WO2009001128A1

WO2009001128A1 - 1,2-cycl0hexane dicarboxamides as cathepsin inhibitors

Info

Publication number: WO2009001128A1
Application number: PCT/GB2008/050484
Authority: WO
Inventors: Alexander Graham Dossetter; Nicola Murdoch Heron
Original assignee: Astrazeneca Ab; Astrazeneca Uk Limited
Priority date: 2007-06-26
Filing date: 2008-06-24
Publication date: 2008-12-31

Abstract

The present invention relates to compounds and compositions for treating diseases associated with cysteine protease activity. The compounds are reversible inhibitors of cysteine proteases, including cathepsins B, K, C, F, H, L, O, S, W and X. Of particular interest are diseases associated with Cathepsin K.

Description

1 ,2-CYCLOHEXANE DICARBOXAMIDES AS CATHEPSIN INHIBITORS

The present invention relates to compounds and compositions for treating diseases associated with cysteine protease activity. The compounds are reversible inhibitors of cysteine proteases, including cathepsins B, K, C, F, H, L, O, S, W and X. Of particular interest are diseases associated with Cathepsin K. In addition this invention also discloses processes for the preparation of such inhibitors.

Cathepsin K is a member of the papain superfamily of cysteine proteases, which also encompasses Cathepsins B, C, F, H, L, O, S, W and X. Cathepsin K is a lysosomal collagenase like enzyme, highly expressed in osteoclast cells and plays a key role in turnover and degradation of the bone organic matrix in skeletal growth and development, but also in diseases. In this respect inhibitors of cathepsin K could be useful agents in the treatment of but not limited to, osteoporosis, osteoarthritis, asthma, rheumatoid arthritis, metastatic bone disease, osteolytic bone cancer and bone related neuropathic pain. The present invention therefore provides a compound of formula (I)

(I) in which: A is a 5- to 7- membered aliphatic ring optionally containing a double bond and optionally comprising an oxygen atom as a ring member and optionally being substituted by up to three substituents each independently selected from halogen, C^alkyl and C_3- 4carbocyclyl;

R is hydrogen or C_1-6 alkyl ; R¹ and R² together with the nitrogen atom to which they are attached form a 5- to 7- membered monocyclic saturated or partially unsaturated heterocyclic ring, which ring shares at least one atom with a second monocyclic saturated, partially unsaturated or unsaturated ring so as to form a bicyclic ring system comprising up to 12 ring atoms, and wherein the bicyclic ring system optionally comprises up to three heteroatoms each independently selected from O, S or N atoms, and is optionally substituted by up to three substituents each independently selected from phenyl, benzyl, naphthyl, C_1-6 alkyl, C_2- ₆alkenyl, C_2-6alkynyl, cyano, halogen, COOR³, COR³, NO₂, OR³, CONR⁴R⁵, NR⁴R⁵, SO₂R³, NSO₂R³, monocyclic heteroaryl comprising up to 7 ring atoms, and bicyclic heteroaryl comprising up to 12 carbon atoms, and wherein (i) phenyl, naphthyl, Ci_-6 alkyl, C_2-6alkenyl, C_2-6alkynyl and benzyl are optionally further substituted by up to three substituents each independently selected from halogen, NR⁴R⁵, SO₂R³, CONR⁴R⁵, cyano, OR³, SO₂NR⁴R⁵, NSO₂R³, NR⁴COR⁵, and Ci_-6 alkyl itself optionally substituted with 1 , 2 or 3 substituents independently selected from halogen, cyano, SO₂R³, NR⁴R⁵, OR³, SO₂NR⁴R⁵, NSO₂R³, NR⁴COR⁵ and CONR⁴R⁵, and (ii) monocyclic or bicyclic heteroaryl are optionally further substituted by up to three substituents each independently selected from halogen, NR⁴R⁵, SO₂NR⁴R⁵, NSO₂R³, NR⁴COR⁵, CONR⁴R⁵ , SO₂R³, cyano, OR³, and phenyl itself optionally substituted with up to three halogen groups, SO₂R³, or Ci_-6 alkyl itself optionally substituted with up to three substituents independently selected from halogen, cyano, SO₂R³, SO₂NR⁴R⁵, NSO₂R³, NR⁴COR⁵, NR⁴R⁵, OR³, C_3-7carbocyclyl and CONR⁴R⁵;

R³ is selected from hydrogen, Ci_-6 alkyl, C3_-7carbocyclyl, phenyl, monocyclic heteroaryl, a 4-7 membered monocyclic saturated heterocyclic ring comprising up to three heteroatoms each independently selected from O, S or N atoms, and wherein Ci_-6 alkyl and phenyl, monocyclic heteroaryl, can each be optionally substituted by up to three groups independently selected from halogen, cyano, CONR⁴R⁵, NR⁴R⁵, SO₂NR⁴R⁵, NSO₂R³ and SO₂R³;

R⁴ and R⁵ are independently hydrogen, Ci_-6 alkyl, COR³, monocyclic heteroaryl comprising up to 7 ring atoms or bicyclic heteroaryl comprising up to 12 ring atoms or together with the nitrogen to which they are attached form a 5- to 7-membered monocyclic saturated heterocyclic ring optionally comprising up to three additional heteroatoms each independently selected from O, S or N atoms and optionally substituted by Ci_-6 alkyl optionally substituted by NR⁶R⁷; R⁶ and R⁷ are independently hydrogen, C_1-6 alkyl, or together with the nitrogen to which they are attached form a 5- to 7-membered monocyclic saturated heterocyclic ring optionally comprising up to three additional heteroatoms each independently selected from O, S or N atoms; and pharmaceutically acceptable salts thereof.

In the context of the present specification, unless otherwise indicated, an alkyl, alkenyl or alkynyl group or an alkyl, alkenyl or alkynyl moiety in a substituent group may be linear or branched. However references to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched-chain alkyl groups such as t-butyl are specific for the branched chain version only. For example, "Ci-3alkyl" includes methyl, ethyl, propyl and isopropyl and examples of "Chalky!" include the examples of "Ci-3alkyl"and additionally t-butyl, pentyl, 2,3-dimethylpropyl, 3- methylbutyl and hexyl. Examples of "Ci.salkyl" include the examples of "C_halky!" and additionally heptyl, 2,3-dimethylpentyl, 1-propylbutyl and octyl. An analogous convention applies to other terms, for example "C₂-₆alkenyl" includes vinyl, allyl, 1-propenyl , 2- butenyl, 3-butenyl, 3-methylbut-l-enyl, 1-pentenyl and 4-hexenyl and examples of "C₂-₆alkynyl" includes ethynyl, 1-propynyl, 3-butynyl, 2-pentynyl and l-methylpent-2- ynyl.

"C_3-4carbocyclyl" is a saturated, partially saturated or unsaturated, monocyclic ring containing 3 to 4 carbon ring atoms wherein a -CH₂- group can optionally be replaced by a -C(O)-. Suitable examples of "C3-4carbocyclyl" are cyclopropyl and cyclobutyl.

"C3-7carbocyclyl" is a saturated, partially saturated or unsaturated, monocyclic ring containing 3 to 7 carbon ring atoms wherein a -CH₂- group can optionally be replaced by a -C(O)-. Suitable examples of "C3-7carbocyclyl" are cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl, cyclohexenyl, 4-oxocyclohex-l-yl and S-oxocyclohept-S-en-l-yl. Aryl groups include phenyl and naphthyl.

"Monocyclic heteroaryl" groups include 5- or 6-membered rings containing one or more heteroatoms selected from N, S, O. Examples include pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyridazinyl, thiazolyl, oxazolyl, pyrazolyl, imidazolyl, furanyl, thiophenyl and triazolyl. Particular examples of monocyclic heteroaryl groups include pyridinyl and especially pyridin-2-yl and pyridin-6-yl. Examples of "a 5- to 7-membered monocyclic saturated or partially saturated heterocyclic ring" include pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, homo-morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, 1,4- diazepanyl and homopiperazinyl. Particular examples of a 5-, 6- or 7-membered monocyclic saturated heterocyclic ring optionally containing one or more O, S or N atoms include pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, 1 ,4-diazepanyl and especially pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, homopiperazin-1-yl and 1,4- diazepan-1-yl.

Examples of "a 4-7 membered monocyclic saturated heterocyclic ring" include azetidinyl pyrrolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, homo- morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl and homopiperazinyl. Particular examples of a 5-, 6- or 7-membered monocyclic saturated heterocyclic ring optionally containing one or more O, S or N atoms include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl and especially azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, homopiperazin-1-yl.

The term "bicyclic ring" refers to bicyclic ring systems containing up to 15 atoms and containing one or more heteroatoms selected from N, S, O. It is to be understood that the definition of "bicyclic ring" includes spiro ring systems. Examples of "a bicyclic ring" include 1,2,3,4-tetrahydroisoquinolinyl, isoindolinyl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- ajpyrazinyl, 4,5,6,7-tetrahydro-thieno[3,2-c]pyridinyl, 4,5,6,7-tetrahydro-thieno[2,3- c]pyridinyl, 5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidinyl, 6,8-dihydro-5H-l,7- naphthyridinyl, 3 ,4-dihydro- 1 H-2,7-naphthyridinyl, 7,8-dihydro-5H- 1 ,6-naphthyridinyl, 3,4-dihydro-lH-2,6-naphthyridinyl, 4,5,6,7-tetrahydro-lH-pyrazolo[4,3-c]pyridinyl, 4,5,6,7-tetrahydroisothiazolo[4,3-c]pyridinyl, 4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridinyl, 4,5,6,7-tetrahydro-lH-imidazo[4,5-c]pyridinyl, octahydro-2H-pyrido[l,2-α]pyrazinyl, octahydropyrrolo[l,2-α]pyrazinyl, 2-(2,7-diazaspiro[4.5]decane), 7-(2,7- diazaspiro[4.5]decane) and 2-(2,8-diazaspiro[4.5]decane), 8-(2,8-diazaspiro[4.5]decane).

Particular examples of a bicyclic ring system optionally containing one or more O, S or N atoms include 1,2,3,4-tetrahydroisoquinolinyl, isoindolinyl, 5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyrazinyl, 4,5,6,7-tetrahydro-thieno[3,2-c]pyridinyl, 5,6,7,8- tetrahydro-pyrido[4,3-d]pyrimidinyl, 6,8-dihydro-5H-l,7-naphthyridinyl, 3,4-dihydro-lH- 2,7-naphthyridinyl, 7,8-dihydro-5H-l,6-naphthyridinyl, 3,4-dihydro-lH-2,6- naphthyridinyl, 2-(2,8-diazaspiro[4.5]decanyl) and especially 1,2,3,4- tetrahydroisoquinolin-2-yl, isoindolin-2-yl, 5,6,7,8-tetrahydro-[l,2,4]triazolo[4,3- a]pyrazin-7-yl, 4,5,6,7-tetrahydro-thieno[3,2-c]pyridin-5-yl, 5,6,7,8-tetrahydro-pyrido[4,3- d]pyrimidin-6-yl, 6,8-dihydro-5H- 1 ,7-naphthyridin-7-yl, 3 ,4-dihydro- 1 H-2,7-naphthyridin- 2-yl, 8-dihydro-5H-l,6-naphthyridin-6-yl, 3,4-dihydro-lH-2,6-naphthyridin-2-yl and 2- (2,8-diazaspiro[4.5]decanyl).

The term "halo" refers to fluoro, chloro, bromo and iodo, such as for example fluoro, chloro, bromo; chloro and fluoro; chloro and bromo; fluoro and bromo.

Where optional substituents are chosen from "up to three" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups. An analogous convention applies to substituents chosen from "1 or 2" groups.

Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates.

