture was cooled to 8°C and chloromethyl chloroformate (2.20 ml) was added. The mixture was stirred and allowed to warm to room temperature overnight. Methanol (20 ml) was added to quench the reaction. Most of the tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine were added. (50 ml) was added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane / acetone) to give 1. 20 g of pure [8-(3-(3-methoxycarbonylbenzamido)propyl]-6, 7-Dihydro-MeBmt]-1-[α-methylene-Sar]-3-cyclosporine was obtained. Molecular formula: C 75 H 126 N 12 O 15 ; Exact mass: 1434.95; MS (m / z ):1435.61(M+1) + HPLC RT: 18.26 min (C8 reverse phase column: 2 50 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; output: 210nm)].

[0371] [8-(3-(3-methoxycarbonylbenzamido)propyl)-6,7-dihydro- MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- closporin [ka]

[0372] [8-(3-(3-methoxycarbonylbenzamide)propanol] in methanol (30 ml) (propyl)-6,7-dihydro-MeBmt]-1-[α-methylene-Sar]-3-cyclo A solution of rosporin (0.62 g, 0.43 mmol) was added to 4-mercapto-1-butanol. (0.28 g, 2.64 mmol) and lithium hydroxide (103 mg, 4.29 mmol) l) was added. The reaction mixture was stirred at room temperature overnight. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (80 ml) and brine (30 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography. (dichloromethane / methanol) to give 115 mg of pure [8-(3-(3 -Methoxycarbonylbenzamido)propyl)-6,7-dihydro-MeBmt]-1 -[(S)-(4-hydroxybutylthio)methyl-Sar-]-3-cyclosporine The obtained molecular formula: C 79 H 136 N 12 O 16 S; Exact mass: 1540.99; MS(m / z):1541.84(M+1) + HPLC RT: 16.83 min. (C8 reverse phase column) Tube: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64 °C; detector: 210 nm)].

[0373] Example 34 [8-(3-(3-carboxybenzamido)propyl)-6,7-dihydro-MeBm t]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporin Phosphorus [ka]

[0374] [8-(3-(3-methoxycarbonylbenzamido)pro] in methanol (8 ml) (S)-(4-hydroxybutylthio)-6,7-dihydro-MeBmt )methyl-Sar]-3-cyclosporine (0.20 g, 0.13 mmol) in a solution Water (3 ml) and lithium hydroxide (15 mg, 0.63 mmol) were added to the reaction mixture. The mixture was stirred at room temperature for 8 hours and evaporated under reduced pressure. 10 ml) was added, and the pH of the aqueous layer was adjusted to 5 by adding hydrochloric acid solution (1.00 N). After separation, the ethyl acetate layer was dried over magnesium sulfate and evaporated to give [8-( 3-(3-carboxybenzamido)propyl)-6,7-dihydro-MeBmt]-1 -[(S)-(4-hydroxybutylthio))methyl-Sar]-3-cyclosporine The obtained molecular formula: C 78 H 134 N 12 O 16 S; Exact mass: 1526.98; MS(m / z):1527.84(M+1) + HPLC RT: 14.99 min (C8 reverse phase column) : 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64 °C ;Detector: 210 nm)].

[0375] Example 35 [8-(4-acetamidobutyl)-6,7-dihydro-MeBmt]-1-[(S)- (4-Hydroxybutylthio)methyl-Sar]-3-cyclosporine

[0376] (5-Cyanopentyl)triphenylphosphonium bromide [ka]

[0377] 6-Bromohexanenitrile (10.00 g, 56.80 mmol) and triphenyl Phosphine (14.90 g, 56.80 mmol) was dissolved in toluene (100 ml). The mixture was stirred and heated at reflux for 3 days. After cooling to room temperature, most of the toluene was removed by decane. The residue was dried in a vacuum for 6 hours. Hexane (160 ml) was then added and mixed. The mixture was stirred at room temperature over the weekend. The precipitate was filtered off and dried in vacuo to give 21.0 g of crude product. The product was obtained. [Molecular formula: C 24 H 25 NP + ; Exact mass: 358.17; MS (m / z ):358.20(M) + ].

[0378] [8-(3-cyanopropyl)-3-acetyl-MeBmt]-1-cyclosporine [ka]

[0379] In a dry flask, under nitrogen, add (5-cyanopentyl)triphenylphosphonium bromide (14.00 g, 32.04 mmol) and anhydrous tetrahydrofuran (50 ml) were added. The reaction mixture was placed in an ice-water bath and sodium tert-butoxide (4.30 g, 44 The mixture was stirred for 3 hours, and then anhydrous tetrahydrofuran (2.84 mmol) was added. 0 ml) in [(3R,4R)-3-acetyloxy-4-methyl-6-oxo-NM A solution of eNle]-l-cyclosporine (7.90 g, 6.40 mmol) was added. The mixture was stirred at 0°C for a further 3 hours, after which saturated ammonium chloride solution (20 ml) was added. The reaction was quenched by adding acetic acid. Most of the tetrahydrofuran was evaporated under reduced pressure. Ethyl acetate (100 ml) and brine (100 ml) were added and the mixture was separated. The extract was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dichloromethane). Purify with hexane / methanol to obtain 7.19 g of [8-(3-cyanopropyl)-3-(methylisothiazolinone)]. Cetyl-MeBmt]-1-cyclosporin was obtained [molecular formula: C 68 H 118 N 12 O1 3;Accurate mass: 1310.89;MS(m / z):1311.58(M+1) + , 13 33.74(M+Na) + HPLC RT: 17.19 min (C8 reverse phase column: 250 m m; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0380] [8-(3-cyanopropyl)-MeBmt]-1-cyclosporine [ka]

[0381] [8-(3-cyanopropyl)-3-acetyl-MeBmt]-1-cyclosporine ( 7.19 g, 5.48 mmol) was dissolved in methanol (40 ml) and water (20 ml). and tetramethylammonium hydroxide pentahydrate (2.98 g, 16.45 mmol) were added. The mixture was stirred at room temperature for 2 hours. Most of the methanol was then evaporated. Ethyl acetate (100 ml) and brine (100 ml) were added and the mixture was separated. The layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (dic Purification with hexane / methanol gave 4.50 g of pure 8-(3-cyanopropyl) )-MeBmt]-1-cyclosporine was obtained [molecular formula: C 66 H 116 N 12 O 12 ; Exact mass: 1268.88;MS(m / z):1269.62(M+1) + , 1291 .76(M+Na) + HPLC RT: 15.78 min (C8 reverse phase column: 250 mm; Acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64°C; Detector: 21 0 nm)].

[0382] [8-(4-aminobutyl)-6,7-dihydro-MeBmt]-1-cyclosporine [ka]

[0383] [8-(3-cyanopropyl)-MeBmt]- in methanol (60 ml) under nitrogen. A solution of 1-cyclosporine (4.50 g, 3.63 mmol) was diluted with nickel(II) chloride. hydrate (0.43 g, 1.81 mmol) was added. The reaction mixture was placed in an ice-water bath. Sodium borohydride (7.04 g, 181.33 mmol) was added in four batches over a 2-hour period. The mixture was stirred at 0°C for a further 2 hours, after which water (10 ml) was added. The alcohol was evaporated under reduced pressure. Ethyl acetate (120 ml) and saturated sodium bicarbonate solution ( 120 ml) was added and the mixture was separated. The organic layer was washed with brine and The mixture was dried over ice and evaporated under reduced pressure. The residue was dissolved in methanol (60 ml). Aqueous ammonium chloride (10% by weight on carbon, 50 mg) and acetic acid (6 drops) were added. The mixture was heated at room temperature under hydrogen. The mixture was filtered, and the filtrate was evaporated under reduced pressure to give 4.63 g of 8-(4 -aminobutyl)-6,7-dihydro-MeBmt]-1-cyclosporin [molecular Formula:C 66 H 122 N 12 O 12 ; Exact mass: 1274.93; MS(m / z): 12 75.71(M+1) + HPLC RT: 11.95 min (C8 reverse phase column: 250 mm Acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64°C; Detectors: 2 10nm)].

[0384] [8-(4-(tert-butoxycarbonyl)aminobutyl)-6,7-dihydro-M eBmt]-1-cyclosporine [ka]

[0385] [8-(4-aminobutyl)-6,7-dihydro-MeBmt]-1-cyclosporine (4.63 g, 3.63 mmol) was dissolved in tetrahydrofuran (50 ml). Sodium bicarbonate solution (25 ml) and di-tert-butyl dicarbonate (0.87 g, 3.99 mmol) was added. The mixture was stirred at room temperature for 2 hours. The furan was evaporated under reduced pressure. Ethyl acetate (30 ml) and brine (30 ml) were added. The mixture was separated and the organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography (hexane / acetone) to give 3.00 g of pure [8 -(4-(tert-butoxycarbonyl)aminobutyl)-6,7-dihydro-MeB mt]-1-cyclosporin [molecular formula: C 71 H 130 N 12 O 14 ;Exact mass : 1374.98; MS (m / z): 1375.64 (M + 1) + , 1397.85(M +Na) + HPLC RT: 17.81 min (C8 reverse phase column: 250 mm; acetonite ethyl acetate / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)] .

