USE OF INHIBITORS OF BRUTONS TYROSINE KINASE (BTK)

1 . A method of inhibiting Bruton's tyrosine kinase (BTK) activity in an individual having a B-cell malignancy comprising:

orally administering to the individual a dose of an irreversible BTK inhibitor;

wherein the dose is an oral dose determined to result in at least about a 90% mean steady state occupancy of the BTK active sites in peripheral blood mononuclear cells in a population of individuals having the B-cell malignancy.

2 - 6 . (canceled)

7 . A compound of Formula (D):

wherein:

L a is CH 2 , NH or S;

Ar is a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl;

Y is an optionally substituted group selected from among alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl;

Z is C(═O), OC(═O), NHC(═O), C(═S), S(═O) x , OS(═O) x , NHS(═O) x , where x is 1 or 2;

R 6 , R 7 , and R 8 are each independently selected from among H, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted C 2 -C 6 heterocycloalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 8 alkylaminoalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C 1 -C 4 alkyl(aryl), substituted or unsubstituted C 1 -C 4 alkyl(heteroaryl), substituted or unsubstituted C 1 -C 4 alkyl(C 3 -C 8 cycloalkyl), or substituted or unsubstituted C 1 -C 4 alkyl(C 2 -C 8 heterocycloalkyl); or

R 7 and R 8 taken together form a bond; and pharmaceutically active metabolites, or pharmaceutically acceptable solvates, pharmaceutically acceptable salts, or pharmaceutically acceptable prodrugs thereof.

8 . A compound of Formula (A):

wherein:

A is independently selected from N or CR 5 ;

R 1 is H, L 2 -(substituted or unsubstituted alkyl), L 2 -(substituted or unsubstituted cycloalkyl), L 2 -(substituted or unsubstituted alkenyl), L 2 -(substituted or unsubstituted cycloalkenyl), L 2 -(substituted or unsubstituted heterocycle), L 2 -(substituted or unsubstituted heteroaryl), or L 2 -(substituted or unsubstituted aryl), where L 2 is a bond, O, S, —S(═O), —S(═O) 2 , C(═O), -(substituted or unsubstituted C 1 -C 6 alkyl), or -(substituted or unsubstituted C 2 -C 6 alkenyl);

R 2 and R 3 are independently selected from H, lower alkyl and substituted lower alkyl;

R 4 is L 3 -X-L 4 -G, wherein,

L 3 is optional, and when present is a bond, optionally substituted or unsubstituted alkyl, optionally substituted or unsubstituted cycloalkyl, optionally substituted or unsubstituted alkenyl, optionally substituted or unsubstituted alkynyl;

X is optional, and when present is a bond, O, —C(═O), S, —S(═O), —S(═O) 2 , —NH, —NR 9 , —NHC(O), —C(O)NH, —NR 9 C(O), —C(O)NR 9 , —S(═O) 2 NH, —NHS(═O) 2 , —S(═O) 2 NR 9 —, —NR 9 S(═O) 2 , —OC(O)NH—, —NHC(O)O—, —OC(O)NR 9 —, —NR 9 C(O)O—, —CH═NO—, —ON═CH—, —NR 10 C(O)NR 10 —, heteroaryl, aryl, —NR 10 C(═NR 11 )NR 10 —, —NR 10 C(═NR 11 )—, —C(═NR 11 )NR 10 —, —OC(═NR 11 )—, or —C(═NR 11 )O—;

L 4 is optional, and when present is a bond, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocycle;

or L 3 , X and L 4 taken together form a nitrogen containing heterocyclic ring;

G is

  wherein,

 R 6 , R 7 and R 8 are independently selected from among H, lower alkyl or substituted lower alkyl, lower heteroalkyl or substituted lower heteroalkyl, substituted or unsubstituted lower cycloalkyl, and substituted or unsubstituted lower heterocycloalkyl;

R 5 is H, halogen, -L 6 -(substituted or unsubstituted C 1 -C 3 alkyl), -L 6 -(substituted or unsubstituted C 2 -C 4 alkenyl), -L 6 -(substituted or unsubstituted heteroaryl), or -L 6 -(substituted or unsubstituted aryl), wherein L 6 is a bond, O, S, —S(═O), S(═O) 2 , NH, C(O), —NHC(O)O, —OC(O)NH, —NHC(O), or —C(O)NH;

each R 9 is independently selected from among H, substituted or unsubstituted lower alkyl, and substituted or unsubstituted lower cycloalkyl;

each R 10 is independently H, substituted or unsubstituted lower alkyl, or substituted or unsubstituted lower cycloalkyl; or

two R 10 groups can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or

R 9 and R 10 can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or

each R 11 is independently selected from H, —S(═O) 2 R 8 , —S(═O) 2 NH 2 , —C(O)R 8 , —CN, —NO 2 , heteroaryl, or heteroalkyl; and

pharmaceutically active metabolites, pharmaceutically acceptable solvates, pharmaceutically acceptable salts, or pharmaceutically acceptable prodrugs thereof.