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.

The essential role of Btk in autoimmune disease is underlined by the observations that Btk-deficient mice are protected in standard preclinical models for rheumatoid arthritis (Jansson and Holmdahl, 1993), systemic lupus erythematosus (Steinberg, B. J. et al., J. Clin. Invest, 70, 587-597, 1982), as well as allergic disease and anaphylaxis (Hata, D. et al., J. Exp. Med. 187, 1235-1247, 1998). In addition, many cancers and lymphomas express Btk and appear to be dependent on Btk function (Davis, R. E. et al., Nature, 463, 88-92, 2010).
Therefore, inhibition of Btk activity may be useful in the treatment of immune disorders such as rheumatoid arthritis, systemic lupus erythematosus, allergic diseases, anaphylaxis and inflammatory conditions. Moreover, inhibition of Btk may be useful in the treatment of cancers of haematopoietic origin including chronic myelogenous leukemia, myeloid leukemia, non-Hodgkin lymphoma and other B cell lymphomas.
The compounds of the present invention may therefore potentially be useful in the treatment of a wide range of disorders, particularly Btk-related diseases or disorders, and may for example be useful in the treatment of autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection, or cancers e.g. of hematopoietic origin or solid tumors.
More particularly, the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof;
wherein,R1 is hydrogen, C1-C6 alkyl optionally substituted by hydroxy;R2 is hydrogen or halogen;R3 is hydrogen or halogen;R4 is hydrogen,R5 is phenyl optionally substituted by halogen; SF5; NR6R7; hydroxy; C1-C6 alkoxy; C1-C6 alkenyl; C1-C6 alkyl carbonyl; C1-C6 alkyl optionally substituted by hydroxy, halogen, or C1-C6 alkoxy; or C3-C6 cycloalkyl optionally substituted by halogen, hydroxy, or C1-C6 alkyl optionally substituted by halogen; orR5 is a 4-14 membered mono- or bicyclic heterocyclyl or heteroaryl ring system comprising 1, 2 or 3 heteroatoms selected from N, S and O that ring being optionally substituted by halogen; hydroxy; C1-C6 alkoxy optionally substituted by hydroxy or halogen; or C1-C6 alkyl optionally substituted by hydroxy or halogen;or R4 and R5 together with the atoms to which they are bound form a piperidone ring, optionally comprising an annulated phenyl ring, any such ring being optionally substituted by C1-C6 alkyl, C1-C6 alkoxy, or C3-C6 cycloalkyl each of which substitution member may optionally be substituted by halogen or hydroxy;R6 and R7 are independently selected from hydrogen or C1-C6 alkyl;or R6 and R7 together with the nitrogen atom to which they are bound form a 4-8 membered saturated azacycloalkane ring, optionally substituted by halogen, hydroxy or C1-C6 alkyl;X is O, S(O)n wherein n is 0, 1 or 2, or
wherein 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 whereinp is 1 or 2,R 11 is C1-C6 alkyl optionally substituted by hydroxy, cyano, halogen, carboxy or C1-C6 alkoxy carbonyloxy; or NR6R7; andR12 is C1-C6 alkyl or NR6R7.
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, R4 is hydrogen, R5 is phenyl substituted by halogen; C1-C6 alkoxy or C1-C6 alkyl optionally substituted by halogen or hydroxy; or C3-C6 cycloalkyl optionally substituted by halogen, hydroxy, C1-C6 alkyl optionally substituted by halogen; X is O, S(O), wherein n is 0, 1 or 2, or
wherein q is 2 or 3, and R10 is absent;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, R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one optionally substituted by C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by hydroxy; X is O, S(O), wherein n is 0, 1 or 2, or
wherein q is 2 or 3, and R10 is absent; 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, R4 is hydrogen, R5 is phenyl substituted by halogen; C1-C6 alkoxy; C1-C6 alkyl optionally substituted by halogen or hydroxy; or C3-C6 cycloalkyl optionally substituted by halogen, hydroxy, or C1-C6 alkyl optionally substituted by halogen; X stands for O and R10 is absent; or X stands for N, and R10 is hydrogen or —CO—R11, 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, R4 is hydrogen; R5 is phenyl substituted by C1-C6 alkoxy; C1-C6 alkyl optionally substituted by halogen or hydroxy; or C3-C6 cycloalkyl optionally substituted by halogen, hydroxy, or C1-C6 alkyl optionally substituted by halogen; X stands for N, R10 is hydrogen or —CO—R11, R11 stands for NR6R7 wherein R6 and R7 are independently hydrogen or methyl; 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, R4 is hydrogen, R5 is azetidine optionally substituted by C1-C6 alkoxy, X stands for N, and R10 is hydrogen or —CO—R11, 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, R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one optionally substituted by C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by hydroxy, X stands for N, and R10 is hydrogen or —CO—R11, 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, R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one substituted by C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by hydroxy in the 6-position of said isoquinolin-ring, X stands for N, and R10 is hydrogen or —CO—R11, 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, R4 is hydrogen, R5 is azetidine optionally substituted by C1-C6 alkoxy, X stands for 0, 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, R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one optionally substituted by C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by hydroxy, X stands for 0, 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, R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one substituted by C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by hydroxy in the 6-position of said isoquinolin-ring, X stands for 0, 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 from each other selected from hydrogen and halogen, R4 is hydrogen, R5 is phenyl substituted one or more times by halogen, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by hydroxy, X stands for O or S, and R10 is absent.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof wherein R1 is methyl or hydroxymethyl, R2 and R3 are independently from each other selected from hydrogen and halogen, R4 is hydrogen, R5 is phenyl substituted one or more times by halogen, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by hydroxy, X stands for N, R10 is hydrogen or —CO—R11, and R11 is NR6R7 wherein R6 and R7 are independently selected from C1-C6-alkyl.
With regard to a compound of formula (I) the following significances represent further embodiments of the invention independently, collectively or in any combination or in any sub-combination thereof:                1. R1 is hydrogen, methyl or hydroxymethyl;        2. R1 is methyl or hydroxymethyl;        3. R2 and R3 are independently hydrogen or fluoro;        4. R1 is methyl or hydroxymethyl and R2 and R3 are independently hydrogen or fluoro;        5. R4 is hydrogen;        6. R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one optionally substituted by C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by hydroxy;        7. R4 together with R5 is a 3,4-dihydro-2H-isoquinolin-1-one optionally substituted by C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by hydroxy in the 6-position of the 3,4-dihydro-2H-isoquinolin-1-one ring;        8. R5 is phenyl optionally substituted by —NR6R7, halogen; C1-C6 alkoxy, C1-C6 alkenyl, C3-C6 cycloalkyl, or C1-C6 alkyl optionally substituted by halogen or hydroxy;        9. R5 is phenyl substituted by —NR6R7, halogen, C1-C6 alkoxy or C1-C6 alkyl optionally substituted by halogen or hydroxy;        10. R5 is phenyl substituted by halogen, C1-C6 alkoxy, C3-C6 cycloalkyl or C1-C6 alkyl optionally substituted by fluoro or hydroxy;        11. R5 is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle, or a 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic heterocycle comprising 1, 2 or 3 heteroatoms selected from N, S and O that ring being optionally substituted by halogen; hydroxy; C1-C6 alkoxy optionally substituted by hydroxy or halogen; or C1-C6 alkyl optionally substituted by hydroxy or halogen;        12. R5 is a 4-, 5-, 6-, or 7-membered monocyclic heterocycle comprising 1 or 2 heteroatoms selected from N, S and O that ring being optionally substituted by halogen; hydroxy; C1-C6 alkoxy optionally substituted by hydroxy or halogen; or C1-C6 alkyl optionally substituted by hydroxy or halogen;        13. R5 is azetidine substituted by C1-C6 alkoxy or C1-C6 alkyl;        14. X is O and R10 is absent or is N and R10 is H or CO—R11;        15. X is O and R10 is absent or is N and R10 is CO—R11;        16. X is O and R10 is absent;        17. X is N and R10 is CO—R11;        18. R11 is NR6R7 and R6 and R7 are independently selected from hydrogen or C1-C6 alkyl;        19. R11 is NR6R7 and R6 and R7 are independently selected from C1-C6 alkyl;        20. R11 is NR6R7 and R6 and R7 are independently selected from C1-C3 alkyl;        21. R11 is NR6R7 and R6 and R7 are methyl.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder mediated by Btk.
In another embodiment the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is selected from:    4-(4-{5-Fluoro-3-[4-(1-fluoro-cyclopropyl)-benzoylamino]-2-methyl-phenyl}-7H-pyrrolo[2′3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    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 dimethylamide,    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 dimethylamide,    4-(4-{5-Fluoro-3-[4-isopropyl-methyl-amino)-benzoylamino]-2-methyl-phenyl}-7H-pyrrolo[2′3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    3-Methyl-1H-indole-6-carboxylic acid {3-[6-(1-dimethylcarbamoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-amide,    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 dimethylamide,    4-{4-[5-Fluoro-2-methyl-3-(4-piperidin-1-yl-benzoylamino)-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-{4-[5-Fluoro-3-(isopropenyl-benzoylamino)-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{5-Fluoro-2-methyl-3-[4-(1-trifluoromethyl-cyclopropyl)-benzoylamino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    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 dimethylamide,    4-(4-{5-Fluoro-3-[4-pentafluorothio-benzoylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{5-Fluoro-3-[4-(2-methoxy-1,1-dimethyl-ethyl)-benzoylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    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 dimethylamide,    1-Methyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylic acid {3-[6-(1-dimethyl-carbamoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-amide,    4-{4-[3-(4-Dimethylamino-benzoylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{3-[2-Fluoro-4-(1-hydroxy-1-methyl-ethyl)-benzoylamino]-2-hydroxymethyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-{4-[3-(4-Cyclopropyl-benzoylamino)-2-hydroxymethyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{5-Fluoro-2-methyl-3-[4-(2,2,2-trifluoro-1-hydroxy-1-methyl-ethyl)-benzoylamino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-{4-[3-(4-Acetyl-benzoylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-{4-[3-(4-Cyclopropyl-benzoylamino)-4-fluoro-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{4-Fluoro-3-[4-(2-hydroxy-1,1-dimethyl-ethyl)-benzoylamino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    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-oxido-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-dioxido-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-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-benzoylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2′3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-Cyclopropyl-N-(5-fluoro-2-methyl-3-{6-[1-(pyrrolidine-1-carbonyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-phenyl)-benzamide,    