RU2467007C2

[1,8]naphthyridine derivatives, useful as inhibitors of hcv virus replication

Abstract

FIELD: chemistry. ^ SUBSTANCE: invention relates to novel derivatives of [1,8]naphthyridine, described by formula I(a), where Z represents -NR41-; A represents phenyl; each R10, R17, R31, R33, R35 and R41 in each case is independently selected from group, consisting of hydrogen, C1-C6alkyl, C1-C6haligenalkyl, phenyl, C3-C6cycloalkyl, -Ls-O-Rs, -Ls-C(O)Rs, -Ls-C(O)ORs and LE-Q-LE-(morpholine); X is selected from group, consisting of bond, -Ls-O-, -Ls-S- and -Ls-C(O)N(Rs)-; R22 is selected from group, consisting of halogen, C1-C6alkyl, phenyl, and phenyl C1-C2alkyl, and, optionally, is substituted with one R26, where R26 in each case is independently selected from group, consisting of halogen, hydroxy, nitro, C1-C6alkyl, -Ls-OSO2Rs; Y is selected from group, consisting of bond, -Ls-O-, -Ls-S(O)-, -Ls-C(O)N(R15) - and -Ls-S-, where R15 represents hydrogen; R50 represents -L1-A1, where A1 is selected from group, consisting of C1-C6alkyl and phenyl and L1 is selected from group, consisting of bond and C1-4alkylene, where A1 is optionally substituted with from one to three R30, and R30 in each case is independently selected from group, consisting of halogen, hydroxy, amino, azido, C1-C6alkyl, -Ls-O-Rs, -Ls-C(O)ORs, -LS-N(RSRS), -Ls-C(=NRs)RS', -Ls-C(O)N(RsRsO, -Ls-N(Rs)C(O)Rs', -LE-Q-LE'- (phenyl or naphthyl) and -LE-Q-LE'-(M5-M6heterocyclyl, which represents pyridine, pyrazine, pyrrolodine, furan, thiophene, piperidine); Ls in each case is independently selected from group, consisting of bond and C1-4alkylene; each RS and Rs' in each case is independently selected from group, consisting of hydrogen, C1-C6alkyl, C3-6alkenyl, C1-6alkoxy, C1-6alkoxyC1-C6alkyl and C1-6alkoxycarbonylC1-C6alkyl; each LE and LE' in each case is independently selected from group, consisting of bond, C1-4alkylene, -C1-4alkylene-NC(O)-C1-4alkylene-; Q in each case is independently selected from group, consisting of bond, -O-, -N(Rs)C(O)-, -C(O)N(Rs)- and -O-SO2-; each R17 and R30 in each case is optionally independently substituted with from one to three substituent(s), selected from group, consisting of halogen and hydroxy; and each heterocyclyl group in -LE-Q-LE'-(M5-M6heterocyclyl) in each case is optionally independently substituted with at least one or two substituents, selected from group, consisting of hydrogen, hydroxy, C1-C6alkyl, C1-6alkoxy, C1-6alkoxycarbonyl, phenyloxy and phenylC1-6alkoxycarbonyl, or to their pharmaceutically acceptable salts. Invention also relates to compounds of formula II(a), pharmaceutical composition based on claimed compounds, application of claimed compounds, method of inhibition of HCV virus replication, method of treating HCV infection. ^ EFFECT: obtained are novel derivatives, useful in treatment of HCV infection.

Term

Projected expiry 20 December 2026.

Parties

Owner: ABBVIE INC
Assignee: ABBOTT LABORATORIES
Applicants: ABBOTT LAB
Inventors: ROCKWAY TODD W, United States of America
BETEBENNER DAVID A, United States of America
KRUEGER ALLAN C, United States of America
IWASAKI NOBUHIKO, United States of America
and 16 more inventorsShow fewer
COOPER CURT S, United States of America
ANDERSON DAVID D, United States of America
KEMPF DALE J, United States of America
MADIGAN DAROLD L, United States of America
MOTTER CHRISTOPHER E, United States of America
SHANLEY JASON P, United States of America
TUFANO MICHAEL D, United States of America
WAGNER ROLF, United States of America
ZHANG ZHUNG, United States of America
MOLLA AKHTERUZZAMAN, United States of America
MO HONGMEI, United States of America
PILOT-MATIAS Tami, United States of America
Masse Sheri Vl., United States of America
CARRICK ROBERT J, United States of America
HE WEPING, United States of America
LU LIANGJUN, United States of America

Examination

Filing to grant: 5.9 years

Reach

Cited by: 1 later patent⁠
Cites: 5 earlier patents⁠
Family: 73 members in 18 offices⁠US10EP9WO9TW7RU6CN5AT4CA4+10

Classification

CPC: C07D471/04A61P1/16A61P31/14A61P31/16A61P43/00
IPC: C07D471 04A61K31 4375A61P31 14

15 claims: 2 independent, 13 dependent

1
A compound or a pharmaceutically acceptable salt of a compound wherein the compound has the formula I (a),wherein Z is -NR41-;A is phenyl;each R10, R17th, R31, R33, R35 and R41 in each case is independently selected from the group consisting of hydrogen, C1-FROM6thalkyl, C1-FROM6thhaloalkyl, phenyl, C3-FROM6thcycloalkyl, -LS-ORS, -LS-C (O) RS, -LS-C (O) ORS and -LE-qlE '- (morpholine) X is selected from the group consisting of a bond, -LS-O-, -LS-S- and -LS-C (O) N (RS) -;R22 is selected from the group consisting of halogen, C1-FROM6thalkyl, phenyl and phenyl C1-FROM2alkyl, and optionally substituted with one R26, where R26 in each case is independently selected from the group consisting of halogen, hydroxy, nitro, C1-FROM6thalkyl, -LS-OSO2RS;Y is selected from the group consisting of a bond, -LS-O-, -LS-S (O) -, -LS-C (O) N (R15) - and -LS-S-, where R15 is hydrogen;R50 is -L1-A1, where A1 is selected from the group consisting of C1-FROM6thalkyl and phenyl, and L1 is selected from the group consisting of a bond and C1-4alkylene, where A1 is optionally substituted from one to three Rthirty, and Rthirty in each case is independently selected from the group consisting of halogen, hydroxy, amino, azido, C1-6alkyl, -LS-ORS, -LS-C (O) ORS, -LS-N (RSRS '), -LS-C (= NRS) RS ', -LS-C (O) N (RSRS '), -LS-N (RS) C (O) RS ', -LE-OLE '- (phenyl or naphthyl) and-LE-qlE '- (M5-M6thheterocyclyl, which is pyridine, pyrazine, pyrrolidine, furan, thiophene, piperidine);LS in each case is independently selected from the group consisting of a bond and C1-4alkylene, each RS and RS ' in each case is independently selected from the group consisting of hydrogen, C1-6alkyl, C3-6alkenyl, C1-6alkoxy, C1-6alkoxy1-6alkyl and C1-6alkoxycarbonylC1-6alkyl, each LE and LE ' in each case is independently selected from the group consisting of a bond, C1-4alkylene, -C1-4alkylene-NC (O) -C1-4alkylene-;Q in each occurrence is independently selected from the group consisting of a bond, -O-, -N (RS) C (O) -, -C (O) N (RS) - and -O-SO2-;each R17th and Rthirty in each case is optionally substituted independently with one to three substituents (s) selected from the group consisting of halogen and hydroxy;and each heterocyclyl group in -LE-qlE '- (M5-M6thheterocyclyl) is in each case optionally substituted independently with at least one or two substituents selected from the group consisting of hydrogen, hydroxy, C1-6alkyl, C1-6alkoxy, C1-6alkylcarbonyl, phenyloxy and phenyl C1-6alkoxycarbonyl. 1. Соединение или фармацевтически приемлемая соль соединения, где соединение имеет формулу I(а),где Z представляет собой -NR41-;А представляет собой фенил;каждый R10, R17, R31, R33, R35 и R41 в каждом случае независимо выбран из группы, состоящей из водорода, C1-С6алкила, C1-С6галогеналкила, фенила, С3-С6циклоалкила, -LS-O-RS, -LS-C(O)RS, -LS-C(O)ORS и -LE-Q-LE'-(морфолин);X выбран из группы, состоящей из связи, -LS-O-, -LS-S- и -LS-C(O)N(RS)-;R22 выбран из группы, состоящей из галогена, C1-С6алкила, фенила и фенилС1-С2алкила, и, необязательно, замещен одним R26, где R26 в каждом случае независимо выбран из группы, состоящей из галогена, гидрокси, нитро, C1-С6алкила, -LS-OSO2RS;Y выбран из группы, состоящей из связи, -LS-O-, -LS-S(O)-, -LS-C(O)N(R15) - и -LS-S-, где R15 представляет собой водород;R50 представляет собой -L1-A1, где А1 выбран из группы, состоящей из C1-С6алкила и фенила, и L1 выбран из группы, состоящей из связи и C1-4алкилена, где А1 необязательно замещен от одного до трех R30, и R30 в каждом случае независимо выбран из группы, состоящей из галогена, гидрокси, амино, азидо, C1-6алкила, -LS-O-RS, -LS-C(O)ORS, -LS-N(RSRS'), -LS-C(=NRS)RS', -LS-C(O)N(RSRS'), -LS-N(RS)C(O)RS', -LE-O-LE'-(фенил или нафтил) и -LE-Q-LE'-(М5-М6гетероциклил, представляющий собой пиридин, пиразин, пирролидин, фуран, тиофен, пиперидин);LS в каждом случае независимо выбран из группы, состоящей из связи и С1-4алкилена;каждый RS и RS' в каждом случае независимо выбран из группы, состоящей из водорода, C1-6алкила, С3-6алкенила, С1-6алкокси, C1-6алкоксиС1-6алкила и С1-6алкоксикарбонилС1-6алкила;каждый LE и LE' в каждом случае независимо выбран из группы, состоящей из связи, С1-4алкилена, -С1-4алкилен-NC(O)-С1-4алкилена-;Q в каждом случае независимо выбран из группы, состоящей из связи, -O-,-N(RS)C(O)-, -C(O)N(RS)- и -O-SO2-;каждый R17 и R30 в каждом случае необязательно независимо замещен от одного до трех заместителем(ями), выбранным из группы, состоящей из галогена и гидрокси;икаждая гетероциклильная группа в -LE-Q-LE'-(М5-М6гетероциклил) в каждом случае необязательно независимо замещена по меньшей мере одним или двумя заместителями, выбранными из группы, состоящей из водорода, гидрокси, C1-6алкила, С1-6алкокси, С1-6алкилкарбонила, фенилокси и фенилС1-6алкоксикарбонила. 1. Соединение или фармацевтически приемлемая соль соединения, где соединение имеет формулу I(а),где Z представляет собой -NR41-;А представляет собой фенил;каждый R10, R17, R31, R33, R35 и R41 в каждом случае независимо выбран из группы, состоящей из водорода, C1-С6алкила, C1-С6галогеналкила, фенила, С3-С6циклоалкила, -LS-O-RS, -LS-C(O)RS, -LS-C(O)ORS и -LE-Q-LE'-(морфолин);X выбран из группы, состоящей из связи, -LS-O-, -LS-S- и -LS-C(O)N(RS)-;R22 выбран из группы, состоящей из галогена, C1-С6алкила, фенила и фенилС1-С2алкила, и, необязательно, замещен одним R26, где R26 в каждом случае независимо выбран из группы, состоящей из галогена, гидрокси, нитро, C1-С6алкила, -LS-OSO2RS;Y выбран из группы, состоящей из связи, -LS-O-, -LS-S(O)-, -LS-C(O)N(R15) - и -LS-S-, где R15 представляет собой водород;R50 представляет собой -L1-A1, где А1 выбран из группы, состоящей из C1-С6алкила и фенила, и L1 выбран из группы, состоящей из связи и C1-4алкилена, где А1 необязательно замещен от одного до трех R30, и R30 в каждом случае независимо выбран из группы, состоящей из галогена, гидрокси, амино, азидо, C1-6алкила, -LS-O-RS, -LS-C(O)ORS, -LS-N(RSRS'), -LS-C(=NRS)RS', -LS-C(O)N(RSRS'), -LS-N(RS)C(O)RS', -LE-O-LE'-(фенил или нафтил) и -LE-Q-LE'-(М5-М6гетероциклил, представляющий собой пиридин, пиразин, пирролидин, фуран, тиофен, пиперидин);LS в каждом случае независимо выбран из группы, состоящей из связи и С1-4алкилена;каждый RS и RS' в каждом случае независимо выбран из группы, состоящей из водорода, C1-6алкила, С3-6алкенила, С1-6алкокси, C1-6алкоксиС1-6алкила и С1-6алкоксикарбонилС1-6алкила;каждый LE и LE' в каждом случае независимо выбран из группы, состоящей из связи, С1-4алкилена, -С1-4алкилен-NC(O)-С1-4алкилена-;Q в каждом случае независимо выбран из группы, состоящей из связи, -O-,-N(RS)C(O)-, -C(O)N(RS)- и -O-SO2-;каждый R17 и R30 в каждом случае необязательно независимо замещен от одного до трех заместителем(ями), выбранным из группы, состоящей из галогена и гидрокси;икаждая гетероциклильная группа в -LE-Q-LE'-(М5-М6гетероциклил) в каждом случае необязательно независимо замещена по меньшей мере одним или двумя заместителями, выбранными из группы, состоящей из водорода, гидрокси, C1-6алкила, С1-6алкокси, С1-6алкилкарбонила, фенилокси и фенилС1-6алкоксикарбонила.
8
A compound or a pharmaceutically acceptable salt of a compound wherein the compound has the formula II (a)where R2 and R3 are independently selected from the group consisting of hydrogen, C1-FROM6thalkyl, C1-FROM6thalkoxycarbonyl and C1-FROM6thalkoxy1-FROM6thalkylaminocarbonyl;R4 is selected from the group consisting of hydrogen, C1-FROM6thalkoxycarbonyl and C1-FROM6thalkoxycarbonylC1-FROM6thalkyl;R7th is selected from the group consisting of hydrogen, C1-FROM6thalkyl, halogen C1-FROM6thalkyl, C1-FROM6thalkoxy, C3-FROM6thcycloalkyl, C1-FROM6thalkoxycarbonylC1-FROM6thalkyl, C1-FROM6thalkoxycarbonylC1-FROM6thalkylamino, cyano1-FROM6thalkoxycarbonylC1-FROM6thalkyl, cyano1-FROM6thalkyl, hydroxyC1-FROM6thalkyl, morpholino, hydrazino, C1-FROM6thalkylamino1-FROM6thalkoxy, C1-FROM6thalkoxy1-FROM6thalkylamino and phenyl;R9 is selected from the group consisting of hydrogen, C1-FROM6thalkyl, C1-FROM6thalkoxy, halogeno1-FROM6thalkyl, phenylC1-FROM6thalkylamino, hydroxy, C1-FROM6thalkoxycarbonylamino1-FROM6thalkyl, C1-FROM6thalkylcarbonyl, amino, halogen, C1-FROM6thalkoxyphenylC1-FROM6thalkoxy, halophenylC1-FROM6thalkoxy, nitrophenylC1-FROM6thalkoxy, cyanophenylC1-FROM6thalkoxy, phenyloxy1-FROM6thalkyl, halogenophenyloxy1-FROM6thalkyl, cyano1-FROM6thalkoxy, phenylC1-FROM6thalkoxy, C1-FROM6thalkylphenylC1-FROM6thalkoxy, C1-FROM6thalkylallyloxy, C1-FROM6thalkoxycarbonyl, halophenylaminocarbonyl, C1-FROM6thalkoxycarbonylphenylC1-FROM6thalkoxy, hydroxyC1-FROM6thalkyl, cyano1-FROM6thalkyl and phenyl;Releven is selected from the group consisting of hydrogen, hydroxy, halogen, haloaryloxy and C1-FROM6thalkyl;R12 is selected from the group consisting of hydrogen, phenylsulfanyl, phenylsulfinyl, phenyloxy, phenylaminocarbonyl, phenyl and phenyl C1-FROM6thalkoxy;where R12 is optionally substituted with one or more substituents independently selected from R16;R16 is selected from the group consisting of halogen, C1-FROM6thalkyl, C1-FROM6thalkoxy, hydroxy, C1-FROM6thalkylaminocarbonyl, amino, C1-FROM6thalkylcarbonylamino, C1-FROM6thalkyl furanylcarbonylamino, (thiophene or pyrazine) carbonylamino, hydroxypyridinylcarbonylamino, hydroxyC1-FROM6thalkylpyridinylcarbonylamino, furanylcarbonylaminoC1-FROM6thalkylcarbonylamino, thiophene1-FROM6thalkylcarbonylamino, phenyloxyphenylC1-FROM6thalkylcarbonylamino, allylaminocarbonyl, C1-FROM6thalkoxycarbonyl, hydroxyC1-FROM6thalkyl, phenylaminocarbonyl, hydroxyphenylaminocarbonyl, azidoC1-C6thalkyl, C1-FROM6thalkylaminonaphthalenesulfonyloxy, C1-FROM6thalkylsulfonyloxy, phenylC1-FROM6thalkylsulfonyloxy, C1-FROM6thalkoxycarbonylC1-FROM6thalkoxy, hydroxycarbonylC1-FROM6thalkoxy, C3-FROM6thcycloalkylcarbonylamino, phenylC1-FROM6thalkoxycarbonylpyrrolidinylcarbonylamino, phenyloxy, iminoC1-FROM6thalkyl, C1-FROM6thalkylthione, phenylC1-FROM6thalkylcarbonylamino, C1-FROM6thalkylphenoxy C1-FROM6thalkylcarbonylamino, phenylC1-FROM6thalkoxy1-FROM6thalkylcarbonylamino, furanylcarbonylaminoC1-FROM6thalkylcarbonylamino, thiophene1-FROM6thalkylcarbonylamino, C1-FROM6thalkylcarbonylpiperidinocarbonylamino, aminocarbonyl, C1-FROM6thalkylaminocarbonyl, hydroxyC1-FROM6thalkyl, amino C1-FROM6thalkyl, C1-FROM6thalkoxy1-FROM6thalkylaminocarbonyl, hydroxyimino1-FROM6thalkyl, C1-FROM6thalkylamino, C1-FROM6thalkylthiocarbonylamino and furanylcarbonylamino C1-FROM6thalkylcarbonylamino;and R13 is selected from the group consisting of hydrogen, aminophenylsulfanyl, phenylC1-FROM6thalkoxy, halophenylC1-FROM6thalkoxy, C1-FROM6thalkylcarbonylaminophenyloxy, C1-FROM6thalkylaminophenyloxy and hydroxyphenyloxy. 8. Соединение или фармацевтически приемлемая соль соединения, где соединение имеет формулу II(а)где R2 и R3 независимо выбраны из группы, состоящей из водорода, C1-С6алкила, C1-С6алкоксикарбонила и С1-С6алкоксиС1-С6алкиламинокарбонила;R4 выбран из группы, состоящей из водорода, C1-С6алкоксикарбонила и С1-С6алкоксикарбонилС1-С6алкила;R7 выбран из группы, состоящей из водорода, C1-С6алкила, галогенС1-С6алкила, C1-С6алкокси, С3-С6циклоалкила, C1-С6алкоксикарбонилС1-С6алкила, С1-С6алкоксикарбонилС1-С6алкиламино, цианоС1-С6алкоксикарбонилС1-С6алкила, цианоС1-С6алкила, гидроксиС1-С6алкила, морфолино, гидразино, С1-С6алкиламиноС1-С6алкокси, С1-С6алкоксиС1-С6алкиламино и фенила;R9 выбран из группы, состоящей из водорода, С1-С6алкила, C1-С6алкокси, галогенС1-С6алкила, фенилС1-С6алкиламино, гидрокси, C1-С6алкоксикарбониламиноС1-С6алкила, C1-С6алкилкарбонила, амино, галогена, C1-С6алкоксифенилС1-С6алкокси, галогенфенилС1-С6алкокси, нитрофенилС1-С6алкокси, цианофенилС1-С6алкокси, фенилоксиС1-С6алкила, галогенфенилоксиС1-С6алкила, цианоС1-С6алкокси, фенилС1-С6алкокси, С1-С6алкилфенилС1-С6алкокси, C1-С6алкилаллилокси, C1-С6алкоксикарбонила, галогенфениламинокарбонила, C1-С6алкоксикарбонилфенилС1-С6алкокси, гидроксиС1-С6алкила, цианоС1-С6алкила и фенила;R11 выбран из группы, состоящей из водорода, гидрокси, галогена, галогенарилокси и C1-С6алкила;R12 выбран из группы, состоящей из водорода, фенилсульфанила, фенилсульфинила, фенилокси, фениламинокарбонила, фенила и фенилС1-С6алкокси;где R12 необязательно замещен одним или несколькими заместителями, независимо выбранными из R16;R16 выбран из группы, состоящей из галогена, C1-С6алкила, C1-С6алкокси, гидрокси, C1-С6алкиламинокарбонила, амино, C1-С6алкилкарбониламино, C1-С6алкилфуранилкарбониламино, (тиофен или пиразин)карбониламино, гидроксипиридинилкарбониламино, гидроксиС1-С6алкилпиридинилкарбониламино, фуранилкарбониламиноС1-С6алкилкарбониламино, тиофенС1-С6алкилкарбониламино, фенилоксифенилС1-С6алкилкарбониламино, аллиламинокарбонила, C1-С6алкоксикарбонила, гидроксиС1-С6алкила, фениламинокарбонила, гидроксифениламинокарбонила, азидоC1-C6алкила, C1-С6алкиламинонафталинсульфонилокси, C1-С6алкилсульфонилокси, фенилС1-С6алкилсульфонилокси, С1-С6алкоксикарбонилС1-С6алкокси, гидроксикарбонилС1-С6алкокси, С3-С6циклоалкилкарбониламино, фенилС1-С6алкоксикарбонилпирролидинилкарбониламино, фенилокси, иминоС1-С6алкила, C1-С6алкилтиона, фенилС1-С6алкилкарбониламино, C1-С6алкилфеноксиС1-С6алкилкарбониламино, фенилС1-С6алкоксиС1-С6алкилкарбониламино, фуранилкарбониламиноС1-С6алкилкарбониламино, тиофенС1-С6алкилкарбониламино, C1-С6алкилкарбонилпиперидинокарбониламино, аминокарбонила, C1-С6алкиламинокарбонила, гидроксиС1-С6алкила, аминоС1-С6алкила, C1-С6алкоксиС1-С6алкиламинокарбонила, гидроксииминоС1-С6алкила, C1-С6алкиламино, C1-С6алкилтиокарбониламино и фуранилкарбониламино С1-С6алкилкарбониламино;иR13 выбран из группы, состоящей из водорода, аминофенилсульфанила, фенилС1-С6алкокси, галогенфенилС1-С6алкокси, C1-С6алкилкарбониламинофенилокси, C1-С6алкиламинофенилокси и гидроксифенилокси. 8. Соединение или фармацевтически приемлемая соль соединения, где соединение имеет формулу II(а)где R2 и R3 независимо выбраны из группы, состоящей из водорода, C1-С6алкила, C1-С6алкоксикарбонила и С1-С6алкоксиС1-С6алкиламинокарбонила;R4 выбран из группы, состоящей из водорода, C1-С6алкоксикарбонила и С1-С6алкоксикарбонилС1-С6алкила;R7 выбран из группы, состоящей из водорода, C1-С6алкила, галогенС1-С6алкила, C1-С6алкокси, С3-С6циклоалкила, C1-С6алкоксикарбонилС1-С6алкила, С1-С6алкоксикарбонилС1-С6алкиламино, цианоС1-С6алкоксикарбонилС1-С6алкила, цианоС1-С6алкила, гидроксиС1-С6алкила, морфолино, гидразино, С1-С6алкиламиноС1-С6алкокси, С1-С6алкоксиС1-С6алкиламино и фенила;R9 выбран из группы, состоящей из водорода, С1-С6алкила, C1-С6алкокси, галогенС1-С6алкила, фенилС1-С6алкиламино, гидрокси, C1-С6алкоксикарбониламиноС1-С6алкила, C1-С6алкилкарбонила, амино, галогена, C1-С6алкоксифенилС1-С6алкокси, галогенфенилС1-С6алкокси, нитрофенилС1-С6алкокси, цианофенилС1-С6алкокси, фенилоксиС1-С6алкила, галогенфенилоксиС1-С6алкила, цианоС1-С6алкокси, фенилС1-С6алкокси, С1-С6алкилфенилС1-С6алкокси, C1-С6алкилаллилокси, C1-С6алкоксикарбонила, галогенфениламинокарбонила, C1-С6алкоксикарбонилфенилС1-С6алкокси, гидроксиС1-С6алкила, цианоС1-С6алкила и фенила;R11 выбран из группы, состоящей из водорода, гидрокси, галогена, галогенарилокси и C1-С6алкила;R12 выбран из группы, состоящей из водорода, фенилсульфанила, фенилсульфинила, фенилокси, фениламинокарбонила, фенила и фенилС1-С6алкокси;где R12 необязательно замещен одним или несколькими заместителями, независимо выбранными из R16;R16 выбран из группы, состоящей из галогена, C1-С6алкила, C1-С6алкокси, гидрокси, C1-С6алкиламинокарбонила, амино, C1-С6алкилкарбониламино, C1-С6алкилфуранилкарбониламино, (тиофен или пиразин)карбониламино, гидроксипиридинилкарбониламино, гидроксиС1-С6алкилпиридинилкарбониламино, фуранилкарбониламиноС1-С6алкилкарбониламино, тиофенС1-С6алкилкарбониламино, фенилоксифенилС1-С6алкилкарбониламино, аллиламинокарбонила, C1-С6алкоксикарбонила, гидроксиС1-С6алкила, фениламинокарбонила, гидроксифениламинокарбонила, азидоC1-C6алкила, C1-С6алкиламинонафталинсульфонилокси, C1-С6алкилсульфонилокси, фенилС1-С6алкилсульфонилокси, С1-С6алкоксикарбонилС1-С6алкокси, гидроксикарбонилС1-С6алкокси, С3-С6циклоалкилкарбониламино, фенилС1-С6алкоксикарбонилпирролидинилкарбониламино, фенилокси, иминоС1-С6алкила, C1-С6алкилтиона, фенилС1-С6алкилкарбониламино, C1-С6алкилфеноксиС1-С6алкилкарбониламино, фенилС1-С6алкоксиС1-С6алкилкарбониламино, фуранилкарбониламиноС1-С6алкилкарбониламино, тиофенС1-С6алкилкарбониламино, C1-С6алкилкарбонилпиперидинокарбониламино, аминокарбонила, C1-С6алкиламинокарбонила, гидроксиС1-С6алкила, аминоС1-С6алкила, C1-С6алкоксиС1-С6алкиламинокарбонила, гидроксииминоС1-С6алкила, C1-С6алкиламино, C1-С6алкилтиокарбониламино и фуранилкарбониламино С1-С6алкилкарбониламино;иR13 выбран из группы, состоящей из водорода, аминофенилсульфанила, фенилС1-С6алкокси, галогенфенилС1-С6алкокси, C1-С6алкилкарбониламинофенилокси, C1-С6алкиламинофенилокси и гидроксифенилокси.

Independent claims2

2,352 paragraphs in 1 section, as filed

This application claims the priority of US Provisional Application No. 60 / 752,473 filed December 21, 2005, which is hereby incorporated by reference in its entirety.

TECHNICAL FIELD OF THE INVENTION

The invention relates to compounds effective for inhibiting the replication of the hepatitis C virus ("HCV"). Also, the present invention relates to methods for the preparation of these compounds, compositions containing these compounds, intermediates for the synthesis of these compounds, as well as methods of using these compounds / compositions for the treatment of HCV infection or mediated conditions / symptoms. In addition, the present invention relates to the use of these compounds for the preparation of medicaments for the treatment of HCV infection.

Prior Art

HCV, a human pathogen, is an RNA virus belonging to the genus Hepacivirus of the Flaviviridae family. A distinctive feature of HCV, like all other viruses of the Flaviviridae family, is enveloped virions that consist of positive-polarity genome RNA encoding all known virus-specific proteins by a single, uninterrupted, open reading frame. The open reading frame contains approximately 9,500 nucleotides encoding a single large polypeptide consisting of approximately 3,000 amino acids. The polypeptide contains capsid protein, envelope proteins E1 and E2, membrane-bound p7 protein, and non-structural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B. The cell protease cleaves the viral protein at the site of the NS2-NS3 compound, which allows the viral protease (NS3 protease) to mediate subsequent cleavage. The NS3 protein also has nucleoside triphosphatase and RNA helicase activity. NS2 and NS4A can also be associated with proteolytic activity. NS5A is a phosphoprotein involved in replication. NS5B is an RNA-dependent RNA polymerase. U.S. Patent No. 2004/2065792, published December 30, 2004, states that inhibition of the above non-structural proteins can inhibit the replication of HCV.

HCV infection is associated with a progressive liver pathology, including cirrhosis and hepatocellular carcinoma. The final stage of the disease in HCV infection of the liver is the most common indication for liver transplantation in adults. In chronic hepatitis C therapy may be an injection of peginterferon-alpha once a week in conjunction with daily intake of ribavirin. Peginterferon-alpha is an interferon-alpha, attached to polyethylene glycol, which provides a reduction in the rate of excretion of the drug from the body. This increases the likelihood of compliance with the regimen of the drug and the clinical antiviral activity compared with daily injections of interferon-alpha. But there are significant limitations on efficacy and tolerability, since a large number of patients have side effects,

Attempts have been made to develop drugs that specifically inhibit the function of the hepatitis C virus. US Pat. No. 6,321,380, Boehringer Ingelheim, specifies tripeptide compounds as inhibitors of HCV serine proteases for the treatment of HCV infection.

Another approach is proposed in ISIS-14803 (Isis Pharmaceuticals), namely an antisense inhibitor complementary to the conserved sequence of hepatitis C virus RNA. This molecule binds to the virus RNA and inhibits the expression of proteins required for replication.

Inhibition of HCV translation by yeast RNA, which binds to cellular polypeptides and prevents their interaction with the internal ribosome of the virus (IRES), is described in Das et al., J. VIROLOGY, 72 (7): 5638-5647 (1998).

For a variety of medical and biological applications, condensed bicyclic heterocyclic compounds have been proposed. Examples of such heterocyclic compounds include naphthyridine, pyridopyrimidine, pyrimidopyrimidine, pyrazolopyrimidine and thiazolo / thienopyrimidine compounds.

Condensed bicyclic compounds of the naphthyridine type have been investigated for use in the treatment of diseases. For example, in Boots WO 93/13097, published on July 8, 1993, it has been proposed to use as a rheumatic antagonist [1,8] naphthyridine compounds such as ethyl 4- (4-methoxyaniline) -6-ethoxy-7-methyl- 1,8-naphthyridine-3-carboxylate. In Boots WO 95/00511, published Jan. 5, 1995, it has been proposed to use, as antirheumatic agents, substituted 4-aminopyridines with fused rings such as 3-ethoxy-5- (2-ethoxy-5-pyridylamino) -2-methyl-1 , 8-naphthyridine. In document Zeneca WO 98/13350, published on April 2, 1998, it has been proposed as antiangiogenic agents compounds [1,8] naphthyridine, such as 2-acetamido-5- (2-fluoro-5-hydroxy-4-methylaniline) -1,8-naphthyridine hydrochloride. In the document Neurogen WO 2004/055004, published on July 1, 2004, naphthyridine compounds are indicated as modulators of the capsaycin receptor, for example specific compounds of 5- (4-trifluoromethylphenylamino) -2- (3-trifluoromethylpyridin-2-yl) -1,6] naphthyridine-7-carboxylic acid and 2-methoxymethyl-4- (4-trifluoromethylphenylamino) -7- (3-trifluoromethylpyridin-2-yl) - [1,8] naphthyridine-3-carboxylic acid.

For the use in the treatment of various diseases, condensed bicyclic pyridopyrimidine compounds have been studied. For example, in the document Pfizer WO 98/05661, published February 12, 1998, compounds of substituted pyridopyrimidine such as [8- (1-ethylpropyl) -2-pyrrolidinone) are proposed as corticoliberin (hormone) CRF (CRH) antagonists for the treatment of Alzheimer's disease and obesity, methyl-5,6,7,8-tetrahydropyrido (2,3-d) pyrimidin-4-yl] - (2,4,6-trimethylphenyl) amine. Pfizer WO 98/23613, published June 4, 1998, proposes fused bicyclic pyrimidine compounds, including pyridopyrimidinylaminophenyl compounds such as (3-ethynylphenyl) pyrido [3,4-d] pyrimidin-4, to treat hyperproliferative diseases such as cancer, -ylamine. In US Pat. No. 6,169,091, Glaxo Wellcome, published January 2, 2001, Bicyclic heteroaromatic compounds such as 4- (4-benzyloxyaniline) pyrido [2,3-d] pyrimidine are proposed as tyrosine kinase inhibitors for the treatment of fibrosis, inflammation, diseases of the nervous system and cancer. In Eli Lilly, WO 01/32632, published May 10, 2001, compounds of 4-substituted pyrimidine, including hydrochloride 2, are proposed as antagonists of mGluR1 for the treatment of neurological disorders mediated by glutamate dysfunction such as convulsions, migraine, psychosis, anxiety disorder and pain trifluoromethyl-4- [2- (2- (2-chlorophenyl) ethylamino] pyrido [2,3-d] pyrimidine In Abbott Laboratories, WO 01/57040, published August 9, 2001, as adenosine kinase inhibitors for the treatment of pain and inflammation, 6,7-disubstituted-4-aminopyrido [2,3-d] pi rimidine, such as 4-amino-6- (4-methylphenyl) -7- (4-bromophenyl) pyrido [2,3-d] pyrimidine. In the document Neurogen, WO 2004/055004, published on July 1, 2004, pyridopyrimidinylaminophenyl compounds such as 2-methyl-2- {4- [2-methyl-7- (3-methylpyridin-2-yl) pyrido [2,3-d] pyrimidin-4-ylamino] phenyl} propionic acid. In US Pat. No. 6,395,733, Pfizer, published May 28, 2002, compounds of heterocyclic pyrimidine with condensed rings, such as 3-chlorophenylpyrido [2,3-d] pyrimidin-4-ylamine, are proposed to treat a hyperproliferative disease such as cancer. such as 2-methyl-2- {4- [2-methyl-7- (3-methylpyridin-2-yl) pyrido [2,3-d] pyrimidin-4-ylamino] phenyl} propionic acid. In US Pat. No. 6,395,733, Pfizer, published May 28, 2002, compounds of heterocyclic pyrimidine with condensed rings, such as 3-chlorophenylpyrido [2,3-d] pyrimidin-4-ylamine, are proposed to treat a hyperproliferative disease such as cancer. such as 2-methyl-2- {4- [2-methyl-7- (3-methylpyridin-2-yl) pyrido [2,3-d] pyrimidin-4-ylamino] phenyl} propionic acid. In US Pat. No. 6,395,733, Pfizer, published May 28, 2002, compounds of heterocyclic pyrimidine with condensed rings, such as 3-chlorophenylpyrido [2,3-d] pyrimidin-4-ylamine, are proposed to treat a hyperproliferative disease such as cancer.

Condensed bicyclic pyrimidopyrimidine compounds have been investigated for use in the disinfestation and treatment of diseases. For example, in US Pat. No. 5,350,749, Dow Elanco, published September 27, 1994, 4-substituted-pyrimido [2,3-d] pyrimidine compounds have been proposed as fungicides, insecticides and maticides. In Warner-Lambert WO 95/19774, published July 27, 1995, pyrimidopyrimidine compounds, such as 4-benzylamino-7-methylaminopyrimido [4,5-d] pyrimidine, have been proposed as tyrosine kinase inhibitors for the treatment of cancer, vascular and psoriasis restenosis.

Condensed bicyclic thienopyrimidine compounds have been investigated for use in the treatment of various diseases. For example, in the Warner-Lambert document WO 95/19774, published July 27, 1995, fused heterocyclic pyrimidine compounds including 4- (3-bromoaniline) thieno [2,3-d ] pyrimidine. US Pat. No. 6,169,091, to Glaxo Wellcome, published January 2, 2001, discloses bicyclic heteroaromatic compounds such as 5-methyl-4- (4-phenoxyaniline) thieno [hydrochloride] hydrochloride as tyrosine kinase inhibitors for the treatment of fibrosis, inflammation, diseases of the nervous system and cancer. 2,3-d] pyrimidine. In Eli Lilly WO 01/32632, published May 10, 2001, as mGluR1 antagonists for the treatment of neurological disorders,

In Bristol-Myers Squibb WO 2004/014852, published Feb. 19, 2004, iminothiazolidinones, including condensed bicyclic derivatives of 2- (4-aminophenyl) -5H-thiazolo [2,3-6], were proposed as inhibitors of the NS5A protein to prevent HCV replication. quinazolin-3-one.

In Bristol-Myers Squibb WO 2004/014313, published Feb. 19, 2004, various forms of combination therapy, including anti-HCV iminothiazolidinone compounds inhibiting the NS5A protein, in combination with other agents capable of influencing the function of HCV have been proposed for the treatment of viral diseases.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formulas I (a), I (b), II (a) or II (b), tautomers of these compounds and pharmaceutically acceptable salts of these compounds or tautomers. These compounds, tautomers or salts can be used, alone or in combination with other drugs or agents, to inhibit the replication of HCV or other viruses. These compounds, tautomers or salts can also be used, alone or in combination with other drugs or agents, to disrupt the function of HCV or other viruses.

The present invention also relates to compositions that contain compounds, tautomers or salts of the present invention. The composition of the present invention may include one or more compounds, tautomers or salts of the present invention. The composition of the present invention may also include one or more other antiviral or therapeutic agents.

In addition, the present invention relates to methods of using the compounds, tautomers or salts of the present invention, or compositions containing said compounds, tautomers or salts, for inhibiting the replication of HCV or other viruses. These methods involve contacting HCV, or another virus, or cells infected with HCV or other said virus with an effective amount of the compound, tautomer or salt of the present invention, thereby inhibiting the replication of HCV or the other virus.

The present invention further relates to methods of using the compounds, tautomers or salts of the present invention, or compositions containing said compounds, tautomers or salts, to inhibit the proliferation or transmission of HCV or other viruses. These methods involve contacting an HCV or other virus or contacting cells infected with HCV or another virus with an effective amount of a compound, tautomer or salt of the present invention, thereby inhibiting the proliferation or transfer of HCV or the other virus.

In addition, the present invention relates to methods of using the compounds, tautomers or salts of the present invention, or compositions containing said compounds, tautomers or salts, for the treatment of viral infections caused by HCV or other viruses. These methods include administering to the patient an effective amount of the compound, tautomer or salts of the present invention, thereby reducing the level of HCV or other viruses in the blood or tissues of the patient.

The present invention also relates to the use of the compounds, tautomers or salts of the present invention for the preparation of medicaments for the treatment of viral infections caused by HCV or other viruses.

In addition, the present invention relates to processes for the preparation of compounds, tautomers or salts of the present invention and intermediates used in said methods.

Other features, objects and advantages of the present invention will be apparent from the following detailed description of the invention. Nevertheless, it should be noted that the detailed description of the invention in which the preferred embodiments of the invention are presented is given only for illustrative purposes and is not limited thereto. Various variations and modifications that fall within the scope of the invention will be apparent to those skilled in the art from the detailed description.

DETAILED DESCRIPTION OF THE INVENTION

The following description is essentially illustrative and is not intended to limit the proposed description, application, or practice.

Connections

The present invention relates to compounds of formula I (a) or I (b), their tautomers and pharmaceutically acceptable salts of compounds or tautomers

wherein Z is -NR41-;

A is carbocyclyl or heterocyclyl and is optionally substituted by one or more R18, where R18 in each case is independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl, -LS-ORS, -LS-SRS, -LS-C (O) RS, -LS-OC (O) RS, -LS-C (O) ORS, -LS-N (RSRS '), -LS-C (= NRS) RS ', -LS-S (O) RS, -LS-SO2RS, -LS-C (O) N (RSRS '), -LS-N (RS) C (O) RS ', -LS-C (= NRS) N (RS 'RS "), -LS-N (RS ') C (= NRS) RS ", -LS-N (RS) C (O) N (RS 'RS "), -LS-N (RS) SO2RS ', -LS-SO2N (RSRS ') and -LS-N (RS) SO2N (RS 'RS ");

each R10, R17th, R31, R33, R35 and R41 in each case is independently selected from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -LS-ORS, -LS-SRS, -LS-C (O) RS, -LS-OC (O) RS, -LS-C (O) ORS, -LS-N (RSRS '), -LS-C (= NRS) RS ', -LS-S (O) RS, -LS-SO2RS, -LS-C (O) N (RSRS '), -LS-N (RS) C (O) RS ', -LS-C (= NRS) N (RS 'RS "), -LS-N (RS ') C (= NRS) RS ", -LS-N (RS) C (O) N (RS 'RS "), -LS-N (RS) SO2RS ', -LS-SO2N (RSRS '), -LS-N (RS) SO2N (RS 'RS "), -LE-qlE '- (C3-C18carbocyclyl) and -LE-qlE '- (M3-M18heterocyclyl);

X is selected from the group consisting of a bond, -LS-O-, -LS-S-, -LS-C (O) -, -LS-N (RS) -, -LS-N (RS) C (O) -, -LS-C (O) N (RS) -, -LS-N (RS) C (O) O-, -LS-OC (O) N (RS) -, -LS-N (RS) C (O) N (RS ') -, -LS-C (= NRS) N (RS ') -, -LS-N (RS ') C (= NRS) -, -LS-S (O) -, -LS-SO2-, -LS-C (O) O- and -LS-OC (O) -;

R22 is carbocyclyl, heterocyclyl, carbocyclylalkyl or heterocyclylalkyl, and is optionally substituted by one or more R26, where R26 in each case is independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl, -LS-ORS, -LS-SRS, -LS-C (O) RS, -LS-OC (O) RS, -LS-C (O) ORS, -LS-N (RSRS '), -LS-C (= NRS) RS ', -LS-S (O) RS, -LS-SO2RS, -LS-OS (O) RS, -LS-OSO2RS, -LS-C (O) N (RSRS '), -LS-N (RS) C (O) RS ', -LS-C (= NRS) N (RS 'RS "), -LS-N (RS ') C (= NRS) RS ", -LS-N (RS) C (O) N (RS 'RS "), -LS-N = C (NRSRS ') (NRSRS '), -LS-N (RS) SO2RS ', -LS-SO2N (RSRS '), -LS-N (RS) SO2N (RS 'RS "), -LE-qlE '- (C3-C18carbocyclyl) and -LE-qlE '- (M3-M18heterocyclyl); or R22 is alkyl, alkenyl or alkynyl and is optionally substituted by one or more R26; or R22 is hydrogen;

Y is selected from the group consisting of a link, -LS-O-, -LS-C (O) -, -LS-S (O)2-, -LS-S (O) -, -LS-OS (O)2-, -LS-OS (O) -, -LS-C (O) O-, -LS-OC (O) -, -LS-OC (O) O-, -LS-C (O) N (R15) -, -LS-N (R15) C (O) -, -LS-C (O) N (R15) O-, -LS-N (R15) C (O) O-, -LS-C (O) N (R15) N (R15') -, -LS-S-, -LS-C (S) -, -LS-C (S) O-, -LS-OC (S) -, -LS-C (S) N (R15) -, -LS-N (R15) -, -LS-N (R15) C (S) -, -LS-N (R15) S (O) -, -LS-N (R15) S (O)2-, -LS-S (O)2N (R15) -, -LS-S (O) N (R15) -, -LS-C (S) N (R15) O- and -LS-C (S) N (R15) N (R15') -, where each R15 and R15' in each case is independently selected from the group consisting of hydrogen, alkyl, alkenyl and alkynyl;

R50 is -L1-A1, where A1 is selected from the group consisting of carbocyclyl, heterocyclyl, alkyl, alkenyl and alkynyl, and L1 is selected from the group consisting of a bond, alkylene, alkenylene and alkynylene, wherein A1 optionally substituted with one or more Rthirty, and Rthirty in each case is independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl, -LS-ORS, -LS-SRS, -LS-C (O) RS, -LS-OC (O) RS, -LS-C (O) ORS, -LS-N (RSRS '), -LS-C (= NRS) RS ', -LS-S (O) RS, -LS-SO2RS, -LS-C (O) N (RSRS '), -LS-N (RS) C (O) RS ', -LS-C (= NRS) N (RS 'RS "), -LS-N (RS ') C (= NRS) RS ", -LS-N (RS) C (O) N (RS 'RS "), -LS-N (RS) SO2RS ', -LS-SO2N (RSRS '), -LS-N (RS) SO2N (RS 'RS "), -LE-qlE '- (C3-C18carbocyclyl) and -LE-qlE '- (M3-M18heterocyclyl), and where L1 optionally substituted with one or more R38, and R38 in each case is independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkoxy, thioalkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkylamino, alkoxycarbonylamino, -LS-ORS, -LS-SRS, -LS-C (O) RS, -LS-OC (O) RS, -LS-C (O) ORS, -LS-N (RSRS '), -LS-C (= NRS) RS ', -LS-S (O) RS, -LS-SO2RS, -LS-C (O) N (RSRS '), -LS-N (RS) C (O) RS ', -LS-C (= NRS) N (RS 'RS "), -LS-N (RS ') C (= NRS) RS ", -LS-N (RS) C (O) N (RS 'RS "), -LS-N (RS) SO2RS ', -LS-SO2N (RSRS '), -LS-N (RS) SO2N (RS 'RS "), carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl, -LE-qlE '- (C3-C18carbocyclyl) and -LE-qlE '- (M3-M18heterocyclyl);

LS in each case is independently selected from the group consisting of a bond, alkylene, alkenylene and alkynylene;

each RS, RS ' and RS " in each case is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, alkoxyalkyl, alkoxyalkoxyalkyl, thioalkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylamino, alkylaminoalkyl, alkoxycarbonylamino and alkoxycarbonylaminoalkyl;

each LE and LE ' in each case is independently selected from the group consisting of a bond, alkylene, alkenylene, alkynylene, -alkylene-O-alkylene-, -alkylene-S-alkylene-, -alkylene-NC (O) -alkylene and-alkylene-C (O ) N-alkylene-;

Q in each occurrence is independently selected from the group consisting of a bond, alkylene, alkenylene, alkynylene, -S-, -O-, -C (O) -, -N (RS) -, -N (RS) C (O) -, -C (O) N (RS) -, -N (RS) C (O) O-, -OC (O) N (RS) -, -N (RS) C (O) N (RS ') -, -C (= NRS) N (RS ') -, -N (RS ') C (= NRS) -, -S (O) -, -SO2-, -O-SO2-, -SO2-O-, -OS (O) -, -S (O) -O-, -C (O) O- and -OC (O) -;

each R10, R15, R15', R17th, R18, R26, Rthirty, R31, R33, R35, R38 and R41 in each case is optionally substituted independently with at least one substituent selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, alkoxy, alkylamino, alkoxycarbonyl and azido; and

In one embodiment, the present invention provides compounds having Formula I (a) or I (b), their tautomers and pharmaceutically acceptable salts of compounds or tautomers, wherein:

Z is -NR41-;

A is carbocyclyl or heterocyclyl and is optionally substituted by one or more R18, where R18 in each case is independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C1-C6thalkyl, C2-C6thalkenyl, C2-C6thalkynyl, -LS-ORS, -LS-SRS, -LS-C (O) RS, -LS-OC (O) RS, -LS-C (O) ORS, -LS-N (RSRS '), -LS-C (= NRS) RS ', -LS-S (O) RS, -LS-SO2RS, -LS-C (O) N (RSRS '), -LS-N (RS) C (O) RS ', -LS-C (= NRS) N (RS 'RS "), -LS-N (RS ') C (= NRS) RS ", -LS-N (RS) C (O) N (RS 'RS "), -LS-N (RS) SO2RS ', -LS-SO2N (RSRS ') and -LS-N (RS) SO2N (RS 'RS ");

each R10, R17th, R31, R33, R35 and R41 in each case is independently selected from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C1-C6thalkyl, C2-C6thalkenyl, C2-C6thalkynyl, C3-C6thcarbocyclyl, M3-M6thheterocyclyl, -LS-ORS, -LS-SRS, -LS-C (O) RS, -LS-OC (O) RS, -LS-C (O) ORS, -LS-N (RSRS '), -LS-C (= NRS) RS ', -LS-S (O) RS, -LS-SO2RS, -LS-C (O) N (RSRS '), -LS-N (RS) C (O) RS ', -LS-C (= NRS) N (RS 'RS "), -LS-N (RS ') C (= NRS) RS ", -LS-N (RS) C (O) N (RS 'RS "), -LS-N (RS) SO2RS ', -LS-SO2N (RSRS '), -LS-N (RS) SO2N (RS 'RS "), -LE-qlE '- (C3-C18carbocyclyl) and -LE-qlE '- (M3-M18heterocyclyl);

R22 is carbocyclyl, heterocyclyl, carbocyclyl C1-C6thalkyl or heterocyclylC1-C6thalkyl and optionally substituted by one or more R26, where R26 in each case is independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C1-C6thalkyl, C2-C6thalkenyl, C2-C6thalkynyl, -LS-ORS, -LS-SRS, -LS-C (O) RS, -LS-OC (O) RS, -LS-C (O) ORS, -LS-N (RSRS '), -LS-C (= NRS) RS ', -LS-S (O) RS, -LS-SO2RS, -LS-OS (O) RS, -LS-OSO2RS, -LS-C (O) N (RSRS '), -LS-N (RS) C (O) RS ', -LS-C (= NRS) N (RS 'RS "), -LS-N (RS ') C (= NRS) RS ", -LS-N (RS) C (O) N (RS 'RS "), -LS-N = C (NRSRS ') (NRSRS '), -LS-N (RS) SO2RS ', -LS-SO2N (RSRS '), -LS-N (RS) SO2N (RS 'RS "), -LE-qlE '- (C3-C18carbocyclyl) and -LE-qlE '- (M3-M18heterocyclyl); or R22 is C1-C6thalkyl, C2-C6thalkenyl or C2-C6thalkynyl and optionally substituted by one or more R26; or R22 is hydrogen;

R50 is -L1-A1, where A1 is selected from the group consisting of carbocyclyl, heterocyclyl, C1-C6thalkyl, C2-C6thalkenyl, C2-C6thalkynyl, and L1 is selected from the group consisting of a bond, C1-C6thalkylene, C2-C6thalkenylene and C2-C6thalkynylene, where A1 optionally substituted with one or more Rthirty, and Rthirty in each case is independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C1-C6thalkyl, C2-C6thalkenyl, C2-C6thalkynyl, -LS-ORS, -LS-SRS, -LS-C (O) RS, -LS-OC (O) RS, -LS-C (O) ORS, -LS-N (RSRS '), -LS-C (= NRS) RS ', -LS-S (O) RS, -LS-SO2RS, -LS-C (O) N (RSRS '), -LS-N (RS) C (O) RS ', -LS-C (= NRS) N (RS 'RS "), -LS-N (RS ') C (= NRS) RS ", -LS-N (RS) C (O) N (RS 'RS "), -LS-N (RS) SO2RS ', -LS-SO2N (RSRS '), -LS-N (RS) SO2N (RS 'RS "), -LE-qlE '- (C3-C18carbocyclyl) and -LE-qlE '- (M3-M18heterocyclyl), and where L1 optionally substituted with one or more R38, and R38 in each case is independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C1-C6thalkoxy, C1-C6ththioalkoxy, C1-C6thalkylcarbonyl, C1-C6thalkoxycarbonyl, C1-C6thalkylcarbonyloxy, C1-C6thalkylamino, C1-C6thalkoxycarbonylamino, -LS-ORS, -LS-SRS, -LS-C (O) RS, -LS-OC (O) RS, -LS-C (O) ORS, -LS-N (RSRS '), -LS-C (= NRS) RS ', -LS-S (O) RS, -LS-SO2RS, -LS-C (O) N (RSRS '), -LS-N (RS) C (O) RS ', -LS-C (= NRS) N (RS 'RS "), -LS-N (RS ') C (= NRS) RS ", -LS-N (RS) C (O) N (RS 'RS "), -LS-N (RS) SO2RS ', -LS-SO2N (RSRS '), -LS-N (RS) SO2N (RS 'RS "), carbocyclyl, heterocyclyl, carbocyclylC1-C6thalkyl, heterocyclylC1-C6thalkyl, -LE-qlE '- (C3-C18carbocyclyl) and -LE-qlE '- (M3-M18heterocyclyl);

LS in each case is independently selected from the group consisting of a bond, C1-C6thalkylene, C2-C6thalkenylene and C2-C6thalkynylene;

each RS, RS ' and RS " in each case is independently selected from the group consisting of hydrogen, C1-C6thalkyl, C2-C6thalkenyl, C2-C6thalkynyl, C1-C6thalkoxy, C1-C6ththioalkoxy, C1-C6thalkoxyC1-C6thalkyl, C1-C6thalkoxyC1-C6thalkoxyC1-C6thalkyl, C1-C6ththioalkoxyC1-C6thalkyl, C1-C6thalkylcarbonyl, C1-C6thalkylcarbonylC1-C6thalkyl, C1-C6thalkoxycarbonyl, C1-C6thalkoxycarbonylC1-C6thalkyl, C1-C6thalkylcarbonyloxy, C1-C6thalkylcarbonyloxyC1-C6thalkyl, C1-C6thalkylamino, C1-C6thalkylaminoC1-C6thalkyl, C1-C6thalkoxycarbonylamino and C1-C6thalkoxycarbonylaminoC1-C6thalkyl;

each LE and LE ' in each case is independently selected from the group consisting of a bond, C1-C6thalkylene, C2-C6thalkenylene and C2-C6thalkynylene, -C1-C6thalkylene-OC1-C6thalkylene-, -C1-C6thalkylene-SC1-C6thalkylene-, -C1-C6thalkylene-NC (O) -C1-C6thalkylene- and -C1-C6thalkylene-C (O) NC1-C6thalkylene-;

Q in each case is independently selected from the group consisting of a bond, C1-C6thalkylene, C2-C6thalkenylene and C2-C6thalkynylene, -S-, -O-, -C (O) -, -N (RS) -, -N (RS) C (O) -, -C (O) N (RS) -, -N (RS) C (O) O-, -OC (O) N (RS) -, -N (RS) C (O) N (RS ') -, -C (= NRS) N (RS ') -, -N (RS ') C (= NRS) -, -S (O) -, -SO2-, -O-SO2-, -SO2-O-, -OS (O) -, -S (O) -O-, -C (O) O- and -OC (O) -;

each R10, R15, R15', R17th, R18, R26, Rthirty, R31, R33, R35, R38 and R41 in each case is optionally substituted independently with at least one substituent selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate C1-C6thalkoxy, C1-C6thalkylamino, C1-C6thalkoxycarbonyl and azido; and

each C3-C18carbocyclyl and M3-M18heterocyclyl group in -LE-qlE '- (C3-C18carbocyclyl) and -LE-qlE '- (M3-M18heterocyclyl) is in each case optionally substituted independently with at least one substituent selected from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C1-C6thalkylene, C2-C6thalkenylene, C2-C6thalkynylene, C1-C6thalkoxy, C1-C6ththioalkoxy, C1-C6thalkoxyC1-C6thalkyl, C1-C6ththioalkoxyC1-C6thalkyl, C1-C6thalkylcarbonyl, C1-C6thalkylcarbonylC1-C6thalkyl, C1-C6thalkoxycarbonyl, C1-C6thalkoxycarbonylC1-C6thalkyl, C1-C6thalkylcarbonyloxy, C1-C6thalkylcarbonyloxyC1-C6thalkyl, C1-C6thalkylamino, C1-C6thalkylaminoC1-C6thalkyl, C1-C6thalkoxycarbonylamino, C3-C7thcarbocyclyloxy, M3-M7thheterocyclyloxy, C3-C7thcarbocycloC1-C6thalkoxy, M3-M7thheterocycloC1-C6thalkoxy, C3-C7thcarbocycloC1-C6thalkoxycarbonyl, M3-M7thheterocycloC1-C6thalkoxycarbonyl, and C1-C6thalkoxycarbonylaminoC1-C6thalkyl.

In one example of this embodiment, A is C5-C6thcarbocyclyl, optionally substituted with one or more R18.

In another example of this embodiment, A is M5-M6thheterocyclyl, optionally substituted with one or more R18.

In another example of this embodiment, Y is -LS-O-, -LS-S-, -LS-C (O) N (R15) - or -LS-N (R15) C (O) -, R15 is hydrogen, C1-C6thalkyl, C2-C6thalkenyl or C2-C6thalkynyl and L1 is C1-C6thalkylene optionally substituted by one or more R38, where A1 is C4-C6thcarbocyclyl or M4-M6thheterocyclyl and optionally substituted with one or more Rthirty.

In yet another example of this embodiment of the invention, Y is -LS-O-, -LS-S-, -LS-C (O) N (R15) - or -LS-N (R15) C (O) -, R15 is hydrogen, C1-C6thalkyl, C2-C6thalkenyl or C2-C6thalkynyl and L1 is a link (i.e. R50 is -A1), where A1 is C4-C6thcarbocyclyl or M4-M6thheterocyclyl and optionally substituted with one or more Rthirty.

In the following example of this embodiment, Y is -LS-O-, -LS-S-, -LS-C (O) N (R15) - or -LS-N (R15) C (O) -, R15 is hydrogen, C1-C6thalkyl, C2-C6thalkenyl or C2-C6thalkynyl and L1 is a link (i.e. R50 is -A1) or C1-C6thalkylene optionally substituted by one or more R38, where A1 is a bicyclic ring (for example, a fused bicyclic ring or bridged bicyclic ring) that contains from 6 to 14 ring atoms and is optionally substituted by one or more Rthirty.

In another example of this embodiment, X is -O- or -S-, and R22 is C5-C6thcarbocyclyl or M5-M6thheterocyclyl and optionally substituted with one or more R26.

In still another example of this embodiment, X is -S- or -O-, and R22 represents <img file="00000002.tif" he="13" wi="22" img-format="tif" img-content="undefined" /> or <img file="00000003.tif" he="13" wi="27" img-format="tif" img-content="undefined" />, where R48 is hydroxy, amino, C1-C6thalkylamino, C1-C6thalkoxy, C1-C6thalkoxycarbonylamino or C1-C6thalkylcarbonyloxy, and R22 (e.g., R48 or a phenyl ring in R22) is optionally substituted by one or more R26.

In another example of this embodiment, A is C5-C6thcarbocyclyl or M5-M6thheterocyclyl and optionally substituted with one or more R18, where

X is -O- or -S-;

R22 represents <img file="00000004.tif" he="13" wi="22" img-format="tif" img-content="undefined" /> or <img file="00000005.tif" he="13" wi="26" img-format="tif" img-content="undefined" />, where R48 is hydroxy, amino, C1-C6thalkylamino, C1-C6thalkoxy, C1-C6thalkoxycarbonylamino or C1-C6thalkylcarbonyloxy, and R22 (e.g., R48 or a phenyl ring in R22) is optionally substituted by one or more R26;

Y is -LS-O-, -LS-S-, -LS-C (O) N (R15) - or -LS-N (R15) C (O) -, where R15 is hydrogen, C1-C6thalkyl, C2-C6thalkenyl or C2-C6thalkynyl;

R50 is -L1-A1, where

L1 is C1-C6thalkylene optionally substituted by one or more R38, and A1 is C4-C6thcarbocyclyl or M4-M6thheterocyclyl and optionally substituted with one or more Rthirty; or

L1 is a link (i.e. R50 is -A1), where A1 is C4-C6thcarbocyclyl or M4-M6thheterocyclyl and optionally substituted with one or more Rthirty; or

L1 is a link (i.e. R50 is -A1) or C1-C6thalkylene optionally substituted by one or more R38, where A1 is a bicyclic ring (for example, a fused bicyclic ring or bridged bicyclic ring) that contains from 6 to 14 ring atoms and is optionally substituted by one or more Rthirty.

Ring atom (s) in the group <img file="00000006.tif" he="21" wi="28" img-format="tif" img-content="undefined" /> or <img file="00000007.tif" he="21" wi="25" img-format="tif" img-content="undefined" /> may be further substituted by S or other heteroatoms.

In another embodiment of the invention, the present invention relates to compounds having the fomuli II (a) or II (b), their tautomers and pharmaceutically acceptable salts of compounds or tautomers,

where R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl and alkoxyalkylaminocarbonyl;

R4 is selected from the group consisting of hydrogen, alkoxycarbonyl and alkoxycarbonylalkyl;

R7th is selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxy, cycloalkyl, alkoxycarbonylalkyl, alkoxycarbonylalkylamino, cyanoalkoxycarbonylalkyl, cyanoalkyl, hydroxyalkyl, morpholino, hydrazino, alkylaminoalkoxy, alkoxyalkylamino and aryl;

R9 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, arylalkylamino, hydroxy, alkoxycarbonylaminoalkyl, alkylcarbonyl, amino, halogen, N- [alkylarylamino (arylsulfanyl) arylalkyl] -N- [(alkoxycarbonyl) alkyl] amino, alkoxyarylalkoxy, haloarylalkoxy, nitroarylalkoxy, cyanoarylalkoxy, aryloxyalkyl, haloaryloxyalkyl, cyanoalkoxy, arylalkoxy, alkylarylalkoxy, haloalkylarylaminocarbonyl, alkylaminoarylaminocarbonyl, arylalkoxy, alkylallyloxy and alkoxycarbonyl;

Releven is selected from the group consisting of hydrogen, hydroxy, haloaryloxy and alkyl;

R12 is selected from the group consisting of hydrogen, arylsulfanyl, arylsulfinyl, aryloxy, mercapto, arylaminocarbonyl, aryl, alkoxyaryl, arylalkoxy and alkylcarbonylaminoaryl; where R12 is optionally substituted with one or more substituents independently selected from R16;

R16 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alkilgeteroarilkarbonilamino, geteroarilkarbonilamino, gidroksigeteroarilkarbonilamino, gidroksialkilgeteroarilkarbonilamino, geteroarilkarbonilaminoalkilkarbonilamino, geteroarilalkilkarbonilamino, ariloksiarilalkilkarbonilamino, allilaminokarbonila, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, gidroksiarilaminokarbonila, alkoxyalkyl, alkoxyarylaminocarbonyl, azidoalk yl, alkylaminoarylsulfonyloxy, alkylsulfonyloxy, arylalkylsulfonyloxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, cycloalkylcarbonylamino, arylalkoxycarbonylheterocyclonylamino, aryloxy, iminoalkyl, alkylthione, arylalkylcarbonylamino, alkylaryloxyalkylcarbonylamino, arylalkoxyalkylcarbonylamino, arylalkoxyalkylcarbonylamino,

R13 is selected from the group consisting of hydrogen, halogen, alkyl, alkylcarbonylaminoarylsulfonyl, aminoarylsulfanyl, arylalkoxy, haloarylalkoxy, alkylcarbonylaminoaryloxy, alkylaminoaryloxy, hydroxyaryloxy, alkylaminocarbonyl arylalkoxy and alkylcarbonylaminoarylalkoxy.

In the subfamily of compounds of this embodiment of the invention, in formulas II (a) or II (b), R12 is selected from the group consisting of

n is an integer selected from the group consisting of zero and one;

R14 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alkilgeteroarilkarbonilamino, geteroarilkarbonilamino, gidroksigeteroarilkarbonilamino, gidroksialkilgeteroarilkarbonilamino, geteroarilkarbonilaminoalkilkarbonilamino, geteroarilalkilkarbonilamino, ariloksiarilalkilkarbonilamino, allilaminokarbonila, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, gidroksiarilaminokarbonila, alkoxyalkyl, alkoxy arylaminocarbonyl and azido keel;

In the next subfamily of compounds of this first embodiment of the invention, in formulas II (a) or II (b), R2 and R3 are independently selected from the group consisting of hydrogen, ethoxycarbonyl, 3-N-methoxy-N-methylaminocarbonyl and methyl;

R4 is selected from the group consisting of hydrogen, t-butoxycarbonyl and ethoxycarbonylmethyl;

R7th is selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, trifluoromethyl, methoxy, ethoxy, cyclopentyl, hydroxyethyl, butyl, 1,1-bis- (ethoxycarbonyl) methyl, ethoxycarbonylmethylamino, 1 , 1-bis (tert-butoxycarbonyl), cyano-1-ethoxycarbonylmethyl, cyano-1-t-butoxycarbonylmethyl, cyanomethyl, morpholinyl, ethoxycarbonylethyl, hydrazino, N, N-dimethylaminoethoxy, methoxyethylamino and cyano-1-ethoxy-carbonylmethyl ;

R9 is selected from the group consisting of hydrogen, methyl, methoxy, phenyl, trifluoromethyl, phenylmethylamino, hydroxy, tert-butoxycarbonylaminomethyl, carbonylamino, methylcarbonyl, amino, bromine, chlorine, fluorine, methyl [1,8] naphthyridin-4-ylamino- (2-phenylsulfanylphen-5-ylmethyl) amino- (N-t-butoxycarbonyl-N-methyl), methoxyphenylmethoxy, bromophenylmethoxy, nitrophenylmethoxy, cyanophenylmethoxy, trifluoromethyl, phenoxymethyl, bromophenoxymethyl, cyanomethoxy, phenylmethoxy, methylallyloxy, propoxy, methylphenylmethoxy, methylphenylmethoxy , fluoro-3-methylphenylamine rbonila, triftormetilfenilaminokarbonila, triftormetilfenilaminokarbonila, N, N-dimetilaminofenilaminokarbonila, and ftorfenilmetoksi hlorfenilmetoksi;

Releven is selected from the group consisting of hydrogen, hydroxy, chlorophenoxy and methyl;

R12 described above in connection with formulas II (a) and II (b);

R13 is selected from the group consisting of hydrogen, chlorine, methyl, methylcarbonylaminophenylsulfanyl, aminophenylsulfanyl, phenylmethoxy, bromophenylmethoxy, methylcarbonylaminophenoxy, N, N-dimethylaminophenoxy, hydroxyphenoxy and methylaminocarbonylphenoxy;

R14 is selected from the group consisting of hydrogen, fluorine, methyl, methoxy, hydroxy, aminocarbonyl, N-methylaminocarbonyl, N, N-dimethylaminocarbonyl, amino, tert-butylcarbonylamino, (2,6-dimethylfuranyl) carbonylamino, thienylcarbonylamino, hydroxypyridinylcarbonylamino, (2- hydroxy-6-methylpyridinyl) carbonylamino, (3-pyrazinyl) carbonylamino, furanylcarbonylaminomethylcarbonylamino, (3-thienyl) propylcarbonylamino, (3-phenoxy) phenylmethylcarbonylamino, N-allylaminocarbonyl, ethoxycarbonyl, 1-hydroxyethyl, aminocarbonyl, ethylaminocarbonyl, phenylamine arbonyl, hydroxyphenylaminocarbonyl, propylaminocarbonyl, hydroxymethyl, hydroxyethyl, azidoethyl and N, N-dimethylaminocarbonyl;

R16 is selected from the group consisting of hydrogen, hydroxy, methylcarbonylamino, methyl, isopropyl, fluorine, methoxy, ethoxy, propoxy, isopropoxy, N, N-dimethylamino-naphth-1-ylsulfonyloxy, ethylsulfonyloxy, isopropylsulfonyloxy, methylsulfonyloxy, benzylsulfonyloxy, ethoxycarbonylmethoxy, tert-butylcarbonylamino, cyclopropylcarbonylamino, benzyloxycarbonylpyrrolidinylcarbonylamino, phenoxy, methylcarbonylamino, iminoethyl, thionoethyl, (S) -1-phenylpropylcarbonylamino, methylphenoxymethylcarbonylamino, (R) -1-phenyl-1-meth (S) -1-phenyl-1-methoxymethylcarbonylamino, furanylcarbonylaminomethylcarbonylamino, thienylpropylcarbonylamino, methylcarbonylpiperidinylcarbonylamino, amino, aminocarbonyl, N-methylaminocarbonyl, ethoxycarbonylmethoxy, isopropylsulfonyloxy, methylsulfonyloxy, ethylsulfonyloxy,

Salts of the compounds of the present invention

The compounds of the present invention or their tautomers can be used in the form of salts. Depending on the particular compound, the salt of this compound may have advantages due to one or more of the physical properties of the salt, such as an increase in pharmaceutical stability at various temperatures and humidity, or the desired solubility in water or oil. In some cases, the salt of the compound can also be used as an adjuvant to dissolve, purify and / or reduce the compound.

If the salt is for administration to a patient, the salt is preferably pharmaceutically acceptable. Pharmaceutically acceptable salts include, but are not limited to, salts commonly used to form alkali metal salts and / or to form addition salts of free acids or free bases. Generally, these salts can be prepared by conventional methods with a compound of the present invention by reacting, for example, a suitable acid or base and a compound.

The pharmaceutically acceptable addition salts of the compounds of the present invention can be obtained from inorganic or organic acids. Examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic acid, nitric, carboxylic, sulfuric and phosphoric acid. Suitable organic acids typically include, for example, organic acids of aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes. Specific examples of suitable organic acid salts include acetate, trifluoroacetate, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, anthranilic acid , mesylate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate, methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sulfonate, cyclohexylaminosulfonate, algenic acid, b-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphorsulfonate cyclopentanepropionate, dodecyl sulfate, glucoheptanoate, glycerophosphate, hemisulphate, heptanoate, hexanoate, nicotinate, 2-naphthalenesulfonate, oxalate, palmate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate and undecanoate.

Pharmaceutically acceptable basic addition salts of the compounds of the present invention include, for example, metal salts and organic salts. Preferred metal salts include, but are not limited to, alkali metal salts (Group Ia), alkaline earth metal salts (Group IIa), and other physiologically tolerable metal salts. Such salts can be obtained from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Non-limiting examples of preferred organic salts can be obtained from tertiary amines and quaternary amine salts such as tromethamine, diethylamine, N, N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. The basic nitrogen-containing groups can be quaternized with agents such as lower alkyl halides (C1-C6th(for example, methyl, ethyl, propyl and butyl chlorides, bromides and iodides), dialkyl sulfates (for example, dimethyl, diethyl, dibutyl and diamyl sulfates), long chain halides (eg decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), aralkyl halides (for example, benzyl and phenethyl bromides) and others.

Solvates, prodrugs and isomers

The compounds of the present invention, their tautomers and their salts can also be in the form of solvates with water, for example hydrates, or with organic solvents such as methanol, ethanol or acetonitrile, thereby forming methanolate, ethanolate or acetonitrile, respectively. The compounds of the present invention may be in any form of a solvate or mixtures thereof.

In one aspect, the compounds, tautomers or salts of the present invention may be in the form of prodrugs. Certain aliphatic or aromatic esters are derived from the acidic groups of the compounds of the present invention. The others are the aliphatic or aromatic esters of the hydroxyl or amino group of the compounds of the present invention. Phosphate prodrugs of hydroxyl groups of the compounds of the present invention are preferred prodrugs.

The compounds of the invention may contain asymmetrically substituted carbon atoms, known as chiral centers. These chiral centers are referred to as "R" or "S" depending on the configuration of the substituents around the chiral carbon atom. As used herein, the terms "R" and "S" designate the configurations defined in "Organometric Chemistry", Section E: Stereochemistry, Recommendations 1974, PURE APPL. CHEM., 45: 11-30 (1976). The compounds of the present invention can exist, without limitation, as single stereoisomers (eg, single enantiomers or single diastereomers), as mixtures of stereoisomers (eg any mixture of enantiomers or diastereomers) or as racemic mixtures. Any single stereoisomers, mixtures and racemates are within the scope of the present invention. Under connections, which are defined herein as single stereoisomers, are understood to mean compounds that are in a form substantially free of other stereoisomers (for example, other enantiomers or diastereomers). "Essentially free" means that at least 80% of the compound in the composition is in the form of the desired stereoisomer; preferably at least 90% of the compound in the composition is in the form of the desired stereoisomer; and more preferably at least 95%, 96%, 97%, 98% or 99% of the compound in the composition is in the form of the desired stereoisomer. If the stereochemistry of the chiral carbon (s) present in the chemical structure is not defined, it is meant that the chemical structure includes compounds in any stereoisomeric form at each chiral center present in the chemical structure.

Specific stereoisomers of the compounds of the present invention can be prepared using a large number of methods known in the art. These methods include, but are not limited to, stereospecific synthesis, chromatographic separation of diastereomers, chromatographic separation of enantiomers, conversion of enantiomers in the enantiomeric mixture to diastereomers, followed by separation of the diastereomers by chromatography and reduction of individual enantiomers and enzymatic separation.

Stereospecific synthesis typically involves the use of suitable optically pure (enantiomerically pure) or essentially optically pure substances and synthesis reactions that do not cause racemization or stereochemical inversion at chiral centers. Stereoisomeric mixtures of compounds, including racemic mixtures obtained as a result of the synthesis reaction, can be separated, for example, by chromatographic methods well known to those skilled in the art. Chromatographic separation of the enantiomers can be carried out by chiral chromatography on polymers, most of which are commercially available. In a non-limiting example, the racemate is placed in a solution and placed on a column containing a chirally stationary phase. The enantiomers can then be separated by HPLC.

