HK1123969A - Compounds and compositions for use in the prevention and treatment of obesity and related syndromes - Google Patents

Description

Compounds and compositions for the prevention and treatment of obesity and related syndromes

Background

a) Field of the invention

The present invention relates to the use of 4-hydroxyisoleucine, isomers, analogs, pharmaceutically acceptable lactones, salts, metabolites, solvates and/or prodrugs thereof in the prevention and treatment of obesity and related syndromes.

b) Brief description of the related art

Worldwide, the prevalence of obesity is increasing. According to the world health organization, there are over 3 billion obese adults (body mass index (BMI) > 30) and 11 billion overweight people (BMI > 25) worldwide. In the united states, more than half of adults are overweight (64.5%), and nearly one-third (30.5%) are obese. Obesity is associated with disorders such as: type 2 diabetes, coronary heart disease, increased incidence of certain cancers, respiratory complications, and osteoarthritis. Overweight or obesity is a recognized life-expectancy shortening factor and is estimated to cause 300,000 early deaths per year in the united states. Medical guidelines for treating obese patients recommend altering dietary habits and increasing physical activity. There are some therapeutic agents to aid in the treatment of obesity, however, they cannot replace lifestyle changes.

Trigonella foenum-graecum (Trigonella foenum-graecum) is a leguminous plant growing in the middle east and Asia, which has been used as a medicinal plant for centuries to treat diseases ranging from dyspepsia to alopecia (Madar and Stark, British Journal of Nutrition, 88, suppl.3, S287-S292, 2002). While two recent studies indicate that rats fed with fenugreek seed extract observed significant reductions in total body weight (Kochhar et al. Journal of Human Ecology, 18: 235-. Thus, the efficacy of fenugreek seed extracts in reducing body weight remains uncertain, and the identification of any claimed active compounds that may be present in these extracts is completely unknown.

4-hydroxy-3-methylvaleric acid (4-hydroxyisoleucine or 4-OH) is a rare substance and makes up about 0.6% of the fenugreek seed content. The (2S, 3R, 4S) isomer of 4-hydroxyisoleucine has been shown to have insulinotropic and insulin sensitizing activity (Broca et al, am. J. physiol.277: E617-E623, 1999; Broca et al, Eur. J. Pharmacol.390: 339-345, 2000; Broca et al, am. Jphysiol. Endocrinol.Metah.287: E463-E471, 2004; PCT publications WO97/32577 and WO 01/15689). 4-hydroxyisoleucine has also been shown to have activity against lipid metabolism disorders (Narender et al, Biorganic & Medicinal Chemistry Letters, 2006, 16: 293-296). A number of chemical analogues of 4-hydroxyisoleucine have been synthesized (see PCT application PCT/IB2006/__ filed on 2/17 2006 (WO 2006/__; originally designated as PCT/US2006/005763 submitted on day 17, month 2, 2006), and these analogs have been shown to be effective in the treatment of diseases of carbohydrate or lipid metabolism, including diabetes (type 1 and type 2 diabetes), prediabetes, and metabolic syndrome, however, none of the above studies has ever shown or suggested that 4-hydroxyisoleucine or its isomer or analog could be used to address the problem of obesity which is becoming increasingly severe, probably because the authors of these studies failed to detect weight loss in any of the treated animals, even if the parameter is measured (see, e.g., Broca et al, 1999; broca et al, 2004; and Narended et al, 2006).

In summary, despite the increasing evidence of positive activity of 4-hydroxyisoleucine, its isomers and analogs for the treatment of diabetes, none of the people have ever demonstrated that 4-hydroxyisoleucine, its stereoisomers or analogs thereof can be used for the prevention and/or treatment of obesity and related syndromes.

In view of the above, there is a great need for new pharmaceutical products to address the emergency situation in the medical field created by the recent rising obesity epidemic. More particularly, alternative and improved methods, compounds and compositions for the prevention and treatment of obesity and related syndromes, such as coronary heart disease, respiratory complications and osteoarthritis, are needed.

There is also a need for pharmaceutical compositions and methods of treatment that prevent the occurrence or progression of excessive weight gain leading to obesity, reduce body weight and/or body fat in overweight and/or obese people, and reduce appetite and/or food intake.

The present invention provides such compounds and methods of use thereof. Thus, the present invention fulfills the above-described needs and others, as will be apparent to those skilled in the art upon review of the following description.

Disclosure of Invention

The invention provides a method for the following purposes: (i) preventing or treating obesity in a mammal, (ii) reducing body weight and/or body fat in a mammal, (iii) reducing appetite and/or food intake in a mammal, and/or (iv) preventing the occurrence or development of excessive weight gain in a mammal (e.g., wherein the occurrence or development of weight gain is associated with administration of one or more antidiabetic agents that stimulate weight gain in a mammal).

The method of the invention comprises the use of a compound selected from the group consisting of: 4-hydroxyisoleucine isomers, 4-hydroxyisoleucine analogs, and pharmaceutically acceptable lactones, salts, metabolites, solvates and/or prodrugs of said isomers and analogs for use in the manufacture of a medicament, which in turn can be used in the above-described methods. The invention also includes methods of preventing and treating the above conditions in a mammal comprising administering such compounds to a mammal in need of such treatment. The mammal treated according to the methods of the invention may be a human, for example a human that is overweight (BMI of at least 25) or obese (BMI of at least 30).

In one aspect of the invention, the compound is an isomer of 4-hydroxyisoleucine or a pharmaceutically acceptable lactone, salt, metabolite, solvate, and/or prodrug thereof.

By way of example, the compound may be the following 4-hydroxyisoleucine isomer:

in other examples, the compound may be one of the following isomers:

and

in other examples, the compound may be one of the following 4-hydroxyisoleucine lactones:

in another aspect of the invention, the compound is a 4-hydroxyisoleucine analog or a pharmaceutically acceptable lactone, salt, metabolite, solvate, and/or prodrug thereof.

In one embodiment of this aspect of the invention, the compound is an analog of formula (I):

wherein

A is CO₂R^A1、C(O)SR^A1、C(S)SR^A1、C(O)NR^A2R^A3、C(S)NR^A2R^A3、C(O)R^A4、SO₃H、S(O)₂NR^A2R^A3、C(O)R^A5、C(OR^A1)R^A9R^A10、C(SR^A1)R^A9R^A10、C(＝NR^A1)R^A5，

Wherein

R^A1Is hydrogen, substitutedOr unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (alkylheterocyclyl) (wherein the alkylene group has 1 to 4 carbon atoms),

R^A2and R^A3Each independently selected from: (a) hydrogen, (b) substituted or unsubstituted C_1-6Alkyl, (C) substituted or unsubstituted C_3-8Cycloalkyl, (d) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms, (e) substituted or unsubstituted C₆Or C₁₀Aryl, and (f) substituted or unsubstituted C_7-16Alkylaryl in which the alkylene radical has from 1 to 6 carbon atoms, or R^A2And R ^A3And N together form a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^A8Wherein R is^A8Is hydrogen or C_1-6An alkyl group, a carboxyl group,

R^A4is substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 4 carbon atoms),

R^A5is a peptide chain of 1-4 natural or unnatural amino acids, whereinThe peptide is linked to C (O) via its terminal amine group,

R^A6and R^A7Each independently hydrogen, substituted or unsubstituted C_1-6Alkyl radical, C_1-4Perfluoroalkyl, substituted or unsubstituted C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_2-12Dialkylamino, N-protected amino, halogen or nitro, and

R^A9and R^A10Each independently selected from: (a) hydrogen, (b) substituted or unsubstituted C_1-6Alkyl, (C) substituted or unsubstituted C_3-8Cycloalkyl, (d) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms, (e) substituted or unsubstituted C ₆Or C₁₀Aryl, and (f) substituted or unsubstituted C_7-16Alkylaryl in which the alkylene radical has from 1 to 6 carbon atoms, or R^A9And R^A10And the parent carbon atoms thereof together form a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^A8Wherein R is^A8Is hydrogen or C_1-6An alkyl group;

b is NR^B1R^B2Wherein

(i)R^B1And R^B2Each independently selected from: (a) hydrogen, (b) an N protecting group, (C) a substituted or unsubstituted C_1-6Alkyl, (d) substituted or unsubstituted C_2-6Alkenyl, (e) substituted or unsubstituted C_2-6Alkynyl, (f) substituted or unsubstituted C_3-8Cycloalkyl, (g) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms, (h) substituted or unsubstituted C₆Or C₁₀Aryl, (i) substituted or unsubstituted C_7-16Alkylaryl group wherein the alkylene radical has from 1 to 6 carbon atoms, (j) substituted or unsubstituted C_1-9Heterocyclyl group, (k) substituted or unsubstituted C_2-15Alkylheterocyclyl wherein the alkylene group has 1 to 6 carbon atoms, (1) C (O) R^B3Wherein R is^B3Selected from substituted orUnsubstituted C_1-6Alkyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 6 carbon atoms), substituted or unsubstituted C _1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 6 carbon atoms), (m) CO₂R^B4Wherein R is^B4Selected from substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 6 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 6 carbon atoms), (n) C (O) NR^B5R^B6Wherein R is^B5And R^B6Each independently selected from hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 6 carbon atoms), substituted or unsubstituted C_1-9Heterocyclic group and substituted or unsubstituted C_2-15An alkylheterocyclyl group (wherein the alkylene group has 1 to 6 carbon atoms), or R^B5And R^B6And N together form a substituted or unsubstituted 5-or 6-membered ring, optionally containing a non-ortho position of O, S or NR ', wherein R' is hydrogen or C_1-6Alkyl, (o) S (O)₂R^B7Wherein R is^B7Selected from substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 6 carbon atoms), substituted or unsubstituted C _1-9Heterocyclyl or substituted or unsubstituted C_2-15An alkylheterocyclyl group in which the alkylene group has from 1 to 6 carbon atoms, and (p) a peptide chain of 1-4 natural or non-natural alpha-amino acid residues, wherein the peptide is linked to N through its terminal carboxyl group, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl or sulfonyl group, or

(ii)R^B1And R^B2And N together form a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^B8Wherein R is^B8Is hydrogen or C_1-6Alkyl, or

(iii) When R is^B1And R^1aTogether being substituted or unsubstituted C_1-4When alkylene, a 5-to 8-membered ring is formed, or

(iv) When R is^B1And R^1aTogether being substituted or unsubstituted C₂Alkylene and R^B1And R^2aTogether being substituted or unsubstituted C_1-2When alkylene is present, [2.2.1 ] is formed]Or [2.2.2]A bicyclic ring system, or

(v) When R is^B1And R³Together being substituted or unsubstituted C_2-6When alkylene, a 4-to 8-membered ring is formed, or

(vi) When R is^B1And R⁴Together being substituted or unsubstituted C_1-3When alkylene, a 6-to 8-membered ring is formed, or

(vii)R^B1Together with A and the parent carbons of A and B form the following rings:

wherein Y and W are each independently O, S, NR^B8Or CR^A9R^A10；R^A9And R^A10Each as defined above, and R^A11And R^A12Each independently selected from: (a) hydrogen, (b) substituted or unsubstituted C _1-6Alkyl, (C) substituted or unsubstituted C_3-8Cycloalkyl, (d) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms, (e) substituted or unsubstituted C₆Or C₁₀Aryl, and (f) substituted or unsubstituted C_7-16Alkylaryl in which the alkylene radical has from 1 to 6 carbon atoms, or R^A9And R^A10And the parent carbon atoms thereof together form a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^A8Wherein R is^A8Is hydrogen or C_1-6An alkyl group;

x is O, S or NR^X1Wherein R is^X1Selected from: (a) hydrogen, (b) an N protecting group, (C) a substituted or unsubstituted C_1-6Alkyl, (d) substituted or unsubstituted C_2-6Alkenyl, (e) substituted or unsubstituted C_2-6Alkynyl, (f) substituted or unsubstituted C_3-8Cycloalkyl, (g) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms, (h) substituted or unsubstituted C₆Or C₁₀Aryl, (i) substituted or unsubstituted C_7-16Alkylaryl group wherein the alkylene radical has from 1 to 6 carbon atoms, (j) substituted or unsubstituted C_1-9Heterocyclyl group, or (k) substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 6 carbon atoms;

R^1aAnd R^1bEach independently is substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15An alkylheterocyclyl group (wherein the alkylene group has 1 to 4 carbon atoms), or R^1aAnd R^2aAnd their basic carbon (base carbon) atoms together form a substituted or unsubstituted C_5-10Monocyclic or fused ring systems, or when R is^1aAnd R⁴Together being substituted or unsubstituted C_1-4Alkylene when forming a 3-to 6-membered ring;

R^2aand R^2bEach independently hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C _7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15An alkylheterocyclyl group (wherein the alkylene group has 1 to 4 carbon atoms), or R^2aAnd R^2bTogether are ═ O, ═ N (C)_1-6Alkyl) ═ CR^2cR^2d(wherein R is^2cAnd R^2dEach independently hydrogen or substituted or unsubstituted C_1-6Alkyl) or substituted or unsubstituted C forming a spiro (spiro ring)_2-5Alkylene moiety, or R^2aAnd R^1aAnd the essential carbon atoms thereof together form a substituted or unsubstituted C_5-10Monocyclic or fused ring systems;

R³is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms) or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 4 carbon atoms); and

R⁴is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C _2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 4 carbon atoms), or when R is⁴And R^1aTogether being substituted or unsubstituted C_1-4When alkylene forms a 3-to 6-membered ring, or when R is⁴And R^B1Together being substituted or unsubstituted C_1-3Alkylene groups form 6-to 8-membered rings.

In other examples, the compound is an analog of formula (II):

wherein X and R⁴Each as defined hereinbefore with reference to formula (I), and R^1aAnd R^2aEach independently is substituted or unsubstituted C_1-6Alkyl, or R^1aAnd R^2aAnd the essential carbon atoms thereof together form a substituted or unsubstituted 6-membered ring.

In other examples, the compound is an analog of formula (III):

wherein A is CO₂R^A1、C(O)SR^A1、C(O)NR^A2R^A3Or C (O) R^A5(ii) a And R is^A1、R^A2、R^A3、R^A5B, X and R⁴Each as defined hereinbefore with reference to formula (I).

In other examples, the compound is an analog of formula (IV):

wherein A is CO₂R^A1、C(O)SR^A1、C(O)NR^A2R^A3Or C (O) R^A5(ii) a B. X and R⁴Each as defined hereinbefore with reference to formula (I); and R is⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹And R¹²Each independently hydrogen, substituted or unsubstituted C _1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 4 carbon atoms).

Other compounds of the invention are in the formula:

or

Wherein A, B and R⁴Each as defined hereinbefore with reference to formula (I), and R^1aAnd R^2aEach independently is substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkene(s)Radical, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C _2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 4 carbon atoms).

In various embodiments of this aspect of the invention, and with reference to the above formula, A is CO₂H, B is NH-p-toluenesulfonyl, R⁴Is H, and R^1aAnd R^2aEach is CH₃(ii) a A is CO₂H, B is NH₂，R⁴Is H, and R^1aAnd R^2aEach being substituted or unsubstituted C_1-6An alkyl group; or A is CO₂H, B is NH₂X is O, and R⁴Is H.

In other examples of this aspect of the invention, the compound is in one of the following formulae:

or

A, X, R therein^2a、R⁴And R^B2Each as defined hereinbefore with reference to formula (I), and R¹⁷、R¹⁸、R¹⁹And R²⁰Each is hydrogen or substituted or unsubstituted C_1-6An alkyl group.

In other examples, the compound is in the formula:

or

A, X, R therein⁴And R^B2Each as defined hereinbefore with reference to formula (I), and R²¹And R²²Each is hydrogen or substituted or unsubstituted C_1-6An alkyl group.

In other examples, the compound is in the formula:

a, X, R therein^2a、R^2bAnd R^B2Each as defined hereinbefore with reference to formula (I). In other examples, the compound is in the formula:

a, X, R therein^1a、R^1b、R^2a、R^2b、R⁴And R^B2Each as defined hereinbefore with reference to formula (I).

In other embodiments, and with reference to the above formula, R^1aAnd R^2aAnd the essential carbon atoms thereof together form a substituted or unsubstituted C _5-10Mono-or fused ring systems, optionally containing non-ortho O, S or NR ', wherein R' is H or C_1-6An alkyl group.

Further examples of compounds of formula (I) are as follows:

and

wherein A, B, X and R⁴Each as defined hereinbefore with reference to formula (I), and R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹And R¹²Each independently hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 4 carbon atoms); and is

R¹³、R¹⁴、R¹⁵And R¹⁶Each independently hydrogen, substituted or unsubstituted C_1-6Alkyl radical, C_1-4Perfluoroalkyl, substituted or unsubstituted C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_2-12Dialkylamino, N-protected amino, halogen or nitro.

Specific examples of compounds useful in the present invention are as follows:

other specific examples include:

and

other examples are:

Examples of configurations of the above-described compounds useful in the present invention (although other configurations may also be used) are as follows:

other examples of compounds useful in the present invention are described below. The invention also includes these compounds per se as compositions of matter (and pharmaceutically acceptable lactones, salts, metabolites, solvates and/or prodrugs thereof) and in pharmaceutical compositions.

Other compounds include analogs of formula (V):

a, R therein^1a、R^1b、R^2a、R⁴And R^B2Each as defined hereinbefore with reference to formula (I); r⁵、R⁶And R⁷Each independently hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 4 carbon atoms); and Z is XR⁴Or NR^B1R^B2Wherein X is O or S, and R^B1And R^B2Each independently selected from: (a) hydrogen, (b) an N protecting group, (C) a substituted or unsubstituted C _1-6Alkyl, (d) substituted or unsubstituted C_2-6Alkenyl, (e) substituted or unsubstituted C_2-6Alkynyl, (f) substituted or unsubstituted C_3-8Cycloalkyl, (g) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms, (h) substituted or unsubstituted C₆Or C₁₀Aryl, (i) substituted or unsubstituted C_7-16Alkylaryl group wherein the alkylene radical has from 1 to 6 carbon atoms, (j) substituted or unsubstituted C_1-9Heterocyclyl group, (k) substituted or unsubstituted C_2-15Alkylheterocyclyl wherein the alkylene group has 1 to 6 carbon atoms, (1) C (O) R^B3Wherein R is^B3Selected from substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 6 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 6 carbon atoms), (m) CO₂R^B4Wherein R is^B4Selected from substituted or unsubstitutedSubstituted C_1-6Alkyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 6 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C _2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 6 carbon atoms), (n) C (O) NR^B5R^B6Wherein R is^B5And R^B6Each independently selected from hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 6 carbon atoms), substituted or unsubstituted C_1-9Heterocyclic group and substituted or unsubstituted C_2-15An alkylheterocyclyl group (wherein the alkylene group has 1 to 6 carbon atoms), or R^B5And R^B6And N together form a substituted or unsubstituted 5-or 6-membered ring, optionally containing a non-ortho position of O, S or NR ', wherein R' is hydrogen or C_1-6Alkyl, (o) S (O)₂R^B7Wherein R is^B7Selected from substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 6 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15An alkylheterocyclyl group (wherein the alkylene group has from 1 to 6 carbon atoms), and (p) a peptide chain of 1-4 natural or non-natural alpha-amino acid residues, wherein the peptide is linked to N through its terminal carboxyl group; or R^B1And R^B2And N together form a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^B8Wherein R is ^B8Is hydrogen or C_1-6An alkyl group.

Other compounds are of formula (V-A):

wherein R is^A1、R^B2And R⁴Each as defined hereinbefore with reference to formula (I); r⁵Is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 4 carbon atoms); and Z is XR as previously defined with reference to formula (V)⁴Or NR^B1R^B2。

As a specific example, the compound may be selected from:

wherein R is^A1、R^B1、R^B2And R⁴As defined hereinbefore with reference to formula (I), and R⁵Is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C ₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 4 carbon atoms).

Other compounds are of formula (VI):

a, B, X, R therein^1a、R^1b、R³And R⁴As previously defined with reference to formula (I). In other examples, the compound is in one of the following formulae:

wherein R is^A1、R^B1、R^B2And R⁴As previously defined with reference to formula (I).

Specific exemplary compounds included within the invention in the above formula are as follows:

and

other specific examples of the compounds of the present invention are as follows:

[ Compound 75 ]]，[ Compound 76]，

[ Compound 202]，[ Compound 65a]，

[ Compound 13e]，[ Compound 62]And are and

[ Compound 104]。

In addition to the methods and compounds described above, the invention also includes pharmaceutical kits and pharmaceutical compositions. The compounds in the kits and compositions of the invention are as described above with reference to the methods of the invention described above.

In one embodiment, such a kit comprises: (1) a compound selected from the group consisting of isomers of 4-hydroxyisoleucine, analogs of 4-hydroxyisoleucine, and pharmaceutically acceptable lactones, salts, metabolites, solvates and/or prodrugs of said isomers and analogs; and (2) instructions for use of the compound: (i) reducing body weight and/or body fat, (ii) preventing the occurrence or development of excess body weight, (iii) reducing appetite and/or reducing food intake, and/or (iv) preventing or treating obesity. Such kits may optionally include other anti-obesity agents (e.g., orlistat, rimonabant, sibutramine, and/or phentermine) and/or anti-diabetic agents (e.g., rosiglitazone, exendin-4, and metformin).

In another embodiment, such a kit comprises: (1) a compound selected from the group consisting of isomers of 4-hydroxyisoleucine, analogs of 4-hydroxyisoleucine, and pharmaceutically acceptable lactones, salts, metabolites, solvates and/or prodrugs of said isomers and analogs; (2) anti-obesity agents (e.g., orlistat, rimonabant, sibutramine, and/or phentermine) and/or anti-diabetic agents (e.g., rosiglitazone, exendin-4, and metformin); and (3) the instructions for using (1) and (2) in combination with each other.

In an example of a pharmaceutical composition of the invention, the composition comprises: (1) a compound selected from the group consisting of isomers of 4-hydroxyisoleucine, analogs of 4-hydroxyisoleucine, and pharmaceutically acceptable lactones, salts, metabolites, solvates and/or prodrugs of said isomers and analogs; and (2) anti-obesity agents (e.g., orlistat, rimonabant, sibutramine, and/or phentermine) and/or anti-diabetic agents (e.g., rosiglitazone, exendin-4, and metformin).

In the kits and compositions of the invention, the compound and any other drug (e.g., any other anti-obesity agent and/or anti-diabetic agent) may be formulated together or separately. Further, the present invention may use other anti-obesity agents and anti-diabetic agents than those described above. Examples of such other agents are provided elsewhere herein.

An advantage of the present invention is that it provides a new tool for addressing the growing problem and unmet medical needs of obesity. More particularly, the present invention provides effective compounds, compositions and methods for maintaining and/or even reducing body fat and total body weight to prevent the occurrence or development of excessive weight gain leading to obesity.

Other objects, advantages and features of the present invention will become more apparent upon reading of the following description of non-limiting preferred embodiments (with reference to the accompanying drawings), which are exemplary and should not be construed as limiting the scope of the invention.

Brief Description of Drawings

Figure 1 is a synthetic scheme diagram showing the synthesis of various 4-hydroxyisoleucine analogs with SSS, SSR, SRS, and SRR configurations.

Figure 2 is a synthetic scheme showing the synthesis of compounds 16 to 34.

Fig. 3 is a synthesis scheme diagram showing the synthesis of compounds 35 to 38.

Figure 4 is a synthetic scheme showing the synthesis of compounds 39 and 40.

Fig. 5 is a synthesis scheme diagram showing the synthesis of compounds 41 to 62.

Fig. 6 is a synthesis scheme diagram showing the synthesis of compounds 63 to 65 a.

Fig. 7 is a synthetic scheme diagram showing the synthesis of compounds 66 to 69.

Figure 8 is a synthetic scheme showing the synthesis of compounds 70 to 76.

Figure 9 is a synthetic scheme showing the synthesis of compounds 77 and 78.

Fig. 10 is a synthesis scheme diagram showing the synthesis of compounds 79 to 85.

Fig. 11 is a synthesis scheme diagram showing the synthesis of compounds 86a to 102 b.

Fig. 12 is a synthesis scheme diagram showing the synthesis of compounds 103 to 123.

Fig. 13 is a synthetic scheme diagram showing the synthesis of compounds 124 to 133.

FIG. 14 is a scheme showing the synthesis of two diastereomers and analogs of (2S, 3R, 4S) -4-hydroxyisoleucine (Compounds 12b and 13 b).

FIG. 15A is a line graph showing delta body weights of DIO mice treated with 25, 50, and 100mg/kg of 4-hydroxyisoleucine (4-OH, compound 14a) for 11 weeks (77 days). Delta body weight values are expressed as body weight on a particular day minus body weight values before treatment initiation. Values represent mean ± SEM. N-7-8 mice/group.^*p＜0.05；^**p＜0.01；^***p＜0.001。

Fig. 15B is a line graph showing food consumption during and after 11 weeks (77 days) of treatment with 4-OH in DIO mice as shown in fig. 15A. Food consumption was measured daily per cage and values are expressed as weekly food consumption (g) per mouse. Values represent mean ± SEM. N-2-3 cages/group.^**p＜0.01。

FIG. 16A is a line graph showing weekly delta body weight values from pre-treatment values of ob/ob mice treated with 100mg/kg of 4-hydroxyisoleucine (4-OH, Compound 14a) for 8 weeks (56 days). Delta body weight values are expressed as body weight on a particular day minus body weight values before treatment initiation. Values represent mean ± SEM. N-7-8 mice/group. ^*p＜0.05；^**p＜0.01。

Fig. 16B is a line graph showing food consumption of ob/ob mice as shown in fig. 16A during and after 8 weeks (56 days) of treatment with 4-OH. Food consumption was measured daily per cage and values are expressed as weekly food consumption (g) per mouse. Treatment of mice began on day 1 of week 1 (day 1, 6-7 week old mice). N-7-8 mice/group, 2 cages/group.

FIG. 17A is a line graph showing weekly weight changes in DIO mice treated with 50mg/kg or 100mg/kg of 4-hydroxyisoleucine (4-OH, Compound 14a) for 5 weeks (35 days).

FIG. 17B is a bar graph showing food consumption of DIO mice treated with 50mg/kg or 100mg/kg of 4-OH for 5 weeks (35 days). Values represent mean ± SEM.

FIG. 17C is a line graph showing weekly weight changes in DIO mice treated with 50mg/kg of 4-OH or 1.5mg/kg rosiglitazone alone and in combination for 5 weeks (35 days).

FIG. 17D is a bar graph showing food consumption of DIO mice treated with 50mg/kg of 4-OH or 1.5mg/kg rosiglitazone alone and in combination for 5 weeks (35 days). Values represent mean ± SEM.

Figure 18A is a line graph showing weekly weight changes in DIO mice treated with 50mg/kg of 4-hydroxyisoleucine (4-OH, compound 14a) or 0.01mg/kg exendin-4 alone and in combination for 3 weeks (21 days).

Figure 18B is a bar graph showing the reduction of epididymal fat in DIO mice treated with 4-OH or exendin-4 alone and in combination for 3 weeks (21 days). Strip 1: a control group; bars 2 and 3: 50mg/kg and 100mg/kg of 4-OH respectively; bars 4 and 5: exendin-4 at 0.01mg/kg and 0.05mg/kg, respectively; strip 6: a combination of 50mg/kg of 4-OH and 0.01mg/kg of Exendin-4. Values represent mean ± SEM.

Figure 18C is a line graph showing a decrease in blood glucose levels in DIO mice treated with 4-OH or exendin-4 alone and in combination for 7 days. Values represent mean ± SEM.

FIG. 19 is a bar graph showing the relative change in body weight (expressed as area under the curve) of mice treated with 50mg/kg or 100mg/kg of 4-hydroxyisoleucine (4-OH, Compound 14a), 25mg/kg or 100mg/kg of metformin, or a combination of 50mg/kg ID1101 and 25mg/kg of metformin for 21 days. Values represent mean ± SEM.

FIG. 20A is a line graph showing the relative change in body weight of mice treated with 50mg/kg of 4-hydroxyisoleucine (4-OH, Compound 14a) or 0.01mg/kg of rimonabant alone and in combination for 4 weeks (28 days). As shown in the figure, on day 22 (arrow), the combination dose was increased as follows: 100mg/kg of 4-OH twice daily (instead of 50mg/kg), 1mg/kg of rimonabant once daily (instead of 0.1mg/kg) and the combination likewise increased. Animals were treated with these higher doses for 1 week. Body weight is expressed in grams (g) as delta body weight from day 1. All data are presented as mean values, n-8 mice/group.

Fig. 20B is a line graph showing the relative change in body weight of mice for the last week of treatment with reference to fig. 20A. The relative change in body weight is expressed in grams (g) as delta body weight from day 22. All data are expressed as mean ± SEM, n ═ 8 mice/group, and are statistically significant compared to DIO control group (0 mg/kg/day):^*p≤0.05；^**p≤0.01；^***p≤0.001。

FIG. 21A is a bar graph showing the weight loss of DIO mice after 21 days of treatment with 25mg/kg or 50mg/kg compound 13 e.

FIG. 21B is a bar graph showing the reduction of epididymal fat pad after 21 days of DIO mice treated with 25mg/kg or 50mg/kg Compound 13 e.

FIGS. 22A and 22B are bar graphs showing the effect of analogs and isomers selected according to the invention on the relative change in body weight of mice. Body weight is expressed in grams (g) as delta body weight from before treatment. All data are expressed as mean ± SEM, n ═ 6 mice/group.

FIG. 23A is a bar graph showing that 4-hydroxyisoleucine prevents weight gain in normal wistar rats fed high fat, high sugar diet (HFHS). All data are expressed as mean ± SEM, n-10 rats/group.

Fig. 23B is a bar graph showing that 4-hydroxyisoleucine reversed the weight gain of obese wistar rats. All data are expressed as mean ± SEM, n-10 rats/group.

FIG. 24 is a scheme showing the synthesis of each of the eight (8) configurational isomers of 4-hydroxyisoleucine.

Detailed Description

The present invention relates to the use of 4-hydroxyisoleucine, its isomers, analogs, lactones, salts and prodrugs for the prevention and treatment of obesity and related syndromes.

The present invention provides therapeutic methods and pharmaceutical compositions for preventing or treating obesity, for preventing the occurrence or development of excessive weight gain, for reducing body weight and/or body fat, and for reducing appetite and/or food intake.

More particularly, the present invention provides methods, compounds, compositions and kits for treating overweight and obese patients, and for preventing the occurrence or development of excessive weight gain leading to obesity.

To provide a clearer and more consistent understanding of the specification and claims, including the scope to be given such terms herein, the following definitions are provided:

A) definition of

The following terms used in the present specification have the following meanings, unless otherwise specified.

The terms "4-hydroxyisoleucine", "4-OH", "isomer of 4-hydroxyisoleucine" and "configurational isomer of 4-hydroxyisoleucine" as used herein generally refer to the compound 4-hydroxy-3-methylpentanoic acid and include all diastereomers and isomers of that compound, but also include pharmaceutically acceptable lactones, salts, crystalline forms, metabolites, solvates, esters and prodrugs thereof.

"administration" and "administering" refer to a method of administering a dose of a pharmaceutical composition to a mammal (e.g., a human), wherein the method is, for example, oral, subcutaneous, topical, intravenous, intraperitoneal, or intramuscular. The preferred method of administration may vary depending on various factors such as the components of the pharmaceutical composition, the site of the underlying or actual disease, and the severity of the disease.

The term "alkenyl" as used herein, unless otherwise specified, denotes a monovalent straight or branched chain group of from 2 to 12 carbon atoms (e.g., 2 to 6 carbon atoms or 2 to 4 carbon atoms) containing one or more carbon-carbon double bonds, such as ethenyl, 1-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like, and may be optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of: (1) alkoxy of 1 to 6 carbon atoms; (2) alkylsulfinyl of 1 to 6 carbon atoms; (3) alkylsulfonyl of 1 to 6 carbon atoms; (4) alkynyl of 2 to 6 carbon atoms; (5) an amino group; (6) an aryl group; (7) arylalkoxy groups in which the alkylene group has 1 to 6 carbon atoms; (8) an azide group; (9) cycloalkyl of 3 to 8 carbon atoms; (10) halogen; (11) a heterocyclic group; (12) (heterocyclic) oxy; (13) (heterocyclic) acyl; (14) a hydroxyl group; (15) hydroxyalkyl of 1 to 6 carbon atoms (ii) a (16) An N-protected amino group; (17) a nitro group; (18) oxy or thioxo; (19) a perfluoroalkyl group of 1 to 4 carbon atoms; (20) perfluoroalkoxy of 1 to 4 carbon atoms; (21) a spiro alkyl group of 3 to 8 carbon atoms; (22) thioalkoxy of 1 to 6 carbon atoms; (23) a thiol group; (24) OC (O) R^AWherein R is^ASelected from (a) substituted or unsubstituted C_1-6Alkyl, (b) substituted or unsubstituted C₆Or C₁₀Aryl, (C) substituted or unsubstituted C7-16 arylalkyl wherein the alkylene group has 1 to 6 carbon atoms, (d) substituted or unsubstituted C_1-9A heterocyclic group and (e) a substituted or unsubstituted C_2-15Heterocycloalkyl (wherein the alkylene group has 1 to 6 carbon atoms); (25) c (O) R^BWherein R is^BSelected from (a) hydrogen, (b) substituted or unsubstituted C_1-6Alkyl, (C) substituted or unsubstituted C₆Or C₁₀Aryl, (d) substituted or unsubstituted C_7-16Aralkyl group (wherein the alkylene group has 1 to 6 carbon atoms), (e) substituted or unsubstituted C_1-9A heterocyclic group and (f) a substituted or unsubstituted C_2-15Heterocycloalkyl (wherein the alkylene group has 1 to 6 carbon atoms); (26) CO 2₂R^BWherein R is^BSelected from (a) hydrogen, (b) substituted or unsubstituted C_1-6Alkyl, (c) substituted or unsubstituted_C6 or C₁₀Aryl, (d) substituted or unsubstituted C_7-16Aralkyl group (wherein the alkylene group has 1 to 6 carbon atoms), (e) substituted or unsubstituted C _1-9A heterocyclic group and (f) a substituted or unsubstituted C_2-15Heterocycloalkyl (wherein the alkylene group has 1 to 6 carbon atoms); (27) c (O) NR^CR^DWherein R is^CAnd R^DEach independently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl (wherein the alkylene groups have from 1 to 6 carbon atoms); (28) s (O) R^EWherein R is^ESelected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl (wherein the alkylene groups have 1 to 6 carbon atoms), and (d) hydroxy; (29) s (O)₂R^EWherein R is^ESelected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl (wherein the alkylene groups have 1 to 6 carbon atoms), and (d) hydroxy; (30) s (O)₂NR^FR^G，R^FAnd R^GEach independently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl (wherein the alkylene groups have from 1 to 6 carbon atoms); and (31) NR^HR^IWherein R is^HAnd R^IEach independently selected from: (a) hydrogen; (b) an N protecting group; (c) alkyl of 1 to 6 carbon atoms; (d) alkenyl of 2 to 6 carbon atoms; (e) alkynyl of 2 to 6 carbon atoms; (f) an aryl group; (g) arylalkyl, wherein the alkylene group has 1 to 6 carbon atoms; (h) cycloalkyl of 3 to 8 carbon atoms; (i) an alkylcycloalkyl group, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms; (j) alkanoyl of 1 to 6 carbon atoms; (k) aroyl of 6 to 10 carbon atoms; (1) alkylsulfonyl of 1 to 6 carbon atoms; and (m) an arylsulfonyl group of 6 to 10 carbon atoms, with the proviso that no two groups are bonded to the nitrogen atom through a carbonyl group or a sulfonyl group.

The terms "alkoxy" and "alkyloxy," as used interchangeably herein, refer to an alkyl group attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted alkoxy groups have 1 to 6 carbons.

The terms "alkyl" and "alkane" as used herein, unless otherwise specified, denote monovalent groups derived from straight or branched chain saturated hydrocarbons of 1 to 6 carbons, such as methyl, ethyl, n-and i-propyl, n-, sec-, i-and t-butyl, neopentyl and the like, and may be optionally substituted with 1, 2, 3 or 4 substituents in the case of alkyl groups of 2 carbons or more independently selected from the following group: (1) alkoxy of 1 to 6 carbon atoms; (2) alkylsulfinyl of 1 to 6 carbon atoms; (3) alkylsulfonyl of 1 to 6 carbon atoms; (4) alkynyl of 2 to 6 carbon atoms; (5) an amino group; (6) an aryl group; (7) arylalkoxy groups in which the alkylene group has 1 to 6 carbon atoms; (8) an azide group; (9) cycloalkyl of 3 to 8 carbon atoms; (10) halogen; (11) a heterocyclic group; (12) (heterocyclic) oxy; (13) (heterocyclic) acyl; (14) a hydroxyl group; (15) hydroxyalkyl of 1 to 6 carbon atoms; (16) an N-protected amino group; (17) a nitro group; (18) oxy or thioxo; (19) a perfluoroalkyl group of 1 to 4 carbon atoms; (20) perfluoroalkoxy of 1 to 4 carbon atoms; (21) A spiro alkyl group of 3 to 8 carbon atoms; (22) thioalkoxy of 1 to 6 carbon atoms; (23) a thiol group; (24) OC (O) R^AWherein R is^ASelected from (a) substituted or unsubstituted C_1-6Alkyl, (b) substituted or unsubstituted C₆Or C₁₀Aryl, (C) substituted or unsubstituted C_7-16Arylalkyl (wherein the alkylene group has 1 to 6 carbon atoms), (d) substituted or unsubstituted C_1-9A heterocyclic group and (e) a substituted or unsubstituted C_2-15Heterocycloalkyl (wherein the alkylene group has 1 to 6 carbon atoms); (25) c (O) R^BWherein R is^BSelected from (a) hydrogen, (b) substituted or unsubstituted C_1-6Alkyl, (C) substituted or unsubstituted C₆Or C₁₀Aryl, (d) substituted or unsubstituted C_7-16Aralkyl group (wherein the alkylene group has 1 to 6 carbon atoms), (e) substituted or unsubstituted C_1-9A heterocyclic group and (f) a substituted or unsubstituted C_2-15Heterocycloalkyl (wherein the alkylene group has 1 to 6 carbon atoms); (26) CO 2₂R^BWherein R is^BSelected from (a) hydrogen, (b) substituted or unsubstituted C_1-6Alkyl, (C) substituted or unsubstituted C₆Or C₁₀Aryl, (d) substituted or unsubstituted C_7-16Aralkyl group (wherein the alkylene group has 1 to 6 carbon atoms), (e) substituted or unsubstituted C_1-9A heterocyclic group and (f) a substituted or unsubstituted C_2-15Heterocycloalkyl (wherein the alkylene group has 1 to 6 carbon atoms); (27) c (O) NR ^CR^DWherein R is^CAnd R^DEach independently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl (wherein the alkylene groups have from 1 to 6 carbon atoms); (28) s (O) R^EWherein R is^ESelected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl (wherein the alkylene groups have 1 to 6 carbon atoms), and (d) hydroxy; (29) s (O)₂R^EWherein R is^ESelected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl (wherein the alkylene groups have 1 to 6 carbon atoms), and (d) hydroxy; (30) s (O)₂NR^FR^G，R^FAnd R^GEach independently selected from (a) hydrogen, (b) alkyl, (c) aryl and (d) arylalkyl (wherein the alkylene groups have from 1 to 6 carbon atoms)) (ii) a And (31) NR^HR^IWherein R is^HAnd R^IEach independently selected from: (a) hydrogen; (b) an N protecting group; (c) alkyl of 1 to 6 carbon atoms; (d) alkenyl of 2 to 6 carbon atoms; (e) alkynyl of 2 to 6 carbon atoms; (f) an aryl group; (g) arylalkyl, wherein the alkylene group has 1 to 6 carbon atoms; (h) cycloalkyl of 3 to 8 carbon atoms; (i) an alkylcycloalkyl group, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms; (j) alkanoyl of 1 to 6 carbon atoms; (k) aroyl of 6 to 10 carbon atoms; (1) alkylsulfonyl of 1 to 6 carbon atoms; and (m) an arylsulfonyl group of 6 to 10 carbon atoms, with the proviso that no two groups are bonded to the nitrogen atom through a carbonyl group or a sulfonyl group.

The term "alkylene" as used herein denotes a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by removal of two hydrogen atoms, e.g., methylene, ethylene, isopropylene, and the like.

The term "alkylsulfinyl," as used herein, refers to an alkyl group attached to the parent molecular moiety through s (o). Exemplary unsubstituted alkylsulfinyl groups have from 1 to 6 carbon atoms.

The term "alkylsulfonyl" as used herein denotes a residue obtained by S (O)₂An alkyl group attached to the parent molecular group. Exemplary unsubstituted alkylsulfonyl groups have from 1 to 6 carbon atoms.

The term "arylsulfonyl" as used herein means a compound formed by S (O)₂An aryl group attached to the parent molecular group.

The term "alkylthio" as used herein, means an alkyl group attached to the parent molecular group through a sulfur atom. Exemplary unsubstituted alkylsulfanyl groups have from 1 to 6 carbon atoms.

The term "alkynyl" as used herein denotes a monovalent straight or branched chain group of 2 to 6 carbon atoms containing a carbon-carbon triple bond, e.g., ethynyl, 1-propynyl, and the like, and may optionally be independently selected from 1, 2, 1, 6,Substituted with 3 or 4 substituents: (1) alkoxy of 1 to 6 carbon atoms; (2) alkylsulfinyl of 1 to 6 carbon atoms; (3) alkylsulfonyl of 1 to 6 carbon atoms; (4) alkynyl of 2 to 6 carbon atoms; (5) an amino group; (6) an aryl group; (7) arylalkoxy groups in which the alkylene group has 1 to 6 carbon atoms; (8) an azide group; (9) cycloalkyl of 3 to 8 carbon atoms; (10) halogen; (11) a heterocyclic group; (12) (heterocyclic) oxy; (13) (heterocyclic) acyl; (14) a hydroxyl group; (15) hydroxyalkyl of 1 to 6 carbon atoms; (16) an N-protected amino group; (17) a nitro group; (18) oxy or thioxo; (19) a perfluoroalkyl group of 1 to 4 carbon atoms; (20) perfluoroalkoxy of 1 to 4 carbon atoms; (21) a spiro alkyl group of 3 to 8 carbon atoms; (22) thioalkoxy of 1 to 6 carbon atoms; (23) a thiol group; (24) OC (O) ^AWherein R is^ASelected from (a) substituted or unsubstituted C_1-6Alkyl, (b) substituted or unsubstituted C₆Or C₁₀Aryl, (C) substituted or unsubstituted C_7-16Arylalkyl (wherein the alkylene group has 1 to 6 carbon atoms), (d) substituted or unsubstituted C_1-9A heterocyclic group and (e) a substituted or unsubstituted C_2-15Heterocycloalkyl (wherein the alkylene group has 1 to 6 carbon atoms); (25) c (O) R^BWherein R is^BSelected from (a) hydrogen, (b) substituted or unsubstituted C_1-6Alkyl, (C) substituted or unsubstituted C₆Or C₁₀Aryl, (d) substituted or unsubstituted C_7-16Aralkyl group (wherein the alkylene group has 1 to 6 carbon atoms), (e) substituted or unsubstituted C_1-9A heterocyclic group and (f) a substituted or unsubstituted C_2-15Heterocycloalkyl (wherein the alkylene group has 1 to 6 carbon atoms); (26) CO 2₂R^BWherein R is^BSelected from (a) hydrogen, (b) substituted or unsubstituted C_1-6Alkyl, (C) substituted or unsubstituted C₆Or C₁₀Aryl, (d) substituted or unsubstituted C_7-16Aralkyl group (wherein the alkylene group has 1 to 6 carbon atoms), (e) substituted or unsubstituted C_1-9A heterocyclic group and (f) a substituted or unsubstituted C_2-15Heterocycloalkyl (wherein the alkylene group has 1 to 6 carbon atoms); (27) c (O) NR^CR^DWherein R is^CAnd R^DEach independently selected from (a) hydrogen, (b) hydrogenb) Alkyl, (c) aryl, and (d) arylalkyl (wherein the alkylene groups have 1 to 6 carbon atoms); (28) s (O) R ^EWherein R is^ESelected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl (wherein the alkylene groups have 1 to 6 carbon atoms), and (d) hydroxy; (29) s (O)₂R^EWherein R is^ESelected from the group consisting of (a) alkyl, (b) aryl, (c) arylalkyl (wherein the alkylene groups have 1 to 6 carbon atoms), and (d) hydroxy; (30) s (O)₂NR^FR^G，R^FAnd R^GEach independently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl (wherein the alkylene groups have from 1 to 6 carbon atoms); and (31) NR^HR^IWherein R is^HAnd R¹Each independently selected from: (a) hydrogen; (b) an N protecting group; (c) alkyl of 1 to 6 carbon atoms; (d) alkenyl of 2 to 6 carbon atoms; (e) alkynyl of 2 to 6 carbon atoms; (f) an aryl group; (g) arylalkyl, wherein the alkylene group has 1 to 6 carbon atoms; (h) cycloalkyl of 3 to 8 carbon atoms; (i) an alkylcycloalkyl group, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms; (j) alkanoyl of 1 to 6 carbon atoms; (k) aroyl of 6 to 10 carbon atoms; (1) alkylsulfonyl of 1 to 6 carbon atoms; and (m) an arylsulfonyl group of 6 to 10 carbon atoms, with the proviso that no two groups are bonded to the nitrogen atom through a carbonyl group or a sulfonyl group.

The term "alpha-amino acid residue" as used herein denotes N (R) ^A)C(R^B)(R^C) C (O) -bond, wherein, as defined herein, R^ASelected from the group consisting of (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl; each as defined herein, R^BAnd R^CEach independently selected from (a) hydrogen, (b) optionally substituted alkyl, (c) optionally substituted cycloalkyl, (d) optionally substituted aryl, (e) optionally substituted arylalkyl, (f) optionally substituted heterocyclyl and (g) optionally substituted heterocycloalkyl. For natural amino acids, R^BIs H, and R^CThose side chains corresponding to naturally occurring natural amino acids or their enantiomeric configurations. Exemplary natural amino acids include alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycineAmino acids include, but are not limited to, amino acids such as, for example, amino acids, amino. The names of most naturally occurring Amino Acids and amido residues are used herein following the Nomenclature specifications suggested by the IUPAC Commission on organic chemistry Nomenclature and the IUPAC-IUB Commission on Biochemistry Nomenclature, as shown in the "Nomenclature of alpha-Amino Acids" (communications, 1974), Biochemistry 14(2), 1975. The invention also contemplates non-naturally occurring (i.e., non-natural) D-or L-amino acid residues, such as homophenylalanine, phenylglycine, cyclohexylglycine, cyclohexylalanine, cyclopentylalanine, cyclobutylalanine, cyclopropylalanine, cyclohexylglycine, norvaline, norleucine, thiazolylalanine (2-, 4-, and 5-substituted), pyridylalanine (2-, 3-, and 4-isomers), naphthylalanine (1-and 2-isomers), and the like. Stereochemistry is as specified in the specification, with bold arrows indicating the orientation of the substituent facing the viewer (away from the paper) and bold dashed lines indicating the orientation of the substituent away from the viewer (into the paper). If there is no stereochemistry indication, it is assumed that the structure definition also includes stereochemistry possible structures.

