MX2008008164A - Anti-viral compounds - Google Patents

Abstract

Compounds effective in inhibiting replication of Hepatitis C virus ("HCV") or other viruses are disclosed. This invention is also directed to compositions comprising such compounds, co-formulation or co-administration of such compounds with other anti-viral or therapeutic agents, processes and intermediates for the syntheses of such compounds, and methods of using such compounds for the treatment of HCV or other viral infections.

Description

ANTI-VIRAL COMPOUNDS This application claims the benefit and incorporates here by reference all the content of the Provisional Application of E. U .A. Do not . 60 / 752,473, filed on December 21, 2005.

CAM PO OF THE I NVE NCION The present invention relates to compounds effective to inhibit the replication of the Hepatitis C virus ("HCV"). The present invention also relates to methods for making said compounds, compositions comprising said compounds, intermediates for the synthesis of said compounds, and methods for using said compounds / compositions for the treatment of HCV infection or conditions / symptoms associated with the same. In addition, the present invention relates to the use of said compounds for the manufacture of medicaments for the treatment of HCV infection.

ANTECE DENTS HCV, a human pathogen, is an RNA virus that belongs to the genus Hepacivirus in the Flaviviridae family. As is characteristic of all other members of the Flaviviridae family, HCV has enveloped virions containing an RNA genome of positive strand structure that encodes all virus-specific proteins in an open, uninterrupted, individual reading frame. . The open reading frame comprises approximately 9500 nucleotides encoding a large, single polyprotein of about 3000 amino acids. The polyprotein comprises a core protein, E1 and E2 envelope proteins, a membrane bound pl protein, and the nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B. A cellular protease cleaves the viral protein at the NS2-NS3 junction allowing a viral protease (NS3 protease) to mediate segmentations or subsequent cleavages. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. NS5A is a phosphoroprotein involved in repiication. NS5B is an RNA-dependent RNA polymerase. The Patent Publication of E. U.A. No. 2004/0265792, published on December 30, 2004, mentions that the inhibition of the aforementioned nonstructural proteins can inhibit the repiication of HCV.

HCV infection is associated with progressive liver pathology, including cirrhosis and hepatocellular carcinoma. End-stage liver disease associated with HCV is the most common indication for liver transplantation among adults. Chronic hepatitis C can be treated with an injection, once a week, of peginterferon-alpha in combination, daily, with ribavarin. Peginterferon-alpha is interferon-alpha linked to polyethylene glycol to reduce the elimination of the drug from the body. This results in improved adherence and clinically superior anti-viral activity when compared to daily interferon-alpha injections. Substantial limitations remain in efficacy and tolerability since many users suffer from side effects and viral elimination from the body is usually inadequate. Attempts have been made to design drugs that specifically inhibit the functions of the hepatitis C virus. Boehringer Ingelheím, patent of E. U.A. No. 6,323, 180 mentions tri-peptide compounds as inhibitors of HCV serine protease proposed for the treatment of HCV infection. Another aspect is ISIS-14803 (Isis Pharmaceuticals), an antisense inhibitor complementary to a conserved sequence of the hepatitis C virus RNA. This molecule binds to the viral RNA and inhibits the expression of proteins required for replication. Inhibition of HCV translation, through yeast RNA that binds to cellular polypeptides and prevents their interaction with the viral internal ribosome entry site (I RES), is described in Das et al, J. VIROLOGY, 72 (7): 5638-5647 (1,998). Heterocyclic, bicyclic, fused compounds have been proposed for various uses related to life-science. Examples of such heterocyclic compounds include naphthyridine compounds, pyridopyrimidine, pyrimidopyrimidine, pyrazolopyrimidine and thiazolo / thienopyrimidine. Fused bicyclic compounds of the naphthyridine type have been investigated for disease treatment uses. For example, Boots WO 93/1 3097, published July 8, 1993, mentions compounds [1,8] naphthyridine, such as 4- (4-mxyanilino) -6-xy-7-ml-1, 8- l naphthyridine-3-carboxylate-hydrochloride, proposed for use as anti-rheumatic agents. Boots WO 95/0051 1, published January 5, 1995, mentions fused ring 4-aminopyridines, such as 3-xy-5- (2-xy-5-pyridylamino) -2-ml- 1, 8- naphthyridine, proposed as anti-rheumatic agents. Zeneca WO 98/1 3350, published on April 2, 1998, mentions compounds [1, 8] naphthyridine, such as 2-acetamido-5- (2-fluoro-5-hydroxy-4-mlanilino) -l hydrochloride, 8-naphthyridine, proposed as anti-angiogenic agents. Neurogen WO 2004/055004, published on July 1, 2004, mentions naphthyridine compounds as capsaicin receptor modulators, the specific compounds being 5- (4-trifluoroml-phenylamino) -2- (3-trifluoroml-pyrid in -2-il) - [1, 6] naphthyridine-7-carboxylic acid, and 2-mxyml-4- (4-trifluoroml-phenylamino) -7- (3-trifluoroml-pyridin-2-yl) - [1, 8] naphthyridine-3-carboxylic acid. Fused bicyclic compounds of the pyridopyrimidine type have been investigated for various uses of disease treatment. For example, Pfizer WO 98/05661, published on February 12, 1,998, mentions substituted pyridopyrimidine compounds, such as 8- (1-l-propyl) -2-ml-5,6,7,8-tetrahydro-pyrido. (2, 3-d) pyrimidin-4-yl] - (2,4,6-triml-phenyl) -amine, as antagonists of CRF (hormone) (CRH) corticotrophin-releasing factor proposed for the treatment of Disease of Alzheimer's and obesity. Pfizer WO 98/2361 3, published June 4, 1998, mentions bicyclic-fused pyrimidine compounds, including pyridopyrimidinyl-aminophenyl compounds, such as (3-nyl-phenyl) -pyrido [3,4-d] pyrimidine- 4-yl-amine, proposed for the treatment of proliferative diseases such as cancer. Glaxo Wellcome Patent of E. U.A. No. 6,169,091, issued January 2, 2001, mentions heteroaromatic bicyclic compounds, such as 4- (4-benzyloxyanilino) pyrido [2,3-d] -pyrimidine, as inhibitors of tyrosine kinase for the treatment of fibrosis, inflammation, diseases of the nervous system and cancer. Eli Lilly WO 01/32632, published May 1, 2001, mentions 4-substituted pyrimidine compounds, including 2-trifluoroml-4- [2- (2- (2-chlorophenyl) lamino] pyrido- [2] hydrochloride. , 3-d] pyrimidine, as mGluRI antagonists proposed for the treatment of neurological disorders associated with glutamate dysfunction such as seizures, migraine, psychosis, anxiety and pain Abbott Laboratories WO 01/57040, published August 9, 2001, mentions 6,7-disubstituted 4-aminopyrido [2,3-d] pyrimidine compounds, such as 4-amino-6- (4-mlphenyl) -7- (4-bromophenyl) pyrido [2,3-d] pyrimidine, as adenosine kinase inhibitors proposed for the treatment of pain and inflammation Neurogen WO 2004/055004, published on July 1, 2004, mentions pyridopyrimidinyl-aminophenyl compounds, such as 2-ml-2-. {4- l2-ml-7- (3-ml-pyridin-2-yl) -pyrido [2,3-d] pyrimidin-4-ylamino] -phenyl} -propionic acid, as capsaicin receptor modulators. Pfizer patent of E. U.A. No. 6, 395,733, issued May 28, 2002, mentions heterocyclic fused ring pyrimidine compounds, such as 3-chloro-phenyl-pyrido [2,3-d] pyrimidin-4-yl-amine, proposed for the treatment of hyperproliferative disease, such as cancer. Fused bicyclic compounds of the pirimidopyrim idine type have been investigated both for the control of pests and for disease treatment uses. For example, Dow Elanco, Patent of E. U .A. No. 5, 350,749, issued September 27, 1994, mentions pyrimido compounds [2, 4-substituted pyrimidine 3-d-pyrimidine for use as fungicides, insecticides and mycides. Warner-Lambert WO 95/1 9774, published July 27, 1995, mentions pyrimidopyrimidine compounds, such as 4-benzyl-7-methylamine and nopyrimido [4,5-d] pyrimidine, as inhibitors of Tyrosine kinase proposed for the treatment of cancer, vascular restenosis and psoriasis. Fused bicyclic compounds of the thienopyrimidine type have been investigated for various uses in the treatment of diseases. For example, Warner-Lambert WO 95/1 9774, published July 27, 1995, mentions heterocyclic fused pyrimidine compounds, including 4- (3-bromoanilino) thieno [2,3-d] pyrimidine, as kinase inhibitors. of tyrosine proposed for the treatment of cancer, vascular restenosis and psoriasis. Glaxo Wellcome, Patent of E. U.A. No. 6, 169,091, issued January 2, 2001, mentions heteroaromatic bicyclic compounds, such as 5-methyl-4- (4-phenoxyanilino) thieno [2,3-d] pyrimidine hydrochloride as inhibitors of tyrosine kinase, proposed for the treatment of fibrosis, inflammation, diseases of the nervous system and cancer. Eli Lilly WO 01/32632, published May 1, 2001, mentions 4-substituted pyrimidine compounds, such as 6-methyl-4- [2,6-dichlorobenzylthio) ethylamino] -thieno hydrochloride [2, 3- d] pirim idine, as mGluR I antagonists for the treatment of neurological disorders associated with glutamate dysfunctions such as seizures, migraine, psychosis, anxiety and pain. Bristol-Myers Squibb WO 2004/014852, published on 1 9 February 2004, mentions iminothiazolidinones, including bicyclic fused derivatives of 2- (4-aminophenyl) -5H-thiazolo [2, 3-6] quinazolin-3-one, as NS5A protein inhibitors proposed to prevent HCV replication. Bristol-Myers Squibb WO 2004/01431 3, published on 1 9 February 2004, mentions combination therapies for the treatment of viral diseases, including iminothiazolidinone, anti-HCV compounds that inhibit NS5A protein in combination with other agents capable of interfering with HCV function.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds having Formulas l (a), l (b), 11 (a) or ll (b), tautomers of these compounds, and pharmaceutically acceptable salts of these compounds or tautomers. These compounds, tautomers or salts can be used, either individually 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, either individually or in combination with other drugs or agents, to interrupt the functions of HCV or other viruses. The present invention also relates to compositions comprising the compounds, tautomers or salts of the present invention. A composition of the present invention may include one or more compounds, tautomers or salts of the present invention. A composition of the present invention may also include one or more anti-viral or therapeutic agents. In addition, the present invention relates to methods for using the compounds, tautomers or salts of the present invention, or compositions comprising them, to inhibit the replication of HCV or other viruses. These methods comprise contacting HCV or other virus, or cells infected with HCV or other virus, with an effective amount of a compound, tautomer or salt of the present invention, thereby inhibiting the replication of HCV or another virus. The present invention also relates to methods for using the compounds, tautomers or salts of the present invention, or compositions comprising them, to inhibit the proliferation or transmission of HCV or other viruses. These methods comprise contacting HCV or other viruses, or contacting cells infected with HCV or other viruses, with an effective amount of a compound, tautomer or salt of the present invention, thereby inhibiting the proliferation or transmission of HCV or other viruses. . In addition, the present invention relates to methods for using the compounds, tautomers or salts of the present invention, or compositions comprising them, for treating HCV or other viral infections. These methods comprise administering to a patient in need of such treatment, an effective amount of a compound, tautomer or salt of the present invention, thereby reducing the level of HCV or other viruses in the blood or tissue in the patient. The present invention also relates to the uses of the compounds, tautomers or salts of the present invention for the manufacture of medicaments for the treatment of HCV or other viral infections. In addition, the present invention relates to methods for making the compounds, tautomers or salts of the present invention, and intermediates employed in these processes. Other aspects, objects and advantages of the present invention are evident in the detailed description that follows. However, it should be appreciated that the detailed description, while indicating preferred embodiments of the present invention, is provided only by way of illustration, and not limitation. Various changes and modifications within the scope of the invention will be apparent to those skilled in the art from the detailed description.

DETAILED DESCRIPTION The following description is illustrative in nature and is not intended to limit the present description, application, or uses.