Acetic acid 2-(4-{4-[3-(4-cyclopropyl-benzoylamino)-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-actyl)-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-acetyl)-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-(pyrrolidine-1-carbonyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-phenyl)-4-(pentafluoro-sulfanyl)-benzamide,    Acetic acid 2-[4-(4-{5-fluoro-2-methyl-3-[4-(pentafluoro-sulfanyl)-benzoylamino]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridin-1-yl]-2-oxo-ethyl ester,    N-(5-Fluoro-3-{6-[1-(2-hydroxy-acetyl)-1,2,3,6-tetrahydro-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}-2-methyl-phenyl)-4-(pentafluoro-sulfanyl)-benzamide,    4-{4-[3-(4-tert-Butyl-benzoylamino)-2-(tert-butyl-diphenyl-silanyloxymethyl)-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-acetyl)-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)-benzoylamino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    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-tert-Butyl-benzoylamino)-5-fluoro-2-methyl-phenyl]-7H-pyrrolo[2,3-d]pyrimidin-6-yl}-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    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-dimethylsulfamoyl-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-phenyl}-benzamide,    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 dimethylamide,    4-{4-[3-(6-Cyclopropyl-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 dimethylamide,    4-(4-{2-Hydroxymethyl-3-[6-(1-hydroxy-1-methyl-ethyl)-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    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,    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-methyl-3-[6-(3,6-dihydro-1-oxido-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-dioxido-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]dec-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-tert-Butoxy-azetidine-1-carbonyl)-amino]-5-fluoro-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{5-Fluoro-3-[(3-isopropoxy-azetidine-1-carbonyl)-amino]-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    5-Fluoro-1,3-dihydro-isoindole-2-carboxylic acid {3-[6-(1-dimethylcarbamoyl-1,2,3,6-tetrahydro-pyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-5-fluoro-2-methyl-phenyl}-amide,    4-[4-(5-Fluoro-2-methyl-3-{[3-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-azetidine-1-carbonyl]-amino}-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    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}-amide,    4-(4-{3-[(3-tert-Butoxy-azetidine-1-carbonyl)-amino]-4-fluoro-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    4-(4-{3-[(3-tert-Butoxy-azetidine-1-carbonyl)-amino]-4-fluoro-2-methyl-phenyl}-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid dimethylamide,    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-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 hydrocarbon moieties having 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.
As used herein, the term "alkenyl" refers to an unsaturated branched or unbranched hydrocarbon moiety having 2 to 20 carbon atoms. It comprises 2 to 20 carbon atoms, Unless otherwise provided, alkenyl refers to moieties 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, iso-propenyl, n-butenyl, sec-butenyl, iso-butenyl, tert-butenyl, n-pentenyl, isopentenyl, neopentenyl, n-hexenyl, 3-methylhexenyl, 2,2-dimethylpentenyl, 2,3-dimethylpentenyl, n-heptenyl, n-octenyl, n-nonenyl, n-decenyl and the like.
As used herein, the term "alkoxy" refers to alkyl-O—, wherein alkyl is defined herein above. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- and the like. Typically, alkoxy groups have about 1-7, more preferably about 1-4 carbons.
As used herein, the term "cycloalkyl" refers to saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms. Unless otherwise provided, cycloalkyl refers to cyclic hydrocarbon groups having between 3 and 9 ring carbon atoms or between 3 and 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 bornyl, indyl, hexahydroindyl, 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 saturated or unsaturated monocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbon atoms as defined for "cycloalkyl", wherein one carbon atom is replaced by a nitrogen atom. Unless otherwise provided, azacycloalkyl refers to cyclic aza-hydrocarbon groups having between 2 and 9 ring carbon atoms and one nitrogen atom or between 2 and 7 ring carbon atoms and one nitrogen atom. Exemplary monocyclic aza-hydrocarbon groups include, but are not limited to, aziridinyl, azetidinly, pyrollidinyl, piperidinyl, azepanyl, dihydroazepinyl and the like.
As used herein, the term "halogen" or "halo" refers to fluoro, chloro, bromo, and iodo.
As used herein the term "heterocyclic", "heterocyclyl" or "heterocyclo" may refer to a saturated or unsaturated non-aromatic ring or ring system, e.g., which is a 4-, 5-, 6-, or 7-membered monocyclic, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or 15-membered tricyclic ring system and contains at least one heteroatom selected from O, S and N, where the N and S can also optionally be oxidized to various oxidation states. The heterocyclic group can be attached at a heteroatom or a carbon atom. The heterocyclyl may include fused or bridged rings as well as spirocyclic rings. Examples of heterocycles include azetidine, tetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine, 1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran, oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, thiomorpholine, and the like.                As used herein, the term "aryloxy" refers to both an —O-aryl and an —O-heteroaryl group, wherein aryl and heteroaryl are defined herein.        As used herein, the term "heteroaryl" refers to a 5-14 membered monocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to 8 heteroatoms selected from N, O or S. Typically, the heteroaryl is a 5-10 membered ring system (e.g., 5-7 membered monocycle or an 8-10 membered bicycle) or a 5-7 membered ring system. Typical heteroaryl groups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-, or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 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 group in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or 8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or 8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinoliyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinoliyl, 1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or 6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-, 7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-4aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or 8-carbzaolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-perimidinyl, 2-, 3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl, 2-, 3-, 4-, 5-, 6-, or I-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or 10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 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 5-1H-pyrazolo[4,3-d]-oxazolyl, 2-, 4-, or 54H-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]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-, 8-, 9-, 10, or 11-4H-pyrido[2,3-c]carbazolyl, 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-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-, or 11-1H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroary groups include, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or 7-indolyl, 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 terms "salt" or "salts" refers to an acid addition or base addition salt of a compound of the invention. "Salts" include in particular "pharmaceutical acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, laurylsulfate, malate, maleate, malonate, mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate salts.
Inorganic acids from which salts can be derived include, 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, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.
The pharmaceutically acceptable salts of the present invention can be synthesized from a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in "Remington's Pharmaceutical Sciences", 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as 2H, 3H, 11C, 13C, 14C, 15N, 18F, 31P, 32P, 35S, 36Cl, 125I respectively. The invention includes various isotopically labeled compounds as defined herein, for example those into which radioactive isotopes, such as 3H and 14C, or those into which non-radioactive isotopes, such as 2H and 13C are present. Such isotopically labelled compounds are useful in metabolic studies (with 14C), reaction kinetic studies (with, for example 2H or 3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an 18F or labeled compound 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 processes analogous to those described in the accompanying Examples and Preparations using an appropriate isotopically-labeled reagents in place of the non-labeled reagent previously employed.
Further, substitution with heavier isotopes, particularly deuterium (i.e., 2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements or an improvement in therapeutic index. It is understood that deuterium in this context is regarded as a substituent of a compound of the formula (I). The concentration of such a heavier isotope, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor" as used herein means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of this invention is denoted deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D2O, d6-acetone, d6-DMSO.
Compounds of the invention, i.e. compounds of formula (I) that contain groups capable of acting as donors and/or acceptors for hydrogen bonds may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of formula (I) by known co-crystal forming procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting in solution compounds of formula (I) with the co-crystal former under crystallization conditions and isolating co-crystals thereby formed. Suitable co-crystal formers include those described in WO 2004/078163. Hence the invention further provides co-crystals 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 (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.
The term "a therapeutically effective amount" of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or prevent a disease, etc. In one non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a condition, or a disorder or a disease (i) mediated by Btk, or (ii) associated with Btk activity, or (iii) characterized by activity (normal or abnormal) of Btk; or (2) reducing or inhibiting the activity of Btk; or (3) reducing or inhibiting the expression of Btk. In another non-limiting embodiment, the term "a therapeutically effective amount" refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reducing or inhibiting the activity of Btk; or reducing or inhibiting the expression of Btk partially or completely.
As used herein, the term "subject" refers to an animal. Typically the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.
As used herein, the term "inhibit", "inhibition" or "inhibiting" refers to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.
As used herein, the term "treat", "treating" or "treatment" of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treat", "treating" or "treatment" refers to alleviating or ameliorating at least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, "treat", "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treat", "treating" or "treatment" refers to preventing or delaying the onset or development or progression of the disease or disorder.
As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically or in quality of life from such treatment.
As used herein, the term "a," "an," "the" and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and plural unless otherwise indicated herein or clearly contradicted by the context.
