MX2008007343A

MX2008007343A - 9-membered heterobicyclic compounds as inhibitors of protein kinases

Info

Publication number: MX2008007343A
Application number: MXMX/A/2008/007343A
Authority: MX
Inventors: Dai Yujia; R Michaelides Michael; L Curtin Michael; R Frey Robin; H Holms James; H Steinman Douglas; J Mcclellan William
Original assignee: Abbott Laboratories; L Curtin Michael; Dai Yujia; R Frey Robin; H Holms James; J Mcclellan William; R Michaelides Michael; H Steinman Douglas
Priority date: 2005-12-08
Filing date: 2008-06-06
Publication date: 2008-10-03

Abstract

Compounds that inhibit protein kinases, compositions containing the compounds and methods of treating cancer using the compounds are disclosed.

Description

HETEROBICICLIC COMPOSITIONS OF 9 MEMBERS AS PROTEIN KINASE INHIBITORS This application claims priority for United States Provisional Patent Application Series No. 60 / 749,074, filed on December 8, 2005.

FIELD OF THE INVENTION This invention relates to compounds that inhibit protein kinases such as Aurora kinases, compositions containing the compounds and methods for treating diseases using the compounds.

BACKGROUND OF THE INVENTION Mitosis is a process by which a complete copy of a duplicated genome is secreted through the microtubule spindle apparatus into two daughter cells. It has been found that Aurora kinases, key mitotic regulators required for genome stability, are overexpressed in human tumors. Given the central role of mitosis in the progression of malignancies, inhibitors of mitosis are expected to be useful for the treatment of a wide variety of tumors. Therefore, there is a need in the therapeutic art for kinase inhibitors Dawn.

BRIEF DESCRIPTION OF THE INVENTION One embodiment of this invention, therefore, relates to compounds that inhibit Aurora kinases, the compounds having the formula (I): A1 is C (0) NHR C (0) N (R1) 2, NHC (0) R, NR C (0) R1, NHC (0) NHR \ NHC (0) N (R) 2, NR C ( 0) NHR1, NR1C (0) N (R) 2, S02NHR1, S02N (R1) 2, NHS02R1, NR S02R1, OC (0) OR1, NHC (0) OR1, NR1C (0) OR1 or R5; R1 is R2, R3, R4 or R5; R2 is phenyl, which is not fused or fused with benzene, heteroarene or R2A; R2A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R3 is heteroaryl, which is not fused or fused with benzene, heteroarene or R3A; R3A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R 4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R 4A; R A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R5 is alkyl, alkenyl or alkynyl, each of which is substituted with one or two independently selected from R5, OR6, SR6, S (0) R6, S02R6, NH2, NHR6, N (R6) 2, C (0) R6, C (0) NH2, C (0) NHR6, C (0) N (R6) 2, NHC (0) R6, NR6C (0) R6, NHS02R6, NR6S02R6, NHC (0) OR6, NR6C (0) OR6, S02NH2, S02NHR6, S02N (R6) 2, NHC (0) NH2, NHC (0) NHR6, NHC (O) N (R6) 2, NR6C (0) N (R6) 2, OH, (O), C (0) OH, CN, NH 2, CF 3, OCF 3, CF 2 CF 3, F, Cl, Br or I; R6 is R7, R8 or R9; R7 is phenyl, which is not fused or fused with benzene, heteroarene or R7A; R7A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R8 is heteroaryl, which is not fused or fused with benzene, heteroarene or R8A; R8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R9 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R9A; R9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; where the portions represented by R, R2, R3, R4, R5 and R6 are independently substituted with one or two independently selected from R10, OR10, SR10, S (0) R10, S02R °, NH2, NHR10, N (R10) 2, C (0) R10, C (0) OR1 °, C (0) NHR10, C (O) N (R10) 2, NHC (0) R10, NR 0C (O) R10, NHC (0) NHR10, NHC (O) N (R0) 2, NR10C (O) NHR10 , NR10C (O) N (R10) 2, S02NHR10, SO2N (R10) 2, NHS02R10, NR1S02R1 °, OC (0) OR10, NHC (0) OR ° or NR1C (0) OR °; R10 is R 11, R 12, R 13 or R 14; R11 is phenyl, which is not fused or fused with benzene, heteroarene or R11A; R11A is cycloalkane, cycloalkene, heterocycloaic, or heterocycloalkene; R12 is heteroaryl, which is not fused or fused with benzene, heteroarene or R12A; R12A is cycloalkane, cycloalkene, heterocycloaic, or heterocycloalkene; R 3 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R13A; R 3A is cycloalkane, cycloalkene, heterocycloaic or heterocycloalkene; R14 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected from R15 or NHC (0) NHR15; R15 is R16, R7 R8; R16 is phenyl, which is not fused or fused with benzene, heteroarene or R16A; R16A is cycloalkane, cycloalkene, heterocycloaic or heterocycloalkene; R17 is heteroaryl, which is not fused or fused with benzene, heteroarene or R17A; R 7A is cycloalkane, cycloalkene, heterocycloaic or heterocycloalkene; R 8 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R18A; R 8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; B1 is H, R19, C (0) NHR19, C (0) N (R19) 2, NHC (0) R19, NR1C (0) R19, NHC (0) NHR19, NHC (0) N (R19) 2, NR 9C (O) NH R19, NR1C (0) N (R19) 2, S02NHR19, S02N (R19) 2, NHS02R19, NR 9S02R19, OC (0) OR19, NHC (0) OR19, or NR19C (0) OR19; R 9 is R 20, R 21, R 22 or R 23; R20 is phenyl, which is not fused or fused with benzene, heteroarene or R20A; R20A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R21 is heteroaryl, which is not fused or fused with benzene, heteroarene or R21A; R21A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R22 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R 2A; R 2A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R23 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected from R24, OR24, SR24, S (0) R24, S02R24, NH2, NHR24, N (R24) 2, C (0) R24, C (0) NH2, C (0) NHR24, C (0) N (R24) 2, NHC (0) R24, NR24C (0) R24, NHS02R24, NR24S02R24, NHC (0) OR24, NR2 C (0) OR24, S02NH2, S02NHR24, S02N (R24) 2, NHC (0) NH2, NHC (0) NHR24, NHC (0) N (R) 2, NR 4C (0) N (R) 2, OH , (O), C (0) OH, CN, NH2, CF3, OCF3, CF2CF3, F, Cl, Br or I; R 24 is R 25, R 26, R 27, alkyl, alkenyl or alkynyl; R25 is phenyl, which is not fused or fused with benzene, heteroarene or R25A; R25A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R26 is heteroaryl, which is not fused or fused with benzene, heteroarene or R26A; R 6A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R27 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unbound or fused with benzene, heteroarene or R27A; R27A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; C1 is O, S, S (O), S02, NH, or N (C2); C2 is R28, R29, R30 or R31; R28 is phenyl, which is not fused or fused with benzene, heteroarene or R28A; R28A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R29 is heteroaryl, which is not fused or fused with benzene, heteroarene or R29A; R29A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R30 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unbound or fused with benzene, heteroarene or R30A; R 30A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R3 is alkyl, alkenyl or alkynyl, each of which is substituted with one or two independently selected from R32 O R32 s r32 S (0) R32 So2R32, NH2, NHR32, N (R32) 2, C (0) R32, C (0) NH2, C (0) NHR32, C (0) N (R3) 2, NHC (0) R32, NR32C (0) R32, NHS02R32, NR32S02R32, NHC (0) OR32, NR32C (O) OR32, S02NH2, S02NHR32, S02N (R32) 2, NHC ( 0) NH2, NHC (0) NHR32, NHC (0) N (R3) 2, NR32C (0) N (R32) 2, OH, (O), C (0) OH, CN, NH2, CF3, OCF3, CF2CF3, F, Cl, Br or I; R32 is R33, R34 or R35; R33 is phenyl, which is not fused or fused with benzene, heteroarene or R33A; R33A is cycloalkane, cycloalkene, heterocycloaic, or heterocycloaiquene; R34 is heteroaryl, which is not fused or fused with benzene, heteroarene or R34A; R34A is cycloalkane, cycloalkene, heterocycloaikan or heterocycloaiken; R35 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R35A; R35A is cycloalkane, cycloalkene, heterocycloaikan or heterocycloaiken; D1 is N, CH or C (D2); D2 is R36, R37, R38 or R39; R36 is phenyl, which is not fused or fused with benzene, heteroarene or R36A; R36A is cycloalkane, cycloalkene, heterocycloaikan or heterocycloaiken; R37 is heteroaryl, which is not fused or fused with benzene, heteroarene or R37A; R37A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R38 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R38A; R38A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R39 is alkyl, alkenyl or alkynyl, each of which is substituted with one or two independently selected from R4o O R4o S R4o S (0) R4 or S02R40, NH2, NHR40, N (R40) 2, C (0) R4 ° , C (0) NH2, C (0) NHR4 °, C (O) N (R40) 2, NHC (0) R40, NR40C (O) R40, NHS02R40, NR40SO2R40, NHC (0) OR40, N R40C (O ) OR40, S02NH2, S02NHR40, SO2N (R40) 2, NHC (0) NH2, NHC (0) NHR40, NHC (O) N (R40) 2, NR 0C (O) N (R0) 2, OH, ( O), C (0) OH, CN, NH 2, CF 3, OCF 3, CF 2 CF 3, F, Cl, Br or I; R40 is R4, R42 or R43; R41 is phenyl, which is not fused or fused with benzene, heteroarene or R41A; R 1A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R42 is heteroaryl, which is not fused or fused with benzene, heteroarene or R 2A; R42A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R43 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R43A; R 3A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; where each previous cyclic portion is independently unsubstituted or substituted or further unsubstituted or further substituted with one or two or three or four independently selected from R44, OR44, SR44, S (0) R44, S02R44, NH2, NHR44, N (R44) 2) C (0) R44, C (0) OR44, C (0) NH2, C (0) NHR44, C (0) N (R4) 2, NHC (0) R44, NR4 C (0) R44, NHS02R44, NR4 S02R44, NHC ( 0) OR44, NR4 C (0) OR44, S02NH2, S02NHR44, S02N (R4) 2, NHC (0) NH2, NHC (0) NHR44, NHC (0) N (R44) 2, N R44C (O) N (R4) 2, C (N) NH2, C (N) NHR44, C (N) N (R44) 2, NHC (N) NH2, NHC (N) NHR44, NHC (N) N (R44) 2, OH , (O), C (0) H, C (0) OH, N02, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I; R44 is R45, R46, R47 or R48; R45 is phenyl, which is not fused or fused with benzene, heteroarene or R45A; R45A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R46 is heteroaryl, which is not fused or fused with benzene, heteroarene or R46A; R 6A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R47 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R47A; R 7A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R48 is alkyl, alkenyl or alkynyl, each of which is substituted with one or two independently selected from R49, OR49, SR49, S (0) R49, S02R49, NH2, NHR49, N (R49) 2, C (0) R49, C (0) NH2, C (0) NHR49, C (0) N (R49) 2, NHC (0) R49, NR49C (0) R49, NHS02R49, NR49S02R49, NHC (0) OR49, N R49C (0 ) OR49, S02NH2, S02NHR49, S02N (R49) 2, NHC (0) NH2, NHC (0) NHR49, NHC (0) N (R49) 2, NR49C (0) N (R49) 2, OP (0) (OH) 2, OP (0) (OH) (OR44), OP (0) (OR4) 2, OH, (0), C (0) OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or 1; R49 is R50, R51, R52, alkyl, alkenyl or alkynyl; R50 is phenyl, which is not fused or fused with benzene, heteroarene or R50A; R50A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R5 is heteroaryl, which is not fused or fused with benzene, heteroarene or R51A; R51A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene, and R52 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R52A; R5 A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; wherein the portions represented by R45, R46, R47 and R49 are independently unsubstituted or substituted with one or two or three or four independently selected from alkyl, alkenyl, alkynyl, OH, (O), C (0) OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I. Another embodiment comprises compounds having the formula (1), and therapeutically acceptable salts, prodrugs and salts of their prodrugs, wherein A1 is C (0) NHR, C (0) N (R) 2, NHC (0) R1, NR C (0) R, NHC (0) NHR1, NHC (O) N (R1) 2, NR1C (0) NHR1, NR1C (0) N (R1) 2, S02NHR1, S02N (R1) 2, NHS02R, NR1S02R1, OC (0) OR1, NHC (0) OR1, NR1C (0) OR1 or R5; ! R1 is R2, R3 or R4; R2 is phenyl, which is not fused or fused with benzene or heteroarene; R3 is heteroaryl, which is not fused or fused with benzene or heteroarene; R 4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; R5 is alkyl, alkenyl or alkynyl, each of which is substituted with one or two independently selected from R6, OR6, SR6, S (0) R6, S02R6, NH2, NHR6, N (R6) 2, C (0) R6, C (0) NH2, C (0) NHR6, C (0) N (R6) 2, NHC (0) R6, NR6C (0) R6, NHC (0) NHR6, OH, (O), C ( 0) OH, CN, NH2, CF3, OCF3, CF2CF3, F, Cl, Br or I; R6 is R7, R8 or R9; R7 is phenyl, which is not fused or fused with benzene or heteroarene; R8 is heteroaryl, which is not fused or fused with benzene or heteroarene; R9 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; wherein the portions represented by R, R2, R3, R4, R5 and R6 are independently substituted with one or two independently selected from R10, OR10, SR10, S (0) R10, S02R10, NH2, NHR10, N (R10) 2 , C (0) R10, C (0) OR1 °, C (0) NHR '°, C (O) N (R10) 2, NHC (0) R10, NR10C (O) R10 or NHC (0) NHR10; R10 is R11, R12, R3 or R14; R11 is phenyl, which is not fused or fused with benzene or heteroarene; R 2 is heteroaryl, which is not fused or fused with benzene or heteroarene; R 3 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; R14 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected from R15 or NHC (0) NHR15; R 15 is R 16, R 17 R 18; R 6 is phenyl, which is not fused or fused with benzene or heteroarene; R 7 is heteroaryl, which is not fused or fused with benzene or heteroarene; R 8 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; B1 is H or R19; R19 is R20, R2, R22 or R23; R20 is phenyl, which is not fused or fused with benzene or heteroarene; R21 is heteroaryl, which is not fused or fused with benzene or heteroarene; R22 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; R23 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected from R24, OR24, N (R2) 2, C (0) N (R24) 2, NHC (0) R24 , NR2 C (0) R24; R 24 is alkyl, alkenyl or alkynyl; C1 is O, S, S (O), S02, NH, or N (C2); C2 is R28, R29 or R30; R28 is phenyl, which is not fused or fused with benzene or heteroarene; R29 is heteroaryl, which is not fused or fused with benzene or heteroarene; R 30 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unbound or fused with benzene or heteroarene; D1 is N, CH or C (D2); D2 is R36, R37 or R38; R36 is phenyl, which is not fused or fused with benzene or heteroarene; R37 is heteroaryl, which is not fused or fused with benzene or heteroarene; R38 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; wherein each preceding cyclic portion is independently unsubstituted or substituted or further unsubstituted or further substituted with one or two or three or four independently selected from R44, OR44, SR44, S (0) R44, S02R44, NH2, NHR44, N ( R44) 2, C (0) R44, C (0) OR44, C (0) NH2, C (0) NHR44, C (0) N (R44) 2, NHC (0) R44, OH, (O), C (0) H, C (0) OH, N02, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I; R44 is R45, R46, R47 or R48; R45 is phenyl, which is not fused or fused with benzene or heteroarene; R46 is heteroaryl, which is not fused or fused with benzene or heteroarene; R47 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; R48 is alkyl substituted with OP (0) (OH) 2; wherein the portions represented by R45, R46 and R47 are independently unsubstituted or substituted with one or two or three or four independently selected from alkyl, alkenyl, alkynyl, OH, (O), C (0) OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I. Yet another embodiment comprises compounds having the formula (I), and therapeutically acceptable salts, prodrugs and salts of their prodrugs, wherein A1 is C (0) NHR or R5; R1 is R2, R3 or R4; R2 is phenyl, which is not fused or fused with benzene or heteroarene; R3 is heteroaryl, which is not fused or fused with benzene or heteroarene; R 4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; R5 is alkyl, alkenyl or alkynyl, each of which is substituted with one or two independently selected from R6, NHC (0) NHR6; R6 is R7, R8 or R9; R7 is phenyl, which is not fused or fused with benzene or heteroarene; R8 is heteroaryl, which is not fused or fused with benzene or heteroarene; R9 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; wherein the portions represented by R1, R2, R3, R4, R5 and R6 are independently substituted with one or two independently selected from R1 °, OR10, SR10, S (0) R10, S02R10, NH2, NHC (0) R1 °, NHC (0) NHR10; R10 is R11, R12, R13 or R14; R11 is phenyl, which is not fused or fused with benzene or heteroarene; R12 is heteroaryl, which is not fused or fused with benzene or heteroarene; R 13 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; R 4 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected from R 15 or NHC (0) NHR 15; R15 is R16, R17 R18; R 6 is phenyl, which is not fused or fused with benzene or heteroarene; R17 is heteroaryl, which is not fused or fused with benzene or heteroarene; R18 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; B1 is H or R19; R 9 is R 20, R 21, R 22 or R 23; R20 is phenyl, which is not fused or fused with benzene or heteroarene; R21 is heteroaryl, which is not fused or fused with benzene or heteroarene; R22 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; R23 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected from R2, OR24 or N (R24) 2; R 24 is alkyl, alkenyl or alkynyl; C is O, S, S (O), S02, NH, or N (C2); C2 is R28, R29 or R30; R28 is phenyl, which is not fused or fused with benzene or heteroarene; R29 is heteroaryl, which is not fused or fused with benzene or heteroarene; R 30 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unbound or fused with benzene or heteroarene; D1 is N, CH or C (D2); D2 is R36, R37 or R38; R36 is phenyl, which is not fused or fused with benzene or heteroarene; R37 is heteroaryl, which is not fused or fused with benzene or heteroarene; R38 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; where each previous cyclic portion is independently unsubstituted or substituted or further unsubstituted or further substituted with one or two or three or four independently selected from R 4 \ OR44, CN, CF 3, OCF 3, CF 2 CF 3, F, Cl, Br or I; R44 is R45, R46, R47 or R48; R45 is phenyl, which is not fused or fused with benzene or heteroarene; R46 is heteroaryl, which is not fused or fused with benzene or heteroarene; R47 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; R48 is alkyl subsituated with OP (0) (OH) 2; wherein the portions represented by R45, R46, and R47 are independently unsubstituted or substituted with one or two or three or four independently selected from alkyl. Still another embodiment comprises compounds having the formula (I), and therapeutically acceptable salts, prodrugs and salts of their prodrugs, wherein A1 is C (0) NHR1 or R5; R1 is R2, R3 or R4; R2 is phenyl; R3 is heteroaryl; R 4 is cycloalkyl or heterocycloalkyl; R5 is alkyl, alkenyl or alkynyl, each of which is substituted with R6, NHC (0) NHR6, R6 is R7 or R9; R7 is phenyl; R8 is heteroaryl; R9 is heterocycloalkyl; wherein the portions represented by R1, R2, R3, R4, R5 and R6 are independently substituted with one or two independently selected from R10, OR10, SR10, S02R1 °, NH2, NHC (0) R10, NHC (0) NHR10; R10 is R1, R12, R13 or R14; R11 is phenyl; R 12 is heteroaryl; R 13 is cycloalkyl; R14 is alkyl, which is unsubstituted or substituted with R16 or NHC (0) NHR16; R16 is phenyl; B1 is H or R19; R19 is R21, R22 or R23; R21 is heteroaryl; R22 is heterocycloalkyl; R23 is alkynyl, which is unsubstituted or substituted with R24, OR24 or N (R24) 2; R24 is alkyl; C1 is S or N (C2); C2 is R30; R30 is cycloalkyl; D1 is N, CH or C (D2); D2 is R37; R37 is heteroaryl; wherein each preceding cyclic portion is independently unsubstituted or substituted or further unsubstituted or further substituted with one or two or three or four independently selected from R44, OR44, CN, CF3, F, Cl, Br or I; R44 is R47 or R48; R47 is heterocycloalkyl; R48 is alkyl substituted with OP (0) (OH) 2; wherein R47 is unsubstituted or substituted with alkyl. Yet another embodiment refers to compositions comprising an excipient and a therapeutically effective amount of a compound having the formula (I). Yet another embodiment refers to methods of treating diseases involving over-expression or down-regulation of Protein kinases in a mammal, the methods comprising administering thereto a therapeutically effective amount of a compound having the formula (I). Yet another embodiment refers to methods for treating cancer in a mammal, comprising administering thereto a therapeutically effective amount of a compound having the formula (I).

Yet another embodiment relates to methods for treating bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer , cancer of the Skin, stomach cancer and thyroid cancer in a mammal, the methods comprising administering thereto a therapeutically effective amount of a compound having the formula (I). Yet another additional embodiment refers to compositions comprising an excipient and a therapeutically effective amount of a compound having the formula (I) and a therapeutically effective amount of an additional therapeutic agent or more than one additional therapeutic agent. Yet another embodiment relates to methods for treating diseases involving the over-expression or down-regulation of protein kinases in a mammal, methods comprising administering thereto a therapeutically effective amount of a compound having the formula (I) and an amount Therapeutically effective of an additional therapeutic agent or more than one additional therapeutic agent, with or without radiation. Another additional embodiment relates to methods for treating bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, leukemia, lymphoma, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer or thyroid cancer in a mammal, the methods comprising administering thereto a therapeutically effective amount of a compound having the formula (I) and a therapeutically effective amount of an additional therapeutic agent or more than one additional therapeutic agent.

