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

1. A process for preparing a compound of 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 of R 3 , or —N(H)R;

Each R is independently H, C 1-6 aliphatic, aryl, heteroaryl, C 3-8 cycloalkyl, or 4- to 8-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 , —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 of R 7 ;

Each R 5 is independently 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 of 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 1-3 alkyl, -L-aryl, or -L-heteroaryl, wherein each of the C 1 -C 3 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 , —N(R 9 ) 2 , C 3 -C 8 cycloalkyl, aryl, heteroaryl or a 4-8 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 4-8 membered heterocyclic ring containing 1-3 groups selected from —N(R 17 )—, —O—, or —S—, wherein each of the carbocyclic ring and the 4-8 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 containing an 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;

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 of 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 R 7 ; or

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

comprising contacting a mixture of a compound of formula 8

wherein each R′ is independently H, C 1-3 alkyl, or two R′ together with the atoms to which they are attached form a 5- or 6-membered ring optionally substituted with 1 to 4 methyl groups, a pyrimidine of formula 7

and an alkali metal carbonate with a palladium catalyst in a suitable solvent.

2. The process of claim 1 , wherein the palladium catalyst is bis-(tri-tert-butylphosphine)palladium(0).

3. The process of claim 1 , wherein the pyrimidine is 4-chloro-2-(methylthio)pyrimidine-5-carbonitrile and the boronate ester is 5-Trifluoromethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine.

4. The process of claim 1 , wherein the suitable solvent is dioxane and the alkali metal carbonate is potassium carbonate.

5. The process of claim 1 , wherein R 2 is —SCH 3 , further comprising the steps of

a) oxidizing a compound of formula 26

wherein R 1 is as previously described, with chlorine in aqueous ethanol to provide a compound of formula 27

b) reacting a compound of formula 27 with a compound of formula R 2 H, wherein R 2 is HNR 4 R 5 , HOR 6 or HSR 6 and R 4 , R 5 and R 6 are as previously described, in the presence of microwave irradiation to provide a compound of formula 28

c) removing the Tos protecting group to provide compounds of formula I.