JP2002537293A - Acetamide acetonitrile derivatives as inhibitors of cathepsin L and / or cathepsin S - Google Patents

Abstract

(57) Abstract: A compound of formula (I) wherein Ar, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are defined; a composition comprising a compound of formula (I) and a carrier or diluent; Use of a compound of formula (I) for use as a medicament, for the manufacture of a medicament for use in inhibiting cysteine proteases in warm-blooded animals, for the treatment of chronic obstructive pulmonary disease in warm-blooded animals Use of a compound of formula (I) in the manufacture of a medicament for use; and administering an effective amount of a compound of formula (I) to a mammal in need of treatment of a cathepsin L or cathepsin S mediated disease state. A method of treating such a disease state in a mammal, comprising: Embedded image

Description

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds that are cysteine protease inhibitors,
In particular, it relates to compounds that are cathepsin L inhibitors and / or cathepsin S inhibitors, especially cathepsin S inhibitors. The invention further relates to methods for their preparation, intermediates useful for their preparation, their use as therapeutics, pharmaceutical compositions containing them, and methods of treating cathepsin L or cathepsin S mediated disease states.

[0002] Cathepsin proteases are important enzymes in normal cell physiology, but they are also associated with several disease states, including inflammation, metastasis, tissue damage after myocardial infarction, bone resorption and muscle wasting in dystrophic diseases. .

[0003] Cathepsins B, H, K, L, N and S are cysteinyl proteases involved in normal proteolysis and are usually localized in the lysosome of cells. However, when these enzymes are found outside of lysosomes, they are associated with their role in a number of disease states, including bone resorption disorders such as osteoporosis.

In recent years, the number of people with longevity has increased dramatically. This has been characterized by an increasing number of people with osteoporosis and other aging-related diseases. Osteoporosis is associated with a high incidence of fractures, resulting in many elderly people becoming bedridden. Therefore, a pharmaceutical composition for treating or preventing the above-mentioned diseases is strongly desired.

[0005] Living bone is constantly being remodeled and replenished by the process of absorption and deposition of protein matrices and calcium minerals. These processes break down bones,
Promoted by osteoclasts, which can be demineralized, and osteoblasts, which are involved in new bone formation. Under normal conditions, these processes are essentially connected and the bone mass changes little. However, the presence of pathological conditions that result in an imbalance between the activity of the cells promotes bone degradation and mineral removal, forming brittle and / or fragile bone structures as seen in osteoporosis . The exact mechanism of this resorption is not known, but the increase in osteoclast activity, as understood by the increase in proteolytic activity, is one factor, and selective inhibition of proteolytic activity halts bone damage and inhibits it. Will do. The lysosomal cysteine proteases, cathepsins B, H, K, L, N and S, have been considered as proteinases involved in osteoclast bone resorption. Because they can degrade insoluble type I collagen at low pH.

[0006] Cathepsins B, H, K, L, N and S are also used for rheumatoid arthritis, osteoarthritis, tumor metastasis, pneumocystis, critidiafushi culata (Critid).
ia fusicuiata), malaria, bruce trypanosoma, schistosomiasis, periodontal disease, heterochromosomal leukodystrophy and muscular dystrophy and have been thought to play a causative role in other diseases. Cathepsin B
, H, K, L, N and S, alone or together, have also been thought to play a causative role in chronic obstructive pulmonary disease (COPD).

In recent years, a number of cysteine protease synthesis inhibitors have been disclosed. U.S. Pat. No. 5,055,451 discloses a series of peptidyl methyl ketones as thiol protease inhibitors; WO 95/15749 discloses peptidyl methyl ketones with heterocyclic leaving groups as cysteine protease inhibitors. In vivo of cathepsin B by peptidyl (acyloxy) methyl ketone
o For inhibition, see Med. Chem. 1994, 37, 1833-40, and these types of compounds as cysteine protease inhibitors are also described in Am. Chem. Soc. 1988, 110, 4429-4431; a specific inactivator of thiol proteinase, peptidyldiazomethylketone, is described in J. Am. Biol. Chem. , 1981, 256, 4,
1923-8 and Methods in Enzymology, 1981,
80,820-5; the inhibitory activity of 1-peptidyl-2-haloacetylhydrazine on cathepsin B and calpain is described in Eur. J. Med. Che
m. , 1993, 28, 297-311 and peptidyl fluoromethyl ketone as a cathepsin B inhibitor and its relevance for the treatment of rheumatoid arthritis.
4, 6, 1201-7. Therefore, there is a great need for specific cysteine protease inhibitors, especially cathepsin L inhibitors or cathepsin S inhibitors.

The present invention discloses compounds having cysteine protease inhibitory activity, and especially compounds having cathepsin L and cathepsin S inhibitory activity. The compounds of the present invention are also effective in treating chronic obstructive pulmonary disease (COPD).

According to the present invention, a compound of formula (I):

[0010]

Embedded image

(Where Ar is phenyl which may be substituted, naphthyl which may be substituted, He
t, C_3-12Cycloalkyl, or optionally substituted 5 or 6 membered hetero
An aryl ring wherein the optional substituents are one or more halo, C_1-6Alkyl C_1-6Arco
Xy, nitro, C_1-6Alkanoylamino, methyl trifluoride, hydroxy, trif
Methoxy, cyano, C_1-6Alkanoyl, C_1-6Alkanoyloxy, amino
, C_1-6Alkylamino, N, N- (C_1-6Alkyl)_TwoAmino, carboxy, mosquito
Rubamoyl, N- (C_1-6Alkyl) carbamoyl, N, N- (C_1-6Alkyl) _Two Carbamoyl, C_1-6Alkoxycarbonyl, mercapto, C_1-6Alkylsul
Fanyl, C_1-6Alkylsulfinyl, C_1-6Alkylsulfonyl, sulfamo
Il, N- (C_1-6Alkyl) sulfamoyl, N, N- (C_1-6Alkyl)_TwoS
Rufamoyl, amino C_1-6Alkyl, N- (C_1-6Alkyl) amino C_1-6Al
Kill, N, N- (C_1-6Alkyl)_TwoAmino C_1-6Alkyl, R⁶S-, R⁶C (O
)-, And R⁶CH_Two-Where R⁶Is C_1-6Alkyl, halo, three
Methyl trifluoride, hydroxy, methoxy trifluoride, cyano, C_1-6Alkoxy, C_1-6 Alkanoyl, C_1-6Alkanoyloxy, amino, C_1-6Alkylamino, N,
N- (C_1-6Alkyl)_TwoAmino, C_1-6Alkanoylamino, nitro, carboki
Si, carbamoyl, N- (C_1-6Alkyl) carbamoyl, N, N- (C_1-6Al
kill)_TwoCarbamoyl, C_1-6Alkoxycarbonyl, mercapto, C_1-6Archi
Rusulfanyl, C_1-6Alkylsulfinyl, C_1-6Alkylsulfonyl, sulf
Famoyl, N- (C_1-6Alkyl) sulfamoyl and N, N- (C_1-6A
Lequil)_TwoOptionally substituted with one or more groups selected from sulfamoyl.
Where Ar is Het linked to the nitrogen, X is -N (R⁷)
-Or -O-; X is -N (R⁷)-, -S (O)_n-, -O-, -SO_TwoN (R⁷)-
Where n = 0−) and R⁷Is H, C_1-6Alkyl (one or more cyano, Het and
And R^Ten) Or R⁷Is C_2-6Alkenyl (R^TenIs replaced by
), Formyl, and R^TenIs optionally substituted 5 or
Is a 6-membered heteroaryl ring, optionally substituted phenyl, or substituted
And the optional substituent is one or more halo, nitro, trifluoride.
Methyl, amino, C_1-6Alkylamino, N, N- (C_1-6Alkyl)_Twoamino,
C_1-6Alkyl, hydroxy, methoxy trifluoride, cyano, C_1-6Alkoxy, C _1-6 Alkanoyl, C_1-6Alkanoyloxy, C_1-6Alkanoylamino, cal
Boxy, carbamoyl, N- (C_1-6Alkyl) carbamoyl, N, N- (C_1-6 Alkyl)_TwoCarbamoyl, C_1-6Alkoxycarbonyl, mercapto, C_1-6A
Rukylsulfanyl, C_1-6Alkylsulfinyl, C_1-6Alkylsulfonyl,
Sulfamoyl, N- (C_1-6Alkyl) sulfamoyl, N, N- (C_1-6Al
kill)_TwoSulfamoyl and phenyl C_1-6Selected from alkoxy; R¹Is H, C_1-6Alkyl (R⁸), C_1-6Alkylsul
Fanil (R⁸), C_2-6Alkenyl, R⁸, R⁸S-
Where R⁸Is phenyl, C_3-12Cycloalkyl, Het or 5 or 6
Membered heteroaryl rings, all of which are C_1-6Alkyl, halo, trifluoride
Methyl, hydroxy, methoxy trifluoride, cyano, C_1-6Alkoxy, C_1-6Al
Canoyl, C_1-6Alkanoyloxy, amino, C_1-6Alkylamino, N, N-
(C_1-6Alkyl)_TwoAmino, C_1-6Alkanoylamino, nitro, carboxy,
Carbamoyl, N- (C_1-6Alkyl) carbamoyl, N, N- (C_1-6Alkyl
)_TwoCarbamoyl, C_1-6Alkoxycarbonyl, mercapto, C_1-6Alkyls
Rufanil, C_1-6Alkylsulfinyl, C_1-6Alkylsulfonyl, sulfa
Moyle, N- (C_1-6Alkyl) sulfamoyl, N, N- (C_1-6Alkyl)_Two
Substituted with one or more groups selected from sulfamoyl and benzyloxy
But if R¹Is C_1-6Alkylsulfanyl (R⁸Has been replaced by
Or R)⁸In the case of S-, X is -SO_TwoN (R⁷)-; R^TwoIs H or C_1-6R is alkyl;^ThreeIs H or C_1-6R is alkyl;^FourIs H, C_1-6Alkyl (one or more hydroxy, C_1-6Alkylsulfanyl
, C_1-6Alkylsulfinyl, C_1-6Alkylsulfonyl, R⁹, R⁹C_1-6Al
Killsulfanyl, R⁹C_1-6Alkylsulfinyl, R⁹C_1-6Alkylsulfoni
Or R)^FourIs C_1-6Alkoxy (one or more C_2-6A
Lucenyl, C_2-6Alkynyl, R⁹, R⁹C_2-6Alkenyl, R⁹C_2-6Alkynyl,
Het and optionally substituted with methyl trifluoride), or R^FourIs C_2-6A
Lucenyl, C_2-6Alkynyl, C_1-6Alkoxycarbonyl, carbamoyl, N-
(C_1-6Alkyl) carbamoyl, N, N- (C_1-6Alkyl)_TwoCarbamoyl,
R⁹-, R⁹S-, R⁹C_1-6Alkylsulfanyl, N- (R⁹C_1-6Alkyl) mosquito
Rubamoyl, N- (HetC_1-6Alkyl) carbamoyl, C_1-6Alkanoylua
Mino, C_1-6Alkylsulfanyl, C_1-6Alkylsulfinyl, C_1-6Archi
Rusulfonyl, where R⁹May be substituted with phenyl, or
A 5- or 6-membered heteroaryl ring which may be substituted,
Is one or more C_1-6Alkyl, halo, methyl trifluoride, hydroxy, methatrifluoride
Kiss, cyano, C_1-6Alkoxy, C_1-6Alkanoyl, C_1-6Alkanoyl oki
Si, amino, C_1-6Alkylamino, N, N- (C_1-6Alkyl)_TwoAmino, C_1-6 Alkanoylamino, nitro, carboxy, carbamoyl, N- (C_1-6Archi
Le) carbamoyl, N, N- (C_1-6Alkyl)_TwoCarbamoyl, C_1-6Alkoki
Cycarbonyl, mercapto, C_1-6Alkylsulfanyl, C_1-6Alkylsulf
Inil, C_1-6Alkylsulfonyl, sulfamoyl, N- (C_1-6Alkyl) s
Rufamoyl and N, N- (C_1-6Alkyl)_TwoSelected from sulfamoyl;
And R^FiveIs H or C_1-6Het is complete containing up to 4 ring heteroatoms
A monocyclic 5-8 membered heterocyclic ring saturated with¹Is H or C_1-6Alkyl, X is O or S, and
R^TwoAnd R^ThreeAr is not pyrimid-4-yl when are both hydrogen; ¹ And R^TwoAre both hydrogen and R^ThreeIs C_1-6Alkyl, X is O, R^FourIs hydrogen, C_{1 -6} Alkyl, phenyl or benzyl, and R^FiveIs H or C_1-4Archi
Ar is not halophenyl;¹And R^ThreeAre both hydrogen
, R^TwoAnd R^FiveIs independently hydrogen or methyl;^FourAre not replaced
When X is O, Ar is 3-methyl
Not -2,4-dichlorophenyl; R¹Is H or C_1-4Alkyl, R ^Two Is H or C_1-4Alkyl, R^ThreeIs hydrogen and R^FourIs hydrogen, C_1-6Archi
Or X and X is O, S, NH or N (C_1-4Alkyl)
Ar is halo, C_1-4Alkyl, CF_Three, C_1-4Alkoxy, CO_TwoH,
CO_Two(C_1-4Alkyl), CONH_Two, NO_Two, CN, CH_TwoN (CH_Three)_Two, S (
C_1-4Alkyl) or mono- or di-chlorobenzyl
Not good phenyl; R¹, R^Two, R^ThreeAnd R^FiveAre all hydrogen and R^FourIs S
O_TwoCH_TwoCH_ThreeAnd X is SO_TwoIs when Ar is not phenyl;
And R¹, R^Two, R^Three, R^FourAnd R^FiveAre all hydrogen and X is SO_TwoNH
Ar is not 4-methylphenyl;) or its pharmaceutically acceptable
Provide Kiruku salt.

As used herein, the term 'alkyl' includes straight chain, branched and cyclic structures. For example, C _1-6 alkyl includes propyl, isopropyl, t-butyl, cyclopropyl and cyclohexyl. However, a reference to an individual alkyl group such as 'propyl' is specified only for the linear form, a reference to an individual branched alkyl group such as 'isopropyl' is specified only for the branched form, And references to individual cycloalkyl groups such as cyclohexyl are specific to cyclic groups only.

An analogous convention applies to other groups, for example “aminoC _1-6 alkyl” includes 1-aminoethyl and 2-aminoethyl. The term "halo" refers to fluoro, chloro, bromo and iodo.

“Het”, unless otherwise specified, is a fully saturated monocyclic 5-8 membered heterocycle containing up to 4 ring heteroatoms. Examples of heteroatoms include nitrogen, oxygen, and sulfur. Examples of "Het" include pyrrolidinyl, imidazolidyl, pyrazolidyl, piperidyl, piperazinyl and morpholinyl. “He
Other examples of t "include pyrrolidinyl, imidazolidyl, pyrazolidyl, piperidyl, piperazinyl, thiomorpholino and morpholino. Preferably" Het "is morpholino.