The separation of the enantiomers can also be carried out by converting the enantiomers in the mixture to diastereomers by reaction with chiral auxiliary reagents. The diastereomers obtained can be separated by column chromatography or by crystallization / recrystallization. This procedure can be used if the compounds to be separated contain a carboxyl, amino or hydroxyl group which will form a salt or a covalent bond with a chiral auxiliary. Non-limiting examples of suitable chiral auxiliary agents include chirally pure amino acids, organic carboxylic acids or organosulfonic acids. After separating the diastereomers by chromatography, the individual enantiomers can be reduced.

Enzymes, such as esterases, phosphatases or lipases, can be used to separate the enantiomer derivatives in an enantiomeric mixture. For example, an ester derivative of a carboxyl group of compounds to be separated can be treated with an enzyme that selectively hydrolyzes only one of the enantiomers of the mixture. The resulting enantiomerically pure acid is then separated from the non-hydrolyzed ester.

Alternatively, the enantiomeric salts in the mixture can be prepared by any method known in the art, including treating the carboxylic acid with a suitable optically pure base, such as alkaloids or phenethylamine, followed by precipitation or crystallization / recrystallization of enantiomerically pure salts. Methods suitable for separating a mixture of stereoisomers, including racemic mixtures, are provided in ENANTIOMERS, RACEMATES, AND RESOLUTIONS (Jacqueset al., 1981, John Wiley and Sons, New York, NY).

The compound of the present invention may have one or more unsaturated carbon-carbon double bonds. All double bond isomers, such as cis (Z) - and trans (E) -isomers and mixtures thereof, are meant for these compounds, unless otherwise indicated. In addition, if the compound exists in several tautomeric forms, said compound is not limited to any particular tautomer, but includes all tautomeric forms.

Certain compounds of the invention can exist in various stable conformational forms that can be separable. Torsion asymmetry due to limited rotation around an asymmetric single bond, for example, as a result of steric hindrance or ring stress, can give different conformers. The compounds of the invention include each conformational isomer of these compounds and mixtures thereof.

Some of the compounds of the invention may also exist in a zwitterionic form, and the scope of the invention includes each zwitterionic form of these compounds and mixtures thereof.

Definitions

The compounds of the present invention are mainly described herein using a standard nomenclature. In the case of these compounds with an asymmetric center (s), it should be understood that all stereoisomers of the compound and mixtures thereof are within the scope of the present invention unless specifically indicated otherwise. Non-limiting examples of stereoisomers include enantiomers, diastereomers and cis trans isomers. If the described compound exists in various tautomeric forms, it is meant that the compound includes all tautomeric forms. Specific compounds are described herein using generic formulas that contain variables (eg, R17th, A1, L1, X, Y or Z). Unless otherwise specified, each variable in such a formula is defined independently of any other variable, and any variable that occurs more than once in the formula is independently determined in each case. If the substituents are described as "independently selected from" the group, then each substituent is selected independently of the other. Each substituent, therefore, may be the same or different from the other (their) substituent (s).

The number of carbon atoms in the hydrocarbon substituent can be determined by the prefix "Cx-Cy", Where x is the minimum number and y is the maximum number of carbon atoms in the substituent. Thus, for example, "C1-C6thalkyl "refers to an alkyl substituent containing 1 to 6 carbon atoms. As another example, C3-C6thcycloalkyl refers to a saturated hydrocarbon ring containing 3 to 6 ring carbon atoms. The multicomponent substituent prefix refers only to the first component immediately following the prefix. For example, the term "alkylaryl" consists of two components: alkyl and aryl. Thus, for example, C1-C6thalkylaryl refers to C1-C6thalkyl attached to the main portion of the molecule via an aryl group. Likewise, alkyl C6th-C10aryl refers to an alkyl group attached to the main body of the molecule through C6th-C10aryl group. Similarly, the "halogen" prefix for haloalkoxyalkyl indicates that the alkoxy component is replaced by one or more halogen radicals, while the "halogen" of the alkoxyhaloalkyl prefix indicates that the alkyl component is replaced by one or more halogen radicals.

In describing the connection element of the other two elements of the depicted chemical structure, the leftmost component of the joint element is a component that is attached to the left member of the depicted structure. For example, if the chemical structure is XLY and L is labeled methylarylethyl, then the chemical compound is X-methyl-aryl-ethyl-Y.

If the join element in the depicted structure is a link, then the left element in the depicted structure is directly connected to the right element of the depicted structure. For example, if a chemical structure is depicted as XLY, and L is defined as a bond, then the chemical structure is XY. Another example, if a chemical group is depicted as -LX, and L is defined as a bond, then the chemical group is -X. Another example, if the chemical structure is depicted as XL1-L2-Y, XL1-L2-L3-Y or XL1-L2- ... -LN-Y, and L1, L2, L3, ..., LN are defined as a bond, then the chemical structure is XY.

If a chemical formula is used to describe the substituent, the dash from the right (or left) side of the formula indicates the part of the group that has the free valence (s).

If the substituent is described as "substituted," the non-hydrogen radical is instead of one or more hydrogen radicals of carbon, nitrogen, or oxygen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent in which at least one non-hydrogen radical is in place of the hydrogen (s) radical (s) on the alkyl substituent. For example, monofluoroalkyl is alkyl substituted with one fluoro radical, and difluoroalkyl is alkyl substituted with two fluoro radicals. It should be pointed out that if two or more substituents are present on the substituent, then each non-hydrogen radical may be the same or different, unless otherwise indicated.

The substituent "may be substituted" if it contains at least one carbon, nitrogen or oxygen atom that is bonded to one or more hydrogen atoms.

If the substituent is described as "optionally substituted", the substituent may be either substituted or unsubstituted. If the substituent is described as being optionally substituted up to a specific number of non-hydrogen radicals, the substituent can be either unsubstituted or substituted up to a specific number of non-hydrogen radicals, or the maximum number of substitutable positions on the substituent, in any case, not more than this number. Thus, for example, if the substituent is described as heteroaryl optionally substituted with up to three non-hydrogen radicals, then any heteroaryl with fewer than three possible positions for substitution may optionally be replaced by as many non-hydrogen radicals as heteroaryl has substitution positions. For example, tetrazolyl (which has only one possible substitution position) may be optionally substituted with one non-hydrogen radical. Another example, if nitrogen in the amino group is described as optionally substituted with up to two non-hydrogen radicals, the primary amino group nitrogen will be optionally substituted with up to two non-hydrogen radicals, while the secondary amino group nitrogen will be optionally substituted with one non-hydrogen radical.

The term "alkenyl" (alone or in combination with another term (s)) denotes a straight or branched chain hydrocarbon substituent containing one or more double bonds and 2-20 carbon atoms, more usually 2-8 carbon atoms and even more often 2-6 carbon atoms. Each carbon-carbon double bond within the alkenyl group can have either a cis- or trans-geometry with respect to groups substituted on a double carbon bond. Non-limiting examples of such substituents include ethenyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl and 3-butenyl.

The term "alkenylene" (alone or in combination with another term (s)) refers to a divalent unsaturated hydrocarbon group which may be linear or branched and which has at least one carbon-carbon double bond. The alkenylene group usually contains 2-20 carbon atoms, more usually 2-8 carbon atoms and, more often, 2-6 carbon atoms. Non-limiting examples of alkenylene groups include -C (H) = C (H) -, -C (H) = C (H) -CH2-, -C (H) = C (H) -CH2-CH2-, -CH2-C (H) = C (H) -CH2-, -C (H) = C (H) -CH (CH3) - and -CH2-C (H) = C (H) -CH (CH2CH3) -.

The term "alkoxy" (alone or in combination with another term (s)) refers to an alkyl group attached to the main portion of the molecule via a hydroxy group (i.e., -O-alkyl). Non-limiting examples of such a substituent include methoxy (-O-CH3), ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and t-butoxy.

The term "alkoxyalkyl" (alone or in combination with another term (s)) refers to an alkoxy group attached to the main body of the molecule via an alkylene group. Non-limiting examples of alkoxyalkyl include tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl and methoxymethyl.

The term "alkoxycarbonyl" (alone or in combination with another term (s)) refers to an alkoxy group attached to the main portion of the molecule via a carbonyl group (i.e., -C (O) -O-alkyl). Representative examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, ethoxycarbonyl (<img file="00000012.tif" he="17" wi="35" img-format="jpg" img-content="undefined" />) and t-butoxycarbonyl.

The term "alkoxycarbonylamino" (alone or in combination with another term (s)) refers to N (RARB) -, where RA is an alkyl-OC (O) -, and RB is alkyl-OC (O) - or hydrogen. RA and RB may be the same or different.

The term "alkoxycarbonylaminoalkyl" (alone or in combination with another term (s)) refers to N (RARB) -alkylene, where RA is an alkyl-OC (O) -, and RB is alkyl-OC (O) - or hydrogen. RA and RB may be the same or different.

The term "alkoxycarbonylalkyl" (alone or in combination with another term (s)) refers to an alkoxycarbonyl group attached to the main portion of the molecule via an alkylene group. Representative examples of alkoxycarbonylalkyl include, but are not limited to, 2-methoxy-2-oxoethyl, 2-ethoxy-2-oxoethyl, 3-methoxy-3-oxopropyl, 3-ethoxy-3-oxopropyl, 4-ethoxy-2- (ethoxycarbonyl ) -4-oxobutyl, 5-methoxy-5-oxopentyl and 6-methoxy-6-oxohexyl.

The term "alkyl" (alone or in combination with another term (s)) denotes a straight or branched chain saturated hydrocarbon substituent, usually containing 1-20 carbon atoms, more often 1-8 carbon atoms and, more often, 1-6 carbon atoms. Non-limiting examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, pentyl, isoamyl, hexyl and octyl.

The term "alkylamino" (alone or in combination with another term (s)) refers to -NRARB, where RA is alkyl and RB is hydrogen or alkyl. RA and RB may be the same or different. For example, C1-C6thalkylamino refers to -NRARB, where RA is C1-C6thalkyl, and RB is hydrogen or C1-C6thalkyl.

The term "alkylaminoalkyl" (alone or in combination with another term (s)) refers to N (RARB) -alkylene, where RA is alkyl, and RB is hydrogen or alkyl. RA and RB may be the same or different. Thus, C1-C6thalkylaminoC1-C6thalkyl refers to N (RARB) -C1-C6thalkylene-, in which RA is C1-C6thalkyl, and RB is hydrogen or C1-C6thalkyl.

The term "alkylcarbonyl" (alone or in combination with another term (s)) refers to an alkyl group attached to the main body of the molecule via a carbonyl group (i.e., -C (O) -alkyl). Representative examples of alkylcarbonyl include, but are not limited to, acetyl, ethylcarbonyl (<img file="00000013.tif" he="15" wi="25" img-format="jpg" img-content="undefined" />), 1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopentyl.

The term "alkylcarbonylalkyl" (alone or in combination with another term (s)) refers to an alkylcarbonyl group attached to the main portion of the molecule via an alkylene group. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxo-propyl, 3-oxobutyl and 3-oxopentyl.

The term "alkylcarbonyloxy" (alone or in combination with another term (s)) refers to an alkylcarbonyl group attached to the main portion of the molecule via a hydroxy group. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy and t-butylcarbonyloxy.

The term "alkylcarbonyloxyalkyl" (alone or in combination with another term (s)) refers to an alkylcarbonyloxy group attached to the main portion of the molecule via an alkylene group. Representative examples of alkylcarbonyloxyalkyl include, but are not limited to, 2- (acetyloxy) ethyl, 3- (acetyloxy) propyl and 3- (propionyloxy) propyl.

The terms "alkylene" or "alkylenyl" (alone or in combination with another term (s)) denote a divalent group derived from a straight or branched saturated hydrocarbon chain, usually containing 1-20 carbon atoms, more often 1-8 carbon atoms and, more often, 1-6 carbon atoms. Representative examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2- and -CH2CH (CH3) CH2-.

The term "alkynyl" (alone or in combination with another term (s)) denotes a straight or branched chain hydrocarbon substituent containing one or more triple bonds and usually 2-20 carbon atoms, more usually 2-8 carbon atoms and, more often, 2-6 carbon atoms. Non-limiting examples of such substituents include ethynyl, 1-propynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl and 3-butynyl.

The terms "alkynylene" (alone or in combination with another term (s)) refers to a divalent unsaturated hydrocarbon group that can be linear or branched and which has at least one carbon-carbon triple bond. Representative alkynylene groups include, for example, -C≡C-, -C≡C-CH2-, -C≡C-CH2-CH2-, -CH2-C≡C-CH2-, -C≡C-CH (CH3) - and -CH2-C≡C-CH (CH2CH3) -.

The term "amino" (alone or in combination with another term (s)) means -NH2. The term "monosubstituted amino" (alone or in combination with another term (s)) denotes an amino substituent in which one hydrogen radical is replaced by a non-hydrogen substituent. The term "disubstituted amino" (alone or in combination with another term (s)) denotes an amino substituent in which both hydrogen atoms are replaced by non-hydrogen substituents which may be the same or different.

The term "aminocarbonyl" (alone or in combination with another term (s)) means -C (O) -NH2, which can also be depicted as:

<img file="00000014.tif" he="19" wi="25" img-format="jpg" img-content="undefined" />.

The term "aminoalkyl" (alone or in combination with another term (s)) means -alkylene-NH2.

The term "aminoalkylcarbonyl" (alone or in combination with another term (s)) means -C (O) -alkylene-NH2. For example, "aminomethylcarbonyl" can be depicted as:

<img file="00000015.tif" he="19" wi="31" img-format="jpg" img-content="undefined" />.

The term "aminosulfonyl" (alone or in combination with another term (s)) means -S (O)2-NH2, which can also be depicted as:

<img file="00000016.tif" he="19" wi="24" img-format="jpg" img-content="undefined" />.

The term "aryl" (alone or in combination with another term (s)) refers to an aromatic carbocyclic group containing 6 to 14 ring carbon atoms. Non-limiting examples of aryl include phenyl, naphthalenyl, anthracenyl and indenyl. The aryl group may be linked to a basic molecular group via any substitutable carbon atom of the group.

The term "arylalkyl" (alone or in combination with another term (s)) refers to an aryl group attached to the main portion of the molecule via an alkylene group. Representative examples of substituted / unsubstituted arylalkyl include, but are not limited to, benzyl, 4- (benzyloxy) benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, 3- (1,3-benzodioxol-5-yl) -2-methylpropyl, 3- (phenoxy) benzyl, 3- (1,3-benzodioxol-5-yl) propyl, 2-phenylethyl, 3-phenylpropyl, 2-naphthylmethyl, 3,5-di-tert-butyl-2-hydroxybenzyl, 3-methoxybenzyl, 3, 4-dimethoxybenzyl, 4- (dimethylamino) benzyl, 4- [3- (dimethylamino) propoxy] benzyl, (6-methoxy-2-naphthyl) methyl and 2-naphth-2-ylethyl.

The term "arylalkylcarbonyl" (alone or in combination with another term (s)) refers to an arylalkyl group attached to the main portion of the molecule via a carbonyl group (i.e., arylalkyl-C (O) -). Representative examples of arylalkylcarbonyl include, but are not limited to, 2-naphthylacetyl and phenylacetyl.

The term "arylalkoxy" (alone or in combination with another term (s)) refers to an arylalkyl group attached to the main portion of the molecule via a hydroxy group (i.e., arylalkyl-O-). Representative examples of arylalkoxy include, but are not limited to, 2-phenylethoxy, 3-naphth-2-ylpropoxy and 5-phenylpentyloxy.

The term "arylalkoxyalkyl" (alone or in combination with another term (s)) refers to an arylalkoxy group attached to the main portion of the molecule via an alkylene group. Representative examples of arylalkoxyalkyl include, but are not limited to, benzyloxymethyl, 2- (benzyloxy) ethyl and (2-phenylethoxy) methyl.

The term "arylalkoxycarbonyl" (alone or in combination with another term (s)) refers to an arylalkoxy group attached to the main portion of the molecule via a carbonyl group. Representative examples of arylalkoxycarbonyl include, but are not limited to, benzyloxycarbonyl and naphth-2-ylmethoxycarbonyl.

The term "arylcarbonyl" (alone or in combination with another term (s)) refers to an aryl group attached to the main portion of the molecule via a carbonyl group. Representative examples of arylcarbonyl include, but are not limited to, benzoyl and naphthoyl.

The term "aryloxy" (alone or in combination with another term (s)) refers to an aryl group attached to the main portion of the molecule via a hydroxy group. Representative examples of substituted / unsubstituted aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3-bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy and 3,5-dimethoxyphenoxy.

The term "aryloxyalkyl" (alone or in combination with another term (s)) refers to an aryloxy group attached to the main portion of the molecule via an alkylene group. Representative examples of aryloxyalkyl include, but are not limited to, 2-phenoxyethyl, 3-naphth-2-yloxypropyl and phenoxymethyl.

The term "aryloxycarbonyl" (alone or in combination with another term (s)) refers to an aryloxy group attached to the main portion of the molecule via a carbonyl group.

The term "arylthio" (alone or in combination with another term (s)) refers to an aryl group attached to the main body of the molecule via a sulfur atom (i.e., aryl-S-). Representative examples of arylthio include, but are not limited to, phenylthio, naphthalene-1-ylthio and naphthalen-2-ylthio.

The term "arylthioalkyl" (alone or in combination with another term (s)) refers to aryl-S-alkylene-. Representative examples of arylthioalkyl include, but are not limited to, (phenylthio) methyl, 2- (phenylthio) ethyl and 3- (phenylthio) propyl.

The term "arylthioalkoxy" (alone or in combination with another term (s)) refers to an arylthioalkyl group attached to the main portion of the molecule via a hydroxy group.

The term "arylthioalkoxyalkyl" (alone or in combination with another term (s)) refers to an arylthioalkoxy group attached to the main portion of the molecule via an alkylene group.

The terms "carbocycle" or "carbocyclic" or "carbocyclyl" (alone or in combination with another term (s)) refer to a saturated (for example "cycloalkyl") partially saturated (e.g., "cycloalkenyl" or "cycloalkynyl") or a fully unsaturated (eg "aryl") ring system containing zero ring heteroatoms and typically 3-18 ring carbon atoms. "Ring atoms" or "ring members" are atoms bonded together to form a ring or rings of a cyclic substituent. The carbocyclic group may, without limitation, include a single ring, or two or more fused rings, or bridged rings or a spiro ring. Carbocyclyl may contain 3-14 ring members (i.e., C3-C14carbocyclyl, such as C3-C14cycloalkyl), 3-10 ring members (i.e., C3-C10carbocyclyl, such as C3-C10cycloalkyl), 3-8 ring members (i.e., C3-C8carbocyclyl, such as C3-C8cycloalkyl), 3 to 6 ring members (i.e., C3-C6thcarbocyclyl, such as C3-C6thcycloalkyl), 4-10 ring members (i.e., C4-C10carbocyclyl, such as C4-C10cycloalkyl and C4-C10cycloalkenyl), 4 to 8 ring members (i.e., C4-C8carbocyclyl, such as C4-C8cycloalkyl and C4-C8cycloalkenyl), or 5-7 ring members (i.e., C5-C7thcarbocyclyl, such as C5-C7thcycloalkyl, C5-C7thcycloalkenyl and phenyl). The substituted carbocyclyl can have either a cis- or trans-geometry. Representative examples of carbocyclyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl, adamantyl, decahydronaphthalenyl, octahydroindenyl, cyclohexenyl, phenyl, naphthyl, fluorenyl, indanyl, 1,2,3, 4-tetrahydro-naphthyl, indenyl, isoindenyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphthenyl (also known as "phenalenyl"), decalinyl and norpynil. The carbocyclyl group may be attached to the main portion of the molecule through any substitutable carbon atom of the group.

The term "carbocyclylalkyl" (alone or in combination with another term (s)) refers to a carbocyclyl group attached to the main body of the molecule via an alkylene group. For example, C3-C10carbocyclyl C1-C6thalkyl refers to C3-C10a carbocyclyl group attached to the main part of the molecule via C1-C6thalkylene. Similarly, C5-C7thcarbocyclyl C1-C6thalkyl refers to C5-C7tha carbocyclyl group attached to the main part of the molecule via C1-C6thalkylene.

The term "carbocyclylalkoxy" (alone or in combination with another term (s)) refers to a carbocyclylalkyl group attached to the main portion of the molecule via an oxy group (i.e., carbocyclylalkylene-O-). For example, C3-C10carbocyclyl C1-C6thalkoxy refers to C3-C10carbocyclyl C1-C6than alkyl group attached to the main part of the molecule through a hydroxy group. Similarly, C5-C7thcarbocyclyl C1-C6thalkoxy refers to C5-C7thcarbocyclyl C1-C6than alkyl group attached to the main part of the molecule through a hydroxy group.

The term "carbocyclylalkoxyalkyl" (alone or in combination with another term (s)) refers to a carbocyclylalkoxy group attached to the main portion of the molecule via an alkylene group (i.e., carbocyclylalkylene-O-alkylene-). For example, C3-C10carbocyclyl C1-C6thalkoxyC1-C6thalkyl refers to C3-C10carbocyclyl C1-C6thalkoxy group attached to the main part of the molecule via C1-C6thalkylene group.

The term "carbocyclylalkoxycarbonyl" (alone or in combination with another term (s)) refers to a carbocyclylalkoxy group attached to the main portion of the molecule via a carbonyl group (i.e., -C (O) -O-alkylene carbocyclyl). For example, C3-C10carbocyclyl C1-C6thalkoxycarbonyl refers to C3-C10carbocyclyl C1-C6thalkoxy group attached to the main body of the molecule via a carbonyl group. By way of non-limiting examples, "phenylethoxycarbonyl" can be depicted as:

<img file="00000017.tif" he="18" wi="46" img-format="jpg" img-content="undefined" />.

The term "carbocyclylalkylcarbonyl" (alone or in combination with another term (s)) refers to a carbocyclylalkyl group attached to the main portion of the molecule via a carbonyl group (i.e., -C (O) -alkylene carbocyclyl). For example, "phenylethylcarbonyl" can be depicted as:

<img file="00000018.tif" he="20" wi="35" img-format="jpg" img-content="undefined" />.

The term "carbocyclylcarbonyl" (alone or in combination with another term (s)) refers to a carbocyclyl group attached to the main portion of the molecule via a carbonyl group (i.e., carbocyclyl-C (O) -). For example, "phenylcarbonyl" can be depicted as:

<img file="00000019.tif" he="21" wi="55" img-format="jpg" img-content="undefined" />.

The term "carbocyclyloxy" (alone or in combination with another term (s)) refers to a carbocyclyl group attached to the main portion of the molecule via a hydroxy group (i.e., carbocyclyl-O-).

The term "carbocyclyloxyalkyl" (alone or in combination with another term (s)) refers to a carbocyclyloxy group attached to the main portion of the molecule via an alkylene group (i.e., carbocyclyl-O-alkylene-).

The term "carbocyclyloxycarbonyl" (alone or in combination with another term (s)) refers to a carbocyclyloxy group attached to the main portion of the molecule via a carbonyl group (i.e., -C (O) -O-carbocyclyl). For example, "phenyloxycarbonyl" can be depicted as:

<img file="00000020.tif" he="15" wi="30" img-format="jpg" img-content="undefined" />.

The term "carbocyclylthio" (alone or in combination with another term (s)) refers to a carbocyclyl group attached to the main body of the molecule via a sulfur atom (i.e., carbocyclyl-S-).

The term "carbocyclylthioalkoxy" (alone or in combination with another term (s)) refers to carbocyclyl-alkylene-S-.

The term "carbocyclylthioalkoxyalkyl" (alone or in combination with another term (s)) refers to carbocyclyl-alkylene-S-alkylene-.

The term "carbocyclylthioalkyl" (alone or in combination with another term (s)) refers to a carbocyclylthio group attached to the main portion of the molecule via an alkylene group (i.e., carbocyclyl-S-alkylene-).

The term "carbocyclylcarbocyclyl" (alone or in combination with another term (s)) refers to a carbocyclyl group attached to the main body of the molecule via another carbocyclyl group (i.e., carbocyclyl-carbocyclyl-). For example, C3-C10carbocyclyl C5-C7thcarbocyclyl refers to C3-C10a carbocyclyl group attached to the main part of the molecule via C5-C7tha carbocyclyl group (i.e., C3-C10carbocyclyl-C5-C7thcarbocyclyl-).

The term "carbocyclylcarbocyclylalkyl" (alone or in combination with another term (s)) refers to a carbocyclylcarbocyclyl group attached to the main portion of the molecule via an alkylene group.

The term "carbocyclylalkoxycarbocyclylalkyl" (alone or in combination with another term (s)) refers to carbocyclyl-alkylene-O-carbocyclyl-alkylene-. For example, C3-C10carbocyclyl C1-C6thalkoxyC5-C7thcarbocyclyl C3-C4alkyl refers to C3-C10carbocyclyl-C1-C6thalkylene-OC5-C7thcarbocyclyl-C3-C4alkylene-.

The term "(carbocyclylalkyl) carbocyclylalkyl" (alone or in combination with another term (s)) refers to carbocyclyl-alkylene-carbocyclyl-alkylene-. For example, C3-C10carbocyclyl C1-C6thalkyl C5-C7thcarbocyclyl C3-C4alkyl refers to C3-C10carbocyclyl-C1-C6thalkylene-C5-C7thcarbocyclyl-C3-C4alkylene-.

The term "carbocyclylalkoxyheterocycloalkyl" (alone or in combination with another term (s)) refers to carbocyclyl-alkylene-O-heterocyclyl-alkylene-.

The term "carbocyclylcarbonylheterocycloalkyl" (alone or in combination with another term (s)) refers to carbocyclyl-C (O) -heterocyclylalkylene-.

The term "carbocyclylheterocycloalkyl" (alone or in combination with another term (s)) refers to carbocyclyl-heterocyclyl-alkylene-.

The term "carbocyclylcarbonylcarbocyclylalkyl" (alone or in combination with another term (s)) refers to carbocyclyl-C (O) -carbocyclyl-alkylene-. For example, C3-C10carbocyclylcarbonylC4-C8carbocyclyl C1-C6thalkyl refers to C3-C10carbocyclyl-C (O) -C4-C8carbocyclyl-C1-C6thalkylene-.

The term "(carbocyclylalkyl) heterocycloalkyl" (alone or in combination with another term (s)) refers to carbocyclyl-alkylene-heterocyclyl-alkylene.

The term "carbonyl" (alone or in combination with another term (s)) refers to -C (O) -, which can also be represented as:

The term "carboxy" (alone or in combination with another term (s)) denotes -C (O) -OH, which can also be depicted as:

The term "carboxyalkyl" (alone or in combination with another term (s)) refers to a carboxy group attached to the main portion of the molecule via an alkylene group. Representative carboxyalkyl examples include, but are not limited to, carboxymethyl, 2-carboxyethyl and 3-carboxypropyl.

The term "cyclic amino" (alone or in combination with another term (s)) denotes a heterocyclyl moiety containing at least one ring nitrogen atom, the remaining ring atoms being carbon and optionally nitrogen or sulfur. Non-limiting examples of such groups include piperidinyl, piperazinyl and thiazine groups.

The term "cycloalkenyl" (alone or in combination with another term (s)) refers to a nonaromatic, partially unsaturated carbocyclyl substituent without heteroatoms as ring members and usually 4-18 carbons as ring members. Representative examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl and octahydronaphthalenyl.

The term "cycloalkyl" (alone or in combination with another term (s)) refers to a saturated carbocyclyl group containing zero ring heteroatoms and typically 3-18 carbons as ring members. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decalinyl and norpynil.

The term "cycloalkylcarbonyl" (alone or in combination with another term (s)) refers to a cycloalkyl group attached to the main portion of the molecule via a carbonyl group.

The term "cyano" (alone or in combination with another term (s)) denotes -CN, which can also be represented as <img file="00000023.tif" he="18" wi="9" img-format="tif" img-content="undefined" />.

The term "dialkylamino" (alone or in combination with another term (s)) refers to -NRARB, where RA and RB are independently selected from alkyl groups.

The term "dialkylaminocarbonyl" (alone or in combination with another term (s)) refers to a dialkylamino group attached to the main portion of the molecule via a carbonyl group (i.e., N (RARB) -C (O) -, where RA and RB are independently selected from alkyl groups).

The term "formyl" (alone or in combination with another term (s)) refers to the group -C (O) H.

The term "halogen" (alone or in combination with another term (s)) denotes a fluorine radical (which may be represented as -F), a chlorine radical (which may be depicted as -Cl), a bromine radical (which can be depicted as -Br) or an iodine radical (which can be depicted as -I).

The prefix "halogen" indicates that the substituent to which the prefix is attached is replaced by one or more independently selected halogen radicals. For example, "haloalkyl" (alone or in combination with another term (s)) means a substituent alkyl in which at least one hydrogen radical has been replaced by a halo radical. Non-limiting examples of haloalkyl include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl and 1,1,1-trifluoroethyl. In another example, "haloalkoxy" (alone or in combination with another term (s)) denotes an alkoxy substituent in which at least one hydrogen radical is replaced by a halo radical. Non-limiting examples of haloalkoxy substituents include chloromethoxy, 1-bromoethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy (also known as "perfluoromethyloxy") and 1,1,1, trifluoroethoxy. It should be noted that if the substituent is substituted by more than one halogen radical, then such halogen radicals may be the same or different (unless otherwise indicated).

The prefix "perhalogen" indicates that each hydrogen radical on the substituent to which the prefix is attached is replaced by an independently selected halo radical, that is, each hydrogen radical on the substituent is replaced by a halogen radical. If all halogen radicals are the same, then the prefix usually determines the halogen radical. Thus, for example, the term "perfluoro" means that each hydrogen radical of the substituent to which the prefix is attached is replaced by a fluorine radical. For example, the term "perfluoroalkyl" means a substituent alkyl, in which each hydrogen radical is replaced by a fluorine radical. Non-limiting examples of perfluoroalkyl substituents include trifluoromethyl (-CF3), perfluoroisopropyl, perfluorobutyl, perfluorodecyl and perfluorododecyl. Another example, the term "perfluoroalkoxy" means an alkoxy substituent in which each hydrogen radical is replaced by a fluorine radical. Non-limiting examples of perfluoroalkoxy substituents include trifluoromethoxy (-O-CF3), perfluoroisopropoxy, perfluorobutoxy, perfluorodeoxy and perfluorododecoxy.

The terms "heterocycle" or "heterocyclo" or "heterocyclyl" (alone or in combination with another term (s)) refer to saturated (for example, "heterocycloalkyl"), partially unsaturated (eg, "heterocycloalkenyl" or "heterocycloalkynyl") or a fully unsaturated (for example "heteroaryl") ring system, usually containing 3-18 ring atoms, in which at least one ring atom is a heteroatom (i.e., nitrogen, oxygen or sulfur) and the remaining atoms the rings are independently selected from the group consisting of coal nitrogen, oxygen and sulfur. The heterocyclyl group can be attached to the main body of the molecule by any substitutionary carbon atom or nitrogen in the group, provided that a stable molecule is formed.

The heterocyclyl can be, but is not limited to, a single ring which typically contains 3 to 14 ring atoms (i.e., M3-M14heterocyclyl), 3 to 8 ring atoms (i.e., M3-M8heterocyclyl), 3 to 6 ring atoms (i.e., M3-M6thheterocyclyl) or 5-6 ring atoms (i.e., M5-M6thheterocyclyl). Non-limiting examples of heterocyclyls with a single ring include furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, izopirrolil, pyrrolinyl, pyrrolidinyl, imidazolyl, izoimidazolil, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oksatiolil, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl , thiazolinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (also known as azoximil), 1,2,5-oxadiazole yl (also known as "furazanyl") and 1,3,4-oxadiazolyl), oxatriazolyl (including 1,2,3,4-oxatriazolyl and 1,2,3,5-oxatriazolyl), dioxazolyl (including 1,2, 3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl and 1,3,4-dioxazolyl), oxathiolanyl, pyranyl (including 1,2-pyranyl and 1,4-pyranyl), dihydropyranyl, dihydropyranyl, pyridinyl, piperidinyl, diazinyl (also known as "1,2-diazinyl"), pyrimidinyl (also known as "1,3-diazinyl") and pyrazinyl (also known as "1,4-diazinyl") ), piperazinyl, triazinyl (also known as "1,3,5-triazinyl"), as-triazinyl (also known as 1,2,4-triazinyl) and v-triazinyl (also known as "1, 2,3-triazinyl)), oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as "pentoxazolyl"), 1,2,6- oxazinyl and 1,4-oxazinyl), isoxazinyl (including o-isoxazinyl and p-iso xazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl), morpholinyl , azepinyl, oxepinyl, thiepinyl and diazepinyl. diazinyl (also known as "1,2-diazinyl"), pyrimidinyl (also known as "1,3-diazinyl") and pyrazinyl (also known as "1,4-diazinyl")), piperazinyl, triazinyl including s-triazinyl (also known as "1,3,5-triazinyl"), as-triazinyl (also known as 1,2,4-triazinyl) and v-triazinyl (also known as "1,2,3-triazinyl" )), oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as "pentoxazolyl"), 1,2,6-oxazinyl and 1,4- oxazinyl), isoxazinyl (including o-isoxazinyl and p-isoxazinyl), oxazolidinyl, isoxazolidine l, oxathiazinyl (including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl and diazepinyl. diazinyl (also known as "1,2-diazinyl"), pyrimidinyl (also known as "1,3-diazinyl") and pyrazinyl (also known as "1,4-diazinyl")), piperazinyl, triazinyl including s-triazinyl (also known as "1,3,5-triazinyl"), as-triazinyl (also known as 1,2,4-triazinyl) and v-triazinyl (also known as "1,2,3-triazinyl" )), oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as "pentoxazolyl"), 1,2,6-oxazinyl and 1,4- oxazinyl), isoxazinyl (including o-isoxazinyl and p-isoxazinyl), oxazolidinyl, isoxazolidine l, oxathiazinyl (including 1,2,5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazinyl and 1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl and diazepinyl. 3-diazinyl ") and pyrazinyl (also known as" 1,4-diazinyl ")), piperazinyl, triazinyl (including s-triazinyl (also known as" 1,3,5-triazinyl "), as-triazinyl (also known 1,2,4-triazinyl) and v-triazinyl (also known as "1,2,3-triazinyl")), oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3 , 6-oxazinyl (also known as "pentoxazolyl"), 1,2,6-oxazinyl and 1,4-oxazinyl), isoxazinyl (including o-isoxazinyl and p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1,2 , 5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazine l and 1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepin, thiepin and diazepinyl. 3-diazinyl ") and pyrazinyl (also known as" 1,4-diazinyl ")), piperazinyl, triazinyl (including s-triazinyl (also known as" 1,3,5-triazinyl "), as-triazinyl (also known 1,2,4-triazinyl) and v-triazinyl (also known as "1,2,3-triazinyl")), oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3 , 6-oxazinyl (also known as "pentoxazolyl"), 1,2,6-oxazinyl and 1,4-oxazinyl), isoxazinyl (including o-isoxazinyl and p-isoxazinyl), oxazolidinyl, isoxazolidinyl, oxathiazinyl (including 1,2 , 5-oxathiazinyl or 1,2,6-oxathiazinyl), oxadiazinyl (including 1,4,2-oxadiazine l and 1,3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepin, thiepin and diazepinyl.

The heterocyclyl may also include, without limitation, two or more rings fused together, such as, for example, naphthyridinyl (including [1,8] naphthyridinyl and [1,6] naphthyridinyl), thiazole pyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, indolizinyl , pyridinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, pyridopyridinyl (including pyrido [3,4-b] pyridinyl, pyrido [3,2-b] pyridinyl and pyrido [4,3-b] pyridinyl), pyridopyrimidine and pteridinyl. Other non-limiting examples of fused ring heterocyclyl include benzo-fused heterocyclics such as indolyl, isoindolyl, indolninyl (also known as "pseudoindolyl"), isoindazolyl (also known as "benzpyrazolyl"), benzazinyl (including quinolinyl (also known as "1-benzazinyl" ) and isoquinolinyl (also known as "2-benzazinyl")), phthalazinyl, quinoxalinyl, benzodiazinyl (including cinnolinyl (also known as "1,2-benzodiazinyl") and quinazolinyl (also known as "1,3-benzodiazinyl")), benzopyranyl (including "chromium" and "isochromenyl"), benzothiopyranyl ( also known as "thiochromenyl"), benzoxazolyl, indoxazinyl (also known as "benzisoxazolyl"), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also known as "coumaronyl"), isobenzofuranyl, benzothienyl (also known as "benzothiophenyl", " thionaphthenyl "and" benzothiofur nyl "), isobenzothienyl (also known as" isobenzothiophenyl "," isothionaphthenyl "and" isobenzothiofuranyl "), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2 , 3,1-benzoxazinyl and 3,1,4-benzoxazinyl), benzisoxazinyl (including 1,

The term "two-folded heterocyclyl" (alone or in combination with another term (s)) denotes saturated, partially saturated or aromatic heterocyclyl containing two fused rings. Non-limiting examples of heterocyclyl with two fused rings include naphthyridinyl (including [1,8] naphthyridinyl and [1,6] naphthyridinyl), thiazolpyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl, pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indolninyl, isoindazolyl, benzazinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodiox Neil, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl,

As ring members, heterocyclyl may contain one or more sulfur atoms; and in some cases, the sulfur atom (s) is oxidized to SO or SO2. The heteroatom (s) of nitrogen in the heterocyclyl can be quaternized or not quaternized and can be oxidized to the N-oxide or not oxidized. In addition, the heteroatom (s) of nitrogen may be N-protected or unprotected.

As used herein, the number of ring atoms in the heterocyclyl moiety can be determined using the prefix "Mx-My", Where x is the minimum number and y is the maximum number of ring atoms in the heterocyclyl moiety.

The term "heterocycloalkoxy" (alone or in combination with another term (s)) refers to a heterocycloalkyl group attached to the main portion of the molecule via a hydroxy group.

The term "heterocycloalkoxyalkyl" (alone or in combination with another term (s)) refers to a heterocycloalkoxy group attached to the main portion of the molecule via an alkylene group (i.e. heterocyclyl-alkylene-O-alkylene-).

The term "heterocycloalkoxycarbonyl" (alone or in combination with another term (s)) refers to a heterocycloalkoxy group attached to the main portion of the molecule via a carbonyl group (i.e., heterocyclyl-alkylene-OC (O) -).

The term "heterocycloalkyl" (alone or in combination with another term (s)) refers to heterocyclyl attached to the main portion of the molecule via an alkylene group (for example, heterocycloC1-C6thalkyl).

The term "heterocycloalkylcarbonyl" (alone or in combination with another term (s)) refers to a heterocycloalkyl group attached to the main portion of the molecule via a carbonyl group (i.e., -C (O) -alkylene-heterocyclyl).

The term "heterocyclocarbonyl" (alone or in combination with another term (s)) refers to heterocyclyl attached to the main body of the molecule via a carbonyl group (i.e., -C (O) -heterocyclyl).

The terms "heterocyclyloxy" or "(heterocyclo) oxy" (alone or in combination with another term (s)) refers to a heterocyclyl group attached to the main portion of the molecule via a hydroxy group.

The term "(heterocyclo) oxyalkyl" (alone or in combination with another term (s)) refers to a heterocyclyloxy group attached to the main portion of the molecule via an alkylene group (i.e. heterocyclyl-O-alkylene-).

The term "(heterocyclo) oxycarbonyl" (alone or in combination with another term (s)) refers to a (heterocyclo) hydroxy group attached to the main portion of the molecule via a carbonyl group (i.e., heterocyclyl-OC (O) .

The term "heterocyclothio" (alone or in combination with another term (s)) refers to heterocyclyl attached to the main body of the molecule via -S-.

The term "heterocyclothioalkoxy" (alone or in combination with another term (s)) refers to heterocyclyl-alkylene-S-.

The term "heterocyclothioalkoxyalkyl" (alone or in combination with another term (s)) refers to heterocyclyl-alkylene-S-alkylene-.

The term "heterocyclothioalkyl" (alone or in combination with another term (s)) refers to a heterocyclothio group attached to the main portion of the molecule via an alkylene group (i.e., heterocyclyl-S-alkylene-).

The term "heterocyclocarbocyclyl" (alone or in combination with another term (s)) refers to heterocyclyl attached to the main body of the molecule via a carbocyclyl group (i.e., heterocyclo-carbocyclyl-).

The term "heterocyclocarbocyclylalkyl" (alone or in combination with another term (s)) refers to a heterocyclo-carbocyclyl group attached to the main portion of the molecule via an alkylene group (i.e., heterocyclylcarbocyclyl-alkylene-).

The term "(heterocyclo) alkoxycarbonyl cycloalkyl" (alone or in combination with another term (s)) refers to a heterocycloalkylene-O-carbocyclyl-alkylene-.

The term "(heterocyclo) carbonylcarbocyclylalkyl" (alone or in combination with another term (s)) refers to heterocyclo-C (O) -carbocyclyl-alkylene-.

The term "(heterocyclo) heterocycloalkyl" (alone or in combination with another term (s)) refers to a heterocyclo-heterocyclo-alkylene-.

The term "(heterocyclo) alkoxyheterocycloalkyl" (alone or in combination with another term (s)) refers to a heterocyclo-alkylene-O-heterocyclo-alkylene-.

The term "(heterocyclo) carbonylheterocycloalkyl" (alone or in combination with another term (s)) refers to heterocyclo-C (O) -heterocycloalkylene-.

The term "(heterocycloalkyl) carbocyclylalkyl" (alone or in combination with another term (s)) refers to a heterocycloalkylene-carbocyclyl-alkylene-.

The term "(heterocycloalkyl) heterocycloalkyl" (alone or in combination with another term (s)) refers to a heterocycloalkylene-heterocyclo-alkylene-. Thus, for example, (M3-M10heterocycloC1-C6thalkyl) M5-M6thheterocycloC1-C3alkyl is M3-M10heterocyclo-C1-C6thalkylene-M5-M6thheterocyclo-C1-C3alkylene-.

The term "heteroaryl" (alone or in combination with another term (s)) denotes an aromatic heterocyclyl, usually containing 5-18 ring atoms. Heteroaryl may be a single ring or two or more fused rings. Non-limiting examples of five-membered heteroaryls include imidazolyl; furanyl; thiophenyl (or thienyl or thiofuranyl); pyrazolyl; oxazolyl; isoxazolyl; thiazolyl; 1,2,3-, 1,2,4-, 1,2,5- and 1,3,4-oxadiazolyl and isothiazolyl. Non-limiting examples of six-membered heteroaryls include pyridinyl; pyrazinyl; pyrimidinyl; pyridazinyl and 1,3,5-, 1,2,4- and 1,2,3-triazinyl. Non-limiting examples of 6/5-membered fused ring heteroaryls include benzothiofuranyl, isobenzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl and anthranil. Non-limiting examples of 6/6-membered fused ring heteroaryls include quinolinyl; isoquinolinyl and benzoxazinyl (including cinnolinyl and quinazolinyl).

The term "heteroarylalkoxy" (alone or in combination with another term (s)) refers to heteroarylalkyl attached to the main portion of the molecule via a hydroxy group (i.e., heteroaryl-alkylene-O-). Representative examples of heteroarylalkoxy include, but are not limited to, 2-pyridin-3-ylethoxy, 1,3-thiazol-5-ylmethoxy, 3-quinolin-3-ylpropoxy and 5-pyridin-4-ylpentyloxy.

The term "heteroarylalkoxyalkyl" (alone or in combination with another term (s)) refers to a heteroarylalkoxy group attached to the main portion of the molecule via an alkylene group (i.e., heteroaryl-alkylene-O-alkylene-). Representative examples of heteroarylalkoxyalkyl include, but are not limited to, (2-pyridin-3-ylethoxy) methyl, (3-quinolin-3-ylpropoxy) methyl, (1,3-thiazol-5-ylmethoxy) methyl and 2- (5- pyridin-4-ylpentyloxy) ethyl.

The term "heteroarylalkoxycarbonyl" (alone or in combination with another term (s)) refers to a heteroarylalkoxy group attached to the main portion of the molecule via a carbonyl group (i.e., heteroaryl-alkylene-OC (O) -). Representative examples of heteroarylalkoxycarbonyl include, but are not limited to, (2-pyridin-3-ylethoxy) carbonyl, (3-quinolin-3-ylpropoxy) carbonyl, 2- (1,3-thiazol-5-ylmethoxy) carbonyl and (5- pyridin-4-ylpentyloxy) carbonyl.

The term "heteroarylalkyl" (alone or in combination with another term (s)) refers to a heteroaryl group attached to the main portion of the molecule via an alkylene group. Representative examples of heteroarylalkyl include, but are not limited to, 3-quinolinylmethyl, 3-pyridinylmethyl, 4-pyridinylmethyl, 1H-imidazol-4-ylmethyl, 1H-pyrrol-2-ylmethyl, pyridin-3-ylmethyl and 2-pyrimidin-2- ylpropyl.

The term "heteroarylalkylcarbonyl" (alone or in combination with another term (s)) refers to a heteroarylalkyl group attached to the main portion of the molecule via a carbonyl group (i.e., heteroaryl-alkylene-C (O) -).

The term "heteroarylcarbonyl" (alone or in combination with another term (s)) refers to a heteroaryl group attached to the main body of the molecule via a carbonyl group. Representative examples of heteroarylcarbonyl include, but are not limited to, pyridin-3-ylcarbonyl, (1,3-thiazol-5-yl) carbonyl and quinolin-3-ylcarbonyl.

The term "heteroaryloxy" (alone or in combination with another term (s)) refers to a heteroaryl group attached to the main portion of the molecule via a hydroxy group. Representative examples of heteroaryloxy include, but are not limited to, pyridin-3-yloxy and quinolin-3-yloxy.

The term "heteroaryloxyalkyl" (alone or in combination with another term (s)) refers to a heteroaryloxy group attached to the main portion of the molecule via an alkylene group (i.e., heteroaryl-O-alkylene-).

The term "heteroaryloxycarbonyl" (alone or in combination with another term (s)) refers to a heteroaryloxy group attached to the main portion of the molecule via a carbonyl group (i.e., heteroaryl-OC (O) -).

The term "heteroarylthio" (alone or in combination with another term (s)) refers to a heteroaryl group attached to the main portion of the molecule via -S-.

The term "heteroarylthioalkoxy" (alone or in combination with another term (s)) refers to heteroaryl-alkylene-S-.

The term "heteroarylthioalkoxyalkyl" (alone or in combination with another term (s)) refers to heteroaryl-alkylene-S-alkylene-.

The term "heteroarylthioalkyl" (alone or in combination with another term (s)) refers to a heteroarylthio group attached to the main portion of the molecule via an alkylene group (i.e., heteroaryl-S-alkylene-).

The term "hydrogen" (alone or in combination with another term (s)) refers to a hydrogen radical and can be depicted as -H.

The term "hydroxy" (itself or in combination with another term (s)) refers to -OH.

The term "hydroxyalkyl" (alone or in combination with another term (s)) refers to an alkyl substituent in which one or more hydrogen radicals are replaced by -OH. Representative examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and 2-ethyl-4-hydroxyheptyl.

The term "keto" (alone or in combination with another term (s)) denotes an oxoradical and can be represented as = O.

The term "iminoalkyl" (alone or in combination with another term (s)) refers to a radical of formula <img file="00000024.tif" he="13" wi="14" img-format="tif" img-content="undefined" />, where H can be optionally substituted with alkyl or hydroxy, and in these cases the substituent will be alkyliminoalkyl or hydroxyiminoalkyl, respectively.

The term "nitro" (alone or in combination with another term (s)) denotes -NO2.

The term "oxo" (alone or in combination with another term (s)) refers to the group = O (i.e., <img file="00000025.tif" he="8" wi="10" img-format="tif" img-content="undefined" />).

The term "hydroxy" (alone or in combination with another term (s)) denotes -O-.

The term "propargyl" (alone or in combination with another term (s)) denotes a monovalent radical depicted as: -CH2-CH≡CH.

The term "sulfonyl" (alone or in combination with another term (s)) means -S (O)2-, which can be depicted as:

The term "sulphinyl" (alone or in combination with another term (s)) denotes -S (O) -, which can also be represented as:

The term "thio" or "thia" (alone or in combination with another term (s)) denotes -S-.

The term "thiol," "mercapto" or "sulfhydryl" (alone or in combination with another term (s)) means a substituent of sulfhydryl (i.e., -SH). Thus, for example, thiolalkyl is a substituent alkyl in which one or more hydrogen radicals are replaced by -SH, with alkylthio being alkyl-S-.

The term "thioalkoxy" (alone or in combination with another term (s)) refers to an alkyl group attached to the main body of the molecule via -S-. Representative examples of thioalkoxy include, but are not limited to, methylthio, ethylthio and butylthio.

The term "thioalkoxyalkyl" (alone or in combination with another term (s)) refers to a thioalkoxy group attached to the main portion of the molecule via an alkylene group (i.e., alkyl-S-alkylene-).

The term "thiocarbonyl" (alone or in combination with another term (s)) denotes carbonyl in which the oxygen atom is replaced by sulfur. Such a substituent can be depicted as -C (S) -, and can also be depicted as:

The term "pharmaceutically acceptable" is used as an adjective, meaning that the noun being determined is suitable for use as a pharmaceutical product or as part of a pharmaceutical product.

The term "therapeutically effective amount" refers to the total amount of each active substance sufficient to achieve a significant effect in the patient, for example, to reduce the amount of the virus.

The term "prodrug" refers to derivatives of compounds of the invention that have chemically or metabolically cleavable groups and becomes, by salvolysis or by physiological conditions, a compound of the invention that is pharmaceutically active in vivo. The prodrug of the compound can be prepared by conventional methods by reacting a functional group of a compound (such as an amino, hydroxy or carboxy group). The prodrug derivative often provides advantages in terms of solubility, tissue compatibility, or delayed release in the mammals (see Bungard, H., DESIGN OF PRODRUGS, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as, for example, esters obtained by reacting an acidic starting material with a suitable alcohol, or amides prepared by reacting the starting acid compound with a suitable amine. Examples of prodrugs include, but are not limited to, acetate, formate,

The term "solvate" refers to the physical combination of a compound of the present invention with one or more solvent molecules, either organic or inorganic. This physical union often involves a hydrogen bond. In certain cases, the solvate can be isolated, for example, if one or more of the solvate molecules are embedded in the crystal lattice of the crystalline body. "Solvate" includes both the liquid phase and the isolated solvates. Examples of solvates include, but are not limited to, hydrates, ethanolates and methanolates.

The term "chiral" refers to molecules that do not have a plane of symmetry and, therefore, do not have a non-superimposing mirror image. A chiral molecule can exist in two forms, dextrorotatory and levorotatory.

The term "stereoisomer" refers to isomers whose atoms are linked in the same order, but have a different three-dimensional structure. The term "stereoisomer" includes, for example, enantiomers and diastereomers.

The term "cis-trans isomer" refers to stereoisomers that differ in the stereochemistry of the double bond or ring. Cis-trans isomers are also called geometric isomers.

The term "enantiomer" refers to stereoisomers of a chiral substance that has a mirror image.

The term "diastereomer" refers to stereoisomers that are not enantiomers, or mirror images of one another.

The term "racemic mixture" refers to a mixture consisting of equal parts of (+) and (-) enantiomers of a chiral substance. Even if individual molecules are chiral, racemic mixtures are optically inactive.

The term "tautomer" refers to isomers that are interconversion. For example, enols and ketones are tautomers, since they are converted into each other when treated with either an acid or a base.

The term "position isomer" refers to any one of two or more structural isomers that differ in the position of a particular substituent or group. Functional groups can be attached to the structurally nonequivalent positions of the carbon skeleton. For example, [1,3] imidazole, depicted as<img file="00000029.tif" he="12" wi="13" img-format="jpg" img-content="undefined" />, and [1,4] imidazole, depicted as <img file="00000030.tif" he="13" wi="13" img-format="jpg" img-content="undefined" />, are positional isomers.

The term "N-protecting group" or "N-protected" refers to groups capable of protecting the amino group from undesired reactions. Commonly used N-protecting groups are described in Greene and Wuts, PROTECTING GROUPS IN CHEMICAL SYNTHESIS (3rd ed., John Wiley & Sons, NY (1999)), which is hereby incorporated by reference in its entirety. Non-limiting examples of N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butyl acetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl or 4-nitrobenzoyl; sulfonyl groups such as benzenesulfonyl or p-toluenesulfonyl; sulfenyl groups such as phenylsulphenyl (phenyl-S-) or triphenylmethylsulphenyl (trityl-S-); sulfinyl groups, such as p-methylphenylsulfinyl (p-methylphenyl-S (O) -) or t-butylsulfinyl (tert-Bu-S (O) -); carbamate-forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1- (p-biphenylyl ) -1-methylethoxycarbonyl, dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl, fluorenyl 9- m ethoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl or phenylthiocarbonyl; alkyl groups such as benzyl, p-methoxybenzyl, triphenylmethyl, or benzyloxymethyl; p-methoxyphenyl; and silyl groups, such as trimethylsilyl. Preferred N-protecting groups include formyl,

In the section "General methods of synthesis and examples" the following abbreviations were used:

AcOH = acetic acid

atm = atmosphere

Boc = N-t-butoxycarbonyl (protecting group)

CDI = 1,1'-carbonyldiimidazole

CH2Cl2= methylene chloride (dichloromethane)

CuI = copper iodide [copper iodide (I)]

DCE = 1,2-dichloroethane

DEAD = diethyl azodicarboxylate

DMA = NN-dimethylacetamide

DMAP = 4-dimethylaminopyridine

DMF = N, N-dimethylformamide

DMSO = dimethyl sulfoxide

EDCI = N-ethyl-N '- (3-dimethylaminopropyl) carbodiimide hydrochloride

EMME = 2-Ethoxymethylenemalonic acid diethyl ester

Et3N = triethylamine

Ether = diethyl ether

EtI = ethyl iodide

EtOAc = ethyl acetate

EtOH = ethanol

Fe = iron

Fe (AcAc) 3 = Iron (III) -acetylacetonate

Chloride Fmoc = 9-fluorenylmethyl chloroformate

HOBt = N-hydroxybenzotriazole

Hünig's base = N, N-diisopropylethylamine

IPA = isopropyl alcohol

K2CO3= potassium carbonate

KOH = potassium hydroxide

LDA = lithium diisopropylamine

MeOH = methanol

MsCl = methanesulfonyl chloride

NaH = sodium hydride

NH2OH · HCl = hydroxylamine hydrochloride

NMP = 1-Methyl-2-pyrrolidinone

Mg2SO4= magnesium sulfate

Na2SO4= sodium sulfate

NH3= ammonium

NH4Cl = ammonium chloride

NH4OH = ammonium hydroxide

PG = protective group, such as Boc- or Troc-

POCl3= phosphorus oxychloride

R-MgCl = Grignard reagent

RI = alkyl iodide or substituted alkyl iodide

SnCl2 = stannous chloride (stannous chloride)

TFA = trifluoroacetic acid

THF = tetrahydrofuran

TLC = thin layer chromatography

Troc = 2,2,2-trichloroethoxycarbonyl- (protecting group)

General methods of synthesis and examples

The following synthesis methods and schemes illustrate the general methods by which the compounds of the present invention can be prepared. The starting materials can be obtained from commercial sources or obtained by methods well known to those skilled in the art. By way of example, synthetic routes similar to those shown below can be used, together with synthesis methods known in the art of organic synthesis, or variants thereof, as will be apparent to those skilled in the art.

The present invention refers to compounds obtained by any synthesis method or metabolic process. Metabolic processes include processes occurring in the human or animal body (in vivo), or the processes taking place in vitro.

If the substituent described herein is not suitable for use in the synthesis method of the present invention, the substituent may be protected with a suitable protecting group, i.e., stable for the reaction conditions used in these methods. The protecting group can be removed at a suitable time in the reaction sequence to obtain the desired intermediate or target compound. Suitable protecting groups and methods for introducing or removing protective substituents are well known in the art, examples are listed in Greene and Wuts,higher.

Preparation of 7-Substituted-4-Substituted- [1,8] Naphthyridine Compounds

The compounds of formulas I (a) or I (b) can be synthesized by reacting <img file="00000031.tif" he="27" wi="45" img-format="tif" img-content="undefined" /> or <img file="00000032.tif" he="27" wi="40" img-format="tif" img-content="undefined" /> from <img file="00000033.tif" he="28" wi="32" img-format="tif" img-content="undefined" />, where A, X, Y, R10, R17th, R22, R31, R33, R35 and R50 are as defined in the embodiments or examples above, and K is Cl or another halogen. Similarly, the synthesis of the compounds of formulas II (a) or II (b) typically involves the reaction of<img file="00000034.tif" he="23" wi="46" img-format="tif" img-content="undefined" /> or <img file="00000035.tif" he="23" wi="48" img-format="tif" img-content="undefined" /> from <img file="00000036.tif" he="28" wi="36" img-format="tif" img-content="undefined" />, where R2, R3, R7th, R9, Releven, R12 and R13 are as defined in the embodiments or examples above, and K is Cl or another halogen. In Schemes 1, 2, 3 and 4, a characteristic method for the preparation of these compounds [1,8] of the naphthyridine type is presented below.

7-Substituted-4-substituted- [1,8] naphthyridine compounds were usually synthesized (Scheme 4) by condensation of the 7-substituted-4-chloro- [1,8] naphthyridine compound 8 with a condensation compound, such as 10, eleven and 12 (Scheme 3). Other 4-substituted [1,8] naphthyridines can be prepared in a similar manner using suitable binding compounds.

Preparation of 6-substituted-2-aminopyridines

According to the typical preparation process shown in Scheme 1, a solution of 2,6-dichloropyridine is treated with ammonium hydroxide in a hermetically sealed metal reactor at a temperature of about 180 ° C for about 40 hours. After cooling to room temperature, the product was filtered to give 6-chloro-2-aminopyridine. A solution of this product and hexane-2,5-dione in benzene was treated with acetic acid, heated at reflux with azeotropic distillation of water for about 20 hours. The reaction mixture was cooled to room temperature, diluted with diethyl ether, washed with dilute hydrochloric acid and water. The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give 6-chloro-2- (2,5-dimethyl-pyrrol-1-yl) -pyridine1. Compound1 was treated with Grignard reagent (R-MgX) in dry tetrahydrofuran (THF) and 1-methyl-2-pyrrolidinone (NMP) at room temperature under nitrogen, iron (III) acetylacetonate [Fe (AcAc)3] and the mixture was stirred at room temperature for about 18 hours. During the reaction, two additions of the Grignard reagent and the iron-based catalyst were carried out. The reaction was quenched by pouring into 5% acetic acid and extracted with ether. The ether layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give 6-substituted-2- (2,5-dimethyl-pyrrol-1-yl) -pyridine2. Compound2 can be directly converted to 6-substituted-2-aminopyridine 4, or functional groups can then be introduced by reaction with an alkyl iodide or substituted alkyl iodide in the presence of lithium diisopropylamide (LDA). In this case, the solution of the compound2 in dry tetrahydrofuran was added dropwise over about 30 minutes to a stirred solution of lithium diisopropylamide in dry tetrahydrofuran at -30 ° C. Then, alkyl iodide or substituted alkyl iodide (RI) in tetrahydrofuran was added dropwise over about 30 minutes, then warmed to room temperature. After two hours, the reaction mixture was quenched by pouring into a saturated solution of sodium chloride, and extracted with ether. The ether solution was dried over magnesium sulfate, filtered, and evaporated in vacuo to give 6-substituted-2- (2,5-dimethyl-pyrrol-1-yl) pyridine3. Solution of both compounds2 or 3 and hydroxylamine hydrochloride in ethanol and water was heated at about 100 ° C for about 16 hours, cooled to room temperature, and extracted with methylene chloride, dried over magnesium sulfate, filtered and evaporated in vacuo to give 6-substituted-aminopyridine 4, in accordance with Scheme 2. The 6-substituent in Scheme 1 is R7th, which is described later.

Scheme 1

Preparation of 7-substituted-4-chloro- [1,8] naphthyridines

The conventional production method shown in Scheme 2 involved mixing 6-substituted 2-aminopyridine 4 and 2-ethoxymethylene-malonic acid diethyl ester (EMME) and heating under stirring to about 100 ° C for about 2.5 hours. The reaction mixture was cooled to room temperature and diluted with hexane, the resulting solid precipitate was filtered and dried in vacuo to give aminomethylenemalonic acid ester5. Compound 5 then dissolved in diphenyl ether, and the resulting solution was heated to a temperature of about 250 ° C for about 30 minutes. After cooling to room temperature, diluting with hexane, the resulting solid was filtered and dried in vacuo to give 7-substituted-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester "E" . A solution of compound6th and potassium hydroxide (KOH) were heated in a sealed metal reactor at a temperature of 180 ° C for about 16 hours, cooled to room temperature and adjusted to pH 6 with 1N HCl. of hydrochloric acid. The precipitate which formed was filtered and dried, yielding 7-substituted [1,8] naphthyridin-4-ol7th. A mixture of compound7th were mixed with phosphorus oxychloride (POCl3) and heated to a temperature of about 50 ° C. with stirring for 6 hours, cooled, quenched by pouring on ice. It was cooled, then pH 10 was adjusted with concentrated ammonium hydroxide and extracted with methylene chloride, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give 7-substituted-4-chloro- [1,8] naphthyridine8. Substituents in the compound8 are shown in scheme 2 in the form R7th, which is described.

Scheme 2

The preparation of aminophenyl condensing agents (10, 11 and 12)

A wide variety of aminophenyl condensing agents is possible. Examples of this set are presented in Scheme 3.

In a typical production method, the substituted 2-chloro-nitrobenzene derivative in dimethylformamide (DMF) was treated with sodium thiophenolate at about 50 ° C for about 2 hours, cooled and diluted with methylene chloride, washed with water, dried over sodium sulfate, filtered and evaporated in vacuo with obtaining a substituted-2-phenylsulfanyl-nitrobenzene derivative. This nitrobenzene derivative was further reduced with stannous chloride (SnCl2) or iron (Fe) in ethanol. The pH of the reaction mixture 12 was adjusted with 1N HCl. sodium hydroxide, extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated in vacuo to give the substituted-2-phenylsulfanyl-aminobenzene derivative10.

Similarly, the corresponding substituted-2-hydroxy-nitrobenzene derivative was dissolved in dimethylformamide, reacted with a solution of sodium phenoxide, stirred and heated at a temperature of up to 100 ° C for about 5 days. The reaction mixture was cooled and diluted with methylene chloride, washed with water, dried over sodium sulfate, filtered and evaporated in vacuo to give a substituted 2-phenoxy-nitrobenzene derivative. This nitrobenzene compound was further reduced with stannous chloride (SnCl2) or iron (Fe) in ethanol. The pH of the reaction mixture 12 was adjusted with 1N HCl. sodium hydroxide, extracted with ethyl acetate, dried over sodium sulfate, filtered and evaporated in vacuo to give the substituted 2-phenoxyaminobenzene derivative 12.

Similarly, any connection 10, where R9 is hydroxy or protected hydroxyl can be further modified by alkylating a hydroxy group using substituted benzyl bromide to give the corresponding 5-substituted-phenoxy-2-substituted-phenylsulfanyl-aminobenzene derivative eleven.

Scheme 3

Preparation of 7-substituted-4-aminophenyl- [1,8] naphthyridines

As shown in Scheme 4, the condensing agent (compound 10, eleven, 12 or the like) suitable for the synthesis of the desired 7-substituted-4-aminophenyl- [1,8] naphthyridine, was dissolved in ethanol and reacted with the compound 8 in ethanol at a temperature of 80 ° C for about 7 hours. The reaction mixture was evaporated in vacuo and recrystallized from tetrahydrofuran with a few drops of methanol. Filtration gave the desired 7-substituted-4-aminophenyl- [1,8] naphthyridine13, 14 or 15.

Scheme 4

Preparation of amide condensing agents

As shown in Scheme 3, a wide variety of aminophenyl condensing agents are possible. Said aminophenyl condensing agents can be used to prepare the desired 7-substituted-4-aminophenyl- [1,8] naphthyridine in accordance with the methods shown in Scheme 4.

Scheme 5 shows aminophenyl compounds with a substituted amide at the 3-position of the phenyl ring.

The substituted aniline in methylene chloride was treated with 4-chloro-3-nitrobenzoyl chloride and N, N-diisopropylamine and stirred at room temperature for about 17 hours. The solvent was removed in vacuo, the resin was dissolved in ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, filtered and evaporated in vacuo to give N-substituted phenyl 4-chloro-3-nitrobenzamide16.

Compound 16 can be further converted by replacing the 4-chloro group to obtain 3-amino-4-substituted phenoxybenzamides 17th and 3-amino-4-substituted phenylsulfanyl-benzamides 18.

Connections 17th can usually be prepared by reacting benzamide 16 in anhydrous N, N-dimethylformamide with 4- (N-t-butoxycarbonyl) aminophenol (N-Boc-4-hydroxyaniline) and potassium carbonate at room temperature, then heating to about 80 ° C for about 5 hours. The reaction mixture was cooled to room temperature, the solvent was removed in vacuo, the residue was treated with ethyl acetate, washed with water and saturated brine. The organic layer was dried over sodium sulfate, filtered and evaporated in vacuo to give 4-N-t-butoxycarbonylamino substituted compound17th. The protecting group Boc can be removed in various ways to provide a compound of structure17th.

Similarly, the compound 16 can be reacted with 4-aminothiophenol and sodium acetate in anhydrous ethanol, by heating under reflux for about 19 hours. After cooling to room temperature, the ethanol was removed in vacuo, the residue was treated with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered and evaporated in vacuo. Trituration of the solid in ethyl acetate-methylene chloride gave the compound18.

<tables num="1"><table frame="none"><tgroup cols="2" rowsep="0" colsep="0"><colspec colname="c0" colwidth="165mm" /><colspec colname="c1" colwidth="5mm" /><tbody><row><entry align="center" rowsep="0" colsep="0">Scheme 5</entry><entry align="left" rowsep="0" colsep="0"> </entry></row><row><entry align="center" rowsep="0" colsep="0"><img file="00000041.tif" he="152" wi="156" img-format="tif" img-content="undefined" />The amide phenyl ring, the phenyloxy ring and the phenylsulfanyl ring can be substituted as described above. Some examples require the use of protecting groups, followed by their removal at a suitable stage. R is as defined above.</entry><entry align="left" rowsep="0" colsep="0"> </entry></row></tbody></tgroup></table></tables>

Preparation of reversible amide condensing agents

The preparation of reversible amide condensing agents is shown in Scheme 6. In a typical production process, 4-fluoro-3-nitroaniline was reacted with a substituted benzoyl chloride, Hunig base (N, N-diisopropylethylamine) in tetrahydrofuran with stirring at room temperature for about 1 hour. To the solution was added water and the resulting solid product (compound19) was collected by filtration and dried in a vacuum oven.

A solution of compound 19, 4-hydroxythiophenol and potassium carbonate in N, N-dimethylformamide were heated to a temperature of about 80 ° C for about 2 hours. After cooling to room temperature, the mixture was poured into ice water, extracted with ethyl acetate, the extracts dried over magnesium sulfate, filtered and evaporated in vacuo to give the 4-hydroxyphenylsulfanyl intermediate. A solution of this intermediate, iron powder and ammonium chloride in tetrahydrofuran and water was heated at reflux for about 3 hours. The resulting mixture was cooled and diluted with methanol and filtered. The filtrate was diluted with water and extracted with methylene chloride. The methylene chloride extracts were dried over magnesium sulfate, filtered and evaporated in vacuo to give the 4-hydroxy analog compound23.

Similarly, the compound 19 can be reacted with 4-aminotiphenol and cesium carbonate in N, N-dimethylformamide at a temperature of about 90 ° C for about 4 hours. After cooling to room temperature, the mixture was poured into ice water and acidified to pH 5 with 1N HCl. of hydrochloric acid. The solution was extracted with ethyl acetate, the extracts were dried over sodium sulfate, filtered, and evaporated in vacuo to give the corresponding 4-aminophenylsulfanyl-3-nitroanilide. The methylene chloride solution of this anilide was reacted with 2,2,2-trichloroethyl chloroformate and pyridine for about 16 hours. The solution was then washed with water, then with a saturated brine solution, and then the extracts were dried over sodium sulfate, filtered and evaporated in vacuo. The residue was triturated in hexane and ethyl acetate to give the corresponding Troc-amino-protected compound22. This Troc-protected amino compound was then dissolved in ethanol and tetrahydrofuran and reacted with iron powder and ammonium chloride at reflux for about 6 hours. The resulting mixture was cooled, diluted with ethanol and filtered. The filtrates were evaporated in vacuo to give a Troc-amino protected compound23.

Similarly, a solution of compound 19 in anhydrous N, N-dimethylformamide can also be reacted with 4-t-butoxycarbonylaminophenol (N-Boc-4-hydroxyaniline) and calcium carbonate at room temperature and then heated to about 80 ° C for about 5 hours. The reaction mixture was cooled to room temperature, the solvent was removed in vacuo and the residue was treated with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, filtered and evaporated in vacuo to give N-Boc protected compound20. Compound20 then dissolved in ethanol, tetrahydrofuran and water and reacted with iron powder and ammonium chloride, heating the mixture to about 90 ° C for about 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate, filtered, and the filtrate was washed with water and saturated saline. The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to give the condensing agent compound22.

Scheme 6

The optimum reaction conditions and reaction time in each individual step may vary depending on the particular reagents and substituents used in the reagents used. Unless otherwise indicated, the solvents, temperature and other reaction conditions can be readily determined and selected by one skilled in the art. The reaction mixtures can be treated by conventional methods, for example, separation of the solvent from the residue and subsequent purification according to methods commonly known in the art, such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography.

It should be appreciated that the above-described embodiments and diagrams and the following examples are given for illustrative purposes only, and not for limitation. From the description provided to those skilled in the art, various changes and modifications within the scope of the present invention will become apparent.

The optimum reaction conditions and the reaction time of each individual step may vary depending on the particular reagents and substituents used in the reagents used. Unless otherwise indicated, solvents, temperatures and other reaction conditions can be readily selected by a person skilled in the art. The reactions can be carried out by conventional means, for example removing the solvent from the precipitate and further purification by techniques commonly used in the art, such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography.

It should be noted that the above-described embodiments and schemes, as well as the following examples, are given by way of example only and are not limiting. Various changes and modifications without departing from the scope of the present invention will be apparent to one skilled in the art based on this disclosure.

Example 1

(7-Methyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) amine

Example 1a

Diethyl 2 - [(6-methyl-pyridin-2-ylamino) -methylene] malonic acid

A mixture of 2-methyl-5-aminopyridine (12.48 g, 115 mmol) and diethyl 2-ethoxymethylenemalonic acid (7.46 mL, 89.2 mmol) was heated at 100 ° C with stirring for 2.5 hours. Cool to room temperature and dilute with hexane. Filtrated and dried in vacuo to give the title compound (21.05 g, 85%).

Example 1b

Ethyl 7-methyl-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester

The diphenyl ether solution was heated to a temperature of 250 ° C. and the product of Example 1a (2.50 g, 9.0 mmol) was added in a few small portions over about 5 minutes, then heated at 250 ° C. for 30 minutes. After cooling to room temperature, it was diluted with hexane. The resulting solid was filtered and dried in vacuo to give the title compound as a tan solid (1.47 g, 71%).

Example 1c

7-Methyl- [1,8] naphthyridin-4-ol

A solution of the product of example 1b (1.30 g, 5.59 mmol) and NaOH (233 mg, 5.82 mmol) in 20 ml water was heated in a sealed metal reactor at a temperature of 180 ° C for 16 hours. Cool to room temperature and adjust the pH to 6 with 1N HCl. HCl. The precipitate which formed was filtered and dried in vacuo to give the title compound as a dark colored solid (743 mg, 82%).

Example 1d

5-Chloro-2-methyl- [1,8] naphthyridine

A mixture of the product of example 1c (320 mg, 2.0 mmol) in 6 ml of POCl3 was heated at 50 ° C with stirring for 6 hours. Cool to room temperature and quench, pouring on ice. The pH was adjusted to pH 10 with NH4OH and extracted with CH2Cl2. Dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a tan solid (322 mg, 90%).

Example 1e

4-Methyl-2-nitro-1-phenylsulfanyl-benzene

A solution of sodium thiophenolate (3.96 g, 30 mmol) in 60 ml of DMF was heated at 50 ° C. with 4-chloro-3-nitrotoluene (2.65 ml, 20 mmol) with stirring for 2 days. Cool to room temperature and dilute CH2Cl2. Wash with water and dry the organic layer over Na2SO4. Filtrated and concentrated in vacuo to give the title compound (4.29 g, 87%)11H NMR (300 MHz, CDCl33) δ ppm: 2.36 (s, 3H), 6.76 (d, J = 8.09 Hz, 1H), 7.16 (d, J = 8.46 Hz, 1H), 7, 45 (m, 3H), 7.58 (m, 2H), 8.03 (s, 1H).