All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g. "such as") provided herein is intended merely to better illuminate the invention and does not pose a limitation on the scope of the invention otherwise claimed.
Any asymmetric atom (e.g., carbon or the like) of the compound(s) of the present invention can be present in racemic or enantiomerically enriched, for example the (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% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration. Substituents at atoms with unsaturated double bonds may, if possible, be present in cis- (Z)- or trans- (E)-form.
Accordingly, as used herein a compound of the present invention can be in the form of one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (antipodes), racemates or mixtures thereof.
Any resulting mixtures of isomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and/or fractional crystallization.
Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by known methods, e.g., by separation of the diastereomeric salts thereof, obtained with an optically active acid or base, and liberating the optically active acidic or basic compound. In particular, a basic moiety may thus be employed to resolve the compounds of the present invention into their optical antipodes, e.g., by fractional crystallization of a salt formed with an optically active acid, e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelic acid, malic acid or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, e.g., high pressure liquid chromatography (HPLC) using a chiral adsorbent.
Furthermore, the compounds of the present invention, including their salts, can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, it is intended that the invention embrace both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including pharmaceutically acceptable salts thereof) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical art, which are known to be innocuous to the recipient, e.g., water, ethanol, and the like. The term "hydrate" refers to the complex where the solvent molecule is water.
The compounds of the present invention, including salts, hydrates and solvates thereof, may inherently or by design form polymorphs.
In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier. The pharmaceutical composition can be formulated for particular routes of administration such as oral administration, parenteral administration, and rectal administration, etc. In addition, the pharmaceutical compositions of the present invention can be made up in a solid form (including without limitation capsules, tablets, pills, granules, powders or suppositories), or in a liquid form (including without limitation solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to conventional pharmaceutical operations such as sterilization and/or can contain conventional inert diluents, lubricating agents, or buffering agents, as well as adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers and buffers, etc.
Typically, the pharmaceutical compositions are tablets or gelatin capsules comprising the active ingredient together with                a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;        b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also        c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired        d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or        e) absorbents, colorants, flavors and sweeteners.
Tablets may be either film coated or enteric coated according to methods known in the art.
Suitable compositions for oral administration include an effective amount of a compound of the invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets may contain the active ingredient in admixture with nontoxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients are, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The 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. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.
Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are advantageously prepared from fatty emulsions or suspensions. Said compositions may be sterilized and/or contain adjuvants, such as preserving, stabilizing, wetting or emulsifying agents, solution promoters, salts for regulating the osmotic pressure and/or buffers. In addition, they may also contain other therapeutically valuable substances. Said compositions are prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or contain about 1-50%, of the active ingredient.
Suitable compositions for transdermal application include an effective amount of a compound of the invention with a suitable carrier. Carriers suitable for transdermal delivery include absorbable pharmacologically acceptable solvents to assist passage through the skin of the host. For example, transdermal devices are in the form of a bandage comprising a backing member, a reservoir containing the compound optionally with carriers, optionally a rate controlling barrier to deliver the compound of the skin of the host at a controlled and predetermined rate over a prolonged period of time, and means to secure the device to the skin.
Suitable compositions for topical application, e.g., to the skin and eyes, include aqueous solutions, suspensions, ointments, creams, gels or sprayable formulations, e.g., for delivery by aerosol or the like. Such topical delivery systems will in particular be appropriate for dermal application, e.g., for the treatment of skin cancer, e.g., for prophylactic use in sun creams, lotions, sprays and the like. They are thus particularly suited for use in topical, including cosmetic, formulations well-known in the art. Such may contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives.
As used herein a topical application may also pertain to an inhalation or to an intranasal application. They may be conveniently delivered in the form of a dry powder (either alone, as a mixture, for example a dry blend with lactose, or a mixed component particle, for example with phospholipids) from a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray, atomizer or nebuliser, with or without the use of a suitable propellant.
The present invention further provides anhydrous pharmaceutical compositions and dosage forms comprising the compounds of the present invention as active ingredients, since water may facilitate the degradation of certain compounds.
Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions are packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e. g., 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 by which the compound of the present invention as an active ingredient will decompose. Such agents, which are referred to herein as "stabilizers," include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers, etc.
The compounds of formula I in free form or in salt form, exhibit valuable pharmacological properties, e.g. Btk modulating properties, e.g. as indicated by in vitro and in vivo tests as provided in the next sections and are therefore indicated for therapy.
Compounds of the invention may be useful in the treatment of an indication selected from: Autoimmune disorders, inflammatory diseases, allergic diseases, airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD), transplant rejection; diseases in which antibody production, antigen presentation, cytokine production or lymphoid organogenesis are abnormal or are undesirable; including rheumatoid arthritis, systemic onset 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 antibodies (ANCA)-associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, allergy (atopic dermatitis, contact dermatitis, allergic rhinitis), atherosclerosis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, ulcerative colitis, morbus Crohn, pancreatitis, glomerolunephritis, Goodpasture's syndrome, Hashimoto's thyroiditis, Grave's disease, antibody-mediated transplant rejection (AMR), graft versus host disease, B cell-mediated hyperacute, acute and chronic transplant rejection; thromboembolic disorders, myocardial infarct, angina pectoris, stroke, ischemic disorders, pulmonary embolism; cancers of haematopoietic origin including but not limited to multiple myeloma; leukemia; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin lymphoma; lymphomas; polycythemia vera; essential thrombocythemia; myelofibrosis with myeloid metaplasia; and Waldenstroem disease.
Thus, as a further embodiment, the present invention provides the use of a compound of formula (I) or a salt thereof in therapy. In a further embodiment, the therapy is selected from a disease which may be treated by inhibition of Btk. In another embodiment, the disease is selected from the afore-mentioned list, suitably rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA), pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, atopic dermatitis, allergic rhinitis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, morbus Crohn, Goodpasture's syndrome, Grave's disease, antibody-mediated transplant rejection (AMR), B cell-mediated hyperacute, acute and chronic transplant rejection; multiple myeloma; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin lymphoma; myelofibrosis with myeloid metaplasia; and Waldenstroem disease, more suitably rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA), systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, chronic autoimmune urticaria, atopic dermatitis, allergic rhinitis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, multiple myeloma; non-Hodgkin lymphoma.
In another embodiment, the invention provides a method of treating a disease which is treated by inhibition of Btk kinase comprising administration of a therapeutically acceptable amount of a compound of formula (I) or a salt thereof. In a further embodiment, the disease is selected from the afore-mentioned list, suitably rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA), pemphigus vulgaris, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, Sjögren's syndrome, autoimmune hemolytic anemia, anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides, cryoglobulinemia, thrombotic thrombocytopenic purpura, chronic autoimmune urticaria, atopic dermatitis, allergic rhinitis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, morbus Crohn, Goodpasture's syndrome, Grave's disease, antibody-mediated transplant rejection (AMR), B cell-mediated hyperacute, acute and chronic transplant rejection; multiple myeloma; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia; non-Hodgkin lymphoma; myelofibrosis with myeloid metaplasia; and Waldenstroem disease, more suitably rheumatoid arthritis, systemic onset juvenile idiopathic arthritis (SOJIA), systemic lupus erythematosus, multiple sclerosis, Sjögren's syndrome, chronic autoimmune urticaria, atopic dermatitis, allergic rhinitis, type 1 diabetes, type 2 diabetes, inflammatory bowel disease, multiple myeloma; non-Hodgkin lymphoma.
Methods of Synthesizing Pyrrolo-Pyrimidines
Agents of the invention, i.e. compounds in accordance to the definition of formula (I), may be prepared by a reaction sequence (shown below) involving Suzuki coupling of a protected boronic esters II with the corresponding aryl halides I′, conveniently furnishing intermediate III. Deprotection of III, e.g. with diluted hydrochloric acid in methanol or the like and acylation, e.g. with an appropriate acetylating agent, e.g. unsubstituted or substituted acetanhydride in the absence or presence of a solvent, of IV is followed by an additional Suzuki coupling with boronic ester VI and acylation of VII (optionally followed by a deprotection step), as shown in Reaction Scheme 1 below, wherein X denotes N, and the group PG refers to a protecting group such as for example, tert-butyloxycarbonyl, that may be easily removed e.g. by diluted hydrochloric acid in methanol or the like.