Compounds The present invention relates to compounds having Formulas 1 (a) or 1 (b), tautomers of the same, and pharmaceutically acceptable salts of the compounds or tautomers, where: Z is -N R41-; A is a carbocyclyl or heterocyclyl, and is optionally substituted with one or more of R 1 8, wherein R 1 8 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORS l -LS-N (RSRS |), -Ls-C (= N RS) RS. -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls-N (Rs) C (0) Rs., -Ls-C (= NRs) N ( Rs Rs-), -LS-N (RS) C (= NRS) RS. -Ls-N (Rs) C (0) N (Rs Rs), -Ls-N (Rs) S02Rs, -Ls-S02N (RsRs.) | And -Ls-N (Rs) S02N (Rs Rs-); R1 0, R17, R31, R33, R35 and R41 are independently selected at each occurrence from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl , alkenyl, alkynyl, carbocyclyl, heterocyclyl, -Ls-O-Rs, -Ls-S-Rs. - Ls-C (0) Rs. -Ls-OC (0) Rs. -Ls-C (0) ORs, - -N (RsRs), -Ls-C (= NRs) Rs -, -LS-S (0) RS, -Ls-S02Rs. -Ls-C (0) N (RsRs), -Ls-N (Rs) C (0) Rs, -Ls-C (= NRs) N (Rs Rs'), -Ls- N (RS) C (= N RS) RS-. -Ls-N (Rs) C (0) N (Rs Rs), -Ls-N (Rs) S02Rs -, -Ls-S02N (RsRs), -Ls-N (Rs) S02N (Rs Rs), -LE -Q-LE - (C3-C8 carbocyclyl) and -LE-Q-LE - (heterocyclyl of M3-M18); X is selected from the group consisting of a bond, -Ls-0-, -Ls-S-, -Ls-C (O) -, -LS-N (RS) -, - Ls-N (Rs) C ( 0) -, -Ls-C (0) N (Rs) -, -Ls-N (Rs) C (0) 0-, -Ls-OC (0) N (Rs) -Ls-N (Rs) C (0) N (Rs) -, -Ls-C (= NRS) N (RS) -. -Ls-N (RS) C (= NRS) -. -Ls-S (0) -, -Ls-S02-, -Ls-C (0) 0-and -Ls-OC (0) -; R22 is carbocyclyl or heterocyclyl, and is optionally substituted with one or more of R26, wherein R26 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl , phosphate, azido, alkyl, alkenyl, alkynyl, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -l_s-OC (0) Rs. -Ls-C (0) ORs, -LS-N (RSRS |). -Ls-C (= NRs) Rs, -Ls-S (0) Rs > -LS-S02RS, -LS-C (0) N (RSRS). -Ls-N (Rs) C (0) Rs-, -Ls-C (= NRS) N (RS Rs-), -LS-N (RS) C (= NRS) RS ·. -Ls-N (Rs) C (0) N (Rs Rs), -Ls-N = C (NRsRs) (NRsRs). -Ls-N (Rs) S02RS, 1 -Ls-S02N (RSRs), -Ls-N (Rs) S02N (Rs Rs ·), - LE-Q-LE- (carbocyclyl of C3-Cie) and -LE- Q-LE - (3-M18 heterocyclyl); or R22 is alkyl, alkenyl or alkynyl, and is optionally substituted with one or more of R26; or R22 is hydrogen; And it is selected from the group consisting of a bond, -O-, -C (O) -, -S (0) 2-, -S (O) -. -OS (0) 2-, - OS (O) -, -C (0) 0-, -OC (O) -. -OC (0) 0-, -C (0) N (R15) -, -N (R15) C (0), -C (0) N (R15) 0-, - N (R1) C (0) 0-, -C (0) N (R15) N (R15), -S-, -C (S) -. -C (S) 0-, -OC (S) -, -C (S) N (R1S), -N (R15) -, -N (R5) C (S) -, -N (R15) S (0) -, -N (R15) S (0) 2-, -S (0) 2N (R15) -, S (0) N (R15), -C (S) N (R15) 0-, and -C (S) N (R1S) N (R15 ') -, wherein R15 and R1S are independently selected at each occurrence from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; R50 is -L1-A1, wherein 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 is optionally substituted with one or more of R30, and R30 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl , -Ls-0-Rs > -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs. -Ls-C (0) ORs, -LS-N (RSRS), -Ls-C (= N RS) RS -. -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls-N (Rs) C (0) Rs, -Ls-C (= NRS) N (RS) RS ..), -Ls-N (Rs) C (= NRs) Rs-. -Ls-N (RS) C (0) N (RS'-Rs), -LS-N (RS) S02RS'-, -LS-S02N (RsRs), -LS-N (RS) S02N (RS RS) ), -LE-Q-LE - (carbocyclyl of C3-C1 8) and -LE-Q-LE - (heterocyclyl of M3-M | 8), and wherein L1 is optionally substituted with one or more of R38, and R38 is independently selected at each occurrence 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-O-Rs -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -Ls-N (RsRs), - Ls-C (= NRs) Rs', -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls-N (Rs) C (0) Rs, - Ls-C (= NRs) N (Rs Rs), -LS-N (RS) C (= N RS) RS, -Ls-N (Rs) C (0) N (Rs Rs "). -Ls-N (Rs) S02Rs. -Ls-S02N (RsRs), -Ls-N (Rs) S02N (Rs-Rs "). Carbocyclyl, heterocyclyl, carbocyclylalkyl, heterocyclylalkyl, -LE-Q-LE - (carbocyclyl of C3-C1 8) and - LE- Q-LE - (heterocyclyl of M3-M1 8); Ls is independently selected at each occurrence of the group consisting of a bond, alkylene, alkenylene and alkynylene; Rs. Rs and s are independently selected at each occurrence from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, alkoxyalkyl, akoxyalkoxyalkyl, thioalkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylamino, alkylaminoalkyl, alkoxycarbonylamino and alkoxycarbonylaminoalkyl; LE and LE- are independently selected at each occurrence of the group consisting of a bond, alkylene, alkenyl, alkynylene, -alkylene-O-alkylene-, alkylene-S-alkylene, -alkylene-NC (0) -alkylene , and alkylene-C (0) N-alkylene; Q is independently selected at each occurrence from the group consisting of a bond, alkylene, alkenylene, alkylene, -S-, -O-, -C (O) -, -N (Rs) -, -N (Rs) C (0), -C (0) N (RS) -, - N (Rs) C (0) 0-, -OC (0) N (Rs) -. -N (Rs) C (0) N (Rs) -. -C (= NRS) N (RS) -, -N (RS) C (= NRS) -, -S (O) -, -SOz-, -O-SO2-, -S02-0-, -OS ( O), -S (0) -0-, -C (0) 0- and -OC (O); R1 0, R1 5, R1 5, R17, R1 8, R2e, R30, R31, R33, R35, R38, and R41 are independently optionally substituted in each occurrence 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 each carbocyclyl portion of C3-C1-8 and heterocyclyl of M3-M8 in-LE-Q-LE- (carbocyclyl of C3-C18) and -LE-Q-LE- (heterocyclyl of M3- M18) is independently optionally substituted in each occurrence with at least one substituent selected from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl, alkylcarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl, alkylamino, alkylaminoalkyl, alkoxycarbonylamino, carbocyclyloxy, heterocyclyloxy, carbocycloalkoxy, heterocycloalkoxy, carbocicloalcoxicarbonilo, heterocycloalkoxycarbonyl, and alkoxycarbonylaminoalkyl. In one embodiment, the present invention relates to compounds having Formula 1 (a) or 1 (b), their tautomers, and pharmaceutically acceptable salts of the compounds or tautomers, wherein: Z is -NR41-; A is a carbocyclyl or heterocyclyl, and is optionally substituted with one or more of R 1 8, wherein R 8 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, Ci-Ce alkyl, C2-Ce alkenyl, C2-Ce alkynyl, -Ls-O-Rs, -Ls-S-Rs, -Ls-C (0) Rs, - Ls-OC (0) Rs, -Ls-C (0) ORs, -LS-N (RSRS), -LS-C (= NRS) RS, -Ls-S (0) Rs, -Ls-S02Rs, - Ls-C (0) N (RsRs), -Ls- N (Rs) C (0) Rs, -LS-C (= NRS) N (RS Rs). -Ls-N (Rs.) C (= NRs) Rs. -Ls-N (Rs) C (0) N (Rs Rs), -Ls-N (Rs) S02Rs, -Ls-S02N (RsRs). -Ls-N (Rs) S02N (Rs Rs); R 0, R 17, R 31, R 33, R 35 and R 41 are independently selected at each occurrence from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl of Ci-C6, C2-C6 alkenyl, C2-C6 alkynyl, C3-Ce carbocyclyl, M3-Me heterocyclyl, -Ls-0-Rs, -Ls-S-Rs, - Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -LS-N (RSRS), -Ls-C (= NRS) RS -Ls-S (0) Rs, -Ls-S02Rs , -Ls-C (0) N (RsRs |). -Ls-N (Rs) C (0) Rs, -Ls-C (= N Rs) N (Rs Rs), -Ls- N (RS) C (= N RS) RS ··. -Ls-N (Rs) C (0) N (Rs Rs), -Ls-N (Rs) S02Rs-, -Ls-S02N (RsRs-), -Ls-N (Rs) S02N (Rs Rs ··) . -LE-Q-LE- (C3-C8 carbocyclyl) and -LE-Q-LE- (3-M1 heterocyclyl 8); X is selected from the group consisting of a link, -Ls-0-, -Ls-S-, -Ls-C (0) -, -Ls-N (Rs) -, - Ls-N (Rs) C (0) -, -Ls-C (0) N (Rs) -, -Ls-N (Rs) C (0) 0-, -Ls-OC (0) N (Rs) -Ls-N (Rs) C (0) N (Rs) -, -Ls-C (= NRs) N (Rs) -. -Ls-N (Rs) C (= NRs) -. -Ls-S (0) -, -Ls-S02-, -Ls-C (0) 0-and -Ls-OC (O) -; R22 is carbocyclyl, heterocyclyl, carbocyclylalkyl of C-C or heterocyclylalkyl of Ci-C6, and is optionally substituted with one or more of R26, wherein R26 is independently selected in each occurrence of the group consisting of halogen, oxo, thioxo, hydroxy , mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C, -Ca alkyl, C2-C6 alkenyl, C2-Ce alkynyl, -Ls-O-Rs, -Ls-S-Rs , -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -LS-N (RSRS), -Ls-C (= NRs) Rs. -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls-N (Rs) C (0) Rs, -Ls-C (= NRs) N (Rs) Rs), -Ls-N (Rs.) C (= NRs) Rs, -Ls-N (Rs) C (0) N (Rs.Rs ..). -Ls-N = C (NRsRs.) (NRsRs), -Ls-N (Rs) S02RS \ -Ls-S02N (RSRs), -Ls-N (Rs) S02N (Rs Rs), - LE-Q-LE - (C3-Ci8 carbocyclyl) and -LE-Q-LE - (heterocyclyl of M3-M8); or R22 is ?? -? - alkyl, C2 - C6 alkenyl, or C2 - Ce alkynyl, and is optionally substituted with one or more of R26; or R22 is hydrogen; And it is selected from the group consisting of a bond, -Ls-0-, -Ls-C (0) -, -Ls-S (0) 2-, -Ls-S (O) -, -Ls-OS ( 0) 2-, -Ls-OS (0) -, -Ls-C (0) 0, -Ls-OC (O) -, -Ls-OC (0) 0-, -Ls-C (0) N (R1 5) -, -Ls-N (R1 5) C (0), -Ls-C (0) N (R1 5) 0-, -Ls-N (R1 5) C (0) 0-, - Ls-C (0) N (R1 5) N (R1 5), -Ls-S-, -Ls-C (S) -, -Ls-C (S) 0-, -Ls-OC (S) - , -LS-C (S) N (R1 5), -LS-N (R1 5) -, -LS-N (R1 5) C (S) -, -Ls-N (R15) S (0) - , -Ls-N (R1 5) S (0) 2-, -Ls-S (0) 2N (R15) -, -Ls-S (0) N (R1 5), -Ls-C (S) N (R1 5) 0-, and -LS-C (S) N (RS) N (R1 5 ') -, wherein R1 5 and R1 5 are independently selected at each occurrence of the group consisting of hydrogen, Ci alkyl -Ce, C2-Ce alkenyl, and C2-C3 alkynyl; R50 is -L1-A1, wherein 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 is optionally substituted with one or more of R30, and R30 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C-alkyl, C6, alkenyl of C2-Ce, alkynyl of C2-Ce, -Ls-O-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -Ls-N (RSRs), -LS-C (= N RS) RS -, -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs) , -Ls- N (Rs) C (0) Rs, -LS-C (= NRS) N (RS Rs). -Ls-N (Rs) C (= NRs) Rs. -Ls-N (RS) C (0) N (RS -Rs), -LS-Nf RSJSOzRS1-, - LS-S02N (RsRs |), -LS-N (RS) S02N (RS RS "), -LE -Q-LE - (carbocyclyl of C3-C1 8) and -LE-Q-LE - (heterocyclyl of M3-M | 8), and wherein L1 is optionally substituted with one or more of R38, and R38 is independently selected in each occurrence of the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, d-C6 alkoxy, d-C6 thioalkoxy, Ci-Ce alkylcarbonyl, CrC6 alkoxycarbonyl Ct-C6 alkylcarbonyloxy, d-C6 alkylamino, d-C6 alkoxycarbonylamino, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC ( 0) Rs, -Ls-C (0) ORs, -LS-N (RSRS ·), -Ls-C (= NRs) Rs, -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls-N (Rs) C (0) Rs, -Ls-C (= NRs) N (Rs Rs). -LS-N (RS) C (= NRS) RS, - Ls-N (Rs) C (0) N (Rs Rs "). -Ls-N (Rs) S02Rs, -Ls-S02N (RsRs). -Ls-N (Rs) S02N (Rs Rs "). Carbocyclyl, heterocyclyl, carbocyclylalkyl of Ci-C6, heterocyclylalkyl of Ci-Ce, -LE-Q-LE - (carbocyclyl of C3-C18) and - LE-Q- LE- (heterocyclyl of M3- 1 8); Ls is independently selected in each occurrence of the group consisting of a bond, alkylene of d-Ce, alkenylene of C2-C6 and alkynylene of C2-C6; Rs. Rs and Rs are independently selected in each occurrence of the group consisting of hydrogen, Ci-C6 alkyl, C2-Ce alkenyl, C2-Ce alkynyl, Cj-Ce alkoxy, d-Ce-thioalkoxy, d-Ce-alkyl alkoxy C, -C6, Ci-Ce-alkoxy of Ci-C6-alkyl of d-Ce, thioalkoxy of d -d-C-C6 alkyl, C-Ce alkylcarbonyl, d-Ce-alkylcarbonyl of Ct -Ce, d-Ce alkoxycarbonyl, d-CB alkoxycarboxylic acid Ci-C6 alkyl, C -Ce alkylcarbonyloxy, Ci-C6 alkylcarbonyloxy Ci-Ce alkyl, Ci-C6 alkylamino) Ci-C6 alkylamino -alkyl Ci-C6, alkoxycarbonylamino of C ^ -e and alkoxycarbonylamino of C ^ -e-al Quilo of C! -Ce; LE and LE are independently selected in each occurrence of the group consisting of a bond, C-C6 alkylene, C2-Ce alkenylene and C2-Ce alkynylene, C2-Ce-0-alkylene alkylene of Ci-C6 -, - Ci-Ce-S-alkylene alkylene of Ci-Ce-, -alkylene of Ci-C6-NC (0) -alkylene of C, -C6-, and alkylene of C1-C6-C (0) N -alkylene of 0, -Ce; Q is independently selected at each occurrence from the group consisting of a bond, alkylene of?, -? ß, alkenylene of C2-Ce, alkynylene of C2-Ce, -S-, -O-, -C (O) -, -N (RS) -, -N (Rs) C (0), -C (0) N (Rs) -. -N (Rs) C (0) 0-, -OC (0) N (Rs) -, -N (Rs) C (0) N (Rs) -, -C (= NRS) N (RS.) - , -N (RS) C (= NRS) -, -S (O) -, -S02-, -0-S02-, -S02-0-, -OS (O), -S (0) -0- , -C (0) 0- and -OC (O); R10 R15 R15- R17 R18 R26 R30 R31 R33 R35 R38 and R41 are independently optionally substituted in each occurrence with at least one substituent selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, C ^ -Ce alkoxy, alkylamino Ci- Cs, C 1 -Ce alkoxycarbonyl, and azido; and each carbocyclyl portion of C3-C18 and heterocyclyl of M3-M18 in -LE-Q-LE- (C3-C18 carbocyclyl) and -LE-Q-LE- (heterocyclyl of M3-M18) is independently optionally substituted in each occurrence with at least one substituent selected from the group consisting of hydrogen , halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C ^ -Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, Ci-Ce alkoxy, Ci-Ce thioalkoxy, (-Ce-Ci-C6 alkyl) alkoxy, Ci-Ce alkyl thioalkoxy, Ci-C alkyl, Ci-C alkylcarbonyl, Ci-Ce alkyl alkylcarbonyl Ci-C, C6 alkoxycarbonyl, Ci-C6 alkoxycarbonyl Ci-Ce alkyl, C, -Ce alkylcarbonyloxy, C 1 -C 6 alkylcarbon Ci-C 6 alkyl, Ci-C 6 alkylamino, d-Ce alkyl alkylamino of Ci-C, C 4 -Ce alkoxycarbonylamino, C 3 -C 7 carbocyclyloxy, heterocyclyloxy of M 3-M 7, C 3 -C 7 carbocycle-C alkoxy, -Ce, M 3 -MI7 heterocycle of d-Ce. carbocycle of C3-C7-Ci-C-alkoxycarbonyl, heterocycle of M3-M7-alc oxycarbonyl of C, -C6, and C 1 -C 6 alkoxycarbonylamino of d -Ce. In one example of this embodiment, A is a C5-Ce carbocyclyl, optionally substituted with one or more of R1 8. In another example of this invention, A is a heterocyclyl of M5-6, optionally substituted with one or more of R1 8. In yet another example of this invention, Y is -Ls-0, -Ls-S-, Ls-C (0) N (R1 5) -, or -Ls-N (R15) C (0) -, R15 is hydrogen,?, -? - alkyl, C2-Ce alkenyl or C2-Ce alkynyl, and L1 is Ci-C6 alkylene optionally substituted with one or more of R38, wherein A1 is a C4-carbocyclyl C6 or heterocyclyl M4-M6 and is optionally substituted with one or more of R30. In still another example of this invention, Y is -Ls-0-, -Ls-S-, -l_s-C (0) N (R1 5) - or -Ls-N (R1 5) C (0) -, R15 is hydrogen, d-Ce alkyl, C2-C6 alkenyl or C2-C6 alkynyl, and L1 is a bond (i.e., R50 is -A1), wherein A1 is a C4-C6 carbocyclyl or heterocyclyl M -M6 and is optionally substituted with one or more of R30. In a further example of this invention, Y is -Ls-0-, -Ls-S-, -Ls-C (0) N (R1 5) - or -Ls-N (R1 5) C (0) -, R 1 is hydrogen, C 1 -Ce alkyl, C 2 -Ce alkenyl or C 2 -Ce alkynyl, and L 1 is a bond (i.e., R 50 is -A 1) or C 1 -C alkylene optionally substituted with one or more of R38, wherein A1 is a bicyclic ring (eg, a fused bicyclic ring or bridged bicyclic ring), which has 6 to 14 atoms in the ring and is optionally substituted with one or more of R30. In another example of this invention, X is -O-, or -S-, and R22 is C5-C6 carbocyclyl or 5-M6 heterocyclyl and is optionally substituted with one or more of R26. In yet another example of this invention, X is -S- or -O-, and R22 is where R is hydroxy, amino, C 1-6 alkylamino, C 1 -Ce alkoxy, Ci-C6 alkoxycarbonylamino or C 1-6 alkoxycarbonyloxy, and R 22 (e.g., R48 or the phenyl ring in R22) is optionally substituted with one or more of R2S. In another example of this embodiment, A is C5-C6 carbocyclyl or 5-Me heterocyclyl and is optionally substituted with one or more of R1 8, wherein: X is -O- or -S-; R 22 is wherein R 48 is hydroxy amino, C-C6 alkylamino, Ci-C6 alkoxy, alkoxycarbonylamino or alkylcarbonyloxy of Ct-Ce, and R22 (for example, R48 or the phenyl ring in R22) is optionally substituted with one or more of R26; Y is -Ls-O-, -Ls-S-, -Ls-C (0) N (R1 5) -, or -Ls-N (R 5) C (0) -, where R 1 S is hydrogen, Ci-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl R50 is -L1-A1, wherein: L1 is C, -Ce alkylene optionally substituted with one or more of R38, and A1 is carbocyclyl C4-C6 or heterocyclyl M4-M6 and is optionally substituted with one or more of R30; and L1 is a bond (ie, R50 is -A1), wherein A1 is C4-C6 carbocyclyl or heterocyclyl-M6 and is optionally substituted with one or more of R30; or L1 is a bond (i.e., Rs or is -A1) or C1-C6 alkylene optionally substituted with one or more of R38, wherein A1 is a bicyclic ring (e.g., a fused bicyclic ring or a bicyclic ring at bridge), which has 6 to 14 atoms in the ring and is optionally substituted with one or more of R30.

