Antitumor compounds

Abstract

The present invention relates to an antitumor compound, which is a compound of general formula I, for the treatment of cancer, wherein X, R1-R4 take different meanings.

Description

[0001] This application is a divisional application of the PCT international application filed on April 27, 2018, with PCT international application number PCT / EP2018 / 060868, Chinese national application number 201880027781.X, and entitled "Antitumor Compounds". Technical Field

[0002] This invention relates to saginata, particularly synthetic analogues of saginata 736 (ET-736), pharmaceutical compositions containing them, methods for their preparation, and their use as antitumor agents. Background Technology

[0003] Sea tunicates are highly effective antitumor agents isolated from the marine tunicate, mangrove sea tunicate (Ecteinascidia turbinata). One of the compounds, ET-743, has the following formula:

[0004]

[0005] According to its International Non-Proprietary Name (INN), this compound is used as the anticancer drug trabectedin for patients with advanced and metastatic soft tissue sarcoma (STS) who have failed or are not suitable for subsequent treatment with anthracyclines and ifosfamide, and for the treatment of recurrent platinum-sensitive ovarian cancer in combination with pegylated liposomal doxorubicin.

[0006] Echinostatin 736 (ET-736) was first discovered by Rinehart and is characterized by the substitution of a tetrahydro-β-carbaline unit for a tetrahydroisoquinoline unit, which is more commonly found in eugenol compounds isolated from natural sources; see, for example, Sakai et al., Proc. Natl. Acad. Sci. USA, 1992, vol. 89, 11456-11460.

[0007]

[0008] U.S. Patent No. 5,149,804 describes tunicate 736 (ET-736) and its structure, isolated from the Caribbean tunicate Ecteina scidiaturbinata. ET-736 protects mice in vivo from P388 lymphoma, B16 melanoma, and Lewis lung cancer at extremely low concentrations.

[0009] WO03014127 describes several synthetic analogues of ET-736 and their cytotoxic activities against tumor cells. Specifically, WO03014127 describes compounds A through D along with their cytotoxic activities against a group of cancer cell lines.

[0010]

[0011] Another compound described in the patent application, PM01183, is currently in clinical trials for the treatment of cancer. PM01183 has the following chemical structure:

[0012]

[0013] PM01183 has been demonstrated to have highly effective in vitro activity against both solid and non-solid tumor cell lines, and significant in vivo activity against several xenografted human tumor cell lines in mice (such as breast cancer, renal cancer, and ovarian cancer). PM01183 exerts its anticancer effect through covalent modification of guanine in the minor groove of DNA, ultimately inducing DNA double-strand breaks, S-phase arrest, and apoptosis in cancer cells.

[0014] Despite the positive results achieved in the clinical application of chemotherapy, research in the field of sucrose compounds remains open to identifying new compounds with optimal activity characteristics, tumor selectivity, reduced systemic toxicity, and / or improved pharmacokinetic properties. Summary of the Invention

[0015] In a first aspect of the invention, a compound of formula I or a pharmaceutically acceptable salt or ester thereof is provided:

[0016]

[0017] in:

[0018] X is -NH- or -O-;

[0019] R1 is -OH or -CN;

[0020] R2 is -C(=O)R a Group;

[0021] R3 is hydrogen or -OR b Group;

[0022] R4 is selected from hydrogen, -CH2OH, -CH2OC (=O)R c -CH2NH2 and -CH2NHProt NH ;

[0023] R a Selected from hydrogen, substituted or unsubstituted C1-C 12Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0024] R b Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0025] R c Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 acetylenic group; and

[0026] Prot NH It is an amino protecting group.

[0027] The condition is that when R4 is hydrogen, then X is -O-.

[0028] Compounds of formula IC or their pharmaceutically acceptable salts or esters are also provided:

[0029]

[0030] in:

[0031] X is -NH-;

[0032] R1 is -OH or -CN;

[0033] R2 is -C(=O)R a Group;

[0034] R3 is hydrogen or -OR b Group;

[0035] R4 is selected from -CH2OH, -CH2O-(C=O)R c -CH2NH2 and -CH2NHProt NH ;

[0036] R a Selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0037] R b Selected from substituted or unsubstituted C1-C 12Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0038] R c Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 acetylenic group; and

[0039] Prot NH It is an amino protecting group.

[0040] Compounds of formula ID or their pharmaceutically acceptable salts or esters are also provided:

[0041]

[0042] in:

[0043] X is -O-;

[0044] R1 is -OH or -CN;

[0045] R2 is -C(=O)R a Group;

[0046] R3 is hydrogen or -OR b Group;

[0047] R4 is selected from hydrogen, -CH2OH, -CH2O-(C=O)R c -CH2NH2 and -CH2NHProt NH ;

[0048] R a Selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0049] R b Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0050] R c Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12Alkenyl groups and substituted or unsubstituted C2-C 12 acetylenic group; and

[0051] Prot NH It is an amino protecting group.

[0052] Also provided are compounds of formula IE or their pharmaceutically acceptable salts or esters:

[0053]

[0054] in:

[0055] X is -NH- or -O-;

[0056] R1 is -OH or -CN;

[0057] R2 is -C(=O)R a Group;

[0058] R3 is hydrogen or -OR b Group;

[0059] R4 is selected from -CH2NH2 and -CH2NHProt NH ;

[0060] R a Selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0061] R b Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 acetylenic group; and

[0062] Prot NH It is an amino protecting group.

[0063] Compounds of formula IA or their pharmaceutically acceptable salts or esters are also provided:

[0064]

[0065] in:

[0066] X is -NH- or -O-;

[0067] R1 is -OH or -CN;

[0068] R2 is -C(=O)R a Group;

[0069] R3 is hydrogen;

[0070] R4 is selected from hydrogen, -CH2OH, CH2O-(C=O)R c -CH2NH2 and CH2NHProt NH ;

[0071] R a Selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0072] R c Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 acetylenic group; and

[0073] Prot NH It is an amino protecting group;

[0074] The condition is that when R4 is hydrogen, then X is -O-.

[0075] Also provided are compounds of formula IB or their pharmaceutically acceptable salts or esters:

[0076]

[0077] in:

[0078] X is -NH- or -O-;

[0079] R1 is -OH or -CN;

[0080] R2 is -C(=O)R a Group;

[0081] R3 is -OR b Group;

[0082] R4 is selected from hydrogen, -CH2OH, -CH2O-(C=O)R c -CH2NH2 and -CH2NHProt NH ;

[0083] R a Selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0084] R b Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0085] R c Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 acetylenic group; and

[0086] Prot NH It is an amino protecting group;

[0087] The condition is that when R4 is hydrogen, then X is -O-.

[0088] Also provided are compounds of formula IF or their pharmaceutically acceptable salts or esters:

[0089]

[0090] in:

[0091] X is -NH- or -O-;

[0092] R1 is -OH;

[0093] R2 is -C(=O)R a Group;

[0094] R3 is hydrogen or -OR b Group;

[0095] R4 is selected from hydrogen, -CH2OH, -CH2O-(C=O)R c -CH2NH2 and -CH2NHProt NH ;

[0096] R a Selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0097] R b Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0098] R c Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 acetylenic group; and

[0099] Prot NH It is an amino protecting group.

[0100] The condition is that when R4 is hydrogen, then X is -O-.

[0101] Also provided are compounds of formula IG or their pharmaceutically acceptable salts or esters:

[0102]

[0103] in:

[0104] X is -NH- or -O-;

[0105] R1 is -OH or -CN;

[0106] R2 is an acetyl group;

[0107] R3 is hydrogen or -OR b Group;

[0108] R4 is selected from hydrogen, -CH2OH, CH2OC (=O)R c -CH2NH2 and -CH2NHProt NH ;

[0109] R b Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0110] R c Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0111] Prot NH It is an amino protecting group.

[0112] The condition is that when R4 is hydrogen, then X is -O-.

[0113] In another aspect of the invention, a pharmaceutical composition is provided comprising a compound according to the invention and a pharmaceutically acceptable carrier.

[0114] In another aspect of the invention, a dosage form comprising the pharmaceutical composition according to the invention is provided.

[0115] In another aspect of the invention, compounds, pharmaceutical compositions or dosage forms according to the invention are provided for use as medicaments.

[0116] In another aspect of the invention, compounds, pharmaceutical compositions or dosage forms according to the invention are provided for treating cancer.

[0117] In another aspect of the invention, the use of the compounds, pharmaceutical compositions or dosage forms according to the invention in the preparation of medicaments for treating cancer is provided.

[0118] In another aspect of the invention, a method for preventing or treating cancer is provided, comprising administering an effective amount of a compound according to the invention, an effective amount of a pharmaceutical composition according to the invention, or an effective amount of a dosage form according to the invention to a patient in need, particularly a human.

[0119] In another aspect of the invention, the use of the compounds according to the invention for treating cancer or for preparing medicaments preferably used for treating cancer is provided.

[0120] In another aspect of the invention, a kit is provided comprising a therapeutically effective amount of the compound according to the invention and a pharmaceutically acceptable carrier. This kit is intended for the treatment of cancer.

[0121] In another aspect of the invention, a method for obtaining a compound of formula I or a pharmaceutically acceptable salt or ester thereof, a compound of formula IA or a pharmaceutically acceptable salt or ester thereof, a compound of formula IB or a pharmaceutically acceptable salt or ester thereof, a compound of formula IC or a pharmaceutically acceptable salt or ester thereof, a compound of formula ID or a pharmaceutically acceptable salt or ester thereof, a compound of formula IE or a pharmaceutically acceptable salt or ester thereof, a compound of formula IF or a pharmaceutically acceptable salt or ester thereof, or a compound of formula IG or a pharmaceutically acceptable salt or ester thereof is provided; comprising the step of reacting a compound of formula II with a compound of formula III to obtain a compound of formula IV:

[0122]

[0123] Wherein (provided that possible substituents are permitted):

[0124] X is -NH- or -O-;

[0125] R2 is -C(=O)R a Group;

[0126] R3 is hydrogen or -OR b Group;

[0127] R4 is selected from hydrogen, -CH2OH, -CH2OC (=O)R c -CH2NH2 and -CH2NHProt NH ;

[0128] R a Selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0129] R b Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0130] R c Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 acetylenic group; and

[0131] Prot NH It is an amino protecting group;

[0132] The condition is that when R4 is hydrogen, then X is -O-.

[0133] The method may include a further step of replacing the cyano group in a compound of formula IV with a hydroxyl group to obtain a compound of formula I, IA, IB, IC, ID, IE, IF, or IG, wherein R1 is OH.

[0134] [Simplified Explanation of the Diagram]

[0135] Figure 1 Assessment of the total tumor diameter of HT1080 tumors in mice treated with placebo, compound C, 4-S, and 12-S.

[0136] Figure 2 Assessment of tumor volume of MDA-MB-231 tumors in mice treated with placebo, compound C, 4-S, and 12-S.

[0137] Figure 3 Assessment of tumor volume of H460 tumors in mice treated with placebo, compound C, 4-S, and 12-S.

[0138] Figure 4 Assessment of tumor volume of H526 tumors in mice treated with placebo, compound C, 4-S, and 12-S.

[0139] Figure 5 Tumor volume assessment of H82 tumors in mice treated with placebo, compound C, 4-S, and 12-S.

[0140] Figure 6 Assessment of tumor volume of A2780 tumors in mice treated with placebo, compound C, 4-S, and 12-S.

[0141] Figure 7 Assessment of tumor volume of HGC-27 tumors in mice treated with placebo, compound C, 4-S, and 12-S.

[0142] Figure 8 Assessment of the total diameter of HT1080 tumors in mice treated with placebo, PM01183, and 4-R.

[0143] Figure 9 Assessment of the total tumor diameter of HT1080 tumors in mice treated with placebo, PM01183, and compound D.

[0144] Figure 10 Assessment of tumor volume of MDA-MB-231 tumors in mice treated with placebo, PM01183, and 4-R.

[0145] Figure 11 Assessment of tumor volume of MDA-MB-231 tumors in mice treated with placebo, PM01183 and compound D.

[0146] Figure 12 Assessment of tumor volume of H460 tumors in mice treated with placebo, PM01183, and 4-R.

[0147] Figure 13 Assessment of tumor volume of H460 tumors in mice treated with placebo, PM01183 and compound D.

[0148] Figure 14 Assessment of tumor volume of A2780 tumors in mice treated with placebo, PM01183, and 4-R.

[0149] Figure 15 Assessment of tumor volume of A2780 tumors in mice treated with placebo, PM01183 and compound D.

[0150] Figure 16Assessment of tumor volume of HGC-27 tumors in mice treated with placebo, PM01183, and 4-R.

[0151] Figure 17 Assessment of tumor volume of HGC-27 tumors in mice treated with placebo, PM01183 and compound D.

[0152] Figure 18 Assessment of the total diameter of HT1080 tumors in mice treated with placebo, compound D, and 12-R.

[0153] Figure 19 Assessment of tumor volume of MDA-MB-231 tumors in mice treated with placebo, compound D, and 12-R.

[0154] Figure 20 Tumor volume assessment of H460 tumors in mice treated with placebo, compound D, and 12-R.

[0155] Figure 21 Assessment of tumor volume of H526 tumors in mice treated with placebo, compound D, and 12-R.

[0156] Figure 22 Assessment of tumor volume of H82 tumors in mice treated with placebo, compound D, and 12-R.

[0157] Figure 23 Assessment of tumor volume of A2780 tumors in mice treated with placebo, compound D, and 12-R.

[0158] Figure 24 Assessment of tumor volume of HGC-27 tumors in mice treated with placebo, compound D, and 12-R.

[0159] Figure 25 Assessment of the total diameter of HT1080 tumors in mice treated with placebo, PM01183, and 19-S.

[0160] Figure 26 Assessment of tumor volume of MDA-MB-231 tumors in mice treated with placebo, PM01183, and 19-S.

[0161] Figure 27 Tumor volume assessment of H460 tumors in mice treated with placebo, PM01183, and 19-S.

[0162] Figure 28 Assessment of tumor volume of A2780 tumors in mice treated with placebo, PM01183, and 19-S.

[0163] Figure 29 Assessment of tumor volume of HGC27 tumors in mice treated with placebo, PM01183, and 19-S.

[0164] Figure 30 Assessment of the total diameter of HT1080 tumors in mice treated with placebo, PM01183, and 19-R.

[0165] Figure 31 Assessment of tumor volume of MDA-MB-231 tumors in mice treated with placebo, PM01183, and 19-R.

[0166] Figure 32 Assessment of tumor volume of H460 tumors in mice treated with placebo, PM01183, and 19-R.

[0167] Figure 33 Assessment of tumor volume of A2780 tumors in mice treated with placebo, PM01183, and 19-R.

[0168] Figure 34 Assessment of tumor volume of HGC-27 tumors in mice treated with placebo, PM01183, and 19-R.

[0169] Figure 35 Assessment of the total tumor diameter of HT1080 tumors in mice treated with placebo, compound C, and 39-S.

[0170] Figure 36 Assessment of tumor volume of MDA-MB-231 tumors in mice treated with placebo, compound C, and 39-S.

[0171] Figure 37 Assessment of tumor volume of H460 tumors in mice treated with placebo, compound C, and 39-S.

[0172] Figure 38 Assessment of tumor volume of H526 tumors in mice treated with placebo, compound C, and 39-S.

[0173] Figure 39 Assessment of tumor volume of H82 tumors in mice treated with placebo, compound C, and 39-S.

[0174] Figure 40 Assessment of tumor volume of A2780 tumors in mice treated with placebo, compound C, and 39-S.

[0175] Figure 41 Assessment of tumor volume of HGC27 tumors in mice treated with placebo, compound C, and 39-S.

[0176] Figure 42 Assessment of the total diameter of HT1080 tumors in mice treated with placebo, compound D, and 47-R.

[0177] Figure 43 Assessment of tumor volume of MDA-MB-231 tumors in mice treated with placebo, compound D, and 47-R.

[0178] Figure 44 Assessment of tumor volume of H460 tumors in mice treated with placebo, compound D, and 47-R.

[0179] Figure 45 Assessment of tumor volume of H526 tumors in mice treated with placebo, compound D, and 47-R.

[0180] Figure 46 Assessment of tumor volume of H82 tumors in mice treated with placebo, compound D, and 47-R.

[0181] Figure 47 Assessment of tumor volume of A2780 tumors in mice treated with placebo, compound D, and 47-R.

[0182] Figure 48 Assessment of tumor volume of HGC27 tumors in mice treated with placebo, compound D, and 47-R.

[0183] Figure 49 Evaluation of the total tumor diameter of HT1080 tumors in mice treated with placebo, ET-736, and 32.

[0184] Figure 50 Assessment of tumor volume of MDA-MB-231 tumors in mice treated with placebo, ET-736, and 32.

[0185] Figure 51 Assessment of tumor volume of H460 tumors in mice treated with placebo, ET-736, and 32.

[0186] Figure 52 Assessment of tumor volume of H526 tumors in mice treated with placebo, ET-736, and 32.

[0187] Figure 53 Tumor volume assessment of H82 tumors in mice treated with placebo, ET-736, and 32.

[0188] Figure 54 Assessment of tumor volume of A2780 tumors in mice treated with placebo, ET-736, and 32.

[0189] Figure 55 Assessment of tumor volume of HGC27 tumors in mice treated with placebo, ET-736, and 32.

[0190] Figure 56 Assessment of the total tumor diameter of HT1080 tumors in mice treated with placebo, PM01183, and 35.

[0191] Figure 57 Assessment of tumor volume of MDA-MB-231 tumors in mice treated with placebo, PM01183, and 35.

[0192] Figure 58 Assessment of tumor volume of H460 tumors in mice treated with placebo, PM01183, and 35.

[0193] Figure 59 Assessment of tumor volume of A2780 tumors in mice treated with placebo, PM01183, and 35.

[0194] Figure 60 Assessment of tumor volume of HGC27 tumors in mice treated with placebo, PM01183, and 35.

[0195] Figure 61 Assessment of tumor volume of PC-3 tumors in mice treated with placebo, 12-S, and 12-R.

[0196] Figure 62 Assessment of tumor volume of PC-3 tumors in mice treated with placebo and 4-S.

[0197] Figure 63 Assessment of tumor volume of DU-145 tumors in mice treated with placebo and 4-S.

[0198] Figure 64 Assessment of tumor volume of 22Rv1 tumors in mice treated with placebo and 4-S.

[0199] Figure 65 Assessment of tumor volume of PC-3 tumors in mice treated with placebo and 39-S.

[0200] Figure 66 Assessment of tumor volume of DU-145 tumors in mice treated with placebo and 39-S.

[0201] Figure 67 Assessment of tumor volume of 22Rv1 tumors in mice treated with placebo and 39-S. Implementation

[0202] The following applies to all aspects of this invention:

[0203] In the compounds of the present invention, the alkyl group may be branched or unbranched, and preferably has 1 to about 12 carbon atoms. A more preferred class of alkyl groups has 1 to about 6 carbon atoms. Even more preferred are alkyl groups having 1, 2, 3, or 4 carbon atoms. Methyl, ethyl, n-propyl, isopropyl, and butyl groups including n-butyl, isobutyl, sec-butyl, and tert-butyl are particularly preferred alkyl groups in the compounds of the present invention.

[0204] In the compounds of the present invention, the alkenyl group may be branched or unbranched, having one or more double bonds and 2 to about 12 carbon atoms. A more preferred class of alkenyl groups has 2 to about 6 carbon atoms. Even more preferred are alkenyl groups having 2, 3, or 4 carbon atoms. In the compounds of the present invention, vinyl, 1-propenyl, 2-propenyl, 1-methylvinyl, 1-butenyl, 2-butenyl, and 3-butenyl are particularly preferred alkenyl groups.

[0205] In the compounds of this invention, the alkynyl group may be branched or unbranched, having one or more triple bonds and 2 to about 12 carbon atoms. A more preferred class of alkynyl groups has 2 to about 6 carbon atoms. Even more preferred are alkynyl groups having 2, 3, or 4 carbon atoms.

[0206] Suitable aryl groups in the compounds of this invention include monocyclic and polycyclic compounds, including polycyclic compounds containing individual and / or fused aryl groups. A typical aryl group comprises 1 to 3 individual and / or fused rings and 6 to about 18 carbon ring atoms. Preferably, the aryl group contains 6 to about 10 carbon ring atoms. Particularly preferred aryl groups include substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted biphenyl, substituted or unsubstituted phenanthryl, and substituted or unsubstituted anthraceneyl.

[0207] Suitable heterocyclic groups include heteroaromatic and heterocyclic groups containing 1 to 3 individual and / or fused rings and 5 to 18 ring atoms. Preferably, the heteroaromatic and heterocyclic groups contain 5 to 10 ring atoms, most preferably 5, 6 or 7 ring atoms. Suitable heteroaromatic groups in the compounds of the present invention contain 1, 2, or 3 heteroatoms selected from N, O, or S atoms and include, for example, coumarinyl groups including 8-coumarinyl groups, quinolinyl groups including 8-quinolinyl groups, isoquinolinyl groups, pyridyl groups, pyrazinyl groups, pyrazolyl groups, pyrimidinyl groups, furanyl groups, pyrroleyl groups, thiophenyl groups, thiazolyl groups, isothiazolyl groups, triazolyl groups, tetrazolyl groups, isoxazolyl groups, oxazolyl groups, imidazolyl groups, indolyl groups, isoindolyl groups, indolyl groups, inazinyl groups, phthalazinyl groups, pteridinyl groups, purinyl groups, oxadiazolyl groups, thiazolyl groups, furazolidyl groups, pyridazinyl groups, triazinyl groups, benzoimidazolyl groups, benzofuranyl groups, benzofuranyl groups, benzothiophenyl groups, benzothiazolyl groups, benzooxazolyl groups, quinazolinyl groups, naphridinyl groups, and furanopyridyl groups. Suitable heteroaromatic groups in the compounds of this invention contain one, two, or three heteroatoms selected from N, O, or S atoms and include, for example, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiopheneyl, tetrahydrothiopiperanyl, piperidinyl, morpholinyl, thiomorpholinyl, oxothiocarboxyl, piperazine, aziridine, oxoheptanyl, thioheptanyl, homopiperidinyl, oxoheptanyl, thioheptanyl, and oxonitrogenyl. basalt, diazonium Base, sulfur and nitrogen 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, dihydroindolyl, 2H-piperanyl, 4H-piperanyl, dioxoquinoyl, 1,3-dioxolanecycloyl, pyrazolinyl, dithianyl, dithiopentanyl, dihydropiperanyl, dihydrothiopheneyl, dihydrofuranyl, pyrazolidineyl, imidazolinyl, imidazodinyl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[4.1.0]heptyl, 3H-indolyl and quinazinyl.

[0208] The above-mentioned groups can be substituted at one or more available positions by one or more suitable groups, such as OR′, =O, SR′, SOR′, SO2R′, NO2, NHR′, NR'R′, =NR′, NHCOR′, N(COR′)2, NHSO2R′, NR'C(=NR')NR'R', CN, halogen, COR′, COOR′, OCOR′, OCONHR′, OCONR'R', CONHR′, CONR'R', protected OH, protected amine, protected SH, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12The R' group is selected from alkynyl, substituted or unsubstituted aryl, and substituted or unsubstituted heterocyclic groups, wherein each R' group is independently selected from hydrogen, OH, NO2, NH2, SH, CN, halogen, COH, COalkyl, CO2H, substituted or unsubstituted C1-C. 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl, substituted or unsubstituted C2-C 12 Alkyne groups, substituted or unsubstituted aryl groups, and substituted or unsubstituted heterocyclic groups. When these groups are substituted themselves, the substituents can be selected from the list above. Additionally, when a substituent has more than one R′ group, each R′ can be the same or different.

[0209] In the compounds of this invention, halogen substituents include F, Cl, Br, and I.

[0210] The terms "pharmaceutically acceptable salt" and "ester" refer to any pharmaceutically acceptable salt or ester that, when administered to a patient, can (directly or indirectly) provide the compound as described herein. However, it should be understood that non-pharmaceutically acceptable salts also fall within the scope of this invention, as they can be used to prepare pharmaceutically acceptable salts. Salt preparation can be carried out by methods known in the art.

[0211] For example, pharmaceutically acceptable salts of the compounds provided herein are synthesized from parent compounds containing a basic or acidic moiety by conventional chemical methods. Typically, these salts are prepared, for example, by reacting the free acid or base of these compounds with a stoichiometric amount of a suitable base or acid in water, an organic solvent, or a mixture of both. Non-aqueous media such as diethyl ether, ethyl acetate, ethanol, 2-propanol, or acetonitrile are generally preferred. Examples of acid addition salts include inorganic acid addition salts (e.g., hydrochlorides, hydrobromates, hydroiodates, sulfates, nitrates, phosphates) and organic acid addition salts (e.g., acetates, trifluoroacetates, maleates, fumarates, citrates, oxalates, succinates, tartrates, malates, mandelates, methanesulfonates, and p-toluenesulfonates). Examples of base addition salts include inorganic salts (e.g., sodium, potassium, calcium, and ammonium salts) and organic base salts (e.g., ethylenediamine, ethanolamine, N,N-dialkylethanolamine, triethanolamine, and basic amino acids).

[0212] The compounds of the present invention may be in crystalline or amorphous form as free compounds or solvates (e.g., hydrates), and all forms are expected to be within the scope of the present invention. Methods of solvation are generally known in the art.

[0213] Stereoisomerism with respect to asymmetric carbons having unspecified stereochemistry is possible, thus in which case the asymmetric carbon can have (R) or (S) configurations. All diastereomers arising from a particular configuration of such asymmetric carbon, together with other asymmetric carbons present in the molecule and mixtures thereof, are considered to be within the scope of this invention. Stereoisomerism with respect to double bonds (geometric isomers) is also possible, thus in some cases, the molecule can exist as (E)-isomers or (Z)-isomers. If the molecule contains multiple double bonds, each double bond will have its own stereoisomerism, which may be the same as or different from the stereoisomerism of the other double bonds in the molecule. Furthermore, the compounds mentioned herein can exist as atropoisomers. Single stereoisomers, including diastereomers, geometric isomers, and atropoisomers of the compounds discussed herein, and mixtures thereof fall within the scope of this invention.

[0214] Furthermore, the compounds mentioned herein may exist in isotopically labeled forms. All pharmaceutically acceptable salts, esters, and isotopically labeled forms of the compounds mentioned herein, as well as mixtures thereof, are considered to be within the scope of this invention.

[0215] The protected forms of the compounds disclosed herein are considered to be within the scope of this invention. Suitable protecting groups are well known to those skilled in the art. A general overview of protecting groups in organic chemistry is provided by Wuts, PGM, and Greene TW in the 4th edition of *Protecting Groups in Organic Synthesis* (Wiley-Interscience), and by Kocienski PJ in the 3rd edition of *Protecting Groups* (Georg Thieme Verlag). These references provide chapters on protecting groups for OH, amine, and SH groups. All of these references are incorporated herein by reference in their entirety.

[0216] Within the scope of this invention, an OH protecting group is defined as an O-bonded portion formed by protecting OH through the formation of a suitable protected OH group. Examples of such protected OH groups include ethers, silyl ethers, esters, sulfonates, sulfenates and sulfinates, carbonates, and carbamates. In the case of ethers, the protecting group of OH may be selected from methyl, methoxymethyl, methylthiomethyl, (phenyldimethylsilyl)methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, [(3,4-dimethoxybenzyl)oxy]methyl, p-nitrobenzyloxymethyl, o-nitrobenzyloxymethyl, [(R)-1-(2-nitrophenyl)ethoxy]methyl, (4-methoxyphenoxy)methyl, guaiacol methyl, [p-phenylphenyl)oxy]methyl, tert-butoxymethyl, 4-pentenoxymethyl, silanoxy, 2-methoxyethoxymethyl, 2-cyanoethoxymethyl, bis(2-chloroethoxy)methyl, 2,2,2-trichloroethoxy Methyl, 2-(trimethylsilyl)ethoxymethyl, mentholoxymethyl, O-bis(2-acetoxy-ethoxy)methyl, tetrahydropiperanyl, tetrahydropiperanyl fluorine, 3-bromotetrahydropiperanyl, tetrahydrothiopiperanyl, 1-methoxycyclohexyl, 4-methoxytetrahydropiperanyl, 4-methoxy-tetrahydrothiopiperanyl, 4-methoxytetrahydrothiopiperanyl S,S-dioxide, 1-[(2-chloro-4-methyl)-phenyl]-4-methoxypiperidin-4-yl, 1-(2-fluorophenyl)-4-methoxypiperidin-4-yl, 1-(4-chlorophenyl)-4-methoxypiperidin-4-yl, 1,4-dioxo-2-yl, tetrahydrothiaranyl 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methylenebenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-hydroxyethyl, 2-bromoethyl, 1-[2-(trimethylsilyl)ethoxy]ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 1-methyl-1-phenoxyethyl, 2,2,2-trichloroethyl, 1,1-dianestigmatyl-2,2,2-trichloroethyl, 1,1,1,3,3,3-hexafluoro-2-phenylisopropyl, 1-(2-cyanoethoxy) 2-Trimethylsilylethyl, 2-(benzylthio)ethyl, 2-(phenylseleno)ethyl, tert-butyl, cyclohexyl, 1-methyl-1′-cyclopropylmethyl, allyl, isopreneyl, cinnamyl, 2-phenylallyl, propargyl, p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, 2,6-dichlorobenzyl, o-nitrobenzyl, p-nitrobenzyl, pentadienylnitrobenzyl, pentadienylnitrohelianyl, halobenzyl, 2,6-dichlorobenzyl, 2,6-Difluorobenzyl, p-cyanobenzyl, fluorobenzyl, 4-fluoroalkoxybenzyl, trimethylsilylxylyl, p-phenylbenzyl, 2-phenyl-2-propyl, p-acylaminobenzyl, p-azidobenzyl, 4-azido-3-chlorobenzyl, 2-trifluoromethylbenzyl, 4-trifluoromethylbenzyl, p-(methylsulfinyl)benzyl, p-siliconecyclobutylbenzyl, 4-acetoxybenzyl, 4-(2-trimethylsilyl)ethoxymethoxybenzyl, 2-naphthylmethyl, 2-pyridinemethyl, 4-pyridinemethyl, 3-methyl-2-pyridinemethyl N-oxide, 2-quinolinylmethyl, 6-methoxy-2-(4-methylphenyl)-4-quinolinmethyl, 1-pyrene Methyl, diphenylmethyl, 4-methoxydiphenylmethyl, 4-phenyldiphenylmethyl, p,p'-dinitrodiphenylmethyl, 5-dibenzocycloheptanyl, triphenylmethyl, tetra(4-tert-butylphenyl)methyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenyl-methyl, tri(p-methoxyphenyl)methyl, 4-(4′-bromobenzoyloxy)phenyldiphenylmethyl, 4,4′,4”-tris(4,5-dichlorobenzoylimidephenyl)methyl, 4,4′,4”-tris(levulinoyl)oxyphenyl)methyl, 4,4′,4”-tris(benzoyloxyphenyl)methyl 4,4′-Dimethoxy-3”-[N-(imidazolylmethyl)]triphenylmethyl, 4,4′-Dimethoxy-3”-[N-(imidazolylethyl)aminoformyl]triphenylmethyl, bis(4-methoxyphenyl)-1′-pyrenemethyl, 4-(17-tetrabenzo[a,c,g,i]pyrenemethyl)-4,4′-dimethoxytriphenylmethyl, 9-anthrayl, 9-(9-phenyl)oxosulfanyl, 9-phenylthioxanthine, 9-(9-phenyl-10-sideoxy)anthrayl, 1,3-benzodithiopentane-2-yl, 4,5-bis(ethoxycarbonyl)-[1,3]dioxolane-2-yl, benzisothiazolyl S,S-di Oxides. For silyl ethers, the protecting group of OH can be selected from trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, 2-norbornenyldimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, di-tert-butylmethylsilyl, bis(tert-butyl)-1-pyrene methoxysilyl, tri(trimethylsilyl)silyl, (2-hydroxystyryl)dimethylsilyl, (2-hydroxystyryl)diisopropylsilyl, tert-butylmethoxyphenylsilyl, tert-butoxydiphenylsilyl, 1,1,3,3-Tetraisopropyl-3-[2-(triphenylmethoxy)ethoxy]disiloxane-1-yl and fluorosilyl. In the case of esters, the protecting group of OH, together with the oxygen atom of the unprotected OH to which it is attached, forms an ester that may be selected from the following: formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trichloroacetamide, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, phenylacetate, diphenylacetate, 3-phenylpropionate, difluoropropionyl, 4-pentenoate, 4-sideoxyvalerate, 4,4-(ethylenedithio)valerate, 5-[3-bis(4-methoxyphenyl)2-methylphenoxy]acetylpropionate, neovalerate, 1 -Adamantane ester, Crotonate, 4-Methoxybutenoate, Benzoate, p-Phenylbenzoate, 2,4,6-Trimethylbenzoate, 4-Bromobenzoate, 2,5-Difluorobenzoate, p-Nitrobenzoate, Pyridinecarboxylate, Nicotinate, 2-(Azidelmethyl)benzoate, 4-Azidelbutyrate, (2-Azidelmethyl)phenylacetate, 2-{[(triphenylmethylthio)oxy]methyl}benzoate, 2-{[(4-methoxytriphenylmethylthio)oxy}benzoate, 2-{[methyl(triphenylmethylthio)amino]methyl}benzoate, 2-{{[(4-methoxytriphenylmethyl)]methyl}benzoate [Thio]methylamino}methyl}benzoate, 2-(allyloxy)phenylacetate, 2-(isopentoxymethyl)benzoate, 6-(acetylpropyloxymethyl)-3-methoxy-2-nitrobenzoate, 6-(acetylpropyloxymethyl)-3-methoxy-4-nitrobenzoate, benzyloxybutyrate, 4-trialkylsilyloxybutyrate, 4-acetoxy-2,2-dimethylbutyrate, 2,2-dimethyl-4-pentenoate, 2-iodobenzoate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate (methylthiomethoxy)butyrate, 2-(methylthio) ...benzenesulfonate (methylthio)benzenesulfonate (methylthio)benzenesulfonate (methylthio)benzenesulfonate (methylthio)benzenesulfonate (methylthio)benzenesulfonate (methylthio)benzenesulfonate (methylth 2-(chloroacetoxymethyl)benzoate, 2-[(2-chloroacetoxy)ethyl]benzoate, 2-[2-[2-(4-methoxybenzyloxy)ethyl]benzoate, 2,6-dichloro-4-methylphenoxyacetic acid ester, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetic acid ester, 2,4-bis(1,1-dimethylpropyl)phenoxyacetic acid ester, dichlorophenylacetic acid ester, isobutyrate, monosuccinate, (E)-2-methyl-2-butenoate, o-(methoxycarbonyl)benzoate, α-naphthyl ester, nitrate, alkyl N,N,N′,N′-Tetramethylphosphonic diamine ester and 2-chlorobenzoate. In the case of sulfonates, sulfenates, and sulfinates, the protecting group of OH, together with the oxygen atom of the unprotected OH, forms a sulfonate, sulfenate, or sulfinate selected from the following: sulfates, allyl sulfonates, methanesulfonates, benzyl sulfonates, toluenesulfonates, 2-[(4-nitrophenyl)ethyl]sulfonates, 2-trifluoromethylbenzenesulfonates, 4-monomethoxytriphenylmethyl sulfate, alkyl 2,4-dinitrophenyl sulfinates, 2,2,5,5-tetramethylpyrrolidone-3-one-1-sulfinate, and dimethylthiophosphonoacyl. In the case of carbonates, the protecting group of OH, together with the oxygen atom of the unprotected OH atom to which it is attached, forms a carbonate selected from the following: methyl carbonate, methoxymethyl carbonate, 9-enylmethyl carbonate, ethyl carbonate, ethyl bromide carbonate, 2-(methylthiomethoxy)ethyl carbonate, 2,2,2-trichloroethyl carbonate, 1,1-dimethyl-2,2,2-trichloroethyl carbonate, 2-(trimethylsilyl)ethyl carbonate, 2-[dimethyl(2-naphthylmethyl)silyl]ethyl carbonate, 2-(phenylsulfonyl)ethyl carbonate, 2-(triphenylphosphine)ethyl carbonate, cis-[4-[[(methoxytriphenylmethyl)sulfinyl]oxy]tetrahydrofuran-3-yl]oxycarbonate, isobutyl carbonate, tert-butyl carbonate, ethylene carbonate, allyl carbonate, cinnamyl carbonate, propargyl carbonate, p-chlorophenyl carbonate, p-nitrobenzene carbonate, 4- Ethoxy-1-naphthalene carbonate, 6-bromo-7-hydroxycoumarin-4-yl methyl carbonate, benzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, anthraquinone-2-ylmethyl carbonate, 2-dansyl ethyl carbonate, 2-(4-nitrophenyl)ethyl carbonate, 2-(2,4-dinitrophenyl)ethyl carbonate, 2-(2-nitrophenyl) Propyl carbonate, 2-(3,4-methylenedioxy-6-nitrophenyl)propyl carbonate, 2-cyano-1-phenylethyl carbonate, 2-(2-pyridyl)amino-1-phenylethyl carbonate, 2-[N-methyl-N-(2-pyridyl)]amino-1-phenylethyl carbonate, benzoyl methyl carbonate, 3′,5'-dimethoxybenzyl carbonate, dithiomethyl carbonate, and S-benzyl thiocarbonate. In the case of carbamates, the protecting group of the OH group, together with the oxygen atom of the unprotected OH group to which it is attached, forms a carbamate, which may be selected from dimethyl thiocarbamate, N-phenylcarbamate, and N-methyl-N-(o-nitrophenyl)carbamate.

