US2008182849A1PendingUtilityA1
Certain Heterocyclic Substituted Imidazo[1,2-A]Pyrazin-8-Ylamines And Methods Of Inhibition Of Bruton's Tyrosine Kinase By Such Compounds
Individually held — no corporate assignee on recordPriority: Jun 30, 2003Filed: Mar 26, 2008Published: Jul 31, 2008
Est. expiryJun 30, 2023(expired)· nominal 20-yr term from priority
C07D 487/04
58
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Claims
Abstract
Compounds of Formula I and all pharmaceutically acceptable forms thereof, are described herein. The variables R 1 , R 2 , R 3 , Z 2 , and Q, shown in Formula I are defined herein. Pharmaceutical compositions containing one or more compounds of Formula I, or a pharmaceutically acceptable form of such compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents are provided herein. Methods of treating patients suffering from certain diseases responsive to inhibition of tyrosine kinase activity are also given. In certain embodiments the diseases are responsive to inhibition of Btk activity and/or B-cell proliferation. Such methods comprise administering to such patients an amount of a compound of Formula I effective to reduce signs or symptoms of the disease. These diseases include cancer, an autoimmune and/or inflammatory disease, or an acute inflammatory reaction. Thus methods of treatment include administering a sufficient amount of a compound or salt as provided herein to decrease the symptoms or slow the progression of these diseases. Other embodiments include methods of treating other animals, including livestock aid domesticated companion animals, suffering from a disease responsive to inhibition of kinase activity. Methods of treatment include administering a compound of Formula I as a single active agent or administering a compound of Formula I in combination with one or more other therapeutic agent. A method for determining the presence of Btk in a sample, comprising contacting the sample with a compound or form thereof of Formula I under conditions that permit detection of Btk activity, detecting a level of Btk activity in the sample, and therefrom determining the presence or absence of Btk in the sample.
Claims
exact text as granted — not AI-modified1 - 62 . (canceled)
63 . A packaged pharmaceutical composition comprising
A) a pharmaceutical composition in a container, which composition comprises at least one pharmaceutically acceptable carrier or excipient and a compound of Formula I:
wherein
R 1 is
X 1 N or CR;
X 2 N or CR;
X 3 Nor CR;
provided that at most one of X 1 , X 2 , and X 3 is N;
each R is independently hydrogen, hydroxy, cyano, halo, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy;
Z 2 is a divalent linking group which is para-phenylene, meta-phenylene, ortho-phenylene, or naphthylene, each of which is substituted with one group R 2 -Q-, where
Q is
wherein
R 4 is
hydrogen,
C 1 -C 6 alkyl,
phenyl,
heteroaryl,
mono-, di-, or trisubstituted phenyl, wherein the substituents are independently hydroxy, nitro, cyano, amino, halo, —CHO, COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloakyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or heteroaryl, or
mono-, di-, or trisubstituted heteroaryl, wherein the substituents are independently hydroxy, nitro, cyano amino, halo, —CHO, —COOH, —CON 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or heteroaryl;
R 2 is
C 1 -C 7 alkyl,
mono-, di-, or tri-substituted C 1 -C 7 alkyl, wherein the substitutents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, or heteroaryl,
C 3 -C 7 cycloalkyl,
mono-, di-, or tri-substituted C 3 -C 7 cycloalkyl, wherein the substitutents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, or heteroaryl,
heterocycloalkyl,
mono-, di-, or tri-substituted heterocycloalkyl, wherein the substitutents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, or heteroaryl,
C 1 -C 6 alkoxy,
mono-, di-, or tri-substituted C 1 -C 6 alkoxy, wherein the substitutents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COON, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, or heteroaryl,
phenyl,
mono-, di-, or trisubstituted phenyl, wherein the substituents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, (C 3 -C 7 cycloalkyl)C 0- C 2 alkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, (heterocycloalkyl)C 0 -C 2 alkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or heteroaryl,
heteroaryl, or
mono-, di-, or tri-substituted heteroaryl, wherein the substituents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, (heterocycloalkyl)C 0 -C 2 alkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or heteroaryl;
R 3 is hydrogen, C 1 -C 7 alkyl, heterocycloalkyl, or C 3 -C 7 cycloalkyl; and
R 6 and R 7 are independently hydrogen, hydroxy, cyano, halo, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy,
or a pharmaceutically acceptable salt or hydrate thereof; and
B) instructions for using the composition to treat a patient suffering from a disease responsive to Btk inhibition.