Still another embodiment refers to: 4-amino-N- (4 - ((3-toluidinocarbonyl) amino) phenyl) thieno- [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((3-fluoroanilino) carbonyl) amino) phenyl) -thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((3-fluoro-4-methylanitino ) carbonyl) amino) -phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((4-toluidinocarbonyl) amino) phenol) thieno [2,3-d ] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((4-fluoroanilino) carbonyl) amino) phenyl) -thieno [2, 3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((3-chloro-4-fluoroanilino) carbonyl) amino) -phenyl) thieno [2,3-d] pyrimidine- 5-carboxamide, 4-amino-N- (4 - (((3-ethylanilino) carbonyl) amino) phenyl) -thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N - (4 - (((3-chloroanilino) carbonyl) amino) phenyl) -thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((3-cyanoanilino) carbonyl) amino) phenyl) -thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((2-fluoroanilino) carbonyl) amino) phenyl) -thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((3- (trifluoromethyl) anilino) carbonyl) amino) -phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino- N- (4 - (((4-fluoro-3- (trifluoromethyl) anilino) carbonyl) -amino) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((3-methoxyanilino) carbonyl) amino) phenyl) -thienp [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (( (5-fluoro-2-methylanilino) carbonyl) amino) -phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((4- (trifluoromethyl) an) Flax) carbonyl) amino) -phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((2-fluoro-5-methylanilino) carbonyl) amino) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((2-toluidinocarbonyl) amino) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((4-methoxyanilino) carbonyl) amino) phenyl) -thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((3 , 5-dimethylamino) carbonyl) amino) phenyl) -thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((2-fluoro-5- (trifluoromethyl) anilino) carbonyl ) -amino) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((anilinocarbonyl) amino) phenyl) thieno [2,3-d] pyrinnidine-5-carboxamide , 4-amino-N- (4 - (((3-chloroanilino) carbonyl) amino) phenyl) -6- (1-methyl-1H-pyrazol-4-yl) thieno [2,3-d] pyrimidine-5 -carboxamide, 4-amino-6- (1-methyl-1) H-pyrazol-4-yl) -N- (4 - ((3-toluidinocarbonyl) amino) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide 4-amino-N- (4 - (((2 -fluoro-5-methylamino) carbonyl) amino) -phenyl) -6- (1-methyl-1H-pyrazol-4-yl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((4-fluoro-3- (trifluoromethyl) anilino) carbonyl) - amino) phenyl) -6- (1-methyl-1H-pyrazol-4-yl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((2-fluoro- 5- (trifluoromethyl) anilino) carbonyl) -amino) phenyl] -6- (1-methyl-1 H-pyrrazol-4-yl) thieno [2,3-d] pyrimidine-5-carboxamide, -amino-6- (1-methyl-1H-pyrazol-4-M) -N- (4 - (((4- (trifluoromethyl) anilino) carbonyl) amino) phenyl) thieno [2,3-d] pyrimidine- 5-carboxamide, 4-amino-6- (1-methyl-1H-pyrazol-4-yl) -N- (4-phenoxyphenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N - (4-phenoxyfentl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4- (3-methylphenoxy) phenyl) -6- (1-metM-1H-pyrazol-4-yl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino- N- (4- (4-chlorophenoxy) phenyl) -6- (1-methyl-1H-pyrazol-4-yl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (4-methylphenoxy) phenyl) -6- (1-methyl-1H-pyrazol-4-yl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4- (3- chlorophenoxy) phenyl) -6- (1-metM-1H-pyrazol-4-yl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-6- (1-methyl-1H-pyrazole-4 -yl) -N- (4- (phenylsulfanyl) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4- (4-methylphenoxy) phenyl) thieno [2,3- d] pyrimidine-5-carboxamide, 4-amino-N- (4-phenoxyphenyl) -6- (1H-pyrazol-4-yl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N - (4-phenoxyphenyl) -6- (3-thienyl) thieno [2,3-d] pyrimidin-5- carboxamide, 4-amino-6- (4-methyl-1-piperazinyl) -N- (4 - ((3-toluidylcarbonyl) amino) phenyl) thieno [2,3-d] pyrimidine -5-carboxamide, 4-amino-N-methyl-N- (4 - ((3-toluidolcarbonyl) amino) phenyl) -thieno [2,3-d] pyrimidine-5-carboxamide, -amino-N- (4-phenoxyphenyl) t-ene [3,2-c] pyridine-3-carboxamide, 4-amino-N- (3-phenoxyphenyl) t Eno [3,2-c] pyridine-3-carboxamide, 4-amino-N- (4-benzylphenyl) thieno [3,2-c] pyridine-3-carboxamide, 4-amino-N- (4 - ((3-toluidinocarbonyl) amino) pheny1) t-ene [3,2-c] pyridine-3-carboxamide, 4-amino-N- (4- (benzoylamino) phenyl) t-ene [3,2-c] pyridin-3-carboxamide, 4-amino-7- (1-methyl-1H-p -razol-4-M) -N- (4 - ((3-toluidinocarbonyl) ami] no) phenyl) thieno [3,2-c] pyridine-3-carboxamide, 4-amino-N- (4- (benzoylamino) phenyl) -7- (1-methyl-1H-pyridol- 4-yl) thieno [3,2-c] pyridine-3-carboxamide, 4-amino-7- (1-methy1-1H-pyrazol-4-yl) -N- (4- phenoxyphenyl) thieno [3,2-c] pyridine-3-carboxamide, 4-amino-7- (1-methyl-1H-p¡razol-4-yl) -N- (3-phenoxyphenyl) t-ene [3 , 2-c] pyridyl-3-carboxamide, 4-amino-N- (4-benzylphenyl) -7- (1-methyl-1H-pyrazol-4-yl) t-ene [3,2-c] pyridine-3-carboxamide, 4-amino-7- (4- (4-methyl-1-piperazinyl) cyclohexyl) -N- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide, 4-amino-7- (4- (4-methyl-1-piperazinyl) cyclohexyl) -N- (3-phenoxyphenol) - 7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide, 4-amino-7- (4- (4-methyl-1-p-piperazinyl) cyclohexyl) -N- (4 - ((3- toluidinocarbonyl) amino) phenyl) -7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((4-aminophenyl) sulfanyl) phenyl) -7- (4- (4 -methyl-1-piperazinyl) cyclohexyl) -7H-pyrrolo [2, 3-d] pyrimidine-5-carboxamide, 4-amino-N- (4-benzylphenyl) -7- (4- (4-methyl-1-piperazinyl) cyclohexyl) -7H-pyrrolo [2,3-d] pyrimidine-5-carboxamide, 4-amino-7- (4- (4-methyl-1-piperazinyl) cyclohexyl) -N- (4- (phenylsulfonyl) phenyl) -7H-pyrrolo [2,3-d] pyrimidine- 5-carboxamide, 4-amino-1- (4- (4-morpholinyl) cyclohexyl) -1H-pyrazolo (3,4-d) pyrimidine-3-carboxylic acid, 4-amino-1- (4- (4- morpholinyl) cyclohexyl) -N- (4-phenoxyphenyl) -1H-pyrazolo (3,4-d) pyrimidine-3-carboxamide, N- (4 - ((E) -2- (4-amino-7- (1 -methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridin-3-yl) ethenyl) phenyl) -N '- (3-methylphenyl) urea 7- (1-methyl-1 H-pyrazole -4-yl) -3 - ((E) -2- (4-phenoxyphenyl) ethenyl) thieno- [3,2-c] pyridin-4-amine, 3- ((E) -2- (1.1) '-biphenyl) -4-ylethenyl) -7- (1-methyl-1 H -pyrazol-4-yl) thieno [3,2-c] pindin-4-amine, 4-amino-N- (4- ( (aniMnocarbonyl) amino) phenyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, 4-amino-N- (4 - (((( 3-fluorophenyl) amino) carbonyl) amino) phenyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, 4-amino-N- (4 - (((cyclohex ilamino) carbonyl) amino) phenyl) -7- (1-) tnet.l-1 H-pyrrazol-4-yl) t-ene [3,2-c] pyridine-3-carboxamide, 4-amino-N- (4 - (((((4-methylphenyl) amino) ) carbonyl) amino) phenyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, 4-amino-N- (4 - (((( 2-methylphenyl) amino) carbonyl) amino) phenyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, 4-amino-N- (3 - ((anilinocarbonyl) amino) phenyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, 4-amino-N- (3 - (( ((2-methylphenyl) annino) carbonyl) amino) phenyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, 4-amino-N- ( 3 - (((((4-methylphenyl) amino) carbonyl) amino) phenyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, 4-amino -N- (3 - ((((3-methylphenyl) annino) carbonyl) annino) phenyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide , 4-amino-N- (3- (benzoylamino) phenyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, 4-amino-N - (1- (anilinocarbonyl) piperidin-4-yl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, 4-amino-N- ( 1-ben zoilpiperidin-4-yl) -7- (1-methyl-1H-pyrazol-4'-yl) thieno [3,2-c] pyridine-3-carboxamide, trans4-amino-N- (4- (benzoylamino) cyclohexyl) ) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, trans4-amino-N- (4 - ((anilinocarbonyl) amino) cyclohexyl) -7 - (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, trans4-amino-N- (4 - ((((2-fluorophenyl) amino) carbonyl) amino ) -cyclohexyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridin-3- carboxamide, 4-amino-N- (4 - ((anilinocarbonyl) amino) benzyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, -amino-N- (3 - ((anilinocarbonyl) amino) benzyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, 4-amino- N - ((1- (aniMnocarbonyl) piperidin-4-yl) methyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, 4-amino -N- (4 - (((anilinocarbonyl) amino) methyl) phenyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, 4-amino -N- (3 - (((anilinocarbonyl) amino) methyl) phenyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, cis-4 -amino-N- (4 - ((anilinocarbonyl) amino) cyclohexyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, cis-4- amino-N - ((1S, 3R) -3 - ((anilinocarbonyl) amino) cyclohexyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide , cis-4-amino-N - ((1S, 3R) -3- (anilinocarbonyl) cyclohexyl) -7- (1-methyl-1H-pyrazol-4-yl) thieno [3,2-c] pyridin-3 -carboxamide, 4-amino-N- (3 - (((anilinocarbonyl) amino) methyl) phenyl) -7- (1- (2-hydroxyethyl) ) -1 H -pyrazol-4-yl) thieno [3,2-c] pyridine-3-carboxamide, 2- (4- (4-amino-3 - (((3- (((anilinocarbonyl) amino) diacid phosphate ) methyl) phenyl) amino) -carbonyl) thieno [3,2-c] pyridin-7-yl) -1H-pyrazol-1-yl) ethyl, 4-amino-N- (4 - ((((2- fluoro-3- (trifluoromethyl) phenyl) amino) carbonyl) -amino) phenyl) -6- (1-methyl-1H-pyrazol-4-yl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((anilinocarbonyl) amino) phenyl) -6- (1-methyl-1H-pyrazol-4-yl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino -N- (4 - ((anilinocarbonyl) amino) phenyl) -6-thien-3-ylthieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((anilinocarbonyl) amino) phenyl) -6-morpholin-4-ylthieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((thien-3-ylamino) carbonyl) amino) phenyl) -thieno [ 2,3-d] pyrimidiri-5-carboxamide, 4-amino-N- (4 - (((cyclopentylamino) carbonyl) amino) phenyl) -thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino -N- (4 - (((pyridin-3-ylamino) carbonyl) amino) phenyl) -thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((( -methylisoxazol-3-yl) amino) carbonyl) amino) -phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((cyclopropylamino) carbonyl) amino) phenyl) -thien [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((((2,4-difluorophenyl) amino) carbonyl) amino) phenyl) -thieno [2,3-d] ] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((((3,4-difluorophenyl) amino) carbonyl) amino) -phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, -amino-N- (4 - ((((3- (mor folin-4-ylmethyl) phenyl) amino) -carbonyl) amino) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((anilinocarbonyl) amino) cyclohexyl) thieno [ 2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((((3,5-dimethylisoxazol-4-yl) amino) carbonyl) - amino) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((1,3-thiazol-2-ylammon) carbonyl) amino) -phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - (((isoxazol-3-ylamino) carbonyl) amino) -phenyl) thieno [2,3-d] pyrimidin-5- carboxamide, 4-amino-N- (1- (anilinocarbonyl) piperidin-4-yl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (3 - ((anilinocarbonyl) amino) phenyl ) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((anilinocarbonyl) amino) phenyl) -6- (3-methoxyprop-1-ynyl) thieno [2,3- d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((anilinocarbonyl) amir: o) phenyl) -6-ethynylthieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((anilinocarbonyl) amino) phenyl) -6- (thien-3-ylethynyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((anilinocarbonyl) amino) phenyl) -6- (3- (dimethylamino) prop-1-ynyl) thieno [2,3-d] pyrimidine-5-carboxannide, 4-amino-N- (4 - ((2-fluorobenzoyl) amino) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((3-fluorobenzoyl) amino) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino -N- (4 - ((4-fluorobenzoyl) amino) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((2-methylbenzoyl) amino) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((3-methylbenzoyl) amino) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((((3- (hydroxymethyl) phenyl) amino) carbonyl) -amino) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (3 - (((anilinocarbonyl) amino) methyl) phenyl) -thieno [2 , 3-d] pyrimidine-5-carboxamide, 4-amino-N- (3 - (((((2-methylphenyl) amino) carbonyl) amino) phenyl) -thieno [2,3-d] pyrimidine-5-carboxamide , 4-amino-N- (3 - ((((((3-methylphenyl) amino) carbonyl) amino) -methyl) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (3 - ((((((3-fluorophenyl) amino) carbonyl) amino) -methyl) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (3 - (((( 3-methylphenyl) amino) carbonyl) amino) phenyl) -thieno [2,3-djpyrimidine-5-carboxamide, 4-amino-N- (3 - ((((4-methylphenyl) amino) carbonyl) amino) phenyl) -tiene [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (3 - ((((2-fluorophenyl) amino) carbonyl) amino) phenyl) -thieno [2,3-d] pyrimidine -5-carboxamide, 4-amino-N- (3 - (((((3-fluorophenyl) amino) carbonyl) amino) phenyl) -thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N - (3 - ((((4-fluorophenyl) amino) c arbonyl) amino) phenyl) -thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (3 - (((((3- (trifluoromethyl) phenyl) amino) carbonyl) -amino) methyl ) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (5- (2 - ((3-fluorophenyl) amino) -2-oxoethyl) -1,3-thiazole-2 - il) thieno [2,3-d] pyrimidine-5-carboxamide, N- (4- (2- (4-aminothieno [2,3-d] pyrimidin-5-yl) ethyl) phenyl) -N'-phenylurea , 4-amino-N- (4 - ((((3- (3-hydroxypropoxy) phenyl) amino) carbonyl) -amino) phenyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N - (4 - ((anilinocarbonyl) amino) benzyl) thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((((3-methylphenyl) amino) carbonyl) amino) benzyl ) -thieno [2,3-d] pyrimidine-5-carboxamide, 4-amino-N- (4 - ((((3-fluorophenyl) amino) carbonyl) amino) benzyl) -thieno [2,3-d] pyrimidine-5-carboxamide, and therapeutically acceptable salts, salts, prodrug, salts of prodrugs and their metabolites.

DETAILED DESCRIPTION OF THE INVENTION The variable portions of the compounds herein are represented by identifiers (uppercase with numerical and / or alphabetic superscripts) and can be specifically modalized. It should be understood that the appropriate valences for all portions and their combinations are maintained, that monovalent portions having more than one atom are linked through their left ends. It should also be understood that a specific modality of a variable portion may be the same or different from another modality specific that has the same identifier. The term "cyclic portion," as used herein, means benzene, cycloalkane, cycloalkyl, cycloalkene, cycloalkenyl, heteroarene, heteroaryl, heterocycloalkane, heterocycloalkyl, heterocycloalkene, heterocycloalkenyl, phenyl, spiroalkyl, spiroalkenyl, spiroheteroalkyl, and spiroheteroalkenyl. The term "cycloalkane," as used herein, means C3-cycloalkane, C4-cycloalkane, C5-cycloalkane and C6-cycloalkane. The term "cycloalkyl," as used herein, means C3-cycloalkyl, C4-cycloalkyl, C5-cycloalkyl and C6-cycloalkyl. The term "cycloalkene," as used herein, means C-cycloalkene, C5-cycloalkene and C6-cycloalkene. The term "cycloalkenyl," as used herein, means C4-cycloalkenyl, C5-cycloalkenyl and C6-cycloalkenyl. The term "heteroarene," as used herein, means furan, imidazole, isothiazole, isoxazole, 1, 2, 3-oxadiazole, 1, 2, 5-oxadiazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole , thiazole, thiophene, triazine and 1,2,3-triazole. The term "heteroaryl," as used herein, means furanyl, imidazolyl, isothiazolyl, isoxazolyl, 1,3-oxadiazoyl, 1,2,5-oxadiazyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl. , tetrazolyl, thiazolyl, thiophenyl, triazinyl and 1,2,3-triazolyl. The term "heterocycloalkane," as used herein, means cycloalkane having one or three CH 2 portions replaced with independently selected from O, S, S (O), S02 or NH and one or two CH portions not replaced or replaced with N and also means cycloalkane having one or two or three CH2 portions not replaced or replaced with independently selected from O, S, S (O), S02 or NH and one or two CH portions replaced with N. The term "heterocycloalkyl," as used herein, means cycloalkyl having one or two or three CH2-substituted portions independently selected from O, S , S (O), S02 or NH and one or two CH portions not replaced or replaced with N and also means cycloalkyl having one or two or three CH2 portions not replaced or replaced with independently selected from O, S, S (O) , S02 or NH and one or two CH portions replaced with N. The term "heterocycloalkene," as used herein, means cycloalkene having one or two or three substituted CH2 portions with independently selected from O, S, S (O), S02 or NH and a ao two CH portions not replaced or replaced with N and also means cycloalkene having one or two or three CH2 portions not replaced or replaced with independently selected O, S, S (O), S02 or NH and one or two CH portions replaced with N. The term "heterocycloalkenyl," as used herein, means cycloalkenyl having one or two or three CH 2 substituted portions independently selected from O, S, S (O), S02 or NH and one or two CH portions not replaced or replaced with N and also means cycloalkenyl having one or two or three CH2 portions not replaced or replaced with independently selected from O, S, S (O), S02 or NH and a or two CH portions replaced with N. The term "alkenyl," as used herein, means C2-alkenyl, C3-alkenyl, C4-alkenyl, C5-alkenyl and C6-alkenyl. The term "alkyl," as used herein, means C 1 -a I q u i I, C 2 -alkyl, C 3 -alkyl, C 4 -alkyl, C 5 to Iq and I 6 and C 6 -alkyl. The term "alkynyl," as used herein, means C2-alkynyl, C3-alkynyl, C4-alkynyl, C5-alkynyl and C6-alkynyl. The term "C2-alkenyl," as used herein, means ethenyl (vinyl). The term "C3-alkenyl," as used herein, means 1-propen-1-yl, 1-propen-2-yl (isopropenyl) and 1-propen-3-yl (allyl). The term "C4-alkenyl," as used herein, means 1-buten-1 - ??, 1 -buten-2-yl, 1,3-butadien-1-yl, 1,3-butadien-2-yl , 2-buten-1-yl, 2-buten-2-yl, 3-buten-1-yl, 3-buten-2-yl, 2-methyl-1-propen-1-yl and 2-methyl-2 -propen-1 -ilo. The term "C5-alkenyl," as used herein, means 2-methylene-3-buten-1-yl, 2-methylenebut-1-yl, 2-methyl-1-buten-1-yl, 2-methyl- 1,3-butadiene-1-yl, 2-methyl-2-buten-1-yl, 2-methyl-3-buten-1-yl, 2-methyl-3-buten-2-yl, 3-methyl -1-buten-1-yl, 3-methyl-1-buten-2-yl, 3-methyl-1,3-butadien-1-yl, 3-methyl-1,3-butadien-2-yl, 3 -methyl-2-buten-1-yl, 3-methyl-2-buten-2-yl, 3-methyl-3-buten-1-yl, 3-methyl-3-buten-2- 1-penten-1-yl, 1-penten-2-yl, 1-penten-3-yl, 1,3-pentadien-1-yl, 1,3-penta-dien-2-yl, 1 , 3-pentadien-3-yl, 1,4-pentad-en-1-yl, 1,4-pentadien-2-yl, 1,4-pentadien-3-yl, 2-penten-1-yl, 2 -penten-2-yl, 2-penten-3-yl, 2,4-pentadien-1-yl, 2,4-pentadien-2-yl, 3-penten-1-yl, 3-penten-2-yl , 4-penten-1-yl and 4-penten-2-yl. The term "C6-alkenyl," as used herein, means 2,2-dimethyl-3-buten-1-yl, 2,3-dimethyl-1-buten-1-yl, 2, 3-dim et i I-1, 3-butadien-1-yl, 2,3-dimethyl-2-buten-1-yl, 2,3-dimethyl-3-buten-1-yl, 2. 3- dimethyl-3-buten-2-yl, 3, 3-dim eti I-1-buten-1-yl, 3, 3-di met i 1-1 -buten-2-yl, 2-ethenyl-1 , 3-butadien-1-yl, 2-ethenyl-2-buten-1-yl, 2-ethyl-1-buten-1-yl, 2-yl-1, 3-butadien-1-yl, 2- ethyl-2-buten-1-yl, 2-ethyl-3-buten-1-yl, 1-hexen-1-yl, 1-hexen-2-yl, 1-hexen-3-yl, 1,3 -hexadien- 1 -yl, 1, 3-hexadien-2-yl, 1,3-hexadien-3-yl, 1,3,5-hexatrien-1-yl, 1, 3,5-hexatrien-2-yl , 1, 3, 5-hexatrien-3-yl, 1,4-hexadien-1-yl, 1,4-hexadien-2-yl, 1,4-hexadien-3-yl, 1,5-hexadien- 1 -yl, 1,5-hexadien-2-yl, 1,5-hexadien-3-yl, 2-hexen-1-yl, 2-hexen-2-yl, 2-hexen-3-yl, 2 , 4-hexadien-1-yl, 2,4-hexadien-2-yl, 2. 4- hexadien-3-yl, 2,5-hexadien-1-yl, 2,5-hexadien-2-yl, 2,5-hexadien-3-yl, 3-hexen-1-yl, 3-hexen- 2-yl, 3-hexen-3-yl, 3,5-hexadien-1-yl, 3,5-hexadien-2-yl, 3,5-hexadien-3-yl, 4-hexen-1-yl, 4-Hexe-2-yl, 4-hexene-3-yl, 5-hexen-1-yl, 5-hexen-2-yl, 5-hexen-3-yl, 2-methylene-3-methyl-3 buten-1-yl, 2-methylene-3-methylbut-1-yl, 2-methylene-3-penten-1-yl, 2-methylene-4-penten-1-yl, 2-methylenepent-1-yl, 2- methylenepent-3-yl, 3-methylene-1-penten-1-yl, 3-methylene-1-penten-2-yl, 3-methylenepent-1-yl, 3-methylene-1,4-pentadien- 1 -yl, 3-methylene-1, 4- pentadien-2-yl, 3-methylene-pent-2-yl, 2-methyl-1-penten-1-yl, 2-methyl-1- pent, en-3-yl, 2-methyl-1, 3-pentadien-1-yl, 2-methyl-1,3-pentadien-3-yl, 2-methyl-1,4-pentadien-1-yl, 2-methyl-1,4-pentadien-3 ilo, 2-methyl-2-penten-1-yl, 2-methyl-2-penten-3-yl, 2-methyl-2,4-pentadien-1-yl, 2-methyl-2,4-pentadien- 3-yl, 2-methyl-3-penten-1-yl, 2-methyl-3-penten-2-yl, 2-methyl-3-penten-3-yl, 2-methyl-4-penten-1 - ilo, 2-methyl-4-penten-2-yl, 2-methyl-4-penten-3-yl, 3-methyl-1-penten-1-yl, 3-methyl-1-penten-2-yl, 3-methyl-1,3-pentadien-1-yl, 3-m eti I-1, 3-pentadien-2-yl, 3-methyl-1,4-pentadien-1-yl, 3-methyl-1, 4-pentadien-2-yl, 3-methyl-2-penten-1-yl, 3-methyl-2-penten-2-yl, 3-methyl-2,4-pentadien-1-yl, 3-methyl- 3-penten-1-yl, 3-methyl-3-penten-2-yl, 3-methyl-4-penten-1-yl, 3-methyl-4-penten-2-yl, 3-methyl-4- penten-3-yl, 4-methyl I-1-penten-1-yl, 4-methyl-1-penten-2-yl, 4-methyl-1-penten-3-yl, 4-methyl-1, 3 -pentadien-1 -yl, 4-methyl-1,3-pentadien-2-yl, 4-methyl-1,3-pentad ien-3-yl, 4-methyl-1,4-pentadien-1-yl, 4-methyl-, 4-pentadien-2-yl, 4-m eti I-1, 4-pentadien-3-yl, 4 -methylene-2-penten-3-yl, 4-methyl-2-penten-1-yl, 4-methyl-2-penten-2-yl, 4-methyl-2-penten-3-yl, 4-methyl -2,4-pentadien-1-yl, 4-methyl-2,4-pentadien-2-yl, 4-methyl-3-penten-1-yl, 4-methyl-3-penten-2-yl, 4 methyl-3-penten-3-yl, 4-methyl-4-penten-1-yl and 4-methyl-4-penten-2-yl. The term "d-alkyl," as used herein, means methyl. The term "C 2 - a I q u i I o," as used herein, means ethyl. The term "C 3 - a I q u i I o," as used herein, means prop-1-yl and prop-2-yl (isopropyl). The term "C 4 - a I q u i I o," as used herein, means but-1-ilo, but-2-yl, 2-methylprop-1-lo and 2-methylprop-2-yl (tert-butyl). The term "C5-alkyl," as used herein, means 2,2-dimethylprop-1-yl (neo-pentyl), 2-m et i I bu t-1-yl, 2-methyl but-2-i it, 3-methylbut-1-yl, 3-methylbut-2-yl, pent-1-yl, pent-2-yl and pent-3-yl. The term "C6-alkyl," as used herein, means 2,2-dimethylbut-1-yl, 2,3-dimethylbut-1-yl, 2,3-dimeti I b ut- 2-i I, 3 , 3-dimethylbut-1-yl, 3, 3-dimethylbut-2-yl, 2-yl I but- 1 -yl hex-1-yl, hex-2-yl, hex-3-yl, 2-methylpent -1-yl, 2-methylpent-2-yl, 2-methylpent-3-yl, 3-methyl-1-pent-1-yl, 3-methylpent-2-yl, 3-methylpent-3-yl, 4-methylpent -1-lyl and 4-methylpent-2-yl. The term "C2-alkynyl," as used herein, means ethynyl (acetylenyl). The term "C 3 - a I q u i n i I o," as used herein, means 1-propin-1-yl and 2-propin-1-yl (propargyl). The term "C -alkynyl," as used herein, means 1-butin-1-yl, 1,3-butad and 1-yl-2-butin-1-yl, 3-butin-1-yl and 3 - butin -2 - i I o. The term "C5-alkynyl," as used herein, means 2-methyl-3-buty n-1-yl, 2-methyl-3-butin-2-yl, 3-methyl-1-butin-1-yl , 1,3-pentadiin-1-yl, 1,4-pentadiin-1-yl, 1,4-pentadiin-3-yl, 2,4-pentadiin-1-yl, 1 -pentin-1-yl, 1 -pentin-3-yl, 2-pentin-1-yl, 3-pentin-1-yl, 3-pe nt i? -2-i lo, 4-pentin-1-yl and 4-pentin-2-yl . The term "C 6 - a I quini I," as used herein, means 2,2-dimethyl-3-butin-1-yl, 3, 3-dim eti I-1-butin-1-yl, 2 -et i I -3-but i n-1-yl, 2-ethynyl-3-butin-1-yl, 1 -hexin-1-yl, 1 -hexin-3-yl, 1,3-hexadiin-1 -yl, 1, 3,5-hexatriin-1-yl, 4-hexadin-1-yl, 1,4-h ex adiin-3- i I, 1,5- hexadiin-1-yl, 1,5-hexadin-3-yl, 2-hexin-1-ylp, 2,5-hexadin-1-yl, 3-hexin-1-yl, 3-hexin-2 ilo, 3,5-hexadiin-2-yl, 4-hexin-1-yl, 4-hexin-2-yl, 4-hexin-3-yl, 5-hexin-1-yl, 5-hexin-2- It, 5-hexin-3-yl, 2-methyl-3-pentin-1-yl, 2-methyl-3-pentin-2-yl, 2-methyl-4-pentin-1-yl , 2-methyl-4-pentin-2-yl, 2-methyl-4-pentin-3-yl, 3-methotl-1 -pentin-1-yl, 3-methyl-4-pentin-1-yl, 3 -methyl-4-pentin-2-yl, 3-methyl-1,4-pentadiin-1-yl, 3-methyl-1,4-pentadiin-3-yl, 3-methyl-4-pentin-1-yl , 3-methyl-4-pentin-3-yl, 4-methyl-1 -pentin-1-yl and 4-methyl-2-pentin-1-yl. The term "C4-cycloalkane," as used herein, means cyclobutane. The term "C5-cycloalkane," as used herein, means cyclopentane. The term "C6-cycloalkane," as used herein, means cyclohexane. The term "C4-cycloalkene," as used herein, means cyclobutene and 1,3-cyclobutadiene. The term "C5-cycloalkene," as used herein, means cyclopentene and 1,3-cyclopentadiene. The term "C6-cycloalkene," as used herein, means cyclohexene, 1,3-cyclohexadiene and 1,4-cyclohexadiene. The term "C3-cycloalkenyl," as used herein, means cycloprop-1-en-1-yl and cycloprop-2-en- 1 -i lo. The term "C4-cycloalkenyl," as used herein, means cyclobut-1-en-1-yl and cyclobut-2-en-1-yl. The term "C5-cycloalkenyl," as used herein, means cyclopent-1-en-1-yl, cyclopent-2-en-1-yl, cyclopent-3-en-1-lo and cyclopenta-1,3-dien-1-yl. The term "C6-cycloalkenyl," as used herein, means cyclohex-1-en-1-yl, cyclohex-2-en-1-ylo, cyclohex-3-en-1-yl, cyclohexa-1, 3 -dien-1-yl, cyclohexa-1, 4-dien-1-yl, cyclohexa-1, 5-dien-1-yl, cyclohexa-2,4-dien-1-yl and cyclohexa-2, 5-dien -1 -ilo. The term "C3-cycloalkyl," as used herein, means cycloprop-1-yl. The term "C4-cycloalkyl," as used herein, means cyclobut-1-yl. The term "C5-cycloalkyl," as used herein, means cyclopent-1-yl. The term "C6-cycloalkyl," as used herein, means cyclohex-1-yl. The compounds of this invention may contain asymmetrically substituted carbon atoms in the R or S configuration, wherein the terms "R" and "S" are as defined in Puré Appl. Chem. (1976) 45, 13-10. Compounds that have asymmetrically substituted carbon atoms with equal amounts of R and S configurations are racemic in those atoms. The atoms that have an excess of one configuration on the other, are assigned the excess configuration, preferably an excess of about 85% -90%, preferably an excess of about 95% -99%, and most preferably an excess of more than about 99%. Accordingly, this invention is intended encompass racemic mixtures and relative and absolute enantiomers of the compounds thereof. The compounds of this invention may also contain carbon-carbon double bonds or carbon-nitrogen double bonds in the Z or E configuration, wherein the term "Z" represents the two largest substituents on the same side of the double bond gn. carbon-carbon or carbon-nitrogen, and the term "E" represents the two largest substituents on opposite sides of a carbon-carbon or carbon-nitrogen double bond. The compounds of this invention may also exist as a mixture of "Z" and "E" isomers. The compounds of this invention may also exist as tautomers or equilibrium mixtures thereof, wherein a proton of a compound is displaced from one atom to another. Examples of tautomers include, but are not limited to, keto-enol, phenol-keto, oxime-nitroso, nitro-aci, imine-enamine and the like. The compounds of this invention which contain NH, C (0) OH, OH or SH portions may have attached to the same prodrug-forming moieties. The prodrug-forming moieties are removed through metabolic processes and release compounds having NH, C (0) OH, OH or SH released in vivo. Prodrugs are useful for adjusting said pharmaceutical properties of the compounds such as solubility and / or hydrophobicity, absorption in the gastrointestinal tract, bioavailability, tissue penetration, and rate of elimination.