“5- or 6-membered heteroaryl ring” means, unless otherwise specified, a partially unsaturated 5- or 6-membered heteroaryl ring containing up to 4 ring heteroatoms selected from nitrogen, oxygen and sulfur. . Examples of "5- or 6-membered heteroaryl rings" include thienyl, furyl, imidazolyl, thiazolyl, pyrimidinyl, pyridinyl, pyrrolyl and pyrazolyl. Examples of "5-membered heteroaryl rings" include:
Thienyl, furyl, imidazolyl, thiazolyl and pyrrolyl are mentioned.

Examples of “C _1-6 alkanoyloxy” include acetoxy and propionyloxy. Examples of “C _1-6 alkoxycarbonyl” include methoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of “C _1-6 alkoxy” include methoxy, ethoxy and propoxy. Examples of “C _1-6 alkanoylamino” include formamide, acetamido and propionylamino. “C _1-6 alkylsulfanyl”
Examples include methylthio and ethylthio. Examples of “C _1-6 alkylsulfinyl” include methylsulfinyl and ethylsulfinyl. Examples of “C _1-6 alkylsulfonyl” include mesyl and ethylsulfonyl. Examples of “C _1-6 alkanoyl” include acetyl and propionyl. Examples of “C _1-6 alkylamino” include methylamino and ethylamino. Examples of “N, N- (C _1-6 alkyl) ₂ amino” include N, N-dimethylamino, N, N-diethylamino and N-ethyl-N-methylamino. Examples of “C _2-6 alkenyl” include vinyl, allyl and 1-propenyl. Examples of “C _2-6 alkynyl” include ethynyl, 1-propynyl and 2-propynyl. Examples of “N- (C _1-6 alkyl) amino C _1-6 alkyl” include 2-N-methylaminoethyl and 3-
N-ethylaminopropyl is mentioned. Examples of “N, N- (C _1-6 alkyl) ₂ amino C _1-6 alkyl” include 2- (N, N-dimethylamino) ethyl and 3
-(N, N-diethylamino) propyl. Examples of “N- (C _1-6 alkyl) carbamoyl” include methylaminocarbonyl and ethylaminocarbonyl. Examples of “N, N- (C _1-6 alkyl) ₂ carbamoyl” include dimethylaminocarbonyl and methylethylaminocarbonyl. Examples of “N- (C _1-6 alkyl) sulfamoyl” include N-methylsulfamoyl and N-ethylsulfamoyl. "N, N- (C _1-6 alkyl) ₂ sulphamoyl" Examples of N, N- dimethylsulfamoyl and N, N- diethylsulfamoyl. Examples of “R ⁹ C _1-6 alkylsulfanyl” include R ⁹ methylthio and R ⁹ ethylthio. Examples of “R ⁹ C _1-6 alkylsulfinyl” include R ⁹ methylsulfinyl and R ⁹ ethylsulfinyl. Examples of “R ⁹ C _1-6 alkylsulfonyl” include R ⁹ mesyl and R ⁹ ethylsulfonyl. Examples of R ⁹ C _2-6 alkenyl include R ⁹ vinyl and R ⁹ allyl. Examples of “C _2-6 alkynyl” include R ⁹ ethynyl, R ⁹ propyn-yl. Examples of “N- (R ⁹ C _1-6 alkyl) carbamoyl” include R ⁹ methylaminocarbonyl and R ⁹ ethylaminocarbonyl. Examples of “N- (HetC _1-6 alkyl) carbamoyl” include morpholinomethyl Aminocarbonyl and 2- (piperidinoethyl) aminocarbonyl. Examples of “C _3-12 cycloalkyl” include cyclopropyl, cyclopentyl and cyclohexyl.

When the optional substituent is selected from “one or more” groups, this definition includes all substituents selected from one of the specifically listed groups, or It is to be understood that this includes selection from two or more of the groups mentioned. For example, when optional substituents are selected from one or more halo, C _1-6 alkoxy and C _1-6 alkyl, examples of possible combinations of substituents include 1) one bromo group, 2) two chloro Groups, 3) one methoxy, ethoxy and propoxy substituent, 4) one fluoro and one methoxy group, 5) one methoxy, one methyl and one ethyl group, and 6) one chloro, one Methoxy and one ethyl group.

In one embodiment, the present invention provides a compound of formula (I) wherein Ar is optionally substituted.
Phenyl, optionally substituted naphthyl, Het, C_3-12Cycloalkyl,
Or an optionally substituted 5- or 6-membered heteroaryl ring,
The substituent is one or more halo, C_1-6Alkoxy, C_1-6Alkyl, nitro, C_1-6Al
Killamino, methyl trifluoride, hydroxy, methoxy trifluoro, cyano, C_1-6
Alkanoyl, C_1-6Alkanoyloxy, amino, C_1-6Alkylamino, N,
N- (C_1-6Alkyl)_TwoAmino, carboxy, carbamoyl, N- (C_1-6Al
Kill) carbamoyl, N, N- (C_1-6Alkyl)_TwoCarbamoyl, C_1-6Arco
Xycarbonyl, mercapto, C_1-6Alkylsulfanyl, C_1-6Alkylsul
Finil, C_1-6Alkylsulfonyl, sulfamoyl, N- (C_1-6Alkyl)
Sulfamoyl, N, N- (C_1-6Alkyl)_TwoSulfamoyl, amino C_1-6A
Lucil, N- (C_1-6Alkyl) amino C_1-6Alkyl, N, N- (C_1-6Archi
Le)_TwoAmino C_1-6Alkyl, R⁶S-, R⁶C (O)-, and R⁶CH_TwoSelect from
Selected, where R⁶Is C_1-6Alkyl, halo, methyl trifluoride, hydroxy, trif
Methoxy, cyano, C_1-6Alkoxy, C_1-6Alkanoyl, C_1-6Alkano
Iloxy, amino, C_1-6Alkylamino, N, N- (C_1-6Alkyl)_TwoAmi
No, C_1-6Alkanoylamino, nitro, carboxy, carbamoyl, N- (C_{1 -6} Alkyl) carbamoyl, N, N- (C_1-6Alkyl)_TwoCarbamoyl, C_1-6
Alkoxycarbonyl, mercapto, C_1-6Alkylsulfanyl, C_1-6Archi
Rusulfinyl, C_1-6Alkylsulfonyl, sulfamoyl, N- (C_1-6Al
Kill) sulfamoyl and N, N- (C_1-6Alkyl)_TwoChoose from Sulfamoyl
Phenyl optionally substituted with one or more selected groups, provided that Ar is nitrogen.
When Het is linked to a prime, X is -N (R⁷)-Or -O-
X is -N (R⁷)-, -S (O)_n-, -O-, -SO_TwoN (R⁷)-
Where n = 0-2 and R⁷Is H, C_1-6Alkyl (one or more cyano, Het
And R^TenOr optionally substituted with⁷Is C_2-6Alkenyl (R ^Ten ), Formyl, and R^TenIs replaced
A good 5 or 6 membered heteroaryl ring, an optionally substituted phenyl, or
Optionally substituted naphthyl, wherein the optional substituent is one or more halo, nitro
B, methyl trifluoride, amino, C_1-6Alkylamino, N, N- (C_1-6Alkyl
)_TwoAmino, C_1-6Alkyl, hydroxy, methoxy trifluoride, cyano, C_1-6A
Lucoxy, C_1-6Alkanoyl, C_1-6Alkanoyloxy, C_1-6Alkanoyl
Amino, carboxy, carbamoyl, N- (C_1-6Alkyl) carbamoyl, N
, N- (C_1-6Alkyl)_TwoCarbamoyl, C_1-6Alkoxycarbonyl, Merka
Put, C_1-6Alkylsulfanyl, C_1-6Alkylsulfinyl, C_1-6Archi
Rusulfonyl, sulfamoyl, N- (C_1-6Alkyl) sulfamoyl, N,
N- (C_1-6Alkyl)_TwoSulfamoyl and phenyl C_1-6Select from alkoxy
Selected; R¹Is H, C_1-6Alkyl (R⁸), C_1-6Archi
Rusulfanyl (R⁸), C_2-6Alkenyl, R⁸, R⁸S
-Where R⁸Is phenyl, C_3-12Cycloalkyl, Het or optionally
A substituted 5- or 6-membered heteroaryl ring, and_1-6Archi
, Halo, methyl trifluoride, hydroxy, methoxy trifluoro, cyano, C_1-6A
Lucoxy, C_1-6Alkanoyl, C_1-6Alkanoyloxy, amino, C_1-6Al
Killamino, N, N- (C_1-6Alkyl)_TwoAmino, C_1-6Alkanoylamino,
Nitro, carboxy, carbamoyl, N- (C_1-6Alkyl) carbamoyl, N
, N- (C_1-6Alkyl)_TwoCarbamoyl, C_1-6Alkoxycarbonyl, Merka
Put, C_1-6Alkylsulfanyl, C_1-6Alkylsulfinyl, C_1-6Archi
Rusulfonyl, sulfamoyl, N- (C_1-6Alkyl) sulfamoyl, N,
N- (C_1-6Alkyl)_TwoAt least one selected from sulfamoyl and benzyloxy
May be substituted with the above groups; provided that if R¹Is C_1-6Alkylsulfanyl
(R⁸) Or R⁸In the case of S-, X is -SO_TwoN (R⁷)-
Must be; R^TwoIs H or C_1-6Alkyl; R^ThreeIs H or C_1-6A
Luquil; R^FourIs an optionally substituted 5- or 6-membered heteroaryl ring
Wherein the optional substituent is one or more C_1-6Alkyl, halo, trifluoride
Chill, hydroxy, methoxy trifluoride, cyano, C_1-6Alkoxy, C_1-6Arca
Noil, C_1-6Alkanoyloxy, amino, C_1-6Alkylamino, N, N- (
C_1-6Alkyl)_TwoAmino, C_1-6Alkanoylamino, nitro, carboxy, mosquito
Rubamoyl, N- (C_1-6Alkyl) carbamoyl, N, N- (C_1-6Alkyl) _Two Carbamoyl, C_1-6Alkoxycarbonyl, mercapto, C_1-6Alkylsul
Fanyl, C_1-6Alkylsulfinyl, C_1-6Alkylsulfonyl, sulfamo
Il, N- (C_1-6Alkyl) sulfamoyl and N, N- (C_1-6Alkyl) _Two Selected from sulfamoyl; and R^FiveIs H or C_1-6Is alkyl)
Or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a compound of formula (I) wherein Ar is substituted
Phenyl, optionally substituted naphthyl or optionally substituted 5
Or a 6-membered heteroaryl ring, wherein said optional substituent is one or more halo, C_{1- 6} Alkoxy, C_1-6Alkyl, nitro, C_1-6Alkanoylamino, trifluoride
Chill, hydroxy, methoxy trifluoride, cyano, C_1-6Alkanoyl, C_1-6Al
Canoyloxy, amino, C_1-6Alkylamino, N, N- (C_1-6Alkyl)_Two
Amino, carboxy, carbamoyl, N- (C_1-6Alkyl) carbamoyl, N
, N- (C_1-6Alkyl)_TwoCarbamoyl, C_1-6Alkoxycarbonyl, Merka
Put, C_1-6Alkylsulfanyl, C_1-6Alkylsulfinyl, C_1-6Archi
Rusulfonyl, sulfamoyl, N- (C_1-6Alkyl) sulfamoyl, N,
N- (C_1-6Alkyl)_TwoSulfamoyl, amino C_1-6Alkyl, N- (C_1-6A
Ruquil) amino C_1-6Alkyl, N, N- (C_1-6Alkyl)_TwoAmino C_1-6Archi
Le, R⁶S-, R⁶C (O)-, and R⁶CH_Two-Where R⁶Is C_{1 -6} Alkyl, halo, methyl trifluoride, hydroxy, methoxy trifluoride, cyano,
C_1-6Alkoxy, C_1-6Alkanoyl, C_1-6Alkanoyloxy, amino, C_{1 -6} Alkylamino, N, N- (C_1-6Alkyl)_TwoAmino, C_1-6Alkanoylua
Mino, nitro, carboxy, carbamoyl, N- (C_1-6Alkyl) carbamoy
Le, N, N- (C_1-6Alkyl)_TwoCarbamoyl, C_1-6Alkoxycarbonyl,
Mercapto, C_1-6Alkylsulfanyl, C_1-6Alkylsulfinyl, C_1-6
Alkylsulfonyl, sulfamoyl, N- (C_1-6Alkyl) sulfamoyl
And N, N- (C_1-6Alkyl)_TwoOne or more groups selected from sulfamoyl
X is -N (R⁷)-, -S (O)_n-, -O-, -SO_TwoN (R⁷)-
Where n = 0-2, R⁷Is H, C_1-6Alkyl (one or more cyano, Het and R^Ten ) Or R⁷Is C_2-6Alkenyl (R^TenHas been replaced by
), Formyl, and R^TenIs an optionally substituted 5- or 6-member
A heteroaryl ring, an optionally substituted phenyl, or an optionally substituted
Naphthyl, wherein the optional substituent is one or more halo, nitro, methyl trifluoride
, Amino, C_1-6Alkylamino, N, N- (C_1-6Alkyl)_TwoAmino, C_1-6A
Alkyl, hydroxy, methoxytrifluoride, cyano, C_1-6Alkoxy, C_1-6Al
Canoyl, C_1-6Alkanoyloxy, C_1-6Alkanoylamino, carboxy,
Carbamoyl, N- (C_1-6Alkyl) carbamoyl, N, N- (C_1-6Alkyl
)_TwoCarbamoyl, C_1-6Alkoxycarbonyl, mercapto, C_1-6Alkyls
Rufanil, C_1-6Alkylsulfinyl, C_1-6Alkylsulfonyl, sulfa
Moyle, N- (C_1-6Alkyl) sulfamoyl, N, N- (C_1-6Alkyl)_Two
Sulfamoyl and phenyl C_1-6Selected from alkoxy; R¹Is H, C_1-6Alkyl (R⁸), C_2-6Alkenyl,
R⁸S-, where R⁸Is C_1-6Alkyl, halo, methyl trifluoride, hydroxy
Si, methoxy trifluoride, cyano, C_1-6Alkoxy, C_1-6Alkanoyl, C_1-6
Alkanoyloxy, amino, C_1-6Alkylamino, N, N- (C_1-6Alkyl
)_TwoAmino, C_1-6Alkanoylamino, nitro, carboxy, carbamoyl, N
− (C_1-6Alkyl) carbamoyl, N, N- (C_1-6Alkyl)_TwoCarbamoyl
, C_1-6Alkoxycarbonyl, mercapto, C_1-6Alkylsulfanyl, C_{1- 6} Alkylsulfinyl, C_1-6Alkylsulfonyl, sulfamoyl, N- (C _1-6 Alkyl) sulfamoyl, N, N- (C_1-6Alkyl)_TwoSulfamoyl
And phenyl optionally substituted with one or more groups selected from benzyloxy
Yes; R^TwoIs H or C_1-6R is alkyl;^ThreeIs H or C_1-6R is alkyl;^FourIs H, C_1-6Alkyl (one or more hydroxy, C_1-6Alkylsulfanyl
, C_1-6Alkylsulfinyl, C_1-6Alkylsulfonyl, R⁹, R⁹C_1-6Al
Killsulfanyl, R⁹C_1-6Alkylsulfinyl and R⁹C_1-6Alkylsul
Optionally substituted with phonyl), or R^FourIs C_1-6Alkoxy (one or more C_{2- 6} Alkenyl, C_2-6Alkynyl, R⁹, R⁹C_2-6Alkenyl, R⁹C_2-6Alkini
, Het and methyl trifluoride) or R^FourIs C_2-6 Alkenyl, C_2-6Alkynyl, C_1-6Alkoxycarbonyl, carbamoyl, N
− (C_1-6Alkyl) carbamoyl, N, N- (C_1-6Alkyl)_TwoCarbamoyl
, R⁹-, R⁹S-, R⁹C_1-6Alkylsulfanyl, N- (R⁹C_1-6Alkyl)
Carbamoyl, N- (HetC_1-6Alkyl) carbamoyl, C_1-6Alkylam
No, C_1-6Alkylsulfanyl, C_1-6Alkylsulfinyl, C_1-6Alkyl
Sulfonyl, where R⁹May be substituted with phenyl or substituted
A 5- or 6-membered heteroaryl ring which may be
One or more C_1-6Alkyl, halo, methyl trifluoride, hydroxy, methoxy trifluoride
Shi, Cyano, C_1-6Alkoxy, C_1-6Alkanoyl, C_1-6Alkanoyloxy
, Amino, C_1-6Alkylamino, N, N- (C_1-6Alkyl)_TwoAmino, C_1-6A
Lucanoylamino, nitro, carboxy, carbamoyl, N- (C_1-6Alkyl
) Carbamoyl, N, N- (C_1-6Alkyl)_TwoCarbamoyl, C_1-6Alkoxy
Carbonyl, mercapto, C_1-6Alkylsulfanyl, C_1-6Alkylsulfi
Nil, C_1-6Alkylsulfonyl, sulfamoyl, N- (C_1-6Alkyl) sul
Famoyl and N, N- (C_1-6Alkyl)_TwoSelected from sulfamoyl;
Then R^FiveIs H or C_1-6Or a pharmaceutically acceptable salt thereof.