[0386] [8-(4-(tert-butoxycarbonyl)aminobutyl)-6,7-dihydro-M eBmt]-1-[α-methylene-Sar]-3-cyclosporine [ka]

[0387] Diisopropylamine (3. 09 ml, 21.82 mmol) of n-butyllithium (2.65 M, 8.23 ml, 21.82 mmol) was added. The reaction mixture was stirred for 1 hour, and then tetrahydrofuran was added. [8-(4-(tert-butoxycarbonyl)aminobutyl) -6,7-dihydro-MeBmt]-1-cyclosporine (3.00 g, 2.18 mmol) The solution of (I) was added over 10 minutes. The mixture was stirred at -78°C for 2 hours. After bubbling carbon dioxide gas for 30 minutes, the mixture was stirred at -78°C for an additional hour. At this point, the cooling bath was removed and the reaction mixture was allowed to warm to room temperature to expel unreacted carbon dioxide. The mixture was cooled to -78°C and chloromethyl chloroformate (1.93 ml, 21.82 m mol) was added. The mixture was stirred and allowed to warm to room temperature overnight. Brine (10 ml) was added. The reaction was quenched by the addition of ethyl acetate. Most of the tetrahydrofuran was removed under reduced pressure. Chilled water (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was extracted with sulfuric acid. The mixture was dried over magnesium and evaporated under reduced pressure. The residue was purified by chromatography (hexane / aq). Purification by acetone gave 0.40 g of pure [8-(4-(tert-butoxycarbonyl) Nyl)aminobutyl)-6,7-dihydro-MeBmt]-1-[α-methylene-Sar ]-3-cyclosporin [molecular formula: C 72 H 130 N 12 O 14 ;Exact mass: 1 386.98; MS(m / z):1387.61(M+1) + , 1409.80(M+N a) + HPLC RT: 19.01 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0388] [8-(4-(tert-butoxycarbonyl)aminobutyl)-6,7-dihydro-M eBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclohexyl Rosporin [ka]

[0389] [8-(4-(tert-butoxycarbonyl)aminobutyric acid] in methanol (15 ml) (ethyl)-6,7-dihydro-MeBmt]-1-[α-methylene-Sar]-3-cyclo A solution of sporin (0.40 g, 0.29 mmol) in 4-mercapto-1-butanol (0.18 ml, 1.73 mmol) and lithium hydroxide (0.07 g, 2.88 mmol) l) was added. The reaction mixture was stirred at room temperature for 7 hours. Most of the methanol was evaporated under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed. Purify the mixture with hexane / acetone 90 / 10 to 75 / 25 to obtain 200 mg of pure water. [8-(4-(tert-butoxycarbonyl)aminobutyl)-6,7-dihydro- MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- Crossporin was obtained [molecular formula: C 76 H 140 N 12 O 15 S; Exact mass: 1493. 03; MS (m / z): 1493.63 (M + 1) + , 1515.88(M+Na) + ; HPLC RT: 17.65 min (C8 reverse phase column: 250 mm; acetonitrile / water (0 0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0390] [8-(4-acetamidobutyl)-6,7-dihydro-MeBmt]-1-[(S)- (4-Hydroxybutylthio)methyl-Sar]-3-cyclosporine [ka]

[0391] [8-(4-(tert-butoxycarbonyl)aminobutyl)-6,7-dihydro- MeBmt]-1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3- Closporin (0.20 g, 0.16 mmol) was dissolved in dichloromethane (15 ml). The mixture was placed in an ice-water bath, trifluoroacetic acid (5 ml) was added, and the mixture was stirred at 0°C for 1 hour. Another portion of dichloromethane (20 ml) was added. The mixture was washed with brine (30 ml), saturated Wash with sodium bicarbonate solution (30 ml), dry over magnesium sulfate, and Evaporation gave crude [8-(4-aminobutyl)-6,7-dihydro-MeBmt]-1-[ (S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporine was obtained. Molecular formula:C 71 H 32 N 12 O 13 S; Exact mass: 1392.98. MS (m / z): 1393.80(M+1) + HPLC RT: 11.38 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector : 210 nm)]. Crude [8-(4-aminobutyl)-6,7-dihydro-MeBmt]- 1-[(S)-(4-hydroxybutylthio)methyl-Sar]-3-cyclosporine Dissolved in dichloromethane (15 ml), acetic acid (48 mg, 0.80 mmol), HBT U (0.18 g, 0.48 mmol), 1-hydroxybenzotriazole (0.06 g , 0.48 mmol), and pyridine (0.50 ml) were added. The mixture was stirred at room temperature for 2 hours. Then, dichloromethane (30 ml) and brine (50 ml) were added and the mixture was stirred. The dichloromethane layer was dried over magnesium sulfate and evaporated under reduced pressure. was purified by chromatography (dichloromethane / methanol) to give 27 mg of [8- (4-acetamidobutyl)-6,7-dihydro-MeBmt]-1-[(S)-(4- Hydroxybutylthio)methyl-Sar]-3-cyclosporin was obtained [molecular formula: C 73 H 134 N 12 O 14 S; Exact mass: 1434.99; MS(m / z): 1435.6 9(M+1) + , 1457.87(M+Na) + ;HPLC RT:16.01min(C8 Reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature temperature: 64°C; detector: 210 nm)].

[0392] Example 36 [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(S)- (4-hydroxybutylthio)methyl-Sar]-3-[(γ-hydroxy)-N-Me Leu]-4-cyclosporine

[0393] [3-Chloroacetyl-MeBmt]-1-[(γ-hydroxy)-N-MeLeu]- 4-Cyclosporin [ka]

[0394] [(γ-hydroxy)-N-MeL in N,N-dimethylformamide (300 ml)] A solution of [eu]-4-cyclosporine (12.17 g, 1.00 mmol) was added to N,N-dicyclosporine. Methylaminopyridine (0.12 g, 0.10 mmol), anhydrous pyridine (16.00 g , 0.20 mol), and chloroacetic anhydride (72.05 g, 0.54 mol) were added to -35 The mixture was added at 0°C. The reaction mixture was stirred at room temperature overnight. The mixture was poured into 800 ml of ice water and The mixture was stirred until the acetic acid had dissolved. Ethyl acetate (500 ml) was added and the mixture was separated. The ethyl layer was diluted with water (100 ml), saturated sodium bicarbonate solution (100 ml), brine (1 The residue was washed with 100 ml of ethyl acetate, dried over magnesium sulfate and evaporated under reduced pressure. Purification by hexane / acetone gave 9.40 g of pure [3-chloroacetone]. Le-MeBmt]-1-[(γ-hydroxy)-N-MeLeu]-4-cyclosporine The molecular formula: C 64 H 113 ClN 11 O 14 ; Exact mass: 1294.82; MS (m / z): 1295.50 (M+1) + ].

[0395] Kuhnt M. et al., 1996, Microbial Biotransf. ormation Products of Cyclosporin A,J.Ant Sebekia b according to the method described in Bioticics, 49(8), 781 enihana biotransformation to [(γ-hydroxy)-N-MeLeu]-4-cyclohexyl Rosporin was prepared.

[0396] [(3R,4R)-3-chloroacetyloxy-4-methyl-6-oxo-N-MeNl e]-1-[(γ-hydroxy)-N-MeLeu]-4-cyclosporine [ka]

[0397] [3-chloroacetyl-MeBmt]-1-[(γ-hydroxybenzoate) in dioxane (125 ml) [hydroxy]-N-MeLeu-4-cyclosporine (9.50 g, 7.34 mmol) To the solution, add water (100 ml), osmium(VIII) oxide solution (0.4% in water, 35 ml ), and sodium metaperiodate (6.60 g, 30.90 mmol) were added. The reaction mixture was stirred at room temperature for 5 hours. Ethyl acetate (100 ml) and brine (100 ml) were added. ) was added and the mixture was separated. The organic layer was washed with saturated sodium bicarbonate solution, brine, and The residue was purified by chromatography (Hexa Purification with ethanol / acetone gave 5.00 g of pure [(3R,4R)-3-chloroacetyl Oxy-4-methyl-6-oxo-N-MeNle]-1-[(γ-hydroxy)-N- MeLeu]-4-cyclosporin [molecular formula: C 62 H 109 ClN 11 O 15 ; Exact mass: 1282.78;MS(m / z):1283.47(M+1) + ;HPLC RT: 14.74 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0398] [3-chloroacetyl-8-cyanomethyl-MeBmt]-1-[(γ-hydroxy)- N-MeLeu]-4-cyclosporine [ka]

[0399] (3-cyanopropyl)triphenylphosphine in anhydrous tetrahydrofuran (120 ml) under nitrogen. To a solution of bis(2-methyl-2-phenyl-2-methyl-2-propanol) (3.07 g, 7.48 mmol), sodium bis(2-methyl-2-phenyl-2-methyl-2-propanol) was added (Trimethylsilyl)amide (1.00 M in tetrahydrofuran, 14 ml, 14.00 The reaction mixture was stirred at room temperature for 1 hour and cooled to -30°C. (3R,4R)-3-chlorooctadecyloxy-4-methyl ... thyl-6-oxo-N-MeNle]-1-[(γ-hydroxy)-N-MeLeu]- A solution of 4-cyclosporine (4.80 g, 3.74 mmol) was added. The mixture was cooled to -3 The mixture was stirred at 0°C for a further 2 hours, and then saturated ammonium chloride solution (20 ml) was added. The reaction was quenched. Most of the tetrahydrofuran was evaporated under reduced pressure. Ethyl acetate ( Water (100 ml) and brine (100 ml) were added and the mixture was separated. The organic layer was extracted with sulphuric acid malate. The residue was purified by chromatography (dichloromethane / methanol) to give 2.00 g of pure [3-chloroacetyl-8-cyanomethyl Le-MeBmt]-1-[(γ-hydroxy)-N-MeLeu]-4-cyclosporine The molecular formula: C 66 H 114 ClN 12 O 14 ; Exact mass: 1333.83; MS (m / z): 1334.56 (M+1) + ].

[0400] [3-acetyl-8-(2-aminoethyl)-6,7-dihydro-MeBmt]-1-[ (γ-hydroxy)-N-MeLeu]-4-cyclosporine [ka]

[0401] [3-chloroacetyl-8-cyanomethyl-MeBmt] in methanol (100 ml) ]-1-[(γ-hydroxy)-N-MeLeu]-4-cyclosporine (0.85 g, 0.63 mmol) was added to a solution of nickel(II) chloride hexahydrate (0.19 g, 0.81 m mol) was added, followed by sodium borohydride (0.38 g, 10.00 mmol) The mixture was stirred at room temperature for another hour, after which most of the methanol was removed. The alcohol was evaporated under reduced pressure. Ethyl acetate (50 ml) and saturated sodium bicarbonate solution (5 0 ml) was added and the mixture was separated. The organic layer was washed with brine and The residue was purified by chromatography (dichloromethane / methanol ) to give 0.61 g of [3-acetyl-8-(2-aminoethyl)-6,7-dihydrochloride]. Doro-MeBmt]-1-[(γ-hydroxy)-N-MeLeu]-4-cyclosporin The molecular formula: C 66 H 120 N 12 O 14 ; Exact mass: 1304.90; MS( m / z): 1305.68 (M+1) + HPLC RT: 12.80 min (C8 reverse phase column) Tube: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64 °C; detector: 210 nm)].