Example 1f

5-Methyl-2-phenylsulfanyl-phenylamine

A solution of the product of Example 1e (1.17 g, 7.0 mmol) in 25 ml of absolute EtOH and SnCl2 (3.58 g, 29.8 mmol) was stirred at room temperature for 16 hours. The pH was adjusted to 12 with 1N HCl. NaOH and extracted with EtOAc. Dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (835 mg, 82%) 11H NMR (300 MHz, CDCl33) δ ppm: 2.30 (2, 3H), 6.62 (d, J = 8.83 Hz, 1H), 6.69 (s, 1H), 7.10 (m, 3H), 7.21 (m, 2H), 7.54 (d, J = 7.72 Hz, 2H).

Example 1g

(7-Methyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) amine

A stirred solution of the product of Example 1d (65 mg, 0.36 mmol) and the product of Example 1f (77 mg, 0.36 mmol) in 3 mL EtOH was heated at 80 ° C. for 7 hours. Concentrated in vacuo. Recrystallized from THF with a few drops of MeOH. Filtration gave the title compound as a hydrochloride salt as a white solid (62 mg, 43%).11H NMR (300 MHz, CDCl33) δ ppm: 1.62 (br s, 1H), 2.43 (s, 3H), 2.52 (s, 3H), 6.02 (d, J = 7.0 Hz, 1H ), 7.05-7.35 (m, 8H), 7.70 (brs, 1H), 8.00 (d, J = 7.0Hz, 1H), 8.85 (d, J = 8.5 Hz, 1H), 10.80 (br s, 1H); MS (ESI +) m / z 358 (M-Cl) +; (ESI-) m / z 356 (M-HCl) -.

Example 2

(5-Methyl-2-phenylsulfanyl-phenyl) - (7-propyl- [1,8] naphthyridin-4-yl) amine

Example 2a

2- (2,5-Dimethyl-pyrrol-1-yl) -6-methyl-pyridine

A solution of 2-methyl-5-aminopyridine (5.0 g, 46 mmol) and hexane-2,5-dione (5.4 mL, 46 mmol) in 60 mL of benzene was treated with HOAc (0.5 mL, 7.9 mmol ). The solution was heated at reflux with azeotropic distillation of water for 20 hours. The mixture was cooled to room temperature and diluted with ether. Wash with dilute HCl and water. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the title compound (4.7 g, 55%).

Example 2b

2- (2,5-Dimethyl-pyrrol-1-yl) -6-propyl-pyridine

A solution of the product of Example 2a (7.53 g, 40.0 mmol) in 30 ml dry THF was added dropwise with stirring to a solution of LDA (42.4 mmol) in 30 ml dry THF at -30 ° C. The mixture was stirred at -30 ° C for 30 minutes. Etl (3.42 mL, 42.0 mmol) in 20 mL of dry THF was added dropwise with stirring for 30 minutes, then warmed to room temperature. After 2 hours, quenched, poured into a saturated NaCl solution, and extracted with ether. Dry over MgSO44, filtered and concentrated in vacuo to give the title compound. The product was purified by chromatography on a silica gel column, eluting with EtOAc / hexane, to give the title compound (5.21 g, 60%).

Example 2c

6-Propyl-pyridin-2-ylamine

A solution of the product of example 2b (348 mg, 1.52 mmol) and NH2OH HCl (530 mg, 7.62 mmol) in a mixture of 4 ml EtOH / 1.5 ml water was heated at 100 ° C for 16 h, cooled to room temperature and extracted with CH2Cl2. Dry over MgSO44, filtered and concentrated in vacuo to give the title compound as an amber oil (223 mg, 100%).

Example 2d

Diethyl 2 - [(6-propyl-pyridin-2-ylamino) -methylene] malonic acid

The product of Example 2c (223 mg, 1.52 mmol) was reacted with diethyl 2-ethoxymethylenemalonic acid (0.350 mL, 1.75 mmol) according to the method described in Example 1a, followed by chromatography on a silica gel column, eluting with EtOAc / hexane, the title compound (386 mg, 80%).

Example 2e

4-Oxo-7-propyl-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester

The product of Example 2d (6.87 g, 22.4 mmol) was heated in diphenyl ether according to the method described in Example 1b to give the title compound as a tan solid (4.73 g, 81% ).

Example 2f

7-Propyl- [1,8] naphthyridin-4-ol

The product of Example 2e (4.73 g, 18.1 mmol) was reacted with NaOH (756 mg, 18.9 mmol) according to the method described in Example 1c to give the title compound as a solid (3 , 42 g, 100%).

Example 2g

5-Chloro-2-propyl- [1,8] naphthyridine

The product of Example 2f (145 mg, 0.76 mmol) was reacted with 4 ml of POCl3 in accordance with the method described in Example 1d, to obtain the title compound as a solid (135 mg, 86%).

Example 2h

(5-Methyl-2-phenylsulfanyl-phenyl) - (7-propyl- [1,8] naphthyridin-4-yl) amine

The product of Example 2g (65 mg, 0.31 mmol) was reacted with the product of Example 1f (68 mg, 0.31 mmol) for 24 hours according to the method described in Example 1g to give the title compound in a hydrochloride salt, a solid which was triturated in ether to give (110 mg, 84%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (t, J = 7.35 Hz, 3H), 2.38 (quint, J = 7.35 Hz, 2H), 2.99 (dd, J = 7, 35 Hz, J = 7.72 Hz, 2H), 6.31 (d, J = 7.35 Hz, 1H), 7.23 (s, 5H), 7.35 (m, 4H), 7.79 (d, J = 8.46 Hz, 1H), 8.38 (d, J = 6.98 Hz, 1H), 9.01 (d, J = 8.46 Hz, 1H), 11.10 (s , 1H), 14.35 (brs, 1H); MS (ESI +) m / z 386 (M-Cl) +; (ESI-) m / z 384 (M-HCl) -.

Example 3

(7-Ethyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) amine

Example 3a

2- (2,5-Dimethyl-pyrrol-1-yl) -6-ethyl-pyridine

To a solution of the product of Example 2a (6.82 g, 36.6 mmol) in 75 ml of dry THF cooled to -40 ° C under N2 n-BuLi was added dropwise as a 2.5 M solution in hexane (16 mL, 40 mmol). The resulting solution was stirred at reduced temperature for thirty minutes, then treated with CH3I (2.4 mL, 38.6 mmol). After completion of the addition, the mixture was allowed to warm to -30 ° C and 20 minutes to room temperature. The reaction was then quenched by pouring into a saturated saline solution, the product was isolated by extraction with EtOAc. Dry over MgSO44, filtered and concentrated in vacuo. Purification by chromatography on a silica gel column, eluting with EtOAc / hexane, gave the title compound (4.42 g, 60%).

Example 3b

6-Ethyl-pyridin-2-ylamine

The product of Example 1a (4.93 g, 0.025 mol) was dissolved in a mixture of EtOH (80 ml) and water (30 ml). Hydroxylamine hydrochloride (8.6 g, 0.123 mol) was added and the resulting mixture was heated to 100 ° C. for 8 hours. The reaction mixture was poured into a dilute solution of sodium hydroxide, the crude product was isolated by extraction with CH2Cl2 and dried over MgSO4, filtered and concentrated in vacuo to give the title compound. The product was used as it was isolated.

Example 3c

Diethyl 2 - [(6-ethyl-pyridin-2-ylamino) -methylene] malonic acid

The crude product of Example 3b was combined with diethyl 2-ethoxymethylenemalonic acid (6.6 ml, 0.032 mol) and the mixture was heated under N2 on an oil bath at a temperature of 100 ° C for 2 hours. Purification by flash chromatography on silica gel, eluting with EtOAc / hexane, to give the title compound (7.16 g, 98%).

Example 3d

7-Ethyl-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester

The product of Example 3c (7.16 g, 0.024 mol) was heated in diphenyl ether according to the method described in Example 1b to give the title compound (4.73 g, 79%) as a tan solid.

Example 3e

7-Ethyl- [1,8] naphthyridin-4-ol

The product of Example 3d (4.70 g, 19.1 mmol) was reacted with NaOH (0.808 g, 20.2 mmol) according to the method of Example 1c to give the title compound as a light green solid (2.43 g, 73%).

Example 3f

5-Chloro-2-ethyl- [1,8] naphthyridine

The product of Example 3e (200 mg, 1.14 mmol) was treated with POCl3 in accordance with the method described in Example 1d, to give the title compound as a brown solid (183 mg, 83%).

Example 3g

(7-Ethyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) amine

The product of Example 3f (88 mg, 0.46 mmol) was reacted with the product of Example 1f (100 mg, 0.46 mmol) for 24 hours according to the method described in Example 1f to give the title compound in as a hydrochloride salt, which was triturated in ether (134 mg, 70%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.34 (t, J = 7.35 Hz, 3H), 3.02 (q, J = 7.35 Hz, 2H), 6.69 (d, J = 6.99 Hz, 1H), 6.97 (d, J = 8.82 Hz, 2H), 7.10 (dd, J = 7.35 Hz, 1H), 7.15 (d, J = 8.82 Hz, 2H), 7.30 (dd, J = 8.09Hz, J = 7.72Hz, 2H), 7.56 (dd, J = 2.94Hz, J = 9.19Hz, 1H), 7 , 71 (d, J = 2.57 Hz, 1H), 7.88 (d, J = 8.82 Hz, 1H), 8.52 (d, J = 6.99 Hz, 1H), 9.02 (d, J = 8.45 Hz, 1H), 11.16 (brs, 1H), 14.56 (brs, 1H); MS (ESI +) m / z 376 (M-Cl) +; (ESI-) m / z 374 (M-HCl) -.

Example 4

4- [2- (7-Ethyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenol

Example 4a

4-Methyl-2-nitro-phenyl ester of trifluoro-methanesulfonic acid

A solution of 4-methyl-2-nitrophenol (6.0 g, 39.1 mmol) and Et3N (16.38 ml, 117.5 mmol) in 100 ml CH2Cl2 in the atmosphere N2 was treated with trifluoromethanesulfonic acid anhydride (7.25 ml, 43.1 mmol) at 0 ° C for 30 min. Quenched by the addition of MeOH. Was washed successively with 10% citric acid, 0.5 M KOH and water. Dry over MgSO44, filtered and concentrated in vacuo to give the title compound, which was purified by chromatography on a silica gel column, eluting with CH2Cl2, which gave an amber oil (11.22 g, 100%).

Example 4b

4- (4-Methyl-2-nitro-phenylsulfanyl) -phenol

The product of Example 4a (11.22 g, 39.3 mmol) and 4-mercaptophenol (4.96 g, 39.3 mmol) in 100 mL of EtOH was treated with Na2CO3 and heated overnight under reflux. Cool to room temperature and quench with water. It was extracted with EtOAc. Dry over MgSO44, filtered and concentrated in vacuo to give the title compound, which was purified by chromatography on a silica gel column, eluting with 25% EtOAc / hexane to give a red oil (8.65 g, 85%).

Example 4c

4- (2-Amino-4-methyl-phenylsulfanyl) -phenol

The product of Example 4b (8.65 g, 31.3 mmol) was reduced with SnCl2 in accordance with the method described in Example 1f, to give the title compound as a white solid (8.51 g, 100%).

Example 4d

4- [2- (7-Ethyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenol

The product of Example 4c (131 mg, 0.530 mmol) was reacted with the product of Example 3f (97 mg, 0.503 mmol) for 21 hours according to the method described in Example 1g to give the title compound as the hydrochloride salt, which was triturated in a 5: 1 ether / THF mixture (210 mg, 98%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.37 (t, J = 7.35 Hz, 3H), 2.33 (s, 3H), 3.05 (q, J = 7.35 Hz, 2H), 6, 29 (d, J = 6.99 Hz, 1H), 6.74 (d, J = 8.46 Hz, 2H), 7.00 (m, 1H), 7.17-7.29 (m, 4H ), 7.84 (d, J = 8.83 Hz, 1H), 8.43 (d, J = 6.98 Hz, 1H), 9.09 (d, J = 8.83 Hz, 1H), 9.90 (s, 1H), 11.12 (brs, 1H), 14.38 (brs, 1H); MS (ESI +) m / z 388 (M-Cl) +; (ESI-) m / z 386 (M-HCl) -.

Example 5

4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 1d (277 mg, 0.156 mmol) was reacted with the product of Example 4c (361 mg, 0.156 mmol) for 5 hours in the same manner as described in Example 1g, and after purification of the crude product by HPLC with TFA, the title a compound in the form of a salt of trifluoroacetic acid (231 mg, 30%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.33 (s, 3H), 2.77 (s, 3H), 6.29 (d, J= 6.99 Hz, 1H), 6.73 (d, J= 8.82 Hz, 2H), 7.01 (d, J= 7.72 Hz, 1H), 7.19 (d, J= 8.46 Hz, 2H), 7.24 (s, 1H), 7.27 (s, 1H), 7.81 (d, J= 8.82 Hz, 1H), 8.44 (d, J= 6.99 Hz, 1H), 9.01 (d, J= 8.82 Hz, 1H), 9.91 (s, 1H), 11.03 (s, 1H), 14.38 (brs, 1H); MS (ESI +) m / z 374 (M + H) +.

Example 6

4- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol

The product of Example 2g (275 mg, 0.133 mmol) was reacted with the product of Example 4c (231 mg, 0.133 mol) for 5 hours according to the method described in Example 1g, and after purification of the crude product by HPLC with TFA, The title compound was obtained as a trifluoroacetic acid salt (288 mg, 42%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J= 7.35 Hz, 2H), 1.85 (m, 2H), 2.33 (s, 3H), 3.00 (t, J= 7.35 Hz 2H), 6.29 (d, J= 6.99 Hz, 1H), 6.73 (d, J= 8.46 Hz, 2H), 7.00 (m, 2H), 7.19 (d, J= 8.46 Hz, 2H), 7.27 (s, 1H), 7.83 (d, J= 8.82 Hz, 1H), 8.43 (d, J= 7.35 Hz, 1H), 9.04 (d, J= 8.46 Hz, 1H), 9.90 (s, 1H), 11.04 (s, 1H), 14.40 (brs, 1H); MS (ESI +) m / z 402 (M + H) +.

Example 7

(5-Methyl-2-phenylsulfanyl-phenyl) - (7-trifluoromethyl- [1,8] naphthyridin-4-yl) amine

Example 7a

2,6-Dibromo-nicotinic acid

A sample of 2,6-dichloro-nicotinic acid (2.50 g, 13.0 mmol) was reacted with 25 ml of a 30% HBr / HOAc mixture in a sealed metal reactor at a temperature of 110 ° C for 2 hours at 177 psi . The mixture was cooled to room temperature, extracted with EtOAc and washed with water. Dry over MgSO44, filtered and concentrated in vacuo to give the title compound as a solid (3.22 g, 88%).

Example 7b

Ethyl 7-bromo-1-t-butyl-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester

The product of Example 7a was subjected to the sequence of reactions described in US Pat. No. 6,818,654, to obtain the title compound.

Example 7c

Ethyl 1-tert-butyl-4-oxo-7-trifluoromethyl-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester

The product of Example 7b (101 mg, 0.28 mmol) was reacted with difluoro-fluorosulfonylacetic acid methyl ester (0.132 ml, 1.43 mmol) in 2 ml DMF with CuI (71 mg, 0.37 mmol) at a temperature 75 ° C for 15 hours in an atmosphere of N2, to give the title compound as a solid (57 mg, 59%).

Example 7d

5-Chloro-2-trifluoromethyl- [1,8] naphthyridine

The product of Example 7c was deprotected with trifluoroacetic acid according to the method described in Example 16b and then treated using the methods described in Examples 1b-1d to give the title compound as a solid (142 mg, 87%). The yield is indicated for the last stage of the reaction sequence.

Example 7e

(5-Methyl-2-phenylsulfanyl-phenyl) - (7-trifluoromethyl- [1,8] naphthyridin-4-yl) amine

The product of Example 7d (65 mg, 0.28 mmol) and the product of Example 1f (61.5 mg, 0.28 mmol) were reacted for 28 hours in accordance with the method described in Example 1g and, after trituration in ether, the in the title compound as hydrochloride salt (131 mg, 99%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 6.43 (d, J = 6.99 Hz, 1H), 7.23 (m, 4H), 7.35 (m, 4H), 8.39 (d, J = 8 , 82 Hz, 1H), 8.55 (d, J = 6.99 Hz, 1H), 9.48 (d, J = 8.46 Hz, 1H), 11.55 (br s, 1H); MS (ESI +) m / z 412 (M-Cl) +; (ESI-) m / z 410 (M-HCl) -.

Example 8

(7-Isopropyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) amine

Example 8a

2- (2,5-Dimethylpyrrol-1-yl) -6-isopropylpyridine

The product of Example 12b (1.5 g, 7.26 mmol) was reacted with isopropylmagnesium bromide (4.35 ml, 8.7 mmol) according to the method described in Example 12c, after 1 hour, a second loading was added from the Grignard reagent and an iron-based catalyst, to obtain the title compound. The product was purified by chromatography on a silica gel column, eluting with 2% EtOAc / hexane (880 mg, 56%).

Example 8b

5-Chloro-2-isopropyl- [1,8] naphthyridine

The product of Example 8a was sequentially treated using the methods described in Examples 2c-2g to obtain the title compound.

Example 8c

(7-Isopropyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) amine

The product of Example 8b (0.098 g, 0.475 mmol) was reacted with the product of Example 1f (0.102 g, 0.475 mmol) for 18 h according to the method described in Example 1g to give the title compound, which was purified by HPLC with TFA. It was transferred to the hydrochloride salt by treatment with 4N hydrochloric acid. HCl in dioxane at room temperature, a hydrochloride salt (0.076 g, 38%) was obtained.11H-NMR (300 MHz, DMSO-d6th) δ ppm. 1.37 (d,J= 6.99 Hz, 6H), 2.38 (s, 3H), 3.30 (m, 1H), 6.32 (d, J= 6.99 Hz, 1H), 7.24 (s, 5H), 7.34 (m, 3H), 7.86 (d, J= 8.82 Hz, 1H), 8.39 (d, J= 7.35 Hz, 1H), 9.08 (d, J= 8.46 Hz, 1H), 11.16 (s, 1H), 14.36 (m, 1H); MS (ESI +) m / z 386.0 (M + H) +.

Example 9

(5-Methoxy-2-phenylsulfanyl-phenyl) - (7-methyl- [1,8] naphthyridin-4-yl) amine

Example 9a

4-Methoxy-2-nitro-1-phenylsulfanyl-benzene

A solution of 1-chloro-4-methoxy-2-nitrobenzene (3.75 g, 20.0 mmol) was reacted with sodium thiophenolate (3.96 g, 30.0 mmol) at 70 ° C for 48 h in accordance with the method described in Example 1e, to give the title compound as a yellow oil after chromatography on a silica gel column, eluting with 25% EtOAc / hexane (2.70 g, 54%).

Example 9b

5-Methoxy-2-phenylsulfanyl-phenylamine

The product of Example 9a (2.70 g, 10.2 mmol) was reacted with SnCl2 (9.40 g, 50.0 mmol) for 22 hours according to the method described in Example 1f to give the title compound as a white solid (2.28 g, 96%).

Example 9c

(5-Methoxy-2-phenylsulfanyl-phenyl) - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 9b (69 mg, 0.30 mmol) was reacted with the product of Example 1d (53 mg, 0.30 mmol) according to the method described in Example 1g to give the title compound as the hydrochloride salt after trituration with a solid (119 mg, 96%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.75 (s, 3H), 3.83 (s, 3H), 6.34 (d, J = 6.99 Hz, 1H), 7.07 (m, 7H), 7.57 (d, J = 8.46 Hz, 1H), 7.76 (d, J = 8.46 Hz, 1H), 8.85 (d, J = 6.99 Hz, 1H), 8, 99 (d, J = 8.46 Hz, 1H), 11.16 (brs, 1H), 14.43 (br s, 1H); MS (ESI +) m / z 374 (M-Cl) +; (ESI-) m / z 372 (M-HCl) -.

Example 10

Ethyl 7-methyl-4- (5-methyl-2-phenylsulfanyl-phenylamino) - [1,8] naphthyridine-3-carboxylic acid

Example 10a

4-Chloro-7-methyl- [1,8] naphthyridine-3-carboxylic acid ethyl ester

The product of Example 1b (1.0 g, 4.30 mmol) was reacted with 12 ml of POCl3 for 4 hours in accordance with the method described in Example 1d to give the title compound as a brownish pink solid (619 mg, 57%).

Example 10b

Ethyl 7-methyl-4- (5-methyl-2-phenylsulfanyl-phenylamino) - [1,8] naphthyridine-3-carboxylic acid

The product of Example 10a (438 mg, 2.03 mmol) was reacted with the product of Example 1f (510 mg, 2.03 mmol) for 10 minutes according to the method described in Example 1g to obtain the title compound, which was purified by chromatography on a silica gel column, eluting with 4% MeOH / CH2Cl2, as a solid (114 mg, 57%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.33 (t, J = 6.99 Hz, 3H), 2.16 (s, 3H), 2.62 (s, 3H), 4.29 (q, J = 7 , 11 Hz, 2H), 6.86 (s, 1H), 7.04 (d, J = 8.09 Hz, 1H), 7.15-7.34 (m, 6H), 7.39 (d , J = 7.72 Hz, 1H), 7.69 (d, J = 8.82 Hz, 1H), 9.17 (s, 1H), 10.13 (s, 1H); MS (ESI +) m / z 430 (M + H) +, (ESI-) m / z 428 (MH) -.

Example 11

7-Methyl-4- (5-methyl-2-phenylsulfanyl-phenylamino) - [1,8] naphthyridine-3-carboxylic acid methoxy-methyl-amide

Example 11a

7-Methyl-4- (5-methyl-2-phenylsulfanyl-phenylamino) - [1,8] naphthyridine-3-carboxylic acid

The product of Example 10 (250 mg, 0.58 mmol) was reacted with 2 mL of 1N HCl. NaOH in 4 ml of dioxane at 65 ° C for 30 min. Cool to room temperature and dilute with water, set to pH 3 with 1N HCl. HCl, and the resulting solid product was isolated by vacuum filtration to obtain the title compound (215 mg, 92%).

Example 11b

7-Methyl-4- (5-methyl-2-phenylsulfanyl-phenylamino) - [1,8] naphthyridine-3-carboxylic acid methoxy-methyl-amide

The product of Example 11a (50.5 mg, 0.125 mmol) was reacted with 1,1'-carbonyldiimidazole (40.8 mg, 0.215 mmol) in 2 ml of DMF under N2 within 30 minutes. N, O-dimethylhydroxylamine hydrochloride (25 mg, 0.215 mmol) was added and stirred at room temperature for 24 hours. The solvent was concentrated in vacuo to give the title compound. After purification of the crude product by HPLC with AA, the product was isolated as a free base (12 mg, 21%).11H NMR (300 MHz, DMSO-D6) δ ppm: 2.23 (s, 3H), 2.67 (s, 3H), 2.89 (s, 3H), 3.39 (s, 3H ), 6.86 (s, 1H), 6.91-7.04 (m, 1H), 7.15-7.35 (m, 7H), 7.44 (d, J= 8.46 Hz, 1H), 8.34 (d, J= 8.09 Hz, 1H), 8.67 (s, 1H); MS (ESI +) m / z 445 (M + H)+, 467 (M + Na)+, MS (ESI-) m / z 443 (MH)-.

Example 12

4- [2- (7-Isobutyl- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol

Example 12a

6-Chloro-pyridin-2-ylamine

A solution of 2,6-dichloropyridine (500 g, 3.37 mol) was treated with NH4OH in a sealed metal reactor at a temperature of 180 ° C for 40 hours. After cooling to room temperature, the product was isolated by suction filtration to give the title compound as a solid (400 g, 92%).

Example 12b

2-Chloro-6- (2,5-dimethylpyrrole-1-yl) pyridine

The product of Example 12a (20 g, 156 mmol) was treated with hexane-2,5-dione (18.3 ml, 156 mmol) for 2 hours according to the method described in Example 2a, to give the title compound (17 , 7 g, 55%).

Example 12c

2- (2,5-Dimethyl-pyrrol-1-yl) -6-isobutyl-pyridine

The product of Example 12b (1.0 g, 4.84 mmol) was treated with 2.0 M isobutylmagnesium chloride (2.90 mL, 5.81 mmol) in 30 mL THF and 3 mL NMP at room temperature under N2. Fe (acac)3 (85 mg, 0.242 mmol) and stirred at room temperature for 18 hours. During the course of the reaction, two additional loads of the Grignard reagent and the catalyst were carried out. The reaction was quenched by pouring into 5% acetic acid and extracting with ether. Dried over Na2SO4, filtered and concentrated in vacuo to give the title compound, which was purified by chromatography on a silica gel column, eluting with 10% EtOAc / hexane (620 mg, 56%).

Example 12d

5-Chloro-2-isobutyl- [1,8] naphthyridine

The product of Example 12c was sequentially treated using the methods described in Examples 2c-2g to obtain the title compound.

Example 12e

4- [2- (7-Isobutyl- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol

The product of Example 12d (100 mg, 45.3 mmol) was reacted with the product of Example 4c (105 mg, 45.3 mmol) for 18 hours according to the method described in Example 1g, and after purifying the crude product with HPLC with TFA, the title compound was obtained as a trifluoroacetic acid salt (90 mg, 47%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm. 0.97 (d,J= 6.62 Hz, 6H), 2.13-2.30 (m, 1H), 2.33 (s, 3H), 2.89 (d, J= 6.99 Hz, 2H), 6.29 (d, J= 6.99 Hz, 1H), 6.73 (d, J= 8.46 Hz, 2H), 7.00 (d, J= 8.09 Hz, 1H), 7.13-7.34 (m, 4H), 7.81 (d, J= 8.46 Hz, 1H), 8.43 (d, J= 6.99 Hz, 1H), 9.03 (d, J= 8.46 Hz, 1H), 10.99 (brs, 1H), 14.36 (brs, 1H); MS (ESI +) m / z 416 (M + H) +; (ESI-) m / z 414 (MH) -.

Example 13

4- [2- (7-Ethoxy- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol

Example 13a

Ethyl 1-tert-butyl-7-chloro-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester

This compound was prepared starting from 2,6-dichloro-nicotinic acid as described in US Pat. No. 6,818,654, to obtain the title compound.

Example 13b

Ethyl 7-chloro-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester

The product of Example 13a (0.282 g, 0.91 mmol) was combined at room temperature with 2 ml of TFA containing 2 drops of sulfuric acid. The resulting mixture was heated at a temperature of 70 ° C for 16.5 hours. The volatile products were removed in vacuo and the residue was suspended in water. The product was collected by vacuum filtration, washed with water and dried in vacuo to afford the title compound as a cream-colored solid (0.214 g, 93%).

Example 13c

[1,8] Naphthyridine-2,5-diol

The product of Example 13b (0.208 g, 0.82 mmol) was reacted as described in Example 1c to give the title compound as a dark brown solid (0.196 g, 97%).

Example 13d

2,5-Dichloro [1,8] naphthyridine

The product of Example 13c (0.111 g, 0.68 mmol) was reacted as described in Example 1d to give the title compound as a pale yellow solid (0.124 g, 91%).

Example 13e

4- [2- (7-Chloro- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] phenol

The product of Example 13d (0.67 g, 3.36 mmol) and the product of Example 4c (0.78 g, 3.36 mmol) in 10 ml ethanol was heated at reflux for 5.5 hours. The reaction mixture was cooled to room temperature and the solvent was removed by concentration in vacuo to give a yellow solid which was used without further purification (1.43 g, 100%) as a residue.

Example 13f

4- [2- (7-Ethoxy- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol

The product of Example 13e (0.025 g, 0.063 mmol) was treated with 2 ml of 21% by weight of NaOEt in EtOH. The resulting mixture was heated at boiling temperature for 4 hours. The solvent was concentrated in vacuo to give an oily residue of a brown color. The crude oil was purified by HPLC with TFA. The title compound was isolated as a trifluoroacetic acid salt to give a light brown powder (20 mg, 78%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.44 (t, J = 6.99 Hz, 3H), 2.32 (s, 3H), 4.56 (q, J = 6.99 Hz, 2H), 6, 24 (d, J = 6.99 Hz, 1H), 6.68-6.81 (m, 2H), 6.98 (d, J = 8.09 Hz, 1H), 7.05-7.34 (m, 3H), 7.34 (d, J = 9.19 Hz, 1H), 8.30 (d, J = 6.99 Hz, 1H), 8.92 (d, J = 9.19 Hz) , 1H), 10.81 (s, 1H), 14.17 (s, 1H); MS (ESI +) m / z 404 (M + H) +; (ESI-) m / z 402 (M + H) -.

Example 14

4- [2- (2,7-Dimethyl- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol

Example 14a

2,7-Dimethyl-1H- [1,8] naphthyridin-4-one

The vessel containing 2-methyl-5-aminopyridine (5.0 g, 46.2 mmol) and ethyl acetoacetate (6.54 mL, 552.3 mmol) and 5 mL of polyphosphoric acid were heated at 120 ° C for 2 hours . It was cooled to room temperature and poured into water, neutralized with 1N HCl. NaOH. Extracted CH2Cl2, dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil which was heated in diphenyl ether at 250 ° C. for 1 hour. The mixture was cooled to room temperature, diluted with hexane, and the product was isolated by suction filtration to give the title compound, which was used without purification.

Example 14b

4-Chloro-2,7-dimethyl- [1,8] naphthyridine

The product of Example 14a (500 mg, 2.87 mmol) was reacted with 10 ml of POCl3 for 2 hours in accordance with the method described in Example 1d to give the title compound, which was used without purification.

Example 14c

4- [2- (2,7-Dimethyl- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol

The product of Example 14b (60 mg, 0.31 mmol) was reacted with the product of Example 4c (72 mg, 0.31 mmol) for 12 hours according to the method described in Example 1g to obtain the title compound in as a crude solid which was purified by HPLC using TFA to give the product as a trifluoroacetic acid salt (45 mg, 37%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.23 (s, 3H), 2.75 (s, 3H), 3.43 (s, 3H), 6.10 (s, 1H), 6.68 (d, J= 8.82 Hz, 2H), 6.99-7.20 (m, 3H), 7.20-7.38 (m, 2H), 7.75 (d, J= 8.82 Hz, 1H), 8.96 (d, J= 8.82 Hz, 1H), 9.86 (s, 1H), 10.78 (s, 1H), 14.21 (s, 1H); MS (APCI) m / z 386 (MH) -.

Example 15

4- [2- (7-Methoxy- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol

Example 15a

4- [2- (7-Chloro- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol

The product of Example 13e (670 mg, 3.36 mmol) was reacted with the product of Example 4c (780 mg, 3.36 mmol) for 5.5 hours in accordance with the method described in Example 1g to give the title of the compound as the hydrochloride salt (1.43 g, 100%).

Example 15b

4- [2- (7-Methoxy- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol

The product of Example 15a (0.100 g, 0.254 mmol) was treated with 5 ml of methanol and powdered NaOMe (95%, 0.27 g, 5 mmol). The resulting mixture was heated at reflux temperature for 18 hours. The solvent was concentrated in vacuo to give an oily residue of an orange color. The crude oil was purified by HPLC (gradient from 0 to 95% CH3CN / 0.1% TFA) to obtain the title compound as the trifluoroacetic acid salt, which was isolated as a yellow powder (75 mg, 76%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.32 (s, 3H), 4.10 (s, 3H), 6.25 (d, J = 7.35 Hz, 1H), 6.65-6.81 (m , 3H), 6.99 (d, J = 8.09 Hz, 1H), 7.13-7.29 (m, 3H), 7.38 (d, J = 9.19 Hz, 1H), 8 , 30 (d, J = 7.35Hz, 1H), 8.94 (d, J = 9.19Hz, 1H), 9.89 (s, 1H), 10.81 (s, 1H), 14 , 21 (s, 1H); MS (ESI +) m / z 390 (M + H) +; (ESI-) m / z 388 (M + H) -.

Example 16

4- [4-Methyl-2 - ([1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

Example 16a

Ethyl 1-tert-butyl-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester

A sample of 2-chloro-nicotinic acid was subjected to the sequence of reactions described in US Pat. No. 6,818,654, to obtain the title compound.

Example 16b

Ethyl 4-hydroxy- [1,8] naphthyridine-3-carboxylic acid ethyl ester

The product of Example 16a (6.36 g, 23.1 mmol) was reacted with 50 ml of trifluoroacetic acid and 1 ml of H2SO4 for 1 hour at room temperature. The solvent was concentrated in vacuo to give the title compound as a solid (5.05 g, 99%).

Example 16c

4-Chloro- [1,8] naphthyridine

The product of Example 16b was reacted according to the methods of Example 1c and Example 1d to obtain the title compound as a solid (106 mg, 96%).

Example 16d

4- [4-Methyl-2 - ([1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 16c as a 0.9 M solution in methanol (0.080 mL, 0.07 mmol) was reacted with the product of Example 4c as a 0.7 M solution in ethanol (0.100 mL, 0.07 mmol) for 18 hour according to the method described in Example 1g to give the crude product, which was purified by HPLC with TFA, to give the title compound as the trifluoroacetic acid salt (0.017 g, 51%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.33 (s, 3H), 6.33 (d, J= 6.99 Hz, 1H), 6.69-6.78 (m, 2H), 7.02 (d, J= 8.09 Hz, 1H), 7.16-7.20 (m, 2H), 7.23-7.29 (m, 2H), 7.92 (dd, J= 8.46, 4.41 Hz, 1H), 8.51 (d, J= 6.99 Hz, 1H), 9.10-9.23 (m, 2H), 11.14 (s, 1H); MS (ESI +) m / z 360.0 (M + H) +, (ESI-) m / z 358.1 (MH) -.

Example 17

4- [2- (7-Isopropyl- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol

The product of Example 8b (100 mg, 0.435 mmol) was reacted with the product of Example 4c (105 mg, 0.435 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, yielding a trifluoroacetic acid salt (90 mg, 47%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (d, J= 6.62 Hz, 6H), 2.13-2.30 (m, 1H), 2.33 (s, 3H), 2.89 (d, J= 6.99 Hz, 2H), 6.29 (d, J= 6.99 Hz, 1H), 6.73 (d, J= 8.46 Hz, 2H), 7.00 (d, J= 8.09 Hz, 1H), 7.13-7.34 (m, 4H), 7.81 (d, J= 8.46 Hz, 1H), 8.43 (d, J= 6.99 Hz, 1H), 9.03 (d, J= 8.46 Hz, 1H), 10.99 (brs, 1H), 14.36 (brs, 1H); MS ESI + m / z 416 (M + H) +; ESI-m / z 414 (MH) -.

Example 18

N- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 18a

N- [4- (4-Methyl-2-nitro-phenylsulfanyl) -phenyl] -acetamide

The product of Example 4a (1 g, 3.51 mmol) was reacted with N- (4-mercapto-phenyl) -acetamide (0.65 g, 351 mmol) for 18 hours according to the method described in Example 4b, to obtain the title compound (1.04 g, 98%).

Example 18b

N- [4- (2-Amino-4-methyl-phenylsulfanyl) -phenyl] -acetamide

The product of Example 18a (0.30 g, 1 mmol) was reacted with SnCl2, as described in Example 1f, to obtain the title compound (0.27 g, 100%) as an amber oil which was used without further purification.

Example 18c

N- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 18b (0.27 g, 1 mmol) was combined with the product of Example 1d (0.178 g, 1 mmol) and reacted according to the method described in Example 1g to give the crude product as a brown solid, which was purified by HPLC with TFA to give the trifluoroacetic acid salt, which was converted to the hydrochloride salt by treatment with 4N hydrochloric acid. HCl in dioxane at room temperature to give the title compound (40.0 mg, 7.5%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.04 (s, 3H), 2.35 (s, 3H), 2.76 (s, 3H), 6.29 (d, J = 6.99 Hz, 1H), 7.24 (m, 5H), 7.50 (d, J = 8.82Hz, 2H), 7.78 (d, J = 8.82Hz, 1H), 8.40 (d, J = 6 , 99 Hz, 1H), 9.02 (m, 1H), 10.08 (s, 1H), 11.09 (s, 1H), 14.37 (s, 1H); MS (ESI +) m / z 415.1 (M + H) +, (ESI-) m / z 413.1 (M-H) -.

Example 19

N- {4- [2- (7-Ethyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide

The product of Example 3f (92 mg, 0.47 mmol) was reacted with the product of Example 18b (130 mg, 0.47 mmol) for 22 hours according to the method described in Example 1g to obtain the title compound in solid product after purification of the crude product by HPLC with TFA as the trifluoroacetic acid salt (68 mg, 26%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.37 (t, J = 7.72 Hz, 1H), 2.04 (s, 3H), 2.35 (s, 3H), 3.05 (q, J = 7 , 72 Hz, 2H), 6.31 (d, J = 6.98 Hz, 1H), 7.15 (d, J = 8.83 Hz, 1H), 7.20-7.35 (m, 3H ), 7.49 (d, J = 8.83 Hz, 2H), 7.82 (d, J = 8.82 Hz, 1H), 8.41 (d, J = 6.99 Hz, 1H), 8.99 (d, J = 8.82 Hz, 1H), 10.04 (s, 1H), 11.01 (brs, 1H), 14.39 (brs, 1H). MS (ESI +) m / z 429 (M + H-Cl) +; (ESI-) m / z 427 (MH-Cl) -.

Example 20

N- {4- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 2g (93 mg, 0.44 mmol) was reacted with the product of Example 18b (123 mg, 0.44 mmol) for 23 hours according to the method described in Example 1g, and after purification of the crude product with HPLC with TFA, the title compound was obtained as the trifluoroacetic acid salt of the solid product (72 mg, 29%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J = 7.35 Hz, 3H), 1.84 (dq, J = 14.75, 7.46 Hz, 2H), 2.04 (s, 3H), 2.35 (s, 3H), 2.99 (t, J = 7.35 Hz, 2H), 6.31 (d, J = 6.99 Hz, 1H), 7.15 (d, J = 8.09 Hz, 1H), 7.20-7.33 (m, 4H), 7.50 (d, J = 8.46 Hz, 2H), 7.81 (d, J = 8.46 Hz, 1H), 8.41 (d, J = 6.99 Hz, 1H), 9.00 (d, J = 8.46 Hz, 1H), 10.05 (s, 1H), 11.02 s, 1H); MS (ESI +) m / z 443 (M + H) +; (ESI-) m / z 441

(MH) -.

Example 21

N- {4- [4-Methyl-2- (7-trifluoromethyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

A solution of the product of Example 7d (50.0 mg, 0.215 mmol) and the product of Example 18b (59.0 mg, 0.215 mmol) in ethanol (2 ml) was stirred in an oil bath preheated to 80 ° C. for 16 hours. The mixture was then cooled to room temperature, ethanol was removed in vacuo and the resulting crude residue was purified by HPLC with TFA to give the title compound as the trifluoroacetic acid salt (22.0 mg, 22%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.03 (s, 3H), 2.32 (s, 3H), 6.33 (d, J= 5.52 Hz, 1H), 7.01 (d, J= 8.09 Hz, 1H), 7.15 (d, J= 8.46 Hz, 1H), 7.21-7.27 (m, 3H), 7.54 (d, J= 8.82 Hz, 2H), 8.01 (d, J= 8.46 Hz, 1H), 8.65 (d, J= 5.51 Hz, 1H), 9.17 (d, J= 8.46 Hz, 1H), 9.42 (s, 1H), 10.04 (s, 1H); MS (ESI +) m / z 469 (M + H-TFA) +, (ESI-) m / z 467 (MH-TFA) -.

Example 22

N- {4- [2- (7-sec-Butyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide

Example 22a

2-sec-Butyl-5-chloro- [1,8] naphthyridine

Example 22b

N- {4- [2- (7-sec-Butyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide

The product of Example 22a (50 mg, 0.226 mmol) was reacted with the product of Example 18b (62 mg, 0.226 mmol) for 16 hours according to the method described in Example 1g, to give the crude title compound, which was purified by HPLC in TFA, which gave the product as a trifluoroacetic acid salt (33 mg, 32%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.85 (t, J = 7.35 Hz, 3H), 1.35 (d, J = 6.99 Hz, 3H), 1.73 (dd, J = 13.60 , 6.99 Hz, 1H), 1.79-1.90 (m, 1H), 2.03 (s, 3H), 2.35 (s, 3H), 3.01-3.13 (m, 1H), 6.32 (d, J = 7.35Hz, 1H), 7.14 (d, J = 7.72Hz, 1H), 7.22-7.32 (m, 4H), 7, 51 (d, J = 8.82 Hz, 2H), 7.84 (d, J = 8.46 Hz, 1H), 8.41 (d, J = 6.99 Hz, 1H), 9.02 d, J = 8.46 Hz, 1H), 10.05 (s, 1H), 11.02 (s, 1H); MS (ESI +) m / z 457 (M + H) +, (ESI-) m / z 455 (MH) -.

Example 23

N- {4- [2- (7-Cyclopentyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide

Example 23a

5-Chloro-2-cyclopentyl- [1,8] naphthyridine

Example 23b

N- {4- [2- (7-Cyclopentyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide

The product of Example 23a (50 mg, 0.215 mmol) was reacted with the product of Example 18b (58 mg, 0.215 mmol) for 16 hours according to the method described in Example 1g to give the crude title compound which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (29 mg, 29%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.71-1.76 (m, 3H), 1.79-1.93 (m, 4H), 2.04 (s, 3H), 2.14 (d, J = 7.72 Hz, 2H), 2.35 (s, 3H), 6.31 (d, J = 6.99 Hz, 1H), 7.14 (d, J = 8.09 Hz, 1H), 7 , 21-7.32 (m, 4H), 7.51 (d, J = 8.82 Hz, 2H), 7.84 (d, J = 8.82 Hz, 1H), 8.40 (d, J = 6.99 Hz, 1H), 8.99 (d, J = 8.46 Hz, 1H), 10.05 (s, 1H), 11.00 (s, 1H); MS (ESI +) m / z 469 (M + H) +, (ESI-) m / z 467 (MH) -.

Example 24

N- (4- {2- [7- (2-Hydroxy-ethyl) - [1,8] naphthyridin-4-ylamino] -4-methylphenylsulfanyl} -phenyl) -acetamide

Example 24a

N- {4- [2- (7-Chloro- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide

The product of Example 13d (200 mg, 1.0 mmol) and the product of Example 18b (215 mg, 1.0 mmol) were reacted according to the method described in Example 1g to give a crude solid product which was purified by HPLC with TFA to give the title compound (200 mg, 48%).

Example 24b

2- {5- [2- (4-Acetylamino-phenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyridin-2-yl} malonic acid diethyl ester

To a slurry of sodium hydride (95%, 0.045 g, 1.8 mmol) in 10 ml of anhydrous THF at 0 ° C. under N2 diethyl malonate (0.32 g, 2.0 mmol) was added dropwise. The mixture was stirred for 30 minutes at room temperature, treated with the product of Example 24a (0.141 g, 0.3 mmol), heated at 110 ° C for two hours, cooled and partitioned between EtOAc and water. The ethyl acetate layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title compound as a yellow glassy product (0.14 g, 84% yield).

Example 24c

N- (4- {2- [7- (2-Hydroxy-ethyl) - [1,8] naphthyridin-4-ylamino] -4-methylphenylsulfanyl} -phenyl) -acetamide

The product of Example 24b (56 mg, 0.10 mmol) was reacted with NaBH4 (40 mg, 1.00 mmol) in 5 mL of EtOH for 24 hours. Quenched with aqueous NH4Cl and adjusted to pH 7 with dilute HCl. Extraction with EtOAc and drying over Na2SO4, filtered and concentrated in vacuo to give the crude title compound, which was purified by HPLC using TFA to give trifluoroacetic acid salt (15 mg, 25%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.04 (s, 3H), 2.35 (s, 3H), 3.16 (t, J = 6.43 Hz, 2H), 3.91 (t, J = 6 , 25 Hz, 2H), 6.31 (d, J = 6.99 Hz, 1H), 7.14 (d, J = 8.09 Hz, 1H), 7.22-7.33 (m, 4H ), 7.51 (d, J = 8.82 Hz, 2H), 7.83 (d, J = 8.82 Hz, 1H), 8.42 (d, J = 6.99 Hz, 1H), 8.94-9.05 (m, 1H), 10.04 (s, 1H), 11.03 (s, 1H), 14.40 (s, 1H); MS

(ESI +) m / z 445 (M + H-TFA) +.

Example 25

N- {4- [2- (7-Butyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide

Example 25a

2-Butyl-6- (2,5-dimethyl-pyrrol-1-yl) -pyridine

The product of Example 2a (1.0 g, 5.37 mmol) was reacted with propyl iodide (0.55 mL, 5.64 mmol) in place of ethyl iodide according to the method described in Example 2b to give the title compound ( 790 mg, 64%).

Example 25b

2-Butyl-5-chloro- [1,8] naphthyridine

The product of Example 2a was subjected to the synthetic reaction sequence of Examples 2b-2g to obtain the title compound.

Example 25c

N- {4- [2- (7-Butyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide

The product of Example 25b (170 mg, 0.77 mmol) was reacted with the product of Example 18b (209 mg, 0.77 mmol) for 19 hours according to the method described in Example 1g, and after purifying the crude product with HPLC with TFA, the title compound was obtained as a trifluoroacetic acid salt as a solid (130 mg, 30%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.95 (t, J = 7.72 Hz, 3H), 1.39 (sext, 2H), J = 7.72 Hz), 1.80 (quint, J = 7.72 Hz, 2H), 2.04 (s, 3H), 2.35 (s, 3H), 3.01 (dd, J = 7.36 Hz, 2H), 6.81 (d, J = 6.99 Hz, 1H), 7.15 (d, J = 8.09 Hz, 1H), 7.22-7.32 (m, 4H), 7.50 (d, J = 8.82 Hz, 2H), 7.82 (d, J = 8.46 Hz, 1H), 8.41 (d, J = 6.99 Hz, 1H), 9.00 (d, J = 8.82 Hz, 1H) , 10.06 (brs, 1H), 11.02 (brs, 1H), 14.41 (brs, 1H); MS (ESI +) m / z 457 (M + H); (ESI-) m / z 455 (MH) -.

Example 26

N- {4- [4-Methyl-2 - ([1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 16c (50 mg, 0.304 mmol) was reacted with the product of Example 18b (83 mg, 0.304 mmol) for 16 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the salt of trifluoroacetic acid (29 mg, 24%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.04 (s, 3H), 2.35 (s, 3H), 6.34 (d, J = 6.99 Hz, 1H), 7.17 (d, J = 7 , 72 Hz, 1H), 7.23 (d, J = 8.46 Hz, 2H), 7.28-7.34 (m, 2H), 7.49 (d, J = 8.82 Hz, 2H ), 7.90 (dd, J = 8.46, 4.41 Hz, 1H), 8.48 (d, J = 6.99 Hz, 1H), 9.11 (dd, J = 8.46, 1.47 Hz, 1H), 9.17 (dd, J = 4.41, 1.47 Hz, 1H), 10.04 (s, 1H), 11.12 (s, 1H); MS (ESI +) m / z 401 (M + H) +, (ESI-) m / z 399 (MH) -.

Example 27

2- {5- [2- (4-Acetylamino-phenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyridin-2-yl} malonic acid diethyl ester

The crude product of Example 24b was purified by chromatography on a silica gel column, eluting with a 3% MeOH / CH2Cl2, then subjected to HPLC with TFA to give the title compound as a trifluoroacetic acid salt (70 mg, 42%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.22 (t, J = 7.17 Hz, 6H), 2.04 (s, 3H), 2.35 (s, 3H), 4.24 (q, J = 6 , 99 Hz, 4H), 5.55 (s, 1H), 6.36 (d, J = 6.99 Hz, 1H), 7.12 (d, J = 8.09 Hz, 1H), 7, 22-7.33 (m, 4H), 7.54 (d, J = 8.82 Hz, 2H), 7.96 (d, J = 8.46 Hz, 1H), 8.46 (d, J = 6.99 Hz, 1H), 9.16 (d, J = 8.46 Hz, 1H), 10.06 (s, 1H), 11.20 (s, 1H), 14.53 (s, 1H ); MS (ESI +) m / z 559 (M + H = TFA) +.

Example 28

Ethyl ester of {5- [2- (4-acetylamino-phenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyridin-2-ylamino} -acetic acid

The product of Example 24a (47 mg, 0.10 mmol) was reacted with glycine ethyl ester hydrochloride (84 mg, 0.10 mmol) in 2 mL of EtOH in a sealed tube at 150 ° C. for 1 hour. Cool to room temperature and concentrate. A pH of 7 with 1 M HCl was set and extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound, which was purified by HPLC with TFA, to give the product as a solid trifluoroacetic acid salt (12 mg, 19%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.22 (t, J = 6.99 Hz, 3H), 2.04 (s, 3H), 2.33 (s, 3H), 4.15 (q, J = 7 , 23 Hz, 2H), 4.27 (d, J = 6.25 Hz, 2H), 6.08 (d, J = 6.99 Hz, 1H), 7.04 (d, J = 5.52 Hz, 1H), 7.07 (d, J = 6.62 Hz, 1H), 7.19-7.30 (m, 4H), 7.57 (d, J = 8.46 Hz, 2H), 8.04 (t, J = 6.62 Hz, 1H), 8.53 (d, J = 9.19 Hz, 1H), 8.72 (t, J = 5.88 Hz, 1H), 10, 08 (s, 1H), 10.43 (s, 1H), 13.43 (d, J = 5.88 Hz, 1H); MS (ESI +) m / z 502 (M + H-TFA) +.

Example 29

2- {5- [2- (4-Acetylamino-phenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyridin-2-yl} malonic acid ethyl ester tert-butyl ester

To a slurry of sodium hydride (95%, 0.025 g, 1.0 mmol) in 5 ml of anhydrous THF at 0 ° C. under N2 tert-butyl ethyl malonate (0.188 g, 1.0 mmol) was added dropwise. The mixture was stirred for 30 minutes at ambient temperature, treated with the product of Example 46a (0.47 g, 0.1 mmol), heated at 110 ° C for 2 hours. The solution was cooled and added to water, acidified with 1 M HCl to pH 4, extracted with EtOAc and washed with saturated saline. Dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound, which was purified by chromatography on silica gel eluting with 1% MeOH in CH2Cl2, to give the title compound as the hydrochloride salt (0.040 g, 64% yield). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.26 (t, J = 7.11 Hz, 3H), 1.49 (s, 9H), 2.0 4 (s, 3H), 2.30 (s, 3H) , 4.16 (q, J = 7.11 Hz, 2H), 5.76 (s, 1H), 6.07 (d, J = 5.88 Hz, 1H), 6.98 (d, J = 7.72 Hz, 1H), 7.11 (d, J = 8.09 Hz, 1H), 7.26 (m, 4H), 7.56 (d, J = 8.82 Hz, 2H), 8 , 03 (d, J = 5.88 Hz, 1H), 8.25 (d, J = 9.93 Hz, 1H), 9.07 (s, 1H), 10.05 (s, 1H), 13 , 18 (s, 1H); MS (ESI +) m / z 587 (M + H) +.

Example 30

Ethyl ester of {5- [2- (4-acetylamino-phenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyridin-2-yl} -cyano-acetic acid

The title compound was prepared according to the procedure of Example 27 using ethyl cyanoacetate (0.240 mg, 2.1 mmol) in place of diethyl malonate. The crude product was purified by chromatography on silica gel eluting with 2% methanol in dichloromethane to give a yellow powder (0.092 g, 55% yield).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.28 (t, J = 6.99 Hz, 3H), 03 (s, 3H), 2.31 (s, 3H), 4.24 (q, J = 6.99 Hz, 2H), 6.15 (d, J = 5.88 Hz, 1H), 7.01 (d, J = 8.09 Hz, 1H), 7.12 (d, J = 1.47 Hz, 1H), 7.17 (d, J = 9.56 Hz, 2H), 7.23 (d, J = 8.46 Hz, 2H), 7.53 (d, J = 8.82 Hz, 2H) , 8.13 (d, J = 5.88 Hz, 1H), 8.60 (d, J = 9.56 Hz, 1H), 9.37 (s, 1H), 10.03 (s, 1H) , 13.09 (s, 1H); MS (ESI +) m / z 512 (M + H) +.

Example 31

(5- [2- (4-Acetylamino-phenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyridin-2-yl} -cyano-acetic acid t-butyl ester

The title compound was prepared according to the procedure of Example 27 using tert-butyl cyanoacetate (0.282 mg, 2.0 mmol) in place of diethyl malonate. The crude product was purified by chromatography on silica gel eluting with 2% methanol in dichloromethane to give a yellow powder (0.067 g, 37% yield).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.52 (s, 9H), 2.03 (s, 3H), 2.30 (s, 3H), 6.14 (d, J = 5.88 Hz, 1H), 6.98-7.27 (m, 6H), 7.53 (d, J = 8.82 Hz, 2H), 8.11 (d, J = 5.88 Hz, 1H), 8.55 (d , J = 9.56 Hz, 1H), 9.33 (s, 1H), 10.03 (s, 1H), 13.12 (s, 1H); MS (ESI +) m / z 540 (M + H) +.

Example 32

N- {4- [2- (7-Cyanomethyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide

The product of Example 31 (0.101 g, 0.19 mmol) was added to 5 ml of trifluoroacetic acid and 5 ml of CH2Cl2. The mixture was stirred at ambient temperature for 2 hours and concentrated in vacuo to give the crude title compound. The residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (0.083 g, 80%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.04 (s, 3H), 2.35 (s, 3H), 4.64 (s, 2H), 6.35 (d, J = 6.99 Hz, 1H), 7.18 (d, J = 8.46 Hz, 1H), 7.23 (d, J = 8.82 Hz, 2H), 7.30 (m, 2H), 7.48 (d, J = 8 , 46 Hz, 2H), 7.85 (d, J = 8.82 Hz, 1H), 8.44 (d, J = 6.99 Hz, 1H), 9.09 (d, J = 8.82 Hz, 1H), 10.04 (s, 1H), 11.14 (s, 1H), 14.58 (s, 1H); MS (ESI +) m / z 440 (M + H) +.

Example 33

N- {4- [3- (7-Methyl- [1,8] naphthyridin-4-ylamino) -biphenyl-4-ylsulfanyl] -phenyl} -acetamide

The product of Example 106c (53 mg, 0.11 mmol) in a mixture of saturated sodium bicarbonate solution (0.5 ml) and toluene (1 ml) was treated with phenyl boronic acid (14 mg, 0.11 mmol) and tetrakistriphenylphosphinopalladium (8 mg, 0.0074 mmol), and the mixture was heated at reflux temperature for 4 hours. The reaction mixture was cooled and partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with a saturated brine solution, dried over sodium sulfate and filtered. The organic layer was concentrated in vacuo to give the crude title compound as an orange oil, which was purified by HPLC with TFA to give the product as a trifluoroacetic acid salt (15 mg, 30%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.06 (s, 3H), 2.77 (s, 3H), 6.44 (d, J = 6.99 Hz, 1H), 7.21 (d, J = 8 , 09 Hz, 1H), 7.36 (d, J = 8.46 Hz, 2H), 7.41-7.52 (m, 3H), 7.58 (d, J = 8.82 Hz, 2H ), 7.71 (d, J = 7.35Hz, 2H), 7.75-7.87 (m, 3H), 8.44 (d, J = 6.62Hz, 1H), 9.02 (d, J = 8.82 Hz, 1H), 10.10 (s, 1H), 11.12 (s, 1H), 14.41 (s, 1H); MS (ESI +) m / z 477 (M + H) +.

Example 34

N- {4- [5-Hydroxy-4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 34a

N- [4- (5-Hydroxy-4-methyl-2-nitro-phenylsulfanyl) -phenyl} -acetamide

A mixture of 2-methyl-4-nitro-5-chlorophenol (1.5 g, 8.0 mmol), 4-acetamidothiophenol (1.6 g, 8.8 mmol) and cesium carbonate (5.74 g, 17.6 mmol) in DMF (10 ml) was heated 2.5 hours at 100 ° C. The mixture was cooled, diluted with ethyl acetate (100 ml), and the organic layer was washed with water and an aqueous 10% sodium chloride solution, then dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was removed in vacuo to give the title compound as a solid (2.5 g, 81%).

Example 34b

N- [4- (2-Amino-5-hydroxy-4-methylphenylsulfanyl) -phenyl} -acetamide

A solution of the product from Example 34a (2.5 g, 6.45 mmol), iron powder (1.79 g, 32 mmol) and ammonium chloride (0.514 g, 9.6 mmol) in methanol (10 mL), tetrahydrofuran (10 ml) and water (5 ml) was heated to reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a pad of celite. The filtrate was concentrated in vacuo to a volume of 10 ml, the solution was diluted with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with 10% sodium chloride, then dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (1.7 g, 91%).

Example 34c

N- {4- [5-Hydroxy-4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 1d (102 mg, 0.570 mmol) was reacted in ethanol (2 ml) with the product of Example 34b (161 mg, 0.560 mmol) for 18 hours in accordance with the method described in Example 1g to give the crude title a compound which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (50 mg, 21%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.05 (s, 3H), 2.12 (s, 3H), 2.75 (s, 3H), 6.31 (d, J = 6.99 Hz, 1H), 6.61 (s, 1H), 7.15 (s, 1H), 7.29 (d, J = 8.46 Hz, 2H), 7.56 (d, J = 8.82 Hz, 2H), 7.77 (d, J = 8.82 Hz, 1H), 8.39 (d, J = 5.52 Hz, 1H), 8.96 (d, J = 8.82 Hz, 1H), 9, 90 (s, 1H), 10.08 (s, 1H), 10.84 (s, 1H), 14.24 (brs, 1H); MS (ESI +) m / z 431 (M + H) +.

Example 35

N- {4- [2- (7-propyl- [1,8] naphthyridin-4-ylamino) -4-trifluoromethyl-phenylsulfanyl] -phenyl} -acetamide

Example 35a

N- [4- (2-Amino-4-trifluoromethyl-phenylsulfanyl) -phenyl] -acetamide

A solution of 2-chloro-5-trifluoromethylphenylamine (250 mg, 1.11 mmol) in DMF was reacted with N- (4-mercapto-phenyl) -acetamide (185 mg, 1.11 mmol) according to the method described in Example 1e, for 16 hours, to obtain the product (350 mg, 88%), which was reduced with SnCl2 in accordance with the method described in Example 1f, to give the title compound as a solid (260 mg, 80%).

Example 35b

N- {4- [2- (7-propyl- [1,8] naphthyridin-4-ylamino) -4-trifluoromethyl-phenylsulfanyl] -phenyl} -acetamide

The product of Example 2g (50 mg, 0.242 mmol) was reacted with the product of Example 35a (79.0 mg, 0.242 mmol) for 16 hours according to the method described in Example 1g to give the crude title compound which was purified by HPLC with TFA, which gave the disulfide trifluoroacetic acid (10.5 mg, 10%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J = 7.35 Hz, 3H), 1.81-1.92 (m, J = 7.35 Hz, 2H), 2.07 (s, 3H ), 3.01 (t, J = 7.54 Hz, 2H), 6.44 (d, J = 6.99 Hz, 1H), 7.11 (d, J = 8.46 Hz, 1H), 7.42-7.49 (m, J = 8.46 Hz, 2H), 7.69 (d, J = 8.82 Hz, 2H), 7.78 (dd, J = 8.82, 1, 47 Hz, 1H), 7.87 (d, J = 8.82 Hz, 1H), 7.91 (d, J = 1.10 Hz, 1H), 8.52 (d, J = 6.99 Hz) , 1H), 9.03 (d, J = 8.46 Hz, 1H), 11.14 (s, 1H); MS (ESI +) m / z 497 (M + H) +, ESI-m / z 495 (MH) -.

Example 36

N- {4- [2- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-trifluoromethyl-phenylsulfanyl] -phenyl} -acetamide

The product of Example 1d (50 mg, 0.280 mmol) was reacted with the product of Example 35a (91 mg, 0.280 mmol) for 16 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the salt of trifluoroacetic acid (21.5 mg, 20%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.07 (s, 3H), 2.78 (s, 3H), 6.43 (d, J = 6.99 Hz, 1H), 7.09-7.15 (m , 1H), 7.44 (d, J = 8.46 Hz, 2H), 7.68 (d, J = 8.46 Hz, 2H), 7.78 (dd, J = 8.64, 1, 65 Hz, 1H), 7.84 (d, J = 8.82 Hz, 1H), 7.92 (d, J = 1.84 Hz, 1H), 8.52 (d, J = 7.35 Hz , 1H), 9.00 (d, J = 8.46 Hz, 1H), 10.19 (s, 1H), 11.12 (s, 1H); MS (ESI +) m / z 469 (M + H-TFA) +, (ESI-) m / z 467 (MH-TFA) -.

Example 37

[2- (4-Acetylamino-phenylsulfanyl) -5-methylphenyl] - [7- (2-hydroxyethyl) - [1,8] naphthyridin-4-yl] -carbamic acid t-butyl ester

The product of Example 24 (22 mg, 0.05 mmol) was reacted with di-t-butyl dicarbonate (16 mg, 0.07 mmol) in 2 ml dry THF. Et3N (8.0 mg, 0.08 mmol) and a catalytic amount of N, N-4-dimethylaminopyridine, and stirred for 2 hours. Poured into water and neutralized with 1 M HCl. Extraction with EtOAc, drying over Na2SO4 and filtered and concentrated in vacuo to give the crude title compound, which was purified by chromatography on a silica gel column, eluting with 1% MeOH / CH2Cl2, yielding the solid product as a free base (7.0 mg, 26%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.59 (s, 9H), 2.03 (s, 3H), 2.25 (s, 3H), 2.96 (t, J = 6.62 Hz, 2H), 3.81 (m, 2H), 4.74 (t, J = 5.33 Hz, 1H), 5.76 (d, J = 6.90 Hz, 1H), 6.63 (s, 1H), 6.85 (m, 2H), 7.22 (d, J = 8.82 Hz, 2H), 7.36 (d, J = 8.09 Hz, 1H), 7.52 (d, J = 8 , 82 Hz, 2H), 7.70 (d, J = 8.46 Hz, 1H), 8.50 (d, J = 8.09 Hz, 1H), 10.00 (s, 1H); MS (ESI-) m / z 545 (M + H) +.

Example 38

N- {4- [2- (7-Butyl- [1,8] naphthyridin-4-ylamino) -4-methyl-benzenesulfinyl] -phenyl} -acetamide

The product of Example 20 (100 mg, 0.226 mmol) was dissolved in HOAc (1 mL) and cooled to 0 ° C. Magnesium bis (monoperoxyphthalate) hexahydrate (56 mg, 0.113 mmol) was added and the reaction mixture was allowed to warm to room temperature. The crude title compound was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (34 mg, 32%).11H NMR (500 MHz, DMSO-d6th) δ ppm: 1.07 (t, J= 7.32 Hz, 3H), 1.91-1.98 (m, 4H), 2.11 (s, 3H), 2.49 (s, 3H), 3.05-3.10 (m, 2H), 6.03 (d, J= 6.84 Hz, 1H), 7.31 (d, J= 8.79 Hz, 2H), 7.35 (s, 1H), 7.48 (d, J= 8.79 Hz, 2H), 7.67 (d, J= 7.81 Hz, 1H), 7.83 (d, J= 8.79 Hz, 1H), 8.10 (d, J= 7.81 Hz, 1H), 8.19 (d, J= 6.84 Hz, 1H), 9.05 (d, J= 8.79 Hz, 1H); MS (ESI +) m / z 459 (M + H-TFA) +; (ESI-) m / z 457 (MH-TFA) -.

Example 39

N- {3-Fluoro-4- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 39a

2-Fluoro-1-methylsulfanyl-4-nitro-benzene

A solution of 1,2-difluoro-4-nitrobenzene (1.50 g, 9.3 mmol) in MeOH (15 mL) was added dropwise a 15% aqueous solution of NaSMe (4.44 mL, 10.3 mmol ) at 5 ° C. and then the mixture was stirred at room temperature for 1 hour and evaporated. The resulting solid was dissolved in 150 ml of EtOAc, washed with H2O (twice) and brine, dried over MgSO4 and evaporated to give a crude product which was purified by washing with cold n-hexane to give the desired product as yellow crystals (1.58 g, 90%).

Example 39b

3-Fluoro-4-methylsulfanyl-phenylamine

The product of Example 39a (1.57 g, 8.4 mmol) and Fe powder (1.41 g, 25.2 mmol) in EtOH (7.5 mL) and HOAc (7.5 mL) were heated stepwise to a temperature 80 ° C and heated at the same temperature for 1 hour. The reaction mixture was evaporated. The residue was partitioned between CH2Cl23 and 10% NaHCO33 and then filtered through celite. The organic layer was washed with H2O, dried over MgSO4 and evaporated to give a crude product which was purified by washing with n-hexane to give the desired product as pale brown crystals (1.08 g, 82%).

Example 39c

N- (3-Fluoro-4-methylsulfanyl-phenyl) -acetamide

The product of Example 39c (1.08 g, 6.9 mmol) and Ac2O (0.97 mL, 10.3 mmol) in pyridine (10 mL) was heated at 50 ° C for 2 hours and then evaporated. The residue was diluted with H2O, acidified to pH 3 with 10% HCl and then extracted with EtOAc. The organic layer was washed with H2O and brine, dried over MgSO4 and evaporated to give the crude product which was purified by washing with n-hexane to give the title compound as colorless crystals (1.26 g, 92%).

Example 39d

N- [3-Fluoro-4- (4-methyl-2-nitro-phenylsulfanyl) -phenyl] -acetamide

The product of Example 39c (1.00 g, 5.0 mmol) and tert-BuSNa (1.88 g, 15.1 mmol) in anhydrous DMF (10 mL) was heated at 160 ° C. for 4 hours in a stream of N2 and then cooled to room temperature. 1-Chloro-4-methyl-2-nitrobenzene (2.36 mL, 17.6 mmol) was added to the reaction mixture at room temperature, and then the mixture was heated at 80 ° C. for 4 hours in a stream of N2. The mixture was diluted with H2O and then extracted with EtOAc. The extract was washed with H2O and brine, dried over MgSO4 and evaporated. The residue was purified by chromatography on a silica gel column eluting with 2: 1 EtOAc / hexanes to give the title compound as yellow crystals (1.04 g, 65%).

Example 39e

N- [4- (2-Amino-4-methylphenylsulfanyl) -3-fluorophenyl] -acetamide

The product of example 39d was reduced with Fe and NH4Cl in accordance with the method described in Example 237e to obtain the title compound.

Example 39f

N- {3-Fluoro-4- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 2g (100 mg, 0.48 mmol) was reacted with the product of Example 39e (140 mg, 0.48 mmol) for 22 hours at 120 ° C. according to the method described in Example 1g, of the title compound as a solid (120 mg, 54%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.99 (t, J = 7.3 Hz, 3H), 1.86 (sextet, J = 7.3 Hz, 2H), 2.06 (s, 3H), 2, 36 (s, 3H), 3.01 (t, J = 7.3Hz, 2H), 6.28 (d, J = 6.9Hz, 1H), 7.12-7.35 (m, 5H ), 7.55 (dd, J = 12.1, 2.2 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 8.42 (d, J = 6.9 Hz) , 1H), 9.04 (d, J = 8.8 Hz, 1H); MS (ESI +) m / z 461 (M + H) +, ESI-m / z 459 (MH) -.

Example 40

N- {3,5-Difluoro-4- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 40a

N- [3,5-Difluoro-4- (4-methyl-2-nitro-phenylsulfanyl) -phenyl] -acetamide

The title compound was prepared using the method of Example 39a, using 1,2,3-trifluoro-5-nitrobenzene instead of 1,2-difluoro-4-nitrobenzene. The product 2,6-difluoro-1-methylsulfanyl-4-nitrobenzene was then subjected to the methods of Examples 39b, 39c and 39d to obtain the title compound.

Example 40b

N- [4- (2-Amino-4-methylphenylsulfanyl) -3,5-difluoro-phenyl] -acetamide

The product of Example 40a was reduced with Fe and NH4Cl in accordance with the method described in Example 237e to obtain the title compound.

Example 40c

N- {3,5-Difluoro-4- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 40c (100 mg, 0.48 mmol) was reacted with the product of Example 2g (140 mg, 0.48 mmol) for 16 hours at 120 ° C. according to the method described in Example 1g to obtain of the title compound as a salt (120 mg, 52%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.99 (t, J = 7.3 Hz, 3H), 1.86 (sextet, J = 7.3 Hz, 2H), 2.06 (s, 3H), 2, 36 (s, 3H), 3.01 (t, J = 7.3Hz, 2H), 6.28 (d, J = 6.9Hz, 1H), 7.12-7.35 (m, 5H ), 7.55 (dd, J = 12.1, 2.2 Hz, 1H), 7.82 (d, J = 8.8 Hz, 1H), 8.42 (d, J = 6.9 Hz) , 1H), 9.04 (d, J = 8.8 Hz, 1H); MS (ESI +) m / z 461 (M + H) +, (ESI-) m / z 459 (MH) -.

Example 41

(7-Methyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-phenoxy-phenyl) -amine

Example 41a

4-Methyl-2-nitro-1-phenoxy-benzene

A solution of sodium phenoxide trihydrate (5.0 g, 30 mmol) and 4-chloro-3-nitrotoluene (2.65 mL, 30 mmol) was heated in 60 mL of DMF at 100 ° C. for 5 days with stirring according to the method , described in example 1c. The product was purified by chromatography on a silica gel column, eluting with CH2Cl2, to give the title compound as an orange solid (1.36 g, 30%).

Example 41b

5-Methyl-2-phenoxy-phenylamine

The product of Example 41a (884 mg, 3.86 mmol) was treated with SnCl2 (3.5 g, 19.0 mmol) for 24 hours in accordance with the method described in Example 1f to give the title compound as a yellow oil (710 mg, 93%).

Example 41c

(7-Methyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-phenoxy-phenyl) -amine

The product of Example 41b (65 mg, 0.36 mmol) was reacted with the product of Example 1d according to the method described in Example 1g to give the title compound, which was triturated in ether to give the product as the hydrochloride salt (12 mg , 8.8%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.95 (t, J = 7.73 Hz, 3H), 1.82 (q, J = 7.72 Hz, 2H), 2.97 (dd, J = 7.73 Hz, 2H), 6.68 (d, J = 6.99 Hz, 1H), 6.99 (d, J = 7.72 Hz, 2H), 7.12 (dd, J = 8.82 Hz, 2H), 7.30 (dd, J = 8.09 Hz, 2H), 7.66 (dd, J = 8.82 Hz, J = 2.58 Hz, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.77 (d, J = 8.82 Hz, 1H), 8.52 (d, J = 6.98 Hz, 1H), 9.07 (d, J = 8, 82 Hz, 1H), 11.26 (brs, 1H), 14.45 (brs, 1H); MS (ESI +) m / z 390 (M-Cl) +; (ESI-) m / z 388 (M-HCl) -.

Example 42

(5-Chloro-2-phenoxy-phenyl) - (7-ethyl- [1,8] naphthyridin-4-yl) -amine

Example 42a

4-Chloro-2-nitro-1-phenoxy-benzene

To a DMF solution (50 ml) was added 1-bromo-2-nitro-4-chlorobenzene (5.0 g, 21.1 mmol), phenol (1.9 g, 21.1 mmol) and Na2CO3 (2.3 g, 21.1 mmol). The solution was heated to 85 ° C and stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. Washed with water and dried over Na2SO4, filtered and concentrated in vacuo to give a yellow oil, which was purified by chromatography on a silica gel column, eluting with hexane: ethyl acetate (90:10) to give the title compound (3.8 g, 74%).

Example 42b

5-Chloro-2-phenoxy-phenylamine

The product of Example 42a (13 g, 52.1 mmol) was reacted with SnCl2 (49.3 g, 260 mmol) according to the method described in Example 1f, to give the title compound as a white solid (9.0 g, 79%).

