5-cyano-4- (pyrrolo [2,3B] pyridine-3-yl) -pyrimidine derivatives useful as protein kinase inhibitors

1. A method of inhibiting PLK protein kinase activity in a biological sample, comprising contacting the biological sample with a compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof; wherein:

R 1 is —H, halogen, C 1-6 aliphatic optionally substituted with 1-3 R 3 , —O(C 1-6 aliphatic) optionally substituted with 1-3 R 3 , or —N(H)R;

Each R is independently H, C 1-6 aliphatic, aryl, heteroaryl, C 3-8 cycloalkyl, or 4-12 membered heterocyclic ring optionally containing 1-3 groups selected from —N(R 17 )—, —O—, or —S—; wherein each of the aliphatic, aryl, heteroaryl, cycloalkyl, and heterocyclic ring are optionally substituted with 1-3 of Q;

Each Q is independently selected from halogen, hydroxy, C 1-6 alkyl, benzyl, oxo, —CF 3 , W, —CN, —NH 2 , —N(H)—W, —N(W) 2 , —N(H)—SO 2 —W, —S(O) 2 —N(H)—W, —S(O) 2 —N(W) 2 , —C(O)—W, —C(O)—N(W) 2 , —N(H)—C(O)—W, —O—C(O)—W, —C(O)—O—W, —SO 2 —W, SW or —OW;

Two Q can be linked together to form a 4- to 8-membered carbocyclic or heterocyclic ring optionally substituted with C 1-3 alkyl or CF 3 ;

Each W is independently selected from —H, C 1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring; each C 1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring is optionally substituted with 1-3 of halogen, —OR 6 , —CN, C 1-6 alkyl or NR 18 R 19 ; or

One W, together with the nitrogen atom to which it is attached and a carbon atom of R, form a 4- to 8-membered ring; or

Two W, together with the same or different nitrogen atom or carbon atom to which they are attached, form a 4- to 8-membered heterocyclic ring;

Each R 18 and R 19 is independently hydrogen or C 1-3 alkyl; or

R 18 and R 19 , together with the nitrogen atom to which they are attached, form a 4- to 8-memebered heterocyclic ring, optionally substituted with C 1-3 alkyl or CF 3 ;

Two W can be linked together to form a 4- to 8-membered cycloalkyl or heterocycloalkyl optionally substituted with C 1-3 alkyl or CF 3 ;

R 2 is —NR 4 R 5 , —OR 6 , —SR 6 , or —NR 10 R 11 ;

Each R 3 is independently halogen, C 1-6 alkyl, aryl, or heteroaryl;

Each R 4 is independently —H or C 1-6 aliphatic optionally substituted with 1-3 R 7 ;

Each R 5 is independently C 1-6 aliphatic optionally substituted with 1-4 R 7 or a 4- to 8-membered monocyclic or 6- to 10-membered bicyclic ring optionally substituted with 1-4 R 7 , or

R 4 and R 5 can be joined together to form a monocyclic or bicyclic ring optionally substituted with 1-3 R 9 ;

Each R 6 is independently H, C 1-6 alkyl, -L-aryl, or -L-heteroaryl, wherein each of the C 1-6 alkyl, -L-aryl, or -L-heteroaryl is optionally and independently substituted with 1-3 R 8 ;

L is C 0-3 alkyl;

Each R 7 is independently oxo, alkyl, halogen, —CN, —OR 9 , —SR 9 , —N(R 9 ) 2 , C 3-8 cycloalkyl, aryl, heteroaryl or a 4- to 8-membered heterocyclic ring containing 1-3 groups selected from —N(R 17 )—, —O—, or —S—, wherein each alkyl, cycloalkyl, 4-8 membered heterocyclic monocyclic or bicyclic ring, aryl, and heteroaryl is optionally and independently substituted with 1-3 R 8 , or