Alternatively, the compounds of formula (I) may also be prepared by a reaction sequence involving Suzuki coupling of boronic esters IX with the corresponding aryl halides I′, followed by an additional Suzuki coupling of V with boronic esters VI and an acylation of VII (optionally followed by a deprotection step), as shown in Reaction Scheme 2 below:

Alternatively, the compounds of formula (I) may also be prepared by a reaction sequence involving Suzuki coupling of boronic esters VI with the corresponding aryl halides III, acylation of intermediate X, followed by deprotection of XI and acylation of XII (optionally followed by a deprotection step), as shown in Reaction Scheme 3 below, wherein X denotes N, and the group PG refers to a protecting group that may be easily removed, such as for example, tert-butyloxycarbonyl.

Alternatively, the compounds of formula (I) may also be prepared by a reaction sequence involving Suzuki coupling of boronic esters XIII with the corresponding aryl halides III, followed by deprotection of XI and acylation of XII (optionally followed by a deprotection step), as shown in Reaction Scheme 4 below, wherein X denotes N, and the group PG refers to a protecting group that may be easily removed, such as for example, tert-butyloxycarbonyl.

Alternatively, the compounds of formula (I) may also be prepared by a Suzuki coupling of boronic esters XIV with the corresponding aryl halides III (optionally followed by a deprotection step), as shown in Reaction Scheme 5 below:

Alternatively, the compounds of formula (I) may also be prepared by urea formation reaction of anilines VII (optionally followed by a deprotection step), as shown in Reaction Scheme 6 below:

Alternatively, the compounds of formula (I) may be prepared by a reaction sequence involving Suzuki coupling of boronic esters XIII with the corresponding aryl halides XVI. Protection of XVII is followed by halogenation XVII, deprotection of XIX, and Suzuki coupling of halide XX with boronic ester IX (optionally followed by a deprotection step), as shown in Reaction Scheme 7 below, wherein the group PG refers to a protecting group that may be easily removed, such as for example, benzenesulfonyl.

Synthesis of the Compound(s) of the Invention


A calla lily plant particularly distinguished by its purple-black flower color, higher flower count, and leaves with white maculation is described.

