AU2002333657A1 - Novel compounds and compositions as cathepsin inhibitors - Google Patents

Description

NOVEL COMPOUNDS AND COMPOSITIONS AS CATHEPSIN INTHBITORS

THE INVENTION

This application is based on and claims pπonty from U.S. Provisional Application S.N. 60/322,318 filed on September 14, 2001, incoφorated herein by reference.

This Application relates to compounds and compositions for treating diseases associated with cysteine protease activity, particularly diseases associated with activity of

cathepsin S.

DESCRIPTION OF THE FffiLD

Cysteine proteases represent a class of peptidases characterized by the presence of

a cysteine residue in the catalytic site of the enzyme. Cysteine proteases are associated

with the normal degradation and processing of proteins. The aberrant activity of cysteine

proteases, e.g., as a result of increase expression or enhanced activation, however, may

have pathological consequences. In this regard, certain cysteine proteases are associated

with a number of disease states, including arthritis, muscular dystrophy, inflammation,

tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic

leukodystrophy and others. An increase in cathepsin S activity contributes to the pathology

and/or symptomatology of a number of diseases. Accordingly, molecules that inhibit the activity of cathepsin S protease are useful as therapeutic agents in the treatment of such diseases. SUMMARY OF THE INVENTION

This Application relates to compounds of Formula I:

I

in which:

X¹ and X² are both methylene or X¹ is ethylene and X² is a bond;

R³ is -CR⁵=CHR⁶, -CR⁵(CR⁶ ₃)₂ or -CR⁷=NR⁸, wherein R⁵ is hydrogen and R⁶ is

hydrogen or (C_1-4)alkyl or R⁵ and R⁶ together with the atoms to which R⁵ and R⁶ are attached form (C_3-12)cycloalkenyl, hetero(C_5-i₂)cycloalkenyl, (C_6-12)aryl, hetero(C_6-12)aryl,

(C _-12)bicycloaryl or hetero(C_8-ι₂)bicycloaryl and R and R together with the atoms to

7 o which R and R are attached form hetero(C_5-12)cycloalkenyl, hetero(C_6-1 )aryl or

hetero(C₈-i₂)bicycloaryl, wherein R³ optionally is substituted by 1 to 5 radicals

independently selected from a group consisting of (C_1- )alkyl, cyano, halo, halo-substituted (C_1-4)alkyl, nitro, ^NEc , -X⁴OR⁹, -X⁴SR⁹, -X C(O)NR⁹R⁹, -X⁴C(O)OR⁹, -X⁴S(O)R¹⁰,

-X⁴S(O)₂R¹⁰ and -X⁴C(O)R¹⁰, wherein X⁴ is a bond or (C_1-2)alkylene, R⁹ at each occurrence independently is hydrogen, (C_1-3)alkyl or halo-substituted (C_1-3)alkyl and R¹⁰ is (Cι_-3)alkyl or halo-substituted (Cι_-3)alkyl; and R⁴ is -C(O)X⁵R^π or -S(O)₂X⁵R^π, wherein X⁵ is a bond, -O- or -NR¹²-, wherein R¹²

is hydrogen or (C_1-6)alkyl, and R¹¹ is (i) (Cι_-6)alkyl optionally substituted by -OR¹³, -SR¹³,

-S(O)R¹³, -S(O)₂R¹³, -C(O)R¹³, -C(O)OR¹³, -C(O)NR¹³R¹⁴, -NR¹ R¹⁴, -NR¹⁴C(O)R¹³,

-NR¹⁴C(O)OR¹³,-NR¹⁴C(O)NR^I3R¹⁴ or -NR¹⁴C( R¹ )NR¹³R¹⁴, wherein R¹³ is (C_3-i₂)cycloalkyl(C₀-₃)alkyl, hetero(C_5-12)cycloalkyl(C₀-₃)alkyl, (C₆.₁₂)aryl(C_0-3)alkyl,

hetero(C_5-ι₂)aryl(Co-₃)alkyl, (C_9-12)bicycloaryl(C_0-3)alkyl or hetero(Cs-i₂)bicycloaryl(Co-₃)alkyl and R¹⁴ at each occurrence independently is hydrogen

or (C_1-6)alkyl, or (ii) (C₃-i₂)cycloalkyl(C_0-3)alkyI, hetero(C_5-12)cycloalkyl(C₀-3)alkyl,

(C_6-i₂)aryl(Co-₃)alkyl, hetero(C₅-ι₂)aryl(Co-₃)alkyl, (C₉-i₂)bicycloaryl(Co_-3)alkyl or

hetero(C_8-ι₂)bicycloaryl(C_0-3)alkyl or (iii) (C₃-₆)cycloalkyl(C_0-3)alkyl, hetero(C₅.₆)cycloalkyl(Co_-3)alkyl_! phenyl(Co-₃)alkyl or hetero(C_5-6)aryl(Co-₃)alkyl

substituted by -X⁶OR¹⁵, -X⁶SR¹⁵, -X⁶S(O)R¹⁵, -X⁶S(O)₂R¹⁵, -X⁶C(O)R¹⁵, -X⁶C(O)OR¹⁵,

-X⁶C(O)NR¹⁵R¹⁶, -X⁶NR¹⁵R¹⁶, -X⁶NR¹⁶C(0)R¹⁵, -X⁶NR¹⁶C(O)OR¹⁵,

-X⁶NR¹⁶C(O)NR¹⁵R¹⁶ , -X⁶NR¹⁶C(O)OR¹⁶, -X⁶NR¹⁶C( R¹⁶)NR¹⁵R¹⁶, wherein X⁶ is a

bond or methylene, R¹⁵ is (C_3-6)cycloalkyl(C_0-3)alkyl, hetero(C_5-6)cycloalkyl(Co_-3)alkyl, phenyl(Co_-3)alkyl or hetero(C₅_₆)aryl(C_0-3)alkyl and R is hydrogen or wherem

R⁴ optionally further contains 1 to 5 substituents which when occurring within an alicyclic

or aromatic ring system are radicals independently selected from a group consisting of

(C_1-6)alkyl, (C_1-6)alkylidene, cyano, halo, nitro, halo-substituted (C_1-3)alkyl, -X⁶NR¹ R¹⁷,

-X⁶NR^I7C(O)OR¹⁷, -X⁶NR¹⁷C(O)NR¹⁷R¹⁷, -X⁶NR C(NR¹⁷)NR^I7R¹⁷, -X⁶OR¹⁷, -X⁶SR¹⁷,

-X⁶C(O)OR¹⁷, -X⁶C(O)NR¹⁷R¹⁷, -X⁶S(O)₂NR¹⁷R¹⁷, -X⁶P(O)(OR¹⁸)OR¹⁷,

-X⁶OP(O)(OR¹⁸)OR¹⁷, -X⁶NR C(O)R^lε, -X⁶S(O)₂R¹⁸ and -X⁶C(O)R¹⁸ and when occurring within an aliphatic moiety are radicals independently selected from a group consisting of cyano, halo, nitro, -NR¹⁷R¹⁷, -NR¹⁷C(O)OR¹⁷, -NR¹⁷C(O)NR¹⁷R¹⁷, -NR¹⁷C(NR¹⁷)NR¹⁷R¹⁷, -OR¹⁷, -SR¹⁷, -C(O)OR¹⁷, -C(O)NR¹⁷R¹⁷, -S(O)₂NR¹⁷R¹⁷,

-P(O)(OR¹⁷)OR¹⁷, -OP(O)(OR¹⁷)OR¹⁷, -NR¹⁷C(O)R¹⁸, -S(O)R¹⁸, -S(0)₂R¹⁸ and -C(O)R¹⁸,

wherein X is a bond or (Cι_-6)alkylene, R at each occurrence independently is hydrogen, (C_1-6)alkyl or halo-substituted (C_1-3)alkyl and R is (C_1-6)alkyl or halo-substituted

(C_1-3)alkyl;

X³ is a group of Formula (a), (b), (c), (d), (e), (f), (g) or (h):

(a) (b) (C)

( ) (e) (t)

(g) (h)

represents a single bond, or a double bond;

X⁷ represents aryl, heteroaryl or NR²⁰R²⁵; n is 0, 1 or 2;

R ,2"0 , is selected from the group consisting of hydrogen, (C_1-6)alkyl, (C_3-i₂)cycloalkyl(C₀-₆)alkyl, hetero(C_5-12)cycloalkyl(Co-₆)alkyl, (C₆-₁₂)aryl(C₀.₆)alkyl and

hetero(C_5-12)aryl(Co-₆)alkyl;

R²¹ is selected from the group consisting of hydrogen, (C_1- )alkyl,

(C_3-12)cycloalkyl(Co-₆)alkyl, hetero(C_5-12)cycloalkyl(C_0-6)alkyl, (C₆.₁₂)aryl(C_0-6)alkyl,

hetero(C_5-12)aryl(Co-₆)alkyl, (C_9-12)bicycloaryl(C₀-₃)alkyl,

hetero(C_8-12)-bicycloaryl(C_0-3)alkyl, -C(0)R²⁶, -C(S)R²⁶, -S(O)₂R²⁶, -C(O)OR²⁶,

-C(O)N(R²⁶)R²⁷, -C(S)N(R²⁶)R²⁷ and -S(O)₂N(R²⁷)R²⁶;

R²³ is selected from -H, (C_1-6)alkyl, (C _-6)alkenyl, (C_3-ι₂)cycloalkyl(Co_-6)alkyl,

hetero(C_5-12)cycloalkyl(C₀-₆)alkyl, (C_6-12)aryl(C_0-6)alkyl or hetero(C_5-i2)aryl(Co-₆)alkyl optionally substituted with amino, -NHC(O)R¹⁵ or -R¹⁵ wherein R¹⁵ is as described above;

R²⁵ is selected from hydrogen, (C_1-6)alkyl, (C_3-12)cycloalkyl(Co_-6)alkyl,

hetero(C₅-₁₂)cycloalkyl(C₀.₆)alkyl, (C_6-12)aryl(Co_-6)alkyl, hetero(C_5-13)aryl(C_0-6)alkyl,

-X⁴NHR¹⁵, -X⁴S(O)₂R²⁶ or -X⁴C(O)R¹⁷NR¹⁷C(O)R¹⁷ wherein R¹⁵, R¹⁷ and X⁴ are as described above;

R²⁶ is selected from the group consisting of hydrogen, (C_1-6)alkyl,

(C_3-12)cycloalkyl(C₀-₆)alkyl, hetero(C_5-12)cycloalkyl(C₀-₆)alkyl, (C_6-12)aryl(C₀-6)alkyl, hetero(C_5-12)aryl(C₀-₆)alkyl, (C_9-12)bicycloaryl(Co-₃)alkyl and hetero(C₈-i₂)-bicycloaryl(C_0-3)alkyl;

R²⁷ is hydrogen, (C_1-6)alkyl, (C_3-12)cycloalkyl(C_0-e)alkyl,

hetero(C_5-i2)cycloalkyl(C₀.₆)alkyl, (C_6-12)aryl(C₀-₆)alkyl or hetero(C_5-12)aryl(C_0-6)alkyl;

R²⁸ is R²⁰ or -O-C(=O)-R²⁹;

R²⁹ is (C_1-6)alkyl, (C_3-12)cycloalkyl(C_0-3)alkyl, hetero(C₅.₁₂)cycloalkyl(Co-₃)alkyl, (C6-ι₂)aryl(C_0-3)alkyl, hetero(C_5-12)aryl(C₀-₃)alkyl, (C_9-ι₂)bicycloaryl(C₀-₃)alkyl or

hetero(C_8-ι )bicycloaryl(Co-₃)alkyl; wherein X³ optionally further contains 1 to 5 substituents which when

occurring within an alicyclic or aromatic ring system are radicals independently selected

from a group consisting of (Q^alkyl, (C_1-6)alkylidene, cyano, halo, nitro, halo-substituted

(C_1-3)alkyl, -X⁶NR¹⁷R¹⁷, -X⁶NR¹⁷C(O)OR¹⁷, -X⁶NR¹⁷C(O)NR¹⁷R¹⁷,

-X⁶NR¹⁷C(NR¹⁷)NR¹⁷R¹⁷, -X⁶OR¹⁷, -X⁶C(O)R¹⁷, -X⁶OR¹⁵, -X⁶SR¹⁷, -X⁶C(O)OR¹⁷,

-X⁶C(O)NR¹⁷R¹⁷, -X⁶S(O)₂NR¹⁷R , -X⁶P(O)(OR⁸)OR¹⁷, -X⁶OP(O)(OR⁸)OR¹⁷, -X⁶NR¹⁷C(O)R¹⁸, -X⁶S(O)R¹⁸, -X⁶S(O)₂R¹⁸ and -X⁶C(O)R¹⁸ and when occurring within an aliphatic moiety are radicals independently selected from a group consisting of cyano,

halo, nitro, -NR¹⁷R¹⁷, -NR¹⁷C(O)OR¹⁷, -NR¹⁷C(O)NR¹⁷R¹⁷, -NR¹⁷C(NR¹⁷)NR¹⁷R¹⁷, -OR¹⁷,

-SR¹⁷, -C(O)OR¹⁷, ~C(O)NR¹⁷R¹⁷, -S(O)₂NR¹⁷R¹⁷, -P(O)(OR¹⁷)OR¹⁷, -OP(O)(OR¹⁷)OR¹⁷,

-NR¹⁷C(O)R¹⁸, -S(O)R¹⁸, -S(O)₂R¹⁸ and -C(O)R¹⁸, wherein R¹⁵, R¹⁷, R¹⁸ and X⁶ are as described above.

A second aspect of the invention is a pharmaceutical composition that contains a

compound of Formula I or their N-oxide derivatives, individual isomers or mixture of

isomers thereof, or pharmaceutically acceptable salts thereof, in admixture with one or more suitable excipients.

A third aspect of the invention is a method for treating a disease in an animal in

which inhibition of cathepsin S can prevent, inhibit or ameliorate the pathology and/or

symptomatology of the disease, which method comprises administering to the animal a

therapeutically effective amount of compound of Formula I or a N-oxide derivative,

individual isomer or mixture of isomers thereof; or a pharmaceutically acceptable salt thereof.

A fourth aspect of the invention is the processes for preparing compounds of

Formula I and the N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable

salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

Definitions:

Unless otherwise stated, the following terms used in the specification and claims are defined for the purposes of this Application and have the following meanings.

"Alicyclic" means a moiety characterized by arrangement of the carbon atoms in

closed non-aromatic ring structures having properties resembling those of aliphatics and

may be saturated or partially unsaturated with two or more double or triple bonds.

"Aliphatic" means a moiety characterized by a straight or branched chain

arrangement of the constituent carbon atoms and may be saturated or partially unsaturated with two or more double or triple bonds.

"Alkyl" represented by itself means a straight or branched, saturated or unsaturated,

aliphatic radical having the number of carbon atoms indicated (e.g., (Ci^alkyl includes

methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, vinyl, allyl,

1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methylallyl, ethynyl,

1-propynyl, 2-propynyl, and the like). Alkyl represented along with another radical (e.g.,

as in arylalkyl) means a straight or branched, saturated or unsaturated aliphatic divalent radical having the number of atoms indicated or when no atoms are indicated means a bond

(e.g., (C6-ιo)aryl(C_0-3)alkyl includes phenyl, benzyl, phenethyl, 1-phenylethyl 3-ρhenylpropyl, and the like). "Alkylene", unless indicated otherwise, means a straight or branched, saturated or unsaturated, aliphatic, divalent radical having the number of carbon atoms indicated (e.g.,

(d^alkylene includes methylene (-CH₂-), ethylene (-CH₂CH₂-), trimethylene

(-CH₂CH₂CH₂-), tetramethylene (-CH₂CH₂CH₂CH₂-) 2-butenylene (-CH₂CH=CHCH₂-),

2-methyltetramethylene (-CH₂CH(CH₃)CH₂CH₂-), pentamethylene

(-CH₂CH₂CH₂CH₂CH₂-) and the like).

"Alkylidene" means a straight or branched saturated or unsaturated, aliphatic,

divalent radical having the number of carbon atoms indicated (e.g. (C_1-6)alkylidene

includes methylene (=CH₂), ethylidene (=CHCH₃), isopropylidene (=C(CH₃)₂),

propylidene (=CHCH₂CH₃), allylidene (=CH-CH=CH₂), and the like).

"Amino" means the radical -NH₂- Unless indicated otherwise, the compounds of the invention containing amino moieties include protected derivatives thereof. Suitable

protecting groups for amino moieties include acetyl, tert-butoxycarbonyl,

benzyloxycarbonyl, and the like. "Animal" includes humans, non-human mammals (e.g., dogs, cats, rabbits, cattle,

horses, sheep, goats, swine, deer, and the like) and non-mammals (e.g., birds, and the like).

"Aromatic" means a moiety wherein the constituent atoms make up an unsaturated

ring system, all atoms in the ring system are sp² hybridized and the total number of pi

electrons is equal to 4n+2.

"Aryl" means a monocyclic or fused bicyclic ring assembly containing the total

number of ring carbon atoms indicated, wherein each ring is comprised of 6 ring carbon atoms and is aromatic or when fused with a second ring forms an aromatic ring assembly.

For example, optionally substituted (C₆.₁₀)aryl as used in this Application includes, but is not limited to, biphenyl-2-yl, 2-bromophenyl, 2-bromocarbonylphenyl, 2-bromo- 5-fluorophenyl, 4-tert-butylphenyl, 4-carbamoylphenyl, 4-carboxy-2-nitrophenyl,

2-chlorophenyl, 4-chlorophenyl, 3-chlorocarbonylphenyl, 4-chlorocarbonylphenyl,

2-chloro-4-fluorophenyl, 2-chloro-6-fluorophenyl, 4-chloro-2-nitrophenyl, 6-chloro-

2-nitrophenyl, 2,6-dibromophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl,

3,4-dichlorophenyl, 2-difluoromethoxyphenyl, 3,5-dimethylphenyl,

2-ethoxycarbonylphenyl, 2-fluorophenyl, 2-iodophenyl, 4-isopropylphenyl,

2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl,

5-methyl-2-nitrophenyl, 4-methylsulfonylphenyl, naphth-2-yl, 2-nitrophenyl, 3-nitrophenyI,

4-nitrophenyl, 2,3,4,5,6-pentafluorophenyl, phenyl, 2-trifluoromethoxyphenyl,

3-trifluoromethoxyρhenyl, 4-trifluoromethoxyphenyl, 2-trifluoromethylphenyl,

3-trifluoromethylphenyl, 4-trifluoromethylρhenyl, 2-trifluoromethylsulfanylphenyl,

4-trifluoromethylsulfanylρhenyl, and the like. Optionally substituted (C_6-10)aryl as used in this Application includes 3-acetylphenyl, 3-tert-butoxycarbonylaminomethyIphenyl,

biphenyl-4-yl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, naphth-2-yl,

3-phenoxyphenyl, phenyl, and the like.

"Bicycloaryl" means a bicyclic ring assembly containing the number of ring carbon

atoms indicated, wherein the rings are linked by a single bond or fused and at least one of the rings comprising the assembly is aromatic, and any carbocyclic ketone, thioketone or

iminoketone derivative thereof (e.g., (C_9-1o)bicycloaryl includes cyclohexylphenyl,

1,2-dihydronaphthyl, 2,4-dioxo-l,2,3,4-tetrahydronaphthyl, indanyl, indenyl,

1,2,3,4-tetrahydronaphthyl, and the like).

"Carbamoyl" means the radical -C(O)NH₂. Unless indicated otherwise, the

compounds of the invention containing carbamoyl moieties include protected derivatives thereof. Suitable protecting groups for carbamoyl moieties include acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, and the like and both the unprotected and

protected derivatives fall within the scope of the invention.

"Carbocyclic ketone derivative" means a derivative containing the moiety

-C(O)-. "Carboxy" means the radical -C(O)OH. Unless indicated otherwise, the

compounds of the invention containing carboxy moieties include protected derivatives

thereof. Suitable protecting groups for carboxy moieties include benzyl, tert-butyl, and the

like.

"Cycloalkyl" means a saturated or partially unsaturated, monocyclic, fused bicyclic

or bridged polycyclic ring assembly containing the number of ring carbon atoms indicated,

and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g.,

(C_3-10)cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl,

2,5-cyclohexadienyl, bicyclo[2.2.2]octyl, adamantan-1-yl, decahydronaphthyl,

oxocyclohexyl, dioxocyclohexyl, thiocyclohexyl, 2-oxobicyclo[2.2.1]hept-l-yl, and the like).

"Cycloalkylene" means a divalent saturated or partially unsaturated, monocyclic

ring or bridged polycyclic ring assembly containing the number of ring carbon atoms indicated, and any carbocyclic ketone, thioketone or iminoketone derivative thereof. For

1 1 example, the instance wherein "R and R together with the carbon atom to which both R

and R² are attached form (C_3-8)cycloalkylene" includes, but is not limited to, the following:

fa Δ "Disease" specifically includes any unhealthy condition of an animal or part thereof

and includes an unhealthy condition that may be caused by, or incident to, medical or veterinary therapy applied to that animal, i.e., the "side effects" of such therapy.