Two R 7 on the same atom or adjacent atoms is joined to form a carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1-3 groups selected from —N(R 17 )—, —O—, or —S—, wherein each of the carbocyclic ring and the 4- to 8-membered heterocyclic ring is optionally and independently substituted with 1-3 R 8 ;

Each R 8 is independently —R, -Q, —R 9 , —OR 9 , —N(R 9 ) 2 , halogen, or —CN;

Each R 9 is independently —H, —N(R 16 ) 2 , C 3-6 carbocyclic ring, C 3-6 heterocyclic ring, or C 1-3 aliphatic, wherein C 3-6 carbocyclic ring, C 3-6 heterocyclic ring and C 1-3 aliphatic are each optionally substituted with 1-3 Q; or

Two R 9 groups together with the N atom to which they are bound form a 4-8 membered ring additionally containing 1 or 2 groups each independently selected from —N(R 17 )—, —O—, or —S—, wherein the 4- to 8-membered ring is optionally and independently substituted with 1-3 of W;

Each R 16 is independently hydrogen or C 1-6 alkyl, or

Two R 16 groups together with the N atom to which they are bound form a 4- to 8-membered ring containing 1 or 2 groups selected from NR 17 , O, or S;

Each R 17 is independently, hydrogen, Q 1 or C 1-4 aliphatic or cycloaliphatic, wherein each C 1-4 aliphatic or cycloaliphatic is optionally substituted with 1-3 of Q;

Q 1 is C 1-6 alkyl, benzyl, —SO 2 —W, —S(O) 2 —N(H)—W, —S(O) 2 —N(W) 2 , —C(O)—W, —C(O)—N(W) 2 —C(O)—N(H)—W, —N(H)—C(O)—W, —O—C(O)—W, —C(O)—O—W, or —SO 2 —W;

R 10 is —H or C 1-6 aliphatic optionally substituted with 1-3 of R 7 ;

R 11 is —C(R 12 R 13 )C(═O)NR 14 R 15 ;

Each of R 12 and R 13 is independently H or C 1-6 aliphatic optionally substituted with 1-3 R 7 ; or

R 12 and R 13 can be joined together to form a ring optionally substituted with 1-3 of R 9 ; or

R 10 and R 12 can be joined together to form a ring optionally substituted with 1-3 of R 9 ; and

Each R 14 and R 15 is independently H, C 1-6 alkyl, carbocyclic, or heterocyclic optionally substituted with 1-3 of R 7 ; or

R 14 and R 15 can be joined together to form a ring optionally substituted with 1-3 of R 9 .

2. A method of treating, melanoma, multiple myeloma, leukemia, colon cancer, breast cancer, gastric cancer, ovarian cancer, cervical cancer, lung cancer, renal cancer, prostate cancer, bladder cancer, pancreatic cancer, or malignant mesothelioma in a patient wherein said method comprises administering to said patient a compound represented by Structural Formula (I):

or a pharmaceutically acceptable salt thereof; wherein:

R 1 is —H, halogen, C 1-6 aliphatic optionally substituted with 1-3 R 3 , —O(C 1-6 aliphatic) optionally substituted with 1-3 R 3 , or —N(H)R;

Each R is independently H, C 1-6 aliphatic, aryl, heteroaryl, C 3-8 cycloalkyl, or 4-12 membered heterocyclic ring optionally containing 1-3 groups selected from —N(R 17 )—, —O—, or —S—;

wherein each of the aliphatic, aryl, heteroaryl, cycloalkyl, and heterocyclic ring are optionally substituted with 1-3 of Q;

Each Q is independently selected from halogen, hydroxy, C 1-6 alkyl, benzyl, oxo, —CF 3 , W, —CN, —NH 2 , —N(H)—W, —N(W) 2 , —N(H)—SO 2 —W, —S(O) 2 —N(H)—W, —S(O) 2 —N(W) 2 , —C(O)—W, —C(O)—N(W) 2 , —N(H)—C(O)—W, —O—C(O)—W, —C(O)—O—W, —SO 2 —W, SW or —OW;