The present invention comprises a new and distinct cultivar of calla lily, botanically known as Zantedeschia spp., and hereinafter referred to by the cultivar name 'Purple Heart'. The new cultivar was asexually reproduced from vegetative cuttings and tissue culture resulting from the cross of the female parent 'Purple Seedling' (unpatented) and the male parent, 'Pacific Pink' (unpatented).
'Purple Heart' is a product of a planned breeding program intended to create new calla lily plants with purple spathes.
The new cultivar was created in Tauranga, New Zealand and has been asexually reproduced repeatedly by tissue culture in New Zealand. The present invention has been found to retain its distinctive characteristics through successive propagations.


Improved technological solutions are introduced for providing a secure and effective and enhanced clustering/grouping solution that is useful, for example, in an online dating forum as well as any number of other industries. The ability to attend live events in person or remotely is coupled with presence location and automatic verification of user devices and identities. This allows secured communication between participants without having to disclose actual contact information of the participants or their device addresses. An improved algorithm that groups members/items effectively based on a variety of matching criteria, with lowered possibilities of errors and more efficient use of processing power, is now introduced.

Even with the absolute explosion of online dating sites and applications in the twenty-first century, the number of single people keeps growing worldwide. For example, in the US, the majority of adults today are unmarried. It's not that people aren't meeting, because online dating has been facilitating countless new meetings and connections. But all these "meetings" aren't turning into lasting love. Part of the reason is in the ways people meet; ways which sculpt shallow, objectifying interactions that are less likely to blossom into relationships. In-person dating events are often cold and dehumanizing, as are online dating sites and apps. Dating algorithms have been shown to be unreliable in making matches. Many recent "dating apps" have socially devolved to encourage superficial interactions and "hookups." Such one-dimensional profile browsing eliminates much of the human element that tends to spark romance. Research shows that one of the key factors in sparking attraction is increasingly vulnerable levels of communication. Online dating may facilitate many connections, but increasingly intimate and vulnerable conversations rarely happen during online dating. Accordingly, there is a need for methods and systems for enhanced online dating, various embodiments of which will now be described in detail herein.

Method and apparatus for improving generation of computerized groupings


An image rejection quadratic filter is tunable to filter image frequencies over a wide band. In one embodiment, the image rejection filter includes in-phase and quadrature phase mixers. The image rejection has a fractional transfer function. The image rejection filter has two sub-circuits, wherein the first sub-circuit produces the imaginary component of the transfer function, and the second sub-circuit produces the real component of the transfer function. The first sub-circuit receives the Q signal, and the second sub-circuit receives the I signal. In one embodiment, to create the fractional transfer function, a multi-feedback looped integrator is used.

1. Field of the Invention
The present invention is directed toward the field of filters, and more particularly toward image rejection notch filters.
2. Art Background
Typically, receivers employ filters to condition both input signals and internally generated reference signals. For example, bandpass, notch, and low pass are types of filters employed in receivers. The frequency response of a filter refers to the characteristics of the filter that condition the signal input to the filter. For example, a bandpass filter may attenuate an input signal across a pre-determined band of frequencies above and below a center frequency of the filter. Filters are designed to exhibit frequency responses based on one or more circuit parameters.
Some receivers are designed to process input signals with a range of input carrier frequencies (e.g., wide band receivers). For example, television receivers must be capable of processing input television signals with carrier frequencies ranging from 55 MHz to 880 MHz. One circuit parameter used to define the frequency response of a filter is the carrier frequency of an input signal.
FIG. 1 illustrates one embodiment for an image rejection mixer, including a resistive-capacitive ("RC") filter output. As shown in FIG. 1, a signal is input (e.g., RF input) to the in-phase ("I") mixer 110 and the quadrature phase ("Q") mixer 120. Also input to the ("I") mixer 110 and quadrature phase ("Q") mixer 120, at the local oscillator ("LO") port, is a local oscillator signal.
As shown in FIG. 1, the I and Q signals are input to the resistor 140 and capacitor 130, respectively. The transfer function of the RC filter may be expressed as:
      A    =                            1          +                                    (                              -                j                            )                        ×            S                                    1          +          S                    =                        (                      1            +            Z                    )                          (                      1            +            S                    )                          where    ,                            S      =              j                                                  wCr                  S    =                  j        ×        Z            =              j        ×                  W          /          Wo
FIG. 2 illustrates a frequency response for the prior art image rejection mixer of FIG. 1. The frequency response of FIG. 2 is normalized. The image frequency, at −1, is attenuated and the desired frequency range is part of the passband of the filter. The transfer function, for the normalized response, may be expressed as:
      (          1      +      X        )              1      +              X        2
Conventionally an image rejection mixer applies a single notch in the baseband after demodulation. When the desired signal has a relatively wide bandwidth, the image rejecting single notch can remove only one image frequency point. In other words, the single notch cannot remove a desired band. For this reason, the conventional image rejection mixer requires multiple stages of down conversion.


A food and beverage container having a lid and a base portion with four upright walls and a bottom. The lid seats on the base portion, and is secured by a pivoting latch handle with a hook portion hinged to the handle. The hook portion has a width where it contacts the lid equal to or greater than its length. The base portion and lid are sealed by an elongated elastomeric member seated in a groove of the lid.

1. Field of the Invention
The field of this invention is within the food and beverage dispenser art. In particular, it relates to those food and beverage dispensers which generally have a spigot for dispensing beverages as well as in some cases soup and other liquid type foods.
2. Background of the Invention and Prior Art
The prior art with regard to food and beverage dispensers incorporates various dispensers. Many of them have lids or covers which seat on top of the dispenser. However, it is not known to date that any such dispensers incorporate an elongated over center latch handle which functions with a dynamic seal.
This invention particularly provides for an over center broad elongated latch handle which seals the entire container. The container is sealed by virtue of a dynamic seal in the form of an O ring or other suitable elastomeric member that is within a groove surrounding the lid or cover. The groove surrounding the lid holds the dynamic seal and merges it against a chamfered or other surface on the base portion container edges.
The net effect is to-provide for a seal and an over center latch which seals the top to the container in a tight and well insulated manner.

Food and beverage dispenser with a dynamic seal


A document image is obtained and fine-grain item-specific information within the document image is encrypted with varying levels of encryption, each encryption level associated is with a specific security access role. When the document image is presented to an end-user, the end-user's security access role determines which portions of the fine-grain item-specific information is decrypted and which portions remain encrypted, such that some portions of the document image are obfuscated from the end-user based on the end-user's security access role.

Increasingly consumers are conducting financial transactions and performing business accounting through consumer-operated devices, such as: Self-Service Terminals (SSTs) without the assistance of a clerk and mobile device owned/operated by the consumers.
For example, it is fairly common for a consumer to now use a mobile device, such as a phone to take a picture of a check and deposit that check with a bank using a mobile application. In another case, a customer may operate an Automated Teller Machine (ATM) and deposit a check that is scanned and sent to other downstream processing within the bank. In yet another situation, a customer at a grocery store may operate a kiosk and pay or attempt to cash a check, the check is scanned or imaged and sent to a remote clerk for viewing or other downstream processing with the retailer and the customer's bank.
Once the check is imaged, the check may need to be viewed for a variety of reasons by a retailer or a bank. This can occur in real time or at a later date if there is some issue with the check.
This creates security issues for the customer because there is a lot of confidential information on a customer's check, such as name, address, account number, etc. In fact, depending on the situation a variety of personnel within an enterprise may be capable of having access to the check image. Access may be needed by the personnel, but depending on the situation the customer's confidential information present in the check image is usually not necessary to resolve whatever issue the personnel is addressing for the customer.
These situations and other situations unnecessarily expose the customer to potential identity theft by unscrupulous personnel within enterprises.


