WO2008040995A1

WO2008040995A1 - Indazoles for use as dpp-iv inhibitors

Info

Publication number: WO2008040995A1
Application number: PCT/GB2007/003788
Authority: WO
Inventors: Adrian Maddaford; Rebecca Glen; David Paul Leese; Terance William Hart
Original assignee: Peakdale Molecular Limited
Priority date: 2006-10-07
Filing date: 2007-10-04
Publication date: 2008-04-10
Also published as: WO2008040974A1; WO2008040995A8; WO2008040995A9

Abstract

The present invention relates to indazole derivatives useful as dipeptidyl peptidase IV (DPP-IV) inhibitors.

Description

INDOLES FOR USE AS DPP-IV INHIBITORS

Field of the Invention

This present invention relates to compounds useful as dipeptidyl peptidase IV (DPP-IV) inhibitors.

Background to the Invention

Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnoπnal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Patients with Type 2 diabetes mellitus are, therefore, at increased risk of macro-vascular and micro-vascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. For this reason, the therapeutic control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.

There are two generally recognized forms of diabetes. In Type 1 diabetes, or insulin- dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are the same or even elevated compared to non-diabetic subjects, however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues, and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance.

Insulin resistance is not primarily due to a diminished number of insulin receptors but to a post-insulin receptor binding defect that is not yet understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver.

The available treatments for Type 2 diabetes, which have not changed substantially in many years, have recognized limitations. While physical exercise and reductions in dietary intake of calories will dramatically improve the diabetic condition, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of saturated fat. Increasing the plasma level of insulin by administration of sulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, which stimulate the pancreatic β-cells to secrete more insulin, and/or by injection of insulin when sulfonylureas or meglitinide become ineffective, can result in insulin concentrations high enough to stimulate the very insulin- resistant tissue. However, dangerously low levels of plasma glucose can result from administration of insulin or insulin secretagogues (sulfonylureas or meglitinide), and an increased level of insulin resistance due to the even higher plasma insulin levels can occur. The biguanides increase insulin sensitivity resulting in some correction of hyperglycemia. However, the two biguanides, phenformin and metformin, can induce lactic acidosis and nausea/diarrhea. Metformin has fewer side effects than phenformin and is often prescribed for the treatment of Type 2 diabetes.

The glitazones (i.e., 5-benzylthiazolidine-2,4-diones) are a more recently described class of compounds with potential for ameliorating many symptoms of Type 2 diabetes. These agents substantially increase insulin sensitivity in muscle, liver and adipose tissue in several animal models or Type 2 diabetes resulting in partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycaemia. The glitazones that are currently marketed are agonists of the peroxisome proliferators activated receptor (PPAR), primarily the PPAR-gamma subtype. PPAR —gamma agonism is generally believed to be responsible for the improved insulin sensitization that is observed with the glitazones. Newer PPAR agonists that are being tested for treatment of Type II diabetes are agonists of the alpha, gamma or delta subtype, or a combination of these, and in many cases are chemically different from glitazones (i.e., they are not thiazolidinediones).

Serious side effects (e.g. liver toxicity) have occurred with some of the glitazones, such as troglitazone. Additional methods of treating the disease are still under investigation. New biochemical approaches that have been recently introduced or are still under development include treatment with alpha-glucosidase inhibitors (e.g. acarbose) and protein tyrosine phosphatase- IB (PTP-IB) inhibitors

Compounds that are inhibitors of the dipeptidyl peptidase-IV enzyme (DPPIV) are also under investigation as drugs that may be useful in the treatment of diabetes, and particularly Type 2 diabetes, see for example WO 97/40832 and WO 98/19998. The usefulness of DPPIV inhibitors in the treatment of Type 2 diabetes is based on the fact that DPPrV in vivo readily inactivates glucagons like peptide- 1 (GLP-I) and gastric inhibitory peptide (GIP). GLP-I and GIP are incretins and are produced when food is consumed. The incretins stimulate production of insulin. Inhibition of DPPIV leads to decreased inactivation of the incretins and this in turn results in increased effectiveness of the incretins in stimulating insulin production by the pancreas. DPPIV inhibition therefore results in an increased level of serum insulin. Advantageously, since the incretins are produced by the body only when food is consumed, DPPIV inhibition is not expected to increase the level of insulin at inappropriate times, such as between meals, which can lead to excessively low blood sugar (hypoglycaemia). Inhibition of DPPIV is therefore expected to increase insulin without increasing the risk of hypoglycaemia, which is a dangerous side effect associated with the use of insulin secretagogues.

DPPIV inhibitors have not been studied extensively to date, especially for utilities other than diabetes. New compounds are needed so that improved DPPIV inhibitors can be found for the treatment of diabetes and potentially other diseases and conditions.

The present inventor(s) have identified indazole derivatives that have DPPIV inhibitory activity.

Statements of the Invention According to a first aspect of the present invention there is provided a compound of Formula I:

(I) wherein

R¹, R², R³ and R⁴ are each independently selected from hydrogen, R¹², hydrocarbyl optionally substituted with R¹², and -(CH₂)_k-heterocyclyl optionally substituted with R¹², wherein each R¹² is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, =NR¹³, -OR¹³, -C(O)R¹³, -C(O)OR¹³, -OC(O)R¹³, -S(O)]R¹³, -N(R¹³)R¹⁴, - C(O)N(R¹³)R¹⁴, -SO₂N(R¹³)R¹⁴ and R¹⁵ and including the proviso that R³ is not F;

wherein R , 13 a _ndj r R> 14 are each independently selected from hydrogen or R 15 ,.

wherein R¹⁵ is selected from hydrocarbyl and -(CH₂)_m-heterocyclyl, and each R¹⁵ is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxy, C_1-6 alkyl and C_1-6 alkoxy;

k is O, 1, 2, 3, 4, 5 or 6;

1 is 0, 1 or 2; m is O, 1, 2, 3, 4, 5 or 6;

or one or more R¹ and R², R² and R³, R³ and R⁴ taken together with the atoms to which they are attached form a carbocycle or a heterocycle, optionally substituted with one or more R¹²; R⁵ is independently selected from hydrogen and hydrocarbyl and each R⁵ is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxyl, and hydrocarbyl wherein each optional hydrocarbyl substituent is optionally and independently substituted with one or more of halogen, hydroxyl and hydrocarbyl optionally and independently substituted with one or more halogen;

R⁷ and R⁸ are each independently selected from hydrogen or R¹²; or R⁷ and R⁸ taken together with the atoms to which they are attached form a carbocycle or a heterocycle, optionally substituted with one or more R¹²; or R⁷ or R⁸ together with R⁹ or R¹⁰, together with the atoms to which they are attached, form a carbocycle (e.g. 6-membered ring) or a heterocycle, optionally substituted with one or more R¹²;

R⁹ and R¹⁰ are independently selected from hydrogen or R¹²; or R⁹ and R¹⁰ taken together with the atoms to which they are attached form a carbocycle or a heterocycle, optionally substituted with one or more R¹²;

Z is selected from the group consisting of hydrocarbyl optionally substituted with R¹², and -(CH₂)_k-heterocyclyl optionally substituted with R¹², wherein each R¹² is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, =NR¹³, -OR¹³, -C(O)R¹³, - C(O)OR¹³, -OC(O)R¹³, -S(O)iR¹³, -N(R¹³)R¹⁴, -C(O)N(R¹³)R¹⁴, -SO₂N(R¹³)R¹⁴ and R¹⁵; or a salt thereof.

