WO2011142825A2

WO2011142825A2 - Novel sulfur containing compounds

Info

Publication number: WO2011142825A2
Application number: PCT/US2011/000841
Authority: WO
Inventors: Satyanarayana Janagani; Venkateshwar Kumar; Vamaraju Ravisankar; Mandava V. Basaveswara Rao
Original assignee: Dissymmetrix (P) Ltd.
Priority date: 2010-05-12
Filing date: 2011-05-12
Publication date: 2011-11-17
Also published as: WO2011142825A3

Abstract

Novel sulfur containing compounds are disclosed as intermediates for preparation of a Sitagliptin of formula (V). A novel synthetic method to prepare Sitagliptin using the said intermediates is also disclosed.

Description

NOVEL SULFUR CONTAINING COMPOUNDS

FIELD OF THE INVENTION

[0001] The present invention provides novel S containing compounds and their use in the preparation of (R)-3-amino-l -(3-trifluoromethyl-5,6-dihydro-8H-[l ,2,4]triazolo[4,3-a]pyrazin-7- yl)-4-(2,4,5-trifluoro-phenyl)-butan-l -one (Sitagliptin). Furthermore, the present invention provides processes for the preparation of Sitagliptin and related compounds useful, for example, in Type II diabetes therapy.

BACKGROUND OF THE INVENTION

[0002] ((R)-3 -amino- 1 -(3 -trifluoromethyl-5,6-dihydro-8H- [ 1 ,2 ,4] triazolo [4,3 -a]pyrazin-7- yl)-4-(2,4,5-trifluoro-phenyl)-butan-l -one, is a dipeptidyl peptidase-4 (DPP-IV) enzyme modulator and is useful in Type 2 diabetes therapy. The compound is also known as Sitagliptin. The compound has the following chemical structure,

V

[0003] Sitagliptin is used either alone or in combination with other oral antihyperglycemic agents (such as metformin or a thiazolidinedione) for treatment of diabetes mellitus type II. The benefit of this medicine is its lower side-effects (e.g., less hypoglycemia, less weight gain) in the control of blood glucose values.

[0004] Sitagliptin works to competitively inhibit the enzyme dipeptidyl peptidase 4 (DPP-4). This enzyme breaks down the incretins GLP-1 and GIP, gastrointestinal hormones that are released in response to a meal {J Clin Pharmacol 46 (8): 876-86). By preventing GLP-1 and GIP inactivation, GLP-1 and GIP are able to potentiate the secretion of insulin and suppress the release of glucagon by the pancreas. This drives blood glucose levels towards normal. As the blood glucose level approaches normal, the amounts of insulin released and glucagon suppressed diminish, thus tending to prevent an "overshoot" and subsequent low blood sugar (hypoglycemia) which is seen with some other oral hypoglycemic agents (Wikipedia).

[0005] International Application Publication No. WO2003/004498 and U.S. Patent No.

6,699,871 , describes the use of sitagliptin and analogs, and the composition thereof. [0006] Several processes for the synthesis of sitagliptin are known. For example, International Application Publication WO2004/085661 discloses the preparation of sitagliptin using S-phenylglycine amide as a chiral auxiliary.

[0007] International Application Publication No. WO2004/087650 discloses the preparation of sitagliptin using the chiral benzyloxylazetidinone as an intermediate.

[0008] International Application Publication Nos. WO2004/085378, WO2005/097733, and

WO2006/081 151 disclose the preparation of sitagliptin which involves an enantioselective reduction of the intermediate chiral enamine in the presence of specific catalysts.

[0009] International Application Publication No. WO2009/085990 discloses the preparation of sitagliptin using various chiral auxiliaries, such as chiral resolving agents.

[0010] While these methods are enabling and useful for preparing sitagliptin, alternative methods for the preparation, particularly for manufacturing scale production, are desirable.

[0011] 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

[0012] Sulfur containing compounds, and use thereof, in the preparation of Sitagliptin are described herein.

[0013] Accordingly, in one aspect of the invention, sulfur containing compounds are provided as useful intermediates for preparation of Sitagliptin.

[0014] Thus, in one embodiment, the sulfur containing compounds provided are according to formula I:

wherein R is alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, phenyl or substituted phenyl; provided that the C attached to S is other than a CH moiety;

R is hydroxy, C 1 -C4 alkoxy, or

and the dotted bond is a single or a double bond;

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof.

[0015] In one particular embodiment, with respect to the compounds of formula I, R¹ is selected from

[0016] In a more particular embodiment, with respect to the compounds of formula I, R¹ is t- Bu.

[0017] In another aspect, a process is provided for preparing the compound sitagliptin, or a compound of formula V:

VI

isomer thereof; with t-Bu-S(0)NH₂ to form the enamine of formula II

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof;

A2) reducing the compound of formula II; a solvate, polymorph thereof; to form the sulfinamide of formula III:

and

separating the diastereomers to obtain the sulfinamide of formula

IV:

A4) deprotecting the compound of formula IV or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof; to form the sitagliptin or the compound of formula V.

In a yet another aspect, methods are provided to prepare compounds of formula V:

V

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof, comprising the step of:

Bl) reacting the (2,4,5-trifluoro-phenyl)-acetaldehyde of formula VII:

VII

isomer thereof; with t-Bu-S( the compound of formula VIII:

VIM

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof;

B2) reacting the compound of formula VIII; a solvate, polymorph thereof; with the metal enolate of formula IX:

IX

to form the sulfinamide of formula IV:

B3) deprotecting the compound of formula IV or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof; to form the sitagliptin or the compound of formula V.

[0019] In a further aspect, another novel process is provided to prepare compounds of formula V, comprising the steps of:

V

CI) reacting the 3-oxo-4-(2,4,5-trifluoro-phenyl)-butyric acid alkyl ester of formula XI:

XI

or an isomer thereof, and wherein R is H or C|-C₄ alkyl; with t-Bu-S(0)NH₂ to form the compound of formula XII:

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof;

C2) reducing the compound of formula XII; a solvate, polymorph thereof; to form the sulfinamine of formula XIII:

and

separating the diastereomers to obtain the compound of formula

XlVa:

XlVa

C4) reacting the compound of formula XlVa with the compound of formula XV:

XV

to form the compound of formula IV; C5) deprotecting the compound formula IV or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof; to form the sitagliptin or the compound of formula V.

[0020] In one particular embodiment, with respect to the methods of the invention, the t- BuS(0)NH₂ is replaced with R¹S(0)NH₂, and wherein R¹ is as described herein.

[0021] In additional aspects, methods are provided for synthesizing the compounds described herein, with representative synthetic protocols and pathways described below.

[0022] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

[0023] 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.

[0024] 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.

[0025] 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.

[0026] 'Acyl' or 'Alkanoyl' refers to a radical -C(O)R20, where R20 is hydrogen, C1 -C8 alkyl, C₃-Cio 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)-C|-C₈ alkyl, -C(O)-(CH₂)_t(C₆-C,₀ aryl), -C(O)-(CH₂),(5-10 membered heteroaryl), - C(0)-(CH₂)_t(C₃-C,o cycloalkyl), and -C(O)-(CH₂)_t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4. [0027] '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, C -Cio aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted Ci-C₄ alkyl, halo, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0028] 'Acylamino' refers to a radical -NR²²C(0)R²³, where R²² is hydrogen, Ci-C₈ alkyl, C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C -Ci₀ aryl, arylalkyl, 5-10 memberd heteroaryl or heteroarylalkyl and R is hydrogen, Ci-C₈ alkyl, C₃-C |₀ 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 benzylcarbonylamino. Particular exemplary 'acylamino' groups are -NR²⁴C(0)-Ci-C₈ alkyl, - NR²⁴C(O)-(CH₂)_t(C₆-C₁₀ aryl), -NR²⁴C(O)-(CH₂)_t(5-10 membered heteroaryl), -NR²⁴C(0)- (CH2 C3-C10 cycloalkyl), and -NR²⁴C(O)-(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.