The atom (s) in the ring in the portion can also be substituted with S or other heterogeneous atoms. In another embodiment, the present invention relates to compounds having Formulas 11 (a) or 11 (b), tautomers of these compounds, and pharmaceutically acceptable salts of these compounds or tautomers, 11 (a) n < b) wherein: R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl, and alkoxyalkylaminocarbonyl; R 4 is selected from the group consisting of hydrogen, alkoxycarbonyl, and alkoxycarbonylalkyl; R7 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, arylalkylamine, 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, alkylalkyloxy, and alkoxycarbonyl; R1 1 is selected from the group consisting of hydrogen, hydroxy, haloaryloxy, and alkyl; R 2 is selected from the group consisting of hydrogen, arylsulfanyl, arylsulfyl, aryloxy, mercapto, arylaminocarbonyl, aryl, alkoxyaryl, arylalkoxy, and alkylcarbonylaminoaryl; wherein R1 2 is optionally substituted with one or more substituents independently selected from R16; R 6 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alkylheteroarylcarbonylamino, heteroarylcarbonylamino, hydroxy hetelocarbonyl, hydroxyalkylcarbonylamino, heteroarylcarbonylaminoalkylcarbonylamino , lamino heteroarilalquilcarboni, ariloxiarilalquilcarbonilamino, alilaminocarbonilo, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, hidroxiarilaminocarbonilo, alkoxyalkyl, alcoxiarilaminocarbonilo, azidoalkyl, alquilaminoarilsulfoniloxi, alkylsulfonyloxy, arylalkylsulfonyloxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, cicloalquiicarbonilamino, arilalcoxicarbonilheterociclocarbonilamino, aryloxy, iminoalkyl, alquiltiona, arilalqu i lamino lcarboni, alk or ilari loxia Iqu i rboni lamino, arylalkoxyalkylcarbonylamino, heteroarylcarbonylaminoalkylcarbonyl amino, heteroarylalkylcarbonyl amine, alkylcarbonylheterocycle bonylamino, amino, aminocarbonyl, alkylaminocarbonyl, hydroxyalkyl, aminoalkyl, alkoxyalkylaminocarbonyl, hydroxyiminoalkyl, heteroaryl substituted with alkyl and heteroaryl; R1 3 is selected from the group consisting of hydrogen, halogen, alkyl, alkylcarbonylarylsulfonyl, aminoarylsulfanyl, arylalkoxy, haloarylalkoxy, alkylcarbonylaminoaryloxy, alkylaminoaryloxy, hydroxyaryloxy, alkylaminocarbonylarylalkoxy and alkylcarbonylaminoarylalkoxy. In a subgroup family of this embodiment within Formulas 11 (a) or 11 (b), R1 2 is selected from the group consisting of, n is an integer selected from the group consisting of zero and one; R 14 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alkylheteroarylcarbonylamino, carbon and lamino, hydroxyheteroarylcarbonylamino, hydroxyalkylcarbonylamino, heteroarylcarbonylaminoalkylcarbonylamino, heteroarylalkylcarbonylamino, aryloxyarylalkylcarbonylamino, alylaminocarbonyl , alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, hydroxyarylaminocarbonyl, alkoxyalkyl, alkoxyarylaminocarbonyl, and azidoalkyl; R 6 is selected from the group consisting of hydrogen, Halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alquilheteroarilcarbonilamino, heteroarylcarbonylamino, hidroxiheteroarilcarbonilamino, hidroxialquilheteroarilcarbon lamino, h eteroaril coal Mam i noalqu i Icarboni lamino, heteroarylalkycarbonylamino, ariloxiarilalquilcarbonilamino, alilaminocarbonilo, alkoxycarbonyl, hydroxyalkyl, ariiaminocarbonilo, hidroxiarilaminocarbonilo alkoxyalkyl, alcoxiarilaminocarbonilo, azidoalkyl, alquilaminoarilsulfoniloxi, alkylsulfonyloxy, arylalkylsulfonyloxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, cycloalkylcarbonylamino, arilalcoxicarbonilheterociclocarbonilamino, aryloxy, iminoalkyl, alquiltiona, arylalkylcarbonylamino, alquilariloxialquilcarbonilamino, arilalcoxialquilcarbonilamino, heteroari Icarboni laminoalqu rbonilamino Mea, heteroarylalkycarbonylamino, alquilcarbonilheterociclocarbonilamino, ino am, aminocarbonyl, alkylaminocarbonyl, hydroxyalkyl , aminoalkyl, alkoxyalkylaminocarbonyl, hydroxyiminoalkyl, heteroaryl substituted with alkyl, and heteroaryl. In a further subgroup of the first modality within the Formula 11 (a) or 11 (b), R 2 and R 3 are independently selected from the group consisting of hydrogen, ethoxycarbonyl, 3-N-methoxy-N-methylaminocarbonyl and methyl; R 4 is selected from the group consisting of hydrogen, t-butoxycarbonyl, and ethoxycarbonylmethyl; R7 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- (t-butoxycarbonyl), cyano-1-ethyoxycarbonylmethyl, cyano-1-t-butoxycarbonylmethyl, cyanomethyl, morpholinyl, ethoxycarbonylethyl, hydrazino? ,? -dimethylaminoethoxy, methoxyethylamino, and cyano-1-ethoxy-carbonylmethyl; R9 is selected from the group consisting of hydrogen, methyl, methyl, phenyl, trifluoromethyl, phenylmethylamino, hydroxy, t-butoxy-carbonylaminomethyl, carbonylamino, methylcarbonyl, amino, bromo, chloro, fluoro, methyl [1,8] naphthyridin-4- ilamino- (2-phenylsulfanylphen-5-flmetfl) amino- (Nt-butoxycarbonyl-N-methyl), methoxyphenylmethoxy, bromophenylmethoxy, nitrophenylmethoxy, cyanophenylmethoxy, trifluoromethyl, phenoxymethyl, bromophenoxymethyl, cyanomethoxy, phenylmethoxy, methylalkyloxy, propoxy, methylphenylmethoxy, methylphenylmethoxy , fluoro-3-methylphenylaminocarbonyl, trifluoromethylphenylaminocarbonyl, trifluoromethylphenylaminocarbonyl, N, N-dimethylaminophenylaminocarbonyl, fluorophenylmethoxy, and chlorophenylmethoxy; R1 1 is selected from the group consisting of hydrogen, hydroxy, chlorophenoxy and methyl; R1 2 is as described above with respect to Formulas 11 (a) and l l (b); R 3 is selected from the group consisting of hydrogen, chloro, methyl, methylcarbonylaminophenylsulfonyl, aminophenylsulfonyl, phenylmethoxy, bromophenylmethoxy, methylcarbonylaminophenoxy, N, N-dimethylaminophenoxy, hydroxyphenoxy, and methylaminocarbonylphenoxy; R 1 4 is selected from the group consisting of hydrogen, fluoro, methyl, methoxy, hydroxy, aminocarbonyl, N-methylaminocarbonyl, N, N-dimethylaminocarbonyl, amino, t-butylcarbonylamino, 2,6-dimethylfuranyl) carbonylamino, thienylcarbonylamino, hydroxypyridinylcarbon lamno, (2-hydroxy-6-methylpyridinyl) -carbonyl lamino, (3-pyrazinyl) carboni lamino, furanylcarbonylamino-methylcarbonylamino, (3-thienyl) propylcarbonylamino, (3-phenoxy) phenylmethylcarbonylamino, N-allylaminocarbonyl, ethoxycarbonyl , 1-hydroxyethyl, aminocarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, hydroxyphenylaminocarbonyl, propylaminocarbonyl, hydroxymethyl, hydroxyethyl, azidoethyl, and N, N-dimethylaminocarbonyl; R16 is selected from the group consisting of hydrogen, hydroxy, methylcarbonylamino, methyl, isopropyl, fluoro, methoxy, ethoxy, propoxy, isopropoxy, N, N-dimethylamino-naphth-1-ylsulfonyloxy, ethylsulphonyloxy, isopropylsulphonyloxy, methylsulphonyloxy, benzylsulphonyloxy, ethoxycarbonylmethoxy, hydroxycarbonylmethoxy, t-butylcarbonylamino, cyclopropylcarbonyl, benzyloxycarbonylpyrrolidinylcarbonylammon, phenoxy, methylcarbonylamino, iminoethyl, thionoethyl, (S) -1- phenylpropylcarbonylamino, methylphenomethylcarbonylamino, (R) -1-phenyl-1-methoxymethylcarbonylamino, (S) ) -1 -phenyl-1 -metoximetilcarbonilamino, furanilcarbonilaminometilcarbonilamino, tienilpropilcarbon lamino, metilcarbonilpiperidinilcarbonilamino, amino, aminocarbonyl, N-methylaminocarbonyl, ethoxycarbonylmethoxy, isopropylsulfonyloxy, methylsulfonyloxy, ethylsulfonyloxy, phenylmethylsulfonyloxy, methylcarbonylamino, N-methylaminocarbonyl, hydroxymethyl, aminoethyl, metoxietilaminocarbonilo, propylaminocarbonyl, N-meto xi-N-methylaminocarbonyl,?,? -diethylaminocarbonyl, N- (2-methoxyethyl) aminocarbonyl, N-ethyl-N-methylaminocarbonyl, N-hydroxy-1-iminoethyl, hydroxyethyl, aminomethyl, N. N-dimethylaminocarbonyl, 2,6-dimethylfuranyl, 1 H- [1,4] triazolyl, and pyridinyl.

Salts of the Compounds of this Invention The compounds of the present invention, or their tautomers, can be used in the form of salts. Depending on the particular compounds, a salt of the compound may be advantageous due to one or more of the physical properties of the salt, such as improved pharmaceutical stability at different temperatures and humidities, or a desirable solubility in water or oil. In some cases, a salt of a compound can also be used as an aid in the isolation, purification, and / or resolution of the compound.

When it is intended to administer a salt 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. In general, these salts can typically be prepared through conventional means with a compound of this invention, for example, the appropriate acid or base with the compound. The pharmaceutically acceptable addition salts of the compounds of this invention can be prepared from an inorganic or organic acid. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroonic acid, carbonic acid, sulfuric acid and phosphoric acid. Organic acids generally include, for example, the aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxy, and sulfonic classes of organic acids. Specific examples of suitable organic acids 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 (pamoate), methanesulfonate, ethanesulfonate, benzenesulfonate, pantothenate, toluenesulfonate, 2-hydroxyethanesulfonate, sufanilate, cyclohexylaminosulfonate, allenic acid, b-hydroxybutyric acid, galactarate, galacturonate, adipate, alginate, bisulfate, butyrate, camphorate, camphor sulfonate, cyclopentanpropionate, dodecyl sulfate, glycoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, and undecanoate.

The pharmaceutically acceptable base addition salts of the compounds of this invention include, for example, metal salts and organic salts. Preferred metal salts include, but are not limited to, alkali metal salts (Group a), alkaline earth metal salts (Group I a), and other acceptable metal salts. Said salts can be made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Non-limiting examples of preferred organic salts can be made from tertiary amines and quaternary amine salts, such as tromethamine, diethylamine,? ,? '- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Groups containing basic nitrogen can be quaternized with agents such as lower alkyl halides (C, -Ce) (for example, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkylsulfates (e.g., dimethyl, diethyl, dibutyl, and diamyl sulfates), long chain halides (eg, decyl, lauryl, mistyl, and stearyl chlorides, bromides and iodides), aralkyl halides (eg, benzyl and phenethyl bromides), and others.

Soivates, Prodrugs, and Isomers The compounds of the present invention, their tautomers, and their salts, may also exist in the form of soivates with water, for example, hydrates, or with organic solvents such as methanol, ethanol or acetonitrile to form, respectively, a methanolate, ethanolate or acetonitrilate. The compounds of the present invention can exist in each form of solvate or mixtures thereof. In one aspect, the compounds, tautomers or salts of the present invention may be in the form of prodrugs. Some are aliphatic or aromatic esters derived from acid groups in compounds of this invention. Other aliphatic or aromatic esters of hydroxyl or amino groups in the compounds of this invention. The present invention also relates to prodrugs of hydroxyl groups in the compounds of the invention. The compounds of the invention may comprise asymmetrically substituted carbon atoms known as chiral centers. These chiral centers are designated as "R ° or" S * depending on the configuration of substituents around the chiral carbon atom. The terms "R" and "S ° used here, are configurations as defined in the Nomenclature of Organic Chemistry, Section E: Stereochemistry, Recommendations 1 974, PURE APPL. CHEM. , 45: 1 1 -30 (1 976). The compounds of this invention may exist, without limitation, as individual stereoisomers (e.g., single enantiomers or diastereomer), mixtures of stereoisomers (e.g., any mixture of enantiomers or diastereomers), or racemic mixtures. All of these individual stereoisomers, mixtures and racemates are encompassed within the scope of the invention. The compounds identified herein as individual stereoisomers are intended to describe compounds that are present in a form that is substantially free of other stereoisomers (e.g., other enantiomers or diastereomers). By "substantially free", it is meant that at least 80% of the compound in a composition is the desired stereoisomer; preferably, at least 90% of the compound in a composition is the desired stereoisomer; and most preferably, at least 95%, 96%, 97%, 98% or 99% of the compound in a composition is the desired stereoisomer. When the stereochemistry of the chiral carbon (s) present in a chemical structure is not specified, the chemical structure is intended to encompass compounds that contain any stereoisomer of each chiral center present in the chemical structure. The individual stereoisomers of the compounds of this invention can be prepared using many methods known in the art. These compounds include, but are not limited to, stereospecific synthesis, chromatographic separation of diastereomers, chromatographic resolution of enantiomers, conversion of enantiomers in an enantiomeric mixture to diastereomers, followed by chromatographic separation of the diastereomers and regeneration of the individual enantiomers, and resolution enzymatic Stereospecific synthesis typically involves the use of appropriate optically pure (enantiomerically pure) or optionally substantial pure materials and synthetic reactions that do not cause racemization or inversion of stereochemistry at chiral centers. Mixtures of stereoisomers of compounds, including racemic mixtures, resulting from a synthetic reaction, can be prepared, for example, by chromatographic techniques as appreciated by those skilled in the art. Chromatographic resolution of enantiomers can be achieved in chiral chromatography resins, many of which are commercially available. In a non-limiting example, the racemate is placed in solution and charged to the column containing a chiral stationary phase. The enantiomers can then be separated through HPLC. Resolution of enantiomers can also be achieved by converting enantiomers into a mixture to diastereomers through reaction with chiral auxiliaries. The resulting diastereomers can be separated through column chromatography or crystallization / re-crystallization. This technique is useful when the compounds to be separated contain a carboxyl, amino or hydroxyl group which will form a salt or covalent bond with the chiral auxiliary. Non-limiting examples of suitable chiral auxiliaries include chirally pure amino acids, organic carboxylic acids or organosulfonic acids. Once the diastereomers are separated through chromatography, the individual enantiomers can be regenerated. Frequently, the chiral auxiliary can be converted and used again. Enzymes, such as esterases, phosphatases or lipases, may be useful for the resolution of enantiomer derivatives in an enantiomeric mixture. For example, an ester derivative of a carboxyl group in the compounds to be separated can be treated with an enzyme, which selectively hydrolyzes only one of the enantiomers in the mixture. The resulting enantiomerically pure acid can then be separated from the non-hydrolyzed ester. Alternatively, salts of enantiomers can be prepared in a mixture, using any method known in the art, including treatment of the carboxylic acid with a suitable optically pure base such as alkaloids or phenethylamine, followed by precipitation or crystallization / re-crystallization of the salts enantiomerically pure. Suitable methods for resolution / separation of a mixture of stereoisomers, including racemic mixtures, can be found in ENANTIOMERS, RACEMATES, AND RESOLUTIONS (Jacques et al., 1981, John Wiley and Sons, New York, NY). A compound of this invention may possess one or more unsaturated carbon-carbon double bonds. All double bond isomers, such as the cis (Z) and trans E isomers, and mixtures thereof, are intended to be encompassed within the scope of a disclosed compound unless otherwise specified. further, when a compound exists in various tautomeric forms, a described compound is not limited to any specific tautomer, but rather encompasses all tautomeric forms. Certain compounds of the invention may exist in different forms, which may be separable. Torsional asymmetry due to restricted rotations around an asymmetric individual link, for example, due to spherical impedance or ring tension, may allow the separation of different conformers. The compounds of the invention include each conformational isomer of these compounds and mixtures thereof. Certain compounds of the invention can also exist in zwitterionic form and the invention includes each zwitterionic form of these compounds and mixtures thereof.