The metabolites of the compounds having the formula (I) produced through in vitro or in vivo metabolic processes, may also have utility for the treatment of diseases associated with overexpression or down-regulation of protein kinases. Certain precursor compounds that can be metabolized in vitro or in vivo to form compounds having the formula (I) may also have utility for treating diseases associated with overexpression or down-regulation of protein kinases. The compounds having the formula (I) can exist as acid addition salts, basic addition salts or zwitterions. The salts of the compounds having the formula (I) can be prepared during isolation or after purification. The acid addition salts are those derived from the reaction of a compound having the formula (I) with acid. Accordingly, salts that include salts of acetate, adipate, alginate, bicarbonate, citrate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorrate, camphor sulfonate, digluconate, formate, fumarate, glycerophosphate, glutamate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactobionate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylene sulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, phosphate, picrate, propionate, succinate, tartrate, thiocyanate, trichloroacetic, trifluoroacetic, toluensulfonate and undecanoate of the compounds having the formula (I) are intended to be encompassed by this invention. The basic addition salts of the compounds are those derived from the reaction of the compounds having the formula (I) with the bicarbonate, carbonate, hydroxide or phosphate of cations such as lithium, sodium, potassium, calcium and magnesium. The compounds having the formula (I) can be administered, for example, buccal, ophthalmic, oral, osmotic, parenterally (intramuscularly, intraperitoneally, intrasternally, intravenously, subcutaneously) rectally, topically, transdermally, vaginally and intra-arterially as well as through intra-articular injection, infusion, and placement in the body, such as, for example, the vasculature. Therapeutically effective amounts of a compound having the formula (I) depend on the treatment recipient, disease treated and its severity, composition comprising it, time of administration, route of administration, duration of treatment, potency, rate of elimination and if another drug is or is not co-administered. The amount of a compound having the formula (I) used to make a composition that will be administered daily to a patient in a single dose or in divided doses is from about 0.03 to about 200 mg / kg body weight. The individual dose compositions contain these amounts or a combination of their submultiples. The compounds having the formula (I) can be administered with or without an excipient. Excipients include, but are not limited to, encapsulators and additives such as accelerators absorption, antioxidants, binders, pH regulators, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, spreading agents, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, release agents, agents of sterilization, sweeteners, solubilizers, wetting agents, mixtures thereof and the like. The excipients for the preparation of compositions comprising a compound having the formula (I) that will be administered orally include, but are not limited to, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol , carbomers, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, povidone interlaced, diglycerides, ethanol, ethylcellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, ground nut oil, hydroxypropylmethylcellulose, isopropanol, isotonic saline, lactose, magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate salts, potato starch, povidone, propylene glycol, Ringer's solution, sunflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate salts , sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acids, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, mixtures of same and similar. The excipients for the preparation of compositions comprising a compound having the formula (I) that will be administered ophthalmic or orally include, but are not limited to, 1,3-butylene glycol, castor oil, corn oil, seed oil of cotton, ethanol, sorbitan fatty acid esters, germ oil, ground walnut oil, glycerol, isopropanol, olive oil, propylene glycols, propylene glycol, sesame oil, water, mixtures thereof and the like. The excipients for the preparation of compositions of a compound having the formula (I) that will be osmotically administered include, but are not limited to, chlorofluorohydrocarbons, ethanol, water, mixtures thereof and the like. The excipients for the preparation of compounds comprising a compound having the formula (I) to be administered parenterally include, but are not limited to, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, ground walnut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, sunflower oil, sesame oil, soybean oil, USP, or isotonic sodium chloride solution, water, mixtures thereof and the like. The excipients for the preparation of compositions comprising a compound having the formula (I) that will be administered rectally or vaginally include, but are not limited to, cocoa butter, polyethylene glycol, wax, mixtures thereof and the like. It is also expected that the compounds that have the formula (I) are useful when used with alkylating agents, angiogenesis inhibitors, antibodies, anti-metabolites, anti-mitotic, anti-proliferative, aurora kinase inhibitors, Bcr-Ab1 kinase inhibitors, biological response modifiers, inhibitors of cyclin-dependent kinase, cell cycle inhibitors, cyclooxygenase-2 inhibitors, leukemia viral oncogene homologous receptor (ErbB2) inhibitors, growth factor inhibitors, protein-90 heat shock inhibitors (HSP-90) , histone deacetylase inhibitors (HDAC), hormonal, immunological therapies, intercalation antibiotics, kinase inhibitors, mammalian target of rapamycin inhibitors, mitogen-activated regulated extracellular signal kinase inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), platinum chemotherapeutics, polo-like kinase inhibitors, proteasome inhibitors, purine analogs, pyrimidin analogues a, receptor tyrosine kinase inhibitors, retinoid / deltoid plant alkaloids, topoisomerase inhibitors, and the like. Alkylating agents include altretamine, AMD-473, AP-5280, apaziquone, bendamustine, brostallicin, busulfan, carboquone, carmustine (BCNU), chlorambucil, Cloretazine ™ (VNP 40101M), cyclophosphamide, decarbazine, estramustine, fotemustine, glufosfamide, ifosfamide , KW-2170, lomustine (CCNU), mafosfamide, melphalan, mitobronitol, mitolactol, nimustine, nitrogen mustard N-oxide, ranimustine, temozolomide, thiotepa, treosulfan, trofosfamide and the like. Inhibitors of angiogenesis include inhibitors of endothelial specific receptor tyrosine kinase (Tie-2), epidermal growth factor receptor (EGFR) inhibitors, insulin growth factor-2 receptor (IGFR-2) inhibitors, inhibitors of metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 inhibitors (MMP-9), platelet-derived growth factor receptor (PDGFR) inhibitors, thrombospodin analogs, factor receptor tyrosine kinase inhibitors of vascular endothelial growth (VEGFR) and similes. Aurora kinase inhibitors include AZD-1152, MLN-8054, VX-680 and the like. Inhibitors of Bcr-Ab1 kinase include DAS ATI N I B® (BMS-354825), GLEEVEC® (imatinib) and the like. CDK inhibitors include AZD-5438, BMI-1040, BMS-032, BMS-387, CVT-2584, f lavopy ridol, GPC-286199, MCS-5A, PD0332991, PHA-690509, seliciclib (CYC-202, R-roscovitine), ZK-304709 and Similar. Inhibitors of COX-2 include ABT-963, ARCOXIA® (etoricoxib), BEXTRA® (valdecoxib), BMS347070, CELEBREX ™ (celecoxib), COX-189 (lumiracoxib), CT-3, DERAMAXX® (deracoxib), JTE- 522, 4-methyl-2- (3,4-dimethylphenyl) -1- (4-sulfamoylphenyl-1 H-pyrrole), MK-663 (etoricoxib), NS-398, parecoxib, RS-57067, SC-58125, SD-8381, SVT-2016, S-2474, T-614, VIOXX® (rofecoxib) and the like.

EGFR inhibitors include ABX-EGF, anti-EGFr immunoliposomes, EGF-vaccine, EMD-7200, ERBITUX® (cetuximab), HR3, IgA antibodies, IRESSA® (gefitinib), TARCEVA® (erlotinib or OSI-774), TP -38, EGFR fusion protein, TYKERB® (lapatinib) and the like. Inhibitors of ErbB2 include CP-724-714, C 1-1033 (canertinib), Herceptin® (trastuzumab), TYKERB® (lapatinib), OMNITARG® (2C4, petuzumab), TAK-165, GW-572016 (ionafarnib), GW-282974, EKB-569, PI-166, dH ER2 (HER2 vaccine), APC-8024 (HER-2 vaccine), bi-specific antibody anti-HER / 2neu, B7.her2lgG3, bi-specific antibodies trifunctional AS HER2 , mAb AR-209, mAb 2B-1 and the like. Histone deacetylase inhibitors include LAQ-824, MS-275, trapoxin, suberoylanilide hydroxamic acid (SAHA), TSA, valproic acid, and the like. Inhibitors of HSP-90 include 17-AAG-nab, 17-AAG, CNF-101, CNF-1010, CNF-2024, 17-DMAG, geldanamycin, IPI-504, KOS-953, MYCOGRAB®, NCS-683664, PU24FCI, PU-3, radicicol, SNX-2112, STA-9090 VER49009 and the like. MEK inhibitors include ARRY-142886, ARRY-438162 PD-325901, PD-98059 and the like. Inhibitors of mTOR include AP-23573, CCI-779, everolimus, RAD-001, rapamycin, temsirolimus and the like. Non-spheroidal anti-inflammatory drugs include AMIGESIC® (salsalate), DOLOBID® (diflunisal), MOTRIN® (ibuprofen), ORUDIS® (cetoprofen), RELAFEN® (nabumetone), FELDENE® (piroxicam) ibuprofin cream, ALEVE® and NAPROSYN® (naproxen), VOLTAREN® (diclofenac), INDOCIN® (indomethacin), CLINORIL® (sulindac), TOLECTIN® (tolmetin), LODINE® (etodolac), TORADOL® (ketorolac), DAYPRO® (oxaprozin) and the like. PDGFR inhibitors include C-451, CP-673, CP-868596 and the like. Platinum chemotherapeutics include cisplatin, ELOXATIN® (oxaliplatin) eptaplatin, lobaplatin, nedaplatin, PARAPLATIN® (carboplatin), satraplatin, and the like. Pole type kinase inhibitors include BI-2536 and the like. Thrombospodin analogs include ABT-510, ABT-567, ABT-898, TSP-1 and the like. VEGFR inhibitors include AVASTIN® (bevacizumab), ABT-869, AEE-788, ANGIOZYME ™, axitinib (AG-13736), AZD-2171, CP-547,632, IM-862, Macugen (pegaptamib), NEXAVAR® (sorafenib, BAY43-9006), pazopanib (GW-786034 ), (PTK-787, ZK-222584), SUTENT® (sunitinib, SU-11248), VEGF trap, vatalanib, ZACTI A ™ (vandetanib, ZD-6474) and the like. Anti-metabolites include ALIMTA® (premetrexed disodium, LY231514, MTA), 5-azacytidine, XELODA® (capecitabine), carmofur, LEUSTAT® (cladribine), clofarabine, cytarabine, cytarabine ocphosphate, cytosine arabinoside, decitabine, deferoxamine, doxifluridine, eflornithine, EICAR, enocitabine, ethnilcitidine, fludarabine, hydroxyurea, 5-f luorouracil (5-FU) alone or in combination leucovorin. GEMZAR® (gemcitabine), hydroxyurea, ALKERAN® (melphalan), mercaptopurine, 6-mercaptopurine riboside, methotrexate, mycophenolic acid, nelarabine, nolatrexed, ocfosate, pelitrexol, pentostatin, raltitrexed, ribavirin, triapine, trimetrexate, S-1, thiazofurin, tegafur, TS-1, vidarabine, UFT and the like. Antibiotics include intercalation antibiotics aclarubicin, actinomycin D, amrubicin, annamicin, adriamycin, BLENOXANE® (bleomycin), daunorubicin, CAELYX® or MYOCET® (doxorubicin), amytrutinin epirbucin, glarbuicin, ZAVEDOS® (idarubicin), mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, VALSTAR® (valrubicin), zinostatin and the like. Topoisomerase inhibitors include aclarubicin, 9-aminocamptothecin, amonafide, amsacrine, becatecarin, belotecan, BN-80915, CAMPTOSAR® (irinotecan hydrochloride), camptothecin, CARDIOXANE® (dexrazoxin), diflomotecan, edarcain, ELLENCE® or PHARMORUBICIN® (epirubicin ), etoposide, exatecan, -hydroxycamptothecin, gimatecan, lurtotecan, mitoxantrone, orathecin, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide, topotecan and the like. Antibodies include AVASTIN® (bevacizumab), CD40-specific antibodies, chTNT-1 / ?, denosumab, ERBITUX® (cetuximab), HUMAX-CD4® (zanolimumab), specific antibodies-IGF1R-, lintuzumab, PANOREX® (edrecolomab), RENCAREX ® (WX G250), RITUXAN® (rituximab), ticilimumab, trastuzimab and the like. Hormone therapies include ARIMIDEX® (anastrozole), AROMASIN® (exemestane), arzoxifene, CASODEX® (bicalutam ida), CETROTIDE® (cetrorelix), degarelix, deslorelin, DESOPAN® (trilostane), dexamethasone, DROGENIL®, (flutamide), EVISTA® (raloxifene), fadrozole, FARESTON® (toremifene), FASLODEX® (fulvestrant), FEMARA®, (letrozole), formestane, glucocorticoids, HECTOROL® or RENAGEL® (doxercalciferol), lasofoxifene, leuprolide acetate, MEGACE® (megesterol ), MIFEPREX® (mifepristone); NILANDRON ™ (nilutamide), NOLVADEX® (tamoxifen citrate), PLENAXIS ™ (abarelix), predisone, PROPECIA® (finasteride), rilostane, SUPREFACT® (buserelin), TRELSTAR® (hormone releasing hormone leutenizing (LHRH)), vantas, VETORYL®, (trilostanoe or modrastano), ZOLADEX® (foshrelin, goserelin) and the like. The deltoids and retinoids include seocalcitol (EB1089, CB1093), lexacalcitrol (KH1060), fenretinide, PANRETIN® (aliretinoin), ATRAGEN® (liposomal tretinoin), TARGRETIN® (bexarotene), LGD-1550 and the like. The plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine, vinorelbine and the like. Proteasome inhibitors include VELCADE® (bortezomib), mg132, NPI-0052, PR-171 and the like. Examples of immunologicals include interferons and others immune enhancing agents. The interferons include interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a, ACTIMMUNE® (interferon gamma-Ib), or interferon gamma-n1, combinations thereof and the like. Other agents include ALFAFERONE®, BAM-002, BEROMUN® (tasonermin), BEXXAR® (tositumomab), CamPath® (alemtuzumab), CTLA4 (cytotoxic lymphocyte antigen 4), decarbazine, denileucin, epratuzumab, GRANOCYTE® (lenograstim), lentinan , interferon alpha leukocyte, imiquimod, MDX-010, melanoma vaccine, mitumomab, molgramostim, M YLOTARG ™ (gemtuzumab ozogamicin), NEUPOGEN® (filgrastim), OncoVAC-CL, OvaRex® (oregovomab), pemtumomab (Y-muHMFG1), PROVENGE®, sargaramostim, sizofilan, teceleucin, TheraCys®, ubenimex, VIRULIZIN®, Z-100, WF-10, PROLEUKIN® (aldesleukin), ZADAXIN® (timalfasin), ZENAPAX® (daclizumab), ZEVALIN® (90Y-I britumomab tiuxetan) and similar. Biological response modifiers are agents that modify the defense mechanisms of living organisms or biological responses, such as survival, growth or differentiation of tissue cells to direct them to have anti-tumor activity and include crestin, lentinan, sizofiran, picibanil PF- 3512676 (CpG-8954), ubenimex and the like. Pyrimidine analogs include cytarabine (ara C), cytosine arabinoside, doxifluridine, FLUDARA® (fludarabine), 5-FU (5-fluorouracil), floxuridine, GEMZAR® (gemcitabine), TOMUDEX® (ratitrexed), TROXATYL ™ (triacetyluridine troxacitabine ) and similar.

Purine analogues include LANVIS® (thioguanine) and PURI-NETHOL® (mercaptopurine). Anti-mitotics include batabulin, epothilone D (KOS-862), N- (2 - ((4-hydroxyphenyl) amino) pyridin-3-yl) -4-methoxybenzenesulfonamide, ixabepilone (BMS 247550), paclitaxel, TAXOTERE® ( docetaxel), PNU100940 (109881), patupilone, XRP-9881, vinflunine, ZK-EPO and the like. The compounds of the present invention are also intended to be used as a radiosensitizer that improves the effectiveness of radiotherapy. Examples of radiotherapy include, but are not limited to, external beam radiotherapy, teletherapy, brachytherapy, and sealed or unsealed source radiation therapy. In addition, the compounds having the formula (I) can be combined with other chemotherapeutic agents such as ABRAXANE ™ (ABI-007), ABT-100 (farnesyl transferase inhibitor), ADVEXIN®, ALTOCOR® or MEVACOR® (lovastatin), AMPLIGEN® (poly I: po I i C12U, a synthetic RNA), APTOS YN ™ (exisulind), ARE DI A® (pamidronic acid), arglabin, L-asparaginase, atamestane (1-methyl-3,17-dione) androsta-1, 4-diene), AVAGE® (tazarotno), AVE-8062, BEC2 (mitomomab), cachectin or cachexin (tumor necrosis factor), canvaxin (vaccine), CeaVac ™ (cancer vaccine), CELEUK® ( celmoleucine), CEPLENE® (histamine dihydrochloride), CERVARIX ™ (human papillomavirus vaccine), CHOP® (C: CYTOXAN® (cyclophosphamide); H: ADRIAMYCIN® (hydroxidexorubicin); O: Vincristine (ONCOVIN®); P : prednisone), CyPat ™, combrestatin A4P, DAB (389) EGF or TransMID-107R ™ (diphtheria toxins), dacarbazine, dactinomycin, 5,6-dimethylxanthenone-4-acetic acid (DMXAA), eniluracil, EVIZON ™ (squalamin lactate), DIMERICINE® (lotion) of liposome T4N5), discodermolide, DX-8951I (exatecan mesylate), enzastaurin, EPO906, GARDASIL® (quadrivalent recombinant human papilloma virus vaccine (Types 6, 11, 16, 18)), gastrinmune, genasens, GMK (vaccine of ganglioside conjugate), GVAX® (prostate cancer vaccine), halofuginone, histerelin, hydroxycarbamide, ibandronic acid, IGN-101, IL-13-PE38, IL-13-PE38QQR (cintredecin besudotox), IL-13-pseudomonas exotoxin , interferon-a, interferon- ?, JUNOVAN ™ or MEPACT ™ (mifamurtide), lonafarnib, 5, 10-methylenetetrahydrofolate, miltefosine (hexadecylphosphocholine), NEOVASTAT® (AE-941), NEUTREXIN® (trimetrexate glucuronate), NIPENT® (pentostatin ), ONCONASE® (a ribonuclease enzyme), ONCOPHAGE® (melanoma vaccine treatment), OncoVAX (IL-2 Vaccine), ORAT HECIN ™ (rubitecan), OSIDEM® (antibody-based cell drug), OvaRex® MAb (murine monoclonal antibody), paditaxel, PANDIMEX ™ (aglycone saponins of ginseng comprising 20 (S) protopanaxadiol (aPPD) aynd 20 (S ) protopanaxatriol (aPPT)), panitumumab, PANVAC®-VF (investigational cancer vaccine), pegaspargase, PEG Interferon A, phenoxodiol, procarbazine, rebimastat, REMOVAB® (catumaxomab), REVLIMID® (lenalidomide), RSR13 (efaproxiral), SO ATULINE® LA (lanreotide), SORIATANE® (acitretin), staurosporine (Streptomyces staurospores), talabostat (PT100), TARGRETIN® (bexarotene), Taxoprexin® (DHA-paclitaxel), TELCYTA ™ (TLK286), temilifen, TE ODAR® (temozolomide), tesmilifene, thalidomide, THERATOPE® (STn-KLH), timitaq (2-amino-3,4-dihydrohydrochloride) 6-methyl-4-oxo-5- (4-pyridylthio) quinazoline), TNFerade ™ (adenovector: DNA carrier containing the gene for tumor necrosis factor-a), TRACLEER® or ZAVESCA® (bosentan), tretinoin ( Retin-A), tetrandrine, TRISENOX® (arsenic trioxide), VIRULIZIN®, ucrain (alkaloid derivative of the superior celandin plant), vitaxin (anti-alpha-beta3 antibody), XCYTRIN® (motexafin gadolinium), XINLAY ™ ( atrasentan), XYOTAX ™ (paclitaxel polyglumex), YONDELIS ™ (trabectedin), ZD-6126, ZINECARD® (dexrazoxane), zometa (zolendronic acid), zorubicin and the like. To determine the inhibitory activity of the representative compounds having the formula (I) for protein kinases, the following assay was used: In 384-well V-bottom propylene plates (Axygen # P-384-120SQ C) , 10 L of recombinant Aurora Kinase-A (AurA, Upstate # 14-511, final concentration of 1 nM) were mixed with 10 μm of biotinylated peptide substrate (Genemed, final concentration 2 μm), and various concentrations of Representative compounds (2% final DMSO) in pH buffer (25 mM HEPES, pH 7.5, 0.5 m DTT, 10 mM mgCl2 100 μ? Na3V04, 0.075 mg / ml Triton X-100). The reaction was started by adding [33 P] -ATP (Perkin Elmer, 5 μm final concentration, 2mCi / umol). The reaction was extinguished after 1 hour through the addition of 50 μ? of stop pH regulator (50 mM EDTA, 2M NaCl final concentration). 80 μl of the stopped reactions were transferred to Steam Plates covered with 384 cavities streptavidin (Perkin Elmer, #S P410A0001 PK), incubated 10 minutes at room temperature, washed 3 times with 0.05% Tween-20 / PBS using an ELX-405 automatic plate washer (BioTeK) and counted in a TopCount Cintillation Plate Reader (Packard). The IC 50 values are shown in Table 1.

TABLE 1 These data demonstrate the utility of the compounds having the formula (I) as Aurora kinase A inhibitors. To determine the activity of other representative compounds of the invention, the Aurora A Activa enzyme was incubated in wells of a 384-well plate. cavities with biotinylated STK-2 substrate (Upstate), 1 mM ATP, and various concentrations of inhibitors in a Hepes pH regulator, pH 7.4 containing MgCl2, sodium orthovanadate and Triton X-1O0. After 1 hour, the reaction was stopped with EDTA and Europium Criptate anti-phospho-STK antibody (Upstate) and SA-XL665 (Upstate) were added to detect the phosphopeptide. The amount of phosphorylation was determined through the resolved time fluorescence ratio of signals at 665 nm and 615 nm. The IC50s were calculated through an exponential adjustment of the inhibition values with the inhibitor concentrations using the Assay Explorer software.