64 . The packaged pharmaceutical composition of claim 63 , wherein the disease responsive to Btk inhibition is cancer.
65 . The packaged pharmaceutical composition of claim 63 , wherein the disease responsive to Btk inhibition is an autoimmune disease, an inflammatory disease, or an acute inflammatory reaction.
66 . A method for treating a patient having a disease responsive to inhibition of Btk activity, comprising administering to the patient an effective amount of a compound of Formula I:
wherein
R 1 is
X 1 N or CR;
X 2 N or CR;
X 3 N or CR;
provided that at most one of X 1 , X 2 , and X 3 is N;
each R is independently hydrogen, hydroxy, cyano, halo, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy;
Z 2 is a divalent linking group which is para-phenylene, meta-phenylene, ortho-phenylene, or naphthylene, each of which is substituted with one group R 2 -Q-, where
Q is
wherein
R 4 is
hydrogen,
C 1 -C 6 alkyl,
phenyl,
heteroaryl,
mono-, di-, or trisubstituted phenyl, wherein the substituents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or heteroaryl, or
mono-, di-, or trisubstituted heteroaryl, wherein the substituents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 Cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or heteroaryl;
R 2 is
C 1 -C 7 alkyl,
mono-, di-, or tri-substituted C 1 -C 7 alkyl, wherein the substitutents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, or heteroaryl,
C 3 -C 7 cycloalkyl,
mono-, di-, or tri-substituted C 3 -C 7 cycloalkyl, wherein the substitutents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, or heteroaryl,
heterocycloalkyl,
mono-, di-, or tri-substituted heterocycloalkyl, wherein the substitutents are independently hydroxy, nitro, cyano, amino, halo, —CHO, COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, or heteroaryl,
C 1 -C 6 alkoxy,
mono-, di-, or tri-substituted C 1 -C 6 alkoxy, wherein the substitutents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, or heteroaryl,
phenyl,
mono-, di-, or trisubstituted phenyl, wherein the substituents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, (heterocycloalkyl)C 0 -C 2 alkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or heteroaryl,
heteroaryl, or
mono-, di-, or tri-substituted heteroaryl, wherein the substituents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, (heterocycloalkyl)C 0 -C 2 alkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or heteroaryl;
R 3 is hydrogen, C 1 -C 7 alkyl, heterocycloalkyl, or C 3 -C 7 cycloalkyl; and
R 6 and R 7 are independently hydrogen, hydroxy, cyano, halo, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy,
or a pharmaceutically acceptable salt or hydrate thereof.
67 . The method of claim 66 , wherein the patient is a human.
68 . The method of claim 66 , wherein the patient is a cat or a dog.
69 . The method of claim 66 , wherein the disease responsive to Btk inhibition is cancer.
70 . The method of claim 66 , wherein the disease responsive to Btk inhibition is an autoimmune disease, an inflammatory disease, or an acute inflammatory reaction.
71 . The method of claim 66 , wherein the compound is administered orally.
72 . The method of claim 66 , wherein the compound is administered intravenously, intramuscularly, or parenterally.
