Sulfonamide compounds as protease inhibitors

• US 20030158231A1
• Filed: 09/09/2002
• Published: 08/21/2003
• Est. Priority Date: 09/14/2001
• Status: Active Grant

• Current Assignee: Celera Corporation (Quest Diagnostics Incorporated)
• Original Assignee: Axys Pharmaceuticals, Inc. (Quest Diagnostics Incorporated)
• Inventors: Palmer, James
• Granted Patent: US 6,900,237 B2
• Time in Patent Office: Days
• US Class Current: 514/331
• CPC Class Codes: C07C 311/46 Y being a hydrogen or a carbon atom
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 213/82 in position 3
• CPC Class Codes: C07D 277/42 Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 295/155 with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/215 Radicals derived from nitrogen analogues of carbonic acid
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention relates to novel cysteine protease inhibitors; the pharmaceutically acceptable salts and N-oxides thereof; their uses as therapeutic agents and the methods of their making.

Claims

1. A compound of Formula I:

2. The compound of claim 1 in which:

R² is hydrogen;

R¹ is —

R⁸, —

X²OR⁸, —

X²C(O)R⁸, —

X²C(OR⁷)R⁷R⁸, —

X²NR⁷R⁸ or —

X²NR⁷C(O)OR⁸ wherein X²is (C_1-6)alkylene;

R⁷is hydrogen or (C_1-6)alkyl;

R⁸ is hydrogen, (C_1-6)alkyl, (C_3-12)cycloalkyl(C_0-3)alkyl, hetero(C_5-12)cycloalkyl(C_0-3)alkyl, (C_6-12)aryl(C_0-3)alkyl or hetero(C_5-13)aryl(C_0-3)alkyl;

wherein within R⁸ said cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring may be substituted with halo, —

R⁹, —

X³OR⁹, —

X³C(O)R⁹, —

X³C(OR⁹)R⁹, —

X³NR⁹R¹⁰ or —

X³NR⁹C(O)OR⁹;

wherein X³ is a bond or (C_1-6)alkylene, R⁹ is hydrogen or (C_1-6)alkyl and R¹⁰ is cycloalkyl;

R³is —

R¹¹, —

X³NR¹¹R¹²or —

X³NR¹²C(O)OR¹¹where R¹¹ is hydrogen, (C_1-6)alkyl, halo(C_1-6)alkyl, (C_3-12)cycloalkyl(C_0-3)alkyl, hetero(C_5-12)cycloalkyl-(C_0-3)alkyl, (C_6-12)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_8-12)bicycloaryl(C_0-3)alkyl;

R⁴is hydrogen or (C_1-6)alkyl;

R⁵ is (C_1-6)alkyl or (C_3-12)cycloalkyl(C_0-3)alkyl;

or R⁴ and R⁵ together with the carbon atom to which R⁴ and R⁵ are attached form (C_3-7)cycloalkylene;

R⁶ is hydrogen or —

X⁴X⁵R¹³, wherein X⁴ is —

C(O)—

, X⁵ is a bond, —

O—

or —

NR¹²—

, wherein R¹² is as defined above, and R¹³ is (C_1-6)alkyl or —

R¹⁴ wherein R¹⁴ is (C_3-12)cycloalkyl(C_0-3)alkyl, hetero(C_5-12)cycloalkyl(C_0-3)alkyl, (C_6-12)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_8-12)bicycloaryl(C_0-3)alkyl; and

within R¹⁴ said cycloalkyl, heterocycloalkyl, aryl, heteroaryl, bicycloaryl or heterobicycloaryl ring may be substituted with —

OCF₃, —

CF₃, —

OH, halo, —

R¹⁶, —

X³OR¹⁶, —

X³OR¹⁵, —

X³C(O)R¹⁵, —

R¹⁵, —

X³C(O)R¹⁶, —

X³C(O)OR¹⁵, —

X³NR¹⁵R¹⁵, —

X³NR¹⁵C(O)OR¹⁵, wherein X³ and R¹⁵ are as defined above and R¹⁶ is (C_3-12)cycloalkyl(C_0-3)alkyl, hetero(C_5-12)cycloalkyl(C_0-3)alkyl, (C_6-12)aryl(C_0-3)alkyl or hetero(C_5-12)aryl(C_0-3)alkyl, and within R¹⁶ said cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring may be substituted with —

R¹⁵, —

R¹⁷, —

X³NR¹⁵R¹⁷, or —

X³NR¹⁵R¹⁵ wherein X³ and R¹⁵ are as defined above and R¹⁷is (C_3-12)cycloalkyl(C_0-3)alkyl, hetero(C_5-12)cycloalkyl(C_0-3)alkyl, (C_6-12)aryl(C_0-3)alkyl or hetero(C_5-12)aryl(C_0-3)alkyl.