Example 42c

(5-Chloro-2-phenoxy-phenyl) - (7-ethyl- [1,8] naphthyridin-4-yl) -amine

The product of Example 42b (100 mg, 0.46 mmol) was reacted with the product of Example 3f (88 mg, 0.46 mmol) according to the method described in Example 1g to obtain the title compound which was triturated in a mixture 2: 1 ether / THF to give the product as the hydrochloride salt (134 mg, 70%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.34 (t, J = 7.35 Hz, 3H), 3.02 (q, J = 7.35 Hz, 2H), 6.69 (d, J = 6.99Hz) , 1H), 6.97 (d, J = 8.82 Hz, 2H), 7.10 (dd, J = 7.35 Hz, 1H), 7.15 (d, J = 8.82 Hz, 2H ), 7.30 (dd, J = 8.09Hz, J = 7.72Hz, 2H), 7.56 (dd, J = 2.94Hz, J = 9.19Hz, 1H), 7, 71 (d, J = 2.57 Hz, 1H), 7.88 (d, J = 8.82 Hz, 1H), 8.52 (d, J = 6.99 Hz, 1H), 9.02 d, J = 8.45 Hz, 1H), 11.16 (brs, 1H), 14.56 (brs, 1H); MS (ESI +) m / z 376 (M-Cl) +; (ESI-) m / z 374 (M-HCl) -.

Example 43

(5-Chloro-2-phenoxy-phenyl) - (7-trifluoromethyl- [1,8] naphthyridin-4-yl) amine

The product of Example 42b (60 mg, 0.27 mmol) was reacted with the product of Example 7d (63 mg, 0.27 mmol) for 24 hours according to the method described in Example 1g to give the crude title compound in as a solid which was triturated in a 4: 1 ether / THF mixture to give the product as the hydrochloride salt (112 mg, 91%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 6.82 (d, J = 6.99 Hz, 1H), 6.98 (d, J = 7.72 Hz, 2H), 7.13 (m, 2H), 7, 32 (dd, J = 7.73Hz, J = 8.82Hz, 2H), 7.57 (dd, J = 2.57Hz, J = 8.82Hz, 1H), 7.71 (d, J = 2.57 Hz, 1H), 8.36 (d, J = 8.82 Hz, 1H), 8.69 (d, J = 6.99 Hz, 1H), 9.42 (d, J = 8.82 Hz, 1H), 11.47 (brs, 1H), 14.40 (brs, 1H); MS (ESI +) m / z 416 (M-Cl) +; (ESI-) m / z 414 (M-HCl) -.

Example 44

4- [4-Benzylamino-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol

Example 44a

4- (4-Amino-2-nitro-phenylsulfanyl) -phenol

A solution of 4-chloro-3-nitroaniline (1.0 g, 5.79 mmol), 4-hydroxythiophenol (0.75 g, 6.00 mmol), cesium carbonate (3.9 g, 12 mmol) in DMSO (10 ml) was heated at 100 ° C for 16 hours. Then, ice water (50 ml) was added to the solution, and the resulting slurry was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. The drying agent was filtered and concentrated in vacuo to give the title compound as a red solid (1.45 g, 92%).

Example 44b

4- (4-Benzylamino-2-nitro-phenylsulfanyl) -phenol

A solution of the product of Example a (0.63 g, 2.4 mmol), benzaldehyde (0.24 g, 2.3 mmol) and sodium cyanoborohydride (0.15 g, 2.4 mmol) in methanol (10 ml), containing 1% acetic acid, was stirred at room temperature for 16 hours. The reaction mixture was quenched with water (20 ml) and the resulting solution was concentrated in vacuo to a yellow solid. The solid was dissolved in ethyl acetate (50 ml) and washed with water, 10% sodium bicarbonate and 10% sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo to give a pale yellow oil. The oil was placed on a silica gel column and eluted with CH2Cl2, followed by 1% methanol in CH2Cl2. The fractions that contained the product were combined and evaporated to dryness to give the title compound as a yellow solid (0.63 g, 77%).

Example 44c

4- (2-Amino-4-benzylamino-phenylsulfanyl) -phenol

The product of Example 44b was reduced with Fe and NH4Cl in accordance with the method described in Example 237e to obtain the title compound.

Example 44d

4- [4-Benzylamino-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol

The product of Example 2g (105 mg, 0.50 mmol) was reacted with the product of Example 44c (161 mg, 0.50 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC using TFA to give the trifluoroacetic acid salt (68 mg, 22%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (t, J = 7.35 Hz, 3H), 1.83 (sext, J = 7.35 Hz, 2H), 2.97 (dd, J = 7, 35 Hz, 2H), 4.29 (m, 2H), 6.15 (d, J = 6.99 Hz, 1H), 6.51 (d, J = 8.46 Hz, 2H), 6.93 (d, J = 8.46 Hz, 2H), 7.22-7.38 (m, 8H), 7.78 (d, J = 8.83 Hz, 1H), 8.95 (d, J = 8.46 Hz, 1H), 9.66 (s, 1H), 10.90 (brs, 1H), 14.21 (brs, 1H); MS (ESI +) m / z 493 (M + H-TFA) +.

Example 45

4- [4-Benzylamino-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 1d (57 mg, 0.319 mmol) was reacted with the product of Example 44c (102 mg, 0.319 mmol) for 72 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the salt of trifluoroacetic acid (169 mg, 91%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.74 (s, 3H), 4.30 (s, 2H), 6.15 (d, J = 6.99 Hz, 1H), 6.52 (d, J = 8 , 46 Hz, 1H), 6.56-7.39 (m, 11H), 7.75 (d, J = 8.46 Hz, 1H), 8.28 (d, J = 7.36 Hz, 1H ), 9.50 (brs, 1H), 10.85 (brs, 1H), 14.25 (brs, 1H); MS (ESI +) m / z 465 (M + H-TFA) +; (ESI-) m / z 463 (MH-TFA) -.

Example 46

N- {4- [4-Methyl-2- (7-morpholin-4-yl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 46a

N- {4- [2- (7-Chloro- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide

The product of Example 13d (200 mg, 1.0 mmol) was reacted with the product of Example 18b (215 mg, 1.0 mmol) for 24 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the salt of trifluoroacetic acid (200 mg, 45%).

Example 46b

N- {4- [4-Methyl-2- (7-morpholin-4-yl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 46a (0.047 g, 0.1 mmol) and morpholine (0.087 g, 1.0 mmol) in ethanol (0.5 ml) was heated in a sealed tube at 110 ° C. for 1 hour, cooled and concentrated. The crude residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (0.030 g, 50%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.04 (s, 3H), 2.33 (s, 3H), 3.56-3.93 (m, 8 H), 6.07 (d, J= 6.99 Hz, 1H), 7.09 (d, J= 8.09 Hz, 1H), 7.20-7.32 (m, 4H), 7.54 (d, J= 8.82 Hz, 2H), 8.07 (t, J= 6.80 Hz, 1H), 8.64 (d, J= 9.56 Hz, 1H), 10.06 (s, 1H), 10.45 (s, 1H), 13.42 (d, J= 5.88 Hz, 1H); MS (ESI +) m / z 486 (M + H)+.

Example 47

(7-Methyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-p-tolylsulfanyl-phenyl) amine

Example 47a

4-Methyl-2-nitro-1-p-tolylsulfanyl-benzene

The product of Example 4a (5.00 g, 17.53 mmol) was reacted with 4-methylthiophenol (2.17 g, 17.53 mmol) in place of thiophenol according to the method described in Example 1e for 18 hours, crude title compound, which was purified by chromatography on a silica gel column, eluting with 5% EtOAc / hexane to give a solid (3.53 g, 78%).

Example 47b

5-Methyl-2-p-tolylsulfanyl-phenylamine

The product of Example 47a was reduced with SnCl2 in accordance with the method described in Example 1f, to obtain the title compound.

Example 47c

(7-Methyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-p-tolylsulfanyl-phenyl) amine

The product of Example 1d (267 mg, 1.56 mmol) was reacted with the product of Example 47b (358 mg, 1.56 mmol) for 48 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC using TFA to give the trifluoroacetic acid salt (347 mg, 46%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.22 (s, 3H), 2.37 (s, 3H), 2.77 (s, 3H), 6.27 (d, J= 7.35 Hz, 1H), 7.04 (d, J= 7.72 Hz, 2H), 7.14 (m, 2H), 7.29 (m, 3H), 7.79 (d, J= 8.82 Hz, 1H), 8.39 (d, J= 6.99 Hz, 1H), 8.95 (d, J= 8.46 Hz, 1H), 11.25 (brs, 1H), 14.39 (brs, 1H); MS (ESI +) m / z 372 (M + H) +.

Example 48

(7-Methyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-m-tolylsulfanyl-phenyl) amine

Example 48a

4-Methyl-2-nitro-1-m-tolylsulfanyl-benzene

The product of Example 4a (9.46 g, 33.17 mmol) was reacted with 3-methylthiophenol (4.12 g, 33.17 mmol) in place of thiophenol according to the method described in Example 1e for 18 hours, crude title compound, which was purified by chromatography on a silica gel column, eluting with 5% EtOAc / hexanes to give a solid (7.50 g, 87%).

Example 48b

5-Methyl-2-m-tolylsulfanyl-phenylamine

The product of Example 48a was reduced with SnCl2 in accordance with the method described in Example 1f, to obtain the title compound.

Example 48c

(7-Methyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-m-tolylsulfanyl-phenyl) amine

The product of Example 1d (267 mg, 1.56 mmol) was reacted with the product of Example 48b (358 mg, 1.56 mmol) for 48 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the trifluoroacetic acid salt (116 mg, 15%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.10 (s, 3H), 2.38 (s, 3H), 2.76 (s, 3H), 6.27 (d, J= 7.35 Hz, 1H), 7.00 (m, 3H), 7.40 (m, 3H), 7.78 (d, J= 8.82 Hz, 1H), 8.37 (d, J= 6.99 Hz, 1H), 8.92 (d, J= 8.82 Hz, 1H), 11.08 (brs, 1H), 14.45 (brs, 1H); MS (ESI +) m / z 372 (M + H) +.

Example 49

[2- (4-Fluoro-phenylsulfanyl) -5-methylphenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

Example 49a

1- (4-Fluoro-phenylsulfanyl) -4-methyl-2-nitro-benzene

The product of Example 4a (5.00 g, 17.53 mmol) was reacted with 4-fluorothiophenol (2.24 g, 17.53 mmol) in place of thiophenol according to the method described in Example 1e for 18 hours, crude title compound, which was purified by chromatography on a silica gel column, eluting with a 5% EtOAc / hexane mixture to give a solid (3.39 g, 74%).

Example 49b

2- (4-Fluoro-phenylsulfanyl) -5-methylphenylamine

The product of Example 49a was reduced with SnCl2 in accordance with the method described in Example 1f, to obtain the title compound.

Example 49c

[2- (4-Fluoro-phenylsulfanyl) -5-methylphenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 1d (167 mg, 0.94 mmol) was reacted with the product of Example 49b (218 mg, 0.94 mmol) for 48 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the salt of trifluoroacetic acid (224 mg, 49%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.37 (m, 3H), 2.77 (m, 3H), 6.29 (d, J= 6.99 Hz, 1H), 7.10 (m, 2H), 7.32 (m, 5H), 7.80 (d, J= 8.46 Hz, 1H), 8.41 (d, J= 6.99 Hz, 1H), 8.95 (d, J= 8.46 Hz, 1H), 11.04 (brs, 1H), 14.43 (brs, 1H); MS (ESI +) m / z 376 (M + H) +.

Example 50

[2- (4-Methoxy-phenylsulfanyl) -5-methylphenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

Example 50a

1- (4-Methoxy-phenylsulfanyl) -4-methyl-2-nitro-benzene

The product of Example 4a (5.0 g, 175 mmol) was reacted with 4-methoxybenzenethiol (2.45 g, 175 mmol) for 18 hours in accordance with the method described in Example 4b to give the product as a solid (3.76 g, 78%).

Example 50b

2- (4-Methoxy-phenylsulfanyl) -5-methylphenylamine

The product of Example 50a was reduced with SnCl2 in accordance with the method described in Example 1f, to obtain the title compound.

Example 50c

[2- (4-Methoxy-phenylsulfanyl) -5-methylphenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 1d (167 mg, 0.94 mmol) was reacted with the product of Example 50b (245 mg, 0.94 mmol) for 48 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC using TFA to give the trifluoroacetic acid salt (325 mg, 70%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.35 (s, 3H), 2.77 (s, 3H), 3.73 (s, 3H), 6.26 (d, J= 6.99 Hz, 1H), 6.85 (d, J= 8.82 Hz, 2H), 7.11 (d, J= 7.72 Hz, 1H), 7.26 (d, J= 8.82 Hz, 2H), 7.31 (s, 1H), 7.80 (d, J= 8.46 Hz, 1H), 8.41 (d, J= 6.99 Hz, 1H), 8.99 (d, J= 8.82 Hz, 1H), 11.04 (brs, 1H), 14.32 (brs, 1H); MS ESI + m / z 388 (M + H) +.

Example 51

[2- (3,4-Dimethoxy-phenylsulfanyl) -5-methylphenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

Example 51a

2- (3,4-Dimethoxy-phenylsulfanyl) -5-methyl-phenylamine

The product of Example 4a (11.25 g, 39.5 mmol) was reacted with 3,4-dimethoxybenzenethiol (6.71 g, 39.5 mmol) for 18 h according to the method described in Example 4b, to give the product as a solid product (7.75 g, 64%).

Example 51b

2- (3,4-Dimethoxy-phenylsulfanyl) -5-methyl-phenylamine

The product of Example 51a was reduced with SnCl2 in accordance with the method described in Example 1f, to obtain the title compound.

Example 51c

[2- (3,4-Dimethoxy-phenylsulfanyl) -5-methylphenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 1d (277 mg, 1.56 mmol) was reacted with the product of Example 51b (430 mg, 1.56 mmol) for 5 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC using TFA to give the trifluoroacetic acid salt (628 mg, 79%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.35 (s, 3H), 2.76 (s, 3H), 3.56 (s, 3H), 3.68 (s, 3H), 6.24 (d, J= 6.99 Hz, 1H), 6.82 (m, 3H), 7.29 (m, 3H), 7.79 (d, J= 8.46 Hz, 1H), 8.38 (d, J= 6.99 Hz, 1H), 8.97 (d, J= 8.46 Hz, 1H), 10.97 (s, 1H), 14.35 (s, 1H); MS (ESI +) m / z 418 (M + H) +.

Example 52

3- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

Example 52a

3- (4-Methyl-2-nitro-phenylsulfanyl) -phenol

The product of Example 4a (10.14 g, 35.6 mmol) was reacted with 3- (4-methyl-2-nitro-phenylsulfanyl) -phenol (4.48 g, 35.6 mmol) for 18 hours in accordance with with the method described in Example 4b, to give the product as a solid product (7.88 g, 85%).

Example 52b

3- (2-Amino-4-methyl-phenylsulfanyl) -phenol

The product of Example 52a was reduced with SnCl2 in accordance with the method described in Example 1f, to obtain the title compound.

Example 52c

3- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 1d (277 mg, 1.56 mmol) was reacted with the product of Example 52b (245 mg, 1.56 mmol) for 5 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC using TFA to give the trifluoroacetic acid salt (399 mg, 52%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.38 (s, 3H), 2.75 (s, 3H), 6.30 (d, J= 6.99 Hz, 1H), 6.53-6.58 (m, 2H), 6.61 (d, J= 8.09 Hz, 1H), 6.90-7.08 (m, 1H), 7.27-7.47 (m, 3H), 7.77 (d, J= 8.46 Hz, 1H), 8.39 (d, J= 6.99 Hz, 1H), 8.94 (d, J= 8.82 Hz, 1H), 9.58 (s, 1H), 10.96 (s, 1H), 14.34 (s, 1H); MS (ESI +) m / z 374 (M + H) +.

Example 53

[3- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-phenylsulfanyl-phenyl] -methanol

Example 53a

Ethyl 4-hydroxy-3-nitro-benzoic acid

A solution of 4-hydroxy-3-nitro-benzoic acid ethyl ester (15.0 g, 76.1 mmol) was reacted with trifluoromethanesulfonic anhydride (14.0 mL, 83.7 mmol) for 15 minutes, as described in Example 4a, to give the title compound as an amber oil (22.26 g, 89%).

Example 53b

Ethyl 3-nitro-4-phenylsulfanyl-benzoic acid

The product of Example 53a (22.6 g, 67.6 mmol) was reacted with sodium thiophenolate (7.54 g, 67.6 mmol) for 24 hours according to the method described in Example 1e to give the title of the compound as a solid (13.2 g, 67%).

Example 53c

Ethyl 3-amino-4-phenylsulfanyl-benzoic acid

The product of Example 53b was reacted with SnCl2 in accordance with the method described in Example 1f, to give the title compound as a solid.

Example 53c

3- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-phenylsulfanyl-benzoic acid ethyl ester

The product of Example 1d (2.06 g, 1.16 mmol) was reacted with the product of Example 53b (3.18 g, 1.16 mmol) for 5 hours according to the method described in Example 1g to yield a crude in the title compound, which was purified by HPLC with TFA to give the trifluoroacetic acid salt (3.61 g, 59%).

Example 53d

[3- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-phenylsulfanyl-phenyl] -methanol

The product of Example 53c (2.30 g, 5.54 mmol) in 60 mL of THF was reacted with LiAlH4 (420 mg, 11.0 mmol) for 18 h, then quenched with dilute HCl. The pH was adjusted to pH 10 with NH4OH. Extracted CH2Cl2, dried over MgSO4, filtered and concentrated in vacuo to give the crude title compound, which was purified by HPLC with TFA to give the trifluoroacetic acid salt (325 mg, 70%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.76 (s, 3H), 3.99 (brs, 1H), 4.58 (s, 2H), 6.31 (d, J= 7.35 Hz, 1H), 7.25 (s, 5H), 7.40 (m, 2H), 7.46 (s, 1H), 7.78 (d, J= 8.82 Hz, 1H), 8.42 (d, J= 6.99 Hz, 1H), 8.95 (d, J= 8.46 Hz, 1H), 11.06 (brs, 1H), 14.44 (brs, 1H); MS (ESI +) m / z 374 (M + H) +.

Example 54

[2- (4-Ethoxy-phenylsulfanyl) -5-methylphenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

Example 54a

1- (4-Ethoxy-phenylsulfanyl) -4-methyl-2-nitro-benzene

The product of Example 4b (500 mg, 1.91 mmol) was reacted with NaH (0.048 g, 2.01 mmol) in 10 mL THF at 0 ° C for 2 hours. The mixture was warmed to room temperature and EtI (0.232 ml, 2.87 mmol) was slowly added, followed by stirring at room temperature for 4 days. The mixture was quenched with water, the layers were separated and dried over MgSO4, filtered and concentrated in vacuo to give the product as a solid (510 mg, 92%). It was reconstituted with SnCl2 in accordance with the method described in Example 1f, to obtain the title compound.

Example 54b

[2- (4-Ethoxy-phenylsulfanyl) -5-methylphenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 1d (250 mg, 1.56 mmol) was reacted with the product of Example 54a (259 mg, 1.56 mmol) for 5 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the salt of trifluoroacetic acid (241 mg, 30%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.31 (t, J= 6.99 Hz, 3H), 2.34 (s, 3H), 2.76 (s, 3H), 3.97 (q, J= 6.99 Hz, 2H), 6.26 (d, J= 7.35 Hz, 1H), 6.83 (d, J= 8.82 Hz, 2H), 7.11 (d, J= 7.72 Hz, 1H), 7.24 (d, J= 8.82 Hz, 2H), 7.27 (s, 1H), 7.30 (s, 1H), 7.80 (d, J= 8.82 Hz, 1H), 8.41 (d, J= 6.99 Hz, 1H), 8.99 (d, J= 8.82 Hz, 1H), 11.01 (s, 1H), 14.38 (s, 1H); MS

(ESI +) m / z 402 (M + H) +.

Example 55

(7-Methyl- [1,8] naphthyridin-4-yl) - [5-methyl-2- (4-propoxy-phenylsulfanyl) -phenyl] -amine

Example 55a

4-Methyl-2-nitro-1- (4-propoxy-phenylsulfanyl) -benzene

The product of Example 4b (600 mg, 2.30 mmol) was reacted with NaH (0.83 g, 2.30 mmol) in 10 mL THF at 0 ° C for 2 hours. The mixture was warmed to room temperature and EtI (0.232 mL, 2.87 mmol) was slowly added, followed by stirring at 50 ° C. for 7 days. The mixture was quenched with water, the layers were separated and dried over MgSO4, filtered and concentrated in vacuo to give the product as a solid (700 mg, 100%). It was reconstituted with SnCl2 in accordance with the method described in Example 1f, to obtain the title compound.

Example 55b

(7-Methyl- [1,8] naphthyridin-4-yl) - [5-methyl-2- (4-propoxy-phenylsulfanyl) -phenyl] -amine

The product of Example 1d (250 mg, 1.56 mmol) was reacted with the product of Example 55a (273 mg, 1.56 mmol) for 5 hours according to the method described in Example 1g to give the crude title compound , which was purified by HPLC with TFA, which gave the salt of trifluoroacetic acid (187 mg, 23%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (t, J= 7.35 Hz, 3H), 1.62-1.79 (m, 2H), 2.34 (s, 3H), 2.76 (s, 3H), 3.86 (t, J= 6.43 Hz, 2H), 6.27 (d, J= 6.99 Hz, 1H), 6.84 (d, J= 8.82 Hz, 2H), 7.11 (d, J= 7.72 Hz, 1H), 7.24 (d, J= 8.46 Hz, 2H), 7.29 (s, 1H), 7.80 (d, J= 8.46 Hz, 1H), 8.42 (d, J= 6.99 Hz, 1H), 8.99 (d, J= 8.46 Hz, 1H), 11.01 (s, 1H), 14.39 (s, 1H); MS (ESI +) m / z 416 (M + H) +.

Example 56

[2- (4-Isopropoxy-phenylsulfanyl) -5-methylphenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

Example 56a

2- (4-Isopropoxy-phenylsulfanyl) -5-methylphenylamine

The product of Example 4b (600 mg, 2.30 mmol) was reacted with NaH (0.83 g, 2.44 mmol) in 10 mL of THF at 0 ° C for 2 hours. It was warmed to room temperature and iso-Pr-I (0.574 mL, 5.74 mmol) was slowly added, followed by stirring at 50 ° C for 10 days. The mixture was quenched with water, the layers were separated and dried over MgSO4, filtered and concentrated in vacuo to give the product as a solid (730 mg, 100%). It was reconstituted with SnCl2 in accordance with the method described in Example 1f, to obtain the title compound.

Example 56b

[2- (4-Isopropoxy-phenylsulfanyl) -5-methylphenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 1d (250 mg, 1.56 mmol) was reacted with the product of Example 56a (427 mg, 1.56 mmol) for 5 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the salt of trifluoroacetic acid (185 mg, 23%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.23 (d, J= 6.25 Hz, 6H), 2.34 (s, 3H), 2.76 (s, 3H), 4.48-4.58 (m, 1H), 6.27 (d, J= 6.99 Hz, 1H), 6.81 (d, J= 8.82 Hz, 2H), 7.14 (d, J= 8.09 Hz, 1H), 7.22 (d, J= 8.82 Hz, 2H), 7.27 (s, 1H), 7.30 (s, 1H), 7.79 (d, J= 8.82 Hz, 1H), 8.41 (d, J= 6.99 Hz, 1H), 8.99 (d, J= 8.46 Hz, 1H), 10.99 (s, 1H), 14.36 (s, 1H); MS (ESI +) m / z 416 (M + H) +.

Example 57

N- (4-Bromo-phenyl) -4- (4-hydroxy-phenylsulfanyl) -3- (7-propyl- [1,8] naphthyridin-4-ylamino) -benzamide

Example 57a

N- (4-Bromo-phenyl) -4-chloro-3-nitro-benzamide

A mixture of 4-bromoaniline (2.58 g, 14.99 mmol) in dry CH2Cl2 (100 ml) was treated with 4-chloro-3-nitrobenzoyl chloride (3.60 g, 17.99 mmol) and N, N-diisopropyl-ethylamine (3.14 ml, 17.99 mmol), and the resulting mixture was stirred at room temperature within 17 hours. The solvent was concentrated in vacuo to give the title compound and the residue was treated with ethyl acetate (100 ml) and washed with water and saturated brine. The organic extract was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a tan solid (5.132 g, 14.45 mmol, 96%).

Example 57b

N- (4-Bromo-phenyl) -4- (4-hydroxy-phenylsulfanyl) -3-nitrobenzamide

A solution of the product of Example 57a (553 mg, 1.557 mmol) in anhydrous DMF (15 mL) was treated with 4-mercaptophenol (196 mg, 1.557 mmol) and cesium carbonate (1.015 g, 3.111 mmol) at room temperature, then heated at 100 ° C C under nitrogen for 3 hours. The reaction mixture was cooled to room temperature and the solvent was concentrated in vacuo to give the title compound. The residue was taken up in H2O (30 ml) and the pH was adjusted to 3 with 1N HCl. aqueous HCl. The aqueous layer was then extracted with ethyl acetate and the combined organic extracts were washed with saturated brine (25 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound. The residue was triturated in methylene chloride and purified by flash chromatography on silica gel with a gradient of 6% to 30% ethyl acetate / methylene chloride to give the title product as a dark yellow solid (517 mg, 1.16 mmol, 75%).

Example 57c

3-Amino-N- (4-bromo-phenyl) -4- (4-hydroxy-phenylsulfanyl) -benzamide

The product of Example 57b was reduced with Fe and NH4Cl in accordance with the method of Example 237e to obtain the title compound.

Example 57d

N- (4-Bromo-phenyl) -4- (4-hydroxy-phenylsulfanyl) -3- (7-propyl- [1,8] naphthyridin-4-ylamino) -benzamide

The product of Example 2g (138 mg, 0.154 mmol) was reacted with the product of Example 57C (64 mg, 0.154 mmol) for 40 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the salt of trifluoroacetic acid (30 mg, 20%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.99 (t, J= 7.35 Hz, 3H), 1.69-1.96 (m, 2H), 3.02 (t, J= 7.35 Hz, 2H), 6.42 (d, J= 6.99 Hz, 1H), 6.87 (d, J= 8.46 Hz, 2H), 7.02 (d, J= 8.46 Hz, 1H), 7.33 (d, J= 8.46 Hz, 2H), 7.54 (d, J= 9.19 Hz, 2H), 7.72 (d, J= 8.82 Hz, 2H), 7.87 (d, J= 8.82 Hz, 1H), 7.98 (dd, J= 8.46, 1.84 Hz, 1H), 8.02 (d, J= 1.84 Hz, 1H), 8.52 (d, J= 6.62 Hz, 1H), 9.09 (d, J= 8.46 Hz, 1H), 10.09 (s, 1H), 10.37 (s, 1H), 11.14 (s, 1H), 14.54 (s, 1H); MS

(ESI +) m / z 585/587 (M + H) +.

Example 58

4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl ester of 5-dimethylamino-naphthalene-1-sulfonic acid

The product of Example 5 (167 mg, 0.94 mmol) was reacted with 5-dimethylamino-naphthalene-1-sulfonyl chloride (245 mg, 0.94 mmol) in 10 mL CH2Cl2 with N, N-diisopropylethylamine (0.530 ml, 410 mmol) for 22 hours. Washed with water and dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound, which was purified by HPLC with TFA to give the trifluoroacetic acid salt (35 mg, 40%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.75 (s, 3H), 2.86 (s, 6H), 6.65 (d, J= 6.99 Hz, 1H), 6.76 (d, J= 9.19 Hz, 2H), 6.87 (d, 2H), 7.16 (d, J= 8.82 Hz, 1H), 7.34 (d, J= 7.72 Hz, 1H), 7.53-7.62 (m, 2H), 7.69-7.79 (m, 3H), 7.97 (d, J= 7.35 Hz, 1H), 8.22 (d, J= 8.82 Hz, 1H), 8.50 (d, J= 6.99 Hz, 1H), 8.60 (d, J= 8.46 Hz, 1H), 8.82 (d, J= 8.82 Hz, 1H); MS 1H), 8.50 (d,J= 6.99 Hz, 1H), 8.60 (d, J= 8.46 Hz, 1H), 8.82 (d, J= 8.82 Hz, 1H); MS (DCI NH3+) m / z 611 (M + H) +.

Example 59

4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl ester of ethanesulfonic acid

The product of Example 5 (100 mg, 0.24 mmol) was reacted with ethanesulfonyl chloride (31.0 mg, 0.24 mmol) for 18 hours in accordance with the method described in Example 58 to give the crude title compound which was purified by HPLC with TFA, which gave the salt of trifluoroacetic acid (20 mg, 14%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 10.98 (s, 1H), 8.89 (d, J= 8.46 Hz, 1H), 8.39 (d, J= 6.99 Hz, 1H), 7.76 (d, J= 8.82 Hz, 1H), 7.45-7.50 (m, 1H), 7.36-7.42 (m, 2H), 7.25 (d, 2H), 7.17 (d, 2H), 6.33 (d, J= 6.99 Hz, 1H), 3.47 (q, J= 7.35 Hz, 2H), 2.75 (s, 3H), 2.40 (s, 3H), 1.34 (t, J= 7.35 Hz, 3H); MS (DCI NH3+) m / z 466 (M + H) +.

Example 60

4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl ester of propan-2-sulfonic acid

The product of Example 5 (80.0 mg, 0.195 mmol) was reacted with propane-2-sulfonyl chloride (27.8 mg, 0.195 mmol) for 18 hours according to the method described in Example 58 to give the crude title compound , which was purified by HPLC with TFA, which gave the salt of trifluoroacetic acid (20 mg, 21%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 8.90 (d, J= 8.46 Hz, 1H), 8.39 (d, J= 6.99 Hz, 1H), 7.76 (d, J= 8.82 Hz, 1H), 7.43-7.49 (m, 1H), 7.35-7.42 (m, 2H), 7.24-7.29 (m, 2H), 7, 12-7.19 (m, 2H), 6.33 (d, J= 6.99 Hz, 1H), 2.75 (s, 3H), 3.66 (m, 1) 2.39 (s, 3H), 1.40 (d, J= 6.99 Hz, 6H); MS (DCI NH3+) m / z 480 (M + H) +.

Example 61

4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl ester of methanesulfonic acid

The product of Example 5 (80 mg, 0.195 mmol) was reacted with methanesulfonyl chloride (22.3 mg, 0.195 mmol) for 18 hours according to the method described in Example 58 to give the crude title compound which was purified by HPLC with TFA, which gave the salt of trifluoroacetic acid (36 mg, 32%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 8.88 (d, J= 8.46 Hz, 1H), 8.39 (d, J= 6.99 Hz, 1H), 7.76 (d, J= 8.46 Hz, 1H), 7.45-7.51 (m, 1H), 7.35-7.42 (m, 2H), 7.26 (d, 2H), 7.19 (d, 2H), 6.33 (d, J= 6.99 Hz, 1H), 3.34 (s, 3H), 2.75 (s, 3H), 2.40 (s, 3H); MS (DCI NH3+) m / z 452 (M + H) +.

Example 62

4- [2- (7-Ethyl- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -phenyl ester of ethanesulfonic acid

The product of Example 4 (20 mg, 0.47 mmol) was reacted with ethanesulfonyl chloride (72 mg, 0.56 mmol) for 22 hours according to the method described in Example 58, to give the crude title compound, which was purified with Using HPLC with TFA, which gave the salt of trifluoroacetic acid (70 mg, 25%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 8.31 (d, 1H), 7.73 (d, 1H), 7.11 (d, 1H), 6.85 (d, 1H), 6.74 (s, 2H ), 6.64 (d, 2H), 6.53 (d, 2H), 5.75 (d, 1H), 2.81 (q, 2H), 2.42 (q, 2H), 1.78 (s, 3H), 0.76 (m, 6H); MS (ESI +)m / z 484 (M + H) +.

Example 63

4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl ester of phenylmethanesulfonic acid

The product of Example 5 (120 mg, 0.294 mmol) was reacted with phenyl methanesulfonyl chloride (55 mg, 0.294 mmol) for 22 hours according to the method described in Example 58 to give the crude title compound which was purified by HPLC with TFA, which gave the salt of trifluoroacetic acid (15 mg, 9%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 8.31 (d, 1H), 7.73 (d, 1H), 7.11 (d, 1H), 6.85 (d, 1H), 6.74 (s, 2H ), 6.64 (d, 2H), 6.53 (d, 2H), 5.75 (d, 1H), 2.81 (q, 2H), 2.42 (q, 2H), 1.78 (s, 3H), 0.76 (m, 6H); MS (ESI +)m / z 484 (M + H) & lt; + &+.

Example 64

Ethyl ester of {4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenoxy} -acetic acid

The product of Example 5 (0.200 g, 0.536 mmol) was suspended in acetone to which K2CO3. The mixture was treated with bromo-ethyl acetate (0.089 g, 0.536 mmol), then the reaction mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, the solid was filtered and concentrated in vacuo to give the crude title compound, which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (24 mg, 10%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.22 (t, J= 6.99 Hz, 3H), 2.34 (s, 3H), 2.74 (s, 3H), 4.20 (q, J= 6.99 Hz, 2H), 5.47 (s, 2H), 6.49 (d, J= 7.72 Hz, 1H), 6.75 (d, J= 8.82 Hz, 2H), 7.00 (d, J= 8.09 Hz, 1H), 7.20 (d, J= 8.46 Hz, 2H), 7.25-7.40 (m, 2H), 7.87 (d, J= 8.82 Hz, 1H), 8.63 (d, J= 7.72 Hz, 1H), 9.06 (d, J= 8.46 Hz, 1H), 9.89 (s, 1H); MS (ESI) m / z 460 (M + H) +, (ESI-) m / z 458 (MH) -.

Example 65

{4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenoxy} -acetic acid

The product of Example 64 (0.246 g, 0.535 mmol) was dissolved in 10 ml of 5% NaOH and 10 ml EtOH, heated to 100 ° C for 2 hours and then stirred at room temperature for 10 hours. The whole solvent was then removed in vacuo and the brown oil redissolved in water to which 2 ml of HCl was added and a yellow precipitate was observed. The precipitate formed was collected by filtration and the solid was dried in vacuo overnight (150 mg, 64%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.33 (s, 3H), 2.75 (s, 3H), 5.42 (s, 2H), 6.46 (d, J= 7.35 Hz, 1H), 6.52 (s, 1H), 6.75 (d, J= 8.46 Hz, 2H), 6.99 (d, J= 8.46 Hz, 1H), 7.15-7.40 (m, J= 8.46 Hz, 4H), 7.85 (s, 1H), 8.62 (s, 1H), 9.08 (d, J= 8.09 Hz, 1H), 9.90 (s, 1H); MS (ESI) m / z 432 (M + H) +, (ESI-) m / z 430 (MH) -.

Example 66

2,2-Dimethyl-N- {4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -propionamide

The product of Example 83 (0.50 g, 0.134 mmol) was dissolved in DMF, treated with 2,2-dimethylpropionyl chloride (0.016 g, 0.134 mmol) and stirred at room temperature for 1 hour. DMF was removed in a stream of N2 and the crude residue was purified by HPLC using TFA to give the title compound as the trifluoroacetic acid salt (40.0 mg, 65%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.22 (s, 9H), 2.35 (s, 3H), 2.76 (s, 3H), 6.33 (d, J= 6.99 Hz, 1H), 7.15 (s, 1H), 7.24 (d, J= 8.46 Hz, 3H), 7.31 (s, 1H), 7.61 (d, J= 8.82 Hz, 2H), 7.80 (s, 1H), 8.42 (s, 1H), 8.96 (s, 1H), 9.27 (s, 1H), 10.99 (s , 1H), MS (ESI +) m / z 457 (M + H) +, (ESI-) m / z 455 (MH) -.

Example 67

N- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -butyramide

The product of Example 83 (0.50 g, 0.134 mmol) was dissolved in DMF and treated with butyryl chloride (0.016 g, 0.134 mmol) and stirred at room temperature for 1 hour. DMF was removed in a stream of N2 and the crude residue was purified by HPLC with TFA to give the title compound as the trifluoroacetic acid salt (41.0 mg, 65%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.91 (t, J= 7.35 Hz, 3H), 1.54-1.65 (m, 2H), 2.27 (t, J= 7.35 Hz, 2H), 2.35 (s, 3H), 2.76 (s, 3H), 6.31 (d, J= 6.99 Hz, 1H), 7.15 (d, J= 8.09 Hz, 1H), 7.21-7.32 (m, 4H), 7.53 (d, J= 8.82 Hz, 2H), 7.78 (d, J= 8.82 Hz, 1H), 8.41 (d, J= 6.99 Hz, 1H), 8.96 (d, J= 8.46 Hz, 1H), 9.98 (s, 1H), 11.00 (s, 1H); MS (ESI +) m / z 443 (M + H) +, (ESI-) m / z 441 (MH) -.

Example 68

{4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -amide of cyclopropanecarboxylic acid

The product of Example 83 (0.50 g, 0.134 mmol) was dissolved in DMF, treated with cyclopropanecarbonyl chloride (0.016 g, 0.134 mmol) and stirred at room temperature for 1 hour. DMF was removed in a stream of N2 and the crude residue was purified by HPLC with TFA to give the title compound as the trifluoroacetic acid salt (25 mg, 40%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.80 (d, J= 6.25 Hz, 4H), 1.71-1.79 (m, 1H), 2.35 (s, 3H), 2.76 (s, 3H), 6.31 (d, J= 7.35 Hz, 1H), 7.16 (d, J= 7.72 Hz, 1H), 7.21-7.32 (m, 4H), 7.51 (d, J= 8.82 Hz, 2H), 7.78 (d, J= 8.82 Hz, 1H), 8.41 (d, J= 7.35 Hz, 1H), 8.96 (d, J= 8.82 Hz, 1H), 10.29 (s, 1H), 10.99 (s, 1H); MS (ESI +) m / z 441 (M + H) +, (ESI-) m / z 439 (MH) -.

Example 69

2- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenylcarbamoyl} -pyrrolidine-1-carboxylic acid benzyl ester

Carbobenzyloxy-proline (0.110 g, 0.443 mmol) was dissolved in THF to which N-methylmorpholine (0.133 g, 0.443 mmol) was added. Then, pure isopropenyl chloroformate (0.053 g, 0.443 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. Then, the product of Example 83 (0.150 g, 0.402 mmol) was added as a THF solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with CH2Cl2, dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound, which was purified by HPLC with TFA, to give the title compound as the trifluoroacetic acid salt (118 mg, 48%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.82-1.98 (m, 3H), 2.22 (s, 2H), 2.35 (s, 3H), 2.75 (s, 3H), 4.27 -4.40 (m, 1H), 4.89-4.98 (m, 1H), 5.00-5.13 (m, 2H), 6.35 (t, J= 6.80 Hz, 1H), 7.06-7.22 (m, 3H), 7.24-7.39 (m, 6H), 7.55 (d, J= 8.46 Hz, 2H), 7.78 (d, J= 8.82 Hz, 1H), 8.44 (d, J= 6.99 Hz, 1H), 8.96 (dd, J= 11.95, 8.64 Hz, 1H), 10.20 (s, 1H), 11.04 (s, 1H), 14.39 (s, 1H); MS (ESI +) m / z 604 (M + H) +, (ESI-) m / z 602 (MH) -.

Example 70

(7-Methyl- [1,8] naphthyridin-4-yl) - [5-methyl-2- (4-phenoxy-phenylsulfanyl) -phenyl] -amine

Example 70a

5-Methyl-2- (4-phenoxy-phenylsulfanyl) -phenylamine

The product of Example 4c (0.500 g, 1.91 mmol) was dissolved in CH2Cl2 with phenylboronic acid (0.701 g, 5.74 mmol), copper (II) acetate (0.659 g, 3.83 mmol) and triethylamine (0.387 g, 3.83 mmol). The mixture was stirred at room temperature for 48 hours, then 2 more equivalents of each reagent were added. The mixture was stirred at room temperature for a further 16 hours, then another 2 equivalents of each reagent were added. The mixture was stirred at room temperature for an additional 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified by chromatography on a silica gel column, eluting with 20% EtOAc / hexane (0.100 g, 15%). The product was reduced with SnCl2 in accordance with the method described in Example 1f, to obtain the title compound (90 mg, 98%).

Example 70b

(7-Methyl- [1,8] naphthyridin-4-yl) - [5-methyl-2- (4-phenoxy-phenylsulfanyl) -phenyl] -amine

The product of Example 1d (50 mg, 0.28 mmol) was reacted with the product of Example 70a (86 mg, 0.28 mmol) for 24 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (64 mg, 50%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.37 (s, 3H), 2.73-2.79 (m, 3H), 6.30 (d, J= 6.99 Hz, 1H), 6.78-6.87 (m, 2H), 6.97 (d, J= 7.72 Hz, 2H), 7.17-7.24 (m, 1H), 7.24-7.28 (m, 2H), 7.32-7.36 (m, 3H), 7, 37-7.46 (m, 2H), 7.79 (d, J= 8.82 Hz, 1H), 8.42 (d, J= 7.35 Hz, 1H), 8.96 (d, J= 8.46 Hz, 1H), 11.00 (s, 1H); MS (ESI +) m / z 450 (M + H) +, (ESI-) m / z 448 (MH) -.

Example 71

N- {3- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 71a

3- (4-Methyl-2-nitro-phenylsulfanyl) -phenylamine

The product of Example 4a (1.00 g, 3.51 mmol) and 3-amino-benzenethiol (658 mg, 5.26 mmol) was dissolved in DMF to which K2CO3 (848 mg, 6.14 mmol). The reaction mixture was then heated to 100 ° C for 16 hours. The reaction mixture was then cooled to room temperature, diluted with water and extracted with ethyl acetate to give the title compound (650 mg, 71%).

Example 71b

N- [3- (4-Methyl-2-nitro-phenylsulfanyl) -phenyl] -acetamide

The product of Example 71a (650 mg, 2.50 mmol) was dissolved in DCM and acetyl chloride (196 mg, 2.50 mmol) was added. The mixture was left stirring at room temperature for 1 hour, then the solid was collected by filtration to give the title compound (690 mg, 61%).

Example 71c

N- [3- (2-Amino-4-methylphenylsulfanyl) -phenyl] -acetamide

The product of Example 71b was reduced with SnCl2 in accordance with the method described in Example 1f, to give the title compound (120 mg, 20%).

Example 71d

N- {3- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 1d (100 mg, 0.559 mmol) was reacted with the product of Example 71c (152 mg, 0.559 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (45 mg, 18%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.97 (s, 3H), 2.38 (s, 3H), 2.74 (s, 3H), 6.26 (d, J= 6.99 Hz, 1H), 6.84 (d, J= 8.46 Hz, 1H), 7.06 (t, J= 8.09 Hz, 1H), 7.25 (d, J= 8.09 Hz, 1H), 7.33-7.41 (m, 2H), 7.41-7.54 (m, 2H), 7.74 (d, J= 8.82 Hz, 1H), 8.33 (d, J= 6.99 Hz, 1H), 8.89 (d, J= 8.82 Hz, 1H), 9.81 (s, 1H), 10.91 (s, 1H); MS (ESI +) m / z 415 (M + H) +, (ESI-) m / z 413 (MH) -.

Example 72

{2- [4- (1-imino-ethyl) -phenylsulfanyl] -5-methylphenyl} - (7-methyl- [1,8] naphthyridin-4-yl) amine

Example 72a

Naphthalene-2-ylmethyl ester of thioacetimidic acid; HBr salt

2-Bromomethyl-naphthalene (2.00 g, 9.05 mmol) and thioacetimide (680 mg, 9.05 mmol) were dissolved in CH3Cl and stirred at room temperature for 1 hour. The product was collected by filtration to give the title compound (1.500 g, 77%).

Example 72b

{2- [4- (1-imino-ethyl) -phenylsulfanyl] -5-methylphenyl} - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 72a (239 mg, 0.805 mmol) and the product of Example 83 (150 mg, 0.403 mmol) were dissolved in EtOH and stirred at room temperature for 1 hour. The solvent was concentrated in vacuo to give the crude title compound, which was purified by HPLC with TFA, to give the title compound as the trifluoroacetic acid salt (118 mg, 70%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.32 (s, 3H), 2.36-2.43 (m, 3H), 2.76 (s, 3H), 6.38 (d, J= 6.99 Hz, 1H), 7.19-7.27 (m, 2H), 7.32-7.45 (m, 5H), 7.79 (d, J= 8.82 Hz, 1H), 8.44 (d, J= 6.99 Hz, 1H), 8.57 (s, 1H), 8.89-9.00 (m, 1H), 9.55 (s, 1H), 11.10 (s, 1H); MS (ESI +) m / z 414

(M + H) +, (ESI-) m / z 412 (MH) -.

Example 73

1- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -ethanethione

The product of Example 18 (265 mg, 0.639 mmol) and Lawesson's reagent (517 mg, 1.28 mmol) were dissolved in 3 ml of toluene and heated to 80 ° C. for 16 hours. The reaction mixture was cooled to room temperature, washed with water, and extracted with EtOAc. Dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound, which was purified by HPLC with TFA, to give trifluoroacetic acid salt (14 mg, 5%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.33 (s, 3H), 2.59 (s, 3H), 2.63 (s, 3H), 3.75 (s, 1H), 6.17 (s, 1H ), 6.88 (d, J= 10.30 Hz, 1H), 7.06-7.21 (m, 3H), 7.21-7.27 (m, 2H), 7.39 (d, J= 8.46 Hz, 1H), 7.78 (d, J= 8.46 Hz, 2H), 8.63 (d, J= 8.82 Hz, 1H), 11.59 (s, 1H); MS (ESI +) m / z 431 (M + H) +, (ESI-) m / z 429 (MH) -.

Example 74

N- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -2-phenyl-butyramide

A 2-phenylbutanoic acid (27 mg, 0.16 mmol) dissolved in 3 ml of DMA was added to a vessel containing 3 equivalents of PS-DCC resin (polymer bound "N, N, '-dicyclohexylcarbodiimide), then HOBt (22 mg, 0.16 mmol), the product of Example 83 (50 mg, 0.134 mmol) and diethylisopropylamine (52 mg, 0.402 mmol). The reaction mixture was heated to 55 ° C. overnight, filtered and transferred to a vessel containing 3 equivalents of MP-carbonate (macroporous carbonate) resin. The reaction vessel and the PS-DCC resin were washed with MeOH and the combined filtrates were shaken over the MP-carbonate resin for 2 hours at room temperature. The MP-carbonate resin was removed by filtration and the reaction mixture was concentrated to dryness. Purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (2 mg, 4%).11H NMR (500 MHz, DMSO-D2O) δ ppm: 0.83-0.89 (m, 3H), 1.66-1.74 (m, J= 7.17, 6.90, 6.90, 6.90, 6.90 Hz, 1H), 2.00-2.08 (m, 1H), 2.32-2.38 (m, 3H) , 2.72-2.75 (m, 3H), 3.53-3.57 (m, 1H), 6.37 (d, J= 7.02 Hz, 1H), 7.14-7.19 (m, 1H), 7.21 (d, J= 8.85 Hz, 2H), 7.24-7.31 (m, 3H), 7.32-7.39 (m, 4H), 7.50 (dd, J= 8.85, 1.53 Hz, 2H), 7.69 (d, J= 8.85 Hz, 1H), 8.39 (d, J= 7.02 Hz, 1H), 8.84-8.88 (m, 1H), 10.28 (s, 1H); MS (ESI +) m / z 519; (ESI-) m / z 517, 631 (M + TFA-H) -.

Example 75

N- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -4-phenyl-butyramide

The title compound was obtained using 4-phenylbutanoic acid (27 mg, 0.16 mmol) as acid, according to the method described in Example 74 (1 mg, 2%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.85-1.92 (m, J= 7.55, 7.55, 7.55, 7.55 Hz, 2H), 2.32 (t, J= 7.32 Hz, 2H), 2.36 (s, 3H), 2.59-2.64 (m, J= 7.63 Hz, 2H), 2.74 (s, 3H), 6.34 (d, J= 7.02 Hz, 1H), 7.17-7.23 (m, 6H), 7.29-7.35 (m, 4H), 7.45 (d, J= 8.85 Hz, 2H), 7.73 (d, J= 8.54 Hz, 1H), 8.36 (d, J= 7.32 Hz, 1H), 8.89 (d, J= 8.54 Hz, 1H); MS (ESI +) m / z 519; (ESI-) m / z 517, 631 (M + TFA-H) -.

Example 76

N- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -2-o-tolyloxy-acetamide

The title compound was prepared using o-tolyloxy-acetic acid (26 mg, 0.16 mmol) as acid, according to the method described in Example 74 (3 mg, 5%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.25 (s, 3H), 2.36 (s, 3H), 2.75 (s, 3H), 4.70 (s, 2H), 6.34 (d, J= 7.32 Hz, 1H), 6.86 (d, J= 7.93 Hz, 1H), 6.90 (t, J= 7.32 Hz, 1H), 7.14-7.20 (m, 2H), 7.21-7.26 (m, 3H), 7.30-7.33 (m, 2H), 7, 48 (d, J= 8.54 Hz, 2H), 7.73 (d, J= 8.85 Hz, 1H), 8.36 (d, J= 7.02 Hz, 1H), 8.88 (d, J= 8.85 Hz, 1H); MS (ESI +) m / z 521; (ESI-) m / z 519, 633 (M + TFA-H) -.

Example 77

N- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -2-p-tolyloxy-acetamide

The title compound was obtained using p-tolyloxy-acetic acid (26 mg, 0.16 mmol) as acid, according to the method described in Example 74 (3 mg, 5%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.24 (s, 3H), 2.36 (s, 3H), 2.75 (s, 3H), 4.64 (s, 2H), 6.33 (d, J= 7.32 Hz, 1H), 6.89 (d, J= 8.54 Hz, 2H), 7.13 (d, J= 8.24 Hz, 2H), 7.21 (d, J= 8.85 Hz, 2H), 7.25-7.29 (m, 1H), 7.31-7.33 (m, 2H), 7.48 (d, J= 8.54 Hz, 2H), 7.72 (d, J= 8.54 Hz, 1H), 8.35 (d, J= 7.02 Hz, 1H), 8.87 (d, J= 8.85 Hz, 1H); MS (ESI +) m / z 521; (ESI-) m / z 519, 633 (M + TFA-H) -.

Example 78

2-Methoxy-N- {4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -2-phenyl-acetamide

The title compound was prepared using, as acid, R-methoxy-phenyl-acetic acid (26 mg, 0.16 mmol) according to the method described in Example 74 (3 mg, 5%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.35 (s, 3H), 2.73 (s, 3H), 3.36 (s, 3H), 4.82 (s, 1H), 6.36 (d, J= 7.02 Hz, 1H), 7.21 (d, J= 8.54 Hz, 3H), 7.28-7.33 (m, 2H), 7.37 (d, J= 7.02 Hz, 1H), 7.41 (t, J= 7.32 Hz, 2H), 7.47 (d, J= 7.02 Hz, 2H), 7.53-7.58 (m, 2H), 7.69 (d, J= 8.85 Hz, 1H), 8.38 (d, J= 7.02 Hz, 1H), 8.86 (d, J= 8.54 Hz, 1H); MS (ESI +) m / z 521; (ESI-) m / z 519, 633 (M + TFA-H) -.

Example 79

2-Methoxy-N- {4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -2-phenyl-acetamide

The title compound was obtained using S-methoxy-phenyl-acetic acid (26 mg, 0.16 mmol) as acid, according to the method described in Example 74 (3 mg, 5%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.35 (s, 3H), 2.73 (s, 3H), 3.36 (s, 3H), 4.82 (s, 1H), 6.36 (d, J= 7.32 Hz, 1H), 7.21 (d, J= 8.54 Hz, 3H), 7.29-7.32 (m, 2H), 7.35-7.38 (m, 1H), 7.41 (t, J= 7.17 Hz, 2H), 7.46-7.49 (m, 2H), 7.54-7.57 (m, 2H), 7.69 (d, J= 8.54 Hz, 1H), 8.38 (d, J= 7.02 Hz, 1H), 8.86 (d, J= 8.54 Hz, 1H); MS (ESI +) m / z 521; (ESI-) m / z 519, 633 (M + TFA-H) -.

Example 80

({4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenylcarbamoyl} -methyl) -amide of furan-3-carboxylic acid

The title compound was obtained using [(furan-2-carbonyl) -amino] -acetic acid (27 mg, 0.16 mmol) as an acid in accordance with the method described in Example 74 (1 mg, 2%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.36 (s, 3H), 2.75 (s, 3H), 4.02 (s, 2H), 6.34 (d, J= 7.02 Hz, 1H), 6.67 (dd, J= 3.66, 1.83 Hz, 2H), 7.16 (d, J= 3.05 Hz, 1H), 7.22 (t, J= 8.85 Hz, 3H), 7.29-7.33 (m, 2H), 7.46 (d, J= 8.85 Hz, 2H), 7.74 (d, J= 8.54 Hz, 1H), 7.85 (s, 1H), 8.37 (d, J= 7.32 Hz, 1H), 8.87 (d, J= 8.85 Hz, 1H); MS (ESI +) m / z 524; (ESI-) m / z 521.

Example 81

N- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -4-thiophen-3-yl-butyramide

The title compound was prepared using 4-thiophen-2-yl-butanoic acid (27 mg, 0.16 mmol) as acid, according to the method described in Example 74 (0.7 mg, 1%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.89-1.96 (m, 2H), 2.34-2.39 (m, 5H), 2.75 (s, 3H), 2.85 (t, J= 7.63 Hz, 2H), 6.34 (d, J= 7.32 Hz, 1H), 6.88 (d, J= 2.44 Hz, 1H), 6.96 (dd, J= 5.19, 3.36 Hz, 1H), 7.18-7.25 (m, 3H), 7.29-7.33 (m, 3H), 7.45 (d, J= 8.85 Hz, 2H), 7.73 (d, J= 8.54 Hz, 1H), 8.36 (d, J= 7.32 Hz, 1H), 8.89 (d, J= 8.54 Hz, 1H); MS (ESI +) m / z 525; (ESI-) m / z 523, 637 (M + TFA-H) -.

Example 82

{4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -amide of 1-acetyl-piperidine-4-carboxylic acid

The title compound was obtained using 1-acetyl-piperidine-4-carboxylic acid as the acid (27 mg, 0.16 mmol) according to the method described in Example 74 (0.7 mg, 1%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.77-1.84 (m, 2H), 2.03 (s, 3H), 2.36 (s, 4H), 2.56-2.64 (m, 2H) , 2.75 (s, 3H), 3.05-3.12 (m, 1H), 3.83-3.91 (m, 1H), 4.37-4.43 (m, 1H), 6 , 30-6.36 (m, 1H), 7.18-7.25 (m, 4H), 7.29-7.34 (m, 2H), 7.41-7.48 (m, 2H) , 7.72-7.77 (m, 1H), 8.34-8.38 (m, 1H), 8.87-8.91 (m, 1H); MS (ESI +) m / z 526; (ESI-) m / z 524, 638 (M + TFA-H) -.

Example 83

[2- (4-Amino-phenylsulfanyl) -5-methylphenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 18 (200 mg, 0.48 mmol) was suspended in 6N HCl. HCl (10 ml) and heated in air to 100 ° C for one hour. The solution was then cooled in an ice bath and basified with solid NaOH (2.64 g). The crude product was isolated by extraction with dichloromethane and purified by HPLC with TFA, which gave the title compound as the trifluoroacetic acid salt (96.1 mg, 37%).11H-NMR (300 MHz, DMSO-d6th) δ ppm; 2.31 (s, 3H), 2.77 (s, 3H), 6.30 (d,J= 6.99 Hz, 1H), 6.57 (d, J= 8.46 Hz, 2H), 6.90 (d, J= 7.72 Hz, 1H), 7.07 (d, J= 8.46 Hz, 2H), 7.23 (m, J= 7.72 Hz, 2H), 7.81 (d, J= 8.82 Hz, 1H), 8.46 (d, J= 7.35 Hz, 1H), 9.04 (d, J= 8.46 Hz, 1H), 11.05 (s, 1H). MS (ESI +) m / z 373.1 (M + H) +; (ESI-) m / z 371.1 (MH) -.

Example 84

4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide

Example 84a

4- (4-Methyl-2-nitro-phenylsulfanyl) -benzoic acid

The product of Example 4a (0.94 g, 3.31 mmol) was reacted with 4-mercapto benzoic acid (0.51 g, 3.31 mmol) in aqueous ethanol at 80 ° C. under a nitrogen atmosphere. The reaction mixture was poured into water and acidified with glacial acetic acid. The solid was collected by filtration, washed with water and dried in vacuo to give the title compound (0.877 g, 91%), sufficiently pure for use as it was isolated.

Example 84b

4- (4-Methyl-2-nitro-phenylsulfanyl) -benzamide

The product of Example 84a (0.3 g, 1.04 mmol) was dissolved in THF (15 mL) and treated with N-methylmorpholine (0.131 mL, 1.19 mmol), then cooled in an ice bath and isobutyl chloroformate (0.148 mL, 1 , 14 mmol). The resulting mixture was allowed to warm to room temperature with stirring for thirty minutes. Further cooled in an ice bath, then ammonia gas was added and warmed to room temperature. The title compound was isolated by adding water and collecting the solid product by vacuum filtration, used without further purification (0.289 g, 96%).

Example 84c

The product of Example 84c (0.289 g, 1.0 mmol) was reacted with tin (0.95 g, 5 mmol) as described in Example 1f to give the title compound as an off-white solid (0.226 g , 88%).

Example 84d

4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide

The product of Example 1d (0.156 g, 0.875 mmol) was reacted with the product of Example 84d (0.226 g, 0.875 mmol) for 24 hours according to the method described in Example 1g to give the crude title compound which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (0.185 g, 38%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.37-2.46 (m, 3H), 2.74 (s, 3H), 6.36 (d, J = 6.99 Hz, 1H), 7.19 (d , J = 8.46 Hz, 2H), 7.31-7.46 (m, 3H), 7.47-7.57 (m, 1H), 7.68 (d, J = 8.46 Hz, 2H), 7.75 (d, J = 8.46 Hz, 1H), 7.90 (s, 1H), 8.39 (d, J = 7.35 Hz, 1H), 8.90 (d, J = 8.46 Hz, 1H), 11.02 (s, 1H); MS (ESI +) m / z 401.0 (M + H) +; (ESI-) m / z 399.0 (MH-).

Example 85

N-Methyl-4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide

Example 85a

N-Methyl-4- (4-nitro-phenylsulfanyl) -benzamide

The product of Example 84b (0.32 g, 1.11 mmol) was reacted as described in Example 84c, using N-methyl amine in methanol instead of ammonia to give the title compound (0.32 g, 94%).

Example 85b

4- (2-Amino-4-methyl-phenylsulfanyl) -N-methyl-benzamide

The product of Example 85a was reacted as described in Example 84d to give the title compound (0.28 g, 97%).

Example 85c

N-Methyl-4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide

The product of Example 85b (0.277 g, 1.05 mmol) was reacted with the product of Example 1d (0.09 g, 0.504 mmol) for 41 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (0.078 g, 28%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.41 (s, 3H), 2.70-2.82 (m, 6H), 6.36 (d, J= 6.99 Hz, 1H), 7.20 (d, J= 8.46 Hz, 2H), 7.35-7.45 (m, 2H), 7.51 (d, 1H), 7.64 (d, J= 8.46 Hz, 2H), 7.75 (d, J= 8.82 Hz, 1H), 8.33-8.45 (m, 2H), 8.90 (d, J= 8.82 Hz, 1H), 11.03 (s, 1H); MS (ESI +) m / z 415.0 (M + H) +; (ESI-) m / z 413.1 (MH) -.

Example 86

3- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide

Example 86a

3- (4-Methyl-2-nitro-phenylsulfanyl) -benzoic acid

The product of Example 84a (0.94 g, 3.29 mmol) was reacted with 3-mercapto-benzoic acid (0.51 g, 3.31 mmol) as described in Example 84b to give the title compound (0 , 77 g, 80%).

Example 86b

3- (4-methyl-2-nitrophenylsulfanyl) -benzamide

The product of Example 86a (0.25 g, 0.86 mmol) was reacted as described in Example 84c to give the title compound (0.238 g, 95%).

Example 86c

3- (4-methyl-2-amino-phenylsulfanyl) -benzamide

The product of Example 86b was reacted as described in Example 84d to give the title compound (0.204 g, 96%).

Example 86d

3- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide

The product of Example 86c (0.204 g, 0.79 mmol) was reacted with the product of Example 1d (0.144 g, 0.79 mmol) for 24 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (0.159 g, 38%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm. 2.39 (s, 3H), 2.74 (s, 3H), 6.31 (d, J = 6.99 Hz, 1H), 7.18-7.55 (m, 6H), 7.61 -7.79 (m, 3H), 7.90 (s, 1H), 8.37 (d, J = 6.99 Hz, 1H), 8.88 (d, J = 8.82 Hz, 1H) ; MS (ESI +) m / z 401.0 (M + H) +; (ESI-) m / z 399.0 (MH) -.

Example 87

N-Methyl-3- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide

Example 87a

N-Methyl-3- (4-methyl-3-nitro-phenylsulfanyl) -benzamide

The product of Example 86a (0.25 g, 0.86 mmol) was reacted as described in Example 84c using N-methylamine in methanol instead of ammonia to give the title compound (0.25 g, 96%).

Example 87b

N-Methyl-3- (4-methyl-2-amino-phenylsulfanyl) -benzamide

The product of Example 87a was reacted as described in Example 84d to give the title compound (0.208 g, 92%).

Example 87c

N-Methyl-3- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide

The product of Example 87b (0.208 g, 0.76 mmol) was reacted with the product of Example 1d (0.136 g, 0.76 mmol) for 24 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (0.204, 49%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.39 (s, 3H), 2.65-2.81 (m, 6H), 6.27 (d, J = 7.35 Hz, 1H), 7.20-7 , 82 (m, 8H), 8.35 (d, J = 6.99 Hz, 2H), 8.87 (d, J = 8.46 Hz, 1H), 10.97 (s, 1H); MS (ESI +) m / z 415.0 (M + H) +; (ESI-) m / z 413.0 (MH) -.

Example 88

N, N-Dimethyl-3- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide

Example 88a

N, N-Dimethyl-3- (4-methyl-2-nitro-phenylsulfanyl) -benzamide

The product of Example 86a (0.25 g, 0.86 mmol) was reacted as described in Example 84c, using N, N-dimethylamine in methanol instead of ammonia to give the title compound (0.26 g, 100%) .

Example 88b

3- (2-Amino-4-methylphenylsulfanyl) -N, N-dimethylbenzamide

The product of Example 88a was reacted as described in Example 84d, to obtain the title compound (0.175 g, 71%).

Example 88c

N, N-Dimethyl-3- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide

The product of Example 88b (0.175 g, 0.610 mmol) was reacted with the product of Example 1d (0.109 g, 0.61 mmol) for 24 hours according to the method described in Example 1g to give the crude title compound which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (0.1552 g, 45%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.40 (s, 3H), 2.75 (s, 6H), 2.92 (s, 3H), 6.34 (d, J= 6.99 Hz, 1H), 7.11-7.53 (m, 7H), 7.76 (d, J= 8.82 Hz, 1H), 8.39 (d, J= 6.99 Hz, 1H), 8.94 (d, J= 8.82 Hz, 1H); MS (ESI +) m / z 429.0 (M + H) +; (ESI-) m / z 427.0 (MH) -.

Example 89

[2- (2-Fluoro-phenylsulfanyl) -5-methylphenyl] - (7-methyl- [1,8] naphthyridin-4- yl) amine

Example 89a

1- (2-Fluoro-phenylsulfanyl) -4-methyl-2-nitro-benzene

The product of Example 4a (1.50 g, 5.3 mmol) and 2-fluorobenzenethiol (0.56 mL, 5.3 mmol) in EtOH (15 mL) was added dropwise to an aqueous Na2CO3 (0.563 g, 5.3 mmol) at room temperature. The mixture was heated to reflux for 1 hour and then evaporated. The residue was diluted with EtOAc, washed with H2O, 5% KOH and saturated brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as yellow crystals which were purified by washing with cold n-hexane to give the title product as yellow crystals (1.15 g, 83%).

Example 89b

2- (2-Fluoro-phenylsulfanyl) -5-methylphenylamine

The product of Example 89a was reduced with Fe and NH4Cl in accordance with the method described in Example 237e to obtain the title compound.

Example 89c

[2- (2-Fluoro-phenylsulfanyl) -5-methylphenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 1d (200 mg, 1.12 mmol) was reacted with the product of Example 89b (260 mg, 1.12 mmol) for 72 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (180 mg, 43%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.32 (s, 3H), 2.62 (s, 3H), 6.11 (brs, 1H), 6.95-7.45 (m, 8H), 8 , 26 (brs, 1H), 8.55-8.70 (m, 1H), 9.08 (brs, 1H); MS (ESI +) m / z 376 (M + H) +, (ESI-) m / z 374 (MH) -.

Example 90

[3- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-phenylsulfanyl-benzyl] -carbamic acid t-butyl ester

Example 90a

3-Nitro-4- (phenylthio) benzonitrile

A solution of sodium thiophenolate (16.29 g, 123.3 mmol) in 150 ml of DMF was heated at 100 ° C. with 4-chloro-3-nitrobenzonitrile (15.0 g, 82.2 mmol) with stirring for 24 hours. The mixture was cooled to room temperature and diluted with EtOAc. Wash with water and dry the organic layer over MgSO4, filtered and concentrated in vacuo to give the title compound, which was purified by chromatography on a silica gel column, eluting with 5% EtOAc / hexanes to give a yellow solid (4.0 g, 19%).

Example 90b

tert-Butyl 3-amino-4- (phenylthio) benzylcarbamate

A solution of the product of Example 90a (4.0 g, 15.6 mmol) and di-t-butyl dicarbonate (1.70 g, 7.79 mmol) was subjected to catalytic reduction using Ra-Ni in MeOH at 60 pounds per square in atmosphere H2. Removal of the catalyst and concentration in vacuo gave the title compound, which was purified by chromatography on a silica gel column eluting with 10% EtOAc / hexane to give a mixture of two examples as a clear oil (2.41 g, 46%).

Example 90d

tert-Butyl (3- (7-methyl-1,8-naphthyridin-4-ylamino) -4- (phenylthio) phenyl) methylcarbamate

The product of Example 1d (557 mg, 3.12 mmol) was reacted with the product of Example 90b (1.032 mg, 3.12 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (310 mg, 17%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.37 (s, 9H), 2.76 (s, 3H), 4.19 (d, J= 6.25 Hz, 2H), 6.29 (d, J= 6.99 Hz, 1H), 7.25 (s, 5H), 7.31 (s, 1H), 7.37 (d, J= 3.31 Hz, 2H), 7.44-7.56 (m, 1H), 7.79 (d, J= 8.82 Hz, 1H), 8.42 (d, J= 6.99 Hz, 1H), 8.94 (d, J= 8.46 Hz, 1H), 11.05 (s, 1H), 14.43 (s, 1H); MS (ESI +) m / z 473 (M + H) +.

Example 91

[2- (2,5-Dimethyl-furan-3-ylsulfanyl) -5-methylphenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

Example 91a

2,5-Dimethyl-3- (4-methyl-2-nitro-phenylsulfanyl) -furan

The title compound was obtained from 1-chloro-4-methyl-2-nitrobenzene (2.00 g, 11.7 mmol), 2,5-dimethyl furan-3-thiol (1.50 g, 11 , 7 mmol) and K2CO3 (3.233 g, 23.4 mmol) was heated in DMF at 100 ° C. for 4 hours. The reaction mixture was then cooled to room temperature, diluted with water and extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (3.5 g, 85%).

Example 91b

2- (2,5-Dimethyl-furan-3-ylsulfanyl) -5-methylphenylamine

The product of Example 91a was reduced with SnCl2 in accordance with the method described in Example 1f, to obtain the title compound.

Example 91c

[2- (2,5-Dimethyl-furan-3-ylsulfanyl) -5-methylphenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 1d (50 mg, 0.217 mmol) was reacted with the product of Example 91b (51 mg, 0.217 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (2.6 mg, 3.2%). 11H NMR (300 MHz, DMSO-d6)? Ppm: 2.15 (d, J= 15.08 Hz, 6H), 2.33 (s, 3H), 2.77 (s, 3H), 5.98 (s, 1H), 6.29 (d, J= 6.99 Hz, 1H), 7.08 (d, J= 8.09 Hz, 1H), 7.24-7.39 (m, 2H), 7.83 (d, J= 8.46 Hz, 1H), 8.47 (d, J= 6.62 Hz, 1H), 9.03 (d, J= 8.46 Hz, 1H), 11.04 (s, 1H); MS (ESI +) m / z 378 (M + H-TFA) +; (ESI +) m / z 399 (M + Na-TFA) -; (ESI +) m / z 773 (2M + Na-TFA) -.

Example 92

(4- {2- [ethoxycarbonylmethyl- (7-methyl- [1,8] naphthyridin-4-yl) -amino] -4-methylphenylsulfanyl} -phenoxy) -acetic acid ethyl ester

The product of Example 5 (200 mg, 0.536 mmol) was suspended in acetone to which K2CO3 (81 mg, 0.589 mmol) and bromoethyl acetate (89 mg, 0.536 mmol). The reaction mixture was then heated to reflux for 4 hours, the reaction mixture was cooled to room temperature and the solvent was removed in vacuo. Purified by HPLC with TFA, which gave the product as trifluoroacetic acid (15 mg, 6%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.21 (td, J= 7.08, 2.39 Hz, 6H), 2.35 (s, 3H), 2.73 (s, 3H), 4.18 (ddd, J= 14.16, 10.66, 7.17 Hz, 4H), 4.76 (s, 2H), 5.46 (s, 2H), 6.47 (d, J= 7.35 Hz, 1H), 6.87 (d, J= 8.82 Hz, 2H), 7.14 (d, J= 8.09 Hz, 1H), 7.21-7.42 (m, 4H), 7.86 (d, J= 8.46 Hz, 1H), 8.61 (d, J= 7.72 Hz, 1H), 9.03 (d, J= 8.46 Hz, 1H); MS (ESI +) m / z 546 (M + H-TFA) +.

Example 93

[3-Chloro-4- (4-chloro-phenoxy) -phenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

Example 93a

2-Chloro-1- (4-chloro-phenoxy) -4-nitro-benzene

A solution of 1,2-dichloro-4-nitrobenzene (9.2 g, 48 mmol), 4-chloro-phenol (6.2 g, 48 mmol) and potassium carbonate (19.9 g, 144 mmol) in DMF (80 ml) was heated to 90oC for 16 hours. After cooling to room temperature, the mixture was poured into water (600 ml) and extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (13.5 g, 99%).

Example 93b

3-Chloro-4- (4-chloro-phenoxy) -phenylamine

A solution of the product of Example 93a (8.49 g, 30 mmol), iron powder (8.4 g, 150 mmol) and ammonium chloride (2.4 g, 45 mmol) in ethanol (180 mL), THF (210 mL) and water (60 ml) was heated to reflux for 16 hours. The resulting mixture was cooled and filtered through a pad of celite. The filtrate was partitioned between water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel, eluting with hexane-hexane / ethyl acetate (8: 2) to give the title compound (6.5 g, 86%).

Example 93c

[3-Chloro-4- (4-chloro-phenoxy) -phenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

The compound of Example 93b (254 mg, 1.0 mmol) and the compound of Example 1d (179 mg, 1.0 mmol) were boiled in ethanol (10 mL) for 16 hours. The mixture was cooled to room temperature and filtered, the solid was washed with ethyl acetate, dried to give the title compound as the hydrochloride salt (411 mg, 95%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.76 (s, 3H), 6.94 (d, J = 7.35 Hz, 1H), 7.10 (m, 2H), 7.33 (d, J = 8 , 46 Hz, 1H), 7.49 (m, 3H), 7.80 (m, 2H), 8.53 (d, J = 6.99 Hz, 1H), 9.18 (d, J = 8 , 82 Hz, 1H), 11.34 (s, 1H), 14.49 (s, 1H); (ESI-) m / z 394 (MH) -.

Example 94

[2- (4-Methoxy-phenylsulfanyl) -5-methylphenyl] - (7-trifluoromethyl- [1,8] naphthyridin-4-yl) amine

The product of Example 7d (50 mg, 0.215 mmol) was reacted with the product of Example 50b (53 mg, 0.215 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified with HPLC with TFA, which gave the product as trifluoroacetic acid (28 mg, 30%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.35 (s, 3H), 3.71 (s, 3H), 6.38 (d, J= 6.99 Hz, 1H), 6.78-6.89 (m, 2H), 7.11-7.19 (m, 1H), 7.23-7.32 (m, 4H), 8, 41 (d, J= 8.46 Hz, 1H), 8.58 (d, J= 6.99 Hz, 1H), 9.43 (d, J= 8.46 Hz, 1H); MS (ESI +) m / z 442 (M + H-TFA) +; (ESI-) m / z 440 (MH-TFA) -.

Example 95

4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -N-phenyl-benzamide

Example 95a

4-Methyl-2-nitro-benzoic acid

A suspension of 4-methyl-2-nitrobenzonitrile (5.00 g, 30.8 mmol) and 50% H2SO4 (25 ml) in HOAc (25 ml) was heated to reflux for 22 hours. The reaction mixture was poured into ice-water (150 g) with stirring and stirred at 5 ° C for 30 minutes. The crystals formed were collected by filtration, washed with H2O and n-hexane and dried at 40 ° C in vacuo to give the title compound as pale brown crystals (4.85 g, 87%).