Definitions The compounds of the present invention are generally described herein using standard nomenclature. For a described compound having the asymmetric center (s), it should be understood that all stereoisomers of the compound and their mixtures are encompassed in the present invention, unless otherwise specified. Nonlimiting examples of stereoisomers include enantiomers, diastereomers, and cis-transisomers. When a described compound exists in various tautomeric forms, the compound is intended to encompass all tautomeric forms. Certain compounds are described herein using general formulas that include variables (e.g., R17, A1, L1, X, Y, or Z). Unless otherwise specified, each variable within that formula is defined independently of any other variable, and any variable that occurs more than once in a formula is defined independently in each occurrence. If the substituents are described as being "independently selected" from a group, each substituent is independently selected from the other. Each substituent, therefore, may be identical to or different from the other substituent (s). The number of carbon atoms in a hydrocarbyl substituent can be indicated 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, "C -Ce alkyl" refers to an alkyl substituent containing from 1 to 6 carbon atoms. As illustrated below, C3-C6 cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon atoms in the ring. A prefix attached to a multi-component substituent only applies to the first component that immediately follows the prefix. To illustrate, the term "alkylaryl" contains two components: alkyl and aryl. Thus, for example, C-C6 alkylaryl refers to an Ci-C6 alkyl attached to the molecular moiety of origin through an aryl group. Also, C6-C1 alkylaryl refers to an alkyl group attached to the parent molecular moiety through an aryl group of C6-C1 0. Similarly, the prefix "halo" in the haloalkoxyalkyl indicates that the alkoxy component is substituted with one or more halogen radicals, while the prefix "halo" in alkoxyhaloalkyl indicates that the alkyl component is substituted with one or more halogen radicals. When words are used to describe a linking element between two other elements of an illustrated chemical structure, the component described further to the left of the linking element is the compound that is attached to the left element in the illustrated structure. To show, if the chemical structure is X-L-Y and L is described as methylarylethyl, then the chemical could be X-methyl-aryl-ethyl-X. If a link element in a described structure is a link, then the left element in the illustrated structure is directly linked to the right element in the illustrated structure. For example, if a chemical structure is shown as X-L-Y and L is selected as a bond, then the chemical structure could be X-Y. For another example, if the chemical portion is represented as -L-X and L is selected as a bond, then the chemical portion could be -X. for yet another example, if a chemical structure is described as X - L - L2 - Y, X - L - L2 - L3 - Y or X - - 1_2 --.... - LN - Y, and L1t l_2, L3, ... LN are selected as links, then the chemical structure could be XY. When a chemical formula is used to describe a substituent, the hyphen on the right (or left) side of the formula indicates the portion of the substituent that has the free valence (s). If a substituent is described as being "substituted", a radical that is not hydrogen is in the place of one or more hydrogen radicals on a carbon, nitrogen or oxygen of the substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent wherein at least one radical that is not hydrogen is in the place of a radical (s) hydrogen in the alkyl substituent. To illustrate, monofluoroalkyl is an alkyl substituted with a fluoro radical, and difluoroalkyl is alkyl substituted with two fluoro radicals. It must be recognized that if there are two or more substitutions in a substituent, each of the radicals that are not hydrogen can be identical or different unless stated otherwise. A substituent is "capable of substitution" if it comprises at least one carbon, nitrogen or oxygen atom that is attached to one or more hydrogen atoms. If a substituent is described as being "optionally substituted", the substituent may be either substituted or unsubstituted. If a substituent is described as being optionally substituted with up to a particular number of radicals that are not hydrogen, that substituent may be either unsubstituted, or substituted up to a particular number of non-hydrogen radicals or up to the maximum number of substitutable positions in the substituent, whichever is less. Thus, for example, if a substituent is described as an optionally substituted heteroaryl with up to three non-hydrogen radicals, then any heteroaryl with less than three substitutable positions could be optionally substituted with up to only as many non-hydrogen radicals as possible. possible since the heteroaryl has substitutable positions. To illustrate, tetrazolyl (which has only one substitutable position) could be optionally substituted with up to a radical that is not hydrogen. To further illustrate, if an amino-nitrogen is described as being optionally substituted with up to two non-hydrogen radicals, then a primary amino nitrogen will be optionally substituted with up to two non-hydrogen radicals, while a secondary amino nitrogen will be optionally substituted with only one radical that is not hydrogen. The term "alkenyl" (alone or in combination with another term (s)) means a straight or branched chain hydrocarbyl substituent containing one or more double bonds and typically from 2 to 20 carbon atoms, more typically from 2 to 8 atoms of carbon, and still very typically from 2 to 6 carbon atoms. Each carbon-carbon double bond can have a geometry either cis or trans within the alkenyl portion, relative to substituted groups in the double bond carbons. Non-limiting examples of said substituents include ethenyl (vinyl), 2-propenyi, 3-propenyl, 1,4-pentynyl, 1,4-butadienyl, 1-butyl, 2-butenin and 3-butenyl. The term "alkenylene" (alone or in combination with another term (s)) refers to a divalent unsaturated hydrocarbyl group, which may be linear or branched and which has at least one carbon-carbon double bond. An alkenylene group typically contains from 2 to 20 carbon atoms, more typically from 2 to 8 carbon atoms, and still very typically from 2 to 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 molecular moiety through an oxy portion (i.e., -O-alkyl). Non-limiting examples of said substituent include methoxy (-0-CH3), ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, and tert-butoxy. The term "alkoxyalkyl" (alone or in combination with another term (s)) refers to an alkoxy group attached to the parent molecular moiety through 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 moiety r of origin through a carbonyl group (i.e., -C (O) -O) -I rent). Representative examples of alkoxycarbonyl include, but are not limit a, methoxycarbonyl, ethoxycarbonyl and tert-butoxycarbonyl. The term "alkoxycarbonylamino" (alone or in combination with another term (s)) refers to N (RARB) -, where RA is alkyl-O-C (O), and RB is alkyl-O-C (O) - or hydrogen. RA and RB can be identical or different. The term "akoxycarbonylaminoalkyl" (alone or in combination with another term (s)) refers to N (RARB) -alkylene-, where RA is alkyl-OC (O), and RB is alkyl-OC (O) - or hydrogen. RA and RB can be identical or different. The term "alkoxycarbonylalkyl" (alone or in combination with another term (s)) refers to an alkoxycarbonyl group attached to the parent molecular moiety through 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)) means a straight or branched chain saturated hydrocarbyl substituent that typically contains from 1 to 20 carbon atoms, more typically from 1 to 8 carbon atoms, and still very typically from 1 to 6 carbon atoms. Non-limiting examples of said substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, iso-amyl, hexyl and octyl. The term "alkylamino" (alone or in combination with another term (s)) refers to -N RARB-, where RA is alkyl, and R B is hydrogen or alkyl. RA and RB can be identical or different. For example, Ct-Ce alkylamino refers to -N RARB, wherein RA is Ci-C6 alkyl, and RB is hydrogen or C, -C6 alkyl. 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 can be identical or different. Thus, C 1 -C 6 alkylamino of Ci-C refers to N (RARB) -alkylene of Ci-Ce, wherein RA is Ci-C6 alkyl, and RB is hydrogen or Ci-C6 alkyl. The term "alkylcarbonyl" (alone or in combination with another term (s)) refers to an alkyl group attached to the parent molecular moiety through a carbonyl group (ie, -C (O) -alkyl). Representative examples of alkylcarbonyl include, but are not they limit a, acetyl, ethylcarbonyl 1 -oxopropyl, 2,2-dimethyl-1-oxopropyl, 1 -oxobutyl and 1 -oxopentyl. The term "aikylcarbonylalkyl" (alone or in combination with another term (s)) refers to an alkylcarbonyl group attached to the parent molecular moiety through an alkylene group. Representative examples of alkylcarbonylalkyl include, but are not limited to, 2-oxopropyl, 3, 3-dimethyl-2-oxopropyl, 3-oxobutyl and 3-oxopentyl. The term "alkylcarbonyloxy" (alone or in combination with another term (s)) refers to an alkylcarbonyl group attached to the parent molecular moiety through an oxy portion. Representative examples of alkylcarbonyloxy include, but are not limited to, acetyloxy, ethylcarbonyloxy, and tert-butylcarbonyloxy. The term "alkylcarbonyloxyalkyl" (alone or in combination with another term (s)) refers to an alkylcarbonyloxy group attached to the parent molecular moiety through an alkylene moiety. Representative examples of alkylcarbonyloxy 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 chain saturated hydrocarbyl chain typically containing from 1 to 20 carbon atoms, more typically from 1 to 8 carbon atoms, and still more typically from 1 to 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)) means a straight or branched chain hydrocarbyl substituent containing one or more triple bonds and typically from 2 to 20 carbon atoms, more typically from 2 to 8 carbon atoms, and still very typically from 2 to 6 carbon atoms. Non-limiting examples of said substituents include, ethynyl, 1-propynyl, 2-propynyl, 3-propynyl, decynyl, 1-butynyl, 2-butynyl, and 3-butynyl. The term "alkynylene" (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 three carbon-carbon bonds. Representative alkynylene groups include, by way of example, -C = C-, -C = C-CH2-, -C = C-CH2-CH2-, -CH2-C = C-CH2-, -C = C-CH (CH3) -, and -CH2-C¾C-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)) means an amino substituent, wherein one of the hydrogen radicals is replaced by a substituent that is not hydrogen. The term "disubstituted amino" (alone or in combination with another term (s)) means an amino substituent, wherein both hydrogen atoms are replaced by substituents that are not hydrogen, which may be identical or different. The term "aminocarbonyl" (alone or in combination with another term (s)) means -C (0) -NH2 I which may also be illustrated as: 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 (0) -alkylene-NH2 - For example, "aminomethylcarbonyl" can be illustrated as: The term "aminosulfonyl" (alone or in combination with another term (s)) means -S (02) -N H2, which may also be illustrated as: The term "aryl" (alone or in combination with another term (s)) refers to an aromatic carbocyclyl containing from 6 to 14 carbon atoms in the ring. Nonlimiting examples of aryls include phenyl, naphthalenyl, anthracenyl and indenyl. An aryl group can be connected to the molecular portion of origin through 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 parent molecular moiety through 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 parent molecular moiety through a carbonyl group (ie, 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 parent molecular moiety through an oxy (i.e., arylalkyl-O-) moiety. Representative examples of arylalkylcarbonyl 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 parent molecular moiety through 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)) refers to an arylaxy group attached to the parent molecular moiety through 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 parent molecular moiety through 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 parent molecular moiety through an oxy group Representative examples of substituted / unsubstituted aryloxy include, but are not limited to a, 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 a bonded aryloxy group to the molecular portion of origin through an alkylene group. Representative examples of aryloxyalkyl include, but are not limited to, 2-phenoxyethylol, 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 parent molecular moiety through a carbonyl group. The term "arylthio" (alone or in combination with another term (s)) refers to an aryl group attached to the molecular portion of origin through a sulfur atom (i.e., aryl-S-). Representative examples of arylthio include, but are not limited to, phenylthio, naphthalene-1 -ylthio, and naphthalene-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 molecular portion of origin through an oxy group. The term "arylthioalkoxyalkyl" (alone or in combination with another term (s)) refers to an arylthioalkoxy group attached to the parent molecular moiety through an alkylene group. The terms "carbocyclyl" or "carbocyclic" (alone or in combination with another term (s)) refer to a partially saturated saturated (eg "cycloalkyl") ring system (eg, "cycloalkenyl" or "cycloalkynyl") ") or completely unsaturated (eg," aryl "), which contains zero ring atoms of heterogeneous atoms and typically 3 to 1 8 ring atoms. "Ring atoms" or "ring members" are atoms joined together to form the ring or rings of a cyclic substituent. A carbocyclyl can be, without limitation, a single ring, or two or more fused rings, or bridged or spiro-rings. A carbocyclyl can contain from 3 to 14 ring members (ie, C3-C14 carbocyclyl, such as C3-C14 cycloalkyl), from 3 to 10 ring members (ie, C3-C0 carbocyclyl, as C3-C10 cycloalkyl), from 3 to 8 ring members (ie, C3-C8 carbocyclyl, such as C3-C8 cycloalkyl), from 3 to 6 ring members (ie, C3-C6 carbocyclyl , such as C3-C6 cycloalkyl), from 4 to 10 ring members (ie, C-C10 carbocyclyl, such as C4-C0 cycloalkyl and C4-Ci0 cycloalkenyl), from 4 to 8 ring members (ie, C4-C8 carbocyclyl, such as C-C8 cycloalkyl and C4-CB cycloalkenyl), or from 5 to 7 ring members (ie, C5-C7 carbocyclyl, such as C5-cycloalkyl) C7, C5-C7 cycloalkenyl and phenyl). A substituted carbocyclyl can have a geometry either cis or trans. Representative examples of carbocyclyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl, adamantyl, decahydro-napphthalenyl, octahydro-indenyl, cyclohexenyl, phenyl, naphthyl, fluorenyl, indanyl , 1,2,3,4-tetrahydro-naphthyl, indenyl, isoindenyl, bicyclodecanyl, anthracenyl, phenanthrene, benzonaphtenyl (also known as "phenalenyl"), decalinyl, and norpinanyl. A carbocyclyl group can be attached to the molecular moiety of origin 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 parent molecular moiety through an alkylene group. For example, C3-C10 carbocyclyl-Ci-Ce alkyl refers to a C3-C0 carbocyclyl group attached to the parent molecular moiety through an alkylene of C ^ Ce Likewise, the carbocyclyl of C5-C7- C ^ Ce alkyl refers to a C5-C7 carbocyclyl group attached to the parent molecular moiety through an alkylene of C ^ -Ce. The term "carbocyclylalkoxy" (alone or in combination with another term (s)) refers to a carbocyclylalkyl group attached to the parent molecular moiety through an oxy group (ie, carbocyclyl-alkylene-O-). For example, the C3-C10 carbocyclyl-C2-C6alkoxy refers to a C3-C10 carbocyclyl group of C6C6alkyl attached to the parent molecular moiety through an oxy group. In the same manner, a C5-C7 carbocyclyl group of Ci-C6 alkoxy refers to a C5-C7 carbocyclyl group of CrCe alkyl attached to the parent molecular moiety through an oxy group. The term "carbocyclylalkoxyalkyl" (alone or in combination with another term (s)) refers to a carbocyclylalkoxy group attached to the parent molecular moiety through an alkylene group (i.e., carbocyclyl-alkylene-O-alkylene). For example, the C3-Cio-alkoxy carbocycle of d-Ce-C-C6 alkyl refers to a C3-C10 carbocyclyl group of C- -CB alkoxy attached to the molecular moiety through a alkylene group of C ^ -Ce. The term "carbocyclylalcoxycarbonyl" (alone or in combination with another term (s)) refers to a carbocyclylalkoxy group attached to the parent molecular moiety through a carbonyl group (i.e., -C (O) -O-alkylene- carbocyclyl). For example, the C3-C10 carbocyclyl-C-C-alkoxycarbonyl refers to a C3-C10 carbocyclyl-C-C6-alkoxy group attached to the parent molecular moiety through a carbonyl group. As a non-limiting example, "phenylethoxycarbonyl" can be illustrated as: The term "carbocyclylalkylcarbonyl" (alone or in combination with another term (s)) refers to a carbocyclylalkyl group attached to the parent molecular moiety through a carbonyl group (i.e., -C (O) -O-alkylene) -carbocyclic). For example, "phenylethylcarbonyl" can be illustrated as: The term "carbocyclylcarbonyl" (alone or in combination with another term (s)) refers to a carbocyclyl group attached to the parent molecular moiety through a carbonyl group (ie, carbocyclyl-C (O) -). For example, "phenylcarbonyl" can be used as: The term "carbocyclyloxy" (alone or in combination with another term (s)) refers to a carbocyclyl group attached to the molecular portion of origin through an oxy portion (ie, carbocyclyl-O-) The term "carbocyclyloxyalkyl" (alone or in combination with another term (s)) refers to a carbocyclyloxy group attached to the parent molecular moiety through an alkylene group (ie, carbocyclyl-O-alkylene). The term "carbocyclyloxycarbonyl" (alone or in combination with another term (s)) refers to a carbocyclyloxy group attached to the parent molecular moiety through a carbonyl group (i.e., -C (O) -O-carbocyclyl) . For example, "phenyloxycarbonyl" can be illustrated as: The term "carbocyclylthio" (alone or in combination with another term (s)) refers to a carbocyclyl group attached to the molecular portion of origin through a sulfur atom (ie, 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 carbocyclicthio group attached to the parent molecular moiety through an alkylene group (ie, carbocyclyl-S-alkylene-). The term "carbocyclylcarbocyclyl" (alone or in combination with another term (s)) refers to a carbocyclyl group attached to the parent molecular moiety through another carbocyclyl group (ie, carbocyclyl-carbocyclyl-). For example, C3-C7 carbocyclyl carbocyclyl C5-C7 carbocyclyl refers to a C3-C10 carbocyclyl group attached to the parent molecular moiety through a C5-C7 carbocyclyl group (ie, carbocyclyl C3-C1 0-carbocyclyl of C5-C7). The term "carbocyclylcarbocyclylalkyl" (alone or in combination with another term (s)) refers to a carbocyclylcarbocyclyl group attached to the parent molecular moiety through an alkylene group. The term "carbocyclylalcoxycarbocyclylalkyl" (alone or in combination with another term (s)) refers to carbocyclyl-alkylene-O-carbocyclyl-alkylene. For example, carbocyclyl C3-C 0-alkoxy Ct-Co-carbocyclyl C3-C7-alkyl C3-C refers to carbocyclyl C3-C10-alkylene Ci-Ce-0-carbocyclyl C5-C7- C3-C4 alkylene. The term "(carbocyclylalkyl) carbocyclylalkyl ° (alone or in combination with another term (s)) refers to carbocyclyl-alkylene-carbocyclyl-alkylene. For example, C3-C10 carbocyclyl-Ci -Ce alkyl-C5- carbocyclyl C7-alkyl C3-C refers to carbocyclyl C3-Ci 0-alkylene of C ^ Ce-carbocyclyl C5-C7-alkylene C3-C4. The term "carbociclilalcoxiheterocicloalquilo" (alone or in combination with another term ( s)) refers to carbocyclyl-alkylene-O- alkylene- heterocyclyl. The term "carbociclilcarbonilheterocicloalquilo" (alone or in combination with another ino term (s)) refers to carbocyclyl-C (O) -heterocyclyl-alk ileno- . The term "carbociclilheterocicloalquilo" (alone or in combination with another term (s)) refers to carbocyclyl-alkylene- heterocyclyl. The term "carbociclilcarbonilcarbociclilalquilo" (alone or in combination with another term (s)) refers to carbocyclyl- is C (O) -carbocyclyl-alkylene- For example, carbocyclylcarbonyl of C3-C1 0-C-C8-carbocyclyl-d-Ce alkyl refers to C3-Ci carbocyclyl 0-C (O) -C4-C8 -carbocyclyl-Ci-Ce- alkylene. 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 illustrated as: The term "carboxy" (alone or in combination with another term (s)) refers to -C (0) -OH, which can also be illustrated as: The term "carboxyalkyl" (alone or in combination with another term (s)) refers to a carboxy group attached to the molecular portion of origin through an alkylene group. Representative examples of carboxyalkyl include, but are not limited to, carboxymethyl, 2-carboxyethyl, and 3-carboxypropyl. The term "cyclic amino" (alone or in combination with another term (s)) means a heterocyclyl moiety comprising at least one nitrogen ring atom, the remaining ring atoms being carbon and optionally nitrogen or sulfur. Limitations of said portions include piperidinyl, piperazinyl and thiazine groups The term "cycloalkenyl" (alone or in combination with another term (s)) refers to a non-aromatic, partially unsaturated carbocyclyl substituent having zero heterogeneous atom ring members and typically from 4 to 1 8 carbon ring members Representative examples of cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, and octane afta le or lo The term "cycloalkyl" (alone or in combination) with another term (s)) refers to a saturated carbocyclyl group containing zero heterogeneous atom ring members and typically 3 to 1 8 members of carbon ring: Non-limiting examples of cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decalinyl and norpinanyl. The term "cycloalkylcarbonyl" (alone or in combination with another term (s)) refers to a cycloalkyl group attached to the parent molecular moiety through a carbonyl group. The term "cyano" (alone or in combination with another term (s)) means -CN, which can also be illustrated as: The term "dialkylamino" (alone or in combination with another term (s)) refers to -N RARB L wherein RA and R B independently are selected from alkyl groups. The term "dialkylaminocarbonyl" (alone or in combination with another term (s)) refers to a dialkylamine group bound to the molecular moiety through a carbonyl group (ie, N (RARB) -C (0) -, wherein RA and RB are independently selected from alkyl groups). The term "formyl" (alone or in combination with another term (s)) refers to a group -C (0) H. The term "halogen" or "halo" (alone or in combination with another term (s)) means a fluorine radical (which can be represented as -F), chloro radical (which can be represented as -Cl), radical bromine (which can be represented as -Br), or radical iodine (which can be represented as -I). The prefix "halo" indicates that the substituent to which the prefix is attached is substituted with one or more independently selected halogen radicals. For example, "haloalkyl" (alone or in combination with another term (s)) means an alkyl substituent, wherein at least one hydrogen radical is replaced with a halogen radical. Non-limiting examples of haloalkyls include chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and 1,1-trifluoroethyl. Further illustrated, "haloalkoxy" (alone or in combination with another term (s)) means an alkoxy substituent, wherein at least one hydrogen radical is replaced by a halogen 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 recognized that if a substituent is replaced by more than one halogen radical, those halogen radicals may be identical or different (unless otherwise stated). The prefix "perhalo" indicates that each hydrogen radical in the substituent to which the prefix is attached is replaced with independently selected halogen radicals, ie, each hydrogen radical in the substituent is replaced with a halogen radical. If all halogen radicals are identical, the prefix will typically identify the halogen radical. Thus, for example, the term "perfluoro" means that each hydrogen radical in the substituent to which the prefix is attached is substituted with a fluoro radical. To illustrate, the term "perfluoroalkyl" means an alkyl substituent, wherein a fluoro radical is in place of each hydrogen radical. Non-limiting examples of perfluoroalkyl substituents include trifluoromethyl (-CF3), perfluoroisopropyl, perfluorobutyl, perfluorodecyl, and perfluorododecyl. To further illustrate, the term "perfluoroalkoxy" means an alkoxy substituent, wherein each hydrogen radical is replaced with a fluoro radical. Non-limiting examples of perfluoroalkoxy substituents include trifluoromethoxy (-O-CF3), perfluoroisopropoxy, perfluorobutoxy, perfluorodecoxy, and perfluorododekoxy. The terms "heterocycle" or "heterocyclyl" (alone or in combination with another term (s)) refers to a saturated (eg, "heterocycloalkyl") ring system, partially unsaturated (eg, "heterocycloalkenyl" or "heterocycloalkynyl") ") or completely unsaturated (eg," heteroaryl ") typically containing from 3 to 18 ring atoms, wherein at least one of the ring atoms is a heterogeneous atom (i.e., nitrogen, oxygen or sulfur) ), the rest of the atoms in the ring independently being selected from the group consisting of carbon, nitrogen, oxygen and sulfur. A heterocyclyl group can be linked to the molecular portion of origin through any substitutable carbon or nitrogen atom in the group, provided that a stable molecule is present. A heterocyclyl can be, without limitation, an individual ring, which typically contains from 3 to 14 ring atoms (ie, M3-14 heterocyclyl), from 3 to 8 ring atoms (ie, 3-ring heterocyclyl). -M8), from 2 to 6 ring atoms (i.e.,? 3-? Heterocyclyl), or from 5 to 6 ring atoms (i.e., heterocyclyl of M5-M6). Non-limiting examples of the individual ring heterocyclyls include furanyl, dihydrofuranyl, tetrahydrofuranyl, pyrrolyl, isopyrrolyl, pyrrolinyl, pyrrolidinyl, imidozolium, isoimidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, dithiolyl, oxathiolyl, oxazolyl, Soxazolyl, thiazolyl, isothiazolyl, thiazolidinyl, isothiazolinyl, thiazolidinyl, isothiazolidinyl, thiodiazolyl, oxathiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,4-oxadiazolyl (also known as "azoximyl"), 1, 2 , 5-oxadiazolyl (also known as "furazanil"), and 1,3,4-oxadiazolyl), oxatriazolyl (including 1, 2, 3,4-oxatriazolyl and 1, 2, 3, 5-oxatriazolyl), dioxazolyl (including 1, 2, 3-dioxazolyl, 1,4-dioxazolyl, 1,2-dioxazolyl, and 1,3-dioxazolyl), oxathiolanyl, pyranyl (including 1,2-pyranyl, and 1,4-pyranyl) ), dihydropyranyl, pyridinyl, piperidinyl, diazinyl (including pyridazinyl (also also known as "1,2-diazinyl"), pirim idini lo (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, 1,2-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-oxadiazinyl) and 1, 3,5,2-oxadiazinyl), morpholinyl, azepinyl, oxepinyl, thiepinyl, and diazepinyl. A heterocyclyl can also includeWithout limitation, two or more ring fused together, such as, for example, naphthyridinyl (including [1, 8] naphthyridinyl, and [1, 6] naphthyridinyl), thiazolopyrimidinyl, thienopyrimidinyl, pirimidopirimidini it, piridopirimidi nile idinilo pirazolopirim, indolizinyl , pyrindinyl, piranopyrroli, 4H-qu inolizinyl, purinyl, pyridopyridinyl (including pyrido [3,4-b] -pyridinyl, pyrido [3,2-b] -pyridinyl, and pyrido [4,3-b] -pyridinyl) , pyridopyrimidine, and pteridinyl. Other nonlimiting examples of heterocyclyls fused ring include heterocyclyls benzo-fused, such as indolyl, isoindolyl, indoleninyl (also known as "pseudoindoilo"), isoindazolyl (also known as "benzpyrazolyl"), benzazinilo (including quinolinyl (also known as " 1 -benzazinilo ") and isoquinolinyl (also known as" 2-benzazinilo ")), phthalazinyl, quinoxalinyl, benzodiazinyl (including cinnolinyl (also known as" 1, 2-benzodiazinyl ") and quinazolinyl (also known as" 1, 3- benzodiazinyl ")), benzopyranyl (including" chromenyl "and" isochromenyl "), benzothiopyranyl (also known as" tiocromenilo "), benzoxazolyl, indoxazinyl (also known as" benzisoxazolyl "), anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl (also known as "coumaronilo"), isobenzofuranyl, benzothienyl (also known as "benzothiophenyl", "thionaphtenyl", and "benzothiofuranyl"), isob enzotienilo (also known as "isobenzothiophenyl", "isothionaphthenyl", and "isobenzothiofuranyl"), benzothiazolyl, benzothiadiazolyl, benzimidazolyl, benzotriazolyl, benzoxazini it (including 1, 3,2-benzoxazinyl, 1, 4,2-benzoxazinyl, 2, 3 1 -benzoxazinilo, and 3, 1, 4-benzoxazinyl), benzisoxazinilo (including 1, 2 benzisoxazinilo and 1, 4-benzisoxazinilo), tetrahydroisoquinolinyl, carbazolyl, xanthenyl, acridinyl and. The term "two fused rings" heterocyclyl (alone or in combination with another term (s)) means a saturated, partially saturated, or aromatic heterocyclyl containing two fused rings. Nonlimiting examples of heterocyclyls two fused rings include naphthyridinyl (including [1, 8] naphthyridinyl, and [1, 6] naphthyridinyl), thiazolopyrimidinyl, thienopyrimidinyl, pyrimidopyrimidinyl, pyridopyrimidinyl, pyrazolopyrimidinyl, indolizinyl, pyrindinyl, pyranopyrrolyl, 4H-quinolizinyl, purinyl , pyridopyridinyl, pteridinyl, indolyl, isoindolyl, indoleninyl, isoindazolyl, benzazinilo, phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl, benzopyranyl, benzothiopyranyl, benzoxazolyl, indoxazinyl, anthranilyl, benzodioxolyl, benzodioxanyl, benzoxadiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, benzothiazolyl, benzothiadiazolyl , benzoimidazolyl, benzotriazolyl, benzoxazinyl, benzoisoxazinyl, and tetrahydroisoquinolinyl. A heterocyclyl may comprise one or more sulfur atoms as ring members; and in some cases the atom (s) of sulfur is oxidized to SO or S02 the atom (s) heterogeneous (s) nitrogen in a heterocyclyl may or may not be quaternized, and may or may not be oxidized to N-oxide. In addition, the heterogeneous atom (s) nitrogen may or may not be N-protected. As used herein, the number of atoms in the ring in a heterocyclyl portion can be identified by the prefix Mx- y ", 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 parent molecular moiety through an oxy group The term "heterocycloalkoxyalkyl" (alone or in combination with another term ( s)) refers to a heterocycloalkoxy group attached to the parent molecular moiety through an alkylene group (ie, heterocyclyl-alkylene-O-alkylene-) The term "heterocycloalkoxycarbonyl" (alone or in combination with another term ( s)) refers to a heterocycloalkoxy group attached to the parent molecular moiety through a carbonyl group (ie, heterocyclyl-alkylene-OC (O) -) .The term "heterocycloalkyl" (alone or in combination) with another term (s)) refers to a heterocyclyl linked to the parent molecular moiety through an alkylene group (eg, Ci-Ce heterocycloalkyl). The term "heterocycloalkylcarbonyl" (alone or in combination with another term (s)) refers to a heterocycloalkyl group attached to the parent molecular moiety through a carbonyl group (i.e., -C (O) -alkylene-heterocyclyl) . The term "heterocyclocarbonyl" (alone or in combination with another term (s)) refers to a heterocyclyl linked to the parent molecular moiety through a carbonyl group (ie, -C (O) -heterocyclyl). The term "heterocyclyloxy" or "(heterocycle) oxy" (alone or in combination with another term (s)) refers to a heterocyclic group attached to the molecular portion of origin through an oxy portion. The term "(heterocycle) oxyalkyl" (alone or in combination with another term (s)) refers to a heterocyclyloxy group attached to the parent molecular moiety through an alkylene group (ie, heterocyclyl-O-alkylene-) . The term "(heterocycle) oxycarbonyl" (alone or in combination with another term (s)) refers to a group (heterocycle) oxy linked to the molecular portion of origin through a carbonyl group (i.e., heterocyclyl- O-) C (O) -). The term "heterocyclic" (alone or in combination with another term (s)) refers to a heterocyclyl linked to the molecular portion of origin through-S-. The term "heterocyclothioalkoxy" (alone or in combination with another term (s)) refers to a heterocyclyl-alkylene-S-. The term "heterocyclothioalkoxyalkyl" (alone or in combination with another term (s)) refers to a heterocyclyl-alkylene-S-alkylene-. The term "heterocyclothioalkyl" (alone or in combination with another term (s)) refers to a heterocyclythium group attached to the parent molecular moiety through an alkylene group (ie, heterocyclyl-S-alkylene-). The term "heterocyclocarbocyclyl" (alone or in combination with another term (s)) refers to a heterocyclyl linked to the parent molecular moiety through a carbocyclyl (i.e., heterocycle-carbocyclyl-) group. The term "heterociclocarbociclilalquilo" (alone or in combination with another term (s)) refers to a group attached to the heterociclocarbociclilo molecular origin portion through an alkylene group (i.e., heterocyclyl - carbocyclyl - alkylene -). The term "(heterocycle) alkoxycarbicyclylalkyl" (alone or in combination with another term (s)) refers to a heterocycle-alkylene-O-carbocyclyl-alkylene-. The term "(heterocycle) carbonylcarbocyclylalkyl" (alone or in combination with another term (s)) refers to a heterocycle-C (O) -carbocyclyl-alkylene- . The term "(heterocycle) heterocycloalkyl" (alone or in combination with another term (s)) refers to a heterocycle-heterocycle-alkylene-. The term "(heterocycle) alkoxyheterocycloalkyl" (alone or in combination with another term (s)) refers to a heterocycle-alkylene-O-heterocycle-alkylene-. The term "(heterocycle) carbonylheterocycloalkyl" (alone or in combination with another term (s)) refers to a heterocyclic ether-C (O) -heterocycle-alkylene-. The term "(heterocycloalkyl) carbocyclylalkyl" (alone or in combination with another term (s)) refers to a heterocycle-alkylene-carbocyclyl-alkylene-. The term "(heterocycloalkyl) heterocycloalkyl" (alone or in combination with another term (s)) refers to a heterocycle-alkylene-heterocycle-alkylene-. Thus, for example, (heterocycle of M3-M10-d-C6 alkyl) -heterocycle of M5-M6-C-C3-alkyl means heterocycle of M3-M-1-alkylene of C-C-heterocycle of M5-M6 -alkylene of C ^ Cs. The term "heteroaryl" (alone or in combination with another term (s)) means an aromatic heterocyclyl which typically contains from 5 to 18 ring atoms. A heteroaryl can be an individual 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 anthranilyl. Non-limiting examples of 6/6 membered fused ring heteroaryls include quinolinyl; isoquinolinyl; and benzoxazinyl (including cinolinyl and quinazolinyl). The term "heteroarylalkoxy" (alone or in combination with another term (s)) refers to a heteroarylalkyl attached to the parent molecular moiety through an oxy group (ie, 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 attached to the parent molecular moiety through an alkylene group (ie, 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 "heteroarylalkyl" (alone or in combination with another term (s)) refers to a heteroaryl attached to the parent molecular moiety through 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 -pyrimidin-2-ylpropyl. The term "heteroarylalkylcarbonyl" (alone or in combination with another term (s)) refers to a heteroarylalkyl group attached to the parent molecular moiety through a carbonyl group (ie, heteroaryl-alkylene-C (O) -) . The term "heteroarylcarbonyl" (alone or in combination with another term (s)) refers to a heteroaryl group attached to the molecular portion of origin through a carbonyl group. Representative examples of heteroarylcarbonium 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 molecular portion of origin through an oxy portion. 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 parent molecular moiety through an alkylene group (ie, heteroaryl-O-alkylene-). The term "heteroaryloxycarbonyl" (alone or in combination with another term (s)) refers to a heteroaryloxy group attached to the parent molecular moiety through a carbonyl group (i.e., heteroaryl-O-C (O) -) . The term "heteroarylthio" (alone or in combination with another term (s)) refers to a heteroaryl group attached to the molecular portion of origin through -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 parent molecular moiety through an alkylene group (ie, heteroaryl-S-alkylene-). The term "hydrogen" (alone or in combination with another term (s)) refers to a hydrogen radical, and can be represented as -H. The term "hydroxy" (alone 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, wherein one or more hydrogen radicals are replaced with -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)) means an oxo radical, and can be represented as = 0. The term "iminoalkyl" (alone or in combination with another term (s)) refers to a radical of the formula wherein H may be optionally substituted with alkyl or hydroxy, in which case the substituent may be alkyliminoalkyl or hydroxyiminoalkyl, respectively. The term "nitro" (alone or in combination with another term (s)) means -N02.

The term "oxo ° (alone or in combination with another term (s)) is refers to a portion = 0 (ie, the term "oxy" (alone or in combination with another term (s)) means - OR - The term "propargyl" (alone or in combination with another term (s)) means the monovalent radical represented as: -CH2-CH = CH The term "sulfonyl" (alone or in combination with another term (s)) means -S (0) 2-, which may also be represented as: The term "sulfinyl" (alone or in combination with another term (s)) means -S (O) -, which may also be represented as: The term "uncle" or "tia °" (alone or in combination with another term (s)) means - S -. The term "thiol", "mercapto", or "sulfhydryl" (alone or in combination with another term (s)) means a sulfhydryl substituent (ie, - SH). Thus, for example, thioalkyl means an alkyl substituent, wherein one or more hydrogen radicals are replaced with -HS, while alkylthio means alkyl-S-. The term "thioalkoxy" (alone or in combination with another term (s)) refers to an alkyl group attached to the molecular portion of origin through-S-. Representative examples of thioalkoxy include, but are not limited to, methylthio, ethylthio, and butylthio. The term "thioalkoxycyclyl" (alone or in combination with another term (s)) refers to a thioalkoxy group attached to the parent molecular moiety through an alkylene group (i.e., alkyl-S-alkylene-). The term "thiocarbonyl" (alone or in combination with another term (s)) means a carbonyl, wherein the oxygen atom has been replaced with a sulfur. Said substituent can be represented as -C (S) -, and can also be represented as: The term "pharmaceutically acceptable" is used adjectivally to imply that the modified name is suitable for use as a pharmaceutical or as a part of a pharmaceutical product. The term "therapeutically effective amount" refers to a total amount of each active substance that is sufficient to show a significant benefit to the patient, for example, a reduction in viral load. The term "prodrug" refers to derivatives of the compounds of the invention, which have chemically or metabolically divisible groups and become, through solvolysis or under physiological conditions, the compounds of the invention that are pharmaceutically active in vivo. A prodrug of a compound can be formed in a conventional manner through the reaction of a functional group of the compound (such as an amino, hydroxy or carboxy group). The prodrug derivative form usually offers solubility advantages, tissue compatibility, or delayed release in a mammalian organism (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 prepared through the reaction of the acidic compound of origin with a suitable alcohol, or amides prepared through the reaction of the acidic compound of origin with a suitable amine. Examples of prodrugs include, but are not limited to, acetate, formate, benzoate or other acylated alcohol derivatives or amine functional groups within the compounds of the invention. The term "solvate" refers to the physical association of a compound of a compound of this invention with one or more solvent molecules, either organic or inorganic. This physical association usually includes a hydrogen bond. In certain cases, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice structure of the crystalline solid. "Solvate" encompasses both solution-phase and isolable solvates. Exemplary 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, are not super-taxable in their mirror image. A chiral molecule can exist in two forms, one on the right and one on the left. The term "stereoisomer" refers to isomers that have their atoms connected in the same order but have different three-dimensional arrangements. The term "stereoisomer" includes, for example, enantiomers and diastereomers. The term "cis-trans isomer" refers to stereoisomers that differ in their stereochemistry over a double bond or ring. The cis-trans isomers are also called geometric isomers. The term "enantiomer" refers to stereoisomers of a chiral substance having a mirror image ratio. The term "diastereomer" refers to stereoisomers that are not enantiomers, or mirror images of each other. The term "racemic mixture" refers to a mixture consisting of enantiomers of equal parts (+) and (-) of a substantial chiral. Although the individual molecules are chiral, the racemic mixtures are optically inactive. The term "tautomer" refers to isomers that are interconvertible. For example, enols and ketones are tautomers since they are inter-converted through the treatment with either acid or base. The term "position isomer" refers to any of two or more constitutional isomers that differ in the position of a particular substituent or group.The functional groups may be attached at positions that are not structurally equivalent on a skeleton or carbon structure. , [1, 3] imidazole, represented as, and [1,4] imidazole, represented as position isomers. The term "N-protecting group" or "N-protected" refers to those groups capable of protecting an amino group against undesirable reactions. The commonly used N-protecting groups are described in Greene and Wuts, PROTECT NG GROUPS IN CHEM ICAL SYNTH ESIS (3rd ed., John Wiley &Sons, NY (1 999), which is incorporated herein by reference in its entirety. Limiting examples of N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, benzoyl, 4-chlorobenzoyl, -bromobenzoyl, or 4-nitrobenzoyl, sulfonyl groups such as benzenesulfonyl or p-toluenesulfonyl, sulfenyl groups such as phenylsulfenyl (phenyl-S-) or triphenylmethylsulfenyl (trityl-S-), sulfinyl groups such as p-methylphenylsulfinyl (p-methylphenyl- S (O) -) or t-butylsulfinyl (t-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-trichloro-ethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, 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, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz). The following abbreviations were used in the Methods General Synthetics and Examples described below: AcOH = acetic acid atm = atmospheres Boc = Nt-butoxycarbonyl (protecting group) CDI = 1, V-carbonyldiimidazole CH2Cl2 = methylene chloride (dichloromethane) Cul = cuprous iodide [copper iodide (I) ] DCE = 1,2-dichloroethane DEAD = diethylazodicarboxylate DMA = NN-dimethylacetamide DMAP = 4-dimethylaminopyridine DMF = N, N-dimethylformamide ida DMSO = dimethyl sulfoxide E DCI = (N-ethyl-N '- ( 3-dimethylaminopropyl) carbodiimide EMME = diethyl ester of 2-ethoxymethylene-malonic acid Et3N = triethylamine Ether = diethyl ether Etl = ethyl iodide EtOAc = ethyl acetate EtOH = ethanol Fe = iron Fe (AcAc) 3 = iron acetylacetonate ( III) Fmoc Chloride = 9-Fluorenylmethyl Chloroformate HOBt = N-Hydroxybenzotriazole Hunig's Base = N-dusopropylethylamine I PA = isopropyl alcohol K2C03 = potassium carbonate KOH = potassium hydroxide LDA = lithium diisopropylamine MeOH = methane ol MsCl = methanesulfonyl chloride NaH = sodium hydride N H2OH »HCl = hydroxylamine hydrochloride NM P = 1 -methyl-2-pyrrolidinone Mg2S04 = magnesium sulphate Na2S04 = sodium sulphate N H3 = ammonia N H4CI = ammonium chloride N H4OH = ammonium hydroxide PG = protective group such as Boc- or Troc- POCI3 = phosphorylated oxy-chloride R-MgCI = reactive of Grignard Rl = alkyl iodide or substituted alkyl iodide SnCl2 = stannous chloride (tin (II) chloride) TFA = trifluoroacetic acid TH F = tetrahydrofuran TLC = thin layer chromatography triflic anhydride = trifluoromethanesulfonic anhydride Troc = 2,2,2-trichloroethoxycarbonyl- (protecting group).