Epithelial cells are attached to microcarriers to form a transplantation material for treatment of skin wounds. Preferably, keratinocyte-covered microcarriers are prepared using microcarriers having a diameter of 50 to 500 .mu.m, and obtaining a coverage of keratinocytes of 30 to 100% of the maximum coverage. An optimum coverage is between 50 and 80% and preferably between 60 and 70%. Keratinocytes are selected from autologous cells, allogenic cells and a combination of these cells. The microcarriers may be pre-coated with eukaryotic cells or an extracellular matrix protein such as collagen before keratinocytes are attached. The keratinocyte-covered microcarriers may be combined with a cryoprotective substance for storage at +3.degree. C. to -196.degree. C. prior to use. Keratinocytes are attached to the microcarriers by pre-culturing the keratinocytes, and then culturing the keratinocytes in the presence of the microcarriers while intermittently stirring. A serum free culture medium may be used. Initial culturing in the presence of the microcarriers may be in the smallest amount of medium required to prevent the keratinocytes from dying, and after keratinocyte attachment, adding medium to provide a volume for optimum growth. The keratinocyte-covered microcarriers are applied to a skin wound and the wound is covered with a protective dressing. A pharmaceutical formulation and kit are prepared containing the keratinocyte-covered microcarriers may.

1. Field of the Invention
The subject-matter of the invention is a new biomaterial which contains epithelial cells on microcarriers (MCs), as well as the preparation and use of said biomaterial for preparing a medicament.
2. Description of the Prior Art
Skin consists of the epidermis, the basement membrane and the dermis. The epidermis forms the outer coat. The dermis consists essentially of fibroblasts with additional substances such as, e.g., collagen. The basement membrane essentially contains keratinocytes which are non-differentiated but proliferating. The epidermis essentially contains differentiated keratinocytes wherein the upper layer is horny. It is true that while the degree of differentiation of the cells is increasing, the ability of the cells to proliferate is decreasing. Accordingly, the non-differentiated keratinocytes exhibit the highest proliferation potency.
Burn wounds and slow-healing wounds (ulcers) usually are treated with skin sheets consisting of autologous keratinocytes (classical method). To this end, a piece of skin is cut off from the patient, the keratinocytes are cultured in vitro, and the expanded skin sheets so obtained are transplanted [Gallico, G. G., et al., New Engl. J. Med. 311 (1984) 448-451 (1); Cuono, C., et al., Lancet (1986) 1123-1124 (2); De Luca, M., et al., Burns 15 (5) (1989) 303-309 (3); Gallico, G. G., Clinics in Plastic Surgery 17 (3) (1990) 519-526 (4); De Luca, M., and Cancedda, R., Burns 18 (1) (1992) 5-9 (5)]. The transfer of thin skin sheets from cell culture flasks to, e.g., Vaseline gauze as well as the fixing thereof onto the wound surface is problematical. The covering of wounds on parts of the body that are difficult to reach is another problem. Besides this, only keratinocytes can be transferred by means of such classical skin sheets. Skin sheets from keratinocytes involve the drawback that these cells are almost completely differentiated when the sheets are being formed, which means that the sheets practically no longer contain any keratinocytes capable of proliferation. Thus, these sheets constitute a transplantation material which cannot grow, or continue growing, after transplantation. Epidermal transplants (classical skin sheets) with allogenic keratinocytes have been carried out in a number of clinics without any immunological rejection reactions being observed (Gboyse, S. T., et al., Plast. Reconst. Surg. 91 (1993) 632 (17); Burt, A. M., et al., Br. Med. J. 298 (1989) 915 (18); Hickerson, W. L., et al., Burns 20/1 (1994) 52 (19)).
From WO 92/06179 (6) and EP-A 0 242 270 (7) biomaterials are known which contain epithelial cells within a collagen gel. In this context, epithelial cells (fibroblasts or keratinocytes) are embedded in gel layers. It is known that such gels may also contain keratinocytes. However, the keratinocytes in the gel are immobilized and are thus incapable of proliferating and differentiating to an appreciable extend after transplantation. Accordingly, keratinocytes from such gels are not able to form a basement membrane and an epidermis. Another drawback of this biomaterial is, in particular, the low rate of migration of the epithelial cells from the biomaterial into the wound. Furthermore, the handling and fixing of these biomaterials is very difficult and laborious.
In WO 90/02796 (8) there is described a three-dimensional cell culture system on the basis of, for instance, cellulose, polyamide, polyester, on which epithelial cells can grow. In this context, an artificial tissue is obtained which is covered with epithelial cells (fibroblasts or keratinocytes) and which is said to be suitable for transplantation. These artificial transplantation materials, too, do not exhibit any advantage over the skin sheets applied in the classical method.

Keratinocytes attached to microcarriers for treatment of skin wounds


A light source device equipped with a concave reflector having an open front end section. Installed in the light source device is a light source having a light emitting unit. The unit is positioned on a focal point of the reflector. A cover is attached to the open front end section of the reflector to cover the open front end section. The cover has an air inflow opening provided at a side section thereof in relation to the open front end section. At least a part of the cover is made of a transparent material. The part is a light passage through which light emitted by the light source and reflected by the reflector passes. The light source device is further equipped with a fan having an air outflow opening. The fan is provided so that airflow created by the fan and blown through the air outflow opening is directed to the air inflow opening of the cover, without obstructing the light passing through the light passage. An air control unit is provided between the air outflow opening of the fan and the air outflow opening of the cover. The air control unit controls the airflow blown through the air outflow opening of the fan so that it is flown into the reflector through the air inflow opening of the cover and directed at least to one specific section of the light source, thus cooling the specific section.