[0217] Within the scope of this invention, an amino protecting group is defined as an N-bonded moiety obtained by protecting an amino group through the formation of a suitable protected amino group. Examples of protected amino groups include carbamates, ureas, amides, heterocyclic systems, N-alkylamines, N-alkenylamines, N-alkynylamines, N-arylamines, imines, enamines, N-metal derivatives, NN derivatives, NP derivatives, N-Si derivatives, and NS derivatives. In the case of carbamates, the protecting group of the amino group, together with the amino group to which it is attached, forms a carbamate, which can be selected from methyl carbamate, ethyl carbamate, 9-enylmethyl carbamate, 2,6-di-tert-butyl-9-enylmethyl carbamate, 2,7-bis(trimethylsilyl)enylmethyl carbamate, 9-(2-sulfonyl)enylmethyl carbamate, 9-(2,7-dibromo)enylmethyl carbamate, 17-tetrabenzo[a,c,g,i]enylmethyl carbamate, 2-chloro-3-indenemethyl carbamate, benzo[f]indene-3-ylmethyl carbamate, 1,1-di-dioxy Benzo[b]-thiophene-2-ylmethylaminocarbamate, 2-methylsulfonyl-3-phenyl-1-prop-2-enylaminocarbamate, 2,7-di-tert-butyl-[9,(10,10-di-side-oxy-10,10,10,10-tetrahydrothiaxanthine acidyl)]aminocarbamate, 2,2,2-trichloroethylaminocarbamate, 2-trimethylsilylethylaminocarbamate, (2-phenyl-2-trimethylsilyl)ethylaminocarbamate, 2-phenylethylaminocarbamate, 2-chloroethylaminocarbamate, 1,1-dimethyl-2-haloethylaminocarbamate, 1,1-dimethyl-2,2-dibromoethylaminocarbamate Formate, 1,1-dimethyl-2,2,2-trichloroethylaminocarbamate, ethyl 2-(2′-pyridyl)ethylaminocarbamate, ethyl 2-(4′-pyridyl)ethylaminocarbamate, 2,2-bis(4′-nitrophenyl)ethylaminocarbamate, 2-[(2-nitrophenyl)disulfide]-1-phenylethylaminocarbamate, 2-(N,N-dicyclohexylformamido)ethylaminocarbamate, tert-butyl aminocarbamate, fluorinated BOC aminocarbamate, 1-adamantylaminocarbamate, 2-adamantylaminocarbamate, 1-(1-adamantyl)-1-methylethylaminocarbamate, 1-methyl-1-(4- Biphenyl) ethyl aminocarbamate, 1-(3,5-di-tert-butylphenyl)-1-methylethyl aminocarbamate, triisopropylsilyloxyaminocarbamate, vinyl aminocarbamate, allyl aminocarbamate, isoamyl aminocarbamate, 1-isopropylallyl aminocarbamate, cinnamyl aminocarbamate, 4-nitrocinnamyl aminocarbamate, 3-(3′-pyridyl)prop-2-enyl aminocarbamate, hexadienyl aminocarbamate, propargyl aminocarbamate, 1,4-but-2-ynyldiaminocarbamate, 8-quinolinyl aminocarbamate, N-hydroxypiperidinyl aminocarbamate, alkyl dithioaminocarbamate, benzyl aminocarbamate, 3,5-Di-tert-butylbenzylaminocarbamate, p-methoxybenzylaminocarbamate, p-nitrobenzylaminocarbamate, p-bromobenzylaminocarbamate, p-chlorobenzylaminocarbamate, 2,4-dichlorobenzylaminocarbamate, 4-methylsulfinylbenzylaminocarbamate, 4-trifluoromethylbenzylaminocarbamate, fluoroaminocarbamate benzyl ester, 2-naphthylmethylaminocarbamate, 9-anthraylmethylaminocarbamate, diphenylmethylaminocarbamate, 4-phenylacetoxybenzylaminocarbamate, 4-azidobenzylaminocarbamate, 4-azidomethoxybenzylaminocarbamate, m-chloro-p-acyloxybenzylaminocarbamate, p-(dihydroxyboryl)-benzylaminocarbamate, 5-benzisoxazolylmethyl Carbamate, 2-(trifluoromethyl)-6-chromone-methylcarbamate, 2-methylthioethylcarbamate, 2-methylsulfonylethylcarbamate, 2-(p-toluenesulfonyl)ethylcarbamate, 2-(4-nitrophenylsulfonyl)ethylcarbamate, 2-(2,4-dinitrobenzenesulfonyl)ethylcarbamate, 2-(4-trifluoromethylbenzenesulfonyl)ethylcarbamate, 2-[1,3-dithionyl]methylcarbamate, 2-phosphonoethylcarbamate, 2-[phenyl(methyl)sulfonyl]ethylcarbamate, 1-methyl-1-(triphenylphosphonium)ethylcarbamate, 1,1-dimethyl-2-cyanoethylcarbamate, 2-Diethylethylaminocarbamate, 2-(4-nitrophenyl)ethylaminocarbamate, 4-methylphenylaminocarbamate, 2,4-dimethylphenylaminocarbamate, m-nitroanilinecarbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethylaminocarbamate, α-nitrobenzylaminocarbamate, o-nitrobenzylaminocarbamate, 3,4-dimethoxy-6-nitrobenzylaminocarbamate, phenyl(o-nitrophenyl)methylaminocarbamate, 2-nitrophenylethylaminocarbamate, 6-nitroceranoylaminocarbamate, 4-methoxybenzoylmethylaminocarbamate, 3′,5′-dimethoxybenzoinaminocarbamate, 9-benzoylmethylaminocarbamate, N-methyl -N-(o-nitrophenyl)aminocarbamate, tert-amylaminocarbamate, 1-methylcyclobutylaminocarbamate, 1-methylcyclohexylaminocarbamate, 1-methyl-1-cyclopropylmethylaminocarbamate, cyclobutylaminocarbamate, cyclopentylaminocarbamate, cyclohexylaminocarbamate, isobutylaminocarbamate, isobornylaminocarbamate, cyclopropylmethylaminocarbamate, p-decoxybenzylaminocarbamate, diisopropylmethylaminocarbamate, 2,2-dimethoxycarbonylvinylaminocarbamate, o-(N,N-dimethylformamido)aminocarbamate benzyl ester, 1,1-dimethyl-3-(N,N-dimethylformamido)aminocarbamate propyl ester, butyryne aminocarbamate, 1,1-Dimethylpropynylaminocarbamate, 2-Iodoethylaminocarbamate, 1-Methyl-1-(4'-pyridyl)ethylaminocarbamate, 1-Methyl-1-(p-phenylazophenyl)ethylaminocarbamate, p-(p-methoxyphenylazo)benzylaminocarbamate, p-(phenylazo)benzylaminocarbamate, 2,4,6-trimethylbenzylaminocarbamate, isonicotinamide carbamate, 4-(trimethylammonium)benzylaminocarbamate, p-cyanobenzylaminocarbamate, di(2-pyridyl)methylaminocarbamate, 2-furanylmethylaminocarbamate, phenylaminocarbamate, 2,4,6-tri-tert-butylphenylaminocarbamate, 1-methyl-1-phenylethylaminocarbamate, and S-benzylthioaminocarbamate. In the case of urea, the protecting group of the amine group can be selected from phenothiazinyl-(10)-carbonyl, N'-p-toluenesulfonamide carbonyl, N'-phenylaminothiocarbonyl, 4-hydroxyphenylaminocarbonyl, 3-hydroxytryptamine carbonyl and N′-phenylaminothiocarbonyl. In the case of amides, the protecting group of the amino group, together with the amino group to which it is attached, forms an amide, which can be selected from formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropionamide, pent-4-enamide, pyridinamide, 3-pyridylformamide, N-benzoylphenylpropionamide, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, 2,2-dimethyl-2-(o-nitrophenyl)acetamide, o-nitrophenoxyacetamide, 3-(o-nitrophenyl)propionamide, 2-methyl-2-(o-nitrophenoxy)propionamide, 3-methyl-3-nitrobutamide, o-nitrocinnamamide, o-nitrobenzamide 3-(4-tert-butyl-2,6-dinitrophenyl)-2,2-dimethylpropionamide, o-(benzyloxymethyl)benzamide, 2-(acetoxymethyl)benzamide, 2-[(tert-butyldiphenylsilyloxy)methyl]benzamide, 3-(3′,6′-disideloxy-2′,4′,5′-trimethylcyclohexyl-1′,4′-diene)-3,3-dimethylpropionamide, o-hydroxytrans-cinnamonamide, 2-methyl-2-(o-phenylazophenoxy)propionamide, 4-chlorobutyramide, acetylacetamide, 3-(p-hydroxyphenyl)propionamide, (N′-dithiobenzyloxycarbonylamino)acetamide, and N-acetylmethionine amide. In the case of heterocyclic systems, the protecting group of the amine group, together with the amine group it is attached to, forms a heterocyclic system, which can be selected from 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dichlorophthalimide, N-tetrachlorophthalimide, N-4-nitrophthalimide, N-thiodiacetyl, N-dithiosuccinimide, N-2,3-diphenylmaleimide, N-2,3-dimethylmaleimide, N-2,5-dimethylpyrrole, N-2,5-bis(triisopropylsilyloxy)pyrrole, N-1,1,4,4-tetramethyldisilazine adduct, N-1,1,3,3-tetramethyl-1,3-Disilazide dihydroindole, N-diphenylsilyldiethylene, N-5-substituted-1,3-dimethyl-1,3,5-triazacyclohexane-2-one, N-5-substituted-1,3-benzyl-1,3,5-triazacyclohexane-2-one, 1-substituted 3,5-dinitro-4-pyridone, and 1,3,5-dioxazine. In the case of N-alkyl, N-alkenyl, N-ynyl, or N-arylamine, the protecting group of the amine group may be selected from N-methyl, N-tert-butyl, N-allyl, N-isopentenyl, N-cinnamyl, N-phenylallyl, N-propynyl, N-methoxymethyl, N-[2-(trimethylsilyl)ethoxy]methyl, N-3-acetoxypropyl, N-cyanomethyl, N-2-azanorbornene, N-benzyl, N-4-methoxybenzyl, N-2,4-dimethoxybenzyl, N... -2-hydroxybenzyl, N-ferroceneylmethyl, N-2,4-dinitrophenyl, o-methoxyphenyl, p-methoxyphenyl, N-9-phenylenazyl, N-enazyl, N-2-aminomethylpyridine N'-oxide, N-7-methoxycoumaryl-4-ylmethyl, N-diphenylmethyl, N-bis(4-methoxyphenyl)methyl, N-5-dibenzocycloheptyl, N-triphenylmethyl, N-(4-methylphenyl)diphenylmethyl and N-(4-methoxyphenyl)diphenylmethyl. In the case of imine, the protecting group of the amine group can be selected from N-1,1-dimethylthiomethylene, N-benzylene, N-p-methoxybenzylene, N-diphenylmethylene, N-[2-pyridyl)methylene]methylene, N-(N′,N′-dimethylaminomethylene), N-(N′,N′-dibenzylaminomethylene), N-(N′,N′-tert-butylaminomethylene), N,N′-isopropylene, N-p-nitrobenzylene, N-salicylene sulfoxide, N-5-chlorosalicylene, N-(5-chloro-2-hydroxyphenyl)phenylmethylene, N-cyclohexylene, and N-tert-butylene. In the case of enamines, the protecting group of the amine group can be selected from N-(5,5-dimethyl-3-sideoxy-1-cyclohexenyl)ethyl, N-2,7-dichloro-9-enylmethylene, N-1-(4,4-dimethyl-2,6-disideoxycyclohexenyl)ethyl, N-(1,3-dimethyl-2,4,6-(1H,3H,5H)-trisideoxypyrimidin-5-yl)-methyl, N-4,4,4-trifluoro-3-sideoxy-1-butenyl, and N-(1-isopropyl-4-nitro-2-sideoxy-3-pyrrololin-3-yl). In the case of N-metal derivatives, the protecting group of the amine group can be selected from N-borane, N-diphenylboronic acid ester, N-diethylboronic acid ester, N-9-boronabicyclononane, N-difluoroboronic acid ester, and 3,5-Bis(trifluoromethyl)phenylboronic acid; and further comprising N-phenyl(pentacarbonylchromium)carbenyl, N-phenyl(pentacarbonyltungsten)carbenyl, N-methyl(pentacarbonylchromium)carbenyl, N-methyl(pentacarbonyltungsten)carbenyl, N-copper chelate, N-zinc chelate and 18-crown-6 derivative. In the case of NN derivatives, the protecting group of the amine group together with the amine group to which it is attached forms the NN derivative, which may be selected from N-nitroamine, N-nitrosoamine, amine N-oxide, azide, triazine derivative, and N-trimethylsilylmethyl-N-benzylhydrazine. In the case of NP derivatives, the protecting group of the amine group together with the amine group to which it is attached forms the NP derivative, which may be selected from diphenylphosphamide, dimethylthiophosphamide, diphenylthiophosphamide, dialkylaminophosphate, dibenzylaminophosphate, diphenylphosphamide and iminotriphenylphosphine. In the case of N-Si derivatives, the protecting group of NH2 can be selected from tert-butyldiphenylsilyl and triphenylsilyl. In the case of NS derivatives, the protected amino group can be selected from N-sulfinyl or N-sulfonyl derivatives. N-sulfinyl derivatives can be selected from benzenesulfinamide, 2-nitrobenzenesulfinamide, 2,4-dinitrobenzenesulfinamide, pentachlorobenzenesulfinamide, 2-nitro-4-methoxybenzenesulfinamide, triphenylmethylsulfonamide, 1-(2,2,2-trifluoro-1,1-diphenyl)ethylsulfinamide, and N-3-nitro-2-pyridinesulfinamide. N-sulfonyl derivatives may be selected from methanesulfonamide, trifluoromethanesulfonamide, tert-butylsulfonamide, benzylsulfonamide, 2-(trimethylsilyl)ethanesulfonamide, p-toluenesulfonamide, benzenesulfonamide, o-methoxybenzenesulfonamide, 2-nitrobenzenesulfonamide, 4-nitrobenzenesulfonamide, 2,4-dinitrobenzenesulfonamide, 2-naphthalenesulfonamide, 4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide, 2-(4-methylphenyl)-6-methoxy-4-methylsulfonamide, 9-anthrasulfonamide, pyridine-2-sulfonamide, benzothiazole- 2-Sulfanamide, benzoylmethylsulfonamide, 2,3,6-trimethyl-4-methoxybenzenesulfonamide, 2,4,6-trimethoxybenzenesulfonamide, 2,6-dimethyl-4-methoxybenzenesulfonamide, pentamethylbenzenesulfonamide, 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide, 4-methoxybenzenesulfonamide, 2,4,6-trimethylbenzenesulfonamide, 2,6-dimethoxy-4-methylbenzenesulfonamide, 3-methoxy-4-tert-butylbenzenesulfonamide, and 2,2,5,7,8-pentamethyl-6-sulfonamide.

[0218] Within the scope of this invention, the protecting group of SH is defined as the S-bonded portion obtained by protecting the SH group through the formation of a suitable protected SH group. Examples of such protected SH groups include thioethers, disulfides, silyl thioethers, thioesters, thiocarbonates, and thioaminocarbamates. In the case of thioethers, the protecting group of SH may be selected from S-alkyl, S-benzyl, S-p-methoxybenzyl, S-o-hydroxybenzyl, S-p-hydroxybenzyl, S-o-acetoxybenzyl, S-p-acetoxybenzyl, S-p-nitrobenzyl, S-o-nitrobenzyl, S-2,4,6-trimethylbenzyl, S-2,4,6-trimethoxybenzyl, S-4-pyridinemethyl, S-2-pyridinemethyl-N-oxide, S-2-quinolinylmethyl, S-9-anthraylmethyl S-9-pyromethyl, S-methyl, S-ferroceneylmethyl, S-diphenylmethyl, S-bis(4-methoxyphenyl)methyl, S-5-dibenzocycloheptyl, S-triphenylmethyl, 4-methoxytriphenylmethyl, S-diphenyl-4-pyridylmethyl, S-phenyl, S-2,4-dinitrophenyl, S-2-quinolinyl, S-tert-butyl, S-1-adamantyl, S-methoxymethyl, S-isobutoxymethyl, S-benzyloxymethyl, S- 1-Ethoxyethyl, S-benzoylthiomethyl, S-phenylthiomethyl, S-acetamidomethyl (Acm), S-trimethylacetamidomethyl, S-benzamidomethyl, S-allyloxycarbonylaminomethyl, SN-[2,3,5,6-tetrafluoro-4-(N′-piperidinyl)-phenyl-N-allyloxycarbonylaminomethyl, S-phthalimidemethyl, S-phenylacetamidomethyl, S-acetylmethyl, S-carboxymethyl, S-cyano Methyl, S-(2-nitro-1-phenyl)ethyl, S-2-(2,4-dinitrophenyl)ethyl, S-2-(4′-pyridyl)ethyl, S-2-cyanoethyl, S-2-(trimethylsilyl)ethyl, S-2,2-bis(ethoxycarbonyl)ethyl, S-(1-m-nitrophenyl-2-benzoyl)ethyl, S-2-phenylsulfonylethyl, S-1-(4-methylphenylsulfonyl)-2-methylpropyl-2-yl, and S-p-hydroxybenzoylmethyl. In the case of disulfides, the protected SH group can be selected from S-ethyl disulfide, S-tert-butyl disulfide, S-2-nitrophenyl disulfide, S-2,4-dinitrophenyl disulfide, S-2-phenylazophenyl disulfide, S-2-carboxyphenyl disulfide, and S-3-nitro-2-pyridyl disulfide. In the case of silyl sulfides, the protecting group of SH can be selected from the groups listed above that protect OH with silyl ethers. In the case of thioesters, the protecting group of SH can be selected from S-acetyl, S-benzoyl, S-2-methoxyisobutyryl, S-trifluoroacetyl, SN-[[p-biphenyl]-isopropoxy]carbonyl]-N-methyl-γ-aminothiobutyrate and SN-(tert-butoxycarbonyl)-N-methyl-γ-aminothiobutyrate.In the case of the thiocarbonate protecting group of SH, it can be selected from S-2,2,2-trichloroethoxycarbonyl, S-tert-butoxycarbonyl, S-benzyloxycarbonyl, S-p-methoxybenzyloxycarbonyl, and S-furoylmethylcarbonyl. In the case of thioaminocarbamate, the protected SH group can be selected from S-(N-ethylaminocarbamate) and S-(N-methoxymethylaminocarbamate).

[0219] The groups mentioned should not be construed as limiting the scope of the invention, as they are mentioned merely as simple descriptions of protecting groups for OH, amine, and SH groups. However, other groups having the aforementioned functions can be understood by those skilled in the art, and they will be understood to be included in the invention as well.

[0220] To provide a more concise description, some quantitative expressions given herein do not use the term "approximately". It should be understood that, whether or not the term "approximately" is explicitly used, each quantity given herein refers to an actual given value, and also implies an approximation of such a given value based on reasonable inference by those skilled in the art, including equivalent and approximate values ​​resulting from the experimental and / or measurement conditions of such a given value.

[0221] In one embodiment, the compound may be a compound of formula I or a pharmaceutically acceptable salt or ester thereof:

[0222]

[0223] in:

[0224] X is -NH- or -O-;

[0225] R1 is -OH or -CN;

[0226] R2 is -C(=O)R a Group;

[0227] R3 is hydrogen or -OR b Group;

[0228] R4 is selected from hydrogen, -CH2OH, -CH2OC (=O)R c -CH2NH2 and -CH2NHProt NH ;

[0229] R a Selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0230] R bSelected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0231] R c Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 acetylenic group; and

[0232] Prot NH It is an amino protecting group.

[0233] The condition is that when R4 is hydrogen, then X is -O-.

[0234] In another embodiment, the compound of formula I can be a compound of formula I or a pharmaceutically acceptable salt or ester thereof:

[0235]

[0236] in:

[0237] X is -NH-;

[0238] R1 is -OH or -CN;

[0239] R2 is -C(=O)R a Group;

[0240] R3 is hydrogen or -OR b Group;

[0241] R4 is selected from -CH2OH, -CH2O-(C=O)R c -CH2NH2 and -CH2NHProt NH ;

[0242] R a Selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0243] R b Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0244] Rc Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 acetylenic group; and

[0245] Prot NH It is an amino protecting group.

[0246] In another embodiment, the compound of formula I may be a compound of formula ID or a pharmaceutically acceptable salt or ester thereof:

[0247]

[0248] in:

[0249] X is -O-;

[0250] R1 is -OH or -CN;

[0251] R2 is -C(=O)R a Group;

[0252] R3 is hydrogen or -OR b Group;

[0253] R4 is selected from hydrogen, -CH2OH, -CH2O-(C=O)R c -CH2NH2 and -CH2NHProt NH ;

[0254] R a Selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0255] R b Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0256] R c Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 acetylenic group; and

[0257] Prot NH It is an amino protecting group.

[0258] In another embodiment, the compound of formula I can be a compound of formula IE or a pharmaceutically acceptable salt or ester thereof:

[0259]

[0260] in:

[0261] X is -NH- or -O-;

[0262] R1 is -OH or -CN;

[0263] R2 is -C(=O)R a Group;

[0264] R3 is hydrogen or -OR b Group;

[0265] R4 is selected from -CH2NH2 and -CH2NHProt NH ;

[0266] R a Selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0267] R b Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 acetylenic group; and

[0268] Prot NH It is an amino protecting group.

[0269] In another embodiment, the compound of formula I can be a compound of formula IA or a pharmaceutically acceptable salt or ester thereof:

[0270]

[0271] in:

[0272] X is -NH- or -O-;

[0273] R1 is -OH or -CN;

[0274] R2 is -C(=O)R a Group;

[0275] R3 is hydrogen;

[0276] R4 is selected from hydrogen, -CH2OH, -CH2O-(C=O)R c -CH2NH2 and -CH2NHProt NH ;

[0277] R a Selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0278] R c Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 acetylenic group; and

[0279] Prot NH It is an amino protecting group;

[0280] The condition is that when R4 is hydrogen, then X is -O-.

[0281] In another embodiment, the compound of formula I can be a compound of formula IB or a pharmaceutically acceptable salt or ester thereof:

[0282]

[0283] in:

[0284] X is -NH- or -O-;

[0285] R1 is -OH or -CN;

[0286] R2 is -C(=O)R a Group;

[0287] R3 is -OR b Group;

[0288] R4 is selected from hydrogen, -CH2OH, -CH2O-(C=O)R c -CH2NH2

[0289] -CH2NHProt NH ;

[0290] R a Selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0291] R b Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0292] R c Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 acetylenic group; and

[0293] Prot NH It is an amino protecting group;

[0294] The condition is that when R4 is hydrogen, then X is -O-.

[0295] In another embodiment, the compound of formula I can be a compound of formula IF or a pharmaceutically acceptable salt or ester thereof:

[0296]

[0297] in:

[0298] X is -NH- or -O-;

[0299] R1 is -OH;

[0300] R2 is -C(=O)R a Group;

[0301] R3 is hydrogen or -OR b Group;

[0302] R4 is selected from hydrogen, -CH2OH, -CH2OC (=O)R c -CH2NH2 and -CH2NHProt NH ;

[0303] R a Selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0304] R b Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0305] R c Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 acetylenic group; and

[0306] Prot NH It is an amino protecting group.

[0307] The condition is that when R4 is hydrogen, then X is -O-.

[0308] In another embodiment, the compound of formula I can be a compound of formula IG or a pharmaceutically acceptable salt or ester thereof:

[0309]

[0310] in:

[0311] X is -NH- or -O-;

[0312] R1 is -OH or -CN;

[0313] R2 is an acetyl group;

[0314] R3 is hydrogen or -OR b Group;

[0315] R4 is selected from hydrogen, -CH2OH, -CH2OC (=O)R c -CH2NH2 and -CH2NHProt NH ;

[0316] R b Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0317] R c Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 acetylenic group; and

[0318] Prot NH It is an amino protecting group.

[0319] The condition is that when R4 is hydrogen, then X is -O-.

[0320] Preferred compounds of formula I, IA, IB, IC, ID, IE, IF, or IG are compounds having formula a or b, or their pharmaceutically acceptable salts or esters:

[0321]

[0322] Note that in compounds with the general formula a or b, R4 may not be hydrogen.

[0323] Preferred compounds of formula I, IA, IB, ID, IF, or IG may be those having formula c or their pharmaceutically acceptable salts or esters:

[0324]

[0325] in:

[0326] R1 is -OH- or -CN;

[0327] R2 is -C(=O)R a Group;

[0328] R3 is hydrogen or -OR b Group;

[0329] R a Selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0330] R b Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0331] Preferred compounds include those of general formulas I, IA, IB, IE, IF, IG, Ia, IAa, IBa, IEa, IFa, IGa, Ib, IAb, IBb, IEb, IFb, and IGb, wherein:

[0332] X is -NH-;

[0333] And R1; R2; R3; R4; R a ;R b ;R c ; and Prot NH As defined above.

[0334] Preferred compounds include those of general formulas I, IA, IB, IE, IF, IG, Ia, IAa, IBa, IEa, IFa, IGa, Ib, IAb, IBb, IEb, IFb, and IGb, wherein:

[0335] X is -O-;

[0336] And R1; R2; R3; R4; R a ;R b ;R c ; and Prot NH As defined above.

[0337] Other preferred compounds include those of general formulas I, IA, IB, IC, ID, IE, IG, Ia, IAa, IBa, ICa, IDa, IEa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, and IGb, wherein:

[0338] R1 is -OH;

[0339] And X; R2; R3; R4; R a ;R b ;R c ; and Prot NH As defined above.

[0340] Further preferred compounds include compounds of general formulas I, IA, IB, IC, ID, IE, IF, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IB, IBb, ICb, IDb, IEb, and IFb, wherein:

[0341] R2 is -C(=O)R a Group, wherein R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Optimal R 2 It is an acetyl group;

[0342] And X; R1; R3; R4; R b ;R c ; and Prot NH As defined above.

[0343] Further preferred compounds include compounds of general formulas I, IB, IC, ID, IE, IF, IG, Ia, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IBb, ICb, IDb, IEb, IFb, and IGb, wherein:

[0344] For compounds of formula I, IC, ID, IE, IF, IG, Ia, ICa, IDa, IEa, IFa, IGa, Ib, ICb, IDb, IEb, IFb, or IGb, R3 is hydrogen or -OR b Group; for compounds of formula IB, IBa, or IBb, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. b The R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, wherein hydrogen is the preferred R3 group.

[0345] And X; R1; R2; R4; R a ;R c ; and Prot NH As defined above.

[0346] Further preferred compounds include compounds of general formulas I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, and IGb, wherein:

[0347] For compounds of formula I, IA, IB, IC, ID, IF, IG, Ia, IAa, IBa, ICa, IDa, IFa, IFa, IGa, IB, IBb, ICb, IDb, IFb, or IGb, R4 is selected from -CH2OH, -CH2OHC(=O)R c -CH2NH2 and -CH2NHProt NH For compounds of formula IE, IEa, or IEb, R4 is selected from -CH2NH2 and -CH2NHProt. NH ;where R c It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. cSelected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and unsubstituted tert-butyl. Preferably, R c It is a methyl group. More preferably, R4 is selected from -CH2OH and -CH2NH2. More preferably, R4 can be -CH2NH2. Most preferably, R4 is -CH2OH;

[0348] And X; R1; R2; R3; R a ; and R b As defined above.

[0349] Further preferred compounds include those of general formulas I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb, wherein:

[0350] X is -NH-;

[0351] R1 is -OH;

[0352] And R2; R3; R4; R a ;R b ;R c ; and Prot NH As defined above.

[0353] Further preferred compounds include compounds of general formulas I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb, wherein:

[0354] X is -NH-;

[0355] For compounds of formulas I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is -C(=O)R a For compounds of the formula IG, IGa, or IGBb, R2 is an acetyl group; where R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0356] And R1; R3; R4; R b ;R c ; and Prot NH As defined above.

[0357] Further preferred compounds include compounds of general formulas I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb, wherein:

[0358] X is -NH;

[0359] For compounds of formula I, IC, IE, IF, IG, Ia, ICa, IEa, IFa, IGa, Ib, ICb, IEb, IFb, or IGb, R3 is hydrogen or -OR. b Group; for compounds of formula IA, IAa, or IAB, R3 is hydrogen; and for compounds of formula IB, IBa, or IBb, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. b The R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, wherein hydrogen is the preferred R3 group.

[0360] And R1; R2; R4; R a ;R c ; and Prot NH As defined above.

[0361] Further preferred compounds include compounds of general formulas I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb, wherein:

[0362] X is -NH-;

[0363] For compounds of the denoted I, IA, IB, IC, IF, IG, Ia, IAa, IBa, ICa, IFa, IGa, Ib, IAb, IBb, ICb, IFb, or IGb, R4 is selected from -CH2OH, -CH2OC(=O)R. c -CH2NH2 and -CH2NHProt NHFor compounds of formula IE, IEa, or IEb, R4 is selected from -CH2NH2 and -CH2NHProt. NH ;where R c It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. c Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, or substituted or unsubstituted tert-butyl. Optimal R c It is a methyl group. More preferably, R4 is selected from CH2OH and CH2NH2. Even more preferably, R4 can be -CH2NH2. The best R4 is -CH2OH;

[0364] And R1; R2; R3; R a ;R b As defined above.

[0365] Further preferred compounds include compounds of general formulas I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb, wherein:

[0366] X is -NH-;

[0367] R1 is -OH;

[0368] For compounds of formulas I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is -C(=O)R. a For compounds of the formula IG, IGa, or IGBb, R2 is an acetyl group; where R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0369] And R3; R4; R b ;R c ; and Prot NH As defined above.

[0370] Further preferred compounds include compounds of general formulas I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb, wherein:

[0371] X is -NH-;

[0372] R1 is -OH;

[0373] For compounds of formula I, IC, IE, IF, IG, Ia, ICa, IEa, IFa, IGa, Ib, ICb, IEb, IFb, or IGb, R3 is hydrogen or -OR. b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; and for compounds of formula IB, IBa, or IBb, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. b The R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, wherein hydrogen is the preferred R3 group.

[0374] And R2; R4; R a ;R c ; and Prot NH As defined above.

[0375] Further preferred compounds include compounds of general formulas I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb, wherein:

[0376] X is -NH-;

[0377] R1 is -OH;

[0378] For compounds of formula I, IA, IB, IC, IF, IG, Ia, IAa, IBa, Ca, IFa, IGa, Ib, IAb, IBb, ICb, IFb, or IGb, R4 is selected from -CH2OH, -CH2OC(=O)R. c -CH2NH2 and -CH2NHProt NH For compounds of formula IE, IEa, or IEb, R4 is selected from -CH2NH2 and -CH2NHProt. NH;where R c It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. c Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Optimal R c It is a methyl group. Preferably, R4 is selected from CH2OH and CH2NH2. More preferably, R4 can be -CH2NH2. The best R4 is -CH2OH;

[0379] And R2; R3; R a ; and R b As defined above.

[0380] Further preferred compounds include compounds of general formulas I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb, wherein:

[0381] X is -NH-;

[0382] For compounds of formula I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is -C(=O)R. a A functional group; and for compounds of the formula IG, IGa, or IGb, R2 is an acetyl group; wherein R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0383] For compounds of formula I, IC, IE, IF, IG, Ia, ICa, IEa, IFa, IGa, Ib, ICb, IEb, IFb, or IGb, R3 is hydrogen or -OR. b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; and for compounds of formula IB, IBa, or IBb, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. bThe R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, with hydrogen being the most preferred R3 group.

[0384] And R1; R4; R c ; and Prot NH As defined above.

[0385] Further preferred compounds include compounds of general formulas I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb, wherein:

[0386] X is -NH-;

[0387] For compounds of formula I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is -C(=O)R. a A functional group; and for compounds of the formula IG, IGa, or IGb, R2 is an acetyl group; wherein R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0388] For compounds of formula I, IA, IB, IC, IF, IG, Ia, IAa, IBa, Ca, IFa, IGa, Ib, IAb, IBb, ICb, IFb, or IGb, R4 is selected from -CH2OH, -CH2OC(=O)R. c -CH2NH2 and -CH2NHProt NH For compounds of formula IE, IEa, or IEb, R4 is selected from -CH2NH2 and -CH2NHProt. NH ;where R c It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. cSelected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Optimal R c It is a methyl group. Preferably, R4 is selected from CH2OH and CH2NH2. More preferably, R4 can be -CH2NH2. The best R4 is -CH2OH;

[0389] And R1; R3; and R b As defined above.

[0390] Further preferred compounds include compounds of general formulas I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb, wherein:

[0391] X is -NH-;

[0392] For compounds of formula I, IC, IE, IF, IG, Ia, ICa, IEa, IFa, IGa, Ib, ICb, IEb, IFb, or IGb, R3 is hydrogen or -OR. b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; and for compounds of formula IB, IBa, or IBb, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. b The R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, with hydrogen being the most preferred R3 group.

[0393] For compounds of formula I, IA, IB, IC, IF, IG, Ia, IAa, IBa, Ca, IFa, IGa, Ib, IAb, IBb, ICb, IFb, or IGb, R4 is selected from -CH2OH, -CH2OC(=O)R. c -CH2NH2 and -CH2NHProt NH For compounds of formula IE, IEa, or IEb, R4 is selected from -CH2NH2 and -CH2NHProt. NH ;where R c It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred.c Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Optimal R c It is a methyl group. Preferably, R4 is selected from CH2OH and CH2NH2. More preferably, R4 can be -CH2NH2. The best R4 is -CH2OH;

[0394] And R1; R2; and R a As defined above.

[0395] Further preferred compounds include compounds of general formulas I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb, wherein:

[0396] X is -NH-;

[0397] R1 is -OH;

[0398] For compounds of formula I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is -C(=O)R. a A functional group; and for compounds of the formula IG, IGa, or IGb, R2 is an acyl group; wherein R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is an acyl group;

[0399] For compounds of formula I, IC, IE, IF, IG, Ia, ICa, IEa, IFa, IGa, Ib, ICb, IEb, IFb, or IGb, R3 is hydrogen or -OR. b Group; for compounds of formula IA, IAa, or IAb, R 3 It is hydrogen; and for compounds of formula IB, IBa, or IBb, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. bThe R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, with hydrogen being the most preferred R3 group.

[0400] And R4, R c and Prot NH As defined above.

[0401] Further preferred compounds include compounds of general formulas I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb, wherein:

[0402] X is -NH-;

[0403] R1 is -OH;

[0404] For compounds of formula I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is -C(=O)R. a A functional group; and for compounds of the formula IG, IGa, or IGb, R2 is an acetyl group; wherein R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0405] For compounds of formula I, IA, IB, IC, IF, IG, Ia, IAa, IBa, Ca, IFa, IGa, Ib, IAb, IBb, ICb, IFb, or IGb, R4 is selected from -CH2OH, -CH2OC(=O)R. c -CH2NH2 and -CH2NHProt NH For compounds of formula IE, IEa, or IEb, R4 is selected from -CH2NH2 and -CH2NHProt. NH ;where R c It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. cSelected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Optimal R c It is a methyl group. Preferably, R4 is selected from CH2OH and CH2NH2. More preferably, R4 can be -CH2NH2. The best R4 is -CH2OH;

[0406] And R3; and R b As defined above.

[0407] Further preferred compounds include compounds of general formulas I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb, wherein:

[0408] X is -NH-;

[0409] For compounds of formula I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is -C(=O)R. a A functional group; and for compounds of the formula IG, IGa, or IGb, R2 is an acyl group; wherein R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0410] For compounds of formula I, IC, IE, IF, IG, Ia, ICa, IEa, IFa, IGa, Ib, ICb, IEb, IFb, or IGb, R3 is hydrogen or -OR. b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; and for compounds of formula IB, IBa, or IBb, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. bThe R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, with hydrogen being the most preferred R3 group.

[0411] For compounds of formula I, IA, IB, IC, IF, IG, Ia, IAa, IBa, Ca, IFa, IGa, Ib, IAb, IBb, ICb, IFb, or IGb, R4 is selected from -CH2OH, -CH2OC(=O)R. c -CH2NH2 and -CH2NHProt NH For compounds of formula IE, IEa, or IEb, R4 is selected from -CH2NH2 and -CH2NHProt. NH ;where R c It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. c Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Optimal R c It is a methyl group. Preferably, R4 is selected from CH2OH and CH2NH2. More preferably, R4 can be -CH2NH2. The best R4 is -CH2OH;

[0412] And R1 is as defined above.

[0413] Further preferred compounds include compounds of general formulas I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb, wherein:

[0414] X is -NH-;

[0415] R1 is -OH;

[0416] For compounds of formula I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is -C(=O)R. a A functional group; and for compounds of the formula IG, IGa, or IGb, R2 is an acetyl group; wherein R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. aSelected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0417] For compounds of formula I, IC, IE, IF, IG, Ia, ICa, IEa, IFa, IGa, Ib, ICb, IEb, IFb, or IGb, R3 is hydrogen or -OR. b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; and for compounds of formula IB, IBa, or IBb, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. b The R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, with hydrogen being the most preferred R3 group.

[0418] For compounds of formula I, IA, IB, IC, IF, IG, Ia, IAa, IBa, Ca, IFa, IGa, Ib, IAb, IBb, ICb, IFb, or IGb, R4 is selected from -CH2OH, -CH2OC(=O)R. c -CH2NH2 and -CH2NHProt NH For compounds of formula IE, IEa, or IEb, R4 is selected from -CH2NH2 and -CH2NHProt. NH ;where R c It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. c Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Optimal R c It is a methyl group. Preferably, R4 is selected from CH2OH and CH2NH2. More preferably, R4 can be -CH2NH2. The best R4 is -CH2OH.

[0419] Further preferred compounds include compounds of general formulas I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb, wherein:

[0420] X is -O-;

[0421] R1 is -OH;

[0422] And R2, R3, R4, R a R b R c and Prot NH As defined above.

[0423] Further preferred compounds include compounds of general formulas I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb, wherein:

[0424] X is -O-;

[0425] For compounds of formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is -C(=O)R a A functional group; and for compounds of the formula IG, IGa, or IGb, R2 is an acetyl group; wherein R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0426] And R1, R3, R4, R b R c and Prot NH As defined above.

