Treatment of indolent or aggressive b-cell lymphomas using a combination comprising btk inhibitors

A method for the prevention, delay of progression or treatment of indolent or aggressive B-cell lymphomas in an individual in need thereof, comprising administering a therapeutically effective amount of a Btk inhibitor, in combination with a therapeutically effective amount of an anti-PD-1 antibody,

• wherein the Btk inhibitor is a compound of Formula (I),
• or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein:
• A is a 5- or 6-membered aromatic ring comprising 0-3 heteroatoms of N, S or O;
• each W is independently —(CH2)— or —C(O)—;
• L is a bond, CH2, NR12, O, or S;
• S/D is a single or double bond, and when a double bond, R5 and R7 are absent;
• m is 0, or an integer of 1-4;
• n is 0, or an integer of 1-4, wherein when n is more than 1, each R2 may be different;
• p is 0, or an integer of 1-2, wherein when p is 0, m is non-zero, and when p is more than 1, each R6 and each R7 may be different;
• R1, R4, R5, R6, and R7 are each independently H, halogen, heteroalkyl, alkyl, alkenyl, cycloalkyl, aryl, saturated or unsaturated heterocyclyl, heteroaryl, alkynyl, —CN, —NR13R14, —OR13, —COR13, —CO2R13, —CONR13R14, —C(═NR13)NR14R15, —NR13COR14, —NR13CONR14R15, —NR13CO2R14, —SO2R13, —NR13SO2NR14R15, or —NR13SO2R14, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heteroaryl, aryl, and saturated or unsaturated heterocyclyl are optionally substituted with at least one substituent R16, wherein (R4 and R5), or (R4 and R6), or (R6 and R7), or (R6 and R6 when p is 2), together with the atoms to which they are attached, can form a ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings optionally substituted with at least one substituent R16;
• R2 is halogen, alkyl, —S-alkyl, —CN, —NR13R14, —OR13, —COR13, —CO2R13, —CONR13R14, —C(═NR13)NR14R15, —NR13COR14, —NR13CONR14R15, —NR13CO2R14, —SO2R13, —NR13SO2NR14R15, or —NR13SO2R14;
• R12 is H or lower alkyl;
• R13, R14 and R15 are each independently H, heteroalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, saturated or unsaturated heterocyclyl, aryl, or heteroaryl;
• wherein (R13 and R14), and/or (R14 and R15) together with the atom(s) to which they are attached, each can form a ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings optionally substituted with at least one substituent R16;
• R16 is halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, oxo, —CN, —ORa, —NRaRb, —CORa, —CO2Ra, —CONRaRb, —C(═NRa)NRbRc, —NRaCORb, —NRaCONRaRb, —NRaCO2Rb, —SO2Ra, —SO2aryl, —NRaSO2NRbRc, or —NRaSO2Rb, wherein Ra, Rb, and Rc are independently hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclyl, wherein (Ra and Rb), and/or (Rb and Rc) together with the atoms to which they are attached, can form a ring selected from cycloalkyl, saturated or unsaturated heterocycle, aryl, and heteroaryl rings.