3. The compound of claim 1 wherein R¹ is 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 4-chlorophenyl, 3-chlorophenyl, 2-chlorophenyl, 4-hydroxyphenyl, 2-acetyl-phenyl, 2-(1-hydroxyethyl)-phenyl, 2-phenylaminoethyl, pyridin-4-ylphenyl, pyridin-3-yl-phenyl, pyridin-2-ylphenyl, 1H-imidazol-2-yl, piperidin-4-yl or 1-methyl-piperidin-4-yl;

and R² is hydrogen.

4. The compound of claim 3 in which R³ is hydrogen, phenethyl, 4-amino-butyl, butyl or 4-benzyloxycarbonylaminobutyl.

5. The compound of claim 4 in which R⁵ is isobutyl, sec-butyl or cyclohexylmethyl;

and R⁴ is hydrogen, or R⁴ and R⁵ together with the carbon atom to which R⁴ and R⁵ are attached form cyclohexyl.

6. The compound of claim 5 in which R⁶ is selected from the group consisting of benzoyl, morpholin-4-ylcarbonyl, acetyl, furan-3-ylcarbonyl, 2-methoxybenzoyl, 3-methoxybenzoyl, naphthalen-2-ylcarbonyl, benzo[1,3]dioxol-5-ylcarbonyl, 3-pyridin-3-ylacryloyl, benzofuran-2-ylcarbonyl furan-2-ylcarbonyl, tert-butoxycarbonyl, biphenyl-4-carbonyl, quinolin-2-ylcarbonyl, quinolin-3-ylcarbonyl, 3-acetylbenzoyl, 4-phenoxybenzoyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, pyridin-3-ylcarbonyl, 3-(tert-butoxycarbonylaminomethyl)benzoyl, 4-carbonylpiperazin-1-ylcarboxylic acid tert-butyl ester, 4-carbonylpiperazin-1-ylcarboxylic acid ethyl ester, 4-(furan-2-ylcarbonyl)piperazin-1-ylcarbonyl, pyridin-4-ylcarbonyl, 1-oxypyridin-4-ylcarbonyl, 1-oxypyridin-3-ylcarbonyl, thiophen-2-ylcarbonyl, thiophen-3-ylcarbonyl, 4-benzoylbenzoyl, 5-methylthiophen-2-ylcarbonyl, 3-chlorothiophen-2-ylcarbonyl, 3-bromothiophen-2-ylcarbonyl, 4-chlorobenzoyl, 3-flouro-4-methoxybenzoyl, 4-methoxy-benzoyl, 4-triflouromethoxybenzoyl, 3,4-diflourobenzoyl, 4-fluorobenzoyl, 3,4-dimethoxy-benzoyl, 3-methylbenzoyl, 4-bromobenzoyl, 4-triflouromethylbenzoyl, 3-benzoylbenzoyl, cyclopentanecarbonyl, benzo[b]thiophen-2-ylcarbonyl, 3-chlorobenzo[b]thiophen-2-ylcarbonyl, formamylmethyl ester, 4-methylpentanoyl, formamylisobutyl ester, formamylmonoallyl ester, formamylisopropyl ester, N,N-dimethylformamyl, N-isopropylformamyl, N-pyridin-4-yl-formamyl, N-pyridin-3-ylformamyl, 3-phenylacryloyl, 1H-indol-5-ylcarbonyl, pyridin-2-ylcarbonyl, pyrazin-2-ylcarbonyl, 3-hydroxypyridin-2-ylcarbonyl, 2-aminopyridin-3-ylcarbonyl, 2-hydroxypyridin-3-ylcarbonyl, 6-aminopyridin-3-ylcarbonyl, 6-hydroxypyridin-3-ylcarbonyl, pyridazin-4-ylcarbonyl, 3-phenoxybenzoyl, 1-oxo-1,3-dihydroisoindol-2-ylcarbonyl, 4-(4-methylpiperazin-1-yl)benzoyl, 4-morpholin-4-ylbenzoyl, 4-[2-(pyridin-3-ylamino)thiazol-4-yl]-benzoyl, 4-(2-dimethylaminothiazol-4-yl)benzoyl, quinolin-6-ylcarbonyl, 4-dimethylamino-benzoyl, 3-aminobenzoyl, 4-methylpiperazin-1-ylcarbonyl and benzylacetyl.

