TW201425313A - Novel pyrrolo pyrimidine derivatives - Google Patents

Abstract

The present invention describes new pyrrolo pyrimidine derivatives and pharmaceutically acceptable salts thereof which appear to interact with Bruton's tyrosine kinase (Btk). Accordingly, the novel pyrrolo pyrimidines may be effective in the treatment of autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection, cancers e.g. of hematopoietic origin or solid tumors.

Description

Novel pyrrolopyrimidine derivatives

The present invention describes novel pyrrolopyrimidine derivatives which are good drug candidates.

The compounds of the invention typically exhibit selective inhibition of Bruton's tyrosine kinase (Btk).

The underlying role of Btk in autoimmune diseases is emphasized by the observation that mice lacking Btk prevent rheumatoid arthritis in standard preclinical models (Jansson and Holmdahl, 1993), systemic lupus erythematosus (Steinberg, BJ et al, J. Clin. Invest, 70, 587-597, 1982) and allergic diseases and allergic reactions (Hata, D. et al., J. Exp. Med. 187, 1235-1247, 1998). In addition, many cancers and lymphomas exhibit Btk and appear to be dependent on Btk function (Davis, R. E. et al, Nature, 463, 88-92, 2010).

Thus, inhibition of Btk activity can be used to treat immune disorders (eg, rheumatoid arthritis), systemic lupus erythematosus, allergic diseases, allergic reactions, and inflammatory conditions. In addition, Btk inhibition can be used to treat hematopoietic origin cancers, including chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin lymphoma, and other B cell lymphomas.

The compounds of the invention may thus potentially be used to treat a wide range of conditions, particularly Btk related diseases or conditions, and may, for example, be used to treat autoimmune disorders, inflammatory diseases, allergic diseases, respiratory diseases (eg asthma and Chronic obstructive pulmonary disease (COPD), graft rejection, or cancer (eg, from hematopoiesis) Source cancer) or solid tumor.

More particularly, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:

Wherein R1 is hydrogen, C ₁ -C ₆ alkyl optionally substituted by hydroxy; R 2 is hydrogen or halogen; R 3 is hydrogen or halogen; R 4 is hydrogen; and R 5 is optionally substituted by the following group: halogen ; SF ₅ ; NR ₆ R ₇ ; hydroxy; C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkenyl; C ₁ -C ₆ alkylcarbonyl; optionally substituted by hydroxy, halogen or C ₁ -C ₆ alkoxy a C ₁ -C ₆ alkyl group; or a C ₃ -C ₆ cycloalkyl group optionally substituted by a halogen, a hydroxyl group or a halogen-substituted C ₁ -C ₆ alkyl group; or the R ₅ group includes 1, 2 or 3 a 4-14 membered monocyclic or bicyclic heterocyclic or heteroaryl ring system selected from the group consisting of heteroatoms of N, S and O, optionally substituted by the following groups: halogen; hydroxy; optionally substituted by hydroxy or halogen the C ₁ -C ₆ alkoxy; or optionally substituted by hydroxyl or halogen of C ₁ -C ₆ alkyl; optionally forming rings comprising hexahydro-phenyl or together form a ring of R4 and R5 combined with the atoms which they are a pyridone ring, any of which may be optionally substituted by a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or a C ₃ -C ₆ cycloalkyl group, each substituted member being optionally substituted with a halogen or a hydroxyl group; R6 and R7 are independently selected hydrogen or C ₁ -C ₆ alkyl ; Formation or R6 and R7 with the nitrogen atom to which they are bound together 4-8-membered saturated azacyclic ring optionally substituted cycloalkane ring of halogen, hydroxy or C ₁ -C ₆ alkyl; X lines O, S (O) _n ( Where n is 0, 1 or 2) or (where q is 2 or 3) and R10 is absent; or X is CH or N; and R10 is hydrogen, hydroxy, -NR6R7, -CO-R11, -S(O) _p- R12 (where p is 1 or 2), R11-based substituent of optionally hydroxy, cyano, halogen, carboxy or C ₁ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group; or NR6R7; R12 and line C ₁ -C ₆ alkyl Base or NR6R7.

In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, and R4 is hydrogen, R5 is phenyl substituted by the following groups: halogen; C ₁ -C ₆ alkoxy or C ₁ -C ₆ alkyl optionally substituted by halogen or hydroxy; or optionally halogen, hydroxy, optionally halogen Substituted C ₁ -C ₆ alkyl substituted C ₃ -C ₆ cycloalkyl; X system O, S(O) _n (where n is 0, 1 or 2) or (where q is 2 or 3) and R10 is absent; and the remaining variables are as defined above.

In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, and R4 is together with R5 Is a 3,4-dihydro-2H-isoquinolin-1-one (which is optionally substituted by a C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl group substituted by a hydroxyl group); X system O , S(O) _n (where n is 0, 1, or 2) or (where q is 2 or 3) and R10 is absent; and the remaining variables are as defined above.

In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, and R4 is hydrogen, R5 system via the group of phenyl substituted with: halogen; C ₁ -C ₆ alkoxy; optionally substituted with halogen or hydroxy or C ₁ -C ₆ alkyl group; or optionally substituted with halogen, hydroxy or optionally halogen Substituted C ₁ -C ₆ alkyl substituted C ₃ -C ₆ cycloalkyl; X represents O and R 10 is absent; or X represents N, and R 10 is hydrogen or —CO—R 11 , and the remaining variables are as defined above .

In another embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, and R4 is hydrogen; R5 system substituted with a phenyl of the group: C ₁ -C ₆ alkoxy; optionally substituted with halogen or hydroxy or C ₁ -C ₆ alkyl group; or optionally substituted with halogen of halogen, hydroxy, or optionally C ₁ -C ₆ alkyl substituted C ₃ -C ₆ cycloalkyl; X represents N, R 10 is hydrogen or -CO-R 11 , and R 11 represents NR ₆ R 7 (wherein R 6 and R 7 are independently hydrogen or methyl); The variables are as defined above.

In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, and R4 is hydrogen, R5 optionally substituted with the system by C ₁ -C ₆ alkoxy azetidine, X represents N, and R10-based hydrogen or -CO-R11, and the remaining variables are as defined above.

In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, and R4 is together with R5 Is a 3,4-dihydro-2H-isoquinolin-1-one (which is optionally substituted by a hydroxy-substituted C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl group), and X represents N. And R10 is hydrogen or -CO-R11, and the remaining variables are as defined above.

In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, and R4 is together with R5 a 3,4-dihydro-2H-isoquinolin-1-one (C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkane which is optionally substituted with a hydroxy group at the 6-position of the isoquinoline ring) Substituted), X represents N, and R10 is hydrogen or -CO-R11, and the remaining variables are as defined above.

In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, and R4 is hydrogen, R5 optionally substituted with the system by C ₁ -C ₆ alkoxy azetidine, X represents O, and the remaining variables are as defined above.

In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, and R4 is together with R5 Is a 3,4-dihydro-2H-isoquinolin-1-one (which is optionally substituted by a C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl group substituted by a hydroxy group), and X represents O. And the remaining variables are as defined above.

In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, and R4 is together with R5 a 3,4-dihydro-2H-isoquinolin-1-one (C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkane which is optionally substituted with a hydroxy group at the 6-position of the isoquinoline ring) Base substitution), X represents O, and the remaining variables are as defined above.

In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, and R2 and R3 are, independently of each other, selected from the group consisting of hydrogen and halogen, R4 Hydrogen, R5 is substituted by halogen, C ₃ -C ₆ cycloalkyl or, optionally, C ₁ -C ₆ alkyl substituted by hydroxy, one or more phenyl groups, X represents O or S, and R 10 is absent.

In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 is methyl or hydroxymethyl, R2 and R3 are, independently of each other, selected from hydrogen and halogen, and R4 is hydrogen, R5 is a phenyl group substituted one or more times with a halogen, a C ₃ -C ₆ cycloalkyl group or, optionally, a C ₁ -C ₆ alkyl group substituted by a hydroxy group, and X represents N, R 10 is hydrogen or -CO-R 11 , and R11-based NR6R7, wherein R6 and R7 are independently selected from C ₁ -C ₆ - alkyl.

With respect to the compounds of formula (I), the following meanings represent other embodiments of the invention independently, collectively, or in any combination or in any sub-combination: 1. R1 is hydrogen, methyl or hydroxymethyl; R1 is methyl or hydroxymethyl; 3. R2 and R3 are independently hydrogen or fluorine; 4. R1 is methyl or hydroxymethyl and R2 and R3 are independently hydrogen or fluorine; 5. R4 is hydrogen; R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one which is optionally substituted by a hydroxy-substituted C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl group as appropriate 7 . R 4 together with R 5 is a 3,4-dihydro-2H-isoquinolin-1-one which is in the 6-position of the 3,4-dihydro-2H-isoquinolin-1-one ring, as the case may be. Substituted by a hydroxy-substituted C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl group; 8. R5 is optionally substituted by the following groups: -NR6R7, halogen, C ₁ -C ₆ Alkoxy, C ₁ -C ₆ alkenyl, C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl optionally substituted by halogen or hydroxy; 9. R5 via -NR6R7, halogen, C ₁ - a C ₆ alkoxy group or a C ₁ -C ₆ alkyl group substituted by a halogen or a hydroxy group; 10. R5 is a halogen, a C ₁ -C ₆ alkoxy group, a C ₃ -C ₆ cycloalkyl group Or fluorine by circumstances Or a hydroxy-substituted C ₁ -C ₆ alkyl substituted phenyl; 11. R5 includes 1, 2 or 3 heteroatoms selected from N, S and O, 4, 5, 6 or 7 member A cyclic heterocyclic ring or a 7-membered, 8-membered, 9-membered, 10-membered, 11-membered or 12-membered bicyclic heterocyclic ring which is optionally substituted by a halogen group; a hydroxy group; optionally substituted by a hydroxy group or a halogen C ₁ -C ₆ alkoxy; or a C ₁ -C ₆ alkyl group optionally substituted by a hydroxy group or a halogen; 12. R 5 is a group consisting of 1 or 2 hetero atoms selected from N, S and O, 4 members, 6 members, 6 members Or a 7-membered monocyclic heterocyclic ring which is optionally substituted by a halogen; a hydroxy group; a C ₁ -C ₆ alkoxy group optionally substituted by a hydroxy group or a halogen; or a C ₁ - optionally substituted by a hydroxy group or a halogen C ₆ alkyl; 13. R5 is azetidine substituted by C ₁ -C ₆ alkoxy or C ₁ -C ₆ alkyl; 14. X is O and R10 is absent or X is N and R10 is H or CO-R11; 15. X is O and R10 is absent or X is N and R10 is CO-R11; 16. X is O and R10 is absent; 17. X is N and R10 is CO-R11; based NR6R7 and R6 and R11 R7 are independently selected from hydrogen or C ₁ -C ₆ alkyl; R11 19. A system NR6R7 and R6 and R7 are independently selected from C ₁ -C ₆ alkyl group;. 20 R11 Based NR6R7 and R6 and R7 are independently selected from C ₁ -C ₃ alkyl;. 21 R11-based system NR6R7 and R6 and R7 methyl. In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament. In another embodiment, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or condition mediated by Btk. In another embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 4-(4-{5-fluoro-3-[4-(1-fluoro-cyclo) Propyl)-benzhydrylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine- Dimethyl decylamine 1-carboxylate, 4-(4-{3-[(3,3-dimethyl-2,3-dihydro-benzofuran-6-carbonyl)-amino]-5-fluoro -2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4- (4-{5-fluoro-2-methyl-3-[(5-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl)-amino]-benzene -7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-(4-{5-fluoro -3-[4-isopropyl-methyl-amino)-benzylidenylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl -3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 3-methyl-1H-indole-6-carboxylic acid {3-[6-(1-dimethylmethylcarbamidine) -1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl} -decylamine, 4-(4-{5-fluoro-3-[4-(2-hydroxy-1,1-dimethyl-ethyl)-benzoylamino]-2-methyl-benzene -7-7H-pyridyl And [2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-{4-[5-fluoro-2-methyl- 3-(4-Hexahydropyridin-1-yl-benzylidenylamino)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro- 2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-{4-[5-fluoro-3-(isopropenyl-benzoylamino)-2-methyl-phenyl]-7H-pyrrole And [2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-(4-{5-fluoro-2-methyl- 3-[4-(1-Trifluoromethyl-cyclopropyl)-benzylidenylamino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3, 6-Dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-{4-[5-fluoro-3-(4-isopropoxy-benzoylamino)-2-methyl -phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-(4-{5 -fluoro-3-[4-pentafluorothio-benzhydrylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3, 6-Dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-(4-{5-fluoro-3-[4-(2-methoxy-1,1-dimethyl-ethyl) -Benzylmercaptoamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1- Dimethylguanamine carboxylic acid, 4-(4-{ 5-fluoro-3-[4-(1-methoxy-1-methyl-ethyl)-benzylidenylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3 -d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 1-methyl-1H-pyrrolo[2,3-b]pyridine-6- Formic acid {3-[6-(1-dimethyl-aminocarbazinyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl]-5-fluoro-2-methyl-phenyl}-decylamine, 4-{4-[3-(4-dimethylamino-benzhydrylamino)-5-fluoro- 2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-( 4-{3-[2-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzylidenylamino]-2-hydroxymethyl-phenyl}-7H-pyrrolo[2 ,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-{4-[3-(4-cyclopropyl-benzamide) Amino)-2-hydroxymethyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl Indoleamine, 4-(4-{5-fluoro-2-methyl-3-[4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-benzimidyl Amino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-{4 -[3-(4-Ethyl-benzhydrylamino)-5- Fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4 -{4-[3-(4-Cyclopropyl-benzhydrylamino)-4-fluoro-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3, 6-Dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-(4-{4-fluoro-3-[4-(2-hydroxy-1,1-dimethyl-ethyl)- Benzylaminoamino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, N-{3-[6-(3,6-Dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2- Methyl-phenyl}-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzamide, N-{3-[6-(3,6-dihydro-2H- Pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-hydroxymethyl-phenyl}-2-fluoro-4-(1-hydroxy-1-methyl -ethyl)-benzamide, 4-tert-butyl-N-{3-[6-(3,6-dihydro-2H-thiopyran-4-yl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzamide, 4-tert-butyl-N-{5-fluoro-2-methyl-3 -[6-(3,6-Dihydro-1-oxoyl-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-phenyl}- Benzylamine, 4-tert-butyl-N-{3-[6-(3,6-dihydro-1,1-dioxyindol-2H-thiophene 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzamide, 4-tert-butyl-N -{3-[6-(1,4-Dioxa-spiro[4.5]indole-7-en-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5 -fluoro-2-methyl-phenyl}-benzamide, 4-tert-butyl-N-{5-fluoro-3-[6-(4-hydroxy-cyclohex-1-enyl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide, 4-{4-[3-(4-cyclopropyl-benzamide) Amino)5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid Dimethyl decylamine, 4-cyclopropyl-N-(5-fluoro-2-methyl-3-{6-[1-(pyrrolidin-1-carbonyl)-1,2,3,6-tetra Hydrogen-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-phenyl)-benzamide, 2-(4-{4-[3-(4) -cyclopropyl-benzimidylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro -2H-pyridin-1-yl)-2-oxo-ethyl ester, 4-cyclopropyl-N-(5-fluoro-3-{6-[1-(2-hydroxy-ethenyl) -1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-methyl-phenyl)benzamide, N-(3-{6-[1-(2-Cyano-ethinyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl}-5-fluoro-2-methyl-phenyl)-4-cyclopropyl-benzamide, N-(5-fluoro-2-methyl-3- {6-[1-(pyrrolidin-1-carbonyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl} -phenyl)-4-(pentafluoro-thio)-benzamide, 2-[4-(4-{5-fluoro-2-methyl-3-[4-(pentafluoro-thio)] --Benzyl decylamino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2- Side oxy-ethyl ester, N-(5-fluoro-3-{6-[1-(2-hydroxy-ethinyl)-1,2,3,6-tetrahydro-pyridin-4-yl] -7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-methyl-phenyl)-4-(pentafluoro-thio)-benzamide, 4-{4-[3 -(4-t-butyl-benzhydrylamino)-2-(t-butyl-diphenyl-nonyloxymethyl)-phenyl]-7H-pyrrolo[2,3-d Pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester, 4-tert-butyl-N-(3-{6-[1-(2-fluoro) -ethinyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-hydroxymethyl-phenyl -benzamide, 4-(4-{5-fluoro-3-[2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzylidenylamino]-2- Methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-methyl Dimethyl decylamine, 4-tert-butyl-N-{5-fluoro-2-methyl-3-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-7H -pyrrolo[2,3-d]pyrimidin-4-yl]-phenyl}-benzamide, 4-{4-[3-(4-t-butyl-benzhydrylamino)- 5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine ,4-tert-butyl-N-{5-fluoro-3-[6-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrole [2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide, 4-tert-butyl-N-{3-[6-(1-dimethylamine) Sulfomethyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-benzene Benzylamine, 4-tert-butyl-N-{3-[6-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H -pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide, 4-{4-[3-(6-tert-butyl-1- side Oxy-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3 ,6-Dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-{4-[3-(6-cyclopropyl-1-o-oxy-3,4-dihydro-1H-iso Quinoline-2-yl)-2-hydroxymethyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}- 3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-(4-{2-hydroxymethyl-3-[6-(1-hydroxy-1-methyl-ethyl) -1-Sideoxy-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6 -Dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-tert-butyl-N-{3-[6-(3,6-dihydro-2H-pyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-hydroxymethyl-phenyl}-benzamide, 4-tert-butyl-N-{3-[6-(3 ,6-Dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzamide Amine, N-{3-[6-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro- 2-methyl-phenyl}-4-dimethylamino-benzamide, 4-tert-butyl-N-{3-[6-(3,6-dihydro-2H-thiopyran- 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide, 4-tert-butyl-N-{2- 3-[6-(3,6-Dihydro-1-oxoyl-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-benzene Benzylamine, 4-tert-butyl-N-{3-[6-(3,6-dihydro-1,1-dioxainyl-2H-thiopyran-4-yl)- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide, 4-tert-butyl-N -{3-[6-(1,4-Dioxa-spiro[4.5]indole-7-en-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2 -hydroxymethyl-phenyl}-benzamide, 4-tert-butyl-N-{3-[6-(4-hydroxy-cyclohex-1-enyl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl]-2-hydroxymethyl-phenyl}-benzamide, 4-tert-butyl-N-{3-[6-(4-dimethylamino)- Cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-hydroxymethyl-phenyl}-benzamide, 4-(4-{3- [(3-Tertioxy-azetidin-1-carbonyl)-amino]-5-fluoro-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidine -6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-(4-{5-fluoro-3-[(3-isopropoxy-nitrogen heterocycle) Butane-1-carbonyl)-amino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine- 1-methyl decylamine 1-carboxylic acid, 5-fluoro-1,3-dihydro-isoindole-2-carboxylic acid {3-[6-(1-dimethylmethylcarbamyl-1,2,3, 6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-decylamine, 4-[4 -(5-fluoro-2-methyl-3-{[3-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-azetidin-1-carbonyl]- Amino}-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro -2H-pyridine-1-carboxylic acid dimethyl decylamine, 3-tert-butoxy-azetidine-1-carboxylic acid {3-[6-(3,6-dihydro-2H-pyran- 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-decylamine, 4-(4-{3-[(3) -T-butoxy-azetidin-1-carbonyl)-amino]-4-fluoro-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3, 6-Dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-(4-{3-[(3-tert-butoxy-azetidin-1-carbonyl)-amino] 4-fluoro-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylhydrazine Amine, 4-tert-butyl-N-{3-[6-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-4- 4-methyl-phenyl}-benzamide, 4-tert-butyl-N-{3-[6-(1,4-dioxa-spiro[4.5]癸-7-ene -8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide, 4-tert-butyl-N-{3- [6-(4-Hydroxy-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide, and 4-tert-butyl-N-{3-[6-(4-dimethylamino-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl] -2-Methyl-phenyl}-benzamide.

As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety having up to 20 carbon atoms. Unless otherwise provided, alkyl refers to a hydrocarbon moiety having from 1 to 16 carbon atoms, from 1 to 10 carbon atoms, from 1 to 7 carbon atoms, or from 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, Neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-decyl, n-decyl and the like .

As used herein, the term "alkenyl" refers to an unsaturated, branched or unbranched hydrocarbon moiety having from 2 to 20 carbon atoms. It includes 2 to 20 carbon atoms, and unless otherwise provided, an alkenyl group means a moiety having 2 to 16 carbon atoms, 2 to 10 carbon atoms, 2 to 7 carbon atoms or 2 to 4 carbon atoms. Representative examples of alkenyl include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, second butenyl, isobutenyl, tert-butenyl, n-pentenyl, isopentenyl , neopentenyl, n-hexenyl, 3-methylhexenyl, 2,2-dimethylpentenyl, 2,3-dimethylpentenyl, n-heptenyl, n-octenyl, Is n-alkenyl, n-alkenyl and the like.

The term "alkoxy" as used herein refers to alkyl-O-, wherein alkyl is as defined above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, third butoxy Base, pentyloxy, hexyloxy, cyclopropoxy-, cyclohexyloxy- and the like. Typically, the alkoxy group has from about 1 to 7 carbons, more preferably from about 1 to 4 carbons.

As used herein, the term "cycloalkyl" refers to a saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon group having from 3 to 12 carbon atoms. Unless otherwise provided, a cycloalkyl group means a cyclic hydrocarbon group having 3 to 9 ring carbon atoms or 3 to 7 ring carbon atoms. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl, and the like. Exemplary bicyclic hydrocarbon groups include mercapto, fluorenyl, hexahydroindenyl, tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2. 1] heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl and the like . Exemplary tricyclic hydrocarbon groups include adamantyl and the like.

As used herein, the term "azacycloalkane" refers to a saturated or unsaturated monocyclic, bicyclic or trihydric radical having from 3 to 12 carbon atoms as defined for "cycloalkyl" as replaced by a nitrogen atom. a cyclic hydrocarbon group. Unless otherwise provided, azacycloalkylene refers to a cyclic aza-hydrocarbon group having 2 to 9 ring carbon atoms and a nitrogen atom or 2 to 7 ring carbon atoms and a nitrogen atom. Exemplary monocyclic aza-hydrocarbon groups include, but are not limited to, aziridine, azetidinyl, pyrrolidinyl, hexahydropyridyl, azepanyl, dihydroindenyl, and the like.