According to another aspect of the present invention, a compound of formula (I) wherein Ar is optionally substituted phenyl, optionally substituted naphthyl, or optionally substituted 5
Or a 6-membered heteroaryl ring, wherein the optional substituent one or more halo, C _1-6 alkoxy, C _1-6 alkyl, nitro, C _1-6 alkanoylamino, trifluoride methyl, hydroxy, trifluoroethylene Methoxy, cyano, C _1-6 alkanoyl, C _1-6 alkanoyloxy, amino, C _1-6 alkylamino, N, N- (C _1-6 alkyl) ₂
Amino, carboxy, carbamoyl, N- (C _1-6 alkyl) carbamoyl, N
, N-(C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkoxycarbonyl, mercapto, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, sulfamoyl, N-(C _{1 -6} alkyl) sulfamoyl, N,
N- (C _1-6 alkyl) ₂ sulfamoyl, amino C _1-6 alkyl, N- (C _1-6 alkyl) amino C _1-6 alkyl, N, N- (C _1-6 alkyl) ₂ amino C _{1 -6} ^{alkyl, R 6 S-, R 6 C} (O) -, and R ⁶ CH ₂ - is selected from, wherein R ⁶ is C _{1 -6} alkyl, halo, trifluoride methyl, hydroxy, trifluoride Methoxy, cyano,
C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, amino, C _{1 -6} alkylamino, N, N-(C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino, nitro Carboxy, carbamoyl, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkoxycarbonyl,
Mercapto, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6
X is phenyl optionally substituted with one or more groups selected from alkylsulfonyl, sulfamoyl, N- (C _1-6 alkyl) sulfamoyl and N, N- (C _1-6 alkyl) ₂ sulfamoyl; —N (R ⁷ ) —, —S (O) _n —, —O—, —SO ₂ N (R ⁷ ) —, where n = 0-2, R ⁷ is H, C _1-6 alkyl (Optionally substituted with one or more cyano, Het and R ¹⁰ ) or R ⁷ is C _2-6 alkenyl (optionally substituted with R ¹⁰ ), formyl, and R ¹⁰ is substituted. An optionally substituted 5- or 6-membered heteroaryl ring, optionally substituted phenyl, or optionally substituted naphthyl, wherein said optional substituents are one or more halo, nitro, methyl trifluoride, amino, C _1-6 alkylamino, N, N- (C _1-6 alkyl ) ₂ amino, C _1-6 alkyl, hydroxy, methoxy trifluoro, cyano, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, C _1-6 alkanoylamino, carboxy,
Carbamoyl, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkoxycarbonyl, mercapto, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, sulfamoyl, N- (C _1-6 alkyl) sulfamoyl, N, N- (C _1-6 alkyl) ₂
Selected from sulfamoyl and phenyl C _1-6 alkoxy; R ¹ is H, C _1-6 alkyl (optionally substituted with R ⁸ ), C _2-6 alkenyl,
R ⁸ S—, where R ⁸ is C _1-6 alkyl, halo, methyl trifluoride, hydroxy, methoxy trifluoro, cyano, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy , Amino, C _1-6 alkylamino, N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino, nitro, carboxy, carbamoyl, N- (
C _1-6 alkyl) carbamoyl, N, N-(C _{1-6 alkyl)} carbamoyl, C _{1 -6} alkoxycarbonyl, mercapto, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkyl Phenyl optionally substituted by one or more groups selected from sulfonyl, sulfamoyl, N- (C _1-6 alkyl) sulfamoyl, N, N- (C _1-6 alkyl) ₂ sulfamoyl and benzyloxy; R ² is H or C _1-6 alkyl; R ³ is H or C _1-6 alkyl; R ⁴ is H, C _1-6 alkyl (one or more hydroxy, C _1-6 alkylsulfanyl, C _{1 -6} alkylsulfinyl, C _1-6 alkylsulfonyl, R ⁹ , R ⁹ C _1-6 alkylsulfanyl, R ⁹ C _1-6 alkylsulfinyl and R ⁹ C _1-6 alkylsulfonyl Good), or R ⁴ is C _1-6 alkoxy (1 or more C _2-6 alkenyl, C _2-6 alkynyl, R ^9, R ⁹ C _2-6 alkenyl, R ⁹ C _2-6 alkynyl, Het and three R ⁴ may be C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxycarbonyl, carbamoyl, N
- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ ^{carbamoyl, R 9 -, R 9 S-} , R 9 C 1-6 alkylsulfanyl, N- (R ⁹ C _{1- 6} alkyl)
Carbamoyl, N-(HetC _1-6 alkyl) carbamoyl, C _1-6 alkanoylamino, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, a C _1-6 alkylsulfonyl, wherein R ⁹ is phenyl An optionally substituted or optionally substituted 5- or 6-membered heteroaryl ring, wherein said optional substituents are one or more of C _1-6 alkyl, halo, methyl trifluoride, hydroxy, trifluoro, of methoxy, cyano, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, amino, C _1-6 alkylamino, N, N- (C _1-6 alkyl) ₂ amino, C _{1 - 6} alkanoylamino, nitro, carboxy, carbamoyl, N-(C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkoxycarbonyl, mercapto, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, sulfamoyl, N-(C _1-6 alkyl)
Selected from sulfamoyl and N, N- (C _1-6 alkyl) ₂ sulfamoyl; and R ⁵ is H or C _1-6 alkyl) or a pharmaceutically acceptable salt thereof.

Ar, X, R¹, R^Two, R^Three, R^FourAnd R^FiveThe preferred meaning of is as follows
is there. Preferred Ar is phenyl which may be substituted, naph which may be substituted.
A tyl or an optionally substituted 5- or 6-membered heteroaryl ring,
The optional substituent is one or more halo, C_1-6Alkoxy, C_1-6Alkyl, nitro, C _1-6 Alkanoylamino, methyl trifluoride, N, N- (C_1-6Alkyl)_Twoamino
And N, N- (C_1-6Alkyl)_TwoAmino C_1-6Selected from alkyl.

In another embodiment of the present invention, preferred Ar is phenyl optionally substituted,
Optionally substituted naphthyl, morpholino or optionally substituted 5- or 6-membered heteroaryl ring, wherein said optional substituents are one or more halo, C _1-6 alkoxy, C _1-6 alkyl, nitro , C _1-6 alkanoylamino, methyl trifluoride, N, N- (C _1-6 alkyl) ₂ amino and N, N- (C _1-6 alkyl) ₂ amino C _1-6 alkyl, When Ar is morpholino, X is -N (
R ⁷ )-or -O-. 5-membered heteroaryl rings are, for example, thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, 1,2
, 3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl or isothiazolyl. The 5-membered ring is suitably thienyl.

More preferred Ar is optionally substituted phenyl, optionally substituted naphthyl and optionally substituted thienyl, wherein said optional substituents are one or more of fluoro, chloro, bromo, methoxy, It is selected from methyl, nitro, acetylamino, trifluoromethyl, N, N-dimethylamino or N, N-dimethylaminomethyl.

In another embodiment of the present invention, more preferred Ar is optionally substituted phenyl, optionally substituted naphthyl, morpholino and optionally substituted thienyl, wherein said optional substituent is 1 Selected from the above fluoro, chloro, bromo, methoxy, methyl, nitro, acetylamino, trifluoromethyl, N, N-dimethylamino or N, N-dimethylaminomethyl, provided that when Ar is morpholino, X is- N (R ⁷⁾ - or can not be -O-.

In particular, Ar is phenyl optionally substituted by 1-3 fluoro, chloro or bromo. In another embodiment of the present invention, in particular, Ar is morpholino or ~ 3 fluoro,
X is not phenyl optionally substituted with chloro or bromo, provided that when Ar is morpholino, X cannot be -N (R < ⁷ >)-or -O-.

More particularly, Ar is phenyl, 2-fluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 2,6-dichlorophenyl, 2,6-dibromophenyl and 2,4,6- Trichlorophenyl.

In another embodiment of the present invention, more particularly Ar is morpholino, phenyl, 2-
Fluorophenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2,4
- dichlorophenyl, 2,6-dichlorophenyl, is a 2,6-dibromophenyl and 2,4,6-trichlorophenyl, provided that when Ar is morpholino, X is -N (R ⁷⁾ - or -O- in There cannot be.

Preferred X is -N (R⁷)-, -S (O)_n-, -O- and -SO_TwoN (R⁷)
Where n = 0-2, R⁷Is H, C_1-6Alkyl (cyano, Het or
R^Ten) Or R⁷Is C_2-6Alkenyl (R^TenReplaced by
And R^TenIs an optionally substituted 5- or 6-membered hetero
An aryl ring or an optionally substituted phenyl, wherein the optional substituent is 1
The above halo, nitro, methyl trifluoride, N, N- (C_1-6Alkyl)_TwoAmino, C _1-6 Alkyl and C_1-6Selected from alkoxy. Het is as defined earlier
(Ie, Het is a fully saturated monocyclic ring containing up to 4 ring heteroatoms)
A 5- to 8-membered heterocyclic ring; for example, pyrrolidinyl, imidazolidinyl, pyrazolidin
Nil, piperidyl, piperazinyl or morpholinyl). X is -SO_TwoN (R⁷)
When-, the nitrogen atom is CR¹R^TwoThe sulfur to the Ar group.

[0029] More preferred X is -N (Me) -, - S -, - SO -, - SO 2 -, - O- and ^{_{-SO 2 N (R 7) -}} ( wherein R ⁷ is hydrogen, methyl, Ethyl, propyl, isobutyl, cyanoethyl, morpholinoethyl, furylethyl, thienylmethyl, pyridylmethyl, phenylallyl or benzyl), wherein said phenylallyl or benzyl is methoxy, nitro, chloro, methyltrifluoride, methyl or N , N-dimethylamino.

In particular, X is —O—, —SO ₂ —, and —SO ₂ N (R ⁷ ) —, where R ⁷ is hydrogen, furylmethyl, thienylmethyl, pyridylmethyl, phenylallyl or benzyl Wherein the benzyl may be substituted by methoxy, nitro, chloro, methyl trifluoride, methyl or N, N-dimethylamino.

[0031] More particularly X is -O -, - SO ₂ -, and -SO ₂ N (R ⁷⁾ - and is,
Where R ⁷ is hydrogen, flu-2-ylmethyl, thien-2-ylmethyl, pyrido-
2-ylmethyl, pyrid-3-ylmethyl, pyrid-4-ylmethyl, phenylallyl or benzyl, wherein said benzyl is substituted by methoxy, nitro, chloro, methyltrifluoride, methyl or N, N-dimethylamino May be.

In another embodiment of the present invention, X is —SO_TwoN (R⁷)-, Preferably R ⁷ Is not hydrogen. In another embodiment of the present invention, X is -SO_TwoN (R⁷)-, Preferably
R⁷Is benzyl which may be substituted, and the optional substituent is represented by R^TenFixed in
It is justified.

Preferred R ¹ are hydrogen, C _2-6 alkenyl and C _1-6 alkyl (optionally substituted with phenyl), wherein said phenyl is halo, cyano, C _1-6 alkoxy, nitro, It may be substituted with one or more groups selected from C _1-6 alkylsulfonyl and benzyloxy.

More preferred R ¹ is hydrogen, methyl, ethyl, propyl, isobutyl, 2-methylbut-2-ene and benzyl, wherein said phenyl is from fluoro, chloro, methoxy, benzyloxy, mesyl, nitro and cyano It may be substituted with one or more selected groups.

In particular, R ¹ is hydrogen and benzyl, in which case said phenyl may be substituted by methoxy, fluoro, chloro, benzyloxy, mesyl, nitro or cyano.

More particularly, R ¹ is hydrogen, benzyl, 2-fluorobenzyl, 3-methoxybenzyl, 3-chlorobenzyl, 3-nitrobenzyl, 4-mesylbenzyl and 4-cyanobenzyl.

In another embodiment of the present invention, preferred R ¹ is hydrogen. Preferably R ² is hydrogen. Preferably R ³ is hydrogen.

[0038] Preferably (may C _1-6 alkylsulfanyl, substituted by C _1-6 alkylsulfinyl and C _1-6 alkylsulfonyl) R ⁴ is hydrogen, C _1-6 alkyl
, C _1-6 alkoxy (optionally substituted by C _2-6 alkynyl), C _1-6 alkoxycarbonyl, carbamoyl, N- (C _1-6 alkyl) carbamoyl, N- (
HetC _1-6 alkyl) carbamoyl, C _1-6 alkylsulfanyl, R ⁹ -and N- (R ⁹ C _1-6 alkyl) carbamoyl (R ⁹ is phenyl or optionally substituted 5- or 6-membered heteroaryl And the optional substituents are selected from one or more C _1-6 alkyl and halo). Het is as defined above (ie, Het is a fully saturated monocyclic 5-8 membered heterocycle containing up to 4 ring heteroatoms; for example, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl or morpholinyl) ).