7. The compound of claim 1 wherein:

R¹ is 4-methoxyphenyl, 3-acetylphenyl, 3-(1-hydroxyethyl)-phenyl, 2-(phenylamino)ethyl or 4-hydroxyphenyl;

R² is hydrogen;

R³ is hydrogen, 2-phenethyl, 4-aminobutyl, or 4-benzyloxycarbonylaminobutyl;

R⁴ is hydrogen;

R⁵ is isobutyl, sec-butyl or cyclohexylmethyl;

or R⁴ and R⁵ together with the carbon atom to which R⁴ and R⁵ are attached form cyclohexyl; and

R⁶ is selected from the group consisting of acetyl, pyridin-3-ylcarbonyl, 3-(tert-butoxycarbonylamino)benzoyl, pyridin-4-ylcarbonyl, 1H-indol-5-ylcarbonyl, benzyloxycarbonyl, 3-aminobenzoyl, 4-methylpiperazin-1-ylcarbonyl, quinolin-6-ylcarbonyl, 4-[2-(pyridin-3-ylamino)thiazol-4-yl]benzoyl, 4-dimethylaminobenzoyl, morpholin-4-yl-carbonyl, 4-(2-dimethylaminothiazol-4-yl)benzoyl, tert-butoxycarbonyl, 4-(4-ethylpiperazin-1-yl)-benzoyl, and 4-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzoyl.

8. The compound of claim 1 in which R⁶ is selected from the group consisting of benzoyl, morpholin-4-ylcarbonyl, acetyl, furan-3-ylcarbonyl, 2-methoxybenzoyl, 3-methoxybenzoyl, naphthalen-2-ylcarbonyl, benzo[1,3]dioxol-5-ylcarbonyl, 3-pyridin-3-ylacryloyl, benzofuran-2-ylcarbonyl, furan-2-ylcarbonyl, tert-butoxycarbonyl, biphenyl-4-carbonyl, quinolin-2-ylcarbonyl, quinolin-3-ylcarbonyl, 3-acetylbenzoyl, 4-phenoxybenzoyl, 3-hydroxybenzoyl, 4-hydroxybenzoyl, pyridin-3-ylcarbonyl, 3-(tert-butoxycarbonylaminomethyl)benzoyl, 4-carbonylpiperazin-1-ylcarboxylic acid tert-butyl ester, 4-carbonylpiperazin-1-ylcarboxylic acid ethyl ester, 4-(furan-2-ylcarbonyl)piperazin-1-ylcarbonyl, pyridin-4-ylcarbonyl, 1-oxypyridin-4-ylcarbonyl, 1-oxypyridin-3-ylcarbonyl, thiophen-2-ylcarbonyl, thiophen-3-ylcarbonyl, 4-benzoylbenzoyl, 5-methylthiophen-2-ylcarbonyl, 3-chlorothiophen-2-ylcarbonyl, 3-bromothiophen-2-ylcarbonyl, 4-chlorobenzoyl, 3-flouro-4-methoxybenzoyl, 4-methoxy-benzoyl, 4-triflouromethoxybenzoyl, 3,4-diflourobenzoyl, 4-fluorobenzoyl, 3,4-dimethoxy-benzoyl, 3-methylbenzoyl, 4-bromobenzoyl, 4-triflouromethylbenzoyl, 3-benzoylbenzoyl, cyclopentanecarbonyl, benzo[b]thiophen-2-ylcarbonyl, 3-chlorobenzo[b]thiophen-2-ylcarbonyl, formamylmethyl ester, 4-methylpentanoyl, formamylisobutyl ester, formamylmonoallyl ester, formamylisopropyl ester, N,N-dimethylformamyl, N-isopropylformamyl, N-pyridin-4-yl-formamyl, N-pyridin-3-ylformamyl, 3-phenylacryloyl, 1H-indol-5-ylcarbonyl, pyridin-2-ylcarbonyl, pyrazin-2-ylcarbonyl, 3-hydroxypyridin-2-ylcarbonyl, 2-aminopyridin-3-ylcarbonyl, 2-hydroxypyridin-3-ylcarbonyl, 6-aminopyridin-3-ylcarbonyl, 6-hydroxypyridin-3-ylcarbonyl, pyridazin-4-ylcarbonyl, 3-phenoxybenzoyl, 1-oxo-1,3-dihydroisoindol-2-ylcarbonyl, 4-(4-methylpiperazin-1-yl)benzoyl, 4-morpholin-4-ylbenzoyl, 4-[2-(pyridin-3-ylamino)thiazol-4-yl]-benzoyl, 3-aminobenzoyl, 4-methylpiperazin-1-ylcarbonyl and benzylacetyl.

10. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 in combination with one or more pharmaceutically acceptable excipient(s).

11. The composition of claim 10 which further comprises one or more active ingredient(s) selected from the group consisting of (i) a therapeutically effective amount of a bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof and (ii) a therapeutically effective amount of an estrogen receptor agonist or a pharmaceutically acceptable salt thereof.

12. The composition of claim 11 wherein the bisphosphonic acid is selected from the group consisting of 1,1-dichloromethylene-1,1-diphosphonic acid, 1-hydroxy-3-pyrrolidin-1-ylpropylidene-1,1-bisphosphonic acid, 1-hydroxyethylidene-1,1-diphosphonic acid, 1-hydroxy-3-(N-methyl-N-pentylamino)propylidene-1,1-bisphosphonic acid, 6-amino-1-hydroxyhexylidene-1,1-bisphosphonic acid, 3-(dimethylamino)-1-hydroxypropylidene-1,1-bisphosphonic acid, 3-amino-1-hydroxypropylidene-1,1-bisphosphonic acid, 2-pyrid-2-ylethylidene-1,1-bisphosphonic acid, 1-hydroxy-2-pyrid-3-ylethylidene-1,1-bisphosphonic acid, 4-chlorophenylthiomethylenebisphosphonic acid and 1-hydroxy-2-(1H-imidazol-1-yl)ethylidene-1,1-bisphosphonic acid or acid ester thereof or a pharmaceutically acceptable salt thereof.

13. The composition of claim 11 wherein the bisphosphonic acid is 1,1-dichloromethylene-1,1-diphosphonic acid or a pharmaceutically acceptable salt thereof.

14. The composition of claim 11 which comprises 1,1-dichloromethylene-1,1-diphosphonate monosodium trihydrate.

15. A method for treating a disease in an animal in which inhibition of a cysteine protease 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 claim 1 or a pharmaceutically acceptable salt thereof.

16. The method of claim 15 wherein the disease is osteoporosis.

17. The method of claim 16 wherein the animal is a human.

18. The method of claim 17 wherein the human is a post-menopausal woman.

19. The method of claim 18 wherein the cysteine protease activity is cathepsin K activity.

20. A process for preparing a compound of claim 1 comprising:

(A) reacting a compound of formula 4

where R¹, R², and R³ are as defined in claim 1 above;

with a compound of formula 5;

where R⁶ is as defined in claim 1 above;

or

(B) reacting a compound of formula 7;

with an acid compound of formula R⁶OH or an acid derivative thereof, wherein R¹, R², R³, R⁴, R⁵ and R⁶ are as defined in claim 1 above; and

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

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

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

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

(G) optionally resolving an individual isomer of a compound of Formula I from a mixture of isomers;

(H) optionally converting a non-derivatized compound of Formula I into a pharmaceutically prodrug derivative;

(I) optionally converting a prodrug derivative of a compound of Formula I to its non-derivatized form; and

(J) optionally modifying any of the R¹, R², R³,R⁴, R⁵ and R⁶ groups.

