# US 8,785,429 B2 · Dihydropyrrolonaphthyridinone compounds as inhibitors of JAK

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- Number: US 8,785,429 B2
- Document ID: US8785429B2
- Status: Granted
- Kind: B2
- Application number: 13/787,514
- Filed: 2013-03-06
- Published: 2013-07-18
- Granted: 2014-07-22
- Earliest claimed: 2009-06-08
- Assignees: Takeda Pharmaceutical Company Limited
- Applicants: Takeda Pharmaceutical Company Limited
- Inventors: John David Lawson; Toufike Kanouni; Michael B. Wallace; Qing Dong
- Web page: https://patentgrep.com/patent/US8785429B2

## CPC

- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61K 31/4375: the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- 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 35/00: Antineoplastic agents
- 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 471/16: Peri-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Disclosed are JAK inhibitors of formula I where G1, R1, R2, R3, R4, R5, R6, and R7 are defined in the specification. Also disclosed are pharmaceutical compositions, kits and articles of manufacture which contain the compounds, methods and materials for making the compounds, and methods of using the compounds to treat diseases, disorders, and conditions involving the immune system and inflammation, including rheumatoid arthritis, hematological malignancies, epithelial cancers (i.e., carcinomas), and other diseases, disorders or conditions associated with JAK.

## Claims

### Claim 1

A method for inhibition of JAK2 and/or JAK3 in a subject suffering from a disease associated with JAK2 and/or JAK3, the method comprising administering to the subject a compound of formula I
or a pharmaceutically acceptable salt thereof, wherein:
G1 is selected from the group consisting of CR8;
R1 is selected from the group consisting of optionally substituted C3-8 cycloalkyl, optionally substituted C3-6 heterocycloalkyl, optionally substituted C4-14 aryl, optionally substituted C1-10 heteroaryl, and optionally substituted C1-6 alkyl;
R2 and R3 are each independently selected from the group consisting of hydrogen and optionally substituted C1-4 alkyl, or R2, R3, and the carbon atom to which they are attached form a carbonyl;
R4 is selected from the group consisting of hydrogen, optionally substituted C1-4 alkyl, optionally substituted C1-4 alkoxy, halo, hydroxy, and amino;
R5 is selected from the group consisting of hydrogen, optionally substituted C1-4 alkyl, C3-8 cycloalkyl, and halo;
R6 and R7 are each independently selected from the group consisting of hydrogen and optionally substituted C1-4 alkyl, or R6, R7, and the carbon atom to which they are attached form a carbonyl;
R8 is selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-4 alkoxy, C1-9 amide, C1-5 oxycarbonyl, cyano, optionally substituted C3-8 cycloalkyl, optionally substituted C4-14 aryl, optionally substituted C1-10 heteroaryl, and halo; and
with the proviso that no more than one carbonyl is formed from R2 and R3 and R6 and R7.

### Claim 2 (depends on 1)

A method according to claim 1, wherein each of R4 and R5 are hydrogen.

### Claim 3 (depends on 1)

A method according to claim 1, wherein G is CR8 and R8 is selected from hydrogen, halo, and optionally substituted C1-6 alkyl.

### Claim 4 (depends on 3)

A method according to claim 3, wherein G is CR8 and R8 is selected from hydrogen, halo, and C1-4 alkyl.

### Claim 5 (depends on 1)

A method according to claim 1, wherein R1 is optionally substituted C3-8 cycloalkyl.

### Claim 6 (depends on 1)

A method according to claim 1, wherein R1 is optionally substituted C3-6 heterocycloalkyl.

### Claim 7 (depends on 1)

A method according to claim 1, wherein R1 is optionally substituted C4-14 aryl.

### Claim 8 (depends on 1)

A method according to claim 1, wherein R1 is optionally substituted C1-10 heteroaryl.

### Claim 9 (depends on 1)

A method according to claim 1, wherein R1 is optionally substituted C1-6 alkyl.

### Claim 10 (depends on 1)

A method according to claim 1, wherein R2, R3, and the carbon atom to which they are attached form a carbonyl.

### Claim 11 (depends on 10)

A method according to claim 10, wherein each of R6 and R7 is hydrogen.