The present invention relates to a light source device for use in, for example, image display apparatus. Particularly, this invention relates to effective cooling of a discharge-lamp light source installed in such a light source device.
Liquid crystal projectors have been introduced as one type of image display apparatus. This type of image display apparatus requires a light source for illuminating a liquid crystal panel (spatial light modulator) that does not emit light. In other words, in this type of image display apparatus, light emitted from a light source device is illuminated onto a liquid crystal panel and modulated thereon. The modulated light is then projected onto a screen to display images thereon.
A light source device for use in this type of image display apparatus has a discharge-lamp light source, such as, a high-pressure mercury lamp, a metal halide lamp or a xenon lamp. It is further equipped with an elliptical reflecting mirror for converging rays of light emitted from the discharge-lamp light source or a parabolic reflecting mirror for reflecting rays of light emitted from the discharge-lamp light source into a parallel beam.
A recent demand for this type of image display apparatus is high intensity of images displayed. High-intensity images require large light output from a discharge-lamp light source. This leads to enhancement of light power for discharge-lamp light sources. For this reason, a fundamental factor in this type of image display apparatus is cooling capacity, the capacity of cooling a discharge-lamp light source.
Higher-intensity images in this type of image display apparatus require lower clearance, one of the specifications for discharge-lamp light sources. This further requires different levels of cooling capacity in accordance with sections of a discharge-lamp light source.
One known type of light source device has an axial-flow fan that guides ambient air to a discharge-lamp light source and cools it with this air. An axial-flow fan is a propeller fan that blows air in the direction parallel to the rotary axis of the fan.
Another recent known type of light source device has a sirocco fan for cooling. A sirocco fan has a multi-blade cylinder that rotates to create airflow in the centrifugal direction from the rotary shaft and a scroll casing that takes the airflow and blows it through an air outflow opening.
A sirocco fan achieves high pressure with effective use of centrifugal force and optimum high static pressure to create a relatively large amount of airflow. It is suitable for local cooling thanks to its airflow directional characteristics and high static pressure.
A light source device is disclosed in Japanese Unexamined Patent Publication No. 2001-125195. In this device, airflow created by a cooling fan is blown into a concave reflector through an air duct. This light source device, however, has an inferior structure with a wide gap (high clearance) between a sirocco fan and a discharge-lamp light source to be cooled by the sirocco fan.
In another light source device disclosed in Japanese Unexamined Patent Publication No. 2002-49098, airflow created by a sirocco fan is blown around a reflector about 1/2 times before guided into the reflector.
In contrast, airflow is blown onto the outer surface of a reflector in still another light source device disclosed in Japanese Unexamined Patent Publication No. 2002-328426.
Due to these inferior structures, the known light source devices are not feasible for cooling a discharge-lamp light source.
In addition, cooling temperatures are the fundamental factors on operating properties in light source devices. In detail, a discharge unit of a discharge-lamp light source requires to be maintained at a relatively high temperature with no excess cooling whereas sealed sections of its both ends require heavy cooling due to, for example, glass-metal junction for the sealed sections.
Moreover, light source devices require precise control of temperature difference inevitably caused by convective airflow within an appropriate range between the upper and lower sections of a discharge unit, for stable operation.
Nevertheless, the known light source devices having the inferior structures discussed above cannot achieve such delicate control.


A scanning unit for an optical position-measuring device includes a semiconductor light source and at least one downstream reflector element that has a defined optical effect on the beams of rays emitted by the semiconductor light source. The optically active surface of the reflector element is arranged in subregions to be reflection-preventive such that no beams of rays are reflected back from the reflector element into the semiconductor light source.

German Published Patent Application No. 10 2006 021 017 describes an optical position-measuring device having a scanning unit. In the scanning unit, a reflector element is arranged in front of a light source in the scanning beam path. The positioning and arrangement of the reflector element provides that the light source is positioned virtually in the plane of detection, which is an important prerequisite in the utilized scanning principle.
The light source used in this position-measuring device is preferably a point light source, which may be configured, for example, as a semiconductor light source in the form of a so-called VCSEL (vertical cavity surface emitting laser). A problem in such light sources is the possibility of radiation being reflected back from the scanning beam path into the light source. Such back-reflections change the mode spectrum of the semiconductor light source.
Furthermore, interference effects by repeatedly reflected beams of rays in the scanning beam path may be produced as a result of such back-reflections. These also entail collapses in the angular spectrum of the light source. In addition, such back-reflections may have the consequence that the correct positioning of the virtual light source in the scanning beam path is no longer ensured. This affects the tolerance behavior of the position-measuring device negatively.
In Japanese Published Patent Application No. 11-243258 and U.S. Pat. No. 7,193,204, this problem in the use of semiconductor light sources in optical position-measuring devices is recognized. Various design approaches have been provided to circumvent the back-reflection problem.
For example, U.S. Pat. No. 7,193,204 provides for the scanning unit to be tilted slightly with respect to the scanned measuring graduation in order to prevent back-reflections or at least to minimize them.
To avoid these disadvantages, Japanese Published Patent Application No. 11-243258 provides for a lambda quarter disk to be arranged in the scanning beam path, which prevents light from being reflected at a polarization-altering orientation back into the semiconductor light source. These design approaches, however, are on the one hand relatively costly, while on the other hand they intervene in the actually ideal scanning beam path such that one must pay the price of a deterioration of the optimal optical conditions in relation to the scanning process. This is true particularly if a tilting between the scanning unit and the measuring graduation is provided, for example.

Scanning unit for an optical position-measuring device


A drag antenna for a sonar system for detecting and/or locating sources of sound in water includes at least two acoustically sensitive lines positioned side-by-side and laterally spaced apart during a trailing operation. The lines are secured to each other at the leading ends and at the trailing ends by respective connecting element in order to lower the production costs for the drag antenna and to achieve a sufficiently constant lateral spacing between the acoustically sensitive lines.

The invention relates to a drag antenna for a sonar system for detecting and/or locating sources of sound in water, and more particularly to a drag antenna of this type that includes at least two side-by-side, laterally spaced-apart, acoustically sensitive lines holding a plurality of electro-acoustical converters (hydrophones) arranged one after another in a direction of the lines wherein the lines are connected at their leading ends with a connecting element that establishes a fixed lateral spacing between the leading ends of the lines.
With a sonar system installed in a towing craft for detecting and locating targets, such drag antennas are used for a more precise determination of the angle of incidence for sound waves radiated by targets in the water or reflected by targets in the water. The at least two parallel-extending, sensitive hydrophone lines or streamers in this case permit a so-called right/left discrimination, meaning a statement as to whether the direction of the sound incidence is on the starboard side or the port side of the drag antenna.
With a drag antenna of this type, known as a twin array (see Joris Jannsen Lok, "17-Ton ALF Heads Dutch Sonar Tests," Jane's Defense Weekly, Mar. 26, 1994, pages 26 to 31), two individual hydrophone streamers are launched separately from the towing craft and are attached at a lateral distance to each other at their leading ends to a towing gear, also called an otter, via a respective pull cable. The towing gear, which in this case accommodates the transmitting section of the so-called active sonar system, is dragged by a towing craft through the water, with the aid of another pull cable. Owing to drag bodies that are attached to the trailing end of the two hydrophone streamers and which have an increased flow resistance, thereby generating a pulling force at the trailing end that is effective in a counter drag direction, the two hydrophone streamers are kept as much as possible in a stretched-out position. Since each hydrophone streamer aligns itself freely in the flow direction behind the front pull cable, a parallel alignment of the two hydrophone streamers, which is advantageous for the right/left discrimination, meaning a constant lateral spacing between the two hydrophone streamers that is sufficient for the line length, is not ensured. Additional and involved methods consequently must be used to detect the exact position of the hydrophones at the moment of sound incidence, so that the exact direction of the sound incidence can be determined.
U.S. Pat. No. 3,414,874 discloses a drag antenna for seismic underwater prospecting in which the leading ends of the drag antenna are connected via a cable (see FIG. 3 thereof). Two otters or drag bodies, arranged at the leading ends of the two outer lines ensure that a lateral force component acts upon the connecting cable during the dragging operation, which lateral force component keeps the connecting cable between the line beginnings stretched tight.


A glow discharge starter having an hermetically sealed envelope containing an ionizable medium, a bimetallic electrode including a first bimetallic element having a curved portion and a free end, and a counter electrode. A first discharge gap having a predetermined spacing is formed between the free end of the first bimetallic element and the counter electrode. The starter includes a second bimetallic element having an end secured to the counter electrode. A portion of the second bimetallic element is positioned adjacent the curved portion of the first bimetallic element such that a second discharge gap having a predetermined spacing is formed therebetween. In the event that the starter encounters a dc current of the wrong polarity, a portion of the second bimetallic element contacts the first bimetallic element so as to extinguish the arc discharge and prevent electrode damage.