[0029] 'Substituted Acylamino' refers to a radical -NR²⁵C(0)R²⁶, wherein:

R²⁵ is independently

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

• C3-C10 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 C1 -C4 alkoxy, unsubstituted C_\- C₄ haloalkyl, unsubstituted C1 -C4 hydroxyalkyl, or unsubstituted C 1 -C4 haloalkoxy or hydroxy; and

R²⁶ is independently

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

• C3-C10 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 C 1 -C4 alkoxy, unsubstituted Cj - C₄ haloalkyl, unsubstituted C i -C₄ hydroxyalkyl, or unsubstituted C1 -C4 haloalkoxy or hydroxyl;

provided at least one of R²⁵ and R²⁶ is other than H. [0030] 'Acyloxy' refers to a radical -OC(0)R²⁷, where R²⁷ is hydrogen, C|-C₈ alkyl, C₃-Ci₀ cycloalkyl, C3-C10 cycloalkylmethyl, 4-10 membered heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroaryl alkyl 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)-Ci-C₈ alkyl, -C(O)-(CH₂),(C₆-Ci₀ aryl), -C(O)-(CH₂)_t(5-10 membered heteroaryl), -C(0)-(CH₂)_t(C₃-Cio cycloalkyl), and -C(O)- (CH₂)_t(4-10 membered heterocycloalkyl), wherein t is an integer from 0 to 4.

[0031] 'Substituted Acyloxy' refers to a radical -OC(0)R , wherein R is independently

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

• C3-C10 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 C1-C4 haloalkyl, unsubstituted C1-C₄ hydroxyalkyl, or unsubstituted C1-C₄ haloalkoxy or hydroxy.

[0032] 'Alkoxy' refers to the group -OR²⁹ where R²⁹ is Ci-C₈ 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.

[0033] '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, C₆-C|₀ aryl, aryloxy, carboxyl, cyano, C₃-Cio 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),(C₆-Ci₀ aryl), -O-(CH₂)_t(5-10 membered heteroaryl), -O-(CH₂)_t(C₃-C|₀ 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 Ci-C₄ alkyl, halo, unsubstituted C1 -C4 alkoxy, unsubstituted C1-C₄ haloalkyl, unsubstituted C1-C₄ hydroxyalkyl, or unsubstituted C1-C₄ haloalkoxy or hydroxy. Particular exemplary 'substituted alkoxy' groups are OCF₃, OCH₂CF₃, OCH₂Ph, OCH₂- cyclopropyl, OCH₂CH₂OH, and OCH₂CH₂NMe₂.

[0034] 'Alkoxycarbonyl' refers to a radical -C(0)-OR³⁰ where R³⁰ represents an C C₈ alkyl, C₃-C|₀ cycloalkyl, C₃-Cio cycloalkylalkyl, 4-10 membered heterocycloalkylalkyl, aralkyl, or 5-10 membered heteroarylalkyl as defined herein. Exemplary "alkoxycarbonyl" groups are C(0)0- C_rC₈ alkyl, -C(O)O-(CH₂)_t(C₆-C₁₀ aryl), -C(O)O-(CH₂)_t(5-10 membered heteroaryl), -C(0)0- (CH₂)_t(C3-C|o cycloalkyl), and -C(O)O-(CH2)_t(4-10 membered heterocycloalkyl), wherein t is an integer from 1 to 4.

[0035] 'Substituted Alkoxycarbonyl' refers to a radical -C(0)-OR³¹ where R³¹ represents:

• CrQ alkyl, C₃-Cio cycloalkyl, C₃-Cio cycloalkylalkyl, or 4-10 membered

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

• C₆-Cio aralkyl, or 5-10 membered heteroarylalkyl, each of which is substituted with unsubstituted Q-C₄ alkyl, halo, unsubstituted Ci-C₄ alkoxy, unsubstituted C]-C₄ haloalkyl, unsubstituted Cj-Q hydroxyalkyl, or unsubstituted Ci-C₄ haloalkoxy or hydroxyl.

[0036] 'Aryloxycarbonyl' refers to a radical -C(0)-OR where R represents an C₆-Cio aryl, as defined herein. Exemplary "aryloxycarbonyl" groups is -C(O)O-(C₆-C i0 aryl).

[0037] 'Substituted Aryloxycarbonyl' refers to a radical -C(0)-OR³³ where R³³ represents

• C₆-Cio aryl, substituted with unsubstituted C1-C4 alkyl, halo, unsubstituted C1-C₄ alkoxy, unsubstituted C1 -C4 haloalkyl, unsubstituted C₁-C₄ hydroxyalkyl, or unsubstituted Q-C4 haloalkoxy or hydroxyl.

[0038] '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).

[0039] 'Substituted Heteroaryloxycarbonyl' refers to a radical -C(0)-OR³⁵ where R³⁵ represents:

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

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

[0040] 'Alkoxycarbonylamino' refers to the group -NR36C(0)OR37, where R36 is hydrogen, CpQ alkyl, C₃-Ci₀ 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-Ci₀ cycloalkyl, C₃-Cio cycloalkylmethyl, 4-10 membered

heterocycloalkyl, aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl as defined herein.

[0041] '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.

[0042] '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)-OR"), 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, trifluoromethoxy, azido, -NR S0₂R , - S0₂NR R ^"', -C(0)R", -C(0)0R ^", -0C(0)R ^", -NR"'C(0)R^", -C(0)NR^"R ^"', -NR R ^"', or - (CR R )_mOR ; wherein each R is independently selected from H, Q-Q alkyl, -(CH₂)_t(C₆-C₁₀ aryl), -(CH₂)_t(5-10 membered heteroaryl), -(CH₂)_t(C₃-Ci₀ 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 Ci-C₄ alkyl, halo, unsubstituted C1 -C4 alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C_t-G_t haloalkoxy or hydroxy. Each of R and R independently represents H or Q-Cg alkyl.

[0043] '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.

[0044] '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-.

[0045] '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), n-propenyl (-CH₂CH=CH₂), isopropenyl (-C(CH₃)=CH₂), vinyl and substituted vinyl, and the like.

[0046] '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-.

[0047] 'Alkenylene' refers to divalent olefinically unsaturated hydrocarbyl groups particularly having up to about 11 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.

[0048] 'AlkynyP 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.

[0049] '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,

[0050] 'Amino' refers to the radical -NH₂.

[0051] '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 - N(R )₂ where each R is independently selected from: • hydrogen, Cj-C₈ alkyl, C₆-Cio aryl_> 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, or C₃-C JO 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 C_!-C₄ alkyl, halo, unsubstituted Ci-C₄ alkoxy, unsubstituted C 1-C4 haloalkyl, unsubstituted C 1-C4 hydroxyalkyl, or unsubstituted C 1 -C4 haloalkoxy or hydroxy; or

• both R³⁸ groups are joined to form an alkylene group.

