# US 2008/0188459 A1 · Non-Steroidal Compounds Useful as Glucocorticoid Receptor Modulators

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- Number: US 2008/0188459 A1
- Document ID: US20080188459A1
- Status: Published application
- Kind: A1
- Application number: 12/065,241
- Filed: 2006-08-25
- Published: 2008-08-07
- Earliest claimed: 2005-08-29
- Assignees: N.V. Organon
- Inventors: Ralf Plate; Christiaan Gerardus Johannes Maria Jans
- Web page: https://patentgrep.com/patent/US20080188459A1

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/44: Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This invention relates to novel amino acid derivatives of formula (I) wherein the R groups have the following meanings: —R1 is —H or -(1-4C)alkyl; —R2 is —C(O)R15 or —S(O)2R15; —R3 is —H, -(1-4C)alkyl or —OR16; —R4 is —H, -(1-4C)alkyl or —OR16; —R6 is —H or —C(R16)NOR16; —R7 is —H, -halogen, -cyano; -(1-6C)alkyl, -(2-6C)alkenyl or -(2-6C)alkynyl, all optionally substituted with -amino, -hydroxyl or -halogen; —R8 is —H, -cyano, -halogen, -nitro; -(1-6C)alkyl, -(2-6C)alkenyl, -(2-6C)alkynyl or —O(1-6C)alkyl, all optionally substituted with -amino, -hydroxyl or -halogen; -(hetero)aryl, optionally substituted with -cyano, -halogen, -(1-4C)alkyl, -(1-4C)alkoxy, -(1-4C)alkoxy(1-4C)alkyl or -(hetero)aryl; —C(R16)NOR16; —C(O)N(R17)2; —C(O)R18, —C(O)OR19, —NHC(O)R20, or —NHS(O)2R21; —R9 is —H, -halogen, -cyano, or -(1-4C)alkyl, optionally substituted with -halogen; —R10 is —H or -(1-4C)alkyl; —R11 is —H; —R12 is —H, -cyano or -(1-4C)alkyl; —R13 is —H, -(1-4C)alkyl, -halogen or -formyl; —R14 is —H, -halogen, -cyano, -(1-4C)alkyl or -(hetero)aryl; or a pharmaceutically acceptable salt thereof. The compounds of this invention are highly specific for the glucocorticoid receptor and may be used for treating inflammatory diseases.

## Claims

### Claim 1

A compound according to general formula I:
or a pharmaceutically acceptable salt thereof.
wherein the R groups have the following meanings:
—R1 is —H or -(1-4C)alkyl;
—R2 is —C(O)R15 or —SO2R15;
—R3 is —H, -(1-4C) alkyl or —OR16;
—R4 is —H, -(1-4C)alkyl or —OR16;
—R6 is —H or —C(R16)NOR16;
—R7 is —H, -halogen, -cyano;
-(1-6C) alkyl, -(2-6C)alkenyl or -(2-6C)alkynyl, all optionally substituted with amino, -hydroxyl or -halogen;
—R8 is —H, -cyano, -halogen, -nitro;
-(1-6C) alkyl, -(2-6C)alkenyl, -(2-6C)alkynyl or —O(1-6C)alkyl, all optionally substituted with -amino, -hydroxyl or -halogen;
-(hetero)aryl, optionally substituted with -cyano, -halogen, -(1-4C)alkyl, -(1-4C)alkoxy, -(1-4C)alkoxy(1-4C)alkyl or -(hetero)aryl;
—C(R16)NOR16, —C(O)N(R17)2, —C(O)R18, —C(O)OR19, —NHC(O)R20, or —NHS(O)2R21;
—R9 is —H, -halogen, -cyano, or -(1-4C)alkyl, optionally substituted with -halogen;
—R10 is —H or -(1-4C)alkyl;
—R11 is —H;
—R12 is —H, -cyano or -(1-4C)alkyl;
—R13 is —H, -(1-4C)alkyl, -halogen or -formyl;
—R14 is —H, -halogen, -cyano, -(1-4C)alkyl or -(hetero)aryl;
—R15 is —H;
-(1-6C)alkyl, -(2-6C)alkenyl, -(2-6C)alkynyl, —O(2-6C)alkyl, —O(2-6C)alkenyl or —O(2-6C)alkynyl, all optionally substituted with one or more —OH, -halogen, -cyano or -(hetero)aryl;
-(hetero)aryl, optionally substituted with -(1-4C)alkyl, -halogen or —NH2;
—NH2, -(di)(1-4C)alkylamino, -(1-4C)alkylthio(1-4C)alkyl, -(1-4C)alkoxy(1-4C)alkyl or —NR16OR16;
—R16 is —H, -(1-6C)alkyl, -(2-6C)alkenyl or -(2-6C)alkynyl;
—R17 is —H;
-(1-6C)alkyl, optionally substituted with -halogen, -(1-4C)alkoxy or -(hetero)aryl, optionally substituted with -halogen, -(1-4C)alkyl or -(1-4C)alkoxy;
-(3-6C)cycloalkyl or -(hetero)aryl, optionally substituted with -halogen, -(1-4C)alkyl or -(1-4C)alkoxy;
—R18 is —H, —NH2 or -(1-4C)alkyl, optionally substituted with —OH, -halogen, -cyano or —S(1-4C)alkyl;
—R19 is —H or -(1-6C)alkyl, optionally substituted with —OH or -halogen; and
—R20 is —H;
-(1-6C)alkyl or -(2-6C)alkenyl, both optionally substituted by -halogen, —O(1-6C)alkyl, -(hetero)aryl, optionally substituted with -(1-4C)alkyl or halogen;
-(3-6C)cycloalkyl, -(1-6C)alkoxy, -(1-6C)alkenyloxy; or
-(hetero)aryl, optionally substituted with -(1-4C)alkyl); —NH2, —NH(1-6C)alkyl or —NH(hetero)aryl);
—R21 is —H or -(1-6C)alkyl.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein —R3, —R6, —R7, —R9, —R12, —R13, —R14 and —R16 are —H and —R are —H or -(1-4C)alkyl.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein —R1 is —H;
—R8 is —H, -cyano or -halogen;
-(hetero)aryl, optionally substituted with -(1-4C)alkyl;
—C(R16)NOR16, —C(O)N(R17)2, —C(O)R18 or —C(O)OR19;
—R10 is -(1-4C)alkyl;
—R15 is -(1-6C)alkyl, optionally substituted with one or more -halogen or -(hetero)aryl;
-(hetero)aryl, optionally substituted with -(1-4C)alkyl or —NH2; or
-(di)(1-4C)alkylamino;
—R17 is -(hetero)aryl, optionally substituted with -(1-4C)alkoxy;
—R18 is -(1-4C)alkyl and
—R19 is -(1-6C)alkyl.