The term "amino" as used herein denotes NH₂A group.

The term "aminoalkyl" refers to an amino group attached to the parent molecular group through an alkyl group.

The terms "4-hydroxyisoleucine analog" and "4-OH analog" as used herein refer to any compound of formulae I, II, III, IV-A, IV-B, IV-C, IV-D, V, V-a and/or VI as described below (including the specific compounds shown in table 1 and figures 1 through 14), and also includes pharmaceutically acceptable lactones, salts, crystalline forms, metabolites, solvates, esters, and prodrugs of compounds of formulae I, II, III, IV-A, IV-B, IV-C, IV-D, V, V-a and/or VI.

The term "aryl" as used herein denotes a mono-or bi-carbocyclic ring system having one or two aromatic rings, such as phenyl, naphthyl, 1, 2-dihydronaphthyl, 1, 2, 3, 4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, and the like, and may be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: (1) alkanoyl of 1 to 6 carbon atoms; (2) alkyl of 1 to 6 carbon atoms; (3) alkoxy of 1 to 6 carbon atoms; (4) alkoxyalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (5) alkylsulfinyl of 1 to 6 carbon atoms; (6) alkylsulfinylalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (7) alkylsulfonyl of 1 to 6 carbon atoms; (8) alkylsulfonylalkyl wherein the alkyl and alkylene groups independently have from 1 to 6 carbon atoms; (9) an aryl group; (10) arylalkyl, wherein the alkyl group has 1 to 6 carbon atoms; (11) an amino group; (12) aminoalkyl of 1 to 6 carbon atoms; (13) an aryl group; (14) arylalkyl, wherein the alkylene group has 1 to 6 carbon atoms; (15) aroyl; (16) an azide group; (17) azidoalkyl of 1 to 6 carbon atoms; (18) a carboxy aldehyde; (19) (carboxyaldehyde) alkyl, wherein the alkylene group has 1 to 6 carbon atoms; (20) cycloalkyl of 3 to 8 carbon atoms; (21) an alkylcycloalkyl group, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms; (22) halogen; (23) haloalkyl of 1 to 6 carbon atoms; (24) a heterocyclic group; (25) (heterocyclyl) oxy; (26) (heterocyclyl) acyl; (27) a hydroxyl group; (28) hydroxyalkyl of 1 to 6 carbon atoms; (29) a nitro group; (30) a nitroalkyl group of 1 to 6 carbon atoms; (31) an N-protected amino group; (32) an N-protected aminoalkyl group wherein the alkylene group has from 1 to 6 carbon atoms; (33) an oxy group; (34) thioalkoxy of 1 to 6 carbon atoms; (35) thioalkoxyalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (36) (CH) ₂)_qCO₂R^AWherein q is an integer from 0 to 4, and R^ASelected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, wherein the alkylene group has 1 to 6 carbon atoms; (37) (CH)₂)_qC(O)NR^BR^CWherein R is^BAnd R^CIndependently selected from (a) hydrogen, (b) an alkaneA group, (c) an aryl group, and (d) an arylalkyl group, wherein the alkylene group has 1 to 6 carbon atoms; (38) (CH)₂)_qS(O)₂R^DWherein R is^DSelected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, wherein the alkylene group has 1 to 6 carbon atoms; (39) (CH)₂)_qS(O)₂NR^ER^FWherein R is^EAnd R^FEach independently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, wherein the alkylene groups have from 1 to 6 carbon atoms; (40) (CH)₂)_qNR^GR^HWherein R is^GAnd R^HEach independently selected from: (a) hydrogen; (b) an N-protecting group; (c) alkyl of 1 to 6 carbon atoms; (d) alkenyl of 2 to 6 carbon atoms; (e) alkynyl of 2 to 6 carbon atoms; (f) an aryl group; (g) arylalkyl, wherein the alkylene group has 1 to 6 carbon atoms; (h) cycloalkyl of 3 to 8 carbon atoms; and (i) alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms, and with the proviso that no two groups are bound to the nitrogen atom through the carbonyl or sulfonyl group; (41) an oxy group; (42) a thiol group; (43) a perfluoroalkyl group; (44) a perfluoroalkoxy group; (45) an aryloxy group; (46) a cycloalkoxy group; (47) a cycloalkylalkoxy group; and (48) an arylalkoxy group.

The term "alkaryl" means an aryl group attached to the parent molecular group through an alkyl group. Exemplary unsubstituted arylalkyl groups have from 7 to 16 carbons.

The term "heterocycloalkylene" means a heterocyclic group attached to a parent molecular group through an alkyl group. Exemplary unsubstituted alkylheterocyclyl groups have from 2 to 10 carbons.

The term "alkylcycloalkyl" denotes a cycloalkyl group attached to the parent molecular group through an alkylene group.

The term "alkylsulfinylalkyl" denotes an alkylsulfinyl group attached to the parent molecular group through an alkyl group.

The term "alkylsulfonylalkyl" denotes an alkylsulfonyl group attached to the parent molecular group through an alkyl group.

The term "aryloxy" as used herein, means an aryl group attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted aryloxy groups have 6 or 10 carbons.

The terms "arylacyl" and "aroyl," as used interchangeably herein, refer to an aryl group attached to a parent molecular group through a carbonyl group. Exemplary unsubstituted aryloxycarbonyl groups have 7 to 11 carbon atoms.

The term "azido" denotes N₃A group, which may also be represented as N ═ N.

The term "azidoalkyl" denotes an azido group attached to a parent molecular group through an alkyl group.

The term "carbonyl" as used herein denotes a C (O) group, which may also be denoted as C ═ O.

The term "carboxyaldehyde" denotes a CHO group.

The term "carboxyaldehyde alkyl" refers to a carboxyaldehyde group attached to the parent molecular group through an alkyl group.

The terms "carboxy" and "carboxy" are used interchangeably herein to denote CO₂And (4) an H group.

The terms "carboxy protecting group" and "carboxy protecting group" as used herein mean the protection of CO expected during synthesis₂Those groups in which the H group is protected from undesired reactions. Commonly used carboxyl protecting Groups are disclosed In Greene, "Protective Groups In Organic Synthesis, 3rd Edition" (protecting Groups In Organic Synthesis, third Edition) "(John Wiley&Sons, New York, 1999), which is incorporated herein by reference.

The terms "compound of the invention" and "compound according to the invention" as used herein refer to the 4-hydroxyisoleucine isomers and 4-hydroxyisoleucine analogs as defined above.

Compounds having the same molecular formula but differing in their nature or their order of atomic incorporation or their arrangement in space of atoms are referred to as "isomers". Isomers in which the connectivity between atoms is the same but the arrangement of atoms in space is different are referred to as "stereoisomers". Stereoisomers that are diastereomers of each other are referred to as "diastereomers", while those that are nonoverlapping enantiomers of each other are referred to as "enantiomers". For example, when a compound has an asymmetric center, it is bound to 4 different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and described by the R-and S-cis laws of Cahn, lngold and Prelog, or by the manner in which the molecule is rotated in the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., the (+) or (-) isomers, respectively). The chiral compounds may exist as individual enantiomers or as mixtures thereof. Mixtures containing equal proportions of enantiomers are referred to as "racemic mixtures".

Asymmetric or chiral centers may be present in the compounds of the present invention. Unless otherwise indicated, the description or naming of a particular compound in the specification and claims is intended to include all individual enantiomers or racemic or otherwise mixtures thereof. Methods for stereochemical determination and stereoisomer separation are well known in the art (see the discussion in "Advanced organic chemistry" chapter 4, 4 th edition j. march, John Wiley and Sons, New York, 1992). The individual stereoisomers of the compounds of the invention are prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers, or by preparation of mixtures of enantiomeric compounds followed by resolution which is well known to those skilled in the art. Examples of such analytical methods are: (1) linking a racemic mixture of enantiomers (designated (+/-)) to a chiral auxiliary, separating the resulting diastereomers by recrystallization or chromatography, and liberating the optically pure product from the auxiliary; or (2) directly separating a mixture of optical enantiomers on a chiral chromatography column. Depending on the configuration of the substituents around the chiral carbon atom, enantiomers are designated herein by the symbol "R" or "S", or drawn by conventional means using bold lines, which define the substituents above the paper surface in three-dimensional space, or hatched lines, which define the substituents below the paper surface in three-dimensional space.

As generally understood by those skilled in the art, an optically pure compound is an enantiomerically pure compound. As used herein, the term "optically pure" is intended to mean a compound comprising at least a sufficient amount of a single enantiomer to produce a compound having the desired pharmacological activity. Preferably, "optically pure" is intended to mean that the compound comprises at least 90% of a single isomer (80% enantiomeric excess, i.e., "e.e"), preferably at least 95% (90% e.e.), more preferably at least 97.5% (95% e.e.), and most preferably at least 99% (98% e.e.). Preferably, the compounds of the present invention are optically pure.

The term "cycloalkyl" as used herein, unless otherwise specified, denotes a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon radical of from 3 to 8 carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.2.1 ].]Heptyl, and the like. The cycloalkyl groups of the present invention may be optionally substituted with: (1) alkanoyl of 1 to 6 carbon atoms; (2) alkyl of 1 to 6 carbon atoms; (3) alkoxy of 1 to 6 carbon atoms; (4) alkoxyalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (5) alkylsulfinyl of 1 to 6 carbon atoms; (6) alkylsulfinylalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (7) alkylsulfonyl of 1 to 6 carbon atoms; (8) alkylsulfonylalkyl wherein the alkyl and alkylene groups independently have from 1 to 6 carbon atoms; (9) an aryl group; (10) arylalkyl, wherein the alkyl group has 1 to 6 carbon atoms; (11) an amino group; (12) aminoalkyl of 1 to 6 carbon atoms; (13) an aryl group; (14) arylalkyl, wherein the alkylene group has 1 to 6 carbon atoms; (15) aroyl; (16) an azide group; (17) azidoalkyl of 1 to 6 carbon atoms; (18) a carboxy aldehyde; (19) (carboxyaldehyde) alkyl, wherein alkylene The group has 1 to 6 carbon atoms; (20) cycloalkyl of 3 to 8 carbon atoms; (21) an alkylcycloalkyl group, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms; (22) halogen; (23) haloalkyl of 1 to 6 carbon atoms; (24) a heterocyclic group; (25) (heterocyclyl) oxy; (26) (heterocyclyl) acyl; (27) a hydroxyl group; (28) hydroxyalkyl of 1 to 6 carbon atoms; (29) a nitro group; (30) a nitroalkyl group of 1 to 6 carbon atoms; (31) an N-protected amino group; (32) an N-protected aminoalkyl group wherein the alkylene group has from 1 to 6 carbon atoms; (33) an oxy group; (34) thioalkoxy of 1 to 6 carbon atoms; (35) thioalkoxyalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (36) (CH)₂)_qCO₂R^AWherein q is an integer from 0 to 4, and R^ASelected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, wherein the alkylene group has 1 to 6 carbon atoms; (37) (CH)₂)_qC(O)NR^BR^CWherein R is^BAnd R^CIndependently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, wherein the alkylene group has from 1 to 6 carbon atoms; (38) (CH)₂)_qS(O)₂R^DWherein R is^DSelected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, wherein the alkylene group has 1 to 6 carbon atoms; (39) (CH) ₂)_qS(O)₂NR^ER^FWherein R is^EAnd R^FEach independently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, wherein the alkylene groups have from 1 to 6 carbon atoms; (40) (CH)₂)_qNR^GR^HWherein R is^GAnd R^HEach independently selected from: (a) hydrogen; (b) an N-protecting group; (c) alkyl of 1 to 6 carbon atoms; (d) alkenyl of 2 to 6 carbon atoms; (e) alkynyl of 2 to 6 carbon atoms; (f) an aryl group; (g) arylalkyl, wherein the alkylene group has 1 to 6 carbon atoms; (h) cycloalkyl of 3 to 8 carbon atoms; and (i) alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms, and with the proviso that no two groups are bound to the nitrogen atom through the carbonyl or sulfonyl group; (41) an oxy group; (42) thiol group(ii) a (43) A perfluoroalkyl group; (44) a perfluoroalkoxy group; (45) an aryloxy group; (46) a cycloalkoxy group; (47) a cycloalkylalkoxy group; and (48) an arylalkoxy group.

By "effective amount" is meant the amount of compound necessary to treat or prevent obesity or related syndromes. The effective amount of active compound to be used in the practice of the present invention for the treatment or prevention of diseases caused or contributed to by obesity varies depending on the mode of administration and the age, weight and general health of the patient. Ultimately, the attending physician or veterinarian will determine the appropriate amount and dosage regimen. An effective amount may also be one that provides relief from one or more symptoms of the condition or disease, or reduces the likelihood of the onset of the disease.

The terms "halogen" and "halo", used interchangeably herein, denote F, Cl, Br and I.

The term "haloalkyl" as defined herein, means a halogen group attached to the parent molecular group through an alkyl group.

The term "heteroaryl" as used herein denotes a subunit of an aromatic heterocycle as defined herein (i.e. which contains 4n +2pi electrons in a monocyclic or polycyclic ring system). Exemplary unsubstituted heteroaryl groups have from 1 to 9 carbons.

Unless otherwise specified, the terms "heterocycle" and "heterocyclyl" used interchangeably herein, mean a 5-, 6-or 7-membered ring containing 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. The 5-membered ring has 0 to 2 double bonds, while the 6-and 7-membered rings have 0 to 3 double bonds. The term "heterocycle" also includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocycles are fused to 1 or 2 rings independently selected from: an aromatic ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring and another monocyclic heterocyclic ring (e.g., indolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, benzofuranyl, benzothienyl, etc.). Heterocyclic compounds include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidyl, homopiperidinyl (homopiperidine) imidazolinyl), pyrazolinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, isoindolyl, triazolyl, tetrazolyl, oxadiazolyl, uricyl, thiadiazolyl, pyrimidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl (dihydroindolinyl), tetrahydroquinolinyl, tetrahydroisoquinolinyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, benzothienyl and the like. Heterocyclic groups also include those of the formulaA compound of (1), wherein

F' is selected from CH₂、CH₂O and O, and G 'is selected from the group consisting of C (O) and (C (R') (R *))_vWherein R' and R * are each independently selected from hydrogen or alkyl of 1 to 4 carbon atoms and v is 1 to 3 and includes groups such as 1, 3-benzodioxole (benzodioxol), 1, 4-benzodioxol (benzodioxolyl), and the like. Any of the heterocyclic groups mentioned herein may be optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from the group consisting of: (1) alkanoyl of 1 to 6 carbon atoms; (2) alkyl of 1 to 6 carbon atoms; (3) alkoxy of 1 to 6 carbon atoms; (4) alkoxyalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (5) alkylsulfinyl of 1 to 6 carbon atoms; (6) alkylsulfinylalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (7) alkylsulfonyl of 1 to 6 carbon atoms; (8) alkylsulfonylalkyl wherein the alkyl and alkylene groups independently have from 1 to 6 carbon atoms; (9) an aryl group; (10) arylalkyl, wherein the alkyl group has 1 to 6 carbon atoms; (11) an amino group; (12) aminoalkyl of 1 to 6 carbon atoms; (13) an aryl group; (14) arylalkyl, wherein the alkylene group has 1 to 6 carbon atoms; (15) aroyl; (16) an azide group; (17) of 1 to 6 carbon atoms An azidoalkyl group; (18) a carboxy aldehyde; (19) (carboxyaldehyde) alkyl, wherein the alkylene group has 1 to 6 carbon atoms; (20) cycloalkyl of 3 to 8 carbon atoms; (21) an alkylcycloalkyl group, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms; (22) halogen; (23) haloalkyl of 1 to 6 carbon atoms; (24) a heterocyclic group; (25) (heterocyclyl) oxy; (26) (heterocyclyl) acyl; (27) a hydroxyl group; (28) hydroxyalkyl of 1 to 6 carbon atoms; (29) a nitro group; (30) a nitroalkyl group of 1 to 6 carbon atoms; (31) an N-protected amino group; (32) an N-protected aminoalkyl group wherein the alkylene group has from 1 to 6 carbon atoms; (33) an oxy group; (34) thioalkoxy of 1 to 6 carbon atoms; (35) thioalkoxyalkyl wherein the alkyl and alkylene groups independently have 1 to 6 carbon atoms; (36) (CH)₂)_qCO₂R^AWherein q is an integer from 0 to 4, and R^ASelected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, wherein the alkylene group has 1 to 6 carbon atoms; (37) (CH)₂)_qC(O)NR^BR^CWherein R is^BAnd R^CIndependently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, wherein the alkylene group has from 1 to 6 carbon atoms; (38) (CH)₂)_qS(O)₂R^DWherein R is^DSelected from the group consisting of (a) alkyl, (b) aryl, and (c) arylalkyl, wherein the alkylene group has 1 to 6 carbon atoms; (39) (CH) ₂)_qS(O)₂NR^ER^FWherein R is^EAnd R^FEach independently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) arylalkyl, wherein the alkylene groups have from 1 to 6 carbon atoms; (40) (CH)₂)_qNR^GR^HWherein R is^GAnd R^HEach independently selected from: (a) hydrogen; (b) an N-protecting group; (c) alkyl of 1 to 6 carbon atoms; (d) alkenyl of 2 to 6 carbon atoms; (e) alkynyl of 2 to 6 carbon atoms; (f) an aryl group; (g) arylalkyl, wherein the alkylene group has 1 to 6 carbon atoms; (h) cycloalkyl of 3 to 8 carbon atoms; and (i) alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms, and with the proviso that no two groups are openA percarbonyl or sulfonyl group is bound to the nitrogen atom; (41) an oxy group; (42) a thiol group; (43) a perfluoroalkyl group; (44) a perfluoroalkoxy group; (45) an aryloxy group; (46) a cycloalkoxy group; (47) a cycloalkylalkoxy group; and (48) an arylalkoxy group.

The terms "heterocyclyloxy" and "(hetero) oxy," used interchangeably herein, refer to a heterocyclic group, as defined herein, appended to the parent molecular group through an oxygen atom. Exemplary unsubstituted heterocyclyloxy groups have 1 to 9 carbons.

The terms "heterocyclylacyl" and "(heterocyclic) acyl," as used interchangeably herein, refer to a heterocyclic group, as defined herein, appended to the parent molecular group through a carbonyl group. Exemplary unsubstituted heterocycloyl groups have from 2 to 10 carbons.

The terms "hydroxy" and "hydroxy", used interchangeably herein, represent an-OH group.

As defined herein, the term "hydroxyalkyl" as used herein denotes an alkyl group as defined herein substituted with 1 to 3 hydroxyl groups (provided that no more than 1 hydroxyl group may be attached to a single carbon atom of the alkyl group), e.g., hydroxymethyl, dihydroxypropyl, and the like.

The term "N-protected amino" as used herein, to an amino group as defined herein attached to an N-protecting group or a nitrogen-protecting group as defined herein.

The terms "N protecting group" and "nitrogen protecting group" as used herein refer to those groups that are intended to protect amino groups from undesired reactions during synthesis. Commonly used N protecting Groups are disclosed In Greene, "Protective Groups In Organic Synthesis, 3rd Edition" (protecting Groups In Organic Synthesis, third Edition) "(John Wiley & Sons, New York, 1999), which is incorporated herein by reference. N-protecting groups include acyl, aroyl or carbamoyl groups (e.g., formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, o-nitrophenoxyacetyl, α -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl) and chiral auxiliaries, such as protected or unprotected D, L or D, L-amino acids (e.g., alanine, leucine, phenylalanine, etc.); sulfonyl groups (e.g., benzenesulfonyl, p-toluenesulfonyl, etc.); a carbamate-forming group (e.g., benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3, 4-dimethoxybenzyloxycarbonyl, 3, 5-dimethoxybenzyloxycarbonyl, 2, 4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4, 5-dimethoxybenzyloxycarbonyl, 3, 4, 5-trimethoxybenzyloxycarbonyl, 1- (p-diphenyl) -1-methylethoxycarbonyl, α -dimethyl-3, 5-dimethoxybenzyloxycarbonyl, diphenoxycarbonyl, t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, N-ethyloxycarbonyl, 2, 2, 2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylsulfanyl, etc.), arylalkyl (e.g., benzyl, triphenylmethyl, benzyloxymethyl, etc.) and silyl (e.g., trimethylsilyl, etc.). Preferred N protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

The term "nitro" as used herein means-NO₂A group.

The term "haloalkyl" denotes a haloalkyl group attached to the parent molecular moiety through an alkyl group.

The term "non-ortho O, S or NR'" refers to a linked oxygen, sulfur, or nitrogen heteroatom substituent wherein the heteroatom substituent does not form a bond to a saturated carbon bonded to another heteroatom.

The term "obesity" as used herein refers to a mammal (e.g., a human) that is or is at risk of becoming overweight, obese, or suffering from an overweight-or obesity-related syndrome. According to established criteria, people with a Body Mass Index (BMI) > 25 are "overweight" and people with a BMI > 30 are "obese".

By "obesity and related syndromes" is meant obesity as defined above and other diseases or conditions associated with obesity including, but not limited to, depression, type 2 diabetes, dyslipidemia, respiratory complications, sleep apnea, hypertension, gallbladder disease, heart disease (e.g., coronary artery disease), osteoarthritis and certain forms of cancer (e.g., endometrial, breast, prostate and colon cancers).

The term "oxo" as used herein means ═ O.

The term "perfluoroalkyl" as used herein, denotes an alkyl group as defined herein, wherein each hydrogen radical bonded to the alkyl group is replaced by a fluorine radical. Examples of perfluoroalkyl groups are trifluoromethyl, pentafluoroethyl, and the like.

The term "perfluoroalkoxy" as used herein refers to an alkoxy group, as defined herein, wherein each hydrogen radical bonded to an alkyl group is replaced with a fluorine radical.

The term "pharmaceutically acceptable salts" as used herein refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are known in the art. For example, s.m.berge et al, in j.pharmaceutical Sciences 66: pharmaceutically acceptable salts are described in detail in 1-19, 1977. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or isolated by reacting the free base with a suitable organic acid. Representative acid addition salts include acetate, adipate, alginate, ascorbic acid, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, heptonate (glucoheptonate), glycerophosphate, hemisulfate, heptonate (heptanate), hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectin (pectate), persulfate, 3-phenylpropionate, salicylate, and mixtures thereof, Phosphates, picrates, pivalates, propionates, stearates, succinates, sulfates, tartrates, thiocyanates, tosylates, undecanoates, valerates, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

The term "pharmaceutically acceptable ester" as used herein means an ester that hydrolyzes in vivo, including esters that readily decompose in the human body to leave the parent compound or salt thereof. For example, suitable ester groups include esters derived from pharmaceutically acceptable aliphatic carboxylic acids (particularly alkanoic, alkenoic, naphthenic and alkanedioic acids), wherein each alkyl or alkenyl group preferably has not more than 6 carbon atoms. Examples of specific esters include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.

The term "prodrug" as used herein denotes a compound that is rapidly converted in vivo, for example by hydrolysis in blood, to the parent compound of the above formula. A full discussion is provided in t.higuchi and v.stella, Pro-drugs as Novel Delivery Systems, volume 14 of a.c.s.symposium Series; edited by Edward b.roche, Bioreversible Carriers in Drug Design (Bioreversible Carriers in Drug Design), american pharmaceutical Association and Pergamon Press, 1987; and Judkins et al, Synthetic Communications 26 (23): 4351-4367, 1996, each of which is incorporated herein by reference.

Prodrugs of isomers and analogs according to the invention may be prepared by modifying functional groups in the following manner: the modification can be cleaved in vivo to release the parent isomer or analog. Prodrugs include modified isomers or analogs wherein the hydroxy or amino group in any of the isomers or analogs is linked to any group that can be cleaved in vivo to regenerate the free hydroxy or amino group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives) and carbamates (e.g., N, N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of formulas I, II, III, IV-A, IV-B, IV-C, IV-D, V, V-A, and/or VI, and the like.

The term "pharmaceutically acceptable prodrug" as used herein means those prodrugs of the compounds of the present invention which are, when possible, suitable for use in contact with human and animal tissues within the scope of sound medical judgment, are free of salts of undue toxicity, irritation, allergic response and the like, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use, as well as the zwitterionic forms of the compounds of the present invention.

"pharmaceutically acceptable active metabolite" is intended to mean a pharmacologically active product produced by the in vivo metabolism of a compound according to the invention.

"pharmaceutically acceptable solvate" is intended to mean a solvate that retains the biological effects and properties of the biologically active components of the isomers and analogs according to the present invention. Examples of pharmaceutically acceptable solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.

"prevention or treatment of obesity" is intended to mean any beneficial prophylactic or therapeutic activity associated with the body weight, appetite or food intake of a mammal (preferably a human), including but not limited to the following: reducing body weight and/or body fat, preventing the occurrence or development of excessive weight gain, reducing appetite, reducing food intake and/or increasing energy expenditure.

"Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system. When the ring system is saturated or partially saturated, the "ring system substituents" further include methylene (double-bonded carbon), oxy (double-bonded oxygen), or thio (double-bonded sulfur).

The term "spiroalkyl" as used herein, means an alkylene diradical that is attached at both ends to the same carbon atom of the parent group to form a spirocyclic group.

The term "sulfonyl", as used herein, means S (O) ₂A group.

The term "thioalkoxy," as used herein, refers to an alkyl group attached to the parent molecular group through a sulfur atom. Exemplary unsubstituted thioalkoxy groups have from 1 to 6 carbons.

The term "thioalkoxyalkyl" refers to a thioalkoxy group attached to the parent molecular group through an alkyl group.

The terms "thiocarbonyl" and "thiocarbonyl" denote a C (S) group, which may also be denoted as C ═ S.

The terms "mercapto" and "thiol" denote an SH group.

The phrase "in combination" means that two or more compounds (e.g., compound 1, compound 2, compound 3, etc.) are administered before, after, and/or simultaneously with the other compounds. In this context, the phrase "two compounds are administered simultaneously" means that compounds 1 and 2 are administered within 48 hours (e.g., 24 hours) of each other. In some embodiments, "combination" includes compounds 1 and 2 administered close enough in time that they have a beneficial effect on the patient that it is better than the effect of compound 1 or 2 administered alone (in the absence of other drugs) over the same course of treatment. In some embodiments, the beneficial effect is the treatment of diabetes and the reduction or prevention of weight gain.

B) Compounds according to the invention

As will be described in detail below, the present inventors have found that hydroxylated amino acids, and more particularly, 4-hydroxyisoleucine, its configurational isomers, analogs, lactones, prodrugs, drug salts, drug esters, metabolites, and solvates thereof, are effective in preventing and/or treating obesity.

The present invention provides methods, compounds and pharmaceutical compositions for treating a mammal (e.g., a human) that is or is at risk of becoming overweight, obese, or suffering from an overweight-or obesity-related syndrome. Specific uses of the methods, compounds and pharmaceutical compositions of the invention include, but are not limited to: preventing or treating obesity, preventing the occurrence or development of excessive weight gain, reducing body weight and/or body fat, and reducing appetite and/or food intake.

i) 4-hydroxyisoleucine isomers

According to an embodiment, the compound used according to the invention is selected from the group consisting of 4-hydroxyisoleucine configurational isomers and pharmaceutically acceptable lactones, salts, crystalline forms, prodrugs, esters, metabolites or solvates thereof. In certain embodiments, the 4-hydroxyisoleucine isomer is selected from the group consisting of:

and

in a preferred embodiment, the 4-hydroxyisoleucine is the (2S, 3R, 4S) isomer (Compound 14 a). In another preferred embodiment, the 4-hydroxyisoleucine is the (2R, 3S, 4R) isomer.

Exemplary prodrugs of the 4-hydroxyisoleucine isomers include those compounds in which a carboxylic acid group and a hydroxyl group are condensed to form one of the following lactones:

the 4-hydroxyisoleucine isomers can be prepared by using techniques available in the art, using readily available starting materials. For example, processes for the preparation of (2S, 3R, 4S) -4-hydroxyisoleucine have been described, see, for example: U.S. patent application US 2003/0219880; Rolland-Fulcrand et al, Eur.J.org.chem.873-877, 2004; and Wang et al, Eur.J.org.chem.834-839, 2002. In addition, the compound can be isolated from seeds of Trigonella foenum-graecum. Methods for preparing other configurational isomers of 4-hydroxyisoleucine or prodrugs thereof have been described in the following references: PCT application PCT/FR2005/02805 filed on 10/11/2005 (published as WO2006/____ on ____/5/2006) and PCT application PCT/IB2006/____ filed on 17/2/2006 (published as WO 2006/____; initially designated as PCT/US2006/005794 filed on 17/2/2006), each of which is incorporated herein by reference. FIG. 24 shows a scheme for synthesis of each of the eight (8) configurational isomers of 4-hydroxyisoleucine.

ii) 4-hydroxyisoleucine analogs

As mentioned above, in addition to all isomeric forms of 4-hydroxyisoleucine, the present invention also relates to the use and/or administration of analogs of 4-hydroxyisoleucine (in any isomeric form) for the prevention and/or treatment of obesity and/or any of its associated syndromes.

In one embodiment, the 4-hydroxyisoleucine analogue according to the present invention is represented by the general formula (I):

and pharmaceutically acceptable lactones, salts, prodrugs, metabolites or solvates thereof.

The substituent A in the compounds of formula (I) may be CO₂R^A1、C(O)SR^A1、C(S)SR^A1、C(O)NR^A2R^A3、C(S)NR^A2R^A3、C(O)R^A4、SO₃H、S(O)₂NR^A2R^A3、C(O)R^A5、C(OR^A1)R^A9R^A10、C(SR^A1)R^A9R^A10、C(＝NR^A1)R^A5，

R^A1Is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 4 carbon atoms),

R^A2and R^A3Each independently selected from: (a) hydrogen, (b) substituted or unsubstituted C _1-6Alkyl, (C) substituted or unsubstituted C_3-8Cycloalkyl, (d) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms, (e) substituted or unsubstituted C₆Or C₁₀Aryl, and (f) substituted or unsubstituted C_7-16Alkylaryl in which the alkylene radical has from 1 to 6 carbon atoms, orR is^A2And R^A3Together with N to form a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^A8Wherein R is^A8Is hydrogen or C_1-6An alkyl group, a carboxyl group,

R^A4is substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 4 carbon atoms),

R^A5is a peptide chain of 1-4 natural or unnatural amino acids, wherein the peptide is linked to C (O) via its terminal amine group,

R^A6and R^A7Each independently hydrogen, substituted or unsubstituted C_1-6Alkyl radical, C_1-4Perfluoroalkyl, substituted or unsubstituted C _1-6Alkoxy, amino, C_1-6Alkylamino radical, C_2-12Dialkylamino, N-protected amino, halogen or nitro, and

R^A9and R^A10Each independently selected from: (a) hydrogen, (b) substituted or unsubstituted C_1-6Alkyl, (C) substituted or unsubstituted C_3-8Cycloalkyl, (d) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms, (e) substituted or unsubstituted C₆Or C₁₀Aryl, and (f) substituted or unsubstituted C_7-16Alkylaryl in which the alkylene radical has from 1 to 6 carbon atoms, or R^A9And R^A10And the parent carbon atoms form together a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^A8Wherein R is^A8Is hydrogen or C_1-6An alkyl group.

The substituent B in the compounds of formula (I) being NR^B1R^B2Wherein R is^B1And R^B2Each independently selected from: (a) hydrogen, (b) an N protecting group, (C) a substituted or unsubstituted C_1-6Alkyl, (d) substituted or unsubstituted C_2-6Alkenyl, (e) substituted or unsubstituted C_2-6Alkynyl, (f) substituted or unsubstituted C_3-8Cycloalkyl, (g) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms, (h) substituted or unsubstituted C₆Or C₁₀Aryl, (i) substituted or unsubstituted C _7-16Alkylaryl group wherein the alkylene radical has from 1 to 6 carbon atoms, (j) substituted or unsubstituted C_1-9Heterocyclyl group, (k) substituted or unsubstituted C_2-15Alkylheterocyclyl wherein the alkylene group has 1 to 6 carbon atoms, (1) C (O) R^B3Wherein R is^B3Selected from substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 6 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 6 carbon atoms), (m) CO₂R^B4Wherein R is^B4Selected from substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 6 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 6 carbon atoms), (n) C (O) NR^B5R^B6Wherein R is^B5And R^B6Each independently selected from hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 6 carbon atoms), substituted or unsubstituted C_1-9Heterocyclic group and substituted or unsubstituted C _2-15Alkanediyl (where the alkylene radical has 1 to 6 carbon atoms)Son) or R^B5And R^B6And N together form a substituted or unsubstituted 5-or 6-membered ring, optionally containing a non-ortho position of O, S or NR ', wherein R' is hydrogen or C_1-6Alkyl, (o) S (O)₂R^B7Wherein R is^B7Selected from substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 6 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15An alkylheterocyclyl group (wherein the alkylene group has from 1 to 6 carbon atoms), and (p) a peptide chain of 1-4 natural or non-natural alpha-amino acid residues, wherein the peptide is linked to N through its terminal carboxyl group, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl or sulfonyl group. Or, R^B1When combined with other substituents of formula I, may form a ring system. In a ring system, R^B1And R^B2Together with N to form a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^B8Wherein R is^B8Is hydrogen or C_1-6An alkyl group. Or, when R is^B1And R^1aTogether being substituted or unsubstituted C_1-4When alkyl, a 5-to 8-membered ring is formed, or when R is^B1And R^1aTogether being substituted or unsubstituted C₂Alkylene and R ^B1And R^2aTogether being substituted or unsubstituted C_1-2When alkylene is present, [2.2.1 ] is formed]Or [2.2.2]A bicyclic ring system. Or, when R is^B1And R³Together being substituted or unsubstituted C_2-6When alkyl, a 4-to 8-membered ring is formed. When R is^B1And R⁴Together being substituted or unsubstituted C_1-3When alkyl, a 6-to 8-membered ring is formed. When R is^B1When the following rings are formed together with A and the parent carbons of A and B, another ring is formed:

wherein Y and W are each independentlyIs O, S, NR^B8Or CR^A9R^A10Wherein R is^A9And R^A10Each as defined above, and R^A11And R^A12Each independently selected from: (a) hydrogen, (b) substituted or unsubstituted C_1-6Alkyl, (C) substituted or unsubstituted C_3-8Cycloalkyl, (d) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms, (e) substituted or unsubstituted C₆Or C₁₀Aryl, and (f) substituted or unsubstituted C_7-16Alkylaryl in which the alkylene radical has from 1 to 6 carbon atoms, or R^A9And R^A10And the parent carbon atoms form together a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^A8Wherein R is^A8Is hydrogen or C_1-6An alkyl group. In one embodiment, the B' substituent is other than R^1a、R^1bOr R⁴Forming a ring.

The substituent X in the compound of formula (I) may be O, S or NR ^X1Wherein R is^X1Selected from: (a) hydrogen, (b) an N protecting group, (C) a substituted or unsubstituted C_1-6Alkyl, (d) substituted or unsubstituted C_2-6Alkenyl, (e) substituted or unsubstituted C_2-6Alkynyl, (f) substituted or unsubstituted C_3-8Cycloalkyl, (g) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms, (h) substituted or unsubstituted C₆Or C₁₀Aryl, (i) substituted or unsubstituted C_7-16Alkylaryl group wherein the alkylene radical has from 1 to 6 carbon atoms, (j) substituted or unsubstituted C_1-9Heterocyclyl group, or (k) substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has from 1 to 6 carbon atoms.

For the compounds of formula (I), R^1aAnd R^1bEach substituent is independently substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group hasHaving 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C _1-9Heterocyclyl or substituted or unsubstituted C_2-15An alkylheterocyclyl group (wherein the alkylene group has 1 to 4 carbon atoms), or R^1aAnd R^2aAnd the essential carbon atoms thereof together form a substituted or unsubstituted C_5-10Monocyclic or fused ring systems, or when R is^1aAnd R⁴Together being substituted or unsubstituted C_1-4Alkylene groups form a 3-to 6-membered ring.

For the compounds of formula (I), R^2aAnd R^2bEach independently hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15An alkylheterocyclyl group (wherein the alkylene group has 1 to 4 carbon atoms), or R^2aAnd R^2bTogether are ═ O, ═ N (C)_1-6Alkyl) ═ CR^2cR^2d(wherein R is^2cAnd R^2dEach independently hydrogen, substituted or unsubstituted C_1-6Alkyl) or substituted or unsubstituted C forming a spiro ring_2-5Alkylene moiety, or R^2aAnd R ^1aAnd the essential carbon atoms thereof together form a substituted or unsubstituted C_5-10Monocyclic or fused ring systems.

Substituent R in the compound of formula (I)³May be hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted alkylcycloalkyl (whereinCycloalkyl group having 3 to 8 carbon atoms and alkylene group having 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms) or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 4 carbon atoms). Or, when R is³And R^B1Together being substituted or unsubstituted C_2-6Alkylene groups may form 4-to 8-membered rings.

Substituent R in the compound of formula (I)⁴Is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C _1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 4 carbon atoms), or when R is⁴And R^1aTogether being substituted or unsubstituted C_1-4When alkylene forms a 3-to 6-membered ring, or when R is⁴And R^B1Together being substituted or unsubstituted C_1-3Alkylene groups form 6-to 8-membered rings.

In certain embodiments, the analogs of the invention are represented by the general formula (I) and the attendant definitions, wherein A is CO₂H, B is NH-p-toluenesulfonyl, R⁴Is H, and R^1aAnd R^2aEach is CH₃。

In certain embodiments, the analogs of the invention are represented by the general formula (I) and the attendant definitions, wherein A is CO₂H, B is NH₂，R⁴Is H, and R^1aAnd R^2aEach being substituted or unsubstituted C_1-6An alkyl group.

In certain embodiments, the analogs of the invention are represented by the general formula (I) and the attendant definitions, wherein R is^1aAnd R^2aAnd the essential carbon atoms thereof together form a substituted or unsubstituted C_5-10A mono-or fused ring system, optionally containing a non-ortho position O, S or NR ', wherein R' is hydrogen or C_1-6An alkyl group.

In certain embodiments, the analogs of the invention are represented by the general formula (II), or a pharmaceutically acceptable lactone, salt, metabolite, solvate, and/or prodrug thereof:

wherein R is^1aAnd R^2aEach independently is substituted or unsubstituted C _1-6Alkyl, or R^1aAnd R^2aAnd the essential carbon atoms thereof together form a substituted or unsubstituted C₆-a cycloaliphatic ring system. In certain embodiments, the analogs of the invention are represented by the general formula (II) and the attendant definitions, wherein R is^1aRepresents an ethyl group, R^2aRepresents a methyl group, X represents O, and R⁴Represents a hydrogen atom. Some examples of this embodiment include the compounds identified as ID numbers 13b, 12b, 218, 219, 220, 221, 222, and 223 in table 1 below.

In certain embodiments, the analogs of the invention are represented by the general formula (II) and the attendant definitions, wherein X represents O, and R represents⁴Represents a hydrogen atom, and R^1aAnd R^2aCombine to form a 6 or 7 membered ring structure. Some examples of this embodiment include compounds identified as ID numbers 12e, 13e, 14e, 15e, 213, 214, 215, 216, 217, 12f, 13f, 14f, 15f, 231, 232, 233, 234, and 235 in table 1 below.

In certain embodiments, the analogs of the invention are represented by the general formula (II) and the attendant definitions, wherein R is^1aRepresents a methyl group, R^2aRepresents a benzyl group, X represents O, and R⁴Represents a hydrogen atom. Some examples of this embodiment include the compounds identified as ID numbers 12d, 13d, 14d, 15d, 238, 239, 240 and 241 in table 1 below.

In certain embodiments, the analogs of the present invention are represented by the general formula (II) and the attendant definitions, wherein R is^1a、R^1bAnd R^2aRepresents a methyl group, X represents O, and R⁴Represents a hydrogen atom. Some examples of this embodiment include the compounds identified as ID numbers 207, 101a, 101b, 208, 209, and 210 in table 1 below. The compound desired for this example has the 2S, 3R configuration.

In certain embodiments, the analogs of the invention are represented by general formula (III), or a pharmaceutically acceptable lactone, salt, metabolite, solvate, and/or prodrug thereof:

wherein B, X and R⁴As defined elsewhere herein (see formula I above), and A is CO₂R^A1、C(O)SR^A1、C(O)NR^A2R^A3Or C (O) R^A5。

In certain embodiments, the analogs of the invention are represented by general formula (IV), or a pharmaceutically acceptable lactone, salt, metabolite, solvate, and/or prodrug thereof:

wherein B, X and R⁴As defined elsewhere herein (see formula I above), and A is CO₂R^A1、C(O)SR^A1、C(O)NR^A2R^A3Or C (O) R^A5And R is⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹And R¹²Independently hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C _2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (where the alkylene group has 1 to 4 carbon atoms), the desired compound of this embodiment has the SSR configuration.

In certain embodiments, the analogs of the invention are represented by the following general formula, or a pharmaceutically acceptable lactone, salt, solvate, and/or prodrug thereof:

wherein R is^1aAnd R^1bEach independently is substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 4 carbon atoms).

In a preferred embodiment of this embodiment, A is CO ₂H, B is NH₂，R⁴Is H, and R^1aAnd R^2aEach being substituted or unsubstituted C_1-6An alkyl group. In another embodiment, preferred 4-OH analogs include those wherein R is^1aAnd R^2aAnd the essential carbon atoms thereof together form a substituted or unsubstituted C_5-10Those of monocyclic or fused ring systems, for example, selected from the following compounds:

and

wherein R is⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹And R¹²Each independently hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 4 carbon atoms); and R¹³、R¹⁴、R¹⁵And R¹⁶Each independently hydrogen, substituted or unsubstituted C_1-6Alkyl radical, C_1-4Perfluoroalkyl, substituted or unsubstituted C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_2-12Dialkylamino, N-Protected amino, halogen or nitro. The most preferred compounds in this series are those wherein A is CO ₂H and is NH₂Those compounds of (1).

In another embodiment, the compound of formula (I) is

Or

Wherein R is¹⁷、R¹⁸、R¹⁹And R²⁰Each is hydrogen or substituted or unsubstituted C_1-6An alkyl group. In another embodiment, the compound of formula (I) is

Wherein R is²¹And R²²Each is hydrogen or substituted or unsubstituted C_1-6An alkyl group.

In another embodiment, the compound of formula (I) is

Further examples of compounds of formula (I) include compounds selected from the following group: compounds identified in table 1 below as having ID numbers 22, 26, 33, 34, 75, 76, 205, 206, 65, 59, 60, 61, 62, 200, 201, 202, 38, 99a, 99b, 100a, 100b, 207, 101a, 101b, 12c, 13c, 14c, 226, 230, 253, and 254.

Further examples of compounds of formula (I) include compounds selected from the following group: compounds identified in table 1 below with ID numbers 204, 102a, 102b, 211, 5a, 82, 203, 5c, 7c, and 225.

In certain embodiments, the analogs of the invention are represented by general formula (V), or a pharmaceutically acceptable lactone, salt, metabolite, solvate, and/or prodrug thereof:

wherein, A, R^1a、R^1b、R^2a、R⁴And R^B2Each as defined above with reference to formula I; wherein R is⁵、R⁶And R⁷Each independently hydrogen, substituted or unsubstituted C _1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C_7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 4 carbon atoms); and wherein Z is XR⁴Or NR^B1R^B2As defined above with reference to formula V.

In certain embodiments, the analogs of the invention are defined by formula (V-a):

or a lactone, salt, metabolite, solvate and/or prodrug thereof, wherein R is^A1、R^B2And R⁴Each as defined hereinbefore in relation to formula I; wherein R is⁵Is hydrogen, substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_3-8Cycloalkyl, substituted or unsubstituted alkylcycloalkyl (wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms), substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, substituted or unsubstituted C₆Or C₁₀Aryl, substituted or unsubstituted C _7-16Alkylaryl (wherein the alkylene radical has 1 to 4 carbon atoms), substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl (wherein the alkylene group has 1 to 4 carbon atoms); and wherein Z is XR⁴Or NR^B1R^B2As defined above with reference to formula V.

Examples of the compound of formula (V) include compounds selected from the following group: identified as compounds having ID numbers 256-263 in Table 1 below.

In certain embodiments, the analogs of the invention are represented by general formula (VI), or a pharmaceutically acceptable lactone, salt, metabolite, solvate, and/or prodrug thereof:

a, B, X, R therein^1a、R^1b、R³And R⁴As previously defined with reference to formula I.

Examples of compounds of formula (VI) include compounds selected from the following group: identified as the compound having ID number 264-.

Wherein R is^A1、R^B1、R^B2And R⁴As previously defined with reference to formula I.

Specific examples of four preferred compounds of the invention (SS, SR, RS and RR in isomeric form, respectively) are as follows and are presented in Table 1 as compounds 270-273.

And

further examples of preferred compounds of the invention are as follows:

[ Compound 75 ]]，[ Compound 76]，

[ Compound 202]，[ Compound 65a]，

[ Compound 13e]，

[ Compound 104]

The invention also includes salts, solvates, crystalline forms, active metabolites and prodrugs of the compounds of formulas (I), (II), (III), (IV-A), (IV-B), (IV-C), (IV-D), (V-A) and (VI). Specific examples of prodrugs include, but are not limited to, compounds of formula (I), (II), (III), (IV-A), (IV-B), (IV-C), (IV-D), (V-A), and (VI) in which the appropriate functionality, such as, but not limited to, the hydroxy, amino, or sulfhydryl groups in these formulae, is properly derivatized with a biologically or chemically labile molecular moiety that can be cleaved in vivo to yield the formulaic compound.

In other embodiments, the compounds of the present invention are selected from the group consisting of the compounds listed in table 1 below. It should be noted that in table 1 below and throughout this document, when an atom is shown as being free of hydrogen, but hydrogen is chemically necessary to form a stable compound, then it should be inferred that hydrogen is part of the compound.

Table 1: structures of exemplary Compounds

The compounds and compositions of the present invention (see below) are prepared by employing techniques available in the art, using readily available starting materials. For example, compounds of formulae I, II, III, IV-A, IV-B, IV-C and/or IV-D herein have been described in PCT application PCT/IB 2006/(published as WO 2006/____; initially assigned PCT/US2006/005794) and U.S. patent application 11256,848, both filed on.2.17.2006, and incorporated herein by reference.

Another aspect of the invention relates to a novel process for the synthesis of the analogues according to the invention. Examples some new and exemplary methods of preparing the compounds of the present invention have been described in the examples section. Such methods are within the scope of the present invention.

D) Pharmaceutical compositions and therapeutic applications

Without wishing to be bound by theory, the inventors have demonstrated that the compounds according to the invention are useful for the prevention and treatment of obesity and related syndromes. Accordingly, the present invention relates to therapeutic methods, compounds and pharmaceutical compositions for preventing or treating obesity, including but not limited to preventing the occurrence or development of excessive weight gain, reducing body weight and/or body fat, and reducing appetite and/or food intake.