More preferred R ⁴ is hydrogen, methyl, methoxy, methoxycarbonyl, ethoxycarbonyl, methylthio, ethylthio, isopropylthio, methylthiomethyl,
Methylthioethyl, ethynyloxy, propynyloxy, carbamoyl, methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl,
Isobutylaminocarbonyl, furyl (optionally substituted with methyl), pyridyl, thienyl (optionally substituted with bromo or methyl), N-methylpyrrolyl, benzylaminocarbonyl, pyridylmethylaminocarbonyl and morpholinoethylaminocarbonyl is there.

In particular, R ⁴ is methoxy, isopropylthio, propynyloxy, furyl (optionally substituted with methyl) and thienyl. More particularly R ⁴ is methoxy, isopropylthio, propyn-1-yloxy, fur-2-yl, 5-Mechirufuru-2-yl and thien-2-yl.

In another embodiment of the present invention, preferred R ⁴ is an optionally substituted 5 or 6
Membered heteroaryl ring, wherein said optional substituents are selected from one or more C _1-6 alkyl and halo.

More preferred R ⁴ is optionally substituted thienyl or furyl, wherein said optional substituents are selected from one or more C _1-6 alkyl and halo. In particular, R ⁴ is thienyl.

More particularly, R ⁴ is thien-2-yl. Preferred R ⁵ is hydrogen or methyl. Further preferred R ⁵ is hydrogen.

According to another aspect of the present invention, there is provided a compound of formula (I) wherein Ar is substituted
Phenyl, optionally substituted naphthyl or optionally substituted 5
Or a 6-membered heteroaryl ring, wherein said optional substituent is one or more halo, C_{1- 6} Alkoxy, C_1-6Alkyl, nitro, C_1-6Alkanoylamino, trifluoride
Chill, N, N- (C_1-6Alkyl)_TwoAmino and N, N- (C_1-6Alkyl)_TwoA
Mino C_1-6X is -N (R⁷)-, -S (O)_n-, -O- or -SO_TwoN (R⁷)-(Here
And n = 0-2, R⁷Is H, C_1-6Alkyl (one or more cyano, Het and R^Tenso
Optionally substituted) or C_2-6Alkenyl (R^TenMay be replaced by
) And R^TenIs an optionally substituted 5- or 6-membered heteroaryl ring
Or optionally substituted phenyl, in which case the optional substituent is one or more
The above halo, nitro, methyl trifluoride, N, N- (C_1-6Alkyl)_TwoAmino, C_{1- 6} Alkyl or C_1-6Selected from alkoxy; R¹Is hydrogen, C_2-6C optionally substituted with alkenyl or phenyl_1-6A
And the phenyl is halo, cyano, C_1-6Alkoxy, nitro, C_1-6 Substituted with one or more groups selected from alkylsulfonyl, and benzyloxy
May be R^TwoIs hydrogen; R^ThreeIs hydrogen; R^FourIs hydrogen, C_1-6Alkyl (C_1-6Alkylsulfanyl, C_1-6Alkylsul
Finil and C_1-6Alkylsulfonyl), C_1-6Al
Koxy (C_2-6Alkynyl), C_1-6Alkoxycarboni
Carbamoyl, N- (C_1-6Alkyl) carbamoyl, N- (HetC_1-6A
Ruquil) carbamoyl, C_1-6Alkylsulfanyl, R⁹-Or N- (R⁹C_{1 -6} Alkyl) carbamoyl, where R⁹Is phenyl or substituted
Or a 5- or 6-membered heteroaryl ring, wherein the optional substituent is one or more C _1-6 Selected from alkyl or halo; and R^FiveIs hydrogen or methyl) or a pharmaceutically acceptable salt thereof.

Another preferred class of compounds is of the formula (I) wherein Ar is phenyl optionally substituted by 1-3 fluoro, chloro or bromo; X is -O-, -S (O ) ₂ — or —SO ₂ N (R ⁷ ) —, wherein R ⁷ is hydrogen, furylmethyl, thienylmethyl, pyridylmethyl, phenylallyl or benzyl, wherein said benzyl is methoxy, nitro, chloro, R ¹ may be hydrogen or benzyl, wherein said phenyl is methoxy, fluoro, chloro, benzyloxy, mesyl, nitro or cyano. It may be substituted; R ² is hydrogen; R ³ is hydrogen; R ⁴ is methoxy, isopropylthio, propynyloxy, furyl (main Le in be which may also be) and thienyl-substituted, and R ⁵ is a compound of a hydrogen), or a pharmaceutically-acceptable salt thereof.

Preferred compounds are the compounds of Examples 156-158 or pharmaceutically acceptable salts thereof. Particularly preferred compounds are described in Examples 5, 19, 20, 27, 31, 38, 42, 43.
, 45, 46, 50, 51, 91, 92, 93, 94, 97, 98, 100, 1
01, 102, 104, 106, 108, 109, 111, 112, 114, 1
15, 116, 117, 120, 122, 126, 141, 143 or 146
Or a pharmaceutically acceptable salt thereof.

Suitable pharmaceutically acceptable salts include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate and maleate and phosphoric and sulfuric acids Salts that form. In other embodiments, suitable salts include, for example, alkali metal salts such as sodium salts, for example, alkaline earth metal salts such as calcium or magnesium salts, for example, triethylamine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, Dibenzylamine, N, N-
An organic amine salt such as a salt with dibenzylethylamine, or a base salt such as an amino acid (salt?) Such as a lysine salt. There may be one or more cations or anions depending on the charged functionality and the valency of the cation or anion. A preferred pharmaceutically acceptable salt is the sodium salt.

Some compounds of formula (I) may have a chiral center. It is to be understood that the present invention covers all such optical isomers and diastereomers of the compounds of formula (I) that have cysteine protease inhibitory activity.

The present invention further relates to all tautomeric forms of the compounds of the formula (I). It is also to be understood that certain compounds of formula (I) can exist in unsolvated as well as solvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms.

Another aspect of the present invention provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof. According to the above aspect of the invention, there is provided a process comprising the following steps (unless otherwise stated, wherein the variables are as defined in formula (I)):
a) Acids of formula (II):

[0051]

Embedded image

Or a reactive derivative thereof and an amine of formula (III)

[0053]

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Reaction with: Suitable reactive derivatives of the acids of the formula (II) are, for example, acyl halides, for example acyl chlorides formed by reaction of the abovementioned acids with inorganic acids such as thionyl chloride; mixed anhydrides Anhydrides formed by the reaction of the above acids with chloroformic acids such as isobutyl chloroformate; active esters such as phenols such as the above acids and pentafluorophenol, pentafluorophenyl acid such as trifluoroacetic acid Esters, alcohols such as 1-hydroxybenzotriazole or 2-
Esters formed by reaction with uronium salts such as (1-benzotriazoyl) -1,1,3,3-tetramethyluronium hexafluorophosphate (V);
Acyl azides, for example, azides formed by the reaction of the above acids with an azide, such as diphenylphosphoryl azide; acyl cyanides, for example, cyanide formed by the reaction of an acid with a cyanide, such as diethylphosphoryl cyanide Or the product of the reaction of the acid with a carbodiimide such as N, N-dicyclohexylcarbodiimide or 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.

The reaction is preferably carried out with a suitable base, for example an alkali or alkaline earth metal carbonate, alkoxide or hydroxide, for example sodium or potassium carbonate, or pyridine, 2,6-lutidine, collidine, 4- Dimethylaminopyridine, tritylamine, morpholine or diazabicyclo- [5.4
. 0] in the presence of an organic amine base such as undec-7-ene. The reaction is also preferably carried out with a suitable inert solvent or diluent such as methylene chloride, acetonitrile, tetrahydrofuran, 1,2-dimethoxyethane, N, N-
It is carried out in dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide and at a temperature in the range, for example, -78 ° to 150 ° C, conveniently at or near ambient temperature.

B) compounds of the formula (IV)

[0057]

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And a compound of formula (V)

[0059]

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Wherein L is a substitutable group. Suitable displaceable groups L are, for example, halogeno or sulphonyloxy groups, for example chloro, bromo, methanesulphonyloxy or toluene-4-sulphonyloxy groups.

The above reaction is preferably carried out in the presence of a suitable base as defined herein, for example potassium carbonate. The reaction is preferably carried out in a suitable inert solvent or diluent such as N, N-dimethylformamide, as defined herein, and-
The reaction is performed at a temperature in the range of 0 to 100 ° C, preferably 25 to 100 ° C.

C) Compound of formula (VI) under standard conditions

[0063]

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Dehydration of For example, such a dehydration reaction may be conventionally performed by reaction with a reagent such as trifluoroacetic anhydride. The above reaction may conveniently be carried out in the presence of a suitable base as defined herein, for example triethylamine. The reaction is also preferably in a suitable inert solvent or diluent, such as dichloromethane, as defined herein, and at a temperature ranging, for example, from -10 ° C to reflux, conveniently from 10 ° C to reflux. Do.

D) for the compounds of formula (I) wherein X is —SO ₂ N (R ⁷ ) —; compounds of formula (VII)

[0066]

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And a compound of formula (VIII)

[0068]

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Reaction wherein L is a displaceable group; the above reaction is conveniently carried out in the presence of a base as defined herein, for example triethylamine. The reaction is also preferably carried out in a suitable inert solvent or diluent, such as tetrahydrofuran, as defined herein, and, for example, -2.
It is carried out at a temperature in the range of 0 ° C to 100 ° C, preferably 0 to 20 ° C.

E) for compounds of formula (I) wherein X is —SO ₂ N (R ⁷ ) —; compounds of formula (IX)

[0071]

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And a compound of formula (X)

[0073]

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Wherein L is a suitable displaceable group as defined above. The reaction is conveniently in the presence of a base as defined herein, for example potassium carbonate, in a suitable inert solvent or diluent as defined herein, for example acetonitrile, and at 25 ° C. to reflux The reaction is conveniently carried out at a temperature in the range from 50 to reflux.

If no commercial product is available, the starting materials required for the above defined method are standard organic chemistry techniques, as defined above, which are similar to the synthesis of known structurally similar compounds. It may be manufactured by a technique similar to the method or a technique similar to the method described in the examples.

For example, some of the optional substituents on the phenyl or naphthyl or heteroaryl ring in the compounds of the present invention may be introduced by standard aromatic substitution reactions, or may be prior to or immediately prior to the methods described above. It will be appreciated that they may be subsequently formed by conventional functional group modifications, and that such are included in the method embodiments of the present invention. Such reactions and modifications include, for example, introduction of substituents by aromatic substitution reactions, reduction of substituents, alkylation of substituents, and oxidation of substituents. Reagents and reaction conditions for such methods are well-known in the chemical arts. Specific examples of the aromatic substitution reaction include introduction of a nitro group using concentrated nitric acid, for example, acyl halide and L under Friedel Crafts conditions.
introduction of an acyl group using ewis acid (eg aluminum trichloride); F
Alkyl halides and Lewis under riedel Crafts conditions
Introduction of an alkyl group using an acid (for example, aluminum trichloride); and introduction of a halogeno group.

Specific examples of the modification include catalytic hydrogenation using, for example, a nickel catalyst, or reduction of a nitro group to an amino group by treatment with iron in the presence of hydrochloric acid while heating;
Oxidation of alkylthio to alkylsulfinyl or alkylsulfonyl.

It will be appreciated that in some of the reactions described herein, it may be necessary / desirable to protect any sensitive groups of the compound. The instances where protection is necessary or desirable and methods for protection are well known to those skilled in the art. Thus, when the reactants include a group such as amino, carboxy or hydroxy, it is desirable to protect that group in some of the reactions described herein.

Suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, for example alkanoyl groups such as acetyl, alkoxycarbonyl groups, for example methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, arylmethoxycarbonyl groups, For example, benzyloxycarbonyl, or an aroyl group, such as benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group, or an aroyl group may be removed by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or phosphoric acid or trifluoroacetic acid, and an arylmethoxy group such as a benzyloxycarbonyl group. The carbonyl group can be, for example, hydrogenated by a catalyst such as palladium carbon, or tris (
It may be removed by treatment with a Lewis acid such as (trifluoroacetic acid) boron.
Other suitable protecting groups for primary amino groups are, for example, alkylamines such as dimethylaminopropylamine, or phthaloyl groups which may be removed by treatment with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an alkanoyl group such as acetyl,
An aroyl group such as benzoyl; and an acetyl group such as an arylmethyl group such as benzyl. The deprotection conditions with the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation with a catalyst such as palladium on carbon.

A suitable protecting group for a carboxy group is, for example, a methyl or ethyl group, which may be removed by hydrolysis with a base, such as sodium hydroxide, or an acid such as an organic acid, such as trifluoroacetic acid. Or an ester-forming group such as a benzyl group which may be removed by hydrogenation over a catalyst such as, for example, palladium on carbon.

Protecting groups may be removed at any stage of the synthesis using conventional techniques well known in the chemical arts. Many of the intermediates defined herein are novel, for example, the intermediate of formula (VI) and the above intermediates provide another aspect of the present invention.

In another aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in a method of treatment of the human or animal body by therapy.

Pharmaceutical compositions for the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the therapeutic treatment of mammals, including humans, particularly in the inhibition of cysteine proteases, generally according to standard pharmaceutical practice. Formulated as

In another aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. In another aspect of the present invention, there is provided a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

In yet another aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in inhibiting cysteine proteases in a warm-blooded animal such as a human. Provide use.

[0087] In yet another aspect of the invention, a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease in a warm-blooded animal such as a human. Provides use of.

A method of treating a Cathepsin L or Cathepsin S mediated disease state comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. Administering an amount.

In another aspect of the present invention, there is provided a method for such inhibition in a warm-blooded animal, such as a human, in need of cysteine protease inhibition, the method comprising: Or administering an effective amount of a pharmaceutically acceptable salt thereof.

In particular, the present invention provides the use of a compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in inhibiting cathepsin S in a warm-blooded animal such as a human. I do.

For the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for therapeutic treatment of mammals, including humans, especially in cysteine protease inhibition, generally as a pharmaceutical composition according to standard pharmaceutical practice. Formulate.

For the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for therapeutic treatment of mammals, including humans, especially in cysteine protease inhibition, generally as a pharmaceutical composition according to standard pharmaceutical practice Formulate.

The pharmaceutical compositions of the present invention may be administered in a standard manner for disease states that one wishes to treat by, for example, oral, rectal, or parenteral administration. For these purposes, the compounds of the invention can be prepared by methods known in the art, for example, as tablets, capsules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders,
They may be formulated in the form of suppositories, ointments, creams, drops and sterile injectable aqueous or oleaginous solutions or suspensions.

Suitable pharmaceutical compositions of the invention are those suitable for oral administration in unit dosage form, such as tablets or capsules containing 100 mg to 1 g of a compound of the invention. In another embodiment, the pharmaceutical composition of the present invention is suitable for intravenous, subcutaneous or intramuscular injection.

Each patient may receive, for example, 1 mg / kg to 100 mg / kg of the compound,
Intravenous, subcutaneous or intramuscular injections may be given, preferably in the range of 5 mg / kg to 20 mg / kg, and the composition is administered 1 to 4 times a day.