[0402] [8-(2-acetamidoethyl)-3-acetyl-6,7-dihydro-MeBmt]- 1-[(γ-hydroxy)-N-MeLeu]-4-cyclosporine [ka]

[0403] [3-acetyl-8-(2-aminoethyl)-6,7-dimethyl-2,4-dimethyl-2,5-dimethyl-2,6 ...6-dimethyl-2,6-dimethyl-2,6-dimethyl -dihydro-MeBmt]-1-[(γ-hydroxy)-N-MeLeu]-4-cyclo sporin (0.80 g, 0.61 mmol) and acetic acid (0.11 g, 1.83 mmol) To the solution, diisopropylethylamine (0.25 g, 1.93 mmol) and HATU (0.70 g, 1.83 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, and then with saturated sodium bicarbonate solution, washed with brine, dried over magnesium sulfate, and The residue was purified by chromatography (dichloromethane / methanol) to give 0 0.55g of pure [8-(2-acetamidoethyl)-3-acetyl-6,7-dihydro -MeBmt]-1-[(γ-hydroxy)-N-MeLeu]-4-cyclosporine The obtained molecular formula: C 68 H 122 N 12 O 15 Exact mass: 1346.92; MS(m / z):1347.63(M+1) + HPLC RT: 13.74 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0404] [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(γ- [Droxy]-N-MeLeu]-4-cyclosporine [ka]

[0405] [8-(2-acetamidoethyl)-3-acetyl-6,7-dihydro-MeBmt] -1-[(γ-hydroxy)-N-MeLeu]-4-cyclosporine (0.50 g, 0 Tetramethylammonium hydroxide (0.37 mmol) was dissolved in methanol (50 ml). To the mixture was added methylparaben pentahydrate (0.22 g, 1.21 mmol). The mixture was stirred at room temperature for 2 days. Then, most of the methanol was evaporated. Ethyl acetate (100 ml) and brine were added. (100 ml) was added and the mixture was separated. The organic layer was dried over magnesium sulfate and reduced The residue was purified by chromatography (dichloromethane / methanol) to give , 0.22 g of [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]- 1-[(γ-hydroxy)-N-MeLeu]-4-cyclosporine was obtained [molecular formula: C 66 H 120 N 12 O 14 ;Accurate mass: 1304.90; MS(m / z): 1305. 72(M+1) + HPLC RT: 12.80 min (C8 reverse phase column: 250 mm; acetone) Trinitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210n m)].

[0406] [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[α-methyl [N-Sar]-3-[(γ-hydroxy)-N-MeLeu]-4-cyclosporine [ka]

[0407] Diisopropylamine (2. A solution of 11 ml of n-butyllithium (2.65 M, 5.3 m The reaction mixture was stirred for 1 hour, and then tetrahydrofuran was added. [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt in a run (6 ml) ]-1-[(γ-hydroxy)-N-MeLeu]-4-cyclosporine (1.60 g, A solution of 1.23 mmol) was added over 10 min. The mixture was stirred at -78 °C for 3 h. Carbon dioxide gas was bubbled through the reaction mixture for 30 minutes, and the mixture was then heated at −78° C. for an additional hour. The cooling bath was then removed and the reaction mixture was allowed to warm to room temperature to remove unreacted carbon dioxide. The mixture was cooled to -78°C and chloromethyl chloroformate (1.32 ml , 14.85 mmol) was added. The mixture was stirred and allowed to warm to room temperature overnight. (5 ml) was added to quench the reaction. Most of the tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography. (hexane / acetone) to give 0.50 g of pure [8-(2-acetamidoethyl) yl)-6,7-dihydro-MeBmt]-1-[α-methylene-Sar]-3-[(γ- Hydroxy)-N-MeLeu]-4-cyclosporine was obtained [molecular formula: C67H120 N12O14;Accurate mass: 1316.90;MS(m / z):1317.66(M+1 ) + HPLC RT: 14.32 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0408] [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(S)- (4-hydroxybutylthio)methyl-Sar]-3-[(γ-hydroxy)-N-Me Leu]-4-cyclosporine [ka]

[0409] [8-(2-acetamidoethyl)-6,7-dihydro- in methanol (20 ml) MeBmt]-1-[α-methylene-Sar]-3-[(γ-hydroxy)-N-MeL A solution of eu]-4-cyclosporine (0.30 g, 0.23 mmol) was added to the 4-mercaptoethanol solution. tert-1-butanol (0.14 ml, 1.38 mmol) and lithium hydroxide (54 mg The reaction mixture was stirred at room temperature for 5 hours. Most of the methanol was The alcohol was evaporated under reduced pressure. Ethyl acetate (30 ml) and brine (30 ml) were added. The mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. was purified by chromatography (dichloromethane / methanol) to give 120 mg of pure [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(S) -(4-hydroxybutylthio)methyl-Sar]-3-[(γ-hydroxy)-NM eLeu]-4-cyclosporin [molecular formula: C 71 H 130 N 12 O 15 S;Accurate Mass: 1422.95; MS(m / z): 1423.74(M+1) + ;HPLC R T: 11.98 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trimethylsilane) fluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0410] Example 37 [8-(3-acetamidopropyl)-6,7-dihydro-MeBmt]-1-[(R -(3-hydroxypropyl)thio-Sar]-3-cyclosporine [ka]

[0411] p-Toluenesulfonic acid potassium salt (4.5 g, 19.91 mmol) and 3-bromo -1-propanol (2.8 g, 20.29 mmol) was added to ethanol (50 ml). The reaction mixture was stirred and heated to reflux for 4 hours. Most of the ethanol was evaporated under reduced pressure. The residue was mixed with ethyl acetate (100 ml). The ethyl acetate layer was washed with brine and Drying over magnesium sulfate and evaporation gave 14.79 g of crude S-(3-hydroxypropyl)propionate. Pyr) 4-methylbenzenesulfonothioate was obtained.

[0412] S-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)4-methyl benzenesulfonothioate [ka]

[0413] S-(3-hydroxypropyl) 4-methylbenzenesulfonothioate (7.20g , 29.26 mmol) was dissolved in dichloromethane (100 ml). -2H-pyran (3.00 g, 35.66 mmol) and p-toluenesulfonic acid monohydrate The mixture was stirred at room temperature overnight. The fluoromethane was washed with sodium bicarbonate solution and brine, dried over magnesium sulfate, and Evaporation under reduced pressure. The residue was purified by chromatography to give 6.50 g of pure S-(3 -((tetrahydro-2H-pyran-2-yl)oxy)propyl)4-methylbenzene The sulfonothioate was obtained [molecular formula: C 15 H 22 O4S2; Exact mass: 330.10 MS (m / z): 330.95 (M+1) + .

[0414] [8-(3-aminopropyl)-6,7-dihydro-MeBmt]-1-[(R)-(3 -((tetrahydro-2H-pyran-2-yl)oxy)propyl)thio-Sar]-3 -Cyclosporin [ka]

[0415] Diisopropylamine (2. 32 ml, 16.33 mmol) of n-butyllithium (2.60 M, 6.40 ml, 16.64 mmol) was added. The reaction mixture was stirred for 1 hour, and then tetrahydrofuran was added. [8-(3-(aminopropyl)-6,7-dihydro-MeBm] in furan (15 ml) A solution of t]-1-cyclosporine (1.50 g, 1.11 mmol) was added over 10 min. The mixture was stirred at -78°C for 2 hours. 3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)4-methylbenzene Sulfonothioate (2.70 g, 8.18 mmol) was added and the mixture was incubated at -78 °C. The cooling bath was then removed and the reaction mixture was allowed to warm to room temperature and stirred for an additional 2 hours. The mixture was stirred for 1 hour. Saturated ammonium chloride solution (20 ml) was added to quench the reaction. A portion of the tetrahydrofuran was removed under reduced pressure. Ethyl acetate (50 ml) and brine ( 50 ml) was added and the mixture was separated. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography (dichloromethane / methanol) to give 0 0.38 g of [8-(3-aminopropyl)-6,7-dihydro-MeBmt]-1-[( R)-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)thio-S ar]-3-cyclosporin was obtained [molecular formula: C 73 H 134 N 12 O 14 S; Accurate quality Quantity:1434.99;MS(m / z):1435.70(M+1) + ;HPLC RT: 14.93 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoride) oroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0416] [8-(3-acetamidopropyl)-6,7-dihydro-MeBmt]-1-[(R -(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)thio-Sar ]-3-Cyclosporin [ka]

[0417] [8-(3-aminopropyl)-6,7-dihydro- in dichloromethane (50 ml) MeBmt]-1-[(R)-(3-((tetrahydro-2H-pyran-2-yl)oxy] [Ci)propyl)thio-Sar]-3-cyclosporine (0.50 g, 0.35 mmol) and acetic acid (50 mg, 0.83 mmol), diisopropylethylamine (90 mg, 0.70 mmol), HOBT (85 mg, 0.56 mmol), and HBTU ( The reaction mixture was stirred at room temperature for 2 hours, and then Wash with saturated sodium bicarbonate solution, brine, dry over magnesium sulfate, and The residue was purified by chromatography (dichloromethane / methanol) to give 142 mg of pure [8-(3-acetamidopropyl)-6,7-dihydro-MeBm t]-1-[(R)-(3-((tetrahydro-2H)-pyran-2-yl)oxy)propan-2-yl]oxy]propan-2-yl 3-cyclosporin (molecular formula: C 75 H 135 N 12 O 15 S;Accurate mass:1477.00;MS(m / z):1477.65(M+1) + . HPLC RT: 18.17 min (C8 reverse phase column: 250 mm; acetonitrile / water (0 0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0418] [8-(3-acetamidopropyl)-6,7-dihydro-MeBmt]-1-[(R -(3-hydroxypropyl)thio-Sar]-3-cyclosporine [ka]

[0419] [8-(3-acetamidopropyl)-6,7-dihydro- -MeBmt]-1-[(R)-(3-((tetrahydro-2H-pyran-2-yl)o [0.14g, 0.09mmol]-3-cyclosporine (0.14g, 0.09mmol) To the solution of 100 ml of 100% ethanol (200 mg) was added Dowex-50WX4. The reaction mixture was stirred at room temperature for 4 hours. The mixture was stirred for 1 hour and then filtered. Most of the methanol was evaporated under reduced pressure and the residue was purified by chromatography. HPLC (dichloromethane / methanol) gave 48 mg of pure [8-(3-aminopropyl)- (R)-(3-hydroxybenzoyl)-6,7-dihydro-MeBmt]-1-[( ... [Cyclosporin (3-hydroxypropyl)thio-Sar]-3- 70 H 128 N 12 O 14 S; Exact mass: 1392.94; MS(m / z): 1393.66(M+1 ) + HPLC RT: 15.38 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)].