It is to be understood that certain compounds of Formula I defined above may exhibit the phenomenon of tautomerism. In particular, tautomerism may affect any heterocyclic groups that bear 1 or 2 oxo substituents. It is to be understood that the present invention includes in its definition any such tautomeric form, or a mixture thereof, which possesses the above-mentioned activity and is not to be limited merely to any one tautomeric form utilised within the formulae drawings or named in the Examples.

It is also to be understood that certain compounds of formula (1) and salts thereof can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms. A suitable pharmaceutically-acceptable salt of a compound of the Formula (I) is, for example, an acid-addition salt of a compound of the Formula (I), for example an acid- addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulphuric, trifluoroacetic, citric, /?αrα-toluenesulphonic, methanesulphonic, tartaric or maleic acid; or, for example, a salt of a compound of the Formula (I) which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt. A further suitable pharmaceutically acceptable salt of a compound of the Formula (I) is, for example, a salt formed within the human or animal body after administration of a compound of the Formula (I).

The compounds of the invention may be administered in the form of a pro-drug that is a compound that is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and/or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula (I) and in vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula (I).

Accordingly, the present invention includes those compounds of the Formula (I) as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula (I) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula (I) may be a synthetically-produced compound or a metabolically-produced compound. A suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology. Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Pro-drugs", by H. Bundgaard p. 113-

191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews. 8, 1-38 (1992); e) H. Bundgaard, et ah, Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al, Chem. Pharm. Bull, 32, 692 (1984); g) T. Higuchi and V. Stella, "Pro-Drugs as Novel Delivery Systems", A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987. A suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of the Formula (I) containing a carboxy group is, for example, a pharmaceutically-acceptable ester, which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically-acceptable esters for carboxy include (l-6C)alkyl esters such as methyl, ethyl and tert-bvXy\, (l-6C)alkoxymethyl esters such as methoxymethyl esters, (l-6C)alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3-phthalidyl esters, (3-8C)cycloalkylcarbonyloxy-(l-6C)alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-l,3- dioxolenylmethyl esters such as 5-methyl-2-oxo-l,3-dioxolen-4-ylmethyl esters and (1- 6C)alkoxycarbonyloxy-(l-6C)alkyl esters such as methoxycarbonyloxymethyl and 1- methoxycarbonyloxyethyl esters.

A suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the Formula (I) containing a hydroxy group is, for example, a pharmaceutically-acceptable ester or ether, which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include (1-

10C)alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, (l-lOC)alkoxycarbonyl groups such as ethoxycarbonyl, N,N-[άi-{\- 4C)alkyl] carbamoyl, 2-dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, 7V-alkylaminomethyl, 7V,7V-dialkylaminomethyl, morpholinomethyl, piperazin- 1 -ylmethyl and 4-(l -4C)alkylpiperazin- 1 -ylmethyl. Suitable pharmaceutically-acceptable ether forming groups for a hydroxy group include α- acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

A suitable pharmaceutically-acceptable pro-drug of a compound of the Formula (I) that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically-acceptable amides from an amino group include, for example an amide formed with (l-lOC)alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, 7V,7V-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(l-4C)alkylpiperazin-l-ylmethyl.

The in vivo effects of a compound of the Formula (I) may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the Formula (I). As stated hereinbefore, the in vivo effects of a compound of the Formula (I) may also be exerted by way of metabolism of a precursor compound (a pro-drug).

Particular novel compounds of the invention include, for example, compounds of the Formula (I), or pharmaceutically-acceptable salts thereof, wherein, unless otherwise stated, each of A, R, R¹ and R² has any of the meanings defined hereinbefore or hereinafter:-

Conveniently A is a 5-7-membered aliphatic ring optionally containing a double bond and optionally comprising an oxygen atom as a ring member and optionally being substituted by up to three substituents independently selected from halogen and C_3- 4carbocyclyl. A double bond can be present in any suitable position of the ring A. An oxygen atom can be present in any suitable position of the ring A, in addition to a double bond if desired.

Conveniently, A is a 5-7-membered aliphatic ring optionally being substituted by 1, 2 or 3 substituents independently selected from halogen and

More conveniently, A is selected from any one of cyclopentane, norpinane, cycloheptane and cyclohexane. More conveniently, A is cyclohexane. Conveniently, R is hydrogen or C_1-4alkyl. More conveniently, R is hydrogen, methyl, ethyl or propyl. More conveniently, R is hydrogen.

Conveniently, R¹ and R² together with the nitrogen atom to which they are attached form a 5- to 6-membered monocyclic saturated or partially saturated heterocyclic ring, which ring is attached and shares at least one atom with a second monocyclic saturated or unsaturated ring so as to form a bicyclic ring system, which bicyclic ring system can optionally contain one or more O, S or N atoms and can optionally be substituted by 1, 2 or 3 substituents as defined hereinbefore or hereinafter. More conveniently, the bicyclic ring system can optionally contain one or more S or N atoms and can be optionally substituted by 1 or 2 substituents as defined hereinbefore or hereinafter. Conveniently, R¹ and R² together with the nitrogen atom to which they are attached form any one of a 1,2,3,4-tetrahydroisoquinolinyl, isoindolinyl, 5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyrazinyl, 4,5,6,7-tetrahydro-thieno[3,2-c]pyridinyl, 5,6,7,8- tetrahydro-pyrido[4,3-d]pyrimidinyl, 6,8-dihydro-5H-l,7-naphthyridinyl, 3,4-dihydro-lH- 2,7-naphthyridinyl, 7,8-dihydro-5H- 1 ,6-naphthyridinyl, 3 ,4-dihydro- 1 H-2,6-naphthyridinyl ring, wherein the 1,2,3,4-tetrahydroisoquinolinyl, isoindolinyl, 5,6,7,8-tetrahydro- [l,2,4]triazolo[4,3-a]pyrazinyl, 4,5,6,7-tetrahydro-thieno[3,2-c]pyridinyl, 5,6,7,8- tetrahydro-pyrido[4,3-d]pyrimidinyl, 6,8-dihydro-5H-l,7-naphthyridinyl, 3,4-dihydro-lH- 2,7-naphthyridinyl, 7,8-dihydro-5H-l,6-naphthyridinyl, 3,4-dihydro-lH-2,6- naphthyridinyl, or a 2-(2,8-diazaspiro[4.5]decanyl) ring which can optionally be substituted by 1 , 2 or 3 substituent groups as defined hereinbefore or hereinafter.

Conveniently, the phenyl, Ci_-6 alkyl, C₂-₆alkenyl, C_2-6alkynyl and benzyl groups stated in part (i) of the definition or R¹ and R² above, can be optionally substituted further by 1 or 2 substituents independently selected from halogen, NR⁴R⁵, SO₂R³, CONR⁴R⁵, cyano, OR³, SO₂NR⁴R⁵, NSO₂R³, NR⁴COR⁵, Ci_-6 alkyl itself optionally substituted with 1, 2 or 3 substituents independently selected from halogen, cyano, SO₂R³, NR⁴R⁵, OR³, SO₂NR⁴R⁵, NSO₂R³, NR⁴COR⁵ or CONR⁴R⁵.

Conveniently, the phenyl, Ci_-6 alkyl, C_2-6alkenyl, C_2-6alkynyl and benzyl groups stated in part (i) of the definition or R¹ and R² above, can be optionally substituted further by halogen, NR⁴R⁵, SO₂R³, CONR⁴R⁵, cyano, OR³, SO₂NR⁴R⁵, NSO₂R³, NR⁴COR⁵, Ci_-6 alkyl itself optionally substituted with 1 , 2 or 3 substituents independently selected from halogen, cyano, SO₂R³, NR⁴R⁵, OR³, SO₂NR⁴R⁵, NSO₂R³, NR⁴COR⁵ or CONR⁴R⁵. Conveniently, the monocyclic heteroaryl group stated in part (ii) of the definition or R¹ and R² above, can be optionally substituted further by halogen, NR⁴R⁵, SO₂NR⁴R⁵, NSO₂R³, NR⁴COR⁵, CONR⁴R⁵, SO₂R³, cyano or OR³.

Conveniently, the bicyclic ring system formed by R¹, R² and the nitrogen to which they are attached can optionally contain one or more O, S or N atoms and can be optionally substituted by 1, 2 or 3 substituents independently selected from C_1-6 alkyl, cyano, halogen, COOR³, COR³, NO₂, OR³, SO₂R³, NSO₂R³, CONR⁴R⁵, NR⁴R⁵ or monocyclic heteroaryl, wherein the Ci_-6 alkyl can optionally be substituted further with 1, 2 or 3 substituents independently selected from halogen, cyano, SO₂R³, NR⁴R⁵, OR³, SO₂NR⁴R⁵, NSO₂R³, NR⁴COR⁵ or CONR⁴R⁵ and wherein the monocyclic heteroaryl can be optionally substituted further by 1 or 2 substituents independently selected from halogen, NR⁴R⁵, SO₂NR⁴R⁵, NSO₂R³, NR⁴COR⁵, CONR⁴R⁵ , SO₂R³, cyano, OR³.

Conveniently, R³ is hydrogen, C₃.₇carbocyclyl or Ci_-6 alkyl itself optionally substituted with NR⁴R⁵. More conveniently, R³ is hydrogen or Ci_-6 alkyl.

Conveniently, R⁴ is hydrogen, Ci_-6 alkyl or phenyl. More conveniently, R⁴ is hydrogen or Ci_-6 alkyl. Conveniently, R⁶ and R⁷ are independently hydrogen or Ci_-6 alkyl. It is to be understood that convenient compounds of the invention include each exemplified compound, each selected independently and pharmaceutically acceptable salts, in vivo hydrolysable esters thereof.

It is also to be understood that each of the following groups of compounds and pharmaceutically acceptable salts, in vivo hydrolysable esters thereof, represents an independent aspect of the invention: (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[(6,7-dimethoxy-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide

(li?,2i?)-N-(l-cyanocyclopropyl)-2-[(6,7-difluoro-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide

(li?,2i?)-N-(l-cyanocyclopropyl)-2-[(7-fiuoro-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide

(li?,2i?)-N-(l-cyanocyclopropyl)-2-{[3-(trifiuoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3- α]pyrazin-7(8H)-yl]carbonyl}cyclohexanecarboxamide (li?,2i?)-N-(l-cyanocyclopropyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)- ylcarbonyl)cyclohexanecarboxamide

(li?,2i?)-N-(l-cyanocyclopropyl)-2-[(5,8-difluoro-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide (li?,2i?)-N-(l-cyanocyclopropyl)-2-(7,8-dihydropyrido[4,3-J]pyrimidin-6(5H)- ylcarbonyl)cyclohexanecarboxamide

(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-{[(35)-3-(hydroxymethyl)-3,4-dihydroisoquinolin-

2(lH)-yl]carbonyl}cyclohexanecarboxamide

(li?,2i?)-7V-(l-cyanocyclopropyl)-2-[(5-fluoro-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide

(li?,2i?)-7V-(l-cyanocyclopropyl)-2-(7,8-dihydro-l,6-naphthyridin-6(5H)- ylcarbonyl)cyclohexanecarboxamide methyl 2-[((li?,2i?)-2-{[(l-cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]-6,7- dimethoxy-l,2,3,4-tetrahydroisoquinoline-3-carboxylate 2-[((li?,2i?)-2-{[(l-cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]-6,7- dimethoxy-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid methyl 2-[((li?,2i?)-2-{[(l-cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]- l,2,3,4-tetrahydroisoquinoline-8-carboxylate methyl 2-[((li?,2i?)-2-{[(l-cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]- 1 ,2,3,4-tetrahydroisoquinoline-3-carboxylate

2-[((li?,2i?)-2-{[(l-cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]-l,2,3,4- tetrahydroisoquinoline-3-carboxylic acid

(li?,2i?)-N-(l-cyanocyclopropyl)-2-(3,4-dihydro-2,7-naphthyridin-2(lH)- ylcarbonyl)cyclohexanecarboxamide (li?,2i?)-7V-(l-cyanocyclopropyl)-2-(5,8-dihydro-l,7-naphthyridin-7(6H)- ylcarbonyl)cyclohexanecarboxamide