General Synthetic Methods and Examples The following synthetic methods and schemes illustrate the general methods by which the compounds of the present invention can be prepared. Starting materials can be obtained from commercial sources or prepared using methods well known to those skilled in the art. As an example, synthetic routes similar to those shown here below can be used, together with synthetic methods known in the synthetic organic chemistry art, or variations thereof, as appreciated by those skilled in the art. The present invention is intended to encompass compounds prepared either through synthetic procedures or metabolic processes. Metabolic procedures include those that exist in the human or animal body (in vivo), or those that exist in vitro. If a substituent described herein is not compatible with the synthetic methods of this invention, the substituent can be protected with a suitable protecting group that is stable to the reaction conditions used in those methods. The protecting group can be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and methods for protecting or deprotecting substituents are well known in the art, examples of which can be found in Greene and Wuts, supra.

Preparation of Compounds [1,8] Naphthyridine 7-Substituted-4-Substituted Compounds of Formulas l (a) or ol (b) can be synthesized by reacting, wherein A, X, Y, R 1 0, R 17, R 22, R31, R33, R35, and R50 have the meanings stated in the above embodiments or examples, and K is Cl or another halogen. Likewise, the synthesis of the compounds of the formulas l l (a) or l l (b) generally involves the reaction of, wherein R 2, R 3, R 7, R 9, R 1, R 1 2, and R 1 3 have the meanings stated in the above embodiments or example, and K is Cl or another halogen. In Schemes 1, 2, 3 and 4 shown below, a representative method for the preparation of these [1, 8] naphthyridine type compounds is shown. The [1, 8] 7-substituted-4-substituted naphthyridine compounds are generally synthesized (Scheme 4) by coupling a 7-substituted 4-chloro- [1,8] naphthyridine compound 8 with a coupling compound such as 1 0, 1 1 and 1 2 (Scheme 3). Other [1, 8] 4-substituted naphthyridines can be prepared in a similar manner, using the appropriate coupling compounds.

Preparation of 6-Substituted 2-Aminopyridines In a typical preparation described in Scheme 1, a solution of 2,6-dichloropyridine was treated with ammonium hydroxide in a sealed metal reactor at 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 hexan-2, 5-dione in benzene was treated with acetic acid, heated under reflux conditions with azeotropic removal of water for about 20 hours. This reaction mixture was cooled to room temperature, diluted with hydrochloric acid and water. The organic layer was dried over magnesium sulfate, filtered and concentrated under vacuum to give 6-chloro-2- (2,5-dimethyl-pyrrol-1-yl-pyridine) 1. Compound 1 was treated with a Grignard reagent (RMgX) and dry tetrahydrofurane (TH F) and 1-methyl-2-pyrrolidinone (N MP) at room temperature under a nitrogen atmosphere and iron acetylacetonate (III) was added. [Fe (AcAc) 3] and the mixture was stirred at room temperature for about 1 8 hours. During the reaction, two addition charges of the Grignard reagent and an iron catalyst were added. The reaction was quenched by draining it to 5% acetic acid and extracting with ether. The ether layer was dried over ammonium sulfate, filtered and concentrated under vacuum to give 2- (2, 5-dimethyl-pyrrol-1-yl) -pyridine 6-substituted 2. Compound 2 can be directly converted to 6-Substituted 2-aminopyridine or can be further functionalized by reacting it with an alkyl iodide or a substituted alkyl iodide in the presence of lithium diisopropylamide (LDA). In this case, a solution of compound 2 in dry tetrahydrofuran was added dropwise over about 30 minutes to a stirred solution of lithium diisopropylamide in dry tetrahydrofuran at -30 ° C. Then, an alkyl iodide or a substituted alkyl iodide (R-1) in tetrahydrofuran was added dropwise over about 30 minutes, then warmed to room temperature. After two hours, the reaction mixture was quenched by draining it into a saturated sodium chloride solution and extracted with ether. The ether solution was dried over magnesium sulfate, filtered and concentrated in vacuo to give 6-substituted 2- (2,5-dimethyl-pyrrol-1-yl) pyridine 3. A solution of either compound 2 or 3 and Hydroxylamine hydrochloride, in ethanol and water, was heated at about 1000 ° C for about 16 hours, cooled to room temperature and extracted with methylene chloride, dried over magnesium sulfate, filtered and concentrated under vacuum providing the 6-substituted aminopyridine 4 used in Scheme 2. The 6-substituent in Scheme 1 is R7, which is described below.

SCHEME 1 Preparation of 4-Chloro- [1, 8] 7-Substituted Naphthyridines A typical preparation described in Scheme 2 is to mix a 6-substituted 2-aminopyridine 4 and diethyl ester of 2-ethoxymethylene-malonic acid (ME ME) and heating at about 100 ° C with stirring for about 2.5 hours. The reaction mixture was cooled to room temperature and diluted with hexane, the resulting solid was filtered and dried under vacuum to give the ester of aminomethylene malonic acid 5. Compound 5 was then dissolved in diphenyl ether and the resulting solution was heated at 250 ° C for approximately 30 minutes. After cooling to room temperature, it was diluted with hexane, the resulting solid was filtered and dried under vacuum to provide the 4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester 7- replaced "E". A solution of compound 6 and potassium hydroxide (KOH) was heated in a sealed metal reactor at 180 ° C for about 16 hours, cooled to room temperature and adjusted to pH 6 with 1 N hydrochloric acid. The resulting precipitate was filtered and dried to give [1, 8] naphthyridin-4-ol 7-substituted 7. A mixture of compound 7 was mixed with phosphorus oxychloride (POCI3) and heated to about 50 ° C with stirring for 6 hours. hours, it cooled and became extinct by emptying it on ice. It was cooled and then the pH was adjusted to 10 with concentrated ammonium hydroxide and extracted with methylene chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 4-chloro- [1,8] naphthyridine. -substituted 8. The substituents for com 8 are shown in Scheme 2 as R7, which has been described above.

SCHEME 2 § 7 & Preparation of Aminophenyl Coupling Agents (10, 11 and 12) A wide variety of amipheniphenyl coupling agents is possible. The agents in Scheme 3 are illustrative of this variety. In a typical preparation, a substituted 2-chloro-nitrobenzene compound in dimethylformamide (DMF) was treated with a 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 concentrated under vacuum to give the substituted 2-phenylsulfanyl-nitrobenzene compound. This nitrobenzene compound was then reduced with stannous chloride (SnCl2) or iron (Fe) in ethanol. The reaction mixture was adjusted to a pH of 12 with 1 N sodium hydroxide, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under vacuum to give the substituted 2-phenylsulfanyl-aminibenzene compound. 0. Similarly, the corresponding substituted 2-hydroxy-nitrobenzene compound was dissolved in dimethylformamide in reaction with sodium pentoxide solution, stirred and heated at 1000 ° C for about 5 days. The reaction mixture was cooled and diluted with methylene chloride, washed with water, dried over sodium sulfate, filtered and concentrated under vacuum to give the 2-phenoxy-nitrobenzene compound. This nitrobenzene compound was then reduced with stannous chloride (SnCl2) and iron (Fe) in ethanol. The reaction mixture was adjusted to a pH of 1 2 with 1 N sodium hydroxide, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under vacuum to give the substituted 2-phenoxy-aminobenzene compound . Similary, the compound 10, wherein R9 is hydroxy or hydroxy protected, can further be modified by alkylation of the hydroxy group using a substituted benzyl bromide to give the 5-substituted-phenoxy-2-substituted-phenylsulfanyl-aminobenzene compound eleven .

SCHEME 3 R9 is as defined above; X is OH, N H2, N HR, halogen, alkyl or alkoxy; R is alkyl, alkoxy, bromo, fluoro, chloro or cyano.

Preparation of 7-Substituted 4-Aminophenyl- [1, 8] naphthyridines As shown in Scheme 4, the coupling agent (compound 10, 11, 12 or the like) suitable for the synthesis of the 7-substituted 4-aminophenyl- [1,8] naphthyridine was dissolved in ethanol and reacted with compound 8 in ethanol at 80 ° C for about 7 hours. The reaction mixture was concentrated under vacuum and recrystallized from tetrahydrofuran with a few drops of methanol. Filtration gave 4-aminophenyl- [1,8] naphthyridine 7- substituted 1 3, 14 or 1 5.

SCHEME 4 X is as defined above; R is as defined above.

Preparation of Amide Coupling Agents As described in Scheme 3, a wide variety of aminophenyl coupling agents are possible. These aminophenyl coupling agents can be used to prepare the 7-substituted 4-aminophenyl- [1, 8] naphthyridine according to the procedures illustrated in Scheme 4. In Scheme 5, aminophenyl compounds with a substitution are described of amide in the 3-phenyl position. An aniline substituted in methylene chloride was treated with 4-chloro-3-nitrobenzoyl chloride and? , δ-propypropylamine and stirred at room temperature for approximately 17 hours. The solvent was removed under vacuum, the residue was dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated under vacuum to give the phenyl-4-chloro-3-nitrobenzamide N -substituted 16. Compound 16 could also be modified through displacement of the 4-chloro group to produce the 3-am-ino-4-substituted phenoxybenzamides 1 7 and the 3-am-ino-4-substituted phenylsulfanylbenzamides 18. The compounds 17 can typically be prepared by reacting the benzamide 1 6 in anhydrous N, N-dimethylformamide with 4- (Nt-butoxycarbonyl) aminophenol (N-Boc-4-hydroxyaniline) and potassium carbonate at room temperature, then heated at about 80 ° C for about 5 hours. The reaction was cooled to room temperature, the solvent was removed under vacuum, the residue was taken up in ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under vacuum to yield the substituted compound 4-Nt-butoxycarbonylamino 17. The Boc protecting group can be removed under a variety of methods to produce compounds of structure 1 7. In a similar manner, compound 1 6 was reacted with 4-aminothiophenol and anhydrous sodium acetate in anhydrous ethanol by heating under reflux for about 1 9 hours. After cooling to room temperature, the ethanol was removed under vacuum, the residue was taken up in water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated under vacuum. Titration of the solid with ethyl acetate-methylene chloride gave compound 18.

SCHEME 5 SL Ifi The phenyl amide ring, the phenoxy ring and the phenylsulfanyl ring can be substituted as described above. Some examples will require the use of protective groups followed by the removal of the protecting group at the appropriate time. R is as defined above.

Preparation of Reverse Amide Coupling Agents The preparation of reverse amide agents for coupling is shown in Scheme 6. In a typical preparation, 4-fluoro-3-nitroaniline was reacted with a substituted benzoyl chloride, Hunig's base ( N, N-diisopropylethylamine) in tetrahydrofuran with stirring at room temperature for about 1 hour. Water was added to the solution and the resulting solid (compound 19) was collected by filtration and dried in a vacuum oven. A solution of the compound 19,4-hydroxythiophenol and potassium carbonate in N. N-dimethylformamide was heated at about 80 ° C for about 2 hours. After cooling to room temperature, the mixture was poured into ice water, extracted with ethyl acetateThe extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to give the intermediate 4-hydroxyphenylsulfanyl. A solution of this intermediate, iron powder and magnesium chloride in tetrahydrofuran and water was heated to 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 concentrated under vacuum to give the 4-hydroxy analog of compound 23. Similarly, a compound 1 9 was reacted with 4-aminothiophenol and cesium carbonate in? , dimethylformamide at about 90 ° C for about 4 hours. After cooling to room temperature, the mixture was poured into ice water and acidified to a pH of 5 with 1 N hydrochloric acid. The solution was extracted with ethyl acetate, the extracts were dried over sodium sulfate, filtered and concentrated under vacuum to give the corresponding 4-aminophenylsulfanyl-3-nitroanilide. A methylene chloride solution of this anilide was then reacted with 2,2,2-trichloroethyl chloroformate and pyridine for about 16 hours. The solution was then washed with water, then with brine and then the extracts were dried over sodium sulfate, filtered and concentrated under vacuum. The residue was titrated with hexane and ethyl acetate to give the Troc-amino-protected compound. This Troc-amino-protected 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 concentrated under vacuum to give the Troc-amino-protected compound 23. Similarly, a solution of compound 1 9 in anhydrous N, N-dimethylformamide was reacted with 4-t-butoxycarbonylaminophenol (N-Boc-4-hydroxyaniline). ) and potassium carbonate at room temperature, and then allowed to stand at about 80 ° C for about 5 hours. The reaction was cooled to room temperature, the solvent was removed under vacuum and the residue was taken up in ethyl acetate, washed with water and brine, dried over sodium sulfate, filtered and concentrated under vacuum to give the compound N -Boc protected 20. Compound 20 was then dissolved in ethanol, tetrahydrofuran and water and reacted with iron powder and ammonium chloride by 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 brine. The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum to give the coupling agent compound 22.

SCHEME 6 The optimum reaction conditions and the reaction times for each individual step may vary depending on the particular reagents employed and substituents present in the reagents used. Unless otherwise specified, solvents, temperatures, and other reaction conditions can be readily selected by one skilled in the art. The reactions can be processed in a conventional manner, for example, by removing the solvent from the residue and further purifying according to methodologies generally known in the art, but not limited to, crystallization, distillation, extraction, titration and chromatography. It should be understood that the modalities and schemes described above and the following examples are provided by way of illustration, and not limitation. Various changes and modifications within the scope of the present invention will be apparent to those skilled in the art from the present disclosure.

Example 1 (7-Methyl- [1,8] naphthyridin-4-l) - (5-methyl-2-phenylsulfanyl-phenyl) -amine Example 1 a 2 - [(6-Methyl-pyridin-2-ylamino) -methylene] -malonic acid diethyl ester A mixture of 2-methyl-5-aminopyridine (12.48 g, 11.5 mmol) and diethyl 2-ethoxime dethien malonic acid ester (7.46 ml, 89.2 mmol) was heated at 1000 ° C with stirring for 2.5 hours. It was cooled to room temperature and diluted with hexane. It was filtered and dried under vacuum to give the title compound (21.05 g, 85%).

Example 1 b 7-Methyl-4-oxo-1,4-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester A solution of diphenyl ether was heated to 250 ° C and the product of Example (2.50 g, 9.0 mmol) was added in several small portions over a period of about 5 minutes, then heated to 250 ° C for 30 minutes. After cooling to room temperature it was diluted with hexane. The resulting solid was filtered and dried under vacuum to give the title compound as a tan solid (1.47 g, 71%).

Example 1 c 7- ethyl- [1,8] naphthyridin-4-ol A solution of the product of Example Ib (1.30 g, 5.59 mmol) and NaOH (233 mg, 5.82 mmol) in 20 mL of water was heated in a sealed metal reactor at 80 ° C for 16 hours. It was cooled to room temperature and the pH adjusted to 6 with 1 N HCl. The resulting precipitate was filtered and dried under vacuum to give the title compound as a black solid (743 mg, 82%).