[0420] Example 36 [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(R)- (4-Hydroxybutyl)thio-Sar]-3-cyclosporine

[0421] 4-(Tosylthio)butylbenzoate [ka]

[0422] p-Toluenethiosulfonic acid potassium salt (20.00 g, 88.36 mmol) and 4 1-Chloro-1-butanol (9.60 g, 88.36 mmol) was dissolved in ethanol (160 m l). The reaction mixture was stirred and heated to reflux for 4 hours. Most of the ethanol was removed under reduced pressure. The residue was mixed with ethyl acetate (100 ml). The ethyl acetate layer was diluted with brine. The resulting mixture was washed with HCl, dried over magnesium sulfate, and evaporated to give 14.79 g of crude S-(4-hydroxybenzoate). (hydroxybutyl) 4-methylbenzenesulfonothioate was obtained.

[0423] S-(4-hydroxybutyl) 4-methylbenzenesulfonothioate (14.79g , 56.90 mmol) was dissolved in acetone (60 ml). Benzoic anhydride (25.74 , 113.80 mmol), 4-(dimethylamino)pyridine (1.39 g, 11.38 1 mmol) and pyridine (30 ml) were added. The mixture was stirred at room temperature overnight. A portion of the acetone and pyridine was evaporated under reduced pressure. Ethyl acetate (100 ml) was added. The ethyl acetate layer was washed with hydrochloric acid solution (1.00 N), brine, saturated sodium bicarbonate solution, and The residue was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. HPLC (hexane / acetone) to give 3.30 g of pure 4-(tosylthio)bromobutane. The obtained methyl benzoate [molecular formula: C 18 H 20 O4S2; Exact mass: 364.08; MS(m / z):364.57(M+1) + HPLC RT: 19.44 min (C8 reverse phase Column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64°C; detector: 210 nm)].

[0424] [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-M eBmt]-1-[(R)-(4-(benzoyloxy)butyl)thio-Sar]-3- Cyclosporine [ka]

[0425] Diisopropylamine (2. 32 ml, 16.33 mmol) of n-butyllithium (2.60 M, 6.28 ml, 16.33 mmol) was added. The reaction mixture was stirred for 1 hour, and then tetrahydrofuran was added. [8-(2-(tert-butoxycarbonyl)aminoethyl) -6,7-dihydro-MeBmt]-1-cyclosporine (2.20 g, 1.63 mmol) The solution of tetrahydrofuran (III) was added over 10 minutes. The mixture was stirred at -78°C for 2 hours. 4-(Tosylthio)butylbenzoate (3.56 g, 9.78 mL) in furan (10 ml) (mmol) was added and the mixture was stirred at -78°C for an additional 2 hours. The cooling bath was then removed. The reaction mixture was then warmed to room temperature and stirred for an additional 2 hours. The reaction was quenched by the addition of tetrahydrofuran. Ethyl acetate (50 ml) and brine (50 ml) were added and the mixture was separated. The layer was dried over magnesium sulfate and evaporated under reduced pressure to give 0.38 g of crude [8-(2-( tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]-1 -[(R)-(4-(benzoyloxy)butyl)thio-Sar]-3-cyclosporine The molecular formula: C 80 H 138 N 12 O 16 S; Exact mass: 1555.01; MS( m / z): 1555.72 (M+1) + HPLC RT: 19.21 min. (C8 reverse phase column) Ram: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 6 4°C; detector: 210 nm)].

[0426] [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-M eBmt]-1-[(R)-(4-hydroxybutyl)thio-Sar]-3-cyclosporin Phosphorus [ka]

[0427] [8-(2-(tert-butoxycarbonyl)aminoethyl)-6, 7-dihydro-MeBmt]-1-[(R)-(4-(benzoyloxy)butyl)thio [-Sar]-3-cyclosporine was dissolved in methanol (10 ml). To the mixture was added ethanol (2.00 g, 83.33 mmol) and water (10 ml). The mixture was stirred at room temperature. Stirred for 2 hours. Most of the methanol was then evaporated under reduced pressure. Ethyl acetate (50 The ethyl acetate layer was diluted with magnesium sulfate and brine (50 ml) was added. The mixture was dried at 77°C and evaporated under reduced pressure. The residue was purified by chromatography (hexane / acetone). 0.38 g of pure [8-(2-(tert-butoxycarbonyl)aminoethyl] (R)-(4-hydroxybutyl)thio -Sar]-3-cyclosporin [molecular formula: C 73 H 134 N 12 O 15 S;Accurate Mass: 1450.98; MS(m / z): 1451.68(M+1) + , 1473.7 9 (M+Na)+; HPLC RT: 17.06 min (C8 reverse phase column: 250 mm; acetone) Trinitrile / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210n m)].

[0428] [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-1-[(R)-(4- Hydroxybutyl)thio-Sar]-3-cyclosporine [ka]

[0429] [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro- MeBmt-1-[(R)-(4-hydroxybutyl)thio-Sar]-3-cyclosporin Phosphorus (0.38 g, 0.26 mmol) was dissolved in dichloromethane (12 ml) and cooled in an ice-water bath. Trifluoroacetic acid (4 ml) was added. The mixture was stirred at 0°C for 3 hours. of dichloromethane (50 ml) was added. The mixture was diluted with brine (50 ml), saturated bicarbonate sodium solution (50 ml), dried over magnesium sulfate and evaporated under reduced pressure. , crude [8-(2-aminoethyl)-6,7-dihydro-MeBmt]1-[(R)-(4 (-hydroxybutyl)thio-Sar]-3-cyclosporin [molecular formula: C 68 H1 26 N 12 O 13 S; Exact mass: 1350.93; MS (m / z): 1351.67( M+1) + HPLC RT: 10.72 min (C8 reverse phase column: 250 mm; acetonite ethyl acetate / water (0.05% trifluoroacetic acid); operating temperature: 64°C; detector: 210 nm)] .

[0430] [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(R)- (4-Hydroxybutyl)thio-Sar]-3-cyclosporine [ka]

[0431] Crude [8-(2-aminoethyl)-6,7-dihydro-MeBmt]-1-[(R)-( 4-Hydroxybutyl)thio-Sar]-3-cyclosporine was dissolved in dichloromethane (15 ml The mixture was dissolved in 100 ml of acetic acid (0.08 g, 1.33 mmol), HBTU (0.30 g, 0. 79 mmol), 1-hydroxybenzotriazole (0.11 g, 0.79 mmol) and diisopropylethylamine (0.50 ml) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was stirred for 1 hour. Most of the solvent was then evaporated under reduced pressure. Ethyl acetate (50 ml) and The ethyl acetate layer was dried over magnesium sulfate and reduced pressure. The residue was purified by chromatography (hexane / acetone) to give 2 5 mg of pure [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]- 1-[(R)-(4-hydroxybutyl)thio-Sar]-3-cyclosporine was obtained [ Molecular formula:C 70 H 129 N 12 O 14 S; Exact mass: 1392.94; MS (m / z) :1393.98(M+1) + , 1415.92(M+Na) + ;HPLC RT:15 0.09 min (C8 reverse phase column: 250 mm; acetonitrile / water (0.05% trifluoromethyl methyl acrylate) acetic acid); operating temperature: 64°C; detector: 210 nm)].

[0432] Example 39 [8-(2-acetamidoethyl)-6,7-dihydro-MeBmt]-1-[(R)- (5-Hydroxypentyl)thio-Sar]-3-cyclosporine

[0433] 5-(Tosylthio)pentyl benzoate [ka]

[0434] In ethanol (100 ml), potassium p-toluenethiosulfonate (11.80 g, 47.71 mmol) and 5-chloro-1-pentanol (5.84 g, 47.71 mmol) The reaction mixture was stirred and heated to reflux overnight. Most of the ethanol was removed under reduced pressure. The residue was mixed with ethyl acetate (100 ml). The ethyl acetate layer was diluted with brine. The resulting mixture was washed with HCl, dried over magnesium sulfate, and evaporated to give 9.16 g of crude S-(5-hydroxybenzoate). 4-Methylbenzenesulfonothioate was obtained.

[0435] S-(5-hydroxypentyl) 4-methylbenzenesulfonothioate (9.16g Benzoic anhydride (15.12 mmol) was dissolved in acetone (60 ml). , 66.83 mmol), 4-(dimethylamino)pyridine (0.82 g, 6.71 mm 10 ml) and pyridine (30 ml) were added. The mixture was stirred at room temperature overnight. Acetone and pyridine were evaporated under reduced pressure. Ethyl acetate (100 ml) was added. The ethyl acetate layer was washed with hydrochloric acid solution (1.00N), brine, saturated sodium bicarbonate solution, and brine. The residue was washed with ethyl acetate, dried over magnesium sulfate and evaporated under reduced pressure. Purification with hexane / acetone gave 7.78 g of pure 5-(tosylthio) pentane. The resulting compound was benzoate [molecular formula: C 19 H 22 O4S2; Exact mass: 378.10; M S(m / z):378.57(M+1) + HPLC RT: 20.24 min (C8 reverse phase column) Ram: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); operating temperature: 6 4°C; detector: 210 nm)].

[0436] [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-M eBmt]-1-[(R)-(5-(benzoyloxy)pentyl)thio-Sar]-3 -Cyclosporin [ka]

[0437] Diisopropylamine (2. 32 ml, 16.33 mmol) of n-butyllithium (2.65 M, 6.16 ml, 16.33 mmol) was added. The reaction mixture was stirred for 1 hour, and then tetrahydrofuran was added. [8-(2-(tert-butoxycarbonyl)aminoethyl) -6,7-dihydro-MeBmt]-1-cyclosporine (2.20 g, 1.63 mmol) The solution of tetrahydrofuran (III) was added over 10 minutes. The mixture was stirred at -78°C for 2 hours. 5-(tosylthio)pentyl benzoate (3.71 g, 9.8 ml) in furan (10 ml) 0 mmol) was added and the mixture was stirred at -78°C for an additional 2 h. The cooling bath was then removed. The reaction mixture was then warmed to room temperature and stirred for an additional 2 hours. The reaction was quenched by adding 100 ml of tetrahydrofuran. Most of the tetrahydrofuran was removed under reduced pressure. Ethyl acetate (80 ml) and brine (80 ml) were added and the mixture was separated. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to give 0.38 g of crude [8-(2- (tert-Butoxycarbonyl)aminoethyl)-6,7-dihydro-MeBmt]- 1-[(R)-(5-(benzoyloxy)pentyl)thio-Sar]-3-cyclosporin Phosphorus obtained [molecular formula: C 81 H 140 N 12 O 16 S; Exact mass: 1569.02; M S(m / z):1569.73(M+1) +HPLC RT: 19.56 min (C8 reverse phase Column: 250 mm; acetonitrile / water (0.05% trifluoroacetic acid); Operating temperature: 64°C; detector: 210 nm)].