The compounds of the invention can exist in different forms, such as free acids, free bases, esters and other prodrugs, salts and tautomers, for example, and the invention includes all variant forms of the compounds.

Hydrocarbyl

The term "hydrocarbyl" as used herein includes reference to moieties consisting exclusively of hydrogen and carbon atoms; such a moiety may comprise an aliphatic and/or an aromatic moiety. The moiety may comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. Examples of hydrocarbyl groups include C_1-6 alkyl (e.g. C₁, C₂, C₃ or C₄ alkyl, for example methyl, ethyl, propyl, isopropyl, n- butyl, sec-butyl or tert-butyl); C_1-6 alkyl substituted by aryl (e.g. benzyl) or by cycloalkyl (e.g cyclopropylmethyl); cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl); alkenyl (e.g. 2-butenyl); alkynyl (e.g. 2-butynyl); aryl (e.g. phenyl, naphthyl or fluorenyl) and the like.

Alkyl

The terms "alkyl" and "C_1-6 alkyl" as used herein include reference to a straight or branched chain alkyl moiety having 1, 2, 3, 4, 5 or 6 carbon atoms. This term includes reference to groups such as methyl, ethyl, propyl (n-propyl or isopropyl), butyl (n-butyl, sec-butyl or tert-butyl), pentyl, hexyl and the like. In particular, alkyl may have 1 , 2, 3 or 4 carbon atoms.

Alkenyl

The terms "alkenyl" and "C_2-6 alkenyl" as used herein include reference to a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at least one double bond, of either E or Z stereochemistry where applicable. This term includes reference to groups such as ethenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, 2-hexenyl and 3-hexenyl and the like.

Alkynyl The terms "alkynyl" and "C_2-6 alkynyl" as used herein include reference to a straight or branched chain alkyl moiety having 2, 3, 4, 5 or 6 carbon atoms and having, in addition, at least one triple bond. This term includes reference to groups such as ethynyl, 1-propynyl,

2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 1- hexynyl, 2-hexynyl and 3-hexynyl and the like.

Alkoxy

The terms "alkoxy" and "Ci_-6 alkoxy" as used herein include reference to -O-alkyl, wherein alkyl is straight or branched chain and comprises 1, 2, 3, 4, 5 or 6 carbon atoms. hi one class of embodiments, alkoxy has 1, 2, 3 or 4 carbon atoms. This term includes reference to groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexoxy and the like.

Cycloalkyl The term "cycloalkyl" as used herein includes reference to an alicyclic moiety having 3, 4,

5, 6, 7 or 8 carbon atoms. The group may be a bridged or polycyclic ring system. More often cycloalkyl groups are monocyclic. This term includes reference to groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl and the like.

Aryl

The term "aryl" as used herein includes reference to an aromatic ring system comprising

6, 7, 8, 9, 10, 11. 12, 13, 14, 15 or 16 ring carbon atoms. Aryl is often phenyl but may be a polycyclic ring system, having two or more rings, at least one of which is aromatic.

This term includes reference to groups such as phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the like.

Carbocyclyl The term "carbocyclyl" as used herein includes reference to a saturated (e.g. cycloalkyl) or unsaturated (e.g. aryl) ring moiety having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 carbon ring atoms. In particular, carbocyclyl includes a 3- to 10-membered ring or ring system and, in particular, a 5- or 6-membered ring, which may be saturated or unsaturated. A carbocyclic moiety is, for example, selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl, bicyclo[2.2.2]octyl, phenyl, naphthyl, fluorenyl, azulenyl, indenyl, anthryl and the like.

Heterocyclyl

The term "heterocyclyl" as used herein includes reference to a saturated (e.g. heterocycloalkyl) or unsaturated (e.g. heteroaryl) heterocyclic ring moiety having from 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen, phosphorus, silicon and sulphur. In particular, heterocyclyl includes a 3- to 10-membered ring or ring system and more particularly a 5- or 6-or 7- membered ring, which may be saturated or unsaturated.

A heterocyclic moiety is, for example, selected from oxiranyl, azirinyl, 1,2-oxathiolanyl, imidazolyl, thienyl, furyl, tetrahydrofuryl, pyranyl, thiopyranyl, thianthrenyl, isoben- zofuranyl, benzofuranyl, chromenyl, 2H-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, morpholinyl, thiomorpholinyl, especially thiomorpholino, indolizinyl, isoindolyl, 377-indolyl, indolyl, benzimidazolyl, cumaryl, indazolyl, triazolyl, tetrazolyl, purinyl, 4.H-quinolizinyl, isoquinolyl, quinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, benzofuranyl, dibenzofuranyl, benzothiophenyl, dibenzothiophenyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, furazanyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromenyl, isochromanyl, chromanyl and the like.

Heterocycloalkyl

The term "heterocycloalkyl" as used herein includes reference to a saturated heterocyclic moiety having 3, 4, 5, 6 or 7 ring carbon atoms and I₅ 2, 3, 4 or 5 ring heteroatoms selected from nitrogen, oxygen, phosphorus and sulphur. The group may be a polycyclic ring system but more often is monocyclic. This term includes reference to groups such as azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, oxiranyl, pyrazolidinyl, imidazolyl, indolizidinyl, piperazinyl, thiazolidinyl, morpholinyl, thiomorpholinyl, quinolinidinyl and the like.

Heteroaryl

The term "heteroaryl" as used herein includes reference to an aromatic heterocyclic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or 16 ring atoms, at least one of which is selected from nitrogen, oxygen and sulphur. The group may be a polycyclic ring system, having two or more rings, at least one of which is aromatic, but is more often monocyclic. This term includes reference to groups such as pyrimidinyl, furanyl, benzo[b]thiophenyl, thiophenyl, pyrrolyl, imidazolyl, pyrrolidinyl, pyridinyl, benzofb] furanyl, pyrazinyl, purinyl, indolyl, benzimidazolyl, quinolinyl, phenothiazinyl, triazinyl, phthalazinyl, 2H- chromenyl, oxazolyl, isoxazolyl, thiazolyl, isoindolyl, indazolyl, purinyl, isoquinolinyl, quinazolinyl, pteridinyl and the like.

Halogen The term "halogen" as used herein includes reference to F, Cl, Br or I. In particular, halogen may be F or Cl.

Substituted The term "substituted" as used herein in reference to a moiety means that one or more, especially up to 5, more especially 1, 2 or 3, of the hydrogen atoms in said moiety are replaced independently of each other by the corresponding number of the described substituents. The term "optionally substituted" as used herein means substituted or unsubstituted.

It will, of course, be understood that substituents are only at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort whether a particular substitution is possible. For example, amino or hydroxy groups with free hydrogen may be unstable if bound to carbon atoms with unsaturated (e.g. olefmic) bonds. Additionally, it will of course be understood that the substituents described herein may themselves be substituted by any substituent, subject to the aforementioned restriction to appropriate substitutions as recognised by the skilled man.

Independently

Where two or more moieties are described as being "each independently" selected from a list of atoms or groups, this means that the moieties may be the same or different. The identity of each moiety is therefore independent of the identities of the one or more other moieties.

The present invention further provides a compound according to the invention which comprises the racemate, the £ or the R enantiomer or a mixture thereof, of a compound according to the invention. Preferably, the compound is the S-enantiomer or the R- enantiomer.

In one embodiment of the compounds of the present invention, the carbon atom marked with an * has the R configuration (according to the Calm Ingold Prelog convention) as depicted in Formula Ia

(Ia) wherein R¹, R², R³, R⁴, R⁵, R⁷, R⁸, R⁹, R¹⁰ and Z are as defined herein. For example R⁷, R⁸, R⁹ and R¹⁰ are H.