(li?,2i?)-2-[(5-chloro-3,4-dihydroisoquinolin-2(lH)-yl)carbonyl]-N-(l- cyanocyclopropyl)cyclohexanecarboxamide

(li?,2i?)-7V-(l-cyanocyclopropyl)-2-{[8-(trifluoromethyl)-3,4-dihydroisoquinolin-2(lH)- yljcarbonyl} cyclohexanecarboxamide

(li?,2i?)-7V-(l-cyanocyclopropyl)-2-[(7-cyano-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide (li?,2i?)-2-[(7-chloro-3,4-dihydroisoquinolin-2(lH)-yl)carbonyl]-N-(l- cyanocyclopropyl)cyclohexanecarboxamide

(li?,2i?)-2-{[l-(2-anilino-2-oxoethyl)-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide

(3S)-N-(tert-butyl)-2-[((lR,2R)-2-{[(l- cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]-l,2,3,4-tetrahydroisoquinoline-3- carboxamide tert-butyl (3R)-2-[((lR,2R)-2-{[(l- cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]-l,2,3,4-tetrahydroisoquinoline-3- carboxylate

(2i?,3i?)-Λ/-(l-cyanocyclopropyl)-2-ethyl-3-[(l-ethyl-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]hexanamide

(\R,2R)-N-(\ -cyanocyclopropyl)-2- { [7-(trifluoromethyl)-3 ,4-dihydroisoquinolin-2( IH)- yl]carbonyl}cyclohexanecarboxamide

(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-{[5-(trifluoromethyl)-3,4-dihydroisoquinolin-2(lH)- yl]carbonyl}cyclohexanecarboxamide

(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[(6-cyano-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[(5,7-dichloro-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide

2-[((li?,2i?)-2-{[(l-cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]-l,2,3,4- tetrahydroisoquinoline-3-carboxamide

(li?,2i?)-N-(l-cyanocyclopropyl)-2-(3,4-dihydro-2,6-naphthyridin-2(lH)- ylcarbonyl)cyclohexanecarboxamide tert-butyl 2-[((li?,2i?)-2-{[(l-cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]-2,8- diazaspiro[4.5]decane-8-carboxylate

(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-{[6-[(methylsulfonyl)amino]-3,4-dihydroisoquinolin-

2(lH)-yl]carbonyl}cyclohexanecarboxamide (li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-({6-[methylsulfonyl]-3,4-dihydroisoquinolin-2(lH)- yl}carbonyl)cyclohexanecarboxamide ( \R,2R)-N-( 1 -cyanocyclopropyl)-2- { [6-(hydroxymethyl)-3 ,4-dihydroisoquinolin-2( IH)- yl]carbonyl}cyclohexanecarboxamide

2-[((li?,2i?)-2-{[(l-cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]isoindoline-l- carboxamide

(li?,2i?)-N-(l-cyanocyclopropyl)-2-(l,3-dihydro-2H-isoindol-2- ylcarbonyl)cyclohexanecarboxamide

(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-(3,4-dihydroisoquinolin-2(lH)- ylcarbonyl)cyclohexanecarboxamide

(li?,2i?)-Λ/-(l-cyanocyclopropyl)-2-[(5-cyano-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide

Compounds of formula (I) can be prepared by any of the following routes:

Route A

(H) (IH) (I)

Route B

(IV) (V) (I) These routes are further illustrated by the following schemes:

(V) (VI) (III) (I)

SCHEME 1

Compounds of the type (I) can be synthesised by combining three building blocks as outlined above. A secondary amine of the type represented by generic structure (V) coupled with a single enantiomer of cyclic 1,2- diacid of the type (VI), then an appropriately substituted 1-aminocyclopropylcarbonitrile (III) is coupled to the remaining acid.

Dehydrating agent

R,R-enantiomer

Vi) VII)

III) N) SCHEME 2

In more detail the chiral cyclic 1 ,2-diacid (VI) can be dehydrated with a suitable reagent such as acetic anhydride, acetyl chloride, dicyclohexylcarbodiimide (DCC), thionylchloride and the such like, preferably acetic anhydride at a temperature between room temperature and 100 ⁰C, then removal of excess dehydrating agent yields a bi-cyclic- anhydride of the type (VII). The anhydride (VII) is reactive towards secondary amines of the type (V) in the presence or absence of a suitable base such as triethylamine, diethylisopropylamine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and the such like or ionic bases such as potassium carbonate, in a suitable aprotic solvent such as dichloromethane (DCM), tetrahydrofuran (THF), diethylether, dimethylformamide (DMF), dimethylacetamide (DMA), tert-butylmethylether (TBME), toluene. The subsequent acid is combined with an appropriately substituted 1-aminocyclopropylcarbonitrile by the use of a coupling agent such as O-(7-azabenzotriazol-l-yl)-Λ/,Λ/,N',N'-tetramethyluronium hexafluorophosphate

(HATU), dicyclohexylcarbodiimide (DCC) / hydroxylbenzotriazole (HOBt), 1- benzotriazolyoxy-tris-dimethylamino-phosphonium hexafluorophosphate (BOP), benzotriazolyoxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP), N, N- dimethylaminoethylcyclohexylcarbodiimide (EDC), 4-(4,6-dimethoxy-l,3,5-triazin-2-yl)- 4-methylmorpholinium chloride (DMTMM), trichloroacetyl chloride, by the formation of an active ester in the presence of a suitable bases triethylamine, diethylisopropylamine, DBU, and the such like or ionic bases such as potassium carbonate, in the presence or absence of an activating base such as 7V,7V-dimethyl-4-amino-pyridine (DMAP) in a suitable solvent dichloromethane (DCM), tetrahydrofuran (THF), diethylether, dimethylformamide (DMF), dimethylacetamide (DMA), tert-butylmethylether (TBME), toluene at a temperature between 0 ⁰C and 60 ⁰C to yield compounds of type (I). A combination of HATU or PyBOP in either DMF or DCM at a temperature between room temperature and 35 ⁰C is preferred.

The chiral cyclic 1,2-diacid of the type (VI) can be produced by methods as shown in the literature - WO2004000825, Eur. J. Org. Chem. 2002, 2948-2952, which include chiral resolution, chiral separation by chromatographic methods, de-symmetrisation using esterase enzymes, such as pig liver esterase as generalised below. resolving enzyme

r n tion

(+/-) racemic Chiral amine R,R-enantiomer

The preferred i?,i?-cyclohexyl-l,2-dicarboxylic acid can be produced by a resolution of commercially available racemic diacid by a resolution process using chiral amines bases to form diastereomeric salts and recystallisation of the single enantiomers, as outlined by Eur. J. Org. Chem. 2002, 2948-2952.

VII) VIII) III)

SCHEME 3

An alternative synthesis of compounds of the type (I) can be made by the route outlined in Scheme 3 above. The previously described chiral 1,2-diacid can be reacted with a suitable alcohol such as benzyl alcohol, substituted benzyl alcohol (for example A- methoxybenzyl alcohol), ethanol, methanol, propan-1-ol, isopropanol, butan-1-ol, at room temperature to 50 ⁰C in a suitable unreactive solvent such as THF, DCM, DMF and the such like to yield an ester-acid of the type (VIII). The reaction with benzyl and substituted benzyl alcohols is preferred. The ester group is now represented by the group PG, as this is formally a protecting group masking the acid. Descriptions of suitable protecting groups in organic synthesis can be found in Green and Wuts Protective groups in Organic synthesis, 1991, John Wiley. In a similar manner to that described above a free acid of the type (VIII) can be coupled with an appropriately substituted 1-aminocyclopropylcarbonitrile (III) by the use of a coupling agent such as HATU, PyBOP, EDC, DCC /HOBt, BOP, PyBOP, EDC, DMTMM, trichloroacetyl chloride, by the formation of an active ester in the presence of a suitable bases triethylamine, diethylisopropylamine, DBU and the such like, or suitable ionic bases such as potassium carbonate, in an appropriate solvent dichloromethane (DCM), tetrahydrofuran (THF), diethylether, dimethylformaide (DMF), dimethylacetamide (DMA), tert-butylmethylether (TBME), toluene at a temperature between 0 ⁰C and 100 ⁰C to yield compounds of the type (IX). An alternative method would be by conversion to an acid chloride with a suitable reagent such as oxalylchloride, thionyl chloride, and the such like, then addition of the secondary amine (V) in the presence of a bases as list above. A combination of HATU or PyBOP in either DMF or DCM between room temperature and 50 ⁰C is preferred. The protecting group can be removed from compounds of the type (IX) to reveal an acid of the type (IV) by the methods described in Green and Wuts, Protective groups in Organic synthesis, 1991, John Wiley. In the preferred case of benzyl group group (PG = CH2-phenyl) this can be removed by treatment with hydrogen gas and a suitable catalyst such as palladium on carbon (5 to 10% loading), palladium hydroxide, and the such like or by transferred hydrogenation using such systems as palladium (II) acetate and ammonium formate in a suitable solvent such as methanol, ethanol, ethylacetate and the such like, and heating between 0 ⁰C and 100 ⁰C. The appropriate secondary amine (V) (HNR1R2) can then be coupled with acids of type (IV) by the use of a coupling agent such as HATU, PyBOP, EDC, DCC /HOBt, BOP, PyBOP, EDC, DMTMM, by the formation of an active ester in the presence of a suitable bases triethylamine, diethylisopropylamine, DBU and the such like, or suitable ionic bases such as potassium carbonate, in an appropriate solvent dichloromethane (DCM), tetrahydrofuran (THF), diethylether, dimethylformaide (DMF), dimethylacetamide (DMA), tert-butylmethylether (TBME), toluene at a temperature between O ⁰C and 100 ⁰C to yield compounds of the type (I). A combination of HATU or PyBOP in either DMF or DCM between room temperature and 50 ⁰C is preferred.

Many of the secondary amines (V) (HNR 1R2) used in the synthesis of examples below are from commercially available sources or from routes described previously in the literature. In general terms the compounds can be made by the routes described below

X) Xl)

SCHEME 4 Outlined in Scheme 4 an appropriately substituted iso-quinoline of the type (X) can be reduced using to yield a tetrahydroisoquinoline of the type (XI). Suitable reducing agents are hydrogen gas in the presence of a metal catalysis such as palladium on carbon, Raney Nickel, rhodium metal on carbon and the such like, in a suitable solvent such as THF, ethanol, methanol, ethyl acetate. Other metal hydride reducing agents can also be employed such as lithium aluminium hydride, metal borohydrides in an inert solvent such as THF, ethyl ether and the such like. For examples in the literature see Tet. Lett. 1993, 34(45), 7239 and J Org. Chem. 1975, 40, 1191.

XII) Xl) SCHEME 5

Outlined in Scheme 5 an appropriately substituted ethylamine of the type (XII) can be cyclised to for a tetrahydroisoquinoline of the type (XI). Suitable conditions are usually formaldehyde or paraformaldehyde in the presence of acid or a Lewis acid. For an example see Synth. Commun, 1984, 14(13), 1221.

XIII) XlV)

Xi) XV)

SCHEME 6

Outlined in Scheme 6 an appropriately substituted benzylamine of the type (XIII) can be cyclised, adding a 2 carbon atom fragment, using oxalyl chloride and a Lewis acid such as aluminium chloride and the such like in a appropriate solvent such as dichloromethane or 1,2-dichloroethane. A protecting group maybe required as represented in the group PG to yield an intermediate such as (XIV). The two carbonyl group could then be reduced by strong hydride reducing agent such as borane, aluminium hydride, lithium aluminium hydride, and the such like, in an inert solvent such as THF, toluene, diethylether and the such like at a temperature between 25 ⁰C and 100 ⁰C. For example see J Am. Chem. Soc. 1954, 76, 6208. Removal of the protecting group would yield the tetrahydroisoquinoline (XI).