TABLE 2 It is expected that, since compounds having the formula (I) inhibit the activity of Aurora kinase A, they may also have the ability as inhibitors of protein kinases having a tight structural homology to Aurora kinase A such as, for example, example, Aurora-kinase B and Aurora-kinase C. Structural homology between protein kinases A, B and C is reported in Nature Reviews / Cancer, Vol: December 4, 2004. Therefore, it is expected that the compounds that have the formula (I) have utility in the treatment of diseases during which protein kinases, such as any or all members of the Aurora-kinase family are expressed. Diseases that involve over-expression or down-regulation of members of the Aurora-kinase family include, but are not limited to, acoustic neuroma, acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute T cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer, bronchogenic carcinoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia (granulocytic), chronic myelogenous leukemia, colon cancer, colo-rectal cancer, craniopharyngioma, cystadenocarcinoma, diffuse large B-cell lymphoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer , endotheliosarcoma, ependymoma, epithelial carcinoma, arithroleukemia, esophageal cancer Aug, estrogen receptor positive breast cancer, essential thrombocythemia, Ewing tumor, fibrosarcoma, follicular lymphoma, germ cell testicular cancer, glioma, heavy chain, hemangioblastoma, hematologic malignancies (leukemias such as acute lymphocytic leukemia and chronic myeloid leukemia) and lymphomas, hepatoma, hepatocellular cancer, hormone-insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer, lymphoid agiosendotheliosarcoma, lymph angiosarcoma, lymphoblastic leukemia , lymphoma (Hodgkin's and non-Hodgkin's), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T cell or B cell origin, leukemia, lymphoma, medullary carcinoma, medulloblastoma, melanoma, meningione, metothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, non-small cell lung cancer, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pandemic cancer, papillary adenocarcinomas, carcinoma papillary, pinealoma, polycythemia vera, prostate cancer, rectal cancer, carcinoma of renal cell, reinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), small cell lung cancer, stomach cancer, cell carcinoma squamous, sinovioma, sweat gland carcinoma, thyroid cancer, Waldenstrom macroglobulinemia, testicular tumors, uterine cancer and Wilms' tumor. It is also expected that the compounds having the formula (I) can inhibit the growth of cells derived from a cancer or neoplasm such as breast cancer (including estrogen receptor positive breast cancer), colorectal cancer, endometrial cancer, lung cancer (including small cell lung cancer), lymphoma (including large diffuse or follicular B cell), lymphoma (including non-Hodgkin's lymphoma), neuroblastoma, ovarian cancer, prostate cancer (including hormone-insensitive prostate cancer) and testicular cancer (including germ cell testicular cancer). It is also expected that compounds having the formula (il) can inhibit the growth of cells derived from a pediatric cancer or neoplasm such as embryonal rhabdomyosarcoma.pediatric lymphoblastic leukemia, pediatric acute myelogenous leukemia, pediatric alveolar rhabdomyosarcoma, pediatric anaplastic ependymoma, pediatric anaplastic large cell lymphoma, pediatric anaplastic medulloblastoma, pediatric central nervous system teratoid / rhabdoid tumor, pediatric bifenotypic acute leukemia, pediatric Burkitts lymphoma, pediatric cancers of the Ewing family such as primitive neuroectodermal tumors, pediatric diffuse anaplastic Wilm tumor, pediatric favorable histology Wilm's tumor, pediatric glioblastoma, pediatric medulloblastoma, pediatric neuroblastoma, pediatric neuroblastoma derived myelomitomatosis, pre-B cell cancers pediatric (such as leukemia), pediatric pseudoarcoma, pediatric rhabdoid kidney tumor, pediatric rhabdomyosarcoma, and pediatric T cell cancers, such like Mnfoma and skin cancer. For example, the involvement of Aurora-kinases in bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, Skin cancer, stomach cancer and lymphoid cancer are reported in Naura Reviews / Cancer, Vol. 4, December, 2204. Compounds having the formula (I) can be made through synthetic chemical procedures, examples of which are shown later. It should be understood that the order of the steps in the procedures can be varied, that the reactants, solvents, and reaction conditions can be replaced by those specifically mentioned, and that the vulnerable portions can be protected and unprotected, as necessary. Protecting groups for C (0) OH portions include, but are not limited to, acetoxymethyl, to I i I, benzoylmethyl, benzyl, benzyloxymethyl, tert-butyl, tert-butyldiphenylsilyl, d if in i I methyl, cyclobutyl, cyclohexyl cyclopentyl, cyclopropyl, diphenylmethylsilyl, ethyl, para-methoxybenzyl, methoxymethyl, methoxyethoxymethyl, methyl, methylthiomethyl, naphthyl, para-nitrobenzyl, phenyl, n-propyl, 2,2,2-trichloroethyl, triethylsilyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, triphenylmethyl, and the like. Protecting groups for C (O) and C (0) H portions include, but are not limited to, 1,3-dioxylketal, diethyl ketal, dimethyl ketal, 1,3- dithianylketal, O-methyloxime, O-phenyloxime, and the like. Protecting groups for NH portions include, but are not limited to, acetyl, alanyl, benzoyl, benzyl (phenylmethyl), benzylidene, benzyloxycarbonyl (Cbz), tert-butoxycarbonyl (Boc), 3,4-dimethoxybenzyloxycarbonyl, diphenylmethyl, diphenylphosphoryl, formyl , methanesulfonyl, para-methoxybenzyloxycarbonyl, phenylacetyl, phthaloyl, succinyl, trichloroethoxycarbonyl; triethylsilyl, trifluoroacetyl, trimethylsilyl, triphenylmethyl, triphenylsilyl, para-toluenesulfonyl, and the like. Protecting groups for OH and SH portions include, but are not limited to, acetyl, allyl, allyloxycarbonyl, benzyloxycarbonyl (Cbz), benzoyl, benzyl, tert-butyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, 3,4-dimethoxybenzyl, , 4-dimethoxybenzyloxycarbonyl, 1,1-dimethyl-2-propenyl, diphenylmethyl, formyl, methanesulfonyl, methoxyacetyl, 4-methoxybenzyloxycarbonyl, para-methoxybenzyl, methoxycarbonyl, methyl, para-toluenesulfonyl, 2,2,2-trichloroethoxycarbonyl, 2,2 , 2-trichloroethyl, triethylsilyl, trifluoroacetyl, 2- (trimethylsilyl) ethoxycarbonyl, 2-trimethylsilylethyl, triphenylmethyl, 2- (triphenylphosphonium) ethoxycarbonyl, and the like. The following abbreviations have the meanings indicated.

ADDP means 1, 1 '- (azodicarbonyl) dipiperidine; AD-mixture-β means a mixture of (DHQD) 2PHAL, K3Fe (CN) 6, K2C03 and K2S04); AIBN means 2,2'-azobis (2-methylpropionitrile); 9-BBN means 9-borabicyclo [3.3.1] nonane; Cp means cyclopentadiene; (DHQD) 2PHAL means hydroquinidine 1,4-phthalazinidiyl diethyl ether; DBU means 1,8-diazabicyclo [5.4.0] undec-7-ene; DIBAL means diisobutylaluminum hydride; DIEA means diisopropylethylamine; DMAP means?,? - dimethylaminopyridine; DME means 1,2-dimethoxyethane; D F means?,? - dimethylformamide; dmpe means 1,2-bis (dimethylphosphino) ethane; DMSO means dimethyl sulfoxide; dppa means diphenylphosphoryl azide; dppb means 1,4-bis (diphenylphosphino) butane; dppe means 1,2-bis (diphenylphosphino) ethane; dppf means 1,1'-bis (diphenylphosphino) ferrocene; dppm means 1,1-bis (diphenylphosphino) methane; EDAC means 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide; Fmoc means fluorenylmethoxycarbonyl; HATU means 0- (7-azabenzotriazol-1-yl) -N, N'N'N'-tetramethyluronium hexaf luorophosphate; HMPA means hexamethylphosphoramide; IPA means isopropyl alcohol; LDA means lithium diisopropylamide; LHMDS means bis (hexamethyldisilylamide) lithium; MP-BH3 means macroporous triethylammonium methylpolystyrene-cyanoborohydride; LAH means lithium aluminum hydride; NCS means N-chlorosuccinimide; PyBOP stands for benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate; TDA-1 means tris (2- (2-methoxyethoxy) ethyl) amine; TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; NCS means N-chlorosuccinimide; NMM means N-methylmorpholine; NMP means N-methylpyrrolidine; and PPh3 means triphenylphosphine.

SCHEME 1 The compounds having the formula (1) can be described herein and converted to compounds having the formula (2) through the first and DPPA followed for hydrolysis of the product with water. The reactions are typically conducted in solvents such as benzene, toluene, THF, mixtures thereof and the like, at temperatures between about 50 ° C and 110 ° C. The introduction of portions represented by A1 can be achieved by reacting the compounds having the formula (1), a compound having the formula H2NR1 or HN (R) 2, a coupling agent and a base, with or without D AP. Examples of coupling agents include DCC, EDCI, and the like. Examples of bases include TEA, DIEA, pyridine and the like. The reactions are typically conducted in solvents such as THF, dichloromethane, DMF, DMSO, chloroform, mixtures thereof and the like at temperatures between about 0 ° C and 25 ° C. The introduction of portions represented by A1 can also be achieved by reacting the compounds having the formula (2) and the appropriate isocyanate, carbonyl chloride, sulfonyl chloride, carbamoyl chloride. Reactions are typically conducted in solvents such as THF, ethyl acetate, dichloromethane, DMF, DSO, chloroform, mixtures thereof and the like at temperatures between about 0 ° C and 110 ° C, depending on the reactivity of the resulting materials. The following examples are presented to provide what is believed to be the most useful and easily understood description of procedures and conceptual aspects of this invention.

EXAMPLE 1A A mixture of 5-amino-4-cyano-thiophene-3-carboxylic acid ethyl ester (2.4 g, prepared as described in Annali. Di Chimica, 64, 833, 1974) in formamide (45 ml) at 170 ° C. it was stirred for 8 hours and concentrated. The concentrate was flash chromatographed on silica gel with 10-50% ethyl acetate / hexanes.

EXAMPLE 1B A mixture of Example 1A (0.62 g) and L¡OH H20 (0.54 g) in THF (54 ml), water (13 ml) and methanol (13 ml) at 80 ° C was stirred for 16 hours, cooled to room temperature environment and concentrated. The concentrate was taken up in water, cooled in an ice bath, stirred for 30 minutes and treated with 1N HCl until acidic, stirred for 30 minutes and filtered.

EXAMPLE 1C A mixture of 1-isocyanato-3-methylbenzene (0.6 ml) was added to a mixture of (4-aminophenyl) carbamic acid tert-butyl ester (1 g) in dichloromethane (48 ml) 0 ° C. The mixture was stirred for 30 minutes, warmed to room temperature, stirred for 24 hours and filtered. The filtrate was suspended in dichloromethane (80 ml), cooled in an ice bath, treated with TFA (50 ml), stirred for 15 minutes, warmed to room temperature, stirred for 18 hours and concentrated. The concentrate was concentrated twice from methanol and toluene.

EXAMPLE 1D Diisopropylethylamine (0.3 ml) was added to a mixture of Example 1B (0.2 g), Example 1C (0.336 g) and HATU (0.452 g) in DMF (5.7 ml) at 0 ° C. The mixture was stirred for 0.5 hour, warmed to room temperature, stirred for 20 hours, cooled to 0 ° C, diluted with water (80 ml), stirred for 1 hour and filtered. The filtrate was washed with water, dried and titered with 2: 1 dichloromethane / methanol. 1 H NMR (400 MHz, DMSO-d 6) d 10.63 (s, 1 H), 8.66 (s, 1 H), 8.55 (s, 1 H), 8.37 (s, 1 H), 8.32 (s, 1 H), 7.98 (br s) , 2H), 7.63 (d, 2H), 7.46 (d, 2H), 7.30 (s, 1H), 7.18 (m, 2H), 6.79 (d, 1H), 2.28 (s, 3H).

EXAMPLE 2 This Example was prepared by substituting 1-fluoro-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Example 1C. H NMR (500 MHz, DMSO-d6) d 10.67 (s, 1H), 8.89 (s, 1H), 8.76 (s, 1H), 8.37 (s, 1H), 8.32 (s, 1H), 8.02 (brs, 2H), 7.64 (d, 2H), 7.51 (s, 1H), 7.47 (d, 2H), 7.30 (m, 1H), 7.12 (d, 1H), 6.78 (m, 1H).

EXAMPLE 3 This Example was prepared by substituting 1-f-luoro-3-isocyanato-4-methylbenzene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (500 MHz, DMSO-d 6) d 10.67 (s, 1 H), 8.76 (s, 1 H), 8.72 (s, 1 H), 8.39 (s, 1 H), 8.34 (s, 1 H), 7.93 (s, 2H), 7.64 (d, 2H), 7.45 (m, 3H), 7.16 (m, 1H), 7.03 (d, 1H), 2.17 (s, 3H).

EXAMPLE 4 This Example was prepared by substituting 1-isocyanato-4-methylbenzene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (400 MHz, DMSO-d 6) d 10.63 (d, 1 H), 8.62 (d, 1 H), 8.51 (d, 1 H), 8.37 (d, 1 H) 8.32 (d, 1 H), 8.00 (brs, 2 H) ), 7.62 (d, 2H), 7.46 (d, 2H), 7.33 (d, 2H), 7.08 (d, 2H), 2.24 (m, 3H).

EXAMPLE 5 This Example was prepared by substituting 1-fluoro-4-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Example 1C. H NMR (500 MHz, DMSO-d6) d 10.66 (s, 1H), 8.68 (s, 2H), 8.37 (s, 1H), 8.32 (s, 1H), 7.92 (brs, 2H), 7.63 (d, 2H), 7.47 (d, 4H), 7.12 (t, 2H). EXAMPLE 6 This Example was prepared by substituting 1-chloro-2-f luoro-4-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (500 MHz, DMSO-d 6) d 10.67 (s, 1 H), 8.86 (s, 1 H), 8.79 (s, 1 H), 8.38 (s, 1 H), 8.33 (s, 1 H), 8.07 (brs, 2H), 7.81 (d, 1H), 7.64 (d, 2H), 7.47 (d, 2H), 7.32 (m, 2H).

EXAMPLE 7 This Example was prepared by substituting 1-e t i I-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Example 1C. H NMR (300 MHz, DMSO-d6) d 10.64 (s, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 8.38 (s, 1H), 8.33 (s, 1H), 7.63 (d, 2H), 7.46 (d, 2H), 7.24 (m, 5H), 6.82 (d, 1H), 2.58 (m, 2H), 1.18 (t, 3H).

EXAMPLE 8 This Example was prepared by substituting 1-chloro-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Example 1C. ?? NMR (500 MHz, DMSO-d6) d 10.67 (s, 1H), 8.87 (s, 1H), 8.78 (s, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 7.72 (s, 1H) ), 7.64 (d, 2H), 7.68 (brs, 2H), 7.47 (d, 2H), 7.28 (m, 2H), 7.02 (d, 1H).

EXAMPLE 9 This Example was prepared by substituting 1-cyano-3-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (300 MHz, DMSO-d 6) d 10.67 (s, 1 H), 9.00 (s, 1 H), 8.86 (s, 1 H), 8.37 (s, 1 H), 8.32 (s, 1 H), 7.98 (m, 1H), 7.99 (brs, 2H), 7.66 (m, 3H), 7.46 (m, 4H).

EXAMPLE 10 This Example was prepared by substituting 1-fluoro-2-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (500 MHz, DMSO-d 6) d 10.68 (s, 1 H), 9.11 (s, 1 H), 8.54 (s, 1 H), 8.38 (s, 1 H), 8.32 (s, 1 H), 8.16 (t, 1H), 7.83 (brs, 2H), 7.66 (d,, 2H), 7.48 (d, 2H), 7.24 (m, 1H), 7.14 (t, 1H), 7.01 (m, 1H).

EXAMPLE 11 This Example was prepared by substituting 1-isocyanato-3-trifluoromethylbenzene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (300 Hz, DMSO-d 6) d 10.67 (s, 1 H), 9.02 (s, 1 H), 8.81 (s, 1 H), 8.38 (s, 1 H), 8.32 (s, 1 H), 8.03 (s, 1H), 8.00 (brs, 2H), 7.65 (d, 2H), 7.56 (m, 2H), 7.48 (d, 2H), 7.31 (d, 1H).

EXAMPLE 12 This Example was prepared by substituting 1-fluoro-4-isocyanato-2-trifluoromethylbenzene for 1-isocyanato-3-methylbenzene in Example 1C. H NMR (300 MHz, DMSO-d6) d 10.67 (s, 1H), 9.01 (s, 1H), 8.83 (s, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 8.02 (dd, 2H), 7.98 (brs, 2H), 7.65 (d, 2H), 7.46 (m, 3H).

EXAMPLE 13 This Example was prepared by substituting 1-isocyanato-3-methoxybenzene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (400 MHz, DMSO-d 6) d 10.64 (s, 1 H), 8.66 (s, 1 H), 8.64 (s, 1 H), 8.38 (s, 1 H), 8.32 (s, 1 H), 8.02 (brs, 2H), 7.63 (d, 2H), 7.47 (d, 2H), 7.19 (s, 1H), 7.16 (d, 1H), 6.93 (d, 1H), 6.55 (d, 1H), 3.74 (s, 3H) ).

EXAMPLE 14 This Example was prepared by substituting 1-fluoro-3-isocyanato-4-methylbenzene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (400 MHz, DMSO-d 6) d 10.66 (s, 1 H), 9.19 (s, 1 H), 8.38 (s, 1 H), 8.32 (s, 1 H), 8.02 (s, 3 H), 7.86 (dd, 1H), 7.66 (d, 2H), 7.49 (d, 2H), 7.19 (t, 1H), 6.74 (m, 1H), 2.23 (s, 3H).

EXAMPLE 15 This Example was prepared by substituting 1-isocyanato-4-trifluoromethylbenzene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (500 MHz, DMSO-d 6) d 10.69 (s, 1 H), 9.09 (s, 1 H), 8.83 (s, 1 H), 8.39 (s, 1 H), 8.34 (s, 1 H), 7.88 (brs, 2H), 7.65 (m, 6H), 7.49 (d, 2H).

EXAMPLE 16 This Example was prepared by substituting 1-fluoro-2-isocyanato-4-methylbenzene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (500 MHz, DMSO-d 6) d 10.67 (s, 1 H), 9.09 (s, 1 H), 8.47 (s, 1 H), 8.39 (s, 1 H), 8.33 (s, 1 H), 8.00 (d, 1H), 7.81 (brs, 2H), 7.65 (d, 2H), 7.47 (d, 2H), 7.10 (m, 1H), 6.80 (s, 1H), 2.28 (s, 3H).

EXAMPLE 17 This Example was prepared by substituting 1-isocyanato-2-methylbenzene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (400 MHz, DMSO-d 6) d 10.65 (s, 1 H), 9.03 (s, 1 H), 8.39 (s, 1 H), 8.34 (s, 1 H), 8.11 (brs, 2 H), 7.89 (s, 1H), 7.84 (d, 1H), 7.64 (d, 2H), 7.48 (d, 2H), 7.15 (m, 2H), 6.94 (t, 1H), 2.25 (s, 3H).

EXAMPLE 18 This Example was prepared by substituting 1-isocyanato-4-methoxybenzene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (400 MHz, DMSO-d 6) d 10.65 (s, 1 H), 8.59 (s, 1 H), 8.43 (s, 1 H), 8.41 (s, 1 H), 8.35 (s, 1 H), 8.08 (brs, 2H), 7.62 (d, 2H), 7.46 (d, 2H), 7.35 (d, 2H), 6.87 (d, 2H), 3.72 (s, 3H).

EXAMPLE 19 This Example was prepared by substituting 1-isocyanato-3,5-dimethylbenzene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (300 MHz, DMSO-d 6) d 10.64 (s, 1 H), 8.64 (s, 1 H), 8.47 (s, 1 H), 8.37 (s, 1 H), 8.32 (s, 1 H), 8.02 (brs, 2H), 7.63 (d, 2H), 7.46 (d, 2H), 7.07 (s, 2H), 6.61 (m, 1H), 2.23 (s, 6H).

EXAMPLE 20 This Example was prepared by substituting 1-f-luoro-2-isocyanato-4-trifluoromethylbenzene for 1-isocyanato-3-methylbenzene in Example 1C. H NMR (500 MHz, DMSO-d6) d 10.69 (s, 1H), 9.21 (s, 1H), 8.88 (d, 1H), 8.64 (dd, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 8.04 (brs, 2H), 7.68 (d, 2H), 7.50 (m, 3H), 7.39 (m, 1H).

EXAMPLE 21 This Example was prepared by substituting isocyanatobenzene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (400 MHz, DMSO-d 6) d 10.64 (s, 1 H), 8.67 (s, 1 H), 8.63 (s, 1 H), 8.38 (s, 1 H), 8.33 (s, 1 H), 8.01 (brs, 2H), 7.63 (d, 2H), 7.46 (m, 4H), 7.28 (m, 2H), 6.97 (m, 1H).

EXAMPLE 22A Bromide (0.75 ml) was added dropwise to a mixture of 5-amino-4-cyanothiophen-3-carboxylic acid ethyl ester (2.9 g) in dichloromethane (150 ml) at 0 ° C. The mixture was stirred for 1.5 hours, diluted with dichloromethane, washed with 10% NaHS03 and brine and dried (MgSO4), filtered and concentrated.

EXAMPLE 22B A mixture of Example 22A (0.2 g), 1-methyl-4- (4, 4, 5, 5-tetramethyl [1, 3,2] dioxaborolan-2-yl) -1 H-pyrazole (0.368) g), Na 2 CO 3 (0.211 g), Pd (PPh 3) 4 (0.05 g) in DME (4 ml) and water (2 ml) at 120 ° C was stirred in a sealed flask for 30 minutes in a synthesizer microwave oven Smith (300W) was cooled to room temperature and partitioned between water and ethyl acetate. The extract was washed with brine, dried (MgSO 4), filtered and concentrated. The concentrate was flash chromatographed on silica gel with 1% methanol / dichloromethane.

EXAMPLE 22C This Example was prepared by substituting Example 22B for 5-amino-4-cyano-thiophene-3-carboxylic acid ethyl ester in Example 1A and Example 1B.

EXAMPLE 22D This Example was prepared by substituting Example 22C and 1-chloro-3-isocyanatobenzene for Example 1B and 1-isocyanato-3-methylbenzene in Examples 1C and 1D, respectively. 1 H NMR (400 MHz, DMSO-de) d 10.63 (s, 1 H), 8.85 (s, 1 H), 8.76 (s, 1 H), 8.32 (s, 1 H), 8.09 (s, 1 H), 7.71 (m, 1H), 7.61 (s, 1H), 7.55 (d, 2H), 7.45 2H), 7.28 (m, 2H), 7.01 (m, 3H), 3.85 (s, 3H) EXAMPLE 23 This Example was prepared substituting Example 22C for the Example 1B in Example 1D. H NMR (400 MHz, DMSO-d6) d 10.61 (s, 1H), 8.66 (s, 1H), 8.54 (s, 1H), 8.32 (s, 1H), 8.08 (s, 1H), 7.60 (s, 1H), 7.53 (d, 2H), 7.44 (d, 2H), 7.29 (s, 1H), 7.22 (d, 1H), 7.15 (t, 1H), 7.00 (brs, 2H), 6.78 (d, 1H) ), 3.84 (s, 3H), 2.27 (s, 3H). EXAMPLE 24 This Example was prepared by substituting Example 22C and 1-f luoro-2-isocyanato-4-methylbenzene for Example 1B and 1-isocyanato-3-methylbenzene in Examples 1C and 1D, respectively. 1 H NMR (400 MHz, DMSO-d 6) d 10.63 (s, 1 H), 9.08 (s, 1H), 8.44 (d, 1H), 8.33 (s, 1H), 8.08 (s, 1H), 7.99 (dd, 1H), 7.60 (m, 1H), 7.55 (m, 2H), 7.45 (m, 2H), 7.09 (dd, 1H), 7.00 (brs, 2H), 6.80 (m, 1H), 3.85 (s, 3H), 2.27 ( s, 3H).

EXAMPLE 25 This Example was prepared by substituting Example 22C and 1-fluoro-4-isocyanato-2-trifluoromethylbenzene for Example 1B and 1-isocyanato-3-methylbenzene in Examples 1C and ID, respectively. H NMR (400 MHz, DMSO-d6) d 10.64 (s, 1H), 9.01 (s, 1H), 8.82 (s, 1H), 8.32 (s, 1H), 8.09 (s, 1H), 8.00 (dd, 1H), 7.64 (m, 1H), 7.60 (s, 1H), 7.55 (d, 2H), 7.44 (m, 3H) ), 7.00 (brs, 2H), 3.85 (s, 3H).

EXAMPLE 26 This Example was prepared by substituting Example 22C and 1-fluoro-2-isocyanato-4-trifluoromethylbenzene for Example 1B and 1-isocyanato-3-methylbenzene in Examples 1C and 1D, respectively. 1 H NMR (500 MHz, DMSO-d 6) d 10.67 (s, 1 H), 9.21 (s, 1 H), 8.87 (d, 1 H), 8.63 (dd, 1 H), 8.33 (s, 1 H), 8.10 (s, 1H), 7.59 (m, 3H), 7.48 (m, 3H), 7.39 (m, 1H), 7.02 (brs, 2H), 3.85 (s, 3H).

EXAMPLE 27 This Example was prepared by substituting Example 22C and 1-isocyanato-4-trif luoromethylbenzene for Example 1B and 1-isocyanato-3-methylbenzene in Examples 1C and ID, respectively. 1 H NMR (500 MHz, DMSO-d 6) d 10.67 (s, 1 H), 9.08 (s, 1 H), 8.84 (s, 1 H), 8.33 (s, 1 H), 8.10 (s, 1 H), 7.65 (m, 4H), 7.60 (s, 1H), 7.56 (d, 2H), 7.47 (d, 2H), 7.02 (brs, 2H), 3.85 (s, 3H).

EXAMPLE 28 This Example was prepared by substituting Example 22C and 4-phenoxyphenylamine for Examples 1B and 1C, respectively, in the Example 1D. 1 H NMR (400 MHz, D SO-d 6) d 10.73 (s, 1 H), 8.33 (s, 1 H), 8.10 (s, 1 H), 7.63 (t, 4 H), 7.39 (t, 2 H), 7.13 (t , 1H), 7.01 (m, 5H), 3.85 (s, 3H).