[0438] [8-(2-(tert-butoxycarbonyl)aminoethyl)-6,7-dihydro-M eBmt]-1-[(R)-(5-hydroxypentyl)thio-Sar]-3-cyclos Porin [ka]

[0439] [8-(2-(tert-butoxycarbonyl)aminoethyl)-6, 7-Dihydro-MeBmt]-1-[(R)-(5-(benzoyloxy)pentyl)thio O-Sar]-3-cyclosporine was dissolved in methanol (25 ml). Aqueous HCl (1.25 g, 52.08 mmol) and water (25 ml) were added. The mixture was cooled to room temperature. The mixture was stirred at rt for 2 h. Most of the methanol was then evaporated under reduced pressure. The ethyl acetate layer was added with magnesium sulfate (0 ml) and brine (50 ml) and separated. The mixture was dried over ice and evaporated under reduced pressure. The residue was purified by chromatography (hexane / acetone). Purification gave 0.22 g of pure [8-(2-(tert-butoxycarbonyl)amino] (R)-(5-hydroxypentyl)-6,7-dihydro-MeBmt]-1-[(R)-(5-hydroxypentyl) Thio-Sar]-3-cyclosporin was obtained [molecular formula: C 7...

Claims

1. A compound of formula (I) or a pharma- ceutically acceptable salt thereof: 【Chemistry 1】 During the ceremony: x is 0 or 1; R ８ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl aryl, or heteroaryl; ８ is 1 or more R １ is replaced by; , R ８ -R １ is not n-butyl or (E)-but-2-enyl; R ２ is ethyl, 1-hydroxyethyl, isopropyl, or n-propyl; W is O, S, or CH ２ and R ３ is H, alkyl or substituted alkyl, alkenyl or substituted alkenyl, alkoxy, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl, cycloa alkenyl or substituted cycloalkenyl, aryl or substituted aryl, or heteroaryl aryl or substituted heteroaryl; ３ may optionally be one or more R １ Place has been replaced; R １ Each of is independently H, halogen, aryl or substituted aryl, hetero Aryl or substituted heteroaryl, CN, OR Ａ , S.R. Ａ , N.R. Ａ R Ｂ , -NR Ａ ( CH ２ ) Ｏ OR Ｂ 、-N((CH ２ ) Ｏ OR Ａ )((CH ２ ) Ｏ OR Ｂ )-C(=O)R Ａ , -C(=O)OR Ａ , -OC(=O)R Ａ , -OC(=O)(C １ -C ６ Alkyl- R Ｈ )、-OC(=O)(CH ２ ) ｏ OR Ａ 、-C(=O)NR Ａ R Ｂ 、-NR Ａ C(= O)R Ｂ 、-N(C(=O)R Ａ )(C(=O)R Ｂ )、-N(C(=O)(C １ -C ６ Alkyl-R Ｈ ))(C(=O)(C １ -C ６ Alkyl-R Ｈ )), -N(C(=O)( C １ -C ６ Alkyl-R Ｈ )) ２ , -NR Ａ C(=O)(CH ２ ) Ｏ OR Ｂ , -NR Ａ C (=O)(CH ２ ) Ｏ OR Ｂ 、-N(C(=O)(CH ２ ) Ｏ OR Ｂ ) ２ 、-NR Ａ C( =O)(CH ２ ) Ｏ NR Ａ R Ｂ 、-NR Ａ (CH ２ ) Ｏ C(=O)OR Ｂ 、-N((CH ２ ) Ｏ C(=O)OR Ａ )((CH ２ ) Ｏ C(=O)OR Ｂ )、-NR Ａ (CH ２ ) Ｏ C (=O)NR Ａ R Ｂ 、-N((CH ２ ) Ｏ C(=O)NR Ａ R Ｂ )((CH ２ ) Ｏ C(= O)NR Ａ R Ｂ ) 、 -NR Ａ (CH ２ ) Ｏ C(=O)NR Ａ (CH ２ ) Ｏ OR Ｂ 、-C( =O)N((CH ２ ) Ｏ OR Ｂ ) ２ 、-N((CH ２ ) Ｏ C(=O)NR Ａ (CH ２ ) Ｏ OR Ｂ )((CH ２ ) Ｏ C(=O)NR Ａ (CH ２ ) Ｏ OR Ｂ )、-C(=O)NR Ａ ( CH ２ ) Ｏ OR Ｂ 、-C(=O)NR Ａ (CH ２ ) Ｏ OR Ｂ 、-C(=O)NR Ａ (CH ２ ) Ｏ NR Ａ R Ｂ 、-N=CR Ａ -NR Ａ R Ｂ 、-NR Ｂ -C(=NH)-NR Ａ R Ｂ 、 O(CH ２ ) ｍ OR Ａ 、O(CH ２ ) ｍ COOR Ａ 、O(CH ２ ) ｍ CONR Ａ R Ｂ 、O (CH ２ ) ｍ CONR Ａ (CH ２ ) ｍ OR Ａ 、O(CH ２ ) ｍ O(CH ２ ) ｍ OR Ａ 、O (CH ２ ) ｍ NR Ａ R Ｂ 、O(CH ２ ) ｍ O(CH ２ ) ｍ NR Ａ R Ｂ、 NR Ｃ (CH ２ ) ｍ NR Ａ R Ｂ 、NR Ｃ (CH) ２ ) ｍ NR Ｃ (CH) ２ ) ｍ NR Ａ R Ｂ、 【Chemistry 2】 wherein the aryl or heteroaryl is selected from the group consisting of halogen, hydroxy, (C １ - C ６ ) alkyl, (CH ２ ) ｐ OR Ａ , (CH ２ ) ｐ N.R. Ａ R Ｂ , (CH ２ ) ｐ C(=O ) N.R. Ａ R Ｂ , and (CH ２ ) ｐ C(=O)OR Ａ The same or different selected from the group consisting of Optionally substituted with one or more groups which may be R ７ teeth, 【Chemistry 3】 and Each R ５ are independently H, alkyl or substituted alkyl, alkenyl or substituted alkoxy. alkynyl, alkynyl or substituted alkynyl, cycloalkyl or substituted cycloalkyl aryl, cycloalkenyl or substituted cycloalkenyl, or aryl or substituted aryl It is: R Ａ and R Ｂ are each independently: hydrogen; one or more groups R Ｄ (C １ -C ６ ) alkyl; (C ２ -C ６ ) alkenyl or (C ２ -C ６ ) alkynyl; (C １ -C ６ ) optionally substituted with alkyl (C ３ -C ７ ) Cycloalkyl ； Halogen, -O(C １ -C ６ ) alkyl, -C(=O)O(C １ -C ６ ) alkyl, amino, alkylamino, and dialkylamino, which may be the same or different; phenyl or benzyl optionally substituted by 1 to 5 groups; Alternatively, 5 or 6 ring atoms and the same or different alkyl groups selected from nitrogen, sulfur, and oxygen. is a complex which may be saturated or unsaturated and contains 1 to 3 heteroatoms which may be different; elementary cyclic ring; Or, R Ａ and R Ｂ are, together with the nitrogen atom to which they are attached, 3-7 forming a saturated or unsaturated heterocyclic ring containing 10 ring atoms, the ring being free of nitrogen, oxygen, and and sulfur; one or more, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; optionally substituted with up to 4 groups; R Ｃ are each independently hydrogen or (C １ -C ６ ) alkyl; R Ｄ are each independently a halogen, a hydroxyl, an O(C １ -C ４ ) alkyl, C(= O) (C １ -C ４ ) alkyl, C(=O)O(C １ -C ４ ) alkyl, or 【Chemistry 4】 (Wherein, Z is CH ２ ,O,S,NH,NCH ３ , NEt, N-isopropyl, N-isopropyl N-Neopentyl, N-CH ２ CH ２ OH, or N-CH ２ CH ２ I am OMe ) and R Ｇ are each independently R Ａ , OR Ａ , S.R. Ａ , N.R. Ａ R Ｂ , -(CH ２ ) ｏ R Ａ , -(CH ２ ) ｏ C(=O)OR Ａ 、-(CH ２ ) ｏ C(=O)NR Ａ R Ｂ 、C(=O)O R Ａ 、OC(=O)R Ａ 、NR Ａ C(=O)R Ｂ 、NR Ａ C(=O)(CH ２ ) Ｏ OR Ａ 、C(=O)O(CH ２ ) Ｏ OR Ａ 、C(=O)OR Ｂ 、C(=O)NR Ａ R Ｂ 、C(= O)NR Ａ (CH ２ ) Ｏ OR Ｂ 、C(=O)N((CH ２ ) Ｏ OR Ａ )((CH ２ ) Ｏ O R Ｂ )、C(=O)N((CH ２ ) Ｏ C(=O)OR Ａ )((CH ２ ) Ｏ C(=O)OR Ｂ )、C(=O)N((CH ２ ) Ｏ NR Ａ R Ｂ )((CH ２ ) Ｏ NR Ａ R Ｂ )、C(=O )N((CH ２ ) Ｏ OC(=O)(CH ２ ) Ｏ OR Ａ )((CH ２ ) Ｏ OC(=O)(C H ２ ) Ｏ OR Ｂ )、C(=O)N((CH ２ ) Ｏ NR Ａ C(=O)(CH ２ ) Ｏ OR Ｂ ) ((CH ２ ) Ｏ NR Ａ C(=O)(CH ２ ) Ｏ OR Ｂ )、C(=O)NR Ａ (CH ２ ) Ｏ NR Ａ R Ｂ 、 【Chemistry 5】 C(=O)NR Ａ (CH ２ ) Ｏ OC(=O)R Ｂ 、C(=O)NR Ａ (CH ２ ) Ｏ C(= O)OR Ｂ 、C(=O)NR Ａ (CH ２ ) Ｏ C(=O)NR Ａ R Ｂ 、C(=O)NR Ａ ( CH ２ ) Ｏ OC(=O)(CH ２ ) Ｏ OR Ｂ or 【Chemistry 6】 and R Ｈ are each independently a halogen; Each Z' is independently CH ２ ,O.S.,N.R. Ａ , N(CH ２ ) ｏ OR Ａ , N(CH ２ ) ｏ NR Ａ R Ｂ 、N(CH ２ ) ｏ COOR Ａ 、N(CH ２ ) ｏ OC(=O)R Ａ 、N( CH ２ ) ｏ C.O.N.R. Ａ R Ｂ , N(CH ２ ) ｏ N.R. Ａ C(=O)R Ｂ , or N(CH ２ ) ｏ OC(=O)(CH ２ ) ｏ OR Ａ and Each o is independently 0, 1, 2, 3, 4, 5, or 6; Each p is independently an integer of 0, 1, 2, 3, 4, or 5; and Each m is independently an integer of 1, 2, 3, 4, or 5.

2. R ８ (C １ -C １２ ) alkyl, (C ２ -C １２ ) alkenyl, (C ２ -C １２ ) Alkynyl, (C ３ -C １２ ) cycloalkyl, or phenyl or CH ２ -Phenyl (Optionally, halogen, hydroxy, (C １ -C ６ ) alkyl 2. The compound of claim 1, wherein the compound is:

3. R ８ But (C １ -C １４ ) alkyl or (C １ -C １４ ) alkenyl. is a compound according to 2.

4. R ８ But (C １ -C ６ ) straight chain alkyl or (C ７ -C １２ ) a straight chain alkyl; 4. The compound according to any one of claims 1 to 3.

5. R ８ - (CH ２ ) ３－１１ - alkyl chain according to any one of claims 1 to 4 Compound.

6. R ２ The compound according to any one of claims 1 to 5, wherein is ethyl.

7. R ７ but, 【Chemistry 7】 The compound according to any one of claims 1 to 6,

8. The compound according to any one of claims 1 to 7, wherein W is O.

9. The compound according to any one of claims 1 to 8, wherein W is S.

10. R ３ is H, (C １ -C １２ ) alkyl, (C ２ -C １２ ) alkenyl, (C ２ -C １ ２ ) alkynyl, (C ３ -C １２ ) cycloalkyl, or phenyl or CH ２ -Fe Nyl (optionally halogen, hydroxy, (C １ -C ６ ) alkyl 10. The compound according to claim 1, wherein the aryl group is substituted with one or more groups which may be the same or different.

2. The compound according to claim 1 .

11. Claims having the structure of formula (II) or (III) or a pharma- ceutically acceptable salt thereof Compound according to claim 1: 【Chemistry 8】 During the ceremony: Y is H or OR ５ where R ５ is H or methyl; m' and n' are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12; R Ａ’ and R Ｂ’ are each independently: hydrogen; one or more groups R Ｄ (C １ -C ６ ) alkyl; (C ２ -C ６ ) alkenyl or (C ２ -C ６ ) alkynyl; (C １ -C ６ ) optionally substituted with alkyl (C ３ -C ７ ) Cycloalkyl ； Halogen, -O(C １ -C ６ ) alkyl, -C(=O)O(C １ -C ６ ) alkyl, amino, alkylamino, and dialkylamino, which may be the same or different; phenyl or benzyl optionally substituted by 1 to 5 groups; Or, R Ａ’ and R Ｂ’ together with the nitrogen atom to which they are attached, Forms a saturated or unsaturated heterocyclic ring containing up to seven ring atoms, which ring is preferably formed from nitrogen, oxygen, or the like. and sulfur; one or more, which may be the same or different, selected from the group consisting of alkyl, phenyl, and benzyl; is optionally substituted with up to 4 groups; and R Ｄ Each of is independently selected from halogen, hydroxy, O(C １ -C ４ ) alkyl, C(=O)(C １ -C ４ ) alkyl, C(=O)O(C １ -C ４ ) alkyl, or 【Chemistry 9】 wherein Z is CH ２ ,O,S,NH,NCH ３ , NEt, N-isopropyl, N -isopropyl, N-neopentyl, N-CH ２ CH ２ OH, or N-CH ２ CH ２ O.M. e.

12. The compound of claim 11 having the structure of formula (IV) or (V): 【Chemistry 10】 In the formula, R １’ each independently represents H, halogen, aryl or substituted aryl, Heteroaryl or substituted heteroaryl, OR Ａ , S.R. Ａ , N.R. Ａ R Ｂ , -NR Ａ (C H ２ ) Ｏ OR Ｂ 、-N((CH ２ ) Ｏ OR Ａ )((CH ２ ) Ｏ OR Ｂ )-C(=O)R Ａ , -C(=O)OR Ａ , -OC(=O)R Ａ , -OC(=O)(C １ -C ６ Alkyl-R Ｈ )、-OC(=O)(CH ２ ) ｏ OR Ａ 、-C(=O)NR Ａ R Ｂ 、-NR Ａ C(=O )R Ｂ 、-N(C(=O)R Ａ )(C(=O)R Ｂ )、-N(C(=O)(C １ -C ６ ア Rukill-R Ｈ ))(C(=O)(C １ -C ６ Alkyl-R Ｈ )), -N(C(=O)(C １ -C ６ Alkyl-R Ｈ )) ２ , -NR Ａ C(=O)(CH ２ ) Ｏ OR Ｂ , -NR Ａ C ( =O)(CH ２ ) Ｏ OR Ｂ 、-N(C(=O)(CH ２ ) Ｏ OR Ｂ ) ２ 、-NR Ａ C(= O)(CH ２ ) Ｏ NR Ａ R Ｂ 、-NR Ａ (CH ２ ) Ｏ C(=O)OR Ｂ 、-N((CH ２ ) Ｏ C(=O)OR Ａ )((CH ２ ) Ｏ C(=O)OR Ｂ )、-NR Ａ (CH ２ ) Ｏ C( =O)NR Ａ R Ｂ 、-N((CH ２ ) Ｏ C(=O)NR Ａ R Ｂ )((CH ２ ) Ｏ C(=O )NR Ａ R Ｂ )、-NR Ａ (CH ２ ) Ｏ C(=O)NR Ａ (CH ２ ) Ｏ OR Ｂ 、-C(= O)N((CH ２ ) Ｏ OR Ｂ ) ２ 、-N((CH ２ ) Ｏ C(=O)NR Ａ (CH ２ ) Ｏ O R Ｂ )((CH ２ ) Ｏ C(=O)NR Ａ (CH ２ ) Ｏ OR Ｂ )、-C(=O)NR Ａ (C H ２ ) Ｏ OR Ｂ 、-C(=O)NR Ａ (CH ２ ) Ｏ OR Ｂ 、-C(=O)NR Ａ (CH ２ ) Ｏ NR Ａ R Ｂ 、-N=CR Ａ -NR Ａ R Ｂ 、-NR Ｂ -C(=NH)-NR Ａ R Ｂ 、O (CH ２ ) ｍ OR Ａ 、O(CH ２ ) ｍ COOR Ａ 、O(CH ２ ) ｍ CONR Ａ R Ｂ 、O( CH ２ ) ｍ CONR Ａ (CH ２ ) ｍ OR Ａ 、O(CH ２ ) ｍ O(CH ２ ) ｍ OR Ａ 、O( CH ２ ) ｍ NR Ａ R Ｂ 、O(CH ２ ) ｍ O(CH ２ ) ｍ NR Ａ R Ｂ 、NR Ｃ (CH ２ ) ｍ NR Ａ R Ｂ 、NR Ｃ (CH) ２ ) ｍ NR Ｃ (CH) ２ ) ｍ NR Ａ R Ｂ 、 【Chemistry 11】 wherein the aryl or heteroaryl is selected from the group consisting of halogen, hydroxy, (C １ - C ６ ) alkyl, (CH ２ ) ｐ OR Ａ , (CH ２ ) ｐ N.R. Ａ R Ｂ , (CH ２ ) ｐ C(=O ) N.R. Ａ R Ｂ , and (CH ２ ) ｐ C(=O)OR Ａ The same or different selected from the group consisting of The alkyl group is optionally substituted with one or more groups which may be substituted.

13. R １’ Is OR Ａ , OCOCH ２ OR Ａ , S.R. Ａ , N.H.R. Ａ , N(R Ａ ) ２ , or N.H.C. OCH ２ OR Ａ 13. The compound of claim 12, wherein

14. R １’ は、OAc、OCOCH ２ Cl、OCOCH ２ CH ３ 、OCOCHMe ２ 、OC OCMe ３ 、OCOCH=CH ２ 、NHCH ２ CH ２ OH、NHCH ２ CH ２ OMe、N (CH ２ CH ２ OH) ２ 、N(CH ２ CH ２ OMe) ２ 、NHCH ２ CHMe ２ 、NHC H ２ CMe ２ ... ２ COOH, NHCH ２ COOCH ３ NMeCH ２ COOH、NMeCH ２ COOCH ３ 、NHCH ２ P. ２ 、NHCH ２ CONHMe 、NXCH ２ ANNMe ２ 、NXCH ２ [NNHCH ２ CH ２ OH、NHCH ２ CON ヨ ２ ヨ ２ |||、|||||| ２ .. ２ 、!|||| ２ [||||||||||| ２ CONMe ２ N(CH ２ COOH) ２ N(CH ２ P. ２ ) ２ N(CH ２ CO NHMe) ２ 、N(CH ２ CONMe ２ ) ２ 、N(CH ２ CONHCH ２ CH ２ OH) ２ 、N(CH ２ [NNHCH ２ CH ２ OMe) ２ 、NXCOCH ２ C-、NHCOCH ２ C H ３ I love you ２ I love you ３ I love you ２ N(COCH ２ Cl) ２ 、N(COCH ２ CH ３ ) ２ 、N(COCHMe ２ ) ２ 、N(COCMe ３ ) ２ , or N(COCH=CH ２ ) ２ 13. The compound of claim 12, wherein

15. R Ａ’ and R Ｂ’ each independently represents H, Me, Et, n-propyl, or isopropyl , isobutyl, neopentyl, cyclopentyl, cyclohexyl, CH ２ CH ２ O.H., C. H ２ CH ２ OMe、 【Chemistry 12】 where Z is CH ２ ,O,S,NH,NCH ３ , NEt, N-isopropyl, N- Isopropyl, N-neopentyl, N-CH ２ CH ２ OH or N-CH ２ CH ２ OMe 13. The compound according to claim 11 or 12,

16. R １ -NR Ａ C(=O)R Ｂ and R １’ OR Ａ The compound according to claim 12, Compound.

17. R １ -NHC(=O)R Ｂ and R １’ The compound of claim 16, wherein is OH. 。

18. The compound of claim 1 having the structure of formula (VI): 【Chemistry 13】 During the ceremony, W is CH ２ , O, or S; Y is H or OR ５ where R ５ is H or methyl; m' and n' are each independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 1. 0; and R １ each independently represents H, halogen, aryl or substituted aryl, heteroaryl, aryl or substituted heteroaryl, OR Ａ , S.R. Ａ , N.R. Ａ R Ｂ , -C(=O)R Ａ , - C(=O)OR Ａ 、-C(=O)NR Ａ R Ｂ 、-NR Ａ C(=O)R Ｂ 、-NR Ａ C(= O)(CH ２ ) Ｏ R Ｂ 、-NR Ａ C(=O)(CH ２ ) Ｏ OR Ｂ 、-NR Ａ C(=O)( CH ２ ) Ｏ N.R. Ａ R Ｂ or -C(=O)NR Ａ (CH ２ ) Ｏ R Ｂ It is.

19. R １ はH、OR Ａ 、SR Ａ 、NR Ａ R Ｂ 、-C(=O)R Ａ 、-C(=O)OR Ａ 、- C(=O)NR Ａ R Ｂ 、-NR Ａ C(=O)R Ｂ 、-NR Ａ C(=O)(CH ２ ) Ｏ R Ｂ 、-NR Ａ C(=O)(CH ２ ) Ｏ OR Ｂ 、-NR Ａ C(=O)(CH ２ ) Ｏ NR Ａ R Ｂ , -C(=O)NR Ａ (CH ２ ) Ｏ R Ｂ , -C(=O)NR Ａ (CH ２ ) Ｏ OR Ｂ , and -C(=O)NR Ａ (CH ２ ) Ｏ N.R. Ａ R Ｂ The compound according to claim 1 to 18 is selected from the group consisting of 2. The compound according to claim 1 .

20. R １ は、O(CH ２ ) ｍ OR Ａ 、O(CH ２ ) ｍ O(CH ２ ) ｍ OR Ａ 、O(CH ２ ) ｍ NR Ａ R Ｂ 、O(CH ２ ) ｍ O(CH ２ ) ｍ NR Ａ R Ｂ 、NR Ｃ (CH ２ ) ｍ NR Ａ R Ｂ , and N.R. Ｃ (CH ２ ) ｍ N.R. Ｃ (CH ２ ) ｍ N.R. Ａ R Ｂ Selected from the group consisting of: The compound according to any one of claims 1 to 19.

21. R １ Is OR Ａ , S.R. Ａ , N.R. Ａ R Ｂ , -C(=O)R Ａ , -C(=O)OR Ａ , and- C(=O)NR Ａ R Ｂ The compound according to any one of claims 1 to 20, selected from the group consisting of Compound.

22. R １ is OH, OMe, OEt, O-isopropyl, O-isobutyl, O-neopentyl O-cyclopentyl, O-cyclohexyl, SH, SMe, S-isopropyl, S- isobutyl, S-neopentyl, S-cyclopentyl, S-cyclohexyl, 【Chemistry 14】 The compound according to any one of claims 1 to 21,

23. R １ teeth, 【Chemistry 15】 where Z is CH ２ ,O,S,NH,NCH ３ , NEt, N-isopropyl, N -isopropyl, N-neopentyl, N-CH ２ CH ２ OH or N-CH ２ CH ２ O.M. The compound according to any one of claims 1 to 22, wherein

24. R １ is H, OH, OMe, OEt, O-isopropyl, O-isobutyl, O-neopentyl O-isopentyl, O-cyclohexyl, OCH ２ CH ２ O.H., O.C.H. ２ CH ２ OCH ３ ,OCH ２ COH、CH ２ COCH ３ ,OCH ２ CONH ２ ,OCH ２ C ONHM%、OCH ２ CONM% ２ ,OCH ２ CONHCH ２ CH ２ OH、OCH ２ CO NHCH ２ CH ２ OMe、OAc、OOCCH ２ Cl、OOCCH ２ OR Ａ 、OOCCH ２ CH ３ , OOCCHMe ２ , OOCCMe ３ , and OC(=O)CCH=CH ２ From The compound according to any one of claims 1 to 23, selected from the group consisting of:

25. R １ is selected from the group consisting of: Compound: 【Chemistry 16】 【change】

26. R １ SH, SMe, SEt, S-isopropyl, S-isobutyl, S-neopentyl , O-cyclopentyl, or S-cyclohexyl. The compound according to claim 1,

27. <h2 style=";text-align:left;direction:ltr">1<h2 style=";text-align:left;direction:ltr"> １ <h2 style=";text-align:left;direction:ltr">は、NH<h2 style=";text-align:left;direction:ltr"> ２ <h2 style=";text-align:left;direction:ltr"> 、NHCH<h2 style=";text-align:left;direction:ltr"> ３ <h2 style=";text-align:left;direction:ltr"> 、NHCH<h2 style=";text-align:left;direction:ltr"> ２ <h2 style=";text-align:left;direction:ltr"> CH<h2 style=";text-align:left;direction:ltr"> ３ <h2 style=";text-align:left;direction:ltr"> 、NHCH<h2 style=";text-align:left;direction:ltr"> ２ <h2 style=";text-align:left;direction:ltr"> CHOH、NHCH<h2 style=";text-align:left;direction:ltr"> ２ <h2 style=";text-align:left;direction:ltr"> C H ２ OMe、NMe ２ 、NEt ２ 、NHCH ２ CHMe ２ 、NHCH ２ CMe ３ 、NHA c、NHCH ２ COOH、NHCH ２ COOCH ３ 、NMeCH ２ COOH、NMeCH ２ COCH ３ 、NHCH ２ အေား ２ 、NHCH ２ CONNHMe、NHCH ２ CONM e ２ 、NXCH ２ [NNHCH ２ CH ２ OH、NHCH ２ [NNHCH ２ CH ２ OMe、 NMeCH ２ CONH ２ 、NMeCH ２ CONHMe、NMeCH ２ CONMe ２ 、N( CH ２ COOH) ２ N(CH ２ P. ２ ) ２ N(CH ２ (Yes) ２ N(C H ２ CONMe ２ ) ２ N(CH ２ P.S. ２ CH ２ OH) ２ N(CH ２ P. CH ２ CH ２ OMe) ２ 、NHCOCH ２ Cl、NHCOCH ２ OR Ａ 、NHCOCH ２ CH ３ 、NHAAMMe ２ 、NHACMe ３ 、NHAICH=CH ２ 、N(RED ２ Cl) ２ 、N(COCH ２ OR Ａ ) ２ 、N(COCH ２ CH ３ ) ２ 、N(COCHMe ２ ) ２ , N(COCMe ３ ) ２ , and N(COCH=CH ２ ) ２ Selected from the group consisting of The compound according to any one of claims 1 to 26.

28. R １ teeth 【Chemistry 17】 wherein Z is CH ２ , O, S, NH, NMe, NEt, N-isopropyl, N- ネオペンチル、N-CH ２ CH ２ OH、NCH ２ CH ２ OCH ３ 、NCH ２ CH ２ OCH ３ 、NCH ２ COOH, NCH ２ COOMe、N-CH ２ P. ２ 、NCH ２ P. Me, or NCH ２ CONMe ２ The compound according to any one of claims 1 to 27, 。

29. R １ The compound according to any one of claims 1 to 28, wherein is selected from the group consisting of: thing: 【Chemistry 18】

30. R １ The compound according to any one of claims 1 to 29, wherein is selected from the group consisting of: thing: 【Chemistry 19】 In the formula, each Z' is independently CH ２ ,O.S.,N.R. Ａ , N(CH ２ ) ｏ OR Ａ , N (CH ２ ) ｏ NR Ａ R Ｂ 、N(CH ２ ) ｏ COOR Ａ 、N(CH ２ ) ｏ OC(=O)R Ａ , N(CH ２ ) ｏ C.O.N.R. Ａ R Ｂ , N(CH ２ ) ｏ N.R. Ａ C(=O)R Ｂ , or N(CH ２ ) ｏ OC(=O)(CH ２ ) ｏ It's ORA.

31. R １ -COOH, -COOMe, -COOEt, -CONH ２ ,-CONHMe,- CONM% ２ ,-CONFIDENCE,-CONFIDENCE ２ ,-COD ２ H ２ OH、-ES NHCH ２ CH ２ OMe、-CON(CH ２ CH ２ OH) ２ 、-CON(CH ２ CH ２ O Me) ２ , or -CONMe ２ The compound according to any one of claims 1 to 30,

32. R １ The compound according to any one of claims 1 to 31, wherein is selected from the group consisting of: thing: 【Chemistry 20】 【change】 【change】 In the formula, Z is CH ２ ,O,S,NH,NCH ３ , NEt, N-isopropyl, N-iso Propyl, N-neopentyl, N-CH ２ CH ２ OH, or N-CH ２ CH ２ OMe de do.