The present invention provides several advantages. For example, individuals diagnosed as overweight or obese are at risk of developing serious conditions, such as heart disease (e.g., coronary artery disease), stroke, hypertension, type 2 diabetes, dyslipidemia, respiratory complications, sleep apnea, osteoarthritis, gallbladder disease, depression, and certain forms of cancer (e.g., endometrial, breast, prostate, and colon cancer). In effectively reducing body weight and/or appetite, the methods of the invention can reduce the risk of developing these conditions in overweight and obese patients. In addition, it is known that even a 5-10% weight loss can contribute to the health of overweight and obese individuals, and the present methods can be used to achieve such a reduction.

According to a preferred embodiment of the invention, the mammal is a human patient in need of treatment by the methods, compounds and/or compositions of the invention and is selected for treatment based on that need. Persons in need of treatment, particularly where obesity is a concern, are art-recognized and include individuals who are or are at risk of becoming overweight (body mass index (BMI) > 25), obese (BMI > 30), or suffering from overweight or obesity-related syndromes. The person in need of treatment may also take or ingest a medicament for the prevention or treatment of disorders of carbohydrate or lipid metabolism, including diabetes (type 1 and type 2 diabetes), prediabetes and metabolic syndrome. The person in need of treatment can also be a person at risk for such a disease or condition and is expected to benefit from treatment (e.g., cure, heal, prevent, alleviate, alter, correct, ameliorate, improve, or affect the disease or condition, a symptom of the disease or condition, or a risk of the disease or condition) based on diagnosis (e.g., medical diagnosis).

Accordingly, a related aspect of the invention relates to the use of a compound of the invention as an active ingredient in a pharmaceutical composition for therapeutic or prophylactic purposes. As used herein, "treating" or "treatment" is intended to mean at least the alleviation of a disease or disorder associated with obesity and related syndromes in a mammal (e.g., a human) by the administration of one or more compounds according to the present invention, and includes the total or partial cure, healing, inhibition (e.g., arresting or reducing the development of, relieving from, ameliorating and/or relieving the condition of the disease (e.g., causing regression of the disease and its clinical symptoms).

As used herein, "prevention" or "prevention" is intended to mean at least a reduction in the likelihood of a disease or condition associated with obesity or a related syndrome. The predisposing factors for obesity identified or suggested in the scientific literature include, but are not limited to: (i) a genetic predisposition that will have the disease condition but has not been diagnosed as having it, (ii) a disorder with fat metabolism, (iii) a sedentary lifestyle, (iv) nutrition, and/or (v) a genetic mutation (e.g., in a leptin recipient). For example, obesity may be prevented or treated by administering a compound of the invention or a composition comprising the same when the human is overweight, when the human exhibits abnormally high blood glucose levels, and/or when the human exhibits reduced glucose tolerance.

The patient may be female or male, and it may be a child, adolescent or adult.

According to a particular aspect, the invention features a method of reducing body weight and/or body fat in a mammal, comprising administering to the mammal a compound according to the invention and/or a composition comprising the compound. In a preferred embodiment, the mammal is an overweight or obese human.

According to another aspect of the invention, the invention features a method of treating an overweight or obese mammal (e.g., a human) including administering to the mammal a compound according to the invention and/or a composition including the compound.

According to another aspect of the invention, the invention features a method of preventing the occurrence or progression of excessive weight gain in a mammal (preferably a human being) comprising administering to said mammal a compound according to the invention and/or a composition comprising the compound. In a related aspect, the methods, compounds and/or compositions according to the invention are used to prevent the occurrence or development of weight gain associated with administration of an antidiabetic agent that stimulates weight gain.

According to another aspect, the invention features a method of reducing appetite and/or food intake in a mammal (preferably a human being) comprising administering to the mammal a compound according to the invention and/or a composition comprising the compound.

According to a particular aspect, the invention features a method of treating (1) overweight or obesity and (2) diabetes or a mammal (e.g., a human) taking an antidiabetic agent, which method includes administering a compound according to the invention and/or a composition including the compound in an amount sufficient to lower the circulating blood glucose concentration of the mammal.

According to certain embodiments, the compounds, compositions, and methods of the present invention are administered in a therapeutically effective dose sufficient to reduce body weight and/or body fat in a subject by about at least 1, 2, 3, 4, 5, 10, 15, 2025, 30, 35, 40, 45, 50, 75 percent or more as compared to the initial level prior to treatment. Typically, the compositions of the present invention are administered until body weight and/or body fat return to normal. Due to the nature of the conditions and diseases targeted by the compounds of the present invention, long-term or lifetime administration to certain patients may be required. In a preferred embodiment, the compounds and pharmaceutical compositions according to the invention are administered from 1 to 3 times per day.

Accordingly, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of 4-hydroxyisoleucine, its isomers, analogs, lactones, salts and prodrugs thereof as described herein, in association with a pharmaceutically acceptable carrier or excipient. Suitable carriers or excipients include, but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof. The pharmaceutical compositions may be administered in any effective conventional manner, including, for example: topical, gastrointestinal, oral, rectal, intravaginal, intravenous, intraperitoneal, intramuscular, intraocular, subcutaneous, intranasal, intrabronchial or intradermal routes.

Acceptable methods for preparing pharmaceutical compositions in suitable pharmaceutical forms are known to those skilled in the art. For example, pharmaceutical formulations may be prepared by conventional techniques of medicinal chemists to produce the desired products for various routes of administration, involving steps such as: mixing, granulating and compressing (as is necessary for tablets), or mixing, filling and dissolving the ingredients appropriately.

Toxicity and therapeutic efficacy of the compounds according to the invention can be assessed by standard pharmaceutical procedures in cell cultures or experimental animals. The therapeutic efficacy of the compounds according to the invention can be evaluated in animal model systems, which can predict efficacy in human diseases. For example, animal models for assessing weight and/or body fat loss include animal models for preventing and/or treating obesity (e.g., diet-induced obesity mice and murine models) or other related animal models in which weight gain or loss can be measured. Relevant parameters that can be measured in animal models include, but are not limited to, energy expenditure, oxygen consumption, calorie intake/food consumption, intestinal lipid absorption, and the like. Animal models for evaluating the efficacy of glucose uptake include animal models related to diabetes and other related animal models in which the rate of glucose infusion can be measured. Animal models for evaluating insulinotropic efficacy include animal models related to diabetes or other related animal models in which insulin secretion can be measured. Alternatively, the biological and/or physiological activity of the compounds according to the present invention can be evaluated in vitro by examining the ability of the compounds to stimulate lipolysis in adipocytes, increasing the expression of genes associated with fat metabolism (e.g., aP2, HSL, FatB1, CPT-1, and AMP kinase). While substances exhibiting toxic side effects may be used, care should be taken to design a delivery system that targets such substances to the affected tissue site to minimize potential damage to uninvolved cells and thereby reduce side effects.

The compounds, compositions and methods of the present invention can be used with a wide range of drugs. Such agents may be selected from anti-obesity agents, anorectic agents, antidiabetic agents, antihypertensive agents, anti-inflammatory agents and the like.

Examples of anti-obesity agents that can be used with the compounds of the present invention include Xenicacal^TM(Roche)、Meridia^TM(Abbott)、Acomplia^TM(Sanofi-Aventis) and sympathomimetic phentermine. A non-limiting list of potentially useful anti-obesity agents is listed in table 2 provided below.

Table 2: known and emerging anti-obesity agents

Name (trade name)	Company(s)	Description of the drugs	Dosage form
				Phenylbutylamine*(lonamin ®, Adipex-P ®, and imitation drugs)	Generic drug	Sympathomimetic appetite suppressants	15-37.5 mg/day
Benzphetamine (Direx ®)	Pharmacia/Pfizer	Sympathomimetic appetite suppressants	25-50mg-1 to 3 times per day
				Bupropion (Tenuate ®, Dospan ®)	Sanofi-Aventis ABCHolding	Sympathomimetic appetite suppressants	25 mg/tablet-3 tablets/day or 75 mg/tablet-1 tablet/day
Benzometrizine	Generic drug	Sympathomimetic appetite suppressants	17.5-35mg-2-3 times per day
				Bromocriptine (Ergoset ®,	Novartis，Mylan，Lek	dopamine receptors	2.5-15 mg/day

Parlodel®)	Pharms	Agonists
				Orlistat (Xenical ®, Zenical ®)	Roche	Lipase inhibitors	120 mg/tablet-3 tablets/day
Sibutramine (Meridia ®, reduction ® reduction ®, reductionTM)	Abbott	Norepinephrine reuptake inhibitors, monoamine reuptake inhibitors, 5-hydroxytryptamine reuptake inhibitors	10-15 mg/day
				Miglitol (Diastabol ®, Glyset ®, Miglibay ®, Plumural ®)	Bayer	Alpha-glucosidase inhibitors	50-100 mg/tablet-3 tablets/day
Bupropion (Quomem ®, WellbutrinXL ®, Zyban ®)	GlaxoSmithKline	Dopamine uptake inhibitors, monoamine uptake inhibitors, norepinephrine reuptake inhibitors	150 mg/tablet-1 to 2 tablets/day
				Radafaxine	GlaxoSmithKline	Noradrenaline/dopamine reuptake inhibitors	-
856464	GlaxoSmithKline	Melanin-concentrating hormone antagonists	-
				869682	GlaxoSmithKline	SGLT2 inhibitors	-
Zonisamide (Excegran ®, Zonegran ®)	DainipponPharmaceutical	Calcium channel antagonists, sodium channel antagonists	-
				Topiramate (Topamax ®)	Ortho-McNeilPharmaceutical	Sodium channel antagonists	-
Rimonabant (Acomplia ®)	Sanofi-Aventis	Cannabinoid 1(CB1) receptor antagonists	-
				SR147778	Sanofi-Aventis	CB1 antagonists	-
AVE1625	Sanofi-Aventis	CB1 antagonists	-
				APD356	Arena Pharmaceuticals	5-hydroxytryptamine 2C receptor agonists	-
AOD9604	MetabolicPharmaceuticals	hGH peptide variants	-
				P57	Phytopharm, Unilever (licensee)	Appetite suppressant from cactus	-
ATL962(Celistat®)	Alizyme, Takeda (licensee)	Lipase inhibitors	-

c-2624，c-5093，c-2735	Merck		-
				PYY3-36	NastechParmaceuticals/Merck	Synthetic form of the appetite suppressing hormone PYY	-
Cp-946，598	Pfizer	CB1 receptor antagonists	-
				SLV-319	SolvayPharm./Bristol-MyersSquibb	CB1 receptor antagonists	-

Table 3 provides typical dosages for several examples of these anti-obesity agents.

Table 3: usual dosage of common anti-obesity agents

Medicine	Dosage and/or administration
		Rosiglitazone	2 to 8 mg/tablet-up to 8mg per day
Pioglitazone	15 to 45 mg/tablet-15 to 45mg per day
		Troglitazone	200 to 400 mg/tablet-200 to 600 mg/tablet per day
Ciglitazone	0.1 mg/tablet

A non-limiting list of effective antidiabetic agents that may be used in combination with the compounds of the present invention includes: insulin, biguanides such as metformin (Glucophage ®, Bristol-Myers Squibb company, U.S.; Stagid ®, Lipa Sante, Europe); sulfonylureas, such as gliclazide (Diamicron ®), glyburide, glipizide (gluconrol ® and gluconrol XL ®, Pfizer), glimepiride (amyl ®, Aventis), chlorpropamide (e.g., diabines ®, Pfizer), tolbutamide, and glibenclamide (e.g., micron ®, Glynase ®, and Diabeta ®); glinides such as repaglinide (Prandin ® or NovoNorm ®; Novo Nordisk), ormitiglilide, nateglinide (Starlix ®), chromone, and BTS-67582; insulin sensitizers, such as glitazones (glitazones), thiazolidinediones such as rosiglitazone maleate (Avandia ®, Glaxo Smith Kline), pioglitazone (Actos ®, EIi Lilly, Takeda),Troglitazone, ciglitazone, isglitazone (isaglitazone), darglitazone, englitazone, CS-011/CI-1037, T174, GI262570, YM-440, MCC-555, JTT-501, AR-H039242, KRP-297, GW-409544, CRE-16336, AR-H049020, LY510929, MBX-102, CLX-0940, GW-501516 and in WO97/41097(DRF-2344), compounds described in WO97/41119, WO97/41120, WO98/45292, WO99/19313(NN622/DRF-2725), WO00/23415, WO00/23416, WO00/23417, WO00/23425, WO00/23445, WO00/23451, WO00/41121, WO00/50414, WO00/63153, WO00/63189, WO00/63190, WO00/63191, WO00/63192, WO00/63193, WO00/63196 and WO 00/63209; glucagon-like peptide 1(GLP-1) receptor agonists, e.g. Exendin-4(1-39) (Ex-4), Byetta ^TM(Amylinpharmaceuticals Inc.), CJC-1131(Conjuchem Inc.), NN-2211(Scios Inc.), and those GLP-1 agonists described in WO98/08871 and WO 00/42026; substances that slow the absorption of carbohydrates, such as alpha-glucosidase inhibitors (e.g., acarbose, miglitol, voglibose, and emiglitate); substances that inhibit gastric emptying, such as glucagon-like peptide 1, cholecystokinin (cholecystokinin), dextrin and pramlintide; glucagon antagonists, e.g. quinoxaline derivatives (e.g. 2-styryl-3- [3- (dimethylamino) propylmethylamino)]-6, 7-dichloroquinoxaline; collins et al, Bioorganic and Medicinal Chemistry Letters 2 (9): 915,918,1992), heaven and heaven analogs (e.g., those described in WO 94/14426), 1-phenylpyrazole derivatives (e.g., those described in us 4,359,474), substituted disilylcyclohexanes (e.g., those described in us 4,374,130), substituted pyridines and biphenyls (e.g., those described in WO 98/04528), substituted pyridylpyrroles (e.g., those described in us 5,776,954), 2, 4-diaryl-5-pyridylimidazoles (e.g., those described in WO98/21957, WO98/08 22109, WO98/22109, and us 5,880,139), 2, 5-substituted arylpyrroles (e.g., those described in WO97/16442 and us 5,837,719), substituted pyrimidinones (pyriminnes), and, Pyridone and pyrimidine compounds (e.g. in WO98/24780, WO98/24782, WO99/24404 And those described in WO 99/32448), 2- (benzimidazol-2-ylthio) -1- (3, 4-dihydroxyphenyl) -1-ethanone (see Madsen et al, j.med.chem.41: 5151-5157, 1998), alkylene hydrazines (e.g., those described in WO99/01423 and WO 00/39088) and other compounds (e.g., those described in WO00/69810, WO02/00612, WO02/40444, WO02/40445 and WO 02/40446); and glucokinase activators such as those described in WO00/58293, WO01/44216, WO01/83465, WO01/83478, WO01/85706, and WO 01/85707.

Other examples of antidiabetic agents which may be used in combination with one or more compounds according to the present invention include imidazolines (e.g., efaraxan, idazoxan, phentolamine, and 1-phenyl-2- (imidazolin-2-yl) benzimidazole); glycogen phosphorylase inhibitors (see, e.g., WO 97/09040); oxadiazolidinediones, dipeptidyl peptidase-IV (DPP-IV) inhibitors, protein tyrosine phosphatase (PTP enzyme) inhibitors, liver enzyme inhibitors involved in the stimulation of gluconeogenesis and/or glycogenosis, glucose uptake modulators, glycogen synthase kinase-3 (GSK-3) inhibitors, compounds that modulate lipid metabolism (e.g., antihyperlipidemic and antilipemic agents), peroxisome proliferator-activated receptor (PPAR) agonists or antagonists (in general), Retinoid X Receptor (RXR) agonists (e.g., ALRT-268, LG-1268, and LG-1069), and antihyperlipidemic or antilipemic agents (e.g., cholestyramine, colestipol, clofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, probucol, and dextrothyroxine).

Examples of antihypertensive agents that can be used with the compounds of the present invention include β -blockers (e.g., alprenolol, atenolol, timolol, pindolol, propranolol, and metoprolol), Angiotensin Converting Enzyme (ACE) inhibitors (e.g., benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril, and ramipril), calcium channel blockers (e.g., nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem, and verapamil), and α -blockers (e.g., doxazosin, urapidil, prazosin, and terazosin).

Examples of anti-inflammatory agents that may be used with the compounds of the present invention include antihistamines and anti-TNF α.

The medicaments described herein may be administered separately when used in combination (e.g., simultaneously or about simultaneously as two pills), which is convenient in the case of medicaments that are already commercially available in a single form. Alternatively, for combinations of drugs that can be taken simultaneously by the same route (e.g., orally), the drugs can be conveniently formulated in the same administration vehicle (e.g., a tablet, capsule, or other pill).

Thus, another aspect of the present invention relates to a pharmaceutical kit or pharmaceutical composition comprising any of the compounds or compositions according to the present invention or any combination thereof described herein and a second anti-obesity agent and/or an anti-diabetic agent. The pharmaceutical kit or composition may comprise a compound or composition according to the invention and a second anti-obesity agent and/or an anti-diabetic agent formulated as a single composition, e.g. a tablet or capsule.

In another embodiment, a pharmaceutical kit may comprise a compound or composition according to the invention and a second anti-obesity agent and/or anti-diabetic agent, formulated separately (e.g., each compound is a tablet, pill, or capsule) by instructions regarding, for example, the order, interval, and/or frequency of administration, to achieve the desired effect (e.g., reducing body weight and/or body fat, preventing the onset or development of excess body weight, reducing appetite and/or food intake, and/or preventing or treating obesity).

Thus, in addition to the above-described methods of treatment, the present invention also includes kits or pharmaceutical packs useful for carrying out the methods. Such kits may include a compound or composition according to the invention and instructions for using the agent in the methods described herein, optionally including one or more additional agents described herein.

One or more of the agents described herein may be administered in a single dose or in multiple doses. When multiple doses are administered, the doses may be spaced apart from each other, for example, by a few hours, a day, or a week. It is to be understood that for any particular patient, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering or instructing the administration of the composition. For example, treatment may be adjusted or stopped after a desired level of weight loss is achieved.

Another related aspect of the invention relates to methods of preventing and treating obesity and related syndromes comprising administering to a patient one or more compounds or compositions according to the invention described herein and one or more anti-obesity agents. The combined agents may be administered at or about the same time as each other, or at different times (5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 12 hours, 24 hours, or 48 hours apart). The inventive combination offers several advantages. For example, because the drug combinations described herein may be used to achieve an enhanced (e.g., increased or synergistic) effect, it may be contemplated that less of each drug may be administered, resulting in a patient having reduced overall exposure to the drug and any adverse side effects of any drug. In addition, greater disease control can be achieved because the drug can fight the disease through different mechanisms.

The compounds, compositions and methods according to the invention described herein may also be combined with other methods of weight loss and management, including methods involving changes in dietary or physical activity and surgical methods.

Administration of drugs

With respect to the treatment methods of the present invention, administration of a compound to a mammal is intended to be limited to a particular mode of administration, dose, or frequency of administration; the present invention encompasses all modes of administration, including oral, intraperitoneal, intramuscular, intravenous, intraarticular, intralesional, subcutaneous, inhalation, or any other route, sufficient to provide a dose sufficient to prevent or treat obesity and/or related syndromes. The one or more compounds may be administered to the mammal in a single dose or in multiple doses. When multiple doses are administered, the doses may be spaced apart from each other, for example, by a few hours, a day, or a week. It will be understood that for any particular patient, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering or instructing the administration of the composition. Exemplary mammals that can be treated using the compounds, compositions and methods of the present invention include humans, primates (e.g., monkeys), farming-related animals (e.g., cows, pigs, sheep, goats, buffalos and horses), and domesticated companion animals (e.g., dogs and cats). The compositions and compositions of the invention may also be administered to rodents (e.g., mice, rats, gerbils, hamsters, guinea pigs, and rabbits), for therapeutic purposes and/or for experimental purposes (e.g., to study the mechanism of action of the compounds, to screen and test the efficacy of the analogs, structural design, etc.).

For clinical use in therapy or prophylaxis, the analog or composition of the invention may generally be administered, for example, orally, subcutaneously, parenterally, intravenously, intramuscularly, colonically, nasally, intraperitoneally, rectally, by inhalation, or buccally. Compositions suitable for use in human or veterinary medicine containing at least one compound according to the invention may be presented in a form which allows administration by an appropriate route. These compositions may be prepared according to conventional methods using one or more pharmaceutically acceptable carriers or excipients. Such carriers include, but are not limited to, diluents, sterile aqueous media, and various non-toxic organic solvents. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in Remington: "The Science and practice of Pharmacy" (20 th edition), editions A.R. Gennaro, Lippincott Williams & Wilkins, 2000, Philadelphia and "Encyclopedia of pharmaceutical Technology", editions J.Swarbrick and J.C. Boylan, 1988. Okayasu 1999, Marcel Dekker, New York. The composition may be in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injections, elixirs or syrups, and may optionally contain one or more substances selected from the group consisting of sweetening agents, flavouring agents, colouring agents and stabilising agents, in order to obtain a pharmaceutically acceptable formulation.

The choice of carrier and the amount of active substance in the carrier will generally be determined by the solubility and chemical properties of the product, the particular mode of administration and the conditions found in pharmaceutical practice. For example, excipients (e.g., sodium citrate, calcium carbonate, and dicalcium phosphate) and disintegrants (e.g., starch, alginic acid, and certain complex silicic acids in combination with lubricants (e.g., magnesium stearate, sodium lauryl sulfate, and talc)) can be used to prepare tablets. For the preparation of capsules, it is advantageous to use high molecular weight polyethylene glycols. When an aqueous suspension is used, it may contain an emulsifier to facilitate suspension. Diluents such as ethanol, polyethylene glycol, propylene glycol, glycerol, chloroform or mixtures thereof may also be used. In addition, low-calorie sweeteners such as isomalt, sorbitol, xylitol may be used in the formulations of the present invention.

For parenteral administration, emulsions, suspensions or solutions of the compositions of the invention in a sterile aqueous solution of a vegetable oil (e.g., sesame, peanut or olive oil), an aqueous organic solution (e.g., water and propylene glycol), an injectable organic ester (e.g., ethyl oleate) or a pharmaceutically acceptable salt may be used. The salt solutions of the compositions of the present invention are particularly useful for administration by intramuscular or subcutaneous injection. An aqueous solution of pure distilled water containing the salt solution may be used for intravenous administration, provided that (i) its pH is appropriately adjusted, (ii) it is appropriately buffered and made isotonic with a sufficient amount of sodium chloride, and (iii) it is sterilized by heating, irradiation, or microfiltration. Suitable compositions containing the analogues of the invention may be dissolved or suspended in a suitable carrier for a spray or suspension or solution aerosol, or may be absorbed or adsorbed onto a suitable solid carrier for a dry powder inhaler. Solid compositions for rectal administration include suppositories formulated according to known methods.

A dose of a pharmaceutical composition contains at least a therapeutically effective amount of a compound according to the invention and preferably consists of one or more pharmaceutical dosage units. The selected dosage can be administered to a human patient in need of treatment. "therapeutically effective amount" is intended to mean the amount of an analog of the invention that, when administered to a patient for the treatment of a disease, has a therapeutic effect on the patient being treated. The therapeutic effect may be objective (i.e., measurable by some test or marker (e.g., weight loss)) or subjective (i.e., the patient produces an indication of the effect or feels the effect).

It will be understood that the amount corresponding to a "therapeutically effective amount" and the appropriate dosage and concentration of the substance in the formulation (i.e., the compound of the invention alone and/or in combination with other drugs) will vary depending upon a number of factors, including: the dosage of the agent to be administered, the route of administration, the nature of the agent, the frequency and manner of administration, the desired therapy, the form in which the agent is administered, the potency of the agent, the sex, age, weight and general condition of the patient to be treated, the nature and severity of the disease to be treated, any complications to be treated, the possibility of treating the disease with other substances, and other factors. However, a therapeutically effective amount can be readily determined by one skilled in the art.

For administration to mammals (particularly humans), it is contemplated that the dosage of each active compound that may be used in adult human therapy will be from about 0.1mg to about 50mg (e.g., from about 5mg to about 100mg, from about 1mg to about 50mg, or from about 5mg to about 25mg) per kg of body weight per day. For example, a typical oral dose may be administered in a range of about 50mg to about 5g (e.g., about 100mg to about 4g, 250mg to 3g, or 500mg to 2g) per day in one or more doses (e.g., 1 to 3 doses). The dosage can be increased or decreased as needed, as can be readily determined by one skilled in the art. For example, if determined to be appropriate, the amount of a particular substance may be reduced when used in combination with another substance. In addition, reference may be made to the standard amounts and methods mentioned herein for administering the substances. In any event, the physician will determine the actual dosage which will be most suitable for an individual.

With respect to administration, it is understood that: the duration of treatment with any compound or composition of the invention will vary depending on several factors, such as those listed herein before for administration. However, one skilled in the art can readily determine the appropriate duration of administration. According to certain embodiments, the compounds of the present invention are administered daily, weekly, or continuously.

The compounds and compositions of the present invention are expected to be primarily effective in the prevention and treatment of obesity and related syndromes. However, because it can affect fat distribution, it is contemplated that the compounds and compositions of the present invention may also be useful in diseases of fat/lipid metabolism including, but not limited to, lipodystrophy, atherosclerosis, and non-alcoholic fatty liver disease.

Examples

The invention is based, in part, on the experimental examples set forth in examples 1 through 11 below. These examples are given to enable those skilled in the art to more fully understand and practice the present invention, and are not intended to limit or restrict the scope thereof.

The examples set forth herein below provide exemplary syntheses of certain representative compounds of the invention. Exemplary methods for determining the effect of the compounds of the invention on body weight and related parameters are also provided. These examples are given to enable those skilled in the art to more fully understand and practice the present invention, and are not intended to limit or restrict the scope thereof.

Example 1: general procedure for the preparation of 4-hydroxyisoleucine isomers and analogs

A) General Experimental procedures

Referring to FIG. 24, a scheme for the synthesis of 8 different configurational isomers of 4-hydroxyisoleucine is shown. Referring to FIGS. 1 through 14, synthetic schemes for exemplary linear and cyclic analogs of 4-hydroxyisoleucine are shown.

FIG. 24 shows the synthesis scheme for 8 different configurational isomers of 4-hydroxyisoleucine (SRS, SRR, SSS, SSR, RSR, RSS, RRR and RRS). Imine intermediate 1 was prepared from p-anisidine and ethyl glyoxylate (Cordova et al, J.Am.chem.Soc.124: 1842-43, 2002). The reaction of imine 1 with 2-butanone in the presence of L-proline as catalyst (followed by silica gel chromatography) produced 2S,3S isomer 2 a. Epimerization at C-3 was achieved using 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN) to produce the 2S, 3R isomer 3 a. The (2S, 3R, 4S), (2S, 3R, 4R), (2S,3S, 4S) and (2S,3S, 4R) isomers of 4-hydroxyisoleucine were obtained from 2a or 3a as follows:

deprotection of the amine moiety of 3a using Cerium Ammonium Nitrate (CAN) (removal of p-methoxyphenyl) and subsequent use of KBH₄Reduction in water and concomitant cyclization provided lactone 11a, which was followed by alkaline hydrolysis using lithium hydroxide and recrystallization from absolute ethanol to yield pure (2S, 3R, 4S) -4-hydroxyisoleucine 14 a. Alternatively, deprotection of the amine moiety of 3a using CAN is followed by isolation of amine intermediate 6a, which is subsequently reduced using potassium borohydride in methanol to yield lactone intermediate 11 a', which is followed by basic hydrolysis using lithium hydroxide and recrystallization from ethanol to yield pure (2S, 3R, 4R) -4-hydroxyisoleucine (compound 15 a). Further purification of compound 15a was performed using preparative HPLC.

Similar reactions starting from compound 2a, using sodium borohydride instead of potassium borohydride for the preparation of lactone 9 a' from aminoketone 4a resulted in the isolation of (2S, 3S, 4S) 4-hydroxyisoleucine (compound 12a) and (2S, 3S, 4R) 4-hydroxyisoleucine (compound 13 a).

When compound 1 is reacted with 2-butanone in the presence of a catalytic amount of D-proline, compound 2aa is formed, which is the enantiomer of compound 2 a. As above, epimerization of C-3 of compound 2aa was achieved using 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN) to yield the 2R, 3S isomer 3 aa. The (2R, 3S, 4R), (2R, 3S, 4S), (2R, 3R, 4R) and (2R, 3R, 4S) isomers (compounds 14aa, 15aa, 12aa and 13aa, respectively) were obtained from compounds 2aa and 3aa by the same reaction sequence as used for the preparation of compounds 14a, 15a, 12a and 13 a.

Figure 1 shows the synthesis of various 4-hydroxyisoleucine analogs with SSS, SSR, SRS, and SRR configurations. Imine intermediate 1 was prepared from p-anisidine and ethyl glyoxylate (Cordova et al, J.Am.chem.Soc.124: 1842-43, 2002). Imine 1 is reacted with an appropriate ketone in the presence of L-proline (as catalyst) to produce the 2S, 3S isomer (2). Epimerization at C-3 is achieved using a base (e.g., 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN)) to produce the 2S, 3R isomer (3). (2S, 3S, 4S), (2S, 3S, 4R), (2S, 3R, 4S) and (2S, 3R, 4R) analogs of 4-hydroxyisoleucine were obtained from 2 or 3, respectively, as follows:

Deprotection of the amine moiety of 2 (removal of the p-methoxyphenyl group) using Cerium Ammonium Nitrate (CAN) to give 4, followed by hydrolysis yields (2S, 3S) -4-one analogs (5). Similarly, deprotection of 3 to yield 6, which upon base hydrolysis yields (2S, 3R) -4-one analog (7). Using NaBH₄Either raney nickel reduction 4 and 6 or deprotection/reduction 2 and 3 as a single step, yields a diastereomeric mixture of lactone (9 and 11) and open-chain intermediate (8 and 10), respectively. Hydrolysis (subsequent purification) of the mixture of 8 and 9 yields (2S, 3S, 4S) and (2S, 3S, 4R) analogs 12 and 13, respectively. Similarly, (2S, 3R, 4S) and (2S, 3R, 4R) analogs (i.e., 14 and 15) are obtained by hydrolysis of a mixture of compounds 10 and 11.

Analogues based on 3-substituted 4-hydroxyproline were synthesized as depicted in FIG. 2. 4-hydroxyproline methyl ester (16) was reacted with chlorotrimethylsilane, triethylamine followed by bromo-phenylfluorene/Pb (NO)₃)₂Reaction to produce the protected intermediate (17). Swern oxidation of 17 using oxalyl chloride and DMSO produced the key intermediate PhF-4-oxoproline methyl ester (18). C-3 alkylation of this intermediate produces various 3-substituted analogs. Monoalkylation of 18 was achieved using n-butyllithium as the base to produce compound 19, while bis-alkylation was performed using KHMDS as the base to produce compound 23. Reduction of the alkylated oxyproline intermediates (19 and 23) yields hydroxyl intermediates 20 and 24, respectively. The basic hydrolysis of 20 produces the acid (21), which, following catalytic hydrogenolysis, provides the desired 3-methyl analog (22). The corresponding dimethyl intermediate (24) was subjected to catalytic hydrogenolysis and in situ protection of Boc anhydride to yield Boc intermediate (25), which was subsequently deprotected and acid hydrolyzed to provide the desired 3-dimethyl analog (26). After alkylation of the key intermediate PhF-4-oxoproline methyl ester (18) with an aldehyde, the reaction sequence described above for the synthesis of Compound 22 (i.e., reduction, base hydrolysis and catalytic hydrogenation) yielded the 3-substituted analog 33 and 34。

As shown in fig. 3, Boc-proline methyl ester was alkylated with allyl bromide and LDA to produce N-Boc- α -allylproline methyl ester (35), which was subsequently converted to the free carboxylic acid by basic hydrolysis (36). N-Boc-alpha-allylproline is then reacted with m-chloroperbenzoic acid to produce the epoxy derivative (37). Removal of the Boc-protecting group using TFA, followed by several freeze-drying steps to remove excess TFA, yielded the desired α -epoxyethylmethyl-proline analog (38).

Figure 4 shows the synthetic route for compound 40. Propylene oxide was used to neutralize the L-proline hydrochloride. The exothermic reaction of propylene oxide with the acid salt results in further reaction of the epoxide with an amine moiety to produce the N-hydroxypropyl substituted amino acid (39). Basic hydrolysis of compound 39 produces the desired acid (40).

Similar reactivity of L-valine ethyl ester (66) (synthesized by reaction of L-valine with thionyl chloride in ethanol) with propylene oxide produced a mono-substituted amino acid (67) as well as a di-substituted amino acid (68) (FIG. 7). The desired N- (2-hydroxypropyl) -L-valine (69) was isolated after basic hydrolysis of the monosubstituted amino acid (67) (FIG. 7). A similar chemical reaction (shown in figure 9) describes a one-step synthesis of N- (2-hydroxypropyl) -L-phenylalanine (77). In this case, L-phenylalanine is used as follows: that is, the acid moiety is not protected as is the case with the ester of valine compound 69. Disubstituted compounds (78) are also found as by-products.

The analogs shown in figure 5 were prepared from the corresponding acids or ketones. For example, a cyclohexyl acid is converted to hydroxamate (41) by reaction with TBTU and N-methyl O-methylhydroxylamine. Hydroxamate (41) is then converted to ketone (43) by reaction with methyllithium. The cyclohexylmethyl ketone (43) is reacted with diethyloxalic acid to produce ethyl 4-cyclohexyl-2-hydroxy-4-oxo-but-2-enoate (47). Compound 47 is reacted with hydroxylamine to form oxazole intermediate (51). The basic hydrolysis of 51 to the acid (55) followed by hydrogenolysis using raney nickel yields the desired analog 2-amino-4-cyclohexyl-4-hydroxy-butanoic acid (59). The above chemical reaction is repeated using the corresponding acid and ketone to obtain analogs such as 2-amino-4-cyclopentyl-4-hydroxy-butyric acid (60), 2-amino-4-hydroxy-4-phenyl-butyric acid (61), and 2-amino-4-hydroxy-5, 5-dimethyl-hexanoic acid (62).

Dippeculine (dippecolic) intermediate (63) was prepared by condensation of α -methylbenzylamine with ethyl glyoxylate (fig. 6). And BH₃Hydroboration of THF yielded the protected form of 5-hydroxy-4-methyl-2-piperidinecarboxylic acid (64). Hydrolysis and catalytic hydrogenolysis resulted in the isolation of 5-hydroxy-4-methyl-2-piperidinecarboxylic acid (65).

The chirality of Boc-protected trans-4-hydroxyproline (71) was converted to compound 72 (FIG. 8) using Mitsunobu reaction conditions (Silverman et al, org. Lett.3: 2481-2484, 2001 and org. Lett.3: 2477, 2001). Hydrolysis of compounds 72 through 73 through 74 and removal of Boc from intermediate 74 using TFA/DCM yields the desired compound 75. The methyl ester derivative of compound 75, compound 76, is prepared by reacting compound 74 with sulfurous chloride in methanol.

Using Cs₂CO₃Protection of the amino acid moiety of (2S, 3R, 4S) -4-hydroxyisoleucine was achieved in one step as a base and BnBr in DMF/water mixture in good overall yield (fig. 10). The reaction mixture contains predominantly open-chain compound (79) and a quantity of the corresponding lactone (80). Oxidation (followed by hydrogenolysis) of the open chain intermediate (79) produces the desired 4-keto analog (82) in good yield. The Grinyard addition of methyl magnesium iodide to protected ketone intermediate (81) produced diphenyl lactone (83) in moderate yield. The lactone (84) is produced in good yield using formic acid and Pd — C catalyst reaction conditions or hydrogenolysis deprotection. Finally, hydrolysis of the lactone with LiOH provided the desired (2S, 3R) analog 85 in 90% isolated yield (fig. 10).

The analogs depicted in FIG. 11 were synthesized starting from the reaction of imine (1) with 1-bromo-3-methylbut-2-ene or 1-bromo-2-methylbut-2-ene to form condensation products 87 and 88, respectively. Removal of the PMP group was accomplished using iodosobenzene diacetate followed by protection with the in situ amino group of Boc anhydride to yield compounds 89 and 90, respectively. Hydrolysis of the ester moiety, followed by reaction with N-iodosuccinimide in DME, yields iodolactones (compounds 93 and 94). nbussnh and AIBN were used to remove the iodine function and subsequently the Boc group using TFA in dichloromethane, resulting in key lactone intermediates (compounds 97 and 98, respectively). Hydrolysis of compound 97 under basic conditions results in the separation of a mixture of enantiomers (SS and RR isomers) of compounds 99a and 99 b. Similarly, basic hydrolysis of compound 98 results in the separation of compounds 100a and 100b (again, enantiomeric mixture of SS and RR isomers) and compounds 101a and 101b (enantiomeric mixture of SS and RR isomers). Compounds 102a and 102b were obtained from compounds 92 and 91, respectively, by removal of the Boc group under acidic conditions.

Starting from (2S, 3R, 4S) -4-hydroxyisoleucine or its lactone form (103), the compound shown in figure 12 is obtained. Direct derivatization of the lactone (103) produces N-Ac (104), N-Bz (105), and N-Bn (106) derivatives. The N-tosylate (107a) and the N, N-xylenesulfonate (108a) are isolated from the reaction mixture involving the reaction of the lactone (103) with p-toluenesulfonyl chloride in dichloromethane in the presence of triethylamine. Basic hydrolysis of the mono-tosylated lactone (107a) yields the N-Ts derivative of (2S, 3R, 4S) -4-hydroxyisoleucine (111a), and similarly, reaction of compound 107a with pyrrolidine in dichloromethane yields the amide analog (112 a). Oxidation of amide (112a) using PCC yields the corresponding 4-keto derivative (113 a). Reaction of o-nitrobenzenesulfonyl chloride with lactone (103) yields the N-Ns derivative (109), which is then further reacted with pyrrolidine in dichloromethane in the presence of triethylamine to yield the corresponding N-Ns amide analog (110).

Surprisingly, the reaction of the lactone (103) with pyrrolidine in dichloromethane produces¹Compounds showing additional methylene signal in H NMR. It is deduced that where N and O are in addition to-CH₂-a group bridged compound, namely amide (116). In this case, the-CH is inferred ₂It seems reasonable that the group is a solvent, i.e. dichloromethane with saidAnd (5) carrying out intermediate reaction. It also seems reasonable to suggest a lactone ring opening to form an amide intermediate with pyrrolidine (pyrollidine) followed by reaction of N and O of said intermediate with dichloromethane to afford compound 116. The bridged amide (116) is methanesulfonic acid and benzylated to give the corresponding derivatives 117 and 118. The reaction of (2S, 3R, 4S) -4-hydroxyisoleucine with CbzCl produces Cbz-lactone (114) in near quantitative yield, which is further subsequently reacted with pyrrolidine to produce the substituted amide (115). Purification of the reaction mixture from the reaction of (2S, 3R, 4S) -4-hydroxyisoleucine with ethyl bromoacetate in a TBME/water mixture resulted in the isolation of the mono-substituted diacid (121a) and the di-substituted triacid (121 b). The N, N-diphenyl derivative of (2S, 3R, 4S) -4-hydroxyisoleucine (123) is obtained by hydrolysis of the corresponding lactone (122), which is prepared in two steps in turn from (2S, 3R, 4S) -4-hydroxyisoleucine.

FIG. 13 depicts the enantioselective synthesis of SS (128) and SR (133) derivatives. A diastereomeric mixture of these two compounds (compound 69) was synthesized using a different method and is shown in fig. 7. (S) -Ethyl lactate (124) is reacted with DHP to produce a THP-protected intermediate (124), which is also converted to aldehyde (126) using DIBAL. The key transformation, reductive amination of aldehyde (126) with L-valine methyl hydrochloride and sodium cyanoborohydride yields the protective compound (127). The ester moiety is base hydrolyzed to the acid and the acid removes the THP group, yielding the desired SS-isomer (128) in excellent overall yield. The above reaction sequence was repeated using (R) -ethyl lactate to obtain SR-isomer (133), which was also excellent in isolated yield.

Figure 14 depicts the synthesis of two diastereomers of (2S, 3R, 4S) -4-hydroxyisoleucine and the analog (12b and 13 b). Mannich condensation of imine (1) with 2-pentanone in the presence of L-proline gives the desired SS-keto intermediate (134). The PMP group was removed using cerium ammonium nitrate followed by reaction with sodium borohydride in methanol to yield the lactone (136) as a mixture of two diastereomers. Basic hydrolysis and purification of the lactone provides the SSS-isomer (12b) and the SSR-isomer (13 b).

B) Specific experimental procedures

Specific reaction conditions used in the preparation of compounds 1 to 136 are as follows:

synthesis of Compound 1

To a stirred toluene solution (400mL) of p-anisidine (50g, 406mmol) in a 1-liter round-bottomed flask was added sodium sulfate (200g, 2.5 equivalents). Ethyl glyoxylate (82mL, 50% in toluene, 406mmol) was slowly added to the above reaction mixture and the mixture was stirred for 30 minutes. After this time, the sodium sulfate was filtered off using celite (celite), and the toluene was removed under reduced pressure. After drying, Compound 1(80g, 95%) was isolated and used for the next reaction.

General procedure for the asymmetric condensation of ketones with imines (1)

Imine 1(1 equivalent) was added dropwise to a mixture of ketone (22 equivalents) and L-proline (0.35 equivalents) in dry DMSO (40ml) at room temperature under nitrogen, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with phosphate buffer (pH7.4), followed by extraction with ethyl acetate (3X 200 mL). The organic phases were combined, MgSO ₄Dried and concentrated under reduced pressure. The desired compound (2) was isolated after purification by silica gel column chromatography. In a few cases, excess ketone was removed under reduced pressure or by silica gel column chromatography.

General procedure for preparation of 4-hydroxyisoleucine isomers

Specific reaction conditions used in the preparation of the compounds 2a to 15a and 2aa to 15aa are as follows.¹H and¹³c NMR spectrum was D₂Of O solution and using methanol (C)¹H is delta 3.34, and¹³c is δ 49.50) as an internal standard in ppm to indicate chemical shift.

Synthesis of Compound 2a

A mixture of 2-butanone (800mL, 22eq) and L-proline (15.8g, 0.35eq) was stirred at room temperature under nitrogen in dry DMF (600 mL). To the reactionThe mixture was slowly added dry DMF (200mL) and Et of Compound 1₃N (22.4ml, 0.40eq) solution. After stirring the reaction mixture at room temperature for 8 hours, the L-proline was filtered off, the excess 2-butanone was removed under reduced pressure and the DMF was removed in vacuo at 50 ℃. By column chromatography (SiO)₂85:15 Hexane/EtOAc) was purified.

Synthesis of Compound 3a

Compound 2a was dissolved in t-BuOMe (15mL) and 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN) (1mL, 0.04eq) was added to the stirred reaction mixture. The reaction mixture was stirred under nitrogen for 2 h. After evaporation of the solvent at room temperature overnight a solid mass was obtained, which was followed by recrystallization from hot ethanol to yield compound 3a (48g, 43% yield).

Synthesis of (2S, 3R, 4S) -4-hydroxyisoleucine (Compound 14a)

To compound 3a (11.6g, 40mmol) in CH was added with stirring at 0 deg.C₃To CN solution (20mL) was added cerium (IV) ammonium nitrate (CAN) (65.6g, 3eq) in water (120 mL). After CAN addition, the color gradually changed from blue to green. The reaction mixture was stirred for 2.5 hours and the progress of the reaction was followed by TLC analysis. After completion, the reaction mixture was extracted with EtOAc (4X 150mL) and the aqueous phase was used for the next step.

The aqueous phase is saturated Na₂CO₃Neutralized to pH7 and cooled to-15 ℃ and stirred. After cooling for 30 min, KBH4(3.2g, 60mmol, 1.5eq) was added to the reaction mixture. The reaction mixture was heated to 0 ℃ for 45 minutes and followed by TLC. Then 2N Na was used₂CO₃The reaction mixture was made basic to pH8-9 and treated with CH₂Cl₂(5X 400 mL). The organic phase is washed with water and Na₂SO₄Dried and evaporated under reduced pressure to give a 90: 10 mixture of lactones (compound 11a (3S, 4R, 5S) and compound 11 a' (3S, 4R, 5R); 3.73g, 62.6%).

To the 90: 10 aqueous lactone mixture (96mL, 0)3M) LiOH (1.1g, 43.3mmol, 1.5eq) was added and the mixture was stirred at room temperature for 2 h. After the reaction was complete, it was acidified by careful addition of AcOH (43.3mmol, 2.4 mL). The reaction mixture was concentrated under reduced pressure and the last traces of water were removed by repeated addition and removal of ethanol. The crude product was crystallized from anhydrous EtOH to yield 1.56g of 98% pure (2S, 3R, 4S) 4-hydroxyisoleucine (compound 14 a). Compound 14a, which yields a white shiny powder, is further purified by preparative HPLC: mp215-222 (subl.); [ alpha ] to ]_D ^H2O+30.7(C，1)；¹H NMR(200MHz)δ3.90(m，¹H)，3.84(m，¹H)，1.91(m，¹H)，1.23(d，J＝5.6Hz，3H)0.95(d，J＝6.6Hz，3H)；¹³CNMR(75MHz)δ174.32，70.46，57.54，41.90，21.30，12.70。

Synthesis of (2S, 3R, 4R) -4-hydroxyisoleucine (Compound 15a)

To compound 3a (11.6g, 40mmol) in CH was added with stirring at 0 deg.C₃To CN solution (20mL) was added Cerium Ammonium Nitrate (CAN) (65.6g, 3eq) in water (120 mL). After CAN addition, the color gradually changed from blue to green. The reaction mixture was stirred for 45 minutes and the progress of the reaction was followed by TLC. After completion, the reaction mixture was extracted with EtOAc (4X 150mL) and the aqueous phase was taken with saturated Na₂CO₃The solution was carefully neutralized to a slightly alkaline pH (. about.8). Using CH₂Cl₂(4X 150mL) the aqueous phase was extracted and the organic extracts combined, washed with brine, anhydrous Na₂SO₄Dried and concentrated under reduced pressure to yield 5.52g (79.7%) of compound 6a as a brown oil.

To a solution of compound 6a in methanol (15mL) cooled to 0 deg.C was added KBH quickly₄(2.58g, 47.8 mmol). The reaction mixture was stirred at 0 ℃ for 45 minutes and then gradually warmed to room temperature. The solvent was removed in vacuo and the mixture was diluted with water. Using CH₂Cl₂The aqueous phase was extracted (4X 150 mL). The organic phase was washed with brine and anhydrous Na₂SO₄Dried and evaporated in vacuo to yield 75: 2 of compound 11 a' (3S, 4R, 5R) to compound 11a (3S, 4R, 5S)5 mixture (2.9g, 70.2%).