Thus in a preferred aspect the invention provides a compound of Formula Ib

(Ib)

wherein R¹, R², R 3^J, τ R>4⁴, r R> 5⁵, τ R> 7', τ R> 8^s, τ R>9^y, n Rl^xO^υ and Z are as defined herein. R'and R² are preferably each independently selected from hydrogen, halogen, cyano, OH, C_1-6 alkyl and -0(C_1-6 alkyl) wherein C_1-6 alkyl and -0(C_1-6 alkyl) are each optionally and independently substituted by one or more halogen.

More preferably R¹ and R² are each independently selected from hydrogen and F.

In one embodiment of the invention R¹ is F and R² is hydrogen.

In a further embodiment of the invention R¹ is hydrogen and R² is F.

In a yet further embodiment of the invention R¹ is F and R² is F.

Preferably R¹, R², and R are each independently selected from hydrogen and F.

In one embodiment of the invention, two of R¹, R² and R⁴ are F, for example R¹ and R⁴.

In one embodiment of the invention R , R^z and R⁴ are F.

R³ and R⁴ are preferably each independently selected from hydrogen, halogen, cyano, OH, C_1-6 alkyl and -0(C_1-6 alkyl) wherein C_1-6 alkyl and -0(C_1-6 alkyl) are each optionally and independently substituted by one or more halogen and including the proviso that where R³ is halogen R³ is not F.

Preferably R³ and R⁴ are each independently hydrogen.

R⁵ is preferably independently selected from hydrogen, C_1-6 alkyl and carbocyclyl optionally and independently substituted with one or more of halogen, hydroxyl, C_1-6 alkyl and OC_1-6 alkyl or carbocyclyl (e.g aryl); wherein each optional C_1-6 alkyl and OC_1-6 alkyl substituent is optionally and independently substituted with one or more halogen; and wherein each optional carbocyclyl substituent is optionally and independently substituted with one or more halogen, hydroxyl, Ci-₆ alkyl optionally substituted with one or more halogen, or OC_1-6 alkyl optionally substituted with one or more halogen. Preferably R⁵ is independently selected from hydrogen, C_1-6 alkyl, C_3-6 cycloalkyl and phenyl optionally and independently substituted with one or more of halogen, hydroxyl, C_1-6 alkyl and OC_1-6 alkyl or phenyl; wherein each optional C_1-6 alkyl and OC_1-6 alkyl substituent is optionally and independently substituted with one or more halogen; and wherein each optional phenyl substituent is optionally and independently substituted with one or more halogen, hydroxyl, C_1-6 alkyl optionally substituted with one or more halogen, or OCi_-6 alkyl optionally substituted with one or more halogen.

More preferably R⁵ is hydrogen or C 1-6 alkyl optionally substituted as described herein.

Preferably still R⁵ is hydrogen.

R and R are preferably each independently selected from hydrogen, hydroxyl, halogen and C_1-6 alkyl wherein C_1-6 alkyl is optionally and independently substituted with one or more halogen; or R and R⁸ taken together with the atoms to which they are attached form C_3-6 cycloalkyl optionally and independently substituted with one or more halogen.

More preferably R⁷ and R⁸ are each independently hydrogen.

R⁹ and R¹⁰ are preferably each independently selected from hydrogen, hydroxyl, halogen and C_1-6 alkyl wherein C_1-6 alkyl is optionally and independently substituted with one or more halogen; or R⁹ and R¹⁰ taken together with the atoms to which they are attached form C_3-6 cycloalkyl optionally and independently substituted with one or more halogen.

More preferably R⁹ and R¹⁰ are each independently hydrogen.

Z is preferably a heterocyclic group, for example a 5, 6 or 7 membered monocyclic or polycyclic heterocyclic ring or ring system.

Preferably Z is a nitrogen-containing heterocyclic group. For example Z may be selected from the group consisting of imidazolyl, 2ϋf-pyrrolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrrolizidinyl, imidazolyl, imidazolidinyl, benzimidazolyl, pyrazolyl, pyrazinyl, pyrazolidinyl, thiazolyl, isothiazolyl, dithiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, piperidyl, piperazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, benzimidazolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolyl, tetrahydroquinolyl, tetraliydroisoquinolyl, decahydroquinolyl, octahydroisoquinolyl, phthalazinyl, naphthyridinyl, quinoxalyl, quinazolinyl, quinazolinyl, cinnolinyl, pteridinyl, azepane, azepanone, diazepanone and azocane.

Preferably Z is a group of Formula (II)

(H)

wherein

R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are each independently selected from hydrogen, R¹², hydrocarbyl optionally and independently substituted with R¹², and -(CH₂)_k-heterocyclyl optionally substituted with R 12.

W and Y are independently selected from N, C, O and S;

R²³ and R²⁴, which may be absent, are each independently selected from hydrogen, R¹², hydrocarbyl optionally and independently substituted with R¹², and -(CH₂)_k-heterocyclyl optionally substituted with R¹²; or R²³ and R²⁴ taken together with the atoms to which they are attached form a carbocycle or a heterocycle, optionally substituted with one or more R 12

R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are preferably each independently selected from hydrogen, halogen, hydroxyl, cyano, CO₂H, CONH₂, C_1-6 alkyl and carbocyclyl wherein the optional C_1-6 alkyl and carbocyclyl substituents are optionally and independently substituted with one or more of halogen, hydroxyl, C_1-6 alkyl and C_1-6 alkoxy wherein the latter alkyl and alkoxy substituents are optionally substituted with one or more halogen.

Preferably R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are each independently selected from hydrogen, CO₂H, CONH₂ and methyl. More preferably R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are each independently hydrogen.

Preferably W and Y are independently selected from C and N. Preferably still W is C and Y is N.

R ³ and R are preferably independently selected from hydrogen, trifluoromethyl, cyano, C_1-6 alkyl, C_1-6 alkoxy, and carbocyclyl wherein the optional C_1-6 alkyl, C_1-6 alkoxy, and carbocyclyl substituents are optionally and independently substituted with one or more of halogen, hydroxyl, C_1-6 alkyl and C_1-6 alkoxy wherein the latter alkyl and alkoxy substiuents are optionally substituted with one or more halogen.

In one embodiment of the invention W is C, Y is N, R²³ is trifluoromethyl and R²⁴ is absent.

hi one embodiment of the invention Z is optionally substituted azepanone or diazepanone. Preferably Z is optionally substituted diazepanone, for example diazeρan-2-one. In a particular embodiment Z is optionally substituted 1, 4 diazepan-2-one. Optional substituents include R¹² and hydrocarbyl optionally and independently substituted with R¹². Preferably Z is azepanone or diazepanone optionally substituted with hydrocarbyl (e.g. ethyl) wherein one or more carbon groups in the hydrocarbyl are optionally substituted with trifluoromethyl.

Illustrative, but non-limiting, examples of the compounds of the present invention that are useful as inhibitors of DPPIV are the following:

or a pharmaceutically acceptable salt thereof.

A preferred compound of the invention is selected from the following

(i) (ϋ) (iii)

(iv)

(V)

In one embodiment the compound of the invention is the compound (iii).

Several methods for preparing the compounds of the invention are illustrated in the Schemes shown in the Examples. Starting materials are made according to procedures known in the art or as illustrated herein.

Any mixtures of final products or intermediates obtained can be separated on the basis of the physico-chemical differences of the constituents, in a known manner, into the pure final products or intermediates, for example by chromatography, distillation, fractional crystallisation, or by the formation of a salt if appropriate or possible under the circumstances.