Intravenous, subcutaneous or intramuscular injections may be given by bolus injection. Alternatively, it may be administered by continuous infusion over a period of time. Alternatively, each patient receives a daily oral dose, which is approximately equal to the parenteral daily dose, and the composition is administered once a day.
Will be administered ~ 4 times.

The following describes representative pharmaceutical dosage forms containing a compound of formula (I) or a pharmaceutically acceptable salt thereof (hereinafter compound X) for use in therapy or prevention in humans:

[0098]

[Table 1]

[0099]

[Table 2]

[0100]

[Table 3]

[0101]

[Table 4]

[0102]

[Table 5]

A buffer, a pharmaceutically acceptable co-solvent such as polyethylene glycol, polypropylene, glycol, glycerol or ethanol, or a complex such as hydroxy-propyl β-cyclodextrin may be used to aid formulation.

Note The above preparations may be obtained by conventional methods well known in the pharmaceutical art. Tablets (a) to (c)
) May be enteric-coated by a conventional method, for example, may be coated with cellulose acetate phthalate.

Inhibition of Cathepsins L and S The pharmaceutically acceptable compounds of the present invention have high activity in vitro against human cathepsin L, human cathepsin S and rabbit cathepsin L and are effective in inhibiting cathepsins L and S. .

Cathepsin L Assay Recombinant human cathepsin L was cloned, expressed in E. coli, and
ca Limited, GB2 306 961A (1997)
(Published May 14, 2008).

Rabbit cathepsin L was obtained by separating the liver homogenate supernatant from (NH ₄ ) ₂ SO ₄ (20-80).
% Saturation), except that it was concentrated by fractionation on Maciewicz R. A. and
Etherington D. J. (Biochem, J. (1988) 25)
6,433-440), purified from rabbit liver, the pellet was dissolved and 20 mM sodium acetate pH 5.5, 1 mM ethylenediaminetetraacetic acid (
(EDTA). The supernatant was applied to a CM Sepharose ion exchange column and eluted by gradient elution (0.25 to 0.75 M NaCl). The activity of the fractions was determined using the synthetic substrate NCBz-Phe-Arg-NHMe as described.
Measured using c. Cathepsin L fractions were pooled and Sephacryl S
Desalting was performed with 100 columns. The active fractions are pooled and 20% saturated (NH ₄ ) ₂ SO ₄
And concentrated with a phenyl sepharose column. The remaining purification steps were as described.

Cathepsin L activity was determined using the fluorogenic substrate NCBz-Phe-Arg-NHMec using the Barrett and Kirschke (1981) Methods.
in Enzymology, 80, 535-561). Inhibitors were identified by their ability to reduce the formation of a fluorescent leaving group (NHMec). Briefly, the assay is as follows: Recombinant human cathepsin L or rabbit cathepsin L ((0.0025 pm
oles) in a solid black 96-well plate in the presence or absence of test compound in 0.1 M sodium acetate buffer pH 4.5, 10 mM cysteine, 0.1% BRIJ® 35 , Preincubated at 25 ° C for 15 minutes. Synthetic substrate, 20 μM N
CBz-Phe-Arg-NHMec was added and the mixture was incubated at 37 C for 30 minutes. The reaction was stopped by the addition of 0.1 M sodium chloroacetate pH 4.3. Fluorescence was measured using a Fluoroskan II plate reader: excitation wavelength 355 nm, emission wavelength 460 nm. The potency of the compounds was determined by calculating the IC ₅₀ for each enzyme from the raw fluorescence data using commercially available PC package software for charts.

Cathepsin S Assay Cloning and Expression of Human Cathepsin S Recombinant human cathepsin S was cloned by the following method and expressed in baculovirus. The cDNA sequence for human cathepsin S is available under the EMBL database accession number M90696. This database sequence was obtained by PCR on mRNA from human tissue using the EMBL database (Accession number M90696).
) Was used to construct a recombinant plasmid carrying an insert having the same DNA sequence as that of cathepsin S. mRNA isolation, PCR and cloning techniques are standard methods well known in the art. Sequencing of the recombinant insert was performed by established DNA sequencing techniques.

PCR was performed and the EcoRI cloning site 5 ′ of 'ATG' of cathepsin S
And an Xbal cloning site 3 'of the' Stop 'codon was introduced. PCR
The product is a baculovirus transfer vector pFASTBAC-1 (Gibco
Bac-to-ba commercially available from BRL-Life Technologies
c (R) Expression System (catalog number 1035)
9-016)) Cloned between EcoRI and XbaI sites. The recombinant construct was used to generate a recombinant baculovirus capable of expressing preprocathepsin S by standard techniques.

Two insect cell lines, Sf9 cells (ATCC number CRL-1711) and T.
Expression of recombinant cathepsin S was tested on baculovirus constructs by infection of ni cells (Invitrogen, catalog number B855-02).

Method for Purifying Cathepsin S Procathepsin S was found in insect cell medium and was activated by acid. Maub
ach et al (Eur. J. Biochem., 250 , 745-750).
According to the method of J., 1997), the medium was made up of an equal volume of 100 mM sodium acetate buffer pH 4.5, 5 mM dithiothreitol (DTT) and 5 mM EDT.
A and mixed for 1 hour at 37 ° C.

Method 2. The pH of the insect cell medium (10 ml) containing procathepsin S was adjusted to 4.5 with glacial acetic acid, and DTT and EDTA were added to 5 mM. Then heat the sample to 37 ° C
For 150 minutes to convert to the active enzyme. 8 ammonium sulfate
0% saturation was added and the pellet was obtained by centrifugation. Put these pellets in 2
ml buffer A (100 mM Tris, 500 mM NaCl, 1 mM
DTA, pH 7.5), and dissolved in 100 μl Thiopropyl-Seph.
The mixture was mixed with arose by a batch method at 4 ° C. for 15 minutes. The unbound fraction was then removed by brief centrifugation and the gel was washed with 2 x 1 ml buffer A. A batch of cathepsin S mixed with 0.4 ml 20 mM DTT was then eluted in buffer A for 15 minutes at 4 ° C.

Measurement of Cathepsin S Activity Cathepsin S activity was determined according to Maubach et al (Eur. J. Biochee).
m. , 250 , 745-750, 1997).
The measurement was performed using Val-Val-Arg-NHMec. Inhibitors were identified by their ability to reduce the formation of a fluorescent leaving group (NHMec). Briefly, the assay is as follows: Recombinant human cathepsin S (1.5 nmoles) was added to solid black 9
In a 6-well plate, 50 mM potassium phosphate buffer pH 6.0-6.2, 20 mM Na ₂ EDTA, 0.1% in the presence or absence of compound
Pre-incubated in BRIJ® at 25 ° C. for 5 minutes. The synthetic substrate, 20 μM Z-Val-Val-Arg-NHMec, was added and the mixture was added to 30
Incubated at 20 ° C for 20 minutes. The reaction is 0.1M sodium chloroacetate
Stopped by the addition of H4.3. Fluorescence was measured using a Fluoroskan II plate reader: excitation wavelength 355 nm, emission wavelength 460 nm. Compound potency was determined by calculating the IC ₅₀ for cathepsin S from the raw fluorescence data using the PC software package for commercial charts.

The following results were obtained in a standard in-vitro test system for cathepsin L inhibition. Activity was described by IC _50. When tested in the above in-vitro test, the compounds of the present invention range from 1 to 10,000.
0nM was the IC ₅₀ in the range of.

The following data of Examples 5, 105 and 120 were obtained.

[0117]

[Table 6]

The invention is illustrated by, but not limited to, the following examples, unless otherwise specified: (i) Temperatures are given in degrees Celsius (° C); operation is at room or ambient temperature, ie, 18
(Ii) the organic solution was dried over anhydrous magnesium sulfate; the solvent was evaporated under reduced pressure (6
(400-4000 Pascals; 4.5-30 mmHg) using a rotary evaporator up to a bath temperature of 60 ° C .; (iii) chromatography means flash chromatography on silica gel; thin layer chromatography (TLC) ) Was performed on silica gel plates; (iv) generally, the course of the reaction followed TLC, and the reaction times are given for illustration only; (v) satisfactory proton nuclear magnetic resonance (NMR) spectra from the final product (Vi) yields are given for illustration only and are not obtained by diligent development of the method; preparations were repeated when more material was needed; (vii) when showing NMR data , Which, unless otherwise noted, are in the form of delta values of the major characteristic protons and tetramethyl Run (TMS) and in association indicated by ppm, as solvent using perdeuterated (perdeuterio) dimethyl sulfoxide (DMSO-δ ₆₎ was measured at 300 MHz; (viii) chemical symbols have their usual meanings Using (SI) units and symbols; (ix) solvent ratios are given as volume percentages; (x) mass spectrometry (MS) using direct loading probes, chemical ionization (CI).
Mode was performed at an electron energy of 70 electron volts; the ionizations indicated were performed by electron impact (EI) or by fast atom bombardment (FAB); when the value of m / z is indicated, generally parent mass ) Are reported only;
And (xi) melting points are uncorrected, (dec) indicates degradation; melting points shown are from materials prepared as defined; substances with different melting points in some formulations due to polymorphism May be isolated.

Example 1 2- [2- (2,3-Dichlorophenoxy) acetamido] -2- ( flu- 2- yl) acetonitrile oxalyl chloride (0.39 g) was prepared by adding 2,3 in dichloromethane (20 ml).
-Added to a suspension of dichlorophenoxyacetic acid (0.69 g). One drop of N, N-dimethylformamide was added and the mixture was stirred at ambient temperature for 14 hours. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (10ml). The above solution of acid chloride was added to a mixture of 2- (2-furyl) -aminoacetonitrile (0.5 g) and triethylamine (0.63 g) in dichloromethane (10 ml) and cooled in an ice bath. The reaction mixture was warmed to ambient temperature and the solvent was removed under reduced pressure. The residue was subjected to column chromatography eluting with dichloromethane to give 2- [2- (2
, 3-Dichlorophenoxy) acetamide] -2- (flu-2-yl) acetonitrile (title compound) (0.65 g). Melting point 112 ° C;

[0120]

Embedded image

Examples 2-19 The following analogs were prepared according to the method of Example 1 using the appropriate acid and substituted aminoacetonitrile:

[0122]

[Table 7]

[0123]

[Table 8]

Examples 21-59 The following analogs were prepared according to the procedure of Example 1 using the appropriate sulfur-containing acid and substituted aminoacetonitrile:

[0125]

[Table 9]

[0126]

[Table 10]

[0127]

[Table 11]

[0128]

[Table 12]

[0129]

[Table 13]

Examples 60-131 and 159-167 Examples 60-131 were prepared according to the procedure of Example 1 using the appropriate sulfonamide, including the acid and substituted aminoacetonitrile. Example 159-1
67 was prepared by applying the appropriate method disclosed herein.

[0131]

[Table 14]

[0132]

[Table 15]

[0133]

[Table 16]

[0134]

[Table 17]

[0135]

[Table 18]

[0136]

[Table 19]

[0137]

[Table 20]

[0138]

[Table 21]

[0139]

[Table 22]

Example 132 The following analog was prepared according to the method of Example 1 using the appropriate (substituted phenyl) -N-methylglycine and substituted aminoacetonitrile:

[0141]

[Table 23]

Examples 133-139 The following analogs were prepared according to the method of Example 1 using the appropriate starting materials:

[0143]

[Table 24]

Examples 140-144 The following analogs were prepared according to the method of Example 1 using the appropriate starting materials:

[0145]

[Table 25]

Example 145 2- [2- (2-Naphthylsulfonyl) acetamide] -acetonitrile 2- [2- (2-naphthylthio) acetamide] -acetonitrile (130 mg
), Methanol (2 ml), tetrahydrofuran (2 ml), oxone (500
mg) and water (1 ml) was stirred at room temperature for 24 hours. The mixture was diluted with water to make a volume of 20 ml, the precipitate was collected, dried and recrystallized from ethyl acetate,
2- [2- (2-naphthylsulfonyl) acetamide] -acetonitrile (130
mg). M / z 289 (MH ⁺ );

[0147]

Embedded image

[0148] Example 146 2- [2- (2,4,6-trichloro-phenoxy) acetamide] -2-methoxyethanol anhydrous acetonitrile trifluoroacetic acid (0.12 ml) of pyridine at -15 ° C. (3 ml) solution of 2-
[2- (2,4,6-Trichlorophenoxy) acetamide] was added dropwise to a stirred mixture of 2-methoxyacetamide (98 mg). The mixture is warmed to ambient temperature,
Thereafter, the mixture was poured into ice water and extracted with ether. Wash the organic phase with brine, dry,
Evaporate to dryness under reduced pressure to obtain 2- [2- (2,4,6-trichlorophenoxy) acetamide] -2-methoxyacetonitrile (70 mg). 123-124
° C; m / z 323 (MH ⁺ );

[0149]

Embedded image

Examples 147-150 The following analogs were prepared according to the method of Example 1 using the appropriate starting materials:

[0151]

[Table 26]

Example 151 2- [2- (2,4-Dichlorophenoxy) acetamide] -2-prop-2 -yloxyacetonitrile N-bromosuccinimide (42 mg) was added to propargyl alcohol (1.5 ml).
) Was added to a stirred solution of 2- [2- (2,4-dichlorophenoxy) acetamide] -2-isopropylthioacetonitrile (52 mg). The mixture was warmed to room temperature, evaporated to dryness under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic phase was purified by medium pressure liquid chromatography on silica using increasingly polar mixtures of ether and hexane as eluent to give 2- [2- (2,4-dichlorophenoxy) acetamide]-. 2-prop-2-yloxyacetonitrile (2
4 mg). 74-75 ° C; m / z 312 (M ⁺ );

[0153]

Embedded image

[0154] Example 152 N-(4-morpholino) ethyl-2-cyano-2- [2- (2,4-dichloro phenoxy) acetamide] acetamide methyl-2- (2,4-dichlorophenoxy) acetamide -2 -Cyanoacetic acid (
100 mg), acetonitrile (0.5 ml) and 4-aminoethylmorpholine were stirred at ambient temperature for 2 hours. The mixture is evaporated to dryness under reduced pressure and the residue is purified by medium pressure liquid chromatography on silica using increasingly polar mixtures of ethyl acetate and chloroform as eluent and triturated with ether / hexane. N- (4-morpholino) ethyl-2-cyano-2- [2- (2,4
-Dichlorophenoxy) acetamide] acetamide (70 mg) was obtained. M / z4
15 (MH ⁺ );

[0155]

Embedded image

[0156] Example 153 4-chlorophenyl-sulfinyl-acetyl-2 (2-furyl) - acetonitrile water (5ml) solution of meta Perio dating sodium (0.33 g) in methanol (
30 ml) was added to a solution of 4-chlorophenylthioacetyl-2 (2-furyl) -acetonitrile (0.4 g) and the mixture was stirred at ambient temperature for 14 hours. The reaction mixture was diluted with water (100ml), extracted with diethyl ether (3x50ml) and dried. The residue obtained by removing the solvent was chromatographed eluting with a mixture of ethyl acetate and dichloromethane (1:20 v / v) to give 0.18 g of 4-chlorophenylsulfinylacetyl-2 (2-furyl) -acetonitrile. Melting point 124 ° C .; calculated C ₁₄ H ₁₁ ClN ₂ O ₃ S is C, 52.1%;
4%; N, 8.7%. Found: C, 52.3%; H, 3.4%;
7%;

[0157]

Embedded image

[0158] Example 154 2-cyano-2- [2- (2,4-dichlorophenoxy) acetyl] Aminoa Setamido N, N- dimethylformamide (20ml) solution of 2,4-dichlorophenoxyacetic acid (1.12 g) , 2-amino-2-cyanoacetamide (0.5 g), 1- (
3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (1.06 g
) And hydroxybenzotriazole (0.75 g) at ambient temperature.
Stirred for hours. The solvent was removed under reduced pressure, the residue was diluted with water and ethyl acetate (2 × 7
5 ml). The ethyl acetate extract was washed with 2M hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and brine, and dried over magnesium sulfate. The solvent was removed to give a solid, which was washed with an acetone-diethyl ether mixture, air dried and dried.
-Cyano-2- [2- (2,4-dichlorophenoxy) acetyl] aminoacetamide was obtained in a yield of 1.1 g. Melting point 190-193 ° C; m / z 302 (MH ⁺ );

Example 155 2-Cyano-2- [2- (2,6-dichlorophenoxy) acetyl] aminoacetamide was also prepared according to the method of Example 154. 207-209 ° C.