[0427] Further preferred compounds include compounds of general formulas I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb, wherein:

[0428] X is -O-;

[0429] For compounds of formula I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGb, R3 is hydrogen or -OR. b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; and for compounds of formula IB, IBa, or IBb, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. b The R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, with hydrogen being the most preferred R3 group.

[0430] And R1, R2, R4, R a R c and Prot NH As defined above.

[0431] Further preferred compounds include compounds of general formulas I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb, wherein:

[0432] X is -O-;

[0433] For compounds of formula I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, IBa, IB, IBb, IDb, IFb, or IGb, R4 is selected from -CH2OH, -CH2OC(=O)R c -CH2NH2 and -CH2NHProt NH For compounds of formula IE, IEa, or IEb, R4 is selected from -CH2NH2 and -CH2NHProt. NH ;where R c It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. c Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Optimal R cIt is a methyl group. Preferably, R4 is selected from CH2OH and CH2NH2. More preferably, R4 can be -CH2NH2. The best R4 is -CH2OH;

[0434] And R1, R2, R3, R a and R b As defined above.

[0435] Further preferred compounds include compounds of general formulas I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb, wherein:

[0436] X is -O-;

[0437] R1 is -OH;

[0438] For compounds of formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is -C(=O)R a A functional group; and for compounds of the formula IG, IGa, or IGb, R2 is an acetyl group; wherein R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0439] And R3, R4, R b R c and Prot NH As defined above.

[0440] Further preferred compounds include compounds of general formulas I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb, wherein:

[0441] X is -O-;

[0442] R1 is -OH;

[0443] For compounds of formula I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGb, R3 is hydrogen or -OR. bGroup; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; and for compounds of formula IB, IBa, or IBb, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. b The R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, with hydrogen being the most preferred R3 group.

[0444] And R2, R4, R a R c and Prot NH As defined above.

[0445] Further preferred compounds include compounds of general formulas I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb, wherein:

[0446] X is -O-;

[0447] R1 is -OH;

[0448] For compounds of formula I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, IBa, IB, IBb, IDb, IFb, or IGb, R4 is selected from -CH2OH, -CH2OC(=O)R c -CH2NH2 and -CH2NHProt NH For compounds of formula IE, IEa, or IEb, R4 is selected from -CH2NH2 and -CH2NHProt. NH ;where R c It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. c Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Optimal R c It is a methyl group. Preferably, R4 is selected from CH2OH and CH2NH2. More preferably, R4 can be -CH2NH2. The best R4 is -CH2OH;

[0449] And R2, R3, Ra and R b As defined above.

[0450] Further preferred compounds include compounds of general formulas I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb, wherein:

[0451] X is -O-;

[0452] For compounds of formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is -C(=O)R a A functional group; and for compounds of the formula IG, IGa, or IGb, R2 is an acetyl group; wherein R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0453] For compounds of formula I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGb, R3 is hydrogen or -OR. b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; and for compounds of formula IB, IBa, or IBb, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. b The R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, with hydrogen being the most preferred R3 group.

[0454] And R1, R4, R c and Prot NH As defined above.

[0455] Further preferred compounds include compounds of general formulas I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb, wherein:

[0456] X is -O-;

[0457] For compounds of formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is -C(=O)R a A functional group; and for compounds of the formula IG, IGa, or IGb, R2 is an acetyl group; wherein R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0458] For compounds of formula I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, IBa, IB, IBb, IDb, IFb, or IGb, R4 is selected from -CH2OH, -CH2OC(=O)R c -CH2NH2 and -CH2NHProt NH For compounds of formula IE, IEa, or IEb, R4 is selected from -CH2NH2 and -CH2NHProt. NH ;where R c It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. c Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Optimal R c It is a methyl group. Preferably, R4 is selected from CH2OH and CH2NH2. More preferably, R4 can be -CH2NH2. The best R4 is -CH2OH;

[0459] And R1, R3, R b As defined above.

[0460] Further preferred compounds include compounds of general formulas I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb, wherein:

[0461] X is -O-;

[0462] For compounds of formula I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGb, R3 is hydrogen or -OR. b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; and for compounds of formula IB, IBa, or IBb, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. b The R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, with hydrogen being the most preferred R3 group.

[0463] For compounds of formula I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, IBa, IB, IBb, IDb, IFb, or IGb, R4 is selected from -CH2OH, -CH2OC(=O)R c -CH2NH2 and -CH2NHProt NH For compounds of formula IE, IEa, or IEb, R4 is selected from -CH2NH2 and -CH2NHProt. NH ;where R c It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. c Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Optimal R c It is a methyl group. Preferably, R4 is selected from CH2OH and CH2NH2. More preferably, R4 can be -CH2NH2. The best R4 is -CH2OH;

[0464] And R1, R2, R a As defined above.

[0465] Further preferred compounds include compounds of general formulas I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb, wherein:

[0466] X is -O-;

[0467] R1 is -OH;

[0468] For compounds of formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is -C(=O)R a A functional group; and for compounds of the formula IG, IGa, or IGb, R2 is an acetyl group; wherein R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0469] For compounds of formula I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGb, R3 is hydrogen or -OR. b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; and for compounds of formula IB, IBa, or IBb, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. b The R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, with hydrogen being the most preferred R3 group.

[0470] And R4, R c and Prot NH As defined above.

[0471] Further preferred compounds include compounds of general formulas I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb, wherein:

[0472] X is -O-;

[0473] R1 is -OH;

[0474] For compounds of formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is -C(=O)R a A functional group; and for compounds of the formula IG, IGa, or IGb, R2 is an acetyl group; wherein R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0475] For compounds of formula I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, IBa, IB, IBb, IDb, IFb, or IGb, R4 is selected from -CH2OH, -CH2OC(=O)R c -CH2NH2 and -CH2NHProt NH For compounds of formula IE, IEa, or IEb, R4 is selected from -CH2NH2 and -CH2NHProt. NH ;where R c It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. c Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Optimal R c It is a methyl group. Preferably, R4 is selected from CH2OH and CH2NH2. More preferably, R4 can be -CH2NH2. The best R4 is -CH2OH;

[0476] And R3 and R b As defined above.

[0477] Further preferred compounds include compounds of general formulas I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb, wherein:

[0478] X is -O-;

[0479] For compounds of formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is -C(=O)R a A functional group; and for compounds of the formula IG, IGa, or IGb, R2 is an acetyl group; wherein R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0480] For compounds of formula I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGb, R3 is hydrogen or -OR. b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; and for compounds of formula IB, IBa, or IBb, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. b The R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, with hydrogen being the most preferred R3 group.

[0481] For compounds of formula I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, IBa, IB, IBb, IDb, IFb, or IGb, R4 is selected from -CH2OH, -CH2OC(=O)R c -CH2NH2 and -CH2NHProt NH For compounds of formula IE, IEa, or IEb, R4 is selected from -CH2NH2 and -CH2NHProt.NH ;where R c It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. c Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Optimal R c It is a methyl group. Preferably, R4 is selected from CH2OH and CH2NH2. More preferably, R4 can be -CH2NH2. The best R4 is -CH2OH;

[0482] And R1 is defined as above.

[0483] Further preferred compounds include compounds of general formulas I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb, wherein:

[0484] X is -O-;

[0485] R1 is -OH;

[0486] For compounds of formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is -C(=O)R a A functional group; and for compounds of the formula IG, IGa, or IGb, R2 is an acetyl group; wherein R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0487] For compounds of formula I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGb, R3 is hydrogen or -OR. b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; and for compounds of formula IB, IBa, or IBb, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. bThe R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, with hydrogen being the most preferred R3 group.

[0488] For compounds of formula I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, IBa, IB, IBb, IDb, IFb, or IGb, R4 is selected from -CH2OH, -CH2OC(=O)R c -CH2NH2 and -CH2NHProt NH For compounds of formula IE, IEa, or IEb, R4 is selected from -CH2NH2 and -CH2NHProt. NH ;where R c It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. c Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Optimal R c It is a methyl group. Preferably, R4 is selected from CH2OH and CH2NH2. More preferably, R4 can be -CH2NH2. The best R4 is -CH2OH.

[0489] Further preferred compounds include compounds of general formulas Ic, IAc, IBc, IDc, and IGC, wherein:

[0490] R1 is -OH;

[0491] And R2, R3, R a and R b As defined above.

[0492] Further preferred compounds include compounds of general formulas Ic, IAc, IBc, IDc, IFc, and IGC, wherein:

[0493] For compounds of formula Ic, IAc, IBc, IDc, or IFc, R2 is -C(=O)R. a Group; and for compounds of formula IGC, R2 is an acetyl group; where R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. aSelected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0494] And R1, R3, R b As defined above.

[0495] Further preferred compounds include compounds of general formulas Ic, IAc, IBc, IDc, IFc, and IGC, wherein:

[0496] For compounds of formula Ic, IDc, IFc, or IGc, R3 is hydrogen or -OR. b Group; for compounds of formula IAc, R3 is hydrogen; and for compounds of formula IBc, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. b The R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, with hydrogen being the most preferred R3 group.

[0497] And R1, R2 and R a As defined above.

[0498] Further preferred compounds include compounds of general formulas Ic, IAc, IBc, IDc, IFc, and IGC, wherein:

[0499] R1 is -OH;

[0500] For compounds of formula Ic, IAc, IBc, IDc, or IFc, R2 is -C(=O)R. a Group; and for compounds of formula IGC, R2 is an acetyl group; where R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0501] And R 3 and Rb As defined above.

[0502] Further preferred compounds include compounds of general formulas Ic, IAc, IBc, IDc, IFc, and IGC, wherein:

[0503] R1 is -OH;

[0504] For compounds of formula Ic, IDc, IFc, or IGc, R3 is hydrogen or -OR. b Group; for compounds of formula IAc, R3 is hydrogen; and for compounds of formula IBc, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. b The R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, with hydrogen being the most preferred R3 group.

[0505] And R2 and R a As defined above.

[0506] Further preferred compounds include compounds of general formulas Ic, IAc, IBc, IDc, IFc, and IGC, wherein:

[0507] For compounds of formula Ic, IAc, IBc, IDc, or IFc, R2 is -C(=O)R. a Group; and for compounds of formula IGC, R2 is an acetyl group; where R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0508] For compounds of formula Ic, IDc, IFc, or IGc, R3 is hydrogen or -OR. b Group; for compounds of formula IAc, R3 is hydrogen; and for compounds of formula IBc, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. bThe R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, with hydrogen being the most preferred R3 group.

[0509] And R1 is defined as above.

[0510] Further preferred compounds include compounds of general formulas Ic, IAc, IBc, IDc, IFc, and IGC, wherein:

[0511] R1 is -OH;

[0512] For compounds of formula Ic, IAc, IBc, IDc, or IFc, R2 is -C(=O)R. a Group; and for compounds of formula IGC, R2 is an acetyl group; where R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0513] For compounds of formula Ic, IDc, IFc, or IGc, R3 is hydrogen or -OR. b Group; for compounds of formula IAc, R3 is hydrogen; and for compounds of formula IBc, R3 is -OR b Group; wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. b The R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, with hydrogen being the most preferred R3 group.

[0514] The following preferred substituents (where possible substituents are permitted) are applicable to compounds of formulas I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, IGb, Ic, IAc, IBc, IDc, IFc, and IGc:

[0515] In the compounds of the present invention, R1 is particularly preferred to be -OH.

[0516] In the compounds of the present invention, R2 is particularly preferred to be a -C(=O)Ra group, wherein R a It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. a The R2 is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. The preferred R2 is acetyl.

[0517] In the compounds of the present invention, R3 is particularly preferably hydrogen or -OR. b Group, wherein R b It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. b The R3 group is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Preferably, R3 is hydrogen and methoxy, with hydrogen being the most preferred R3 group.

[0518] In the compounds of the present invention, R4 is particularly preferably selected from H, -CH2OH, -CH2OC(=O)R. c -CH2NH2 and -CH2NHProt NH ;where R c It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. c Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Optimal R c It is a methyl group. Preferably, R4 is selected from CH2OH and CH2NH2. More preferably, R4 can be -CH2NH2. The best R4 is -CH2OH.

[0519] In compounds of general formulas I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, and IGb, for compounds of formulas I, IA, IB, IC, ID, IF, IG, Ia, IAa, IBa, ICa, IDa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IFb, or IGb, particularly preferably R4 is selected from -CH2OH, -CH2OC(=O)R c -CH2NH2 and -CH2NHProt NH For compounds of formula IE, IEa, or IEb, R4 is selected from -CH2NH2 and -CH2NHProt. NH ;where R c It is a substituted or unsubstituted C1-C6 alkyl group. R is particularly preferred. c Selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. Optimal R c It is a methyl group. Preferably, R4 is selected from CH2OH and CH2NH2. More preferably, R4 can be -CH2NH2. The best R4 is -CH2OH.

[0520] When R4 is -CH2OH or -CH2OC(=O)R c When R4 is -CH2NH2 or -CH2NHProt, the compounds of formulas Ia, IAa, IBa, ICa, IDa, IFa, and IGa are particularly preferred, especially when R4 is -CH2NH2 or -CH2NHProt. NH Compounds of formula Ib, Iab, IBb, ICb, IDb, IEb, IFb, and IGb are particularly preferred.

[0521] In the compounds of the present invention, X is particularly preferred to be -NH-.

[0522] Alternatively, in the compounds of the present invention, X is particularly preferred to be -O-.

[0523] Preferred compounds according to the present invention include:

[0524] Compounds of formulas I, IA, IB, IC, ID, IF, IG, Ia, IAa, IBa, ICa, IDa, IFa, IGa, IGa, IBb, IBb, ICb, IDb, IFb, and IGb, wherein:

[0525] R4 is selected from -CH2OH and -CH2OC(=O)R c ;

[0526] More preferably, compounds of formulas Ia, IAa, IBa, ICa, IDa, IFa, and IGa and / or compounds in which R4 is -CH2OH.

[0527] Compounds of formulas I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, and IGb, wherein:

[0528] R4 is selected from -CH2NH2 and -CH2NHProt NH ;and

[0529] Prot NH It is an amine protecting group.

[0530] More preferably, compounds of formulas Ib, IAb, IBb, ICb, IDb, IEb, IFb, and IGb and / or compounds in which R4 is -CH2NH2.

[0531] Compounds of formulas Ic, IAc, IBc, IDc, IFc, and IGC, wherein

[0532] For compounds of formula Ic, IAc, IBc, IDc, or IFc, R2 is -C(=O)R. a Group; for compounds of formula IGC, R2 is an acetyl group;

[0533] For compounds of formula Ic, IDc, IFc, and IGc, R3 is hydrogen or -OR. b Group; for IAc compounds, R3 is hydrogen; or for IBc compounds, R3 is -OR b Group;

[0534] R a Selected from hydrogen and substituted or unsubstituted C1-C6 alkyl groups; and

[0535] R b It is a substituted or unsubstituted C1-C6 alkyl group.

[0536] The particularly preferred compounds according to the invention include:

[0537] Compounds of formulas I, IA, IB, IC, IF, IG, Ia, IAa, IBa, ICa, IFa, IGa, IB, IAb, IBb, ICb, IFb, and IGb, wherein

[0538] X is -NH-;

[0539] R4 is selected from -CH2OH and -CH2OC(=O)R c ;

[0540] and

[0541] R c Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 Alkyne group.

[0542] More preferably, compounds of formula Ia, IAa, IBa, ICa, IFa, IGa and / or compounds in which R4 is -CH2OH.

[0543] Compounds of formulas I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, IGa, IBb, IBb, IDb, IFb, and IGb, wherein

[0544] X is -O-;

[0545] R4 is selected from -CH2OH and -CH2OC(=O)R c ;

[0546] and

[0547] R c Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 Alkyne group.

[0548] More preferably, compounds of formula Ia, IAa, IBa, IDa, IFa, IGa and / or compounds in which R4 is -CH2OH.

[0549] Compounds of formulas I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb, wherein

[0550] X is -NH-;

[0551] R4 is selected from -CH2NH2 and -CH2NHProt NH ;

[0552] and

[0553] Prot NH It is an amine protecting group.

[0554] More preferably, compounds of formula Ib, IAb, IBb, ICb, IEb, IFb, IGb and / or compounds in which R4 is -CH2NH2.

[0555] Compounds of formulas I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb, wherein

[0556] X is -O-;

[0557] R4 is selected from -CH2NH2 and -CH2NHProt NH ;

[0558] and

[0559] Prot NH It is an amine protecting group.

[0560] More preferably, compounds of formula Ib, IAb, IBb, IDb, IEb, IFb, IGb and / or compounds in which R4 is -CH2NH2.

[0561] Compounds of formulas I, IA, IB, IC, ID, IF, IG, Ia, IAa, IBa, ICa, IDa, IFa, IGa, IGa, IBb, IBb, ICb, IDb, IFb, and IGb, wherein...

[0562] For compounds of formulas I, IA, IB, IC, ID, IF, Ia, IAa, IBa, ICa, IDa, IFa, Ib, IAb, IBb, ICb, IDb, or IFb, R2 is -C(=O)R. a Group; and for formula IG, IGa or IGb, R2 is an acetyl group;

[0563] For compounds of formula I, IC, ID, IF, IG, Ia, ICa, IDa, IFa, IGa, Ib, ICb, IDb, IFb, or IGb, R3 is hydrogen or -OR b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; or for compounds of formula IB, IBa, or IBb, R3 is -OR b Group;

[0564] R4 is selected from -CH2OH and -CH2OC(=O)R c ;

[0565] R a Selected from hydrogen and substituted or unsubstituted C1-C6 alkyl groups;

[0566] R b It is a substituted or unsubstituted C1-C6 alkyl group; and

[0567] R c It is a substituted or unsubstituted C1-C6 alkyl group.

[0568] More preferably, compounds of formula Ia, IAa, IBa, ICa, IDa, IFa, IGa and / or compounds in which R4 is -CH2OH.

[0569] Compounds of formulas I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, and IGb, wherein

[0570] For compounds of formulas I, IA, IB, IC, ID, IF, Ia, IAa, IBa, ICa, IDa, IFa, Ib, IAb, IBb, ICb, IDb, or IFb, R2 is -C(=O)R. a Group; and for formula IG, IGa or IGb, R2 is an acetyl group;

[0571] For compounds of formula I, IC, ID, IE, IF, IG, Ia, ICa, IDa, IEa, IFa, IGa, Ib, ICb, IDb, IEb, IFb, or IGb, R3 is hydrogen or -OR b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; or for compounds of formula IB, IBa, or IBb, R3 is -OR b Group;

[0572] R4 is selected from -CH2NH2 and -CH2NHProt NH ;

[0573] R a Selected from hydrogen and substituted or unsubstituted C1-C6 alkyl groups;

[0574] R b It is a substituted or unsubstituted C1-C6 alkyl group; and

[0575] Prot NH It is an amine protecting group.

[0576] More preferably, compounds of formula Ib, IAb, IBb, ICb, IDb, IEb, IFb, IGb and / or compounds in which R4 is -CH2NH2.

[0577] Compounds of formulas Ic, IAc, IBc, IDc, IFc, and IGC, wherein

[0578] For compounds of formula Ic, IAc, IBc, IDc, or IFc, R2 is -C(=O)R. a Group; and for compounds of formula IGC, R2 is an acetyl group;

[0579] For compounds of formula Ic, IDc, IFc, and IGc, R3 is hydrogen or -OR b Group; for compounds of formula IAc, R3 is hydrogen; or for compounds of formula IBc, R3 is -OR b Group;

[0580] R a It is a substituted or unsubstituted C1-C6 alkyl group; and

[0581] R b It is a substituted or unsubstituted C1-C6 alkyl group.

[0582] The preferred compounds according to the present invention include:

[0583] Compounds of formulas I, IA, IB, IC, IF, IG, Ia, IAa, IBa, ICa, IFa, IGa, IB, IAb, IBb, ICb, IFb, and IGb, wherein

[0584] X is -NH-;

[0585] For compounds of formula I, IA, IB, IC, IF, Ia, IAa, IBa, ICa, IFa, Ib, IABb, IBb, ICb, or IFb, R2 is -C(=O)R. a Group; and for formula IG, IGa or IGb, R2 is an acetyl group;

[0586] For compounds of formula I, IC, IF, IG, Ia, ICa, IFa, IGa, Ib, ICb, IFb, or IGb, R3 is hydrogen or -OR b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; or for compounds of formula IB, IBa, or IBb, R3 is -OR b Group;

[0587] R4 is -CH2OH;

[0588] R a Selected from hydrogen and substituted or unsubstituted C1-C6 alkyl groups; and

[0589] R b It is a substituted or unsubstituted C1-C6 alkyl group.

[0590] More preferably, compounds of formula Ia, IAa, or IBa, ICa, IFa, IGa are preferred.

[0591] Compounds of formulas I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, IGa, IBb, IBb, IDb, IFb, and IGb, wherein

[0592] X is -O-;

[0593] For compounds of formulas I, IA, IB, ID, IF, Ia, IAa, IBa, IDa, IFa, Ib, IAB, IBb, IDb, or IFb, R2 is -C(=O)R. a Group; and for formula IG, IGa or IGb, R2 is an acetyl group;

[0594] For compounds of formula I, ID, IF, IG, Ia, IDa, IFa, IGa, Ib, IDb, IFb, or IGb, R3 is hydrogen or -OR b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; or for compounds of formula IB, IBa, or IBb, R3 is -OR b Group;

[0595] R4 is -CH2OH;

[0596] R a Selected from hydrogen and substituted or unsubstituted C1-C6 alkyl groups; and R b It is a substituted or unsubstituted C1-C6 alkyl group.

[0597] Compounds of formula Ia, IAa, IBa, IDa, IFa, or IGa are particularly preferred.

[0598] Compounds of formulas I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb, wherein

[0599] X is -NH-;

[0600] For compounds of formula I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is -C(=O)R. a Group; and for formula IG, IGa or IGb, R2 is an acetyl group;

[0601] For compounds of formula I, IC, IE, IF, IG, Ia, ICa, IEa, IFa, IGa, Ib, ICb, IEb, IFb, or IGb, R3 is hydrogen or -OR b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; or for compounds of formula IB, IBa, or IBb, R3 is -OR b Group;

[0602] R4 is selected from -CH2NH2 and -CH2NHProt NH ;

[0603] R a Selected from hydrogen and substituted or unsubstituted C1-C6 alkyl groups;

[0604] R b It is a substituted or unsubstituted C1-C6 alkyl group; and

[0605] Prot NH It is an amine protecting group.

[0606] More preferably, compounds of formula Ib, IAb, IBb, ICb, IEb, IFb, IGb and / or compounds in which R4 is -CH2NH2.

[0607] Compounds of formulas I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb, wherein

[0608] X is -O-;

[0609] For compounds of formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is -C(=O)R a Group; and for formula IG, IGa or IGb, R2 is an acetyl group;

[0610] For compounds of formula I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGb, R3 is hydrogen or -OR b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; or for compounds of formula IB, IBa, or IBb, R3 is -OR b Group;

[0611] R4 is selected from -CH2NH2 and -CH2NHProt NH ;

[0612] R a Selected from hydrogen and substituted or unsubstituted C1-C6 alkyl groups;

[0613] R b It is a substituted or unsubstituted C1-C6 alkyl group; and

[0614] Prot NH It is an amine protecting group.

[0615] More preferably, compounds of formula Ib, IAb, IBb, IDb, IEb, IFb, IGb and / or compounds in which R4 is -CH2NH2.

[0616] Compounds of formulas I, IA, IB, IC, ID, IF, IG, Ia, IAa, IBa, ICa, IDa, IFa, IGa, IGa, IB, IBb, ICb, IDb, IFb, and IGb, wherein

[0617] For compounds of formulas I, IA, IB, IC, ID, IF, Ia, IAa, IBa, ICa, IDa, IFa, Ib, IAb, IBb, ICb, IDb, or IFb, R2 is -C(=O)R. a Group; and for formula IG, IGa or IGb, R2 is an acetyl group;

[0618] For compounds of formula I, IC, ID, IF, IG, Ia, ICa, IDa, IFa, IGa, Ib, ICb, IDb, IFb, or IGb, R3 is hydrogen or -OR b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; or for compounds of formula IB, IBa, or IBb, R3 is -OR b Group;

[0619] R4 is -CH2OH;

[0620] R a It is a substituted or unsubstituted C1-C6 alkyl group; and

[0621] R b It is a substituted or unsubstituted C1-C6 alkyl group.

[0622] More preferably, compounds of formula Ia, IAa, IBa, ICa, IDa, IFa, or IGa are preferred.

[0623] Compounds of formulas I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, and IGb, wherein

[0624] For compounds of formula I, IA, IB, IC, ID, IE, IF, Ia, IAa, IBa, ICa, IDa, IEa, IFa, Ib, IAb, IBb, ICb, IDb, IEb, or IFb, R2 is -C(=O)R a Group; and for formula IG, IGa or IGb, R2 is an acetyl group;

[0625] For compounds of formula I, IC, ID, IE, IF, IG, Ia, ICa, IDa, IEa, IFa, IGa, Ib, ICb, IDb, IEb, IFb, or IGb, R3 is hydrogen or -OR b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; or for compounds of formula IB, IBa, or IBb, R3 is -OR b Group;

[0626] R4 is selected from -CH2NH2 and -CH2NHProt NH ;

[0627] R a It is a substituted or unsubstituted C1-C6 alkyl group;

[0628] R b It is a substituted or unsubstituted C1-C6 alkyl group; and

[0629] Prot NH It is an amine protecting group.

[0630] More preferably, compounds of formula Ib, IAb, IBb, ICb, IDb, IEb, IFb, IGb and / or compounds in which R4 is -CH2NH2.

[0631] Compounds of formulas I, IA, IB, IC, IF, IG, Ia, IAa, IBa, ICa, IFa, IGa, IB, IAb, IBb, ICb, IFb, and IGb, wherein

[0632] X is -NH-;

[0633] For compounds of formula I, IA, IB, IC, IF, Ia, IAa, IBa, ICa, IFa, Ib, IABb, IBb, ICb, or IFb, R2 is -C(=O)R. aGroup; and for formula IG, IGa or IGb, R2 is an acetyl group;

[0634] For compounds of formula I, IC, IF, IG, Ia, ICa, IFa, IGa, Ib, ICb, IFb, or IGb, R3 is hydrogen or -OR b Group; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; or for compounds of formula IB, IBa, or IBb, R3 is -OR b Group;

[0635] R4 is -CH2OC(=O)R c ;

[0636] R a Selected from hydrogen and substituted or unsubstituted C1-C6 alkyl groups;

[0637] R b It is a substituted or unsubstituted C1-C6 alkyl group; and

[0638] R c It is a substituted or unsubstituted C1-C6 alkyl group.

[0639] More preferably, compounds of formula Ia, IAa, IBa, ICa, IFa, or IGa are preferred.

[0640] Compounds of formulas Ic, IAc, IBc, IDc, IFc, and IGC, wherein

[0641] For compounds of formula Ic, IAc, IBc, IDc, or IFc, R2 is -C(=O)R. a Group; and for formula IGC, R2 is an acetyl group;

[0642] For compounds of formula Ic, IDc, IFc, or IGc, R3 is hydrogen or methoxy; for compounds of formula IAc, R3 is hydrogen; or for compounds of formula IBc, R3 is methoxy; and

[0643] R a It is a substituted or unsubstituted C1-C6 alkyl group.

[0644] The particularly preferred compounds according to the invention include:

[0645] Compounds of formulas I, IA, IB, IC, IF, IG, Ia, IAa, IBa, ICa, IFa, IGa, IB, IAb, IBb, ICb, IFb, and IGb, wherein

[0646] X is -NH-;

[0647] For compounds of formula I, IA, IB, IC, IF, Ia, IAa, IBa, ICa, IFa, Ib, IABb, IBb, ICb, or IFb, R2 is -C(=O)R. a Group; and for formula IG, IGa or IGb, R2 is an acetyl group;

[0648] For compounds of formula I, IC, IF, IG, Ia, ICa, IFa, IGa, Ib, ICb, IFb, or IGb, R3 is hydrogen or methoxy; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; or for compounds of formula IB, IBa, or IBb, R3 is methoxy.

[0649] R4 is -CH2OH; and

[0650] R a It is a substituted or unsubstituted C1-C6 alkyl group.

[0651] Even better are compounds of formulas Ia, IAa, IBa, ICa, IFa, and IGa.

[0652] Compounds of formulas I, IA, IB, ID, IF, IG, Ia, IAa, IBa, IDa, IFa, IGa, IGa, IBb, IBb, IDb, IFb, and IGb, wherein

[0653] X is -O-;

[0654] For compounds of formulas I, IA, IB, ID, IF, Ia, IAa, IBa, IDa, IFa, Ib, IAB, IBb, IDb, or IFb, R2 is -C(=O)R. a For compounds of the formula IG, IGa, or IGBb, R2 is an acetyl group.

[0655] For compounds of formula I, ID, IF, IG, Ia, IDa, IFa, IGa, Ib, IDb, IFb, or IGb, R3 is hydrogen or methoxy; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; or for compounds of formula IB, IBa, or IBb, R3 is methoxy.

[0656] R4 is CH2OH; and

[0657] R a It is a substituted or unsubstituted C1-C6 alkyl group.

[0658] Even better are compounds of formulas Ia, IAa, IBa, IDa, IEa, IFa, and IGa.

[0659] Compounds of formulas I, IA, IB, IC, IE, IF, IG, Ia, IAa, IBa, ICa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IEb, IFb, and IGb, wherein

[0660] X is -NH-;

[0661] For compounds of formulas I, IA, IB, IC, IE, IF, Ia, IAa, IBa, ICa, IEa, IFa, Ib, IAb, IBb, ICb, IEb, or IFb, R2 is -C(=O)R. a For compounds of the formula IG, IGa, or IGBb, R2 is an acetyl group.

[0662] For compounds of formula I, IC, IE, IF, IG, Ia, ICa, IEa, IFa, IGa, Ib, ICb, IEb, IFb, or IGBb, R3 is hydrogen or methoxy; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; or for compounds of formula IB, IBa, or IBb, R3 is methoxy.

[0663] R4 is selected from -CH2NH2 and -CH2NHProt NH ;

[0664] R a It is a substituted or unsubstituted C1-C6 alkyl group; and

[0665] Prot NH It is an amine protecting group.

[0666] Even more preferably, compounds of formula Ib, IAb, IBb, ICb, IEb, IFb, IGb and / or wherein R4 is -CH2NH2 is a compound.

[0667] Compounds of formulas I, IA, IB, ID, IE, IF, IG, Ia, IAa, IBa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, IDb, IEb, IFb, and IGb, wherein

[0668] X is -O-;

[0669] For compounds of formulas I, IA, IB, ID, IE, IF, Ia, IAa, IBa, IDa, IEa, IFa, Ib, IAb, IBb, IDb, IEb, or IFb, R2 is -C(=O)R. a For compounds of the formula IG, IGa, or IGBb, R2 is an acetyl group.

[0670] For compounds of formula I, ID, IE, IF, IG, Ia, IDa, IEa, IFa, IGa, Ib, IDb, IEb, IFb, or IGBb, R3 is hydrogen or methoxy; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; or for compounds of formula IB, IBa, or IBb, R3 is methoxy.

[0671] R4 is selected from -CH2NH2 and -CH2NHProt NH ;

[0672] R a It is a substituted or unsubstituted C1-C6 alkyl group; and

[0673] Prot NH It is an amine protecting group.

[0674] Even more preferably, compounds of formula Ib, IAb, IBb, IDb, IEb, IFb, IGb and / or wherein R4 is -CH2NH2 is a compound.

[0675] Compounds of formulas I, IA, IB, IC, ID, IF, IG, Ia, IAa, IBa, ICa, IDa, IFa, IGa, IGa, IB, IBb, ICb, IDb, IFb, and IGb, wherein

[0676] For compounds of formulas I, IA, IB, IC, ID, IF, Ia, IAa, IBa, ICa, IDa, IFa, Ib, IAb, IBb, ICb, IDb, or IFb, R2 is -C(=O)R. a For compounds of the formula IG, IGa, or IGBb, R2 is an acetyl group.

[0677] For compounds of formula I, IC, ID, IF, IG, Ia, ICa, IDa, IFa, IGa, Ib, ICb, IDb, IFb, or IGb, R3 is hydrogen or methoxy; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; or for compounds of formula IB, IBa, or IBb, R3 is methoxy.

[0678] R4 is -CH2OH;

[0679] R a Selected from methyl, ethyl, n-propyl, isopropyl, and butyl, including n-butyl, tert-butyl, isobutyl, and tert-butyl.

[0680] Even more preferred are compounds of the formulas Ia, IAa, IBa, ICa, IDa, IEa, IFa, or IGa.

[0681] Compounds of formulas I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, and IGb, wherein

[0682] For compounds of formulas I, IA, IB, IC, ID, IE, IF, Ia, IAa, IBa, ICa, IDa, IEa, IFa, Ib, IAb, IBb, ICb, IDb, IEb, or IFb, R2 is -C(=O)R. a For compounds of the formula IG, IGa, or IGBb, R2 is an acetyl group.

[0683] For compounds of formula I, IC, ID, IE, IF, IG, Ia, ICa, IDa, IEa, IFa, IGa, Ib, ICb, IDb, IEb, IFb, or IGBb, R3 is hydrogen or methoxy; for compounds of formula IA, IAa, or IAb, R3 is hydrogen; or for compounds of formula IB, IBa, or IBb, R3 is methoxy.

[0684] R4 is selected from -CH2NH2 and -CH2NHProt NH ;

[0685] R a Selected from methyl, ethyl, n-propyl, isopropyl, and butyl, including n-butyl, tert-butyl, isobutyl, and tert-butyl; and

[0686] Prot NH It is an amine protecting group.

[0687] Even more preferably, compounds of the formula Ib, IAb, IBb, ICb, IDb, IEb, IFb, IGb and / or wherein R4 is -CH2NH2 is a compound.

[0688] Compounds of formula Ic or IAc, IDc, IFc and IGC, wherein

[0689] For compounds of formula Ic, IAc, IDc, or IFc, R2 is -C(=O)R. a Group; and for compounds of formula IGC, R2 is an acetyl group;

[0690] R 3 It is hydrogen; and

[0691] R a Selected from methyl, ethyl, n-propyl, isopropyl, and butyl, including n-butyl, tert-butyl, isobutyl, and tert-butyl.

[0692] Compounds of formulas Ic, IBc, IDc, IFc, and IGC, wherein

[0693] For compounds of formula Ic, IBc, IDc, or IFc, R2 is -C(=O)R. a Group; and for compounds of formula IGC, R2 is an acetyl group;

[0694] R3 is a methoxy group; and

[0695] R a Selected from methyl, ethyl, n-propyl, isopropyl, and butyl, including n-butyl, tert-butyl, isobutyl, and tert-butyl.

[0696] The compounds according to the present invention, even more preferably, include:

[0697] Compounds of formulas I, IA, IC, IF, IG, Ia, IAa, ICa, IFa, IGa, Ib, IAb, ICb, IFb, and IGb, wherein

[0698] X is -NH-;

[0699] R2 is an acetyl group;

[0700] R3 is hydrogen; and

[0701] R4 is -CH2OH.

[0702] The best are compounds of formula Ia, IAa, ICa, IFa, or IGa.

[0703] Compounds of formulas I, IA, ID, IF, IG, Ia, IAa, IDa, IFa, IGa, IB, IAb, IDb, IFb, and IGb, wherein...

[0704] X is -O-;

[0705] R2 is an acetyl group;

[0706] R3 is hydrogen; and

[0707] R4 is -CH2OH.

[0708] The best are compounds of formula Ia, IAa, IDa, IFa, or IGa.

[0709] Compounds of formulas I, IA, IC, IE, IF, IG, Ia, IAa, ICa, IEa, IFa, IGa, Ib, IAb, ICb, IEb, IFb, and IGb, wherein...

[0710] X is -NH-;

[0711] R2 is an acetyl group;

[0712] R3 is hydrogen; and

[0713] R4 is -CH2NH2.

[0714] The best are compounds of formula Ib, Iab, ICb, IEb, IFb or IGb.

[0715] Compounds of formulas I, IA, ID, IE, IF, IG, Ia, IAa, IDa, IEa, IFa, IGa, Ib, IAb, IDb, IEb, IFb, and IGb, wherein...

[0716] X is -O-;

[0717] R2 is an acetyl group;

[0718] R3 is hydrogen; and

[0719] R4 is -CH2NH2.

[0720] The best are compounds of formula Ib, IAb, IDb, IEb, IFb or IGb.

[0721] Compounds of formulas I, IA, IC, ID, IF, IG, Ia, IAa, ICa, IDa, IFa, IGa, IB, IAb, ICb, IDb, IFb, and IGb, wherein...

[0722] R2 is an acetyl group;

[0723] R3 is hydrogen; and

[0724] R4 is -CH2OH.

[0725] The best are compounds of formula Ia, IAa, ICa, IDa, IFa, or IGa.

[0726] Compounds of formulas I, IA, IC, ID, IF, IG, Ia, IAa, ICa, IDa, IFa, IGa, IB, IAb, ICb, IDb, IFb, and IGb, wherein...

[0727] R1 is -OH;

[0728] R2 is an acetyl group;

[0729] R3 is hydrogen; and

[0730] R4 is -CH2OH.

[0731] The best are compounds of formula Ia, IAa, ICa, IDa, IFa, or IGa.

[0732] Compounds of formulas I, IA, IC, ID, IE, IF, IG, Ia, IAa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, ICb, IDb, IEb, IFb, and IGb, wherein

[0733] R2 is an acetyl group;

[0734] R3 is hydrogen; and

[0735] R4 is -CH2NH2.

[0736] The optimal compounds are those with the formulas Ib, IAb, ICb, IDb, IEb, IFb, or IGb.