As used herein, the term "halogen" or "halo" refers to fluoro, chloro, bromo and iodo.

As used herein, the terms "heterocycle", "heterocyclyl" or "heterocycle" may mean a saturated or unsaturated non-aromatic ring or ring system, for example, a member of 4 members, 5 members, 6 members. Or 7 members of single ring, 7 members, 8 members, 9 members, 10 members, 11 members or 12 members with double or 10 members, 11 members, 12 members, 13 members, 14 members or 15 members of the three-ring ring system and Containing at least one hetero atom selected from O, S and N, wherein N and S may also be oxidized to various oxidation states as the case may be. The heterocyclic group can be attached to a hetero atom or a carbon atom. Heterocyclyl groups can include fused or bridged rings as well as spirocyclic rings. Examples of the heterocyclic ring include azetidine, tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, hexahydropyrazine, hexahydropyridine, 1, 3-dioxolan, imidazolium, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxygen sulfur Disulfide , 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, and the like.

As used herein, the term "aryloxy" refers to both -O-aryl and -O-heteroaryl, wherein aryl and heteroaryl are as defined herein.

As used herein, the term "heteroaryl" refers to a 5-14 membered monocyclic- or bicyclic- or tricyclic aromatic ring system having from 1 to 8 heteroatoms selected from N, O or S. Typically, a heteroaryl is a 5-10 membered ring system (e.g., a 5-7 membered monocyclic or 8-10 membered bicyclic ring) or a 5-7 membered ring system. Typical heteroaryls include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4- or 5-imidazolyl, 3-, 4- or 5-pyrazole , 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 3- or 5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3- or 4-pyridyl, 3- or 4- Pyridazinyl, 3-, 4- or 5-pyrazinyl, 2-pyrazinyl and 2-, 4- or 5-pyrimidinyl.

The term "heteroaryl" also refers to a radical in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, wherein the attached group or point is on a heteroaromatic ring. Non-limiting examples include 1-, 2-, 3-, 5-, 6-, 7- or 8-oxazinyl, 1-, 3-, 4-, 5-, 6- or 7-isodecyl , 2-, 3-, 4-, 5-, 6- or 7-fluorenyl, 2-, 3-, 4-, 5-, 6- or 7-carbazolyl, 2-, 4-, 5- -, 6-, 7- or 8-mercapto, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-quinolizinyl, 2-, 3-, 4-, 5- -, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-isoquinolinyl, 1-, 4-, 5-, 6- , 7- or 8-pyridazinyl, 2-, 3-, 4-, 5- or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7- or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7- or 8- Orolinyl, 2-, 4-, 6- or 7-acridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- or 8-4aH carbazolyl, 1-, 2 -, 3-, 4-, 5-, 6-, 7- or 8-carbazolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8- or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-cyridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7- , 8- or 9-Acridine, 1-, 2-, 4-, 5-, 6-, 7-, 8- or 9-naphthyldiazepine, 2-, 3-, 4- , 5-, 6-, 8-, 9- or 10-phenanthroline, 1-, 2-, 3-, 4-, 6-, 7-, 8- or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9- or 10-phenothiazine, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9 -or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6- or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9- or 10- Benzoisoquinolyl, 2-, 3-, 4- or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10 -or 11-7H-pyrazino[2,3-c]oxazolyl, 2-, 3-, 5-, 6- or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7- or 8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3- or 5-H-pyrazolo[4 , 3-d]-oxazolyl, 2-, 4- or 5-4H-imidazo[4,5-d]thiazolyl, 3-, 5- or 8- Pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5- or 6-imidazo[2,1-b]thiazolyl, 1-, 3-, 6-, 7-, 8 - or 9-furo[3,4-c] Orolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10- or 11-4H-pyrido[2,3-c]oxazolyl, 2-, 3 -, 6- or 7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6- or 7 - benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6- or 7-benzothiazolyl, 1- , 2-, 4-, 5-, 6-, 7-, 8- or 9-benzoxapinyl, 2-, 4-, 5-, 6-, 7- or 8-benzaldehyde Azinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10- or 11-1H-pyrrolo[1,2-b][2]benzazepine base. Typical fused heteroaryl groups include, but are not limited to, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7 -or 8-isoquinolyl, 2-, 3-, 4-, 5-, 6- or 7-fluorenyl, 2-, 3-, 4-, 5-, 6- or 7-benzo[ b] thienyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl, 2-, 4-, 5-, 6- or 7-benzimidazolyl and 2-, 4-, 5-, 6- or 7-benzothiazolyl.

As used herein, the term "salt" or "salts" refers to an acid or base addition salt of a compound of the invention. In particular, "salt" contains "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts which retain the biological effectiveness and properties of the compounds of the invention and which are generally biologically or otherwise desirable. In many cases, the compounds of the invention are capable of forming acidic and/or basic salts by virtue of the presence of amine groups and/or carboxyl groups or similar groups.

Inorganic acids and organic acids can be used to form pharmaceutically acceptable acid addition salts, for example, acetate, aspartate, benzoate, besylate, bromide/hydrobromide, hydrogencarbonate Salt/carbonate, hydrogen sulfate/sulfate, camphor sulfonate, chloride/hydrochloride, chlorophylline, citrate, Ethylenedisulfonate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionic acid Salt, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methyl sulfate, naphthate, naphthalene sulfonate, nicotinic acid, nitric acid Salt, octadecanoate, oleate, oxalate, palmitate, bamotate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearic acid Acid salts, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.

The inorganic acid from which the salt can be derived includes, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonate Acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Inorganic bases and organic bases can be used to form pharmaceutically acceptable base addition salts.

The inorganic base from which the salt can be derived includes, for example, an ammonium salt and a metal salt of the first to XII rows of the periodic table. In certain embodiments, the salts can be derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

The organic base from which the salt can be derived may include, for example, a primary amine, a secondary amine, and a tertiary amine, a substituted amine comprising a naturally occurring substituted amine, a cyclic amine, an alkali ion exchange resin, and the like. Certain organic amines include isopropylamine, benzathine, choline salt, diethanolamine, diethylamine, lysine, meglumine, hexahydropyrazine, and tromethamine.

The pharmaceutically acceptable salts of the present invention can be synthesized from basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the compounds in the free acid form with a stoichiometric amount of a suitable base such as a hydroxide, carbonate, bicarbonate or the like of Na, Ca, Mg or K, Alternatively, it can be prepared by reacting the free base form of the compound with a stoichiometric amount of the appropriate acid. These reactions are usually carried out in water or an organic solvent or a mixture of the two. Generally, if feasible, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. A list of other suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th Edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Any of the formulae given herein are also intended to represent unlabeled forms of the compounds as well as isotopically labeled forms. Isotopically labeled compounds have structures depicted by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes which may be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, for example ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, respectively. , ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²⁵ I. The invention includes various isotopically labeled compounds as defined herein, such as those in which a radioisotope (e.g., ³ H and ¹⁴ C) is present or in which a non-radioactive isotope (e.g., ² H and ¹³ C) is present. The isotopically labeled compounds can be used for metabolic studies (using ¹⁴ C), reaction kinetic studies (eg, using ² H or ³ H), detection or imaging techniques (eg, positron emission tomography (PET) or single photon) Computerized tomography (SPECT), including drug or matrix distribution analysis or radiotherapy for patients. In particular, ¹⁸ F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by the use of appropriate isotope by methods analogous to those described in the accompanying examples and preparations. The labeled reagent is prepared in place of the previously used unlabeled reagent.

In addition, heavier isotopes, particularly guanidine (i.e., ² H or D) substitutions, may provide certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It should be understood that the oxime in this context can be considered as a substituent of the compound of formula (I). The concentration of this heavier isotope (specifically, helium) can be defined by the isotope enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotope abundance of a given isotope and the natural abundance. If the substituent of the compound of the invention is designated as hydrazine, then the isotopic enrichment factor for each of the specified ruthenium atoms of the compound is at least 3500 (incorporating 52.5% 氘 at each designated 氘 atom), at least 4000 (incorporating 60% 氘) , at least 4500 (incorporated with 67.5% 氘), at least 5,000 (incorporating 75% 氘), at least 5,500 (incorporating 82.5% 氘), at least 6,000 (incorporating 90% 氘), at least 6333.3 (incorporating 95% 氘), at least 6466.7 (incorporated 97% 氘), at least 6600 (incorporating 99% 氘) or at least 6633.3 (including 99.5% 氘).

The pharmaceutically acceptable solvates of the present invention comprise those in which the crystallization solvent can be substituted by an isotope, for example, D ₂ O, d ₆ -acetone, d ₆ -DMSO.

The invention comprising a group capable of functioning as a donor and/or acceptor for hydrogen bonding The compound (i.e., the compound of formula (I)) can be capable of forming a co-crystal using a suitable co-crystal former. Such co-crystals can be prepared from compounds of formula (I) by known co-crystal formation procedures. The procedures comprise grinding, heating, co-liming, co-melting or contacting and separating the co-crystals formed therefrom in a solution of the compound of formula (I) in a solution of the compound of formula (I) under crystallization conditions. Suitable co-crystal formers include those described in WO 2004/078163. Accordingly, the present invention further provides a cocrystal comprising a compound of formula (I).

As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives known to those skilled in the art (eg, , antibacterial agent, antifungal agent), isotonic agent, absorption delaying agent, salt, preservative, drug stabilizer, adhesive, excipient, disintegrating agent, lubricant, sweetener, flavoring agent, dyeing agent And the like and combinations thereof (for example, see Remington's Pharmaceutical Sciences, 18th ed., Mack Printing, 1990, pp. 1289-1329). The present invention encompasses its use in therapeutic or pharmaceutical compositions in addition to any conventional carrier which is incompatible with the active ingredient.

The term "therapeutically effective amount" of a compound of the invention means that the individual is allowed to produce a biological or medical response (eg, to reduce or inhibit enzyme or protein activity) or to ameliorate symptoms, alleviate the condition, slow or delay disease progression, or prevent disease, and the like. The amount of the compound of the invention. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the invention that is effective for administration to an individual: (1) at least partially alleviating, inhibiting, preventing, and/or ameliorating (i) Btk is mediated or (ii) related to Btk activity or (iii) characterized by Btk activity (normal or abnormal) a condition or disorder or disease; or (2) reducing or inhibiting Btk activity; or (3) reducing or inhibiting the performance of Btk. In another non-limiting embodiment, the term "therapeutically effective amount" refers to an amount effective to at least partially reduce or inhibit Btk activity or partially or completely reduce or inhibit upon administration of a cell or tissue or non-cellular biological material or medium. The amount of the compound of the invention represented by Btk.

As used herein, the term "individual" refers to an animal. Typically, the animal is a mammal. For example, an individual also refers to a primate (eg, a male or female human), a cow, a sheep, a goat, a horse, a dog, a cat, a rabbit, a rat, a mouse, a fish, a bird, and the like. In certain embodiments, the system is a primate. In other embodiments, the system is human.

As used herein, the term "inhibiting, inhibiting, or inhibiting" refers to alleviating or suppressing a given condition, symptom or condition or disease, or significantly reducing the baseline activity of a biological activity or process.

In one embodiment, the term "treat, treating, or treating" as used herein refers to amelioration of the disease or condition (ie, slowing or preventing or reducing the disease or at least A development of a clinical condition. In another embodiment, "treat, treating, or treating" refers to alleviating or ameliorating at least one physical parameter comprising physical parameters that are incomprehensible to such patients. In still another embodiment, "treat, treating, or treating" refers to physically modulating a disease or condition (eg, stabilizing a sensible symptom) or physiologically modulating a disease or condition (eg, stabilizing physics) Parameter) or both. In still another embodiment, "treat, treating, or treating" refers to preventing or delaying the onset or progression or progression of a disease or condition.

As used herein, an individual "needs" the treatment if it benefits from a treatment in biological, medical or quality of life.

The terms "a" ("a", "an"), "the" ("the", as used herein, are used in the context of the present invention (especially in the context of the claims), unless otherwise indicated herein. "and" and similar terms are understood to encompass both singular and plural.

All methods set forth herein can be carried out in any suitable order unless otherwise indicated herein or otherwise clearly contradicted. The use of any and all examples or example language (e.g., "such as") is intended to be illustrative of the invention and is not intended to limit the scope of the invention.

Any asymmetric atom of the compounds of the invention (e.g., carbon or the like) may exist as a racemic or enantiomerically enriched form, such as (R)-, (S)- or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% of the (R)- or (S)-configuration. An anomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess. Substituents having an unsaturated double bond on the atom may exist in the cis-(Z)- or trans-(E)- form if possible.

Thus, the compounds of the invention as used herein may exist in one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, which are substantially pure Geometry (cis or trans) isomers, diastereomers, optical isomers (enantiomer), racemic isomer or a mixture thereof.

Any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomeric, by physicochemical differences in their constituents, for example, by chromatography and/or fractional crystallization. Isomer, racemic isomer.

Any of the resulting racemic isomers of the final product or intermediate can be resolved into the optical antipodes by known methods, for example, by separation of the diastereomeric salts thereof using optically active acids or bases. And release optically active acidic or basic compounds. In particular, it is thereby possible to use an alkaline moiety for optically active acids by, for example, fractional crystallization (eg tartaric acid, benzhydryl tartaric acid, diethyl tartaric acid, di-O, O'-p-toluene) Salts formed from formamyl tartaric acid, phenylglycolic acid, malic acid or camphor-10-sulfonic acid) split the compounds of the invention into their optical enantiomers. The racemic product can also be resolved by palm chromatography (e.g., high pressure liquid chromatography (HPLC)) using a palmitic adsorbent.

Further, the compound of the present invention (including a salt thereof) may also be obtained in the form of its hydrate or contain other solvents for its crystallization. The compounds of the invention may form solvates inherently or by design with pharmaceutically acceptable solvents, including water; therefore, the invention is intended to cover both fused and non-complexed forms. The term "solvate" refers to a molecular complex of a compound of the invention (including a pharmaceutically acceptable salt thereof) with one or more solvent molecules. These solvent molecules are commonly used in medical technology and are known to be harmless to the recipient, such as water, ethanol, and the like. The term "hydrate" refers to a complex of water in a solvent molecule.

The compounds of the invention (including salts, hydrates and solvates thereof) may be formed intrinsic or by design to form polymorphs.

In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be formulated for specific routes of administration, for example, oral administration, parenteral administration, and rectal administration. Furthermore, the pharmaceutical compositions of the present invention can be prepared in solid form, including but not limited to capsules, troches, pills, granules, powders or suppositories, or in liquid form, including but not limited to solutions, suspensions or emulsions. The pharmaceutical compositions can be subjected to conventional pharmaceutical operations (e.g., sterilization) and/or can contain conventional inert diluents, lubricants or buffers, and adjuvants (e.g., preservatives, stabilizers, wetting agents, emulsifying agents, buffers, and the like).

In general, pharmaceutical compositions include lozenges or gelatin capsules of the active ingredient together with: a) diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; b) a lubricant such as cerium oxide, talc, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; for tablets, c) binders such as magnesium aluminum silicate, starch Paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary, d) a disintegrant such as starch, agar, alginic acid or its sodium salt Or an effervescent mixture; and/or e) an absorbent, a coloring agent, a flavoring agent, and a sweetener.

Tablets can be film coated or enteric coated according to methods known in the art.

Compositions suitable for oral administration comprise an effective amount of a tablet, a lozenge, an aqueous or oily suspension, a dispersible powder or granule, an emulsion, a hard Or a soft capsule or a compound of the invention in the form of a syrup or elixir. Compositions intended for oral use can be prepared according to any of the methods known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives. The agent is intended to provide a pharmaceutically elegant and palatable preparation. Tablets may contain a mixture of the active ingredient in admixture with a pharmaceutically acceptable pharmaceutically acceptable excipient. For example, the excipients are: an inert diluent such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; a granulating agent and a disintegrating agent, for example, corn starch or alginic acid; a binder, For example, starch, gelatin or gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc. Such tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may be presented in the form of a hard gelatin capsule in which the active ingredient is mixed with an inert solid diluent (for example, calcium carbonate, calcium phosphate or kaolin) or may be in the form of a soft gelatin capsule containing the active ingredient Mix with water or oil media (for example, peanut oil, liquid paraffin or olive oil).

Certain injectable compositions are isotonic aqueous solutions or suspensions, and suppositories are preferably prepared from fatty emulsions or suspensions. The compositions may be sterilized and/or contain adjuvants such as preservatives, stabilizers, wetting or emulsifying agents, dissolution promoters, salts for regulating osmotic pressure and/or buffers. In addition, it may also contain other therapeutically valuable substances. The compositions are prepared according to conventional mixing, granulating or coating methods and contain from about 0.1% to about 75% or from about 1% to about 50% by weight of active ingredient.

Compositions suitable for transdermal administration comprise an effective amount of a compound of the invention and a suitable carrier. Carriers suitable for delivery via the dermis comprise an absorbable, pharmaceutically acceptable solvent to aid passage through the skin of the host. By way of example, the transdermal device is in the form of a bandage, including a backing member; a reservoir containing the compound, optionally with a carrier; optionally a rate controlling barrier to deliver the compound to the host at a controlled, predetermined rate for a prolonged period of time Skin; and components that secure the device to the skin.

Compositions suitable for topical application (e.g., to the skin and eyes) comprise an aqueous solution, suspension, ointment, cream, gel, or sprayable formulation delivered, for example, by aerosol or the like. Such topical delivery systems are particularly useful for dermal administration to, for example, treat skin cancer, for prophylactic use, for example, sunscreens, lotions, sprays, and the like. Therefore, it is especially suitable for topical applications, including cosmetic formulations well known in the art. These formulations may contain solubilizers, stabilizers, penetration enhancers, buffers, and preservatives.

As used herein, topical application can also be by inhalation or intranasal application. It is in the form of a dry powder (either alone, in the form of a mixture of dry blends with lactose or mixed component particles with, for example, phospholipids) from a dry powder inhaler or with a suitable propellant, or with a suitable propellant. The aerosol spray presentation is conveniently delivered from a pressurized container, pump, ejector, nebulizer or nebulizer.

The invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the invention as active ingredients, as water promotes degradation of certain compounds.

Can use anhydrous or low moisture components in low moisture or low humidity conditions An anhydrous pharmaceutical composition and dosage form of the invention are prepared. Anhydrous pharmaceutical compositions can be prepared and stored to maintain their anhydrous character. Thus, the anhydrous composition is encapsulated using known materials to prevent exposure to water so that it can be included in a suitable formulation set. Examples of suitable packaging include, but are not limited to, hermetic sealing foils, plastics, unit dose containers (eg, vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosage forms that comprise one or more agents that reduce the rate of decomposition of the compounds of the invention as the active ingredient. Such agents referred to herein as "stabilizers" include, but are not limited to, antioxidants (e.g., ascorbic acid), pH buffers or salt buffers, and the like.

The compound of formula I in free form or in salt form exhibits valuable pharmacological properties, for example, Btk modulating properties, for example as indicated in the in vitro and in vivo tests provided in the following section and thus indicated for use in therapy .

The compounds of the invention are useful in the treatment of anemia selected from the group consisting of autoimmune disorders, inflammatory diseases, allergic diseases, respiratory diseases (such as asthma and chronic obstructive pulmonary disease (COPD)), graft rejection; with abnormal or undesirable Antibody production, antigen presentation, cytokine production, or lymphoid organogenesis, including rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, pemphigus vulgaris, idiopathic thrombocytopenic purpura , systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, Emboled platelet hypoglycemia, chronic autoimmune urticaria, allergies (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis Hardening, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, morbus Crohn, pancreatitis, glomerulonephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, Grave's disease, antibody-mediated graft rejection (AMR), graft versus host disease, B cell-mediated hyperacute, acute and chronic grafts Rejection; thromboembolic disorder, myocardial infarction, angina pectoris, stroke, ischemic disorder, pulmonary embolism; hematopoietic original cancer, including but not limited to multiple myeloma; leukemia; acute myeloid leukemia; chronic myelogenous leukemia; Cellular leukemia; myeloid leukemia; non-Hodgkin's lymphoma; lymphoma; polycythemia vera; essential thrombocytosis; myeloid metaplasia with myelofibrosis; and Waldenstrom disease (Waldenstroem disease).

Thus, according to another embodiment, the invention provides the use of a compound of formula (I) or a salt thereof in therapy. In another embodiment, the selected therapy can treat the disease by inhibiting Btk. In another embodiment, the disease is selected from the above list, suitably rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic Lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, embolic platelet hypoglycemia, chronic Autoimmune urticaria, atopic dermatitis, allergic rhinitis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, Crohn's disease, Goodpasture's syndrome, Graves' disease, antibodies Mediated graft Rejection (AMR), B cell-mediated hyperacute, acute and chronic graft rejection; multiple myeloma; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymph Tumor; medullary metaplasia with myelofibrosis; and Waldenstrom disease, more suitable for rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), systemic lupus erythematosus, multiple Sexual sclerosis, Sjogren's syndrome, chronic autoimmune urticaria, atopic dermatitis, allergic rhinitis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, multiple myeloma; non-Hodgkin's lymphoma.

In another embodiment, the invention provides a method of treating a condition for treatment by inhibition of Btk kinase comprising administering a therapeutically acceptable amount of a compound of formula (I) or a salt thereof. In another embodiment, the disease is selected from the above list, suitably rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic Lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemia, embolic platelet hypoglycemia, chronic Autoimmune urticaria, atopic dermatitis, allergic rhinitis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, Crohn's disease, Goodpasture's syndrome, Graves' disease, antibodies Mediated graft rejection (AMR), B cell-mediated hyperacute, acute and chronic graft rejection; multiple myeloma; acute myeloid leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; He Jiejin's lymphoma; myeloid metaplasia with myelofibrosis; and Waldenstrom disease, more Suitable for rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), systemic lupus erythematosus, multiple sclerosis, Schuelder's syndrome, chronic autoimmune urticaria, atopic dermatitis, allergic rhinitis, Type 1 diabetes, type 2 diabetes, inflammatory bowel disease, multiple myeloma; non-Hodgkin's lymphoma.