"Halo" means fluoro, chloro, bromo or iodo.

"Halo-substituted alkyl", as an isolated group or part of a larger group, means

"alkyl" substituted by one or more "halo" atoms, as such terms are defined in this Application. Halo-substituted alkyl includes haloalkyl, dihaloalkyl, trihaloalkyl,

perhaloalkyl and the like (e.g. halo-substituted (C_1-3)alkyl includes chloromethyl,

dichloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, perfluoroethyl,

2,2,2-trifluoro-l,l-dichloroethyl, and the like).

"Heteroatom moiety" includes -N= -NR-, -N⁺(O , -O-, -S- or -S(O)₂-, wherein

R is hydrogen, (C_1-6)alkyl or a protecting group.

"Heterocycloalkylene" means cycloalkylene, as defined in this Application,

provided that one or more of the ring member carbon atoms indicated, is replaced by

heteroatom moiety selected from -N=, -NR-, -O-, -S- or -S(0)₂-, wherein R is hydrogen or (C_1-6)alkyl. For example, the instance wherein R¹ and R² together with the carbon atom

to which both R¹ and R² are attached form hetero(C_3-8)cycloalkylene" includes, but is not

limited to, the following:

in which R is hydrogen, or a protecting group.

"Heteroaryl" means aryl, as defined in this Application, provided that one or more

of the ring carbon atoms indicated are replaced by a heteroatom moiety selected from -N=,

-NR-, -1^(0^")=, -O- or -S-, wherein R is hydrogen, (C_1-6)alkyl, a protecting group or

represents the free valence which serves as the point of attachment to a ring nitrogen, and

each ring is comprised of 5 or 6 ring atoms. For example, optionally substituted hetero(C_5-13)aryl as used in this Application includes, but is not limited to, 4-amino-

2-hydroxypyrimidin-5-yl, dibenzofuranyl, benzothiazol-2-yl, lH-benzoimidazol-2-yl,

2-bromopyrid-5-yl, 5-bromopyrid-2-yl, 4-carbamoylthiazol-2-yl, 3-carboxypyrid-4-yl,

5-carboxy-2,6-dimethylpyrid-3-yl, 3,5-dimethylisoxazol-4-yl, 5-ethoxy-

2,6-dimethylpyrid-3-yl, 5-fluoro-6-hydroxypyrimidin-4-yl, fur-2-yl, fur-3-yl, 5-hydroxy-

4,6-dimethylpyrid-3-yl, 8-hydroxy-5 ,7~dimefhylquinolin-2-yl,

5-hydroxymethylisoxazol-3-yl, 3-hydroxy-6-methylpyrid-2-yl, 3-hydroxypyrid-2-yl, lH-imidazol-2-yl, lH-imidazol-4-yl, lH-indol-3-yl, isothiazol-4-yl, isoxazol-4-yl,

2-methylfur-3-yl, 5-methylfur-2-yl, 1 -methyl- lH-imidazol-2-yl, 5-methyl-

3H-imidazol-4-yl, 5-methylisoxazol-3-yl, 5-methyl-2H-pyrazol-3~yl, 3-methylpyrid-2-yl,

4-methylpyrid-2-yl, 5-methylpyrid-2-yl, 6-methylpyrid-2-yl, 2-methylpyrid-3-yl,

2-methylthiazol-4-yl, 5-nitropyrid-2-yl, 2H-pyrazol-3-yl, 3H-pyrazol-4-yl, pyridazin-3-yl,

pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 5-pyrid-3-yl-2H-[l,2,4]triazol-3-yl, pyrimidin-4-yl, pyrimidin-5-yl, lH-pyrrol-3-yl, quinolin-2-yl, lH-tetrazol-5-yl, thiazol-2-yl, thiazol-5-yl,

thien-2-yl, thien-3-yl, 2H-[l,2,4]triazol-3-yl, 3H-[l,2,3]triazol-4-yl,

5-trifluoromethylpyrid-2-yl, and the like. Suitable protecting groups include tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the

like. Optionally substituted hetero(C_5-10)aryl as used in this Application to define R⁴ includes benzofur-2-yl, fur-2-yl, fur-3-yl, pyrid-3-yl, pyrid-4-yl, quinol-2-yl, quinol-3-yl,

thien-2-yl, thien-3-yl, and the like.

"Heterobicycloaryl" means bicycloaryl, as defined in this Application, provided

that one or more of the ring carbon atoms indicated are replaced by a heteroatom moiety

selected from -N=, -NR-, -O- or -S-, wherein R is hydrogen, (C_1-6)alkyl, a protecting group or represents the free valence which serves as the point of attachment to a ring nitrogen,

and any carbocyclic ketone, thioketone or iminoketone derivative thereof. For example,

optionally substituted hetero(C₈-io)bicycloaryl as used in this Application includes, but is

not limited to, 2-amino-4-oxo-3,4-dihydropteridin-6-yl, and the like. In general, the term

heterobicycloaryl as used in this Application includes, for example, benzo[l,3]dioxol-5-yl,

3 ,4-dihydro-2H-[ 1 , 8]naphthyridinyl, 3 ,4-dihydro-2H-quin linyl, 2,4-dioxo-3 ,4-dihydro-

2H-quinazolinyl, l,2,3,4,5,6-hexahydiO[2,21bipyridinylyl, 3-oxo-

2,3-dihydrobenzo[l,4]oxazinyl, 5,6,7,8-tetrahydroquinolinyl, and the like.

"Ηeterocycloalkyl" means cycloalkyl, as defined in this Application, provided that

one or more of the ring carbon atoms indicated are replaced by a heteroatom moiety

selected from -N=, -NR-, -O- or -S-, wherein R is hydrogen, (Cι.₆)alkyl, a protecting group or represents the free valence which serves as the point of attachment to a ring nitrogen,

and any carbocyclic ketone, thioketone or iminoketone derivative thereof (e.g., the term

hetero(C₅,₁o)cycloalkyl includes imidazolidinyl, morpholinyl, piperazinyl, piperidyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, and the like). Suitable protecting groups include

tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, 4-methoxybenzyl, 2-nitrobenzyl, and the

like. Both the unprotected and protected derivatives fall within the scope of the invention.

"Hydroxy" means the radical -OH. Unless indicated otherwise, the compounds of the invention containing hydroxy radicals include protected derivatives thereof. Suitable protecting groups for hydroxy moieties include benzyl and the like.

"Iminoketone derivative" means a derivative containing the moiety -C(NR)-,

wherein R is hydrogen or (C_1-6)alkyl.

"Isomers" mean compounds of Formula I having identical molecular formulae but

differ in the nature or sequence of bonding of their atoms or in the arrangement of their

atoms in space. Isomers that differ in the arrangement of their atoms in space are termed

"stereoisomers". Stereoisomers that are not mirror images of one another are termed

"diastereomers" and stereoisomers that are nonsuperimposable mirror images are termed "enantiomers" or sometimes "optical isomers". A carbon atom bonded to four nonidentical

substituents is termed a "chiral center". A compound with one chiral center has two

enantiomeric forms of opposite chirality is termed a "racemic mixture". A compound that

has more than one chiral center has 2"^"1 enantiomeric pairs, where n is the number of chiral

centers. Compounds with more than one chiral center may exist as ether an individual

diastereomers or as a mixture of diastereomers, termed a "diastereomeric mixture". When one chiral center is present a stereoisomer may be characterized by the absolute

configuration of that chiral center. Absolute configuration refers to the arrangement in

space of the substituents attached to the chiral center. Enantiomers are characterized by

the absolute configuration of their chiral centers and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Conventions for stereochemical nomenclature, methods

for the determination of stereochemistry and the separation of stereoisomers are well

known in the art (e.g., see "Advanced Organic Chemistry", 4th edition, March, Jerry, John

Wiley & Sons, New York, 1992). It is understood that the names and illustration used in this Application to describe compounds of Formula I are meant to be encompassed all

possible stereoisomers. Thus, for example, the name morpholine-4-carboxylic acid [1-(1- benzoyl-4-oxo-pyrrolidin-3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-arnide is meant

to include morpholine-4-carboxylic acid [S-l-(l-benzoyl-4-oxo-pyrrolidin-3-ylcarbamoyl)-

2-phenylmethanesulfonyl-ethyl]-amide and morpholine-4-carboxylic acid [R-l-(l-benzoyl- 4-oxo-pyπOlidin-3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide and any mixture,

racemic or otherwise, thereof.

"Ketone derivative" means a derivative containing the moiety -C(O)-. For

example, for 2-acetoxy-azetidin-3-yl, the "carbocyclic ketone derivative" would be 2-

acetoxy-4-oxo-azetidin-3-yl.

"Nitro" means the radical -NO . "Optional" or "optionally" means that the subsequently described event or

circumstance may or may not occur, and that the description includes instances where the

event or circumstance occurs and instances in which it does not. For example, the phrase

"wherem within R³ and R⁴ any alicyclic or aromatic ring system may be substituted further

by 1-5 radicals..." means that R³ and R⁴ may or may not be substituted in order to fall

within the scope of the invention.

"Oxoalkyl" means alkyl, as defined above, wherein one of the number of carbon

atoms indicated is replaced by an oxygen group (-O-), e.g., oxo(C_2-6)alkyl includes

methoxymethyl, etc.

"N-oxide derivatives" means derivatives of compounds of Formula I in which

nitrogens are in an oxidized state (i.e., O-Ν) and which possess the desired

pharmacological activity.

"Pathology" of a disease means the essential nature, causes and development of the

disease as well as the structural and functional changes that result from the disease processes. "Pharmaceutically acceptable" means that which is useful in preparing a

pharmaceutical composition that is generally safe, non-toxic and neither biologically nor

otherwise undesirable and includes that which is acceptable for veterinary use as well as

human pharmaceutical use.

"Pharmaceutically acceptable salts" means salts of compounds of Formula I which

are pharmaceutically acceptable, as defined above, and which possess the desired

pharmacological activity. Such salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or with organic acids such as acetic acid, propionic acid, hexanoic acid,

heptanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic

acid, succinic acid, malic acid, maleic acid, fumaric acid, tartatic acid, citric acid, benzoic

acid, σ-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, madelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid,

benzenesulfonic acid, -chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,

p-toluenesulfonic acid, camphorsulfonic acid, 4-methyIbicyclo[2.2.2]oct-2-ene-

1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis(3-hydroxy-2-ene-l-carboxylic

acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid,

muconic acid and the like.

Pharmaceutically acceptable salts also include base addition salts which may be

formed when acidic protons present are capable of reacting with inorganic or organic bases.

Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include

ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like.

"Prodrug" means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula I. For example an ester of a compound of

Formula I containing a hydroxy group may be convertible by hydrolysis in vivo to the parent molecule. Alternatively an ester of a compound of Formula I containing a carboxy

group may be convertible by hydrolysis in vivo to the parent molecule. Suitable esters of

compounds of Formula I containing a hydroxy group, are for example acetates, citrates,

lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates,

maleates, methylene-bis-b-hydroxynaphthoates, gentisates, isethionates,

di-p-toluoyltartrates, methanesulphonates, ethanesulphonates, benzenesulphonates,

p-toluenesulphonates, cyclohexylsulphamates and quinates. Suitable esters of compounds

of Formula I containing a carboxy group, are for example those described by

F.J.Leinweber, Drug Metab. Res., 1987, 18, page 379. An especially useful class of esters

of compounds of Formula I containing a hydroxy group, may be formed from acid moieties selected from those described by Bundgaard et al., J. Med. Chem., 1989, 32, page

2503-2507, and include substituted (aminomethyl)-benzoates, for example, dialkylamino-

methylbenzoates in which the two alkyl groups may be joined together and/or interrupted

by an oxygen atom or by an optionally substituted nitrogen atom, e.g. an alkylated nitrogen

atom, more especially (morpholino-methyl)benzoates, e.g. 3- or 4-(morpholinomethyl)-

benzoates, and (4-alkylpiperazin-l-yl)benzoates, e.g. 3- or

4-(4-alkylpiperazin-l-yl)benzoates.

"Protected derivatives" means derivatives of compounds of Formula I in which a reactive site or sites are blocked with protecting groups. Protected derivatives of

compounds of Formula I are useful in the preparation of compounds of Formula I or in themselves may be active cathepsin S inhibitors. A comprehensive list of suitable

protecting groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis,

3rd edition, John Wiley & Sons, Inc. 1999.

"Therapeutically effective amount" means that amount which, when administered

to an animal for treating a disease, is sufficient to effect such treatment for the disease.

"Thioketone derivative" means a derivative containing the moiety -C(S)-.

"Treatment" or "treating" means any administration of a compound of the present invention and includes:

(1) preventing the disease from occurring in an animal which may be predisposed to

the disease but does not yet experience or display the pathology or symptomatology of the

disease,

(2) inhibiting the disease in an animal that is experiencing or displaying the pathology

or symptomatology of the diseased (i.e., arresting further development of the pathology

and/or symptomatology), or

(3) ameliorating the disease in an animal that is experiencing or displaying the

pathology or symptomatology of the diseased (i.e., reversing the pathology and/or

symptomatology) .

Nomenclature:

The compounds of Formula I and the intermediates and starting materials used in

their preparation are named in accordance with TUPAC rules of nomenclature in which the characteristic groups have decreasing priority for citation as the principle group as follows: acids, esters, amides, etc. Alternatively, the compounds are named by AutoNom 4.0

(Beilstein Information Systems, Inc.). For example, a compound of Formula I in which R³ is phenyl, R⁴ is morpholine-4-carbonyl and X³ is l-benzoyl-4-oxo-pyrrolidin-3-ylamino; that is, a compound having the following structure:

is named morpholine-4-carboxylic acid ri-(l-benzoyl-4-oxo-pyrrolidin-3-ylcarbamoyl^")-2-

phenylmethanesulf onyl-ethyl] -amide .

Presently Preferred Embodiments:

While the broadest definition of the invention is set forth in the Summary of the

Invention, certain aspects of the invention are preferred. For example, for a compound of

Formula I, in which X¹ and X² are both methylene or X¹ is ethylene and X² is a bond; R³ is -CR⁵=CHR⁶, -CR⁵(CR⁶ ₃)₂ or -CR⁷=NR⁸, wherein R⁵ is hydrogen and R⁶ is hydrogen

or (C_1- )alkyl or R⁵ and R⁶ together with the atoms to which R⁵ and R⁶ are attached form

(C_3-12)cycloalkenyl, (C_6-12)aryl, hetero(C_6-12)aryl or (C_9-12)bicycloaryl and R⁷ and R⁸

together with the atoms to which R and R are attached form hetero(C_5-12)cycloalkenyl or

hetero(C₆.₁ )aryl, wherein R³ optionally is substituted by 1 to 5 radicals independently selected from a group consisting of (C_1- )alkyl, cyano, halo, halo-substituted (C_1-4)alkyl,

-X⁴OR⁹ and -X⁴C(O)OR⁹, wherein X⁴ is a bond or (C_1- )alkylene, R⁹ at each occurrence

independently is (C_1-3)alkyl or halo-substituted (C_1-3)alkyl; R⁴ is -C(O)X⁵R^u or

-S(O)₂X⁵Rⁿ, wherein X⁵ is a bond, -O- or -NR¹²-, wherein R¹² is hydrogen or

(Cι_-6)alkyl, and R¹¹ is (i) (C_I-6)alkyl or (ii) hetero(C_5-ι₂)cycloalkyl(C_0-3)alkyl, (C_6-i₂)aryl(C_0- )alkyl, hetero(C_5-ι₂)aryl(Co_-3)alkyl, (C_9-12)bicycloaryl(C_0-3)alkyl or

hetero(C_B-i2)bicycloaryl(Co-₃)alkyl or (iii) hetero(C₅-₆)cycloalkyl(C_0-3)alkyl or phenyl(C_0-3)alkyl substituted by -X⁶OR¹⁵, -X⁶C(O)R¹⁵ or -X⁶NR¹⁶C(O)OR¹⁶, wherem X⁶

is a bond or methylene, R¹⁵ is phenyl(Co-₃)alkyl or hetero(C_5-6)aryl(C_0-3)alkyl and R¹⁶ is

hydrogen or (Cι_-6)alkyl; wherein R⁴ optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring system are radicals independently

selected from a group consisting of (Cι_-6)alkyl, halo, -X⁶NR¹⁷R¹⁷, -X⁶OR¹⁷,

-X⁶C(O)OR¹⁷, -X⁶NC(O)R¹⁶ and -X⁶C(O)R¹⁸, R¹⁷ at each occurrence independently is

hydrogen, ( ^alkyl or halo-substituted (C₁-₃)alkyl and R¹⁸ is (Cι_-6)alkyl or halo-substituted (Cι_-3)alkyl.

In particular, X³ is a group of Formula (a), (b) or (c) in which: n is 0, 1 or 2; R²⁰ is selected from the group consisting of hydrogen and (C_1-6)alkyl; R²¹ is selected from the

group consisting of (C_1-9)alkyl, (C_6-12)aryl(Co-₆)alkyl, -C(O)R²⁶, -S^)^²⁶, -C(O)OR²⁶ and

-C(O)N(R²⁶)R²⁷; R²³ is selected from (Cι_₆)alkyl optionally substituted with amino, -

NHC(O)R¹⁵ or -R¹⁵ wherein R¹⁵ is as described above; R²⁵ is selected from (C_1-6)alkyl,

(C_6-12)aryl(C₀-₆)alkyl, -X⁴S(O)₂R²⁶ or -X⁴C(O)R¹⁷NR¹⁷C(O)R¹⁷ wherein R¹⁷ and X⁴ are

as described above and R²⁶ is as described below; R²⁶ is selected from the group consisting

of (Cι_-6)alkyl, hetero(C₅.ι₂)cycloalkyl(C_0-6)alkyl, (C_6-ι₂)aryl(C₀.₆)alkyl,

hetero(C_5-12)aryl(Co-₆)alkyl and (C_9-12)bicycloaryl(Co-₃)alkyl; R²⁷ is (C_1-6)alkyl; herein X³

optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring system are radicals independently selected from a group consisting of (C_1-6)alkyl, cyano, halo, -X⁶OR¹⁷, -X⁶C(O)R¹⁷ and -X⁶OR¹⁵.

R³ more preferably is selected from the group consisting of phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, vinyl, 2-difluoromethoxyphenyl, l-oxy-pyridin-2-yl, 4- methoxyphenyl, 4-methylphenyl, 2-methylphenyl, 4-chlorophenyl, 3,5-dimethylphenyl, 4-

trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 2-bromophenyl, naphthalen-2-yl, 3,4-

dichlorophenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 3-trifluoromethoxyphenyl,

2,3,4,5,6-pentafluoro-phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-cyano-phenyl, 2-

trifluoromethylphenyl, 4-tert-butyl-phenyl, 3-chlorophenyl, 4-bromophenyl, 2-fluoro-3-

chloro-phenyl, 2-fluoro-3-methyl-phenyl, 3-fluorophenyl, 2,5-difluorophenyl, 3-

bromophenyl, 2,5-dichlorophenyl, 2,6-difluorophenyl, 3-cyano-phenyl, 4-cyano-phenyl,

2-trifluoromethoxyphenyl, 2,3-difluorophenyl, biphenyl, 2-bromo-5-fluoro-phenyl, 4-

fluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 2,4,6-trifluorophenyl, 2,4,5-

trifluorophenyl, 2,3,4-trifluorophenyl, 2-chloro-5-trifluoromethylphenyl, 2,4-bis- trifluoromethylphenyl, 2,5,6-trifluorophenyl, 2-fluoro-3-trifluoromethylphenyl, 2-fluoro-4-

trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl, 2,3,5-trifluorophenyl, 2-fluoro-5-

trifluoromethylphenyl, 5-fluoro-2-trifluoromethylphenyl, 4-fluoro-3-trifluoromethylphenyl,

2-methoxyphenyl, 3,5-bis-trifluoromethylphenyl, 4-difluoromethoxyphenyl, 3-

difluoromethoxyphenyl, 2,6-dichlorophenyl, 4-carboxyphenyl, cyclohexyl, cyclopropyl,

isopropyl, thiophen-2-yl, 5-chloro-thiophen-2-yl and 3,5-dimethyl-isoxazol-4-yl.