[0737] Compounds of formula Ic or IAc, IDc, IFc, IGC, wherein

[0738] R2 is an acetyl group; and

[0739] R3 is hydrogen.

[0740] Compounds of formula Ic or IBc, IDc, IFc, IGC, wherein:

[0741] R2 is an acetyl group; and

[0742] R3 is a methoxy group.

[0743] • Compounds of the following formula according to the invention, or pharmaceutically acceptable salts or esters thereof:

[0744]

[0745]

[0746] Particularly preferred are compounds of the following formula or their pharmaceutically acceptable salts or esters:

[0747]

[0748] According to the invention, the following compounds or their pharmaceutically acceptable salts or esters:

[0749]

[0750] Particularly preferred are compounds of the following formula or their pharmaceutically acceptable salts or esters:

[0751]

[0752] More preferably, compounds of the following formula or their pharmaceutically acceptable salts or esters:

[0753]

[0754]

[0755] Even more preferred are the following compounds according to the invention or their pharmaceutically acceptable salts or esters:

[0756]

[0757] The preferred options are the following compounds according to the invention, or their pharmaceutically acceptable salts or esters:

[0758]

[0759] In another preferred embodiment, the above-described preferred options regarding different substituents are combined. The invention also relates to such combinations of preferred substituents (where possible substituents) in compounds of formula I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, IGb, Ic, IAc, IBc, IDc, IFc, or IGc.

[0760] An important characteristic of the above-mentioned compounds is their biological activity, and in particular their cytotoxic activity. In this respect, we have surprisingly found that the compounds of the present invention exhibit enhanced antitumor activity, as shown in Examples 27 and 29 to 40.

[0761] Compositions comprising compounds of formula I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, IGb, Ic, IAc, IBc, IDc, IFc, or IGc, and their uses.

[0762] In another embodiment of the invention, a pharmaceutical composition comprising the compound according to the invention and its pharmaceutically acceptable carrier is provided. Examples of administration methods include, but are not limited to, oral, topical, parenteral, sublingual, rectal, vaginal, ocular, and intranasal administration. Parenteral administration includes subcutaneous injection, intravenous, intramuscular, intrasternal injection, or infusion techniques. Preferably, the composition is administered parenterally. The pharmaceutical compositions of the invention can be formulated to make the compounds of the invention bioavailable when administered to animals, preferably humans. The compositions can be in the form of one or more dose units, wherein, for example, tablets can be single dose units, and containers for the compounds according to the invention can contain the compound in liquid or aerosol form and can contain single or multiple dose units.

[0763] Pharmaceutically acceptable carriers or excipients may be granular, such that the composition is, for example, in tablet or powder form. The carrier may be a liquid, and the composition may be, for example, an oral syrup or an injectable liquid. Alternatively, the carrier may be a gas or liquid to provide an aerosol composition for, for example, inhalation administration. Powders may also be used in inhalation formulations. The term "carrier" refers to a diluent, adjuvant, or excipient administered with the compounds of the present invention. Such pharmaceutical carriers may be liquids, such as water, and oils including those of petroleum, animal, plant, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. Carriers may be saline, gum arabic, gelatin, starch paste, talc, keratin, colloidal silica, urea, disaccharides, and the like. Additionally, adjuvants, stabilizers, thickeners, lubricants, and colorants may be used. In one embodiment, when administered to animals, the compounds and compositions according to the invention, as well as the pharmaceutically acceptable carriers, are sterile. When the compounds according to the invention are administered intravenously, water is a preferred carrier. Saline solutions, glucose solutions, and glycerol solutions can also be used as liquid carriers, especially for injectable solutions. Suitable drug carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skim milk powder, glycerol, propylene glycol, water, ethanol, and the like. If desired, the composition may also contain small amounts of wetting agents, emulsifiers, or pH buffers.

[0764] When intended for oral administration, the composition is preferably in solid or liquid form, wherein semi-solid, semi-liquid, suspension and gel forms are included in what is considered as solid or liquid form herein.

[0765] As a solid composition for oral administration, the composition can be formulated into powders, granules, tablets, pills, capsules, chewing gum, film tablets, or similar dosage forms. Such solid compositions typically contain one or more inert diluents. Additionally, one or more of the following substances may be present: binders, such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, or gelatin; excipients such as starch, lactose, or dextrin; disintegrants such as alginate, sodium alginate, corn starch, and the like; lubricants such as magnesium stearate; gliding agents such as colloidal silica; sweeteners such as sucrose or saccharin; flavoring agents such as peppermint, methyl salicylate, or orange flavorings; and coloring agents.

[0766] When the composition is in capsule form (e.g., gelatin capsule), in addition to the materials of the types described above, it may also contain liquid carriers such as polyethylene glycol, cyclodextrin, or fatty oils.

[0767] The composition may be in liquid form, such as an elixir, syrup, solution, emulsifier, or suspension. The liquid may be used for oral administration or by injection. When intended for oral administration, the composition may contain one or more of a sweetener, preservative, dye / coloring agent, and flavor enhancer. In compositions intended for injection administration, one or more of a surfactant, preservative, wetting agent, dispersant, suspending agent, buffer, stabilizer, and isotonic agent may also be included.

[0768] Preferred routes of administration are parenteral, including but not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, intracerebral, intraventricular, intrathecal, intravaginal, intravaginal, or transdermal administration. The preferred method of administration is left to the practitioner's judgment and will depend in part on the site of the medical condition (e.g., cancer site). In a more preferred embodiment, the compound according to the invention is administered intravenously. Infusion times of up to 24 hours are preferred, more preferably 1 to 12 hours, and most preferably 1 to 6 hours. Short infusion times that allow for treatment without overnight hospitalization are particularly desirable. However, infusions may be 12 to 24 hours, or even longer if necessary. Infusions can be administered at appropriate intervals, such as 1 to 4 weeks.

[0769] The liquid compositions of the present invention, whether they are solutions, suspensions, or other similar forms, may further include one or more of the following: a sterile diluent, such as water for injection, saline solution (preferably physiological saline), Ringer's solution, isotonic sodium chloride; a fixed oil, such as synthetic monoglycerides or diglycerides, polyethylene glycol, glycerol, or other solvents; an antibacterial agent, such as benzyl alcohol or methylparaben; and a tension modifier, such as sodium chloride or glucose. Parenteral compositions may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass, plastic, or other materials. Physiological saline is a preferred adjuvant.

[0770] The effective dosage of the compounds according to the invention for treating a specific disease or condition will depend on the nature of the disease or condition and can be determined using standard clinical techniques. Furthermore, in vitro or in vivo assays may be employed as needed to help determine the optimal dosage range. The precise dosage used in the composition also depends on the route of administration and the severity of the disease or condition, and should be determined based on the practitioner's judgment and the individual patient's circumstances.

[0771] This composition contains an effective amount of the compound of the present invention to obtain a suitable dosage. The correct dosage of the compound will depend on the specific formulation, mode of application and its specific site, host, and the disease being treated (e.g., cancer), and if so, the type of tumor. Factors such as age, weight, sex, diet, time of administration, excretion rate, host condition, drug combination, responsiveness, and disease severity should be considered. It can be administered continuously or periodically within the maximum tolerated dose.

[0772] Typically, the amount is at least about 0.01% (by weight) of the compound of the present invention, and may comprise at least 80% (by weight) of the composition. When intended for oral administration, the amount may vary from about 0.1% to about 80% (by weight) of the composition. A preferred oral composition may comprise about 4% to about 50% (by weight) of the compound of the present invention.

[0773] The preferred compositions of the present invention are prepared such that the parenteral dose unit comprises about 0.01% to about 10% (by weight) of the compound of the present invention. More preferably, the parenteral dose unit comprises about 0.5% to about 5% (by weight) of the compound of the present invention.

[0774] For intravenous administration, the composition is suitable at a dose of about 0.1 mg / kg to about 250 mg / kg of animal body weight, preferably about 0.1 mg / kg to about 20 mg / kg of animal body weight, and even more preferably from about 1 mg / kg to about 10 mg / kg of animal body weight.

[0775] The compounds of the present invention can be administered by any convenient route, such as by infusion or bolus, or by absorption through the epithelium or the inner layer of the skin or mucous membrane.

[0776] In specific embodiments, it may be desirable to apply one or more compounds or compositions of the present invention topically to the area requiring treatment. In one embodiment, administration may be made by direct injection at the site (or pre-site) of cancer, tumor, or pre-tumor tissue.

[0777] It can also be administered to the lungs, for example, by using an inhaler or nebulizer, and in combination with a nebulizer, or by infusion in a fluorocarbon or synthetic pulmonary surfactant. In some embodiments, the compounds of the present invention can be formulated into suppositories with conventional binders and carriers such as triglycerides.

[0778] The compositions of this invention may take the form of solutions, suspensions, emulsifiers, tablets, pills, balls, capsules, liquid-containing capsules, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other suitable form. Other examples of suitable drug carriers are described in EW Martin's *Remington's Pharmaceutical Sciences*.

[0779] The pharmaceutical compositions can be prepared using methods known in the pharmaceutical industry. For example, compositions intended for injection can be prepared by mixing the compounds of the present invention with water or other physiologically suitable diluents such as phosphate-buffered saline to form a solution. Surfactants may be added to promote the formation of a homogeneous solution or suspension.

[0780] The preferred composition according to the present invention comprises:

[0781] • Pharmaceutical compositions comprising the compounds of the present invention and disaccharides. Particularly preferred disaccharides are selected from lactose, trehalose, sucrose, maltose, isomaltose, cellodisaccharide, isosaccharide, isotrehalose, diboronic acid, mesylate, gentiodisaccharide, and mixtures thereof.

[0782] • Lyophilized pharmaceutical compositions comprising the compounds of the present invention and disaccharides. Particularly preferred disaccharides are selected from lactose, trehalose, sucrose, maltose, isomaltose, cellodisaccharide, isosaccharide, isotrehalose, diboronic acid, mesylate, gentiodisaccharide, and mixtures thereof.

[0783] In embodiments of the invention, the ratio of the active substance to the disaccharide is determined based on the solubility of the disaccharide, and also based on the lyophilization properties of the disaccharide when the formulation is freeze-dried. It is envisioned that such an active substance:disaccharide ratio (w / w) may be about 1:10 in some embodiments, about 1:20 in others, and about 1:50 in still others. Other embodiments are envisioned to have such a ratio in the range of about 1:5 to about 1:500, and in some embodiments, a ratio in the range of about 1:10 to about 1:500.

[0784] Compositions containing compounds of the present invention can be lyophilized. Compositions containing compounds of the present invention are typically present in vials containing a specific amount of such compound.

[0785] We have found that the compounds and compositions of the present invention are particularly effective in treating cancer.

[0786] Therefore, as previously stated, the present invention provides a method for treating patients in need (particularly humans affected by cancer), the method comprising administering a therapeutically effective amount of the compound or composition of the present invention to the affected individual. The present invention provides compounds or compositions for use as medicaments. The present invention provides compounds or compositions for treating cancer, preferably selected from lung cancer including non-small cell lung cancer and small cell lung cancer, colon cancer, breast cancer, pancreatic cancer, sarcoma, ovarian cancer, prostate cancer, and gastric cancer.

[0787] Therefore, the compounds and compositions according to the present invention are useful for inhibiting the proliferation or growth of tumor cells or cancer cells, or for treating cancer in animals.

[0788] The compounds and compositions according to the invention exhibit excellent activity in treating cancers such as lung cancer (including non-small cell lung cancer and small cell lung cancer), colon cancer, breast cancer, pancreatic cancer, sarcoma, ovarian cancer, prostate cancer, and gastric cancer. The preferred cancers are selected from lung cancer (including non-small cell lung cancer and small cell lung cancer), breast cancer, pancreatic cancer, and colorectal cancer.

[0789] In this application, "cancer" means any malignant disease including tumors, tumor formation, and other diseases that produce malignant tissues or cells.

[0790] Unless otherwise specified, the term "treating" as used herein means reversing, reducing, alleviating, or inhibiting the progression of a disease or condition to which such terms apply, or one or more symptoms of such a disease or condition. Unless otherwise specified, the term "treatment" as used herein refers to the act of treatment, as defined above.

[0791] The compounds and compositions according to the invention can be administered to animals that have already undergone surgical treatment for cancer. In one embodiment of the invention, another treatment method is radiotherapy.

[0792] In a specific embodiment of the invention, the compound or composition according to the invention is administered simultaneously with radiotherapy. In another specific embodiment, radiotherapy is administered before or after the application of the compound or composition of the invention, preferably at least 1 hour, 3 hours, 5 hours, 12 hours, 1 day, 1 week, 1 month, more preferably several months (e.g., up to 3 months) before or after the application of the compound or composition of the invention.

[0793] Depending on the type of cancer being treated, any radiotherapy regimen can be used. For example, but not as a limitation, X-ray radiation can be administered; in particular, high-energy megavolts (radiation with energies greater than 1 MeV) can be used for deep tumors, and electron beams and positive voltage X-ray radiation can be used for skin cancer. Gamma-ray radioactive isotopes, such as radium, cobalt, and radioactive isotopes of other elements, can also be administered.

[0794] In another embodiment of the invention, a kit is provided comprising a therapeutically effective amount of the compound according to the invention and a pharmaceutically acceptable carrier.

[0795] In one implementation, the kit according to the implementation is used to treat cancer, preferably selected from cancers including non-small cell lung cancer and small cell lung cancer, colon cancer, breast cancer, pancreatic cancer, sarcoma, ovarian cancer, prostate cancer and stomach cancer.

[0796] In another embodiment of the invention, a method is provided for obtaining a compound of formula I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IFa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, or IGb, or a pharmaceutically acceptable salt or ester thereof, comprising the step of reacting a compound of formula II with a compound of formula III to obtain a compound of formula IV:

[0797]

[0798] Wherein (if possible substituents are allowed):

[0799] X is -NH- or -O-;

[0800] R2 is -C(=O)R a Group;

[0801] R3 is hydrogen or -OR b Group;

[0802] R4 is selected from hydrogen, -CH2OH, -CH2OC (=O)R c and -CH2NHProt NH ;

[0803] R a Selected from hydrogen, substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0804] R b Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group;

[0805] R c Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C2-C 12 Alkenyl groups and substituted or unsubstituted C2-C 12 alkynyl group; and

[0806] Prot NH It is an amino protecting group;

[0807] The condition is that when R4 is hydrogen, then X is -O-.

[0808] Particularly preferred is when R4 is -CH2NHProt in compound IV. NH The method includes the step of deprotecting such amino groups to provide compounds of formula I, IA, IB, IC, ID, IE, IG, Ia, IAa, IBa, ICa, IDa, IEa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, or IGb, wherein R4 is -CH2NH2 and R1 is a cyano group.

[0809] In a preferred embodiment, the method further includes the step of replacing the cyano group in the compound of formula IV or the compound of formula I, IA, IB, IC, ID, IE, IG, Ia, IAa, IBa, ICa, IDa, IEa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, or IGb with a hydroxyl group, wherein R4 is -CH2NH2 and R1 is a cyano group, to obtain the compound of formula I, IA, IB, IC, ID, IE, IF, IG, Ia, IAa, IBa, ICa, IDa, IEa, IGa, Ib, IAb, IBb, ICb, IDb, IEb, IFb, or IGb, wherein R1 is OH.

[0810] A preferred method according to the present invention includes:

[0811] • The method using compound of formula II, wherein:

[0812] R2 is -C(=O)R a Group, wherein R a It is substituted or unsubstituted C1-C 12 Alkyl group. Particularly preferred R a Selected from substituted or unsubstituted C1-C6 alkyl groups. More preferably, R a The compound is selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl, with methyl being the preferred R. a .

[0813] A method for selecting a compound of formula III from formulas IIIa, IIIb, and IIIc:

[0814]

[0815] in

[0816] X is selected from -NH- or -O-;

[0817] R3 is selected from hydrogen and OR b , where R b It is substituted or unsubstituted C1-C 12 Alkyl group. Particularly preferred R b Selected from substituted or unsubstituted C1-C6 alkyl groups. More preferably, R bSelected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted n-propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted sec-butyl, and substituted or unsubstituted tert-butyl. More preferably, R 3 It is hydrogen or methoxy. Ideally, R... 3 It is hydrogen;

[0818] R4 is selected from -CH2OH and -CH2NHProt. NH Among them, Prot NH It is an amino protecting group.

[0819] Particularly preferred is the compound of formula IIIa or IIIb.

[0820] • The step of using a compound of formula III, IIIa or IIIb, wherein R4 is -CH2OH.

[0821] The preferred method is to use a compound of formula IIIa or IIIb, wherein R4 is as defined above.

[0822] It is preferable to use the steps of a compound of formula IIIa, where R4 is as defined above.

[0823] • The step of using a compound of formula III, IIIa or IIIb, wherein R4 is -CH2NHProt NH .

[0824] The preferred method is to use a compound of formula IIIa or IIIb, wherein R4 is as defined above.

[0825] It is preferable to use the steps of a compound of formula IIIb, where R4 is as defined above. Example

[0826] Compound 1 was prepared according to Example 20 of WO 01 / 87895.

[0827] Reference compounds A, B, C, D, E, F, ET-736, and PM01183 were prepared according to the description in WO 03 / 014127 (compounds 19, 18, 44, 43, 2, 1, 26, and 27, respectively).

[0828] Example 1.

[0829]

[0830] L-tryptophan (2-S) (533 mg, 3.0 mmol, Sigma-Aldrich) was added to a solution of acetic acid (20 mL, 0.04 M) of 1 (0.5 g, 0.80 mmol). The reaction mixture was stirred at 23 °C for 16 h, and then the acetic acid was evaporated. A saturated aqueous solution of NaHCO3 was added and the mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 1:1) gave compounds 3-S (616 mg, 97%) and 3a-S (12 mg, 2%).

[0831] 3-S

[0832] R f =0.50 (hexane:EtOAc, 1:1).

[0833] 1 H NMR (300MHz, CDCl3): δ7.71(s,1H),7.36(dd,J=7.9,1.0Hz,1H),7.27(dd,J=8.2,0.9Hz,1H),7.13(ddd,J=8.3,7.0,1.2Hz,1H),7.03(ddd,J= 8.0,7.0,1.0Hz,1H),6.62(s,1H),6.26(d,J=1.4Hz,1H),6.04(d,J=1.3Hz,1H),5.75(s,1H),5.14(dd,J=11.7,1.2Hz,1H),4.60(s,1H),4.41 (s,1H),4.36-4.24(m,2H),4.21(d,J=2.7Hz,1H),3.82(s,3H),3.52(s,1H),3.50-3.47(m,1H),3.45(dq,J=8.4,2.2Hz,1H),3.35(t,J=10.1H z,1H),3.01-2.78(m,5H),2.62(dd,J=15.3,4.7Hz,1H),2.41(s,1H),2.38(s,3H),2.37-2.31(m,1H),2.28(s,3H),2.17(s,3H),2.06(s,3H).

[0834] ESI-MS m / z: 794.2 (M+H) + .

[0835] 3a-S

[0836] R f =0.70 (hexane:EtOAc, 1:1).

[0837] 1H NMR(500MHz,CDCl3):δ7.83(s,1H),7.38(dt,J=7.9,0.9Hz,1H),7.25(dt,J=8.3,0.9Hz,1H),7.11(ddd,J=8.2,7.1,1.2Hz,1H),7.02(ddd,J=8.0,7.0,1.0Hz,1H),6.62(s,1H),6.24(d,J=1.4Hz,1H),6.03(d,J=1.3Hz,1H),5.79(s,1H),5.13(d,J=11.7Hz,1H),4.60(s,1H),4.39(s,1H),4.36-4.22(m,3H),4.17-4.09(m,1H),3.91(dd,J=10.5,8.6Hz,1H),3.83(s,3H),3.51-3.41(m,2H),3.04-2.92(m,3H),2.72(dd,J=15.1,4.0Hz,1H),2.54-2.41(m,2H),2.38(s,3H),2.35-2.30(m,1H),2.29(s,3H),2.21-2.16(m,1H),2.18(s,3H),2.12(s,3H);2.05(s,3H)。

[0838] 13 C NMR(101MHz,CDCl3):δ171.2,170.7,168.6,147.5,145.8,143.0,141.1,140.4,135.6,130.1,129.5,126.7,122.2,121.2,120.9,119.4,118.4,118.2,118.2,113.6,113.5,110.9,110.0,109.1,102.1,91.4,67.2,63.4,61.3,60.4,59.7,59.1,54.8,54.6,47.7,42.0,41.6,31.6,24.0,22.6,21.0,15.9,14.2,9.7。

[0839] ESI-MS m / z:836.2(M+H) + 。

[0840]

[0841] AgNO3 (3.40 g, 23.3 mmol) was added to a solution of 3-S (616 mg, 0.77 mmol) in CH3CN:H2O (1.39:1, 51 mL, 0.015 M). After incubation at 23 °C for 3 hours, the reaction mixture was quenched with a 1:1 mixture of saturated NaCl and saturated NaHCO3 aqueous solutions, stirred for 15 min, diluted with CH2Cl2, stirred for 5 min, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give 4-S (471 mg, 78%).

[0842] R f =0.50(CH2Cl2:CH3OH,9:1).

[0843] 1 H NMR (500MHz, CDCl3): δ7.71(s,1H),7.36(dd,J=7.8,1.1Hz,1H),7.26(dd,J=7.8,1.1Hz,1H),7.12(ddd,J=8.2,7.0,1.2Hz,1H),7.03(ddd,J =8.0,7.1,1.0Hz,1H),6.64(s,1H),6.23(d,J=1.3Hz,1H),6.01(d,J=1.4Hz,1H),5.75(s,1H),5.25(d,J=11.4Hz,1H),4.92(s,1H),4.52(br s,3H),4.22(dd,J=11.4,2.2Hz,1H),4.19(s,1H),3.83(s,3H),3.54(br s,2H),3.35(t,J=10.2Hz,1H),3.26(s,1H),3.01-2.93(m,3H),2.88(brs,3H),2.63 (dd,J=15.2,4.8Hz,1H),2.38(s,3H),2.36-2.31(m,2H),2.28(s,3H),2.05(s,3H).

[0844] 13C NMR (126MHz, CDCl3): δ171.9,168.6,147.5,145.4,142.9,141.2,140.7, 135.5,130.4,126.8,122.3,122.0,121.3,119.4,118.4,115.2,112.8,1 11.0,110.0,109.6,101.8,81.9,76.8,65.2,62.8,62.5,60.4,58.1,57. 9,55.9,55.1,53.4,51.6,41.8,41.3,39.6,24.1,23.8,20.5,15.8,9.7.

[0845] ESI-MS m / z: 767.3 (M-H2O+H) + .

[0846] (+)-HR-ESI-TOF-MS m / z 767.2788[M-H2O+H] + (Calculated value C) 41 H 43 N4O9S: 767.2745).

[0847]

[0848] AgNO3 (180 mg, 1.07 mmol) was added to a CH3CN:H2O (1.39:1, 2.4 mL, 0.015 M) solution containing 3a-S (30 mg, 0.035 mmol). After incubation at 23°C for 3 hours, the reaction mixture was quenched with a 1:1 mixture of saturated NaCl and saturated NaHCO3 aqueous solutions, stirred for 15 minutes, diluted with CH2Cl2, stirred for 5 minutes, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give 4a-S (24 mg, 83%).

[0849] R f =0.60(CH2Cl2:CH3OH,9:1).

[0850] 1H NMR (400MHz, CDCl3): δ7.81(s,1H),7.37(d,J=7.8Hz,1H),7.30-7.21(m,1H),7.06(dddt,J=34.7,8.0,7.1,1.1Hz,2H),6.63(s,1H),6.22(d,J=1.3 Hz,1H),6.02(dd,J=12.9,1.4Hz,1H),5.74(s,1H),5.25-5.21(m,1H),4. 89(d,J=8.7Hz,1H),4.55-4.45(m,2H),4.30-4.18(m,1H),4.14(dd,J=10. 5,4.2Hz,1H),4.00-3.88(m,2H),3.82(s,3H),3.56-3.44(m,2H),3.23(d ,J=9.0Hz,1H),2.95(d,J=15.7Hz,2H),2.87-2.78(m,2H),2.71(dd,J=15. 0,3.9Hz,1H),2.48(dd,J=15.1,9.6Hz,1H),2.37(s,3H),2.35-2.29(m,1H ),2.28(s,3H),2.22-2.16(m,1H),2.15(s,3H),2.12(s,3H),2.03(s,3H).

[0851] ESI-MS m / z: 809.2 (M-H2O+H) + .

[0852] Example 2

[0853]

[0854] D-tryptophan (2-R) (533 mg, 3.0 mmol, Sigma-Aldrich) was added to a solution of 1 (0.5 g, 0.80 mmol) in acetic acid (20 mL, 0.04 M). The reaction mixture was stirred at 23 °C for 16 hours, and then the acetic acid was evaporated. A saturated aqueous solution of NaHCO3 was added and the mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 1:1) gave compound 3-R (479 mg, 75%).

[0855] R f =0.44 (hexane:EtOAc, 1:1).

[0856] 1H NMR (400MHz, CDCl3): δ7.61(s,1H),7.39(d,J=7.8Hz,1H),7.29(d,J=9.6Hz,1H),7.12(t,J=7.3Hz,1H),7.03(t,J=7.3Hz,1 H),6.60(s,1H),6.25(s,1H),6.03(s,1H),5.75(s,1H),5.04(d,J=11.7Hz,1H),4.62(s,1H),4.37(s,1H),4.32-4.25(m,1H ),4.22(d,J=2.7Hz,1H),4.19-4.09(m,1H),3.82(s,3H),3.77(s,1H),3.64(d,J=9.0Hz,1H),3.49-3.41(m,2H),3.02-2.90 (m,2H),2.60-2.52(m,2H),2.45(d,J=14.7Hz,2H),2.40(s,3H),2.28(s,3H),2.22-2.14(m,2H),2.18(s,3H),2.10(m,3H).

[0857] ESI-MS m / z: 794.3 (M+H) + .

[0858]

[0859] AgNO3 (3.03 g, 18.1 mmol) was added to a solution of 3-R (479 mg, 0.60 mmol) in CH3CN:H2O (1.39:1, 40 mL, 0.015 M). After incubation at 23 °C for 3 hours, the reaction mixture was quenched with a 1:1 mixture of saturated aqueous NaCl and NaHCO3, stirred for 15 min, diluted with CH2Cl2, stirred for 5 min, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give 4-R (428 mg, 91%).

[0860] R f =0.45 (CH2Cl2:CH3OH, 9:1).

[0861] 11H NMR (400 MHz, CDCl3): δ 7.62(s,1H),7.39(d,J=8.1Hz,1H),7.28(d,J=8.1Hz,1H),7.11(ddd,J=8.2,7.0,1.2Hz,1H),7.02(ddd,J=7.9,7.1,1.0Hz,1H),6.61(s,1H),6.22(d,J=1.3Hz,1H),5.99(d,J=1.3Hz,1H),5.73(s,1H),5.17(dd,J=11.5,1.2Hz,1H),4.86(s,1H),4.56-4.47(m,2H),4.17(dd,J=5.1,1.6Hz,1H),4.08(dd,J=11.5,2.1Hz,1H),3.81(s,3H),3.78(d,J=3.8Hz,1H),3.64(dd,J=10.8,3.8Hz,2H),3.51(d,J=5.1Hz,1H),3.48-3.43(m,2H),3.24(d,J=8.6Hz,1H),3.00-2.80(m,2H),2.57(s,1H),2.55-2.43(m,1H),2.40(s,3H),2.27(s,3H),2.19-2.12(m,1H),2.16(s,3H),2.08(s,3H).

[0862] 13 13C NMR (101 MHz, CDCl3): δ 171.8,168.6,147.6,145.4,143.0,141.3,140.7,136.0,131.1,130.0,129.6,126.6,122.1,121.6,121.2,119.4,118.4,115.6,112.9,111.1,110.6,101.8,81.7,65.8,62.7,61.8,60.4,60.3,57.9,57.8,56.1,55.0,52.1,42.2,41.3,41.1,23.8,23.4,20.5,15.7,9.8.

[0863] ESI-MS m / z:767.6(M-H2O+H) + .

[0864] (+)-HR-ESI-TOF-MS m / z:767.2799[M-H2O+H] + (Calculated value C 41 H 43 N4O9S:767.2745).

[0865] Example 3: Synthesis of allyl N-[(R)-(2-amino-3-(1H-indol-3-yl)propyl)]aminocarbamate (9-R)

[0866]

[0867] Di-tert-butyl dicarbonate (4.6 g, 20.8 mmol) was added to a solution of D-tryptophan (2-R) (2.0 g, 10.4 mmol) in CH3CN (42 mL, 4 mL / mmol). The reaction mixture was stirred at 23 °C for 3 hours and concentrated under vacuum. Rapid column chromatography (CH2Cl2:CH3OH from 99:1 to 85:15) gave 5-R (2.2 g, 73%).

[0868] R f =0.5(CH2Cl2:CH3OH,9:1).

[0869] 1 H NMR (400MHz, CDCl3): δ8.13(s,1H),7.67(dd,J=7.8,1.1Hz,1H),7.38(dd,J=8.1,1.3Hz,1H),7.29-7.10(m,2H),7.06(s,1H),4.82 (s,1H),4.00(s,1H),3.71(dd,J=11.0,3.8Hz,1H),3.62(dd,J=11.0,5.5Hz,1H),3.01(d,J=6.7Hz,2H),2.14(s,1H),1.44(s,9H).

[0870]

[0871] Phthalimide (2.7 g, 18.2 mmol) and triphenylphosphine (4.8 g, 18.2 mmol) were added to a solution of 5-R (2.4 g, 8.2 mmol) in CH2Cl2 (50 mL, 6 mL / mmol), and the mixture was cooled at 0 °C. A solution of diethyl azodicarbonate in CH2Cl2 (25 mL, 3 mL / mmol) was added for 15 min. The reaction was stirred at 23 °C for 16 h and concentrated under vacuum. The residue was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give 6-R (3.3 g, 96%).

[0872] R f =0.7(CH2Cl2:CH3OH,9:1).

[0873] 1H NMR (400MHz, CDCl3): δ8.50(s,1H),7.81(dd,J=5.5,3.1Hz,2H),7.66(dd,J=5.6,3.2Hz,2H),7.60(d,J=7.8Hz,1H),7.35(d,J=8.0Hz,1H), 7.19-7.04(m,3H).,4.81(s,1H),4.40(s,1H),3.83(dd,J=13.9,3.7Hz,1H),3.72(dd,J=13.9,9.9Hz,1H),3.08-3.01(m,2H),1.23(s,9H).

[0874]

[0875] Hydrazine monohydrate (37 mL, 774 mmol) was added to a solution of 6-R (3.25 g, 7.74 mmol) in ethanol (231 mL, 30 mL / mmol). The reaction mixture was stirred in a sealed tube at 80 °C for 2.25 h and concentrated under vacuum. Rapid column chromatography (EtOAc:CH3OH, 100:1 to 50:50) gave 7-R (2.15 g, 96%).

[0876] R f =0.2(EtOAc:CH3OH,6:4).

[0877] 1 H NMR (400MHz, CD3OD): δ7.60(d,J=7.9Hz,1H),7.33(d,J=8.1Hz,1H),7.13-7.04(m,2H),7.05- 6.96(m,1H),4.02-3.94(m,1H),2.99-2.87(m,3H),2.78(dd,J=13.1,9.7Hz,1H),1.39(s,9H).

[0878] ESI-MS m / z: 290.2 (M+H) + .

[0879]

[0880] 7-R (2.15 g, 7.4 mmol) was added to CH3CN (74 mL, 10 mL / mmol) and DMF (7.4 mL, 7.4 mmol / mmol).

[0881] N,N-diisopropylethylamine (1.06 mL, 5.9 mmol) and propylene chloroformate (7.9 mL, 74 mmol) were added to a solution of 1 mL / mmol. The reaction was stirred at 23 °C for 16 hours. The mixture was diluted with EtOAc, and NH4Cl was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue obtained was purified by rapid column chromatography (hexane:EtOAc, 100:1 to 1:100) to give 8-R (1.69 g, 61%).

[0882] R f =0.4 (hexane:EtOAc, 1:1).

[0883] 1 H NMR (400MHz, CDCl3): δ8.25(s,1H),7.62(d,J=7.8Hz,1H),7.35(dd,J=8.1,0.9Hz,1H),7.16(dddd, J=27.8,8.0,7.0,1.1Hz,2H),7.04(d,J=2.4Hz,1H),5.90(ddt,J=17.3,10.7,5.6Hz,1H),5.34-5.22 (m,1H),5.20(dt,J=10.5,1.4Hz,1H),5.12(s,1H),4.82(s,1H),4.55(dq,J=5.4,1.7Hz,2H),4.02( s,1H),3.35(dt,J=10.0,4.7Hz,1H),3.21(s,1H),2.95(ddd,J=21.6,15.4,9.1Hz,2H),1.42(s,9H).

[0884] ESI-MS m / z: 274.3 (M-Boc+H) + .

[0885]

[0886] Trifluoroacetic acid (30 mL, 8.3 mL / mmol) was added to a solution of 8-R (1.30 g, 3.50 mmol) in CH2Cl2 (58 mL, 16.6 mL / mmol). The reaction mixture was stirred at 23 °C for 1.5 h and concentrated under vacuum to obtain crude 9-R, which was used in the next step without further purification.

[0887] R f =0.2(CH2Cl2:CH3OH,9:1).

[0888] 1H NMR (400MHz, CDCl3): δ7.95(s,1H),7.53(d,J=7.8Hz,1H),7.36(d,J=8.1Hz,1H),7.17(s,1H),7.09(t,J=7.5Hz,1H),7.03(t,J=7.5Hz,1H),5.87(ddt, J=16.4,10.8,5.6Hz,1H),5.34-5.13(m,2H),4.50(d,J=5.5Hz,2H),3.62(b s,1H),3.42(dd,J=14.9,3.9Hz,1H),3.36-3.20(m,1H),3.11-3.00(m,2H).

[0889] ESI-MS m / z: 274.3 (M+H) + .

[0890] Example 4: Synthesis of allyl N-[(S)-(2-amino-3-(1H-indol-3-yl)propyl)]aminocarbamate (9-S)

[0891]

[0892] Di-tert-butyl dicarbonate (4.6 g, 20.8 mmol) was added to a solution of L-tryptophan (2-S) (2.0 g, 10.4 mmol) in CH3CN (42 mL, 4 mL / mmol). The reaction mixture was stirred at 23 °C for 3 hours and concentrated under vacuum. Rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) gave 5-S (2.24 g, 73%).

[0893] R f =0.5(CH2Cl2:CH3OH,9:1).

[0894] 1 H NMR (400MHz, CDCl3): δ8.10(s,1H),7.65(dd,J=7.8,1.1Hz,1H),7.37(dd,J=8.1,1.3Hz,1H),7.23-7.11(m,2H),7.06(s,1H),4.81 (s,1H),3.99(s,1H),3.70(dd,J=11.0,3.8Hz,1H),3.61(dd,J=11.0,5.5Hz,1H),3.00(d,J=6.7Hz,2H),2.01(s,1H),1.42(s,9H).

[0895]

[0896] Phthalimide (1.33 g, 9.1 mmol) and triphenylphosphine (2.4 g, 9.1 mmol) were added to a solution of 5-S (1.2 g, 4.13 mmol) in CH₂Cl₂ (24.8 mL, 6 mL / mmol), and the mixture was cooled to 0 °C. A solution of diethyl azodicarbonate (3 mL, 10.32 mmol) in CH₂Cl₂ (12.4 mL, 3 mL / mmol) was added for 15 min. The reaction was stirred at 23 °C for 16 h and concentrated under vacuum. The residue obtained was purified by rapid column chromatography (CH₂Cl₂:CH₃OH, 99:1 to 85:15) to give 6-S (2.8 g, >100%).

[0897] R f =0.7(CH2Cl2:CH3OH,9:1).

[0898] 1 H NMR (400MHz, CDCl3): δ8.49(s,1H),7.80(dd,J=5.4,3.1Hz,2H),7.66(dd,J=5.6,3.2Hz,2H),7.60(d,J=7.8Hz,1H),7.34(d,J=8.0Hz,1H), 7.21-7.04(m,3H).,4.74(s,1H),4.42(s,1H),3.83(dd,J=13.9,3.7Hz,1H),3.72(dd,J=13.9,9.9Hz,1H),3.10-3.01(m,2H),1.23(s,9H).

[0899]

[0900] Hydrazine monohydrate (10 mL, 207 mmol) was added to a solution of 6-S (0.86 g, 2.07 mmol) in ethanol (72 mL, 36 mL / mmol). The reaction mixture was stirred in a sealed tube at 80 °C for 2.25 h and concentrated under vacuum. Rapid column chromatography (EtOAc:CH3OH, 100:1 to 50:50) gave 7-S (1.0 g, 84%).

[0901] R f =0.2(EtOAc:CH3OH,6:4).

[0902] 1H NMR (400MHz, CD3OD): δ7.61(d,J=7.9Hz,1H),7.35(d,J=8.1Hz,1H),7.13-6 .97(m,2H),7.09(s,1H),4.06-3.96(m,1H),3.01-2.76(m,4H),1.38(s,9H).

[0903] ESI-MS m / z: 290.3 (M+H) + .

[0904]

[0905] N,N-diisopropylethylamine (0.5 mL, 2.6 mmol) and allyl chloroformate (3.5 mL, 33 mmol) were added to a solution of 7-S (0.95 g, 3.3 mmol) in CH3CN (33 mL, 10 mL / mmol) and DMF (3.3 mL, 1 mL / mmol). The reaction was stirred at 23 °C for 20 h. The mixture was diluted with EtOAc, and NH4Cl was added and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue obtained was purified by rapid column chromatography (hexane:EtOAc, 100:1 to 1:100) to give 8-S (0.88 g, 73%).