Method for synthesizing pyrrolopy-pyrimidine

The agent of the invention (i.e., a compound according to formula (I)) can be prepared by involving the following reaction sequence (shown below): subjecting the protected boronate II to the corresponding aryl halide I' to Suzuki Coupling, thereby conveniently providing intermediate III. Deprotecting III, for example, using dilute hydrochloric acid in methanol or the like and, for example, using a suitable deuterating agent (eg, unsubstituted or substituted acetic anhydride) to deuterize IV in the absence or presence of a solvent, Subsequent Suzuki coupling is carried out using borate VI and deuteration is carried out on VII (subsequent deprotection step), as shown in the reaction of Figure 1 below, where X represents N and the group PG is readily For example, a protecting group such as a third butoxycarbonyl group which is removed by dilute hydrochloric acid in methanol or the like.

Reaction Figure 1:

Alternatively, the compound of formula (I) can be prepared by a reaction sequence involving the following: Suzuki coupling of borate IX with the corresponding aryl halide I', followed by additional Suzuki of V with borate VI Coupling and deuteration of VII (subsequent deprotection step as appropriate), as shown in Figure 2 below:

Reaction Figure 2:

Alternatively, the compound of formula (I) can be prepared by a reaction sequence involving the following: Suzuki coupling of boric acid ester VI with the corresponding aryl halide III, deuteration of intermediate X, followed by XI Deprotection and deuteration of XII (subsequent deprotection step), as shown in Figure 3 below, wherein X represents N, and group PG refers to a protecting group that can be easily removed, such as Tributoxycarbonyl.

Reaction Figure 3:

Alternatively, the compound of formula (I) can be prepared by a reaction sequence involving: Suzuki coupling of borate XIII with the corresponding aryl halide III, followed by deprotection of XI and deuteration of XII (A deprotection step is then carried out as appropriate), as shown in the reaction of Figure 4 below, wherein X represents N, and the group PG refers to a protecting group which can be easily removed, such as a third butoxycarbonyl group.

Reaction Figure 4:

Alternatively, the compound of formula (I) can also be prepared by subjecting the borate XIV to the corresponding aryl halide III by Suzuki coupling, optionally followed by a deprotection step, as shown in Figure 5 below. :

Reaction Figure 5:

Alternatively, the compound of formula (I) can be prepared by the urea forming reaction of aniline VII (subsequently followed by a deprotection step) as shown in the reaction scheme of Figure 6 below:

Reaction Figure 6:

Alternatively, the compound of formula (I) can be prepared by a reaction sequence involving: Suzuki coupling of borate XIII with the corresponding aryl halide XVI, protection of XVII, followed by halogenation of XVII, XIX Deprotection is carried out, and the halide XX is subjected to Suzuki coupling with the boronic ester IX (subsequent deprotection step), as shown in the reaction of Figure 7, wherein the group PG refers to a protecting group which can be easily removed. Group, such as phenylsulfonyl.

Reaction Figure 7:

Synthesis of the compounds of the invention:

Experimental part abbreviation:

AcOH acetic acid

BOC tert-butyloxycarbonyl

COMU: hexafluorophosphoric acid (1-cyano-2-ethoxy-2-oxooxyethyleneaminooxy)dimethylamino-morpholinyl-carbonium

Cs ₂ CO ₃ strontium carbonate

DCM: dichloromethane

DIPEA: ethyl-diisopropyl-amine, Hünig base, DIEA

DMA: N,N-dimethylacetamide

DMAP: dimethyl-pyridin-4-yl-amine

DMF: N,N-dimethylformamide

DMSO: dimethyl hydrazine

EtOAc: ethyl acetate

EtOH: ethanol

HATU: O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

Hrs: hour

LDA: lithium diisopropyl guanamine

MeCN: acetonitrile

MeOH: methanol

NaBH ₄ : sodium borohydride

NaH sodium hydride

Na ₂ SO ₄ sodium sulfate

NH ₄ OH: 25% ammonia solution (ammonia hydrogen solution)

Pd/C: palladium on carbon

Pd ₂ (dba) ₃ : 叁 (dibenzylideneacetone) dipalladium (0)

TEA: Triethylamine

TFA: trifluoroacetic acid

THF: tetrahydrofuran

Rt: residence time

R.t. room temperature

Xantphos: 4,5-bis-diphenylphosphino-9,9-dimethyl-9H-dibenzopyran

¹ H-NMR spectra were recorded on a Bruker 600 MHz, Bruker 500 MHz or Bruker 400 MHz NMR spectrometer. The effective peaks are tabulated in order: diversity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad) and number of protons. Electrospray ionization (ESI) mass spectra were recorded on an Agilent 1100 Series mass spectrometer. Mass spectrometry results are reported as a ratio of mass to charge.

The detailed analytical HPLC chromatographic methods mentioned in the preparations and examples below are summarized as follows:

Preparative LC/MS Method 1:

A preparative Waters chromatography instrument equipped with a mircomass ZQ MS detector and a Waters X bridge C18-ODB (5 μm) 30 x 150 mm column. Peak detection was reported at 210 nm wavelength.

Solvent A: Water containing 1 mM ammonium bicarbonate.

Solvent B: Acetonitrile containing 0.04% formic acid.

Flow rate: 50 ml/min

Gradient: time [minutes] Solvent A [%] Solvent B [%]

LC/MS Method 1:

Waters Acquity UPLC instrument equipped with a diode array detector, a Waters SQD single quadrupole mass spectrometer and a Waters Acquity HSS T3 (1.8 μm) 2.1 x 50 mm column. Peak detection was reported at full scan and at 210-315 nm. Column temperature: 50 ° C.

Solvent A: Water containing 0.05% ammonium acetate and 0.05% formic acid.

Solvent B: Acetonitrile containing 0.04% formic acid.

Flow rate: 1.2 ml/min

Gradient: time [minutes] Solvent A [%] Solvent B [%]

Mass range: ESI +/-: 120-1200 m/z

All reagents, starting materials and intermediates used in these examples are available from commercial sources or can be readily known by those skilled in the art. Method preparation.

Example 1 4-(4-{5-fluoro-3-[4-(1-fluoro-cyclopropyl)-benzylidenylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3 -d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

(1) 4-(4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester, intermediate 1

4-Chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (2.6 g, in 1-propanol (120 ml) and aqueous sodium carbonate (2M, 10.23 ml, 20.46 mmol) Add 4-(4,4,5,5-tetramethyl-[1,2,3] to a mixture of 9.30 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.52 g, 0.74 mmol) Dioxon 2-Benzyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.02 g, 9.77 mmol). The mixture was heated to 100 ° C for 18 hours. After cooling, the brown mixture was diluted with 200 mL water and extracted with DCM. The organic layer was washed with brine (2x) and dried over sodium sulfate then filtered and evaporated. The residue was purified by flash chromatography over EtOAc (EtOAc:EtOAc:

MS (ESI): 335 [M + H] +, 1H-NMR (DMSO-d 6): δ (ppm) 12.64 (br s, 1H), 8.56 (s, 1H), 6.59 (s, 2H), 4.08 (br s, 2H), 3.57 (m, 2H), 2.55 (m, 2H), 1.45 (s, 9H).

(2) 4-Chloro-6-(1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine, intermediate 2

To a solution of compound intermediate 1 (2.60 g, 7.77 mmol) in 10 ml of DCM was added 30 ml of 95:5 TFA/water. The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and basified by addition of 2N sodium hydroxide and extracted with DCM. The organic layer was washed with brine (2×), dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting EtOAc (EtOAc)

MS (ESI): 235 [M + H] +, 1H-NMR (DMSO-d 6): δ (ppm) 9.70 (br s, 2H), 8.56 (s, 1H), 6.58 (s, 1H), 6.55 (br s, 1H), 3.80 (m, 2H), 3.30 (m, 2H), 2.80 (m, 2H).

(3) 4-(4-Chloro-6-(1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine, intermediate 3

To a suspension of the amine intermediate 2 (0.75 g, 3.20 mmol) in DCM (30 ml) Stir the mixture for 20 hours at room temperature Time. The solvent was evaporated under reduced pressure. The residue was purified by flash chromatography eluting EtOAc EtOAc EtOAc

MS (ESI): 306 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.65 (s, 1H), 8.55 (s, 1H), 6.60 (s, 1H), 6.57 (s, 1H), 3.90 (m, 2H), 3.36 (m, 2H), 2.77 (s, 6H), 2.57 (m, 2H).

(4) 2-(Fluoro-2-methyl-3-nitro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaboron Intermediate 4

1-Bromo-5-fluoro-2-methyl-3-nitro-benzene (5.0 g, 21.37 mmol) and bis(diphenylphosphino)ferrocene dichloride in 200 ml of dioxane To a mixture of palladium (II) (0.78 g, 1.06 mmol) was added bis-(pentamidine)-diboron (8.14 g, 32.0 mmol) and potassium acetate (7.34 g, 74.8 mmol). The mixture was heated to 100 ° C for 6 hours. After cooling, the brown mixture was diluted with 200 mL water and extracted with EtOAc. The organic layer was washed with sodium bicarbonate (1×) and brine (2×) and dried over sodium sulfate, then filtered and evaporated. The residue was purified by flash chromatography over EtOAc (EtOAc)

MS (ESI): 281 [M] ⁺ , ¹ H-NMR (DMSO-d ₆ ): δ (ppm) 7.79 (d, 1H), 7.55 (d, 1H), 2.48 (s, 3H), 1.31 (s) , 12H).

(5) 5-Fluoro-2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron -2-yl)-phenylamine, intermediate 5

The nitro compound intermediate 4 (12.4 g, 44.1 mmol) was dissolved in 300 mL EtOAc and Pd / C 10% (Pd) (4.0 g). The mixture was hydrogenated at room temperature under normal pressure for 18 hours. The mixture was filtered through Kieselgur (Supelco) and evaporated. The residue was purified by flash chromatography eluting EtOAc (EtOAc)

MS (ESI): 252 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 6.52 (m, 2H), 5.11 (br s, 2NH), 2.19 (s, 3H), 1.29 (s, 12H).

(6) 4-[4-(3-Amino-5-fluoro-2-methyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-di Hydrogen-2H-pyridine-1-carboxylic acid dimethyl decylamine, intermediate 6

To a chlorine compound intermediate 3 (3.94 g, 15.70 mmol) and dichlorobis(triphenylphosphine)palladium in 1-propanol (150 ml) and aqueous sodium carbonate (2M, 6.54 ml, 13.08 mmol) To the mixture of II) (0.73 g, 1.04 mmol) was added boronic acid compound intermediate 5 (4.0 g, 13.08 mmol). The mixture was heated at 100 ° C for 16 hours. After cooling, the brown mixture was diluted with 200 mL water and extracted with EtOAc. The organic layer was washed with brine (2x) and dried over sodium sulfate then filtered and evaporated. Silicon dioxide by flash chromatography (98: 2: 0.2 EtOAc / methanol / ammonia to 9: 1: 0.1 EtOAc / MeOH / NH 4 OH) to provide the residue was purified on a yellow solid of intermediate compound 6 meters.

MS (ESI): 395 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 11.80 (br s, 1H), 8.87 (s, 1H), 6.70 (m, 1H), 6.55 (m, 1H), 6.48 (br s, 1H), 6.38 (br s, 1H), 4.05 (br s, 2H), 3.90 (br s, 2NH), 3.55 (m, 2H), 2.90 (s, 6H), 2.65 (m, 2H), 2.10 (s, 3H).

(7) 4-(4-{5-Fluoro-3-[4-(1-fluoro-cyclopropyl)-benzylidenylamino]-2-methyl-phenyl}-7H-pyrrolo[ 2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

An anilino compound intermediate 6 (80 mg, 0.203 mmol), 4-(1-fluoro-cyclopropyl)-benzoic acid (for preparation see WO 07/090752) (40 mg, 0.223 mmol) and COMU (130) Mg, 0.304 mmol) was dissolved in DIPEA (0.071 ml, 0.406 mmol) and DMA (1.0 ml). The solution was stirred at room temperature for 18 hr. The reaction was diluted with 10 ml EtOAc and extracted with a H.sub.2 extractor using water. The aqueous layer was extracted with EtOAc (5×). The combined organic layers were dried over sodium sulfate and evaporated. The residue was purified by preparative LC/MS method 1 to afford compound 1 as a beige solid.

MS (ESI): 557 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.43 (br s, 1H), 10.07 (s, 1H), 8.83 (s, 1H), 8.03(d, 2H), 7.49 (m, 1H), 7.43 (d, 2H), 7.23 (m, 1H), 6.59 (br s, 1H), 6.33 (s, 1H), 3.90 (m, 2H), 3.33 (m, 2H), 2.77 (s, 6H), 2.54 (m, 2H), 2.12 (s, 3H), 1.55 (m, 2H), 1.26 (m, 2H).

The following Examples 2-14 were prepared as outlined in Reaction Scheme 1 and using Intermediate Intermediate 6 and appropriate benzoic acid as starting materials as illustrated for Example 1.

Example 2 4-(4-{3-[(3,3-Dimethyl-2,3-dihydro-benzofuran-6-carbonyl)-amino]-5-fluoro-2-methyl-phenyl} -7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

LC/MS (Method 1): rt: 1.01 min, MS (ESI): 569 [M+H] ⁺

Example 3 4-(4-{5-fluoro-2-methyl-3-[(5-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl)-amino] -phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

LC/MS (Method 1): rt: 1.14 min, MS (ESI): 573 [M+H] ⁺

Example 4 4-(4-{5-fluoro-3-[4-isopropyl-methyl-amino)-benzylidenylamino]-2-methyl-phenyl}-7H-pyrrolo[2, 3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

LC/MS (Method 1): rt: 1.05 min, MS (ESI): 570 [M+H] ⁺

Example 5 3-methyl-1H-indole-6-carboxylic acid {3-[6-(1-dimethylaminocarbamimidyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H- Pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-decylamine

LC/MS (Method 1): rt: 0.95 min, MS (ESI): 552 [M+H] ⁺

Example 6 4-(4-{5-fluoro-3-[4-(2-hydroxy-1,1-dimethyl-ethyl)-benzylidenylamino]-2-methyl-phenyl}-7H -pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

LC/MS (method 1): rt: 0.88 min, MS (ESI): 571 [M+H] ⁺

Example 7 4-{4-[5-fluoro-2-methyl-3-(4-hexahydropyridin-1-yl-benzylidenylamino)-phenyl]-7H-pyrrolo[2,3-d Pyrimidine-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

LC/MS (Method 1): rt: 1.07 min, MS (ESI): 582 [M+H] ⁺

Example 8 4-{4-[5-fluoro-3-(isopropenyl-benzylidenylamino)-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl }-3,6-Dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

LC/MS (method 1): rt: 1.04 min, MS (ESI): 539 [M+H] ⁺

Example 9 4-(4-{5-fluoro-2-methyl-3-[4-(1-trifluoromethyl-cyclopropyl)-benzylidenylamino]-phenyl}-7H-pyrrolo[ 2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

LC/MS (Method 1): rt: 1.08 min, MS (ESI): 607 [M+H] ⁺

Example 10 4-{4-[5-fluoro-3-(4-isopropoxy-benzylidenylamino)-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidine- 6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

LC/MS (Method 1): rt: 1.04 min, MS (ESI): 459 [M+H] ⁺

Example 11 4-(4-{5-fluoro-3-[4-pentafluorothio-benzylidenylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidine- 6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

LC/MS (Method 1): rt: 1.07 min, MS (ESI): 625[M+H] ⁺

Example 12 4-(4-{5-fluoro-3-[4-(2-methoxy-1,1-dimethyl-ethyl)-benzylidenylamino]-2-methyl-phenyl} -7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

LC/MS (Method 1): rt: 1.04 min, MS (ESI): 585 [M+H] ⁺

Example 13 4-(4-{5-fluoro-3-[4-(1-methoxy-1-methyl-ethyl)-benzylidenylamino]-2-methyl-phenyl}-7H- Pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

LC/MS (method 1): rt: 0.98 min, MS (ESI): 571 [M+H] ⁺

Example 14 1-methyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid {3-[6-(1-dimethyl-aminocarbamimidyl-1,2,3,6-tetrahydro- Pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-decylamine

LC/MS (Method 1): rt: 0.85 min, MS (ESI): 553 [M+H] ⁺

Example 15 4-{4-[3-(4-Dimethylamino-benzhydrylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidine -6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Add DIPEA (0.372 ml, 2.13 mmol), 4-dimethylaminobenzimidamide to a solution of aniline intermediate 6 (84 mg, 0.213 mmol) in DCM / pyridine (2:1, 30 ml) Chlorine (43 mg, 0.234 mmol) and DMAP (2.6 mg, 0.021 mmol). The resulting mixture was stirred at room temperature for 75 hr. The solvent was removed in vacuo and the resulting Jiyou (MeCN / H ₂ O) mixture was purified by reverse phase HPLC to provide Example 15.

MS (ESI): 542 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.41 (br s, 1H), 9.63 (s, 1H), 8.81 (s, 1H), 7.88 (d, 2H), 7.48 (m, 1H), 7.16 (m, 1H), 6.77 (d, 2H), 6.58 (br s, 1H), 6.32 (s, 1H), 3.89 (br s, 2H) , 3.32 (m, 2H), 3.00 (s, 6H), 2.76 (s, 6H), 2.54 (m, 2H), 2.10 (s, 3H).

Example 16 4-(4-{3-[2-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzylidenylamino]-2-hydroxymethyl-phenyl}-7H-pyrrole And [2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

(1) 4-{4-[3-Amino-2-(t-butyl-diphenyl-nonyloxymethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidine- 6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, intermediate 7

Intermediate 7 was prepared analogously to Intermediate 6 by using boronic acid ester intermediate 27 instead of boronic acid ester intermediate 5.

MS (ESI): 631 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.24 (br s, 1H), 8.52 (s, 1H), 7.32 (m, 2H), 7.28-7.27(m,4H), 716-7.15(m,5H), 6.90(d,1H), 6.71(d,1H),6.53(m,1H),6.16(s,1H),5.28(br s , 2H), 4.82 (s, 2H), 3.88 (m, 6H), 3.31 (m, 2H), 2.75 (s, 6H), 2.44 (m, 2H), 0.81 (s, 9H).

(2) 2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzoic acid, intermediate 8

Intermediate 8 was prepared analogously to Intermediate 35 by using 4-fluoro-terephthalic acid 4-methyl ester instead of Intermediate 34 (J. Med. Chem., 52 (19), 5950-5966; 2009).

MS (ESI): 197 [MH ] -, 1 H-NMR (DMSO-d 6): δ (ppm) 7.80 (t, 1H), 7.35 (m, 1H), 7.32 (m, 1H), 5.27 (br s, 1H), 1.42 (s, 6H).

(3) 4-(4-{2-(Third butyl-diphenyl-nonyloxymethyl)-3-[2-fluoro-4-(1-hydroxy-1-methyl-ethyl) -benzylidenylamino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine Intermediate 9

Add HATU (38 mg, 0.100) to a mixture of intermediate 7 (58 mg, 0.091 mmol), intermediate 8 (27 mg, 0.137 mmol) and DIPEA (0.059 ml, 0.337 mmol) in DMF (10 ml) Mm). The resulting mixture was stirred at room temperature for 22 hr. With EtOAc and the mixture was diluted with saturated NaHCO ₃ solution. The organic layer was washed with brine and dried by Na ₂ SO _4. The solvent was removed in vacuo, and the crude product was purified by reverse phase HPLC (H ₂ O / MeCN) to provide intermediate 9.

(4) 4-(4-{3-[2-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzylidenylamino]-2-hydroxymethyl-phenyl}- 7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Example 16 was prepared analogously to Step 8 of Example 37 by using Intermediate 9 instead of Intermediate 31.

LC/MS (Method 1): rt: 1.94 min, MS (ESI): 573 [M+H] ⁺

Example 17 4-{4-[3-(4-Cyclopropyl-benzimidyl)-2-hydroxymethyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl} -3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Example 17 was prepared analogously to Example 16 by using 4-cyclopropylbenzoic acid instead of Intermediate 8 in Step 3.

LC/MS (Method 1): rt: 2.32 min, MS (ESI): 537 [M+H] ⁺

Example 18 4-(4-{5-fluoro-2-methyl-3-[4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-benzylidenylamino] -phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Analogous to Intermediate 9 was prepared by using Intermediate 6 instead of Intermediate 7 and using 4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-benzoic acid instead of Intermediate 8. Example 18 (WO2007/145834).

MS (ESI): 611 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.43 (br s, 1H), 10.10 (s, 1H), 8.83 (s, 1H), 8.03 (d, 2H), 7.77 (d, 2H), 7.49 (m, 1H), 7.22 (m, 1H), 6.77 (s, 1H), 6.60 (br s, 1H), 6.34 (s, 1H), 3.90 (m, 2H), 3.35 (m, 2H), 2.77 (s, 6H), 2.55 (m, 2H), 2.10 (s, 3H), 1.75 (s, 3H).

Example 19 4-{4-[3-(4-Ethyl-benzhydrylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidine-6 -yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Example 19 was prepared analogously to Example 18 by using 4-ethyi-benzoic acid instead of 4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-benzoic acid.

MS (ESI): 541 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.42 (br s, 1H), 10.24 (s, 1H), 8.82 (s, 1H), 8.11 (m, 4H), 7.48 (m, 1H), 7.24 (m, 1H), 6.59 (s, 1H), 6.33 (s, 1H), 3.89 (m, 2H), 3.34 (m, 2H), 2.76 (s, 6H), 2.65 (s, 3H), 2.53 (m, 2H), 2.13 (s, 3H).

Example 20 4-{4-[3-(4-Cyclopropyl-benzhydrylamino)-4-fluoro-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3 ,6-Dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

(1) 4-[4-(3-Amino-4-fluoro-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine 1-carboxylic acid dimethyl decylamine, intermediate 10

Intermediate 10 was prepared analogously to Intermediate 6 by using 3-amino-4-fluoroboronic acid instead of Intermediate 5.

MS (ESI): 381 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.32 (br s, 1H), 8.74 (s, 1H), 7.68 (m, 1H), 7.39 (m, 1H), 7.13 (m, 1H), 6.84 (s, 1H), 6.58 (s, 1H), 5.36 (br s, 2H), 3.91 (s, 2H), 3.37 (m, 2H), 2.77 (s, 6H), 2.62 (m, 2H).

(2) 4-{4-[3-(4-Cyclopropyl-benzhydrylamino)-4-fluoro-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl }-3,6-Dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Intermediate 10 (80 mg, 0.210 mmol), 4-cyclopropyl-benzhydryl chloride (J. Med. Chem., 52(14), 4329-4337; 2009), which was obtained in pyridine (2 ml). A mixture of 76 mg, 0.421 mmol) and DMAP (2.6 mg, 0.021 mmol) was stirred at room temperature overnight. The mixture was evaporated to dryness, then saturated aqueous NaHCO ₃ was added, and the mixture was extracted with DCM. The organic layer was dried, filtered and evaporated to dry. By flash chromatography (silica gel, EtOAc / MeOH / NH ₃ gradient) to afford Example 20 to obtain.

MS (ESI): 525 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.44 (br s, 1H), 10.20 (s, 1H), 8.80 (s, 1H), 8.47(d,1H), 8.09(m,1H), 7.92(d,2H), 7.49(t,1H), 7.25(d,1H), 6.93(s,1H),6.60(s,1H),3.91 (m, 2H), 3.35 (m, 2H), 2.77 (s, 6H), 2.62 (m, 2H), 2.02 (m, 1H), 1.04 (m, 2H), 0.78 (m, 2H).

Example 21 4-(4-{4-Fluoro-3-[4-(2-hydroxy-1,1-dimethyl-ethyl)-benzylidenylamino]-phenyl}-7H-pyrrolo[2 ,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Example 21 was prepared analogously to Intermediate 9 by using Intermediate 10 instead of Intermediate 7 and using 4-(2-hydroxy-1,1-dimethyl-ethyl)-benzoic acid instead of Intermediate 8.

MS (ESI): 557 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.41 (br s, 1H), 10.21 (s, 1H), 8.80 (s, 1H), 8.50 (m, 1H), 8.10 (m, 1H), 7.94 (d, 2H), 7.54 (d, 2H), 7.48 (m, 1H), 6.93 (s, 1H), 6.60 (s, 1H), 4.74 (br s, 1H), 3.91 (m, 2H), 3.48 (m, 2H), 3.34 (m, 2H), 2.77 (s, 6H), 2.62 (m, 2H), 1.27 (s, 6H).

Example 22 N-{3-[6-(3,6-Dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2- Methyl-phenyl}-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzamide

(1) 4-Chloro-6-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine, intermediate 11

Similar to Intermediate 1 by using 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester instead of 4-(4,4,5,5-tetramethyl-[1,2,3] Dioxon Intermediate 11 was prepared as the tert-butyl 3-methyl)-3,6-dihydro-2H-pyridine-1-carboxylate.

MS (ESI): 236 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.69 (br s, 1H), 8.56 (s, 1H), 6.67 (m, 1H), 6.58 (s, 1H), 4.29 (m, 2H), 3.84 (m, 2H), 2.50 (m, 2H).

(2) 3-[6-(3,6-Dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2- Methyl-phenylamine, intermediate 12

Intermediate 12 was prepared analogously to Intermediate 6 by using Intermediate 11 instead of Intermediate 3.

MS (ESI): 325 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.34 (br s, 1H), 8.77 (s, 1H), 6.62 (m, 1H), 6.56 (m, 1H), 6.37 (m, 1H), 6.25 (s, 1H), 5.37 (br s, 2H), 4.27 (m, 2H), 3.80 (m, 2H), 2.45 (m, 2H), 1.89 (s, 3H).

(3) N-{3-[6-(3,6-Dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro -2-methyl-phenyl}-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzamide

Example 22 was prepared analogously to Intermediate 9 by using Intermediate 12 instead of Intermediate 7.

MS (ESI): 505 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.45 (br s, 1H), 9.95 (s, 1H), 8.83 (s, 1H), 7.73 (m, 1H), 7.63 (m, 1H), 4.43 (m, 2H), 7.19 (m, 1H), 6.65 (s, 1H), 6.34 (s, 1H), 5.32 (s, 1H), 4.29 (s, 2H), 3.81 (m, 2H), 2.47 (m, 2H), 2.15 (s, 3H), 1.46 (s, 6H).

Example 23 N-{3-[6-(3,6-Dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-hydroxymethyl- Phenyl}-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzamide

(1) 2-(Third butyl-diphenyl-nonyloxymethyl)-3-[6-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl]-phenylamine, intermediate 13

Intermediate 13 was prepared analogously to Intermediate 7 by using Intermediate 11 instead of Intermediate 6.

MS (ESI): 561 [M+H] ⁺ , ¹ H-NMR (DMSO-d ₆ ): δ (ppm) 12.25 (br s, 1H), 8.52 (s, 1H), 7.40-7.10 (m, 11H) ), 6.90 (d, 1H), 6.71 (d, 1H), 6.59 (s, 1H), 6.16 (s, 1H), 5.28 (s, 2H), 4.81 (s, 2H), 4.27 (m, 2H) , 3.78 (m, 2H), 2.37 (m, 2H), 0.82 (s, 9H).

(2) N-{2-(Tertiary butyl-diphenyl-nonyloxymethyl)-3-[6-(3,6-dihydro-2H-pyran-4-yl)-7H- Pyrrolo[2,3-d]pyrimidin-4-yl]-phenyl}-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzamide, intermediate 14

Intermediate 14 was prepared analogously to Intermediate 9 by using Intermediate 13 instead of Intermediate 7.

(3) N-{3-[6-(3,6-Dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-hydroxyl Methyl-phenyl}-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzamide

Example 23 was prepared analogously to Step 4 of Example 16 by using Intermediate 14 instead of Intermediate 9.

MS (ESI): 503 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.42 (s, 1H), 10.39 (d, 1H), 8.82 (s, 1H), 8.19 (d, 1H), 7.86 (t, 1H), 7.52-7.30 (m, 4H), 6.62 (br s, 1H), 6.42 (s, 1H), 5.65 (m, 1H), 5.26 (s, 1H) , 4.63 (m, 2H), 4.27 (m, 2H), 3.80 (m, 2H), 2.41 (m, 2H), 1.45 (s, 6H).

Example 24 4-tert-butyl-N-{3-[6-(3,6-dihydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl] -5-fluoro-2-methyl-phenyl}-benzamide

(1) 4-Chloro-6-(3,6-dihydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine, intermediate 15

Similar to Intermediate 1 by using 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaboron Instead of 4-(4,4,5,5-tetramethyl-[1,2,3]dioxon Intermediate 15 was prepared as the tert-butyl 3-methyl)-3,6-dihydro-2H-pyridine-1-carboxylate.

MS (ESI): 252 [M+H] ⁺

(2) 3-[6-(3,6-Dihydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2- Methyl-phenylamine, intermediate 16

Intermediate 16 was prepared analogously to Intermediate 6 by using Intermediate 15 instead of Intermediate 3.

MS (ESI): 341 [M+H] ⁺

(3) 4-tert-butyl-N-{3-[6-(3,6-dihydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-4 -yl]-5-fluoro-2-methyl-phenyl}-benzamide

Example 24 was prepared analogously to Example 15 by using Intermediate 16 instead of Intermediate 6 and using <RTI ID=0.0>0>

MS (ESI): 501 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.39 (s, 1H), 9.97 (s, 1H), 8.82 (s, 1H), 7.95 (d, 2H), 7.56 (d, 2H), 7.47 (m, 1H), 71.19 (m, 1H), 6.78 (m, 1H), 6.34 (s, 1H), 3.37 (m, 2H), 2.82 ( m, 2H), 2.66 (m, 2H), 2.11 (s, 3H), 1.32 (s, 9H).

Example 25 4-tert-butyl-N-{5-fluoro-2-methyl-3-[6-(3,6-dihydro-1-oxo-yl-2H-thiopyran-4-yl)-7H- Pyrrolo[2,3-d]pyrimidin-4-yl]-phenyl}-benzamide

Example 24 (160 mg, 0.32 mmol) was dissolved in acetic acid (5 mL) and hydrogen peroxide (0.033 ml, 0.32 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was treated with sodium bisulfite solution (10%, 10 ml) for 10 min, diluted with water, basified with 2N sodium hydroxide and extracted with EtOAc. The organic layer was washed with brine (2×), dried over sodium sulfate, filtered and evaporated. Silicon dioxide by flash chromatography:; The residue was purified on a compound (9 1 0.1 EtOAc / MeOH / NH 4 OH to 85:: 15 1.5 EtOAc / MeOH / NH 4 OH) to provide a beige solid of Example 25 .

MS (ESI): 517 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.49 (br s, 1H), 9.99 (s, 1H), 8.85 (s, 1H), 7.96 (d, 2H), 7.55 (d, 2H), 7.49 (m, 1H), 7.21 (m, 1H), 6.49 (br s, 1H), 6.46 (s, 1H), 3.69 (m, 1H), 3.50 (m, 1H), 3.13 (m, 1H), 295 (m, 1H), 2.89 (m, 1H), 2.80 (m, 1H), 2.13 (s, 3H), 1.31 (s, 9H).

Example 26 4-tert-butyl-N-{3-[6-(3,6-dihydro-1,1-dioxainyl-2H-thiopyran-4-yl)-7H-pyrrolo[2,3 -d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzamide

Example 24 (160 mg, 0.32 mmol) was dissolved in DCM (15 ml) then trifluoroacetic acid (5 ml) and hydrogen peroxide (0.065 ml, 0.64 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was treated with sodium bisulfite solution (10%, 10 ml) for 10 min, diluted with water, basified with 2N sodium hydroxide and extracted with EtOAc. The organic layer was washed with brine (2×), dried over sodium sulfate, filtered and evaporated. Silicon dioxide by flash chromatography (98: 2: 0.2 EtOAc / MeOH / NH 4 OH to 95: 5: 0.5 EtOAc / MeOH / NH 4 OH) The residue was purified on a compound to provide a beige solid of Example 26 .

MS (ESI): 533 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.45 (br s, 1H), 9.93 (s, 1H), 8.84 (s, 1H), 7.91(d,2H), 7.56(d,2H), 7.49(m,1H), 7.21(m,1H),6.41(m,2H), 4.00(m,2H),3.36(m,2H),3.07 (m, 2H), 2.16 (s, 3H), 1.33 (s, 9H).

Example 27 4-tert-butyl-N-{3-[6-(1,4-dioxa-spiro[4.5]癸-7-ene-8-yl)-7H-pyrrolo[2,3-d] Pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzamide

(1) 4-Chloro-6-(1,4-dioxa-spiro[4.5]dec-7-ene-8-yl)-7H-pyrrolo[2,3-d]pyrimidine, intermediate 17

Similar to Intermediate 1 by using 1,4-dioxaspiro[5,5]indole-7-ene-8-boronic acid pinacol ester instead of 4-(4,4,5,5-tetramethyl- [1,2,3]diboron Intermediate 17 was prepared as the tert-butyl 3-methyl)-3,6-dihydro-2H-pyridine-1-carboxylate.

MS (ESI): 292 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.59 (br s, 1H), 8.54 (s, 1H), 6.54 (s, 1H), 6.50 (br s, 1H), 3.93 (m, 4H), 2.61 (m, 2H), 2.43 (m, 2H), 1.83 (m, 2H).

(2) 3-[6-(1,4-Dioxa-spiro[4.5]indole-7-en-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- 5-fluoro-2-methyl-phenylamine, intermediate 18

Intermediate 18 was prepared analogously to Intermediate 6 by using Intermediate 17 instead of Intermediate 3.

MS (ESI): 381 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.24 (br s, 1H), 8.75 (s, 1H), 6.55 (m, 1H), 6.46(br s,1H), 6.38(m,1H), 6.21(s,1H), 5.36(s,2NH),3.91(m,4H),2.55(m,2H),2.41(m,2H) , 1.88 (s, 3H), 1.78 (m, 2H).

(3) 4-tert-butyl-N-{3-[6-(1,4-dioxa-spiro[4.5]indole-7-en-8-yl)-7H-pyrrolo[2,3 -d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzamide

Example 27 was prepared analogously to Example 15 by using Intermediate 18 instead of Intermediate 6 and 4-t-butyl benzamidine chloride instead of 4-dimethylaminobenzhydrin.

MS (ESI): 541 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.36 (br s, 1H), 9.98 (s, 1H), 8.82 (s, 1H), 7.96(d,2H), 7.58(d,2H), 7.48(m,1H), 7.21(m,1H), 6.50(br s,1H), 6.29(s,1H),3.93(m,4H), 2.58 (m, 2H), 2.43 (m, 2H), 2.12 (s, 3H), 1.81 (m, 2H), 1.33 (s, 9H).

Example 28 4-tert-butyl-N-{5-fluoro-3-[6-(4-hydroxy-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl] -2-methyl-phenyl}-benzamide

(1) 4-tert-butyl-N-{5-fluoro-3-[6-(4-hydroxy-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -yl]-2-methyl-phenyl}-benzamide, intermediate 19

A mixture of Example 27 (450 mg, 0.832 mmol) and TFA (6 ml). The solvent was removed in vacuo and purified by flash chromatography (silica gel, EtOAc / MeOH / NH ₄ OH gradient) to afford crude product was purified intermediate 19.

MS (ESI): 497 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.47 (br s, 1H), 9.97 (s, 1H), 8.83 (s, 1H), 7.94(d,2H), 7.57(d,2H), 7.48(m,1H), 7.20(m,1H), 6.65(br s,1H), 6.40(s,1H),3.11(m,2H), 2.86 (m, 2H), 2.53 (m, 2H), 2.11 (s, 3H), 1.33 (s, 9H).

(2) 4-tert-butyl-N-{5-fluoro-3-[6-(4-hydroxy-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -yl]-2-methyl-phenyl}-benzamide

To deposit in MeOH (25 ml) of the Intermediate 19 (100 mg, 0.201 mmol) was added a solution of _{NaBH 4 (9.1 mg, 0.242 mg} ). The mixture was stir for 2 hr at room temperature, then the solvent was removed in vacuo, and purified by flash chromatography (silica gel, EtOAc / MeOH / NH ₄ OH gradient) to afford Example 28 The crude mixture.

MS (ESI): 499 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.31 (br s, 1H), 9.96 (s, 1H), 8.79 (s, 1H), 7.94(d,2H), 7.57(d,2H), 7.47(m,1H), 7.18(m,1H), 6.50(br s,1H), 6.24(s,1H),4.73(br s,1H) , 3.80 (m, 1H), 2.51 (m, 2H), 2.44 (m, 1H), 2.39 (m, 1H), 2.10 (s, 3H), 1.84 (m, 1H), 1.59 (m, 1H), 1.33 (s, 9H).

Example 29 4-{4-[3-(4-Cyclopropyl-benzhydrylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidine-6 -yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

(1) 4-[4-(3-Amino-5-fluoro-2-methyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-di Hydrogen-2H-pyridine-1-carboxylic acid tert-butyl ester, intermediate 20

For the Suzuki coupling of the chlorine compound intermediate 1 (0.63 g, 1.88 mmol) and the boronate derivative intermediate 5 (0.52 g, 2.07 mmol), The same procedure as described in Step 6 of Example 1 was used to provide compound intermediate 20 as a beige solid.

MS (ESI): 424 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.33 (br s, 1H), 8.76 (s, 1H), 6.54 (m, 2H), 6.40(d,1H), 6.26(s,1H), 5.36(s,2NH), 4.05(br s,2H), 3.51(m,2H), 1.99(m,2H),1.88(s,3H), 1.42 (s, 9H).

(2) 4-{4-[3-(Cyclopropyl-benzhydrylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidine- 6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester, intermediate 21

To a solution of 4-cyclopropylbenzoic acid (0.58 g, 3.57 mmol) in toluene (2 ml) was added sulphur chloride (1.29 ml, 17.87 mmol). The mixture was stirred at 80 ° C for 2 hours and then evaporated under reduced pressure. The residue was dissolved in pyridine (5 ml). The pyridine was evaporated under reduced pressure and the residue was crystallisjjjjjjjjj The residue was purified by flash chromatography eluting EtOAc (EtOAc)

MS (ESI): 568 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.43 (br s, 1H), 9.93 (s, 1NH) 8.82 (s, 1H), 7.89 (d, 2H), 7.46 (m, 1H), 7.24 (d, 2H), 7.18 (m, 1H), 6.57 (br s, 1H), 6.33 (s, 1H), 4.06 (br s, 2H), 3.52 (m, 2H), 2.48 (m, 2H), 2.10 (s, 3H), 2.01 (m, 1H), 1.42 (s, 9H), 1.02 (m, 2H), 0.76 (m, 2H).

(3) 4-Cyclopropyl-N-{5-fluoro-2-methyl-3-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl]-phenyl}-benzamide, intermediate 22

The BOC protecting group of compound intermediate 21 (1.0 g, 1.76 mmol) was removed as described in step 2 of Example 1 to afford compound intermediate 22 as a beige solid.

MS (ESI): 468 [M+H] ⁺ , ¹ H-NMR (DMSO-d ₆ ): δ (ppm) 12.33 (br s, 1H), 9.94 (s, 1NH) 8.80 (s, 1H), 7.89 (d, 2H), 7.47 (m, 1H), 7.24 (d, 2H), 7.19 (m, 1H), 6.62 (br s, 1H), 6.24 (s, 1H), 3.41 (br s, 2H), 2.88 (m, 2H), 2.33 (m, 2H), 2.10 (s, 3H), 2.01 (m, 1H), 1.04 (m, 2H), 0.77 (m, 2H).

(4) 4-{4-[3-(4-Cyclopropyl-benzhydrylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d] Pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

The amine compound intermediate 22 (0.2 g, 0.51 mmol) was deuterated as described in Step 3 of Example 1 to provide compound Example 29 as a beige solid.

MS (ESI): 539 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.42 (br s, 1H), 9.93 (s, 1NH) 8.82 (s, 1H), 7.89 (d, 2H), 7.46 (m, 1H), 7.24 (d, 2H), 7.18 (m, 1H), 6.59 (br s, 1H), 6.32 (s, 1H), 3.90 (br s, 2H), 3.33 (m, 2H), 2.76 (s, 6H), 2.53 (m, 2H), 2.10 (s, 3H), 2.02 (m, 1H), 1.03 (m, 2H), 0.77 (m, 2H).

Example 30 4-cyclopropyl-N-(5-fluoro-2-methyl-3-{6-[1-(pyrrolidin-1-carbonyl)-1,2,3,6-tetrahydro-pyridine-4- -7H-pyrrolo[2,3-d]pyrimidin-4-yl}-phenyl)-benzamide

Amino compound intermediate 22 (0.2 g, 0.51 mmol) was deuterated using pyrrolidine-1-carbonyl chloride as described in Step 3 of Example 1 to provide beige Compound Example 30 in the form of a color solid.

MS (ESI): 565 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.41 (br s, 1H), 9.93 (s, 1NH) 8.82 (s, 1H), 7.89 (d, 2H), 7.45 (m, 1H), 7.24 (d, 2H), 7.18 (m, 1H), 6.58 (br s, 1H), 6.32 (s, 1H), 3.93 (br s, 2H), 3.38 (m, 2H), 3.29 (m, 4H), 2.52 (m, 2H), 2.10 (s, 3H), 2.0 (m, 1H), 1.75 (m, 4H), 1.04 (m, 2H), 0.76 (m, 2H).

Example 31 2-(4-{4-[3-(4-cyclopropyl-benzhydrylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d acetate Pyrimidin-6-yl}-3,6-dihydro-2H-pyridin-1-yl)-2-oxo-ethyl ester

The amine compound intermediate 22 (0.15 g, 0.32 mmol) was triturated using chlorocarbonylmethyl acetate as described in step 3 of Example 1 to afford compound 31 as a beige solid.

MS (ESI): 568 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.45 (br s, 1H), 9.94 (s, 1NH) 8.83 (s, 1H), 7.89 (d, 2H), 7.47 (m, 1H), 7.22 (d, 2H), 7.19 (m, 1H), 6.58 (br s, 1H), 6.34 (s, 1H), 4.86 (m, 2H), 4.15 (m, 2H), 3.57 (m, 2H), 2.59 (m, 2H), 2.10 (s, 3H), 2.08 (s, 3H), 2.01 (m, 1H), 1.03 (m, 2H), 0.77 ( m, 2H).

Example 32 4-cyclopropyl-N-(5-fluoro-3-{6-[1-(2-hydroxy-ethenyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H -pyrrolo[2,3-d]pyrimidin-4-yl}-2-methyl-phenyl)benzamide

The ethyl hydrazide compound of Example 31 (100 mg, 0.17 mmol) was dissolved in THF (1 ml) and EtOH (1 ml) and 2N sodium hydroxide solution (0.31 ml, 0.62 mmol). The mixture was stirred at room temperature for 5 minutes. The mixture was diluted with water and extracted with DCM (3×). The organic layer was washed with brine (2×), dried over sodium sulfate, filtered and evaporated. Silicon dioxide in the residue was purified by flash chromatography on (:: 2 EtOAc to _{98 0.2 EtOAc / MeOH / NH 4} OH) to provide a beige solid forms of the compound of Example 32.

MS (ESI): 526 [M+H] ⁺ , ¹ H-NMR (DMSO-d ₆ ): δ (ppm) 12.47 (br s, 1H), 9.95 (s, 1NH) 8.82 (s, 1H), 7.89 (d, 2H), 7.47 (m, 1H), 7.24 (d, 2H), 7.18 (m, 1H), 6.61 (m, 1H), 6.33 (m, 1H), 4.63 (m, 2H), 4.04 ( m, 4H), 3.68 (m, 1H), 3.54 (m, 1H), 2.57 (m, 2H), 2.10 (s, 3H), 2.01 (m, 1H), 1.04 (m, 2H), 0.77 (m) , 2H).