R⁴ more preferably is selected from the group consisting of benzoyl, morpholine-4- carbonyl, acetyl, furan-3-carbonyl, 2-methoxy-benzoyl, 3-methoxy-benzoyl, naphthalene-2-

carbonyl, benzo[l,3]dioxole-5-carbonyl, 3-pyridin-3-yl-acryloyl, benzofuran-2-carbonyl,

furan-2-carbonyl, tert-butoxy-carbonyl, biphenyl-4-carbonyl, quinoline-2-carbonyl,

quinoline-3-carbonyl, 3-acetyl-benzoyl, 4-phenoxy-benzoyl, 3-hydroxy-benzoyl, 4-

hydroxy-benzoyl, pyridine-3-carbonyl, 3-(tert-butoxycarbonylamino-methyl)-benzoyl, 4- carbonyl-piρerazine-1-carboxylic acid tert-butyl ester, 4-carbonyl-piperazine-l -carboxylic acid ethyl ester, 4-(furan-2-carbonyl)-piρerazine-l-carbonyl, pyridme-4-carbonyl, 1-oxy- pyridine-4-carbonyl, l-oxy-pyridine-3-carbonyl, thiophene-2-carbonyl, thiophene-3- carbonyl, 4-benzoyl-benzoyl, 5-methyl-thiophene-2-carbonyl, 3-chloro-thiophene-2-

carbonyl, 3-bromo-thiophene-2-carbonyl, 4-chloro-benzoyl, 3-flouro-4-methoxy-benzoyl,

4-methoxy-benzoyl, 4-triflouromethoxy-benzoyl, 3,4-diflouro-benzoyl, 4-fluoro-benzoyl,

3,4-dimethoxy-benzoyl, 3-methyl-benzoyl, 4-bromo-benzoyl, 4-triflouromethyl-benzoyl, 3-benzoyl-benzoyl, cyclopentane-carbonyl, benzo[b]thiophene-2-carbonyl, 3-chloro-

benzo[b]thiophene-2-carbonyl, benzenesulfonyl, naphthalene-2-sulfonyl, 5-methyl-

thiophene-2-sulfonyl, thiophene-2-sulfonyl, formamyl-methyl ester, 4-methyl-pentanoyl,

formamyl-isobutyl ester, formamyl-monoallyl ester, formamyl-isopropyl ester, N,N-

dimethyl-formamyl, N-isopropyl-formamyl, N-pyridin-4-yl-formamyl, N-pyridin-3-yl- formamyl, 3-phenyl-acryloyl, lH-indole-5-carbonyl, pyridine-2-carbonyl, pyrazine-2-

carbonyl, 3-hydroxy-pyridine-2-carbonyl, 2-amino-pyridine-3-carbonyl, 2-hydroxy-

pyridine-3 -carbonyl, 6-amino-pyridine-3-carbonyl, 6-hydroxy-pyridine-3-carbonyl,

pyridazine-4-carbonyl, 3-phenoxy-benzoyl and l-oxo-l,3-dihydro-isoindole-2-carbonyl. X³ more preferably is selected from a group consisting of 4-amino-3-oxo-azepane-l-

carboxylic acid benzyl ester, 4-amino-3-oxo-azepane-l-carboxylic acid isobutyl ester, 4-

amino-l-benzoyl-azepan-3-one, 4-amino-l-benzenesulfonyl-azepan-3-one, 4-amino-l-

(pyridine-2-sulfonyl)-azepan-3-one, 4-amino-l-(l-oxy-pyridine-2-sulfonyl)-azepan-3-one,

4-amino-l-(3,4-dichloro-benzenesulfonyl)-azepan-3-one, 4-amino-l-(2-flouro- benzenesulfonyl)-azepan-3-one, 4-amino-l-(3,4-dimethoxy-benzenesulfonyl)-azepan-3-

one, 4-amino-l-(2-cyano-benzenesulfonyl)-azepan-3-one, 4-amino-l-(naphthalene-l- sulfonyl)-azepan-3-one, 4-amino-l-(thiophene-2-sulfonyl)-azepan-3-one, 4-amino-l-

(thiazole-2-sulfonyl)-azepan-3-one, 4-amino-l-(pyrrolidine-l-suIfonyl)-azepan-3-one, 4-

amino-l-methanesulfonyl-azepan-3-one, 4-amino-l-(pyrrolidine-l-carbonyl)-azepan-3- one, 4-amino-3-oxo-azepane-l-carboxylic-acid-dimethylamide, 4-amino-3-oxo-azeρane-l-

carboxylic-acid-benzylamide, 4-amino- l-benzyl-azepan-3-one, 4-amino-l-benzyl-

piperidin-3-one, 4-amino- 1 -benzoyl-piρeridin-3-one, 4-amino- l-benzoyl-pyrrolidin-3-one, 4-amino-l-benzyl-pyrrolidin-3-one, 4-amino-l-benzenesulfonyl-pyrrolidin-3-one, 4-amino-

l-(5-methyl-hexyl)-pyrrolidin-3-one, l-ethyl-2-oxo-3-(toluene-4-sulfonylamino)-

butylamino, 1 -ethyl-2-oxo-3-(4-phenoxy-benzenesulf onylamino)-propylamino, 1 -ethyl-2-

oxo-3-[4-(pyridin-3-yloxy)-benzenesulfonylamino]-propylamino, 3-(dibenzofuran-2-

sulfonylamino)-l-ethyl-2-oxo-butylamino, l-ethyl-3-[4-methyl-2-(4-methyl-

pentanoylaι no)-pentanoylamino]-2-oxo-propylamino, 5-amino-l-[(4-methoxy- phenylsulfamoyl)-methyl]-pentylamino, 5-benzyloxycarbonylamino-l-[(4-methoxy-

phenylsulfamoyl)-methyl]-pentylamino, l-[(4-methoxy-phenylsulfamoyl)-methyl]-3-

phenyl-propylamino, 1 - { [4-( 1 -hydroxy-ethyl)-phenylsulf amoyl] -methyl } -3-phenyl-

propylamino, l-[(4-acetyl-phenylsulfamoyl)-methyl]-3-phenyl-propylamino, l-[(4- hydroxy-phenylsulfamoyl)-methyl]-3-phenyl-propylamino and 3-phenyl-l-[(2-

phenylamino-ethylsulfamoyl)-methyl] -propylamino; and the N-oxide derivatives, prodrag

derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the Ν-oxide

derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.

Reference to the preferred embodiments set forth above is meant to include all

combinations of particular and preferred groups.

Particular compounds of the invention may be prepared by joining C* of one of the fragments (Al to A72) shown in Table 1 to the nitrogen atom (*Ν) of one of the fragments (Bl to B80) shown in Table 2, and joining the methine carbon atom (CH*) of one of the fragments (Bl to B80) shown in Table 2 to the acyl carbon atom (C*) of one

of the fragments (CI to C37) depicted in Table 3.

TABLE 1

TABLE 2

TABLE 3

O 03/024924

-34-

Pharmacology and Utility:

The compounds of the invention are selective inhibitors of cathepsin S and, as

such, are useful for treating diseases in which cathepsin S activity contributes to the

pathology and/or symptomatology of the disease. For example, the compounds of the

invention are useful in treating autoimmune disorders, including, but not limited to,

juvenile onset diabetes, multiple sclerosis, pemphigus vulgaris, Graves' disease,

myasthenia gravis, systemic lupus erythemotasus, rheumatoid arthritis and Hashimoto's

thyroiditis, allergic disorders, including, but not limited to, asthma, and allogeneic immune

responses, including, but not limited to, organ transplants or tissue grafts.

Cathepsin S also is implicated in disorders involving excessive elastolysis, such as chronic obstructive pulmonary disease (e.g., emphysema), bronchiolitis, excessive airway elastolysis in asthma and bronchitis, pneumonities and cardiovascular disease such as

plaque rupture and atheroma. Cathepsin S is implicated in fibril formation and, therefore,

inhibitors of cathepsins S are of use in treatment of systemic amyloidosis.

The cysteine protease inhibitory activities of the compounds of the invention can be determined by methods known to those of ordinary skill in the art. Suitable in vitro

assays for measuring protease activity and the inhibition thereof by test compounds are

known. Typically, the assay measures protease induced hydrolysis of a peptide based

substrate. Details of assays for measuring protease inhibitory activity are set forth in

Examples 14-17, infra.

Administration and Pharmaceutical Compositions:

In general, compounds of Formula I will be administered in therapeutically

effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with one or more therapeutic agents. A therapeutically effective amount

may vary widely depending on the severity of the disease, the age and relative health of the

subject, the potency of the compound used and other factors. For example, therapeutically

effective amounts of a compound of Formula I may range from about 1 micrograms per

kilogram body weight (μg kg) per day to about 1 milligram per kilogram body weight

(mg/kg) per day, typically from about 10 μg/kg/day to about 0.1 mg/kg/day. Therefore, a

therapeutically effective amount for a 80 kg human patient may range from about 100

μg/day to about 100 mg/day, typically from about 1 μg/day to about 10 mg/day. In general,

one of ordinary skill in the art, acting in reliance upon personal knowledge and the disclosure of this Application, will be able to ascertain a therapeutically effective amount of a compound of Formula I for treating a given disease.

The compounds of Formula I can be administered as pharmaceutical compositions

by one of the following routes: oral, systemic (e.g., transdermal, intranasal or by

suppository) or parenteral (e.g., intramuscular, intravenous or subcutaneous).

Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained

release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate

composition and are comprised of, in general, a compound of Formula I in combination

with at least one pharmaceutically acceptable excipient. Acceptable .excipients are

non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the

active ingredient. Such excipient may be any solid, liquid, semisolid or, in the case of an

aerosol composition, gaseous excipient that is generally available to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose,

sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate,

glycerol monostearate, sodium chloride, dried skim milk, and the like. Liquid and

semisolid excipients may be selected from water, ethanol, glycerol, propylene glycol and

various oils, including those of petroleum, animal, vegetable or synthetic origin (e.g.,

peanut oil, soybean oil, mineral oil, sesame oil, and the like). Preferred liquid carriers,

particularly for injectable solutions, include water, saline, aqueous dextrose and glycols.

The amount of a compound of Formula I in the composition may vary widely

depending upon the type of formulation, size of a unit dosage, kind of excipients and other

factors known to those of skill in the art of pharmaceutical sciences. In general, a

composition of a compound of Formula I for treating a given disease will comprise from

0.01%w to 10%w, preferably 0.3%w to l%w, of active ingredient with the remainder being the excipient or excipients. Preferably the pharmaceutical composition is administered in a single unit dosage form for continuous treatment or in a single unit dosage form ad

libitum when relief of symptoms is specifically required. Representative pharmaceutical

formulations containing a compound of Formula I are described in Example 10, infra.

Chemistry:

Processes for Making Compounds of Formula I:

Compounds of the invention may be prepared by the application or adaptation of

known methods, by which is meant methods used heretofore or described in the literature,

for example those described by R.C. Larock in Comprehensive Organic Transformations,

VCH publishers, 1989.

In the reactions described hereinafter it may be necessary to protect reactive

functional groups, for example hydroxy, amino, imino, thio or carboxy groups, where these

are desired in the final product, to avoid their unwanted participation in the reactions.

Conventional protecting groups may be used in accordance with standard practice, for

examples see T.W. Greene and P. G. M. Wuts in "Protective • Groups in Organic

Chemistry" John Wiley and Sons, 1991.

Compounds of Formula I, in which X³ is a compound of formula (a) (as defined in

the Summary of the Invention), can be prepared by proceeding as in the following Reaction Scheme 1:

Reaction Scheme 1

1 7 A. 7O 71 in which each X , X , R , R , R and R are as defined for Formula I in the Summary of the Invention.

Compounds of Formula I can be prepared by condensing an acid of Formula 2 with

an amino compound of formula (a). The condensation reaction can be effected with an

appropriate coupling agent (e.g., benzotriazol-1-yloxytrispyrrolidinophosphonium

hexafluorophosphate (PyBOP^®), 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide

hydrochloride (EDCI), 0-benzotriazol-l-yl-N,N,N',N-tetramethyluronium

hexafluorophosphate (HBTU), 1,3-dicyclohexylcarbodiimide (DCC), or the like) and

optionally an appropriate catalyst (e.g., 1-hydroxybenzotriazole (HOBt), 1-hydroxy-

7-azabenzotriazole (HOAt), 0-(7-azabenzotrizol-l-yl)-l, 1,3,3, tetra- methyluroniumhexafluorophosphate (HATU), or the like) and non-nucleophilic base (e.g.,

triethylamine, N-methylmorpholine, and the like, or any suitable combination thereof) at ambient temperature and requires 5 to 10 hours to complete.

An oxidation step, if required, can be carried out with an oxidizing agent (e.g.,

Oxone^®, metachloroperbenzoic acid or the like) in a suitable solvent (e.g., methanol, water,

or the like, or any suitable combination thereof) at ambient temperature and requires 16 to

24 hours to complete. Detailed descriptions for the synthesis of a compound of Formula

I by the processes in Reaction Scheme 1 are set forth in the Examples 1 to 11, infra.

Compounds of Formula I, where X is a compound of formula (b) (as defined in

the Summary of the Invention), can be prepared by proceeding as in the following Reaction Scheme 2:

Reaction Scheme 2

in which each X¹, X², R³, R⁴, R²⁰, R²³ and R²⁵ are as defined for Formula I in the Summary

of the Invention.

Compounds of Formula I can be prepared by condensing an acid of Formula 2 with

an amino compound of formula (b). The condensation reaction can be effected with an appropriate coupling agent (e.g., benzotriazol-1-yloxytrispyrrolidinophosphonium

hexafluorophosphate (PyBOP^®), l-(3-dimethylarrnnopropyl)-3-ethylcarbodiimide

hydrochloride (EDCI), 0-benzotriazol-l-yl-N,N,N',N-tetramethyluronium

hexafluorophosphate (HBTU), 1,3-dicyclohexylcarbodiimide (DCC), or the like) and

optionally an appropriate catalyst (e.g., 1-hydroxybenzotriazole (HOBt), 1-hydroxy-

7-azabenzotriazole (HOAt), 0-(7-azabenzotrizol-l-yl)-l,l,3,3, tetra-

methyluroniumliexafluorophosphate (HATU), or the like) and non-nucleophilic base (e.g.,

triethylamine, N-methylmorpholine, and the like, or any suitable combination thereof) at

ambient temperature and requires 5 to 10 hours to complete.

An oxidation step, if required, can be carried out with an oxidizing agent (e.g.,

Oxone^®, metachloroperbenzoic acid or the like) in a suitable solvent (e.g., methanol, water,

or the like, or any suitable combination thereof) at ambient temperature and requires 16 to

24 hours to complete.

Compounds of Formula 1 in which X³ is a compound of formula (c) (as defined in

the Summary of the Invention), can be prepared by reacting a compound of Formula 2 with

a compound of Formula (c) according to the following reaction scheme:

Reaction Scheme 3

I

in which each X A¹, X _v2^z, - Rr.3^J, - Rr.4 , r R,20 , τ R,23^J and R >25 ^D are as defined for Formula I in the Summary

of the invention.

Additional Processes for Preparing Compounds of Formula I:

A compound of Formula I can be prepared as a pharmaceutically acceptable acid

addition salt by reacting the free base form of the compound with a pharmaceutically

acceptable inorganic or organic acid. Alternatively, a pharmaceutically acceptable base

addition salt of a compound of Formula I can be prepared by reacting the free acid form

of the compound with a pharmaceutically acceptable inorganic or organic base. Inorganic

and organic acids and bases suitable for the preparation of the pharmaceutically acceptable

salts of compounds of Formula I are set forth in the definitions section of this Application. Alternatively, the salt forms of the compounds of Formula I can be prepared using salts

of the starting materials or intermediates.

The free acid or free base forms of the compounds of Formula I can be prepared

from the corresponding base addition salt or acid addition salt form. For example, a

compound of Formula I in an acid addition salt form can be converted to the corresponding

free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium

hydroxide, and the like). A compound of Formula I in a base addition salt form can be

converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc).

The N-oxides of compounds of Formula I can be prepared by methods known to

those of ordinary skill in the art. For example, N-oxides can be prepared by treating an

unoxidized form of the compound of Formula I with an oxidizing agent (e.g.,

trifluoroperacetic acid, permaleic acid, perbenzoic acid, peracetic acid,

77iet -chloroperoxybenzoic acid, or the like) in a suitable inert organic solvent (e.g., a

halogenated hydrocarbon such as dichloromethane) at approximately 0°C. Alternatively,

the N-oxides of the compounds of Formula I can be prepared from the N-oxide of an

appropriate starting material.

Compounds of Formula I in unoxidized form can be prepared from N-oxides of

compounds of Formula I by treating with a reducing agent (e.g., sulfur, sulfur dioxide,

triphenyl phosphine, lithium borohydride, sodium borohydride, phosphorus trichloride,

tribromide, or the like) in an suitable inert organic solvent (e.g., acetonitriϊe, ethanol, aqueous dioxane, or the like) at 0 to 80°C.

Prodrug derivatives of the compounds of Formula I can be prepared by methods

known to those of ordinary skill in the art (e.g., for further details see Saulnier et α/. (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, appropriate

prodrugs can be prepared by reacting a non-derivatized compound of Formula I with a

suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbonochloridate, p rα-nitrophenyl

carbonate, or the like).

Protected derivatives of the compounds of Formula I can be made by means known

to those of ordinary skill in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene,

Protecting Groups in Organic Synthesis, 3^rd edition, John Wiley & Sons, Inc. 1999.

Compounds of the present invention may be conveniently prepared, or formed during the

process of the invention, as solvates (e.g. hydrates). Hydrates of compounds of the present

invention may be conveniently prepared by recrystallisation from an aqueous/organic

solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.

Compounds of Formula I can be prepared as their individual stereoisomers by reacting a

racemic mixture of the compound with an optically active resolving agent to form a pair

of diastereoisomeric compounds, separating the diastereomers and recovering the optically

pure enantiomer. While resolution of enantiomers can be carried out using covalent

diasteromeric derivatives of compounds of Formula I, dissociable complexes are preferred

(e.g., crystalline diastereoisomeric salts). Diastereomers have distinct physical properties

(e.g., melting points, boiling points, solubilities, reactivity, etc.) and can be readily

separated by taking advantage of these dissimilarities. The diastereomers can be separated

by chromatography or, preferably, by separation/resolution techniques based upon differences in solubility. The optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization. A more

detailed description of the techniques applicable to the resolution of stereoisomers of compounds from their racemic mixture can be found in Jean Jacques Andre Collet, Samuel

H. Wilen, Enantiomers, Racemates and Resolutions, John Wiley & Sons, Inc. (1981).

In summary, the compounds of Formula I are made by a process which comprises:

(A) reacting a compound of Formula 2:

2 with a compound of the formula (a):

(a)

in which X¹, X², R³, R⁴, R²⁰ and R²¹ are as defined in the Summary of the

Invention for Formula I; or

(B) reacting a compound of Formula 2 with a compound of the formula (b):

( ) 0 7^*^ 7^ in which R , R and R are as defined in the Summary of the Invention for Formula

I; or

(C) reacting a compound of Formula 2 with a compound of the formula (c):

(c) in which R²⁰, R²³ and R²⁵ are as defined in the Summary of the Invention for

Formula I; and

(D) optionally converting a compound of Formula I into a pharmaceutically acceptable salt;

(E) optionally converting a salt form of a compound of Formula I to non-salt form;

(F) optionally converting an unoxidized form of a compound of Formula I into a pharmaceutically acceptable N-oxide;

(G) optionally converting an N-oxide form of a compound of Formula I its

unoxidized form;

(H) optionally resolving an individual isomer of a compound of Formula I from a

mixture of isomers;

(I) optionally converting a non-derivatized compound of Formula I into a

pharmaceutically prodrug derivative; and

(J) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form. O 03/024924

-46-

Examples:

The present invention is further exemplified, but not limited by, the following

examples that illustrate the preparation of compounds of Formula I (Examples) and

intermediates (References) according to the invention.

REFERENCE 1

3-amino-4-hydroxy-pyrrolidine-l-carboxylic acid tert-butyl ester

6-Oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (12. lg,

65.3mmol) was dissolved in a 8: 1 methanol/water mixture (108mL). Aiirmoriium chloride

(15g) and sodium azide (21.4g, 329mmol) was added and the mixture was heated at 60°C

overnight. After dilution with ether (500mL), the mixture was washed with saturated

aqueous NaHCO₃ (200mL) and brine (200mL), dried with MgSO₄ and evaporated under

vacuum. The crude product was dissolved in methanol (200mL). 10% Palladium on

activated carbon (1.5g) was added and the mixture was stirred at ambient temperature

under a hydrogen atmosphere until TLC analysis showed the disappearance of the starting

material. The mixture was filtered through a pad of Celite and evaporated to dryness under

vacuum. The product was purified by flash chromatography on silica gel. Eluent: 5%

methanol in ethyl acetate to 20% methanol, 3% triethylamine in ethyl acetate. Yield: 4.3g 3 -amino-4-hydroxy-ρyrrolidine-l -carboxylic acid tert-butyl ester as yellowish solid.