Example 1 d 5-Chloro-2-methyl- [1,8] naphthyridine A mixture of the product of Example 1c (320 mg, 2.0 mmol) in 6 ml of POCI 3 was heated at 50 ° C with stirring for 6 hours. It was cooled to room temperature and extinguished by flushing to ice. The pH was adjusted to 10 with NH 4 OH and extracted with CH 2 Cl 2. Dry over Na2SO4, filter and concentrate 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 thiophenolate sodium (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. It was cooled to room temperature and diluted with CH 2 Cl 2 - Washed with water and the organic layer was dried over Na 2 SO 4. Filtered and concentrated in vacuo to give the title compound (4.29 g, 87%)? NMR (300 MHz, CDCl 3) d 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-phen i lamina A solution of the product of Example le (1.17 g, 7.0 mmol) in 25 ml of absolute EtOH and SnCl 2 (3.58 g, 29.8 mmol) was stirred at room temperature for 16 hours. The pH was adjusted to 12 with 1N NaOH and extracted with EtOAc. Dry over Na 2 SO 4, filter and concentrate in vacuo to give the title compound (835 mg, 82%) 1 H NMR (300 MHz, CDCl 3) d 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- ethyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-phenylsulfanyl-phenyl) -amine A stirred solution of the product of Example 1 (65 mg, 0.36 mmol) and the product of Example 1f (77 mg, 0.36 mmol) in 3 mL of EtOH was heated at 80 ° C for 7 h. It was concentrated under vacuum. It was recrystallized from THF with a few drops of MeOH. Filtration gave the title compound as the hydrochloride salt as a white solid (62 mg, 43%) 1H NMR (300MHz, CDCl 3) d ppm: 1.62 (brs, 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 = 7.0 Hz, 1H) 8.85 (d, J = 8.5 Hz, 1H) 10.80 ( brs, 1H); MS (ESI +) m / z 358 (M-CI) +; (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-aminopindin (5.0 g, 46 mmol) and hexan-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 under reflux with the azeotropic removal of water for 20 hours. It was cooled to room temperature and diluted with ether. It was washed with diluted HCl and water. The organic layer was dried over MgSO4, filtered and concentrated under vacuum 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 of dry THF was added dropwise with stirring to a solution of LDA (42.4 mmol) in 30 mL dry THF at -30 ° C. It was stirred at -30 ° C for 30 minutes. Etl (3.42 mL, 42.0 mmol) in 20 mL dry THF was added dropwise with stirring for 30 minutes then it was warmed to room temperature. After 2 hours it was quenched by draining to a saturated NaCl solution and extra with ether. Dried over MgSO4, filtered and concentrated in vacuo to give the title compound. The product was purified through silica gel column chromatography eluting with EtOAc / hexane to give the title compound (5.21 g, 60%).

Example 2c 6-Propyl-pyridin-2-i lamina A solution of the product of Example 2b (348 mg, 1.52 mmol) and NH2OH HCI (530 mg, 7.62 mmol) in 4 mL of EtOH / 1.5 mL of water. It was heated at 100 ° C for 16 hours, cooled to room temperature and extra with CH 2 Cl 2. Drying over MgSO4 was filtered and concentrated under vacuum to give the title compound as an amber oil (223 mg, 100%).

Example 2d 2 - [(6-Propyl-pyridin-2-ylam) -methyl] -malonic acid ethyl ester The product of Example 2c (223 mg, 1.52 mmole) was rea with diethyl ether of 2-ethoxime dethylene-ion 0.350 ml, 1.75 mmol) following the procedure in Example 1 to give the title compound After column chromatography on silica gel eluting with EtOAc / hexane (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 following the procedure in Example Ib to give the title compound as a tan solid (4.73 g, 81%).

Example 2f 7-Propyl-. { 1.8} naftiridin-4-ol The product of Example 2e (4.73 g, 18.1 mmol) was rea with NaOH (756 mg, 18.9 mmol) following the procedure of 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 rea with 4 mL POCI 3 following the procedure of Example 1d to give the title compound as a solid (135 mg, 86%).

Example 2h (5-Methyl-2-phenylsulfanyl-phenyl) - (7-propyl- [, 8] naphthyridin-4-yl) -amine The product from Example 2g (65 mg, 0.3 mmol) was rea with the product of Example 1f (68 mg, 0.31 mmol) for 24 hours following the procedure of Example 1g to give the title compound as a hydrochloride salt as a solid which was titrated with ether giving (110 mg, 84%). ? NMR (300 MHz, DMSO-de) d ppm: 0.97 (t, J = 7.35 Hz, 3H) 2.38 (qnt, 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, 1 H) 8.38 (d, J = 6.98 Hz, 1 H) 9.01 (d , J = 8.46 Hz, 1 H) 1 1. 1 0 (s, 1 H) 14.35 (br s, 1 H); MS (ESI-) m / z 386 (M-CI) +; (ESI-) m / z 384 (-HCl) -.

Example 3 (7-Ethyl- [1,8] naphthridin-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 an N 2 atmosphere was added dropwise n-BuLi as a 2.5M solution in hexanes ( 16 ml, 40 mmol). The resulting solution was stirred at low temperature for 30 minutes then treated with CH3I (2.4 ml, 38.6 mmol). At the end of the addition, the mixture was allowed to warm to -30 ° C and then 20 minutes at room temperature. The reaction was subsequently quenched by pouring into brine solution, the product was quenched through with EtOAc. It was dried over MgSO4, filtered and concentrated in vacuo. Purification through silica gel column chromatography eluting with EtOAc / hexane gave the title compound (4.42 g, 60%).

Example 3b 6-Ethyl-pyridin-2-ylamine The product of Example (4.93 g, 0.025 mol) was dissolved in a mixture of EtOH (80 ml) and water (30 ml). To this was added hydroxylamine hydrochloride (8.6 g, 0..1 mole) and the resulting mixture was heated at 1000 ° C for 8 hours. The reaction mixture was poured into dilute sodium hydroxide solution and the crude product was isolated by extraction with CH2Cl2 and dried over MgSO4, filtered and concentrated under vacuum to give the title compound. The material was used as it was isolated.

Example 3c 2 - [(6-Ethyl-pyridin-2-ylamino) -methylene] malonic acid diethyl ester The crude product of Example 3b was combined with 2-ethoxime-dethylene-malonic acid diethyl ester (6.6 ml, 0.032 mol) and the mixture was heated under an N2 atmosphere in an oil bath at 1000 ° C for 2 hours. Purified via flash chromatography on silica gel eluting with EtOAc / hexane to give the title compound (7.16 g, 98%).

Example 3d Ester © Italic deO acid 7 - ??? - 4-? ? -1, 4-dihydro- | [1l, 8] ima1ftirDdioiia-3-carboxylic The product from Example 3c (7.16 g, 0.024 mol) was heated in biphenyl ether following the procedure in Example Ib to give the title compound (4.73 g, 79%) as a tan solid.

Example 3 © 7-Ethyl- [1,8] nairphyridin-4-ol The product of Example 3d (4.70 g, 19.1 mmol) was reacted with NaOH (0.808 g, 20.2 mmol) following the procedure of Example 1c to give the title compound as a light green solid (2.43 g, 73%).

Example 3ff S.Cyoro-2-etiI- [Hl8] na < ftididiinia The product of Example 3e (200 mg, 1.14 mmol) was treated with POCI3 following the procedure of Example id to give the title compound as a brown solid (183 mg, 83%).

Example 3 (7-EíSS- | H, 8.} N &Ufai im- -l - { 5-m®M-2 - $ @ mUsuW3iñ - $ @ ñ) -amma 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 following the procedure of Example 1f to give the title compound as a hydrochloride salt, which it was titrated with ether giving (134 mg, 70%). 1H MR (300 M z, DMSO-d6) d 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 = 8.09 Hz, J = 7.72 Hz, 2.H) 7.56 (dd, J = 2.94 Hz, J = 9.19 Hz. 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 (br s, 1H) 14.56 (br s, 1H); MS (ESI +) m / z 376 (M-CI) +; (ESI-) m / z 374 (-HCl) -.

Example 4 4- [2- (7-Ethyl- [1,8-naphthyridin-4-lamino) -4-methyl-phenylsulfanyl] phenol Example 4a Esfier 4-imi © ¾ -2-iniiíiro-f © Bii8JíCO of ftiriffluoro-meitansiid acid. ionic A solution of 4-methyl-2-nitro-phenol (6.0 g, 39.1 mmol) and Et 3 N (16.38 mL, 117.5 mmol) in 100 mL of CH 2 Cl 2 under an N 2 atmosphere was treated with trifluoromethanesulfonic anhydride (7.25 mL, 43.1 mmol). at 0 ° C for 30 minutes. It was quenched through the addition of MeOH. It was washed sequentially with 10% citric acid, 0.5 m KOH and water. Dried over MgSO4, filtered and concentrated in vacuo to give the title compound which was purified through silica gel column chromatography eluting with CH2Cl2 to give an amber oil (11.22 g, 100%).

Example 4b 4- (4-Met0-2-niiro-ffenoOsiuiOffain) il) -ffenol 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 Na 2 CO 3 and heated overnight under efflux. It was cooled to room temperature and extinguished with water. It was extracted with EtOAc. It was dried over MgSO4 > it was filtered and concentrated under vacuum to give the title compound, which was purified through silica gel column chromatography 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 from Example 4b (8.65 g, 31.3 mmol) was reduced with SnCl 2 following the procedure of 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-methyl-phenylsulfanyl] -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 following the procedure of Example 1g to give the title compound as a hydrochloride salt, which it was titrated with 5: 1 ether / THF giving (210 mg, 98%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 1.37 (t, J = 7.35 Hz, 3 H) 2.33 (s, 3 H) 3.05 (q, J = 7.35 Hz, 2 H) 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 (br s, 1H) 14.38 (br s, 1H); MS (ESI +) m / z 388 (M-CI) +, (ESI-) m / z 386 (M-HCl) -.

Example 5 4- [4- ethyl-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 through the procedure in Example 1g to give the title compound after purification of the crude product. HPLC with TFA as the trifluoroacetic acid salt (231 mg, 30%). 'H NMR (300 MHz, DMSO-de) d 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, .T = 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 (br.s, 1H); MS (ESI +) m / z 374 (+ H) +.

EXAMPLE 6 4- [4-Meinl-2- (7-propH- [1,8] na (ftiir din-4-ylammon) -phinyinyl sulininyl] -pholium 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 following the procedure of Example 1g to give the title compound after purification of the crude product through HPLC with TFA as the trifluoroacetic acid salt (288 mg, 42%). 1H NMR (300 Hz, DMSO-de) 6 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 (br. S, 1H); MS (ESI +) m / z 402 (M + H) +.

Example 7 (5-M © llií-2-ff © ny suiBífflin) -ff © ír.ilí- (7-ftiráf 0iiiorom © fitB- 1. © limalFft-s-.ia.ini - ^ - óO) - ainraomia Example 7a Acid 2, S-DÍ bromo-rDicoííiniico A sample of 2,6-dichloro-nicotinic acid (2.50 g, 13.0 mmoles) was reacted with 25 ml of 30% Br / HOAc in a metal reactor sealed at 110 ° C for 2 hours at 12.4431 kg / cm2. It was cooled to room temperature and extracted with EtOAc and washed with water. Dried over MgSO4, filtered and concentrated in vacuo to give the title compound to give the title compound as a solid (3.22 g, 88%).

Example 7b Eslides * acid of 7-toiroinn acid) © -1l-l-eir-tou1-5B-4-ojiO-1,4-d.l) idiro [1,8] raaffti5nd] üinia-3-ca [r! Bojnll5co The product of Example 7a was subjected to the reaction sequence in US Pat. No. 6,818,654 to give the title compound.

EXAMPLE 7c Silyic acid ¾-4 r r r-foM4iO-4-o.io-7-ftir5ffOMOiroimel.iO-H, 4- dolhiidiro- [1, 8] inia1F < thiridine-3-cairobole The product of Example 7b (101 mg, 0.28 mmol) was reacted with difluoro-fluorosulfonyl-acetic acid methyl ester (0.132 mL, 1.43 mmol) in 2 mL of DF with Cul (71 mg, 0.37 mmol) at 75 ° C. for 15 hours under an atmosphere of N2 giving the title compound as a solid (57 mg, 59%).

Example 7d S-Cloro-2-ltnfiuoiroimiel.oll-fl .ejnaftiiridina The product of Example 7c was deprotected with trifluoroacetic acid following the procedure of Example 16b and then treated sequentially using the procedures of Examples 1b-1d to give the title compound as a solid (142 mg, 87%). The performance is for the last step of the sequence.

Example 7 © (5-Mey-2-p-n-sulphon-U-phenyl) - (7-pyrimidine) - [1,8 J-BB-4-y-J) - The product of Example 7d (65 mg, 0.28 mmol) and the product of Example 1f (61.5 mg, 0.28 mmol) was reacted for 28 hours following the procedure of Example 1g to give the title compound as a hydrochloride salt after titration with ether giving (131 mg, 99%). 1 H NMR (300 MHz, DMSO-de) d 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 (brs, 1H); MS (ESI ±) m / z 412 (M-CI) +; (ESI-) m / z 410 (M-HCI) -.

Example 8 (7-lsopropyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-phenylsulphanyl-phenyl) -amine Example 8a 2- (2,5-Dimethyl-pyrrol-1-yl) -6-isopropyl-pyridine The product of Example 1 2b (1.5 g, 7.26 mmol) was reacted with isopropylmagnesium bromide (4.35 ml, 8.7 mmol) following the procedure of Example 12c, after 1 hour, a second charge of the reagent was provided. of Grignard and the iron catalyst giving the title compound. The product was purified by column chromatography on silica gel eluting with 2% EtOAc / hexane to give (880 mg, 56%).

Example 8b 5-Chloro-2-isopropyl- [1,8] naphthyridine The product of Example 8a was treated sequentially using the procedures of Examples 2c-2g to give the title compound.

Example 8c (7-lsopropyl- [1,8] naphthyridin-4-yl) - (5-methyl-2-phenylsulfan-yl-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 hours following the procedure of Example 1g to give the title compound, which was purified through HPLC with TFA. It was converted to the hydrochloride salt through treatment with 4N HCl in dioxane at room temperature gave the hydrochloride salt (0.076 g, 38%). H NMR (300 Hz, D SO-de) d 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 (+ H) +.

EXAMPLE 9 (5-Meinon-2-phenylane-11-phenyl) - (7-methyl4- [il, 8-N-amino-1-yl-5-yl-5-a) -am5 in) a Example 9a 4-Rfle4oHÍ-2-nitro-1-phenylisulfan i-benzene A solution of 1-chloro-4-methoxy-2-nitro-benzene (3.75 g, 20.0 mmol) was reacted with sodium thiophenolate (3.96 g, 30.0 mmol) at 70 ° C for 48 hours following the procedure in Example giving the title compound as a yellow oil followed by column chromatography on silica gel eluting with 25% EtOAc / hexane (2.70g, 54%).

Example 9b 5-Rfle4oKi-2-phenylsuifan5l-fphenylamine The product from Example 9a (2.70 g, 10.2 mmol) was reacted with SnCl 2 (9.40 g, 50.0 mmol) for 22 hours following the procedure of Example 1f to give the title compound as a white solid (2.28 g, 96%).

Ejenra Do 9c The product of Example 9b (69 mg, 0.30 mmol) was reacted with the product of Example 1d (53 mg, 0.30 mmol) following the procedure of Example 1g to give the title compound as a hydrochloride salt after titration with solid ( 119 mg, 96%). 1 H NMR (300 MHz, D SO-de) d ppm: 2.75 (s, .3 H) 3.83 (s, 3 H) 6.34 (d, J = 6.99 Hz, 1 H) 7.07 (m, 7 H) 7.57 (d, J = 8.46 Hz, 1H) 7.76 (d, J = 8.46 Hz, 1H) 8.85 (d, J = 6.99Hz, 1 H) 8.99 (d, J = 8.46 Hz, 1H) 11.16 (br s, 1H) 14.43 (brs. 1 HOUR); MS (ESI +) m / z 374 (M-CI) +; (ESI-) m / z 372 (M-HCl) -.

EXAMPLE 10 7-Methyl-4- (S-methyl-2-phenylsulfanyl-phenylamines) ethyl ester - [1, 8] naf ti cid i na -3 -car box Mico EXAMPLE 10a 4-Chloro-7-methyl- [1,8-naphthymidine-3-carbohydrate ethyl ester The product of Example Ib (1.0 g, 4.30 mmol) was reacted with 12 mL of POCI3 for 4 hours following the procedure of Example 1d to give the title compound as a brown-pink solid (619 mg, 57%).

EXAMPLE 10b 7-Methyl-4- (5-methyl-2-phenylsulfanyl-phenylamino) [1,8] naphthyriane-3-c-carboxylic acid ethyl ester The product from Example 10a (438 mg, 2.03 mmol) was reacted with the product of Example 1f (510 mg, 2.03 mmol) for 10 minutes following the procedure of Example 1g to give the title compound which was purified through chromatography of silica gel column eluting with 4% eOH / CH2Cl2 as a solid (114 mg, 57%). 1 H NMR (300 MHz, D SO-de) d 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 (M-H) -.

Example 11 7-Methyl-4- (5-methyl-2-phenylsulfanM-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 NaOH in 4 mL of dioxane at 65 ° C for 30 minutes. It was cooled to room temperature and diluted with water, the pH was adjusted to 3 with 1N HCl and the resulting solid was isolated by vacuum filtration to give 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 an N2 atmosphere for 30 minutes. ??, - -dimethylhydroxylamine hydrochloride (25 mg, 0.215 mmol) was added and stirred at room temperature for 24 hours. The solvent was concentrated under vacuum to give the title compound. After purification of the crude product through HPLC with AA, the product was isolated as the free base (12 mg, 21%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.23 (s, 3 H) 2.67 (s, 3 H) 2.89 (s, 3 H) 3.39 (s, 3 H) 6.86 (s, 1 H) 6.91-7.04 (m, 1 H ) 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); S (ESI +) m / z 445 (M + H) +, 467 (+ Na) +, MS (ESI-) m / z 443 (M-H) -.

Example 112 4 [2- (7-.sotouttS8- | [1I, 83iroaff4.ir.tíiira ^ phenol Example 12a 6 - C I o go o - p o r S tí i ira - 2 - 51 a mm o n a A solution of 2,6-dichloropyridine (500 g, 3.37 mol) was treated with NH 4 OH in a metal reactor sealed at 180 ° C for 40 hours. After cooling to room temperature the product was isolated through suction filtration to give the title compound as a solid (400 g, 92%).

EXAMPLE H2b 2-Chloro-S- (2,5-dtiniii-4iii-p5rro! -1-N) -p 5 -yricolino The product of Example 12a (20 g, 156 mmol) was treated with hexane-2,5-dione (18.3 ml, 156 mmol) for 2 hours following the procedure of Example 2a to give the title compound (17.7 g 55%).