Example 33 N-(3-{6-[1-(2-Cyano-ethinyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2,3-d Pyrimidin-4-yl}-5-fluoro-2-methyl-phenyl)-4-cyclopropyl-benzene Formamide

The amino compound intermediate 22 (30 mg, 0.064 mmol), cyanoacetic acid (11 mg, 0.128 mmol) and HATU (61 mg, 0.16 mmol) were dissolved in DIPEA (0.056 ml, 0.321 mmol) and DMF (1.0 ml) in. The solution was stirred at room temperature for 24 hr. The reaction was diluted with DCM and washed with saturated sodium hydrogen carbonate solution and brine (2×). The organic layer was dried over sodium sulfate and evaporated. The residue was purified by flash chromatography over EtOAc (EtOAc)

MS (ESI): 536 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 9.56 (br s, 1NH) 8.76 (s, 1H), 7.85 (d, 2H), 7.43 (m, 1H), 7.19 (d, 2H), 7.09 (m, 1H), 6.53 (m, 1H), 6.29 (m, 1H), 4.16 (m, 2H), 3.94 (m, 2H), 3.63 ( m, 2H), 2.56 (m, 2H), 2.10 (s, 3H), 2.01 (m, 1H), 1.01 (m, 2H), 0.74 (m, 2H).

Example 34 N-(5-fluoro-2-methyl-3-{6-[1-(pyrrolidin-1-carbonyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrole And [2,3-d]pyrimidin-4-yl}-phenyl)-4-(pentafluoro-thio)-benzamide

(1) 4-(4-{5-Fluoro-2-methyl-3-[4-(pentafluoro-thio)-benzylidenylamino]-phenyl}-7H-pyrrolo[2, 3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester, intermediate 23

Intermediate 23 was prepared analogously to Intermediate 9 by using Intermediate 20 instead of Intermediate 7 and using 4-(pentafluoro-thio)-benzoic acid instead of Intermediate 8.

MS (ESI): 654 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.44 (br s, 1H), 10.33 (s, 1H), 8.83 (s, 1H), 8.18(d,2H), 8.12(d,2H), 7.50(m,1H), 7.24(m,1H),6.57(m,1H),6.34(s,1H),4.06(m,2H),3.51 (m, 2H), 2.49 (m, 2H), 2.12 (s, 3H), 1.42 (s, 9H).

(2) N-{5-fluoro-2-methyl-3-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d] Pyrimidin-4-yl]-phenyl}-4-(pentafluoro-thio)-benzamide, intermediate 24

Intermediate 24 was prepared analogously to Intermediate 22 by using Intermediate 23 instead of Intermediate 21.

MS (ESI): 554 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.42 (br s, 1H), 10.43 (s, 1H), 8.83 (s, 1H), 8.23(d,2H), 8.13(d,2H), 7.51(m,1H), 7.24(m,1H), 6.54(m,1H),6.31(s,1H),3.52(m,2H),2.99 (m, 2H), 2.45 (m, 2H), 2.13 (s, 3H).

(3) N-(5-fluoro-2-methyl-3-{6-[1-(pyrrolidin-1-carbonyl)-1,2,3,6-tetrahydro-pyridin-4-yl]- 7H-pyrrolo[2,3-d]pyrimidin-4-yl}-phenyl)-4-(pentafluoro-thio)-benzamide

Example 34 was prepared analogously to Example 30 by using Intermediate 24 instead of Intermediate 22.

MS (ESI): 651 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.42 (br s, 1H), 10.32 (s, 1H), 8.82 (s, 1H), 8.18(d,2H), 8.12(d,2H), 7.48(m,1H), 7.23(m,1H), 6.59(m,1H),6.33(s,1H),3.93(m,2H),3.38 (m, 2H), 3.29 (m, 4H), 2.50 (m, 2H), 2.12 (s, 3H), 1.75 (m, 4H).

Example 35 2-[4-(4-{5-fluoro-2-methyl-3-[4-(pentafluoro-thio)-benzylidenylamino]-phenyl}-7H-pyrrolo[2]-pyrrolo[2] ,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxo-ethyl ester

Example 35 was prepared analogously to Example 31 by using Intermediate 24 instead of Intermediate 22.

MS (ESI): 654 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.47 (br s, 1H), 10.34 (s, 1H), 8.83 (s, 1H), 8.19(d,2H), 8.12(d,2H), 7.49(m,1H), 7.25(m,1H), 6.60(m,1H),6.37(s,1H),4.86(s,2H),4.16 (m, 2H), 3.58 (m, 2H), 2.60 (m, 2H), 2.12 (s, 3H), 2.08 (s, 3H).

Example 36 N-(5-fluoro-3-{6-[1-(2-hydroxy-ethenyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2, 3-d]pyrimidin-4-yl}-2-methyl-phenyl)-4-(pentafluoro-thio)-benzamide

Example 36 was prepared analogously to Example 32 by using Example 35 instead of Example 31.

MS (ESI): 612 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.43 (br s, 1H), 10.47 (s, 1H), 8.84 (s, 1H), 8.22(d,2H), 8.12(d,2H), 7.50(m,1H), 7.24(m,1H), 6.60(m,1H),6.35(s,1H),4.86(s,2H), 4.20 (m, 2H), 4.16 (m, 2H), 3.51 (m, 2H), 2.58 (m, 2H), 2.13 (s, 3H), 2.08 (s, 3H).

Example 37 4-{4-[3-(4-Tertiary-benzylideneamino)-2-(t-butyl-diphenyl-nonyloxymethyl)-phenyl]-7H-pyrrole And [2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

(1) (2-Bromo-nitro-benzyloxy)-tert-butyl-diphenyl-formane, intermediate 25

To a solution of (2-bromo-6-nitro-phenyl)-methanol (10.0 g, 43.1 mmol) and imidazole (5.87 g, 86.0 mmol) in DMF (20 ml). Tributyl-chloro-diphenyl-formane was added dropwise. The mixture was stirred at 50 ° C for 1 hour. The mixture was diluted with EtOAc and washed with brine (2×). The organic layer was dried over sodium sulfate and evaporated. The residue was taken up in heptane and stirred at room temperature for 3 h. The solid was filtered to afford compound intermediate 25 as a beige solid.

MS (ESI): 471 [M + H] +, 1 H-NMR (CDCl 3): δ (ppm) 7.80 (m, 6H), 7.40 (m, 6H), 7.24 (m, 1H), 5.10 (s , 2H), 0.99 (s, 9H).

(2) 2-[2-(Tertiary butyl-diphenyl-nonyloxymethyl)-3-nitro-phenyl]-4,4,5,5-tetramethyl-[1,3 , 2] boron trioxide , intermediate 26

Adding a mixture of intermediate 25 (5.0 g, 10.63 mmol) and bis(diphenylphosphino)ferrocene dichloropalladium (II) (0.43 g, 0.52 mmol) in 60 ml of dioxane - (Pentylene)-diboron (5.4 g, 21.26 mmol) and potassium acetate (6.25 g, 63.7 mmol). The mixture was heated to 90 ° C for 4 hours. in After cooling, the brown mixture was filtered through celite (EtOAc) and evaporated. The residue was purified by flash chromatography eluting EtOAc (EtOAc)

MS (ESI): no peak, ¹ H-NMR (CDCl ₃ ): δ (ppm) 7.65 (m, 5H), 7.30 (m, 8H), 5.30 (s, 2H), 1.10 (s, 12H), 0.97 (s, 9H).

(3) 2-(Terbutyl-diphenyl-nonyloxymethyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron -2-yl)-phenylamine, intermediate 27

The nitro compound intermediate 26 (10.0 g, 19.32 mmol) was dissolved in 300 mL EtOAc and Pd / C 10% (Pd) (2.0 g). The mixture was hydrogenated at room temperature under normal pressure for 20 hours. The mixture was filtered through a pad of Celite and evaporated. The residue was purified by flash chromatography eluting EtOAc EtOAc EtOAc

MS (ESI): 488 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 7.63 (m, 4H), 7.44 (m, 2H), 7.39 (m, 4H), 7.03 (t, 1H), 6.91 (d, 1H), 6.84 (d, 1H), 5.10 (s, 2H), 5.08 (s, 2H), 0.99 (s, 12H), 0.98 (s, 9H).

(4) 4-tert-butyl-N-[2-t-butyl-diphenyl-nonyloxymethyl)-3-(4,4,5,5-tetramethyl-[1,3 , 2] boron trioxide -2-yl)-phenyl]-benzamide, Intermediate 28

The anilino compound intermediate 27 (92.0 g, 189 mmol) was dissolved in DCM (1.l) and triethylamine (80 ml). To the mixture was added 4-tert-butyl benzamidine chloride at 0 ° C for 5 minutes. The mixture was stirred at room temperature for 1 hour. The mixture was washed with saturated ammonium chloride solution and brine (2×) and evaporated. The residue was taken up in hexane and stirred at room temperature for 3 hr. The solid was filtered to afford compound intermediate 28 as a beige solid.

MS (ESI): 648 [M + H] +, 1 H-NMR (CDCl 3): δ (ppm) 9.85 (br s, 1H), 7.80 (m, 2H), 7.60 (m, 6H), 7.35- 7.25 (m, 9H), 5.30 (s, 2H), 1.35 (s, 9H), 1.05 (s, 18H).

(5) 4-{4-[3-(4-Terbutyl-benzylidenylamino)-2-(t-butyl-diphenyl-nonyloxymethyl)-phenyl]- 7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine 3-carboxylic acid tert-butyl ester, intermediate 29

For the Suzuki coupling between the chlorine compound intermediate 1 (0.50 g, 1.49 mmol) and the boronate derivative intermediate 28 (1.45 g, 2.24 mmol), the same procedure as described in step 6 of Example 1 was used. Compound intermediate 29 is provided as a beige solid.

MS (ESI): 820 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.33 (s, 1H), 10.02 (s, 1H), 8.68 (s, 1H), 7.78 (m, 2H), 7.75 (m, 1H), 7.46 (m, 2H), 7.40 (m, 1H), 7.25 (m, 2H), 7.12 (m, 1H), 7.11 (m, 8H), 6.54 ( Br s, 1H), 6.30 (s, 1H), 4.97 (s, 2H), 4.07 (m, 2H), 3.52 (m, 2H), 2.43 (m, 2H), 1.41 (s, 9H), 1.30 ( s, 9H), 0.53 (s, 9H).

(6) 4-tert-butyl-N-{2-(t-butyl-diphenyl-nonyloxymethyl)-3-[6-(1,2,3,6-tetrahydro-pyridine 4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-benzamide, intermediate 30

The BOC protecting group of compound intermediate 29 (0.92 g, 1.12 mmol) was removed as described in step 2 of Example 1 to afford compound intermediate 30 as a beige solid.

MS (ESI): 720 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.50 (s, 1H), 10.08 (s, 1H), 8.72 (s, 1H), 7.80 (m, 2H), 7.75 (m, 1H), 7.53 (m, 1H), 7.42 (m, 1H), 7.26 (m, 2H), 7.15 (m, 2H), 7.11 (m, 8H), 6.56 ( Br s,1H), 6.42 (s,1H), 4.99 (s,2H), 3.85 (m, 2H), 3.32 (m, 2H), 2.67 (m, 2H), 1.29 (s, 9H), 0.52 ( s, 9H).

(7) 4-{4-[3-(4-Terbutyl-benzylidenylamino)-2-(t-butyl-diphenyl-nonyloxymethyl)-phenyl]- 7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, intermediate 31

The amine compound intermediate 30 (0.1 g, 0.14 mmol) was deuterated as described in step 3 of Example 1 to provide compound intermediate 31 as a beige solid.

MS (ESI): 791 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.35 (s, 1H), 10.04 (s, 1H), 8.70 (s, 1H), 7.79 (m, 2H), 7.74 (m, 1H), 7.53 (m, 1H), 7.47 (m, 2H), 7.43 (m, 1H), 7.27 (m, 2H), 7.14-7.11 (m, 8H), 6.57 (br s, 1H), 6.30 (s, 1H), 4.98 (s, 2H), 3.91 (m, 2H), 3.32 (m, 2H), 2.76 (s, 6H), 2.52 (m, 2H), 1.31 (s, 9H), 0.53 (s, 9H).

(8) 4-{4-[3-(4-Tertiary-benzylideneamino)-2-hydroxymethyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidine- 6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Compound Intermediate 31 (65 mg, 0.082 mmol) was dissolved in EtOAc EtOAc (EtOAc) The mixture was stirred at room temperature for 20 hours. The solvent was removed under reduced pressure. Silicon dioxide in the residue was purified by flash chromatography on (:: 5 95 0.5 EtOAc / MeOH / NH 4 OH) to provide a beige solid forms of the compound of Example 37.

MS (ESI): 553 [M+H] ⁺ , ¹ H-NMR (DMSO-d ₆ ): δ (ppm) 12.44 (s, 1H), 10.53 (s, 1NH) 8.83 (s, 1H), 8.23 ( m,1H), 7.91 (d, 2H), 7.60 (d, 2H), 7.51 (m, 1H), 7.35 (m, 1H), 6.60 (br s, 1H), 6.45 (s, 1H), 4.69 ( s, 2H), 3.90 (br s, 2H), 3.33 (m, 2H), 2.77 (s, 6H), 2.54 (m, 2H), 1.33 (s, 9H).

Example 38 4-tert-butyl-N-(3-{6-[1-(2-fluoro-ethenyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrole [2,3-d]pyrimidin-4-yl}-2-hydroxymethyl-phenyl)-benzamide

(1) 4-tert-butyl-N-(2-(t-butyl-diphenyl-decyloxymethyl)-3- {6-[1-(2-Fluoro-ethenyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl }-Phenyl)-benzamide, intermediate 32

To a solution of intermediate 30 (100 mg, 0.139 mmol) in pyridine (5 ml) was added EtOAc-EtOAc (EtOAc) The mixture was stirred at room temperature for 20 hr and then the solvent was removed in vacuo. Using flash chromatography (silica gel, EtOAc / MeOH / NH ₃ gradient) to obtain the crude product was purified intermediate 32.

(2) 4-tert-butyl-N-(3-{6-[1-(2-fluoro-ethinyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H -pyrrolo[2,3-d]pyrimidin-4-yl}-2-hydroxymethyl-phenyl)-benzamide

Example 38 was prepared analogously to Step 8 of Example 37 by using Intermediate 32 instead of Intermediate 31.

MS (ESI): 542 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.46 (br s, 1H), 10.52 (s, 1H), 8.83 (s, 1H), 8.21(d,1H), 7.90(d,2H), 7.59(d,2H), 7.50(t,1H),7.34(d,1H),6.61(br,s),6.44(s,1H),5.91 (br s,1H), 5.25 (m, 2H), 4.67 (s, 2H), 4.18 (m, 1H), 4.08 (m, 1H), 3.67 (m, 1H), (3.47 m, 1H), 2.57 (m, 1H), 2.51 (m, 1H), 1.32 (s, 9H).

Example 39 4-(4-{5-fluoro-3-[2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzylidenylamino]-2-methyl-phenyl}- 7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

(1) 4-chlorocarbonyl-3-fluoro-benzoic acid methyl ester, intermediate 33

2-Fluoro-terephthalic acid 4-methyl ester (J. Med. Chem., 52 (19), 5950-5966; 2009) (500 mg, 2.25 mmol) was suspended in DCM (10 ml). Then add chlorophyll chloride (5.08 ml, 58.0 mmol) and a drop of DMF. The resulting mixture was refluxed for 14 hr. The solvent was removed in vacuo and the crude intermediate 33 obtained was used in the next step without purification.

(2) N-(3-bromo-5-fluoro-2-methyl-phenyl)-3-fluoro-terephthalic acid monodecylamine methyl ester, intermediate 34

3-Bromo-5-fluoro-2-methylaniline (515 mg, 2.53 mmol) was dissolved in pyridine (20 mL). Intermediate 33 (547 mg, 2.53 mmol) and DMAP (3.09 mg, 0.025 mmol) were then added and the mixture was stirred at room temperature for 2 hr. The solvent was removed in vacuo and H ₂ O with EtOAc and the residue was absorbed. The organic layer was washed with a NaHCO ₃ solution and brine and then dried over Na ₂ SO ₄ . The solvent was removed in vacuo and the residue was crystallised from EtOAc to afforded Intermediate 34.

(3) N-(3-bromo-5-fluoro-2-methyl-phenyl)-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzamide, intermediate 35

Intermediate 34 (75 mg, 0.195 mmol) was dissolved in THF (10 mL). Methylmagnesium bromide (0.390 ml, 1.17 mmol) was then added dropwise and stirring was continued for 3 hr. The mixture was concentrated to dryness and then diluted with MeOH / DMSO. The resulting precipitate was filtered to give a white solid intermediate 35.

MS (ESI): 384 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 10.04 (br s, 1H), 7.63 (m, 1H), 7.42 (m, 2H), 7.36 (m, 2H), 5.27 (s, 1H), 2.24 (s, 3H), 1.40 (s, 6H).

(4) 2-Fluoro-N-[5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron -2-yl)-phenyl]-4-(1-hydroxy-1-methyl-ethyl)-benzamide, intermediate 36

Intermediate 36 was prepared analogously to Intermediate 4 by using Intermediate 35 instead of 1-bromo-5-fluoro-2-methyl-3-nitro-benzene.

(5) 4-(4-{5-Fluoro-3-[2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzoylamino]-2-methyl-benzene -7}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Example 39 was prepared analogously to Example 37 by using the boronic acid ester intermediate 36 instead of the boronic ester intermediate 28 in step 5.

MS (ESI): 575 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.43 (s, 1H), 9.93 (s, 1H), 8.83 (s, 1H), 7.74 (m, 1H), 7.64 (d, 1H), 7.43 (m, 2H), 7.18 (dd, 1H), 6.60 (s, 1H), 6.34 (s, 1H), 5.30 (s, 1H), 3.90 ( m, 2H), 3.33 (m, 2H), 2.77 (s, 6H), 2.54 (m, 2H), 2.15 (s, 3H), 1.46 (s, 6H).

Example 40 4-tert-butyl-N-{5-fluoro-2-methyl-3-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2, 3-d]pyrimidin-4-yl]-phenyl}-benzamide

(1) N-(3-Bromo-5-fluoro-2-methyl-phenyl)-4-t-butyl-benzamide, intermediate 37

Intermediate 37 was prepared analogously to Intermediate 34 by using 4-t-butyl-benzhydrin chloride instead of Intermediate 33.

MS (ESI): 364 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 10.11 (br s, 1H), 7.90 (d, 2H), 7.55 (d, 2H), 7.49 (d, 1H), 7.32 (d, 1H), 2.32 (s, 3H), 1.38 (s, 9H).

(2) 4-tert-butyl-N-[5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron -2-yl)-phenyl]-benzamide, intermediate 38

Intermediate 38 was prepared analogously to Intermediate 4 by using Intermediate 37 instead of 1-bromo-5-fluoro-2-methyl-3-nitro-benzene.

MS (ESI): 412 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 9.85 (br s, 1H), 7.90 (d, 2H), 7.55 (d, 2H), 7.35 (d, 1H), 7.22 (d, 1H), 2.35 (s, 3H), 1.40 (s, 6H), 1.32 (m, 15H).

(3) 4-tert-butyl-N-{5-fluoro-2-methyl-3-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrole [2,3-d]pyrimidin-4-yl]-phenyl}-benzamide

Example 40 was prepared analogously to Intermediate 30 in Step 6 of Example 37 by using Intermediate 38 instead of Intermediate 28 in Step 5 of Example 37.

MS (ESI): 484 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.55 (s, 1H), 9.98 (s, 1H), 8.85 (s, 1H), 8.71 (br s,1H), 7.92 (d, 2H), 7.56 (d, 2H), 7.50 (m, 1H), 7.18 (m, 1H), 6.56 (m, 1H), 6.43 (s, 1H), 3.80 (m, 2H), 3.28 (m, 2H), 2.67 (m, 2H), 2.10 (s, 3H), 1.32 (s, 9H).

Example 41 4-{4-[3-(4-Terbutyl-benzylidenylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidine- 6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Example 41 was prepared similarly to Step 7 of Example 37 by using Example 40 instead of Intermediate 30.

MS (ESI): 555 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.44 (s, 1H), 9.98 (s, 1H), 8.83 (s, 1H), 7.95 (d, 2H), 7.58 (d, 2H), 7.48 (m, 1H), 7.22 (m, 1H), 6.60 (s, 1H), 6.33 (s, 1H), 5.30 (s, 1H), 3.90 ( m, 2H), 3.32 (m, 2H), 2.77 (s, 6H), 2.55 (m, 2H), 2.12 (s, 3H), 1.34 (s, 9H).

Example 42 4-tert-butyl-N-{5-fluoro-3-[6-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide

To a solution of Example 40 (90 mg, 0.186 mmol) and DIPEA (0.098 ml The resulting mixture was stirred at room temperature for 1 hr then quenched with water and diluted with EtOAc. With saturated brine solution and the organic layer was washed with NaHCO _3, dried using Na ₂ SO _4, and filtered. The solvent was removed in vacuo, and the crude product was purified by reverse phase HPLC (MeCN / H ₂ O gradient) to give a pale yellow solid of Example 42.

MS (ESI): 562 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.48 (br s, 1H), 9.97 (s, 1H), 8.82 (s, 1H), 7.93 (d, 2H), 7.56 (d, 2H), 7.46 (m, 1H), 7.19 (m, 1H), 6.61 (s, 1H), 6.36 (s, 1H), 3.92 (m, 2H), 3.31 (m, 2H), 2.94 (s, 3H), 2.62 (m, 2H), 2.10 (s, 3H), 1.31 (s, 9H).

Example 43 4-tert-butyl-N-{3-[6-(1-dimethylaminesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzamide

Example 43 was prepared analogously to Example 42 by using N,N-dimethylaminoamine sulfonyl chloride instead of methanesulfonyl chloride.

MS (ESI): 591 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.48 (br s, 1H), 9.97 (s, 1H), 8.82 (s, 1H), 7.93 (d, 2H), 7.56 (d, 2H), 7.46 (m, 1H), 7.20 (m, 1H), 6.59 (s, 1H), 6.34 (s, 1H), 3.93 (m, 2H), 3.40 (m, 2H), 2.76 (s, 6H), 2.57 (m, 2H), 2.09 (s, 3H), 1.31 (s, 9H).

Example 44 4-tert-butyl-N-{3-[6-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide

(1) 4-tert-butyl-N-{2-methyl-3-[6-(1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3 -d]pyrimidin-4-yl]-phenyl}-benzamide, intermediate 39

Intermediate 39 was prepared analogously to Intermediate 30 in Step 6 of Example 37 by using Intermediate 48 instead of Intermediate 28 in Step 5 of Example 37.

MS (ESI): 465 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.29 (br s, 1H), 9.92 (s, 1H), 8.78 (s, 1H), 7.94(d,2H), 7.53(d,2H), 7.45(m,1H), 7.37(m,2H), 6.60(br s,1H), 6.20(s,1H), 3.40(m,2H), 2.88 (m, 2H), 2.32 (m, 2H), 2.13 (s, 3H), 1.31 (s, 9H).

(2) 4-tert-butyl-N-{3-[6-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide

Methanesulfonium chloride (0.021 ml, 0.258 mmol) was added dropwise to a solution of intermediate 39 (80 mg, 0.172 mmol) and TEA (0.048 ml, 0.344 mmol). The resulting mixture was stirred at room temperature for 16 hr then quenched with water and EtOAc. The organic layer was dried over Na ₂ SO ₄ and filtered. The solvent was removed in vacuo, and purified by flash chromatography (silica gel, EtOAc / MeOH / NH ₃ gradient) to afford crude product was purified Example 44.

MS (ESI): 544 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.34 (br s, 1H), 9.92 (s, 1H), 8.81 (s, 1H), 7.94(d,2H), 7.54(d,2H), 7.46(m,1H), 7.37(m,2H), 6.60(br s,1H),6.31(s,1H),3.92(m,2H), 3.36 (m, 2H), 2.93 (s, 3H), 2.61 (m, 2H), 2.14 (s, 3H), 1.32 (s, 9H).

Example 45 4-{4-[3-(6-Tert-butyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]- 7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

(1) 2-(6-Tert-butyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-6-(4,4,5,5-tetraacetic acid) Methyl-[1,3,2]diboron -2-yl)-benzyl ester, intermediate 40

Similar to Intermediate 4 by using 2-bromo-6-(6-t-butyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl acetate Intermediate 40 was prepared instead of 1-bromo-5-fluoro-2-methyl-3-nitro-benzene (WO 2010/000633).

(2) 4-{4-[3-(6-Tert-butyl-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-benzene -7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Example 45 was prepared analogously to Intermediate 6 by using Intermediate 40 instead of Intermediate 5.

MS (ESI): 579 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 8.83 (s, 1H), 7.88 (m, 1H), 7.68 (m, 1H), 7.58 (m, 1H), 7.44 (m, 1H), 7.42 (m, 1H), 6.61 (s, 1H), 6.58 (s, 1H), 5.24 (m, 1H), 4.39 (m, 2H), 4.02 ( m,1H), 3.92 (m, 2H), 3.89 (m, 1H), 3.36 (m, 2H), 3.29 (m, 1H), 3.13 (m, 1H), 2.78 (s, 6H), 2.55 (m) , 2H), 1.33 (s, 9H).

Example 46 4-{4-[3-(6-Cyclopropyl-1-o-oxy-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-7H -pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

(1) 2-(6-cyclopropyl-1-indolyl-3,4-dihydro-1H-isoquinolin-2-yl)-6-(4,4,5,5-tetramethyl acetate Base-[1,3,2]diboron -2-yl)-benzyl ester, intermediate 41

Similar to intermediate 4 by using 2-bromo-6-(6-cyclopropyl-1-o-oxy-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl acetate Intermediate 41 (WO 2010/000633) was prepared by 1-bromo-5-fluoro-2-methyl-3-nitro-benzene.

(2) 4-{4-[3-(6-Cyclopropyl-1-o-oxy-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl ]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Example 46 was prepared analogously to Intermediate 6 by using Intermediate 41 instead of Intermediate 5.

MS (ESI): 563 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 8.81 (s, 1H), 7.80 (d, 1H), 7.66 (d, 1H), 7.56 (t, 1H), 7.50 (d, 1H), 7.09 (m, 1H), 7.08 (m, 1H), 6.60 (s, 1H), 6.54 (s, 1H), 5.15 (m, 1H), 4.36 ( m, 2H), 3.98 (m, 1H), 3.91 (m, 2H), 3.89 (m, 1H), 3.35 (m, 2H), 3.24 (m, 1H), 3.09 (m, 1H), 2.77 (s) , 6H), 2.55 (m, 2H), 2.00 (m, 1H), 1.04 (m, 2H), 0.78 (m, 2H).

Example 47 4-(4-{2-hydroxymethyl-3-[6-(1-hydroxy-1-methyl-ethyl)-1-yloxy-3,4-dihydro-1H-isoquinoline- 2-yl]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

(1) 2-Bromo-6-[6-(1-hydroxy-1-methyl-ethyl)-1-oxooxy-3,4-dihydro-1H-isoquinolin-2-yl]- Benzaldehyde, intermediate 42

2,6-Dibromo-benzaldehyde (1.60 g, 6.06 mmol), Pd ₂ (dba) ₃ (222 mg, 0.243 mmol), xantphos (210) in dioxane (60 ml) under argon Add 6-(1-hydroxy-1-methyl-ethyl)-3,4-dihydro-2H-isoquinoline to a mixture of mg, 0.364 mmol) and Cs ₂ CO ₃ (2.77 g, 8.49 mmol) 1-ketone (US 2009/0306041) (995 mg, 4.85 mmol). The resulting mixture was refluxed overnight. After cooling to room temperature, water was added and the mixture was extracted three times with EtOAc. The combined organic layers were dried, filtered and evaporated to dry. The crude product was purified by flash chromatography (EtOAc, EtOAc/EtOAc)

(2) 2-(3-Bromo-2-hydroxymethyl-phenyl)-6-(1-hydroxy-1-methyl-ethyl)-3,4-dihydro-2H-isoquinoline-1 -ketone, intermediate 43

To a solution of the intermediate 42 (320 mg, 0.824 mmol) from THF (10 ml), EtOAc (EtOAc, EtOAc. ). The resulting mixture was stir for 2 hr at room temperature, then add _saturated aqueous NaHCO (5 ml). Additional water was added and the mixture was extracted three times with EtOAc. The combined organic layers were dried, filtered and evaporated to dry. The crude product was purified by flash chromatography (EtOAc, EtOAc/EtOAc)

MS (ESI): 390 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 7.83 (d, 1H), 7.63 (d, 1H), 7.48 (m, 1H), 7.47 (s, 1H), 7.36 (m, 1H), 7.34 (m, 1H), 5.16 (s, 1H), 4.92 (m, 1H), 4.53 (m, 1H), 4.46 (m, 1H), 3.96 ( m, 1H), 3.77 (m, 1H), 3.25 (m, 1H), 3.07 (m, 1H), 1.45 (s, 6H).

(3) 2-bromo-6-[6-(1-hydroxy-1-methyl-ethyl)-1-oxooxy-3,4-dihydro-1H-isoquinolin-2-yl] -benzyl ester, intermediate 44

Add TEA (0.085 ml, 0.610 mmol), DMAP (7.5 mg, 0.061 mmol) and acetic anhydride (62 mg, 0.610 mmol) to a solution of intermediate 43 (238 mg, 0.610 mmol) in DCM (6 ml) ). The resulting mixture was stirred at room temperature for 24 hr. The solvent was removed in vacuo and the crude was purified by flash chromatography eluting eluting eluting

MS (ESI): 432 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 7.82 (d, 1H), 7.70 (m, 1H), 7.47 (m, 3H), 7.44 (m, 1H), 5.16 (s, 1H), 5.11 (m, 1H), 5.04 (m, 1H), 4.03 (m, 1H), 3.67 (m, 1H), 3.18 (m, 1H), 3.09 ( m, 1H), 1.97 (s, 3H), 1.45 (s, 6H).

(4) 2-[6-(1-Hydroxy-1-methyl-ethyl)-1-oxooxy-3,4-dihydro-1H-isoquinolin-2-yl)-6-( 4,4,5,5-tetramethyl-[1,3,2]diboron -2-yl]-benzyl ester, intermediate 45

Intermediate 45 was prepared analogously to Intermediate 4 by using Intermediate 44 instead of 1-bromo-5-fluoro-2-methyl-3-nitro-benzene.

MS (ESI): no ^{peak, 1 H-NMR (DMSO-} d 6): δ (ppm) 7.82 (d, 1H), 7.66 (m, 1H), 7.48-7.46 (m, 4H), 5.29 (d, 1H), 5.15 (s, 1H), 4.99 (d, 1H), 4.02 (m, 1H), 3.65 (m, 1H), 3.16 (m, 1H), 3.09 (m, 1H), 1.92 (s, 3H) ), 1.45 (s, 6H), 1.31 (s, 12H).

(5) 4-(4-{2-Hydroxymethyl-3-[6-(1-hydroxy-1-methyl-ethyl)-1-yloxy-3,4-dihydro-1H-iso Quinoline-2-yl]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Example 47 was prepared analogously to Intermediate 6 by using Intermediate 45 instead of Intermediate 5 followed by basic removal of the acetate protecting group using LiOH in MeOH/water.

MS (ESI): 581 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.47 (br s, 1H), 8.82 (s, 1H), 7.86 (d, 1H), 7.66(d,1H), 7.57(t,1H), 7.49(m,3H), 6.60(s,1H),6.55(s,1H),5.21(m,1H),5.16(s,1H),4.37 (m, 2H), 4.02 (m, 1H), 3.90 (m, 2H), 3.35-3.25 (m, 3H), 3.13 (m, 1H), 2.77 (s, 6H), 2.55 (m, 2H), 1.46 (s, 6H).

Example 48 4-tert-butyl-N-{3-[6-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrole [2,3-d]pyrimidin-4-yl]-2-hydroxymethyl-phenyl}-benzamide

Example 48 was prepared analogously to Intermediate 29 by using Intermediate 11 instead of Intermediate 1 and then using the TBAF in THF to remove the TBDPS protecting group.

MS (ESI): 483 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.44 (br s, 1H), 10.52 (s, 1H), 8.82 (s, 1H), 8.21(d,1H), 7.90(d,2H), 7.58(d,2H), 7.50(t,1H),7.35(d,1H), 6.64(br s,1H),6.42(s,1H), 5.91 (m, 1H), 4.68 (d, 2H), 4.28 (m, 2H), 3.81 (m, 2H), 2.46 (m, 2H), 1.32 (s, 9H).

Example 49 4-tert-butyl-N-{3-[6-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl] -5-fluoro-2-methyl-phenyl}-benzamide

Example 49 was prepared analogously to Intermediate 6 by using Intermediate 11 instead of Intermediate 3 and Intermediate 38 instead of Intermediate 5.

MS (ESI): 485 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.44 (br s, 1H), 9.97 (s, 1H), 8.82 (s, 1H), 7.94 (d, 2H), 7.57 (d, 2H), 7.50 (m, 1H), 7.20 (m, 1H), 6.64 (s, 1H), 6.32 (s, 1H), 4.28 (s, 2H), 3.80 (m, 2H), 2.47 (m, 2H), 2.11 (s, 3H), 1.32 (s, 9H).

Example 50 N-{3-[6-(3,6-Dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2- Methyl-phenyl}-4-dimethylamino-benzamide

(1) N-(3-Bromo-5-fluoro-2-methyl-phenyl)-4-dimethylamino-benzamide, intermediate 46

Intermediate 46 was prepared analogously to intermediate 34 by using 4-dimethylamino-benzhydrin chloride instead of intermediate 33.

MS (ESI): 353 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 9.77 (br s, 1H), 7.85 (d, 2H), 7.45 (d, 1H), 7.31 (d, 1H), 6.77 (d, 2H), 3.00 (s, 6H), 2.24 (s, 3H).

(2) 4-Dimethylamino-N-[5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl- [1,3,2]dioxaboron -2-yl)-phenyl]-benzamide, intermediate 47

Intermediate 47 was prepared analogously to Intermediate 4 by using Intermediate 46 instead of 1-bromo-5-fluoro-2-methyl-3-nitro-benzene.

(3) N-{3-[6-(3,6-Dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro -2-methyl-phenyl}-4-dimethylamino-benzamide

Example 50 was prepared analogously to Example 49 by using Intermediate 47 instead of Intermediate 38.

MS (ESI): 472 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.43 (br s, 1H), 9.64 (s, 1H), 8.82 (s, 1H), 7.88(d,2H), 7.46(d,1H), 7.15(d,1H), 6.78(d,2H), 6.64(s,1H),6.31(s,1H), 4.28(s,2H),3.80 (m, 2H), 3.00 (s, 6H), 2.47 (m, 2H), 2.10 (s, 3H).

Example 51 4-tert-butyl-N-{3-[6-(3,6-dihydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl] -2-methyl-phenyl}-benzamide

(1) 4-tert-butyl-N-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaboron -2-yl)-phenyl]-benzamide, intermediate 48

2-Methyl-3-(4,4,5,5-tetramethyl-[] in DCM (4 l) and triethylamine (330 ml, 2.38 mol) at 0 ° C for 25 min. 1,3,2]diboron To a solution of 2-yl)-phenylamine (370.0 g, 1.58 mol) was added dropwise dropwise to a mixture of 4-t-butyl benzamidine chloride (290 ml, 1.58 mol). The mixture was stirred at room temperature for 1 hour. The mixture was washed with water, saturated sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate and evaporated. The residue was taken up in heptane (1 l) and stirred at room temperature for 1 hour. The solid was filtered off and dried to afford intermediate 48 as a beige solid.

MS (ESI): 394 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 9.80 (s, 1H), 7.92 (d, 2H), 7.56 (d, 2H), 7.38 (m, 2H), 7.20 (m, 1H), 2.36 (s, 3H), 1.31 (s, 21 H).

(2) 4-tert-butyl-N-{3-[6-(3,6-dihydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-4 -yl]-2-methyl-phenyl}-benzamide

For Suzuki coupling between chloride intermediate 15 (0.25 g, 0.99 mmol) and boronate intermediate 48 (0.78 g, 1.98 mmol), the same protocol as described in Step 1 of Example 1 was used to provide Example 51 in the form of a beige solid.

MS (ESI): 483 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.33 (br s, 1H), 9.91 (s, 1H), 8.80 (s, 1H), 7.93 (d, 2H), 7.59 (m, 1H), 7.55 (d, 2H), 7.38 (m, 2H), 6.76 (m, 1H), 6.29 (s, 1H), 3.35 (m, 2H), 2.82 (m, 2H), 2.64 (m, 2H), 2.14 (s, 3H), 1.32 (s, 9H).

Example 52 4-tert-butyl-N-{2-methyl-3-[6-(3,6-dihydro-1-oxo-yl-2H-thiopyran-4-yl)-7H-pyrrolo[2 , 3-d]pyrimidin-4-yl]-phenyl}-benzamide.

The compound of Example 51 (240 mg, 0.50 mmol) was dissolved in ethyl acetate (5 ml) and hydrogen peroxide (0.051 ml, 0.50 mmol). The mixture was stirred at room temperature for 4 hours. The mixture was treated with 10% sodium hydrogen sulfite solution (10 ml) for 10 min, diluted with water, basified with 2N sodium hydroxide and extracted with EtOAc. The organic layer was washed with brine (2×), dried over sodium sulfate, filtered and evaporated. Silicon dioxide in the residue was purified by flash chromatography on (: 1: 0.1 EtOAc / MeOH / NH 4 OH to 8:: 2 EtOAc to _{9 0.2 EtOAc / MeOH / NH 4} OH 4) to provide a beige solid of Compound Example 52.

MS (ESI): 499 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.45 (br s, 1H), 9.95 (s, 1H), 8.84 (s, 1H), 7.96 (d, 2H), 7.57 (d, 2H), 7.52 (m, 1H), 7.41 (m, 2H), 6.49 (br s, 1H), 6.42 (s, 1H), 3.72 (m, 1H), 3.49 (m, 1H), 3.15 (m, 1H), 2.96 (m, 1H), 2.89 (m, 1H), 2.77 (m, 1H), 2.17 (s, 3H), 1.34 (s, 9H).

Example 53 4-tert-butyl-N-{3-[6-(3,6-dihydro-1,1-dioxainyl-2H-thiopyran-4-yl)-7H-pyrrolo[2,3 -d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide

The compound of Example 51 (250 mg, 0.51 mmol) was dissolved in DCM (5 ml), then trifluoroacetic acid (5 ml) and hydrogen peroxide (0.079 ml, 0.78 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was treated with 10% sodium hydrogen sulfite solution (10 ml) for 10 min, diluted with water, basified with 2N sodium hydroxide and extracted with EtOAc. The organic layer was washed with brine (2×), dried over sodium sulfate, filtered and evaporated. Silicon dioxide in the residue was purified by flash chromatography on (:: 2 EtOAc to _{98 0.2 EtOAc / MeOH / NH 4} OH) to afford a yellow solid compound of Example 53 meters.

MS (ESI): 515 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.47 (br s, 1H), 9.93 (s, 1H), 8.84 (s, 1H), 7.94 (d, 2H), 7.60 (m, 1H), 7.56 (d, 2H), 7.49 (m, 1H), 7.40 (m, 1H), 6.48 (m, 1H), 6.43 (s, 1H), 4.00 (m, 2H), 3.36 (m, 2H), 3.07 (m, 2H), 2.16 (s, 3H), 1.33 (s, 9H).

Example 54 4-tert-butyl-N-{3-[6-(1,4-dioxa-spiro[4.5]癸-7-ene-8-yl)-7H-pyrrolo[2,3-d] Pyrimidin-4-yl]-2-hydroxymethyl-phenyl}-benzamide

Example 54 was prepared analogously to Intermediate 29 by using Intermediate 17 instead of Intermediate 1 and then using the TBAF in THF to remove the TBDPS protecting group.

MS (ESI): 539 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.34 (br s, 1H), 10.51 (s, 1H), 8.80 (s, 1H), 8.21(d,1H), 7.90(d,2H), 7.59(d,2H), 7.49(t,1H),7.33(d,1H),6.48(m,1H),6.39(s,1H), 5.90 (m, 1H), 4.67 (m, 2 H), 3.91 (m, 4H), 2.57 (m, 2H), 2.42 (m, 2H), 1.79 (m, 2H), 1.32 (s, 9H).

Example 55 4-tert-butyl-N-{3-[6-(4-hydroxy-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-hydroxy Methyl-phenyl}-benzamide

(1) 4-tert-butyl-N-{2-hydroxymethyl-3-[6-(4-o-oxy-cyclohex-1-enyl)-7H-pyrrolo[2,3-d Pyrimidin-4-yl]-phenyl}-benzamide, intermediate 49

Intermediate 49 was prepared analogously to Intermediate 19 by using Example 54 instead of Example 27.

MS (ESI): 495 [M+H] ⁺

(2) 4-tert-butyl-N-{3-[6-(4-hydroxy-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- 2-hydroxymethyl-phenyl}-benzamide

Add ruthenium (III) chloride heptahydrate (66.3 mg, 0.178 mmol) and NaBH ₄ (6.1 mg, 0.162) to a solution of intermediate 49 (80 mg, 0.162 mmol) in MeOH/DCM (1:1). Mm). The resulting mixture was stirred at room temperature for 2 hr. Water was added and the mixture was extracted three times with DCM / isopropanol (3:1). The combined organic layers were dried, filtered and evaporated to dry. Using flash chromatography (silica gel, EtOAc / MeOH / NH ₃ gradient) to give the resulting residue was purified Example 55.

MS (ESI): 497 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.29 (br s, 1H), 10.51 (s, 1H), 8.79 (s, 1H), 8.19(d,1H), 7.90(d,2H), 7.59(d,2H), 7.49(t,1H),7.34(d,1H),6.49(m,1H),6.35(s,1H),5.89 (m, 1H), 4.72 (m, 1H), 4.67 (m, 2H), 3.80 (m, 1H), 2.65-2.35 (m, 3H), 2.11 (m, 1H), 1.84 (m, 1H), 1.59 (m, 1H), 1.33 (s, 9H).

Example 56 4-tert-butyl-N-{3-[6-(4-dimethylamino-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl] -2-hydroxymethyl-phenyl}-benzamide

To a solution of intermediate 49 (100 mg, 0.202 mmol) in DCM /MeOH /EtOAc (EtOAc) The mixture was stirred at room temperature for 15 min then sodium cyanoborohydride (12.7 mg, 0.202 mmol). The mixture was stirred at room temperature overnight and then quenched with 2N EtOAc (3 mL). After stirring for an additional 30 min, water and 2N NaOH were added. The mixture was extracted with EtOAc and EtOAc evaporated. Using flash chromatography (silica gel, EtOAc / MeOH / NH ₄ OH gradient) to obtain Example 56 to give the residue.

MS (ESI): 524 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.31 (br s, 1H), 10.51 (s, 1H), 8.79 (s, 1H), 8.19(m,1H), 7.90(d,2H), 7.59(d,2H), 7.49(t,1H),7.34(d,1H),6.57(m,1H),6.35(s,1H),5.89 (m, 1H), 4.66 (m, 2H), 2.60-2.15 (m, 5H), 2.27 (m, 3H), 1.99 (m, 1H), 1.48 (m, 1H), 1.31 (s, 9H).

Example 57 4-(4-{3-[(3-Tertioxy-azetidin-1-carbonyl)-amino]-5-fluoro-2-methyl-phenyl}-7H-pyrrole [2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Intermediate 6 (50 mg, 0.127 mmol), 4-nitrophenyl chloroformate (25.6 mg, 0.127 mmol), pyridine (12 mg, 0.152 mmol) and DMAP (1.5) in THF (2 ml) A mixture of mg, 0.013 mmol) was stirred at room temperature for 5 hr. Additional 4-nitrophenyl chloroformate (25.6 mg, 0.127 mmol) was then added and stirring was continued at room temperature for 72 hr. Pyridine (100 mg, 1.27 mmol) and 3-tert-butoxy-azetidine hydrochloride (US 2009/0105209) (105 mg, 0.634 mmol) were then added and the mixture was stirred for 1 hr. The mixture was diluted in EtOAc and aqueous NH ₄ OH (2 M) in. The organic layer was washed with brine, dried by Na ₂ SO _4, filtered, and evaporated to dryness. The crude product was purified by flash chromatography eluting EtOAc EtOAc

MS (ESI): 550 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.45 (br s, 1H), 8.80 (s, 1H), 7.97 (br s, 1H) , 7.44 (m, 1H), 7.00 (m, 1H), 6.57 (br s, 1H), 6.27 (s, 1H), 4.52 (m, 1H), 4.17 (m, 2H), 3.87 (m, 2H) , 3.75 (m, 2H), 3.30 (m, 2H), 2.74 (s, 6H), 2.49 (m, 2H), 2.03 (s, 3H), 1.13 (s, 9H).

Example 58 4-(4-{5-fluoro-3-[(3-isopropoxy-azetidin-1-carbonyl)-amino]-2-yl Phenyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Example 58 was prepared analogously to Example 57 by using 3-isopropoxy-azetidine hydrochloride instead of 3-t-butoxy-azetidine hydrochloride.

MS (ESI): 536 [M+H] ⁺ , ¹ H-NMR (CDCl ₃ ): δ (ppm) 12.24 (br s, 1H), 8.86 (s, 1H), 7.78 (m, 1H), 6.93 ( m,1H), 6.49 (m, 1H), 6.33 (s, 1H), 6.28 (m, 1H), 4.39 (m, 1H), 4.24 (m, 2H), 4.03 (m, 2H), 3.97 (m) , 2H), 3.62 (m, 1H), 3.47 (m, 2H), 2.86 (s, 6H), 2.62 (m, 2H), 2.11 (s, 3H), 1.16 (d, 6H).

Example 59 5-fluoro-1,3-dihydro-isoindole-2-carboxylic acid {3-[6-(1-dimethylaminocarbamimidyl-1,2,3,6-tetrahydro-pyridine-4- -7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-decylamine

Example 59 was prepared analogously to Example 57 by using 5-fluoro-2,3-dihydro-1H-isoindole instead of 3-t-butoxy-azetidine hydrochloride.

MS (ESI): 558 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.40 (br s, 1H), 8.81 (s, 1H), 7.96 (s, 1H), 7.56 (m, 1H), 7.41 (m, 1H), 7.26 (m, 1H), 7.14 (m, 1H), 7.04 (m, 1H), 6.58 (s, 1H), 5.30 (s, 1H), 4.78 (m, 4H), 3.89 (m, 2H), 3.34 (m, 2H), 2.76 (s, 6H), 2.52 (m, 2H), 2.11 (s, 3H).

Example 60 4-[4-(5-fluoro-2-methyl-3-{[3-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-azetidin-1 -carbonyl]-amino}-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Similar to Example 57, by replacing 3-3-butoxy-aza by using 3-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-azetidine hydrochloride. Example 60 (WO 2009/077334) was prepared by cyclobutane hydrochloride.

MS (ESI): 644 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.35 (br s, 1H), 8.76 (s, 1H), 8.10 (s, 1H), 7.39 (m, 1H), 7.00 (m, 1H), 6.54 (m, 1H), 6.23 (s, 1H), 5.63 (m, 1H), 4.75 (m, 1H), 4.25 (m, 2H), 3.87 (m, 2H), 3.85 (m, 2H), 3.82 (m, 2H), 2.72 (s, 6H), 2.46 (m, 2H), 2.01 (s, 3H).

Example 61 3-tert-butoxy-azetidin-1-carboxylic acid {3-[6-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-decylamine

Example 61 was prepared analogously to Example 57 by using Intermediate 12 instead of Intermediate 6.

MS (ESI): 480 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.40 (br s, 1H), 8.80 (s, 1H), 7.95 (s, 1H), 7.43 (m, 1H), 7.00 (m, 1H), 6.62 (br s, 1H), 6.26 (s, 1H), 4.52 (m, 1H), 4.27 (m, 2H), 4.18 (m, 2H), 3.79 (m, 2H), 3.75 (m, 2H), 2.44 (m, 2H), 2.04 (s, 3H), 1.13 (s, 9H).

Example 62 4-(4-{3-[(3-Tertioxy-azetidin-1-carbonyl)-amino]-4-fluoro-phenyl}-7H-pyrrolo[2,3- d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Example 62 was prepared analogously to Example 57 by using Intermediate 10 instead of Intermediate 6.

MS (ESI): 536 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.36 (br s, 1H), 8.77 (s, 1H), 8.49 (m, 1H), 8.33 (s, 1H), 7.90 (m, 1H), 7.39 (m, 1H), 6.88 (s, 1H), 6.59 (s, 1H), 4.53 (m, 1H), 4.21 (m, 2H), 3.91 (m, 2H), 3.78 (m, 2H), 3.37 (m, 2H), 2.77 (s, 6H), 2.60 (m, 2H), 1.14 (s, 9H).

Example 63 4-(4-{3-[(3-Tertioxy-azetidin-1-carbonyl)-amino]-4-fluoro-2-methyl-phenyl}-7H-pyrrole [2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

(1) 4-[4-(3-Amino-4-fluoro-2-methyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-di Hydrogen-2H-pyridine-1-carboxylic acid dimethyl decylamine, intermediate 50

Similar to intermediate 6 by using 5-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboron Intermediate 10 was prepared in place of Intermediate 5 by -2-yl) phenylamine.

MS (ESI): 395 [M ] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.28 (br s, 1H), 8.75 (s, 1H), 7.03 (m, 1H), 6.68 ( m, 1H), 6.54 (s, 1H), 6.25 (s, 1H), 5.00 (br s, 2H), 3.88 (s, 2H), 3.32 (m, 2H), 2.75 (s, 6H), 2.50 ( m, 2H), 2.03 (s, 3H).

(2) 4-(4-{3-[(3-Tertioxy-azetidin-1-carbonyl)-amino]-4-fluoro-2-methyl-phenyl}-7H -pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine

Example 62 was prepared analogously to Example 57 by using Intermediate 50 instead of Intermediate 6.

MS (ESI): 550 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.36 (br s, 1H), 8.79 (s, 1H), 8.04 (m, 1H), 7.37 (m, 1H), 7.21 (m, 1H), 6.57 (m, 1H), 6.25 (s, 1H), 4.54 (m, 1H), 4.14 (m, 2H), 3.89 (m, 2H), 3.70 (m, 2H), 3.32 (m, 2H), 2.75 (s, 6H), 2.50 (m, 2H), 2.13 (s, 3H), 1.14 (s, 9H).

Example 64 4-tert-butyl-N-{3-[6-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl] -2-methyl-phenyl}-benzamide

(1) 4-tert-butyl-N-[2-methyl-3-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-phenyl]-benzamide, intermediate 51

Intermediate 51 was prepared analogously to Intermediate 6 by substituting 6-chloro-7-deazaindole for Intermediate 3 and Intermediate 48 for Intermediate.

MS (ESI): 385 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.22 (br s, 1H), 9.94 (s, 1H), 8.82 (s, 1H), 7.94 (d, 2H), 7.60 (m, 1H), 7.58 (d, 2H), 7.37 (m, 1H), 6.30 (m, 1H), 2.12 (s, 3H), 1.31 (s, 9H).

(2) N-[3-(7-Benzenesulfonyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methyl-phenyl]-4-t-butyl- Benzamide, intermediate 52

NaH (1.172 g, 29.3 mmol) was added portionwise to a solution of intermediate 51 (7.51 g, 19.54 mmol) in THF (500 ml). The mixture was stirred at 0 <0>C for 3 hr then benzene sulfonium chloride (3.70 ml, 25.4 mmol) was added and stirring was continued at room temperature overnight. Using saturated NH ₄ Cl solution and the reaction mixture was quenched and extracted with EtOAc. The organic layer was dried, filtered and evaporated to dry. Purification by flash chromatography (silica gel, hexane/EtOAc gradient) afforded Intermediate 52.

MS (ESI): 525 [M+H] ⁺ , ¹ H-NMR (DMSO-d ₆ ): δ (ppm) 9.97 (s, 1H), 9.10 (s, 1H), 8.21. (d, 2H), 8. (d, 1H), 7.92 (d, 2H), 7.78 (t, 1H), 7.69 (t, 2H), 7.60 (m, 1H), 7.53 (d, 2H), 7.51 (d, 1H), 7.37 ( t, 1H), 7.32 (d, 1H), 6.62 (d, 1H), 2.12 (s, 3H), 1.31 (s, 9H).

(3) N-[3-(7-Benzenesulfonyl-6-bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methyl-phenyl]-4- Tributyl-benzamide, intermediate 53

LDA (1.5 M in THF, 16.24 ml, 24.36 mmol) was slowly added to a solution of intermediate 52 (4.26 g, 8.12 mmol) in THF (150 ml). The resulting mixture was stirred at -78 <0>C for 1.5 hr then a solution of <RTI ID=0.0>> Continue to stir for 2 hr at -78 ℃, then by addition of saturated NH ₄ Cl solution and the reaction mixture was warmed to room temperature and quenched. The mixture was extracted with EtOAc and EtOAc evaporated. Purification by flash chromatography (silica gel, hexane/EtOAc gradient) afforded Intermediate 53.

MS (ESI): 603 [M+H] ⁺

(4) N-[3-(6-Bromo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-2-methyl-phenyl]-4-t-butyl-benzamide Amine, intermediate 54

To a solution of intermediate 53 (3.82 g, 6.33 mmol) in EtOAc (EtOAc (EtOAc) . The mixture was stirred at 0 &lt;0&gt;C for 1 hr then an additional solution of potassium succinate in THF (1 M, 2.00 <RTIgt; By the addition of saturated aqueous NaHCO ₃ to terminate the reaction, and the mixture was extracted with EtOAc. The organic layer was dried, filtered and evaporated to dry. Purification by flash chromatography (silica gel, hexane/EtOAc gradient) afforded Intermediate 54.

MS (ESI): 463 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 13.10 (br s, 1H), 9.97 (s, 1H), 8.82 (s, 1H), 7.93(d,2H), 7.54(d,1H), 7.48(d,1H), 7.40-7.32(m,2H),6.41(s,1H),2.12(s,3H),1.31(s,9H) .

(5) 4-tert-butyl-N-{3-[6-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidine-4 -yl]-2-methyl-phenyl}-benzamide

Example 64 was prepared analogously to Intermediate 11 by using Intermediate 54 instead of 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine.

MS (ESI): 467 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.33 (br s, 1H), 9.93 (s, 1H), 8.82 (s, 1H), 7.94(d,2H), 7.54(d,2H), 7.48(m,1H), 7.37(m,2H), 6.63(br s,1H), 6.25(s,1H), 4.36(m,2H), 3.81 (m, 2H), 2.46 (m, 2H), 2.16 (s, 3H), 1.33 (s, 9H).

Example 65 4-tert-butyl-N-{3-[6-(1,4-dioxa-spiro[4.5]癸-7-ene-8-yl)-7H-pyrrolo[2,3-d] Pyrimidin-4-yl]-2-methyl-phenyl}-benzamide

Example 65 was prepared analogously to Intermediate 17 by using Intermediate 54 instead of 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine.

MS (ESI): 523 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.28 (br s, 1H), 9.91 (s, 1H), 8.78 (s, 1H), 7.94 (d, 2H), 7.54 (d, 2H), 7.49 (m, 1H), 7.37 (m, 2H), 6.46 (br s, 1H), 6.23 (s, 1H), 3.90 (s, 4H), 2.55 (m, 2H), 2.41 (m, 2H), 2.14 (s, 3H), 1.79 (m, 2H), 1.31 (s, 9H).

Example 66 4-tert-butyl-N-{3-[6-(4-hydroxy-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-yl Phenyl-phenyl}-benzamide

(1) 4-tert-butyl-N-{2-methyl-3-[6-(4-o-oxy-cyclohex-1-enyl)-7H-pyrrolo[2,3-d] Pyrimidin-4-yl]-phenyl}-benzamide, intermediate 55

Intermediate 55 was prepared analogously to Intermediate 19 by using Example 65 instead of Example 27.

MS (ESI): 479 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.35 (br s, 1H), 9.92 (s, 1H), 8.78 (s, 1H), 7.94 (d, 2H), 7.53 (d, 2H), 7.49 (m, 1H), 7.36 (m, 2H), 6.64 (br s, 1H), 6.35 (s, 1H), 3.15 (m, 2H), 2.83 (m, 2H), 2.52 (m, 2H), 2.13 (s, 3H), 1.31 (s, 9H).

(2) 4-tert-butyl-N-{3-[6-(4-hydroxy-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]- 2-methyl-phenyl}-benzamide

Example 66 was prepared analogously to Step 2 of Example 28 by using Intermediate 55 instead of Intermediate 19.

MS (E SI): 481 [M+H] ⁺ , ¹ H-NMR (DMSO-d ₆ ): δ (ppm) 12.21 (br s, 1H), 9.93 (s, 1H), 8.77 (s, 1H) , 7.94 (d, 2H), 7.53 (d, 2H), 7.43 (m, 1H), 7.37 (m, 2H), 6.47 (br s, 1H), 6.18 (s, 1H), 4.75 (s, 1H) , 3.76 (m, 1H), 2.44 (m, 2H), 2.35 (m, 2H), 2.14 (s, 3H), 1.83 (m, 2H), 1.31 (s, 9H).

Example 67 4-tert-butyl-N-{3-[6-(4-dimethylamino-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl] -2-methyl-phenyl}-benzamide

Example 67 was prepared analogously to Example 56 by using Intermediate 55 instead of Intermediate 49.

MS (ESI): 508 [M + H] +, 1 H-NMR (DMSO-d 6): δ (ppm) 12.23 (br s, 1H), 9.94 (s, 1H), 8.78 (s, 1H), 7.94 (d, 2H), 7.53 (d, 2H), 7.48 (m, 1H), 7.35 (m, 2H), 6.53 (br s, 1H), 6.21 (s, 1H), 2.61 (m, 2H), 2.51 (m, 1H), 2.42 (m, 1H), 2.40 br s, 6H), 2.24 (m, 1H), 2.16 (s, 3H), 2.05 (m, 1H), 1.56 (m, 1H), 1.28 (s, 9H).

Biological part Inhibition of Btk enzyme activity

The inhibitory activity of the compounds of the invention against Btk was evaluated in a biochemical enzyme assay. An 8-point serial dilution of the test compound was used on a Thermo CatX workstation equipped with Innovadyne Nanodrop Express to prepare an assay plate in a 384-well format. An assay plate was prepared by adding 50 nl/well of a solution of the compound in 90% DMSO. The kinase reaction was initiated by gradually adding the following: 4.5 μl/well in kinase buffer (50 mM HEPES (pH 7.5), 1 mM DTT, 0.02% Tween 20, 0.02% BSA, 0.6% DMSO, 10 mM β-glycerophosphate Peptide/ATP solution (4 μM FITC-Ahx-TSELKKVVALYDYMPMNAND-NH2, 164 μM ATP) in ester and 10 μM sodium orthovanadate, 18 mM MgCl ₂ , 1 mM MnCl ₂ ) and 4.5 μl/well in kinase buffer Enzyme solution in solution (6.4 nM full length human recombinant BTK). The kinase reaction was incubated at 30 ° C for 60 minutes and then by adding 16 μl/well of stop solution (100 mM HEPES (pH 7.5), 5% DMSO, 0.1% Caliper coating reagent, 10 mM EDTA and 0.015% Brij35). ) to terminate it. Kinase activity was calculated by isolating phosphorylated and unphosphorylated peptides at the Caliper LC3000 workstation and calculating the kinase activity from the amount of newly formed phosphopeptides. Inhibition data was calculated by comparison to a control reaction without enzyme (100% inhibition) and no inhibitor (0% inhibition). The inhibitor concentration (IC50) required for 50% inhibition was calculated from the inhibition of the inhibitor concentration.

Inhibition of cell Btk activity

Alternatively, the ability of the compounds of the invention to inhibit Btk-dependent FcG receptor-induced IL-8 secretion in human cells can also be assessed. Human bone marrow The leukemia-like THP1 cell line (ATCC TIB202) was grown in RPMI 1640 medium supplemented with 10% FCS and 15 nM 1,25-dihydroxyvitamin D3 for 4 days and then used to induce bone marrow-like differentiation. A sufficient number of tissue-culture grade 384-well plates were coated with human IgG of unknown specificity by incubation with 40 μl/well of 50 μg/ml IgG solution in PBS overnight at 4 °C. On the day of the experiment, the plates were washed 5 times on a Molecular Devices Aquamax DW4 plate washer using 80 μl of water. The test compound solution in 90% DMSO was added to each well on a Hamilton Microlab Star Liquid Disposal Station until 40 μl/well of tissue culture medium was obtained and the total DMSO concentration was adjusted to 0.1%. The differentiated THP1 cells were then added at 40 μl/well to reach a final density of 5'000 cells/well in 80 μl of medium. After 24 hours, IL-8 secretion was measured in the supernatant by IL-8 HTRF analysis following the protocol of the supplier (CisBio international). Inhibition data was calculated by comparison to a control broth without IgG stimulating enzyme (100% inhibition) and no inhibitor (0% inhibition). The inhibitor concentration (IC50) required for 50% inhibition was calculated from the inhibition of the inhibitor concentration.

Inhibition of Btk activity in blood

Alternatively, the inhibitory activity of the compounds of the invention in the blood is evaluated in the following in vitro B cell activity assay. Whole blood was collected from the abdominal aorta of anesthetized adult male Lewis rats and anticoagulated with 100 U/ml heparin sodium. Then supplemented with 100 U/ml penicillin (penicillin), 100 mg/ml streptomycin, 2 mM L-glutamine, 50 mg/ml dextran 40 and 5% FCS (Fetaclone I, Gibco) High glucose DMEM (Amimed) diluted the blood to 50%. Then, 190 μl of pre-diluted blood was mixed with 10 μl of serial dilutions of the test compound in DMSO in a 96-well U-bottom microtiter plate (Nunc). The culture was incubated at 37 ° C, 5% CO ₂ for 1 hour, then 30 μl of rat IL-4 (Beckton-Dickinson, final concentration 5 ng/ml) and goat anti-rat IgM (Serotec, final concentration) 15 ug/ml), and the culture was incubated for 24 hours. After staining the B cell subset with PE-Cy5-labeled anti-rat CD45RA (Beckton-Dickinson) and staining the active marker CD86 (PE-labeled anti-rat CD86 (Beckton-Dickinson)), by flow Cytometry to measure B cell activation. All staining procedures were performed in 96 deep well V-bottom microtiter plates (Corning) with BD lysis solution (Beckton-Dickinson) at room temperature for 30 min. Cell count data was acquired on a FACScalibur flow cytometer (BD Biosciences) and lymphocyte subsets were strobed according to size and size and the performance of CD45RA and active markers was further analyzed. Data on inhibition of B cell activity were calculated from the percentage of cells positively stained for active markers in the CD45RA positive population. Inhibition data was calculated by comparison to control cultures without anti-IgM and IL-4 (100% inhibition) and no inhibitor (0% inhibition). The inhibitor concentration (IC50) required for 50% inhibition was calculated from the inhibition of the inhibitor concentration.

application

The compounds of the invention are generally useful for treating an indication selected from the group consisting of autoimmune disorders, inflammatory diseases, allergic diseases, respiratory diseases (eg, asthma and chronic obstructive pulmonary disease (COPD)), based on, for example, biological test results. Graft rejection; diseases with abnormal or undesired antibody production, antigen presentation, cytokine production, or lymphoid organogenesis, including rheumatoid arthritis, systemic juvenile idiopathic arthritis (SOJIA), gout, blisters Sore, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjogren's syndrome, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, cold Globulinemia, embolic platelet hypoglycemia, chronic autoimmune urticaria, allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel Disease, ulcerative colitis, Crohn's disease, pancreatitis, glomerulonephritis, Goodpasch's syndrome, Hashimoto's thyroiditis, Leifu Si's disease, antibody-mediated graft rejection (the AMR), graft versus host disease, hyperacute mediated B cell acute And chronic graft rejection; thromboembolic disorders, myocardial infarction, angina pectoris, stroke, ischemic condition, pulmonary embolism; hematopoietic origin cancer, including but not limited to multiple myeloma; leukemia; acute myeloid leukemia; chronic myelos Leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin's lymphoma; lymphoma; polycythemia vera; essential thrombocytosis; myeloid metaplasia with myelofibrosis; Trojan disease.

In another embodiment, the selected therapy can treat the disease by an antagonist of Bruton's tyrosine kinase.

In another embodiment, the invention provides a method of treating a condition for treatment by modulation of Btk comprising administering a therapeutically acceptable amount of a compound of formula (I) or a salt thereof. In another embodiment, the disease is selected from the above list.

combination

The compounds of the invention may be administered simultaneously with or before or after administration of one or more additional therapeutic agents. The compounds of the invention may be administered separately or together with the other pharmaceutical agents by the same or different administration routes.

The compounds of formula (I) may be administered as the sole active ingredient or together with (eg, as an adjuvant) other drugs, for example, immunosuppressive or immunomodulatory agents or other anti-inflammatory agents (eg, for Treating or preventing allograft or xenograft acute or chronic rejection or inflammatory or autoimmune disorders) or chemotherapeutic agents (eg, malignant cell antiproliferative agents). For example, a compound of formula (I) can be used in combination with a calcineurin inhibitor, such as cyclosporin A or FK 506; an mTOR inhibitor, such as rapamycin, 40- O-(2-hydroxyethyl)-rapamycin, CCI779, ABT578, AP23573, AP23464, AP23675, AP23841, TAFA-93, biolimus-7 or biolimus-9; ascomycin with immunosuppressive properties ( Ascomycin), such as ABT-281, ASM981, etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; leflunomide; mizoribine ); mycophenolic acid or salt; mycophenolate mofetil; 15-deoxyspirin or an immunorepressor homologue, analog or derivative thereof; PKC inhibitors, such as those disclosed in WO 02/38561 or WO 03/82859, such as the compounds of Examples 56 or 70; JAK3 kinase inhibitors, such as N-benzyl-3,4-dihydroxy-benzylidene-cyanide Ethyl acetamide α-cyano-(3,4-dihydroxy)-N-benzylcinnamoylamine (tyrhostin AG 490), lycopene 25-C (prodigiosin 25) -C)(PNU156804), [4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] (WHI-P131), [4-(3'-bromo-4) '-Hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] (WHI-P154), [4-(3',5'-Dibromo-4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] WHI-P97, KRX-211, 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-hexahydropyridin-1-yl}-3-side oxygen a base-propionitrile (in free form or in a pharmaceutically acceptable salt form, such as monocitrate (also known as CP-690, 550)) or a compound as disclosed in WO 04/052359 or WO 05/066156; Alcohol-1-phosphate receptor modulators, such as FTY720 (fingolimod) or compounds disclosed in WO 2005/000833; immunosuppressive monoclonal antibodies, such as white blood cell receptors (eg, Monoclonal antibodies such as MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86 or its ligands; other immunomodulatory compounds, for example having at least a portion of CTLA4 Recombinant binding of an extracellular domain or a mutant thereof (eg, at least an extracellular portion of CTLA4 or a mutant thereof linked to a non-CTLA4 protein sequence, such as CTLA4Ig (eg, referred to as ATCC 68629) or a mutant thereof (eg, LEA29Y)) Molecules; adhesion molecule inhibitors such as LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists; or chemotherapeutic agents such as paclitaxel, gemcitabine , cisplatinum, doxorubicin or 5-fluorouracil; or an anti-infective agent. Other combination partners of the compounds of formula (I) may be selected from PI3K inhibitors (eg, pan- or alpha, beta, gamma, delta selective inhibitors), TNF inhibitors, IL1 beta inhibitors, IL17 inhibitors, and IL6 or IL receptors. Inhibitor.

