Therapeutically active compounds and their methods of use

1. A method for preparing a compound of formula (Ia) wherein:

ring A is selected from phenyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, wherein ring A is optionally substituted with up to two substituents independently selected from halo, —C1-C4 alkyl, —C1-C4 haloalkyl, —C1-C4 hydroxyalkyl, —NH-S(O)2-(C1-C4 alkyl), —S(O)2NH(C1-C4 alkyl), —CN, —S(O)2-(C1-C4 alkyl), C1-C4 alkoxy, —NH(C1-C4 alkyl), —OH, —OCF3, —CN, —C(O)NH2, —C(O)NH(C1-C4 alkyl), —C(O)-N(C1-C4 alkyl)2, and cyclopropyl optionally substituted with OH;

R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, —O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with —OH, —NH2, —CN, —O-C1-C4 alkyl, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)2;

R 2 and R 5 are each independently selected from: —(C1-C6 alkyl), —(C1-C6 alkyl)-C(O)-NH2, —(C2-C6 alkenyl or alkynyl), —(C1-C6 alkylene)-O-(C1-C6 alkyl), —(C0-C6 alkylene)-C(O)N(R 6 )-C1-C6 alkyl), —(C0-C6 alkylene)-Q and —(C0-C6 alkylene)-C(O)-(C1-C6 alkyl), wherein:

any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more —OH, —O(C1-C4 alkyl), —CO2H, or halo;

any terminal methyl moiety present in R 2 and R 5 is optionally replaced with —CH2OH, CF3, —CH2F, —CH2CL, C(O)CH3, C(O)CF3, CN, or CO2H;

Q is selected from carbocyclyl and heterocyclyl, and of which is substituted woth 0-3 instances of halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, =O, —C(O)-C1-C4 alkyl, and CN; wherein

R 1 and R 2 are optionally taken together to form a carbocyclyl or a heterocyclyl either of which is optionally substituted with up to 3 substituents independently selected from halo, e.g., fluoro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, =O, aryl, heteroaryl, —SO2C1-C4 alkyl, —CO2C1-C4 alkyl, —C(O)aryl, and —C(O)C1C4 alkyl; or

R 4 and R 5 are optionally taken together to form a carbocyclyl, or a heterocyclyl either of which is optionally substituted with up to 3 substituents independently selected from halo, e.g., fluoro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, =O, —OH, aryl, heteroaryl, —SO2C1-C4 alkyl, —CO2C1-C4 alkyl, —C(O)aryl, and —C(O)C1-C4 alkyl;

R 7 and R 8 are H;

comprising a reaction between

2. The method of claim 1 wherein the reaction takes place between 40-120 ° C.

3. The method of claim 1 wherein

is prepared by a method comprising a reaction between

4. The method of claim 3 wherein the reaction takes place between 20-50 ° C.

5. The method of claim 1 wherein

is prepared by a method comprising a reaction between

6. The method of claim 5 wherein the reaction takes place in the presence of a palladium catalyst and a base.

7. The method of claim 6 wherein the palladium catalyst is Pd(PPh3)4.

8. The method of claim 7 wherein the base is K2CO3.

9. A method for preparing a compound of Formula (Ia) wherein:

ring A is selected from phenyl, pyrazolyl, oxazolyl, isoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, and thiazolyl, wherein ring A is optionally substituted with up to two substituents independently selected from halo, —C1-C4 alkyl, —C1-C4 haloalkyl, —C1-C4 hydroxyalkyl, —NH-S(O)2-(C1-C4 alkyl), —S(O)2NH(C1-C4 alkyl), —CN, —S(O)2-(C1-C4 alkyl), C1-C4 alkoxy, —NH(C1-C4 alkyl), —OH, —OCF3, —CN, —C(O)NH2, —C(O)NH(C1-C4 alkyl), —C(O)-N(C1-C4 alkyl)2, and cyclopropyl optionally substituted with OH;

R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, —O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently optionally substituted with —OH, —NH2, —CN, —O-C1-C4 alkyl, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)2;

R 2 and R 5 are each independently selected from: —(C1-C6 alkyl), —(C1-C6 alkyl)-C(O)-NH2, —(C2-C6 alkenyl or alkynyl), —(C1-C6 alkylene)-O-(C1-C6 alkyl), —(C0-C6 alkylene)-C(O)N(R 6 )-(C1-C6 alkyl), —(C0-C6 alkylene)-Q and —(C0-C6 alkylene)-C(O)-(C1-C6 alkyl), wherein:

any alkyl or alkylene moiety present in R 2 and R 5 is optionally substituted with one or more —OH, —O(C1-C4 alkyl), —CO2H, or halo;

any terminal methyl moiety present in R 2 and R 5 is optionally replaced with —CH2OH, CF3, —CH2F, —CH2CL, C(O)CH3,C(O)CF3, CN, or CO2H;

Q is selected from carbocyclyl and heterocyclyl, and of which is substituted with 0-3 instances of halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, =O, —C(O)-C1-C4 alkyl, and CN; wherein

R 1 and R 2 are optionally taken together to form a carbocyclyl or a heterocyclyl either of which is optionally substituted with up to 3 substituents independently selected from halo, e.g., fluoro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, =O, —OH, aryl, heteroaryl, —SO2C1-C4 alkyl, —CO2C1-C4 alkyl, —C(O)aryl, and —C(O)C1-C4 alkyl; or