Example 95b

4-Methyl-2-nitro-N-phenyl-benzamide

The product of Example 95a (1.00 g, 5.5 mmol) and SOCl2 (4.03 ml, 55.0 mmol) was boiled for 2 hours. Excess SOCL2 was removed under reduced pressure to give the acid chloride of the corresponding acid as a pale yellow oil. To the solution of the acid chloride prepared above in THF (15 mL) aniline (0.53 mL, 5.8 mmol) and Et3N (1.17 mL, 8.3 mmol) at 5 ° C, and the mixture was stirred at room temperature for 3.5 days. The reaction mixture was evaporated. The residue was diluted with H2O, acidified to pH 3 with 10% HCl and then extracted with EtOAc. The extract was washed with 10% NaHCO33, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as pale brown crystals which were purified by washing with n-hexane to give the desired product as pale brown crystals (0.80 g, 57%).

Example 95c

2-Amino-4-methyl-N-phenyl-benzamide

The product of Example 95b was reduced with Fe and NH4Cl in accordance with the method described in Example 237e to obtain the title compound.

Example 95d

4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -N-phenyl-benzamide

The product of Example 1d (150 mg, 0.84 mmol) was reacted with the product of Example 95c (190 mg, 0.84 mmol) for 6 hours according to the method described in Example 1g to give the crude title compound, which was purified by chromatography on a silica gel column, eluting with a 50: 1 CH2Cl2/ MeOH to give the title compound (210 mg, 68%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.40 (s, 3H), 2.68 (s, 3H), 6.62 (d, J= 6.9 Hz, 1H), 6.98 (t, J= 7.3 Hz, 1H), 7.19 (t, J= 7.3 Hz, 2H), 7.36 (s, 1H), 7.38 (d, J= 8.3 Hz, 1H), 7.52 (d, J= 7.3 Hz, 2H), 7.67 (d, J= 8.8 Hz, 1H), 7.78 (d, J= 8.3 Hz, 1H), 8.40 (d, J= 6.9 Hz, 1H), 8.94 (d, J= 8.8 Hz, 1H); MS (ESI +) m / z 369 (M + H), ESI-m / z 367 (MH).

Example 96

N- [3- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-phenylsulfanyl-phenyl] -acetamide

Example 96a

3-Nitro-4-phenylsulfanyl-phenylamine

A mixture of 2-nitro-4-chloroaniline (1.0 g, 5.79 mmol), sodium thiophenolate (0.84 g, 6.4 mmol) in DMF (10 mL) was heated at 100 ° C for 2.5 hours. The mixture was cooled, diluted with ethyl acetate (100 ml), and the organic layer was washed with water, 20% aqueous potassium hydroxide solution and aqueous 10% sodium chloride solution, then dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was concentrated in vacuo to give the title compound as a red solid (0.98 g, 69%).

Example 96b

N- (3-Nitro-4-phenylsulfanyl-phenyl) -acetamide

The product of Example 96a (0.98g, 3.97 mmol) in pyridine (10 ml) was treated with acetic anhydride (0.38 g, 3.74 mmol) and heated at 80 ° C for 2 hours, the solvent was concentrated in vacuo, which gave the title compound as a red oil which was used without further purification (0.96 g, 98%).

Example 96c

N- (3-Amino-4-phenylsulfanyl-phenyl) -acetamide

The product solution of Example 96b was reduced with Fe and NH4Cl in accordance with the method described in Example 237e to obtain the title compound.

Example 96d

N- [3- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-phenylsulfanyl-phenyl] -acetamide

The product of Example 1d (100 mg, 0.560 mmol) was reacted with the product of Example 96c (140 mg, 0.560 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (77 mg, 27%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.08 (s, 3H), 2.75 (s, 3H), 6.33 (d, J = 7.35 Hz, 1H), 7.06-7.26 (m , 4H), 7.43-7.61 (m, 2H), 7.77 (d, J = 8.46 Hz, 1H), 7.97 (d, J = 1.84 Hz, 1H), 8 , 39 (d, J = 6.99 Hz, 1H), 8.89 (d, J = 8.82 Hz, 1H), 10.36 (s, 1H), 11.02 (s, 1H), 14 , 36 (s, 1H); MS (ESI +) m / z 401 (M + H) +, (ESI-) m / z 399 (M + H) -.

Example 97

[2- (4-Methoxy-phenylsulfanyl) -5-methylphenyl] - (7-propyl- [1,8] naphthyridin-4-yl) amine

The product of Example 2g (275 mg, 1.33 mmol) was reacted with the product of Example 50b (326 mg, 1.33 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (392 mg, 56%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J= 7.35 Hz, 3H), 1.85 (m, 2H), 2.34 (s, 3H), 3.00 (t, J= 7.54 Hz, 2H), 3.72 (s, 3H), 6.27 (d, J= 6.99 Hz, 1H), 6.84 (d, J= 8.82 Hz, 2H), 7.11 (d, J= 7.72 Hz, 1H), 7.27 (m, 4H), 7.83 (d, J= 8.82 Hz, 1H), 8.41 (d, J= 6.99 Hz, 1H), 9.02 (d, J= 8.46 Hz, 1H), 11.06 (brs, 1H), 14.37 (brs, 1H); MS (ESI +) m / z 416 (M + H) +.

Example 98

3- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 2g (275 mg, 1.33 mmol) was reacted with the product of Example 52b (307 mg, 1.33 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (305 mg, 45%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (t, J= 7.35 Hz, 3H), 1.75-1.94 (m, 2H), 2.38 (s, 3H), 2.98 (t, J= 7.35 Hz, 2H), 6.30 (d, J= 6.99 Hz, 1H), 6.49-6.66 (m, 3H), 6.91-7.04 (m, 1H), 7.29-7.44 (m, 3H), 7, 79 (d, J= 8.82 Hz, 1H), 8.39 (d, J= 7.35 Hz, 1H), 8.96 (d, J= 8.46 Hz, 1H), 9.57 (s, 1H), 10.95 (s, 1H), 14.34 (s, 1H); MS (ESI +) m / z 402 (M + H-TFA) +.

Example 99

4- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl ester of propan-2-sulfonic acid

The product of Example 6 (120 mg, 0.274 mmol) was reacted with isopropylsulfonyl chloride (43 mg, 0.30 mmol), N, N-diisopropylethylamine (43 mg, 0.33 mmol) and a catalytic amount of DMAP in CH2Cl2 for 18 hours to give the crude title compound, which was purified by HPLC using TFA, to give the product as trifluoroacetic acid (40 mg, 23%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 8.75 (d, J= 8.54 Hz, 1H), 8.20 (d, J= 6.71 Hz, 1H), 7.58 (d, J= 8.54 Hz, 1H), 7.26 (d, J= 7.93 Hz, 1H), 7.17-7.21 (m, 2H), 7.08 (d, J= 9.16 Hz, 2H), 6.95 (d, J= 8.54 Hz, 2H), 6.15 (d, J= 6.71 Hz, 1H), 3.43-3.51 (m, J= 13.43, 1H), 2.79 (t, J= 7.63, 7.63 Hz, 2H), 2.20 (s, 3H), 1.61-1.67 (m, 2H), 1.21 (d, J= 6.71 Hz, 6H), 0.78 (t, J= 7.32 Hz, 3H); MS

(ESI +) m / z 508 (M + H) +.

Example 100

4- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl ester of methanesulfonic acid

The product of Example 6 (100 mg, 0.228 mmol) was reacted with methanesulfonyl chloride (28 mg, 0.251 mmol), N, N-diisopropylethylamine (88.4 mg, 0.684 mmol) and a catalytic amount of DMAP in CH2Cl2 for 18 hours to give the crude title compound, which was purified by HPLC with TFA, to give the product as a trifluoroacetic acid salt (20 mg, 15%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (t, J= 7.35 Hz, 3H), 1.77-1.90 (m, 2H), 2.40 (s, 3H), 2.98 (t, J= 7.54 Hz, 2H), 3.43 (s, 3H), 6.34 (d, J= 6.99 Hz, 1H), 7.19 (d, 2H), 7.27 (d, 2H), 7.36-7.40 (m, 2H), 7.48 (d, 1H), 7 , 78 (d, J= 8.82 Hz, 1H), 8.39 (d, J= 6.99 Hz, 1H), 8.91 (d, J= 8.46 Hz, 1H); MS (DCI NH3 +) 480m / z (M + H) +.

Example 101

4- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl ester of ethanesulfonic acid

The product of Example 6 (100 mg, 0.228 mmol) was reacted with ethanesulfonyl chloride (28 mg, 0.228 mmol), N, N-diisopropylethylamine (88.5 mg, 0.685 mmol) and a catalytic amount of DMAP in dichloroethane for 18 hours to give a crude The title compound, which was purified by HPLC with TFA, gave the product as trifluoroacetic acid (30 mg, 22%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (t, J= 7.35 Hz, 3H), 1.34 (t, J= 7.17 Hz, 3H), 1.79-1.87 (m, 2H), 2.40 (s, 3H), 2.98 (t, J= 7.54 Hz, 2H), 3.47 (q, J= 7.35 Hz, 2H), 6.34 (d, J= 7.35 Hz, 1H), 7.14-7.19 (m, 2H), 7.27 (d, 2H), 7.39 (s, 2H), 7.46 (d, 1H), 7 , 78 (d, J= 8.46 Hz, 1H), 8.39 (d, J= 6.99 Hz, 1H), 8.92 (d, J= 8.82 Hz, 1H); MS (ESI +) m / z 494 (M + H) +.

Example 102

4- [2- (7-Ethyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl ester of propan-2-sulfonic acid

The product of Example 4 (100 mg, 0.233 mmol) was reacted with isopropylsulfonyl chloride (40 mg, 0.280 mmol), N, N-diisopropylethylamine (90 mg, 0.70 mmol) and catalytic amount of DMAP in dichloroethane for 18 hours to give a crude The title compound, which was purified by HPLC with TFA, gave the product as trifluoroacetic acid (12 mg, 12%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 8.93 (d, J= 8.46 Hz, 1H), 8.40 (d, J= 7.35 Hz, 1H), 7.79 (d, J= 8.82 Hz, 1H), 7.46 (d, 1H), 7.37 (s, 2H), 7.27 (d, 2H), 7.15 (d, J= 8.82 Hz, 2H), 6.35 (d, J= 6.99 Hz, 1H), 3.66 (m, J= 7.72 Hz, 1H), 3.03 (q, J= 7.72 Hz, 2H), 2.40 (s, 3H), 1.40 (d, 6H), 1.36 (t, 3H); MS (ESI +)m / z 494 (M + H) +.

Example 103

4- [2- (7-Ethyl- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -phenyl ester of phenylmethanesulfonic acid

The product of Example 4 (98 mg, 0.228 mmol) was reacted with benzylsulfonyl chloride (43 mg, 0.228 mmol), N, N-diisopropylethylamine (88 mg, 0.686 mmol) and a catalytic amount of DMAP in dichloroethane for 18 hours to yield the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (35 mg, 23%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.35 (t, J= 7.54 Hz, 3H), 2.39 (s, 3H), 3.03 (q, J= 7.72 Hz, 2H), 4.94 (s, 2H), 6.33 (d, J= 6.99 Hz, 1H), 7.07 (d, J= 8.82 Hz, 2H), 7.25 (d, J= 8.82 Hz, 2H), 7.38-7.49 (m, 8H), 7.79 (d, J= 8.82 Hz, 1H), 8.39 (d, J= 6.99 Hz, 1H), 8.91 (d, J= 8.82 Hz, 1H); MS (ESI +) m / z 542 (M + H) +.

Example 104

N- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxymethyl] -phenyl} -acetamide

Example 104a

4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenol

The product of example 1d (893 mg, 5 mmol) and 2-amino-4-methylphenol (616 mg, 5 mmol) in ethanol (20 ml) was boiled for 4 hours. The mixture was cooled to room temperature and evaporated. The residue was triturated in hexane / ethyl acetate (3: 1) to give the title compound in quantitative yield as the hydrochloride salt.

Example 104b

(2-hydroxy-5-methyl-phenyl) - (7-methyl- [1,8] naphthyridin-4-yl) -carbamic acid tert-butyl ester

To a mixture of the product of Example 104a (1.51 g, 5 mmol) and di-t-butyl dicarbonate (2.4 g, 11 mmol) in 20 ml of anhydrous THF was added NaOH (40 ml, 1N, 40 mmol). The solution was stirred at room temperature for 40 hours and poured into water, neutralized with citric acid and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel eluting with 2% methanol in dichloromethane to give the title compound (1.70 g, 93%).

Example 104c

N- {4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxymethyl] -phenyl} -acetamide

A solution of the product of Example 104b (37 mg, 0.1 mmol), N- (4-chloromethyl-phenyl) -acetamide (22 mg, 0.12 mmol), cesium carbonate (130 mg, 0.4 mmol) and tetrabutylammonium iodide (0.001 g) in DMF (1 ml) was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried with magnesium sulfate, filtered and concentrated in vacuo to give the title compound. To the residue was added dichloromethane (2 ml) and trifluoroacetic acid (2 ml) and stirred at room temperature for 2 hours. The solvent was evaporated and the crude residue was purified by chromatography on silica gel, eluting with a mixture of 2% methanol in dichloromethane to 5% methanol in dichloromethane to give the title compound as the trifluoroacetic acid salt (11 mg, 21%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.00 (s, 3H), 2.31 (s, 3H), 2.74 (s, 3H), 5.05 (s, 2H), 6.36 (d, J = 6.99 Hz, 1H), 7.12 (d, J = 8.46 Hz, 2H), 7.25 (m, 3H), 7.40 (d, J = 8.46 Hz, 2H), 7.93 (d, J = 8.46 Hz, 1H), 8.43 (d, J = 6.99 Hz, 1H), 8.98 (d, J = 8.46 Hz, 1H), 9, 89 (s, 1H), 10.65 (s, 1H), 14.25 (s, 1H); MS (ESI +) m / z 413 (M + H) +.

Example 105

2- {5- [2- (4-Acetylamino-phenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyridin-2-yl} -propionic acid ethyl ester

To a slurry of sodium hydride (95%, 0.025 g, 1.0 mmol) in 5 ml of anhydrous THF at 0 ° C. under N2 2-methylmalonic acid diethyl ester (0.174 g, 1.0 mmol) was added dropwise. The mixture was stirred for 30 minutes at room temperature, treated with the product of Example 24a (0.047 g, 1.0 mmol), kept in a microwave reactor at 120 ° C for 1 hour, cooled, partitioned between ethyl acetate and water and neutralized with 1 M HCl. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound. The residue was purified by chromatography on silica gel eluting with 1% methanol in dichloromethane to give the title compound (0.031 g, 62%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.14 (t, J = 7.17 Hz, 3H), 1.52 (d, J = 7.35 Hz, 3H), 2.04 (s, 3H), 2, 30 (s, 3H), 4.10 (m, 3H), 6.17 (s, br, 1H), 7.04 (m, 3H), 7.26 (d, J = 8.82 Hz, 2H), 7.48 (d, J = 7.35 Hz, 1H), 7.57 (d, J = 8.46 Hz, 2H), 8.45 (d, J = 8.46 Hz, 1H) , 8.78 (d, J = 8.82 Hz, 1H), 9.11 (s, 1H), 10.05 (s, 1H); (ESI +) m / z 501 (M + H) +.

Example 106

N- {4- [4-Bromo-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 106a

N- {4- [4-Bromo-2-nitro-phenylsulfanyl] -phenyl} -acetamide

A mixture of 2-fluoro-4-bromonitrobenzene (0.875 g, 3.9 mmol),

4-acetamidothiophenol (0.797 g, 4.29 mmol) and cesium carbonate (1.4 g, 4.29 mmol) in DMF (8 mL) was heated 2.5 hours at 100 ° C. The mixture was cooled, poured onto ice, and the resulting solid was collected by filtration and dried in vacuo to give the title compound as a yellow solid (1.4 g, 100%).

Example 106b

N- [4- (2-Amino-4-bromo-phenylsulfanyl] -phenyl} -acetamide

A solution of the product of Example 106a (1.4 g, 3.9 mmol), iron powder (0.874 g, 15.6 mmol) and ammonium chloride (0.253 g, 4.68 mmol) in methanol (6 mL), THF (6 ml) and water (2 ml) was heated to reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a pad of celite. The filtrate was concentrated in vacuo to a volume of 10 ml, the solution was diluted with water (50 ml) and extracted with ethyl acetate. The combined extracts were washed with 10% sodium chloride, then dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (1.2 g, 92%).

Example 106c

N- {4- [4-Bromo-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 1d (106 mg, 0.59 mmol) was reacted in ethanol (2 ml) with the product of Example 106b (200 mg, 0.59 mmol) for 18 hours according to the method described in Example 1g, crude title compound, which was purified by HPLC with TFA to give the product as a trifluoroacetic acid salt (53 mg, 19%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.05 (s, 3H), 2.77 (s, 3H), 6.41 (d, J = 6.99 Hz, 1H), 7.02 (d, J = 8 , 82 Hz, 1H), 7.33 (d, J = 8.46 Hz, 2H), 7.58 (d, J = 8.82 Hz, 2H), 7.65 (dd, J = 8.46 , 2.21 Hz, 1H), 7.77 (d, J = 2.21 Hz, 1H), 7.81 (d, J = 8.82 Hz, 1H), 8.48 (d, J = 6 , 99 Hz, 1H), 8.96 (d, J = 8.82 Hz, 1H), 10.11 (s, 1H), 11.06 (s, 1H), 14.53 (s, 1H); MS (DCI / NH3) m / z 479 (M + H) +.

Example 107

N- {4- [2- (7-Hydrazino [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide

The title compound was prepared according to the procedure of Example 47 using hydrazine hydrate (0.050 g, 1.0 mmol) in place of morpholine. The crude product was purified by HTP using HPLC with TFA to give the title compound as the trifluoroacetic acid salt (0.0125 g, 19%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.04 (s, 3H), 2.33 (s, 3H), 6.13 (d, J= 7.35 Hz, 1H), 7.06 (d, J= 8.09 Hz, 1H), 7.09-7.19 (m, 1H), 7.19-7.32 (m, 4H), 7.57 (d, J= 8.82 Hz, 2H), 8.10 (d, J= 6.99 Hz, 1H), 8.62 (d, J= 9.56 Hz, 1H), 10.09 (s, 1H), 10.53 (s, 1H), 13.64 (s, 1H); MS (ESI +) m / z 431 (M + H)+.

Example 108

N- (4- {2- [7- (2-Dimethylamino-ethoxy) - [1,8] naphthyridin-4-ylamino] -4-methylphenylsulfanyl} -phenyl) -acetamide

The title compound was prepared according to the procedure of Example 27 using N, N-dimethylethanolamine (0.044 g, 0.5 mmol) in place of diethyl malonate. The crude product was purified by HPLC with TFA to give the title compound as the trifluoroacetic acid salt (0.05 g, 70%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.04 (s, 3H), 2.35 (s, 3H), 2.92 (s, 6H), 3.64-3.68 (m, 2H), 4.73 -4.86 (m, 2H), 6.31 (d, J= 6.99 Hz, 1H), 7.14 (d, J= 8.82 Hz, 1H), 7.24 (d, J= 8.46 Hz, 2H), 7.27-7.32 (m, 2H), 7.36 (d, J= 8.82 Hz, 1H), 7.51 (d, J= 8.46 Hz, 2H), 8.33 (d, J= 6.99 Hz, 1H), 8.95 (d, J= 9.19 Hz, 1H), 9.87 (s, 1H), 10.07 (s, 1H), 10.88 (s, 1H), 14.23 (s, 1H); MS (ESI +) m / z 488 (M + H)+.

Example 109

N- (4- {2- [7- (2-Methoxyethylamino) - [1,8] naphthyridin-4-ylamino] -4-methylphenylsulfanyl} -phenyl) -acetamide

The title compound was prepared according to the procedure of Example 47 using 2-methoxyethylamine (75 mg, 1.0 mmol) in place of morpholine. The crude product was purified by HPLC with TFA to give the title compound as the trifluoroacetic acid salt (10 mg, 17%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.04 (s, 3H), 2.33 (s, 3H), 3.31 (s, 3H), 3.56 (t, J= 4.96 Hz, 2H), 3.60-3.67 (m, 2H), 6.05 (d, J= 6.99 Hz, 1H), 6.95 (d, J= 9.19 Hz, 1H), 7.05 (d, J= 8.09 Hz, 1H), 7.20-7.31 (m, J= 7.91, 7.91 Hz, 4H), 7.56 (d, J= 8.46 Hz, 2H), 7.96-8.11 (m, 1H), 8.33-8.49 (m, 2H), 10.07 (s, 1H), 10.32 (s, 1H), 13.42 (d, J= 5.88 Hz, 1H); MS (ESI +) m / z 474 (M + H)+.

Example 110

(7-Isobutyl- [1,8] naphthyridin-4-yl) - [2- (4-methoxy-phenylsulfanyl) -5-methylphenyl] -amine

The product of Example 12d (60 mg, 0.271 mmol) was reacted with the product of Example 50b (66 mg, 0.271 mmol) for 25 hours to give the crude title compound, according to the procedure described in Example 1g, which was triturated in 3: 1 ether / THF, to give the title compound as the hydrochloride salt (121 mg, 96%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (d, J = 6.62 Hz, 6H), 2.24 (m, J = 6.62 Hz, 1H), 2.34 (s, 3H), 2, 89 (d, J = 7.35Hz, 2H), 3.72 (s, 3H), 6.27 (d, J = 6.99Hz, 1H), 6.84 (d, J = 8.46 Hz, 2H), 7.10 (d, J = 8.09 Hz, 1H), 7.23-7.32 (m, 4H), 7.81 (d, J = 8.46 Hz, 1H), 8.41 (d, J = 6.99 Hz, 1H), 9.07 (d, J = 8.46 Hz, 1H), 11.09 (brs, 1H), 14.40 (brs, , 1H); MS (ESI +) m / z 430 (M-Cl) +; (ESI-) m / z 428 (M-HCl) -.

Example 111

[5- [2- (4-Amino-phenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyridin-2-yl} -cyano-acetic acid ethyl ester

The product of Example 30 (19 mg, 0.037 mmol), 2 ml of ethanol and 1 M of hydrochloric acid (1.5 ml) was combined and heated at 90 ° C for 3 hours, cooled and concentrated in vacuo to give the title compound . The crude product was purified by HPLC with TFA to give the title compound as the trifluoroacetic acid salt (10 mg, 46%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.28 (t, J= 6.99 Hz, 3H), 2.28 (s, 3H), 4.25 (q, J= 7.11 Hz, 2H), 6.14 (d, J= 5.88 Hz, 1H), 6.67 (d, J= 8.46 Hz, 2H), 6.86 (d, J= 7.72 Hz, 1H), 6.98-7.28 (m, 5H), 8.15 (d, J= 5.88 Hz, 1H), 8.65 (d, J= 9.56 Hz, 1H), 9.49 (s, 1H), 13.14 (s, 1H); MS (ESI +) m / z 470 (M + H)+.

Example 112

N- {4- [2- (7-Isobutyl- [1,8] naphthyridin-4-ylamino) -4-methylphenylsulfanyl] -phenyl} -acetamide

The product of Example 12d (50 mg, 0.226 mmol) was reacted with the product of Example 18b (62 mg, 0.226 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (35 mg, 33%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (d, J= 6.62 Hz, 7H), 2.03 (s, 3H), 2.23 (s, 1H), 2.35 (s, 3H), 2.89 (d, J= 7.35 Hz, 2H), 6.31 (d, J= 7.35 Hz, 1H), 7.14 (d, J= 8.09 Hz, 1H), 7.21-7.33 (m, 4H), 7.50 (d, J= 8.46 Hz, 2H), 7.80 (d, J= 8.82 Hz, 1H), 8.41 (d, J= 6.99 Hz, 1H), 8.99 (d, J= 8.82 Hz, 1H), 10.04 (s, 1H); MS (ESI +) m / z 457 (M + H-TFA) +; (ESI-) m / z 455 (MH-TFA) -.

Example 113

N-Methyl-4- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide

The product of Example 85b (0.155 g, 0.57 mmol) was reacted with the product of Example 2g as a 3.15 M solution in ethanol (0.18 mL, 0.57 mmol) for 24 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC using TFA, to give the product as a trifluoroacetic acid salt (0.180 g, 56%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (t, J= 7.35 Hz, 3H), 1.72-1.91 (m, 2H), 2.41 (s, 3H), 2.75 (d, J= 4.41 Hz, 3H), 2.97 (t, J= 7.35 Hz, 2H), 6.36 (d, J= 6.99 Hz, 1H), 7.20 (d, J= 8.46 Hz, 2H), 7.33-7.47 (m, 2H), 7.50 (d, 1H), 7.63 (d, J= 8.46 Hz, 2H), 7.77 (d, J= 8.82 Hz, 1H), 8.30-8.44 (m, J= 6.62, 6.62 Hz, 2H), 8.91 (d, J= 8.82 Hz, 1H), 10.86-11.09 (s, 1H); MS (ESI +) m / z 443.2 (M + H) +; (ESI-) m / z 441.2 (MH) -.

Example 114

N-Methyl-3- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -benzamide

The product of Example 87b (0.155 g, 0.57 mmol) was reacted with the product of Example 2g as a 3.15 M solution in ethanol (0.18 mL, 0.57 mmol) for 24 hours in accordance with the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, to give the product as a trifluoroacetic acid salt (0.042 g, 13%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J = 7.35 Hz, 3H), 1.76-1.91 (m, 2H), 2.39 (s, 3H), 2.70 (d , J = 4.41 Hz, 3H), 2.91-3.04 (m, 2H), 6.27 (d, J = 6.99 Hz, 1H), 7.18-7.42 (m, 4H), 7.42-7.51 (m, 1H), 7.55-7.63 (m, 2H), 7.76 (d, J = 8.82 Hz, 1H), 8.28-8 , 41 (m, J = 6.99 Hz, 2H), 8.88 (d, J = 8.46 Hz, 1H), 10.95 (s, 1H); MS (ESI +) m / z 443.2 (M + H) +; (ESI-) m / z 441.2 (MH) -.

Example 115

{4- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -methanol

Example 115a

[4- (4-Methyl-2-nitro-phenylsulfanyl) -phenyl] -methanol

The product of Example 84b (0.5 g, 1.73 mmol) was dissolved in THF (15 mL) and cooled in an ice bath. To a cold solution under a nitrogen atmosphere, diborane was added as a 1.0 M solution in THF (3.6 mL, 3.6 mmol), and the resulting mixture was allowed to warm to room temperature and stirred overnight. The crude product was isolated by extraction (ether / water) and dried with MgSO4, filtered and concentrated in vacuo to give the crude title compound. Purification by flash chromatography on silica gel gave the alcohol as a light yellow solid (0.392 g, 82%).

Example 115b

[4- (2-Amino-4-methyl-phenylsulfanyl) -phenyl] -methanol

The product of Example 115a (0.389 g, 1.41 mmol) was reacted with tin chloride (1.4 g, 7.05 mmol) as described in Example 1f to give the title compound in quantitative yield as an orange oil .

Example 115c

{4- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -methanol

The product of Example 2g as a 3.15 M solution in ethanol (0.08 mL, 0.25 mmol) was reacted with the product of Example 115b (0.061 g, 0.25 mmol) for 18.5 h according to method , described in Example 1g, to give the crude title compound, which was purified by HPLC using TFA, to give the product as a trifluoroacetic acid salt (0.0195 g, 14%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J = 7.35 Hz, 3H), 1.75-1.93 (m, 2H), 2.31-2.42 (s, 3H), 2 , 91-3.08 (m, 2H), 4.42 (s, 2H), 6.30 (d, J = 6.99 Hz, 1H), 7.11-7.42 (m, 7H), 7.81 (d, J = 8.46 Hz, 1H), 8.39 (d, J = 6.99 Hz, 1H), 8.98 (d, J = 8.82 Hz, 1H), 11, 01 (s, 1H); MS (ESI +) m / z 416.2 (M + H) +, (ESI-) m / z 414.3 (MH) -.

Example 116

4- [4- (4-Bromo-benzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] -phenol

Example 116a

4- [2-Amino-4- (4-bromo-benzyloxy) -phenylsulfanyl] -phenol

A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromo-4-bromomethylbenzene using the conditions described in Example 237c to give 4- (4-bromo-benzyloxy) -1-chloro-2-nitro benzene which was sequentially treated using the methods described in Examples 237d and 237e to obtain the title product.

Example 116b

4- [4- (4-Bromo-benzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 116a was reacted with the product of Example 237b using the method of Example 237f using the product of Example 116a instead of the product of Example 237e to give the crude title compound which was purified by HPLC with TFA to give the title compounds in the form of a salt of trifluoroacetic acid (19 mg, 17%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.72 (s, 3H), 5.13 (s, 2H), 6.63 (m, 2H), 7.03 (dd, J = 8.82, 2.57 Hz , 1H), 7.10 (m, 2H), 7.21 (d, J = 8.46 Hz, 2H), 7.40 (m, 2H), 7.54 (d, J = 8.09 Hz , 1H), 7.66 (d, J = 8.46 Hz, 1H) , 1H), 9.69 (s, 1H), 11.08 (m, 1H); MS (ESI +) m / z 545, 547 (M + H) +.

Example 117

N- {4- [4-Hydroxy-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 2g (35 mg, 0.17 mmol) was reacted in ethanol (1 ml) with the product of Example 232b (46 mg, 0.17 mmol) for 18 hours according to the method described in Example 1g, crude title compound, which was purified by HPLC with TFA to give the product as a trifluoroacetic acid salt (15 mg, 20%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (t, J = 7.35 Hz, 3H), 1.72-1.92 (m, 2H), 2.01 (s, 3H), 2.98 (t , J = 7.35Hz, 2H), 6.30 (d, J = 7.35Hz, 1H), 6.89 (d, J = 2.57Hz, 1H), 6.91-6.98 (m, 1H), 7.04 (s, 2H), 7.38 (d, J = 8.82 Hz, 3H), 7.78 (d, J = 8.82 Hz, 1H), 8.34 (d, J = 6.99 Hz, 1H), 8.93 (d, J = 8.82 Hz, 1H), 9.94 (s, 1H), 10.28 (s, 1H), 10.94 (s, 1H), 14.30 (s, 1H); MS (ESI +) m / z 445 (M + H) +.

Example 118

[2- (2,5-Dimethyl-furan-3-ylsulfanyl) -5-methylphenyl] - (7-isobutyl- [1,8] naphthyridin-4-yl) amine

The product of Example 12d (80 mg, 0.362 mmol) was reacted with the product of Example 91b (85 mg, 0.362 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (28 mg, 19%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (d, J= 6.62 Hz, 6H), 2.14 (d, J= 13.97 Hz, 6H), 2.19-2.30 (m, 1H), 2.33 (s, 3H), 2.90 (d, J= 7.35 Hz, 2H), 5.97 (s, 1H), 6.28 (d, J= 7.35 Hz, 1H), 7.08 (d, J= 8.09 Hz, 1H), 7.21-7.35 (m, 2H), 7.83 (d, J= 8.82 Hz, 1H), 8.46 (d, J= 6.99 Hz, 1H), 9.05 (d, J= 8.82 Hz, 1H), 11.02 (brs, 1H); MS

(ESI +) m / z 418 (M + H-TFA) +.

Example 119

N- {4- [4- (2-Methyl-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 119a

N- {4- [2-Amino-4- (2-methyl-benzyloxy) -phenylsulfanyl] -phenyl} -acetamide

A mixture of the product of Example 232b (28 mg, 0.085 mmol), 2-methylbenzyl bromide (13 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 ml) was stirred at room temperature for 15 hours. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to give the title compound (32 mg, 100%).

Example 119b

N- {4- [4- (2-Methyl-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 ml) with the product of Example 119a (32 mg, 0.085 mmol) for 18 hours according to the method described in Example 1g to give the crude title a compound which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (23 mg, 42%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (t, J = 7.35 Hz, 3H), 1.69-1.94 (m, 2H), 2.02 (s, 3H), 2.32 (s , 3H), 2.99 (t, J = 7.35 Hz, 2H), 5.14 (s, 2H), 6.32 (d, J = 6.99 Hz, 1H), 6.98-7 , 30 (m, 7H), 7.41 (dd, J = 11.40, 8.82 Hz, 4H), 7.80 (d, J = 8.82 Hz, 1H), 8.38 (d, J = 6.99 Hz, 1H), 8.97 (d, J = 8.46 Hz, 1H), 9.98 (s, 1H), 11.02 (s, 1H), 14.37 (s, 1H); MS (ESI +) m / z 549 (M + H) +.

Example 120

N- {4- [4- (3-Methyl-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 120a

N- {4- [2-Amino-4- (3-methyl-benzyloxy) -phenylsulfanyl] -phenyl} -acetamide

A mixture of the product of Example 232b (28 mg, 0.085 mmol), 3-methylbenzyl bromide (13 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 mL) was stirred at room temperature for 15 hours. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to give the title compound (32 mg, 100%).

Example 120b

N- {4- [4- (3-Methyl-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 ml) with the product of Example 120a (32 mg, 0.085 mmol) for 18 hours according to the method described in Example 1g to give the crude title a compound which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (14 mg, 26%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (t, J = 7.35 Hz, 3H), 1.62-1.93 (m, 2H), 2.02 (s, 3H), 2.31 (s , 3H), 2.99 (t, J = 7.35 Hz, 2H), 5.11 (s, 2H), 6.30 (d, J = 6.99 Hz, 1H), 6.97-7 , 33 (m, 8H), 7.34-7.50 (m, 3H), 7.80 (d, J = 8.82 Hz, 1H), 8.36 (d, J = 6.99 Hz, 1H), 8.97 (d, J = 8.82 Hz, 1H), 9.97 (s, 1H), 11.01 (s, 1H), 14.36 (s, 1H); MS (ESI +) m / z 549 (M + H) +.

Example 121

(5-Bromo-2-phenylsulfanyl-phenyl) - (7-methyl- [1,8] naphthyridin-4-yl) amine

Example 121a

5-Bromo-2-phenylsulfanyl-phenylamine

A solution of 4-bromo-2-nitrophenol (10.0 g, 45.9 mmol) and Et3N (14.0 mL, 137.6 mmol) in 100 mL CH2Cl2 in the atmosphere N2 was treated with trimethanesulfonic anhydride (8.5 ml, 50.5 mmol) at 0 ° C for 30 min. Quenched by the addition of MeOH. Was washed successively with 10% citric acid, 0.5 M KOH and water. Dry over MgSO44, filtered and concentrated in vacuo to give the title compound, which was purified by chromatography on a silica gel column, eluting with CH2Cl2, yielding an amber oil (15.2 g, 95%).

Example 121b

(4-Bromo-2-nitrophenyl) (phenyl) sulfane

The product of Example 121a (15.2 g, 43.4 mmol) and benzenethiol (4.4 mL, 43.4 mmol) in 100 mL of EtOH was treated with Na2CO3 and heated overnight at reflux. Cool to room temperature and quench with water. It was extracted with EtOAc. Dry over MgSO44, filtered and concentrated in vacuo to give the title compound, which was purified by chromatography on a silica gel column eluting with 5% EtOAc / hexane to give a yellow oil (13.3 g, 99%).

Example 121c

5-Bromo-2- (phenylthio) benzenamine

The product of Example 121b (2.0 g, 6.45 mmol) was reduced with SnCl2 in accordance with the method described in Example 1f, to obtain the title compound as a clear oil (1.8 g, 100%).

Example 121d

(5-Bromo-2-phenylsulfanyl-phenyl) - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 1d (278 mg, 1.56 mmol) was reacted with the product of Example 121c (437 mg, 1.56 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (129 mg, 15%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.77 (s, 3H), 6.43 (d, J= 6.99 Hz, 1H), 7.20 (d, J= 8.46 Hz, 1H), 7.34 (s, 5H), 7.69 (dd, J= 8.82, 2.21 Hz, 1H), 7.81 (m, 2H), 8.47 (d, J= 6.99 Hz, 1H), 8.95 (d, J= 8.46 Hz, 1H); MS (ESI +) m / z 422 (M + H-TFA) +.

Example 122

4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenol

Example 122a

4- (4-methyl-2-nitrophenoxy) phenol

A solution of hydroquinone (3.2 g, 29.0 mmol) and K2CO3 (8.0 g, 54.0 mmol) in 40 ml of DMF was heated at 100 ° C. with 1-fluoro-4-methyl-2-nitrobenzene (3.0 g, 19.3 mmol) with stirring for 24 hours . The mixture was cooled to room temperature and diluted with EtOAc. Wash with water and dry the organic layer over MgSO4, filtered and concentrated in vacuo to give the title compound, which was purified by chromatography on a silica gel column, eluting with 5% EtOAc / hexane to give an orange oil (1.89 g, 40%).

Example 122b

4- (2-Amino-4-methylphenoxy) phenol

The product of Example 122a (1.89 g, 7.71 mmol) was reduced with SnCl2 in accordance with the method described in Example 1f, to give the title compound as a white solid (1.42 g, 86%).

Example 122c

4- (4-Methyl-2- (7-methyl-1,8-naphthyridin-4-ylamino) phenoxy) phenol

The product of Example 1d (278 mg, 1.56 mmol) was reacted with the product of Example 122b (336 mg, 1.56 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (226 mg, 31%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.34 (s, 3H), 2.74 (s, 3H), 6.56 (d, J= 6.99 Hz, 1H), 6.64-6.71 (m, 2H), 6.75-6.81 (m, 2H), 6.89 (d, J= 8.46 Hz, 1H), 7.26 (dd, J= 8.46, 1.84 Hz, 1H), 7.31 (s, 1H), 7.76 (d, J= 8.82 Hz, 1H), 8.48 (d, J= 6.99 Hz, 1H), 8.95 (d, J= 8.46 Hz, 1H), 9.34 (s, 1H), 10.91 (s, 1H), 14.36 (s, 1H); MS (ESI +) m / z 358 (M + H-TFA) +.

Example 123

Bis [3- (7-methyl- [1,8] naphthyridin-4-ylamino) -4-phenylsulfanyl-benzyl] -carbamic acid t-butyl ester

The product of Example 1d (556 mg, 3.12 mmol) was reacted with the product of Example 90c (1.032 g, 3.12 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (228 mg, 31%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.35 (s, 9H), 2.76 (s, 6H), 4.45 (s, 4H), 6.28 (d, J= 6.99 Hz, 2H), 7.20-7.31 (m, 12H), 7.34 (s, 4H), 7.77 (d, J= 8.82 Hz, 2H), 8.40 (d, J= 6.99 Hz, 2H), 8.90 (d, J= 8.82 Hz, 2H), 11.00 (s, 2H), 14.40 (s, 2H); MS (ESI +) m / z 829 (M + H-TFA) +.

Example 124

(5-Bromo-2-phenoxy-phenyl) - (7-propyl- [1,8] naphthyridin-4-yl) -amine

Example 124a

4-Bromo-2-nitro-1-phenoxybenzene

A solution of phenol (2.35 g, 25.0 mmol) and K2CO3 (9.4 g, 68.1 mmol) in 40 ml of DMF was heated at 100 ° C. with 4-bromo-1-fluoro-2-nitrobenzene (5.0 g, 22.7 mmol) with stirring for 24 hours . The mixture was cooled to room temperature and diluted with EtOAc. Wash with water and dry the organic layer over MgSO4, filtered and concentrated in vacuo to give the title compound, which was purified by chromatography on a silica gel column eluting with 15% EtOAc / hexane to give a yellow oil (6.6 g, 99%).

Example 124b

5-Bromo-2-phenoxybenzenamine

The product of Example 124a (6.6 g, 22.5 mmol) was reduced with SnCl2 in accordance with the method described in Example 1f, to give the title compound as a brown oil (5.9 g, 100%).

Example 124c

N- (5-Bromo-2-phenoxyphenyl) -7-propyl-1,8-naphthyridin-4-amine

The product of Example 2g (275 mg, 1.33 mmol) was reacted with the product of Example 124b (351 mg, 1.33 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (470 mg, 65%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.95 (t, J= 7.35 Hz, 3H), 1.72-1.93 (m, 2H), 2.91-3.02 (m, 2H), 6.70 (d, J= 6.99 Hz, 1H), 6.97 (d, J= 7.72 Hz, 2H), 7.10 (t, J= 8.27 Hz, 2H), 7.27-7.36 (m, 2H), 7.68 (dd, J= 8.82, 2.57 Hz, 1H), 7.78 (d, J= 8.46 Hz, 1H), 7.82 (d, J= 2.57 Hz, 1H), 8.52 (d, J= 6.99 Hz, 1H), 8.89 (d, J= 8.82 Hz, 1H), 10.90 (s, 1H), 14.49 (s, 1H); MS (ESI +) m / z 436 (M + H-TFA) +.

Example 125

(5-Bromo-2-phenoxy-phenyl) - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 1d (278 mg, 1.56 mmol) was reacted with the product of Example 124b (412 mg, 1.56 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (206 mg, 25%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.73 (s, 3H), 6.69 (d, J= 7.35 Hz, 2H), 6.96 (d, J= 7.72 Hz, 2H), 7.05-7.15 (m, 3H), 7.24-7.36 (m, 2H), 7.68 (dd, J= 8.82, 2.57 Hz, 1H), 7.75 (d, J= 8.46 Hz, 1H), 7.82 (d, J= 2.21 Hz, 1H), 8.52 (d, J= 6.99 Hz, 1H), 8.86 (d, J= 8.82 Hz, 1H), 10.93 (s, 1H), 14.49 (s, 1H); MS (ESI +) m / z 408 (M + H-TFA) +.

Example 126

4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N- (2-methoxyethyl) benzamide

Example 126a

Methyl 4- (4-chloro-2-nitrophenoxy) benzoate

A mixture of 1,4-dichloro-2-nitrobenzene (20.0 g, 104.2 mmol) and methyl 4-hydroxybenzoate (15.85 g, 104.2 mmol) in 150 mL of EtOH was treated with Na2CO3 and heated overnight at reflux. Cool to room temperature and quench with water. It was extracted with EtOAc. Dry over MgSO44, filtered and concentrated in vacuo to give the title compound, which was purified by chromatography on a silica gel column eluting with 10% EtOAc / hexanes to give the title compound as a yellow solid (29.6 g, 92% ).

Example 126b

4- (4-Chloro-2-nitrophenoxy) benzoic acid

The compound of Example 126a (29.6 g, 96.2 mmol) in 200 mL of MeOH was treated with aqueous LiOH (1 M) and heated at reflux for 1 hour. Cool to room temperature and acidify with aqueous HCl (1 M). The precipitate formed was filtered, washed with H2O and dried in air to give the title compound as a yellow solid (28.2 g, 100%).

Example 126c

4- (4-Chloro-2-nitrophenoxy) benzoyl chloride

The product of Example 126b (4.0 g, 13.6 mmol) in 40 mL CH2Cl2 was treated with oxalyl chloride (3.5 g, 27.2 mmol) and DMF (catalytic amount). The mixture was stirred for 12 hours. The mixture was concentrated in vacuo to give the title compound as a yellow oil (4.2 g, 100%).

Example 126d

4- (4-Chloro-2-nitrophenoxy) -N- (2-methoxyethyl) benzamide

The compound of Example 126c (1.0 g, 3.2 mmol) in CH2Cl2 was added to a mixture of 2-methoxyethanamine (722 mg, 9.61 mmol) in CH2Cl2. The mixture was stirred for 12 hours. The mixture was concentrated in vacuo to give the title compound, which was purified by chromatography on a silica gel column eluting with 50% EtOAc / hexanes to give the title compound as a yellow oil (1.1 g, 100%).

Example 126e

4- (2-Amino-4-chlorophenoxy) -N- (2-methoxyethyl) benzamide

The product of Example 126d (1.0 g, 2.85 mmol) was reduced with SnCl2 in accordance with the method described in Example 1f, to give the title compound as a clear oil (900 mg, 100%).

Example 126f

4- (4-Chloro-2- (7-methyl-1,8-naphthyridin-4-ylamino) phenoxy) -N- (2-methoxyethyl) benzamide

The product of Example 1d (111 mg, 0.62 mmol) was reacted with the product of Example 126e (200 mg, 0.62 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (89.4 mg, 25%). 11H NMR (300 MHz, DMSO-D6th) δ ppm: 2.73 (s, 3H), 3.25 (s, 3H), 3.32-3.50 (m, 4H), 6.72 (d, J= 6.99 Hz, 1H), 6.97 (d, J= 8.82 Hz, 2H), 7.30 (d, J= 8.82 Hz, 1H), 7.61 (dd, J= 8.82, 2.57 Hz, 1H), 7.70-7.80 (m, 4H), 8.42 (t, J= 5.15 Hz, 1H), 8.53 (d, J= 6.99 Hz, 1H), 8.82 (d, J= 8.82 Hz, 1H), 10.90 (s, 1H), 14.54 (s, 1H); MS (ESI +) m / z 463 (M + H-TFA) +.

Example 127

4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N-propyl-benzamide

Example 127a

4- (4-Chloro-2-nitrophenoxy) -N-propylbenzamide

The product of Example 126c (1.0 g, 3.2 mmol) was reacted with propane-1-amine (568 mg, 9.61 mmol) for 12 hours in accordance with the method described in Example 126d, title compound (1.02 g, 100%).

Example 127b

4- (2-Amino-4-chlorophenoxy) -N-propylbenzamide

The product of Example 127a (1.0 g, 2.99 mmol) was reduced with SnCl2 in accordance with the method described in Example 1f, to obtain the title compound as a clear oil (834 mg, 92%).

Example 127c

4- (4-Chloro-2- (7-methyl-1,8-naphthyridin-4-ylamino) phenoxy) -N-propylbenzamide

The product of Example 1d (111 mg, 0.62 mmol) was reacted with the product of Example 127b (190 mg, 0.62 mmol) for 18 hours in accordance with the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (45.9 mg, 13%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.86 (t, J= 7.54 Hz, 3H), 1.39-1.60 (m, 2H), 2.72 (s, 3H), 3.08-3.26 (m, 2H), 6.72 (d, J= 6.99 Hz, 1H), 6.96 (d, J= 8.82 Hz, 2H), 7.29 (d, J= 8.82 Hz, 1H), 7.61 (dd, J= 8.82, 2.57 Hz, 1H), 7.69-7.80 (m, 4H), 8.34 (t, J= 5.52 Hz, 1H), 8.53 (d, J= 6.99 Hz, 1H), 8.82 (d, J= 8.46 Hz, 1H), 10.91 (s, 1H), 14.55 (s, 1H); MS (ESI +) m / z 447 (M + H-TFA) +.

Example 128

4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N-methoxy-N-methyl-benzamide

Example 128a

4- (4-Chloro-2-nitrophenoxy) -N-methoxy-N-methylbenzamide

The product of Example 126c (1.0 g, 3.20 mmol) was reacted with N-methoxymethanamine (391 mg, 6.41 mmol) for 12 hours in accordance with the method described in Example 126d to give the title compound (1.03 g, 100%).

Example 128b

4- (2-Amino-4-chlorophenoxy) -N-methoxy-N-methylbenzamide

The product of Example 128a (1.0 g, 2.97 mmol) was reduced with SnCl2 in accordance with the method described in Example 1f, to give the title compound as a clear oil (911 mg, 100%).

Example 128c

4- (4-Chloro-2- (7-methyl-1,8-naphthyridin-4-ylamino) phenoxy) -N-methoxy-N-methylbenzamide

The product of Example 1d (111 mg, 0.62 mmol) was reacted with the product of Example 128b (192 mg, 0.62 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (50.9 mg, 15%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.72 (s, 3H), 3.19 (s, 3H), 3.42 (s, 3H), 6.71 (d, J= 6.99 Hz, 1H), 6.94 (d, J= 8.82 Hz, 2H), 7.36 (d, J= 8.82 Hz, 1H), 7.50 (d, J= 8.82 Hz, 2H), 7.63 (dd, J= 8.82, 2.57 Hz, 1H), 7.72 (d, J= 8.82 Hz, 1H), 7.75 (d, J= 2.57 Hz, 1H), 8.53 (d, J= 6.99 Hz, 1H), 8.81 (d, J= 8.46 Hz, 1H), 10.88 (s, 1H), 14.46 (s, 1H); MS (ESI +) m / z 449 (M + H-TFA) +.

Example 129

4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N, N-diethylbenzamide

Example 129a

4- (4-chloro-2-nitrophenoxy) -N, N-diethylbenzamide

The compound of Example 126c (1.0 g, 3.2 mmol) in CH2Cl2 was added to a mixture of diethylamine (469 mg, 6.41 mmol) in CH2Cl2. The mixture was stirred for 12 hours. The mixture was concentrated in vacuo to give the title compound, which was purified by chromatography on a silica gel column, eluting with 50% EtOAc / hexane to give a yellow oil (1.1 g, 100%).

Example 129b

4- (2-Amino-4-chlorophenoxy) -N, N-diethylbenzamide

The product of Example 129a (1.0 g, 2.87 mmol) was reduced with SnCl2 in accordance with the method described in Example 1f, to obtain the title compound as a clear oil (772 mg, 85%).

Example 129c

4- (4-Chloro-2- (7-methyl-1,8-naphthyridin-4-ylamino) phenoxy) -N, N-diethylbenzamide

The product of Example 1d (111 mg, 0.62 mmol) was reacted with the product of Example 129b (199 mg, 0.62 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (49.2 mg, 14%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.01 (s, 6H), 2.73 (s, 3H), 3.35 (s, 1H), 3.53-3.81 (m, 4H), 6.70 (d, J= 7.35 Hz, 1H), 6.93 (d, J= 8.46 Hz, 2H), 7.22 (d, J= 8.82 Hz, 2H), 7.34 (d, J= 8.82 Hz, 1H), 7.62 (dd, J= 8.82, 2.57 Hz, 1H), 7.73 (d, J= 6.25 Hz, 1H), 7.75 (s, 1H), 8.53 (d, J= 6.99 Hz, 1H), 8.82 (d, J= 8.82 Hz, 1H), 10.92 (s, 1H), 14.55 (s, 1H); MS (ESI +) m / z 461 (M + H-TFA) +.

Example 130

4- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N-propyl-benzamide

The product of Example 2g (75 mg, 0.36 mmol) was reacted with the product of Example 127b (111 mg, 0.36 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (25.8 mg, 12%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.86 (t, J= 7.35 Hz, 3H), 0.95 (t, J= 7.35 Hz, 3H), 1.37-1.56 (m, 2H), 1.72-1.88 (m, 2H), 2.96 (t, J= 7.54 Hz, 2H), 3.08-3.22 (m, 2H), 6.72 (d, J= 6.99 Hz, 1H), 6.97 (d, J= 8.82 Hz, 2H), 7.29 (d, J= 8.82 Hz, 1H), 7.61 (dd, J= 8.82, 2.57 Hz, 1H), 7.75 (d, J= 8.82 Hz, 4H), 8.34 (t, J= 5.70 Hz, 1H), 8.52 (d, J= 6.99 Hz, 1H), 8.85 (d, J= 8.82 Hz, 1H), 10.90 (s, 1H), 14.55 (s, 1H); MS (ESI +) m / z 475 (M + H-TFA) +.

Example 131

4- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N- (2-methoxyethyl) benzamide

The product of Example 2g (75 mg, 0.36 mmol) was reacted with the product of Example 126e (116 mg, 0.36 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (101.7 mg, 46%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.95 (t, J= 7.35 Hz, 3H), 1.70-1.90 (m, 2H), 2.90-3.01 (m, 2H), 3.24 (s, 3H), 3.32-3, 47 (m, 4H), 6.73 (d, J= 6.99 Hz, 1H), 6.98 (d, J= 8.82 Hz, 2H), 7.29 (d, J= 8.82 Hz, 1H), 7.61 (dd, J= 8.82, 2.57 Hz, 1H), 7.71-7.81 (m, 4H), 8.42 (t, J= 4.78 Hz, 1H), 8.53 (d, J= 6.99 Hz, 1H), 8.85 (d, J= 8.82 Hz, 1H), 10.92 (s, 1H), 14.57 (s, 1H); MS (ESI +) m / z 491 (M + H-TFA) +.

Example 132

4- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N-methoxy-N-methyl-benzamide

The product of Example 2g (75 mg, 0.36 mmol) was reacted with the product of Example 128b (111 mg, 0.36 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (76.3 mg, 36%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.88-1.03 (m, 3H), 1.70-1.91 (m, 2H), 2.88-3.00 (m, 2H), 3.18 ( s, 3H), 3.42 (s, 3H), 6.71 (d, J= 7.35 Hz, 1H), 6.94 (d, J= 8.82 Hz, 2H), 7.36 (d, J= 8.82 Hz, 1H), 7.50 (d, J= 8.82 Hz, 2H), 7.59-7.66 (m, 1H), 7.71-7.79 (m, 2H), 8.53 (d, J= 6.99 Hz, 1H), 8.84 (d, J= 8.82 Hz, 1H), 10.89 (s, 1H), 14.54 (s, 1H); MS (ESI +) m / z 477 (M + H-TFA) +.

Example 133

4- [4-Chloro-2 - ([1,8] naphthyridin-4-ylamino) -phenoxy] -N-ethyl-N-methyl-benzamide

Example 133a

4- (4-Chloro-2-nitrophenoxy) -N-ethyl-N-methylbenzamide

The compound of Example 126c (1.0 g, 3.2 mmol) in CH2Cl2 was added to a mixture of N-methylethanamine (379 mg, 6.41 mmol) in CH2Cl2. The mixture was stirred for 12 hours. The mixture was concentrated in vacuo to give the title compound, which was purified by chromatography on a silica gel column eluting with 50% EtOAc / hexane to give a yellow oil (1.03 g, 100%).

Example 133b

4- (2-Amino-4-chlorophenoxy) -N-ethyl-N-methylbenzamide

The product of Example 133a (1.0 g, 2.99 mmol) was reduced with SnCl2 in accordance with the method described in Example 1f, to obtain the title compound as a clear oil (751 mg, 83%).

Example 133c

4- (2- (1,8-Naphthyridin-4-ylamino) -4-chlorophenoxy) -N-ethyl-N-methylbenzamide

The product of Example 16c (100 mg, 0.61 mmol) was reacted with the product of Example 133b (185 mg, 0.61 mmol) for 18 hours in accordance with the method described in Example 1g to give the crude title compound which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (141 mg, 42%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.86-1.18 (m, 3H), 2.62-2.92 (m, 5H), 6.76 (d, J= 7.35 Hz, 1H), 6.94 (d, J= 8.82 Hz, 2H), 7.25 (d, J= 8.09 Hz, 2H), 7.34 (d, J= 8.82 Hz, 1H), 7.63 (dd, J= 8.82, 2.57 Hz, 1H), 7.75 (d, J= 2.57 Hz, 1H), 7.85 (dd, J= 8.46, 4.41 Hz, 1H), 8.61 (d, J= 6.99 Hz, 1H), 8.96 (dd, J= 8.64, 1.29 Hz, 1H), 9.14 (dd, J= 4.23, 1.29 Hz, 1H), 11.06 (s, 1H), 14.74 (s, 1H); MS (ESI +) m / z 433 (M + H-TFA) +.

Example 134

4- [4- (4-Bromo-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 1d (100 mg, 0.559 mmol) was reacted with the product of Example 116a (224 mg, 0.559 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (129 mg, 61%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.76 (s, 3H), 5.12 (s, 2H), 6.26 (d, J = 6.99 Hz, 1H), 6.65 (d, J = 8 , 45 Hz, 2H), 7.07-7.25 (m, 5H), 7.39 (d, J = 8.45 Hz, 2H), 7.60 (d, J = 8.45 Hz, 2H ), 7.81 (d, J = 8.45 Hz, 1H), 8.39 (d, J = 7.35 Hz, 1H), 8.99 (d, J = 8.45 Hz, 1H), 9.78 (s, 1H), 11.05 (brs, 1H), 14.40 (brs, 1H); MS (ESI +) m / z 544, 546 (M + H-TFA) +; (ESI-) m / z 542, 544 (MH-TFA) -.

Example 135

4- [4- (3-Bromo-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromo-3-bromomethylbenzene using the conditions described in Example 237c to give 4- (3-bromo-benzyloxy) -1-chloro-2-nitro benzene which was sequentially treated using the methods described in Examples 237d and 237e to obtain 4- [2-amino-4- (3-bromo-benzyloxy) -phenylsulfanyl] -phenol.

The product of Example 1d (57 mg, 0.319 mmol) was reacted with 4- [2-amino-4- (3-bromo-benzyloxy) phenylsulfanyl] -phenol (128 mg, 0.319 mmol) for 28 hours according to the method , described in Example 1g, to give the crude title compound, which was purified by HPLC with TFA, to give the product as trifluoroacetic acid (118 mg, 56%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.76 (3H), 5.15 (s, 2H), 6.25 (d, J = 6.99 Hz, 1H), 6.65 (d, J = 8.46 Hz, 2H), 7.06-7.68 (m, 8H), 7.80 (d, J = 8.46 Hz, 1H), 8.39 (d, J = 6.99 Hz, 1H), 8.99 (d, J = 8.45 Hz, 1H), 9.78 (s, 1H), 11.02 (brs, 1H), 14.39 (brs, 1H); MS (ESI +) m / z 544, 546 (M + H-TFA) +; (ESI-) m / z 542, 544 (MH-TFA) -.

Example 136

4- [4- (3-Bromo-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 2g (62 mg, 0.30 mmol) was reacted with 4- [2-amino-4- (3-bromo-benzyloxy) phenylsulfanyl] -phenol (120 mg, 0.30 mmol) for 48 hours in accordance with the method described in Example 1g, to give the crude title compound, which was purified by HPLC with TFA, to give the product as trifluoroacetic acid (86 mg, 41%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J = 7.73 Hz, 3H), 1.85 (dt, J = 7.73 Hz, 2H), 3.00 (dd, J = 7.72 Hz, 2H), 5.15 (s, 2H), 6.27 (d, J = 7.35 Hz, 1H), 6.66 (d, J = 8.82 Hz, 2H), 7.07- 7.69 (m, 7H), 7.65 (s, 1H), 7.83 (d, J = 8.82 Hz, 1H), 8.41 (d, J = 6.99 Hz, 1H), 9.03 (d, J = 8.82 Hz, 1H), 9.81 (s, 1H), 11.05 (brs, 1H), 14.43 (brs, 1H); MS (ESI +) m / z572, 574 (M + H-TFA) +; (ESI-) m / z 570-572 (MH-TFA) -.

Example 137

4- [4- (4-Bromo-benzyloxy) -2 - ([1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 16c (50 mg, 0.30 mmol) was reacted with the product of Example 116a (120 mg, 0.30 mmol) for 26 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC using TFA, which gave the product as trifluoroacetic acid (95 mg, 49%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 5.12 (s, 2H), 6.30 (d, J = 7.35 Hz, 1H), 6.64 (d, J = 8.82 Hz, 2H), 7, 08-7.25 (m, 3H), 7.39 (d, J = 8.09 Hz, 2H), 7.60 (d, J = 8.09 Hz, 2H), 7.91 (dd, J = 4.42 Hz, 1H), 8.46 (d, J = 6.98 Hz, 1H), 9.12 (d, J = 8.46 Hz, 2H), 9.17 (d, J = 4 , 42 Hz, 1H), 9.78 (s, 1H), 11.10 (brs, 1H), 14.49 (brs, 1H); (ESI +) m / z 529, 531 (M + H-TFA) +; (ESI-) m / z 528, 530 (MH-TFA) -.

Example 138

4- [4- (3-Bromo-benzyloxy) -2 - ([1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 16c (50 mg, 0.30 mmol) was reacted with 4- [2-amino-4- (3-bromo-benzyloxy) phenylsulfanyl] -phenol (120 mg, 0.30 mmol) for 40 hours in accordance with the method described in Example 1g, to give the crude title compound, which was purified by HPLC with TFA, to give the product as trifluoroacetic acid (87 mg, 45%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 5.15 (s, 2H), 6.30 (d, J = 6.99 Hz, 1H), 6.66 (d, J = 8.83 Hz, 2H), 7, 08-7.47 (m, 6H), 7.56 (d, J = 7.72 Hz, 1H), 7.65 (m, 1H), 7.92 (dd, J = 4.41 Hz, J 8.46 Hz, 1H), 8.18 (d, J = 6.99 Hz, 1H), 9.14 (dd, J = 8.83 Hz, 1H), 9.17 (dd, J = 5 , 88 Hz, J = 1.84 Hz, 1H), 9.80 (s, 1H), 11.16 (brs, 1H), 14.53 (brs, 1H); MS (ESI +) m / z 529, 531 (M + H-TFA) =; (ESI-) m / z 528, 530 (MH-TFA) -.

Example 139

4- [4- (3-Fluoro-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromomethyl-3-fluorobenzene using the conditions described in Example 237c to give 1-chloro-4- (3-fluoro-benzyloxy) -2-nitro benzene which was sequentially treated using the methods described in Examples 237d and 237e to obtain 4- [2-amino-4- (3-fluoro-benzyloxy) -phenylsulfanyl] -phenol.

The product of Example 1d (53 mg, 0.30 mmol) was reacted with 4- [2-amino-4- (3-fluoro-benzyloxy) phenylsulfanyl] -phenol (102 mg, 0.30 mmol) for 20 hours in accordance with the method described in Example 1g, to give the crude title compound, which was purified by HPLC with TFA, to give the product as trifluoroacetic acid (60 mg, 33%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.76 (s, 3H), 5.16 (s, 2H), 6.27 (d, J = 6.99 Hz, 1H), 6.64 (d, J = 8 , 46 Hz, 2H), 7.03-7.36 (m, 7H), 7.45 (m, J = 6.26 Hz, 1H), 7.80 (d, J = 8.82 Hz, 1H ), 8.39 (d, J = 6.98Hz, 1H), 8.99 (d, J = 8.82Hz, 1H), 9.78 (s, 1H), 11.02 (br s , 1H), 14.39 (brs, 1H); MS (ESI +) m / z, 484 (M + H-TFA) +; (ESI-) m / z, 482 (MH-TFA) -.

Example 140

4- [4- (4-Fluoro-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromomethyl-4-fluorobenzene using the conditions described in Example 237c to give 1-chloro-4- (4-fluoro-benzyloxy) -2-nitro benzene which was sequentially treated using the methods described in Examples 237d and 237e to give 4- [2-amino-4- (4-fluoro-benzyloxy) -phenylsulfanyl] -phenol.

The product of Example 1d (53 mg, 0.30 mmol) was reacted with 4- [2-amino-4- (4-fluoro-benzyloxy) phenylsulfanyl] -phenol (102 mg, 0.30 mmol) for 18 hours in accordance with the method described in Example 1g, to give the crude title compound, which was purified by HPLC with TFA, to give the product as trifluoroacetic acid (115 mg, 64%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.76 (s, 3H), 5.11 (s, 2H), 6.26 (d, J = 6.99 Hz, 1H), 6.65 (d, J = 8 , 46 Hz, 2H), 7.10 (d, J = 8.82 Hz, 2H), 7.15-7.27 (m, 4H), 7.49 (m, J = 5.88 Hz, 2H ), 7.81 (d, J = 8.46 Hz, 1H), 8.40 (d, J = 6.98 Hz, 1H), 8.98 (d, J = 8.46 Hz, 1H), 9.78 (s, 1H), 11.03 (brs, 1H), 14.36 (brs, 1H); MS (ESI +) m / z, 484 (M + H-TFA) +; (ESI-) m / z, 482 (MH-TFA) -.

Example 141

4- [4- (4-Fluoro-benzyloxy) -2 - ([1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 16c (50 mg, 0.30 mmol) was reacted with 4- [2-amino-4- (4-fluorobenzyloxy) phenylsulfanyl] phenol (102 mg, 0.30 mmol) for 20 hours in accordance with the method described in Example 1g, to give the crude title compound, which was purified by HPLC with TFA, to give the product as trifluoroacetic acid (99 mg, 56%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 5.11 (s, 2H), 6.31 (d, J = 6.99 Hz, 1H), 6.64 (d, J = 8.45 Hz, 2H), 7, 08-7.27 (m, 6H), 7.50 (m, J = 5.51 Hz, 2H), 7.91 (d, J = 4.41 Hz, 1H), 8.47 (d, J = 6.98 Hz, 1H), 9.13 (dd, J = 1.47 Hz, J = 8.45 Hz, 1H), 9.17 (dd, J = 1.47 Hz, J = 4.05 Hz, 1H), 9.79 (s, 1H), 11.14 (brs, 1H), 14.50 (brs, 1H); MS (ESI +) m / z, 470 (M + H-TFA) +; (ESI-) m / z, 468 (MH-TFA) -.

Example 142

4- [4- (3-Fluoro-benzyloxy) -2 - ([1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 16c (50 mg, 0.30 mmol) was reacted with 4- [2-amino-4- (3-fluoro-benzyloxy) phenylsulfanyl] -phenol (102 mg, 0.30 mmol) for 22 hours in accordance with the method described in Example 1g, to give the crude title compound, which was purified by HPLC with TFA, to give the product as trifluoroacetic acid (75 mg, 43%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 5.16 (s, 2H), 6.31 (d, J = 7.36 Hz, 1H), 6.64 (d, J = 8.82 Hz, 2H), 7, 09-7.28 (m, 6H), 7.29 (2, 1H), 7.44 (m, J = 6.61 Hz, 1H), 7.93 (dd, J = 4.41 Hz, 1H ), 8.47 (d, J = 6.98Hz, 1H), 9.14 (dd, J = 1.47Hz, J = 8.46Hz, 1H), 9.18 (dd, J = 1 , 47 Hz, J = 4.41 Hz, 1H), 9.79 (s, 1H), 11.16 (brs, 1H), 14.52 (brs, 1H); MS (ESI +) m / z, 470 (M + H-TFA) +; (ESI-) m / z, 468 (MH-TFA) -.

Example 143

4- [4- (4-Chloro-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

Example 143a

4- [2-Amino-4- (4-chloro-benzyloxy) -phenylsulfanyl] -phenol

A solution of 4-chloro-3-nitro-phenol was reacted with 1-chloro-4-bromomethylbenzene using the conditions described in Example 237c to give 4- (4-chloro-benzyloxy) -1-chloro-2-nitrobenzene , which was sequentially treated using the methods described in Examples 237d and 237e to obtain the title compound.

Example 143b

4- [4- (4-Chloro-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 2g (85 mg, 0.41 mmol) was reacted with the product of Example 143a (146 mg, 0.41 mmol) for 26 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (89 mg, 68%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J = 7.35 Hz, 3H), 1.83 (sext, J = 7.35 Hz, 2H), 3.00 (dd, J = 7, 35 Hz, 2H), 5.13 (s, 2H), 6.27 (d, J = 6.99 Hz, 1H), 6.64 (d, J = 8.82 Hz, 2H), 7.05 -7.25 (m, J = 8.45Hz, 4H), 7.48 (m, 4H), 7.83 (d, J = 8.45Hz, 1H), 8.40 (d, J = 6.99 Hz, 1H), 9.00 (d, J = 8.46 Hz, 1H), 9.78 (s, 1H), 11.03 (br s, 1H), 14.40 (br. s, 1H); MS (ESI +) m / z, 528, 530 (M + H-TFA) +; (ESI-) m / z, 526, 528 (MH-TFA) -.

Example 144

4- [4- (3-Chloro-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

Example 144a

4- [2-Amino-4- (3-chloro-benzyloxy) -phenylsulfanyl] -phenol

A solution of 4-chloro-3-nitro-phenol was reacted with 1-chloro-3-bromomethylbenzene using the conditions described in Example 237c to give 4- (3-chloro-benzyloxy) -1-chloro-2-nitrobenzene , which was sequentially treated using the methods described in Examples 237d and 237e to obtain the title compound.

Example 144b

4- [2-Amino-4- (3-chloro-benzyloxy) -phenylsulfanyl] -phenol

The product of Example 2g (85 mg, 0.41 mmol) was reacted with the product of Example 144a (146 mg, 0.41 mmol) for 24 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (85 mg, 65%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J = 7.32 Hz, 3H), 1.85 (sext, J = 7.35 Hz, 2H), 3.00 (dd, J = 7, 72 Hz, 2H), 5.15 (s, 2H), 6.26 (d, J = 6.99 Hz, 1H), 6.65 (d, J = 8.83 Hz, 2H), 7.07 -7.25 (m, 5H), 7.35-7.54 (m, 3H), 7.83 (d, J = 8.46 Hz, 1H), 8.40 (d, J = 7.36 Hz, 1H), 9.02 (d, J = 8.46 Hz, 1H), 9.79 (s, 1H), 11.02 (bs, 1H), 14.39 (brs, 1H ); MS (ESI +) m / z, 528, 530 (M + H-TFA) +; (ESI-) m / z, 526, 528 (MH-TFA) -.

Example 145

4- [4- (3-Fluoro-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 2g (85 mg, 0.41 mmol) was reacted with 4- [2-amino-4- (3-fluoro-benzyloxy) phenylsulfanyl] -phenol (141 mg, 0.41 mmol) for 24 hours in accordance with the method described in Example 1g, to give the crude title compound, which was purified by HPLC with TFA, to give the product as trifluoroacetic acid (95 mg, 37%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J = 7.36 Hz, 3H), 1.85 (sext, J = 7.72 Hz, 2H), 3.00 (dd, J = 7, 36 Hz, 2H), 5.16 (s, 2H), 6.27 (d, J = 7.35 Hz, 1H), 6.66 (d, J = 8.83 Hz, 2H), 7.09 -7.34 (m, 7H), 7.43 (m, J = 6.25Hz, 1H), 7.83 (d, J = 8.83Hz, 1H), 8.40 (d, J = 6.99 Hz, 1H), 9.03 (d, J = 8.83 Hz, 1H), 9.80 (s, 1H), 11.04 (brs, 1H), 14.45 (br. s, 1H); MS (ESI +) m / z, 512 (M + H-TFA) +; (ESI-) m / z, 510 (MH-TFA) -.

Example 146

4- [4- (3-Chloro-benzyloxy) -2 - ([1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 16c (50 mg, 0.30 mmol) was reacted with the product of Example 144a (107 mg, 0.30 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (109 mg, 60%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.77 (s, 3H), 5.16 (s, 2H), 6.25 (d, J = 6.98 Hz, 1H), 6.66 (d, J = 8 , 83 Hz, 2H), 7.07-7.25 (m, J = 8.46 Hz, 5H), 7.38-7.53 (m, 3H), 7.80 (d, J = 8, 45 Hz, 1H), 8.40 (d, J = 6.99 Hz, 1H), 8.99 (d, J = 8.83 Hz, 1H), 9.79 (s, 1H), 11.02 (brs, 1H), 14.38 (brs, 1H); MS (ESI +) m / z 500 (M + H-TFA) +; (ESI-) m / z 498 (MH-TFA) -.

Example 147

4- [4- (4-Chloro-benzyloxy) -2 - ([1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 16c (50 mg, 0.30 mmol) was reacted with the product of Example 143a (107 mg, 0.30 mmol) for 24 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (50 mg, 27%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 5.14 (s, 2H), 6.31 (d, J = 7.36 Hz, 1H), 6.64 (d, J = 8.82 Hz, 2H), 7, 05-7.40 (m, J = 8.46 Hz, 4H), 7.46 (m, J = 5.52 Hz, 3H), 7.93 (m, J = 4.41 Hz, 1H), 8.48 (d, J = 6.98Hz, 1H), 9.17 (m, J = 1.47Hz, J = 5.88Hz, 3H), 9.79 (s, 1H), 11, 15 (brs, 1H), 14.54 (brs, 1H); MS (ESI +) m / z, 486 (M + H-TFA) +; (ESI-) m / z, 484 (MH-TFA) -.

Example 148

4- [4- (3-Chloro-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 1d (71 mg, 0.40 mmol) was reacted with the product of Example 144a (143 mg, 0.41 mmol) for 24 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (122 mg, 49%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.77 (s, 3H), 5.16 (s, 2H), 6.25 (d, J = 6.98 Hz, 1H), 6.66 (d, J = 8 , 83 Hz, 2H), 7.07-7.25 (m, J = 8.46 Hz, 5H), 7.38-7.53 (m, 3H), 7.80 (d, J = 8, 45 Hz, 1H), 8.40 (d, J = 6.99 Hz, 1H), 8.99 (d, J = 8.83 Hz, 1H), 9.79 (s, 1H), 11.02 (brs, 1H), 14.38 (brs, 1H); MS (ESI +) m / z 500 (M + H-TFA) +; (ESI-) m / z 498 (MH-TFA) -.

Example 149

4- [4-Benzyloxy-2 - ([1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol

A solution of 4-chloro-3-nitro-phenol was reacted with bromomethyl-benzene using the conditions described in Example 237c to give 4-benzyloxy-1-chloro-2-nitrobenzene which was sequentially treated using the methods described in Examples 237d and 237e, to give 4- (2-amino-4-benzyloxy-phenylsulfanyl) -phenol.

The product of Example 16c (100 mg, 0.559 mmol) was reacted with 4- (2-amino-4-benzyloxy-phenylsulfanyl) -phenol (224 mg, 0.559 mmol) for 18 hours according to the method described in Example 1g, to give the crude title compound, which was purified by HPLC with TFA, to give the product as trifluoroacetic acid (mg,%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 5.14 (s, 2H), 6.31 (d, J= 6.99 Hz, 1H), 6.61-6.69 (m, 2H), 7.08-7.23 (m, 5H), 7.32-7.46 (m, 5H), 7, 92 (dd, J= 8.46, 4.41 Hz, 1H), 8.47 (d, J= 6.99 Hz, 1H), 9.10-9.21 (m, 2H), 9.77 (s, 1H), 11.14 (s, 1H); MS (ESI +) m / z 452 (M + H-TFA) +; (ESI-) m / z 450 (MH-TFA) -.

Example 150

4- [4- (4-Chloro-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 1d (100 mg, 0.559 mmol) was reacted with the product of Example 143a (224 mg, 0.559 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (mg,%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.77 (s, 3H), 5.16 (s, 2H), 6.26 (d, J= 6.99 Hz, 1H), 6.65 (d, J= 8.46 Hz, 2H), 7.09-7.24 (m, 5H), 7.37-7.44 (m, 3H), 7.51 (s, 1H), 7.81 (d, J= 8.82 Hz, 1H), 8.40 (d, J= 6.99 Hz, 1H), 8.99 (d, J= 8.82 Hz, 1H), 9.80 (s, 1H), 11.04 (s, 1H); MS (ESI +) m / z 500 (M + H-TFA) +; (ESI-) m / z 498 (MH-TFA) -.

Example 151

4- [4-Benzyloxy-2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 1d (50 mg, 0.280 mmol) was reacted with 4- (2-amino-4-benzyloxy-phenylsulfanyl) -phenol (91 mg, 0.280 mmol) for 18 hours according to the method described in Example 1g, to give the crude title compound, which was purified by HPLC with TFA, to give the product as trifluoroacetic acid (22 mg, 17%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.76 (s, 3H), 5.13 (s, 2H), 6.26 (d, J= 6.99 Hz, 1H), 6.65 (d, J= 8.46 Hz, 2H), 7.08-7.22 (m, 5H), 7.32-7.46 (m, 5H), 7.80 (d, J= 8.46 Hz, 1H), 8.39 (d, J= 6.99 Hz, 1H), 8.99 (d, J= 8.46 Hz, 1H), 9.78 (s, 1H), 11.01 (s, 1H); MS (ESI +) m / z 466 (M + H-TFA) +; (ESI-) m / z 464 (MH-TFA) -.

Example 152

4- [4-Benzyloxy-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 2g (50 mg, 0.241 mmol) was reacted with 4- (2-amino-4-benzyloxy-phenylsulfanyl) -phenol (78 mg, 0.241 mmol) for 18 hours according to the method described in Example 1g, to give the crude title compound, which was purified by HPLC with TFA, to give the product as trifluoroacetic acid (2 mg, 2%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J= 7.35 Hz, 3H), 1.78-1.91 (m, J= 7.43, 7.43, 7.43, 7.43, 7.43 Hz, 2H), 3.00 (t, J= 7.54 Hz, 2H), 5.13 (s, 2H), 6.27 (d, J= 6.99 Hz, 1H), 6.65 (d, J= 8.82 Hz, 2H), 7.09-7.23 (m, 5H), 7.32-7.46 (m, 5H), 7.82 (d, J= 8.82 Hz, 1H), 8.39 (d, J= 6.99 Hz, 1H), 9.02 (d, J= 8.82 Hz, 1H), 9.78 (s, 1H), 11.00 (s, 1H); MS (ESI +) m / z 494 (M + H-TFA) +; (ESI-) m / z 492 (MH-TFA) -.

Example 153

N- {4- [4- (3-Methoxybenzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 153a

N- {4- [2-Amino-4- (3-methoxy-benzyloxy) -phenylsulfanyl] -phenyl} -acetamide

A mixture of the product of Example 232b (28 mg, 0.085 mmol), 3-methoxybenzyl bromide (19 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 mL) was stirred at room temperature for 15 hours. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to give the title compound (33 mg, 100%).

Example 153b

N- {4- [4- (3-Methoxybenzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 ml) with the product of Example 153a (33 mg, 0.085 mmol) for 18 hours according to the method described in Example 1g to give the crude title a compound which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (14 mg, 30%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (t, J = 7.35 Hz, 3H), 1.69-1.93 (m, 2H), 2.02 (s, 3H), 2.99 (t , J = 6.99 Hz, 2H), 3.75 (s, 3H), 5.13 (s, 2H), 6.29 (d, J = 7.35 Hz, 1H), 6.91 (dd , J = 8.09, 2.57 Hz, 1H), 6.95-7.05 (m, 2H), 7.13 (d, J = 8.82 Hz, 2H), 7.16-7, 24 (m, 2H), 7.31 (t, J = 8.09 Hz, 1H), 7.38 (d, J = 8.46 Hz, 1H), 7.42 (d, J = 8.82 Hz, 2H), 7.80 (d, J = 8.82 Hz, 1H), 8.35 (d, J = 6.99 Hz, 1H), 8.97 (d, J = 8.82 Hz, 1H), 9.97 (s, 1H), 11.00 (s, 1H), 14.36 (s, 1H); MS (ESI +) m / z 565 (M + H) +.

Example 154

N- {4- [4- (3-Bromo-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 154a

N- {4- [2-Amino-4- (3-bromo-benzyloxy) -phenylsulfanyl] -phenyl} -acetamide

A mixture of the product of Example 232b (28 mg, 0.085 mmol), 3-bromobenzyl bromide (24 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 mL) was stirred at room temperature for 15 hours. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to give the title compound (37 mg, 100%).

Example 154b

N- {4- [4- (3-Bromo-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 ml) with the product of Example 154a (37 mg, 0.085 mmol) for 18 hours according to the method described in Example 1g to give the crude title a compound which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (15 mg, 30%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (t, J = 7.35 Hz, 3H), 1.65-1.90 (m, 2H), 2.02 (s, 3H), 2.99 (t , J = 7.54 Hz, 2H), 5.17 (s, 2H), 6.29 (d, J = 6.99 Hz, 1H), 7.14 (d, J = 8.82 Hz, 2H ), 7.17-7.27 (m, 2H), 7.28-7.40 (m, 3H), 7.42 (d, J = 8.46 Hz, 2H), 7.55 (d, J = 7.72 Hz, 1H), 7.66 (s, 1H), 7.80 (d, J = 8.46 Hz, 1H), 8.37 (d, J = 6.99 Hz, 1H) , 8.97 (d, J = 8.82 Hz, 1H), 9.98 (s, 1H), 11.00 (s, 1H), 14.37 (s, 1H); MS (ESI +) m / z 613 (M + H) +.

Example 155

N- {4- [4- (3-Nitro-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 155a

N- {4- [2-Amino-4- (3-nitro-benzyloxy) -phenylsulfanyl] -phenyl} -acetamide

A mixture of the product of Example 232b (28 mg, 0.085 mmol), 3-nitrobenzimide (21 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 mL) was stirred at room temperature for 15 hours. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to give the title compound (34 mg, 100%).

Example 155b

N- {4- [2- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4- (3-nitro-benzyloxy) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 ml) with the product of Example 155a (34 mg, 0.085 mmol) for 18 hours according to the method described in Example 1g to give the crude title a compound which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (13 mg, 29%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J = 7.35 Hz, 3H), 1.72-1.92 (m, 2H), 2.02 (s, 3H), 2.99 (t, , J = 7.54 Hz, 2H), 5.32 (s, 2H), 6.30 (d, J = 6.99 Hz, 1H), 7.15 (d, J = 8.46 Hz, 2H ), 7.19-7.25 (m, 1H), 7.27 (d, J = 2.57 Hz, 1H), 7.38 (d, J = 8.82 Hz, 1H), 7.43 (d, J = 8.46 Hz, 2H), 7.72 (t, J = 7.91 Hz, 1H), 7.81 (d, J = 8.82 Hz, 1H), 7.91 (d , J = 7.72 Hz, 1H), 8.22 (d, J = 8.82 Hz, 1H), 8.32 (s, 1H), 8.37 (d, J = 7.35 Hz, 1H ), 8.97 (d, J = 8.82 Hz, 1H), 9.98 (s, 1H), 11.01 (s, 1H), 14.37 (s, 1H); MS (ESI +) m / z 580 (M + H) +.

Example 156

N- {4- [4- (4-Cyano-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 156a

N- {4- [2-Amino-4- (4-cyano-benzyloxy) -phenylsulfanyl] -phenyl} -acetamide

A mixture of the product of Example 232b (28 mg, 0.085 mmol), 4-cyanobenzyl bromide (19 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 mL) was stirred at room temperature for 15 hours. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to give the title compound (33 mg, 100%).

Example 156b

N- {4- [4- (4-Cyano-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 ml) with the product of Example 156a (33 mg, 0.085 mmol) for 18 hours according to the method described in Example 1g to give the crude title a compound which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (12 mg, 21%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (t, J = 7.35 Hz, 3H), 1.69-1.92 (m, 2H), 2.02 (s, 3H), 2.99 (t , J = 7.54 Hz, 2H), 5.27 (s, 2H), 6.30 (d, J = 6.99 Hz, 1H), 7.14 (d, J = 8.82 Hz, 2H ), 7.17-7.27 (m, 2H), 7.37 (d, J = 8.46 Hz, 1H), 7.42 (d, J = 8.82 Hz, 2H), 7.64 (d, J = 8.09 Hz, 2H), 7.81 (d, J = 8.82 Hz, 1H), 7.89 (d, J = 8.46 Hz, 2H), 8.38 (d , J = 6.99 Hz, 1H), 8.97 (d, J = 8.82 Hz, 1H), 9.98 (s, 1H), 11.01 (s, 1H), 14.38 , 1H); MS (ESI +) m / z 560 (M + H) +.

Example 157

N- {4- [4- (2-Bromo-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 157a

N- {4- [2-Amino-4- (2-bromo-benzyloxy) -phenylsulfanyl] -phenyl} -acetamide

A mixture of the product of Example 232b (56 mg, 0.17 mmol), 2-bromobenzyl bromide (26 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 ml) was stirred at room temperature 15 hour. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to give the title compound (75 mg, 100%).

Example 157b

N- {4- [2-Bromo-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 2g (35 mg, 0.17 mmol) was reacted in ethanol (1 ml) with the product of Example 157a (75 mg, 0.17 mmol) for 18 hours according to the method described in Example 1g, the crude title compound, which was purified by HPLC with TFA, to give the product as a trifluoroacetic acid salt (18 mg, 29%). 11H-NMR (300 MHz, DMSO-d6th), δ ppm: 0.97 (t, J = 7.35 Hz, 3H), 1.72-1.92 (m, 2H), 2.02 (s, 3H), 2.99 t, J = 7.35 Hz, 2H), 5.17 (s, 2H), 6.33 (d, J = 6.99 Hz, 1H), 7.16 (d, J = 8.46 Hz, 2H), 7.18-7.28 (m, 2H), 7.28-7.51 (m, 5H), 7.60 (dd, J = 7.54, 1.65 Hz, 1H), 7 , 69 (d, J = 6.99 Hz, 1H), 7.81 (d, J = 8.82 Hz, 1H), 8.39 (d, J = 6.99 Hz, 1H), 8.97 (d, J = 8.82 Hz, 1H), 9.99 (s, 1H), 11.02 (s, 1H), 14.37 (s, 1H): MS (ESI +) m / z 613 (M + H) +.

Example 158

N- {4- [4- (4-Bromo-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 158a

N- {4- [2-Amino-4- (4-bromo-benzyloxy) -phenylsulfanyl] -phenyl} -acetamide

A mixture of the product of Example 232b (28 mg, 0.085 mmol), 4-bromobenzyl bromide (24 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 mL) was stirred at room temperature for 15 hours. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to give the title compound (37 mg, 100%).

Example 158b

N- {4- [4- (4-Bromo-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 ml) with the product of Example 158a (37 mg, 0.085 mmol) for 18 hours according to the method described in Example 1g to give the crude title a compound which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (26 mg, 42%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (t, J = 7.35 Hz, 3H), 1.67-1.92 (m, 2H), 2.02 (s, 3H), 2.99 (t, , J = 7.54 Hz, 2H), 5.14 (s, 2H), 6.30 (d, J = 6.99 Hz, 1H), 7.14 (d, J = 8.46 Hz, 2H ), 7.16-7.26 (m, 2H), 7.31-7.49 (m, 5H), 7.53-7.66 (m, 2H), 7.80 (d, J = 8 , 46 Hz, 1H), 8.37 (d, J = 6.99 Hz, 1H), 8.97 (d, J = 8.82 Hz, 1H), 9.97 (s, 1H), 11, 00 (s, 1H), 14.37 (s, 1H); MS (ESI +) m / z 615 (M + H) +.

Example 159

N- {4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -acetamide

Example 159a

N- [4- (4-Chloro-2-nitro-phenoxy) -phenyl] -acetamide

A mixture of 2-fluoro-5-chloronitrobenzene (0.5 g, 2.85 mmol), 4-acetamidophenol (0.45 g, 3.00 mmol) and cesium carbonate (0.98 g, 3.00 mmol) in DMSO (5 ml) was heated at 90 ° C for 6 hours. The mixture was cooled, diluted with ethyl acetate (100 ml) and the organic layer was washed with water, a 20% aqueous solution of potassium hydroxide and an aqueous 10% sodium chloride solution, then dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was concentrated in vacuo to give the title compound as a tan solid (0.71 g, 81%).

Example 159b

N- [4- (2-Amino-4-chloro-phenoxy) -phenyl} -acetamide

The product of Example 159a was reduced with Fe and NH4Cl in accordance with the method described in Example 237e to obtain the title compound.

Example 159c

N- {4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -acetamide

The product of Example 1d (50 mg, 0.280 mmol) was reacted with the product of Example 159b (77 mg, 0.280 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (25 mg, 17%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.92-2.11 (m, 3H), 2.74 (s, 3H), 6.69 (d, J = 6.99 Hz, 1H), 6.87-6 , 99 (m, 2H), 7.07 (d, J = 9.19 Hz, 1H), 7.45-7.57 (m, 3H), 7.69 (d, J = 2.57 Hz, 1H), 7.77 (d, J = 8.82 Hz, 1H), 8.52 (d, J = 6.99 Hz, 1H), 8.91 (d, J = 8.46 Hz, 1H) , 9.93 (s, 1H), 10.92 (s, 1H), 14.50 (s, 1H); MS (ESI +) m / z 419 (M + H) +, (ESI-) m / z 417 (MH) -.

Example 160

[2- (3,4-Dimethylphenylsulfanyl) -5-methylphenyl] - (7-propyl- [1,8] naphthyridin-4-yl) amine

The product of Example 2g (70 mg, 0.338 mmol) was reacted with the product of Example 4c using 3,4-dimethylbenzenethiol instead of 4-mercaptophenol for 20 hours according to the method described in Example 1g to give the crude title compound, which was triturated in a 4: 1 ether / THF mixture to give the title compound as the hydrochloride salt (135 mg, 88%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.99 (t, J = 7.35 Hz, 3H), 1.82 (m, J = 7.35 Hz, 2H), 1.93 (s, 3H), 2, (S, 3H), 2.36 (s, 3H), 2.99 (q, J = 7.35 Hz, 2H), 6.20 (d, J = 6.99 Hz, 1H), 6, 94 (m, 3H), 7.32 (m, 2H), 7.34 (s, 1H), 7.80 (d, J = 8.82 Hz, 1H), 8.33 (d, J = 7 , 35 Hz, 1H), 8.97 (d, J = 8.82 Hz, 1H), 10.96 (bs, 1H), 14.29 (bs, 1H); MS (ESI +) m / z 414 (M-Cl) +; (ESI-) m / z 412 (M-HCl) -.

Example 161

(7-Ethyl- [1,8] naphthyridin-4-yl) - [2- (4-methoxy-phenylsulfanyl) -5-methylphenyl] -amine

The product of Example 3f (79 mg, 0.41 mmol) was reacted with the product of Example 50b (88 mg, 0.41 mmol) for 23 hours according to the method described in Example 1g to give the crude title compound, which was triturated in 3: 1 ether / THF to give the title compound (162 mg, 90%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.37 (t, J = 7.35 Hz, 3H), 2.34 (s, 3H), 3.05 (q, J = 7.35 Hz, 2H), 3, 72 (s, 3H), 6.27 (d, J = 6.98Hz, 1H), 6.85 (m, J = 8.82Hz, J = 2.20Hz, 2H), 7.10 ( d, J = 8.09 Hz, 1H), 7.23-7.32 (m, 4H), 7.83 (d, J = 8.83 Hz, 1H), 8.41 (d, J = 6 , 98 Hz, 1H), 9.11 (d, J = 8.83 Hz, 1H), 11.16 (brs, 1H), 14.39 (brs, 1H); MS (ESI +) m / z 402 (M-Cl) +; (ESI-) m / z 400 (M-HCl) -.

Example 162

4- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N-methyl-benzamide

Example 162a

4- (4-Chloro-2-nitro-phenoxy) -N-methyl-benzamide

The product of Example 126c (225 mg, 0.72 mmol) was reacted with methylamine (1.0 mL, 2.0 mmol) in THF (20 mL) at room temperature. THF was removed under reduced pressure. The crude residue was purified by flash chromatography, eluting with hexane / ethyl acetate (30:70) to give the title compound (110 mg, 50%).

Example 162b

4- (2-Amino-4-chloro-phenoxy) -N-methyl-benzamide

The product of Example 162a (200 mg, 0.65 mmol) was reacted with SnCl2, as described in Example 1f, to obtain the title compound (100 mg, 55%).

Example 162c

4- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N-methyl-benzamide

The product of Example 2g (64 mg, 0.31 mmol) was reacted with the compound of Example 162b (85.0 mg, 0.31 mmol) in ethanol (5 mL) at 85 ° C. in a sealed tube for 18 hours, to give the crude title compound, which was purified by HPLC using TFA, to give the product as trifluoroacetic acid (25 mg, 31%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 8.85 (d, J= 8.82 Hz, 1H), 8.53 (d, J= 7.35 Hz, 1H), 8.33 (d, J= 4.17 Hz, 1H), 7.71-7.78 (m, 4H), 7.61 (dd, J= 8.82, 2.57 Hz, 1H), 7.29 (d, 1H), 6.97 (d, J= 8.82 Hz, 2H), 6.73 (d, J= 6.99 Hz, 1H), 2.93-3.00 (t, 2H), 2.71 (d, 3H), 1.76-1.87 (m, 2H), 0.95 (t, J= 7.35 Hz, 3H); MS (ESI +)m / z 561 (M + H) +.

Example 163

The oxime of 1- {4- [4-chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -ethanone

Example 163a

1- [4- (2-Amino-4-chloro-phenoxy) phenyl] ethanone

The product of Example 164a (1.0 g, 3.4 mmol) was reacted with SnCl2, as described in Example 1f, to obtain the title compound (0.70 g, 78%).

Example 163b

The oxime of 1- [4- (2-amino-4-chloro-phenoxy) phenyl] ethanone

Hydroxylamine hydrochloride (41.8 mg, 0.60 mmol) and diisopropylethylamine (82 mg, 0.63 mmol) were added to the product of Example 163a (150 mg, 0.57 mmol) in ethanol (15 mL). The reaction mixture was heated at 60 ° C for 3 hours. The reaction mixture was cooled and poured into water. The solution was extracted with ethyl ether. The organic layer was washed with water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (65 mg, 42%).

Example 163c

The oxime of 1- {4- [4-chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -ethanone

The product of Example 2g (45 mg, 0.217 mmol) was reacted with the compound of Example 163b (60.0 mg, 0.217 mmol) in ethanol (10 ml) at 85 ° C. in a sealed tube for 18 hours to yield the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (25 mg, 31%). 11H NMR (500 MHz, DMSO-d6th) δ ppm: 0.98 (t, J= 7.32, 2.44 Hz, 3H), 1.81-1.88 (m, 2H), 2.09 (s, 3H), 2.99 (t, 2H), 6.74 (d, J= 7.32 Hz, 1H), 6.97 (d, J= 9.28 Hz, 2H), 7.26 (d, J= 9.28 Hz, 1H), 7.56 (d, J= 8.79 Hz, 2H), 7.61 (dd, J= 9.03, 2.69 Hz, 1H), 7.75 (d, J= 2.44 Hz, 1H), 7.77-7.79 (m, 1H), 8.57 (d, J= 6.84 Hz, 1H), 8.93 (d, J= 8.30 Hz, 1H); MS (ESI +) m / z 447 (M + H) +.

Example 164

1- {4- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -ethanol

Example 164a

1- [4- (4-Chloro-2-nitro-phenoxy) phenyl] ethanone

1-Bromo-4-chloro-2-nitrobenzene (5 g, 21.2 mmol) was added to a solution of 4-hydroxyacetophenone (2.87 g, 21.1 mmol) and K2CO3 (7.28 g, 0.052 mol) in DMF (50 ml). The mixture was heated at 80 ° C for 15 hours. The reaction mixture was poured into water. The aqueous phase was extracted with ethyl acetate (2 ×) and the combined phases were washed with water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the crude title compound. The crude product was purified by flash chromatography, eluting with a mixture (hexane / ethyl acetate 70:30) to give the title compound (4.8 g, 77.8%).

Example 164b

1- [4- (4-Chloro-2-nitro-phenoxy) -phenyl] -ethanol

The product of Example 164a (0.7 g, 2.4 mmol) was added to ethanol (30 ml) and sodium borohydride (115 g, 3.11 mmol) was added in portions. The reaction mixture was stirred for 1 hour and then the excess sodium borohydride was decomposed by the dropwise addition of acetic acid. The reaction mixture was poured onto an ice / water mixture and extracted with ethyl acetate. The organic phase was washed with water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (0.634 g, 90%).

Example 164c

1- [4- (2-Amino-4-chloro-phenoxy) -phenyl] -ethanol

The product of Example 164b (0.58 g, 1.9 mmol) was reduced with SnCl2, as described in Example 1f, to obtain the title compound (0.36 g, 70%).

Example 164d

1- {4- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -ethanol

The product of Example 2g (125 mg, 0.60 mmol) was reacted with the compound of Example 164c (160 mg, 0.60 mmol) in ethanol (10 mL) at 85 ° C. in a sealed tube for 18 hours to obtain a crude The title compound, which was purified by HPLC with TFA, gave the product as trifluoroacetic acid (40 mg, 12%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 8.91 (d, J= 8.82 Hz, 1H), 8.52 (d, J= 6.99 Hz, 1H), 7.78 (d, J= 8.82 Hz, 1H), 7.70 (d, J= 2.57 Hz, 1H), 7.56 (dd, J= 8.82, 2.57 Hz, 1H), 7.23 (d, J= 8.46 Hz, 2H), 7.12 (d, J= 8.82 Hz, 1H), 6.87-6.94 (m, 2H), 6.69 (d, J= 6.99 Hz, 1H), 4.63 (q, J= 6.25 Hz, 1H), 2.97 (t, J= 7.54 Hz, 2H), 1.75-1.88 (m, J= 7.35, 7.35, 7.35, 7.35 Hz, 2H), 1.19 (d, J= 6.25 Hz, 3H), 0.95 (t, J= 7.35 Hz, 3H); MS (ESI-) m / z 432 (MH) -.

Example 165

4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl ester of propan-2-sulfonic acid

Example 165a

4-Chloro-1- (4-methoxy-phenoxy) -2-nitro-benzene

1-Bromo-4-chloro-2-nitrobenzene (10 g, 42.2 mmol) was added to a solution of 4-methoxyphenol (5.3 g, 42.2 mmol) and K2CO3 (14.5 g, 105 mmol) in DMF (50 mL). The mixture was heated at 80 ° C for 16 hours. The reaction mixture was poured into water. The aqueous phase was extracted with ethyl acetate and the combined phases were washed with water, saturated brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the crude title compound. The crude product was purified by chromatography on silica gel, eluting with a mixture (hexane / ethyl acetate 90:10) to obtain the title compound (8.0 g, 67%).

Example 165b

4- (4-Chloro-2-nitro-phenoxy) -phenol

To the compound of Example 165a (0.98 g, 3.5 mmol) in CH2Cl2 (20 ml) was added boron tribromide (0.95 g, 3.90 mmol). The reaction mixture was stirred for 18 hours. Methanol was added to decompose the excess of boron tribromide. The reaction mixture was poured into water and extracted with methylene chloride. The phases were separated. The organic phase was washed with water, saturated brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the crude title compound. The crude product was purified by chromatography on silica gel, eluting with a mixture (hexane / ethyl acetate 90:10) to give the title compound (0.57, 60%).

Example 165c

4- (2-Amino-4-chloro-phenoxy) -phenol

The product of Example 165b (1.0 g, 3.7 mmol) was reacted with SnCl2, as described in Example 1f, to obtain the title compound (0.7 g, 78%).

Example 165d

4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenol

The product of Example 1d (80 mg, 4.5 mmol) was reacted with the product of Example 165c (106 mg, 4.5 mmol) in ethanol (15 mL) at 85 ° C. in a sealed tube for 18 hours to obtain a crude The title compound, which was purified by HPLC with TFA, gave the product as trifluoroacetic acid (40 mg, 18%).

Example 165e

4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl ester of propan-2-sulfonic acid

The product of Example 165d (43 mg, 0.085 mmol) was reacted with isopropylsulfonyl chloride (14.5 mg, 0.102 mmol), N, N-diisopropylethylamine (33 mg, 0.255 mmol) and catalytic amount of DMAP in CH2Cl2 for 18 hours to give the crude title compound, which was purified by HPLC with TFA, to give the product as trifluoroacetic acid (16 mg, 31%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.38 (d, J= 6.99 Hz, 6H), 2.73 (s, 3H), 3.54-3.65 (m, 1H), 6.69 (d, J= 6.99 Hz, 1H), 7.01 (d, J= 9.19 Hz, 2H), 7.20 (d, J= 9.19 Hz, 2H), 7.27 (d, J= 8.82 Hz, 1H), 7.60 (dd, J= 8.82, 2.57 Hz, 1H), 7.70-7.75 (m, 2H), 8.51 (d, J= 6.99 Hz, 1H), 8.81 (d, J= 8.82 Hz, 1H); MS (ESI +)m / z 484 (M + H) +.

Example 166

4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N-methyl-benzamide

The product of Example 1d (100 mg, 0.562 mmol) was reacted with the compound of Example 162b (155.0 mg, 0.562 mmol) in ethanol (5 mL) at 85 ° C. in a sealed tube for 18 hours to yield the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (40 mg, 13%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 8.82 (d, J= 8.46 Hz, 1H), 8.53 (d, J= 6.99 Hz, 1H), 8.33 (d, J= 4.41 Hz, 1H), 7.71-7.78 (m, 4H), 7.61 (dd, J= 8.82, 2.57 Hz, 1H), 7.30 (d, J= 8.82 Hz, 1H), 6.96 (d, J= 8.82 Hz, 2H), 6.72 (d, J= 6.99 Hz, 1H), 2.71-2.77 (m, 6H); MS (ESI +)m / z 419 (M + H) +.

Example 167

[2- (4-Aminomethyl-phenoxy) -5-chloro-phenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

Example 167a

4- (4-Chloro-2-nitro-phenoxy) -benzonitrile

1-Bromo-4-chloro-2-nitrobenzene (10 g, 42.3 mmol) was added to a solution of 4-cyanophenol (5.0 g, 42.3 mmol) and K2CO3 (14.6 g, 0.10 mol) in DMF (50 ml). The mixture was heated at 80 ° C for 15 hours. The reaction mixture was poured into water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with water, brine and dried over sodium sulfate. The organic phase was filtered and concentrated in vacuo. The residue was purified by flash chromatography, eluting with a mixture (hexane / ethyl acetate = 4: 1) to give the product (9.0 g, 77.8%).

Example 167b

4- (2-Amino-4-chloro-phenoxy) -benzonitrile

To the product of Example 116a (0.5 g, 1.8 mmol) in absolute ethanol (20 ml) was added BiCl3 (0.86 g, 27.3 mmol) and NaBH4 (0.55 g, 14.6 mmol), with cooling in an ice / water bath. The mixture was stirred for 20 h. The reaction mixture was filtered through celite to remove bismuth. The solution was concentrated under reduced pressure. The residue was treated with 5% HCl for 15 hours and then basified with ammonium hydroxide (pH 10). The solution was extracted with ethyl acetate. The ethyl acetate layer was washed with water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound as a solid (0.34 g, 77%).

Example 167c

4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -benzonitrile

The product of Example 1d (100 mg, 0.408 mmol) was reacted with the compound of Example 167b (100 mg, 0.408 mmol) in ethanol (10 ml) at 85 ° C. in a sealed tube for 18 hours to give the crude title compound , which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (125 mg, 44%).

Example 167d

[2- (4-Aminomethyl-phenoxy) -5-chloro-phenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 167c (88 mg, 0.175 mmol) was reacted with lithium aluminum hydride (13.3 mg, 0.351 mmol) in THF (5 mL) at 60 ° C for 15 hours to give the crude title compound which was purified with Using HPLC with TFA, which gave the product as trifluoroacetic acid (15 mg, 14%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 11.04 (s, 1H), 8.92 (d, J= 8.82 Hz, 1H), 8.54 (d, J= 6.99 Hz, 1H), 8.18 (s, 2H), 7.72-7.80 (m, 2H), 7.59 (dd, J= 9.01, 2.76 Hz, 1H), 7.40 (d, J= 8.82 Hz, 2H), 6.99-7.12 (m, 3H), 6.74 (d, J= 6.99 Hz, 1H), 3.97 (q, J= 5.52 Hz, 2H), 2.74 (s, 3H); MS (ESI +)m / z 391 (M + H) +.

Example 168

3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N, N-dimethylbenzamide

Example 168a

3- (4-Chloro-2-nitro-phenoxy) -benzoic acid

To a solution of DMF (50 ml) was added 1-bromo-2-nitro-4-chlorobenzene (10.0 g, 42.2 mmol), 3-hydroxybenzoic acid (5.8 g, 42.0 mmol) and K2CO3 (17.5 g, 0.13 mol). The solution was heated to 85 ° C and stirred overnight. The reaction mixture was poured into distilled water and extracted with ethyl acetate. The combined organic layers were washed with distilled water, brine and dried over Na2SO4, filtered and concentrated in vacuo to give a crude oil. The resulting oil was purified by chromatography on a silica gel column, eluting with CH2Cl2/ MeOH (90:10) to give the title compound (7.4 g, 60%).

Example 168b

3- (4-Chloro-2-nitro-phenoxy) benzoyl chloride

The product of Example 168a (2.0 g, 6.8 mmol) was treated with oxalyl chloride (9.0 g, 13.6 mmol) and a catalytic amount of DMF at 60 ° C. for 5 hours. The excess oxalyl chloride was removed in vacuo. The residue was washed with benzene to give the desired product (2.2 g, 94%).

Example 168c

3- (4-Chloro-2-nitro-phenoxy) -N, N-dimethyl-benzamide

Dimethylamine (0.6 g, 13.3 mmol) was added to the product of Example 168b (2.0 g, 6.4 mmol) in THF (25 mL) and the reaction mixture was stirred for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 5% HCl, water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (1.9 g, 87%).

Example 168d

3- (2-Amino-4-chloro-phenoxy) -N, N-dimethyl-benzamide

The product of Example 168c (1.5 g, 4.6 mmol) was reacted with SnCl2, as described in Example 1f, to obtain the title compound (0.91 g, 68%).

Example 168e

3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N, N-dimethylbenzamide

The product of Example 2g (177 mg, 0.86 mmol) was reacted with the product of Example 168d (249 mg, 0.86 mmol) in ethanol (5 mL) at 85 ° C. in a sealed tube for 18 hours to give a crude The title compound, which was purified by HPLC using TFA, gave the product as trifluoroacetic acid (100 mg, 20.2%). 11H NMR (500 MHz, DMSO-d6th) δ ppm: 8.86 (d, J= 8.79 Hz, 1H), 8.52 (d, J= 6.84 Hz, 1H), 7.74 (d, 1H), 7.72 (d, 1H), 7.60 (dd, J= 8.79, 2.93 Hz, 1H), 7.28-7.33 (m, 1H), 7.27 (d, 2H), 7.06 (d, J= 7.81 Hz, 1H), 6.99 (dd, J= 8.06, 2.69 Hz, 1H), 6.71 (d, J= 6.84 Hz, 1H), 2.96 (t, 2H), 2.91 (s, 3H), 2.70 (s, 3H), 1.79-1.86 (m, 2H), 0 , 96 (t, J= 7.49 Hz, 3H); MS (ESI +) m / z 461 (M + H) +.

Example 169

3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -benzoic acid ethyl ester

Example 169a

Ethyl 3- (4-chloro-2-nitro-phenoxy) -benzoic acid

HCl gas was bubbled into the product of Example 168a (2.0 g, 6.8 mmol) in ethanol (50 ml) with cooling for 10 hours. Excess ethanol was removed in vacuo. The solid was taken up in ethyl acetate. The organic layer was washed with saturated NaHCO33, water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (2.0 g, 91%).

Example 169b

Ethyl 3- (2-amino-4-chloro-phenoxy) -benzoic acid

The product of Example 169a (1.5 g, 4.7 mmol) was reacted with SnCl2, as described in Example 1f, to obtain the title compound (1.0 g, 73%).

Example 169c

3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -benzoic acid ethyl ester

The product of Example 2g (113 mg, 0.55 mmol) was reacted with the compound of Example 169b (160 mg, 0.55 mmol) in ethanol (5 mL) at 85 ° C. in a sealed tube for 18 hours to give a crude The title compound, which was purified by HPLC with TFA, gave the product as trifluoroacetic acid (200 mg, 63%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 8.76 (d, J= 8.46 Hz, 1H), 8.54 (d, J= 6.99 Hz, 1H), 7.74 (dd, J= 5.70, 3.13 Hz, 2H), 7.58-7.65 (m, J= 5.70, 5.70, 2.57 Hz, 2H), 7.29-7.43 (m, 3H), 7.20 (dd, J= 7.72, 2.21 Hz, 1H), 6.68 (d, J= 6.99 Hz, 1H), 4.23 (q, J= 6.99 Hz, 2H), 2.96 (t, J= 7.54 Hz, 2H), 1.77-1.85 (m, 2H), 1.29 (t, 3H), 0.95 (t, J= 7.35 Hz, 3H); MS (ESI +) m / z 461 (M + H) +.

Example 170

1- {3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -ethanol

Example 170a

1- [3- (4-Chloro-2-nitro-phenoxy) phenyl] ethanone

1-Bromo-4-chloro-2-nitrobenzene (10 g, 42.2 mmol) was added to a solution of 3-hydroxyacetophenone (5.5 g, 42.2 mmol) and K2CO3 (11.7 g, 84.6 mmol) in DMF (50 mL). The mixture was heated at 80 ° C for 16 hours. The reaction mixture was poured into water. The aqueous phase was extracted with ethyl acetate (2 ×) and the combined phases were washed with water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound. The crude product was purified by flash chromatography, eluting with a mixture (hexane / ethyl acetate 70:30) to give the title compound (8.6 g, 70%).

Example 170b

1- [3- (4-Chloro-2-nitro-phenoxy) -phenyl] -ethanol

To the product of Example 170a (1.8 g, 6.2 mmol) in ethanol (50 ml), sodium borohydride (0.32 g, 8.64 mmol) was added in portions. The reaction mixture was stirred at room temperature for 16 hours. Excess sodium borohydride was decomposed by the addition of acetic acid. The reaction mixture was poured onto ice / water and extracted with ethyl acetate. The organic phase was washed with water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound. The crude residue was purified by chromatography on silica gel, eluting with a hexane / ethyl acetate / methanol mixture (75: 15: 5) to give the desired product (0.98 g, 54%).

Example 170c

1- [3- (2-Amino-4-chloro-phenoxy) -phenyl] -ethanol

The product of Example 170b (0.98 g, 3.3 mmol) was reduced with SnCl2, as described in Example 1f, to obtain the title compound (0.61 g, 70%).

Example 170d

1- {3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -ethanol

The product of Example 2g (140 mg, 0.68 mmol) was reacted with the compound of Example 170c (178 mg, 0.68 mmol) in ethanol (5 mL) at 85 ° C. in a sealed tube for 18 hours to give a crude The title compound, which was purified by HPLC with TFA, gave the product as trifluoroacetic acid (110 mg, 30%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 8.86 (d, J= 8.46 Hz, 1H), 8.53 (d, J= 7.35 Hz, 1H), 7.77 (d, J= 8.82 Hz, 1H), 7.71 (d, J= 2.57 Hz, 1H), 7.58 (dd, J= 8.82, 2.57 Hz, 1H), 7.17-7.22 (d, 2H), 7.01 (d, J= 7.72 Hz, 1H), 6.87 (s, 1H), 6.78 (dd, J= 7.54, 2.02 Hz, 1H), 6.68 (d, J= 6.99 Hz, 1H), 4.55-4.62 (q, J= 6.62 Hz, 1H), 2.96 (t, J= 7.54 Hz, 2H), 1.76-1.86 (m, 2H), 1.12 (d, J= 6.62 Hz, 3H), 0.95 (t, J= 7.35 Hz, 3H); MS (ESI +) m / z 434 (M + H) +.

Example 171

3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -benzamide

Example 171a

3- (4-Chloro-2-nitro-phenoxy) -benzamide

The product of Example 168b (1.8 g, 6.13 mmol) was added to cold NH4OH (15 ml) and stirred for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (1.66 g, 92%).

Example 171b

3- (2-Amino-4-chloro-phenoxy) -benzamide

The product of Example 171a (0.56 g, 1.9 mmol) was reacted with SnCl2, according to the method described in Example 1f, to obtain the title compound (0.60 g, 83%).

Example 171c

3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -benzamide

The product of Example 2g (140 mg, 0.68 mmol) was reacted with the product of Example 171b (178 mg, 0.68 mmol) in ethanol (5 mL) at 85 ° C. in a sealed tube for 18 hours to give a crude The title compound, which was purified by HPLC with TFA, gave the product as trifluoroacetic acid (110 mg, 30%). 11H NMR (500 MHz, DMSO-d6th) δ ppm: 8.81 (d, J= 8.54 Hz, 1H), 8.45 (d, J= 7.32 Hz, 1H), 6.76-6.79 (m, 2H), 6.64 (d, J= 8.54 Hz, 2H), 6.44 (s, 1H), 6.37 (t, J= 7.93 Hz, 1H), 6.31 (d, J= 8.54 Hz, 1H), 7.16 (dd, J= 7.93, 2.44 Hz, 1H), 6.84 (d, J= 7.32 Hz, 1H), 2.95 (t, J= 7.32 Hz, 2H), 1.80 (m, 2H), 0.95 (t, J= 7.32 Hz, 3H); MS (ESI +) m / z 433 (M + H) +.

Example 172

3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N-ethyl-benzamide

Example 172a

To the product of Example 168b (1.6 g, 5.1 mmol) in THF (25 mL) was added ethylamine (0.4 g, 8.0 mmol) and the reaction mixture was stirred for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 5% HCl, water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (1.4 g, 85%).

Example 172b

3- (2-Amino-4-chloro-phenoxy) -N-ethyl-benzamide

The product of Example 172a (0.90 g, 2.8 mmol) was reacted with SnCl2, as described in Example 1f, to obtain the title compound (0.65 g, 81%).

Example 172c

3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N-ethyl-benzamide

The product of Example 2g (128 mg, 0.62 mmol) was reacted with the compound of Example 172b (180 mg, 0.62 mmol) in ethanol (10 mL) at 85 ° C. in a sealed tube for 18 hours to give a crude The title compound, which was purified by HPLC with TFA, gave the product as trifluoroacetic acid (70 mg, 20%). 11H NMR (500 MHz, DMSO-d6th) δ ppm: 8.84 (d, J= 8.82 Hz, 1H), 8.53 (d, J= 7.26 Hz, 1H), 8.39 (t, J= 5.45 Hz, 1H), 7.72-7.76 (m, 2H), 7.60 (dd, J= 8.82, 2.59 Hz, 1H), 7.54 (d, J= 7.78 Hz, 1H), 7.32-7.36 (m, 2H), 7.25 (d, J= 8.82 Hz, 1H), 7.09 (dd, J= 7.78, 2.59 Hz, 1H), 6.70 (d, J= 7.26 Hz, 1H), 3.19-3.25 (m, 2H), 2.96 (t, J= 7.52 Hz, 2H), 1.79-1.84 (m, 2H), 1.08 (t, J= 7.00 Hz, 3H), 0.95 (t, J= 7.52 Hz, 3H); MS (ESI +) m / z 461 (M + H) +.

Example 173

3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N-phenyl-benzamide

Example 173a

To the product of Example 168b (0.81 g, 2.6 mmol) in THF (25 mL) was added benzylamine (0.25 g, 2.6 mmol) and N, N-diisopropylethylamine (0.67 g, 5.2 mmol). The reaction mixture was stirred for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 5% HCl, water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (0.8 g, 85%).

Example 173b

3- (2-Amino-4-chloro-phenoxy) -N-phenyl-benzamide

The product of Example 173a (0.84 g, 2.3 mmol) was reacted with SnCl2, as described in Example 1f, to give the desired product (0.60 g, 77%).

Example 173c

3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N-phenyl-benzamide

The product of Example 2g (131 mg, 0.63 mmol) was reacted with the compound of Example 173b (214 mg, 0.63 mmol) in ethanol (10 mL) at 85 ° C. in a sealed tube for 18 hours to give a crude The title compound, which was purified by HPLC with TFA, gave the product as trifluoroacetic acid (125 mg, 31%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 10.11 (s, 1H), 8.80 (d, J= 8.82 Hz, 1H), 8.53 (d, J= 6.99 Hz, 1H), 7.67-7.75 (m, 4H), 7.58-7.67 (m, 2H), 7.40-7.46 (m, 2H), 7, 30-7.37 (m, 3H), 7.08-7.18 (m, 2H), 6.70 (d, J= 7.35 Hz, 1H), 2.92 (t, 2H), 1.73-1.82 (m, 2H), 0.92 (t, J= 7.35 Hz, 3H); MS (ESI +) m / z 509 (M + H) +.

Example 174

3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N- (3-hydroxy-phenyl) -benzamide

Example 174a

N- [3- (t-Butyl-dimethyl-silanyloxy) -phenyl] -3- (4-chloro-2-nitro-phenoxy) -benzamide

To a product of 3- (tert-butyl-dimethyl-silanyloxy) -phenylamine (1.0 g, 4.2 mmol) and N (2.0 g, 4.2 mmol) in THF (25 mL) , N-diisopropylethylamine (0.67 g, 5.2 mmol). The reaction mixture was stirred for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 5% HCl, water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (1.3 g, 85%).

Example 174b

3- (4-Chloro-2-nitro-phenoxy) -N- (3-hydroxy-phenyl) -benzamide

To the product of Example 174a (1.5 g, 3.0 mmol) in THF (25 mL) was added tetrabutylammonium fluoride (0.94 g, 3.6 mmol). The reaction mixture was stirred for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (1.0 g, 86%).

Example 174c

3- (2-Amino-4-chloro-phenoxy) -N- (3-hydroxy-phenyl) -benzamide

The product of Example 174b (1.0 g, 2.6 mmol) was reacted with SnCl2, as described in Example 1f, to obtain the title compound (0.71 g, 84%).

Example 174d

3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N- (3-hydroxy-phenyl) -benzamide

The product of Example 2g (144 mg, 0.70 mmol) was reacted with the compound of Example 174c (247 mg, 0.70 mmol) in ethanol (10 ml) at 85 ° C. in a sealed tube for 18 hours to give a crude The title compound, which was purified by HPLC with TFA, gave the product as trifluoroacetic acid (123 mg, 27%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 10.02 (s, 1H), 9.45 (s, 1H), 8.81 (d, J= 8.82 Hz, 1H), 8.53 (d, J= 7.35 Hz, 1H), 7.74 (m, 2H), 7.69 (d, 2H), 7.61 (dd, 1H), 7.43 (s, 2H), 7.33 (s , 2H), 7.17 (m, 1H), 7.12 (s, 2H), 6.71 (d, J= 6.99 Hz, 1H), 6.52 (m, 1H), 2.93 (t, J= 7.54 Hz, 2H), 1.72-1.86 (m, 2H), 0.93 (t, J= 7.35 Hz, 3H); MS (ESI +) m / z 525 (M + H) +.

Example 175

3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N-propyl-benzamide

Example 175a

3- (4-Chloro-2-nitro-phenoxy) -N-propyl-benzamide

To the compound of Example 168b (1.0 g, 3.2 mmol) in THF (25 ml) was added n-propylamine (0.38 g, 6.4 mmol), and the reaction mixture was stirred for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with 5% HCl, water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (0.88 g, 82%).

Example 175b

3- (2-Amino-4-chloro-phenoxy) -N-propyl-benzamide

The product of Example 175a (0.88 g, 2.6 mmol) was reacted with SnCl2, as described in Example 1f, to obtain the title compound (0.61 g, 76%).

Example 175c

3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N-propyl-benzamide

The product of Example 2g (110 mg, 0.53 mmol) was reacted with the compound of Example 175b (162 mg, 0.53 mmol) in ethanol (10 mL) at 85 ° C. in a sealed tube for 18 hours to obtain a crude The title compound, which was purified by HPLC with TFA, gave the product as trifluoroacetic acid (50 mg, 16%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.85 (t, J= 7.54 Hz, 3H), 0.95 (t, J= 7.35 Hz, 3H), 1.42-1.54 (m, 2H), 1.75-1.88 (m, 2H), 2.96 (t, J= 7.54 Hz, 2H), 3.15 (q, 2H), 6.69 (d, J= 6.99 Hz, 1H), 7.09 (dd, J= 7.54, 2.39 Hz, 1H), 7.26 (d, J= 8.82 Hz, 1H), 7.32-7.36 (m, 2H), 7.54 (d, J= 8.09 Hz, 1H), 7.60 (dd, J= 8.82, 2.57 Hz, 1H), 7.72-7.77 (m, 2H), 8.39 (t, J= 5.70 Hz, 1H), 8.52 (d, J= 7.35 Hz, 1H), 8.82 (d, J= 8.82 Hz, 1H); MS (ESI +) m / z 475 (M + H) +.

Example 176

{3- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -methanol

Example 176a

3- (4-Chloro-2-nitro-phenoxy) -benzaldehyde

To a DMF solution (50 ml) was added 1-bromo-2-nitro-4-chlorobenzene (10.0 g, 42.2 mmol), 3-hydroxybenzaldehyde (5.2 g, 42.2 mmol) and K2CO3 (11.5 g, 84.6 mmol). The solution was heated to 85 ° C and stirred overnight. The reaction mixture was poured into distilled water and extracted with ethyl acetate. The combined organic layers were washed with distilled water, brine and dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound. The resulting solid was purified by chromatography on a silica gel column, eluting with hexane / ethyl acetate (4: 1) to give the title compound (4.4 g, 41%).

Example 176b

[3- (4-Chloro-2-nitro-phenoxy) -phenyl] -methanol

To the product of Example 176a (2.0 g, 7.2 mmol) in ethanol (25 ml) was added sodium borohydride (0.32 g, 8.6 mmol). The reaction mixture was stirred for 4 hours. Excess sodium borohydride was decomposed by the addition of acetic acid. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was separated and washed with water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (1.9 g, 94%).

Example 176c

[3- (2-Amino-4-chloro-phenoxy) -phenyl] -methanol

The product of Example 176b (1.9 g, 6.8 mmol) was reacted with SnCl2, as described in Example 1f, to obtain the title compound (1.4 g, 83%).

Example 176d

{3- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -methanol

The product of Example 1d (110 mg, 0.62 mmol) was reacted with the compound of Example 176c (153 mg, 0.62 mmol) in ethanol (10 mL) at 85 ° C. in a sealed tube for 18 hours to give a crude The title compound, which was purified by HPLC with TFA, gave the product as trifluoroacetic acid (50 mg, 16%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 8.96-9.00 (m, 1H), 8.52 (d, J= 6.99 Hz, 1H), 7.70-7.74 (m, 2H), 7.57 (dd, J= 9.01, 2.39 Hz, 1H), 7.15-7.25 (m, 2H), 7.00 (d, J= 7.72 Hz, 1H), 6.88 (s, 1H), 6.82 (dd, 1H), 6.68 (d, J= 6.99 Hz, 1H), 4.37 (s, 2H), 2.74 (s, 3H); MS (ESI +) m / z 392 (M + H) +.

Example 177

1- {3- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -ethanol

The product of Example 1d (125 mg, 0.70 mmol) was reacted with the compound of Example 170c (184 mg, 0.70 mmol) in ethanol (10 ml) at 85 ° C. in a sealed tube for 18 hours to give a crude The title compound, which was purified by HPLC using TFA, gave the product as trifluoroacetic acid (59 mg, 16%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.15 (d, J= 6.25 Hz, 3H), 2.62 (s, 3H), 4.60 (q, J= 6.37 Hz, 1H), 6.64 (d, J= 7.35 Hz, 1H), 6.73-6.79 (m, 1H), 6.89 (s, 1H), 7.01 (d, J= 7.72 Hz, 1H), 7.16 (t, J= 8.09 Hz, 2H), 7.56 (dd, J= 8.82, 2.57 Hz, 1H), 7.68-7.72 (m, 2H), 8.53 (d, J= 6.99 Hz, 1H), 9.18 (d, J= 8.46 Hz, 1H); MS (ESI +) m / z 406 (M + H) +.

Example 178

3- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N- (3-hydroxy-phenyl) -benzamide

The product of Example 1d (125 mg, 0.70 mmol) was reacted with the compound of Example 174c (237 mg, 0.70 mmol) in ethanol (10 mL) at 85 ° C. in a sealed tube for 18 hours to give a crude The title compound, which was purified by HPLC with TFA, gave the product as trifluoroacetic acid (120 mg, 28%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 10.00 (s, 1H), 8.81 (d, J= 8.46 Hz, 1H), 8.55 (d, J= 6.99 Hz, 1H), 7.72-7.75 (m, 2H), 7.65-7.71 (m, 1H), 7.62 (dd, J= 9.01, 2.76 Hz, 1H), 7.42 (s, 2H), 7.30 (d, J= 8.82 Hz, 1H), 7.26 (s, 1H), 7.16 (dd, J= 7.35, 2.57 Hz, 1H), 7.10 (d, J= 5.52 Hz, 2H), 6.71 (d, J= 6.99 Hz, 1H), 6.48-6.55 (m, 1H), 2.69 (s, 3H); MS (ESI-) m / z 495 (MH) -.

Example 179

[5-Chloro-2- (4-isopropyl-phenoxy) -phenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

Example 179a

4-Chloro-1- (4-isopropyl-phenoxy) -2-nitro-benzene

1-Bromo-4-chloro-2-nitrobenzene (12 g, 50.7 mmol) was added to a solution of 4-isopropylphenol (8.3 g, 60.8 mmol) and K2CO3 (14.0 g, 101 mmol) in DMF (70 mL). The mixture was heated at 80 ° C for 16 hours. The reaction mixture was poured into water. The aqueous phase was extracted with ethyl acetate and the combined phases were washed with water, saturated brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the crude title compound. The crude product was purified by chromatography on silica gel eluting with a mixture (hexane / ethyl acetate 90:10) to give the title compound (13.5 g, 92%).

Example 179b

5-Chloro-2- (4-isopropyl-phenoxy) -phenylamine

The product of Example 179a (13.7 g, 46.8 mmol) was reacted with SnCl2, as described in Example 1f, to obtain the title compound (10.3 g, 84.4%).

Example 179

[5-Chloro-2- (4-isopropyl-phenoxy) -phenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 1d (120 mg, 0.67 mmol) was reacted with the compound of Example 179b (175 mg, 0.67 mmol) in ethanol (10 mL) at 85 ° C. in a sealed tube for 18 hours to give a crude The title compound, which was purified by HPLC with TFA, gave the product as trifluoroacetic acid (60 mg, 17%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 8.86 (d, J= 8.46 Hz, 1H), 8.51 (d, J= 7.35 Hz, 1H), 7.75 (d, 1H), 7.70 (d, 1H), 7.55 (dd, J= 7.87, 1H), 7.14 (m, 3H), 6.89 (d, J= 8.64, 2.76 Hz, 2H), 6.67 (d, J= 6.98 Hz, 1H), 2.79 (m, 1H), 2.73 (s, 3H), 1.09 (d, J= 6.99 Hz, 6H); MS (ESI +) m / z 404 (M + H) +.

Example 180

{2- [3- (1-Azido-ethyl) -phenoxy] -5-chloro-phenyl} - (7-propyl- [1,8] naphthyridin-4-yl) amine

Example 180a

2- [3- (1-Azido-ethyl) -phenoxy] -5-chloro-phenylamine

To the product of example 170c in toluene (25 ml) was added diphenylphosphoryl azide (1.72 g, 6.23 mmol), followed by 1,8-diazabicyclo [4.3.0] undec-7-ene (0.95 g, 6.2 mmol). The mixture was stirred at 25 ° C for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound. The crude product was purified on silica gel eluting with hexane / ethyl acetate / methanol (85: 17: 3) to give the title compound (700 mg, 50%).

Example 180b

{2- [3- (1-Azido-ethyl) -phenoxy] -5-chloro-phenyl} - (7-propyl- [1,8] naphthyridin-4-yl) amine

The product of Example 2g (130 mg, 0.63 mmol) was reacted with the compound of Example 180a (181 mg, 0.63 mmol) in ethanol (10 mL) at 85 ° C. in a sealed tube for 18 hours to give a crude The title compound, which was purified by HPLC with TFA, gave the product as trifluoroacetic acid (11 mg, 11%). 11H NMR (500 MHz, DMSO-d6th) δ ppm: 0.91 (t, J= 7.42 Hz, 3H), 1.23 (d, J= 6.59 Hz, 3H), 1.74-1.81 (m, 2H), 2.91 (t, J= 7.69 Hz, 2H), 4.61 (q, J= 6.59 Hz, 1H), 6.67 (d, J= 7.14 Hz, 1H), 6.82 (s, 2H), 6.99 (d, J= 7.14 Hz, 1H), 7.21 (d, J= 8.79 Hz, 2H), 7.52 (dd, J= 8.79 Hz, 1H), 7.64 (d, J= 2.75 Hz, 1H), 7.65 (d, J= 8.79 Hz, 1H), 8.48 (d, J= 6.04 Hz, 1H), 8.81 (d, J= 8.79 Hz, 1H); MS (ESI +) m / z 459 (M + H) +.

Example 181

3- [4-Fluoro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N, N-dimethylbenzamide

Example 181a

Ethyl 3- (4-fluoro-2-nitro-phenoxy) -benzoic acid

2,5-difluoronitrobenzene (5.0 g, 31.4 mmol), ethyl 3-hydroxybenzoate (5.2 g, 31.4 mmol) and K2CO3 (8.7 g, 62.8 mmol) was added to DMF (50 mL). The solution was heated to 85 ° C and stirred for 16 hours. The reaction mixture was cooled. The reaction mixture was poured into distilled water and extracted with ethyl acetate. The combined organic layers were washed with distilled water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the crude title compound. The crude product was purified by chromatography on a silica gel column, eluting with hexane / ethyl acetate (90:10) to give the title compound (7.0 g, 73%).

Example 181b

3- (4-Fluoro-2-nitro-phenoxy) -benzoic acid

The product of Example 181a (3.0 g, 9.8 mmol) was added to a THF / H solution2O (5: 1). Lithium hydroxide monohydrate (0.82 g, 19.5 mmol) was added in one portion. The solution was heated to 60 ° C for 2 hours. The reaction mixture was cooled. Distilled water was added. The pH was adjusted to 4.0 with 10% HCl. The mixture was extracted with ethyl acetate. The combined organic phases were washed with water, saturated NaHCO33, water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (2.65 g, 97%).

Example 181c

3- (4-Fluoro-2-nitro-phenoxy) -benzoyl chloride

The product of Example 181b (1.6 g, 5.6 mmol) was treated with oxalyl chloride (0.86 g, 6.7 mmol) and catalytic amount of DMF at room temperature for 6 hours. The excess oxalyl chloride was removed in vacuo. The residue was washed with benzene to obtain the title compound (1.66 g, 94%).

Example 181d

3- (4-Fluoro-2-nitro-phenoxy) -N, N-dimethyl-benzamide

The product of Example 181c (1.0 g, 3.4 mmol) was added to THF (25 mL) and dimethylamine (0.31 g, g, 6.8 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice / water and extracted with ethyl acetate. The organic phase was washed with 5% HCl, water, brine and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (0.90 g, 87%).

Example 181e

3- (2-Amino-4-fluoro-phenoxy) -N, N-dimethyl-benzamide

The product of Example 181d (1.1 g, 3.4 mmol) was reduced with SnCl2, as described in Example 1f, to obtain the title compound (0.88 g, 88%).

Example 181f

3- [4-Fluoro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N, N-dimethylbenzamide

The product of Example 2g (110 mg, 0.53 mmol) was reacted with the compound of Example 181e (154 mg, 0.53 mmol) in ethanol (10 mL) at 85 ° C. in a sealed tube for 18 hours to give a crude The title compound, which was purified by HPLC with TFA, gave the product as trifluoroacetic acid (65 mg, 20%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.95 (t, J= 7.35 Hz, 3H), 1.74-1.87 (m, 2H), 2.66 (s, 3H), 2.90 (s, 3H), 2.96 (t, 2H), 6 , 71 (d, J= 6.99 Hz, 1H), 6.82 (s, 1H), 6.91 (dd, J= 8.27, 1.65 Hz, 1H), 7.01 (d, J= 7.72 Hz, 1H), 7.27 (t, J= 7.91 Hz, 1H), 7.36-7.45 (m, 2H), 7.56 (dd, J= 8.82, 2.94 Hz, 1H), 7.75 (d, J= 8.46 Hz, 1H), 8.52 (d, J= 6.99 Hz, 1H), 8.83 (d, J= 8.46 Hz, 1H); MS (ESI +) m/z 445 (M + H) +.

Example 182

{2- [4- (1-Amino-ethyl) -phenoxy] -5-chloro-phenyl} - (7-methyl- [1,8] naphthyridin-4-yl) amine

Example 182a

1- [4- (1-Azido-ethyl) -phenoxy] -4-chloro-2-nitro-benzene

To the product of Example 164b (0.30 g, 1.0 mmol) in toluene (20 ml) was added diphenylphosphoryl azide (0.36 g, 6.26 mmol) followed by 1,8-diazabicyclo [4.3.0] undec -7-ene (0.19 g, 1.3 mmol). The mixture was stirred at 25 ° C for 18 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layers were washed with 5% HCl, sat. NaCl (1 ×), dried over sodium sulfate, filtered and concentrated in vacuo to give the crude title compound. The crude product was purified by chromatography on silica gel, eluting with a hexane / ethyl acetate / methanol mixture (85: 15: 5) to obtain the title compound (300 mg, 94%).

Example 182b

[1- [4- (4-Chloro-2-nitrophenoxy) -phenyl] -ethyl} -carbamic acid benzyl ester

To the product of Example 182a (1.3 g, 4.1 mmol) in THF (20 ml) was added trimethylphosphine (4.7 g, 5.4 mmol). The mixture was then stirred for 30 minutes at room temperature, the reaction mixture was treated with benzyl chloroformate (0.85 g, 5.0 mmol) and stirred for 18 hours. The reaction mixture was poured into 0.1 M potassium phosphate buffer, pH 7.0, and extracted with methylene chloride. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo to give the crude title compound. The residue was taken up in cold ethyl ether. The resulting white precipitate was collected to obtain the title compound (1.9 g, 74%).

Example 182c

[1- [4- (2-Amino-4-chloro-phenoxy) -phenyl] -ethyl} -carbamic acid benzyl ester

The product of Example 182b (1.0 g, 2.34 mmol) was reacted with SnCl2, as described in Example 237e, to obtain the title compound (0.75 g, 80%).

Example 182d

{2- [4- (1-Amino-ethyl) -phenoxy] -5-chloro-phenyl} - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 1d (120 mg, 0.67 mmol) was reacted with the compound of Example 182b (266 mg, 0.67 mmol) in ethanol (10 mL) at 85 ° C. in a sealed tube for 18 hours. The ethanol was then removed in vacuo. The crude compound was then treated with an excess of 48% HBr for 10 hours. Excess HBr was removed in vacuo and the crude residue was purified by HPLC with TFA, which gave the title compound as trifluoroacetic acid (15 mg, 17%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.38 (d, J= 6.62 Hz, 3H), 2.74 (s, 3H), 4.36 (q, 1H), 6.72 (d, J= 6.99 Hz, 1H), 7.03 (d, J= 8.82 Hz, 2H), 7.13 (d, J= 8.82 Hz, 1H), 7.39 (d, J= 8.82 Hz, 2H), 7.59 (dd, J= 8.82, 2.57 Hz, 1H), 7.72-7.78 (m, 2H), 8.24 (s, 2H), 8.53 (d, J= 7.35 Hz, 1H), 8.88 (d, J= 8.82 Hz, 1H); MS (ESI-) m / z 403 (MH) -.

Example 183

N- {4- [2- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-trifluoromethyl-phenylsulfanyl] -phenyl} -acetamide

Example 183a

N- [4- (2-Nitro-4-trifluoromethyl-phenylsulfanyl) -phenyl] -acetamide

The title compound was prepared from 1-chloro-2-nitro-4-trifluoromethylbenzene (250 mg, 1.10 mmol), N- (4-mercapto-phenyl) -acetamide (185 mg, 1.10 mmol) and K2CO3 (268 mg, 1.94 mmol) was heated in DMF at 100 ° C for 16 hours. The reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate (350 mg, 88%).

Example 183b

N- [4- (2-Amino-4-trifluoromethyl-phenylsulfanyl) -phenyl] -acetamide

The product of Example 183a (350 mg, 0.985 mmol) and Pt (IV) O2 (4 mg, 0.2 mmol) was placed in a 50 ml round-bottomed flask and dissolved in 1 ml of EtOH and 1 ml of THF. The reaction mixture was placed in vacuo and H2, using a balloon with hydrogen. The feed from the bottle was carried out overnight and the next day the reaction mixture was purged and saturated with N2, filtered and concentrated in vacuo to give the title compound (260 mg, 80%).

Example 183c

N- {4- [2- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-trifluoromethyl-phenylsulfanyl] -phenyl} -acetamide

The product of Example 1d (50 mg, 0.280 mmol) was reacted with the product of Example 183b (91 mg, 0.280 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (18 mg, 16%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.07 (s, 3H), 2.78 (s, 3H), 6.43 (d, J= 6.99 Hz, 1H), 7.09-7.15 (m, 1H), 7.44 (d, J= 8.46 Hz, 2H), 7.68 (d, J= 8.46 Hz, 2H), 7.78 (dd, J= 8.64, 1.65 Hz, 1H), 7.84 (d, J= 8.82 Hz, 1H), 7.92 (d, J= 1.84 Hz, 1H), 8.52 (d, J= 7.35 Hz, 1H), 9.00 (d, J= 8.46 Hz, 1H), 10.19 (s, 1H), 11.12 (s, 1H); MS (ESI +) m / z 469 (M + H-TFA) +; (ESI-) m / z 467 (MH-TFA) -.

Example 184

[5-Methyl-2- (1H- [1,2,4] triazol-3-ylsulfanyl) -phenyl] - (7-propyl- [1,8] naphthyridin-4-yl) amine

Example 184a

5-Methyl-2- (1H- [1,2,4] triazol-3-ylsulfanyl) -phenylamine

The title compound was prepared from 1-chloro-4-methyl-2-nitrobenzene (3.00 g, 17.5 mmol), 1H- [1,2,4] triazole-3-thiol (1.94 g, 19.2 mmol) and K2CO3 (4.22 g, 30.6 mmol) was heated in DMF at 100 ° C. for 16 hours. The reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (1.1 g, 26%).

Example 184b

5-Methyl-2- (1H- [1,2,4] triazol-3-ylsulfanyl) -phenylamine

The product of Example 184a was reduced with SnCl2 in accordance with the method described in Example 1f, to obtain the title compound.

Example 184c

[5-Methyl-2- (1H- [1,2,4] triazol-3-ylsulfanyl) -phenyl] - (7-propyl- [1,8] naphthyridin-4-yl) amine

The product of Example 2g (60 mg, 0.290 mmol) was reacted with the product of Example 184b (60 mg, 0.290 mmol) for 18 hours according to the method described in Example 1g to give the crude title compound, which was purified with HPLC with TFA, which gave the product as trifluoroacetic acid (17 mg, 16%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J= 7.35 Hz, 3H), 1.78-1.91 (m, 2H), 2.38 (s, 3H), 2.99 (t, 2H), 6.33 (d, J= 6.99 Hz, 1H), 7.29-7.39 (m, 2H), 7.46 (d, J= 8.09 Hz, 1H), 7.83 (d, J= 8.82 Hz, 1H), 8.44 (d, J= 6.99 Hz, 1H), 9.00 (d, J= 8.46 Hz, 1H), 11.07 (s, 1H), 14.16-14.55 (m, 2H); MS (ESI +) m / z 377 (M + H-TFA) +; (ESI-) m / z 375 (MH-TFA) -.

Example 185

[2- (2-Amino-phenylsulfanyl) -5-methylphenyl] - (7-propyl- [1,8] naphthyridin-4-yl) amine

Example 185a

2- (4-Methyl-2-nitro-phenylsulfanyl) -phenylamine

The title compound was prepared from 1-chloro-4-methyl-2-nitrobenzene (3.00 g, 17.5 mmol), 2-amino-benzenethiol (2.41 g, 19.23 mmol) and K2CO3 (4.22 g, 30.6 mmol) was heated in DMF at 100 ° C. for 16 hours. The reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate (0.990 g, 21%).

Example 185b

N- [2- (4-Methyl-2-nitro-phenylsulfanyl) -phenyl] -acetamide

The product of Example 185a (0.990, 3.80 mmol) was dissolved in CH2Cl, to which was added acetyl chloride (0.328 g, 4.183 mmol). The reaction mixture was stirred at room temperature for 1 hour, after which the title compound was collected by filtration (910 mg, 79%).

Example 185c

N- [2- (2-Amino-4-methyl-phenylsulfanyl) -phenyl] -acetamide

The product of Example 185b was reduced with SnCl2 in accordance with the method described in Example 1f, to obtain the title compound.

Example 185d

N- {2- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 2g (150 mg, 0.726 mmol) was reacted with the product of Example 185c (198 mg, 0.726 mmol) for 42 hours according to the method described in Example 1g to give the crude title compound, which was purified with HPLC with TFA, which gave the product as trifluoroacetic acid (150 mg, 46%).

Example 185e

[2- (2-Amino-phenylsulfanyl) -5-methylphenyl] - (7-propyl- [1,8] naphthyridin-4-yl) amine

The product of Example 185d was dissolved in a 50% mixture of HCl: H2O and heated to 100 ° C for 1 hour. The reaction mixture was then cooled to room temperature, made alkaline with 2N HCl. NaOH and extracted with CH2Cl2. Dried over Na2SO4, filtered and concentrated in vacuo to give the crude title compound. Purified by HPLC with TFA, which gave the product as trifluoroacetic acid (87 mg, 64%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J= 7.35 Hz, 3H), 1.79-1.92 (m, J= 7.43, 7.43, 7.43, 7.43, 7.43 Hz, 2H), 2.32 (s, 3H), 3.00 (t, J= 7.54 Hz, 2H), 6.34 (d, J= 6.99 Hz, 1H), 6.49 (t, J= 7.54 Hz, 1H), 6.68 (d, J= 6.99 Hz, 1H), 6.92 (d, J= 8.09 Hz, 1H), 7.05-7.13 (m, 1H), 7.15-7.20 (m, 1H), 7.24 (d, J= 8.46 Hz, 1H), 7.28 (s, 1H), 7.84 (d, J= 8.82 Hz, 1H), 8.42 (d, J= 6.99 Hz, 1H), 9.06 (d, J= 8.82 Hz, 1H); MS (ESI +) m / z 401 (M + H-TFA) +; (ESI-) m / z 399 (MH-TFA) -.

Example 186

N- {3- [3-Methyl-5- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 186a

3-Amino-benzenethiol copper

3-Amino-benzenethiol (2.00 g, 15.98 mmol) was treated under the conditions described in Example 187a to obtain the title compound (3.67 g, 100%).

Example 186b

3- (3-Methyl-5-nitro-phenylsulfanyl) -phenylamine

The title compound was prepared according to the procedure described in Example 187d using the compound of Example 187c (400 mg, 1.85 mmol) and the compound of Example 186a (348 mg, 1.85 mmol) to give the title compound ( 300 mg, 62%).

Example 186c

N- [3- (3-Methyl-5-nitro-phenylsulfanyl) -phenyl] -acetamide

The title compound was prepared according to the procedure of Example 185b using the compound of Example 186b (115 mg, 0.442 mmol) and acetyl chloride (52 mg, 0.663 mmol) to give (130 mg, 97%).

Example 186d

N- [3- (3-Amino-5-methylphenylsulfanyl) -phenyl] -acetamide

The title compound was prepared according to the procedure described in Example 183b using the product of Example 186c (130 mg, 0.430 mmol) and PtO2 (2 mg, 0.009 mmol) to give (73 mg, 62%).

Example 186f

N- {3- [3-Methyl-5- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 2g (70 mg, 0.338 mmol) was reacted with the product of Example 186d (73 mg, 0.338 mmol) for 16 hours according to the method described in Example 1g to give the crude title compound which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (14 mg, 10%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.96 (t, J= 7.35 Hz, 3H), 1.75-1.89 (m, 2H), 2.03 (s, 3H), 2.36 (s, 3H), 2.98 (t, J= 7.54 Hz, 2H), 6.85 (d, J= 7.35 Hz, 1H), 7.06-7.14 (m, 2H), 7.22 (s, 2H), 7.35 (t, J= 7.91 Hz, 1H), 7.47 (d, 1H), 7.76-7.82 (m, 2H), 8.45 (d, J= 7.35 Hz, 1H), 8.98 (d, J= 8.82 Hz, 1H), 10.07 (s, 1H), 10.97 (s, 1H); MS

(ESI +) m / z 443 (M + H-TFA) +; (ESI-) m / z 441 (MH-TFA) -.

Example 187

N- {4- [3-Methyl-5- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 187a

N- (4-Mercapto-phenyl) -acetamide copper

N- (4-Mercapto-phenyl) -acetamide (1.00 g, 5.98 mmol) and Cu2O (385 mg, 27.0 mmol) was dissolved in EtOH and heated to reflux for 24 hours. During this time, the reaction mixture was cooled to room temperature and the title compound was collected by filtration (1.374 g, 100%).

Example 187b

2-Bromo-4-methyl-6-nitro-phenylamine

The title compound was prepared by dissolving 4-methyl-2-nitro-phenylamine (20.0 g, 131 mmol) in 200 ml of HOAc. The reaction mixture was then heated to 100 ° C until the reaction mixture became homogeneous. At this point, the reaction mixture was cooled to room temperature and Br2 (25.21 g, 157 mmol) was added dropwise over 10 minutes. An orange solid formed and, after completion of the addition, the reaction mixture was diluted with water and the title compound was collected by filtration (29 g, 96%).

Example 187c

1-Bromo-3-methyl-5-nitro-benzene

The title compound was prepared in accordance with Example 187b (10.0 g, 43.2 mmol), dissolved in 60 ml MeOH and 8 ml H2SO4 (conc.). This mixture was heated to 85 ° C, then NaNO2 (7.466 g, 108.2 mmol) at such a rate that no bubbles form above the reaction mixture. After completion of the addition, the reaction mixture was allowed to stir at 85 ° C for an additional 30 minutes. The reaction mixture was then cooled to room temperature, diluted with water and extracted with CH2Cl2. Dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (8.00 g, 85%).

Example 187d

N- [4- (3-Methyl-5-nitro-phenylsulfanyl) -phenyl] -acetamide

The title compound was prepared from the compound of Example 187c (400 mg, 1.85 mmol), the compounds of Example 187a (425 mg, 1.852 mmol), 10 ml quinoline and 2 ml pyridine, which was heated to 170 ° C. for 22 hours. During this time, the reaction mixture was cooled to room temperature and quenched with 30% HCl and extracted with ether and dried over Na2SO4, filtered and concentrated in vacuo to give the title compound. Purify by column chromatography on silica gel, eluting with a mixture of 30% ethyl acetate and hexane (280 mg, 50%).

Example 187e

N- [4- (3-Amino-5-methylphenylsulfanyl) -phenyl] -acetamide

The title compound was obtained by carrying out the process of Example 183b using the product of Example 187d (280 mg, 0.926 mmol) and PtO2 (2 mg, 0.009 mmol) to give the title compound (240 mg, 95%).

Example 187f

N- {4- [3-Methyl-5- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 2g (70 mg, 0.338 mmol) was reacted with the product of Example 187e (198 mg, 0.726 mmol) for 16 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (5 mg, 4%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.96 (t, J= 7.35 Hz, 3H), 1.76-1.89 (m, 2H), 2.05 (s, 3H), 2.33 (s, 3H), 2.97 (t, J= 7.54 Hz, 2H), 6.80 (d, J= 7.35 Hz, 1H), 6.95 (s, 1H), 7.10 (d, J= 15.44 Hz, 2H), 7.46 (d, J= 8.82 Hz, 2H), 7.67 (d, J= 8.82 Hz, 2H), 7.78 (d, J= 8.82 Hz, 1H), 8.46 (d, J= 6.99 Hz, 1H), 8.96 (d, J= 8.46 Hz, 1H), 10.14 (s, 1H), 10.90 (s, 1H); MS (ESI +) m / z 443 (M + H-TFA) +; (ESI-) m / z 441 (MH-TFA) -.

Example 188

[3- (4-Amino-phenylsulfanyl) -5-methylphenyl] - (7-propyl- [1,8] naphthyridin-4-yl) amine

The product of Example 187 (60 mg, 0.136 mmol) was treated under the conditions of the method of Example 185 to obtain the title compound (10 mg, 18%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.96 (t, J= 7.35 Hz, 3H), 1.76-1.89 (m, 2H), 2.30 (s, 3H), 2.97 (t, J= 7.54 Hz, 2H), 6.65 (d, J= 8.46 Hz, 2H), 6.74-6.83 (m, 2H), 6.94 (s, 1H), 7.03 (s, 1H), 7.23 (d, J= 8.46 Hz, 2H), 7.78 (d, J= 8.82 Hz, 1H), 8.45 (d, J= 6.99 Hz, 1H), 8.96 (d, J= 8.46 Hz, 1H), 10.90 (s, 1H); MS (ESI +) m / z 401 (M + H-TFA) +.

Example 189

(3-Benzyloxy-phenyl) - (7-propyl- [1,8] naphthyridin-4-yl) -amine

Example 189a

1-Benzyloxy-3-nitro-benzene

3-Nitro-phenol (1.00 g, 7.189 mmol) was treated with benzyl bromide (1.352 g, 7.91 mmol) and K2CO3 (1.242 g, 8.986 mmol) in DMF. The reaction mixture was heated to 100 ° C for 1 hour, after which the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (1.6 g, 97%).

Example 189b

3-Benzyloxy-phenylamine

The title compound was prepared according to the procedure described in Example 183b using the product of Example 189a (1.600 g, 6.98 mmol) and PtO2 (15 mg, 0.070 mmol) to give (1.00 g, 72%).

Example 189c

(3-Benzyloxy-phenyl) - (7-propyl- [1,8] naphthyridin-4-yl) -amine

The product of Example 2g (30 mg, 0.145 mmol) was reacted with the product of Example 189b (29 mg, 0.145 mmol) for 16 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (27 mg, 50%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (t, J= 7.35 Hz, 3H), 1.77-1.90 (m, J= 7.35 Hz, 2H), 2.99 (t, J= 7.35 Hz, 2H), 5.17 (s, 2H), 6.80 (d, J= 6.99 Hz, 1H), 7.06 (dd, J= 8.46, 1.10 Hz, 1H), 7.09-7.15 (m, J= 3.68 Hz, 2H), 7.37-7.51 (m, 5H), 7.82 (d, J= 8.82 Hz, 1H), 8.46 (d, J= 7.35 Hz, 1H), 9.03 (d, J= 8.82 Hz, 1H), 11.00 (s, 1H); MS (ESI +) m / z 370 (M + H-TFA) +; (ESI-) m / z 368 (MH-TFA) -.

Example 190

[3- (4-Bromo-benzyloxy) -phenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

Example 190a

1- (4-Bromo-benzyloxy) -3-nitro-benzene

3-Nitrophenol (1.00 g, 7.189 mmol) was treated with 4-bromo-benzyl bromide (1.976 g, 7.90 mmol) according to the method of Example 189a to give the title compound (2.1 g, 97% ).

Example 190b

3- (4-Bromo-benzyloxy) -phenylamine

The title compound was obtained by reduction of the product of Example 190a with SnCl2 in accordance with the method described in Example 1f.

Example 190c

[3- (4-Bromo-benzyloxy) -phenyl] - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 1d (50 mg, 0.316 mmol) was reacted with the product of Example 190b (88 mg, 0.316 mmol) for 16 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (80 mg, 60%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.75 (s, 3H), 5.16 (s, 2H), 6.81 (d, J= 7.35 Hz, 1H), 7.04-7.14 (m, 3H), 7.43 (d, J= 8.46 Hz, 2H), 7.51 (t, J= 8.09 Hz, 1H), 7.62 (d, J= 8.46 Hz, 2H), 7.79 (d, J= 8.82 Hz, 1H), 8.47 (d, J= 6.99 Hz, 1H), 9.00 (d, J= 8.46 Hz, 1H), 10.98 (s, 1H); MS (ESI +) m / z 422 (M + H-TFA) +; (ESI-) m / z 419 (MH-TFA) -.

Example 191

N- {4- [3-Fluoro-5- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -acetamide

Example 191a

N- [4- (3-Fluoro-5-nitro-phenoxy) -phenyl] -acetamide

To a solution of N- (4-hydroxyphenyl) acetamide (1.00 g, 6.5 mmol) in DMSO (12 mL) was added dropwise a 1 M solution of t-BuOK / THF (7.13 mL, 7.13 mmol) at at room temperature and the mixture was stirred at room temperature for 30 minutes in a stream of N2. 1.3-difluoro-5-nitrobenzene (0.89 ml, 7.8 mmol) was added at room temperature, and then the mixture was stirred at room temperature for 2 hours and at 50 ° C for 2 hours in a stream of N2. The reaction mixture was cooled to room temperature, diluted with H2O and then extracted with EtOAc. The extract was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a pale brown solid which was purified by washing the iso-Pr2O, to give the desired product in the form of crystals of light brown color (1.73 g, 92%).

Example 191b

N- [4- (3-Amino-5-fluoro-phenoxy) -phenyl] -acetamide

The product of Example 191a was reduced with Fe and NH4Cl in accordance with the method described in Example 237E to obtain the title compound.

Example 191c

N- {4- [3-Fluoro-5- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -acetamide

The product of Example 3f (150 mg, 0.84 mmol) was reacted with the product of Example 191b (190 mg, 0.84 mmol) for 6 hours in accordance with the method described in Example 1g to give the crude title compound, which was purified by chromatography on a silica gel column, eluting with a 50: 1 CH2Cl2/ MeOH to give the title compound (210 mg, 68%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.40 (s, 3H), 2.68 (s, 3H), 6.62 (d, J= 6.9 Hz, 1H), 6.98 (t, J= 7.3 Hz, 1H), 7.19 (t, J= 7.3 Hz, 2H), 7.36 (s, 1H), 7.38 (d, J= 8.3 Hz, 1H), 7.52 (d, J= 7.3 Hz, 2H), 7.67 (d, J= 8.8 Hz, 1H), 7.78 (d, J= 8.3 Hz, 1H), 8.40 (d, J= 6.9 Hz, 1H), 8.94 (d, J= 8.8 Hz, 1H); MS (ESI +) m / z 369 (M + H) +, (ESI-) m / z 367 (MH) -.

Example 192

4- [3-Fluoro-5- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N, N-dimethylbenzamide

Example 192a

4- (3-Fluoro-5-nitro-phenoxy) -benzoic acid methyl ester

To a solution of 4-hydroxybenzoic acid methyl ester (3.00 g, 19.5 mmol) in DMSO (30 ml) was added t-BuOK (2.56 g, 21.5 mmol) at room temperature and the mixture was stirred at room temperature in 30 minutes in current N2. At room temperature, 1,3-difluoro-5-nitrobenzene (2.34 ml, 20.5 mmol) was added dropwise. The mixture was heated at 90 ° C for 2 hours in a flow of N2. The reaction mixture was cooled to room temperature, diluted with H2O and then extracted with EtOAc. The extract was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a dark brown oil which crystallized in iso-Pr2O. The crystals were collected by filtration to give the desired product as pale yellow crystals (1.92 g, 40%). The filtrate gave a further quantity of product (1.46 g, 30%) as crystals of pale yellow crystals by chromatography on a silica gel column, eluting with a 4: 1 EtOAc / hexane mixture.

Example 192b

4- (3-Fluoro-5-nitro-phenoxy) -benzoic acid

The product of Example 192a (3.30 g, 11.3 mmol) and 2N HCl. NaOH (11.3 mL, 22.7 mmol) in MeOH (33 mL) was boiled for 30 minutes and then evaporated. The residue was dissolved in H2O and acidified to pH 2 with 10% HCl with stirring. The precipitate formed was collected by filtration, washed with H2O and dried in vacuo overnight to give the title compound as pale yellow crystals (3.03 g, 96%).

Example 192c

4- (3-Fluoro-5-nitro-phenoxy) -N, N-dimethyl-benzamide

The product of Example 192b (1.00 g, 3.6 mmol) and SOCl2 (3.97 mL, 54.1 mmol) was refluxed for 1 hour. Excess SOCL2 was removed under reduced pressure to give the corresponding acid chloride as a pale brown oil. To a solution of a mixture of 2N hydrochloric acid. Me2NH / THF (18.0 mL, 36.1 mmol) was added dropwise a solution of the resulting acid chloride in THF (10 mL) at 5 ° C for 15 minutes. The mixture was stirred at 5 ° C for 1 hour and then evaporated. The residue was taken up in H2O and the resulting solid was collected by filtration. The solid was washed with H2O and dried in vacuo to give the title compound as pale yellow crystals (1.09 g, 99%).

Example 192d

4- (3-Amino-5-fluoro-phenoxy) -benzoic acid methyl ester

The product of Example 192c was reduced with Fe and NH4Cl in accordance with the method described in Example 237e to obtain the title compound.

Example 192e

4- [3-Fluoro-5- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N, N-dimethylbenzamide

The product of Example 1d (80 mg, 0.45 mmol) was reacted with the product of Example 192d (130 mg, 0.45 mmol) for 20 hours according to the method described in Example 1g to give the crude title compound, which was purified by trituration with EtOAc to give the product (150 mg, 79%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.77 (s, 3H), 2.98 (brs, 6H), 6.97-7.08 (m, 2H), 7.12 (d, J= 7.0 Hz, 1H), 7.18-7.25 (m, 1H), 7.23 (d, J= 8.8 Hz, 2H), 7.53 (d, J= 8.8 Hz, 2H), 7.79 (d, J= 8.5 Hz, 1H), 8.59 (d, J= 7.0 Hz, 1H), 9.00 (d, J= 8.5 Hz, 1H); MS (ESI +) m / z 417 (M + H) +, (ESI-) m / z 415 (MH) -.

Example 193

4- [3-Chloro-5- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenol

Example 193a

1-Chloro-3,5-dinitro-benzene

To a mixture of tert-BuONO (5.41 mL, 41.0 mmol) and CuCl2 (4.41 g, 32.8 mmol) in CH3CN (100 mL) was slowly added 3,5-dinitroaniline (5.00 g, 27.3 mmol) at 58-60 ° C. After addition, the mixture was heated at 65 ° C for 30 minutes and then evaporated. The residue was diluted with EtOAc 200 ml, washed with 20% HCl, 10% NaHCO33 and a saturated saline solution. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give the title compound, which was purified by chromatography on a silica gel column eluting with 10: 1 EtOAc / hexanes to give the title product as pale yellow crystals (4.60 g, 83% %).

Example 193b

4- (3-Chloro-5-nitro-phenoxy) -phenol

The product of Example 193a (1.00 g, 5.0 mmol), hydroquinone (0.50 g, 4.5 mmol), and K2CO3 (0.78 g, 5.6 mmol) in DMF (10 mL) was heated at 110 ° C. for 3.5 hours. The reaction mixture was cooled to room temperature, diluted with H2O and then extracted with EtOAc. The extract was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound. The residue was treated with iso-Pr2O and insoluble products were filtered off. The filtrate was evaporated and purified by chromatography on a silica gel column eluting with 5: 2 EtOAc / hexanes to give the title product as a pale yellow oil (0.51 g, 43%).

Example 193c

4- (3-Amino-5-chloro-phenoxy) -phenol

The product of Example 192c was reduced with Fe and NH4Cl in accordance with the method described in Example 237e to obtain the title compound.

Example 193d

4- [3-Chloro-5- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenol

The product of Example 2g (100 mg, 0.48 mmol) was reacted with the product of Example 134c (140 mg, 0.48 mmol) for 17 hours according to the method described in Example 1g to give the crude title compound, which was purified by trituration with EtOAc to give the title compound (140 mg, 71%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J= 7.4 Hz, 3H), 1.86 (sextet, J= 7.4 Hz, 2H), 3.00 (t, J= 7.4 Hz, 2H), 6.87 (d, J= 8.8 Hz, 2H), 6.95 (d, J= 1.8 Hz, 1H), 6.99-7.07 (m, 2H), 7.04 (d, J= 8.8 Hz, 2H), 7.28 (d, J= 1.8 Hz, 1H), 7.81 (d, J= 8.8 Hz, 1H), 8.57 (d, J= 7.0 Hz, 1H), 9.02 (d, J= 8.8 Hz, 1H); MS (ESI +) m / z 406, 408 (M + H) +, (ESI-) m / z 404, 406 (MH) -.

Example 194

N- {4- [3-Chloro-5- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -acetamide

Example 194a

N- [4- (3-Chloro-5-nitro-phenoxy) -phenyl] -acetamide

The product of Example 193a (1.06 g, 5.2 mmol), N- (4-hydroxyphenyl) acetamide (0.70 g, 4.5 mmol) and K2CO3 (0.79 g, 5.7 mmol) in DMF (14 mL) was heated at 110 ° C for 6 hours. The reaction mixture was cooled to room temperature, diluted with H2O and then extracted with EtOAc. The extract was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude title compound as pale brown crystals that were purified by washing the iso-Pr2O, to give the desired product as pale brown crystals (1.28 g, 92%).

Example 194b

N- [4- (3-Amino-5-chloro-phenoxy) -phenyl] -acetamide

The product of Example 192c was reduced with Fe and NH4Cl in accordance with the method described in Example 237e to obtain the title compound.

Example 194c

N- {4- [3-Chloro-5- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -acetamide

The product of Example 2g (100 mg, 0.48 mmol) was reacted with the product of Example 194bc (130 mg, 0.48 mmol) for 22 hours according to the method described in Example 1g to give the crude title compound, which was purified by trituration in EtOAc to give the product (110 mg, 51%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.00 (t, J= 7.0 Hz, 3H), 1.87 (sextet, J= 7.0 Hz, 2H), 2.08 (s, 3H), 3.01 (t, J= 7.0 Hz, 2H), 7.01 (s, 1H), 7.07 (d, J= 7.0 Hz, 1H), 7.07 (s, 1H), 7.14 (d, J= 7.2 Hz, 2H), 7.30 (s, 1H), 7.72 (d, J= 7.2 Hz, 2H), 7.76 (d, J= 8.7 Hz, 1H), 8.55 (d, J= 7.0 Hz, 1H), 9.03 (d, J= 8.7 Hz, 1H); MS (ESI +) m / z 447, 449 (M + H) +, (ESI-) m / z445, 447 (MH) -.

Example 195

4- [3-Chloro-5- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxymethyl] -N-methyl-benzamide

Example 195a

Methyl 4- (3-chloro-5-nitro-phenoxymethyl) -benzoic acid

The product of Example 13a (2.50 g, 12.3 mmol), 4-hydroxymethylbenzoic acid methyl ester (2.30 g, 13.6 mmol), and K2CO3 (2.14 g, 15.4 mmol) in DMF (50 mL) was heated at 110 ° C. for 16 hours. The reaction mixture was cooled to room temperature and diluted with H2O. The precipitate formed was collected by filtration and washed with H2O and iso-Pr2O to obtain the title compound as pale brown crystals (2.54 g).

Example 195b

4- (3-Chloro-5-nitro-phenoxymethyl) -benzoic acid

The product of Example 195a (2.50 g, 13.5 mmol) and 2N HCl. NaOH (7.77 mL, 15.5 mmol) in MeOH (25 mL) was boiled for 1 hour and then evaporated. The residue was dissolved in H2O and acidified to pH 2 with 10% HCl with stirring. The precipitate formed was collected by filtration, washed with H2O and dried in vacuo overnight to give the title compound as pale brown crystals (2.30 g, 62%).

Example 195c

4- (3-Chloro-5-nitro-phenoxymethyl) -N-methyl-benzamide

The product of Example 195b (0.70 g, 2.3 mmol) and SOCl2 (2.50 ml, 34.1 mmol) was boiled for 1 hour. Excess SOCL2 was removed under reduced pressure to give the corresponding acid chloride as a pale solid. To a solution of 2N hydrochloric acid. MeNH2/ THF (11.4 mL, 22.8 mmol) was added dropwise a solution of the acid chloride prepared above in THF (7 mL) at 5 ° C. The mixture was stirred at 5 ° C for 1 hour and then evaporated. The residue was taken up in H2O was acidified to pH 2 with 10% HCl, and then the resulting solid was collected by filtration. The solid was washed with H2O and iso-Pr2O and dried in vacuo to give the title compound as pale brown crystals (0.69 g, 95%).

Example 195d

4- (3-Amino-5-chloro-phenoxymethyl) -N-methyl-benzamide

The product of Example 195c was reduced with Fe and NH4Cl in accordance with the method described in Example 237e to obtain the title compound.

Example 195e

4- [3-Chloro-5- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxymethyl] -N-methyl-benzamide

The product of Example 1d (100 mg, 0.56 mmol) was reacted with the product of Example 195d (160 mg, 0.56 mmol) for 15 hours according to the method described in Example 1g to give the crude title compound, which was purified by trituration with EtOAc to give the product (240 mg, 99%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.75 (s, 3H), 2.79 (d, J= 4.4 Hz, 3H), 5.26 (s, 2H), 6.90 (d, J= 7.0 Hz, 1H), 7.14 (br t, J= 1.9 Hz, 1H), 7.18 (brt, J= 1.9 Hz, 1H), 7.20 (br t, J= 1.9 Hz, 1H), 7.53 (d, J= 8.5 Hz, 2H), 7.77 (d, J= 8.8 Hz, 1H), 7.87 (d, J= 8.5 Hz, 2H), 8.47 (brs, 1H), 8.50 (d, J= 7.0 Hz, 1H), 9.08 (d, J= 8.8 Hz, 1H), 11.08 (brs, 1H); MS (ESI +) m / z 433, 435 (M + H) +, (ESI-) m / z 431, 433 (MH) -.

Example 196

[3- (4-Bromo-benzyloxy) -5-chloro-phenyl] - (7-propyl- [1,8] naphthyridin-4-yl) amine

Example 196a

1- (4-Bromo-benzyloxy) -3-chloro-5-nitro-benzene

The product of Example 193a (0.75 g, 3.7 mmol), 4-bromobenzyl alcohol (0.77 g, 4.1 mmol) and K2CO3 (0.64 g, 4.6 mmol) in DMF (15 mL) was heated at 110 ° C for 23 hours. The reaction mixture was cooled to room temperature, diluted with H2O was acidified to pH 2 with 10% HCl and then extracted with EtOAc. The extract was washed with H2O and brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude title compound. The residue was treated with 50 ml of a mixture of n-hexane and EtOAc (3: 1) and silica gel. After stirring at room temperature for 30 minutes, the mixture was filtered through celite. The filtrate was evaporated and the resulting solid was washed with iso-Pr2O to obtain the title compound as pale yellow crystals (0.70 g).

Example 196b

3- (4-Bromo-benzyloxy) -5-chloro-phenylamine

The product of Example 196a was reduced with Fe and NH4Cl in accordance with the method described in Example 237e to obtain the title compound.

Example 196c

[3- (4-Bromo-benzyloxy) -5-chloro-phenyl] - (7-propyl- [1,8] naphthyridin-4-yl) amine

The product of Example 2g (100 mg, 0.39 mmol) was reacted with the product of Example 196b (120 mg, 0.39 mmol) for 22 hours according to the method described in Example 1g to give the crude title compound, which was purified by trituration with EtOAc to give the title compound (1990 mg, 100%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.96 (t, J= 7.4 Hz, 3H), 1.83 (sextet, J= 7.4 Hz, 2H), 2.97 (t, J= 7.4 Hz, 2H), 5.18 (s, 2H), 6.91 (d, J= 6.7 Hz, 1H), 7.05-7.17 (m, 3H), 7.43 (d, J= 8.4 Hz, 2H), 7.63 (d, J= 8.4 Hz, 2H), 7.73 (d, J= 8.5 Hz, 1H), 8.51 (d, J= 6.7 Hz, 1H), 9.05 (d, J= 8.5 Hz, 1H); MS (ESI +) m / z 482, 484, 486 (M + H) +, (ESI-) m / z 480, 482, 484 (MH) -.

Example 197

N- {4- [3-Chloro-5- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxymethyl] -phenyl} -acetamide

Example 197a

4-Acetylamino-benzyl ester of acetic acid

To a solution of 4-hydroxymethylaniline (2.00 g, 15.9 mmol) in pyridine (20 ml) was added Ac2O (3.76 mL, 39.8 mmol) dropwise over 5 minutes at room temperature, and the mixture was allowed to stir for 1 hour and then evaporated. The residue was diluted with H2O (20 ml) and acidified to pH 3 with conc. HCl at 5 ° C with stirring. The resulting crystals were collected by filtration, washed with a small amount of cold H2O and dried at room temperature in vacuo overnight to give the title compound as pale brown crystals (2.90 g, 88%).

Example 197b

N- (4-Hydroxymethyl-phenyl) -acetamide

The product of Example 197a (4.00 g, 19.3 mmol) in THF (40 mL) was added dropwise to an aqueous solution of LiOH (0.91 g, 21.2 mmol) at room temperature for 10 minutes. The mixture was allowed to stir at room temperature for 27 hours and then evaporated. The aqueous residue was diluted with H2O, pH 4 was adjusted with 10% HCl and then extracted with EtOAc. The extract was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound, which was purified by washing with cold EtOAc to give the title compound as colorless crystals (2.92 g, 92%).

Example 197c

N- [4- (3-Chloro-5-nitro-phenoxymethyl) phenyl] -acetamide

The product of Example 193a (1.00 g, 4.9 mmol) and the product of Example 197b (0.90 g, 5.4 mmol) and K2CO3 (0.86 g, 6.2 mmol) in DMF (20 ml) was heated at 100 ° C for 10 hours. The reaction mixture was cooled to room temperature, diluted with H2O. The resulting solid was collected by filtration, washed with H2O and dried in vacuo to give a brown crystal which was purified by chromatography on a silica gel column eluting with 5: 2 EtOAc / hexane to give the title compound as a dark orange solid (0.47 g, 30% ).

Example 197d

N- [4- (3-Amino-5-chloro-phenoxymethyl) phenyl] acetamide

The product of Example 196c was reduced with Fe and NH4Cl in accordance with the method described in Example 237e to obtain the title compound.

Example 197e

N- {4- [3-Chloro-5- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxymethyl] -phenyl} -acetamide

The product of Example 1d (70 mg, 0.39 mmol) was reacted with the product of Example 197d (110 mg, 0.39 mmol) for 23 hours according to the method described in Example 1g to give the crude title compound, which was purified by trituration with EtOAc to give the title compound (140 mg, 82%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.05 (s, 3H), 2.75 (s, 3H), 5.11 (s, 2H), 6.90 (d, J= 7.0 Hz, 1H), 7.12 (brs, 1H), 7.17 (brs, 2H), 7.38 (d, J= 8.5 Hz, 2H), 7.61 (d, J= 8.5 Hz, 2H), 7.78 (d, J= 8.9 Hz, 1H), 8.50 (d, J= 7.0 Hz, 1H), 9.12 (d, J= 8.9 Hz, 1H), 10.06 (s, 1H), 11.17 (brs, 1H); MS (ESI +) m / z 433, 435 (M + H) +, (ESI-) m / z 431, 433 (MH) -.

Example 198

(5-Methyl-2-phenoxy-phenyl) - (7-propyl- [1,8] naphthyridin-4-yl) -amine

The product of Example 2g (82 mg, 0.40 mmol) was reacted with the product of Example 42b (88 mg, 0.40 mmol) for 24 hours according to the method described in Example 1g to give the crude title compound, which was triturated in a 3: 1 ether / THF mixture to give the title compound as the hydrochloride salt (159 mg, 93%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.95 (t, J = 7.73 Hz, 3H), 1.82 (q, J = 7.72 Hz, 2H), 2.97 (dd, J = 7.73 Hz, 2H), 6.68 (d, J = 6.99 Hz, 1H), 6.99 (d, J = 7.72 Hz, 2H), 7.12 (dd, J = 8.82 Hz, 2H), 7.30 (dd, J = 8.09 Hz, 2H), 7.66 (dd, J = 8.82 Hz, J = 2.58 Hz, 1H), 7.71 (d, J = 2.2 Hz, 1H), 7.77 (d, J = 8.82 Hz, 1H), 8.52 (d, J = 6.98 Hz, 1H), 9.07 (d, J = 8, 82 Hz, 1H), 11.26 (brs, 1H), 14.45 (brs, 1H); MS (ESI +) m / z 390 (M-Cl) +; (ESI-) m / z 388 (M-HCl) -.

Example 199

2,2-Dimethyl-N- {3- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -propionamide

Example 199a

3- (4-Methyl-2-nitro-phenylsulfanyl) -phenylamine

The title compound was prepared from 3-amino-benzenethiol (5.034 g, 40.21 mmol), 1-chloro-4-methyl-2-nitrobenzene (4.600 g, 26.81 mmol) and K2CO3 (6.484 g, 46.92 mmol) dissolved in DMF and heated to 100 ° C for 16 hours. During this time, the reaction mixture was cooled to room temperature and diluted with water, extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (2.3 g, 32%).

Example 199b

N- [3- (4-Methyl-2-nitro-phenylsulfanyl) -phenyl] -acetamide

The title compound was prepared using 3- (4-methyl-2-nitro-phenylsulfanyl) -phenylamine (8.20 g, 31.50 mmol) and acetyl chloride (2.72 g, 34.65 mmol) dissolved in CH2Cl2. The reaction mixture was stirred at room temperature for 2 hours, after which the title compound was collected by filtration (8.78 g, 92%).

Example 199c

N- [3- (2-Amino-4-methylphenylsulfanyl) -phenyl] -acetamide

The product of Example 199b was reduced with SnCl2 in accordance with the method described in Example 14, to obtain the title compound.

Example 199d

N- {3- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The title compound was prepared from the product of example 2g (750 mg, 3.63 mmol) and the product of example 199c (988 mg, 3.63 mmol), combining in 10 ml of EtOH and heating to 80 ° C for 40 hours. After cooling to room temperature, the solvent was removed in vacuo to give the title compound (1.2 g, 74%).

Example 199e

[2- (3-Amino-phenylsulfanyl) -5-methylphenyl] - (7-propyl- [1,8] naphthyridin-4-yl) amine

The title compound was obtained by treating the product of example 199d (1.20 g, 2.71 mmol) with 10 ml of a 50% solution of HCl in water. This reaction mixture was heated to 100 ° C for 1 hour. During this time, the reaction mixture was cooled to room temperature and basified with 2N HCl. NaOH. The reaction mixture was further extracted with CH2Cl2, then dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (720 mg, 66%).

Example 199f

2,2-Dimethyl-N- {3- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -propionamide

The title compound was prepared using 2,2-dimethylpropionic acid (26 mg, 0.16 mmol) as an acid according to the method described in Example 74, to give the title compound (3 mg, 5%). 11H NMR (500 MHz, DMSO-D2O) δ ppm: 0.97 (t, J= 7.48 Hz, 3H), 1.16 (s, 9H), 1.79-1.86 (m, 2H), 2.39 (s, 3H), 2.94-3.00 (m, 2H), 6.31 (d, J= 7.02 Hz, 1H), 6.87 (d, J= 8.24 Hz, 1H), 7.07 (t, J= 7.93 Hz, 1H), 7.33-7.38 (m, 3H), 7.43-7.49 (m, 1H), 7.57-7.61 (m, 1H), 7, 72 (d, J= 8.85 Hz, 1H), 8.28 (d, J= 7.02 Hz, 1H), 8.86 (d, J= 8.85 Hz, 1H), 9.10 (s, 1H); MS (ESI +) m / z 485 (M + TFA + H) +; (ESI-) m / z 483 (M + TFA-H).

Example 200

{3- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -amide 2,5-dimethyl-furan-3-carboxylic acid

The title compound was prepared using 2,5-dimethyl-furan-3-carboxylic acid (26 mg, 0.16 mmol) as acid, according to the method described in Example 74, to give the title compound (3 mg , 5%). 11H NMR (500 MHz, DMSO-D2O) δ ppm: 0.93 (t, J= 7.32 Hz, 3H), 1.70-1.77 (m, 2H), 2.26 (s, 3H), 2.39 (s, 3H), 2.47 (s, 3H), 2 , 82-2.86 (m, 2H), 6.27 (d, J= 7.02 Hz, 1H), 6.53 (s, 1H), 6.86 (d, J= 8.24 Hz, 1H), 7.08 (t, J= 7.93 Hz, 1H), 7.35 (s, 1H), 7.38 (dt, J= 7.63, 2.14 Hz, 2H), 7.54 (d, J= 7.93 Hz, 1H), 7.61 (t, J= 2.14 Hz, 1H), 7.66 (d, J= 8.54 Hz, 1H), 8.26 (d, J= 7.02 Hz, 1H), 8.82 (d, J= 8.85 Hz, 1H); MS (ESI +) m / z 523 (M + TFA + H) +; (ESI-) m / z 521 (M + TFA-H) -.

Example 201

{3- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -amide of thiophene-2-carboxylic acid

The title compound was obtained using thiophene-2-carboxylic acid (26 mg, 0.16 mmol) as an acid, according to the method described in Example 74, to give the title compound (3 mg, 5%). 11H NMR (500 MHz, DMSO-D2O) δ ppm: 0.90 (t, J= 7.32 Hz, 3H), 1.67-1.75 (m, 2H), 2.40 (s, 3H), 2.76-2.82 (m, 2H), 6.27 (d, J= 7.32 Hz, 1H), 6.88 (d, J= 7.93 Hz, 1H), 7.10 (t, J= 7.93 Hz, 1H), 7.22-7.26 (m, 1H), 7.36 (s, 1H), 7.38-7.42 (m, 2H), 7.57-7, 60 (m, 2H), 7.65 (d, J= 8.54 Hz, 1H), 7.86 (dd, J= 5.03, 1.07 Hz, 1H), 7.90 (dd, J= 3.81, 1.07 Hz, 1H), 8.25 (d, J= 7.02 Hz, 1H), 8.81 (d, J= 8.54 Hz, 1H), MS (ESI +) m / z 511 (M + TFA + H) +.

Example 202

6-Hydroxy-N- {3- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -nicotinamide

The title compound was prepared using 6-hydroxy-nicotinic acid (26 mg, 0.16 mmol) as the acid, according to the method described in Example 74, to give the title compound (3 mg, 5%). 11H NMR (500 MHz, DMSO-D2O) δ ppm: 0.92 (t, J= 7.32 Hz, 3H), 1.69-1.77 (m, 2H), 2.37-2.42 (m, 3H), 2.82-2.88 (m, 2H), 6, 24 (d, J= 7.02 Hz, 1H), 6.46 (d, J= 9.46 Hz, 1H), 6.87 (d, J= 8.54 Hz, 1H), 7.09 (t, J= 8.09 Hz, 1H), 7.32-7.37 (m, 2H), 7.39 (d, J= 7.93 Hz, 1H), 7.55-7.60 (m, 2H), 7.67 (d, J= 8.85 Hz, 1H), 7.91 (dd, J= 9.76, 2.75 Hz, 1H), 8.09 (d, J= 2.44 Hz, 1H), 8.24 (d, J= 7.02 Hz, 1H), 8.82 (d, J= 8.54 Hz, 1H); MS (ESI +) m / z 522 (M + TFA + H) +; (ESI-) m / z 520 (M + TFA-H).

Example 203

2-Hydroxy-6-methyl-N- {3- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -nicotinamide

The title compound was prepared using 2-hydroxy-6-methyl-nicotinic acid as the acid (26 mg, 0.16 mmol) according to the method described in Example 74 to give the title compound (3 mg, 5% ). 11H NMR (500 MHz, DMSO-D2O) δ ppm: 0.89 (t, J= 7.48 Hz, 3H), 1.64-1.71 (m, J= 7.48, 7.48, 7.48, 7.48 Hz, 2H), 2.36 (s, 3H), 2.40 (s, 3H), 2.76-2.81 (m, 3H ), 6.22 (d, J= 7.02 Hz, 1H), 6.46 (d, J= 7.32 Hz, 1H), 6.86 (d, J= 8.24 Hz, 1H), 7.10 (t, J= 7.93 Hz, 1H), 7.14-7.18 (m, 1H), 7.35 (s, 1H), 7.39 (d, J= 8.24 Hz, 1H), 7.57-7.59 (m, 1H), 7.62 (d, J= 8.54 Hz, 2H), 8.21 (d, J= 7.32 Hz, 1H), 8.27 (d, J= 7.32 Hz, 1H), 8.82 (d, J= 8.85 Hz, 1H); MS (ESI +) m / z 536 (M + TFA + H) +.

Example 204

{3- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -amide of pyrazine-2-carboxylic acid

The title compound was obtained using pyrazine-2-carboxylic acid (26 mg, 0.16 mmol) as the acid, according to the method described in Example 74, to give the title compound (3 mg, 5%). 11H NMR (500 MHz, DMSO-D2O) δ ppm: 0.87 (t, J= 7.48 Hz, 3H), 1.63-1.70 (m, 2H), 2.40 (s, 3H), 2.74-2.78 (m, 2H), 6.28 (d, J= 7.02 Hz, 1H), 6.94 (d, J= 8.54 Hz, 1H), 7.13 (t, J= 7.93 Hz, 1H), 7.36 (d, J= 1.22 Hz, 1H), 7.40 (d, J= 7.93 Hz, 1H), 7.53 (dd, J= 7.63, 1.53 Hz, 1H), 7.61 (d, J= 7.93 Hz, 1H), 7.65 (d, J= 8.54 Hz, 1H), 7.76 (t, J= 1.83 Hz, 1H), 8.25 (d, J= 7.02 Hz, 1H), 8.78-8.84 (m, 2H), 8.94 (d, J= 2.44 Hz, 1H); MS (ESI +) m / z 507 (M + TFA + H) +.

Example 205

({3- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenylcarbamoyl} -methyl) -amide of furan-2-carboxylic acid

The title compound was prepared using [(furan-2-carbonyl) -amino] -acetic acid (26 mg, 0.16 mmol) as acid (according to the method described in Example 74) to give the title compound (3 mg, 5%). 11H NMR (500 MHz, DMSO-D2O) δ ppm: 0.96 (t, J= 7.32 Hz, 3H), 1.78-1.86 (m, 2H), 2.39 (s, 3H), 2.94-3.01 (m, 2H), 6.34 (d, J= 7.02 Hz, 1H), 6.62-6.68 (m, 1H), 6.87 (d, J= 7.63 Hz, 1H), 7.02-7.12 (m, 2H), 7.14-7.22 (m, 2H), 7.37 (d, J= 5.49 Hz, 2H), 7.48 (d, J= 8.54 Hz, 1H), 7.51 (s, 1H), 7.72 (d, J= 8.85 Hz, 1H), 7.81-7.87 (m, 2H), 8.33 (d, J= 7.02 Hz, 1H), 8.86 (d, J= 8.54 Hz, 1H); MS (ESI +) m / z 552 (M + TFA + H) +.

Example 206

N- {3- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -4-thiophen-2-yl-butyramide

The title compound was prepared using 4-thiophen-2-yl-butanoic acid as the acid (26 mg, 0.16 mmol) according to the method described in Example 74 to give the title compound (3 mg, 5% ). 11H NMR (500 MHz, DMSO-D2O) δ ppm: 0.96 (t, J= 7.32 Hz, 3H), 1.79-1.84 (m, 2H), 1.85-1.89 (m, 2H), 2.28 (t, J= 7.48 Hz, 2H), 2.39 (s, 3H), 2.79-2.84 (m, 2H), 2.92-2.98 (m, 2H), 6.29 (d, J= 7.02 Hz, 1H), 6.82-6.88 (m, 2H), 6.96 (dd, J= 4.88, 3.36 Hz, 1H), 7.05 (t, J= 7.93 Hz, 1H), 7.22 (dd, J= 8.24, 1.22 Hz, 1H), 7.31 (dd, J= 5.03, 1.07 Hz, 1H), 7.35-7.38 (m, 2H), 7.45-7.51 (m, 2H), 7.70 (d, J= 8.54 Hz, 1H), 8.27 (d, J= 7.32 Hz, 1H), 8.84 (d, J= 8.54 Hz, 1H); MS (ESI +) m / z 553 (M + TFA + H) +.

Example 207

N- {3- [4-Methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl} -2- (3-phenoxy-phenyl) -acetamide

The title compound was prepared using (3-phenoxy-phenyl) -acetic acid (26 mg, 0.16 mmol) as an acid in accordance with the method described in Example 74 to give the title compound (3 mg, 5% ). 11H NMR (500 MHz, DMSO-D2O) δ ppm: 0.96 (t, J= 7.32 Hz, 3H), 1.77-1.85 (m, 2H), 2.39 (s, 3H), 2.92-2.99 (m, 2H), 3.55 (s, 2H), 6.32 (d, J= 7.32 Hz, 1H), 6.84-6.90 (m, 2H), 6.96 (s, 1H), 7.00 (d, J= 7.63 Hz, 2H), 7.07 (ddd, J= 7.78, 4.12, 3.97 Hz, 2H), 7.16 (t, J= 7.48 Hz, 1H), 7.23 (d, J= 9.15 Hz, 1H), 7.33-7.42 (m, 5H), 7.44-7.47 (m, 1H), 7.49 (s, 1H), 7.69 (d, J= 8.85 Hz, 1H), 8.27 (d, J= 7.02 Hz, 1H), 8.85 (d, J= 8.54 Hz, 1H); MS (ESI +) m / z 611 (M + TFA + H) +.

Example 208

N-Allyl-3- [4-chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -benzamide

Example 208a

Methyl 3- (4-chloro-2-nitro-phenoxy) -benzoic acid

1-Bromo-4-chloro-2-nitrobenzene (7.00 g, 29.60 mmol) was dissolved in DMF to which K2CO3 (5.11 g, 37.01 mmol) and 3-hydroxy-benzoic acid methyl ester (4.95 g, 32.57 mmol). The reaction mixture was then heated to 100 ° C for 2 hours. The reaction mixture was cooled to room temperature and diluted with water and extracted with ethyl acetate. The solvent was dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (7.2 g, 79%).

Example 208b

Methyl 3- (2-amino-4-chloro-phenoxy) -benzoic acid

The product of Example 208a (7.20 g, 23.40 mmol) was reduced with SnCl2 (13.310 g, 70.20 mmol) according to the method described in Example 1f, to obtain the title compound (6.2 g, 95%).

Example 208c

Methyl 3- [4-chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -benzoic acid methyl ester

The product of Example 1d (175 mg, 0.979 mmol) and the product of Example 208b (272 mg, 0.979 mmol) were dissolved in 2 ml of absolute EtOH and heated to 80 ° C. for 16 hours. After that, the reaction mixture was cooled and the solvent was removed to give the title compound as a brown foam, which was used further without purification (410 mg, 93%).

Example 208d

3- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -benzoic acid

The product of Example 208c (447 mg, 1.065 mmol) was dissolved in 5 ml of a 1: 1 solution (THF: water). LiOH (51 mg, 2.129 mmol) was added and the reaction mixture was heated to 60 ° C for 2 hours. The reaction mixture was then allowed to cool to room temperature and neutralized with HOAc. The product was extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (180 mg, 42%).

Example 208e

N-Allyl-3- [4-chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -benzamide

The product of Example 208d (60 mg, 0.147 mmol) was dissolved in THF to which N-methyl morpholine (49 mg, 0.162 mmol) and isopropenyl chloroformate (36 mg, 0.295 mmol) were added. The reaction mixture was stirred at room temperature for 1 hour, then allylamine (42 mg, 0.739 mmol) was added and the reaction mixture was stirred at room temperature for an additional 1 hour. THF was then removed in a stream of N2 and then the crude oil was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (8.0 mg, 9.5%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.92 (s, 3H), 2.74 (s, 2H), 3.86 (d, J= 5.15 Hz, 2H), 5.04-5.16 (m, 2H), 5.73-5.98 (m, 1H), 6.73 (d, J= 6.99 Hz, 1H), 7.10 (dd, J= 7.72, 2.21 Hz, 1H), 7.27-7.43 (m, 3H), 7.51-7.65 (m, 2H), 7.69-7.82 (m, 2H ), 8.54 (d, J= 7.35 Hz, 1H), 8.82 (d, J= 8.46 Hz, 1H); MS (ESI +) m / z 445 (M + TFA + H) +; (ESI-) m / z 443 (M + TFA-H) -.

Example 211

(5-Chloro-2-phenoxy-phenyl) - (7-phenyl- [1,8] naphthyridin-4-yl) amine

Example 211a

2- (2,5-Dimethyl-pyrrol-1-yl) -6-phenyl-pyridine

2-Chloro-6- (2,5-dimethyl-pyrrol-1-yl) -pyridine (0.097 g, 0.47 mmol), prepared as described in Example 8a, was reacted for 24 hours with tributylphenyl- stannane (0.185 ml, 0.564 mmol) under a nitrogen atmosphere in toluene at 75 ° C in the presence of 2 mol% tetrakis (triphenylphosphine) palladium (0). The volatile products were then removed under reduced pressure to give a crude product which was purified by flash chromatography on silica gel to give the title compound (0.103 g, 88%).

Example 211b

6-Phenyl-pyridin-2-ylamine

The substituted pyridine described in Example 211a (0.289 g, 1.7 mmol) was reacted as described in Example 2c to give the title compound in quantitative yield.

Example 211c

5-Chloro-2-phenyl- [1,8] naphthyridine

The product of Example 211b was reacted according to the methods of Examples 2d, 2e, 2f and 2g to obtain the title compound.

Example 211d

(5-Chloro-2-phenoxy-phenyl) - (7-phenyl- [1,8] naphthyridin-4-yl) amine

The product of Example 211f (0.108 g, 0.45 mmol) was reacted with the product of Example 42b (0.100 g, 0.46 mmol) for 28 hours according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (0.144 g, 57%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 6.75 (d, J = 6.99 Hz, 1H), 6.99 (d, J = 7.72 Hz, 2H), 7.11 (t, J = 7.35 Hz, 1H), 7.18 (d, J = 8.82 Hz, 1H), 7.32 (t, J = 7.91 Hz, 2H), 7.59 (dd, J = 8.82, 2 , 57 Hz, 1H), 7.64 (m, 3H), 7.75 (d, J = 2.57 Hz, 1H), 8.36 (dd, J = 6.62, 2.94 Hz, 2H ), 8.51 (d, J = 9.19 Hz, 1H), 8.61 (d, J = 6.99 Hz, 1H), 9.10 (d, J = 8.82 Hz, 1H); MS (ESI +) m / z 423.9 (M + H) +; (ESI -) - m / z 422.0 (MH) -.

Example 212

Methyl 2- (7-methyl- [1,8] naphthyridin-4-ylamino) -biphenyl-4-carboxylic acid methyl ester

Example 212a

4-Bromo-3-nitro-benzoic acid methyl ester

Commercially available 4-bromo-3-nitro-benzoic acid (1.17 g, 4.76 mmol) was dissolved in methanol (5 mL) containing five drops of concentrated sulfuric acid. The mixture was heated in air at 90 ° C for six hours, and more MeOH (7 mL) was added followed by concentrated sulfuric acid (0.6 mL). Heating continued for another 24 hours. Extraction (ethyl acetate-water) followed by drying over MgSO4, filtration and concentration in vacuo gave the title compound in quantitative yield.

Example 212b

Methyl 2-nitro-biphenyl-4-carboxylic acid methyl ester

The product of Example 212a (0.100 g, 0.384 mmol) was combined with iodobenzene (0.375 ml, 3.35 mmol) and copper powder (0.188 g, 2.96 mmol), and the mixture was heated in a sealed tube to 218 ° C for 90 minutes. The reaction mixture was then diluted with dichloromethane and filtered through celite. The crude product obtained by concentration in vacuo was purified by flash chromatography on silica gel (ethyl acetate-hexane) to give the title compound (0.0847 g, 86%).

Example 212c

2-Amino-biphenyl-4-carboxylic acid methyl ester

The product of Example 212b (0.0795 g, 0.309 mmol) was dissolved in ethanol (2 ml), and Pt (IV) oxide (5.2 mg) was added to this solution. The reaction mixture was degassed in vacuo then held in hydrogen under one atmosphere atmosphere for 3 hours at room temperature. The catalyst was removed by filtration through celite and the filtrate was concentrated in vacuo to give the title compound in quantitative yield.

Example 212d

Methyl 2- (7-methyl- [1,8] naphthyridin-4-ylamino) -biphenyl-4-carboxylic acid methyl ester

The product of Example 1d (0.0552 g, 0.309 mmol) was reacted with the product of Example 212c (0.070 g, 0.309 mmol) for 92 h according to the procedure of Example 1g to give the crude title compound which was purified by HPLC with AA. The resulting solid was triturated in 4N HCl. HCl in dioxane to form the hydrochloride salt, which was collected by vacuum filtration (0.0747 g, 55%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.72 (s, 3H), 3.91 (s, 3H), 6.27 (d, J= 6.99 Hz, 1H), 7.30 (m, J= 6.99 Hz, 3H), 7.52 (m, 2H), 7.74 (d, J= 8.82 Hz, 1H), 7.79 (d, J= 8.09 Hz, 1H), 8.09 (d, J= 1.47 Hz, 1H), 8.16 (dd, J= 7.91, 1.65 Hz, 1H), 8.30 (d, J= 6.99 Hz, 1H), 9.15 (d, J= 8.82 Hz, 1H), 11.54 (s, 1H); MS (ESI +) m / z 369.9 (M + H) +.

Example 213

(4-Methyl-biphenyl-2-yl) - (7-propyl- [1,8] naphthyridin-4-yl) amine

Example 213a

4-Methyl-2-nitro-biphenyl

To a solution of commercially available 1-bromo-4-methyl-2-nitrobenzene (0.107 g, 0.49 mmol) in anhydrous toluene (3 ml), CsCO3 (0.305 g, 0.94 mmol) followed by phenylboronic acid (0.062 g, 0.49 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo [3.3.3] undecane as a 0.1 M solution in toluene (0.200 ml, 4 mol%). Nitrogen was bubbled into the resulting suspension for three minutes, then palladium acetate (0.0043 g, 4 mol%) was added, the reaction vessel sealed and placed in an 80 ° C. oil bath and heated for 22 hours. Subsequent filtration through celite and removal of volatile products in vacuo gave a crude product (0.105 g, 100%) that was sufficiently pure for use as it was isolated.

Example 213b

4-Methyl-biphenyl-2-ylamine

The product of Example 213a was reacted as described in Example 212c to give the title amine (0.088 g, 100%).

Example 213c

(4-Methyl-biphenyl-2-yl) - (7-propyl- [1,8] naphthyridin-4-yl) amine

The product of Example 2g (0.106 g, 0.49 mmol) was reacted with the product of Example 213b (0.088 g, 0.49 mmol) for 65 h according to the procedure of Example 1g to give the crude title compound which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (0.122 g, 52%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.96 (t, J = 7.35 Hz, 3H), 1.81 (d, J = 7.72 Hz, 2H), 2.43 (s, 3H), 2, 89-3.02 (m, 2H), 6.31 (d, J = 6.99 Hz, 1H), 7.14-7.58 (m, 8 H), 7.77 (d, J = 8 , 46 Hz, 1H), 8.32 (d, J = 7.35 Hz, 1H), 8.91 (d, J = 8.46 Hz, 1H), 10.91-11.08 (m, 1H ); MS (ESI +) m / z354.0 (M + H) +; (ESI-) m / z 351.9 (MH) -.

Example 214

(4-Methyl-biphenyl-2-yl) - (7-propyl- [1,8] naphthyridin-4-yl) amine

Example 214a

4'-Methoxy-4-methyl-2-nitro-biphenyl

1-Bromo-4-methyl-2-nitro-benzene (0.107 g, 0.49 mmol) was reacted as described in Example 213a, using 4-methoxyphenylboronic acid (0.074 g, 0.49 mmol) instead of boronic acid, the title biphenyl in quantitative yield and a sufficient degree of purity for use as it is isolated in the next step.

Example 214b

4'-Methoxy-4-methyl-biphenyl-2-ylamine

The product of Example 214a was reacted as described in 212c to give the title amine (0.107 g, 100%).

Example 214c

(4'-Methoxy-4-methyl-biphenyl-2-yl) - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 1d (0.088 g, 0.49 mmol) was reacted with the product of Example 214b (107 mg, 0.49 mmol) for 65 h according to the method described in Example 1g to give the crude title compound, which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (0.106 g, 45%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.41 (s, 3H), 2.72 (s, 3H), 3.66 (s, 3H), 6.29 (d, J = 6.99 Hz, 1H), 6.84 (d, J = 8.82 Hz, 2H), 7.27-7.53 (m, 5H), 7.75 (d, J = 8.46 Hz, 1H), 8.32 (d , J = 6.99 Hz, 1H), 8.90 (d, J = 8.46 Hz, 1H), 10.88-11.05 (m, 1H); MS (ESI +) m / z 356.0 (M + H) +; (ESI-) m / z 354.1 (MH) -.

Example 215

N- [4'-Methyl-2 '- (7-methyl- [1,8] naphthyridin-4-ylamino) -biphenyl-4-yl] -acetamide

Example 215a

N- (4'-Methyl-2'-nitro-biphenyl-4-yl) -acetamide

1-Bromo-4-methyl-2-nitrobenzene (0.102 g, 0.49 mmol) was reacted as described in Example 213a using N- [4- (4,4,5,5-tetramethyl- [1 , 3,2] dioxaborolan-2-yl) -phenyl] -acetamide (0.130 g, 0.49 mmol) in place of phenylboronic acid and heating for 18 hours at 100 ° C. The reaction mixture was filtered through Celite, the volatile products were removed in vacuo and the crude product was purified by flash chromatography on silica gel, eluting with EtOAc-hexane to give the title biphenyl (0.051 mg, 38%).

Example 215b

N- (2'-Amino-4'-methyl-biphenyl-4-yl) -acetamide

The product of Example 215a (0.062 g, 0.23 mmol) was reacted as described in Example 212c to give the title amine in quantitative yield.

Example 215

N- [4'-Methyl-2 '- (7-methyl- [1,8] naphthyridin-4-ylamino) -biphenyl-4-yl] -acetamide

The product of Example 1d (0.041 g, 0.23 mmol) was reacted with the product of Example 215b (0.062 g, 0.23 mmol) for 46 hours at 100 ° C. according to the method described in Example 1g, The title compound, which was purified by HPLC with TFA, gave the product as a trifluoroacetic acid salt (0.073 g, 60%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.98 (s, 3H), 2.42 (s, 3H), 2.72 (s, 3H), 6.28 (d, J= 6.99 Hz, 1H), 7.27-7.56 (m, 7H), 7.74 (d, J= 8.46 Hz, 1H), 8.33 (d, J= 7.35 Hz, 1H), 8.94 (d, J= 8.82 Hz, 1H), 9.95 (s, 1H), 11.06 (s, 1H); MS (ESI +) m / z 383.1 (M + H) +, (ESI-) m / z 381.1 (MH) -.

Example 216

N- [4'-Methyl-2 '- (7-methyl- [1,8] naphthyridin-4-ylamino) -biphenyl-3-yl] -acetamide

Example 216a

N- (4'-Methyl-2'-nitro-biphenyl-3-yl) -acetamide

1-Bromo-4-methyl-2-nitrobenzene (0.107 g, 0.49 mmol) was reacted as described in Example 215a using 3-acetamidophenylboronic acid (0.086 g, 0.49 mmol) in place of phenylboronic acid, dicyclohexylamine (4 mol%) instead of 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo [3.3.3.] Undecane and using dioxane in place of toluene, to give the title biphenyl (0.0552 g, 42%).

Example 216b

N- (2'-Amino-4'-methyl-biphenyl-3-yl) -acetamide

The product of Example 216a (0.070 g, 0.26 mmol) was reacted as described in Example 212c to give the title amine in quantitative yield.

Example 216

N- [4'-Methyl-2 '- (7-methyl- [1,8] naphthyridin-4-ylamino) -biphenyl-3-yl] -acetamide

The product of Example 1g (0.046 g, 0.26 mmol) was reacted with the product of Example 216b (0.063g, 0.26 mmol) for 47 hours at 100 ° C. according to the method described in Example 1g, The title compound, which was purified by HPLC using TFA, gave the product as a trifluoroacetic acid salt (0.085 g, 64%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.93 (s, 3H), 2.43 (s, 3H), 2.71 (s, 3H), 6.34 (d, J = 6.99 Hz, 1H), 7.04 (d, J = 7.35 Hz, 1H), 7.17 (t, J = 7.72 Hz, 1H), 7.22-7.31 (m, 1H), 7.36 (s , 1H), 7.40-7.54 (m, 2H), 7.72 (d, J = 8.46 Hz, 1H), 7.77 (s, 1H), 8.36 (s, 1H) , 8.88 (d, J = 8.82 Hz, 1H), 9.88 (s, 1H), 10.99 (s, 1H); MS (ESI +) m / z 383.0 (M + H) +; (ESI-) m / z 381.1 (MH) -.

Example 217

(3'-Methoxy-4-methyl-biphenyl-2-yl) - (7-methyl- [1,8] naphthyridin-4-yl) amine

Example 217a

3'-Methoxy-4-methyl-2-nitro-biphenyl

1-Bromo-4-methyl-2-nitrobenzene (0.107 g, 0.49 mmol) was reacted as described in Example 216a using 3-methoxyphenylboronic acid (0.074 g, 0.45 mmol) in place of 3-acetamidophenylboronic acid , to give the title biphenyl (0.083 g, 76%).

Example 217b

3'-Methoxy-4-methyl-biphenyl-2-ylamine

The product of Example 217b (0.083 g, 0.34 mmol) was reacted as described in Example 212c to give the title amine in quantitative yield.

Example 217c

(3'-Methoxy-4-methyl-biphenyl-2-yl) - (7-methyl- [1,8] naphthyridin-4-yl) amine

The product of Example 1d (0.065 g, 0.36 mmol) was reacted with the product of Example 217b (0.072 g, 0.34 mmol) for 96 hours at 100 ° C. according to the method described in Example 1g, The title compound, which was purified by HPLC with TFA, gave the trifluoroacetic acid salt (0.102 g, 64%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.43 (s, 3H), 2.72 (s, 3H), 3.62 (s, 3H), 6.29 (d, J = 7.35 Hz, 1H), 6.77 (dd, J = 7.91, 2.02 Hz, 1H), 6.87-7.00 (m, 2H), 7.17 (t, J = 7.91 Hz, 1H), 7 , 36 (s, 1H), 7.41-7.46 (m, 1H), 7.51-7.56 (m, 1H), 7.75 (d, J = 8.46 Hz, 1H), 8.32 (d, J = 7.35 Hz, 1H), 8.91 (d, J = 8.82 Hz, 1H), 11.99-12.22 (s, 1H); MS (ESI +) m / z 356.0 (M + H) +; (ESI-) m / z 354.0 (MH) -.

Example 218

(7-Propyl- [1,8] naphthyridin-4-yl) - (4-trifluoromethyl-biphenyl-2-yl) amine

Example 218a

2-Nitro-4-trifluoromethyl-biphenyl

Commercially available 1-bromo-2-nitro-4-trifluoromethyl-benzene (0.130 g, 0.48 mmol) was reacted with phenylboronic acid (0.072 g, 0.59 mmol) as described in Example 213a, using dioxane instead of toluene, chloride bis (triphenylphosphine) -palladium (II) instead of palladium acetate, and obtaining 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo [3.3.3.] undecane. The reaction is completely complete after three hours, and the biphenyl title in the title is isolated in quantitative yield, of sufficient purity for use as it is isolated.

Example 218b

4-Trifluoromethyl-biphenyl-2-ylamine

The product of Example 218a was reacted as described in Example 212c using a 3: 1 mixture of THF / EtOH (4 mL) instead of ethanol to give the title amine in quantitative yield.

Example 218c

(7-Propyl- [1,8] naphthyridin-4-yl) - (4-trifluoromethyl-biphenyl-2-yl) amine

The product of Example 2g as a 3.15 M solution in ethanol (0.078 mL, 0.24 mmol) was reacted with the product of Example 218b (0.057 g, 0.24 mmol) for 64 hours at 100 ° C. according to by the method described in Example 1g. As the initial product was consumed, the product of example 2g (0.103 ml, 0.32 mmol) was periodically added and the heating continued at 100 ° C (70 hours). The crude title compound was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (0.0058 g, 5%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.96 (t, J= 7.35 Hz, 3H), 1.73-1.92 (m, 2H), 2.90-3.02 (m, 2H), 6.37 (d, J= 6.99 Hz, 1H), 7.32 (d, J= 7.72 Hz, 3H), 7.48 (dd, J= 7.91, 1.65 Hz, 2H), 7.80 (d, J= 8.82 Hz, 1H), 7.86 (d, J= 8.09 Hz, 1H), 7.94-8.03 (m, 2H), 8.35 (d, J= 6.99 Hz, 1H), 8.91 (d, J= 8.82 Hz, 1H); MS (ESI +) m / z 408.1 (M + H) +; (ESI-) m / z 406.2 (MH) -.

Example 219

(5-Methyl-biphenyl-2-yl) - (7-propyl- [1,8] naphthyridin-4-yl) amine

Example 219a

2-Bromo-4-methyl-1-nitro-benzene

To a vessel containing 90% tert-butylnitrile (1.47 ml, 11.2 mmol) and copper (II) bromide (2.0 g, 8.95 mmol) in CH3CN (40 ml) at 70 ° C under a nitrogen atmosphere was added dropwise a solution of commercially available 5-methyl-2-nitro-phenylamine (1.13 g, 7.46 mmol) in CH3CN (8 ml). After twenty minutes, the reaction mixture was quenched by pouring into dilute HCl and the crude product was isolated by extraction with ether, drying with MgSO4 and concentration in vacuo. Flash chromatography on silica gel gave the title compound (0.811 g, 50%).

Example 219b

5-Methyl-2-nitro-biphenyl

The product of Example 219a (0.20 g, 0.93 mmol) was reacted with phenylboronic acid (0.135 g, 1.11 mmol) for 19.5 h at 80 ° C as described in Example 218a. The reaction mixture was cooled and filtered through celite, and the filtrate was concentrated in vacuo to give a crude product which was purified by flash chromatography on silica gel to give the title biphenyl (0.187 g, 94%) as a yellow oil.

Example 219c

5-Methyl-biphenyl-2-ylamine

The product of Example 219b (0.0885 g, 0.41 mmol) was reacted according to the method described in Example 212c to give the title amine (0.0724 g, 96%).

Example 219d

(5-Methyl-biphenyl-2-yl) - (7-propyl- [1,8] naphthyridin-4-yl) amine

The product of Example 2g as a 4.1 M solution in ethanol (0.10 mL, 0.40 mmol) was reacted with the product of Example 219c (0.0724 g, 0.40 mmol) for 66 hours at 100 ° C according to the method described in Example 1g. As the initial product was consumed, a second addition of the product of Example 2g (0.03 ml, 0.12 mmol) was required, and heating was continued at 100 ° C. (19 hours). The crude title compound was purified by HPLC using TFA to give the product as a trifluoroacetic acid salt (0.060 g, 32%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.95 (t, J= 7.35 Hz, 3H), 1.70-1.89 (m, 2H), 2.46 (s, 3H), 2.88-3.00 (m, 2H), 6.28 (d, J= 6.99 Hz, 1H), 7.11-7.53 (m, 8 H), 7.76 (d, J= 8.82 Hz, 1H), 8.30 (d, J= 6.99 Hz, 1H), 8.91 (d, J= 8.82 Hz, 1H), 10.98 (s, 1H); MS (ESI +) m / z 354.2 (M + H) +.

Example 220

[2- (4-Amino-phenylsulfanyl) -5-methylphenyl] - (7-propyl- [1,8] naphthyridin-4-yl) amine

The product of Example 20 (0.197 g, 0.445 mmol) was reacted as described in Example 83 to give the crude title compound, which was purified by HPLC with TFA, to give the product as a trifluoroacetic acid salt. 11H NMR (500 MHz, DMSO-d6th) δ ppm: 0.98 (t, J= 7.25 Hz, 3H), 1.80-1.91 (m, 2H), 2.31 (s, 3H), 2.96-3.04 (m, 2H), 6.31 (d, J= 6.96 Hz, 1H), 6.57 (d, J= 8.69 Hz, 2H), 6.91 (d, J= 8.11 Hz, 1H), 7.07 (d, J= 8.69 Hz, 2H), 7.18-7.29 (m, 2H), 7.83 (d, J= 8.69 Hz, 1H), 8.45 (d, J= 6.96 Hz, 1H), 9.06 (d, J= 8.69 Hz, 1H), 11.03 (s, 1H); MS (ESI +) m / z 401.1 (M + H) +; (ESI-) m / z 399.1 (MH) -.

Example 221

4- [4-Phenoxymethyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] phenol

Example 221a

(4-Bromo-3-nitro-phenyl) -methanol

Commercially available 4-bromo-3-nitro-benzoic acid (5.95 g, 0.024 mol) was reacted as described in Example 115a to give the title compound with a quantitative yield of a crude product that was pure enough to be used, as it is highlighted.

Example 221b

1-Bromo-2-nitro-4-phenoxymethylbenzene

The product of Example 221a (0.5 g, 2.15 mmol) was combined with phenol (0.203 g, 2.15 mmol) and triphenylphosphine (0.735 g, 2.80 mmol) in anhydrous THF (7 mL) under nitrogen and the resulting the solution was cooled in an ice bath. To the cold solution was added dropwise diisopropyl azodicarboxylate (0.467 ml, 2.37 mmol). Stirring at 0 ° C. was continued for 15 minutes, then the cold bath was removed and the reaction mixture allowed to warm to room temperature and held for 90 minutes, then quenched and processed, poured into dilute HCl and extracted with ether. The combined extracts were dried over MgSO44, filtered and concentrated in vacuo to give the crude title compound, which was purified by flash chromatography on silica gel, eluting with EtOAc-hexane, to give the title compound (0.162 g, 25%).

Example 221c

4- (2-Nitro-4-phenoxymethyl-phenylsulfanyl) -phenol

The product of Example 221b (0.16 g, 0.52 mmol) was reacted with 90% 4-mercapto-phenol (0.073 g, 0.52 mmol) in DMF at 80 ° C under a nitrogen atmosphere in the presence of potassium carbonate (0.126 g, 0.91 mmol). After 18 hours, the reaction mixture was quenched by pouring into dilute HCl and extracting with ether. The combined extracts were dried over MgSO44, filtered and concentrated in vacuo to give the crude title compound. The crude product was purified by flash chromatography on silica gel eluting with EtOAc-hexane to give the title compound (0.155 g, 84%).

Example 221d

4- (2-Amino-4-phenoxymethyl-phenylsulfanyl) -phenol

The product of Example 221c (0.154 g, 0.43 mmol) was reacted with tin (0.41 g, 2.17 mmol), as described in Example 1f, to obtain the title compound (0.132 g, 100%).

Example 221

4- [4-Phenoxymethyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] phenol

The product of Example 2g as a 4.1 M solution in ethanol (0.050 mL, 0.205 mmol) was reacted with the product of Example 221d (0.066 g, 0.205 mmol) for 16.5 h according to the method described in Example 1g. As the initial product was consumed, a second addition of the product of Example 2g (0.025 ml, 0.102 mmol) was required, and heating was continued at 80 ° C. (12 hours). The crude title compound was purified by HPLC with TFA to give the product as a trifluoroacetic acid salt (0.0269 g, 21.5%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J= 7.54 Hz, 3H), 1.76-1.99 (m, 2H), 3.00 (t, J= 7.35 Hz, 2H), 5.12 (s, 2H), 6.31 (d, J= 6.99 Hz, 1H), 6.79 (d, J= 8.82 Hz, 2H), 6.91-7.07 (m, 4H), 7.17-7.37 (m, 4H), 7.43-7.55 (m, 2H), 7, 84 (d, J= 8.82 Hz, 1H), 8.47 (d, J= 7.35 Hz, 1H), 9.04 (d, J= 8.46 Hz, 1H), 9.97 (s, 1H); MS (ESI +) m / z 494.2 (M + H) +; (ESI-) m / z 492.2 (MH) -.

Example 222

4- [2- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-phenoxymethyl-phenylsulfanyl] -phenol

The product of Example 1d (0.037 g, 0.205 mmol) was reacted with the product of Example 221d (0.066 g, 0.205 mmol) for 16.5 hours according to the method described in Example 1g to give the crude title compound which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (0.041 g, 34%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.77 (s, 3H), 5.13 (s, 2H), 6.31 (d, J= 6.99 Hz, 1H), 6.79 (d, J= 8.46 Hz, 2H), 6.88-7.12 (m, 4H), 7.20-7.36 (m, 4H), 7.46-7.56 (m, 2H), 7, 81 (d, J= 8.82 Hz, 1H), 8.48 (d, J= 6.99 Hz, 1H), 9.02 (d, J= 8.46 Hz, 1H), 10.01 (s, 1H); MS (ESI +) m / z 466.3 (M + H) +; (ESI-) m / z 464.2 (MH) -.

Example 223

4- [4- (4-Bromo-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

Example 223a

1-Bromo-4- (4-bromo-phenoxymethyl) -2-nitro-benzene

The product of Example 221a (0.5 g, 2.15 mmol) was reacted as described in Example 221b using 4-bromo-phenol (0.372 g, 2.15 mmol) in place of phenol to give the title compound as solid product of white color (0.238 g, 29%).

Example 223b

4- [4- (4-Bromo-phenoxymethyl) -2-nitro-phenylsulfanyl] -phenol

The product of Example 223a (0.236 g, 0.61 mmol) was reacted as described in Example 221c to give the title compound (0.188 g, 71%).

Example 223c

4- [2-Amino-4- (4-bromo-phenoxymethyl) phenylsulfanyl] -phenol

The product of Example 223b (0.186 g, 0.43 mmol) was reacted as described in Example 221d to give the title compound (0.121 g, 70%).

Example 223

4- [4- (4-Bromo-phenoxymethyl) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 1d (0.03 g, 0.167 mmol) was reacted with the product of Example 223c (0.060 g, 0.15 mmol) for 17.5 h according to the method described in Example 1g. As the initial product was consumed, the second addition of the product of Example 1d (0.016 g, 0.09 mmol) was required, and heating was continued at a temperature of 80 ° C (18 h). The crude title compound was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (0.056 g, 55%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.77 (s, 3H), 5.12 (s, 2H), 6.30 (d, J= 6.99 Hz, 1H), 6.79 (d, J= 8.82 Hz, 2H), 6.92-7.08 (m, 3H), 7.25 (d, J= 8.82 Hz, 2H), 7.42-7.54 (m, 4H), 7.81 (d, J= 8.82 Hz, 1H), 8.47 (d, J= 6.99 Hz, 1H), 9.01 (d, J= 8.46 Hz, 1H), 9.98 (s, 1H); MS (ESI +) m / z 546.0 (M + H) +.

Example 224

4- [4- (4-Bromo-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 2g as a 4.1 M solution in ethanol (0.055 mL, 0.225 mmol) was reacted with the product of Example 223c (0.060 g, 0.15 mmol) for 17.5 h according to the method described in Example 1g. As the initial product was consumed, a second addition of the product of Example 2g (0.028 mL, 0.114 mmol) was required, and heating was continued at a temperature of 80 ° C (18 h). The crude title compound was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (0.044 g, 41%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J= 7.35 Hz, 3H), 1.77-1.96 (m, 2H), 3.00 (t, J= 7.54 Hz, 2H), 5.13 (s, 2H), 6.31 (d, J= 6.99 Hz, 1H), 6.79 (d, J= 8.82 Hz, 2H), 6.91-7.07 (m, 3H), 7.26 (d, J= 8.46 Hz, 2H), 7.40-7.56 (m, 4H), 7.84 (d, J= 8.82 Hz, 1H), 8.47 (d, J= 6.99 Hz, 1H), 9.04 (d, J= 8.82 Hz, 1H), 9.98 (s, 1H); MS (ESI +) m / z 573.9 (M + H) +; (ESI-) m / z 572.1 (MH) -.

Example 225

4- [4- (3-Bromo-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

Example 225a

1-Bromo-4- (3-bromo-phenoxymethyl) -2-nitro-benzene

The product of Example 221a (0.5 g, 2.15 mmol) was reacted as described in Example 221b using 3-bromo-phenol (0.372 g, 2.15 mmol) in place of phenol to give the title compound (0.832 g, 56%).

Example 225b

4- [4- (3-Bromo-phenoxymethyl) -2-nitro-phenylsulfanyl] -phenol

The product of Example 225a (0.462 g, 1.19 mmol) was reacted as described in Example 221c to give the title compound (0.412 g, 80%).

Example 225c

4- [2-Amino-4- (3-bromo-phenoxymethyl) phenylsulfanyl] -phenol

The product of Example 225b (0.412 g, 0.95 mmol) was reacted as described in Example 221d to give the title compound (0.310 g, 81%).

Example 225

4- [4- (3-Bromo-phenoxymethyl) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 1d (0.034 g, 0.193 mmol) was reacted with the product of Example 225c (0.078 g, 0.193 mmol) for 15 hours according to the method described in Example 1g. As the initial product was consumed, a second addition of the product of Example 1d (0.019 g, 0.109 mmol) was required, and heating was continued at a temperature of 80 ° C (18 h). The crude title compound was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (0.041 g, 32%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.77 (s, 3H), 5.15 (s, 2H), 6.30 (d, J= 7.35 Hz, 1H), 6.79 (d, J= 8.46 Hz, 2H), 6.95-7.08 (m, 2H), 7.16 (d, 1H), 7.20-7.30 (m, 4H), 7.45-7, 55 (m, 2H), 7.81 (d, J= 8.82 Hz, 1H), 8.47 (d, J= 7.35 Hz, 1H), 9.01 (d, J= 8.46 Hz, 1H), 9.98 (s, 1H); Ms (ESI +) m / z 546.0 (M + H) +; (ESI-) m / z 542.0.

Example 226

4- [4- (3-Bromo-benzyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenol

The product of Example 2g as a 4.1 M solution in ethanol (0.075 mL, 0.308 mmol) was reacted with the product of Example 225c (0.078 g, 0.193 mmol) for 15 hours according to the method described in Example 1g. As the initial product was consumed, the second addition of the product of Example 2g (0.028 mL, 0.114 mmol) was required, and heating was continued at a temperature of 80 ° C (18 hours). The crude title compound was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (0.038 g, 28%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.98 (t, J= 7.35 Hz, 3H), 1.85 (d, J= 7.35 Hz, 2H), 3.00 (t, J= 7.54 Hz, 2H), 5.16 (s, 2H), 6.31 (d, J= 7.35 Hz, 1H), 6.79 (d, J= 8.46 Hz, 2H), 6.95-7.09 (m, 2H), 7.16 (d, 1H), 7.18-7.34 (m, 4H), 7.42-7, 58 (m, 2H), 7.84 (d, J= 8.46 Hz, 1H), 8.48 (d, J= 6.99 Hz, 1H), 9.04 (d, J= 8.46 Hz, 1H), 9.98 (s, 1H), 10.99-11.19 (m, 1H); MS (ESI +) m / z 573.9 (M + H) +; (ESI-) m / z 572.3 (MH) -.

Example 227

(7-Methyl- [1,8] naphthyridin-4-yl) - [5-methyl-2- (pyridin-2-ylsulfanyl) -phenyl] -amine

Example 227a

2- (4-Methyl-2-nitro-phenylsulfanyl) -pyridine

The title compound was prepared by reacting 4-methyl-2-nitro-phenyl ester of trifluoro-methanesulfonic acid (3.50 g, 12.27 mmol) with pyridine-2-thiol (2.046 g, 18.41 mmol) and K2CO3 (2.968 g, 21.48 mmol) in DMF at 100 ° C for 16 hours. The reaction mixture was then cooled to room temperature and diluted with water, extracted with EtOAc, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (2.52 g, 78%).

