WO2011154677A1

WO2011154677A1 - Substituted n-[1-cyano-2-(phenyl)ethyl] 1-aminocycloalk-1-ylcarboxamide compounds - 760

Info

Publication number: WO2011154677A1
Application number: PCT/GB2010/050963
Authority: WO
Inventors: Rhonan Ford; Elizabeth Kinchin; Andrew Mather; Antonio Mete; Ian Millichip; Andrew Geoffrey Stanier
Original assignee: Astrazeneca Ab; Astrazeneca Uk Limited
Priority date: 2010-06-09
Filing date: 2010-06-09
Publication date: 2011-12-15

Abstract

The present invention provides compounds of formula (I) in which, n, R¹, R² and Q are as defined in the specification, a process for their preparation, pharmaceutical compositions containing them and their use in therapy.

Description

SUBSTITUTED N-[l-CYANO-2-(THENYL)ETHYLl 1-AMINOCYCLOALK-l- YLCARBOXAMIDE COMPOUNDS - 760

The present invention relates to nitrile compounds, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.

Dipeptidyl peptidase I (DPPI; EC 3.4.14.1), also known as cathepsin C, is a lysosomal cysteine protease belonging to the papain family having a molecular weight of 200 kDa. DPPI was first discovered by Gutman and Fruton in 1948 (J Biol Chem, 174, 851-858); however, the cDNA of the human enzyme was first described in 1995 (Paris et al. 1995, FEBS Lett, 369, 326-330). DPPI is the only member of the papain family that is functional as a tetramer, consisting of four identical subunits. Each subunit is composed of an N-terminal fragment, a heavy chain and a light chain (Dolenc et al. 1995, J Biol Chem, 270, 21626- 21631).

DPPI is constitutively expressed in many tissues with highest levels in lung, kidney, liver and spleen. DPPI catalyses the removal of dipeptides from the N-terminal end of polypeptide substrates with broad specificity. Recent data suggest that besides being an important enzyme in lysosomal protein degradation, DPPI also functions as a key enzyme in the activation of granule serine proteases in cytotoxic T lymphocytes and natural killer cells (granzymes A and B), mast cells (chymase and tryptase) and neutrophils (cathepsin G and elastase).

Mast cells are found in many tissues but are present in greater numbers along the epithelial linings of the body, such as the skin, respiratory tract and gastrointestinal tract. In humans, two types of mast cells have been identified. The T-type, which expresses only tryptase, and the MC-type, which expresses both tryptase and chymase. In humans, the T- type mast cells are located primarily in alveolar tissue and intestinal mucosa while the TC- type cells predominate in skin and conjunctiva. Tryptase and chymase appear to be important mediators of allergic diseases, being involved in processes of inflammation,

bronchoconstriction and mucus secretion.

Neutrophils play a critical role in host defence against invading pathogens.

Neutrophils are produced in the bone marrow and are fully mature when released into the circulation to take up their role as the first line of cellular defence. Pro -inflammatory mediators and chemotactic attractants activate neutrophils and draw them to the site of infection, where they act to engulf bacteria by phagocytosis, assaulting them with an arsenal of anti-bacterial compounds that use both oxidative and non-oxidative methods of attack. The powerful serine protease, neutrophil elastase, is one of those anti-bacterial compounds that are clearly involved in destroying bacteria. Neutrophil elastase is released into the phagolysome surrounding the microorganism, which it proceeds to destroy. Neutrophil elastase is able to attack the outer membrane protein, OmpA, in gram-negative bacteria, helping to directly kill the pathogen by degrading its membrane, as well as enabling other anti -bacterial compounds to gain access to the pathogen. In addition, neutrophil elastase may help process other antibacterial compounds, converting them from inactive pro-peptides into their active states, such as for cathelicidin.

Yet neutrophil elastase can also cause problems for its host. It is one of the most destructive enzymes in the body, with the capability of degrading extracellular matrix proteins (including collagens, proteoglycan, fibronectin, platelet receptors, complement receptor, thrombomodulin, lung surfactant and cadherins) and key plasma proteins (including coagulation and complement factors, immunoglobulin, several proteases and protease inhibitors). Under physiological conditions, endogenous protease inhibitors, such as al- antitrypsin, tightly regulate the activity of neutrophil elastase. However, at inflammatory sites, neutrophil elastase is able to evade regulation, and once unregulated it can induce the release of pro-inflammatory cytokines, such as interleukin-6 and interleukin-8, leading to acute lung injury. It can even impair host defence against infection by degrading phagocyte surface receptors and opsonins. Its negative role is illustrated by its involvement in the tissue destruction and inflammation that characterise numerous diseases, including hereditary emphysema, chronic obstructive pulmonary disease, cystic fibrosis, adult respiratory distress syndrome, ischemic-reperfusion injury and rheumatoid arthritis.

There is strong evidence associating tryptase and chymase with a number of mast cell mediated allergic, immunological and inflammatory diseases. The fact that neutrophil elastase, cathepsin G and proteinease 3 also seem to play significant roles in these types of diseases point to DPPI being a valid therapeutic target due to its central role in activating these proteases (Adkison et al. 2002, J Clin Invest, 109, 363-271; Pham et al. 2004, J

Immunol, 173, 7277-7281).

It is known from the International Patent Application WO 2004/110988, that certain nitrile derivatives are inhibitors of DPPI. One of the disclosed compounds is (5)-2-amino-N- ((S)-2-(biphenyl-4-yl)- 1 -cyanoethyl)butanamide. There is no disclosure in this document of a nitrile compound which bears a saturated carbocyclic ring (for example cyclopentyl) between the NH₂ and amide groups. We have now found that such compounds possess potent DPPI activity and/or have other desirable pharmacological activity profiles.

In accordance with the present invention, there is therefore provided a compound of formula (I)

(I) wherein

y represents 0, 1 or 2;

n is 1, 2, 3 or 4;

R¹ is hydroxyl, halogen, Ci_₃alkoxy (optionally substituted with one or more substituents selected from halogen, hydroxy and Ci_₃alkoxy) or Ci_₃alkyl (optionally substituted with one or more substituents independently selected from halogen, hydroxy and Ci_₃alkoxy);

R is selected from hydrogen, halogen, CN, CF₃, Ci_₃alkyl and Ci_₃alkoxy;

Q represents phenyl, a 5- to 10-membered heteroaryl ring system or Q is of the formula

A

wherein X is CH or N, Y is CH or N and B is a 5- or 6-membered heterocyclic ring containing 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen and sulphur; the phenyl , 5- to 10-membered heteroaryl ring system and ring system A being optionally substituted by more or more substituents independently selected from halogen, carboxyl, hydroxyl, oxo, nitro, cyano, mercapto, Ci_₆alkyl group, Ci_₆alkoxy (the alkyl and alkoxy groups being optionally substituted by one or more substituents independently selected from hydroxyl, halogen, Ci_₆alkoxy, C₃-₆cycloalkyl, NR⁶¹S0₂R⁶², S(0)vR⁶³, NR⁶⁵R⁶⁶, phenyl and C-linked morpholinyl), C₃_₆cycloalkyl, C₂_₆alkenyl, trifluoromethyl, Ci_₆alkylcarbonyl, Ci_₆alkylcarbonyloxy, Ci_₆alkoxycarbonyl, -NR⁵³R⁵⁴, -C(0)NR⁵⁵R⁵⁶, NR⁵⁷C(0)R⁵⁸, S0₂NR⁵⁹R⁶⁰, NR⁶¹S0₂R⁶², S(0)_vR⁶³, OS(0₂)R⁶⁴, benzyloxy and Ci_₆alkylpiperazinyl;

R⁵³ and R⁵⁴ each independently represent hydrogen, Ci_₆alkyl or C₃_₆cycloalkyl, or R⁵³ and R⁵⁴ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;

v is 0, 1 or 2;

R⁵⁵ and R⁵⁶ each independently represent hydrogen, Ci_₆alkyl or C₃_₆cycloalkyl, or R⁵⁵ and R⁵⁶ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;

R⁵⁹ and R⁶⁰ each independently represent hydrogen, Ci_₆alkyl or C₃_₆cycloalkyl, or R⁵⁹ and R⁶⁰ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;

each R⁵⁷, R⁵⁸, R⁶¹, R⁶², R⁶³ and R⁶⁴ independently represents a hydrogen atom or a Ci_₆alkyl or C₃_₆cycloalkyl group; provided that R⁶², R⁶³ and R⁶⁴ are not hydrogen;

R⁶⁵ and R⁶⁶ each independently represent hydrogen, Ci_₆alkyl or C₃_₆cycloalkyl, or R⁶⁵ and R⁶⁶ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;

or a pharmaceutically-acceptable salt thereof.

In another aspect of the present invention, there is therefore provided a compound of formula

(I) as hereinabove defined.

Definitions

Unless otherwise stated, halogen is CI, F, Br or I;

Unless otherwise stated, cycloalkyl is a non-aromatic carbocyclic ring containing the requisite number of carbon atoms, optionally containing, where possible, up to 3 double bonds, and optionally substituted with 1 to 3 substituents selected from (Ci-6)alkyl,

(Ci-6)alkoxy, -OH, -CN and halo, and wherein each substituent may be the same or different. Examples of suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentene, cyclopenta-l,3-diene, cyclohexene and cyclohexa-1,4- diene (optionally substituted as stated above).

Examples of suitable heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl or naphthyridinyl, preferably furyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, indolyl, benzothienyl, benzoxazolyl, benzoxazinyl, benzothiazinyl, benzimidazolyl, benzothiazolyl, indazolyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl or naphthyridinyl.

The present invention allows for heteroaryl groups to be optionally substituted by on oxo group. For example in the definition of Q a heteroaryl group such as pyridine could be substituted by an oxo group to form a pyridone. These 'heteroaryl' groups are within the scope of the invention.

Unless otherwise stated alkyl and alkoxy groups containing the requisite number of carbon atoms can be branched or unbranched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy (-OCH₃), ethoxy (-OCH₂CH₃), n-propoxy, i-propoxy, n-butoxy, sec- butoxy and t-butoxy.

A saturated 4- to 7-membered heterocyclic ring may be partially unsaturated but not fully unsaturated. A heterocylic ring will contain at least one ring heteroatom selected from nitrogen, oxygen and sulphur. It is, for example, morpholinyl, piperidinyl, piperazinyl or pyrrolidinyl.

Examples of ring system A include:

wherein X and Y are as hereinabove defined, R' is selected from hydrogen, C₃_₇cycloalkyl and Ci_₆alkyl the alkyl group being optionally substituted by 1 or 2 substituents

independently selected from halogen, Ci_₄alkyoxy, C₃_₇cycloalkyl, amino, alklylamino and dialklylamino;, and the ring system being optionally further substituted as hereinabove defined. In another aspect, the ring system A has no further substituents in addition to R'.

For the avoidance of doubt, it should be understood that the definitions of the heterocyclic rings in formula (I) are not intended to include unstable structures or any O-O, 0-S or S-S bonds and that a substituent, if present, may be attached to any suitable ring atom provided the resulting compound is not unstable.

"Pharmaceutically acceptable salt" means a physiologically or toxicologically tolerable salt and includes, when appropriate, pharmaceutically acceptable base addition salts and pharmaceutically acceptable acid addition salts. For example (i) where a compound of the invention contains one or more acidic groups, for example carboxy groups, pharmaceutically acceptable base addition salts that can be formed include sodium, potassium, calcium, magnesium and ammonium salts, or salts with organic amines, such as, diethylamine, N-methyl-glucamine, diethanolamine or amino acids (e.g. lysine) and the like; (ii) where a compound of the invention contains a basic group, such as an amino group, pharmaceutically acceptable acid addition salts that can be formed include hydrochlorides, hydrobromides, sulfates, phosphates, acetates, citrates, lactates, tartrates, mesylates, tosylates,

benzenesulfonates, maleates, fumarates, xinafoates, p-acetamidobenzoates, succinates, ascorbates, oleates, bisulfates, furoates, propionates, stearates, isethionates and the like.

In one embodiment, pharmaceutically acceptable salts may include salts of

pharmaceutically acceptable organic acids, especially carboxylic and sulfonic acids, including, but not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, butyrate, camphorate, camphorsulfonate, camsylate, citrate, p- chlorobenzenesulfonate, cyclopentate, 2,5-dichlorobesylate, digluconate, edisylate, esylate, fumarate, formate, gluconate, glucoheptanoate, glutamate, glutarate, glycerophosphate, glycolate, heptanoate, hexanoate, hippurate, 2-hydroxyethane sulfonate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate, 2-naphthalenesulfonate, napsylate, nicotinate, orotate, oxalate, pantothenate, pamoate, pamoic, pectinate, 3- phenylpropionate, pivalate, propionate, pivalate, saccharin, salicylate, stearate, succinate, tartrate, trans-cinnamate, trifluoroacetic acid salt, xinafoate, xylate (p-xylene-2-sulfonic acid), undecanoate;

and of inorganic acids such as hydrobromide, hydrochloride, hydroiodide, sulphate, bisulfate, phosphate, nitrate, hemisulfate, thiocyanate, persulfate, phosphoric and sulfonic acids.

Salts which are not pharmaceutically acceptable may still be valuable as intermediates. Hemisalts of acids and bases can also be formed, for example, hemisulfate and hemicalcium salts.

For a review of suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

The compounds of the invention can exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when the solvent is water.

Where compounds of the invention exist in one or more geometrical, optical,

enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and trans-forms, E- and Z-forms, R-, S- and meso-forms, keto-, and enol-forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate such isomers can be prepared by the application of adaptation of known methods (e.g. asymmetric synthesis).

In one aspect the invention relates to compounds of the formula (I) in which the stereochemistry at the carbon adjacent to the NH group and substituted by cyano has the S stereochemistry.

In another aspect the invention relates to a compound of the formula (I) wherein:

y represents 0, 1 or 2;

n is 1, 2, 3 or 4;

R¹ is hydroxyl, halogen, Ci_₃alkoxy (optionally substituted with one or more substituents selected from halogen, hydroxy or Ci_₃alkoxy) or Ci_₃alkyl (optionally substituted with one or more substituents selected from halogen, hydroxy or Ci_₃alkoxy)

R is selected from hydrogen, halogen, CN, CF₃, Ci_₃alkyl or Ci_₃alkoxy; Q represents phenyl or a 5- to 10-membered heteroaryl ring system, the phenyl or 5- to 10-membered heteroaryl ring system being optionally substituted by halogen, carboxyl, hydroxyl, oxo, nitro, cyano, mercapto, Ci_₆alkyl group (itself optionally substituted by hydroxyl, Ci_₆alkoxy, NR⁶⁵R⁶⁶, phenyl or C-linked morpholinyl),

C₃_₆cycloalkyl, C₂-₆alkenyl, trifluoromethyl, Ci_₆alkoxy, Ci_₆alkylcarbonyl,

Ci_₆alkylcarbonyloxy, Ci_₆alkoxycarbonyl, -NR⁵³R⁵⁴, -C(0)NR⁵⁵R⁵⁶, NR⁵⁷C(0)R⁵⁸, S0₂NR⁵⁹R⁶⁰, NR⁶¹S0₂R⁶², S(0)_vR⁶³, OS(0₂)R⁶⁴, benzyloxy and Ci_₆alkylpiperazinyl; R⁵³ and R⁵⁴ each independently represent hydrogen, Ci_₆alkyl or C₃_₆cycloalkyl, or R⁵³ and R⁵⁴ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;

v is 0, 1 or 2;

Each R⁵⁷, R⁵⁸, R⁶¹, R⁶², R⁶³ and R⁶⁴ independently represents a hydrogen atom or a Ci_₆alkyl or C₃_₆cycloalkyl group; R⁶², R⁶³ and R⁶⁴ are not hydrogen;

or a pharmaceutically-acceptable salt thereof.

1 2

Further values of R , R , y, n and Q are as follows. Such values may be used where appropriate with any of the definitions, claims or embodiments defined hereinbefore or hereinafter:

y represents 0, 1 or 2.

y represents 0.

y represents 1.

y represents 0 or 1.

n represents 1 , 2, 3, or 4 . n represents 1.

n represents 2.

n represents 3.

n represents 4.

n represents 2 or 3.

R¹ is Ci_₃alkyl optionally substituted with one or more substituents selected from halogen, hydroxy or Ci_₃alkoxy.

R¹ is Ci_₃alkyl optionally substituted with one or more substituents selected from halogen or hydroxy.

R¹ is Ci_₃alkyl optionally substituted with one or more substituents selected from halogen. R¹ is Ci_₃alkyl optionally substituted with one or more substituents selected from alkoxy. R¹ is Ci_₃alkyl optionally substituted with one or more substituents selected from Ci_₃alkoxy. R is selected from hydrogen, halogen, CN, CF₃, Ci_₃alkyl or Ci_₃alkoxy;

R is hydrogen.

Q represents phenyl or a 5- to 10-membered heteroaryl ring system which is optionally substituted by at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the phenyl or heteroaryl ring system being optionally substituted by at least one substituent selected from halogen, carboxyl, hydroxyl, oxo, nitro, cyano, mercapto, Ci_₆alkyl group (itself optionally substituted by hydroxyl, Ci_₆alkoxy, NR⁶⁵R⁶⁶, phenyl or morpholinyl),

Ci_₆alkylcarbonyloxy, Ci_₆alkoxycarbonyl, -NR⁵³R⁵⁴, -C(0)NR⁵⁵R⁵⁶, NR⁵⁷C(0)R⁵⁸, S0₂NR⁵⁹R⁶⁰, NR⁶¹S0₂R⁶², S(0)_vR⁶³, benzyloxy and Ci_₆alkylpiperazinyl;

v is 0, 1 or 2;

R⁵⁹ and R⁶⁰ each independently represent hydrogen, Ci_₆alkyl or C₃_₆cycloalkyl, or R⁵⁹ and R⁶⁰ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; each R , R , R , R , R and R independently represents a hydrogen atom or a Ci_₆alkyl or C₃_₆cycloalkyl group;

R⁶⁵ and R⁶⁶ each independently represent hydrogen, Ci_₆alkyl or C₃_₆cycloalkyl, or R⁶⁵ and R⁶⁶ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring.

Q represents phenyl optionally substituted by at least one substituent selected from halogen, carboxyl, hydroxyl, oxo, nitro, cyano, mercapto, Ci_₆alkyl, Ci_₆alkoxy (the alkyl and alkoxy groups being optionally substituted by hydroxyl, halogen, NR⁶⁵R⁶⁶, S(0)_vR⁶³ , NR⁶¹S0₂R⁶² , phenyl or morpholinyl), C₃_₆cycloalkyl, C₂_₆alkenyl, trifluoromethyl, Ci_₆alkoxy, Ci_ ₆alkylcarbonyl,

Ci_₆alkylcarbonyloxy, Ci_₆alkoxycarbonyl, -NR⁵³R⁵⁴, -C(0)NR⁵⁵R⁵⁶, NR⁵⁷C(0)R⁵⁸, S0₂NR⁵⁹R⁶⁰, NR⁶¹S0₂R⁶², S(0)_vR⁶³, OS0₂R⁶⁴, benzyloxy and Ci_₆alkylpiperazinyl;

v is 0, 1 or 2;

each R⁵⁷, R⁵⁸, R⁶¹, R⁶², R⁶³ and R⁶⁴ independently represents a hydrogen atom or a Ci_₆alkyl or C₃_₆cycloalkyl group;

Q represents phenyl optionally substituted by at least one substituent selected from halogen, carboxyl, hydroxyl, nitro, cyano, mercapto, Ci_₆alkyl group (itself optionally substituted by hydroxyl, Ci_₆alkoxy, NR⁶⁵R⁶⁶, phenyl or morpholinyl),

C₃_₆cycloalkyl, C₂_₆alkenyl, trifluoromethyl, Ci_₆alkoxy, Ci_₆alkylcarbonyl, Ci_₆alkylcarbonyloxy, Ci_₆alkoxycarbonyl, -NR R , -C(0)NR⁵⁵R , NR^{5 /}C(0)R , S0₂NR⁵⁹R⁶⁰, NR⁶¹S0₂R⁶², S(0)_vR⁶³, benzyloxy and Ci_₆alkylpiperazinyl;

v is 0, 1 or 2;

Q represents a 5- to 10-membered heteroaryl ring system which is optionally substituted by at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the heteroaryl ring system being optionally substituted by at least one substituent selected from halogen, carboxyl, hydroxyl, oxo, nitro, cyano, mercapto, Ci_₆alkyl group (itself optionally substituted by hydroxyl, Ci_₆alkoxy, NR⁶⁵R⁶⁶, phenyl or morpholinyl),

C₃_₆cycloalkyl, C₂_₆alkenyl, trifluoromethyl, Ci_₆alkoxy, Ci_₆alkylcarbonyl,

Ci_₆alkylcarbonyloxy, Ci_₆alkoxycarbonyl, -NR⁵³R⁵⁴, -C(0)NR⁵⁵R⁵⁶, NR⁵⁷C(0)R⁵⁸, S0₂NR⁵⁹R⁶⁰, NR⁶¹S0₂R⁶², S(0)_vR⁶³, OS(0₂)R⁶⁴ and benzyloxy and Ci_₆alkylpiperazinyl; R⁵³ and R⁵⁴ each independently represent hydrogen, Ci_₆alkyl or C₃_₆cycloalkyl, or R⁵³ and R⁵⁴ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;

v is 0, 1 or 2;

R⁵⁵ and R⁵⁶ each independently represent hydrogen, Ci_₆alkyl or C₃_₆cycloalkyl, or R⁵⁵ and R⁵⁶ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R and R each independently represent hydrogen, Ci_₆alkyl or C₃_₆cycloalkyl, or R and R⁶⁰ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;

Q represents a 5- to 6-membered heteroaryl ring system which is optionally substituted by at least one ring heteroatom selected from nitrogen, oxygen and sulphur, the heteroaryl ring system being optionally substituted by at least one substituent selected from halogen, carboxyl, hydroxyl, oxo, nitro, cyano, mercapto, Ci_₆alkyl group (itself optionally substituted by one or more substituents independently selected from hydroxyl, haogen, Ci_₆alkoxy, NR⁶⁵R⁶⁶, phenyl and morpholinyl),

v is 0, 1 or 2;

R⁶⁵ and R⁶⁶ each independently represent hydrogen, Ci_₆alkyl or C₃_₆cycloalkyl, or R⁶⁵ and R⁶⁶ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring. Q represents phenyl optionally substituted by at least one substituent selected from halogen, carboxyl, hydroxyl, nitro, cyano, mercapto, Ci_₆alkyl group (itself optionally substituted by hydroxyl, Ci_₆alkoxy, NR⁶⁵R⁶⁶, phenyl or morpholinyl),

v is 0, 1 or 2;

Q represents phenyl optionally substituted by at least one substituent selected from halogen, cyano, trifluoromethyl, CONR⁵⁵R⁵⁶, S0₂NR⁵⁹R⁶⁰, S(0)_vR⁶³, OS(0₂)R⁶⁴;

v is 0, 1 or 2;

R⁶³ and R⁶⁴ independently represents a Ci_₆alkyl.

Q represents phenyl optionally substituted by at least one substituent selected from halogen, cyano, trifluoromethyl, S0₂NR⁵⁹R⁶⁰, S(0)_vR⁶³, OS(0₂)R⁶⁴

v is 0, 1 or 2; R and R each independently represent hydrogen, Ci_₆alkyl or C₃_₆cycloalkyl, or R and R⁶⁰ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;

R⁶³ and R⁶⁴ independently represents a Ci_₆alkyl.

Q represents benzoxazolinone, benzothiazolone, dioxobenzisothiazol and isoindolinone optionally substituted by at least one substituent selected from halogen, carboxyl, hydroxyl, oxo, nitro, cyano, mercapto, Ci_₆alkyl group (itself optionally substituted by hydroxyl, Ci_₆alkoxy, NR⁶⁵R⁶⁶, phenyl or morpholinyl),

v is 0, 1 or 2;

In one aspect Q is optionally substituted phenyl, pyridyl, pyrimidyl, pyridazyl, or pyrazolyl wherein the optional substituents are as hereinabove defined.

In one aspect of the invention, Q is of the formula A.

In one aspect X is N and Y is N. In another aspect X is CH and Y is N.

In yet another aspect X is N and Y is CH.

In yet another aspect X is CH and Y is CH.

In one aspect of the invention, the ring system of formula A is selected from:

wherein R' is selected from hydrogen, C3_₇cycloalkyl and Ci_₆alkyl the alkyl group being optionally substituted by 1 or 2 substituents independently selected from halogen, Ci_

4alkyoxy, C3_₇cycloalkyl, amino, alklylamino and dialklylamino; and the ring system being optionally further substituted as hereinabove defined. In another aspect, the ring system A has no further substituents in addition to R' .

In another aspect R' is selected from hydrogen, C3_₇cycloalkyl and Ci_₆alkyl the alkyl group being optionally substituted by 1 or 2 substituents independently selected from halogen, Ci_₄alkyoxy, C3_₇cycloalkyl, alklylamino and dialklylamino.

In one aspect, when Q is heteroaryl, it is optionally substituted by a substituent selected from Ci_₄alkyl, Ci_₄alkoxy, halogen, C3_₇cycloalkyl, carbamoyl, Ci_₄alkylcarbamoyl, and di Ci_ ₄alkylcarbamoyl the alkyl group being optionally substituted by 1 or 2 substituents independently selected from halogen, alkoxy, amino, Ci_₄alkylamino and di Ci_₄alkylamino.

In another aspect, when Q is heteroaryl, it is substituted by an oxo group and optionally substituted by one further substituent selected from Ci_₄alkyl, Ci_₄alkoxy, halogen, C_3- ₇cycloalkyl, carbamoyl, Ci_₄alkylcarbamoyl and di Ci_₄alkylcarbamoyl the alkyl group being optionally substituted by 1 or 2 substituents independently selected from halogen, alkoxy, amino, Ci_₄alkylamino and di Ci_₄alkylamino.

In another aspect, when Q is phenyl, it is substituted by 1 or 2 substituents independently selected from cyano, halogen, Ci_₄alkyl, Ci_₄alkoxy, halogen, C₃_₇Cycloalkyl, alkaylsulphonyl, alkylsulphonyloxy, carbamoyl, Ci_₄alkylcarbamoyl and di Ci_₄alkylcarbamoyl; the alkyl and alkoxy groups group being optionally substituted by 1 or 2 substituents independently selected from halogen, alkoxy, alkylsulphonyl, alkylsulphonamido, amino, Ci_₄alkylamino, di Ci_₄alkylamino and morpholino.

In one aspect, a group optionally substituted by One or more' substituents is optionally substituted by 1 to 3 substituents.

In another aspect, a group optionally substituted by One or more' substituents is optionally substituted by 1 or 2 substituents.

In yet another aspect, a group optionally substituted by One or more' substituents is optionally substituted by 1 substituent.

In yet another aspect, a group optionally substituted by One or more' substituents is optionally unsubstituted.

In one aspect , the phenyl, 5- to 10-membered heteroaryl ring system and ring system A in Q are optionally substituted by substituents independently selected from halogen, hydroxyl, oxo, cyano, Ci_₆alkyl group, Ci_₆alkoxy (the alkyl and alkoxy groups being optionally substituted by one or more substituents independently selected from hydroxyl, halogen, Ci_ ealkoxy, C₃-₆cycloalkyl, NHS0₂R⁶², S(0)₂R⁶³ and NR⁶⁵R⁶⁶), C₃_₆cycloalkyl, trifluoromethyl, Ci_₆alkylcarbonyl, -NR⁵³R⁵⁴, -C(0)NR⁵⁵R⁵⁶, NHC(0)R⁵⁸, S0₂NR⁵⁹R⁶⁰, NHS0₂R⁶²,

S(0)₂R⁶³, OS(0₂)R⁶⁴, benzyloxy and Ci_₆alkylpiperazinyl;

wherein

R⁵³ and R⁵⁴ each independently represent hydrogen or Ci_₆alkyl or R⁵³ and R⁵⁴ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;

R⁵⁵ and R⁵⁶ each independently represent hydrogen or Ci_₆alkyl or R⁵⁵ and R⁵⁶ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring; R and R each independently represent hydrogen or Ci_₆alkyl or R and R together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;

each R⁵⁸, R⁶², R⁶³ and R⁶⁴ independently represents a hydrogen atom or a

Ci_₆alkyl or C₃_₆cycloalkyl group; provided that R⁶², R⁶³ and R⁶⁴ are not hydrogen;

R⁶⁵ and R⁶⁶ each independently represent hydrogen or Ci_₆alkyl or R⁶⁵ and R⁶⁶ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring.

