CN1753673A - Prodrugs of gaba analogs, compositions and uses thereof - Google Patents

Abstract

The present invention provides prodrugs of GABA analogs, pharmaceutical compositions of prodrugs of GABA analogs and methods of making prodrugs of GABA analogs. The invention also provides methods of using prodrugs of GABA analogs and methods of using pharmaceutical compositions of prodrugs of GABA analogs for treating or preventing common diseases and/or disorders.

Description

Prodrugs of GABA analogues, compositions and applications thereof

This application claims 35 U.S.C. §119(e) requirements of U.S. Provisional Application 60/297,521 filed June 11, 2001, U.S. Provisional Application 60/298,514 filed June 14, 2001, and U.S. Provisional Application 60/298,514 filed March 19, 2002 These documents are hereby incorporated by reference for the benefit of provisional application 60/366,090.

1. Field of invention

The present invention generally relates to prodrugs of GABA analogs, pharmaceutical compositions of GABA analog prodrugs, preparation methods of GABA analog prodrugs, application methods of GABA analog prodrugs and GABA analog prodrugs. More specifically, the present invention relates to the prodrug of gabapentin and pregabalin, the pharmaceutical composition of the prodrug of gabapentin and pregabalin, the preparation method of the prodrug of gabapentin and pregabalin, the prodrug of gabapentin and pregabalin and the prodrug of gabapentin and pregabalin Methods of application of the pharmaceutical composition.

2. Background of the invention

Gamma ("γ")-aminobutyric acid ("GABA") is a major inhibitory transmitter in the mammalian central nervous system. GABA is not efficiently transported from the bloodstream to the brain (ie GABA does not efficiently cross the blood-brain barrier). Thus, brain cells provide virtually all of the GABA found in the brain (BABA is biosynthesized by the decarboxylation of glutamate with pyridoxal phosphate).

GABA regulates neuronal excitability by binding to specific membrane proteins (i.e., GABAA receptors), resulting in ion channel opening. The entry of chloride ions into and through the ion channel causes hyperpolarization of the recipient cell, preventing the transmission of nerve impulses to other cells. Low levels of GABA have been observed in individuals with epileptic seizures, movement disorders (eg, multiple sclerosis, action tremor, tardive dyskinesia), panic, anxiety, depression, alcoholism, and manic behavior.

The suggestion of low GABA levels in many common conditions and/or common medical diseases has stimulated intense interest in the preparation of GABA analogs with superior pharmaceutical properties to GABA, such as the ability to cross the blood-brain barrier. Accordingly, a variety of GABA analogs with important pharmaceutical properties have been synthesized in the art (see, for example, Satzinger et al., U.S. Patent 4,024,175; Silverman et al., U.S. Patent 5,563,175; Horwell et al., U.S. Patent 6,020,370; Silverman et al. , U.S. Patent 6,028,214; Horwell et al., U.S. Patent 6,103,932; Silverman et al., U.S. Patent 6,117,906; Silverman, International Publication WO 92/09560; Silverman et al., International Publication WO 93/23383; Horwell et al., International Publication WO 97/29101 , HORWELL et al., International Publication WO 97/33858; Horwell et al., International Publication WO 97/33859; Bryans et al., International Publication WO 98/17627; Guglietta et al., International Publication WO 99/08671; Publication WO 99/21824; Bryans et al. International Publication WO 99/31057; Belliotti et al. International Publication WO 99/31074; Bryans et al. International Publication WO 99/31075; Bryans et al. International Publication WO 99/61424; et al., International Publication WO 00/15611; Bryans, International Publication WO 00/31020; Bryans et al.,

International Publication WO 00/50027; and Bryans et al., International Publication WO 02/00209).

For example, pharmaceutically important GABA analogs include gabapentin (1), pregabalin (2), vigabatrin (3) and baclofen (4) shown above. Gabapentin, a lipophilic GABA analog that can cross the blood-brain barrier, has been clinically used in the treatment of epilepsy since 1994. Gabapentin may also have useful therapeutic effects in chronic pain disorders (such as neuropathic pain, muscular and skeletal pain), psychosis (such as panic, anxiety, depression, alcoholism, and manic behavior), motor sclerosis, action tremor, tardive dyskinesia), etc. (Magnus, Epilepsia, 1999, 40: S66-S72). Gabapentin is also currently used clinically for the management of neuropathic pain. Pregabalin, which has greater efficacy than gabapentin in clinical models of pain and epilepsy, is currently in phase III clinical trials.

An important problem with many GABA analogs is the intramolecular reaction of the γ-amino group with the carboxyl functional group to form a γ-lactam, such as gabapentin below. Due to the toxicity of the gamma-lactam (5), its formation poses serious difficulties for the formulation of gabapentin. For example, the toxicity (LD ₅₀ , mouse) of gabapentin is greater than 8000 mg/kg, while the toxicity (LD ₅₀ , mouse) of the corresponding lactam (5) is 300 mg/kg. Therefore, for safety reasons, the formation of by-products such as lactams must be minimized during the synthesis of GABA analogs and/or formulation and/or storage of GABA analogs or compositions of GABA analogs (especially in

in the case of gabapentin).

The problem of lactam contamination of GABA analogs has been partially overcome, especially in the Lactam contamination issues in the case of gabapentin. However, attempts to prevent lactam contamination have not been entirely successful in the synthesis or storage of GABA analogs such as gabapentin or combinations thereof.

Rapid systemic clearance is another important issue for many GABA analogs, including gabapentin, so frequent dosing is required to maintain therapeutic and prophylactic concentrations in the systemic circulation (Bryans et al., Med. Res. REV., 1999, 19 , 149-177). A dosing regimen of gabapentin in doses of 300-600 mg three times daily is typically used for anticonvulsant therapy. Higher doses (1800-3600 mg/day divided doses) are generally used in the treatment of neuropathic pain.

Sustained-release formulations are a conventional solution for rapid systemic clearance and are known to those skilled in the art (see, for example, "Remington's Pharmaceutical Sciences," Philadelphia College of Pharmacy and Science, 17TH Edition, 1985). Osmotic delivery systems are also known methods for sustained drug delivery (see eg Verma et al., Drug Dev. Ind. Pharm., 2000, 26:695-708). Many GABA analogs, including gabapentin and pregabalin, are not absorbed through the large intestine. Instead, these compounds are generally absorbed in the small intestine by the large neutral amino acid transporter ("LNAA") (Jezyk et al., Pharm. RES., 1999, 16, 519-526). The rapid passage of conventional dosage forms through the proximal absorption zone of the gastrointestinal tract has hindered the successful application of sustained release technology to many GABA analogs.

Therefore, there is a great need for effective sustained release regimens of GABA analogs to minimize the increase in dosing frequency due to the rapid systemic clearance of these compounds. There is also a need for pure GABA analogs, (especially gabapentin and pregablin analogs) that are substantially pure and do not spontaneously lactamize during formulation or storage.

3. Summary of invention

The present invention addresses these and other needs by providing prodrugs of GABA analogs, pharmaceutical compositions of prodrugs of GABA analogs, and methods of preparing prodrugs of GABA analogs. The present invention also provides the application method of the prodrug of the GABA analog, and the method of using the pharmaceutical composition of the prodrug of the GABA analog to treat or prevent common diseases and/or conditions.

Importantly, the prodrugs provided by the present invention can have significant pharmaceutical advantages with particular application in medicine. First, the moieties of the prodrugs of the GABA analogs provided herein are generally unstable in vivo (ie, enzymatic or chemical cleavage yields large amounts of the GABA analog prior to clearance of the prodrug from the patient). Second, the derivatives of the motif provided by cleavage of the motif from the prodrug and any metabolites thereof are generally non-toxic when administered to mammals according to the dosing regimen generally followed by GABA analogs.

The compounds of the present invention have a moiety attached to the gamma amino group of the GABA analog. This motif may be directly attached to the gamma amino group of the GABA analog, or optionally may be attached to the amino group of an alpha-amino acid motif or the hydroxyl group of an alpha-hydroxy acid moiety which itself is attached to the gamma amino group of the GABA analog .

The compounds of the invention may also have a moiety attached to the carboxyl group of the GABA analog. The carboxyl group is generally an ester or thioester group. A large number of ester or thioester groups can be used to form carboxyl moieties.

Thus, the compounds of the present invention may comprise up to 4 motifs, including 1 carboxyl motif and up to 3 amino motifs sequentially attached to the gamma amino group (i.e., so that the motifs are sequentially sequenced from the N- end cleavage). The compounds of the invention may comprise 2 amino moieties and 1 carboxyl moiety, 2 amino moieties, 1 amino moiety and 1 carboxyl moiety or 1 amino moiety. Preferably in compounds of the invention comprising an amino moiety and a carboxyl moiety, the carboxyl moiety is hydrolyzed prior to complete cleavage of the moiety to which the amino group is attached.

A first aspect of the present invention provides a compound of formula (I), formula (II) or formula (III):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

m, n, t and u are independently 0 or 1;

X is 0 or NR ¹⁶ ;

W is O or NR ¹⁷ ;

Y is O or S;

R ¹ is selected from hydrogen, R ²⁴ C(O)-, R ²⁵ OC(O)-, R ²⁴ C(S)-, R ²⁵ OC(S)-, R ²⁵ SC(O)-, R ²⁵ SC( S)-, (R ⁹ O)(R ¹⁰ O)P(O)-, R ²⁵ S-,

Each R ^is independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkyl Amino, alkylsulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, Aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted Cycloheteroalkyl, dialkylamino, substituted dialkylamino, halogen, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroaryl alkyl, heteroalkoxy, substituted heteroalkoxy, heteroaryloxy, and substituted heteroaryloxy, or optionally R ^{and R} together with the atoms to which they are bound form a cycloheteroalkyl or substituted cycloheteroalkyl ring;

R ^{and R} are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, ring Heteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;

R and ^R are independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl ^, cycloheteroalkane group, substituted cycloheteroalkyl, heteroarylalkyl and substituted heteroarylalkyl, or optionally ^R and ^R together with the carbon atoms to which they are bound form cycloalkyl, substituted cycloalkyl, ring Heteroalkyl, substituted cycloheteroalkyl, or bridged cycloalkyl rings;

R ^{and R} are independently selected from hydrogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, Substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, hetero Arylalkyl and substituted heteroarylalkyl, or optionally ^R and ^R taken together with the carbon atom to which they are bound form cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

^R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cyano, cycloalkyl , substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, alkoxycarbonyl, substituted Alkoxycarbonyl, cycloheteroalkoxycarbonyl, substituted cycloheteroalkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, heteroaryloxycarbonyl, substituted heteroaryloxycarbonyl, and nitro;

R ⁷ , R ⁹ , R ¹⁰ , R ¹⁵ , R ¹⁶ and R ¹⁷ are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl , cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;

R and ^R are independently selected from hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl ^, substituted aryl, arylalkyl, substituted arylalkyl , carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroaryl Alkyl, or optionally R and ^R together with the carbon atoms ^to which they are bound form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

R and ^R are independently selected from hydrogen, acyl, substituted acyl, ^alkyl , substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted Cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl , or optionally R ²⁰ and R ²¹ together with their bonded carbon atoms form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

^R22 and ^R23 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl, or optionally ^R22 and ^R23 are combined with them The carbon atoms of are taken together to form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring;

^R is selected from hydrogen, acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; and

^R is selected from acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cyclohetero Alkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

In a second aspect, the invention provides pharmaceutical compositions of compounds of the invention. The pharmaceutical compositions generally comprise one or more compounds of the invention and a pharmaceutically acceptable excipient.

In a third aspect, the present invention provides a method of treating or preventing epilepsy, depression, anxiety, psychosis, syncope, hypokinesia, cranial abnormalities, neurodegenerative diseases, panic, pain (especially neuropathic pain and muscle and bone pain), inflammatory disease (ie, arthritis), insomnia, gastrointestinal disease, or alcohol withdrawal syndrome. The methods generally comprise administering to a patient in need of such treatment or prophylaxis a therapeutically effective amount of a compound of the invention.

In a fourth aspect, the present invention provides a pharmaceutical composition for use in the treatment or prevention of epilepsy, depression, anxiety, psychosis, syncope, hypokinesia, cranial abnormalities, neurodegenerative diseases in a patient in need of such treatment or prevention , panic, pain (especially neuropathic pain and musculoskeletal pain), inflammatory disease (ie, arthritis), insomnia, gastrointestinal disease, or alcohol withdrawal syndrome. The methods generally comprise administering to a patient in need of such treatment or prophylaxis a therapeutically effective amount of a pharmaceutical composition of the invention.

In a fifth aspect, the invention encompasses a GABA analog derivative compound, MG, wherein M is a motif and G is derived from a GABA analog, HG, wherein H is hydrogen, for administration to a patient in need thereof. Once the motif M is cleaved from G, and any of its metabolites exhibit a carcinogenic toxic dose (TD ₅₀ ) of greater than 0.2 mmol/kg/day to rats. Moreover, the motif M is cleaved from G in vivo at a sufficient rate upon colonic administration to rats to produce:

(i) colonically administered equimolar doses of HG to obtain a maximum concentration of plasma HG ( _Cmax ) that is at least 120% of the _Cmax of plasma HG; and

(ii) An AUC of at least 120% of the AUC is obtained by colonic administration of equimolar doses of H-G.

Preferably M-G is a derivative of formula (XIV):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

R is hydrogen, or R and ^R together with the atoms to which they are bonded form an azetidine, substituted azetidine, pyrrolidine or substituted pyrrolidine ring; and

Y, R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are as defined above.

Most preferably M is a derivative of formula (XV):

Wherein: n, X, R ¹ and R ² are as defined above.

4. Detailed Description of the Invention

4.1 Definition

" Active transport or active transport method " refers to the movement of molecules across a cell membrane as follows:

a) depend directly or indirectly on energy-mediated approaches (i.e. driven by ATP hydrolysis, ion gradients, etc.);

or

b) Facilitated diffusion occurs through interactions with specific transporters

" Alkyl " means a saturated or unsaturated, straight-chain, branched-chain or cyclic monovalent hydrocarbon group derived by the removal of a hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Typical alkyl groups include, but are not limited to, methyl; ethyl such as ethyl, vinyl, ethynyl; propyl such as prop-1-yl, prop-2-yl, cycloprop-1-yl, prop-1- En-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1 -yl, prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butyl such as but-1-yl, but-2-yl, 2-methyl-prop-1-yl, 2-Methyl-prop-2-yl, cyclobut-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1 -yl, but-2-en-1-yl, but-2-en-2-yl, but-1,3-dien-1-yl, but-1,3-dien-2-yl, ring But-1-en-1-yl, cyclobut-1-en-3-yl, cyclobut-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yne -3-yl, but-3-yn-1-yl and the like.

The term " alkyl " is specifically meant to include groups having any degree or level of saturation, i.e., groups having exclusively carbon-carbon single bonds, groups having one or more carbon-carbon double bonds, groups having one or Groups with multiple carbon-carbon triple bonds and groups with mixtures of carbon-carbon single, double and triple bonds. The expressions "alkanyl", "alkenyl" and "alkynyl" are used when a particular level of saturation is intended. Preferably the alkyl group contains 1-20 carbon atoms, more preferably 1-10 carbon atoms.

" Alkanyl " means a saturated branched, straight chain or cyclic alkyl group derived by the removal of a hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl groups include, but are not limited to, methyl, ethyl, propyl such as prop-1-yl, prop-2-yl (isopropyl), cycloprop-1-yl, etc.; butyl such as but-1- Base, but-2-yl (sec-butyl), 2-methyl-prop-1-yl (isobutyl), 2-methyl-prop-2-yl (tert-butyl), cyclobutan-1- Base etc.

" Alkenyl " means an unsaturated branched, straight chain or cycloalkyl group having at least one carbon-carbon double bond derived by the removal of a hydrogen atom from a single carbon atom of a parent olefin. The double bond of the group can be in cis or trans configuration. Typical alkenyl groups include, but are not limited to, vinyl; propenyl such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), Pro-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyl such as but-1-en-1-yl, but-1- En-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl , But-1,3-dien-1-yl, but-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, ring But-1,3-dien-1-yl and the like.

" Alkynyl " means an unsaturated branched, straight chain or cycloalkyl group having at least one carbon-carbon triple bond derived by the removal of a hydrogen atom from a single carbon atom of a parent alkynyl group. Typical alkynyl groups include but are not limited to ethynyl; propynyl such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyl such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl and the like.

" Acyl " means the group -C(O)R, where R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, hetero Arylalkyl. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl, and the like.

" Acylamino " (or alternatively "acylamido") refers to the group -NR'C(O)R, wherein R' and R are each independently hydrogen, alkyl, cycloalkyl, ring as defined herein Heteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, heteroarylalkyl. Representative examples include, but are not limited to, formylamino, acetylamino (i.e., acetylamino), cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino (i.e., benzylamino), benzylcarbonylamino wait.

" Acyloxy " refers to the group -OC(O)R, where R is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, as defined herein radical or heteroarylalkyl. Representative examples include, but are not limited to, acetoxy (or acetate), butyloxy (or butoxy), benzoyloxy, and the like.

" Alkylamino " means a group -NHR in which R represents alkyl or cycloalkyl as defined herein. Representative examples include, but are not limited to, methylamino, ethylamino, 1-methylethylamino, cyclohexylamino, and the like.

" Alkoxy " refers to the group -OR in which R represents alkyl or cycloalkyl as defined herein. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclohexyloxy, and the like.

" Alkoxycarbonyl " refers to the group -C(O)-alkoxy where alkylhydrogen is as defined herein.

" Alkylsulfonyl " refers to the group -S(O) _2R , where R is alkyl or cycloalkyl as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, and the like.

" Alkylsulfinyl " refers to the group -S(O)R, where R is alkyl or cycloalkyl as defined herein. Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl, butylsulfinyl, and the like.

" Alkylthio " refers to a group -SR where R is alkyl or cycloalkyl as defined herein which may be optionally substituted as described herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio, butylthio, and the like.

" Amino " refers to the group _-NH2- .

" Aryl " refers to a monovalent aromatic hydrocarbon radical derived by removal of a hydrogen atom from a single carbon atom in a parent aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from the following: acethanene, acenaphthene, acephenanthrylene, anthracene, azulene, benzene, onium, perene, fluoranthene, fluorene, hexacene, naphthotetracene, hexalene, Trans-benzobiindene, cis-benzobiindene, indane, indene, naphthalene, octacene, octaphene, octacene, ovalene, penta-2,4-diene, and Pentacene, pentacyclopentadiene, phetaphene, perylene, phenalene, phenanthrene, perylene, pleiadene, pyrene, picanthracene, rubin, triphenylene, ternaphthalene, etc. Preferred aryl groups contain 6-20 carbon atoms, more preferably 6-12 carbon atoms.

" Arylalkyl " means a non-cyclic alkyl group in which a hydrogen atom bonded to a carbon atom, usually a terminal or SP ³ carbon atom, is replaced by an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethen-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthyleth-1-yl, 2- Naphthylvin-1-yl, naphthobenzyl, 2-naphthophenyleth-1-yl, etc. Where a specific alkyl moiety is intended, the terms arylalkanyl, arylalkenyl and/or arylalkynyl are used. Preferably the arylalkyl is (C ₆ -C ₃₀ )arylalkyl, for example the alkanyl, alkenyl or alkynyl portion of the arylalkyl is (C ₁ -C ₁₀ ) and the aryl portion is ( C ₆ -C ₂₀ ), more preferably arylalkyl is (C ₆ -C ₂₀ )arylalkyl, for example the alkanyl, alkenyl or alkynyl portion of arylalkyl is (C ₁ -C ₈ ), and the aryl moiety is (C ₆ -C ₁₂ ).

" Arylalkoxy " means an -O-arylalkyl group in which the arylalkyl group is as defined herein.

" Aryloxycarbonyl " means the group -C(O)-O-aryl wherein aryl is as defined herein.

" AUC " is the area under the plasma drug concentration-vs-time curve extrapolated from time zero to infinity.

" Bridged cycloalkyl " refers to a group selected from the group consisting of:

in:

A is (CR ³⁵ R ³⁶ ) _b ;

R ³⁵ and R ³⁶ are independently selected from hydrogen and methyl;

R ³³ and R ³⁴ are independently selected from hydrogen and methyl;

b is an integer from 1 to 4; and

c is an integer of 0-2.

" Carbamoyl " refers to the group -C(O)N(R) ₂ , wherein each R group is independently hydrogen, alkyl, cycloalkyl, or aryl as defined herein, which may optionally be Replace, as defined herein.

" Carboxy " means the group -C(O)OH.

"Carcinogenic potency (TD ₅₀ )" (see Peto et al., Environmental Health Perspectives 1984, 58, 1-8) is defined as the dose in mg/kg body weight that causes tumors in half of the animals tested at the end of their standard life span for a defined animal species Chronic dose-grades per day. Since the associated tumors frequently occur in control animals, the _TD50 is more clearly defined as: the dose-level in mg/kg bw/day if administered chronically during the standard lifespan of the species in question , will likely remain tumor-free during this period. _TD50 can be calculated for any particular type of tumor, for any particular tissue, or any combination thereof.

" Cmax " is the highest observed plasma drug concentration following administration of an extravascular dose _of drug.

" Compounds of the invention " refers to compounds encompassed by the formulas described herein, which include any specific compound within the scope of a formula whose structure is disclosed herein. The compounds of the present invention can be identified by their chemical structures and/or chemical names. When chemical structure and chemical name conflict, the chemical structure determines the identity of the compound. The compounds of the present invention may contain one or more chiral centers and/or double bonds and may therefore be present as stereoisomers such as double bond isomers (i.e. geometric isomers), optical enantiomers or diastereoisomers body exists. Accordingly, the chemical structures depicted herein encompass all possible enantiomers and stereoisomers of the compounds shown, including stereoisomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) stereopure) and mixtures of enantiomers and stereoisomers. Enantiomeric and stereoisomeric mixtures can be resolved into their constituent optical antipodes or stereoisomers using separation techniques or chiral synthesis techniques known to those skilled in the art. The compounds of the present invention may also exist in various tautomeric forms, including enol forms, keto forms or mixtures thereof. Accordingly, the structural formulas described herein include all possible tautomeric forms of the compounds shown. Compounds of the invention also include isotopically labeled compounds in which one or more atoms have an atomic mass other than that normally found in nature. Examples of isotopes that may be included in compounds of the invention include, but are not limited to ^{, 2H} , ^3H , ^13C , 14C, ^{15N , 18O, 17O, 31P, 32P , 35S , 18F , and 36} Cl. Furthermore, it should be understood that when illustrating a partial structure of a compound of the invention, square brackets indicate the point of attachment of that partial structure to the remainder of the molecule.

A " composition of the invention " refers to at least one compound of the invention and a pharmaceutically acceptable excipient by which the compound is administered to a human. When administered to humans, the compounds of the present invention are administered in isolated form, which means isolated from synthetic organic reaction mixtures.

" Cyano " means the group -CN.

" Cycloalkyl " means a saturated or unsaturated cycloalkyl group. Where a particular level of saturation is intended, the term "cycloalkyl" or "cycloalkenyl" is used. Typical cycloalkyl groups include, but are not limited to, those derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, etc. Group. Preferably the cycloalkyl group is (C ₃ -C ₁₀ )cycloalkyl group, more preferably (C ₃ -C ₇ )cycloalkyl group.

" Cycloheteroalkyl " refers to a saturated or unsaturated alkyl group in which one or more carbon atoms (and any attached hydrogen atoms) are independently replaced by the same or different heteroatoms. Typical heteroatoms replacing carbon atoms include, but are not limited to, N, P, O, S, Si, etc., where the term "cycloheteroalkanyl" or "cycloheteroalkenyl" is used if a particular level of saturation is intended. Typical cycloheteroalkyl groups include, but are not limited to, epoxides, imidazolidines, morpholines, piperazines, piperidines, pyrazolidines, pyrrolidines, quinuclidines, and the like.

" Cycloheteroalkoxycarbonyl " refers to the group -C(O)-OR, wherein R is cycloheteroalkyl as defined above.

" Derived from bile acids " refers to moieties structurally related to compounds of formula (XVII) or (XVIII):

wherein each of D, E and F is independently H or OH.

The moiety has the same structure as the above compound except for the 1 or 2 position. At these positions, the hydrogen atoms bound to the hydroxyl moiety of the hydroxyl and/or carboxyl groups have been replaced by a covalent bond serving as a binding point for another moiety, preferably a GABA analog or a GABA analog derivative.

" Derived from a GABA analog " refers to a moiety that is structurally equivalent to a GABA analog. The moiety has the same structure as the compound, except for the 1 or 2 position. At these positions, the hydrogen atom bound to the hydroxyl moiety of the amino and (optional) carboxyl groups has been replaced by a covalent bond that serves as a point of attachment for the other moiety.

" Dialkylamino " means a group -NRR' wherein R and R' independently represent alkyl or cycloalkyl as defined herein. Representative examples include, but are not limited to, dimethylamino, methylethylamino, bis(1-methylethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino, etc.

Unless otherwise indicated, " GABA analogs " refer to compounds having the following structure:

in:

R is hydrogen, or R and ^R together form an azetidine, a substituted azetidine, a pyrrolidine or a substituted pyrrolidine ring with the atoms bound to them;

R ^{and R} are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, ring heteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; and

R and ^R are independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl ^, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl, or optionally R ^and R ^and Together with the carbon atoms to which they are bound, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkyl ring.

" Halogen " means fluorine, chlorine, bromine or iodine.

" Heteroalkoxy " means -O-heteroalkyl, wherein heteroalkyl is as defined herein.

" Heteroalkyl, heteroalkanyl, heteroalkenyl, heteroalkynyl " means alkyl, alkanyl, alkenyl, and alkynyl, respectively, in which one or more carbon atoms (and any attached hydrogen atoms) are each independently substituted with the same or different heteroatoms. Typical heteroatom groups include, but are not limited to: -O-, -S-, -OO-, -SS-, -OS-, -NR'-, =NN=, -N=N-, -N=N -NR', -PH-, -P(O) ₂ -, -OP(O) ₂ -, -S(O)-, -S(O) ₂ -, -S _n H ₂ -, etc., wherein R' is hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl.

" Heteroaryl "refers to a monovalent heteroaromatic group derived by removal of a hydrogen atom from a single atom of a heteroaromatic ring system. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsine, carbazole, β-carboline, chroman, chromene, cinnoline, furan, imidazole, Indazole, indole, indoline, indolizine, isobenzofuran, isobenzopyran, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, Oxadiazole, oxazole, thidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine ), quinazoline, quinoline, quinazine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, etc. Preferably the heteroaryl is a 5-20 membered heteroaryl, more preferably a 5-10 membered heteroaryl. Preferred heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.

" Heteroaryloxycarbonyl " refers to the group -C(O)-OR where R is heteroaryl as defined herein.

" Heteroarylalkyl " refers to an acyclic alkyl group in which one hydrogen atom bonded to a carbon atom, usually a terminal or SP ³ carbon atom, is replaced by a heteroaryl group. Where a specific alkyl moiety is intended, the terms heteroarylalkanyl, heteroarylalkenyl and/or heteroarylalkynyl are used. In preferred embodiments, heteroarylalkyl is 6-30 membered heteroarylalkyl, for example the alkanyl, alkenyl or alkynyl moiety of heteroarylalkyl is 1-10 membered, and heteroaryl The base part is 5-20 membered heteroaryl, more preferably 6-20 membered heteroarylalkyl, for example, the alkanyl, alkenyl or alkynyl part of heteroarylalkyl is 1-8 membered, and heteroaryl The base part is 5-12-membered heteroaryl.

" Passive diffusion " refers to the uptake of an agent that is not mediated by a specific transporter. Reagents that are substantially non-passively diffusible have an in vitro velocity of less than 5 x 10 ^-6 cm/sec, usually less than 1 x 10 ^-6 cm/sec (lacking an efflux mechanism) across a standard cell monolayer (e.g. Caco-2). permeability.

" Pharmaceutically acceptable " means approved or may be approved by a federal or state government, or listed in the US Pharmacopoeia or other recognized pharmacopoeia for use in animals, more particularly humans.

" Pharmaceutically acceptable salt " refers to a salt of a compound of the present invention that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. These salts include: (1) acid addition salts, which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or with organic acids such as acetic acid, propionic acid ,, caproic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4- hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2 -Naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo 2.2.2-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid , tert-butylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, adienedioic acid, etc.; or (2) when the acidic protons present in the parent compound are Salts formed when metal ions such as alkali metal ions, alkaline earth ions or aluminum ions are substituted; or complexes formed with organic bases such as ethanolamine, diethylamineamine, triethanolamine, N-methylglucamine, etc.

" Pharmaceutically acceptable excipient " refers to a diluent, adjuvant, excipient or carrier with which a compound of the present invention is administered.

" Patient " includes humans. The terms "human" and "patient" are used interchangeably herein. " Dreventing or prevention" refers to reducing the risk of a disease or disorder (ie, such that at least one clinical symptom of disease does not develop in patients exposed to or susceptible to the disease but who have not yet experienced or exhibited symptoms of the disease).

" Prodrug " refers to a derivative of a drug molecule that requires transformation in vivo to release the active drug. Prodrugs are usually, though not necessarily, pharmacologically inactive until converted to the parent drug.

" Motive " refers to a form of protecting group that, when used to mask a functional group within a drug molecule, converts a drug into a prodrug. Typically the motif is bound to the drug by a bond that is cleaved in vivo either enzymatically or non-enzymatically.

" Protecting group " refers to a group of atoms which, when bound to a reactive functional group in a molecular shield, reduces or prevents the reactivity of the functional group. Examples of protecting groups can be found in Green et al., "Protective Groups in Organic Chemistry (Protective Groups in Organic Chemistry)", (Wiley, ^2nd ED. 1991) and Harrison et al., "Compendium of Synthetic Organic Methods , 1-8 (John Wiley and Sons, 1971-1996). Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES"), trityl and substituted trityl, allyloxycarbonyl, 9-fluorenylmethyloxy carbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC"), and the like. Representative hydroxy protecting groups include, but are not limited to, groups in which the hydroxy group is acylated or alkylated such as benzyl, and trityl ethers as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilanes base ethers and allyl ethers.

"Substituted" refers to groups in which one or more hydrogen atoms are each independently replaced by the same or different substituents. Typical substituents include but are not limited to -X, -R ²⁹ , =O ^- , -OR ²⁹ , -SR ²⁹ , -S ^- , =S, -NR ²⁹ R ³⁰ , =NR ²⁹ , -CX ₃ , -CF ₃ , -CN, -OCN, -SCN, -NO, -NO ₂ , =N ₂ , -N ₃ , -S(O) ₂ O, -S(O) ₂ OH, -S(O) ₂ R ²⁹ , -OS(O ₂ )O ^- , -OS(O) ₂ R ²⁹ , -P(O)(O ^- ) ₂ , -P(O)(OR ²⁹ )(O ^- ), -OP(O)( OR ²⁹ )(OR ³⁰ ), -C(O)R ²⁹ , -C(S)R ²⁹ , -C(O)OR ²⁹ , -C(O)NR ²⁹ R ³⁰ , -C(O)O-, -C(S)OR ²⁹ , -NR ³¹ C(O)NR ²⁹ R ³⁰ , -NR ³¹ C(S)NR ²⁹ R ³⁰ , -NR ³¹ C(NR ²⁹ )NR ²⁹ R ³⁰ and -C(NR ²⁹ ) NR ²⁹ R ³⁰ , wherein each X is independently halogen; each R ²⁹ and R ³⁰ is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted aryl Alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl , substituted heteroarylalkyl, -NR ³¹ R ³² , -C(O)R ³¹ or -S(O) ₂ R ³¹ , or optionally R ²⁹ and R ³⁰ together with the atoms to which they are simultaneously bonded form a ring hetero Alkyl or substituted cycloheteroalkyl ring; and ^R and ^R are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, Cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted Heteroarylalkyl.

" Transporter " refers to a protein that plays a direct or indirect role in the transport of molecules into and/or through a cell. For example, a transporter can be, but is not limited to, a solute-carrying transporter, a co-transporter, a counter transporter, a mono-transporter, a co-transporter, an antiporter, a pump, an equilibrium transporter, a concentrating Transport agents and other proteins that regulate active transport, energy-dependent transport, facilitated diffusion, exchange mechanisms, and specific uptake mechanisms. A transporter can also be, but is not limited to, a membrane-bound protein that recognizes a substrate and affects its entry and exit from a cell via a carrier-mediated transporter or a receptor-regulated transporter. A transport protein can also be, but is not limited to, an intracellularly expressed protein involved in transporting a substrate through or out of the cell. A transporter can also be, but is not limited to, a cell surface exposed protein or glycoprotein that does not directly transport a substrate but binds to the substrate to keep it in the vicinity of a receptor, or a transporter that affects the entry or passage of a substrate into or through a cell. Examples of carrier proteins include: intestinal and hepatic bile acid transporters, dipeptide transporters, oligopeptide transporters, monosaccharide transporters (eg SGLT1), phosphate transporters, monocarboxylic acid transporters, beta-glycoprotein transporters, Organic anion transporters (OATs) and organic cation transporters. Examples of receptor-regulated transporters include: viral receptors, immunoglobulin receptors, bacterial toxin receptors, plant lectin receptors, bacterial adhesion receptors, vitamin transporters, and cytokine growth factor receptors.

" Treating or treatment " of any disease or condition refers, in one embodiment, to ameliorating the disease or condition (ie, halting or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treating" or "treatment" refers to improving at least one physical parameter that may not be discernible in a patient. In yet another embodiment, "treating or treatment" refers to inhibiting a disease or condition either physically (eg, stabilizing discernible symptoms), physiologically (eg, stabilizing a physical parameter), or simultaneously. In yet another embodiment, "treating" refers to delaying the onset of a disease or condition.

" Therapeutically effective amount " means an amount of a compound which, when administered to a patient to treat a disease, is sufficient to effect treatment of the disease. The "therapeutically effective amount" will vary with the compound, the disease and its severity, and the age, weight, etc. of the patient to be treated.

Reference will now be made in more detail to the preferred embodiments of the invention. While the invention has been described in conjunction with the preferred embodiments, it will be understood that it is not intended to limit the invention to these preferred embodiments. On the contrary, this application is intended to cover alternatives, modifications and equivalents, which may be included within the spirit and scope of the invention as defined by the appended claims.

4.2 Compounds of the invention

Those skilled in the art will recognize that compounds of formulas (I), (II) and (III) have certain structural features in common. These compounds are all GABA analogs (ie derivatives of gamma-aminobutyric acid) that have incorporated motifs. In particular, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , X and Y are common substituents found in compounds of formulas (I), (II) and (III).

Compounds of the present invention include compounds of formula (I), formula (II) or formula (III)

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

n, t, u, X, Y, R ¹ , R ^{2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 20} , R ²¹ , R ²² and R ²³ are as defined above.

In a preferred embodiment, the compounds of formula (I), (II) and (III) do not include the following compounds:

When R ³ and R ⁶ are both hydrogen, R ⁴ and R ⁵ are not both hydrogen or not all methyl;

In the compound of formula (I), when n is O or when n is 1, and X is NR ¹⁶ , then R ¹ is not hydrogen;

In compounds of formula (I), none of R ¹ , R ⁷ O-, R ²⁴ C(O)-, R ²⁵ C(O)- and R ²⁵ O- is a bile acid-derived moiety;

In the compound of formula (I), when R ¹ is R ²⁴ C(O)- and n is 0, R ²⁴ is not methyl, tert-butyl, 2-aminoethyl, 3-aminopropyl, benzyl phenyl, phenyl or 2-(benzoyloxymethyl)phenyl;

In the compound of formula (I), when R ¹ is R ²⁵ OC(O)-, R ²⁵ is not R ²⁶ C(O)CR ¹³ R ¹⁴ -, wherein R ²⁶ is selected from hydrogen, alkyl, substituted Alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl;

In the compound of formula (I), when R ¹ is R ²⁵ OC (O)- and n is 0, R ²⁵ is not methyl, tert-butyl or benzyl;

In the compound of formula (I), when n is 0 and R ¹ is R ²⁵ C(O)OCR ¹³ R ¹⁴ OC(O)-, if either R ¹³ or R ¹⁴ is hydrogen, alkoxycarbonyl , substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, then the other of R ¹³ or R ¹⁴ is not hydrogen;

In the compound of formula (I), when n is 1, X is NH, R ³ , R ⁵ and R ⁶ are each hydrogen, and R ⁴ is cyclohexyl, then R ² is not benzyl;

In a compound of formula (II), when t is 1 and u is 0, neither R nor R is ² -hydroxyl-3- ^methyl -5-chlorophenyl; and

In compounds of formula (II), t is 1 when u is 1 and X is 0.

In one embodiment of the compounds of formula (I), (II) and (III), when ^R3 and ^R6 are each hydrogen, ^R4 and ^R5 are not both hydrogen or not both methyl.

In one embodiment of the compounds of formula (I), R ¹ is other than hydrogen when n is 0 or when n is 1 and X is NR ¹⁶ . In another embodiment of the compounds of formula (I), none of R ¹ , R ⁷ O-, R ²⁴ C(O)-, R ²⁵ C(O)- or R ²⁵ O- is a moiety derived from a bile acid . In another embodiment of the compounds of formula (I), when R ¹ is R ²⁴ C(O)— and n is 0, R ²⁴ is not alkyl, substituted alkyl, arylalkyl, aryl or substituted aryl. In another embodiment of the compound of formula (I), when R ¹ is R ²⁴ C(O)- and n is 0, then R ²⁴ is not C _1-4 alkanyl, benzyl, phenyl or Substituted phenyl. In another embodiment of the compounds of formula (I), when R ¹ is R ²⁴ C(O)- and n is 0, R ²⁴ is not methyl, tert-butyl, 2-aminoethyl, 3- Aminopropyl, benzyl, phenyl or 2-(benzoyloxymethyl)-phenyl. In another embodiment of the compounds of formula (I), when R ¹ is R ²⁵ OC(O)—, R ²⁵ is other than R ²⁶ C(O)CR ¹³ R ¹⁴ —. In another embodiment of the compounds of formula (I), when R ¹ is R ²⁵ OC(O)— and n is 0, R ²⁵ is not alkyl or arylalkyl. In another embodiment of the compounds of formula (I), when R ¹ is R ²⁵ OC(O)— and n is 0, R ²⁵ is other than C _1-4 alkanyl or benzyl. In another embodiment of the compounds of formula (I), when R ¹ is R ²⁵ OC(O)- and n is 0, R ²⁵ is other than methyl, tert-butyl or benzyl. In another embodiment of the compounds of formula (I), when n is 0 and R ¹ is R ²⁵ C(O)OCR ¹³ R ¹⁴ OC(O)—, if either R ¹³ or R ¹⁴ is hydrogen , alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, then the other of ^R or ^R is not hydrogen. In another embodiment of the compounds of formula (I), when ^R3 , ^R5 and ^R6 are each hydrogen, ^R4 is not cyclohexyl. In another embodiment of the compounds of formula (I), when n is 1, X is NH, ^R3 , ^R5 , ^R6 are each hydrogen and ^R2 is benzyl, ^R4 is other than cyclohexyl.

In one embodiment of the compound of formula (II), neither ^R20 nor ^R21 is 2-hydroxy-3-methyl-5-chlorophenyl. In one embodiment of the compound of formula (II), t is 1 when u is 1 and X is 0.

In one embodiment of the compounds of formula (I), (II) and (III), n is 0. In another embodiment, n is 1. When n is 1 and X is ^NR6 , the alpha-amino acid is preferably in the L-stereochemical configuration.

In another embodiment of the compounds of formula (I) and (II), R ^is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkanyl, substituted aryl Alkanyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyi and substituted cycloheteroalkyi. In a preferred embodiment, Y is O and ^R7 is hydrogen. In another embodiment, Y is O and R is ^alkanyl , substituted alkanyl, alkenyl, substituted alkenyl, aryl or substituted aryl. Preferably R ⁷ is methyl, ethyl, benzyl, -C(CH ₃ )=CH ₂ , -CH ₂ C(O)N(CH ₃ ) ₂ ,

or

wherein V is O or CH ₂ .

In a preferred embodiment of the compounds of formula (I), (II) and (III), R ^is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, Substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, hetero Arylalkyl and substituted heteroarylalkyl. ^Preferably R is selected from the group consisting of hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkyl, heteroarylalkyl and substituted The heteroaryl chain alkyl.

In another embodiment of the compounds of Formulas (I), (II) and (III), X is NH and ^R is hydrogen, cycloalkyl or alkanyl. Preferably ^R2 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl or cyclohexyl. In another embodiment, X is NH and ^R is substituted alkanyl. Preferably R ² is -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH _{2 CH2SCH3 , CH2SH , -CH2} ( _{CH2 ) 3NH2 or -CH2CH2CH2NHC} (NH) _NH2 . In another embodiment, X is NH and R ^is selected from aryl, arylalkanyl, substituted arylalkanyl, and heteroarylalkanyl.

Preferably ^R2 is phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl or 2-indolyl. In another embodiment, X is NR ¹⁶ and R ² and R ¹⁶ and the atoms to which they are joined together form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

Preferably ^R2 and ^R16 together with the atoms to which they are bound form an azetidine, pyrrolidine or piperidine ring.

In another embodiment of the compounds of formula (I), (II) and (III), ^R3 is hydrogen. In another embodiment, ^R6 is hydrogen. In another embodiment, R ^{and R} are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, and substituted cycloalkyl. Preferably ^R3 and ^R6 are independently selected from hydrogen and alkanyl. More preferably ^R3 is hydrogen or alkanyl and ^R6 is hydrogen.

In another preferred embodiment of the compounds of formula (I), (II) and (III), R ^{and R} are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted ring Alkyl, cycloheteroalkyl, and substituted cycloheteroalkyl. Preferably ^R4 and ^R5 are independently selected from hydrogen, alkanyl and substituted alkanyl.

In another embodiment of the compounds of formula (I), (II) and (III), R ⁴ and R ⁵ together with the carbon atom to which they are bound form a cycloalkyl or substituted cycloalkyl ring. Preferably ^R4 and ^R5 together with the carbon atom to which they are bound form a cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, cyclohexyl or substituted cyclohexyl ring. In another embodiment, ^R4 and ^R5 together with the carbon atom to which they are bound form a cycloheteroalkyl or substituted cycloheteroalkyl ring. In another embodiment, ^R4 and ^R5 together with the carbon atoms to which they are bound form a bridged cycloalkyl ring.

In one embodiment of the compound of formula (I), n is 1, R ¹ is R ²⁴ C(O)- or R ²⁴ C(S)-, and R ²⁴ is alkyl, substituted alkyl, heteroalkane radical, substituted heteroalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Preferably R ²⁴ is methyl, ethyl, 2-propyl, tert-butyl, —CH ₂ OCH(CH ₃ ) ₂ , phenyl or 3-pyridyl.

In another embodiment of the compounds of formula (I), n is 1, R ¹ is R ²⁵ OC(O)- or R ²⁵ SC(O)-, and R ²⁵ is alkyl, substituted alkyl, hetero Alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Preferably R ²⁵ is ethyl, 2-propyl, neopentyl, —CH ₂ OCH(CH ₃ ) ₂ , phenyl or 2-pyridyl.

A preferred embodiment of the compound of formula (I) includes the compound of formula (IV):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

n, Y, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹³ , R ¹⁴ , R ¹⁶ and R ²⁵ are as defined above.

In a preferred embodiment, the compound of formula (IV) does not include the following compounds: when R ¹³ or R ¹⁴ is hydrogen, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or In the case of substituted cycloalkoxycarbonyl, the other of R ¹³ or R ¹⁴ is not hydrogen; and R ²⁵ C(O) is not a moiety derived from bile acid.

In one embodiment of the compound of formula (IV), R ^{and R} are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkane radical, substituted cycloalkyl, cycloalkoxycarbonyl or heteroaryl (preferably when R ¹³ is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R ¹⁴ is methyl). More preferably R and ^R are independently hydrogen, ^methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxy Carbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl, Benzyl, phenethyl or 3-pyridyl.

In another embodiment of the compounds of formula (IV), ^R13 and ^R14 are independently hydrogen, alkanyl, substituted alkanyl, cycloalkyl or substituted cycloalkyl. Preferably ^R13 and ^R14 are hydrogen, alkanyl or cycloalkyl. More preferably ^R13 and ^R14 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl or cyclohexyl. Even more preferably R is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl or ^cyclohexyl and R is ^hydrogen , or R ^is methyl and ^R14 is methyl.

In another embodiment of the compounds of formula (IV), ^R13 and ^R14 are independently hydrogen, aryl, arylalkyl or heteroaryl. More preferably ^R13 and ^R14 are independently hydrogen, phenyl, benzyl, phenethyl or 3-pyridyl. Even more preferably ^R13 is phenyl, benzyl, phenethyl or 3-pyridyl and ^R14 is hydrogen.

In another embodiment of the compounds of formula (IV), ^R13 and ^R14 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, carbamoyl or cycloalkoxycarbonyl. Preferably when R ¹³ is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R ¹⁴ is methyl. More preferably ^R is methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl or cyclohexyloxycarbonyl, And R ¹⁴ is methyl.

In another embodiment of the compounds of formula (IV), R ¹³ and R ¹⁴ and the carbon atom to which they are bound together form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably R ¹³ and R ¹⁴ together with the carbon atom to which they are bound form a cycloalkyl ring. More preferably R ¹³ and R ¹⁴ together with the carbon atom to which they are bound form a cyclobutyl, cyclopentyl or cyclohexyl ring.

In another embodiment of the compound of formula (IV), R is ^acyl , substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, Cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted Heteroarylalkyl. Preferably R ²⁵ is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl. More preferably R is ^methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethyl Oxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl )-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-( 1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolane- 2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1 -(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-benzene Ethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl)-2-phenylethyl, 1-(1,3-diox Alk-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styrene , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In another embodiment of the compounds of formula (IV), R ²⁵ is acyl or substituted acyl. More preferably R ²⁵ is acetyl, propionyl, butyryl, benzoyl or phenylacetyl.

In another embodiment of the compounds of Formula (IV), R ²⁵ is alkanyl or substituted alkanyl. Preferably R is ^methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxy Diethyl ethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl) -Ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1 , 3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolane-2 -yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenylethyl 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl or 1-(1,3-dioxane -2-yl)-2-phenylethyl. More preferably R ²⁵ is methyl, ethyl, propyl, isopropyl, butyl, 1,1-dimethoxyethyl or 1,1-diethoxyethyl.

In another embodiment of the compounds of formula (IV), R ²⁵ is aryl, arylalkyl or heteroaryl. Preferably R ²⁵ is phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl.

In another embodiment of the compounds of Formula (IV), R ²⁵ is cycloalkyl or substituted cycloalkyl. More preferably R ²⁵ is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In another embodiment of the compound of formula (IV), R is ^acyl , substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, Cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted Heteroarylalkyl; while R and ^R are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl ^, substituted aryl, arylalkyl, Substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R ^is When alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl, R ¹⁴ is methyl). Preferably R is ^acyl , substituted acyl, alkyl, substituted alkyl, aryl ^, arylalkyl, cycloalkyl or heteroaryl, and R and ^R are independently hydrogen, alkyl, substituted Alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl, cycloalkoxycarbonyl or heteroaryl (preferably when ^R is alkoxycarbonyl, substituted alkoxycarbonyl , cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl, R ¹⁴ is methyl). More preferably R is ^methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethyl Oxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl )-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-( 1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolane- 2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1 -(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-benzene Ethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl)-2-phenylethyl, 1-(1,3-diox Alk-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styrene base, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl, and R ¹³ and R ¹⁴ are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, iso Butyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or 3-pyridyl. Even more preferably R is ^methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl base, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2- Phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, cyclohexyl or 3-pyridyl, and ^R13 and ^R are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxy ylcarbonyl, isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl or 3-pyridyl.

In another embodiment of the compound of formula (IV), R is ^acyl , substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, Cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted Heteroarylalkyl, while ^R and ^R together with the atoms to which they are bonded form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably ^R25 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, while ^R13 and ^R14 together with the atoms to which they are bound form cycloalkyl or a substituted cycloalkyl ring. More preferably R is ^methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethyl Oxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl )-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-( 1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolane- 2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1 -(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-benzene Ethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl)-2-phenylethyl, 1-(1,3-diox Alk-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styrene In base, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl, and R ¹³ and R ¹⁴ and the atoms they are bound together form a cyclobutyl, cyclopentyl or cyclohexyl ring.

In another embodiment of the compounds of formula (IV), R is ^acyl or ^substituted acyl, and R and ^R are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxy arylcarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl , heteroaryl or substituted heteroaryl (preferably when R ¹³ is alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl, R ¹⁴ is methyl). Preferably ^R is acetyl, propionyl, butyryl, benzoyl or phenylacetyl, and R and ^R are independently hydrogen, alkyl, ^substituted alkyl, alkoxycarbonyl, substituted alkoxy Carbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, Heteroaryl or substituted heteroaryl (preferably when R ¹³ is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R ¹⁴ is methyl).

In another embodiment of the compounds of formula (IV), R is ^alkanyl or substituted alkanyl, and ^R and ^R are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted ring Alkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when ^R is alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl , R ¹⁴ is methyl). Preferably R is ^methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxy Diethyl ethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl) -Ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1 , 3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolane-2 -yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1- (1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenylethyl 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl or 1-(1,3-dioxane -2-yl)-2-phenethyl, while R ^{and R} are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl , arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl, or substituted heteroaryl (Preferably when R ¹³ is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R ¹⁴ is methyl).

In another embodiment of the compound of formula (IV), R ²⁵ is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, or substituted heteroaryl, and R ¹³ and ^R is independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl , cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R ¹³ is alkoxycarbonyl, substituted alkoxy When carbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl, R ¹⁴ is methyl). Preferably R ²⁵ is phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, and R ¹³ and R ¹⁴ are independently hydrogen, alkyl, substituted alkyl, Alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxy Carbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R ¹³ is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R ¹⁴ is methyl).

In another embodiment of the compounds of formula (IV), R is ^cycloalkyl or substituted cycloalkyl, and R ^{and R} are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, Substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted ring Alkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when ^R is alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl , R ¹⁴ is methyl). Preferably R is ^cyclopropyl , cyclobutyl, cyclopentyl or cyclohexyl, and R and ^R are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl ^, Aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl radical or substituted heteroaryl (preferably when R ¹³ is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R ¹⁴ is methyl).

In another embodiment of the compound of formula (IV), R is ^acyl , substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, Cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted Heteroarylalkyl, and R ¹³ and R ¹⁴ are independently hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl, or heteroaryl. Preferably R is ^acyl , substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R ^{and R} are independently hydrogen, alkanyl, substituted Alkanyl, cycloalkyl or substituted cycloalkyl. More preferably R is ^acyl , substituted acyl, alkyl, ^substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R and ^R are independently hydrogen, methyl, ethyl propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl or cyclohexyl. In the above embodiments, R is preferably ^methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1 , 1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-diox Alk-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propane base, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3- Dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxy Benzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy Base-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1 , 3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, benzene Ethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In another embodiment of the compound of formula (IV), R is ^acyl , substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R ^and R ¹⁴ is independently hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl, or heteroaryl. Preferably R is ^acyl , substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R ^{and R} are independently hydrogen, aryl, aryl Alkyl or heteroaryl. More preferably R is ^acyl , substituted acyl, alkyl ^, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R and ^R are independently hydrogen, phenyl, benzyl base, phenethyl or 3-pyridyl. In the above embodiments, R is preferably ^methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1 , 1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-diox Alk-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propane base, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3- Dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxy Benzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy Base-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1 , 3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, benzene Ethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In another embodiment of the compound of formula (IV), R is ^acyl , substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R ^and R ¹⁴ is independently hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl, or heteroaryl. Preferably R is ^acyl , substituted acyl, alkyl, substituted alkyl, aryl ^, arylalkyl, cycloalkyl or heteroaryl, and R and ^R are independently hydrogen, alkyl, substituted Alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl (preferably when ^R is alkoxycarbonyl, substituted alkoxycarbonyl, When carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, R ¹⁴ is methyl; more preferably R ¹³ is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl , butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl or cyclohexyloxycarbonyl, and R ¹⁴ is methyl). In the above embodiments, R is preferably ^methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1 , 1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-diox Alk-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propane base, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3- Dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxy Benzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy Base-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1 , 3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, benzene Ethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In another embodiment of the compound of formula (IV), R is ^acyl , substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R ^and R ¹⁴ and the atoms to which they are bonded together form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably R ^is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, while ^R and ^R together with the atoms to which they are bound form a cycloalkane radical or substituted cycloalkyl ring. More preferably ^R is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R and ^R together with the atoms to which they ^are bound form a ring Butyl, cyclopentyl or cyclohexyl rings. In the above embodiments, R is preferably ^methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1 , 1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl, 1-(1,3-diox Alk-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propane base, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3- Dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxy Benzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy Base-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolan-2-yl)-2-phenethyl, 1-(1 , 3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, benzene Ethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In another embodiment of the compounds of formula (I) and (III), R ^is

m is 0, and R ⁸ , R ¹¹ and R ¹² are as defined above.

In one embodiment of the compounds of formula (I) and (III), R is ^acyl , alkoxycarbonyl, aryloxycarbonyl, cycloalkoxycarbonyl or carbamoyl, ^R is hydrogen, alkoxy carbonyl, alkyl, aryl, arylalkyl or cyano, and ^R is hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl or arylalkyl.

In another embodiment of the compounds of formula (I) and (III), R ^is selected from acetyl, propionyl, butyryl, isobutyryl, pivaloyl, cyclopentanecarbonyl, cyclohexanecarbonyl, benzene Formyl, phenylacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl , cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl , N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-sec-butylcarbamoyl, N-tert-butylcarbamoyl, N-cyclopentyl Carbamoyl, N-cyclohexylcarbamoyl, N-phenylcarbamoyl, N-benzylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N-diisopropylcarbamoyl, N,N-dibutylcarbamoyl, N,N-dibenzylcarbamoyl, N-pyrrolidinyl Carbamoyl, N-piperidinylcarbamoyl and N-morpholinylcarbamoyl. More preferably ^R is selected from acetyl, propionyl, butyryl, isobutyryl, cyclohexanecarbonyl, benzoyl, phenylacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy ylcarbonyl, butoxycarbonyl, cyclohexyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl Acyl, N-isopropylcarbamoyl, N-phenylcarbamoyl, N-benzylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N , N-dipropylcarbamoyl, N-pyrrolidinylcarbamoyl, N-piperidinylcarbamoyl and N-morpholinylcarbamoyl.

In another embodiment of the compounds of formula (I) and (III), R ^is selected from hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy ylcarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl and cyano. More preferably ^R is selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

In another embodiment of the compounds of formula (I) and (III), R ^is selected from hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy oxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl and benzyloxycarbonyl. More preferably ^R12 is selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

In another embodiment of the compounds of formula (I) and (III), R ^is selected from hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, arylalkyl, and ^R and R ¹² together with the carbon atoms to which they are bound form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably ^R11 is selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, while ^R8 and ^R12 and the carbon to which they are bound The atoms are taken together to form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. More preferably R ¹¹ is hydrogen or methyl, and R ⁸ and R ¹² form cyclopent-1-ene, cyclohex-1-ene, 2-cyclopenten-1-one, 2 - cyclohexen-1-one, 2-(5H)-furanone or 5,6-dihydro-pyran-2-one ring.

In another embodiment of the compounds of formula (I) and (III), R ^is selected from hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, arylalkyl, and ^R and R ¹¹ together with the carbon atoms to which they are bound form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably R ¹² is selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R ⁸ and R ¹¹ are bound to their carbon atoms taken together to form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. More preferably R ¹² is selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R ⁸ and R ¹¹ are bound to their carbon The atoms together form a gamma-butyrolactone, delta-valerolactone or 2,2-dimethyl-1,3-dioxane-4,6-dione ring.

In another embodiment of the compounds of formula (I) and (III), R ^is

And R is selected from the ^group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. Preferably R ¹⁵ is methyl, ethyl, propyl, isopropyl, cyclopentyl, cyclohexyl, phenyl, 4-hydroxyphenyl, benzyl, 4-hydroxybenzyl or 3-pyridyl.

In another embodiment of formulas (I) and (III), R ^is

wherein ^R is hydrogen, alkyl, substituted alkyl, acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, heterocycloalkyl, substituted cycloheteroalkane radical, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;

Z is O, N or S; and

Ar is aryl, substituted aryl, heteroaryl or substituted heteroaryl.

Preferably Z and _CH2OC (O)- are conjugated to each other (for example in relation to 1,4 or 1,2 of a six-membered ring system).

In another embodiment of formulas (I) and (III), R ^is

or

where q is 0 or 1;

R and ^R are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl ^, and substituted heteroaryl;

R and ^R are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, ^and substituted heteroaryl; or and combinations thereof carbon atoms together form a cycloalkyl ring;

R ⁴² and R ⁴³ are independently alkyl, substituted alkyl, cycloalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted aryl or together with the carbon atom to which they are bound forming an aryl, substituted aryl, heteroaryl, or substituted aryl ring;

and ^R37 are as defined above.

In a preferred embodiment of the compounds of formulas (I)-(IV), Y is O, R ³ , R ⁶ and R ⁷ are hydrogen, and R ⁴ and R ⁵ together with the carbon atoms to which they are bound form cycloalkane radical, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, bridged cycloalkyl, or substituted bridged cycloalkyl ring.

In another preferred embodiment of the compounds of formulas (I)-(IV), R ⁴ and R ⁵ together with the carbon atom to which they are bound form a cycloalkyl or substituted cycloalkyl ring. In one embodiment, n is 0, t is 0 and u is 0. In another embodiment n is 1 and R is hydrogen, methyl, 2-propyl, ² -butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl , 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ SCH ₃ , CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH ₂ or -CH ₂ CH ₂ CH ₂ NHC(NH)NH ₂ . In another embodiment, n is ¹ and R and ^R together with the atoms to which they are joined form a pyrrolidine ring.

In another preferred embodiment of the compounds of formulas (I)-(IV), R ⁴ and R ⁵ and the carbon atom to which they are bound together form a cyclobutyl or substituted cyclobutyl ring. Preferably the substituted cyclobutyl ring is substituted with one or more substituents selected from the group consisting of alkanyl, substituted alkanyl, halogen, hydroxy, carboxyl and alkoxycarbonyl.

In another preferred embodiment of the compounds of formulas (I)-(IV), R ⁴ and R ⁵ and the carbon atom to which they are bound together form a cyclopentyl or substituted cyclopentyl ring. Preferably the cyclopentyl ring is substituted with alkanyl, substituted alkanyl, halo, hydroxy, carboxy or alkoxycarbonyl. More preferably the cyclopentyl ring is substituted with an alkanyl group. Even more preferably said cyclopentyl ring is selected from

和

and

Preferably in a more specific version of the above embodiment, ^R7 is hydrogen.

In another preferred embodiment of the compounds of formulas (I)-(IV), R ⁴ and R ⁵ together with the carbon atom to which they are bound form a cyclohexyl or substituted cyclohexyl ring. Preferably the cyclohexyl ring is substituted with alkanyl, substituted alkanyl, halo, hydroxy, carboxy or alkoxycarbonyl. More preferably the cyclohexyl ring is substituted with an alkanyl group. Even more preferably said cyclohexyl ring is selected from

和

and

Preferably in a more specific version of the above embodiment, ^R7 is hydrogen.

In another preferred embodiment of the compounds of formulas (I)-(IV), R ⁴ and R ⁵ together with the carbon atom to which they are bound form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

In one embodiment, n is zero. In another embodiment n is 1 and R is hydrogen, methyl, 2-propyl, ² -butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl , 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ SCH ₃ , CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH ₂ or -CH ₂ CH ₂ CH ₂ NHC(NH )NH ₂ . In another embodiment, n is ¹ and R and ^R together with the atoms to which they are bound form a pyrrolidine ring. Preferably ^R4 and ^R5 together with the carbon atom to which they are bound form a cycloheteroalkanyl ring. More preferably the cycloheteroalkanyl ring is selected from

or

where Z is O, S(O) _p or NR ¹⁸

P is 0, 1 or 2; and

R ¹⁸ is selected from hydrogen, alkyl, substituted alkyl, acyl and alkoxycarbonyl. More preferably the cycloheteroalkanyl ring is selected from

和

and

Preferably, in a more specific version of the above embodiment, R ⁷ is hydrogen.

In another embodiment of the compounds of formulas (I)-(IV), ^R4 and ^R5 and the carbon atom to which they are bound together form a bridged cycloalkyl ring. In one embodiment, n is zero. In another embodiment n is 1 and R is hydrogen, methyl, 2-propyl, ² -butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl , 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ SCH ₃ , CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH ₂ or -CH ₂ CH ₂ CH ₂ NHC(NH )NH ₂ . In another embodiment, n is 1 and ^R2 and ^R16 together with the atoms to which they are bound form a pyrrolidine ring. Preferably the bridged cycloalkyl group is

或

or

Preferably in a more specific version of the above embodiment, ^R7 is hydrogen.

In another embodiment of the compounds of formulas (I)-(IV), Y is O, ^R and R are hydrogen, ^R is ^alkyl or cycloalkyl, ^R is hydrogen or alkyl, and R ³ is hydrogen or alkyl. In one embodiment, n is zero. In another embodiment, n is ¹ and R is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-Hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ SCH ₃ , CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH ₂ or -CH ₂ CH ₂ CH ₂ NHC(NH) _NH2 . In another embodiment, n is 1 and ^R2 and ^R16 together with the atoms to which they are bound form a pyrrolidine ring. Preferably ^R4 is cycloalkyl, ^R5 is hydrogen or methyl, and ^R3 is hydrogen or methyl. Preferably ^R3 is hydrogen, ^R4 is isobutyl and ^R5 is hydrogen.

In another embodiment of the compounds of formulas (I)-(IV), Y is O, ^R and ^R are hydrogen or alkanyl, R ^{and R} are hydrogen, and ^R is a substituted heteroalkane base.

Preferably ^R4 is

A is NR ¹⁹ , O or S;

B is alkyl, substituted alkyl, alkoxy, halogen, hydroxy, carboxyl, alkoxycarbonyl, or amino;

R ¹⁹ is hydrogen, alkyl, cycloalkyl or aryl;

j is an integer of 0-4;

k is an integer from 1 to 4; and

l is an integer of 0-3.

More preferably, k is 1.

In another embodiment of the compounds of formulas (I)-(IV), Y is O, ^R and ^R are hydrogen or alkanyl, R ^{and R} are hydrogen, and ^R is substituted alkane radical, cycloalkyl or substituted cycloalkyl. Preferably R ^is selected from

Preferably ^R4 is

和

and

h is an integer from 1 to 6; and

i is an integer of 0-6.

More preferably h is 1, 2, 3 or 4 and i is 0 or 1 . Even more preferably ^R is selected from

和

and

Preferably compounds of formulas (I)-(IV) are derived from GABA analogs of formula (XIII):

Wherein the GABA analog of formula (XIII) is selected from:

1-Aminomethyl-1-cyclohexaneacetic acid;

1-Aminomethyl-1-(3-methylcyclohexane)acetic acid;

1-Aminomethyl-1-(4-methylcyclohexane)acetic acid;

1-Aminomethyl-1-(4-isopropylcyclohexane)acetic acid;

1-Aminomethyl-1-(4-tert-butylcyclohexane)acetic acid;

1-aminomethyl-1-(3,3-dimethylcyclohexane)acetic acid;

1-aminomethyl-1-(3,3,5,5-tetramethylcyclohexane)acetic acid;

1-Aminomethyl-1-cyclopentaneacetic acid;

1-Aminomethyl-1-(3-methylcyclopentane)acetic acid;

1-aminomethyl-1-(3,4-dimethylcyclopentane)acetic acid;

7-Aminomethyl-bicyclo[2.2.1]hept-7-ylacetic acid;

9-Aminomethyl-bicyclo[3.3.1]non-9-ylacetic acid;

4-Aminomethyl-4-(tetrahydropyran-4-yl)acetic acid;

3-aminomethyl-3-(tetrahydropyran-3-yl)acetic acid;

4-Aminomethyl-4-(tetrahydrothiopyran-4-yl)acetic acid;

3-Aminomethyl-3-(tetrahydrothiopyran-3-yl)acetic acid;

3-Aminomethyl-5-methyl-hexanoic acid;

3-Aminomethyl-5-methyl-heptanoic acid;

3-Aminomethyl-5-methyl-octanoic acid;

3-Aminomethyl-5-methyl-nonanoic acid;

3-Aminomethyl-5-methyl-decanoic acid;

3-Aminomethyl-5-cyclopropyl-hexanoic acid;

3-Aminomethyl-5-cyclobutyl-hexanoic acid;

3-Aminomethyl-5-cyclopentyl-hexanoic acid;

3-Aminomethyl-5-cyclohexyl-hexanoic acid;

3-Aminomethyl-5-phenyl-hexanoic acid;

3-Aminomethyl-5-phenyl-pentanoic acid;

3-Aminomethyl-4-cyclobutyl-butanoic acid;

3-Aminomethyl-4-cyclopentyl-butanoic acid;

3-Aminomethyl-4-cyclohexyl-butanoic acid;

3-Aminomethyl-4-phenoxy-butyric acid;

3-Aminomethyl-5-phenoxy-hexanoic acid; and

3-Aminomethyl-5-benzylsulfanyl-pentanoic acid.

Particularly preferred embodiments of formula (I) include compounds of formulas (V) and (VI):

wherein R ¹ , R ² , R ⁷ and R ¹⁶ are as defined above.

In one embodiment of the compounds of formula (V) and (VI), n is 0. In another embodiment n is 1 and R is hydrogen, methyl, 2-propyl, ² -butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl , 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH ₂ or -CH ₂ CH ₂ CH ₂ NHC( NH) _NH2 . Preferably in the above embodiments ^R7 is hydrogen.

In another embodiment of the compounds of formula (V) and (VI), n is 1, R ¹ is R ²⁴ C(O)- or R ²⁴ C(S)-; and R ²⁴ is alkyl, substituted Alkyl, heteroalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Preferably R ²⁴ is methyl, ethyl, 2-propyl, tert-butyl, —CH ₂ OCH(CH ₃ ) ₂ , phenyl or 3-pyridyl. Preferably in this embodiment ^R7 is hydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl or substituted aryl. More preferably R ⁷ is hydrogen, methyl, ethyl, benzyl, -C(CH ₃ )=CH ₂ , -CH ₂ C(O)N(CH ₃ ) ₂ ,

or

wherein V is O or CH ₂ .

Most preferably ^R7 is hydrogen.

In another embodiment of the compounds of formula (V) and (VI), n is 1, R ¹ is R ²⁵ OC(O)- or R ²⁵ SC(O)-; and R ²⁵ is alkyl, substituted Alkyl, heteroalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Preferably R ²⁵ is ethyl, 2-propyl, neopentyl, —CH ₂ OCH(CH ₃ ) ₂ , phenyl or 2-pyridyl. Preferably in this embodiment ^R7 is hydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl or substituted aryl. More preferably R ⁷ is hydrogen, methyl, ethyl, benzyl, -C(CH ₃ )=CH ₂ , -CH ₂ C(O)N(CH ₃ ) ₂ ,

或

or

wherein V is O or CH ₂ .

Most preferably ^R7 is hydrogen.

In another embodiment of the compounds of formula (V) and (VI), R ^is

And R is selected from the ^group consisting of alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl.

Preferably R ¹⁵ is methyl, ethyl, propyl, isopropyl, cyclopentyl, cyclohexyl, phenyl, 4-hydroxyphenyl, benzyl, 4-hydroxybenzyl or 3-pyridyl. In a more specific version of this embodiment, R ^is hydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl, or substituted aryl. More preferably R ⁷ is hydrogen, methyl, ethyl, benzyl, -C(CH ₃ )=CH ₂ , -CH ₂ C(O)N(CH ₃ ) ₂ ,

或

or

wherein V is O or CH ₂ .

Preferably ^R7 is hydrogen.

A particularly preferred embodiment of the compounds of formulas (V) and (VI) are compounds selected from the group consisting of: 1-{[((5-methyl-2-oxo-1,3-dioxolane-4- En-4-yl)methoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid and 3-{[((5-methyl-2-oxo-1,3-dioxolane-4 -en-4-yl)methoxy)carbonyl]aminomethyl}-5-methyl-hexanoic acid.

In another embodiment of the compounds of formula (V) and (VI), R ^is

m is 0, and R ⁸ , R ¹¹ and R ¹² are as defined above. In one embodiment of the compounds of formula (V) and (VI), R ¹¹ is acyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkoxycarbonyl, carbamoyl or substituted carbamoyl, R ⁸ is hydrogen, alkoxycarbonyl, alkyl, aryl, arylalkyl or cyano, and ^R is hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl or arylalkyl. In another embodiment of the compounds of formula (V) and (VI), R ^is selected from acetyl, propionyl, butyryl, isobutyryl, pivaloyl, cyclopentanecarbonyl, cyclohexanecarbonyl, benzene Formyl, phenylacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl , cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl , N-isopropylcarbamoyl, N-butylcarbamoyl, N-isobutylcarbamoyl, N-sec-butylcarbamoyl, N-tert-butylcarbamoyl, N-cyclopentyl Carbamoyl, N-cyclohexylcarbamoyl, N-phenylcarbamoyl, N-benzylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N,N-diisopropylcarbamoyl, N,N-dibutylcarbamoyl, N,N-dibenzylcarbamoyl, N-pyrrolidinyl Carbamoyl, N-piperidinylcarbamoyl and N-morpholinylcarbamoyl. In another embodiment of the compounds of formula (V) and (VI), R ^is selected from acetyl, propionyl, butyryl, isobutyryl, cyclohexanecarbonyl, benzoyl, phenylacetyl, methoxy ylcarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, cyclohexyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylaminomethyl Acyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-phenylcarbamoyl, N-benzylcarbamoyl, N,N-dimethyl Carbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N-pyrrolidinylcarbamoyl, N-piperidinylcarbamoyl, and N-morpholinylamino formyl.

In one embodiment of the compounds of formula (V) and (VI), R ^is selected from hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy Carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl and cyano. Preferably ^R is selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

In another embodiment of the compounds of formula (V) and (VI), R ^is selected from hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy oxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl and benzyloxycarbonyl. Preferably ^R12 is selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

In another embodiment of the compounds of formula (V) and (VI), R ^is selected from hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, arylalkyl, and ^R and R ¹² together with the carbon atoms to which they are bound form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably R ¹¹ is selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R ⁸ and R ¹² are bound to their carbon atoms taken together to form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. More preferably R ¹¹ is hydrogen or methyl, and R ⁸ and R ¹² together with the carbon atom to which they are bound form 2-cyclopenten-1-one, 2-cyclohexen-1-one, 2-(5H) -furanone or 5,6-dihydro-pyran-2-one ring.

In another embodiment of the compounds of formula (V) and (VI), R ^is selected from hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, arylalkyl, and ^R and R ¹¹ and the carbon atoms to which they are bound together form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably R ¹² is selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R ⁸ and R ¹¹ are bound to their carbon atoms taken together to form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. More preferably ^R12 is selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and ^R8 and ^R11 and their combination The carbon atoms together form a gamma-butyrolactone, delta-valerolactone or 2,2-dimethyl-1,3-dioxane-4,6-dione ring.

In a more specific version of the embodiments of the compounds of formula (V) and (VI) above, R ^is hydrogen, alkanyl, substituted alkenyl, alkenyl, substituted alkenyl, aryl or substituted aryl. More preferably R ⁷ is hydrogen, methyl, ethyl, benzyl, -C(CH ₃ )=CH ₂ , -CH ₂ C(O)N(CH ₃ ) ₂ ,

或

or

wherein V is O or CH ₂ .

Most preferably ^R7 is hydrogen.

A particularly preferred embodiment of the compounds of formulas (V) and (VI) are compounds selected from the group consisting of:

1-{(1-Methyl-3-oxo-but-1-enyl)aminomethyl}-1-cyclohexanepiperidinium acetate;

1-{1-[(2-Oxo-tetrahydrofuran-3-ylidene)ethylaminomethyl}-1-cyclohexanepiperidinium acetate;

piperidinium 1-{(2-carbomethoxy-cyclopent-1-enyl)aminomethyl}-1-cyclohexaneacetate; and

piperidinium 1-{(1-methyl-2-(ethoxycarbonyl)-3-ethoxy-3-oxoprop-1-enyl)aminomethyl}-1-cyclohexaneacetate.

In a particularly preferred embodiment, the compound of formula (IV) has the structure of formula (VII) or (VIII):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

n, R ² , R ⁷ , R ¹³ , R ¹⁴ , R ¹⁶ and R ²⁵ are as defined above.

In a preferred embodiment, the compounds of formula (VII) and (VIII) do not include the following compounds:

If either R ¹³ or R ¹⁴ is hydrogen, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, then R ¹³ or R ¹⁴ the other is not hydrogen; and

R ²⁵ C(O) is not a bile acid derived moiety.

In one embodiment of the compounds of formula (VII) and (VIII), n is 0. In another embodiment, n is 1. When n is 1, the α-amino acid is preferably in the L-stereochemical configuration.

In another embodiment of the compounds of formula (VII) and (VIII), R ^is hydrogen, alkanyl, substituted alkanyl, alkenyl, substituted alkenyl, aryl, or substituted aryl . Preferably R ⁷ is hydrogen, methyl, ethyl, benzyl, -C(CH ₃ )=CH ₂ , -CH ₂ C(O)N(CH ₃ ) ₂ ,

或

or

wherein V is O or CH ₂ .

Most preferably ^R7 is hydrogen.

In another embodiment of the compounds of formula (VII) and (VIII), n is 0. In another embodiment of the compounds of formula (VII) and (VIII), n is 1, R is hydrogen and R is ^hydrogen , methyl, ² -propyl, 2-butyl, isobutyl, tert Butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, _-CH2OH , -CH(OH)CH _3. -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH ₂ or —CH ₂ CH ₂ CH ₂ NHC(NH)NH ₂ . Preferably ^R16 is hydrogen and ^R2 is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclohexyl, phenyl or benzyl. In another embodiment, n is ¹ and R and ^R together with the atoms to which they are bound form a pyrrolidine ring.

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, ^R13 is methyl and ^R14 is hydrogen.

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, ^R13 is ethyl and ^R14 is hydrogen.

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, ^R13 is propyl and ^R14 is hydrogen.

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, ^R13 is isopropyl and ^R14 is hydrogen .

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, ^R13 is butyl and ^R14 is hydrogen.

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, ^R13 is isobutyl and ^R14 is hydrogen .

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, ^R13 is sec-butyl and ^R14 is hydrogen .

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, ^R13 is tert-butyl and ^R14 is hydrogen .

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, ^R13 is cyclopentyl and ^R14 is hydrogen .

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, ^R13 is cyclohexyl and ^R14 is hydrogen.

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, ^R13 is methyl and ^R14 is methyl .

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R ¹³ is methoxycarbonyl and R ¹⁴ is methyl.

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R ¹³ is ethoxycarbonyl and R ¹⁴ is methyl.

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R ¹³ is propoxycarbonyl and R ¹⁴ is methyl.

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R ¹³ is isopropoxycarbonyl and R ¹⁴ For methyl.

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R ¹³ is butoxycarbonyl and R ¹⁴ is methyl.

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R ¹³ is isobutoxycarbonyl and R ¹⁴ For methyl.

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R ¹³ is sec-butoxycarbonyl and R ¹⁴ For methyl.

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R ¹³ is tert-butoxycarbonyl and R ¹⁴ For methyl.

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R ¹³ is cyclohexyloxycarbonyl and R ¹⁴ For methyl.

In another embodiment of the compounds of formula (VII) and (VIII), R is selected from ^{the group} consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, Isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl) -Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1, 3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-di Ethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-di Methoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxane-2- base)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolane-2- Base)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl , 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R ¹³ is phenyl and R ¹⁴ is hydrogen .

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, ^R13 is benzyl and ^R14 is hydrogen.

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, ^R13 is phenethyl and ^R14 is hydrogen .

In another embodiment of the compounds of formula (VII) and (VIII), R ^is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, iso Pentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethyl Oxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-dioxan-2-yl )-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-dioxolan-2-yl )-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R ¹³ is 3-pyridyl and R ⁴ is hydrogen.

Particularly preferred embodiments of the compounds of formula (VII) and (VIII) include compounds selected from the group consisting of:

1-{[(α-acetoxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-propionyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-butyryloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-isobutyryloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-pivaloyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-Benzoyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-acetoxybutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-butyryloxybutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-isobutyryloxybutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-benzoyloxybutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-acetoxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-propionyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-butyryloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-isobutyryloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-pivaloyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-2,2-diethoxypropionyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-2-(1,3-dioxolan-2-yl)propionyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-(2-Amino-2-methylpropionyl)oxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-Benzoyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-nicotinoyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-acetoxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-butyryloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-isobutyryloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-Benzoyloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-acetoxybenzyloxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(α-benzoyloxybenzyloxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(1-(3-methylbutyryloxy)-2-phenylethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[(1-Benzoyloxy-2-phenylethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid;

1-{[N-(α-isobutyryloxyethoxy)carbonyl]-4-bromophenylalanyl (ananinyl)-aminomethyl}-1-cyclohexaneacetic acid;

3-{[(α-isobutyryloxyethoxy)carbonyl]aminomethyl}-5-methylhexanoic acid;

3-{[(α-isobutyryloxyisobutoxy)carbonyl]aminomethyl}-5-methylhexanoic acid; and

3-{[(α-Benzoyloxyisobutoxy)carbonyl]aminomethyl}-5-methylhexanoic acid.

In one embodiment, compounds of the invention have the structure of formula (II):

In one embodiment of the compound of formula (II), when ^R3 , ^R5 and ^R6 are hydrogen, ^R4 is not phenyl or substituted phenyl. More preferably ^R4 is not 4-chlorophenyl.

In a preferred embodiment, the compound of formula (II) has the structures of formulas (IX) and (X):

In one embodiment of the compounds of formula (IX) and (X), t is zero. In another embodiment, t is ¹ and R is hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, t-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-Hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH ₂ or -CH ₂ CH ₂ CH ₂ NHC(NH )NH ₂ .

In another embodiment of the compounds of formula (IX) and (X), R ^{and R} are independently selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted hetero Aryl. Preferably ^R20 and ^R21 are independently selected from alkyl, substituted aryl and heteroaryl. In one embodiment, R ²⁰ is methyl and R ²¹ is methyl. Preferably in this last embodiment ^R7 is hydrogen, methyl, ethyl, benzyl, -C( _CH3 )= _CH2 , _-CH2C (O)N( _CH3 ) ₂ ,

或

or

wherein V is O or CH ₂ .

Most preferably ^R7 is hydrogen.

In another embodiment of the compounds of formula (IX) and (X), R ²⁰ and R ²¹ and the carbon atom to which they are bound together form a cycloalkyl or substituted cycloalkyl ring. In one embodiment, R ²⁰ and R ²¹ and the carbon atom to which they are bound together form a cyclohexyl ring. Preferably in this last embodiment ^R7 is hydrogen, methyl, ethyl, benzyl, -C( _CH3 )= _CH2 , _-CH2C (O)N( _CH3 ) ₂ ,

或

or

wherein V is O or CH ₂ .

Most preferably ^R7 is hydrogen.

In one embodiment, compounds of the invention have the structure of formula (III):

In one embodiment of the compound of formula (III), n is 1, R ¹ is hydrogen and R ² is arylalkyl. Preferably ^R2 is benzyl. In another embodiment of the compounds of formula (III), n is 0 and R ¹ is R ²⁵ OC(O)—. Preferably R ²⁵ is alkyl or substituted alkyl. More preferably R ²⁵ is ethyl. In another embodiment of the compounds of formula (III), ^R22 and ^R23 are hydrogen. In another embodiment, ^R22 and ^R23 are alkyl or substituted alkyl. Preferably ^R22 and ^R23 are methyl.

In a preferred embodiment, the compound of formula (III) has the structure of formula (XI):

In one embodiment of the compound of formula (XI), n is 1, X is NH, Y is 0, ^R1 is hydrogen, ^R2 is benzyl, ^R22 is methyl and ^R23 is methyl. In another embodiment, n is 0, Y is 0, ^R1 is ^R25OC (O)-, ^R25 is ethyl, ^R22 is hydrogen and ^R23 is hydrogen.

In another embodiment, the compound of formula (III) has the structure of formula (XII):

In one embodiment of the compound of formula (XII), n is 1, X is NH, Y is 0, ^R1 is hydrogen, ^R2 is benzyl, ^R22 is methyl and ^R23 is methyl. In another embodiment, n is 0, Y is 0, ^R1 is ^R25OC (O)-, ^R25 is ethyl, ^R22 is hydrogen and ^R23 is hydrogen.

The invention also includes derivatives of GABA analogs, MG, wherein M is a motif and G is a derivative of the GABA analog, HG, wherein H is hydrogen, for administration to a patient in need thereof. Once the motif M is cleaved from G and any of its metabolites, it exhibits a carcinogenic toxic dose (TD ₅₀ ) to rats greater than 0.2 mmol/kg/day. Moreover, upon colonic administration to rats, the motif M is cleaved from G at a sufficient rate in vivo:

₍ i) a Cmax of plasma HG that is at least 120% of the maximum concentration ( _Cmax ) of plasma HG obtained by colonic administration of equimolar doses of HG; and

(ii) An AUC of at least 120% of the AUC obtained by colonic administration of equimolar doses of H-G.

Preferably M-G has the structure of formula (XIV):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein:

M is the primitive;

Y is O or S;

R is hydrogen, or R and ^R together form an azetidine, a substituted azetidine, a pyrrolidine or a substituted pyrrolidine ring with the atoms bound to them;

R ^{and R} are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, ring Heteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl;

R and ^R are independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl ^, substituted arylalkyl, cycloalkyl, substituted Cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl, or optionally R ⁴ and R ⁵ and together with the carbon atoms to which they are bound form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, or bridged cycloalkyl ring; and

^R is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted Cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.

In a preferred embodiment, M has the structure of formula (XV):

in:

n, X, ^R1 and ^R2 are as defined above.

In one embodiment, M-G includes compounds wherein H-G, once cleaved from M, is substantially free of any lactam having the structure of formula (XVI):

wherein R is hydrogen and R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above.

Preferably the motif M or any metabolite formed from M does not form formaldehyde or pivalic acid upon cleavage of GM. In one embodiment, upon colonic administration to rats, the motif M is cleaved from G in vivo at a sufficient rate to yield at least 200% of the _Cmax of plasma HG obtained by colonically administered equimolar doses of HG , most preferably at least 1000% of the _Cmax of plasma HG. Preferably, upon colonic administration to rats, the motif M is cleaved from G in vivo at a sufficient rate to produce an AUC of at least 200%, most preferably at least 500%, of the AUC of plasma obtained by colonically administered equimolar doses of HG. AUC of plasma HG. In another embodiment, following oral administration (e.g., using an osmotic mini-pump device) to a dog at a dose of about 60 μmol equivalents of HG/kg, motif M is cleaved from HG at a sufficient rate in vivo to produce at least Plasma concentration 12 hours after administration that is 200% of the plasma HG concentration obtained with an equimolar dose of HG after administration in the same manner.

4.3 Synthesis of compounds of the present invention

The compounds of the present invention can be obtained by the synthetic methods shown in schemes 1-17. Those skilled in the art will recognize that a preferred synthetic route to the compounds of the invention is to combine the motif with a GABA analog. Various methods have been described in the art of synthesis of GABA analogs (see, for example, Satzinger et al., U.S. Patent 4,024,175; Silverman et al., U.S. Patent 5,563,175; Horwell et al., U.S. Patent 6,020,370; Silverman et al., U.S. Patent 6,028,214; Horwell et al. et al., U.S. Patent 6,103,932; Silverman et al., U.S. Patent 6,117,906; Silverman, International Publication WO 92/09560; Silverman et al., International Publication WO 93/23383; Horwell et al., International Publication WO 97/29101; Publication WO 97/33858; Horwell et al. International Publication WO 97/33859; Bryans et al. International Publication WO 98/17627; Guglietta et al. International Publication WO 99/08671; Bryans et al. International Publication WO 99/21824; People such as Belliotti, International Publication WO 99/31074; Bryans et al., International Publication WO 99/31075; Bryans et al., International Publication WO 99/61424; Bryans et al., International Publication WO 99/61424; Bryans et al., International Publication WO 00 /15611; Bryans, International Publication WO 00/31020; and Bryans et al., International Publication WO 00/50027). Other methods are known in the art of GABA analog synthesis and are readily available to those skilled in the art. The motifs described herein are known in the art and can be prepared by established methods and incorporated into GABA analogs (see, for example, Green et al., "Protective Groups in Organic Chemistry (protective groups in organic chemistry) ", (Wiley, Second Edition, 1991); Harrison et al., "Compendium of Synthetic Organic Methods (Brief Description of Organic Synthetic Methods)", Volumes 1-8 (John Wiley and Sons, 1971-1996); "Beilstein Handbook of Organic Chemistry (Beilstein Handbook of Organic Chemistry), "Beilstein Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al., "Reactions for Organic Synthesis," vol. 1-17, Wiley Interscience; Trost et al., "Comprehensive Organic Synthesis (Comprehensive Organic Synthesis)", Pergamon Press, 1991; "Theilheimer's Synthetic Methods of Organic Chemistry (Theilheimer's Synthetic Methods of Organic Chemistry), "vol. Advanced Organic Chemistry), "Wiley Interscience, 1991; Larock" Comprehensive Organic Transformations, "VCH Publisher, 1989; Paquette, "Encyclopedia of Reagents for Organic Synthesis (Encyclopedia of Organic Synthetic Reagents), "John Wiley & Sons , 1995, Bodanzsky, "Principles of Peptide Synthesis (peptide synthesis principle), "Springer Verlag, 1984; Bodanzsky, "Practice of Peptide Synthesis (peptide synthesis practice)" Springer Verlag, 1984).

Accordingly, starting materials for the preparation of the compounds of the present invention and their intermediates are commercially available or may be prepared by known synthetic methods. Other methods for synthesizing the prodrugs described herein are described in the art, or will be readily apparent to one of skill in the art considering the references provided above, and can be used to synthesize the compounds of the invention. Therefore, the methods shown in the routes in this article are illustrative rather than comprehensive.

In either of the following routes, after functionalization of the amino group of the GABA analog with a radical or other protecting group, the carboxylic acid group can be converted to an ester or thioester by a number of synthetic methods known to those skilled in the art. In a preferred embodiment, esters can be obtained by reacting GABA analogs with alcohols or thiols in the presence of coupling agents such as carbodiimide and dimethylaminopyridine. In another preferred embodiment, esters can be obtained by reacting GABA analogs with alkyl halides in the presence of a base. Other methods of converting GABA analogs to esters or thioesters are within the scope of the references provided herein, which are familiar to those skilled in the art.

As shown in Scheme 1 above, the adduct (7) can be obtained by directly combining the carboxylic acid with the terminal amino (or hydroxyl) group of the GABA analog derivative (6). Reagents for such reactions are known to those skilled in the art and include, but are not limited to, carbodiimides, ammonium salts, phosphonium salts, and the like. Alternatively, the reaction of carboxylic acid derivatives such as acid chlorides, symmetrical anhydrides or mixed anhydrides with GABA analogs (6) in the presence of bases (eg hydroxides, tertiary amines, etc.) can be used for the synthesis of (7).

Route 2

As shown in Figure 2, GABA analog derivatives (6) can be converted to carbamates (8) by treatment with various carbonic acid derivatives in the presence of a base (eg, hydroxide, tertiary amine, etc.). Alternatively, known alcohol additions to isocyanates (9) or (10) can be used for the synthesis of (8).

As shown in Scheme 3, GABA analog derivatives (6) can be converted to thioamides (11) by treatment with thioacids in the presence of couplers. Reagents for carrying out such reactions are known to those skilled in the art and include, but are not limited to, carbodiimides, ammonium salts, phosphonium salts, and the like. Alternatively, the reaction of thioacid derivatives such as thioacid chlorides, symmetrical anhydrides or mixed anhydrides with (6) in the presence of bases (eg hydroxides, tertiary amines, etc.) can be used to synthesize thioamides (11). In another method, amides (7) can be converted to thioamides (11) by heating in the presence of phosphorus pentasulfide (when n=0).

The corresponding thiocarbonate derivatives (i.e., P=O, Q=S and P=SQ=O, respectively) (wherein W is chloride, imidazolyl or 4-nitrophenoxy) and GABA analogs Derivative (6) reacts in the presence of base to synthesize thiocarbamate (12) and (13). Thiocarbamates (13) can also be formed by reacting thiols with isocyanates (9) or (10). Can be reacted by GABA analog derivatives (6) with dithiocarbonate derivatives (i.e. P and Q=S) (wherein W is chloride, imidazolyl or 4-nitrophenoxy) in the presence of a base Instead, dithiocarbamate (14) (P=S, Q=S) is prepared (see Scheme 4).

Route 4

One method for the synthesis of compounds of formula (IV) is exemplified in scheme 5.

Route 5

Treatment of chloroformate (15) with an aromatic leaving group such as p-nitrophenol in the presence of a base affords p-nitrophenyl carbonate (16). Interchange of halides affords iodide (17), which is reacted with a metal or a tetraalkylammonium salt of a carboxylic acid to yield compound (18). Treatment of (18) with GABA analog derivatives (19), optionally in the presence of trimethylsilyl chloride, affords compounds of formula (IV). Methods for preparing related acyloxyalkylcarbamate compounds have been described in the art (Alexander, US Patent 4,760,057; Alexander, US Patent 4,916,230; Alexander, US Patent 5,466,811; Alexander, US Patent 5,684,018).

Alternatively, compounds of formula (IV) can be prepared from carbonates (18) in a stepwise manner as shown in Scheme 6. Here the reaction of (18) with an optionally protected α-amino acid (20) as an ester affords an intermediate (21) which upon deprotection (if desired) affords compound (22), which can then be modified using methods known in the art It was coupled to the GABA analog (23) by known standard peptide coupling reagents.

Route 6

Another method for the synthesis of compounds of formula (IV) is carried out by carbonylation of GABA analogue derivatives (19) to intermediate carbamates by modification of methods disclosed in the art. collected from the alkylation reaction (Butcher, Synlett, 1994, 825-6; Ferres et al., US Patent 4,036,829). Carbon dioxide gas is bubbled into a solution containing (19) and a base (eg _{CS2CO3 , Ag2CO3} or AgO) in _a solvent such as DMF or NMP. An activated halide is added, optionally in the presence of iodide ion as a catalyst, and the carbonylation is continued until the reaction is complete. This method is shown in Scheme 7 for the preparation of compounds of formula (IV) from halides (24).

Route 7

Alternatively, compounds of formula (IV) can be prepared in a stepwise manner as shown in Scheme 8. Carbonylation and alkylation of the carboxy-protected α-amino acid (20) affords an intermediate (21), which upon deprotection couples with a GABA analog (23), as previously shown in Scheme 6.

Route 8

But another method for the synthesis of compounds of formula (IV) relies on the oxidation of ketocarbamate derivatives of GABA analogs (Gallop et al., titled "Methods for Synthesis of prodrugs from 1-Acyl-Alkyl Derivatives and Compositions Thereof (by 1-acyl-alkyl derivatives and methods for the synthesis of prodrugs of their derivatives)" co-pending US patent application). As shown in Scheme 9, oxidation of ketocarbamate (25) affords compounds of formula (IV). Preferred solvents include, but are not limited to, t-butanol, diethyl ether, acetic acid, hexane, dichloroethane, dichloromethane, ethyl acetate, acetonitrile, methanol, chloroform, and water. Generally, an oxidizing agent can be an organism (such as yeast or bacteria), or a chemical agent (such as an enzyme or a peroxide). Preferred oxidizing agents include those successfully used to oxidize Baeyer-Villager ketones to esters or lactones (Strukul, Angnew. Chem. Int. ED., 1998, 37, 1198; Renz et al., Eur. J. Org. Chem .1999, 737; Beller et al., in "Transition Metals in Organic Synthesis" Chapter 2, Wiley VCH; Stewart, Current Organic Chemistry, 1998, 2, 195; Kayser et al., Synlett, 1999, 1, 153).

Route 9

Other compounds of the present invention can be synthesized from suitable ketocarbamate derivatives by Baeyer-Villager type oxidations, provided they do not contain chemical functionalities that are readily decomposed or transformed under the reaction conditions.

Ketocarbamate (25) can be prepared from the corresponding α-hydroxyketone compound (26) either directly by reaction with isocyanate (9) or by first converting the α-hydroxyketone compound to a halochloroformate or the activated carbonate intermediate (27), which is then reacted with compound (19), as exemplified in Scheme 10.

Route 10

Alternatively, keto carbamates (25) can be prepared in a stepwise manner via α-amino acid carbamates (28) as shown in Scheme 11 according to the coupling method described above.

Route 11

Note that one preparation of the isocyanate derivative of the GABA analog used in Scheme 10 above (ie compound (9)) starts from the appropriate hexaanhydride (29) as shown in Scheme 12. Opening of the anhydride ring by reaction with an alcohol or thiol nucleophile affords carboxylic acid (30). Conversion of _this compound to _intermediate The product acyl azide. Curtis rearrangement of the acyl azide intermediate by thermal decomposition in a suitable solvent such as toluene at temperatures ranging from 0°C to 120°C affords the isocyanate (9). The isocyanate is optionally not isolated, but formed in situ, and its formation terminated by reaction with a-hydroxyketone (26) to give the desired product (25).

Route 12

A method for the synthesis of oxodioxolenyl methyl carbamate prodrug (36) is disclosed in Scheme 13. Treatment of hydroxyketones (31) with phosgene or carbonyldiimidazole in the presence of base affords cyclic carbonates (32). Radical bromination with N-bromosuccinimide and azoisobutyronitrile affords the bromide (33), which is converted to the alcohol (34). Alcohol (34) was converted to dicarbonate (35) by reaction with 4-nitrophenyl chloroformate, which was then reacted with GABA analog derivative (19) to give prodrug (36). Alternatively, compound (34) is reacted with isocyanate (9) to give compound (36), wherein n is 0.

Route 13

The prodrug (41) can be synthesized by the method disclosed in Scheme 14. Coupling of carboxylic acid (37) with alcohol (38) such as dicyclohexylcarbodiimide and pyridine affords ester (39). Conversion of ester (39) to activated carbonate (40) by reaction with 4-nitrophenyl chloroformate followed by reaction with GABA analog derivative (19) afforded prodrug (41).

Route 14

It can be synthesized simply by reacting a reactive carbonyl compound (42) with a GABA analog derivative (19) (where R ¹⁶ =H) under the dehydration conditions shown in Scheme 15, optionally in the presence of a secondary amine as a catalyst Enamine prodrugs such as (43).

Route 15

Compound (III) can be synthesized by the route shown in Scheme 16.

Reaction of GABA analogs (23) with α-activated ester derivatives (44) affords amino esters (45).

Amino endcapping of (45) by acylation affords (46) (eg, using methods described above), and esterification of the free under standard conditions affords diesters (47). Dieckman condensation followed by decarboxylation affords ketone (48). This is followed by peroxyacid oxidation to afford the lactone (III).

Route 16

Imine prodrugs (II) can be synthesized as described in Scheme 17 by treating ketones or ketone derivatives (49) with GABA analog derivatives (50) under dehydrating conditions.

Route 17

Phosphorous prodrugs can be synthesized by conventional methods known in the art. Similarly, prodrugs with S-N bonds can be synthesized by using methods described in the art.

4.4 Therapeutic Applications of the Compounds of the Invention

According to the invention, the compounds and/or compositions of the invention are administered to patients, preferably humans, suffering from epilepsy, depression, anxiety, psychosis, syncope, hypokinesia, cranial abnormalities, neurodegenerative diseases, panic, Pain (especially neuropathic pain and musculoskeletal pain), inflammatory disease (ie, arthritis), insomnia, gastrointestinal disease, or alcohol withdrawal syndrome. Also in certain embodiments, the compounds and/or compositions of the present invention may be administered to a patient, preferably a human, as a prophylactic against various diseases or conditions. Accordingly, the compounds and/or compositions of the present invention may be administered as a prophylactic measure to patients predisposed to epilepsy, depression, anxiety, psychosis, syncope, hypokinesia, cranial abnormalities, neurodegenerative diseases, panic, Pain (especially neuropathic pain and musculoskeletal pain), inflammatory disease (ie, arthritis), insomnia, gastrointestinal disorders, and alcohol withdrawal syndrome. Thus, the compounds and/or compositions of the present invention can be used to prevent one disease or condition while treating another (e.g., preventing psychosis and treating gastrointestinal disorders; preventing neuropathic pain and treating alcohol withdrawal syndrome ).

Treatment of epilepsy, depression, anxiety, psychosis, syncope, hypokinesia, cranial abnormalities, neurodegenerative diseases, panic, pain (especially neuropathic pain) with the compounds and/or compositions of the present invention can be determined by methods known in the art. and muscle and bone pain), inflammatory diseases (i.e., arthritis), insomnia, gastrointestinal disorders, and ethanol withdrawal syndrome (see, for example, Satzinger et al., U.S. Patent 4,024,175; Satzinger et al., U.S. Patent 4,087,544; Woodruff , US Patent 5,084,169; Silverman et al, US Patent 5,563,175; Singh, US Patent 6,001,876; Horwell et al, US Patent 6,020,370; Silverman et al, US Patent 6,028,214; Horwell et al, US Patent 6,103,932; Silverman et al, US Patent 6,117,906 ; Silverman, International Publication WO 92/09560; Silverman et al., International Publication WO 93/23383; Horwell et al., International Publication WO 97/29101, Horwell et al., International Publication WO 97/33858; Horwell et al., International Publication WO 97/33858; 97/33859; Bryans et al. International Publication WO 98/17627; Guglietta et al. International Publication WO 99/08671; Bryans et al. International Publication WO 99/21824; Bryans et al. International Publication WO 99/31057; Magnus-Miller Bryans et al., International Publication WO 99/31075; Bryans et al., International Publication WO 99/61424; Pande, International Publication WO 00/23067; Bryans, International Publication WO 00/31020; Bryans et al. people, International Publication WO 00/50027; and Bryans et al., International Publication WO 02/00209). The compounds and/or compositions of the present invention may be used for the treatment or prevention of epilepsy, depression, anxiety, psychosis, syncope, hypokinesia, cranial abnormalities, neurodegenerative diseases, panic by methods described in the art (see above) , pain (especially neuropathic pain and musculoskeletal pain), inflammatory disease (ie, arthritis), insomnia, gastrointestinal disorders, and alcohol withdrawal syndrome. Thus, those skilled in the art will be able to analyze and use the compounds and/or compositions of the present invention for the treatment or prevention of epilepsy, depression, anxiety, psychosis, syncope, hypokinesia, cranial abnormalities, neurodegenerative diseases, panic, pain (especially neuropathic pain and muscular and skeletal pain), inflammatory diseases (ie, arthritis), insomnia, gastrointestinal disorders, and alcohol withdrawal syndrome.

4.5 Therapeutic/Prophylactic Dosing

The compounds and/or compositions of the invention can advantageously be used in human medicine. As described in section 4.4 above, the compounds or compositions of the present invention are useful in the treatment or prevention of epilepsy, depression, anxiety, psychosis, syncope, hypokinesia, cranial abnormalities, neurodegenerative diseases, panic, pain (especially neuropathic pain) and muscle and bone pain), inflammatory disease (ie, arthritis), insomnia, gastrointestinal disease, or alcohol withdrawal syndrome.

When the compound or composition of the present invention is used to treat or prevent the above-mentioned diseases or conditions, it can be administered or applied singly or in combination with other agents. The compounds and/or compositions of the present invention may also be administered or used singly, in combination with other pharmaceutically active agents, including other compounds of the present invention.

The invention provides methods of treatment and prevention by administering to a patient a therapeutically effective amount of a composition or compound of the invention. The patient may be an animal, more preferably a mammal, most preferably a human.

A compound or composition of the invention, comprising one or more compounds of the invention, is preferably administered orally. The compounds and/or compositions of the present invention may also be administered by other conventional routes, such as by infusion or bolus injection, through epithelial or mucosal and skin linings (eg, oral mucosa, rectal and intestinal mucosa, etc.). Administration can be systemic or local. A variety of delivery systems are known that can be used to administer the compounds and or compositions of the invention (eg, encapsulation in liposomes, microparticles, microcapsules, capsules, etc.). Methods of administration include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectal, inhalation, or topical Administration, in particular to the ear, nose, eye or skin.

In a particularly preferred embodiment, the compounds and/or compositions of the invention may be delivered by a sustained release system, preferably an oral sustained release system. In one embodiment, a pump can be used (see Langer, supra; Sefton, 1987, CRC Crit Ref Biomed Eng. 14:201; Saudek et al., 1989, N. Engl. J Med. 321:574).

In another embodiment, polymeric materials can be used (see "Medical Applications of Controlled Release (controlled release pharmaceutical applications)," Langer and Wise (eds.), CRC Press., Boca Raton, Florida (1974); "Controlled Drug Bioavailability (Controlled Drug Bioavailability), "Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, 1983, J Macromol. Sci. Rev. Macromol Chem.23 : 61; see also Levy et al., 1985, Science 228: 190; During et al., 1989, Ann. Neurol. 25: 351; Howard et al., 1989, J. Neurosurg. 71: 105). In a preferred embodiment, polymeric materials are used for oral sustained release delivery. Preferred polymers include sodium carboxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and hydroxyethylcellulose (most preferably hydroxypropylmethylcellulose). Other preferred cellulose ethers have been described (Alderman, Int. J. Pharm. Tech. & Prod. Mfr., 1984, 5(3) 1-9). Factors affecting drug release are known to those skilled in the art and described in the art (Bamba et al., Int. J. Pharm., 1979, 2, 307).

In another embodiment, enteric coated formulations can be used for oral sustained release administration. Preferred coating materials include polymers with pH-dependent stability (i.e., pH-controlled release), polymers with slow or pH-dependent swelling, dissolution or erosion rates (i.e., time-controlled release), by enzymatic Polymers that degrade (ie, enzyme-controlled release) and polymers that form thin film layers that are disrupted by pressurization (ie, pressure-controlled release).

In another embodiment, an osmotic delivery system is used for oral release administration (Verma et al., Drug Dev. Ind. Pharm., 2000, 26:695-708). In a preferred embodiment, OROS ^™ osmotic devices are used in oral sustained release delivery devices (Theeuwes et al., US Patent 3,845,770; Theeuwes et al., US Patent 3,916,899).

In another embodiment, a controlled release system can be placed near the target of the compounds and/or compositions of the invention so that only a fraction of the systemic dose is required (see, e.g., Goodson, in "Medical Applications of Controlled Release") Medical applications), "supra, vol.2, pp.115-138 (1984)). Other controlled release systems as described in Langer, 1990, Science 249: 1527-1533 may also be used.

The compounds and/or compositions of the invention preferably provide a GABA analog (eg gabapentin and pregablin) when administered in vivo to a patient. While not intending to be bound by theory, the moieties of the compounds and/or compositions of the invention may be chemically and/or enzymatically cleaved. One or more enzymes present in the stomach, lumen, intestinal tissue, blood, liver, brain, or any suitable tissue of a mammal can enzymatically cleave a moiety of a compound or composition of the invention. The cleavage mechanism is not critical to the invention. Preferably, GABA analogs formed by cleavage of prodrugs from compounds of the invention do not contain significant lactam contamination (preferably less than 0.5 wt%, more preferably less than 0.2 wt%, most preferably less than 0.1 wt%). The extent to which lactam contaminants are released by the prodrugs of the invention can be assessed using standard in vitro assays.

While not intending to be bound by theory, the compounds and/or compositions of the invention may be moieties prior to absorption from the gastrointestinal tract (e.g., in the stomach or intestinal lumen) and/or after absorption from the gastrointestinal tract (e.g., in the intestinal tract). tissue, blood, liver or other suitable mammalian tissue) is lysed. If the moiety of the compound of the invention is cleaved prior to intestinal absorption, the resulting GABA analog can be routinely absorbed into the systemic circulation (eg, via large neutral amino acid transporters located in the small intestine). If the moiety of the compounds of the invention is cleaved after absorption from the gastrointestinal tract, these GABA analog prodrugs may have the opportunity to be absorbed into the systemic circulation by passive diffusion, active transport, or both passive diffusion and active transport.

If the moieties of the compounds of the invention are cleaved after absorption from the gastrointestinal tract, these GABA analog prodrugs may have the opportunity to be absorbed from the large intestine into the systemic circulation. In this case, the compounds or compositions according to the invention are preferably administered as a sustained release system. In a preferred embodiment, the compound or composition of the invention is delivered by oral sustained release administration. Preferably in this embodiment, the compound or composition of the invention is administered twice a day (more preferably once a day).

4.6 Compositions of the invention

The compositions of the invention comprise a therapeutically effective amount of one or more compounds of the invention, preferably in purified form, and a suitable amount of a pharmaceutically acceptable excipient to provide a suitable dosage form for the patient. When administered to a patient, the compounds of the invention and pharmaceutically acceptable excipients are preferably sterile. Water is a preferred vehicle when administering the compounds of the invention intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, chlorine Sodium chloride, anhydrous skimmed milk, glycerin, propylene glycol, water, ethanol, etc. The compositions of the present invention, if desired, can also contain minor amounts of wetting and emulsifying agents, or pH buffering agents. In addition, auxiliaries, stabilizers, thickeners, lubricants and colorants may be used.

In one embodiment, the compositions of the invention are free of lactam by-products formed by intramolecular cyclization. In a preferred embodiment, the compositions of the present invention are also stable for long-term storage (preferably greater than 1 year) and do not form significant amounts of lactams (preferably less than 0.5 wt. % lactams, more preferably less than 0.2 wt. % lactam, most preferably less than 0.1 wt% lactam).

Pharmaceutical compositions containing the compounds of this invention can be prepared by conventional methods of mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing. The pharmaceutical compositions can be prepared in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or auxiliaries, which facilitate the preparation of the compounds of the present invention into pharmaceutically acceptable preparations. Proper formulation is dependent upon the route of administration chosen.

Dosage forms of the compositions of the present invention may be solutions, suspensions, emulsions, tablets, pills, pills, capsules, capsules containing liquids, powders, sustained release formulations, suppositories, emulsions, aerosols, sprays, suspensions or any other forms suitable for the application. In one embodiment, the pharmaceutically acceptable excipient is a capsule (see eg Grosswald et al., US Patent 5,698,155). Examples of other suitable pharmaceutical excipients have been described in the art (see Remington's Pharmaceutical Sciences (Remington Pharmaceutical Sciences), Philadelphia College of Pharmacy and Science (Philadelphia College of Pharmacy and Science), 17th Edition, 1985). Preferred compositions of the invention are prepared for oral delivery, especially for oral sustained release administration.

For example, compositions for oral delivery may be tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups or elixirs. Oral compositions may contain one or more optional agents, such as sweetening agents such as fructose, aspartame or saccharin, flavoring agents such as peppermint, oil of wintergreen or cherry coloring agents and preservatives, to provide a pharmaceutically palatable formulation. preparation. Also in the case of tablets or pills, the composition may be coated to delay degradation and absorption in the gastrointestinal tract, thereby providing long lasting action. Selectively permeable membranes surrounding osmotically active driving compounds are also suitable for orally administered compounds and compositions of the invention. In these later platforms, fluid from the surrounding environment of the capsule is absorbed by the drive compound, which expands through the pores to displace the reagent or reagent composition. These delivery platforms can provide an essentially zero order delivery profile compared to the tapered pattern of an immediate rate formulation. A time delay material such as glyceryl monostearate or glyceryl stearate may also be employed. Oral compositions can include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. These excipients are preferably of pharmaceutical grade.

For oral liquid preparations such as suspensions, elixirs and solutions, suitable carriers, excipients or diluents include water, saline, alkylene glycols (such as propylene glycol), polyalkylene glycols (such as polyethylene glycol) Oils, alcohols, slightly acidic buffers between pH 4 and pH 6 (eg, about 5 mM to about 50 mM acetate, citrate, ascorbate), and the like. In addition, flavoring agents, preservatives, coloring agents, bile salts, acyl endoxaloids, etc. may be added.

Administration of the compositions by other routes is also contemplated. For buccal administration, the dosage form of the composition may be tablets, lozenges and the like prepared in a conventional manner. Liquid pharmaceutical formulations suitable for use with nebulizers and liquid spray devices and EHD aerosol devices generally comprise a compound of the invention and a pharmaceutically acceptable excipient. Preferred pharmaceutically acceptable excipients are liquids such as alcohols, water, polyethylene glycol or perfluorocarbons. Optionally adding another substance modifies the aerosol properties of the solution or suspension of the compound of the invention. Preferably the substance is a liquid such as alcohol, glycol, polyethylene glycol or fatty acid. Other methods of preparing liquid drug solutions or suspensions suitable for aerosol devices are known to those skilled in the art (see, eg, Biesalski, US Patent 5,112,598; Biesalski, US Patent 5,556,611). The compounds of the invention may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, eg containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the aforementioned formulations, the compounds of the present invention may also be formulated as a precipitation formulation. Such long acting formulations may be administered by implantation (eg subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be prepared with suitable polymeric or hydrophobic materials (eg, emulsions in acceptable oils) or ion exchange resins, or as slightly soluble derivatives, eg, as slightly soluble salts.

When the compound of the present invention is acidic, it may be included in any of the above formulations as the free acid, pharmaceutically acceptable salt, solvate or hydrate. Pharmaceutically acceptable base tinctures retain the activity of the free acids, can be prepared by reaction with bases, and tend to be more soluble in water and other protic solvents than the corresponding free acid forms.

4.7 Application method and dosage

The compounds of the present invention, or compositions thereof, are generally employed in an effective amount to achieve the desired purpose. Use for the treatment or prevention of diseases or conditions such as epilepsy, depression, anxiety, psychosis, syncope, hypokinesia, cranial abnormalities, neurodegenerative diseases, panic, pain (especially neuropathic pain and muscular and skeletal pain) ), inflammatory disease (ie arthritis), insomnia, gastrointestinal disease or alcohol withdrawal syndrome, the compounds of the present invention or compositions thereof are administered or applied in a therapeutically effective amount.

The amount of a compound of the invention disclosed herein that is effective in treating a particular disease or condition depends on the nature of the disease or condition and can be determined by standard clinical techniques known in the art as previously described. In addition, in vitro or in vivo assays can optionally be used to help identify optimal dosage ranges. The amount of a compound of the invention administered will of course depend on the subject being treated, the subject's weight, the severity of the affliction, the mode of administration and the judgment of the prescribing physician.

For example, dosages can be delivered in pharmaceutical compositions by single administration, multiple applications, or controlled release. In a preferred embodiment, the compounds of the invention are delivered by oral sustained release administration. Preferably in this embodiment, the compound of the invention is administered twice a day (more preferably once a day). Doses can be repeated intermittently, given alone or in combination with other agents, and can be continued for the length of time necessary to effectively treat the disease or condition.

A suitable oral dosage range will depend on the potency of the parent GABA analog drug, but will generally be from about 0.001 mg to about 200 mg of the compound of the invention/kg body weight. When the GABA analog is gabapentin, typical adult daily doses of the parent drug are 900 mg/day to 3600 mg/day, while the dose of the gabapentin prodrug can be adjusted to provide equimolar amounts of gabapentin. Other GABA analogs may be more potent than gabapentin (eg pregabalin), and lower doses are appropriate (measured on an equimolar basis) for the parent drug and any prodrugs. Dosage ranges can be readily determined by methods known to those skilled in the art.

The compounds of the invention are preferably tested for in vitro and in vivo therapeutic or prophylactic activity of interest prior to use in humans. For example, in vitro assays can be used to determine whether administration of a particular compound of the invention or a combination of compounds of the invention is preferred for reducing convulsions. Compounds of the invention can also be demonstrated to be effective and safe using animal model systems.

Preferably, a therapeutically effective dose of a compound of the invention described herein will provide therapeutic benefit while causing substantially no toxicity. The toxicity of the compounds of the present invention can be determined using standard pharmaceutical methods and can be readily determined by one skilled in the art. The dose ratio of toxic to therapeutic effects is the therapeutic index. The compounds of the invention preferably exhibit particularly high therapeutic indices for the treatment of diseases and disorders.

The dosage of the compounds of the invention described herein lies within a range of circulating concentrations that include the effective dose with little or no toxicity.

4.8. Combination therapy

In certain embodiments of the invention, compounds of the invention may be used in combination therapy with at least one other therapeutic agent. Compounds of the invention and therapeutic agents may act additively, more preferably synergistically. In a preferred embodiment, compositions containing compounds of the invention are administered concurrently with other therapeutic agents, which may be part of the same composition as the compounds of the invention or as a different composition. In another embodiment, a composition comprising a compound of the invention may be administered before or after another therapeutic administration.

5. Example

The invention is further defined with reference to the following examples which describe in detail the preparation of the compounds and compositions of the invention and the testing of the compounds and compositions of the invention. It will be apparent to those skilled in the art that various modifications can be made in the materials and methods without departing from the scope of the invention.

In the following examples, the following abbreviations have the following meanings. If an abbreviation is not defined, it has its generally accepted meaning.

AIBN ＝ 2,2'-Azobis(isobutyronitrile)

Atm = atmospheric pressure

Boc = tert-butoxycarbonyl

Cbz ＝ Benzyloxy (carbobenzyloxy)

CPM = counts per minute

DCC ＝ Dicyclohexylcarbodiimide

DMAP = 4-N, N-dimethylaminopyridine

DMEM = extreme eagle medium

DMF = N,N-Dimethylformamide

DMSO = dimethyl sulfoxide

Fmoc ＝ 9-fluorenylmethoxycarbonyl

g = gram

h = hours

HBSS = Hanks buffered saline solution

L = liter

LC/MS = liquid chromatography/mass spectrometry

M = mole

min = points

ml = milliliter

mmol = millimole

NBS ＝ N-Bromosuccinimide

NHS = N-hydroxysuccinimide

PBS = Phosphate Buffered Saline

THF = Tetrahydrofuran

TFA = trifluoroacetic acid

TMS = Trimethylsilyl

μL = microliter

μM = micromole

v/v = volume to volume

Example 1

1-{[(α-pivaloyloxymethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (51)

Step A: p-nitrophenyl chloromethyl carbonate (52)

p-Nitrophenol (100 g, 0.72 moles) was dissolved in anhydrous THF (3 L) and stirred vigorously. To this solution was added chloromethyl chloroformate (70 mL, 0.79 moles) followed by triethylamine (110 mL) at room temperature. After stirring for 1 h, the reaction mixture was filtered and the filtrate was concentrated, then diluted with ethyl acetate (1 L). The organic solution was washed with 10% potassium carbonate (3 x 500 mL) and 1N HCl (2 x 300 mL), brine (2 x 300 mL), and dried over anhydrous sodium sulfate. Removal of the solvent gave 157 g (95%) of the title compound (52) as a solid. The compound is unstable to LC-MS. ¹ H NMR (CDCl ₃ , 400 MHz): 5.86 (s, 2H), 7.44 (d, J=9 Hz, 2H), 8.33 (d, J=9 Hz, 2H).

Step B: iodomethyl p-nitrophenyl carbonate (53)

Under a nitrogen atmosphere, p-nitrophenyl chloromethyl carbonate (52) (100 g, 0.43 moles), sodium iodide (228 g, 1.30 moles) and 50 g of anhydrous molecular sieves (4 Å) were added to 2 L of acetone while mechanically Stir. The resulting mixture was stirred at 40° C. for 5 h (monitored by ¹ H NMR). When stirring was complete, the solid material was removed by filtration, and the solvent was removed under reduced pressure. The residue was redissolved in dichloromethane (1 L) and washed twice with saturated aqueous sodium carbonate (300 mL) and then with water (300 mL). The organic layer was separated and dried over anhydrous sodium sulfate. Removal of the solvent gave 123.6 g (89%) of the title compound (53) as a solid on standing. The compound was found to be unstable to LC-MS. ¹ H NMR (CDCl ₃ , 400MHz): 6.06 (s, 2H), 7.42 (d, J=9Hz, 2H), 8.30 (d, J=9Hz, 2H). ¹³ C NMR (CDCl ₃ , 100MHz): 155.1 , 151.0, 146.0, 125.8, 125.7, 121.9, 33.5.

Step C: Silver trimethyl acetate (54)

Pivalic acid (50 g, 0.49 moles) was dissolved in acetonitrile (1.3 L), then silver oxide (70 g, 0.29 moles) was added with vigorous stirring. Then 660 mL of water was added under nitrogen atmosphere. The resulting suspension was stirred at 70 °C in the dark for 1 h. After filtration through a pad of celite, the solvent was removed to afford 86 g (82%) of the title compound (54) as an off-white solid, which was used in the next reaction without further purification. The other silver salts described in this application were prepared according to similar methods.

Step D: p-nitrophenyl pivaloyloxymethyl carbonate (55)

To a solution of iodomethyl p-nitrophenyl carbonate (53) (62 g, 0.19 moles) in dry toluene (1 L) was added silver trimethyl acetate (80 g, 0.38 moles). After stirring at 55 °C under nitrogen atmosphere for 3 h, the reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was washed with 10% potassium carbonate (500 mL). Removal of the solvent gave 43 g (75%) of the title compound (55) as a yellow oil. ¹ H NMR (CDCl ₃ , 400MHz): 1.25(s, 9H), 5.88(s, 2H), 7.40(d, J=9Hz, 2H), 8.29(d, J=9HZ, 2H). ¹³ CNMR(CDCl ₃ , 100MHz): 177.0, 155.3, 151.6, 145.8, 125.6, 121.9, 83.1, 39.1, 27.0.

Step E: 1-{[(α-pivaloyloxymethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid

(51)

Gabapentin free base (24 g, 0.14 moles) was slurried in anhydrous dichloromethane (100 mL) and treated with chlorotrimethylsilane (18.6 mL, 0.28 moles) and triethylamine (10 mL, 0.15 moles) respectively . The resulting suspension was heated and stirred until complete dissolution of any solids was achieved. Add the above gabapentin solution to slow reflux via an equalizing addition funnel, and mechanically stir p-nitrophenyl pivaloyloxymethylcarbonate (55) in dichloromethane (100 mL) under a nitrogen atmosphere. (20 g, 67 mmol) and triethylamine (10 mL, 0.15 moles). The resulting yellow solution was stirred for 1.5 h. When stirring was complete (monitored by ninhydrin staining), the mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate (500 mL), washed with 1N HCl (3 x 100 mL), brine (2 x 100 mL), and dried over anhydrous sodium sulfate. After removing the solvent, the crude product was dissolved in ethanol (300 mL), and then 1 g of 5% Pd/C was added. The resulting mixture was stirred under a 50 psi hydrogen atmosphere for 15 minutes, then filtered through a pad of celite. After concentration, the residue was dissolved in ethyl acetate, washed with 5% _H2SO4 , and dried over anhydrous sodium sulfate _. After removal of the solvent under reduced pressure, the residue was chromatographed on silica gel (4:1 hexane:ethyl acetate) to afford 15 g (68%) of the title compound (51) as a solid. Mp: 79-81°C; ¹ HNMR (CDCl ₃ , 400MHz): 1.21 (s, 9H), 1.3-1.5 (m, 10H), 2.32 (s, 2H), 3.26 (s, 2H), 5.33 (M, 1H), 5.73(s, 2H). ¹³ C NMR (CDCl ₃ , 400MHz): 21.7, 26.2, 27.3, 34.3, 38.2, 39.2, 80.6, 155.9, 176.8, 178.0. MS (ESI) m/z 328.36 (MH ) ^- , 330.32(M+H) ⁺ , 352.33(M+Na) ⁺ .

