Prodrugs of gaba analogs, compositions and uses thereof

Prodrugs of GABA analogs, and their compositions and applications

This application requires 35 USC §119(e) for the United States provisional application 60/297,521 filed on June 11, 2001, the United States provisional application 60/298,514 filed on June 14, 2001 and the United States filed on March 19, 2002 The benefits of provisional application 60/366,090, which are incorporated herein by reference.

1. Field of the Invention The present invention generally relates to prodrugs of GABA analogs, pharmaceutical compositions of GABA analog prodrugs, preparation methods of prodrugs of GABA analogs, and pharmaceutical compositions of GABA analog prodrugs and GABA analog prodrugs Method of application. More specifically, the present invention relates to a prodrug of gabapentin and pregabalin, a pharmaceutical composition of a prodrug of gabapentin and pregabalin, a method for preparing a prodrug of gabapentin and pregabalin, a prodrug of gabapentin and pregabalin and a prodrug of gabapentin and pregabalin Application method of pharmaceutical composition.

2. Background of the invention Gamma ("γ")-aminobutyric acid ("GABA") is a major inhibitory transmitter in the central nervous system of mammals. GABA is not effectively transported from the bloodstream to the brain (ie, GABA does not effectively cross the blood-brain barrier). Therefore, brain cells provide essentially all of the GABA found in the brain (BABA is biosynthesized by the decarboxylation of glutamate and pyridoxal phosphate).

GABA modulates the excitability of neurons by binding to specific membrane proteins (ie, GABAA receptors), thereby causing ion channels to open. The entry and passage of chloride ions through the ion channel causes hyperpolarization of the recipient cell, thereby preventing the transmission of nerve impulses to other cells. Low levels of GABA have been observed in individuals with seizures, motor disorders (such as multiple sclerosis, action tremor, tardive dyskinesia), panic, anxiety, depression, alcoholism, and manic behavior.

The suggestion of low GABA levels in a variety of common diseases and/or common medical diseases has stimulated a keen interest in the preparation of GABA analogs that have better pharmaceutical properties than GABA (such as the ability to penetrate the blood-brain barrier). Therefore, 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; , 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 WO93/23383; 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; Bryans et al., International Publication Publish WO 99/21824; Bryans et al., International Publication WO99/31057; Belliotti et al., International Publication WO 99/31074; Bryans et al., International Publication WO 99/31075; Bryans et al., International Publication WO 99/61424; Bryans 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 is a lipophilic GABA analogue that can pass through the blood-brain barrier. It has been used in clinical treatment of epilepsy since 1994. Gabapentin may also have useful therapeutic effects on the following diseases: chronic pain (such as neuropathic pain, muscle and bone pain), psychosis (such as panic, anxiety, depression, alcoholism, and manic behavior), movement disorders (such as multiple Sexual sclerosis, motor tremor, tardive dyskinesia) and so on (Magnus, Epilepsia, 1999, 40: S66-S72). At present, gabapentin is also used for clinical control of neuropathic pain. Pregabalin, which has a 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 between the γ-amino group and the carboxyl functional group to form the γ-lactam, such as the following gabapentin. Due to the toxicity of γ-lactam (5), its formation brings serious difficulties to gabapentin preparations. For example, the toxicity of gabapentin (LD50, mice) is greater than 8000 mg/kg, and the corresponding toxicity (LD50, mice) of lactam (5) is 300 mg/kg. Therefore, due to safety reasons, it is necessary to minimize the formation of by-products such as lactam during the synthesis of GABA analogs and/or the preparation and/or storage of GABA analogs or GABA analog compositions (especially inIn the case of gabapentin).

The problem of lactam contamination of GABA analogues has been partially overcome through the application of specific additional purification steps, precise selection of adjuvant materials in pharmaceutical compositions, and careful control steps (Augurt et al., US Patent 6,054,482), especially in The problem of lactam contamination in the case of gabapentin. However, attempts to prevent lactam contamination have not been completely successful in the synthesis or storage of GABA analogs such as gabapentin or a combination thereof.

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

Sustained release formulations are a conventional solution for rapid system clearance, which are known to those skilled in the art (see, for example, "Remington's Pharmaceutical Sciences," Philadelphia College of Pharmacyand Science, 17TH Edition, 1985). Osmotic delivery systems are also known methods for the continuous delivery of drugs (see, for example, 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. In contrast, these compounds are generally absorbed by a large neutral amino acid transporter ("LNAA") in the small intestine (Jezyk et al., Pharm. RES., 1999, 16, 519-526). The rapid passage of conventional dosage forms through the proximal absorption region of the gastrointestinal tract has prevented 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 that are substantially pure and do not spontaneously lactamize during formulation or storage (especially gabapentin and pregablin analogs).

3. Summary of the invention The present invention addresses these and other needs by providing prodrugs of GABA analogs, pharmaceutical compositions of prodrugs of GABA analogs, and methods for preparing prodrugs of GABA analogs. The present invention also provides methods for applying prodrugs of GABA analogs, and methods for using the pharmaceutical compositions of prodrugs of GABA analogs to treat or prevent common diseases and/or disorders.

Importantly, the prodrugs provided by the present invention can have significant pharmaceutical advantages for specific applications in medicine. First, the motifs of the prodrugs of GABA analogs provided by the present invention are generally unstable in vivo (ie, a large amount of GABA analogs are generated by enzymatic or chemical cleavage before the prodrug is removed from the patient). Second, the motif derivatives provided by cleavage of the motif from the prodrug and any of its metabolites are generally non-toxic when administered to mammals according to the dosing regimen that generally follows GABA analogs.

The compound of the present invention has a motif connected to the γ amino group of the GABA analog. This motif can be directly connected to the γ amino group of the GABA analog, or optionally can be connected to the amino group of the α-amino acid motif or the hydroxyl group of the α-hydroxy acid motif, and the motif itself is connected to the γ amino group of the GABA analog .

The compound of the present invention may also have a motif connected 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 groups.

Therefore, the compound of the present invention may include up to 4 motifs, including 1 carboxyl motif and up to 3 amino motifs attached to the γ amino group in sequence (ie, so that each motif sequentially starts from the N- of the GABA analog End cleavage). The compound of the present invention may contain 2 amino motifs and 1 carboxyl motif, 2 amino motifs, 1 amino motif and 1 carboxyl motif or 1 amino motif. Preferably, in the compound of the present invention comprising an amino group and a carboxy group, the carboxy group is hydrolyzed before the complete cleavage of the group connected to the amino group.

The 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 O or NR16; W is O or NR17; Y is O or S; R1 Selected from hydrogen, R24C(O)-, R25OC(O)-, R24C(S)-, R25OC(S)-, R25SC(O)-, R25SC(S)-, (R9O)(R10O)P(O) -, R25S-,Each R2 is independently selected from hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, acylamino, substituted acylamino, alkylamino, substituted alkylamino , Alkylsulfinyl, substituted alkylsulfinyl, alkylsulfonyl, substituted alkylsulfonyl, alkylthio, substituted alkylthio, alkoxycarbonyl, substituted alkoxycarbonyl, aryl Group, 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 R2 and R16 together with the atoms to which they are bound to form a cycloheteroalkyl group or a substituted cycloheteroalkyl group Ring; R3 and R6 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, Cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; R4 and R5 are independently selected from hydrogen, alkyl, substituted Alkyl, acyl, substituted acyl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroarylalkyl and substituted The heteroarylalkyl group, or optionally R4 and R5 together with the carbon atoms to which they are bound, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, or bridged cycloalkyl ring ; R8 and R12 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, heteroaryl Alkyl group and substituted heteroarylalkyl group, or optionally R8 and R12 together with the carbon atoms to which they are bound, form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R11 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 alkoxy Carbonyl, cycloheteroalkoxycarbonyl, substituted cycloheteroalkoxycarbonyl, aryloxycarbonyl, substitutedAryloxycarbonyl, heteroaryloxycarbonyl, substituted heteroaryloxycarbonyl and nitro; R7, R9, R10, R15, R16 and R17 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, Substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, hetero Aryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; R13 and R14 are independently selected from hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxy Carbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, Heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl, or optionally R13 and R14 together with the carbon atoms to which they are bound form cycloalkyl, substituted cycloalkyl, cyclohetero Alkyl or substituted cycloheteroalkyl ring; R20 and R21 are independently selected from hydrogen, acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted aryl Alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkane And substituted heteroarylalkyl groups, or optionally R20 and R21 together with the carbon atoms to which they are bound to form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R22 and R23 Independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl, or optionally R22 and R23 together with the carbon atoms to which they are bound to form a cycloalkane Group, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R24 is selected from hydrogen, acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, aryl Alkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl Group, heteroarylalkyl and substituted heteroarylalkyl; and R25 is selected from acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted aryl Alkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkane Group and substituted heteroarylalkyl., Arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted R13 and R14 are independently selected from hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, and aryl. , Substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl, Substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally R13 and R14 together with the carbon atoms to which they are bound to form cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted The cycloheteroalkyl ring; R20 and R21 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 R20 and R21 together with the carbon atoms to which they are bound 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 together with the carbon atoms to which they are bound to form cycloalkyl, substituted Cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R24 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, heteroaryl And R25 is selected from the group consisting of 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., Arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted R13 and R14 are independently selected from hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, and aryl. , Substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl, Substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl, or optionally R13 and R14 together with the carbon atoms to which they are bound form cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted The cycloheteroalkyl ring; R20 and R21 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 R20 and R21 together with the carbon atoms to which they are bound 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 together with the carbon atoms to which they are bound to form cycloalkyl, substituted Cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R24 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, heteroaryl And R25 is selected from the group consisting of 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.Alkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl, or optionally R13 and R14 form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring together with the carbon atom to which they are bound; R20 and R21 are independently selected from hydrogen, acyl, substituted acyl, alkane Group, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, hetero Alkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally R20 and R21 together with the carbon atoms to which they are bound to form a cycloalkyl group , 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 together with the carbon atoms to which they are bound form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R24 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 R25 is selected from acyl, substituted acyl, alkane Group, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, hetero Alkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.Alkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl, or optionally R13 and R14 form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring together with the carbon atom to which they are bound; R20 and R21 are independently selected from hydrogen, acyl, substituted acyl, alkane Group, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, hetero Alkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl, or optionally R20 and R21 together with the carbon atoms to which they are bound to form a cycloalkyl group , 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 together with the carbon atoms to which they are bound form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; R24 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 R25 is selected from acyl, substituted acyl, alkane Group, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, hetero Alkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl.Alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl, or optionally R22 and R23 together with the carbon atoms to which they are bound to form cycloalkyl, substituted cycloalkyl, ring Heteroalkyl or substituted cycloheteroalkyl ring; R24 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 And R25 is selected from the group consisting of 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 .Alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl, or optionally R22 and R23 together with the carbon atoms to which they are bound to form cycloalkyl, substituted cycloalkyl, ring Heteroalkyl or substituted cycloheteroalkyl ring; R24 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 And R25 is selected from the group consisting of 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 .

In a second aspect, the invention provides pharmaceutical compositions of the compounds of the invention. The pharmaceutical composition generally comprises one or more compounds of the present invention and pharmaceutically acceptable excipients.

In the third aspect, the present invention provides methods for the treatment or prevention of the following diseases: epilepsy, depression, anxiety, psychosis, fainting seizures, hypokinesia, cranial abnormalities, neurodegenerative diseases, panic, pain (especially neuropathic pain and muscle and Bone pain), inflammatory disease (i.e. arthritis), insomnia, gastrointestinal disease, or alcohol withdrawal syndrome. The method generally involves administering a therapeutically effective amount of a compound of the invention to a patient in need of such treatment or prevention.

In a fourth aspect, the present invention provides a pharmaceutical composition for the treatment or prevention of the following diseases in patients in need of such treatment or prevention: epilepsy, depression, anxiety, psychosis, fainting seizures, 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 method generally includes administering a therapeutically effective amount of the pharmaceutical composition of the present invention to a patient in need of such treatment or prevention.

In the fifth aspect, the present invention includes a GABA analog derivative compound for administration to a patient in need of treatment, MG, wherein M is a motif and G is derived from a GABA analog, HG (wherein H is hydrogen). Once the motif M is cleaved from G, and any of its metabolites show a carcinogenic toxic dose (TD50) greater than 0.2mmol/kg/day to rats. Moreover, when the rats are administered to the colon, the motif M is cleaved from G at a sufficient rate to produce: (i) administering equimolar doses of HG through the colon to obtain at least 120% of the Cmax of plasma HG The maximum concentration of plasma HG (Cmax); and (ii) administering equimolar doses of HG through the colon to obtain an AUC of at least 120% of the AUC.

Preferably MG is a derivative of formula (XIV):Or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: R is hydrogen, or R and R6 together with the atoms to which they bind form azetidine, substituted azetidine, pyrrolidine or substituted The pyrrolidine ring; and Y, R3, R4, R5, R6 and R7 are as defined above.

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

Among them: n, X, R1 and R2 are as defined above.

4. Detailed description of the invention 4.1 Definition "Activity transport or activity transport method" refers to the following molecular movement across the cell membrane: a) Directly or indirectly depends on energy-mediated methods (that is, driven by ATP hydrolysis, ion gradient, etc.); Or b) Facilitated diffusion mediated by interaction with a specific transporter occurs. "Alkyl" refers to a saturated or unsaturated, straight line derived by removing a hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Chain, branched or cyclic monovalent hydrocarbon group. Typical alkyl groups include, but are not limited to, methyl; ethyl groups such as ethyl, vinyl, and ethynyl; propyl groups such as prop-1-yl, prop-2-yl, cycloprop-1-yl, and prop-1-yl. En-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl; cycloprop-2-ene-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-ene-1 -Base, 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 so on.

The term "alkyl" specifically means to include groups with any degree or level of saturation, that is, groups with unique carbon-carbon single bonds, groups with one or more carbon-carbon double bonds, groups with one or Groups with multiple carbon-carbon triple bonds and groups with a mixture of carbon-carbon single bonds, double bonds, and triple bonds. When referring to a specific level of saturation, the expressions "alkanyl", "alkenyl" and "alkynyl" are used. Preferably the alkyl group contains 1-20 carbon atoms, more preferably 1-10 carbon atoms.

"Alkyl" refers to a saturated branched, straight chain or cyclic alkyl group derived by removing one hydrogen atom from a single carbon atom of the parent alkane. Typical chain alkyl 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-yl Base, but-2-yl (sec-butyl), 2-methyl-prop-1-yl (isobutyl), 2-methyl-prop-2-yl (tert-butyl), cyclobut-1- Base and so on.

"Alkenyl" refers to an unsaturated branched, straight chain, or cyclic alkyl group having at least one carbon-carbon double bond derived by removing one hydrogen atom from a single carbon atom of the parent olefin. The double bond of the group can be in cis or trans conformation. Typical alkenyl groups include but are not limited to vinyl; propenyl groups such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), Prop-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 so on.

"Alkynyl" refers to an unsaturated branched, straight or cyclic alkyl group having at least one carbon-carbon triple bond derived by removing one hydrogen atom from a single carbon atom of the 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 so on.

"Acyl" refers to 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 "acyl amido") refers to the group -NR'C(O)R, where 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 (ie acetamido), cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino (ie benzoylamino), benzylcarbonylamino Wait.

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

"Alkylamino" means the group -NHR, where R represents an alkyl group or a cycloalkyl group 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, where 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 alkylhydro 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 the group -SR, where R is an 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 group derived by removing one hydrogen atom on a single carbon atom in the parent aromatic ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrene, acenaphthene, acephenanthrylene, anthracene, azulene, benzene, pyridine, pyridine, fluoranthene, fluorene, hexacene, naphthotetraacene, hexalene, Trans-benzobiindene, cis-benzobiindene, indane, indene, naphthalene, octacene, octaphene, octalene, egg benzene, penta-2,4-diene, and Pentabenzene, pentacyclopentadiene, phetaphene, perylene, phenalene, phenanthrene, anthracene, pleiadene, pyrene, anthracene, Yuhong province, triphenylene, trinaphthalene, etc. Preferably the aryl group contains 6-20 carbon atoms, more preferably 6-12 carbon atoms.

"Arylalkyl" refers to an acyclic alkyl group in which the hydrogen atom bound to a carbon atom, usually a terminal or SP3 carbon atom, is replaced by an aryl group. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethyl-1-yl, 2-phenylvin-1-yl, naphthylmethyl, 2-naphthylethyl-1-yl, 2- Naphthylethylene-1-yl, naphthobenzyl, 2-naphthophenyleth-1-yl and the like. Where a specific alkyl moiety is to be specified, the terms arylalkenyl, arylalkenyl and/or arylalkynyl are used. Preferably the arylalkyl group is a (C6-C30) arylalkyl group, for example, the alkenyl, alkenyl or alkynyl part of the arylalkyl group is (C1-C10), and the aryl part is (C6-C20) , More preferably the arylalkyl group is (C6-C20) arylalkyl, for example, the alkyl, alkenyl or alkynyl part of the arylalkyl group is (C1-C8), and the aryl part is (C6- C12).

"Arylalkoxy" refers to -O-arylalkyl in which the arylalkyl group is as defined herein.

"Aryloxycarbonyl" refers to the group -C(O)-O-aryl, where aryl is as defined herein.

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

"Bridged cycloalkyl" refers to a group selected from:Wherein: A is (CR35R36)b; R35 and R36 are independently selected from hydrogen and methyl; R33 and R34 are independently selected from hydrogen and methyl; b is an integer of 1-4; and c is an integer of 0-2.

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

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

"Carcinogenic potency (TD50)" (see Peto et al., Environmental Health Perspectives 1984, 58, 1-8) is defined as the amount of mg/kg body weight that causes half of the tested animals to have tumors at the end of their standard life span for a certain animal species Chronic dose-level in days. Since related tumors often occur in control animals, TD50 is more clearly defined as: a dose-grade in mg/kg body weight/day, if this dose-grade is chronically administered during the standard lifespan of the species, It will be possible to remain tumor-free during this period. The TD50 of any specific type of tumor, any specific tissue, or any combination of them can be calculated.

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

"The compound of the present invention" refers to a compound encompassed by the general formula described herein, which includes any specific compound within the scope of the general formula whose structure is disclosed herein. The compounds of the present invention can be identified by their chemical structure and/or chemical name. When the 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 therefore can be used as stereoisomers such as double bond isomers (ie geometric isomers), optical enantiomers or diastereomers The body exists. Therefore, the chemical structure described herein includes all possible optical enantiomers and stereoisomers of the compound shown, including the pure form of the stereoisomers (e.g., geometrically pure, optically pure, or diastereomeric Body pure) and mixtures of enantiomers and stereoisomers. The enantiomers and stereoisomer mixtures can be resolved into their constituent optical enantiomers 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 multiple tautomeric forms, including enol forms, ketone forms, or mixtures thereof. Therefore, the structural formula described herein includes all possible tautomeric forms of the compounds shown. The compounds of the present invention also include isotopically-labeled compounds in which the atomic weight of one or more atoms is different from the atomic weight usually found in nature. Examples of isotopes that can be included in the compounds of the present invention include, but are not limited to, 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl. Moreover, it should be understood that when a partial structure of the compound of the present invention is exemplified, the square brackets indicate the binding point of the partial structure to the rest of the molecule.

"The composition of the present invention" refers to at least one compound of the present invention and a pharmaceutically acceptable excipient, through which the compound is administered to a human. The compounds of the present invention are administered in an isolated form when administered to humans, which means separation from the synthetic organic reaction mixture.

"Cyano" means the group -CN.

"Cycloalkyl" refers to saturated or unsaturated cycloalkyl. If a specific saturation level is to be specified, 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 a (C3-C10) cycloalkyl group, more preferably a (C3-C7) 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 that replace carbon atoms include, but are not limited to, N, P, O, S, Si, etc., wherein if a specific saturation level is to be specified, the term "cycloheteroalkyl" or "cycloheteroalkenyl" is used. Typical cycloheteroalkyl groups include, but are not limited to, epoxides, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, quinuclidine, and the like.

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

"Derived from bile acid" refers to the part structurally related to the compound of formula (XVII) or (XVIII):Each of D, E, and F is independently H or OH.

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

"Derived from GABA analogs" refers to parts that are structurally similar to GABA analogs. The structure of the part is the same as the compound except for the 1 or 2 position. At these positions, the hydrogen atom bonded to the hydroxyl moiety of the amino group and (optionally) carboxyl group has been replaced by a covalent bond that serves as the bonding point of the other moiety.

"Dialkylamino" means the group -NRR', where 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 and the like.

Unless otherwise indicated, "GABA analogs" refer to compounds having the following structure:Wherein: R is hydrogen, or R and R6 and their combined atoms together form an azetidine, substituted azetidine, pyrrolidine or substituted pyrrolidine ring; R3 and R6 are independently selected from hydrogen, Alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, Heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; and R4 and R5 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 R4 and R5 and the carbon atoms to which they are combined together form cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl Or a bridged cycloalkyl ring.

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

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

"Heteroalkyl, heteroalkyi, heteroalkenyl, and heteroalkynyl" refer to alkyl, alkenyl, alkenyl and alkynyl, respectively, in which one or more carbon atoms (and any attached hydrogen atoms) Each is independently substituted by 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-, -SnH2-, etc., where R'is hydrogen, Alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, or substituted aryl.

"Heteroaryl" refers to a monovalent heteroaromatic group derived by removing one 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, benzopyran, cinnoline, furan, imidazole, Indazole, indole, indoline, indolizine, isobenzofuran, isobenzopyran, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, Oxadiazole, oxazole, pyridine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine (pyrrolizine ), quinazoline, quinoline, quinazine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, etc. Preferably, the heteroaryl group is a 5-20 membered heteroaryl group, more preferably a 5-10 membered heteroaryl group. 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 a hydrogen atom bonded to a carbon atom, usually a terminal or SP3 carbon atom, is replaced by a heteroaryl group. Where a specific alkyl moiety is to be designated, the terms heteroarylalkenyl, heteroarylalkenyl and/or heteroarylalkynyl are used. In a preferred embodiment, the heteroarylalkyl group is a 6-30 membered heteroarylalkyl group, for example, the alkyl, alkenyl, or alkynyl portion of the heteroarylalkyl group is 1-10 membered, and the heteroarylalkyl group is 1-10 membered. The base moiety is a 5-20 membered heteroaryl group, more preferably a 6-20 membered heteroarylalkyl group. For example, the alkenyl, alkenyl or alkynyl moiety of the heteroarylalkyl group is 1-8 membered, and the heteroaryl The moiety is a 5--12 membered heteroaryl group.

"Passive diffusion" refers to the uptake of an agent that is not mediated by a specific transporter. Reagents that are basically incapable of passive diffusion have a permeability of less than 5×10-6 cm/sec in vitro, usually less than 1×10-6 cm/sec (lack of an outflow mechanism) across standard cell monolayers (such as Caco-2) .

"Pharmaceutically acceptable" means approved or approved by the federal or national government, or listed in the U.S. Pharmacopeia or other recognized pharmacopeia for use in animals, more specifically humans.

"Pharmaceutically acceptable salt" refers to a salt of the compound of the present invention, which is pharmaceutically acceptable and has 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 formed with organic acids such as acetic acid, propionic acid , Hexanoic acid, cyclopentane propionic 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-butyl acetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, adiponic acid, etc.; or (2) when the acidic protons present in the parent compound are Metal ions such as salts formed when 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 that is administered with the compound of the present invention.

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

"Prodrug" refers to a derivative of a drug molecule that needs to be transformed in the body to release an active drug. Prodrugs are usually (although not required) have no pharmacological activity prior to conversion to the parent drug.

"Motif" refers to a form of protecting group that converts a drug into a prodrug when it is used to shield a functional group in a drug molecule. Usually the motif is bound to the drug through a bond, which is cleaved enzymatically or non-enzymatically in vivo.

"Protecting group" refers to a group of atoms that reduces or prevents the reactivity of the functional group when combined with the reactive functional group in the molecular shield. Examples of protecting groups can be found in Green et al., "Protective Groups in Organic Chemistry" (Wiley, 2ndED.1991) and Harrison et al., "Compendium of Synthetic Organic Methods" ", Volumes 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"), trimethylsilane Group ("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 ether and alkyl ether, tetrahydropyranyl ether, trialkylsilane Base ether and allyl ether.

"Substituted" refers to a group in which one or more hydrogen atoms are each independently substituted with the same or different substituents. Typical substituents include but are not limited to -X, -R29, =O-, -OR29, -SR29, -S-, =S, -NR29R30, =NR29, -CX3, -CF3, -CN, -OCN,- SCN, -NO, -NO2, =N2, -N3, -S(O)2O, -S(O)2OH, -S(O)2R29, -OS(O2)O-, -OS(O)2R29, -P(O)(O-)2, -P(O)(OR29)(O-), -OP(O)(OR29)(OR30), -C(O)R29, -C(S)R29, -C(O)OR29, -C(O)NR29R30, -C(O)O-, -C(S)OR29, -NR31C(O)NR29R30, -NR31C(S)NR29R30, -NR31C(NR29)NR29R30 and -C(NR29)NR29R30, wherein each X is independently halogen; each R29 and R30 is independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl Group, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, Substituted heteroarylalkyl, -NR31R32, -C(O)R31 or -S(O)2R31, or optionally R29 and R30 together with the atoms to which they bind at the same time form a cycloheteroalkyl group or a substituted cycloheteroalkyl group Ring; and R31 and R32 are independently hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, ring Heteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl.

"Transport protein" refers to a protein that plays a direct or indirect role in the process of transporting molecules into and/or through the cell. For example, the transporter can be, but is not limited to, a solute-carrying transporter, a co-transporter, a counter transporter, a single transporter, a co-transporter, an antiporter, a pump, a balanced transporter, and a concentrated transporter. Transporters and other proteins that regulate active transport, energy-dependent transport, promote diffusion, exchange mechanisms, and specific absorption mechanisms. The transporter can also be, but is not limited to, a membrane-bound protein that recognizes the substrate and affects its entry into and exit from the cell via a carrier-regulated transporter or receptor-regulated transporter. The transport protein can also be, but is not limited to, a protein that is involved in intracellular expression by transporting the substrate through or out of the cell. The transport protein can also be, but is not limited to, a protein or glycoprotein exposed on the cell surface that does not directly transport the substrate but binds to the substrate to keep it near the receptor, or a transport protein that affects the entry or passage of the substrate into or through the cell. Examples of carrier proteins include: intestinal and liver bile acid transporters, dipeptide transporters, oligopeptide transporters, monosaccharide transporters (such as SGLT1), phosphate transporters, monocarboxylic acid transporters, β-glycoprotein transporters, Organic anion transporter (OAT) and organic cation transporter. 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.

The "treating or treatment" of any disease or condition refers in one embodiment to ameliorate the disease or condition (ie stop or reduce 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 the patient. In yet another embodiment, "treating or treatment" refers to inhibiting physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing physical parameters) or simultaneously inhibiting a disease or condition. In yet another embodiment, "treating (treating or treatment)" refers to delaying the onset of a disease or condition.

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

Reference is now made in more detail to the preferred embodiments of the present invention. Although the present invention is described in conjunction with the preferred embodiments, it is understood that this does not mean that the present invention is limited to these preferred embodiments. On the contrary, this application is intended to cover alternatives, modifications and equivalent solutions that can be included within the concept and scope of the present invention as defined by the appended claims.

4.2 Compounds of the present invention Those skilled in the art will recognize that the compounds of formula (I), (II) and (III) have certain structural features in common. These compounds are all GABA analogs (i.e. derivatives of γ-aminobutyric acid) that have bound motifs. Specifically, R2, R3, R4, R5, R6, X and Y are co-substituents found in the compounds of formula (I), (II) and (III).

The 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, R1, R2, R3, R4, R5, R6, R7, R20, R21, R22 and R23 are as described above definition.

In a preferred embodiment, the compounds of formula (I), (II) and (III) do not include the following compounds: when R3 and R6 are both hydrogen, R4 and R5 are not both hydrogen or both are methyl;

In the compound of formula (I), when n is O or when n is 1, and X is NR16, then R1 is not hydrogen; in the compound of formula (I), R1, R7O-, R24C(O)- , R25C(O)- and R25O- are not moieties derived from bile acid; in the compound of formula (I), when R1 is R24C(O)- and n is 0, R24 is not methyl, tert-butyl Group, 2-aminoethyl, 3-aminopropyl, benzyl, phenyl or 2-(phenacyloxymethyl)phenyl; in the compound of formula (I), when R1 is R25OC(O) -When R25 is not R26C(O)CR13R14-, where R26 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 heteroaryl Alkyl; in the compound of formula (I), when R1 is R25OC(O)- and n is 0, R25 is not methyl, tert-butyl or benzyl; in the compound of formula (I), when n When R1 is R25C(O)OCR13R14OC(O)-, if either R13 or R14 is hydrogen, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted Cycloalkoxycarbonyl, the other of R13 or R14 is not hydrogen; in the compound of formula (I), when n is 1, X is NH, R3, R5 and R6 are each hydrogen, and R4 is cyclohexyl When, then R2 is not benzyl; in the compound of formula (II), when t is 1, and u is 0, neither R20 nor R21 is 2-hydroxy-3-methyl-5-chlorophenyl; and In the compound of formula (II), when u is 1 and X is 0, t is 1.

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 both are methyl.

In one embodiment of the compound of formula (I), when n is 0 or when n is 1 and X is NR16, R1 is not hydrogen. In another embodiment of the compound of formula (I), none of R1, R7O-, R24C(O)-, R25C(O)- or R25O- are moieties derived from bile acids. In another embodiment of the compound of formula (I), when R1 is R24C(O)- and n is 0, R24 is not alkyl, substituted alkyl, arylalkyl, aryl or substituted aryl. base. In another embodiment of the compound of formula (I), when R1 is R24C(O)- and n is 0, then R24 is not C1-4 alkyl, benzyl, phenyl, or substituted phenyl. In another embodiment of the compound of formula (I), when R1 is R24C(O)- and n is 0, R24 is not methyl, tert-butyl, 2-aminoethyl, 3-aminopropyl, Benzyl, phenyl, or 2-(benzoyloxymethyl)-phenyl. In another embodiment of the compound of formula (I), when R1 is R25OC(O)-, R25 is not R26C(O)CR13R14-. In another embodiment of the compound of formula (I), when R1 is R25OC(O)- and n is 0, R25 is not alkyl or arylalkyl. In another embodiment of the compound of formula (I), when R1 is R25OC(O)- and n is 0, R25 is not C1-4 alkyl or benzyl. In another embodiment of the compound of formula (I), when R1 is R25OC(O)- and n is 0, R25 is not methyl, tert-butyl or benzyl. In another embodiment of the compound of formula (I), when n is 0 and R1 is R25C(O)OCR13R14OC(O)-, if either R13 or R14 is hydrogen, alkoxycarbonyl, substituted alkane For oxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, the other of R13 or R14 is not hydrogen. In another embodiment of the compound of formula (I), when R3, R5, and R6 are each hydrogen, R4 is not cyclohexyl. In another embodiment of the compound of formula (I), when n is 1, X is NH, R3, R5, and R6 are each hydrogen and R2 is benzyl, R4 is not 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), when u is 1 and X is 0, t is 1.

In one embodiment of the compounds of formula (I), (II) and (III), n is zero. In another embodiment, n is 1. When n is 1 and X is NR6, it is preferred that the α-amino acid is in the L-stereochemical configuration.

In another embodiment of the compounds of formula (I) and (II), R7 is selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, aryl chain alkyl, substituted aryl chain Alkyl, cycloalkyl, substituted cycloalkyl, cycloheterochain alkyl and substituted cycloheterochain alkyl. In a preferred embodiment, Y is O and R7 is hydrogen. In another embodiment, Y is O and R7 is an alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, or substituted aryl. Preferably R7 is methyl, ethyl, benzyl, -C(CH3)=CH2, -CH2C(O)N(CH3)2,

or Where V is O or CH2.

In a preferred embodiment of the compounds of formula (I), (II) and (III), R2 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, heteroaryl Alkyl and substituted heteroarylalkyl. Preferably R2 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyi, substituted arylalkyi, cycloalkyl, heteroarylalkyl and substituted Heteroaryl chain alkyl.

In another embodiment of the compounds of formula (I), (II), and (III), X is NH and R2 is hydrogen, cycloalkyl, or alkane. Preferably R2 is hydrogen, methyl, isopropyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl or cyclohexyl. In another embodiment, X is NH and R2 is a substituted alkane. Preferably, R2 is -CH2OH, -CH(OH)CH3, -CH2CO2H, -CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, -CH2CH2SCH3, CH2SH, -CH2(CH2)3NH2 or -CH2CH2CH2NHC(NH)NH2. In another embodiment, X is NH, and R2 is selected from the group consisting of aryl, arylalkyl, substituted arylalkyl, and heteroarylalkyl.

Preferably R2 is phenyl, benzyl, 4-hydroxybenzyl, 4-bromobenzyl, 2-imidazolyl or 2-indolyl. In another embodiment, X is NR16, and R2 and R16 together with the atoms to which they are bound form a cycloheteroalkyl or substituted cycloheteroalkyl ring.

Preferably, R2 and R16 together with the atoms to which they are bonded 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, R3 and R6 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 alkane. More preferably, R3 is hydrogen or an alkyl group, and R6 is hydrogen.

In another preferred embodiment of the compounds of formula (I), (II) and (III), R4 and R5 are independently selected from hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl , Cycloheteroalkyl and substituted cycloheteroalkyl. Preferably R4 and R5 are independently selected from hydrogen, alkane and substituted alkyi.

In another embodiment of the compounds of formula (I), (II) and (III), R4 and R5 together with the carbon atom to which they are attached form a cycloalkyl or substituted cycloalkyl ring. Preferably, R4 and R5 together with the carbon atom to which they are bonded 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 attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring. In another embodiment, R4 and R5 together with the carbon atoms to which they are attached form a bridged cycloalkyl ring.

In one embodiment of the compound of formula (I), n is 1, R1 is R24C(O)- or R24C(S)-, and R24 is alkyl, substituted alkyl, heteroalkyl, substituted heteroalkane Group, aryl, substituted aryl, heteroaryl, or substituted heteroaryl. Preferably R24 is methyl, ethyl, 2-propyl, tert-butyl, -CH2OCH(CH3)2, phenyl or 3-pyridyl.

In another embodiment of the compound of formula (I), n is 1, R1 is R25OC(O)- or R25SC(O)-, and R25 is alkyl, substituted alkyl, heteroalkyl, aryl, Substituted aryl, heteroaryl or substituted heteroaryl. Preferably R25 is ethyl, 2-propyl, neopentyl, -CH2OCH(CH3)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, R2, R3, R4, R5, R6, R7, R13, R14, R16 and R25 are as defined above.

In a preferred embodiment, the compound of formula (IV) does not include the following compounds: when R13 or R14 is hydrogen, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted In the case of cycloalkoxycarbonyl, the other of R13 or R14 is not hydrogen; and R25C(O) is not a part derived from bile acid.

In one embodiment of the compound of formula (IV), R13 and R14 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl, Substituted cycloalkyl, cycloalkoxycarbonyl or heteroaryl (preferably when R13 is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R14 is methyl). More preferably R13 and R14 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, Ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexoxycarbonyl, phenyl, benzyl , Phenethyl or 3-pyridyl.

In another embodiment of the compound of formula (IV), R13 and R14 are independently hydrogen, alkane, substituted alkyi, cycloalkyl, or substituted cycloalkyl. Preferably R13 and R14 are hydrogen, alkane 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 R13 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl or cyclohexyl and R14 is hydrogen, or R13 is methyl and R14 is methyl.

In another embodiment of the compound 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 compound of formula (IV), R13 and R14 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, carbamoyl, or cycloalkoxycarbonyl. Preferably, when R13 is an alkoxycarbonyl group, a cycloalkoxycarbonyl group or a carbamoyl group, R14 is a methyl group. More preferably, R13 is methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl or cyclohexoxycarbonyl, and R14 is methyl.

In another embodiment of the compound of formula (IV), R13 and R14 and the carbon atom to which they are bound together form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. Preferably, R13 and R14 form a cycloalkyl ring together with the carbon atom to which they are bonded. More preferably, R13 and R14 and the carbon atom to which they are bonded together form a cyclobutyl, cyclopentyl or cyclohexyl ring.

In another embodiment of the compound of formula (IV), R25 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, ring Alkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted hetero Arylalkyl. Preferably R25 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl. More preferably R25 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxy Ethyl, 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-dioxolane-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-Dioxolane-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenylethyl Group, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolane-2-yl)-2-phenethyl, 1-(1,3-dioxane -2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In another embodiment of the compound of formula (IV), R25 is acyl or substituted acyl. More preferably, R25 is acetyl, propionyl, butyryl, benzoyl or phenylacetyl.

In another embodiment of the compound of formula (IV), R25 is an alkyl or substituted alkyl. Preferably R25 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxy Ethyl, 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-dioxolane-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-Dioxolane-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-phenethyl or 1-(1,3-dioxane- 2-yl)-2-phenethyl. More preferably, R25 is methyl, ethyl, propyl, isopropyl, butyl, 1,1-dimethoxyethyl or 1,1-diethoxyethyl.

In another embodiment of the compound of formula (IV), R25 is aryl, arylalkyl or heteroaryl. Preferably R25 is phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl.

In another embodiment of the compound of formula (IV), R25 is cycloalkyl or substituted cycloalkyl. More preferably, R25 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In another embodiment of the compound of formula (IV), R25 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, ring Alkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted hetero Arylalkyl; and R13 and R14 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted aryl Group alkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R13 is alkoxycarbonyl , In the case of substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl, R14 is methyl). Preferably R25 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R13 and R14 are independently hydrogen, alkyl, substituted alkyl, Alkoxycarbonyl, aryl, arylalkyl, carbamoyl, cycloalkyl, cycloalkoxycarbonyl or heteroaryl (preferably when R13 is alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxy In the case of a carbonyl group, a substituted cycloalkoxycarbonyl group or a carbamoyl group, R14 is a methyl group). More preferably R25 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxy Ethyl, 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-dioxolane-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-Dioxolane-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenylethyl Group, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolane-2-yl)-2-phenethyl, 1-(1,3-dioxane -2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl Or 3-pyridyl, and R13 and R14 are independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl , Methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, cyclohexoxycarbonyl , Phenyl, benzyl, phenethyl or 3-pyridyl. Even more preferably R25 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl , 1,1-Dimethoxybenzyl, 1,1-diethoxybenzyl, 1,1-dimethoxy-2-phenethyl, 1,1-diethoxy-2-benzene Ethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, cyclohexyl or 3-pyridyl, and R13 and R14 Independently hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl, cyclohexyl, methoxycarbonyl, ethoxycarbonyl, Isopropoxycarbonyl, cyclohexyloxycarbonyl, phenyl, benzyl, phenethyl, or 3-pyridyl.

In another embodiment of the compound of formula (IV), R25 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, ring Alkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted hetero Arylalkyl, and R13 and R14 together with the atoms to which they are combined form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. Preferably R25 is an acyl group, substituted acyl group, alkyl group, substituted alkyl group, aryl group, arylalkyl group, cycloalkyl group or heteroaryl group, and R13 and R14 together with the atoms to which they bind form a cycloalkyl group or substituted Cycloalkyl ring. More preferably R25 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxy Ethyl, 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-dioxolane-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-Dioxolane-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy-2-phenylethyl Group, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolane-2-yl)-2-phenethyl, 1-(1,3-dioxane -2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl, and R13 and R14 together with their bonded atoms form a cyclobutyl, cyclopentyl or cyclohexyl ring.

In another embodiment of the compound of formula (IV), R25 is acyl or substituted acyl, and R14 and R14 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, Aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl Group or substituted heteroaryl (preferably when R13 is alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl, R14 is methyl). Preferably R25 is acetyl, propionyl, butyryl, benzoyl or phenylacetyl, and R13 and R14 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aromatic Group, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl Or substituted heteroaryl (preferably when R13 is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R14 is methyl).

In another embodiment of the compound of formula (IV), R25 is alkane or substituted alkane, and R13 and R14 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkane Oxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxy Carbonyl, heteroaryl or substituted heteroaryl (preferably when R13 is alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl, R14 is methyl base). Preferably R25 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, neopentyl, 1,1-dimethoxy Ethyl, 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-dioxolane-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-Dioxolane-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-phenethyl or 1-(1,3-dioxane- 2-yl)-2-phenethyl, and R13 and R14 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, aryl Alkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when When R13 is an alkoxycarbonyl group, a cycloalkoxycarbonyl group or a carbamoyl group, R14 is a methyl group).

In another embodiment of the compound of formula (IV), R25 is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, or substituted heteroaryl, and R13 and R14 are independently Ground is hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkane Group, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R13 is alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkane In the case of an oxycarbonyl group, a substituted cycloalkoxycarbonyl group or a carbamoyl group, R14 is a methyl group). Preferably R25 is phenyl, 4-methoxyphenyl, benzyl, phenethyl, styryl or 3-pyridyl, and R13 and R14 are independently hydrogen, alkyl, substituted alkyl, alkoxy Carbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted Cycloalkoxycarbonyl, heteroaryl or substituted heteroaryl (preferably when R13 is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R14 is methyl).

In another embodiment of the compound of formula (IV), R25 is cycloalkyl or substituted cycloalkyl, and R13 and R14 are independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkane Oxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, cycloalkyl, substituted cycloalkyl, cycloalkoxycarbonyl, substituted cycloalkoxy Carbonyl, heteroaryl or substituted heteroaryl (preferably when R13 is alkoxycarbonyl, substituted alkoxycarbonyl, cycloalkoxycarbonyl, substituted cycloalkoxycarbonyl or carbamoyl, R14 is methyl base). Preferably R25 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, and R13 and R14 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 (Preferably when R13 is alkoxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R14 is methyl).

In another embodiment of the compound of formula (IV), R25 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, ring Alkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted hetero Arylalkyl, and R13 and R14 are independently hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl, or heteroaryl. Preferably R25 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R13 and R14 are independently hydrogen, alkyl, substituted alkane Group, cycloalkyl or substituted cycloalkyl. More preferably R25 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R13 and R14 are independently hydrogen, methyl, ethyl, propyl Group, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopentyl or cyclohexyl. In the above embodiment, R25 is preferably 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-dioxane -2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolane-2-yl)-propyl , 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-di Oxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxy Benzyl, 1-(1,3-dioxolane-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy -2-Phenylethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolane-2-yl)-2-phenethyl, 1-(1, 3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl Group, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In another embodiment of the compound of formula (IV), R25 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl, or heteroaryl, and R13 and R14 are independently Ground is hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl, or heteroaryl. Preferably R25 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R13 and R14 are independently hydrogen, aryl, arylalkyl or Heteroaryl. More preferably, R25 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R13 and R14 are independently hydrogen, phenyl, benzyl, benzene Ethyl or 3-pyridyl. In the above embodiment, R25 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-dioxane -2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolane-2-yl)-propyl , 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-di Oxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxy Benzyl, 1-(1,3-dioxolane-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy -2-Phenylethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolane-2-yl)-2-phenethyl, 1-(1, 3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl Group, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In another embodiment of the compound of formula (IV), R25 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl, or heteroaryl, and R13 and R14 are independently Ground is hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl, or heteroaryl. Preferably R25 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R13 and R14 are independently hydrogen, alkyl, substituted alkyl, Alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl (preferably when R13 is alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, In the case of cycloalkoxycarbonyl or substituted cycloalkoxycarbonyl, R14 is methyl; more preferably R13 is methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, Isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl or cyclohexyloxycarbonyl, and R14 is methyl). In the above embodiments, R25 is preferably 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-dioxane -2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolane-2-yl)-propyl , 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-di Oxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxy Benzyl, 1-(1,3-dioxolane-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy -2-Phenylethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolane-2-yl)-2-phenethyl, 1-(1, 3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl Group, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In another embodiment of the compound of formula (IV), R25 is acyl, substituted acyl, alkyl, substituted alkyl, aryl, arylalkyl, cycloalkyl or heteroaryl, and R13 and R14 are Together with the atoms to which they are bound, a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring is formed. Preferably R25 is an acyl group, substituted acyl group, alkyl group, substituted alkyl group, aryl group, arylalkyl group, cycloalkyl group or heteroaryl group, and R13 and R14 together with the atoms to which they are combined form a cycloalkyl group or substitutedofcycloalkyl ring. More preferably, R25 is an acyl group, a substituted acyl group, an alkyl group, a substituted alkyl group, an aryl group, an arylalkyl group, a cycloalkyl group or a heteroaryl group, and R13 and R14 together with the atoms bound to them form a cyclobutyl group, Cyclopentyl or cyclohexyl ring. In the above embodiments, R25 is preferably 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-dioxane -2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3-dioxolane-2-yl)-propyl , 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxybutyl, 1-(1,3-di Oxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxybenzyl, 1,1-diethoxy Benzyl, 1-(1,3-dioxolane-2-yl)-benzyl, 1-(1,3-dioxan-2-yl)-benzyl, 1,1-dimethoxy -2-Phenylethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolane-2-yl)-2-phenethyl, 1-(1, 3-dioxan-2-yl)-2-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4-methoxyphenyl, benzyl, phenethyl Group, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or 3-pyridyl.

In another embodiment of the compounds of formula (I) and (III), R1 ism is 0, and R8, R11, and R12 are as defined above.

In one embodiment of the compounds of formula (I) and (III), R11 is acyl, alkoxycarbonyl, aryloxycarbonyl, cycloalkoxycarbonyl or carbamoyl, R8 is hydrogen, alkoxycarbonyl, Alkyl, aryl, arylalkyl or cyano, and R12 is hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, or arylalkyl.

In another embodiment of the compounds of formula (I) and (III), R11 is selected from acetyl, propionyl, butyryl, isobutyryl, pivaloyl, cyclopentanecarbonyl, cyclohexanecarbonyl, benzyl Acyl, 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-cyclopentylamino Formyl, 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-pyrrolidinylamino Formyl, N-piperidinylcarbamoyl and N-morpholinylcarbamoyl. More preferably R11 is selected from acetyl, propionyl, butyryl, isobutyryl, cyclohexanecarbonyl, benzoyl, phenylacetyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy Carbonyl, butoxycarbonyl, cyclohexyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl , 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), R8 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy Carbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, and cyano. More preferably, R8 is selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

In another embodiment of the compounds of formula (I) and (III), R12 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy Carbonyl, 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), R11 is selected from hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, arylalkyl, and R8 and R12 are associated with them The combined carbon atoms together form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. Preferably R11 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R8 and R12 form together with the carbon atom to which they are bonded Cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. More preferably, R11 is hydrogen or methyl, and R8 and R12 and the carbon atoms to which they are combined together form cyclopent-1-ene, cyclohex-1-ene, 2-cyclopenten-1-one, 2-cyclohexyl En-1-one, 2-(5H)-furanone or 5,6-dihydro-pyran-2-one ring.

In another embodiment of the compounds of formula (I) and (III), R12 is selected from hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, arylalkyl, and R8 and R11 are associated with them The bonded carbon atoms together form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. Preferably R12 is selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R8 and R11 form a ring together with the carbon atom to which they are bonded Alkyl, 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 form together with the carbon atom to which they are bonded γ-butyrolactone, δ-valerolactone or 2,2-dimethyl-1,3-dioxane-4,6-dione ring.

In another embodiment of the compounds of formula (I) and (III), R1 isAnd R15 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl. Preferably R15 is methyl, ethyl, propyl, isopropyl, cyclopentyl, cyclohexyl, phenyl, 4-hydroxyphenyl, benzyl, 4-hydroxybenzyl or 3-pyridyl.

In another embodiment of formula (I) and (III), R1 isWhere R37 is hydrogen, alkyl, substituted alkyl, acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, heterocycloalkyl, substituted cycloheteroalkyl , 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 formula (I) and (III), R1 is

or Wherein q is 0 or 1; R38 and R39 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; R40 and R41 are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; or the carbon to which they are bonded Atoms together form a cycloalkyl ring; R42 and R43 are independently alkyl, substituted alkyl, cycloalkyl, substituted alkyl, aryl, substituted aryl, heteroaryl and substituted aryl or and and The carbon atoms to which they are bonded together form an aryl, substituted aryl, heteroaryl or substituted aryl ring; and R37 is as defined above.

In a preferred embodiment of the compound of formula (I)-(IV), Y is O, R3, R6 and R7 are hydrogen, and R4 and R5 together with the carbon atom to which they are bound form a cycloalkyl, substituted ring Alkyl, cycloheteroalkyl, substituted cycloheteroalkyl, bridged cycloalkyl, or substituted bridged cycloalkyl ring.

In another preferred embodiment of the compounds of formula (I)-(IV), R4 and R5 together with the carbon atom to which they are bonded form a cycloalkyl or substituted cycloalkyl ring. In one embodiment, n is zero, t is zero and u is zero. In another embodiment, n is 1, and R2 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)CH3, -CH2CO2H, -CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, -CH2SCH3, CH2SH, -CH2(CH2)3NH2 or -CH2CH2CH2NHC(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.

In another preferred embodiment of the compounds of formula (I)-(IV), R4 and R5 together with the carbon atom to which they are bound form a cyclobutyl or substituted cyclobutyl ring. Preferably, the substituted cyclobutyl ring is substituted by one or more substituents selected from the group consisting of alkane, substituted alkane, halogen, hydroxy, carboxy, and alkoxycarbonyl.

In another preferred embodiment of the compounds of formula (I)-(IV), R4 and R5 together with the carbon atom to which they are bound form a cyclopentyl or substituted cyclopentyl ring. Preferably, the cyclopentyl ring is substituted with a chain alkyl group, substituted chain alkyl group, halogen, hydroxy group, carboxyl group or alkoxycarbonyl group. More preferably, the cyclopentyl ring is substituted with a chain alkyl group. Even more preferably the cyclopentyl ring is selected fromwith Preferably, in a more specific version of the above embodiment, R7 is hydrogen.

In another preferred embodiment of the compounds of formula (I)-(IV), R4 and R5 together with the carbon atom to which they are bound form a cyclohexyl or substituted cyclohexyl ring. Preferably, the cyclohexyl ring is substituted with a chain alkyl group, substituted chain alkyl group, halogen, hydroxy group, carboxyl group or alkoxycarbonyl group. More preferably, the cyclohexyl ring is substituted by a chain alkyl group. Even more preferably the cyclohexyl ring is selected fromwith

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

In another preferred embodiment of the compounds of formula (I)-(IV), R4 and R5 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 R2 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)CH3, -CH2CO2H, -CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, -CH2CH2SCH3, CH2SH, -CH2(CH2)3NH2 or -CH2CH2CH2NHC(NH)NH2. In another embodiment, n is 1, and R2 and R16 together with the atoms to which they are bonded form a pyrrolidine ring. Preferably, R4 and R5 and the carbon atom to which they are bonded together form a cyclic heterochain alkyl ring. More preferably, the cycloheterochain alkyl ring is selected fromor Wherein Z is O, S(O)p or NR18P is 0, 1 or 2; and R18 is selected from hydrogen, alkyl, substituted alkyl, acyl and alkoxycarbonyl. More preferably, the cycloheterochain alkyl ring is selected fromwith Preferably, in a more specific version of the above embodiment, R7 is hydrogen.

In another embodiment of the compounds of formula (I)-(IV), R4 and R5 together with the carbon atom to which they are attached form a bridged cycloalkyl ring. In one embodiment, n is zero. In another embodiment, n is 1, and R2 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)CH3, -CH2CO2H, -CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, -CH2CH2SCH3, CH2SH, -CH2(CH2)3NH2 or -CH2CH2CH2NHC(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 the bridged cycloalkyl isor Preferably, in a more specific version of the above embodiment, R7 is hydrogen.

In another embodiment of the compounds of formula (I)-(IV), Y is O, R6 and R7 are hydrogen, R4 is alkyl or cycloalkyl, R5 is hydrogen or alkyl, and R3 is hydrogen or alkane. base. In one embodiment, n is zero. In another embodiment, n is 1 and R2 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)CH3, -CH2CO2H, -CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, -CH2CH2SCH3, CH2SH,- CH2(CH2)3NH2 or -CH2CH2CH2NHC(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 formula (I)-(IV), Y is O, R5 and R7 are hydrogen or alkane, R3 and R6 are hydrogen, and R4 is a substituted heteroalkyl.

Preferably R4 is

A is NR19, O or S; B is alkyl, substituted alkyl, alkoxy, halogen, hydroxy, carboxy, alkoxycarbonyl or amino; R19 is hydrogen, alkyl, cycloalkyl or aryl; j Is an integer of 0-4; k is an integer of 1-4; and l is an integer of 0-3.

More preferably, k is 1.

In another embodiment of the compounds of formula (I)-(IV), Y is O, R5 and R7 are hydrogen or alkyl, R3 and R6 are hydrogen, and R4 is substituted alkyl, cycloalkyl Or substituted cycloalkyl. Preferably R4 is selected from Preferably R4 iswith h is an integer of 1-6; 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 R4 is selected fromwith Preferably, the compounds of formula (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 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-butyric acid; 3-aminomethyl-4-cyclopentyl-butyric acid Acid; 3-Aminomethyl-4-cyclohexyl-butyric acid; 3-aminomethyl-4-phenoxy-butyric acid; 3-aminomethyl-5-phenoxy-hexanoic acid; and 3-amino Methyl-5-benzylsulfanyl-pentanoic acid.

Particularly preferred embodiments of formula (I) include compounds of formula (V) and (VI):Wherein R1, R2, R7 and R16 are as defined above.

In one embodiment of the compounds of formula (V) and (VI), n is zero. In another embodiment, n is 1, and R2 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)CH3, -CH2CO2H, -CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, -CH2CH2SCH3, -CH2SH , -CH2(CH2)3NH2 or -CH2CH2CH2NHC(NH)NH2. Preferably in the above embodiment, R7 is hydrogen.

In another embodiment of the compounds of formula (V) and (VI), n is 1, R1 is R24C(O)- or R24C(S)-; and R24 is alkyl, substituted alkyl, heteroalkyl , Aryl, substituted aryl, heteroaryl or substituted heteroaryl. Preferably R24 is methyl, ethyl, 2-propyl, tert-butyl, -CH2OCH(CH3)2, phenyl or 3-pyridyl. Preferably in this embodiment, R7 is hydrogen, an alkyl group, a substituted alkyl group, an alkenyl group, a substituted alkenyl group, an aryl group, or a substituted aryl group. More preferably R7 is hydrogen, methyl, ethyl, benzyl, -C(CH3)=CH2, -CH2C(O)N(CH3)2,or Where V is O or CH2.

Most preferably R7 is hydrogen.

In another embodiment of the compounds of formula (V) and (VI), n is 1, R1 is R25OC(O)- or R25SC(O)-; and R25 is alkyl, substituted alkyl, heteroalkyl , Aryl, substituted aryl, heteroaryl or substituted heteroaryl. Preferably R25 is ethyl, 2-propyl, neopentyl, -CH2OCH(CH3)2, phenyl or 2-pyridyl. Preferably in this embodiment R7 is hydrogen, alkanyl, substituted alkenyl, alkenyl, substituted alkenyl, aryl or substituted aryl. More preferably R7 is hydrogen, methyl, ethyl, benzyl, -C(CH3)=CH2, -CH2C(O)N(CH3)2,or Where V is O or CH2.

Most preferably R7 is hydrogen.

In another embodiment of the compounds of formula (V) and (VI), R1 is

And R15 is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl.

Preferably R15 is methyl, ethyl, propyl, isopropyl, cyclopentyl, cyclohexyl, phenyl, 4-hydroxyphenyl, benzyl, 4-hydroxybenzyl or 3-pyridyl. In a more specific version of this embodiment, R7 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, or substituted aryl. More preferably R7 is hydrogen, methyl, ethyl, benzyl, -C(CH3)=CH2, -CH2C(O)N(CH3)2,or Where V is O or CH2.

Preferably R7 is hydrogen.

A particularly preferred embodiment of the compound of formula (V) and (VI) is a compound selected from the group consisting of: 1-{[((5-methyl-2-oxo-1,3-dioxolan-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), R1 is

m is 0, and R8, R11, and R12 are as defined above. In one embodiment of the compound of formula (V) and (VI), R11 is an acyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a cycloalkoxycarbonyl group, a carbamoyl group or a substituted carbamoyl group, and R8 is hydrogen , Alkoxycarbonyl, alkyl, aryl, arylalkyl or cyano, and R12 is hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl or arylalkyl. In another embodiment of the compound of formula (V) and (VI), R11 is selected from acetyl, propionyl, butyryl, isobutyryl, pivaloyl, cyclopentanecarbonyl, cyclohexanecarbonyl, benzyl Acyl, 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-cyclopentylamino Formyl, 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-pyrrolidinylamino Formyl, N-piperidinylcarbamoyl and N-morpholinylcarbamoyl. In another embodiment of the compound of formula (V) and (VI), R11 is selected from acetyl, propionyl, butyryl, isobutyryl, cyclohexanecarbonyl, benzoyl, phenylacetyl, methoxy Carbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, cyclohexyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, carbamoyl, N-methylcarbamoyl , N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-phenylcarbamoyl, N-benzylcarbamoyl, N,N-dimethylamino Formyl, N,N-diethylcarbamoyl, N,N-dipropylcarbamoyl, N-pyrrolidinylcarbamoyl, N-piperidinylcarbamoyl and N-morpholinylcarbamoyl Acyl.

In one embodiment of the compounds of formula (V) and (VI), R8 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl , Propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl and cyano. Preferably R8 is selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl.

In another embodiment of the compounds of formula (V) and (VI), R12 is selected from hydrogen, methyl, ethyl, propyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxy Carbonyl, 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), R11 is selected from hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, arylalkyl, and R8 and R12 are associated with them The combined carbon atoms together 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, and R8 and R12 form a ring together with the carbon atom to which they are bonded Alkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. More preferably, R11 is hydrogen or methyl, and R8 and R12 together with the carbon atom to which they are combined 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), R12 is selected from hydrogen, alkoxycarbonyl, alkyl, substituted alkyl, aryl, arylalkyl, and R8 and R11 are combined with The carbon atoms to which they bind together form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring. Preferably R12 is selected from hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R8 and R11 form a ring together with the carbon atom to which they are bonded Alkyl, substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl ring. More preferably, R12 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl and butoxycarbonyl, and R8 and R11 together with the carbon atom to which they are bonded Form γ-butyrolactone, δ-valerolactone or 2,2-dimethyl-1,3-dioxane-4,6-dione ring.

In a more specific version of the embodiment of the compound of formula (V) and (VI) above, R7 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, aryl, or Substituted aryl. More preferably R7 is hydrogen, methyl, ethyl, benzyl, -C(CH3)=CH2, -CH2C(O)N(CH3)2,or

Where V is O or CH2.

Most preferably R7 is hydrogen.

A particularly preferred embodiment of the compound of formula (V) and (VI) is a compound selected from: 1-{(1-methyl-3-oxo-but-1-enyl)aminomethyl}-1 -Piperidinium cyclohexaneacetate; 1-{1-[(2-oxo-tetrahydrofuran-3-yl subunit) ethylaminomethyl}-1-piperidinium cyclohexaneacetate; 1-{( 2-Carbomethoxy-cyclopent-1-enyl)aminomethyl}-1-cyclohexane piperidinium acetate; and 1-{(1-methyl-2-(ethoxycarbonyl) )-3-Ethoxy-3-oxoprop-1-enyl)aminomethyl}-1-cyclohexane piperidinium acetate.

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, R2, R7, R13, R14, R16 and R25 are as defined above.

In a preferred embodiment, the compounds of formula (VII) and (VIII) do not include the following compounds: if any of R13 or R14 is hydrogen, alkoxycarbonyl, substituted alkoxycarbonyl, carbamoyl, ring For alkoxycarbonyl or substituted cycloalkoxycarbonyl, the other of R13 or R14 is not hydrogen; and R25C(O) is not a moiety derived from bile acid.

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

In another embodiment of the compounds of formula (VII) and (VIII), R7 is hydrogen, alkanyl, substituted alkenyl, alkenyl, substituted alkenyl, aryl, or substituted aryl. Preferably R7 is hydrogen, methyl, ethyl, benzyl, -C(CH3)=CH2, -CH2C(O)N(CH3)2,or Where V is O or CH2.

Most preferably R7 is hydrogen.

In another embodiment of the compounds of formula (VII) and (VIII), n is zero. In another embodiment of the compounds of formula (VII) and (VIII), n is 1, R16 is hydrogen and R2 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)CH3, -CH2CO2H, -CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, -CH2CH2SCH3, -CH2SH, -CH2(CH2)3NH2 or -CH2CH2CH2NHC(NH)NH2. 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 R2 and R16 together with the atoms to which they are bonded form a pyrrolidine ring.

In another embodiment of the compounds of formula (VII) and (VIII), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolane-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-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, R13 is methyl and R14 is hydrogen.

In another embodiment of the compounds of formula (VII) and (VIII), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolane-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-phenethyl, 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), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 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-phenethyl, 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), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolane-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-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, R13 is isopropyl and R14 is hydrogen.

In another embodiment of the compounds of formula (VII) and (VIII), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolane-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-phenethyl, 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), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolane-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-phenethyl, 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), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolane-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-phenethyl, 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), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 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-phenethyl, 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 formula (VII) and (VIII) compound to another embodiment of the composition, R25 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-dioxolane-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolane-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-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolane-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, R13 is cyclopentyl and R14 is hydrogen.

In another embodiment of the compounds of formula (VII) and (VIII), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolane-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-phenethyl, 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), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolane-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-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, R13 is methyl and R14 is methyl.

In another embodiment of the compounds of formula (VII) and (VIII), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 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-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4 -Methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R13 is methoxycarbonyl and R14 is methyl.

In another embodiment of the compounds of formula (VII) and (VIII), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolane-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-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4 -Methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R13 is ethoxycarbonyl and R14 is methyl.

In another embodiment of the compounds of formula (VII) and (VIII), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 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-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, R13 is propoxycarbonyl and R14 is methyl.

In another embodiment of the compounds of formula (VII) and (VIII), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolane-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-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4 -Methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R13 is isopropoxycarbonyl and R14 is methyl .

In another embodiment of the compounds of formula (VII) and (VIII), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolane-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-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4 -Methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R13 is butoxycarbonyl and R14 is methyl.

In another embodiment of the compounds of formula (VII) and (VIII), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolane-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-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4 -Methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R13 is isobutoxycarbonyl and R14 is methyl .

In another embodiment of the compounds of formula (VII) and (VIII), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 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-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, R13 is sec-butoxycarbonyl and R14 is methyl .

In another embodiment of the compounds of formula (VII) and (VIII), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 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-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4 -Methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R13 is tert-butoxycarbonyl and R14 is methyl .

In another embodiment of the compounds of formula (VII) and (VIII), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolane-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-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4 -Methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R13 is cyclohexyloxycarbonyl and R14 is methyl .

In another embodiment of the compounds of formula (VII) and (VIII), R25 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-dioxolane-2-yl)- Ethyl, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3 -Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethyl Oxybutyl, 1-(1,3-dioxolane-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-phenethyl, 1,1-diethoxy-2-phenethyl, 1-(1,3-dioxolane-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, R13 is phenyl and R14 is hydrogen.

In another embodiment of the compounds of formula (VII) and (VIII), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolane-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-phenethyl, 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), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolane-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-phenethyl, 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), R25 is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isoamyl Group, sec-pentyl, neopentyl, 1,1-dimethoxyethyl, 1,1-diethoxyethyl, 1-(1,3-dioxolan-2-yl)-ethyl Group, 1-(1,3-dioxan-2-yl)-ethyl, 1,1-dimethoxypropyl, 1,1-diethoxypropyl, 1-(1,3- Dioxolane-2-yl)-propyl, 1-(1,3-dioxan-2-yl)-propyl, 1,1-dimethoxybutyl, 1,1-diethoxy Butyl, 1-(1,3-dioxolane-2-yl)-butyl, 1-(1,3-dioxan-2-yl)-butyl, 1,1-dimethoxy Benzyl, 1,1-diethoxybenzyl, 1-(1,3-dioxolane-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-phenethyl, acetyl, propionyl, butyryl, benzoyl, phenylacetyl, phenyl, 4 -Methoxyphenyl, benzyl, phenethyl, styryl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and 3-pyridyl, R13 is 3-pyridyl and R4 is hydrogen.

Particularly preferred embodiments of the compounds of formula (VII) and (VIII) include compounds selected from: 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-pivaloyloxy Ethoxy)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-ring Hexane acetic acid;

1-{[(α-isobutyryloxybutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid; 1-{[(α-benzoyloxybutoxy)carbonyl]aminomethyl Yl}-1-cyclohexaneacetic acid; 1-{[(α-acetoxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid; 1-{[(α-propionyloxyiso Butoxy)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 Yl}-1-cyclohexaneacetic acid; 1-{[(α-2,2-diethoxypropionyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid; 1- {[(α-2-(1,3-Dioxolane-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-cyclohexane Acetic 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-benzyl Acyloxybenzyloxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid; 1-{[(1-(3-methylbutyryloxy)-2-phenylethoxy)carbonyl]amino Methyl}-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-isobutyl Acyloxyethoxy)carbonyl]aminomethyl}-5-methylhexanoic acid; 3-{[(α-isobutyryloxyisobutoxy)carbonyl]aminomethyl}-5-methylhexanoic acid Acid; and

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

In one embodiment, the compound of the invention has 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 formula (IX) and (X):In one embodiment of the compounds of formula (IX) and (X), t is zero. In another embodiment, t is 1 and R2 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)CH3, -CH2CO2H, -CH2CH2CO2H, -CH2CONH2, -CH2CH2CONH2, -CH2CH2SCH3, -CH2SH, -CH2(CH2)3NH2 or -CH2CH2CH2NHC(NH)NH2.

In another embodiment of the compounds of formula (IX) and (X), R20 and R21 are independently selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl . Preferably R20 and R21 are independently selected from alkyl, substituted aryl and heteroaryl. In one embodiment, R20 is methyl and R21 is methyl. Preferably in this last embodiment, R7 is hydrogen, methyl, ethyl, benzyl, -C(CH3)=CH2, -CH2C(O)N(CH3)2,or Where V is O or CH2.

Most preferably R7 is hydrogen.

In another embodiment of the compounds of formula (IX) and (X), R20 and R21 together with the carbon atom to which they are bound form a cycloalkyl or substituted cycloalkyl ring. In one embodiment, R20 and R21 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,or Where V is O or CH2.

Most preferably R7 is hydrogen.

In one embodiment, the compound of the invention has the structure of formula (III):

In one embodiment of the compound of formula (III), n is 1, R1 is hydrogen and R2 is arylalkyl. Preferably R2 is benzyl. In another embodiment of the compound of formula (III), n is 0 and R1 is R25OC(O)-. Preferably R25 is an alkyl group or a substituted alkyl group. More preferably, R25 is ethyl. In another embodiment of the compound 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 groups.

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 present invention also includes a GABA analog derivative for administration to a patient in need of treatment, MG, wherein M is a motif, G is a GABA analog, and a derivative of HG (where H is hydrogen). Once motif M is cleaved from G and any of its metabolites, the carcinogenic dose (TD50) to rats is greater than 0.2mmol/kg/day. Moreover, when the rats are administered to the colon, the motif M is cleaved from G at a sufficient rate to produce: (i) at least the maximum plasma HG concentration (Cmax) obtained by administering equimolar doses of HG through the colon And (ii) an AUC that is at least 120% of the AUC obtained by administering an equimolar dose of HG through the colon.

Preferably MG has the structure of formula (XIV):Or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: M is a motif; Y is O or S; R is hydrogen, or R and R6 together with the atoms bound to them form azetidine, Substituted azetidine, pyrrolidine or substituted pyrrolidine ring; R3 and R6 are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted aryl Cycloalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, and substituted heteroarylalkyl; R4 and R5 are independently selected from hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted ring Alkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl, or optionally R4 and R5 and their combination The carbon atoms together form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, or bridged cycloalkyl ring; and R7 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):Among them: n, X, R1 and R2 are as defined above.

In one embodiment, MG includes a compound in which once HG is cleaved from M, there is substantially no lactam having the structure of formula (XVI):Where R is hydrogen, and R3, R4, R5 and R6 are as defined above.

Preferably, the motif M or any metabolite formed by M does not form formaldehyde or pivalic acid when GM is cleaved. In one embodiment, when administering colon administration to rats, the motif M is cleaved from G at a sufficient rate in vivo to produce at least 200% of the Cmax of plasma HG obtained by administering equimolar doses of HG through the colon, The Cmax of plasma HG is most preferably at least 1000%. Preferably, when the rat is administered to the colon, the motif M is cleaved from G at a sufficient rate to produce at least 200%, and most preferably at least 500%, of the AUC of plasma obtained by administering equimolar doses of HG through the colon. AUC of plasma HG. In another embodiment, after administering a dose of about 60 μmol equivalent of HG/kg to a dog orally (for example, using an osmotic mini-pump device), the element M is cleaved from HG at a sufficient rate to produce at least in progress. The plasma concentration of 200% of the plasma HG concentration obtained from the equimolar dose of HG after administration in the same manner is the plasma concentration 12 hours after the administration.

4.3 Synthesis of the compound of the present invention The compound of the present invention can be obtained by the synthetic method shown in Route 1-17. Those skilled in the art will recognize that the preferred synthetic route for the compounds of the invention is to combine motifs with GABA analogs. Various methods have been described in the synthesis technology 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 U.S. Patent 6,103,932; Silverman et al. U.S. Patent 6,117,906; Silverman, International Publication WO92/09560; 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 WO98/17627; Guglietta et al., International Publication WO 99/08671; Bryans et al., International Publication WO 99/21824; Bryans Et al., International Open 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; Bryans et al., International Publication WO00/15611; Bryans, International Publication WO 00/31020; and Bryans et al., International Publication WO 00/50027). Other methods are known in GABA analog synthesis technology and can be easily obtained by 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" ", (Wiley, Second Edition, 1991); Harrison et al., "Compendium of Synthetic Organic Methods", Vol. 1-8 (John Wiley and Sons, 1971-1996); "Beilstein Handbook of Organic Chemistry (Beilstein Handbook of Organic Chemistry), "Beilstein Institute 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 )", Pergamon Press, 1991; "Theilheimer's Synthetic Methods of Organic Chemistry," Vol. 1-45, Karger, 1991; March, "Advanced Organic Chemistry, "Wiley Interscience, 1991 ; Larock "Comprehensive Organic Transformations (Comprehensive Organic Transformations)," VCH Publisher, 1989; Paquette, "Encyclopedia of Reagents for Organic Synthesis (Encyclopedia of Organic Synthesis Reagents)," John Wiley & Sons, 1995, Bodanzsky, "Principles of Peptide Synthesis," Springer Verlag, 1984; Bodanzsky, "Practice of Peptide Synthesis" Springer Verlag, 1984).

Therefore, the raw materials used to prepare the compound of the present invention and its intermediate products are commercially available or can be prepared by known synthetic methods. Other methods for synthesizing the prodrugs described herein are as described in the art, or are very obvious to those skilled in the art considering the references provided above, and can be used to synthesize the compounds of the present invention. Therefore, the method shown in the course of this article is an illustration rather than a synthesis.

In any of the following routes, after functionalizing the amino group of the GABA analog with a motif or other protecting group, the carboxylic acid group can be converted into an ester or thioester by many synthetic methods known to those skilled in the art. In a preferred embodiment, GABA analogs can be reacted with alcohols or thiols in the presence of coupling agents (for example, carbodiimide and dimethylaminopyridine) to obtain esters. In another preferred embodiment, the GABA analog can be reacted with an alkyl halide in the presence of a base to obtain an ester. Other methods of converting GABA analogs into esters or thioesters are within the scope of the references provided herein that are familiar to those skilled in the art.

As shown in Scheme 1 above, the carboxylic acid can be directly combined with the terminal amino (or hydroxyl) group of the GABA analog derivative (6) to obtain the adduct (7). Reagents for carrying out this reaction are known to those skilled in the art, and include but are not limited to carbodiimide, ammonium salt, phosphonium salt 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 synthesis (7).

Route 2

As shown in Fig. 2, the GABA analog derivative (6) can be converted into carbamate (8) by treatment with various carbonic acid derivatives in the presence of a base (e.g., hydroxide, tertiary amine, etc.). Alternatively, a known alcohol addition to isocyanate (9) or (10) can be used for synthesis (8).

As shown in Scheme 3, the GABA analog derivative (6) can be converted to the thioamide (11) by treatment with a thioacid in the presence of a coupling agent. The reagents used to carry out this reaction are known to those skilled in the art, and include, but are not limited to, carbodiimide, ammonium salt, phosphonium salt, and the like. Alternatively, the reaction of a thioacid derivative such as thioacid chloride, symmetrical anhydride or mixed anhydride with (6) in the presence of a base (such as hydroxide, tertiary amine, etc.) can be used to synthesize thioamide (11). In another method, the amide (7) can be converted to the thioamide (11) by heating in the presence of phosphorus pentasulfide (when n=0).

Can be derived from the corresponding thiocarbonate derivatives (ie P=O, Q=S and P=SQ=O, respectively) (where W is chloride, imidazolyl or 4-nitrophenoxy) and GABA analogs The derivative (6) reacts in the presence of a base to synthesize thiocarbamates (12) and (13). It is also possible to form thiocarbamate (13) by reacting thiol with isocyanate (9) or (10). It can be reacted by GABA analog derivative (6) and dithiocarbonate derivative (ie P and Q=S) (where 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 4A method for synthesizing the compound of formula (IV) is exemplified in Route 5.

Route 5The chloroformate (15) is treated with an aromatic leaving group such as p-nitrophenol in the presence of a base to obtain p-nitrophenyl carbonate (16). The halides are exchanged to obtain iodide (17), and this iodide is reacted with a metal or a tetraalkylammonium salt of a carboxylic acid to obtain compound (18). Optionally, treatment (18) with a GABA analog derivative (19) in the presence of trimethylsilyl chloride gives the compound of formula (IV). Methods of preparing related acyloxyalkyl carbamate 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, the compound of formula (IV) can be prepared from carbonate (18) in a stepwise manner as shown in Scheme 6. Here (18) is reacted with α-amino acid (20) optionally protected as an ester to obtain intermediate product (21), which provides compound (22) when deprotected (if necessary), and then used in the art Known standard peptide coupling agents couple it with the GABA analog (23).

Route 6Another method of synthesizing the compound of formula (IV) is carried out by carbonylation of GABA analog derivatives (19) into intermediate carbamates, which is carried out in a modification of the method disclosed in the art. It is collected by 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 alkali (e.g. CS2CO3, Ag2CO3 or AgO) in a solvent such as DMF or NMP. Optionally, an activated halide is added in the presence of an 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 halide (24).

Route 7Alternatively, the compound of formula (IV) can be prepared in a stepwise manner as shown in Scheme 8. The carbonylation and alkylation of the carboxy-protected α-amino acid (20) provides the intermediate product (21), which is coupled with the GABA analog (23) during deprotection, as shown in Scheme 6 above.

Route 8But 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 synthesizing prodrugs of their derivatives) co-pending U.S. patent application). As shown in Scheme 9, oxidation of the ketocarbamate (25) yields the compound of formula (IV). Preferred solvents include, but are not limited to, tert-butanol, diethyl ether, acetic acid, hexane, dichloroethane, dichloromethane, ethyl acetate, acetonitrile, methanol, chloroform, and water. Generally, the oxidant may be an organism (such as yeast or bacteria), or a chemical agent (such as enzymes or peroxides). The preferred oxidant package is successfully used to oxidize the ketone Baeyer-Villager to an oxidant for ester or lactone (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 9Other compounds of the present invention can be synthesized by Baeyer-Villager type oxidation from suitable ketone carbamate derivatives, provided that they do not contain chemical functional groups that are easily decomposed or transformed under reaction conditions.

Ketone carbamate (25) can be prepared from the corresponding α-hydroxy ketone compound (26) by the following method: directly by reacting with isocyanate (9), or first converting the α-hydroxy ketone compound into a halogenated chloroformate Or the activated carbonate intermediate product (27), and then react with compound (19), as illustrated in Route 10.

Route 10

Alternatively, the keto carbamate (25) can be prepared in a stepwise manner through the α-amino acid carbamate (28) shown in Route 11 according to the above-mentioned coupling method.

Route 11Note that one method of preparing the isocyanate derivative of the GABA analog used in Scheme 10 above (ie, compound (9)) starts from the appropriate hexavalent anhydride (29) as shown in Scheme 12. The anhydride ring is opened by reacting with alcohol or thiol nucleophile to obtain carboxylic acid (30). Convert this compound into an intermediate acyl azide in a 2-step sequence (i.e., first activate the carboxyl group to a mixed anhydride, acid halide or synthetic equivalent, and then replace it with an azide) or directly (e.g., by treatment with PH2P(O)N3) nitride. The acyl azide intermediate product is subjected to Curtis rearrangement by thermal decomposition in a suitable solvent (for example toluene) at a temperature of 0°C to 120°C to obtain isocyanate (9). Optionally, the isocyanate is not separated, but formed in situ, and its formation is terminated by reaction with α-hydroxyketone (26) to obtain the target product (25).

Route 12A method for the synthesis of oxodioxolenyl methyl carbamate prodrug (36) is disclosed in Route 13. The hydroxy ketone (31) is treated with phosgene or carbonyl diimidazole in the presence of a base to obtain the cyclic carbonate (32). The free radical is brominated with N-bromosuccinimide and azoisobutyronitrile to obtain bromide (33), which is converted to alcohol (34). The alcohol (34) is converted into a dicarbonate (35) by reaction with 4-nitrophenyl chloroformate, and then it is reacted with the GABA analog derivative (19) to obtain the prodrug (36). Alternatively, compound (34) is reacted with isocyanate (9) to obtain compound (36), where n is zero.

Route 13

The prodrug (41) can be synthesized by the method disclosed in Route 14. Coupling of carboxylic acid (37) and alcohol (38) (e.g., dicyclohexylcarbodiimide and pyridine) gives ester (39). The ester (39) is converted into the activated carbonate (40) by reaction with 4-nitrophenyl chloroformate, and then the prodrug (41) is obtained by reaction with the GABA analog derivative (19).

Route 14The alkene can be simply synthesized by reacting the active carbonyl compound (42) with the GABA analog derivative (19) (wherein R16=H) under the dehydration conditions shown in Scheme 15 optionally in the presence of a secondary amine as a catalyst. Amine prodrugs such as (43).

Route 15Compound (III) can be synthesized through the route shown in Route 16.

The GABA analog (23) is reacted with the α-activated ester derivative (44) to give the amino ester (45).

The amino group of (45) is capped by acylation to obtain (46) (for example, using the above-mentioned method), and the free ester is acidified under standard conditions to obtain the diester (47). Dieckman condensation followed by decarboxylation gave ketone (48). Then, peroxyacid oxidation is performed to obtain lactone (III).

Route 16The imine prodrug (II) can be synthesized by treating the ketone or ketone derivative (49) with the GABA analog derivative (50) under dehydrating conditions as described in Route 17.

Route 17

Phosphorus prodrugs can be synthesized by conventional methods known in the art. Similarly, prodrugs with SN bonds can be synthesized by using methods described in the art.

4.4 Therapeutic application of the compounds of the present invention. According to the present invention, the compounds and/or compositions of the present invention are administered to patients suffering from the following diseases, preferably humans: epilepsy, depression, anxiety, psychosis, fainting seizures, hypokinesia, cranial abnormalities , Neurodegenerative disease, panic, pain (especially neuropathic pain and muscle and bone 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 can be administered to patients, preferably humans, as preventive measures against various diseases or conditions. Therefore, the compound and/or composition of the present invention can be used as a preventive measure for patients who are susceptible to the following diseases: epilepsy, depression, anxiety, psychosis, fainting seizures, hypokinesia, cranial abnormalities, neurodegenerative diseases, panic, Pain (especially neuropathic pain and muscle and bone pain), inflammatory disease (i.e. arthritis), insomnia, gastrointestinal disease and alcohol withdrawal syndrome. Therefore, the compounds and/or compositions of the present invention can be used to prevent one disease or condition while simultaneously treating another disease and condition (e.g., prevention of psychosis and treatment of gastrointestinal diseases; prevention of neuropathic pain and treatment of alcohol withdrawal syndrome ).

It can be determined by methods known in the art that the compounds and/or compositions of the present invention treat epilepsy, depression, anxiety, psychosis, fainting seizures, hypokinesia, cranial abnormalities, neurodegenerative diseases, panic, pain (especially neuropathic pain) And muscle and bone pain), inflammatory diseases (i.e. arthritis), insomnia, gastrointestinal diseases and alcohol withdrawal syndrome (see, for example, Satzinger et al., U.S. Patent 4,024,175; Satzinger et al., U.S. Patent 4,087,544; Woodruff , U.S. Patent 5,084,169; Silverman et al., U.S. Patent 5,563,175; Singh, U.S. Patent 6,001,876; 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 WO99/08671; Bryans et al., International Publication WO 99/21824; Bryans et al., International Publication WO 99/31057; Magnus-Miller et al., International Publication WO 99/37296; Bryans International Publication WO 99/31075; Bryans et al. International Publication WO99/61424; Pande, International Publication WO 00/23067; Bryans, International Publication WO00/31020; Bryans et al., International Publication WO 00/50027; and Bryans Et al., International Open WO 02/00209). The compounds and/or compositions of the present invention can be used to treat or prevent epilepsy, depression, anxiety, psychosis, fainting seizures, hypokinesia, cranial abnormalities, neurodegenerative diseases, panic attacks by methods described in the art (see above) , Pain (especially neuropathic pain and muscle and bone pain), inflammatory disease (ie arthritis), insomnia, gastrointestinal disease and alcohol withdrawal syndrome. Therefore, those skilled in the art can analyze and use the compounds and/or compositions of the present invention to treat or prevent epilepsy, depression, anxiety, psychosis, fainting seizures, hypokinesia, cranial abnormalities, neurodegenerative diseases, panic, pain (especially It is neuropathic pain and muscle and bone pain), inflammatory disease (ie arthritis), insomnia, gastrointestinal disease and alcohol withdrawal syndrome.

4.5 Therapeutic/Prophylactic Administration The compounds and/or compositions of the present invention can be advantageously used in human medicine. As described in section 4.4 above, the compounds or compositions of the present invention are used to treat or prevent epilepsy, depression, anxiety, psychosis, fainting seizures, hypokinesia, cranial abnormalities, neurodegenerative diseases, panic, pain (especially neuropathic pain). And muscle and bone pain), inflammatory disease (i.e. 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 used alone or in combination with other agents. The compound and/or composition of the present invention can also be administered or used alone or in combination with other pharmaceutically active agents, including other compounds of the present invention.

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

The compound or composition of the present invention, which contains one or more compounds of the present invention, is preferably administered orally. The compounds and/or compositions of the present invention can also be administered by other conventional routes, such as by infusion or pill injection, through epithelial or mucosa and skin lining (such as oral mucosa, rectum and intestinal mucosa, etc.). Administration can be systemic or local. A variety of delivery systems are known delivery systems that can be used to administer the compounds and or compositions of the present invention (for example, encapsulation in liposomes, microparticles, microcapsules, capsules, etc.). Administration methods include, but are not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, oral, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectal, inhalation or topical Administration, especially to the ears, nose, eyes or skin.

In a particularly preferred embodiment, the compounds and/or compositions of the present invention can be delivered via 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," Langer and Wise (eds.), CRC Pres., 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 carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and hydroxyethyl cellulose (most preferably hydroxypropyl methyl cellulose). 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 are 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). Polymers that degrade (ie, controlled release by enzymes) and polymers that form membrane layers that are destroyed by pressurization (ie, controlled release by pressure).

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, the OROSTM osmotic device is used in an oral sustained release delivery device (Theeuwes et al., US Patent 3,845,770; Theeuwes et al., US Patent 3,916,899).

In another embodiment, the controlled release system can be placed near the target of the compound and/or composition of the present invention, so that only a portion of the system dose is required (see, for example, Goodson, in "Medical Applications of Controlled Release (Controlled Release Medical applications)," supra, vol. 2, pp. 115-138 (1984)). It can also be applied to other controlled release systems described in Langer, 1990, Science 249: 1527-1533.

The compounds and/or compositions of the present invention preferably provide GABA analogs (e.g., gabapentin and pregablin) when administered to a patient in vivo. Although not intending to be bound by theory, the motifs of the compounds and/or compositions of the present invention can be cleaved chemically and/or enzymatically. One or more enzymes present in the stomach, intestinal lumen, intestinal tissue, blood, liver, brain or any suitable tissue of a mammal can enzymatically cleave the motif of the compound or composition of the present invention. The cleavage mechanism is not important to the present invention. Preferably, the GABA analog formed by cleavage of the prodrug from the compound of the present invention does not contain large amounts of lactam contaminants (preferably less than 0.5 wt%, more preferably less than 0.2 wt%, and most preferably less than 0.1 wt%). The degree of release of lactam contaminants from the prodrugs of the present invention can be evaluated using standard in vitro analysis methods.

Although not intending to be bound by theory, the motifs of the compounds and/or compositions of the present invention may be absorbed by the gastrointestinal tract (e.g., in the stomach or intestine) and/or after being absorbed by the gastrointestinal tract (e.g., in the intestine). Tissue, blood, liver, or other suitable mammalian tissue) is lysed. If the motif of the compound of the present invention is cleaved before being absorbed by the intestinal tract, the resulting GABA analog can be routinely absorbed into the systemic circulation (for example, by a large neutral amino acid transporter located in the small intestine). If the motif of the compound of the present invention is cleaved after being absorbed by the gastrointestinal tract, these GABA analog prodrugs may have the opportunity to be absorbed into the systemic circulation through passive diffusion, active transport, or simultaneous passive diffusion and active transport.

If the motif of the compound of the present invention is cleaved after being absorbed by 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 compound or composition of the present invention is 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 The composition of the present invention The composition of the present invention contains a therapeutically effective amount of one or more of the compounds of the present invention, preferably in a purified form, and an appropriate amount of pharmaceutically acceptable excipients, so as to provide patients with suitable administration form. When administered to a patient, the compound of the present invention and pharmaceutically acceptable excipients are preferably sterile. When the compound of the invention is administered intravenously, water is a preferred excipient. It is also possible to use saline solution and dextrose and glycerol aqueous solutions as liquid excipients, especially for injection. 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, anhydrous skim milk, glycerin, propylene glycol, water, ethanol, etc. If necessary, the composition of the present invention may also contain small amounts of wetting and emulsifying agents or pH buffering agents. In addition, auxiliary agents, stabilizers, thickeners, lubricants and coloring agents can be used.

In one embodiment, the composition of the present invention does not contain lactam by-products formed by intramolecular cyclization. In a preferred embodiment, the composition of the present invention is also stable for long-term storage (preferably more than 1 year), and does not form a large amount of lactam (preferably less than 0.5 wt% lactam, more preferably less than 0.2 wt%). % Lactam, most preferably less than 0.1 wt% lactam).

The pharmaceutical composition containing the compound of the present invention can be prepared by conventional mixing, dissolving, granulating, dragee, grinding, emulsifying, encapsulating, entrapping or freeze-drying methods. The pharmaceutical composition can be prepared in a conventional manner using one or more physiologically acceptable carriers, diluents, excipients or adjuvants, thereby facilitating the preparation of the compounds of the present invention into pharmaceutical preparations. The appropriate formulation depends on the chosen route of administration.

The dosage form of the composition of the present invention can be a solution, suspension, emulsion, tablet, pill, pill, capsule, liquid-containing capsule, powder, sustained-release preparation, suppository, emulsion, aerosol, spray, suspension or any Other forms suitable for application. In one embodiment, the pharmaceutically acceptable excipient is a capsule (see, for example, 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, Philadelphia College of Pharmacy and Science, 17th edition, 1985). The preferred composition of the present invention is 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 sweeteners such as fructose, aspartame or saccharin, flavoring agents such as peppermint, wintergreen oil or cherry coloring agents and preservatives to provide a pharmaceutically palatable preparation. Moreover, in the case of tablets or pills, the composition may be coated to delay degradation and absorption in the gastrointestinal tract, thereby providing a long-term sustained effect. The selectively permeable membrane surrounding the osmotic activity driving compound is also suitable for oral administration of the compounds and compositions of the present invention. In these later platforms, liquid from the surrounding environment of the capsule is absorbed by the driving compound, which expands through the pore size to replace the reagent or reagent composition. These delivery platforms can provide a substantially zero-order delivery curve compared to the tapered pattern of the instant rate formulation. Time delay materials such as glyceryl monostearate or glyceryl stearate can also be used. Oral compositions may include standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, 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 glycol (e.g. propylene glycol), polyalkylene glycol (e.g. polyethylene glycol) Oil, alcohol, slightly acidic buffer between pH 4 and pH 6 (for example, about 5 mM to about 50 mM acetate, citrate, ascorbate) and the like. In addition, flavoring agents, preservatives, coloring agents, bile salts, acyl endotoxins, etc. can be added.

Other ways to administer the composition can also be considered. For buccal administration, the dosage form of the composition may be tablets, lozenges, etc. prepared by conventional methods. Liquid pharmaceutical formulations suitable for use with nebulizers and liquid spray devices and EHD aerosol devices generally include the compound of the present invention and pharmaceutically acceptable excipients. Preferably, the pharmaceutically acceptable excipient is a liquid such as alcohol, water, polyethylene glycol or perfluorocarbon. Optionally add another substance to change the aerosol properties of the solution or suspension of the compound of the present invention. Preferably this substance is a liquid such as alcohol, ethylene glycol, polyethylene glycol or fatty acid. Other preparation methods of liquid drug solutions or suspensions suitable for aerosol devices are known to those skilled in the art (for example, see Biesalski, US Patent 5,112,598; Biesalski, US Patent 5,556,611). The compound of the present invention can also be formulated into rectal or vaginal compositions such as suppositories or retention enemas, for example, it contains a conventional suppository base such as cocoa butter or other glycerides. In addition to the aforementioned formulations, the compounds of the present invention can also be formulated into precipitation formulations. Such long-acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the present invention can be prepared with suitable polymeric or hydrophobic materials (e.g., emulsions in acceptable oils) or ion exchange resins, or made into sparingly soluble derivatives, for example sparingly soluble salts.

When the compound of the present invention is acidic, it can be included in any of the aforementioned formulations as a free acid, pharmaceutically acceptable salt, solvate or hydrate. The pharmaceutically acceptable base tincture retains the activity of the free acid, can be prepared by reaction with a base, and tends to be more soluble in water and other protic solvents than the corresponding free acid form.

4.7 Application method and dosage The compound or composition of the present invention is generally applied in an effective amount to achieve the desired purpose. For the treatment or prevention of the following diseases or conditions such as: epilepsy, depression, anxiety, psychosis, fainting seizures, hypokinesia, cranial abnormalities, neurodegenerative diseases, panic, pain (especially neuropathic pain and muscle and bone pain) ), inflammatory disease (i.e. arthritis), insomnia, gastrointestinal disease or alcohol withdrawal syndrome, the compound of the present invention or its composition is administered or applied in a therapeutically effective amount.

The amount of the compound of the present 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 the aforementioned standard clinical techniques known in the art. In addition, in vitro or in vivo tests can optionally be used to help identify the optimal dosage range. The administration amount of the compound of the present invention of course depends on the subject to be treated, the weight of the subject, the severity of the pain, the method of administration, and the judgment of the prescribing physician.

For example, a dose can be delivered in a pharmaceutical composition 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). The dosage can be repeated intermittently, can be provided alone or in combination with other drugs, and can continue to be effective for the length of time required to treat the disease or condition.

A suitable oral dosage range depends on the potency of the parent GABA analog drug, but is generally about 0.001 mg to about 200 mg of the compound of the present invention per kilogram of body weight. When the GABA analog is gabapentin, the typical daily dose of the parent drug for adults is 900 mg/day to 3600 mg/day, and the dose of the gabapentin prodrug can be adjusted to provide an equimolar amount of gabapentin. Other GABA analogs may be more effective than gabapentin (e.g. pregabalin), and lower doses are appropriate for the parent drug and any prodrugs (measured on an equimolar basis). The dosage range can be easily determined by methods known to those skilled in the art.

The compounds of the present invention are preferably tested for target therapeutic or prophylactic activity in vitro and in vivo before being used in humans. For example, in vitro tests can be used to determine whether the administration of a particular compound of the invention or a combination of compounds of the invention is preferred for reducing convulsions. Using animal model systems can also prove that the compounds of the present invention are effective and safe.

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

The dosage of the compounds of the present invention described herein is within a circulating concentration range that includes effective dosages with little or no toxicity.

4.8. Combination Therapy In certain embodiments of the present invention, the compound of the present invention may be used in combination therapy with at least one other therapeutic agent. The compound of the present invention and the therapeutic agent may act additively, more preferably synergistically. In a preferred embodiment, the composition containing the compound of the present invention is administered simultaneously with other therapeutic agents, which may be part of the composition as the compound of the present invention or as a different composition. In another embodiment, a composition comprising a compound of the invention may be administered before or after the administration of another treatment.

5. Examples The present invention is further defined with reference to the following examples, which describe in detail the preparation of the compounds and compositions of the present invention and the application tests of the compounds and compositions of the present invention. It is obvious to those skilled in the art that various modifications to the raw materials and methods can be implemented without departing from the protection scope of the present 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 = carbobenzyloxy CPM = counts per minute DCC = Dicyclohexyl carbodiimide DMAP = 4 -N,N-dimethylaminopyridine DMEM = limit eagl e medium DMF = N,N-dimethylformamide

DMSO = dimethyl sulfoxide Fmoc = 9-fluorenyl methoxycarbonyl g = g h = hour HBSS = Hanks buffered salt solution L = liter LC/MS = liquid chromatography/mass spectrometry M = mole min = minute ml = milliliter mmol = Millimoles 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 11-{[(α-pivaloyloxymethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (51) Step A: p-nitrophenyl chloromethyl carbonate ( 52) Dissolve p-nitrophenol (100g, 0.72 moles) in anhydrous tetrahydrofuran (3L) and stir vigorously. To this solution was added chloromethyl chloroformate (70 mL, 0.79 moles) at room temperature, followed by triethylamine (110 mL). 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 (3×500 mL), 1N HCl (2×300 mL), brine (2×300 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. 1H NMR (CDCl3, 400MHz): 5.86 (s, 2H), 7.44 (d, J=9 Hz, 2H), 8.33 (d, J=9 Hz, 2H).

Step B: p-Nitrophenyl methyl iodocarbonate (53) was mixed with p-nitrophenyl chloromethyl methyl carbonate (52) (100g, 0.43moles), sodium iodide (228g, 1.30moles) and 50g under nitrogen atmosphere Anhydrous molecular sieve (4) was added to 2L acetone while mechanically stirring. The resulting mixture was stirred at 40°C for 5 h (monitored by 1H NMR). When the stirring was completed, the solid matter 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. The solvent was removed to obtain 123.6 g (89%) of the title compound (53), which was a solid on standing. The compound was found to be unstable to LC-MS. 1H NMR (CDCl3, 400MHz): 6.06 (s, 2H), 7.42 (d, J=9Hz, 2H), 8.30 (d, J=9Hz, 2H). 13C NMR (CDCl3, 100MHz): 155.1, 151.0, 146.0 , 125.8, 125.7, 121.9, 33.5.

Step C: Silver Trimethyl Acetate (54) Dissolve pivalic acid (50 g, 0.49 moles) in acetonitrile (1.3 L), then add silver oxide (70 g, 0.29 moles), and stir vigorously. 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 filtering with a Celite filter pad, the solvent was removed to obtain 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 are prepared according to similar methods.

Step D: Solution of p-nitrophenyl pivaloyloxymethyl carbonate (55) to p-nitrophenyl iodomethyl carbonate (53) (62g, 0.19 moles) in dry toluene (1L) Add silver trimethyl acetate (80 g, 0.38 moles). After stirring for 3 h at 55°C under a nitrogen atmosphere, the reaction mixture was cooled to room temperature and filtered with a Celite filter pad. 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. 1H NMR (CDCl3, 400MHz): 1.25 (s, 9H), 5.88 (s, 2H), 7.40 (d, J = 9Hz, 2H), 8.29 (d, J = 9HZ, 2H). 13CNMR (CDCl3, 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) were pulped, and then treated with chlorotrimethylsilane (18.6 mL, 0.28 moles) and triethylamine (10 mL, 0.15 moles). The resulting suspension is heated and stirred until complete dissolution of any solids is achieved. Add the above gabapentin solution to a slow reflux by equalizing the funnel, and mechanically stir the p-nitrophenyl pivaloyloxymethyl carbonate in dichloromethane (100 mL) under a nitrogen atmosphere (55) (20 g, 67 mmol) and triethylamine (10 mL, 0.15 moles). The resulting yellow solution was stirred for 1.5h. When the stirring is complete (monitored by ninhydrin staining), the mixture is filtered, and the filtrate is concentrated. The residue was dissolved in ethyl acetate (500 mL), washed with 1N HCl (3×100 mL), brine (2×100 mL), and dried over anhydrous sodium sulfate. After removing the solvent, dissolve the crude product in ethanol (300 mL), and then add 1 g 5% Pd/C. The resulting mixture was stirred under 50 psi hydrogen atmosphere for 15 minutes, and then filtered through a Celite filter pad. After concentration, the residue was dissolved in ethyl acetate, washed with 5% H2SO4, and dried over anhydrous sodium sulfate. After the solvent was removed under reduced pressure, the residue was chromatographed using silica gel (4:1 hexane:ethyl acetate) to obtain 15 g (68%) of the title compound (51) as a solid. Mp: 79-81°C; 1HNMR (CDCl3, 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).13C NMR (CDCl3, 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 21-{[(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 minutes and 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 water. The ether layer was dried with Na2SO4 and evaporated under reduced pressure to give 2.4 g (97%) of the title compound (57) as a beige solid. 1H NMR (CDCl3): 1.93 (d, 3H), 6.55 (q, 1H), 7.42 (d, 2H), 8.28 (d, 2H).

Step B: α-acetoxyethyl-p-nitrophenyl carbonate (58) will be 1-chloroethyl-p-nitrophenyl carbonate (57) (0.5g, 2mmol) in acetic acid (15mL) The mixture with mercury acetate (1.5g, 4.4mmol) was stirred at room temperature for 24h. After removing acetic acid under reduced pressure, the residue was dissolved in ether and washed with water, 0.5% (v/v) NaHCO3 aqueous solution and water. The ether layer was dried with Na2SO4 and concentrated to dryness. The resulting residue was chromatographed on silica gel (hexane:ethyl acetate (95:5)) to obtain 0.45 g (84%) of the title compound (58). 1H NMR (CDCl3, 400MHz): 1.55 (d, J = 5.6 Hz, 3H), 2.07 (s, 3H), 6.78 (q, J = 5.6 Hz, 1H), 7.36 (d, J = 9.6 Hz, 2H) , 8.22 (d, J=9.6 Hz, 2H).

Step C: 1-{[(α-acetoxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (56) to gabapentin (633mg, 3.7mmol) contained in dichloromethane (20mL) To a mixture with triethylamine (1.03 mL, 7.4 mmol) was added trimethylchlorosilane (0.93 mL, 7.4 mmol), and the mixture was stirred until a clear solution 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 (3×10 mL), and the combined organic extracts were dried with MgSO4. After filtration, the organic solvent was removed under reduced pressure. The resulting residue was chromatographed on silica gel (hexane:ethyl acetate (4:1)) to obtain 700 mg (63%) of the title compound (56). 1H NMR (CDCl3, 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)+. By dissolving in water (5mL), adding an equimolar amount of 0.5N NaHCO3 is then lyophilized to quantitatively convert the acid form to the corresponding sodium salt.

Example 31-{[(αbenzoyloxybenzyloxy)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 at room temperature was added DMAP (1.21 g, 9.9 mmol) and p-nitrophenyl-chloroformate (1.99 g, 9.9 mmol), respectively. After stirring for 3 h at room temperature, the reaction was terminated with water and extracted with ethyl acetate/hexane (2×100 mL). The combined organic extracts were dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain 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 gabapentin (1.70g, 9.9mmol) in CH2Cl2 at 0°C Triethylamine (2.76 mL, 19.8 mmol) and TMSC1 (2.51 mL, 19.8 mmol) were added to the suspension. The reaction was stirred for 30 minutes at room temperature. 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 with Na2SO4. After the solvent was removed under reduced pressure, the residue was purified by silica gel chromatography, eluting with 5% methanol in CH2Cl2 to give 3.78 g (90%, over two steps) of the title compound (61). 1H NMR (CDCl3, 400MHz): δ 1.48-1.35 (m, 10H), 2.30 (s, 2H), 3.24 (d, J = 7.2 Hz, 2H), 5.58 (t, J = 6.8 Hz, 1H), 6.85 (s, 1H), 7.50-7.33 (m, 8H), 7.93 (d, J=7.2 Hz, 2H).

Step C: 1-{[(α-benzoyloxybenzyloxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (59) to 1-{[(α-benzene in 40mLCH2Cl2 at room temperature) A solution of formylbenzyloxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (61) (1.89g, 4.6mmol) was added 77% mCPBA (2.07g, 9.2mmol) and NaHCO3 (O.78g, 9.2 mmol), 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 extract was washed with brine and dried over Na2SO4. After the solvent was removed under reduced pressure, the residue was purified by reverse phase preparative HPLC (acetonitrile-water, 0.1% formic acid) to obtain 960 mg (49%) of the title compound (59). 1H NMR (CDCl3, 400MHz): δ 1.58-1.35 (m, LOH), 2.34 (s, 2H), 3.26 (dd, J = 6.8, 0.8 Hz, 2H), 5.38 (t, J = 6.8 Hz, 1H ), 7.46-7.26 (M, 5H), 7.63-7.55 (M, 3H), 7.89 (s, 1H), 8.08 (dd, J=8.8, 1.2 Hz, 2H).

Example 41-{[(α-Acetoxybenzyloxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (62) According to the method of Example 3, using 1-hydroxy-1-phenyl-propane 2-ketone was substituted for benzoin to obtain 300 mg of the title compound (62). 1H NMR (CDCl3, 400MHz): δ 1.41 (m, 10H), 2.19 (s, 3H), 2.33 (s, 2H), 3.27 (dd, J=6.6, 1.6 Hz, 2H), 5.36 (t, J = 6.6 Hz, 1H), 7.40 (M, 3H), 7.52 (M, 2H), 7.63 (s, 1H).

Example 51-{[(α-Benzoyloxyethoxy)carbonylaminomethyl}-1-cyclohexaneacetic acid (63) According to the method of Example 3, using 2-hydroxy-1-phenyl- Instead of benzoin with 1-acetone, 5 mg of the title compound (63) was obtained. 1H NMR (CDCl3, 400MHz): δ1.44-1.36 (m, 10H), 1.62 (d, J = 5.6 Hz, 3H), 2.34 (s, 2H), 3.24 (d, J = 6.8 Hz, 2H), 5.28 (t, J=6.8 Hz, 1H), 7.06 (qJ=5.6 Hz, 1H), 7.44 (M, 2H), 7.56 (M, 1H), 8.03 (dd, J=8.4, 1.6 Hz, 2H).

Example 61-{[(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-propane dithiol 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 obtain a white solid, which was recrystallized with a 1:1 mixture of ether and hexane to obtain 17.0 g (87%) of the title compound (65) as white crystalline needles. 1H NMR (CDCl3, 400MHz): δ 1.91 (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 2-phenyl-1 in THF at -30°C A solution of 3-dithiane (65) (4.0 g, 20.4 mmol) was added to a solution of 1.6 M n-butyllithium in THF (15.3 mL, 24.4 mmol). After stirring for 30 minutes at -30°C, a solution of phenylacetyl aldehyde (2.45 g, 20.4 mmol) in tetrahydrofuran was added dropwise at -30°C. The resulting reaction mixture was stirred for another 1 h at 0°C. The reaction was terminated 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 hexane) to give 2.63 g (71%) of the title compound (66). 1H NMR (CDCl3, 400MHz): δ 1.97 (m, 2H), 2.23 (dd, J = 4.0, 1.2 Hz, 1H), 2.43 (dd, J = 13.6, 10.2 Hz, 1H), 2.77 (M, 4H) ), 3.02 (d, J=13.6 Hz, 1H), 4.07 (M, 1H), 7.44-7.13 (M, 8H), 8.02 (dd, J=8.4, 1.4 Hz, 2H).

Step C: 2-Hydroxy-1,3-diphenyl-propan-1-one (67) is added to 2-phenyl-1-(2-phenyl- [1,3]-Dithian-2-yl)-ethanol (66) (2.50 g, 7.9 mmol) was added to mercury perchlorate hydrate (4.1 g, 10.3 mmol). The resulting mixture was stirred at room temperature for 5 minutes, and thin layer chromatography showed that the reaction was complete. The mixture was diluted with ethyl acetate, filtered through a Celite filter pad, the filtrate was washed with saturated NaHCO3, brine, and dried over Na2SO4. The solvent was removed under reduced pressure, and the crude product was purified by silica gel flash chromatography (20% ethyl acetate in hexane) to give 1.32 g (74%) of the title compound (67). 1H NMR (CDCl3, 400MHz): δ 2.90 (dd, J = 14.4, 7.0 Hz, 1H), 3.20 (dd, J = 14.4, 4.0 Hz, 1H), 3.70 (d, J = 6.8 Hz, 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-cyclohexaneacetic acid (64) According to the method of Example 3, with 2- Hydroxy-1,3-diphenyl-propan-1-one was substituted for benzoin to obtain 181 mg of the title compound (64). 1H NMR (CDCl3, 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 = 6.6 Hz, 1H), 7.16 (t, J = 5.6 Hz, 1H), 7.33-7.25 (M, 5H), 7.40 (M, 2H), 7.57 (m, 1H), 8.02 (M , 2H).

Example 71-{[(1-(3-Methylbutyryloxy)-2-phenylethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (68) according to the method of Example 6 And 3-methylbutyraldehyde was used to replace the benzaldehyde in step A to obtain 95 mg of the title compound (68). 1H NMR (CDCl3, 400MHz): δ 0.88-0.90 (M, 6H), 1.16-1.29 (m, 10H), 2.06 (M, 1H), 2.16 (M, 2H), 2.26 (M, 2H), 3.08 (d, J=6.8 Hz, 2H), 3.19 (M, 2H), 5.22 (t, J=6.8 Hz, 1H), 6.93 (t, J=6 Hz, 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, and using butyraldehyde instead of phenyl ethyl in step B Aldehyde to obtain 240 mg of the title compound (69). 1H NMR (CDCl3, 400MHz): δ 0.99 (t, J = 7.6 Hz, 3H), 1.52-1.38 (M, 12H), 1.89 (M, 2H), 2.31 (s, 2H), 3.24 (M, 2H) ), 5.34 (t, J=6.6 Hz, 1H), 6.70 (t, J=5.6 Hz, 1H), 7.42 (M, 2H), 7.56 (M, 1H), 8.04 (M, 2H).

Example 91-{[(α-Acetoxybutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (70) According to the method of Example 6, and using acetaldehyde instead of benzaldehyde in step A, respectively And butyraldehyde was used instead of phenylacetaldehyde in step B to obtain 42 mg of the title compound (70). 1HNMR (CD3OD, 400MHz): δ 0.95 (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=5.6 Hz, 1H).

Example 101-{[(α-Butyryloxybutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (71) According to the method of Example 3, and using butyroin instead of benzoin, 210 mg of Title compound (71). 1H NMR (CDCl3, 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 111-{[(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) will be 1-iodoethyl-p-nitrophenyl carbonate (73) (0.51g, A mixture of 1.5 mmol) and silver propionate (0.54 g, 3 mmol) 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 obtained residue was subjected to silica gel chromatography (20% CH2Cl2/hexane, then 40% CH2Cl2/hexane) to obtain 0.39 g (92%) of the title compound (74). 1H NMR (CDCl3, 400MHz): 1.16 (t, J = 7.6 Hz, 3H), 1.61 (d, J = 5.6 Hz, 3H), 2.41 (q, J = 7.6 Hz, 2H), 6.84 (q, 1H, J=5.6 Hz), 7.39 (d, J=9.2 Hz, 2H), 8.28 (d, J=9.2 Hz, 2H).

Step C: 1-{[(α-propionyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (72) was added to gabapentin (160mg, 2.76mmol) in dichloromethane (30mL) ) And triethylamine (0.77 mL, 5.5 mmol) was added trimethylchlorosilane (0.71 mL, 5.5 mmol), and the resulting mixture was stirred until a clear solution formed. 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 (3×10 mL), and the combined organic extracts were dried with MgSO4. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparative HPLC (acetonitrile, water, 1% formic acid) to obtain 190 mg (44%) of the title compound (72). 1HNMR (CD3OD, 400MHz): 1.09 (t, J = 7.6 Hz, 3H), 1.36-1.54 (m, 10H), 1.44 (d, J = 5.6 Hz, 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 121-{[(α-Butyryloxyethoxy)carbonyl]aminomethyl}cyclohexaneacetic acid (75)

Step A: α-Butyryloxyethyl-p-nitrophenyl carbonate (76) will be 1-iodoethyl-p-nitrophenyl carbonate (73) (1.5g, A mixture of 4.5 mmol) and silver butyrate (1.3 g, 6.7 mmol) was stirred in an oil bath at 90° C. for 24 h. The reaction mixture was filtered under reduced pressure and the filtrate was concentrated. The obtained residue was subjected to silica gel chromatography (20% CH2Cl2/hexane, then 40% CH2Cl2/hexane) to obtain 0.46 g (36%) of the title compound (76). 1H NMR (CDCl3, 400MHz): 0.95 (t, J = 7.6 Hz, 3H), 1.61 (d, J = 5.6 Hz, 3H), 1.67 (m. 2H), 2.41 (t, J = 7.6 Hz, 2H) , 6.84 (q, 1H, J = 5.6 Hz), 7.39 (d, J = 9.2 Hz, 2H), 8.28 (d, J = 9.2 Hz, 2H). MS (ESI) m/z 298.28 (M+H) +.

Step B: 1-{[(α-butyryloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (75) was added to gabapentin (530mg, 3.1 A mixture of mmol) and triethylamine (0.89 mL, 6.4 mmol) was added to trimethylchlorosilane (0.83 mL, 6.4 mmol), and the resulting 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 (3×10 mL), and the combined organic phase was dried with MgSO 4 and then concentrated in vacuo. The resulting residue was purified by reverse phase preparative HPLC (acetonitrile, water, 1% formic acid) to obtain 70 mg (21%) of the title compound (75). 1H NMR (CD3OD, 400MHz): 0.95 (t, J = 7.6 Hz, 3H), 1.32-1.58 (m, 10H), 1.42 (d, J = 5.6 Hz, 3H), 1.67 (M, 2H), 2.24 ( s, 2H), 2.30 (t, J = 7.6 Hz, 2H), 3.24 (s, 2H), 6.74 (q, J = 5.6 Hz, 1H). MS (ESI) m/z 330.28(M+H)+.

The acid form was quantitatively converted into the corresponding sodium salt by the following method: dissolving in water (5 mL), adding an equimolar amount of 0.5N NaHCO3, and then lyophilizing.

Example 131 -{[(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) was obtained. 1H NMR (CD3OD, 400MHz): 1.12 (d, J = 7.2 Hz, 3H), 1.14 (d, J = 7.2 Hz, 3H), 1.32-1.58 (m, 10H), 1.44 (d, J = 5.6 Hz, 3H), 2.28 (s, 2H), 2.56 (M, 1H), 3.25 (m, 2H), 6.73 (q, J = 5.6 Hz, 1H). MS (ESI) m/z 330.30 (M+H)+ .

The acid form was quantitatively converted into the corresponding sodium salt by the following method: dissolving in water (5 mL), adding an equimolar amount of 0.5N NaHCO3, and then lyophilizing.

Example 141-{[(α-Pivaloyloxyethoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (78) According to the method of Example 12, using silver trimethylacetate instead of butyric acid Salt to obtain 80 mg (36%) of the title compound (78). 1H NMR (CDCl3, 400MHz): 1.13 (s, 9H), 1.32-1.58 (m, 10H), 1.41 (d, J = 5.6 Hz, 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 into the corresponding sodium salt by the following method: dissolving in water (5 mL), adding an equimolar amount of 0.5N NaHCO3, and then lyophilizing.

Example 151-{(α-Acetoxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (79) According to the method of Example 2 with 1-chloro-2-methylpropane chloroformic acid Substitution of 1-chloroethyl chloroformate with chloroformate gave 212 mg (38%) of the title compound (79). 1H NMR (CD3OD, 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=4.4 Hz, 1H); MS (ESI) mlz330.30 (M+H)+.

Example 161-{[(α-Propionyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (80)

According to the method of Example 11 and using 1-chloro-2-methylpropyl-p-nitrophenyl carbonate instead of 1-chloroethyl-p-nitrophenyl carbonate, 190 mg (44%) of the title compound was obtained (80). 1H NMR (CD3OD, 400MHz): 0.90 (d, J = 6.6 Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H), 0.98 (T, J = 7.6 Hz, 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 171-{[(α-butyryloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (81) According to the method of Example 2, and using chloroformic acid 1-chloro- 2-methylpropyl ester and mercury butyrate replaced 1-chloroethyl chloroformate and mercury acetate to obtain 95 mg (36%) of the title compound (81). 1H NMR (CD30D, 400MHz): 1.12 (t, J = 7.6 Hz, 3H), 1.13 (d, J = 6.6 Hz, 3H), 1.14 (d, J = 6.6 Hz, 3H), 1.32-1.58 (m, 10H), 1.87 (m, 2H), 2.22 (m, 1H), 2.42 (s, 2H), 2.46 (t, J = 7.6 Hz, 2H), 3.44 (m, 2H), 6.78 (d, J = 4.8 Hz, 1H). MS (ESI) m/z 358.30 (M+H)+.