33. R １ but, 【Chemistry 21】 The compound according to any one of claims 1 to 32,

34. ( Ｇ はH、﯁|| ２ 、\\e、\\c、!\e ２ 、!44 ２ 、! H.H.H. ２ C.M.E. ３ 34. The compound of claim 33, wherein

35. R １ The compound according to any one of claims 1 to 34, wherein is selected from the group consisting of: thing: 【Chemical 22】

36. R １ Is OR Ａ , OCOCH ２ OR Ａ , S.R. Ａ , N.H.R. Ａ , N(R Ａ ) ２ , or NHCO CH ２ OR Ａ The compound according to any one of claims 1 to 35,

37. R １ は、OAc、OCOCH ２ Cl、OCOCH ２ CH ３ 、OCOCHMe ２ 、OCO CMe ３ 、OCOCH=CH ２ 、NHCH ２ CH ２ OH、NHCH ２ CH ２ OMe、N( CH ２ CH ２ OH) ２ 、N(CH ２ CH ２ OMe) ２ 、NHCH ２ CHMe ２ 、NHCH ２ CMe ２ ... ２ COOH, NHCH ２ COOCH ３ NMeCH ２ C •||、||||| ２ .. ３ 、\CH ２ .. ２ 、\CH ２ |||||、 NXCH ２ ANNMe ２ 、NXCH ２ [NNHCH ２ CH ２ OH、NHCH ２ [NHC _ ２ ヨ ２ |||、|||||| ２ .. ２ 、!|||| ２ [||||||||||| ２ CONMe ２ N(CH ２ COOH) ２ N(CH ２ P. ２ ) ２ N(CH ２ CON HMe) ２ 、N(CH ２ CONMe ２ ) ２ 、N(CH ２ CONHCH ２ CH ２ OH) ２ 、 N (CH ２ [NNHCH ２ CH ２ OMe) ２ 、NXCOCH ２ C-、NHCOCH ２ CH ３ I love you ２ I love you ３ I love you ２ N(COCH ２ C l) ２ 、N(COCH ２ CH ３ ) ２ 、N(COCHMe ２ ) ２ 、N(COCMe ３ ) ２ 、 or N(COCH=CH ２ ) ２ The compound according to any one of claims 1 to 36,

38. R １ is halogen, hydroxy, (C １ -C ６ ) alkyl, (C ３ -C ７ ) Cycloal キル、″R Ａ 、(32 ２ ) ) ｐ 92 Ａ 、(32 ２ ) ) ｐ 82 Ａ 2 Ｂ 、(32 ２ ) ) ｐ 3(49) R Ａ , (CH ２ ) ｐ C(=O)NR Ａ R Ｂ , and (CH ２ ) ｐ C(=O)OR Ａ Choose from Aryl optionally substituted with one or more groups which may be the same or different heteroaryl; where p is 0, 1, 2, 3, 4, 5, 6; and R Ａ and R Ｂ are each independently: hydrogen; one or more groups R Ｄ (C １ - C ６ ) alkyl; (C ２ -C ６ ) alkenyl or (C ２ -C ６ ) alkynyl; (C １ -C ６ ) optionally substituted with alkyl (C ３ -C ７ ) cycloalkyl; Halogen, -O(C １ -C ６ ) alkyl, -C(=O)O(C １ -C ６ ) alkyl, and the same or different, selected from amino, alkylamino and dialkylamino. phenyl optionally substituted by 1 to 5 groups; Alternatively, 5 or 6 ring atoms and the same or different ring atoms selected from nitrogen, sulfur, and oxygen Heterocyclic rings, which may be saturated or unsaturated, containing 1 to 3 heteroatoms, which may be different. is a cyclic ring; Or, R Ａ and R Ｂ are, together with the nitrogen atom to which they are attached, 3-7 forming a saturated or unsaturated heterocyclic ring containing 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, Sulfur may optionally contain another heteroatom selected from the group consisting of alkyl, phenyl, and benzyl, may be substituted by R Ｄ are each independently a halogen, a hydroxyl, an O(C １ -C ４ ) alkyl, C(= O) (C １ -C ４ ) alkyl, C(=O)O(C １ -C ４ ) alkyl, or 【Chemistry 23】 wherein Z is CH ２ ,O,S,NH,NCH ３ , NEt, N-isopropyl, N -isopropyl, N-neopentyl, N-CH ２ CH ２ OH, or N-CH ２ CH ２ O.M. The compound of claim 1, wherein:

39. R １ teeth 【Chemistry 24】 and In the formula, Rx is H, (C １ -C ６ ) alkyl or (C ３ -C ７ ) cycloalkyl Ry is H, (C １ -C ６ ) alkyl, (C ３ -C ７ ) cycloalkyl, OR Ａ , S.R. Ａ , NR Ａ R Ｂ , -C(=O)R Ａ , -C(=O)OR Ａ , or -C(=O)NR Ａ R Ｂ and t is 1, 2, 3, or 4.

40. Rx is H or Me; and Ry is -C(=O)OR Ａ Or -C(=O)NR Ａ R Ｂ 40. The compound of claim 39, wherein:

41. R １ teeth, 【Chemistry 25】 where Z is CH ２ ,O,S,NH,NCH ３ , NEt, N-isopropyl, N -isopropyl, N-neopentyl, N-CH ２ CH ２ OH, or N-CH ２ CH ２ O.M.

41. The compound of claim 40, wherein:

42. R Ａ and R Ｂ are each independently H, Me, Et, n-propyl, isopropyl, or i-propyl. isobutyl, neopentyl, cyclopentyl, cyclohexyl, CH ２ CH ２ OH, CH ２ CH ２ OMe、 【Chemistry 26】 where Z is CH ２ ,O,S,NH,NCH ３ , NEt, N-isopropyl, N- Isopropyl, N-neopentyl, N-CH ２ CH ２ OH, or N-CH ２ CH ２ OMe The compound according to any one of claims 1 to 41,

43. R Ａ is H, Me, Et, n-propyl, isopropyl, n-butyl, or isobutyl; 43. The compound of claim 42.

44. R Ａ and R Ｂ are each independently H, Me, Et, isopropyl, isobutyl, cyclohexane 43. The compound of claim 42, which is cyclopentyl or cyclohexyl.

45. R Ａ and R Ｂ Each of the groups is independently H, (C １ -C ６ ) alkyl, phenyl, CH ２ -phenyl, (C １ -C ６ ) alkyl-OH, (CH ２ ) ｐ O (CH ２ ) ｍ OH, or (CH ２ ) ｐ O (CH ２ ) ｍ O (CH ２ ) ｍ OH, (C １ -C ６ ) alkylO(C １ -C ４ ) alkyl, (CH ２ ) ｐ O (CH ２ ) ｍ O (C １ -C ４ ) alkyl, or (CH ２ ) ｐ O (CH ２ ) ｍ O (CH ２ ) ｍ O (C １ -C ４ ) alkyl according to any one of claims 1 to 44. The compound according to any one of claims 1 to 5.

46. R Ａ and R Ｂ each independently represents H or (C １ -C ６ ) alkyl, claim 1 The compound according to any one of claims 1 to 45.

47. R Ａ and R Ｂ are each independently H, Me, Et, isopropyl, isobutyl, cyclohexane 47. The compound of claim 46, which is cyclopentyl or cyclohexyl.

48. R Ａ and R Ｂ together with the nitrogen atom to which they are attached, 【Chemistry 27】 wherein R Ｃ are H, Me, Et, n-Pr, i-Pr, n-Bu、i-Bu、t-Bu、CH ２ CMe ３ 、Ph、CH ２ P.S. ２ CH ２ OH , or C.H. ２ CH ２ O (C １ -C ４ ) alkyl, The compound described.

49. The compound according to claim 1, having a structure selected from the group consisting of the following structures: Pharmaceutically acceptable salts: 【Chemistry 28】 【change】 【change】 【change】 where x is 0 or 1; m is 2, 3, 4, 5, 6, 7, or 8; and Y is H, O H, or OMe; W is O or S; and each R ａ are independently the parts shown in Table 1 minutes; 【Table 1】 【change】 【change】 【change】 【change】 【change】 【change】 【change】

50. 50. The compound of any one of claims 1 to 49, wherein x is 0.

51. 50. The compound of any one of claims 1 to 49, wherein x is 1.

52. At least one compound according to any one of claims 1 to 51 and a pharma- ceutically acceptable and a carrier or diluent.

53. 1. A method for treating or preventing a viral infection in a mammalian species in need thereof, comprising: a therapeutically effective amount of at least one compound according to any one of claims 1 to 51 administering to said mammalian species.

54. 1. A method for treating or preventing Hepatitis C viral infection in a mammalian species in need thereof, comprising: The method comprises administering to a subject a therapeutically effective amount of at least one administering a compound to said mammalian species.

55. 1. A method for treating or preventing Hepatitis B virus infection in a mammalian species in need thereof, comprising: The method comprises administering to a subject a therapeutically effective amount of at least one administering a compound to said mammalian species.

56. 1. A method for treating or preventing HIV infection in a mammalian species in need thereof, said method comprising: a therapeutically effective amount of at least one compound according to any one of claims 1 to 51 administering to said mammalian species.

57. 1. A method of inhibiting cyclophilin in a subject in need thereof, said method comprising: A cyclophilin-inhibiting amount of at least one compound according to any one of claims 1 to 51. administering to said subject an

58. The present invention relates to a method for treating or preventing a disease mediated by cyclophilin in a mammalian species in need thereof.

52. A method of administering a therapeutically effective amount of the compound according to any one of claims 1 to 51. The method comprises administering at least one compound to said mammalian species.

59. 16. A method for treating or preventing a disease in a mammalian species in need thereof, said method comprising: A method for treating a mammalian species comprising administering to the mammal a therapeutically effective amount of at least one compound according to any one of claims 1 to 51. wherein the disease is inflammation, respiratory inflammation, rheumatoid arthritis, and dry eye. A method selected from the group consisting of

60. 1. A method for treating or preventing a disease in a mammalian species in need thereof, said method comprising: A therapeutically effective amount of at least one compound according to any one of claims 1 to 51 is administered to said mammal. and administering to a species of the same species the disease is a neurodegenerative disease, e.g., Alzheimer's disease, Parkinson's disease, Kinesiology, Huntington's disease and ALS; traumatic brain injury; stroke; brain, heart and kidney damage ischemia-reperfusion injury, and myocardial infarction.

61. 1. A method for treating or preventing a disease in a mammalian species in need thereof, said method comprising: A therapeutically effective amount of at least one compound according to any one of claims 1 to 51 is administered to said mammal. and administering to a subject of the present invention a therapeutic agent for the treatment of a disease comprising administering to said subject ... abdominal aortic aneurysm, cardiac hypertrophy, aortic rupture, pulmonary artery hypertension, myocarditis and myocardial fibrosis, ischemic heart disease.

62. 1. A method for treating or preventing a disease or condition in a mammalian species in need thereof, said method comprising: comprising a therapeutically effective amount of at least one compound according to any one of claims 1 to 51. and administering to said mammalian species, said disease or condition being cancer, obesity, diabetes, muscular dystrophy, trophy, pulmonary disease, liver disease, kidney disease, hair loss.

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