EXAMPLE 29 This Example was prepared by substituting 4-phenoxyphenylamine for Example 1C in Example 1D. 1 H NMR (300 MHz, DMSO-d 6) d 10.76 (s, 1 H), 8.39 (s, 1 H), 8.32 (s, 1 H), 7.74 (m, 2 H), 7.39 (m, 2 H), 7.13 (m, 1H), 7.07 (m, 2H), 7.01 (m, 2H).

EXAMPLE 30A A mixture of 1-fluoro-4-nitrobenzene (0.5 g), 3-methylphenol (0.383 g), 37% w / w KF-AI203 (0.4 g) and 18-crown-6 (0.093 g) in acetonitrile (6 ml) ) at reflux was stirred for 24 hours, cooled and partitioned between water and ethyl acetate. The extract was washed with water, dried (MgSO 4), filtered and concentrated. The concentrate was flash chromatographed on silica gel with 0-10% ethyl acetate / hexanes.

EXAMPLE 30B A mixture of Example 30A (0.36 g), iron powder (0.45 g) and NH4CI (0.086 mg) in ethanol (46 ml), THF (17 ml) and water (6 ml) 85 ° C was stirred for 7 hours, cooled to room temperature, stirred for 18 hours, heated and filtered through diatomaceous earth (Celite®) while heating. The filtrate was concentrated and partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO 4), filtered and concentrated. The concentrate was flash chromatographed on silica gel with 10% ethyl acetate / hexanes.

EXAMPLE 30C This Example was prepared by substituting Example 22C and 30B for Examples 1B and 1C, respectively, in Example 1D. 1 H NMR (400 MHz, DMSO-d 6) d 10.73 (s, 1 H), 8.33 (s, 1 H), 8.10 (s, 1 H), 7.63 (m, 3 H), 7.26 (t, 1 H), 7.03 (m, 2H), 6.99 (brs, 2H), 6.95 (d, 1H), 6.84 (m, 1H), 6.80 (dd, 1H), 3.85 (s, 3H), 2.29 (s, 3H).

EXAMPLE 31 This Example was prepared by substituting Example 22C and 4- (4-chlorophenoxy) -phenylamine (prepared by substituting 4-chlorophenol for 3-methylphenol in Example 30B) for Examples 1B and 1C, respectively, in Example 1D. 1 H NMR (400 MHz, DMSO-d 6) d 10.76 (s, 1 H), 8.33 (s, 1 H), 8.10 (s, 1 H), 7.66 (d, 2 H), 7.61 (s, 1 H), 7.42 (d, 2H), 7.08 (d, 2H), 7.03 (d, 2H), 6.98 (brs, 2H), 3.85 (s, 3H).

EXAMPLE 32 This Example was prepared by substituting Example 22C and 4- (4-methyl-phenoxy) phenylamine (prepared by substituting 4-methylphenol for 3-methylphenol in Example 30 B) for Examples 1B and 1C, respectively, in Example 1D. H NMR (400 MHz, DMSO-d6) d 10.71 (s, 1H), 8.33 (s, 1H), 8.10 (s, 1H), 7.63 (s, 1H), 7.60 (brs, 2H), 7.19 (d, 2H), 6.96 (m, 6H), 3.85 (s, 3H), 2.29 (s, 3H).

EXAMPLE 33 This Example was prepared by substituting Example 22C and 4- (3-chlorophenoxy) -phenylamine (prepared by substituting 3-chlorophenol for 3-methylphenol in Example 30 B) for Examples 1B and 1C, respectively, in Example 1D. 1 H NMR (400 MHz, DMSO-d 6) d 10.78 (S, 1 H), 8.33 (s, 1 H), 8.10 (s, 1 H), 7.68 (d, 2 H), 7.62 (s, 1 H), 7.40 (t, 1H), 7.19 (m, 1H), 7.11 (d, 2H), 7.06 (t, 1H), 6.97 (m, 3H), 3.85 (s, 3H).

EXAMPLE 34 This Example was prepared by substituting Example 22C and 4-phenylsulfanylphenylamine for Examples 1B and 1C, respectively, in Example 1D. H NMR (400 MHz, DMSO-d6) d 10.84 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 7.67 (m, 2H), 7.59 (d, 1H), 7.38 (m, 4H), 7.28 (m, 3H), 6.96 (brs, 2H), 3.84 (s, 3H).

EXAMPLE 35 This Example was prepared by substituting 4- (4-methylphenoxy) phenylamine (prepared by replacing 4-methylphenol for 3-methylphenol in Example 30B) for Example 1C in Example 1D. 1 H NMR (300 MHz, DMSO-d 6) d 10.73 (s, 1 H), 8.38 (s, 1 H), 8.31 (s, 1 H), 7.96 (m, 2 H), 7.71 (d, 2 H), 7.19 (d, 2H), 7.01 (d, 2H), 6.91 (d, 2H), 2.29 (s, 3H).

EXAMPLE 36 This Example was prepared as described in Examples 22B and 22C by substituting 4- (4, 4, 5, 5-tet ra m et i I [1, 3,2] dioxaborolan-2-yl) -1H-pyrazole for 1 -methyl-4- (4,4,5,5-tetramethyl [1,3,2] dioxaborolan-2-yl) -1H-pyrazole in Example 22B and coupling the product thereof as described in Example 1D substituting 4-phenoxyphenylamine for Example 1C. H NMR (400 MHz, DMSO-d6) d 10.74 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 7.70 (s, 1H), 7.65 (m, 2H), 7.38 (m, 2H), 7.13 (t, 1H), 7.03 (m, 7H).

EXAMPLE 37 This Example was prepared as described in Examples 22B and 22C replacing 4,4,5,5-tetramethyl-2-thiophen-3-yl [1, 3,2] dioxaborolane for 1-methyl-4- (4,4,5,5-tetramethyl) [1.3.2] ] oxaborolan-2-yl) -1H-pyrazole in Example 22B and coupling the product thereof as described in Example 1D substituting 4-phenoxyphenylamine for Example 1C. H NMR (500 MHz, DMSO-d6) d 10.71 (s, 1H), 8.37 (s, 1H), 7.85 (m, 1H), 7.68 (m, 1H), 7.58 (d, 2H), 7.39 (t, 2H), 7.28 (d, 1H), 7.13 (t, 2H), 7.01 (t, 5H).

EXAMPLE 38A A mixture of Example 22A (0.1 g) and 1-methylpiperazine (1 mL) was stirred at 130 ° C for 8 hours, cooled and partitioned between water and ethyl acetate. The extract was washed with water and brine and dried (MgSO 4), filtered and concentrated.

EXAMPLE 38B This Example was prepared by substituting Example 38A for 5-amino-4-cyano-thiophene-3-carboxylic acid ethyl ester in Examples 1A-D. 1 H NMR (400 MHz, DMSO-d 6) d 10.60 (s, 1 H), 8.65 (s, 1 H), 8.56 (s, 1 H), 8.20 (s, 1 H), 7.64 (d, 2 H), 7.50 (s, 2H), 7.46 (d, 2H), 7.30 (s, 1H), 7.23 (m, 1H), 7.15 (t, 1H), 6.79 (d, 1H), 3.12 (m, 4H), 2.43 (m, 4H) ), 2.28 (s, 3H), 2.18 (s, 3H).

EXAMPLE 39A 1 M borane-THF in THF (0.28 ml) was added a mixture of N- (4- (formylamino) phenyl) -N '- (3-methylphenol) urea (0.05 g, prepared by substituting formic acid for Example 1B in Example 1D) in THF (2 ml) at 0 ° C. The mixture was stirred for 1.5 hours at room temperature, cooled to 0 ° C, treated with methanolic HCl (2 mL), stirred at reflux for 1 hour, cooled to room temperature and concentrated. The concentrate was concentrated twice from methanol and then flash chromatographed on silica 5% methanol / dichloromethane.

EXAMPLE 39B This Example was prepared by substituting Example 39A for the Example 1C in Example 1D. 1 H NMR (500 Hz, DMSO-d 6) d 8.70 (s, 1 H), 8.57 (s, 1 H), 8.31 (s, 1 H), 7.37 (d, 4 H), 7.35 (brs, 2 H), 7.26 (s, 2H), 7.20 (d, 1H), 7.14 (m, 1H), 7.09 (d, 3H), 6.78 (d, 1H), 3.42 (s, 3H).

EXAMPLE 40A A mixture of 3-bromothieno [3,2-c] pyridin-4-ylamine (2 g, prepared as described in WO 05/010009) and PdCI2 (dppf) dichloromethane (0.715 g) in methanol (60 ml) and triethylamine (3.7 ml) in a sealed tube under CO (4.218 kg / cm2) was stirred at 100 ° C for 16 hours, cooled to room temperature, filtered and concentrated. The concentrate was titrated with water and filtered.

EXAMPLE 40B To suspension of Example 40A (0.87 g) in 9 HCl (50 mL) was heated to reflux for 18 hours, filtered hot and concentrated.

EXAMPLE 40C This Example was prepared by substituting Example 40B and 4-phenoxyphenylamine for Examples 1B and 1C, respectively, in Example 1D. 1 H NMR (DMSO-d 6, 300 Hz) d 10.79 (s, 1 H), 8.28 (s, 1 H), 7.87 (d, 1 H), 7.77 (d, 2 H), 7.39 (m, 2 H), 7.25 (d, 1H), 7.13 (t, 1H), 7.07 (d, 2H), 7.01 (d, 2H), 6.80 (brs, 2H).

EXAMPLE 41 This Example was prepared by substituting Example 40B and 3-phenoxyphenylamine for Examples 1B and 1C, respectively, in Example 1D. 1 H NMR (DMSO-d 6, 300 MHz) d 10.82 (s, 1 H), 8.28 (s, 1 H), 7.86 (d, 1 H), 7.56 (d, 1 H), 7.40 (m, 4 H), 7.24 (d, 1H), 7.17 (t, 1H), 7.07 (d, 2H), 6.81 (d, 1H), 6.73 (brs, 2H).

EXAMPLE 42 This Example was prepared by substituting Example 40B and 4-benzylphenylamine for Examples 1B and 1C, respectively, in Example 1D. 1 H NMR (DMSO-d 6, 300 MHz) d 10.69 (s, 1 H), 8.25 (s, 1 H), 7.86 (d, 1 H), 7.66 (d, 2 H), 7.24 (m, 8 H), 6.78 (brs, 2H), 3.93 (s, 2H).

EXAMPLE 43 This Example was prepared by substituting Example 40B for Example 1B in Example 1D. H NMR (DMSO-d6, 300 MHz) d 10.67 (s, 1H), 8.67 (s, 1H), 8.57 (s, 1H), 8.26 (s, 1H), 7.87 (d, 1H), 7.67 (d, 2H), 7.47 (d, 2H), 7.30 (s, 1H), 7.23 (m, 2H), 7.15 (t, 1H), 6.83 (s, 2H), 6.80 (d, 1H), 2.28 (s, 3H) ).

EXAMPLE 44 This Example was prepared by substituting Example 40B and N- (4-aminophenyl) benzamide for Examples 1B and 1C, respectively in Example 1D. H NMR (DMSO-d6, 300 MHz) d 10.76 (s, 1H), 10.28 (s, 1H), 8.29 (s, 1H), 7.98 (d, 2H), 7.88 (d, 1H), 7.81 (d, 2H), 7.74 (d, 2H), 7.56 (m, 3H), 7.26 (d, 1H), 6.83 (brs, 2H).

EXAMPLE 45A A mixture of Example 40B (0.73 g) in DMF (30 ml) at room temperature was treated with NIS (1.42 g), stirred for 18 hours, diluted with water, treated with 10% aqueous Na2S203 and filtered.

EXAMPLE 45B This Example was prepared by substituting Example 45A and (4-aminophenyl) carbamic acid tert-butyl ester for Examples 1B and 1C, respectively, in Example 1D. The Boc protecting group was removed by treatment of the product thereof with TFA as described in Example 1C.

EXAMPLE 45C A mixture of Example 45B (1.93 g), 1-methyl-4- (4, 4,5,5-tetramethyl [1, 3,2] dioxaborolan-2-yl) -1 H-pyrazole (1.08 g), PdCl 2 (dppf) (0.19 g) and Na 2 CO 3 (1.3 g) in DME (30 ml) and water (10 ml) at 80 ° C was stirred for 18 hours, cooled, treated with water and ethyl acetate and filtered.

EXAMPLE 45D A mixture of Example 45C (0.03 g) in DMF (0.5 ml) at -20 ° C was treated with 1-isocyanato-3-methylbenzene (0.1 ml), warmed to room temperature and stirred for 18 hours and filtered, The filtrate was chromatographed by flash-evaporation on silica gel with 0-8% methanol / dichloromethane. 1 H NMR (300 Hz, DMSO-d 6) d 10.70 (s, 1 H), 8.67 (s, 1 H), 8.57 (s, 1 H), 8.33 (s, 1 H), 8.14 (d, 1 H), 8.06 (s, 1H), 7.86 (d, 1H), 7.67 (d, 2H), 7.47 (d, 2H), 7.30 (s, 1H), 7.23 (d, 1H), 7.15 (t, 1H), 6.82 (s, 2H) ), 6.79 (d, 1H), 3.93 (s, 3H), 2.28 (s, 3H).

EXAMPLE 46 This Example was prepared by substituting Example 45B and N- (4-aminophenyl) benzamide for Examples 1B and 1C, respectively, in Example 1D then substituting the product thereof for Example 45B in Example 45C. 1 H NMR (DMSO-d 6, 300 MHz) d 10.80 (s, 1 H), 10.29 (s, 1 H), 8.36 (s, 1 H), 8.14 (s, 1 H), 8.06 (s, 1 H), 7.97 (d, 2H), 7.87 (s, 1H), 7.77 (m, 4H), 7.56 (m, 3H), 6.83 (brs, 2H), 3.93 (s, 3H).

EXAMPLE 47 This Example was prepared by substituting Example 45B and 4-phenoxyphenylamine for Examples 1B and 1C, respectively, in Example 1D then substituting the product thereof for Example 45B in Example 45C. 1 H NMR (DMSO-d 6, 300 Hz) d 10.84 (s, 1 H), 8.36 (s, 1 H), 8.14 (s, 1 H), 8.06 (s, 1 H), 7.87 (s, 1 H), 7.80 (d, 2H), 7.39 (m, 2H), 7.13 (t, 1H), 7.09 (d, 2H), 7.03 (d, 2H), 6.81 (brs, 2H), 3.93 (s, 3H).

EXAMPLE 48 This Example was prepared by substituting Example 45B and 3-phenoxyphenylamine for Examples 1B and 1C, respectively, in Example 1D then substituting the product thereof for Example 45B in Example 45C. 1 H NMR (DMSO-d 6, 300 MHz) d 10.85 (s, 1 H), 8.35 (s, 1 H), 8.13 (s, 1 H), 8.05 (s, 1 H), 7.85 (s, 1 H), 7.58 (d, 1H), 7.46 (m, 2H), 7.42 (d, 2H), 7.17 (t, 1H), 7.08 (d, 2H), 6.81 (m, 1H), 6.73 (brs, 2H), 3.92 (s, 3H) ).

EXAMPLE 49 This Example was prepared by substituting Example 45B and 4-benzylphenylamine for Examples 1B and 1C, respectively, in Example 1D then substituting the product thereof for Example 45B in Example 45C. H NMR (DMSO-d6, 300 MHz) d 10.75 (s, 1H), 8.32 (s, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.67 (d, 2H), 7.32-7.18 (m, 7H), 6.79 (brs, 2H), 3.94 (s, 2H), 3.93 (s, 3H).

EXAMPLE 50A This Example was prepared as described in Example 40A and Example 40B, except replacing 5-iodo-7- (4- (4-methyl-piperazin-1-yl) cyclohexyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (WO2005 / 74603) for 3-bromo-thieno [3,2-c] pyridin-4-ylamine in Example 40A.

EXAMPLE 50B This Example was prepared by substituting Example 50A and 4-phenoxyphenylamine for Examples 1B and 1C, respectively, in Example 1D. 1 HNMR (DMSO-d6, 300MHz) d 10.13 (s, 1H), 8.30 (s, 1H), 8.12 (s, 1H), 7.93 (brs, 2H), 7.70-7.74 (m, 1H), 7.66-7.70 (m, 1H), 7.36-7.44 (m, 2H), 7.08-7.17 (m, 1H), 6.98-7.07 (m, 4H), 4.60-4.72 (m, 1H), 3.32 (hidden, 1H), 2.48 -2.59 (m, 4H), 2.33-2.48 (m, 4H), 2.15-2.23 (m, 4H), 1.96-2.15 (m, 3H), 1.74-1.85 (m, 2H), 1.53-1.68 (m, 2H).

EXAMPLE 51 This Example was prepared by substituting Example 50A and 3-phenoxyphenylamine for Examples 1B and 1C, respectively, in the Example 1D. 1HNMR (DMSO-d6, 300MHz) d 10.12 (s, 1H), 8.28 (s, 1H), 8.11 (s, 1H), 7.87 (bs, 2H), 7.49-7.56 (m, 1H), 7.33-7.46 ( m, 4H), 7.13-7.21 (m, 1H), 7.06-7.10 (m, 1H), 7.03-7.06 (m, 1H), 6.74-6.81 (m, 1H), 4.58-4.71 (m, 1H), 2.32-2.60 (m, 8H), 2.25-2.30 (m, 1H), 1.93-2.24 (m, 7H), 1.73-1.85 (m, 2H), 1.52-1.68 (m, 2H).

EXAMPLE 52 This Example was prepared by substituting Example 50A for Example 1B in Example 1D. 1H NR (DMSO-d6, 300MHz) d 10.03 (s, 1H), 8.64 (s, 89H), 8.56 (s, 1H), 8.30 (s, 1H), 8.11 (s, 1H), 7.99 (bs, 2H) ), 7.59-7.63 (m, 1H), 7.56-7.59 (m, 1H), 7.45-7.48 (m, 1H), 7.42-7.45 (m, 1H), 7.31 (s, 1H), 7.20-7.26 (m , 1H), 7.15 (t, 1H), 6.79 (d, 1H), 4.59-4.72 (m, 1H), 2.37-2.51 (m, 9H), 2.28 (s, 3H), 2.20 (s, 3H), 1.96-2.16 (m, 4H), 1.74-1.86 (m, 2H), 1.53-1.68 (m, 2H).

EXAMPLE 53 This Example was prepared by substituting Example 50A and 4- (4-aminophenylsulfanyl) phenylamine for Examples 1B and 1C, respectively, in Example 1D. HNMR (DMSO-d6, 300MHz) d 10.09 (s, 1H), 8.29 (s, 1H), 8.11 (s, 1H), 7.88 (bs, 2H), 7.59-7.63 (m, 1H), 7.56-7.59 ( m, 1H), 7.17-7.21 (m, 1H), 7.14-7.17 (m, 1H), 7.08-7.11 (m, 1H), 7.05-7.08 (m, 1H), 6.81-6.83 (m, 1H), 6.79-6.81 (m, 1H), 5.47 (s, 2H), 4.58-4.71 (m, 1H), 2.56-2.70 (m, 9H), 2.20 (s, 3H), 1. 94-2.16 (m, 4H), 1.73-1.85 (m, 2H), 1.52-1.67 (m, 2H).

EXAMPLE 54 This Example was prepared by substituting Example 50A and 4-benzylphenylamine for Examples 1B and 1C, respectively, in Example 1D. 1 HNMR (DMSO-d6, 300MHz) d 10.04 (s, 1H), 8.29 (s, 1H), 8.11 (s, 1H), 7.92 (bs, 2H), 7.60-7.63 (m, 1H), 7.57-7.60 (m, 1H), 7.15-7.34 (m, 7H), 4.59-4.72 (m, 1H), 3.93 (s, 2H), 2.37-2.59 (m, 8H), 2.25-2.29 (m, 1H), 2.22 (s, 3H), 1.94-2.15 (m, 4H), 1.74-1.85 (m, 2H), 1.53-1.68 (m, 2H).

EXAMPLE 55 This Example was prepared by substituting Example 50A and 4-Benzenesulfonylphenylamine for Examples 1B and 1C, respectively, in Example 1D. 1 HNMR (DMSO-d6, 300MHz) d 10.41 (s, 1H), 8.34 (s, 1H), 8.13 (s, 1H), 7.96 (s, 5H), 7.92-7.94 (m, 1H), 7.87 (bs) , 2H), 7.59-7.73 (m, 3H), 4.59-4.72 (m, 1H), 2.36-2.48 (m, 8H), 2.16-2.22 (m, 4H), 1.94-2.16 (m, 4H), 1.75 -1.85 (m, 2H), 1.53-1.69 (m, 2H).

EXAMPLE 56A This Example was prepared as described in Examples 40A and 40B substituting 3-iodo-1 - (4-morpholin-4-ylcyclohexyl) -1H-prazolo [3,4-d] pyrimidin-4-ylamine (prepared as described in WO 05/74603) for 3-bromothieno [3, 2-c] pyridin-4-ylamine in Example 40A.

EXAMPLE 56B This Example was prepared by substituting Example 56A and 4-phenoxyphenylamine for Examples 1B and 1C, respectively, in Example 1D. 1H NMR (DMSO-d6, 300MHz) d 10.41 (s, 1H), 8.53 (s, 1H), 8.25 (s, 1H), 8.06 (bs, 1H), 7.83-7.87 (m, 1H), 7.79-7.83 (m, 1H), 7.36-7.45 (m, 2H), 7.10-7.17 (m, 1H), 6.99-7.09 (m, 4H), 4.83-4.96 (m, 1H), 3.55-3.63 (m, 4H) , 2.47-2.57 (m, 4H), 2.29-2.42 (m, 1H), 2.09-2.29 (m, 2H), 1.96-2.09 (m, 4H), 1.40-1.57 (m, 2H).

EXAMPLE 57A This Example was prepared by substituting 3-bromo-7-iodo-thieno [3,2-c] pyridin-4-ylamine (prepared as described in WO 05/10009) for Example 45B in Example 45C.

EXAMPLE 57B A mixture of 4-ethynylphenylamine (0.3 g), 4,4,5,5-tetramethyl [1,2,2] -dioxaborolane (0.56 ml) and ZrCp2CIH (0.083 g) in THF (6 ml) was stirred at 50 ° C for 1.5 hours and concentrated. The concentrate was flash chromatographed on silica gel with 30% ethyl acetate / hexanes.

EXAMPLE 57C This Example was prepared by substituting Examples 57A and 57B for Example 45B and 1-methyl-4- (4,4,5,5-tetramethyl [1, 3,2] -dioxaborolan-2-yl) -1 H-pyrazole, respectively, in Example 45C. 1 H NMR (300 MHz, DMSO-d 5) d 3.92 (s, 3 H) 5.32 (s, 2 H) 6.01 (s, 2 H) 6.57 (d, 2 H) 6.86 (d, 1 H) 7.27-7.42 (m, 3 H) 7.60 (s, 1 H) 7.85 (s, 1 H) 7.99 (s, 1 H) 8. 1 (s, 1 H).

EXAMPLE 58A This Example was prepared by substituting Example 57B for Example 45C in Example 45D.

EXAMPLE 58B This Example was prepared by substituting Examples 57A and 58A for Example 45B and 1-methyl-4- (4, 4, 5, 5-tetramethyl [1, 3,2] -dioxaborolan-2-yl) -1 H-pyrazole, respectively, in Example 45C. 1 H NMR (300 MHz, DMSO-d 6) d 2.28 (s, 3 H) 3.93 (s, 3 H) 6.08 (s, 2 H) 6.80 (d, 1 H) 7.00 (d, 1 H) 7.16 (t, 1 H) 7.20-7.27 (m, 1H) 7.31 (s, 1H) 7.44-7.54 (m, 2H) 7.54-7.68 (m, 3H) 7.73 (s, 1H) 7.86 (s, 1H) 8.01 (s, 1H) 8.12 (s, 1H) ) 8.62 (s, 1H) 8.79 (s, 1H).

EXAMPLE 59 This Example was prepared by substituting 1-ethynyl-4-phenoxybenzene for 4-ethynylphenylamine in Example 57B then substituting the product thereof and EXAMPLE 57A for 1-methyl-4- (4, 4,5,5-tetramethyl [1, 3 , 2] dioxaborolan-2-yl) -1 H-pyrazole and EXAMPLE 45B, respectively, in Example 45C. 1 H NMR (300 MHz, DMSO-d 6) d 3.93 (s, 3 H) 6.10 (s, 2 H) 6.99-7.11 (m, 5 H) 7.16 (t, 1 H) 7.36-7.47 (m, 2 H) 7.61-7.78 (m , 4H) 7.86 (s, 1H) 8.02 (s, 1H) 8.12 (s, 1H).

EXAMPLE 60 This Example was prepared by substituting Example 57A and 2- (2-biphenyl-4-yl-vinyl) -4,4,5,5-tetramethyl [1,3,2] dioxaborlane for Example 45B and 1-methyl-4 - (4,4,5,5-tetramethyl [1,2,2] dioxaborolan-2-yl) -1H-pyrazole, respectively, in Example 45C. 1 H NMR (300 MHz, DMSO-d 6) d 3.93 (s, 3 H) 6.11 (s, 2 H) 7.13 (d, 1 H) 7.33-7.42 (m, 1H) 7.48 (t, 2H) 7.68-7.85 ( m, 8H) 7.87 (s, 1H) 8.03 (s, 1H) 8.13 (s, 1H). Examples 61-65 were prepared following the procedures of Example 45D and replacing the appropriate isocyanate (X) for 1- isocyanate-3-methylbenzene EXAMPLE 61 X = 1-isocyanatobenzene. 1 H NMR (300 MHz, DMSO-d 6)? 10.72 (s, 1H), 8.70 (s, 1H), 8.66 (s, 1H), 8.33 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.87 (s, 1H), 7.67 ( d, J = 8.8Hz, 2H), 7.43-7.50 (m, 4H), 7.25-7.31 (m, 2H), 6.97 (t, J = 7.3Hz, 1H), 6.83 (s, 2H), 3.93 (s) , 3H).