9. A compound selected from the group consisting of:

benzyl (1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-carbamate;

benzyl (1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-2-methyl-butyl)-carbamate;

tert-butyl (1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-carbamate;

benzyl (1S-{1S-[(3-acetyl-phenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-carbamate;

N-{1S-[1S-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-2-methylbutyl}-4-methylpiperazine-1-carboxamide;

benzyl {1S-[2-(4-methoxyphenylsulfamoyl)-ethylcarbamoyl]-2-methyl-butyl}-carbamate;

(2-cyclohexyl-1S-{3-phenyl-1S-[(2-phenylaminoethylsulfamoyl)-methyl]-propylcarbamoyl}ethyl)-carbamic acid tert-butyl ester;

4-dimethylamino-N-(1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenyl-propylcarbamoyl}-3-methylbutyl)-benzamide;

quinoline-6-carboxylic acid (1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-amide;

morpholine-4-carboxylic acid (2-cyclohexyl-1S-{3-phenyl-1S-[(2-phenylamino-ethylsulfamoyl)methyl]-propylcarbamoyl}ethyl)amide;

4-(2-dimethylaminothiazol-4-yl)-N-{1SS-[2-(4-methoxyphenylsulfamoyl)-ethylcarbamoyl]-3-methyl-butyl}benzamide;

2S-acetylamino-3-cyclohexyl-N-{1-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenyl-propyl}propionamide;

2R-acetylamino-3-cyclohexyl-N-{1-[(4-methoxyphenylsulfamoyl)methyl]-3-phenyl-propyl}propionamide;

2RS-acetylamino-3-cyclohexyl-N-{1-[(4-hydroxyphenylsulfamoyl)methyl]-3-phenyl-propyl}-propionamide;

benzyl [6-(4-methoxyphenylsulfamoyl)-5S-(4-methyl-2S-{4-[2-(pyridin-3-ylamino)thiazol-4-yl]-benzoylamino}pentanoylamino)hexyl]carbamate;

N-(1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenylpropylcarbamoyl}-3-methyl-butyl)-4-[2-(pyridin-3-ylamino)thiazol-4-yl]-benzamide;

N-(1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenyl-propylcarbamoyl}-3-methyl-butyl)-nicotinamide;

N-(1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenylpropylcarbamoyl}-3-methyl-butyl)-isonicotinamide;

N-{1-[1-(4-methoxyphenylsulfamoylmethyl)-3-phenylpropylcarbamoyl]-3-methylbutyl}-1H-indole-5-carboxamide;

tert-butyl [3-(1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenylpropylcarbamoyl}-3-methyl-butylcarbamoyl)phenyl]-carbamate;

3-amino-N-(1S-{1S-[(4-methoxyphenylsulfamoyl)-methyl]-3-phenylpropylcarbamoyl}-1-3-methyl-butyl)-benzamide;

N-(1S-{5-amino-1S-[(4-methoxyphenylsulfamoyl)methyl]pentylcarbamoyl}-3-methyl-butyl)-4-[2-(pyridin-3-ylamino)-thiazol-4-yl]-benzamide;

benzyl [1S-(1S-{[3-(1-hydroxyethyl)phenylsulfamoyl]methyl}-3-phenylpropyl-carbamoyl)-3-methylbutyl]-carbamate;

morpholine 4-carboxylic acid (1S-{5-amino-1S-[(4-methoxyphenylsulfamoyl)methyl]-pentylcarbamoyl}-2-phenylmethanesulfonylethyl)amide;

(5S-[2S-(morpholin-4-ylcarbonyl)amino]-3-phenylmethanesulfonylpropionylamino}-6-phenylsulfamoylhexyl)carbamic acid benzyl ester;

morpholine 4-carboxylic acid (1S-{1S-[(4-methoxyphenylsulfamoyl)methyl]-3-phenylpropylcarbamoyl}2-phenylmethanesulfonylethyl)amide;

N-(1S-{1S-[(4-methoxy-phenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-cyclohexyl)-4-[2-(4-methylpiperazin-1-yl)thiazol-4-yl]benzamide; and

N-(1S-{1S-[(4-methoxy-phenylsulfamoyl)-methyl]-3-phenyl-propylcarbamoyl}-cyclohexyl)-4-(4-propylpiperazin-1-yl)-benzamide;

or

a pharmaceutically acceptable salt thereof.