Examples 156-158 The following analogs were prepared according to the method of Example 1 using the appropriate starting materials:

[0161]

[Table 27]

Examples 168-176 The following analogs were prepared according to the method of Example 1 using the appropriate starting materials:

[0163]

[Table 28]

Preparation of Starting Materials The starting materials in the above examples are either commercially available or are readily prepared from known materials by standard methods. For example, the following reactions (Methods AM) are illustrative and do not limit the preparation of some of the starting materials used in the above reactions.

Method A 2- (2-furyl) -aminoacetonitrile hydrochloride ammonium chloride (25 g) was added to a solution of 2-furfural aldehyde (25 g) in diethyl ether (250 ml). A solution of sodium cyanide (17 g) in water (80 ml) was added over 20 minutes. The reaction mixture was stirred at ambient temperature for 14 hours, the aqueous phase was removed and the organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution (2 × 100
ml), dried and evaporated to dryness. Residue is diethyl ether (250 ml)
And cooled to 0 ° C. While maintaining the temperature at 10 ° C. or lower, hydrogen chloride gas was rushed through the solution. 2- (2-furyl) -aminoacetonitrile hydrochloride (
The title compound was filtered and dried to obtain 33 g.

[0166]

Embedded image

Following the methods outlined in Method A1-4 Method A, using the appropriate aldehyde, the following compounds were prepared: A12- [2- (5-Methylfuryl)]-aminoacetonitrile hydrochloride; A22 -(3-furyl)]-aminoacetonitrile hydrochloride; A3 2- (2-thienyl)]-aminoacetonitrile hydrochloride; A4 2- [2- (4-bromothienyl)]-aminoacetonitrile hydrochloride.

Method B 2- (2-pyridyl) -aminoacetonitrile hydrobromide 2-pyridinecarboxaldehyde (25 g) was cooled (0 ° C.) in water (75 ml).
Was added to the solution of sodium cyanide (12.6 g) in 30 minutes. The mixture was stirred at 0 ° C. for 10 minutes and acetic acid (15.5 g) was added over 30 minutes. The mixture was stirred at ambient temperature for 14 hours, the 2-hydroxy-2- (2-pyridyl) -acetonitrile was filtered and dried. The solid cyanohydrin was cooled to 0 ° C. with ammonium chloride (60.9 g) and ammonia (31 ml) in water (170 ml).
) Was added to the solution and the mixture was stirred at ambient temperature for 14 hours. The solid is filtered and water (3
x 100 ml). The combined aqueous extracts were diluted with dichloromethane (7 × 100
ml). The dichloromethane extract was dried and the solvent was removed under reduced pressure.
The residue was suspended in diethyl ether (200ml) and HBr in acetic acid was added.
The solid 2- (2-pyridyl) -aminoacetonitrile hydrobromide was filtered, washed with diethyl ether (4 × 50 ml) and dried under vacuum to give 4.7 g.

The following compounds were prepared according to the method outlined in Method B1-2 Method B using the appropriate cyanohydrin; B1 2- (3-pyridyl) -aminoacetonitrile hydrochloride, mp 148 ° C .; B2 2- (4-pyridyl)]-aminoacetonitrile hydrochloride.

[0170] Method C penta-chlorophenoxy acetate pentachlorophenol (5 g), and stirred under reflux for 3 hours a mixture of acetone (80 ml), Mechiruburomo acetate (1.74 ml) and potassium carbonate (7.8 g), cooled, filtered The filtrate was evaporated to dryness under reduced pressure to obtain methyl-2- (pentachlorophenoxy) acetic acid (6.27 g). M / z 336 (M ⁺ ), the obtained compound was used without further purification.

Methyl-2- (pentachlorophenoxy) acetic acid (2 g), tetrahydrofuran (12 ml), methanol (10 ml) and 4M sodium hydroxide (4.6)
ml) of the mixture was stirred at ambient temperature for 3 hours. The solution was concentrated under reduced pressure to 5 ml,
Dilute with water and acidify with glacial acetic acid. The precipitate was collected, washed with water, and dried to obtain pentachlorophenoxyacetic acid (1.89 g). M / z 322 (M ⁺ )

[0172] Method D 2- [2- (2,4,6- trichlorophenoxy) acetamide] -2 methoxide Shiasetamido 2,4,6-trichlorophenol (7.5 g), acetone (150 ml),
A mixture of methyl bromoacetic acid (3.52 ml) and potassium carbonate (15.72 g) was stirred under reflux for 3 hours, cooled, and filtered. The filtrate was evaporated to dryness under reduced pressure to obtain methyl-2- (2,4,6-trichlorophenoxy) acetic acid (10.2 g). M
/ Z268 (M ⁺ ), and the obtained compound was used without further purification.

A mixture of methyl-2- (2,4,6-trichlorophenoxy) acetic acid (10.1 g), methanol (30 ml) and concentrated aqueous ammonia (50 ml) was stirred at ambient temperature for 16 hours. The insoluble solid was collected, washed with water, dried and evaporated to dryness under reduced pressure to give 2- (2,4,6-trichlorophenoxy) acetamide (8.52 g). M / z 254 (MH ^<+> ).

A mixture of glyoxylic acid monohydrate (1.5 g) and dichloroethane (50 ml) was stirred under reflux until the volume reached 25 ml. 2- (2,4,6-Trichlorophenoxy) acetamide (4.1 g) was added and the mixture was stirred under reflux for 5 hours, cooled, and the insoluble solid was collected to give 2- [2- (2,4,4). 6-Trichlorophenoxy) acetamide] -glycolic acid (2.98 g) was obtained. M / z 328 (MH ⁺ )
The obtained compound was used without further purification.

Thionyl chloride (4 ml) was added to a stirred solution of 2- [2- (2,4,6-trichlorophenoxy) acetamido] glycolic acid (500 mg) in 1: 1 dichloromethane: tetrahydrofuran (10 ml) and the mixture was added. Was stirred at ambient temperature under argon for 2.5 hours and evaporated to dryness under reduced pressure. Dissolve the residue in methanol,
The mixture was stirred at ambient temperature under argon for 0.3 hours and evaporated to dryness under reduced pressure. The residue was treated with concentrated aqueous ammonia (20 ml) and the mixture was stirred at ambient temperature for 18 hours. The insoluble solid was collected and purified by medium pressure liquid chromatography on silica using 2% methanol in dichloromethane as eluent to give 2- [2- (
2,4,6-trichlorophenoxy) acetamide] -2-methoxyacetamide (
100 mg). M / z 341 (MH ⁺ )

Following the procedure outlined in Method D1, using the appropriate starting materials, the following compounds were prepared: D1 2- [2- (2,4, -dichlorophenoxy) acetamide] -2-methoxya Cetamide. M / z 306 (MH ⁺ )

[0177] The method E 2- [2- (2,4,6- trichlorophenoxy) acetamide] -2-isopropoxy Ropi Lucio acetamide concentrated sulfuric acid (0.5ml), 2- [2- ( 2,4, 6-Trichlorophenoxy) acetamide] glycolic acid (1 g), glacial acetic acid (5 ml) and 2-propanethiol (1.13 ml) were added to a stirred ice-cooled mixture and the mixture was left at ambient temperature for 16 hours. The mixture was treated with water and extracted with ethyl acetate. The extract was washed with water and then with brine, dried, evaporated to dryness under reduced pressure to give 2- [2- (2,
4,6-trichlorophenoxy) acetamide] -2-isopropylthioacetic acid (1
. 29 g) were obtained and the obtained compound was used without further purification. M / z 386 (
MH ⁺ ) 2- [2- (2,4,6-trichlorophenoxy) acetamide] -2-isopropylthioacetic acid (1.14 g), methanol (7 ml) and concentrated sulfuric acid (0.2
ml) was stirred at ambient temperature for 4 hours. The mixture was basified with aqueous sodium bicarbonate, the resulting mixture was extracted with ethyl acetate, the extract was dried and evaporated to dryness under reduced pressure to give methyl-2- [2- (2,4,6- Trichlorophenoxy) acetamide-
2-isopropylthioacetic acid (1.29 g) was obtained, and the obtained compound was used without further purification. M / z 400 (MH ^<+> ) methyl-2- [2- (2,4,6-trichlorophenoxy) acetamide-2-
A mixture of isopropylthioacetic acid (0.99 g) and concentrated aqueous ammonia (20 ml) was stirred at ambient temperature for 18 hours. The insoluble solid was collected, washed with water, and 2- [2- (
2,4,6-Trichlorophenoxy) acetamide] -2-isopropylthioacetamide (0.79 g) was obtained, and the obtained compound was used without further purification. M /
z385 (MH ^<+> ).

Following the procedure outlined in Method E1 and using the appropriate starting materials, the following compounds were prepared: E1 2- [2- (2,4-Dichlorophenoxy) acetamide] -2-isopropylthioa Cetamide. M / z 351 (MH ⁺ )

[0179] Method F (2S) -2- [2- ( 2,4- dichlorophenoxy) acetamide] -4-main switch Lucio butyl amide 2,4-dichlorophenoxy acetyl chloride (1.2 g) 2-S- Methioninamide hydrochloride (0.91 g), N, N-dimethylformamide (10 ml)
And a stirred mixture of 4-methylmorpholine (0.8 ml) was added dropwise to the ice-cooled mixture and stirred at ambient temperature for 2 hours. Water was added and the mixture was extracted with chloroform. The extract was washed with water, 1M hydrochloric acid, then brine, dried and evaporated to dryness under reduced pressure. The residue was triturated with ether, the insoluble solid was collected and (2S) -2- [2-
(2,4-dichlorophenoxy) acetamide] -4-methylthiobutyramide (
1.25 g). M / z 351 (MH ^<+> ).

Method G Ethyl (3-chlorophenylthio) acetic acid A mixture of 3-chlorothiophenol (6.0 g) and potassium carbonate (7.45 g) in acetone (50 ml) was stirred at ambient temperature for 30 minutes, and ethyl bromoacetic acid was added. (6.06 ml) was added. The mixture was stirred for 14 hours and filtered. The filtrate was evaporated to dryness and the residue was chromatographed eluting with a mixture of dichloromethane and isohexane (1: 1 v / v) to give 9.22 g of ethyl (3-chlorophenylthio) acetic acid as an oil. M / z 231 (MH ^<+> ).

Method H Ethyl 3-chlorophenylsulfonylacetate Ethyl (3-chlorophenylthio) acetic acid (3 ml) in dichloromethane (75 ml)
. The solution of 5 g) was cooled to 0 ° C. in an ice bath and m-chloroperbenzoic acid (3.16 g) was added in several portions. The mixture was stirred for 30 minutes and ethyl bromoacetic acid (6.06
ml) was added. The mixture was stirred for 3 hours and further treated with m-chloroperbenzoic acid (3.
16g) was added all at once. The mixture was stirred for 2 hours and filtered. The filtrate was washed with 5% aqueous sodium thiosulfate solution (3 × 50 ml), saturated aqueous sodium hydrogen carbonate (3 × 50 ml)
(50 ml) and brine (50 ml) and dried. The oil obtained by removing the solvent was subjected to chromatography eluting with a mixture of dichloromethane and isohexane (1: 1 v / v) to obtain 2.92 g of ethyl 3-chlorophenylsulfonylacetic acid as an oil. M / z 280 (M + NH ₄ ) ⁺ .

Method I 3-Chlorophenylsulfonylacetic acid A mixture of ethyl 3-chlorophenylsulfonylacetic acid (2.9 g) in a mixture of methanol (20 ml) and tetrahydrofuran (30 ml) and an aqueous 2M sodium hydroxide solution (28 ml) was added at ambient temperature. Stir for 14 hours. The solvent was removed under reduced pressure, water (10 ml) was added to the residue and acidified to pH 1-2 with concentrated hydrochloric acid. 3-Chlorophenylsulfonylacetic acid was filtered and dried to obtain 2.5 g.

[0183] Method J Ethyl 2- (3-chlorobenzyl) -2- (2-chlorophenyl) sulfonyl acetic acid N, hydrogen to a solution of ethyl N- dimethylformamide (75 ml) 2-chlorophenyl sulfonyl acetate (1.50 g) Sodium chloride (0.25 g) was added and the mixture was stirred for 30 minutes. 3-Chlorobenzyl bromide (0.83 ml) was added and the mixture was stirred for 14 hours. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate (75ml), washed with 2M hydrochloric acid (3x25ml) and water (25ml) and dried. The oil obtained by removing the solvent was chromatographed eluting with a mixture of dichloromethane and isohexane (1: 1 v / v) to give ethyl 2-
(3-chlorobenzyl) -2- (2-chlorophenyl) sulfonylacetic acid, 1.7
4 g were obtained. M / z 387 (MH ^<+> ).

Method K N- (N-morpholinosulfonyl) -N (benzyl) glycine N- (N-morpholinosulfonyl) -N (benzyl) glycine methyl ester (Method L) (1.3 g) was added to ethanol (25 ml). Upon dissolution, aqueous 2M sodium hydroxide (9.9 ml) was added and the mixture was stirred at ambient temperature for 20 hours.
The reaction mixture was reduced to a small volume, diluted with water (25 ml), acidified with 2M HCl and extracted with dichloromethane (3 × 25 ml). The combined dichloromethane extracts were dried. The solvent was removed and the residue was triturated with isohexane to give the title compound, 0.1.
9 g were obtained. Melting point 168 [deg.] C.