Two Q can be linked together to form a 4- to 8-membered carbocyclic or heterocyclic ring optionally substituted with C 1-3 alkyl or CF 3 ;

Each W is independently selected from —H, C 1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring; each C 1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring is optionally substituted with 1-3 of halogen, —OR 6 , —CN, C 1-6 alkyl or NR 18 R 19 ; or

One W, together with the nitrogen atom to which it is attached and a carbon atom of R, form a 4- to 8-membered ring; or

Two W, together with the same or different nitrogen atom or carbon atom to which they are attached, form a 4- to 8-membered heterocyclic ring;

Each R 18 and R 19 is independently hydrogen or C 1-3 alkyl; or

R 18 and R 19 , together with the nitrogen atom to which they are attached, form a 4- to 8-membered heterocyclic ring, optionally substituted with C 1-3 alkyl or CF 3 ;

Two W can be linked together to form a 4- to 8-membered cycloalkyl or heterocycloalkyl optionally substituted with C 1-3 alkyl or CF 3 ;

R 2 is —NR 4 R 5 , —OR 6 , —SR 6 , or —NR 10 R 11 ;

Each R 3 is independently halogen, C 1-6 alkyl, aryl, or heteroaryl;

Each R 4 is independently —H or C 1-6 aliphatic optionally substituted with 1-3 R 7 ;

Each R 5 is independently C 1-6 aliphatic optionally substituted with 1-4 R 7 or a 4- to 8-membered monocyclic or 6- to 10-membered bicyclic ring optionally substituted with 1-4 R 7 , or

R 4 and R 5 can be joined together to form a monocyclic or bicyclic ring optionally substituted with 1-3 R 9 ;

Each R 6 is independently H, C 1-6 alkyl, -L-aryl, or -L-heteroaryl, wherein each of the C 1-6 alkyl, -L-aryl, or -L-heteroaryl is optionally and independently substituted with 1-3 R 8 ;

L is C 0-3 alkyl;

Each R 7 is independently oxo, alkyl, halogen, —CN, —OR 9 , —SR 9 , —N(R 9 ) 2 , C 3-8 cycloalkyl, aryl, heteroaryl or a 4- to 8-membered heterocyclic ring containing 1-3 groups selected from —N(R 17 )—, —O—, or —S—, wherein each alkyl, cycloalkyl, 4-8 membered heterocyclic monocyclic or bicyclic ring, aryl, and heteroaryl is optionally and independently substituted with 1-3 R 8 , or

Two R 7 on the same atom or adjacent atoms is joined to form a carbocyclic ring or a 4- to 8-membered heterocyclic ring containing 1-3 groups selected from —N(R 17 )—, —O—, or —S—, wherein each of the carbocyclic ring and the 4- to 8-membered heterocyclic ring is optionally and independently substituted with 1-3 R 8 ;

Each R 8 is independently —R, -Q, —R 9 , —OR 9 , —N(R 9 ) 2 , halogen, or —CN;

Each R 9 is independently —H, —N(R 16 ) 2 , C 3-6 carbocyclic ring, C 3-6 heterocyclic ring, or C 1-3 aliphatic, wherein C 3-6 carbocyclic ring, C 3-6 heterocyclic ring and C 1-3 aliphatic are each optionally substituted with 1-3 Q; or

Two R 9 groups together with the N atom to which they are bound form a 4-8 membered ring additionally containing 1 or 2 groups each independently selected from —N(R 17 )—, —O—, or —S—, wherein the 4- to 8-membered ring is optionally and independently substituted with 1-3 of W;

Each R 16 is independently hydrogen or C 1-6 alkyl, or

Two R 16 groups together with the N atom to which they are bound form a 4- to 8-membered ring containing 1 or 2 groups selected from NR 17 , O, or S;