When both R groups are hydrogen, -N(R )₂ is an amino group. Exemplary ' substituted amino' groups are -NR³⁹-Ci-C₈ alkyl, -NR³⁹-(CH₂)_t(C₆-Ci₀ aryl), -NR³⁹-(CH₂)_t(5-10 membered heteroaryl), -NR³⁹-(CH₂)_t(C₃-Ci₀ cycloalkyl), and -NR³⁹-(CH₂)_t(4-10 membered

heterocycloalkyl), wherein t is an integer from 0 to 4, each R independently represents H or Ci- 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 C_!-C₄ alkyl, halo, unsubstituted C1-C₄ alkoxy, unsubstituted C C₄ haloalkyl, unsubstituted C 1 -C4 hydroxyalkyl, or unsubstituted C]-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.

[0052] 'Alkylamino' refers to the group -NHR⁴⁰, wherein R⁴⁰ is Ci-Cg alkyl;

[0053] 'Substituted Alkylamino' refers to the group -NHR⁴¹, wherein R⁴¹ is Ci-Q alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C₃-C|₀ 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 C 1-C₄ alkyl, halo, unsubstituted C 1-C₄ alkoxy, unsubstituted C 1 -C₄ haloalkyl, unsubstituted C 1-C₄ hydroxyalkyl, or unsubstituted C 1-C₄ haloalkoxy or hydroxy.

[0054] 'Alkylarylamino' refers to the group -NR⁴²R⁴³, wherein R⁴² is aryl and R⁴³ is C,-C₈ alkyl.

[0055] 'Substituted Alkylarylamino' refers to the group -NR⁴⁴R⁴⁵, wherein R⁴⁴ is aryl and R⁴⁵ is Ci-C₈ alkyl; and the alkyl group is substituted with halo, substituted or unsubstituted amino, hydroxy, C₃-Ci₀ 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 C 1 -C4 alkyl, halo, cyano, unsubstituted C1-C4 alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted C]-C₄ hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0056] 'Arylamino' means a radical -NHR⁴⁶ where R⁴⁶ is selected from C₆-Ci₀ aryl and 5-10 membered heteroaryl as defined herein.

[0057] 'Substituted Arylamino' refers to the group -NHR⁴⁷, wherein R⁴⁷ is independently selected from C6-C₁₀ aryl and 5-10 membered heteroaryl; and any aryl or heteroaryl groups present, may themselves be substituted by unsubstituted Ci-C₄ alkyl, halo, cyano, unsubstituted C1-C4 alkoxy, unsubstituted C1 -C4 haloalkyl, unsubstituted C1 -C4 hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0058] 'Dialkylamino' refers to the group -NR⁴⁸R⁴⁹, wherein each of R⁴⁸ and R⁴⁹ are independently selected from Ci-C₈ alkyl.

[0059] '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-C₁₀ cycloalkyl, 4-10 membered heterocycloalkyl, C -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 C1 -C4 alkoxy, unsubstituted C1-4 haloalkyl, unsubstituted Cj-C₄ hydroxyalkyl, or unsubstituted C1 -C4 haloalkoxy or hydroxy.

[0060] 'Diarylamino' refers to the group -NR⁵²R⁵³, wherein each of R⁵² and R⁵³ are independently selected from C₆-Cio aryl.

[0061] 'Aminosulfonyl' or 'Sulfonamide' refers to the radical -S(0₂)NH₂.

[0062] 'Substituted aminosulfonyl' or 'substituted sulfonamide' refers to a radical such as -

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

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

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

• C3-C10 cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Cj₀ 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.

[0063] 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-C,₀ cycloalkyl), and -S(O₂)N(R⁵⁵)-(CH₂)_t(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 Ci-C₄ alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted Ci-C₄ haloalkoxy or hydroxy.

[0064] '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.

[0065] '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 Ci-C₄ alkyl, halo, cyano, unsubstituted C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1 -C4 hydroxyalkyl, or unsubstituted Q-C4

haloalkoxy or hydroxy.

[0066] '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.

[0067] '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, C|-C₈ haloalkyl, cyano, hydroxy, Ci-C₈ alkoxy, and amino.

[0068] Examples of representative substituted aryls include the following

[0069] In these formulae one of R56 and R57 may be hydrogen and at least one of R56 and R⁵⁷ is each independently selected from Ci-C₈ alkyl, Ci-Cg haloalkyl, 4-10 membered

heterocycloalkyl, alkanoyl, Ci-C₈ 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-Ci₀ cycloalkyl, 4-10 membered heterocycloalkyl, C6-C₁₀ aryl, substituted aryl, 5-10 membered heteroaryl.

[0070] 'Fused Aryl' refers to an aryl having two of its ring carbon in common with a second aryl ring or with an aliphati^ ring.

[0071] 'Arylalkyloxy' refers to an -O-alkylaryl radical where alkylaryl is as defined herein.

[0072] '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 Q-C4 alkoxy, unsubstituted Ci-₄ haloalkyl, unsubstituted Ci-

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

[0073] 'Azido' refers to the radical -N₃.

[0074] 'Carbamoyl or amido' refers to the radical -C(0)NH₂.

[0075] 'Substituted Carbamoyl or substituted amido' refers to the radical -C(0)N(R⁶²)₂ wherein each R⁶² is independently

• Ci-C₈ 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 CpC₄ alkyl, halo, unsubstituted CpC₄ alkoxy, unsubstituted C|-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),(C₆- C,o aryl), -C(O)N⁶⁴-(CH₂),(5-10 membered heteroaryl), -C(O)NR⁶⁴-(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 Ci-C₈ alkyl and any aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups present, may themselves be substituted by unsubstituted Ci-C₄ alkyl, halo, unsubstituted CpC₄ alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted C 1 -C4

hydroxyalkyl, or unsubstituted C|-C₄ haloalkoxy or hydroxy. [0076] 'Carboxy' refers to the radical -C(0)OH.

[0077] '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.

[0078] '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

[0079] 'Cyano' refers to the radical -CN.

[0080] 'Halo' or 'halogen' refers to fluoro (F), chloro (CI), bromo (Br) and iodo (I).

Particular halo groups are either fluoro or chloro.

[0081] '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.

[0082] '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.

[0083] Examples of re resentative heteroaryls include the following:

wherein each Y is selected from carbonyl, N, NR , O and S; and R is independently hydrogen, Ci-C₈ alkyl, C3-C₁0 cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Cio aryl, and 5-10 membered heteroaryl.

[0084] 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, C C₈ alkyl, C3-C₁0 cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Cio aryl, and 5-10 membered heteroaryl.

[0085] 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(R⁶ )₂, NR , O and S; and each Y is selected from NR⁶⁷, O and S; and R⁶⁷ is independently hydrogen, C_rC₈ alkyl, C₃-Ci₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Cio 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, amino sulfonyl,

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.

[0086] 'Hydroxy' refers to the radical -OH.

[0087] 'Nitro' refers to the radical -N0₂.