In another aspect , the phenyl, 5- to 10-membered heteroaryl ring system and ring system A in Q are optionally substituted by substituents independently selected from halogen, hydroxyl, oxo, cyano, Ci_₆alkyl group, Ci_₆alkoxy (the alkyl and alkoxy groups being optionally substituted by one or more substituents independently selected from hydroxyl, halogen, Ci_ ealkoxy, C₃-₆cycloalkyl, NHS0₂R , S(0)₂R^w and NR^b5R^bb), C₃_₆cycloalkyl, trifluoromethyl, Ci_₆alkylcarbonyl, -NR⁵³R⁵⁴, -C(0)NR⁵⁵R⁵⁶, NHC(0)R⁵⁸, S0₂NR⁵⁹R⁶⁰, NHS0₂R⁶², S(0)₂R⁶³, OS(0₂)R⁶⁴, benzyloxy and Ci_₆alkylpiperazinyl;

wherein

R and R each independently represent hydrogen or Ci_₄alkyl;

R⁵⁵ and R⁵⁶ each independently represent hydrogen or Ci_₄alkyl

R⁵⁹ and R⁶⁰ each independently represent hydrogen or Ci_₄alkyl

R⁶⁵ and R⁶⁶ each independently represent hydrogen or Ci_₄alkyl .

A class of com ounds is of the formula (Γ):

wherein n and Q is are as hereinabove defined; or a pharmaceutically-acceptable salt thereof. In another aspect the invention relates to a compound of the formula (Γ). Examples of compounds of the invention include but are not limited to:

(S)- 1 -Amino-N-( 1 -cyano-2-(4'-cyanobiphenyl-4-yl)ethyl)cyclohexanecarboxamide trifluoroacetic acid salt;

(S)- 1 -Amino-N-( 1 -cyano-2-(4'-(ethylsulfonyl)biphenyl-4-yl)ethyl)cyclopentanecarboxamide trifluoroacetic acid salt;

(5)-l-Amino-N-(l-cyano-2-(4-(3-(3-methoxypropyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)cyclopentanecarboxamide trifluoroacetic acid salt;

(5)-l-Amino-N-(l-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)cyclopentanecarboxamide trifluoroacetic acid salt;

(S)- 1 -Amino-N-( 1 -cyano-2-(4'-cyanobiphenyl-4-yl)ethyl)cyclopentanecarboxamide trifluoroacetic acid salt;

(S)- 1 -Amino-N-( 1 -cyano-2-(4'-(ethylsulfonyl)biphenyl-4-yl)ethyl)cyclohexanecarboxamide; (S)- 1 -Amino-N-( 1 -cyano-2-(4'-cyanobiphenyl-4-yl)ethyl)cyclobutanecarboxamide;

(5)-l-Amino-N-(l-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)cyclohexanecarboxamide trifluoroacetic acid salt;

(S)- 1 -Amino-N-( 1 -cyano-2-(4-(2-oxoindolin-6-yl)phenyl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-(l -cyano-2-(4-(l -methyl-6-oxo- 1 ,6-dihydropyridin-3- yl)phenyl)ethyl)cyclohexanecarboxamide;

(5)-5-(4-(2-(l-Aminocyclohexanecarboxamido)-2-cyanoethyl)phenyl)-N,3- dimethylpicolinamide;

(S)- 1 -Amino-N-(l -cyano-2-(4-(l -methyl-6-oxo- 1 ,6-dihydropyridazin-3- yl)phenyl)ethyl)cyclohexanecarboxamide;

(5)-4-Amino-N-(l-cyano-2-(4-(6-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3- yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide;

(S)- 1 -Amino-N-( 1 -cyano-2-(4-(2-(2-methoxyethyl)- 1 -oxoisoindolin-5 - yl)phenyl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-(l -cyano-2-(4-(l -isopropyl-6-oxo- 1 ,6-dihydropyridin-3- yl)phenyl)ethyl)cyclohexanecarboxamide;

(5)-l-Amino-N-(l-cyano-2-(4-(7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3- yl)phenyl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-( 1 -cyano-2-(4-( 1 -ethyl-6-oxo- 1 ,6-dihydropyridin-3 - yl)phenyl)ethyl)cyclohexanecarboxamide;

1 -Amino-N- {( IS)- 1 -cyano-2-[4-(2 -methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,2-benzisothiazol-5- yl)phenyl]ethyl}cyclohexanecarboxamide;

(S)- 1 -Amino-N-( 1 -cyano-2-(4-(2-(2-(dimethylamino)ethyl)- 1 -oxoisoindolin-5 - yl)phenyl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-( 1 -cyano-2-(4-(l -(difluoromethyl)-6-oxo- 1 ,6-dihydropyridin-3- yl)phenyl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-(l -cyano-2-(4-(5-fiuoro- 1 -methyl-6-oxo- 1 ,6-dihydropyridin-3- yl)phenyl)ethyl)cyclohexanecarboxamide trifluoroacetic acid salt;

(5)-4-(4-(2-(l-Aminocyclohexanecarboxamido)-2-cyanoethyl)phenyl)picolinamide trifluoroacetic acid salt;

(S)- 1 -Amino-N-( 1 -cyano-2-(4-(2-(2-hydroxyethyl)- 1 -oxoisoindolin-5 - yl)phenyl)ethyl)cyclohexanecarboxamide;

{S)-tert-QvXy\ 1 -(2-(4-(6-carbamoylpyridin-3 -yl)phenyl)- 1 - cyanoethylcarbamoyl)cyclohexylcarbamate;

(S)- 1 -Amino-N-(l -cyano-2-(4-(l -oxoisoindolin-5 -yl)phenyl)ethyl)cyclohexanecarboxamide; (S)- 1 -Amino-N-( 1 -cyano-2-(4-(l -(2-methoxyethyl)- lH-pyrazol-4- yl)phenyl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-( 1 -cyano-2-(4-(l -(2-morpholinoethyl)- lH-pyrazol-4- yl)phenyl)ethyl)cyclohexanecarboxamide;

(5)-4'-(2-(l-Aminocyclohexanecarboxamido)-2-cyanoethyl)biphenyl-4-carboxamide;

1 -Amino-N- {(IS)- 1 -cyano-2-[4-(l , 1 -dioxido-2,3-dihydro- 1 ,2-benzisothiazol-5- yl)phenyl]ethyl}cyclohexanecarboxamide;

(S)-N-(2-(4-( lH-Pyrazol-4-yl)phenyl)- 1 -cyanoethyl)- 1 -aminocyclohexanecarboxamide trifluoroacetic acid salt;

(5)-4'-(2-(l-Aminocyclohexanecarboxamido)-2-cyanoethyl)-3-fiuorobiphenyl-4-carboxamide trifluoroacetic acid salt;

(S)- 1 -Amino-N-(l -cyano-2-(4-(l -(2-methoxyethyl)-6-oxo- 1 ,6-dihydropyridin-3- yl)phenyl)ethyl)cyclohexanecarboxamide trifluoroacetic acid salt;

(5)-4'-(2-(l-Aminocyclohexanecarboxamido)-2-cyanoethyl)biphenyl-4-yl methanesulfonate; (S)- 1 -Amino-N-(l -cyano-2-(4-(l -methyl-6-oxo- 1 ,6-dihydropyridin-3- yl)phenyl)ethyl)cycloheptanecarboxamide;

(S)- 1 -Amino-N-(l -cyano-2-(4-(4-methyl-5-oxo-4,5-dihydropyrazin-2- yl)phenyl)ethyl)cyclohexanecarboxamide trifluoroacetic acid salt;

(5)-l-Amino-N-(l-cyano-2-(4-(6-isopropyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3- yl)phenyl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-( 1 -cyano-2-(4'-(methylsulfonylmethyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-( 1 -cyano-2-(3'-(methylsulfonamidomethyl)biphenyl-4- yl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-(l -cyano-2-(4-(2-methoxypyrimidin-5- yl)phenyl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-( 1 -cyano-2-(3'-(2-morpholinoethoxy)biphenyl-4- yl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-( 1 -cyano-2-(4-(6-oxo- 1 ,6-dihydropyridazin-3- yl)phenyl)ethyl)cyclohexanecarboxamide;

(S)- 1 -amino-N-(l -cyano-2-(4-(l -(2-methoxyethyl)-6-oxo-l ,6-dihydropyridazin-3- yl)phenyl)ethyl)cyclohexanecarboxamide;

(S)-N-(2-(4-( lH-Pyrazol-4-yl)phenyl)- 1 -cyanoethyl)- 1 -aminocycloheptanecarboxamide; (S)- 1 -Amino-N-(l -cyano-2-(4-(l -isopropyl-6-oxo- 1 ,6-dihydropyridin-3- yl)phenyl)ethyl)cyclopentanecarboxamide;

(S)- 1 -Amino-N-(l -cyano-2-(4-(l -methyl-6-oxo- 1 ,6-dihydropyridin-3- yl)phenyl)ethyl)cyclopentanecarboxamide;

(S)-N-(2-(4-( lH-Pyrazol-4-yl)phenyl)- 1 -cyanoethyl)- 1 -aminocyclopentanecarboxamide; (S)- 1 -Amino-N-(l -cyano-2-(4-(l -oxoisoindolin-5-yl)phenyl)ethyl)cyclopentanecarboxamide; (S)- 1 -Amino-N-( 1 -cyano-2-(4-(pyridin-4-yl)phenyl)ethyl)cyclohexanecarboxamide;

1 -Amino-N- {(IS)- 1 -cyano-2-[4-(2,2-dioxido-l ,3-dihydro-2-benzothiophen-5- yl)phenyl]ethyl}cyclopentanecarboxamide; (S)- 1 -Amino-N-( 1 -cyano-2-(4-(l -(cyclobutylmethyl)-2-oxo- 1 ,2-dihydropyrimidin-5- yl)phenyl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-(l -cyano-2-(4-(l -oxoisoindolin-5-yl)phenyl)ethyl)cycloheptanecarboxamide; (S)- 1 -amino-N-(l -cyano-2-(4-(l -ethyl-6-oxo-l ,6-dihydropyridazin-3- yl)phenyl)ethyl)cyclopentanecarboxamide;

(S)- 1 -Amino-N-( 1 -cyano-2-(4-( 1 -ethyl-6-oxo- 1 ,6-dihydropyridin-3 - yl)phenyl)ethyl)cyclopentanecarboxamide;

(S)- 1 -Amino-N-(l -cyano-2-(4-(l -methyl-6-oxo- 1 ,6-dihydropyridazin-3- yl)phenyl)ethyl)cyclopentanecarboxamide;

(S)- 1 -Amino-N-( 1 -cyano-2-(4-( 1 -ethyl-6-oxo- 1 ,6-dihydropyridin-3 - yl)phenyl)ethyl)cycloheptanecarboxamide;

(S)- 1 -Amino-N-(l -cyano-2-(4-(l -isopropyl-6-oxo- 1 ,6-dihydropyridazin-3- yl)phenyl)ethyl)cyclopentanecarboxamide;

(S)- 1 -Amino-N-(l -cyano-2-(4-(l -ethyl-6-oxo- 1 ,6-dihydropyridazin-3- yl)phenyl)ethyl)cycloheptanecarboxamide;

(S)- 1 -Amino-N-( 1 -cyano-2-(4-(6-oxo- 1 ,6-dihydropyridin-3 - yl)phenyl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-( 1 -cyano-2-(4-( 1 -methyl-2-oxo- 1 ,2-dihydropyrimidin-5 - yl)phenyl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-( 1 -cyano-2-(4-(l -methyl-2-oxo- 1 ,2-dihydropyridin-4- yl)phenyl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-( 1 -cyano-2-(4-(l -(N,N-dimethylsulfamoyl)- lH-pyrazol-4- yl)phenyl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-( 1 -cyano-2-(4-(2 -methyl- 1 -oxoisoindolin-5 - yl)phenyl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-(l -cyano-2-(4-(2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)cyclohexanecarboxamide;

1 -Amino-N-[( 1 S)- 1 -cyano-2- {4-[2-(l -methylethyl)- 1 , 1 -dioxido-2,3-dihydro- 1 ,2- benzisothiazol-5-yl]phenyl}ethyl]cyclopentanecarboxamide;

(5)-4'-(2-(l-Aminocyclopentanecarboxamido)-2-cyanoethyl)biphenyl-4-yl methanesulfonate; (S)- 1 -Amino-N-( 1 -cyano-2-(4-(l -methyl- lH-pyrazol-4- yl)phenyl)ethyl)cyclohexanecarboxamide; and

(S)- 1 -Amino-N-(l -cyano-2-(4-(l -isopropyl-6-oxo- 1 ,6-dihydropyridazin-3- yl)phenyl)ethyl)cyclohexanecarboxamide;

and pharmaceutically acceptable salts of any one thereof.

It should be noted that each of the chemical compounds listed above represents a particular and independent aspect of the invention.

In another aspect the invention relates to a compound of the formula (I) as hereinabove defined excluding any 1 of the specific examples or pharmaceutically acceptable salts thereof.

In yet another aspect the invention relates to a compound of the formula (Γ) as hereinabove defined excluding any 1 of the specific examples or pharmaceutically acceptable salts thereof.

The skilled person will recognise that the compounds of the invention may be prepared, in known manner, in a variety of ways. The routes below are merely illustrative of some of the methods that can be employed for the synthesis of compounds of formula (I).

The present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises reacting a compound of formula II)

2

wherein R and Q are as defined in formula (I), with a compound of formula (III)

wherein PG represents a protecting group (e.g. tert-butoxycarbonyl), R , n and y are as defined in formula (I), and optionally thereafter carrying out one or more of the following procedures:

• converting a compound of formula (I) into another compound of formula (I)

• removing any protecting groups

• forming a pharmaceutically acceptable salt.

The process of the invention is conveniently carried out in the presence of a base such as dizsopropylethylamine or triethylamine and an activating agent such as a "uranium" reagent (for example, 2-(l-H-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate) or a dehydrating agent (for example, propane phosphonic acid anhydride). The reaction is conveniently carried out in an organic solvent such as N,N-dimethylformamide or

tetrahydrofuran at a temperature, for example, in the range from 20 °C to 100 °C, in particular at ambient temperature (25°C).

Compounds of formula (II) may be prepared by contacting a compound of formula (IV)

wherein PG 2 represents a protecting group (e.g. tert-butoxycarbonyl) and R 2 , and Q are as defined in formula (II), with a suitable reagent to remove the protecting group PG . An example of a suitable reagent is formic acid.

Compounds of formula (IV) may be prepared by reacting a compound of formula (V)

wherein PG₂ and R are as defined in formula (IV) and Hal represents a halogen (e.g. I or Br), with a compound of formula (VI) or an ester thereof

OH

I

HO Q (VI)

in the presence of a catalyst such as ¾z^'5[¾z5(l,2-diphenylphosphino)ethane]palladium(0) or 1,1 ¾z5(di-fert-butylphosphino)ferrocene palladium dichloride and a base such as potassium carbonate. The reaction is conveniently carried out in a solvent such as dioxane/water mixture at a temperature, for example, in the range from 20°C to 100°C, particularly at 75°C. Compounds of formula (V) may be prepared from a compound of formula (VII)

2

in which PG₂ and R are as defined in formula (V) and Hal represents a halogen (e.g. I or Br), using standard literature procedures for the dehydration of an amide, for example with (methoxycarbonylsulfamoyl)tri-ethyl ammonium hydroxide, which can be prepared in situ with triethylamine and methyl chlorosulfonylcarbamate, in a solvent such as dichloromethane at a temperature in the range from -20°C to 35°C, for example at 0 °C.

Compounds of formula (VII) may be prepared by reacting a compound of formula (VIII)

in which PG₂ and R² are as defined in formula (VII) and Hal represents a halogen (e.g. I or Br), with an aqueous ammonia solution, using standard literature procedures for the formation of an amide, for example, in the presence of a base such as N-ethyl-morpholine and an activating agent such as a "uranium" reagent (for example, 2-(l-H-benzotriazole-l-yl)- 1,1,3,3-tetramethyluronium tetrafluoroborate). The reaction is conveniently carried out in an organic solvent such as N,N-dimethylformamide, at a temperature in the range from -20°C to 100°C, for example at 0°C.

Compounds of formula (VIII) are either commercially available, are known in the literature (e.g. from Tetrahedron: Asymmetry, 1998, 9, 503) or may be prepared using known techniques.

Other compounds of formula (IV) in which Q represent a heteroaryl group may be prepared by reacting a compound of formula (X)

in which PG₂ and a leaving group such as halogen, with a compound of formula (VI) or formula (XI), Q- B(OH)₂, in which Q represents a heteroaryl group to form a compound of formula (XII)

2

in which PG₂, R and Q are as defined above. Compounds of formula (XII) can then be converted to compounds of formula (IV) by processes known in the art, for example, as described in Bioorg. Med. Chem. Lett. 2002, 12, 3059 or Published US Patent Application No. 2007/0099835.

The present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises reacting a compound of formula (X

1 2 3

wherein R , R , n, y, and Q are as defined above and PG represents a protecting group (e.g. tert-butoxycarbonyl), using standard literature procedures for the dehydration of an amide, for example with (methoxycarbonylsulfamoyl)tri-ethyl ammonium hydroxide, which can be prepared in situ with triethylamine and methyl chlorosulfonylcarbamate, in a solvent such as dichloromethane at a temperature in the range from -20°C to 25°C, for example at 0 °C.

A compound of formula (XIII), may be prepared by reacting a compound of formula (XIV)

1 2 3

wherein R , R , n, y, and Q are as defined above and PG represents a protecting group (e.g. tert-butoxycarbonyl),

with a halide of formula (XV) in which Q is defined as in formula (I)

Q-Br/I (XV) in the presence of a catalyst such as bis[bis(l,2-diphenylphosphino)ethane]palladium(0) and a base such as potassium carbonate. The reaction is conveniently carried out in a solvent such as dioxane/water mixture at a temperature, for example, in the range from 20°C to 100°C, particularly at 75 °C.

A compound of formula (XIV) may be prepared by reacting a compound of formula (XVI)

1 2 3

wherein R , R , n, y, and Q are as defined above and PG represents a protecting group (e.g. tert-butoxycarbonyl) with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) in the presence of a suitable catalyst such as 1 , l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex and l,l'-bis(diphenylphosphino)ferrocene or 1,1 ¾z5(di-fert-butylphosphino)ferrocene palladium dichloride, with a suitable base such as potassium acetate, in a solvent such as dimethylsulfoxide at a temperature in the range 60°C to 100°C, for example at 80°C.

l/Br (XVI)

A compound of formula (XVI) may be prepared by reacting a compound of formula (XVII)

2

wherein R is as defined above, with a compound of formula (III)

1 3

wherein R , n, and y are as defined above and PG represents a protecting group (e.g. tert- butoxycarbonyl) in the presence of a base such as dizsopropylethylamine or triethylamine and a dehydrating agent (for example, propane phosphonic acid anhydride). The reaction is conveniently carried out in an organic solvent such as N,N-dimethylformamide or tetrahydrofuran at a temperature, for example, in the range from 20°C to 100°C, in particular at ambient temperature (25 °C).

Compounds of formula (XVII) may be prepared by reacting a compound of formula (XVIII)

(XVIII)

m which PG 2" and R 2 are as defined in formula (VII), with an aqueous ammonia solution, using standard literature procedures for the formation of an amide, for example, in the presence of a base such as N-ethyl-morpholine and an activating agent such as a "uranium" reagent (for example, 2-(l-H-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium

tetrafluoroborate). The reaction is conveniently carried out in an organic solvent such as N,N- dimethylformamide, at a temperature in the range from -20°C to 100°C, for example at 0°C.

Compounds of formulae (III), (VIII), (XV) and (XVIII) are either commercially available, are known in the literature or may be prepared using known techniques.

It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the reagents may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups.

The protection and deprotection of functional groups is described in 'Protective Groups in Organic Chemistry', edited by J.W.F. McOmie, Plenum Press (1973) and 'Protective Groups in Organic Synthesis', 3^rd edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1999).

The compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, trifluoroacetic acid salt, sulphate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulphonate or /?-toluenesulphonate.

The compounds of formula (I) and pharmaceutically acceptable salts thereof may exist in solvated, for example hydrated, as well as unsolvated forms, and the present invention encompasses all such solvated forms.

Compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses the use of all geometric and optical isomers (including atropisomers) of the compounds of formula (I) and mixtures thereof including racemates. The use of tautomers and mixtures thereof also form an aspect of the present invention. Enantiomerically pure forms are particularly desired.

The compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as inhibitors of dipeptidyl peptidase I activity, and thus may be used in the treatment of:

1. respiratory tract: obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases;

hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension; antitussive activity including treatment of chronic cough associated with inflammatory and secretory conditions of the airways, and iatrogenic cough; acute and chronic rhinitis including rhinitis medicamentosa, and vasomotor rhinitis; perennial and seasonal allergic rhinitis including rhinitis nervosa (hay fever); nasal polyposis; acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus; 2. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma gangrenosum, skin sarcoid, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Weber-Christian syndrome, erythema multiforme; cellulitis, both infective and non-infective; panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions;

3. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial;

4. genitourinary: nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo -vaginitis; Peyronie's disease; erectile dysfunction (both male and female);

5. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease;

6. other auto-immune and allergic disorders including rheumatoid arthritis, irritable bowel syndrome, systemic lupus erythematosus, multiple sclerosis, Hashimoto's thyroiditis, Graves' disease, Addison's disease, diabetes mellitus, idiopathic thrombocytopaenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome and Sazary syndrome;

7. oncology: treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and,

8. infectious diseases: virus diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, para-influenza; bacterial diseases such as tuberculosis and mycobacterium avium, leprosy; other infectious diseases, such as fungal diseases, chlamydia, Candida, aspergillus, cryptococcal meningitis, Pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis.

Thus, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in therapy.

In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in therapy.

In the context of the present specification, the term "therapy" also includes "prophylaxis" unless there are specific indications to the contrary. The terms "therapeutic" and

"therapeutically" should be construed accordingly.

Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.

In particular, the compounds of the invention (including pharmaceutically acceptable salts) may be used in the treatment of asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper- responsiveness)}, chronic obstructive pulmonary disease (COPD) or allergic rhinitis.

The invention also provides a method of treating, or reducing the risk of, an obstructive airways disease or condition (e.g. asthma or COPD) which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.

In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in treating COPD.

In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in treating asthma.

In a further aspect, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in the manufacture of a medicament for use in treating allergic rhinitis.

In a further aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in treating allergic rhinitis.

In a further aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in treating COPD.

In a further aspect, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in treating asthma.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, the daily dosage of the compound of the invention, if inhaled, may be in the range from 0.05 micrograms per kilogram body weight ^g/kg) to 100 micrograms per kilogram body weight ^g/kg). Alternatively, if the compound is

administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ^g/kg) to 100 milligrams per kilogram body weight (mg/kg).

The compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a

pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. to the skin or to the lung and/or airways) in the form, e.g., of creams, solutions, suspensions, heptafluoroalkane (HFA) aerosols and dry powder formulations, for example, formulations in the inhaler device known as the Turbuhaler^®; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); or by rectal administration in the form of suppositories.

Dry powder formulations and pressurized HFA aerosols of the compounds of the invention (that is, compounds of formula (I) and pharmaceutically acceptable salts thereof) may be administered by oral or nasal inhalation. For inhalation, the compound is desirably finely divided. The finely divided compound preferably has a mass median diameter of less than 10 micrometres (μιη), and may be suspended in a propellant mixture with the assistance of a dispersant, such as a C8-C20 fatty acid or salt thereof, (for example, oleic acid), a bile salt, a phospholipid, an alkyl saccharide, a perfluorinated or polyethoxylated surfactant, or other pharmaceutically acceptable dispersant.

The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler.

One possibility is to mix the finely divided compound of the invention with a carrier substance, for example, a mono-, di- or polysaccharide, a sugar alcohol, or another polyol. Suitable carriers are sugars, for example, lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol; and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound.

Another possibility is to process the finely divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled into the drug reservoir of a multidose inhaler, for example, that known as the Turbuhaler^® in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active ingredient, with or without a carrier substance, is delivered to the patient.

For oral administration the compound of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a

concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

For the preparation of soft gelatine capsules, the compound of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules.

Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, saccharine and/or carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

The compounds of the invention (that is, compounds of formula (I) and pharmaceutically acceptable salts thereof) may also be administered in conjunction with other compounds used for the treatment of the above conditions.

The invention therefore further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered concurrently or sequentially or as a combined preparation with another therapeutic agent or agents, for the treatment of one or more of the conditions listed.

In particular, for the treatment of the inflammatory diseases such as (but not restricted to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis, and inflammatory bowel disease, the compounds of the invention may be combined with the following agents: non-steroidal anti-inflammatory agents

(hereinafter NSAIDs) including non-selective cyclo-oxygenase COX-1 / COX-2 inhibitors whether applied topically or systemically (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, azapropazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); selective COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, lumarocoxib, parecoxib and etoricoxib); cyclo-oxygenase inhibiting nitric oxide donors (CINODs); glucocorticosteroids (whether administered by topical, oral, intramuscular, intravenous, or intra-articular routes); methotrexate; leflunomide;

hydroxychloroquine; d-penicillamine; auranofm or other parenteral or oral gold preparations; analgesics; diacerein; intra-articular therapies such as hyaluronic acid derivatives; and nutritional supplements such as glucosamine.

The present invention still further relates to the combination of a compound of the invention together with a cytokine or agonist or antagonist of cytokine function, (including agents which act on cytokine signalling pathways such as modulators of the SOCS system) including alpha-, beta-, and gamma-interferons; insulin- like growth factor type I (IGF-1); interleukins (IL) including IL1 to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-a) inhibitors such as anti-TNF monoclonal antibodies (for example infliximab; adalimumab, and CDP-870) and TNF receptor antagonists including immunoglobulin molecules (such as etanercept) and low-molecular-weight agents such as pentoxyfylline.

In addition the invention relates to a combination of a compound of the invention with a monoclonal antibody targeting B-Lymphocytes (such as CD20 (rituximab), MRA-aIL16R and T-Lymphocytes, CTLA4-Ig, HuMax 11-15).

The present invention still further relates to the combination of a compound of the invention with a modulator of chemokine receptor function such as an antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCRl, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX₃CRI for the C-X₃-C family.

The present invention further relates to the combination of a compound of the invention with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-9 and MMP-12, including agents such as doxycycline.

The present invention still further relates to the combination of a compound of the invention and a leukotriene biosynthesis inhibitor, 5 -lipoxygenase (5-LO) inhibitor or 5 -lipoxygenase activating protein (FLAP) antagonist such as; zileuton; ABT-761; fenleuton; tepoxalin; Abbott-79175; Abbott-85761; a N-(5-substituted)-thiophene-2-alkylsulfonamide; 2,6-di-tert- butylphenolhydrazones; a methoxytetrahydropyrans such as Zeneca ZD-2138; the compound SB-210661; a pyridinyl-substituted 2-cyanonaphthalene compound such as L-739,010; a 2- cyanoquinoline compound such as L-746,530; or an indole or quinoline compound such as MK-591, MK-886, and BAY x 1005.

The present invention further relates to the combination of a compound of the invention and a receptor antagonist for leukotrienes (LT) B4, LTC4, LTD4, and LTE4 selected from the group consisting of the phenothiazin-3-ls such as L-651,392; amidino compounds such as CGS-25019c; benzoxalamines such as ontazolast; benzenecarboximidamides such as BIIL 284/260; and compounds such as zafirlukast, ablukast, montelukast, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A), and BAY x 7195.

The present invention still further relates to the combination of a compound of the invention and a phosphodiesterase (PDE) inhibitor such as a methylxanthanine including theophylline and aminophylline; a selective PDE isoenzyme inhibitor including a PDE4 inhibitor an inhibitor of the isoform PDE4D, or an inhibitor of PDE5.

The present invention further relates to the combination of a compound of the invention and a histamine type 1 receptor antagonist such as cetirizine, loratadine, desloratadine,

fexofenadine, acrivastine, terfenadine, astemizole, azelastine, levocabastine,

chlorpheniramine, promethazine, cyclizine, or mizolastine; applied orally, topically or parenterally.