[0906] R f =0.5 (hexane:EtOAc, 1:1).

[0907] 1 H NMR (400MHz, CDCl3): δ8.17(s,1H),7.63(d,J=7.8Hz,1H),7.20(dd,J=8.1,0.9Hz,1H ),7.13(dddd,J=27.8,8.0,7.0,1.1Hz,2H),7.06(d,J=2.4Hz,1H),5.90(ddt,J=17.3, 10.7,5.6Hz,1H),5.31-5.18(m,2H),5.09(s,1H),4.80(s,1H),4.59-4.52(m,2H),4. 03(s,1H),3.37(dt,J=10.0,4.7Hz,1H),3.21(s,1H),3.05-2.87(m,2H),1.42(s,9H).

[0908] ESI-MS m / z: 274.3 (M-Boc+H) + .

[0909]

[0910] Trifluoroacetic acid (19 mL, 8.3 mL / mmol) was added to a CH₂Cl₂ (38 mL, 16.6 mL / mmol) solution of 8-S (0.875 g, 2.3 mmol). The reaction mixture was stirred at 23 °C for 2 hours and concentrated under vacuum to obtain crude 9-S, which was used in the next step without further purification.

[0911] R f =0.2(CH2Cl2:CH3OH,9:1).

[0912] 1 H NMR (400MHz, CD3OD): δ7.56 (d, J = 7.8Hz, 1H), 7.37 (d, J = 8.1Hz, 1H), 7.21 (s, 1H), 7.13 (t, J = 7.5Hz, 1H), 7.05 (t, J = 7.5Hz, 1H), 5.94 (ddt, J = 16. 4,10.8,5.6Hz,1H),5.34-5.16(m,2H),4.56(d,J=5.5Hz,2H),3.60(bs, 1H), 3.43 (dd, J=14.9, 3.9Hz, 1H), 3.37-3.31 (m, 1H), 3.14-2.99 (m, 2H).

[0913] ESI-MS m / z: 274.3 (M+H) + .

[0914] Example 5

[0915]

[0916] 9-R (0.95 g, 3.50 mmol) was added to a solution of acetic acid (58 mL, 0.08 M) containing 1 (1.45 g, 2.33 mmol). The reaction mixture was stirred at 50 °C for 18 hours, and then the acetic acid was evaporated. A saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4. Rapid column chromatography (hexane:EtOAc, 1:1) gave compound 10-R (1.3 g, 64%).

[0917] R f =0.5 (hexane:EtOAc, 1:1).

[0918] 1H NMR (400MHz, CDCl3): δ7.66(s,1H),7.36(d,J=7.9Hz,1H),7.27(d,J=7.9Hz,1H),7.10(ddd,J=8.3,7.0,1.3Hz,1H),7.01(td,J=7.5,7.0,1.0Hz,1H),6 .62(s,1H),6.23(d,J=1.4Hz,1H),6.01(d,J=1.4Hz,1H),5.99-5.89(m,1H) ,5.79(s,1H),5.44-5.21(m,2H),5.14-4.99(m,2H),4.63(ddd,J=7.3,4.4, 1.5Hz,2H),4.36(s,1H),4.33-4.24(m,1H),4.29-4.26(m,1H),4.21(d,J=2 .7Hz,1H),4.19-4.13(m,3H),3.80(s,3H),3.56(s,1H),3.48-3.43(m,3H), 3.27(dt,J=13.2,4.0Hz,1H),3.04-2.88(m,2H),2.56(dd,J=15.2,3.8Hz,1 H),2.49-2.35(m,2H),2.31(s,3H),2.28(s,3H),2.17(s,3H),2.07(s,3H).

[0919] ESI-MS m / z: 877.3 (M+H) + .

[0920]

[0921] To a solution of 10-R (600 mg, 0.68 mmol) in CH₂Cl₂ (12 mL, 18 mL / mmol), bis(triphenylphosphine)palladium(II) dichloride (77 mg, 0.1 mmol) and acetic acid (0.4 mL, 6.8 mmol) were added. Tributyltin hydride (1.1 mL, 4.08 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 h and concentrated under vacuum. The resulting crude product was diluted with EtOAc, and the mixture was extracted with a saturated aqueous solution of NH₄Cl using EtOAc. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 100:1 to 1:100, EtOAc:CH₃OH, 100:1 to 1:100) gave 11-R (440 mg, 82%).

[0922] R f =0.5(CH2Cl2:CH3OH, 1:1).

[0923] 1 H NMR (400MHz, CDCl3): δ7.64(s,1H),7.38(d,J=7.9Hz,1H),7.29(d,J=8.1Hz,1H),7.11(ddt,J=8.3,7.0,1.4Hz,1H),7.03(ddt, J=8.3,7.0,1.4Hz,1H),6.58(s,1H),6.24(d,J=1.5Hz,1H),6.02(d,J=1.5Hz,1H),5.02(d,J=11.8Hz,1H),4.63(s,1H),4.36(s ,1H),4.28(d,J=5.1Hz,1H),4.21(d,J=2.2Hz,1H),4.16(s,1H),3.80(s,3H),3.51-3.39(m,4H),3.32-3.13(m,3H),2.95(d,J= 8.9Hz,2H),2.89-2.76(m,2H),2.73-2.57(m,1H),2.42(d,J=14.8Hz,1H),2.36(s,3H),2.25(s,3H),2.16(s,3H),2.09(s,3H).

[0924] ESI-MS m / z: 793.2 (M+H) + .

[0925]

[0926] AgNO3 (3.64 g, 21.4 mmol) was added to a solution of 11-R (850 mg, 1.07 mmol) in CH3CN:H2O (1.39:1, 70 mL, 0.015 M). After 17 hours at 23 °C, the reaction was quenched with a 1:1 mixture of saturated NaCl and saturated NaHCO3 aqueous solutions, stirred for 15 min, diluted with CH2Cl2, stirred for 5 min, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give 12-R (553 mg, 66%).

[0927] R f =0.3(CH2Cl2:CH3OH,9:1).

[0928] 11H NMR (500 MHz, CDCl3): δ 7.60(s,1H),7.38(d,J=7.9Hz,1H),7.28(d,J=7.9Hz,1H),7.11(ddt,J=8.3,7.1,1.2Hz,1H),7.02(ddt,J=8.3,7.1,1.2Hz,1H),6.58(s,1H),6.22(s,1H),6.00(s,1H),5.16(d,J=11.5Hz,1H),4.87(s,1H),4.54(s,1H),4.51(d,J=3.3Hz,1H),4.17(d,J=5.4Hz,1H),4.07(dd,J=11.3,2.2Hz,1H),3.81(s,3H),3.52(d,J=5.1Hz,1H),3.24(d,J=8.8Hz,2H),2.99-2.78(m,4H),2.66(dd,J=14.9,3.5Hz,1H),2.49-2.39(m,2H),2.38(s,3H),2.28(m,2H),2.25(s,3H),2.21-2.16(m,2H),2.15(s,3H),2.08(s,3H).

[0929] 13 13C NMR (101 MHz, CD3OD): δ 171.7,169.4,148.7,145.9,143.7,141.4,140.9,136.9,130.8,130.0,129.7,126.0,121.4,121.0,119.7,119.1,118.4,117.5,114.9,110.8,107.5,106.4,102.1,91.3,63.2,60.0,59.0,58.6,55.3,54.6,52.7,52.4,48.4,45.8,42.5,40.2,24.5,23.2,19.2,15.0,8.2.

[0930] ESI-MS m / z:766.2(M-H2O+H) + .

[0931] (+)-HR-ESI-TOF-MS m / z:766.2972[M-H2O+H] + (Calculated value C 41 H 44 N5O8S+:766.2905).

[0932]

[0933] AgNO3 (2.66 g, 16 mmol) was added to a solution of 10-R (700 mg, 0.8 mmol) in CH3CN:H2O (1.39:1, 87.5 mL, 0.015 M). After incubation at 23 °C for 20 hours, the reaction mixture was quenched with a 1:1 mixture of saturated NaCl and saturated NaHCO3 aqueous solutions, stirred for 15 min, diluted with CH2Cl2, stirred for 5 min, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give 13-R (438 mg, 63%).

[0934] R f =0.40(CH2Cl2:CH3OH,9:1).

[0935] 1 H NMR (400MHz, CDCl3): δ7.64(s,1H),7.37(d,J=7.9Hz,1H),7.32-7.20(m,1H),7.11(t,J=7.7Hz,1H),7.01(t,J=7.4Hz, 1H),6.62(s,1H),6.21(s,1H),6.05-5.90(m,1H),5.99(s,1H),5.75(d,J=6.0Hz,1H),5.40-5.07(m,4H),4.88(d,J=14. 7Hz,1H),4.68-4.50(m,3H),4.28-4.13(m,1H),4.08(dt,J=11.4,2.4Hz,1H),3.83(s,3H),3.68-3.40(m,4H),3.37-3.1 9(m,2H),2.98-2.79(m,2H),2.59-2.36(m,3H),2.29(s,3H),2.27(s,3H),2.14(s,3H),2.10-2.16(m,1H),2.08(s,3H).

[0936] ESI-MS m / z: 850.3 (M-H2O+H) + .

[0937] Example 6

[0938]

[0939] 9-S (627 mg, 2.29 mmol) was added to a solution of acetic acid (37.5 mL, 0.08 M) at 1 (955 mg, 1.5 mmol). The reaction mixture was stirred at 50 °C for 18 hours, and then the acetic acid was evaporated. A saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4. Rapid column chromatography (hexane:EtOAc, 1:1) gave compound 10-S (756 mg, 58%).

[0940] R f =0.4 (hexane:EtOAc, 1:1).

[0941] 1 H NMR (400MHz, CDCl3): δ7.78(s,1H),7.36(d,J=7.9Hz,1H),7.24(d,J=7.9Hz,1H),7.10(ddd,J=8.3,7.0,1.3Hz,1H),7.01(td,J=7.5,7.0,1. 0Hz,1H),6.68(s,1H),6.23(d,J=1.4Hz,1H),6.01(d,J=1.4Hz,1H),6.07-5.93(m,1H),5.82(s,1H),5.41-5.19(m,2H),5.1(d,J=11.7Hz,1H) ,4.66(dt,J=5.9,1.3Hz,1H),4.57(s,1H),4.37(s,1H),4.33-4.20(m,3H),3.81(s,3H),3.46(d,J=4.2Hz,2H),3.22-3.13(m,1H),3.11-2.8 8(m,4H),2.66(dd,J=15.2,4.2Hz,1H),2.51(dd,J=15.3,6.0Hz,1H),2.43-2.32(m,2H),2.31(s,3H),2.26(s,3H),2.19(s,3H),2.04(s,3H). ESI-MS m / z:877.3(M+H) + .

[0942]

[0943] To a solution of 10-S (650 mg, 0.72 mmol) in CH₂Cl₂ (13.3 mL, 18 mL / mmol), bis(triphenylphosphine)palladium(II) dichloride (83 mg, 0.11 mmol) and acetic acid (0.42 mL, 7.4 mmol) were added. Tributyltin hydride (1.2 mL, 4.4 mmol) was added at 0 °C, and the reaction mixture was stirred at 23 °C for 0.5 h and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 100:1 to 1:100, EtOAc:CH₃OH, 100:1 to 1:100) gave 11-S (445 mg, 78%).

[0944] R f =0.5(CH2Cl2:CH3OH, 1:1).

[0945] 1 H NMR (400MHz, CDCl3): δ7.74(s,1H),7.36(d,J=7.9Hz,1H),7.26(d,J=8.1Hz,1H),7.12(ddt,J=8.3,7.0,1.4Hz, 1H),7.02(ddt,J=8.3,7.0,1.4Hz,1H),6.62(s,1H),6.26(d,J=1.5Hz,1H),6.04(d,J=1.5Hz,1H),5.12(d,J=11 .8Hz,1H),4.59(s,1H),4.42(s,1H),4.36-4.17(m,3H),3.81(s,3H),3.51-3.39(m,3H),2.98-2.75(m,4H),2.6 9-2.60(m,2H),2.47(d,J=16.1Hz,1H),2.38(s,3H),2.35-2.17(m,2H),2.28(s,3H),2.13(s,3H),2.04(s,3H).

[0946] ESI-MS m / z: 793.3 (M+H) + .

[0947]

[0948] AgNO3 (1.84 g, 11 mmol) was added to a solution of 11-S (435 mg, 0.55 mmol) in CH3CN:H2O (1.39:1, 38.5 mL, 0.015 M). After 24 hours at 23 °C, the reaction was quenched with a 1:1 mixture of saturated NaCl and saturated NaHCO3 aqueous solutions, stirred for 15 min, diluted with CH2Cl2, stirred for 5 min, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give 12-S (152 mg, 35%).

[0949] R f =0.2(CH2Cl2:CH3OH,9:1).

[0950] 1 H NMR (500MHz, CD3OD): δ7.34(dd,J=7.7,1.5Hz,1H), 7.28(dd,J=7.7,1.5Hz,1H), 7.04(ddt,J=8.2,7.0,1.1Hz,1H), 6.95(ddt,J=8.2,7.0,1.2Hz,1H),6.55(s,1H),6.31-6.25(m,1H),6.15-6.05(m,1H),5.31(d,J=11.4Hz,1H),4.91( s,1H),4.64(s,1H),4.40-4.19(m,3H),3.76(s,3H),3.64(d,J=5.2Hz,1H),3.44(d,J=9.0Hz,1H),3.03-2.85(m,4H) ,2.85-2.65(m,2H),2.59(d,J=15.6Hz,1H),2.52-2.39(m,2H),2.37(s,3H),2.27(s,3H),2.09(s,3H),2.00(s,3H).

[0951] 13C NMR (126MHz, CD3OD): δ171.4,169.3,148.6,145.8,143.5,141.2,140.8, 136.5,131.2,130.3,129.5,126.3,121.6,121.2,119.8,119.4,118.6,11 7.5,114.9,111.0,107.5,107.4,102.2,91.1,63.5,60.5,59.2,58.5,55 .3,54.7,53.4,52.7,48.6,44.7,42.7,39.9,24.3,23.4,19.2,15.1,8.2.

[0952] ESI-MS m / z: 766.2 (M-H2O+H) + .

[0953] (+)-HR-ESI-TOF-MS m / z:766.2958[M-H2O+H] + (Calculated value C) 41 H 44 N5O8S: 766.2905).

[0954]

[0955] AgNO3 (29 mg, 0.17 mmol) was added to a solution of 10-S (5 mg, 0.006 mmol) in CH3CN:H2O (1.39:1, 0.5 mL, 0.015 M). After incubation at 23 °C for 20 hours, the reaction mixture was quenched with a 1:1 mixture of saturated aqueous NaCl and NaHCO3, stirred for 15 min, diluted with CH2Cl2, stirred for 5 min, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give 13-S (5 mg, 100%).

[0956] R f =0.40(CH2Cl2:CH3OH,9:1).

[0957] 1H NMR (400MHz, CDCl3): δ7.75(s,1H),7.37(d,J=7.9Hz,1H),7.32-7.20(m,1H),7.12(t,J=7.7Hz,1H),7.02(t,J=7.4 Hz,1H),6.84(s,1H),6.24(s,1H),6.08-5.97(m,1H),6.01(s,1H),5.87(s,1H),5.42-5.19(m,4H),4.88(s,1H),4. 69-4.65(m,2H),4.58(s,1H),4.28-4.13(m,2H),3.84(s,3H),3.68-3.40(m,2H),3.24-3.15(m,2H),3.08-2.90(m, 2H),2.73-2.57(m,2H),2.53-2.37(m,3H),2.34(s,3H),2.25(s,3H),2.14(s,3H),2.10-2.16(m,1H),2.03(s,3H).

[0958] ESI-MS m / z: 850.3 (M-H2O+H) + .

[0959] Example 7: Synthesis of reference compounds 14-S and 15-S

[0960]

[0961] L-tryptophan (50 mg, 0.24 mmol) was added to a solution of acetic acid (1 mL, 0.08 M) containing 50 mg (0.08 mmol). The reaction mixture was stirred at 50 °C for 17 hours, and then the acetic acid was evaporated. A saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 80:20) gave compound 14-S (58 mg, 90%).

[0962] R f =0.20(CH2Cl2:CH3OH,10:1).

[0963] 1H NMR (400MHz, CDCl3): δ7.77(s,1H),7.39(d,J=7.9Hz,1H),7.25(d,J=7.9Hz,1H),7.13(ddd,J=8.2,7.0,1.2Hz,1H),7 .04(td,J=7.5,7.1,1.0Hz,1H),6.56(s,1H),6.24(d,J=1.3Hz,1H),6.03(d,J=1.3Hz,1H),5.15(d,J=11.7Hz,1H),4.6 2(s,1H),4.43(s,1H),4.35(dd,J=11.7,2.1Hz,1H),4.28(dd,J=5.2,1.6Hz,1H),4.20(s,1H),3.78(s,3H),3.52-3.41 (m,4H),3.07-2.88(m,2H),2.91-2.80(m,2H),2.42-2.21(m,2H),2.35(s,3H),2.27(s,3H),2.14(s,3H),2.04(s,3H).

[0964] ESI-MS m / z: 808.6 (M+H) + .

[0965]

[0966] AgNO3 (164 mg, 1.45 mmol) was added to a solution of 14-S (52 mg, 0.066 mmol) in CH3CN:H2O (2:1, 4.5 mL, 0.015 M). After incubation at 23 °C for 20 hours, a mixture of 1:1 saturated aqueous solutions of NaCl and NaHCO3 was added, and the mixture was stirred for 15 minutes. The solution was diluted with CH2Cl2, stirred for 30 minutes, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue obtained was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 70:30) to give 15-S (18 mg, 35%).

[0967] R f =0.15(CH2Cl2:CH3OH,9:1).

[0968] 1H NMR (400MHz, CD3OD): δ7.76(s,1H),7.40(d,J=7.8Hz,1H),7.25(d,J=7.8Hz,1H),7.14(t,J=7.4Hz,1H),7.04(t,J=7.4H z,1H),6.58(s,1H),6.23(d,J=1.3Hz,1H),6.01(d,J=1.3Hz,1H),5.28(d,J=12.7Hz,1H),4.95(s,1H),4.53(s,1H),4.28 (dd,J=11.4,2.0Hz,1H),4.21(s,1H),3.80(s,3H),3.58(s,1H),3.52-3.47(m,2H),3.28(s,1H),3.03(dd,J=15.8,5.2Hz ,1H),2.91-2.82(m,3H),2.44(d,J=15.4Hz,1H),2.36(s,3H),2.35-2.31(m,1H),2.28(s,3H),2.15(s,3H),2.03(s,3H).

[0969] 13 C NMR (101MHz, CDCl3): δ173.7,171.2,168.7,147.5,145.7,142.8,141.2,140.8,135.6,129.8,126.3,122.8,121.5,121.2,119.9,118.6,117.7, 115.0,111.1,101.9,81.5,66.8,62.9,60.4,57.9,55.8,55.1,52.3,42. 3,41.3,38.3,31.9,29.4,28.9,24.5,24.0,23.8,22.7,20.5,16.0,9.7.

[0970] ESI-MS m / z: 781.6 (M-H2O+H) + .

[0971] (+)-HR-ESI-TOF-MS m / z:781.2610[M-H2O+H] + (Calculated value C) 41 H 41 N4O 10 S:781.2538).

[0972] Example 8

[0973] Synthesis of A)(S)-5-methoxy-tryptamine (17-S)

[0974]

[0975] A suspension of H₂SO₄ (0.31 mL, 5.57 mmol) and 5-methoxy-L-tryptophan (16-S) (1.0 g, 4.26 mmol, Chem-Impex) in THF (13.4 mL, 0.3 M) was carefully added to a LiAlH₄ (23.4 mL, 1.0 M, 23.4 mmol) solution at -40 °C. The reaction mixture was placed at 23 °C, heated at 80 °C for 3 h, and then heated at 23 °C for 18 h. The mixture was cooled to -21 °C and carefully quenched with NaOH ₂N until an alkaline pH was reached. EtOAc was added, and the mixture was passed through… The mixture was filtered and washed with CH3OH. The crude product was concentrated under vacuum to obtain 17-S as the crude product, which was used in the next step without further purification.

[0976] R f =0.2(CH2Cl2:CH3OH,4:1).

[0977] 1 H NMR (400MHz, CDCl3): δ7.19 (dt, J=8.8, 0.7Hz, 1H), 7.06-7.00 (m, 2H), 6.72 (dd, J=8.8, 2.4Hz, 1H), 3.77 (s, 3H), 3.63 -3.48(m,1H),3.42-3.33(m,1H),3.17-3.06(m,1H),2.86(ddt,J=14.3,6.1,0.8Hz,1H),2.66(dd,J=14.3,7.5Hz,1H).

[0978] ESI-MS m / z: 221.4 (M+H) + .

[0979] Synthesis of B)(R)-5-methoxy-tryptophanol (17-R)

[0980]

[0981] A suspension of H₂SO₄ (0.31 mL, 5.75 mmol) and 5-methoxy-D-tryptophan (16-R) (0.5 g, 2.13 mmol, Aldrich) in THF (6.7 mL, 0.3 M) was carefully added to a solution of LiAlH₄ (11.7 mL, 1.0 M in THF) at -40 °C. The reaction mixture was placed at 23 °C, heated at 80 °C for 3.5 h, and then heated at 23 °C for 18 h. The mixture was cooled to -21 °C and carefully quenched with NaOH ₂N until an alkaline pH was reached. EtOAc was added, and the mixture was passed through… The product was filtered and washed with CH3OH. The crude product was concentrated under vacuum to obtain 17-R as the crude product, which was used in the next step without further purification.

[0982] R f =0.2(CH2Cl2:CH3OH,4:1).

[0983] 1 H NMR (400MHz, CD3OD): δ7.20 (d, J=8.9Hz, 1H), 7.06-6.96 (m, 2H), 6.71 (dd, J=8.8, 2.5Hz,1H),3.75(s,3H),3.62-3.52(m,1H),3.37(dd,J=10.8,7.0Hz,1H),3.09(br s, 1H), 2.82 (dd, J = 14.3, 5.9 Hz, 1H), 2.62 ( dd, J = 14.4, 7.6 Hz, 1H).

[0984] ESI-MS m / z: 221.6 (M+H) + .

[0985] Example 9

[0986]

[0987] 17-S (469 mg, 2.13 mmol) was added to a solution of acetic acid (10.6 mL, 0.08 M) at 1 (530 mg, 0.85 mmol). The reaction mixture was stirred at 50 °C for 18 hours, and then the acetic acid was evaporated. A saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 1:1) gave compound 18-S (420 mg, 60%).

[0988] R f =0.3 (hexane:EtOAc, 1:1).

[0989] 1 H NMR (400MHz, CD3OD): δ7.13(d,J=8.8Hz,1H),6.80(d,J=2.4Hz,1H),6.66(dd,J=8.8,2.5Hz,1H),6.51 (s,1H),6.27(s,1H),6.11(s,1H),5.21(d,J=11.7Hz,1H),4.67(s,1H),4.49-4.29(m,4H),3.75(s,3H ),3.73(s,3H),3.47(t,J=5.8Hz,3H),3.37(d,J=5.1Hz,1H),3.01-2.81(m,2H),2.75(d,J=7.4Hz,1H) ,2.66(dd,J=15.1,4.1Hz,1H),2.55-2.35(m,4H),2.34(s,3H),2.28(s,3H),2.11(s,3H),1.99(s,3H)

[0990] ESI-MS m / z: 824.3 (M+H) + .

[0991]

[0992] AgNO3 (2.60 g, 15.3 mmol) was added to a solution of 18-S (420 mg, 0.519 mmol) in CH3CN:H2O (1.39:1, 36 mL, 0.015 M). After incubation at 23 °C for 3 hours, the reaction mixture was quenched with a 1:1 mixture of saturated aqueous NaCl and NaHCO3, stirred for 15 min, diluted with CH2Cl2, stirred for 5 min, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give 19-S (250 mg, 60%).

[0993] R f =0.45 (CH2Cl2:CH3OH, 9:1).

[0994] 1H NMR (500MHz, CD3OD): δ7.15(dd,J=8.9,0.6Hz,1H),6.82(dd,J=2.4,0.6Hz,1H),6.68(dd,J=8.8,2.5Hz,1H),6.54(s,1H),6. 27(d,J=1.3Hz,1H),6.08(d,J=1.3Hz,1H),5.30(d,J=11.5Hz,1H),4.62(s,1H),4.34(dd,J=11.4,2.0Hz,1H),4.31-4.27(m, 2H),3.76(s,3H),3.75(s,3H),3.66-3.58(m,1H),3.55-3.45(m,2H),3.42(d,J=7.8Hz,1H),2.93-2.73(m,3H),2.68(dd,J=1 5.1, 4.2Hz, 1H), 2.54 (d, J = 15.4Hz, 1H), 2.42 (dd, J = 15.1, 10.1Hz, 2H), 2.35 (s, 3H), 2.29 (s, 3H), 2.09 (s, 3H), 2.00 (s, 3H).

[0995] 13 C NMR (126MHz, CD3OD): δ172.7,170.8,155.1,149.9,147.2,145.0,142.6,1 42.2,133.1,132.4,132.1,131.3,128.1,122.5,121.6,120.3,116.4,113. 0,112.9,111.4,109.0,103.6,100.8,92.5,66.6,65.0,61.7,60.4,59.9,5 6.7,56.1,54.8,54.1,51.7,44.1,41.3,30.7,25.4,24.7,20.6,16.3,9.5.

[0996] ESI-MS m / z: 798.1 (M-H2O+H) + .

[0997] (+)-HR-ESI-TOF-MS m / z:797.2899[M-H2O+H] + (Calculated value C) 42 H 45 N4O 10 S797.2851).

[0998] Example 10

[0999]

[1000] 17-R (220 mg, 1.0 mmol) was added to a solution of acetic acid (6.25 mL, 0.08 M) at 1 (311 mg, 0.50 mmol). The reaction mixture was stirred at 50 °C for 18 hours, and then the acetic acid was evaporated. A saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 1:1) gave compound 18-R (280 mg, 68%).

[1001] R f =0.3 (hexane:EtOAc, 1:1).

[1002] 1 H NMR (400MHz, CDCl3): δ7.53(s,1H),7.18(d,J=8.7Hz,1H),6.82(d,J=2.4Hz,1H),6.78(dd,J=8.6,2.3Hz,1H),6 .60(s,1H),6.23(s,1H),6.02(s,1H),5.76(s,1H),5.04(d,J=11.7Hz,1H),4.62(s,1H),4.36(s,1H),4.28(d,J =5.0Hz,1H),4.24-4.09(m,3H),3.81(s,3H),3.79(s,3H),3.64(s,1H),3.47-3.40(m,3H),3.01-2.90(m,2H),2 .53(d,J=6.9Hz,2H),2.45-2.41(m,1H),2.40(s,3H),2.27(s,3H),2.22-2.14(m,1H),2.18(s,3H),2.06(s,3H).

[1003] ESI-MS m / z: 824.3 (M+H) + .

[1004]

[1005] AgNO3 (2.04 g, 12.0 mmol) was added to a solution of 18-R (330 mg, 0.40 mmol) in CH3CN:H2O (1.39:1, 28 mL, 0.015 M). After incubation at 23 °C for 3 hours, the reaction was quenched with a 1:1 mixture of saturated aqueous NaCl and NaHCO3 solutions, stirred for 15 min, diluted with CH2Cl2, stirred for 5 min, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The resulting residue was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give 19-R (224 mg, 69%).

[1006] R f =0.44(CH2Cl2:CH3OH,9:1).

[1007] 1 H NMR (500MHz, CD3OD): δ7.14(dd,J=8.8,0.5Hz,1H),6.83(d,J=2.5Hz,1H),6.68(dd,J=8.8,2.5Hz,1H),6.59(s,1H),6.26(d,J=1. 4Hz,1H),6.07(d,J=1.4Hz,1H),5.21(d,J=11.5Hz,1H),4.68-4.55(m,1H),4.32-4.25(m,2H),4.12(dd,J=11.5,2.1Hz,1H),3.75( s,3H),3.74(s,3H),3.60(d,J=5.2Hz,1H),3.57-3.45(m,3H),3.41(d,J=8.8Hz,1H),2.97-2.83(m,3H),2.73(dd,J=15.0,3.4Hz,1 H),2.69(d,J=14.9Hz,1H),2.34(s,3H),2.30(s,3H),2.20(dd,J=15.1,10.4Hz,1H),2.12(s,3H),2.11-2.08(m,1H),2.05(s,3H).

[1008] 13C NMR (126MHz, CD3OD): δ173.0,170.8,155.0,149.8,147.3,145.0,142.8,14 2.3,133.5,133.1,132.2,132.1,131.1,130.5,127.8,122.5,121.7,120.0 ,116.4,113.5,112.9,111.4,110.2,103.5,100.9,92.6,66.8,64.5,61.3,60.4,60.0,56.8,56.1,55.9,54.1,44.1,41.3,25.6,24.5,20.6,16.2,9.6.

[1009] ESI-MS m / z: 797.4 (M-H2O+H) + .

[1010] (+)-HR-ESI-TOF-MS m / z:797.2896[M-H2O+H] + (Calculated value C) 42 H 45 N4O 10 S797.2851).

[1011] Example 11 Synthesis of allyl N-[(S)-2-amino-3-(5-methoxy-1H-indole-3-yl)propyl)]aminocarbamate (24-S)

[1012]

[1013] Di-tert-butyl dicarbonate (13.7 g, 62.8 mmol) was added to a solution of 17-S (6.9 g, 31.4 mmol) in CH3CN (126 mL, 4 mL / mmol). The reaction mixture was stirred at 23 °C for 5.5 h and concentrated under vacuum. Rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) gave 20-S (4.5 g, 45%).

[1014] R f =0.6(CH2Cl2:CH3OH,9:1).

[1015] 1H NMR (400MHz, CDCl3): δ8.04 (s, 1H), 7.25 (d, J = 8.4Hz, 1H), 7.10 (d, J = 2.4Hz, 1H), 7.03 (s, 1H), 6.87 (dd, J = 8. 8, 2.5Hz, 1H), 4.83 (s, 1H), 3.98 (s, 1H), 3.87 (s, 3H), 3.73-3.58 (m, 2H), 2.96 (d, J = 6.6Hz, 2H), 1.42 (s, 9H).

[1016]

[1017] Phthalimide (4.5 g, 30.9 mmol) and triphenylphosphine (8.1 g, 30.9 mmol) were added to a solution of 20-S (4.5 g, 14 mmol) in CH₂Cl₂ (84 mL, 6 mL / mmol), and the mixture was cooled to 0 °C. A solution of 40% diethyl azodicarbonate in CH₂Cl₂ (10.4 mL, 35 mmol) was added for 15 min. The reaction was stirred at 23 °C for 18 h and concentrated under vacuum. The residue obtained was purified by rapid column chromatography (hexane:EtOAc, 99:1 to 85:15) to give 21-S (5.8 g, 92%).

[1018] R f =0.55 (hexane:EtOAc, 1:1).

[1019] 1 H NMR (400MHz, CDCl3): δ8.48(s,1H),7.78(dd,J=5.5,3.1Hz,2H),7.69-7.61(m,2H),7.21(d,J=8.8Hz,1H),7.06(dd,J=18.5,2.4H z, 2H), 6.81 (dd, J = 8.8, 2.4Hz, 1H), 4.87 (s, 1H); 4.39 (s, 1H), 3.87 (s, 3H), 3.83-3.66 (m, 2H), 2.98 (d, J = 6.1Hz, 2H), 1.20 (s, 9H).

[1020]

[1021] Hydrazine monohydrate (61.1 mL, 1260 mmol) was added to a solution of 21-S (6.29 g, 14 mmol) in ethanol (420 mL, 30 mL / mmol). The reaction mixture was stirred in a sealed tube at 80 °C for 2 hours and concentrated under vacuum. Rapid column chromatography (CH₂Cl₂:CH₃OH, 100:1 to 50:50) gave 22-S (4.2 g, 95%).

[1022] R f =0.1(CH2Cl2:CH3OH,8:2).

[1023] 1 H NMR (400MHz, CDCl3): δ7.22(d,J=8.8Hz,1H),7.12(d,J=2.4Hz,1H),7.06(s,1H),6.76( dd,J=8.8,2.4Hz,1H),4.06-3.97(m,1H),3.82(s,3H),3.06-2.82(m,4H),1.37(s,9H).

[1024]

[1025] N,N-diisopropylethylamine (1.8 mL, 10 mmol) and allyl chloroformate (13.3 mL, 125 mmol) were added to a solution of 22-S (4.0 g, 12.52 mmol) in CH3CN (125 mL, 10 mL / mmol) and DMF (12 mL, 1 mL / mmol). The reaction was stirred at 23 °C for 5 hours. The mixture was diluted with EtOAc, NH4Cl was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (hexane:EtOAc, 100:1 to 1:100) to give 23-S (2.65 g, 52%).

[1026] R f =0.5 (hexane:EtOAc, 1:1).

[1027] 1 H NMR (400MHz, CDCl3): δ8.11(s,1H),7.28-7.20(m,1H),7.04(d,J=13.1Hz,2H),6.8 5(dd,J=8.9,2.4Hz,1H),5.97-5.82(m,1H),5.33-5.24(m,1H),5.19(dt,J=10.4,1 .3Hz,1H),5.11(s,1H),4.82(s,1H),4.55(d,J=5.6Hz,2H),4.01(s,1H),3.86(s,3 H), 3.37 (d, J = 13.7Hz, 1H), 3.21 (s, 1H), 2.89 (dd, J = 14.5, 7.0Hz, 1H), 1.41 (s, 9H).

[1028]

[1029] Trifluoroacetic acid (54 mL, 8.3 mL / mmol) was added to a CH2Cl2 (106 mL, 16.6 mL / mmol) solution of 23-S (2.60 g, 6.44 mmol). The reaction mixture was stirred at 23 °C for 1.5 h and concentrated under vacuum to give 24-S (3.9 g, 100%).

[1030] R f＝ 0.1 (CH2Cl2:CH3OH, 9:1).

[1031] 1 H NMR (400MHz, CD3OD): δ8.27(s,1H),7.25(dd,J=9.0,2.4Hz,1H),7.10(s,1H),6.96(d,J=2.3Hz,1H),6.87(dd,J=9.0,2.4Hz,1H),5.81(ddt,J=16.3,10 .9,5.7Hz,1H),5.23(dd,J=19.3,13.6Hz,2H),4.49(d,J=5.9Hz,2H),3.82( s,3H),3.81-3.55(m,1H),3.62-3.39(m,2H),3.08(qd,J=15.1,7.3Hz,2H).

[1032] Example 12

[1033]

[1034] 24-S (117 mg, 0.35 mmol) was added to a solution of acetic acid (6 mL, 0.08 M) at 1 (120 mg, 0.19 mmol). The reaction mixture was stirred at 23 °C for 18 hours, and then the acetic acid was evaporated. A saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 1:1) gave compound 25-S (95 mg, 54%).

[1035] R f =0.4 (hexane:EtOAc, 1:1).

[1036] 1H NMR (400MHz, CDCl3): δ7.64(s,1H),7.14(d,J=8.8Hz,1H),6.80(s,1H),6.77(d,J=8.8Hz,1H),6.68(s,1H),6.24(s,1 H),6.03(s,1H),6.02-5.93(m,1H),5.76(s,1H),5.38(d,J=10.5Hz,1H),5.26(d,J=10.5Hz,1H),5.11(d,J=11.7Hz,1 H),4.66(d,J=5.6Hz,2H),4.57(s,1H),4.37(s,1H),4.33-4.19(m,3H),3.82(s,3H),3.79(s,3H),3.46(s,2H),3.17( s,1H),3.10-2.90(m,3H),2.68-2.45(m,2H),2.38-2.33(m,1H),2.32(s,3H),2.27(s,3H),2.16(s,3H),2.04(s,2H).

[1037] ESI-MS m / z: 907.1 (M+H) + .

[1038]

[1039] To a solution of 25-S (90 mg, 0.1 mmol) in CH₂Cl₂ (2 mL, 18 mL / mmol), bis(triphenylphosphine)palladium(II) dichloride (12 mg, 0.1 mmol) and acetic acid (0.056 mL, 0.99 mmol) were added. Tributyltin hydride (0.16 mL, 0.60 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 h and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 100:1 to 1:100, EtOAc:CH₃OH, 100:1 to 1:100) gave 26-S (75 mg, 92%).

[1040] R f =0.25(CH2Cl2:CH3OH, 1:1).

[1041] 1H NMR (400MHz, CDCl3): δ7.62(s,1H),7.15(d,J=9.3Hz,1H),6.81-6.76(m,2H),6.72(s,1H),6.25(d,J=1 .2Hz,1H),6.03(d,J=1.2Hz,1H),5.12(d,J=11.7Hz,1H),4.57(s,1H),4.41(s,1H),4.36-4.24(m,2H),4 .20(d,J=11.7Hz,1H),3.82(s,3H),3.79(s,3H),3.44(dd,J=22.0,7.1Hz,2H),3.08-2.78(m,4H),2.73- 2.64(m,2H),2.41-2.22(m,3H),2.28(s,3H),2.25-2.15(m,1H),2.14(s,3H),2.08(s,3H),2.04(s,3H).

[1042] ESI-MS m / z: 823.3 (M+H) + .

[1043]

[1044] AgNO3 (335 mg, 1.7 mmol) was added to a solution of 26-S (70 mg, 0.085 mmol) in CH3CN:H2O (1.39:1, 6 mL, 0.015 M). After incubation at 23 °C for 18 hours, the reaction was quenched with a 1:1 mixture of saturated aqueous NaCl and NaHCO3 solutions, stirred for 15 min, diluted with CH2Cl2, stirred for 5 min, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give 27-S (23 mg, 33%).

[1045] R f =0.2(CH2Cl2:CH3OH,9:1).