REFERENCE 2 4-Amino-3-hydroxy-azepane-l-carboxylic acid benzyl ester O 03/024924

-47-

Sodium hydride (60% in mineral oil, lOg, 250mmol) was suspended in dry DMF. Allyl-carbamic acid benzyl ester (19. lg, lOOmmol) was added drop wise at ambient temperature. After stirring for 5 minutes, 5-bromo- 1-pentene (25g, 168mmol) was added drop wise. Stirring was continued at 50°C for 1 hour. The reaction was quenched with water and then partitioned between diethyl ether and water. The ether layer was washed with water and brine, dried with MgSO and evaporated under vacuum. Flash chromatography (ethyl acetate/hexane 1:9) gave allyl-pent-4-enyl-carbamic acid benzyl ester (15.5g).

Allyl-pent-4-enyl-carbamic acid benzyl ester (15.5g, 59.8mmol) was dissolved in dichloromethane and bis(trϊcyclohexylphosphine)benzylidene ruthenium(rV) dichloride (lg) was added. The mixture was refluxed under a nitrogen atmosphere until TLC analysis showed complete reaction. The solvent was evaporated under vacuum and the residue was purified by flash chromatography (ethyl acetate/hexane 1:9) to give 2,3,4,7-Tetrahydro- azepine-1 -carboxylic acid benzyl ester (7.8g). To a solution of 2,3, 4,7-tetrahydro-azepine-l -carboxylic acid benzyl ester (4.5g,

19.45mmol) in dichloromethane (50mL) was added m-chloroperbenzoic acid (60mmol). The mixture was stirred at ambient temperature for 16 hours. Saturated aqueous K₂CO₃ solution was added and the mixture was extracted with dichloromethane. The combined organic layers were washed with saturated aqueous NaHCO₃ and brine, dried with MgSO and evaporated under vacuum. The crude epoxide was dissolved in an 8:1 methanol/water mixture (lOOmL). Ammonium chloride (3.2g, 60mmol) and sodium azide (3.9g, 60mmol) were added and the mixture was heated at 60°C for 48 hours. Most of the solvent was removed under vacuum. The residue was extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous NaHCO₃ (200mL) and brine (200mL), dried with MgSO₄ and evaporated under vacuum. Flash chromatography of the residue

(hexane/ethyl acetate 3:1) gave 4-azido-3-hydroxy-azepane-l-carboxylic acid benzyl ester

(3.3g).

To a solution of 4-azido-3-hydroxy-azepane-l -carboxylic acid benzyl ester (3.3g,

11.37mmol) in methanol (50mL) was added triethylamine (5mL) and 1,3-propanedithiol (3.42mL, 35mmol). The mixture was stirred at ambient temperature until TLC analysis

showed complete consumption of the starting material. A white precipitate was removed

by filtration and the filtrate was evaporated to dryness. The residue was triturated with a

1:1 hexane/diethyl ether mixture to remove excess dithiol and dried under vacuum to yield

4-amino-3-hydroxy-azepane-l -carboxylic acid benzyl ester.

REFERENCE 3

25- Amino-N-(4-methoxyphenyl)-4-phenylbutane- 1 -sulfonamide hydrochloride

A solution comprised of crude tert-butyl l-(4-methoxyphenylsulfamoylmethyl)-3-

phenylpropylcarbamate (1.92 g, 4.42 mmol), prepared as in Reference Example 2, in DCM (10 mL) was treated with a 4M solution of hydrogen chloride in dioxane (11 mL). The

mixture was stirred for 16 hours at room temperature and diluted with diethyl ether. A

resulting precipitate was collected by filtration, washed several times with diethyl ether and

hexane and pumped dry to provide 2S-amino-N-4-methoxyphenyl-4-phenylbutane-l-

sulfonamide hydrochloride with quantitative mass recovery. 1H ΝMR (DMSO): 2.05 (2H,

m); 2.6-2.7 (2H, m); 3.4 (3H, m*); 3.72 (3H, s); 6.9 (2H, d, J=7 Hz); 7.25 (5H, m); 7.3 (2H, d, J=7 Hz); 8.5 (br. s); 10.0 (IH, s).

EXAMPLE 1 Morpholine-4-carboxylic acid ri-(l-benzoyl-4-oxo-pyrrolidin-3-ylcarbamovD-2-

phenylmethanesulfonyl-ethyll-amide

(Compound 1)

2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid (lg,

2.8mmol), 3-amino-4-hydroxy-pyrrolidine-l-carboxylic acid tert-butyl ester (700mg, 3.46mmol) prepared as in Reference 1, EDC (1.5g, 7.8mmol), and HOBt (1.5g, 9.6mmol) were combined. Dichloromethane (lOmL) was added and then 4-methylmorpholine (1.5mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (200mL) the solution was washed with saturated aqueous NaHCO₃ (lOOmL) and brine (lOOmL), dried with MgSO and evaporated under vacuum. 3-Hydroxy-4-{2-

[(mo holine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionylamino}-pyrrolidine- 1-carboxylic acid tert-butyl ester (1.05g, 1.94mmol) was obtained as yellowish foam and was dissolved in dichloromethane (6mL). Trifluoroacetic acid (6mL) was added and the mixture was stirred at ambient temperature for 1 hour. Evaporation under vacuum gave crude morpholine-4-carboxylic acid [l-(4-hydroxy-pyrrolidin-3-ylcarbamoyl)-2-

phenylmethanesulfonyl-ethyl]-amide as TFA salt, which was used without further purification.

Morpholine-4-carboxylic acid [l-(4-hydroxy-pyrrolidin-3-ylcarbamoyl)-2- phenylmethanesulfonyl-ethyl]-amide TFA salt (2l5mg, 0.39mmol) was dissolved in 1,4- dioxane (20mL). Saturated aqueous NaHCO₃ solution (lOmL) was added followed by

benzoyl chloride (0.2mL, 1.72mmol). The mixture was stirred at ambient temperature for

1 hour and then extracted with ethyl acetate. The combined organic layers were washed

with saturated aqueous NaHCO₃ and brine, dried with MgSO and evaporated under

vacuum. The residue was purified by flash chromatography on silica gel (Eluent: 5%

methanol in ethyl acetate to 20% methanol in ethyl acetate) to yield morpholine-4- carboxylic acid [l-(l-benzoyl-4-hydiOxy-pyrrolidin-3-ylcarbamoyl)-2-phenylmethane-

sulfonyl-ethyl] -amide (92mg).

Morpholine-4-carboxylic acid [l-(l-benzoyl-4-hydroxy-pyπOlidin-3-ylcarbamoyl)-

2-phenylmethanesulfonyl-ethyl]-amide (92mg, 0.169mmol) was dissolved in DMSO

(5mL). Triethylamine (0.5mL) and then SO₃ pyridine complex (150mg) were added and

the mixture was stirred at ambient temperature for 3 hours. After dilution with ethyl

acetate (lOOmL), the solution was washed with water (50mL) and brine, dried with MgSO and evaporated under vacuum. The residue was purified by flash chromatography on silica

gel (Eluent: 5% methanol in ethyl acetate) to yield morpholine-4-carboxylic acid [T-(l- benzoyl-4-oxo-pyrrolidin-3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethyll-amide as a

mixture of diastereomers (Yellowish solid; 38mg); 1H NMR: (DMSO) 8.50-8.35 (m, IH),

7.55-7.34 (m, 10H), 7.16-6.95 (m, IH), 4.80-4.65 (m, IH), 4.54-4.22 (m, 3H), 3.98-3.25

(m, 14H); MS: (M+H)⁺ 543.

EXAMPLE 2 Morpholine-4-carboxylic acid ri-(l-benzenesulfonyl-4-oxo-pyrrolidin-3-ylcarbamoyl')

2-phenylmethanesulfonyl-ethyll-amide

(Compound 2)

Morpholine-4-carboxylic acid [l-(l-benzenesulfonyl-4-oxo-pyrrolidin-3-

ylcarbamoyl) 2-phenylmethanesulfonyl-ethyl] -amide was prepared following the procedure

detailed in Example 1, substituting benzenesulfonyl chloride for benzoyl chloride; H

NMR: (DMSO) [8.35 (d, J=7.4Hz), 8.28 (d, J=7.6Hz), IH], 7.87-7.62 (m, 5H), 7.41-7.32

( , 5H), 7.06-6.98 (m, IH), 4.72-4.60 (m, IH), 4.45 (s, 2H), 4.42-4.23 (m, IH), 3.92-3.79

(m, 2H), 3.55-3.20 (m, 11H), 3.06-2.97 (m, IH). MS: (M+H)⁺ 579.

EXAMPLE 3 4-{2-r(Moφholine-4-carbonyl)-amino1-3-phenylmethanesulfonyl-propionylamino}-3-

oxo-azepane-1 -carboxylic acid benzyl ester

(Compound 3)

Crude 4-amino-3-hydroxy-azepane-l-carboxylic acid benzyl ester (150mg,

0.57mmol) prepared as in Reference 2, 2-[(morpholine-4-carbonyl)-amino]-3- phenylmethanesulfonyl-propionic acid (400mg, 1.12mmol), EDC (400mg, 2.1mmol), and

HOBt (400mg, 2.5mmol) were combined. Dichloromethane (lOmL) was added followed by 4-methylmorpholine (0.5mL). The mixture was stirred at ambient temperature for 2

hours. After dilution with ethyl acetate (lOOmL) the solution was washed with IN HCI,

saturated aqueous NaHCO₃ and brine, dried with MgSO₄ and evaporated under vacuum.

The residue was purified by flash chromatography (ethyl acetate/methanol 9:1) to yield 3-

hydroxy-4- { 2- [(morpholine-4-carbonyl)-amino] -3 -phenylmethanesulf onyl-propionyl-

amino}-azepane-l -carboxylic acid benzyl ester (320mg).

3 -Hydroxy-4- { 2- [(morpholine-4-carbonyl)-amino] -3 -phenylmethanesulf onyl-

propionylamino}-azepane-l -carboxylic acid benzyl ester (lOO g, 0.167mmol) was

dissolved in DMSO (5mL). Triethylamine (0.3mL) and then SO₃ pyridine complex

(150mg) were added and the mixture was stirred at ambient temperature for 3 hours. After

dilution with ethyl acetate (lOOmL), the solution was washed with water (50mL) and brine,

dried with MgSO₄ and evaporated under vacuum. The residue was purified by flash

chromatography on silica gel (Eluent: 5% methanol in ethyl acetate) to yield 4-{2-

r(moφholine-4-carbonyl)-aminol-3-phenylmethanesulfonyl-propionylarnino)-3-oxo-

azepane-l-carboxylic acid benzyl ester (75mg); ^XH NMR: (DMSO) 8.23-8.08 (m, IH),

7.40-7.29 (m, 10H), 7.06-6.98 ( , IH), 5.20-5.09 (m, 2H), 4.79-4.65 (m, IH), 4.52-4.31

(m, 3H), 4.02-3.80 (m, 2H), 3.62-3.23 (m, 11H), 3.00-2.78 (m, IH), 1.88-1.55 (m, 4H);

MS: (M+H)⁺ 601.

EXAMPLE 4

Morpholine-4-carboxylic acid ri-(3-benzenesulfonylamino-2-oxo-propylcarbamoyl)-2- phenylmethanesulfonyl-ethyll-amide (Compound 4)

N-(3-Amino-2-hydroxy-propyl)-benzenesulfonamide TFA salt was prepared as

outlined in Renee L. DesJarlais et al. J. Am. Chem. Soc. 1998, 120, 9114-9115.

2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid

(50mg, 0.14mmol), Ν-(3-amino-2-hydroxy-propyl)-benzenesulfonamide TFA salt (60mg,

0.17mmol), EDC (lOOmg, 0.52mmol), and HOBt (lOOmg, 0.64mmol) were combined.

DMF (3mL) was added and then 4-methylmorpholine (0.3mL). The mixture was stirred

at ambient temperature for 3 hours. After dilution with ethyl acetate (lOOmL) the solution

was washed with IN HCI, saturated aqueous NaHCO₃ and brine, dried with MgSO₄ and

evaporated under vacuum. The residue was dissolved in acetone (5mL). Jones reagent

was added until the orange color persisted. The mixture was stirred for 2 hours, quenched with isopropanol, and diluted with ethyl acetate (lOOmL). The solution was washed with water, saturated aqueous NaHCO₃ and brine, dried with MgSO₄ and evaporated under

vacuum. The crude product was recrystallized from ethyl acetate/diethyl ether to give morpholine-4-carboxylic acid ri-(3-benzenesulfonylarmno-2-oxo-propylcarbamoylV2-

phenylmethanesulfonyl-ethyll-amide as white solid (19mg); 1H NMR: (DMSO) 8.17 (t,

J=5.7Hz, IH), 7.93 (t, J=5.9Hz, IH), 7.76-7.48 (m, 5H), 7.36-7.29 (m, 5H), 7.05 (d,

J=8.1Hz, IH), 4.68-4.59 (m, IH), 4.45 (s, 2H), 3.89 (d, J=5.7Hz, 2H), 3.79-3.75 (m, 2H),

3.56-3.22 (m, 10H); MS: (M+H)⁺ 567.

EXAMPLE 5 N-|lS-riS-(4-Methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyn 2-

benzylsulf onylethyl I -morpholine-4-carboxamide

(Compound 7)

A mixture comprised of 2S-morpholin-4-ylcarbonylamino-3-benzylsulfonyl-

propionic acid (0.194 g, 0.599 mmol), 25-amino-N-(4-memoxyphenyl)-4-phenylbutane-l-

sulfonamide hydrochloride (0.222 g, 0.599 mmol), prepared as in Reference 3, and HATU

(0.228 g, 0.599 mmol) in DMF (5 mL) was treated with 4-methylmorpholine (0.198 g, 1.80

mmol). The mixture was stirred at room temperature for approximately 12 hours and then

partitioned among a 4:1:2:3 mixture (100 mL total) of ethyl acetate, THF, water, and brine,

respectively. The organic phase was separated and washed with saturated aqueous sodium

bicarbonate (30 mL), brine (30 mL), dried (MgSO₄), filtered and concentrated. The residue

was triturated with of 5:1 ether/ethyl acetate (100 mL), collected by filtration, washed with ether (30 mL), hexane (30 mL), and pumped dry to provide N-U5-H5-(4-

methoxyphenylsulfamoylmethyl)-3-phenyIpropylcarbamoyn-2-benzyIsulfonylethyl}-

morpholme-4-carboxamide. TLC R_f (ethyl acetate): 0.65; 1H ΝMR (DMSO): 1.74 (IH,

m); 1.92 (IH, m); 2.39-2.61 (2H, m); 3.1-3.35 (2H, 2xdd*); 3.34 (4H, m); 3.42-3.65 (6H,

m*); 3.72 (3H, s); 4.24 (IH, m); 4.51 (2H, s); 4.61 (IH, m); 6.88 (2H, d, J=9 Hz); 7.1-7.34 (8H, m); 7.4 (5H, s); 8.12 (IH, d, J=8.7 Hz); MS (M+l): 673. Proceeding as in Example 5 the following compounds of Formula I were prepared:

N- { IS- r5-amino- lS-(4-methoxyphenylsulf amoyl-methyDpentylcarbamoyl } -2- benzylsulfonylethyl-morpholine-4-carboxamide hydrobromide (Compound 5); 1H ΝMR

(DMSO): 1.15-1.73 (6H, m*); 2.71 (2H, m); 3.05-3.25 (2H, 2xdd); 3.37 (4H, m); 3.45-3.6

(6H, m*); 3.72 (3H, s); 4.21 (IH, m); 4.49 (2H, dd); 4.5 (IH, in*); 6.89 (2H, d, J=8.9 Hz);

7.09 (IH, m*); 7.15 (2H, d, J=8.9 Hz); 7.39 (5H, s); 7.73 (3H, br. s); 8.03 (IH, d, J=8.6

Hz); 9.47 (IH, s); MS (M+l): 640, free base); and

Benzyl 6-(4-methoxyphenylsulfamoyl)-55-(25-morpholin-4-ylcarbonylamino-3-

benzylsulfonyl-propionylamino)hexylcarbamate (Compound 6); TLC Rf (ethyl acetate):

0.3; 1H ΝMR (DMSO): 1.1-1.65 (6H, m); 2.94 (2H, q, J=6 Hz); 3.05-3.22 (2H, 2xdd);

3.34 (4H, m*); 3.35-3.59 (2H, m*); 3.53 (4H, br s); 3.71 (3H, s); 4.19 (IH, m*); 4.53 (2H,

dd, J=15 Hz); 4.57 (IH, m*); 5.00 (2H, s); 6.89 (2H, d, J=8.4 Hz); 7.05 (IH, d, J=8 Hz); 7.15 (2H, d, J=8.4 Hz); 7.24 (IH, t); 7.3-7.45 (10H, 2xs); 7.99 (IH, J=8 Hz); MS (M+):

774.

EXAMPLE 6

Morpholine-4-carboxylic acid [(R)-l-(6-oxo-eyclohex-l-enylcarbamoyl)-2-

phenylmethanesulfonyl-ethyll-amide

(Compound 8)

A solution of 2-ammo-cyclohexane-l,3-diol (0.55 g) in dimethylformamide (30ml)

was treated with diisopropylethylamine (1.6ml, 9.2mmol). After stirring at room

temperature for 5 minutes the mixture was treated with (R)-2-[(morpholine-4-carbonyl)- amino] -3 -phenylmethanesulf onyl-propionic acid (1.73g, 4.86mmol) followed by HATU

(1.68g, 4.42mmol). This mixture was stiιτed at room temperature overnight and then

evaporated. The residue was subjected to flash chromatography on silica eluting with ethyl

acetate and then a mixture of ethyl acetate and methanol to give morpholine-4-carboxylic acid [(R)- 1 -(2,6-dihydroxy-cyclohexylcarbamoyl)-2-phenyImethanesulfonyl-ethyl]-amide

as a white solid (210mg). MS: 470 (MHT).

A solution of morpholine-4-carboxylic acid [(R)-l-(2,6-dihydroxy-

cyclohexylcarbamoyl)-2-phenylmethanesulfonyl-ethyl] -amide (90mg, 0.19mmol) in

methylene chloride (6ml) was treated with Dess-Martin periodinane (162mg, O.38mmol).

After stirring at room temperature for 2 hours the reaction mixture was washed with a

solution of Na₂S₂O₃ in water (0.26M), then with saturated aqueous bicarbonate solution then with water, then dried over Na₂SO and then evaporated under reduced pressure. The

residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane to give morpholine-4-carboxylic acid [(R)-l-(6-oxo-cyclohex-l- enylcarbamoyiy2-phenylmethanesulfonyl-ethvπ-amide (8mg). 1H NMR (CDC1₃) : 9.00

(s, IH), 7.82 (t, J=5Hz, IH), 7.53-7.38 (m, 5H), 6.06 (d, J=6Hz, IH), 5.00 ( , IH), 4.47-

4.27 (m, 2H), 3.85 (m, IH), 3.77-3.62 (m, 4H), 3.48-3.36 (m, 4H), 3.27 (m, IH), 2.58-2.46

(m, 4H), 2.08-1.97 ( , 2H). MS: 450 (MH"). EXAMPLE 7

Morpholine-4-carboxylic acid [(R)-2-cyclopropylmethanesulfonyl- l-(6-oxo-cyclohex-

1 -enylcarbamoyD-ethyll -amide

(Compound 9)

A mixture of (R)-3-cyclopropylmethanesulfonyl-2-[(morpholine-4-carbonyl)-

aminoj-propionic acid (0.352g, 1.1 mmol) and N-cyclohexylcarbodiimide N'-

methylpolystyrene (1.93 mmol/g, 1.03g) in DCM (lOmL) was treated with

hydroxybenzotriazole (0.27g, 2 mmol). After stirring at room temperature for 5 minutes

the mixture was treated with 2-amino-cyclohexane-l,3-diol (0.0.131g, 1 mmol) and stirring was continued for a further 2 days. The reaction mixture was treated with PS Trisamine

(3.75 mmol/g, 1.3g) and after stirring at room temperature for 2 hours the resin was filtered

off and washed with DCM. The combined filtrate plus washings were evaporated under

reduced pressure to give morpholine-4-carboxylic acid [(R)-2-cyclopiOpylmethanesulfonyl- l-(2,6-dihydroxy-cyclohexylcarbamoyl)-ethyl]-amide (0.32g) as pale yellow thick oil. MS: 434 (MH").

Dess Martin Periodinane (0.688 g, 1.62 mmol) was added to a solution of the

[(R)-2-cyclopiOpylmethanesulfonyl-l-(2,6-dihydiOxy-cyclohexylcarbamoyl)-ethyl]-amide (0.32g) in DCM (lOmL) and the mixture was stirred at room temperature for 3 hours then treated with resin bound Na₂S₂O₃ (1.5 mmol/g, 1.9g) and stirred at room temperature for

a further 24 hours. The reaction mixture was diluted with DCM ( 20mL) , then filtered.

