Compositions and methods for inhibition of the JAK pathway
AssigneeRigel Pharmaceuticals, Inc.
InventorsHui Li, Vanessa Taylor, Somasekhar Bhamidipati, John Ramphal, Kin Tso, Arvinder Sran, Holger Keim, Vadim Markovtsov, David Carroll, Sambaiah Thota, Ankush Argade, Jeffrey Wayne Clough, Rajinder Singh, Robin Cooper
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Abstract
The invention encompasses compounds having formula I and the compositions and methods using these compounds in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases, particularly JAK3, are therapeutically useful.
Claims4
A method of inhibiting an activity of a JAK kinase, comprising contacting the JAK kinase with an amount of a compound according to formula I effective to inhibit an activity of the JAK kinase
- or therapeutically acceptable salt thereof, wherein:
- ring A is phenyl;
- ring B is benzofuranyl;
- q is 0, 1, 2 or 3;
- p is 0;
- R is hydrogen or lower alkyl;
- X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl, substituted cycloalkynyl;
- Y is a covalent bond;
- alk is a covalent bond;
- R1 is —C(O)NR4R5
- each R2 independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxyl ester, alkynyl, substituted alkynyl, hydroxyl, acyl, halo, acylamino, aminocarbonyl, and cyano;
- R4 is hydrogen;
- and
- R5 is morpholinoethyl.
A method of inhibiting an activity of a JAK kinase, comprising contacting the JAK kinase with an amount of a compound according to formula I effective to inhibit an activity of the JAK kinase
- or therapeutically acceptable salt thereof, wherein:
- ring A is aryl or heteroaryl;
- ring B is tetrahydroisoquinolinyl;
- q is 0, 1, 2 or 3 when ring A is monocyclic or q is 0, 1, 2, 3, 4, or 5 when ring A is bicyclic or tricyclic;
- p is 0, 1, 2, 3, 4, or 5;
- R is hydrogen or lower alkyl;
- X is selected from the group consisting of hydrogen, alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl, substituted cycloalkynyl;
- Y is selected from the group consisting of a covalent bond, oxygen and sulfur;
- alk is a covalent bond, straight or branched chain C1-6 alkylene group, or straight or branched chain substituted C1-6 alkylene group, wherein if both Y and alk is a covalent bond, then R1 is attached to ring B by a single covalent bond;
- R1 is selected from the group consisting of cyano, —C(O)NR4R5, and —C(S)NR4R5;
- each R2 independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxyl ester, alkynyl, substituted alkynyl, hydroxyl, acyl, oxo, halo, acylamino, aminocarbonyl, and cyano;
- each R3 independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, carboxyl, carboxyl ester, alkynyl, substituted alkynyl, hydroxyl, acyl, oxo and halo;
- or
- R3 and R4, together with the intervening atoms bound thereto form a heterocyclic or a substituted heterocyclic fused to the tetrahydroisoquinolinyl ring;
- and
- R4 and R5 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, cycloalkyl, substituted cycloalkyl, and acyl;
- or
- R4 and R5 together with the nitrogen atom bound thereto, form a heterocyclic or substituted heterocyclic.
Dependencies are inferred from the claim text.