WO2011071520A1

WO2011071520A1 - Processes for the preparation of (s)-3-(aminomethyl)-5-methylhexanoic acid

Info

Publication number: WO2011071520A1
Application number: PCT/US2010/003102
Authority: WO
Inventors: Satyanarayana Janagani; Venogopala Roa Bandi; Venkata Rao Thanneru; Venkateswara Rao Kadali
Original assignee: Dissymmetrix (Pvt) Ltd.
Priority date: 2009-12-07
Filing date: 2010-12-07
Publication date: 2011-06-16

Abstract

Novel hexanoic acid and novel tetrahydrooxazindione compounds are disclosed as intermediates for preparation of (S)-Pregabalin of formula (I). A novel synthetic method to prepare (S)-Pregabalin using the said intermediates is also disclosed.

Description

PROCESSES FOR THE PREPARATION OF (S)-3-(AMINOMETHYL)-5-

METHYLHEXANOIC ACID

FIELD OF THE INVENTION

[0001] The present invention provides processes for the preparation of (S)-3-(aminomethyl)- 5-methylhexanoic acid and compounds useful as CNS modulators. In some embodiments, the invention provides processes for the preparation of (S)-3-(aminomethyl)-5-methylhexanoic acid. In particular embodiments, the invention provides processes for the preparation of (S)-3- (aminomethyl)-5-methylhexanoic acid starting from ethyl (S)-5-methyl-3-[((S)-l-phenylethyl carbamoyl)-methyl] hexanoate.

BACKGROUND OF THE INVENTION

[0002] (S)-3-(Aminomethyl)-5-methylhexanoic acid, is a CNS modulator and is useful in anticonvulsant therapy. The compound is also knon as (S)-Pregabalin, γ-amino butyric acid or (S)-3-isobutyl GAB A. The compound has the following chemical structure,

I

[0003] (S)-Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for generalized anxiety disorder and is approved for this use in the European Union. It was designed as a more potent successor to gabapentin. Pregabalin is marketed by Pfizer under the trade name Lyrica.

[0004] Recent studies have shown that pregabalin is effective at treating chronic pain in disorders such as fibromyalgia and spinal cord injury. In June 2007, pregabalin became the first medication approved by the U.S. Food and Drug Administration specifically for the treatment of fibromyalgia.

[0005] Several processes for the synthesis of (S)-Pregabalin are known. For example, U.S. Pat. No. 5,599,973 ("the '973 patent") discloses the preparation of (S)-Pregabalin using a stoichiometric amount of (4R,5S)-(+) 4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary that may be recycled. See, e.g., the '973 patent, col. 14, 1.29 to col. 18, 1.23 (example 1). In general, however, the route disclosed in the '973 patent is of limited use on an industrial scale, principally due to the low temperature required for the reaction (e.g., -78° C), the use of pyrophoric reagent (e.g., butyl lithium), and a low overall yield (e.g., 59%, 65%).

[0006] U.S. Pat. No. 5,616,793 discloses methods of making (S)-3-(aminomethyl)-5- methylhexanoic acid starting from isovaleraldehyde. The method involves a reaction of (R)-(-)-3- carbamoylmethyl)-5-methylhexanoic acid with a Hofmann reagent to obtain the desired (S)-(+)- 3-(aminomethyl)-5-methylhexanoic acid

[0007] U.S. Pat. No. 6,891 ,059 discloses the synthesis of (S)-Pregabalin via an asymmetric hydrogenation of a cyano-substituted alkenyl to the corresponding cyano alkane followed by the reduction of cyano to produce the desired (S)-3-(aminomethyl)-5-methyl hexanoic acid.

[0008] Another process is disclosed by G. M. Sammis, et al., J. Am. Chem. Soc, 125(15): 4442-43 (2003), in which an aluminum salen catalyst is used in the conjugate addition of hydrogen cyanide to a, β-unsaturated imides.This process is also not practical for large scale production due to the use of highly poisonous reagents. In addition, the last reduction step requires high hydrogen pressure, which only adds to the difficulties required for adapting this process for use on an industrial scale.

[0009] U.S. Publication Nos. 2007/0191636 and 2007/0197827 also disclose processes for preparing (S)-Pregabalin.

[0010] U.S. Publication Nos. 2008/0306292 discloses synthesis of Pregabalin via carbamic acid derivative.

[0011] International Publication WO 2009/087650, discloses synthesis of Pregabalin from substituted cyclopropane intermediate and a process for enzymatic resolution of racemic

Pregaballin.

[0012] While these methods are enabling and useful for preparing Pregabalin, alternative methods for the preparation, particularly for manufacturing scale production, are desirable.

[0013] Citation of any reference in this application is not to be construed as an admission that such reference is prior art to the present application.

SUMMARY OF THE INVENTION

[0014] Compounds, and use thereof, in the preparation of (S)-Pregabalin are described herein.

[0015] Accordingly, in one aspect, a process is provided for preparing (S)-3-aminomethyl-5- methyl-hexanoic acid of formula I:

or a solvate, polymorph, isotopic variant, or isomer thereof, comprising the steps of:

A 1 ) reacting a hexanoate of formula VII

VII

or an isomer thereof with NH₂NH₂ to form an hydrazino compound of formula VIII or an isomer thereof:

VIII

A2) heating the hydrazino compound of formula VIII or an isomer thereof; and reacting it with NaN0₂ to form an amine of formula IX or an isomer thereof:

A3) hydrolyzing the amide of formula IX or an isomer thereof to (S)-3-aminomethyl- 5-methyl-hexanoic acid of formula I or a solvate, polymorph, isotopic variant, or isomer thereof; wherein R is independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl; and R^3a is independently substituted or unsubstituted alkyl.

[0016] In another aspect, methods are provided to prepare compounds of formula VII:

VII

or an isomer thereof; wherein R² and R^3a are as described herein.

[0017] In one embodiment, a process is provided to prepare compounds of formula VII, comprising the steps of: reacting malonic acid dialkyl ester (II):

with (S)-l-phenyl-ethylamine of formula III or a salt or isomer thereof:

III

to form a substituted N-((S)-l-phenyl-ethyl)-malonamic acid alkyl ester of formula IV or an isomer thereof:

IV

B2) reacting the substituted N-((S)- 1 -phenyl-ethyl)-malonamic acid alkyl ester of formula IV or an isomer thereof with 5-methyl-hex-2-enoic acid alkyl ester of formula V

V

or an is. imer thereof to form a substituted hexanedioic acid dialkyl ester of formula VI isomer thereof:

VI

B3) removing the a-C0₂R^! group of the 3-isobutyl-4-((S)-l- phenyl-ethylcabamoyl)-hexanedioic acid dialkyl ester of formula VI or an isomer thereof, followed by separation of the isomers to form ethyl-(S)-5-methyl-3-[((S)- 1 -phenyl -ethyl carbamoyl)-methyl] hexanoate of formula VII:

VII or an isomer thereof;

wherein each of R and R is independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl; and R^3a is substituted or unsubstituted alkyl.

[0018] In yet another aspect, another novel process is provided to prepare compounds of formula VII, comprising the steps of:

CI) reacting malonic acid (XI):

O O

HO XX OH

XI

with (S)-l -phenyl-ethylamine of formula III or a salt or isomer thereof:

III

and acetone, to form a cyclic compound of formula XII or an isomer thereof:

XII

C2) reacting the cyclic compound of formula XII or an isomer thereof with 5- methyl-hex-2-enoic acid alkyl ester of formula V

V

, or an isomer thereof

to form a cyclic compound of formula XIII or an isomer thereof:

XIII

C3) reacting the cyclic compound of formula XIII or an isomer thereof with an alkoxide, to form a com ound of formula XIV:

or an isomer thereof;

C4) removing the a-C0₂R³ group of the compound of formula XIV or an isomer thereof, followed by separation of the isomers to form ethyl-(S)-5-methyl- 3-[((S)-l-phenyl-ethyl carbamoyl)-methyl] hexanoate of formula VII:

VII isomer thereof; or

C3') heating the compound of formula XIII, or an isomer thereof, followed by separation of the isomers to form the hexanoate of formula VII

VII or an isomer thereof;

wherein each of R and R is independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl; and R^3a is independently substituted or unsubstituted alkyl.

[0019] In yet another aspect, compounds are provided that have formula VI, VII, VIII, IX, XII, XIII, or XIV:

VI Vl l VIII

IX XII XII I or

or a solvate, polymorph, isotopic variant, or isomer thereof;

and wherein each of R², R³, and R^3a is independently substituted or unsubstituted alkyl.

[0020] Further aspect of the invention provides the use of compounds of formula VI, VII, VII

2 3 or a solvate, polymorph, isotopic variant, or isomer thereof ; and wherein each of R , R , and R is independently substituted or unsubstituted alkyl; in preparation of (S)-Pregabalin.

10021) Further aspect of the invention provides the use of compounds of formula VI, VII, VIII, IX, XII, XIII, or XIV:

or a solvate, polymorph, isotopic variant, or isomer thereof; and wherein each of R², R³, and R^3a is independently substituted or unsubstituted alkyl; in preparation of (S)-Pregabalin.

[0022] In additional aspects, methods are provided for synthesizing the compounds described herein, with representative synthetic protocols and pathways described below.

[0023] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.

DESCRIPTION OF FIGURES

[0024] FIGURE 1- Ή NMR of Compound VIII (R² = Me) in CDC1₃.

[0025] FIGURE 2- Ή NMR of Compound IX (R² = Me) in CDC1₃.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0026] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.

[0027] When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and

compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term "substituted" is to be defined as set out below. It should be further understood that the terms "groups" and "radicals" can be considered interchangeable when used herein.

[0028] The articles "a" and "an" may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example "an analogue" means one analogue or more than one analogue.

[0029] 'Acyl' or 'Alkanoyl' refers to a radical -C(0)R²⁰, where R²⁰ is hydrogen, Ci-Cg alkyl, C3-C10 cycloalkyl, C₃-Cio cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5- 10 membered heteroaryl or heteroarylalkyl as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. Exemplary 'acyl' groups are -C(0)H, -C(0)-C₁-C₈ alkyl, -C(O)- (CH₂)_t(C₆-C,o aryl), -C(O)-(CH₂)_t(5-10 membered heteroaryl), -C(O)-(CH₂)_t(C₃-C₁₀ cycloalkyl), and -C(O)-(CH₂)_t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.

[0030] 'Substituted Acyl' or 'Substituted Alkanoyl' refers to a radical -C(0)R²¹, wherein R²¹ is independently

• Ci-C₈ alkyl, substituted with halo or hydroxy; or

• C₃-Cio cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Ci₀ aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1 -C4 alkyl, halo, unsubstituted C1-C₄ alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted Ci-C₄ hydroxyalkyl, or unsubstituted C1-C₄ haloalkoxy or hydroxy.

[0031] 'Acylamino' refers to a radical -NR² C(0)R²³, where R²² is hydrogen, C|-C₈ alkyl, C₃-Cio cycloalkyl, 4-10 membered heterocycloalkyl, C₆-C|₀ aryl, arylalkyl, 5-10 memberd heteroaryl or heteroarylalkyl and R²³ is hydrogen, Ci-C₈ alkyl, C₃-Cio cycloalkyl, 4- 10

membered heterocycloalkyl, C₆-Cio aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, as defined herein. Exemplary 'acylamino' include, but are not limited to, formylamino, acetylamino, cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino and benzylcarbonyl amino. Particular exemplary 'acylamino' groups are -NR²⁴C(0)-Ci-C₈ alkyl, - NR²⁴C(0)-(CH₂),(C₆-C,o aryl), -NR²⁴C(0)-(CH₂)_t(5- 10 membered heteroaryl), -NR²⁴C(0)- (CH₂)_t(C₃-Cio cycloalkyl), and -NR²⁴C(0)-(CH₂)_t(4- 10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, and each R²⁴ independently represents H or Ci-C₈ alkyl.

[0032] 'Substituted Acylamino' refers to a radical -NR²⁵C(0)R²⁶, wherein: R is independently

• H, Ci-C₈ alkyl, substituted with halo or hydroxy; or

• C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-C₁₀ aryl, arylalkyl, 5- 10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C₄ alkoxy, unsubstituted C|- C₄ haloalkyl, unsubstituted C1-C₄ hydroxyalkyl, or unsubstituted C]-C₄ haloalkoxy or hydroxy; and

R²⁶ is independently

• H, Ci-C₈ alkyl, substituted with halo or hydroxy; or

• C₃-Cio cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Cio aryl, arylalkyl, 5- 10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted Ci-C₄ alkoxy, unsubstituted C_\- C₄ haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxyl;

provided that at least one of R" and R ^o is other than H.

[0033] 'Acyloxy' refers to a radical -OC(0)R²⁷, where R²⁷ is hydrogen, C C₈ alkyl, C₃-C₁₀ cycloalkyl, C₃-C]₀ cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein. Representative examples include, but are not limited to, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl and benzylcarbonyl. Exemplary 'acyl' groups are -C(0)H, -C(0)-C_rC₈ alkyl, -C(O)-(CH₂)_t(C₆-Ci₀ aryl), -C(O)-(CH₂),(5-10 membered heteroaryl), -C(O)-(CH₂)_t(C₃-Ci₀ cycloalkyl), and -C(O)- (CH₂)_t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.

[0034] 'Substituted Acyloxy' refers to a radical -OC(0)R²⁸, wherein R²⁸ is independently

• Ci-C₈ alkyl, substituted with halo or hydroxy; or

• C₃-Cio cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Ci₀ aryl, arylalkyl, 5-10. membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1-C₄ alkyl, halo, unsubstituted C1-C₄ alkoxy, unsubstituted C1-C₄ haloalkyl, unsubstituted C 1-C₄ hydroxyalkyl, or unsubstituted C1-C₄ haloalkoxy or hydroxy.

[0035] 'Alkoxy' refers to the group -OR²⁹ where R²⁹ is Q-Q alkyl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n- pentoxy, n-hexoxy, and 1 ,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms. [0036] 'Substituted alkoxy' refers to an alkoxy group substituted with one or more of those groups recited in the definition of "substituted" herein, and particularly refers to an alkoxy group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C -C|₀ aryl, aryloxy, carboxyl, cyano, C₃-Ci₀ cycloalkyl, 4-10 membered

heterocycloalkyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(0)₂- and aryl-S(0)₂-. Exemplary 'substituted alkoxy' groups are -O-(CH₂)_t(C₆-Ci₀ aryl), -O-(CH₂)_t(5-10 membered heteroaryl), -0-(CH₂)_t(C₃-Cio cycloalkyl), and -O-(CH₂)_t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted CpC₄ alkyl, halo, unsubstituted C)-C₄ alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted Ci-C₄ haloalkoxy or hydroxy. Particular exemplary 'substituted alkoxy' groups are OCF₃, OCH₂CF₃, OCH₂Ph, OCH₂- cyclopropyl, OCH₂CH₂OH, and OCH₂CH₂NMe₂.

[0037] 'Alkoxycarbonyl' refers to a radical -C(0)-OR³⁰ where R³⁰ represents an Ci-C₈ alkyl, C₃-Cio cycloalkyl, C₃-Ci₀ cycloalkylalkyl, 4-10 membered heterocycloalkylalkyl, aralkyl, or 5-10 membered heteroarylalkyl as defined herein. Exemplary "alkoxycarbonyl" groups are C(0)0- C,-C₈ alkyl, -C(O)O-(CH₂)_t(C₆-Ci₀ aryl), -C(O)O-(CH₂)_t(5-10 membered heteroaryl), -C(0)0- (CH₂)t(C₃-Cio cycloalkyl), and -C(0)0-(CH₂)_t(4- 10 membered heterocycloalkyl), wherein t is an integer from 1 to 4.

[0038] 'Substituted Alkoxycarbonyl' refers to a radical -C(0)-OR³¹ where R³¹ represents:

• Ci-C alkyl, C₃-Ci₀ cycloalkyl, C₃-Cio cycloalkylalkyl, or 4-10 membered

heterocycloalkylalkyl, each of which is substituted with halo, substituted or unsubstituted amino, or hydroxy; or

• C₆-Ci₀ aralkyl, or 5-10 membered heteroarylalkyl, each of which is substituted with unsubstituted CpC₄ alkyl, halo, unsubstituted C)-C₄ alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted CpC₄ hydroxyalkyl, or unsubstituted C|-C₄ haloalkoxy or hydroxyl.

[0039] 'Aryloxycarbonyl' refers to a radical -C(0)-OR³² where R³² represents an C₆-Cio aryl, as defined herein. Exemplary "aryloxycarbonyl" groups is -C(0)0-(C₆-Cio aryl).

[0040] 'Substituted Aryloxycarbonyl' refers to a radical -C(0)-OR³³ where R³³ represents

• C -Cio aryl, substituted with unsubstituted Ci-C₄ alkyl, halo, unsubstituted C1 -C4 alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted C1 -C4 hydroxyalkyl, or unsubstituted C1 -C4 haloalkoxy or hydroxyl. [0041] 'Heteroaryloxycarbonyl' refers to a radical -C(0)-OR³⁴ where R³⁴ represents a 5-10 membered heteroaryl, as defined herein. An exemplary "aryloxycarbonyl" group is -C(0)0-(5- 10 membered heteroaryl).

[0042] 'Substituted Heteroaryloxycarbonyl' refers to a radical -C(0)-OR³⁵ where R³⁵ represents:

• 5-10 membered heteroaryl, substituted with unsubstituted C1-C4 alkyl, halo,

unsubstituted C_!-C₄ alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted Ci-C₄ hydroxyalkyl, or unsubstituted C1 -C4 haloalkoxy or hydroxyl.

[0043] 'Alkoxycarbonylamino' refers to the group -NR³⁶C(0)OR³⁷, where R³⁶ is hydrogen, Ci-Cg alkyl, C₃-Cio cycloalkyl, C₃-Cio cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein, and R³⁷ is Ci-C₈ alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5- 10 membered heteroaryl or heteroarylalkyl as defined herein.

[0044] 'Alkyl' means straight or branched aliphatic hydrocarbon having 1 to 20 carbon atoms. Particular alkyl has 1 to 12 carbon atoms. More particular is lower alkyl which has 1 to 6 carbon atoms. A further particular group has 1 to 4 carbon atoms. Exemplary straight chained groups include methyl, ethyl n-propyl, and n-butyl. Branched means that one or more lower alkyl groups such as methyl, ethyl, propyl or butyl is attached to a linear alkyl chain, exemplary branched chain groups include isopropyl, iso-butyl, t-butyl and isoamyl.

[0045] 'Substituted alkyl' refers to an alkyl group as defined above substituted with one or more of those groups recited in the definition of "substituted" herein, and particularly refers to an alkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of acyl, acylamino, acyloxy (-O-acyl or— OC(0)R²⁰), alkoxy, alkoxycarbonyl, alkoxycarbonylamino (- NR -alkoxycarbonyl or -NH-C(0)-OR²⁷), amino, substituted amino, aminocarbonyl (carbamoyl or amido or -C(0)-NR ₂), aminocarbonylamino (-NR -C(0)-NR ₂), aminocarbonyloxy (-0- C(0)-NR 2), aminosulfonyl, sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, heteroaryl, nitro, thiol, -S-alkyl, -S-aryl, -S(0)-alkyl,-S(0)-aryl, -S(0)₂-alkyl, and -S(0)₂-aryl. In a particular embodiment 'substituted alkyl' refers to a Ci-C₈ alkyl group substituted with halo, cyano, nitro, trifluoromethyl, trifiuoromethoxy, azido, -NR S0₂R , - S0₂NR^"R ^", -C(0)R^", -C(0)OR^", -OC(0)R^", -NR ^"C(0)R", -C(0)NR^"R ^", -NR ^'R ^"', or - (CR R )_mOR ; wherein each R is independently selected from H, C|-C₈ alkyl, -(CH₂)_t(C₆-C 10 aryl), -(CH₂)_t(5-10 membered heteroaryl), -(CH₂),(C₃-C|₀ cycloalkyl), and -(CH₂)_t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C₄ alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted CJ-C₄ haloalkoxy or hydroxy. Each of R and R independently represents H or Cj-C₈ alkyl.

[0046] 'Alkylene' refers to divalent saturated alkene radical groups having 1 to 1 1 carbon atoms and more particularly 1 to 6 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as methylene (-CH₂-), ethylene (-CH₂CH₂-), the propylene isomers (e.g., -CH₂CH₂CH₂- and -CH(CH₃)CH₂-) and the like.

[0047] 'Substituted alkylene' refers to those groups recited in the definition of "substituted" herein, and particularly refers to an alkylene group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,

alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, amino-carbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl- S(0)₂- and aryl-S(0)₂-.

[0048] 'Alkenyl' refers to monovalent olefinically unsaturated hydrocarbyl groups preferably having 2 to 1 1 carbon atoms, particularly, from 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (- CH=CH₂), «-propenyl (-CH₂CH=CH₂), isopropenyl (-C(CH₃)=CH₂), vinyl and substituted vinyl, and the like.

[0049] 'Substituted alkenyl' refers to those groups recited in the definition of 'substituted' herein, and particularly refers to an alkenyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,

alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(0)₂- and aryl-S(0)₂-.

[0050] 'Alkenylene' refers to divalent olefinically unsaturated hydrocarbyl groups particularly having up to about 1 1 carbon atoms and more particularly 2 to 6 carbon atoms which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. This term is exemplified by groups such as ethenylene (-CH=CH-), the propenylene isomers (e.g., -CH=CHCH₂- and -C(CH₃)=CH- and -CH=C(CH₃)-) and the like. [0051] 'Alkynyl' refers to acetylenically or alkynically unsaturated hydrocarbyl groups particularly having 2 to 1 1 carbon atoms, and more particularly 2 to 6 carbon atoms which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of alkynyl unsaturation. Particular non-limiting examples of alkynyl groups include acetylenic, ethynyl (- C≡CH), propargyl (-CH₂C≡CH), and the like.

[0052] 'Substituted alkynyl' refers to those groups recited in the definition of "substituted" herein, and particularly refers to an alkynyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,

[0053] 'Amino' refers to the radical -NH₂.

[0054] 'Substituted amino' refers to an amino group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to the group -

38 38

N(R )₂ where each R is independently selected from:

• hydrogen, Cj-Q alkyl, C₆-Cio aryl, 5-10 membered heteroaryl, 4-10 membered

heterocycloalkyl, or C₃-Cio cycloalkyl; or

• Ci-C₈ alkyl, substituted with halo or hydroxy; or

• -(CH₂)_t(C₆-Cio aryl), -(CH₂)_t(5-10 membered heteroaryl), -(CH₂)_t(C₃-Ci₀ cycloalkyl) or -(CH₂)_t(4-10 membered heterocycloalkyl) wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted Ci-C₄ alkyl, halo, unsubstituted C 1 -C4 alkoxy, unsubstituted C1-C₄ haloalkyl, unsubstituted C1-C₄ hydroxyalkyl, or unsubstituted C₍-C₄ haloalkoxy or hydroxy; or

• both R groups are joined to form an alkylene group.

When both R³⁸ groups are hydrogen, -N(R³⁸)₂ is an amino group. Exemplary ' substituted amino' groups are -NR³⁹-C,-C₈ alkyl, -NR³⁹-(CH₂)_t(C₆-C₁₀ aryl), -NR³⁹-(CH₂)_t(5-10 membered heteroaryl), -NR³⁹-(CH₂)_t(C₃-C₁₀ cycloalkyl), and -NR³⁹-(CH₂)_t(4- 10 membered

heterocycloalkyl), wherein t is an integer from 0 to 4, each R³⁹ independently represents H or C_\- C₈ alkyl; and any alkyl groups present, may themselves be substituted by halo, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C₄ alkyl, halo, unsubstituted Ci-C₄ alkoxy, unsubstituted C1 -C4 haloalkyl, unsubstituted C1-C₄ hydroxyalkyl, or unsubstituted C1-C₄ haloalkoxy or hydroxy. For the avoidance of doubt the term "substituted amino" includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino and substituted dialkylamino as defined below.

[0055] 'Alkylamino' refers to the group -NHR⁴⁰, wherein R⁴⁰ is Ci-Cs alkyl;

[0056] 'Substituted Alkylamino' refers to the group -NHR⁴¹, wherein R⁴¹ is Ci-C₈ alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C₃-Cio cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Cio aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C₄ alkyl, halo, unsubstituted Cj-C₄ alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted Q-C4

haloalkoxy or hydroxy.

[0057] 'Alkylarylamino' refers to the group -NR⁴²R⁴³, wherein R⁴² is aryl and R⁴³ is C_rC₈ alkyl.

[0058] 'Substituted Alkylarylamino' refers to the group -NR⁴⁴R⁴⁵, wherein R⁴⁴ is aryl and R⁴⁵ is Cj-Cg alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C3-C₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆-C₁₀ aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or

heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, cyano, unsubstituted C1-C₄ alkoxy, unsubstituted C1-C₄ haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted Ci-C₄ haloalkoxy or hydroxy.

[0059] 'Arylamino' means a radical -NHR⁴⁶ where R⁴⁶ is selected from C₆-Cio aryl and 5-10 membered heteroaryl as defined herein.

[0060] 'Substituted Arylamino' refers to the group -NHR⁴⁷, wherein R⁴⁷ is independently selected from C₆-Cio aryl and 5-10 membered heteroaryl; and any aryl or heteroaryl groups . present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, cyano, unsubstituted C1-C₄ alkoxy, unsubstituted C1-C₄ haloalkyl, unsubstituted C1-C₄ hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0061] 'Dialkylamino' refers to the group -NR⁴⁸R⁴⁹, wherein each of R⁴⁸ and R⁴⁹ are independently selected from Ci-C₈ alkyl.

[0062] 'Substituted Dialkylamino' refers to the group -NR⁵⁰R⁵¹, wherein each of R⁵⁹ and R⁵¹ are independently selected from Ci-C₈ alkyl; and at least one of the alkyl groups is independently substituted with halo, hydroxy, C₃-Cio cycloalkyl, 4-10 membered heterocycloalkyl, C₆-C₍o aryl, 5-10 membered heteroaryl, aralkyl or heteroaralkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C₄ alkoxy, unsubstituted C 1 -4 haloalkyl, unsubstituted C1-C₄ hydroxyalkyl, or unsubstituted Ci-C₄ haloalkoxy or hydroxy. [0063] 'Diarylamino' refers to the group -NR⁵²R⁵³, wherein each of R⁵² and R⁵³ are independently selected from C₆-Ci₀ aryl.

[0064] 'Aminosulfonyl' or 'Sulfonamide' refers to the radical -S(0₂)NH₂.

[0065] 'Substituted aminosulfonyl' or 'substituted sulfonamide' refers to a radical such as -

S(0₂)N(R⁵⁴)₂ wherein each R⁵⁴⁸ is independently selected from:

• H, Cj-Cs alkyl, C₃-Ci₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Ci₀ aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or

• C]-C₈ alkyl substituted with halo or hydroxy; or

• C₃-Cio cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Ci₀ aryl, aralkyl, 5-10

membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C₄ haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy; provided that at least one R⁵⁴ is other than H.

[0066] Exemplary 'substituted aminosulfonyl' or 'substituted sulfonamide' groups are - S(02)N(R⁵⁵)-C,-C₈ alkyl, -S(O₂)N(R⁵⁵)-(CH₂)_t(C₆-C₁₀ aryl), -S(O₂)N(R⁵⁵)-(CH₂)_t(5-10 membered heteroaryl), -S(O₂)N(R⁵⁵)-(CH₂)_t(C₃-Cj₀ cycloalkyl), and -S(O₂)N(R⁵⁵)-(CH₂),(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4; each R⁵⁵ independently represents H or Ci-C₈ alkyl; and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C₄ alkyl, halo, unsubstituted C1 -C4 alkoxy, unsubstituted C1-C₄ haloalkyl, unsubstituted C1-C₄ hydroxyalkyl, or unsubstituted Ci-C₄ haloalkoxy or hydroxy.

[0067] 'Aralkyl' or 'arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups, as defined above. Particular aralkyl or arylalkyl groups are alkyl groups substituted with one aryl group.

[0068] 'Substituted Aralkyl' or 'substituted arylalkyl' refers to an alkyl group, as defined above, substituted with one or more aryl groups; and at least one of the aryl groups present, may themselves be substituted by unsubstituted C1 -C4 alkyl, halo, cyano, unsubstituted C|-C₄ alkoxy, unsubstituted C1 -C4 haloalkyl, unsubstituted C1 -C4 hydroxyalkyl, or unsubstituted C1 -C4

haloalkoxy or hydroxy.

[0069] 'Aryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, mono-cyclic or poly-cyclic that includes from 5 to 12 ring members, more usually 6 to 10. Where the aryl group is a monocyclic ring system it

preferentially contains 6 carbon atoms. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0070] 'Substituted Aryl' refers to an aryl group substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to an aryl group that may optionally be substituted with 1 or more substituents, for instance from 1 to 5 substituents, particularly 1 to 3 substituents, in particular 1 substituent. Particularly, 'Substituted Aryl' refers to an aryl group substituted with one or more of groups selected from halo, Ci-C₈ alkyl, Ci-C₈ haloalkyl, cyano, hydroxy, Ci-C₈ alkoxy, and amino.

[0071] Examples of representative substituted aryls include the following

[0072] In these formulae one of R and R may be hydrogen and at least one of R and R is each independently selected from Q-Q alkyl, Q-Q haloalkyl, 4-10 membered

heterocycloalkyl, alkanoyl, Ci-Cs alkoxy, heteroaryloxy, alkylamino, arylamino,

heteroarylamino, NR⁵⁸COR⁵⁹, NR⁵⁸SOR⁵⁹ _,NR⁵⁸S0₂R⁵⁹, COOalkyl, COOaryl, CONR⁵⁸R⁵⁹, CONR⁵⁸OR⁵⁹, NR⁵⁸R⁵⁹, S0₂NR⁵⁸R⁵⁹, S-alkyl, SOalkyl, S0₂alkyl, Saryl, SOaryl, S0₂aryl; or R⁵⁶ and R⁵⁷may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O or S. R⁶⁰, and R⁶¹ are independently hydrogen, C|-C₈ alkyl, Ci-C₄ haloalkyl, C₃-Cio cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Cio aryl, substituted aryl, 5-10 membered heteroaryl.

[0073] 'Fused Aryl' refers to an aryl having two of its ring carbon in common with a second aryl ring or with an aliphatic ring.

[0074] 'Arylalkyloxy' refers to an -O-alkylaryl radical where alkylaryl is as defined herein.

[0075] 'Substituted Arylalkyloxy' refers to an -O-alkylaryl radical where alkylaryl is as defined herein; and any aryl groups present, may themselves be substituted by unsubstituted C_\-

C₄ alkyl, halo, cyano, unsubstituted C(-C₄ alkoxy, unsubstituted C|-₄ haloalkyl, unsubstituted d-

C₄ hydroxyalkyl, or unsubstituted Ci-C₄ haloalkoxy or hydroxy.

[0076] 'Azido' refers to the radical -N₃.

[0077] 'Carbamoyl or amido' refers to the radical -C(0)NH₂. [0078] 'Substituted Carbamoyl or substituted amido' refers to the radical -C(0)N(R⁶²)₂ wherein each R is independently

• H, Ci-C₈ alkyl, C₃-Cio cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Cio aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or

• Ci-Cg alkyl substituted with halo or hydroxy; or

• C₃-Cio cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Cio aryl, aralkyl, 5-10

membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted Ci-C₄ alkyl, halo, unsubstituted Ci-C₄ alkoxy, unsubstituted C1 -C4 haloalkyl, unsubstituted Ci-C₄ hydroxyalkyl, or unsubstituted C1 -C4 haloalkoxy or hydroxy; provided that at least one R is other than H.

Exemplary 'Substituted Carbamoyl' groups are -C(O) NR⁶⁴-C C₈ alkyl, -C(0)NR⁶⁴-(CH₂)_t(C₆- C10 aryl), -C(O)N⁶⁴-(CH₂)_t(5-10 membered heteroaryl), -C(G)NR⁶ -(CH₂)_t(C₃-C,₀ cycloalkyl), and -C(O)NR⁶⁴-(CH₂)_t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4, each R⁶⁴ independently represents H or C C₈ alkyl and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C₄ alkyl, halo, unsubstituted C_!-C₄ alkoxy, unsubstituted Q-C4 haloalkyl, unsubstituted C1-C₄

hydroxyalkyl, or unsubstituted Q-C4 haloalkoxy or hydroxy.

[0079] 'Carboxy' refers to the radical -C(0)OH.

[0080] 'Cycloalkyl' refers to cyclic non-aromatic hydrocarbyl groups having from 3 to 10 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.

[0081] 'Substituted cycloalkyl' refers to a cycloalkyl group as defined above substituted with one or more of those groups recited in the definition of 'substituted' herein, and particularly refers to a cycloalkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent

[0082] 'Cyano' refers to the radical -CN.

[0083] 'Halo' or 'halogen' refers to fluoro (F), chloro (CI), bromo (Br) and iodo (I).

Particular halo groups are either fluoro or chloro.

[0084] 'Hetero' when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, cycloalkenyl, e.g. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms. [0085] 'Heteroaryl' means an aromatic ring structure, mono-cyclic or polycyclic, that includes one or more heteroatoms and 5 to 12 ring members, more usually 5 to 10 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulphur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five. Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups. Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine. Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole and imidazoimidazole. Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuran, benzthiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole, isobenzofuran, indole, isoindole, isoindolone, indolizine, indoline, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine, triazolopyrimidine, benzodioxole and pyrazolopyridine groups. Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, chroman, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups. Particular heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.

[0086] Examples of representative heteroaryls include the following:

wherein each Y is selected from carbonyl, N, NR , O and S; and R is independently hydrogen, Ci-C alkyl, C₃-Cio cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Cio aryl, and 5-10 membered heteroaryl.

[0087] Examples of representative aryl having hetero atoms containing substitution include the following:

wherein each W is selected from C(R )₂, NR , O and S; and each Y is selected from carbonyl, NR⁶⁶, O and S; and R⁶⁶ is independently hydrogen, Ci-C₈ alkyl, C₃-Ci₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Ci₀ aryl, and 5-10 membered heteroaryl.

[0088] As used herein, the term 'heterocycloalkyl' refers to a 4-10 membered, stable heterocyclic non-aromatic ring and/or including rings containing one or more heteroatoms independently selected from N, O and S, fused thereto. A fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring. Examples of heterocyclic rings include, but are not limited to, morpholine, piperidine (e.g. 1 -piperidinyl, 2-piperidinyl, 3- piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 1 -pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. 4- tetrahydro pyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine. Further examples include thiomorpholine and its S-oxide and S,S-dioxide (particularly thiomorpholine). Still further examples include azetidine, piperidone, piperazone, and N-alkyl piperidines such as N- methyl piperidine. Particular examples of heterocycloalkyl groups are shown in the following illustrative examples:

wherein each W is selected from CR , C(R^b )2, NR , O and S; and each Y is selected from NR⁶⁷, O and S; and R⁶⁷ is independently hydrogen, Ci-Cg alkyl, C₃-Ci₀ cycloalkyl, 4-10 membered heterocycloalkyl, C6-Ci₀ aryl, 5-10 membered heteroaryl, These heterocycloalkyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl (carbamoyl or amido), aminocarbonylamino, aminosulfonyl,

sulfonylamino, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, halogen, hydroxy, keto, nitro, thiol, -S-alkyl, -S-aryl, -S(0)-alkyl ,-S(0)-aryl, -S(0)₂-alkyl, and -S(0)₂-aryl. Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivatives.

[0089] 'Hydroxy' refers to the radical -OH.

[0090] 'Nitro' refers to the radical -N0₂.

[0091] 'Substituted' refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s). Typical substituents may be selected from the group consisting of:

halogen, -R⁶⁸, -0\ -O, -OR⁶⁸, -SR⁶⁸, -S\ =S, -NR⁶⁸R⁶⁹, =NR⁶⁸, -CC1₃, -CF₃, -CN, -OCN, -SCN, - NO, -N0₂, =N₂, -N₃, -S(0)₂0\ -S(0)₂OH, -S(0)₂R⁶⁸, -OS(0₂)0^', -OS(0)₂R⁶⁸, -P(0)(0 )₂, - P(0)(OR⁶⁸)(0^"), -OP(0)(OR⁶⁸)(OR⁶⁹), -C(0)R⁶⁸, -C(S)R⁶⁸, -C(0)0R⁶⁸, -C(0)NR⁶⁸R⁶⁹, -C(0)0^', -C(S)OR⁶⁸, -NR⁷⁰C(O)NR⁶⁸R⁶⁹, -NR⁷⁰C(S)NR⁶⁸R⁶⁹, -NR^7IC(NR⁷⁰)NR⁶⁸R⁶⁹ and

-C(NR⁷⁰)NR⁶⁸R⁶⁹;

wherein each R⁶⁸, R⁶⁹, R⁷⁰ and R⁷¹ are independently:

• hydrogen, Ci-C₈ alkyl, C6-C|₀ aryl, arylalkyl, C₃-Cio cycloalkyl, 4-10 membered

heterocycloalkyl, 5-10 membered heteroaryl, heteroarylalkyl; or

• Ci-C₈ alkyl substituted with halo or hydroxy; or

• C₆-Cio aryl, 5-10 membered heteroaryl, C₆-Ci₀ cycloalkyl or 4-10 membered

heterocycloalkyl each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted C|-C₄ alkoxy, unsubstituted C|-C₄ haloalkyl, unsubstituted C|-C₄ hydroxyalkyl, or unsubstituted C 1-C4 haloalkoxy or hydroxy. [0092] In a particular embodiment, substituted groups are substituted with one or more substituents, particularly with 1 to 3 substituents, in particular with one substituent group.

[0093] In a further particular embodiment the substituent group or groups are selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, -NR⁷²S0₂R⁷³, -S0₂NR⁷³R⁷², - C(0)R⁷³, -C(0)OR⁷³, -OC(0)R⁷³, -NR⁷²C(0)R⁷³, -C(0)NR⁷³R⁷², -NR⁷³R⁷², -(CR⁷²R⁷²)_mOR⁷², wherein, each R⁷³ is independently selected from H, Ci-C₈ alkyl, -(CH₂)_t(C₆-C_!o aryl), -(CH₂)_t(5- 10 membered heteroaryl), -(CH₂)_t(C₃-Cio cycloalkyl), and -(CH₂)_t(4-10 membered

heterocycloalkyl), wherein t is an integer from 0 to 4; and

• any alkyl groups present, may themselves be substituted by halo or hydroxy; and

• any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C)-C₄ alkyl, halo, unsubstituted Ci-C₄ alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted Ci-C₄ hydroxyalkyl, or unsubstituted Ci- C₄ haloalkoxy or hydroxy. Each R independently represents H or d-Qalkyl.

[0094] 'Substituted sulfanyl' refers to the group -SR⁷⁴, wherein R⁷⁴ is selected from:

• C]-C₈ alkyl, C₃-C₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆-C₁₀ aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or

• Ci-C₈ alkyl substituted with halo, substituted or unsubstituted amino, or hydroxy; or

membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1-C4 alkyl, halo, unsubstituted Ci-C₄ alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted Ci-C₄ hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0095] Exemplary 'substituted sulfanyl' groups are -S-(Ci-C₈ alkyl) and -S-(C₃-Cio cycloalkyl), -S-(CH₂),(C₆-C,₀ aryl), -S-(CH₂)_t(5- 10 membered heteroaryl), -S-(CH₂)_t(C₃-Ci₀ cycloalkyl), and -S-(CH₂)_t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1 -C4 alkyl, halo, unsubstituted Ci-C₄ alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted C|-C₄ hydroxyalkyl, or unsubstituted C1 -C4 haloalkoxy or hydroxy. The term 'substituted sulfanyl' includes the groups 'alkylsulfanyl' or 'alkylthio', 'substituted alkylthio' or 'substituted alkylsulfanyl', 'cycloalkylsulfanyl' or 'cycloalkylthio', 'substituted cycloalkylsulfanyl' or 'substituted cycloalkylthio', 'arylsulfanyl' or 'arylthio' and

'heteroarylsulfanyl' or 'heteroarylthio' as defined below.

[0096] 'Alkylthio' or 'Alkylsulfanyl' refers to a radical -SR⁷⁵ where R⁷⁵ is a C|-C₈ alkyl or group as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio and butylthio. (0097] 'Substituted Alkylthio'or 'substituted alkylsulfanyl' refers to the group -SR.⁷⁶ where R⁷⁶ is a Ci-C₈ alkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.

[0098] 'Cycloalkylthio' or 'Cycloalkylsulfanyl' refers to a radical -SR⁷⁷ where R⁷⁷ is a C₃- Cio cycloalkyl or group as defined herein. Representative examples include, but are not limited to, cyclopropylthio, cyclohexylthio, and cyclopentylthio.

[0099] 'Substituted cycloalkylthio' or 'substituted cycloalkylsulfanyl' refers to the group -

SR where R is a C₃-Ci₀ cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.

[00100] 'Arylthio' or 'Arylsulfanyl' refers to a radical -SR⁷⁹ where R⁷⁹ is a C₆-Ci₀ aryl group as defined herein.

[00101] 'Heteroarylthio' or 'Heteroarylsulfanyl' refers to a radical -SR⁸⁰ where R⁸⁰ is a 5-10 membered heteroaryl group as defined herein.

[00102] 'Substituted sulfinyl' refers to the group -S(0)R⁸¹, wherein R⁸¹ is selected from:

• Ci-C₈ alkyl, C₃-Ci₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Cio aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or

• C₃-Cio cycloalkyl, 4-10 membered heterocycloalkyl, C₆-C₁₀ aryl, aralkyl, 5-10

membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted Ci-C₄ alkyl, halo, unsubstituted C)-C₄ alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted Ci-C₄ hydroxyalkyl, or unsubstituted Ci-C₄ haloalkoxy or hydroxy.

[00103] Exemplary 'substituted sulfinyl' groups are -S(0)-(Ci-C₈ alkyl) and -S(O)-(C₃-Ci₀ cycloalkyl), -S(O)-(CH₂)_t(C₆-Ci₀ aryl), -S(O)-(CH₂),(5-10 membered heteroaryl), -S(O)- (CH₂)_t(C₃-Cio cycloalkyl), and -S(O)-(CH )_t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C|-C₄ alkyl, halo, unsubstituted Ci-C₄ alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted Ci-C₄ hydroxyalkyl, or unsubstituted C 1 -C4

haloalkoxy or hydroxy. The term substituted sulfinyl includes the groups 'alkylsulfinyl',

'substituted alkylsulfinyl', 'cycloalkylsulfinyl', 'substituted cycloalkylsulfinyl', 'arylsulfinyl' and 'heteroarylsulfinyl' as defined herein.

[00104] 'Alkylsulfinyl' refers to a radical -S(0)R⁸² where R⁸² is a Ci-Cg alkyl group as defined herein. Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl and butylsulfinyl.

[00105] 'Substituted Alkylsulfinyl' refers to a radical -S(0)R⁸³ where R⁸³ is a C_rC₈ alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy. [00106] 'Cycloalkylsulfinyl' refers to a radical -S(0)R⁸⁴ where R⁸⁴ is a C3-C10 cycloalkyl or group as defined herein. Representative examples include, but are not limited to,

cyclopropylsulfinyl, cyclohexylsulfinyl, and cyclopentylsulfinyl. Exemplary 'cycloalkylsulfinyl' groups are S(O)-C₃-Ci₀ cycloalkyl.

[00107] 'Substituted cycloalkylsulfinyl' refers to the group -S(0)R⁸⁵ where R⁸⁵ is a C₃-C_{I 0} cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.

[00108] 'Arylsulfinyl' refers to a radical -S(0)R⁸⁶ where R⁸⁶ is a C₆-C₁₀ aryl group as defined herein.

[00109] 'Heteroarylsulfinyl' refers to a radical -S(0)R⁸⁷ where R⁸⁷ is a 5-10 membered heteroaryl group as defined herein.

[00110] 'Substituted sulfonyl' refers to the group -S(0)₂R⁸⁸, wherein R⁸⁸ is selected from:

• Ci-C₈ alkyl, C₃-Cio cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Cio aryl, aralkyl,

5-10 membered heteroaryl, and heteroaralkyl; or

• C₃-Ci₀ cycloalkyl, 4-10 membered heterocycloalkyl, C -Cio aryl, aralkyl, 5-10

membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C1 -C4 alkyl, halo, unsubstituted Ci-C₄ alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted C1 -C4 hydroxyalkyl, or unsubstituted Ci-C₄ haloalkoxy or hydroxy.

[00111] Exemplary 'substituted sulfonyl' groups are -S(0)₂-(Ci-C₈ alkyl) and -S(O)₂-(C₃-Ci₀ cycloalkyl), -S(O)₂-(CH₂)_t(C₆-C,₀ aryl), -S(0)₂-(CH₂),(5- 10 membered heteroaryl), -S(0)₂- (CH₂)_t(C₃-Cio cycloalkyl), and -S(O)₂-(CH₂)_t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted C1-C₄ alkyl, halo, unsubstituted C1-C₄ alkoxy, unsubstituted C1 -C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted Ci-C₄

haloalkoxy or hydroxy. The term substituted sulfonyl includes the groups alkylsulfonyl, substituted alkylsulfonyl, cycloalkylsulfonyl, substituted cycloalkylsulfonyl, arylsulfonyl and heteroarylsulfonyl.

[00112] 'Alkylsulfonyl' refers to a radical -S(0)₂R⁸⁹ where R⁸⁹ is an Ci-C₈ alkyl group as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl and butylsulfonyl.

[00113] 'Substituted Alkylsulfonyl ' refers to a radical -S(0)₂R⁹⁰ where R⁹⁰ is an C,-C₈ alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy.

[001141 'Cycloalkylsulfonyl' refers to a radical -S(0)₂R⁹¹ where R⁹¹ is a C₃-Ci₀ cycloalkyl or group as defined herein. Representative examples include, but are not limited to,

cyclopropylsulfonyl, cyclohexylsulfonyl, and cyclopentylsulfonyl. [00115] 'Substituted cycloalkylsulfonyl' refers to the group -SCO^R⁹² where R⁹² is a C₃-Ci₀ cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.

[00116] 'Arylsulfonyl' refers to a radical -S(0)₂R⁹³ where R⁹³ is an C₆-Cio aryl group as defined herein.

[00117] 'Heteroarylsulfonyl' refers to a radical -S(0)₂R⁹⁴ where R⁹⁴ is an 5-10 membered heteroaryl group as defined herein.

[00118] 'Sulfo' or 'sulfonic acid' refers to a radical such as -S0₃H.

[00119] 'Substituted sulfo' or 'sulfonic acid ester' refers to the group -S(0)₂OR⁹⁵, wherein R⁹⁵ is selected from:

• Ci-C alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C₆-C₁₀ aryl, aralkyl, 5-10 membered heteroaryl, and heteroaralkyl; or

• C₃-Cio cycloalkyl, 4-10 membered heterocycloalkyl, C₆-C)₀ aryl, aralkyl, 5-10

membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted Ci-C₄ alkyl, halo, unsubstituted C C₄ alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1 -C4 hydroxyalkyl, or unsubstituted C_!-C₄ haloalkoxy or hydroxy.

[00120] Exemplary 'Substituted sulfo' or 'sulfonic acid ester' groups are— S(0)₂-0-(Ci-C₈ alkyl) and -S(O)₂-O-(C₃-C₁₀ cycloalkyl), -S(O)₂-O-(CH₂)_t(C₆-C₁₀ aryl), -S(O)₂-O-(CH₂)_t(5-10 membered heteroaryl), -S(O)₂-O-(CH₂),(C₃-Ci₀ cycloalkyl), and -S(O)₂-O-(CH₂)_t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C₄ alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted Ci-C₄ hydroxyalkyl, or unsubstituted Ci-C₄ haloalkoxy or hydroxy.

[00121] 'Thiol' refers to the group -SH.

[00122] 'Aminocarbonylamino' refers to the group -NR⁹⁶C(0)NR⁹⁶R⁹⁶ where each R⁹⁶ is independently hydrogen C|-C₈ alkyl, C₃-Ci₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Ci₀ aryl, aralkyl, 5- 10 membered heteroaryl, and heteroaralkyl, as defined herein; or where two R⁹⁶ groups, when attached to the same N, are joined to form an alkylene group.

[00123] 'Bicycloaryl' refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent bicycloaromatic ring system. Typical bicycloaryl groups include, but are not limited to, groups derived from indane, indene, naphthalene, tetrahydronaphthalene, and the like. Particularly, an aryl group comprises from 8 to 1 1 carbon atoms.

[00124] 'Bicycloheteroaryl' refers to a monovalent bicycloheteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent bicycloheteroaromatic ring system. Typical bicycloheteroaryl groups include, but are not limited to, groups derived from benzofuran, benzimidazole, benzindazole, benzdioxane, chromene, chromane, cinnoline, phthalazine, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, benzothiazole, benzoxazole, naphthyridine, benzoxadiazole, pteridine, purine, benzopyran, benzpyrazine, pyridopyrimidine, quinazoline, quinoline, quinolizine, quinoxaline, benzomorphan, tetrahydroisoquinoline, tetrahydroquinoline, and the like. Preferably, the bicycloheteroaryl group is between 9-1 1 membered bicycloheteroaryl, with 5-10 membered heteroaryl being particularly preferred. Particular bicycloheteroaryl groups are those derived from benzothiophene, benzofuran, benzothiazole, indole, quinoline, isoquinoline, benzimidazole, benzoxazole and benzdioxane.

[00125] 'Compounds of the present invention', and equivalent expressions, are meant to embrace the compounds as hereinbefore described, in particular compounds according to any of the formulae herein recited and/or described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g., hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.

[00126] 'Cycloalkylalkyl' refers to a radical in which a cycloalkyl group is substituted for a hydrogen atom of an alkyl group. Typical cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclopropylethyl, cyclobutylethyl, cyclopentyl ethyl, cyclohexyl ethyl, cycloheptylethyl, and cyclooctyl ethyl, and the like.

[00127] 'Heterocycloalkylalkyl' refers to a radical in which a heterocycloalkyl group is substituted for a hydrogen atom of an alkyl group. Typical heterocycloalkylalkyl groups include, but are not limited to, pyrrolidinylmethyl, piperidinylmethyl, piperazinylmethyl,

morpholinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinylethyl, morpholinylethyl, and the like.

[00128] 'Cycloalkenyl' refers to cyclic hydrocarbyl groups having from 3 to 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems and having at least one and particularly from 1 to 2 sites of olefinic unsaturation. Such cycloalkenyl groups include, by way of example, single ring structures such as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.

[00129] 'Substituted cycloalkenyl' refers to those groups recited in the definition of

"substituted" herein, and particularly refers to a cycloalkenyl group having 1 or more

substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(0)₂- and aryl-S(0)₂-.

[00130] 'Fused Cycloalkenyl' refers to a cycloalkenyl having two of its ring carbon atoms in common with a second aliphatic or aromatic ring and having its olefinic unsaturation located to impart aromaticity to the cycloalkenyl ring.

[00131] 'Ethenyl' refers to substituted or unsubstituted -(C=C)-.

[00132] 'Ethylene' refers to substituted or unsubstituted -(C-C)-.

[00133] 'Ethynyl' refers to -(C≡C)-.

[00134] 'Hydrogen bond donor' group refers to a group containg O-H, or N-H functionality. Examples of 'hydrogen bond donor' groups include -OH, -NH₂, and -NH-R⁹⁷ and wherein R⁹⁷ is alkyl, acyl, cycloalkyl, aryl, or heteroaryl.

[00135] 'Dihydroxyphosphoryl' refers to the radical -PO(OH)₂.

[00136] 'Substituted dihydroxyphosphoryl' refers to those groups recited in the definition of "substituted" herein, and particularly refers to a dihydroxyphosphoryl radical wherein one or both of the hydroxyl groups are substituted. Suitable substituents are described in detail below.

[00137] 'Aminohydroxyphosphoryl' refers to the radical -PO(OH)NH₂.

[00138] 'Substituted aminohydroxyphosphoryl' refers to those groups recited in the definition of "substituted" herein, and particularly refers to an aminohydroxyphosphoryl wherein the amino group is substituted with one or two substituents. Suitable substituents are described in detail below. In certain embodiments, the hydroxyl group can also be substituted.

[00139] 'Nitrogen-Containing Heterocycloalkyl' group means a 4 to 7 membered non- aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g. 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2- pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2- pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N-methyl piperazine.

Particular examples include azetidine, piperidone and piperazone.

[00140] 'Thioketo' refers to the group =S.

[00141] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable. [00142] 'Pharmaceutically acceptable' means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[00143] 'Pharmaceutically acceptable salt' refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic 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-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N- methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term "pharmaceutically acceptable cation" refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

[00144] 'Pharmaceutically acceptable vehicle' refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

[00145] 'Prodrugs' refers to compounds, including derivatives of the compounds of the invention,which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N- alkylmorpholine esters and the like. [00146] 'Solvate' refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, ethanol, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. 'Solvate' encompasses both solution-phase and isolable solvates.

Representative solvates include hydrates, ethanolates and methanolates.

[00147] 'Subject' includes humans. The terms 'human', 'patient' and 'subject' are used interchangeably herein.

[00148] 'Therapeutically effective amount' means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

[00149] 'Preventing' or 'prevention' refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.

[00150] The term 'prophylaxis' is related to 'prevention', and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[00151] 'Treating' or 'treatment' of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment 'treating' or 'treatment' refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, 'treating' or 'treatment' refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, "treating" or "treatment" relates to slowing the progression of the disease. [00152] 'Compounds of the present invention', and equivalent expressions, are meant to embrace compounds of the Formula(e) as hereinbefore described, which expression includes the prodrugs, the pharmaceutically acceptable salts, and the solvates, e.g., hydrates, where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits.

[00153] When ranges are referred to herein, for example but without limitation, Ci-C₈ alkyl, the citation of a range should be considered a representation of each member of said range.

[00154] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly the Ci to Cg alkyl, C₂-C₈ alkenyl, aryl, C₇-Ci₂ substituted aryl, and C₇-Ci₂ arylalkyl esters of the compounds of the invention.

[00155] As used herein, the term 'isotopic variant' refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an 'isotopic variant' of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium (²H or D), carbon- 13 (¹³C), nitrogen- 15 (¹⁵N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be ²H/D, any carbon may be ^l3C, or any nitrogen may be ¹⁵N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon- 14, i.e. ^I4C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting isotopes, such as "C, ^l8F, ^l50 and

13

N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. [00156] All isotopic variants of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the invention.

[00157] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed 'isomers'. Isomers that differ in the arrangement of their atoms in space are termed 'stereoisomers'.

[00158] Stereoisomers that are not mirror images of one another are termed 'diastereomers' and those that are non-superimposable mirror images of each other are termed 'enantiomers'. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a 'racemic mixture'.

[00159] 'Tautomers' refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.

[00160] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[00161] As used herein a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an "S" form of the compound is substantially free from the "R" form of the compound and is, thus, in enantiomeric excess of the "R" form. The term "enantiomerically pure" or "pure enantiomer" denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91 % by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound. [00162] As used herein and unless otherwise indicated, the term "enantiomerically pure R- compound" refers to at least about 80% by weight R-compound and at most about 20% by weight S-compound, at least about 90% by weight R-compound and at most about 10% by weight S-compound, at least about 95% by weight R-compound and at most about 5% by weight S-compound, at least about 99% by weight R-compound and at most about 1% by weight S- compound, at least about 99.9% by weight R-compound or at most about 0.1 % by weight S- compound. In certain embodiments, the weights are based upon total weight of compound.

[00163] As used herein and unless otherwise indicated, the term "enantiomerically pure S- compound" or "S-compound" refers to at least about 80% by weight S-compound and at most about 20% by weight R-compound, at least about 90% by weight S-compound and at most about 10% by weight R-compound, at least about 95% by weight S-compound and at most about 5% by weight R-compound, at least about 99% by weight S-compound and at most about 1 % by weight R-compound or at least about 99.9% by weight S-compound and at most about 0.1% by weight R-compound. In certain embodiments, the weights are based upon total weight of compound.

[00164] In the compositions provided herein, an enantiomerically pure compound or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R-compound. In certain embodiments, the enantiomerically pure R- compound in such compositions can, for example, comprise, at least about 95% by weight R- compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. In certain embodiments, the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[00165] The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.

[00166] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art. THE COMPOUNDS AND PROCESSES TO MAKE THEM

[00167] In certain aspects, the present invention provides certain compounds useful as intermediates for preparation of (S)-Pregabalin. In additional aspect, the present invention provides use of these certain compounds in preparation of (S)-Pregabalin. In yet additional aspect, the invention provides a novel process for preparation of (S)-Pregabalin.

[00168] Accordingly, in one aspect, a process is provided for preparing (S)-3-aminomethyl-5- methyl-hexanoic acid of formula I:

Al) reacting a hexanoate of formula VII

VII

VIII

IX ; and

[00169] In one embodiment, with respect to the process to prepare compounds of formula I, R is substituted or unsubstituted alkyl. In another embodiment, R² is ethyl, methyl, or benzyl.

[00170] In one particular embodiment, with respect to the process to prepare compounds of formula I, R² is Me.

[00171] In one embodiment, with respect to the process to prepare compounds of formula I, R^3a is substituted or unsubstituted alkyl. In another embodiment, R^3a is ethyl, methyl, or benzyl.

[00172] In one particular embodiment, with respect to the process to prepare compounds of formula I, R^3a is Et.

[00173] In one embodiment, with respect to the process to prepare compounds of formula I, the reaction step Al) occurs in a solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, N-methyl pyrrolidinone, N,N-dimethyl formamide, dimethyl sulfoxide, and combinations thereof. In another embodiment, the reaction step Al ) occurs in a solvent selected from the group consisting of methanol, ethanol, and isopropyl alcohol.

[00174] In one particular embodiment, with respect to the process to prepare compounds of formula I, the reaction step Al) occurs in ethanol.

[00175] In one embodiment, with respect to the process to prepare compounds of formula I, the reaction step Al) occurs at a temperature from about 50 °C to about 120 °C.

[00176] In one particular embodiment, with respect to the process to prepare compounds of formula I, the reaction step Al) occurs at a temperature around 80 °C.

[00177] In one particular embodiment, with respect to the process to prepare compounds of formula I, the reaction step Al) occurs at a reflux temperature of ethanol.

[00178] In one particular embodiment, with respect to the process to prepare compounds of formula I, the reaction step Al ) occurs for a period of 1 -10 hr.

[00179] In one particular embodiment, with respect to the process to prepare compounds of formula I, the reaction step Al ) occurs for a p iod of about 4 hr. [00180] In one embodiment, with respect to the process to prepare compounds of formula I, the reaction step A2) occurs in a solvent selected from the group consisting of H₂0, methanol, ethanol, THF, DMSO, DMF, acetonitrile, and combinations thereof. In another embodiment, the reaction occurs in H₂0, methanol, or ethanol.

[00181] In one particular embodiment, with respect to the process to prepare compounds of formula I, the reaction step A2) occurs in H₂0.

[00182] In one embodiment, with respect to the process to prepare compounds of formula I, the reaction step A2) occurs in the presence of an acid.

[00183] In another embodiment, with respect to the process to prepare compounds of formula I, the reaction step A2) occurs in the presence of cone. HC1, H₂S0₄, or HBr.

[00184] In one particular embodiment, with respect to the process to prepare compounds of formula I, the reaction step A2) occurs in the presence of cone. HC1.

[00185] In one embodiment, with respect to the process to prepare compounds of formula I, the reaction step A2) occurs at a temperature from about 50 °C to about 120 °C.

[00186] In one particular embodiment, with respect to the process to prepare compounds of formula I, the reaction step A2) occurs at a temperature between 45-70 °C.

[00187] In another particular embodiment, with respect to the process to prepare compounds of formula I, the reaction step A2) occurs at a temperature around 55-60 °C.

[00188] In one particular embodiment, with respect to the process to prepare compounds of formula I, the reaction step A2) occurs for a period of 0.1 -5 hr.

[00189] In one particular embodiment, with respect to the process to prepare compounds of formula I, the reaction step A2) occurs for a period of about 1.5 hr.

[00190] In one embodiment, with respect to the process to prepare compounds of formula I, the reaction step A3) occurs in a solvent selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, N-methyl pyrrolidinone, N,N-dimethyl formamide, dimethyl sulfoxide, and combinations thereof.

[00191] In one particular embodiment, with respect to the process to prepare compounds of formula I, the reaction step A3) occurs in water.

[00192] In one embodiment, with respect to the process to prepare compounds of formula I, the reaction step A3) occurs at a temperature from about 50 °C to about 120 °C.

[00193] In one particular embodiment, with respect to the process to prepare compounds of formula I, the reaction step A3) occurs at a temperature between 100-1 10 °C.

[00194J In one embodiment, with respect to the process to prepare compounds of formula I, the reaction step A3) occurs in the presence of an acid. [00195] In another embodiment, with respect to the process to prepare compounds of formula I, the reaction step A3) occurs in the presence of cone. HC1, H₂S0₄, or HBr.

[00196] In one particular embodiment, with respect to the process to prepare compounds of formula I, the reaction step A3) occurs in the presence of HBr.

[00197] In one embodiment, with respect to the process to prepare compounds of formula I, the reaction step A3) occurs in the presence of a base.

[00198] In one embodiment, with respect to the process to prepare compounds of formula I, the reaction step A3) occurs in the presence of sodium hydroxide solution.

[00199] In one particular embodiment, with respect to the process to prepare compounds of formula I, the reaction step A3) occurs for a period of 0.1-10 hr.

[00200] In one particular embodiment, with respect to the process to prepare compounds of formula I, the reaction step A3) occurs for a period of about 5 hr.

[00201] In another aspect, methods are provided to prepare compounds of formula VII:

VI I

or an isomer thereof; wherein R² is as described for formula I; and R^3a is substituted or unsubstituted alkyl.

[00202] In one embodiment, a process is provided to prepare compounds of formula VII, comprising the steps of: reacting malonic acid dialkyl ester (II):

II

with (S)-l -phenyl-ethylamine of formula III or a salt or isomer thereof:

ill to form a substituted N-((S)-l -phenyl-ethyl)-malonamic acid alkyl ester of formula IV or an isomer thereof:

IV

B2) reacting the substituted N-((S)-1 -phenyl-ethyl)-malonamic acid alkyl ester of formula IV or an isomer thereof with 5-methyl-hex-2-enoic acid alkyl ester of formula V

V

or an isomer thereof,

to form a substituted hexanedioic acid dialkyl ester of formula VI or an isomer thereof:

VI

B3) removing the 0C-CO₂R group of the 3-isobutyl-4-((S)-l - phenyl-ethylcabamoyl)-hexanedioic acid dialkyl ester of formula VI or an isomer thereof, followed by separation of the isomers to form the hexanoate of formula VII:

VI I or an isomer thereof; wherein each of R and R is independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl; and R ^a is substituted or unsubstituted alkyl.

[00203] In one embodiment, with respect to the process to prepare compounds of formula VII, each of R and R is independently alkyl.

[00204] In one embodiment, with respect to the process to prepare compounds of formula VII, R¹ is Me or Et.

[00205] In one embodiment, with respect to the process to prepare compounds of formula VII, R² is Me or Et.

[00206] In one particular embodiment, with respect to the process to prepare compounds of formula VII, R¹ is Et, and R² is Me.

[00207] In one particular embodiment, with respect to the process to prepare compounds of formula VII, R^3a is Me or Et. In a particular embodiment, R^3a is Et.

[00208] In one embodiment, with respect to the process to prepare compounds of formula VII, the reaction step B l ) occurs in the absence of any solvent.

[00209] In one embodiment, with respect to the process to prepare compounds of formula VII, the reaction step Bl ) occurs at a temperature from about 50 °C to about 130 °C.

[00210] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the reaction step B l ) occurs at a temperature between 120-125 °C.

[00211] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the reaction step B l ) occurs for a period of 0.5-5 hr.

[00212] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the reaction step B l ) occurs for a period of about 2.5 hr.

[00213] In one embodiment, with respect to step B2 of the process to prepare compounds of formula VII, the compound of formula V is an E isomer. In another embodiment, it is a Z isomer.

[00214] In one embodiment, with respect to the process to prepare compounds of formula VII, the reaction step B2) occurs in a solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, N-methyl pyrrolidinone, Ν,Ν-dimethyl formamide, dimethyl sulfoxide, and combinations thereof.

[00215] In another embodiment, with respect to the process to prepare compounds of formula VII, the reaction step B2) occurs in a solvent selected from the group consisting of methylene chloride, ethylene chloride, and tetrahydrofuran.

[00216] In one particular embodiment, with respect to the process to prepare compounds of formula VII, reaction step B2) occurs in CH2CI2.

[00217] In one particular embodiment, with respect to the process to prepare compounds of formula VII, reaction step B2) occurs in THF.

[00218] In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step B2) occurs at a temperature from about 0 °C to about 50 °C.

[00219] In one particular embodiment, with respect to the process to prepare compounds of formula VII, reaction step B2) occurs at a temperature between 5-25 °C.

[00220] In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step B2) occurs in the presence of a catalyst.

[00221] In one embodiment, with respect to the process to prepare compounds of formula VII, B2) occurs in the presence of triethylamine, Ν,Ν-diisopropylethylamine (DIPEA), pyridine, 4- dimethylaminopyridine (DMAP), imidazole, l ,8-diazabicyclo[5.4.0]undec-7-ene (DBU), NaH, or a combination thereof.

[00222] In one particular embodiment, with respect to the process to prepare compounds of formula VII, reaction step B2) occurs in the presence of triethylamine.

[00223] In one particular embodiment, with respect to the process to prepare compounds of formula VII, reaction step B2) occurs in the presence of NaH.

[00224] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the reaction step B2) occurs for a period of 0.5-5 hr.

[00225] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the reaction step B2) occurs for a period of about 1.5 hr.

[00226] In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step B3) occurs in a solvent selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, N-methyl pyrrolidinone, N,N-dimethyl formamide, dimethyl sulfoxide, and combinations thereof.

[00227] In one particular embodiment, with respect to the process to prepare compounds of formula VII, reaction step B3) occurs in water and dimethyl sulfoxide. [00228] In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step B3) occurs at a temperature from about 100 °C to about 200 °C.

[00229] In one particular embodiment, with respect to the process to prepare compounds of formula VII, reaction step B3) occurs at a temperature between 145-155 °C.

[00230] In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step B3) occurs in the presence of a catalyst.

[00231] In one particular embodiment, with respect to the process to prepare compounds of formula VII, reaction step B3) occurs in the presence of NaCl.

[00232] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the reaction step B3) occurs for a period of 0.5-5 hr.

[00233] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the reaction step B3) occurs for a period of about 2.5 hr.

[00234] In yet another aspect, another novel process is provided to prepare compounds of formula VII, comprising the steps of:

reacting malonic acid (XI):

XI

with (S)-l-phenyl-ethylamine of formula III or a salt or isomer thereof:

III

and acetone, to form a cyclic compound of formula XII or an isomer thereof:

XII

V

, or an i mer thereof to form a cyclic com ound of formula XIII or an isomer thereof:

XIII

C3) reacting the cyclic compound of formula XIII or an isomer thereof with an alkoxide, to form a compound of formula XIV:

or an isomer thereof;

C4) removing the a-C0₂R³ group of the compound of formula XIV or an isomer thereof, followed by separation of the isomers to form the hexanoate of formula VII:

VI I or an isomer thereof; or

C3') heating the compound of formula XIII, or an isomer thereof, followed by separation of the isomers to form the hexanoate of formula VII:

VII or an isomer thereof;

[00235] In one embodiment, with respect to the process to prepare compounds of formula VII, each of R and R is independently alkyl.

[00236] In one particular embodiment, with respect to the process to prepare compounds of formula VII, R² is Me, and R³ is Et.

[00237] In one embodiment, with respect to the process to prepare compounds of formula VII, R^3a is independently alkyl.

[00238] In one particular embodiment, with respect to the process to prepare compounds of formula VII, R^3a is Me or Et. In a more particular embodiment, R^3a is Et.

[00239] In one embodiment, with respect to the reaction step CI) of process to prepare compounds of formula VII, the said acetone is replaced with any other compatible ketone. In another embodiment, acetone is replaced with dialkyl or diaryl ketone.

[00240] In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step CI ) occurs in the presence of a catalyst.

[00241J In another embodiment, with respect to the process to prepare compounds of formula VII, reaction step CI ) occurs in the presence of trifluoroacetic acid, 4-(trifluoromethyl)benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, acetic anhydride, a Lewis acid or a combination thereof.

[00242] In one particular embodiment, with respect to the process to prepare compounds of formula VII, reaction step CI ) occurs in the presence of p-toluenesulfonic acid.

[00243J In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step CI ) occurs in a solvent selected from the group consisting of toluene, benzene, or any other inert solvent useful for azeotropic removal of water.

100244] In one particular embodiment, with respect to the process to prepare compounds of formula VII, reaction step CI) occurs in toluene. [00245] In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step CI) occurs at a temperature from about 80 °C to about 120 °C.

[00246] In one embodiment, with respect to step C2 of the process to prepare compounds of formula VII, the compound of formula V is an E isomer. In another embodiment, it is a Z isomer.

[00247] In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step C2) occurs in a solvent selected from the group consisting of methylene chloride, ethylene chloride, tetrachloroethane, carbon tetrachloride, or other chlorocarbon solvent.

[00248] In one particular embodiment, with respect to the process to prepare compounds of formula VII, reaction step C2) occurs in CH₂C1₂.

[00249] In one embodiment, with respect to the process to prepare compounds of formula VII, the reaction step C2) occurs at a temperature from about 30 °C to about 120 °C.

[00250] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the reaction step C2) occurs at a temperature around 50 °C.

[00251] In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step C2) occurs in the presence of a catalyst.

[00252] In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step C2) occurs in the presence of triethylamine, Ν,Ν-diisopropylethylamine (DIPEA), pyridine, 4-dimethylaminopyridine (DMAP), imidazole, l ,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or a combination thereof.

[00253] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the reaction step C2) occurs in the presence of triethylamine.

[00254] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the reaction step C2) occurs for a period of 0.5-10 hr.

[00255] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the reaction step C2) occurs for a period of about 2 hr.

[00256] In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step C3) occurs in the presence of an alkoxide selected from NaOMe and NaOEt.

[00257] In one particular embodiment, with respect to the process to prepare compounds of formula VII, reaction step C3) occurs in the presence of NaOEt.

[00258] In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step C3) occurs in a solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, N-methyl pyrrolidinone, Ν,Ν-dimethyl formamide, dimethyl sulfoxide, and combinations thereof. [00259] In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step C3) occurs in a solvent selected from the group consisting of methanol, ethanol, and isopropyl alcohol.

[00260] In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step C3) occurs in ethanol.

[00261] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the reaction step C3) occurs for a period of 0.5-15 hr.

[00262] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the reaction step C3) occurs for a period of about 2 hr.

[00263] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the reaction step C3) occurs at a temperature from about 0 °C to about 50 °C.

[00264] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the reaction step C3) occurs at a temperature from about 25 °C.

[00265] In one embodiment, with respect to the process to prepare compounds of formula VII, the conversion of the compound of formula XIII to the compound VII is carried out via formation of compound XIV (step C4). In another embodiment, the conversion of the compound of formula XIII to the compound VII is carried out using step C3'.

[00266] In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step C4) or C3') occurs in a solvent selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, N-methyl pyrrolidinone, N,N-dimethyl formamide, dimethyl sulfoxide, and combinations thereof.

[00267] In one particular embodiment, with respect to the process to prepare compounds of formula VII, reaction step C4) or C3') occurs in water and dimethyl sulfoxide.

[00268] In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step C4) or C3') occurs at a temperature from about 100 °C to about 200 °C.

[00269] In one particular embodiment, with respect to the process to prepare compounds of formula VII, reaction step C4) or C3') occurs at a temperature between 145-155 °C.

[00270] In one embodiment, with respect to the process to prepare compounds of formula VII, reaction step C4) or C3') occurs in the presence of a catalyst.

[00271] In one particular embodiment, with respect to the process to prepare compounds of formula VII, reaction step C4) or C3') occurs in the presence of NaCl.

[00272] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the reaction step C4) or C3') occurs for a period of 0.5-15 hr. [00273] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the reaction step C4) or C3') occurs for a period of about 2 hr.

[00274] In one embodiment, with respect to the process to prepare compounds of formula VII, the separation of the hexanoate of formula VII:

occurs by crystallization.

[00275] In one embodiment, with respect to the process to prepare compounds of formula VII, R^3a is Et.

[00276] In one embodiment, with respect to the process to prepare compounds of formula VII, the crystallization occurs in alcohol.

[00277] In one particular embodiment, with respect to the process to prepare compounds of formula VII, the crystallization occurs in i-propanol.

[00278] In yet another aspect, compounds are provided that have formula VI, VII, VIII, IX, XII, XIII, or XIV:

or a solvate, polymorph, isotopic variant, or isomer thereof ;

2 3

and wherein each of R , and R is independently substituted or unsubstituted alkyl.

[00279] In one particular embodiment, with respect to the compounds of formula VI, VII, VIII, IX, XII, XIII, or XIV, the compound is according to formula VI; and R² is Me.

[00280] In one particular embodiment, with respect to the compounds of formula VI, VII, VIII, IX, XII, XIII, or XIV, the compound is according to formula VII; and R² is Me.

[00281] In one particular embodiment, with respect to the compounds of formula VI, VII, VIII, IX, XII, XIII, or XIV, the compound is according to formula VIII; and R² is Me.

[00282] In one particular embodiment, with respect to the compounds of formula VI, VII, VIII, IX, XII, XIII, or XIV, the compound is according to formula IX; and R² is Me.

[00283] In one particular embodiment, with respect to the compounds of formula VI, VII, VIII, IX, XII, XIII, or XIV, the compound is according to formula XII; and R² is Me.

[00284] In one particular embodiment, with respect to the compounds of formula VI, VII, VIII, IX, XII, XIII, or XIV, the compound is according to formula XIII; and R² is Me

[00285] In one particular embodiment, with respect to the compounds of formula VI, VII, VIII, IX, XII, XIII, or XIV, the compound is according to formula XIV; R² is Me; and R³ is Et.

[00286] In one particular embodiment, with respect to the compounds of formula VI, VII, XIII or XIV; R^3a is Me or Et. In a more particular embodiment, R^3a is Et.

[00287] Further aspect of the invention provides the use of compounds of formula VI, VII, VIII, IX, XII, XIII, or XIV:

or

or a solvate, polymorph, isotopic variant, or isomer thereof ; in preparation of (S)-Pregabalin.

[00288] In one particular embodiment, (S)-Pregabalin is prepared using the compound of formula VI as an intermediate; and R² is Me.

[00289] In one particular embodiment, (S)-Pregabalin is prepared using the compound of formula VII as an intermediate; and R² is Me.

[00290] In one particular embodiment, (S)-Pregabalin is prepared using the compound of formula VIII as an intermediate; and R² is Me.

[00291] In one particular embodiment, (S)-Pregabalin is prepared using the compound of formula IX as an intermediate; and R² is Me.

[00292] In one particular embodiment, (S)-Pregabalin is prepared using the compound of formula XII as an intermediate; and R² is Me.

[00293] In one particular embodiment, (S)-Pregabalin is prepared using the compound of formula XIII as an intermediate; and R² is Me

[00294] In one particular embodiment, (S)-Pregabalin is prepared using the compound of formula XIV as an intermediate; R² is Me; and R³ is Et.

[00295] In one particular embodiment, with respect to the compounds of formula VI, VII, XIII or XIV; R^3a is Me or Et. In a more particular embodiment, R^3a is Et.

[00296] With regard to compounds of formula I, in certain embodiments, the compound is selected from the compounds listed in Table 1.

[00297] In yet another aspect of the present invention, a process is provided for preparing (S)- 3-aminomethyl-5-methyl-hexanoic acid of formula I:

I

lymorph, isotopic variant, or isomer thereof, comprising the steps of:

Dl) reacting malonic acid dialkyl ester (II):

I I

with (S)-l-phenyl-ethylamine of formula III or a salt or isomer thereof:

IV

D2) reacting the substituted N-((S)- 1 -phenyl-ethyl)-malonamic acid alkyl ester of formula IV or an isomer thereof with 5-methyl- hex-2- acid alkyl ester of formula V

V

or an isomer thereof

to form a substituted 3-isobutyl-4-((S)-l -phenyl-ethylcabamoyl) hexanedioic acid dialkyl ester of formula VI or an isomer thereof:

VI

D3) removing the a-C0₂R' group of the 3-isobutyl-4-((S)-l - phenyl-ethylcabamoyl)-hexanedioic acid dialkyl ester of formula VI or an isomer thereof, followed by separation of the isomers to form the hexanoate of formula (VII):

VII or an isomer thereof;

D4) reacting the hexanoate of formula VII

VII

VIII D5) heating the hydrazino compound of formula VIII or an thereof; and reacting it with NaN0₂ to form an amine of formula

IX or an isomer thereof:

IX ; and

D6) hydrolyzing the amide of formula IX or an isomer thereof to (S)-3-aminomethyl-5-methyl-hexanoic acid of Formula I or a solvate, polymorph, isotopic variant, or isomer thereof;

wherein R is independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl; wherein each of R², R³, and R^3a is independently substituted or unsubstituted alkyl;

and wherein step Dl is same as step Bl ; step D2 is same as step B2; step D3 is same as step B3; step D4 is same as step Al ; step D5 is same as step A2; step D6 is same as step A3; and steps Al, A2, A3, Bl , B2, and B3 are as described herein.

[00298] In yet another aspect of the present invention, a process is provided for preparing (S)- 3-aminomethyl-5-methyl-hexanoic acid of formula I:

El) reacting malonic acid (XI):

XI

with (S)-l -phenyl-ethylamine of formula III or a salt or isomer thereof:

and acetone, to form a cyclic compound of formula XII or an isomer thereof:

XII

E2) reacting the cyclic compound of formula XII or an isomer thereof with 5- methyl-hex-2-enoic acid alkyl ester of formula V

V

or an isomer thereof,

to form a cyclic compound of formula XIII or an isomer thereof:

XII I

E3) reacting the cyclic compound of formula XIII or an isomer thereof with an alkoxide, to form a com ound of formula XIV:

or an isomer thereof;

E4) removing the a-C0₂R³ group of the compound of formula XIV or an isomer thereof, followed by separation of the isomers to form ethyl-(S)-5-methyl- 3-[((S)-l -phenyl-ethyl carbamoyl)-methyl] hexanoate of formula VII:

VII or an isomer thereof; or

E3') heating the compound of formula XIII, or an isomer thereof, followed by separation of the isomers to form the hexanoate of formula VII:

VII or an isomer thereof;

E5) reacting the hexanoate of formula VII

VII or an isomer thereof with NH₂NH₂ to form an hydrazino compound of formula VIII or an isomer thereof:

VI I I E6) heating the hydrazino compound of formula VIII or an isomer thereof; and reacting it with NaN0₂ to form an amine of formula IX or an isomer thereof:

l^x ; and

E7) hydrolyzing the amide of formula IX or an isomer thereof to (S)-3- aminomethyl-5-methyl-hexanoic acid of Formula I or a solvate, polymorph, isotopic variant, or isomer thereof;

wherein R is independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl; ; and each of R³, and R^3a is independently substituted or unsubstituted alkyl;

and wherein step El is same as step CI ; step E2 is same as step C2; step E3 is same as step B3; step E4 is same as step C4; step E5 is same as step Al ; step E6 is same as step A2; step E7 is same as step A3; and steps Al , A2, A3, CI , C2, C3, and C4 are as described herein.

[00299] In a most particular embodiment, with respect to the formulae V, VI, VII, XIII or XIV, R^3a is Et.

[00300] In a most particular embodiment, with respect to the formulae II, III, IV, VI, VII, VIII, IX, XII, XIII or XIV, R¹ or R² is Me.

[00301] In a most particular embodiment, with respect to the formula XIV, R³ is Et.

[00302] In one particular embodiment, with respect to the formula V, the compound is

[00303] In one particular embodiment, with respect to the formula VI, the compound

and wherein R² is Me.

100304] In one particular embodiment, with respect to the formula VII, the compound is

and wherein R is Me.

[00305] In one particular embodiment with respect to the formula XIII, the compound is

and wherein R is Me.

[00306] In one particular embodiment with respect to the formula XIV, the compound is

and wherein R is Me; and R as described herein.

[00307] In one particular embodiment, with respect to compounds of formulae with R¹ group; each R¹ is independently C₁ -C4 alkyl. In another particular embodiment, each R¹ is independently Me or Et.

[00308] In one particular embodiment, with respect to compounds of formulae with R² group; each R is independently C₁ -C4 alkyl. In another particular embodiment, each R is independently Me or Et.

[00309] In one particular embodiment, with respect to compounds of formulae with R³ group;

3 " 3

each R is independently C| -C₄ alkyl. In another particular embodiment, each R is independently Me or Et.

[00310] In one particular embodiment, with respect to compounds of formulae with R^3a group; each R^3a is independently C₁-C4 alkyl. In another particular embodiment, each R^3a is

independently Me or Et.

[00311] Additional embodiments within the scope of the present invention are set forth in non-limiting fashion elsewhere herein and in the examples. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner. [00312] In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the formulae above. Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N- alkylmorpholinyl esters and the like.

[00313] Certain compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21 -24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Preferred are the Ci to C₈ or CrQalky^ C₂-C₈ alkenyl, aryl, substituted aryl, and arylalkyl esters of the compounds of the invention.

GENERAL SYNTHETIC PROCEDURES

[00314] The compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. See, e.g., Synthetic Scheme, below. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[00315] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991 , and references cited therein. [00316] The compounds of this invention, for example, may be prepared by the reaction of a chloro derivative with an appropriately substituted amine and the product isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography or HPLC. The following schemes are presented with details as to the preparation of representative fused heterocyclics that have been listed hereinabove. The compounds of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

[00317] The compounds of the present invention may be prepared by a variety of processes well known for the preparation of compounds of this type, for example reaction schemes, and general procedures as described below.

[00318] The syntheses of representative compounds of this invention are carried out in accordance with the methods set forth above and using the appropriate reagents, starting materials, and purification methods known to those skilled in the art. All starting materials in the following general syntheses may be commercially available or obtained by conventional methods known to those skilled in the art.

[00319] In this specification, especially in "Representative Synthetic Methods", the following abbreviations can be used:

BEP 2-bromo-l-ethylpyridinium tetrafluoroborate

BOP benzotriazol- 1 -yloxy-tris(dimethylamino)phosphonium

hexafluorophosphate

CDI 2-chloro-l ,3-dimethylimidazolinium chloride

DCC dicyclohexylcarbodiimide

DCM dichloromethane

DME 1 ,2-dimethoxyethane, dimethoxyethane

DMF N,N-dimethylformamide

DMSO dimethyl sulfoxide

EDC l -ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrogen chloride

EtOAc ethyl acetate

EtOH ethanol

HOBt 1 -hydroxybenzotriazole

MeOH methanol

NMP N-methyl-2-pyrroliidone

THF tetrahydrofuran

TFA trifluoroacetic acid

uM μΜ uL

Synthesis of Compound of formula I

(S)-3-(Aminomethyl)-5-methylhexanoic acid

Method A

Scheme 1

Step Al

(S)-3-(2-Hydrazinyl-2-oxoethyl)-5-methyl-N-((S)-l-phenylethyl) hexanamide (VIII)

[00320] A mixture of (S)-ethyl 5-methyl-3-[2-oxo-2-((S)- 1 -phenylethylamino)ethyl] hexanoate (VII) (50.0 g, 0.156 mol) and hydrazine hydrate (9.4 g, 0.187 mol) in ethanol was heated to reflux and stirred for 4 hours. Ethanol was removed under vacuum and the residue was partitioned between ethyl acetate (200 ml) and water (200 ml). The aqueous layer was extracted with ethyl acetate (2X100 ml) and the combined organics were washed with brine (2X100 ml), dried (MgS0₄), filtered and concentrated under reduced pressure. Hexane (200ml) was added to the resulting residue and the mixture was stirred for 30 min. The mixture was filtered and the cake was washed with hexane (50 ml) to obtain (S)-3-(2-hydrazinyl-2-oxoethyl)-5-methyl-N-

((S)-l -phenylethyl) hexanamide (VIII) (42 g) as a white solid;

Purity by HPLC: 99.7%, Yield: 84%, m. p: 138-140 °C; Ή NMR (CDCI3): δ 0.9 (d/d, 6H),1.2 (m, 2H), 1.5 (d, 3H), 1.7 (m,lH), 2.2 (m, 2H), 2.3 (m, 2H&1H), 3.7 (s,3H), 5.1 (m,lH),6.1 (d,lH), 2.2&7.3 (m,5H), 7.8 (s, 1H);

Mass: 306.5 [M+l ].

Step A2

(S)-3-(Aminomethyl)-5-methyl-N-((S)-l-phenylethyl)hexanamide (IX)

[00321] In a round bottom flask fitted with a mechanical stirrer and a condensor, was charged with water (250 ml), cone, hydrochloric acid (50 ml) and (S)-3-(2-hydrazinyl-2-oxoethyl)-5- methyl-N-((S)-l -phenylethyl) hexanamide (VII, 50g, 0.163 mol). The reaction mixture was gradually heated to 55-60 °C. A solution of sodium nitrite (13 g in 25ml water, 0.18 mol) was slowly added at 55- 60°C over a period of 30 min. and the mixture was maintained at the same temeperature for an hour. The reaction mixture, up on completion (TLC), was cooled to 30°C and the pH was adjusted to 12 with 50% sodium hydroxide solution. The aqueous layer was extracted with ethyl acetate (3 x 100ml), washed with water (150 ml), dried over anhydrous sodium sulphate, filtered and the filtrate was concentrated under reduced pressure to yield (S)-3- (aminomethyl)-5-methyl-N-((S)-l -phenyl ethyl)hexanamide (IX) as an oil. Yield 40 g;

Purity by HPLC: 95.2%, Yield: 88%;

Ή NMR (CDC1₃) δ 0.9 (d/d, 6H), 1.2 (m, 2H), 1.4 (d, 3H), 1.6 (m, 1 H), 1.8 (m, 1H), 2.1 (m, 2H), 2.6 (m, 2H), 3.3(s, 2H), 5.1 (m, 1 H), 7.1 (d, 1H), 7.3 (m,5H);

Mass: 263.2 [M+l ].

Step A3

(S)-3-(Aminomethyl)-5-methylhexanoic acid

[00322] A mixture of (S)-3-(aminomethyl)-5-methyl-N-((S)-l -phenylethyl)hexanamide (40 g), aqueous HBr (46 ml), and water (23 ml) was heated to 100-1 10 °C. The reaction was stirred at this temperature for 5 hours before cooling to ambient temeperature. The pH was adjusted to 12 using 47% sodium hydroxide solution and extracted with dichloromethane. The organic layer was separated. Evaporation of the organic layer recovered phenethylamine. The pH of the aqueous layer was further adjusted to 3 with cone. HCl, and was extracted twice with iso-butanol ( 2 x 75ml ). The combined organic layer was treated with triethyl amine (20 g) and cooled to 10 °C . The solids were filtered, washed with iso-butanol (20 ml) and vacuum dried to obtain the crude (S)-3-(aminomethyl)-5-methylhexanoic acid (pregabalin) as a white solid (15 g);

Purity by HPLC: 95.6%, Yield: 83%;

" H NMR (DMSO D₂O) 5 0.9 (d/d, 6H), 1 .2 (m, 2H), 1.4 (d, 3H), 1 .6 (m, 1 H), 2.1 (m, 1 H), 2.3 (m,2H), 3.0(m,2H). Purification of (S)-Pregabalin

[00323] A mixture of crude pregabalin (25 g), isopropyl alcohol (500 ml) and water (125 ml) was heated to reflux for 30 minutes. The reaction mixture was filtered and the filtrate was cooled to 0-5 °C.The reaction mixture was stirred for one hour at 0-5 °C. The solids were filtered, washed with mixture of isopropyl alcohol and water and vacuum dried to obtain the pure pregablin (lO g);

Purity by HPLC: 99.8%, m. p:185-186 °C, Specific Opetical Rotation: (+) 10.5-11° [C = 1.05% in water] IR (KBr): 2955 cm^"1, 2896 cm^"1, 2873 cm^"1, 1645 cm^"1, 1367 cm^"1;

Ή NMR (DMSO D₂0) 6 0.9 (d/d, 6H), 1.2 (m, 2H), 1.4 (d, 3H), 1.6 (m, 1H), 2.1 (m, 1H), 2.3

(m,2H), 3.0(m,2H);

Mass: 160.1 (M+l).

Synthesis of (S)-ethyl 5-methyi-3-[2-oxo-2-((S)-l-phenylethylamino)ethyl] hexanoate (VII)

Method B

Scheme 2

II III IV

VII VI

Step Bl

yV-((S)-l-Phenylethyi)maionamic acid ethyl ester (IV) [00324] Diethyl malonate (792 g) was heated to 120 - 125 °C and was treated slowly with (S)- phenethyl amine over a period of 30 minutes. The mixure was agitated for an additional 2 hours and excess diethyl malonate was distilled off under vacuum. The residue was cooled and triturated with heaxnes (500 ml). The solid was filtered, washed with heaxnes (100 ml) and vacuum dried to obtain the crude.compound. The crude material was crystallized from

diisopropyl ether to obtain pure N-((S)- 1 -phenylethyl)malonamic acid ethyl ester (IV) as a white solid (420 g, m.p. 55 - 56 °C).

Step B2

S-IsobutyM-^S^l-phenylethylcarbamoy -hexanedioic acid diethyl ester (VI)

[00325] To a stirred suspension of NaH (14 g) in THF (700 ml) at 5 °C was added N-((S)-1 - phenylethyl)malonamic acid ethyl ester (83 g) in THF (100 ml) during one hour. Ethyl-5-methyl- 2-hexenoate (50 g) was then added during 30 minutes and the mixture was warmed to ambient temperature and stirred for an additional 3 hours. The reaction mixture was poured over crushed ice and extracted with ethyl acetate (2 x 500 ml). The combined organic extracts were washed with water (2 x 500 ml) followed by brine and concentrated to obtain 3-isobutyl-4-((S)-l- phenylethylcarbamoy -hexanedioic acid diethyl ester (VI) (110 g) as an off-white solid. The crude compound was used as such in the ensuing step.

Step B3

Ethyl (S)-5-methyl-3-[((S)-l-phenylethylcarbamoyl)-methyl] hexanoate (VII)

[00326] Sodium chloride (27g, 0.46 mol) and water (22. lg, 1.23 mol) were added to a solution of 3-isobutyl-4-((S)-l -phenylethylcarbamoyl⁾-hexanedioic acid diethyl ester (VI) (l OOg, 0.140 mol) in 166 ml of DMSO. The mixture was heated to 145-155 °C, and stirred for 8 hours .The reaction mixture was cooled to 10 °C, and water (260 ml) and ethyl acetate (250 ml) were added and stirred for 30 min. The aqueous phase was separated and extracted with ethyl acetate (2 x 100 ml). The combined organic layers were washed with water (250 ml), and dried over sodium sulphate, filtered, and concentrated under vacuum. The residue was triturated with a mixture of toluene (100 ml) and isopropyl ether (100 ml). The solids were collected by filtration, and vacuum dried to obtain (S)-ethyl 5-methyl-3-[2-oxo-2-((S)-l -phenylethylamino)ethyl] hexanoate (VII) (50 g), as a white solid solid;

Purity by HPLC: 99.5%, m. p: 128-130 °C;

Ή NMR (CDC1₃) 5 0.9 (d/d, 6H),1.2 (m, 2H), 1.5 (d, 3H), 1.7 (m,l H), 2.2 (m, 2H), 2.3 (m, 2H&1 H), 3.7 (s,3H), 5.1 (m,l H),6.1 (d,l H), 2.2&7.3 (m,5H). Alternate Synthesis of (S)-ethyl 5-methyl-3-[2-oxo-2-((S)-l-phenylethylamino)ethyl] hexanoate (VII)

Method C

Scheme 3

R³ is as described herein. Step CI

2,2-Dimethyl-3-[(lS)-l-phenylethyl]-l,3-oxazinane-4,6-dione (XII)

[00327] The compound can be prepared essentially using the procedure reported for similar compound in Chemistry Letters (1992), (3), 485-8

Step C2

Ethyl 3-[2,2-dimethyl-4,6-dioxo-3-[(lS)-l-phenylethyl]-l,3-oxazinan-5-yl]-5-methyI- hexanoate (XIII)

[00328] A mixture of 2,2-dimethyl-3-[(l S)-l -phenylethyl]-l ,3-oxazinane-4,6-dione (1 .0 eq) and ethyl-5-methyl-2-hexenoate (1.0 eq) is treated with triethylamine ( 2 eq.) in dichloromethane and the mixture is heated to reflux for several hours until the the disappearance of the starting compounds. The reaction is quenched with water, and the organic layer was separated. The organic layer was then washed sequencially with dilute HCl, sat. NaHC0₃ solution and water, dried (MgS0₄), filtered and concentrated under vacuum to obtain ethyl 3-[2,2-dimethyl-4,6- dioxo-3 -[( 1 S)- 1 -phenyl ethyl] - 1 ,3 -oxazinan-5-yl] -5-methyl-hexanoate (XIII) .

Step C3

Compound XIV

[00329] The compound XIV can be prepared by reacting XIII with an alkoxide. The compound XIV may be used as such without further purification for Step C4.

Step C3' and Step C4

Ethyl (S)-5-methyl-3-[((S)-l-phenylethylcarbamoyl)-methyl] hexanoate (VII)

[00330] Sodium chloride {21 g, 0.46 mol) and water (22.1 g, 1.23 mol) were added to a solution of ethyl 3-[2,2-dimethyl-4,6-dioxo-3-[(l S)-l-phenylethyl]-l,3-oxazinan-5-yl]-5-methyl- hexanoate (XIII) for Step C3' (or compound XIV for Step C4) (0.140 mol) in 166 ml of DMSO. The mixture was heated to 145-155 °C, and stirred for 8 hours .The reaction mixture was cooled to 10 °C, and water (260 ml) and ethyl acetate (250 ml) were added and stirred for 30 min. The aqueous phase was separated and extracted with ethyl acetate (2 x 100 ml). The combined organic layers were washed with water (250 ml), and dried over sodium sulphate, filtered, and concentrated under vacuum. The residue was triturated with a mixture of toluene (100 ml) and isopropyl ether (100 ml). The solids were collected by filtration, and vacuum dried to obtain (S)- ethyl -5-methyl-3-[2-oxo-2-((S)-l-phenylethylamino)ethyl] hexanoate (VII), as a white solid; Purity by HPLC: 99.5%, m. p: 128-130 °C;

'H NMR (CDC1₃) δ 0.9 (d/d, 6H),1.2 (m, 2H), 1.5 (d, 3H), 1.7 (m,l H), 2.2 (m, 2H), 2.3 (m, 2H&1 H), 3.7 (s,3H), 5.1 (m,lH),6.1 (d,lH), 2.2&7.3 (m,5H).

Exemplary Compounds of the Invention

[00331] The following compounds have been or can be prepared according to the methods of the invention. The mass spect data for some of the representative compounds are given in Table 1 below.

[00332] Table 1 : Mass Spect Data for Exemplary Compounds of the Invention

[003331 The NMR data of exemplary compounds of the invention is provided in Table 2.

[00334] Table 2: NMR Data for Exemplary Compounds of the Invention ID NMR (5)

Ή NMR (D₂0): 0.88 (3H, d, J=6.5 Hz), 0.90 (3H, d, J=6.5 Hz), 1.21 (2H, t,

I

J=7 Hz), 1.52-1.75 (1H, m), 2.1-2.4 (3H, m), 2.89-3.06 (2H, m).

VIII

SEE FIGURE 1

(R² = Me)

IX

SEE FIGURE 2

(R² = Me)

[00335] From the foregoing description, various modifications and changes in the compositions and methods of this invention will occur to those skilled in the art. All such modifications coming within the scope of the appended claims are intended to be included therein.

[00336] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

[00337] At least some of the chemical names of compounds of the invention as given and set forth in this application, may have been generated on an automated basis by use of a

commercially available chemical naming software program, and have not been independently verified. Representative programs performing this function include the Lexichem naming tool sold by Open Eye Software, Inc. and the Autonom Software tool sold by MDL, Inc. In the instance where the indicated chemical name and the depicted structure differ, the depicted structure will control.

[00338] Chemical structures shown herein were prepared using ISIS /DRAW. Any open valency appearing on a carbon, oxygen or nitrogen atom in the structures herein indicates the presence of a hydrogen atom. Where a chiral center exists in a structure but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral structure are encompassed by the structure.

Claims

WHAT IS CLAIMED IS:

A process for preparing (S)-3-aminomethyl-5-methyl-hexanoic acid of formula I:

I

Al) reacting a compound of formula VII

VI I

VI I I

A2) heating the hydrazino compound of formula VIII or an isomer thereof; reacting it with NaN0₂ to form an amine of formula IX or an isomer thereof:

IX and

A3) hydrolyzing the amide of formula IX or an isomer thereof to (S)-3-aminomethyl- 5-methyl-hexanoic acid of Formula I or a solvate, polymorph, isotopic variant, or isomer thereof; wherein R² is independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl; and R^3a is independently substituted or unsubstituted alkyl.

2. The process of claim 1, wherein R is substituted or unsubstituted alkyl.

3. The process of claim 1 , wherein R is Me, Et, or benzyl.

4. The process of any of claims 1-3, wherein R² is Me.

5. The process of any of claims 1-4, wherein R^3a is Me, Et, or benzyl.

6. The process of any of claims 1-5, wherein R^3a is Et.

7. The process of any of claims 1-6, wherein the reaction step Al) occurs in a solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, N-methyl pyrrolidinone, Ν,Ν-dimethyl formamide, dimethyl sulfoxide, and combinations thereof.

8. The process of any of claims 1-6, wherein the reaction step Al) occurs in ethanol.

9. The process of any of claims 1-8, wherein the reaction step Al) occurs at a

temperature from about 50 °C to about 120 °C.

10. The process of any of claims 1-8, wherein the reaction step Al) occurs at a

temperature around 80 °C or a reflux temperature of ethanol.

1 1. The process of any of claims 1-10, wherein the reaction step Al) occurs for a period of 1 -lO hr.

12. The process of any of claims 1-10, wherein the reaction step Al) occurs for a period of 4 hr.

13. The process of any of claims 1 -12, wherein in the reaction step Al ), the hydrazine is in the form of hydrazine hydrate.

14. The process of any of claims 1 - 13, wherein the reaction step A2) occurs in a solvent selected from the group consisting of H₂0, methanol, or ethanol.

15. The process of any of claims 1 -13, wherein the reaction step A2) occurs in H₂0.

16. The process of any of claims 1 -15, wherein the reaction step A2) occurs in the

presence of an acid.

17. The process of any of claims 1 -15, wherein the reaction step A2) occurs in the

presence of cone. HC1, H₂S0₄, or HBr.

18. The process of any of claims 1 - 15, wherein the reaction step A2) occurs in the

presence of cone. HC1.

19. The process of any of claims 1 -18, wherein the reaction step A2) occurs at a

temperature from about 50 °C to about 120 °C.