[0185]

Embedded image

Method L N- (N-morpholinosulfonyl) -N (benzyl) glycine methyl ester N- (N-morpholinosulfonyl) glycine methyl ester (method M) in acetonitrile (10 ml) (1.4 g), benzyl bromide (1.06 g) and potassium carbonate (0.83 g) were stirred at ambient temperature for 24 hours. The reaction mixture is filtered, the filtrate is evaporated to dryness and the residue obtained is chromatographed eluting with a mixture of ethyl acetate and isohexane (1: 1 v / v) to give the title compound, 1
. 3 g were obtained.

[0187]

Embedded image

The following compounds were prepared according to the procedures of Methods K and L using the appropriate starting materials: N- (N-morpholinosulfonyl) -N- (3-trifluoromethylbenzyl)
Glycine N- (N-morpholinosulfonyl) -N- (3-nitrobenzyl) glycine

Method M N- (N-morpholinosulfonyl) glycine methyl ester Glycine methyl ester hydrochloride (9.2 g) was added to 1M dichloromethane (73 m
1M sulfuryl chloride solution in 1) was added and the mixture was cooled to -78 ° C. A solution of triethylamine (7.3 g) in dichloromethane (100 ml) was added dropwise over 1 hour. The mixture was stirred at -78 ° C for 1 hour and morpholine (6.
2 g) and triethylamine (7.3 g) were added and the mixture was warmed to ambient temperature. The reaction mixture was washed with water (3 × 100 ml), dried, the solvent was removed and the resulting residue was triturated with ether to give a solid which was filtered. The filtrate is evaporated to dryness,
4.3 g of the title compound were obtained.

[0190]

Embedded image

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/415 A61K 31/415 4C072 31/4164 31/4164 4C086 31/429 31/429 4C206 31/4402 31 / 4402 4H006 31/4406 31/4406 31/4409 31/4409 31/5377 31/5377 A61P 11/00 A61P 11/00 43/00 111 43/00 111 C07C 311/13 C07C 311/13 311/19 311 / 19 323/52 323/52 323/60 323/60 C07D 207/327 C07D 207/327 213/57 213/57 231/18 231/18 233/84 233/84 307/38 307/38 333/24 333 / 24 409/04 409/04 409/12 409/12 417/04 417/04 513/04 331 513/04 331 (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, B , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG) , ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH , CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE , SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, Z, VN, YU, ZA, ZW (72) Inventor Oldfield, John Cheshire Sk. 10.4 Tge, Maclesfield, Alder Ray Park (72) Inventor Johnston, Craig Cheshire Sk. 10, UK 4TG, McLesfield, Alder Ray Park (72) Inventors Edwards, Philip Nail Cheshire Sk.10, UK England, 4.4TG, MacLesfield, Alder Ray Park F-term (reference) 4C023 EA05 EA08 4C037 HA31 4C055 AA01 BA01 BA35 CA01 CA35 DA01 DA32. AA02 AA03 HA12 KA01 MA02 MA05 ZA59 4H006 AA01 AA03 AB20

Claims (14)