As used herein, the terms "co-administered" or "combined administration" or the like are meant to encompass the administration of a selected therapeutic agent to a single patient and are intended to encompass a therapeutic regimen that does not require administration of the agent at the same time or at the same time.

The term "pharmaceutical combination" as used herein means a product obtained by mixing or combining more than one active ingredient, and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that the active ingredient (e.g., a compound of formula (I)) is administered to a patient simultaneously with the auxiliary agent in a single entity or dosage form. The term "non-fixed combination" means that the active ingredient (eg, a compound of formula (I)) and the accessory agent are formed into separate entities simultaneously, in parallel or sequentially, and without specific time constraints, to the patient, wherein the administration can be The therapeutically effective concentration of the two compounds is provided in the patient. The latter also applies to cocktail therapy, for example by administering 3 or more active ingredients.

In one embodiment, the invention provides a product comprising a compound of formula (I) and at least one additional therapeutic agent, for use as a combined preparation for simultaneous, separate or sequential use in therapy. In one embodiment, the therapy treats a disease or condition mediated by Btk kinase. The product provided in the form of a combined preparation comprises a composition comprising a compound of formula (I) and other therapeutic agents in the same pharmaceutical composition, or comprising a compound of formula (I) in a separate form (for example in the form of a kit) and others Therapeutic agent.

In one embodiment, the invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic agent. Optionally, the pharmaceutical composition can include a pharmaceutically acceptable excipient as set forth above.

In one embodiment, the invention provides a kit comprising two or more separate pharmaceutical compositions, wherein at least one pharmaceutical composition comprises a compound of formula (I). In one embodiment, the kit includes means for independently accommodating the compositions, such as a container, a split bottle or a split foil package. An example of such a set is a blister package, as is commonly used for encapsulating tablets, capsules, and the like.

The kits of the present invention can be used to administer different dosage forms (e.g., oral and parenteral dosage forms), to administer separate compositions at different dosage intervals, or to adjust dosages relative to one another from separate compositions. To aid compliance, the kits of the present invention typically include instructions for administration.

In the combination therapies of the invention, the compounds of the invention may be made and/or formulated with other therapeutic agents by the same or different manufacturers. In addition, the invention can be The compound is brought into combination therapy with other therapeutic agents: (i) prior to the delivery of the combination product by the physician (eg, in the case of a kit comprising the compound of the invention and other therapeutic agents); (ii) prior to the administration of the combination By the physician himself (or under the guidance of a physician); (iii) by the patient himself, for example, during the sequential administration of the compounds of the invention and other therapeutic agents.

Accordingly, the invention provides the use of a compound of formula (I) for the treatment of a disease or condition mediated by Btk kinase, wherein an agent administered with another therapeutic agent is prepared. The invention also provides the use of another therapeutic agent for the treatment of a disease or condition mediated by Btk, wherein the agent is administered with a compound of formula (I).

The invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by Btk, wherein a compound of formula (I) is prepared for administration with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by Btk, wherein the additional therapeutic agent is prepared for administration with a compound of formula (I). The invention also provides a compound of formula (I) for use in a method of treating a disease or condition mediated by Btk, wherein a compound of formula (I) is administered with another therapeutic agent. The invention also provides another therapeutic agent for use in a method of treating a disease or condition mediated by Btk, wherein the additional therapeutic agent is administered with a compound of formula (I).

Claims (17)

a compound of formula (I) or a pharmaceutically acceptable salt thereof, Wherein R1 is hydrogen, C ₁ -C ₆ alkyl optionally substituted by hydroxy; R 2 is hydrogen or halogen; R 3 is hydrogen or halogen; R 4 is hydrogen; and R 5 is optionally substituted by the following group: halogen ; SF ₅ ; NR ₆ R ₇ ; hydroxy; C ₁ -C ₆ alkoxy; C ₁ -C ₆ alkenyl; C ₁ -C ₆ alkylcarbonyl; optionally substituted by hydroxy, halogen or C ₁ -C ₆ alkoxy a C ₁ -C ₆ alkyl group; or a C ₃ -C ₆ cycloalkyl group optionally substituted by a halogen, a hydroxyl group or a halogen-substituted C ₁ -C ₆ alkyl group; or the R ₅ group includes 1, 2 or 3 a 4 to 14 membered monocyclic or bicyclic heterocyclic or heteroaryl ring system selected from the group consisting of heteroatoms of N, S and O, which are optionally substituted by the following groups: halogen; hydroxy; optionally substituted by hydroxy or halogen the C ₁ -C ₆ alkoxy; or optionally substituted by hydroxyl or halogen of C ₁ -C ₆ alkyl; optionally forming rings comprising hexahydro-phenyl or together form a ring of R4 and R5 combined with the atoms which they are a pyridone ring, any of which may be optionally substituted by a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or a C ₃ -C ₆ cycloalkyl group, and each substituted member may be optionally substituted with a halogen or a hydroxyl group; and R7 are independently selected hydrogen or C ₁ -C ₆ Formation or R6 and R7 with the nitrogen atom to which they are bound together with 4-8 saturated azacycloalkane ring optionally substituted with the halogen, hydroxy or C ₁ -C ₆ alkyl;; X-based group O, S (O) _n (where n is 0, 1, or 2) or (where q is 2 or 3) and R10 is absent; or X is CH or N; and R10 is hydrogen, hydroxy, -NR6R7, -CO-R11, -S(O) _p- R12, wherein p is 1 or 2, R11-based substituent of optionally hydroxy, cyano, halogen, carboxy or C ₁ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl group; or NR6R7; R12 and line C ₁ -C ₆ alkyl Or NR6R7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 is hydrogen; and R5 is benzene substituted by the following group group: halogen; C ₁ -C ₆ alkoxy; optionally substituted with halogen or hydroxy or C ₁ -C ₆ alkyl group; or optionally substituted with the halogen, optionally halogen or hydroxy C ₁ -C ₆ alkyl Substituted C ₃ -C ₆ cycloalkyl; X-form O, S(O) _n (where n is 0, 1 or 2) or (where q is 2 or 3), and R10 does not exist; and the remaining variables are as defined in claim 1. A compound according to claim 1 or 2, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, and R4 together with R5 is 3,4-dihydrogen. -2H-isoquinolin-1-one, which is optionally substituted by a hydroxy-substituted C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl group; X-form O, S(O) _n (wherein n is 0, 1 or 2) or (where q is 2 or 3) and R10 does not exist; and the remaining variables are as defined in claim 1. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 is hydrogen, and R5 is benzene substituted by the following group group: halogen; C ₁ -C ₆ alkoxy; optionally substituted with halogen or hydroxy or C ₁ -C ₆ alkyl group; or optionally substituted with the halogen, optionally halogen or hydroxy C ₁ -C ₆ alkyl Substituted C ₃ -C ₆ cycloalkyl; X represents O and R 10 is absent; or X represents N, and R 10 is hydrogen or -CO-R 11 , and the remaining variables are as defined in claim 1. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, R4 is hydrogen; and R5 is benzene substituted by the following group group: C ₁ -C ₆ alkoxy; optionally substituted with halogen or hydroxy or C ₁ -C ₆ alkyl group; unsubstituted or optionally substituted with halogen or the C ₁ -C ₆ alkyl halogen, hydroxy or optionally C ₃ -C ₆ cycloalkyl; X represents N, R 10 is hydrogen or -CO-R 11 ; R 11 represents NR ₆ R 7 , wherein R 6 and R 7 are independently hydrogen or methyl; and the remaining variables are as claimed in claim 1 definition. The acceptable compound of a requested item or a pharmaceutically salt thereof, wherein R1-based hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or a fluorine-based, R4-based hydrogen, R5 system optionally substituted with C ₁ -C ₆ alkoxy-substituted azetidine, X represents N, and R10 is hydrogen or -CO-R11, and the remaining variables are as defined in claim 1. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, and R4 together with R5 is 3,4-dihydro-2H - isoquinolin-1-one, which is optionally substituted with a hydroxyl group of the optionally substituted C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl; X represents N, and R10 -CO-R11 or hydrogen-based And the remaining variables are as defined in claim 1. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, and R4 together with R5 is 3,4-dihydro-2H -isoquinolin-1-one substituted at the 6-position of the isoquinoline ring by a hydroxy substituted C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl group; X represents N, and R10 is hydrogen or -CO-R11, and the remaining variables are as defined in claim 1. The acceptable compound of a requested item or a pharmaceutically salt thereof, wherein R1-based hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or a fluorine-based, R4-based hydrogen, R5 system optionally substituted with C ₁ -C ₆ alkoxy substituted azetidine, X represents O, and the remaining variables are as defined in claim 1. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, methyl or hydroxymethyl, R2 and R3 are independently hydrogen or fluoro, and R4 together with R5 is 3,4-dihydro-2H -isoquinolin-1-one, which is optionally substituted by a hydroxy-substituted C ₃ -C ₆ cycloalkyl or C ₁ -C ₆ alkyl group as appropriate; X represents O, and the remaining variables are as claimed As defined in 1. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 4-(4-{5-fluoro-3-[4-(1-fluoro-cyclopropyl)-benzimidamide 2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1- Dimethylguanamine carboxylic acid, 4-(4-{3-[(3,3-dimethyl-2,3-dihydro-benzofuran-6-carbonyl)-amino]-5-fluoro-2 -methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-(4 -{5-fluoro-2-methyl-3-[(5-methyl-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carbonyl)-amino]-phenyl} -7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-(4-{5-fluoro-3 -[4-isopropyl-methyl-amino)-benzylidenylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)- 3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 3-methyl-1H-indole-6-carboxylic acid {3-[6-(1-dimethylmethylcarbamyl)- 1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-indole Amine, 4-(4-{5-fluoro-3-[4-(2-hydroxy-1,1-dimethyl-ethyl)-benzoylamino]-2-methyl-phenyl} -7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-{4-[5-fluoro-2 -methyl-3-(4-hexahydropyridin-1-yl-benzhydrylamino)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6 -Dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-{4-[ 5-fluoro-3-(isopropenyl-benzylidenylamino)-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6- Dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-(4-{5-fluoro-2-methyl-3-[4-(1-trifluoromethyl-cyclopropyl)-benzene Mercaptoamino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro- 2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-{4-[5-fluoro-3-(4-isopropoxy-benzoylamino)-2-methyl-phenyl]- 7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-(4-{5-fluoro-3- [4-pentafluorothio-benzylidenylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro- 2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-(4-{5-fluoro-3-[4-(2-methoxy-1,1-dimethyl-ethyl)-benzamide Aminoamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylhydrazine Amine, 4-(4-{5-fluoro-3-[4-(1-methoxy-1-methyl-ethyl)-benzoylamino]-2-methyl-phenyl}- 7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 1-methyl-1H-pyrrolo[2, 3-b]pyridine-6-carboxylic acid {3-[6-(1-dimethyl-aminomethylamino-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-decylamine, 4-{4-[3-(4-dimethylamino-benzamide) Amino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid Methyl decylamine, 4-(4-{3-[2-fluoro-4-() 1-hydroxy-1-methyl-ethyl)-benzylidenylamino]-2-hydroxymethyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3 ,6-Dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-{4-[3-(4-cyclopropyl-benzoguanidino)-2-hydroxymethyl-phenyl ]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid Baseline amine, 4-(4-{5-fluoro-2-methyl-3-[4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-benzamide Amino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-{ 4-[3-(4-Ethyl-benzhydrylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl} -3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-{4-[3-(4-cyclopropyl-benzoguanidino)-4-fluoro-phenyl ]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-(4-{4-fluoro- 3-[4-(2-Hydroxy-1,1-dimethyl-ethyl)-benzylidenylamino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl -3,6-Dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, N-{3-[6-(3,6-dihydro-2H-pyran-4-yl)-7H- Pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzene Formamide, N-{3-[6-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- Hydroxymethyl-phenyl}-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzamide, 4-tert-butyl-N-{3-[6-(3 ,6-Dihydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2- Base-phenyl}-benzamide, 4-tert-butyl-N-{5-fluoro-2-methyl-3-[6-(3,6-dihydro-1-oxo-yl-2H -thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-phenyl}-benzamide, 4-tert-butyl-N-{3-[6-(3,6-dihydro-1,1-dioxainyl-2H-thiopyran-4-yl)-7H-pyrrolo[2,3 -d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzamide, 4-tert-butyl-N-{3-[6-(1,4-dioxo) Hetero-spiro[4.5]dec-7-en-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzene Indoleamine, 4-tert-butyl-N-{5-fluoro-3-[6-(4-hydroxy-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidine-4 -yl]-2-methyl-phenyl}-benzamide, 4-{4-[3-(4-cyclopropyl-benzylidenyl)-5-fluoro-2-methyl- Phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-cyclopropyl-N- (5-fluoro-2-methyl-3-{6-[1-(pyrrolidin-1-carbonyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl}-phenyl)-benzamide, 2-(4-{4-[3-(4-cyclopropyl-benzoguanidino)-5 -fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridin-1-yl)-2-oxo Base-ethyl ester, 4-cyclopropyl-N-(5-fluoro-3-{6-[1-(2-hydroxy-ethenyl)-1,2,3,6-tetrahydro-pyridine- 4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-methyl-phenyl)benzamide, N-(3-{6-[1-(2 -cyano-ethenyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-5-fluoro-2 -methyl-phenyl)-4-cyclopropyl-benzamide, N-(5-fluoro-2-methyl-3-{6-[1-(pyrrolidin-1-carbonyl)-1, 2,3,6-tetrahydro- Pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-phenyl)-4-(pentafluoro-thio)-benzamide, 2-[2-[4- (4-{5-fluoro-2-methyl-3-[4-(pentafluoro-thio)-benzylidenylamino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidine -6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxo-ethyl ester, N-(5-fluoro-3-{6-[1-(2- Hydroxy-ethinyl-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-methyl-phenyl )-4-(pentafluoro-thio)-benzamide, 4-{4-[3-(4-t-butyl-benzylidenylamino)-2-(t-butyl-di Phenyl-decyloxymethyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl Ester, 4-tert-butyl-N-(3-{6-[1-(2-fluoro-ethinyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H- Pyrrolo[2,3-d]pyrimidin-4-yl}-2-hydroxymethyl-phenyl)-benzamide, 4-(4-{5-fluoro-3-[2-fluoro-4- (1-hydroxy-1-methyl-ethyl)-benzylidenylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3 ,6-Dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-tert-butyl-N-{5-fluoro-2-methyl-3-[6-(1,2,3, 6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-phenyl}-benzene Formamide, 4-{4-[3-(4-t-butyl-benzylidenylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3- d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-tert-butyl-N-{5-fluoro-3-[6-(1 -methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl} - Benzamide, 4-tert-butyl-N-{3-[6-(1-dimethylaminesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H -pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzamide, 4-tert-butyl-N-{3-[6- (1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-benzene Benzoylamine, 4-{4-[3-(6-t-butyl-1-oxooxy-3,4-dihydro-1H-isoquinolin-2-yl)-2- Hydroxymethyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-{4 -[3-(6-cyclopropyl-1-o-oxy-3,4-dihydro-1H-isoquinolin-2-yl)-2-hydroxymethyl-phenyl]-7H-pyrrolo[ 2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-(4-{2-hydroxymethyl-3-[6- (1-hydroxy-1-methyl-ethyl)-1-oxooxy-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-7H-pyrrolo[2,3 -d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-tert-butyl-N-{3-[6-(3,6- Dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-hydroxymethyl-phenyl}-benzamide, 4-third Butyl-N-{3-[6-(3,6-dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3- d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzamide, N-{3-[6-(3,6-dihydro-2H-pyran-4- -7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-4-dimethylamino-benzamide, 4- Tributyl-N-{3-[6-(3,6-dihydro-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- Methyl-phenyl}-benzamide, 4-tert-butyl-N-{2-methyl-3-[6-(3,6-dihydro-1-oxo-yl-2H-thiopyran-4-yl)-7H-pyrrolo[2 ,3-d]pyrimidin-4-yl]-phenyl}-benzamide, 4-tert-butyl-N-{3-[6-(3,6-dihydro-1,1-dioxo Ionic 2-H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide, 4-third --N-{3-[6-(1,4-dioxa-spiro[4.5]indole-7-en-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl ]-2-hydroxymethyl-phenyl}-benzamide, 4-tert-butyl-N-{3-[6-(4-hydroxy-cyclohex-1-enyl)-7H-pyrrole [2,3-d]pyrimidin-4-yl]-2-hydroxymethyl-phenyl}-benzamide, 4-tert-butyl-N-{3-[6-(4-dimethyl Amino-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-hydroxymethyl-phenyl}-benzamide, 4-(4- {3-[(3-Tertioxy-azetidin-1-carbonyl)-amino]-5-fluoro-2-methyl-phenyl}-7H-pyrrolo[2,3- d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-(4-{5-fluoro-3-[(3-isopropoxy-) Azetidin-1-carbonyl)-amino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H -pyridine-1-carboxylic acid dimethyl decylamine, 5-fluoro-1,3-dihydro-isoindole-2 -formic acid {3-[6-(1-dimethylaminocarbamimidyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine- 4-yl]-5-fluoro-2-methyl-phenyl}-decylamine, 4-[4-(5-fluoro-2-methyl-3-{[3-(2,2,2-3) Fluoro-1-trifluoromethyl-ethoxy)-azetidin-1-carbonyl]-amino}-phenyl)-7H-pyrrolo[2,3-d] Pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 3-tert-butoxy-azetidine-1-carboxylic acid {3-[6- (3,6-Dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-indole Amine, 4-(4-{3-[(3-tert-butoxy-azetidin-1-carbonyl)-amino]-4-fluoro-phenyl}-7H-pyrrolo[2, 3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-(4-{3-[(3-tert-butoxy-nitrogen) Heterocyclobutane-1-carbonyl)-amino]-4-fluoro-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-di Hydrogen-2H-pyridine-1-carboxylic acid dimethyl decylamine, 4-tert-butyl-N-{3-[6-(3,6-dihydro-2H-pyran-4-yl)-7H- Pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide, 4-tert-butyl-N-{3-[6-(1,4- Dioxa-spiro[4.5]dec-7-en-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide ,4-tert-butyl-N-{3-[6-(4-hydroxy-cyclohex-1-enyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2- Methyl-phenyl}-benzamide, and 4-tert-butyl-N-{3-[6-(4-dimethylamino-cyclohex-1-enyl)-7H-pyrrole [2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzene Amides. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 4-{4-[3-(4-ethenyl-benzhydrylamino)-5-fluoro-2-methyl Phenyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine; 4-{4-[3-(4-Cyclopropyl-benzhydrylamino)-4-fluoro-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3 ,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine; 4-(4-{4-fluoro-3-[4-(2-hydroxy-1,1-dimethyl-ethyl) -benzylidenylamino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethyl decylamine ;N-{3-[6-(3,6-Dihydro-2H-pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2 -methyl-phenyl}-2-fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzamide; N-{3-[6-(3,6-dihydro-2H -pyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-hydroxymethyl-phenyl}-2-fluoro-4-(1-hydroxy-1- Methyl-ethyl)-benzamide; 4-t-butyl-N-{3-[6-(3,6-dihydro-2H-thiopyran-4-yl)-7H-pyrrolo[ 2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzamide; 4-t-butyl-N-{5-fluoro-2-methyl- 3-[6-(3,6-Dihydro-1-oxoyl-2H-thiopyran-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-phenyl} -benzimidamide; 4-tert-butyl-N-{3-[6-(3,6-dihydro-1,1-dioxo-yl-2H-thiopyran-4-yl)-7H- Pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-benzamide; 4-tert-butyl-N-{3-[ 6-(1,4-Dioxa-spiro[4.5]dec-7-yl-8-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2- Methyl-phenyl}-benzamide; 4-tert-butyl-N-{5-fluoro-3-[6-(4-hydroxy-cyclohex-1-enyl)-7H-pyridyl [2,3-d]pyrimidin-4-yl]-2-methyl-phenyl}-benzamide; 4-{4-[3-(4-cyclopropyl-benzimidamide) 5-(fluoro-2-methyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid Baseline amine; 4-cyclopropyl-N-(5-fluoro-2-methyl-3-{6-[1-(pyrrolidin-1-carbonyl)-1,2,3,6-tetrahydro- Pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-phenyl)-benzamide; 2-(4-{4-[3-(4-ring) Propyl-benzhydrylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H -pyridin-1-yl)-2-oxo-ethyl ester; and 4-cyclopropyl-N-(5-fluoro-3-{6-[1-(2-hydroxy-ethenyl)- 1,2,3,6-Tetrahydro-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-methyl-phenyl)benzamide. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 12 and one or more pharmaceutically acceptable carriers. A combination comprising a therapeutically effective amount of a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and one or more therapeutically active auxiliary agents. A use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for modulating Btk activity in an individual. A compound according to any one of claims 1, 2 and 4 to 12, or a pharmaceutically acceptable salt thereof, for use as a medicament. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable compound thereof The use of a salt for the manufacture of a medicament for the treatment of a condition or disease mediated by Btk.