# US 2014/0194413 A1 · Inhibitors of bruton's tyrosine kinase

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- Number: US 2014/0194413 A1
- Document ID: US20140194413A1
- Status: Published application
- Kind: A1
- Application number: 14/024,354
- Filed: 2013-09-11
- Published: 2014-07-10
- Earliest claimed: 2008-06-24
- Assignees: Roche Palo Alto LLC
- Applicants: Roche Palo Alto LLC
- Inventors: Nolan James Dewdney; Rama K. Kondru; Bradley E. Loe; Yan Lou; Joel McIntosh; Timothy D. Owens; Michael Soth
- Web page: https://patentgrep.com/patent/US20140194413A1

## CPC

- C07D 417/14: containing three or more hetero rings
- 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 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/02: Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 35/02: specific for leukemia
- 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 401/10: linked by a carbon chain containing aromatic rings
- C07D 401/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

This application discloses 5-phenyl-1H-pyridin-2-one and 6-phenyl-2H-pyridazin-3-one derivatives according to generic Formulae I-IV: wherein, variables R, X, Y1, Y2, Y2′, Y3, Y4, n and m are defined as described herein, which inhibit Btk. The compounds disclosed herein are useful to modulate the activity of Btk and treat diseases associated with excessive Btk activity. The compounds are further useful to treat inflammatory and auto immune diseases associated with aberrant B-cell proliferation such as rheumatoid arthritis. Also disclosed are compositions comprising compounds of Formulae I-IV and at least one carrier, diluent or excipient.

## Claims

### Claim at position 1

1-18. (canceled)

### Claim 19

A compound of Formula IV,
wherein:
R is H, —R1, —R1-R2-R3, —R1-R3, or —R2—R3;
R1 is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, and is optionally substituted with R1′;
R1′ is lower alkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cycloalkyl, heterocycloalkyl, cyano, or lower haloalkyl;
R2 is —C(═O), —C(═O)O, —C(═O)N(R2′), —(CH2)q, or —S(═O)2;
R2′ is H or lower alkyl;
q is 1, 2, or 3;
R3 is H or R4;
R4 is lower alkyl, lower alkoxy, lower heteroalkyl, aryl, arylalkyl, alkylaryl, heteroaryl, alkyl heteroaryl, heteroaryl alkyl, cycloalkyl, alkyl cycloalkyl, cycloalkyl alkyl, heterocycloalkyl, alkyl heterocycloalkyl, or heterocycloalkyl alkyl, and is optionally substituted with one or more lower alkyl, hydroxy, oxo, lower hydroxyalkyl, lower alkoxy, halogen, nitro, amino, cyano, lower alkylsulfonyl, or lower haloalkyl;
X is CH or N;
Y1 is H or lower alkyl;
Y2 is Y2a or Y2b;
Y2a is H or halogen;
Y2b is lower alkyl, optionally substituted with one or more Y2b′;
Y2b′ is hydroxy, lower alkoxy, or halogen;
each Y2′ is independently Y2′a or Y2′b;
Y2′a is halogen;
Y2′b is lower alkyl, optionally substituted with one or more Y2′b′;
Y2′b′ is hydroxy, lower alkoxy, or halogen;
n is 0, 1, 2, or 3.
Y3 is H, halogen, or lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of hydroxy, lower alkoxy, amino, and halogen;
m is 0 or 1;
Y4 is Y4a, Y4b, Y4c, or Y4d;
Y4a is H or halogen;
Y4b is lower alkyl, optionally substituted with one or more substituents selected from the group consisting of lower haloalkyl, halogen, hydroxy, amino, cyano and lower alkoxy;
Y4c is lower cycloalkyl, optionally substituted with one or more substituents selected from the group consisting of lower alkyl, lower haloalkyl, halogen, hydroxy, amino, and lower alkoxy; and
Y4d is amino, optionally substituted with one or more lower alkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 19)

The compound of claim 19, wherein Y1 is methyl and X is CH.

### Claim 21 (depends on 20)

The compound of claim 20, wherein m is 0 and n is 0.

### Claim 22 (depends on 21)

The compound of claim 21, wherein Y2 is hydroxymethyl.

### Claim at position 6

23-25. (canceled)

### Claim 26 (depends on 19)

A method for treating an inflammatory and/or autoimmune condition comprising administering to a patient in need thereof a therapeutically effective amount of the Btk inhibitor compound of claim 19.

### Claim at position 8

27-28. (canceled)

### Claim 29 (depends on 19)

A method for treating rheumatoid arthritis comprising administering to a patient in need thereof a therapeutically effective amount of the Btk inhibitor compound of claim 19.

### Claim at position 10

30-31. (canceled)

### Claim 32 (depends on 19)

A method for treating asthma comprising administering to a patient in need thereof a therapeutically effective amount of the Btk inhibitor compound of claim 19.