Compounds of the invention may be in the form of salts. In particular, the salts may be pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., US₃ 1985, p. 1418, the disclosure of which is hereby incorporated by reference; see also Stahl et al, Eds, "Handbook of Pharmaceutical Salts Properties Selection and Use ", Verlag Helvetica Chimica Acta and Wiley-VCH, 2002. The disclosure thus includes pharmaceutically-acceptable salts of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. For example the conventional non-toxic salts or the quaternary ammonium salts which are formed, e.g. from inorganic or organic acids or bases. Examples of such acid addition salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3- phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, tosylate, and undecanoate. Base salts include ammonium salts, alkali metal salts such as sodium and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth. Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides and others.

The invention includes prodrugs for the active pharmaceutical species of the invention, for example in which one or more functional groups are protected or derivatised but can be converted in vivo to the functional group, as in the case of esters of carboxylic acids convertible in vivo to the free acid, or in the case of protected amines, to the free amino group. The term "prodrug," as used herein, represents in particular compounds which are rapidly transformed in vivo to the parent compound, for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A. C. S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987; H Bundgaard, ed, Design of Prodrugs, Elsevier, 1985; and Judkins, et al. Synthetic Communications, 26(23), 4351-4367 (1996), each of which is incorporated herein by reference.

Also to be mentioned as metabolic activations of prodrugs are nucleotide activation, phosphorylation activation and decarboxylation activation. For additional information, see "The Organic Chemistry of Drug Design and Drug Action", R B Silverman (particularly Chapter 8, pages 497 to 546), incorporated herein by reference.

The use of protecting groups is fully described in 'Protective Groups in Organic Chemistry', edited by J W F McOmie, Plenum Press (1973), and 'Protective Groups in Organic Synthesis', 2nd edition, T W Greene & P G M Wutz, Wiley-Interscience (1991).

Thus, it will be appreciated by those skilled in the art that, although protected derivatives of compounds of the disclosure may not possess pharmacological activity as such, they may be administered, for example parenterally or orally, and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives are therefore examples of "prodrugs". All prodrugs of the described compounds are included within the scope of the disclosure.

Some groups mentioned herein (especially those containing heteroatoms and conjugated bonds) may exist in tautomeric forms and all these tautomers are included in the scope of the disclosure. More generally, many species may exist in equilibrium, as for example in the case of organic acids and their counterpart anions; a reference herein to a species accordingly includes reference to all equilibrium forms thereof.

The compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. All diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica). AU stereoisomers are included within the scope of the disclosure. Where a single enantiomer or diasteromer is disclosed, the disclosure also covers the other enantiomers or diastereomers, and also racemates; in this regard, particular reference is made to the specific compounds listed herein.

Geometric isomers may also exist in the compounds of the present disclosure. The present disclosure contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond and designates such isomers as of the Z or E configuration, wherein the term "Z" represents substituents on the same side of the carbon—carbon double bond and the term "E" represents substituents on opposite sides of the carbon— carbon double bond.

The disclosure therefore includes all variant forms of the defined compounds, for example any tautomer or any pharmaceutically acceptable salt, ester, acid or other variant of the defined compounds and their tautomers as well as substances which, upon administration, are capable of providing directly or indirectly a compound as defined above or providing a species which is capable of existing in equilibrium with such a compound.

Administration & Pharmaceutical Formulations

The compounds of the invention in free form or in pharmaceutically acceptable salt form possess pharmacological activity. They are therefore intended for use as a pharmaceutical. In particular they inhibit DPPIV.

Where used in therapy, the compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, by any other parenteral route, as an oral or nasal spray or via inhalation, The compounds may be administered in the form of pharmaceutical preparations comprising prodrug or active compound either as a free compound or, for example, a pharmaceutically acceptable non-toxic organic or inorganic acid or base addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses. Typically, therefore, the pharmaceutical compounds of the invention may be administered orally or parenterally ("parenterally" as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion) to a host to obtain an protease-inhibitory effect. In the case of larger animals, such as humans, the compounds may be administered alone or as compositions in combination with pharmaceutically acceptable diluents, excipients or carriers.

Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

In the treatment, prevention, control, amelioration, or reduction of risk of conditions which require inhibition of DPPIV enzyme activity, an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. Preferably, the dosage level will be about 0.1 to about 250 mg/kg per day; more preferably about 0.5 to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to 250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about OA to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions are preferably provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0, 800.0, 900.0 and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. The dosage regimen may be adjusted to provide the optimal therapeutic response.

According to a further aspect of the invention there is thus provided a pharmaceutical composition including a compound of the invention, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

Pharmaceutical compositions of this invention for parenteral injection suitably comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol or phenol sorbic acid. It may also be desirable to include isotonic agents such as sugars or sodium chloride, for example. Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents (for example aluminum monostearate and gelatin) which delay absorption.

hi some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are suitably made by forming microencapsule matrices of the drug in biodegradable polymers, for example polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations may also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable media just prior to use.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is typically mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or one or more: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- fϊlled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycol, for example.

Suitably, oral formulations contain a dissolution aid. The dissolution aid is not limited as to its identity so long as it is pharmaceutically acceptable. Examples include nonionic surface active agents, such as sucrose fatty acid esters, glycerol fatty acid esters, sorbitan fatty acid esters (e.g. sorbitan trioleate), polyethylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene alkyl ethers, methoxypolyoxyethylene alkyl ethers, polyoxyethylene alkylphenyl ethers, polyethylene glycol fatty acid esters, polyoxyethylene alkylamines, polyoxyethylene alkyl thioethers, polyoxyethylene polyoxypropylene copolymers, polyoxyethylene glycerol fatty acid esters, pentaerythritol fatty acid esters, propylene glycol monofatty acid esters, polyoxyethylene propylene glycol monofatty acid esters, polyoxyethylene sorbitol fatty acid esters, fatty acid alkylolamides, and alkylamine oxides; bile acid and salts thereof (e.g. chenodeoxycholic acid, cholic acid, deoxycholic acid, dehydrocholic acid and salts thereof, and glycine or taurine conjugate thereof); ionic surface active agents, such as sodium laurylsulfate, fatty acid soaps, alkylsulfonates, alkylphosphates, ether phosphates, fatty acid salts of basic amino acids; triethanolamine soap, and alkyl quaternary ammonium salts; and amphoteric surface active agents, such as betaines and aminocarboxylic acid salts.

The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may also be of a composition such that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, and/or in delayed fashion. Examples of embedding compositions include polymeric substances and waxes.

The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.

The active compounds may be in finely divided form, for example it may be micronised.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as water or other solvents, solubilizing agents and emulsifϊers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof. Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolisable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilisers, preservatives, excipients and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p 33 et seq.

Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

Advantageously, the compounds of the invention may be orally active, have rapid onset of activity and low toxicity. The compounds of the invention may have the advantage that they are more efficacious, less toxic, longer acting, have a broader range of activity, more potent, produce fewer side effects, more easily absorbed than, or have other useful pharmacological properties over, compounds known in the prior art.