[0088] '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, -R , -O^", =0, -OR , -SR⁶⁸, -S^", =S, -NR R , =NR , -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)OR⁶⁸, -C(0)NR⁶⁸R⁶⁹, -C(0)0^", -C(S)OR⁶⁸, -NR⁷⁰C(O)NR⁶⁸R⁶⁹, -NR⁷⁰C(S)NR⁶⁸R⁶⁹, -NR⁷¹C(NR⁷⁰)NR⁶⁸R⁶⁹ and

-C(NR⁷⁰)NR⁶⁸R⁶⁹;

wherein each R , R , R and R are independently:

• hydrogen, Ci-C₈ alkyl, C₆-Ci₀ aryl, arylalkyl, C₃-Ci₀ cycloalkyl, 4-10 membered

heterocycloalkyl, 5-10 membered heteroaryl, heteroaryl alkyl; or

• C|-C₈ alkyl substituted with halo or hydroxy; or ,

• C -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 Ci-C₄ alkoxy, unsubstituted C]-C₄ haloalkyl, unsubstituted C1-C₄ hydroxyalkyl, or unsubstituted C1-C₄ haloalkoxy or hydroxy.

[0089] 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.

[0090] 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 R is independently selected from H, C_\-C_% alkyl, -(CH₂)_t(C₆-C₁₀ 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 C1-C₄ alkyl, halo, unsubstituted Ci-C₄ alkoxy, unsubstituted C1-C₄ haloalkyl, unsubstituted C i-C₄ hydroxyalkyl, or unsubstituted Ci- C₄ haloalkoxy or hydroxy. Each R independently represents H or Ci-C₆alkyl.

[0091] ' Substituted sulfanyl' refers to the group -SR⁷⁴, wherein R⁷⁴ is selected from:

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

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

• C₃-Cio cycloalkyl, 4-1 0 membered heterocycloalkyl, C₆-Cio aryl, aralkyl, 5-10

membered heteroaryl, or heteroaralkyl, each of which is substituted by unsubstituted C|-C₄ alkyl, halo, unsubstituted C 1-C₄ alkoxy, unsubstituted C1-C₄ haloalkyl, unsubstituted C1-C₄ hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy.

[0092] Exemplary 'substituted sulfanyl' groups are -S-(C|-C₈ alkyl) and -S-(C₃-Cio

cycloalkyl), -S-(CH₂)_t(C₆-C,₀ aryl), -S-(CH₂)_t(5- 10 membered heteroaryl), -S-(CH₂),(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 C1-C4 alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1-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 ' cycloalkyl thio', 'substituted cycloalkylsulfanyl' or 'substituted cycloalkylthio', 'arylsulfanyl' or 'arylthio' and

'heteroarylsulfanyl' or 'heteroarylthio' as defined below.

[0093] 'Alkylthio' or 'Alkylsulfanyl' refers to a radical -SR.⁷⁵ where R⁷⁵ is a Ci-C₈ alkyl or group as defined herein. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio and butylthio.

[0094] 'Substituted Alkylthio 'or 'substituted alkylsulfanyl' refers to the group -SR⁷⁶ where R⁷⁶ is a Ci-C₈ alkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.

[0095] '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.

[0096] 'Substituted cycloalkylthio' or 'substituted cycloalkylsulfanyl' refers to the group - SR⁷⁸ where R⁷⁸ is a C₃-Ci₀ cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.

[0097] 'Arylthio' or 'Arylsulfanyl' refers to a radical -SR⁷⁹ where R⁷⁹ is a C₆-Cio aryl group as defined herein.

[0098] 'Heteroarylthio' or 'Heteroarylsulfanyl' refers to a radical -SR⁸⁰ where R⁸⁰ is a 5-10 membered heteroaryl group as defined herein.

[0099] 'Substituted sulfinyP refers to the group -S(0)R^{8 i}, wherein R⁸¹ is selected from:

• 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, substituted or unsubstituted amino, or hydroxy; 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 C1 -C4 alkyl, halo, unsubstituted C1 -C4 alkoxy, unsubstituted C1-C₄ haloalkyl, unsubstituted C1-C₄ hydroxyalkyl, or unsubstituted C1-C₄ haloalkoxy or hydroxy.

[00100] Exemplary 'substituted sulfinyl' groups are -S(0)-(Ci-C₈ alkyl) and -S(O)-(C₃-Ci₀ cycloalkyl), -S(O)-(CH₂),(C₆-C|₀ aryl), -S(O)-(CH₂),(5- 10 membered heteroaryl), -S(O)- (CH₂)_t(C₃-Cio cycloalkyl), and -S(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 C1-C4 alkyl, halo, unsubstituted C1 -C4 alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted C1-C4 hydroxyalkyl, or unsubstituted C1-C4

haloalkoxy or hydroxy. The term substituted sulfinyl includes the groups 'alkylsulfinyl', 'substituted alkylsulfinyl', 'cycloalkylsulfinyl', 'substituted cycloalkylsulfinyl', 'arylsulfinyF and 'heteroarylsulfinyF as defined herein.

[00101] 'Alkylsulfinyl' refers to a radical -S(0)R82 where R82 is a C1 -C8 alkyl group as defined herein. Representative examples include, but are not limited to, methylsulfinyl, ethylsulfinyl, propyl sulfinyl and butylsulfinyl.

100102] 'Substituted Alkylsulfinyl' refers to a radical -S(0)R⁸³ where R⁸³ is a C_rCg alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy.

[00103] 'Cycloalkylsulfinyl' refers to a radical -S(0)R⁸⁴ where R⁸⁴ is a C₃-Ci₀ 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.

[00104] 'Substituted cycloalkylsulfinyl' refers to the group -S(0)R⁸⁵ where R⁸⁵ is a C3-C10 cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.

[00105] 'Arylsulfinyl' refers to a radical -S(0)R⁸⁶ where R⁸⁶ is a C₆-C]₀ aryl group as defined herein.

[00106] 'Heteroarylsulfinyl' refers to a radical -S(0)R⁸⁷ where R⁸⁷ is a 5-10 membered heteroaryl group as defined herein.

[00107] 'Substituted sulfonyl' refers to the group -S(0)₂R⁸⁸, wherein R⁸⁸ is selected from:

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

• C3-C10 cycloalkyl, 4- 10 membered heterocycloalkyl, C₆-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 C1 -C4 haloalkoxy or hydroxy.

[001081 Exemplary 'substituted sulfonyl' groups are -S(0)₂-(C_rC₈ alkyl) and -S(O)₂-(C₃-Ci₀ cycloalkyl), -S(O)₂-(CH₂)_t(C₆-C,₀ aryl), -S(O)₂-(CH₂)_t(5-10 membered heteroaryl), -S(0)₂- (CH₂),(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 Ci-C₄ alkyl, halo, unsubstituted C1-C₄ alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted C1-C₄ hydroxyalkyl, or unsubstituted C1-C4 haloalkoxy or hydroxy. The term substituted sulfonyl includes the groups alkylsulfonyl, substituted alkylsulfonyl, cycloalkylsulfonyl, substituted cycloalkylsulfonyl, arylsulfonyl and heteroarylsulfonyl.

[00109] 'Alkylsulfonyl' refers to a radical -S(0)₂R⁸⁹ where R⁸⁹ is an d-C₈ alkyl group as defined herein. Representative examples include, but are not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl and butylsulfonyl.

[00110] 'Substituted Alkylsulfonyl' refers to a radical -S(0)₂R⁹° where R⁹⁰ is an C_rC₈ alkyl group as defined herein, substituted with halo, substituted or unsubstituted amino, or hydroxy.

[00111] '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.