[Claims] 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:(Wherein, Ar is phenyl which may be substituted, naphthyl which may be substituted
, Het, C_3-12Cycloalkyl, or optionally substituted 5 or 6 members
A heteroaryl ring, wherein said optional substituents are one or more halo, C_1-6Alkoxy
, C_1-6Alkyl, nitro, C_1-6Alkanoylamino, methyl trifluoride, hydro
Xy, methoxy trifluoride, cyano, C_1-6Alkanoyl, C_1-6Alkanoyl oki
Si, amino, C_1-6Alkylamino, N, N- (C_1-6Alkyl)_TwoAmino, Cal
Boxy, carbamoyl, N- (C_1-6Alkyl) carbamoyl, N, N- (C_1-6 Alkyl)_TwoCarbamoyl, C_1-6Alkoxycarbonyl, mercapto, C_1-6A
Rukylsulfanyl, C_1-6Alkylsulfinyl, C_1-6Alkylsulfonyl,
Sulfamoyl, N- (C_1-6Alkyl) sulfamoyl, N, N- (C_1-6Al
kill)_TwoSulfamoyl, amino C_1-6Alkyl, N- (C_1-6Alkyl) amino
C_1-6Alkyl, N, N- (C_1-6Alkyl)_TwoAmino C_1-6Alkyl, R⁶S-,
R⁶C (O)-, and R⁶CH_Two-Selected from; R⁶Is C_1-6Alkyl, halo,
Methyl trifluoride, hydroxy, methoxy trifluoride, cyano, C_1-6Alkoxy,
C_1-6Alkanoyl, C_1-6Alkanoyloxy, amino, C_1-6Alkylamino
, N, N- (C_1-6Alkyl)_TwoAmino, C_1-6Alkanoylamino, nitro, mosquito
Ruboxy, carbamoyl, N- (C_1-6Alkyl) carbamoyl, N, N- (C_{1 -6} Alkyl)_TwoCarbamoyl, C_1-6Alkoxycarbonyl, mercapto, C_1-6
Alkylsulfanyl, C_1-6Alkylsulfinyl, C_1-6Alkylsulfonyl
, Sulfamoyl, N- (C_1-6Alkyl) sulfamoyl and N, N- (C_{1 -6} Alkyl)_TwoMay be substituted with one or more groups selected from sulfamoyl.
Where Ar is Het linked to the nitrogen, X is -N (R ⁷ )-Or -O-; X is -N (R⁷)-, -S (O)_n-, -O- or
Is -SO_TwoN (R⁷N is 0, 1 or 2; R⁷Is H, C_1-6Al
Kill (one or more cyano, Het and R^Ten), C_2-6A
Lucenyl (R^TenOr formyl; R^TenIs replaced
Optionally substituted 5- or 6-membered heteroaryl ring, optionally substituted phenyl
Or optionally substituted naphthyl, wherein the optional substituent is one or more
Halo, nitro, methyl trifluoride, amino, C_1-6Alkylamino, N, N- (C_{1 -6} Alkyl)_TwoAmino, C_1-6Alkyl, hydroxy, methoxy trifluoro, cyano
, C_1-6Alkoxy, C_1-6Alkanoyl, C_1-6Alkanoyloxy, C_1-6Al
Canoylamino, carboxy, carbamoyl, N- (C_1-6Alkyl) carbamo
Il, N, N- (C_1-6Alkyl)_TwoCarbamoyl, C_1-6Alkoxycarbonyl
, Mercapto, C_1-6Alkylsulfanyl, C_1-6Alkylsulfinyl, C_{1- 6} Alkylsulfonyl, sulfamoyl, N- (C_1-6Alkyl) sulfamoyl
, N, N- (C_1-6Alkyl)_TwoSulfamoyl and phenyl C_1-6Alkoxy
Selected from; R¹Is H, C_1-6Alkyl (R⁸), C_1-6 Alkylsulfanyl (R⁸), C_2-6Alkenyl, R⁸
Or R⁸S-; R⁸Is phenyl, C_3-12Cycloalkyl, Het or 5
Or 6-membered heteroaryl rings, all of which are C_1-6Alkyl, halo
, Methyl trifluoride, hydroxy, methoxy trifluoride, cyano, C_1-6Alkoxy
, C_1-6Alkanoyl, C_1-6Alkanoyloxy, amino, C_1-6Alkylam
No, N, N- (C_1-6Alkyl)_TwoAmino, C_1-6Alkanoylamino, nitro,
Carboxy, carbamoyl, N- (C_1-6Alkyl) carbamoyl, N, N- (
C_1-6Alkyl)_TwoCarbamoyl, C_1-6Alkoxycarbonyl, mercapto, C_{1 -6} Alkylsulfanyl, C_1-6Alkylsulfinyl, C_1-6Alkylsulfoni
Le, sulfamoyl, N- (C_1-6Alkyl) sulfamoyl, N, N- (C_1-6 Alkyl)_TwoOne or more groups selected from sulfamoyl and benzyloxy
May be substituted, provided that if R₁Is C_1-6Alkylsulfanyl (R⁸so
Optionally substituted) or R⁸In the case of S-, X is -SO_TwoN (R⁷)-
R^TwoIs H or C_1-6Alkyl; R^ThreeIs H or C_1-6Alkyl; R ^Four Is H, C_1-6Alkyl (one or more hydroxy, C_1-6Alkylsulfanyl, C_{1 -6} Alkylsulfinyl, C_1-6Alkylsulfonyl, R⁹, R⁹C_1-6Alkyls
Rufanil, R⁹C_1-6Alkylsulfinyl and R⁹C_1-6Alkylsulfonyl
), C_1-6Alkoxy (one or more C_2-6Alkenyl, C_{2- 6} Alkynyl, R⁹, R⁹C_2-6Alkenyl, R⁹C_2-6Alkynyl, Het and three
May be substituted with methyl fluoride), C_2-6Alkenyl, C_2-6Alkynyl,
C_1-6Alkoxycarbonyl, carbamoyl, N- (C_1-6Alkyl) carbamoy
Le, N, N- (C_1-6Alkyl)_TwoCarbamoyl, R⁹-, R⁹S-, R⁹C_1-6Al
Killsulfanyl, N- (R⁹C_1-6Alkyl) carbamoyl, N- (HetC_{1- 6} Alkyl) carbamoyl, C_1-6Alkanoylamino, C_1-6Alkyl sulfa
Nil, C_1-6Alkylsulfinyl or C_1-6Alkylsulfonyl; R⁹
Is an optionally substituted phenyl, or an optionally substituted 5- or 6-membered
A heteroaryl ring wherein said optional substituents are one or more C_1-6Alkyl, halo,
Methyl trifluoride, hydroxy, methoxy trifluoride, cyano, C_1-6Alkoxy,
C_1-6Alkanoyl, C_1-6Alkanoyloxy, amino, C_1-6Alkylamino
, N, N- (C_1-6Alkyl)_TwoAmino, C_1-6Alkanoylamino, nitro, mosquito
Ruboxy, carbamoyl, N- (C_1-6Alkyl) carbamoyl, N, N- (C_{1 -6} Alkyl)_TwoCarbamoyl, C_1-6Alkoxycarbonyl, mercapto, C_1-6
Alkylsulfanyl, C_1-6Alkylsulfinyl, C_1-6Alkylsulfonyl
, Sulfamoyl, N- (C_1-6Alkyl) sulfamoyl and N, N- (C_{1 -6} Alkyl)_TwoR selected from sulfamoyl; R^FiveIs H or C_1-6Alkyl
Het is a fully saturated monocyclic 5-8 membered heterocycle containing up to 4 ring heteroatoms
Where: R¹Is H or C_1-6X is O or S;
And R^TwoAnd R^ThreeWhen both are hydrogen, Ar is not pyrimid-4-yl
K; R¹And R^TwoAre both hydrogen and R^ThreeIs C_1-6Alkyl, X is O, R^FourBut water
Elementary, C_1-6Alkyl, phenyl or benzyl, and R^FiveIs H or C_{1- Four} Ar is not halophenyl when it is alkyl;¹And R^ThreeBut both are water
Prime and R^TwoAnd R^FiveIs independently hydrogen or methyl;^FourIs replaced
When pyrrolyl, thienyl, or furyl is not present and X is O,
r is not 3-methyl-2,4-dichlorophenyl; R¹Is hydrogen or C_1-4A
It is R^TwoIs hydrogen or C_1-4Alkyl, R^ThreeIs hydrogen and R^FourBut
Hydrogen, C_1-6Alkyl or phenyl and X is O, S, NH or N
(C_1-4Alkyl), Ar is halo, C_1-4Alkyl, CF_Three, C_1-4Al
Coxy, CO_TwoH, CO_Two(C_1-4Alkyl), CONH_Two, NO_Two, CN, CH_TwoN
(CH_Three)_Two, S (C_1-4Alkyl) or mono- or di-chlorobenzyl
Not an optionally substituted phenyl; R¹, R^Two, R^ThreeAnd R^FiveIs all hydrogen
And R^FourIs SO_TwoCH_TwoCH_ThreeAnd X is SO_TwoWhen Ar is
Not phenyl; and R¹, R^Two, R^Three, R^FourAnd R^FiveAre all hydrogen,
And X is SO_TwoAr is not 4-methylphenyl when it is NH). 2. The compound according to claim 1, wherein Ar is optionally substituted phenyl, optionally substituted naphthyl, morpholino or optionally substituted 5-membered heteroaryl ring. Wherein the optional substituent is one or more halo, C _1-6 alkoxy, C _1-6 alkyl, nitro, C _1-6 alkanoylamino, methyl trifluoride, N, N- (C _1-6 alkyl ) Selected from ₂ amino and N, N- (C _1-6 alkyl) ₂ amino C _1-6 alkyl, provided that when Ar is morpholino,
X is -N (R ⁷⁾ - or the compound can not be -O-. 3. The compound according to claim 1 or 2, wherein X is —N
(R ⁷ ) —, —S (O) _n —, —O— or —SO ₂ N (R ⁷ ) —;
= Be 0 to 2; R ⁷ is H, C _1-6 alkyl optionally or R ⁷ (cyano, Het or R ¹⁰ have may be substituted with) is substituted by a C _2-6 alkenyl (R ¹⁰ Good)
R ¹⁰ is an optionally substituted 5 or 6 membered heteroaryl ring or an optionally substituted phenyl, wherein said optional substituents are one or more halo, nitro, methyl trifluoride, N, Het is selected from N- (C _1-6 alkyl) ₂ amino, C _1-6 alkyl and C _1-6 alkoxy; Het is a fully saturated monocyclic 5-8 membered heterocycle having up to 4 ring heteroatoms Compounds that are rings. 4. The compound according to claim 1, 2 or 3, wherein R ¹
Is hydrogen, C _2-6 alkenyl or C _1-6 alkyl (optionally substituted with phenyl), wherein said phenyl is halo, cyano, C _1-6 alkoxy, nitro, C _1-6 alkylsulfonyl And a compound optionally substituted with one or more groups selected from benzyloxy. 5. The compound according to claim 1, wherein R ² and R ³ are both hydrogen. 6. The compound according to claim 1, 2, 3, 4 or 5, wherein R ⁵ is hydrogen or methyl. 7. A compound according to any one of the preceding claims, wherein
R ⁴ is hydrogen, C _1-6 alkyl (C _1-6 alkylsulfanyl, optionally substituted by C _1-6 alkylsulfinyl and C _1-6 alkylsulfonyl), C _1-6 alkoxy (C _2-6 Alkynyl), C _1-6 alkoxycarbonyl, carbamoyl, N- (C _1-6 alkyl) carbamoyl, N- (HetC _1-6 alkyl) carbamoyl, C _1-6 alkylsulfanyl, R ⁹ Or N- (R ⁹ C _1-6 alkyl) carbamoyl; R ⁹ is phenyl or an optionally substituted 5- or 6-membered heteroaryl ring, wherein said optional substituent is one or more C _{1 -6} is selected from alkyl and halo; and Het is a monocyclic 5-8 membered heterocycle is fully saturated containing a ring hetero atom up to 4 compounds. 8. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable diluent or carrier. 9. A compound of formula (I) or a medicament thereof for use as a medicament
Pharmaceutically acceptable salts:(Wherein, Ar is phenyl which may be substituted, naphthyl which may be substituted
, Het, C_3-12Cycloalkyl, or optionally substituted 5 or 6 members
A heteroaryl ring, wherein said optional substituents are one or more halo, C_1-6Alkoxy
, C_1-6Alkyl, nitro, C_1-6Alkanoylamino, methyl trifluoride, hydro
Xy, methoxy trifluoride, cyano, C_1-6Alkanoyl, C_1-6Alkanoyl oki
Si, amino, C_1-6Alkylamino, N, N- (C_1-6Alkyl)_TwoAmino, Cal
Boxy, carbamoyl, N- (C_1-6Alkyl) carbamoyl, N, N- (C_1-6 Alkyl)_TwoCarbamoyl, C_1-6Alkoxycarbonyl, mercapto, C_1-6A
Rukylsulfanyl, C_1-6Alkylsulfinyl, C_1-6Alkylsulfonyl,
Sulfamoyl, N- (C_1-6Alkyl) sulfamoyl, N, N- (C_1-6Al
kill)_TwoSulfamoyl, amino C_1-6Alkyl, N- (C_1-6Alkyl) amino
C_1-6Alkyl, N, N- (C_1-6Alkyl)_TwoAmino C_1-6Alkyl, R⁶S-,
R⁶C (O)-, and R⁶CH_Two-Selected from; R⁶Is C_1-6Alkyl, halo,
Methyl trifluoride, hydroxy, methoxy trifluoride, cyano, C_1-6Alkoxy,
C_1-6Alkanoyl, C_1-6Alkanoyloxy, amino, C_1-6Alkylamino
, N, N- (C_1-6Alkyl)_TwoAmino, C_1-6Alkanoylamino, nitro, mosquito
Ruboxy, carbamoyl, N- (C_1-6Alkyl) carbamoyl, N, N- (C_{1 -6} Alkyl)_TwoCarbamoyl, C_1-6Alkoxycarbonyl, mercapto, C_1-6
Alkylsulfanyl, C_1-6Alkylsulfinyl, C_1-6Alkylsulfonyl
, Sulfamoyl, N- (C_1-6Alkyl) sulfamoyl and N, N- (C_{1 -6} Alkyl)_TwoMay be substituted with one or more groups selected from sulfamoyl.
Where Ar is Het linked to the nitrogen, X is -N (R ⁷ )-Or -O-; X is -N (R⁷)-, -S (O)_n-, -O- or
Is -SO_TwoN (R⁷N is 0, 1 or 2; R⁷Is H, C_1-6Al
Kill (one or more cyano, Het and R^Ten), C_2-6A
Lucenyl (R^TenOr formyl; R^TenIs replaced
Optionally substituted 5- or 6-membered heteroaryl ring, optionally substituted phenyl
Or optionally substituted naphthyl, wherein the optional substituents are one or more
B, nitro, methyl trifluoride, amino, C_1-6Alkylamino, N, N- (C_1-6 Alkyl)_TwoAmino, C_1-6Alkyl, hydroxy, methoxy trifluoride, cyano,
C_1-6Alkoxy, C_1-6Alkanoyl, C_1-6Alkanoyloxy, C_1-6Arca
Noylamino, carboxy, carbamoyl, N- (C_1-6Alkyl) carbamoy
Le, N, N- (C_1-6Alkyl)_TwoCarbamoyl, C_1-6Alkoxycarbonyl,
Mercapto, C_1-6Alkylsulfanyl, C_1-6Alkylsulfinyl, C_1-6
Alkylsulfonyl, sulfamoyl, N- (C_1-6Alkyl) sulfamoyl
, N, N- (C_1-6Alkyl)_TwoSulfamoyl and phenyl C_1-6Alkoxy
Selected from; R¹Is H, C_1-6Alkyl (R⁸), C_1-6 Alkylsulfanyl (R⁸), C_2-6Alkenyl, R⁸
Or R⁸S-; R⁸Is phenyl, C_3-12Cycloalkyl, Het or 5
Or 6-membered heteroaryl rings, all of which are C_1-6Alkyl, halo
, Methyl trifluoride, hydroxy, methoxy trifluoride, cyano, C_1-6Alkoxy
, C_1-6Alkanoyl, C_1-6Alkanoyloxy, amino, C_1-6Alkylam
No, N, N- (C_1-6Alkyl)_TwoAmino, C_1-6Alkanoylamino, nitro,
Carboxy, carbamoyl, N- (C_1-6Alkyl) carbamoyl, N, N- (
C_1-6Alkyl)_TwoCarbamoyl, C_1-6Alkoxycarbonyl, mercapto, C_{1 -6} Alkylsulfanyl, C_1-6Alkylsulfinyl, C_1-6Alkylsulfoni
Le, sulfamoyl, N- (C_1-6Alkyl) sulfamoyl, N, N- (C_1-6 Alkyl)_TwoSubstituted with one or more groups selected from sulfamoyl and benzyloxy.
May be replaced, provided that R¹Is C_1-6Alkylsulfanyl (R⁸so
Optionally substituted) or R⁸In the case of S-, X is -SO_TwoN (R⁷)-
R^TwoIs H or C_1-6Alkyl; R^ThreeIs H or C_1-6Alkyl; R ^Four Is H, C_1-6Alkyl (one or more hydroxy, C_1-6Alkylsulfanyl, C_{1 -6} Alkylsulfinyl, C_1-6Alkylsulfonyl, R⁹, R⁹C_1-6Alkyls
Rufanil, R⁹C_1-6Alkylsulfinyl and R⁹C_1-6Alkylsulfonyl
), C_1-6Alkoxy (one or more C_2-6Alkenyl, C_{2- 6} Alkynyl, R⁹, R⁹C_2-6Alkenyl, R⁹C_2-6Alkynyl, Het and three
May be substituted with methyl fluoride), C_2-6Alkenyl, C_2-6Alkynyl,
C_1-6Alkoxycarbonyl, carbamoyl, N- (C_1-6Alkyl) carbamoy
Le, N, N- (C_1-6Alkyl)_TwoCarbamoyl, R⁹-, R⁹S-, R⁹C_1-6Al
Killsulfanyl, N- (R⁹C_1-6Alkyl) carbamoyl, N- (HetC_{1- 6} Alkyl) carbamoyl, C_1-6Alkanoylamino, C_1-6Alkyl sulfa
Nil, C_1-6Alkylsulfinyl or C_1-6Alkylsulfonyl; R⁹
Is an optionally substituted phenyl, or an optionally substituted 5- or 6-membered
A heteroaryl ring wherein said optional substituents are one or more C_1-6Alkyl, halo,
Methyl trifluoride, hydroxy, methoxy trifluoride, cyano, C_1-6Alkoxy,
C_1-6Alkanoyl, C_1-6Alkanoyloxy, amino, C_1-6Alkylamino
, N, N- (C_1-6Alkyl)_TwoAmino, C_1-6Alkanoylamino, nitro, mosquito
Ruboxy, carbamoyl, N- (C_1-6Alkyl) carbamoyl, N, N- (C_{1 -6} Alkyl)_TwoCarbamoyl, C_1-6Alkoxycarbonyl, mercapto, C_1-6
Alkylsulfanyl, C_1-6Alkylsulfinyl, C_1-6Alkylsulfonyl
, Sulfamoyl, N- (C_1-6Alkyl) sulfamoyl and N, N- (C_{1 -6} Alkyl)_TwoR selected from sulfamoyl; R^FiveIs H or C_1-6Alkyl
Het is a fully saturated monocyclic 5-8 membered heterocycle containing up to 4 ring heteroatoms
Where: R¹, R^Two, R^Three, R^FourAnd R^FiveAre all hydrogen and X
Is NH, Ar is CO_TwoNot phenyl monosubstituted with H; and R^Two , R^Three, R^FourAnd R^FiveAre all hydrogen and R¹Is methyl and X is NH
When Ar is 4- (CO_TwoH) not -phenyl). 10. Use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in inhibiting cysteine proteases in warm-blooded animals: (In the formula, Ar is an optionally substituted phenyl, an optionally substituted naphthyl, Het, C _3-12 cycloalkyl, or an optionally substituted 5- or 6-membered heteroaryl ring, The substituent is one or more halo, C _1-6 alkoxy,
C _1-6 alkyl, nitro, C _1-6 alkanoylamino, methyl trifluoride, hydroxy, methoxy trifluoride, cyano, C _1-6 alkanoyl, C _1-6 alkanoyloxy, amino, C _1-6 alkylamino N, N- (C _1-6 alkyl) ₂ amino, carboxy, carbamoyl, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkoxycarbonyl , mercapto, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, sulfamoyl, N-(C _1-6 alkyl) sulphamoyl, N, N- (C _1-6 alkyl) ₂ sulphamoyl , amino C _1-6 alkyl, N-(C _1-6 alkyl) amino C _{1 -6} alkyl, N, N-(C _1-6 alkyl) ₂ amino C _1-6 alkyl, R ⁶ S-, R ⁶
C (O) -, and R ⁶ CH ₂ - is selected from; R ⁶ is C _1-6 alkyl, halo, trifluoride methyl, hydroxy, trifluoride methoxy, cyano, C _1-6 alkoxy, C _{1- 6} alkanoyl, C _1-6 alkanoyloxy, amino, C _1-6 alkylamino, N,
N- (C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino, nitro, carboxy, carbamoyl, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl C _1-6 alkoxycarbonyl, mercapto, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, sulfamoyl, N-(C _1-6 alkyl) sulphamoyl and N, N- (C _{1 -6} alkyl) be one or more phenyl which may be substituted with a group selected from ₂ sulphamoyl; provided that when Het which Ar is linked to the nitrogen, X is -N (R ⁷⁾ -
Or the -O- rather; X is ^{-N (R 7) -, -} S (O) n -, - O- or -S
O ₂ N (R ⁷ ) —; n is 0, 1 or 2; R ⁷ is H, C _1-6 alkyl (
1 or more cyano, optionally substituted with Het and R ^10), C _2-6 alkenyl (optionally substituted with R ¹⁰ be also be) or formyl; R ¹⁰ is 5 or may be substituted A 6-membered heteroaryl ring, optionally substituted phenyl, or optionally substituted naphthyl, wherein said optional substituents are one or more halo, nitro, methyl trifluoride, amino, C _1-6 alkylamino , N, N- (C _1-6 alkyl) ₂ amino, C _1-6 alkyl, hydroxy, methoxy trifluoride, cyano, C _1-6
Alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, C _1-6 alkanoylamino, carboxy, carbamoyl, N- (C _1-6 alkyl) carbamoyl,
N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkoxycarbonyl, mercapto, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, sulfamoyl, N-(C _1-6 alkyl) sulfamoyl, N
, N- (C _1-6 alkyl) ₂ sulfamoyl and phenyl C _1-6 alkoxy; R ¹ is H, C _1-6 alkyl (optionally substituted with R ⁸ ), C _1-6 alkyl Sulfanyl (optionally substituted with R ⁸ ), C _2-6 alkenyl, R ⁸ or R ⁸ S—; R ⁸ is phenyl, C _3-12 cycloalkyl, Het or 5 or 6
Membered heteroaryl rings, all of which are C _1-6 alkyl, halo, methyl trifluoride, hydroxy, methoxy trifluoro, cyano, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyl Oxy, amino, C _1-6 alkylamino, N, N-
(C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino, nitro, carboxy,
Carbamoyl, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkoxycarbonyl, mercapto, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, sulfamoyl, N- (C _1-6 alkyl) sulfamoyl, N, N- (C _1-6 alkyl) ₂
May be substituted with one or more groups selected from sulphamoyl and benzyloxy, with the proviso that if R ¹ is (optionally substituted with R ⁸⁾ C _1-6 alkylsulfanyl or R ⁸ S- of Wherein X is —SO ₂ N (R ⁷ ) —; R ² is H or C _1-6 alkyl; R ³ is H or C _1-6 alkyl; R ⁴ is H, C _{1- 6} alkyl (1 or more hydroxy, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, C _1-6 alkylsulfonyl, R ^9, R ⁹ C _1-6 alkylsulfanyl, R ⁹ C _1-6 alkylsulfinyl and R ⁹ C _1-6 alkylsulfonyl optionally substituted), C _1-6 alkoxy (one or more C _2-6 alkenyl, C _2-6 alkynyl, R ⁹ , R ⁹ C _2-6 alkenyl, R ⁹ C _2-6 alkynyl, substituted with Het and trifluoride methyl There may be), C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkoxycarbonyl, carbamoyl, N-(C _1-6 alkyl) carbamoyl, N
, N- (C _1-6 alkyl) ₂ ^{carbamoyl, R 9 -, R 9 S-} , R 9 C 1-6 alkylsulfanyl, N- (R ⁹ C _1-6 alkyl) carbamoyl, N- (HetC _{1- 6} alkyl) carbamoyl, C _1-6 alkanoylamino, C _1-6 alkylsulfanyl,
C _1-6 be alkylsulfinyl or C _1-6 alkylsulfonyl; R ⁹ is a substituted phenyl optionally or optionally substituted 5 or 6 membered heteroaryl ring, wherein optional substituents are 1 C _1-6 alkyl, halo, methyl trifluoride, hydroxy, methoxy trifluoride, cyano, C _1-6 alkoxy, C _1-6 alkanoyl, C _1-6 alkanoyloxy, amino, C _1-6 alkyl Amino, N, N-
(C _1-6 alkyl) ₂ amino, C _1-6 alkanoylamino, nitro, carboxy,
Carbamoyl, N- (C _1-6 alkyl) carbamoyl, N, N- (C _1-6 alkyl) ₂ carbamoyl, C _1-6 alkoxycarbonyl, mercapto, C _1-6 alkylsulfanyl, C _1-6 alkylsulfinyl, Selected from C _1-6 alkylsulfonyl, sulfamoyl, N- (C _1-6 alkyl) sulfamoyl and N, N- (C _1-6 alkyl) ₂ sulfamoyl; R ⁵ is H or C _1-6 alkyl; And Het is a fully saturated monocyclic 5-8 membered heterocycle containing up to 4 ring heteroatoms). 11. Use of a compound of formula (I) as defined in claim 10 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in the treatment of chronic obstructive pulmonary disease in a warm-blooded animal. 12. A method of treating a cathepsin L or cathepsin S mediated disease state in a mammal, wherein the mammal in need of such treatment is a compound of formula (I) as defined in claim 10 or a pharmaceutically acceptable salt thereof. A method of treatment comprising administering an effective amount of a salt. 13. A process for preparing a compound of formula (I) according to claim 1, comprising: a) an acid of formula (II) Or a reactive derivative thereof and an amine of formula (III) B) a compound of formula (IV) And a compound of formula (V) Wherein L is a displaceable group; c) a compound of formula (VI) under standard conditions Dehydration; d) X is -SO ₂ N (R ⁷⁾ - in the case of those compounds of formula (I) (VII)
Compound of the formula And a compound of formula (VIII) (Where L is a substitutable group); e) In the case of a compound of formula (I) where X is —SO ₂ N (R ⁷ ) —, a compound of formula (IX) Formula 11 And a compound of formula (X) (Wherein L is a substitutable group). 14. An intermediate of formula (VI): Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , X and Ar are as defined in claim 1.