Example 181-{[(α-isobutyryloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (82) According to the method of Example 2, and using chloroformic acid 1-chloro 2-methylpropyl ester and mercury isobutyrate replaced 1-chloroethyl chloroformate and mercury acetate to obtain 95 mg (36%) of the title compound (82). 1H NMR (CD3OD, 400MHz): 0.95 (d, J = 7.2 Hz, 3H), 0.97 (d, J = 7.2 Hz, 3H), 1.05 (d, J = 6.6 Hz, 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 191-{[(α-pivaloyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (83) According to the method of Example 12, using 1-chloro-2 -Methylpropyl-p-nitrophenyl carbonate and silver trimethyl acetate instead of 1-chloroethyl-p-nitrophenyl carbonate and silver butyrate, to obtain 10 mg (9%) of the title compound (83) . 1H NMR (CD3OD, 400MHz): 0.98 (d, J = 6.6 Hz, 3H), 0.99 (d, J = 6.6 Hz, 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 201-2{[(α-Benzoyloxyisobutoxy)carbonyl]aminomethyl-1-cyclohexaneacetic acid (84) According to the method of Example 11, using 1-chloro-2- Methylpropyl-p-nitrophenyl carbonate and silver benzoate replaced 1-chloroethyl 1-p-nitrophenyl carbonate and silver propionate to obtain 109 mg (40%) of the title compound (84). 1H NMR (CD3OD, 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) 0 To a mixture of p-nitrophenol (5.76g, 41.5mmol) and isopropenyl chloroformate (5g, 41.5mmol) in dichloromethane (200mL) was added pyridine ( 3.4mL, 42mmol) solution. The resulting mixture was stirred at 0°C for 30 minutes and 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 water again. The ether layer was dried with Na2SO4 and evaporated under reduced pressure to obtain 8.7 g (94%) of the title compound (86) as a beige solid. 1H NMR (CDCl3, 400MHz): 2.05 (s, 3H), 4.81 (M, 1H), 4.95 (d, J = 2 Hz, 1H), 7.42 (d, J = 9.2 Hz, 2H), 8.28 (d, J =9.2Hz, 2H).

Step B: 2-Chloroisopropyl-p-nitrophenyl carbonate (87) Dissolve isopropenyl-p-nitrophenyl carbonate (86) (8.7g, 39mmol) in 4M hydrogen chloride in a sealed container /Dioxane. The mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure to obtain 10 g (100%) of the title compound (87), which was used in the next reaction without further purification. 1H NMR (CDCl3, 400MHz): 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) will be in dichloromethane (20mL) 2-chloroisopropyl-p-nitrophenyl carbonate (87) (0.5 g, 1.93mmol) and mercury acetate (1.0g, 3.13mmol) were stirred at room temperature for 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/hexane, then 40% CH2Cl2/hexane) to obtain 227 mg (50%) of the title compound (88). 1H NMR (CDCl3, 400MHz): 1.90 (s, 6H), 2.07 (s, 3H), 7.28 (d, 2H, J=9.2 Hz), 8.28 (d, J=9.2 Hz, 2H).

Step D: 1-{(α-acetoxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (85) to gabapentin (257mg, 1.5mmol) contained in dichloromethane (30mL) To a mixture with triethylamine (0.46 mL, 3.3 mmol) was added trimethylchlorosilane (0.38 mL, 3 mmol), and the mixture was stirred until clear. A solution containing α-acetoxyisopropyl-p-nitrophenyl carbonate (88) (0.23 g, 0.8 mmol) in dichloromethane (10 mL) was added and stirred 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 (3×10 mL), and the combined organic extracts were dried with MgSO 4 and concentrated in vacuo. The resulting residue was chromatographed with silica gel (hexane:ethyl acetate (4:1)) to obtain 40 mg (16%) of the title compound (85). 1H NMR (CD3OD, 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 221-{[(α-Butyryloxyisopropoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (89) According to the method of Example 21, and using mercury butyrate instead of mercury acetate, 5 mg (5%) of the title compound (89). 1H NMR (CD3OD, 400MHz): 0.99 (t, J = 7.6 Hz, 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, using mercury isobutyrate instead of mercury acetate , To obtain 109 mg (43%) of the title compound (90). 1H NMR (CD3OD, 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, using mercury benzoate instead of mercury acetate, 170 mg (58%) of the title compound (91) was obtained. 1H NMR (CDCl3, 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 (1.71g, 10mmol) and triethylamine (3.06mL, 22mmol) in dichloromethane (150mL) was added trimethyl Chlorosilane (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 (3×20 mL), and the combined organic phase was dried with MgSO 4 and then concentrated in vacuo. The residue was chromatographed on silica gel and eluted with hexane:ethyl acetate (1:4) to give 2.37 g (77%) of the title compound. 1HNMR (CDCl3, 400MHz): δ 1.04 (d, J = 6.4 Hz, 3H), 1.06 (d, J = 6.4 Hz, 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=5.6 Hz), 1H). MS (ESI) m/z 306.34 (M+H+).

Step B: 1-{[(α-nicotinoyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (92) in acetone at room temperature (93) (268mg, 0.88mmol ), a mixture of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (158 μL, 1.01 mmol) and niacin (637 mg, 5.2 mmol) was stirred for 48 hours. After filtration, the filtrate was concentrated in vacuo, and the resulting residue was purified by reverse phase preparative HPLC method to obtain 50 mg (14%) of the title compound. 1HNMR (CD3OD, 400MHz): δ 1.07 (d, J = 6.8 Hz, 3H), 1.09 (d, J = 6.8 Hz, 3H), 1.32-1.58 (m, 10H), 2.19 (M, 1H), 2.26 (s, 2H), 3.23 (M, 2H), 6.78 (d, J = 4.8 Hz, 1H), 7.58 (m, 1H), 8.39 (d, J = 6.4 Hz, 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-cyclohexaneacetic acid (94) Step A: 1-{[( α-Chloroisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetate benzyl ester (95) To a solution of (93) (1.02g, 3.34mmol) in dichloromethane was added 1,3 -Dicyclohexylcarbodiimide (758 mg, 3.67 mmol). After stirring for 30 minutes at room temperature, 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 with Na2SO4 and concentrated. The residue was chromatographed on silica gel and eluted with 10% ethyl acetate/hexane to give 820 mg (62%) of the title compound. 1H NMR (CDCl3, 400MHz): δ 1.03 (d, J = 6.4 Hz, 3H), 1.05 (d, J = 6.4 Hz, 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: Add 1 mL of concentrated sulfuric acid 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, and then diluted with 200 mL of dichloromethane. The organic solution was washed successively with water (3×80 mL) and saturated sodium chloride solution (80 mL), and then dried over anhydrous sodium sulfate. The mixture was filtered and concentrated to obtain 2,2-diethoxypropionic acid in quantitative yield as an oil. 1H NMR (CDCl3, 400MHz): δ 1.30 (t, 6H), 1.61 (s, 3H), 3.57 (q, 4H), 8.62 (s, 1H). The acid form was quantitatively converted into its cesium salt by the following method: the acid was dissolved in water (25 mL), then treated with an equimolar amount of cesium carbonate, and then lyophilized. 1H NMR (D2O, 400MHz): 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}-1-cyclohexaneacetate benzyl ester (97) will be at room temperature A mixture of (95) (200 mg, 0.51 mmol) and sodium iodide (114 mg, 0.76 mmol) in acetone was stirred for 1 h. Cesium 2,2-diethoxypropionate (96) (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 silica gel flash column chromatography, eluting with 10% ethyl acetate/hexane to give 100 mg (37%) of the title compound. MS (ESI) m/z 522.34 (M+H+).

Step D: 1-{[(α-2,2diethoxypropionyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (94) hydrogen atmosphere and room temperature (97 ) (200mg, 0.38mmol) and 5% Pd-C (catalytic amount) mixture was stirred for 16h. After filtration, the filtrate was concentrated, and the resulting residue was purified by reverse phase preparative HPLC method to obtain 98 mg (60%) of the title compound. 1H NMR (CDCl3, 400MHz): δ 0.97 (D, J = 6.8 Hz, 6H), 1.19 (t, J = 6.4 Hz, 3H), 1.21 (t, J = 6.4 Hz, 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-cyclohexaneacetic acid (98) According to the method of Example 26, And use 2-amino-2-methylpropionic acid instead of 2,2-diethoxypropionic acid to obtain the title compound. 1H NMR (CDCl3, 400MHz): δ 0.97 (d, J = 6.8 Hz, 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 = 4.8 Hz, 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 (9.1mL, 100mmol) and 1,3-propanediol (10mL, 100mmol) in dichloromethane at 0°C was added boron trifluoride diethyl etherate ( 6.4 mL, 50 mmol). 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% NaHCO3, and brine again. The organic phase was separated, dried with Na2SO4, and then concentrated to obtain 16 g (100%) of the title compound as a yellow liquid. It was taken to the next step without further purification. 1H NMR (CDCl3, 400MHz): δ 1.057 (D, J = 7.2 Hz, 3H), 1.059 (d, J = 7.2 Hz, 3H), 1.80 (M, 1H), 1.97-2.08 (m, 2H), 2.82 (M, 4H), 4.00 (d, J=5.2 Hz, 1H).

Step B: 2-isopropyl-2-(α-hydroxybutyl)-1,3-dithiane (101) was added to (100)(4g, 24.7) in anhydrous tetrahydrofuran (50mL) at -20°C mmol) was added dropwise n-butyllithium (1.6M in hexane, 18.5mL, 29.6mmol). The stirred mixture was heated at room temperature for 4 h, and then cooled to -20°C again. To this solution, a solution of n-butyraldehyde (2.7 mL, 29.6 mmol) in anhydrous tetrahydrofuran (10 mL) was slowly added. The resulting mixture was stirred at a temperature between -20°C and room temperature for 16 h, the reaction was terminated with saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was separated and dried with Na2SO4. After the solvent was removed under reduced pressure, the residue was subjected to flash column chromatography on silica gel and eluted with 5% ethyl acetate/hexane to give 5 g (85%) of the title compound as a yellow oil. 1HNMR (CDCl3, 400MHz): δ 0.96 (t, J = 7.2 Hz, 3H), 1.11 (d, J = 6.8, Hz, 3H), 1.17 (d, J = 6.8 Hz, 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) was added to a solution of (101) (5.0 g, 21.4 mmol) in acetonitrile (270 mL) in methanol (30 mL) under vigorous stirring In the Hg(ClO4)2 solution. The resulting mixture was stirred for 2 h at room temperature. 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 obtain 2.8 g (91%) of the title compound as a colorless liquid. 1H NMR (CDCl3, 400 MHz): S 0.91 (t, J = 7.2 Hz, 3H), 1.09 (d, J = 7.2 Hz, 3H), 1.10 (d, J = 7.2 Hz, 3H), 1.35-1.46 ( M, 4H), 1.75 (M, 1H), 2.80 (M, 1H), 3.45 (d, J=5.2 Hz, 1H), 4.29 (M, 1H).

Step D: 2-Methylheptan-3-one-4-p-nitrophenyl carbonate (103) was added to (102) (1.1 g, 7.6 mmol), chlorine in anhydrous dichloromethane at 0°C To a mixture of p-nitrophenyl formate (1.84 g, 9.2 mmol) was slowly added a solution of 4-dimethylaminopyridine (1.12 g, 9.2 mmol) in dichloromethane. After stirring for 1 h at 0°C and 4 h at room temperature, the reaction was terminated with 10% citric acid. The organic phase was separated, dried with Na2SO4, and concentrated in vacuo. Flash column chromatography of the residue, eluting with 30% dichloromethane/hexane, afforded 2 g (85%) of the title compound as a beige solid. 1H NMR (CDCl3, 400MHz): δ 0.99 (t, J = 7.6 Hz, 3H), 1.12 (d, J = 6.8 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 1.51 (M, 2H), 1.84 (M, 2H), 2.82 (M, 1H), 5.17 (M, 1H), 7.42 (d, J=6.8 Hz, 2H), 8.25 (d, J=6.8 Hz, 2H).

Step E: 1-{[(α-isobutyrylbutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (104) was added to gabapentin (820mg, 4.8mmol) in dichloromethane (20mL) ) And triethylamine (1.35 mL, 9.6 mmol) was added trimethylchlorosilane (1.22 mL, 9.6 mmol), and the resulting 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 (3×10 mL), and the combined organic extracts were dried with MgSO 4 and then concentrated under vacuum. The residue was chromatographed on silica gel, eluting with hexane: ethyl acetate (4:1) to remove p-nitrophenol, and then eluting with hexane: ethyl acetate (1: 4) to obtain the title (72%) Compound. 1H NMR (CDCl3, 400MHz): δ 0.91 (t, J = 7.2 Hz, 3H), 1.04 (d, J = 6.8 Hz, 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 (104) (780mg) in dichloromethane (20mL) , 2.3mmol) solution was added m-chloroperoxybenzoic acid (1.03g, 4.6mmol) and NaHCO3 (386mg, 4.6mmol). After stirring at room temperature for 16 hours, another batch of m-chloroperoxybenzoic acid (791 mg, 4.6 mmol) and NaHCO3 (386 mg, 4.6 mmol) were added. The resulting mixture was stirred for another 8 h, and then treated with 10% citric acid. After filtration, the organic layer was separated, dried with Na2SO4 and concentrated. The residue was purified by reverse phase preparative HPLC method to obtain 79 mg (11%) of the title compound. 1HNMR (CDCl3, 400MHz): δ 0.94 (t, J = 7.2 Hz, 3H), 1.153 (d, J = 7.2 Hz, 3H), 1.150 (d, J = 7.2 Hz, 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 = 6.8 Hz, 1H, NH), 6.71 (t, J=5.6 Hz, 1H). MS (ESI) MLZ 358.30 (M+H+).

The above acid was quantitatively converted into the corresponding sodium salt by the following method: the acid was dissolved in water (5 mL), and then an equimolar amount of 0.5N NaHCO3 was added and lyophilized.

Example 291 -{[(α-Isobutyryloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid methyl ester (105) Step A: 1-{[(α-chloroisobutyl (Oxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid methyl ester (106) A mixture of (93) (1.0 g, 3.3 mmol), benzene (90 mL) and methanol (10 mL) was cooled to 0°C. Slowly add trimethylsilyldiazomethane at 0°C until the yellow color remains. The mixture was stirred at 0°C for 30 minutes until the reaction was complete (monitored by TLC). After removing the solvent under reduced pressure, the resulting residue was chromatographed on silica gel and eluted with 10% ethyl acetate/hexane to obtain 760 mg (72%) of the title compound. MS (ESI) m/z 320.24 (M+H+).

Step B: 1-{{[(α-isobutyryloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid methyl ester (105) will be (106) (760mg, A mixture of 2.38 mmol), silver carbonate (394 mg, 1.4 mmol) and isobutyric acid (442 μl, 4.76 mmol) 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 another 24 hours. After filtration, the filtrate was concentrated and the resulting residue was purified by silica gel flash column chromatography, eluting with 10% ethyl acetate/hexane to give 560 mg (63%) of the title compound. 1H NMR (CDCl3, 400MHz): δ 0.94 (d, J = 6.8 Hz, 3H), 0.96 (D, J = 6.8 Hz, 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=4.8 Hz, 1H). MS (ESI) m/z 372.38 (M+H+).

Example 30 1-{[(α-Benzoyloxyisobutoxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid methyl ester (107) The 1-{[(α-benzoyloxyisobutyl A mixture of oxy)carbonyl]aminomethyl}-1-cyclohexaneacetic acid (84) (150 mg, 0.38 mmol), benzene (18 mL) and methanol (2 mL) was cooled to 0°C. Slowly add trimethylsilyldiazomethane at 0°C until the yellow color remains. The mixture was stirred at 0°C for 30 minutes until the reaction was complete (monitored by TLC). After removing the solvent under reduced pressure, the residue was chromatographed on silica gel and eluted with 5% ethyl acetate/hexane to give 98 mg (64%) of the title compound. 1H NMR (CDCl3, 400MHz): δ 1.02 (d, J = 6.4 Hz, 3H), 1.03 (d, J = 6.4 Hz, 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) and acetonitrile (20mL). The reaction mixture was shaken at 25°C for 4h. The precipitated was removed by filtration Dicyclohexylurea. 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. With ethyl acetate ( 100 mL) was diluted with the reaction mixture and washed with 0.5M aqueous citric acid (2×100 mL) and water (2×100 mL). The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was dissolved in trifluoroacetic acid ( 40mL) and stand at 22-25°C for 2h. The solvent was removed under reduced pressure. The residue was dissolved in water (4mL) and filtered with a 0.25μM nylon membrane filter, and then passed through HPLC (Phenomenex 250×21.2mm, with 5μm LUNAC18 column, eluted with 100% water for 5 minutes, and then purified with 0-60% acetonitrile and 0.05% TFA in water at a rate of 20 mL/min for 20 minutes). The pure fractions were combined, and the solvent was removed under reduced pressure to obtain 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 aminomethyl}-1-cyclohexaneacetic acid (108) at 0°C To a stirred suspension of (109) (200 mg, 0.51 mmol) in dichloromethane 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 obtain 92 mg of the title compound. 1H-NMR (CD3OD, 400MHz): δ 1.10 (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 = 5.6 Hz, 1H), 7.17 (d, J = 2.0, 8.0 Hz, 2H), 7.42 (DD, J = 2.0, 8.0 Hz, 2H).

Example 323-{[(α-isobutyryloxyethoxy)carbonyl]aminomethyl}-5-methylhexanoic acid (110) Step A: α-isobutyryloxyethyl-p-nitro Phenyl carbonate (111)

A solution of 1-chloroethyl-p-nitrophenyl carbonate (57) (2.0g, 8.14mmol) and mercury isobutyrate (6.13g, 16.29mmol) in dichloromethane (10mL) at 45°C Stir for 24h. The reaction was then cooled to room temperature and diluted with hexane to precipitate the mercury salt. The precipitate was filtered with a Celite filter pad, and the filtrate was concentrated under vacuum to give 2.5 g of crude product. The residue was chromatographed on silica gel with gradient elution from 10% dichloromethane/hexane to 20% dichloromethane/hexane to give 1.2 g (52%) of the title compound. 1H-NMR (CDCl3, 400MHz): δ 1.21-1.99 (M, 6H), 1.62 (d, J = 5.6 Hz, 3H), 2.61 (M, 1H), 6.84 (q, J = 5.6 Hz, 1H) , 7.41 (dt, J=6.8, 2.4 Hz, 2H), 8.29 (dt, J=6.8, 2.4 Hz, 2H).

Step B: 3-{[(α-isobutyryloxyethoxy)carbonyl]aminomethyl-5-methylhexanoic acid (110) to pregabalin in anhydrous dichloromethane (10mL) at 0°C (2) A stirred suspension of (150 mg, 0.94 mmol) was added with triethylamine (0.26 mL, 1.88 mmol) and trimethylchlorosilane (0.24 mL, 1.88 mmol). After stirring for 15 minutes at 0°C, 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, first eluting with dichloromethane to remove the nitrophenol, and then eluting with 30% ethyl acetate in dichloromethane to give 130 mg (48%) of the title compound. It is a mixture of two diastereomers. 1H-NMR (CDCI3, 400MHz): δ 0.90 (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=6.0 Hz, 1H), 6.79 (M, 1H).