The filtrate was washed with a solution of 0.25 M Na₂S₂O₃,then with saturated NaHCO₃,

then dried (MgSO ), and then evaporated under reduced pressure. The residue was

subjected to column chromatography eluting with a mixture of ethyl acetate and heptane

to give morpholine-4-carboxylic acid (R)-2-cyclopropylmethanesulf onyl- 1 -(6-oxo-

cvclohex-1-enylcarbamoylVethyll-amide. 1H NMR (CDC1₃): 9.00 (s, IH), 7.78 (t, IH),

6.18 (d, IH), 4.9 (m, IH), 3.85 (m, IH), 3.77-3.62 (m, 4H), 3.58-3.45 (dd, IH), 3.48-3.36

(m, 4H), 3.0 (d, 2H), 2.55-2.42 (m, 4H), 2.08-1.97 (m, 2H), 1.2 (m, IH), 0.8-0.7 (m, 2H),

0.6-0.4 (m, 2H). MS: 414 (MH*).

EXAMPLE 8

Morρholine-4-carboxylic acid r(R)-l -(3,4-dioxo-cyclopentylcarbamoylV2- phenylmethanesulfonyl-ethyl -amide

(Compound 10)

A solution of 4-amino-cycloρentane-l, 2-diol; compound with trifluoroacetic acid (745mg, 3.23mmol) in DMF (15ml) was treated with DIPEA (1.12ml, 6.4mmol) and the mixture was stirred for 5 minutes at room temperature. Then (R)-2-[(Morρholine-4- carbonyl)-amino] -3 -phenylmethanesulf onyl-propionic acid (1.15g, 3.23mmol) was added followed by HATU (1.23g, 3.24mmol). This mixture was stirred at room temperature overnight and then evaporated. The residue was subjected to flash chromatography on silica eluting with ethyl acetate and then with a mixture of ethyl acetate and methanol to give morpholine-4-carboxylic acid [(R)-l-(3,4-dihydroxy-cyclopentylcarbamoyl)-2-

phenylmethanesulfonyl-ethyl]-amide as a brown solid (680mg). LC/MS: RT=2.64min. (215 and 254nM), MH⁺=456.

A solution of morpholine-4-carboxylic acid [(R)-l-(3,4-dihydroxy- cyclopentylcarbamoyl)-2-phenylmethanesulfonyl-ethy]]-amide (670mg, 1.47mmol) in

methylene chloride (40ml) was treated with Dess-Martin periodinane (624mg, 1.47mmol) and the reaction stirred at room temperature overnight. More Dess-Martin periodinane (642mg, 1.51mmol) was added and the reaction stiffed at room temperature for 6hours and then overnight. The reaction mixture was washed with a solution of Na S O3 in water (0.26M), then with saturated aqueous bicarbonate solution , then with water, then dried over Na SO and then evaporated under reduced pressure. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane, then with ethyl acetate to give morpholine-4-carboxylic acid r(R)-l-(3.4-dioxo- cyclopentylcarbamoyl -2-phenylmethanesulfonyl-ethyll-amide as an off white solid (45mg). 1H NMR (C C1₃): 7.50-7.38 (m, 5H), 6.62 (m, IH), 5.91 (d, J=5Hz, IH), 4.81 (m, IH), 4.58-4.35 (m, 3H), 3.73-3.61 (m, 5H), 3.44-3.32 (m, 4H), 3.22 (m, IH), 2.72-2.12 (m, 4H). MS: 452 (MH").

EXAMPLE 9 Morpholine-4-carboxylic acid r2-(2-difluoromethoxy-phenylmethanesulfonyl - 1 -(2- oxo~cyclohexylcarbamoyl)-ethyl]-amide

(Compound 11)

3-(2-Difluoromethoxy-phenylmethanesulfonyl)-2-[(morpholine-4-cafbonyl)-

amino]-propionic acid (lOOmg, 0.237mmol), 2-aminocyclohexanol (58mg, 0.5mmol), EDC

(lOOmg, 0.52mmol), and HOBt (lOOmg, 0.64mmol) were combined. Dichloromethane

(2mL) was added and then 4-methylmorpholine (0.2mL). The mixture was stirred at ambient temperature for 2h. After dilution with ethyl acetate (lOOmL) the solution was

washed with IN aqu. HCI (30mL), sat. aqu. NaHCO₃ (30mL) and brine (30mL), dried with

MgSO₄ and evaporated under vacuum. The crude product was dissolved in dichloromethane (lOmL). Dess-Martin periodinane (300mg, 0.71mmol) was added, and

the reaction mixture was stirred at ambient temperature for lh. After dilution with ethyl

acetate (lOOmL), the solution was washed with 0.26M Na₂S₂O₃ in sat. aqu. NaHCO₃

(30mL), sat. aqu. NaHCO₃ and brine, dried with MgSO , and evaporated under vacuum.

Purification by flash-chromatography on silica gel (ethyl acetate hexane) gave morpholine-

4-carboxylic acid r2-(2-difluoromethox v-phenylmethanesulf onyl)- 1 -(2-oxo- cyclohexylcarbamoylV ethyl] -amide (78mg, 0.151mmol) as a white solid. Mixture of

diastereomers: 1H NMR: (DMSO) [8.03 (d, J=7.2Hz), 7.96 (d, J=7.2Hz), IH], 7.50-7.42 (m, 2H), 7.30-7.21 (m, 2H), 7.10 (t, J_H,_F=74HZ, IH), 7.03 (d, J=8.4Hz, IH), 4.78-4.69 (m, 1H), 4.54 (s, 2H), 4.41-4.33 (m, IH), 3.62-3.25 ( , 10H), 2.55-1.40 (m, 8H). MS: (M+H)⁺

518.

By proceeding in similar manner to Example 9 but using 2-aminocyclopentanol

there was prepared morpholine-4-carboxylic acid [2-(2-difluoiOmethoxy-

phenylmethanesulfonyl)-l-(2-oxo-cyclopentylcarbamoyl)-ethyll-amide (Compound 12)

as a mixture of diastereomers: 1H NMR: (DMSO) [8.19 (d, J=8Hz), 7.15 (d, J=8Hz),

IH], 7.49-7.42 ( , 2H), 7.30-7.21 (m, 2H), 7.10 (t, J_H;F=74Hz, IH), [7.02 (d, J=8.4Hz),

7.00 (d, J=8.4Hz), IH], 4.77-4.70 (m, IH), [4.53 (s), 4.52 (s), 2H], 4.10-3.91 (m, IH),

3.60-3.23 (m, 10H), 2.28-1.70 (m, 6H). MS: (M+H)⁺ 504.

By proceeding in similar manner to Example 9 but using 2-aminocyclobutanol

there was prepared morpholme-4-carboxylic acid r2-(2-difluoromethoxy- phenylmethanesulfonyl -l-(2-oxo-cyclobutylcaι-bamoyl)-ethyl)-amide (Compound 13)

as a mixture of diastereomers: ^!H NMR: (DMSO) 8.49 (d, J=7.6Hz, IH), 7.48-7.42 (m,

2H), 7.30-7.21 ( , 2H), 7.11 (t, J_H,_F=74Hz, IH), 7.02 (d, J=8.8Hz, IH), 4.88-4.67 (m,

2H), 4.53 (s, 2H), 3.64-3.23 (m, 10H), 2.93-2.70 (m, 2H), 2.23-1.99 (m, 2H). MS: (M+H)⁺

EXAMPLE 10

(Morpholine-4-carboxylic acid f 1 -(2-benzylcarbamoyl-2-oxo-ethylcarbamoyl)-2-

phenylmethanesulfonyl-ethyn-amide)

(Compound 14)

Isoserine (3.1 lg, 29.6mmol) was dissolved in l,4-dioxane/H₂O 3:1 (40mL). K₂CO₃

(0.5g) and NaHCO₃ (0.5g) was added. Di-tert-butyl dicarbonate (6.45g, 29.6mmol) was

added and the mixture was stirred at ambient temperature over night. The reaction mixture

was extracted with dichloromethane (3xl00mL). The combined organic phases were washed with brine, dried with MgSO₄, and evaporated under vacuum. The crude 3-tert-

butoxycarbonylamino-2-hydroxy-propionic acid (4.76g, 23.2mmol) was obtained as a

colorless oil, which solidified on standing, and was used without further purification.

3-tert-butoxycarbonylamino-2-hydroxy-propionic acid (1.5g, 7.31mmol), benzylamine (l.lmL, lO.Ommol), EDC (2.5g, 13.1mmol), and HOBt (2.0g, 12.8mmol)

were combined. Dichloromethane (15mL) was added and then 4-methylmorpholine

(2mL). The mixture was stirred at ambient temperature for 2h. After dilution with ethyl

acetate (300mL) the solution was washed with IN aqu. HCI (lOOmL), sat. aqu. NaHCO₃

(lOOmL) and brine (lOOmL), dried with MgSO and evaporated under vacuum. Yield:

1.83g, 6.22mmol (2-Benzylcarbamoyl-2-hydroxy-ethyl)-carbamic acid tert-butyl ester.

(2-Benzylcarbamoyl-2-hydroxy-ethyl)-carbamic acid tert-butyl ester (0.2g,

0.68mmol) was dissolved in dichloromethane (2mL) and trifluoroacetic acid (2mL). After

stirring for 2h at ambient temperature, the solution was evaporated under vacuum and the residue was dried under high vacuum. To this residue were added EDC (200mg, 1.05mmol), HOBt (200mg, 1.28mmol), 2-[(Morpholine-4-carbonyl)-amino]-3-

phenylmethanesulfonyl-propionic acid (200mg, 0.56mmol), dichloromethane (5mL) and

4-methylmorpholine (0.5mL). The mixture was stiffed at ambient temperature for 2h.

After dilution with ethyl acetate (lOOmL) the solution was washed with IN aqu. HCI

(30mL), sat. aqu. NaHCO₃ (30mL) and brine (30mL), dried with MgSO and evaporated

under vacuum. The crude product was dissolved in dichloromethane (lOmL). Dess-Martin

periodinane (500mg, l.lδmmol) was added, and the reaction mixture was stirred at

ambient temperature for lh. After dilution with ethyl acetate (lOOmL), the solution was

washed with 0.26M Na₂S₂O₃ in sat. aqu. NaHCO₃ (30mL), sat. aqu. NaHCO₃ and brine,

dried with MgSO₄, and evaporated under vacuum. The product (morpholine-4-carboxylic

acid [l-(2-benzylcarbamoyl-2-oxo-ethylcarbamoyl)-2-ρhenylmethanesulfonyl-ethyl1- amide) was crystallized from ethyl acetate/diethylether and was obtained as a white solid

(153mg, 0.29mmol). 1H NMR: (DMSO) 9.24 (t, J=6.4Hz, IH), 8.19 (t, J=5.6Hz, IH),

7.39-7.19 (m, 10H), 7.08 (d, J=8Hz, IH), 4.83-4.76 (m, IH), 4.49 (s, 2H), 4.48-4.33 (m, 2H), 4.31 (d, J=6.8Hz, 2H), 3.68-3.25 (m, 10H). MS: (M+H)⁺ 531.

EXAMPLE 11

Acetic acid 3-{2-[(morpholine-4-carbonyl)-amiι o]-3-phenylmethanesulfonyl-

propionylamino }-4-oxo-azetidin-2-yl ester

(Compound 15)

Acetic acid 3-benzyloxycarbonylamino-4-oxo-azetidin-2-yl ester was prepared as

outlined in J.C. Arnould et al. Eur. J. Med. Chem 1992, 27, 131-140.

Acetic acid 3-benzyloxycarbonylamino-4-oxo-azetidin-2-yl ester (lOOmg,

0.36mmol) was hydrogenated on a Parr shaker over 10% palladium on carbon (lOOmg)

in ethyl acetate (20mL) at 50 psi for 5h. The mixture was filtered through Celite and evaporated. Acetic acid 3-amino-4-oxo-azetidin-2-yl ester was obtained in quantitative

yield.

2-[(Morpholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionic acid

(lOOmg, 0.28mmol), acetic acid 3-amino-4-oxo-azetidin-2-yl ester (52mg, 0.36mmol),

EDC (lOOmg, 0.52mmol), and HOBt (lOOmg, 0.64mmol) were combined.

Dichloromethane (2mL) was added and then 4-methylmorpholine (0.2mL). The mixture

was stirred at ambient temperature for 2h. After dilution with ethyl acetate (lOOmL) the

solution was washed with IN aqu. HCI (30mL), sat. aqu. NaHCO₃ (30mL) and brine (30mL), dried with MgSO and evaporated under vacuum. The residue was subjected to

flash chromatography on silica gel (ethyl acetate) to give acetic acid 3-{2-r(morpholine-4- carbonyl)-aminol-3-phenylmethanesulfonyl-propionylamino}-4-oxo-azetidin-2-yl ester

(17mg,^' 0.035mmol). 1H NMR: (DMSO) 9.18 (s, IH), 8.72 (d, J=6.4Hz, IH), 7.41-7.30 (m, 5H), 7.08 (m, IH), 5.76 (s, IH), 4.80-4.61 (m, 2H), 4.49 (s, 2H), 3.63-3.22 (m, 10H),

2.08 (s, 3H). MS: (M+H)⁺ 483.

EXAMPLE 12

Morpholine-4-carboxylic acid ri-(4-oxo-tetrahydiO-furan-3-ylcarbamoyl)-2-

phenylmethanesulfonyl-ethyll-amide

(Compound 16)

4-Amino-tetrahydro-furan-3-ol was prepared as outlined in Marquis, Robert W. et

al. J. Med. Chem 2001, 44, 725-736.

2-[(Morpholine-4-carbonyi)-amino]-3-phenylmethanesulfonyl-propionic acid

(lOOmg, 0.28mmol), 4-aminotetrahydiOfuran-3-ol (lOOmg, 0.96ramol), EDC (200mg,

1.04mrnol), and HOBt (200mg, 1.28mmol) were combined. DMF (2mL) was added and

then 4-methylmorpholine (0.2mL). The mixture was stirred at ambient temperature for 2h. After dilution with ethyl acetate (lOOmL) the solution was washed with IN aqu. HCI (30mL), sat. aqu. NaHCO₃ (30mL) and brine (30mL), dried with MgSO and evaporated

under vacuum. The crude product was dissolved in dichloromethane (lOmL). Dess-Martin periodinane (300mg, 0.71mmol) was added, and the reaction mixture was stirred at

ambient temperature for lh. After dilution with ethyl acetate (lOOmL), the solution was

washed with 0.26M Na₂S₂O₃ in sat. aqu. NaHCO₃ (30mL), sat. aqu. NaHCO₃ and brine,

dried with MgSO , and evaporated under vacuum. Purification by flash-chromatography

on silica gel (ethyl acetate) gave moιpholine-4-carboxylic acid ri-(4-oxo-tetrahydro-furan-

3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide (8.6mg, 0.020mmol) as a colorless

glass. Mixture of diastereomers: 1HNMR: (DMSO) [8.42 (d, J=6.8Hz), 7.15 (d, J=7.2Hz),

IH], 7.40-7.32 (m, 5H), [7.06 (d, J=8Hz), 7.05 (d, J=8Hz), IH], 4.78-4.68 (m, IH), [4.49

(s), 4.48 (s), 2H], 4.32-3.75 (m, 5H), 3.60-3.23 (m, 10H). MS: (M+H)⁺ 440.

EXAMPLE 13

Morρholine-4-carboxylic acid \ 1 -(2-hydroxy- 1.1 -dimethyl-3-oxo-3-phenyl- piOpylcarbamoyl)-2-phenylmethanesulfonyl-ethyl1-amide

(Compound 17)

Step 1 To a flask fitted with a septum and stirbar under a nitrogen atmosphere

containing 4.1 g (20 mmol) of 2-phenyl-l,3-dithiane (Aldrich) was added dry distilled

THF (20 mL). The solution was cooled to -30 °C and n-butyl lithium (1.6M in

pentane, 16.8 mmol, 10.5 mL) was added slowly by syringe. The reaction mixture was

warmed to -20 °C and held at that temperature for 30 minutes, and then held at -10 °C

for 15 minutes. The yellow solution was cooled to -78 °C and (l,l-dimethyl-2-oxo-

ethyl)-carbamic acid tert-butyl ester (1.5 g, 8 mmol, in 5 ml THF) was added rapidly (over 30 seconds) and 60 seconds later a solution of 2 mL acetic acid and 5 mL THF

was added rapidly. The cooling bath was removed and 4 minutes later water was added

and the mixture was extracted with ethyl acetate. The solvent was removed under reduced pressure and then recrystallized from 10 ml of ethyl acetate. The white

crystals were washed three times with ethyl acetate and dried under reduced pressure to afford [2-hydroxy-l,l-dimethyl-2-(2-phenyl-[l,3]dithian-2-yl)-ethyl]-carbarmc acid

tert-butyl ester (1.6g, 52%).

Step 2 To [2-hydroxy-l,l-dimethyl-2-(2-phenyl-[l,3]dithian-2-yl)-ethyl]- carbamic acid tert-butyl ester (1 g, 2.6 mmol) in 4.8 mL dioxane at 10 °C was added hydrochloric acid (4.8 mL, 4M in dioxane). The solution was warmed to 23 °C. After 2 hours the solution was concentrated to 4 ml and diluted with ether to afford a white precipitate that was collected by filtration. The mother liquor was concentrated to a paste and triturated with ether. The solids were combined to afford 726 mg of 2-amino- 2-methyl-l-(2-phenyl-[l,3]dithian-2-yl)-propan-l-ol (98% yield).

Step 3 2-Amino-2-methyl-l-(2-phenyl-[l,3]dithian-2-yl)-ρropan-l-ol and

2-[(morpholine-4-carbonyI)-amino]-3-phenylmethanesulfonyl-propionic acid were coupled using the standard peptide coupling conditions hereinbefore described to afford morpholine-4-carboxylic acid { l-[2-hydroxy-l,l-dimethyl-2-(2-phenyl-[l,3]dithian-2- yl)-ethylcarbamoyl]-2-phenylmethanesulfonyl-ethyl} -amide (270mg, 78%).

Step 4 To morpholine-4-carboxylic acid { l-[2-hydroxy-l,l-dimethyl-2-(2- phenyl-[ 1 ,3] dithian-2-yl)-ethylcarbamoyl] -2-phenylmethanesulf onyl-ethyl } -amide (200 mg, 0.32 mmol) in 5.25 ml of 4:1 acetonitrile: water at 23 °C was simultaneously added finely ground HgCl₂ (192 mg, 0.7 mmol) and finely ground calcium carbonate (80 mg, 0.8 mmol) with stirring. The mixture was stirred for 10 minutes and then diluted with ethyl acetate. Methylene chloride was added and the organics were washed with water. After separation the organic layer concentrated to a gum that solidified upon addition of ether. The ether was removed under reduced pressure to afford a white solid. The solid was dissolved in a minimum of hot methylene chloride and filtered to remove insoluble

material. The solution was concentrated to afford morpholine-4-carboxylic acid [l-(2-

hydroxy-l,l-dimethyl-3-oxo-3-phenyl-propylcarbamoyl)-2-phenylmethanesulfonyl-

ethyl]-amide (165mg, 100% yield).

Step 5 [ 1 -(2-hydroxy- 1 , 1 -dimethyl-3-oxo-3-phenyl-propylcarbamoyl)-2-

phenylmethanesulfonyl-ethyl] -amide was oxidized in the usual manner to afford

morphohne-4-carboxylic acid [l-(2-hydroxy-Ll-dimethyl-3-oxo-3-phenyl-

propylcarbamoyl)-2-phenylmethanesulfonyl-ethyl1-amide. ¹HNMR: (CDC1 ) [8.0 (d, J

= 8 Hz) IH], 7.7-7.2 (m, 10H), [5.9 (d, J = 6Hz) IH], [4.8 (d, J = 6Hz) IH], [4.3 (d, J =

14, Hz) IH], [4.1 (d, J = 14 Hz) IH], 3.7 (m, 4H), 3.36 (m, 4H), [3.3 (d, J = 2 Hz) IH],

[3.29 (d, J = 2 Hz) IH], 1.7(s, 6H). LCMS: elution time = 3.71 min. 527.6(M-1),

529.6(M+1). (MS: API 150EX. LC: HP Agilent 1100 Series. Column: Phenomenex, 5u ODS3 100A 100X3mm.; Flow Rate: 2ml/min. Two solvent gradient: Solvent A,

99% water, 1% acetonitrile, 0.1% AcOH. Solvent B, 99% actonitrile, 1% water, 0.1%

AcOH. Gradient from 100% A, 0% B to 0% A, 100% B from t = 0 to t = 6min. Then

gradient back to 100% A, 0% B from t = 7 to t = 15 min.).