### Claim 12 (depends on 1)

A method according to claim 1, wherein R6, R7, and the carbon atom to which they are attached form a carbonyl.

### Claim 13 (depends on 12)

A method according to claim 12, wherein each of R2 and R3 is hydrogen.

### Claim 14 (depends on 1)

A method according to claim 1, in which the compound is selected from:
tert-butyl 4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate;
4-(piperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one;
3-oxo-3-(4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidin-1-yl)propanenitrile;
tert-butyl 4-methyl-4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate;
4-(4-methylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one;
3-(4-methyl-4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidin-1-yl)-3-oxopropanenitrile;
tert-butyl 4-ethyl-4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate;
4-(4-ethylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one;
3-(4-ethyl-4-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidin-1-yl)-3-oxopropanenitrile;
4-(pentan-3-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one;
4-(1-cyclopropyl-3-hydroxypropyl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one;
tert-butyl 3-((5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)methyl)pyrrolidine-1-carboxylate;
4-(pyrrolidin-3-ylmethyl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridine-5(1H)-one;
tert-butyl 3-(5-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)piperidine-1-carboxylate;
4-(piperidin-3-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one;
4-(4-ethyl-l-propionylpiperidin-4-yl)-3,4-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-5(1H)-one;
4-(4-ethyl-1-(pyrimidin-4-yl) piperidin-4-yl)-3,4-dihydropyrrolo [4,3,2-de][2,6]naphthyridin-5(1H)-one;
(S)-4-(1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-4,5-dihydropyrrolo [4,3,2-de][2,6]naphthyridin-3(1H)-one;
(R)-4-(1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-4,5-dihydropyrrolo [4,3,2-de][2,6]naphthyridin-3(1H)-one;
(R)-4-(3-methyl-1-oxo-1-(pyrrolidin-1-yl)butan-2-yl)-4,5-dihydropyrrolo [4,3,2-de][2,6]naphthyridin-3(1H)-one;
(R)-4-(4-methyl-1-oxo-1-(pyrrolidin-1-yl)pentan-2-yl)-4,5-dihydropyrrolo [4,3,2-de][2,6]naphthyridin-3(1H)-one;
(R)-N-cyclopentyl-3-methyl-2-(3-oxopyrrolo [4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;
(2R,3R)-N-cyclopentyl-3-methyl-2-(3-oxopyrrolo [4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)pentanamide;
(2R,3S)-N-cyclopentyl-3-methyl-2-(3-oxopyrrolo [4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)pentanamide;
(R)-N-cyclopentyl-2-cyclopropyl-2-(3-oxopyrrolo [4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)acetamide;
(R)-N-cyclopentyl-3,3-dimethyl-2-(3-oxopyrrolo [4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;
(R)-N,2-dicyclopentyl-2-(3-oxopyrrolo [4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)acetamide;
(R)-N-cyclopentyl-4,4,4-trifluoro-2-(3-oxopyrrolo [4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;
(R)-N-cyclopentyl-3-hydroxy-3-methyl-2-(3-oxopyrrolo [4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;
(R)-2-(6-chloro-3-oxopyrrolo [4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-cyano-N-cyclopentylpropanamide;
N-cyclopentyl-1-(3-oxopyrrolo [4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)cyclopentanecarboxamide;
(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-(cyanomethyl)-3-methylbutanamide;
1-((R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)pyrrolidine-3-carbonitrile;
(R)-1-(2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)piperidine-4-carbonitrile;
(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-(4-cyanophenyl)-3-methylbutanamide;
(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-(3-cyanophenyl) -3-methylbutanamide;
(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-((S)-1-cyanobutan -2-yl)-3-methylbutanamide;
(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-((R)-1-cyanobutan -2-yl)-3-methylbutanamide;
(R)-1-(2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)azetidine-3-carbonitrile;
(R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-(2-cyanoethyl)-3,3-dimethylbutanamide;
(R)-1-(2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3,3-dimethylbutanoyl)azetidine-3-carbonitrile;
(R)-1-(2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)azetidine-3-carbonitrile;
(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoic acid;
(2R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methyl-N-(tetrahydrofuran-3-yl)butanamide;
(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methyl-N-(1,1-dioxidotetrahydrothien-3-yl)butanamide;