73 . A method for increasing sensitivity of cancer cells to chemotherapy, comprising administering to a patient undergoing chemotherapy with a chemotherapeutic agent, a sufficient amount to increase the sensitivity of cancer cells to the chemotherapeutic agent, of a compound of Formula I:
wherein
R 1 is
X 1 N or CR;
X 2 N or CR;
X 3 N or CR;
provided that at most one of X 1 , X 2 , and X 3 is N;
each R is independently hydrogen, hydroxy, cyano, halo, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy;
Z 2 is a divalent linking group which is para-phenylene, meta-phenylene, ortho-phenylene, or naphthylene, each of which is substituted with one group R 2 -Q-, where
Q is
wherein
R 4 is
hydrogen,
C 1 -C 6 alkyl,
phenyl,
heteroaryl,
mono-, di-, or trisubstituted phenyl, wherein the substituents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 0 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloakyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or heteroaryl, or
mono-, di-, or trisubstituted heteroaryl, wherein the substituents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 0 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or heteroaryl;
R 2 is
C 1 -C 7 alkyl,
mono-, di-, or tri-substituted C 1 -C 7 alkyl, wherein the substitutents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, or heteroaryl,
C 3 -C 7 cycloalkyl,
mono-, di-, or tri-substituted C 3 -C 7 cycloalkyl, wherein the substitutents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, or heteroaryl,
heterocycloalkyl,
mono-, di-, or tri-substituted heterocycloalkyl, wherein the substitutents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, or heteroaryl,
C 1 -C 6 alkoxy,
mono-, di-, or tri-substituted C 1 -C 6 alkoxy, wherein the substitutents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, or heteroaryl,
phenyl,
mono-, di-, or trisubstituted phenyl, wherein the substituents are independently hydroxy, nitro, cyano, amino, halo, —CHO, COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, (heterocycloalkyl)C 0 -C 2 alkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or heteroaryl,
heteroaryl, or
mono-, di-, or tri-substituted heteroaryl, wherein the substituents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, (heterocycloalkyl)C 0 -C 2 alkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or heteroaryl;
R 3 is hydrogen, C 1 -C 7 alkyl, heterocycloalkyl, or C 3 -C 7 cycloalkyl; and
R 6 and R 7 are independently hydrogen, hydroxy, cyano, halo, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy,
or a pharmaceutically acceptable salt or hydrate thereof
74 . A method for inhibiting ATP hydrolysis, comprising contacting cells expressing Btk, in an amount sufficient to detectably decrease the level of ATP hydrolysis in vitro, with a compound of Formula I.
Wherein
R 1 is
X 1 N or CR;
X 2 N or CR;
X 3 N or CR;
provided that at most one of X 1 , X 2 , and X 3 is N;
each R is independently hydrogen, hydroxy, cyano, halo, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy;
Z 2 is a divalent linking group which is para-phenylene, meta-phenylene, ortho-phenylene, or naphthylene, each of which is substituted with one group R 2 -Q-, where
Q is
wherein
R 4 is
hydrogen,
C 1 -C 6 alkyl,
phenyl,
heteroaryl,
mono-, di-, or trisubstituted phenyl, wherein the substituents are independently hydroxy, nitro, cyano, amino, halo, —CHO, COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or heteroaryl, or
mono-, di-, or trisubstituted heteroaryl, wherein the substituents are independently hydroxy, nitro, cyano, amino, halo, —CHO, COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or heteroaryl;
R 2 is
C 1 -C 7 alkyl,
mono-, di-, or tri-substituted C 1 -C 7 alkyl, wherein the substitutents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOR, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, or heteroaryl,
C 3 -C 7 cycloalkyl,
mono-, di-, or tri-substituted C 3 -C 7 cycloalkyl, wherein the substitutents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, or heteroaryl,
heterocycloalkyl,
mono-, di-, or tri-substituted heterocycloalkyl, wherein the substitutents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, or heteroaryl,
C 1 -C 6 alkoxy,
mono-, di-, or tri-substituted C 1 -C 6 alkoxy, wherein the substitutents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, heterocycloalkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, phenyl, or heteroaryl,
phenyl,
mono-, di-, or trisubstituted phenyl, wherein the substituents are independently hydroxy, nitro, cyano, amino, halo, —CHO, —COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, (heterocycloalkyl)C 0 -C 2 alkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or heteroaryl,
heteroaryl, or
mono-, di-, or tri-substituted heteroaryl, wherein the substituents are independently hydroxy, nitro, cyano, amino, halo, —CHO, COOH, —CONH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkoxy)C 1 -C 6 alkoxy, mono-(C 1 -C 6 alkyl)amino, di-(C 1 -C 6 alkyl)amino, aminoC 1 -C 6 alkyl, C 1 -C 6 alkylthio, mono-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, di-(C 1 -C 6 alkyl)aminoC 1 -C 6 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 2 alkyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxycarbonyl, (heterocycloalkyl)C 0 -C 2 alkyl, amido, sulfonamido, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or heteroaryl;
R 3 is hydrogen, C 1 -C 7 alkyl, heterocycloalkyl, or C 3 -C 7 cycloalkyl; and
R 6 and R 7 are independently hydrogen, hydroxy, cyano, halo, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl, or C 1 -C 2 haloalkoxy,
or a pharmaceutically acceptable salt or hydrate thereof
75 . The method of claim 74 , wherein the cells are present in a mammal.
76 . The method of claim 75 , wherein the mammal is a human.
77 . The method of claim 75 , wherein the mammal is a cat or dog.Join the waitlist — get patent alerts
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