[00112] ' Substituted cycloalkylsulfonyl' refers to the group -S(0)₂R⁹² where R⁹² is a C₃-C₁₀ cycloalkyl, substituted with halo, substituted or unsubstituted amino, or hydroxy.

[00113] 'Arylsulfonyl' refers to a radical -S(0)₂R⁹³ where R⁹³ is an C₆-C₁₀ aryl group as defined herein.

[00114] 'Heteroarylsulfonyl' refers to a radical -S(0)₂R⁹⁴ where R⁹⁴ is an 5-10 membered heteroaryl group as defined herein.

[00115] 'Sulfo' or 'sulfonic acid' refers to a radical such as -S0₃H.

[00116] 'Substituted sulfo' or 'sulfonic acid ester' refers to the group -S(0)₂OR⁹⁵, wherein R⁹⁵ is selected from:

• Ci-C₈ alkyl, C₃-Ci₀ cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Cio aryl, aralkyl,

5-10 membered heteroaryl, and heteroaralkyl; or

• Ci-C alkyl substituted with halo, substituted or unsubstituted amino, 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 Ci-C₄ alkyl, halo, unsubstituted C1 -C4 alkoxy, unsubstituted Ci-C₄ haloalkyl, unsubstituted C1 -C4 hydroxyalkyl, or unsubstituted C1 -C4 haloalkoxy or hydroxy.

[00117] Exemplary 'Substituted sulfo' or 'sulfonic acid ester' groups are -S(0)₂-0-(Ci-C₈ alkyl) and -S(O)₂-O-(C₃-C,₀ cycloalkyl), -S(O)₂-O-(CH₂)_t(C₆-C₁₀ aryl), -S(O)₂-O-(CH₂),(5-10 membered heteroaryl), -S(O)₂-O-(CH₂),(C₃-Ci₀ cycloalkyl), and -S(O)₂-O-(CH₂),(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 CpC₄ alkoxy, unsubstituted C1-C4 haloalkyl, unsubstituted C1 -C4 hydroxyalkyl, or unsubstituted C1 -C4 haloalkoxy or hydroxy.

[00118] 'Thiol' refers to the group -SH. [001191 'Aminocarbonylamino' refers to the group -NR⁹⁶C(0)NR⁹⁶R⁹⁶ where each R⁹⁶ is independently hydrogen Ci-C₈ alkyl, C₃-Cio cycloalkyl, 4-10 membered heterocycloalkyl, C₆-Cio 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 alkyl ene group.

[00120] '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.

[00121] '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.

[00122] '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.

[00123] '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, cyclopentylethyl, cyclohexylethyl, cycloheptylethyl, and cyclooctylethyl, and the like.

[00124] '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, mo holinylmethyl, pyrrolidinylethyl, piperidinylethyl, piperazinyl ethyl, morpholinylethyl, and the like.

[00125] '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.

[00126] '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-.

[00127] '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.

[00128] 'Ethenyl' refers to substituted or unsubstituted -(C=C)-.

[00129] 'Ethylene' refers to substituted or unsubstituted -(C-C)-.

[00130] 'Ethynyl' refers to -(C≡C)-.

[00131] '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.

[00132] 'Dihydroxyphosphoryl' refers to the radical -PO(OH)₂.

[00133] '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.

[00134] 'AminohydroxyphosphoryP refers to the radical -PO(OH)NH₂.

[00135] '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.

[00136] '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.

[00137] 'Thioketo' refers to the group =S.

[00138] 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.

[00139] '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.

[00140] '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.

[00141] 'Pharmaceutically acceptable vehicle' refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

[00142] '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.

[00143] '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.

[00144] 'Subject' includes humans. The terms 'human', 'patient' and 'subject' are used interchangeably herein.

[00145] '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.

[00146] '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.

[00147] 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.

[00148] '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.

[00149] '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.

[00150] When ranges are referred to herein, for example but without limitation, Q-Q alkyl, the citation of a range should be considered a representation of each member of said range.

[00151] 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 C₈ alkyl, C₂-C₈ alkenyl, aryl, C₇-C|₂ substituted aryl, and C₇-Ci₂ arylalkyl esters of the compounds of the invention.

[00152] 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. ¹⁴C, 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 ⁿC, ¹⁸F, ¹⁵0 and ¹³N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[00153] All isotopic variants of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the invention.

[00154] 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'.

[00155] 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'.

[00156] '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.

[00157] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[00158] 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.

[00159] 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.

[00160] 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.

[00161] 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.

[00162] 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.

[00163] 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

[00164] In certain aspects, the present invention provides certain compounds useful as intermediates for the preparation of Sitagliptin. In additional aspect, the present invention includes the use of such compounds in the preparation of Sitagliptin. In yet additional aspect, the invention provides a novel process for the preparation of Sitagliptin.

[00165] Thus, in one aspect the present invention provides a compound according to formula I:

wherein R is alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, phenyl or substituted phenyl; provided that the C attached to S is other than CH moiety;

R² is hydroxy, Ci-C₄ alkoxy, or

and the dotted bond is a single or a double bond;

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof. [00166] In one embodiment, with respect to the compound of formula I, the compound is according to formula la lb, Ic, Id, Ie, or If:

and wherein R¹ is as in formula I; and R³ is Cj-C₄ alkyl; or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof.

[00167] In one embodiment, with respect to the compound of formula I, la-If, R¹ is alkyl or substituted alkyl.

[00168] In another embodiment, with respect to the compound of formula I, la-If, R¹ is

wherein R^la, R^lb, or R^lc is independently alkyl.

[00169] In another embodiment, with respect to the compound of formula I, la-If, R¹ is

wherein R^la, R^lb, or R^lc is independently Me, Et, or n-Pr.

[00170] In another embodiment, with respect to the compound of formula I, la-If, R¹ is substituted or unsubstituted

[00171] In another embodiment, with respect to the compound of formula I, Ia-If, R¹ is substituted or unsubstituted

wherein each R^la is independently H, Me, Et, i-Pr, or n-Pr; provided that at least one R^la is other than H.

[00172] In one particular embodiment, with respect to the compound of formula I, Ia-If, R¹ is selected fro

[00173] In another particular embodiment, with respect to the compound of formula I, Ia-If, R¹ is t-Bu.

[00174] In one embodiment, with respect to the compound of formula I, the dotted bond is a single bond.

[00175] In another embodiment, with respect to the compound of formula I, the dotted bond is a double bond.

[00176] In one embodiment, with respect to the compound of formula I, the compound is according to formula Ila or lib:

or and wherein R³ is Ci-C₄ alkyl; or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof.

[00177] In one embodiment, with respect to the compound of formula I, the compound is according to formula Ilia or Illb:

and wherein R³ is C₁ -C4 alkyl; or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof.

[00178] In one embodiment, with respect to the compound of formula I, Ic, If, lib, and Illb, R³ is Me, Et, i-Pr, n-Pr, i-Bu, n-Bu, or t-Bu. In one particular embodiment, R³ is Me or Et.

[00179] In one embodiment, with respect to the compound of formula I, the compound is according to formula IV:

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof.

[00180] In one embodiment, with respect to the compound of formula I, the compound is according to formula IVa or IVb:

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof.

[00181] An another aspect of the present invention provides a process for preparing the compound sitagliptin or a compound of formula V:

V

Al) reacting the l -(3-trifluoromethyl-5,6-dihydro-8H- [ 1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluoro-phenyl)-butane-l ,3-dione of formula VI:

VI

isomer thereof; with t-Bu-S(0)NH₂ to form the enamine of formula

II:

II

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof;

A2) reducing the compound formula II; a solvate, polymorph or isomer thereof; to form the sulfinamide of formula Ilia:

separating the diastereomers to obtain the sulfinamide of fo:

[00182] In one embodiment, with respect to the above process, 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, dimethyl formamide, dimethyl sulfoxide, and combinations thereof.

100183] In one particular embodiment, with respect to the above process, the reaction step Al) occurs in ethanol. [00184] In one embodiment, with respect to the above process, the reaction step Al) occurs at a temperature from about 50 °C to about 120 °C.

[00185] In one particular embodiment, with respect to the above process, the reaction step Al) occurs at a temperature around 80 °C or a reflux temperature of ethanol.

[00186] In one embodiment, with respect to the above process, the reaction step A2) occurs in an acidic medium.

[00187] In one particular embodiment, with respect to the above process, the reaction step A2) occurs in acetic acid.

[00188] In one embodiment, with respect to the above process, the reaction step A2) occurs under catalytic hydrogenation conditions.

[00189] In one embodiment, with respect to the above process, the reaction step A2) occurs in the presence of H₂ and Pd on C.

[00190] In another embodiment, with respect to the above process, the reaction step A2) occurs in the presence of boranehydrides.

[00191] In another embodiment, with respect to the above process, the reaction step A2) occurs in the presence of NaBH₄.

[00192] In one embodiment, with respect to the above process, the reaction step A2) occurs at a temperature from about 20 °C to about 70 °C.

[00193] In one particular embodiment, with respect to the above process, the reaction step A2) occurs at about 20 °C.

[00194] In one embodiment, with respect to the above process, the separation step A3) is carried out using crystallization.

[00195] In one particular embodiment, with respect to the above process, the crystallization is carried out in EtOAc, or ethanol.

[00196] In one embodiment, with respect to the above process, the reaction step A4) occurs in an acidic media.

[00197] In one particular embodiment, with respect to the above process, the reaction step A4) occurs in dil. HC1.

[00198] Yet another aspect of the present invention provides a process for preparing compound of sitagliptin or a compound of formula V:

V

Bl) reacting the (2,4,5-trifluoro-phenyl)-acetaldehyde of formula VII:

VII

isomer thereof; with t-Bu-S( the compound of formula VIII:

VII I

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof;

B2) reacting the compound of formula VIII; a solvate, polymorph or isomer thereof; with the metal enolate of formula IX:

IX

to form the sulfanamide of formula IV:

[00199] In one embodiment, with respect to the above process, the reaction step Bl) 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

[00200J In one particular embodiment, with respect to the above process, the reaction step Bl) occurs in ethanol.

[00201] In one embodiment, with respect to the above process, the reaction step Bl) occurs at a temperature from about 50 °C to about 120 °C.

[00202] In one particular embodiment, with respect to the above process, the reaction step Bl) occurs at a temperature around 80 °C or a reflux temperature of ethanol.

[00203] In one embodiment, with respect to the above process, the metal enolate of formula IX is formed by reacting the compound of formula X:

X

with an alkyl lithium, alkyl sodium, or alkylMgBr.

[00204] In one embodiment, with respect to the above process, the reaction step B2) occurs in an aprotic solvent.

[00205] In one particular embodiment, with respect to the above process, the reaction step B2) occurs in diethyl ether, or THF.

[00206] In one embodiment, with respect to the above process, the reaction step B3) occurs in an acidic media.

(00207] In one particular embodiment, with respect to the above process, the reaction step B3) occurs in dil. HC1. [00208] In another embodiment, with respect to the above process, the reaction step B3) occurs in dil. H₂S0₄.

[00209] A further aspect of the invention provides a process for preparing the compound of sitagliptin or a compound of formula V:

V

or an isomer thereof, and wherein R is H or Ci-C₄ alkyl; with t-Bu-S(0)NH₂ to form the compound of formula XII:

XII

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof;

XIII

and

C3) separating the diastereomers to obtain the compound of formula

XlVa:

XlVa

C4) reacting the compound of formula XlVa with the compound of formula XV:

XV

to form the compound of formula IV;

C5) deprotecting the compound of formula IV or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof; to form the sitagliptin or the compound of formula V.

[00210] In one particular embodiment, with respect to the above process, R³ is H, Me, Et, or i- Pr.

100211] In one embodiment, with respect to the above process, the reaction step CI) 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

[00212] In one particular embodiment, with respect to the above process, the reaction step CI) occurs in ethanol. [00213] In one embodiment, with respect to the above process, the reaction step CI) occurs at a temperature from about 50 °C to about 120 °C.

[00214] In one embodiment, with respect to the above process, the reaction step CI) occurs at a temperature around 80 °C or a reflux temperature of ethanol.

[00215] In one embodiment, with respect to the above process, the reaction step C2) occurs in an acidic media.

[00216] In one particular embodiment, with respect to the above process, the reaction step C2) occurs in acetic acid.

[00217] In one embodiment, with respect to the above process, the reaction step C2) occurs under catalytic hydrogenation conditions.

[00218] In one embodiment, with respect to the above process, the reaction step C2) occurs in the presence of H₂ and Pd on C.

[00219] In another embodiment, with respect to the above process, the reaction step C2) occurs in the presence of a borohydride.

[00220] In one particular embodiment, with respect to the above process, the reaction step C2) occurs in the presence of NaBH₄.

[00221] In one embodiment, with respect to the above process, the reaction step C2) occurs at a temperature from about 20 °C to about 70 °C.

[00222] In one particular embodiment, with respect to the above process, the reaction step C2) occurs at about 20 °C.

[00223] In one embodiment, with respect to the above process, the separation step C3) is carried out using crystallization.

[00224] In one embodiment, with respect to the above process, the separation step C3) is carried out using a sigle solvent or a mixture of solvents.

[00225] In one particular embodiment, with respect to the above process, the crystallization is carried out in EtOAc or EtOH.

[00226] In one embodiment, with respect to the above process, the reaction step C4) 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

[00227] In one particular embodiment, with respect to the above process, the reaction step C4) occurs in presence of ethanol.

[00228] In one embodiment, with respect to the above process, the reaction step C5) occurs in an acidic media. [00229] In one embodiment, with respect to the above process, the reaction step C5) occurs in dil. HC1.

[00230] In one embodiment, t-BuS(0)NH₂ as described herein is according to formula:

[00231] In one embodiment, t-BuS(0)NH₂ as described herein is according to formula:

[00232] In one embodiment, with respect to the above process, the t-Bu group in the compound of formulae Ila-IVb, VIII, and XII-XIVa is substituted with R¹ group.

[00233] Another aspect of the invention provides the use of a compound of any one of formulae I-IVb, VIII, and XII-XIVa in the preparation of Sitagliptin.

[00234] In particular aspects, the present invention provides composition of compounds according to formula la and Id. In one particular embodiment with respect to formula la and Id,

R¹ is t-Bu.

[00235] In particular aspects, the present invention provides composition of compounds according to formula lb and Ie. In one particular embodiment with respect to formula lb and Ie, R¹ is t-Bu.

[00236] In particular aspects, the present invention provides composition of compounds according to formula Ic and If. In one particular embodiment with respect to formula Ic and If, R¹ is t-Bu. In another particular embodiment with respect to formula Ic and If, R is Me, Et, i-Pr, or t-Bu.

[00237] In additional aspect, the present invention provides composition of any one of compounds selected from the compounds listed in Table 1.

[00238] 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.

[00239] 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 th° 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.

[00240] 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)alkyl esters. Preferred are the C\ to C₈ or Ci-C₆alkyl_; C₂-C₈ alkenyl, aryl, substituted aryl, and arylalkyl esters of the compounds of the invention.

GENERAL SYNTHETIC PROCEDURES

[00241] 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.

[00242] 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.

[00243] 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.

[00244] 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.

[00245] 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.

[00246] In this specification, especially in "Representative Synthetic Methods", the following abbreviations can be used:

BEP 2-bromo- 1 -ethylpyridinium tetrafluoroborate

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

hexafluorophosphate

CDI 2-chloro- 1 ,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 hydrog

EtOAc ethyl acetate

EtOH ethanol

HOBt 1 -hydroxybenzotriazole

MeOH methanol

NMP N-methyl-2-pyrroliidone

THF tetrahydrofuran

TFA trifluoroacetic acid

uM μΜ

uL PREPARATION OF THE COMPOUNDS OF THE INVENTION

Representative Synthetic Schemes

Scheme 2

Scheme 4

PREPARATION OF SITAGLIPTIN USING THE COMPOUNDS OF THE INVENTION

Representative Synthetic Schemes

Scheme 5

XX

wherein R is as described herein.

Scheme 7

Representative Methods for Preparation of Sitagliptin

Method A

Scheme 9

V * Any one skilled in art will recognize that either isomers of t-Bu-S(0)NH₂ can be used in the Scheme 9. The R- isomer will yield compounds of formulale II, Ilia or IV wherein the bond between S and C of t-butyl group to be above the plane and with S- isomer it will be below the plane.

Step Al

2-Methyl-propane-2-sulfinic acid [(Z)-3-oxo-l-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl- 5,6-dihydro-8H- [ 1 ,2,4] triazolo [4,3-a] pyrazin-7-yl)-propenyl] -amide (II)

[00247] A mixture of 1 -(3-Methyl-5,6-dihydro-8H-[ 1 ,2,4]triazolo[4,3-a]pyrazin-7-yl)-4- (2,4,5-trifluoro-phenyl)-butane-l,3-dione (VI, may was prepared according to the method described in Journal of the American Chemical Society (2004), 126(40), 13002-13009) (40.6 g, 0.1 mol) and t-Bu-S(0)NH₂ (12.1 g, 0.1 mol) and a catalytic amount of PTSA in toluene (400 mL) is heated to reflux and stirred for several hours. The mixture is cooled and washed with aq. Sat. NaHC03 solution. Evaporation of the organic layer yields the desired crude 2-methyl- propane-2-sulfinic acid [(Z)-3-oxo-l -(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro- 8H-[l,2,4]triazolo[4,3-a]pyrazin-7-yl)-propenyl]-amide (II).

Step A2

2-Methyl-propane-2-sulfinic acid [3-oxo-l-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6- dihydro-8H- [ 1 ,2,4] triazolo [4,3-a] py razin-7-yl)-propyl] -amide (Ilia)

[00248] The crude 2-methyl-propane-2-sulfinic acid [(Z)-3-oxo-l-(2,4,5-trifiuoro-benzyl)-3- (3-trifluoromethyl-5,6-dihydro-8H-[l ,2,4]triazolo[4,3-a]pyrazin-7-yl)-propenyl]-amide (0.02M) was suspended in a mixture of dichloromethane (100 mL) and acetic acid (10 mL) and was treated with NaBH₄ (0.025M) during 30 minutes. After the reaction was completed, the mixture was made alkaline using 5% aq. NaOH solution. The organic layer was separated and washed successively with water and brine. The organic layer was concentrated and the crude

diastereomeric mixture.

Step A3

2-MethyI-propane-2-suIfinic acid [(R)-3-oxo-l-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl- 5,6-dihydro-8H-[l,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-amide (IV)

[00249] The crude diastereomeric mixture obtained above was crystallized from isopropanol to separate the desired isomer. HPLC purity 99.87%

Step A4 (R)-3- Amino-l-(3-trifluoromethyl-5,6-dihydro-8H- [ 1 ,2,4] triazolo [4,3-a] pyrazin-7-yl)-4- 2,4,5-trifluoro-phenyl)-butan-l-one (V, Sitagliptin)

[00250] The tert-butyl sulfinimide can be deprotected with the aid of an acid such as HC1 to yield the title compound.

Method B

Scheme 10

Step Bl

2-Methyl-propane-2-sulfinic acid [2-(2,4,5-trifluoro-phenyl)-eth-(Z)-ylidene]-amide (VIII)

[00251] A mixture of (2,4,5-trifluoro-phenyl)-acetaldehyde (VII) (17.4 g, 0.1 mol) and t-Bu- S(0)NH₂ (12.1 g, 0.1 mol) and catalytic amount of PTSA in toluene (200 mL) is heated to reflux and stirred for several hours. The mixture is cooled and washed with aq. Saturated NaHC0₃ solution. Evaporation of the organic phase affords the crude 2-methyl-propane-2-sulfinic acid [2- (2,4,5-trifluoro-phenyl)-eth-(Z)-ylidene]-amide (VIII) .

Step B2

2-Methyl-propane-2-sulfinic acid [(R)-3-oxo-l-(2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl- 5,6-dihydro-8H-[l,2,4]triazolo[4,3-a]pyrazin-7-yl)-propyl]-amide (IV)

[00252] A solution of the crude 2-methyl-propane-2-sulfinic acid [2-(2,4,5-trifluoro-phenyl)- eth-(Z)-ylidene]-amide (VIII) in an aprotic sclent is treated with a metal enolate of l -[3- (trifluoromethyl)-6,8-dihydro-5H-imidazo[l ,2-a]pyrazin-7-yl]ethanone. The reaction is carried usually at lower temperatures. It should be noted here that the addition takes place in a stereoselective manner. The usual work up yields 2-methyl-propane-2-sulfinic acid [3-oxo-l- (2,4,5-trifluoro-benzyl)-3-(3-trifluoromethyl-5,6-dihydro-8H-[l ,2,4]triazolo[4,3-a]pyrazin-7-yl)- propyl]-amide (III).

Step B3

(R)-3-Amino-l-(3-trifluoromethyI-5,6-dihydro-8H-[l,2,4]triazolo[4,3-a]pyrazin-7-yl)-4- 2,4,5-trifluoro-phenyl)-butan-l-one (V, Sitagliptin)

[00253] The tert-butyl sulflnimide can be deprotected with the aid of an acid such as HC1 to yield the title compound.

Method C

Scheme 11

step C2 Reduction

Chiral

XlVa XIII

[00254] PTSA assisted condensation of tert-butylsulfinimide with XI gives rise to XII which on reduction, affords a mixture of diastereomers that are separated by crystallization to yield XlVa. The subsequent condensation of the desired diastereomer of XIV with XV gives rise to IV which on deprotection furnishes V.

Exemplary Compounds of the Invention

[00255] 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.

[00256] Table 1: Exemplary Compounds of the Invention

[00257] 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.

[00258] 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.

[00259] 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.