Compounds of the invention may be useful in the therapy of a variety of diseases and conditions. In particular, compounds of the invention may be useful in the treatment or prevention of diseases or disorders which can be prevented, alleviated or treated by modulation of DPPIV activity (referred to herein as DPPIV mediated diseases or disorders). Such diseases include but are not limited to Type II diabetes and related disorders, arthritis, obesity and osteoporosis. Diseases, disorders and conditions related to Type II diabetes include hyperglycmia, impaired glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, reduced HDL levels, excessive HDL levels, atherosclerosis and its sequelae, vascular restinosis, irritable bowel syndrome, inflammatory bowel disease including Crohn's disease and ulcerative colitis, other inflammatory conditions, pancreatitis, neurodegenerative disease, depression, retinopathy, nephropathy, neuropathy, retinopathy, hypertension, Syndrome X, ovarian hyperandrogenism (polycystic ovarian syndrome), and other disorders where insulin resistance is a component. Other conditions or diseases that may be treated and/or prevented by the compounds of the invention include growth hormone deficiency, neutropenia, intestinal injury, autoimmune diseases for example, rheumatoid arthritis, multiple sclerosis, Graves' disease and Hashimoto's thyroiditis, inflammatory disorders such as asthma, HIV infection or AIDS, hematopoiesis, neuronal disorders, cancer including tumour metastasis (for example, T cell lymphoma, T cell acute lymphoblastic leukaemia, thyroid carcinomas, basal cell carcinomas and breast carcinomas), benign prostatic hypertrophy and gingivitis. The compounds of the invention may also be useful in altering sperm motility for example improving sperm motility or reducing sperm motility the latter rendering the compounds of the invention useful as a male contraceptive.

Thus a further aspect of the invention provides a method of treating or preventing a DPPIV-mediated disease, or disorder as described herein, in a subject which method comprises administering to said subject a compound or composition according to the invention. Preferably the subject is human.

The extent of protection includes counterfeit or fraudulent products which contain or purport to contain a compound of the invention irrespective of whether they do in fact contain such a compound and irrespective of whether any such compound is contained in a therapeutically effective amount.

Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith.

Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

EXAMPLES Synthesis of Compounds l-(lH-mdazol-3-yl)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- a]pyrazin-7(8H)-yl]butan-2-amme (42)

BoC₂O NBS, BzOOH

Preparation of 37 To a solution of 2-fluoroacetophenone (15.32 g, 0.11 mol) in ethylene glycol (50ml) was added hydrazine hydrate (5.65ml, O.l lόmol). The reaction mixture was stirred at room temperature for 2h then heated at 165 ⁰C over the weekend. Upon cooling the reaction mixture was poured into dichloromethane (100ml), washed twice with water, dried over MgSO₄ and evaporated to give a yellow solid. This was recrystallised from dichloromethane/hexane to give indole 37 (8.3 g, 57%) as a yellow solid.

Preparation of 38

A solution of indazole 37 (4.8g, 36.3mmoi), triethylamine (5.57ml, 40.0mmol) and 4- dimethylaminopyridine (886mg, 7.26mmol) in acetonitrile (50ml) was cooled to 0 ⁰C before the dropwise addition of di-tert-butyl dicarbonate (9.5g, 43.6mmol) in acetonitrile (30ml). The reaction mixture stirred for 30min then evaporated. The residue was partitioned between dichloromethane and water and acidified with IM HCl_(aq). The organic phase was washed with brine, dried over MgSO₄ and evaporated. The residue was purified on silica, eluting with 10% ethyl acetate/hexanes to give 38 (7.57 g, 90%) as a pale yellow oil.

Preparation of 39

A mixture of indazole 38 (7.53g , 32.42mmol), N-bromosuccinimide (6.34g, 35.66mmol) and benzoyl peroxide (785mg, 3.24mmol) in carbon tetrachloride (150 ml) was heated at reflux temperature for 3h. The reaction mixture was filtered, evaporated and the residue purified on silica, eluting with 10% ethyl acetate/hexanes to give 39 (6.55 g, 65%) as a white solid.

Preparation of 9

To a solution of 3-nitropropionic acid (1.Og, 8.4mmol) and triazole base 1 (2.4g,

10.5mmol) in acetonitrile (2OmL) at 0⁰C was added N-methylmorpholine (0.92mL, 8.4mmol), followed by l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.42g, 12.6mmol) and the reaction mixture stirred for Ih. The reaction mixture was allowed to self warm to room temperature and stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with water, sat. NaHCO_3(aq), and brine. The organic phase was dried over MgSO₄, evaporated and the residue triturated with diethyl ether to give amide 9 (2.1g, 85%) as a white solid.

Preparation of 40

A mixture of indazole 39 (6.55 g , 21.05 mmol) and trimethylamine solution (25% in water, 100 ml) was heated at reflux temperature for 30min. The reaction mixture was evaporated then co-evaporated with methanol. The residue was triturated from a mixture of ethyl acetate (45ml), hexane (5ml) and methanol (ImI). The solid was filtered, stirred in hexane and filtered again to give 40 (5.0 g, 88%) as a cream solid.

Preparation of 41 To a solution of amide 9 (l.Og, 3.4mmol) in dimethylformamide (5OmL) at 0°C was added sodium hydride (60% in mineral oil, 0.14g, 3.4mmol) and the reaction mixture stirred for 5min. The reaction mixture was allowed to self warm to room temperature and stirred for lOmin. To this was then added ammonium salt 40 (0.92g, 3.4mmol) and the reaction mixture stirred for 30min. The reaction mixture was diluted with ethyl acetate and washed with sat. NH_4(aq), water and brine. The organic phase was dried over MgSO₄, evaporated and purified on silica, eluting with ethyl acetate to give nitroindazole 41 (0.17g, 12%) as a yellow oil.

Preparation of 42

A mixture of nitroindazole 41 (0.17g, 1.3mmol), ammonium formate (0.2g) and 5% palladium on carbon (0.2g) in methanol (25mL) was heated at reflux temperature for 5h. The reaction mixture was filtered through celite, evaporated and purified on silica, eluting with 7% (16% NH₃/methanol)/dichloromethane to give indazole 42 (0.09g, 57%) as a cream solid, m/z (relative intensity) 394.23 [M+H]⁺

l-(7-fluoro-lH-indazoI-3-yI)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro[l,2,4]triazoIo[4,3-a]pyrazm~7(8H)-yI]butan-2-amine (53)

N '2₅H".4 BoC₂O NBS, BzOOH

This was prepared by the above route in a similar way to indazole 42. 7-Fluoroindazole 53 was obtained as a white foam (411.13 [M+H]⁺). l-(6-fluoro-lH-indazol-3-yI)-4-oxo-4-[3-(trifluoromethyI)-5,6- dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yI]butan-2-amine (60)

NBS, BzOOH

This was prepared by the above route in a similar way to indazole 42. 6-Fluoroindazole 60 was obtained as a white foam (411.13 [M+H]⁺).

l-(6,7-difluoro-lH-indazol-3-yl)-4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro[l,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]butan-2-amine (68)

Preparation of 62

To a solution of acid 61 (4.8g, 14.8mmol) in tetrahydrofuran (10OmL) at O⁰C was added N-methylmorpholine (1.8mL, 16.3mmol) and isobutyl chloroformate (2.ImL, 16.3mmol). After 30min a solution Of NaBH₄ (1.6g, 44.5mmol) in methanol/ice water (1 :1, 1OmL) was added dropwise over 5min. The reaction mixture was stirred for lOmin, diluted with saturated NaHCO₃(_aq) and extracted with ethyl acetate. The organic phase was dried over MgSO₄ and evaporated. The residue was dissolved in dichloromethane (15OmL) and PPh₃ (4.7g, 17.8mmol), iodine (4.5g, 17.8mmol) and imidazole (1.3g, 19.3mmol) added. The reaction mixture was stirred for 2h and then passed through a plug of silica, eluting with dichloromethane. The product-containing fractions were combined, washed with aqueous sodium thiosulfate, dried over MgSO₄ and evaporated to give iodide 62 (5.2g, 84%) as a yellow solid.

Preparation of 63

To a suspension of zinc (1.9g, 28.6mmol) in toluene (3.5mL) was added 1,2- dibromoethane (0.12mL, 1.4mmol) and the mixture stirred vigorously at 65⁰C for 20min. The mixture was cooled to room temperature, chlorotrimethylsilane (0.036mL, 0.3mmol) added and stirred for 30min. In a second flask a mixture of LiCl (0.4Og, 9.5mmol) and CuCN (0.43g, 4.8mmol) in tetrahydrofuran (5mL) was stirred for 15min. To the zinc reaction was added a solution of iodide 62 (2.Og, 4.8mmol) in toluene/dimethylacetamide (7:2, 4.5mL) and the mixture stirred for lOmin, then allowed to settle. The zinc supernatant was transferred to a third flask, cooled to -10°C and the LiCl/CuCN mixture added. The reaction mixture was stirred for 1 Omin at O⁰C and then cooled to -2O⁰C and 2,3,4-trifluorobenzoyl chloride (0.73mL, 5.7mmol) was added. The reaction mixture was stirred at O⁰C for 30min and then poured into ethyl acetate/water. The organic phase was separated, dried over MgSO₄ and evaporated. The residue was purified on silica, eluting with 3:1 hexane/ethyl acetate to give ketone 63 (1.Og₅ 46%) as a yellow solid.

Preparation of 64

To a stirred solution of ketone 63 (1.Og, 2.2mmol) in 1,4-dioxane (4OmL) was added 10% NaOH(aq) (1OmL). The reaction mixture stirred for 2h, diluted with IN HCl_(aq) and extracted with ethyl acetate. The organic phase was dried over MgSO₄ and evaporated to give acid 64 (0.8g, 100%).

Preparation of 65 To a stirred mixture of acid 64 (0.8Og, 2.2mmol), N-methylmorpholine (0.6ImL, 5.5mmol), triazole base Ia (0.53g, 2.3mmol) in acetonitrile (2OmL) was added l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.45g, 2.3mmol) and the reaction mixture was stirred for 2h. The reaction mixture was diluted with ethyl acetate and washed with IN HCl_(aq). The organic phase was dried over MgSO₄ and evaporated. The residue was purified on silica, eluting with hexane/ethyl acetate to give amide 65 (0.9 Ig, 77%) as a pale yellow oil.

Preparation of 66

A mixture of 65 (0.9 Ig, lJmmoI), hydrazine monohydrate (1OmL) and ethylene glycol (1OmL) was heated at 100⁰C for 2h. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO₄ and evaporated. The residue was purified on silica, eluting with 3:1 hexane/ethyl acetate to give indazole 66 (0.34g, 38%). Preparation of 67

A mixture of indazole 66 (0.34g, 0.6mmol) and trifluoroacetic acid (1OmL) was stirred for 45min. The reaction mixture was diluted with dichloromethane and then made basic with sat. NaHCθ₃(aq). The organic phase was separated and the aqueous phase extracted with ethyl acetate. The organic phases were dried over MgSO₄ and evaporated. The residue was purified on silica, eluting with 10% (16%NH₃/methanol)/dichloromethane to give amine 67 (0.13g, 49%) as an off white solid, m/z (relative intensity) 429.99 [M+H]⁺. (98.3% e.e).

Preparation of 68

A mixture of amine 67 (0.09Og, 0.21mmol) in water (0.2mL) and industrial methylated spirits (0.5mL) was heated to 50°C and H₃PO₄ (14μL, 0.21mmol) added. The mixture was stirred for Ih and evaporated. The residue was triturated with refluxing diethyl ether and filtered to give salt 68 (105mg, 95%) as a white solid.

4-[3-amino-4-(6,7-difluoro-ljH^r-indazol-3-yl)butanoyl]-3-(2,2,2-trifluoroethyl)-l,4- diazepan-2-one (82)

The synthesis of 3-(2,2,2-trifluoroethyl)-l,4-diazepan-2-one (83) is described by Biftu, T. et al., Bioorg. Med. Chem. Lett. (2006).

Preparation of 69 A mixture of 2,3,4-trifluoroacetophenone (6.8g, 39.1mmol), hydrazine monohydrate (2mL) and ethylene glycol (2OmL) was stirred at room temperature for 2h and then heated at reflux temperature overnight. The reaction was cooled, diluted with ethyl acetate, washed with water, dried over MgSO₄ and evaporated to gave indazole 69 (6.4g, 97%) as a yellow solid.

Preparation of 70

To a solution of indazole 69 (6.16g, 36.7mmol) in acetonitrile (15OmL) at 0⁰C was added sodium hydride (60% in mineral oil, 1.6 Ig, 40.3mmol) and the reaction mixture stirred for 30min. Boc₂O (8.4Og, 38.5mmol) was then added and the reaction mixture stirred a further 30min. The reaction mixture was quenched with methanol, diluted with ethyl acetate, washed with brine, dried over MgSO₄ and evaporated. The residue was purified on silica, eluting with 4:1 hexane/ethyl acetate to give Boc protected indazole 70 (5.45g, 55%) as a yellow solid.

Preparation of 71 A mixture of Boc protected indazole 70 (5.45g, 20.3mmol), N-bromosuccinimide (3.98g, 22.36mmol) and benzoyl peroxide (0.49g, 2.0mmol) in CCl₄ (10OmL) was heated at reflux temperature for 6h. The reaction mixture was cooled, filtered and evaporated. The residue was purified on silica, eluting with 6:1 hexane/ethyl acetate to give bromide 71 (4.86g, 69%) as a white solid.

Preparation of 72

To a solution of bromide 71 (4.86g, 14.0mmol) in ethanol (50OmL) was added a solution of KCN (1.0Og, 15.4mmol) in water (10OmL). The reaction mixture was heated at 50°C for 8h, cooled and diluted with brine. The mixture was extracted with ethyl acetate, dried over MgSO₄ and evaporated to give nitrile 72 (2.7g, 100%) was a yellow solid.

Preparation of 73

A solution of nitrile 72 (2.7g, 14.0mmol) in methanol (5OmL) was added to a mixture of acetyl chloride (HOmL) in methanol (66OmL) and heated at 50°C for 3d. The reaction mixture was concentrated to one third volume, diluted with brine and extracted with ethyl acetate. The organic phase was dried over MgSO₄, evaporated and the residue purified on silica, eluting with 2:1 hexane/ethyl acetate to give ester 73 (1.6Og, 50%) as a yellow solid.

Preparation of 74

To a solution of ester 73 (1.95g, 8.63mmol) in dimethylformamide (5OmL) at 0°C was added sodium hydride (60% in mineral oil, 0.36g, 9.06mmol) and stirred for 15min. SEM-Cl (1.6OmL, 9.06mmol) was then added and the reaction mixture stirred for lOmin at 0⁰C, then warmed to room temperature. After 4h the reaction mixture was quenched with IM HCl_(aq₎ and extracted with ethyl acetate. The organic phase was dried over MgSO₄, evaporated and the residue purified on silica, eluting with 4:1 hexane/ethyl acetate to give SEM protected indazole 74 (0.57g, 19%) and the N-2 isomer (0.55g, 18%). Preparation of 75

To a solution of SEM protected indazole 74 (0.57g, l.όmmol) in methanol (4OmL) was added 10% NaOH_(aq) (15ml) and the mixture heated at 50°C for 2.5h. The reaction mixture was cooled, quenched with IM HCl_(aq) and diluted with brine and ethyl acetate. The organic phase was separated, dried over MgSO₄ and evaporated to give acid 75 (0.55g, 100%) as an orange oil.

Preparation of 76 To a suspension of ethyl potassium malonate (287mg, 1.69mmol) in tetrahydrofuran (15mL) was added MgCl₂ (160mg, 1.69mol) and the reaction mixture heated at 40°C for Ih. In a second flask carbonyldiimidazole (273mg, 1.69mmol) was added to a solution of acid 75 (550mg, l.όlmmol) in tetrahydrofuran (15mL) and heated at 40°C for Ih. The two reactions were combined and heated at reflux temperature for 4h. The reaction mixture was cooled, diluted with IM HCl_(aq) and extracted with ethyl acetate. The organic phase was dried over MgSO₄, evaporated and the residue purified on silica, eluting with 4:1 hexane/ethyl acetate to give β-keto aster 76 (410mg, 62%) as a yellow oil.

Preparation of 77 A mixture of β-keto aster 76 (485mg, 1.18mmol), ammonium acetate (453mg, 5.88mmol) and toluene (25ml) was heated at reflux temperature for 5h, cooled to room temperature and stirred for 3d. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO₄ and evaporated to give enamine 77 (445mg, 92%) as an orange oil.

Preparation of 78

To a solution of enamine 77 (445mg, l.Oδmmol) in methanol (2OmL) was added NaCNBH₃ (204mg, 3.24mmol), followed by acetyl chloride (0.154mL, 2.16mmol) over 5min. The reaction . mixture was stirred for 30min, diluted with sat. NaHC0_3(aq) and extracted with ethyl acetate. The organic phase was dried over MgSO₄ and evaporated to give β-amino aster 78 (278mg, 62%) Preparation of 79

A mixture of β-amino aster 78 (278mg, 0.67mmol), Boc₂O (146mg, 0.67mmol) and dichloromethane (2OmL) was stirred for 24h. The reaction mixture was evaporated to give crude Boc-protected amine 79 which was used without purification in the next step.

Preparation of 80

To a solution of crude Boc-protected amine 79 (344mg, 0.67mmol) in methanol (3OmL) was added 10% NaOH(_aq) (1OmL) and the reaction mixture heated at 45⁰C for 90min. The reaction mixture was cooled, quenched with IM HCl_(aq), diluted with brine and extracted with ethyl acetate. The organic phase was separated, dried over MgSO₄ and evaporated to give 80 (300mg, 92% from 78) as an orange foam.

Preparation of 81

To a solution of acid 80 (0.2g, 0.41mmol) in dichloromethane (5mL) was added triethylamine (64 μl, 0.45mmol) followed by 2-chloro-l-methylpyridinium iodide (105 mg, 0.41mmoi). This was stirred at room temperature for Ih, and then the amine 83 (80mg, 0.41mmol) was added. The reaction mixture was then stirred at room temperature overnight. The reaction mixture was evaporated and the residue purified on silica, eluting with 2:1 ethyl acetate/hexane to give amide 81 (90 mg, 33%) as an off white solid.

Preparation of 82

A mixture of amide 81 (90mg, 0.14mmol) and trifluoroacetic acid (ImI) was stirred for 30min at room temperature. The reaction mixture was diluted with dichloromethane and washed with 2M NaOH_(aq). The aqueous phase was extracted with ethyl acetate and the organic phases were dried over MgSO₄ and evaporated. This residue was purified on silica, eluting with 90:10:1 dichloromethane/methanol/(16% NH₃/methanol) to give indazole 82 as a pair of diastereoisomers. These diastereoisomers were then separated by HPLC (4:1:0.1 water/acetonitrile/TFA) to give the two diastereoisomers, 82a (4mg, 6%), and 82b (5mg, 8%).

l-(4J-difluoro-lg-indazol-3-vπ-4-oxo-4-[3-(trifluoroinethylV5,6- dihvdroFl,2,41tπazoIof4,3-αlpyrazin-7(8/r)-vnbutan-2-amine (96)

This was prepared by the above route in a similar way to indazole 82. 4,7- Difluoroindazole 96 was obtained as a colourless foam (430.02 [M+H]⁺).

l-(4,6-diflttoro-l_JH^r-indazol-3-vIV4-oxo-4-[3-(trifluoromethylV5,6- dihydrofl,2,41triazolo[4,3-glpyrazin-7(8jg)-yllbutaii-2-amine (110)

This was prepared by the above route in a similar way to indazole 82. 4,6- Difluoroindazole 110 was obtained as a colourless foam (430.02 [M+H]⁺).

Determination of DPP-IV activity

Experimental

DPP-IV inhibitory activity of compounds was tested by employing an enzyme assay that measures the ability of test compounds to inhibit the activity of a human recombinant DPP-IV expressed in insect Sf9 cells (available from MDS Pharma Services). A test compound was pre-incubated with 0.02 μg/ml of the DPP-IV enzyme in Tris-HCl buffer pH 8.0 for 15 mins at 15⁰C. The reaction was initiated by addition of 20 μM Ala-Pro- AFC (where AFC = 7-amino-trifluoromethyl-coumarin) for another 30 minute incubation period. Determination of the amount of AFC formed was read spectrofluorimetrically with excitation at 400nm and emission at 510nm. Percentage inhibitions are shown in Table 1

Table 1

Claims

1. A compound of Formula I:

(I) wherein

R¹, R², R³ and R⁴ are each independently selected from hydrogen, R¹², hydrocarbyl optionally substituted with R¹², and -(CH₂)k-heterocyclyl optionally substituted with R¹², wherein each R¹² is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, =NR¹³, -OR¹³, -C(O)R¹³, -C(O)OR¹³, -OC(O)R¹³, -S(O)iR¹³, -N(R¹³)R¹⁴, - C(O)N(R¹³)R¹⁴, -SO₂N(R¹³)R¹⁴ and R¹⁵;

wherein R¹³ and R¹⁴ are each independently selected from hydrogen or R¹⁵;

k is O, 1, 2, 3, 4, 5 or 6;

1 is 0, 1 or 2; m is 0, 1, 2, 3, 4, 5 or 6; or one or more R¹ and R², R² and R³, R³ and R⁴ taken together with the atoms to which they are attached form a carbocycle or a heterocycle, optionally substituted with one or more R¹²;

R⁵ is independently selected from hydrogen and hydrocarbyl and each R⁵ is optionally and independently substituted with one or more of halogen, cyano, amino, hydroxyl, and hydrocarbyl wherein each optional hydrocarbyl substituent is optionally and independently substituted with one or more of halogen, hydroxyl and hydrocarbyl optionally and independently substituted with one or more halogen;

R⁷ and R⁸ are each independently selected from hydrogen or R¹²; or R⁷ and R⁸ taken together with the atoms to which they are attached form a carbocycle or a heterocycle, optionally substituted with one or more R¹²; or R⁷ or R⁸ together with R⁹ or R¹⁰ form a carbocycle or a heterocycle optionally substituted with one or more R¹²;

Z is selected from the group consisting of hydrocarbyl optionally substituted with R¹², and -(CH₂)_k-heterocyclyl optionally substituted with R¹², wherein each R¹² is independently selected from halogen, trifluoromethyl, cyano, nitro, oxo, =NR ³, -OR ³, -C(O)R , - C(O)OR¹³, -OC(O)R¹³, -S(O)iR¹³, -N(R¹³)R¹⁴, -C(O)N(R¹³)R¹⁴, -SO₂N(R¹³)R¹⁴ and R¹⁵;

or a salt thereof.

2. A compound as claimed in claim 1 wherein the compound is of Foπnula Ib

(Ib)

r

R> 9, R τ.1ⁱ0^υ and Z are as defined in claim 1.

3. A compound as claimed in claim 1 or 2 wherein RWd R² are each independently selected from hydrogen, halogen, cyano, OH, C_1-6 alkyl and -0(C_1-6 alkyl) wherein C_1-6 alkyl and -0(C_1-6 alkyl) are each optionally and independently substituted by one or more halogen.

4. A compound as claimed in claim 3 wherein R¹ and R² are each independently selected from hydrogen and F.

5. A compound as claimed in claim 4 wherein R is F and R is hydrogen.

6. A compound as claimed in claim 4 wherein R¹ is hydrogen and R² is F.

7. A compound as claimed in claim 4 wherein R is F and R is F.

8. A compound as claimed in any one preceding claim wherein R³ and R⁴ are each independently selected from hydrogen, halogen, cyano, OH, C_1-6 alkyl and -0(C_1-6 alkyl) wherein C_1-6 alkyl and -0(C_1-6 alkyl) are each optionally and independently substituted by one or more halogen.

9. A compound as claimed in claim 8 wherein R³ and R⁴ are each independently hydrogen.

10. A compound as claimed in any one preceding claim wherein R⁵ is independently selected from hydrogen, C_1-6 alkyl and carbocyclyl optionally and independently substituted with one or more of halogen, hydroxyl, C_1-6 alkyl and OC_1-6 alkyl or carbocyclyl; wherein each optional C_1-6 alkyl and OC_1-6 alkyl substituent is optionally and independently substituted with one or more halogen; and wherein each optional carbocyclyl substituent is optionally and independently substituted with one or more halogen, hydroxyl, C_1-6 alkyl optionally substituted with one or more halogen, or OC_1-6 alkyl optionally substituted with one or more halogen.

11. A compound as claimed in claim 10 wherein R⁵ is independently selected from hydrogen, C_1-6 alkyl, C3-6 cycloalkyl and phenyl optionally and independently substituted with one or more of halogen, hydroxyl, C_1-6 alkyl and OC_1-6 alkyl or phenyl; wherein each optional C_1-6 alkyl and OC_1-6 alkyl substituent is optionally and independently substituted with one or more halogen; and wherein each optional phenyl substituent is optionally and independently substituted with one or more halogen, hydroxyl, C_1-6 alkyl optionally substituted with one or more halogen, or OC_1-6 alkyl optionally substituted with one or more halogen.

12. A compound as claimed in claim 11 wherein R⁵ is hydrogen or C_1-6 alkyl.

13. A compound as claimed in claim 12 wherein R⁵ is hydrogen.

14. A compound as claimed in any one preceding claim wherein R⁷ and R⁸ are each independently selected from hydrogen, hydroxyl, halogen and C_1-6 alkyl wherein C_1-6 alkyl is optionally and independently substituted with one or more halogen; or R⁷ and R⁸ taken together with the atoms to which they are attached form C_3-6 cycloalkyl optionally and independently substituted with one or more halogen.

15. A compound as claimed in claim 14 wherein R and R are each independently hydrogen.

16. A compound as claimed in any one preceding claim wherein R⁹ and R¹⁰ are each independently selected from hydrogen, hydroxyl, halogen and Ci_-6 alkyl wherein Ci_-6 alkyl is optionally and independently substituted with one or more halogen; or R⁹ and R¹⁰ taken together with the atoms to which they are attached form C_3-6 cycloalkyl optionally and independently substituted with one or more halogen.

17. A compound as claimed in claim 16 wherein R⁹ and R¹⁰ are each independently hydrogen.

18. A compound as claimed in any one preceding claim wherein Z is a heterocyclic group.

19. A compound as claimed in claim 18 wherein Z is a nitrogen-containing heterocyclic group.

20. A compound as claimed in claim 19 wherein Z is a group of Formula (II)

(II) wherein

R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are each independently selected from hydrogen, R¹², hydrocarbyl optionally and independently substituted with R¹², and -(CH₂)_k-heterocyclyl optionally substituted with R¹²; W and Y are independently selected from N, C, O and S; and

R²³ and R²⁴, which may be absent, are each independently selected from hydrogen, R¹², hydrocarbyl optionally and independently substituted with R¹², and -(CH₂)rheterocyclyl optionally substituted with R ; or R²³ and R ⁴ taken together with the atoms to which they are attached form a carbocycle or a heterocycle, optionally substituted with one or more R¹².

21. A compound as claimed in claim 20 wherein R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are each independently selected from hydrogen, halogen, hydroxyl, cyano, CO₂H, CONH₂,

C_1-6 alkyl and carbocyclyl wherein the optional C_1-6 alkyl and carbocyclyl substituents are optionally and independently substituted with one or more of halogen, hydroxyl, C_1-6 alkyl and C_1-6 alkoxy wherein the latter alkyl and alkoxy substituents are optionally substituted with one or more halogen.

22. A compound as claimed in claim 21 wherein R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are each independently selected from hydrogen, CO₂H, CONH₂ and methyl.

23. A compound as claimed in claim 22 wherein R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²² are each independently hydrogen.

24. A compound as claimed in any of claims 20 to 23 wherein W and Y are independently selected from C and N.

25. A compound as claimed in claim 24 wherein W is C and Y is N.

26. A compound as claimed in any of claims 20 to 25 wherein R²³ and R²⁴ are independently selected from hydrogen, trifluoromethyl, cyano, C_1-6 alkyl, C_1-6 alkoxy, and carbocyclyl wherein the optional C_1-6 alkyl, C_1-6 alkoxy, and carbocyclyl substituents are optionally and independently substituted with one or more of halogen, hydroxyl, C_1-6 alkyl and C_1-6 alkoxy wherein the latter alkyl and alkoxy substiuents are optionally substituted with one or more halogen.

27. A compound as claimed in any one of claims 20 to 26 wherein W is C, Y is N, R²³ is trifluoromethyl and R²⁴ is absent.

28. A compound as claimed in any one preceding claim wherein the compound is selected from the following

29. A compound as claimed in any one preceding claim for use as a pharmaceutical.

30. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 28 in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

31. A method of treating or preventing a DPPIV-mediated disease or disorder in a subject which method comprises administering to said subject a compound as claimed in any one of claims 1 to 28 or a composition as claimed in claim 30.

32. A method as claimed in claim 31 wherein the DPPIV-mediated disease or disorder is Type II diabetes or a related disease or disorder.

33. A method as claimed in claim 32 wherein the DPPIV-mediated disease or disorder is selected from the group consisting of arthritis, obesity and osteoporosis.

34. A method as claimed in claim 32 wherein the Type II diabetes related disease or disorder is selected from the group consisting of hyperglycemia, impaired glucose tolerance, insulin resistance, obesity, lipid disorders, dyslipidemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, reduced HDL levels, excessive HDL levels, atherosclerosis and its sequelae, vascular restinosis, irritable bowel syndrome, inflammatory bowel disease including Crohn's disease and ulcerative colitis, inflammatory conditions, pancreatitis, neurodegenerative disease, depression, retinopathy, nephropathy, neuropathy, retinopathy, hypertension, Syndrome X, ovarian hyperandrogenism (polycystic ovarian syndrome), and other disorders where insulin resistance is a component.

35. Use of a compound as claimed in any one of claims 1 to 28 in the manufacture of a medicament for the treatment or prevention of a DPPIV mediated disease or disorder.