The present invention still further relates to the combination of a compound of the invention and a proton pump inhibitor (such as omeprazole) or a gastroprotective histamine type 2 receptor antagonist.

The present invention further relates to the combination of a compound of the invention and an antagonist of the histamine type 4 receptor. The present invention still further relates to the combination of a compound of the invention and an alpha- l/alpha-2 adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, ephedrine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorepinephrine

hydrochloride.

The present invention further relates to the combination of a compound of the invention and an anticholinergic agents including muscarinic receptor (Ml, M2, and M3) antagonist such as atropine, hyoscine, glycopyrrrolate, ipratropium bromide, tiotropium bromide, oxitropium bromide, pirenzepine or telenzepine.

The present invention still further relates to the combination of a compound of the invention and a beta-adrenoreceptor agonist (including beta receptor subtypes 1-4) such as isoprenaline, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, or pirbuterol, or a chiral enantiomer thereof.

The present invention further relates to the combination of a compound of the invention and a chromone, such as sodium cromoglycate or nedocromil sodium.

The present invention still further relates to the combination of a compound of the invention with a glucocorticoid, such as flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide or mometasone furoate.

The present invention further relates to the combination of a compound of the invention with an agent that modulates a nuclear hormone receptor such as PPARs.

The present invention still further relates to the combination of a compound of the invention together with an immunoglobulin (Ig) or Ig preparation or an antagonist or antibody modulating Ig function such as anti-IgE (for example omalizumab). The present invention further relates to the combination of a compound of the invention and another systemic or topically-applied anti-inflammatory agent, such as thalidomide or a derivative thereof, a retinoid, dithranol or calcipotriol.

The present invention still further relates to the combination of a compound of the invention and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines.

The present invention further relates to the combination of a compound of the invention together with an antibacterial agent such as a penicillin derivative, a tetracycline, a macrolide, a beta-lactam, a fluoroquinolone, metronidazole, an inhaled aminoglycoside; an antiviral agent including acyclovir, famciclovir, valaciclovir, ganciclovir, cidofovir, amantadine, rimantadine, ribavirin, zanamavir and oseltamavir; a protease inhibitor such as indinavir, nelfmavir, ritonavir, and saquinavir; a nucleoside reverse transcriptase inhibitor such as didanosine, lamivudine, stavudine, zalcitabine or zidovudine; or a non-nucleoside reverse transcriptase inhibitor such as nevirapine or efavirenz.

The present invention still further relates to the combination of a compound of the invention and a cardiovascular agent such as a calcium channel blocker, a beta-adrenoceptor blocker, an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin-2 receptor antagonist; a lipid lowering agent such as a statin or a fibrate; a modulator of blood cell morphology such as pentoxyfylline; thrombolytic, or an anticoagulant such as a platelet aggregation inhibitor.

The present invention further relates to the combination of a compound of the invention and a CNS agent such as an antidepressant (such as sertraline), an anti-Parkinsonian drug (such as deprenyl, L-dopa, ropinirole, pramipexole, a MAOB inhibitor such as selegine and rasagiline, a comP inhibitor such as tasmar, an A-2 inhibitor, a dopamine reuptake inhibitor, an NMDA antagonist, a nicotine agonist, a dopamine agonist or an inhibitor of neuronal nitric oxide synthase), or an anti-Alzheimer's drug such as donepezil, rivastigmine, tacrine, a COX-2 inhibitor, propentofylline or metrifonate. The present invention still further relates to the combination of a compound of the invention and an agent for the treatment of acute or chronic pain, such as a centrally or peripherally- acting analgesic (for example an opioid or derivative thereof), carbamazepine, phenytoin, sodium valproate, amitryptiline or other anti-depressant agent-s, paracetamol, or a nonsteroidal anti-inflammatory agent.

The present invention further relates to the combination of a compound of the invention together with a parenterally or topically-applied (including inhaled) local anaesthetic agent such as lignocaine or a derivative thereof.

A compound of the present invention can also be used in combination with an anti- osteoporosis agent including a hormonal agent such as raloxifene, or a biphosphonate such as alendronate.

The present invention still further relates to the combination of a compound of the invention together with a: (i) tryptase inhibitor; (ii) platelet activating factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitors including VLA-4 antagonist; (vi) cathepsin; (vii) kinase inhibitor such as an inhibitor of tyrosine kinase (such as Btk, Itk, Jak3 or MAP, for example Gefitinib or Imatinib mesylate), a serine / threonine kinase (such as an inhibitor of a MAP kinase such as p38, TNK, protein kinase A, B or C, or IKK), or a kinase involved in cell cycle regulation (such as a cylin dependent kinase); (viii) glucose-6 phosphate dehydrogenase inhibitor; (ix) kinin- B.subl . - or B.sub2. -receptor antagonist; (x) anti-gout agent, for example colchicine; (xi) xanthine oxidase inhibitor, for example allopurinol; (xii) uricosuric agent, for example probenecid, sulfinpyrazone or benzbromarone; (xiii) growth hormone secretagogue; (xiv) transforming growth factor (TGF ); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor for example basic fibroblast growth factor (bFGF); (xvii) granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) capsaicin cream; (xix) tachykinin NK.subl . or NK.sub3. receptor antagonist such as NKP-608C, SB-233412 (talnetant) or D- 4418; (xx) elastase inhibitor such as UT-77 or ZD-0892; (xxi) TNF-alpha converting enzyme inhibitor (TACE); (xxii) induced nitric oxide synthase (iNOS) inhibitor; (xxiii)

chemoattractant receptor-homologous molecule expressed on TH2 cells, (such as a CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) agent modulating the function of Toll-like receptors (TLR), (xxvi) agent modulating the activity of purinergic receptors such as P2X7; (xxvii) inhibitor of transcription factor activation such as NFkB, API, or STATS; or (xxviii) a glucocorticoid receptor agonist.

In a further aspect the present invention provides a combination (for example for the treatment of COPD, asthma or allergic rhinitis) of a compound of formula (I) or a

pharmaceutically acceptable salt thereof as hereinbefore defined and one or more agents independently selected from:

• a non-steroidal glucocorticoid receptor (GR-receptor) agonist;

• a selective β₂ adrenoceptor agonist (such as metaproterenol, isoproterenol,

isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, pirbuterol or indacaterol);

• a phosphodiesterase inhibitor (such as a PDE4 inhibitor);

• a protease inhibitor (such as a neutrophil elastase or matrix metalloprotease MMP-12 inhibitor);

• a glucocorticoid;

• an anticholinergic agent;

• a modulator of chemokine receptor function (such as a CCR1 receptor antagonist); and

• an inhibitor of kinase function (such as the kinases p38 or IKK).

The invention also provides a pharmaceutical product comprising, in combination, a preparation of a first active ingredient which is a compound of formula (I) or a

pharmaceutically acceptable salt thereof as hereinbefore defined, and a preparation of a second active ingredient which is

• a non-steroidal glucocorticoid receptor (GR-receptor) agonist;

• a selective β₂ adrenoceptor agonist;

• a phosphodiesterase inhibitor;

• a protease inhibitor;

• a glucocorticoid; • an anticholinergic agent;

• a modulator of chemokine receptor function; or

• an inhibitor of kinase function;

for simultaneous, sequential or separate use in therapy.

In another aspect, the invention provides a kit comprising a preparation of a first active ingredient which is a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, and a preparation of a second active ingredient which is

• a non-steroidal glucocorticoid receptor (GR-receptor) agonist;

• a selective β₂ adrenoceptor agonist;

• a phosphodiesterase inhibitor;

• a protease inhibitor;

• a glucocorticoid;

• an anticholinergic agent;

• a modulator of chemokine receptor function; or

• an inhibitor of kinase function;

and instructions for the simultaneous, sequential or separate administration of the preparations to a patient in need thereof.

A compound of the invention can also be used in combination with an existing therapeutic agent for the treatment of cancer, for example suitable agents include:

(i) an antiproliferative/antineoplastic drug or a combination thereof, as used in medical oncology, such as an alkylating agent (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan or a nitrosourea); an antimetabolite (for example an antifolate such as a fluoropyrimidine like 5-fluorouracil or tegafur, raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or paclitaxel); an antitumour antibiotic (for example an anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin or

mithramycin); an antimitotic agent (for example a vinca alkaloid such as vincristine, vinblastine, vindesine or vinorelbine, or a taxoid such as taxol or taxotere); or a topoisomerase inhibitor (for example an epipodophyllotoxin such as etoposide, teniposide, amsacrine, topotecan or a camptothecin);

(ii) a cytostatic agent such as an antioestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene), an oestrogen receptor down regulator (for example fulvestrant), an antiandrogen (for example bicalutamide, flutamide, nilutamide or cyproterone acetate), a LHRH antagonist or LHRH agonist (for example goserelin, leuprorelin or buserelin), a progestogen (for example megestrol acetate), an aromatase inhibitor (for example as anastrozole, letrozole, vorazole or exemestane) or an inhibitor of 5a-reductase such as finasteride;

(iii) an agent which inhibits cancer cell invasion (for example a metalloproteinase inhibitor like marimastat or an inhibitor of urokinase plasminogen activator receptor function);

(iv) an inhibitor of growth factor function, for example: a growth factor antibody (for example the anti-erbb2 antibody trastuzumab, or the anti-erbbl antibody cetuximab [C225]), a farnesyl transferase inhibitor, a tyrosine kinase inhibitor or a serine/threonine kinase inhibitor, an inhibitor of the epidermal growth factor family (for example an EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3- morpholinopropoxy)quinazolin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7- bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) or 6-acrylamido-N-(3-chloro- 4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine (CI 1033)), an inhibitor of the platelet-derived growth factor family, or an inhibitor of the hepatocyte growth factor family;

(v) an antiangiogenic agent such as one which inhibits the effects of vascular endothelial growth factor (for example the anti-vascular endothelial cell growth factor antibody bevacizumab, a compound disclosed in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354), or a compound that works by another mechanism (for example linomide, an inhibitor of integrin ανβ3 function or an angiostatin);

(vi) a vascular damaging agent such as combretastatin A4, or a compound disclosed in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;

(vii) an agent used in antisense therapy, for example one directed to one of the targets listed above, such as ISIS 2503, an anti-ras antisense;

(viii) an agent used in a gene therapy approach, for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; or

(ix) an agent used in an immunotherapeutic approach, for example ex -vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte -macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti -idiotypic antibodies.

The invention will now be illustrated by the following non-limiting Examples in which, unless stated otherwise:

(i) when given, 1H NMR spectra were recorded on Bruker Avance 600 (600 MHz), a Bruker DRX 500 (500 MHz) or a Varian Unitylnova 500 MHz, 400 MHz or 300 MHz instrument. Either the central peaks of chloroform-<i (CDC1₃; 5H 7.27 ppm), dimethylsulfoxide-<i_<i (d₆- DMSO; δ_Η 2.50 ppm) or methanol-^ (CD₃OD; δ_Η 3.31 ppm), or an internal standard of tetramethylsilane (TMS; δ_Η 0.00 ppm) were used as references;

(ii) Mass spectra were recorded on an Agilent MSD (+ve and -ve APCI and/or electrospray (e.g. in multimode)) following analytical HPLC. Where values for m/z are given, generally only ions which indicate the parent mass are reported, and the mass ions quoted are the positive or negative mass ions: [M]⁺, [M+H]⁺, [M-H]^~, [M+H-BOC]⁺ or [M+2H-BOC]⁺;

(iii) the title and sub-title compounds of the examples and preparations were named using the IUPAC name program Struct=Name 9.0.7 from CambridgeSoft Corporation.

(iv) unless stated otherwise, reverse phase HPLC was conducted using a SunFire^® reverse phase silica column, available from Waters Corp.;

(v) Unless stated otherwise, starting materials were commercially available. All solvents and commercial reagents were of laboratory grade and were used as received. All operations were carried out at ambient temperature, i.e. in the range 17 to 28°C and, where appropriate, under an atmosphere of an inert gas such as nitrogen;

(vi) Analytical HPLC was carried out using either a Waters XBridge™ C8 3.5 μιη column eluting with a gradient of acetonitrile in either 0.1% aqueous trifluoroacetic acid, 0.1% aqueous formic acid, 0.1 % aqueous ammonium acetate or 0.1 % aqueous ammonia; a Waters XBridge™ CI 8 3.5 μιη column with a gradient of acetonitrile in 0.1% aqueous ammonia; a Waters Symmetry CI 8 3.5 μιη column with a gradient of acetonitrile in 0.1% aqueous trifiuoroacetic acid; a Waters Sunfire™ C8 3.5 μιη column with a gradient of acetonitrile in 0.1% aqueous trifiuoroacetic acid; or a Phenomenex Gemini™ C18 3 μιη column with a gradient of acetonitrile in 0.1% aqueous trifiuoroacetic acid. UV spectra of the eluted peaks were measured using a diode array on an Agilent 1100® system, or equivalent;

(vii) the following abbreviations are used:

AIBN 2,2 ' -Azobisisobutyronitrile

Burgess reagent Methyl (carboxysulfamoyl)triethyl ammonium

hydroxide inner salt

CbzCl Benzyloxycarbonylchloride

d Day(s)

DCE 1 ,2-Dichloroethane

DCM Dichloromethane

DMF N, N-Dimethylformamide

DMSO Dimethyl sulfoxide

g Gram(s)

h Hour(s)

HATU 2-( 1 H-7- Azabenzotriazol- 1 -yl)- 1 , 1 ,3 ,3 -tetramethyluronium

hexafluorophosphate

HM-N Argonaut Isolute ® diatomaceous earth cartridge

HPLC High performance liquid chromatography

Hunig's Base Diisopropylethylamine (DIPEA)

LCMS Liquid chromatography- mass spectroscopy

min Minute(s)

mL Millilitre(s)

ft-BuLi n-Butyllithium

NMP 1 -Methylpyrrolidin-2-one

HPLC high performance liquid chromatography

RT Room temperature

SCX Strong cation exchange resin TBAF Tetrabutylammonium fluoride

TBTU 2-( 1 H-Benzo [d] [ 1 ,2,3 Jtriazol- 1 -yl)- 1 , 1 ,3 ,3 -tetramethylisouronium tetrafluoroborate

TEA Triethylamine

TFA Trifluoroacetic acid

THF tetrahydrofuran

Example 1: (S)-l-Amino- V-(l-cyano-2-(4'-cyanobiphenyl-4- yl)ethyl)cyclohexanecarboxamide trifluoroacetic acid salt

(i) (S)-tert- uty\ l-amino-3-(4-iodophenyl)-l-oxopropan-2-ylcarbamate

(5)-2-(tert-Butoxycarbonylamino)-3-(4-iodophenyl)propanoic acid (35.1 g) was dissolved in DMF (200 mL) and to the resulting solution was added N-ethylmorpholine (17.0 mL) followed by TBTU (28.8 g). The mixture was stirred at room temperature for 0.5h and then cooled to 0°C. Aqueous ammonia (1 1.1 mL) was added and the mixture was allowed to warm to room temperature. The mixture was stirred for 16h and was then poured into water and the resulting precipitate removed by filtration. The solid was dried in vacuo to give the sub-titled compound (34.2 g). m/e (APCI+) 291 [M+2H-BOC]⁺

(ii) (S)-tert- utyl l-amino-3-(4'-cyanobiphenyl-4-yl)-l-oxopropan-2-ylcarbamate

(S)-tert-Butyl l-amino-3-(4-iodophenyl)-l-oxopropan-2-ylcarbamate (Example 1, step (i), 3.17 g) and 4-cyanophenylboronic acid (1.19 g) in dioxane (5 mL) were treated with 1,1

¾z5(di-fert-butylphosphino)ferrocene palladium dichloride (0.08 g) and the mixture was stirred at room temperature for 15 min under nitrogen. An aqueous solution of potassium carbonate (2M, 8.1 mL) was added and the mixture was stirred for 18h at 75°C. The reaction mixture was extracted with ethyl acetate, dried and evaporated to afford the sub-titled compound (3.13 g). m/e (APCI+) 266 [M+2H-BOC]⁺

1H NMR (400 MHz, CDC1₃) δ 7.74 - 7.70 (m, 2H), 7.68 - 7.65 (m, 2H), 7.56 - 7.52 (m, 2H), 7.35 (d, 2H), 5.87 - 5.78 (m, 1H), 5.39 - 5.30 (m, 1H), 5.08 - 4.98 (m, 1H), 4.45 - 4.37 (m, 1H), 3.20 - 3.07 (m, 2H), 1.42 (s, 9H). iii) (S)-2- Amino-3-(4 '-cyanobiphenyl-4-yl)propanamide

(S)-tert-Butyl l-amino-3-(4'-cyanobiphenyl-4-yl)-l-oxopropan-2-ylcarbamate (Example 1, step (ii), 3.13 g) was dissolved in dichloromethane (30 mL) and TFA (1.32 mL) was added. The dichloromethane was distilled off on a rotary evaporator at atmospheric pressure to leave ~5 mL of solvent. The reaction was monitored by HPLC/MS and when complete was partitioned between water and dichloromethane. The organic extract was dried (magnesium sulfate) and evaporated to dryness. The solid was purified on silica eluting with ethyl acetate then ethyl acetate containing 10% methanol to afford the sub-titled compound (1.95 g). m/e (APCI+) 266 [M+H]⁺

1H NMR (400 MHz, CDC1₃) δ 7.73 (dd, 2H), 7.67 (dd, 2H), 7.56 (dt, 2H), 7.36 (dt, 2H), 7.11 (s, 1H), 5.38 (s, 1H), 3.68 (dd, 1H), 3.32 (dd, 1H), 2.84 (dd, 1H), 1.49 (s, 2H).

(iv) (S)-tert- utyl l-(l-amino-3-(4'-cyanobiphenyl-4-yl)-l-oxopropan-2- lcarbamoyl)cyclohexylcarbamate

To (S)-2-amino-3-(4'-cyanobiphenyl-4-yl)propanamide (Example 1, step (iii), 0.3 g) and 1- (tert-butoxycarbonylamino)cyclohexanecarboxylic acid (0.28 g) in DMF (5 mL) was added triethylamine (0.39 mL) followed by TBTU (0.55 g). The mixture was stirred at room temperature for 2 h. The mixture was poured into water and diethyl ether (20 mL) and the mixture separated. The aqueous layer was further extracted with diethyl ether and the combined organic extracts dried over magnesium sulfate. The residue after evaporation was purified by chromatography on silica eluting with methanol / dichloromethane / triethylamine (10/90/1) to afford the sub-titled compound (60 mg). m/e (APCI+) 491 [M+H]⁺, 391 [M+2H-BOC]

(v) (S)-tert- uty\ l-(l-cyano-2-(4'-cyanobiph

yl)ethylcarbamoyl)cyclohexylcarbamate

To (S)-tert-butyl 1 -(1 -amino-3-(4'-cyanobiphenyl-4-yl)- 1 -oxopropan-2- ylcarbamoyl)cyclohexylcarbamate (Example 1, step (iv), 0.55 g) in dichloromethane (3 mL) was added Burgess' reagent (0.32 g) and the mixture stirred overnight. The mixture was poured into water (10 mL) and extracted with dichloromethane (2 x 5 mL). The combined organic layers were dried (magnesium sulfate) and evaporated to dryness. Recrystallisation from ethyl acetate / z^'sohexane afforded the sub-titled compound (185 mg) as a white solid which was collected by filtration and dried under vacuum.

1H NMR (400 MHz, DMSO) δ 8.04 (d, 1H), 7.90 - 7.81 (m, 4H), 7.68 (d, 2H), 7.43 (d, 2H), 6.18 (s, 1H), 5.01 (q, 1H), 3.24 - 3.09 (m, 2H), 1.86 - 1.40 (m, 8H), 1.37 (s, 9H), 1.31 - 1.11 (m, 2H).

Example 1: (S)-l-Amino-N-(l-cyano-2-(4'-cyanobiphenyl-4- yl)ethyl)cyclohexanecarboxamide trifluoroacetic acid salt

To (S)-tert-butyl 1 -(1 -cyano-2-(4'-cyanobiphenyl-4-yl)ethylcarbamoyl)cyclohexylcarbamate (Example 1, step (v), 180 mg) was added formic acid (2 mL) and the mixture heated to 80°C for 45 min. The mixture was allowed to cool to room temperature and partially evaporated to give a solution that was diluted with methanol (2 mL) and purified by preparative

chromatography on a Waters SunFire column eluting with acetonitrile / 0.1% TFA(aq) to afford the titled compound as a white solid (30 mg).

1H NMR (400 MHz, DMSO) δ 9.14 (d, 1H), 8.17 (s, 2H), 7.93 (d, 2H), 7.87 (d, 2H), 7.73 (d, 2H), 7.44 (d, 2H), 5.16 - 5.08 (m, 1H), 3.32 - 3.18 (m, 2H), 1.99 - 1.87 (m, 1H), 1.85 - 1.75 (m, 1H), 1.75 - 1.65 (m, 1H), 1.62 - 1.40 (m, 6H), 1.34 - 1.19 (m, 1H), 3.76 (s, 1H). m/e (MultiMode+) 373 [M+H]⁺

Example 2: (S)-l-Amino- V-(l-cyano-2-(4'-(ethylsulfonyl)biph

yl)ethyl)cyclopentanecarboxamide trifluoroacetic acid salt

(i) (S)-2-Amino-3-(4-iodophenyl)propanamide

(S)-tert-Butyl l-amino-3-(4-iodophenyl)-l-oxopropan-2-ylcarbamate (Example 1, step (i), 2.41 g) was stirred in dichloromethane (125 mL) and to the suspension was added trifluoroacetic acid (8 mL). The mixture was stirred for 2h then concentrated in vacuo to ~10 mL. The residue was stirred for 2 days, dissolved in ethyl acetate / dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was dried and evaporated to the sub-titled compound (1.52 g). m/e (APCI+) 291 [M+H]

1H NMR (400 MHz, CDC1₃) δ 7.61 (d, 2H), 7.26 (s, 1H), 7.03 (d, 2H), 6.40 (s, 1H), 3.55 (s, 1H), 3.09 (dd, 1H), 2.71 (dd, 1H), 1.81 (s, 2H). (ii) (S)-tert-Buty\ l-(l-amino-3-(4-iodophenyl)-l-oxopropan-2- ylcarbamoyl)cyclopentylcarbamate

To l-(tert-butoxycarbonylamino)cyclopentanecarboxylic acid (1.90 g) and (5)-2-amino-3-(4- iodophenyl)propanamide (Example 2, step (i), 2.40 g) in DMF (40 mL) was added triethylamine (3.46 mL) followed by TBTU (3.98 g) and the mixture stirred at room temperature for 1 day. The mixture was poured into water and diethyl ether (20 mL) and then separated. The aqueous layer was further extracted with diethyl ether and the combined organic extracts were dried over magnesium sulfate. The residue after evaporation was purified by chromatography on silica eluting with methanol / dichloromethane / triethylamine (10/90/1) to afford the sub-titled compound (20 g). m/e (APCI+) 401 [M+H-BOC]

(iii) (S)-tert-Buty\ l-(l-amino-3-(4'-(ethylsulfonyl)biphenyl-4-yl)-l-oxopropan-2- ylcarbamoyl)cyclopentylcarbamate

(S)-tert-Butyl 1 -( 1 -amino-3 -(4-iodophenyl)- 1 -oxopropan-2- ylcarbamoyl)cyclopentylcarbamate (Example 2, step (ii), 0.30 g), potassium carbonate (165 mg) and 4-(ethylsulfonyl)phenylboronic acid (0.26 g) were stirred in dioxane (15 mL) and to the mixture was added l,l-¾z5(di-tert-butylphosphino)ferrocene palladium dichloride (4 mg). The reaction mixture was stirred under nitrogen for 15min and then potassium carbonate (165 mg) in 0.6mL of water was added. The reaction mixture was heated at 90°C for 3h. LCMS showed the reaction was incomplete. Acetonitrile (5 mL) was added to the mixture, followed by a further 5 mg of 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride. The mixture was heated to 100°C for 4h and then cooled to room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The ethyl acetate was washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The crude material was purified by flash silica chromatography eluting with methanol / dichloromethane (1/9) to afford the sub-titled compound (200 mg). m/e (APCI-) 543 [M-H]^~

(iv) (S)-tert- uty\ l-(l-cyano-2-(4'-(ethylsulfonyl)biph

yl)ethylcarbamoyl)cyclopentylcarbamate

To (S)-tert-butyl l-(l-amino-3-(4'-(ethylsulfonyl)biphenyl-4-yl)-l-oxopropan-2- ylcarbamoyl)cyclopentylcarbamate (Example 2, step (iii), 0.25 g) in dichloromethane (4 mL) was added Burgess' reagent (131 mg) and the mixture stirred overnight. The mixture was then poured into water (5 mL) and then extracted with ethyl acetate (3 x 5 mL). The combined organic extracts were dried over magnesium sulfate and evaporated to yield the sub-titled compound as an oil (200 mg). m/e (APCI-) 524 [M-H]^~

Example 2: (S)-l-Amino- V-(l-cyano-2-(4'-(ethylsulfonyl)biph

yl)ethyl)cyclopentanecarboxamide trifluoroacetic acid salt

To

l-(l-cyano-2-(4'-(ethylsulfonyl)biphenyl-4- yl)ethylcarbamoyl)cyclopentylcarbamate (Example 2, step (iv), 200 mg) was added formic acid (3 mL) and the mixture stirred at room temperature for 2 h. The mixture was diluted with water (5 mL) and basified to pH 8 with 0.880 ammonia. The aqueous was extracted with ethyl actate (3 x 15 mL) and the combined organic layers dried over magnesium sulfate. The solvent was evaporated to yield a crude oil which was purified by preparative HPLC chromatography on a Waters SunFire column eluting with 0.1% TFA (aq) / methanol to afford the titled compound (90 mg). m/e (MultiMode+) 426 [M+H]

1H NMR (400 MHz, DMSO) δ 8.96 (d, 1H), 8.15 (s, 3H), 7.98 - 7.91 (m, 4H), 7.74 (d, 2H), 7.45 (d, 2H), 5.17 - 5.09 (m, 1H), 3.42 - 3.18 (m, 4H), 2.13 - 1.99 (m, 1H), 1.91 - 1.67 (m, 7H), 1.13 (t, 3H).

Example 3: (S)-l-Amino- V-(l-cyano-2-(4-(3-(3-methoxypropyl)-2-oxo-2,3- dihydrobenzo [d] oxazol-5-yl)phenyl)ethyl)cyclopentanecarboxamide trifluoroacetic acid salt

(i) (S)-tert-Buty\ l-(l-amino-l-oxo-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)propan-2-ylcarbamoyl)cyclopentylcarbamate

(S)-tert-Butyl 1 -( 1 -amino-3 -(4-iodophenyl)- 1 -oxopropan-2- ylcarbamoyl)cyclopentylcarbamate (Example 2, step (ii), 1 g) in acetonitrile (25 niL) was treated with potassium acetate (0.59 g) and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (0.67 g). Water (1.5 mL) was added followed by 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride (0.01 g) and the mixture was stirred under nitrogen at 95°C for 17h. The cooled reaction mixture was concentrated to a reduced volume and the residue partitioned between water (50 mL) and diethyl ether (2 x 50 mL). The organic phase was collected, dried over magnesium sulphate and filtered. The filtrate was passed through flash silica gel and the pad washed with more diethyl ether (50 mL). The product was then eluted off the silica gel using ethyl acetate as eluant. The ethyl acetate solution was concentrated to dryness to afford the sub-titled compound (0.9 g). m/e (APCI+) 500 [M-H]^~

(ii) (S)-tert-Buty\ l-(l-amino-3-(4-(3-(3-methoxypropyl)-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)-l-oxopropan-2-ylcarbamoyl)cyclopentylcarbamate

To

l-(l-amino-l-oxo-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)propan-2-ylcarbamoyl)cyclopentylcarbamate (Example 3, step (i), 0.25 g), 5- bromo-3-(3-methoxypropyl)benzo[d]oxazol-2(3H)-one (143 mg) and aqueous potassium carbonate (2M, 0.75 mL) in acetonitrile (30 mL) under a nitrogen atmosphere was added 1,1 ¾z^'s(di-tert-butylphosphino)ferrocene palladium dichloride (10 mg) and the mixture heated at 80°C for 3h. The mixture was concentrated to dryness and the residue purified by

chromatography on silica eluting with ethyl acetate to afford the sub-titled compound (170 mg). m/e (APCI+) 481 [M+2H-BOC] (iii) (S)-tert-Butyl l-(l-cyano-2-(4-(3-(3-methoxypropyl)-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)ethylcarbamoyl)cyclopentylcarbamate

To a solution of (S)-tert-butyl l-(l-amino-3-(4-(3-(3-methoxypropyl)-2-oxo-2,3- dihydrobenzo[d]oxazol-5-yl)phenyl)-l-oxopropan-2-ylcarbamoyl)cyclopentylcarbamate (Example 3, step (ii), 220 mg) in dichloromethane (3 mL) was added Burgess' reagent (117 mg) and the mixture stirred overnight. The mixture was poured into water (20 mL) and extracted with dichloromethane (3 x 20 mL). The combined organic extracts were dried over magnesium sulfate to afford the sub-titled compound (200 mg). m/e (APCI+) 463 [M+2H-BOC]

To (S)-tert-butyl 1 -(1 -cyano-2-(4-(3-(3-methoxypropyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethylcarbamoyl)cyclopentylcarbamate (Example 3, step (iii), 200 mg) was added formic acid (2 mL) and the mixture stirred at rt for 4h. The mixture was purified by preparative HPLC chromatography (Waters SunFire Column, eluant Methanol / 0.1% aqueous trifluoroacetic acid) to afford the titled compound (50 mg). m/e (MultiMode+) 463 [M+H]⁺

1H NMR (400 MHz, DMSO) δ 8.96 (d, 1H), 8.15 (s, 3H), 7.67 (d, 2H), 7.55 (s, 1H), 7.42 - 7.39 (m, 4H), 5.10 (q, 1H), 3.94 (t, 2H), 3.38 (t, 2H), 3.30 - 3.20 (m, 2H), 3.17 (s, 3H), 2.13 - 2.02 (m, 1H), 1.95 (quintet, 2H), 1.89 - 1.67 (m, 7H).

Example 4: (S)-l-Amino- V-(l-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)cyclopentanecarboxamide trifluoroacetic acid salt

(i) (S)-tert-Buty\ l-(l-amino-3-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)-l-oxopropan-2-ylcarbamoyl)cyclopentylcarbamate

To (S)-tert-butyl l-(l-amino-l-oxo-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)propan-2-ylcarbamoyl)cyclopentylcarbamate (Example 3, step (i), 0.25 g), 5- bromo-3-methylbenzo[d]oxazol-2(3H)-one (114 mg) and aqueous potassium carbonate (2M, 0.75 mL) in acetonitrile (11 mL) under a nitrogen atmosphere was added 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride (10 mg) and the mixture heated at 80°C for 3h. The mixture was concentrated to dryness and the residue purified on a silica column eluting with ethyl acetate to afford the sub-titled compound (105 mg). m/e (APCI-) 521 [M-H]^~

(ii) (S)-ieri-Buty\ l-(l-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethylcarbamoyl)cyclopentylcarbamate

To (S)-tert-butyl l-(l-amino-3-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)- l-oxopropan-2-ylcarbamoyl)cyclopentylcarbamate (Example 4, step (i), 100 mg) in dichloromethane (3 mL) was added Burgess' reagent (59 mg) and the mixture stirred for 18h and then poured into water (5 mL) and dichloromethane (5 mL). The mixture was shaken and the organic layer separated. The aqeous layer was further extracted with dichloromethane (3 x 5 mL) and the combined organic extracts were dried over magnesium sulfate to afford the sub-titled compound (90 mg). m/e (APCI+) 405 [M+2H-BOC]

To (S)-tert-butyl 1 -(1 -cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethylcarbamoyl)cyclopentylcarbamate (Example 4, step (ii), 90 mg) was added formic acid (3 mL) and the mixture stirred for 4h at room temperature. The solution was purified by preparative HPLC Chromatography (Waters SunFire Column) eluting with 0.1% aqueous trifluoroacetic acid / methanol to afford the titled compound (23 mg).

1H NMR (400 MHz, DMSO) δ 8.96 (d, 1H), 8.15 (s, 3H), 7.67 (d, 2H), 7.56 (s, 1H), 7.43 - 7.38 (m, 4H), 5.10 (q, 1H), 3.41 (s, 3H), 3.30 - 3.15 (m, 2H), 2.15 - 1.98 (m, 1H), 1.91 - 1.65 (m, 7H). m/e (MultiMode+) 405 [M+H]

Example 5: (S)-l-Amino-N-(l-cyano-2-(4'-cyanobiphenyl-4- yl)ethyl)cyclopentanecarboxamide trifluoroacetic acid salt

(i) (S)-tert-Buty\ l-(l-amino-3-(4'-cyanobiphenyl-4-yl)-l-oxopropan-2- ylcarbamoyl)cyclopentylcarbamate

l-(tert-Butoxycarbonylamino)cyclopentanecarboxylic acid (0.53 g), (5)-2-amino-3-(4'- cyanobiphenyl-4-yl)propanamide (Example 1, step (iii), 0.61 g) and N-ethyl-N- z^'sopropylpropan-2-amine (1.01 mL) were dissolved in DMF (10 mL) and to the solution was added TBTU (1.11 g). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated to dryness and the residue purified by chromatography on silica eluting with ethyl acetate in z^'sohexane (20/80) and then ethyl acetate in z^'sohexane (50:50) to afford the sub-titled compound (1.05 g). m/e (APCI+) 377 [M+2H-BOC] 1H NMR (400 MHz, CDC1₃) δ 7.73 (d, 2H), 7.69 (d, 2H), 7.54 (d, 2H), 7.34 (d, 2H), 7.11 (s, 1H), 6.90 (d, 1H), 5.72 (s, 1H), 5.54 (s, 1H), 4.72 (td, 1H), 3.34 (dd, 1H), 3.13 (dd, 1H), 2.42 - 2.31 (m, 1H), 1.78 - 1.55 (m, 7H), 1.33 (s, 9H).

(ii) (S)-tert- uty\ l-(l-cyano-2-(4'-cyanobiph

yl)ethylcarbamoyl)cyclopentylcarbamate

(S)-tert-Butyl 1 -( 1 -amino-3 -(4'-cyanobiphenyl-4-yl)- 1 -oxopropan-2- ylcarbamoyl)cyclopentylcarbamate (Example 5, step (i), 1.05 g) in dichloromethane (15 mL) was treated with Burgess' reagent (1.31 g) and the mixture was stirred at room

temperature for 72 h. The reaction was evaporated onto silica and purified on silica eluting with ethyl acetate in z^'so hexane (30/70). The resulting compound was purified by preparative HPLC chromatography (Waters SunFire column) eluting with acetonitrile in 0.1% aqueous TFA to afford the sub-titled compound (0.41 g).

+

m/e (APCI+) 359 [M+2H-BOC]

1H NMR (400 MHz, CDCI₃) δ 7.73 (dt, 2H), 7.67 (dt, 2H), 7.58 (dt, 2H), 7.42 (d, 2H), 5.15 (dd, 1H), 4.81 (s, 1H), 3.17 (dd, 1H), 3.10 (dd, 1H), 2.25 (s, 1H), 1.83 - 1.65 (m, 8H), 1.44 (s, 9H). Example 5: (S)-l-Amino-N-(l-cyano-2-(4'-cyanobiphenyl-4- yl)ethyl)cyclopentanecarboxamide trifluoroacetic acid salt

To (S)-tert-butyl 1 -(1 -cyano-2-(4'-cyanobiphenyl-4-yl)ethylcarbamoyl)cyclopentylcarbamate (Example 5, step (ii), 0.16 g) was added formic acid (2 mL) and the mixture heated to 50°C for 10 min. The mixture was evaporated to dryness, dissolved in methanol (3 mL) and purified on preparative HPLC chromatography (Waters SunFire column) eluting with acetonitrile in 0.1% aqueous TFA to afford the titled compound (0.136 g).

1H NMR (400 MHz, CDC1₃) δ 7.95 (d, IH), 7.72 (d, 2H), 7.65 (d, 2H), 7.57 (d, 2H), 7.38 (d, 2H), 5.06 (dd, IH), 3.20 (d, 2H), 2.29 - 2.15 (m, 2H), 2.14 - 2.02 (m, 2H), 2.00 - 1.44 (m, 6H). m/e (MultiMode+) 359 [M+H]

Example 6: (S)-l-Amino-N-(l-cyano-2-(4'-(ethylsulfonyl)biphj

yl)ethyl)cyclohexanecarboxamide

(i) (S)-tert-Buty\ l-(l-amino-3-(4-iodophenyl)-l-oxopropan-2- ylcarbamoyl)cyclohexylcarbamate

(S)-2-Amino-3-(4-iodophenyl)propanamide (Example 2, step (i), 6.5 g), \-{tert- butoxycarbonylamino)cyclohexanecarboxylic acid (5.45 g) and N-ethyl-N-z^'sopropylpropan-2- amine (9.76 mL) were dissolved in DMF (30 mL) and to the solution was added TBTU (10.8 g). The reaction mixture was stirred, at room temperature for 2 h. The reaction mixture was poured into water (250 mL) and the products extracted into diethyl ether (3 x 500 mL). The combined organic extracts were dried over magnesium sulfate and concentrated to dryness to afford the sub -titled compound as a gum (10.8 g). m/e (APCI +ve) 416 [M+2H-BOC]

(ii) (S)-ieri-Buty\ l-(l-cyano-2-(4'-(ethylsulfonyl)biph

yl)ethylcarbamoyl)cyclohexylcarbamate

(S)-tert-Butyl l-(l-amino-3-(4'-(ethylsulfonyl)biphenyl-4-yl)-l-oxopropan-2- ylcarbamoyl)cyclohexylcarbamate (Example 6, step (i), 0.38 g) in dichloromethane (10 mL) was stirred with Burgess' reagent (0.49 g) for 17h. The reaction mixture was concentrated to dryness and the residue purified on silica gel eluting with ethyl acetate to afford the sub-titled compound (240 mg) as a solid. m/e (APCI+) 440 [M+2H-BOC]

Example 6: (S)-l-Amino- V-(l-cyano-2-(4'-(ethylsulfonyl)biphi

yl)ethyl)cyclohexanecarboxamide

(S)-tert-Butyl 1 -( 1 -cyano-2-(4'-(ethylsulfonyl)biphenyl-4- yl)ethylcarbamoyl)cyclohexylcarbamate (Example 6, step (ii), 240 mg) in formic acid (2 mL) was heated for 5 min at 50 °C after which time LCMS indicated deprotection had occured. The cooled reaction mixture was concentrated under vacuum at 50°C and the residue dissolved in water then basified with 0.880 ammonia. The basified mixture was extracted into dichloromethane (100 mL) and the extract dried over magnesium sulfate. After concentration the extract was purified on a silica column eluting with ethyl acetate to afford the titled compound (1 10 mg).

1H NMR (500 MHz, DMSO) δ 7.94 (s, 4H), 7.73 (d, 2H), 7.44 (d, 2H), 5.00 (t, 1H), 3.23 - 3.19 (m, 2H), 1.69 (td, 1H), 1.60 - 1.1 1 (m, 13H), 3.36 - 3.30 (m, 2H). m/e (MultiMode+) 440 [M+H] Example 7: (S)-l-Amino- V-(l-cyano-2-(4'-cyanobiphi

yl)ethyl)cyclobutanecarboxamide

(i) l-(terf-Butoxycarbonylamino)cyclobutanecarboxylic acid

1-Aminocyclobutanecarboxylic acid (1.02 g) was dissolved in tetrahydrofuran (14 mL) and water (6 mL) and treated with di-tert-butyl dicarbonate (2.71 g) and triethyl amine (3.5 mL). The mixture was stirred for 72 h at room temperature and then partially evaporated and partitioned between ethyl acetate (3 x 30 mL) and water (20 mL). The layers were separated and the organic layer was dried and evaporated to afford the sub -titled compound (2.330 g).

1H NMR (400 MHz, CDC1₃) δ 6.34 (s, 0.4H), 5.26 (s, 0.6H), 2.71 - 2.62 (m, 2H), 2.40 - 2.15 (m, 2H), 2.12 - 1.98 (m, 2H), 1.44 (s, 9H). (ii) (S)-tert-Buty\ l-(l-amino-3-(4'-cyanobiphenyl-4-yl)-l-oxopropan-2- ylcarbamoyl)cyclobutylcarbamate

To a mixture of l-(tert-butoxycarbonylamino)cyclobutanecarboxylic acid (Example 7, step (i), 0.34 g), (S)-2-amino-3-(4'-cyanobiphenyl-4-yl)propanamide (Example 1, step (iii), 0.42 g) and N-ethyl-N-z^'sopropylpropan-2-amine (0.69 mL) in DMF (10 mL) was added TBTU (0.76 g). The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated to dryness and absorbed onto silica and purified by chromatography on a silica column and eluted with ethyl acetate in z^'sohexane (20:80), then ethyl acetate in z^'so hexane (30:70) and finally ethyl acetate in z^'sohexane (50:50) to afford after evaporation of the relevant fractions the sub -titled compound (0.59 g) m/e (APCI+) 363 [M+2H-BOC]

1H NMR (400 MHz, CDC1₃) δ 7.72 (d, 2H), 7.69 (d, 2H), 7.54 (d, 2H), 7.33 (d, 2H), 6.98 (d, 1H), 6.91 (s, 1H), 6.17 (s, 1H), 6.00 (s, 1H), 4.68 (ddt, 1H), 3.35 - 3.24 (m, 1H), 3.08 (dd, 1H), 2.76 - 2.62 (m, 1H), 2.43 - 2.31 (m, 1H), 2.23 - 2.12 (m, 1H), 2.09 - 2.01 (m, 1H), 1.94 - 1.84 (m, 1H), 1.84 - 1.83 (m, 1H), 1.33 (s, 9H). (iii) (S)-tert-Buty\ l-(l-cyano-2-(4'-cyanobiphi

yl)ethylcarbamoyl)cyclobutylcarbamate

To (S)-tert-butyl 1 -(1 -amino-3-(4'-cyanobiphenyl-4-yl)- 1 -oxopropan-2- ylcarbamoyl)cyclobutylcarbamate (Example 7, step (ii), 0.59 g) in dichloromethane (15 mL) was added Burgess' reagent (0.76 g) and the mixture was stirred at room temperature for 72 h. The reaction mixture was absorbed onto silica and purified by chromatography on silica eluting with ethyl acetate in z^'sohexane (20:80) and then ethyl acetate in z^'sohexane (30:70) to afford the sub-titled compound (0.422 g). m/e (APCI+) 345 [M+2H-BOC]

1H NMR (400 MHz, CDC1₃) δ 7.72 (d, 2H), 7.66 (d, 2H), 7.57 (d, 2H), 7.42 (d, 2H), 5.63 (s, 0.5H), 5.32 (s, 0.5H), 5.17 (dd, 1H), 3.21 - 3.11 (m, 2H), 2.83 - 2.29 (m, 2H), 2.20 - 1.83 (m, 5H), 1.44 (s, 9H). Example 7: (S)-l-Amino-7V-(l-cyano-2-(4'-cyanobiphi

yl)ethyl)cyclobutanecarboxamide

To (iS)-tert-butyl 1 -( 1 -cyano-2-(4'-cyanobiphenyl-4-yl)ethylcarbamoyl)cyclobutylcarbamate (Example 7, step (iii), 200 mg) was added formic acid (2 mL) and the mixture heated to 50°C for 30 min. The mixture was diluted with water (10 mL) and the solution was basified to ~ pH 8-9 with 0.880 ammonia solution and then extracted with dichloromethane (2 x 10 mL). The combined organic extracts were dried (magnesium sulfate) and evaporated to give a solid. The crude product was purified on silica eluting with ethyl acetate in z^'sohexane (20/80) increasing to ethyl acetate in z^'so hexane (50/50). The resulting material was then repurified on preprative HPLC chromatography (Waters SunFire column) eluting with acetonitrile in 0.1% aqueous trifluoroacetic acid to afford the purifed compound as a trifluoroacetic acid salt salt.

Conversion to the free base by partitioning between saturated sodium bicarbonate and dichloromethane which was dried with magnesium sulfate and evaporated afforded the titled compound (100 mg).

1H NMR (400 MHz, CDC1₃) δ 7.84 (d, 1H), 7.73 (dd, 2H), 7.67 (dd, 2H), 7.58 (dt, 2H), 7.40 (d, 2H), 5.18 - 5.1 1 (m, 1H), 3.20 - 3.10 (m, 2H), 2.75 - 2.65 (m, 1H), 2.61 - 2.52 (m, 1H), 2.04 - 1.93 (m, 2H), 1.88 - 1.78 (m, 2H), 1.77 (s, 2H). m/e (MultiMode+) 345 [M+H] Example 8: (S)-l-Amino- V-(l-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)cyclohexanecarboxamide trifluoroacetic acid salt

(i) (S)-tert-Buty\ l-(l-amino-l-oxo-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)propan-2-ylcarbamoyl)cyclohexylcarbamate

A mixture of 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (6.92 g), (S)-tert-bvA.y\ l-(l-amino-3-(4-iodophenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 6, step (i), 10.8 g) and potassium acetate (6.17 g) in acetonitrile (100 mL) and water (16 mL) was treated with 1,1 ¾z5(di-tert-butylphosphino)ferrocene palladium dichloride (0.1 g) and the mixture stirred and heated under reflux for 4 h. The cooled reaction mixture was concentrated under vacuum and the residue partitioned between water (100 mL) and diethyl ether (500 mL). The organic extract was dried over magnesium sulfate and concentrated to dryness to afford an oil. The crude product was chromatographed on silica gel eluting with z^'sohexane / diethyl ether (40:60) to afford the sub-titled compound (6.95 g).

1H NMR (500.303 MHz, CDC1₃) δ 7.74 (d, 2H), 7.21 (d, 2H), 7.05 (s, 1H), 6.39 - 6.34 (m, 1H), 5.23 (s, 1H), 4.82 (s, 1H), 4.76 - 4.70 (m, 1H), 3.35 - 3.29 (m, 1H), 3.15 - 3.09 (m, 1H), 2.04 - 1.98 (m, 1H), 1.96 - 1.86 (m, 2H), 1.69 - 1.50 (m, 7H), 1.34 (s, 12H), 1.30 (s, 9H). m/e (MultiMode⁺) 416 [M+2H-Boc]⁺

(ii) (S)-4-(3-Amino-2-(l-(tei"i-butoxycarbonylamino)cyclohexanecarboxamido)-3- oxopropyl)phenylboronic acid

(S)-tert-butyl l-(l-amino-l-oxo-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)propan-2-ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i), 1 g) was dissolved in 50% aqueous acetone (30 mL). The solution was treated with ammonium acetate (0.329 g) and sodium periodate (0.913 g) and stirred at ambient temperature for 20 h. The acetone was removed under vacuum at room temperature and the remaining aqueous treated with saturated brine (50 mL). The mixture was extracted with ethyl acetate (2 x 75 mL) and the organic extract further washed with 10% aqueous sodium metabisulfite solution (50 mL). The extract was dried over magnesium sulfate and concentrated to dryness. The solid residue was triturated with diethyl ether and collected by filtration to afford the sub-titled compound

(670 mg). 1H NMR (399.826 MHz, DMSO) δ 7.90 (d, 2H), 7.65 (d, 2H), 7.46 - 7.40 (m, 1H), 7.23 - 7.09 (m, 4H), 6.98 - 6.90 (m, 1H), 4.44 - 4.36 (m, 1H), 3.13 - 3.05 (m, 1H), 2.94 - 2.86 (m, 1H), 1.79 - 1.60 (m, 3H), 1.48 - 1.08 (m, 16H). m/e (MultiMode⁺) 334 [M+2H-Boc]⁺

(i) (S)-ieri-Buty\ l-(l-amino-3-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate

(5)-4-(3-Amino-2-(l-(tert-butoxycarbonylamino)cyclohexanecarboxamido)-3- oxopropyl)phenylboronic acid (Example 8, step (ii), 300 mg), potassium acetate (204 mg) and 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one (158 mg) in a mixture of water (1 mL) and acetonitrile (20 mL) was stirred under nitrogen with 1 ,1 ¾z5(di-tert-butylphosphino)ferrocene palladium dichloride (5 mg). The mixture was stirred and heated at 80°C for 20 h. The cooled reaction mixture was concentrated to dryness, and the residue purified by chromatography on silica eluting with ethyl acetate to afford the sub-titled compound (300 mg). m/e (APCI+) 537 [M+H]

Example 8: (S)-l-Amino- V-(l-cyano-2-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5- yl)phenyl)ethyl)cyclohexanecarboxamide trifluoroacetic acid salt

(S)-tert-Butyl l -(l-amino-3-(4-(3-methyl-2-oxo-2,3-dihydrobenzo[d]oxazol-5-yl)phenyl)-l- oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i), 300 mg) in

dichloromethane (10 mL) was stirred with Burgess' reagent (266 mg) for 17 h. The reaction mixture was concentrated to dryness and formic acid (1 mL) was added. The mixture was stirred at room temperature for 2 h and then the volatiles were removed under reduced pressure. Water (20 mL) was added to the residue and the mixture was basified with 0.880 ammonia. The aqueous was extracted with ethyl acetate (2 x 75 mL) and the combined extracts were dried over magnesium sulfate and concentrated to dryness. The crude product was purified by reversed phase HPLC eluting with a gradient of methanol in 0.1 % aqueous trifluoroacetic acid (Waters SunFire column) to afford the titled compound as a solid (26 mg).

1H NMR (400 MHz, d₆-DMSO) δ 9.13 (d, 1H), 8.18 (s, 3H), 7.68 (d, 2H), 7.56 (s, 1H), 7.45 - 7.34 (m, 4H), 5.14 - 5.07 (m, 1H), 3.40 (s, 3H), 3.29 - 3.15 (m, 2H), 2.00 - 1.67 (m, 3H), 1.64 - 1.42 (m, 6H), 1.34 - 1.21 (m, 1H). m/e (MultiMode+) 419 [M+H]

Example 9: (S)-l-Amino- V-(l-cyano-2-(4-(2-oxoindolin-6- yl)phenyl)ethyl)cyclohexanecarboxamide

(i) (S)-tert-Buty\ l-(l-amino-l-oxo-3-(4-(2-oxoindolin-6-yl)phenyl)propan-2- ylcarbamoyl)cyclohexylcarbamate

Potassium carbonate (161 mg) was added in water (1.6 mL) to (S)-tert-butyl l-(l-amino-3-(4- iodophenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 6, step (i), 300 mg), 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)indolin-2-one (151 mg) and 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride (49.3 mg) in degassed acetonitrile (5 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at 80°C for 2 h. The reaction mixture was allowed to cool to room temperature, filtered, evaporated then partitioned between ethyl acetate and water. The organics were dried over magnesium sulfate and evaporated to afford crude material as a brown gum. The crude product was absorbed onto Celite and purified by chromatography on silica eluting with 70% to 100% ethyl acetate in z^'sohexane. Pure fractions were evaporated to dryness to afford the sub-titled compound (221 mg). 1H NMR (500 MHz, DMSO) δ 10.43 (s, 1H), 7.50 (d, 1H), 7.46 (d, 2H), 7.25 (t, 4H), 7.20 (s, 1H), 7.16 (dd, 1H), 6.98 (s, 1H), 6.95 (s, 1H), 4.48 - 4.40 (m,lH), 3.50 (s, 2H), 3.15 (d, 1H), 2.93 (dd, 1H), 1.74 - 1.64 (m, 3H), 1.48 - 1.38 (m, 3H), 1.35 (s, 10H), 1.32 - 1.22 (m, 2H), 1.15 - 1.08 (m, 1H). m/e (APCI+) 521 [M+H]⁺

Burgess' reagent (145 mg) was added to (S)-tert-butyl 1-(1 -amino- l-oxo-3 -(4-(2-oxoindolin- 6-yl)phenyl)propan-2-ylcarbamoyl)cyclohexylcarbamate (Example 9, step (i), 211 mg) in dichloromethane (25 mL) at 20°C under air. The resulting suspension was stirred at room temperature for 16 h. Burgess' reagent (70 mg) was added and the mixture stirred for a further 4 h. The reaction mixture was filtered and the resulting solid was used without further purification. To the crude product (162 mg) was added formic acid (3.7 mL) and the mixture heated to 50°C for 15 min. The mixture was cooled and diluted with methanol. The mixture was evaporated to dryness, dissolved in methanol (10 mL) and re-evaporated to dryness. The material was purified by preparative HPLC on a Waters X-Bridge column eluting with methanol in aqueous 0.1% trifluoroacetic acid as eluent. The fractions containing the desired compound were combined, evaporated and then dissolved in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate. The combined organic phases were dried over magnesium sulfate and evaporated. The residue was then triturated with diethyl ether and evaporated to afford the titled compound (54 mg).

1H NMR (500 MHz, DMSO) δ 10.45 (s, 1H), 7.55 (d, 2H), 7.36 (d, 2H), 7.27 (d, 1H), 7.19 (dd, 1H), 7.00 (s, 1H), 4.97 (t, 1H), 3.50 (s, 2H), 3.22 - 3.12 (m, 2H), 1.69 (dd, 1H), 1.54 (dt, 2H), 1.48 (d, 2H), 1.44 - 1.38 (m, 1H), 1.37 - 1.30 (m, 1H), 1.27 (d, 1H), 1.15 (t, 2H). m/e (MultiMode+) 403 [M+H]⁺

Example 10 : Amino- V-(l -cyano-2-(4-(l-methyl-6-oxo- 1 ,6-dihydropyridin-3- y])phenyl)ethyl)cyclohexanecarboxamide

(i) (S)-tert- utyl l-(l-amino-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)phenyl)-l- oxopropan-2-ylcarbamoy])cyclohexylcarbamate

(iS)-tert-Butyl 1 -( 1 -amino-3 -(4-iodophenyl)- 1 -oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (1.5 g) and l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (684 mg) in acetonitrile (8 mL) and water (lmL) with potassium acetate (571 mg) was bubbled through with nitrogen and then 1 , 1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (5mg) was added and the mixture was heated at 85°C for 18 h. The reaction mixture was allowed to cool to room temperature and absorbed onto silica for purification by

chromatography on silica eluting with ethyl acetate, then ethyl acetate / methanol (2:98) as eluent to afford the subtitled compound. m/e (APCI+) 497 [M+H]

(ii) (S)-tert-Buty\ l-(l-cyano-2-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate

(S)-tert-butyl 1 -(1 -amino-3-(4-(l -methyl-6-oxo-l ,6-dihydropyridin-3-yl)phenyl)- 1 - oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (1.08g) in dichloromethane (30 mL) was treated with Burgess' reagent (1.05 g) and stirred at room temperature for 72 h. The solvent was partially evaporated and the resulting mixture was purified by chromatography on silica using ethyl acetate as eluent to afford the subtitled compound (1.07g). m/e (APCI+) 479 [M+H]⁺

Example 10: (S)-l-Amino-N-(l-cyano-2-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethyl)cyclohexanecarboxamide

(S)-tert-Butyl 1 -(1 -cyano-2-(4-(l -methyl-6-oxo- 1 ,6-dihydropyridin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (Example 10, step (ii), 789 mg) in formic acid (4 mL) was heated at 50°C for 20 mins. The solvent was evaporated and the mixture azeotroped with acetonitrile. The crude product was purified by reversed phase HPLC eluting with acetonitrile / 0.1% aqueous trifluoroacetic acid. The solvent was evaporated and the residue azeotroped with methanol. The product converted to the free base by passing through a PL-HCO₃ cartridge in methanol / dichloromethane. The solvent was evaporated and dried to afford the titled compound (73 mg). 1H NMR (400 MHz, d₆-DMSO) δ 8.12 (d, IH), 7.81 (dd, IH), 7.52 (d, 2H), 7.33 (d, 2H), 6.47 (d, IH), 4.94 (t, IH), 3.50 (s, 3H), 3.15 (d, 2H), 1.75 - 1.63 (m, IH), 1.53 (dd, 4H), 1.37 (s, IH), 1.27 (d, 2H), 1.18 (d, 2H). m/e (MultiMode+) 379 [M+H]⁺

Example 11 : (S)-5-(4-(2-(l-Aminocyclohexanecarboxamido)-2-cyanoethyl)phenyl)- V,3- dimethylpicolinamide

(i) (S)-tert- uty\ l-(l-amino-3-(4-(5-methyl-6-(methylcarbamoyl)pyridin-3-yl)phi oxopropan-2-ylcarbamoyl)cyclohexylcarbamate

Potassium carbonate (250 mg) in water (2 mL) was added to (S)-tert-butyl 1-(1 -amino- 1-oxo- 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2- ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i), 466 mg), 5-bromo-N,3- dimethylpicolinamide (207 mg) and 1,1 ¾z5(di-tert-butylphosphino)ferrocene palladium dichloride (59 mg) in degassed acetonitrile (12 mL) at 20°C under nitrogen. The resulting solution was stirred at 80 °C for 4 h. The reaction mixture was cooled, filtered and diluted with ethyl acetate, and washed with water. The aqueous was further extracted with dichloromethane and the organics were combined and dried over magnesium sulfate. The crude product was purified by chromatography on silica eluting with ethyl acetate in z^'sohexane (70:30 to 100:0) to afford the sub-titled compound (156 mg). m/e (APCI+) 438 [M+2H-Boc]

(ii) (S)-tert-Buty\ l-(l-cyano-2-(4-(5-methyl-6-(methylcarbamoyl)pyridin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate

Burgess' reagent (138 mg) was added to (S)-tert-butyl l-(l-amino-3-(4-(5-methyl-6- (methylcarbamoyl)pyridin-3 -yl)phenyl)- 1 -oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 11, step (i), 156 mg) in dichloromethane (25 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane, and washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to afford sub-titled compound as a crude product (198 mg). m/e (APCI+) 520 [M+H]⁺

Example 11 : (S)-5-(4-(2-(l-Aminocyclohexanecarboxamido)-2-cyanoethyl)ph

dimethylpicolinamide

To (S)-tert-butyl 1 -(1 -cyano-2-(4-(5-methyl-6-(methylcarbamoyl)pyridin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (Example 11, step (ii), 198 mg) was added formic acid (3.6 mL) and the mixture stirred at 50°C for 15 minutes. The reaction mixture was allowed to cool to room temperature and then azeotroped with methanol. The crude material was purified by reversed phase HPLC eluting with a gradient of methanol in aqueous 0.1% trifluoroacetic acid. The fractions containing the desired compound were evaporated and then washed with saturated aqueous sodium bicarbonate solution and extracted into

dichloromethane. The combined organics were dried over magnesium sulfate and then evaporated to dryness to give the titled compound (32 mg).

1H NMR (500 MHz, DMSO) δ 8.72 (d, IH), 8.61 (q, IH), 8.03 (d, IH), 7.75 (d, 2H), 7.44 (d, 2H), 5.00 (t, IH), 3.25 - 3.17 (m, 2H), 2.79 (d, 3H), 2.61 (s, 3H), 1.73 - 1.08 (m, 10H). m/e (MultiMode+) 420 [M+H]

Example 12: (S)-l-Amino- V-(l-cyano-2-(4-(l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)phenyl)ethyl)cyclohexanecarboxamide

(i) (S)-tert- uty\ l-(l-amino-3-(4-(l-methyl-6-oxo-l,6-dihydropyridazin-3-yl)ph oxopropan-2-ylcarbamoyl)cyclohexylcarbamate

Potassium carbonate (276 mg) in water (1 mL) was added to (S)-tert-butyl 1-(1 -amino- 1-oxo- 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2- ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i) 515 mg), 6-bromo-2-methylpyridazin- 3(2H)-one (189 mg) and 1,1 ¾z5(di-tert-butylphosphino)ferrocene palladium dichloride (50 mg) in degassed acetonitrile (6 mL) at 20°C under nitrogen. The resulting solution was stirred at 80°C for 50 mins. The reaction mixture was cooled, filtered and diluted with ethyl acetate, and washed with water. The combined organic phases were dried over magnesium sulfate, filtered and evaporated to afford crude product which was purified chromatography on silica eluting with a gradient of methanol in ethyl acetate. Pure fractions were evaporated to dryness to afford the subtitled compound (385 mg).

1H NMR (500 MHz, DMSO) δ 8.02 (d, IH), 7.76 (d, 2H), 7.52 (d, IH), 7.28 (d, 2H), 7.24 (s, IH), 7.22 (s, IH), 7.03 (d, IH), 6.96 (s, IH), 4.48 - 4.40 (m, IH), 3.73 (s, 3H), 3.16 (d, IH), 2.95 (dd, IH), 1.78 - 1.63 (m, 3H), 1.48 - 1.37 (m, 4H), 1.35 (s, 9H), 1.31 - 1.20 (m, 2H), 1.15 - 1.07 (m, IH). m/e (APCI+) 498 [M+H]⁺

(ii) (S)-tert-Buty\ l-(l-cyano-2-(4-(l-methyl-6-oxo-l,6-dihydropyridazin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate

(iS)-tert-Butyl 1 -( 1 -amino-3 -(4-( 1 -methyl-6-oxo- 1 ,6-dihydropyridazin-3 -yl)phenyl)- 1 - oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 12, step (i), 385 mg) and Burgess' Reagent (369 mg) were dissolved in dichloromethane (25 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane, and washed with water. The organic phase was dried through a phase separation cartridge and evaporated to afford crude product which was purified by chromatography on silica eluting a gradient of methanol in dichloromethane. Pure fractions were evaporated to dryness to afford the sub-titled compound (377 mg). 1H NMR (500 MHz, DMSO) δ 8.29 (d, IH), 8.04 (d, IH), 7.82 (d, 2H), 7.40 (d, 2H), 7.04 (d, IH), 6.50 (d, IH), 5.08 - 4.95 (m, IH), 3.73 (s, 3H), 3.13 - 3.06 (m, 2H), 1.82 - 1.54 (m, 3H), 1.44 (dd, 4H), 1.37 (s, 9H), 1.31 - 1.19 (m, 2H), 1.15 - 1.09 (m, IH). m/e (APCI+) 381 [M+2H-Boc]⁺

(S)-tert-Butyl 1 -(1 -cyano-2-(4-(l -methyl-6-oxo- 1 ,6-dihydropyridazin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (Example 12, step (ii) 377 mg) was dissolved in formic acid (3.9 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at 50°C for 10 mins. The reaction mixture was allowd to cool to room temperature and was then azeotroped with methanol. The crude material was purified by preparative HPLC on a Waters X-Bridge column eluting with a gradient of methanol in aqueous 0.1%

trifluoroacetic acid. The fractions containing the desired compound were evaporated and then washed with saturated aqueous sodium bicarbonate solution and extracted with

dichloromethane. The combined organic phases were dried over magnesium sulfate and evaporated to dryness to afford the sub-titled compound (143 mg).

1H NMR (500 MHz, DMSO) δ 8.04 (d, IH), 7.83 (d, 2H), 7.40 (d, 2H), 7.04 (d, IH), 4.98 (t, IH), 3.73 (s, 3H), 3.20 (d, 2H), 1.68 (td, IH), 1.60 - 1.44 (m, 4H), 1.44 - 1.37 (m, IH), 1.36 - 1.30 (m, 1H), 1.26 (d, 1H), 1.15 (t, 2H). m/e (MultiMode+) 380 [M+H]⁺

Example 13: (S)-4-Amino- V-(l-cyano-2-(4-(6-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-3-yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide

(i) Methyl 5-bromo-3-methylpicolinate

Sulfuric acid (0.025 mL) was added to 5-bromo-3-methylpicolinic acid (1 g) in methanol (20 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at reflux for 19 h. The reaction mixture was allowed to cool to room temperature and evaporated to dryness. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium hydrogen carbonate. The combined organic phases was dried over magnesium sulfate, filtered and evaporated to afford the sub-titled compound (1.019 g).

1H NMR (500 MHz, DMSO) δ 8.62 (s, 1H), 8.16 (s, 1H), 3.86 (s, 3H), 2.46 (s, 3H). m/e (APCI+) 232 [M+H]⁺

(ii) Methyl 5-bromo-3-(bromomethyl)picolinate

Methyl 5-bromo-3-methylpicolinate (Example 13, step (i), 800 mg) in dichloromethane (20 mL) was treated with N-bromosuccinide (619 mg) and AIBN (57 mg). The mixture was stirred and irradiated with a 500W halogen lamp for 3.5 h. The reaction mixture was allowed to cool to room temperature and diluted with dichloromethane, and washed with water. The organic was dried over magnesium sulfate, filtered and evaporated to afford the sub-titled compound (1.03 g). m/e (APCI+) 312 [M+H]

(iii) 3-Bromo-6-methyl-5H-pyrrolo[3,4-b]pyridin-7(6H)-one

Methanamine (2M in tetrahydrofuran, 9.1 mL) was added to methyl 5-bromo-3- (bromomethyl)picolinate (Example 13, step (ii), 1.03 g) in tetrahydrofuran (5 mL) at 20 °C under nitrogen. The resulting suspension was stirred at 70°C for 30 min.

The reaction mixture was cooled, filtered and evaporated to dryness to afford crude product which was purified by chromatography on silica eluting with ethyl acetate in dichloromethane (5:95 to 100:0). The solid that was collected during the filtration was dissolved in ethyl acetate and washed with water, extracted with dichloromethane, then washed with saturated aqueous hydrogen carbonate solution and extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate, combined with the pure material from the column to afford the sub-title compound (0.372 g).

1H NMR (400 MHz, DMSO) δ 8.82 (d, 1H), 8.37 (d, 1H), 4.48 (s, 2H), 3.10 (s, 3H). m/e (APCI+) 229 [M+H]+

(iv) (S)-tert-Buty\ l-(l-amino-3-(4-(6-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-3-yl)phenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate

Potassium carbonate (235 mg) in water (2 mL) was added to

1-(1 -amino- 1-oxo- 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2- ylcarbamoyl)cyclohexylcarbamate (Example 8, step (ii), 439 mg), 3-bromo-6-methyl-5H- pyrrolo[3,4-b]pyridin-7(6H)-one (Example 134, step (iii), 193 mg) and 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride (56 mg) in degassed acetonitrile (12 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at 80°C for 35 min. The reaction mixture was cooled, filtered, diluted with ethyl acetate, and washed with water. The aqueous was further extracted with dichloromethane and the combined organic phases were dried over magnesium sulfate, filtered and evaporated to afford crude product.

The crude product was purified by chromatography on silica eluting with a gradient 15 to 25% methanol in ethyl acetate. Pure fractions were evaporated to dryness to afford the subtitled compound (391 mg). m/e (APCI+) 536 [M+H]⁺

(v) (S)-terf-Butyl l-(l-cyano-2-(4-(6-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 3-yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate

Burgess' reagent (348 mg) was added to (S)-tert-butyl l-(l-amino-3-(4-(6-methyl-7-oxo-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)phenyl)-l-oxopropan-2- ylcarbamoyl)cyclohexylcarbamate (Example 13, step (iv), 391 mg) in dichloromethane (25 mL) at 20°C under nitrogen. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane, and washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by chromatography on silica eluting with a gradient of 10 to 40% methanol in ethyl acetate. Pure fractions were evaporated to dryness to afford the subtitled compound (360 mg). m/e (APCI+) 518 [M+H]⁺

To (S)-tert-butyl 4-(l -cyano-2-(4-(6-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3- yl)phenyl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (0.186 g) was added formic acid (9.67 mL) and the mixture heated to 50°C for 15 min. The mixture was cooled and diluted in methanol, and then evaporated to dryness. The residue was collected by filtration and the filtrate purified by preparative HPLC on a Waters X-Bridge column eluting with methanol in aqueous 0.1% trifluoroacetic acid. The fractions containing the desired compound were combined, in dichloromethane and washed with saturated aqueous sodium hydrogen carbonate solution. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was then triturated with diethyl ether and evaporated to afford a solid. The resulting solid (70 mg) was suspended in water (2.2 mL) and acetonitrile (0.11 mL), and stirred at room temperature for 3 days. The suspension was filtered, washed with water and the solid dried under vacuum at 50°C to afford the titled compound (56 mg).

1H NMR (500 MHz, DMSO) δ 8.99 (d, IH), 8.32 (d, IH), 7.77 (d, 2H), 7.46 (d, 2H), 5.03 (t, IH), 4.54 (s, 2H), 3.66 - 3.53 (m, 3H), 3.46 (dt, IH), 3.27 - 3.18 (m, 2H), 3.13 (s, 3H), 1.89 (ddd, IH), 1.74 (ddd, IH), 1.17 (dd, 2H). m/e (MultiMode+) 420 [M+H]

Example 14: (S)-l-Amino- V-(l-cyano-2-(4-(2-(2-methoxyethyl)-l-oxoisoindolin-5- yl)phenyl)ethyl)cyclohexanecarboxamide

(i) 6-Chloro-2-ethylpyridazin-3(2H)-one

6-Chloropyridazin-3(2H)-one (139 mg), iodoethane (0.258 mL) and potassium carbonate (162 mg) were dissolved in acetonitrile (5 mL) and sealed into a microwave tube. The reaction was heated to 100°C for 60 min in the microwave reactor. The reaction mixture was allowed to cool and was filtered and evaporated to give a gum which was dissolved in dichloromethane and washed with water and then evaporated to give the sub-titled compound (109 mg). m/e (APCI+) 161 [Μ+Η]

(ii) (S)-tert-Buty\ l-(l-amino-3-(4-(l-ethyl-6-oxo-l,6-dihydropyridazin-3-yl)ph oxopropan-2-ylcarbamoyl)cyclohexylcarbamate

Potassium carbonate (190 mg) in water (1.3 mL) was added to

l-(l-amino-l- oxo-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2- ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i), 354 mg), 6-chloro-2-ethylpyridazin- 3(2H)-one (Example 14, step (i), 109 mg) and 1,1 ¾z5(di-tert-butylphosphino)ferrocene palladium dichloride (50 mg) in degassed acetonitrile (8 mL) at 20°C under at atmosphere of nitrogen. The resulting solution was stirred at 90°C for 4 h. The reaction mixture was allowed to cool, filtered and evaporated to dryness and redissolved in dichloromethane, washed with water, separated and evaporated. The crude material was purified by chromatography on silica, eluting with ethyl acetate to afford the sub-titled compound (211 mg). m/e (APCI+) 411 [M-Boc]

(iii) (S)-terf-Butyl l-(l-cyano-2-(4-(l-ethyl-6-oxo-l,6-dihydropyridazin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate

(S)-tert-Butyl 1 -( 1 -amino-3 -(4-( 1 -ethyl-6-oxo- 1 ,6-dihydropyridazin-3 -yl)phenyl)- 1 - oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 14, step (ii), 211 mg) and Burgess' Reagent (161 mg) were dissolved in dichloromethane (25 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at room temperature for 17 h. The reaction mixture was diluted with dichloromethane and was washed with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to afford the sub-titled compound (214 mg). m/e (APCI+) 394 [M-Boc]⁺

Example 14: (S)-l-Amino- V-(l-cyano-2-(4-(l-ethyl-6-oxo-l,6-dihydropyridazin-3- yl)phenyl)ethyl)cyclohexanecarboxamide

(S)-tert- utyl 1 -(1 -cyano-2-(4-(l -ethyl-6-oxo- 1 ,6-dihydropyridazin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (Example 14, step (iii), 214 mg) was dissolved in formic acid (3.7 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at 50°C for 15 min. The reaction mixture was allowed to cool to room temperature, azeotroped with methanol and then redissolved in methanol and filtered. The crude material was then purified by preparative HPLC on a Waters X-Bridge column using a gradient of methanol in aqueous 0.1% trifluoroacetic acid as eluent. The fractions containing the desired compound were evaporated, washed with satuarted aqueous sodium hydrogen carbonate solutuion and extracted into dichloromethane. The combined organic phases were dried over magnesium sulfate and evaporated to dryness to give the a product which was repurified by repeated HPLC chromatography to afford the titled compound (19 mg).

1H NMR (500 MHz, DMSO) δ 8.03 (d, IH), 7.84 (d, 2H), 7.41 (d, 2H), 7.03 (d, IH), 4.98 (t, IH), 4.16 (q, 2H), 3.20 (d, 2H), 1.68 (td, IH), 1.50 (qdd, 5H), 1.37 - 1.30 (m, 4H), 1.28 (s, IH), 1.15 (t, 2H). m/e (MultiMode+) 394 [M+H]

Example 15: (S)-l-Amino- V-(l-cyano-2-(4-(2-(2-methoxyethyl)-l-oxoisoindolin-5- yl)phenyl)ethyl)cyclohexanecarboxamide

(i) 5-Bromo-2-(2-methoxyethyl)isoindolin-l-one

A stirred solution of methyl 4-bromo-2-(bromomethyl)benzoate (1 g) in ethanol was treated with 2-methoxyethanamine (1.021 mL) and the mixture stirred and heated at reflux for 40 min. The reaction mixture was cooled to room temperature and diluted with water (100 mL). The resulting mixture was filtered and the filtrate extracted with ethyl acetate, dried over magnesium sulfate and evaporated to give a an oil. The oil was dissolved in diethyl ether and filtered and re-evaporated to afford the sub-titled compound (0.811 g). m/e (APCI+) 272 [M+H]+

(ii) (S)-tert- uty\ l-(l-amino-3-(4-(2-(2-methoxyethyl)-l-oxoisoindolin-5-yl)phi oxopropan-2-ylcarbamoyl)cyclohexylcarbamate

Potassium carbonate (268 mg) in water (1 mL) was added to (S)-tert-butyl 1-(1 -amino- 1-oxo- 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2- ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i), 500 mg) and 5-bromo-2-(2- methoxyethyl)isoindolin-l-one (Example 14, step (i), 262 mg) and 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride (51 mg) in degassed acetonitrile (6 mL) at 20°C under an atmosphere of nitrogen. The resulting suspension was stirred at 80°C for 30 min. The reaction mixture was cooled, evaporated to dryness and redissolved in ethyl acetate, and washed with water. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product which was purified by chromatography on silicaeluting with a gradient of 2 to 5% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford the sub-titled compound (337 mg).

1H NMR (500 MHz, DMSO) δ 7.84 (s, 1H), 7.72 (d, 2H), 7.61 (d, 2H), 7.55 (d, 1H), 7.29 (d, 2H), 7.24 (d, 2H), 6.97 (s, 1H), 4.57 (s, 2H), 4.50 - 4.41 (m, 1H), 3.70 (t, 2H), 3.57 (t, 2H), 3.27 (s, 3H), 3.18 (d, 1H), 2.95 (dd, 1H), 1.75 - 1.63 (m, 3H), 1.48 - 1.37 (m, 4H), 1.35 (s, 9H), 1.31 - 1.23 (m, 2H), 1.14 - 1.07 (m, 1H). m/e (APCI+) 579 [M+H]

(iii) (S)-tert-Buty\ l-(l-cyano-2-(4-(2-(2-methoxyethyl)-l-oxoisoindolin-5- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate

(S)-tert-Butyl 1 -(1 -amino-3-(4-(2-(2-methoxyethyl)- 1 -oxoisoindolin-5-yl)phenyl)- 1 - oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 15, step (ii), 331 mg) and Burgess' Reagent (273 mg) were dissolved in dichloromethane (15 mL) at 20°C under nitrogen. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was diluted with dichloromethane, and washed with water. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford the sub-titled compound (390 mg). m/e (APCI+) 561 [M+H]⁺

(S)-tert-Butyl 1 -( 1 -cyano-2-(4-(2-(2-methoxyethyl)- 1 -oxoisoindolin-5 - yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (390 mg) was dissolved in formic acid (8.0 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at 50°C for 10 min. The reaction mixture was cooled, azeotroped with methanol and then redissolved in methanol and filtered. The crude material was then purified by preparative HPLC on a Waters X-Bridge column eluting with a gradient of methanol in aqueous 0.1% trifluoroacetic acid. The fractions containing the desired compound were evaporated, washed with saturated aqueous sodium hydrogen carbonate and extracted into dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated to dryness to afford the subtitled compound (105 mg).

1H NMR (500 MHz, DMSO) δ 7.87 (s, IH), 7.77 - 7.72 (m, 2H), 7.69 (d, 2H), 7.41 (d, 2H), 4.99 (t, IH), 4.57 (s, 2H), 3.70 (t, 2H), 3.57 (t, 2H), 3.28 (s, 3H), 3.20 (d, 2H), 1.69 (td, IH), 1.60 - 1.51 (m, 2H), 1.51 - 1.46 (m, 2H), 1.45 - 1.38 (m, IH), 1.37 - 1.30 (m, IH), 1.29 - 1.22 (m, 1H), 1.19 - 1.11 (m, 2H). m/e (MultiMode+) 461 [M+H]+

Example 16: (S)-l-Amino- V-(l-cyano-2-(4-(l-isopropyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethyl)cyclohexanecarboxamide

(i) 5-Bromo-l-isopropylpyridin-2(lH)-one

Potassium tert-butoxide (324 mg) was added to 5-bromopyridin-2(lH)-one (502 mg) in dimethoxyethane (10 mL) at 20°C under nitrogen and stirred for 25 min. Potassium carbonate (279 mg) and 2-iodopropane (0.481 mL) were added to the reaction mixture and the resulting suspension was stirred at 95°C for 3 h. The reaction mixture was cooled, filtered and evaporated to dryness and redissolved in dichloromethane, and washed with 0.1M

hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford a mixture of products as a solid. The crude product was purified by chromatography on silica eluting with a gradient of 30 to 50% ethyl acetate in z^'sohexane to afford the sub-titled compound (382 mg).

1H NMR (500 MHz, DMSO) δ 7.97 (d, IH), 7.48 (dd, IH), 6.36 (d, IH), 4.98 (hept, IH), 1.29 (d, 6H). m/e (APCI+) 216 [M+H]⁺

(ii) (S)-terf-Butyl l-(l-amino-3-(4-(l-isopropyl-6-oxo-l,6-dihydropyridin-3-yl)ph oxopropan-2-ylcarbamoyl)cyclohexylcarbamate

Water (1 mL) was added to

l-(l-amino-l-oxo-3-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i), 258 mg), 5-bromo-l-isopropylpyridin-2(lH)-one (108 mg) and 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride and potassium carbonate mix (309 mg/mmol Br) (309 mg, 0.47 mmol) in degassed acetonitrile (6 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at 80 °C for 70 min. The reaction mixture was cooled, filtered and diluted with ethyl acetate, and washed with water. The organic layers were dried over magnesium sulfate, filtered and evaporated to afford crude product.

The crude product was purified by chromatography on silica eluting with a gradient 0 to 10% methanol in ethyl acetate to afford the sub-titled compound (192 mg).

1H NMR (500 MHz, DMSO) δ 7.89 (d, 1H), 7.73 (dd, 1H), 7.54 - 7.45 (m, 3H), 7.27 - 7.17 (m, 4H), 6.96 (s, 1H), 6.47 (d, 1H), 5.09 (hept, 1H), 4.42 (dd, 1H), 3.13 (d, 1H), 2.91 (dd, 1H), 1.78 - 1.61 (m, 3H), 1.49 - 1.38 (m, 4H), 1.35 (d, 15H), 1.29 - 1.20 (m, 2H), 1.15 - 1.09 (m, 1H). m/e (APCI+) 526 [M+H]

(iii) (S)-tert-Buty\ l-(l-cyano-2-(4-(l-isopropyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate

(S)-tert-Butyl 1 -( 1 -amino-3 -(4-( 1 -isopropyl-6-oxo- 1 ,6-dihydropyridin-3 -yl)phenyl)- 1 - oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 16, step (ii), 192 mg) and Burgess' Reagent (174 mg) were dissolved in dichloromethane (25 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at room temperature for 17 h.

The reaction mixture was diluted with dichloromethane, and washed with water. The organic layer was passed through a phase separation cartridge and evaporated to afford the sub-titled compound (180 mg). m/e (APCI+) 507 [M+H]

Example 16: (S)-l-Amino-N-(l-cyano-2-(4-(l-isopropyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethyl)cyclohexanecarboxamide

(S)-tert-Butyl 1 -(1 -cyano-2-(4-(l -isopropyl-6-oxo- 1 ,6-dihydropyridin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (180 mg) was dissolved in formic acid (2.0 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at 50°C for 15 min. The reaction mixture was azeotroped with methanol, then redissolved in methanol and filtered. The crude material was purified by preparative HPLC on a Waters X-Bridge column eluting with methanol in aqueous 0.1% trifluoroacetic acid. The fractions containing the desired compound were evaporated then washed with saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated to dryness to afford the sub-titled compound (75 mg). 1H NMR (500 MHz, DMSO) δ 7.95 (d, IH), 7.76 (dd, IH), 7.56 (d, 2H), 7.34 (d, 2H), 6.47 (d, IH), 5.10 (hept, IH), 4.95 (t, IH), 3.20 - 3.11 (m, 2H), 1.69 (td, IH), 1.61 - 1.46 (m, 4H), 1.45 - 1.39 (m, IH), 1.36 (d, 6H), 1.34 - 1.31 (m, IH), 1.31 - 1.24 (m, IH), 1.15 (dd, 2H). m/e (MultiMode+) 407 [M+H]⁺

Example 17: (S)-l-Amino- V-(l-cyano-2-(4-(7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 3-yl)phenyl)ethyl)cyclohexanecarboxamide

(i) 3-Bromo-5H-pyrrolo[3,4-b]pyridin-7(6H)-one

Ammonia in water (0.413 mL) was added to methyl 5-bromo-3-(bromomethyl)picolinate (Example 13, step (ii), 420 mg) in tetrahydrofuran (5 mL) at 20°C under an atmosphere of nitrogen. The resulting suspension was stirred at 70°C for 2 h. A further 2 mL of ammonia solution was added after 60 min. After 2 h the reaction mixture was cooled, diluted with water and the solid collected by fhitration. The solid was then washed with diethyl ether and dried under vacuum to afford the sub-titled compound (158 mg).

1H NMR (500 MHz, DMSO) δ 9.04 (s, 1H), 8.83 (d, 1H), 8.36 (d, 1H), 4.40 (s, 2H). m/e (APCI+) 215 [M+H] (ii) (S)-tert-Buty\ l-(l-amino-l-oxo-3-(4-(7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3- yl)phenyl)propan-2-ylcarbamoyl)cyclohexylcarbamate

Potassium carbonate (205 mg) in water (1 mL) was added to (S)-tert-butyl 1-(1 -amino- 1-oxo- 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2- ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i), 382 mg), 3-bromo-5H-pyrrolo[3,4- b]pyridin-7(6H)-one (Example 17, step (i), 158 mg) and 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride (48 mg) in degassed acetonitrile (6 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at 80°C for 35 min. The reaction mixture was allowed to cool to room temperature and filtered. The supematanet was diluted with ethyl acetate, and washed with water. The aqueous layer was further extracted with dichloromethane and the organics were combined, dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by chromatography on silica eluting with methanol / dichloromethane (2:98 to 8:92). Pure fractions were evaporated to dryness to afford the sub-titled compound (178 mg).

1H NMR (500 MHz, DMSO) δ 8.97 (d, 2H), 8.27 (s, 1H), 7.69 (d, , 2H), 7.57 (d, 1H), 7.34 (d, 2H), 7.25 (d, 2H), 6.97 (s, 1H), 4.51 - 4.40 (m, 3H), 3.19 (dd, 1H), 2.96 (dd, 1H), 1.68 (d, 3H), 1.54 - 1.39 (m, 3H), 1.35 (s, 9H), 1.31 - 1.13 (m, 4H). m/e (APCI+) 467 [M-tBu]

(iii) (S)-tert-buty\ l-(l-cyano-2-(4-(7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate

(S)-tert-Butyl l-(l-amino-l-oxo-3-(4-(7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3- yl)phenyl)propan-2-ylcarbamoyl)cyclohexylcarbamate (Example 17, step (ii), 178 mg) and Burgess' Reagent (163 mg) were dissolved in dichloromethane (25 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at room temperature for 19 h. The reaction mixture was filtered and the filtrate was washed with water, dried over magnesium sulfate and evaporated to give crude product. The solid was suspended in dichloromethane (25 mL) and Burgess' Reagent (99 mg) was added and stirred at room temperature for 3 h. After 3 h Et₃N (500 μί) was added. After 3.5 h the reaction mixture was sonicated for 45 min, then allowed to stir for 17 h. The solid was filtered off and the filtrate washed with water and combined with the previous crude product. The crude product was purified by chromatography on silica eluting with methanol / dichloromethane (2:98 to 8:92). Pure fractions were evaporated to dryness to afford the sub-titled compound (45 mg). m/e (APCI+) 504 [M+H] Example 17: (S)-l-Amino- V-(l-cyano-2-(4-(7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 3-yl)phenyl)ethyl)cyclohexanecarboxamide

(S)-tert-Butyl l-(l-cyano-2-(4-(7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (45 mg) was dissolved in formic acid (1.03 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at 50°C for 10 min. The reaction mixture was cooled and azeotroped with methanol. The crude material was then purified by preparative HPLC on a Waters X-Bridge column using a gradient of methanol in aqueous 0.1% trifluoroacetic acid as eluent. The fractions containing the purified compound were evaporated, washed with saturated aqueous sodium hydrogen carbonate solution and extracted into dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated to dryness to afford (19 mg).

1H NMR (500 MHz, DMSO) δ 9.00 (d, 1H), 8.98 (s, 1H), 8.30 (d, 1H), 7.76 (d, 2H), 7.46 (d, 2H), 5.00 (t, 1H), 4.45 (s, 2H), 3.22 (d, 2H), 1.69 (td, 1H), 1.59 - 1.39 (m, 5H), 1.37 - 1.30 (m, 1H), 1.29 - 1.22 (m, 1H), 1.19 - 1.09 (m, 2H). m/e (MultiMode+) 404 [M+H] Example 18: (S)-l-Amino- V-(l-cyano-2-(4-(l-ethyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethyl)cyclohexanecarboxamide

(i) 5-bromo-l-ethylpyridin-2(lH)-one

Potassium tert-butoxide (328 mg) was added to 5-bromopyridin-2(lH)-one (509 mg) in dimethoxyethane (15 mL) at 20°C under an atmosphere of nitrogen and stirred for 30 min. Potassium carbonate (283 mg) and iodoethane (0.236 mL) were added to the reaction mixture and the resulting suspension was stirred at 95°C for 3 h. The reaction mixture was cooled and filtered, evaporated to dryness and redissolved in dichloromethane, and washed with 0.1M hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford an oil which was purified by chromatography on silica eluting with 30 to 50% ethyl acetate in z^'sohexane. Pure fractions were evaporated to dryness to afford the subtitled compound (367 mg).

1H NMR (500 MHz, DMSO) δ 8.04 (d, IH), 7.50 (dt, IH), 6.35 (d, IH), 3.88 (q, 2H), 1.19 (t, 3H). m/e (APCI+) 204 [M+H]⁺

(ii) (S)-tert-Buty\ l-(l-amino-3-(4-(l-ethyl-6-oxo-l,6-dihydropyridin-3-yl)ph

oxopropan-2-ylcarbamoyl)cyclohexylcarbamate

Potassium carbonate (207 mg) in water (1 mL) was added to (S)-tert-butyl 1-(1 -amino- 1-oxo- 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2- ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i), 387 mg), 5-bromo-l-ethylpyridin- 2(lH)-one (152 mg) and 1,1 ¾z5(di-tert-butylphosphino)ferrocene palladium dichloride (50 mg) in degassed acetonitrile (6 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at 80°C for 20 min. The reaction mixture was cooled, filtered and redissolved in dichloromethane. The combined organic layers were passed through a phase separation cartridge and purified by chromatography on silica eluting with 0 to 10% methanol in ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound

(258 mg). m/e (APCI+) 511 [M+H]+

(iii) (S)-tert-Buty\ l-(l-cyano-2-(4-(l-ethyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate

(S)-tert-Butyl 1 -( 1 -amino-3 -(4-( 1 -ethyl-6-oxo- 1 ,6-dihydropyridin-3 -yl)phenyl)- 1 -oxopropan- 2-ylcarbamoyl)cyclohexylcarbamate (Example 18, step (ii), 258 mg) and Burgess' Reagent (241 mg) were dissolved in dichloromethane (25 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at room temperature for 17 h. The reaction mixture was diluted with dichloromethane, and washed with water. The organic layers were passed through a phase separation cartridge and evaporated to afford the sub-titled compound (239 mg). m/e (APCI+) 494 [M+H]

Example 18: (S)-l-Amino- V-(l-cyano-2-(4-(l-ethyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethyl)cyclohexanecarboxamide

(S)-tert- utyl 1 -( 1 -cyano-2-(4-( 1 -ethyl-6-oxo- 1 ,6-dihydropyridin-3 - yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (Example 18, step (iii), 239 mg) was dissolved in formic acid (2.4 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at 50°C for 15 min. The reaction mixture was allowed to cool, azeotroped with methanol and redissolved in methanol and filtered. The crude material was then purified by preparative HPLC on a Waters X-Bridge column using a gradient of methanol in aqueous 0.1% trifluoroacetic acid as eluent. The fractions containing the desired compound were evaporated, washed with saturated aqueous sodium hydrogen carbonate solution and extracted into dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated to dryness to give the sub-titled compound (102 mg).

1H NMR (500 MHz, DMSO) δ 8.11 (d, 1H), 7.80 (dd, 1H), 7.54 (d, 2H), 7.33 (d, 2H), 6.46 (d, lH), 4.95 (t, 1H), 3.98 (q, 2H), 3.19 - 3.11 (m, 2H), 1.69 (td, 1H), 1.58 (td, 1H), 1.54 - 1.45 (m, 3H), 1.45 - 1.31 (m, 2H), 1.30 - 1.22 (m, 4H), 1.21 - 1.09 (m, 2H). m/e (MultiMode+) 393 [M+H]

Example 19: l-Amino- V-{(15)-l-cyano-2-[4-(2-methyl-l,l-dioxido-2,3-dihydro-l,2- benzisothiazol-5-yl)phenyl]ethyl}cyclohexanecarboxamide

i) V-a-({l-[(tei"i-Butoxycarbonyl)amino]cyclohexyl}carbonyl)-4-(2-methyl-l,l-dioxido- 2,3-dihydro- 1 ,2-benzisothiazol-5-yl)-L-phenylalaninamide

Potassium carbonate (172 mg) in water (1 mL) was added to (S)-tert-butyl 1-(1 -amino- 1-oxo- 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2- ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i), 321 mg), 5-bromo-2-methyl-2,3- dihydro-l,2-benzisothiazole 1,1 -dioxide (163 mg) and 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride (48 mg) in degassed acetonitrile (6 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at 80°C for 35 min. The reaction mixture was cooled, filtered, diluted with ethyl acetate and washed with water. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by chromatography on silica eluting with 40 to 100% ethyl acetate in z^'sohexane. Pure fractions were evaporated to dryness to afford the sub-titled compound (224 mg).

IH NMR (400 MHz, DMSO) δ 7.92 (d, IH), 7.83 (d, 2H), 7.63 (d, 2H), 7.54 (d, IH), 7.31 (d, 2H), 7.23 (d, 2H), 6.94 (s, IH), 4.50 - 4.46 (m, IH), 4.45 (s, 2H), 3.19 (d, IH), 2.95 (dd, IH), 2.84 (s, 3H), 1.75 - 1.63 (m, 3H), 1.50 - 1.22 (m, 14H), 1.14 (s, 2H). m/e (APCI+) 471 [M-Boc]⁺ ii) tert-Butyl [l-({(15)-l-cyano-2-[4-(2-methyl-l,l-dioxido-2,3-dihydro-l,2- benzisothiazol-5-yl)phenyl]ethyl}carbamoyl)cyclohexyl] carbamate

Burgess' Reagent (187 mg) was added to N- -({l-[(tert- butoxycarbonyl)amino]cyclohexyl} carbonyl)-4-(2 -methyl- 1 , 1 -dioxido-2,3-dihydro-l ,2- benzisothiazol-5-yl)-L-phenylalaninamide (Example 19, step (i), 224 mg) in dichloromethane (25 mL) at 20°C. The resulting solution was stirred at room temperature for 20 h. The reaction mixture was diluted with dichloromethane and washed with water. The organic was dried over magnesium sulfate, filtered and evaporated to afford the sub-titled compound (208 mg). m/e (APCI+) 453 [M-Boc] Example 19: l-Amino- V-{(lS)-l-cyano-2-[4-(2-methyl-l,l-dioxido-2,3-dihydro-l,2- benzisothiazol-5-yl)phenyl]ethyl}cyclohexanecarboxamide

To tert-butyl [ 1 -( {( IS)- 1 -cyano-2-[4-(2 -methyl- 1 , 1 -dioxido-2,3-dihydro- 1 ,2-benzisothiazol-5- yl)phenyl]ethyl}carbamoyl)cyclohexyl]carbamate (Example 19, step (ii), 207 mg) was added formic acid (4.3 mL) and the mixture heated to 50°C for 20 min. The mixture was azeotroped with methanol and purified by preparative HPLC on a Waters X-Bridge column using a gradient of methanol in aqueous 0.1% trifluoroacetic acid as eluent. The fractions containing the desired compound were combined, evaporated and then dissolved in dichloromethane and washed with saturated sodium hydrogen carbonate. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was triturated with diethyl ether and evaporated to afford the sub-titled compound (98 mg).

1H NMR (500 MHz, DMSO) δ 7.93 (d, 1H), 7.86 (d, 2H), 7.70 (d, 2H), 7.43 (d, 2H), 5.00 (t, 1H), 4.45 (s, 2H), 3.21 (d, 2H), 2.84 (s, 3H), 1.69 (td, 1H), 1.60 - 1.45 (m, 4H), 1.44 - 1.30 (m, 2H), 1.27 (d, 1H), 1.15 (t, 2H). m/e (MultiMode+) 453 [M+H]

Example 20: (S)-l-Amino- V-(l-cyano-2-(4-(2-(2-(dimethylamino)ethyl)-l-oxoisoindolin- 5-yl)phenyl)ethyl)cyclohexanecarboxamide

(i) 5-Bromo-2-(2-(dimethylamino)ethyl)isoindolin-l-one

Nl,Nl-Dimethylethane-l,2-diamine (0.515 g) was added to a solution of methyl 5-bromo-3- (bromomethyl)picolinate (Example 13, step (ii), 2 g) in ethanol (15 mL) at 20°C. The resulting suspension was stirred under reflux for 17 h. The reaction mixture was cooled, and evaporated to dryness to afford crude product which was purified by reversed phase hplc (SunFire™ prep C₈, 30-70% 0.1% aq TFA / MeCN). The sub-titled compound was isolated as a colourless solid (600 mg).

1H NMR (500 MHz, DMSO) δ 9.38 (s, 1H), 7.94 (s, 1H), 7.71 (d, 1H), 7.64 (d, 1H), 4.52 (s, 2H), 3.95 - 3.82 (m, 2H), 3.50 - 3.18 (m, 2H), 2.85 (d, 6H).

(ii) (S)-tert- utyl l-(l-amino-3-(4-(2-(2-(dimethylamino)ethyl)-l-oxoisoindolin-5- yl)phenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate

Potassium carbonate (241 mg) in water (5 mL) was added to (S)-tert-butyl 1 -(1 -amino- 1-oxo- 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2- ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i), 300 mg), 5-bromo-2-(2- (dimethylamino)ethyl)isoindolin-l-one (Example 20, step (i), 165 mg) and 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride (1 1 mg) in acetonitrile (15 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at 90°C for 17 h.

The reaction mixture was cooled, concentrated to dryness under vacuum, and the residue applied to a flash silica column. The crude product was purified by eluting with a 5% triethylamine in acetonitrile. Pure fractions were evaporated to dryness to afford the sub-titled compound (300 mg).

1H NMR (500 MHz, CDC1₃) δ 7.88 (d, 1H), 7.70 - 7.59 (m, 2H), 7.55 (d, 2H), 7.32 (d, 2H), 7.12 (s, 1H), 6.45 (s, 1H), 5.29 (d, 2H), 4.83 (d, 1H), 4.58 (s, 2H), 3.87 (s, 2H), 3.27 (s, 2H), 2.85 (s, 2H), 2.49 (s, 6H), 1.95 (d, 2H), 1.70 - 1.49 (m, 4H), 1.47 - 1.16 (m, 13H).

Burgess' reagent (493 mg) was added to {S)-tert- viy\ l-(l-amino-3-(4-(2-(2- (dimethylamino)ethyl)- 1 -oxoisoindolin-5 -yl)phenyl)- 1 -oxopropan-2- ylcarbamoyl)cyclohexylcarbamate (Example 20, step (ii), 490 mg) in dichloromethane (15 mL) at 20°C under nitrogen. The solution was stirred at room temperature for 16 h and concentrated to dryness. The residue was dissolved in formic acid (2 mL), and the solution was stirred and heated at 50°C for 10 min. The reaction mixture was concentrated under reduced pressure and the crude product was purified by reversed phase hplc chromatography (SunFire™ prep C₈, 30-90% 0.1% aq TFA / MeCN). Pure fractions were freeze dried to afford the title compound TFA salt. The product was converted to the free base by passing through a PL-HCO₃ cartridge in methanol / dichloromethane. The solvent was evaporated and dried to afford the titled compound (67 mg).

1H NMR (400 MHz, CDCI₃) δ 8.40 (d, IH), 7.90 (d, IH), 7.70 - 7.55 (m, 4H), 7.37 (d, 2H), 5.19 - 5.08 (m, IH), 4.55 (s, 2H), 3.75 (t, 2H), 3.14 (d, 2H), 2.60 (t, 2H), 2.29 (s, 6H), 2.04 - 1.82 (m, 2H), 1.73 - 1.58 (m, 2H), 1.45 - 1.16 (m, 8H). m/e (APCI+) 474 [M+H] Example 21: (S)-l-Amino- V-(l-cyano-2-(4-(l-(difluoromethyl)-6-oxo-l,6- dihydropyridin-3-yl)phenyl)ethyl)cyclohexanecarboxamide

(i) V-[(2£)-5-Bromo-l-(difluoromethyl)pyridin-2(lH)-ylidene]acetamide

A mixture of N-(5-bromopyridin-2-yl)acetamide (158 g) and sodium 2-chloro-2,2- difiuoroacetate (135 g) in acetonitrile(1600 mL) was heated to reflux for 48 h. After cooling to room temperature and filtering, the filtrate was concentrated under vacuum and the residue (200 g, crude) used for next step without further purification.

(ii) 5-Bromo-l-(difluoromethyl)pyridin-2(lH)-one

N-[(2E)-5-Bromo-l-(difiuoromethyl)pyridin-2(lH)-ylidene]acetamide (Example 21 step (i), crude, 200g) was dissolved in a mixture of acetonitrile (100 mL) and 1% aqueous KHSO₄ solution (500 mL), and the mixture was heated to reflux for 2 h. The mixture was cooled to room temperature, the solvent was removed in vacuo and the aqueous phase was extracted with ethyl acetate ( 3 x 1000 mL). The combined organic layers were dried over Na₂S0₄ and concentrated. The residue was purified by silica gel column (eluting with petrol ether / ethyl acetate using gradients from 10: 1 to 4: 1) to give the sub-titled compound (86 g) as a white solid.

1H NMR (400 MHz, CDC1₃) δ 7.73-7.44 (m, 1H), 7.55 (s, 1H), 7.37 (m, 1H), 6.49 (dd,lH).

(iii) l-(Difluoromethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one

A mixture of 5-bromo-l-(difluoromethyl)pyridin-2(lH)-one (32 g), 4,4,4',4',5,5,5',5'- octamethyl-2,2'-bi(l,3,2-dioxaborolane) (38 g), potassium acetate ( 46 g) and Pd(dppf)Cl₂ (6.4 g, 0.01 mol) in 1, 4-dioxane(460 mL) was heated under reflux for 2 hrs. After cooling to room temperature and filtering, the filtrate was concentrated to give the crude product, which was purified by silica gel column (eluting with petrol ether / ethyl acetate using gradients from 100: 1 to 20: 1) to give the sub-titled compound (16.0 g).

1H NMR (400 MHz, CDC1₃) δ 7.95-7.65 (m, 1H), 7.76 (s, 1H), 7.56 (dd,lH), 6.48 (d, 2H), 1.24 (brs, 9H).

(iv) (S)-tert-Buty\ l-(l-amino-3-(4-(l-(difluoromethyl)-6-oxo-l,6-dihydropyridin-3- yl)phenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate

Potassium acetate (229 mg) in water (5 mL) was added to (S)-tert-butyl l-(l-amino-3-(4- iodophenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 6, step (i), 400 mg), l-(difluoromethyl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (Example 21, step (iii), 210 mg) and 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (15 mg) in acetonitrile (20 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at 90°C for 17 h. The reaction mixture was cooled, concentrated to dryness under vacuum, and the residue partitioned between ethyl acetate ( 50 mL) and water (50 mL). The organic phase was dried (magnesium sulfate) and concentrated to afford the sub-titled compound as a gum (450 mg) which was used crude in the subsequent reaction. m/e (APCI+) 533 [M+H]

(v) (S)-tert-Buty\ l-(l-cyano-2-(4-(l-(difluoromethyl)-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate

Burgess' reagent (403 mg) was added to (S)-tert-butyl l-(l-amino-3-(4-(l-(difluoromethyl)-6- oxo-l,6-dihydropyridin-3-yl)phenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 21, step (iv), 450 mg) in dichloromethane (20 mL) at 20°C under nitrogen. The resulting solution was stirred at room temperature for 3 days. The reaction mixture was directly transferred to a flash silica column and the products eluted with ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound (390 mg). m/e (APCI-) 513 [M-H]⁺

Example 21: (S)-l-Amino- V-(l-cyano-2-(4-(l-(difluoromethyl)-6- dihydropyridin-3-yl)phenyl)ethyl)cyclohexanecarboxamide

To (S)-tert-butyl l-(l-cyano-2-(4-(l-(difluoromethyl)-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (390 mg) was added formic acid (lOmL) and the mixture stirred at ambient temperature for 1 h. The solution was evaporated to dryness and the residue purified by preparative reversed phase HPLC (SunFire™ prep C₈, 10-90% 0.1% aq TFA / MeCN). The fractions containing the desired compound were combined and concentrated to dryness to afford a gum. The product was converted to the free base by passing through a PL-HCO3 cartridge in methanol / dichloromethane. The solvent was evaporated and dried to afford the titled compound (110 mg). 1H NMR (500 MHz, CDC1₃) δ 8.41 (d, IH), 7.75 (t, IH), 7.74 - 7.56 (m, 2H), 7.49 - 7.29 (m, 4H), 6.67 (d, IH), 5.11 (dt, IH), 3.27 - 3.05 (m, 2H), 2.05 - 1.82 (m, 2H), 1.71 - 1.63 (m, 3H), 1.42 - 1.22 (m, 5H). m/e (APCI+) 415 [M+H]⁺

Example 22: (S)-l-Amino- V-(l-cyano-2-(4-(5-fluoro-l-methyl-6-oxo-l,6-dihydropyridin- 3-yl)phenyl)ethyl)cyclohexanecarboxamide trifluoroacetic acid salt

(i) 5-Bromo-3-fluoro-l-methylpyridin-2(lH)-one

5-Bromo-3-fluoropyridin-2-ol (2.5 g), Methyl iodide (0.893 mL) and potassium carbonate (3.60 g) were slurried in DME (25 mL) and stirred at 50°C for 18h. The mixture was cooled to room temperature, diluted with water (15 mL) and extracted with diethyl ether (3 x 15 mL). 5 The combined organics were dried over sodium sulfate, filtered and concentrated to give the sub-titled compound (3.49 g).

1H NMR (600 MHz, DMSO) δ 7.92 - 7.96 (m, 1H) 7.68 (dd, 1H) 3.47 (s, 3H).

o

(ii) (S)-tert-Buty\ l-(l-amino-3-(4-(5-fluoro-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate

A solution of (S)-tert-butyl l-(l-amino-l-oxo-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)propan-2-ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i)

500 mg), potassium acetate (191 mg) and 5-bromo-3-fluoro-l-methylpyridin-2(lH)-one (2000 mg) in mixture of acetonitrile (15 mL) and water (5 mL) was stirred under an atmosphere of nitrogen. 1,1 ¾z5(Di-tert-butylphosphino)ferrocene palladium dichloride (19 mg) was added to the mixture and heated at 90 °C for 4h. After standing at RT for 24h the reaction mixture was concentrated to dryness, and the residue purified on silica gel using ethyl acetate as eluant. The sub-titled compound (200 mg) was isolated as a brown foam. m/e (APCI+) 515 [M+H]

(iii) (S)-tert-Buty\ l-(l-cyano-2-(4-(5-fluoro-l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate

Burgess' reagent (185 mg) was added to (S)-tert-butyl l-(l-amino-3-(4-(l-(difluoromethyl)-6- oxo-l,6-dihydropyridin-3-yl)phenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 22, step (ii), 200 mg) in dichloromethane (20 mL) at 20°C under nitrogen. The resulting solution was stirred at room temperature for 17h. The reaction mixture was directly transferred to a flash silica column and the products eluted with ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound (200 mg).

m/e (APCI+) 497 [M+H]⁺

Example 22: (S)-l-Amino- V-(l-cyano-2-(4-(5-fluoro-l-methyl-6-oxo-l,6-dihydropyridin- 3-yl)phenyl)ethyl)cyclohexanecarboxamide Trifluoroacetate

To (S)-tert-butyl 1 -(1 -cyano-2-(4-(5-fluoro-l -methyl-6-oxo- 1 ,6-dihydropyridin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (200 mg) was added formic acid (1 mL) and the mixture stirred at room temperature for 4h. The mixture was evaporated to dryness, and the residue purified by preparative reversed phase HPLC (SunFire™ prep C₈, 10-90% 0.1% aq TFA / MeCN). The fractions containing the desired compound were combined and isolated by freeze drying to afford the titled compound (80 mg).

1H NMR (500 MHz, DMSO) δ 9.13 (t, 1H), 8.19 (s, 3H), 8.08 - 7.96 (m, 1H), 7.88 (dd, 1H), 7.58 (d, 2H), 7.36 (d, 2H), 5.13 - 4.75 (m, 1H), 3.58 (s, 3H), 3.19 (ddd, 2H), 2.04 - 1.87 (m, 1H), 1.85 - 1.75 (m, 1H), 1.71 (d, 1H), 1.66 - 1.39 (m, 6H), 1.43 - 1.16 (m, 1H). m/e (APCI+) 397 [M+H]⁺

Example 23: (S)-4-(4-(2-(l-Aminocyclohexanecarboxamido)-2- cyanoethyl)phenyl)picolinamide trifluoroacetic acid salt

(i) (S)-tert-Buty\ l-(l-cyano-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate

(S)-tert-Butyl 1 -( 1 -amino- 1 -oxo-3-(4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2- yl)phenyl)propan-2-ylcarbamoyl)cyclohexylcarbamate (Example 8 step (i),

1.4 g) in dichloromethane (25 mL) was treated with Burgess reagent (1.3 g) and the mixture stirred at room temperature for 5h. The reaction mixture was diluted with dichloromethane (50 mL), and the solution washed with water (2 x 50 mL). The organic phase was collected and dried over magnesium sulfate, then concentrated to a semi-solid. The crude material was purified on silica gel eluting with 5% ether in dichloromethane. Pure fractions were evaporated to dryness to afford the sub-titled compound (1.4 g). m/e (APCI-) 496 [M-H] (ii) (S)-tert- uty\ l-(2-(4-(2-carbamoylpyridin-4-yl)ph

cyanoethylcarbamoyl)cyclohexylcarbamate

A solution of (S)-tert-butyl l-(l-cyano-2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (Example 23 step (i),

569 mg), potassium acetate (225 mg) and 4-bromopicolinamide (230 mg) in mixture of acetonitrile (15 mL) and water (5 mL), was stirred under an atmosphere of nitrogen. 1,1

¾z5(di-fert-butylphosphino)ferrocene palladium dichloride (22 mg) was added and the mixture heated at 90 °C for 4h. The reaction mixture was concentrated to dryness and the residue purified on silica gel using ethyl acetate as eluant. Pure fractions were evaporated to dryness to afford the sub-titled compound (90 mg). m/e (APCI+) 490 [M-H]

(S)-tert-Butyl 1 -(2-(4-(2-carbamoylpyridin-4-yl)phenyl)- 1 - cyanoethylcarbamoyl)cyclohexylcarbamate (90 mg) was stirred at room temperature with formic acid (1 mL) for 4h. The formic acid was removed under vacuum, and the residue treated with saturated aqueous sodium bicarbonate (15 mL). The products were extracted into dichloromethane (20 mL), and the extract dried and concentrated to a gum. The crude product was purified by reversed phase HPLC (Sunfire 10%-90% acetonitrile / 0.1% aq TFA). The product containing fractions were combined and freeze dried to afford the title compound as a colourless solid (30 mg).

^!Η ΝΜΚ (500 MHz, DMSO) δ 9.16 (d, 1H), 8.65 (d, 1H), 8.31 - 8.28 (m, 1H), 8.23 - 8.13 (m, 4H), 7.91 (dd, 1H), 7.84 (d, 2H), 7.74 (d, 1H), 7.48 (d, 2H), 5.21 - 4.98 (m, 1H), 3.30 (dd, 1H), 3.22 (dd, 1H), 1.92 (td, 1H), 1.84 - 1.75 (m, 1H), 1.70 (d, 1H), 1.61 - 1.39 (m, 5H), 1.27 (d, 1H).

m/e (APCI+) 392 [M+H]⁺

Example 24: (S)-l-Amino- V-(l-cyano-2-(4-(2-(2-hydroxyethyl)-l-oxoisoindolin-5- yl)phenyl)ethyl)cyclohexanecarboxamide

(i) 5-bromo-2-(2-hydroxyethyl)isoindolin-l-one

2-aminoethanol (lg) was added to a solution of methyl 5-bromo-3-(bromomethyl)picolinate (Example 13, step (ii), 1.4 g) in ethanol (15 mL) at 20 °C. The resulting suspension was stirred and heated under reflux for 15 min. The reaction mixture was cooled to rt, diluted with water (50 mL), and the suspension filtered. The solid was washed with diethyl ether and dried at 40°C under vacuum to afford the sub-titled compound (630 mg).

1H NMR (500 MHz, CDC1₃) δ 7.64 (d, 1H), 7.61 - 7.54 (m, 2H), 4.50 (s, 2H), 3.93 - 3.87 (m, 2H), 3.79 - 3.64 (m, 2H).

Example 24: (S)-l-amino-N-(l-cyano-2-(4-(2-(2-hydroxyethyl)-l-oxoisoindolin-5- yl)phenyl)ethyl)cyclohexanecarboxamide

(S)-tert-Butyl 1 -( 1 -cyano-2-(4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (Example 23, step (i), 350 mg), 5-bromo-2- (2-hydroxyethyl)isoindolin-l-one (Example 24, step (i), 198 mg), and potassium acetate (207 mg) in a mixture of water (5 mL) and acetonitrile (15 mL) under a nitrogen atmosphere, was treated with 1 , 1 £z^'s(di-tert-butylphosphino)ferrocene palladium dichloride (14 mg). The resulting mixture was stirred and heated at 90°C for 6h. The reaction mixture was cooled to rt and diluted with water (75ml). The products were extracted into dichloromethane (2 x 50 mL), and the combined extracts dried over magnesium sulfate. The solution was concentrated to an oil, treated with formic (1 mL), and stirred for 4h at ambient temperature. The formic acid was removed under reduced pressure, and the residue treated with 2 molar ammonia in methanol (50ml). After stirring for 3h the excess ammonia and solvent were removed under reduced pressure. The residue was purified by reversed phase HPLC (SunFire™ prep C₈, 10- 90% 0.1% aq TFA / MeCN), and the freeze dried product was converted to the free base by passing through a PL-HCO₃ cartridge in methanol / dichloromethane. The solvent was evaporated and dried to afford the titled compound (50 mg).

1H NMR (500 MHz, DMSO) δ 7.87 (s, 1H), 7.80 - 7.57 (m, 4H), 7.41 (d, 2H), 4.99 (t, 1H), 4.86 (t, 1H), 4.60 (s, 2H), 3.70 - 3.51 (m, 4H), 3.27 - 3.03 (m, 2H), 1.74 - 1.06 (m, 10H).

m/e (APCI+) 447 [M+H] Example 25: (S)-tert-Buty\ l-(2-(4-(6-carbamoylpyridin-3-yl)ph

cyanoethylcarbamoyl)cyclohexylcarbamate

(i) (S)-tert-Buty\ l-(2-(4-(6-carbamoylpyridin-3-yl)ph

cyanoethylcarbamoyl)cyclohexylcarbamate

300 mg), potassium acetate (178mg) and 4-bromopicolinamide (121mg) in mixture of acetonitrile (15 mL) and water (5 mL), was stirred under an atmosphere of nitrogen. 1,1 ¾z^'5(di-tert-butylphosphino)ferrocene palladium dichloride (12 mg) was added and the mixture heated at 90 °C for 4h. After standing at rt for 24h the reaction mixture was concentrated to dryness and the residue purified on silica gel using ethyl acetate as eluant to afford the subtitled comound (450 mg). m/e (APCI+) 492 [M+H]⁺

Example 25: (S)-tert-Buty\ l-(2-(4-(6-carbamoylpyridin-3-yl)phenyl)-l- cyanoethylcarbamoyl)cyclohexylcarbamate

(S)-tert-Butyl 1 -(2-(4-(6-carbamoylpyridin-3 -yl)phenyl)- 1 - cyanoethylcarbamoyl)cyclohexylcarbamate (450 mg) in formic acid (2 mL) was stirred at 50°C for 5 min. The deprotection was monitored by LC / MS during the heating period and when the starting material had dissappeared the formic acid was removed under reduced pressure. The residue was basified with saturated aqueous sodium bicarbonate solution and the products extracted into dichloromethane (100 mL). The dried extracts were concentrated to dryness to afford a solid which was purified on silica gel using acetonitrile as eluant. The titled compound was isolated as a solid (80 mg).

1H NMR (500 MHz, CDC1₃) δ 8.79 (s, 1H), 8.44 (d, 1H), 8.27 (d, 1H), 8.06 (d, 1H), 7.80 (s, 1H), 7.61 (d, 2H), 7.44 (d, 2H), 5.62 (s, 1H), 5.23 - 5.07 (m, 1H), 3.19 - 3.03 (m, 2H), 2.07 - 1.82 (m, 2H), 1.80 - 0.95 (m, 10H). m/e (APCI+) 392 [M+H]⁺

Example 26: (S)-l-Amino- V-(l-cyano-2-(4-(l-oxoisoindolin-5- yl)phenyl)ethyl)cyclohexanecarboxamide

(i) (S)-tert-Buty\ l-(l-amino-3-(4-(l-(difluoromethyl)-6-oxo-l,6-dihydropyridin-3- yl)phenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate

Potassium carbonate (178 mg) in water (5 mL) was added to (S)-tert-butyl l-(l-cyano-2-(4- (4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (Example 23 step (i), 300 mg), 5-bromoisoindolin-l-one (141 mg) and 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride (12 mg) in degassed acetonitrile (15 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at 90°C for 4h. The reaction mixture was concentrated to dryness and the residue purified by chromatography on silica eluting with ethyl acetate to afford the sub-titled compound (180 mg) as a colourless solid.

A solution of

l-(l-cyano-2-(4-(l-oxoisoindolin-5- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (Example 26, step (i), 180 mg) in formic (2 mL) was heated at 50°C for 10 minutes. The excess formic acid was removed under vacuum at 50°C, and the residue basified with saturated aqueous sodium bicarbonate solution. The precipitated solid was extracted into dichloromethane (100 mL). The extract was dried over magnesium sulphate and concentrated to dryness to afford a gum. The crude product was purified on silica gel using acetonitrile as eluant. The title compound (70 mg) was isolated as a colourless solid. 1H NMR (400 MHz, CD₃OD) δ 7.86 - 7.76 (m, 2H), 7.75 - 7.70 (m, 1H), 7.68 - 7.62 (m, 2H), 7.41 (d, 2H), 5.05 (dd, 1H), 4.50 (s, 2H), 3.25 - 3.13 (m, 2H), 1.86 - 1.66 (m, 2H), 1.59 - 1.21 (m, 8H). m/e (APCI+) 403[M+H]⁺

Example 27: (S)-l-Amino- V-(l-cyano-2-(4-(l-(2-methoxyethyl)-lH-pyrazol-4- yl)phenyl)ethyl)cyclohexanecarboxamide

(i) (S)-terf-Butyl l-(l-amino-3-(4-(l-(2-methoxyethyl)-lH-pyrazol-4-yl)ph

oxopropan-2-ylcarbamoyl)cyclohexylcarbamate

Potassium acetate (76 mg) in water (0.5 mL) was added to (S)-tert-butyl l-(l-amino-3-(4- iodophenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 6, step (i), 200 mg) and l-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (98 mg) in degassed acetonitrile (4 mL) at 20°C under an atmosphere of nitrogen. 1 , 1 bis(di-tert- butylphosphino)ferrocene palladium dichloride (5 mg) was added. The resulting mixture was stirred at 80°C for 18 h. Further additions of l-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (33mg), potassium acetate (25mg) and 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride (5 mg) were made, with stirring at 80°C for 18 h. The reaction was repeated using {S)-tert- vXy\ l-(l-amino-3-(4-iodophenyl)-l- oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (100 mg). The combined, cooled products were purified by chromatography on silica, eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound (111 mg). m/e (APCI+) 414 [M+H]⁺

(ii) (S)-tert-Bx\t \ l-(l-cyano-2-(4-(l-(2-methoxyethyl)-lH-pyrazol-4- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate

Burgess' reagent (103 mg) was added to (S)-tert-butyl l-(l-amino-3-(4-(l-(2-methoxyethyl)- lH-pyrazol-4-yl)phenyl)- 1 -oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 27, step (i), 111 mg) in dichloromethane (10 mL) at 20°C under nitrogen. The resulting solution was stirred at room temperature for 18 h. The reaction mixture was partially evaporated and the crude product was purified by chromatography on silica, eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound (125 mg). m/e (APCI+) 496 [M+H]

(iii) (S)-l-Amino- V-(l-cyano-2-(4-(l-(2-methoxyethyl)-lH-pyrazol-4- yl)phenyl)ethyl)cyclohexanecarboxamide

To (S)-tert-butyl 1 -(1 -cyano-2-(4-( 1 -(2-methoxyethyl)- lH-pyrazol-4- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (Example 27, step (ii) 125mg) was added formic acid (1 mL) and the mixture was heated at 48°C for 25 min. Sodium bicarbonate solution was added to the cooled mixture which was then extracted with dichloromethane (3x40ml). The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by preparative HPLC on a Waters Sunfire column eluting with acetonitrile in aqueous 0.1% trifluoroacetic acid. The product was loaded onto PL-HC03 MP cartridge in dichloromethane/acetonitrile and eluted with dichloromethane. The solvent was evaporated and the residue was dried under vacuum at 45°C to afford the titled compound (27 mg).

1H NMR (500 MHz, DMSO) δ 8.13 (s, 1H), 7.86 (d, 1H), 7.51 (d, 2H), 7.26 (d, 2H), 4.92 (t, 1H), 4.26 (t, 2H), 3.70 (t, 2H), 3.23 (s, 3H), 3.23 - 2.97 (m, 2H), 1.77 - 1.07 (m, 10H). m/e (MultiMode+) 396 [M+H]⁺

Example 28: (S)-l-Amino- V-(l-cyano-2-(4-(l-(2-morpholinoethyl)-lH-pyrazol-4- yl)phenyl)ethyl)cyclohexanecarboxamide

(i) (S)-tert-Buty\ l-(l-amino-3-(4-(l-(2-morpholinoethyl)-lH-pyrazol-4-yl)ph

oxopropan-2-ylcarbamoyl)cyclohexylcarbamate

Potassium acetate (76 mg) in water (0.5 mL) was added to (S)-tert-butyl l-(l-amino-3-(4- iodophenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 6, step (i), 200 mg) and 4-(2-(4-(4,4,5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- IH-pyrazol- 1 -yl)ethyl)morpholine (119 mg) in degassed acetonitrile (2 mL) at 20°C under an atmosphere of nitrogen. 1,1 bis(Di- tert-butylphosphino)ferrocene palladium dichloride (8 mg) was added. The resulting mixture was stirred at 80°C for 18 h. The reaction was repeated using (S)-tert-butyl l-(l-amino-3-(4- iodophenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (100 mg). The combined, cooled products were purified by chromatography on silica, eluting with a gradient of 0-4% methanol in ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound (224mg). m/e (APCI+) 569 [M+H] (ii) (S)-tert-Buty\ l-(l-cyano-2-(4-(l-(2-morpholinoethyl)-lH-pyrazol-4- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate

Burgess' reagent (188 mg) was added to (S)-tert-butyl l-(l-amino-3-(4-(l-(2- morpholinoethyl)- lH-pyrazol-4-yl)phenyl)- 1 -oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 28, step (i), 224 mg) in dichloromethane (10 mL) at 20°C under nitrogen. The resulting solution was stirred at room temperature for 18 h. The crude product was purified by chromatography on silica, eluting with a gradient of 0-5% methanol in ethyl acetate, followed by 1% methanol and 2% triethylamine in ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound (43 mg). m/e (APCI+) 551 [M+H]

To {S)-tert- viy\ 1 -(1 -cyano-2-(4-( 1 -(2-morpholinoethyl)- lH-pyrazol-4- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (Example 28, step (ii) 43 mg) was added formic acid (2 mL) and the mixture was heated at 45°C for 40 min. Acetonitrile was added and the solvent was evaporated. Sodium bicarbonate solution was added to the cooled mixture which was extracted with dichloromethane (3 x 40 mL). The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by preparative HPLC on a Waters Sunfire column eluting with acetonitrile in aqueous 0.1% trifluoroacetic acid. Sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3 x 40 mL). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was dried under vacuum at 45°C to afford the titled compound (7 mg).

1H NMR (500 MHz, DMSO) δ 8.16 (s, 1H), 7.85 (s, 1H), 7.50 (d, 2H), 7.26 (d, 2H), 4.92 (t, 1H), 4.22 (t, 2H), 3.54 (s, 4H), 3.21 - 2.95 (m, 2H), 2.72 (t, 2H), 2.41 (s, 4H), 1.68 (dd, 1H), 1.62 - 1.30 (m, 6H), 1.26 (d, 1H), 1.21 - 1.08 (m, 2H). m/e (MultiMode+) 451 [M+H]⁺

Example 29: (S)-4'-(2-(l-Aminocyclohexanecarboxamido)-2-cyanoethyl)biphenyl-4- carboxamide

(i) (S)-tert-Buty\ l-(l-cyano-2-(4-iodophenyl)ethylcarbamoyl)cyclohexylcarbamate

Burgess' reagent (277 mg) was added to (S)-tert-butyl l-(l-amino-3-(4-iodophenyl)-l- oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 6, step (i), 300 mg) in dichloromethane (8 mL) at 20°C under nitrogen. The resulting solution was stirred at room temperature for 18 h. The reaction mixture was partially evaporated and the crude product was purified by chromatography on silica, eluting with 50% z^'sohexane in ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound (220 mg). m/e (APCI+) 398 [M+H]

(ii) (S)-tert-Butyl l-(2-(4'-carbamoylbiphenyl-4-yl)-l- cyanoethylcarbamoyl)cyclohexylcarbamate

Potassium acetate (87 mg) in water (1 mL) was added to

l-(l-cyano-2-(4- iodophenyl)ethylcarbamoyl)cyclohexylcarbamate (Example 29, step (i), 220 mg) and 4- carbamoylphenylboronic acid (73 mg) in degassed acetonitrile (8 mL) at 20°C under an atmosphere of nitrogen. 1,1 ¾z5(Di-tert-butylphosphino)ferrocene palladium dichloride (5 mg was added. The resulting mixture was stirred at 80°C for 18 h. The cooled mixture was purified by chromatography on silica, eluting with a gradient of 50-0% z^'sohexane in ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound (135 mg). m/e (APCI+) 391 [M+H]

Example 29: (S)-4'-(2-(l-Aminocyclohexanecarboxamido)-2-cyanoethyl)biplienyl-4- carboxamide

To (S)-tert-butyl l-(2-(4'-carbamoylbiphenyl-4-yl)-l- cyanoethylcarbamoyl)cyclohexylcarbamate (Example 29, step (ii) 135 mg) was added formic acid (2 mL) and the mixture was heated at 50°C for 20 min. Methanol was added and the solvent was evaporated. The sample was purified on a Gemini-NX CI 8 5um 1 10A AXIA column eluting on a 5 to 95 gradient of methanol in water (0.1% TFA). The solvent was evaporated and the residue was loaded onto PL-HC03 MP cartridge in dichloromethane and methanol and eluted with dichloromethane. The solvent was evaporated and the residue was dried under vacuum at 45°C to afford the titled compound (25 mg).

1H NMR (400 MHz, DMSO) δ 8.00 (s, 1H), 7.95 (d, 2H), 7.74 (d, 2H), 7.68 (d, 2H), 7.40 (d, 2H), 7.37 (s, 1H), 4.98 (t, 1H), 3.19 (d, 2H), 1.75 - 1.07 (m, 10H).

m/e (MultiMode+) 391 [M+H]⁺

Example 30: l-Amino- V-{(lS)-l-cyano-2-[4-(l,l-dioxido-2,3-dihydro-l,2-benzisothiazol- 5-yl)phenyl]ethyl}cyclohexanecarboxamide

(i) N-a-({l-[(tei"i-butoxycarbonyl)amino]cyclohexyl}carbonyl)-4-(l,l-dioxido-2,3- dihydro- 1 ,2-benzisothiazol-5-yl)-L-phenylalaninamide

Potassium acetate (114mg) in water (0.5 mL) was added to (S)-tert-butyl 1-(1 -amino- l-oxo-3- (4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)phenyl)propan-2- ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i), 200 mg) and 5-bromo-2,3-dihydro- 1 ,2-benzisothiazole 1,1 -dioxide (96 mg) in degassed acetonitrile (4 mL) at 20°C under an atmosphere of nitrogen. 1,1 ¾z5(di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added. The resulting mixture was stirred at 80°C for 18 h. The reaction was repeated using (S)-tert-butyl 1 -(1 -amino- 1 -oxo-3-(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2- yl)phenyl)propan-2-ylcarbamoyl)cyclohexylcarbamate (1 OOmg).

The combined, cooled products were purified by chromatography on silica, eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound (361 mg). m/e (APCI+) 457 [M+H]

(ii) tert-butyl [l-({(lS)-l-cyano-2-[4-(l,l-dioxido-2,3-dihydro-l,2-benzisothiazol-5- yl)phenyl] ethyl} carbamoyl)cyclohexyl] carbamate

Burgess' reagent (309 mg) was added to N-a-({l-[(tert- butoxycarbonyl)amino]cyclohexyl} carbonyl)-4-(l , 1 -dioxido-2,3-dihydro- 1 ,2-benzisothiazol- 5-yl)-L-phenylalaninamide (Example 30, step (i), 361 mg) in dichloromethane (10 mL) at 20°C under nitrogen. The resulting solution was stirred at room temperature for 18 h.

The reaction mixture was partially evaporated and the crude product was purified by chromatography on silica, eluting with 50% isohexane in ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound (152 mg). m/e (APCI+) 439 [M+H]

To tert-butyl [ 1 -( {( 1 S)- 1 -cyano-2-[4-(l , 1 -dioxido-2,3-dihydro- 1 ,2-benzisothiazol-5- yl)phenyl]ethyl}carbamoyl)cyclohexyl]carbamate

(Example 30, step (ii) 152mg) was added formic acid (2 mL) and the mixture was heated at 50°C for 20 min. Methanol was added and the solvent was evaporated. The residue was purified on a SunFire Prep C8 lOum 30x100 OBD column eluting on a 5 to 95 gradient of methanol in aqueous 0.1% trifiuoroacetic acid. The product was loaded onto PL-HC03 MP cartridge in dichloromethane/methanol and then eluted with dichloromethane. The solvent was evaporated. 5% Acetonitrile/water (2 mL) was added and the mixture was stirred for 3 days. The suspension was filtered and the solid was washed with a water and the residue was dried under vacuum at 45°C to afford the titled compound (18 mg).

1H NMR (400 MHz, DMSO) δ 7.91 - 7.79 (m, 4H), 7.69 (d, 2H), 7.43 (d, 2H), 4.99 (t, 1H), 4.45 (s, 2H), 3.21 (d, 2H), 1.74 - 1.07 (m, 10H). m/e (MultiMode+) 439 [M+H]⁺

Example 31: (5)- V-(2-(4-(lH-Pyrazol-4-yl)phenyl)-l-cyanoethyl)-l- aminocyclohexanecarboxamide trifiuoroacetic acid salt

(i) (5)-tert-Butyl 4-(4-(3-amino-2-(l-(teri- butoxycarbonylamino)cyclohexanecarboxamido)-3-oxopropyl)phenyl)-lH-pyrazole-l- carboxylate

Potassium acetate (114 mg) in water (1 mL) was added to (S)-tert-butyl l-(l-amino-3-(4- iodophenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 6, step (i), 300 mg) and tert-butyl 4-(4,4, 5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- IH-pyrazole- 1 -carboxylate (171 mg) in degassed acetonitrile (8 mL) at 20°C under an atmosphere of nitrogen. 1,1 bis(di- tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added. The resulting mixture was stirred at 85°C for 18 h. The cooled mixture was purified by chromatography on silica, eluting with 50-0% z^'sohexane in ethyl acetate. Pure fractions were evaporated to dryness to afford the sub -titled compound (101 mg). m/e (APCI+) 456 [M+H]

(ii) (S)-tert-Buty\ 4-(4-(2-(l-(tei"i-butoxycarbonylamino)cyclohexanecarboxamido)-2- cyanoethyl)phenyl)-lH-pyrazole-l-carboxylate

Burgess' reagent (87 mg) was added to (S)-tert-butyl 4-(4-(3-amino-2-(l-(tert- butoxycarbonylamino)cyclohexanecarboxamido)-3-oxopropyl)phenyl)-lH-pyrazole-l- carboxylate (Example 31, step (i), 101 mg) in dichloromethane (8 mL) at 20°C under nitrogen. The resulting solution was stirred at room temperature for 18 h.

The reaction mixture was partially evaporated and the crude product was purified by chromatography on silica, eluting with 50%-0% isohexane in ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound (63 mg). m/e (APCI+) 436 [M+H]⁺

Example 31: (5)- V-(2-(4-(lH-Pyrazol-4-yl)phenyl)-l-cyanoethyl)-l- aminocyclohexanecarboxamide trifluoroacetic acid salt

To

4-(4-(2-(l -(tert-butoxycarbonylamino)cyclohexanecarboxamido)-2- cyanoethyl)phenyl)-lH-pyrazole-l-carboxylate (Example 31, step (ii) 63mg) was added formic acid (1.5 mL) and the mixture was heated at 50°C for 20 min. Methanol was added and the solvent was evaporated. The residue was purified on a SunFire Prep C8 lOum 30x100 OBD column eluting on an 11 to 46 gradient of methanol in aqueous 0.1%

trifluoroacetic acid. The solvent was evaporated and the residue was dried under vacuum at 45°C to afford the titled compound (13 mg). 1H NMR (400 MHz, DMSO) δ 9.10 (d, 1H), 8.17 (s, 3H), 8.04 (s, 2H), 7.41 (dd, 4H), 5.09 - 5.01 (m, 1H), 3.22 - 3.08 (m, 2H), 1.98 - 1.88 (m, 1H), 1.87 - 1.76 (m, 1H), 1.75 - 1.65 (m, 1H), 1.64 - 1.38 (m, 6H), 1.35 - 1.19 (m, 1H). m/e (MultiMode+) 338[M+H] Example 32: (S)-4'-(2-(l-Aminocyclohexanecarboxamido)-2-cyanoethyl)-3- fluorobiphenyl-4-carboxamide trifluoroacetic acid salt

(i) (S)-tert-Butyl l-(2-(4'-carbamoyl-3'-fluorobiphenyl-4-yl)-l- cyanoethylcarbamoyl)cyclohexylcarbamate

Potassium acetate (77 mg) in water (1 mL) was added to (S)-tert-butyl l-(l-cyano-2-(4- iodophenyl)ethylcarbamoyl)cyclohexylcarbamate (Example 29, step (i), 194 mg) and 4- carbamoyl-3-fluorophenylboronic acid (71 mg) in degassed acetonitrile (8 mL) at 20°C under an atmosphere of nitrogen. 1,1 ¾z^'s(Di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) was added. The resulting mixture was stirred at 80°C for 18 h. The cooled mixture was purified by chromatography on silica, eluting with a gradient of 50-0% isohexane in ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound (91mg). m/e (APCI+) 409 [M+H]⁺

(ii) (S)-4'-(2-(l-Aminocyclohexanecarboxamido)-2-cyanoethyl)-3-fluorobiphi

carboxamide trifluoroacetic acid salt

To (S)-tert-butyl l -(2-(4'-carbamoyl-3'-fluorobiphenyl-4-yl)-l- cyanoethylcarbamoyl)cyclohexylcarbamate (Example 32, step (i) 91mg) was added formic acid (2 mL) and the mixture was heated at 50°C for 20 min. Methanol was added and the solvent was evaporated. The sample was purified on a Gemini-NX CI 8 5um 1 10A 30x100 AXIA column eluting on a 17 to 52 gradient of methanol in aqueous 0.1%trifluoroacetic acid. The solvent was evaporated and the residue was dried under vacuum at 45°C to afford the titled compound (26 mg).

1H NMR (400 MHz, DMSO) δ 9.12 (d, 1H), 8.17 (s, 3H), 7.79 - 7.57 (m, 7H), 7.43 (d, 2H), 5.16 - 5.08 (m, 1H), 3.32 - 3.16 (m, 2H), 1.99 - 1.87 (m, 1H), 1.86 - 1.75 (m, 1H), 1.76 - 1.65 (m, 1H), 1.65 - 1.38 (m, 6H), 1.34 - 1.20 (m, 1H) m/e (MultiMode+) 409 [M+H]

Example 33: (S)-l-Amino- V-(l-cyano-2-(4-(l-(2-methoxyethyl)-6-oxo-l,6- dihydropyridin-3-yl)phenyl)ethyl)cyclohexanecarboxamide trifluoroacetic acid salt

(i) 5-Bromo-l-(2-methoxyethyl)pyridin-2(lH)-one

Potassium tert-butoxide (322 mg) was added to 5-bromopyridin-2(lH)-one (500 mg) in DME (15 mL) at 20°C under nitrogen and the mixture was stirred for 25 min. Potassium carbonate (278 mg) and l-bromo-2-methoxyethane (0.27 mL) were added to the reaction and the resulting suspension was stirred at 85°C for 3 h. The reaction mixture was cooled and filtered through PTFE and evaporated to dryness. The residue was redissolved in dichloromethane and washed with 0.1M hydrochloric acid. The organic layer was dried over magnesium sulphate, filtered and evaporated. The crude product was purified by flash silica

chromatography using 40% ethyl acetate in z^'sohexane as eluent. Pure fractions were evaporated to dryness to afford the sub-titled compound (437 mg).

1H NMR (500 MHz, CDC1₃) δ 7.48 (d, IH), 7.36 (dd, IH), 6.49 (d, IH), 4.16 - 4.00 (m, 2H), 3.70 - 3.60 (m, 2H), 3.33 (s, 3H). m/e (APCI+) 233 [M+H]

(ii) (S)-terf-Butyl l-(l-amino-3-(4-(l-(2-methoxyethyl)-6-oxo-l,6-dihydropyridin-3- yl)phenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate

Potassium acetate (136 mg) in water (0.5 mL) was added to (S)-4-(3-amino-2-(l-(tert- butoxycarbonylamino)cyclohexanecarboxamido)-3 -oxopropyl)phenylboronic acid (Example 8, step (i), 300 mg) and 5-bromo-l-(2-methoxyethyl)pyridin-2(lH)-one (Example 33, step (i), 161 mg) in degassed acetonitrile (8 mL) at 20°C under an atmosphere of nitrogen. 1,1 bis(di- tert-butylphosphino)ferrocene palladium dichloride (15 mg) was added. The resulting mixture was stirred at 82°C for 18 h. Further additions of potassium acetate (60mg) in water (0.5 mL) and 1,1 ¾z5(di-tert-butylphosphino)ferrocene palladium dichloride (5 mg) were made, with stirring at 82°C for 4 h. The cooled mixture was purified by chromatography on silica, eluting with methanol 0-3% in ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound (472 mg). m/e (APCI+) 541 [M+H] (iii) (S)-terf-Butyl l-(l-cyano-2-(4-(l-(2-methoxyethyl)-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate

Burgess' reagent (275 mg) was added to (S)-tert-butyl l-(l-amino-3-(4-(l-(2-methoxyethyl)- 6-oxo- 1 ,6-dihydropyridin-3-yl)phenyl)- 1 -oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 33, step (ii), 312 mg) in dichloromethane (10 mL) at 20°C under nitrogen. The resulting solution was stirred at room temperature for 18 h.

The reaction mixture was partially evaporated and the crude product was purified by chromatography on silica, eluting with ethyl acetate. Pure fractions were evaporated to dryness to afford the sub-titled compound (98 mg). m/e (APCI+) 523 [M+H]⁺

(iv) (S)-l-Amino- V-(l-cyano-2-(4-(l-(2-methoxyethyl)-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethyl)cyclohexanecarboxamide trifluoroacetic acid salt

To {S)-tert-bvAy\ l-(l-cyano-2-(4-(l-(2-methoxyethyl)-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (Example 33, step (iii) 98mg) was added formic acid (2 mL) and the mixture was heated at 45°C for 25 min. Acetonitrile was added and the solvent was evaporated. The sample was purified on SunFire Prep C8 lOum 30x100 OBD column eluting on a 5 to 39 gradient of acetonitrile in 0.1% aqueous trifluoroacetic acid. The solvent was evaporated and the residue was dried under vacuum at 45 °C to afford the titled compound (36 mg).

1H NMR (500 MHz, DMSO) 5 9.11 (d, IH), 8.30 - 8.10 (m, 3H), 7.99 (d, IH), 7.81 (dd, IH), 7.53 (d, 2H), 7.35 (d, 2H), 6.49 (d, IH), 5.08 (dd, IH), 4.14 (t, 2H), 3.61 (t, 2H), 3.24 (s, 3H), 3.23 - 3.12 (m, 2H), 2.04 - 1.16 (m, 10H). m/e (MultiMode+) 423 [M+H]"

Example 34: (S)-4'-(2-(l-Aminocyclohexanecarboxamido)-2-cyanoethyl)biplienyl-4-yl methanesulfonate

(i) (S)-4'-(3-Amino-2-(l-(tert-butoxycarbonylamino)cyclohexanecarboxamido)-3- oxopropyl)biphenyl-4-yl methanesulfonate

(S)-tert-Butyl 1 -( 1 -amino-3 -(4-iodophenyl)- 1 -oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i), 740 mg) and 4-(methylsulfonyloxy)phenylboronic acid (310 mg) in acetonitrile (20 mL) with water (2 mL) and potassium acetate (423 mg) was bubbled through with nitrogen. 1,1 ¾z5(Di-tert-butylphosphino)ferrocene palladium dichloride (12 mg) was added and the mixture was heated at 85°C for 18 h. The mixture was purified by

chromatography on silica eluting with 60% ethyl acetate /z^'sohexane to afford the sub-titled compound (496 mg). m/e (APCI+) 460 [M+2H-BOC] (ii) (S)-4'-(2-(l-(tei"i-Butoxycarbonylamino)cyclohexanecarboxamido)-2- cyanoethyl)biphenyl-4-yl methanesulfonate

(iS)-4'-(3 - Amino-2-( 1 -(tert-butoxycarbonylamino)cyclohexanecarboxamido)-3 - oxopropyl)biphenyl-4-yl methanesulfonate (Example 34, step (i), 496 mg) in dichloromethane (25 mL) was treated with Burgess' reagent (422 mg) and the mixture was stirred at room temperature for 18 h. The solvent was partially evaporated and the mixture purified by chromatography on silica using 40-60% ethyl acetate/zsohexane as eluent to afford the subtitled compound (354 mg). m/e (APCI+) 442 [M+2H-BOC]

Example 34: (S)-4'-(2-(l-Aminocyclohexanecarboxamido)-2-cyanoethyl)biphenyl-4-yl methanesulfonate

(5)-4'-(2-(l-(tert-Butoxycarbonylamino)cyclohexanecarboxamido)-2-cyanoethyl)biphenyl-4- yl methanesulfonate (Example 34, step (ii), 354 mg) in formic acid (2 mL) was heated at 50°C for 20 min. The mixture was evaporated with methanol and then purified by HPLC using 20- 90% methanol/0.1%) aqueous trifluoroacetic acid as eluent. The residue was loaded onto PL- HC03 MP cartridge in methanol and then eluted with a methanol. The solvent was evaporated and dried to afford the titled compound (99 mg).