R 4 and R 5 are optionally taken together to form a carbocyclyl or a heterocyclyl either of which is optionally substituted with up to 3 substituents independently selected from halo, e.g., fluoro, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, =O, —OH, aryl, heteroaryl, —SO2C1-C4 alkyl, —CO2C1-C4 alkyl, —C(O)aryl, and —C(O)C1-C4 alkyl;

R 7 and R 8 are H;

comprising a reaction between

10. The method of claim 9 wherein the reaction takes place in the presence of a palladium catalyst and a base.

11. The method of claim 10 wherein the palladium catalyst is Pd(PPh3)4.

12. The method of claim 11 wherein the base is K2CO3.

13. The method of claim 9 wherein

is prepared by a method comprising a reaction between

14. The method of claim 13 wherein the reaction takes place between 30-60 ° C.

15. The method of claim 13 wherein

is prepared by a method comprising a reaction between

16. The method of claim 15 wherein the reaction takes place between 20-60 ° C.

17. The method of claim 16 wherein the reaction takes place in the presence of a base.

18. The method of claim 17 wherein the base is selected from CsF, NaHCO3, Na2CO3, DIPEA, TEA, pyridine or a combination thereof.

19. The method of claim 18 wherein the base is a mixture of CsF and DIPEA.

20. The method of claim 3 wherein

is prepared by a method comprising a reaction between

and POCl3.

21. The method of claim 20 wherein the reaction takes place at 80-110 ° C.

22. The method of claim 21 wherein

is prepared by a method comprising a reaction between

in the presence of a base.

23. The method of claim 22 wherein the base is an alkoxide base dissolved in the corresponding alcohol.

24. The method of claim 23 wherein the alkoxide is sodium ethoxide dissolved in ethanol.

25. The method of claim 22 wherein the reaction takes place at 20-110° C.

26. The method of claim 20 wherein the reaction additionally takes place in the presence of PCl5.

27. The method of claim 1 wherein R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C1-C4 alkyl, C1-C4 haloalkyl, —O-C1-C4 alkyl, and CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 is independently substituted with 0-3 instances of —OH, —CN, —O-C1-C4 alkyl, —NH(C1-C4 alkyl), or —N(C1-C4 alkyl)2; and

R 2 and R 5 are each independently selected from: —(C1-C6 alkyl), —(C1-C6 alkyl)-C(0)-NH2, —(C1-C6 alkyl)-CO2H, —(C2-C6 alkenyl or alkynyl), —(C1-C6 alkylene)-O-(C1-C6 alkyl), —(C0-C6 alkylene)-C(O)N(R 6 )-(C1-C6 alkyl), and —(C0-C6 alkylene)-C(O)-(C1-C6 alkyl), wherein:

any alkyl or alkylene moiety present in R 2 and R 5 is substituted with 0-3 instances of —OH, —O(C1-C4 alkyl), —CO2H, or halo; and

any terminal methyl moiety present in R 2 and R 5 can be replaced with —CH2OH, CF3, —CH2F, —CH2Cl, C(O)CH3, C(O)CF3, CN, or CO2H;

R 1 and R 2 can be taken together to form a carbocyclyl substituted with 0-3 substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, =O, —OH and —C(O)C1-C4 alkyl; or

R 4 and R 5 can be taken together to form a carbocyclyl substituted with 0-3 substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy, —CN, =O, —OH and —C(O)C1-C4 alkyl;

28. The method of claim 1 wherein ring A is:

wherein R 9 is selected from hydrogen, halo, and —C1-C4 haloalkyl; each X a is independently N or C-R 9a , provided that when one X a is N, then the other two X a are both C-R 9a ; and R 9a is selected from hydrogen, halo, and —C1-C4 haloalkyl.

29. The method of claim 1 wherein ring A is

wherein R 9 is selected from hydrogen, halo, and —C1-C4 haloalkyl.

30. The method of claim 1 wherein R 1 , R 3 , R 4 , and R 6 are each independently selected from hydrogen, C1-C4 alkyl, and —CN, wherein each said alkyl moiety of R 1 , R 3 , R 4 , and R 6 are each independently substituted with 0-1 instances of —OH, —NH2, —CN, —O-C1-C4 alkyl; and R 2 and R 5 are each independently selected from —(C1-C6 alkyl) and —(C0-C6 alkylene)-Q.

31. The method of claim 1 wherein Q is selected from pyridinyl, tetrahydrofuranyl, cyclobutyl, cyclopropyl, phenyl, pyrazolyl, morpholinyl and oxetanyl, wherein Q is substituted with 0-2 substituents independently selected from C1-C4 alkyl, C1-C4 haloalkyl, =O, fluoro, chloro, and bromo.

32. The method of claim 31 wherein Q is cyclopropyl.

33. The method of claim 1 wherein R 1 and R 2 are taken together to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo[2.2.1]heptanyl, oxobicyclo[3.1.0]hexanyl, azetidinyl, any of which is substituted with 0-2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, —OH, —C(O)CH3, fluoro, and chloro.

34. The method of claim 1 wherein R 4 and R 5 are taken together to form cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl, bicyclo[2.2.1]heptanyl, oxobicyclo[3.1.0]hexanyl, or azetidinyl, any of which is substituted with 0-2 substituents independently selected from C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, —OH, —C(O)CH3, fluoro, and chloro.

35. The method of claim 1 wherein the compound is