US 8,618,098 B2Granted

Inhibitors of bruton's tyrosine kinase

AssigneeRoche Palo Alto LLC

InventorsNolan James Dewdney, Rama K. Kondru, Bradley E. Loe, Yan Lou, Joel McIntosh, Timothy D. Owens, Michael Soth

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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.

Claims6

Dependent claims

A method for the therapeutic treatment of B-cell lymphoma and/or leukemia comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I:

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, 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.

27 more elements

A method for the therapeutic treatment of B-cell lymphoma and/or leukemia comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula II,

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, 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.

28 more elements

A method for the therapeutic treatment of rheumatoid arthritis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I:

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, substituted with one or more Y2′b′;
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;
Y4c 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;
Y4b 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.

26 more elements

A method for the therapeutic treatment of rheumatoid arthritis comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula II,

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, 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.

26 more elements

A method for the therapeutic treatment of asthma comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula I:

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, 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.

29 more elements

A method for the therapeutic treatment of asthma comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula II,

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, 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.

26 more elements

Dependencies are inferred from the claim text.

Facts

Application: 13/358,557Filed 26 Jan 2012 · division
Priority: 24 Jun 2008
Published: US 2012/0129845 A124 May 2012
Granted: 31 Dec 2013
Term ends: Not estimatedThe source records don’t support an estimate.

Classification35 codes

C07D 417/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms,…
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/16
Drugs for disorders of the alimentary tract or the digestive system: for liver or gallbladder disorders, e.g. hepatoprotective agents,…
A61P 3/10
For glucose homeostasis: for hyperglycaemia, e.g. antidiabetics

Family

Application61/075,277Us provisional application · filed 24 Jun 2008
Application12/456,911Parent of this division · filed 24 Jun 2009
Application12/987,187Parent of this division · filed 10 Jan 2011
US 2012/0129845 A1Pre-grant publication · published 24 May 2012
US 8,124,604 B2Parent of this division
US 7,902,194 B2Parent of this division
US 2009/0318448 A1Published application
US 2011/0105479 A1Published application
US 8,618,098 B2This patent

From the US filing history. Foreign family members aren’t listed.