Example 227b

5-Methyl-2- (pyridin-2-ylsulfanyl) -phenylamine

The product of Example 277a (2.250 g, 10.23 mmol) was reduced with SnCl2 (5.820 g, 30.70 mmol) for 2 hours at 80 ° C. according to the method described in Example 1f, to give the title compound, which was purified by chromatography on a silica gel column, eluting with 30% EtOAc / hexane ( 1.52 g, 70%).

Example 227c

(7-Methyl- [1,8] naphthyridin-4-yl) - [5-methyl-2- (pyridin-2-ylsulfanyl) -phenyl] -amine

The product of Example 227b (60 mg, 0.278 mmol) was reacted with the product of Example 1d (50 mg, 0.278 mmol) for 16 hours according to the method described in Example 1g to give the crude title compound which was purified by HPLC with TFA, which gave the product as trifluoroacetic acid (24 mg, 28%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.44 (s, 3H), 2.73 (s, 3H), 6.45 (d, J= 6.99 Hz, 1H), 7.02-7.12 (m, J= 7.72, 1.10 Hz, 2H), 7.40-7.49 (m, 2H), 7.50-7.58 (m, J= 1.84 Hz, 1H), 7.72 (dd, J= 8.46, 3.31 Hz, 2H), 8.21-8.27 (m, J= 2.94, 0.74 Hz, 1H), 8.38 (d, J= 6.99 Hz, 1H), 8.85 (d, J= 8.82 Hz, 1H), 10.99 (s, 1H); MS (ESI +) m / z 359 (M + H-TFA) +; (ESI-) m / z 357 (MH-TFA) -.

Example 228

(5-Chloro-2-phenoxy-phenyl) - [1,6] naphthyridin-5-yl-amine

Example 228a

2-Trimethylsilanylethynyl-nicotinonitrile

In a suitably sized pressure vessel, commercially available 2-chloro-nicotinonitrile (1.5 g, 10.8 mmol) with triphenylphosphine (0.228 g, 8 mol%) and palladium (II) acetate (0.083 g, 3 , 5 mol%) in triethylamine (20 ml). Nitrogen was bubbled into the resulting suspension at room temperature for five minutes, then trimethylsilylacetylene (8.5 ml, 60.1 mmol) was added, the vessel sealed and placed in an oil bath at 80 ° C. After 18.5 hours, the pressure tube was cooled to room temperature and the contents filtered. The filtrate was concentrated in vacuo and the crude product was purified by flash chromatography on silica gel eluting with EtOAc / hexane to give the title compound (1.62 g, 75%) as a tan solid.

Example 228b

2- (2,2-Dimethoxy-ethyl) -nicotinonitrile

The product of Example 228a (1.62 g, 8.09 mmol) was reacted with sodium methoxide as a 25 wt% solution (8.74 g, 40.4 mmol) in methanol (5 mL) for two hours at a temperature 80 ° C. The crude product was isolated by ether extraction, dried over MgSO4, filtered and concentrated in vacuo to give the title compound (1.46 g, 94%), sufficiently pure for use as it was isolated.

Example 228c

2- (2,2-Dimethoxy-ethyl) -nicotinamide

The product of Example 228b (1.46 g, 7.6 mmol) was dissolved in methanol (20 ml), to which sodium carbonate as 3N was added at room temperature at room temperature. solution (35 ml), then hydrogen peroxide as a 15% solution (35 ml). The reaction mixture was stirred for 4.5 hours, then exfoliated by addition of ethyl acetate and solid sodium chloride. The aqueous phase was extracted several times with ethyl acetate and the organic layers were combined, mixed with solid sodium bisulfite, then dried over MgSO4, filtered and concentrated in vacuo to give the title compound (1.36 g, 85%), sufficiently pure for use as it was isolated.

Example 228d

[1,6] Naphthyridin-5-ol

The product of Example 228c (1.36 g, 6.47 mmol) was dissolved in benzene (35 mL), and pyridinium p-toluenesulfonate (0.20 g, 0.8 mmol) was added to this solution. The mixture was heated to reflux for 23 hours, then concentrated in vacuo to give the title compound in quantitative yield, which was pure enough to be used as it was isolated.

Example 228e

5-Chloro- [1,6] naphthyridine

The product of Example 228d (0.250 g, 1.71 mmol) was combined with phosphorus oxychloride (4 mL) and heated under nitrogen at 80 ° C for 18.5 hours, then vacuum distilled to remove volatile products. The residue was mixed with ice and basified (pH 7-8) with concentrated ammonium hydroxide. The title compound was collected by vacuum filtration, washed with water and dried in vacuo to give a solid product of gray color (0.245 g, 87%), sufficiently pure for use as it was isolated.

Example 228f

(5-Chloro-2-phenoxy-phenyl) - [1,6] naphthyridin-5-yl-amine

The product of Example 228e (0.040 g, 0.24 mmol) was reacted with the product of Example 42b (0.048 g, 0.24 mmol) for 48 hours at 100 ° C. according to the method described in Example 1g to give a crude The title compound, which was purified by HPLC with TFA, gave the product as a trifluoroacetic acid salt (0.046 g, 40%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 6.96 (d, J= 7.35 Hz, 2H), 7.00-7.10 (m, 2H), 7.22-7.39 (m, 4H), 7.66 (dd, J= 8.46, 4.41 Hz, 1H), 7.91 (d, J= 1.84 Hz, 1H), 8.07 (d, J= 6.25 Hz, 1H), 8.76 (d, J= 8.46 Hz, 1H), 9.07 (d, J= 3.31 Hz, 1H); MS (ESI +) m / z 348.0 (M + H) +; (ESI-) m / z 346.1 (MH) -.

Example 229

N- {4- [4-Methyl-2 - ([1,6] naphthyridin-5-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 228e (0.040 g, 0.24 mmol) was reacted with the product of Example 18b as a 1.5 M solution in ethanol (0.162 mL, 0.24 mmol) for 17.5 h at 100 ° C in according to the method described in Example 1g. As the initial product was consumed, a second addition of the product of Example 228e (0.027 g, 0.16 mmol) was required, and heating was continued at 100 ° C (24 h) to give the crude title compound, which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (0.038 g, 27%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.02 (s, 3H), 2.36 (s, 3H), 7.12-7.37 (m, 5H), 7.38-7.53 (m, 3H) , 7.73-7.92 (m, J= 8.64, 4.60 Hz, 2H), 8.94 (d, J= 8.46 Hz, 1H), 9.18 (d, J= 4.04 Hz, 1H), 9.99 (s, 1H); MS (ESI +) m / z 401.3 (M + H) +; (ESI-) m / z 399.0 (MH) -.

Example 230

(5-Methyl-2-phenylsulfanyl-phenyl) - [1,8] naphthyridin-4-yl-amine

The product of Example 16c (0.051 g, 0.31 mmol) was reacted with the product of Example 1f (0.066 g, 0.31 mmol) for 22.5 h according to the method described in Example 1g. As the initial product was consumed, the second addition of the product of Example 16c (0.018 g, 0.113 mmol) was required and the heating was continued at 80 ° C (22 h) to give the crude title compound, which was purified by HPLC with ammonium acetate, to give the product was obtained as a free base, which was then treated with trifluoroacetic acid to give the corresponding trifluoroacetic acid salt (0.062 g, 43%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.38 (s, 3H), 6.36 (d, J= 6.99 Hz, 1H), 7.23 (s, 5H), 7.30-7.42 (m, 3H), 7.89 (dd, J= 8.46, 4.41 Hz, 1H), 8.46 (d, J= 6.99 Hz, 1H), 9.03-9.10 (m, 1H), 9.15 (dd, J= 4.41, 1.47 Hz, 1H), MS (ESI +) m / z 344.0 (M + H) +; (ESI-) m / z 342.0 (MH) -.

Example 231

N- {4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 231a

N- (4- (5-Chloro-2-nitrophenylsulfanyl) phenyl) acetamide

A mixture of 2,4-dichloronitrobenzene (0.25 g, 1.3 mmol), 4-acetamido-thiophenol (0.26 g, 1.43 mmol) and cesium carbonate (0.466 g, 1.43 mmol) in DMF ) was heated 2.5 hours at 100 ° C. The mixture was cooled, diluted with ethyl acetate (100 ml), and the organic layer was washed with water and an aqueous 10% sodium chloride solution, then dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was removed in vacuo. The residue was purified by chromatography on a silica gel column, eluting with CH2Cl2/ methanol to give the title compound as a yellow solid product (0.25 g, 63%).

Example 231b

N- (4- (5-chloro-2-nitrophenylthio) phenyl) acetamide

A solution of the product of Example 231a (0.25 g, 0.77 mmol), iron powder (0.29 g, 5.2 mmol) and ammonium chloride (0.084 g, 1.6 mmol) in methanol (2 mL), tetrahydrofuran (2 ml) and water (0.7 ml) was heated to reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a pad of celite. The filtrate was concentrated in vacuo to a volume of 10 ml, the solution was diluted with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with a 10% sodium chloride solution, then dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (0.20 g, 87%).

Example 231c

N- {4- [5-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 1d (48 mg, 0.27 mmol) was reacted in ethanol (2 ml) with the product of Example 231b (78 mg, 0.27 mmol) for 18 hours according to the method described in Example 1g, the crude title compound, which was purified by HPLC with TFA, to give the product as the trifluoroacetic acid salt (12 mg, 28%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.06 (s, 3H), 2.77 (s, 3H), 6.39 (d, J = 7.35 Hz, 1H), 6.96 (d, J = 1 , 84 Hz, 1H), 7.38 (d, J = 8.82 Hz, 2H), 7.51 (s, 2H), 7.62 (d, J = 8.82 Hz, 2H), 7, 81 (d, J = 8.82 Hz, 1H), 8.47 (d, J = 7.35 Hz, 1H), 8.97 (d, J = 8.82 Hz, 1H), 10.15 (d, s, 1 H), 11.01 (s, 1 H), 14.48 (s, 1 H); MS (DCI / NH3) m / z 435 (M + H) +.

Example 232

N- {4- [4-Cyanomethoxy-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 232a

N- [4- (4-Hydroxy-2-nitro-phenylsulfanyl] -phenyl} -acetamide

A mixture of 3-nitro-4-chlorophenol (1.59 g, 8.97 mmol), 4-acetamidothiophenol (2 g, 10.76 mmol) and cesium carbonate (7.0 g, 21.53 mmol) in DMF (20 ml) was heated 2.5 hours at 100 ° C. The mixture was cooled, poured onto ice, and the resulting solid was collected by filtration and dried in vacuo to give the title compound as a yellow solid (2.7 g, 100%).

Example 232b

N- [4- (2-Amino-4-hydroxy-phenylsulfanyl] -phenyl} -acetamide

A solution of the product of Example 232a (2.7 g, 8.97 mmol), iron powder (2.0 g, 35.9 mmol) and ammonium chloride (0.58 g, 10.76 mmol) in methanol (6 mL) , THF (6 ml) and water (2 ml) was heated to reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a pad of celite. The filtrate was concentrated in vacuo to a volume of 10 ml, the solution was diluted with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined extracts were washed with a 10% sodium chloride solution, then dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (2.46 g, 77%).

Example 232c

N- [4- (2-Amino-4-cyanomethoxy-phenylsulfanyl] -phenyl} -acetamide

A mixture of the product of Example 232b (56 mg, 0.17 mmol), 2-bromoacetonitrile (20 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 ml) was stirred at room temperature 15 hour. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to give the title compound (53 mg, 100%).

Example 232d

N- {4- [4-Cyanomethoxy-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 1d (30 mg, 0.17 mmol) was reacted in ethanol (1 ml) with the product of Example 232c (53 mg, 0.17 mmol) for 18 hours according to the method described in Example 1g, crude title compound, which was purified by HPLC with TFA, to give the product as a trifluoroacetic acid salt (9 mg, 19%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.03 (s, 3H), 2.76 (s, 3H), 5.23 (s, 2H), 6.32 (d, J = 6.99 Hz, 1H), 7.18 (d, J = 8.46 Hz, 2H), 7.23 (dd, J = 8.82, 2.57 Hz, 1H), 7.31 (d, J = 2.57 Hz, 1H ), 7.38 (d, J = 8.82 Hz, 1H), 7.45 (d, J = 8.82 Hz, 2H), 7.80 (d, J = 8.46 Hz, 1H), 8.41 (d, J = 6.99 Hz, 1H), 8.96 (d, J = 8.46 Hz, 1H), 10.01 (s, 1H), 11.04 (s, 1H), 14.42 (s, 1H); MS (ESI +) m / z 456 (M + H) +.

Example 233

N- {4- [4-Benzyloxy-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 233a

N- [4- (2-Amino-4-benzyloxy-phenylsulfanyl] -phenyl} -acetamide

A mixture of the product of Example 232b (56 mg, 0.17 mmol), benzyl bromide (21 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 mL) was stirred at room temperature for 15 hours. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to give the title compound (62 mg, 100%).

Example 233b

N- {4- [4-Benzyloxy-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 1d (30 mg, 0.17 mmol) was reacted in ethanol (1 ml) with the product of Example 233a (62 mg, 0.17 mmol) for 18 hours according to the method described in Example 1g, crude title compound, which was purified by HPLC using TFA, to give the product as a trifluoroacetic acid salt (24 mg, 47%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.02 (s, 3H), 2.75 (s, 3H), 5.15 (s, 2H), 6.29 (d, J = 7.35 Hz, 1H), 7.12 (d, J = 8.82 Hz, 2H), 7.16-7.27 (m, 2H), 7.29-7.52 (m, 8 H), 7.78 (d, J = 8.82 Hz, 1H), 8.36 (d, J = 6.99 Hz, 1H), 8.94 (d, J = 8.82 Hz, 1H), 9.97 (s, 1H), 11.00 (s, 1H), 14.34 (s, 1H); MS (ESI +) m / z 507 (M + H) +.

Example 234

N- {4- [4- (2-Methyl-allyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

Example 234a

N- {4- [2-Amino-4- (2-methyl-allyloxy) -phenylsulfanyl] -phenyl} -acetamide

A mixture of the product of Example 232b (56 mg, 0.17 mmol), 2-methyl-3-bromopropene (20 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 mL) was stirred at room temperature for 15 hours. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to give the title compound (55 mg, 100%).

Example 234b

N- {4- [4- (2-Methyl-allyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide

The product of Example 1d (30 mg, 0.17 mmol) was reacted in ethanol (1 ml) with the product of Example 234a (55 mg, 0.17 mmol) for 18 hours according to the method described in Example 1g, crude title compound, which was purified by HPLC with TFA, to give the product as a trifluoroacetic acid salt (12 mg, 25%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 1.76 (s, 3H), 2.02 (s, 3H), 2.75 (s, 3H), 4.52 (s, 2H), 4.98 (s, 1H ), 5.05 (s, 1H), 6.30 (d, J = 7.35 Hz, 1H), 7.04-7.19 (m, 4H), 7.36 (s, 1H), 7 , 41 (d, J = 8.46 Hz, 2H), 7.78 (d, J = 8.82 Hz, 1H), 8.37 (d, J = 6.99 Hz, 1H), 8.94 (d, J = 8.46 Hz, 1H), 9.97 (s, 1H), 10.99 (s, 1H), 14.33 (s, 1H); MS (ESI +) m / z 471 (M + H) +.

Example 235

N- {4- [2- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-propoxy-phenylsulfanyl] -phenyl} -acetamide

Example 235a

N- [4- (2-Amino-4-propoxy-phenylsulfanyl) -phenyl} -acetamide

Example 235b

N- {4- [2- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-propoxy-phenylsulfanyl] -phenyl} -acetamide

The product of Example 1d (30 mg, 0.17 mmol) was reacted in ethanol (1 ml) with the product of Example 235a (55 mg, 0.17 mmol) for 18 hours according to the method described in Example 1g, crude title compound, which was purified by HPLC with TFA, to give the product as a trifluoroacetic acid salt (14 mg, 30%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (t, J = 7.35 Hz, 3H), 1.59-1.83 (m, 2H), 2.02 (s, 3H), 2.75 (s , 3H), 3.97 (t, J = 6.43 Hz, 2H), 6.31 (d, J = 7.35 Hz, 1H), 7.04-7.18 (m, 4H), 7 , 25-7.45 (m, J = 8.64, 3.86 Hz, 3H), 7.77 (d, J = 8.46 Hz, 1H), 8.35 (d, J = 7.35 Hz, 1H), 8.94 (d, J = 8.82 Hz, 1H), 9.96 (s, 1H), 10.99 (s, 1H), 14.31 (s, 1H); MS (ESI +) m / z 459 (M + H) +.

Example 236

4- [4- (4-Acetylamino-phenylsulfanyl) -3- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxymethyl] benzoic acid methyl ester

Example 236a

4- [4- (4-Acetylamino-phenylsulfanyl) -3-amino-phenoxymethyl] -benzoic acid methyl ester

A mixture of the product of Example 232b (28 mg, 0.085 mmol), 4-carbomethoxybenzyl bromide (22 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 ml) was stirred at room temperature for 15 hours. The next day, the reaction mixture was poured onto ice and the solid was collected by filtration to give the title compound (35 mg, 100%).

Example 236b

4- [4- (4-Acetylamino-phenylsulfanyl) -3- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxymethyl] benzoic acid methyl ester

The product of Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 ml) with the product of Example 236a (35 mg, 0.085 mmol) for 18 hours according to the method described in Example 1g to give the crude title a compound which was purified by HPLC with TFA, which gave the product as a trifluoroacetic acid salt (22 mg, 37%). 11H-NMR (300 MHz, DMSO-d6th) δ ppm: 0.97 (t, J = 7.35 Hz, 3H), 1.75-1.93 (m, 2H), 2.02 (s, 3H), 2.99 (t, , J = 7.54 Hz, 2H), 3.86 (s, 3H), 5.26 (s, 2H), 6.30 (d, J = 6.99 Hz, 1H), 7.14 (d , J = 8.82 Hz, 2H), 7.17-7.27 (m, 2H), 7.37 (d, J = 8.46 Hz, 1H), 7.42 (d, J = 8, 82 Hz, 2H), 7.59 (d, J = 8.46 Hz, 2H), 7.80 (d, J = 8.46 Hz, 1H), 7.99 (d, J = 8.09 Hz , 2H), 8.36 (d, J = 7.35Hz, 1H), 8.97 (d, J = 8.46 Hz, 1H), 9.98 (s, 1H), 11.01 (s , 1H), 14.38 (s, 1H); MS (ESI +) m / z 593 (M + H) +.

Example 237

4- [4- (4-Methoxybenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] -phenol

Example 237a

2-Amino-6-methyl-nicotinonitrile

2-Chloro-6-methyl-nicotinonitrile (25 g, 0.164 mol) and liquid ammonia (250 ml) in 500 ml of ethanol were reacted in a sealed vessel to carry out the reactions at elevated pressure at 130 ° C for 20 hours. The reaction mixture was concentrated in vacuo and the residue was washed with water (2.times.50 ml), then dried in a vacuum oven for 24 hours to give the title compound as a light yellow solid (18 g, 82%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.30 (s, 3H), 6.52 (d, J= 7.7 Hz, 1H), 6.78 (s, 2H), 7.73 (d, J= 7.7 Hz, 1H).

Example 237b

N '- (3-Cyano-6-methyl-pyridin-2-yl) -N, N-dimethylformamidine

A solution of the product of Example 237a (10 g, 75.19 mmol) and dimethylacetal N,Ndimethylformamide (11 ml, 82.71 mmol) in toluene (100 ml) was heated at reflux for 6 hours. After cooling to room temperature, the solution was concentrated in vacuo to give the title compound as a yellow solid (13.78 g, 98%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 2.41 (s, 3H), 3.06 (s, 3H), 3.14 (s, 3H), 6.87 (d, J= 7.7 Hz, 1H), 7.89 (d, J= 8.1 Hz, 1H), 8.59 (s, 1H).

Example 237c

1-Chloro-4- (4-methoxy-benzyloxy) -2-nitro-benzene

A solution of 4-chloro-3-nitro-phenol (0.5 g, 2.88 mmol), 1-chloromethyl-4-methoxybenzene (0.496 g, 3.17 mmol), potassium carbonate (1.19 g, 8 , 64 mmol) and tetrabutylammonium iodide (0.005 g, 0.0135 mmol) in N, Ndimethylformamide (5 ml) was stirred at room temperature for 16 hours. Then, ice water (10 ml) was added to the solution, and the resulting solid was collected by filtration and dried in a vacuum oven to obtain the title compound (0.812 g, 96%).

Example 237d

4- [4- (4-Methoxy-benzyloxy) -2-nitro-phenylsulfanyl] -phenol

A solution of the product of Example 237c (0.812 g, 2.76 mmol), 4-hydroxythiophenol (0.419, 3.32 mmol) and cesium carbonate (2.16 g, 6.64 mmol) in N, Ndimethylformamide (5 ml) was heated to 100 ° C for 16 hours. After cooling to room temperature, the mixture was poured into ice water (20 ml) and the resulting solution was acidified with 1N HCl. aqueous hydrochloric acid. The solution was then extracted with ethyl acetate (3 × 10 mL), the combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (1.06 g, 100%).

Example 237e

4- [2-Amino-4- (4-methoxy-benzyloxy) -phenylsulfanyl] -phenol

A solution of the product of Example 237d (1.06 g, 2.76 mmol), iron powder (0.63 g, 11.04 mmol) and ammonium chloride (0.18 g, 3.31 mmol) in methanol (18 mL) , tetrahydrofuran (18 ml) and water (6 ml) was heated to reflux for 3 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a pad of celite. The filtrate was concentrated in vacuo to a volume of 10 ml, the solution was diluted with water (50 ml) and extracted with ethyl acetate (2 x 50 ml). The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuo to give the title compound (0.99 g, 100%).

Example 237f

4- [4- (4-Methoxybenzyloxy) -2- (7-methylpyrido [2,3-d] pyrimidin-4-ylamino) phenylsulfanyl] -phenol

A solution of the product of Example 237b (28.4 mg, 0.151 mmol) and the product of Example 237e (53.3 mg, 0.151 mmol) in acetic acid (1 mL) was stirred in an oil bath preheated to 130 ° C. in for 20 minutes. The mixture was then cooled to room temperature, acetic acid was removed in vacuo and the resulting residue was triturated with methanol to give the title compound as a tan solid (26.5 mg, 35%).11H-NMR (300 MHz, DMSO-d6th) δ ppm: 9.92 (s, 1H), 9.63 (s, 1H), 8.70 (d, J = 8.09 Hz, 1H), 8.55 (s, 1H), 7.52 (d, J = 8.46 Hz, 1H), 7.38 (d, J = 8.82 Hz, 2H), 7.27 (s, 1H), 7.06-7.18 (m , 3H), 6.94 (d, J = 8.46 Hz, 3H), 6.61-6.72 (m, 2H), 5.02 (s, 2H), 3.75 (s, 3H) , 2.66 (s, 3H); MS (ESI +) m / z 497.2 (M + H) +, (ESI-) m / z 495.3 (MH) -.

Biological research

Representative compounds of the invention were analyzed according to the procedures described below.

The following abbreviations were used:

<tables num="2"><table frame="none"><tgroup cols="2" rowsep="0" colsep="0"><colspec colname="c0" colwidth="24mm" /><colspec colname="c1" colwidth="136mm" /><tbody><row><entry align="justify" rowsep="0" colsep="0">IC50</entry><entry align="justify" rowsep="0" colsep="0">concentration leading to 50% inhibition</entry></row><row><entry align="justify" rowsep="0" colsep="0">TC50</entry><entry align="justify" rowsep="0" colsep="0">concentration leading to 50% toxicity</entry></row><row><entry align="justify" rowsep="0" colsep="0">DMEM </entry><entry align="justify" rowsep="0" colsep="0">Dulbecco's Modified Eagle's Medium ™</entry></row><row><entry align="justify" rowsep="0" colsep="0">RNA </entry><entry align="justify" rowsep="0" colsep="0">ribonucleic acid</entry></row><row><entry align="justify" rowsep="0" colsep="0">RT-PCR </entry><entry align="justify" rowsep="0" colsep="0">polymerase chain reaction with reverse transcription</entry></row><row><entry align="justify" rowsep="0" colsep="0">SEAP </entry><entry align="justify" rowsep="0" colsep="0">secreted alkaline phosphatase</entry></row></tbody></tgroup></table></tables>

The genome of the hepatitis C virus encodes a large polypeptide that, after processing, provides the necessary functional components for the synthesis of daughter RNAs. Selectable cell lines producing high and stable levels of HCV subgenomic RNA (replicons) were obtained from human hepatoma cells (Huh7), as described in Ikedaet al., J. VIROLOGY, 76 (6): 2997-3006 (2002), and Blight et al., SCIENCE, 290: 1972-1974 (2000). It is believed that the mechanism of RNA replication in these cell lines is the same as replication of full-length HCV RNA in infected hepatocytes. The compounds of the present invention are HCV RNA replication inhibitors in the replicon assays described below.

Evaluation of HCV inhibitors in HCV replicon

The inhibitory effect of representative compounds of the invention was evaluated for replicons of genotypes 1a and 1b of HCV. They were also evaluated by MTT analysis for cytotoxicity to host cells. The cell lines were maintained in accordance with the methods described by Yiet al., VIROLOGY, 304 (2): 197-210 (2002).

A. RNA analysis and SEAP analysis

The aim of these assays was to evaluate the efficacy of the compounds to inhibit the replication of HCV genotype 1a and 1b replication in vitro.

Cells with genotype 1a and / or 1b replicas were placed in a 96-well plate containing DMEM medium with 5% fetal bovine serum in an amount of 3-5 × 103 cells per well. The next day, the culture medium was removed and replaced with a fresh medium containing eight serial dilutions of the compound. The untreated control culture was treated in the same manner, but no inhibitor was added to the medium. The plates were incubated in a CO incubator2 at 37 ° C. On day 4, 100 μl of lysis buffer (RTL) (Qiagen) was added to each well after removal of the culture medium. RNA was purified according to the manufacturer's instructions (Qiagen RNAeasy) and eluted in 200 μl of water. The quantitative level of HCV RNA was measured in a portion (5 μl from 200 μl) of RNA purified by RT-PCR in real time. Primers and probes were prepared based on a specific sequence of the 5'-untranslated region (5'UTR). The RT-PCR reaction was carried out at 48 ° C for 30 minutes, then 40 cycles, setting 95 ° C, 15 s; 54 ° C, 30 s and 72 ° C, 40 s. Alternatively, SEAP activity was measured in each culture supernatant after four days of incubation with the compound according to the manufacturer's instructions. The percentage reduction of HCV or SEAP RNA in the presence of the compound and the concentration,50) was calculated using a nonlinear regression analysis using the Prism program (version 4.0, GraphPad software, San Diego, CA).

In testing using the above-described method, the characteristic compounds of the present invention inhibited replication of the HCV replicon at an IC50 in the range of about 0.3 nM to about 100 μM.

B. Cytotoxic analysis

The aim of this assay was to demonstrate the toxicity of the compounds to host cells carrying the virus, in vitro.

The cytotoxicity of the compounds was measured using a cell proliferation assay based on mitochondrial enzymes / viability assay in cells with a replicon. Briefly, cells with a HCV replicon were placed in a 96-well plate containing DMEM medium with 5% FCS in an amount of 3-5 × 103 cells per well. On day 1, the culture medium was removed and replaced with a fresh medium containing eight serial dilutions of the compound. The untreated control culture was treated in the same manner, but no inhibitor was added to the medium. The plates were incubated in a CO incubator2 at 37 ° C. On day 4, a base solution of a tetrazolium salt, MTT (4 mg / ml in PBS, Sigma cat. # M 2128) in an amount of 25 μl per well was added to each well. The plates were further incubated for 4 hours, treated with 20% SDS plus 0.02N. HCl in an amount of 50 μl per well for lysing the cells. After overnight incubation, the optical density was measured by reading the plates at a wavelength of 570/650 nm. The percentage of reduction of the formazan blue with respect to the control was calculated and the concentration resulting in 50% toxicity was calculated (TC50), using nonlinear regression analysis, using the Prism program (version 4.0, GraphPad software, San Diego, CA).

When tested using the above-described method, the TC value50 of the representative compounds of the present invention had larger corresponding IC values50 of these compounds.

Pharmaceutical compositions and use

The present invention relates to pharmaceutical compositions containing the compounds of the invention. By way of non-limiting example, the pharmaceutical composition of the present invention comprises one or more compounds of the present invention, wherein each compound is independently selected from the formulas I (a), I (b), II (a), II (b). Preferably, each compound is independently selected from Examples 1-237.

The present invention also relates to a pharmaceutical composition comprising pharmaceutically acceptable salts, solvates or prodrugs of the compounds of the present invention. The pharmaceutically acceptable salts can be zwitterion ions or can be prepared from pharmaceutically acceptable inorganic or organic acids or bases. Preferably, the acceptable salt of the compound of the invention retains the biological efficacy of the free acid or base of the compound without causing nonspecific toxicity, irritation or allergic reactions, has a suitable benefit / risk relationship and is effective for the intended use and is not undesirable from a biological or other point of view. Non-limiting examples of pharmaceutically acceptable salts include, but are not limited to, the following salts: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentane propionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulphate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isethionate) , lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. The basic groups containing nitrogen can also be quaternized with agents such as lower alkyl halides (eg, methyl, ethyl, propyl or butyl chlorides, bromides or iodides), dialkyl sulfates (eg, dimethyl, diethyl, dibutyl or diamyl sulfates), long-chain alkyl halides The chain (for example, decyl, lauryl, myristyl or stearyl chlorides, bromides or iodides), aralkyl halides (eg, benzyl or phenethyl bromides). Other salts that can be used in the present invention include alkali or alkaline earth metal salts such as sodium, potassium, calcium or magnesium, or organic bases. Examples of acids that can be used and form pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, maleic acid, succinic acid, citric acid or other suitable inorganic or organic acids. include alkali metal or alkaline earth metal salts such as sodium, potassium, calcium or magnesium, or organic bases. Examples of acids that can be used and form pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, maleic acid, succinic acid, citric acid or other suitable inorganic or organic acids. include alkali metal or alkaline earth metal salts such as sodium, potassium, calcium or magnesium, or organic bases. Examples of acids that can be used and form pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, maleic acid, succinic acid, citric acid or other suitable inorganic or organic acids.

The present invention also relates to pharmaceutical compositions containing a compound of the invention (or a salt, solvate or prodrug thereof) and other therapeutic agent. In a non-limiting example, the pharmaceutical composition of the present invention comprises 1, 2, 3 or more of the compounds of the invention (or their salts, solvates or prodrugs) and 1, 2, 3 or more other therapeutic agents. By way of non-limiting example, these other therapeutic agents may be selected from antiviral agents (eg, anti-HIV agents or other anti-HCV agents), immunomodulators, anti-cancer or chemotherapeutic agents, or anti-inflammatory agents. Specific examples of other therapeutic agents include, but are not limited to, ribavirin; interferons (eg IFN alpha 2a or 2b); protease inhibitors; immunosuppressive agents; antibodies (eg, therapeutic monoclonal or chimeric antibodies); antisense or siRNA; HIV inhibitors; hepatitis B inhibitors (HBV); means for the treatment of cirrhosis and inflammation of the liver; IFN-omega (BioMedicines Inc., Emeryville, CA); BILN-2061, inhibitor of serine proteases (Boehringer Ingelheim Pharma KG, Ingelheim, Germany); Summetrel, an antiviral agent (Endo Pharmaceuticals Holdings Inc., Chadds Ford, PA); roferon, A IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); Pegasus, PEGylated IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); Pegasis and ribavirin, PEGylated IFN-alpha 2a / ribavirin (F. Hoffmann-La Roche LTD, Basel, Switzerland); CellCept, HCV IgG immunosuppressant (F. Hoffmann-La Roche LTD, Basel, Switzerland); welfiron, lymphoblastic IFN-alpha n1 (GlaxoSmithKline plc, Uxbridge, UK); albuferon-alpha, albumin IFN-alpha 2b (Human Genome Sciences Inc., Rockville, MD); levovirin, ribavirin (ICN Pharmaceuticals, Costa Mesa, CA); IDN-6556, an inhibitor of caspase (Idun Pharmaceuticals Inc., San Diego, CA); IP-501, antifibrotic agent (Indevus Pharmaceuticals Inc., Lexington, MA); actumun, INF-gamma (InterMune Inc., Brisbane, CA); Infergen A, IFN alfacon-1 (InterMune Pharmaceuticals Inc., Brisbane, CA); ISIS 14803, antisense oligonucleotides (ISIS Pharmaceuticals Inc., Carlsbad, CA / Elan Pharmaceuticals Inc., New York, NY); JTK-003, an inhibitor of RdRp (Japan Tobacco Inc., Tokyo, Japan); Pegasus and Conjugate, PEGylated IFN-alpha 2a / immune modulator (Maxim Pharmaceuticals Inc., San Diego, CA); clonal, immune modulator (Maxim Pharmaceuticals Inc., San Diego, CA); tsivatsir, IgG IgV immunosuppressant (Nabi Biopharmaceuticals Inc., Boca Raton, FL); intron A and zadaxin IFN-alpha 2b / alpha 1-thymosin (RegeneRx Biopharmiceuticals Inc., Bethesda, MD / SciClone Pharmaceuticals Inc., San Mateo, CA); levovirin, an inhibitor of IMPDH (Ribapharm Inc., Costa Mesa, CA); viramidine, IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); heptazim, ribozyme (Ribozyme Pharmaceuticals Inc., Boulder, CO); intron A, IFN-alpha 2b (Schering-Plow Corporation, Kenilworth, NJ); PEG-intron, PEGylated IFN-alpha 2b (Schering-Plow Corporation, Kenilworth, NJ); rebetron, IFN-alpha 2b / ribavirin (Schering-Plow Corporation, Kenilworth, NJ); Ribavirin (Schering-Plow Corporation, Kenilworth, NJ); PEG-intron / ribavirin, PEGylated IFN-alpha 2b / ribavirin (Schering-Plow Corporation, Kenilworth, NJ); ask, immune modulator (SciClone Pharmaceuticals Inc., San Mateo, CA); rebif, IFN-beta 1a (Serono, Geneva, Switzerland); IFN-beta and EMZ701, IFN-beta and EMZ701 (Transition Therapeutics Inc., Ontario, Canada); T67, a beta-tubulin inhibitor (Tularik Inc., South San Francisco, CA); VX-497, an inhibitor of IMPDH (Vertex Pharmaceuticals Inc., Cambridge, MA); VX-950 / LY-570310, a serine protease inhibitor (Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and Co., Inc., Indianapolis, IN); omniferon, natural IFN-alpha (Viragen Inc., Plantation, FL); XTL-002, monoclonal antibody (XTL Biopharmaceuticals); an inhibitor of IMPDH (Vertex Pharmaceuticals Inc., Cambridge, MA); VX-950 / LY-570310, a serine protease inhibitor (Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and Co., Inc., Indianapolis, IN); omniferon, natural IFN-alpha (Viragen Inc., Plantation, FL); XTL-002, monoclonal antibody (XTL Biopharmaceuticals); an inhibitor of IMPDH (Vertex Pharmaceuticals Inc., Cambridge, MA); VX-950 / LY-570310, a serine protease inhibitor (Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and Co., Inc., Indianapolis, IN); omniferon, natural IFN-alpha (Viragen Inc., Plantation, FL); XTL-002, monoclonal antibody (XTL Biopharmaceuticals);<img file="00000043.tif" he="18" wi="54" img-format="tif" img-content="undefined" /> (herein referred to as compound VX-950, Vertex Pharmaceuticals Inc.); <img file="00000044.tif" he="25" wi="52" img-format="tif" img-content="undefined" /> (herein referred to as compound SCH503034, Schering-Plow Co.) and <img file="00000045.tif" he="22" wi="42" img-format="tif" img-content="undefined" /> (herein referred to as Compound GS9137, Gilead Sciences, Inc., Foster City, CA). Any other desired therapeutic agents may also be included in the pharmaceutical composition of the present invention.

In one embodiment, the pharmaceutical composition of the present invention comprises one or more of the compounds of the present invention (or their salts, solvates or prodrugs) and one or more other antiviral agents.

In another embodiment, the pharmaceutical composition of the present invention comprises one or more of the compounds of the present invention (or their salts, solvates or prodrugs) and one or more other anti-HCV agents. In one example, each compound of the present invention is independently selected from the formulas I (a), I (b), II (a), II (b) or Examples 1-237 and each anti-HCV agent is independently selected from RNA-dependent inhibitors HCV RNA polymerase (eg, nucleoside or non-nucleoside-type polymerase inhibitors), HCV protease inhibitors or HCV helicase inhibitors.

In another embodiment, the pharmaceutical composition of the present invention comprises one or more of the compounds of the present invention (or their salts, solvates or prodrugs) and two or more other anti-HCV inhibitors. Preferably, each compound of the present invention is independently selected from the formulas I (a), I (b), II (a), II (b) or from Examples 1-237. Other anti-HCV inhibitors may be selected from the same class of inhibitors (eg, all selected from inhibitors of the RNA-dependent HCV RNA polymerase or HCV protease inhibitors) or selected from different class of inhibitors (eg, one or more selected from RNA inhibitors dependent HCV RNA polymerase, and the other or others are selected from HCV protease inhibitors).

In yet another embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or prodrug thereof) and at least one inhibitor of the RNA-dependent HCV RNA polymerase. Preferably, each compound of the present invention is independently selected from the formulas I (a), I (b), II (a), II (b) or Examples 1-237.

In another embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or prodrug thereof) and at least one HCV protease inhibitor. Preferably, the compound of the present invention is selected from the formulas I (a), I (b), II (a), II (b) or Examples 1-237.

In yet another embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or prodrug thereof), at least one inhibitor of the RNA-dependent HCV RNA polymerase and at least one HCV protease inhibitor. Preferably, the compound of the present invention is selected from the formulas I (a), I (b), II (a), II (b) or Examples 1-237.

In yet another embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or prodrug thereof) and two or more anti-HCV agents, each independently selected from inhibitors of the RNA-dependent HCV RNA polymerase or HCV protease inhibitors. Preferably, the compound of the present invention is selected from the formulas I (a), I (b), II (a), II (b) or Examples 1-237.

In yet another embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or prodrug thereof) and three or more other anti-HCV agents, each independently selected from RNA-dependent RNA polymerase inhibitors HCV or HCV protease inhibitors. Preferably, the compound of the present invention is selected from the formulas I (a), I (b), II (a), II (b) or Examples 1-237.

Non-limiting examples of inhibitors of RNA-dependent HCV RNA polymerase include compounds described in WO0190121 (A2), US6348587B1, WO0160315, WO0132153, EP1162196A1 and WO0204425. Non-limiting examples of HCV protease inhibitors include BILN-2061, VX-950 and SCH503034.

In another embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention (or a salt, solvate or prodrug thereof) and one or more other antiviral agents, such as anti-HBV or HIV agents. Non-limiting examples of agents against HBV include adefovir, lamivudine and tenofovir. Non-limiting examples of anti-HIV drugs include ritonavir, lopinavir, indinavir, nelfinavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC -125, L-870812, S-1360, enfuvirtide, tert-1249 and other inhibitors of protease, reverse transcriptase, integrase or fusion inhibitors of HIV.

In one embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention selected from the formulas I (a), I (b), II (a), II (b) or from Examples 1-237, or its salt, solvate or prodrug and at least one anti-HBV agent. In another embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention selected from the formulas I (a), I (b), II (a), II (b) or from Examples 1-237, or salt, solvate or prodrug and at least one anti-HIV agent. In yet another embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention selected from the formulas I (a), I (b), II (a), II (b) or from Examples 1-237, or its salt,

In yet another embodiment, the pharmaceutical composition of the present invention comprises at least one compound of the present invention selected from the formulas I (a), I (b), II (a), II (b) or from Examples 1-237, or its salt, solvate or prodrug, and at least one agent suitable for treating inflammation of the liver.

The pharmaceutical composition of the present invention typically comprises a pharmaceutically acceptable carrier or excipient. Non-limiting examples of suitable pharmaceutically acceptable carriers / excipients include sugars (for example, lactose, glucose or sucrose), starches (eg, corn starch or potato starch), cellulose or derivatives thereof (eg sodium carboxymethyl cellulose, ethylcellulose or cellulose acetate), oils (for example, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil or soybean oil), glycols (eg, propylene glycol), buffer substances (for example, magnesium hydroxide if aluminum hydroxide), agar, alginic acid, powdered tragacanth, malt, gelatin, talc, cocoa butter, pyrogen-free water, isotonic solution, Ringer's solution, ethanol or phosphate buffer solutions. Lubricants, coloring agents, release agents, coating agents, sweeteners, fragrances or perfumes, preservatives or antioxidants can also be included in the pharmaceutical composition of the present invention, as is apparent to one skilled in the art.

The pharmaceutical composition of the present invention can be administered to a patient in various ways, such as oral, parenteral, sublingual, rectal, topical, or by inhalation spray. Topical application may include the use of transdermal administration, such as transdermal patches or iontophoresis devices. Parenteral administration includes, but is not limited to, subcutaneous, intravenous, intramuscular or intrasternal injection or infusion methods.

The pharmaceutical compositions of the present invention can be prepared depending on their administration methods by methods well known in the art. For example, a sterile injectable preparation can be prepared as a sterile injectable aqueous or oily suspension using suitable dispersing or wetting agents and suspending agents. Suppositories for rectal administration can be prepared by mixing the drugs with a suitable, non-irritating excipient such as cocoa butter or polyethylene glycols that retain a solid form at normal temperature but become liquid at the rectal temperature and will thus melt in the rectum and release medicines. Solid dosage forms for oral administration may be capsules, tablets, pills, powders or granules. In such solid dosage forms, the active compounds can be mixed with at least one inert diluent, such as sucrose, lactose or starch. Solid dosage forms may also contain substances other than inert diluents, such as lubricants. In the case of capsules, tablets and pills, dosage forms may also contain buffering agents. Tablets and pills can additionally contain enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs containing inert diluents commonly used in the art. Liquid dosage forms may also contain wetting, emulsifying, suspending, sweetening, flavoring or perfume substances. The pharmaceutical compositions of the present invention may also be administered in the form of liposomes, as described in US Pat. No. 6,703,403. A pharmaceutical composition that can be used in the present invention refers to those described, for example, in Hoover, John E., REMINGTON'S PHARMACEUTICAL SCIENCES (Mack Publishing Co., Easton, PA: 1975), and Lachman, L., eds., PHARMACEUTICAL DOSAGE FORMS (Marcel Decker, New York, NY, 1980).

The present invention further relates to methods of using the compounds of the present invention (or their salts, solvates or prodrugs) to inhibit the replication of HCV. In one embodiment, the methods comprise contacting an HCV virus with an effective amount of a compound of the present invention (or a salt, solvate or prodrug thereof), thereby inhibiting the replication of the HCV virus. In another embodiment, the methods comprise contacting cells infected with the HCV virus with an effective amount of a compound of the present invention (or a salt, solvate or prodrug thereof), thereby inhibiting the replication of the HCV virus in cells. In yet another embodiment, the methods comprise contacting the HCV virus or infected cells with an effective amount of two or more of the compounds of the present invention (or their salts, solvates or prodrugs), thereby inhibiting the replication of the HCV virus. As used herein, the term "inhibition" means a significant reduction or decrease in inhibitory activity (eg, viral replication). In most cases, the representative compounds of the present invention can reduce the replication of the HCV virus (eg, in HCV replicon analysis as described above) by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more. or decrease, of inhibitory activity (eg, viral replication). In most cases, the representative compounds of the present invention can reduce the replication of the HCV virus (eg, in HCV replicon analysis as described above) by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more. or decrease, of inhibitory activity (eg, viral replication). In most cases, the representative compounds of the present invention can reduce the replication of the HCV virus (eg, in HCV replicon analysis as described above) by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more.

The compounds of the present invention can inhibit all subtypes of HCV. Examples of HCV subtypes that can be treated in accordance with the present invention include, but are not limited to, HCV genotypes 1, 2, 3, 4, 5 and 6, including the HCV genotypes 1a, 1b, 2a, 2b, 2c or 3a. In one embodiment, the compound or compounds of the present invention (or their salts, solvates or prodrugs) are used to inhibit HCV 1a genotype replication. In another embodiment, the compound or compounds of the present invention (or their salts, solvates or prodrugs) are used to inhibit HCV 1b genotype replication. In yet another embodiment, the compound or compounds of the present invention (or their salts, solvates or prodrugs) are used to inhibit the replication of both the HCV, 1a and 1b genotypes.

The present invention also relates to methods of using the compounds of the present invention (or their salts, solvates or prodrugs) for the treatment of HCV infection. These methods typically involve administering a therapeutically effective amount of a compound of the present invention (or a salt, solvate or prodrug thereof) to a patient with HCV, thereby reducing the level of HCV virus in the patient's blood or liver. As used herein, the term "treatment" refers to the treatment, reduction, inhibition of progress, or to the prevention of a disease or condition, or one or more symptoms of such disease or condition to which the term is applied. The term "treatment" refers to the act of treatment. In one embodiment, the methods comprise administering a therapeutically effective amount of two or more of the compounds of the present invention (or their salts, solvates or prodrugs) to a patient suffering from HCV, thereby reducing the level of the HVC virus in the patient's blood or liver. Preferably, the compound (s) used in these processes have Formula I (a), I (b), II (a), II (b) or selected from the compounds of Examples 1- 237, or represents their salt, solvate or prodrug thereof.

In another aspect, the present invention provides methods for using the pharmaceutical composition of the present invention for the treatment of HCV infection. For this purpose, any pharmaceutical composition described herein can be used. These methods typically involve administering a therapeutically effective amount of the pharmaceutical composition of the present invention to a patient suffering from HCV, thereby reducing the level of HCV virus in the patient's blood or liver. If the pharmaceutical composition comprises another therapeutic agent (s), then its action may also be directed to other diseases, disorders or conditions of the patient.

In one embodiment, the pharmaceutical composition to be administered contains at least one compound of the present invention selected from the formulas I (a), I (b), II (a), II (b) or from Examples 1-237, or a salt, solvate or prodrug thereof, and at least one further anti-HCV agent selected from inhibitors of RNA-dependent HCV RNA polymerase, HCV protease inhibitors or HCV helicase inhibitors. In another embodiment, the pharmaceutical composition to be administered comprises at least one compound of the present invention selected from the formulas I (a), I (b), II (a), II (b) or from Examples 1-237, or its salt, solvate or prodrug, and at least two further anti-HCV agents, each independently selected from inhibitors of RNA-dependent HCV RNA polymerase, HCV protease inhibitors or HCV helicase inhibitors. In yet another embodiment, the pharmaceutical composition to be administered comprises at least one compound of the present invention selected from the formulas I (a), I (b), II (a), II (b) or from Examples 1-237, or a salt, solvate or prodrug thereof and 1, 2 or more inhibitors of the RNA-dependent HCV RNA polymerase (eg, inhibitors described in WO0190121 (A2), US6348587B1, WO0160315, WO0132153, EP1162196A1 and WO0204425). In yet another embodiment, the pharmaceutical composition to be administered comprises at least one compound of the present invention selected from the formulas I (a), I (b), II (a), II (b) or Examples 1-237, or its salt, solvate or prodrug and 1, 2 or more HCV protease inhibitors (eg, BILN-2061, VX-950 and SCH503034). contains at least one compound of the present invention selected from the formulas I (a), I (b), II (a), II (b) or from Examples 1-237, or a salt, solvate or prodrug thereof, and 1, 2 or more inhibitors of the RNA-dependent HCV RNA polymerase (eg, the inhibitors described in WO0190121 (A2), US6348587B1, WO0160315, WO0132153, EP1162196A1 and WO0204425). In yet another embodiment, the pharmaceutical composition to be administered comprises at least one compound of the present invention selected from the formulas I (a), I (b), II (a), II (b) or Examples 1-237, or its salt, solvate or prodrug and 1, 2 or more HCV protease inhibitors (eg, BILN-2061, VX-950 and SCH503034). contains at least one compound of the present invention selected from the formulas I (a), I (b), II (a), II (b) or from Examples 1-237, or a salt, solvate or prodrug thereof, and 1, 2 or more inhibitors of the RNA-dependent HCV RNA polymerase (eg, the inhibitors described in WO0190121 (A2), US6348587B1, WO0160315, WO0132153, EP1162196A1 and WO0204425). In yet another embodiment, the pharmaceutical composition to be administered comprises at least one compound of the present invention selected from the formulas I (a), I (b), II (a), II (b) or Examples 1-237, or its salt, solvate or prodrug and 1, 2 or more HCV protease inhibitors (eg, BILN-2061, VX-950 and SCH503034). 2 or more inhibitors of RNA-dependent HCV RNA polymerase (eg, inhibitors described in WO0190121 (A2), US6348587B1, WO0160315, WO0132153, EP1162196A1 and WO0204425). In yet another embodiment, the pharmaceutical composition to be administered comprises at least one compound of the present invention selected from the formulas I (a), I (b), II (a), II (b) or Examples 1-237, or its salt, solvate or prodrug and 1, 2 or more HCV protease inhibitors (eg, BILN-2061, VX-950 and SCH503034). 2 or more inhibitors of RNA-dependent HCV RNA polymerase (eg, inhibitors described in WO0190121 (A2), US6348587B1, WO0160315, WO0132153, EP1162196A1 and WO0204425). In yet another embodiment, the pharmaceutical composition to be administered comprises at least one compound of the present invention selected from the formulas I (a), I (b), II (a), II (b) or Examples 1-237, or its salt, solvate or prodrug and 1, 2 or more HCV protease inhibitors (eg, BILN-2061, VX-950 and SCH503034).

In yet another embodiment, the pharmaceutical composition to be administered comprises at least one compound of the present invention selected from the formulas I (a), I (b), II (a), II (b) or from Examples 1-237, or a salt, solvate or prodrug thereof, and at least one antiviral agent selected from anti-HIV agents, anti-HBV agents, anti-hepatitis A, hepatitis D, hepatitis E or hepatitis G.

In a further aspect, the present invention relates to methods of using the compound (s) of the present invention and another therapeutic agent thereof for the treatment of HCV infection. The methods comprise administering a therapeutically effective amount of the compound (s) of the present invention and another therapeutic agent to the patient suffering from HCV, thereby reducing the level of the HVC virus in the blood or liver of the patient. Each compound of the present invention (or a salt, solvate or prodrug thereof) and the other therapeutic agent (s) may be combined into a common composition and administered to a patient simultaneously. They can also be administered simultaneously in different compositions. In addition, they can be entered sequentially.

In one embodiment, the compound (s) of the present invention include one or more compounds selected from the formulas I (a), I (b), II (a), II (b), or from examples 1-237, or a salt, solvate or prodrug thereof, and the other therapeutic agent (s) to be administered (s) comprises one or more agents selected from inhibitors of RNA-dependent HCV RNA polymerase inhibitors HCV proteases or HCV helicase inhibitors. In another embodiment, the compound (s) of the present invention include one or more compounds selected from the formulas I (a), I (b), II (a), II (b) or from Examples 1 -237, or a salt, solvate or prodrug thereof, and the other therapeutic agent (s) to be administered (a) comprises two or more agents selected from inhibitors of the RNA-dependent HCV RNA polymerase, HCV protease inhibitors or HCV helicase inhibitors. In yet another embodiment, the compound (s) of the present invention include one or more compounds selected from the formulas I (a), I (b), II (a), II (b) or Examples 1 -237 or their salts, solvates or prodrugs, and the other therapeutic agent (s) to be administered (a) includes one, two or more inhibitors of the RNA-dependent HCV RNA polymerase (eg, the inhibitors described in WO0190121 (A2), US6348587B1, WO0160315, WO0132153, EP1162196A1 and WO0204425). In yet another embodiment, the compound (s) of the present invention include one or more compounds selected from Formula I (a), I (b), II (a), II (b) or from Examples 1-237, or a salt, solvate or prodrug thereof, and the other therapeutic agent (s) to be administered (a) comprises one,

The compound of the present invention (or a salt, solvate or prodrug thereof) may also be co-administered with other desirable drugs, such as anti-HIV agents, anti-HBV agents, anti-hepatitis A, hepatitis D, hepatitis E, hepatitis G, or other antiviral drugs.

The compound of the present invention (or a salt, solvate or prodrug thereof) thereof may be administered to a patient in a unit dose or in divided doses. A typical daily dosage can vary, without limitation, from 0.1 to 200 mg / kg of body weight, for example, from 0.25 to 100 mg / kg of body weight. The unit dosage formulations may contain these amounts or their subunits to produce a daily dose. Preferably, each dose contains a sufficient amount of a compound of the present invention that effectively reduces the level of the HVC virus in the patient's blood or liver. The amount of active ingredient or active ingredients that is combined to form a single dosage form may vary depending on the recipient and the particular mode of administration. Clear,

In yet another embodiment, the compounds of the formulas I (a), I (b), II (a), II (b) or their pharmaceutically acceptable salts, stereoisomers or tautomers can be administered as an active pharmaceutical alone, or used in combination with one or more other agents, for the treatment of infections or symptoms mediated by other RNA-containing viruses.

Treatment or prophylaxis of an infection caused by RNA-containing viruses can be effected by a combination therapy comprising a therapeutically effective amount of the first antiviral agent, provided that one or more of the compounds or their salts are compounds of the formulas I (a), I (b), II ( a), II (b), together with a therapeutically effective amount of the second agent, provided that one or more compounds are selected from the group consisting of another antiviral agent; immune modulator of the recipient; an interferon derivative such as interferon-alpha, pegylated-interferon-alpha, interferon-beta and interferon-gamma; cytokine; vaccines; a nucleoside analogue; inhibitors of basic enzymes that lead to HCV dysfunction, examples of which are enzymes of the metalloprotease HCV, serine protease HCV, inosine monophosphate dehydrogenase (IMPDH) and helicikase HCV; protein inhibitors of viral particles, such as HCV NS4B protein and HCV NS5a protein; and agents that inhibit HCV function, such as HCV penetration, HCV assembly and HCV yield. Also included are vaccines containing HCV antigens, or combinations of antigens and adjuvants directed against HCV. In addition, they include agents that interact with host cell components and block the synthesis of viral proteins by inhibiting the internal ribosome planting site of the virus (IRES) initiating the HCV replication transfer stage, or by blocking the maturation and release of viral particles, directed to the proteins of the membrane of the viroporin family, such as, for example, HCV P7. such as HCV NS4B protein and HCV NS5a protein; and agents that inhibit HCV function, such as HCV penetration, HCV assembly and HCV yield. Also included are vaccines containing HCV antigens, or combinations of antigens and adjuvants directed against HCV. In addition, they include agents that interact with host cell components and block the synthesis of viral proteins by inhibiting the internal ribosome planting site of the virus (IRES) initiating the HCV replication transfer stage, or by blocking the maturation and release of viral particles, directed to the proteins of the membrane of the viroporin family, such as, for example, HCV P7. such as HCV NS4B protein and HCV NS5a protein; and agents that inhibit HCV function, such as HCV penetration, HCV assembly and HCV yield. Also included are vaccines containing HCV antigens, or combinations of antigens and adjuvants directed against HCV. In addition, they include agents that interact with host cell components and block the synthesis of viral proteins by inhibiting the internal ribosome planting site of the virus (IRES) initiating the HCV replication transfer stage, or by blocking the maturation and release of viral particles, directed to the proteins of the membrane of the viroporin family, such as, for example, HCV P7. or combinations of antigens and adjuvants directed against HCV. In addition, they include agents that interact with host cell components and block the synthesis of viral proteins by inhibiting the internal ribosome planting site of the virus (IRES) initiating the HCV replication transfer stage, or by blocking the maturation and release of viral particles, directed to the proteins of the membrane of the viroporin family, such as, for example, HCV P7. or combinations of antigens and adjuvants directed against HCV. In addition, they include agents that interact with host cell components and block the synthesis of viral proteins by inhibiting the internal ribosome planting site of the virus (IRES) initiating the HCV replication transfer stage, or by blocking the maturation and release of viral particles, directed to the proteins of the membrane of the viroporin family, such as, for example, HCV P7.

In one embodiment, the present invention provides a method of treating or preventing an infection caused by an RNA-containing virus comprising administering to the patient a therapeutically effective amount of a compound of the formulas I (a), I (b), II (a), II (b) or a pharmaceutically acceptable salt.

In another embodiment, the present invention provides a method of treating or preventing an infection caused by an RNA-containing virus comprising co-administering to a patient one or more agents selected from the group consisting of a recipient and a second antiviral immune modulator or a combination thereof and a therapeutically effective the amount of the compound of formulas I (a), I (b), II (a), II (b) or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention provides a method of treating or preventing an infection caused by an RNA-containing virus comprising co-administering to a patient one or more agents selected from the group consisting of interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamma, cytokine, vaccine and vaccine containing an antigen and an adjuvant and a second antiviral agent, or a combination thereof, with a therapeutically effective amount of a compound of formula I (a), I (b), II (a), II (b) or him a pharmaceutically acceptable salt.

In yet another embodiment, the present invention provides a method of treating or preventing an infection caused by an RNA-containing virus comprising co-administration to a patient of one or more agents selected from the group consisting of an immune modulator of the recipient and a second antiviral agent that inhibits HCV replication by inhibiting functions of the host cell associated with viral replication, or a combination thereof, with a therapeutically effective amount of a compound of the formulas I (a), I (b), II (a), II (b) or its pharmacist tically acceptable salt.

In another embodiment, the present invention provides a method of treating or preventing an infection caused by an RNA-containing virus comprising co-administering to a patient an agent or combination of agents for treating or reducing symptoms of HCV infection, including cirrhosis and inflammation of the liver, with a therapeutically effective amount of a compound of formulas I (a), I (b), II (a), II (b) or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides a method of treating or preventing an infection caused by an RNA-containing virus comprising co-administration to the patient of one or more agents that are effective for treating a patient with a disease caused by hepatitis B virus (HBV), together with a therapeutically effective amount compounds of the formulas I (a), I (b), II (a), II (b) or a pharmaceutically acceptable salt thereof.

In yet another embodiment, the present invention provides a method for treating or preventing an infection caused by an RNA-containing virus comprising co-administration to the patient of one or more agents that are effective for treating a patient with a disease caused by the human immunodeficiency virus (HIV), together with a therapeutically effective by the amount of a compound of the formulas I (a), I (b), II (a), II (b) or a pharmaceutically acceptable salt thereof.

The phrase "combination therapy" includes the administration of each agent in a sequential manner in a manner that provides a satisfactory effect from a combination of drugs, and also includes simultaneous administration of these agents at substantially the same time, for example by oral administration or by one capsule with a fixed ratio of these active agents or by taking sets of individual capsules of each agent. "Combination therapy" also includes co-administration or sequential administration by oral, intravenous, intramuscular or other parenteral route to the body, including direct absorption through the mucosa, for example sinus sinuses. Sequential administration also includes combinations of drugs in which individual agents can be administered at different times and / or in different ways,

The present invention also relates to the use of the compounds of the invention or pharmaceutically acceptable salts, solvates or prodrugs thereof for the preparation of medicaments for the treatment of HCV or other viral infections. In one embodiment, the present invention relates to the use of a compound of the present invention selected from the formulas I (a), I (b), II (a), II (b) or a salt, solvate or prodrug thereof for the manufacture of a medicament for the treatment HCV infection. In another embodiment, the present invention relates to the use of two or more compounds of the present invention (or salts, solvates or prodrugs thereof) for the manufacture of a medicament for the treatment of HCV infection, wherein each of two or more compounds is independently selected from the formulas I (a) , I (b), II (a), II (b).

In yet another embodiment, the present invention relates to the use of at least one compound of the present invention (or a salt, solvate or prodrug thereof) and at least one additional therapeutic agent for the preparation of a medicament for the treatment of HCV infection. Preferably, the compound (s) of the present invention is selected from the compounds of the formulas I (a), I (b), II (a), II (b), and the additional therapeutic agent (s) can be selected, for example, but without limitation, antiviral agents (eg, anti-HIV agents or other anti-HCV agents), immunomodulators, anti-cancer or chemotherapeutic agents, and anti-inflammatory drugs. Specific examples of other therapeutic agents include, but are not limited to, ribavirin; interferons (eg IFN alpha 2a or 2b); protease inhibitors; immunosuppressive agents; antibodies (eg, therapeutic monoclonal or chimeric antibodies); antisense or siRNA; HIV inhibitors; hepatitis B inhibitors (HBV); means for the treatment of cirrhosis and inflammation of the liver; IFN-omega (BioMedicines Inc., Emeryville, CA); BILN-2061, inhibitor of serine proteases (Boehringer Ingelheim Pharma KG, Ingelheim, Germany); Summetrel, an antiviral agent (Endo Pharmaceuticals Holdings Inc., Chadds Ford, PA); roferon, A IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); Pegasus, PEGylated IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); Pegasis and ribavirin, PEGylated IFN-alpha 2a / ribavirin (F. Hoffmann-La Roche LTD, Basel, Switzerland); CellCept, HCV IgG immunosuppressant (F. Hoffmann-La Roche LTD, Basel, Switzerland); welfiron, lymphoblastic IFN-alpha n1 (GlaxoSmithKline plc, Uxbridge, UK); albuferon-alpha, albumin IFN-alpha 2b (Human Genome Sciences Inc., Rockville, MD); levovirin, ribavirin (ICN Pharmaceuticals, Costa Mesa, CA); IDN-6556, an inhibitor of caspase (Idun Pharmaceuticals Inc., San Diego, CA); IP-501, antifibrotic agent (Indevus Pharmaceuticals Inc., Lexington, MA); actumun, INF-gamma (InterMune Inc., Brisbane, CA); Infergen A, IFN alfacon-1 (InterMune Pharmaceuticals Inc., Brisbane, CA); ISIS 14803, antisense oligonucleotides (ISIS Pharmaceuticals Inc., Carlsbad, CA / Elan Pharmaceuticals Inc., New York, NY); JTK-003, an inhibitor of RdRp (Japan Tobacco Inc., Tokyo, Japan); Pegasus and Conjugate, PEGylated IFN-alpha 2a / immune modulator (Maxim Pharmaceuticals Inc., San Diego, CA); clonal, immune modulator (Maxim Pharmaceuticals Inc., San Diego, CA); civacir, IgG IgV immunosuppressant (Nabi Biopharmaceuticals Inc., Boca Raton, FL); intron A and zadaxin IFN-alpha 2b / alpha 1-thymosin (RegeneRx Biopharmiceuticals Inc., Bethesda, MD / SciClone Pharmaceuticals Inc., San Mateo, CA); levovirin, an inhibitor of IMPDH (Ribapharm Inc., Costa Mesa, CA); viramidine, IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); heptazim, ribozyme (Ribozyme Pharmaceuticals Inc., Boulder, CO); intron A, IFN-alpha 2b (Schering-Plow Corporation, Kenilworth, NJ); PEG-intron, PEGylated IFN-alpha 2b (Schering-Plow Corporation, Kenilworth, NJ); rebetron, IFN-alpha 2b / ribavirin (Schering-Plow Corporation, Kenilworth, NJ); Ribavirin (Schering-Plow Corporation, Kenilworth, NJ); PEG-intron / ribavirin, PEGylated IFN-alpha 2b / ribavirin (Schering-Plow Corporation, Kenilworth, NJ); ask, immune modulator (SciClone Pharmaceuticals Inc., San Mateo, CA); rebif, IFN-beta 1a (Serono, Geneva, Switzerland); IFN-beta and EMZ701, IFN-beta and EMZ701 (Transition Therapeutics Inc., Ontario, Canada); T67, a beta-tubulin inhibitor (Tularik Inc., South San Francisco, CA); VX-497, an inhibitor of IMPDH (Vertex Pharmaceuticals Inc., Cambridge, MA); VX-950 / LY-570310, a serine protease inhibitor (Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and Co., Inc., Indianapolis, IN); omniferon, natural IFN-alpha (Viragen Inc., Plantation, FL); XTL-002, monoclonal antibody (XTL Biopharmaceuticals); Compound VX-950 (Vertex Pharmaceuticals Inc.); Compound SCH503034 (Schering-Plow Co.) and Compound GS9137 (Gilead Sciences, Inc., Foster City, CA). IFN-beta and EMZ701 (Transition Therapeutics Inc., Ontario, Canada); T67, a beta-tubulin inhibitor (Tularik Inc., South San Francisco, CA); VX-497, an inhibitor of IMPDH (Vertex Pharmaceuticals Inc., Cambridge, MA); VX-950 / LY-570310, a serine protease inhibitor (Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and Co., Inc., Indianapolis, IN); omniferon, natural IFN-alpha (Viragen Inc., Plantation, FL); XTL-002, monoclonal antibody (XTL Biopharmaceuticals); Compound VX-950 (Vertex Pharmaceuticals Inc.); Compound SCH503034 (Schering-Plow Co.) and Compound GS9137 (Gilead Sciences, Inc., Foster City, CA). IFN-beta and EMZ701 (Transition Therapeutics Inc., Ontario, Canada); T67, a beta-tubulin inhibitor (Tularik Inc., South San Francisco, CA); VX-497, an inhibitor of IMPDH (Vertex Pharmaceuticals Inc., Cambridge, MA); VX-950 / LY-570310, a serine protease inhibitor (Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and Co., Inc., Indianapolis, IN); omniferon, natural IFN-alpha (Viragen Inc., Plantation, FL); XTL-002, monoclonal antibody (XTL Biopharmaceuticals); Compound VX-950 (Vertex Pharmaceuticals Inc.); Compound SCH503034 (Schering-Plow Co.) and Compound GS9137 (Gilead Sciences, Inc., Foster City, CA). a serine protease inhibitor (Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and Co., Inc., Indianapolis, IN); omniferon, natural IFN-alpha (Viragen Inc., Plantation, FL); XTL-002, monoclonal antibody (XTL Biopharmaceuticals); Compound VX-950 (Vertex Pharmaceuticals Inc.); Compound SCH503034 (Schering-Plow Co.) and Compound GS9137 (Gilead Sciences, Inc., Foster City, CA). a serine protease inhibitor (Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and Co., Inc., Indianapolis, IN); omniferon, natural IFN-alpha (Viragen Inc., Plantation, FL); XTL-002, monoclonal antibody (XTL Biopharmaceuticals); Compound VX-950 (Vertex Pharmaceuticals Inc.); Compound SCH503034 (Schering-Plow Co.) and Compound GS9137 (Gilead Sciences, Inc., Foster City, CA).

In yet another embodiment, the present invention relates to the use of at least one compound of the present invention selected from Formula I (a), I (b), II (a), II (b) (or a salt, solvate or prodrug thereof ), and at least one anti-HIV agent for the preparation of a medicament for the treatment of HIV or HCV infection. In yet another embodiment, the present invention relates to the use of at least one compound of the present invention selected from the formulas I (a), I (b), II (a), II (b) (or a salt, solvate or prodrug thereof) , and at least one agent for hepatitis A, hepatitis B, hepatitis D, hepatitis E or hepatitis G for the preparation of a medicament for the treatment of viral hepatitis.

The foregoing description of the present invention is given only for illustration and description and is not exhaustive or limiting of the invention in practice. Modifications and changes are possible in light of the information described or can be found in the practice of the invention. Therefore, it should be noted that the scope of the invention is defined by the claims and equivalent objects.

Every citation, both waysCites: the store holds 4 of 5

Citations
Document	Relation	Office	Cited during
US11739073B2	Cited by	United States of America	Applicant
WO2005007652A	Cites	World Intellectual Property Organization (WIPO)	–
WO9313097A	Cites	World Intellectual Property Organization (WIPO)	–
WO9500511A	Cites	World Intellectual Property Organization (WIPO)	–
WO2005047288A	Cites	World Intellectual Property Organization (WIPO)	–

73 members in 18 offices

This recordMember, by publication datePriority claim8 more offices are in the list below

Priority claims10

Priority claims
Document	Office	Kind	Date
60752473	United States of America	–	2005-12-21
75247305	United States of America	P	2005-12-21
75247305	United States of America	P	2005-12-21
11613836	United States of America	–	2006-12-20
61383606	United States of America	A	2006-12-20
61383606	United States of America	A	2006-12-20
11613836	–	–	–
60752473	–	–	–
US20050752473P	–	–	–
US20060613836	–	–	–

Members73

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AU2006330924A1	Australia	A1	2007-07-05
CA2633757A1	Canada	A1	2007-07-05
CA2633760A1	Canada	A1	2007-07-05
WO2007076034A2	World Intellectual Property Organization (WIPO)	A2	2007-07-05
WO2007076035A2	World Intellectual Property Organization (WIPO)	A2	2007-07-05
CA2633752A1	Canada	A1	2007-07-19
WO2007081517A2	World Intellectual Property Organization (WIPO)	A2	2007-07-19
US2007197558A1	United States of America	A1	2007-08-23
WO2007081517A8	World Intellectual Property Organization (WIPO)	A8	2007-09-20
US2007232627A1	United States of America	A1	2007-10-04
US2007232645A1	United States of America	A1	2007-10-04
WO2007076034A3	World Intellectual Property Organization (WIPO)	A3	2007-10-04
WO2007076035A3	World Intellectual Property Organization (WIPO)	A3	2007-10-04
TW200738707A	Taiwan Province of China	A	2007-10-16
TW200745107A	Taiwan Province of China	A	2007-12-16
WO2007081517A3	World Intellectual Property Organization (WIPO)	A3	2007-12-21
TW200800991A	Taiwan Province of China	A	2008-01-01
TW200831513A	Taiwan Province of China	A	2008-08-01
KR20080080395A	Republic of Korea	A	2008-09-03
EP1971611A1	European Patent Office (EPO)	A1	2008-09-24
EP1979348A2	European Patent Office (EPO)	A2	2008-10-15
EP1979349A2	European Patent Office (EPO)	A2	2008-10-15
CA2672737A1	Canada	A1	2008-11-06
WO2008133753A2	World Intellectual Property Organization (WIPO)	A2	2008-11-06
WO2008133753A3	World Intellectual Property Organization (WIPO)	A3	2008-12-24
IL192306A0	Israel	A0	2008-12-29
CN101384591A	China	A	2009-03-11
CN101384592A	China	A	2009-03-11
HK1122291A	Hong Kong, China	A	2009-05-15
HK1122291A1	Hong Kong, China	A1	2009-05-15
HK1122292A	Hong Kong, China	A	2009-05-15
CN101443334A	China	A	2009-05-27
JP2009521460A	Japan	A	2009-06-04
JP2009521479A	Japan	A	2009-06-04
JP2009521480A	Japan	A	2009-06-04
EP2094276A2	European Patent Office (EPO)	A2	2009-09-02
RU2008129782A	Russian Federation	A	2010-01-27
RU2008129810A	Russian Federation	A	2010-01-27
RU2008129807A	Russian Federation	A	2010-02-20
BRPI0620440A2	Brazil	A2	2010-06-29
US7763731B2	United States of America	B2	2010-07-27
EP1979349B1	European Patent Office (EPO)	B1	2010-07-28
AT475660T	Austria	T	2010-08-15
ATE475660T1	Austria	T1	2010-08-15
DE602006015861D1	Germany	D1	2010-09-09
US2010256139A1	United States of America	A1	2010-10-07
ES2348557T3	Spain	T3	2010-12-09
EP2094276A4	European Patent Office (EPO)	A4	2011-01-05
US7910595B2	United States of America	B2	2011-03-22
US7915411B2	United States of America	B2	2011-03-29
US2011160233A1	United States of America	A1	2011-06-30
EP2345652A1	European Patent Office (EPO)	A1	2011-07-20
NZ569817A	New Zealand	A	2011-10-28
ZA200805418B	South Africa	B	2011-12-28
EP1979348B1	European Patent Office (EPO)	B1	2012-01-18
ZA200805304B	South Africa	B	2012-01-25
RU2441010C2	Russian Federation	C2	2012-01-27
RU2441869C2	Russian Federation	C2	2012-02-10
AT541844T	Austria	T	2012-02-15
ATE541844T1	Austria	T1	2012-02-15
AU2006330924B2	Australia	B2	2012-03-15
ES2378473T3	Spain	T3	2012-04-12
ZA201107667B	South Africa	B	2012-07-25
US8236950B2	United States of America	B2	2012-08-07
CN102702193A	China	A	2012-10-03
CN102702194A	China	A	2012-10-03
EP1971611B1	European Patent Office (EPO)	B1	2012-10-10
RU2467007C2This record	Russian Federation	C2	2012-11-20
US8338605B2	United States of America	B2	2012-12-25
ES2395386T3	Spain	T3	2013-02-12
TWI392676B	Taiwan Province of China	B	2013-04-11
TWI392677B	Taiwan Province of China	B	2013-04-11
TWI399380B	Taiwan Province of China	B	2013-06-21

[1,8]naphthyridine derivatives, useful as inhibitors of hcv virus replication

Abstract

Term

TECHNICAL FIELD OF THE INVENTION

Priority claims10

Members73

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Titles3

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