EXAMPLE 62 X = 1-Fluoro-3-isocyanatobenzene. H NMR (300 MHz, DMSO-d6) d 10.73 (s, 1H), 8.88 (s, 1H), 8.75 (s, 1H), 8.34 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.87 (s, 1H), 7.68 (d, J = 8.8Hz, 2H), 7.44-7.53 (m, 3H), 7.31 (td, J = 8.1, 6.8Hz, 1H), 7.12 (ddd, J = 8.1, 2.0, 0.7Hz, 1H), 6.83 (s, 2H), 6.74-6.82 (m, 1H), 3.93 (s, 3H).

EXAMPLE 63 X = socianatocyclohexane. 1 H NMR (300 MHz, DMSO-d 6) d . 65 (s, 1H), 8.35 (s, 1H), 8.31 (s, 1H), 8.13 (s, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.59 (d, J = 9.2Hz , 2H), 7.38 (d, J = 9.2Hz, 2H), 6.82 (s, 2H), 6.08 (d, J = 8.1Hz, 1H), 3.93 (s, 3H), 1.75-1.85 (m, 2H) , 1.60-1.72 (m, 2H), 1.47-1.59 (m, 1H), 1.08-1.40 (m, 5H).

EXAMPLE 64 X = 1-isocyanato-4-methylbenzene. 1 H NMR (300 MHz, DMSO-d 6) d 10.71 (s, 1 H), 8.67 (s, 1 H), 8.57 (s, 1 H), 8.33 (s, 1 H), 8.14 (d, J = 0.7 Hz, 1 H) , 8.06 (s, 1H), 7.87 (d, J = 1.0Hz, 1H), 7.66 (d, J = 9.2Hz, 2H), 7.46 (d, J = 9.2Hz, 2H), 7.34 (d, J = 8.5Hz, 2H), 7.08 (d, J = 8.5Hz, 2H), 6.83 (s, 2H), 3.93 (s, 3H), 2.24 (s, 3H).

EXAMPLE 65 X = 1-isocyanato-2-methylbenzene. 1 H NMR (300 MHz, DMSO-d 6) d 10.72 (s, 1 H), 9.05 (s, 1 H), 8.33 (s, 1 H), 8.14 (s, 1 H), 8.06 (s, 1 H), 7.91 (s, 1H), 7.83-7.87 (m, 2H), 7.68 (d, J = 8.8Hz, 2H), 7.48 (d, J = 8.8Hz, 2H), 7.11-7.20 (m, 2H), 6.94 (td, J = 7.4, 1.2Hz, 1H), 6.83 (s, 2H), 3.93 (s, 3H), 2.25 (s, 3H).

EXAMPLE 66A This Example was prepared by substituting tert-butyl ester of (3-aminophenyl) carbamic acid for (4-aminophenyl) carbamic acid tert-butyl ester in Example 45B.

EXAMPLE 66B This Example was prepared by substituting Example 66A and isocyanatobenzene for Example 45C and 1-isocyanato-3-methylbenzene, respectively, in Example 45D. 1 H NMR (300 MHz, DMSO-d 6) d 10.79 (s, 1 H), 8.77 (s, 1 H), 8.60 (s, 1 H), 8.36 (s, 1 H), 8.14 (s, 1 H), 8.07 (s, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.43-7.49 (m, 2H), 7.24-7.38 (m, 5H), 6.97 (t, J = 7.3Hz, 1H), 6.80 (s) , 2H), 3.93 (s, 3H).

EXAMPLE 67 This Example was prepared by substituting Example 66A and 1-isocyanato-2-methylbenzene for Example 45C and 1-isocyanato-3-methylbenzene, respectively, in Example 45D. 1 H NMR (300 MHz, DMSO-d 6) d 10.81 (s, 1 H), 9.15 (s, 1 H), 8.37 (s, 1 H), 8.14 (s, 1 H), 8.07 (s, 1 H), 8.00-8.03 ( m, 1H), 7.86-7.90 (m, 3H), 7.31-7.38 (m, 1H), 7.25-7.31 (m, 2H), 7.11-7.20 (m, 2H), 6.94 (td, J = 7.4, 1.2 Hz, 1H), 6.80 (s, 2H), 3.93 (s, 3H), 2.26 (s, 3H).

EXAMPLE 68 This Example was prepared by substituting Example 66A and 1-isocyanato-4-methylbenzene for Example 45C and 1-isocyanato-3-methylbenzene, respectively, in Example 45D. 1 H NMR (300 MHz, DMSO-de) d 10.78 (s, 1 H), 8.73 (s, 1 H), 8.49 (s, 1 H), 8.36 (s, 1 H), 8.14 (s, 1 H), 8.06 (s, 1H), 7.96-7.98 (m, 1H), 7.87 (d, J = 0.7Hz, 1H), 7.26-7.37 (m, 5H), 7.09 (d, J = 8.5Hz, 2H), 6.80 (s, 2H) ), 3.93 (s, 3H), 2.24 (s, 3H).

EXAMPLE 69 This Example was prepared by substituting Example 66A for the Example 45C in Example 45D. H NMR (300 MHz, DMSO-d6) d 10.79 (s, 1H), 8.80 (s, 1H), 8.55 (s, 1H), 8.36 (s, 1H), 8.14 (s, 1H), 8.06 (s, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.26-7.38 (m, 4H), 7.20-7.26 (m, 1H), 7.15 (t, J = 7.6Hz, 1H), 6.76-6.82 (m, 3H), 3.93 (s, 3H), 2.28 (s, 3H).

EXAMPLE 70 This Example was prepared by substituting Example 45A and N- (3-aminophenyl) benzamide for Example 1B and EXAMPLE 1C, respectively, in Example 1D and substituting the product thereof for Example 45B in Example 45C. 1 H NMR (300 MHz, DMSO-de) d 10.86 (s, 1 H), 10.35 (s, 1 H), 8.36-8.39 (m, 2 H), 8.14 (s, 1 H), 8.07 (s, 1 H), 7.98 ( dd, J = 8.3, 1.5Hz, 2H), 7.87 (d, J = 1.0Hz, 1H), 7.50-7.63 (m, 4H), 7.44-7.48 (m, 1H), 7.35 (t, J = 8.0Hz , 1H), 6.82 (s, 2H), 3.93 (s, 3H).

EXAMPLE 71A This Example was prepared as described in Example 1D substituting Example 45A and 4-aminopiperidine-1-tert-butylcarboxylate for Example 1B and EXAMPLE 1C, respectively, and substituting the product thereof for Example 45B in Example 45C. The Boc group was removed with TFA as described in Example 1 C. EXAMPLE 71B This Example was prepared by substituting Example 71A and isocyanatobenzene for 45C and 1-isocyanato-3-methylbenzene, respectively, in Example 45D. 1H MR (300 MHz, DMSO-d6) d 8.84 (d, J = 7.5Hz, 1H), 8.54 (s, 1H), 8.12 (s, 1H), 8.11 (s, 1H), 8.02 (s, 1H) , 7.84 (d, J = 1.0Hz, 1H), 7.46 (d, J = 7.8Hz, 2H), 7.23 (t, J = 8.0Hz, 2H), 6.97 (s, 2H), 6.93 (t, J = 7.3Hz, 1H), 3.98-4.17 (m, 3H), 3.92 (s, 3H), 2.97 (t, J = 11.5Hz, 2H), 1.89 (dd, J = 12.7, 3.2Hz, 2H), 1.44- 1.59 (m, 2H).

EXAMPLE 72 A mixture of Example 71A (75 mg), benzoic acid (26 mg), HoBT (57 mg) and NMM (0.23 ml) in DMF (2 ml) at 0 ° C was treated with EDCI (80 mg), allowed to warm at room temperature, it was stirred for 5 hours, diluted with water and extracted with ethyl acetate. The extract was dried (Na2SO4), filtered and concentrated. The concentrate was titrated with dichloromethane, filtered and dried with air. 1 H NMR (300 MHz, DMSO-d 6) d 8.86 (d, J = 7.5 Hz, 1 H), 8.12 (s, 1 H), 8.11 (d, J = 0.7Hz, 1H), 8.02 (s, 1H), 7.84 (d, J = 1.0Hz, 1H), 7.44-7.49 (m, 3H), 7.36-7.41 (m, 2H), 6.95 (s, 2H) ), 4.33-4.52 (brm, 1H), 4.04-4.17 (brm, 1H), 3.92 (s, 3H), 3.52-3.71 (brm, 1H), 2.94-3.27 (brm, 2H), 1.77-2.03 (brm) , 2H), 1.39-1.64 (brm, 2H).

EXAMPLE 73A This Example was prepared by substituting tert-butyl trans-4-aminocyclohexylcarbamate for Example 71A in Example 72 and removing the Boc group with TFA as described in Example 1 C.

EXAMPLE 73B This example was prepared by coupling Examples 45A and 73A as described in Example 72 and substituting the product thereof for Example 45B in Example 45C.1H R (300 MHz, DMSO-d6) d 8.80 (d, J = 7.8 Hz, 1H), 8.27 (d, J = 8.1Hz, 1H), 8.11 (s, 1H), 8.09 (s, 1H), 8.02 (s, 1H), 7.82-7.88 (m, 3H), 7.42-7.55 (m, 3H), 6.97 (s, 2H), 3.92 (s, 3H), 3.73-3.85 (brm, 2H), 1.89-2.01 (brm, 4H), 1.39-1.57 (m, 4H).

EXAMPLE 74A A solution cooled with ice of trans-4- tert-butyl aminocyclohexylcarbamate (250 mg) and isocyanatobenzene (0.11 ml) in DMF (5 ml) was treated with NMM (0.22 ml), stirred at room temperature for 5 hours, diluted with water and filtered. The filtrate was dissolved in dichloromethane (10 mL) and treated with TFA (1 mL). The mixture was stirred at room temperature for 3 hours and concentrated.

EXAMPLE 74B This example was prepared by coupling Examples 45A and 74A as described in Example 72 and substituting the product thereof for Example 45B in Example 45C.1H NMR (300 MHz, DMSO-d6) d 8.77 (d, J = 7.8 Hz, 1H), 8.32 (s, 1H), 8.11 (s, 1H), 8.08 (s, 1H), 8.02 (s, 1H), 7.83 (s, 1H), 7.37 (d, J = 7.5Hz, 2H ), 7.17-7.25 (m, 2H), 6.96 (s, 2H), 6.88 (t, J = 7.3Hz, 1H), 6.10 (d, J = 7.5Hz, 1H), 3.92 (s, 3H), 3.74 -3.87 (brm, 1H), 3.38-3.49 (brm, 1H), 1.89-1.99 (brm, 4H), 1.21-1.54 (m, 4H).

EXAMPLE 75 This Example was prepared by substituting 1-fluoro-2-isocyanatobenzene for isocyanatobenzene in Example 74A and then Example 74B. 1 H NMR (300 MHz, DMSO-d 6) d 8.77 (d, J = 7.8 Hz, 1 H), 8.09-8.17 (m, 3 H), 8.08 (s, 1 H), 8.02 (s, 1 H), 7.83 (s, 1H), 7.16 (ddd, J = 11.8, 8.1, 1.5Hz, 1H), 7.07 (t, J = 7.1Hz, 1H), 6.96 (s, 2H), 6.87-6.95 (m, 1H), 6.62 (d, J = 7.5Hz, 1H), 3.92 (s, 3H), 3.75-3.88 (m, 1H), 3.39-3.51 (m, 1H) ), 1.88-2.02 (m, 4H), 1.37-1.56 (m, 2H), 1.20-1.36 (m, 2H).

EXAMPLE 76 This Example was prepared by substituting tert-butyl 4-aminobenzyl carbamate for tert-butyl trans-4-aminocyclohexylcarbamate in Examples 74A and 74B. H NMR (300 MHz, DMSO-d6) d 9.42 (t, J = 5.8Hz, 1H), 8.71 (s, 1H), 8.70 (s, 1H), 8.16 (s, 1H), 8.11 (d, J = 0.7Hz, 1H), 8.02 (s, 1H), 7.84 (d, J = 0.7Hz, 1H), 7.41-7.47 (m, 4H), 7.24-7.31 (m, 4H), 7.02 (s, 2H), 6.92-6.99 (m, 1H), 4.45 (d, J = 5.8Hz, 2H), 3.92 (s, 3H).

EXAMPLE 77 This Example was prepared by substituting tert-butyl 3-aminobenzyl carbamate for tert-butyl trans-4-aminocyclohexylcarbamate in Examples 74A and 74B. 1 H NMR (300 MHz, DMSO-d 6) d 9.48 (t, J = 5.9 Hz, 1 H), 8.68 (s, 1 H), 8.62 (s, 1 H), 8.19 (s, 1 H), 8.11 (s, 1 H) , 8.02 (s, 1H), 7.84 (s, 1H), 7.36-7.47 (m, 4H), 7.23-7.30 (m, 3H), 7.03 (s, 2H), 6.93-7.01 (m, 2H), 4.49 (d, J = 5.8Hz, 2H), 3.92 (s, 3H).

EXAMPLE 78A This Example was prepared by substituting 3-bromo-7-iodothieno [3,2-c] pyridin-4-amine for Example 45B in Example 45C and substituting the product thereof for 3-bromo-thieno [3,2-c] ] pyridin-4-ylamine in Examples 40A and 40B.

EXAMPLE 78B This example was prepared by coupling Example 78A and 4- (aminomethyl) -N-phenylpiperidine-l-carboxamide (prepared by substituting tert-butyl piperidin-4-ylmethylcarbamate for tert-butyl trans-4-aminocyclohexylcarbamate in Example 74A) as is described in Example 72. H NMR (300 MHz, DMSO-d6) d 8.97 (t, J = 5.6Hz, 1H), 8.45 (s, 1H), 8.12 (s, 1H), 8.11 (s, 1H) , 8.02 (s, 1H), 7.84 (s, 1H), 7.45 (d, J = 7.8Hz, 2H), 7.18-7.25 (m, 2H), 6.99 (s, 2H), 6.91 (t, J = 7.3 Hz, 1H), 4.14 (d, J = 12.9Hz, 2H), 3.92 (s, 3H), 3.23 (t, J = 5.9Hz, 2H), 2.79 (t, J = 11.9Hz, 2H), 1.72- 1.86 (m, 3H), 1.08-1.24 (m, 2H).

EXAMPLE 79 This Example was prepared by replacing 78A and tert-butyl 4-aminobenzylcarbamate for benzoic acid and 71A, respectively, in Example 72, removing the Boc group with TFA as described in Example 1C and substituting the product thereof for tert-butyl trans-4-aminocyclohexylcarbamate in Example 74A. 1 H NMR (300 MHz, D SO-d 6) d 10.78 (s, 1 H), 8.53 (s, 1 H), 8.35 (s, 1 H), 8.14 (s, 1 H), 8.06 (s, 1 H), 7.86 (s) , 1H), 7.71 (d, J = 7.8Hz, 2H), 7.39-7.43 (m, 2H), 7.32 (d, J = 8.1Hz, 2H), 7.19-7.25 (m, 2H), 6.87-6.93 ( m, 1H), 6.80 (s, 2H), 6.59 (t, J = 6.4Hz, 1H), 4.29 (d, J = 5.8Hz, 2H), 3.93 (s, 3H).

EXAMPLE 80 This Example was prepared by replacing Example 78A and tert-butyl 3-aminobenzylcarbamate for benzoic acid and Example 71A, respectively, in Example 72, removing the Boc group with TFA as described in Example 1C and substituting the product thereof. for tert-butyl trans-4-aminocyclohexylcarbamate in Example 74A. 1 H NMR (300 MHz, DMSO-d 6) d 10.81 (s, 1 H), 8.56 (s, 1 H), 8.34 (s, 1 H), 8.13 (d, J = 0.7 Hz, 1 H), 8.06 (s, 1 H) , 7.86 (d, J = 0.7Hz, 1H), 7.72-7.74 (m, 1H), 7.62-7.66 (m, 1H), 7.39-7.43 (m, 2H), 7.35 (t, J = 8.0Hz, 1H ), 7.18-7.25 (m, 2H), 7.10 (d, J = 7.8Hz, 1H), 6.89 (t, J = 7.3Hz, 1H), 6.78 (s, 2H), 6.64 (t, J = 5.9Hz) , 1H), 4.32 (d, J = 6.4Hz, 2H), 3.93 (s, 3H).

EXAMPLE 81A A mixture of (1S, 4S) -4- (tert-butoxycarbonylamino) - Cyclohexanecarboxylic (245 mg) in toluene (10 ml) was treated with triethylamine (0.14 ml) and DPPA (0.22 ml), heated at 70 ° C for 45 minutes, cooled to room temperature and treated with aniline (0.18 ml). . The mixture was stirred overnight at room temperature, diluted with ether and washed with 0.5 N HCl, saturated NaHCO3, water and brine and dried (Na2SO4), filtered and concentrated. The concentrate was purified through silica gel chromatography to provide (1 S, 4S) -4- (3-phenylureido) -cyclohexylcarbamate tert-butyl, which was dissolved in dichloromethane (2 mL) and TFA (2 mL) , stirred at room temperature for 12 hours and concentrated.

EXAMPLE 81B This Example was prepared by substituting Example 78A and Example 81A for benzoic acid and Example 71A respectively, in Example 72. 1 H NMR (300 MHz, DMSO-d 6) d 8.78 (d, J = 6.8Hz, 1H), 8.41 (s, 1H), 8.11 (s, 1H), 8.07 (s, 1H), 8.02 (s, 1H), 7.84 (s, 1H), 7.37 (d, J = 7.5Hz, 2H), 7.21 (t, J = 7.8Hz, 2H), 6.85- 6.93 (m, 3H), 6.17 (d, J = 6.8Hz, 1H), 3.92 (s, 3H), 3.83-3.90 (m, 1H), 3.66-3.73 (m, 1H), 1.62-1.79 (m, 8H).

EXAMPLE 82 This Example was prepared by substituting cis-3- (ter- racemic butoxycarbonylamino) cyclohexanecarboxylic acid for cis-4- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid in Examples 81A and 81B. 1 H NMR (300 MHz, DMSO-d 6) d 8.81 (d, J = 7.8 Hz, 1 H), 8.30 (s, 1 H), 8.11 (s, 1 H), 8.07 (s, 1 H), 8.02 (s, 1 H) , 7.83 (s, 1H), 7.37 (d, J = 7.8Hz, 2H), 7.21 (t, J = 7.8Hz, 2H), 6.93 (s, 2H), 6.88 (t, J = 7.1Hz, 1H) , 6.16 (d, J = 7.8Hz, 1H), 3.91 (s, 3H), 3.78-3.94 (m, 1H), 3.47-3.62 (m, 1H), 2.11-2.20 (m, 1H), 1.73-1.92 (m, 3H), 1.00-1.48 (m, 4H). EXAMPLE 83A (±) (1R, 3S) -3-amino-N-phenylcyclohexanecarboxamide This Example was prepared by substituting (±) - (1 R, 3S) -3- (tert-butoxycarbonylamino) cyclohexanecarboxylic acid and aniline for benzoic acid and Example 71A respectively, in Example 72 and removing the Boc group with TFA as described in Example 1 C.

EXAMPLE 83 B This Example was prepared by substituting Example 78A and Example 83A for benzoic acid and Example 71A respectively, in Example 72. 1H NMR (300 MHz, DMSO-d6) d 9.91 (s, 1H), 8.85 (d, J = 7.8Hz, 1H), 8.11 (s, 1H), 8.09 (s, 1H), 8.01 (s, 1H), 7.83 (s, 1H), 7.60 (d, J = 7.8Hz, 2H), 7.28 (t, J = 8.0Hz, 2H), 7.02 ( t, J = 7.3Hz, 1H), 6.95 (s, 2H), 3.91 (s, 3H), 3.83-3.97 (m, 1H), 2.00-2.09 (m, 1H), 1. 77-1.96 (m, 3H), 1.13-1.61 (m, 4H) EXAMPLE 84A 4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -1 H-pyrazole (2 g) was added portionwise to an ice-cold suspension of NaH (280 mg) in DMF (25 mi). The mixture was stirred at 0 ° C for 30 minutes, treated with (2-bromoethoxy) (tert-butyl) diphenylsilane (4.16 g), heated at 50 ° C for 2 hours, quenched with water and extracted with ethyl acetate. ethyl. The extract was dried (Na2SO4), filtered and concentrated, and the concentrate was purified through silica gel chromatography.

EXAMPLE 84B This Example was prepared by replacing Example 78A and tert-butyl 3-aminobenzylcarbamate for benzoic acid and Example 71A respectively, in Example 72.

EXAMPLE 84C This Example was prepared by substituting Example 84B and Example 84A for Example 45B and 1-methyl-4- (4,4,5,5-tetramethyl- [1, 3, 2] dioxaborolan-2-yl) -1 H -pirazol in Example 45C, removing the Boc group with TFA as described in Example 1C and substituting the product thereof for tert-butyl (1R, 4R) -4-aminocyclohexylcarbamate in Example 74A.

EXAMPLE 84D Example 84C (0.71 g) and 1M TBAF in THF (1.8 ml) in THF (10 ml) were stirred at room temperature for 4 hours, diluted with water and extracted with dichloromethane and methanol. The extract, with the solid in the adjacent surface layer, was combined, concentrated and chromatographed on silica gel. The product was further purified by titration with DMF / water / methanol. 1 H NMR (300 MHz, DMSO-d 6) 5 10.85 (s, 1 H), 8.57 (s, 1 H), 8.39 (s, 1 H), 8.16 (d, J = 0.7 Hz, 1 H), 8.08 (s, 1 H) , 7.90 (d, J = 0.7Hz, 1H), 7.71-7.74 (m, 1H), 7.64 (d, J = 7.5Hz, 1H), 7.41 (dd, J = 8.6, 1.2Hz, 2H), 7.35 ( t, J = 8.0Hz, 1H), 7.18-7.25 (m, 2H), 7.11 (d, J = 7.8Hz, 1H), 6.94 (s, 2H), 6.89 (t, J = 7.3Hz, 1H), 6.64 (t, J = 6.1Hz, 1H), 4.95 (t, J = 5.3Hz, 1H), 4.32 (d, J = 6.1Hz, 2H), 4.23 (t, J = 5.6Hz, 2H), 3.80 ( q, J = 5.1Hz, 2H).

EXAMPLE 85A A mixture of Example 84D (164 mg) in dimethylacetamide (2.5 ml) was treated with (tBuO) 2 PNET2 (0.31 ml) and tetrazole (132 mg), stirred at room temperature for 2 hours, cooled to -10 ° C and it was treated with 30% H202 (0.1 ml). The mixture was stirred at room temperature for 2.5 hours, treated with 30% H202 (0.3 ml), stirred for 3 hours and partitioned between 10% Na2S203 and ethyl acetate. The extract was dried (Na2SO), filtered and concentrated, and the concentrate was purified through silica gel chromatography.

EXAMPLE 85B A mixture of Example 85A (90 mg) in methanol (5 ml) was treated with 4M HCl in dioxane (0.2 ml), stirred for 1 hour, diluted with diethyl ether and filtered. H NMR (300 MHz, DMSO-d6) d 11.09 (s, 1H), 8.90 (s, 1H), 8.90 (s, 2H), 8.76 (s, 1H), 8.33 (d, J = 0.7Hz, 1H) , 8.07 (s, 1H), 8.01 (d, J = 1.0Hz, 1H), 7.63-7.68 (m, 2H), 7.35-7.47 (m, 3H), 7.13-7.28 (m, 3H), 6.89 (t , J = 7.3Hz, 1H), 6.74-6.81 (m, 1H), 4.46 (t, J = 5.1Hz, 2H), 4.33 (d, J = 4.1Hz, 2H), 4.20-4.27 (m, 2H) .

EXAMPLE 86 This Example was prepared by substituting Example 22C and 2-fluoro-1-isocyanato-3- (trifluoromethyl) benzene for Example 1B and 1-isocyanato-3-methylbenzene, respectively, in Examples 1C and 1D, respectively. 1 H NMR (400 MHz, DMSO-d 6) d 10.65 (s, 1 H,) 9.18 (s, 1 H), 8.82 (d, J = 2.46 Hz, 1 H), 8.45 (m, 1 H), 8.33 (s, 1 H) , 8.09 (s, 1H), 7.60 (m, 1H), 7.57 (d, J = 8.90Hz, 2H), 7.47 (d, J = 9.21Hz, 2H), 7.35 (m, 2H), 7.00 (brs, 2H) 3.85 (s, 3H).