Each R 17 is independently, hydrogen, Q 1 or C 1-4 aliphatic or cycloaliphatic, wherein each C 1-4 aliphatic or cycloaliphatic is optionally substituted with 1-3 of Q;

Q 1 is C 1-6 alkyl, benzyl, —SO 2 —W, —S(O) 2 —N(H)—W, —S(O) 2 —N(W) 2 , —C(O)—W, —C(O)—N(W) 2 , —C(O)—N(H)—W, —N(H)—C(O)—W, —O—C(O)—W, —C(O)—O—W, or —SO 2 —W;

R 10 is —H or C 1-6 aliphatic optionally substituted with 1-3 of R 7 ;

R 11 is —C(R 12 R 13 )C(═O)NR 14 R 15 ;

Each of R 12 and R 13 is independently H or C 1-6 aliphatic optionally substituted with 1-3 R 7 ; or

R 12 and R 13 can be joined together to form a ring optionally substituted with 1-3 of R 9 ; or

R 10 and R 12 can be joined together to form a ring optionally substituted with 1-3 of R 9 ; and

Each R 14 and R 15 is independently H, C 1-6 alkyl, carbocyclic, or heterocyclic optionally substituted with 1-3 of R 7 ; or

R 14 and R 15 can be joined together to form a ring optionally substituted with 1-3 of R 9 .

3. The method of claim 2 , wherein R 1 is halogen.

4. The method of claim 2 , wherein R 1 is methyl optionally substituted with 1-3 R 3 and each R 3 is independently halo.

5. The c method of claim 4 , wherein R 1 is —CF 3 .

6. The method of claim 4 , wherein R 1 is —NHR and R is H, C 1-6 aliphatic, aryl, or C 3-8 cycloalkyl.

7. The method of claim 6 , wherein R is H, C 1-6 alkyl, or aryl.

8. The method of claim 6 , wherein R 2 is —NR 4 R 5 , wherein R 4 is H or C 1-6 aliphatic optionally substituted with 1-3 R 7 , and R 5 is C 1-6 aliphatic optionally substituted with 1-4 R 7 or a 3- to 6-membered monocyclic or 6- to 10-membered bicyclic ring optionally substituted with 1-4 R 7 .

9. The method of claim 8 , wherein R 4 is H, and R 5 is C 1-4 alkyl and optionally substituted with 1-4 R 7 .

10. The method of claim 9 , wherein R 5 is ethyl substituted at the carbon atom attached to the nitrogen atom with R 7 .

11. The method of claim 10 , wherein R 7 is phenyl, pyridyl, or pyrimidyl, and is optionally substituted with 1-3 of R 8 .

12. The method of claim 8 , wherein

R 7 is phenyl substituted at the para-position with —R or —N(R 9 ) 2 ;

R is 4- to 8-membered heterocyclic ring optionally containing 1-3 groups each independently selected from —N(R 17 )—, —O—, or —S—, and the heterocyclic ring is optionally substituted with 1-3 of Q;

Each Q is independently selected from halogen, hydroxy, C 1-6 alkyl, benzyl, —CF 3 , W, —C(O)—W, —C(O)—N(W) 2 , —C(O)—O—W;

Each W is independently selected from —H, C 1-6 alkyl, or cycloalkyl;

Each R 9 is independently —H, C 3-6 heterocyclic ring, or C 1-3 aliphatic, wherein C 3-6 heterocyclic ring and C 1-3 aliphatic are each optionally substituted with 1-3 Q; or

Two R 9 groups together with the N atom to which they are bound form a 4- to 8-membered ring containing additional 1 or 2 groups each independently selected from —bN(R 17 )—, —O—, or —S—, wherein the 4- to 8-membered ring is optionally and independently substituted with 1-3 of W.

13. The method of claim 8 , wherein R 7 is

14. The method of claim 8 , wherein R 7 is pyrimidinyl optionally substituted with 1-3 of R 8 ,5-pyrimidyl optionally substituted at the 2-position with R 8 , or pyridinyl optionally substituted with 1-3 of R 8 .