[1046] 1H NMR (400MHz, CDCl3): δ7.62(s,1H),7.15(d,J=7.8Hz,1H),6.78(s,1H),6.75(d,J=7.8Hz,1H),6.21(d,J=1.5H z,1H),6.01(d,J=1.5Hz,1H),5.78(s,1H),5.22(d,J=11.5Hz,1H),4.90(s,1H),4.58-4.42(m,3H),4.29-4.10( m,2H),3.84-3.80(m,1H),3.83(s,3H),3.79(s,3H),3.53-3.48(m,2H),3.22(d,J=8.7Hz,1H),3.12(s,1H),3.0 2(d,J=12.8Hz,1H),2.89-2.64(m,3H),2.46(s,3H),2.42-2.34(m,2H),2.27(s,3H),2.12(s,3H),2.03(s,3H).

[1047] 13 C NMR (126MHz, CDCl3): δ172.1,168.7,154.0,147.6,145.6,143.0,141.2,1 40.8,131.6,130.6,129.6,127.1,121.8,120.9,118.4,115.2,112.5,111 .8,101.8,100.2,81.5,62.6,60.6,58.0,57.8,56.0,55.8,55.0,42.3,41 .4,31.9,29.7,27.8,26.9,25.6,24.0,22.7,20.5,16.0,14.1,13.6,9.7.

[1048] ESI-MS m / z: 796.3 (M-H2O+H) + .

[1049] (+)-HR-ESI-TOF-MS m / z:796.3062[M-H2O+H] + (Calculated value C) 42 H 46 N5O9S796.3011).

[1050] Example 13 Synthesis of allyl N-[(R)-2-amino-3-(5-methoxy-1H-indole-3-yl)propyl)]aminocarbamate (24-S)

[1051]

[1052] Di-tert-butyl dicarbonate (4.67 g, 21.4 mmol) was added to a solution of 17-R (2.35 g, 10.7 mmol) in CH3CN (43 mL, 4 mL / mmol). The reaction mixture was stirred at 23 °C for 2.5 h and concentrated under vacuum. Rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) gave 20-R (1.7 g, 50%).

[1053] R f =0.6(CH2Cl2:CH3OH,9:1).

[1054] 1 H NMR (400MHz, CDCl3): δ8.05(s,1H),7.25(d,J=8.9Hz,1H),7.09(d,J=2.4Hz,1H),7.02(d,J=2.4Hz,1H),6.86(dd,J=8.8,2.4Hz,1H),4. 83(s,1H),3.98(s,1H),3.87(s,3H),3.69(td,J=9.2,7.5,5.3Hz,1H),3.61(dd,J=10.9,5.6Hz,1H),2.95(d,J=6.8Hz,2H),1.42(s,9H).

[1055]

[1056] Phthalimide (1.72 g, 11.7 mmol) and triphenylphosphine (3.06 g, 11.7 mmol) were added to a solution of 20-R (1.7 g, 5.3 mmol) in CH₂Cl₂ (32 mL, 6 mL / mmol), and the mixture was cooled to 0 °C. A solution of 40% diethyl azodicarbonate in CH₂Cl₂ (4.0 mL, 13.2 mmol) was added for 15 min. The reaction was stirred at 23 °C for 16 h and concentrated under vacuum. The residue obtained was purified by rapid column chromatography (hexane:EtOAc, 99:1 to 85:15) to give 21-R (2.0 g, 84%).

[1057] R f =0.45 (hexane:EtOAc, 1:1).

[1058] 1H NMR (400MHz, CDCl3): δ8.31(s,1H),7.80(dd,J=5.4,3.0Hz,2H),7.67(dd,J=5.4,3.0Hz,2H),7.30-7.12(m,2H),7.08(dd,J=15.2,2.4Hz,1H), 6.84 (dd, J=8.8, 2.4Hz, 1H), 4.85 (d, J=9.2Hz, 1H), 4.43 (q, J=5.3Hz, 1H), 3.86 (s, 3H), 3.83-3.68 (m, 2H), 3.01 (d, J=5.4Hz, 2H), 1.22 (s, 9H).

[1059]

[1060] To a solution of 21-R (2.0 g, 4.45 mmol) in ethanol (133 mL, 30 mL / mmol), hydrazine monohydrate (21.6 mL, 445 mmol) was added. The reaction mixture was stirred in a sealed tube at 80 °C for 2 hours and concentrated under vacuum. Rapid column chromatography (CH₂Cl₂:CH₃OH, 100:1 to 50:50) gave 22-R (1.15 g, 81%).

[1061] R f =0.1(CH2Cl2:CH3OH,8:2).

[1062] 1 H NMR (400MHz, CDCl3): δ7.21(d,J=8.8Hz,1H),7.12(s,1H),7.05(s,1H),6.75(dd,J=8.8,2.4Hz,1H),3.95 (ddd,J=10.7,8.7,5.4Hz,1H),3.82(s,3H),2.98-2.79(m,3H),2.75(dd,J=13.1,9.4Hz,1H),1.37(s,9H).

[1063]

[1064] N,N-diisopropylethylamine (0.5 mL, 2.7 mmol) and allyl chloroformate (3.7 mL, 34 mmol) were added to a solution of 22-R (1.1 g, 3.4 mmol) in CH3CN (34 mL, 10 mL / mmol) and DMF (3.4 mL, 1 mL / mmol). The reaction was stirred at 23 °C for 19 h. The mixture was diluted with EtOAc, NH4Cl was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue obtained was purified by rapid column chromatography (hexane:EtOAc, 100:1 to 1:100) to give 23-R (0.95 g, 69%).

[1065] R f =0.5 (hexane:EtOAc, 1:1).

[1066] 1 H NMR (400MHz, CDCl3): δ8.55 (s, 1H), 7.20 (d, J = 8.8Hz, 1H), 7.05 (s, 1H), 6.98-6 .87(m,1H),6.82(dt,J=8.8,1.8Hz,1H),5.96-5.81(m,1H),5.37-5.22(m,2H), 5.22-5.14(m,1H),5.02-4.97(m,1H),4.60-4.47(m,2H),4.00(s,1H),3.84(s, 3H), 3.31 (s, 1H), 3.19 (s, 1H), 2.88 (td, J = 14.5, 13.3, 5.9Hz, 2H), 1.40 (s, 9H).

[1067]

[1068] Trifluoroacetic acid (19 mL, 8.3 mL / mmol) was added to a solution of 23-R (0.94 g, 2.3 mmol) in CH2Cl2 (39 mL, 16.6 mL / mmol). The reaction mixture was stirred at 23 °C for 1.5 h and concentrated under vacuum to give 24-R (0.72 g, 100%).

[1069] R f =0.1(CH2Cl2:CH3OH, 9:1).

[1070] 1H NMR (400MHz, CD3OD): δ7.27(d,J=8.8,1H),7.18(s,1H),7.04(d,J=2.4Hz,1H),6.80(ddd,J=8.8,2.4,0.9Hz,1H),5.95(ddt,J=16.4,10.8,5.5Hz,1H) ,5.32(d,J=17.1Hz,1H),5.20(d,J=10.5Hz,1H),4.60-4.53(m,2H),3.83( s,3H),3.59(dt,J=11.4,5.5Hz,1H),3.47-3.30(m,2H),3.13-2.94(m,2H).

[1071] Example 14

[1072]

[1073] 24-R (0.54 mg, 1.8 mmol) was added to a solution of acetic acid (45 mL, 0.08 M) at 1 (0.71 g, 1.14 mmol). The reaction mixture was stirred at 23 °C for 7 hours, and then the acetic acid was evaporated. A saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 1:1) gave compound 25-R (670 mg, 65%).

[1074] R f =0.4 (hexane:EtOAc, 1:1).

[1075] 1H NMR (400MHz, CDCl3): δ7.52(s,1H),7.17(d,J=8.8Hz,1H),6.83-6.73(m,2H),6.61(s,1H),6.23(d,J=1.0Hz,1H),6.02(d,J=1.0H z,1H),6.05-5.89(m,1H),5.75(s,1H),5.44-5.30(m,1H),5.25(d,J=10.4Hz,1H),5.13-4.99(m,2H),4.71-4.59(m,2H),4.36(s, 1H),4.30-4.07(m,3H),3.80(s,3H),3.79(s,3H),3.61-3.53(m,1H);3.48-3.41(m,3H),3.26(dt,J=13.3,3.8Hz,1H),3.04-2.88 (m,2H),2.52(dd,J=14.9,3.7Hz,1H),2.46-2.35(m,2H),2.31(s,3H),2.29(s,3H),2.16(s,3H),2.12-2.02(m,1H),2.09(s,3H).

[1076] ESI-MS m / z: 907.3 (M+H) + .

[1077]

[1078] To a solution of 25-R (745 mg, 0.82 mmol) in CH₂Cl₂ (15 mL, 18 mL / mmol), bis(triphenylphosphine)palladium(II) dichloride (92 mg, 0.1 mmol) and acetic acid (0.47 mL, 8.2 mmol) were added. Tributyltin hydride (1.33 mL, 4.9 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 0.75 h and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 100:1 to 1:100, EtOAc:CH₃OH, 100:1 to 1:100) gave 26-R (680 mg, >100%).

[1079] R f =0.25(CH2Cl2:CH3OH, 1:1).

[1080] 1H NMR (400MHz, CDCl3): δ7.57(s,1H),7.16(d,J=8.8Hz,1H),6.85-6.72(m,2H),6.57(s,1H),6.21(d,J=1.4H z,1H),6.00(d,J=1.3Hz,1H),5.05-4.97(m,1H),4.63(s,1H),4.35(s,1H),4.31-4.09(m,4H),3.80(s,3H), 3.78(s,3H),3.50-3.40(m,3H),3.24(dq,J=9.9,5.3Hz,1H),2.95(s,1H),2.91-2.75(m,2H),2.62(dd,J=1 4.8,3.6Hz,1H),2.43-2.28(m,2H),2.36(s,3H),2.25(s,3H),2.22-2.14(m,1H),2.15(s,3H),2.08(s,3H).

[1081] ESI-MS m / z: 823.3 (M+H) + .

[1082]

[1083] AgNO3 (2.70 g, 16.0 mmol) was added to a solution of 26-R (660 mg, 0.80 mmol) in CH3CN:H2O (1.39:1, 56 mL, 0.015 M). After incubation at 23 °C for 16.5 hours, the reaction was quenched with a 1:1 mixture of saturated aqueous NaCl and NaHCO3 solutions, stirred for 15 min, diluted with CH2Cl2, stirred for 5 min, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give 27-R (271 mg, 42%).

[1084] R f =0.1(CH2Cl2:CH3OH,9:1).

[1085] 1H NMR (400MHz, CDCl3): δ7.46(s,1H),7.16(d,J=8.9Hz,1H),6.83(s,1H),6.72(d,J=8.9Hz,1H),6.58(s,1H),6.20( d,J=1.8Hz,1H),5.99(d,J=1.8Hz,1H),5.76(s,1H),5.15(d,J=11.4Hz,1H),4.86(s,1H),4.52(m,2H),4.17(d,J=5 .3Hz,1H),4.07(d,J=11.4Hz,1H),3.80(s,3H),3.78(s,3H),3.55-3.43(m,2H),3.32-3.20(m,2H),3.01-2.82(m, 4H),2.68-2.59(m,1H),2.44-2.31(m,1H),2.38(s,3H),2.30-2.19(m,1H),2.26(s,3H),2.15(s,3H),2.07(s,3H).

[1086] 13 C NMR (101MHz, CD3OD): δ171.7,171.3,153.8,153.3,148.0,147.6,145.4,14 5.4,143.1,141.3,140.7,131.6,131.4,131.2,129.3,126.8,121.6,120.9 ,118.3,115.6,112.2,111.8,101.8,100.2,81.7,63.5,63.1,61.7,58.0,5 7.8,56.1,55.8,55.0,42.2,42.1,41.4,41.0,25.1,23.8,20.5,16.0,9.7.

[1087] ESI-MS m / z: 796.3 (M-H2O+H) + .

[1088] (+)-HR-ESI-TOF-MS m / z:796.3045[M-H2O+H] + (Calculated value C) 42 H 46 N5O9S796.3011).

[1089] Example 15: Synthesis of reference compounds 28-S and 29-S

[1090]

[1091] 16-S (675 mg, 2.88 mmol) was added to a solution of acetic acid (9 mL, 0.08 M) at 1 (450 mg, 0.72 mmol). The reaction mixture was stirred at 52 °C for 3 hours, and then the acetic acid was evaporated. A saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 80:20) gave compound 28-S (400 mg, 66%).

[1092] R f =0.35(CH2Cl2:CH3OH,10:1).

[1093] 1 H NMR (400MHz, CDCl3): δ7.65(s,1H),7.15(d,J=8.7Hz,1H),6.85-6.76(m,2H),6.57(s,1H),6.25(d,J =1.4Hz,1H),6.04(d,J=1.3Hz,1H),5.16(d,J=11.7Hz,1H),4.62(s,1H),4.44(s,1H),4.35(dd,J=11. 7,2.0Hz,1H),4.29(dd,J=5.2,1.6Hz,1H),4.22(d,J=2.7Hz,1H),3.80(s,3H),3.79(s,3H),3.52-3. 43(m,3H),3.02-2.81(m,4H),2.41-2.31(m,2H),2.36(s,3H),2.29(s,3H),2.15(s,3H),2.05(s,3H).

[1094] ESI-MS m / z: 838.6 (M+H) + .

[1095]

[1096] AgNO3 (1.20 g, 7.16 mmol) was added to a solution of 28-S (400 mg, 0.48 mmol) in CH3CN:H2O (2:1, 33 mL, 0.015 M). After incubation at 23 °C for 16 hours, a mixture of 1:1 saturated aqueous solutions of NaCl and NaHCO3 was added, and the mixture was stirred for 15 minutes. The solution was diluted with CH2Cl2, stirred for 30 minutes, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue obtained was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 70:30) to give 29-S (179 mg, 45%).

[1097] R f =0.25(CH2Cl2:CH3OH,9:1).

[1098] 1 H NMR (500MHz, CD3OD): δ7.17(d,J=8.9Hz,1H),6.83(d,J=2.4Hz,1H),6.70(dd,J=8.9,2.4Hz,1H),6.66(s,1 H),6.29(d,J=1.3Hz,1H),6.10(d,J=1.3Hz,1H),5.32(d,J=11.6Hz,1H),4.65(s,1H),4.57(s,1H),4.48(s, 1H),4.38(dd,J=11.7,2.1Hz,1H),3.75(s,3H),3.73(s,3H),3.41-3.35(m,1H),3.16-2.91(m,5H),2.71(dd ,J=15.3,11.4Hz,2H),2.54(s,1H),2.42-2.36(m,2H),2.38(s,3H),2.37(s,3H),2.28(s,3H),1.99(s,3H).

[1099] 13 C NMR (126MHz, CDCl3):d 171.3,170.6,155.2,149.8,147.5,145.4,142.8,142.4,133.0,131.8,130.0,128.0,122.2,121.8,115.5,113.9,113.3,113.2,111.4 ,109.1,103.8,100.9,91.6,65.4,61.9,60.3,59.4,57.1,56.4,56.2,55.2,53.4,43.7,40.8,38.3,30.7,26.4,24.7,20.4,16.5,9.6.

[1100] ESI-MS m / z: 811.3 (M-H2O+H) + .

[1101] (+)-HR-ESI-TOF-MS m / z:811.2682[M-H2O+H] + (Calculated value C) 42 H 43 N4O 11 S811.2644).

[1102] Example 16: Synthesis of reference compounds 28-R and 29-R

[1103]

[1104] 16-R (66 mg, 0.3 mmol) was added to a solution of acetic acid (1 mL, 0.08 M) of 1 (50 mg, 0.08 mmol). The reaction mixture was stirred at 50 °C for 6 hours, and then the acetic acid was evaporated. A saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 80:20) gave compound 28-R (50 mg, 75%).

[1105] R f =0.20(CH2Cl2:CH3OH,10:1).

[1106] 1 H NMR (400MHz, CDCl3): 7.63(s,1H),7.16(d,J=8.8Hz,1H),6.81(d,J=2.4Hz,1H),6.77(dd,J=8.8,2.3Hz,1H),6.56(s,1H),6.2 1(d,J=1.2Hz,1H),6.00(d,J=1.2Hz,1H),5.77(s,1H),5.00(d,J=11.8Hz,1H),4.63(s,1H),4.35(s,1H),4.27(d,J=5.0Hz,1H ),4.22-4.04(m,3H),3.79(s,3H),3.77(s,3H),3.48-3.40(m,2H),3.00(dd,J=15.3,4.8Hz,1H),2.92(d,J=5.4Hz,2H),2.71( dd,J=15.3,10.1Hz,1H),2.46(d,J=14.9Hz,1H),2.34(s,3H),2.26(s,3H),2.21(d,J=15.0Hz,1H),2.15(s,3H),2.07(s,3H).

[1107] ESI-MS m / z: 838.8 (M+H) + .

[1108]

[1109] AgNO3 (304 mg, 1.80 mmol) was added to a solution of 28-R (50 mg, 0.06 mmol) in CH3CN:H2O (2:1, 4.2 mL, 0.015 M). After incubation at 23 °C for 3 hours, a mixture of 1:1 saturated aqueous NaCl and NaHCO3 solutions was added, and the mixture was stirred for 15 minutes. The solution was diluted with CH2Cl2, stirred for 30 minutes, and extracted with CH2Cl2. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue obtained was purified by rapid column chromatography (CH2Cl2:CH3OH from 99:1 to 70:30) to give 29-R (30 mg, 60%).

[1110] R f =0.15(CH2Cl2:CH3OH,9:1).

[1111] 1 H NMR (400MHz, CDCl3): 7.68 (s, 1H), 7.14 (d, J = 8.8Hz, 1H), 6.80 (d, J = 2.4Hz, 1H), 6.76 (dd, J = 8.8, 2.4Hz, 1H), 6.57 (s, 1H), 6.17 (d, J = 1.3Hz, 1H),5.95(d,J=1.3Hz,1H),5.75(s,1H),5.12(d,J=11.5Hz,1H),4.85(s,1H),4.56-4.46(m,2H),4.17(s,1H),4.10(dd,J=9.9,4.9Hz,1H),4 .05(dd,J=11.4,2.0Hz,1H),3.78(s,3H),3.76(s,3H),3.51(s,1H),3.48-3.42(m,2H),3.23(s,1H),3.00(dd,J=15.3,4.9Hz,1H),2.90-2.7 7(m,2H),2.71(dd,J=15.2,9.9Hz,1H),2.48(d,J=14.6Hz,1H),2.34(s,3H),2.25(s,3H),2.20(d,J=14.6Hz,1H),2.14(s,3H),2.05(s,3H).

[1112] 13C NMR(101MHz, CDCl3):175.6,171.0,168.7,154.1,147.3,145.6,143.1,1 41.3,140.8,131.1,130.4,126.5,121.9,121.5,121.3,115.5,112.9,11 2.7,112.0,109.1,101.9,100.2,81.5,62.8,61.7,60.4,57.9,57.8,56. 0,55.8,54.8,53.4,42.5,41.2,40.3,29.7,24.6,23.8,20.5,15.9,9.8.

[1113] ESI-MS m / z: 811.6 (M-H2O+H) + .

[1114] (+)-HR-ESI-TOF-MS m / z:811.2687[M-H2O+H] + (Calculated value C) 42 H 43 N4O 11 S811.2644).

[1115] Example 17

[1116]

[1117] To a solution of compound 1 (2.0 g, 3.21 mmol) in acetonitrile (200 mL, 0.01 M), 2-benzofuran-3-yl-ethylamine hydrochloride (30) (1.90 g, 9.65 mmol, Sigma Aldrich) and cyanuric chloride (TCT) (200 mg, 10%) were added. The reaction mixture was stirred at 85 °C for 24 hours, then a saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 9:1 to 1:9) gave compound 31 (1.95 g, 79%).

[1118] R f =0.5 (hexane:EtOAc, 1:1).

[1119] 1H NMR (400MHz, CDCl3): δ7.38-7.36(m,2H),7.19-7.10(m,2H),6.64(s,1H),6.20(d,J=1. 5Hz,1H),6.05(d,J=1.5Hz,1H),5.76(s,1H),5.05(d,J=11.7Hz,1H),4.54(s,1H),4.33 -4.24(m,2H),4.23-4.16(m,2H),3.81(s,3H),3.49-3.38(m,2H),3.28-3.21(m,1H),3. 06-2.78(m,5H),2.57-2.50(m,2H),2.37(s,3H),2.27(s,3H),2.21(m,3H),2.08(s,3H).

[1120] ESI-MS m / z: 765.3 (M+H) + .

[1121]

[1122] Compound 31 (380 mg, 0.49 mmol) was added to a solution of CH3CN:H2O (1.39:1, 25 mL, 0.015 M) with AgNO3 (1.30 g, 7.45 mmol). After incubation at 23 °C for 5 hours, a mixture of 1:1 saturated aqueous solutions of NaCl and NaHCO3 was added, and the mixture was stirred for 15 minutes. The solution was diluted with CH2Cl2, stirred for 5 minutes, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue obtained was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give compound 32 (175 mg, 47%).

[1123] R f =0.40(CH2Cl2:CH3OH,9:1).

[1124] 1H NMR (400MHz, CDCl3): δ7.35(ddd,J=10.7,7.6,1.1Hz,2H),7.14(dtd,J=19.7,7.3,1.3Hz,2H),6.65(s,1H),6.16(d,J=1.5Hz, 1H),6.01(d,J=1.5Hz,1H),5.75(s,1H),5.15(dd,J=11.5,1.2Hz,1H),4.80(s,1H),4.48(d,J=3.2Hz,1H),4.44(s,1H),4.20-4 .06(m,2H),3.81(s,1H),3.50(d,J=18.8Hz,1H),3.30(ddd,J=12.6,7.9,5.1Hz,1H),3.22(d,J=9.1Hz,1H),2.99(d,J=17.9Hz, 1H),2.84(dd,J=19.2,12.0Hz,3H),2.59-2.49(m,2H),2.36(s,3H),2.27(s,3H),2.21-2.14(m,1H),2.18(s,3H),2.06(s,3H).

[1125] 13 C NMR (101MHz, CDCl3): δ171.2,168.7,154.4,150.0,147.9,145.5,142.9,140.9,140.8,131.3,129.0,127.7,123.7,122.2,121.2,120.8,118.9 ,118.3,115.5,113.5,111.7,101.7,82.1,62.7,61.7,60.3,57.8,57.4 ,55.9,55.0,42.2,41.3,39.7,38.2,29.7,23.7,21.3,20.6,15.9,9.7.

[1126] ESI-MS m / z: 738.6 (M-H2O+H) + .

[1127] (+)-HR-ESI-TOF-MS m / z:756.2654[M+H] + (Calculated value C) 40 H 42 N3O 10 S 756.2585).

[1128] Example 18

[1129]

[1130] 2-(5-methoxybenzofuran-3-yl)-ethylamine hydrochloride (33) (Diverchim, ref: DW04590) (444 mg, 1.60 mmol). The reaction mixture was stirred at 50 °C for 6 days, and then acetic acid was evaporated. A saturated aqueous solution of NaHCO3 was added and the mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 1:1) gave 34 (270 mg, 43%).

[1131] R f =0.3 (hexane:EtOAc, 1:1).

[1132] 1 H NMR (400MHz, CDCl3): δ7.25 (d, J = 9.1Hz, 1H), 6.80-6.73 (m, 2H), 6.63 (s, 1H), 6.18 (d, J = 1.4Hz, 1H), 6.03 (d, J = 1.4 Hz,1H),5.78(s,1H),5.03(dd,J=11.5,1.3Hz,1H),4.52(s,1H),4.29(s,1H),4.26(dd,J=4.7,1.5Hz,1H),4.23-4.1 6(m,2H),3.80(s,3H),3.78(s,3H),3.46-3.43(m,1H),3.43-3.37(m,1H),3.24(s,1H),3.03(d,J=18.0Hz,1H),2.91 (dd,J=17.9,9.2Hz,1H),2.87-2.72(m,2H),2.53-2.47(m,2H),2.36(s,3H),2.27(s,3H),2.20(s,3H),2.06(s,3H).

[1133] ESI-MS m / z: 795.8 (M+H) + .

[1134]

[1135] AgNO3 (2.20 g, 13.0 mmol) was added to a solution of 34 (345 mg, 0.43 mmol) in CH3CN:H2O (1.39:1, 30 mL, 0.015 M). After incubation at 23 °C for 3 hours, a mixture of 1:1 saturated aqueous solutions of NaCl and NaHCO3 was added, and the mixture was stirred for 15 minutes. The solution was diluted with CH2Cl2, stirred for 5 minutes, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give 35 (175 mg, 51%).

[1136] R f =0.35(CH2Cl2:CH3OH,9:1).

[1137] 1 H NMR (500MHz, CD3OD): δ7.27(d,J=9.0Hz,1H), 6.90(d,J=2.6Hz,1H), 6.80(dd,J=9.0,2.6Hz,1H) ,6.57(s,1H),6.23(d,J=1.2Hz,1H),6.05(d,J=1.2Hz,1H),5.23(d,J=11.5Hz,1H),4.27-4.08( m,4H),3.77(s,3H),3.75(s,3H),3.63(d,J=14.1Hz,2H),3.40-3.34(m,2H),2.93-2.87(m,5H), 2.80(d,J=15.5Hz,1H),2.57-2.54(m,2H),2.34(s,3H),2.30(s,3H),2.14(s,3H),2.05(s,3H).

[1138] 13 C NMR (126MHz, CD3OD): δ171.9,170.6,157.5,147.0,145.0,142.3,141.0,132.2,131.1,129.1,122.2,120.9,120.2,116.3,115.1,114.0,112. 7,111.4,103.5,102.7,92.9,62.0,60.3,59.8,59.4,56.5,56.2,56.0 ,54.0,43.8,41.2,40.7,30.8,30.3,28.7,24.5,21.6,20.6,16.2,9.6.

[1139] ESI-MS m / z: 768.6 (M-H2O+H)+ .

[1140] (+)-HR-ESI-TOF-MS m / z:768.2630[M-H2O+H] + (Calculated value C) 41 H 42 N3O 10 S768.2585).

[1141] Example 19

[1142]

[1143] A suspension of H₂SO₄ (7.14 mL, 72.9 mmol) and (S)-2-amino-3-(benzofuran-3-yl)propionic acid (36-S) (prepared as described in Tetrahedron Asymmetry 2008, 19, 500-511) in THF (85 mL, 0.003 M) was carefully added to a solution of LiAlH₄ (148 mL, 1.0 M, 148 mmol) at -40 °C. The reaction mixture was placed at 23 °C, heated at 80 °C for 3 h, and then heated at 23 °C for 18 h. The mixture was cooled to -21 °C and carefully quenched with NaOH ₂N until an alkaline pH was reached. EtOAc was added, and the mixture was passed through… The product was filtered and washed with CH3OH. The crude product was concentrated under vacuum to give compound 37-S (3.93 g, >100%).

[1144] R f =0.1(CH2Cl2:CH3OH,4:1).

[1145] 1 H NMR (400MHz, CD3OD): δ7.67-7.62(m,1H),7.61(s,1H),7.51-7.41(m,1H),7.34-7.18(m,2H),3.69-3.48(m,1H),3.44(dd,J= 10.8, 6.6Hz, 1H), 3.18 (dtd, J = 7.4, 6.4, 4.6Hz, 1H), 2.88 (ddd, J = 14.4, 6.1, 1.0Hz, 1H), 2.68 (ddd, J = 14.4, 7.5, 0.9Hz, 1H).

[1146] Example 20

[1147]

[1148] A suspension of H₂SO₄ (3.1 mL, 57.8 mmol) and (R)-2-amino-3-(benzofuran-3-yl)-propionic acid (36-R) (prepared as described in Tetrahedron Asymmetry 2008, 19, 500-511) in THF (67.4 mL, 0.003 M) in THF was carefully added to a solution of LiAlH₄ (118 mL, 1.0 M THF solution, 118 mmol) at -40 °C. The reaction mixture was placed at 23 °C, heated at 80 °C for 3 h, and then heated at 23 °C for 18 h. The mixture was cooled to -21 °C and carefully quenched with NaOH ₂N until an alkaline pH was reached. EtOAc was added, and the mixture was passed through… The product was filtered and washed with CH3OH. The crude product was concentrated under vacuum. Rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15, siloxaneamine) was performed to give compound 37-R (2.77 g, 68%).

[1149] R f =0.1(CH2Cl2:CH3OH,4:1).

[1150] 1 H NMR (400MHz, CD3OD): δ7.63-7.52(m,1H),7.56(s,1H),7.46-7.33(m,1H),7.21(dtd,J=19.9,7.3,1.3Hz,2H),3.57(dd,J=10.7,4.6Hz,1H ), 3.42(dd,J=10.8,6.6Hz,1H), 3.15(dtd,J=7.6,6.3,4.6Hz,1H), 2.84(ddd,J=14.4,6.0,1.0Hz,1H), 2.64(ddd,J=14.4,7.5,0.9Hz,1H).

[1151] Example 21

[1152]

[1153] To a solution of compound 1 (850 mg, 1.36 mmol) in CH3CN (136 mL, 0.01 M), (S)-2-amino-3-(benzofuran-3-yl)prop-1-ol (37-S) (1.30 g, 6.83 mmol) and cyanuric chloride (TCT) (170 mg, 20%) were added. The reaction mixture was stirred at 85 °C for 24 h, and then a saturated aqueous solution of NaHCO3 was added, followed by extraction with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 9:1 to 1:9) gave compound 38-S (750 mg, 69%).

[1154] R f =0.25 (hexane:EtOAc, 1:1).

[1155] 1 H NMR (400MHz, CDCl3): δ7.39-7.33(m,1H),7.33-7.29(m,1H),7.20(ddd,J=8.3,7.2,1.4Hz,1H),7.14(td,J=7.4,1.0Hz,1H),6.61(s ,1H),6.21(d,J=1.4Hz,1H),6.06(d,J=1.4Hz,1H),5.74(s,1H),5.08(d,J=11.2Hz,1H),4.58(s,1H),4.37(s,1H),4.32-4.23(m,2H) ,4.19(d,J=2.7Hz,1H),3.81(s,3H),3.52-3.41(m,3H),3.36-3.29(m,1H),3.13(d,J=9.8Hz,1H),3.00-2.81(m,3H),2.57(dd,J=15. 7,4.9Hz,1H),2.50(d,J=15.2Hz,1H),2.37(s,3H),2.31-2.25(m,1H),2.29(s,3H),2.16(s,3H),2.10(d,J=7.2Hz,1H),2.05(s,3H).

[1156] ESI-MS m / z: 795.2 (M) + .

[1157]

[1158] AgNO3 (4.70 g, 28.0 mmol) was added to a solution of compound 38-S (890 mg, 1.12 mmol) in CH3CN:H2O (1.39:1, 75 mL, 0.015 M). After incubation at 23 °C for 18 hours, a mixture of 1:1 saturated aqueous solutions of NaCl and NaHCO3 was added, and the mixture was stirred for 15 minutes. The solution was then diluted with CH2Cl2, stirred for 5 minutes, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue obtained was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give compound 39-S (500 mg, 57%).

[1159] R f =0.30(CH2Cl2:CH3OH,9:1).

[1160] 1 H NMR (400MHz, CDCl3): δ7.38-7.33(m,1H),7.33-7.28(m,1H),7.23-7.16(m,1H),7.16-7.09(m,1H),6.62(s,1H),6. 18(d,J=1.4Hz,1H),6.03(d,J=1.4Hz,1H),5.71(s,1H),5.19(d,J=11.2Hz,1H),4.85(s,1H),4.49(s,2H),4.24-4.1 0(m,3H),3.81(s,3H),3.54(d,J=4.9Hz,1H),3.49(d,J=2.3Hz,3H),3.33(t,J=10.1Hz,2H),3.22(s,1H),2.98(s,1H ),2.84(d,J=7.6Hz,2H),2.62-2.53(m,2H),2.37(s,3H),2.30-2.24(m,1H),2.28(s,3H),2.14(s,3H),2.04(s,3H).

[1161] 13C NMR (126MHz, CDCl3): δ172.0,170.7,156.1,150.6,149.9,147.1,145.0,142.4,142.2,132.0,131.4,128.7,125.5,123.8,122.6,121.6,120. 1,116.5,114.4,112.3,103.5,92.6,66.0,65.1,62.2,60.4,59.7,56.6 ,56.1,54.8,54.1,51.6,44.0,41.3,38.3,30.8,24.8,20.6,16.3,9.6.

[1162] ESI-MS m / z: 768.2 (M-H2O+H) + .

[1163] (+)-HR-ESI-TOF-MS m / z:768.2652[M-H2O+H] + (Calculated value C) 41 H 42 N3O 10 S768.2585)

[1164] Example 22

[1165]

[1166] To a solution of compound 1 (100 mg, 0.16 mmol) in CH3CN (16 mL, 0.01 M), (R)-2-amino-3-(benzofuran-3-yl)prop-1-ol (37-R) (307 mg, 1.6 mmol) and cyanuric chloride (TCT) (40 mg, 40%) were added. The reaction mixture was stirred at 85 °C for 44 hours, and then a saturated aqueous solution of NaHCO3 was added, followed by extraction with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 9:1 to 1:9) gave compound 38-R (95 mg, 75%).

[1167] R f =0.3 (hexane:EtOAc, 1:1).

[1168] 1H NMR (400MHz, CDCl3): δ7.42-7.27(m,2H),7.28 -7.09(m,2H),6.58(s,1H),6.20(d,J=1.4Hz,1H),6.05(d,J=1.4Hz,1H),5.79(s,1H ),5.00(d,J=11.4Hz,1H),4.59(s,1H),4.34(s,1H),4.31-4.16(m,4H),3.80(s,3H) ,3.79-3.76(m,1H),3.63(s,1H),3.54-3.40(m,4H),2.99-2.87(m,2H),2.68(d,J=1 5.0Hz,1H),2.56-2.47(m,1H),2.38(s,3H),2.27(s,3H),2.17(s,3H),2.07(s,3H).

[1169] ESI-MS m / z: 795.2 (M+H) + .

[1170]

[1171] AgNO3 (601 mg, 3.58 mmol) was added to a solution of compound 38-R (95 mg, 0.11 mmol) in CH3CN:H2O (1.39:1, 11 mL, 0.015 M). After incubation at 23 °C for 18 hours, a mixture of 1:1 saturated aqueous solutions of NaCl and NaHCO3 was added, and the mixture was stirred for 15 minutes. The solution was diluted with CH2Cl2, stirred for 5 minutes, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue obtained was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give compound 39-R (66 mg, 70%).

[1172] R f =0.3(CH2Cl2:CH3OH,9:1).

[1173] 1H NMR (400MHz, CDCl3): δ7.39-7.31(m,2H),7.23-7.07(m,2H),6.59(s,1H),6.17(d,J=1.4Hz,1H), 6.01(d,J=1.4Hz,1H),5.75(s,1H),5.12(dd,J=11.3,1.2Hz,1H),4.84(s,1H),4.56-4.43(m,2H) ,4.19-4.07(m,3H),3.79(s,3H),3.83-3.74(m,1H),3.66-3.51(m,3H),3.24(s,1H),2.99-2.79( m,2H),2.75-2.64(m,1H),2.59-2.43(m,2H),2.38(s,3H),2.27(s,3H),2.16(s,3H),2.07(s,3H).

[1174] 13 C NMR (101MHz, CD3OD): δ170.5,169.1,154.9,148.9,148.5,145.7,143.6, 141.1,140.8,130.6,129.9,127.1,124.1,122.4,122.4,121.2,120.3,11 8.7,118.2,115.1,113.6,110.9,102.1,91.1,65.0,63.3,60.2,59.0,58 .4,55.4,54.5,52.7,52.3,42.5,38.7,29.4,23.5,23.2,19.1,14.8,8.3.

[1175] ESI-MS m / z: 768.2 (M-H2O+H) + .

[1176] (+)-HR-ESI-TOF-MS m / z:767.2628[M-H2O+H] + (Calculated value C) 41 H 42 N3O 10 S768.2585).

[1177] Example 23 Synthesis of allyl-N-[(S)-2-amino-3-(benzofuran-3-yl)propyl]aminocarbamate (44-S).

[1178]

[1179] Di-tert-butyl dicarbonate (2.28 g, 10.4 mmol) was added to a CH3CN (21 mL, 4 mL / mmol) solution of compound 37-S (1.0 g, 5.22 mmol). The reaction mixture was stirred at 23 °C for 2 h and concentrated under vacuum. Rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) gave compound 40-S (0.5 g, 33%).

[1180] R f =0.7(CH2Cl2:CH3OH,9:1).

[1181] 1 H NMR (400MHz, CDCl3): δ7.64(d,J=7.6Hz,1H),7.49(s,1H),7.46(d,J=7.6Hz,1H),7.36-7.1 9(m,2H),4.94(s,1H),3.98(s,1H),3.71-3.56(m,2H),2.93(d,J=6.9Hz,2H),1.41(s,9H).

[1182]

[1183] Phthalimide (0.55 g, 3.77 mmol) and triphenylphosphine (0.99 g, 3.77 mmol) were added to a solution of compound 40-S (0.5 g, 1.71 mmol) in CH₂Cl₂ (11 mL, 6 mL / mmol), and the mixture was cooled. A solution of 40% diethyl azodicarbonate in CH₂Cl₂ (1.26 mL, 4.29 mmol) was added at 0 °C for 15 min. The reaction was stirred at 23 °C for 18 h and concentrated under vacuum. The residue obtained was purified by rapid column chromatography (hexane:EtOAc, 99:1 to 40:60) to give compound 41-S (0.68 g, 94%).

[1184] R f =0.8(CH2Cl2:CH3OH,9:1).

[1185] 1 H NMR (400MHz, CDCl3): δ7.89-7.79(m,2H),7.83-7.62(m,2H),7.65-7.55(m,2H),7.49-7.42(m,1H),7.33-7.20(m,2H ), 4.83 (d, J = 9.0Hz, 1H), 4.39 (ddt, J = 12.1, 6.3, 2.9Hz, 1H), 3.88-3.70 (m, 2H), 2.96 (d, J = 6.4Hz, 2H), 1.24 (s, 9H).

[1186]

[1187] Hydrazine monohydrate (3.6 mL, 73.8 mmol) was added to an ethanol (25 mL, 30 mL / mmol) solution of compound 41-S (345 mg, 0.82 mmol). The reaction mixture was stirred in a sealed tube at 80 °C for 2 hours and concentrated under vacuum. Rapid column chromatography (CH2Cl2:CH3OH, 100:1 to 50:50) gave compound 42-S (233 mg, 98%).

[1188] R f =0.1(CH2Cl2:CH3OH,8:2).

[1189] 1 H NMR (400MHz, CDCl3): δ7.62(d,J=7.5Hz,1H),7.49-7.42(m,2H),7.33-7.18(m,2H),4.85(d ,J=8.8Hz,1H),3.91(s,1H),2.91-2.76(m,3H),2.67(dd,J=13.1,6.8Hz,1H),1.25(s,9H).

[1190]

[1191] To a solution of compound 42-S (280 mg, 0.96 mmol) in CH3CN (10 mL, 10 mL / mmol) and DMF (16 mL, 1 mL / mmol), N,N-diisopropylethylamine (0.14 mL, 0.77 mmol) and allyl chloroformate (1.02 mL, 9.64 mmol) were added. The reaction was stirred at 23 °C for 2 hours. The mixture was diluted with EtOAc, NH4Cl was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue obtained was purified by rapid column chromatography (hexane:EtOAc, 100:1 to 1:100) to give compound 43-S (445 mg, >100%).

[1192] R f =0.5 (hexane:EtOAc, 1:1).

[1193] 1H NMR (400MHz, CDCl3): δ7.60 (d, J=7.6Hz, 1H), 7.52-7.43 (m, 2H), 7.34-7.20 (m, 2H), 5.90 (ddt, J=16.4, 10.8, 5.6Hz, 1H), 5. 32-5.17(m,2H),4.93-4.86(m,1H),4.56(d,J=5.6Hz,2H),4.08-3.98(m,1H),3.40-3.21(m,2H),2.88(m,2H),1.25(s,9H).

[1194]

[1195] Trifluoroacetic acid (4 mL, 8.3 mL / mmol) was added to a CH2Cl2 solution (8 mL, 16.6 mL / mmol) of compound 43-S (160 mg, 0.43 mmol). The reaction mixture was stirred at 23 °C for 1.5 h and concentrated under vacuum. Rapid column chromatography (CH2Cl2:CH3OH, 100:1 to 50:50) gave compound 44-S (175 mg, >100%).

[1196] R f =0.2(CH2Cl2:CH3OH,9:1).

[1197] 1 H NMR (400MHz, CD3OD): δ7.72(s,1H),7.64(dt,J=8.4,0.9Hz,1H),7.49(dt,J=8.4,0.9Hz,1H) ,7.37-7.22(m,2H),5.94(ddt,J=16.3,10.7,5.5Hz,1H),5.32(dq,J=17.3,1.7Hz,1H),5.19( dq,J=10.6,1.5Hz,1H),4.56(dt,J=5.7,1.5Hz,2H),3.56(qd,J=7.0,4.4Hz,1H),3.46-3.32 (m,1H),3.32-3.24(m,1H),3.03(dd,J=14.8,6.9Hz,1H),2.91(ddd,J=14.8,7.1,0.9Hz,1H).

[1198] Example 24 Synthesis of allyl-N-[(R)-2-amino-3-(benzofuran-3-yl)propyl]carbamate (44-R).

[1199]

[1200] Di-tert-butyl dicarbonate (6.27 g, 28.76 mmol) was added to a CH3CN (58 mL, 4 mL / mmol) solution of compound 37-R (2.75 g, 14.4 mmol). The reaction mixture was stirred at 23 °C for 2.5 h and concentrated under vacuum. Rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) gave compound 40-R (3.7 g, 88%).

[1201] R f =0.6(CH2Cl2:CH3OH,9:1).

[1202] 1 H NMR (400MHz, CDCl3): δ7.64(d,J=7.6Hz,1H),7.52-7.43(m,2H),7.35-7.20(m,2H),4.85(d,J=8.2Hz,1H),4 .00(bs,1H),3.69(dd,J=11.0,4.0Hz,1H),3.62(dd,J=10.9,5.1Hz,1H),2.94(d,J=6.9Hz,2H),1.42(s,9H).

[1203]

[1204] Phthalimide (4.1 g, 28 mmol) and triphenylphosphine (7.3 g, 28 mmol) were added to a solution of compound 40-R (3.7 g, 12.7 mmol) in CH2Cl2 (76 mL, 6 mL / mmol), and the mixture was cooled at 0 °C. A solution of 40% diethyl azodicarbonate in CH2Cl2 (9.4 mL, 31.7 mmol) was added for 15 min. The reaction was stirred at 23 °C for 16 h and concentrated under vacuum. The residue obtained was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give compound 41-R (4.05 g, 76%).

[1205] R f =0.8(CH2Cl2:CH3OH,9:1).

[1206] 1H NMR (400MHz, CDCl3): δ7.67-7.68(m,4H),7.61(d,J=7.5Hz,1H),7.58(s,1H),7.46(d,J=7.5Hz,1H),7.27(dtd,J=17 .2,7.3,1.4Hz,2H),4.84(d,J=9.0Hz,1H),4.46-4.30(m,1H),3.89-3.66(m,2H),2.97(d,J=6.4Hz,2H),1.24(s,9H).

[1207]

[1208] Hydrazine monohydrate (41.5 mL, 856 mmol) was added to a solution of compound 41-R (4.0 g, 9.5 mmol) in ethanol (285 mL, 30 mL / mmol). The reaction mixture was stirred in a sealed tube at 80 °C for 2 hours and concentrated under vacuum. Rapid column chromatography (CH2Cl2:CH3OH, 100:1 to 50:50) gave compound 42-R (2.2 g, 80%).

[1209] R f =0.1(CH2Cl2:CH3OH,8:2).

[1210] 1 H NMR (400MHz, CDCl3): δ7.60(d,J=7.5Hz,1H),7.45(s,1H),7.44(d,J=7.1Hz,1H),7.25(dtd,J=18.8,7.3,1.3H z, 2H), 4.94 (d, J = 8.8Hz, 1H), 3.98-3.78 (m, 1H), 2.90-2.77 (m, 2H), 2.65 (dd, J = 13.1, 7.0Hz, 1H), 1.40 (s, 9H).

[1211]

[1212] To a solution of compound 42-R (2.2 g, 7.6 mmol) in CH3CN (76 mL, 10 mL / mmol) and DMF (7.6 mL, 1 mL / mmol), N,N-diisopropylethylamine (1.1 mL, 6.08 mmol) and allyl chloroformate (8.05 mL, 76 mmol) were added. The reaction was stirred at 23 °C for 7 hours. The mixture was diluted with EtOAc, NH4Cl was added, and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue obtained was purified by rapid column chromatography (hexane:EtOAc, 100:1 to 1:100) to give compound 43-R (2.3 g, 81%).

[1213] R f =0.7 (hexane:EtOAc, 1:1).

[1214] 1 H NMR (400MHz, CDCl3): δ7.60 (d, J = 7.5Hz, 1H), 7.52-7.43 (m, 2H), 7.34-7.20 (m, 2H), 5 .90(ddt,J=17.3,10.8,5.6Hz,1H),5.29(d,J=17.2,1H),5.20(d,J=10.4,1H),5.10( t,J=6.2Hz,1H),4.86(d,J=8.4Hz,1H),4.56(d,J=5.4,2H),4.08-3.97(m,1H),3.36( dt,J=10.7,4.7Hz,1H),3.30-3.23(m,1H),2.87(td,J=14.8,6.5Hz,2H),1.41(s,9H).

[1215]

[1216] Trifluoroacetic acid (30 mL, 8.3 mL / mmol) was added to a solution of compound 43-R (1.32 g, 3.52 mmol) in CH2Cl2 (60 mL, 16.6 mL / mmol). The reaction mixture was stirred at 23 °C for 1.5 h and concentrated under vacuum. Rapid column chromatography (CH2Cl2:CH3OH, 100:1 to 50:50) gave compound 44-R (0.90 g, 94%).

[1217] R f =0.2(CH2Cl2:CH3OH,9:1).

[1218] 1H NMR (400MHz, CDCl3): δ7.75(s,1H),7.69-7.61(m,1H),7.54-7.46(m,1H),7 .39-7.24(m,2H),5.95(ddt,J=16.3,10.8,5.5Hz,1H),5.32(dd,J=17.3,1.8 Hz,1H),5.24-5.16(m,1H),4.57(dt,J=5.7,1.5Hz,2H),3.68(qd,J=7.1,4.2 Hz, 1H), 3.48 (dd, J = 14.8, 4.2Hz, 1H), 3.42-3.30 (m, 1H), 3.14-2.95 (m, 2H).

[1219] Example 25

[1220]

[1221] Compound 44-S (1370 mg, 6 mmol) and cyanuric chloride (TCT) (184 mg, 20%) were added to a CH3CN (120 mL, 0.01 M) solution of compound 1 (750 mg, 1.2 mmol). The reaction mixture was stirred at 85 °C for 23 hours, then a saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 9:1 to 1:9) gave compound 45-S (755 mg, 72%).

[1222] R f =0.36 (hexane:EtOAc, 1:1).

[1223] 1H NMR (400MHz, CDCl3): δ7.38-7.28(m,2H),7.23-7.08(m,2H),6.67(s,1H),6.19(d,J=1.4Hz,1H),6.09-5.95(m,1H),6.04(d,J=1.4Hz,1H), 5.92(s,1H),5.80(s,1H),5.44-5.34(m,1H),5.26(dq,J=10.4,1.3Hz,1H),5.08(dd,J=11.4,1.1Hz,1H),4.70-4.63(m,2H),4.56(s,1H),4. 34(s,1H),4.31-4.18(m,3H),3.80(s,3H),3.50-3.39(m,2H),3.24-3.15(m,1H),3.00(dt,J=12.2,6.0Hz,2H),2.95(d,J=5.2Hz,2H),2.60 (dd,J=15.4,4.5Hz,2H),2.44(dd,J=15.6,5.2Hz,1H),2.29(s,3H),2.27(s,3H),2.25-2.20(m,1H),2.18(s,3H),2.12(s,1H),2.04(s,3H).

[1224] ESI-MS m / z: 878.2 (M+H) + .

[1225]

[1226] To a solution of compound 45-S (750 mg, 0.85 mmol) in CH₂Cl₂ (15.3 mL, 18 mL / mmol), bis(triphenylphosphine)palladium(II) dichloride (96 mg, 0.14 mmol) and acetic acid (0.5 mL, 8.5 mmol) were added. Tributyltin hydride (1.4 mL, 5.1 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 30 min and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 100:1 to 1:100 and CH₂Cl₂:CH₃OH, 100:1 to 1:100) gave compound 46-S (430 mg, 64%).

[1227] R f =0.3(CH2Cl2:CH3OH, 1:1).

[1228] 1H NMR (400MHz, CDCl3): δ7.37-7.29(m,2H),7.22-7.11(m,2H),6.57(s,1H),6.21(d,J=1.5Hz,1H),6.06(d,J=1.5Hz,1H),5.07(d,J= 11.5Hz,1H),4.57(s,1H),4.37(s,1H),4.29-4.23(m,2H),4.14(s,1H),3.79(s,3H),3.50-3.47(m,2H),3.38(d,J=8.7Hz,1H),2.95 -2.71(m,4H),2.68-2.52(m,2H),2.51-2.38(m,1H),2.35(s,3H),2.33- 2.26(m,1H),2.29(s,3H),2.17-2.08(m,1H),2.10(s,3H),2.04(s,3H).

[1229] ESI-MS m / z: 794.3 (M+H) + .

[1230]

[1231] AgNO3 (2.4 g, 14 mmol) was added to a solution of compound 46-S (550 mg, 0.7 mmol) in CH3CN:H2O (1.39:1, 49 mL, 0.015 M). After incubation at 23 °C for 16 hours, the reaction was quenched with a 1:1 mixture of saturated aqueous NaCl and NaHCO3 solutions, stirred for 15 min, diluted with CH2Cl2, stirred for 5 min, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give compound 47-S (53 mg, 10%).

[1232] R f =0.1(CH2Cl2:CH3OH,9:1).

[1233] 1H NMR (500MHz, CDCl3): δ7.36(d,7.9Hz,1H),7.33(d,7.4Hz,1H),7.23(t,J=7.4Hz,1H),7.16(t,J=7.4Hz,1H),6.77(s ,1H),6.20(s,1H),6.04(s,1H),5.92(s,1H),5.20(d,J=11.1Hz,1H),4.90(s,1H),4.50(s,1H),4.46-4.39(m,1H),4 .25(d,J=11.1Hz,1H),4.20(s,1H),3.84(s,3H),3.81(d,J=4.2Hz,1H),3.58(s,1H),3.40-3.14(m,3H),2.90(t,J=1 3.0Hz,1H),2.76(m,3H),2.50(s,3H),2.46-2.37(m,1H),2.32-2.26(m,2H),2.30(s,3H),2.15(s,3H),2.04(s,3H).

[1234] 13 C NMR (126MHz, CD3OD): δ170.5,169.2,154.6,149.1,148.7,145.7,143.5, 141.0,140.9,131.2,129.6,126.9,124.4,122.5,121.4,119.7,118.7,1 15.0,112.7,111.0,110.7,102.1,91.2,63.5,61.2,59.2,58.5,55.3,54 .7,53.4,52.7,43.3,42.5,39.9,36.9,29.3,24.1,23.6,19.1,15.0,8.2.

[1235] ESI-MS m / z: 767.2 (M-H2O+H) + .

[1236] (+)-HR-ESI-TOF-MS m / z:767.2794[M-H2O+H] + (Calculated value C) 41 H 43 N4O9S767.2745).

[1237] Example 26

[1238]

[1239] Compound 44-R (825 mg, 3 mmol) and cyanuric chloride (TCT) (248 mg, 40%) were added to a CH3CN (100 mL, 0.01 M) solution of compound 1 (621 mg, 1 mmol). The reaction mixture was stirred at 85 °C for 66 hours, then a saturated aqueous solution of NaHCO3 was added, and the mixture was extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 9:1 to 1:9) gave compound 45-R (530 mg, 58%).

[1240] R f =0.4 (hexane:EtOAc, 1:1).

[1241] 1 H NMR (400MHz, CDCl3): δ7.42-7.28(m,2H),7.23-7.08(m,2H),6.60(s,1H),6.20(d,J=1.4Hz,1H),6.04(d,J=1.4Hz,1H),6.0 1-5.92(m,1H),5.77(s,1H),5.44-5.20(m,2H),5.09(s,1H),5.04-4.96(m,1H),4.71-4.55(m,2H),4.34(s,1H),4.30-4.18 (m,3H),3.79(s,3H),3.53(dd,J=10.2,4.4Hz,1H),3.46(m,2H),3.50-3.40(m,1H),3.03-2.87(m,2H),2.67(d,J=15.0Hz,1 H),2.47(dd,J=15.6,3.7Hz,1H),2.40-2.32(m,2H),2.30(s,3H),2.29(s,3H),2.19-2.12(m,2H),2.16(s,3H),2.09(s,3H).

[1242] ESI-MS m / z: 878.3 (M+H) + .

[1243]

[1244] To a solution of compound 45-R (552 mg, 0.63 mmol) in CH₂Cl₂ (11.3 mL, 18 mL / mmol), bis(triphenylphosphine)palladium(II) dichloride (70.7 mg, 0.1 mmol) and acetic acid (0.36 mL, 6.3 mmol) were added. Tributyltin hydride (1.02 mL, 3.8 mmol) was added at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 h and concentrated under vacuum. The resulting crude product was diluted with EtOAc, and the mixture was extracted with EtOAc by adding saturated aqueous NH₄Cl solution. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. Rapid column chromatography (hexane:EtOAc, 100:1 to 1:100, EtOAc:CH₃OH, 100:1 to 1:100) gave compound 46-R (423 mg, 85%).

[1245] R f =0.3(CH2Cl2:CH3OH, 1:1).

[1246] 1 H NMR (400MHz, CDCl3): δ7.45-7.28(m,2H),7.23-7.08(m,2H),6.56(s,1H),6.19(d,J=1.4Hz,1H),6.05 (d,J=1.4Hz,1H),4.98(d,J=11.5Hz,1H),4.59(s,1H),4.34(s,1H),4.27(dd,J=5.1,1.7Hz,1H),4.22- 4.16(m,2H),3.80(s,3H),3.49-3.39(m,2H),3.31(dq,J=9.8,5.5,4.5Hz,2H),2.95(s,1H),2.83(d,J= 5.6Hz,2H),2.74-2.51(m,3H),2.35(s,3H),2.32-2.21(m,2H),2.26(s,3H);2.16(s,3H),2.06(s,3H).

[1247] ESI-MS m / z: 794.3 (M+H) + .

[1248] C)

[1249]

[1250] AgNO3 (1.76 g, 10.4 mmol) was added to a solution of compound 46-R (412 mg, 0.52 mmol) in CH3CN:H2O (1.39:1, 36 mL, 0.015 M). After 22 hours at 23 °C, the reaction was quenched with a 1:1 mixture of saturated aqueous NaCl and NaHCO3, stirred for 15 min, diluted with CH2Cl2, stirred for 5 min, and extracted with CH2Cl2. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by rapid column chromatography (CH2Cl2:CH3OH, 99:1 to 85:15) to give compound 47-R (175 mg, 43%).

[1251] R f =0.1(CH2Cl2:CH3OH,9:1).

[1252] 1 H NMR (500MHz, CDCl3): δ7.34(dd,J=11.1,7.9Hz,2H),7.22-7.07(m,2H),6.57(s,1H),6.17(d,J=1 .2Hz,1H),6.01(d,J=1.2Hz,1H),5.11(d,J=11.2Hz,1H),4.84(s,1H),4.53-4.47(m,2H),4.21-4 .07(m,2H),3.80(s,3H),3.56(d,J=5.1Hz,1H),3.43(s,1H),3.24(d,J=9.1Hz,1H),2.98-2.78(m ,4H),2.72-2.58(m,2H),2.38(s,3H),2.35-2.27(m,2H),2.28(s,3H),2.14(s,3H),2.08(s,3H).

[1253] 13 C NMR (101MHz, CD3OD): δ170.6,169.1,155.0,148.8,145.6,143.7,141.1, 140.8,130.9,129.7,126.9,124.2,122.4,121.1,119.6,118.9,118.7,1 15.0,113.2,112.5,111.0,102.1,91.3,63.3,60.4,59.0,58.4,55.3,54 .6,52.6,51.1,44.9,42.4,39.8,38.7,29.4,24.0,23.2,19.1,15.0,8.3.

[1254] ESI-MS m / z: 767.2 (M-H2O+H) + .

[1255] (+)-HR-ESI-TOF-MS m / z:767.2806[M-H2O+H] + (Calculated value C) 41 H 43 N4O9S767.2745).

[1256] Example 27: In vitro bioassay for detecting antitumor activity

[1257] The purpose of this assay is to evaluate the in vitro cell growth inhibition (the ability to delay or stop the growth of tumor cells) or cytotoxic (the ability to kill tumor cells) activity of the test sample.

[1258] cell lines

[1259] A549 CCL-185 Humans lung Lung cancer (NSCLC) HT29 HTB-38 Humans colon Colorectal adenocarcinoma MDA-MB-231 HTB-26 Humans breast Breast cancer PSN1 CRM-CRL-3211 Humans pancreas pancreatic cancer PC-3 CRL-1435 Humans prostate Prostate adenocarcinoma 22Rv1 CRL-2505 Humans prostate Prostate cancer

[1260] Cytotoxic activity was assessed using SBR and MTT colorimetric assays.

[1261] A colorimetric assay using the sulfonylrhodamine B (SRB) reaction has been used to provide quantitative measurements of cell growth and viability (according to the technique described in Skehan et al., J. Natl. Cancer Inst. 1990, 82, 1107-1112). Another colorimetric assay based on the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to formazan has also been used to assess antiproliferative activity (according to the technique described in Mosmann et al., J. Immunol. Meth. 1983, 65, 55-63).

[1262] These assays were performed using 96-well cell culture microplates according to the standards of the American National Standards Institute and the Society for Laboratory Automation and Screening (ANSI SLAS1-2004(R2012) 10 / 12 / 2011). All cell lines used in this study were obtained from the American Type Culture Collection (ATCC) and derived from different types of human cancers.

[1263] A549, HT29, MDA-MB-231, and PSN1 cells were maintained in Dulbecco-modified Eagle medium (DMEM), while PC-3 and 22Rv1 cells were maintained in Los Angeles Memorial Institute medium (RPMI). All cell lines were supplemented with 10% fetal bovine serum (FBS), 2 mM L-glutamine, 100 U / mL penicillin, and 100 U / mL streptomycin at 37°C, 5% CO2, and 98% humidity. For experiments, cells were harvested from subconfluent cultures using trypsin digestion and resuspended in fresh medium before counting and plate seeding.

[1264] A549, HT29, MDA-MB-231, and PSN1 cells were seeded in 150 μL aliquots into 96-well microtiter plates, 5000 cells per well, and allowed to adhere to the plate surface in drug-free medium for 18 hours (overnight). Subsequently, one control (untreated) plate for each cell line was fixed (described below) and used as a zero-time reference. The culture plates were then treated with the test compound (50 μL aliquots of 4X stock solution in complete medium supplemented with 4% DMSO) using 10 2 / 5 serial dilutions (concentration range 10 to 0.003 μg / mL) and three aliquots of culture (1% final concentration in DMSO). After 72 hours of treatment, the antitumor effect was measured using the SRB method: briefly, cells were washed twice with PBS, fixed in 1% glutaraldehyde solution for 15 min at room temperature, rinsed twice with PBS, and stained in 0.4% SRB solution for 30 min at room temperature. The cells were then rinsed several times with 1% acetic acid solution and air-dried at room temperature. SRB were then extracted in 10 mM Trizma alkaline solution, and the absorbance at 490 nm was measured using an automated spectrophotometer.

[1265] Seed appropriate numbers of PC-3 and 22Rv1 cells into 96-well plates to achieve a final cell density in the range of 5,000 to 15,000 cells per well (depending on the cell line) for the assay, and incubate in medium at 37°C, 5% CO2, and 98% humidity for 24 hours. Then, add the compound or DMSO to the medium to achieve a final volume of 200 μL and the desired compound concentration in 1% (v / v) DMSO, starting with 0.1 μg / mL in 1% (v / v) DMSO. At this point, treat a set of "zero-time control plates" treated with 1% (v / v) DMSO with MTT as described below. The remainder of the plates are incubated for 72 hours under the above conditions. Then, add 50 μL of 1 mg / mL MTT solution in medium to the wells and incubate at 37°C for 6–8 hours to generate formazan crystals. The culture medium was then removed and 100 μL of pure DMSO was added to each well to dissolve the formazan product in the colored solution. The absorbance at 540 nm was finally measured in a PolarStar Omega microplate multi-label reader (BMGLabtech, Ortenberg, Germany).

[1266] The effects on cell growth and viability were assessed using the NCI algorithm (Boyd MR and Paull KD. Drug Dev. Res. 1995, 34, 91-104). Values ​​obtained from triplicate cultures were fitted to a four-parameter logistic curve using nonlinear regression analysis. Three reference parameters (according to the aforementioned NCI algorithm) were calculated using automatic interpolation of the fitted curve: GI... 50 = The concentration of a compound that produces 50% cell growth inhibition compared to the control culture; TGI = Total cell growth inhibition (cell inhibition effect) compared to the control culture; LC 50 = The concentration of the compound that produces a 50% net cell-killing cytotoxic effect).

[1267] Tables 1-7 illustrate the bioactivity data of the compounds of the present invention and the bioactivity data of reference compounds. Tables 8-9 provide information on the bioactivity of several compounds of the present invention compared with their analogs having carboxylic acid groups. Compounds A, B, E, F, ET-736, PM01183, 14-S, 15-S, 28-S, 28-R, 29-S, and 29-R are not part of this invention.

[1268] Table 1. Bioactivity (Molluscote)

[1269]

[1270] Table 2. Bioactivity (moles)

[1271]

[1272] Table 3. Bioactivity (moles)

[1273]

[1274] Table 4. Bioactivity (Molluscote)

[1275]

[1276] Table 5. Bioactivity (Molluscote)

[1277]

[1278] Table 6. Bioactivity (Molluscote)

[1279]

[1280] Table 7. Bioactivity (Molluscote)

[1281]

[1282] Table 8. Bioactivity (Mollus)

[1283]

[1284] Table 9. Bioactivity (Molluscote)

[1285]

[1286] Compared to reference compounds, the compounds of the present invention exhibit high in vitro activity. This indicates that the compounds of the present invention possess high cytotoxicity against cancer cells and can be used to treat cancer.

[1287] Example 28: MTD and MTMD Measurement

[1288] Female CD-1 or athymic naked-Fox1 nu / nu mice (Envigo) were used for all experiments. Animals (N = 10 / cage) were housed in individually ventilated cages. In the Techniplast SPA (Technical Intensive Treatment for Rodents), a 12-hour light-dark cycle was conducted at 21-23°C and 40-60% humidity. Mice were allowed free access to an irradiated standard rodent diet (Tecklad 2914C) and sterile water. Animals were acclimatized for five days before individual tattooing confirmation. The animal protocol was reviewed and approved by the regional agency's Animal Care and Use Committee.

[1289] Mice were randomly assigned to experimental groups and administered the compound intravenously. For MTD (maximum tolerated dose) assays, a single administration was given; for MTMD (maximum tolerated multiple doses) assays, weekly administration was given for three consecutive weeks. Animals were given a white formulation or a compound dissolved in the test formulation at different concentrations. The administration rate was always 10 mL / kg. Following administration, changes in clinical signs of systemic toxicity, body weight, and mortality were monitored for up to 14 days.

[1290] The results of MTD are summarized in Table 10.

[1291] Table 10

[1292]

[1293] The results of MTMD are summarized in Table 11.

[1294] Table 11

[1295]

[1296] Examples 29-40: In vivo xenotransplantation

[1297] Female athymic nu / nu mice (Harlan Laboratories Models, SL Barcelona, ​​Spain, or Envigo, Spain) were used in all experiments. Animals were housed in individual, well-ventilated cages. In the Plus, Techniplast SPA, up to 10 mice per cage were subjected to a 12-hour light-dark cycle at 21-23°C and 40-60% humidity. Mice were allowed free access to an irradiated standard rodent diet (Tecklad 2914C) and sterile water. Animals were acclimatized for at least 5 days before tumor cell suspension was implanted into the tumor.

[1298] cell lines

[1299]

[1300] *Cell cultures collected in Europe

[1301] HT1080 cells were maintained in vitro at 37°C in Eagle (MEME) (Sigma-Aldrich, Co.) minimal basal medium with 5% CO2. At 4-6 weeks of age, each animal was intramuscularly injected into the gastrointestinal tract using a 26G needle and a 1cc syringe, and then in situ implanted into 10 x 10⁻⁶ cells suspended in serum- and antibiotic-free medium. 6 One HT1080 cell.

[1302] MDA-MB-231 cells were maintained in vitro at 37°C and 5% CO2 in Dulbecco modified Eagle medium (Sigma-Aldrich, Co). Upon reaching confluence, the cultured cells were passaged every 3 to 5 days. At 4–6 weeks of age, each animal was subcutaneously implanted (using a 26G needle and a 1cc syringe on the right ventral side) and suspended in 0.05 mL of a 50%... (Corning Incorporated Life Sciences) and a solution consisting of 7.5 x 10⁻⁶ serum- or antibiotic-free culture medium. 6 One MDA-MB-231 cell.

[1303] H460 cells were maintained in vitro at 37°C and 5% CO2 in Dulbecco modified Eagle medium (Sigma-Aldrich, Co). Upon reaching confluence, the cultured cells were passaged every 3 to 5 days. At 4–6 weeks of age, each animal was subcutaneously implanted (using a 26G needle and a 1cc syringe on the right ventral side) and suspended in 0.05 mL of a 50% CO2 solution. (Corning Incorporated Life Sciences) and a solution consisting of 50% serum- or antibiotic-free culture medium at a concentration of 5 × 10⁻⁶. 6 H460 cells.

[1304] A2780 cells were maintained in vitro in RPMI-1640 (Sigma-Aldrich, Co.) at 37°C and 5% CO2. Upon reaching confluence, the cultured cells were passaged every 3 to 5 days. At 4–6 weeks of age, each animal was subcutaneously implanted (using a 26G needle and a 1cc syringe on the right ventral side) into 0.05 mL of a solution of 50%... (Corning Incorporated LifeSciences) and a solution consisting of 50% serum- or antibiotic-free culture medium at a concentration of 10 x 10⁻⁶. 6 A2780 cells.

[1305] HGC27 cells were maintained in vitro at 37°C and 5% CO2 in Iscove modified Dulbecco medium (Sigma-Aldrich, Co.). Upon reaching confluence, the cultured cells were passaged every 3 to 5 days. At 4–6 weeks of age, each animal was subcutaneously implanted (using a 26G needle and a 1cc syringe on the right ventral side) and suspended in 0.05 mL of a mixture of 50%... (Corning Incorporated Life Sciences) and a solution consisting of 50% serum- or antibiotic-free culture medium, 5x10 6HGC-27 cells.

[1306] H526 cells were maintained in vitro at 37°C and 5% CO2 in RPMI-1640 medium (Sigma-Aldrich, Co). H526 cells were grown as a suspension and maintained by adding fresh medium every 2 to 3 days as cell density increased. The culture was re-established weekly by centrifugation of the suspension, followed by re-suspending in a 1×10⁻⁶ medium solution. 5 Cells / ml of fresh culture medium. At 4–6 weeks of age, each animal was subcutaneously implanted (using a 26G needle and a 1cc syringe on the right ventral side) and suspended in 0.05 mL of 50% [cells / ml] fresh culture medium. (Corning Incorporated Life Sciences) and a solution consisting of 50% serum- or antibiotic-free culture medium at a concentration of 5 × 10⁻⁶. 6 One H526 cell.

[1307] H82 cells were maintained in vitro at 37°C and 5% CO2 in RPMI-1640 medium (Sigma-Aldrich, Co). H82 cells were grown as a suspension and maintained by adding fresh medium every 2 to 3 days as cell density increased. The culture was re-established weekly by centrifugation of the suspension, followed by re-suspending in a 1×10⁻⁶ medium solution. 5 Cells / ml of fresh culture medium. At 4-6 weeks of age, animals were subcutaneously implanted (using a 26G needle and a 1cc syringe on the right ventral side) and suspended in 0.05 mL of 50% (Corning Incorporated Life Sciences) and a solution consisting of 50% serum- or antibiotic-free culture medium at a concentration of 5 × 10⁻⁶. 6 One H82 cell.

[1308] PC3 cells were maintained in vitro at 37°C and 5% CO2 in RPMI-1640 medium (Sigma-Aldrich, Co). Upon reaching confluence, the cultured cells were passaged every 3 to 5 days. At 4–6 weeks of age, each female athymic mouse was subcutaneously implanted (using a 26G needle and a 1cc syringe on the right ventral side) into 0.05 mL of 50% CO2 medium. 3x10 of the matrix (Corning Incorporated Life Sciences) and a solution consisting of 50% serum- or antibiotic-free culture medium. 6 PC3 cells. In this model, female animals were used instead of males because PC-3 growth is not hormone-dependent.

[1309] DU-145 cells were maintained in vitro at 37°C and 5% CO2 in RPMI-1640 medium (Sigma-Aldrich, Co.). Upon reaching confluence, the cultured cells were passaged every 3 to 5 days. At 4–6 weeks of age, each male athymic mouse was subcutaneously implanted (using a 26G needle and a 1cc syringe on the right ventral side) into 0.05 mL of 50% CO2 medium. 5 × 10⁵ of a solution consisting of a matrix (Corning Incorporated Life Sciences) and 50% serum- or antibiotic-free culture medium. 6 DU-145 cells were suspended.

[1310] 22Rv1 cells were maintained in vitro at 37°C and 5% CO2 in RPMI-1640 medium (Sigma-Aldrich, Co). After reaching confluence, the cultured cells were passaged every 3 to 5 days. At 4–6 weeks of age, each male athymic mouse was subcutaneously implanted (using a 26G needle and a 1cc syringe on the right ventral side) into 0.05 mL of 50% CO2 medium. 5 × 10⁵ of a solution consisting of a matrix (Corning Incorporated Life Sciences) and 50% serum- or antibiotic-free culture medium. 6 22Rv1 cells.

[1311] Treatment tolerance is assessed by monitoring changes in body weight, clinical signs of systemic toxicity, and evidence of local damage at the injection site.

[1312] In xenotransplantation studies using the HT1080 cell line:

[1313] - The total diameter (tumor + stent) was measured using digital calipers (Fowler Sylvac, S235PAT). Starting from the first day of treatment (day 0), the total diameter and animal weight were measured 2-3 times per week.

[1314] When the total diameter reached a length of approximately 7.0-8.0 mm, mice were randomly assigned to treatment and control groups (N = 8-10 / group) based on body weight and tumor measurements using NewLab Oncology software (version 2.25.06.00).

[1315] The comparison of the median total diameter (tumor + stent) in the treatment group with that in the control group was used to evaluate the antitumor efficacy.

[1316] - When their total support diameter reaches approximately 18 mm, the animals are euthanized.

[1317] In xenotransplantation studies using other cell lines:

[1318] -Use the equation (a·b) 2 The tumor volume was calculated as (a: length (longest diameter)) / 2, where a: length (longest diameter) and b: width (shortest diameter) were measured in mm using digital calipers (Fowler Sylvac, S235PAT). Tumor size and weight were recorded 2-3 times per week starting from the first day of treatment.

[1319] -When the tumor reaches approximately 150-250mm 3 Using NewLab Oncology software (version 2.25.06.00), tumor-bearing animals (N=8-10 / group) were randomly assigned to the treatment group based on body weight and tumor measurements.

[1320] - The antitumor efficacy was evaluated by comparing the median tumor volume between the treatment group and the control group.

[1321] - When the tumor reaches approximately 2000mm 3 Euthanasia may be performed on animals when severe necrosis is observed.

[1322] Treatments that produce a mortality rate >20% and / or a net weight loss of 20% are considered toxic.

[1323] The tables and figures summarize the data obtained from the complete experimental groups, i.e., those groups that maintained the initial number of animals, n = 8–10. However, once the tumor length > 18 mm or the tumor size > 2000 mm, the data were significantly reduced. 3 Once the first animal is sacrificed, the experimental group will be considered incomplete. Therefore, data generated on and after the sacrifice date will not be shown (i.e., not in tables or graphs).

[1324] Example 29: In vivo study to determine the roles of 4-S and 12-S in several xenograft models

[1325] 4-S, 12-S, and Compound C are provided in lyophilized vials of the lyophilized product. Each vial is reconstituted with water to a concentration of 0.5 mg / mL for infusion. Further dilution with 5% dextran solution is performed to the dosage formulation concentration for injection. The administration doses of 4-S, 12-S, and Compound C are 1.25 mg / kg, 0.25 mg / kg, and 3.0 mg / kg, respectively.

[1326] The placebo was provided in the form of a freeze-dried cake containing 100 mg sucrose, 6.8 mg potassium dihydrogen phosphate, and an appropriate amount of phosphoric acid, pH 3.8-4.5, and was reconstituted with water for infusion.

[1327] In these experiments, whenever possible, 4-S, 12-S, and compound C, along with a placebo, were administered intravenously once weekly for three weeks on days 0, 7, and 14.

[1328] Example 29a: In vivo study to determine the role of 4-S and 12-S in human fibrosarcoma xenografts

[1329] The aim of this study was to compare the antitumor activities of 4-S and 12-S with those of compound C using a human sarcoma xenograft model.

[1330] The tumor model used in this study was the HT1080 cell line.

[1331] Table 12 reports the assessment of the total diameter (tumor + scaffold) of HT1080 tumors in mice treated with placebo, compound C, 4-S, and 12-S. These results also show... Figure 1 middle.

[1332] Table 12

[1333]

[1334]

[1335] Example 29b: In vivo study to determine the role of 4-S and 12-S in human breast xenografts.

[1336] The aim of this study was to compare the antitumor activities of 4-S and 12-S with those of compound C using a human breast cancer xenograft model. The tumor model used in this study was the MDA-MB-231 cell line.

[1337] Table 13 reports the median tumor volume assessment of MDA-MB-231 tumors in mice treated with placebo, compound C, 4-S, and 12-S. These results also show... Figure 2 middle.

[1338] Table 13

[1339]

[1340] Example 29c: In vivo study to determine the role of 4-S and 12-S in human lung tumor xenografts.

[1341] The aim of this study was to compare the antitumor activities of 4-S and 12-S with those of compound C using three different human lung cancer xenograft models. These models correspond to non-small cell lung cancer (H-460 cell line) and small cell lung cancer (H526 and H82 cell lines).

[1342] Table 14 reports the median tumor volume assessment of H460 tumors in mice treated with placebo, compound C, 4-S, and 12-S. These results also show... Figure 3 middle.

[1343] Table 14

[1344]

[1345] Table 15 reports the median tumor volume assessment of H526 tumors in mice treated with placebo, compound C, 4-S, and 12-S. These results also show... Figure 4 middle.

[1346] Table 15

[1347]

[1348] Table 16 reports the median tumor volume assessment of H82 tumors in mice treated with placebo, compound C, 4-S, and 12-S. These results also show... Figure 5 middle.

[1349] Table 16

[1350]

[1351] Example 29: In vivo study to determine the roles of 4-S and 12-S in human ovarian tumor xenografts

[1352] The aim of this study was to compare the antitumor activities of 4-S and 12-S with those of compound C using a human ovarian cancer xenograft model.

[1353] The tumor model used in this study was A2780.

[1354] Table 17 reports the volume assessment of A2780 tumors in mice treated with placebo, compound C, 4-S, and 12-S. These results also show... Figure 6 middle.

[1355] Table 17

[1356]

[1357] Example 29e: In vivo study to determine the role of 4-S and 12-S in human gastric tumor xenografts.

[1358] The aim of this study was to compare the antitumor activities of 4-S and 12-S compounds with those of compound C using a human gastric cancer xenograft model. The tumor model used in this study was HGC27.

[1359] Table 18 reports the tumor volume growth of HGC27 tumors in mice treated with placebo, compound C, 4-S, and 12-S. These results also show... Figure 7 middle.

[1360] Table 18

[1361]

[1362] Example 30: In vivo study to determine the role of 4-R in several xenograft models

[1363] 4-R is provided in lyophilized vials. The 4-R cake is reconstituted with water to a concentration of 0.5 mg / mL for infusion. The 4-R stock solution is further diluted in 5% glucose solution to the dosage concentration for injection. The dosage of 4-R is 0.30 mg / kg.

[1364] Compound D is provided in vials. Each vial is first reconstituted by completely dissolving it in DMSO and then adding Kolliphor ELP (BASF) / anhydrous ethanol (1:1, v / v) to a concentration of 0.8 mg / mL. It is then further diluted to the dosage concentration with lactate buffer (pH 4.0). The dosage of Compound D is 0.5 mg / kg.

[1365] PM01183 is supplied as a lyophilized vial. Each vial is reconstituted with water to a concentration of 0.2 mg / mL for infusion. It is further diluted with 5% glucose or 0.9% sodium chloride solution to the dosage concentration for injection. The dosage is 0.18 mg / kg.

[1366] The placebo was provided as a lyophilized cake containing 100 mg sucrose, 6.8 mg potassium dihydrogen phosphate, and an appropriate amount of phosphoric acid, pH 3.8-4.5, and was reconstituted with water for infusion.

[1367] In these experiments, whenever possible, 4-R, compound D, and PM01183, along with a placebo, were administered intravenously once weekly for three weeks on days 0, 7, and 14.

[1368] Example 30a: In vivo study to determine the role of 4-R in human fibrosarcoma xenografts

[1369] The aim of this study was to compare the antitumor activity of 4-R and compound D with that of PM01183 using a human sarcoma xenograft model.

[1370] The tumor model used in this study was the HT1080 cell line.

[1371] Table 19 reports the assessment of the total diameter (tumor + scaffold) of HT1080 tumors in mice treated with placebo, PM01183, and 4-R. These results also show... Figure 8 middle.

[1372] Table 19

[1373]

[1374] Table 20 reports the evaluation of the total diameter (tumor + scaffold) of HT1080 tumors in mice treated with placebo, PM01183, and compound D. These results also show... Figure 9 middle.

[1375] Table 20

[1376]

[1377] Example 30b: In vivo study to determine the role of 4-R in human breast xenografts.

[1378] The aim of this study was to compare the antitumor activity of 4-R and compound D with that of PM01183 using a human breast cancer xenograft model.

[1379] The tumor model used in this study was the MDA-MB-231 cell line.

[1380] Table 21 reports the median tumor volume assessment of MDA-MB-231 tumors in mice treated with placebo, PM01183, and 4-R. These results also show... Figure 10 middle.

[1381] Table 21

[1382]

[1383] Table 22 reports the volume assessment of MDA-MB-231 tumors in mice treated with placebo, PM01183, and compound D. These results also show... Figure 11 middle.

[1384] Table 22

[1385]

[1386]

[1387] Example 30c: In vivo study to determine the role of 4-R in human lung tumor xenografts.

[1388] The aim of this study was to compare the antitumor activity of 4-R and compound D with that of PM01183 using a human lung cancer xenograft model.

[1389] The tumor model used in this study was the H-460 cell line.

[1390] Table 23 reports the volume assessment of H460 tumors in mice treated with placebo, PM01183, and 4-R. These results also show... Figure 12 middle.

[1391] Table 23

[1392]

[1393] Table 24 reports the volume assessment of H460 tumors in mice treated with placebo, PM01183, and compound D. These results also show... Figure 13 middle.

[1394] Table 24

[1395]

[1396] Example 30: In vivo study to determine the role of 4-R in human ovarian tumor xenografts.

[1397] The aim of this study was to compare the antitumor activity of 4-R and compound D with that of PM01183 using a human ovarian cancer xenograft model.

[1398] The tumor model used in this study was A2780.

[1399] Table 25 reports the volume assessment of A2780 tumors in mice treated with placebo, PM01183, and 4-R. These results also show... Figure 14 middle.

[1400] Table 25

[1401]

[1402] Table 26 reports the volume assessment of A2780 tumors in mice treated with placebo, PM01183, and compound D. These results also show... Figure 15 middle.

[1403] Table 26

[1404]

[1405] Example 30e: In vivo study to determine the role of 4-R in human gastric tumor xenografts

[1406] The aim of this study was to compare the antitumor activity of 4-R and compound D with that of PM01183 using a human gastric cancer xenograft model.

[1407] The tumor model used in this study was HGC27.

[1408] Table 27 reports the tumor volume growth of HGC27 tumors in mice treated with placebo, PM01183, and 4-R. These results also show... Figure 16 middle.

[1409] Table 27

[1410]

[1411] Table 28 reports the tumor volume growth of HGC27 tumors in mice treated with placebo, PM01183, and compound D. These results also show... Figure 17 middle.

[1412] Table 28

[1413]

[1414]

[1415] Example 31: In vivo study to determine the role of 12-R in several xenograft models

[1416] 12-R is provided in lyophilized vials. The 12-R filter cake is reconstituted with water to a concentration of 0.5 mg / mL for infusion. The 12-R stock solution is further diluted in 5% glucose solution to the dosage concentration for injection. The dosage of 12-R is 0.05 mg / kg.

[1417] Compound D is provided in vials. Each vial is first reconstituted by completely dissolving it in DMSO and then adding Kolliphor ELP (BASF) / anhydrous ethanol (1:1, v / v) to a concentration of 0.8 mg / mL. It is then further diluted to the dosage concentration with lactate buffer (pH 4.0). The dosage of Compound D is 0.5 mg / kg.

[1418] The placebo was provided as a lyophilized cake containing 100 mg sucrose, 6.8 mg potassium dihydrogen phosphate, and an appropriate amount of phosphoric acid, pH 3.8-4.5, and was reconstituted with water for infusion.

[1419] In these experiments, whenever possible, 12-R, compound D, and placebo were administered intravenously once a week on days 0, 7, and 14 for three consecutive weeks.

[1420] Example 31a: In vivo study to determine the role of 12-R in human fibrosarcoma xenografts.

[1421] The aim of this study was to compare the antitumor activity of 12-R with that of compound D using a human sarcoma xenograft model.

[1422] The tumor model used in this study was the HT1080 cell line.

[1423] Table 29 reports the assessment of the total diameter (tumor + scaffold) of HT1080 tumors in mice treated with placebo, compound D, and 12-R. These results also show... Figure 18 middle.

[1424] Table 29

[1425]

[1426] Example 31b: In vivo study to determine the role of 12-R in human breast xenografts.

[1427] The aim of this study was to compare the antitumor activity of 12-R with that of compound D using a human breast cancer xenograft model.

[1428] The tumor model used in this study was the MDA-MB-231 cell line.

[1429] Table 30 reports the median tumor volume assessment of MDA-MB-231 tumors in mice treated with placebo, compound D, and 12-R. These results also show... Figure 19 middle.

[1430] Table 30

[1431]

[1432]

[1433] Example 31c: In vivo study to determine the role of 12-R in human lung tumor xenografts.

[1434] The aim of this study was to compare the antitumor activity of 12-R with that of compound D using three different human lung cancer xenograft models. These models correspond to non-small cell lung cancer (H460 cell line) and small cell lung cancer (H526 and H82 cell lines).

[1435] Table 31 reports the volume assessment of H460 tumors in mice treated with placebo, compound D, and 12-R. These results also show... Figure 20 middle.

[1436] Table 31

[1437]

[1438]

[1439] Table 32 reports the median tumor volume assessment of H526 tumors in mice treated with placebo, compound D, and 12-R. Results also showed... Figure 21 middle.

[1440] Table 32

[1441]

[1442] Table 33 reports the median tumor volume assessment of H82 tumors in mice treated with placebo, compound D, and 12-R. Results also showed... Figure 22 middle.

[1443] Table 33

[1444]

[1445]

[1446] Example 31d: In vivo study to determine the role of 12-R in human ovarian tumor xenografts.

[1447] The aim of this study was to compare the antitumor activity of 12-R with that of compound D using a human ovarian cancer xenograft model.

[1448] The tumor model used in this study was A2780.

[1449] Table 34 reports the volume assessment of A2780 tumors in mice treated with placebo, compound D, and 12-R. These results also show... Figure 23 middle.

[1450] Table 34

[1451]

[1452] Example 31e: In vivo study to determine the role of 12-R in human gastric tumor xenografts.

[1453] The aim of this study was to compare the antitumor activity of 12-R with that of compound D using a human gastric cancer xenograft model.

[1454] The tumor model used in this study was HGC27.

[1455] Table 35 reports the tumor volume growth of HGC27 tumors in mice treated with placebo, compound D, and 12-R. These results also show... Figure 24 middle.

[1456] Table 35

[1457]

[1458] Example 32: In vivo study to determine the role of 19-S in several xenograft models.

[1459] 19-S is provided in lyophilized vials. The 19-S filter cake is reconstituted with water to a concentration of 0.5 mg / mL for infusion. The 19-S stock solution is further diluted in 5% glucose solution to the dosage concentration for injection. The dosage of 19-S is 0.75 mg / kg.

[1460] PM01183 is supplied as a lyophilized vial. Each vial is reconstituted with water to a concentration of 0.2 mg / mL for infusion. The PM01183 stock solution is further diluted in 5% glucose solution to the dosage concentration for injection. The dosage is 0.18 mg / kg.

[1461] The placebo was provided as a lyophilized cake containing 100 mg sucrose, 6.8 mg potassium dihydrogen phosphate, and an appropriate amount of phosphoric acid, pH 3.8-4.5, and was reconstituted with water for infusion.

[1462] In these trials, whenever possible, 19-S and PM01183, along with a placebo, were administered intravenously once weekly for three weeks on days 0, 7, and 14.

[1463] Example 32a: In vivo study to determine the role of 19-S in human fibrosarcoma xenografts.

[1464] The aim of this study was to compare the antitumor activity of 19-S and PM01183 using a human sarcoma xenograft model.

[1465] The tumor model used in this study was the HT1080 cell line.

[1466] Table 36 reports the assessment of the total diameter (tumor + scaffold) of HT1080 tumors in mice treated with placebo, PM01183, and 19-S. These results also show... Figure 25 middle.

[1467] Table 36

[1468]

[1469] Example 32b: In vivo study to determine the role of 19-S in human breast cancer xenografts.

[1470] The aim of this study was to compare the antitumor activity of 19-S and PM01183 using a human breast cancer xenograft model.

[1471] The tumor model used in this study was the MDA-MB-231 cell line.

[1472] Table 37 reports the median tumor volume assessment of MDA-MB-231 tumors in mice treated with placebo, PM01183, and 19-S. These results also show... Figure 26 middle.

[1473] Table 37

[1474]

[1475]

[1476] Example 32c: In vivo study to determine the role of 19-S in human lung cancer xenografts.

[1477] The aim of this study was to compare the antitumor activity of 19-S and PM01183 using a human lung cancer xenograft model.

[1478] The tumor model used in this study was the H-460 cell line.

[1479] Table 38 reports the median tumor volume assessment of H-460 tumors in mice treated with placebo, PM01183, and 19-S. These results also show... Figure 27 middle.

[1480] Table 38

[1481]

[1482] Example 32d: In vivo study to determine the role of 19-S in human ovarian tumor xenografts.

[1483] The aim of this study was to compare the antitumor activity of 19-S and PM01183 using a human ovarian cancer xenograft model.

[1484] The tumor model used in this study was A2780.

[1485] Table 39 reports the median tumor volume assessment of A2780 tumors in mice treated with placebo, PM01183, and 19-S. These results also show... Figure 28 middle.

[1486] Table 39

[1487]

[1488] Example 32e: In vivo study to determine the role of 19-S in human gastric tumor xenografts.

[1489] The aim of this study was to compare the antitumor activity of PM01183 and 19-S using a human gastric cancer xenograft model.

[1490] The tumor model used in this study was HGC27.

[1491] Table 40 reports the median tumor volume assessment of HGC27 tumors in mice treated with placebo, PM01183, and 19-S. These results also show... Figure 29 middle.

[1492] Table 40

[1493]

[1494]

[1495] Example 33: In vivo study to determine the role of 19-R in several xenograft models

[1496] 19-R is provided in lyophilized vials. The 19-R filter cake is reconstituted with water to a concentration of 0.5 mg / mL for infusion. The 19-R stock solution is further diluted in 5% glucose solution to the dosage concentration for injection. The dosage of 19-R is 0.15 mg / kg.

[1497] PM01183 is supplied as a lyophilized vial. Each vial is reconstituted with water to a concentration of 0.2 mg / mL for infusion. The PM01183 stock solution is further diluted in 5% glucose solution to the dosage concentration for injection. The dosage is 0.18 mg / kg.

[1498] The placebo was provided as a lyophilized cake containing 100 mg sucrose, 6.8 mg potassium dihydrogen phosphate, and an appropriate amount of phosphoric acid, pH 3.8-4.5, and was reconstituted with water for infusion.

[1499] In these trials, whenever possible, 19-R and PM01183, along with a placebo, were administered intravenously once weekly for three weeks on days 0, 7, and 14.

[1500] Example 33a: In vivo study to determine the role of 19-R in human fibrosarcoma xenografts.

[1501] The aim of this study was to compare the antitumor activity of 19-R with that of PM01183 using a human sarcoma xenograft model.

[1502] The tumor model used in this study was the HT1080 cell line.

[1503] Table 41 reports the assessment of the total diameter (tumor + scaffold) of HT-1080 tumors in mice treated with placebo, PM01183, and 19-R. These results also show... Figure 30 middle.

[1504] Table 41

[1505]

[1506] Example 33b: In vivo study to determine the role of 19-R in human breast cancer xenografts.

[1507] The aim of this study was to compare the antitumor activity of 19-R with that of PM01183 using a human breast cancer xenograft model.

[1508] The tumor model used in this study was the MDA-MB-231 cell line.

[1509] Table 42 reports the median tumor volume assessment of MDA-MB-231 tumors in mice treated with placebo, PM01183, and 19-R. These results also show... Figure 31 middle.

[1510] Table 42

[1511]

[1512]

[1513] Example 33c: In vivo study to determine the role of 19-R in human lung tumor xenografts.

[1514] The aim of this study was to compare the antitumor activity of 19-R with that of PM01183 using a human lung cancer xenograft model.

[1515] The tumor model used in this study was the H-460 cell line.

[1516] Table 43 reports the median tumor volume assessment of H460 tumors in mice treated with placebo, PM01183, and 19-R. These results also show... Figure 32 middle.

[1517] Table 43

[1518]

[1519] Example 33d: In vivo study to determine the role of 19-R in human ovarian tumor xenografts.

[1520] The aim of this study was to compare the antitumor activity of 19-R and PM01183 using a human ovarian cancer xenograft model.

[1521] The tumor model used in this study was A2780.

[1522] Table 44 reports the median tumor volume assessment of A2780 tumors in mice treated with placebo, PM01183, and 19-R. These results also show... Figure 33 middle.

[1523] Table 44

[1524]

[1525] Example 33e determines the role of 19-R in human gastric tumor xenografts through in vivo studies.

[1526] The aim of this study was to compare the antitumor activity of 19-R with that of PM01183 using a human gastric cancer xenograft model.

[1527] The tumor model used in this study was HGC27.

[1528] Table 45 reports the median tumor volume assessment of HGC-27 tumors in mice treated with placebo, PM01183, and 19-R. These results also show... Figure 34 middle.

[1529] Table 45

[1530]

[1531]

[1532] Example 34: In vivo study to determine the role of 39-S in several xenograft models.

[1533] Compounds 39-S and C are provided in lyophilized vials containing lyophilized products. Each vial is reconstituted with sterile water to a concentration of 0.5 mg / mL for injection. Further dilution with 5% dextrose solution is performed to the dosage concentration for injection. The dosages for 39-S and C are 1.25 mg / kg and 3 mg / kg, respectively.

[1534] The placebo was provided in vials of lyophilized product. Each vial (200 mg sucrose + 13.6 mg potassium dihydrogen phosphate + appropriate amount of phosphoric acid, pH 3.8–4.5) was reconstituted with 2 mL of sterile water for injection. Further dilution with 5% glucose injection was performed.

[1535] In these experiments, 39-S and compound C, along with a placebo, were administered intravenously at a volume of 10 mL / kg per week.

[1536] Example 34a: In vivo study to determine the role of 39-S in human fibrosarcoma xenografts.

[1537] The aim of this study was to evaluate the antitumor activity of compound 39-S by comparing its antitumor activity with that of compound C using a human sarcoma xenograft model.

[1538] The tumor model used in this study was the HT1080 cell line.

[1539] Table 46 reports the assessment of the total diameter (tumor + scaffold) of HT1080 tumors in mice treated with placebo, compound C, and 39-S. These results also show... Figure 35 middle.

[1540] Table 46

[1541]

[1542]

[1543] Example 34b: In vivo study to determine the role of 39-S in human breast cancer xenografts.

[1544] The aim of this study was to compare the antitumor activity of 39-S and compound C using a human breast cancer xenograft model.

[1545] The tumor model used in this study was the MDA-MB-231 cell line.

[1546] Table 47 reports the median tumor volume assessment of MDA-MB-231 tumors in mice treated with placebo, compound C, and 39-S. These results also show... Figure 36 middle.

[1547] Table 47

[1548]

[1549]

[1550] Example 34c: In vivo study to determine the role of 39-S in human lung cancer xenografts.

[1551] The aim of this study was to compare the antitumor activity of 39-S and compound C using three different human lung cancer xenograft models. These models correspond to non-small cell lung cancer (H-460 cell line) and small cell lung cancer (H526 and H82 cell lines).

[1552] Table 48 reports the median tumor volume assessment of H460 tumors in mice treated with placebo, compound C, and 39-S. These results also show... Figure 37 middle.

[1553] Table 48

[1554]

[1555] Table 49 reports the median tumor volume assessment of H526 tumors in mice treated with placebo, compound C, and 39-S. These results also show... Figure 38 middle.

[1556] Table 49

[1557]

[1558] Table 50 reports the median tumor volume assessment of H82 tumors in mice treated with placebo, compound C, and 39-S. These results also show... Figure 39 middle.

[1559] Table 50

[1560]

[1561] Example 34d: In vivo study to determine the role of 39-S in human ovarian tumor xenografts.

[1562] The aim of this study was to compare the antitumor activity of 39-S and compound C using a human ovarian cancer xenograft model.

[1563] The tumor model used in this study was A2780.

[1564] Table 51 reports the volume assessment of A2780 tumors in mice treated with placebo, compound C, and 39-S. These results also show... Figure 40 middle.

[1565] Table 51

[1566]

[1567]

[1568] Example 34e: In vivo study to determine the role of 39-S in human gastric tumor xenografts.

[1569] The aim of this study was to compare the antitumor activity of 39-S and compound C using a human gastric cancer xenograft model. The tumor model used in this study was HGC27.

[1570] Table 52 reports the tumor volume growth of HGC27 tumors in mice treated with placebo, compound C, and 39-S. These results also show... Figure 41 middle.

[1571] Table 52

[1572]

[1573]

[1574] Example 35: In vivo study to determine the role of 47-R in several xenograft models.

[1575] Compound 47-R is provided in lyophilized vials containing the lyophilized product. Each vial is reconstituted with sterile water to a concentration of 0.5 mg / mL for injection. Further dilution with 5% dextrose solution is performed to the dosage concentration for injection. The dosage of 47-R is 0.1 mg / kg.

[1576] Compound D is provided as a powdered pharmaceutical substance. Each vial is first reconstituted by complete dissolution in DMSO (Fisher) and then by adding Kolliphor ELP (Basf) / anhydrous ethanol (Merk) (1:1, v / v) at a concentration of 0.8 mg / mL. It is further diluted to the dosage concentration with lactate buffer (pH 4.0). The dosage of Compound D is 0.5 mg / kg.

[1577] The placebo was provided in vials of lyophilized product. Each vial (200 mg sucrose + 13.6 mg potassium dihydrogen phosphate + appropriate amount of phosphoric acid, pH 3.8–4.5) was reconstituted with 2 mL of sterile water for injection. Further dilution with 5% glucose injection was performed.

[1578] In these experiments, 47-R and compound D, along with placebo, were administered intravenously at a volume of 10 mL / kg per week.

[1579] Example 35a: In vivo study to determine the role of 47-R in human fibrosarcoma xenografts.

[1580] The aim of this study was to evaluate the antitumor activity of compound 47-R by comparing its antitumor activity with that of compound D using a human sarcoma xenograft model.

[1581] The tumor model used in this study was the HT1080 cell line.

[1582] Table 53 reports the assessment of the total diameter (tumor + scaffold) of HT1080 tumors in mice treated with placebo, compound D, and 47-R. These results also show... Figure 42 middle.

[1583] Table 53

[1584]

[1585] Example 35b: In vivo study to determine the role of 47-R in human breast cancer xenografts.

[1586] The aim of this study was to compare the antitumor activity of 47-R and compound D using a human breast cancer xenograft model.

[1587] The tumor model used in this study was the MDA-MB-231 cell line.

[1588] Table 54 reports the median tumor volume assessment of MDA-MB-231 tumors in mice treated with placebo, compound D, and 47-R. These results also show... Figure 43 middle.

[1589] Table 54

[1590]

[1591]

[1592] Example 35c: In vivo study to determine the role of 47-R in human lung cancer xenografts.

[1593] The aim of this study was to compare the antitumor activity of 47-R with that of compound D using three different human lung cancer xenograft models. These models correspond to non-small cell lung cancer (H-460 cell line) and small cell lung cancer (H526 and H82 cell lines).

[1594] Table 55 reports the median tumor volume assessment of H460 tumors in mice treated with placebo, compound D, and 47-R. These results also show... Figure 44 middle.

[1595] Table 55

[1596]

[1597]

[1598] Table 56 reports the median tumor volume assessment of H526 tumors in mice treated with placebo, compound D, and 47-R. These results also show... Figure 45 middle.

[1599] Table 56

[1600]

[1601]

[1602] Table 57 reports the median tumor volume assessment of H526 tumors in mice treated with placebo, compound D, and 47-R. These results also show... Figure 46 middle.

[1603] Table 57

[1604]

[1605] Example 35d: In vivo study to determine the role of 47-R in human ovarian tumor xenografts.

[1606] The aim of this study was to compare the antitumor activity of 47-R with that of compound D using a human ovarian cancer xenograft model.

[1607] The tumor model used in this study was A2780.

[1608] Table 58 reports the volume assessment of A2780 tumors in mice treated with placebo, compound D, and 47-R. These results also show... Figure 47 middle.

[1609] Table 58

[1610]

[1611] Example 35e: In vivo study to determine the role of 47-R in human gastric tumor xenografts.

[1612] The aim of this study was to compare the antitumor activity of 47-R with that of compound D using a human gastric cancer xenograft model.

[1613] The tumor model used in this study was HGC27.

[1614] Table 59 reports the tumor volume growth of HGC27 tumors in mice treated with placebo, compound D, and 47-R. These results also show... Figure 48 middle.

[1615] Table 59

[1616]

[1617]

[1618] Example 36: In vivo study to determine the role of 32 in several xenograft models.

[1619] Compounds 32 and ET-736 are provided in lyophilized vials containing the lyophilized product. Each vial is reconstituted with sterile water to a concentration of 0.5 mg / mL for injection. It is further diluted with 5% dextrose solution to the dosage concentration for injection. The dosage of 32 and ET-736 is 0.5 mg / kg.

[1620] The placebo was provided as a lyophilized product. Each vial (200 mg sucrose + 13.6 mg potassium dihydrogen phosphate + appropriate amount of phosphoric acid, pH 3.8–4.5) was reconstituted with 2 mL of sterile water for injection. Further dilution with 5% glucose injection was performed.

[1621] In these experiments, 32 and ET-736, as well as placebo, were administered intravenously at a volume of 10 mL / Kg per week.

[1622] Example 36a: In vivo study to determine the role of 32 in human fibrosarcoma xenografts.

[1623] The aim of this study was to evaluate the antitumor activity of compound 32 by comparing its antitumor activity with that of ET-736 using a human sarcoma xenograft model.

[1624] The tumor model used in this study was the HT-1080 cell line.

[1625] Table 60 reports the assessment of the total diameter (tumor + scaffold) of HT1080 tumors in mice treated with placebo, ET-736, and 32. These results also show... Figure 49 middle.

[1626] Table 60

[1627]

[1628] Example 36b: In vivo study to determine the role of 32 in human breast cancer xenografts.

[1629] The aim of this study was to compare the antitumor activity of 32 and ET-736 using a human breast cancer xenograft model.

[1630] The tumor model used in this study was the MDA-MB-231 cell line.

[1631] Table 61 reports the median tumor volume assessment of MDA-MB-231 tumors in mice treated with placebo, ET-736, and 32. These results also show... Figure 50 middle.

[1632] Table 61

[1633]

[1634]

[1635] Example 36c: In vivo study to determine the role of 32 in human lung cancer xenografts.

[1636] The aim of this study was to compare the antitumor activity of 32 and ET-736 using three different human lung cancer xenograft models. These models correspond to non-small cell lung cancer (H-460 cell line) and small cell lung cancer (H526 and H82 cell lines).

[1637] Table 62 reports the median tumor volume assessment of H460 tumors in mice treated with placebo, ET-736, and 32. These results also show... Figure 51 middle.

[1638] Table 62

[1639]

[1640]

[1641] Table 63 reports the median tumor volume assessment of H526 tumors in mice treated with placebo, ET-736, and 32. These results also show... Figure 52 middle.

[1642] Table 63

[1643]

[1644] Table 64 reports the median tumor volume assessment of H82 tumors in mice treated with placebo, ET-736, and 32. These results also show... Figure 53 middle.

[1645] Table 64

[1646]

[1647] Example 36d: In vivo study to determine the role of 32 in human ovarian tumor xenografts.

[1648] The aim of this study was to compare the antitumor activity of 32 and ET-736 using a human ovarian cancer xenograft model.

[1649] The tumor model used in this study was A2780.

[1650] Table 65 reports the volume assessment of A2780 tumors in mice treated with placebo, ET-736, and 32. These results also show... Figure 54 middle.

[1651] Table 65

[1652]

[1653] Example 36e: In vivo study to determine the role of 32 in human gastric tumor xenografts.

[1654] The aim of this study was to compare the antitumor activity of 32 and ET-736 using a human gastric cancer xenograft model.

[1655] The tumor model used in this study was HGC27.

[1656] Table 66 reports the tumor volume growth of HGC27 tumors in mice treated with placebo, ET-736, and 32. These results also show... Figure 55 middle.

[1657] Table 66

[1658]

[1659] Example 37: In vivo study to determine the role of 35 in several xenograft models.

[1660] Compound 35 is provided in lyophilized vials containing the lyophilized product. Each vial is reconstituted with sterile water to a concentration of 0.5 mg / mL for injection. It is further diluted with 5% dextrose solution to an administration concentration for injection. The administration dose of 35 is 0.25 mg / kg.

[1661] PM01183 is supplied in lyophilized vials. Each vial is reconstituted with sterile water to a concentration of 0.5 mg / mL for injection. It is further diluted with 5% glucose or 0.9% sodium chloride solution to the dosage concentration for injection. The dosage of PM01183 is 0.18 mg / kg.

[1662] Placebo was provided in vials of lyophilized product, each vial (200 mg sucrose + 13.6 mg potassium dihydrogen phosphate + phosphoric acid, pH 3.8–4.5) reconstituted with 2 mL of sterile water for injection. Further dilution with 5% glucose injection was also provided.

[1663] In this experiment, compounds 35 and PM01183, along with a placebo, were administered intravenously at a volume of 10 mL / kg per week.

[1664] Example 37a: In vivo study to determine the role of 35 in human fibrosarcoma xenografts.

[1665] The aim of this study was to evaluate the antitumor activity of compounds 35 and PM01183 using a human sarcoma xenograft model.

[1666] The tumor model used in this study was the HT-1080 cell line.

[1667] Table 67 reports the assessment of the total diameter (tumor + scaffold) of HT1080 tumors in mice treated with placebo, PM01183, and 35. These results also show... Figure 56 middle.

[1668] Table 67

[1669]

[1670] Example 37b: In vivo study to determine the role of 35 in human breast cancer xenografts.

[1671] The aim of this study was to compare the antitumor activity of 35 and PM01183 using a human breast cancer xenograft model.

[1672] The tumor model used in this study was the MDA-MB-231 cell line.

[1673] Table 68 reports the median tumor volume assessment of MDA-MB-231 tumors in mice treated with placebo, PM01183, and 35. These results also show... Figure 57 middle.

[1674] Table 68

[1675]

[1676] Example 37c: In vivo study to determine the role of 35 in human lung cancer xenografts.

[1677] The aim of this study was to compare the antitumor activity of 35 and PM01183 using a human lung cancer xenograft model.

[1678] The tumor model used in this study was the H460 cell line.

[1679] Table 69 reports the median tumor volume assessment of H460 tumors in mice treated with placebo, PM01183, and 35. These results also show... Figure 58 middle.

[1680] Table 69

[1681]

[1682]

[1683] Example 37d: In vivo study to determine the role of 35 in human ovarian tumor xenografts

[1684] The aim of this study was to compare the antitumor activity of 35 and PM01183 using a human ovarian cancer xenograft model. The tumor model used in this study was A2780.

[1685] Table 70 reports the volume assessment of A2780 tumors in mice treated with placebo, PM01183, and 35. These results also show... Figure 59 middle.

[1686] Table 70

[1687]

[1688] Example 37e: In vivo study to determine the role of 35 in human gastric tumor xenografts.

[1689] The aim of this study was to compare the antitumor activity of 35 and PM01183 using a human gastric cancer xenograft model.

[1690] The tumor model used in this study was HGC27.

[1691] Table 71 reports the volume increase of HGC27 tumors in mice treated with placebo, PM01183, and 35. These results also show... Figure 60 middle.

[1692] Table 71

[1693]

[1694] Example 38: In vivo study to determine the role of 12-S and 12-R in human prostate xenografts.

[1695] 12-S and 12-R are provided in lyophilized vials containing the lyophilized product. Each vial is reconstituted with water to a concentration of 0.5 mg / mL for infusion. It is further diluted with 5% dextrose solution to the dosage concentration for injection. The dosages for 12-S and 12-R are 0.25 mg / kg and 0.05 mg / kg, respectively.

[1696] The placebo was provided as a lyophilized cake containing 100 mg sucrose, 6.8 mg potassium dihydrogen phosphate, and an appropriate amount of phosphoric acid, pH 3.8-4.5, and was reconstituted with water for infusion.

[1697] In these trials, whenever possible, 12-S and 12-R, as well as placebo, were administered intravenously once a week for three weeks on days 0, 7, and 14.

[1698] The aim of this study was to compare the antitumor activity of 12-S and 12-R using a human prostate cancer xenograft model.

[1699] The tumor model used in this study was the PC-3 cell line.

[1700] Table 72 reports the median tumor volume assessment of PC-3 tumors in mice treated with placebo, 12-S, and 12-R. These results also show... Figure 61 middle.

[1701] Table 72

[1702]

[1703]

[1704] Example 39: In vivo study to determine the role of 4-S in human prostate xenografts.

[1705] The aim of this study was to compare the antitumor activity of 4-S using three different human prostate cancer xenograft models. These models correspond to the PC-3, DU-145, and 22Rv1 cell lines.

[1706] Compound 4-S is provided in lyophilized vials containing the lyophilized product. Each vial is reconstituted with sterile water to a concentration of 0.5 mg / mL for injection. It is further diluted with 5% dextran solution to the dosage form for injection. The dosage of 4-S varied according to studies, being 1.25 mg / kg for the PC-3 tumor model, 1.00 mg / kg for the DU-145 tumor model, and 0.75 mg / kg for the 22Rv1 tumor model.

[1707] The placebo was provided as a lyophilized cake containing 100 mg sucrose, 6.8 mg potassium dihydrogen phosphate, and an appropriate amount of phosphoric acid, pH 3.8-4.5, and was reconstituted with water for infusion.

[1708] In these experiments, whenever possible, 4-S was administered intravenously weekly on days 0, 7, and 14, along with a placebo, for three consecutive weeks.

[1709] Table 73 reports the median tumor volume assessment of PC-3 tumors in mice treated with placebo and 4-S. These results also show... Figure 62 middle.

[1710] Table 73

[1711]

[1712] Table 74 reports the median tumor volume assessment of DU-145 tumors in mice treated with placebo and 4-S. These results also show... Figure 63 middle.

[1713] Table 74

[1714]

[1715] Table 75 reports the median tumor volume assessment of 22Rv1 tumors in mice treated with placebo and 4-S. These results also show... Figure 64 middle.

[1716] Table 75

[1717]

[1718] Example 40: In vivo study to determine the role of 39-S in human prostate xenografts.

[1719] The aim of this study was to compare the antitumor activity of 39-S using three different human prostate cancer xenograft models. These models correspond to the PC-3, DU-145, and 22Rv1 cell lines.

[1720] Compound 39-S is provided in lyophilized vials containing the lyophilized product. Each vial is reconstituted with sterile water to a concentration of 0.5 mg / mL for injection. It is further diluted with 5% dextran solution to the dosage concentration for injection. The dosage of 39-S varies according to studies, being 1.25 mg / kg for the PC-3 tumor model, 1.00 mg / kg for the DU-145 tumor model, and 0.75 mg / kg for the 22Rv1 tumor model.

[1721] The placebo was provided as a lyophilized cake containing 100 mg sucrose, 6.8 mg potassium dihydrogen phosphate, and an appropriate amount of phosphoric acid, pH 3.8-4.5, and was reconstituted with water for infusion.

[1722] In these experiments, whenever possible, 39-S and placebo were administered intravenously once a week on days 0, 7, and 14 for three consecutive weeks.

[1723] Table 76 reports the median tumor volume assessment of PC-3 tumors in mice treated with placebo and 39-S. These results also show... Figure 65 middle.

[1724] Table 76

[1725]

[1726] Table 77 reports the median tumor volume assessment of DU-145 tumors in mice treated with plac...

Claims

1. A compound of formula Ic or a pharmaceutically acceptable salt thereof: Ic in: R1 is -OH or -CN; R2 is -C(=O)R a Group; R3 is hydrogen; and R a It is an unsubstituted C1-C6 alkyl group.

2. The compound according to claim 1, wherein R1 is -OH.

3. The compound according to claim 1, wherein R a It is selected from unsubstituted methyl, unsubstituted ethyl, unsubstituted n-propyl, unsubstituted isopropyl, unsubstituted n-butyl, unsubstituted isobutyl, unsubstituted sec-butyl and unsubstituted tert-butyl.

4. The compound according to claim 1, wherein R2 is an acetyl group.

5. The compound according to claim 1, having the following formula or a pharmaceutically acceptable salt thereof: 、 。 6. The compound according to claim 1, having the following formula or a pharmaceutically acceptable salt thereof: 。 7. The compound according to claim 1, having the following formula: 。 8. The compound according to claim 1, wherein the salt is selected from hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, sodium salt, potassium salt, calcium salt, ammonium salt, ethylenediamine salt, ethanolamine salt, N,N-dialkylethanolamine salt, triethanolamine salt, and basic amino acid salts.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier thereof.

10. A dosage form comprising the pharmaceutical composition according to claim 9.

11. Use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, or a composition according to claim 9, or a dosage form according to claim 10, for the preparation of a medicament for treating cancer.

12. The use according to claim 11, wherein the cancer is selected from lung cancer, colorectal cancer, breast cancer, pancreatic cancer, sarcoma, ovarian cancer, and gastric cancer.

13. The use according to claim 12, wherein the cancer is selected from lung cancer, breast cancer, pancreatic cancer, and colorectal cancer.

14. The use according to claim 11, wherein the cancer is non-small cell lung cancer.

15. The use according to claim 11, wherein the cancer is small cell lung cancer.

16. The use according to claim 11, wherein the cancer is colon cancer.

17. The use according to claim 11, wherein the cancer is prostate cancer.

18. A method for obtaining a compound as defined in claim 1 or a pharmaceutically acceptable salt thereof, comprising the steps of: Reaction of compound II with compound III yields compound IV: in: X is -O-; R2 is -C(=O)R a Group; R3 is hydrogen; R4 is hydrogen; and R a It is an unsubstituted C1-C6 alkyl group.

19. The method of claim 18, further comprising the step of substituting the cyano group in the IV compound with a hydroxyl group.

20. A kit comprising a therapeutically effective amount of the compound according to any one of claims 1 to 8 and a pharmaceutically acceptable carrier.

21. The kit of claim 20, further comprising instructions for using the compound to treat cancer.

22. The kit according to claim 21, wherein the cancer is selected from lung cancer, colorectal cancer, breast cancer, pancreatic cancer, sarcoma, ovarian cancer, prostate cancer, and gastric cancer.

23. The kit according to claim 21, wherein the cancer is non-small cell lung cancer.

24. The kit according to claim 21, wherein the cancer is small cell lung cancer.

25. The kit according to claim 21, wherein the cancer is colon cancer.

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