EXAMPLE 87 This Example was prepared by substituting Example 22C and isocyanatobenzene for Example 1B and 1-isocyanato-3-methylbenzene, respectively, in Examples 1C and 1D, respectively. H NMR (500 MHz, DMSO-d6) d 10.64 (s, 1H), 8.69 (s, 1H), 8.64 (s, 1H), 8.33 (s, 1H), 8.09 (s, 1H), 7.60 (s, 1H), 7.54 (d, J = 9.15Hz, 2H), 7.45 (m, 4H), 7.28 (m, 2H), 7.02 (brs, 2H), 6.96 (t, J = 7.32Hz, 1H), 3.85 ( s, 3H). EXAMPLE 88 This Example was prepared as described in Examples 22B-C by replacing 4,4,5,5-tetramethyl-2-thiophen-3-yl- [1, 3,2] dioxaborlane for 1-methyl-4- (4, 4,5,5-tetramethyl- [1,2] dioxaborolan-2-yl) -1H-pyrazole in Example 22B and coupling as described in Example 1D but substituting 1- (4-aminophenyl) 3-phenylurea for Example 1C. 1 H NMR (400 MHz, DMSO-d 6) d 10.58 (s, 1 H), 8.66 (s, 1 H), 8.61 (s, 1 H), 8.36 (s, 1 H), 7.83 (m, 1 H), 7.67 (m, 2H), 7.45 (m, 5H), 7.27 (m, 3H), 7.07 (brs, 2H), 6.96 (t, J = 7.36Hz, 1H).

EXAMPLE 89 This Example was prepared by substituting morpholine for 1-methylpiperazine in Example 38A and following the procedures of Example 1, but substituting the product thereof for 5-amino-4-cyano-thiophene-3-carboxylic acid ethyl ester in Example 1A and isocyanatobenzene during 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (500 MHz, DMSO-d 6) d 10.64 (s, 1 H), 8.68 (s, 1 H), 8.64 (s, 1 H), 8.22 (s, 1 H), 7.67 (d, J = 8.85 Hz, 2 H) , 7.50 (brs, 2H), 7.46 (t, J = 9.15Hz, 4H), 7.28 (m, 2H), 6.97 (t, J = 7.32Hz, 1H), 3.70 (m, 4H), 3.10 (m, 4H).

EXAMPLE 90 This Example was prepared as described in Example 1 by substituting 3-isocyanatothiophene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (400 MHz, DMSO-d 6) d 10.63 (s, 1 H), 8.89 (s, 1 H), 8.63 (s, 1 H), 8.37 (s, 1 H), 8.32 (s, 1 H), 7.98 (brs, 2H), 7.63 (d, J = 8.90Hz, 2H), 7.47 (d, J = 8.90Hz, 2H), 7.43 (m, 1H), 7.28 (dd, J = 3.07, 1.23Hz, 1H), 7.05 ( dd, J = 4.91, 1.23Hz, 1H).

EXAMPLE 91 This Example was prepared as described in Example 1 by substituting isocyanatocyclopentane for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (400 MHz, DMSO-d 6) d 10.57 (s, 1 H), 8.35 (s, 1 H), 8.31 (s, 1 H), 8.25 (s, 1 H), 7.92 (brs, 2 H), 7.56 (d, J = 8.90Hz, 2H), 7.38 (d, J = 9.21Hz, 2H), 6.11 (d, J = 7.06Hz, 1H), 3.94 (m, 1H), 1.84 (m, 2H), 1.63 (m, 2H), 1.53 (m, 2H), 1.36 (m, 2H).

EXAMPLE 92 This Example was prepared as described in Example 1 by substituting 3-isocyanatopyridine for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (400 Hz, DMSO-d 5) d 10.65 (s, 1 H), 8.83 (s, 2 H), 8.62 (s, 1 H), 8.37 (s, 1 H), 8.32 (s, 1 H), 8.19 (d, J = 3.38Hz, 1H), 7.95 (m, 1H), 7.96 (brs, 2H), 7.65 (d, J = 8.90Hz, 2H), 7.48 (d, J = 8.90Hz, 2H), 7.32 (m, 1 HOUR).

EXAMPLE 93A This Example was prepared as described in Example 1C substituting 1-isocyanato-4-nitrobenzene and 5-methylisoxazole-3-amine for 1-isocyanato-3-methylbenzene and (4-aminophenyl) carbamic ter-butyl ester acid, respectively, in Example 1C.

EXAMPLE 93B A mixture of Example 93A (700 mg), iron powder (830 mg), NH 4 Cl (155 mg) in ethanol (25 ml), THF (28 ml) and water (11 ml) at 85 ° C was stirred for 9 hours. , cooled to room temperature and filtered through diatomaceous earth (CELITE®) with ethanol. The filtrate was concentrated and the concentrate was purified through silica gel chromatography.

EXAMPLE 93C This Example was prepared by substituting Example 93B for Example 1C in Example 1D. 1 H NMR (400 MHz, DMSO-d 6) d 10.71 (s, 1 H), 9.44 (s, 1 H), 8.87 (s, 1 H), 8.46 (s, 1 H), 8.39 (s, 1 H), 8.28 (brs, 2H), 7.65 (d, J = 8.90Hz, 2H), 7.47 (d, J = 9.21Hz, 2H), 6.53 (s, 1H), 2.37 (s, 3H). EXAMPLE 94 This Example was prepared as described in Example 1 by substituting isocyanatocyclopropane for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (300 MHz, DMSO-d 6) d 10.62 (s, 1 H), 8.39 (s, 1 H), 8.34 (s, 1 H), 8.31 (s, 1 H), 7.92 (brs, 2 H), 7.56 (d, J = 9.16Hz, 2H), 7.41 (d, J = 9.16Hz, 2H), 6.37 (s, 1H), 2.54 (m, 1H), 0.63 (m, 2H), 0.40 (m, 2H).

EXAMPLE 95 This Example was prepared as described in Example 1 substituting 2,4-difluoro-1-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (500 MHz, DMSO-d 6) d 10.67 (s, 1 H), 9.05 (s, 1 H), 8.49 (s, 1 H), 8.37 (s, 1 H), 8.32 (s, 1 H), 8.10 (m, 1H), 7.65 (d, J = 8.54Hz, 4H), 7.47 (d, J = 8.54Hz, 2H), 7.31 (t, J = 8.85Hz, 1H), 7.05 (t, J = 7.93Hz, 1H) .

EXAMPLE 96 This Example was prepared as described in Example 1 by substituting 1,2-difluoro-4-isocyanatobenzene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (500 Hz, DMSO-d 6) d 10.67 (s, 1 H), 8.87 (s, 1 H), 8.77 (s, 1 H), 8.37 (s, 1 H), 8.32 (s, 1 H), 7.95 (brs, 2H), 7.68 (m, 1H), 7.64 (d, J = 8.85Hz, 2H), 7.47 (d, J = 8.85Hz, 2H), 7.34 (m, 1H), 7.12 (d, J = 9.15Hz, 1 HOUR).

EXAMPLE 97A A mixture of 3- (morpholinomethyl) aniline (0.46 g), triethylamine (0.37 ml) and 4-nitrophenylcarbon hydrochloride (0.53 g) at room temperature was stirred for 2 hours, treated with triethylamine (0.37 ml) and 4-aminophenylcarbamate. of tert-butyl (0.5 g) was stirred for 18 hours and partitioned between water and ethyl acetate. The extract was washed with water and brine and dried (Na2SO4), filtered and concentrated. The concentrate was purified through silica gel chromatography to provide tert-butyl 4- (3- (3- (morpholinomethyl) phenyl) ureido) phenylcarbamate, which was dissolved in dichloromethane (30 ml), cooled in a The ice bath was treated with TFA (1.8 ml), stirred for 30 minutes, warmed to room temperature, stirred for 18 hours and concentrated with an azeotrope of toluene / methanol.

EXAMPLE 97B This Example was prepared by substituting Example 97A for Example 1C in Example 1D. H NMR (400 MHz, DMSO-d6) d 10.63 (s, 1H), 8.65 (s, 1H), 8.63 (s, 1H), 8.37 (s, 1H), 8.32 (s, 1H), 7.96 (brs, 2H), 7.63 (d, J = 8.90Hz, 2H), 7.47 (d, J = 8.90Hz, 3H), 7.34 (d, J = 8.90Hz, 1H), 7.23 (t, J = 7.67Hz, 1H) , 6.92 (d, J = 7.36Hz, 1H), 3.59 (m, 4H), 3.47 (s, 2H), 2.40 (s, 4H). EXAMPLE 98 This Example was prepared by substituting Example 74A for Example 1C in Example 1D. 1 H NMR (400 MHz, DMSO-d 6) d 9.34 (brs, 1H), 8.83 (d, J = 7.67Hz, 1H), 8.37 (s, 1H), 8.30 (s, 1H), 8.28 (s, 1H) , 8.04 (brs, 2H), 7.37 (m, 2H), 7.21 (m, 2H), 6.88 (m, 1H), 6.08 (d, J = 6.44Hz, 1H), 3.44 (brs, 1H), 1.94 ( m, 4H), 1.47 (m, 2H), 1.28 (m, 2H).

EXAMPLE 99 This Example was prepared as described in Example 93 by substituting 3,5-dimethylisoxazole-4-amine for 5-methylisoxazole-3-amine. 1 H NMR (300 MHz, DMSO-d 6) d 10.66 (s, 1 H), 8.84 (s, 1 H), 8.40 (S, 1 H), 8.34 (s, 1 H), 8.01 (brs, 2 H), 7.70 (s, 1H), 7.61 (d, J = 9.16Hz, 2H), 7.46 (d, J = 8.82Hz, 2H), 2.29 (s, 3H), 2.13 (s, 3H).

EXAMPLE 100 This Example was prepared as described in Example 93 by substituting thiazole-2-amine for 5-methylisoxazole-3-amine. H NMR (400 MHz, DMSO-d6) d 10.67 (s, 1H) 10.46 (s, 1H), 8.98 (s, 1H), 8.38 (s, 1H), 8.32 (s, 1H), 7.98 (brs, 2H) ), 7.67 (d, J = 8.90Hz, 2H), 7.50 (d, J = 8.90Hz, 2H), 7.37 (d, J = 3.68Hz, 1H), 7.11 (d, J = 3.07Hz, 1H).

EXAMPLE 101 This Example was prepared as described in Example 93 by substituting isoxazole-3-amine for 5-methylisoxazole-3-amine. 1 H NMR (500 MHz, DMSO-d 6) d 10.69 (s, 1 H), 9.58 (s, 1 H), 8.86 (s, 1 H), 8.74 (s, 1 H), 8.38 (s, 1 H), 8.32 (s, 1H), 7.83 (brs, 2H), 7.67 (d, J = 8.24Hz, 2H), 7.48 (d, J = 8.54Hz, 2H), 6.85 (s, 1H).

EXAMPLE 102 This Example was prepared as described in Example 1 by substituting tert-butyl piperidin-4-ylcarbamate and isocyanatobenzene for tert-butyl ester of (4-aminophenyl) carbamic acid and 1-isocyanato-3-methylbenzene, respectively, in Example 1 C. 1 H NMR (400 MHz, DMSO-d 6) d 9.10 (brs, 1H), 8.85 (d, J = 7.67Hz, 1H), 8.53 (s, 1H), 8.34 (s, 1H), 8.26 (s, 1H) , 7.94 (brs, 1H), 7.46 (d, J = 7.67Hz, 2H), 7.22 (m, 2H), 6. 93 (t, J = 7.36Hz, 1H), 4.14 (d, J = 13.50Hz, 2H), 4.06 (m, 1H), 2.95 (t, J = 11.66Hz, 2H), 1.88 (d, J = 12.27) Hz, 2H), 1.53 (m, 2H).

EXAMPLE 103 This Example was prepared as described in Example 1 by substituting tert-butyl ester of (3-aminophenyl) carbamic acid and isocyanatobenzene for tert-butyl ester of (4-aminophenyl) -carbamic acid and 1-isocyanato-3-methylbenzene, respectively , in Example 1B. 1 H NMR (500 MHz, DMSO-d 6) d 10.74 (s, 1 H), 8.78 (s, 1 H), 8.61 (s, 1 H), 8.41 (s, 1 H), 8.32 (s, 1 H), 8.12 (brs, 1H), 7.97 (m, 1H), 7.46 (d, J = 7.63Hz, 2H), 7.34 (m, 1H), 7.29 (t, J = 8.24Hz, 5H), 6.98 (t, J = 7.32Hz, 1 HOUR).

EXAMPLE 104A A solution of Example 1A (750 mg) in THF (34 mL) at -78 ° C was treated with 2M LDA in THF (5.1 mL), stirred for 2 hours, treated with iodide (855 mg) in THF (6 mL). mi), stirred for 1 hour, warmed to 0 ° C, stirred for 2 hours, quenched with saturated NH 4 Cl and extracted with ethyl acetate. The extract was washed with 10% Na 2 SO 3 and brine and dried (MgSO 4), filtered and concentrated. The concentrate was purified through silica gel chromatography.

EXAMPLE 104B Example 104A (50 mg), 3-methoxyprop-1-y (0.015 ml), CI2Pd (PPh3) 2 (5 mg), Cul (0.8 mg), triethylamine (0.36 ml) and DF (0.18 ml) were degassed With nitrogen, it was heated in a sealed tube at 60 ° C for 40 minutes with stirring in a Smith Synthesizer microwave oven (at 200W). The mixture was partitioned between water and dichloromethane and the extract was washed with brine and dried (MgSO 4), filtered and concentrated. The concentrate was purified by silica gel chromatography.

EXAMPLE 104C This Example was prepared as described in Example 1 by substituting Example 104B for Example 1A in Example 1B and isocyanatobenzene for 1-isocyanato-3-methylbenzene in Example 1C. 1 H NMR (500 MHz, DMSO-d 6) d 10.87 (s, 1 H), 8.70 (s, 1 H), 8.64 (s, 1 H), 8.39 (s, 1 H), 7.47 (m, 10 H), 6.97 (s, 1H), 4.38 (s, 2H), 3.22 (s, 3H).

EXAMPLE 105 This Example was prepared as described in Example 104 by substituting ethynyltrimethylsilane for 3-methoxyprop-1-yl. 1 H NMR (400 MHz, DMSO-d 6) d 10.84 (s, 1 H), 8.71 (s, 1 H), 8.64 (s, 1 H), 8.40 (s, 1H), 7.65 (d, J = 8.90Hz, 2H), 7.47 (t, J = 8.90Hz, 6H), 7.28 (t, J = 8.59, Hz, 2H), 6.97 (t, J = 7.36 Hz, 1H), 5.08 (s, 1H).

EXAMPLE 106 This Example was prepared as described in Example 104 substituting 3-ethynylthiophene for 3-methoxyprop-1-yl. H NMR (500 MHz, DMSO-d6) d 10.94 (s, 1H), 8.71 (s, 1H), 8.65 (s, 1H), 8.40 (s, 1H), 7.89 (m, 1H), 7.70 (d, J = 8.85Hz, 2H), 7.66 (m, 1H), 7.47 (m, 6H), 7.28 (t, J = 7.63Hz, 2H), 7.10 (d, J = 5.19Hz, 1H), 6.97 (t, J = 7.32Hz, 1H).

EXAMPLE 107 This Example was prepared as described in Example 104 substituting N, N-dimethylprop-2-in-1-amine for 3-methoxyprop-1-yl. 1 H NMR (400 MHz, DMSO-d 6) d 10.84 (s, 1 H), 8.69 (s, 1 H), 8.64 (s, 1 H), 8.38 (s, 1 H), 7.65 (d, J = 9.21 Hz, 2 H) , 7.46 (m, 6H), 7.27 (t, J = 8.59Hz, 2H), 6.97 (t, J = 7.36Hz, 1H), 3.54 (s, 2H), 2.12 (s, 6H).

EXAMPLE 108 This Example was prepared as described in Example 1D substituting N- (4-aminophenyl) -2-fluorobenzamide for Example 1C. 1 H NMR (500 MHz, DMSO-d 6) d 10.74 (s, 1 H), 10.45 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 8.02 (brs, 2H), 7.71 (m, 5H), 7.58 (m, 1H), 7.35 (m, 2H).

EXAMPLE 109 This Example was prepared as described in Example 1D substituting N- (4-aminophenyl) -3-fluorobenzamide for Example 1C. 1H NR (500 MHz, DMSO-d6) d 10.75 (s, 1H), 10.36 (s, 1H), 8.40 (s, 1H), 8.33 (s, 1H), 7.78 (m, 8H), 7.60 (s, 1H), 7.46 (s, 1H).

EXAMPLE 110 This Example was prepared as described in Example 1D substituting N- (4-aminophenyl) -4-fluorobenzamide for Example 1C. 1 H NMR (500 MHz, DMSO-d 6) d 10.74 (s, 1 H), 10.30 (s, 1 H), 8.41 (s, 1 H), 8.34 (s, 1 H), 8.05 (m, 2 H), 7.90 (brs, 2H), 7.78 (d, J = 8.24Hz, 2H), 7.71 (d, J = 8.24Hz, 2H), 7.37 (t, J = 8.85, 8.24Hz, 1H).

EXAMPLE 111 This Example was prepared as described in Example 1D substituting N- (4-aminophenyl) -2-methylbenzamide for Example 1C. 1 H NMR (400 MHz, DMSO-d 6) d 10.70 (s, 1 H), 10.30 (s, 1 H), 8.40 (s, 1 H), 8.32 (s, 1 H), 8.01 (brs, 2 H), 7.76 (d, J = 8.90Hz, 2H), 7.68 (d, J = 8.90Hz, 2H), 7.46 (d, J = 7.67Hz, 1H), 7.39 (m, 1H), 7.30 (m, 2H), 2.40 (s, 3H).

EXAMPLE 112 This Example was prepared as described in Example 1D substituting N- (4-aminophenyl) -3-methylbenzamide for Example 1C. H NMR (400 MHz, DMSO-d6) d 10.71 (s, 1H), 10.22 (s, 1H), 8.40 (s, 1H), 8.33 (s, 1H), 8.03 (brs, 2H), 7.77 (m, 4H), 7.70 (d, J = 9.21Hz, 2H), 7.40 (m, 2H), 2.41 (s, 3H).

EXAMPLE 113A A solution of CaCl2 (104 mg) in ethanol (2.3 ml) was treated with methyl 3- (3- (4-aminophenyl) ureido) benzoate (150 mg) in THF (2.3 ml) and NaBH4 (71 mg), and The mixture was stirred at reflux for 18 hours, treated with NaBH 4 (280 mg) in 4 portions for 8 hours, cooled to room temperature and concentrated. The concentrate was treated with water and washed with dichloromethane. The heterogeneous water layer was filtered, and the solid was collected, washed with water and dried with air.

EXAMPLE 113B This Example was prepared as described in Example 1D substituting Example 113A for Example 1C. H NMR (500 MHz, DMSO-d5) d 10.69 (s, 1H), 8.69 (s, 1H), 8.66 (s, 1H), 8.43 (s, 1H), 8.36 (s, 1H), 7.96 (brs, 2H), 7.63 (d, J = 8.85Hz, 2H), 7.48 (d, J = 8.85Hz, 2H), 7.43 (s, 1H), 7.32 (d, J = 8.24Hz, 1H), 7.22 (t, J = 7.93Hz, 1H), 6.92 (d, J = 7.63Hz, 1H), 4.47 (s, 2H), 3.70 (brs, 1H).

EXAMPLE 114 This Example was prepared by substituting tert-butyl 3-aminobenzylcarbamate for Example 1C in Example 1D, removing the Boc group with TFA as described in Example 1C and substituting the product thereof and isocyanatobenzene for Example 45C and 1-isocyanate 3-methylbenzene, respectively, in Example 45D. 1 H NMR (500 MHz, DMSO-d 6) d 10.75 (s, 1 H), 8.57 (s, 1 H), 8.39 (s, 1 H), 8.32 (s, 1 H), 7.97 (br s, 2 H), 7.69 (s) , 1H), 7.62 (d, J = 7.32Hz, 1H), 7.41 (d, J = 7.63Hz, 2H), 7.35 (t, J = 7.63Hz, 1H), 7.22 (t, J = 7.32Hz, 2H ), 7.11 (d, J = 7.32Hz, 1H), 6.89 (t, J = 6.71Hz, 1H), 6.64 (s, 1H), 4.32 (d, J = 5.19Hz, 2H).

EXAMPLE 115 This Example was prepared as described in Example 1 by substituting (3-aminophenyl) carbamic acid tert-butyl ester and 1-isocyanato-2-methylbenzene for (4-aminophenyl) carbamic acid tert-butyl ester and 1-isocyanate- 3-methylbenzene, respectively, in Example 1B. H NMR (500 MHz, DMSO-d6) d 10.74 (s, 1H), 9.15 (s, 1H), 8.41 (s, 1H), 8.33 (s, 1H), 8.00 (s, 1H), 7.88 (m, 4H), 7.30 (m, 3H), 7.16 (m, 2H), 6.95 (t, J = 7.32Hz, 1H), 2.26 (s, 3H).

EXAMPLE 116 This Example was prepared by substituting tert-butyl 3-aminobenzylcarbamate for Example 1C in Example 1D, removing the Boc group with TFA as described in Example 1C and substituting the product thereof for Example 45C in Example 45D. 1 H NMR (500 MHz, DMSO-d 6) d 10.75 (s, 1 H), 8.48 (s, 1 H), 8.39 (s, 1 H), 8.33 (s, 1 H), 7.90 (br s, 2 H), 7.68 (s) , 1H), 7.62 (d, J = 7.93Hz, 1H), 7.35 (t, J = 7.93Hz, 1H), 7.25 (s, 1H), 7.18 (d, J = 7.93Hz, 1H), 7.10 (m , 2H), 6.71 (d, J = 7.32Hz, 1H), 6.62 (t, J = 5.80Hz, 1H), 4.32 (d, J = 5.80Hz, 2H), 2.24 (s, 3H).

EXAMPLE 117 This Example was prepared by substituting tert-butyl 3-aminobenzylcarbamate for Example 1C in Example 1D, removing the Boc group with TFA as described in Example 1C and substituting the product thereof and 1-fluoro-3-isocyanatobenzene for the Example 45C and 1-isocyanato-3-methylbenzene, respectively, in Example 45D. 1 H NMR (500 MHz, DMSO-d 6) d 10.75 (m, 1 H), 8. 84 (m, 1H), 8.39 (m, 1H), 8.32 (m, 1H), 7.98 (m, 2H), 7.68 (m, 1H), 7.62 (d, J = 8.24Hz, 1H), 7.47 (d , J = 12.21Hz, 1H), 7.35 (t, J = 7.93Hz, 1H), 7.24 (m, 1H), 7.11 (d, J = 7.63Hz, 1H), 7.05 (d, J = 9.15Hz, 1H ), 6.72 (m, 2H), 4.32 (d, J = 6.10Hz, 2H).

EXAMPLE 118 This Example was prepared as described in Example 1 by substituting (3-aminophenyl) carbamic acid tert-butyl ester for (4-aminophenyl) carbamic acid tert-butyl ester in Example 1B. 1 H NMR (500 MHz, DMSO-d 6) d 10.74 (m, 1 H), 8.77 (m, 1 H), 8.55 (m, 1 H), 8.41 (m, 1 H), 8.33 (m, 1 H), 7.97 (m, 1H), 7.75 (m, 2H), 7.29 (m, 5H), 7.16 (t, J = 7.63Hz, 1H), 6.80 (d, J = 7.32Hz, 1H), 2.28 (s, 3H).

EXAMPLE 119 This Example was prepared as described in Example 1 by substituting tert-butyl ester of (3-aminophenyl) carbamic acid and 1-isocyanato-4-methylbenzene for tert-butyl ester of (4-aminophenyl) carbamic acid and 1-isocyanate- 3-methylbenzene, respectively, in Example 1B. 1 H NMR (500 MHz, DMSO-d 6) d 10.73 (s, 1 H), 8.74 (s, 1 H), 8.51 (s, 1 H), 8.41 (s, 1 H), 8.33 (s, 1 H), 7.96 (s, 1H), 7.77 (br s, 2H), 7.30 (m, 5H), 7.09 (m, 2H), 2.24 (s, 3H).

EXAMPLE 120 This Example was prepared as described in Example 1 by substituting tert-butyl ester of (3-aminophenyl) carbamic acid and 1-fluoro-2-isocyanatobenzene for (4-aminophenyl) carbamic acid tert-butyl ester and 1-isocyanate- 3-methylbenzene, respectively, in Example 1B. 1H N MR (500 MHz, DMSO-d6) d 10.75 (s, 1H), 9.21 (s, 1H), 8.54 (d, J = 2.14Hz, 1H), 8.41 (s, 1H) 8.33 (s, 1H) , 8.17 (t, J = 8.24Hz, 1H), 7.98 (s, 1H), 7.73 (br s, 2H), 7.35 (m, 1H), 7.30 (m, 2H), 7.24 (m, 1H), 7.15 (t, J = 7.32Hz, 1H), 7.01 (m, 1H).

EXAMPLE 121 This Example was prepared as described in Example 1 by substituting tert-butyl ester of (3-aminophenol) carbamic acid and 1-fluoro-3-isocyanatobenzene for tert-butyl ester of (4-aminophenyl) carbamic acid and 1 - isocyanate-3-methylbenzene, respectively, in Example 1B. H NMR (500 MHz, DMSO-d6) d 10.75 (s, 1H), 8.85 (s, 2H), 8.41 (s, 1H), 8.32 (s, 1H), 7.97 (s, 1H), 7.96 (br s) , 2H), 7.50 (d, J = 11.90Hz, 1H), 7.36 (m, 1H), 7.29 (m, 3H), 7.12 (d, J = 7.93Hz, 1H), 6.79 (t, J = 6.10Hz , 1 HOUR).

EXAMPLE 122 This Example was prepared as described in Example 1 substituting tert-butyl ester of (3-aminophenyl) carbamic acid and 1-fluoro-4-isocyanatobenzene for tert-butyl ester of (4-aminophenyl) carbamic acid and 1-isocyanato-3-methylbenzene, respectively, in Example 1B 1 H NMR (500 MHz, DMSO-d 6) d 10.73 (m, 1 H), 8.78 (m, 1 H), 8.65 (m, 1 H), 8.40 (m, 1 H), 8.33 (m, 1 H ), 7.97 (m, 1 H), 7.78 (m, 2H), 7.47 (m, 2H), 7.33 (m, 1 H), 7.28 (m, 2H), 7.13 (t, J = 8.85Hz, 2H) .

