METHODS OF TREATING AND PREVENTING ALLOANTIBODY DRIVEN CHRONIC GRAFT VERSUS HOST DISEASE

1 . A method of treating alloantibody driven chronic graft versus host disease (cGVHD) in a patient, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (A) having the structure:

wherein:

A is N;

R 1 is phenyl-O-phenyl or phenyl-S-phenyl;

R 2 and R 3 are independently H;

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, halogen, CN, OH, substituted or unsubstituted alkyl or substituted or unsubstituted heteroalkyl or substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;

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 10 and R 11 can together form a 5-, 6-, 7-, or 8-membered heterocyclic ring; or

each R 11 is independently selected from H or substituted or unsubstituted alkyl; or a pharmaceutically acceptable salt thereof, thereby treating the GVHD in the patient.

2 . The method of claim 1 , wherein L 3 , X and L 4 taken together form a nitrogen containing heterocyclic ring.

3 . The method of claim 2 , wherein the nitrogen containing heterocyclic ring is a piperidine group.

4 . The method of claim 1 , wherein G is

5 . The method of claim 1 , wherein the compound of Formula (A) is (R)-1-(3-(4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidin-1-yl)prop-2-en-1-one (ibrutinib)

or a pharmaceutically acceptable salt thereof.

6 . The method of claim 1 , wherein the cGVHD is non-sclerodermatous cGVHD.

7 . The method of claim 1 , wherein the cGVHD is multi-organ cGVHD.

8 . The method of claim 1 , wherein the cGVHD is bronchiolitis obliterans syndrome.

9 . The method of claim 1 , wherein the cGVHD is lung cGVHD.

10 . The method of claim 1 , wherein fibrosis is reduced.

11 . The method of claim 1 , wherein the patient has received a cell transplantation.

12 . The method of claim 9 , wherein the cell transplantation is a hematopoietic cell transplantation.

13 . The method of claim 9 , wherein the cell transplantation is an allogeneic bone marrow or hematopoietic stem cell transplant.

14 . The method of claim 9 , wherein the compound of Formula (A) is administered concurrently with an allogeneic bone marrow or hematopoietic stem cell transplant.

15 . The method of claim 9 , wherein the compound of Formula (A) is administered subsequent to an allogeneic bone marrow or hematopoietic stem cell transplant.

16 . The method of claim 1 , wherein the compound of Formula (A) is administered at a dosage of between about 0.1 mg/kg per day to about 100 mg/kg per day.

17 . The method of claim 1 , wherein the amount of the compound of Formula (A) administered is about 40 mg/day, about 140 mg/day, about 420 mg/day, about 560 mg/day, or about 840 mg/day.

18 . The method of claim 1 , wherein the compound of Formula (A) is administered from day 1 to about day 1000 following allogeneic bone marrow or hematopoietic stem cell transplant.

19 . The method of claim 1 , wherein the compound of Formula (A) is administered orally.

20 . The method of claim 1 , wherein the compound of Formula (A) is administered in combination with one or more additional therapeutic agents.