(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methyl-N-(2-(methylsulfonyl)ethyl)butanamide;
(R)-N-(1,1 -dioxidotetrahydro-2H-thiopyran-4-yl)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanamide;
4-{(1R)-1-[(1,1-dioxidothiomorpholin-4-yl)carbonyl]-2-methylpropyl}-6-fluoro-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;
(R)-N-(cyclopropylmethoxy)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanamide;
(2R)-N-(3,3-difluorocyclopentyl)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanamide;
(R)-3-(fluoromethyl)-1-(3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile;
(R)-1-(2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)-3-methylazetidine-3-carbonitrile;
(R)-3-methyl-1-(3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile;
(R)-4-(1-morpholino-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;
(R)-4-(1-(4-methylpiperazin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;
4-((2R)-1-(3-hydroxypyrrolidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;
(R)-N-cyclopentyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;
4-((2R)-1-(3-(4-fluorophenyl)pyrrolidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;
4-((2R)-1-(3-(dimethylamino)pyrrolidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;
4-((2R)-1-(3-(methoxymethyl)pyrrolidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;
4-((2R)-1-(3-methylpiperidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;
(R)-4-(1-(4-(2-hydroxypropan-2-yl)piperidin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;
(R)-4-(1-(4-(methylsulfonyl)piperazin-1-yl)-1-oxobutan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;
(R)-4-(1-oxo-1-(4-(pyridin-2-yl)piperazin-1-yl)butan-2-yl)-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;
(R)-N-cyclopropyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin -4(1H,3H,5H)-yl)butanamide;
(R)-N-(cyclopropylmethyl)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;
(R)-N-isobutyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;
(R)-N-isobutyl-N-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;
(2R)-N-(1-hydroxypropan-2-yl)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;
(R)-N-(2-hydroxy-2-methylpropyl)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;
(R)-N-((S)-2,3-dihydroxypropyl)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;
(R)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-phenylbutanamide;
(R)-N-(1-(methylsulfonyl)piperidin-4-yl)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;
(2R)-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N-((tetrahydrofuran-2-yl)methyl)butanamide;
(2R)-N-(1-cyano ethyl)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanamide;
(R)-4-(1-(3,3-difluoroazetidin-1-yl)-3-methyl-1-oxobutan -2-yl)-6-fluoro-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;
(R)-4-(1-(1,1-dioxidothiazolidin-3-yl)-3-methyl-1-oxobutan-2-yl)-6-fluoro-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;
(R)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N,3-dimethyl-N-(2-(methylsulfonyl)ethyl)butanamide;
(R)-N-(cyanomethyl)-2-(6-fluoro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-N,3-dimethylbutanamide;
(R)-4-(1-(3-(difluoromethyl)azetidin-1-yl)-3-methyl-1-oxobutan-2-yl)-6-fluoro-4,5-dihydropyrrolo[4,3,2-de][2,6]naphthyridin-3(1H)-one;
(R)-1-(3-methyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile;
(R)-1-(3,3-dimethyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile;
(R)-N-(cyanomethyl)-3,3-dimethyl-2-(3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanamide;
(S)-1-((R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)pyrrolidine-2-carbonitrile;
(R)-1-((R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)pyrrolidine-2-carbonitrile;
(2S,4S)-1-((R)-2-(6-chloro-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-methylbutanoyl)-4-fluoropyrrolidine-2-carbonitrile;
(R)-1-(3,3-dimethyl-2-(6-methyl-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H ,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile;
(R)-1-(3-methyl-2-(6-methyl-3-oxopyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)butanoyl)azetidine-3-carbonitrile;
stereoisomers of any of the aforementioned compounds; and
pharmaceutically acceptable salts of any one of the aforementioned stereoisomers or compounds.

### Claim 15 (depends on 1)

A method according to claim 1, further comprising administering at least one additional pharmacologically active agent.

### Claim 16 (depends on 15)

A method according to claim 15, wherein the additional pharmacologically active agent is a DMARD.

### Claim 17 (depends on 16)

A method according to claim 16, wherein the DMARD is methotrexate.