EXAMPLE 123 This Example was prepared by substituting tert-butyl 3-aminobenzylcarbamate for Example 1C in Example 1 D, removing the Boc group with TFA as described in Example 1C and substituting the product thereof and 1-isocyanate-3- (trif. luoromethyl) benzene for Example 45C and 1-isocyanato-3-methylbenzene, respectively, in Example 45D. 1 H NMR (500 MHz, DMSO-d 6) 5 10.75 (s, 1 H), 9.04 (s, 1 H), 8.39 (s, 1 H), 8.32 (s, 1 H), 7.97 (br s, 2 H), 7.63 (m, 6H), 7.35 (s, 1 H), 7.11 (s, 1 H), 6.82 (s, 1 H), 4.34 (s, 2H).

EXAMPLE 124 This Example was prepared by substituting 2- (2-aminothiazol-5-yl) -N- (3-fluorophenyl) acetamide for Example 1C in Example 1D. 1 H NMR (500 MHz, DMSO-d 6) d 12.95 (br s, 1 H), 10.47 (s, 1 H), 8.61 (s, 1H), 8.32 (s, 1H), 7.97 (br s, 2H), 7.61 (d, J = 11.90Hz, 1H), 7.44 (s, 1H), 7.34 (m, 2H), 6.90 (t, J = 6.41Hz, 1H), 3.91 (s, 2H).

EXAMPLE 125A A solution of 4-amino-N-methoxythieno [2,3-d] pyrimidine-5-carboxamide (3 mmole) (prepared by substituting O-methylhydroxylamine for Example 1C in Example 1D) in THF (12 mL) was added to a suspension of LAH (235 mg) in THF (12 mL) at -78 ° C. The mixture was stirred for 30 minutes, treated sequentially with water (0.24 ml), 1 M NaOH (0.24 ml) and water, (0.72 ml), filtered through diatomaceous earth (CELITE®) and concentrated.

EXAMPLE 125B A solution of (4-nitrobenzyl) triphenylphosphonium bromide (1.66 g) in THF (20 ml) at 0 ° C was treated with 1.6M n-butyl lithium in hexanes (2.2 ml), stirred for 40 minutes, treated with Example 125A in THF (20 mL) was stirred at 0 ° C for 3 hours and at room temperature for 18 hours, treated with 5% methanol in dichloromethane, washed with water and dried (Na2SO4), filtered and concentrated. The concentrate was titrated with methanol and dried with air.

EXAMPLE 125C This example was prepared as described in Example 93B and substituting Example 125B for Example 93A.

EXAMPLE 125D A mixture of Example 125C (110 mg) and 5% Pd on carbon (50 mg) in methanol (10 ml) was stirred under hydrogen (4,218 kg / cm2) at 50 ° C for 40 hours, filtered and concentrated.

EXAMPLE 125E This example was prepared as described for Example 45D and substituting Example 125D and isocyanatobenzene for Example 45C and 1-isocyanato-3-methylbenzene, respectively. 1 H NMR (400 MHz, DMSO-d 6) d 8.65 (s, 1 H), 8.61 (s, 1 H), 8.25 (s, 1 H), 7.44 (d, J = 7.98 Hz, 2 H), 7.35 (d, J = 8.59Hz, 2H), 7.27 (t, J = 7.98Hz, 2H), 7.15 (d, J = 8.29Hz, 2H), 7.10 (s, 1H), 6.99 (s, 2H), 6.95. (m, 1H), 3.22 (t, J = 8.29Hz, 2H), 2.90 (t, J = 8.29Hz, 2H).

EXAMPLE 126 This Example was prepared by substituting 1- (4-aminophenyl) -3- (3- (3-hydroxypropoxy) phenyl) urea for Example 1C in Example 1D. 1 HOUR NMR (500 MHz, DMSO-d6) d 10.68 (s, 1H), 8.70 (s, 1H), 8.66 (s, 1H), 8.48 (br s, 1H), 8.41 (s, 1H), 8.36 (s, 1H), 7.95 (brs, 1H), 7.63 (d, J = 8.85Hz, 2H), 7.47 (d, J = 8.85Hz, 2H), 7.22 (m, 1H), 7.16 (t, J = 8.24Hz , 1H), 6.89 (d, J = 7.93Hz, 1H), 6.54 (m, 1H), 4.00 (t, J = 6.41Hz, 2H), 3.56 (t, J = 6.41Hz, 2H), 1.86 (m , 2H).

EXAMPLE 127 This Example was prepared by substituting tert-butyl 4- (aminomethyl) phenylcarbamate for Example 1C in Example 1D, removing the Boc group with TFA as described in Example 1C and substituting the product thereof and isocyanatobenzene for Example 45C and 1-isocyanato-3-methylbenzene, respectively, in Example 45D. 1 H NMR (400 MHz, DMSO-d 6) d 9.50 (t, J = 6.14 Hz, 1 H), 9.06 (s, 1 H), 8.68 (s, 1 H), 8.66 (s, 1 H), 8.31 (s, 1 H) , 8.27 (s, 1H), 7.81 (br s, 1H), 7.43 (m, 4H), 7.27 (m, 4H), 6.96 (t, J = 7.36Hz, 1H), 4.44 (d, J = 5.83Hz , 2H).

EXAMPLE 28 This Example was prepared by substituting tert-butyl 4- (aminomethyl) phenylcarbamate for Example 1C in Example 1D, removing the Boc group with TFA as described in Example 1C and substituting the product thereof for Example 45C in Example 45D. 1 H NMR (400 MHz, DMSO-d 6) d 9.52 (t, J = 5.83Hz, 1H), 9.21 (brs, 1H), 8.67 (s, 1H) 8.59 (s, 1H), 8.34 (s, 1H), 8.30 (s, 1H), 7.92 (br s , 1H), 7.43 (d, J = 8.59Hz, 2H), 7.29 (d, J = 5.83Hz, 2H), 7.25 (s, 1H), 7.21 (d, J = 8.59Hz, 1H), 7.14 (m , 1H), 6.78 (d, J = 7.98Hz, 1H), 4.44 (d, J = 5.83Hz, 2H), 2.27 (s, 3H).

EXAMPLE 129 This Example was prepared by substituting tert-butyl 4- (aminomethyl) phenylcarbamate for Example 1C in Example 1D, removing the Boc group with TFA as described in Example 1C and substituting the product thereof and 1-fluoro-3- isocyanatobenzene for Example 45C and 1-isocyanato-3-methylbenzene, respectively, in Example 45D. 1 H NMR (400 MHz, DMSO-d 6) d 9.52 (t, J = 5.83 Hz, 1 H), 9.18 (brs, 1 H), 8.95 (s, 1 H), 8.80 (s, 1 H), 8.34 (s, 1 H) , 8.30 (s, 1H), 7.91 (br s, 1H), 7.49 (m, 1H), 7.43 (d, J = 8.59Hz, 2H), 7.29 (m, 3H), 7.11 (m, 1H), 6.77 (s, 1H), 4.45 (d, J = 5.83Hz, 2H).

Claims

REIVI DICACIO ES

1. - A compound having the formula (I): or a pharmaceutically acceptable salt thereof, wherein: A1 is C (0) NHRC (0) N (R1) 2l NHC (0) R1, NR1C (0) R1, NHC (0) NHR1, NHC (0) N (R1) 2, NR1C (0) NHR1, NR1C (0) N (R1) 2, S02NHR1, S02N (R) 2, NHS02R1, NR1S02R1, OC (0) OR1, NHC (0) OR1, NR1C (0) OR1 or R5; R is R2, R3, R4 or R5; R2 is phenyl, which is not fused or fused with benzene, heteroarene or R2A; R2A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R3 is heteroaryl, which is not fused or fused with benzene, heteroarene or R3A; R3A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R 4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R 4A; R 4A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R5 is alkyl, alkenyl or alkynyl, each of which is substituted with one or two independently selected from R6, OR6, SR6, S (0) R6, S02R6, NH2, NHR6, N (R6) 2, C (0) R6, C (0) NH2, C (0) NHR6, C (0) N (R6) 2, NHC (0) R6, NR6C (0) R6, NHS02R6, NR6S02R6, NHC (0) OR6, NR6C (0) OR6, S02NH2, S02NHR6, S02N (R6) 2, NHC (0) NH2, NHC (0) NHR6, NHC (0) N (R6) 2, NR6C (0) N (R6) 2, OH, (O), C (0) OH, CN, NH2, CF3, OCF3, CF2CF3, F, Cl, Br or I; R6 is R7, R8 or R9; R7 is phenyl, which is not fused or fused with benzene, heteroarene or R7A; R7A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R8 is heteroaryl, which is not fused or fused with benzene, heteroarene or R8A; R8A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R9 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R9A; R9A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; wherein the portions represented by R1, R2, R3, R4, R5 and R6 are independently substituted with one or two independently selected from R0, OR10, SR10, S (0) R10, S02R1 °, NH2, NHR10, N (R10 ) 2, C (0) R10, C (0) OR1 °, C (0) NHR1 °, C (O) N (R0) 2, NHC (0) R1 °, NR10C (O) R10, NHC (0 ) NHR10, NHC (O) N (R10) 2, NR 0C (O) NHR10, NR10C (O) N (R10) 2, S02NHR10, SO2N (R10) 2, NHS02R10, NR1S02R10, OC (0) OR °, NHC (0) OR1 ° or NR1C (0) OR1 °; R10 is R1, R12, R13 or R14; R1 is phenyl, which is not fused or fused with benzene, heteroarene or R11A; R11A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R12 is heteroaryl, which is not fused or fused with benzene, heteroarene or R12A; R12A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R 13 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R 13A; R13A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R 4 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected from R 15 or NHC (0) NHR 15; R 5 is R 16, R 17 R 18; R16 is phenyl, which is not fused or fused with benzene, heteroarene or R16A; R 6A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R17 is heteroaryl, which is not fused or fused with benzene, heteroarene or R7A; R17A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R18 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R18A; R18A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; B1 is H, R19, C (0) NHR19, C (0) N (R9) 2, NHC (0) R19, NR1C (0) R19, NHC (0) NHR19, NHC (0) N (R19) 2 , N R19C (0) NHR 9, NR1 C (0) N (R19) 2, S02NHR19, S02N (R19) 2, NHS02R19, NR19S02R19, OC (0) OR19, NHC (0) OR19, or NR 9C (0) OR19; R19 is R20, R21, R22 or R23; R20 is phenyl, which is not fused or fused with benzene, heteroarene or R20A; R20A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R 2 is heteroaryl, which is not fused or fused with benzene, heteroarene or R 1A; R21A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R22 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R22A; R22A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R23 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected from R24, OR24, SR24, S (0) R24, S02R24, NH2, NHR24, N (R24) 2, C (0) R24, C (0) NH2, C (0) NHR24, C (0) N (R24) 2, NHC (0) R24, NR24C (0) R24, NHS02R24, NR24S02R24, NHC (0) OR24, N R24C (0) OR24, S02NH2, S02NHR24, S02N (R4) 2, NHC (0) NH2, NHC (0) NHR24, NHC (0) N (R4) 2, NR2 C (0) N (R24) 2 , OH, (O), C (0) OH, CN, NH 2, CF 3, OCF 3, CF 2 CF 3, F, Cl, Br or I; R 24 is R 25, R 26, R 27, alkyl, alkenyl or alkynyl; R25 is phenyl, which is not fused or fused with benzene, heteroarene or R25A; R25A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R26 is heteroaryl, which is not fused or fused with benzene, heteroarene or R26A; R25A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R27 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unbound or fused with benzene, heteroarene or R27A; R27A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; C1 is O, S, S (O), S02, NH, or N (C2); C2 is R28, R29, R30 or R31; R28 is phenyl, which is not fused or fused with benzene, heteroarene or R28A; R28A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R29 is heteroaryl, which is not fused or fused with benzene, heteroarene or R29A; R29A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R30 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unbound or fused with benzene, heteroarene or R30A; R 30A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R31 is alkyl, alkenyl or alkynyl, each of which is substituted with one or two independently selected from R32 O R32 S R32 S (0) R32, S02R32, NH2, NHR32, N (R32) 2, C (0) R32 , C (0) NH2, C (0) NHR32, C (0) N (R32) 2, NHC (0) R32, NR32C (0) R32, NHS02R32, NR32S02R32, NHC (0) OR32, NR32C (0) OR32, S02NH2, S02NHR32, S02N (R32) 2, NHC (0) NH2, NHC (0) NHR32, NHC (0) N (R3) 2, NR32C (0) N (R32) 2, OH, (O), C (0) OH, CN, NH2, CF3, OCF3, CF2CF3, F, Cl, Br or I; R32 is R33, R34 or R35; R33 is phenyl, which is not fused or fused with benzene, heteroarene or R33A; R33A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R34 is heteroaryl, which is not fused or fused with benzene, heteroarene or R34A; R3 A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R35 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R35A; R35A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; D1 is N, CH or C (D2); D2 is R36, R37, R38 or R39; R36 is phenyl, which is not fused or fused with benzene, heteroarene or R36A; R36A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R37 is heteroaryl, which is not fused or fused with benzene, heteroarene or R37A; R37A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R38 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R38A; 38A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R39 is alkyl, alkenyl or alkynyl, each of which is substituted with one or two independently selected from R40, OR40, SR40, S (0) R40, S02R40, NH2, NHR40, N (R0) 2, C (0) ) R40, C (0) NH2, C (0) NHR40, C (O) N (R0) 2, NHC (0) R40, NR 0C (O) R40, NHS02R40, NR40SO2R40, NHC (0) OR °, NR 0C (O) OR40, S02NH2, S02NHR40, SO2N (R0) 2, NHC (0) NH2, NHC (0) NHR40, NHC (O) N (R40) 2, NR 0C (O) N (R40) 2 , OH, (O), C (0) OH, CN, NH2, CF3I OCF3, CF2CF3, F, Cl, Br or I; R40 is R41, R42 or R43; R41 is phenyl, which is not fused or fused with benzene, heteroarene or R41A; R 4 A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R42 is heteroaryl, which is not fused or fused with benzene, heteroarene or R42A; R42A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R43 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R43A; R43A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; wherein each preceding cyclic portion is independently unsubstituted or substituted or further unsubstituted or further substituted with one or two or three or four independently selected from R44, OR44, SR44, S (0) R44, S02R44, NH2, NHR44, N (R44) 2, C (0) R44, C (0) OR44, C (0) NH2, C (0) NHR44, C (0) N (R4) 2, NHC (0) R44, NR4C ( 0) R44, NHS02R44, NR 4S02R44, NHC (0) OR44, NR 4C (0) OR44, S02NH2, S02NHR44, S02N (R4) 2, NHC (0) NH2, NHC (0) NHR44, NHC (0) N (R44) 2, N R44C (O) N (R) 2, C (N) NH2, C (N) NH R44, C (N) N (R4) 2, NHC (N) NH2, NHC (N) NH R44, NHC (N) N (R44) 2, OH, (O), C (0) H, C (0) OH, N02, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I; R44 is R45, R46, R47 or R48; R45 is phenyl, which is not fused or fused with benzene, heteroarene or R45A; R 5A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R46 is heteroaryl, which is not fused or fused with benzene, heteroarene or R 6A; R46A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R47 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R7A; R47A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R48 is alkyl, alkenyl or alkynyl, each of which is substituted with one or two independently selected from R49, OR49, SR49, S (0) R49, S02R49, NH2, NHR49, N (R49) 2, C (0) R49, C (0) NH2, C (0) NHR49, C (0) N (R49) 2, NHC (0) R49, NR 9C (0) R49, NHS02R49, NR 9S02R49, NHC (0) OR49, NR49C ( 0) OR49, S02NH2, S02NHR49, S02N (R49) 2, NHC (0) NH2, NHC (0) NHR49, NHC (0) N (R9) 2, NR49C (0) N (R49) 2, OP (0 ) (OH) 2, OP (0) (OH) (OR44), OP (0) (OR44) 2, OH, (O), C (0) OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I; R49 is R50, R51, R52, alkyl, alkenyl or alkynyl; R50 is phenyl, which is not fused or fused with benzene, heteroarene or R50A; R50A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; R51 is heteroaryl, which is not fused or fused with benzene, heteroarene or R51A; R51A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; and R52 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene, heteroarene or R52A; R52A is cycloalkane, cycloalkene, heterocycloalkane or heterocycloalkene; wherein the portions represented by R45, R46, R47 and R49 are independently unsubstituted or substituted with one or two or three or four independently selected from alkyl, alkenyl, alkynyl, OH, (O), C (0) OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein A1 is C (0) NHR1, C (0) N ( R1) 2, NHC (0) R1, NR C (0) R, NHC (0) NHR, NHC (0) N (R1) 2, NR1C (0) NHR1, NR 1 C (O) N (R 1) 2, S02NHR1, S02N (R1) 2, NHS02R1, NR1S02R1, OC (0) OR1, NHC (0) OR1, NR1C (0) OR1 or R5; R1 is R2, R3 or R4; R2 is phenyl, which is not fused or fused with benzene or heteroarene; R3 is heteroaryl, which is not fused or fused with benzene or heteroarene; R 4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; R5 is alkyl, alkenyl or alkynyl, each of which is substituted with one or two independently selected from R6, OR6, SR6, S (0) R6, S02R6, NH2I NHR6, N (R6) 2, C (0) R6 , C (0) NH2, C (0) NHR6, C (0) N (R6) 2, NHC (0) R6, NR6C (0) R6, NHC (0) NHR6, OH, (O), C (0) ) OH, CN, NH2, CF3, OCF3, CF2CF3, F, Cl, Br or I; R6 is R7, R8 or R9; R7 is phenyl, which is not fused or fused with benzene or heteroarene; R8 is heteroaryl, which is not fused or fused with benzene or heteroarene; R9 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; wherein the portions represented by R1, R2, R3, R4, R5 and R6 are independently substituted with one or two independently selected from R0, OR10, SR10, S (0) R10, S02R10, NH2, NHR10, N (R10) 2, C (0) R10, C (0) OR10, C (0) NHR10, C (O) N (R10) 2, NHC (0) R10, NR10C (O) R10 or NHC (0) NHR10; R10 is R 1, R 12, R 13 or R 14; R11 is phenyl, which is not fused or fused with benzene or heteroarene; R12 is heteroaryl, which is not fused or fused with benzene or heteroarene; R 13 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; R14 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected from R15 or NHC (0) NHR15; R15 is R16, R17 R18; R16 is phenyl, which is not fused or fused with benzene or heteroarene; R17 is heteroaryl, which is not fused or fused with benzene or heteroarene; R18 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; B1 is H or R19; R19 is R20, R21, R22 or R23; R20 is phenyl, which is not fused or fused with benzene or heteroarene; R21 is heteroaryl, which is not fused or fused with benzene or heteroarene; R22 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; R23 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected from R24, OR24, N (R24) 2, C (0) N (R24) 2, NHC (0) R24 , NR24C (0) R24; R 24 is alkyl, alkenyl or alkynyl; C is O, S, S (O), S02, NH, or N (C2); C2 is R28, R29 or R30; R28 is phenyl, which is not fused or fused with benzene or heteroarene; R29 is heteroaryl, which is not fused or fused with benzene or heteroarene; R 30 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unbound or fused with benzene or heteroarene; D1 is N, CH or C (D2); D2 is R36, R37 or R38; R36 is phenyl, which is not fused or fused with benzene or heteroarene; R37 is heteroaryl, which is not fused or fused with benzene or heteroarene; R38 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; wherein each preceding cyclic portion is independently unsubstituted or substituted or else unsubstituted or in addition substituted with one or two or three or four independently selected from R44, OR44, SR44, S (0) R44, S02R44, NH2, NHR44, N (R4) 2, C (0) R44, C (0) OR44, C ( 0) NH2, C (0) NHR44, C (0) N (R44) 2, NHC (0) R44, OH, (O), C (0) H, C (0) OH, N02, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I; R44 is R45, R46, R47 or R48; R45 is phenyl, which is not fused or fused with benzene or heteroarene; R46 is heteroaryl, which is not fused or fused with benzene or heteroarene; R47 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; R48 is alkyl substituted with OP (0) (OH) 2; wherein the portions represented by R45, R46 and R47 are independently unsubstituted or substituted with one or two or three or four independently selected from alkyl, alkenyl, alkynyl, OH, (O), C (0) OH, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I.

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein: A1 is C (0) NHR or R5; R1 is R2, R3 or R4; R2 is phenyl, which is not fused or fused with benzene or heteroarene; R3 is heteroaryl, which is not fused or fused with benzene or heteroarene; R 4 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; R5 is alkyl, alkenyl or alkynyl, each of which is substituted with one or two independently selected from R6, NHC (0) NHR6; R6 is R7, R8 or R9; R7 is phenyl, which is not fused or fused with benzene or heteroarene; R8 is heteroaryl, which is not fused or fused with benzene or heteroarene; R9 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; wherein the portions represented by R1, R2, R3, R4, R5 and R6 are independently substituted with one or two independently selected from R10, OR10, SR10, S (0) R10, S02R1 °, NH2, NHC (0) R10, NHC (0) NHR10; R10 is R11, R12, R13 or R14; R 1 is phenyl, which is not fused or fused with benzene or heteroarene; R12 is heteroaryl, which is not fused or fused with benzene or heteroarene; R 13 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; R14 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected from R15 or NHC (0) NHR15; R 5 is R 16, R 17 R 18; R16 is phenyl, which is not fused or fused with benzene or heteroarene; R17 is heteroaryl, which is not fused or fused with benzene or heteroarene; R18 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; B1 is H or R19; R19 is R20, R21, R22 or R23; R20 is phenyl, which is not fused or fused with benzene or heteroarene; R21 is heteroaryl, which is not fused or fused with benzene or heteroarene; R22 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; R23 is alkyl, alkenyl or alkynyl, each of which is unsubstituted or substituted with one or two independently selected from R24, OR24 or N (R24) 2; R 24 is alkyl, alkenyl or alkynyl; C1 is O, S, S (O), S02, NH, or N (C2); C2 is R28, R29 or R30; R28 is phenyl, which is not fused or fused with benzene or heteroarene; R29 is heteroaryl, which is not fused or fused with benzene or heteroarene; R 30 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is unbound or fused with benzene or heteroarene; D1 is N, CH or C (D2); D2 is R36, R37 or R38; R36 is phenyl, which is not fused or fused with benzene or heteroarene; R37 is heteroaryl, which is not fused or fused with benzene or heteroarene; R38 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; wherein each preceding cyclic portion is independently unsubstituted or substituted or further unsubstituted or further substituted with one or two or three or four independently selected from R44, OR44, CN, CF3, OCF3, CF2CF3, F, Cl, Br or I; R44 is R45, R46, R47 or R48; R45 is phenyl, which is not fused or fused with benzene or heteroarene; R46 is heteroaryl, which is not fused or fused with benzene or heteroarene; R47 is cycloalkyl, cycloalkenyl, heterocycloalkyl or heterocycloalkenyl, each of which is not fused or fused with benzene or heteroarene; R48 is alkyl subsituated with OP (0) (OH) 2; wherein the portions represented by R45, R46, and R47 are independently unsubstituted or substituted with one or two or three or four independently selected from alkyl.

4. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein: A1 is C (0) NHR1 or R5; R1 is R2, R3 or R4; R2 is phenyl; R3 is heteroaryl; R 4 is cycloalkyl or heterocycloalkyl; R5 is alkyl, alkenyl or alkynyl, each of which is substituted with R6, NHC (0) NHR6; R6 is R7 or R9; R7 is phenyl; R8 is heteroaryl; R9 is heterocycloalkyl; where the portions represented by R1, R2, R3, R4, R5 and R6 are independently substituted with one or two independently selected from R10, OR 0, SR 0, S02R10, NH2, NHC (0) R10, NHC (0) NHR10; R 0 is R 1, R 2, R 3 or R 4; R 1 is phenyl; R 12 is heteroaryl; R 3 is cycloalkyl; R14 is alkyl, which is unsubstituted or substituted with R16 or NHC (0) NHR16; R16 is phenyl; B1 is H or R19; R19 is R21, R22 or R23; R21 is heteroaryl; R22 is heterocycloalkyl; R23 is alkynyl, which is unsubstituted or substituted with R24, OR24 or N (R2) 2; R24 is alkyl; C1 is S or N (C2); C2 is R30; R30 is cycloalkyl; D1 is N, CH or C (D2); D2 is R37; R37 is heteroaryl; wherein each preceding cyclic portion is independently unsubstituted or substituted or else unsubstituted or in addition substituted with one or two or three or four independently selected from R44, OR44, CN, CF3, F, Cl, Br or I; R44 is R47 or R48; R47 is heterocycloalkyl; R48 is alkyl substituted with OP (0) (OH) 2; wherein R47 is unsubstituted or substituted with alkyl.

5. A composition comprising an excipient and a therapeutically effective amount of a compound of claim 1.

6. A method for treating cancer in a mammal comprising administering thereto a therapeutically effective amount of a compound of claim 1.

7. - The method according to claim 6, wherein the cancer is breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer or thyroid cancer.

8. - A method for treating cancer in a mammal comprising administering thereto a therapeutically effective amount of a compound of claim 1 and a therapeutically effective amount of an additional therapeutic agent or more than one additional therapeutic agent, with or without radiation.

9. - The method according to claim 8, wherein the cancer is breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, leukemia, lymphoma, cancer lung, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, skin cancer, stomach cancer or thyroid cancer.