According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a therapeutic agent. According to a further feature of the invention there is provided a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a therapeutic agent, where it is desirable to have inhibition of Cathepsin K.

According to a further feature of the present invention there is provided a method for producing inhibition of a cysteine protease in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof.

The invention also provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament; and the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of a cysteine protease in a warm blooded animal, such as man. In particular the compounds of the invention are useful in the treatment of inflammation and immune disorders such as, but not limited to, osteoporosis, rheumatoid arthritis, osteoarthritis, metastatic bone disease, osteolytic bone disease and bone related neuropathic pain. In particular the invention provides the use of a compound of the formula (I) of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of Cathepsin K in a warm blooded animal, such as man. In order to use a compound of the formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment of mammals including humans, in particular in the inhibition of a cysteine protease, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides a pharmaceutical composition, which comprises a compound of the formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier. The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions. A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule, which contains between 1 mg and 1 g of the compound of this invention.

In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous, intramuscular or intra-articular injection. Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkg^"1 to 100 mgkg^"1 of the compound, preferably in the range of 0.1 mgkg^"1 to 20 mgkg^"1 of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose, which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.

The invention further relates to combination therapies wherein a compound of the invention, or a pharmaceutically acceptable salt thereof, 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 (but not restricted to) osteoporosis, rheumatoid arthritis, osteoarthritis, metastatic bone disease, osteolytic bone disease and bone related neuropathic pain, the compounds of the invention may be combined with agents listed below.

Non-steroidal anti-inflammatory agents (hereinafter NSAIDs) including nonselective cyclo-oxygenase COX-I / 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; auranofϊn 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, or a pharmaceutically acceptable salt thereof, 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-I); interleukins (IL) including ILl to 17, and interleukin antagonists or inhibitors such as anakinra; tumour necrosis factor alpha (TNF-α) 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, with a modulator of chemokine receptor function such as an antagonist of CCRl, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCRlO and CCRl 1 (for the C-C family); CXCRl,

CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX₃CRl for the C-X₃- C family.

The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, with an inhibitor of matrix metalloprotease (MMPs), i.e., the stromelysins, the collagenases, and the gelatinases, as well as aggrecanase; especially collagenase-1 (MMP-I), collagenase-2 (MMP-8), collagenase-3 (MMP- 13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-IO), 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, and an antagonist of the histamine type 4 receptor. The present invention still further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, and a beta-adrenoceptor 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, and combinations of aminosalicylates and sulfapyridine such as sulfasalazine, mesalazine, balsalazide, and olsalazine; and immunomodulatory agents such as the thiopurines, and corticosteroids such as budesonide. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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, nelfinavir, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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 non-steroidal anti-inflammatory agent. The present invention further relates to the combination of a compound of the invention, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, or a pharmaceutically acceptable salt thereof, 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, JNK, 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 (TGFβ); (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. sub 1. 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; or (xxvii) inhibitor of transcription factor activation such as NFkB, API, or STATS.

A compound of the invention, or a pharmaceutically acceptable salt thereof, 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-fiuorouracil 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 epipodophyllo toxin 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 5α-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, AZD 1839), 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 αvβ3 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 trans fection 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 in the following non-limiting Examples, in which standard techniques known to the skilled chemist and techniques analogous to those described in these Examples may be used where appropriate.

1 H NMR spectra were recorded using a Bruker DPX300 FT spectrometer or via Flow NMR process using an AVANCE 500 FT spectrometer, and using d6- dimethylsulphoxide (d6-DMSO) or deuterated chloroform (CDCl₃) with the data expressed as chemical shifts in ppm from internal standard TMS on the δ scale and with multiplicity (b=broad, s=singlet, d=doublets, t=triplet, q=quartet, qn=quintet, sx=sextet, h= heptet), and integration. Low resolution mass spectra were obtained using a Waters liquid chromatography mass spectrometry system, where purity was determined by UV absorption at a wavelength of 254 nm, and the mass ion was determined by electrospray ionisation (Micromass instrument). The reverse phase column used was a 4.6 mm x 50 mm Phenomenex Synergi Max-RP 8OA and the solvent system was water containing 0.1% formic acid and acetonitrile unless otherwise stated. A typical run was 5.5 minutes with a 4.0 minute gradient from 0 -95% acetonitrile.

Microwave reactions were performed in a Smith Synthesiser (300 Kwatts) on either the normal or high setting using appropriate tubes recommended by the manufacturer.

Purification by column chromatography was typically performed using silica gel (Merck 7734 grade) and solvent mixtures and gradients are recorded herein. Purification by reverse phase high performance chromatography was typically performed using a Perkin Elmer instrument using UV detection at 254 nm and a Cl 8 1500 x 21.2 mm Phenomenex column 100 A. Acidic conditions (0.1 to 0.5% formic acid) or basic conditions (ammonia to pHIO) were used with gradiant solvent mixtures of acetonitrile and water.

SCX columns were supplied from International Sorbent Technology and used as directed in this specification. High purity and dry solvents were supplied from Aldrich and used as delivered.

The following abbreviations are used herein:

BOP 1 -benzotriazolyoxy-tris-dimethylamino-phosphonium hexafluorophosphate

PyBOP benzotriazolyoxy-tris-pyrrolidino-phosphonium hexafluorophosphate EDC N^-dimethylaminoethylcyclohexylcarbodiimide]

DMTMM 4-(4,6-dimethoxy-l,3,5-t5riazin-2-yl)-4-methylmorpholinium chloride

HATU O-(7-azabenzotriazol- 1 -yl)-Λ/,Λ/,N',N'-tetramethyluronium hexafluorophosphate

NMP l-methyl-2-pyrrolidinone DMAP Λ/,Λ/-dimethyl-4-amino-pyridine

DIPEA di-zsø-propylethylamine

HPLC high performance liquid chromatography TBAF tetrα-butylammomum fluoride

LCMS liquid Chromatraphy / Mass Spectrometry

DMF di-methylformamide

TFA trifluoroacetic acid

NaHMDS sodium hexamethyldisilylamide

DMA dimethylacetamide

DEAD diethylazodicarboxylate mCPBA metø-chloroperbenzioc acid

DMSO dimethylsulphoxide

DBU l,8-diazabicyclo[5.4.0]undec-7-ene

DCM dichloromethane

Reagent 10 1.0M Hydrochloric acid in methanol solution

Example 1

(lR,2R)-Λ^L(l-cyanocyclopropyl)-2-[(6,7-dimethoxy-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide

(li?,2R)-Cyclohexane-l,2-dicarboxylic acid (150 mg, 0.87 mmol) was suspended in acetic anhydride (2 mL) and stirred at 80 ⁰C for 1 hour. The mixture was cooled, concentrated in vacuo, azeotroped once with toluene and dried under vacuum to give (3ai?,7ai?)-hexahydro-2-benzofuran-l,3-dione as a white solid. It was taken up in DMF (5 mL), 6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline hydrochloride (230 mg, 0.87 mmol) added followed by triethylamine (0.13 mL, 0.87 mmol) to free up the base and the mixture stirred at room temperature for 3 hours. 1-Aminocyclopropanecarbonitrile hydrochloride (114 mg, 0.95 mmol) was added followed by triethylamine (0.36 mL) and benzotriazol-1- yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP, 473mg, 0.91 mmol) and the solution stirred over the weekend. DMF was removed in vacuo and the residue partitioned between ethyl acetate (2 x 30 mL) and brine (10 mL). The separated organic portion was adsorbed onto silica for purification by flash chromatography (0-80% ethyl acetate / isohexane) to give the product as a brittle white solid (119 mg, 33%). MS (+ve ESI) : 411.9 (M+H)⁺

¹R NMR (400 MHz, DMSO) δ 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H),2.4-3.0 (m, 4H), 3.75 (m, 8H), 4.5 (m, 2H), 6.75 (m, 2H), 8.7 (s, IH)

Example 2

(l/f,2/f)-Λ^/-(l-cyanocyclopropyl)-2-[(6,7-difluoro-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide

Following on in a similar manner to example 1 except using 6,7-difluoro-l,2,3,4- tetrahydroisoquinoline [WO 2004094371] (147 mg, 0.87 mmol) furnished the desire compound as a white solid (63.0 mg, 19%) MS (+ve ESI) : 388.3 (M+Η)⁺

¹U NMR (400 MHz, DMSO) δ 0.8-1.0 (m, 2H), 1.2 (m, 2H), 1.35 (m, 4H), 1.8 (m, 4H), 2.5 (m, IH), 2.7-3.0 (m, 3H), 3.6-3.8 (m, 2H), 4.4-4.7 (m, 2H), 7.3 (m, 2H), 8.65 (s, IH)

Example 3 (l/f,2/f)-Λ^/-(l-cyanocyclopropyl)-2-[(7-fluoro-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide

Following Example 1 but starting with 7-fluoro-l,2,3,4-tetrahydroisoquinoline hydrochloride (327 mg, 1.74 mmol) furnished the desired compound as a colourless gum (48.0 mg, 22 % yield). MS (+ve ESI) : 370 (M+H)⁺ 1R NMR (400.132 MHz, DMSQ) δ 0.83 (m, IH), 0.99 (m, IH), 1.13 - 1.41 (m, 6H), 1.64 ■ 1.82 (m, 4H), 2.45 (m, IH), 2.63 - 2.99 (m, 3H), 3.58 - 3.82 (m, 2H), 4.47 - 4.79 (m, 2H), 6.96 - 7.15 (m, 2H), 7.20 (m, IH), 8.65 (s, IH)

Example 4 (lRjlRJ-N^l-cyanocyclopropylJ-l-IP^trifluoromethylJ-Sjό- dihydro [ 1 ,2,4] triazolo [4,3-α] pyr azin-7(8H)-yl] carbonyl} cyclohexanecarboxamide

Following Example 1 but starting with 3-(trifluoromethyl)-5,6,7,8- tetrahydro[l,2,4]triazolo[4,3-α]pyrazine hydrochloride (199 mg, 0.87 mmol) and DIPEA (0.15 mL, 0.87 mmol). ΗATU (364 mg, 0.96 mmol) was used in place of benzotriazol-1- yloxytripyrrolidinophosphonium. Purification by flash column chromatography on silica gel (elution with 0-100 % ethyl acetate/isohexane) furnished the desired compound as a white solid (60.0 mg, 17 % yield). MS (+ve ESI) : 411 (M+Η)⁺

¹R NMR (400 MHz, DMSO) δ 0.8-1.1 (m, 2H), 1.3 (m, 6H), 1.75 (m, 4H), 3.0 (m, IH), 3.8-4.3 (m, 4H), 4.7 (d, IH), 5.0 (m, 2H), 8.7 (s, IH) Example 5

(lR,2R)-N-(l-cyanocyclopropyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)- ylcarbonyl)cyclohexanecarboxamide

Following Example 1 but starting with 4,5,6,7-tetrahydrothieno[3,2-c]pyridine hydrochloride (176 mg, 1.00 mmol). Water (20 mL) and DCM (50 mL) were added, the layers separated and organics washed with a saturated solution of potassium carbonate (100 mL). The organics were dried (magnesium sulphate) and concentrated to furnished the desired compound as a colourless gum (380 mg, 11 % yield). MS (+ve ESI) : 358 (M+Η)⁺

¹H NMR (400.132 MHz, CDCl₃) δ 0.88 - 1.72 (1OH, m), 1.82 (2H, m), 2.57 (IH, m), 2.77 - 3.04 (3H, m), 3.59 and 4.23 (IH, m), 3.82 (IH, m), 4.65 (2H, m), 6.50 (IH, m), 6.78 (IH, m), 7.13 (IH, m)

Example 6

(lR,2R)-N-(l-cyanocyclopropyl)-2-[(5,8-difluoro-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide

Following Example 1 but starting with 5,8-difluoro-l,2,3,4-tetrahydroisoquinoline (206 mg, 1.0 mmol). Purification by reverse phase ΗPLC (ΗCOOΗ 0.5%, CH₃CN, H₂O) furnished the desired compound as a white foam (74.0 mg, 19 % yield). MS (+ve ESI) : 388 (M+H)⁺ ¹H NMR (400.132 MHz, CDCl₃) δ 0.97 - 1.92 (HH, m), 2.61 (IH, m), 2.79 (2H, m), 2.98 (2H, m), 3.55 - 4.07 (2H, m), 4.73 (2H, m), 6.70 (IH, m), 6.88 (2H, m)

Example 7 (IR, 2R )-iV-(l-cyanocy clopropyl)-2-(7,8-dihydropyrido[4,3-</]pyrimidin-6(5H)- ylcarbonyl)cyclohexanecarboxamide

Following Example 1 but starting with 5,6,7,8-tetrahydropyrido[4,3-J]pyrimidine (135 mg, 1.0 mmol) furnished the desired compound as a white foam (63.0 mg, 18 % yield). MS (+ve ESI) : 354 (M+Η)⁺

¹H NMR (400.132 MHz, CDCl₃) δ 1.00 - 1.90 (12H, m), 2.55 (IH, m), 2.92 - 3.20 (3H, m), 3.70 and 4.19 (IH, m), 3.90 (IH, m), 4.71 (IH, m), 4.83 (IH, m), 6.40 (IH, m), 8.51 (IH, m), 9.02 (IH, m)

Example 8

(lR,2R)-Λ^L(l-cyanocyclopropyl)-2-{[(3S)-3-(hydroxymethyl)-3,4-dihydroisoquinolin- 2(lH)-yl]carbonyl}cyclohexanecarboxamide

(35)-l,2,3,4-tetrahydroisoquinolin-3-ylmethanol (82.0 mg, 0.50 mmol) was added to a stirred solution of (3ai?,7ai?)-hexahydro-2-benzofuran-l,3-dione (77.0 mg, 0.50 mmol) and DIPEA (0.88 uL, 0.50 mmol) in DCM (2.5 mL). The reaction was stirred overnight and then concentrated in vacuo. To the residue was added fresh THF (2.5 mL) followed by l-aminocyclopropanecarbonitrile hydrochloride (65.0 mg 0.55 mmol), DMTMM (153 mg 0.55 mmol) and DIPEA (88 uL, 0.50 mmol) was added and the reaction stirred for 4 nights, poured into water (30 mL) and extracted with ethyl acetate (2 x 25 mL), the organics were washed with sat. sodium carbonate solution (25 mL), water (25 mL), IM HCl (25 mL), water (25 mL) and then brine (25 mL), dried over MgSO₄, filtered and concentrated in vacuo. Purified on the basic preparative HPLC (NH₄OH modifier).

LCMS retention time 1.75 min. (+ve ESI) : 382 (M+H)⁺

Example 9

(lR,2R)-Λ^L(l-cyanocyclopropyl)-2-[(5-fluoro-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide

Following Example 8, but starting with 5-fluoro-l,2,3,4-tetrahydroisoquinoline hydrochloride (188 mg, 1 mmol) and triethylamine (140 υl, lmmol) furnished the desired compound as a white foam (61.0 mg, 33 % yield). MS (+ve ESI) : 370 (M+Η)⁺

¹H NMR (400.132 MHz, CDCl₃) δ 0.94 - 1.90 (12H, m), 2.77 (4H, m), 3.48 - 4.18 (2H, m), 4.58 - 4.90 (2H, m), 6.54 (IH, m), 6.91 (2H, m), 7.16 (IH, m) Example 10

(lR,2R)-N-(l-cyanocyclopropyl)-2-(7,8-dihydro-l,6-naphthyridin-6(5H)- ylcarbonyl)cyclohexanecarboxamide

A mixture of 5,6,7, 8-tetrahydro-l,6-naphthyridine (134 mg, 1 mmol) and (3ai?,7ai?)-hexahydro-2-benzofuran-l,3-dione (154 mg, 1.00 mmol) in DCM (5 mL) was stirred at room temperature for 18 hours. The reaction mixture was concentrated, dissolved in TΗF (5 mL) and used crude in the next step. To this solution was added DIPEA (175 ul, lmmol), l-aminocyclopropanecarbonitrile (65.0 mg, 0.55mmol) and the mixture stirred for 15 mins at RT. DMTMM (305 mg, 1.1 mmol) was added and the mixture stirred for 48 hours. The reaction mixture was partitioned between ethyl acetate (30 mL) and water (30 mL) and the water extracted a further with ethyl acetate (2 x 30 mL). The combined organics were washed with sodium carbonate solution (25 mL), water (20 mL) and then IN HCl solution (20 mL). The organics were dried (magnesium sulphate) and concentrated. Purification by reverse phase ΗPLC (ΗCOOΗ 0.5%, CH₃CN, H₂O) furnished the desired compound as a pink gum (69.0 mg, 20 % yield). MS (+ve ESI) : 353 (M+H)⁺ 1H NMR (400.132 MHz, CDC13) δ 0.99 - 1.94 (12H, m), 2.60 (IH, m), 2.91 - 3.22 (3H, m), 3.58 - 4.26 (2H, m), 4.54 - 4.96 (2H, m), 6.74 (IH, m), 7.16 (IH, m), 7.45 (IH, t), 8.44 (IH, m) Example 11 methyl 2-[((lR,2R)-2-{[(l-cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]-

6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline-3-carboxylate

Following Example 8, but starting with methyl l,2,3,4-tetrahydroisoquinoline-3- carboxylate (134 mg, 1 mmol) furnished the desired compound as a white foam (126 mg, 27 % yield). MS (+ve ESI) : 470 (M+H)⁺

¹H NMR (400.132 MHz, CDCl₃) δ 0.99 - 2.12 (HH, m), 2.65 (2H, m), 2.98 - 3.19 (3H, m), 3.60 and 3.70 (3H, s), 3.85 (3H, s), 3.87 (3H, s), 4.33 and 4.61 (IH, d), 4.85 (IH, d), 5.43 (IH, t), 6.60 (3H, m)

Example 12 2-[((lR,2R)-2-{[(l-cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]-6,7- dimethoxy-l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

A mixture of methyl 2-[((lR,2/?)-2-{[(l- cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]-6,7-dimethoxy-l,2,3,4- tetrahydroisoquinoline-3-carboxylate (58.0 mg, 0.12 mmol), pyridine (3 mL) and anhydrous lithium iodide (199 mg, 1.48 mmol) was heated to 150 ⁰C in the microwave for 30 min. The pyridine was removed in vacuo and the residue azeotroped with toluene. The residue was taken up in brine (30 mL), acidified with acetic acid (c.f. 10 mL) and extracted with EtOAc (3 x 30 mL). The organics were dried (magnesium sulphate), filtered and concentrated. The residue was purified by reverse phase HPLC (HCOOH 0.5%, CH₃CN, H₂O) to furnish the desired compound as a white solid (11.0 mg, 20% yield) MS (+ve ESI): 454 (M+H)⁺

¹H NMR (400.132 MHz, CDCl₃) δ 0.96 - 3.39 (16H, m), 3.85 (6H, m), 4.26 - 4.87 (3H, m), 5.28 (IH, m), 6.58 - 6.74 (3H, m)

Example 13 methyl 2-[((lR,2R)-2-{[(l-cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]- l,2,3,4-tetrahydroisoquinoline-8-carboxylate

Following Example 8, but starting with methyl l,2,3,4-tetrahydroisoquinoline-8- carboxylate (67.0 mg, 0.5 mmol) furnished the desired compound as a colourless gum (55.0 mg, 27 % yield).

MS (+ve ESI) : 408 (M+H)⁺

¹H NMR (400.132 MHz, CDCl₃) δ 0.90 - 1.89 (12H, m), 2.59 (IH, m), 2.99 (3H, m), 3.77 (2H, m), 3.90 and 3.93 (3H, s), 4.99 - 5.26 (2H, m), 6.77 (IH, m), 7.28 (2H, m), 7.87 (IH, m) Example 14 methyl 2-[((lR,2R)-2-{[(l-cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]- l,2,3,4-tetrahydroisoquinoline-3-carboxylate

Following Example 8, but starting with methyl l,2,3,4-tetrahydroisoquinoline-3- carboxylate (134 mg, 1 mmol) furnished the desired compound as a white foam (133 mg, 33 % yield). MS (+ve ESI) : 410 (M+H)⁺

¹H NMR (400.132 MHz, CDCl₃) δ 0.90 - 1.96 (12H, m), 2.54 - 3.35 (4H, m), 3.60 and 3.63 (3H, s), 4.55 - 4.85 (2H, m), 5.20 (IH, m), 6.75 (IH, m), 7.18 (4H, m)

Example 15

2-[((l/f,2/f)-2-{[(l-cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]-l,2,3,4- tetrahydroisoquinoline-3-carboxylic acid

Following Example 8, but starting with methyl 2-[((\R,2R)-2-{[(\- cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]-l,2,3,4-tetrahydroisoquinoline-3- carboxylate (70.0 mg, 0.17 mmol) furnished the desired compound as a white solid (47.0 mg, 70 % yield). MS (+ve ESI): 396 (M+H)⁺ ¹H NMR (400.132 MHz, CDCl₃) δ 0.89 - 1.89 (12H, m), 2.34 - 2.87 (IH, m), 3.32 (4H, m), 4.61 - 5.45 (3H, m), 6.95 - 7.26 (5H, m)

Example 16 (lR,2R)-N-(l-cyanocyclopropyl)-2-(3,4-dihydro-2,7-naphthyridin-2(lH)- ylcarbonyl)cyclohexanecarboxamide

Following Example 8, but starting with l,2,3,4-tetrahydro-2,7-naphthyridine dihydrochloride (207 mg, 1 mmol) and triethylamine (279 υl, 2 mmol) furnished the desired compound as a white solid (15 mg, 4 % yield). MS (+ve ESI) : 353 (M+Η)⁺

¹H NMR (400.132 MHz, CDCl₃) δ 0.94 - 1.98 (1OH, m), 2.31 - 2.65 (2H, m), 2.80 - 3.07 (3H, m), 3.35 - 4.07 (3H, m), 4.65 - 4.84 (2H, m), 6.86 (IH, m), 7.08 (IH, d), 8.39 (2H, m) ² WO2002064574

Example 17

(lR,2R)-N-(l-cyanocyclopropyl)-2-(5,8-dihydro-l,7-naphthyridin-7(6H)- ylcarbonyl)cyclohexanecarboxamide

Following Example 8, but starting with 5,6,7,8-tetrahydro-l,7-naphthyridine³ (132 mg, 0.98 mmol) furnished the desired compound as a white solid (15.0 mg, 7 % yield). MS (+ve ESI) : 353 (M+H)⁺

¹H NMR (400.132 MHz, CDCl₃) δ 0.92 - 1.97 (1OH, m), 2.63 (IH, m), 2.95 (4H, m), 3.85 (3H, m), 4.82 (2H, m), 7.08 (2H, m), 7.46 (IH, d), 8.43 (IH, d) 3J. Het. Chem 2001, 38, 535

Example 18

(lR,2R)-2-[(5-chloro-3,4-dihydroisoquinolin-2(lH)-yl)carbonyl]-N-(l- cyanocyclopropyl)cyclohexanecarboxamide

Following Example 8, but starting with 5-chloro-l,2,3,4-tetrahydroisoquinoline hydrochloride (132 mg, 0.65 mmol) and triethylamine (0.11 mL, 0.78 mmol) in a solution of dry DMF (2 mL) furnished the desired intermediate. Using Pybop (354 mg, 0.68 mmol) in place of DMTMM furnished the desired compound as a white solid (105 mg, 42 % yield). MS (+ve ESI) : 386 (M+Η)⁺