[00260] 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:

1. A compound according to formula I:

I

wherein R¹ is alkyl, substituted alkyl, haloalkyl, cycloalkyl, substituted cycloalkyl, phenyl or substituted phenyl; provided that the C attached to S is other than CH moiety;

R² is hydroxy, C₁-C4 alkoxy, or

and the dotted bond is a single or a double bond;

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof.

2.

The compound according to claim 1 , wherein R¹ is t-Bu.

The compound according to any one of claims 1 -3, wherein the dotted bond is a single bond.

The compound according to any one of claims 1 -3, wherein the dotted bond is a double bond.

The compound according to claim 1 , wherein the compound is according to formula Ila or lib:

and wherein R³ is C₁-C4 alkyl; or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof.

The compound according to claim 1 , wherein the compound is according to formula Ilia or Illb:

and wherein R is Ci-C₄ alkyl; or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof.

The compound according to claim 1 , wherein the compound is according to formula IVa o

or a solvate, polymorph, phe~naceutically acceptable salt or isomer thereof.

9. A process for preparing the compound sitagliptin, or a compound of formula V:

V

Al) reacting the l-(3-trifluoromethyl-5,6-dihydro-8H- [l,2,4]triazolo[4,3-a]pyrazin-7-yl)-4-(2,4,5-trifluoro-phenyl)-butane-l ,3-dione of formula VI:

VI

or an isomer thereof; with t-Bu-S(0)NH₂ to form the enamine of formula

II:

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof;

A2) reducing the compound of formula II; a solvate, polymorph or isomer thereof; to form the sulfinamide of formula Ilia:

A3) separating the diastereomers to obtain the sulfanamide of formula IV:

IV ; and

A4) deprotecting the compound of formula IV or a solvate, polymorph, larmaceutically acceptable salt or isomer thereof; to form the sitagliptin or the mpound of formula V.

10. The process of claim 9, wherein the reaction step Al) occurs in a solvent selected from the group consisting of methanol, ethanol, isopropyl alcohol, acetonitnle, ethyl acetate, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, N-methyl pyrrolidinone, dimethyl formamide, dimethyl sulfoxide, and combinations thereof.

11. The process of claim 9, wherein the reaction step Al) occurs in ethanol.

12. The process of claim 9, wherein the reaction step Al) occurs at a temperature from about 50 °C to about 120 °C.

13. The process of claim 9, wherein the reaction step Al) occurs at a temperature around 80 °C or a reflux temperature of ethanol.

14. The process of claim 9, wherein the reaction step A2) occurs in an acidic media.

15. The process of claim 9, wherein the reaction step A2) occurs in acetic acid...

16. The process of claim 9, wherein the reaction step A2) occurs under catalytic

hydrogenation conditions.

17. The process of claim 9, wherein the reaction step A2) occurs in the presence of H2 and Pd on C.

18. The process of claim 9, wherein the reaction step A2) occurs in the presence of

boranehydrides.

19. The process of claim 9, wherein the reaction step A2) occurs in the presence of

20. The process of claim 9, wherein the reaction step A2) occurs at a temperature from about 20 °C to about 70 °C.

21. The process of claim 9, wherein the reaction step A2) occurs at about 20 °C.

22. The process of claim 9, wherein the separation step A3) is carried out using

crystallization.

23. The process of claim 22, wherein the crystallization is carried out in EtOAc, or ethanol.

24. The process of claim 9, wherein the reaction step A4) occurs in an acidic media.

25. The process of claim 9, wherein the reaction step A4) occurs in dil. HC1.

26. A process for preparing the compound sitagliptin, or a compound of formula V:

V

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof, comprising the steps of:

B 1 ) reacting the (2,4,5-trifluoro-phenyl)-acetaldehyde of formula VII:

VII

isomer thereof; with t-Bu-S( the compound of formula VIII:

VIII

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof;

IX to form the sulfanamide of formula IV:

IV ; and

27. The process of claim 26, wherein the reaction step Bl) 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, dimethyl formamide, dimethyl sulfoxide, and combinations thereof.

28. The process of claim 26, wherein the reaction step Bl) occurs in ethanol.

29. The process of claim 26, wherein the reaction step Bl) occurs at a temperature from about 50 °C to about 120 °C.

30. The process of claim 26, wherein the reaction step Bl) occurs at a temperature around 80 °C or a reflux temperature of ethanol.

31. The process of claim 26, wherein the metal enolate of formula IX is formed by

reacting the compound of formula

X

with an alkyl lithium, alkyl sodium, or alkylMgBr.

32. The process of claim 26, wherein the reaction step B2) occurs in an aprotic solvent.

33. The process of claim 26, wherein the reaction step B2) occurs in diethyl ether or THF.

34. The process of claim 26, wherein the reaction step B3) occurs in an acidic media.

35. The process of claim 26, wherein the reaction step B3) occurs in dil. HC1.

36. The process of claim 26, wherein the reaction step B3) occurs in dil. H₂S0₄.

37. A process for preparing the compound sitagliptin, or a compound of formula V:

V

XI

or a solvate, polymorph, pharmaceutically acceptable salt or isomer thereof;

C2) reducing the compound of formula XII; a solvate, polymorph or isomer thereof; to form the sulfinamine of formula XIII:

XIII

separating the diastereomers to obtain the compound of formula

XlVa:

; and

C4) reacting the compound of formula XlVa with the compound of formula XV:

XV

to form the compound of formula IV:

I ; and

38. The process according to claim 37, wherein R is H, Me, Et, or i-Pr.

39. The process of claim 37, wherein the reaction step CI) 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, dimethyl formamide, dimethyl sulfoxide, and combinations thereof.

40. The process of claim 37, wherein the reaction step CI) occurs in ethanol.

41. The process of claim 37, wherein the reaction step CI ) occurs at a temperature from about 50 °C to about 120 °C.

42. The process of claim 37, wherein the reaction step CI) occurs at a temperature around 80 °C or a reflux temperature of ethanol.

43. The process of claim 37, wherein the reaction step C2) occurs in an acidic medium.

44. The process of claim 37, wherein ₆₃e reaction step C2) occurs in acetic acid.

45. The process of claim 37, wherein the reaction step C2) occurs under catalytic hydrogenation conditions.

46. The process of claim 37, wherein the reaction step C2) occurs in the presence of H₂ and Pd on C.

47. The process of claim 37, wherein the reaction step C2) occurs in the presence of a borohydride.

48. The process of claim 37, wherein the reaction step C2) occurs in the presence of NaBH₄.

49. The process of claim 37, wherein the reaction step C2) occurs at a temperature from about 20 °C to about 70 °C.

50. The process of claim 37, wherein the reaction step C2) occurs at about 20 °C.

51. The process of claim 37, wherein the separation step C3) is carried out using

crystallization.

52. The process of claim 51, wherein the crystallization is carried out in a single solvent or in a mixture of solvents.

53. The process of claim 37, wherein the reaction step C4) 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, dimethyl formamide, dimethyl sulfoxide, and combinations thereof.

54. The process of claim 37, wherein the reaction step C4) occurs in presence of ethanol.

55. The process of claim 37, wherein the reaction step C5) occurs in an acidic media.

56. The process of claim 37, wherein the reaction step C5) occurs in dil. HC1.

57. A compound selected from the compounds listed in Table 1.

58. The use of any one of compounds according to formulae I-IVb, VIII, and XII-XIVa in the preparation of Sitagliptin.

59. The use of any one of compounds selected from the compounds listed in Table 1 in the preparation of Sitagliptin.