Compound 11 a'/aqueous solution of compound 11a (100mL) was treated with LiOH (805mg, 33.7mmol) and stirred at room temperature for 1 h, after which it was carefully acidified with AcOH (1.91mL, 33.72 mmol). After concentration under reduced pressure, trace amounts of water were removed by repeated addition and removal of absolute ethanol. Crude off-white solid was obtained from a 90% cold ethanol solution. Further recrystallization from 90% ethanol yielded 1.4g of compound 15a to compound 14a in a 75: 25 diastereoisomeric ratio. Repeated recrystallization increased the purity of compound 15a to 90% and further purified using preparative HPLC to yield pure (2S, 3R, 4R) 4-hydroxyisoleucine (compound 15a) as a white lustrous material: mp202-204 ℃ (subl.); [ alpha ] to ]_D ^H2O-21.6(c，0.5)；¹H-NMR(300MHz)54.05(m，1H)，3.80(d，J＝4.2Hz，1H)，2.13(m，1H)1.20(d，J＝6.3Hz，3H)，1.05(d，J＝7.2Hz，3H)；¹³C NMR(75MHz)δ174.49，69.13，59.97，39.12，20.71，9.38。

Synthesis of (2S, 3S, 4S) -4-hydroxyisoleucine (Compound 12a)

Compound 2a (5.6g, 20mmol) was dissolved in acetonitrile (10mL), and an aqueous solution (60mL) of Cerium Ammonium Nitrate (CAN) (33g, 60mmol) was added with stirring at 0 ℃. After CAN addition, the color gradually changed from blue to green. The reaction mixture was stirred for 45 minutes and extracted with ethyl acetate (4X 150 mL). The water phase is saturated Na₂CO₃Neutralize and carefully adjust pH to 7. After cooling the reaction mixture to-15 ℃ for 90 minutes, KBH was added₄(1.6g, 60mmol, 1.5 eq). The reaction mixture was warmed to 0 ℃ for 45 minutes and then 2N Na was used₂CO₃Treatment to pH8-9 followed by CH₂Cl₂(5X 400 mL). Washing the organic phase with water and anhydrous Na₂SO₄Dried and evaporated under reduced pressure to give 1.42g of a 75: 25 mixture of lactones (compound 9a (3S, 4S, 5S) and compound 9 a' (3S, 4S, 5R)).

To the lactone mixture in water (35mL) was added LiOH (395mg, 16.5)mmol, 1.5eq) and the mixture was stirred at room temperature for 2 hours. After this time, the reaction mixture was carefully acidified with AcOH (16.5mmol, 0.9 mL). The solvent was removed under vacuum, and repeated addition and removal of absolute ethanol resulted in complete removal of water. The crude product obtained was dissolved in 90% EtOH and left overnight. The isolated white solid was filtered, washed several times with EtOH, and recrystallized from 90% EtOH to obtain white crystals of (2S, 3S, 4S) -4-hydroxyisoleucine (compound 12a, 500 mg). Further purification using preparative HPLC formed a pure lustrous material: mp253-255 ℃; [ alpha ] to ]_D ^H2O+28(c，0.25)；¹H NMR(300MHz)54.11(m，1H)，3.87(d，J＝2.7Hz，1H)，2.21(m，1H)，1.23(d，J＝6.3Hz，3H)，0.92(d，J＝7.5Hz，3H)；¹³C NMR(75MHz)δ174.64，71.39，60.39，38.97，21.11，6.19。

Synthesis of (2S, 3S, 4R) -4-hydroxyisoleucine (Compound 13a)

To a solution of compound 2a (11.6g, 40mmol) in acetonitrile (20mL) was added an aqueous solution of cerium (IV) ammonium nitrate (CAN) (65.6g, 120mmol) (120mL) with stirring at 0 ℃. After the addition of CAN, the reaction mixture gradually changed in color from blue to green. The reaction mixture was stirred for 45 minutes and extracted with ethyl acetate (4X 150 mL). The water phase is saturated Na₂CO₃The solution was carefully neutralized to pH8, followed by CH₂Cl₂(4X 150 mL). The combined organic extracts were washed with brine, anhydrous Na₂SO₄Dried above and concentrated under reduced pressure to yield 4g of compound 4a as a brown oil.

To a 0 ℃ solution of compound 4a in MeOH (15mL) was added NaBH quickly₄(962mg, 1.1eq, 25.43 mmol). The reaction mixture was stirred vigorously at 0 ℃ for 45 minutes and then gradually warmed to room temperature. The solvent was removed under reduced pressure and the residue was diluted with water and CH was used₂Cl₂The aqueous phase was extracted (4X 150 mL). The combined organic phases were washed with brine, anhydrous Na₂SO₄Dried and evaporated in vacuo to yield 2g of a mixture of compound 9 a' (3S, 4S, 5R) and compound 9a (3S, 4S, 5S)A compound (I) is provided.

The mixture was dissolved in water (40mL) and LiOH (556.9mg, 18.6mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and carefully acidified with AcOH (1.31 mL). The solvent was removed under vacuum. The crude product was dissolved in a minimal amount of water and the compound was loaded onto a bed using dowex 50 w.times.8 (H) ⁺) Resin (50g) packed column. The column was first eluted with water (4X 50mL) and then 2M NH₄OH elution collects fractions. The isolated product was dissolved in 90% EtOH and left overnight. The isolated solid (250mg) was filtered, washed with cold EtOH, and recrystallized from 90% EtOH to obtain a mixture of diastereomers.

The diastereomeric mixture of compounds 12a and 13a was purified by preparative HPLC to yield (2S, 3S, 4R) 4-hydroxyisoleucine (compound 13a) as a white, lustrous powder: mp173-175 ℃; [ alpha ] to]_D ^H2O+6.0(c，0.25)；¹H NMR(300MHz)δ4.02(d，J＝3Hz，1H)，3.81(m，1H)，2.12(m，1H)1.28(d，J＝6.6Hz，3H)，0.97(d，J＝7.2Hz，3H)；¹³C NMR(75MHz)δ174.93，70.18，56.34，40.46，21.24，12.15。

(2R, 3S, 4R) -4-Hydroxyisoleucine (Compound 14aa), (2R, 3S, 4S) -4-Hydroxyisoleucinem Acid (Compound 15aa), (2R, 3R, 4R) -4-hydroxyisoleucine (Compound 12aa), and synthesis of (2R, 3R, 4S) -4-hydroxyisoleucine (Compound 13aa)

The experimental procedures used for the synthesis of compounds 14aa, 15aa, 12aa and 13aa are the same as those used for compounds 14a, 15a, 12a and 13a except that compound 1 is reacted with 2-butanone in the presence of D-proline to produce compound 2aa (the enantiomer of compound 2 a). Physical and NMR data for compounds 14aa, 15aa, 12aa and 13aa are as follows:

(2R, 3S, 4R) -4-Hydroxyisoleucine (Compound 14aa)：mp217-225℃(subl.)，[α]_D ^H2O-31(c，1)；¹H NMR(200MHz)53.89(m，1H)，3.84(m，1H)，1.90(m，1H)1.23(d，J＝6.4Hz，3H)，0.95(d，J＝7Hz，3H)；¹³C NMR(50MHz)δ174.36，70.43，57.51，41.91，21.30，12.6。

(2R.3S, 4S) -4-hydroxyisoleucine (Compound 15aa) ：mp200-204℃(subl.)；[α]_D ^H2O+22(C，0.5)；¹H NMR(200MHz)54.04(m，1H)，3.80(m，1H)，2.12(m，1H)，1.19(d，J＝6.2Hz，3H)1.05(d，J＝7.2Hz，3H)；¹³C NMR(50MHz)δ174.55，69.12，59.97，39.12，20.73，9.40。

(2R, 3R, 4R) -4-Hydroxyisoleucine (Compound 12aa)：mp 250-254℃；[α]_D ^H2O-30(c，0.25)；¹H-NMR(200 MHz)54.10(m，1H)，3.87(d，J＝2.6Hz 1H)，2.23(m，1H)1.23(d，J＝6.6Hz，3H)，0.92(d，J＝7.2Hz，3H)；¹³C NMR(50MHz)δ174.64，71.29，60.35，38.96，21.12，6.22。

(2R, 3R, 4S) -4-Hydroxyisoleucine (Compound 13aa)：mp173℃；[α]_D ^H2O-5.6(c，0.25)；¹H NMR(300MHz)54.01(d，J＝2.7Hz，1H)，3.80(m，1H)，2.11(m，1H)1.27(d，J＝6.3Hz，3H)，0.97(d，J＝7.2Hz，3H)；¹³C NMR(75MHz)δ174.96，70.18，56.35，40.44，21.23，12.10。

General procedure for Synthesis of exemplary Linear and Cyclic analogs of 4-hydroxyisoleucine

General procedure for isomerization of Mannich condensation product (2)

To a solution of the (2S, 3S) isomer (2) in the minimum amount of solvent was added 0.4 equivalents of DBN (1, 4-diazabicyclo [4.3.0] non-5-ene) and the mixture was stirred overnight at room temperature in an open flask. The solvent was evaporated by blowing a stream of argon over the reaction mixture. The crude mixture is again dissolved in the minimum amount of solvent and the procedure is repeated several times until the ratio of the two diastereomers remains unchanged. The solvent was evaporated under reduced pressure and the residue was purified using high resolution silica gel chromatography to obtain predominantly the (2S, 3R) diastereomer.

The following compounds were prepared using the general procedure described above.

Synthesis of (2S, 3S) -ethyl 2- (4-methoxyphenylamino) -3-methyl-4-oxo-hexanoate (2b)

2 b: yellow oil (72%).¹H NMR(CDCl₃，300MHz)：δ1.04(t，3J(H₈，H₇)＝7.2Hz，3H，H₈)，1.21(t，3J(H₁，H₂)＝7.2Hz，3H，H1)，1.24(d，3J(H₉，H₅)＝7.2Hz，3H，H₉)，2.55(q，3J(H₇，H₈)＝7.2Hz 2H，H₇)，3.03(m，1H，H₅)，3.73(s，3H，H₁₇)，3.90(brs，1H，H₁₀)，4，15(q，3J(H₂，H₁)＝7.2Hz，1H，H₂)，4.30(m，1H，H₄)；6.63-6.66(d，3J(H₁₂，H₁₃)＝9.1Hz，2H，H₁₂，H₁₆)，6.75-6.78(d，3J(H₁₂，H₁₃)＝9.1Hz，2H，H₁₃，H₁₅)。¹³C NMR(CDCl₃，75MHz)：δ7.53(C₈)，12.51(C₉)，14.08(C₁)，34.32(C₇)，48.37(C₅)，55.59(C₁₇)，59.65(C₄)，61.43(C₂)，114.71，115.61(C₁₂，C₁₃，C₁₅，C₁₆)，140.76(C₁₁)，152.96(C₁₄)，172.85(C₃)，211.81(C₆)。MSm/z：294(M+1)，316(M+23)。

Synthesis of (2S, 3R) -ethyl 2- (4-methoxyphenylamino) -3-methyl-4-oxo-hexanoic acid ester (3b)

3 b: yellow oil (60%).¹H NMR(CDCl₃，300MHz)：δ1.06(t，3J(H₈，H₇)＝7.2Hz，3H，H₈)，1.22(m，6H，H₁，H₉)，2.55(q，3J(H₇，H₈)＝7.2Hz 2H，H₇)，3.03(m，1H，H₅)，3.73(s，3H，H₁₇)，3.90(brs，1H，H₁₀)，4.15(q，3J(H₂，H₁)＝7.2Hz，1H，H₂)，4.26(m，1H，H₄)，6.63-6.66(d，3J(H₁₂，H₁₃)＝9.1Hz，2H，H₁₂，H₁₆)，6.75-6.78(d，3J(H₁₂，H₁₃)＝9.1Hz，2H，H₁₃，H₁₅)。¹³C NMR(CDCl₃，75MHz)：δ7.46(C₈)，13.22(C₉)，14.08(C₁)，34.94(C₇)，48.29(C₅)，55.59(C₁₇)，60.69(C₄)，61.07(C₂)，114.71，115.77(C₁₂，C₁₃，C₁₅，C₁₆)，140.70(C₁₁)，153.03(C₁₄)，172.68(C₃)，212.10(C₆)。MSm/z：294(M+1)，316(M+23)。

Synthesis of (S) -ethyl 2- (4-methoxyphenyl-amino) -2- ((S) -2-oxo-cyclohexyl) -acetate (2e)

2 e: brown oil (85%).¹H NMR(CDCl₃，200MHz)：δ1.21(t，3J(H₁，H₂)＝7.2Hz，3H，H₁)，1.65-2.49(m，8H，H₇，H₈，H₉，H₁₀)，2.81(m，1H，H₅)，3.74(s，3H，H₁₈)，3.87(brs，1H，H₁₁)，4.14(q，3J(H₂，H₁)＝7.2Hz，1H，H₂)，4.23(d，3J(H₄，H₅)＝5.3Hz，1H，H₄)，6.70-6.73(d，3J(H₁₃，H₁₄)＝9.2Hz，2H，H₁₃，H₁₇)，6.75-6.78(d，3J(H₁₂，H₁₃)＝9.2Hz，2H，H₁₄，H₁₆)。¹³C NMR(CDCl₃，75 MHz)：δ14.08(C₁)，24.71(C₈)，26.81(C₉)，29.54(C₁₀)，41.78(C₇)，53.50(C₅)，55.64(C₁₈)，58.05(C₄)，61.08(C₂)；114.70，116.01(C₁₃，C₁₄，C₁₆，C₁₇)，141.08(C₁₂)，152.99(C₁₅)，173.40(C₃)，210.02(C₆)。MS(IC)m/z：306(M+1)。

Synthesis of (S) -ethyl 2- (4-methoxyphenyl-amino) -2- ((R) -2-oxo-cyclohexyl) -acetate (3e)

3 e: orange oil (60%, 98% purity).¹H NMR(CDCl₃，300MHz)：δ1.22(t，3J(H₁，H₂)＝7.2Hz，3H，H₁)，1.65-2.49(m，8H，H₇，H₈，H₉，H₁₀)，3.11(m，1H，H₅)，3.74(S，3H，H₁₈)，3.99(d，3J(H₄，H₅)＝3.7Hz，1H，H₄)，4.15(q，3J(H₂，H₁)＝7.2Hz，1H，H₂)，4.24(brs，1H，H₁₁)，6.62-6.65(d，3J(H₁₃，H₁₄)＝8.7Hz，2H，H₁₃，H₁₇)，6.75-6.78(d，3J(H₁₂，H₁₃)＝8.7Hz，2H，H₁₄，H₁₆).¹³CNMR(CDCl₃，75MHz)：δ14.04(C₁)，24.47(C₈)，26.77(C₉)，30.45(C₁₀)，41.73(C₇)，53.51(C₅)，55.61(C₁₈)，58.99(C₄)，61.09(C₂)，114.67，115.53(C₁₃，C₁₄，C₁₆，C₁₇)，142.09(C₁₂)，152.69(C₁₅)，172.97(C₃)，210.87(C₆)。MS(IC)m/z：306(M+1)。

Synthesis of (S) -ethyl 2- (4-methoxyphenyl amino) 2- ((S) -2-oxo-cyclohexyl) -acetate (2f)

2 f: a yellow solid recrystallized from ethyl acetate (65%).¹H NMR(CDCl₃，200MHz)：1.20(t，3J(H₁，H₂)＝7.1Hz，3H，H₁)，1.31-2.02(m，8H，H₈，H₉，H₁₀，H₁₁)，2.52(m，2H，H₇)，2.92(m，1H，H₅)，3.73(s，3H，H₁₉)，3.92(brs，1H，H₁₂)，4.13(q，3J(H₂，H₁)＝7，1Hz，1H，H₂)，4.26(d，3J(H₄，H₅)＝5.9Hz，1H，H₄)，6.64-6.68(d，3J(H₁₄，H₁₅)＝9Hz，2H，H₁₄，H₁₈)，6.73-6.78(d，3J(H₁₄，H₁₅)＝9Hz，2H，H₁₅，H₁₇)。¹³C NMR(CDCl₃，75MHz)：δ14.11(C₁)，24.71，27.12，29.22，29.80(C₈，C₉，C₁₀，C₁₁)，43.86(C₇)，55.16(C₅)，55.64(C₁₉)，60.62(C₄)，61.17(C₂)，114.72，115.99(C₁₄.C₁₅.C₁₇.C₁₈)，140.93(C₁₃)，153.05(C₁₆)，173.14(C₃)，214.34(C₆)。MS(E)m/z：342(M+23)。

Synthesis of (S) -ethyl 2- (4-methoxyphenyl amino) -2- ((R) -2-oxo-cycloheptyl) -acetate (3f)

3 f: yellow oil (99% purity).¹H NMR(CDCl₃，300MHz)：δ1.23(t，3J(H₁，H₂)＝7.2Hz，3H，H₁)，1.32-2.03(m，8H，H₈，H₉，H₁₀，H₁₁)，2.54(m，2H，H7)，3.03(m，1H，H₅)，3.73(s，3H，H₁₉)，4.16(q，3J(H₂，H₁)＝7.2Hz，1H，H₂)，4.29(brs，1H，H₁₂)，4.31(d，3J(H₄，H₅)＝4.7Hz，1H，H₄)，6.66-6.69(d，3J(H₁₄，H₁₅)＝9.1Hz，2H，H₁₄，H₁₈)，6.76-6.80(d，3J(H₁₄，H₁₅)＝9.1Hz，2H，H₁₅，H₁₇)。¹³CNMR(CDCl₃，75MHz)：δ14.09(C₁)，24.15，27.11，28.94，29.82(C₈，C₉，C₁₀，C₁₁)，43.80(C₇)，54.29(C₅)，55.62(C₁₉)，60.60(C₄)，61.21(C₂)，114.79，115.15(C₁₄.C₁₅.C₁₇.C₁₈)，140.92(C13)，152.66(C₁₆)，172.50(C₃)，214.09(C₆)。MS(E)m/z：342(M+23)。

Synthesis of (2S, 3S) -ethyl 2- (4-methoxyphenylamino) -4-methyl-3-phenylpentanoate (2c)

2 c: a yellow solid recrystallized from hexane ether (75%).¹H NMR(CDCl₃，200MHz)：δ1.25(t，3J(H₁，H₂)＝7.1Hz，3H，H₁)，2.15(s，3H，H₇)，3.51(brs，1H，H₁₄)，3.74(s，3H，H₂₁)，4.19(q，3J(H₂，H₁)＝7.1Hz，1H，H₂)，4.25(d，3J(H₄，H₅)＝8.5Hz，1H，H₄)，4.64(d，3J(H₅，H₄)＝8.5Hz1 1H，H₅)，6.58-6.62(d，3J(H₁₆，H₁₇)＝9Hz，2H，H₁₆，H₂₀)，6.70-6.74(d.3J(H₁₆，H₁₇)＝9Hz，2H，H₁₇，H₁₉)，7.24-7.37(m，5H，H₉，H₁₀，H₁₁，H₁₂，H₁₃)。¹³C(CDCl₃.75MHz)：δ14.09(C₁)，29.19(C₇)，55.60(C21)，59.78(C₅)61.29(C₂)，61.53(C₄)，114.49，116.12(C₁₆，C₁₇，C₁₉，C₂₀)，128.12(C₁₁)，129.04.129.19(C₉，C₁₀，C₁₂，C₁₃)，134.34(C₈)，140.61(C₁₅)，153.01(C₁₈)，173.22(C₃)，206.09(C₆)。MS(E)m/z：364(M+23)。

Synthesis of (2S, 3R) -ethyl 2- (4-methoxyphenylamino) -4-methyl-3-phenylpentanoate (3c)

3 c: yellow oil (90% purity).¹H NMR(CDCl₃，300MHz)：δ0.88(t，3J(H₁，H₂)＝7.1Hz，3H，H₁)，2.17(s，3H，H₇)，3.74(s，3H，H₂₁)，3.78(brs，1H，H₁₄)，3.84(q，3J(H₂，H₁)＝7.1Hz，1H，H₂)，4.11(d，3J(H₄，H₅)＝8.7Hz，1H，H₄)，4.55(d，3J(H₅，H₄)＝8.7Hz，1H，H₅)，6.65-6.68(d，3J(H₁₆，H₁₇)＝9Hz，2H，H₁₆，H₂₀)，6.72-6.75(d，3J(H₁₆，H₁₇)＝9Hz，2H，H₁₇，H₁₉)，7.32(brs，5H，H₉，H₁₀，H₁₁，H₁₂，H₁₃)。¹³C NMR(CDCl₃，75MHz)：δ13.31(C₁)，29.53(C₇)，55.11(C₂₁)，60.40(C₂)61.07，61.77(C₄，C₅)，114.30，116.19(C₁₆，C₁₇，C₁₉，C₂₀)，127.77(C₁₁)，128.63，128.92(C₉，C₁₀，C₁₂，C₁₃)，133.82(C₈)，140.70(C₁₅)，152.96(C₁₈)，172.54(C₃)，205.21(C₆)。MS(E)m/z：364(M+23)。

Synthesis of (2S, 3S) -ethyl 3-phenyl-2- (4-methoxyphenylamino) -4-oxopentanoate ester (2d)

2 d: yellow solid (60%).¹HNMR(CDCl₃，300MHz)：δ1.26(t，3J(H₁，H₂)＝7.1Hz，3H，H₁)，2.04(s，3H，H₇)，3.09(m，2H，H₈)，3.34(m，1H，H₅)，3.75(s，3H，H₂₂)，4.08(brs，1H，H₁₅)，4.18(q，3J(H₂，H₁)＝7.1Hz，1H，H₂)，4.19(m，1H，H₄)，6.49-6.52(d，3J(H₁₇，H₁₈)＝9Hz，2H，H₁₇，H₂₁)，6.73-6.76(d，3J(H₁₇，H₁₈)＝9Hz，2H，H₁₈，H₂₀)，7.24-7.37(m，5H，H₉，H₁₀，H₁₁，H₁₂，H₁₃)。¹³C(CDCl₃，75MHz)：δ14.14(C₁)，30.98(C₇)，34.67(C₈)，55.68(C₂₂)，57.02(C₅)，58.41(C₄)，61.52(C₂)，114.81，115.32(C₁₇，C₁₈，C₂₀，C₂₁)，126.69(C₁₂)，128.64，129.05(C₁₀，C₁₁，C₁₃，C₁₄)，138.66(C₉)，140.35(C₁₆)，152.93(C₂₂)，172.52(C₃)，209.36(C₆)。MS(E)m/z：356(M+1)，378(M+23)。

Synthesis of (2S, 3R) -ethyl 3-phenyl-2- (4-methoxyphenyl amino) -4-oxopentanoate (3d)

3 d: yellow oil (99% purity).¹H NMR(CDCl₃，300MHz)：δ1.20(t，3J(H₁，H₂)＝7.2Hz，3H，H₁)，2.08(s，3H，H₇)，2.98(m，2H，H₈)，3.43(m，1H，H₅)，3.74(s，3H，H₂₂)，4.13(m，3H，H₂，H₄)，4.45(brs，1H，H₁₅)，6.58-6.61(d，3J(H₁₇，H₁₈)＝8.8Hz，2H，H₁₇，H₂₁)，6.76-6.79(d，3J(H₁₇，H₁₈)＝8.8Hz，2H，H₁₈，H₂₀)，7.17-7.30(m，5H，H₉，H₁₀，H₁₁，H₁₂，H₁₃)。¹³C NMR(CDCl₃，75MHz)：δ13.93(C₁)，31.01(C₇)，34.53(C₈)，55.33(C₂₂)，55.67(C₅)，58.79(C₄)，60.99(C₂)，114.48，115.47(C₁₇，C₁₈，C₂₀，C₂₁)，126.49(C₁₂)，128.46，128.79(C₁₀，C₁₁，C₁₃，C₁₄)，138.02(C₉)，140.70(C₁₆)，152.73(C₂₂)，172.75(C₃)，209.77(C₆)。MS(E)m/z：356(M+1)，378(M+23)。

Para-methoxybenzene obtained by deprotecting gamma-oxygen-alpha- (4-methoxyphenyl amino) ester with Cerium Ammonium Nitrate (CAN) General procedure for the (PMP) group

To the gamma-oxo-alpha- (4-methoxyphenylamino) ester (10mmol) in CH at 0 deg.C ₃CN (6mL.) solution cerium ammonium nitrate (CAN, 3 equivalents) in water (60mL) was added dropwise rapidly with stirring. The reaction mixture was stirred at 0 ℃ for 45 minutes. CH (CH)₂Cl₂(60mL) was added to the reaction mixture and the phases were separated. The organic phase was washed with 0.1N aqueous HCl (60 mL). Combining the aqueous phases and using CH₂Cl₂(3X 130mL) and extracted with Na₂CO₃Basification of the aqueous phase to pH7 with solution (2N) and another application of CH₂Cl₂(3X 150 mL). The combined organic phases were over MgSO₄Dried and concentrated under reduced pressure to obtain the gamma-oxo-alpha-amino ester. The following compounds were prepared using the general procedure described above.

Synthesis of (2S, 3R) -ethyl 2-amino-3-methyl-4-oxopentanoate (6a)

6 a: oil (88%) was clarified.¹H NMR(CDCl₃，300MHz)：δ1.16(d，3J(H₈，H₅)＝7.5Hz，3H，H₈)，1.24(t，3J(H₁，H₂)＝7.2Hz，3H，H₁)，1.70(brs，1H，H₉)，2.17(s，3H，H₇)，2.92(m，1H，H₅)，3.53(d，3J(H₄，H₅)＝6.4Hz，1H，H₄)，4.16(q，3J(H₂，H₁)＝7，2Hz，2H，H₂)。¹³C NMR(CDCl₃，75MHz)：δ13.25(C₈)，14.00(C₁)，28.73(C₇)，50.18(C₅)，56.72(C₄)，60.89(C₂)，174.26(C₃)，210.06(C₆)。MS(IC)m/z：174(M+1)。

Synthesis of (2S 3S) -ethyl 2-amino-3-methyl-4-oxopentanoate (4a)

4 a: oil (88%) was clarified.¹H NMR(CDCl₃，300MHz)：δ1.11(d，3J(H₈，H₅)＝7.1Hz，3H，H₈)，1.25(t，3J(H₁，H₂)＝7.2Hz，3H，H₁)，1.70(brs，1H，H₉)，2.20(s，3H，H₇)，2.92(m，1H，H₅)，3.86(d，3J(H₄，H₅)＝4.9Hz，1H，H₄)，4.16(q，3J(H₂，H₁)＝7，2Hz，2H，H₂)。¹³C(CDCl₃，50MHz)：δ10.82(C₈)，14.07(C₁)，28.24(C₇)，49.64(C₅)，55.26(C₄)，61.16(C₂)，174.18(C₃)，209.80(C₆)。MS(IC)m/z：174(M+1)。

Synthesis of (2S, 3S) -ethyl 2-amino-3-methyl-4-oxohexanoate ester (4b)

4 b: oil (84%) was clarified.¹H NMR(CDCl₃，300MHz)：δ1.04(t，3J(H₈，H₇)＝7.2Hz，3H，H₈)，1.11(d，3J(H₉，H₅)＝7.2Hz，3H，H₉)，1.25(t，3J(H₁，H₂)＝7.2Hz，3H，H₁)，2.52(q，3J(H₇，H₈)＝7.2Hz，2H，H₇)，2.91(m，1H，H₅)，3.84(d，3J(H₄，H₅)＝5.0Hz，1H，H₄)，4.16(q，3J(H₂，H₁)＝7.2Hz，1H，H₂)。¹³CNMR(CDCl₃，75MHz)：δ7.58(C₈)，11.23(C₉)，14.09(C₁)，34.03(C₇)，48.74(C₅)，55.45(C₄)，61.10(C₂)，174.15(C₃)，212.44(C₆)。MS(IC)m/z：188(M+1)。

Synthesis of (2S, 3R) -ethyl 2-amino-3-methyl-4-oxohexanoate ester (6b)

6 b: oil (84%) was clarified.¹H NMR(CDCl₃，300MHz)：δ1.02(t，3J(H₈，H₇)＝7.2 Hz，3H，H₈)，1.14(d，3J(H₉，H₅)＝7.2Hz，3H，H₉)，1.24(t，3J(H₁，H₂)＝7.2Hz，3H，H₁)，2.50(q，3J(H₇，H₈)＝7.2Hz，2H，H₇)，2.91(m，1H，H₅)，3.53(d，3J(H₄，H₅)＝6.5Hz，1H，H₄)，4.16(q，3J(H₂，H₁)＝7.2Hz，1H，H₂)。¹³CNMR(CDCl₃，75MHz)：δ7.46(C₈)，13.69(C₉)，14.09(C₁)，34.98(C₇)，49.22(C₅)，57.04(C₄)，60.94(C₂)，174.48(C₃)，212.89(C₆)。MS(IC)m/z：188(M+1)。

Synthesis of (S) -ethyl 2-amino-2- ((S) -2-oxocyclohexyl) acetate (4e)

4 e: oil (80%) was clarified.¹H NMR(CDCl₃，300MHz)：δ1.26(t，3J(H₁，H₂)＝7.2Hz，3H，H₁)，1.62-2.09(m，6H，H₈，H₉，H₁₀)，2.25-2.45(m，2H，H₇)，2.78(m，1H，H₅)，3.93(d，3J(H₄，H₅)＝3.8Hz，1H，H₄)，4.17(q，3J(H₂，H₁)＝7.2Hz，1H，H₂)。¹³C NMR(CDCl₃，75MHz)：δ14.14(C₁)，24.68，26.94，27.68(C₈，C₉，C₁₀)，41.94(C₇)，53.44，53.91(C₄，C₅)，60.96(C₂)，174.40(C₃)，210.90(C₆)。

(S) -Ethyl 2-amino-2- ((R) -2-oxocyclohexyl) acetate (6 e)) Synthesis of (2)

6 e: oil (80%) was clarified. ¹H NMR(CDCl₃，300MHz)：δ1.26(t，3J(H₁，H₂)＝7.2Hz，3H，H₁)，1.62-2.09(m，6H，H₈，H₉，H₁₀)，2.25-2.45(m，2H，H₇)，2.98(m，1H，H₅)，3.35(d，3J(H₄，H₅)＝4.7Hz，1H，H₄)，4.1，7(q，3J(H₂，H₁)＝7.2Hz，1H，H₂)。¹³C NMR(CDCl₃，75MHz)：δ14.14(C₁)，24.87，27.11，30.76(C₈，C₉，C₁₀)，41.94(C₇)，53.70，55.33(C₄，C₅)，60.96(C2)，174.40(C₃)，211.20(C₆)。

Synthesis of (S) -ethyl 2-amino-2- ((S) -2-oxocycloheptyl) acetate (4f)

4 f: oil (80%) was clarified.¹H NMR(CDCl₃，300MHz)：δ1.26(t，3J(H₁，H₂)＝7.2Hz，3H，H₁)，1.31-2.02(m，8H，H₈，H₉，H₁₀，H₁₁)，2.52(m，2H，H7)，2.92(m，1H，H₅)，3.83(d，3J(H₄，H₅)＝4.7Hz，1H，H₄)，4.18(q，3J(H₂，H₁)＝7.2Hz，1H，H₂)。¹³C NMR(CDCl₃，75MHz)：δ14.15(C₁)，23.92，26.55，29.57，29.87(C₈，C₉，C₁₀，C₁₁)，43.87(C₇)，55.24，56.08(C₄，C₅)，61.03(C₂)，174.58(C₃)，214.71(C₆)。

Synthesis of (S) -ethyl 2-amino-2- ((R) -2-oxocyclohexyl) acetate (6f)

6 f: oil (80%) was clarified.¹H NMR(CDCl₃，300MHz)：δ1.28(t，3J(H₁，H₂)＝7.2Hz，3H，H₁)，1.31-2.02(m，8H，H₈，H₉，H₁₀，H₁₁)，2.52(m，2H，H₇)，3.07(m，1H，H₅)，3.56(d，3J(H₄，H₅)＝4.9Hz，1H，H₄)，4.18(q，3J(H₂，H₁)＝7.2Hz，1H，H₂)。¹³C NMR(CDCl₃，50MHz)：δ13.95(C₁)，23.67，28.19，29.23，29.45(C₈，C₉，C₁₀，C₁₁)，43.73(C₇)，54.87，57.20(C₄，C₅)，60.78(C₂)，174.23(C₃)，214.33(C₆)。

Synthesis of (2S, 3S) -ethyl 2-amino-4-oxo-3-benzenepentanoate (4c)

4 c: oil (65%) was clarified.¹H NMR(CDCl₃，200MHz)：δ1.24(t，3J(H₁，H₂)＝7.1Hz，3H，H₁)，1.47(brs，2H，H₁₄)，2.06(s，3H，H₇)，4.12(m，4H，H₂，H₅，H₄)，7.20-7.33(m，5H，H₉，H₁₀，H₁₁，H₁₂，H₁₃)。¹³C NMR(CDCl₃，50MHz)：δ13.85(C₁)，29.03(C₇)，55.79(C₄)，60.92(C₂)，62.20(C₅)，127.86(C₁₁)，128.85，129.02(C₉，C₁₀，C₁₂，C₁₃)，134.27(C₈)，173.34(C₃)，206.69(C₆)。

Synthesis of (2S, 3R) -ethyl 2-amino-4-oxo-3-benzenepentanoate (6c)

6 c: oil (65%) was clarified.¹H NMR(CDCl₃，300MHz)：δ0.91(t，3J(H₁，H₂)＝7.1Hz，3H，H₁)，1.63(brs，2H，H₁₄)，2.08(s，3H，H₇)，3.93(m，4H，H₂，H₅，H₄)，7.18-7.31(m，5H，H₉，H₁₀，H₁₁，H₁₂，H₁₃)。¹³C NMR(CDCl₃，75 MHz)：δ13.56(C₁)，29.79(C₇)，57.18(C₄)，60.50(C₂)，63.54(C₅)，127.77(C₁₁)，128.66，128.91(C₉，C₁₀，C₁₂，C₁₃)，134.73(C₈)，173.73(C₃)，206.59(C₆)。

Synthesis of (2S, 3S) -ethyl 2-amino-3-phenyl-4-oxopentanoate (4d)

4 d: oil (50%) was clarified.¹H NMR(CDCl₃，300MHz)：δ1.26(t，3J(H₁，H₂)＝7.2Hz，3H，H₁)，2.02(s，3H，H₇)，2.96(m，2H，H₈)，3.27(m，1H，H₅)，3.79(d，3J(H₄，H₅)＝5.3Hz，1H，H₄)，4.13(m，1H，H₂)，7.14-7.31(m，5H，H₁₀，H₁₁，H₁₂，H₁₃，H₁₄)。¹³C NMR(CDCl₃，75MHz)：δ14.12(C₁)，30.61(C₇)，33.41(C₈)，55.04(C₅)，57.41(C₄)，61.35(C₂)，126.46(C₁₂)，12 8.51，128.97(C₁₀，C₁₁，C₁₃，C₁₄)，138.95(C9)，173.83(C₃)，209.71(C₆)。

Synthesis of (2S, 3R) -ethyl 2-amino-3-phenyl-4-oxopentanoate (6d)

6 d: oil (50%) was clarified.¹H NMR(CDCl₃，300MHz)：1.27(t，3J(H₁，H₂)＝7.2Hz，3H，H₁)，2.04(s，3H，H₇)，2.96(m，2H，H₈)，3.27(m，1H，H₅)，3.44(d，3J(H₄，H₅)＝5.9Hz，1H，H₄)，4.17(m，1H，H₂)，7.17-7.33(m，5H，H₁₀，H₁₁，H₁₂，H₁₃，H₁₄)。¹³C NMR(CDCl₃，75MHz)：δ14.10(C₁)，31.18(C₇)，34.73(C₈)，55.40(C₅)，56.55(C₄)，61.09(C₂)，126.52(C₁₂)，128.56，128.84(C₁₀，C₁₁，C₁₃，C₁₄)，138.62(C₉)，174.78(C₃)，210.43(C₆)。

General procedure for hydrolysis of gamma-oxo-alpha-amino esters

To gamma-oxo-alpha-amino esters₂O/MeOH solution (0.35M) was added dropwise to 2N aqueous KOH (1.1 eq) and the reaction mixture was stirred at room temperature for 24 h. 2N aqueous HCl was added to adjust the pH to 6. The solvent was evaporated under reduced pressure and the crude product was purified by silica gel column chromatography. The following compounds were prepared using the general procedure described above.

Synthesis of (2S, 3S) -2-amino-3-methyl-4-oxopentanoic acid (5a)

5 a: oil (50%).¹H NMR(D₂O，300MHz)：δ1.26(d，3J(H₆，H₃)＝7.5Hz，3H，H₆)，2.33(S，3H，H₅)，3.36(m，1H，H₃)，4.10(d，3J(H₂，H₃)＝3.7Hz，1H，H₂)。¹³C NMR(D₂O，50MHz)：δ10.85(C₆)，28.15(C₅)，46.61(C₃)，55.17(C₂)，173.48(C₁)，214.76(C₄)。

Synthesis of (2S, 3R) -2-amino-3-methyl-4-oxopentanoic acid (7a)

7 a: oil (56%).¹H NMR(D₂O，300MHz)：δ1.31(d，3J(H₆，H₃)＝7.5Hz，3H，H₆)，2.30(s，3H，H₅)，3.36(m，1H，H₃)，3.95(d，3J(H₂，H₃)＝5.1Hz，1H，H₂)。¹³C NMR(D₂O，50MHz)：δ12.48(C₆)，28.38(C₅)，46.76(C₃)，56.39(C₂)，173.32(C₁)，214.54(C₄)。

Synthesis of (2S, 3S) -2-amino-3-methyl-4-hexanoic acid (5b)

5 b: orange oil (80%).¹H NMR(D₂O，200MHz)：δ1.02(t，3J(H₆，H₅)＝6.9Hz，3H，H₆)，1.21(d，3J(H₇，H₃)＝7.5Hz，3H，H₇)，2.67(m，2H，H₅)，3.35(m，1H，H₃)，4.04(d.3J(H₂，H₃)＝4.1Hz.1H.H₂)。¹³C NMR(D₂O.50MHz)：δ7.30(C₆)，11.20(C₇)，34.56(C₅)，45.64(C₃)，56.72(C₂)，173.53(C₁)，217.49(C₄)。

Synthesis of (2S, 3R) -2-amino-3-methyl-4-hexanoic acid (7b)

7 b: orange oil (80%).¹H NMR(D₂O.200MHz)：δ1.02(m，3H，H₆)，1.29(d，3J(H₇，H₃)＝7.5Hz，3H，H₇)，2.67(m，2H，H₅)，3.35(m，1H，H₃)，3.89(d，3J(H₂，H₃)＝4.7Hz，1H，H₂)，¹³C NMR(D₂O，50 MHz)：δ7.30(C₆)，12.99(C₇)，34.75(C₅)，45.64(C₃)，55.50(C₂)，173.32(C₁)，217.70(C₄)。

Synthesis of (S) -2-amino-2- ((S) -2-cyclohexyl) acetic acid (5e)

5 e: yellow oil (63%).¹H NMR(D₂O，300MHz)：δ1.72(m，4H，H6，H₇)，1.89-2.17(m，4H，H₅，H₈)，2.54(m，1H，H₃)，3.25(m，1H，H₃)，4.17(d，3J(H₂，H₃)＝2.2Hz，1H，H₂)，¹³C NMR(D₂O，50MHz)：δ24.54(C₆)，27.10(C₇)，27.87(C₈)，41.74(C₅)，50.75(C₂)，53.66(C₃)，173.66(C₁)，215.30(C₄)。

Synthesis of (S) -2-amino-2- ((R) -2-cyclohexyl) acetic acid (7e)

7 e: oil (63%).¹H NMR(D₂O，300MHz)：δ1.72(m，4H，H₆，H₇)，1.89-2.17(m，4H，H₅，H₈)，2.54(m，1H，H₃)，3.25(m，1H，H₃)，3.74(d，3J(H₂，H₃)＝4.9Hz，1H，H₂)。¹³C NMR(D₂O，50MHz)：5 24.76(C₆)，27.44(C₇)，31.34(C₈)，42.06(C₅)，50.75(C₂)，55.14(C₃)，173.66(C₁)，215.54(C₄)。

Synthesis of (S) -2-amino-2- ((S) -2-cycloheptyl) acetic acid (5f)

5 f: clear oil (70%).¹H NMR(D₂O，300MHz)：δ1.31-2.01(m，8H，H₆，H₇，H₈，H₉)，2.45-2.77(m，2H，H₅)，3.43(m，1H，H₃)，4.05(d，3J(H₂，H₃)＝2.6Hz，1H，H₂)。¹³C NMR(D₂O，75MHz)：δ23.22，25.97，29.29，29.71(C₆，C₇，C₈，C₉)；43.48(C₅)，51.64(C₃)，55.96(C₂)，173.73(C₁)，219.05(C₄)。

Synthesis of (S) -2-amino-2- ((R) -2-cycloheptyl) acetic acid (7f)

7 f: oil (70%) was clarified.¹H NMR(D₂O，300MHz)：δ1.31-2.01(m，8H，H₆，H₇，H₈，H₉)，2.45-2.77(m，2H，H₅)，3.43(m，1H，H₃)，3.87(d，3J(H₂，H₃)＝4.1Hz，1H，H₂)。¹³C NMR(D₂O，75MHz)：δ23.22，27.91，28.93，29.26(C₆，C₇，C₈，C₉)，43.79(C₅)，51.39(C₃)，57.39(C₂)，173.53(C₁)，219.52(C₄)。

Synthesis of (2S, 3S) -2-amino-4-oxo-3-benzenepentanoic acid (5c)

5 c: oil (60%) was clarified.¹H NMR(D₂O，300MHz)：δ2.20(s，3H，H₅)，4.08(d，3J(H₂，H₃)＝6.8Hz，1H，H₂)，4.59(d，3J(H₃，H₂)＝6.8Hz，1H，H₃)，7.28-7.49(m，5H，H₇，H₈，H₉，H₁₀，H₁₁)。¹³C NMR(D₂O，75MHz)：δ29.12(C₅)，57.28(C₂)，58.55(C₃)，128.68(C₉)，129.73，130.05(C₇，C₈，C₁₀，C₁₁)，133.44(C₆)，173.43(C₁)，211.17(C₄)。

Synthesis of (2S, 3R) -2-amino-4-oxo-3-benzenepentanoic acid (7c)

7 c: oil (60%) was clarified.¹H NMR(D₂O，300MHz)：δ2.23(s，3H，H₅)，4.37(d，3J(H₂，H₃)＝6.1Hz，1H，H₂)，4.57(d，3J(H₃，H₂)＝6.1Hz，1H，H₃)，7.28-7.49(m，5H，H₇，H₈，H₉，H₁₀，H₁₁)。¹³C NMR(D₂O，75MHz)：δ29.13(C₅)，56.01(C₂)，58.94(C₃)，129.20(C₉)，129.50，130.13(C₇，C₈，C₁₀，C₁₁)，132.03(C₆)，173.43(C₁)，211.17(C₄)。

Synthesis of (2S, 3S) -2-amino-3-phenyl-4-oxopentanoic acid (5d)

5 d: oil (70%) was clarified.¹H NMR(D₂O，300MHz)：δ2.01(s，3H，H₅)，2.96(m，2H，H₆)，3.61(m，1H，H₃)，4.01(m，1H，H₂)，7.29-7.46(m，5H，H₈，H₉，H₁₀，H₁₁，H₁₂)。¹³C NMR(D₂O，75MHz)：δ31.10(C₅)，33.69(C₆)，54.10(C₃)，55.59(C₂)，127.40(C₁₀)，129.32，129.43(C₈，C₉，C₁₁，C₁₂)，138.07(C₇)，173.82(C₁)，214.92(C₄)。

Synthesis of (2S, 3R) -2-amino-3-phenyl-4-oxopentanoic acid (7d)

7 d: oil (70%) was clarified.¹H NMR(D₂O，300MHz)：δ2.10(s，3H，H₅)，2.92-3.20(m，2H，H₆)，3.76(m，1H，H₃)，3.81(m，1H，H₂)，7.29-7.46(m，5H，H₈，H₉，H₁₀，H₁₁，H₁₂)。¹³C NMR(D₂O，75MHz)：δ30.97(C₅)，34.35(C₆)，53.77(C₃)，55.59(C₂)，127.54(C₁₀)，129.22，129.32(C₈，C₉，C₁₁，C₁₂)，137.91(C7)，173.37(C₁)，215.26(C₄)。

General procedure for the reduction of gamma-oxo-alpha-amino-esters

General one-step process involving deprotection-reduction of γ -oxo- α -amino-esters:

to a solution of gamma-oxo-alpha-amino-ester (10mmol) in MeCN (6mL) was added an aqueous solution of CAN (3 equivalents) (60mL) and the temperature of the reaction mixture was rapidly dropped and maintained at 0 ℃. The reaction mixture was stirred at 0 ℃ for 45 minutes. To the reaction mixture was added dichloromethane (60mL) and the phases separated. The organic phase was washed with aqueous HCl (0.1N, 60mL), and the aqueous phases were combined and washed twice with dichloromethane. Using Na ₂CO₃Solution (2N) basified the aqueous phase to pH7 and cooled to 0 ℃. Add NaBH to the above solution₄(1.5 equiv.) the mixture was stirred at 0 ℃ for 90 minutes. The reaction mixture was extracted with dichloromethane (3X 200 mL). The organic phases were combined, MgSO₄Dried and concentrated under reduced pressure. The crude product containing the aminolactone or γ -hydroxy- α -amino-ester is purified by silica gel column chromatography to obtain the pure compound.

General procedure for reduction of γ -oxo- α -amino-esters using sodium borohydride:

to a solution of gamma-oxo-alpha-amino-ester (10mmol) in MeCN (6mL) was added NaBH₄(1.2 eq.) and the reaction mixture was stirred for 90 minutes. Water (40mL) was added to neutralize excess hydride followed by dichloromethane (40 mL). After phase separation, the aqueous phase was extracted with dichloromethane (2X 50 mL). The organic phases were combined, MgSO₄Dried and concentrated under reduced pressure. The crude gamma-hydroxy-alpha-amino-ester was purified by silica gel column chromatography to obtain the pure product.

Sodium borohydride and CeCl₃·7H₂General procedure for O reduction of γ -oxo- α -amino-esters:

to a solution of gamma-oxo-alpha-amino-ester (10mmol) in MeOH (30mL) at 0 deg.C was added CeCl₃·7H₂O (0.4 equiv.). The reaction mixture was stirred at 0 ℃ for 5 minutes, followed by addition of water (40mL) to neutralize excess hydride, followed by addition of dichloromethane (40 mL). After phase separation, the aqueous phase was extracted with dichloromethane (2X 50 mL). The organic phases were combined, MgSO ₄Dried and concentrated under reduced pressure. The crude γ -hydroxy- α -amino-ester was purified by silica gel column chromatography to obtain pure product.

General procedure for reduction of γ -oxo- α -amino-esters using raney nickel:

to a solution of γ -oxo- α -amino-ester (10mmol) in MeOH (30mL) was added multiple spoons of commercially available raney nickel at room temperature to obtain a gray black solution, and the reaction mixture was vigorously stirred. The reaction mixture was cooled to 0 ℃ and purged with hydrogen. The reaction mixture was stirred at room temperature under hydrogen atmosphere (1atm) for 24 hours. The crude reaction mixture was filtered through celite and the synthesis reaction mixture containing the aminolactone and/or γ -hydroxy- α -amino-ester was subsequently purified by silica gel column chromatography to obtain the pure product.