¹U NMR (400.132 MHz, DMSQ) δ 0.73 - 0.88 (m, IH), 0.99 (m, IH), 1.10 - 1.42 (m, 6H), 1.60 - 1.83 (m, 4H), 2.44 (m, IH), 2.65 - 3.01 (m, 3H), 3.59 - 3.88 (m, 2H), 4.51 - 4.79 (m, 2H), 7.15 - 7.29 (m, 2H), 7.32 (d, IH), 8.65 (s, IH) Example 19 (lR^RJ-N^l-cyanocyclopropyl^-IIS-^rifluoromethylJ-S^-dihydroisoquinolin- 2(lH)-yl]carbonyl}cyclohexanecarboxamide

Following Example 8, but starting with 8-trifluoromethyl-l,2,3,4- tetrahydroisoquinoline hydrochloride (154 mg, 0.65 mmol) furnished the desired compound as a white solid (126 mg, 46 % yield). MS (+ve ESI) : 420 (M+H)⁺ 1R NMR (400.132 MHz, DMSQ) δ 0.71 (m, IH), 0.97 (m, IH), 1.18 - 1.41 (m, 6H), 1.65 ■ 1.82 (m, 4H), 2.45 (m, IH), 2.67 - 3.12 (m, 3H), 3.70 - 3.87 (m, 2H), 4.61 - 4.92 (m, 2H), 7.42 (m, IH), 7.48 - 7.64 (m, 2H), 8.68 (d, IH)

Example 20 (l/f,2/f)-Λ^/-(l-cyanocyclopropyl)-2-[(7-cyano-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide

Following Example 8, but starting with 7-cyano-l,2,3,4-tetrahydroisoquinoline hydrochloride (126 mg, 0.65 mmol) furnished the desired compound as a white solid (92.0 mg, 37 % yield).

MS (+ve ESI) : 377 (M+Η)⁺

¹U NMR (400.132 MHz, DMSQ) δ 0.76 - 0.89 (m, IH), 0.99 (m, IH), 1.13 - 1.41 (m, 6H), 1.66 - 1.82 (m, 4H), 2.44 (m, IH), 2.75 - 3.08 (m, 3H), 3.61 - 3.87 (m, 2H), 4.50 - 4.86 (m,

2H), 7.39 (t, IH), 7.63 (t, IH), 7.73 (d, IH), 8.66 (s, IH) Example 21

(lR,2R)-2-[(7-chloro-3,4-dihydroisoquinolin-2(lH)-yl)carbonyl]-N-(l- cyanocyclopropyl)cyclohexanecarboxamide

Following Example 8, but starting with 7-chloro-l,2,3,4-tetrahydroisoquinoline hydrochloride (103 mg, 0.5 mmol) furnished the desired compound as a white solid (64.0mg, 16 % yield). MS (+ve ESI) : 386 (M+Η)⁺

¹H NMR (400.132 MHz, CDCl₃) δ 0.94 - 1.89 (HH, m), 2.59 (IH, m), 2.77 - 3.00 (3H, m), 3.54 - 4.05 (3H, m), 4.68 (2H, m), 6.65 (IH, m), 7.11 (3H, m)

Example 22

(lR,2R)-2-{[l-(2-anilino-2-oxoethyl)-3,4-dihydroisoquinolin-2(lH)-yl]carbonyl}-N-(l- cyanocyclopropyl)cyclohexanecarboxamide

Following Example 8, but starting with Λ/-phenyl-2-(l,2,3,4-tetrahydroisoquinolin- l-yl)acetamide (1.07 g, 4 mmol) furnished the desired compound as a white foam (69.0 mg, 14 % yield). MS (+ve ESI) : 485 (M+Η)⁺ 1H NMR (400.132 MHz, CDCl₃) δ 0.66 - 1.93 (9H, m), 2.56 - 3.28 (9H, m), 3.50 - 4.41 and 5.37 (2H, m), 5.83 - 6.03 (IH, m), 6.67 and 6.97 (IH, m), 7.01 - 7.72 (9H, m), 8.76 and 9.10 and 9.19 (IH, m) Example 23

(3S)-N-(tert-butyϊ)-2-[((lR,2R)-2-{[(l- cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]-l,2,3,4- tetrahydroisoquinoline-3-carboxamide

Following Example 8, but starting with (3<S)-N-(tert-butyl)- 1,2,3,4- tetrahydroisoquinoline-3-carboxamide (117 mg, 0.5 mmol) furnished the desired compound as a white foam (57.0 mg, 13 % yield). MS (+ve ESI) : 451 (M+H)⁺ 1H NMR (400.132 MHz, CDCl₃) δ 0.92 - 1.98 (19H, m), 2.59 - 3.31 (4H, m), 3.58 (IH, m), 4.34 (IH, m), 4.86 (3H, m), 6.63 (2H, m), 7.16 (4H, m)

Example 24 tert-butyl (3R)-2-[((lR,2R)-2-{[(l- cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]-l,2,3,4- tetrahydroisoquinoline-3-carboxylate

Following Example 8, but starting with (3R)-7V-(tøt-butyl)-l,2,3,4- tetrahydroisoquinoline-3-carboxamide hydrochloride (135 mg, 0.5 mmol) and triethylamine (1 mmol) furnished the desired compound as a colourless gum (12.0 mg, 3 % yield). MS (-ve ESI) : 450 (M+H)⁺ ¹H NMR (400.132 MHz, CDCl₃) δ 0.96 (IH, m), 1.07 - 1.97 (9H, m), 1.57 (9H, s), 2.47 - 3.33 (6H, m), 4.59 - 4.81 (2H, m), 4.99 and 5.10 (IH, m), 6.36 (IH, m), 7.10 - 7.24 (4H, m)

Example 25

(2R,3R)-N-(l-cyanocyclopropyl)-2-ethyl-3-[(l-ethyl-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl] hexanamide

Following Example 8, but starting with 1 -ethyl- 1, 2,3, 4-tetrahydroisoquinoline (126 mg, 0.5 mmol) and triethylamine (1.00 mmol) furnished the desired compound as a colourless gum (6.12 mg, 2 % yield). LCMS retention time 2.20 min (+ve ESI) : 380 (M+Η)⁺

Example 26 (lR^RJ-N^l-cyanocyclopropyl^-IIT-^rifluoromethylJ-S^-dihydroisoquinolin- 2(lH)-yl]carbonyl}cyclohexanecarboxamide

Following Example 8, but starting with 7-trifluoromethyl-l,2,3,4- tetrahydroisoquinoline hydrochloride (119 mg, 0.5 mmol) and triethylamine (1.00 mmol) furnished the desired compound as a white foam (51.0 mg, 12 % yield). MS (-ve ESI) : 420 (M+Η)⁺ ¹H NMR (400.132 MHz, CDCl₃) δ 0.93 - 1.88 (HH, m), 2.58 (IH, m), 2.86 - 3.10 (3H, m), 3.62 - 4.05 (2H, m), 4.76 (2H, m), 6.53 (IH, m), 7.27 (IH, m), 7.42 (2H, m)

Example 27 (lR^RJ-N^l-cyanocyclopropyl^-lβ-^rifluoromethylJ-S^-dihydroisoquinolin- 2(lH)-yl]carbonyl}cyclohexanecarboxamide

Following Example 8, but starting with 5-trifluoromethyl-l,2,3,4- tetrahydroisoquinoline hydrochloride (119 mg, 0.5 mmol) and triethylamine (1.00 mmol) furnished the desired compound as a colourless gum (35.0 mg, 8 % yield). MS (-ve ESI) : 420 (M+Η)⁺

¹H NMR (400.132 MHz, CDCl₃) δ 0.92 - 1.96 (12H, m), 2.57 (IH, m), 3.03 (3H, m), 3.55 and 4.06 (IH, m), 3.79 (IH, m), 4.53 - 4.98 (2H, m), 6.50 (IH, m), 7.31 (2H, m), 7.53 (IH, m)

Example 28

(l/f,2/f)-Λ^/-(l-cyanocyclopropyl)-2-[(6-cyano-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide

Following Example 8, but starting with 6-cyano-l,2,3,4-tetrahydroisoquinoline hydrochloride (126 mg, 0.65 mmol) and triethylamine (0.10 mL, 0.80 mmol) furnished the desired compound as a white solid (75.0 mg, 31 % yield). ¹U NMR (400.132 MHz, DMSO) δ 0.75 - 1.02 (m, 2H), 1.11 - 1.42 (m, 6H), 1.67 - 1.81 (m, 4H), 2.45 (m, IH), 2.67 - 3.04 (m, 3H), 3.60 - 3.86 (m, 2H), 4.52 - 4.89 (m, 2H), 7.44 (m, IH), 7.61 - 7.71 (m, 2H), 8.72 (d, IH)

Example 29

(l/f,2/f)-Λ^/-(l-cyanocyclopropyl)-2-[(5,7-dichloro-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide

Following Example 8, but starting with 5,7-dichloro-l,2,3,4-tetrahydroisoquinoline hydrochloride^ 20 mg, 0.50 mmol) and triethylamine (70.0 ul, 0.50 mmol) furnished the desired compound as a white solid (94.0 mg, 45 % yield). MS (+ve ESI) : 420 (M+Η)⁺

¹H NMR (400.132 MHz, CDCl₃) δ 0.98 - 1.90 (12H, m), 2.56 (IH, m), 2.73 - 3.02 (3H, m), 3.48 - 4.19 (2H, m), 4.53 - 4.86 (2H, m), 6.58 (IH, m), 7.06 (IH, d), 7.28 (IH, d)

Example 30

2-[((lR,2R)-2-{[(l-cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]-l,2,3,4- tetrahydroisoquinoline-3-carboxamide

Following Example 8, but starting with l,2,3,4-tetrahydroisoquinoline-3- carboxamide (103 mg, 0.50 mmol) furnished the desired compound as a yellow solid (33.0 mg, 17 % yield). MS (+ve ESI) : 393 (M+H)⁺

¹R NMR (400.13 MHz, CDCl₃) δ 0.97 - 2.03 (1OH, m), 2.54 - 3.31 (3H, m), 3.62 (IH, m),

4.33 - 5.09 (3H, m), 5.50 (IH, s), 6.62 (IH, m), 7.09 - 7.25 (7H, m)

Example 31

(lR,2R)-N-(l-cyanocyclopropyl)-2-(3,4-dihydro-2,6-naphthyridin-2(lH)- ylcarbonyl)cyclohexanecarboxamide

Following Example 8, but starting with l,2,3,4-tetrahydro-2,6-naphthyridine dihydrochloride (156 mg, 0.75 mmol) furnished the desired compound as a white foam (21.0 mg, 6 % yield). MS (+ve ESI) : 353 (M+Η)⁺

¹R NMR (400.13 MHz, CDCl₃) δ 0.99 - 2.60 (HH, m), 2.95 (4H, m), 3.61 and 4.12 (IH, m), 3.83 (IH, t), 4.58 - 4.94 (2H, m), 6.62 (IH, m), 7.10 (IH, m), 8.06 - 8.49 (3H, m)

Example 32 tert-bntyl 2-[((l/f,2/f)-2-{[(l-cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]-

2,8-diazaspiro [4.5] decane-8-carboxylate

A mixture of tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate hydrochloride (359 mg, 1.30 mmol), 7V,7V-diisopropylethylamine (226 υl, 1.30 mmol, 1 equivalent) and (3ai?,7ai?)-hexahydro-2-benzofuran-l,3-dione (0.20 g, 1.30 mmol) in DCM (6 mL) was stirred at room temperature for 2 hours. To this solution was added HATU (0.69 g, 1.82 mmol) and 7V,7V-diisopropylethylamine (0.68 mL, 3.89 mmol) followed by 1- aminocyclopropanecarbonitrile hydrochloride (0.20 g, 1.69 mmol), then allowed to stir at room temperature for 64 hours. The reaction mixture was diluted with DCM (50 mL), washed with water (30 mL), then the organic layer was passed through a phase separation cartridge and concentrated in vacuo to give a crude gum. The crude gum was purified by reverse phase HPLC HPLC (HCOOH 0.5%, CH₃CN, H₂O) to furnish the desired compound as a white solid (442 mg, 74 % yield). MS (-ve ESI) : 457 (M-H)⁺

¹U NMR (400.13 MHz, CDCl₃) δ 1.06 - 1.43 (m, 6H), 1.45 (d, 9H), 1.47 - 1.95 (m, 12H), 2.51 - 2.73 (m, 2H), 3.22 - 3.83 (m, 8H), 7.04 (d, IH)

Example 33

(l/f,2R)-Λ^L(l-cyanocyclopropyl)-2-{[6-[(methylsulfonyl)amino]-3,4- dihydroisoquinolin-2(lH)-yl]carbonyl}cyclohexanecarboxamide

Following Example 32, but starting with TV-(1, 2,3,4-tetrahydroisoquinolin-6- yl)methanesulfonamide hydrochloride (51.0 mg, 0.21 mmol) furnished the desired compound as a white solid (24.0 mg, 27 % yield).