20. The process of any of claims 1 -18, wherein the reaction step A2) occurs at a temperature between 55-60 °C.

21. The process of any of claims 1 -20, wherein the reaction step A2) occurs for a period of 0.1 -5 hr.

22. The process of any of claims 1 -20, wherein the reaction step A2) occurs for a period of about 1.5 hr.

23. The process of any of claims 1 -22, wherein the reaction step A3) occurs in a solvent selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, N-methyl pyrrolidinone, Ν,Ν-dimethyl formamide, dimethyl sulfoxide, and combinations thereof.

24. The process of any of claims 1-23, wherein the reaction step A3) occurs in water.

25. The process of any of claims 1 -24, wherein the reaction step A3) occurs at a

temperature from about 50 °C to about 120 °C.

26. The process of any of claims 1-24, wherein the reaction step A3) occurs at a

temperature between 100-1 10 °C.

27. The process of any of claims 1 -26, wherein the reaction step A3) occurs in the

presence of an acid.

28. The process of any of claims 1 -26, wherein the reaction step A3) occurs in the

presence of cone. HC1, H₂S0₄, or HBr.

29. The process of any of claims 1 -26, wherein the reaction step A3) occurs in the

presence of aqueous HBr.

30. The process of any of claims 1-26, wherein the reaction step A3) occurs in the

presence of a base.

31. The process of any of claims 1 -26, wherein the reaction step A3) occurs in the

presence of sodium hydroxide solution.

32. The process of any of claims 1 -31 , wherein the reaction step A3) occurs for a period of 0.1 -10 hr.

33. The process of any of claims 1 -31 , wherein the reaction step A3) occurs for a period of about 5 hr.

34. The process of claim 1 , wherein the compound of formula VII is prepared by

Bl ) reacting malonic acid dialkyl ester (II):

I I with (S)-l -phenyl-ethylamine of formula III or a salt or isomer thereof:

IV

V , or an isomer thereof, to form a substituted hexanedioic acid dialkyl ester of formula VI or an isomer thereof:

VI

B3) removing the a-C0₂R' group of the 3-isobutyl-4-((S)-l - phenyl-ethylcabamoyl)-hexanedioic acid dialkyl ester of formula VI or an isomer thereof, followed by separation of the isomers to form the hexanoate of formula VII:

, or an isomer thereof;

wherein each of R^{1 ,} and R² is independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl; and R^3a is substituted or unsubstituted alkyl.

35. The process according to claim 34, wherein each of R¹ and R² is independently alkyl.

36. The process according to claim 34, wherein R¹ is Me or Et.

37. The process according to claim 34, wherein R is Me or Et.

38. The process according to claim 34, wherein R¹ is Et, and R² is Me.

39. The process of any of claims 34-38, wherein R^3a is Me or Et.

40. The process of any of claims 34-38, wherein R^3a is Et.

41. The process of any of claims 34-40, wherein the reaction step Bl) occurs in absence of any solvent.

42. The process of any of claims 34-41 , wherein the reaction step Bl) occurs at a

temperature from about 50 °C to about 130 °C.

43. The process of any of claims 34-41 , wherein the reaction step Bl) occurs at a

temperature between 120-125 °C.

44. The process of any of claims 34-43, wherein the reaction step Bl) occurs for a period of 0.5-5 hr.

45. The process of any of claims 34-43, wherein the reaction step Bl) occurs for a period of about 2.5 hr.

46. The process of any of claims 34-43, wherein the reaction step B2) occurs in a solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, N-methyl pyrrolidinone, Ν,Ν-dimethyl formamide, dimethyl sulfoxide, and combinations thereof.

47. The process of any of claims 34-46, wherein the reaction step B2) occurs in a solvent selected from the group consisting of methylene chloride, ethylene chloride, and tetrahydrofuran.

48. The process of any of claims 34-46, wherein the reaction step B2) occurs in CH₂C1₂ or tetrahydrofuran.

49. The process of any of claims 34-48, wherein the reaction step B2) occurs at a temperature from about 0 °C to about 50 °C.

50. The process of any of claims 34-48, wherein the reaction step B2) occurs at a

temperature between 5-25 °C.

51. The process of any of claims 34-50, wherein the reaction step B2) occurs in the

presence of a catalyst.

52. The process of any of claims 34-51 , wherein the reaction step B2) occurs in the

presence of triethylamine, Ν,Ν-diisopropylethylamine (DIPEA), pyridine, 4- dimethylaminopyridine (DMAP), imidazole, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), NaH or a combination thereof.

53. The process of any of claims 34-52, wherein the reaction step B2) occurs in the

presence of triethylamine or NaH.

54. The process of any of claims 34-53, wherein the reaction step B2) occurs for a period of 0.5-5 hr.

55. The process of any of claims 34-53, wherein the reaction step B2) occurs for a period of about 1.5 hr.

56. The process of any of claims 34-55, wherein the reaction step B3) occurs in a solvent selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, N-methyl pyrrolidinone, Ν,Ν-dimethyl formamide, dimethyl sulfoxide, and combinations thereof.

57. The process of any of claims 34-55, wherein the reaction step B3) occurs in water and dimethyl sulfoxide.

58. The process of any of claims 34-57, wherein the reaction step B3) occurs at a

temperature from about 100 °C to about 200 °C.

59. The process of any of claims 34-57, wherein the reaction step B3) occurs at a

temperature between 145-155 °C.

60. The process of any of claims 34-59, wherein the reaction step B3) occurs in the

presence of a catalyst.

61. The process of any of claims 34-60, wherein the reaction step B3) occurs in the

presence of NaCl.

62. The process of any of claims 34-61 , wherein the reaction step B3) occurs for a period of 0.5-5 hr.

63. The process of any of claims 34-61 , wherein the reaction step B3) occurs for a period of about 2.5 hr.

64. The process of claim 1 , wherein the compound of formula VII is prepared by

C 1 ) reacting maloni c acid (XI) :

XI

with (S)-l-phenyl-ethylamine of formula III or a salt or isomer thereof:

and acetone, to form a cyclic compound of formula XII or an isomer thereof:

XII

V , or an isomer thereof,

to form a cyclic compound of formula XIII or an isomer thereof:

XI II

; or an isomer thereof;

C4) removing the oc-C0₂R^J group of the compound of formula XIV or an isomer thereof, followed by separation of the isomers to form the hexanoate of formula VII:

VI I , or an isomer thereof; or

VI I , or an isomer thereof;

65. The process according to claim 64, wherein each of R² and R³ is independently alkyl.

66. The process according to claim 64, wherein R² is Me, and R³ is Et.

67. The process according to any of claims 64-66, wherein R^3a is independently alkyl.

68. The process according to any of claims 64-66, wherein R^3a is Et.

69. The process of any of claims 64-68, wherein the reaction step CI) occurs in the

presence of a catalyst.

70. The process of any of claims 64-68, wherein the reaction step CI) occurs in the presence of trifluoroacetic acid, 4-(trifluoromethyl)benzoic acid, p-toluenesulfonic acid, methanesulfonic acid, acetic anhydride, a Lewis acid or a combination thereof.

71. The process of any of claims 64-68, wherein the reaction step CI) occurs in the

presence of p-toluenesulfonic acid.

72. The process of any of claims 64-71 , wherein the reaction step CI) occurs in a solvent selected from the group consisting of toluene, benzene, or any other inert solvent useful for azeotropic removal of water.

73. The process of any of claims 64-71, wherein the reaction step CI) occurs in toluene.

74. The process of any of claims 64-73, wherein the reaction step CI) occurs at a

temperature from about 80 °C to about 120 °C.

75. The process of any of claims 64-74, wherein the reaction step C2) occurs in a solvent selected from the group consisting of methylene chloride, ethylene chloride, or tetrachloroethane.

76. The process of any of claims 64-74, wherein the reaction step C2) occurs in CH₂C1₂.

77. The process of any of claims 64-76, wherein the reaction step C2) occurs at a

temperature from about 30 °C to about 120 °C.

78. The process of any of claims 64-76, wherein the reaction step C2) occurs at a

temperature around 50 °C.

79. The process of any of claims 64-78, wherein the reaction step C2) occurs in the

presence of a catalyst.

80. The process of any of claims 64-79, wherein the reaction step C2) occurs in the

presence of triethylamine, Ν,Ν-diisopropylethylamine (DIPEA), pyridine, 4- dimethylaminopyridine (DMAP), imidazole, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or a combination thereof.

81. The process of any of claims 64-79, wherein the reaction step C2) occurs in the

presence of triethylamine.

82. The process of any of claims 64-81 , wherein the reaction step C2) occurs for a period of 0.5-10 hr.

83. The process of any of claims 64-82, wherein the reaction step C3) occurs in the

presence of an alkoxide selected from NaOMe and NaOEt.

84. The process of any of claims 64-82, wherein the reaction step C3) occurs in the

presence of NaOEt.

85. The process of any of claims 64-84, wherein the reaction step C3) occurs in methanol, ethanol or isopropyl alcohol.

86. The process of any of claims 64-85, wherein the reaction step C3) occurs in ethanol.

87. The process of any of claims 64-86, wherein the reaction step C3) occurs at a

temperature from about 0 °C to about 50 °C.

88. The process of any of claims 64-86, wherein the reaction step C3) occurs at a

temperature around 25 °C.

89. The process of any of claims 64-88, wherein the reaction step C3) occurs for a period of 0.5-15 hr.

90. The process of any of claims 64-88, wherein the reaction step C3) occurs for a period of about 2 hr.

91. The process of any of claims 64-90, wherein the reaction step C4) or C3') occurs in a solvent selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, N-methyl pyrrolidinone, Ν,Ν-dimethyl formamide, dimethyl sulfoxide, and combinations thereof.

92. The process of any of claims 64-90, wherein the reaction step C4) or C3') occurs in water and dimethyl sulfoxide.

93. The process of any of claims 64-92, wherein the reaction step C4) or C3') occurs at a temperature from about 100 °C to about 200 °C.

94. The process of any of claims 64-92, wherein the reaction step C4) or C3') occurs at a temperature between 145-155 °C.

95. The process of any of claims 64-92, wherein the reaction step C4) or C3') occurs in the presence of a catalyst.

96. The process of any of claims 64-92, wherein the reaction step C4) or C3') occurs in the presence of NaCl.

97. The process of any of claims 64-96, wherein the reaction step C4) or C3') occurs for a period of 0.5-15 hr.

98. The process of any of claims 64-96, wherein the reaction step C4) or C3') occurs for a period of about 2 hr.

99. The process of either of claims 34 or 64, wherein the separation of the hexanoate of formula VII:

VII

occurs by crystallization.

100. The process of claim 99, wherein R^3a is Et.

101. The process according to claim 100, wherein the crystallization occurs in i-PrOH.

102. A compound according to formula VI, VII, VIII, IX, XII, XIII, or XIV:

VI VII VIII

IX XII XII I or

or a solvate, polymorph, isotopic variant, or isomer thereof; and wherein each of R R³, and R^3a is independently substituted or unsubstituted alkyl.

103. The compound according to claim 102, wherein the compound is according to formula VI; and R² is Me.

1 04. The compound according to claim 102, wherein the compound is according to formula VII; and R² is Me.

105. The compound according to claim 102, wherein the compound is according to formula VIII; and R² is Me.

106. The compound according to claim 102, wherein the compound is according to

formula IX; and R² is Me.

107. The compound according to claim 102, wherein the compound is according to

formula XII; and R² is Me.

108. The compound according to claim 102, wherein the compound is according to

formula XIII; and R² is Me

109. The compound according to claim 102, wherein the compound is according to

formula XIV; R² is Me; and R³ is Et.

1 10. The compound according to any one of claims 102-104, or 108-109, wherein the compound is according to formula VI, VII, XIII or XIV; and R^3a is Et.

1 1 1. The use of compound of any one of claims 102-1 10, in preparation of (S)-Pregabalin.

1 12. A process for preparing (S)-3-aminomethyl-5-methyl-hexanoic acid of formula I:

reacting malonic acid dialkyl ester (II)

I I

with (S)-l -phenyl-ethylamine of formula III or a salt or isomer thereof:

III

IV D2) reacting the substituted N-((S)-1 -phenyl-ethyl)-malonamic acid alkyl ester of formula IV or an isomer thereof with 5-methyl-hex-2- acid alkyl ester of formula V

V , or an isomer thereof, to form a substituted 3-isobutyl-4-((S)-l-phenyl-ethylcabamoyl)- hexanedioic acid dialkyl ester of formula VI or an isomer thereof:

VI

; or an isomer thereof;

reacting ethyl-(S)-5-methyl-3-[((S)-l -phenyl-ethyl carbamoyl)-methyl] hexanoate of formula VII

VII

VIII

D5) heating the hydrazino compound of formula VIII or an isomer thereof; and reacting it with NaN0₂ to form an amine of formula IX or an isomer thereof:

wherein R is independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl;

wherein each of R², R³, and R^3a is independently substituted or unsubstituted alkyl;

and wherein step Dl is same as step Bl ; step D2 is same as step B2; step D3 is same as step B3; step D4 is same as step Al ; step D5 is same as step A2; step D6 is same as step A3; and steps Al , A2, A3, Bl , B2, and B3 are as described herein.

1 13. A process for preparing (S)-3-aminomethyl-5-methyl-hexanoic acid of formula I:

El) reacting malonic acid (XI): with (S)-l-phenyl-ethylamine of formula III or a salt or isomer

and acetone, to form a cyclic compound of formula XII or an isomer thereof:

XII

V , or an isomer thereof, to form a cyclic com ound of formula XIII or an isomer thereof:

XI I I

E3) reacting the cyclic compound of formula XIII or an isomer thereof with an alkoxide to form a compound of formula XIV:

; or an isomer thereof; E4) removing the a-C0₂R³ group of the compound of formula XIV or an isomer thereof, followed by separation of the isomers to form the hexanoate of formula VII:

v" ; or an isomer thereof; or

v" ; or an isomer thereof;

E5) reacting the hexanoate of formula VII

VII

VII I

E6) heating the hydrazino compound of formula VIII or an isomer thereof; and reacting it with NaN0₂ to form an amine of formula IX or an isomer thereof:

wherein R is independently substituted or unsubstituted alkyl or substituted or unsubstituted aryl; and each of R³, and R^3a is independently substituted or unsubstituted alkyl;

and wherein step El is same as step CI ; step E2 is same as step C2; step E3 is same as step B3; step E4 is same as step C4; step E3' is same as step C3'; step E5 is same as step Al ; step E6 is same as step A2; step E7 is same as step A3; and steps Al , A2, A3, CI , C2, C3, and C4 are as described herein.