In preheat fluorescent lamp circuits, a glow discharge starter is connected in shunt with the discharge path through the lamp and in series with the lamp electrodes. The glow discharge starter contains a pair of electrodes, at least one of which comprises a heat-deformable bimetallic element, within a glass envelope containing an ionizable medium. When heated as a result of a glow discharge within the starter, the bimetallic element bends towards the other electrode.
At starting, the open circuit voltage of the ballast exceeds the breakdown voltage of the starter and produces a glow discharge therein which heats the bimetallic element and causes it to engage the other electrode in the starter. The closure of the switch effectively short circuits the lamp electrodes in series across the ballast, thereupon the increased current flow through the electrodes raises them rapidly to an electron-emitting temperature. Simultaneously, the glow discharge in the starter is extinguished and the bimetallic element begins to cool and withdraw from the contacted electrode. When contact is broken, a voltage pulse induced by the induction of the ballast, appears across the opposed electrodes of the lamp thereby initiating an arc discharge within the lamp. If lamp ignition does not occur after the first voltage pulse, the glow discharge sequence is repeated until lamp ignition occurs. After the main voltage through the lamp has started, the voltage drop thereacross is less than the breakdown voltage of the starter so that the starter does not develop a glow discharge and its electrodes remain disengaged.
Glow discharge starters are generally designed for operation on either ac or dc circuits. Typically, a starter intended for use on only dc circuits requires the electrode which is connected to the positive polarity to have a surface area at least 10 times that of the other electrode.
A typical glow discharge starter intended for use on only ac current applications may encounter problems if operated on dc. More specifically, in a typical ac glow discharge starter containing a single bimetallic electrode, if the post of the counter electrode is connected to the positive polarity while the bimetallic electrode is connected to the negative polarity, a sustained arc may be established between the electrodes. This sustained arc, if not immediately extinguished, may damage the starter electrodes and cause failure of the glow discharge starter.
In the above example, this problem can be prevented if it were possible to insure that the positive polarity is always connected to the bimetallic electrode and the negative polarity is connected to the counter electrode. Since many glow discharge starters are often enclosed within a lamp base or a container and generally do not contain polarity markings, it is difficult to insure the proper polarity to the electrodes.
Lamp ballasts intended for use with emergency lighting systems often operate lamps on ac current during normal operation. However, immediately following a power failure the lamps may briefly encounter a dc voltage before the ballast of emergency lighting system switches to a high frequency ac voltage. If the electrodes of an ac starter happen to be connected to the wrong polarity during this brief encounter with the dc voltage, failure of the starter as described above may occur.
To overcome the difficulties mentioned above, the present invention proposes the incorporation of a second bimetallic element to act as a safety mechanism. In the event that the starter encounters a dc voltage of the wrong polarity, a portion of the second bimetallic element contacts the first bimetallic element so as to extinguish the arc discharge and prevent electrode damage.
The use of a second bimetallic elements in a glow discharge starter is well known. For example, U.S. Pat. No. 2,376,669, which issued to DeToro on May 22, 1945, described a glow discharge starter containing a pair of bimetallic strips 6 and 9.

AC/DC-operable glow discharge starter having two bimetals


An input and feedback system for use with simulator devices immobilizes a portion of the user's body using a securement device which holds the immobilized portion in a fixed position. Pressure sensors are disposed upon the securement device to detect the force resulting from any attempted motion of the immobilized body part. Signals describing these forces are sent to a processing unit which applies this information to a simulated environment and provides sensory feedback to the user of the this simulated environment. Feedback is provided via vibrating elements which provide a sensation to the user corresponding to the motion of the user's muscles which occur in the simulated environment. Feedback is also provided via a screen which is disposed in front of the head of the user. Such immobilizing devices may be used to allow input and feedback based on the motion of various parts of the user's body, such as the head, arms, legs, and torso.

1. Field of the Invention
This invention relates to an input system for computer interaction. More specifically, this invention relates to an input system which provides feedback matched to the user's input.
2. Description of the Related Art
A common type of interactive computer experience is the simulation, in which a user is presented with a representation of the experience of performing some other activity. One well-known type of simulator is the flight simulator, in which a user interacts with a computer which presents the user with the visual experience of flying an aircraft. There are many other types of simulators, and training for many activities is carried out through the use of simulators of various kinds.
In order to increase the realism of a simulation, it is desirable to provide an input system which is as similar as possible to the input which would be used in the actual activity. For extremely realistic flight simulators, this can mean providing complete replica cockpits of the aircraft being simulated. However, for simulated activities which are based on ordinary bodily motion (for example, sports simulators of many kinds), providing an intuitive and convenient means to track the actual effort of the muscles of a user is problematic.
Furthermore, in providing output and feedback to the user, greater realism results in a greater impression of being "inside" the simulation. This is referred to as making the experience more "immersive". A perfectly immersive simulation is one in which the user is able to treat the simulation as reality in their actions and responses to what occurs within the simulated environment.
In order to provide more immersive and effective simulations, there is a need for improved input and feedback systems which provide intuitive control and effective feedback to the user as they work in the simulated environment.


An embodiment method defines a demodulation reference signal (DMRS) pattern for transmitting DMRSs for rank 3 or rank 4 transmissions. The DMRS pattern specifies 12 REs in total per physical resource block (PRB) for carrying DMRSs on three or four antenna ports in antenna ports 7-14 for rank 3 or rank 4 transmissions. DMRS settings for transmitting DMRS according to the DMRS pattern may be specified using a downlink control information table.

For downlink demodulations, Long Term Evolution (LTE) specifications define demodulation reference signals (DMRSs) to enable UEs to estimate the reference signals and derive channel equalizers for data equalization and channel decoding. The DMRSs may be carried in specific resource elements (REs) in each slot and the location of the REs may be specifically determined according to antenna configurations (or transmission modes). For different antenna ports, different REs for carrying the DMRSs are used with different orthogonal cover code (OCC) schemes, resulting in different overhead, and different channel estimation accuracy.

This patent is subject to a terminal disclaimer.

System and method for demodulation reference signal overhead reduction


A computer system and methods for creating an agency relationship among clients of a computer system with respect to personal privileged, or otherwise sensitive permissions and/or attributes, is described. The system and methods allow a querying client to obtain permission and/or attributes from a queried client, even if the queried client is unavailable.

Access to data stores or computer-readable mediums is often governed or regulated by permissions. Permissions expressly or impliedly indicate which users may access a data store, and to what extent. Permissions often impliedly or indirectly indicate a user's permitted access by referring to a permissions group of which the user is a member. A permissions group typically includes a set of member data store users with a common degree or level of permitted access; an association with a data store, set of data stores, or part of a data store; and a definition of the common degree or level of permitted access. Permissions often indicate the degree or level of access to an associated data store, set of data stores, or part of a data store with a set of modifiable variables, a set of preset parameters, a reference to a set of modifiable variables, or a reference to a set of preset parameters specifying whether the data entries in the associated storage may be viewed, modified, deleted, or created.
The existing systems address permissions and attributes stored on a server, and accessible to a querying client when the server is online and permissions are satisfied. However, some or all permissions and attributes may be stored on a client's local storage medium, such as hard drive in a workstation, or memory in a cell-phone or PDA, where they are inaccessible when the client is unavailable.
The present computer system and methods address these and other needs.

Client agents for obtaining attributes from unavailable clients