MS (+ve ESI) : 430.2 (M+Η)⁺

¹U NMR (400.132 MHz, DMSQ) δ 0.81 (m, IH), 0.98 (m, IH), 1.12 - 1.44 (m, 6H), 1.73 (m, 4H), 2.44 (m, IH), 2.76 - 3.10 (m, 3H), 3.20 (d, 3H), 3.62 - 3.89 (m, 2H), 4.54 - 4.93

(m, 2H), 7.50 (m, IH), 7.69 - 7.79 (m, 2H), 8.72 (d, IH)

The Λ/-(l,2,3,4-tetrahydroisoquinolin-6-yl)methanesulfonamide hydrochloride used as a starting material was prepared as follows:

Synthesis of tert-butyl 6-[(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(lH)- carboxylate

To a solution of 6-amino-2-7V-boc- 1,2,3, 4-tetrahydroisoquino line (0.20 g, 0.81 mmol) and triethylamine (168 ul, 1.21 mmol) in DCM (10 mL) was added methanesulfonyl chloride (69.0 uL, 0.89 mmol) allowed to stir at room temperature for 16 hours. The reaction mixture was diluted with DCM (50 mL), washed with water (50 mL), saturated sodium bicarbonate solution (50 mL) and dried (MgSO₄) to give a crude solid. The crude was purified by flash column chromatography (silica isohexane / ethyl acetate 4:1) to give a white solid (69.0 mg, 26.1%).

¹H NMR (400.132 MHz, CDCl_3.)δ 1.49 (s, 9H), 2.82 (t, 2H), 3.00 (s, 3H), 3.64 (t, 2H), 4.54 (s, 2H), 6.32 (s, IH), 7.03 (s, 2H), 7.09 (d, IH) N-(l,2,3,4-tetrahydroisoquinolin-6-yl)methanesulfonamide hydrochloride

A solution of tert-butyl 6-[(methylsulfonyl)amino]-3,4-dihydroisoquinoline-2(lH)- carboxylate (69.0 mg, 0.21 mmol) in 1.0 M methanol hydrochloric acid ( reagent 10) (10 mL) was allowed to stir at room temperature for 16 hours. Reaction mixure was concentrated in-vacuo to dryness to give a white solid (55.2 mg, 100%). MS (+ve ESI) : 227.03 (M+H)⁺

¹R NMR (400.132 MHz, DMSQ)δ 2.99 (m, 5H), 3.31 (m, 2H), 4.19 (s, 2H), 7.06 (s, IH), 7.10 (m, IH), 7.19 (d, IH), 9.43 (s, 2H), 9.77 (s, IH) Example 34

(lR,2R)-Λ^L(l-cyanocyclopropyl)-2-({6-[methylsulfonyl]-3,4-dihydroisoquinolin-2(lH)- yl}carbonyl)cyclohexanecarboxamide

Following Example 32, but starting with 6-(methylsulfonyl)-l,2,3,4- tetrahydroisoquinoline hydrochloride (51.0 mg, 0.2 mmol) furnished the desired compound as a white solid (6.13 mg, 6 % yield).

LCMS retention time 1.33 min (+ve ESI) : 444.7 (M+Η)⁺

The Λ/-(l,2,3,4-tetrahydroisoquinolin-6-yl)methanesulfonyl hydrochloride used as a starting material was prepared as follows: tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(lH)-carboxylate

To a solution of tert-butyl nitrite (0.70 mL, 6.04 mmol) and copper(II) bromide (1.10 g, 4.83 mmol) in anhydrous acetonitrile (10 mL) at 60 ⁰C was added 6-amino-2-7V- boc-l,2,3,4-tetrahydroisoquinoline (1.00 g, 4.03 mmol) portionwise. The reaction mixture was then heated at 80 ⁰C for 2 hours. The reaction mixture was diluted with DCM (100 mL) and washed with 0.5N HC 1 (50 mL). The aqueous layer was extracted with DCM (100 mL) and the combined organic layers were washed with brine (50 mL) and dried (MgSO₄) to give a dark crude oil. The crude material was purified by flash column chromatography (isohexane to 10% DCM) to give an orange oil (737 mg, 59%). 1R NMR (400.132 MHz, CDCl₃) δ 1.49 (s, 9H), 2.80 (m, 2H), 3.63 (m, 2H), 4.50 (m, 2H), 6.95 (m, IH), 7.27 (m, 2H) tert-butyl 6-(methylsulfonyl)-3,4-dihydroisoquinoline-2(lH)-carboxylate

To a mixture of tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(lH)-carboxylate (200 mg, 0.64 mmol), sodium methansulfinate (78 mg, 0.77 mmol), L-proline (15.0 mg, 0.13 mmol) and 2M sodium hydroxide solution (65 uL, 0.13 mmol) in DMSO (2 mL) was added copper iodide (12.0 mg, 0.06 mmol). The reaction mixture was blanketed with argon and heated at 95 ⁰C in a seled tube for 64 hours. The reaction mixture was diluted with water (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (2 x 50 mL), the combined organics were washed with brine, dried (MgSO₄) and concentrated in vacuo to give a crude gum. The crude gum was purified by flash column chromatography (isohexane to 50% ethyl acetate/isohexane) to give a colourless oil (39 mg, 20%.

¹U NMR (300.072 MHz, CDCl₃) δ 1.50 (s, 9H), 2.93 (t, 2H), 3.05 (s, 3H), 3.69 (t, 2H), 4.66 (s, 2H), 7.31 (d, IH), 7.73 - 7.77 (m, 2H) iV-(l,2,3,4-tetrahydroisoquinolin-6-yl)methanesulfbnyl hydrochloride

A solution of tert-butyl 6-(methylsulfonyl)-3,4-dihydroisoquinoline-2(lH)- carboxylate

(63.0 mg, 0.20 mmol) in methanol hydrochloric acid (reagent 10) (10 mL) was allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated under reduce pressure to dryness to give a yellow solid (51.0 mg, 100%). Example 35

(lRjlRJ-N^l-cyanocyclopropylJ-l-IIό^hydroxymethylJ-S^-dihydroisoquinolin-

2(lH)-yl]carbonyl}cyclohexanecarboxamide

Following Example 8, but starting with l,2,3,4-tetrahydroisoquinolin-6-ylmethanol hydrochloride (162 mg, 0.84 mmol), furnished the desired compound as a white solid (118 mg, 48 % yield). MS (-ve ESI) : 380 (M-H)⁺

¹R NMR (400.132 MHz, DMSQ) δ 0.75 - 1.04 (m, 2H), 1.12 - 1.43 (m, 6H), 1.73 (m, 4H), 2.46 (m, IH), 2.66 - 3.01 (m, 3H), 3.51 - 3.81 (m, 2H), 4.45 (d, 2H), 4.49 - 4.72 (m, 2H), 5.08 (t, IH), 7.08 - 7.22 (m, 3H), 8.65 (s, IH) The l,2,3,4-tetrahydroisoquinolin-6-ylmethanol used as a starting material was prepared as follows:

A solution of tert-butyl 6-(hydroxymethyl)-3,4-dihydroisoquinoline-2(lH)- carboxylate (0.90 g, 3.42 mmol) in methanol hydrochloric acid (reagent 10) (20 mL) was allowed to stir at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to afford a white solid (675 mg, 99% yield) and used directly in the next step. MS (+ve ESI) : 164 (M+H)⁺ Example 36

2-[((iR,2R)-2-{[(i- cyanocyclopropyl)amino]carbonyl}cyclohexyl)carbonyl]isoindoline-l-carboxamide

Following Example 8, but starting isoindoline-1-carboxamide (313 mg, 1.93 mmol) furnished the desired compound as a white solid (273 mg, 38 % yield). MS (+ve ESI) : 379 (M+H)⁺

¹U NMR (400.13 MHz, CDCl₃) δl.01 - 1.06 (IH, m), 1.38 - 1.48-1.56 (7H, m), 1.89 - 1.91 (2H, m), 1.98 (2H, m), 2.95 - 3.00-3.08 (2H, m), 4.96 - 4.99 (IH, m), 5.38 - 5.41 (IH, m), 5.48-5.51 (2H, m), 6.47 (IH, s), 7.30 - 7.33 (IH, m), 7.35 - 7.38 (2H, m), 7.64 (IH, m), 7.90 (IH, s)

The isoindoline-1-carboxamide used as a starting material was prepared as follows:

2-(ter£-butoxycarbonyl)isoindoline-l-carboxylic acid (1.5 g, 5.69 mmol) and triethylamine (0.87 mL, 6.26 mmol) in tetrahydrofuran (15 mL) were cooled to -17 ⁰C. Ethyl chloro formate (0.60 mL, 6.26 mmol) was added dropwise and after 10 minutes concentrated ammonium hydroxide (10 mL) was added. The mixture was stirred at 0 to 4 ⁰C for 2h. Saturated ammonium chloride solution (25 mL) was added and the layers separated. The aqueous layer was re-extracted with THF (25 mL) and the combined organics dried (MgSO₄) and concentrated under reduced pressure to give a white solid (1.32 g) which was used without further purification. The solid was dissolved in 1 ,A- dioxane (15 mL) and 4M hydrogen chloride in 1,4-dioxane (10 mL) added . The mixture was stirred for Ih and then concentrated under reduced pressure. The residue was dissolved in methanol, absorbed onto an IsoluteSCX column, washed with methanol and eluted with 7N ammonia in methanol to furnish the desired compound as a white solid (646 mg, 60 % yield).