Example 333-{[(α-isobutyryloxyisobutoxy)carbonyl]aminomethyl}-5-methyl-hexanoic acid (112)

Step A: Add 1-chloro-2-methylpropyl-p-nitrophenyl carbonate (113) to p-nitrophenol (4.06g, 29mmol) and 1-chloro- To the ice-cold reaction mixture of 2-methylpropyl chloroformate (5.0 g, 29 mmol) was added a solution of pyridine (2.78 mL, 32 mmol) in dichloromethane (50 mL). The mixture was stirred at 0°C for 30 min, and then at room temperature for 1 h. After evaporating the solvent under reduced pressure, the residue was dissolved in ether and washed with water, 10% citric acid and water again. 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. 1H NMR (CDCl3, 400MHz): δ 1.12 (d, J = 6.6 Hz, 3H), 1.13 (d, J = 6.6 Hz, 3H), 2.29 (M, 1H), 6.24 (d, J = 4.8 Hz, 1H), 7.42 (d, J=9.2 Hz, 2H), 8.28 (d, J=9.2 Hz, 2H).

Step B: α-Isobutyryloxyisobutyl-p-nitrophenyl carbonate (114) was prepared according to the method of (111), and (113) was used instead of (57) to obtain the title compound with a yield of 15% And the recovery rate of its raw materials is 70%. 1H-NMR (CDCl3, 400MHz): δ 1.07 (d, J = 6.8 Hz), 1.21 (M, 6H), 2.18 (M, 1H), 2.26 (M, 1H), 6.60 (d, J = 5.2 Hz) , 1H), 7.42 (M, 2H), 8.28 (M, 2H).

Step C: 3-{[(α-isobutyryloxyisobutoxy)carbonyl]oxymethyl}-5-methyl-hexanoic acid (112) was prepared according to the method of (110) with (114) Instead of (111), the title compound was obtained as a mixture of two diastereomers with a yield of 51%. 1H-NMR (CDCl3, 400MHz): δ 0.89 (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 343-{[(α-benzoyloxyisobutoxy)carbonyl]aminomethyl-5-methyl-hexanoic acid (115) Step A: α-benzoyloxyisobutyl-p Nitrophenyl carbonate (116)

According to the preparation method of (111), substituting (113) for (57) and substituting mercury benzoate for mercury isobutyrate, the title compound was obtained with a yield of 11% and a recovery rate of 50% of the raw material. 1H-NMR (CDCl3, 400MHz): δ 1.15 (d, J = 3.2 Hz, 3H), 1.16 (d, J = 3.2 Hz, 3H), 2.30 (m, 1H), 6.87 (d, J = 4.4 Hz) , 1H), 7.42 (dd, J = 7.2, 2.0 Hz, 2H), 7.48 (t, J = 7.6 Hz, 2H), 7.62 (t, J = 7.6 Hz, 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) was prepared according to the method of (110) and replaced with (116) (111), the title compound was obtained as a mixture of two diastereomers with a yield of 58%. 1H-NMR (CDCl3, 400MHz): δ 0.87 (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]aminomethyl}-1-cyclohexyl Alkylacetic acid (117) Step A: Benzyl 2-diazo-3-oxo-butyric acid (118) to benzyl acetoacetate (5.0 g, 26.01 mmol) in acetonitrile (200 mL) at 0°C and Triethylamine (10.9 mL, 78.03 mmol) was added dropwise to the solution of 4-acetamido-benzenesulfonyl azide (6.25 g, 26.01 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 ether/petroleum ether (3×100 mL). Filter the combined organic extracts with a Celite filter pad cut off of silica gel. The solvent was removed under reduced pressure to obtain 4.74 g of the title compound as a beige crystal. 1H-NMR (CDCl3, 400MHz): δ 2.49 (s, 3H), 5.27 (s, 2H), 7.38 (M, 5H).

Step B: Benzyl 2-hydroxy-3-oxo-butyric acid (119) A solution of the diazo compound (118) (4.74 g, 21.74 mmol) in THF (110 mL) and H2O (50 mL) and Rh2 (OAc)2 (77mg, 0.17mmol) was heated together under reflux for 4 hours and cooled 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 give 4.5 g of crude product. 1H-NMR (CDCl3, 400MHz): 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 carbonyl diimidazole (6.88g, 42.45 mmol) was added to a solution of alcohol (119) (4.50 g, 21.22 mmol) in dry THF (50 mL). 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/hexane. The organic layer was separated, washed with saturated NH4Cl, brine, and dried over Na2SO4. After filtration and concentration, the crude product was purified by silica gel flash chromatography, eluting with 20% ethyl acetate in hexane to give 2.6 g of the title compound. 1H-NMR (CDCl3, 400MHz): δ 2.48 (s, 3H), 5.27 (s, 2H), 7.37 (br.s, 5H).

Step D: 5-Methyl-2-oxo-1.3-dioxocyclopent-4-enyl-4-carboxylic acid (121) to a solution of compound (120) (2.6 g, 10.92 mmol) in 50 mL ethanol 260 mg PD/C (5%) was added, and the resulting mixture was stirred under hydrogen atmosphere for 1 h. Filtration and removal of the solvent under reduced pressure gave 1.62 g of the title compound. 1H-NMR (CD3OD, 400MHz): δ 2.41 (s, 3H).

Step E: 4-Hydroxymethyl-5-methyl-2-oxo-1.3-dioxol-4-ene (122) in anhydrous dichloromethane (50mL) at 0 °C acid (121 ) (1.62g, 11.10mmol) and anhydrous DMF (112μL), add oxalyl chloride (6.1mL, 2M solution, 12.2mmol) dropwise. 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 dry dichloromethane (65 mL) and cooled to -78°C. A solution of Bu4NBH4 (3.14 g, 12.2 mmol, in 20 mL of dichloromethane) was added dropwise to this solution within 10 minutes. After stirring at -78°C for 1 h, the reaction of the mixture was carefully terminated with 0.1N HCl (30 mL) and warmed to room temperature. The aqueous layer was separated, extracted with EtOAc (3×50 mL), and the combined organic extracts were washed with brine, and dried over Na2SO4. After the solvent was removed under reduced pressure, column chromatography was performed on silica gel and eluted with 50% EtOAc in dichloromethane to obtain 767 mg of the title compound. 1H-NMR (CD3OD, 400MHz): 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) Suspend alcohol (122) (767 mg, 5.9 mmol) and 1-isocyanatomethyl-1-cyclohexane Benzyl Acetate (5.9 mmol) in toluene The liquid refluxed overnight. After removing the solvent under reduced pressure, the residue was purified by flash column chromatography, eluting with 30% EtOAc in hexane to give 510 mg of the title compound. 1H-NMR (CD3OD, 400MHz): δ 1.58-1.30 (m, 10H), 2.18 (s, 3H), 2.35 (s, 2H), 3.17 (d, J = 6.8 Hz, 2H), 4.80 (s, 2H), 5.11 (s, 2H), 5.44 (t, J=6.8 Hz, 1H), 7.36 (m, 5H).

Step G: 1-{[((5-Methyl-2-oxo-1.3-dioxocyclopent-4-en-4-yl)methoxy)carbonyl]-aminomethyl}-1-cyclohexyl Alkylacetic acid (117) To a solution of compound (123) (510 mg, 1.41 mmol) in ethanol (20 mL) was added 59 mg PD/C (5%), and the resulting mixture was stirred under hydrogen atmosphere for 1 h. Filtration and removal of volatiles under reduced pressure gave a crude product, which was purified by preparative LC/MS method to obtain 105 mg of the title compound. 1H-NMR (CD3OD, 400MHz): δ 1.52-1.36 (m, 10H), 2.16 (s, 3H), 2.27 (s, 2H), 3.22 (s, 2H), 4.86 (s, 2H).

Example 361-{(1-Methyl-3-oxo-but-1-carbonyl)aminomethyl}-1-cyclohexane piperidinium acetate (124) 2,4-pentanedione (103 μL, 1mmol), gabapentin (171mg, 1mmol) and piperidine (99μL, 1mmol) were mixed with anhydrous methanol (10mL). The resulting mixture was heated to reflux for 4h. The solvent was removed under reduced pressure to obtain the title compound with a purity greater than 90%. 1H NMR (CDCl3, 400MHz): δ1.34-1.62(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 371-1-{[(2-oxo-tetrahydrofuran-3-yl subunit) 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 with anhydrous methanol (10 mL). After heating under reflux for 6 hours, the solvent was removed under reduced pressure to obtain the title compound with a purity greater than 90%. 1H NMR (CDCl3, 400MHz): δ 1.34-1.62 (m, 12H), 1.71 (m, 4H), 1.94 (s, 3H), 2.24 (s, 2H), 2.81 (T, J = 7.6 Hz, 2H ), 2.99 (M, 4H), 3.31 (d, J = 6.4 Hz, 2H), 4.23 (t, J = 7.6 Hz, 2H), 5.17 (s, br, 2H), 8.64 (t, J = 6.4 Hz , 1H). MS (ESI) m/z 280.34 (MH-).

Example 381-{(2-Carbonmethoxy-cyclopent-1-enyl)aminomethyl}-1-cyclohexane piperidinium acetate (126) The methyl 2-oxocyclopentanecarboxylate ( 124 μL, 1 mmol), gabapentin (171 mg, 1 mmol) and piperidine (99 μL, 1 mmol) were mixed with anhydrous methanol (10 mL). After heating and refluxing for 16 hours, the solvent was removed under reduced pressure to obtain the title compound with a purity greater than 90%. 1H NMR (CDCl3, 400MHz): δ 1.29-1.60 (M, 12H), 1.72 (M, 4H), 1.79 (M, J = 7.6 Hz, 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}-1-cyclohexaneacetic acid piperidine Onium (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 and refluxing for 16 hours, the solvent was removed under reduced pressure to obtain the title compound with a purity greater than 90%. 1H NMR (CDCl3, 400MHz): δ 1.28 (t, J = 7.2 Hz, 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 = 5.2 Hz, 2H), 4.20 (q, J = 7.2 Hz, 4H), 4.35 (s, br, 2H), 7.79 (t, J = 5.2 Hz) , 1H). MS (ESI) m/z 354.38 (MH-).

Example 401-{[(α-(2-(2-methyl-1,3-dioxolane-2-yl)carboxyisobutoxy)carbonyl]-aminomethyl}-1-cyclohexane Acetic acid (128) step A: 2-methyl-1,3-dioxolane-2-carboxylic acid (129) was added to ethyl pyruvate (11.1mL) in anhydrous dichloromethane (100mL) at 0°C , 0.1 mol) and ethylene glycol (5.6 mL, 0.1 mol) were added to the boron trifluoride dietherate (6.4 mL, 0.05 mol) and a catalytic amount of acetic acid. The resulting mixture was stirred at 40°C 16 h, then diluted with 100 mL of dichloromethane. The organic solution was washed successively with saturated sodium chloride solution (2×80 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 for 3 h at room temperature (monitored by TLC), citric acid was added to adjust the pH to 4. The product was extracted with dichloromethane, dried with Na2SO4, and concentrated to obtain 5.1 g (38%) of the title compound (129), which is a Clear liquid. This material was used in the next reaction without further purification. 1HNMR (CDCl3, 400MHz): 51.55 (s, 3H), 4.03 (m, 4H).

Step B: Benzyl 1-{[(α-(2-(2-methyl-1,3-dioxolane-2-yl)carboxyisobutoxy)carbonyl]aminomethyl}-1-ring Benzyl Hexane Acetate (130)

At room temperature, 1-{[(α-chloroisobutoxy)carbonylaminomethyl}-1-cyclohexaneacetate benzyl ester (95) (1g, 2.53mmol), (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 give 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-dioxolane-2-yl)carboxyisobutoxy)carbonyl]-aminomethyl}-1-cyclohexyl Alkylacetic acid (128) was stirred for 16h with a mixture of (130) (470mg, 0.96mmol) and 5% Pd-C (catalytic amount) in ethanol under hydrogen atmosphere and room temperature. Filtration and concentration gave 382mg (100%) of The title compound (128). 1H NMR (CDCl3, 400MHz): δ 0.96 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 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=4.8 Hz, 1H). MS (ESI) m/z 402.32 (M+H+). Quantitatively convert the acid form into the corresponding sodium salt by the following method: Dissolve in water (5mL), add an equimolar amount of 0.5N NaHCO3, and then Freeze-dried.

Example 41 Determination of Caco-2 Cell Permeability of Prodrugs in Vitro The passive permeability of the prodrugs of the present invention can be evaluated in vitro using methods known in the art (for example, see Stewart et al., PHARM.RES., 1995, 12. , 693). For example, the permeability can be evaluated by examining the flow of the prodrug through a monolayer of cultured polarized cells (e.g., Caco-2 cells). Caco-2 cells (passages less than 28) obtained from continuous cultures were seeded on Transwell polycarbonate filters at high density. DMEM/10% bovine fetal serum + 0.1 mM non-essential amino acids + 2 mM L-GLn, 5% CO2/95%, 37°C were used to feed the cells until the day of the experiment. In the presence of overflow pump inhibitors (250μM MK-571, 250μM verapamil, 1mM ofloxacin), at pH 6.5 and at the top (with 1mM CaCl2, 1MM MgCl2, 150mM NaCl, 3mM KCl, 1mM NaH2PO4, 5mM glucose in 50mM MES buffer) and at pH 7.4 on the bottom side (in the presence of 10mM Permeability studies were performed in HEPES Hanks average salt solution. Place the insert on a 12-well or 24-well plate containing buffer and incubate at 37°C for 30 min. Add the prodrug (200μM) to the top and bottom compartments (donor), and use LC/MS/MS to measure the prodrug and/or released in the opposite compartment (recipient) at 1 hour intervals The concentration of the parent drug. Use the following equation to calculate the apparent permeability value (Papp): Papp=Vr(dC/dt)//(AC0) where Vr is the volume of the receiving compartment in mL; dC/dt is the difference between the prodrug and the parent drug Flux (μM/S), which is determined based on the slope of the concentration versus time curve in the receiving compartment; C0 is the initial concentration of the prodrug in μM; A is the membrane surface area in cm2. Preferably, the prodrug with significant penetration through the cell exhibits a value of Papp1×10-6cm/s, more preferably the value of Papp1×10-65cm/s, and even more preferably the value of Papp5 ×10-5cm/s. The typical Papp values obtained for GABA analog prodrugs are shown in the following table:

The data in this table indicates that the prodrugs disclosed herein have high cell permeability and should be well absorbed by the intestine. Except for compound (83), the top-to-bottom permeability of the prodrugs exceeds their bottom-to-top permeability. This suggests that these compounds can be substrates for active transport mechanisms present in the apical membrane of Caco cells (although certain components of this permeability through the cell are regulated by passive diffusion). The greater the bottom-to-top permeability of (83) indicates that despite the presence of outflow pump inhibitors MK-571, verapamil and ofloxacin, this compound can flow through the bottom membrane.

Example 42 Absorption of gabapentin after intracolon administration of gabapentin or gabapentin prodrug to rats. A sustained-release oral dosage form that slowly releases the drug within 6-24 hours generally releases a large amount of dose in the colon. Therefore, drugs suitable for this dosage form preferably exhibit good colonic absorption. This experiment was conducted to evaluate the application of gabapentin prodrugs in oral sustained-release dosage forms.

Step A: The dosing regimen was used to obtain rats and pre-inserted the ascending colon and jugular vein. The animals were awake during the experiment. All animals were fasted overnight until 4 hours after taking the drug. Gabapentin or gabapentin prodrugs (59), (63), (69), (72), (77), (79), (85), (117) and gabapentin are administered by intubation at a dose equivalent to 25 mg gabapentin/kg The solution of (126) (in water or PEG 400) is applied directly to the colon. Blood samples (0.5 mL) were obtained from the jugular vein at intervals of 8 hours, and the reaction was immediately terminated by adding acetonitrile/methanol to prevent the previous conversion of the prodrug. Analyze blood samples as follows.

Step B: Sample preparation for colonic absorption of drugs 1. In a blank 1.5 mL eppendorf tube, add 300 μL of 50/50 acetonitrile/methanol and 20 μL of p-chlorophenylalanine as internal standards.

2. Collect rat blood at different time points, immediately add 100 μL of blood to the eppendorf tube, and stir 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. Stir the sample and centrifuge 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 Shidmadzu 10ADVp binary pump and CTC HTS-PAL autosampler was used for analysis. The Zorbax XDB C84.6×150 mm column was heated to 45°C during the analysis. The mobile phase is 0.1% formic acid (A) and acetonitrile and 0.1% formic acid (B). The gradient conditions are: 5% B flow for 1 minute, then 98% B elution for 3 minutes, and then keep 98% B elution for 2.5 minutes. Revert the mobile phase to 5% B elution for 2 minutes. Use TurboIonSpray source for API 2000. The analysis was completed in positive ion mode, and the MRM transformation 172/137 was used to analyze gabapentin (the MRM transformation used was 426/198 for (59), 364/198 for (63), and 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. Use Analyst1.1 quantitative software to integrate the peaks. After colonic administration of each of these prodrugs, the maximum plasma concentration of gabapentin (Cmax) and the area under the time curve of gabapentin plasma concentration (AUC) were significantly greater than (>2 times) that of gabapentin itself produced by colonic administration The area under the curve. For example, the Cmax and AUC values of gabapentin provided by the prodrug (77) are 10 times greater than gabapentin itself. This data indicates that the compounds of the present invention can be formulated into compositions suitable for promoting absorption and/or effective sustained release of GABA analogs, thereby minimizing the frequency of administration due to the rapid systemic clearance of GABA analogs.

Example 43 The sustained release of gabapentin after the prodrug was administered to hunting dogs using a mini pump. Gabapentin or gabapentin prodrugs (77) and (82) (at a dose equal to 10 mg gabapentin/kg) were dissolved in a suitable solvent (e.g., water) , PEG 400, etc.) and fill it into a pre-weighed Alzet(R) mini osmotic pump device (model 2001D) (Durect Corp., Cupertino, CA). Pre-equilibration was performed by soaking the filled Alzet(R) in permeated saline at 37°C for 3 hours and storing in a sealed container at 4°C overnight. Then four fasted male hounds (approximately 6.5 kg) were taken orally. The animals eat 4 hours after each dose. Blood samples (1.0 mL) were taken at intervals within 48 hours, and the plasma was processed immediately. The plasma samples were lyophilized and stored at -80°C until analysis using the method described above. The plasma concentration of gabapentin 12 hours after administration provided by the two prodrugs is twice the concentration of gabapentin seen after the administration of gabapentin itself in the Alzet(R) device. This data further proves that the compound of the present invention can be made into a composition suitable for effective sustained release of GABA analogs.

Example 44 Absorption of pregabalin after administration of pregabalin or pregabalin prodrug in the colon of rats The protocol of Example 41 was repeated with pregabalin and pregabalin prodrugs (110) and (112). After colonic administration of each of these prodrugs, the maximum plasma concentration (Cmax) of pregabalin and the area under the curve of pregabalin plasma concentration versus time (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. Therefore, the present embodiment is considered to be an illustration rather than a limitation, and the present invention is not limited by the details provided herein, but may be modified within the scope and equivalents of the appended claims.

All publications and patents cited herein are fully incorporated by reference.