By proceeding in a similar manner to Example 13 but using

3-(2-difluoromethoxy-phenylmethanesulfonyl)-2-[(moιτJholine-4-carbonyl)-amino]- propionic acid in step 3 there was prepared morpholine-4-carboxylic acid [2-(2-

difluoromethoxy-phenylmethanesulfony -l-(Ll-dimethyl-2,3-dioxo-3-phenyl- propylcarbamoyD-ethyn-amide. LC-MS: elution time = 3.95 min. 593.4(M-1), 596.2(M+1). (MS: API 150EX. LC: HP Agilent 1100 Series. Column: Phenomenex,

5u ODS3 100A 100X3mm.; Flow Rate: 2ml/min. Two solvent gradient: Solvent A, 99% water, 1% acetonitrile, 0.1% AcOH. Solvent B, 99% actonitrile, 1% water, 0.1%

AcOH. Gradient from 100% A, 0% B to 0% A, 100% B from t = 0 to t = 6min. Then

gradient back to 100% A, 0% B from t = 7 to t = 15 min.)

EXAMPLE 14

Cathepsin S Assay

Solutions of test compounds in varying concentrations were prepared in 10 μL of

dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 μL, comprising: MES,

50 mM (pH 6.5); EDTA, 2.5 mM; and NaCl, 100 mM). Human cathepsin S (0.158 pMoles

in 25 μL of assay buffer) was added to the dilutions. The assay solutions were mixed for

5-10 seconds on a shaker plate, covered and incubated for 30 minutes at ambient

temperature. Z-Val-Val-Arg-AMC (9 nMoles in 25 μL of assay buffer) was added to the

assay solutions and hydrolysis was followed spectrophotometrically at (λ 460 nm) for 5

minutes. Apparent inhibition constants (K,) were calculated from the enzyme progress

curves using standard mathematical models.

EXAMPLE 15 Cathepsin B Assay Solutions of test compounds in varying concentrations were prepared in 10 μL of

dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 μL, comprising: N,N-

bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES), 50 mM (pH 6);

polyoxyethylenesorbitan monolaurate, 0.05%; and dithiothreitol (DTT), 2.5 mM). Human

cathepsin B (0.025 pMoles in 25 μL of assay buffer) was added to the dilutions. The assay

solutions were mixed for 5-10 seconds on a shaker plate, covered and incubated for 30

minutes at ambient temperature. Z-FR-AMC (20 nMoles in 25 μL of assay buffer) was

added to the assay solutions and hydrolysis was followed spectrophotometrically at (λ 460

nm) for 5 minutes. Apparent inhibition constants (Kj) were calculated from the enzyme

progress curves using standard mathematical models.

EXAMPLE 16

Cathepsin K Assay

Solutions of test compounds in varying concentrations were prepared in 10 μL of

dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 μL, comprising: MES,

50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin K (0.0906

pMoles in 25 μL of assay buffer) was added to the dilutions. The assay solutions were

mixed for 5-10 seconds on a shaker plate, covered and incubated for 30 minutes at ambient

temperature. Z-Phe-Arg-AMC (4 nMoles in 25 μL of assay buffer) was added to the assay

solutions and hydrolysis was followed spectrophotometrically at (λ 460 nm) for 5 minutes.

Apparent inhibition constants (Kj) were calculated from the enzyme progress curves using standard mathematical models. EXAMPLE 17 Cathepsin L Assay

Solutions of test compounds in varying concentrations were prepared in 10 μL of

dimethyl sulfoxide (DMSO) and then diluted into assay buffer (40 μL, comprising: MES,

50 mM (pH 5.5); EDTA, 2.5 mM; and DTT, 2.5 mM). Human cathepsin L (0.05 pMoles

in 25 μL of assay buffer) was added to the dilutions. The assay solutions were mixed for

5-10 seconds on a shaker plate, covered and incubated for 30 minutes at ambient

temperature. Z-Phe-Arg-AMC (1 nMoles in 25 μL of assay buffer) was added to the assay

solutions and hydrolysis was followed spectrophotometrically at (λ 460 nm) for 5 minutes.

Apparent inhibition constants (Kj) were calculated from the enzyme progress curves using standard mathematical models.

Some of the compounds of the invention tested according to the above-described assays for protease inhibition were observed to exhibit selective cathepsin S inhibitory activity. The apparent inhibition constants (Kj) for compounds of the invention, against Cathepsin S, were in the range from about 10^"10M to about 10^"7M.

EXAMPLE 18 Representative Pharmaceutical Formulations Containing a Compound of

Formula I

ORAL FORMULATION Compound of Formula I 10- 100 mg

Citric Acid Monohydrate 105 mg

Sodium Hydroxide 18 mg

Flavoring

Water • q.s. to 100 mL

INTRAVENOUS FORMULATION

Compound of Formula I 0.1 - 10 mg

Dextrose Monohydrate q.s. to make isotonic

Citric Acid Monohydrate 1.05 mg

S odium Hydroxide 0.18 mg

Water for Injection q.s. to 1.0 mL

TABLET FORMULATION Compound of Formula I 1 %

Microcrystalline Cellulose 73%

Stearic Acid 25%

Colloidal Silica 1%.

Claims (16)

1. WE CLAIM:

   A compound of Formula I:

   in which:

   X¹ and X² are both methylene or X¹ is ethylene and X² is a bond;

   R³ is -CR⁵=CHR⁶, -CR⁵(CR⁶ ₃)₂ or -CR⁷=NR⁸, wherein R⁵ is hydrogen and R⁶ is

   hydrogen or (Cι- )alkyl or R⁵ and R⁶ together with the atoms to which R⁵ and R⁶ are

   attached form (C_3-12)cycloaIkenyl, hetero(C_5-12)cycloalkenyl, (C_6-ι₂)aryl, hetero(C_6-12)aryl,

   (C9-)₂)bicycloaryl or hetero(C₈-ι )bicycloaryl and R⁷ and R⁸ together with the atoms to

   which R⁷ and R⁸ are attached form hetero(C_5-1 )cycloalkenyl, hetero(C_6-i₂)aryl or

   hetero(C_8-12)bicycloaryl, wherein R³ optionally is substituted by 1 to 5 radicals

   independently selected from a group consisting of (Cι- )alkyl, cyano, halo, halo-substituted

   (C_1-4)alkyl, nitro, -X⁴NR⁹R⁹, -X⁴OR⁹, -X⁴SR⁹, -X⁴C(O)NR⁹R⁹, -X⁴C(O)OR⁹,

   -X⁴S(O)R¹⁰, -X⁴S(O)₂R¹⁰ and ~X⁴C(O)R¹⁰, wherem X⁴ is a bond or (Cι_-2)alkylene, R⁹ at

   each occurrence independently is hydrogen, ( _-3)alkyl or halo-substituted (Cι_-3)alkyl and R ,ιo i •s (C_1-3)alkyl or halo-substituted (C_1-3)aϊkyl; and R⁴is -C(0)X⁵Rⁿ or -S(O)₂X⁵Rⁿ, wherein X⁵ is a bond, -O- or -NR¹²-, wherein

   R¹² is hydrogen or (C_1-6)alkyl, and R¹¹ is (i) (C_1-6)alkyl optionally substituted by -OR¹³,

   -SR¹³, -S(O)R¹³, -S(O)₂R¹³, -C(O)R¹³, -C(O)OR¹³, -C(O)NR¹³R¹⁴, -NR¹³R¹⁴,

   -NR¹⁴C(O)R¹³, -NR¹ C(O)OR¹³,-NR¹⁴C(O)NR¹³R¹⁴ or -NR¹⁴C(NR¹⁴)NR¹³R¹⁴, wherein

   R¹³ is (C_3-12)cycloalkyl(Co_-3)alkyl, hetero(C_5-12)cycloalkyl(C_0-3)alkyl, (C_6-i₂)aryl(C_0-3)alkyl,

   lιetero(C_5-12)aryl(C_0-3)alkyl, (C _-12)bicycloaιyl(Co-₃)alkyl or

   hetero(C_8-12)bicycloaryl(Co-₃)alkyl and R¹⁴ at each occurrence independently is hydrogen

   or (C_1-6)alkyl, or (ii) (C_3-12)cycloalkyl(C₀-₃)alkyl, hetero(C₅-i₂)cycloalkyl(C_0-3)alkyl,

   (C_6-i₂)aιyl(Co_-3)alkyl, hetero(C_5-i₂)aryl(Co_-3)alkyl, (C_9-ι₂)bicycloaryl(Co-₃)alkyl or

   hetero(C_8-i₂)bicycloaryl(Co_-3)alkyl or (iii) (C_3-6)cycloalkyl(Co-₃)alkyl,

   hetero(C_5-6)cycloalkyl(C_0-3)alkyl, phenyl(C_0- )alkyl or hetero(C_5-6)aryl(C_0-3)alkyl

   substituted by -X⁶OR¹⁵, -X⁶SR¹⁵, -X⁶S(O)R¹⁵, -X⁶S(O)₂R¹⁵, -X⁶C(O)R¹⁵,

   -X⁶C(O)OR¹⁵, -X⁶C(O)NR¹⁵R¹⁶, -X⁶NR¹⁵R¹⁶, -X⁶NR¹⁶C(O)R¹⁵, -X°NR¹⁶C(O)OR¹⁵,

   -X⁶NR¹⁶C(O)NR¹⁵R¹⁶ , -X⁶NR¹⁶C(O)OR¹⁶, -X⁶NR¹⁶C(NR¹⁶)NR¹⁵R¹⁶, wherein X⁶ is a

   bond or methylene, R¹⁵ is (C_3-6)cycloalkyl(Co-₃)alkyl, hetero(C_5-6)cycloalkyl(Co-₃)alkyl,

   phenyl(C₀.₃)alkyl or hetero(C_5-6)aryl(Co-₃)alkyl and R¹⁶ is hydrogen or (C_1-6)alkyl; wherein

   R⁴ optionally further contains 1 to 5 substituents which when occurring within an alicyclic

   or aromatic ring system are radicals independently selected from a group consisting of

   (C_1-6)alkyl, (C_1-6)alkylidene, cyano, halo, nitro, halo-substituted (C_1-3)alkyl, -X⁶NR¹⁷R¹⁷,

   -X⁶NR¹⁷C(O)OR¹⁷, -X⁶NR¹⁷C(O)NR¹⁷R¹⁷, -X⁶NR¹⁷C(NR¹⁷)NR¹⁷R¹⁷, -X⁶OR¹⁷,

   -X⁶SR¹⁷, -X C(O)OR¹⁷, -X⁶C(O)NR¹⁷R¹⁷, -X⁶S(O)₂NR¹⁷R¹⁷, -X⁶P(O)(OR¹⁸)OR¹⁷,

   -X⁶OP(O)(OR¹⁸)OR¹⁷, -X⁶NR¹⁷C(O)R¹⁸, -X⁶S(O)R¹⁸, -X⁶S(O)₂R¹⁸ and -X⁶C(O)R¹⁸ and

   when occurring within an aliphatic moiety are radicals independently selected from a group consisting of cyano, halo, nitro, -NR¹⁷R¹⁷, -NR¹⁷C(O)OR¹⁷, -NR¹⁷C(O)NR¹⁷R¹⁷,

   -NR¹⁷C(NR¹⁷)NR¹⁷R¹⁷, -OR¹⁷, -SR¹⁷, -C(O)OR¹⁷, -C(O)NR¹⁷R¹⁷, -S(O)₂NR¹⁷R¹⁷,

   -P(O)(OR¹⁷)OR¹⁷, -OP(O)(OR¹⁷)OR¹⁷, -NR¹⁷C(O)R¹⁸, -S(O)R¹⁸, -S(O)₂R¹⁸ and

   -C(O)R¹⁸, wherein X⁶ is a bond or (C_1-6)alkylene, R¹⁷ at each occurrence independently

   is hydrogen, (C_1-6)alkyl or halo-substituted (C^alkyl and R¹⁸ is (C_1-6)alkyl or

   halo-substituted (C_1-3)alkyl;

   X³ is a group of Formula (a), (b) or (c):

   (a) (b) (c)

   n is 0, 1 or 2;

   R²⁰ is selected from the group consisting of hydrogen, (C_1-6)alkyl,

   (C₃-i₂)cycloalkyl(C_0-6)alkyl, hetero(C₅-ι₂)cycloalkyl(Co-₆)alkyl, (C_6-ι₂)aιyl(Co_-6)alkyl and

   heteiO(C_5-ι₂)aryl(C₀-_δ)alkyl;

   R²¹ is selected from the group consisting of hydrogen, (C_1- )alkyl,

   (C₃-i2)cycloalkyl(C₀-₆)alkyl, hetero(C_5-12)cycloalkyl(C_0-6)alkyl, (C_6-ι₂)aryl(C_0-6)alkyl,

   hetero(C_5-12)aryl(C_0-6)alkyl, (C_9-12)bicycloaryl(C_0-3)alkyl, hetero(C_8-12)-

   bicycloaryl(C_0-3)alkyl, -C(O)R²⁶, -C(S)R²⁶, -S(O)₂R²⁶, -C(O)OR²⁶, -C(O)N(R²⁶)R²⁷,

   -C(S)N(R²⁶)R²⁷ and -S(O)₂N(R²⁷)R²⁶;

   R²³ is selected from (C_1-6)alkyl, (C_4-6)alkenyl, (C_3-12)cycloalkyl(C_0-6)alkyl,

   hetero(C₅-i2)cycloalkyl(C₀-6)alkyl, (C₆.₁₂)aryl(Co-₆)alkyl or hetero(C_5-12)aryl(C₀-₆)alkyl optionally substituted with amino, -NHC(O)R¹⁵ or -R¹⁵ wherein R¹⁵ is as described above;

   R²⁵ is selected from hydrogen, (C_1-6)alkyl, (C₃.₁₂)cycloalkyl(C_0-6)alkyl,

   hetero(C_5-12)cycloalkyl(C₀-₆)alkyl, (C_6-12)aryl(C_0-6)alkyl, hetero(C_5-ι₃)aryl(C_0-6)alkyl,

   -X⁴NHR¹⁵, -X⁴S(O)₂R²⁶ or -X⁴C(O)R¹⁷NR¹⁷C(O)R¹⁷ wherein R¹⁵, R¹⁷ and X⁴ are as

   described above;

   R²⁶ is selected from the group consisting of hydrogen, (C_1-6)alkyl,

   (C_3-12)cycloalkyl(C₀-₆)alkyl, hetero(C_5-12)cycloalkyl(C_0-6)alkyl, (C_6-12)aryl(C₀-₆)alkyl,

   hetero(C₅.₁₂)aryl(Co_-6)alkyl, (C_9-i₂)bicycloaryl(Co-₃)alkyl or

   hetero(C₈.₁₂)-bicycloaryl(Co_-3)alkyl;

   R²⁷ is hydrogen, (C_1-6)alkyl, (C_3-ι₂)cycloalkyl(C_0-6)alkyl,

   hetero(C_5-12)cycloalkyl(C_0-6)alkyl, (C_6-12)aryl(C₀-₆)alkyl or hetero(C_5-i₂)aryl(C₀-₆)alkyl;

   wherein X³ optionally further contains 1 to 5 substituents which when occurring

   within an alicyclic or aromatic ring system are radicals independently selected from a group consisting of (C_1-6)alkyl, (Q^alkylidene, cyano, halo, nitro, halo-substituted

   (C_1-3)alkyl, -X⁶NR¹⁷R¹⁷, -X⁶NR¹⁷C(O)OR¹⁷, -X⁶NR¹⁷C(O)NR¹⁷R¹⁷,

   -X⁶NR¹⁷C(NR¹⁷)NR¹⁷R¹⁷, -X⁶OR¹⁷, -X⁶C(O)R¹⁷, -X⁶OR¹⁵, -X⁶SR¹⁷, -X⁶C(O)OR¹⁷,

   -X⁶C(O)NR¹⁷R¹⁷, -X⁶S(O)₂NR¹⁷R¹⁷, -X⁶P(O)(OR⁸)OR¹⁷, -X⁶OP(O)(OR⁸)OR¹⁷,

   -X⁶NR^I7C(O)R¹⁸, -X⁶S(O)R¹⁸, -X°S(O)₂R¹⁸ and -X⁶C(O)R¹⁸ and when occurring within

   an aliphatic moiety are radicals independently selected from a group consisting of cyano,

   halo, nitro, -NR¹⁷R¹⁷, -NR¹⁷C(O)OR¹⁷, -NR¹⁷C(O)NR¹⁷R¹⁷, -NR¹⁷C(NR¹⁷)NR¹⁷R¹⁷,

   -OR¹⁷, -SR¹⁷, -C(O)OR¹⁷, -C(O)NR^I7R¹⁷, -S(O)₂NR¹⁷R¹⁷, -P(O)(OR¹⁷)OR¹⁷, -OP(O)(OR¹⁷)OR¹⁷, -NR¹⁷C(O)R¹⁸, -S(O)R¹⁸, -S(O)₂R¹⁸ and -C(O)R¹⁸, wherein R¹⁵,

   R¹⁷, R¹ and X are as described above; and the N-oxide derivatives, prodrug derivatives,

   protected derivatives, individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such compounds and the N-oxide

   derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of

   isomers thereof.
2. 2. The compound of claim 1 in which X¹ and X² are both methylene or X¹ is ethylene

   and X² is a bond; R³ is -CR⁵=CHR⁶, -CR⁵(CR ₃)₂ or -CR⁷=NR⁸, wherem R⁵ is hydrogen

   and R⁶ is hydrogen or (C_1- )alkyl or R⁵ and R⁶ together with the atoms to which R⁵ and R⁶

   are attached form (C_3-12)cycloalkenyl, (C₆_₁₂)aryl, hetero(C_6-i₂)aryl or (C_9-12)bicycloaryl and

   R⁷ and R⁸ together with the atoms to which R⁷ and R⁸ are attached form

   hetero(C₅.i₂)cycloalkenyl or hetero(C_6-12)aryl, wherein R³ optionally is substituted by 1 to

   5 radicals independently selected from a group consisting of (C_1-4)alkyl, cyano, halo,

   halo-substituted (C_1-4)alkyl, -X⁴OR⁹ and -X⁴C(O)OR⁹, wherein X⁴ is a bond or

   (Cι.₂)alkylene, R⁹ at each occurrence independently is (C_1-3)alkyl or halo-substituted (C_1-3)alkyl; and the N-oxide derivatives, prodrug derivatives, protected derivatives,

   individual isomers and mixtures of isomers thereof; and the pharmaceutically acceptable

   salts and solvates of such compounds and the Ν-oxide derivatives, prodrug derivatives,

   protected derivatives, individual isomers and mixtures of isomers thereof.
3. 3. The compound of claim 2 in which R⁴ is -C(O)X⁵R^π or -S(O)₂X⁵Rⁿ, wherein X⁵

   is a bond, -O- or -ΝR¹²-, wherein R¹² is hydrogen or (C_1-6)alkyl, and R¹¹ is (i) (C_1-6)alkyl

   or (ii) hetero(C_5-12)cycloalkyl(C_0-3)alkyl, (C_6-12)aryl(C_0-3)alkyl, hetero(C_5-i₂)aryl(Co_-3)alkyl, (C_9-12)bicycloaryl(C₀-₃)alkyl or hetero(C_8-12)bicycloaryl(Co_-3)alkyl or (iii) hetero(C_5-6)cycloalkyl(C_0-3)alkyl or phenyl(C_0-3)alkyl substituted by -X⁶OR¹⁵, -X⁶C(O)R¹⁵

   or -X^δΝR¹⁶C(O)OR¹⁶, wherein X⁶ is a bond or methylene, R¹⁵ is phenyl(C_0-3)alkyl or hetero(C₅.₆)aryl(C_0-3)alkyl and R¹⁶ is hydrogen or (C_1-6)alkyl; wherein R⁴ optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring

   system are radicals independently selected from a group consisting of (C_1-6)alkyl, halo,

   -X⁶NR¹⁷R¹⁷, -X⁶OR¹⁷, -X⁶C(O)OR¹⁷, -X⁶NC(O)R¹⁶ and -X⁶C(O)R¹⁸, R¹⁷ at each

   occurrence independently is hydrogen, (C_1-6)alkyl or halo-substituted (C_1-3)alkyl and R¹⁸

   is (C_1-6)alkyl or halo-substituted (Cι_-3)alkyl; and the N-oxide derivatives, prodrug

   derivatives, protected derivatives, individual isomers and mixtures of isomers thereof; and

   the pharmaceutically acceptable salts and solvates of such compounds and the Ν-oxide

   derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of

   isomers thereof.
4. 4. The compound of claim 3 in which X is a group of Formula (a), (b) or (c):

   (a) (b) (c)

   n is 0, 1 or 2;

   R²⁰ is selected from the group consisting of hydrogen and (C_1-6)alkyl;

   R²¹ is selected from the group consisting of (C_1-9)alkyl, (Cg.₁₂)aryl(C₀_₅)alkyl, - C(O)R²⁶, -S(0)₂R²⁶, -C(O)OR²⁶ and -C(O)N(R²⁶)R²⁷;

   R²³ is selected from ( ^alkyl optionally substituted with amino, -NHC(O)R¹⁵ or

   -R¹⁵ wherein R¹⁵ is as described above; R²⁵ is selected from (C_1-6)alkyl, (C_6-i₂)aryl(C₀-₆)alkyl, -X⁴S(O)₂R²⁶ or -

   X⁴C(O)R¹⁷NR¹⁷C(O)R¹⁷ wherein R¹⁷ and X⁴ are as described above and R²⁶ is as

   described below;

   R²⁶ is selected from the group consisting of (C_1-6)alkyl,

   hetero(C_5-1 )cycloalkyl(Co_-6)alkyl, (C_6-12)aryl(C_0-6)alkyl, hetero(C_5-12)aryl(C₀-₆)alkyl and

   (C_9-12)bicycloaryl(Co_-3)alkyl;

   R²⁷ is (C_1-6)alkyl;

   wherein X³ optionally further contains 1 to 5 substituents which when occurring

   within an alicyclic or aromatic ring system are radicals independently selected from a

   group consisting of (C_1-6)alkyl, cyano, halo, -X⁶OR¹⁷, -X⁶C(O)R¹⁷ and -X⁶OR¹⁵; and the

   N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and

   mixtures of isomers thereof; and the pharmaceutically acceptable salts and solvates of such

   compounds and the Ν-oxide derivatives, prodrug derivatives, protected derivatives,

   individual isomers and mixtures of isomers thereof.
5. 5. The compound of claim 4 in which R³ is selected from the group consisting of

   phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, vinyl, 2-difluoromethoxyphenyl, 1-oxy-

   pyridin-2-yl, 4-methoxyphenyl, 4-methylphenyl, 2-methylphenyl, 4-chlorophenyl, 3,5-

   dimethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 2-bromophenyl,

   naphthalen-2-yl, 3,4-dichlorophenyl, 3-methylphenyl, 3-trifluoromethylphenyl, 3-

   trifluoro ethoxyphenyl, 2,3,4,5,6-pentafluoro-phenyl, 2-fluorophenyl, 2-chlorophenyl, 2- cyano-phenyl, 2-trifluoromethylphenyl, 4-tert-butyl-phenyl, 3-chlorophenyl, 4-

   bromophenyl, 2-fluoro-3-chloro-phenyI, 2-fluoro-3-methyl-phenyl, 3-fluorophenyl, 2,5- difluorophenyl, 3-bromophenyl, 2,5-dichlorophenyl, 2,6-difluorophenyl, 3-cyano-phenyl, 4-cyano-phenyl, 2-trifluoromethoxyphenyl, 2,3-difluorophenyl, biphenyl, 2-bromo-5-

   fluoro-phenyl, 4-fluorophenyl, 3,4-difluorophenyl, 2,4-difluorophenyl, 2,4,6-

   trifluorophenyl, 2,4,5-trifluorophenyl, 2,3,4-trifluorophenyl, 2-chloro-5-

   trifluoromethylphenyl, 2,4-bis-trifluoromethylphenyl, 2,5,6-trifluorophenyl, 2-fluoro-3-

   trifluoromethylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-5-trifluoromethylphenyl,

   2,3,5-trifluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 5-fluoro-2-trifluoromethylphenyl,

   4-fluoro-3-trifluoromethylphenyl, 2-methoxyphenyl, 3,5-bis-trifluoromethylphenyl, 4-

   difluoromethoxyphenyl, 3-difluoromethoxyphenyl, 2,6-dichlorophenyl, 4-carboxyphenyl,

   cyclohexyl, cyclopropyl, isopropyl, thiophen-2-yl, 5-chloro-thiophen-2-yl and 3,5-

   dimethyl-isoxazol-4-yl.
6. 6. The compound of claim 5 in which R⁴ is benzoyl, morpholine-4-carbonyl, acetyl,

   furan-3-carbonyl, 2-methoxy-benzoyl, 3-methoxy-benzoyl, naphthalene-2-carbonyl,

   benzo[l,3]dioxole-5-carbonyl, 3-pyridin-3-yl-acryloyl, benzofuran-2-carbonyl, furan-2-

   carbonyl, tert-butoxy-carbonyl, biphenyl-4-carbonyl, quinoline-2-carbonyl, quinoline-3-

   carbonyl, 3-acetyl-benzoyl, 4-phenoxy-benzoyl, 3-hydroxy-benzoyl, 4-hydroxy-benzoyl,

   pyridine-3-carbonyl, 3-(tert-butoxycarbonylamino-methyl)-benzoyl, 4-carbonyl-piperazme-

   1-carboxylic acid tert-butyl ester, 4-carbonyl-piperazine-l-carboxylic acid ethyl ester, 4-

   (furan-2-carbonyl)-piperazine-l-carbonyl, pyridine-4-carbonyl, l-oxy-pyridine-4-carbonyl,

   l-oxy-pyridine-3-carbonyl, thiophene-2-carbonyl, thiophene-3-carbonyl, 4-benzoyl-

   benzoyl, 5-methyl-thiophene-2-carbonyl, 3-chloro-thiophene-2-carbonyl, 3-bromo- thiophene-2-carbonyl, 4-chloro-benzoyl, 3-flouro-4-methoxy-benzoyl, 4-methoxy-benzoyl,

   4-triflouromethoxy-benzoyl, 3,4-diflouro-benzoyl, 4-fluoro-benzoyl, 3,4-dimethoxy-

   benzoyl, 3-methyl-benzoyl, 4-bromo-benzoyl, 4-triflouromethyl-benzoyl, 3-benzoyl- benzoyl, cyclopentane-carbonyl, benzo[b]thiophene-2-carbonyl, 3-chloro-

   benzo[b]thiophene-2-carbonyl, benzenesulfonyl, naphthalene-2-sulfonyl, 5-methyl-

   thiophene-2-sulfonyl, thiophene-2-sulfonyl, formamyl-methyl ester, 4-methyl-pentanoyl, formamyl-isobutyl ester, formamyl-monoallyl ester, formamyl-isopropyl ester, N,N-

   dimethyl-formamyl, N-isopropyl-formamyl, N-pyridin-4-yl-formamyl, N-pyridin-3-yl-

   formamyl, 3-phenyl-acryloyl, lH-indole-5-carbonyl, pyridine-2-carbonyl, pyrazine-2-

   carbonyl, 3-hydroxy-pyridine-2-carbonyl, 2-amino-pyridine-3-carbonyl, 2-hydroxy-

   pyridine-3-carbonyl, 6-amino-pyridine-3-carbonyl, 6-hydroxy-pyridine-3-carbonyl,

   pyridazine-4-carbonyl, 3-phenoxy-benzoyl and l-oxo-l,3-dihydro-isoindole-2-carbonyl.
7. 7. The compound of claim 6 in which X is selected from a group consisting of 4-

   amino-3-oxo-azepane-l-carboxylic acid benzyl ester, 4-amino-3-oxo-azepane-l-carboxylic

   acidisobutyl ester, 4-amino-l-benzoyl-azeρan-3-one, 4-amino- 1-benzenesulf onyl-azepan-

   3 -one, 4-amino- 1 -(pyridine-2-sul onyl)-azepan-3 -one, 4-amino- 1 -( 1 -oxy-pyridine-2-

   sulfonyl)-azepan-3-one, 4-amino-l-(3,4-dichloro-benzenesulfonyl)-azepan-3-one, 4-amino-

   l-(2-flouro-benzenesulfonyl)-azepan-3-one, 4-amino-l-(3,4-dimethoxy-benzenesulfonyl)- azepan-3-one, 4-amino-l-(2-cyano-benzenesulfonyl)-azepan-3-one, 4-amino-l- (naphthalene-l-sulfonyl)-azepan-3-one, 4-amino-l-(thiophene-2-sulfonyl)-azepan-3-one,

   4-anτino-l-(thiazole-2-sulfonyl)-azepan-3-one, 4-amino-l-(pyrrolidine-l-sulfonyl)-azepan-

   3-one, 4-amino- l-methanesulfonyl-azepan-3 -one, 4-amino- l-(pyrrolidine- 1-carbonyl)-

   azepan-3-one, 4-amino-3-oxo-azepane-l -carboxylic-acid-dimethylamide, 4-amino-3-oxo-

   azepane-1-carboxylic-acid-benzylamide, 4-amino-l-benzyl-azepan-3-one, 4-amino-l- benzyl-piperidin-3-one, 4-amino-l-benzoyl-piperidin-3-one, 4-amino- 1-benzoyl- pyrrolidin-3-one, 4-amino-l-benzyl-pyrrolidin-3-one, 4-amino- 1 -benzenesulfonyl- pyrrolidin-3-one, 4-amino-l-(5-methyl-hexyl)-pyrrolidin-3-one, l-ethyl-2-oxo-3-(toluene- 4-sulfonylamino)-butylamino, l-ethyl-2-oxo-3-(4-phenoxy-benzenesulfonylamino)- propylamino, l-ethyl-2-oxo-3-[4-(pyridin-3-yloxy)-benzenesulfonylamino]-propylamino, 3-(dibenzofuran-2-sulfonylamino)-l-ethyl-2-oxo-butylamino, l-ethyl-3-[4-methyl-2-(4- methyl-pentanoyIamino)-pentanoylamino]-2-oxo-propylamino, 5-amino- l-[(4-methoxy- phenylsulfamoyl)-methyl]-pentylamino, 5-benzyloxycarbonylamino-l-[(4-methoxy- phenylsulfamoyl)-methyl]-pentylamino, l-[(4-methoxy-phenylsulfamoyl)-methyl]-3- phenyl-propylamino, l-{ [4-(l-hydroxy-ethyl)-phenylsulfamoyl]-methyl }-3-phenyI- propylamino, l-[(4-acetyl-phenylsulfamoyl)-methyl]-3-phenyl-propylamino, l-[(4- hydiOxy-phenylsulfamoyl)-methyl]-3-ρhenyl-propylamino and 3-phenyl-l-[(2- phenylamino-ethylsulfamoyl)-methyl]-propylamino.
8. 8. The compound of claim 7 selected from the group consisting of morpholine-4- carboxylic acid (l-{ 5-amino-l-[(4-methoxy-phenylsulfamoyl)-methyl]-pentylcarbamoyl}- 2-phenylmethanesulf onyl-ethyl)-amide, (6-(4-methoxy-phenylsulf amoyl)-5- { 2-

   [(mo holine-4-carbonyl)-amino]-3-phenylmethane-sulfonyl-propionylamino}-hexyl)- carbamic acid benzyl ester, morpholine-4-carboxylic acid (l-{ l-[(4-methoxy- phenylsulfamoyl)-methyl]-3-phenyl-ρropylcarbamoyl}-2-ρhenylmethanesulfonyl-ethyl)- amide, morpholine-4-carboxylic acid [l-(3-benzenesulfonylamino-2-oxo- propylcarbamoyl)-2-phenylmethanesulfonyl-ethyl] -amide, morpholine-4-carboxylic acid [l-(l-benzoyl-4-oxo-pyrrolidin-3-ylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide, morpholine-4-carboxylic acid [l-(l-benzenesulfonyl-4-oxo-pyrrolidin-3-ylcarbamoyl)-2- phenylmethanesulfonyl-ethyl]-amide and 4-{2-[(MorphoIine-4-carbonyl)-amino]-3- phenylmethanesulfonyl-propionylamino}-3-oxo-azepane-l-carboxylic acid benzyl ester.
9. 9. A pharmaceutical composition comprising a therapeutically effective amount of a

   compound of Claim 1 in combination with a pharmaceutically acceptable excipient.
10. 10. A method for treating a disease in an animal in which inhibition of Cathepsin S can

    prevent, inhibit or ameliorate the pathology and or symptomology of the disease, which

    method comprises administering to the animal a therapeutically effective amount of

    compound of Claim 1 or a N-oxide derivative or individual isomer or mixture of isomers

    thereof; or a pharmaceutically acceptable salt or solvate of such compounds and the

    N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers and mixtures of isomers thereof.
11. 11. The use of a compound of Claim 1 in the manufacture of a medicament for treating

    a disease in an animal in which Cathepsin S activity contributes to the pathology and or

    symptomology of the disease.
12. 12. A process for preparing a compound of Formula I:

    in which:

    X¹ and X² are both methylene or X¹ is ethylene and X² is a bond;

    R³ is -CR⁵=CHR⁶, -CR⁵(CR⁶ ₃)₂ or -CR⁷=NR⁸, wherein R⁵ is hydrogen and R⁶ is

    hydrogen or (C_1- )alkyl or R⁵ and R⁶ together with the atoms to which R⁵ and R⁶ are

    attached form (C_3-12)cycloalkenyl, hetero(C_5-12)cycloalkenyl, (C_6-ι₂)aryl, hetero(C_6-ι₂)aryl,

    (C_9-12)bicycloaryl or hetero(C_8-12)bicycloaryl and R⁷ and R⁸ together with the atoms to

    which R⁷ and R⁸ are attached form hetero(C₅.i2)cycloalkenyl, hetero(C_6-12)aryl or

    hetero(C_8-12)bicycloaryl, wherein R³ optionally is substituted by 1 to 5 radicals

    independently selected from a group consisting of (C_1- )alkyl, cyano, halo, halo-substituted

    (C_1-4)alkyl, nitro, -X⁴NR⁹R⁹, -X⁴OR⁹, -X⁴SR⁹, -X⁴C(O)NR⁹R⁹, -X⁴C(O)OR⁹,

    -X⁴S(O)R¹⁰, -X⁴S(O)₂R¹⁰ and -X⁴C(O)R¹⁰, wherein X⁴ is a bond or (C_1-2)alkylene, R⁹ at

    each occurrence independently is hydrogen, (C_1-3)alkyl or halo-substituted (C_1-3)alkyl and

    R¹⁰ is (C_1-3)alkyl or halo-substituted (C_1-3)alkyl; and

    R⁴ is -C(0)X⁵R^π or -S(O)₂X⁵R^π, wherein X⁵ is a bond, -O- or -NR¹²-, wherein

    R¹² is hydrogen or (C_1-6)alkyl, and R¹¹ is (i) (C_1-6)alkyl optionally substituted by -OR¹³,

    -SR¹³, -S(O)R¹³, ~S(O)₂R¹³, -C(O)R¹³, -C(O)OR¹³, -C(O)NR¹³R¹⁴, -NR¹³R¹⁴,

    -NR¹⁴C(O)R¹³, -NR¹⁴C(O)OR^,3,-NR¹⁴C(O)NR¹³R¹⁴ or -NR¹⁴C(NR^I4)NR¹³R¹⁴, wherein

    R¹³ is (C_3-j₂)cycloalkyl(Co-₃)alkyl, hetero(C_5-ι₂)cycloalkyl(Co_-3)alkyl, (C₆.₁₂)aryl(C_0-3)alkyl,

    hetero(C_5-12)aryl(C_0-3)alkyl, (C_9-12)bicycloaryl(C_0-3)alkyl or hetero(C_8-ι )bicycloaryl(Co_-3)alkyl and R¹⁴ at each occurrence independently is hydrogen

    or (C_1-6)alkyl, or (ii) (C_3-12)cycloalkyl(Co,₃)alkyl, hetero(C_5-ι₂)cycloalkyl(Co_-3)alkyl, (C_6-12)aryl(C_0-3)alkyl, hetero(C_5-i2)aryl(C₀-₃)alkyl, (C_9-12)bicycloaryl(C_0-3)alkyl or

    hetero(C_8-i2)bicycloaryl(Co-₃)alkyl or (iii) (C_3-6)cycloalkyl(C_0-3)alkyl, hetero(C_5-6)cycloalkyl(Co-₃)alkyl, phenyl(Co_-3)alkyl or hetero(C_5-6)aryl(Co-₃)alkyl

    substituted by -X⁶OR¹⁵, -X⁶SR¹⁵, -X⁶S(O)R¹⁵, -X⁶S(O)₂R¹⁵, -X⁶C(O)R¹⁵,

    -X⁶C(O)OR¹⁵, -X⁶C(O)NR¹⁵R¹⁶, -X⁶NR¹⁵R¹⁶, -X⁶NR¹⁶C(O)R¹⁵, -X⁶NR¹⁶C(O)OR¹⁵,

    -X⁶NR¹⁶C(O)NR¹⁵R¹⁶ , -X⁶NR¹⁶C(O)OR¹⁶, -X⁶NR¹⁶C(NR¹⁶)NR¹⁵R¹⁶, wherein X⁶ is a

    bond or methylene, R¹⁵ is (C_3-6)cycloalkyl(Co-₃)alkyl, hetero(C_5-6)cycloalkyl(Co-₃)alkyl,

    phenyl (Co_-3)alkyl or hetero(C_5-6)aryl(Co-₃)alkyl and R¹⁶ is hydrogen or (Cι_-6)alkyl; wherein

    R⁴ optionally further contains 1 to 5 substituents which when occurring within an alicyclic

    or aromatic ring system are radicals independently selected from a group consisting of

    (C_1-6)alkyl, cyano, halo, nitro, halo-substituted (C_1-3)alkyl, -X⁶NR¹⁷R¹⁷,

    -X⁶NR¹⁷C(O)OR¹⁷, -X⁶NR^I7C(O)NR^I7R¹⁷, -X⁶NR^I7C(NR¹⁷)NR¹⁷R¹⁷, -X⁶OR¹⁷,

    -X⁶SR¹⁷, -X⁶C(O)OR¹⁷, -X⁶C(O)NR¹⁷R¹⁷, -X⁶S(O)₂NR¹⁷R¹⁷, -X⁶P(O)(OR¹⁸)OR¹⁷,

    -X⁶OP(O)(OR¹⁸)OR¹⁷, -X⁶NR¹⁷C(O)R¹⁸, -X⁶S(O)R¹⁸, -X⁶S(O)₂R¹⁸ and -X⁶C(O)R¹⁸ and

    when occurring within an aliphatic moiety are radicals independently selected from a group

    consisting of cyano, halo, nitro, -NR¹⁷R¹⁷, -NR¹⁷C(O)OR¹⁷, -NR¹⁷C(O)NR¹⁷R¹⁷,

    -NR¹⁷C(NR¹⁷)NR¹⁷R¹⁷, -OR¹⁷, -SR¹⁷, -C(O)OR¹⁷, -C(O)NR¹⁷R¹⁷, -S(O)₂NR¹⁷R¹⁷,

    -P(O)(OR¹⁷)OR¹⁷, -OP(O)(OR¹⁷)OR¹⁷, -NR¹⁷C(O)R¹⁸, -S(O)R¹⁸, -S(O)₂R¹⁸ and

    -C(O)R¹⁸, wherein X⁶ is a bond or (C_1-6)alkylene, R¹⁷ at each occurrence independently

    is hydrogen, (C_1-6)alkyl or halo-substituted (C_1- )alkyl and R¹⁸ is (C_1-6)alkyl or halo-substituted (C_1-3)alkyl;

    X³ is a group of Formula (a), (b) or (c):

    (a) (b) (c)

    n is 0, 1 or 2;

    R²⁰ is selected from the group consisting of hydrogen, (C_1-6)alkyl,

    (C₃-ι₂)cycloalkyl(Co-₆)alkyl, hetero(C₅-i₂)cycloalkyl(C₀-₆)alkyl, (C_6-ι₂)aryl(C_0-(₅)alkyl and hetero(C_5-12)aryl(C₀-₆)alkyl;

    R²¹ is selected from the group consisting of hydrogen, (C_1-9)alkyl,

    (C_3-i₂)cycloalkyl(C₀-₆)alkyl, hetero(C_5-i₂)cycloalkyl(Co_-6)alkyl, (C_6-12)aryl(C_0-6)alkyl,

    hetero(C_5-12)aryl(Co-₆)alkyl, (C_9-12)bicycloaryl(C_0-3)alkyl, hetero(C_8-12)-

    bicycloaryl(C_0-3)alkyl, -C(O)R²⁶, -C(S)R²⁶, -S(O)₂R²⁶, -C(O)OR²⁶, -C(O)N(R²⁶)R²⁷, -

    C(S)N(R²⁶)R²⁷ and -S(O)₂N(R²⁷)R²⁶;

    R²³ is selected from (C_1-6)alkyl, (C_4-6)alkenyl, (C_3-12)cycloalkyl(Co_-6)alkyl,

    hetero(C_5-ι₂)cycloalkyl(C₀.₆)alkyl, (C₆-i₂)aryl(C₀.6)alkyl or hetero(C₅-ι₂)aryl(C_0-6)alkyl

    optionally substituted with amino, -NHC(O)R or ~R wherein R is as described above;

    R²⁵ is selected from hydrogen, (Cι_-6)alkyl, (C₃-ι₂)cycloalkyl(Co-₆)alkyl,

    hetero(C_5-i2)cycloalkyl(Co_-6)alkyl, (C₆-i₂)aryl(C₀-6)alkyl, hetero(C_5-i₃)aryl(Co-₆)alkyl, -

    X⁴NHR¹⁵, -X S(O)₂R²⁶ or -X C(O)R¹⁷NR¹⁷C(O)R¹⁷ wherein R¹⁵, R¹⁷ and X⁴ are as described above;

    R²⁶ is selected from the group consisting of hydrogen, (C_1-6)alkyl,

    (C_3-ι₂)cycloalkyl(Co-₆)alkyl, hetero(C_5-i2)cycloalkyl(C_0-6)alkyl, (C₆_ι₂)aιyl(C₀-₆)alkyl,

    hetero(C5-i2)aryl(Co-6)alkyl, (C_9-12)bicycloaryl(C₀-₃)alkyl and hetero(C_8-i₂)- bicycloaryl(Co_-3)alkyl;

    R²⁷ is hydrogen, (C_1-6)alkyl, (C_3-12)cycloalkyl(C₀-₆)alkyl,

    hetero(C_5-12)cycloalkyl(Co-₆)alkyl, (C_6-12)aryl(Co-₆)alkyl or hetero(C_5-12)aryl(Co.₆)alkyl;

    wherein X³ optionally further contains 1 to 5 substituents which when occurring

    within an alicyclic or aromatic ring system are radicals independently selected from a

    group consisting of (C_1-6)alkyl, cyano, halo, nitro, halo-substituted

    (C_1-3)alkyl, -X⁶NR¹⁷R¹⁷, -X⁶NR¹⁷C(O)OR¹⁷, -X⁶NR¹⁷C(O)NR¹⁷R¹⁷,

    -X⁶NR¹⁷C(NR¹⁷)NR¹⁷R¹⁷, -X⁶OR¹⁷, -X⁶C(O)R¹⁷, -X⁶OR¹⁵, -X⁶SR¹⁷, -X⁶C(O)OR¹⁷,

    -X⁶C(O)NR¹⁷R¹⁷, -X⁶S(O)₂NR¹⁷R¹⁷, -X⁶P(O)(OR⁸)OR¹⁷, -X⁶OP(O)(OR⁸)OR¹⁷,

    -X⁶NR^I7C(O)R¹⁸, -X⁶S(O)R¹⁸, -X⁶S(O)₂R¹⁸ and -X°C(O)R¹⁸ and when occurring within

    an aliphatic moiety are radicals independently selected from a group consisting of cyano,

    halo, nitro, -NR¹⁷R¹⁷, -NR¹⁷C(O)OR¹⁷, -NR¹⁷C(O)NR¹⁷R¹⁷, -NR¹⁷C(NR¹⁷)NR¹⁷R¹⁷,

    -OR¹⁷, -SR¹⁷, -C(O)OR¹⁷, -C(O)NR¹⁷R¹⁷, -S(O)₂NR¹⁷R¹⁷, -P(O)(OR¹⁷)OR¹⁷,

    -OP(O)(OR¹⁷)OR¹⁷, -NR¹⁷C(O)R¹⁸, -S(O)R¹⁸, -S(O)₂R¹⁸ and -C(O)R¹⁸, wherein R¹⁵,

    R , R and X are as described above; said process comprising:

    (A) reacting a compound of Formula 2:

    2 with a compound of the formula (a):

    (a) in which X¹, X², R³, R⁴, R²⁰ and R²¹ are as defined in the Summary of the

    Invention for Formula I; or

    (B) reacting a compound of Formula 2 with a compound of the formula (b):

    ( ) in which R ,20 , R T_Ϊ23 and R _>2₅ are as defined in the Summary of the Invention for Formula

    I; or

    (C) reacting a compound of Formula 2 with a compound of the formula (c):

    (c) in which R²⁰, R²³ and R²⁵ are as defined in the Summary of the Invention for

    Formula I; and

    (D) optionally converting a compound of Formula I into a pharmaceutically acceptable salt; (E) optionally converting a salt form of a compound o f Formula I to non-salt form;

    (F) optionally converting an unoxidized form of a compound of Formula I into a

    pharmaceutically acceptable N-oxide;

    (G) optionally converting an N-oxide form of a compound of Formula I its

    unoxidized form;

    (H) optionally resolving an individual isomer of a compound of Formula I from a

    mixture of isomers;

    (I) optionally converting a non-derivatized compound of Formula I into a

    pharmaceutically prodrug derivative; and

    (J) optionally converting a prodrug derivative of a compound of Formula I to its

    non-derivatized form.
13. 13. A compound of Formula lx :

    lx

    in which:

    X¹ and X² are both methylene or X¹ is ethylene and X² is a bond;

    R³ is -CR⁵=CHR⁶, -CR⁵(CR⁶ ₃)₂ or -CR⁷=ΝR⁸, wherein R⁵ is hydrogen and R⁶ is hydrogen or (C_1-4)alkyl or R⁵ and R⁶ together with the atoms to which R⁵ and R⁶ are

    attached form (C_3-12)cycloalkenyl, hetero(C_5-12)cycloalkenyl, (C6-ι₂)aryl, hetero(C_6-12)aryl,

    (C9-ι₂)bicycloaryl or hetero(C_8-12)bicycloaryl and R⁷ and R⁸ together with the atoms to

    7 Q which R and R are attached form hetero(C_5-12)cycloalkenyl, hetero(C_6-12)aryl or

    hetero(C_8-12)bicycloaryl, wherein R³ optionally is substituted by 1 to 5 radicals

    independently selected from a group consisting of (C_1-4)alkyl, cyano, halo, halo-substituted (C_1-4)alkyl, nitro, -X⁴NR⁹R⁹, -X⁴OR⁹, -X⁴SR⁹, -X⁴C(O)NR⁹R⁹, -X⁴C(O)OR⁹, -X⁴S(O)R¹⁰,

    -X⁴S(O)₂R¹⁰ and -X⁴C(O)R¹⁰, wherein X⁴ is a bond or (C_1-2)alkylene, R⁹ at each

    occurrence independently is hydrogen, (C_1-3)alkyl or halo-substituted (C_1-3)alkyl and R¹⁰

    is (C_1-3)alkyl or halo-substituted (C_1-3)alkyl; and

    R⁴ is -C(O)X⁵R^π or -S(O)₂X⁵Rⁿ, wherein X⁵ is a bond, -O- or -NR¹²-, wherein R¹²

    is hydrogen or (C_1-6)alkyl, and R¹¹ is (i) (C_1-6)alkyl optionally substituted by -OR¹³, -SR¹³, -S(O)R¹³, -S(O)₂R¹³, -C(O)R¹³, -C(O)OR¹³, -C(O)NR¹³R¹⁴, -NR¹³R¹⁴, -NR¹⁴C(O)R¹³,

    -NR¹⁴C(O)OR¹³,-NR¹⁴C(O)NR¹³R¹⁴ or -NR¹⁴C(NR¹⁴)NR¹³R¹⁴, wherein R¹³ is (C_3-ι₂)cycloalkyl(C₀.₃)alkyl, hetero(C_5-ι₂)cycIoalkyl(C_0-3)alkyl, (C₆_₁₂)aryl(C_0-3)alkyl,

    hetero(C_5-i2)aryl(Co_-3)alkyl, (C₉.i₂)bicycloaryl(Co-₃)alkyl or

    hetero(C_8-12)bicycloaryl(Co-₃)alkyl and R¹⁴ at each occurrence independently is hydrogen

    or (Cι_-6)alkyl, or (ii) (C_3-12)cycloalkyl(C_0-3)alkyl, .hetero(C_5-12)cycloalkyl(Co_-3)alkyl,

    (C_6-12)aryl(C_0-3)alkyl, hetero(C_5-12)aryl(C_0-3)alkyl, (C_9-12)bicycloaryl(Co_-3)alkyl or

    hetero(C_8-12)bicycloaryl(C_0-3)alkyl or (iii) (C_3-6)cycloalkyl(C_0-3)alkyl,

    hetero(C_5-6)cycloalkyl(C_0-3)alkyl, phenyl (Co-₃)alkyl or hetero(C_5-6)aryl(C_0-3)alkyl substituted by -X⁶OR¹⁵, -X⁶SR¹⁵, -X⁶S(O)R¹⁵, -X⁶S(O)₂R¹⁵, -X⁶C(O)R¹⁵, -X⁶C(O)OR¹⁵,

    -X⁶C(O)NR¹⁵R¹⁶, -X⁶NR¹⁵R¹⁶, -X⁶NR¹⁶C(O)R¹⁵, -X⁶NR¹⁶C(O)OR¹⁵,

    -X⁶NR¹⁶C(O)NR¹⁵R¹⁶ , -X⁶NR¹⁶C(O)OR¹⁶, -X⁶NR¹⁶C(NR¹⁶)NR¹⁵R¹⁶, wherein X⁶ is a bond or methylene, R¹⁵ is (C_3-6)cycloalkyl(Co_-3)alkyl, hetero(C5_-6)cycloalkyl(C₀-₃)alkyl,

    phenyl(C_0-3)alkyl or hetero(C₅.₆)aryl(C_0-3)alkyl and R¹⁶ is hydrogen or ( ^alkyl; wherein

    R⁴ optionally further contains 1 to 5 substituents which when occurring within an alicyclic or aromatic ring system are radicals independently selected from a group consisting of

    (C_1-6)alkyl, (C_1-6)alkylidene, cyano, halo, nitro, halo-substituted (C_1-3)alkyl, -X⁶NR¹⁷R¹⁷,

    -X⁶NR¹⁷C(O)OR¹⁷, -X⁶NR¹⁷C(O)NR¹⁷R¹⁷, -X⁶NR¹⁷C(NR¹⁷)NR¹⁷R¹⁷, -X⁶OR¹⁷, -X⁶SR¹⁷,

    -X⁶C(O)OR¹⁷, -X⁶C(O)NR¹⁷R¹⁷, -X⁶S(O)₂NR¹⁷R¹⁷, -X⁶P(O)(OR¹⁸)OR¹⁷,

    -X⁶OP(O)(OR¹⁸)OR¹⁷, -X⁶NR¹⁷C(O)R¹⁸, -X⁶S(O)R¹⁸, -X⁶S(O)₂R¹⁸ and -X⁶C(O)R¹⁸ and when occurring within an aliphatic moiety are radicals independently selected from a group

    consisting of cyano, halo, nitro, -NR¹⁷R¹⁷, -NR¹⁷C(O)OR¹⁷, -NR¹⁷C(O)NR¹⁷R¹⁷,

    -NR¹⁷C(NR¹⁷)NR¹⁷R¹⁷, -OR¹⁷, -SR¹⁷, -C(O)OR¹⁷, -C(O)NR¹⁷R¹⁷, -S(O)₂NR¹⁷R¹⁷,

    -P(O)(OR¹⁷)OR¹⁷, -OP(O)(OR¹⁷)OR¹⁷, -NR¹⁷C(O)R¹⁸, -S(O)R¹⁸, -S(O)₂R¹⁸ and -C(O)R¹⁸, wherein X is a bond or R¹⁷ at each occurrence independently is hydrogen,

    (C_1-6)alkyl or halo-substituted (C_1-3)alkyl and R¹⁸ is (C_1-6)alkyl or halo-substituted (C_1-3)alkyl;

    X³ is a group of Formula (a), (b), (c), (d), (e), (f), (g) or (h):

    (a) (b) (C)

    (e) (f⁾

    (g) (h)

    =-~. represents a single bond, or a double bond;

    X^ represents aryl, heteroaryl or NR²⁰R²⁵;

    n is 0, 1 or 2;

    R²⁰ is selected from the group consisting of hydrogen, (C_1- )alkyl,

    (C_3-12)cycloalkyl(C_0-6)alkyl, hetero(C_5-12)cycloalkyl(C_0-6)alkyl, (C_6-12)aryl(C₀-₆)alkyl and

    hetero(C_5-12)aryl(C₀.₆)alkyl;

    R²¹ is selected from the group consisting of hydrogen, (C_1-9)alkyl,

    (C_3-12)cycloalkyl(Co_-6)alkyl, hetero(C₅.₁₂)cycloalkyl(C₀.₆)alkyl, (C_6-12)aryl(Co_-6)alkyl,

    hetero(C₅.ι₂)aryl(Co-₆)alkyl, (C₉-i₂)bicycloaryl(C_0-3)alkyl,

    hetero(C_8-ι₂)-bicycloaryl(C_0-3)alkyl, -C(O)R²⁶, -C(S)R²⁶, -S(O)₂R²⁶, -C(O)OR²⁶,

    -C(O)N(R²⁶)R²⁷, -C(S)N(R²⁶)R²⁷ and -S(O)₂N(R²⁷)R²⁶;

    R²³ is selected from -H, (C_1-6)alkyl, (C _-6)alkenyl, (C_3-i₂)cycloalkyl(C_0-6)alkyl,

    hetero(C_5-12)cycloalkyl(C_0-6)alkyl, (C_6-12)aryl(C₀-₆)alkyl or hetero(C_5-12)aryl(Co-₆)alkyl optionally substituted with amino, -NHC(O)R¹⁵ or -R¹⁵ wherein R¹⁵ is as described above;

    R²⁵ is selected from hydrogen, (C_1-6)alkyl, (C_3-i₂)cycloalkyl(C_0-6)alkyl, hetero(C_5-12)cycloalkyl(C₀-₆)alkyl, (C_6-j₂)aryl(C_0-6)alkyl, hetero(C_5-i₃)aryl(C_0-6)alkyl,

    -X⁴NHR¹⁵, -X⁴S(O)₂R²⁶ or -X⁴C(O)R¹⁷NR¹⁷C(O)R¹⁷ wherein R¹⁵, R¹⁷ and X⁴ are as

    described above;

    R²⁶ is selected from the group consisting of hydrogen, (C_1-6)alkyl,

    (C_3-i₂)cycloalkyl(C₀-₆)alkyl, hetero(C_5-12)cycIoalkyl(C₀.₆)alkyl, (C_6-12)aryl(C_0-6)alkyl,

    hetero(C_5-12)aryl(Co-₆)alkyl, (C₉.₁₂)bicycloaryl(Co-₃)alkyl and

    hetero(C_8-12)-bicycloaryl(C_0-3)alkyl;

    R²⁷ is hydrogen, (C_1-6)alkyl, (C₃-ι₂)cycloalkyl(C_0-6)alkyl,

    hetero(C_5-12)cycloalkyl(Co-₆)alkyl, (C_6-12)aryl(Co-₆)alkyl or hetero(C_5-12)aryl(Co_-6)alkyl;

    R²⁸ is R²⁰ or -O-C(=O)-R²⁹;

    R²⁹ is (C_1-6)alkyl, (C_3-12)cycloalkyl(C₀-₃)alkyl, hetero(C₅-₁₂)cycloalkyl(Co_-3)alkyl,

    (C_6-12)aryl(C₀-₃)alkyl, hetero(C_5-12)aryl(C₀-3)alkyl, (C_9-12)bicycloaryl(Co-₃)alkyl or

    hetero(C₈_i2)bicycloaryl(Co.₃)alkyl; wherein X³ optionally further contains 1 to 5 substituents which when occurring

    within an alicyclic or aromatic ring system are radicals independently selected from a

    group consisting of (C_1-6)alkyl, (C_1-6)alkylidene, cyano, halo, nitro, halo-substituted

    (C_1-3)alkyl, -X⁶NR¹⁷R¹⁷, -X⁶NR¹⁷C(O)OR¹⁷, -X⁶NR¹⁷C(O)NR¹⁷R¹⁷,

    -X⁶NR¹⁷C(NR¹⁷)NR¹⁷R¹⁷, -X⁶OR¹⁷, -X⁶C(O)R¹⁷, -X⁶OR¹⁵, -X⁶SR¹⁷, -X⁶C(O)OR¹⁷,

    -X⁶C(O)NR¹⁷R¹⁷, -X⁶S(O)₂NR¹⁷R¹⁷, -X⁶P(O)(OR⁸)OR¹⁷, -X⁶OP(O)(OR⁸)OR¹⁷,

    -X⁶NR^I7C(O)R^lδ, -X⁶S(O)R¹⁸, -X⁶S(O)₂R¹⁸ and -X°C(O)R¹⁸ and when occurring within

    an aliphatic moiety are radicals independently selected from a group consisting of cyano,

    halo, nitro, -NR¹⁷R¹⁷, -NR¹⁷C(O)OR¹⁷, -NR¹⁷C(O)NR¹⁷R¹⁷, -NR¹⁷C(NR¹⁷)NR¹⁷R¹⁷, -OR¹⁷, -SR¹⁷, -C(O)OR¹⁷, -C(O)NR¹⁷R¹⁷, -S(O)₂NR¹⁷R¹⁷, -P(O)(OR¹⁷)OR¹⁷, -OP(O)(OR¹⁷)OR¹⁷,

    -NR¹⁷C(O)R¹⁸, -S(O)R¹⁸, -S(O)₂R¹⁸ and -C(O)R¹⁸, wherein R¹⁵, R¹⁷, R¹⁸ and X⁶ are as described above; or one of N-oxide derivatives, prodrug derivatives, protected derivatives, individual isomers

    and mixtures of isomers of compounds of formula lx; or one of pharmaceutically

    acceptable salts and solvates of such compounds and the Ν-oxide derivatives, prodrug

    derivatives, protected derivatives, individual isomers and mixtures of isomers formula lx.
14. 14. A compound of claim 13, wherein R²³ is selected from (C_1-6)alkyl, (C_4-6)alkenyl,

    (C_3-i₂)cycloalkyl(Co-₆)alkyl, hetero(C_5-i₂)cycloalkyl(Co-₆)alkyl, (C_6-ι₂)aryl(C₀-₆)alkyl

    or hetero(C_5-12)aryl(Co-₆)alkyl optionally substituted with amino, -ΝHC(O)R¹⁵ or -R¹⁵

    wherein R¹ is as described above;
15. 15. A compound of claim 13, selected from the group consisting of:

    Morpholine-4-carboxylic acid [l-(l-benzoyl-4-oxo-pyrrolidin-3-ylcarbamoyl)-2- phenylmethanesulfonyl-ethyl]-amide;

    Morpholine-4-carboxylic acid [l-(l-benzenesulfonyl-4-oxo-pyrrolidin-3-ylcarbamoyl) 2-phenylmethanesulfonyl-ethyl]-amide;

    4-{2-[(Mθ holine-4-carbonyl)-amino]-3-phenylmethanesulfonyl-propionylamino}-3- oxo-azepane-1 -carboxylic acid benzyl ester;

    Morpholine-4-carboxylic acid [l-(3-benzenesulfonylamino-2-oxo-propylcarbamoyl)-2- phenylmethanesulfonyl-ethyl]-amide; or N-{ lS-[lS-(4-Methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl] 2- benzylsulf onylethyl } -morpholine-4-carboxamide.
16. 16. A compound of claim 13, selected from the group consisting of: Morpholine-4-carboxylic acid [(R)-l-(6-oxo-cyclohex-l-enylcarbamoyl)-2- phenylmethanesulfonyl-ethyl]-amide;

    Morpholine-4-carboxylic acid [(R)-2-cyclopropylmethanesulfonyl- l-(6-oxo-cyclohex- 1 -enylcarbamoyl)-ethyl] -ami de; Morpholine-4-carboxylic acid [(R)- 1 -(3 ,4-dioxo-cyclopentylcarbamoyl)-2- phenylmethanesulfonyl-ethyl]-amide;

    Moφholine-4-carboxylic acid [2-(2-difluoromethoxy-phenylmethanesulfonyl)- 1 -(2- oxo-cyclohexylcarbamoyl)-ethyl]-amide;

    Morpholine-4-carboxylic acid [2-(2-difluoromethoxy-ρhenylmethanesulfonyl)-l-(2- oxo-cyclopentylcarbamoyl)-ethyl]-amide;

    Moφholine-4-carboxylic acid [2-(2-difluoromethoxy-phenylmethanesulfonyl)- 1-(2- oxo-cyclobutylcarbamoyl)-ethyl]-amide;

    (Moφholine-4-carboxylic acid [ 1 -(2-benzylcarbamoyl-2-oxo-ethyIcarbamoyl)-2- phenylmethanesulfonyl-ethyl]-amide);

    Acetic acid 3-{ 2-[(moφholine-4-carbonyl)-amino]-3-phenylmethanesulfonyl- propionylamino }-4-oxo-azetidin-2-yl ester;

    Moφholine-4-carboxylic acid [l-(2-hydroxy- 1,1 -dimethyl -3 -oxo-3-phenyl- propylcarbamoyl)-2-phenylmethanesulfonyl-ethyl]-amide;

    Moφholine-4-carboxylic acid [l-(4-oxo-tetrahyαxo-furan-3-ylcarbamoyl)-2- phenylmethanesulfonyl-ethyl]-amide; or

    Moφholine-4-carboxylic acid [2-(2-difluoromethoxy-phenylmethanesulfonyl)-l-(l,l- dimethyl-2,3-dioxo-3-phenyl-propylcarbamoyl)-ethyl]-amide.