¹R NMR (400.13 MHz, DMSOd₆) δ 3.60 (brs, IH), 4.19 (s, 2H), 4.67 (s, IH), 7.22 (m, 4H), 7.41 (d, IH), 7.53 (brs, IH)

Example 37

(l/f,2R)-Λ^L(l-cyanocyclopropyl)-2-(l,3-dihydro-2H-isoindol-2- ylcarbonyl)cyclohexanecarboxamide

Following Example 8, but starting isoindoline (83.0 mg, 0.7 mmol) furnished the desired compound as a dry film (130 mg, 38 % yield). LCMS retention time 1.81 min MS (+ve ESI) : 337 (M+Η)⁺

Example 38

(lR,2R)-Λ^L(l-cyanocyclopropyl)-2-(3,4-dihydroisoquinolin-2(lH)- ylcarbonyl)cyclohexanecarboxamide

Following Example 8 but starting with 1,2,3,4-tetrahydroisoquinoline (97.0 mg, 0.73 mmol) furnished the desired compound as a colourless gum (70.0 mg, 29 % yield). MS (-ve ESI) : 350 (M-H)

¹R NMR (400.13 MHz, CDCl₃) δ 0.93 - 0.98 (IH, m), 1.01 - 1.11 (IH, m), 1.27-1.71 (6H, m), 1.83 (4H, m), 2.61 (IH, t), 2.83 (IH, t), 2.92 (2H, m), 3.54 and 4.00 (IH, m), 3.69 (IH, m), 4.64-4.80 (2H, m), 6.59 and 6.60 (IH, s), 7.11 - 7.12 (IH, m), 7.13 - 7.14 (IH, m), 7.15 - 7.20 (2H, m)

Example 39

(lR,2R)-Λ^L(l-cyanocyclopropyl)-2-[(5-cyano-3,4-dihydroisoquinolin-2(lH)- yl)carbonyl]cyclohexanecarboxamide

Following Example 8 but using l,2,3,4-tetrahydroisoquinoline-5-carbonitrile (54.0 mg, 0.28 mmol) and (3aR,7aR)-hexahydro-2-benzofuran-l,3-dione (43.0 mg, 0.50 mmol), 1-aminocyclopropanecarbonitrile hydrochloride (98.0 mg, 0.83 mmol) and PyBOP coupling reagent (174 mg 0.33 mmol) with triethylamine (194 uL, 1.39 mmol) furnished the desired compound as a white solid (51.0 mg 48% yield) MS (-ve ESI) : 375 (M-H)

¹H NMR (400.132 MHz, CDC13) δ 1.02 - 1.53 (7H, m),1.64 (IH, m),1.84 (3H, m),2.58 (IH, m),2.86 - 3.47 (4H, m),3.57 - 4.20 (2H, m),4.57 - 4.96 (2H, m),6.62 (IH, d),7.32 (2H, m),7.54 (IH, m)

The l,2,3,4-tetrahydroisoquinoline-5-carbonitrile used as a starting material was prepared as follows: tert-butyl 5-carbamoyl-3,4-dihydroisoquinoline-2(lH)-carboxylate

To a slurry of the 2-(tert-butoxycarbonyl)-l,2,3,4-tetrahydroisoquinoline-5- carboxylic acid (1.39 g, 5.00 mmol), HATU (2.10 g, 5.50 mmol) and ammonium chloride (535 mg, 10.0 mmol) in DMF (25 mL) was added DIPEA (2.62 mL, 15.0 mmol) and the reaction stirred overnight. The mixture was diluted with ethyl acetate (100 mL) and washed with water (2 x 50 mL), 2M NaOH (50 mL), NaHCO₃ (50 mL) solution and then brine (30 mL), dried over magnesium sulphate, filtered and concentrated in vacuo to yield a white solid (688 mg, 50%). MS (+ve ESI) : 262 (M+NH₂)

¹H NMR (400.132 MHz, CDC13) δ 1.49 (9H, s),3.06 (2H, t),3.62 (2H, s),4.60 (2H, s),5.69 (2H, m),7.24 (5H, m),7.36 (IH, m). tert-hx\ty\ 5-cyano-3,4-dihydroisoquinoline-2(lH)-carboxylate

To pyridine (5 mL), stirring at 0 ⁰C under a blanket of argon was added the POCl₃

(0.81 mL, 8.72 mmol) dropwise followed by the tert-hvXy\ 5-carbamoyl-3,4- dihydroisoquinoline-2(lΗ)-carboxylate (688 mg, 2.49 mmol) portionwise. The mixture was allowed to warm to ambient temperature and stirred for 5 hours, solution turned pink initially and then sandy in colour. The reaction was poured into warm water (50 mL) and extracted with ethyl acetate (2 x 50 mL) and the combined organics washed with brine (30 mL), dried over magnesium sulphate, filtered and concentrated in vacuo. Flash column chromatography (40% EtOAc / hexanes) gave the product as a white solid (103 mg, 16%). MS (+ve ESI) : 258 (M+H)

¹H NMR (400.132 MHz, CDC13) δ 1.50 (9H, s),3.03 (2H, t),3.71 (2H, t),4.60 (2H, s),7.29 (IH, t),7.34 (IH, d),7.52 (IH, d)

4.0M Hydrochloric acid solution (4 mL) was added to a stirred solution oϊtert- butyl 5-cyano-3,4-dihydroisoquinoline-2(lH)-carboxylate (100 mg, 0.39 mmol) and the reaction stirred for 1 hour, after about 15 mins a white precipitate had formed, ether (30 mL) was added and the solid filtered off (54.0 mg, 71%). The material was used in this crude form.

MS (+ve ESI) : 159 (M+H)

Assay for identification of cathepsin K inhibitors

QFRET Technology (Quenched Fluorescent Resonance Energy Transfer) was used to measure the inhibition by test compounds of cathepsin K-mediated cleavage of the synthetic peptide Z-Phe-Arg-AMC. Compounds were screened at twelve concentrations (3.5x10-8 - lOuM) , on two separate occasions and the mean pIC50 values reported.

0.5nM [final] rhuman cathepsin K in phosphate buffer was added to a 384-well black micro titre plate containing investigative compounds. The enzyme and compound were pre-incubated at room temperature for 30 minutes before the addition of 5OmM

[final] Z-Phe-Arg-AMC synthetic substrate in phosphate buffer. The plates were covered and incubated for Ih at room temperature, protected from light. Following the incubation the reaction was stopped with 7.5% [final] acetic acid. Relative fluorescence was measured using the Ultra plate reader at a wavelength of 360nm excitation and 425nm emission.

Data was corrected for background fluorescence (minimum controls without enzyme). This data was used to plot inhibition curves and calculate pIC50 values by nonlinear regression using a variable slope, offset=zero model in Origin 7.5 analysis package. Reproducibility of data was assessed using a quality control statistical analysis package whereby internal variability of the assayed indicated a repeat testing (n=3) if pIC50 SD was > 0.345.

The compounds of the Examples have Cat K FRET competitive binding as measured by the assay described above at pIC50 > 6.5.

Claims

1. A compound of formula (I)

(I) in which:

A is a 5- to 7- membered aliphatic ring optionally containing a double bond and optionally comprising an oxygen atom as a ring member and optionally being substituted by up to three substituents each independently selected from halogen, Ci_-2alkyl and C_3- 4carbocyclyl;

R is hydrogen or C_1-6 alkyl ;

R¹ and R² together with the nitrogen atom to which they are attached form a 5- to 7- membered monocyclic saturated or partially unsaturated heterocyclic ring, which ring shares at least one atom with a second monocyclic saturated, partially unsaturated or unsaturated ring so as to form a bicyclic ring system comprising up to 12 ring atoms, and wherein the bicyclic ring system optionally comprises up to three heteroatoms each independently selected from O, S or N atoms, and is optionally substituted by up to three substituents each independently selected from phenyl, benzyl, naphthyl, Ci_-6 alkyl, C_2-6alkenyl, C_2-6alkynyl, cyano, halogen, COOR³, COR³, NO₂, OR³, CONR⁴R⁵, NR⁴R⁵, SO₂R³, NSO₂R³, monocyclic heteroaryl comprising up to 7 ring atoms, and bicyclic heteroaryl comprising up to 12 carbon atoms, and wherein

(i) phenyl, naphthyl, Ci_-6 alkyl, C_2-6alkenyl, C_2-6alkynyl and benzyl are optionally further substituted by up to three substituents each independently selected from halogen, NR⁴R⁵, SO₂R³, CONR⁴R⁵, cyano, OR³, SO₂NR⁴R⁵, NSO₂R³, NR⁴COR⁵, and Ci_-6 alkyl itself optionally substituted with 1 , 2 or 3 substituents independently selected from halogen, cyano, SO₂R³, NR⁴R⁵, OR³, SO₂NR⁴R⁵, NSO₂R³, NR⁴COR⁵ and CONR⁴R⁵, and

(ii) monocyclic or bicyclic heteroaryl are optionally further substituted by up to three substituents each independently selected from halogen, NR⁴R⁵, SO₂NR⁴R⁵, NSO₂R³,

NR⁴COR⁵, CONR⁴R⁵ , SO₂R³, cyano, OR³, and phenyl itself optionally substituted with up to three halogen groups, SO₂R³, or Ci_-6 alkyl itself optionally substituted with up to three substituents independently selected from halogen, cyano, SO₂R³, SO₂NR⁴R⁵, NSO₂R³, NR⁴COR⁵, NR⁴R⁵, OR³, C_3-7carbocyclyl and CONR⁴R⁵; R³ is selected from hydrogen, Ci_-6 alkyl, C3_-7carbocyclyl, phenyl, monocyclic heteroaryl, a 4-7 membered monocyclic saturated heterocyclic ring comprising up to three heteroatoms each independently selected from O, S or N atoms, and wherein Ci_-6 alkyl and phenyl, monocyclic heteroaryl, can each be optionally substituted by up to three groups independently selected from halogen, cyano, CONR⁴R⁵, NR⁴R⁵, SO₂NR⁴R⁵, NSO₂R³ and SO₂R³;

R⁴ and R⁵ are independently hydrogen, Ci_-6 alkyl, COR³, monocyclic heteroaryl comprising up to 7 ring atoms or bicyclic heteroaryl comprising up to 12 ring atoms or together with the nitrogen to which they are attached form a 5- to 7-membered monocyclic saturated heterocyclic ring optionally comprising up to three additional heteroatoms each independently selected from O, S or N atoms and optionally substituted by Ci_-6 alkyl optionally substituted by NR⁶R⁷;

R⁶ and R⁷ are independently hydrogen, Ci_-6 alkyl, or together with the nitrogen to which they are attached form a 5- to 7-membered monocyclic saturated heterocyclic ring optionally comprising up to three additional heteroatoms each independently selected from O, S or N atoms; and pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, wherein A is a 5 -7-membered aliphatic ring optionally being substituted by up to three substituents independently selected from halogen and Cβ^carbocyclyl.

3. A compound according to any one of claims 1 to 3, wherein R¹ and R² together with the nitrogen atom to which they are attached form a 5- to 6-membered monocyclic saturated heterocyclic ring, which ring is attached and shares at least one atom with a second monocyclic saturated or unsaturated ring so as to form a bicyclic ring system, which bicyclic ring system can optionally contain up to three additional heteroatoms independently selected from O, S or N atoms and can optionally be substituted by up to three substituents as defined in claim 1.

4. A compound according to claim 3 and wherein the second ring is selected from an unsaturated 5-membered ring comprising only N, only S or only O heteroatoms, a 6- membered unsaturated ring optionally comprising one heteroatom, or a saturated 5- or 6- membered ring optionally comprising one heteroatom and linked to the first ring so as to form a spiro ring system.

5. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises:

(a) treating a compound of formula (II):

(H)

with a compound of formula (III):

≡N

H-N R

(in)

where R, R¹ and R² are as defined in any one of claims 1 to 5, or (b) treatment of a compound of formula (IV):

(IV)

with a compound of formula (V):

N-H R2⁷ (V)

where R, R¹ and R² are as defined in any one of claims 1 to 5, and optionally after (a) or (b) forming a pharmaceutically acceptable salt.

6. A compound of formula (I) as defined in any one of claims 1 to 5 for use in therapy.

7. A compound of formula (I) as defined in any one of claims 1 to 5 for use in therapy, where it is desirable to have inhibition of Cathepsin K.

8. A compound of formula (I) as defined in any one of claims 1 to 5 for use in the treatment of osteoporosis, rheumatoid arthritis, osteoarthritis, metastatic bone disease, osteolytic bone disease or bone related neuropathic pain.

9. A pharmaceutical composition which comprises a compound of the formula (I) as defined in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

10. A method for producing inhibition of a cysteine protease in a mammal in need of such treatment, which comprises administering to said mammal an effective amount of a compound as defined in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

11. Use of a compound of the formula (I) as defined in any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the inhibition of Cathepsin K in a warm blooded animal.