The following compounds were prepared using the general procedure described above.

Synthesis of Compound 8b

8 b: by a one-step deprotection-reduction sequence, a diastereomeric mixture (56%) was obtained as a clear oil.¹H NMR(CDCl₃，300MHz)：δ0.77(d，3J(H₆，H₅)＝7.2Hz，3H，H₆)，0.91(t，3J(H₉，H₈)＝7.2Hz，3H，H₉)，1.25(t，3J(H₁，H₂)＝7.2Hz，3H，H₁)，1.31-1.59(m，1H，H₇)，1.99(m，1H，H₅)，3.62(d，3J(H₄，H₅)＝2.8Hz，1H，H₄)，3.78(m，1H，H₇)，4.16(q，3J(H₂，H₁)＝7.2Hz，2H，H₂)。

Synthesis of Compound 9b

9 b: by a one-step deprotection-reduction sequential process or reduction of the unprotected ethyl ester, a diastereomeric mixture (40%) was obtained as a clear oil.¹H NMR(CDCl₃，300MHz)：δ1.07(t，3J(H₈，H₇)＝7.5Hz，3H，H₈)，1.23(d，3J(H₅，H₄)＝5.3Hz，3H，H₅)，1.63(m，1H，H₄)，1.85(m，1H，H₇)，3.24(d，3J(H2，H₄)＝11.3Hz，1H，H₂)，3.91(m，1H，H₆)。¹H NMR(CDCl₃，300MHz)：δ1.06(t，3J(H₈，H₇)＝7.2Hz，3H，H₈)，1.17(d，3J(H₅，H₄)＝6.8Hzl 3H，H₅)，1.43-1.67(m，1H，H₇)，2.34(m，1H，H₄)，3.26(d，3J(H₂，H₄)＝10.5Hz，1H，H₂)，4.41(m，1H，H₆)，MS(IC)m/z：144(M+1)。

Synthesis of Compound 8e

8 e: by a one-step deprotection-reduction sequential process or reduction of the unprotected ethyl ester using raney nickel, a diastereomeric mixture (56%) was obtained as a clear oil. ¹H NMR(CDCl₃，200MHz)：δ1.23(t，3J(H₁，H₂)＝7.1Hz，3H，H₁)，1.15-1，98(m，9H，H₅，H₇，H₈，H₉，H₁₀)，3.15(brs，3H，H₁₁，H₁₂)，3.46(m，1H，H₆)，3.61(d，3J(H₄₁，H₅)＝2.7Hz，1H，H₄₁)，3.91(d，3J(H₄₂，H₅)＝2.9Hz，1H，H₄₂)，4.14(q，3J(H₂，H₁)＝7.1Hz，2H，H₂)。¹³C₁ NMR(CDCl₃，50MHz)：δ14.11(C₁)，19.17，25.33，25.61(C₈，C₉，C₁₀)，33.01(C₇)，42.33(C₅)，58.69(C₄)，61.09(C₂)，70.77(C₆)，174.47(C₃)，¹³C₂ NMR(CDCl₃，50 MHz)δ14.11(C₁)，24.65，25.07，25.33(C₈，C₉，C₁₀)，35.57(C₇)，47.83(C₅)，54.51(C₄)，60.84(C₂)，70.22(C₆)，175.10(C3)。

The compound (3S, 3aS, 8aS) -3-amino-octahydrocyclohepta [ b]Process for preparing furan-2-one (9f-SSS)Synthesis of

9f (sss): obtained as clear oil (68%) by a one-step deprotection-reduction sequential process.¹H NMR(CDCl₃，300MHz)：δ1.12-2.37(m，10H，H₄，H₅，H₆，H₇，H₈)，2.40(m，1H，H₃)，3.30(d，3J(H₂，H₃)＝10.9Hz，1H，H₂)，4.51(m，1H，H₉)。¹³CNMR(CDCl₃，75MHz)：δ25.59，25.70，29.59，30.67，30.73(C₄，C₅，C₆，C₇，C₈)，46.47(C₃)，56.22(C₂)，82.61(C₉)，178.30(C₁)。

The compound (3S, 3aS, 8aR) -3-amino-octahydrocyclohepta [ b]Synthesis of furan-2-one (9f-SSR)

9f (SSR): upon Raney nickel reduction of the amino ester intermediate, a decant oil (55%) was obtained.¹H NMR(CDCl₃，300MHz)：δ1.10-2.25(m，11H，H₃，H₄，H₅，H₆，H₇，H₈)，3.23(d，3J(H₂，H₃)＝11.5Hz，1H，H₂)，4.02(m，1H，H₉)。¹³C NMR(CDCl₃，75MHz)：δ24.24，25.28，27.11，28.47，32.78(C₄，C₅，C₆，C₇，C₈)，50.42(C₃)，58.23(C₂)，82.04(C₉)，178.04(C₁)。

The compound (3S, 4S, 5S) -3-amino-5-methyl-4-phenyl-dihydrofuran-2 (3H) -one (9c-SSS) Synthesis of (2)

9c (sss): by one step of a deprotection-reduction step or by using NaBH₄Or NaBH₄/CeCl₃·7H₂Obtained by reduction of the amino ester with O as a clear oil (37%).¹H NMR(CDCl₃，200MHz)：δ0.99(d，3J(H₅，H₄)＝6.6Hz，3H，H₅)，1.57(brs，2H，H₁₂)，3.62(dd，3J(H₃，H₂)＝11.7Hz，3J(H₃，H₄)＝8.1Hz，1H，H₃)，4.09(d，3J(H₂，H₃)＝11.7Hz，1H，H₂) 4.86 (quint), 3J (H)₄，H₅)＝3J(H₄，H₃)＝7.1Hz，1H，H₄)，7.21-7.37(m，5H，H₇，H₈，H₉，H₁₀，H₁₁)，¹³C NMR(CDCl₃，50MHz)：δ16.88(C₅)，52.07，52.60(C₂，C₃)，77.10(C₄)，127.76，128.96(C₇，C₈，C₉，C₁₀，C₁₁)，135.11(C₆)，177.66(C₁)。

The compound (3S, 4S, 5R) -3-amino-5-methyl-4-phenyl-dihydrofuran-2 (3H) -one (9c-SSR) Synthesis of (2)

9c (SSR): obtained by reduction of the amino ester using raney nickel as a clear oil (37%).¹HNMR(CDCl₃，300MHz)：δ1.41(d，3J(H₅，H₄)＝6.0Hz，3H，H₅)，1.76(brs，2H，H₁₂)，2.93(t，3J(H₃，H₂)＝3J(H₃，H₄)＝11.1Hz，1H，H₃)，3.94(d，3J(H₂，H₃)＝12.1Hz，1H，H₂)，4.53(m，1H，H₄)，7.27-7.41(m，5H，H₇，H₈，H₉，H₁₀，H₁₁)。¹³C NMR(CDCl₃，75MHz)：δ1 8.48(C₅)，58.63，59.11(C₂，C₃)，78.79(C₄)，127.56，129.08(C₇，C₈，C₁₀，C₁₁)，127.68(C₉)，135.80(C₆)，176.60(C₁)。

Synthesis of Compound 9d

9 d: a1: 1 diastereomeric mixture (68%) as clear oil was obtained by a one-step deprotection-reduction sequential process.¹H₁ NMR(CDCl₃，300MHz)：δ1,25(d，3J(H₁₂，H₁₁)＝6.0Hz，3H，H₁₂)，2.14(m，1H，H₃)，2.74-3.11 (m，2H，H₄)，3.45(d，3J(H₂，H₃)＝11.3Hz，1H，H₂)，4.20(m，1H，H₁₁)，7.20-7.37(m，5H，H₆，H₇，H₈，H₉，H₁₀)。¹³C₁ NMR(CDCl₃，75 MHz)：δ19.17(C₁₂)，35.98(C₄)，53.34(C₃)，56.42(C₂)，78.01(C₁₁)，126.64(C₈)，128.58，128.85(C₆，C₇，C₉，C₁₀)，138.05(C₅)，177.32(C₁)。¹H₂ NMR(CDCl₃，300MHz)：δ1.33(d，3J(H₁₂，H₁₁)＝6.8Hz，3H，H₁₂)，2.72(m，1H，H₃)，2.74-3.11(m，2H，H₄)，3.52(d，3J(H₂，H₃)＝10.9Hz，1H，H₂)，4.66(m，1H，H₁₁)，7.20-7.37(m，5H，H₆，H₇，H₈，H₉，H₁₀)。¹³C₂ NMR(CDCl₃，75 MHz)：δ15.92(C₁₂)，33.88(C₄)，47.89(C₃)，53.91(C2)，76.12(C₁₁)，126.44(C₈)，128.21，128.58(C₆，C₇，C₉，C₁₀)，137.51(C₅)，177.76(C₁)。

Synthesis of Compound 11b

11 b: the diastereomeric mixture (40%) was obtained as a clear oil by a one-step deprotection-reduction sequential process or reduction of the aminoethyl ester. ¹H₁ NMR(CDCl₃，300MHz)：δ1.03(m，6H，H₈，H₅)，1.51-1.75(m，2H，H₇，H₄)，3.73(d，3J(H₂，H₄)＝7.8Hz，1H，H₂)，3.86(m，1H，H₆)。¹H₂ NMR(CDCl₃，300MHz)：δ0.90(d，3J(H₅，H₄)＝7.2Hz，3H，H₅)，1.04(t，3J(H₈，H₇)＝7.5Hz，3H，H₈)，1.56-1.84(m，1H，H₇)，2.57(m，1H，H₄)，3.83(d，3J(H₂，H₄)＝6.9Hz，1H，H₂)，4.26(m，1H，H₆)。¹³C₂ NMR(CDCl₃，50MHz)：δ6.45(C8)，9.84(C₅)，23.08(C₇)，38.15(C₄)，56.14(C₂)，81.73(C₆)，178.45(C₁)。MS(IC)m/z：144(M+1)。

Synthesis of (S) -ethyl 2-amino-2- ((1R.2S) -2-hydroxycyclohexyl) acetate (8e-SSR)

8e (SSR): obtained as clear oil (62%) by a one-step deprotection-reduction sequential process.¹H NMR(CDCl₃，300MHz)：δ1.24(t，3J(H₁，H₂)＝7.2Hz，3H，H₁)，1.00-1.91(m，9H，H₅，H₇，H₈，H₉，H₁₀)，3.49(m，5H，H₁₁，H₁₂，H₆，H₄)，4.13(q，3J(H₂，H₁)＝7.2Hz，2H，H₂)。¹³C NMR(CDCl₃，75MHz)：δ14.07(C₁)，24.09，25.28，27.78(C₈，C₉，C₁₀)，34.94(C₇)，46.96(C₅)，60.37(C₄)，60.70(C₂)，75.19(C₆)，174.65(C₃)。

Synthesis of Compound 11f

11 f: the diastereomeric mixture (72%) was obtained as a clear oil by a one-step deprotection-reduction sequential process or reduction of the corresponding amino ester using raney nickel.¹H₁ NMR(CDCl₃，200MHz)：δ1.18-2.55(m，11H，H₃，H₄，H₅，H₆，H₇，H₈)，3.82(d，3J(H₂，H₃)＝8.1Hz，1H，H₂)，4.61(m，1H，H₉)。¹³C₁ NMR(CDCl₃，50MHz)：δ20.63，21.38，28.40，30.45，31.15(C₄，C₅，C₆，C₇，C₈)，45.51(C₃)，54.68(C₂)，80.28(C₉)，178.44(C₁)。¹H₂ NMR(CDCl₃，200MHz)：δ1.18-2.57(m，11H，H₄，H₅，H₆，H₇，H₈，H3)，3.61(d，3J(H₂，H₃)＝6.8Hz，1H，H₂)，4.44(m，1H，H₉)。¹³C₂ NMR(CDCl₃，50MHz)：δ22.90，24.30，25.42，26.71，33.10(C₄，C₅，C₆，C₇，C₈)，46.00(C₃)，54.68(C₂)，83.80(C₉)，177.94(C₁)。

Synthesis of (2s, 3R4R) -ethyl 2-amino-4-hydroxy-3-benzenevalerate (10c-SRR)

10c (SRR): obtained as clear oil (60%) by a one-step deprotection-reduction sequential process.¹H NMR(CDCl₃，200MHz)：δ1.02(t，3J(H₁，H₂)＝7.1Hz，3H，H₁)，1.09(d，3J(H₇，H₆)＝6.4Hz，3H，H₇)，2.59(brs，3H，H₁₄，H₁₅)，2.93(dd，3J(H₅，H₆)＝3.2Hz，3J(H₅，H₄)＝8.1Hz，1H，H₅)，3.98(q，3J(H₂，H₁)＝7.1Hz，2H，H₂)，4.00(d，3J(H₄，H₅)＝8.1Hz 1H，H₄)，4.34(m，1H，H₆)，7.06-7.33(m，5H，H₉，H₁₀，H₁₁，H₁₂，H₁₃)。¹³C NMR(CDCl₃，50MHz)：δ13.70(C₁)，20.40(C₇)，54.40(C₅)，57.14(C₄)，60.65(C₂)，68.05(C₆)，126.89(C₁₁)，128.05，129.56(C₉，C₁₀，C₁₂，C₁₃)，138.24(C8)，174.38(C₃)。

Synthesis of (2S.3R4S) -ethyl 2-amino-4-hydroxy-3-phenylpentanoate (10c-SRS)

10c (SRS): by using NaBH₄Or NaBH₄/CeCl₃·7H₂O is obtained by reducing the amino ester to obtain the clarified oil.¹H NMR(CDCl₃，200MHz)δ0.82(t，3J(H₁，H₂)＝7.2Hz，3H，H₁)，0.91(d，3J(H₇，H₆)＝6.2Hz，3H，H₇)，2.71(brs，4H，H₁₄，H₁₅，H₅)，3.76(m，1H，H₆)，3.86(d，3J(H₄，H₅)＝10.0Hz 1H，H₄)，3.98(q，3J(H₂，H₁)＝7.1Hz，2H，H₂)，7.06-7.33(m，5H，H₉，H₁₀，H₁₁，H₁₂，H₁₃)。

Synthesis of (2S, 3R4S) -ethyl 2-amino-4-hydroxy-3-phenylpentanoate (11c-SRR)

11c (SRR): by using NaBH₄Or Raney nickel reduction of the amino ester as a clear oil (37%).¹H NMR(CDCl₃，300MHz)δ：1.16(d，3J(H₅，H₄)＝6.5Hz，3H，H₅)，3.69(m，1H，H₃)，4.09(d，3J(H₂，H₃)＝8.1Hz，1H，H₂)，4.84(m，1H，H₄)，7.08-7.39(m，5H，H₇，H₈，H₉，H₁₀，H₁₁)。¹³C NMR(CDCl₃，75MHz)：δ16.22(C₅)，51.99，56.00(C₂，C₃)，76.75(C₄)，127.87(C₉)，128.85，129.07(C₇，C₈，C₁₀，C₁₁)，133.20(C₆)，178.94(C₁)。

Synthesis of 11d

11 d: the SSR isomer was obtained as the major product as clear oil (60%) by a one-step deprotection-reduction sequential process or reduction of the corresponding amino ester using sodium borohydride. By using NaBH₄Or NaBH₄/CeCl₃Reduction of the corresponding amino ester gave the SSS isomer as the major product as a clear oil (75%). ¹H₁ NMR(CDCl₃，300MHz)：δ1.26(m，3H，H₁₂)，2.24(brs，2H，H₁₃)，2.39-3.11(m，3H，H₄，H₃)，3.85(d，3J(H₂，H₃)＝6.5Hz，1H，H₂)，4.14(m，1H，H₁₁)，7.19-7.33(m，5H，H₆，H₇，H₈，H₉，H₁₀)。¹³C₁(CDCl₃，75MHz)：δ20.34(C₁₂)，30.65(C₄)，46.82(C₃)，55.08(C₂)，68.22(C₁₁)，126.11(C₈)，128.66(C₆，C₇，C₉，C₁₀)，139.74(C₅)，174.21(d)。¹H₂ NMR(CDCl₃，300MHz)：δ 1.26(m，3H，H₁₂)，2.24(brs，2H，H₁₃)，2.39-3.11(m，3H，H₄，H₃)，3.89(d，3J(H₂，H₃)＝7.2Hz，1H，H₂)，4.42(m，1H，H₁₁)，7.19-7.33(m，5H，H₆，H₇，H₈，H₉，H₁₀)。¹³C₂ NMR(CDCl₃，75MHz)：δ19.80(C₁₂)，32.00(C₄)，47.40(C₃)，52.56(C₂)，78.07(C₁₁)，126.51(C₈)，128.66(C₆，C₇，C₉，C₁₀)，138.46(C₅)，178.02(C₁)。

General procedure for hydrolysis of aminolactones and/or gamma-hydroxy-alpha-amino esters

To aminolactones and/or gamma-oxo-alpha-amino esters₂O/MeOH solution (0.35M) 1.2 equivalents of LiOH were added dropwise. The reaction mixture was stirred at room temperature for 24 hours, followed by the addition of 1.2 equivalents of acetic acid. The solvent was evaporated under reduced pressure and the crude product was purified by recrystallization and/or using Dowex.

The following compounds were prepared using the general procedure described above.

Synthesis of (2S, 3S, 4S) -2-amino-4-hydroxy-3-methylhexanoic acid (12b)

12 b: 75% as white solid.¹H NMR(D₂O，300MHz)：δ0.90(d，3J(H₇，H₃)＝7.1Hz，3H，H₇)，0.93(t，3J(H₆，H₅)＝7.2Hz，3H，H₆)，1.56(m，2H，H₅)，2.35(m，1H，H3)，3.84(m，1H，H₄)，3.88(d，3J(H₂，H₃)＝2.65Hz，1H，H₂)。¹³C NMR(D₂O，75MHz)：δ5.77(C₆)，9.86(C₇)，27.76(C₅)，36.74(C₃)，60.48(C₂)，77.05(C₄)，174.51(C₁)。MS(El)m/z：132.0675(M-C2 H₅)；150℃。

Synthesis of (2S, 3S, 4R) -2-amino-4-hydroxy-3-methylhexanoic acid (13b)

13 b: 75% as white solid.¹H NMR(D₂O，300MHz)：δ0,96(t，3J(H6，H₅)＝7,2Hz，3H，H₆)，0,99(d，3J(H₇，H₃)＝7,1Hz，3H，H₇)，1,50-1,67(m，2H，H₅，H₅)，2,23(m，1H，H₃)，3,56(m，1H，H₄)，3,99(d，3J(H₂，H₃)＝3,01Hz，1H，H₂)。¹³C NMR(D₂O，75MHz)：δ9,52(C₆)，11,78(C₇)，27,48(C₅)，38,02(C₃)，56,11(C₂)，75,38(C₄)，174,77(C₁)。MS(El)m/z：116，1068(M-CO2H)；165℃。

Synthesis of (S) -2-amino-2- ((1S, 2S) -2-hydroxycyclohexyl) acetic acid (12e)

12 e: 60% as white solid.¹H NMR(D₂O，300MHz)：δ1.24-2.01(m，8H，H₅，H₆，H₇，H₈)，2.13(m，1H，H₃)，3.84(d，3J(H₂，H₃)＝3.0 Hz，1H，H₂)，4.22(m，1H，H₄)。¹³C NMR(D₂O，75MHz)δ：19.07，20.20，25.27(C₆，C₇，C₈)，33.27(C₅)，41.11(C₃)，59.86(C₂)，70.69(C₄)，174.44(C₁)。MS(E1)m/z：128.1070(M-CO₂H)；175℃。

Synthesis of (S) -2-amino-2- ((1S.2R) -2-hydroxycyclohexyl) acetic acid (13e)

13 e: 60% as white solid.¹H NMR(D₂O，300MHz)：δ1.19-1.40(m，4H)，1.62-1.80(m，3H)，1.85-2.05(m，2H)，3.46(m，1H，H₄)，3.98(d，3J(H₂，H₃)＝2.8Hz，1H，H₂)。¹³C(D₂O，75MHz)：δ(ppm)：24.41，25.24，26.44(C₆，C₇，C₈)，35.49(C₅，45.50(C₃)，56.68(C₂)，70.94(C₄)(C₄)，174.27(C₁)。MS(El)m/z：128.1083(M-CO₂H)，170℃。MS(El)m/z：174(M+H)+.

Synthesis of (S) -2-amino-2- ((1S, 2S) -2-hydroxycycloheptyl) acetic acid (12f)

12 f: 68% as a white solid.¹H NMR(D₂O，300MHz)：δ1.34-1.98(m，10H，H₅，H₆，H₇，H₈，H₉)，2.32(m，1H，H₃)，3.88(d，3J(H₂，H₃)＝2.2Hz，1H，H₂)，4.26(m，1H，H₄)。¹³C NMR(D₂O，75MHz)：δ20.89，21.17，27.63，28.63(C₆，C₇，C₈，C₉)，36.26(C₇)，43.56(C₃)，60.67(C₂)，74.35(C₄)，174.63(C₁)。MS(El)m/z：142.1237(M-CO₂H)；185℃。

Synthesis of (S) -2-amino-2- ((1S, 2R) -2-hydroxycyclohexyl) acetic acid (13f)

13 f: 68% as a white solid.¹H NMR(D₂O，300MHz)：δ1.39-1.92(m，10H，H₅，H₆，H₇，H₈，H₉)，2.10(m，1H，H₃)，3.70(m，1H，H₄)，3.99(d，3J(H₂，H₃)＝2.5Hz，1H，H₂)。¹³C NMR(D₂O，75MHz)：δ21.43，25.45，27.25，27.69(C₆，C₇，C₈，C₉)，36.50(C₅)，47.48(C₃)，58.31(C₂)，73.03(C₄)，174.64(C₁)。MS(El)m/z：142.1222(M-CO₂H)；170℃。

Synthesis of (2S, 3S, 4S) -2-amino-4-hydroxy-3-benzenepentanoic acid (12c)

12 c: 37% as white solid.¹H(D₂O，300MHz)：δ1.13(d，3J(H₅，H₄)＝6.4Hz，1H，H₅)，3.20(dd，3J(H₃，H₄)＝4.9Hz，3J(H₃，H₂)＝6.5Hz，1H，H₃)，4.16(d，3J(H₂，H₃)＝6.5Hz，1H，H₂)，4.43(m，1H，H₄)，7.3-7.45(m，5H，H₇，H₈，H₉，H₁₀，H₁₁)；¹³C NMR(D₂O，50MHz)δ21.04(C₅)，52.48(C₃)，58.54(C₂)，68.33(C₄)，128.60(C₉)，129.35，130.36(C₇，C₈，C₁₀，C₁₁)，134.89(C₆)，173.73(C₁)。MS(El)m/z：191.0934(M-H2O)；125℃。

Synthesis of (2S, 3S, 4R) -2-amino-4-hydroxy-3-phenylpentanoic acid (13c)

13 c: 37% as white solid.¹H NMR(D₂O，300MHz)：δ1.19(d，3J(H₅，H₄)＝6.1Hz，3H，H₅)，3.30(dd，3J(H₃，H₄)＝8.3Hz，3J(H₃，H₂)＝4.2Hz，1H，H₃)，4.27(d，3J(H₂，H₃)＝4.2Hz，1H，H₂)，4.35(m，1H，H₄)，7.29-7.45(m，5H，H₇，H₈，H₉，H₁₀，H₁₁)。¹³C NMR(D₂O，75MHz)：δ21.40(C₅)，52.92(C₃)，56.27(C₂)，67.39(C₄)，128.50(C₉)，129.44(C₇，C₈，C₁₀，C₁₁)，136.14(C₆)，173.92(C₁)。MS(El)m/z：191.0932(M-H₂O)；160℃。

(2S, 3S, 4S) -2-amino-3-phenyl-3-hydroxypentanoic acid (12d) and (2S, 3S, 4R) -2-amino-3-benzene Synthesis of a mixture of 3-hydroxyvaleric acid (13d) radicals

12d and 13 d: 60: 40 mixture of diastereomers, 63% as a white solid.¹H₁ NMR(D₂O，300MHz)：δ1.24(d，3J(H₅，H₄)＝6.4Hz，3H，H₅)，2.29(m，1H，H₃)，2.76(m，2H，H₆)，3.95(m，1H，H₄)，4.08(d，3J(H₂，H₃)＝1.5Hz，1H，H₂)，7.28-7.42(m，5H，H₈，H₉，H_10，11，H₁₂)。¹³C₁ NMR(D₂O，75MHz)：δ21.17(C₅)，32.46(C₆)，46.72(C₃)，54.95(C₂)，67.03(C₄)，126.99(C₁₀)，129.12，129.64(C₈，C₉，C₁₁，C₁₂)，139.64(C₇)，174.33(C₁)。¹H₂ NMR(D₂O，300 MHz)：δ1.16(d，3J(H₅，H₄)＝6.8Hz，3H，H₅)，2.61(m，1H，H₃)，2.66-2.97(m，2H，H₆)，3.90(d，3J(H₂，H₃)＝1.9Hz，1H，H₂)，4.16(m，1H，H₄)，7.31-7.40(m，5H，H₈，H₉，H₁₀，H₁₁，H₁₂)。¹³C₂ NMR(D₂O，75MHz)：δ21.05(C₅)，29.69(C₆)，46.22(C₃)，59.06(C₂)，70.98(C₄)，126.99(C₁₀)，129.02，129.34(C₈，C₉，C₁₁，C₁₂)，140.74(C₇)，173.85(C₁)。MS(El)mz：205.1124(M-H₂O)′170℃。MS(El)m/z：223.1206(M)，160℃。

Synthesis of (2S, 3R, 4S) -2-amino-4-hydroxy-3-methylhexanoic acid (14b)

14 b: 75% as white solid.¹H NMR(D₂O，300MHz)：δ0.96(m，6H，H₆，H₇)，1.60(m，2H，H₅)，2.01(m，1H，H₃)，3.60(m，1H，H₄)，3.90(d，3J(H₂，H₃)＝4.1Hz，1H，H₂)。¹³C NMR(D₂O，75MHz)：δ9.30(C₆)，12.59(C₇)，27.51(C₅)，39.61(C₃)，57.27(C₂)，75.35(C₄)，174.20(C₁)。MS(El)m/z：132.0661(M-C2 H₅)，140℃。

(2S, 3R, 4R) -2-amino-4-hydroxy-3-methylSynthesis of aminocaproic acid (15b)

15 b: 75% as white solid.¹H NMR(D₂O，300MHz)：δ0.89(t，3J(H₆，H₅)＝7.1Hz，3H，H₆)，1.06(d，3J(H₇，H₃)＝7.3Hz，3H，H₇)，1.51(m，2H，H₅)，2.25(m，1H，H₃)，3.73(m，1H，H₄)，3.82(d，3J(H₂，H₃)＝3.2 Hz，1H，H₂)。¹³CNMR(D₂O，75MHz)：δ9.04(C₆)，9.86(C₇)，27.60(C₅)，36.64(C₃)，60.23(C₂)，74.37(C₄)，174.27(C₁)。MS(El)m/z：116.1079(M-CO₂H)，115℃。

Synthesis of (S) -2-amino-2- ((1R, 2S) -2-hydroxycyclohexyl) acetic acid (14e)

14 e: 60% as white solid.¹H NMR(D₂O，300MHz)：δ1.05-2.05(m，9H，H₅，H₆，H₇，H₈，H3)，3.65(m，1H，H₄)，3.87(d，3J(H₂，H₃)＝4.9Hz，1H，H₂)。¹³C NMR(D₂O，75MHz)：δ24.36，24.98，26.84(C₆，C₇，C₈)，35.42(C₅)，45.88(C₃)，57.65(C₂)，72.55(C₄)，173.97(C₁)；MS(El)m/z：128.1070(M-CO₂H)，165℃。

Synthesis of (S) -2-amino-2- ((1R, 2R) -2-hydroxycyclohexyl) acetic acid (15e)

15 e: 60% as white solid.¹H NMR(D₂O，300MHz)：δ1.26-2.11(m，9H，H3，H₅，H₆，H₇，H₈)，3.76(d，3J(_H2，H₃)＝4.4Hz，1H，H₂)，4.12(m，1H，H₄)。¹³C NMR(D₂O，75MHz)：δ19.36，23.78，25.4(C₆，C₇，C₈)，33.07(C₅)，40.96(C₃)，59.35(C₂)，68.32(C₄)，174.44(C₁)。MS(El)m/z：128.1083(M-CO₂H)；120℃。

Synthesis of (S) -2-amino-2- ((1R, 2S) -2-hydroxycycloheptyl) acetic acid (14f)

14 f: 68% as a white solid.₁H NMR(D₂O，300MHz)：δ1.32-1.81(m，10H，H₅，H₆，H₇，H₈，H₉)，2.19(m，1H，H3)，3.82(d，3J(H₂，H₃)＝3.7Hz，1H，H₂)，4.16(m，1H，H₄)。¹³C NMR(D₂O，75MHz)：δ21.12，24.36，26.94，27.86(C₆，C₇，C₈，C₉)，35.98(C₅)，43.45(C₃)，60.92(C₂)，71.54(C₄)，174.79(C₁)。MS(El)m/z：142.1236(M-CO₂H)，165℃。

Synthesis of (S) -2-amino-2- ((1R2R) -2-hydroxycycloheptyl) acetic acid (15f)

15 f: 68% as a white solid.¹H NMR(D₂O，300MHz)：δ1.32-1.89(m，11H，H₃，H₅，H₆，H₇，H₈，H₉)，3.90(d，3J(H₂，H₃)＝3.4Hz，1H，H₂)，4.05(m，1H，H₄)。¹³C NMR(D₂O，75MHz)：δ21.89，24.89，27.07，28.27(C₆，C₇，C₈，C₉)，36.02(C₅)，48.65(C₃)，57.68(C₂)，73.43(C₄)，174.14(C₁)。MS(El)m/z：169.1105(M-H₂O)，160℃。

Synthesis of (2S, 3R.4R) -2-amino-4-hydroxy-3-phenylpentanoic acid (15c)

15 c: 37% as white solid.¹H NMR(D₂O，300MHz)：δ1.31(d，3J(H₅，H₄)＝6.2Hz，3H，H₅)，3.08(m，1H，H₃)，4.14(d，3J(H₂，H₃)＝5.0Hz，1H，H₂)，4.53(m，1H，H₄)，7.37-7.42(m，5H，H₇，H₈，H₉，H₁₀，H₁₁)。¹³C NMR(MeOD，50MHz)：δ22.13(C₅)，52.60(C₃)，60.98(C₂)，69.71(C₄)，128.59(C₉)，129.64，131.47(C₇，C₈，C₁₀，C₁₁)，138.01(C₆)，173.26(C₁)。MS(El)m/z：191.0952(M-H₂O)，180℃。

Synthesis of (2S, 3R, 4S) -2-amino-3-phenyl-3-hydroxypentanoic acid (14d)

14 d: 63% as white solid.¹H NMR(D₂O，300MHz)：δ1.31(d，3J(H₅，H₄)＝6.4Hz，3H，H₅)，2.46(m，1H，H₃)，2.66-3.14(m，2H，H₆)，3.65(d，3J(H₂，H₃)＝3Hz，1H，H₂)，4.12(m，1H，H₄)，7.33-7.43(m，5H，H₈，H₉，H₁₀，H₁₁，H₁₂)。¹³C NMR(D₂O，75MHz)：δ20.79(C₅)，30.03(C₆)，45.77(C₃)，56.95(C₂)，68.17(C₄)，127.16(C₁₀)，129.39(C₈，C₉，C₁₁，C₁₂)，139.43(C₇)，174.38(C₁)。MS(El)m/z：223.1206(M)，225℃。

Synthesis of (2S, 3R, 4R) -2-amino-3-phenyl-3-hydroxypentanoic acid (15d)

15 d: 63% as white solid.¹H NMR(D₂O，300MHz)：δ1.26(d，3J(H5，H₄)＝6.5Hz，3H，H₅)，2.45(m，1H，H3)，2.83(m，2H，H₆)，3.86(d，3J(H₂，H₃)＝2.2Hz，1H，H₂)，3.91(m，1H，H₄)，7.32-7.44(m，5H，H₈，H₉，H₁₀，H₁₁，H₁₂)。¹³C NMR(D₂O，75MHz)：δ21.49(C₅)，34.81(C₆)，46.87(C₃)，55.19(C₂)，67.99(C₄)，127.14(C₁₀)，129.25，129.57(C₈，C₉，C₁₁，C₁₂)，139.43(C₇)，174.44(C₁)。MS(El)m/z：205.1099(M-H₂O)，180℃。

Synthesis of Compound 17

A solution of 4-hydroxyproline methyl ester hydrochloride (16) (10.0g, 55.3mmol) and chlorotrimethylsilane (15.0g, 138.1mmol) in dichloromethane (200mL) was stirred at 0 ℃. To the solution was added triethylamine (19.6g, 193.4 mmol). The solution was then heated to reflux for 1 hour. The mixture was cooled to 0 ℃ and then a solution of methanol (3.3mL) in dichloromethane (16.5mL) was added. The reaction mixture was stirred at room temperature for 1 hour. To the resulting mixture were added PhF-Br (17.7g, 55.3mmol), triethylamine (5.59g, 55.3mmol) and Pb (NO)₃)₂(16.5g, 49.8 mmol). The mixture was stirred at room temperature under nitrogen for 12 hours. The mixture was filtered and the solvent was evaporated. The residue was dissolved in a solution of citric acid (23g) in methanol (230 mL). The mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the residue redissolved in ethyl acetate (300mL) and washed with water (200mL) and brine. The organic layer was dried over magnesium sulfate and evaporated to give crude compound N-PhF-4-hydroxyproline methyl ester (17) with a purity of 60% (20g, 94%). Thus, it was used without further purification.

Synthesis of Compound 18

A solution of oxalyl chloride (1.98g, 15.6mmol) in dry dichloromethane (45mL) was stirred under nitrogen at-60 ℃. DMSO (2.0mL, 27.9mmol) was added dropwise to the solution over 5 minutes. The mixture was stirred at the same temperature for 15 minutes. Then, a solution of N-PhF-4-hydroxyproline methyl ester (17) (4.30g, 11.15mmol) in methylene chloride (45mL) was added dropwise over 10 minutes using an addition funnel. The reaction mixture was stirred at-60 ℃ for 45 minutes. Then, triethylamine (5.97g, 59.0mmol) was added to the mixture, and the temperature was brought to 0 ℃. The reaction mixture was poured into an extraction funnel and washed with water (50 mL). The organic layer was dried over magnesium sulfate and evaporated. The crude product was purified by silica gel chromatography to give pure methyl N-PhF-4-hydroxyproline (18) (2.3g, 54%).

Synthesis of Compound 19

A solution of N-PhF-4-hydroxyproline methyl ester (18) (3.00g, 7.82mmol) in THF (30mL) and HMPA (3mL) was stirred at-55 ℃ under nitrogen. To this solution was added a 2.5M solution of butyllithium in hexane (3.30mL, 8.22 mmol). The mixture was stirred at-55 ℃ for 1 hour. Methyl iodide (1.46mL, 23.46mmol) was then added and the reaction mixture was brought to-10 ℃. The mixture was stirred at this temperature for 30 minutes. Then cooled to-50 ℃ and 10% H added₃PO₄(10mL) of the solution. The mixture was extracted with ether (2X 50 mL). The combined organic phases were washed with brine and dried over magnesium sulfate. The solvent was removed under reduced pressure and the crude product was purified by silica gel chromatography to give pure N-PhF-3-methyl-4-hydroxyproline methyl ester (19) (1.0 g; 30%). 19:¹H NMR(500 MHz，CDCl₃)：δ7.71(m，2H)，7.50(m，2H)，7.41-7.37(m，4H)，7.28-7.23(m，5H)，3.75(d，1H)；3.35(d，1H)，3.27(d，1H)，3.11(s，3H)，2.53(m，1H)，1.05(d，3H)。

synthesis of Compound 23

A solution of N-PhF-4-hydroxyproline methyl ester (18) (34g, 2.17mmol) in THF (50mL) and HMPA (15mL) was stirred at-78 deg.C under nitrogen. To this solution was added 0.5M solution of KHMDS in toluene (17.4mL, 8.70 mmol). The mixture was stirred at-78 ℃ for 1 hour. Methyl iodide (1.35mL, 21.7mmol) was then added and the reaction mixture was stirred for 12 hours. Adding 10% KH to the mixture₂PO₄An aqueous solution. The mixture was extracted with ethyl acetate (2X 25mL) A compound (I) is provided. The organic extracts were collected, washed with brine and dried over sodium sulfate and concentrated under reduced pressure. The crude product was dissolved in hexane: ethyl acetate (3: 1) and filtered on silica gel to give pure N-PhF-3, 3-dimethyl-4-hydroxyproline methyl ester (23) (0.63 g.70%). 23:¹H NMR(500MHz，CDCl₃)：δ7.74(d，1H)，7.67(d，1H)，7.43-7.25(m，11H)，3.97(d，1H)，3.75(d，1H)，3.43(s，1H)，2.95(s，3H)，1.37(s，3H)，0.84(s，3H)。

synthesis of Compound 27

A solution of N-PhF-4-hydroxyproline methyl ester (18) (1.30g, 3.39mmol) in THF (10mL) and HMPA (15mL) was stirred at-78 deg.C under nitrogen. To this solution was added a 1.0M solution of LiHMDS in THF (8.80mL, 8.80 mmol). The mixture was stirred at-78 ℃ for 1 hour. Acetaldehyde (1.75 eq) was added and the reaction mixture was brought to-55 ℃. After stirring for 3 hours, 10% H was added₃PO₄(5mL) aqueous solution. The organic extracts were collected, washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to afford pure methyl N-PhF-3- (2-hydroxy-ethyl) -4-hydroxyproline (27).¹H NMR was consistent with the structure.

Synthesis of Compound 28

A solution of N-PhF-4-hydroxyproline methyl ester (18) (1.30g, 3.39mmol) in THF (10mL) and HMPA (15mL) was stirred at-78 deg.C under nitrogen. To this solution was added a 1.0M solution of LiHMDS in THF (8.80mL, 8.80 mmol). The mixture was stirred at-78 ℃ for 1 hour. Benzaldehyde (600 μ L, 5.93mmol, 1.75 equiv.) was then added and the reaction mixture was brought to-55 ℃. After stirring for 3 hours, 10% H was added ₃PO₄(5mL) aqueous solution. The mixture was extracted with ether (2X 25 mL). The organic extracts were collected, washed with brine and dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to afford pure N-PhF-3-hydroxyphenylmethyl-4-hydroxyproline methyl ester (28) (0.98g, 60%).¹H NMR was consistent with the structure.

Synthesis of Compound 20

A solution of N-PhF-3-methyl-4-hydroxyproline methyl ester (19) (1.00g, 2.52mmol) in THF/methanol (1: 1) (20mL) was stirred at-78 ℃. To this solution was added a solution of sodium borohydride (0.238g, 6.29mmol) in methanol (5 mL). The mixture was stirred for 5 days and the reaction was still not completed. The mixture was brought to-10 ℃ and stirred for 2 hours. LC-MS analysis showed the presence of two compounds of the same molecular weight but different retention times, i.e. two diastereomers. The reaction mixture was cooled at-70 ℃ and 10% H was added₃PO₄(10mL) of an aqueous solution. After the mixture was concentrated under reduced pressure, the resulting mixture was extracted with ethyl acetate (2X 25 mL). The organic extracts were collected, washed with brine and dried over sodium sulfate and concentrated. The crude compound was purified by silica gel chromatography to afford pure N-PhF-3-methyl-4-hydroxy-proline methyl ester (20) (0.485 g; 49%). 20: ¹H NMR(500MHz，CDCl₃)：δ7.74(d，1H)，7.67(d，1H)，7.43-7.25(m，11H)，3.97(d，1H)，3.75(d，1H)，3.43(s，1H)，2.95(s，3H)，1.37(s，3H)，0.84(s，3H)。

Synthesis of Compound 24

A solution of N-PhF-3, 3-dimethyl-4-hydroxyproline methyl ester (23) (0.860g, 2.09mmol) in THF/methanol (1: 1) (12mL) was stirred at-78 ℃. To the solution was added sodium borohydride (0.158g, 4.18 mmol). The mixture was brought to-10 ℃ and stirred for 3 hours, then cooled at-70 ℃ and 10% H was added₃PO₄(10mL) of an aqueous solution. After the reaction mixture was concentrated under reduced pressure, the resulting mixture was extracted with ethyl acetate (2X 25 mL). The organic extracts were collected, washed with brine and dried over sodium sulfate and concentrated. The crude compound was purified by silica gel chromatography to provide pure N-PhF-3, 3-dimethyl-4-hydroxyproline methyl ester (24) (600mg, 69%). 24:¹H NMR(500MHz，CDCl₃)：δ7.75(d，1H)，7.60(m，3H)，7.54(d，1H)，7.44(t，1H)，7.30-7.21(m，6H)，7.08(t，1H)，4.14(t，1H)，3.58(t，1H)，3.33(s，3H)，2.95(t，1H)，2.69(s，1H)，0.79(s，3H)，0.50(s，3H)。

synthesis of Compound 29

A solution of N-PhF-3-hydroxyphenylmethyl-4-hydroxyproline methyl ester (27) in THF/methanol (1: 1) (20mL) was stirred at-78 ℃. To this solution was added sodium borohydride (2.5 equivalents) and the mixture was stirred for 12 hours before the temperature was brought to-10 ℃. Then 10% of H is added₃PO₄(10mL) of the aqueous solution, and the mixture was concentrated under reduced pressure. The resulting mixture was extracted with ethyl acetate (2X 25 mL). The organic extracts were collected, washed with brine and dried over sodium sulfate and concentrated. The crude compound was purified by silica gel chromatography to afford pure N-PhF-3- (2-hydroxy-ethyl) -4-hydroxy-proline methyl ester (29) (1.3g) as an oil. Without any purification, the product was used for further reactions.

Synthesis of Compound 30

A solution of N-PhF-3-hydroxyphenylmethyl-4-hydroxyproline methyl ester (28) (0.980g, 1.97mmol) in THF/methanol (1: 1) (20mL) was stirred at-78 ℃. To the solution was added sodium borohydride (0.187g, 4.92 mmol). The mixture was stirred for 12 hours and then allowed to reach-10 ℃. LC-MS analysis showed the reaction was complete. Thus, 10% H was added₃PO₄(10mL) of an aqueous solution. The reaction mixture was concentrated under reduced pressure, and the resulting mixture was extracted with ethyl acetate (2 × 25 mL). The organic extracts were collected, washed with brine and dried over sodium sulfate and concentrated to give pure N-PhF-3-hydroxyphenylmethyl-4-hydroxy-proline methyl ester (30) (1.3g, 85% purity) as an oil. Without any purification, the product was used as such in the next reaction.

Synthesis of Compound 21

A solution of N-PhF-3-methyl-4-hydroxyproline methyl ester (20) (0.485g, 1.21mmol) in ethanol (7mL) was stirred at room temperature. To the solution was added 4N NaOH solution (6mL, 24.3mmol), and the mixture was heated to reflux for 5 days. After LC-MS analysis showed no starting material present, 10% KH was used₂PO₄The reaction mixture is neutralized with an aqueous solution. Using acetic acidThe mixture was extracted with ethyl ester (2X 25 mL). The organic extracts were collected, washed with brine and dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by trituration using ethyl acetate/hexane to give N-PhF-3-methyl-4-hydroxyproline (21) in an HPLC purity of 95% purity (0.290 g; 62%).

Synthesis of Compound 25

A solution of N-PhF-3, 3-dimethyl-4-hydroxyproline methyl ester (24) (0.595g, 1.44mmol) in THF (40mL) was stirred in a Parr reactor at room temperature. To this solution was added (BoC)₂O (0.690g, 3.17mmol) and 10% palladium on charcoal (200 mg). The vessel was sealed and hydrogen (75psi) was added. The mixture was stirred at room temperature for 12 hours. After the reaction was complete, the mixture was filtered and evaporated. The crude compound was triturated with hexanes and dried to afford Boc intermediate (25).

Synthesis of Compound 26

BOC intermediate (25) (0.163g, 0.597mmol) was dissolved in dioxane (3mL) and concentrated HCl (3mL) was added. The mixture was stirred at 60 ℃ for 4 days. At this stage, LC-MS indicated the reaction was complete. White precipitates formed during the reaction were removed by filtration, the filtrate was concentrated under reduced pressure, and water was removed using a freeze-dryer to provide 26.

Synthesis of Compound 31

A solution of 860mg of N-PhF-3- (2-hydroxy-ethyl) -4-hydroxyproline methyl ester (29) (2mmol) in ethanol (10mL) was stirred at room temperature. To this solution was added 2N aqueous NaOH (1.5mL, 3.00mmol) and the mixture was stirred at room temperature for 5 hours. More NaOH pellets (0.100g, 2.50mmol) were added. The reaction mixture was stirred at room temperature for an additional 24 hours. When HPLC showed 25% conversion, 2N aqueous KOH (1.0mL, 2.0mmol) was added and the mixture was stirred for 6 days. The reaction mixture was concentrated under reduced pressure, and the residue was redissolved in ethyl acetate (25 mL). The mixture was washed with HCl (0.5N). The organic layer was washed with brine and dried over sodium sulfate, and concentrated. The crude compound was purified by silica gel chromatography to afford pure N-PhF-3- (2-hydroxy-ethyl) -4-hydroxyproline (31) (400mg, 48%).

Synthesis of Compound 32

To a solution of N-PhF-3-hydroxyphenylmethyl-4-hydroxyproline methyl ester (30) (0.968g, 1.97mmol) in ethanol (10mL) at room temperature was added an aqueous 2N NaOH solution (1.5mL, 3mmol) and the mixture was stirred for 5 h. When little progress was observed by HPLC, more NaOH (0.100g, 2.50mmol) was added and the reaction mixture was stirred at room temperature for an additional 24 hours. At this stage, 25% Hydrolysis (HPLC) was observed. Thus, 2N aqueous KOH (1.0mL, 2.0mmol) was added and the mixture was stirred for 6 days. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (25 mL). The mixture was washed with HCl (0.5N), then the organic layer was washed with brine and dried over sodium sulfate. The reaction mixture was concentrated and the crude compound was purified by silica gel chromatography to give pure N-PhF-3-hydroxyphenylmethyl-4-hydroxyproline (32) (400mg, 43%).

Synthesis of Compound 22

A solution of N-PhF-3-methyl-4-hydroxyproline (21) (0.290g, 0.752mmol) in ethanol (45mL) and acetic acid (5mL) was stirred in a Parr reactor at room temperature. To the solution was added 10% palladium on carbon (0.400 g). The reactor was sealed and hydrogen (100Psi) was added. The mixture was stirred for 2 hours. After completion, the catalyst was removed by filtration, and the solvent was removed under reduced pressure. Water (20mL) was added to the reaction mixture, and the mixture was washed with ether (2X 25 mL). Water/acetic acid was removed using 3 freeze drying procedures to obtain compound 22.

Synthesis of Compound 33

A solution of N-PhF-3-hydroxyethyl-4-hydroxyproline (31) (0.300g, 0.722mmol) in ethanol (45mL) and acetic acid (5mL) was stirred in a Parr reactor at room temperature. To the solution was added 10% palladium on carbon (0.100 g). The reactor was sealed and hydrogen (100Psi) was added. The mixture was stirred for 1 hour. After completion, the mixture was filtered and concentrated under reduced pressure. Water (20mL) was added to the reaction mixture, and the mixture was washed with ether (2X 25 mL). Water/acetic acid was removed using a freeze drying cycle to obtain compound 33.

Synthesis of Compound 34

A solution of N-PhF-3-hydroxyphenylmethyl-4-hydroxyproline (32) (0.420g, 0.880mmol) in ethanol (45mL) and acetic acid (5mL) was stirred in a Parr reactor at room temperature. To the solution was added 10% palladium on carbon (0.100 g). The reactor was sealed and hydrogen (100Psi) was added. The mixture was stirred for 1 hour. After completion, the mixture was filtered and concentrated under reduced pressure. Water (20mL) was added to the reaction mixture, and the mixture was washed with ether (2X 25 mL). The water/acetic acid was removed using a freeze drying cycle to obtain compound 34.

Synthesis of Compound 35

Boc-proline methyl ester (10g, 43.67mmol) was dissolved in anhydrous tetrahydrofuran (100 mL). The solution was cooled to-78 ℃. To the cooled solution was added 2M LDA solution (52.4mmol, 26.2 mL). The enolization reaction was stirred at-78 ℃ for 45 minutes, followed by the addition of 1.2 equivalents of allyl bromide. The alkylation was allowed to proceed at-78 deg.C overnight. The reaction mixture was then heated to-20 ℃. The reaction was finally quenched by addition of saturated ammonium chloride solution (100mL), followed by addition of ethyl acetate (100mL), and the two layers were separated. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to yield a yellow oil. The crude product was purified by silica gel column chromatography to obtain pure 35(6 g).

Synthesis of Compound 36

To a solution of compound 35 in ethanol (30mL) was added 2 equivalents of 4N aqueous KOH, and the mixture was stirred for 48 hours. The reaction mixture was concentrated under reduced pressure, followed by addition of water (50 mL). The basic solution was acidified with HCl (2N) to adjust the pH to 3. The reaction mixture was then extracted with ethyl acetate (100 mL). The organic phase was concentrated and then recrystallized from an ethyl acetate/hexane mixture to yield pure Boc- α -allylproline (36) (2.5 g).

Synthesis of Boc-alpha-epoxyethylmethylproline (37)

Boc- α -allylproline (36) (2g) was dissolved in dichloromethane (40mL) and THF (10 mL). M-chloroperbenzoic acid (2g) was added and the reaction was stirred for 24 hours. The crude reaction mixture was concentrated and extracted with EtOAc/saturated bicarbonate solution. The crude epoxidized allylproline was purified by silica gel column chromatography to give pure Boc- α -epoxyethylmethylproline (37) (1.1 g).

Synthesis of alpha-epoxyethylmethyl-proline (38)

The Boc- α -epoxyethylmethylproline (37) obtained above was dissolved in dichloromethane (5mL), trifluoroacetic acid (5mL) was added to the solution, and the reaction mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, followed by addition of dichloromethane and concentration of the mixture again. This was repeated three times, followed by addition of water (30mL) and freeze-drying 2 times to yield pure α -epoxyethylmethyl-proline (38) (680 mg). 38: MS: m + H ⁺＝172。

Synthesis of Compound 39

To a solution of L-proline methyl ester hydrochloride (5g, 30mmol) in water (20mL) was added excess propylene oxide (20 mL). An exothermic reaction was observed and the mixture was stirred overnight. After concentrating the reaction mixture under reduced pressure, the crude product was purified by reverse phase chromatography to give 39(2.3g, 42%). 39: MS: m + H⁺＝188。

Synthesis of Compound 40

The above methyl ester (39) was hydrolyzed in ethanol using 2 equivalents of 2N aqueous KOH and stirred for 48 hours. The reaction mixture was neutralized with HCl (0.5N) before freeze-drying. The crude product thus obtained was purified by reverse phase chromatography to obtain 40(1.15g, 52%) as a clear oil. 40: MS: M + H⁺＝174。

Synthesis of cyclohexanecarboxylic acid methoxy-methyl-amide (41)

A solution of cyclohexylcarboxylic acid (6.30g, 49.1mmol) in acetonitrile (30mL) was stirred at room temperature. To this solution were added N, N-Diisopropylethylamine (DIEA) (12.7g, 98.3mmol) and TBTU (16.6g, 51.6 mmol). The mixture was stirred for 10 minutes. Then, a solution of N, O-dimethylhydroxylamine hydrochloride (5.75g, 59.0mmol) and DIEA (6.35g, 49.1mmol) in acetonitrile (30mL) was added. The mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and the crude mixture was dissolved in ethyl acetate (250mL) and washed with 0.5N NaOH (2X 100mL), 0.5N HCl (2X 100mL) and brine. The organic layer was dried over magnesium sulfate and concentrated. The resulting oil was redissolved in hexane/ethyl acetate (3: 1) and filtered through silica gel. The mixture was concentrated to give compound 41(7.4g, 88%). 41: ¹H NMR(500MHz，CDCl₃)：δ¹H NMR(CDCl₃)：3.68(s，3H)，3.16(s，3H)，2.67(m，1H)，1.81-1.23(m，10H)。

Synthesis of cyclopentanecarboxylic acid methoxy-methyl-amide (42)

To a stirred solution of cyclopentylcarboxylic acid (6.00g, 52.6mmol) in acetonitrile (30mL) was added DIEA (13.6g, 105.1mmol) and TBTU (17.7g, 55.2mmol) at room temperature and the mixture was stirred for 10 min. Then, a solution of N, O-dimethylhydroxylamine hydrochloride (6.15g, 63.1mmol) and DIEA (6.79g, 52.6mmol) in acetonitrile (30mL) was added. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure and the crude product was redissolved in ethyl acetate (250mL) and washed with 0.5N NaOH (2X 100mL), 0.5N HCl (2X 100mL) and brine. The organic phase was dried over magnesium sulfate and concentrated. The resulting oil was redissolved in hexane/ethyl acetate (3: 1) and filtered through silica gel. After removal of the solvent, pure cyclopentanecarboxylic acid methoxy-methyl-amide (42) (8g, 97%) was obtained.

Synthesis of 1-cyclohexyl-ethanone (43)

A solution of cyclohexane/carboxylic acid methoxy-methyl-amide (41) (4.1g, 23.9mmol) in dry THF (45mL) was stirred at-78 deg.C under nitrogen. To this solution was added 1.6M methyllithium in THF (15mL,23.9mmol) of solution. The reaction mixture was warmed to 0 ℃ and the mixture was stirred for an additional 1 hour. A0.5M HCl solution (40mL) was then added and the mixture was extracted with ethyl acetate (2X 50 mL). The organic extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure to give 1-cyclohexyl-ethanone (43) (2.83g, 94%) as an oil. 43: ¹H NMR(500MHz，CDCl₃)：δ2.33(m，1H)，2.13(s，3H)，1.88-1.66(m，5H)，1.37-1.16(m，5H)。

Synthesis of 1-cyclopentyl-ethanone (44)

A solution of cyclopentanecarboxylic acid methoxy-methyl-amide (42) (6.20g, 39.44mmol) in dry THF (60mL) was stirred at-78 deg.C under nitrogen. To this solution was added a 1.6M solution of methyllithium in THF (24.6mL, 39.44 mmol). The temperature of the reaction mixture was brought to 0 ℃ and the mixture was stirred for 1 hour. A0.5M HCl solution (20mL) was added and the mixture was extracted with ethyl acetate (2X 50 mL). The organic extracts were combined, dried over magnesium sulfate and evaporated to give 1-cyclopentyl-ethanone (44) (3.40g, 77%) as a colourless oil. 44:¹H NMR(500MHz，CDCl₃)：δ2.86(m，1H)，2.16(s，3H)，1.84-1.57(m，8H)。

synthesis of 4-cyclohexyl-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester (47)

A solution of sodium ethoxide was prepared by dissolving sodium (1.00g, 43.7mmol) in dry ethanol (100 mL). To the solution were added cyclohexylmethyl ketone (43) (4.60g, 36.4mmol) and diethyloxalic acid (5.33g, 36.4 mmol). The mixture was stirred at room temperature for 2 hours. After removal of the solvent, water (25mL) and ice (14g) were added. The mixture was treated with concentrated HCl (7mL) and then extracted with ethyl acetate (2X 100 mL). The organic extracts were combined, washed with brine and dried over sodium sulfate. The crude product obtained after concentrating the reaction mixture under reduced pressure was redissolved in hexane/ethyl acetate (3: 1) and filtered through a plug of silica gel. Removal of the solvent provided ethyl 4-cyclohexyl-2-hydroxy-4-oxo-but-2-enoate (47) (5.2g, 63%) as an orange oil. 47: ¹H NMR(500MHz，CDCl₃)：δ6.39(s，1H)，4.35(q，2H)，2.37(m，1H)，1.91-1.69(m，5H)，1.42-1.24(m，8H)。

Synthesis of 4-cyclopentyl-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester (48)

A solution of sodium ethoxide was prepared by dissolving sodium (0.84g, 36.4mmol) in dry ethanol (80 mL). To the solution was added cyclopentylmethyl ketone (44) (3.40g, 30.3mmol) and diethyl oxalic acid (4.43g, 30.3 mmol). The mixture was stirred at room temperature for 12 hours. After removal of the solvent, water (15mL) and ice (10g) were added. The mixture was treated with concentrated HCl (5mL) and then extracted with ethyl acetate (2X 100 mL). The organic extracts were combined, washed with brine and dried over sodium sulfate. After removal of the solvent, the crude product was redissolved in hexane/ethyl acetate (3: 1) and filtered through silica gel. Removal of the solvent yielded 4-cyclopentyl-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester (48) (3.7g, 58%) as an orange oil. 48:¹H NMR(500MHz，CDCl₃)：δ6.39(s，1H)，4.35(q，2H)，2.89(m，1H)，1.82-1.64(m，8H)，1.36(t，3H)。

synthesis of ethyl 2-hydroxy-4-oxo-4-phenyl-but-2-enoate (49)

A solution of sodium ethoxide was prepared by dissolving sodium (4.59g, 200mmol) in dry ethanol (450 mL). To the solution were added acetophenone (45) (20.0g, 166.4mmol) and diethyl oxalic acid (24.3g, 166.4 mmol). The mixture was stirred at room temperature for 12 hours. After removal of the solvent, water (80mL) and ice (60g) were added. The mixture was treated with concentrated HCl (25mL) and then extracted with ethyl acetate (2X 200 mL). The organic extracts were combined, washed with brine and dried over sodium sulfate. The crude product obtained after removal of the solvent was redissolved in hexane/ethyl acetate (3: 1) and filtered through silica gel. Removal of the solvent under reduced pressure yielded ethyl 2-hydroxy-4-oxo-4-phenyl-but-2-enoate (49) (22g, 60%) as an orange oil. 49: ¹H NMR(500MHz，CDCl₃)：δ8.00(d，2H)，7.61(t，1H)，7.51(t，2H)，7.08(s，1H)，4.40(q，2H)，1.42(t，3H)。

2-hydroxy-5, 5-dimethyl-4-oxo-hex-2-enoic acid ethyl ester(50) Synthesis of (2)

A solution of sodium ethoxide was prepared by dissolving sodium (2.75g.120mmol) in dry ethanol (250 mL). To the solution was added pinacolone (46) (10.0g, 99.8mmol) and diethyl oxalic acid (14.6g, 99.8 mmol). The mixture was stirred at room temperature for 12 hours. After removal of the solvent, water (50mL) and ice (25g) were added. The mixture was treated with concentrated HCl (7mL) and then extracted with ethyl acetate (2X 150 mL). The organic extracts were combined, washed with brine and dried over sodium sulfate. The crude product obtained after removal of the solvent was redissolved in hexane/ethyl acetate (3: 1) and filtered through silica gel. The solvent was removed under reduced pressure to give ethyl 2-hydroxy-5, 5-dimethyl-4-oxo-hex-2-enoate (50) (22g, 60%) as a colorless oil. 50:¹H NMR(500MHz，CDCl₃)：δ6.54(s，1H)，4.35(q，2H)，1.38(t，3H)，1.22(s，9H)。

synthesis of 5-cyclohexyl-isoxazole-3-carboxylic acid ethyl ester (51)

A solution of ketene (47) (5.10g, 22.4mmol) in absolute ethanol/THF (1: 1) (60mL) was stirred at room temperature. To the solution was added hydroxylamine hydrochloride (1.72g, 24.7mmol), and the mixture was stirred under nitrogen for 12 hours. The mixture was then heated at reflux using soxlet packed with molecular sieves for 2 hours. After cooling the reaction mixture, the solvent was removed under reduced pressure. Water (100mL) was added and the mixture was extracted with dichloromethane (2X 100 mL). The organic extracts were collected and dried over sodium sulfate. After removal of the solvent, the crude product was purified by silica gel chromatography to afford ethyl 5-cyclohexyl-isoxazole-3-carboxylate (51) (2.8g, 56%) as a colorless oil. 51: ¹H NMR(500MHz，CDCl₃)：δ6.37(s，1H)，4.42(q，2H)，2.83(m，1H)，2.06(m，2H)，1.81(m，2H)，1.75(m，1H)，1.48-1.26(m，8H)。

Synthesis of ethyl 5-cyclopentyl-isoxazole-3-carboxylate (52)

A solution of cyclopentyl-enone (48) (3.70g, 17.4mmol) in absolute ethanol/THF (1: 1) (50mL) was stirred at room temperature. To the solution was added hydroxylamine hydrochloride (1.33g, 19.1mmol),the resulting mixture was stirred under nitrogen for 12 hours. The mixture was then heated using soxhlet reflux packed with molecular sieves for 2 hours. After cooling the reaction mixture, the solvent was evaporated under reduced pressure. Water (50mL) was added and the mixture was extracted with dichloromethane (2X 50 mL). The organic extracts were combined, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography to give 5-cyclopentyl-isoxazole-S-carboxylic acid ethyl ester (52) (2g, 55%) as a colourless oil. 52:¹H NMR(500MHz，CDCl₃)：δ6.38(s，1H)，4.42(q，2H)，3.25(m，1H)，2.11(m，2H)，1.80-1.69(m，6H)，1.41(t，3H)。

synthesis of ethyl 5-phenyl-isoxazole-3-carboxylate (53)

A solution of phenyl-enone (49) (5.00g, 22.7mmol) in absolute ethanol/THF (1: 1) (60mL) was stirred at room temperature. To the solution was added hydroxylamine hydrochloride (1.73g, 25.0mmol) and the resulting mixture was stirred under nitrogen for 12 hours. The mixture was then heated using soxhlet reflux packed with molecular sieves for 2 hours. The reaction mixture was allowed to cool and the solvent was evaporated. Water (100mL) was added and the mixture was extracted with dichloromethane (2X 100 mL). The organic extracts were combined, dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography to give ethyl 5-phenyl-isoxazole-3-carboxylate (53) (3.89g, 79%) as a colourless oil. 53: ¹H NMR(500MHz，CDCl₃)：δ7.80(d，2H)，7.50(m，3H)，6.93(s，1H)，4.47(q，2H)，1.44(t，3H)。

Synthesis of ethyl 5-tert-butyl-isoxazole-3-carboxylate (54)

A solution of tert-butyl-enone (50) (6.00g, 30.0mmol) in absolute ethanol/THF (1: 1) (70mL) was stirred at room temperature. To the solution was added hydroxylamine hydrochloride (2.29g, 33.0mmol), and the resulting mixture was stirred under nitrogen for 12 hours. The mixture was then heated using soxhlet reflux packed with molecular sieves for 2 hours. The reaction mixture was allowed to cool and the solvent was evaporated. Water (100mL) was added and the mixture was extracted with dichloromethane (2X 100 mL). The organic extracts were combined and dried over sodium sulfateDried and concentrated. The crude product was purified by silica gel chromatography to give 5-tert-butyl-isoxazole-3-carboxylic acid ethyl ester (54) (3g, 51%) as a colourless oil. 54:¹H NMR(500MHz，CDCl₃)：δ6.37(s.1H)，4.43(q，2H)，1.41(t，3H)，1.37(s，9H)。

synthesis of 5-cyclohexyl-isoxazole-3-carboxylic acid (55)

A solution of cyclohexyl isoxazole ethyl ester (51) (2.80g, 12.5mmol) in ethanol (30mL) was stirred at room temperature. To this solution was added 2M NaOH solution (9.4mL, 18.8 mmol). Within a few minutes, a precipitate formed and the reaction mixture became a thick paste. TLC showed the reaction was complete. To the reaction mixture was added 0.5M HCl to adjust the pH to 3-4, and then the mixture was extracted with ethyl acetate (2 × 100 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, and concentrated to provide 5-cyclohexyl-isoxazole-3-carboxylic acid (55) (2.2 g.90%) as white crystals. 55: ¹H NMR(500MHz，CDCl₃)：δ9.60(broad，1H)，6.44(s，1H)，2.86(m，1H)，2.08(m，2H)，1.83(m，2H)，1.74(m，1H)，1.50-1.28(m，5H)。

Synthesis of 5-cyclopentyl-isoxazole-3-carboxylic acid (56)

A solution of ethyl cyclopentylisoxazole (52) (2.00g, 9.56mmol) in ethanol (30mL) was stirred at room temperature. To this solution was added 2M NaOH solution (7.2mL, 14.4 mmol). After 5 min, TLC showed the reaction was complete. To the reaction mixture was added 0.5M HCl to adjust the pH to 3-4, followed by extraction of the mixture with ethyl acetate (2 × 75 mL). The organic extracts were combined, washed with brine, dried over sodium sulfate, and concentrated to provide 5-cyclopentyl-isoxazole-3-carboxylic acid (56) (1.6g, 92%) as white crystals. 56:¹H NMR(500MHz，CDCl₃)：δ9.75(broad，1H)，6.45(s，1H)，3.26(m，1H)，2.13(m，2H)，1.80-1.70(m，6H)。

synthesis of 5-phenyl-isoxazole-3-carboxylic acid (57)

Stirring of phenyl-substituted isoxazole ethyl ester at room temperature(53) (1.89g, 8.70mmol) in ethanol (30 mL). To this solution was added 2M NaOH solution (6.5mL, 13.1 mmol). After 5 min, TLC showed the reaction was complete. Before extracting the mixture with ethyl acetate (2 × 75mL), 0.5M HCl was added to the reaction mixture to adjust the pH to 3-4. The organic extracts were combined, washed with brine, dried over sodium sulfate, and concentrated to afford 5-phenyl-isoxazole-3-carboxylic acid (57) (1.54g, 94%) as a white solid. 57:¹H NMR(500MHz，CDCl₃): δ 9.4 (width, 1H), 7.83(d, 2H), 7.51(m, 3H), 6.99(s, 1H).

Synthesis of 5-tert-butyl-isoxazole-3-carboxylic acid (58)

A solution of tert-butyl-substituted isoxazole ethyl ester (54) (2.97g, 15.1mmol) in ethanol (30mL) was stirred at room temperature. To this solution was added 2M NaOH solution (11.3mL, 22.6 mmol). After 5 min, TLC showed the reaction was complete. Before extracting the mixture with ethyl acetate (2 × 75mL), 0.5M HCl was added to the reaction mixture to adjust the pH to 3-4. The organic extracts were combined, washed with brine, dried over sodium sulfate, and concentrated to afford 5-tert-butyl-isoxazole-3-carboxylic acid (58) (1.54g, 94%) as a white solid. 58:¹H NMR(500MHz，CDCl₃)：δ6.44(s，1H)，1.39(s，9H)。

synthesis of 2-amino-4-cyclohexyl-4-hydroxy-butanoic acid (59)

A solution of the above cyclohexyl-substituted isoxazolecarboxylic acid (55) (2.20g, 11.3mmol) in ethanol/water (1: 1) (80mL) was stirred in a Parr reactor at room temperature. To this solution was added a Raney-Ni (2g) suspension (previously washed 5 times with ethanol/water (1: 1)). The reactor was sealed and hydrogen (120psi) was added. The mixture was stirred at room temperature for 3 hours. LC-MS analysis showed that the reaction was not complete. The mixture was stirred for an additional 12 hours at which point LC-MS analysis showed complete exhaustion of the starting material and the predominant compound was one with a non-hydrogenated double bond. The mixture was filtered and the catalyst was washed with ethanol and water. To the filtrate were added 10% palladium on charcoal (0.6g) and acetic acid (10 mL). The reactor was sealed and hydrogen (120psi) was added. The mixture was stirred at room temperature For 12 hours. The mixture was then heated at 50 ℃ for 4 days by a hydrogen pressure of 180 psi. The mixture was filtered, the filtrate was concentrated under reduced pressure, and water was removed by freeze-drying. The green solid 2-amino-4-cyclohexyl-4-hydroxy-butyric acid (59) thus obtained was further purified by reverse phase chromatography (100% water). Pure fractions were identified by LCMS, collected and freeze dried. 59: MS: m + H⁺＝202。

Synthesis of 2-amino-4-cyclopentyl-4-hydroxy-butyric acid (60)

60 was synthesized according to the procedure described above for compound 59 using ethanol/water (1: 1) (60mL) solution of cyclopentyl-substituted isoxazolecarboxylic acid (56) (1.48g, 8.17mmol), Raney-Ni (1.5g), 10% palladium on carbon (0.6g), acetic acid (10mL) and heating at 50 ℃ for 4 days by hydrogen pressure of 180 psi. Purification was performed using reverse phase chromatography. Pure fractions were identified by LCMS, collected and freeze dried. 60: MS: m + h⁺＝187。

Synthesis of 2-amino-4-hydroxy-4-phenyl-butyric acid (61)

Synthesis 61 was synthesized according to the procedure described above for compounds 59 and 60 using: a solution of phenyl-substituted isoxazolecarboxylic acid (57) (0.800g, 4.23mmol) in ethanol/water (1: 1) (40mL), Raney-Ni (1g), 10% palladium on charcoal (0.6g), acetic acid (10mL) and heated at 50 ℃ for 4 days by hydrogen pressure of 180 psi. Purification was performed using reverse phase chromatography. Pure fractions were identified by LCMS, collected and freeze dried.

Synthesis of 2-amino-4-hydroxy-5, 5-dimethyl-hexanoic acid (62)

2-amino-4-hydroxy-5, 5-dimethyl-hexanoic acid (62) was synthesized according to the procedure described above for compounds 59, 60 and 61, using: tert-butyl-substituted isoxazole (58) (2.0g, 11.8mmol) in ethanol/water (1: 1) (40mL), Raney-Ni (2g), 10% palladium on charcoal (0.6g), acetic acid (10mL) and heated by 180psi of hydrogen pressure at 50 ℃ for 4 days. Purification was performed using reverse phase chromatography. Pure fractions were identified by LCMS, collected and freeze dried. 62: MS: m + H⁺＝17。

Synthesis of 1- (1-phenylethyl) -6-ethoxycarbonyl-4-methyl-3, 4-didehydropiperidine (63)

α -methylbenzylamine (20g) was dissolved in a solution of toluene (60mL) and 50% ethyl glyoxylate in toluene (20 mL). The flask was equipped with a magnetic stir bar and dean-stark trap. The solution was refluxed (110 ℃ oil bath) for 90 minutes and then cooled to room temperature. The crude reaction mixture was evaporated at 35 ℃ to yield a black red oil, to which was added dichloromethane (150mL), followed by isoprene (22.5 g). The mixture was cooled to-65 ℃ using cryocool and then trifluoroacetic acid (19g) and BF were added dropwise thereto₃-Et₂O (23.5g) mixture. The temperature of the reaction solution was maintained in the range of-65 ℃ to-55 ℃ and the reaction was stirred at-65 ℃ for 90 minutes, then it was warmed to-15 ℃, followed by addition of water and sodium bicarbonate to adjust the pH of the mixture to 8. The organic layer was separated from the aqueous layer, followed by MgSO ₄And drying. After evaporation a red oil was obtained. The oil was filtered over silica gel using 95% hexane/ethyl acetate. After evaporation a yellow oil was obtained which was recrystallized from hexane at-75 ℃. The solid was filtered and then recrystallized again from cold hexane to give 1- (1-phenylethyl) -6-ethoxycarbonyl-4-methyl-3, 4-didehydropiperidine (63) (8.3g) as a beige crystalline solid. 63: MS: m + H⁺：274。

Synthesis of 1- (1-phenylethyl) -6-ethoxycarbonyl-4-methyl-3, 4-didehydropiperidine (64)

Methyl ethyl 4, 5-dehydro-4-pipecolite (63) (2g, 7.3mmol) was dissolved in THF (40 mL). The reaction mixture was cooled to-78 ℃ and 1M BH was added dropwise₃THF (21.9mL, 21.9mmol) solution. The mixture was brought to 0 ℃ and stirred at 0 ℃ for 1 hour. 3N aqueous NaOH (7.3mL, 21.9mmol) was added dropwise followed by 30% H₂O₂(-2.5 mL, 21.9 mmol). The mixture was stirred at room temperature for 2 hours. Water (20mL) was added, THF was evaporated under reduced pressure, and the final product was extracted with ethyl acetate. Clear oil was obtained, purified by flash chromatography and identified using LCMSA fraction containing the desired end product. 64: MS: m + H⁺：292。¹H NMR(500MHz，CDCl₃)：δ7.4-7.2(m，5Ha)，4.2(t，3H)，3.96(m，1H)，3.4(m，1H)，3.18(m，1H)，2.69(m，1H)，2.0-1.3(m，4H)11.3(m，3H)，1.0(d，3H)。

Synthesis of 5-hydroxy-4-methyl-2-piperidinecarboxylic acid (65)

Compound 64 was subjected to basic hydrolysis in ethanol using 2 equivalents of 2N NaOH overnight. The intermediate N-phenethyl-protected hydroxy-piperidine carboxylic acid obtained from this reaction was hydrogenated in ethanol/water (H)₂Pd/C10%) overnight. After filtration, the final product was freeze-dried, purified by reverse phase chromatography (100% water), and freeze-dried to obtain pure 5-hydroxy-4-methyl-2-piperidinecarboxylic acid (65). 65: MS: m + H⁺＝160。

Synthesis of Compound 64a

Ethyl 4, 5-dehydro-4-pipecolic acid methyl ester (63) (1g, 3.65mmol) was dissolved in acetone/water (10 mL). To this solution was added osmium tetroxide (50mg, 0.183mmol, 5 mol%) and NMO (430mg, 1 eq). An exothermic reaction started immediately. The reaction was stirred overnight. HPLC analysis showed the formation of a mixture of two isomers in a ratio of-60/40. The reaction mixture was concentrated under reduced pressure and purified by flash silica gel chromatography to yield 20% of the desired compound (64 a). 64 a: MS: m + H⁺＝308。

Synthesis of 4-methyl-4, 5-dihydroxyhexahydropiperidinecarboxylic acid (65a)

The basic hydrolysis of di-hydroxyhexahydropiperidine carboxylate (64a) was carried out overnight in a KOH/EtOH/water mixture. The reaction mixture was neutralized to pH7 using 0.5N HCl and the free acid was recovered from water/ethyl acetate by extraction. Three extractions with ethyl acetate yielded the acid intermediate as a colourless oil (310 mg). MS: m + H ⁺280. The removal of the phenethyl portion was accomplished under hydrogenolysis conditions in ethanol/water using Pd/C10% (10 wt%), 120PSI hydrogen pressure. After the reaction was carried out overnight, the reaction mixture was,the reaction mixture was filtered to remove the catalyst and the ethanol was evaporated. Water (20mL) was added and the product lyophilized, then purified using RP chromatography to give 4-methyl-4, 5-dihydroxyhexahydropiperidinecarboxylic acid (65a) (125 mg). Of Compound 65a¹H NMR conformed to the specified structure and showed the presence of a mixture of isomers.

Synthesis of N- (2-hydroxypropyl) -L-valine ethyl ester (67)

To a suspension of L-valine (2g) in ethanol (50mL) cooled to-10 ℃ was slowly added thionyl chloride (2 equiv.). The reaction mixture was then refluxed for 4 hours and then stirred overnight. After removal of the solvent under reduced pressure, ethanol was added and the resulting suspension was concentrated again. The desired final product (66) was further dried in a desiccator over NaOH (quantitative yield). 66: MS: m + H⁺146. The above ethyl ester (2g) was then dissolved in water (10mL) in a sealed pyrex. The reaction mixture was stirred at 50 ℃ for 4 hours, then cooled, concentrated under reduced pressure and freeze-dried. The crude product was further purified by reverse phase column chromatography to give N- (2-hydroxypropyl) -L-valine ethyl ester (67) (1.5 g). 67: MS: m + H ⁺204. The disubstituted compound (68) is also isolated from the reaction mixture.

Synthesis of N- (2-hydroxypropyl) -L-valine (69)

Basic hydrolysis of N- (2-hydroxypropyl) -L-valine ethyl ester (67) was performed overnight in ethanol using 2N aqueous KOH (4 equivalents). The resulting mixture was then heated at 50 ℃ for 4 days. The mixture was evaporated and then water was added. The reaction product was neutralized to pH7 using HCl (0.5N). The mixture was freeze-dried and then purified by reverse phase column chromatography to give N- (2-hydroxypropyl) -L-valine (69) (1.02g, 34%). 69: MS: m + H⁺＝176。

Synthesis of N-Boc trans-4-hydroxyproline (71)

Trans-4-hydroxyproline (70) (5g, 38mmol) was dissolved in dioxane/water (1: 1) (50mL) and NaHCO was added to the solution₃(80mmol) and Boc anhydride (30mmol, 6.5 g). The reaction was stirred for 4 hours. Addition of NaHCO₃To maintain the pH above 7. The crude reaction mixture was acidified using 0.5N HCl. The dioxane was evaporated. The N-Boc trans-4-hydroxyproline was recovered by extraction using EtOAc/water. Using MgSO₄The organic phase was dried and then evaporated to yield N-Boc-4-hydroxyproline (71) (5.6g, 82%) as a clear oil.

Synthesis of Compound 72

A solution of N-Boc trans-4-hydroxyproline (71) (5g, 21.6mmol) and triphenylphosphine (11.8g, 45mmol) in anhydrous THF (150mL) was cooled to 4 ℃ in an ice bath. To the solution was added DEAD (6.5mL, 45 mmol). The reaction was allowed to stir at room temperature for 24 hours. The reaction mixture was evaporated to give a yellow oil. The crude product was purified by silica gel column chromatography to give the desired cyclic lactone (72) (2.1g, 45%).

Synthesis of Compound 73

Cyclolactone (72) (2.1g, 9.8mmol) was dissolved in dry methanol (100 mL). To the solution was added sodium azide (2.34g, 36 mmol). The reaction mixture was heated at 45 ℃ overnight. After evaporation of the crude reaction mixture, the oil obtained was purified by silica gel column chromatography to yield N-Boc-cis-4-hydroxyproline methyl ester (73) (1.3g, 54%).

Synthesis of Compound 74

N-Boc-cis-4-hydroxyproline methyl ester (73) (1.3g, 5.3mmol) was dissolved in ethanol (20 mL). To this solution was added 2N aqueous NaOH (5.3mL, 10.6 mmol). The reaction was terminated after 4 hours and acidified with 10% citric acid. The ethanol was evaporated and the final product was recovered using ethyl acetate/water extraction. The organic layer was dried over sodium sulfate, filtered and concentrated to yield N-Boc-cis-4-hydroxyproline (74) (960mg, 78%).

Synthesis of Compound 75

N-Boc-) cis-4-hydroxyproline (74) (500mg) was dissolved in30% TFA/dichloromethane (10 mL). The reaction was stirred for 1 hour, then concentrated under reduced pressure. Water (50mL) was added and the cis-4-hydroxyproline TFA salt was recovered by freeze drying to yield a light yellow solid. The yellow solid was treated with ether and acetone. The solid was redissolved in 50mL of water three times and lyophilized to give cis-4-hydroxyproline (75) (260mg) as a beige solid. 75: MS: m + H ⁺＝132。¹HNMR(500MHz，D₂O): δ 4.6(m, 1H), 4.23(m, 1H), 3.5(m, 1H), 3.39(m, 1H), 2.53(m, 1H), 2.29(m, 1H). Ent-75 (Compound 201) can be synthesized according to the synthetic route (70 → 75) using D-N-Boc-cis-4-hydroxyproline.

Synthesis of cis-4-hydroxyproline methyl ester hydrochloride (76)

Boc-) cis-4-hydroxyproline (74) (450mg, 1.95mmol) was dissolved in methanol (10mL) and cooled to 0 ℃. To the above solution was added 1.8 equivalents of thionyl chloride. The solution was heated to 45 ℃ for 4 hours and then stirred at room temperature overnight. The reaction mixture was then concentrated under reduced pressure and the cis-4-hydroxyproline methyl ester hydrochloride started to crystallize during evaporation. The crystals were filtered and washed several times with ether. The crystals were finally dried in a vacuum oven for 24 hours (40 ℃) to yield 76(354mg, -100%). 76: MS: m + H⁺＝146.¹H NMR(500MHz，D₂O): Δ 4.47(m, 2H), 3.91(s, 3H, OMe), 3.52(m, 2H), 2.57-2.47(m, 2H). Ent-76 (compound 202) can be synthesized using D-N-Boc-cis-4-hydroxyproline according to the synthetic route (70 → 74, 74 → 76).

N- (-hydroxypropyl) -L-phenylalanine (77)

To an aqueous suspension of L-phenylalanine (1g, 6mmol) in a capped Pyrex tube was added propylene oxide (10mL), followed by 48% HBr (1 mL). The suspension was heated at 80 ℃ for 15min and then at room temperature for 18 h. The reaction mixture was filtered and the crude product was purified by reverse phase chromatography to give the desired N- (2-hydroxypropyl) -L-phenylalanine (77). 77: MS: m + H ⁺224. And also fromThe disubstituted compound (78) is isolated from the reaction mixture.

Synthesis of Compounds 79 and 80

(2S, 3R, 4S) -4-hydroxyisoleucine (496.2mg, 3.4mmol) and Cs₂CO₃(1.1g, 3.4mmol) in DMF: H₂The suspension in O (10: 1) was stirred at room temperature for 15 minutes before heating to 40-45 ℃ and benzyl bromide (1.2mL, 10.2mmol) was added in portions. The reaction mixture was stirred at 40-45 ℃ for 48-110h and then cooled to room temperature. After addition of water (20mL), the product was extracted with ethyl acetate (5 × 10mL) and concentrated in vacuo to give the crude. The crude product was purified by silica gel column chromatography (EtOAc: hexane, 20: 80) to obtain compound 79(436mg, 31% yield) and compound 80(425mg, 30% yield) as clear liquids. 79:¹H NMR(500MHz，D₂o): δ 0.66(d, J ═ 6.40Hz, 3H), 1.06(d, J ═ 6.18Hz, 3H), 2.14(m, 1H), 3.19(d, J ═ 13.32Hz, 2H), 3.37(m, 2H), 4.10(d, J ═ 13.16Hz, 2H), 5.21(d, J ═ 11.75Hz, 1H), 5.34(d, J ═ 12.33Hz, 1H), 7.23-7.32(m, 10H), 7.34-7.44(m, 3), 7.47(d, J ═ 7.65Hz, 2H). Compound 80:¹H NMR(500MHz，CDCl₃)：δ1.23(d，J＝7.30Hz，3H)，1.34(d，J＝5.90Hz，3H)，2.10(m，1H)，3.58(d，J＝10.14Hz，1H)，3.78(s，4H)，4.25(m，1H)，7.25(m，2H)，7.33(t，J＝7.45Hz，4H)，7.44(d，J＝7.51Hz，4H)。

synthesis of Compound 81

Compound 79(218mg, 0.5mmol), N-methylmorpholine N-oxide (91.5mg, 0.7mmol) and powdered 4A molecular sieve (266mg) were placed in a flame-dried flask under nitrogen pressure and a mixture of anhydrous acetonitrile and dichloromethane (3ml) (2: 1) was added thereto. Tetrapropylammonium perruthenate (19.6mg, 0.02mmol) was added to the above suspension, followed by follow-up of the reaction by TLC. After concentrating the reaction mixture under reduced pressure, the crude product was taken up in dichloromethane, filtered through a pad of silica and the mixture was washed with ethyl acetate A pad. After removal of the solvent on a rotary evaporator and drying, compound 81 was obtained as a clear oil (213mg, 98% yield). Compound 81:¹HNMR(500MHz，CDCl₃)：δ0.95(d，J＝6.59Hz，3H)，1.73(s，3H)，3.15(m，1H)，3.25(d，J＝13.39Hz，2H)，3.59(d，J＝11.40Hz，2H)，3.94(d，J＝13.55Hz，2H)，5.23(d，J＝12.19Hz，1H)，5.32(d，J＝12.25Hz，1H)，7.19-7.29(m，10H)，7.36-7.47(m，5H)。

synthesis of Compound 82

To a suspension of Pd-C (44.4mg) in 96: 4 MeOH/HCOOH mixture (2.5mL) was added a solution of compound 81(44.4mg, 0.1mmol) in 96: 4 MeOH/HCOOH mixture (2.5 mL). The reaction mixture was stirred at room temperature for 30 minutes before adding more HCOOH (0.5mL) and the progress of the reaction was monitored by HPLC. The reaction mixture was filtered through filter paper and the solvent was removed on a rotary evaporator to obtain compound 82 as a white solid (10mg, 63% yield). Compound 82:¹H NMR(500MHz，D₂O)：¹H NMR(500MHz，D₂O)：δ1.33(d，J＝7.46Hz，3H)，2.30(s，3H)，3.39(m，1H)，4.03(d，J＝3.94Hz，1H)。

synthesis of Compound 83

To a solution of compound 81(80mg, 0.19mmol) in dry THF (1.6mL) at 0 deg.C was slowly added a 3M solution of MeMgI in THF (0.29mL, 0.29 mmol). The reaction mixture was stirred for 4 hours, then quenched with saturated aqueous ammonium chloride (3mL), followed by extraction with ethyl acetate (5X 3 mL). The organic phase was concentrated under vacuum to obtain the crude product, and the crude product was purified by silica gel column chromatography (ethyl acetate: hexane, 10: 90) to obtain compound 83:¹H NMR(500MHz，CDCl₃): δ 1.16(d, J ═ 7.50Hz, 3H), 1.23(s, 3H), 1.32(s, 3H), 2.32 (quintuple, J ═ 7.88Hz, 1H), 3.82(d, J ═ 14.26Hz, 2H), 4.01(d, J ═ 8.89Hz, 2H), 4.05(d, J ═ 14.12Hz, 2H), 7.25(dd, J ═ 6.32Hz, J ═ 8.27Hz, 2H), 7.33(t, J ═ 7.45Hz, 4H), 7.44(d, J ═ 7.51Hz, 4H) 。

Synthesis of Compound 84

To a suspension of Pd-C (56mg) in a 96: 4 mixture of MeOH: HCOOH (2.5mL) was added a solution of compound 83(56mg, 0.17mmol) in a 96: 4 mixture of MeOH: HCOOH (1 mL). The reaction mixture was stirred at room temperature for 30 minutes before adding more HCOOH (0.5mL) and the progress of the reaction was monitored by HPLC. The reaction mixture was filtered through filter paper and the solvent was removed on a rotary evaporator to obtain compound 84 as a white solid (8mg, 73% yield). Compound 84:¹H NMR(500MHz，D₂o): δ 1.11(d, J ═ 7.21Hz, 3H), 1.51(s, 3H), 1.57(s, 3H), 2.89 (quintuple, J ═ 7.5Hz, 1H), 4.87(d, J ═ 7.81Hz, 1H).

Synthesis of Compound 85

An ethanol solution (0.5mL) of 84(25mg, 0.17mmol) was added to an aqueous solution of LiOH (0.5M, 0.5mL, 0.24mmol), and the mixture was stirred at room temperature for 30 minutes. The pH of the reaction mixture was brought to-7 by careful addition of aqueous HCl (0.1M), and after dilution with more water, the mixture was freeze-dried to obtain compound 85 as a white solid (25mg, 90% yield). Compound 85:¹H NMR(500MHz，D₂o): δ 1.06(d, J ═ 7.17Hz, 3H), 1.29(s, 3H), 1.42(s, 3H), 2.03 (quintuple, J ═ 6.69Hz, 1H), 3.97(d, J ═ 5.36Hz, 1H).

Synthesis of Compound 87

To a solution of imine 1(200mg, 0.97mmol) in dry DMF (2mL) at 0 ℃ under argon was added 1-bromo-3-methylbut-2-ene (86a) (146. mu.L, 1.26mmol) followed by (82mg, 1.26mmol) and one drop of TMSCI. The reaction mixture was allowed to warm to room temperature over 45 minutes. After cooling to 0 ℃, saturated NH was used₄The reaction mixture was neutralized with Cl and extracted with diethyl ether (3 × 50 mL). The organic phase was washed with brine and over Na₂SO₄Drying, filtering with cotton swab, concentrating, and purifying with silica gel column chromatography(ethyl acetate/hexane, 10/90) to give compound 87 as an organic oil (2.89g, 83% yield). The same procedure when starting material with 1-bromo-2-methylbut-2-ene (86b) instead of 1-bromo-3-methylbut-2-ene (86a) yields compound 88.

Synthesis of Compound 89

To a solution of iodosobenzene diacetate (930mg, 2.8mmol) in dry MeOH (9.5mL) under argon was added a solution of alkene intermediate 87(200mg, 0.61mmol) in dry MeOH (1.5mL) over a period of 30 minutes. After stirring the reaction mixture at room temperature for 30 minutes, the mixture was neutralized with 1N HCl (25 mL). The reaction mixture was stirred for another 90 minutes and CH was used₂Cl₂(2X 40mL) followed by washing the organic phase with 0.1M HCl (25 mL). Will CH ₂Cl₂(20mL) was added to the combined acidic aqueous phases and purified by addition of solid Na₂CO₃The mixture was basified and di-tert-butylbicarbonate (788mg, 3.6mmol) was added. The reaction mixture was stirred for 90 minutes before pouring the aqueous phase and CH was used₂Cl₂The mixture was extracted (2X 40 mL). In Na₂SO₄The combined organic phases were dried over, filtered through a cotton swab, concentrated, and purified by silica gel column chromatography (ethyl acetate/hexane, 10/90) to obtain compound 89 as a pale yellow organic oil (106mg, 54% yield). The same procedure yielded compound 90 when the starting material was substituted for compound 87 with compound 88.

Synthesis of Compound 91

To a solution of compound 89(707mg, 2.6mmol) in a mixture of 1: 1 THF: EtOH (10mL) was added a 1N NaOH solution (83.2mL, 83.2mmol) and the mixture was heated under reflux for 12 h. The reaction mixture was cooled to room temperature, concentrated and extracted with ethyl acetate (2 × 50 mL). In Na₂SO₄The combined organic phases were dried, filtered through a cotton swab, and concentrated to obtain unreacted compound 89. 1N HCl was carefully added to acidify the aqueous phase to pH2 and extracted with ethyl acetate (3X 50 mL). In Na₂SO₄Combined by dryingThe organic phase was filtered through a cotton-tipped swab and concentrated to obtain compound 91. The above procedure was repeated for the recovered compound 89 to obtain compound 91 as a white solid in an overall yield of 445.5mg (72% yield). The same procedure yielded compound 92 when the starting material was substituted for compound 89 with compound 90.

Synthesis of Compound 93

To a solution of compound 91(741mg, 3mmol) in dimethoxyethane (30mL) under argon at-20 deg.C (ice/MeOH mixture) was added N-iodosuccinimide (1.05g, 4.6mmol) portionwise. The reaction mixture was stirred at room temperature for 12 hours, neutralized with brine, and extracted with diethyl ether (3 × 50 mL). The combined organics were washed with Na₂S₂O₅Washed with saturated aqueous solution of (3) over Na₂SO₄Dried, filtered through a cotton swab and concentrated to give iodolactone intermediate 93 as a pink solid (1.108g, 98% yield). The same procedure yielded compound 94 when the starting material was substituted for compound 91 with compound 92.

Synthesis of Compound 95

To a solution of iodolactone 93(705mL, 1.9mmol) in distilled benzene (5mL) under argon pressure was added tetrabutyltin hydride (824. mu.L, 3mmol) and AIBN (recrystallized from MeOH, 43.4mg, 0.19 mmol). The reaction mixture was heated to reflux for 6 hours. Adding CCl to the reaction mixture₄(5mL) and heating at reflux was continued for another 12 hours. The reaction mixture was cooled, concentrated in vacuo, and the crude product was purified by silica gel column chromatography (ethyl acetate/hexane, 10/90) to obtain compound 95(406mg, 88% yield) as a white solid. The same procedure yielded compound 96 when compound 94 was substituted for compound 93 from the starting material.

Synthesis of Compound 97

To a stirred mixture of compound 95(210mg, 0.87mmol) in dry CH under argon₂Cl₂Trifluoroacetic acid (2.34mL, 30mmol) was added to the solution and the mixture was allowed to warm to room temperature over 4 hours. ConcentrationAfter condensation of the reaction mixture, the aminolactone intermediate 97 was obtained as a white solid (205mg, 93% yield). The same procedure yielded compound 98 when the starting material was substituted for compound 95 with compound 96.

(2S, 4S) -and (2R, 4R) -2-amino-4-hydroxy-3, 3-dimethylpentanoic acid (Compounds 99a and 99b) Synthesis of racemic mixtures of

To a solution of aminolactone 97(144mg, 0.56mmol) in distilled water (1.7mL) was added LiOH (34mg, 1.4 mmol). The reaction mixture was stirred at room temperature for 25 minutes and the pH of the reaction mixture was adjusted to 6-7 by careful dropwise addition of acetic acid. The reaction mixture was then concentrated in vacuo. To remove residual water, the crude product was dissolved in anhydrous EtOH and concentrated again in vacuo, after which the process was repeated 3 more times. The crude product was recrystallized from a minimal amount of EtOH at-20 ℃. The solid was filtered and washed with EtOH to obtain a racemic mixture of (2S, 4S) -and (2R, 4R) -2-amino-4-hydroxy-3, 3-dimethylpentanoic acid (compounds 99a and 99b) as a white solid (66mg, 73% yield). ¹H NMR(200MHz，D₂O)：δ1.04(2s，3H)，1.05(2s，3H)，1.22(d，J＝6.34Hz，3H)，3.65(s，1H)，3.83(q，J＝6.10Hz，1H)。13C(75MHz，D₂O)：δ17.30，20.16，21.68，38.47，62.05，73.93，173.60。IR(KBr)：3 191，2973，2880，1610，1492，1398，1344，1105cm^-1。MS(m/z)：162(M+1)，184(M+Na)，323(2M+1)。

Exo-xiao of (2S, 3S) and (2R, 3R) -2-amino-4-hydroxy-3, 4-dimethylpentanoic acid (100a and 100b) The racemic mixture (2S, 3R) and (2S, R) -2-amino-4-hydroxy-3, 4-di-pivalic acid (101a and 101b) Synthesis of racemic mixtures of

The procedures for synthesizing compounds 100(a and b) and 101(a and b) are the same as those for compound 99, except that aminolactone 98 is used as a starting material instead of compound 97.

The physical and NMR data for the mixture of compounds 100a and 100b are as follows:¹H NMR(300MHz，D₂O)：δ1.01(d，J＝7.17Hz，3H)，1.25(s，3H)，1.37(s，3H)，1.98(m，1H)，3.93(d，J＝5.61Hz，1H)。¹³C NMR(50MHz，D₂O)：δ11.32，25.19，29.16，43.59，57.41，73.86，174.57.IR(KBr)：32982，2924，2659，1783，1629，1527，1471，1393，1278，1172，1134，1061，934，549 cm^-1。MS(m/z)：162(M+1)，184(M+Na)，323(2M)，345(2M+Na)。

compound 101a&101b mixture the physical and NMR data are as follows:¹H NMR(200 MHz，D₂O)：δ1.01(d，J＝7.34Hz，3H)，1.33(s，3H)，1.41(s，3H)，2.19(m，1H)，4.16(d，J＝5.61Hz，1H)。¹³C NMR(50 MHz，D₂O)：δ8.17，25.07，28.03，46.14，56.52，73.64，174.91.IR(KBr)：3400，3120，3036，2975，1781，1692，1620，1598，1499，1393，1356，1185，1148，1083，942，883，680，531cm^-1。MS(m/z)：162(M+1)，184(M+Na)，323(2M+1)，345(2M+Na)。

synthesis of 2-amino-3, 4-dimethylpent-4-enoic acid (Compound 102a)

A solution of compound 92(450mg, 1.85mmol) in a mixture of 1N HCl: HCOOH (2.9mL) (1: 3) was stirred at 50 ℃ for 12 h. After cooling the reaction mixture to room temperature, toluene (1mL) was added and the mixture was concentrated in vacuo to remove HCOOH and the process was repeated twice. The crude mixture was lyophilized for 12 hours, diluted with a minimal amount of ethyl acetate (250 μ L), and treated with propylene oxide (3.5 mL). The reaction mixture was stirred at room temperature for 6 hours and filtered. The precipitate was washed with hexane and lyophilized for 12 hours to obtain a racemic mixture of the diastereomer of 2-amino-3, 4-dimethylpent-4-enoic acid (compound 102a) as a white solid (186mg, 70% yield). ¹H NMR(300MHz，D₂O)：1.06(d，J＝7.17Hz，3H)，1.13(d，J＝7.17Hz，3H)，1.71(s，3H)，1.81(s，3H)，2.64(m，1H)，2，83(m，1H)，3.55(d，J＝8，64Hz，2H)，3.88(d，J＝3.75Hz，1H)，4.92(s，1H)，4.94(s，1H)，5.01(s，1H)，5.06(s，1H)。¹³C NMR(50MHz，D₂O)：δ12.17，16.09，18.79，21.04，40.67，42.90，56.52，57.91，113.84，114.94，144.81，145.01，174.26，174.45.IR(KBr)：3092，2976，2672，2102，1626，1589，1516，1401，1327，1185，901，716cπfl.MS(m/z)：166(M+Na)，287(2M)。Anal.Calcd for C₇H₁₃NO₂：C，58.72；H，9.15；N，9.78。Found：C，58.53；H，9.02；N，9.61。

Similarly, 102b was synthesized from compound 91. Compound 102 b:¹H(300MHz，D₂O)：δ1.06and1.13(2d，J＝7.17Hz，3H，H6，H₆) 1.71 and 1.81(2s, 3H, H)₇ et H₇) 2.64 and 2.83(2m, 1H, H3 et H)₃)，3.55(d，J＝8.64Hz，2H，N H₂)，3.88(d，J＝3.75Hz，1H，H₂)，4.92，4.94，5.01，5.06(2x2s，1H，H₅ et H₅)。¹³C NMR(50MHz，D₂O)：δ12.17，16.09，18.79，21.04，40.67，42.90，56.52，57.91，113.84，114.94，144.81，145.01，174.26，174.45.IR(KBr)：3092，2976，2672，2102，1626，1589，1516，1401，1327，1185，901，716cm^-1。MS(m/z)：166(M+Na)，287(M+M)。

Synthesis of Compound 103

(2S, 3R, 4S) -4-hydroxyisoleucine (100mg, 0.68mmol) was heated under reflux in aqueous HCl (6N) or HBr for 6 hours. The reaction mixture was cooled to room temperature and neutralized to pH7 using NaOH. After concentration, the crude product was purified by silica gel chromatography (ethyl acetate: hexane, 1: 4) to give compound 103(62mg, 70% yield) as a white solid.¹H NMR(500MHz，CDCl₃): δ 1.24(d, J ═ 7.42Hz, 3H), 1.52(d, J ═ 7.10Hz, 3H), 2.85 (quintuple, J ═ 7.42Hz, 1H), 4.71(m, 2H).

Synthesis of Compound 104

Chemical combinationSubstance 103(100mg, 0.48mmol) was dissolved in pyridine (2mL), followed by addition of acetic anhydride (0.07mL, 0.718mmol) and stirring of the mixture at room temperature overnight. After concentration, the residue was taken up in water and the pH was adjusted to 3-4 using aqueous HCl (0.1M) (0.1M). The aqueous phase was extracted with ethyl acetate (4X 5ml) and concentrated. Recrystallisation from hexane/ethyl acetate yielded compound 104 as a white solid (18mg, 22% yield). Compound 104:¹H NMR(500MHz，CDCl₃): δ 4.74(1H, dd, J ═ 5.57Hz, J ═ 7.65Hz), 4.41(1H, quartet (quad), J ═ 6.64Hz), 2.68(1H, quintuple, J ═ 7.42Hz), 2.08(3H, s), 1.45(3H, s), 0.95(3H, d, J ═ 7.30 Hz).

Synthesis of Compound 105

To compound 103(100mg, 0.48mmol) in anhydrous CH₂Cl₂(2mL) solution pyridine (0.12mL, 1.44mmol) was added and after addition of benzoyl chloride (0.06mL, 0.53mmol) the mixture was cooled to 0 ℃. The reaction mixture was stirred at 0 ℃ for 1 hour, at room temperature overnight, and then refluxed for 5.5 hours. More pyridine (0.48mmol) and benzoyl chloride (0.48mmol) were added to the cooled mixture, which was stirred overnight. The reaction mixture was diluted with ethyl acetate (5mL) and washed with 1N HCl (4X 8mL) until pH 3-4. With saturated NaHCO₃(5mL) and then the organic phase was washed with water (5mL) to pH 8. The organic layer was concentrated and the crude product was recrystallized from hexane/ethyl acetate to give the title compound 105 as a white solid (40mg, 36% yield). Compound 105:¹H NMR(500MHz，CDCl₃): δ 7.82(2H, d, J ═ 8.0Hz), 7.55(1H, t, J ═ 7.41Hz), 7.47(2H, t, J ═ 7.62Hz), 4.92(1H, dd, J ═ 5.29Hz, J ═ 8.02Hz), 4.47(1H, quartet, J ═ 6.6Hz), 2.84(1H, quintuple, J ═ 7.34Hz), 1.51(3H, d, J ═ 7.05Hz), 1.02(3H, d, J ═ 7.36 Hz).

Synthesis of Compound 106

To a solution of compound 103(100mg, 0.48mmol) and triethylamine (0.067mL, 0.48mmol) in dry THF (1.8mL) at 0 deg.C were added benzaldehyde (0.07mL, 0.71mmol) and tris (tert-butyl ether) successively Sodium acetoxyborohydride (149mg, 0.67 mmol). The reaction mixture was stirred at 0 ℃ for 3 hours, and after addition of water (10mL), extracted with ethyl acetate (4X 5 mL). The organic phases were combined and concentrated in vacuo to give the crude product. The crude product was purified by silica gel column chromatography (EtOAc: hexane, 1: 4) to obtain compound 106(45mg, 43% yield) as a white solid. Compound 106:¹H NMR(500MHz，CDCl₃)：δ7.3-7.2(5H，m)，4.0(3H，m)，3.2(1H，d，J＝Hz)，2.0(1H，m)，1.4(3H，d，J＝Hz)，1.1(3H，d，J＝Hz)。

synthesis of Compounds 107a, b and 108a, b

To a solution of compound 103(1g, 4.76mmol) in dichloromethane (15mL) was added triethylamine (2mL, 14.3mmol) at 0 ℃ and after 15 minutes p-toluenesulfonyl chloride (1.36g, 7.14 mmol). The resulting compound was slowly warmed to room temperature and then stirred overnight. After addition of water (30mL), the reaction mixture was extracted with dichloromethane (5X 10mL) and ethyl acetate (2X 10 mL). The organic phases were combined and saturated NaHCO was used₃The aqueous solution and brine were washed and concentrated in vacuo to afford the crude as an orange residue. The crude product was purified by silica gel column chromatography (ethyl acetate: hexane, ranging from 5: 95 to 25: 75) to obtain compound 107a (982mg, 73% yield) as a white solid and 108a (31mg, 15% yield) as a white solid. 107 a:¹H NMR(500MHz，CDCl₃): δ 7.79(2H, d, J ═ 8.17Hz), 7.34(2H, d, J ═ 8.20Hz), 4.83(1H, d, J ═ 3.59Hz), 4.37(1H, q, J ═ 6.72Hz), 4.10(1H, dd, J ═ 3.95Hz, J ═ 7.53Hz), 2.54(1H, quintuple, J ═ 7.27Hz), 2.44(3H, s), 1.37(3H, d, J ═ 6.95Hz), 1.08(3H, d, J ═ 7.40 Hz). 108 a: ¹H NMR(500MHz，CDCl₃): δ 7.98(2H, d, J ═ 8.14Hz), 7.32(4H, dd, J ═ 8.08Hz), 7.16(2H, d, J ═ 7.95Hz), 4.78(1H, d, J ═ 11.29Hz), 4.52(1H, m), 2.47(3H, s), 2.40(3H, s), 2.34-2.17(1H, m), 1.41(3H, d, J ═ 6.26Hz), 1, 15(3H, d, J ═ 7.28 Hz). N-Cbz derivatives 107b and 108b were synthesized according to the above synthetic route using Cbz-Cl or Cbz-anhydride as electrophile.

Synthesis of Compound 109

To a solution of compound 103(1g, 4.76mmol) in dichloromethane (15mL) was added triethylamine (2mL, 14.3mmol) and o-nitrobenzenesulfonyl chloride (1.62g, 7.14mmol) at 0 ℃. The resulting mixture was allowed to warm to room temperature and stirred overnight. Water (30mL) was added and the mixture was stirred for 1 hour. The crude product was extracted with dichloromethane (5X 15mL) and ethyl acetate (15 mL). The organic phases were combined and washed with saturated NaHCO₃The aqueous solution (30mL) and brine (70mL) were washed and concentrated. The crude product was purified by silica gel column chromatography to obtain compound 109(0.77g, 65% yield) as a white solid. Compound 109:¹H NMR(500MHz，CDCl₃): δ 1.17(d, J ═ 7.43Hz, 3H), 1.42(d, J ═ 6.39Hz, 3H), 2.57 (quintuple, J ═ 7.44Hz, 1H), 4.40(m, 2H), 5.94(d, NH, 1H), 7.77(dd, J ═ 3.36Hz, J ═ 5.54Hz, 2H), 7.97(t, J ═ 4.51Hz, 1H), 8.15(dd, J ═ 3.57 Hz, J ═ 5.31Hz, 1H).

Synthesis of Compound 110

Pyrrolidine (0.38mL, 4.54mmol) was added dropwise to a solution of compound 109(476mg, 1.51mmol) in dichloromethane (8mL) at 0 ℃. The mixture was stirred at 5 ℃ overnight and then at room temperature for 2 hours. To the mixture was added dichloromethane (5mL) and water (4mL) and the pH was adjusted to 6-7 by careful dropwise addition of HCl (1N), followed by CH₂Cl₂(4X 5mL) and ethyl acetate (5 mL). The organic phases were combined, Na₂SO₄Dried and concentrated to give compound 110 as a white solid (290mg, 60% yield). Compound 110:¹H NMR(500MHz，CDCl₃)：δ0.97(d，＝6.83 Hz，3H)，1.18(d，＝5.95Hz，3H)，1.69(bs，1H)，1.77-1.94(m，4H)，2.92(m，1H)，3.21(m，1H)，3.49(m，1H)，3.84(m，1H)，4.29(d，＝4.58Hz，1H)，7.68(m，2H)，7.91(m，1H)，8.00(m，1H)。

synthesis of Compounds 111a, b

To a solution of compound 107a (200mg, 0.71mmol) in ethanol (2.6mL) and THF (0.7mL) was added dropwise an aqueous solution of LiOH (33mg, 0.78 mmol). The reaction mixture was stirred at room temperature overnight. Before the solvent was removed, the pH was adjusted to 6 by careful dropwise addition of aqueous HCl (1N). The product was dried under reduced pressure to give compound 111a as a white solid (207mg, 98% yield). Compound 111 a:¹H NMR(500MHz，CDCl₃): δ 7.77(2H, d, J ═ 7.88Hz), 7.47(2H, d, J ═ 7.79Hz), 3.96(1H, quintuple, J ═ 5.75Hz), 3, 49(1H, d, J ═ 7.77Hz), 2.46(3H, s), 1.87(1H, m), 1.03(3H, d, J ═ 6.21Hz), 0.84(3H, d, J ═ 6.77 Hz). The N-CBz derivative (111b) was synthesized according to the above synthetic route.

Synthesis of Compounds 112a, b

To 0 deg.C cooled Compound 107a (200mg, 0.71mmol) in anhydrous CH₂Cl₂Pyrrolidine (0.18mL, 2.12mmol) was added to the solution and the mixture was stirred at 5 ℃ for 48 h. Adding CH to the mixture₂Cl₂(5mL) and water (3mL), the pH was adjusted to 6 by careful dropwise addition of aqueous HCl (1N). Using CH₂Cl₂The crude product was extracted (5mL) and EtOAc (3X 5mL), and the organic phases were combined and washed with Na₂SO₄Dried and concentrated. The crude product was purified by silica gel column chromatography to obtain compound 112a (154mg, 62% yield) as a white solid. Compound 112 a:¹H NMR(500MHz，CDCl₃)：0.93(d，J＝6.64Hz，3H)，1.17(d，J＝5.94Hz，3H)，1.58(m，1H)，1.70-1.76(m，2H)，1.88(m，2H)，2.42(s，3H)，2.97(m，1H)，3.05(m，1H)，3.11(m，1H)，3.21(m，1H)，3.34(m，1H)，3.89(m，2H)，6.07(d，J＝9.12Hz，1H)，7.29(d，J＝7.31Hz，2H)，7.73(d，J＝7.59Hz，2H)。¹³C-NMR(500MHz，CDCl₃): δ 14.3, 21.0, 22.4, 24.7, 26.7, 44.5, 46.8, 47.3, 58.2, 68.8, 128.3, 130.3, 137.8, 144.4, 170.9. The N-CBz derivative (112b) was synthesized according to the above synthetic route.

Synthesis of Compounds 113a, b

To compound 112a (100mg, 0.28mmol) in anhydrous CH₂Cl₂PCC (225mg, 1.17mmol) was added to the solution (15mL) and the resulting mixture was stirred at room temperature. The reaction mixture was filtered through a pad of celite and concentrated. The crude product was purified by silica gel column chromatography to obtain compound 113a (86mg, 82% yield) as an oil. Compound 113 a:¹H NMR(500MHz，CDCl₃): δ 1.02(d, J ═ 6.6Hz, 3H), 1.6(m, 1H), 1.73(m, 1H), 1.83(m, 1H), 2.19(s, 3H), 2.41(s, 3H), 2.86(m, 1H), 3.02(m, 1H), 3.21(m, 1H), 3.32(m, 1H), 4.16(t, J ═ 8.79Hz, 1H), 5.62(bs, 1H), 7.27(d, J ═ 11.45 z, 2H), 7.69(d, J ═ 8.07Hz, 2H). The N-CBz derivative (113b) was synthesized according to the above synthetic route.

Synthesis of Compound 114

To a mixture of (2S, 3R, 4S) -4-hydroxyisoleucine (442.7mg, 3.0mmol) and NaOH (132mg, 3.3mmol) in water (11mL) and tert-butanol (6mL) was added CbzCl (561mg, 3.3mmol) dropwise. The resulting reaction mixture was stirred at room temperature. The reaction mixture was acidified to pH2 using 1M HCl. The mixture was extracted with DCM (2X 100 mL). The organic phase is passed through Na₂SO₄Dried and evaporated to give 114(790mg, 99%) as a white solid. 114:¹H NMR(500MHz，CDCl₃)：δ1.00(d，J＝7.07Hzl 3H)1 1.44(d，J＝6.31Hz，3H)，2.59(m，1H)，4.39(m，1H)，4.66(m，1H)，5.14(s，2H)，5.52(br，1H)，7.37(m，5H)。

synthesis of Compound 115

To compound 114(1g, 3.8mmol) in anhydrous CH₂Cl₂Pyrrolidine (0.94mL, 11.4mmol) was added dropwise to the solution (10mL) and the mixture was stirred at room temperature for 6 hours. Water (3mL) was added to the reaction mixture and extracted with dichloromethane (4X 10mL) and EtOAc (10 mL). The organic phases were combined and washed with aqueous HCl (1N, 6mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (EtOAc: hexane: methanol, 1: 1/8) to obtain a clear liquidCompound 115(694mg, 55% yield). Compound 115:¹H NMR(500MHz，CDCl₃)：δ0.97(d，J＝7.0Hz，3H)，1.19(d，J＝6.14Hz，3H)，1.81-1.91(m，2H)，1.92-2.00(m，3H)，3.40-3.58(m，4H)，3.60-3.73(m，2H)，4.51(dd，1H)5.10(s，2H)，5.82(d，51H)，7.27-7.32(m，5H)。

synthesis of Compound 116

To compound 103(1g, 4.76mmol) in 5 min anhydrous CH₂Cl₂Pyrrolidine (2.36mL, 26.8mmol) was added dropwise to the solution (10mL) and the resulting pale yellow mixture was stirred at room temperature overnight. Water (10mL) was added to the reaction mixture and the pH was adjusted to 5 using aqueous HCl (1N, 16 mL). The aqueous phase was extracted with dichloromethane (5X 10mL) and EtOAc (10 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (EtOAc: hexane: methanol, 1: 1/8) to give compound 116(694mg, 55% yield) as a white solid. Compound 116: ¹H NMR(500MHz，CDCl₃)：δ4.60(1H，d，J＝10.43Hz)，4.28(1H，d，J＝10.31Hz)，3.69(1H，m)，3.49(3H，m)，3.34(2H，m)，2.26(1H，bs)，2.00-1.83(4H，m)，1.74(1H，m)，1，25(3H，d，J＝7.28Hz)，0.78(3H，d，J＝6.64Hz)。

Synthesis of Compound 117

To compound 116(100mg, 0.5mmol) in CH at 0 deg.C₂Cl₂(3mL) Triethylamine (0.21mL, 1.5mmol) was added to the solution and the mixture was stirred for 15 minutes. P-toluenesulfonyl chloride (105mg, 0.55mmol) was added, and the resulting mixture was allowed to warm to room temperature and stirred overnight. Water (6mL) was added and the mixture was stirred for another 30 minutes. The aqueous phase was extracted with dichloromethane (3X 15mL) and EtOAc (2X 5 mL). The combined organic phases were washed with saturated NaHCO₃Washed (15mL) with brine (30mL), dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to obtain compound 117(129mg, 71% yield) as a white solid. Compound 117:¹H NMR(500MHz，CDCl₃)：δ0.75(d，J＝6.62Hz，3H)，1.35(d，J＝6.07Hz，3H)，1.80-2.07(m，4H)，2.42(s，3H)，3.09-3.15(m，1H)，3.45-3.55(m，3H)，3.75(m，1H)，3.84(m，1H)，4.70(d，J＝10.86Hz，1H)，5.44(d，J＝10.62Hz，1H)，7.29(d，J＝7.89Hz，2H)，7.84(d，J＝7.84Hz，2H)。

synthesis of Compound 118

To a solution of compound 116(200mg, 0.94mmol) in dry THF (4mL) was added NaH (47mg, 1.18mmol), and the mixture was stirred at room temperature for 30 min. Benzyl bromide (177mg, 1.04mmol) was added and the reaction mixture was stirred for 15 h. Water (4mL) was added and the mixture was stirred for another 30 minutes. The aqueous phase was extracted with dichloromethane (4X 4mL) and EtOAc (4 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography to obtain compound 118(185mg) as a white solid. Compound 118: ¹H NMR(500MHz，CDCl₃)：δ0.81(d，J＝6.31Hz，3H)，1.30(d，J＝5.98Hz，3H)，1.70-1.82(m，1H)，1.86-1.94(m，1H)，2.14-2.22(m，1H)，3.16-3.21(m，1H)，3.26-3.32(m，1H)，3.36(d，J＝10.63Hz，1H)，3.41-3.46(m，2H)，3.73(d，J＝14.24Hz，1H)，3.96-3.99(m，2H)，4.24(d，J＝10.29Hz，1H)，4.44(d，J＝10.24Hz，1H)，7.18-7.28(m，5H)。

Synthesis of Compound 119

To a solution of compound 103(1.05g, 5mmol) in methanol (20mL) under nitrogen pressure was added pyrrolidine (2.2mL, 25mmol) and the reaction mixture was stirred at room temperature overnight. After removal of the solvent, the crude product was purified by silica gel column chromatography (dichloromethane: methanol, 90: 10) to give compound 119(618mg, 61% yield) as a white solid. Compound 119:¹H NMR(500MHz，CDCl₃)：δ0.90(d，J＝6.98Hz，3 H)，1.87(d，J＝6.11Hz，3 H)，1.92(m，1H)，1.97(m，2H)，2.05(m，2H)，3.46(m，2 H)，3.57(m，1H)，3.94(m，2H)，4.29(m，1H)。¹³CNMR(500MHz，CDCl₃)：δ14.4，23.3，25.0，26.8，42.7，47.4，48.6，57.9，73.2，169.1。

to a solution of compound 119(50mg, 0.25mmol) and triethylamine (0.1mL, 0.8mmol) in dichloromethane (3mL) under nitrogen pressure was added a solution of p-toluenesulfonyl chloride (53mg, 0.28mmol) in dichloromethane (0.5mL), and the resulting reaction mixture was stirred at room temperature overnight. After removal of the solvent, the crude product was purified by silica gel column chromatography (dichloromethane: methanol, 80: 20) to obtain compound 112(49mg, 55% yield) as a pale yellow solid.

Synthesis of Compound 120

To a solution of compound 119(50mg, 0.25mmol) in dichloromethane (1mL) was added a 1M solution of LiHMDS in hexane (0.55mL, 0.55mmol) at 0 ℃ under nitrogen pressure. After 15 min, the reaction mixture was cooled to-78 ℃ and benzyl bromide (213mg, 1.25mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. After completion of the reaction, it was quenched with methanol, concentrated, and the crude product was purified by silica gel column chromatography to give compound 120(49mg, 55% yield) as a colorless liquid. Compound 120: ¹H NMR(500MHz，CDCl₃)：δ0.77(d，J＝6.98Hz，3H)，1.19(d，J＝5.86Hz，3H)，1.67(m，1H)，1.92(m，4H)，3.27-3.37(m，3 H)，3.51-3.61(m，3H)，3.70(m，1H)，3.80(d，J＝13.01Hz，1H)，7.32(m，5H)。

Of Compounds 121a and 121b

In a round-bottomed flask, (2S, 3R, 4S) -4-hydroxyisoleucine (295mg, 2.0mmol), Cs₂CO₃(1.3g，4mmol)、BnEt₃NBr (227mg, 1.0mmol) and BrCH₂COOEt (0.24mL, 2.2mmol) was added sequentially^tBuOMe/H₂O (1: 1, 20 mL). The resulting mixture was stirred at 40 ℃ for 48 hours. The pH of the mixture was then adjusted to 4. The solvent was removed under reduced pressure and the crude product was purified by HPLC to afford compound 121a (360mg) and 121b (20mg) as white solids (92% of the total after lyophilization). 121 a:¹H NMR(500MHz，D₂O)：δ3.88(m，1 H)，3.81(d，J＝5.77Hz，1H)，3.53-3.70(dd，2H)，1.96(m，1H)，1.29(d，J＝6.32Hz，3H)，0.98(d，J＝7.22Hz，3H)。121b：¹H NMR(500MHz，D₂O)：δ3.76-4.08(m，6H)，2.10(m，1H)，1.37(d，J＝6.50Hz，3H)，1.08(d，J＝7.45Hz，3H)。

synthesis of Compound 123

A solution of diphenyllactone (122) (154mg, 0.5mmol) obtained from (2S, 3R, 4S) -4-hydroxyisoleucine in EtOH (3mL) was added dropwise to a solution of LiOH (0.6mmol, 0.2M). The resulting mixture was stirred at room temperature overnight and monitored by TLC. After adjusting the pH to 6, the solvent was removed under reduced pressure and the crude product was purified by HPLC to provide pure hydrophobic compound 123(24.5mg, 15%). The diastereomeric product was also recovered in 70% of the product during purification. 123:¹H NMR(500MHz，CD3OD)：δ7.23-7.40(m，10H)，3.82-3.96(m，5H)，3.37(d，J＝11.77Hz，1H)，2.10(m，1H)，1.33(d，J＝6.26Hz，3H)，1.00(d，J＝6.73Hz，3H)。

synthesis of Compound 125

To a solution of commercially available (S) -methyl lactate (124) (590mg, 5.0mmol) and p-toluenesulfonic acid (minor crystals) in THF (5mL) at 0 deg.C under nitrogen was added DHP (0.42mL, 5.5mmol) dropwise. The resulting mixture was stirred at room temperature for 3 hours. After evaporation of the solvent, and purification of the crude product by silica gel column chromatography to afford compound 125 as a clear oil (0.86g, 92% yield).

Synthesis of Compound 126

DIBAL (10mL, 10.0mmol, 1.0M in toluene) was added dropwise to a solution of compound 125(752.4mg, 4.0mmol) in toluene (25mL) at-78 deg.C under nitrogen. The resulting mixture was stirred at-78 ℃ for 2.5 hours, followed by addition of CH₃OH (3mL) was quenched. After 5 minutes, concentrated potassium sodium tartrate solution (25mL) was added and the resulting mixture was warmed to room temperature for 15 minutes. The mixture was extracted with ethyl acetate (3X 00 mL). After removal of the solvent under reduced pressure, are obtained asAnd the crude product was purified by silica gel column chromatography to provide 126 as a nice oil (620mg, 98% yield).

Synthesis of Compound 127

Use (iPr)₂NEt (0.70mL, 4.0mol) and valine methyl ester hydrochloride (670mg, 4.0mmol) and sodium cyanoborohydride (4.0mL, 4.0mmol, 1.0M in THF) the oil (126) obtained above was dissolved in methanol (25mL) at 0 ℃. The reaction mixture was stirred at room temperature overnight. After evaporation, the crude product was purified by silica gel column chromatography to provide 127(920mg, 66%) as a clear oil. The other diastereomer was also present in the reaction mixture, but was removed by chromatography. 127:¹HNMR(500MHz，CDCl₃)：δ0.89(d，J＝6.71Hz，3H)，0.91(d，J＝6.80Hz，3H)，1.14(d，J＝6.33Hz，3H)，1.83-1.89(m，5H)，2.33(m，1H)，2.58(m，1H)，2.94(m，J＝6.35Hz，1H)，3.68(s，3H)，3.74(m，1H)，3.82(m，1H)，3.88(m，1H)，5.24(s，1H)。

synthesis of Compound 128

To a solution of compound 127(546.2mg, 2.0mmol) in ethanol (2mL) was added NaOH (2.5mL, 2.5mmol, 1.0M in H dropwise ₂O in)). The resulting mixture was stirred at room temperature overnight. HCl (4mL, 1.0M) was then added. The resulting mixture was stirred at room temperature for another 4 hours. The mixture was evaporated in vacuo. The crude product was recrystallized from 2% methanol (in dichloromethane) to afford 128 as a white solid (285mg, 95% yield). 128:¹H NMR(500MHz，CDCl₃)：δ1.06(d，J＝6.92Hz，3H)，1.12(d，J＝6.90Hz，3H)，1.26(d，J＝6.12Hz，3H)，2.37(m，1H)，3.02(m，1H)，3.24(d，J＝12.92Hz，1H)，3.85(d，1H)，4.15(m，1H)。

synthesis of Compound 133

Compound 133(SR) isomer was synthesized according to the above synthetic route for SS-isomer starting from (R) -methyl lactate (129) with an overall yield of 60%. 133:¹H NMR(500MHz，CDCl₃)：δ1.06(d，J＝6.86Hz，6H)，1.12(d，J＝7.08Hz，3H)，2.33(m，1H)，3.03(m，1H)，3.21(d，J＝12.96Hz，1H)，3.68(d，J＝3.77Hz，1H)，4.19(m，1H)。

synthesis of Compound 134

To a mixture of 2-pentanone (22 eq) and L-proline (0.35 eq) in DMSO (40mL) at room temperature under nitrogen was added imine 1(1 eq) dropwise and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with phosphate buffer (pH7.4, 150mL) and then extracted with ethyl acetate (3X 200 mL). The organic phase is over MgSO₄Dried and concentrated in vacuo. Purification by silica gel column chromatography gave compound 134 isolated in 72% yield.

Synthesis of Compound 135

To compound 134(10mmol) in CH with stirring at 0 deg.C₃CN (6mL) solution ceric ammonium nitrate (CAN, 3 equivalents) in water (60mL) was added. The mixture was stirred at 0 ℃ for 30 minutes. Adding CH to the reaction mixture ₂Cl₂(60mL) and the aqueous phase was separated using CH₂Cl₂Extracting twice: once after acidification with 0.1N HCl and once with Na₂CO₃(2N) neutralization (pH 7). The combined organic phases were over MgSO₄Dried and concentrated in vacuo to afford the deprotected amine 135 in 84% isolated yield.

Synthesis of Compound 136

To a solution of compound 135(10mmol) in MeOH at 0 deg.C was added NaBH₄(12mmol) and the mixture was stirred at 0 ℃ for 90 min. After addition of water (40mL), CH was used₂Cl₂The reaction mixture was extracted (3X 90 mL). The combined organic phases were over MgSO₄Dried and concentrated in vacuo to yield intermediate 136 in 89% isolated yield.

Synthesis of (2S, 3S, 4S) -2-amino-4-hydroxy-3-methyl-hexanoic acid (Compound 12b)

To compound 136(10mmol) in MeOH/H₂To a solution of O (1/10, 30mL) was added LiOH (12 mmol). The mixture was stirred at room temperature overnight. Acetic acid (12mmol) was added and the reaction mixture was concentrated. Water was removed from the crude product by repeated addition and evaporation of absolute ethanol. The crude product was recrystallized from EtOH to give (2S, 3S, 4S) -2-amino-4-hydroxy-3-methyl-hexanoic acid (compound 12b) in 50% isolated yield.¹H NMR(300MHz，D₂O)：δ0.97(m，6H)，1.55(m，1H)，2.23(m，2H)，3.56(m，1H)，3.99(d，J＝2.8Hz，1H)。¹³C NMR(75MHz，D₂O)：δ9.52，11.78，27.48，38.02，56.11，75.38，174.77。MS(IC)m/z：162[M+H]⁺. Purifying the filtrate by silica gel column chromatography to isolate compound 13b, and¹h NMR was consistent with the structure.

C) Other 4-hydroxyisoleucine analogs

4-hydroxyisoleucine analogs in which the 3-and 4-positions are substituted with groups other than methyl can also be prepared using commercially available or known precursors using standard chemical reactions known in the art for the synthesis of alpha-amino acids. Examples of synthetic procedures that can be used for these preparations are described in Rolland-Fulcrand et al, Eur.J.org.chem., 873-773, 2004; kassem et al, Tetrahedron: assymetry 12: 2657-61, 2001; wang et al, eur.j.org.chem., 834-39, 2002; tamura et al, j.org.chem.69: 1475-80, 2004; jamieson et al, org.biomol.chem.2: 808-9, 2004; gull and Schollkopf, Synthesis 1985: 1052, 1985; lnghardt et al, Tetrahedron 32: 6469-82, 1991; and Dong et al, j.org.chem.64: 2657-66, 1999.

Example 2: weight gain and diet of diet-induced obese (DIO) -mice with 4-hydroxyisoleucine Influence of consumption of substances

The objective of this study was to evaluate the effect of chronic administration of 4-hydroxyisoleucine (4-OH, compound 14a) on food consumption and weight gain in DIO-mice. These two parameters are monitored: 1 week before initiation of treatment, then 77 days of treatment, and another 12 days after treatment.

C57BL/6 mice received and were fed a high fat diet (60% of the calories from fat) at weeks 7-8 for several weeks. A total of 32 animals were used in this study. Animals were divided into 4 groups (3 treatment groups, 1 control group, all animals were on a high fat diet). Each group consisted of 8 animals. Mice were randomly grouped according to body weight and basal blood glucose values after 5 ± 0.5 hour starvation period.

The test agent was dissolved in reverse osmosis water. 4-hydroxyisoleucine was divided into aliquots and stored at 4 ℃. Control animals received twice daily reverse osmosis water (group 1). Mice from groups 2, 3 and 4 were treated twice daily with 100mg/kg, 50mg/kg and 25mg/kg of 4-hydroxyisoleucine (4-OH, compound 14a), respectively. All groups were treated by oral gavage. Treatment started on day 0 and ended on day 77. Body weight was measured daily and weekly values are shown in figure 15A. Food consumption was tested daily and started on average weekly 1 week before treatment started as shown in figure 15B. Similarly, as shown in fig. 15A and 15B, food consumption was monitored during the treatment period and continued for 12 days after treatment cessation.

Treatment was well tolerated for all subjects receiving 4-hydroxyisoleucine (4-OH, compound 14 a). Modulation of body weight gain was observed in animals receiving compound 14a at 50mg/kg and 100mg/kg three weeks prior to treatment (fig. 15A). However, this effect on weight gain was sustained for mice receiving 100mg/kg of 4-OH twice daily and was very significant from day 28 to day 84 of treatment. This decrease in weight gain paralleled a slight decrease in food consumption for the first week of treatment (fig. 15A and 15B). Similarly, weight gain and food consumption were monitored 12 days after treatment cessation, and values from day 84 and day 89 are shown in fig. 15A and 15B. In FIGS. 15A and 15B, weight gain and food consumption over time showed an increase in the first week after cessation of treatment with 100mg/kg of 4-OH. This indicates that the continuous presence of 4-OH is necessary to maintain efficacy (reduction in weight gain) in mice fed a high fat diet.

In conclusion, this study demonstrates that chronic administration of 4-hydroxyisoleucine (4-OH) is significantly effective in controlling weight gain when administered at dose levels of 100mg/kg twice daily, and that continuous exposure to 4-hydroxyisoleucine may be necessary to maintain long-term efficacy, particularly when a high-fat diet is sustained.

Example 3: effect of 4-hydroxyisoleucine on ob/ob mouse weight gain and food consumption

The objective of this study was to evaluate the effect of long-term administration of 4-hydroxyisoleucine (4-OH, compound 14a) on food consumption and weight gain in ob/ob mice, a genetic model of obesity. Monitoring body weight gain and food consumption: 1 week before treatment initiation, 56 days of treatment.

A total of 16 animals were used in this study. Animals were divided into 2 groups (1 treatment group, one control group, all on a standard diet). Each group consisted of 8 animals. Mice were randomly grouped according to body weight values.

The treatment is carried out for 8 weeks, the test agent being dissolved in reverse osmosis water. 4-hydroxyisoleucine was divided into aliquots and stored at 4 ℃. Control animals received twice daily reverse osmosis water (group 1). Mice from group 2 were treated twice daily with 100mg/kg of 4-OH. All groups were treated by oral gavage. Treatment began on day 0 and ended on day 56 (fig. 16A and 16B). Body weight was measured daily and weekly values are shown in figure 16A. Food consumption was tested daily and started on average weekly 1 week before treatment started as shown in figure 16B. Similarly, as shown in fig. 16B, food consumption was monitored during the treatment period.

4-hydroxyisoleucine (4-OH) treatment was well tolerated in all mice. During the course of treatment, modulation of body weight gain was observed in animals receiving 100mg/kg of 4-OH (FIG. 16A). The body weight gain of ob/ob mice decreased significantly from day 21 to day 56 compared to the control group. This reduction in weight gain paralleled a slight decrease in the first three weeks of treatment, but not later food consumption (fig. 16B).

In conclusion, long-term administration of 4-OH significantly reduced the weight gain in a strict genetic model of obesity (ob/ob mouse model). Thus, the results of this study confirm that: the compounds according to the invention, more specifically 4-hydroxyisoleucine (4-OH, compound 14a), show great potential for the treatment of different metabolic diseases, such as overweight, obesity and diabetes.

Example 4: for long-term treatment of 4-hydroxyisoleucine and rosiglitazone, administered alone or in combination Function of

The objective of this study was to evaluate the effect of chronic administration of 4-hydroxyisoleucine (4-OH, compound 14a) and rosiglitazone, administered alone or in combination, on food consumption and weight gain in DIO-mice. These two parameters are monitored: 1 week before initiation of treatment, then 28 days of treatment, and another 7 days after treatment.

A total of 72 animals were used in this study. Animals were divided into 6 groups (5 treatment groups, 1 control group, all animals were on a high fat diet). Each group consisted of 12 animals. Mice were randomly grouped according to body weight and basal blood glucose values after 5 ± 0.5 hour starvation period.

For four week treatment, the test article was dissolved in reverse osmosis water. 4-hydroxyisoleucine was divided into aliquots and stored at 4 ℃ (dosed to groups 2, 3 and 6), while rosiglitazone was freshly prepared daily and stored at 4 ℃ between AM and PM dosing in groups 4, 5 and 6. Control animals received twice daily reverse osmosis water (group 1). Mice from groups 2 and 3 were treated twice daily with 50mg/kg and 100mg/kg of 4-OH, respectively. Mice from groups 4 and 5 received 1.5mg/kg and 5mg/kg rosiglitazone, respectively. For group 6, the treatment included 50mg/kg of 4-OH +1.5mg/kg rosiglitazone. All groups were treated by oral gavage. Treatment began on day 0 and ended on day 28 (fig. 17A and 17C).

Treatment was well tolerated for all patients receiving 4-hydroxyisoleucine (4-OH) or rosiglitazone (Rosi), alone or in combination. Modulation of body weight gain was observed in all animals receiving 4-OH (FIG. 17A) or a combination of rosiglitazone (1.5mg/kg) and 4-OH (50mg/kg) (FIG. 17C) at 100mg/kg relative to the group treated with rosiglitazone alone.

Food consumption was tested and averaged weekly starting 1 week prior to initiation of treatment, as shown in figures 17B and 17D for week 1. Similarly, food consumption was monitored 1 week after treatment cessation, as shown in figures 17B and 17D for week 5. In fig. 17B, bar graphs depict food consumption over time for each treatment group. The first appearing solid bars in each group show food consumption for the control group. The second and third bars in each group show consumption by animals treated with 50mg/kg or 100mg/kg of 4-OH, respectively. In the first week of treatment, food consumption was reduced in the 4-OH treatment group, while consumption returned to pre-treatment levels for the other treatment periods of the study.

The animals of the rosiglitazone treated group had significant weight gain relative to the other groups, which could be attributed to increased food consumption (fig. 17D). In fig. 17D, the food consumption of the control animals is represented by the first appearing solid bars in each bar group. The second, third and fourth bars in each group represent food consumption of animals treated with 4-OH (50mg/kg), rosiglitazone (1.5mg/kg) and the drug combination, respectively. Again, 4-OH resulted in a decrease in food consumption in the first week, but not during treatment. In contrast, animals treated with rosiglitazone showed an increase in food consumption; however, this effect was not found when the two drugs were co-administered. 4-hydroxyisoleucine is capable of modulating the body weight gain induced by rosiglitazone.

Taken together, these results demonstrate that 4-hydroxyisoleucine (4-OH, compound 14a) can be used therapeutically alone to modulate weight gain. These results also indicate that the compounds according to the invention (more specifically 4-hydroxyisoleucine) can be used in combination with rosiglitazone to control the undesirable side effects of weight gain induced by this antidiabetic agent.

Example 5: long-term administration of 4-hydroxyisoleucine and exendin-4 alone or in combination Therapeutic effects

The objective of this study was to evaluate the effect of chronic administration of 4-hydroxyisoleucine (4-OH, compound 14a) and exendin-4, administered alone or in combination, on the weight gain and glycemic response in diet-induced obese (DIO) -C57BI/6 mice. Glycemic response was monitored by Oral Glucose Tolerance Test (OGTT) performed on days 0, 7, 14 and 21 of treatment.

A total of 56 animals were used in this study. Animals were divided into 7 groups (5 treatment groups, 1 normal diet control group, and one high fat diet control group). Each group consisted of 8 animals. Mice were randomly grouped according to body weight and basal blood glucose values after 5 ± 0.5 hour starvation period. For three weeks treatment, the test agent was dissolved in sterile saline for injection (USP). 4-hydroxyisoleucine was stored at 4 ℃ (administered to groups 3, 4 and 7), while frozen aliquots of exendin-4 were thawed on each day of administration for administration to groups 5, 6 and 7. Control animals received sterile saline twice daily (groups 1 and 2). Mice from groups 3 and 4 were treated twice daily with 50mg/kg and 100mg/kg of 4-OH, respectively. Animals from groups 5 and 6 received sterile saline as AM treatment, while PM treatment consisted of 0.05mg/kg and 0.01mg/kg of Exendin-4, respectively. For group 7, AM treatment consisted of 50mg/kg of 4-OH only, while PM treatment consisted of 0.01mg/kg of exendin-4 +50mg/kg of 4-OH. All groups were treated by subcutaneous injection.

On days 0, 7, 14 and 21, animals starved for about 5 hours were subjected to the Oral Glucose Tolerance Test (OGTT) 5 hours after administration of the AM test agent. Whole blood glucose levels were monitored using a handheld glucometer prior to OGTT until 2 hours after glucose challenge.

No relevant clinical signs or test agent-related deaths were observed after the test agent was administered.

The effect of treatment on weight gain is shown in figure 18A. A reduction in body weight gain was observed in animals treated with 50mg/kg and 0.01mg/kg of 4-OH or exendin-4, respectively (figure 18A). This effect appeared to be increased in animals receiving a combination treatment of 50mg/kg 4-OH and 0.01mg/kg exendin-4 (figure 18A).

As shown in FIG. 18B, a decrease in epididymal fat weight in high fat diet animals was noted in animals treated with 100mg/kg (bar 3) 4-OH. Exendin-4 at 0.01mg/kg was not effective at 0.01mg/kg (bar 4) in reducing epididymal fat, but was effective at 0.05mg/kg (bar 5). For mice treated with 4-OH (50mg/kg) and Exendin-4 (0.01mg/kg), weight loss was accompanied by a decrease in epididymal fat (bar 6).

4-OH was consistently effective in reducing blood glucose levels after OGTT challenge after 7, 14 and 21 days of treatment when administered as a single dose of 50mg/kg (FIG. 18C shows the general results obtained after 7 days). Exendin-4 at 0.01mg/kg is also effective. There is a tendency that: on days 7 (fig. 18C) and 14 (not shown), the combination therapy was more effective than the compound administered alone.

Taken together, these results support the therapeutic use of a compound according to the invention, more specifically 4-hydroxyisoleucine (4-OH, compound 14a), in combination with exendin-4, for example, to promote the efficacy of a reduced dose of exendin-4. Furthermore, the 4-hydroxyisoleucine/exendin-4 combination has a positive effect on weight control associated with reduced epididymal fat, and the combination of exendin-4 with the compounds according to the invention can also reduce undesirable visceral fat in humans.

Example 6: dietary induction by 4-hydroxyisoleucine and metformin administered alone or in combination The effect of obese C57BL/6 mouse body weight

Metformin is a widely used drug for the treatment of type 2 diabetes. It reduces blood glucose levels by increasing insulin sensitivity, particularly by decreasing hepatic glucose production and increasing glucose utilization (Stumvoll et al, n.engl.j.med., 333 (9): 550-4, 1995). Metformin has been shown to reduce body weight in most studies conducted in type 2 diabetic patients (Hundal et al, Drugs 63 (18): 1879-94, 2003). It also induces weight loss in obese individuals without diabetes (Glueck et al, Metabolism 50 (7): 856-61, 2001).

The objective of this study was to determine the effect of 4-hydroxyisoleucine (4-OH, compound 14a) and metformin, administered alone or in combination, on the body weight of diet-induced obesity (DIO) mice, a well-known animal model of obesity and type 2 diabetes.

C57BL/6 mice received and were fed a high fat diet (60% of calories from fat) at 7-8 weeks of age for 8 weeks. Animals with fasting plasma glucose values between 200mg/dL and 220mg/dL were included in the study. Animals were randomly assigned to control and treatment groups based on their body weight and blood glucose levels (n-8). Animals were treated twice daily by oral gavage with 4-OH (50 or 100mg/kg body weight), metformin (25 and 100mg/kg body weight) or a combination of 4-OH and metformin (50 and 25mg/kg body weight, respectively). The control group received vehicle (water) only. Animals were treated for 21 days. Mouse body weights were measured on day 1 and on days 3, 7, 10, 14, 17, and 21 of treatment. All data are expressed as mean ± SEM.

As shown in figure 19, DIO mice treated with 4-hydroxyisoleucine (4-OH) (100mg/kg) and metformin (100mg/kg) for 21 days showed a reduction in their body weight compared to vehicle treated mice, however, the effect of only 4-OH was significant (p < 0.01 and p ═ 0.27 for 4-OH and metformin, respectively). When administered alone, 4-OH (50mg/kg) and metformin (25mg/kg) had no significant effect on body weight compared to control DIO mice, however, when used in combination, they induced a significant body weight loss relative to control (p < 0.05). The combined effect was significantly different (p < 0.05) compared to metformin alone (25mg/kg) and almost significant (p ═ 0.066) compared to 4-OH alone (50 mg/kg).

In conclusion, 4-hydroxyisoleucine (4-OH, compound 14a) is as effective in reducing body weight in the DIO murine model as metformin. When administered together, the medicaments show an improved effect on weight loss. Since 4-hydroxyisoleucine and metformin have both anti-diabetic and anti-obesity properties, combination therapy can be used to treat both related diseases. It is also conceivable to use other compounds according to the invention together with metformin for reducing body weight.

Example 7: diet induction by 4-hydroxyisoleucine and rimonabant administered alone or in combination The effect of obese C57BL/6 mouse body weight

The objective of this study was to determine the effect of 4-hydroxyisoleucine (4-OH, compound 14a) and rimonabant (5- (4-chlorophenyl) -1- (2, 4-dichlorophenyl) -4-methyl-N- (piperidin-1-yl) -1H-pyrazole-3-carboxamide), administered alone or in combination, on diet-induced obesity (DIO) -C57BL/6 mouse body weight.

C57BL/6 mice received and were fed a high fat diet (60% of calories from fat) at 7-8 weeks of age for 8 weeks. Animals were randomized into control and treatment groups 7 days prior to treatment based on their body weight and fasting blood glucose values (n-8). Animals were treated by oral gavage with 4-OH (50mg/kg body weight; group 2) twice daily, rimonabant (0.1 mg/kg; group 3) once daily in the afternoon, and a combination of the two treatments (4-OH 50mg/kg twice daily + rimonabant 0.1mg/kg once daily; group 4). The control group (group 1) received vehicle (water) alone twice weekly. After 3 weeks (22 days) of treatment, the dose increases were as follows: 4-OH 100mg/kg twice daily (group 2), rimonabant 1mg/kg once daily (group 3), and combinations (4-OH 100mg/kg twice daily + rimonabant 1mg/kg once daily; group 4). Animals were treated with these higher doses for 1 week. Body weights of all groups were recorded daily from day 6 to day 28.

After 21 days of treatment (low dose treatment), a slight decrease in body weight gain in response to 4-OH and rimonabant was observed, but there was no apparent beneficial effect of combining more than two compounds used alone (fig. 20A). As shown in FIGS. 20A and 20B, an increase in 4-OH dose from 50mg/kg to 100mg/kg and rimonabant dose from 0.1mg/kg to 1mg/kg immediately reduced the body weight of the mice. More interestingly, the combination of the two compounds resulted in greater weight loss in the animals compared to the individual compounds. The reduction was statistically significant compared to untreated controls from day 25 to day 28 (fig. 20B).

In conclusion, both 4-hydroxyisoleucine dosed twice daily at 100mg/kg and rimonabant dosed once daily at 1mg/kg were effective in reducing body weight in the DIO mouse model. When administered together, the two compounds show an increased effect on weight loss. Thus, the combination of rimonabant with a compound according to the invention, in particular 4-hydroxyisoleucine with rimonabant, can prove to be very effective in the treatment of obesity in humans.

Example 8: compound 13e for weight gain in a diet-induced obesity (DIO) mouse model Influence of

The objective of this study was to determine the effect of one analog according to the invention (i.e. compound 13e) on the body weight of a diet-induced obesity (DIO) mouse model.

C57BL/6 mice received and were fed a high fat diet (60% of calories from fat) at 7-8 weeks of age for 8 weeks. Mice were randomly divided into control and treatment groups using fasting glucose and body weight values (n-8). The mean baseline blood glucose for all groups was between 213mg/dL and 215 mg/dL. Animals were treated twice daily by oral gavage with Compound 13e (25 or 50mg/kg body weight) and control groups received vehicle only (200mM bicarbonate buffer/0.1% Tween-20)^TMpH 9). Animals were treated for 21 days. Mouse body weights were measured on a frequency basis during the treatment period. At the end of the study, epididymal fat pads were isolated and weighed. Data are expressed as mean weight ± SEM and mean fat pad weight ± SEM.

Figure 21B shows the relative change in body weight at 21 days post treatment as expressed in delta body weight from day 0 of treatment. As depicted in the figure, DIO mice treated with compound 13e showed weight loss compared to vehicle treated mice, and the effect was dose dependent.

Fig. 21B shows the relative change in weight of the epididymal fat pad in grams/10 grams of body weight. As can be seen, compound 13e induced weight loss was associated with a reduction in epididymal fat pad weight.

In conclusion, compound 13e was able to reduce weight gain in a putative obesity model (DIO mouse model). Since this effect is associated with a reduction in epididymal fat pad weight, this suggests that the compound according to the invention (more specifically compound 13e) can be useful in reducing visceral fat and treating obesity in humans when used as monotherapy.

Example 9: c57BL/6 of 4-hydroxyisoleucine analogs and isomers on high fat diets Effect of weight gain in mice

C57BL/6 mice received and were fed standard commercial food at 7-8 weeks of age for 1 week (compliant period). Animals were randomized into control and treatment groups (n-6) based on their body weight values 7 days prior to treatment. The animals were then transferred to a high fat diet (60% of calories from fat) and treated for 3 days by oral gavage with 4-hydroxyisoleucine (4-OH, compound 14a) or different 4-OH analogs and isomers at a dose of 50mg/kg body weight. The control group (control HFD) received vehicle (water) only, and the group remained on standard food (chow) (control lean). Mouse body weights were recorded daily. Two different experiments were performed, the effect of selected analogues and isomers according to the invention on weight gain is shown in fig. 22A (experiment 1) and fig. 22B (experiment 2).

The body weight of the C57BL/6 mice on the high fat diet (control HFD) increased rapidly compared to the normal diet (control lean meat; see FIGS. 22A and 22B). Treatment with 100mg/kg of 4-OH twice daily over 3 days reduced the weight gain induced by the high fat diet (fig. 22A) and in one experiment, the mouse body weight was reduced compared to the pre-treatment values (fig. 22B). At the same dose, the 2R, 3S, 4R-isomers of 4-hydroxyisoleucine analogs (compound #76, compound #65a, compound #62, compound #202, compound #104, and compound #75) and 4-hydroxyisoleucine reduced the weight gain induced by the high fat diet. Two of these compounds (compound #65a and compound #62) showed greater potency than the SRS isomer of 4-OH (compound #14 a).

These results demonstrate that 4-hydroxyisoleucine analogs and isomers according to the present invention (more specifically the compounds exemplified in figures 22A and 22B) are effective in reducing mouse weight gain due to a high fat diet. These results also indicate a great potential of the compounds of the invention for the treatment of obesity.

Example 10: prevention of weight gain by 4-hydroxyisoleucine in a diet-induced obese rat model

The objective of this study was to evaluate the effect of 4-hydroxyisoleucine (4-OH, compound 14a) on food consumption, tissue weight and weight gain in high fat, high carbohydrate diet (HFHS) fed normal Wistar rats.

Rats were acclimatized for 1 week prior to initiation of treatment and fed a standard diet, followed by a high fat, high sugar diet (HFHS) on day 28 of treatment. A total of 30 animals were used in this study. The animals were divided into 3 groups, each consisting of 10 animals: HFHS was fed to 1 group and treated; 1 untreated control group was fed standard diet; and 1 untreated group fed HFHS. Animals were housed separately and food consumption was monitored daily.

For 4 weeks treatment, the test compound was dissolved in reverse osmosis water. 4-hydroxyisoleucine was divided into aliquots and stored at 4 ℃. Treated animals received 100 mg/kg/dose of 4-OH orally twice daily. Control animals received water twice daily.

The treatment was well tolerated for the group receiving 4-OH. Modulation of body weight was observed for all animals receiving 4-OH and could be attributed to a reduction in epididymis and perirenal adipose tissue (fig. 23A). Muscle, brown fat and organ weights were not affected by treatment (data not shown). Although food consumption was reduced in treated animals, differences in consumption relative to untreated animals could not be accounted for as differences in weight gain (data not shown).

The results of this study support the principle of using the compounds of the invention (more specifically 4-hydroxyisoleucine) for the prevention of obesity, including the prevention of weight gain and the prevention of visceral fat gain.

Example 11: 4-hydroxyisoleucineReversing weight gain in a diet-induced obese rat model

The objective of this study was to evaluate the effect of chronic administration of 4-hydroxyisoleucine (4-OH, compound 14a) on food consumption, tissue weight and body weight gain in Wistar obese rats.

A total of 30 animals were used in this study. Rats were acclimatized for 1 week and fed standard chow. Animals were randomly divided into 3 groups of 10 animals each. During the 28 day period, both groups were fed a high fat, high sugar diet (HFHS) and 1 untreated control group was fed a standard diet. Animals were housed separately and food consumption was monitored daily.

The same feeding regimen was maintained for the 3 groups over the next 28 days; however, group 1 fed HFHS was treated twice daily by oral administration of 100 mg/kg/dose of 4-OH. For 28 days of treatment, 4-OH was dissolved in reverse osmosis water, divided into small portions and stored at 4 ℃. Untreated animals received water twice daily.

The treatment was well tolerated for the group receiving 4-OH. Modulation of body weight was observed for all animals receiving 4-OH and could be attributed to a reduction in epididymis and perirenal adipose tissue (fig. 23B). Muscle, brown fat and organ weight were not affected by treatment. Although food consumption was reduced in treated animals, differences in consumption relative to untreated animals could not be accounted for as differences in weight gain (data not shown).

The results of this study support the principle of using the compounds of the invention (more specifically 4-hydroxyisoleucine) for the prophylactic treatment of obesity (more specifically for reducing the accumulated weight gain and visceral fat).

Claims (85)

1. Use of a compound selected from the group consisting of isomers of 4-hydroxyisoleucine, analogs of 4-hydroxyisoleucine, and pharmaceutically acceptable lactones, salts, metabolites, solvates and/or prodrugs of said isomers and analogs in the manufacture of a medicament for the treatment or prevention of obesity in a mammal.

2. Use of a compound selected from the group consisting of isomers of 4-hydroxyisoleucine, analogs of 4-hydroxyisoleucine, and pharmaceutically acceptable lactones, salts, metabolites, solvates and/or prodrugs of said isomers and analogs for the manufacture of a medicament for reducing body weight and/or body fat in a mammal.

3. Use of a compound selected from the group consisting of isomers of 4-hydroxyisoleucine, analogs of 4-hydroxyisoleucine, and pharmaceutically acceptable lactones, salts, metabolites, solvates and/or prodrugs of said isomers and analogs for the manufacture of a medicament for reducing appetite and/or reducing food intake in a mammal.

4. Use of a compound selected from the group consisting of isomers of 4-hydroxyisoleucine, analogs of 4-hydroxyisoleucine, and pharmaceutically acceptable lactones, salts, metabolites, solvates and/or prodrugs of said isomers and analogs in the manufacture of a medicament for preventing the onset or progression of excessive weight gain in a mammal.

5. The use of claim 4, wherein the occurrence or progression of weight gain is associated with administration of an anti-diabetic agent that stimulates weight gain in a mammal.

6. The use of claim 1, 2, 3 or 4, wherein the mammal is a human.

7. The use of claim 6, wherein the human is overweight or obese.

8. The use of claim 7, wherein the human has a Body Mass Index (BMI) of at least 25.

9. The use of claim 8, wherein the human has a Body Mass Index (BMI) of at least 30.

10. The use of claim 1, 2, 3 or 4, wherein the compound is an isomer of 4-hydroxyisoleucine or a pharmaceutically acceptable lactone, salt, metabolite, solvate, and/or prodrug thereof.

11. The use of claim 10, wherein the isomer of 4-hydroxyisoleucine is

12. The use of claim 10, wherein the isomer of 4-hydroxyisoleucine is selected from the group consisting of:

and

13. the use of claim 10, wherein the lactone of 4-hydroxyisoleucine is selected from the group consisting of:

14. the use of claim 1, 2, 3 or 4, wherein the compound is a 4-hydroxyisoleucine analog or a pharmaceutically acceptable lactone, salt, metabolite, solvate, and/or prodrug thereof.

15. The use of claim 14, wherein the compound is of formula (I):

wherein

A is CO₂R^A1、C(O)SR^A1、C(S)SR^A1、C(O)NR^A2R^A3、C(S)NR^A2R^A3、C(O)R^A4、SO₃H、S(O)₂NR^A2R^A3、C(O)R^A5、C(OR^A1)R^A9R^A10、C(SR^A1)R^A9R^A10、C(＝NR^A1)R^A5，

OrWherein

R^A1Comprises the following steps: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 4 carbon atoms;

R^A2and R^A3Are independently selected fromFrom: (a) hydrogen, (b) substituted or unsubstituted C_1-6Alkyl, (C) substituted or unsubstituted C_3-8Cycloalkyl, (d) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms, (e) substituted or unsubstituted C₆Or C₁₀Aryl, and (f) substituted or unsubstituted C_7-16Alkylaryl in which the alkylene radical has from 1 to 6 carbon atoms, or R^A2And R^A3Together with N to form a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR ^A8Wherein R is^A8Is hydrogen or C_1-6An alkyl group;

R^A4comprises the following steps: substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 4 carbon atoms;

R^A5a peptide chain of 1-4 natural or unnatural amino acids, wherein the peptide is linked to c (o) through its terminal amine group;

R^A6and R^A7Each independently hydrogen, substituted or unsubstituted C_1-6Alkyl radical, C_1-4Perfluoroalkyl, substituted or unsubstituted C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_2-12Dialkylamino, N-protected amino, halogen or nitro, and

R^A9and R^A10Each independently selected from: (a) hydrogen, (b) substituted or unsubstituted C_1-6Alkyl, (C) substituted or unsubstituted C_3-8Cycloalkyl, (d) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms, (e) substituted or unsubstituted C ₆Or C₁₀Aryl, and (f) substituted or unsubstituted C_7-16Alkylaryl in which the alkylene radical has from 1 to 6 carbon atoms, or R^A9And R^A10And the parent carbon atoms form together a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^A8Wherein R is^A8Is hydrogen or C_1-6An alkyl group;

b is NR^B1R^B2Wherein

(i)R^B1And R^B2Each independently selected from: (a) hydrogen, (b) an N protecting group, (C) a substituted or unsubstituted C_1-6Alkyl, (d) substituted or unsubstituted C_2-6Alkenyl, (e) substituted or unsubstituted C_2-6Alkynyl, (f) substituted or unsubstituted C_3-8Cycloalkyl, (g) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms, (h) substituted or unsubstituted C₆Or C₁₀Aryl, (i) substituted or unsubstituted C_7-16Alkylaryl group wherein the alkylene radical has from 1 to 6 carbon atoms, (j) substituted or unsubstituted C_1-9Heterocyclyl group, (k) substituted or unsubstituted C_2-15Alkylheterocyclyl wherein the alkylene group has 1 to 6 carbon atoms, (1) C (O) R^B3Wherein R is^B3Selected from: substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; substituted or unsubstituted C _1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, in which the alkylene radical has 1 to 6 carbon atoms, (m) CO₂R^B4Wherein R is^B4Selected from: substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl in which the alkylene radical has 1 to 6 carbon atoms, (n) C (O) NR^B5R^B6Wherein R is^B5And R^B6Each independently selected from: hydrogen; substituted or unsubstitutedC of (A)_1-6An alkyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; and substituted or unsubstituted C_2-15An alkylheterocyclic group in which the alkylene group has 1 to 6 carbon atoms, or R^B5And R^B6And N together form a substituted or unsubstituted 5-or 6-membered ring, optionally containing a non-ortho position of O, S or NR ', wherein R' is hydrogen or C_1-6Alkyl, (o) S (O)₂R^B7Wherein R is^B7Selected from: substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; substituted or unsubstituted C _1-9A heterocyclic group; or substituted or unsubstituted C_2-15An alkylheterocyclyl group wherein the alkylene group has from 1 to 6 carbon atoms, and (p) a peptide chain of 1-4 natural or non-natural alpha-amino acid residues wherein the peptide is linked to N through its terminal carboxyl group, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl or sulfonyl group, or

(ii)R^B1And R^B2Together with N to form a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^B8Wherein R is^B8Is hydrogen or C_1-6Alkyl, or

(iii) When R is^B1And R^1aTogether being substituted or unsubstituted C_1-4When alkylene, a 5-to 8-membered ring is formed, or

(iv) When R is^B1And R^1aTogether being substituted or unsubstituted C₂Alkylene and R^B1And R^2aTogether being substituted or unsubstituted C_1-2When alkylene is present, [2.2.1 ] is formed]Or [2.2.2]A bicyclic ring system, or

(v) When R is^B1And R³Together being substituted or unsubstituted C_2-6When alkylene, a 4-to 8-membered ring is formed, or

(vi) When R is^B1And R⁴Together being substituted or unsubstituted C_1-3When alkylene is formedA 6-to 8-membered ring, or

(vii)R^B1Together with A and the parent carbons of A and B form the following rings:

wherein Y and W are each independently O, S, NR^B8Or CR^A9R^A10Wherein R is^A9And R^A10Each as defined above, and R^A11And R^A12Each independently selected from: (a) hydrogen, (b) substituted or unsubstituted C _1-6Alkyl, (C) substituted or unsubstituted C_3-8Cycloalkyl, (d) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms, (e) substituted or unsubstituted C₆Or C₁₀Aryl, and (f) substituted or unsubstituted C_7-16Alkylaryl in which the alkylene radical has from 1 to 6 carbon atoms, or R^A9And R^A10And the parent carbon atoms form together a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^A8Wherein R is^A8Is hydrogen or C_1-6An alkyl group;

x is O, S or NR^X1Wherein R is^X1Selected from: (a) hydrogen, (b) an N protecting group, (C) a substituted or unsubstituted C_1-6Alkyl, (d) substituted or unsubstituted C_2-6Alkenyl, (e) substituted or unsubstituted C_2-6Alkynyl, (f) substituted or unsubstituted C_3-8Cycloalkyl, (g) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms, (h) substituted or unsubstituted C₆Or C₁₀Aryl, (i) substituted or unsubstituted C_7-16Alkylaryl group wherein the alkylene radical has from 1 to 6 carbon atoms, (j) substituted or unsubstituted C_1-9Heterocyclyl group, or (k) substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 6 carbon atoms;

R^1aAnd R^1bEach independently is: substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15An alkylheterocyclic group in which the alkylene group has 1 to 4 carbon atoms, or R^1aAnd R^2aAnd the essential carbon atoms thereof together form a substituted or unsubstituted C_5-10Monocyclic or fused ring systems, or when R is^1aAnd R⁴Together being substituted or unsubstituted C_1-4Alkylene when forming a 3-to 6-membered ring;

R^2aand R^2bEach independently is: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C _7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 4 carbon atoms; or R^2aAnd R^2bTogether are: o; is N (C)_1-6Alkyl groups); as CR^2cR^2dWherein R is^2cAnd R^2dEach independently hydrogen or substituted or unsubstituted C_1-6An alkyl group; or substituted or unsubstituted C forming a spiro ring_2-5An alkylene moiety; or R^2aAnd R^1aAnd the essential carbon atoms thereof together form a substituted or unsubstituted C_5-10Monocyclic or fused ring systems;

R³comprises the following steps: hydrogen; getSubstituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 4 carbon atoms; and

R⁴comprises the following steps: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C _2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene radical has from 1 to 4 carbon atoms, or when R is⁴And R^1aTogether being substituted or unsubstituted C_1-4When alkylene forms a 3-to 6-membered ring, or when R is⁴And R^B1Together being substituted or unsubstituted C_1-3Alkylene groups form 6-to 8-membered rings.

16. The use of claim 15, wherein the compound is a compound of formula (II):

wherein X and R⁴Each as defined hereinbefore with reference to formula (I), and R^1aAnd R^2aEach independently is substituted or unsubstituted C_1-6Alkyl, or R^1aAnd R^2aAnd the essential carbon atoms thereof together form a substituted or unsubstitutedA substituted 6 membered ring.

17. The use of claim 15, wherein the compound is a compound of formula (III):

wherein A is CO₂R^A1、C(O)SR^A1、C(O)NR^A2R^A3Or C (O) R^A5(ii) a And R is^A1、R^A2、R^A3、R^A5B, X and R⁴Each as defined hereinbefore with reference to formula (I).

18. The use of claim 15, wherein the compound is a compound of formula (IV):

wherein A is CO₂R^A1、C(O)SR^A1、C(O)NR^A2R^A3Or C (O) R^A5And wherein B, X and R ⁴Each as defined hereinbefore with reference to formula (I), and wherein R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹And R¹²Each independently is: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkane heterocyclesWherein the alkylene group has 1 to 4 carbon atoms.

19. The use of claim 15, wherein the compound is:

or

Wherein A, B and R⁴Each as defined hereinbefore with reference to formula (I), and R^1aAnd R^2aEach independently is: substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C ₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has from 1 to 4 carbon atoms.

20. The use of claim 15, wherein a is CO₂H, B is NH-p-toluenesulfonyl, R⁴Is H, and R^1aAnd R^2aEach is CH₃。

21. The use of claim 15, wherein a is CO₂H, B are NH₂，R⁴Is H, and R^1aAnd R^2aEach being substituted or unsubstituted C_1-6An alkyl group.

22. Use according to claim 15Wherein A is CO₂H, B are NH₂X is O, and R⁴Is H.

23. The use of claim 15, wherein the compound is

Or

A, X, R therein^2a、R⁴And R^B2Each as defined hereinbefore with reference to formula (I), and R¹⁷、R¹⁸、R¹⁹And R²⁰Each is hydrogen or substituted or unsubstituted C_1-6An alkyl group.

24. The use of claim 15, wherein the compound is

Or

A, X, R therein⁴And R^B2Each as defined hereinbefore with reference to formula (I), and R²¹And R²²Each is hydrogen or substituted or unsubstituted C_1-6An alkyl group.

25. The use of claim 15, wherein the compound is

A, X, R therein^2a、R^2bAnd R^B2Each as defined hereinbefore with reference to formula (I).

26. The use of claim 15, wherein the compound is

A, X, R therein^1a、R^1b、R^2a、R^2b、R⁴And R^B2Each as defined hereinbefore with reference to formula (I).

27. The use of claim 15, wherein R^1aAnd R^2aAnd the essential carbon atoms thereof together form a substituted or unsubstituted C_5-10Monocyclic or fused ring systems, optionally containing a non-ortho position of O, S or NR ', wherein R' is H or C_1-6An alkyl group.

28. The use of claim 15, wherein the compound of formula (I) is selected from:

and

wherein A, B, X and R⁴Each as defined hereinbefore with reference to formula (I), and R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹And R¹²Each independently is: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or notSubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 4 carbon atoms; and

R¹³、R¹⁴、R¹⁵and R¹⁶Each independently hydrogen, substituted or unsubstituted C _1-6Alkyl radical, C_1-4Perfluoroalkyl, substituted or unsubstituted C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_2-12Dialkylamino, N-protected amino, halogen or nitro.

29. The use of claim 15, wherein the compound is selected from the group consisting of:

and

30. the use of claim 15, wherein the compound is selected from the group consisting of:

31. the use of claim 15, wherein the compound is:

32. the use of claim 15, wherein the compound is:

33. the use of claim 15, wherein the compound is of formula (V):

a, R therein^1a、R^1b、R^2a、R⁴And R^B2Each as defined hereinbefore with reference to formula (I); r⁵、R⁶And R⁷Each independently is: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 4 carbon atoms; and Z is XR as previously defined with reference to formula (V) ⁴Or NR^B1R^B2。

34. The use of claim 15, wherein the compound is of formula (V-a):

wherein R is^A1、R^B2And R⁴Each as defined hereinbefore with reference to formula (I); r⁵Comprises the following steps: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 4 carbon atoms; and Z is XR as previously defined with reference to formula (V)⁴Or NR^B1R^B2。

35. The use of claim 34, wherein the compound is selected from the group consisting of:

wherein R is^A1、R^B1、R^B2And R⁴As previously defined with reference to formula (I), and wherein R⁵Comprises the following steps: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C _2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; getSubstituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has from 1 to 4 carbon atoms.

36. The use of claim 15, wherein the compound is of formula (VI):

a, B, X, R therein^1a、R^1b、R³And R⁴As previously defined with reference to formula (I).

37. The use of claim 36, wherein the compound is selected from the group consisting of:

wherein R is^A1、R^B1、R^B2And R⁴As previously defined with reference to formula (I).

38. The use of claim 37, wherein the compound is selected from the group consisting of:

and

39. the use of claim 15, wherein the compound is selected from the group consisting of:

[ Compound 75 ]]，[ Compound 76]，

[ Compound 202]，[ Compound 65a]，

[ Compound 13e]，[ Compound 62]And are and

[ Compound 104]。

40. A pharmaceutical kit, comprising: (1) a compound selected from the group consisting of isomers of 4-hydroxyisoleucine, analogs of 4-hydroxyisoleucine, and pharmaceutically acceptable lactones, salts, metabolites, solvates and/or prodrugs of said isomers and analogs; and (2) instructions for use of the compound: (i) reducing body weight and/or body fat, (ii) preventing the occurrence or development of excess body weight, (iii) reducing appetite and/or reducing food intake, and/or (iv) preventing or treating obesity.

41. A pharmaceutical kit, comprising: (1) a compound selected from the group consisting of isomers of 4-hydroxyisoleucine, analogs of 4-hydroxyisoleucine, and pharmaceutically acceptable lactones, salts, metabolites, solvates and/or prodrugs of said isomers and analogs; (2) anti-obesity and/or anti-diabetic agents; and (3) the instructions for using (1) and (2) in combination with each other.

42. A pharmaceutical composition, comprising: (1) a compound selected from the group consisting of isomers of 4-hydroxyisoleucine, analogs of 4-hydroxyisoleucine, and pharmaceutically acceptable lactones, salts, metabolites, solvates and/or prodrugs of said isomers and analogs; and (2) an anti-obesity agent and/or an anti-diabetic agent.

43. The kit or composition of claim 40, 41 or 42, comprising an additional anti-obesity agent.

44. The kit or composition of claim 40, 41 or 42 which includes a further antidiabetic agent.

45. The kit or composition of claim 41 or 42, wherein the compound and the anti-obesity agent and/or the anti-diabetic agent are formulated separately.

46. The kit or composition of claim 43, wherein the anti-obesity agent is selected from the group consisting of: orlistat, rimonabant, sibutramine, and phentermine.

47. The kit or composition of claim 44, wherein the anti-diabetic agent is selected from rosiglitazone, exendin-4 and metformin.

48. The kit or composition of claim 40, 41 or 42, wherein the compound is an isomer of 4-hydroxyisoleucine or a pharmaceutically acceptable lactone, salt, metabolite, solvate, and/or prodrug thereof.

49. The kit or composition of claim 48, wherein the isomer of 4-hydroxyisoleucine is

50. The kit or composition of claim 48, wherein the isomer of 4-hydroxyisoleucine is selected from the group consisting of:

and

51. the kit or composition of claim 48, wherein the lactone of 4-hydroxyisoleucine is selected from the group consisting of:

or

52. The kit or composition of claim 40, 41 or 42, wherein the compound is a 4-hydroxyisoleucine analog or a pharmaceutically acceptable lactone, salt, metabolite, solvate, and/or prodrug thereof.

53. The kit or composition of claim 52, wherein the compound is of formula (I):

wherein

A is CO₂R^A1、C(O)SR^A1、C(S)SR^A1、C(O)NR^A2R^A3、C(S)NR^A2R^A3、C(O)R^A4、SO₃H、S(O)₂NR^A2R^A3、C(O)R^A5、C(OR^A1)R^A9R^A10、C(SR^A1)R^A9R^A10、C(＝NR^A1)R^A5，

OrWherein

R^A1Comprises the following steps: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C _3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 4 carbon atoms;

R^A2and R^A3Each independently selected from: (a) hydrogen, (b) substituted or unsubstituted C_1-6Alkyl, (C) substituted or unsubstituted C_3-8Cycloalkyl, (d) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms, (e) substituted or unsubstituted C₆Or C₁₀Aryl, and (f) substituted or unsubstituted C_7-16Alkylaryl in which the alkylene radical has from 1 to 6 carbon atoms, or R^A2And R^A3Together with N to form a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^A8Wherein R is^A8Is hydrogen or C_1-6An alkyl group;

R^A4comprises the following steps: substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C ₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 4 carbon atoms;

R^A5a peptide chain of 1-4 natural or unnatural amino acids, wherein the peptide is linked to c (o) through its terminal amine group;

R^A6and R^A7Each independently hydrogen, substituted or unsubstituted C_1-6Alkyl radical, C_1-4Perfluoroalkyl, substituted or unsubstituted C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_2-12Dialkylamino, N-protected amino, halogen or nitro, and

R^A9and R^A10Each independently selected from: (a) hydrogen, (b) substituted or unsubstituted C_1-6Alkyl, (C) substituted or unsubstituted C_3-8Cycloalkyl, (d) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms, (e) substituted or unsubstituted C₆Or C₁₀Aryl, and (f) substituted or unsubstituted C_7-16Alkylaryl in which the alkylene radical has from 1 to 6 carbon atoms, or R^A9And R^A10And the parent carbon atoms form together a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^A8Wherein R is^A8Is hydrogen or C_1-6An alkyl group;

B is NR^B1R^B2Wherein

(i)R^B1And R^B2Each independently selected from: (a) hydrogen, (b) an N protecting group, (C) a substituted or unsubstituted C_1-6Alkyl, (d) substituted or unsubstituted C_2-6Alkenyl, (e) substituted or unsubstituted C_2-6Alkynyl, (f) substituted or unsubstituted C_3-8Cycloalkyl, (g) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms, (h) substituted or unsubstituted C₆Or C₁₀Aryl, (i) substituted or unsubstituted C_7-16Alkylaryl group wherein the alkylene radical has from 1 to 6 carbon atoms, (j) substituted or unsubstituted C_1-9Heterocyclyl group, (k) substituted or unsubstituted C_2-15Alkylheterocyclyl wherein the alkylene group has 1 to 6 carbon atoms, (1) C (O) R^B3Wherein R is^B3Selected from: substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, in which the alkylene radical has 1 to 6 carbon atoms, (m) CO₂R^B4Wherein R is^B4Selected from: substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; substituted or unsubstituted C _1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl in which the alkylene radical has 1 to 6 carbon atoms, (n) C (O) NR^B5R^B6Wherein R is^B5And R^B6Each independently selected from: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; and substituted or unsubstituted C_2-15An alkylheterocyclic group in which the alkylene group has 1 to 6 carbon atoms, or R^B5And R^B6And N together form a substituted or unsubstituted 5-or 6-membered ring, optionally containing a non-ortho position of O, S or NR ', wherein R' is hydrogen or C_1-6Alkyl, (o) S (O)₂R^B7Wherein R is^B7Selected from: substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15An alkylheterocyclyl group wherein the alkylene group has from 1 to 6 carbon atoms, and (p) a peptide chain of 1-4 natural or non-natural alpha-amino acid residues wherein the peptide is linked to N through its terminal carboxyl group, with the proviso that no two groups are bound to the nitrogen atom through a carbonyl or sulfonyl group, or

(ii)R^B1And R^B2Together with N to form a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^B8Wherein R is^B8Is hydrogen or C_1-6Alkyl, or

(iii) When R is^B1And R^1aTogether being substituted or unsubstituted C_1-4When alkylene, a 5-to 8-membered ring is formed, or

(iv) When R is^B1And R^1aTogether being substituted or unsubstituted C₂Alkylene and R^B1And R^2aTogether being substituted or unsubstituted C_1-2When alkylene is present, [2.2.1 ] is formed]Or [2.2.2]A bicyclic ring system, or

(v) When R is^B1And R³Together being substituted or unsubstituted C_2-6When alkylene, a 4-to 8-membered ring is formed, or

(vi) When R is^B1And R⁴Together being substituted or unsubstituted C_1-3When alkylene, a 6-to 8-membered ring is formed, or

(vii)R^B1Together with A and the parent carbons of A and B form the following rings:

wherein Y and W are each independently O, S, NR^B8Or CR^A9R^A10Wherein R is^A9And R^A10Each as defined above, and R^A11And R^A12Each independently selected from: (a) hydrogen, (b) substituted or unsubstituted C_1-6Alkyl, (C) substituted or unsubstituted C_3-8Cycloalkyl, (d) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms, (e) substituted or unsubstituted C₆Or C₁₀Aryl, and (f) substituted or unsubstituted C_7-16Alkylaryl in which the alkylene radical has from 1 to 6 carbon atoms, or R ^A9And R^A10And the parent carbon atoms form together a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^A8Wherein R is^A8Is hydrogen or C_1-6An alkyl group;

x is O, S or NR^X1Wherein R is^X1Selected from: (a) hydrogen, (b) an N protecting group, (C) a substituted or unsubstituted C_1-6Alkyl, (d) substituted or unsubstituted C_2-6Alkenyl, (e) substituted or unsubstituted C_2-6Alkynyl, (f) substituted or unsubstituted C_3-8Cycloalkyl, (g) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms, (h) substituted or unsubstituted C₆Or C₁₀Aryl, (i) substituted or unsubstituted C_7-16Alkylaryl group wherein the alkylene radical has from 1 to 6 carbon atoms, (j) substituted or unsubstituted C_1-9Heterocyclyl group, or (k) substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 6 carbon atoms;

R^1aand R^1bEach independently is: substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C ₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15An alkylheterocyclic group in which the alkylene group has 1 to 4 carbon atoms, or R^1aAnd R^2aAnd the essential carbon atoms thereof together form a substituted or unsubstituted C_5-10Monocyclic or fused ring systems, or when R is^1aAnd R⁴Together being substituted or unsubstituted C_1-4Alkylene when forming a 3-to 6-membered ring;

R^2aand R^2bEach independently is: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 4 carbon atoms; or R^2aAnd R^2bTogether are: o; is N (C)_1-6Alkyl groups); as CR^2cR^2dWherein R is^2cAnd R^2dEach independently hydrogen or substituted or unsubstituted C _1-6An alkyl group; or substituted or unsubstituted C forming a spiro ring_2-5An alkylene moiety; or R^2aAnd R^1aAnd the essential carbon atoms thereof together form a substituted or unsubstituted C_5-10Monocyclic or condensed ringsA system;

R³comprises the following steps: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 4 carbon atoms; and

R⁴comprises the following steps: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C _2-15Alkylheterocyclyl, wherein the alkylene radical has from 1 to 4 carbon atoms, or when R is⁴And R^1aTogether being substituted or unsubstituted C_1-4When alkylene forms a 3-to 6-membered ring, or when R is⁴And R^B1Together being substituted or unsubstituted C_1-3Alkylene groups form 6-to 8-membered rings.

54. The kit or composition of claim 53, wherein the compound is a compound of formula (II):

wherein X and R⁴Each as defined hereinbefore with reference to formula (I), and R^1aAnd R^2aEach independently is substituted or unsubstituted C_1-6An alkyl group, a carboxyl group,or R^1aAnd R^2aAnd the essential carbon atoms thereof together form a substituted or unsubstituted 6-membered ring.

55. The kit or composition of claim 53, wherein the compound is a compound of formula (III):

wherein A is CO₂R^A1、C(O)SR^A1、C(O)NR^A2R^A3Or C (O) R^A5(ii) a And R is^A1、R^A2、R^A3、R^A5B, X and R⁴Each as defined hereinbefore with reference to formula (I).

56. The kit or composition of claim 53, wherein the compound is a compound of formula (IV):

wherein A is CO₂R^A1、C(O)SR^A1、C(O)NR^A2R^A3Or C (O) R^A5B, X and R⁴Each as defined hereinbefore with reference to formula (I), and wherein R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹And R¹²Independently are: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C _2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; getSubstituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has from 1 to 4 carbon atoms.

57. The kit or composition of claim 53, wherein the compound is:

or

Wherein A, B and R⁴Each as defined hereinbefore with reference to formula (I), and R^1aAnd R^2aEach independently is: substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has from 1 to 4 carbon atoms.

58. The kit or composition of claim 53, wherein A is CO ₂H, B is NH-p-toluenesulfonyl, R⁴Is H, and R^1aAnd R^2aEach is CH₃。

59. The kit or composition of claim 53, wherein A is CO₂H, B are NH₂，R⁴Is H, and R^1aAnd R^2aEach being substituted or unsubstituted C_1-6Alkyl radical。

60. The kit or composition of claim 53, wherein A is CO₂H, B are NH₂X is O, and R⁴Is H.

61. The kit or composition of claim 53, wherein the compound is

Or

A, X, R therein^2a、R⁴And R^B2Each as defined hereinbefore with reference to formula (I), and R¹⁷、R¹⁸、R¹⁹And R²⁰Each is hydrogen or substituted or unsubstituted C_1-6An alkyl group.

62. The kit or composition of claim 53, wherein the compound is

Or

A, X, R therein⁴And R^B2Each as defined hereinbefore with reference to formula (I), and R²¹And R²²Each is hydrogen or substituted or unsubstituted C_1-6An alkyl group.

63. The kit or composition of claim 53, wherein the compound is

A, X, R therein^2a、R^2bAnd R^B2Each as defined hereinbefore with reference to formula (I).

64. The kit or composition of claim 53, wherein the compound is

A, X, R therein^1a、R^1b、R^2a、R^2b、R⁴And R^B2Each as defined hereinbefore with reference to formula (I).

65. The kit or composition of claim 53, wherein R ^1aAnd R^2aAnd the essential carbon atoms thereof together form a substituted or unsubstituted C_5-10Monocyclic or fused ring systems, optionally containing a non-ortho position of O, S or NR ', wherein R' is H or C_1-6An alkyl group.

66. The kit or composition of claim 53, wherein the compound of formula (I) is selected from:

and

wherein A, B, X and R⁴Each as defined hereinbefore with reference to formula (I), and R⁵、R⁶、R⁷、R⁸、R⁹、R¹⁰、R¹¹And R¹²Each independently is: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 4 carbon atoms; and

R¹³、R¹⁴、R¹⁵and R¹⁶Each independently hydrogen, substituted or unsubstituted C_1-6Alkyl radical, C_1-4Perfluoroalkyl, substituted or unsubstituted C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_2-12Dialkylamino, N-protected amino, halogen or nitro.

67. The kit or composition of claim 53, wherein the compound is selected from the group consisting of:

and

68. the kit or composition of claim 53, wherein the compound is selected from the group consisting of:

69. the kit or composition of claim 53, wherein the compound is:

70. the kit or composition of claim 53, wherein the compound is:

71. the kit or composition of claim 53, wherein the compound is of formula (V):

a, R therein^1a、R^1b、R^2a、R⁴And R^B2Each as defined hereinbefore with reference to formula (I); r⁵、R⁶And R⁷Each independently is: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 4 carbon atoms; and Z is XR as previously defined with reference to formula (V) ⁴Or NR^B1R^B2。

72. The kit or composition of claim 53, wherein the compound is of formula (V-A), or a pharmaceutically acceptable lactone, salt, metabolite, solvate, and/or prodrug thereof:

wherein R is^A1、R^B2And R⁴Each as defined hereinbefore with reference to formula (I); r⁵Comprises the following steps: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 4 carbon atoms; and Z is XR as previously defined with reference to formula (V)⁴Or NR^B1R^B2。

73. The kit or composition of claim 72, wherein the compound is selected from the group consisting of:

wherein R is^A1、R^B1、R^B2And R⁴As previously defined with reference to formula (I), and wherein R⁵Comprises the following steps: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C _2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has from 1 to 4 carbon atoms.

74. The kit or composition of claim 53, wherein the compound is of formula (VI):

a, B, X, R therein^1a、R^1b、R³And R⁴As previously defined with reference to formula (I).

75. The kit or composition of claim 74, wherein the compound is selected from the group consisting of:

and

wherein R is^A1、R^B1、R^B2And R⁴As previously defined with reference to formula (I).

76. The kit or composition of claim 75, wherein the compound is selected from the group consisting of:

and

77. the kit or composition of claim 53, wherein the compound is selected from the group consisting of:

[ Compound 75 ]]，[ Compound 76]，

[ Compound 202]，[ Compound 65a]，

[ Compound 13e]，[ Compound 62]And are and

[ Compound 104]。

78. A compound of formula (V):

or a pharmaceutically acceptable lactone, salt, metabolite, solvate and/or prodrug thereof, wherein

A is CO₂R^A1、C(O)SR^A1、C(S)SR^A1、C(O)NR^A2R^A3、C(S)NR^A2R^A3、C(O)R^A4、SO₃H、S(O)₂NR^A2R^A3、C(O)R^A5、C(OR^A1)R^A9R^A10、C(SR^A1)R^A9R^A10、C(＝NR^A1)R^A5，

OrWherein

R^A1Comprises the following steps: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C _3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkyl heterocyclic radicalWherein the alkylene group has 1 to 4 carbon atoms;

R^A2and R^A3Each independently selected from: (a) hydrogen, (b) substituted or unsubstituted C_1-6Alkyl, (C) substituted or unsubstituted C_3-8Cycloalkyl, (d) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms, (e) substituted or unsubstituted C₆Or C₁₀Aryl, and (f) substituted or unsubstituted C_7-16Alkylaryl in which the alkylene radical has from 1 to 6 carbon atoms, or R^A2And R^A3Together with N to form a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^A8Wherein R is^A8Is hydrogen or C_1-6An alkyl group;

R^A4comprises the following steps: substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C ₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 4 carbon atoms;

R^A5a peptide chain of 1-4 natural or unnatural amino acids, wherein the peptide is linked to c (o) through its terminal amine group;

R^A6and R^A7Each independently hydrogen, substituted or unsubstituted C_1-6Alkyl radical, C_1-4Perfluoroalkyl, substituted or unsubstituted C_1-6Alkoxy, amino, C_1-6Alkylamino radical, C_2-12Dialkylamino, N-protected amino, halogen or nitro, and

R^A9and R^A10Each independently selected from: (a) hydrogen, (b) substituted or unsubstituted C_1-6Alkyl, (C) substituted or unsubstituted C_3-8Cycloalkyl, (d) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and alkyleneThe radical having 1 to 4 carbon atoms, (e) substituted or unsubstituted C₆Or C₁₀Aryl, and (f) substituted or unsubstituted C_7-16Alkylaryl in which the alkylene radical has from 1 to 6 carbon atoms, or R^A9And R^A10And the parent carbon atoms form together a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^A8Wherein R is^A8Is hydrogen or C_1-6An alkyl group;

Z is XR⁴Or NR^B1R^B2Wherein X is O or S, and R^B1And R^B2Each independently selected from: (a) hydrogen, (b) an N-protecting group, (C) a substituted or unsubstituted C_1-6Alkyl, (d) substituted or unsubstituted C_2-6Alkenyl, (e) substituted or unsubstituted C_2-6Alkynyl, (f) substituted or unsubstituted C_3-8Cycloalkyl, (g) substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 10 carbon atoms, (h) substituted or unsubstituted C₆Or C₁₀Aryl, (i) substituted or unsubstituted C_7-16Alkylaryl group wherein the alkylene radical has from 1 to 6 carbon atoms, (j) substituted or unsubstituted C_1-9Heterocyclyl group, (k) substituted or unsubstituted C_2-15Alkylheterocyclyl wherein the alkylene group has 1 to 6 carbon atoms, (1) C (O) R^B3Wherein R is^B3Selected from: substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclyl, in which the alkylene radical has 1 to 6 carbon atoms, (m) CO₂R^B4Wherein R is^B4Selected from: substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C _7-16Alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15Alkylheterocyclic group in which the alkylene group has 1 to 6 carbon atoms, (n) C(O)NR^B5R^B6Wherein R is^B5And R^B6Each independently selected from: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; substituted or unsubstituted C_1-9Heterocyclic group and substituted or unsubstituted C_2-15An alkylheterocyclic group in which the alkylene group has 1 to 6 carbon atoms, or R^B5And R^B6And N together form a substituted or unsubstituted 5-or 6-membered ring, optionally containing a non-ortho position of O, S or NR ', wherein R' is hydrogen or C_1-6Alkyl, (o) S (O)₂R^B7Wherein R is^B7Selected from: substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 6 carbon atoms; substituted or unsubstituted C_1-9Heterocyclyl or substituted or unsubstituted C_2-15An alkylheterocyclyl group wherein the alkylene group has 1 to 6 carbon atoms, and (p) a peptide chain of 1-4 natural or non-natural alpha-amino acid residues wherein the peptide is linked to N through its terminal carboxyl group; or R ^B1And R^B2And N together form a substituted or unsubstituted 5-or 6-membered ring, optionally containing O or NR^B8Wherein R is^B8Is hydrogen or C_1-6An alkyl group;

R^2acomprises the following steps: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has 1 to 4 carbon atoms; or R^2aAnd R^2bTogether are: o; is N (C)_1-6Alkyl groups); as CR^2cR^2dWherein R is^2cAnd R^2dEach independently hydrogen or substituted or unsubstituted C_1-6An alkyl group; or substituted or unsubstituted C forming a spiro ring_2-5An alkylene moiety; or R^2aAnd R^1aAnd the essential carbon atoms thereof together form a substituted or unsubstituted C_5-10Monocyclic or fused ring systems;

R^1aand R^1bEach independently is: substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C _2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15An alkylheterocyclic group in which the alkylene group has 1 to 4 carbon atoms, or R^1aAnd R^2aAnd the essential carbon atoms thereof together form a substituted or unsubstituted C_5-10Monocyclic or fused ring systems, or when R is^1aAnd R⁴Together being substituted or unsubstituted C_1-4Alkylene when forming a 3-to 6-membered ring;

R⁴comprises the following steps: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene radical has from 1 to 4 carbon atoms, or when R is⁴And R^1aTogether being substituted or unsubstituted C _1-4When alkylene forms a 3-to 6-membered ring, or when R is⁴And R^B2Together being substituted or unsubstituted C_1-3Alkylene when forming a 6-to 8-membered ring;

R⁵、R⁶and R⁷Each independently is: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has from 1 to 4 carbon atoms.

79. The compound of claim 78, wherein the compound is of formula (V-A):

z, R therein^A1、R^B2And R⁴Each as defined with reference to formula (V); and R is⁵Comprises the following steps: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C _2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkyl heterocyclic radicalWherein the alkylene group has 1 to 4 carbon atoms.

80. The compound of claim 79, wherein the compound is selected from the group consisting of:

wherein R is^A1、R^B1、R^B2And R⁴As previously defined with reference to formula (I), and wherein R⁵Comprises the following steps: hydrogen; substituted or unsubstituted C_1-6An alkyl group; substituted or unsubstituted C_3-8A cycloalkyl group; substituted or unsubstituted alkylcycloalkyl, wherein the cycloalkyl group has 3 to 8 carbon atoms and the alkylene group has 1 to 4 carbon atoms; substituted or unsubstituted C_2-6An alkenyl group; substituted or unsubstituted C_2-6An alkynyl group; substituted or unsubstituted C₆Or C₁₀An aryl group; substituted or unsubstituted C_7-16Alkaryl, wherein the alkylene group has from 1 to 4 carbon atoms; substituted or unsubstituted C_1-9A heterocyclic group; or substituted or unsubstituted C_2-15Alkylheterocyclyl, wherein the alkylene group has from 1 to 4 carbon atoms.

81. The compound of claim 78, wherein the compound is of formula (VI):

a, B, X, R therein^1a、R^1b、R³And R⁴As previously defined with reference to formula (V).

82. The compound of claim 81, wherein the compound is selected from the group consisting of:

and

wherein R is^A1、R^B1、R^B2And R⁴As previously defined with reference to formula (V).

83. The compound of claim 82, wherein the compound is selected from the group consisting of:

and

84. a compound selected from the group consisting of:

[ Compound 75 ]]，[ Compound 76]，

[ Compound 202]，[ Compound 65a]，

[ Compound 13e]，[ Compound 62]And are and

[ Compound 104]，

Or a pharmaceutically acceptable lactone, salt, metabolite, solvate and/or prodrug thereof.

85. A pharmaceutical composition comprising a compound of any one of claims 78-84 and a pharmaceutically acceptable diluent, carrier or excipient.