15. The method of claim 14 , wherein R 7 is

16. The method of claim 11 , wherein one R 8 is aryl, heteroaryl, C 3 -C 8 cycloalkyl, or 4- to 8-membered heterocyclic ring each optionally substituted with 1-3 of Q.

17. The method of claim 11 , wherein one R 8 is Q, and wherein Q is —NHW, —NW 2 , —NH—SO 2 W, —NH—COW, —CO—NHW, —CO—NW 2 , —SO 2 NHW, —SO 2 —NW 2 , —SW, —OW, or —W.

18. The method of claim 17 , wherein W is C 1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring; each C 1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring is optionally substituted with 1-3 of halogen, —OR 6 , —CN, C 1-6 alkyl, C 1-6 alkyl or —NR 18 R 19 .

19. The method of claim 18 , wherein W is C 1-6 alkyl or heterocyclic ring; each C 1-6 alkyl, aralkyl, cycloalkyl or heterocyclic ring is optionally substituted with 1-3 of halogen, —OR 6 , —CN, C 1-6 alkyl, C 1-6 alkyl or —NR 18 R 19 .

20. The method of claim 11 , wherein one R 8 is —R 9 , —OR 9 or —N(R 9 ) 2 .

21. The method of claim 20 , wherein R 9 is independently H, C 3-6 carbocyclic ring, C 3-6 heterocyclic ring, or C 1-3 aliphatic, wherein C 3-6 carbocyclic ring, C 3-6 heterocyclic ring and C 1-3 aliphatic are each optionally substituted with 1-3 Q; or

Two R 9 groups, together with the N atom to which they are bound, form a 4- to 8-membered ring optionally containing additional 1 or 2 groups selected from —N(R 17 )—, —O—, or —S—, wherein the 4- to 8-membered ring is optionally and independently substituted with 1-3 of W.

22. The method of claim 8 , wherein R 7 is a 4- to 10-membered heterocyclic monocyclic or bicyclic ring optionally substituted with 1-3 of R 8 .

23. The method of claim 22 , wherein R 7 is a 4- to 6-membered heterocyclic monocyclic ring optionally substituted with 1-3 of R 8 .

24. The method of claim 23 , wherein R 8 is Q selected from —C(O)—W, —C(O)—N(W) 2 —C(O)—O—W or —SO 2 —W.

25. The method of claim 22 , wherein R 7 is a C 3 -C 8 carbocycle optionally substituted with 1-3 R 8 .

26. The method of claim 25 , wherein one R 8 is Q selected from hydroxy, —NH 2 , —N(H)—W, |—N(W) 2 , —N(H)—SO 2 —W, —C(O)—N(W) 2 , —N(H)—C(O)—W, or —O—C(O)—W.

27. The method of claim 6 , wherein R 2 is —NR 10 R 11 .

28. The method of claim 27 , wherein R 10 is —H and R 11 is —C(R 12 R 13 )C(═O)NR 14 R 15 , wherein R 12 is H; R 13 is C 1-3 alkyl; R 14 is H; and R 15 is alkyl substituted with trifluoromethyl or hydroxy, or R 15 is cycloalkyl substituted with hydroxy.

29. The method of claim 6 , wherein R 2 is −OR 6 or —SR 6 ; and R 6 is optionally substituted phenyl.

30. The method of claim 1 , wherein the compounds of structural formula (I) is any one of compounds I-1 through I-304 or a pharmaceutically acceptable salt thereof:

31. The method of claim 2 , wherein the compound of structural formula (I) is any one of compounds IA-1 through IA-14 or a pharmaceutically acceptable salt thereof:

32. The method of claim 2 , wherein the compound of structural formula (I) is any one of compounds II-1 through II-16, or II-0, or a pharmaceutically acceptable salt thereof: