2,4-DIAMINO-PYRIMIDINE COMPOUNDS AND METHOD FOR MAKING AND USING THE COMPOUNDS

1 . A method for treating a proliferative disorder, comprising administering to a subject a therapeutically effective amount of a compound, or a composition comprising the compound, wherein the compound has a formula 1

or salt thereof, wherein:

ring A is cycloaliphatic;

ring B is aryl;

R 1 is (C1-C10)alkyl, (C3-C10)cycloalkyl, halo, aryl, or heteroaryl; and

R 2 and R 3 are independently hydrogen or (C1-C6)alkyl.

2 . The method according to claim 1 wherein the hyperproliferative disorder is a hyperproliferative skin disease.

3 . The method according to claim 2 wherein the hyperproliferative disorder is epidermal hyperproliferation.

4 . The method according to claim 1 wherein the hyperproliferative disorder is a hematological malignancy.

5 . The method according to claim 4 where the hematological malignancy is leukemia, acute myeloid leukemia (AML), DLBCL, ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocytic leukemia, or B-cell prolymphocytic leukemia.

6 . The method according to claim 1 , wherein cycloaliphatic ring A is substituted with —CONH 2 .

7 . The method according to claim 1 , wherein ring A is a carboxamide substituted (C6-C12) cycloalkyl, (C6-C12) cycloalkenyl, (C6-C12) bicycloalkyl or a (C6-C12) bicycloalkenyl ring.

8 . The method according to claim 1 , wherein ring B is a mono-, di- or tri-substituted phenyl ring.

9 . The method according to claim 1 , wherein ring B is substituted with a substituent selected from (C1-10)amide, (C3-C10)cycloamide, (C1-C10)alkyl, (C1-C10)alkoxyl, (C3-C10)cycloalkoxyl, halo, (C3-C10)cycloalkyl or (C3-C10)heterocycloalkyl.

10 . The method according to claim 9 , wherein the substituent is methyl or fluoro.

11 . The method according to claim 1 , wherein the A ring is selected from

12 . The method according to claim 1 , wherein the B ring is selected from

13 . The method according to claim 1 , wherein R 1 is aryl or heteroaryl.

14 . The method according to claim 1 , wherein R 1 is F, CH 3 ,

15 . The method according to claim 1 , having a formula selected from

wherein the A ring, the B ring, R 1 , R 2 and R 3 are as stated in claim 1 .

16 . The method according to claim 11 , having a formula

17 . The method according to claim 1 , having a formula selected from

wherein the A ring, the B ring, R 2 and R 3 are as stated in claim 1 , and R 4 is selected from (C1-C6)alkyl, cyano, halo and hydrogen.

18 . The method according to claim 17 , wherein R 4 is methyl or fluoro.

19 . The method according to claim 1 , having a formula selected from

wherein the A ring, the B ring, and R 2 and R 3 are as stated in claim 1 .

20 . The method according to claim 15 , wherein (C1-C10)alkyl is methyl and (C1-C10)cycloalkyl is cyclopropyl.

21 . The method according to claim 1 , wherein the compound is selected from:

(1S,2S,3R,4R)-3-((5-(pyridin-3-yl)-2-((4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(2S,3R)-3-((2-((3-fluoro-4-(4-(methylsulfonyl)piperazin-1-yl)phenyl)amino)-5-(pyridin-3-yl)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(pyridin-3-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-methyl-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-cyclopropyl-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(furan-3-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-phenyl-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(pyridin-3-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(pyridin-4-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(2-fluorophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(3-fluorophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(4-fluorophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(3-cyanophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(4-cyanophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(5-fluoropyridin-3-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

(1S,2S,3R,4R)-3-((5-(2-fluoropyridin-4-yl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide;

1S,2R)-2-((5-(3-cyanophenyl)-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)cyclohexane-1-carboxamide;

(1S,2S,3R,4R)-3-((5-bromo-2-((3-(pyrrolidine-1-carbonyl)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide; or

(1S,2S,3R,4R)-3-((5-bromo-2-((4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)amino)pyrimidin-4-yl)amino)bicyclo[2.2.1]hept-5-ene-2-carboxamide.

22 . A method for treating a hyperproliferative skin disease or a hematological malignancy, comprising administering to a subject a therapeutically effective amount of a compound, or a composition comprising the compound, wherein the compound has a formula 1

or salt thereof, wherein:

ring A is selected from

ring B is selected from

R 1 is (C1-C10)alkyl, (C3-C10)cycloalkyl, halo, aryl, or heteroaryl; and

R 2 and R 3 are independently hydrogen or (C1-C6)alkyl.