### Claim 4

A compound selected from the group of
rel-N-[(2R,10R,14bR)-8-bromo-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-2,2,2-trifluoroacetamide;
rel-N-[(2R,10R,14bR)-8-cyano-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-2,2,2-trifluoroacetamide;
rel-2,2-dichloro-N-[(2R,10R,14bR)-8-cyano-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
rel-2,2,2-trifluoro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide
rel-N-[(2R,10R,14bR)-8-cyano-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-4-methyl-1,2,3-thiadiazole-5-carboxamide;
rel-N-[(2R,10R,14bR)-8-cyano-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-2,2-difluoroacetamide;
rel-N-[(2R,10R,14bR)-8-cyano-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]methanesulfonamide;
rel-N-[(2R,10R,14bR)-8-cyano-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]ethanesulfonamide;
rel-N′-[(2R,10R,14bR)-8-cyano-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-N,N-dimethylaminosulfamide;
rel-N-[(2R,10R,14bR)-8-cyano-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-3,5-dimethylisoxazole-4-carboxamide;
rel-N-[(2R,10R,14bR)-8-acetyl-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-2,2,2-trifluoroacetamide;
rel-N-[(2R,10R,14bR)-8-acetyl-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-4-methyl-1,2,3-thiadiazole-5-carboxamide;
rel-2,2,2-trifluoro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-8-[1-(hydroxyimino)ethyl]-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
rel-2,2,2-trifluoro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyridin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
rel-2,2-dichloro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyridin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
rel-2-chloro-2,2-difluoro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyridin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
rel-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyridin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
rel-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyridin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]isoxazole-5-carboxamide;
rel-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyridin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-5-methyl-isoxazole-3-carboxamide;
rel-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyridin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-4-methyl-1,2,3-thiadiazole-5-carboxamide;
rel-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyridin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-2-thiophenacetamide;
rel-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyridin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]methanesulfonamide;
rel-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyridin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]ethanesulfonamide;
rel-N′-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyridin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-N,N-dimethylaminosulfamide;
rel-2,2-difluoro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyridin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
rel-4-amino-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyridin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-1,2,5-oxadiazole-3-carboxamide;
rel-2,2,2-trifluoro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyrimidin-2-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
rel-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyrimidin-2-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-4-methyl-1,2,3-thiadiazole-5-carboxamide;
rel-2,2,2-trifluoro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyrazin-2-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
methyl rel-(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-2-(2,2,2-trifluoroacetylamino)dibenzo[c,f]pyrido[1,2-a]azepine-8-carboxylate;
ethyl rel-(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl 2-(2,2,2-trifluoroacetylamino)dibenzo[c,f]pyrido[1,2-a]azepine-8-carboxylate;
propyl rel-(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl 2-(2,2,2-trifluoroacetylamino)dibenzo[c,f]pyrido[1,2-a]azepine-8-carboxylate;
rel-(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-N-phenyl-2-(2,2,2-trifluoroacetylamino)dibenzo[c,f]pyrido[1,2-a]azepine-8-carboxamide;
rel-(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-N-(pyridin-4-yl)-2-(2,2,2-trifluoroacetylamino)dibenzo[c,f]pyrido[1,2-a]azepine-8-carboxamide;
rel-(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-N-(2-methoxypyrimidin-5-yl)-10-methyl-2-(2,2,2-trifluoroacetylamino)dibenzo[c,f]pyrido[1,2-a]azepine-8-carboxamide;