Example 2

1-{[(α-acetoxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (56)

Step A: 1-Chloroethyl-p-nitrophenyl carbonate (57)

To an ice-cold reaction mixture containing p-nitrophenol (1.39 g, 10 mmol) and pyridine (0.81 g, 10 mmol) in dichloromethane (60 mL) was added 1-chloroethyl chloroformate (1.2 mL, 11 mmol). The mixture was stirred at 0 °C for 30 min, then at room temperature for 1 h. After removing the solvent under reduced pressure, the residue was dissolved in ether, washed with water, 10% citric acid and water. The ether layer was dried over _Na2SO4 and evaporated under _reduced pressure to give 2.4 g (97%) of the title compound (57) as a beige solid. ¹ H NMR (CDCl ₃ ): 1.93 (d, 3H), 6.55 (q, 1H), 7.42 (d, 2H), 8.28 (d, 2H).

Step B: α-Acetoxyethyl-p-nitrophenyl carbonate (58)

A mixture of 1-chloroethyl-p-nitrophenyl carbonate (57) (0.5 g, 2 mmol) and mercury acetate (1.5 g, 4.4 mmol) in acetic acid (15 mL) was stirred at room temperature for 24 h. After removal of acetic acid under reduced pressure, the residue was dissolved in ether and washed with water, 0.5% (v/v) aqueous NaHCO ₃ and water. _The ether layer was dried over _Na2SO4 and concentrated to dryness. The resulting residue was chromatographed on silica gel (hexane:ethyl acetate (95:5)) to give 0.45 g (84%) of the title compound (58). ¹ H NMR (CDCl ₃ , 400MHz): 1.55(d, J=5.6Hz, 3H), 2.07(s, 3H), 6.78(q, J=5.6Hz, 1H), 7.36(d, J=9.6Hz, 2H), 8.22 (d, J = 9.6 Hz, 2H).

Step C: 1-{[(α-Acetoxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (56)

To a mixture containing gabapentin (633 mg, 3.7 mmol) and triethylamine (1.03 mL, 7.4 mmol) in dichloromethane (20 mL) was added trimethylchlorosilane (0.93 mL, 7.4 mmol), and the mixture was stirred until a clear solution is formed. A solution containing α-acetoxyethyl-p-nitrophenyl carbonate (58) (1 g, 3.7 mmol) in dichloromethane (10 mL) was added, and the resulting mixture was stirred for 30 minutes. The reaction mixture was washed with 10% citric acid (20 mL), and the organic layer was separated. The aqueous layer was further extracted with ether (3 x 10 mL), and the combined organic extracts were dried over MgSO ₄ . After filtration, the organic solvent was removed under reduced pressure. The resulting residue was chromatographed on silica gel (hexane:ethyl acetate (4:1)) to give 700 mg (63%) of the title compound (56). ¹ H NMR (CDCl ₃ , 400MHz): 1.27-1.60(m, 10H), 1.55(d, 3H), 2.08(s, 3H), 2.38(s, 2H), 3.25(m, 2H), 5.31(t , 1H), 6.81 (q, 1H). MS (ESI) m/z 302.22 (M+H) ⁺ . The acid form was quantitatively converted to the corresponding sodium salt by dissolving in water (5 mL), adding an equimolar amount of 0.5N _NaHCO3 , and then lyophilizing.

Example 3

1-{[(α-benzoyloxybenzyloxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (59)

Step A: α-Benzoylbenzyl p-nitrophenyl carbonate (60)

To a solution of benzoin (2.0 g, 9.4 mmol) in 60 _{mL CH2Cl2} was added DMAP (1.21 g, 9.9 mmol) and p-nitrophenyl-chloroformate (1.99 g, 9.9 mmol) respectively at room temperature. After stirring at room temperature for 3 h, the reaction was quenched with water and extracted with ethyl acetate/hexane (2 x 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to give the title compound (60), which was used in the next reaction without purification.

Step B: 1-{[(α-Benzoylbenzyloxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid

(61)

To a suspension of gabapentin (1.70 g, 9.9 mmol) _{in CH2Cl2} was added triethylamine (2.76 mL, 19.8 mmol) and TMSCl (2.51 mL, 19.8 mmol) at 0 °C. The reaction was stirred at room temperature for 30 minutes. To this mixture was added compound (60) in _CH2Cl2 (prepared in Step A above), and the resulting mixture was stirred at _room temperature for 5 h. The reaction mixture _was diluted with dichloromethane, washed with brine, and the organic layer was dried over _Na2SO4 . After removal of the solvent under reduced pressure, the residue was purified by silica gel chromatography eluting with 5% methanol in _CH2Cl2 to afford 3.78 _g (90% over two steps) of the title compound (61). ¹ H NMR (CDCl ₃ , 400MHz): δ1.48-1.35(m, 10H), 2.30(s, 2H), 3.24(d, J=7.2Hz, 2H), 5.58(t, J=6.8Hz, 1H ), 6.85 (s, 1H), 7.50-7.33 (m, 8H), 7.93 (d, J=7.2Hz, 2H).

Step C: 1-{[(α-benzoyloxybenzyloxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid

(59)

To a solution of 1-{[(α-benzoylbenzyloxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (61) (1.89 g, 4.6 mmol) in 40 mL CH ₂ Cl ₂ at room temperature 77% mCPBA (2.07 g, 9.2 mmol) and NaHCO ₃ (0.78 g, 9.2 mmol) were added, and the resulting mixture was stirred at room temperature overnight. _The reaction mixture was acidified with 10% citric acid and extracted with _CH2Cl2 . The organic extracts were washed with brine and _dried over _Na2SO4 . After removing the solvent under reduced pressure, the residue was purified by reverse phase preparative HPLC (acetonitrile-water, 0.1% formic acid) to afford 960 mg (49%) of the title compound (59). ¹ H NMR (CDCl ₃ , 400MHz): δ1.58-1.35(m, LOH), 2.34(s, 2H), 3.26(dd, J=6.8, 0.8Hz, 2H), 5.38(t, J=6.8Hz , 1H), 7.46-7.26 (M, 5H), 7.63-7.55 (M, 3H), 7.89 (s, 1H), 8.08 (dd, J=8.8, 1.2Hz, 2H).

Example 4

1-{[(α-Acetoxybenzyloxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (62)

According to the method of Example 3, and substituting benzoin with 1-hydroxy-1-phenyl-propan-2-one, 300 mg of the title compound (62) was obtained. ¹ H NMR (CDCl ₃ , 400MHz): δ1.41(m, 10H), 2.19(s, 3H), 2.33(s, 2H), 3.27(dd, J=6.6, 1.6Hz, 2H), 5.36(t , J=6.6Hz, 1H), 7.40(M, 3H), 7.52(M, 2H), 7.63(s, 1H).

Example 5

1-{[(α-Benzoyloxyethoxy)carbonylaminomethyl}-1-cyclohexaneacetic acid (63)

According to the method of Example 3, substituting 2-hydroxy-1-phenyl-1-propanone for benzoin, 5 mg of the title compound (63) was obtained. ¹ H NMR (CDCl ₃ , 400MHz): δ1.44-1.36(m, 10H), 1.62(d, J=5.6Hz, 3H), 2.34(s, 2H), 3.24(d, J=6.8Hz, 2H ), 5.28(t, J=6.8Hz, 1H), 7.06(qJ=5.6Hz, 1H), 7.44(M, 2H), 7.56(M, 1H), 8.03(dd, J=8.4, 1.6Hz, 2H ).

Example 6

1-{[(1-Benzoyloxy-2-phenylethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid

(64)

Step A: 2-Phenyl-1,3-dithiane (65)

To a solution of benzaldehyde (10.6 g, 100 mmol) and 1,3 _- propaneedithiol in _CH2Cl2 (150 mL) was added _BF3 dropwise at room temperature. _Et2O (6.3 mL, 50 mmol) and the resulting mixture were stirred at room temperature for 2 h. The reaction mixture was then diluted with _CH2Cl2 , filtered and _the filtrate was washed with brine, _{saturated NaHCO3} , brine and dried over _Na2SO4 . The solvent was removed under reduced pressure to give a white solid, which was recrystallized from a 1:1 mixture of ether and hexanes to give 17.0 g (87%) of the title compound (65) as white crystalline needles. ¹ H NMR (CDCl ₃ , 400MHz): δ1.91(M, 1H), 2.14(M, 1H), 2.89(M, 2H), 3.04(M, 2H), 5.16(s, 1H), 7.35-7.28 (M, 3H), 7.46 (M, 2H).

Step B: 2-Phenyl-1-(2-phenyl-[1,3]-dithian-2-yl)-ethanol (66)

To a solution of 2-phenyl-1,3-dithiane (65) (4.0 g, 20.4 mmol) in THF was added 1.6 M n-butyl in THF (15.3 mL, 24.4 mmol) at -30°C Lithium solution. After stirring at -30°C for 30 minutes, a solution of phenylacetylaldehyde (2.45 g, 20.4 mmol) in tetrahydrofuran was added dropwise at -30°C. The resulting reaction mixture was stirred at 0 °C for an additional 1 h. The reaction was quenched with saturated _NH4Cl solution and extracted with ethyl acetate. The _combined organic extracts were washed with saturated _NH4Cl solution, brine and dried over _Na2SO4 . After filtration and concentration, the crude product was purified by silica gel flash chromatography (25% ethyl acetate in hexanes) to afford 2.63 g (71%) of the title compound (66). ¹ H NMR (CDCl ₃ , 400MHz): δ1.97(m, 2H), 2.23(dd, J=4.0, 1.2Hz, 1H), 2.43(dd, J=13.6, 10.2Hz, 1H), 2.77(M , 4H), 3.02 (d, J = 13.6Hz, 1H), 4.07 (M, 1H), 7.44-7.13 (M, 8H), 8.02 (dd, J = 8.4, 1.4Hz, 2H).

Step C: 2-Hydroxy-1,3-diphenyl-propan-1-one (67)

To 2-phenyl-1-(2-phenyl-[1,3]-dithian-2-yl)-ethanol (66) in 100 mL of a 9:1 mixture of acetonitrile and water (2.50 g, 7.9 mmol) was added to a solution of mercury perchlorate hydrate (4.1 g, 10.3 mmol). The resulting mixture was stirred at room temperature for 5 minutes, and TLC showed the reaction to be complete. The mixture was diluted with ethyl acetate, filtered through a pad of celite, the filtrate was washed with saturated NaHCO ₃ , brine, and dried over Na ₂ SO ₄ . The solvent was removed under reduced pressure and the crude product was purified by silica gel flash chromatography (20% ethyl acetate in hexanes) to afford 1.32 g (74%) of the title compound (67). ¹ H NMR (CDCl ₃ , 400MHz): δ2.90(dd, J=14.4, 7.0Hz, 1H), 3.20(dd, J=14.4, 4.0Hz, 1H), 3.70(d, J=6.8Hz, 1H ), 5.35 (M, 1H), 7.28-7.11 (M, 5H), 7.53 (m, 2H), 7.65 (M, 1H), 7.93 (d, J=7.2HZ, 2H).

Step D: 1-{[(1-Benzoyloxy-2-phenylethoxy)carbonyl]aminomethyl}-1-cyclohexyl

Alkaneacetic acid (64)

According to the method of Example 3, substituting 2-hydroxy-1,3-diphenyl-propan-1-one for benzoin, 181 mg of the title compound (64) was obtained. ¹ H NMR (CDCl ₃ , 400MHz): δ1.45-1.29(m, 10H), 2.24(d, J=13.6Hz, 1H), 2.28(d, J=13.6Hz, 1H), 3.22(M, 4H ), 5.26(t, J=6.6Hz, 1H), 7.16(t, J=5.6Hz, 1H), 7.33-7.25(M, 5H), 7.40(M, 2H), 7.57(m, 1H), 8.02 (M, 2H).

Example 7 1-{[(1-(3-methylbutyryloxy)-2-phenylethoxy)carbonyl]aminomethyl

Base}-1-cyclohexaneacetic acid (68)

According to the method of Example 6, and substituting 3-methylbutyraldehyde for benzaldehyde in step A, 95 mg of the title compound (68) were obtained. ¹ H NMR (CDCl ₃ , 400MHz): δ0.88-0.90(M, 6H), 1.16-1.29(m, 10H), 2.06(M, 1H), 2.16(M, 2H), 2.26(M, 2H) , 3.08(d, J=6.8Hz, 2H), 3.19(M, 2H), 5.22(t, J=6.8Hz, 1H), 6.93(t, J=6Hz, 1H), 7.31-7.23(M, 5H ).

Example 8

1-{[(α-Benzoyloxybutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (69)

According to the method of Example 6, butyraldehyde was used instead of phenylacetaldehyde in Step B, 240 mg of the title compound (69) were obtained. ¹ H NMR (CDCl ₃ , 400MHz): δ0.99(t, J=7.6Hz, 3H), 1.52-1.38(M, 12H), 1.89(M, 2H), 2.31(s, 2H), 3.24(M , 2H), 5.34(t, J=6.6Hz, 1H), 6.70(t, J=5.6Hz, 1H), 7.42(M, 2H), 7.56(M, 1H), 8.04(M, 2H).

Example 9

1-{[(α-acetoxybutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (70)

According to the method of Example 6, and replacing the benzaldehyde in step A with acetaldehyde and the phenylacetaldehyde in step B with butyraldehyde, 42 mg of the title compound (70) were obtained. ¹ HNMR (CD ₃ OD, 400MHz): δ0.95(M, 3H), 1.52-1.31(M, 12H), 1.72(M, 2H), 2.02(s, 3H), 2.27(s, 2H), 3.20 (s, 2H), 6.67 (t, J=5.6Hz, 1H).

Example 10

1-{[(α-butyryloxybutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (71)

According to the method of Example 3, but using butyroin instead of benzoin, 210 mg of the title compound (71) was obtained. ¹ H NMR (CDCl ₃ , 400MHz); 80.93 (M, 6H), 1.37-1.76 (M, 16H), 2.30 (M, 4H), 3.23 (M, 2H), 5.25 (broad triplet, 1H), 6.73 ( M, 1H). MS (ESI) m/z 356.45 (MH) ⁺ .

Example 11

1-{[(α-propionyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (72)

Step A: 1-iodoethyl-p-nitrophenyl carbonate (73)

A mixture of 1-chloroethyl-p-nitrophenyl carbonate (0.5 g, 2 mmol) and NaI (0.6 g, 4 mmol) in anhydrous acetone was stirred at 40 °C for 3 h. After filtration, the filtrate was concentrated under reduced pressure to obtain 480 mg (72%) of the title compound (73), which was used in the next reaction without further purification.

Step B: α-propionyloxyethyl-p-nitrophenyl carbonate (74)

A mixture of 1-iodoethyl-p-nitrophenyl carbonate (73) (0.51 g, 1.5 mmol) and silver propionate (0.54 g, 3 mmol) in toluene (20 mL) was stirred at 50 °C for 24 h. The reaction mixture was filtered to remove solids, and the filtrate was concentrated under reduced pressure. The resulting residue was chromatographed on silica gel ( ₂₀ % _CH2Cl2 /hexanes, then 40% _CH2Cl2 /hexanes) to afford 0.39 _g (92%) of the title compound (74). ¹ H NMR (CDCl ₃ , 400MHz): 1.16(t, J=7.6Hz, 3H), 1.61(d, J=5.6Hz, 3H), 2.41(q, J=7.6Hz, 2H), 6.84(q, 1H, J=5.6Hz), 7.39(d, J=9.2Hz, 2H), 8.28(d, J=9.2Hz, 2H).

Step C: 1-{[(α-propionyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid

(72)

To a mixture of gabapentin (160 mg, 2.76 mmol) and triethylamine (0.77 mL, 5.5 mmol) in dichloromethane (30 mL) was added trimethylchlorosilane (0.71 mL, 5.5 mmol), and the resulting mixture Stir until a clear solution forms. To the above solution was added a solution of α-propionyloxyethyl-p-nitrophenyl carbonate (74) (0.39 g, 1.4 mmol) in dichloromethane (10 mL). After stirring for 30 minutes the reaction mixture was washed with 10% citric acid (20 mL), and the organic layer was separated. The aqueous layer was further extracted with ether (3 x 10 mL), and the combined organic extracts were dried over MgSO ₄ . After removing the solvent under reduced pressure, the residue was purified by reverse phase preparative HPLC (acetonitrile, water, 1% formic acid) to afford 190 mg (44%) of the title compound (72). ¹ HNMR (CD ₃ OD, 400MHz): 1.09(t, J=7.6Hz, 3H), 1.36-1.54(m, 10H), 1.44(d, J=5.6Hz, 3H), 2.28(s, 2H), 2.31 (q, J = 7.6 Hz, 2H), 3.22 (s, 2H), 6.67 (q, J = 5.6 Hz, 1H). MS (ESI) m/z 316.25 (M+H) ⁺ .

Example 12

1-{[(α-butyryloxyethoxy)carbonyl]aminomethyl}cyclohexaneacetic acid (75)

Step A: α-Butyryloxyethyl-p-nitrophenyl carbonate (76)

A mixture of 1-iodoethyl-p-nitrophenyl carbonate (73) (1.5 g, 4.5 mmol) and silver butyrate (1.3 g, 6.7 mmol) in toluene (40 mL) was dissolved in oil at 90 °C Stir in the bath for 24h. The reaction mixture was filtered under reduced pressure and the filtrate was concentrated. The resulting residue was chromatographed on silica gel (20% _CH2Cl2 /hexanes, then 40% _CH2Cl2 /hexanes) to afford 0.46 g (36%) of the _title compound ( ₇₆ ). ¹ H NMR (CDCl ₃ , 400MHz): 0.95(t, J=7.6Hz, 3H), 1.61(d, J=5.6Hz, 3H), 1.67(m.2H), 2.41(t, J=7.6Hz, 2H), 6.84(q, 1H, J=5.6Hz), 7.39(d, J=9.2Hz, 2H), 8.28(d, J=9.2Hz, 2H). MS(ESI) m/z 298.28(M+ H) ⁺ .

Step B: 1-{[(α-butyryloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid

(75)

To a mixture containing gabapentin (530 mg, 3.1 mmol) and triethylamine (0.89 mL, 6.4 mmol) in dichloromethane (30 mL) was added trimethylchlorosilane (0.83 mL, 6.4 mmol), and the resulting The mixture was stirred until a clear solution formed. To this solution was added a solution of α-butyryloxyethyl-p-nitrophenyl carbonate (76) (0.46 g, 1.6 mmol) in dichloromethane (10 mL), and the resulting mixture was stirred for 30 minutes . The reaction mixture was washed with 10% citric acid (20 mL), and the organic phase was separated. The aqueous phase was further extracted with ether (3 x 10 mL), and the combined organic phases were dried over MgSO ₄ and concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC (acetonitrile, water, 1% formic acid) to afford 70 mg (21%) of the title compound (75). ¹ H NMR (CD ₃ OD, 400MHz): 0.95(t, J=7.6Hz, 3H), 1.32-1.58(m, 10H), 1.42(d, J=5.6Hz, 3H), 1.67(M, 2H) , 2.24(s, 2H), 2.30(t, J=7.6Hz, 2H), 3.24(s, 2H), 6.74(q, J=5.6Hz, 1H).MS(ESI) m/z 330.28(M+ H) ⁺ .

The acid form was quantitatively converted to the corresponding sodium salt by dissolving in water (5 mL), adding an equimolar amount of 0.5N _NaHCO3 , and then lyophilizing.

Example 13

1-{[(α-isobutyryloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (77)

According to the method of Example 2, and using silver isobutyrate instead of silver butyrate, 70 mg (21%) of the title compound (77) were obtained. ¹ H NMR (CD ₃ OD, 400MHz): 1.12(d, J=7.2Hz, 3H), 1.14(d, J=7.2Hz, 3H), 1.32-1.58(m, 10H), 1.44(d, J= 5.6Hz, 3H), 2.28(s, 2H), 2.56(M, 1H), 3.25(m, 2H), 6.73(q, J=5.6Hz, 1H).MS(ESI) m/z 330.30(M+ H) ⁺ .

The acid form was quantitatively converted to the corresponding sodium salt by dissolving in water (5 mL), adding an equimolar amount of 0.5N _NaHCO3 , and then lyophilizing.

Example 14

1-{[(α-pivaloyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (78)

Following the procedure of Example 12, and substituting trimethylsilver acetate for butyrate, 80 mg (36%) of the title compound (78) were obtained. ¹ H NMR (CDCl ₃ , 400MHz): 1.13(s, 9H), 1.32-1.58(m, 10H), 1.41(d, J=5.6Hz, 3H), 2.27(s, 2H), 3.25(M, 2H ), 5.41 (t, 1H), 6.73 (q, J = 5.6 Hz, 1H). MS (ESI) m/z 344.20 (M+H) ⁺ .

The acid form was quantitatively converted to the corresponding sodium salt by dissolving in water (5 mL), adding an equimolar amount of 0.5N _NaHCO3 , and then lyophilizing.

Example 15

1-{(α-Acetoxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (79)

Following the procedure of Example 2, substituting 1-chloro-2-methylpropyl chloroformate for 1-chloroethyl chloroformate, 212 mg (38%) of the title compound (79) were obtained. ¹ H NMR (CD ₃ OD, 400MHz): 0.99 (M, 6H), 1.32-1.58 (m, 10H), 1.88 (M, 1H), 2.08 (s, 3H), 2.38 (s, 2H), 3.25 ( s, 2H), 6.52 (d, J=4.4Hz, 1H); MS (ESI) mlz 330.30 (M+H) ⁺ .

Example 16

1-{[(α-propionyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (80)

According to the method of Example 11, and substituting 1-chloro-2-methylpropyl-p-nitrophenyl carbonate for 1-chloroethyl-p-nitrophenyl carbonate, 190 mg (44%) of the title compound were obtained (80). ¹ H NMR (CD ₃ OD, 400MHz): 0.90 (d, J=6.6Hz, 3H), 0.91 (d, J=6.6Hz, 3H), 0.98 (T, J=7.6Hz, 3H), 1.32-1.58 (m, 10H), 1.83(m, 1H), 2.18(s, 2H), 2.28(q, J=7.6Hz, 2H), 3.25(s, 2H), 6.52(d, J=4.4Hz, 1H) .MS (ESI) mlz 344.34 (M+H) ⁺ .

Example 17

1-{[(α-butyryloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (81)

According to the method of Example 2, and replace 1-chloroethyl chloroformate and mercury acetate with 1-chloro-2-methylpropyl chloroformate and mercury butyrate respectively, obtain 95 mg (36%) of the title compound ( 81). ¹ H NMR (CD ₃ OD, 400MHz): 1.12 (t, J=7.6Hz, 3H), 1.13 (d, J=6.6Hz, 3H), 1.14 (d, J=6.6Hz, 3H), 1.32-1.58 (m, 10H), 1.87(m, 2H), 2.22(m, 1H), 2.42(s, 2H), 2.46(t, J=7.6Hz, 2H), 3.44(m, 2H), 6.78(d, J = 4.8 Hz, 1H). MS (ESI) m/z 358.30 (M+H) ⁺ .

Example 18

1-{[(α-isobutyryloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (82)

According to the method of Example 2, and replace 1-chloroethyl chloroformate and mercury acetate with 1-chloro-2-methylpropyl chloroformate and mercury isobutyrate respectively, obtain 95 mg (36%) of the title compound ( 82). ¹ H NMR (CD ₃ OD, 400MHz): 0.95(d, J=7.2Hz, 3H), 0.97(d, J=7.2Hz, 3H), 1.05(d, J=6.6Hz, 3H), 1.06(d , J=6.6Hz, 3H), 1.32-1.58(m, 10H), 1.98(m, 1H), 2.24(s, 2H), 2.45(m, 1H), 3.24(m, 2H), 6.42(d, J = 4.8 Hz, 1H). MS (ESI) m/z 358.27 (M+H) ⁺ .

Example 19

1-{[(α-pivaloyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (83)

According to the method of embodiment 12, and replace 1-chloroethyl-p-nitrophenyl carbonate and butyl with 1-chloro-2-methylpropyl-p-nitrophenyl carbonate and trimethyl silver acetate respectively silver acid to afford 10 mg (9%) of the title compound (83). ¹ H NMR (CD ₃ OD, 400MHz): 0.98(d, J=6.6Hz, 3H), 0.99(d, J=6.6Hz, 3H), 1.19(s, 9H), 1.32-1.58(m, 10H) , 2.08 (m, 1H), 2.28 (s, 2H), 3.21 (m, 2H), 6.49 (d, 1H); MS (ESI) m/z 372.31 (M+H) ⁺ .

Example 20

1-{[(α-Benzoyloxyisobutoxy)carbonyl]aminomethyl-1-cyclohexaneacetic acid (84)

According to the method of Example 11, and replace 1-chloroethyl 1-p-nitrophenylcarbonate and propionic acid with 1-chloro-2-methylpropyl-p-nitrophenyl carbonate and silver benzoate respectively Silver, yielded 109 mg (40%) of the title compound (84). ¹ H NMR (CD ₃ OD, 400MHz): 1.18(d, J=7.2Hz, 6H), 1.32-1.58(m, 10H), 2.42(M, 1H), 2.28(s, 2H), 3.45(s, 2H), 6.99 (d, J = 4.8 Hz, 1H), 7.76 (M, 2H), 7.92 (M, 1H), 8.26 (M, 2H). MS (ESI) m/z 392.22 (M+H) ⁺ .

Example 21

1-{[(α-Acetoxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (85)

Step A: Isopropenyl-p-nitrophenyl carbonate (86)

To a mixture of p-nitrophenol (5.76 g, 41.5 mmol) and isopropenyl chloroformate (5 g, 41.5 mmol) in dichloromethane (200 mL) was added pyridine in dichloromethane (50 mL) at 0 °C (3.4 mL, 42 mmol). The resulting mixture was stirred at 0 °C for 30 min, then at room temperature for 1 h. After removing the solvent under reduced pressure, the residue was dissolved in ether and washed with water, 10% citric acid and again with water. The _ether layer was dried over _Na2SO4 and evaporated under reduced pressure to afford 8.7 g (94%) of the title compound (86) as a beige solid. ¹ H NMR (CDCl ₃ , 400MHz): 2.05(s, 3H), 4.81(M, 1H), 4.95(d, J=2Hz, 1H), 7.42(d, J=9.2Hz, 2H), 8.28(d , J=9.2Hz, 2H).

Step B: 2-Chloroisopropyl-p-nitrophenyl carbonate (87)

Isopropenyl-p-nitrophenyl carbonate (86) (8.7 g, 39 mmol) was dissolved in 4M hydrogen chloride/dioxane in a sealed container. The mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure to afford 10 g (100%) of the title compound (87), which was used in the next reaction without further purification. ¹ H NMR (CDCl ₃ , 400 MHz): 2.10 (s, 6H), 7.42 (d, 2H, J = 9.2 Hz), 8.28 (d, J = 9.2 Hz, 2H).

Step C: α-Acetoxyisopropyl-p-nitrophenyl carbonate (88)

A mixture of 2-chloroisopropyl-p-nitrophenyl carbonate (87) (0.5 g, 1.93 mmol) and mercury acetate (1.0 g, 3.13 mmol) in dichloromethane (20 mL) was stirred at room temperature 24h. The reaction mixture was filtered to remove solids, and the filtrate was concentrated under reduced pressure. The resulting residue was chromatographed on silica gel ( ₂₀ % _CH2Cl2 /hexanes, then 40% _CH2Cl2 /hexanes) to afford 227 _mg (50%) of the title compound (88). ¹ H NMR (CDCl ₃ , 400 MHz): 1.90 (s, 6H), 2.07 (s, 3H), 7.28 (d, 2H, J=9.2Hz), 8.28 (d, J=9.2Hz, 2H).

Step D: 1-{(α-Acetoxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (85)

To a mixture containing gabapentin (257 mg, 1.5 mmol) and triethylamine (0.46 mL, 3.3 mmol) in dichloromethane (30 mL) was added trimethylchlorosilane (0.38 mL, 3 mmol), and the mixture was stirred to clarify. Add a solution containing α-acetoxyisopropyl-p-nitrophenyl carbonate (88) (0.23 g, 0.8 mmol) in dichloromethane (10 mL) and stir for 30 minutes. The reaction mixture was washed with brine (10 mL), and the organic layer was separated. The aqueous layer was further extracted with ether (3 x 10 mL), and the combined organic extracts were dried over MgSO ₄ and concentrated in vacuo. The resulting residue was chromatographed on silica gel (hexane:ethyl acetate (4:1)) to afford 40 mg (16%) of the title compound (85). ¹ H NMR (CD ₃ OD, 400MHz): 1.32-1.58(m, 10H), 1.80(s, 6H), 2.02(s, 3H), 2.27(s, 2H), 3.30(s, 2H).MS( ESI) m/z 316.21 (M+H) ⁺ .

Example 22

1-{[(α-butyryloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (89)

Following the procedure of Example 21, and substituting mercury butyrate for mercury acetate, 5 mg (5%) of the title compound (89) was obtained. ¹ H NMR (CD ₃ OD, 400MHz): 0.99(t, J=7.6Hz, 3H), 1.32-1.58(m, 10H), 1.60(M, 2H), 1.85(s, 6H), 2.22(t, J=7.6, 2H), 2.27 (s, 2H), 3.20 (s, 2H). MS (ESI) m/z 344.24 (M+H) ⁺ , 366.30 (M+Na) ⁺ .

Example 23

1-{[(α-isobutyryloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (90)

According to the method of Example 21, and using mercury isobutyrate instead of mercury acetate, 109 mg (43%) of the title compound (90) were obtained. ¹ H NMR (CD ₃ OD, 400MHz): 1.19(dJ=7.2Hz, 6H), 1.32-1.58(m, 10H), 1.82(s, 6H), 2.38(s, 2H), 3.25(s, 2H) .MS (ESI) 344.22 (M+H) ⁺ , 366.24 (M+Na) ⁺ .

Example 24

1-{[(α-Benzoyloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (91)

According to the method of Example 21, and using mercury benzoate instead of mercury acetate, 170 mg (58%) of the title compound (91) were obtained. ¹ H NMR (CDCl ₃ , 400MHz): 1.32-1.58(m, 10H), 1.95(s, 6H), 2.30(s, 2H), 3.20(d, J=6.8, 2H), 5.41(t, J= 6.8 Hz, 1H), 7.40 (M, 2H), 7.52 (m, 1H), 7.98 (m, 2H). MS (ESI) m/z 400.29 (M+Na) ⁺ .

Example 25

1-{[(α-nicotinoyloxyisobutoxy)carbonyl]oxymethyl}-1-cyclohexaneacetic acid (92)

Step A: 1-{[(α-Chloroisobutoxy)carbonylaminomethyl-1-cyclohexaneacetic acid (93)

To a mixture containing gabapentin (1.71 g, 10 mmol) and triethylamine (3.06 mL, 22 mmol) in dichloromethane (150 mL) was added trimethylchlorosilane (1.4 mL, 11 mmol), and the resulting mixture was stirred until clear (approximately 20 minutes). Then a solution containing 1-chloro-2-methylpropyl chloroformate (1.27 mL, 11 mmol) in dichloromethane (10 mL) was added at 0°C and stirred at room temperature for 60 minutes. The reaction mixture was washed with 10% citric acid (30 mL), and the organic layer was separated. The aqueous layer was further extracted with ether (3 x 20 mL), and the combined organic phases were dried over MgSO ₄ and concentrated in vacuo. Chromatography of the residue on silica gel eluting with hexane:ethyl acetate (1:4) afforded 2.37 g (77%) of the title compound. ¹ HNMR (CDCl ₃ , 400MHz): δ1.04(d, J=6.4Hz, 3H), 1.06(d, J=6.4Hz, 3H), 1.36-1.53(m, 10H), 2.15(M, 1H) , 2.34 (s, 2H), 3.24 (M, 2H), 5.39 (t, 1H), 6.32 (d, J=5.6Hz), 1H). MS (ESI) m/z 306.34 (M+H ⁺ ).

Step B: 1-{[(α-nicotinoyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid

(92)

(93) (268 mg, 0.88 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (158 μL, 1.01 mmol) and nicotinic acid ( 637mg, 5.2mmol) the mixture was stirred for 48h. After filtration, the filtrate was concentrated in vacuo and the resulting residue was purified by reverse phase preparative HPLC to afford 50 mg (14%) of the title compound. ¹ HNMR (CD ₃ OD, 400MHz): δ1.07(d, J=6.8Hz, 3H), 1.09(d, J=6.8Hz, 3H), 1.32-1.58(m, 10H), 2.19(M, 1H ), 2.26(s, 2H), 3.23(M, 2H), 6.78(d, J=4.8Hz, 1H), 7.58(m, 1H), 8.39(d, J=6.4Hz, 1H), 8.76(d , J = 4.4 Hz, 1H), 9.10 (s, 1H). MS (ESI) m/z 393.42 (M+H ⁺ ).

Example 26

1-{[(α-2,2-diethoxypropionyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexane

Acetic acid (94)

Step A: Benzyl 1-{[(α-chloroisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetate

(95)

To a solution of (93) (1.02 g, 3.34 mmol) in dichloromethane was added 1,3-dicyclohexylcarbodiimide (758 mg, 3.67 mmol). After stirring at room temperature for 30 minutes, benzyl alcohol (380 μL, 3.67 mmol) and 4-(dimethylamino)pyridine (catalytic amount) were added. The resulting mixture was stirred at room temperature for 16 h. After filtration, _the filtrate was washed with 10% citric acid, dried over _Na2SO4 and concentrated. Chromatography of the residue on silica gel eluting with 10% ethyl acetate/hexanes afforded 820 mg (62%) of the title compound. ¹ H NMR (CDCl ₃ , 400MHz): δ1.03(d, J=6.4Hz, 3H), 1.05(d, J=6.4Hz, 3H), 1.36-1.53(m, 10H), 2.13(M, 1H ), 2.35(s, 2H), 3.22(M, 2H), 5.11(s, 2H), 5.49(t, 1H), 6.32(d, J=4.8Hz), 1H), 7.34(m, 5H). MS (ESI) m/z 396.24 (M+H ⁺ ).

Step B: Cesium 2,2-diethoxypropionate (96)

1 mL of concentrated sulfuric acid was added to a stirred solution of 14 mL (0.2 mol) of pyruvic acid and 80 mL of triethyl orthoformate at 10°C. The resulting mixture was stirred at 5-10 °C for 1 h, then diluted with 200 mL of dichloromethane. The organic solution was washed successively with water (3 x 80 mL) and saturated sodium chloride solution (80 mL), then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to give 2,2-diethoxypropanoic acid in quantitative yield as an oil. ¹ H NMR (CDCl ₃ , 400 MHz): δ 1.30 (t, 6H), 1.61 (s, 3H), 3.57 (q, 4H), 8.62 (s, 1H). The acid form was quantitatively converted to its cesium salt by dissolving the acid in water (25 mL) and treating with an equimolar amount of cesium carbonate followed by lyophilization. ¹ H NMR (D ₂ O, 400 MHz): δ 0.98 (t, 6H), 1.28 (s, 3H), 3.22 (q, 2H), 3.47 (q, 2H).

Step C: 1-{[(α-2,2-diethoxypropionyloxyisobutoxy)carbonyl]aminomethyl

Benzyl}-1-cyclohexaneacetate (97)

A mixture of (95) (200 mg, 0.51 mmol) and sodium iodide (114 mg, 0.76 mmol) in acetone was stirred at room temperature for 1 h. Cesium (96) 2,2-diethoxypropionate (300 mg, 1.02 mmol) and DMF (20 mL) were added, and the resulting mixture was stirred at 40° C. for 18 h. After filtration, the filtrate was concentrated and the resulting residue was purified by flash column chromatography on silica gel eluting with 10% ethyl acetate/hexanes to afford 100 mg (37%) of the title compound. MS (ESI) m/z 522.34 (M+H ⁺ ).

Step D: 1-{[(α-2,2diethoxypropionyloxyisobutoxy)carbonyl]aminomethyl

Base}-1-cyclohexaneacetic acid (94)

A mixture of (97) (200 mg, 0.38 mmol) and 5% Pd—C (catalytic amount) was stirred at room temperature under hydrogen atmosphere for 16 h. After filtration, the filtrate was concentrated and the resulting residue was purified by reverse phase preparative HPLC to afford 98 mg (60%) of the title compound. ¹ H NMR (CDCl ₃ , 400MHz): δ0.97(D, J=6.8Hz, 6H), 1.19(t, J=6.4Hz, 3H), 1.21(t, J=6.4Hz, 3H), 1.32- 1.58(m, 10H), 1.51(s, 3H), 2.06(M, 1H), 2.30(s, 2H), 3.23(M, 2H), 3.46(M, 2H), 3.56(M, 2H), 5.30 (t, 1H, NH), 6.59 (d, J = 4.8 Hz, 1H). MS (ESI) m/z 432.24 (M+H ⁺ ).

Example 27

1-{[(α-(2-amino-2-methylpropionyl)oxyisobutoxy)carbonyl]aminomethyl}-1-ring

Hexaneacetic acid (98)

Following the procedure of Example 26, substituting 2-amino-2-methylpropionic acid for 2,2-diethoxypropionic acid, the title compound was obtained. ¹ H NMR (CDCl ₃ , 400MHz): δ0.97(d, J=6.8Hz, 6H), 1.44(s, 3H), 1.45(s 3H), 1.32-1.58(m, 10H,), 2.05(M , 1H), 2.30(s, 2H), 3.23(m, 2H), 5.50(t, 1H, NH), 6.58(d, J=4.8Hz, 1H). MS(ESI) m/z 373.48(M+ H ⁺ ).

Example 28

1-{[(α-isobutyryloxybutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (99)

Step A: 2-Isopropyl-1,3-dithiane (100)

To a mixture of isobutyraldehyde (9.1 mL, 100 mmol) and 1,3-propanediol (10 mL, 100 mmol) in dichloromethane was added boron trifluoride diethyl etherate (6.4 mL, 50mmol). The resulting mixture was stirred at 0°C for 30 minutes and at room temperature for 30 minutes. The reaction mixture was washed with brine, 5% NaHCO ₃ and brine again. The organic phase was separated and dried over _Na2SO4 , then _concentrated to give 16 g (100%) of the title compound as a yellow liquid. It was carried on to the next step without further purification. ¹ H NMR (CDCl ₃ , 400MHz): δ1.057(D, J=7.2Hz, 3H), 1.059(d, J=7.2Hz, 3H), 1.80(M, 1H), 1.97-2.08(m, 2H ), 2.82 (M, 4H), 4.00 (d, J=5.2Hz, 1H).

Step B: 2-Isopropyl-2-(α-hydroxybutyl)-1,3-dithiane (101)

To a solution of (100) (4 g, 24.7 mmol) in anhydrous tetrahydrofuran (50 mL) was added n-butyllithium (1.6M in hexane, 18.5 mL, 29.6 mmol) dropwise at -20°C. The stirred mixture was heated at room temperature for 4 h, then cooled to -20 °C again. To this solution was slowly added a solution of n-butyraldehyde (2.7 mL, 29.6 mmol) in anhydrous THF (10 mL). The resulting mixture was stirred at a temperature between -20 °C and room temperature for 16 h, quenched with saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was separated and _dried over _Na2SO4 . After removal of the solvent under reduced pressure, the residue was flash column chromatographed on silica gel with 5% ethyl acetate/hexane to afford 5 g (85%) of the title compound as a yellow oil. ¹ HNMR (CDCl ₃ , 400MHz): δ0.96(t, J=7.2Hz, 3H), 1.11(d, J=6.8, Hz, 3H), 1.17(d, J=6.8Hz, 3H), 1.42- 1.52(M, 2H), 1.76(M, 1H), 1.87-1.95(M, 2H), 2.04(M, 2H), 2.62(M, 4H), 2.94(M, 2H), 4.03(d, J= 5.2HZ, 1H).

Step C: 4-Hydroxy-2-methylheptan-3-one (102)

To a solution of (101 ) (5.0 g, 21.4 mmol) in acetonitrile (270 mL) was added a solution of Hg(ClO ₄ ) ₂ in methanol (30 mL) with vigorous stirring. The resulting mixture was stirred at room temperature for 2 h. After filtration, the filtrate was concentrated under reduced pressure without heating. The residue was purified by silica gel flash column chromatography (10% ethyl acetate/hexane) to give 2.8 g (91%) of the title compound as a colorless liquid. ¹ H NMR (CDCl ₃ , 400 MHz): S 0.91(t, J=7.2Hz, 3H), 1.09(d, J=7.2Hz, 3H), 1.10(d, J=7.2Hz, 3H), 1.35- 1.46 (M, 4H), 1.75 (M, 1H), 2.80 (M, 1H), 3.45 (d, J=5.2Hz, 1H), 4.29 (M, 1H).

Step D: 2-Methylheptan-3-one-4-p-nitrophenyl carbonate (103)

To a mixture of (102) (1.1 g, 7.6 mmol), p-nitrophenyl chloroformate (1.84 g, 9.2 mmol) in anhydrous dichloromethane was slowly added 4 in dichloromethane at 0 °C. - A solution of dimethylaminopyridine (1.12 g, 9.2 mmol). After stirring for 1 h at 0°C and 4 h at room temperature, the reaction was quenched with 10% citric acid. The organic phase was _separated , dried over _Na2SO4 , and concentrated in vacuo. Flash column chromatography of the residue eluting with 30% dichloromethane/hexanes afforded 2 g (85%) of the title compound as a beige solid. ¹ H NMR (CDCl ₃ , 400MHz): δ0.99(t, J=7.6Hz, 3H), 1.12(d, J=6.8Hz, 3H), 1.18(d, J=6.8Hz, 3H), 1.51( M, 2H), 1.84 (M, 2H), 2.82 (M, 1H), 5.17 (M, 1H), 7.42 (d, J=6.8Hz, 2H), 8.25 (d, J=6.8Hz, 2H).

Step E: 1-{[(α-isobutyrylbutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid

(104)

To a mixture containing gabapentin (820 mg, 4.8 mmol) and triethylamine (1.35 mL, 9.6 mmol) in dichloromethane (20 mL) was added trimethylchlorosilane (1.22 mL, 9.6 mmol), and the resulting The mixture was stirred for 20 minutes. To this solution was added (103) (1 g, 3.2 mmol) in dichloromethane (10 mL), and the resulting mixture was stirred for 60 minutes. The reaction mixture was washed with 10% citric acid (20 mL), and the organic layer was separated. The aqueous layer was further extracted with ether (3 x 10 mL), and the combined organic extracts were dried over MgSO ₄ and concentrated in vacuo. Chromatography of the residue on silica gel eluting with hexane:ethyl acetate (4:1) to remove p-nitrophenol followed by hexane:ethyl acetate (1:4) gave (72%) the title compound. ¹ H NMR (CDCl ₃ , 400MHz): δ0.91(t, J=7.2Hz, 3H), 1.04(d, J=6.8Hz, 3H), 1.12(d, J=6.8HZ, 3H), 1.36- 1.53(m, 12H), 1.74(M, 2H), 2.33(s, 2H), 2.78(M, 1H), 3.22(M, 2H), 5.11(M, 1H), 5.48(t, 1H, NH) .MS (ESI) m/z 342.24 (M+H ⁺ ).

Step F: 1-{[(α-isobutyryloxybutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid

(99)

To a solution of (104) (780 mg, 2.3 mmol) in dichloromethane (20 mL) was added m-chloroperoxybenzoic acid (1.03 g, 4.6 mmol) and NaHCO ₃ (386 mg, 4.6 mmol). After stirring at room temperature for 16 h, another batch of m-chloroperoxybenzoic acid (791 mg, 4.6 mmol) and NaHCO ₃ (386 mg, 4.6 mmol) were added. The resulting mixture was stirred for a further 8 h, then treated with 10% citric acid. After filtration, the organic layer was separated, dried _{over Na2SO4} and concentrated. The residue was purified by reverse phase preparative HPLC to afford 79 mg (11%) of the title compound. ¹ HNMR (CDCl ₃ , 400MHz): δ0.94(t, J=7.2Hz, 3H), 1.153(d, J=7.2Hz, 3H), 1.150(d, J=7.2Hz, 3H), 1.32-1.58 (M, 12H), 1.74(M, 2H), 2.28(s, 2H), 2.56(m, 1H), 3.23(m, 2H), 5.27(t, J=6.8Hz, 1H, NH), 6.71( t, J = 5.6 Hz, 1H). MS (ESI) MLZ 358.30 (M+H ⁺ ).

The above acids were quantitatively converted to the corresponding sodium salts by dissolving the acids in water (5 mL), followed by the addition of an equimolar amount of 0.5 N NaHCO ₃ and lyophilization.

Example 29

Methyl 1-{[(α-isobutyryloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetate

(105)

Step A: Methyl 1-{[(α-chloroisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetate

(106)

A mixture of (93) (1.0 g, 3.3 mmol), benzene (90 mL) and methanol (10 mL) was cooled to 0 °C. Trimethylsilyldiazomethane was added slowly at 0°C until the yellow color remained. The mixture was stirred at 0 °C for 30 minutes until the reaction was complete (monitored by TLC). After removal of the solvent under reduced pressure, the resulting residue was chromatographed on silica gel eluting with 10% ethyl acetate/hexanes to afford 760 mg (72%) of the title compound. MS (ESI) m/z 320.24 (M+H ⁺ ).

Step B: 1-{{[(α-isobutyryloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexane

Acid methyl ester (105)

A mixture of (106) (760 mg, 2.38 mmol), silver carbonate (394 mg, 1.4 mmol) and isobutyric acid (442 μl, 4.76 mmol) in chloroform was stirred at room temperature for 24 h. Another batch of silver carbonate (394 mg, 1.4 mmol) and isobutyric acid (442 μL, 4.76 mmol) was added, and the resulting mixture was stirred for an additional 24 hours. After filtration, the filtrate was concentrated and the resulting residue was purified by flash column chromatography on silica gel, eluting with 10% ethyl acetate/hexanes to afford 560 mg (63%) of the title compound. ¹ H NMR (CDCl ₃ , 400MHz): δ0.94(d, J=6.8Hz, 3H), 0.96(D, J=6.8Hz, 3H), 1.15(d, J=7.2HZ, 3H), 1.17( d, J=7.2HZ, 3H), 1.32-1.58(m, 10H), 2.01(m, 1H), 2.19(s, 2H), 2.55(m, 1H), 3.18(m, 2H), 3.67(s , 3H), 5.33 (t, 1H), 6.56 (d, J=4.8Hz, 1H). MS (ESI) m/z 372.38 (M+H ⁺ ).

Example 30

Methyl 1-{[(α-benzoyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetate

(107)

A mixture of 1-{[(α-benzoylisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (84) (150 mg, 0.38 mmol), benzene (18 mL) and methanol (2 mL) Cool to 0 °C. Trimethylsilyldiazomethane was added slowly at 0°C until the yellow color remained. The mixture was stirred at 0 °C for 30 minutes until the reaction was complete (monitored by TLC). After removal of the solvent under reduced pressure, the residue was chromatographed on silica gel eluting with 5% ethyl acetate/hexanes to afford 98 mg (64%) of the title compound. ¹ H NMR (CDCl ₃ , 400MHz): δ1.02(d, J=6.4Hz, 3H), 1.03(d, J=6.4Hz, 3H), 1.32-1.52(m, 10H), 2.14(M, 1H ), 2.27(s, 2H), 3.17(M, 2H), 3.62(s, 3H), 5.40(t, 1H), 6.81(d, J=4.8Hz, 1H), 7.40(M, 2H), 7.54 (M, 1H), 8.12 (m, 2H). MS (ESI) m/z 406.29 (M+H ⁺ ).

Example 31

1-{(N-[(α-isobutyryloxyethoxy)carbonyl]-4-bromophenylalanyl]aminomethyl

-1-Cyclohexaneacetic acid (108)

Step A: 1-{(4-Bromophenylalanyl)aminomethyl}-1-cyclohexaneacetate (109)

Add N-Boc-4-bromophenylalanine (1.72g, 5mmol), dicyclohexylcarbodiimide (1.24g, 6mmol), N-hydroxysuccinimide (0.7g, 6mmol) into a 40mL vial ) and acetonitrile (20 mL). The reaction mixture was shaken at 25 °C for 4 h. Precipitated dicyclohexylurea was removed by filtration. To the filtrate was added an aqueous solution (30 mL) of gabapentin hydrochloride (1.04 g, 6 mmol) and sodium hydroxide (0.4 g, 10 mmol). The reaction was stirred at 22-25 °C for 16 h. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 0.5M aqueous citric acid (2 x 100 mL) and water (2 x 100 mL). The organic phase was separated, dried ( _MgSO4 ), filtered and concentrated under reduced pressure. The residue was dissolved in trifluoroacetic acid (40 mL) and left standing at 22-25 °C for 2 h. The solvent was removed under reduced pressure. The residue was dissolved in water (4 mL), filtered with a 0.25 μM nylon membrane filter, then passed through HPLC (Phenomenex 250×21.2 mm, with a 5 μm LUNAC18 column, 100% water for 5 minutes, and then 0-60 % acetonitrile and 0.05% TFA at a rate of 20 mL/min for 20 minutes). The pure fractions were combined and the solvent was removed under reduced pressure to give 1.7 g (70%) of the title compound (109) as a white solid. MS (ESI) m/z 397.02, 399.01 (M+H ⁺ ).

Step B: 1-{[N-[(α-isobutyryloxyethoxy)carbonyl]-4-bromophenylalanine amino

Methyl}-1-cyclohexaneacetic acid (108)

To a stirred suspension of (109) (200 mg, 0.51 mmol) in dichloromethane at 0 °C was added triethylamine (141 μL, 1.01 mmol) and trimethylchlorosilane (129 mL, 1.01 mmol). The resulting mixture was stirred at 0°C for 15 minutes and a solution of α-isobutyryloxyethyl-p-nitrophenyl carbonate (111) (144 mg, 0.51 mmol) in dichloromethane was added. The mixture was stirred at room temperature for 7 h (monitored by LC/MS), then the reaction mixture was diluted with dichloromethane and acidified with citric acid. _The organic layer was separated, washed with brine, and dried over _Na2SO4 . After filtration and concentration, the crude product was purified by preparative LC/MS to afford 92 mg of the title compound. ¹ H-NMR (CD ₃ OD, 400MHz): δ1.10(M, 6H), 1.46-1.25(m, 13H), 2.20(m, 2H), 2.48(M, 1H), 2.84(m, 1H) , 3.06(M, 1H), 3.17(M, 1H), 4.36(m, 1H), 6.67(q, J=5.6Hz, 1H), 7.17(d, J=2.0, 8.0Hz, 2H), 7.42( DD, J = 2.0, 8.0 Hz, 2H).

Example 32

3-{[(α-isobutyryloxyethoxy)carbonyl]aminomethyl}-5-methylhexanoic acid (110)

Step A: α-isobutyryloxyethyl-p-nitrophenyl carbonate (111)

A solution of 1-chloroethyl-p-nitrophenyl carbonate (57) (2.0 g, 8.14 mmol) and mercuric isobutyrate (6.13 g, 16.29 mmol) in dichloromethane (10 mL) was dissolved at 45° C. Under stirring for 24h. The reaction was then cooled to room temperature and diluted with hexanes to precipitate mercury salts. The precipitate was filtered through a pad of celite, and the filtrate was concentrated under vacuum to give 2.5 g of crude product. The residue was chromatographed on silica gel eluting with a gradient of 10% dichloromethane/hexane to 20% dichloromethane/hexane to afford 1.2 g (52%) of the title compound. ¹ H-NMR (CDCl ₃ , 400MHz): δ1.21-1.99 (M, 6H), 1.62 (d, J=5.6Hz, 3H), 2.61 (M, 1H), 6.84 (q, J=5.6Hz, 1H), 7.41 (dt, J=6.8, 2.4Hz, 2H), 8.29 (dt, J=6.8, 2.4Hz, 2H).

Step B: 3-{[(α-isobutyryloxyethoxy)carbonyl]aminomethyl-5-methylhexanoic acid

(110)

To a stirred suspension of pregabalin (2) (150 mg, 0.94 mmol) in anhydrous dichloromethane (10 mL) was added triethylamine (0.26 mL, 1.88 mmol) and trimethylchlorosilane (0.24 mL, 1.88 mmol). After stirring at 0 °C for 15 minutes, a solution of α-isobutyryloxyethyl-p-nitrophenyl carbonate (111) (267 mg, 0.94 mmol) in dichloromethane (3 mL) was added. The resulting mixture was stirred at room temperature for 1.5 h. The reaction mixture was acidified with citric acid and extracted with dichloromethane. _The combined organic extracts were washed with brine and dried over _Na2SO4 . After filtration and evaporation, the crude product was purified by silica gel chromatography, eluting first with dichloromethane to remove the nitrophenol, then with 30% ethyl acetate in dichloromethane to give 130 mg (48%) of the title compound, It is a mixture of two diastereoisomers. ¹ H-NMR (CDCI ₃ , 400MHz): δ0.90 (m, 6H), 1.70 (M, 8H), 1.46 (d, J=5.6HZ, 3H), 1.66 (1H, M), 2.15 (M, 1H), 2.33(M, 2H), 2.53(m, 1H), 3.12(m, 1H), 3.29(M, 1H), 5.08(t, J=6.0Hz, 1H), 6.79(M, 1H).

Example 33

3-{[(α-isobutyryloxyisobutoxy)carbonyl]aminomethyl}-5-methyl-hexanoic acid (112)

Step A: 1-Chloro-2-methylpropyl-p-nitrophenyl carbonate (113)

To an ice-cold reaction mixture containing p-nitrophenol (4.06 g, 29 mmol) and 1-chloro-2-methylpropyl chloroformate (5.0 g, 29 mmol) in dichloromethane (200 mL) was added in Solution of pyridine (2.78 mL, 32 mmol) in dichloromethane (50 mL). The mixture was stirred at 0 °C for 30 min, then at room temperature for 1 h. After evaporation of the solvent under reduced pressure, the residue was dissolved in ether and washed with water, 10% citric acid and again with water. The ether layer was separated, dried over _Na2SO4 , and evaporated _under reduced pressure to give 7.9 g (100%) of the title compound as a beige solid. ¹ H NMR (CDCl ₃ , 400MHz): δ1.12(d, J=6.6Hz, 3H), 1.13(d, J=6.6Hz, 3H), 2.29(M, 1H), 6.24(d, J=4.8 Hz, 1H), 7.42 (d, J=9.2Hz, 2H), 8.28 (d, J=9.2Hz, 2H).

Step B: α-isobutyryloxyisobutyl-p-nitrophenyl carbonate (114)

Following the preparation of (111), substituting (113) for (57), the title compound was obtained in 15% yield with 70% recovery of starting material. ¹ H-NMR (CDCl ₃ , 400MHz): δ1.07(d, J=6.8Hz), 1.21(M, 6H), 2.18(M, 1H), 2.26(M, 1H), 6.60(d, J= 5.2Hz, 1H), 7.42(M, 2H), 8.28(M, 2H).

Step C: 3-{[(α-isobutyryloxyisobutoxy)carbonyl]oxymethyl}-5-methyl-hexanoic acid

(112)

Following the preparation of (110) and substituting (114) for (111), the title compound was obtained as a mixture of two diastereoisomers in 51% yield. ¹ H-NMR (CDCl ₃ , 400MHz): δ0.89(m, 12H), 1.17(m, 8H), 1.65(m, 1H), 2.02(m, 1H), 2.16(m, 1H), 2.33( m, 2H), 2.56(m, 1H), 3.13(m, 1H), 3.30(m, 1H), 5.00(m, 1H), 6.57-6.56(m, 1H).

Example 34

3-{[(α-Benzoyloxyisobutoxy)carbonyl]aminomethyl-5-methyl-hexanoic acid (115)

Step A: α-Benzoyloxyisobutyl-p-nitrophenyl carbonate (116)

Following the preparation of (111), substituting (113) for (57) and mercury benzoate for mercury isobutyrate, the title compound was obtained in 11% yield and 50% recovery of starting material. ¹ H-NMR (CDCl ₃ , 400MHz): δ1.15(d, J=3.2Hz, 3H), 1.16(d, J=3.2Hz, 3H), 2.30(m, 1H), 6.87(d, J= 4.4Hz, 1H), 7.42(dd, J=7.2, 2.0Hz, 2H), 7.48(t, J=7.6Hz, 2H), 7.62(t, J=7.6Hz, 1H), 8.09(dd, J= 8.0, 1.0 Hz, 2H), 8.27 (dd, J=7.2, 2.0 Hz, 2H).

Step B: 3-{[(α-Benzoyloxyisobutoxy)carbonyl]aminomethyl}-5-methyl-hexanoic acid

(115)

Following the preparation of (110) and substituting (116) for (111), the title compound was obtained as a mixture of two diastereoisomers in 58% yield. ¹ H-NMR (CDCl ₃ , 400MHz): δ0.87(m, 6H), 1.05(m, 6H), 1.16(m, 2H), 1.64(m, 1H), 2.17(m, 2H), 2.32( m, 2H), 3.12(m, 1H), 3.29(m, 1H), 5.01(br s, 1H), 6.82(m, 1H), 7.44(m, 2H), 7.57(m, 1H), 8.05( m, 2H).

Example 35

1-{[((5-methyl-2-oxo-1,3-dioxol-4-en-4-yl)methoxy)carbonyl]ammonia

Methyl}-1-cyclohexaneacetic acid (117)

Step A: Benzyl 2-diazo-3-oxo-butanoic acid (118)

To a solution of benzyl acetoacetate (5.0 g, 26.01 mmol) and 4-acetamido-benzenesulfonyl azide (6.25 g, 26.01 mmol) in acetonitrile (200 mL) was added dropwise triethyl Amine (10.9 mL, 78.03 mmol). The resulting mixture was stirred at 0 °C for 30 min and at room temperature for 4 h. After concentration under reduced pressure, the residue was triturated with 2:1 diethyl ether/petroleum ether (3 x 100 mL). The combined organic extracts were filtered through a pad of Celite truncated with silica gel. The solvent was removed under reduced pressure to give 4.74 g of the title compound as beige crystals. ¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.49 (s, 3H), 5.27 (s, 2H), 7.38 (M, 5H).

Step B: Benzyl 2-hydroxy-3-oxo-butanoic acid (119)

A solution of diazo compound (118) (4.74 g, 21.74 mmol) in THF (110 mL) and H ₂ O (50 mL) was heated at reflux with Rh ₂ (OAc) ₂ (77 mg, 0.17 mmol) for 4 hours, and cool to room temperature. The mixture was concentrated under vacuum, and the aqueous residue was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over _Na2SO4 , filtered, and concentrated _in vacuo to afford 4.5 g of crude product. ¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.28 (s, 3H), 3.90 (s, 1H), 4.82 (s, 1H), 5.26 (m, 2H), 7.37 (m.5H).

Step C: 4-Benzyloxycarbonyl 5-methyl-2-oxo-1.3-dioxol-4-ene (120)

To a suspension of carbonyldiimidazole (6.88 g, 42.45 mmol) in THF (50 mL) was added a solution of alcohol (119) (4.50 g, 21.22 mmol) in anhydrous THF (50 mL) at 0°C. The resulting mixture was stirred at 0°C for 5 hours and at room temperature overnight. The mixture was concentrated in vacuo and the residue was partitioned with water and ethyl acetate/hexanes. The organic layer was separated, washed with saturated _NH4Cl , brine, and _dried over _Na2SO4 . After filtration and concentration, the crude product was purified by flash chromatography on silica gel eluting with 20% ethyl acetate in hexanes to afford 2.6 g of the title compound. ¹ H-NMR (CDCl ₃ , 400 MHz): δ 2.48 (s, 3H), 5.27 (s, 2H), 7.37 (br.s, 5H).

Step D: 5-Methyl-2-oxo-1.3-dioxol-4-enyl-4-carboxylic acid (121)

To a solution of compound (120) (2.6 g, 10.92 mmol) in 50 mL of ethanol was added 260 mg of PD/C (5%), and the resulting mixture was stirred under a hydrogen atmosphere for 1 h. Filtration and removal of solvent under reduced pressure gave 1.62 g of the title compound. ¹ H-NMR (CD ₃ OD, 400 MHz): δ2.41 (s, 3H).

Step E: 4-Hydroxymethyl-5-methyl-2-oxo-1.3-dioxol-4-ene (122)

To a solution of acid (121) (1.62 g, 11.10 mmol) and dry DMF (112 μL) in dry dichloromethane (50 mL) was added oxalyl chloride (6.1 mL, 2M solution, 12.2 mmol) dropwise at 0°C. After stirring at 0 °C for 30 minutes and at room temperature for 1 h, the solvent was removed under reduced pressure. The residue was dissolved in anhydrous dichloromethane (65 mL), and cooled to -78°C. To this solution was added a solution of _Bu4NBH4 (3.14 _g , 12.2 mmol in 20 mL of dichloromethane) dropwise over 10 min. After stirring at -78 °C for 1 h, the mixture was carefully quenched with 0.1 N HCl (30 mL) and allowed to warm to room temperature. The aqueous layer was separated, extracted with EtOAc (3 x 50 _mL ), the combined organic extracts were washed with brine, and dried over _Na2SO4 . After removal of the solvent under reduced pressure, column chromatography on silica gel eluting with 50% EtOAc in dichloromethane afforded 767 mg of the title compound. ¹ H-NMR (CD ₃ OD, 400 MHz): δ 2.09 (s, 3H), 4.34 (s, 2H).

Step F: 1-{[((5-Methyl-2-oxo-1,3-dioxol-4-en-4-yl)methoxy)

Carbonyl]-aminomethyl}-1-cyclohexane benzyl acetate (123)

A suspension of alcohol (122) (767 mg, 5.9 mmol) and benzyl 1-isocyanatomethyl-1-cyclohexaneacetate (5.9 mmol) in toluene was refluxed overnight. After removal of the solvent under reduced pressure, the residue was purified by flash column chromatography eluting with 30% EtOAc in hexanes to afford 510 mg of the title compound. ¹ H-NMR (CD ₃ OD, 400MHz): δ1.58-1.30 (m, 10H), 2.18 (s, 3H), 2.35 (s, 2H), 3.17 (d, J=6.8Hz, 2H), 4.80 (s, 2H), 5.11 (s, 2H), 5.44 (t, J=6.8Hz, 1H), 7.36 (m, 5H).

Step G: 1-{[((5-Methyl-2-oxo-1.3-dioxol-4-en-4-yl)methoxy)carbonyl

Base]-aminomethyl}-1-cyclohexaneacetic acid (117)

To a solution of compound (123) (510 mg, 1.41 mmol) in ethanol (20 mL) was added 59 mg of PD/C (5%), and the resulting mixture was stirred under a hydrogen atmosphere for 1 h. Filtration and removal of volatiles under reduced pressure gave the crude product, which was purified by preparative LC/MS to give 105 mg of the title compound. ¹ H-NMR (CD ₃ OD, 400MHz): δ1.52-1.36(m, 10H), 2.16(s, 3H), 2.27(s, 2H), 3.22(s, 2H), 4.86(s, 2H) .

Example 36

1-{(1-Methyl-3-oxo-butan-1-carbonyl)aminomethyl}-1-cyclohexanepiperidinium acetate

(124)

2,4-Pentanedione (103 μL, 1 mmol), gabapentin (171 mg, 1 mmol) and piperidine (99 μL, 1 mmol) were mixed into anhydrous methanol (10 mL). The resulting mixture was heated to reflux for 4h. The solvent was removed under reduced pressure to give the title compound with a purity greater than 90% ¹ H NMR (CDCl ₃ , 400 MHz): δ 1.34-1.62 (M, 12H), 1.71 (M, 4H), 1.94 (s, 3H), 1.96 ( s, 3H), 2.26(s, 2H), 2.98(M, 4H), 3.38(d, J=6Hz, 2H), 4.90(s, 1H), 5.20(s, br, 2H), 8.64(t, J = 6 Hz, 1H). MS (ESI) m/z 252.35 (MH ^- ).

Example 37

1-1-{[(2-oxo-tetrahydrofuran-3-ylidene)ethyl]aminomethyl}-1-cyclohexaneacetic acid

Piperidinium (125)

2-Acetylbutyrolactone (108 μL, 1 mmol), gabapentin (171 mg, 1 mmol) and piperidine (99 μL, 1 mmol) were mixed into anhydrous methanol (10 mL). After heating at reflux for 6 h, the solvent was removed under reduced pressure to afford the title compound with a purity greater than 90%. ¹ H NMR (CDCl ₃ , 400MHz): δ1.34-1.62(m, 12H), 1.71(m, 4H), 1.94(s, 3H), 2.24(s, 2H), 2.81(T, J=7.6Hz , 2H), 2.99(M, 4H), 3.31(d, J=6.4Hz, 2H), 4.23(t, J=7.6Hz, 2H), 5.17(s, br, 2H), 8.64(t, J= 6.4 Hz, 1H). MS (ESI) m/z 280.34 (MH-).

Example 38

1-{(2-Carbonmethoxy-cyclopent-1-enyl)aminomethyl}-1-cyclohexanepiperidinium acetate

(126)

Methyl 2-oxocyclopentanecarboxylate (124 μL, 1 mmol), gabapentin (171 mg, 1 mmol) and piperidine (99 μL, 1 mmol) were mixed into anhydrous methanol (10 mL). After heating to reflux for 16 h, the solvent was removed under reduced pressure to obtain the title compound with a purity greater than 90%. ¹ H NMR (CDCl ₃ , 400MHz): δ1.29-1.60(M, 12H), 1.72(M, 4H), 1.79(M, J=7.6Hz, 2H), 2.24(s, 2H), 2.49(t , J=7.6Hz, 2H), 2.55(t, J=7.6Hz, 2H), 2.99(M, 4H), 3.24(d, J=6.8Hz, 2H), 3.63(s, 3H), 5.06(s , br, 2H), 7.93 (s, br, 1H). MS (ESI) m/z 294.36 (MH-).

Example 39

1-{(1-methyl-2-(ethoxycarbonyl)-3-ethoxy-3-oxoprop-1-enyl)aminomethyl

Base}-1-cyclohexane piperidinium acetate (127)

Diethyl acetylmalonate (202 mg, 1 mmol), gabapentin (171 mg, 1 mmol) and piperidine (99 μL, 1 mmol) were mixed into absolute ethanol (10 mL). After heating to reflux for 16 h, the solvent was removed under reduced pressure to obtain the title compound with a purity greater than 90%. ¹ H NMR (CDCl ₃ , 400MHz): δ1.28(t, J=7.2Hz, 6H), 1.38-1.64(m, 12H), 1.75(m, 4H), 1.96(s, 3H), 2.23(s , 2H), 2.99(m, 4H), 3.24(d, J=5.2Hz, 2H), 4.20(q, J=7.2Hz, 4H), 4.35(s, br, 2H), 7.79(t, J= 5.2 Hz, 1H). MS (ESI) m/z 354.38 (MH ^- ).

Example 40

1-{[(α-(2-(2-methyl-1,3-dioxolan-2-yl)carboxyisobutoxy)carbonyl]-amino

Methyl}-1-cyclohexaneacetic acid (128)

Step A: 2-Methyl-1,3-dioxolane-2-carboxylic acid (129)

To a stirred mixture containing ethyl pyruvate (11.1 mL, 0.1 mol) and ethylene glycol (5.6 mL, 0.1 mol) in anhydrous dichloromethane (100 mL) was added boron trifluoride diether at 0 °C mixture (6.4 mL, 0.05 mol) and a catalytic amount of acetic acid. The resulting mixture was stirred at 40 °C for 16 h, then diluted with 100 mL of dichloromethane. The organic solution was washed successively with saturated sodium chloride solution (2 x 80 mL). The organic layer was separated, and the combined organic extracts were concentrated. The residue was treated with 1N sodium hydroxide at room temperature. After stirring at room temperature for 3 h (monitored by TLC), the pH was adjusted to 4 by adding citric acid. The product was extracted with _{dichloromethane} , dried over _Na2SO4 , and concentrated to give 5.1 g (38%) of the title compound (129) as a clear liquid. This material was used in the next reaction without further purification. ¹ H NMR (CDCl ₃ , 400 MHz): 51.55 (s, 3H), 4.03 (m, 4H).

Step B: Benzyl 1-{[(α-(2-(2-methyl-1,3-dioxolan-2-yl)carboxyisobutoxy

Base) carbonyl] aminomethyl}-1-cyclohexane acetic acid benzyl ester (130)

Benzyl 1-{[(α-chloroisobutoxy)carbonylaminomethyl}-1-cyclohexaneacetate (95) (1 g, 2.53 mmol), (129) ( A mixture of 673 mg, 5.1 mmol), silver carbonate (557 mg, 2.53 mmol) and triethylamine (709 μl, 5.1 mmol) was stirred for 16 h. After filtration, the filtrate was concentrated. The resulting residue was purified by silica gel chromatography eluting with 15% ethyl acetate/hexane to afford 510 mg (41%) of the title compound (130). MS (ESI) m/z 492.40 (M+H ⁺ ).

Step C: 1-{[(α-(2-(2-methyl-1,3-dioxolan-2-yl)carboxyisobutoxy)carbonyl

Base]-aminomethyl}-1-cyclohexaneacetic acid (128)

A mixture of (130) (470 mg, 0.96 mmol) and 5% Pd—C (catalytic amount) in ethanol was stirred at room temperature under hydrogen atmosphere for 16 h. Filtration and concentration afforded 382 mg (100%) of the title compound (128). ¹ H NMR (CDCl ₃ , 400MHz): δ0.96(d, J=6.8Hz, 3H), 0.97(d, J=6.8Hz, 3H), 1.32-1.58(m, 10H), 1.59(s, 3H ), 2.06(M, 1H), 2.32(s, 2H), 3.26(m, 2H), 4.08(M, 4H), 5.29(t, 1H, NH), 6.55(d, J=4.8Hz, 1H) .MS (ESI) m/z 402.32 (M+H ⁺ ). The acid form was quantitatively converted to the corresponding sodium salt by dissolving in water (5 mL), adding an equimolar amount of 0.5N _NaHCO3 , and then lyophilizing.

Example 41

In vitro assay of Caco-2 cell permeability of prodrugs

The passive permeability of the prodrugs of the invention can be assessed in vitro using methods known in the art (see eg Stewart et al., PHARM. RES., 1995, 12, 693). For example, permeabilization can be assessed by examining the flow of the prodrug through a cultured monolayer of polarized cells (eg, Caco-2 cells). Caco-2 cells (passage less than 28) from continuous culture were seeded at high density onto Transwell polycarbonate filters. The cells were fed with DMEM/10% fetal calf serum + 0.1 mM non-essential amino acids + 2 mM L-GLn, 5% CO ₂ /95%, 37°C until the day of the experiment. In the presence of overflow pump inhibitors (250 μM MK-571, 250 μM verapamil, 1 mM ofloxacin), at pH 6.5 and on top (in the presence of 1 mM CaCl ₂ , 1MM MgCl ₂ , 150 mM NaCl, 3 mM KCl , 1 mM NaH ₂ PO ₄ , 5 mM glucose in 50 mM MES buffer) and on the bottom side (in Hanks mean salt solution containing 10 mM HEPES) at pH 7.4. Inserts were placed in 12- or 24-well plates containing buffer and incubated at 37°C for 30 min. The prodrug (200 μM) was added to the top and bottom side compartments (donor), and the prodrug and/or released prodrug in the opposite compartment (acceptor) was measured at 1 hour intervals using LC/MS/MS. Concentration of parent drug. Calculate the apparent permeability value (Papp) using the following equation:

P _app =V _r (dC/dt)//(AC ₀ )

Here _Vr is the volume of the receiving compartment in mL; dC/dt is the flux (μM/S) of the prodrug and parent drug, which is determined from the slope of the curve of concentration versus time in the receiving compartment; C ₀ is the initial concentration of prodrug in μM; A is the membrane surface area in ^cm2 . Preferably prodrugs with significant permeability across cells exhibit a P _app value > 1 x 10 ^-6 cm/s, more preferably a P _app value > 1 x 10 ^-6 cm/s, still more preferably P A _value of ≥5×10 ⁻⁵ cm/s. Typical P _values obtained for prodrugs of GABA analogs are shown in the table below: compound P _app (top to bottom side)(cm/s) P _app (bottom side to top)(cm/s) Ratio AB/BA (51) 1.06×10 ^-4 1.25×10 ^-5 8.5 (56) 3.1×10 ^-5 2.0×10 ^-6 15.5 (62) 2.10×10 ^-5 6.40×10 ^-6 3.3 (68) 8.43×10 ^-5 2.26×10 ^-5 3.7 (69) 1.84×10 ^-4 5.22×10 ^-6 35.2 (70) 1.78×10 ^-5 1.68×10 ^-6 10.6 (71) 8.10×10 ^-5 1.99×10 ^-5 4.1 (72) 2.51×10 ^-5 1.26×10 ^-6 2.0 (77) 7.41×10 ^-5 1.43×10 ^-5 5.2 (78) 1.37×10 ^-4 2.46×10 ^-6 5.6 (80) 6.62×10 ^-5 8.75×10 ^-6 7.6 (81) 8.65×10 ^-5 1.27×10 ^-5 6.8 (82) 1.25×10 ^-4 1.82×10 ^-6 6.9 (83) 1.29×10 ^-5 4.48×10 ^-5 0.3 (84) 1.26×10 ^-4 1.57×10 ^-5 8.1 (89) 5.85×10 ^-5 2.34×10 ^-6 25.0 (90) 9.22×10 ^-5 5.75×10 ^-6 16.0

The data in this table indicate that the prodrugs disclosed herein are highly cell permeable and should be well absorbed by the intestine. With the exception of compound (83), the top-to-bottom side permeability of the prodrugs exceeded their bottom-side to top permeability. This suggests that these compounds may be substrates for an active transport mechanism present in the apical membrane of Caco cells (although some components of this permeability across the cell are regulated by passive diffusion). The greater bottom-to-top permeability of (83) indicated that this compound could flow through the bottom-side membrane despite the presence of the efflux pump inhibitors MK-571, verapamil and ofloxacin.

Example 42

Gabapentin following intracolonic administration of gabapentin or a gabapentin prodrug to rats

Absorption

Sustained-release oral dosage forms, which release the drug slowly over a period of 6-24 hours, generally deliver a substantial dose in the colon. Drugs suitable for use in such dosage forms therefore preferably exhibit good colonic absorption. This experiment was performed to evaluate the use of gabapentin prodrugs in oral sustained release dosage forms.

Step A: Dosing regimen

Rats were obtained commercially and precannulated in the ascending colon and jugular vein. Animals were awake during the experiment. All animals were fasted overnight until 4 hours after dosing. Gabapentin or gabapentin prodrugs (59), (63), (69), (72), (77), (79), (85), (117) and A solution of (126) (in water or PEG 400) was applied directly to the colon. Blood samples (0.5 mL) were obtained from the jugular vein at intervals over 8 hours, and the reaction was stopped immediately by the addition of acetonitrile/methanol to prevent the previous step conversion of the prodrug. Blood samples were analyzed as described below.

Step B: Sample Preparation for Colonically Absorbed Drugs

1. In a blank 1.5mL eppendorf tube, add 300μL 50/50 acetonitrile/methanol and 20μL p-chlorophenylalanine as internal standard.

2. Rat blood was collected at different time points, and 100 μL of blood was immediately added to an eppendorf tube and stirred to mix.

3. Add 10 μL of gabapentin standard solution (0.04, 0.2, 1, 5, 25, 100 μg/ml) to 90 μL of blank rat blood to form the final calibration standard (0.004, 0.02, 0.1, 0.5, 2.5, 10 μg/ml) , then add 300 µL of 50/50 acetonitrile/methanol to each tube, followed by 20 µL of p-chlorophenylalanine.

4. The sample was stirred and centrifuged at 14,000 rpm for 10 minutes.

5. Take the supernatant for LC/MS/MS analysis.

Step C: LC/MS/MS Analysis

An API 2000 LC/MS/MS spectrometer equipped with a Shidmadzu 10ADVp binary pump and a CTC HTS-PAL autosampler was used for the analysis. A Zorbax XDB C8 4.6 x 150mm column was heated to 45°C during the analysis. The mobile phases were 0.1% formic acid (A) and acetonitrile with 0.1% formic acid (B). Gradient conditions were: 5% B for 1 minute, then 98% B for 3 minutes, then hold 98% B for 2.5 minutes. Return the mobile phase to 5% B and elute for 2 min. Use TurboIonSpray source for API 2000. The analysis was done in positive ion mode and MRM transitions 172/137 were used for the analysis of gabapentin (MRM transitions used were 426/198 for (59), 364/198 for (63), 392/198 for (69), 316/198 for (72), 330/198 for (77), 330/198 for (79), 316/198 for (85) and 327.7/153.8 for (117)). Inject 20 μL of sample. The peaks were integrated using Analyst 1.1 quantitative software. Following colonic administration of each of these prodrugs, the maximum plasma concentration (C _max ) of gabapentin and the area under the time curve (AUC) of the plasma concentration of gabapentin were significantly greater (>2-fold) than that produced by colonic administration of gabapentin itself. The area under the curve of . For example, the prodrug (77) provided gabapentin _Cmax and AUC values 10-fold greater than gabapentin itself. This data suggests that the compounds of the invention can be formulated in compositions suitable for enhanced absorption and/or effective sustained release of the GABA analog, thereby minimizing dosing frequency due to the rapid systemic clearance of the GABA analog.

Example 43

Sustained release of gabapentin following prodrug administration to hunting dogs using a mini pump

Dissolve gabapentin or gabapentin prodrugs (77) and (82) (at a dose equal to 10 mg gabapentin/kg) in a suitable solvent (e.g. water, PEG 400, etc.) and fill it into pre-weighed Alzet® mini osmotic Pump unit (Model 2001D) (Durect Corp., Cupertino, CA). Pre-equilibration was performed by soaking the filled Alzet(R) in permeate saline for 3 hours at 37°C and stored overnight at 4°C in a sealed container. Four fasting male hounds were then administered orally (approximately 6.5 kg). Animals were fed 4 hours after each dose. Blood samples (1.0 mL) were taken at intervals over 48 hours, and plasma was processed immediately. Plasma samples were lyophilized and stored at -80°C until analysis using the method described above. Both prodrugs provided plasma concentrations of gabapentin at 12 hours post-dose that were 2-fold greater than those seen after administration of gabapentin itself in the Alzet(R) device. This data further demonstrates that the compounds of the invention can be formulated into compositions suitable for effective sustained release of GABA analogs.

Example 44

Intracolonic pregabalin or pregabalin prodrug administration in rats

absorb

The protocol of Example 41 was repeated with pregabalin and pregabalin prodrugs (110) and (112). Following colonic administration of each of these prodrugs, the maximum plasma concentration ( _Cmax ) of pregabalin and the area under the pregabalin plasma concentration versus time curve (AUC) were significantly greater than the area under the curve produced by colonic administration of pregabalin itself (> 2 times).

Finally, it should be noted that there are alternative ways of implementing the invention. Accordingly, the present embodiments are to be considered as illustrative rather than limiting, and the invention is not to be limited by the details presented herein but may be modified within the scope and equivalents of the appended claims.

All publications and patents cited herein are incorporated by reference in their entirety.

Claims (117)

1. Compounds of formula (I), formula (II) or formula (III) or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: m, n, t and u are independently 0 or 1; X is 0 or NR ¹⁶ ; W is O or NR ¹⁷ ; Y is O or S; R ¹ is selected from hydrogen, R ²⁴ C(O)-, R ²⁵ OC(O)-, R ²⁴ C(S)-, R ²⁵ OC(S)-, R ²⁵ SC(O)-, R ²⁵ SC( S)-, (R ⁹ O)(R ¹⁰ O)P(O)-, R ²⁵ S-,

and

Each R ^is independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkyl Amino, alkylsulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, Aryl, substituted aryl, arylalkyl, substituted arylalkyl, aryloxy, substituted aryloxy, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted Cycloheteroalkyl, dialkylamino, substituted dialkylamino, halogen, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroaryl alkyl, heteroalkoxy, substituted heteroalkoxy, heteroaryloxy and substituted heteroaryloxy, or optionally R ² and R ¹⁶ together with the atoms to which they are bound form a cycloheteroalkyl or substituted cycloheteroalkyl ring; R ^{and R} are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, ring Heteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R and ^R are independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl ^, cycloheteroalkane radical, substituted cycloheteroalkyl, heteroarylalkyl and substituted heteroarylalkyl, or optionally R and ^R together with the carbon atoms to which they are bound form cycloalkyl, substituted ^cycloalkyl , Cycloheteroalkyl, substituted cycloheteroalkyl, or bridged cycloalkyl rings; R ^{and R} are independently selected from hydrogen, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, Substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, hetero Arylalkyl and substituted heteroarylalkyl, or optionally ^R and ^R together with the carbon atom to which they are bound form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkane base ring; ^R is selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cyano, cycloalkyl , substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, alkoxycarbonyl, substituted Alkoxycarbonyl, cycloheteroalkoxycarbonyl, substituted cycloheteroalkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, heteroaryloxycarbonyl, substituted heteroaryloxycarbonyl, and nitro; R ⁷ , R ⁹ , R ¹⁰ , R ¹⁵ , R ¹⁶ and R ¹⁷ are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl , cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; R and ^R are independently selected from hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl ^, substituted aryl, arylalkyl, substituted arylalkyl , carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroaryl Alkyl, or optionally R and ^R together with the carbon atoms ^to which they are bound form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R and ^R are independently selected from hydrogen, acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl ^, substituted arylalkyl, cycloalkyl, substituted Cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl , or optionally R ²⁰ and R ²¹ and the carbon atoms to which they are bound together form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R ²² and R ²³ are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, and substituted arylalkyl, or optionally R ²² and R ²³ and their The bonded carbon atoms are taken together to form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; ^R is selected from hydrogen, acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, Cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; ^R is selected from acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cyclohetero Alkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; and The provisos are: When R ³ and R ⁶ are both hydrogen, R ⁴ and R ⁵ are not both hydrogen or not all methyl; In the compound of formula (I), when n is 0 or when n is 1, and X is NR ¹⁶ , R ¹ is not hydrogen; In compounds of formula (I), none of R ¹ , R ⁷ O-, R ²⁴ C(O)-, R ²⁵ C(O)- and R ²⁵ O- is a bile acid-derived moiety; In the compound of formula (I), when R ¹ is R ²⁴ C(O)- and n is 0, R ²⁴ is not methyl, tert-butyl, 2-aminoethyl, 3-aminopropyl, benzyl phenyl, phenyl or 2-(benzoylmethyl)phenyl; In the compound of formula (I), when R ¹ is R ²⁵ OC(O)-, R ²⁵ is not R ²⁶ C(O)CR ¹³ R ¹⁴ -, wherein R ²⁶ is selected from hydrogen, alkyl, substituted Alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; In the compound of formula (I), when R ¹ is R ²⁵ OC (O)- and n is 0, R ²⁵ is not methyl, tert-butyl or benzyl; In the compound of formula (I), when n is 0 and R ¹ is R ²⁵ C(O)OCR ¹³ R ¹⁴ OC(O)-, if either R ¹³ or R ¹⁴ is hydrogen, alkoxycarbonyl , substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, then the other of R ¹³ or R ¹⁴ is not hydrogen; In the compound of formula (I), when n is 1, X is NH, R ³ , R ⁵ and R ⁶ are each hydrogen, and R ⁴ is cyclohexyl, R ² is not benzyl; In a compound of formula (II), when t is 1 and u is 0, neither R nor R is ² -hydroxyl-3- ^methyl -5-chlorophenyl; and In compounds of formula (II), t is 1 when u is 1 and X is 0. 2. The compound of claim 1 having the formula (I):

3. The compound of claim 1, wherein R is selected from ^{the group} consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted ring Alkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl. 4. The compound of claim 1, wherein Y is O and ^R7 is hydrogen. 5. The compound of claim 1, wherein Y is O, and R is ^alkanyl , substituted alkanyl, alkenyl, substituted alkenyl, aryl, or substituted aryl. 6. The compound of claim 5, wherein R ⁷ is methyl, ethyl, benzyl, -C(CH ₃ )=CH ₂ , -CH ₂ C(O)N(CH ₃ ) ₂ , or

wherein V is O or CH ₂ . 7. The compound of claim 1, wherein n is zero. 8. The compound of claim 1, wherein n is 1 and X is NH. 9. The compound of claim 8, wherein R ^is selected from hydrogen, alkanyl, substituted alkanyl, aryl, substituted aryl, arylalkanyl, substituted arylalkanyl, cycloalkyl , heteroarylalkyl, and substituted heteroarylalkanyl. 10. The compound of claim 8, wherein ^R is selected from hydrogen, alkanyl and cycloalkyl. 11. The compound of claim 10, wherein ^R is selected from hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl and cyclohexyl. 12. The compound of claim 8, wherein ^R2 is selected from substituted alkanyl. 13. The compound of claim 12, wherein ^R2 is selected from the _group consisting _{of -CH2OH} , -CH(OH) _CH3 , _{-CH2CO2H , -CH2CH2CO2H} , _{-CH2CONH2 ,} -CH ₂ CH ₂ CONH ₂ , —CH ₂ CH ₂ SCH ₃ , CH ₂ SH, —CH ₂ (CH ₂ ) ₃ NH ₂ , and —CH ₂ CH ₂ CH ₂ NHC(NH)NH ₂ . 14. The compound of claim 8, wherein R ^is selected from the group consisting of aryl, arylalkalkyi, substituted arylalkalkyi and heteroarylalkalkyi. 15. The compound of claim 14, wherein ^R is selected from the group consisting of phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl and 2-indolyl. 16. The compound of claim 1, wherein n is 1, X is ^NR16 , and ^R2 and ^R16 together with the atoms to which they are bound form a cycloheteroalkyl or substituted cycloheteroalkyl ring. 17. The compound of claim 16, wherein ^R2 and ^R16 and the atoms to which they are bonded together form an azetidine, pyrrolidine or piperidine ring. 18. The compound of claim 1, wherein R ^{and R} are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, and substituted cycloalkyl. 19. The compound of claim 1, wherein ^R3 and ^R6 are independently selected from hydrogen and alkanyl. 20. The compound of claim 1, wherein ^R3 and ^R6 are both hydrogen. 21. The compound of claim 1, wherein R ^and R are ^{independently} selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl , substituted cycloheteroalkyl, heteroaryl, and substituted heteroaryl. 22. The compound of claim 1, wherein ^R4 and ^R5 are independently selected from hydrogen, alkanyl and substituted alkanyl. 23. The compound of claim 1, wherein R ⁴ is hydrogen and R ⁵ is selected from C _1-6 alkanyl. 24. The compound of claim 1, wherein ^R4 and ^R5 together with the carbon atom to which they are bound are cycloalkyl or substituted cycloalkyl. 25. The compound of claim 1, wherein R ^{and R} , together with the carbon atoms to which they are bound, are a group selected from the group consisting of cyclobutyl, substituted cyclobutyl, cyclopentyl, substituted cyclopentyl, Cyclohexyl and substituted cyclohexyl. 26. The compound of claim 1, wherein ^R4 and ^R5 together with the carbon atom to which they are bound are cycloheteroalkyl or substituted cycloheteroalkyl. 27. The compound of claim 1, wherein ^R4 and ^R5 together with the carbon atom to which they are bound are a bridged cycloalkyl group. 28. A compound of claim 1 or 2 derived from a GABA analog of formula (XIII):

Wherein the GABA analog of formula (XIII) is selected from: 1-Aminomethyl-1-cyclohexaneacetic acid; 1-Aminomethyl-1-(3-methylcyclohexane)acetic acid; 1-Aminomethyl-1-(4-methylcyclohexane)acetic acid; 1-Aminomethyl-1-(4-isopropylcyclohexane)acetic acid; 1-Aminomethyl-1-(4-tert-butylcyclohexane)acetic acid; 1-aminomethyl-1-(3,3-dimethylcyclohexane)acetic acid; 1-aminomethyl-1-(3,3,5,5-tetramethylcyclohexane)acetic acid; 1-Aminomethyl-1-cyclopentaneacetic acid; 1-Aminomethyl-1-(3-methylcyclopentane)acetic acid; 1-aminomethyl-1-(3,4-dimethylcyclopentane)acetic acid; 7-Aminomethyl-bicyclo[2.2.1]hept-7-ylacetic acid; 9-Aminomethyl-bicyclo[3.3.1]non-9-ylacetic acid; 4-Aminomethyl-4-(tetrahydropyran-4-yl)acetic acid; 3-aminomethyl-3-(tetrahydropyran-3-yl)acetic acid; 4-Aminomethyl-4-(tetrahydrothiopyran-4-yl)acetic acid; 3-Aminomethyl-3-(tetrahydrothiopyran-3-yl)acetic acid; 3-Aminomethyl-5-methyl-hexanoic acid; 3-Aminomethyl-5-methyl-heptanoic acid; 3-Aminomethyl-5-methyl-octanoic acid; 3-Aminomethyl-5-methyl-nonanoic acid; 3-Aminomethyl-5-methyl-decanoic acid; 3-Aminomethyl-5-cyclopropyl-hexanoic acid; 3-Aminomethyl-5-cyclobutyl-hexanoic acid; 3-Aminomethyl-5-cyclopentyl-hexanoic acid; 3-Aminomethyl-5-cyclohexyl-hexanoic acid; 3-Aminomethyl-5-phenyl-hexanoic acid; 3-Aminomethyl-5-phenyl-pentanoic acid; 3-Aminomethyl-4-cyclobutyl-butanoic acid; 3-Aminomethyl-4-cyclopentyl-butanoic acid; 3-Aminomethyl-4-cyclohexyl-butanoic acid; 3-Aminomethyl-4-phenoxy-butyric acid; 3-Aminomethyl-5-phenoxy-hexanoic acid; and 3-Aminomethyl-5-benzylsulfanyl-pentanoic acid. 29. A compound of formula (IV): or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: Y, R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ¹³ , R ¹⁴ , R ¹⁶ and R ²⁵ are as defined in claim 1; With the proviso that if either R ¹³ or R ¹⁴ is hydrogen, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, then R ¹³ or R the other of ¹⁴ is not hydrogen; and R ²⁵ C(O) is not a bile acid derived moiety. 30. The compound of claim 29, wherein Y is O and ^R7 is hydrogen. 31. The compound of claim 29, wherein Y is O and R is ^alkanyl , substituted alkanyl, alkenyl, substituted alkenyl, aryl, or substituted aryl. 32. The compound of claim 31, wherein R ⁷ is methyl, ethyl, benzyl, -C(CH ₃ )=CH ₂ , -CH ₂ C(O)N(CH ₃ ) ₂ ,

or

wherein V is O or CH ₂ . 33. The compound of claim 29, wherein n is zero. 34. The compound of claim 29, wherein n is 1 and X is NH. 35. The compound of claim 29 derived from a GABA analog of formula (XIII):

Wherein the GABA analog of formula (XIII) is selected from: 1-Aminomethyl-1-cyclohexaneacetic acid; 1-Aminomethyl-1-(3-methylcyclohexane)acetic acid; 1-Aminomethyl-1-(4-methylcyclohexane)acetic acid; 1-Aminomethyl-1-(4-isopropylcyclohexane)acetic acid; 1-Aminomethyl-1-(4-tert-butylcyclohexane)acetic acid; 1-aminomethyl-1-(3,3-dimethylcyclohexane)acetic acid; 1-aminomethyl-1-(3,3,5,5-tetramethylcyclohexane)acetic acid; 1-Aminomethyl-1-cyclopentaneacetic acid; 1-Aminomethyl-1-(3-methylcyclopentane)acetic acid; 1-aminomethyl-1-(3,4-dimethylcyclopentane)acetic acid; 7-Aminomethyl-bicyclo[2.2.1]hept-7-ylacetic acid; 9-Aminomethyl-bicyclo[3.3.1]non-9-ylacetic acid; 4-Aminomethyl-4-(tetrahydropyran-4-yl)acetic acid; 3-aminomethyl-3-(tetrahydropyran-3-yl)acetic acid; 4-Aminomethyl-4-(tetrahydrothiopyran-4-yl)acetic acid; 3-Aminomethyl-3-(tetrahydrothiopyran-3-yl)acetic acid; 3-Aminomethyl-5-methyl-hexanoic acid; 3-Aminomethyl-5-methyl-heptanoic acid; 3-Aminomethyl-5-methyl-octanoic acid; 3-Aminomethyl-5-methyl-nonanoic acid; 3-Aminomethyl-5-methyl-decanoic acid; 3-Aminomethyl-5-cyclopropyl-hexanoic acid; 3-Aminomethyl-5-cyclobutyl-hexanoic acid; 3-Aminomethyl-5-cyclopentyl-hexanoic acid; 3-Aminomethyl-5-cyclohexyl-hexanoic acid; 3-Aminomethyl-5-phenyl-hexanoic acid; 3-Aminomethyl-5-phenyl-pentanoic acid; 3-Aminomethyl-4-cyclobutyl-butanoic acid; 3-Aminomethyl-4-cyclopentyl-butanoic acid; 3-Aminomethyl-4-cyclohexyl-butanoic acid; 3-Aminomethyl-4-phenoxy-butyric acid; 3-Aminomethyl-5-phenoxy-hexanoic acid; and 3-Aminomethyl-5-benzylsulfanyl-pentanoic acid. 36. A compound of formula (VII) or (VIII): or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: n, R ² , R ⁷ , R ¹³ , R ¹⁴ , R ¹⁶ and R ²⁵ are as defined in claim 1; With the proviso that if either R ¹³ or R ¹⁴ is hydrogen, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, then R ¹³ or R the other of ¹⁴ is not hydrogen; and R ²⁵ C(O) is not a bile acid derived moiety. 37. The compound of claim 36, wherein ^R7 is hydrogen. 38. The compound of claim 36, wherein R is ^alkanyl , substituted alkanyl, alkenyl, substituted alkenyl, aryl, or substituted aryl. 39. The compound of claim 38, wherein R ⁷ is methyl, ethyl, benzyl, -C(CH ₃ )=CH ₂ , -CH ₂ C(O)N(CH ₃ ) ₂ ,

or

wherein V is O or CH ₂ . 40. The compound of claim 36, wherein n is zero. 41. The compound of claim 36, wherein n is 1. 42. The compound of claim 40, wherein R ¹³ is methyl, R ⁷ and R ¹⁴ are hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl Base, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolane -2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-di Oxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxo Pentyl-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, benzene Acetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 43. The compound of claim 40, wherein R ¹³ is ethyl, R ⁷ and R ¹⁴ are hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl Base, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolane -2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-di Oxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxo Pentyl-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, benzene Acetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 44. The compound of claim 40, wherein R ¹³ is propyl, R ⁷ and R ¹⁴ are hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl Base, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolane -2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-di Oxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxo Pentyl-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, benzene Acetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 45. The compound of claim 40, wherein R ¹³ is isopropyl, R ⁷ and R ¹⁴ are hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec Butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolyl Cyclo-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl , 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl , 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl , 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3- Dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-di Oxolane-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, Phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 46. The compound of claim 40, wherein R ¹³ is butyl, R ⁷ and R ¹⁴ are hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl Base, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolane -2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-di Oxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxo Pentyl-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, benzene Acetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 47. The compound of claim 40, wherein R ¹³ is isobutyl, R ⁷ and R ¹⁴ are hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec Butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolyl Cyclo-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl , 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl , 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl , 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3- Dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-di Oxolane-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, Phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 48. The compound of claim 40, wherein R ¹³ is sec-butyl, R ⁷ and R ¹⁴ are hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- Butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolyl Cyclo-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl , 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl , 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl , 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3- Dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-di Oxolane-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, Phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 49. The compound of claim 40, wherein R ¹³ is tert-butyl, R ⁷ and R ¹⁴ are hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec Butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolyl Cyclo-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl , 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl , 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl , 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3- Dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-di Oxolane-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, Phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 50. The compound of claim 40, wherein R ¹³ is cyclopentyl, R ⁷ and R ¹⁴ are hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec Butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolyl Cyclo-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl , 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl , 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl , 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3- Dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-di Oxolane-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, Phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 51. The compound of claim 40, wherein R ¹³ is cyclohexyl, R ⁷ and R ¹⁴ are hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl Base, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolane -2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-di Oxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxo Pentyl-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, benzene Acetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 52. The compound of claim 40, wherein R ¹³ is phenyl, R ⁷ and R ¹⁴ are hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl Base, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolane -2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-di Oxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxo Pentyl-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, benzene Acetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 53. The compound of claim 40, wherein R ¹³ is benzyl, R ⁷ and R ¹⁴ are hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl Base, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolane -2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3-di Oxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxo Pentyl-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, benzene Acetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 54. The compound of claim 40, wherein R ¹³ is phenethyl, R ⁷ and R ¹⁴ are hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec Butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolyl Cyclo-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl , 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl , 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl , 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3- Dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenylethyl, 1,1-diethoxy-2-phenylethyl, 1-(1,3-di Oxolane-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl, Phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 55. The compound of claim 40, wherein R ¹³ is 3-pyridyl, R ⁷ and R ¹⁴ are hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxo Pentyl-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutanyl base, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl Base, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1,3 -dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3- Dioxolan-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzoyl , phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 56. The compound of claim 40, wherein R ¹³ is methyl, R ¹⁴ is methyl, R ⁷ is hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl , sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-di Oxolane-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxy Propyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxy Butyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl)- Butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-(1, 3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3 -Dioxolan-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, benzyl Acyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 57. The compound of claim 40, wherein R ¹³ is methoxycarbonyl, R ¹⁴ is methyl, R ⁷ is hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, iso Butyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3 -Dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethyl Oxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethyl Oxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl )-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-( 1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1 , 3-dioxolane-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, Benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 58. The compound of claim 40, wherein R ¹³ is ethoxycarbonyl, R ¹⁴ is methyl, R ⁷ is hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, iso Butyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3 -Dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethyl Oxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethyl Oxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl )-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-( 1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1 , 3-dioxolane-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, Benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 59. The compound of claim 40, wherein R ¹³ is propoxycarbonyl, R ¹⁴ is methyl, R ⁷ is hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, iso Butyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3 -Dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethyl Oxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethyl Oxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl )-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-( 1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1 , 3-dioxolane-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, Benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 60. The compound of claim 40, wherein R ¹³ is isopropoxycarbonyl, R ¹⁴ is methyl, R ⁷ is hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1, 3-dioxolane-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-di Ethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-di Methoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxane-2- base)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1- (1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-( 1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl , benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl . 61. The compound of claim 40, wherein R ¹³ is butoxycarbonyl, R ¹⁴ is methyl, R ⁷ is hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, iso Butyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3 -Dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethyl Oxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethyl Oxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl )-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-( 1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1 , 3-dioxolane-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, Benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 62. The compound of claim 40, wherein R ¹³ is isobutoxycarbonyl, R ¹⁴ is methyl, R ⁷ is hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1, 3-dioxolane-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-di Ethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-di Methoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxane-2- base)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1- (1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-( 1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl , benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl . 63. The compound of claim 40, wherein R ¹³ is sec-butoxycarbonyl, R ¹⁴ is methyl, R is hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, iso Butyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3 -Dioxolan-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethyl Oxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethyl Oxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxan-2-yl )-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1-( 1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1 , 3-dioxolane-2-yl)-2-phenylethyl, 1-(1,3-dioxan-2-yl)-2-phenylethyl, acetyl, propionyl, butyryl, Benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl. 64. The compound of claim 40, wherein R ¹³ is tert-butoxycarbonyl, R ¹⁴ is methyl, R ⁷ is hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1, 3-dioxolane-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-di Ethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-di Methoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxane-2- base)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1- (1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-( 1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl , benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl . 65. The compound of claim 40, wherein R ¹³ is cyclohexyloxycarbonyl, R ¹⁴ is methyl, R ⁷ is hydrogen, and R ²⁵ is selected from methyl, ethyl, propyl, isopropyl, butyl, Isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1, 3-dioxolane-2-yl)-ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-di Ethoxypropyl, 1-(1,3-dioxolan-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-di Methoxybutyl, 1,1-diethoxybutyl, 1-(1,3-dioxolan-2-yl)-butyl, 1-(1,3-dioxane-2- base)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolan-2-yl)-benzyl, 1- (1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-phenethyl, 1-( 1,3-dioxolan-2-yl)-2-phenethyl, 1-(1,3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl , benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl . 66. The compound of claim 41, wherein R is ^hydrogen , and ^R is selected from hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, benzene Base, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH ₂ , and -CH ₂ CH _{2 CH2NHC} (NH) _NH2 . 67. The compound of claim 66, wherein ^R7 is hydrogen. 68. The compound of claim 66, wherein R ⁷ is methyl, ethyl, benzyl, -C(CH ₃ )=CH ₂ , -CH ₂ C(O)N(CH ₃ ) ₂ ,

or wherein V is O or CH ₂ . 69. The compound of claim 41, wherein R ⁷ is hydrogen, and R ² and R ¹⁶ together with the atoms to which they are bound form a pyrrolidine ring. 70. A compound of formula (V) or (VI):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: ^R1 is

m is 0; and n, R ² , R ⁷ , R ⁸ , R ¹¹ , R ¹² and R ¹⁶ are as defined in claim 1 . 71. The compound of claim 70, wherein n is 0, R ⁷ is hydrogen, R ¹ is R ¹¹ -K-, wherein R ¹¹ is selected from acetyl, propionyl, butyryl, isobutyryl, cyclohexanecarbonyl, Benzoyl, phenylacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, cyclohexyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, Carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-phenylcarbamoyl, N-benzylamino Formyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N-pyrrolidinylcarbamoyl, N-piperidinyl Carbamoyl and N-morpholinylcarbamoyl; and K is an alkenylene group selected from the group consisting of 1,2-ethenylene, 1,2-propenyl-1-ene, 1,2-butenyl-1-ene, 3-methyl-1,2 -butenyl-1-ene, 2-phenyl-1,2-vinyl-1-ene, 3-phenyl-1,2-propenyl-1-ene, 2-methoxycarbonyl-1, 2-vinyl-1-ene, 2-ethoxycarbonyl-1,2-vinyl-1-ene, 2-butoxycarbonyl-1,2-vinyl-1-ene, 1-methyl- 1,2-vinyl-1-ene, 1-methyl-1,2-propenyl-1-ene, 1-methyl-1,2-butenyl-1-ene, 1,3-dimethyl Base-1,2-butenyl-1-ene, 1-methyl-2-phenyl-1,2-vinyl-1-ene, 1-methyl-3-phenyl-1,2-propene Base-1-ene, 1-methyl-2-methoxycarbonyl-1,2-vinyl-1-ene, 1-methyl-2-ethoxycarbonyl-1,2-vinyl-1- ene, 1-methyl-2-butoxycarbonyl-1,2-vinyl-1-ene, 1-ethyl-1,2-vinyl-1-ene, 1-ethyl-1,2- propenyl-1-ene, 1-ethyl-1,2-butenyl-1-ene, 1-ethyl-3-methyl-1,2-butenyl-1-ene, 1-ethyl -2-phenyl-1,2-vinyl-1-ene, 1-ethyl-3-phenyl-1,2-propenyl-1-ene, 1-ethyl-2-methoxycarbonyl- 1,2-vinyl-1-ene, 1-ethyl-2-ethoxycarbonyl-1,2-vinyl-1-ene, 1-ethyl-2-butoxycarbonyl-1,2- Vinyl-1-ene, 1-isopropyl-1,2-vinyl-1-ene, 1-isopropyl-1,2-propenyl-1-ene, 1-isopropyl-1,2 -Butenyl-1-ene, 1-isopropyl-3-methyl-1,2-butenyl-1-ene, 1-isopropyl-2-phenyl-1,2-vinyl- 1-ene, 1-isopropyl-3-phenyl-1,2-propenyl-1-ene, 1-isopropyl-2-methoxycarbonyl-1,2-vinyl-1-ene, 1-isopropyl-2-ethoxycarbonyl-1,2-vinyl-1-ene, 1-isopropyl-2-butoxycarbonyl-1,2-vinyl-1-ene, 1- Phenyl-1,2-vinyl-1-ene, 1-phenyl-1,2-propenyl-1-ene, 1-phenyl-1,2-butenyl-1-ene, 1-benzene Base-3-methyl-1,2-butenyl-1-ene, 1,2-diphenyl-1,2-vinyl-1-ene, 1,3-diphenyl-1,2- propenyl-1-ene, 1-phenyl-2-methoxycarbonyl-1,2-vinyl-1-ene, 1-phenyl-2-ethoxycarbonyl-1,2-vinyl-1 -ene, 1-phenyl-2-butoxycarbonyl-1,2-vinyl-1-ene, 1-benzyl-1,2-vinyl-1-ene, 1-benzyl-1,2 -propenyl-1-ene, 1-benzyl-1,2-butenyl-1-ene, 1-benzyl-3-methyl-1,2-butenyl-1-ene, 1-benzyl Base-2-phenyl-1,2-vinyl-1-ene, 1-benzyl-3-phenyl-1,2-propenyl-1-ene, 1-benzyl-2-methoxycarbonyl -1,2-vinyl-1-ene, 1-benzyl-2-ethoxycarbonyl-1,2-vinyl-1-ene, 1-benzyl-2-butoxycarbonyl-1,2 -Venyl-1-ene, 1-methoxycarbonyl-1,2-vinyl-1-ene, 1-methoxycarbonyl-1,2-propenyl-1-ene, 1-methoxycarbonyl -1,2-butenyl-1-ene, 1-methoxycarbonyl-3-methyl-1,2-butenyl-1-ene, 1-methoxycarbonyl-2-phenyl-1 , 2-vinyl-1-ene, 1-methoxycarbonyl-3-phenyl-1,2-propenyl-1-ene, 1,2-dimethoxycarbonyl-1,2-vinyl- 1-ene, 1-methoxycarbonyl-2-ethoxycarbonyl-1,2-vinyl-1-ene, 1-methoxycarbonyl-2-butoxycarbonyl-1,2-vinyl- 1-ene, 1-ethoxycarbonyl-1,2-ethenyl-1-ene, 1-ethoxycarbonyl-1,2-propenyl-1-ene, 1-ethoxycarbonyl-1,2 -butenyl-1-ene, 1-ethoxycarbonyl-3-methyl-1,2-butenyl-1-ene, 1-ethoxycarbonyl-2-phenyl-1,2-ethene Base-1-ene, 1-ethoxycarbonyl-3-phenyl-1,2-propenyl-1-ene, 1-ethoxycarbonyl-2-methoxycarbonyl-1,2-vinyl- 1-ene, 1,2-diethoxycarbonyl-1,2-vinyl-1-ene, 1-ethoxycarbonyl-2-butoxycarbonyl-1,2-vinyl-1-ene, 1-butoxycarbonyl-1,2-vinyl-1-ene, 1-butoxycarbonyl-1,2-propenyl-1-ene, 1-butoxycarbonyl-1,2-butenyl -1-ene, 1-butoxycarbonyl-3-methyl-1,2-butenyl-1-ene, 1-butoxycarbonyl-2-phenyl-1,2-vinyl-1- ene, 1-butoxycarbonyl-3-phenyl-1,2-propenyl-1-ene, 1-butoxycarbonyl-2-methoxycarbonyl-1,2-vinyl-1-ene, 1-butoxycarbonyl-2-ethoxycarbonyl-1,2-vinyl-1-ene and 1,2-dibutoxycarbonyl-1,2-vinyl-1-ene. 72. The compound of claim 70, wherein n is 1, R is ^hydrogen , and ^R is selected from hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclopentyl, Cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH _{2 ,} and - _{CH2CH2CH2NHC (} NH) _{NH2 .} 73. The compound of claim 72, wherein R ⁷ is hydrogen. 74. The compound of claim 72, wherein R ⁷ is methyl, ethyl, benzyl, -C(CH ₃ )=CH ₂ , -CH ₂ C(O)N(CH ₃ ) ₂ ,

or

wherein V is O or CH ₂ . 75. The compound of claim 70, wherein n is 1, ^R7 is hydrogen, and ^R2 and ^R16 form a pyrrolidine ring together with the atoms bound to them. 76. The compound of claim 70, wherein n is 0, R ⁷ is hydrogen, and R ⁸ and R ¹² form cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted carbon atoms together Cycloheteroalkyl ring. 77. The compound of claim 76, wherein R and R together form cyclopent- ^{1- ene} , cyclohex-1-ene, 2-cyclopenten-1-one, 2-ring Hexen-1-one, 2-(5H)-furanone or 5,6-dihydro-pyran-2-one ring. 78. The compound of claim 77, wherein R ¹¹ is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl. 79. The compound of claim 70, wherein n is 0, R ⁷ is hydrogen, and R ⁸ and R ¹¹ form cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted carbon atoms together Cycloheteroalkyl ring. 80. The compound of claim 79, wherein R ⁸ and R ¹¹ form γ-butyrolactone, 6-valerolactone or 2,2-dimethyl-1,3-dioxane together with their bonded carbon atoms -4,6-diketone ring. 81. The compound of claim 80, wherein R ¹² is selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl. 82. A compound of formula (V) or (VI): or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: ^R1 is And n, R ² , R ⁷ , R ¹⁵ and R ¹⁶ are as defined in claim 1. 83. The compound ^of claim 82, wherein n is 0, R is hydrogen, and ^R is selected from methyl, ethyl, propyl, isopropyl, cyclopentyl, cyclohexyl, phenyl, 4-hydroxybenzene base, benzyl, 4-hydroxybenzyl and 3-pyridyl. 84. The compound of claim 82, wherein n is 1, R is ^hydrogen , and ^R is selected from hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclopentyl, Cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl, 2-indolyl, -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH _{2 ,} and - _{CH2CH2CH2NHC (} NH) _{NH2 .} 85. The compound of claim 84, wherein R ⁷ is hydrogen. 86. The compound of claim 84, wherein R ⁷ is methyl, ethyl, benzyl, -C(CH ₃ )=CH ₂ , -CH ₂ C(O)N(CH ₃ ) ₂ ,

or

wherein V is O or CH ₂ . 87. The compound of claim 82, wherein n is 1, ^R7 is hydrogen, and ^R2 and ^R16 form a pyrrolidine ring together with the atoms bound to them. 88. The compound of claim 1 having the structure of formula (IX) or (X),

Or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: t, R ² , R ⁷ , R ²⁰ and R ²¹ are as defined in claim 1. 89. The compound of claim 88, wherein t is zero. 90. The compound of claim 88, wherein t is 1, and ^R is selected from hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl , Benzyl, 4-Hydroxybenzyl, 4-Bromobenzyl, 2-Imidazolyl, 2-Indolyl, -CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ CO ₂ H, -CH ₂ CH ₂ CO ₂ H, -CH ₂ CONH ₂ , -CH ₂ CH ₂ CONH ₂ , -CH ₂ CH ₂ SCH ₃ , -CH ₂ SH, -CH ₂ (CH ₂ ) ₃ NH ₂ , and -CH ₂ CH ₂ CH ₂ NHC(NH)NH ₂ . 91. The compound of claim 89 or 90, wherein R ^{and R} are independently selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. 92. The compound of claim 89 or 90, wherein ^R20 and ^R21 and the carbon atom to which they are bonded together form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. 93. The compound of claims 91 and 92, wherein R ⁷ is hydrogen, methyl, ethyl, benzyl, -C(CH ₃ )=CH ₂ , -CH ₂ C(O)N(CH ₃ ) ₂ ,

or

wherein V is O or CH ₂ . 94. The compound of claim 1 having formula (XI) or (XII):

or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: n, R ¹ , R ² , R ²² and R ²³ are as defined in claim 1 . 95. The compound of claim 94, wherein n is 1, X is NH, R ¹ is hydrogen, and R ² is arylalkyl. 96. The compound of claim 95, wherein R ² is benzyl. 97. The compound of claim 94, wherein n is 0 and ^R1 is ^R25OC (O)-. 98. The compound of claim 97, wherein R is selected from ^{the group} consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. 99. The compound of claim 98, wherein R ²⁵ is ethyl. 100. The compound of claim 94, wherein R ²² and R ²³ are independently selected from hydrogen, alkyl and substituted alkyl. 101. The compound of any one of claims 94-100, wherein R ²² is methyl and R ²³ is hydrogen. 102. The compound of any one of claims 94-100, wherein R ²² is methyl and R ²³ is methyl. 103. A method of treating or preventing epilepsy, depression, anxiety, psychosis, syncope, hypokinesia, cranial abnormalities, neurodegenerative disease, panic, pain, inflammatory disease, insomnia, gastrointestinal disease, or Alcohol withdrawal syndrome, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1, 29, 36, 70, 82, 88 or 94. 104. A method of treating or preventing neuropathic pain, muscular pain or bone pain in a patient, said method comprising administering a therapeutically effective amount of a drug according to claims 1, 29, 36, 70, 82, to a patient in need of such treatment. The compound of any one of 88 or 94. 105. A method for treating or preventing epilepsy, depression, anxiety, psychosis, syncope, hypokinesia, cranial abnormalities, neurodegenerative disease, panic, pain, inflammatory disease, insomnia, gastrointestinal disease or alcohol withdrawal in a patient A syndromic pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1, 29, 36, 70, 82, 88 or 94 and a pharmaceutically acceptable excipient. 106. A pharmaceutical composition for treating or preventing neuropathic pain, muscle pain or bone pain in a patient, said composition comprising a therapeutically effective amount of Any one of the compounds and pharmaceutically acceptable excipients. 107. A GABA analog derivative, MG, for administration to a patient in need of treatment, wherein M is a motif, and G is derived from a GABA analog HG, wherein H is hydrogen, and wherein the motif M is derived from G and It is cleaved on any of its metabolites, showing a carcinogenic toxic dose (TD ₅₀ ) to rats greater than 0.2 mmol/kg/day, and the motif M is released from Cracked on G to produce: (i) a maximum concentration Cmax of plasma HG that is at least 120% of the _Cmax of plasma HG obtained by colonically administering an equimolar _dose of HG; and (ii) An AUC of at least 120% of the AUC obtained by colonic administration of equimolar doses of H-G. 108. A GABA analog derivative, M-G, for administration to a patient in need thereof, wherein M is a motif, and G is derived from a GABA analog H-G, wherein H is hydrogen, wherein M-G has the structure of formula (XIV) : Or a pharmaceutically acceptable salt, hydrate or solvate of said compound, wherein: Y is O or S; R is hydrogen, or R and ^R together form an azetidine, a substituted azetidine, a pyrrolidine or a substituted pyrrolidine ring with the atoms bound to them; R ^{and R} are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, ring Heteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R and ^R are independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl ^, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl, or optionally R ^and R ^and together with the carbon atoms to which they are bound form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkyl ring; ^R is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted Cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; and Wherein, once the motif M is cleaved from G and any of its metabolites, it exhibits a carcinogenic toxic dose (TD ₅₀ ) to rats greater than 0.2 mmol/kg/day, and the motif M is administered to rats in the colon M is cleaved from G in vivo at a sufficient rate to produce: (i) a maximum concentration Cmax of plasma HG that is at least 120% of the _Cmax of plasma HG obtained by colonically administering an equimolar _dose of HG; and (ii) An AUC of at least 120% of the AUC obtained by colonic administration of equimolar doses of H-G. 109. A GABA analog derivative, M-G, for administration to a patient in need thereof, wherein M is a motif and G is derived from a GABA analog H-G, wherein H is hydrogen, and wherein M-G has the structure of formula (XIV), And M has the structure of formula (XV):

Wherein: n, X, R ¹ and R ² are as defined in claim 1; and And wherein once the motif M is cleaved from G and any of its metabolites, it exhibits a carcinogenic toxic dose (TD ₅₀ ) to rats greater than 0.2mmol/kg/day, and when rats are administered colonically Meta M is cleaved from G in vivo at a sufficient rate to produce: ₍ i) a maximum plasma HG concentration Cmax of at least 120% of the _Cmax of plasma HG obtained by colonically administered equimolar doses of HG; and (ii) An AUC of at least 120% of the AUC obtained by colonic administration of equimolar doses of H-G. 110. The GABA analog derivative of any one of claims 107-109, M-G, wherein H-G once cleaved from M substantially does not contain a lactam with the structure of formula (XVI); wherein R is hydrogen. 111. The GABA analog derivative, M-G, of any one of claims 107-109, wherein M is substantially free of formaldehyde when M is cleaved from G and any of its metabolites. 112. The GABA analog derivative, M-G, of any one of claims 107-109, wherein M is substantially free of pivalic acid when M is cleaved from G and any of its metabolites. 113. The GABA analog derivative according to any one of claims 107-109, MG, wherein the motif M is cleaved from G at a sufficient rate in vivo when carrying out colon administration to rats to produce at least A _Cmax of plasma HG that is 200% of the _Cmax of plasma HG achieved with an equimolar dose of HG. 114. The GABA analog derivative according to any one of claims 107-109, MG, wherein the motif M is cleaved from G at a sufficient rate in vivo when carrying out colon administration to rats to produce at least The _Cmax of plasma HG that is 1000% of the _Cmax of plasma HG achieved with an equimolar dose of HG. 115. The GABA analog derivative of any one of claims 107-109, M-G, wherein the motif M is cleaved from G in vivo at a sufficient rate to produce at least a The AUC of plasma H-G that is 200% of the AUC of plasma H-G achieved with the administration of equimolar doses of H-G. 116. The GABA analog derivative according to any one of claims 107-109, M-G, wherein the motif M is cleaved from G in vivo at a sufficient rate to produce at least a The AUC of plasma H-G that is 500% of the AUC of plasma H-G achieved by administering an equimolar dose of H-G. 117. The GABA analog derivative of any one of claims 107-109, M-G, wherein after oral administration to the dog at a dose of about 60 μmol equivalent of H-G/kg using a sustained release device, the motif M is in vivo at Cleavage from G at a rate sufficient to produce a plasma H-G concentration at 12 h post-dose that is at least 200% of that obtained from an equimolar dose of H-G following the same dosing regimen.