1H NMR (399.826 MHz, DMSO) δ 7.76 (dt, 2H), 7.63 (d, 2H), 7.43 (dt, 2H), 7.39 (d, , 2H), 4.98 (t, 1H), 3.41 (s, 3H), 3.21 - 3.17 (m, 2H), 1.74 - 1.65 (m, 1H), 1.61 - 1.37 (m, 5H), 1.37 - 1.22 (m, 2H), 1.21 - 1.08 (m, 2H). m/e (MultiMode+) 442 [M+H]

Example 35: (S)-l-Amino-N-(l-cyano-2-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethyl)cycloheptanecarboxamide

(i) (S)-tert-Buty\ l-(l-amino-3-(4-iodophenyl)-l-oxopropan-2- ylcarbamoyl)cycloheptylcarbamate

(S)-2-Amino-3-(4-iodophenyl)propanamide (1.13 g), l-(tert- butoxycarbonylamino)cycloheptanecarboxylic acid (1 g), N-ethyl-N-isopropylpropan-2-amine (0.677 mL) and 2-(lH-benzo[d][l,2,3]triazol-l-yl)-l,l,3,3-tetramethylisouronium

tetrafluoroborate (1.25 g) were stirred at room temperature in dry DMF (10 mL). After 3 days the reaction mixture was diluted with water (40 mL) and the products extracted with ether. The extract was dried over magnesium sulfate and concentrated to afford the sub-titled compound (2 g).

1H NMR (500 MHz, CDC1₃) δ 7.55 (d, 2H), 7.11 - 6.99 (m, 1H), 6.89 (d, 2H), 6.22 (d, 1H), 5.26 (s, 1H), 4.77 (s, 1H), 4.68 - 4.58 (m, 1H), 3.15 - 3.02 (m, 2H), 2.25 - 2.14 (m, 1H), 1.88 - 1.76 (m, 1H), 1.74 - 1.63 (m, 1H), 1.60 - 1.39 (m, 7H), 1.36 - 1.20 (m, 11H). m/e (APCI-) 528 [M-H]^~

(ii) (S)-tert-Buty\ l-(l-amino-3-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3-yl)ph

oxopropan-2-ylcarbamoyl)cycloheptylcarbamate

(S)-tert-Butyl 1 -( 1 -amino-3 -(4-iodophenyl)- 1 -oxopropan-2- ylcarbamoyl)cycloheptylcarbamate (Example 35, step (i), 400 mg), l-methyl-5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2(lH)-one (213 mg) and potassium acetate (148 mg) in a mixture of acetonitrile (15 mL) and water (10 mL) and under a nitrogen atmosphere was treated with 1,1 ¾z5(di-tert-butylphosphino)ferrocene palladium dichloride (16 mg) and the mixture stirred and heated at 90 °C for 3h. The reaction mixture was cooled and diluted with water (100ml). The products were extracted into ethyl acetate (2x 100ml) and the combined extracts washed with 10% aq potassium cabonate (50ml) followed by 5%> aq citric acid (50 mL). The organic phase was dried and concentrated to dryness to afford the sub-titled compound (320 mg). m/e (APCI+) 512 [M+H]

(iii) (S)-tert-Buty\ l-(l-cyano-2-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethylcarbamoyl)cycloheptylcarbamate

(S)-tert-Butyl 1 -( 1 -amino-3 -(4-( 1 -methyl-6-oxo- 1 ,6-dihydropyridin-3 -yl)phenyl)- 1 - oxopropan-2-ylcarbamoyl)cycloheptylcarbamate (Example 35, step (ii), 320 mg) in dichloromethane (10 mL) was stirred overnight at room temperature with Burgess' reagent (299 mg). The resulting solution was purified by chromatography on silica eluting with ethyl acetate to afford the sub-titled compound (300 mg). m/e (APCI+) 493 [M+H]

Example 35: (S)-l-Amino- V-(l-cyano-2-(4-(l-methyl-6-oxo-l,6-dihydropyridin-3- yl)phenyl)ethyl)cycloheptanecarboxamide

(S)-tert-Butyl 1 -(1 -cyano-2-(4-(l -methyl-6-oxo- 1 ,6-dihydropyridin-3- yl)phenyl)ethylcarbamoyl)cycloheptylcarbamate (Example 35, step (iv), 300 mg) was treated with formic acid (10 mL) and the solution heated at 50°C for 20 min. The reaction mixture was concentrated under vacuum and the residue purified by reversed phase hplc (Sunfire with 0.1% aq trifluoroacetic acid / acetonitrile as eluent) to afford the titled compound (180 mg).

1H NMR (500 MHz, D₂0) δ 8.00 - 7.67 (m, 2H), 7.40 (d, 2H), 7.25 (d, 2H), 6.58 (d, 1H), 5.22 - 5.01 (m, 1H), 3.51 (s, 3H), 3.36 - 3.21 (m, 1H), 3.13 (dd, 1H), 2.04 - 1.84 (m, 1H), 1.81 - 1.63 (m, 1H), 1.58 - 1.17 (m, 10H). m/e (MultiMode+) 393 [M+H]⁺

Example 36: (S)-l-Amino- V-(l-cyano-2-(4-(4-methyl-5-oxo-4,5-dihydropyrazin-2- yl)phenyl)ethyl)cyclohexanecarboxamide trifluoroacetic acid salt

(i) (S)-tert-Buty\ l-(l-amino-3-(4-(4-methyl-5-oxo-4,5-dihydropyrazin-2-yl)phenyl)-l- oxopropan-2-ylcarbamoyl)cyclohexylcarbamate

A mixture of (S)-tert-butyl l-(l-amino-l-oxo-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)phenyl)propan-2-ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i), 220 mg), 5- chloro-l-methylpyrazin-2(lH)-one (62 mg) and potassium acetate (0.427 mL) in acetonitrile (4 mL) and water (0.5 mL) was degassed with nitrogen and then 1,1 bis(di-tert- butylphosphino)ferrocene palladium dichloride (14 mg) was added. The mixture was warmed to 80°C for 10 h and then allowed to cool to room temperature. The mixture was evaporated and diluted with ethyl acetate (10 mL) and then poured into water (4 mL). The layers were shaken and separated. The aqueous extract was further extracted with ethyl acetate (3 x 15 mL) and the combined organic extracts dried over magnesium sulphate. The residued after evaporation was purified by chromatography on silica eluting with ethyl acetate / methanol (95:5) to afford the sub-titled compound (50 mg). m/e (APCI+) 398 [M+2H-BOC] ii) (S)-tert-Buty\ l-(l-cyano-2-(4-(4-methyl-5-oxo-4,5-dihydropyrazin-2- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate

To a solution of (S)-tert-butyl l-(l-amino-3-(4-(4-methyl-5-oxo-4,5-dihydropyrazin-2- yl)phenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 36, step (i), 45 mg) in dichloromethane (3 mL) was added Burgess' reagent (43 mg) and the mixture stirred at room temperature for 18h. The solution was poured into water (5 mL) and diluted with

dichloromethane (5 mL). The layers were shaken, separated and further extracted with dichloromethane (3 x 5 mL). The combined organic extracts were dried over magnesium sulfate and evaporated to afford the sub-titled compound (50 mg). m/e (APCI+) 380 [M+2H-BOC]

To

1 -(1 -cyano-2-(4-(4-methyl-5-oxo-4,5-dihydropyrazin-2- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (50 mg) was added formic acid (3 mL) and the mixture stirred and heated to 40°C for lh. The mixture was allowed to cool to room temperature and purified by preparative HPLC chromatography (SunFire column eluting with acetonitrile / 0.1% aqueous trifluoroacetic acid) to afford the titled compound (11 mg).

Example 37: (S)-l-Amino- V-(l-cyano-2-(4-(6-isopropyl-7-oxo-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-3-yl)phenyl)ethyl)cyclohexanecarboxamide

(i) 3-Bromo-6-isopropyl-5H-pyrrolo[3,4-b]pyridin-7(6H)-one

Propan-2-amine (0.619 mL) was added to methyl 5-bromo-3-(bromomethyl)picolinate (405 mg) in tetrahydrofuran (5 mL) at 20°C under an atmosphere of nitrogen. A solid formed almost instantly and the resulting suspension was stirred at 70°C for 30 min.

The reaction mixture was cooled and evaporated to dryness then triturated with ether and the solid collected by filtration and dried under vacuum to afford crude product.

The crude material was partitioned between dichloromethane and water. The organic was dried over magnesium sulfate, filtered and evaporated to afford the sub-titled compound (117 mg).

1H NMR (500 MHz, DMSO) δ 8.83 (d, 1H), 8.38 (d, 1H), 4.48 - 4.40 (m, 3H), 1.24 (d, 6H). m/e (APCI+) 256 [M+H]⁺

(ii) (S)-tert-Buty\ l-(l-amino-3-(4-(6-isopropyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-3-yl)phenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate

Potassium carbonate (127 mg) in water (1 mL) was added to (S)-tert-butyl 1-(1 -amino- 1-oxo- 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl)propan-2- ylcarbamoyl)cyclohexylcarbamate (Example 8, step (i), 236 mg), 3-bromo-6-isopropyl-5H- pyrrolo[3,4-b]pyridin-7(6H)-one (117 mg) and 1,1 ¾z5(di-tert-butylphosphino)ferrocene palladium dichloride (30 mg) in degassed acetonitrile (6 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at 80°C for 30 min. The reaction mixture was cooled, filtered, diluted with ethyl acetate and washed with water. The aqueous was further extracted with dichloromethane and the combined organic layers were dried over magnesium sulfate, filtered and evaporated to afford crude product. The crude product was purified by chromatography on silica eluting with 0 to 10% methanol in dichloromethane. Pure fractions were evaporated to dryness to afford the sub-titled compound (217 mg).

1H NMR (500 MHz, DMSO) δ 8.96 (s, 1H), 8.27 (s, 1H), 7.68 (d, 2H), 7.57 (d, 1H), 7.34 (d, 2H), 7.24 (d, 2H), 6.97 (s, 1H), 4.53 - 4.43 (m, 4H), 3.21 (d, 1H), 2.96 (dd, 1H), 1.74 - 1.62 (m, 3H), 1.51 (d, 3H), 1.45 - 1.40 (m, 2H), 1.35 (s, 9H), 1.26 (d, 6H), 1.15 - 1.10 (m, 2H). m/e (APCI+) 564 [M+H]⁺

(iii) (S)-ieri-Buty\ l-(l-cyano-2-(4-(6-isopropyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-3-yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate

(S)-tert-Butyl l-(l-amino-3-(4-(6-isopropyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3- yl)phenyl)-l-oxopropan-2-ylcarbamoyl)cyclohexylcarbamate (Example 37, step (ii), 217 mg) and Burgess' Reagent (183 mg) were dissolved in dichloromethane (25 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at room temperature for 18 h. The reaction mixture was diluted with dichloromethane, and washed with water. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford crude product which was purified by chromatography on silica eluting with 2 to 7% methanol in

dichloromethane. Pure fractions were evaporated to dryness to afford the sub-titled compound (143 mg). 1H NMR (500 MHz, DMSO) δ 8.99 (d, 1H), 8.42 - 8.28 (m, 2H), 7.74 (d, 2H), 7.45 (d, 2H), 6.68 (s, 1H), 5.11 - 5.00 (m, 1H), 4.52 - 4.43 (m, 3H), 3.23 - 3.06 (m, 2H), 1.83 - 1.39 (m, 8H), 1.37 (s, 9H), 1.26 (d, 6H), 1.22 - 1.08 (m, 2H). m/e (APCI+) 546 [M+H]

Example 37: (S)-l-Amino-N-(l-cyano-2-(4-(6-isopropyl-7-oxo-6,7-dihydi

pyrrolo[3,4-b]pyridin-3-yl)phenyl)ethyl)cyclohexanecarboxamide

(S)-tert-Butyl l-(l-cyano-2-(4-(6-isopropyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3- yl)phenyl)ethylcarbamoyl)cyclohexylcarbamate (Example 37, step (i), 140 mg) was dissolved in formic acid (2.9 mL) at 20°C under an atmosphere of nitrogen. The resulting solution was stirred at 50°C for 15 min. The reaction mixture was allowed to cool to room temperature and redissolved in methanol and filtered. The crude material was then purified by preparative HPLC on a Waters X-Bridge column using a gradient of methanol in aqueous 0.1%

trifluoroacetic acid as eluent. The fractions containing the desired compound were evaporated, washed with saturated aqueous sodium carbonate solution and extracted into

dichloromethane. The combined organic layers were dried over magnesium sulfate and evaporated. The residue was suspended in water (2.1 mL) and acetonitrile (0.11 mL) and stirred at room temperature for 25 h. The solid was collected by filtration and then dried under vacuum to afford the titled compound (58 mg).

1H NMR (500 MHz, DMSO) δ 8.99 (d, 1H), 8.31 (d, 1H), 7.76 (d, 2H), 7.46 (d, 2H), 5.01 (t, 1H), 4.52 - 4.44 (m, 3H), 3.25 - 3.18 (m, 2H), 1.69 (td, 1H), 1.60 - 1.38 (m, 5H), 1.36 - 1.30 (m, 1H), 1.26 (d, 7H), 1.19 - 1.10 (m, 2H). m/e (MultiMode+) 446 [M+H] The following compounds were prepared by methods analogous to those outlined in Example 6 and Example 12 from the corresponding iodide or boronate .

Ex. Name Structure NMR m/e No.

(S)-l-Amino-N-(l- (399.826 MHz, DMSO)

41 δ 477 cyano-2-(3'-(2- 10.17 (s, IH), 9.15 (d, morpholinoethoxy)bip

henyl-4- ^"ao^° o IH), 8.19 (s, 3H), 7.64 (d,

2H), 7.44 - 7.38 (m, 3H), yl)ethyl)cyclohexanec 7.29 (d, IH), 7.26 - 7.23 arboxamide (m, IH), 7.01 (dd, IH),

5.09 (dd, IH), 4.43 (t, 2H), 4.08 - 3.34 (m, 10H), 3.29 - 3.15 (m, 2H), 2.01 - 1.89 (m, IH), 1.89 - 1.77 (m, IH), 1.76 - 1.66 (m, IH), 1.62 - 1.40 (m, 6H), 1.36 - 1.21 (m, IH).

(S)-l-Amino-N-(l- (500 MHz, DMSO)

42 δ 366 cyano-2-(4-(6-oxo- 13.19 (s, IH), 8.02 (d,

1 ,6-dihydropyridazin- IH), 7.81 (d, 2H), 7.39 (d, 3- 2H), 6.99 (d, IH), 4.98 (t, yl)phenyl)ethyl)cyclo H IH), 3.20 (d, IH), 3.17 (d, hexanecarboxamide IH), 1.68 (td, IH), 1.60 - 1.45 (m, 4H), 1.41 (dd,

IH), 1.34 (dd, IH), 1.26

(d, IH), 1.20 - 1.09 (m,

2H).

(S)-l-amino-N-(l- (500 MHz, DMSO) 8.03

43 δ 424 cyano-2-(4-(l-(2- (d, IH), 7.84 (d, 2H), 7.41 methoxyethyl)-6-oxo- (d, 2H), 7.04 (d, IH), 4.99 1 ,6-dihydropyridazin- (t, 1H), 4.31 (t, 2H), 3.75 3- (t, 2H), 3.25 (s, 3H), 3.20 yl)phenyl)ethyl)cyclo o (d, 2H), 1.68 (td, IH), 1.59 hexanecarboxamide - 1.45 (m, 4H), 1.41 (dd,

IH), 1.34 (dd, IH), 1.26

(d, IH), 1.19 - 1.08 (m,

2H).

Pharmacological Analysis

Biological Assay

Fluorescence assay for recombinant human (rh) DPP1

The activity of DPP 1 was determined by measuring the enzymatic release of aminomethyl coumarin (AMC) from the peptide substrate (H-Gly-Arg-AMC), which leads to an increase in fluorescence intensity at λεχ =350nm and λειη =450nm. The assay was carried out in black 384 well plates in a final volume of 50μ1 at 22°C. The assay conditions contained the following: 25mM piperazine buffer pH5.0; 50mM NaCl, 5mM DTT; 0.01% (v/v) Triton X- 100; ΙΟΟμΜ H-Gly-Arg-AMC and rhDPPl (~50pM). Potential inhibitors were made up in DMSO and then diluted in the assay to give a final concentration of not exceeding 1% (v/v) DMSO. A 10-point half-log dilution series of the inhibitors (highest concentration typically 10μΜ) was tested and the pIC₅o determined using a 4-paramater logistic equation in a nonlinear curve fitting routine. A standard DPP1 inhibitor (vinyl sulfone, see below, or Example 24 from WO2009/074829) was used as a positive control in the assay. Routinely, inhibitors were pre-incubated with rhDPPl for 30-60min prior to the addition of the peptide substrate to start the reaction for a further 60min at 22°C. After that the plates were immediately read in a fluorescence plate reader using the above emission and excitation wavelengths [modified from Kam, CM, Gotz, MG, Koot, G, McGuire, MJ, Thiele, DL, Hudig, D & Powers, JC (2004). Arch Biochem Biophys, 427, 123-134 & McGuire, MJ, Lipsky, PE & Thiele, DL (1992). Arch Biochem Biophys, 295, 280-288]. The results obtained are shown in Table 1 below.

Table 1

Compound of Example DPPl activity, pIC₅₀

1 8.6

2 7.6

3 8.3

4 8.5

5 8.1

6 8.5

7 6.2

8 9.2

9 8.7

10 8.5

1 1 8.3

12 8.7

13 8.3

14 8.2

15 8.1

16 8.6

17 8.6

18 8.5

19 8.6

20 8.4

21 7.9

22 7.9

23 7.7

24 8.5

25 8.6

26 9.3

27 8.3 Compound of Example DPPl activity, pIC₅₀

28 7.9

29 8.6

30 8.6

31 8.6

32 8.7

33 7.7

34 8.9

35 6.8

36 8.1

37 7.8

38 8.3

39 8.6

40 7.6

41 8.9

42 7.9

43 8.4

44 5.8

45 6.7

46 6.8

47 5.6

48 6.9

49 8

50 8

51 7.5

52 6.7

53 6.9

54 6.9

55 6.5 Compound of Example DPP1 activity, pIC₅₀

56 6.6

57 7.1

58 6.7

59 7.5

60 7.4

61 7.8

62 8.4

63 8.9

64 8.4

65 9.2

66 8

67 8.1

68 8.6

69 8.2

Measurement of Stability in Human Microsomes

Hepatic microsomes, prepared from humans by standard ultracentrifugation methods, are used which have been stored at -70°C.

The compounds to be incubated are added from a concentrated stock in DMSO (O.lmM), 1% v/v to a suspension of microsomal protein (final concentration 1 mg.ml^"1) in a suitable vial. After a 2 min pre-incubation at 37°C, the cofactor NADPH is added (final concentration of 1 mM) and the reactions allowed to proceed. At appropriate time points (eg. 0, 5, 10, 20 and 30 min), an aliquot (100 μί) is taken from the incubation and added to 2-3 volumes of methanol to terminate the reactions and denature the microsomal enzymes. Control incubations may also be conducted from which NADPH or compound have been omitted. Once the incubations have been quenched, the samples are shaken for 5 min and then centrifuged for 15 min at 3000 rpm and 4°C. The supernatants are taken and analysed by HPLC-MSMS. The resultant peak areas of the incubated compounds are used to produce a plot of ln[residual concentration] versus time. The t½ and CLint of the loss of the parent compound from the incubation can then be determined from the elimination rate.

Claims

1. A compound of formul

(I) wherein

y represents 0, 1 or 2;

n is 1, 2, 3 or 4;

R¹ is hydroxyl, halogen, Ci_3alkoxy (optionally substituted with one or more substituents selected from halogen, hydroxy and Ci_3alkoxy) or Ci_3alkyl (optionally substituted with one or more substituents independently selected from halogen, hydroxy and Ci_₃alkoxy);

R is selected from hydrogen, halogen, CN, CF₃, Ci_₃alkyl and Ci_₃alkoxy;

A

wherein X is CH or N, Y is CH or N and B is a 5- or 6-membered heterocyclic ring containing 1 to 3 ring heteroatoms independently selected from nitrogen, oxygen and sulphur; the phenyl , 5- to 10-membered heteroaryl ring system and ring system A being optionally substituted by more or more substituents independently selected from halogen, carboxyl, hydroxyl, oxo, nitro, cyano, mercapto, Ci_6alkyl group, Ci_6alkoxy (the alkyl and alkoxy groups being optionally substituted by one or more substituents independently selected from hydroxyl, halogen, Ci_₆alkoxy, C₃-₆cycloalkyl, NR^blS0₂R , S(0)vR , NR^b5R , phenyl and C-linked morpholinyl), C₃_₆cycloalkyl, C₂_₆alkenyl, trifluoromethyl, Ci_₆alkylcarbonyl, Ci_₆alkylcarbonyloxy, Ci_₆alkoxycarbonyl, -NR⁵³R⁵⁴, -C(0)NR⁵⁵R⁵⁶, NR⁵⁷C(0)R⁵⁸, S0₂NR⁵⁹R⁶⁰, NR⁶¹S0₂R⁶², S(0)_vR⁶³, OS(0₂)R⁶⁴, benzyloxy and Ci_₆alkylpiperazinyl;

v is 0, 1 or 2;

or a pharmaceutically-acceptable salt thereof.

2. A compound or pharmaceutically acceptable salt thereof according to claim 1 wherein the stereochemistry at the carbon bearing the mandatory cyano group has the S

stereochemistry.

3. A compound according to claim 1 which is of the formula (Γ):

wherein n and Q are as defined in claim 1 ;

or a pharmaceutically acceptable salt thereof.

4. A compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof wherein n is 2 or 3.

5. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof wherein Q is optionally substituted phenyl, pyridyl, pyrimidyl, pyridazyl, or pyrazolyl.

6. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof wherein Q is selected from the following ring systems:

wherein X is CH or N, Y is CH or N and R' is selected from hydrogen, C₃_₇cycloalkyl and Ci_₆alkyl, the alkyl group being optionally substituted by 1 or 2 substituents independently selected from halogen, Ci_₄alkyoxy, C3_₇cycloalkyl, amino, alklylamino and dialklylamino; and the ring system being optionally further substituted as defined in claim 1.

7. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof wherein the phenyl, 5- to 10-membered heteroaryl ring system and ring system A in Q are optionally substituted by substituents independently selected from halogen, hydroxyl, oxo, cyano, Ci_₆alkyl group, Ci_₆alkoxy (the alkyl and alkoxy groups being optionally substituted by one or more substituents independently selected from hydroxyl, halogen, Ci_₆alkoxy, C₃_₆cycloalkyl, NHS0₂R⁶², S(0)₂R⁶³ and NR⁶⁵R⁶⁶), C₃_₆cycloalkyl, trifluoromethyl,

Ci_₆alkylcarbonyl, -NR⁵³R⁵⁴, -C(0)NR⁵⁵R⁵⁶, NHC(0)R⁵⁸, S0₂NR⁵⁹R⁶⁰, NHS0₂R⁶²,

S(0)₂R⁶³, OS(0₂)R⁶⁴, benzyloxy and Ci_₆alkylpiperazinyl;

wherein R and R each independently represent hydrogen or Ci_₆alkyl or R and R together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;

R⁵⁵ and R⁵⁶ each independently represent hydrogen or Ci_₆alkyl or R⁵⁵ and R⁵⁶ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;

R⁵⁹ and R⁶⁰ each independently represent hydrogen or Ci_₆alkyl or R⁵⁹ and R⁶⁰ together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring;

Ci_₆alkyl or C3_₆cycloalkyl group; provided that R⁶², R⁶³ and R⁶⁴ are not hydrogen;

8. A compound of the formula (I) according to claim 1 being:

(S)- 1 -Amino-N-( 1 -cyano-2-(4-(2-oxoindolin-6-yl)phenyl)ethyl)cyclohexanecarboxamide; (S)- 1 -Amino-N-(l -cyano-2-(4-(l -methyl-6-oxo- 1 ,6-dihydropyridin-3- yl)phenyl)ethyl)cyclohexanecarboxamide;

(5)-4-Amino-N-(l-cyano-2-(4-(6-methyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridm^ yl)phenyl)ethyl)tetrahydro-2H-pyran-4-carboxamide;

(S)- 1 -Amino-N-(l -cyano-2-(4-(5-fluoro- 1 -methyl-6-oxo- 1 ,6-dihydropyridin-3- yl)phenyl)ethyl)cyclohexanecarboxamide trifluoroacetic acid salt;

(S)- 1 -Amino-N-( 1 -cyano-2-(4-(2-(2-hydroxyethyl)- 1 -oxoisoindolin-5 - yl)phenyl)ethyl)cyclohexanecarboxamide; (S)-tert-Butyl 1 -(2-(4-(6-carbamoylpyridin-3 -yl)phenyl)- 1 - cyanoethylcarbamoyl)cyclohexylcarbamate;

(S)- 1 -Amino-N-(l -cyano-2-(4-(l -oxoisoindolin-5-yl)phenyl)ethyl)cyclohexanecarboxamide; (S)- 1 -Amino-N-( 1 -cyano-2-(4-(l -(2-methoxyethyl)- lH-pyrazol-4- yl)phenyl)ethyl)cyclohexanecarboxamide;

(5)-4'-(2-(l-Aminocyclohexanecarboxamido)-2-cyanoethyl)biphenyl-4-carboxamide;

(5)-4'-(2-(l-Aminocyclohexanecarboxamido)-2-cyanoethyl)-3-fluorobiphenyl-4-carboxamide trifluoroacetic acid salt;

(iS)-N-(2-(4-( lH-Pyrazol-4-yl)phenyl)- 1 -cyanoethyl)- 1 -aminocyclopentanecarboxamide; (S)- 1 -Amino-N-(l -cyano-2-(4-(l -oxoisoindolin-5-yl)phenyl)ethyl)cyclopentanecarboxamide; (S)- 1 -Amino-N-( 1 -cyano-2-(4-(pyridin-4-yl)phenyl)ethyl)cyclohexanecarboxamide;

1 -Amino-N- {(IS)- 1 -cyano-2-[4-(2,2-dioxido-l ,3-dihydro-2-benzothiophen-5- yl)phenyl]ethyl}cyclopentanecarboxamide;

(S)- 1 -Amino-N-( 1 -cyano-2-(4-(l -(cyclobutylmethyl)-2-oxo- 1 ,2-dihydropyrimidin-5- yl)phenyl)ethyl)cyclohexanecarboxamide;

(S)- 1 -Amino-N-(l -cyano-2-(4-(l -ethyl-6-oxo- 1 ,6-dihydropyridazin-3- yl)phenyl)ethyl)cycloheptanecarboxamide; (S)- 1 -Amino-N-( 1 -cyano-2-(4-(6-oxo- 1 ,6-dihydropyridin-3 - yl)phenyl)ethyl)cyclohexanecarboxamide;

(5)-4'-(2-(l-Aminocyclopentanecarboxamido)-2-cyanoethyl)biphenyl-4-yl methanesulfonate; (S)- 1 -Amino-N-( 1 -cyano-2-(4-(l -methyl- lH-pyrazol-4- yl)phenyl)ethyl)cyclohexanecarboxamide; or

or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

10. A compound of formula (I) as claimed in any one of claims 1 to 8 or a

pharmaceutically acceptable salt thereof for use in therapy.

11. A compound of formula (I) as claimed in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for use in treating asthma, chronic obstructive pulmonary disease or allergic rhinitis.

12. Use of a compound of formula (I) as claimed in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating asthma, chronic obstructive pulmonary disease or allergic rhinitis.

13. A method of treating asthma, chronic obstructive pulmonary disease or allergic rhinitis in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I) as claimed in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

14. A combination of a compound of formula (I) as claimed in any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof and one or more agents independently selected from:

• a non-steroidal glucocorticoid receptor agonist;

• a selective β₂ adrenoceptor agonist;

• a phosphodiesterase inhibitor;

• a protease inhibitor;

• a glucocorticoid;

• an anticholinergic agent;

• a modulator of chemokine receptor function; and

• an inhibitor of kinase function .