rel-(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-N-(2-methoxyphenyl)-10-methyl-2-(2,2,2-trifluoroacetylamino)-dibenzo[c,f]pyrido[1,2-a]azepine-8-carboxamide;
rel-2,2,2-trifluoro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(2-methyltetrazol-5-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
rel-2-chloro-2,2-difluoro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(2-methyltetrazol-5-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
rel-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(2-methyltetrazol-5-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-4-methyl-1,2,3-thiadiazole-5-carboxamide;
rel-2,2,2-trifluoro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyrimidin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
rel-2,2,2-trifluoro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyridin-2-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
rel-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyrimidin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-4-methyl-1,2,3-thiadiazole-5-carboxamide;
rel-2,2-chloro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyrimidin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
rel-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyrimidin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]methanesulfonamide;
rel-2-chloro-2,2-difluoro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyrimidin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
rel-5-amino-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-(pyrimidin-4-yl)dibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-1,2,5-oxadiazole-4-carboxamide;
rel-2,2,2-trifluoro-N-[(2R,4S, 10R,14bR)-1,2,3,4,10,14b-hexahydro-4,10-dimethyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
rel-N-[(2R,10R,14bR)-8-cyano-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-N′-methyl-N′-methoxyurea;
rel-N-[(2R,10R,14bR)-8-cyano-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-2-hydroxyacetamide;
rel-(2R,10R,14bR)-2-[(N,N-dimethylaminocarbonyl)amino]-1,2,3,4,10,14b-hexahydro-10-methyl-N-phenyldibenzo[c,f]pyrido[1,2-a]azepine-8-carboxamide;
rel-2,2,2-trifluoro-N-[(2R,10R,14bR)-8-[4,5-dihydrooxazol-2-yl]-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
rel-2,2,2-trifluoro-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-10-methyl-8-nitrodibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide;
rel-2,2,2-trifluoro-N-[(2R,10R,14bR)-8-formyl-1,2,3,4,10,14b-hexahydro-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]acetamide; or
rel-N-[(2R,10R,14bR)-1,2,3,4,10,14b-hexahydro-8-[1-(hydroxyimino)ethyl]-10-methyldibenzo[c,f]pyrido[1,2-a]azepin-2-yl]-4-methyl-1,2,3-thiadiazole-5-carboxamide.

### Claim 5 (depends on 1)

A pharmaceutical composition which comprises a compound of formula I according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

### Claim at position 6

6-7. (canceled)

### Claim 8

A method for treating a disease, condition or disorder responsive to glucocorticoid receptor activity, wherein the disease, condition or disorder is selected from the group consisting of rheumatic disease, dermatological disease, allergic disorder, pulmonary condition and immune and inflammatory disease, the method comprising administering to an individual a therapeutically effective amount of the compound of formula I or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 8)

The method of claim 8, wherein the disease is rheumatoid disease.

### Claim 10 (depends on 9)

The method of claim 9, wherein the rheumatoid disease is selected from the group consisting of rheumatoid arthritis, juvenile arthritis and ankylosing spoldylitis.

### Claim 11 (depends on 8)

The method of claim 8, wherein the condition is a pulmonary condition selected from the group consisting of asthma and chronic obstructive pulmonary disease.

### Claim 12 (depends on 8)

The method of claim 8, wherein the dermatological disease is selected from the group consisting of psoriasis and pemphigus.

### Claim 13 (depends on 8)

The method of claim 8, wherein the allergic disorder is selected from the group consisting of allergic rhinitis, atopic dermatitis and contact dermatitis.

### Claim 14 (depends on 8)

The method of claim 8, wherein the pulmonary disorder is selected from the group consisting of asthma and chronic obstructive pulmonary disease.

### Claim 15 (depends on 8)

The method of claim 8, wherein the immune and inflammatory disease is selected from the group consisting of Crohn disease, ulcerative colitis, systemic lupus erythematosus, autoimmune chronic active hepatitis, osteoarthritis, tendonitis and bursitis.