Axis 12c 2- (2,5 Bomeíí8-p5ir [roB-H-DD) -6-ssotou450-pDr5i-Sfna The product from Example 12b (1.0 g, 4.84 mmol) was treated with 2.0 isobutyl magnesium chloride (2.90 mL, 5.81 mmol) in 30 mL, THF and 3 mL NMP at room temperature under an atmosphere of N2. Fe (acac) 3 (85 mg, 0.242 mmol) was added and stirred at room temperature for 18 hours. During the course of the reaction, two additional charges of the Grignard reagent and catalyst were added. The reaction was quenched by draining to 5% acetic acid and extracted with ether. Dry over Na2SO4, filter and concentrate in vacuo to give the title compound which was purified through silica gel column chromatography eluting with 10% EtOAc / hexane to give (620 mg, 56%).

Example H2d S-Chloro-Z-isobutyl-Cl.einaphthyridine The product of Example 12c was treated sequentially using the procedures of Examples 2c-2g to give the title compound.

Example 12e 4- [2- (7-lsobutyl- [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 following the procedure of Example 1g to give the title compound after purification of the crude product through HPLC with TFA as the trifluoroacetic acid salt (90 mg, 47%). 1 H NMR (300 MHz, DMSO-de) 8 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 (br. S., 1H), 14.36 (br. S., 1 HOUR); MS (ESI +) m / z 416 (M + H) +; (ESI-) m / z 414 (M-H) -.

Example 13 4- [2- (7-Ethoxy- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol Example 13a 1-tert-Butyl-7-chloro-4-oxo-1-dihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester This compound was prepared from 2,6-dichloro-nicotinic acid as described in US Pat. No. 6,818,654 to give the title compound.

Example 13b 7-Chloro-4-oxo-1,4-d ihydro- [1,8] naphthyridine-3-carboxylic acid ethyl ester The product of Example 13a (0.282 gm, 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 70 ° C for 16.5 hours. The volatiles were removed under vacuum and the residue was suspended in water. The product was collected by vacuum filtration, washed with water and dried under vacuum to give the title compound as a cream colored solid (0.214 gm, 93%).

Example 13c [1, 8] Naphthyridine-2,5-diol The product of Example 13b (0.208 gm, 0.82 mmol) was reacted as described in Example 1 c to give the title compound as a dark brown solid (0.196 gm, 97%).

Example 13d 2,5 Dichloro- [1,8] naphthyrid ina The product of Example 1 3c (0.1 1 1 gm, 0.68 mmol) was reacted as described in Example 1 d to give the title compound as a pale yellow solid (0. 1 24 gm, 91%).

Example ü 3e 4- (2- (7-C [gold- [H, 8] naphyriirid i ini-4-ilamSrio) -4-methyl-1-phenyl-1-oly-ol-IFenol 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 of ethanol were heated under reflux for 5.5 hours. The reaction mixture was cooled to room temperature and the solvent was removed, concentrated under vacuum leaving a yellow solid which was used without further purification (1.43 g, 100%).

Example 13ff The product of Example 13e (0.025 g, 0.063 mmol) was treated with 2 ml and 21% by weight NaOEt in EtOH. The resulting mixture was refluxed for 4 hours. The solvent was concentrated under vacuum leaving a brown oily residue. 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%). 1H NMR (300 VI Hz, DMSO-de) d 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-1 H- [1,8] naphthyridin-4-one A flask 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 was heated at 120 ° C for 2 hours. It was cooled to room temperature and poured into water, neutralized with 1 N NaOH. Extraction with CH2Cl2 was dried over MgSO4, filtered and concentrated under vacuum to give a yellow oil which was heated in diphenyl ether at 250 ° C for 1 hour. It 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 POCI3 for 2 hours following the procedure of Example 1 d to give the title compound, which was used without purification.

Example H4c 4- [2- (2,7-Diraief.iil- [1l, 8] inia1f1..iridDin-1-giamiinium) -4-met-1FeinollsuDIFanDll] - ffeooi 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 following the procedure of Example 1g to give the title compound as a crude solid, which was purified by HPLC with TFA to give the product as a trifluoroacetic acid salt (45 mg, 37%). 1 H NMR (300 MHz, DMSO-de) d ppm: 2.23 (s, 3 H) 2.75 (s, 3 H) 3.43 (s, 3 H) 6.10 (s, 1 H) 6.68 (d, J = 8.82 Hz, 2 H) 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, 1 H) 10.78 (s, 1H) 14.21 (s, 1H); MS (APCI) m / z 386 (M-H) -.

Example 15 Ifeimol Example USa 4- [2- (7-Cfloiro- [1], 8] inia1fíBC-Dir-SfTi-4- am5íTio) -4-me4ill-1fe! Tiils ífanH] -feinol 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 following the procedure of Example 1g to give the title compound as the hydrochloride salt (1.43 g) , 100%).

Example 15b 4- [2- (7- ethoxy- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -phenol The product from Example 15a (0.100 g, 0.254 mmol) was treated with 5 mL of methanol and NaOMe powder (95%, 0.27 g, 5 mmol). The resulting mixture was refluxed 18 hours. The solvent was concentrated under vacuum leaving orange oily residue. The crude oil was purified by HPLC (gradient 0 to 95% CH3CN / 0.1% TFA) to give the title compound as a trifluoroacetic acid salt which was isolated as a yellow powder (75 mg, 76%). 1 H NMR (300 MHz, DMSO-de) d ppm: 2.32 (s, 3 H) 4.10 (s, 3 H) 6.25 (d, J = 7.35 Hz, 1 H) 6.65-6.81 (m, 3 H) 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 = 7.35 Hz, 1H) 8.94 (d, J = 9.19 Hz, 1H) 9.89 (s, 1H) 10.81 (s, 1H) 14.21 (s, 1H); MS (ESI +) m / z 390 (M + H) +; (ESI-) m / z 388 (+ H) -.

Example 16 4- [4-Methyl-2 - ([1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol Example 16a 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 reaction sequence in the US Pat. No. 6,881,865 to give the title compound.

Example 16b Escleir eftílico defl acid 4-lhi5diro ti- | [H, 8] iraaff4oir5dSin) a-3-cairlbonDlicico 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 under vacuum to give the title compound as a solid (5.05 g, 99%).

Example 16c 4-Cioro- [1,8] nafftirfcline The product of Example 16b was subjected to the reactions following the procedures of Example 1 c and Example 1 d to give the title compound as a solid (106 mg, 96%).

Example 16d 4- [4-Mei5l-2 - ([1, 8 | naft5ridin - < ¾-ylam) phenylsuyl? Il3-phenol The product of Example 16c as a 0.9M solution in methanol (0.080 ml, 0.07 mmol) was reacted with the product of Example 4c as a 0.7 solution in ethanol (0.100 ml, 0.07 mmol) for 18 hours following the procedure of 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%). * H NMR (300 MHz, DMSO-d6) d 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, 1 H); MS (ESI +) m / z 360.0 (M + H) +, (ESI-) m / z 358.1 (M-H) -.

Example 117 4-. { 2- (7-0 $ opiro | p ..- fi], @] roafftt.nd ^ 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 following the procedure of Example 1g yielding the crude title compound which was purified through HPLC with TFA giving the trifluoroacetic acid salt (90 mg, 47%). 1 H NMR (300 MHz, DMSO-de) d 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 (br. s., 1H), 14.36 (br. s. , 1 HOUR); MS ESI + m / z 416 (M + H) +; ESI-m / z 414 (M-H) -.

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 mmoies) was reacted with N- (4-mercapto-phenyl) -acetamide (0.65 g, 351 mmoies) for 18 hours following the procedure of Example 4b to give 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 gm, 1 mmoies) was reacted with SnCl 2 as described in Example 1f to give the title compound (0.27 gm, 100%) as an amber oil, which was used without further purification.

Example 18c N-. { 4- [4-ethyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamida The product of Example 18c (0.27 gm, 1 mmoies) was combined with the product of Example 1d (0.178 gm, 1 mmol) and reacted according to the procedure described in Example 1g to give the crude product as a brown solid. which was purified via HPLC with TFA to yield the trifluoroacetic acid salt, which was converted to the hydrochloride salt through treatment with 4N HCl in dioxane at room temperature to give the title compound (40.0 mg, 7.5%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.04 (s, 3 H) 2.35 (s, 3 H) 2.76 (s, 3 H) 6.29 (d, J = 6.99 Hz, 1 H) 7.24 (m, 5 H) 7.50 ( d, J = 8.82 Hz, 2H) 7.78 (d, J = 8.82 Hz, 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-methy1-phenylsulfanyl] -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 following the procedure of Example 1g to give the title compound as a solid after purification of the crude product. HPLC with TFA as a trifluoroacetic acid salt (68 mg, 26%). ? NMR (300 MHz, D SO-d6) d 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, 1.H) 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 (br s, 1H) 14.39 (br s, 1H). MS (ESI +) m / z 429 (+ H-CI) +; (ESI-) m / z 427 (M-H-CI) -.

Example 2fl > feimsJ) -aceiam idla 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 following the procedure of Example 1g to give the title compound after purification of the crude product through HPLC with TFA as a solid trifluoroacetic acid salt (72 mg, 29%). 1H NMR (300 MHz, DMSO-d6) d 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 (M-H) -.

EXAMPLE 21 M.4l4- [4-Meilyl 2- (7-riffliuioiromeiSI- [1, 8] nafíí? Rid ^ s ^ l-4-i ^ a? ^ (^ I? 1O) - fenilsullfani9] -fe? ? i0.}. -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 a pre-heated oil bath at 80 ° C for 16 hours. hours. The mixture was then cooled to room temperature, the ethanol was removed under vacuum, and the resulting crude residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (22.0 mg, 22%). 1 H NMR (300 MHz, DMSO-de) d 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, 1, H), 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 (M-H-TFA) -.

Example 22 N-. { 4-. { 2- (7-sec-Butyl- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl} - phenyl } -acetamide Example 22a 2-sec-Butyl-5-chloro- [1,8] naphthyridine Example 22b N- (4- [2- (7-sec-Butyl- [1,8] naphthyridin-4-Hamino) -4-methyl-phenylsulfanyl} - phenylj-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 following the procedure of Example 1 g to give the crude title compound, which was purified at HPLC in TFA affording the product as a trifluoroacetic acid salt (33 mg, 32%). * H NMR (300 MHz, DMSO-de) d 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 = 7.35 Hz, 1H), 7.14 (d, J = 7.72 Hz, 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 (M-H) -.

EXAMPLE 23 N- (4- [2- (7-Cyclopentyl- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -phenyl} -acetamide Example 23a 5-Chloro-2-cyclopentyl- [1,8] naphthyridine Example 23b N-. { 4- [2- (7-Cyclopentyl- [1,8] naphthyridin-4-ylamino) -4-methyl phenylsulfanyl] -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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA to yield the product as a trifluoroacetic acid salt (29 mg, 29%). 1H (300 MHz, DMSO-d6) d 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 (M-H) -.

Example 24 N- (4-. {2- [7- (2-Hydroxy-ethyl) - [1,8] naphthyridin-4-ylamino] -4-methyl-phenylsulfanyl}. Phenyl) -acetamide Example 24a N-. { 4- [2- (7-Chloro- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -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 following the procedure of Example 1g to give a crude solid which was purified by HPLC with TFA to give the composed of the title 200 mg, 48%).

EJemple 24b 2- Acetic acid ester. { 5- [2- (4-acetylamino-phenylsu-fainyl) -5- meio II -fe ti or mi m oj - [1, 8] inia1Ftiir.doini-2-y} -mallóiniiico To a slurry of sodium borohydride (95%, 0.045 g, 1.8 mmoles) in 10 ml anhydrous THF at 0 ° C under an atmosphere of 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 1110 ° C for 2 hours, cooled and partitioned between EfOAc and water. The ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, filtered and concentrated to give the title compound as a yellow glass, (0.14 g, 84% yield).

Example 24c ffeiniBlIs lffairiijlll-IFoiniolIJi-aceliainnijda The product of Example 24b (56 mg, 0.10 mmol) was reacted with NaBH 4 (40 mg, 1 .00 mmol) in 5 ml EtOH for 24 hours. It was quenched with aqueous NH CI and the pH was adjusted to 7 with diluted HCl. It was extracted with EtOAc and dried over Na 2 SO 4, filtered and concentrated in vacuo to give the crude title compound, which was purified by HPLC with TFA to give the trifluoroacetic acid salt (15 mg, 25%). 1 H NMR (300 MHz, DMSO-de) d ppm: 2.04 (s, 3H) 2.35 (s, 3H) 3.16 (t, J = 6.43 Hz, 2H) 3.91 (t, J = 625 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); S (ESI +) m / z 445 (M + H-TFA) +.

Example 25 N-. { 4- [2- (7-Butyl- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -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 following the procedure of 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 sequence in Examples 2b-2g to give the title compound.

Example 25c N-14- [2- (7-Butyl- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -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 following the procedure of Example 1 g to give the title compound after purification of the crude product through HPLC with TFA as a trifluoroacetic acid salt as a solid (130 mg, 30%). 1H NMR (300 MHz, DMSO-d6) d ppm: 0.95 (t, J = 7.72 Hz, 3H) 1.39 (sixth, 2H), J = 7.72 Hz) 1.80 (qnt, 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) 722-7.32 (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 (br s, 1H ) 11.02 (br s, 1H) 14.41 (br s, 1H); MS (ESI +) m / z 457 (M + H); (ESI-) m / z 455 (M-H) -.

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 following the procedure of Example 1g to give the crude title compound which was purified through HPLC with TFA to yield the trifluoroacetic acid salt (29 mg, 24%). H NMR (300 MHz, DMSO-d6) d 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 (M-H) -.

Example 27 2- Diethyl ester. { 5- [2- (4-Acetylamino-phenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyridin-2-yl} -malonic The crude product from Example 24b was purified through silica gel column chromatography eluting with 3% MeOH / CH2CI2 followed by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (70 mg, 42%). 1 H NMR (300 MHz, DMSO-de) d 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) +.

Ejom llo 28 Ester eioOoco deí ácido. { S- [2- (4-ace1tillainniDno-feiniillsuQfairtil) -S-m®ti1l-1Fero5iamiinioJ- [1f8] | iraa1Fíindirí-2-il anniiinioj-acetico The product of Example 24a (47 mg, 0.10 mmol) was reacted with the glycine ethyl ester hydrochloride (84 mg, 0.10 mmol) in 2 ml of EtOH in a sealed tube at 150 ° C for 1 hour. It was cooled to room temperature and concentrated. The pH was adjusted to 7 with 1M HCl and extracted with EtOAc, dried over Na 2 SO 4, filtered and concentrated under vacuum to give the crude title compound, which was purified by HPLC with TFA to give the product as a solid. of trifluoroacetic acid (12, mg, 19%). 1H NR (300 Hz, DMSO-de) d ppm: 1.22 (t, J = 6.99 Hz, 3H) 2.04 (s, 3H) 2.33 (s, 3H) 4.15 (q, J = 723 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) +.

EXHIBIT 29 ESOOR íÍÍICO D ESTERER TOTTILIICO < 2® (l acid 2- { 5- [2- (4-ac © 4iiamiroo 1? © n 5 II s no 0 ff a ira ol) - S - mre © i 5 II - ff® n l¡ if they were a o} - [D, S] ireaWDFOiSSBTi-Z-yj-inniaOdirooco To a slurry of sodium borohydride (95%, 0.025 g, 1.0 mmol) in 5 ml anhydrous THF at 0 ° C under N2 was malonate added tert-butyl acetate (0.188 g, 1.0 mmol) dropwise. The mixture was stirred for 30 minutes at room 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 through 1M HCl to a pH of 4 and extracted with EtOAc and washed with saturated brine. It was dried over Na2S0, filtered and concentrated under vacuum giving the crude title compound, which was purified by chromatography on silica eluting with 1% MeOH in CH2Cl2 to give the title compound as a hydrochloride salt (0: 040 g, 64% yield). 1H NR (300 MHz, DMSO-d6) d ppm: 1.26 (t, J = 7.11 Hz, 3H) 1.49 (s, 9H) 2.04 (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); S (ESI +) m / z 587 (M + H) +.

Example 30 Esíeir © ttóüco (5- [2- (4-ac®ttSlamñiroo-ffeim lsy [ffaroíO) -5-m © tt5ll- ferooBainniiinioJ-fH t®Jm3 >! HWM '} -2-'u. - i3im < Qi-3icé 'iCo The title compound was prepared according to the procedure of Example 27 by substituting ethyl cyanoacetate (0.240 mg, 2.1 mmol) for diefilo malonate. The crude product was purified by chromatography on silica eluting with 2% methanol in dichloromethane to give a yellow powder (0.092 g, 55% yield). 1 H NMR (300 MHz, DMSO-d 6) S ppm: 1.28 (t, J = 6.99 Hz, 3 H) 03 (s, 3 H) 2.31 (s, 3 H) 4.24 (q, J = 6.99 Hz, 2 H) 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) , 1 HOUR); MS (ESI +) m / z 512 (M + H) +.

EXAMPLE 31 Tertiary butyl ester of the acid. { 5- [2- (4-acetylamino-phenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyrid i n-2-yl} -acetic acid The title compound was prepared according to the procedure of Example 27 by substituting tert-butyl cyanoacetate (0.282 mg, 2.0 mmol) for diethyl malonate. The crude product was purified by chromatography on silica eluting with 2% methanol in dichloromethane to give a yellow powder (0.067 g, 37% yield). 'H NMR (300 MHz, DMSO-de) d 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-methyl-phenylsulfanyl] -phenyl} -acetamide The product of Example 31 (0.101 g, 0.19 mmol) was added to my trifluoroacetic acid and 5 ml of CH2Cl2. The mixture was stirred at room 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 the trifluoroacetic acid salt (0.083 g, 80%). 1 H NMR (300 MHz, D SO-d 6) d ppm: 2.04 (s, 3 H) 2.35 (s, 3 H) 4.64 (s, 2 H) 6.35 (d, J = 6.99 Hz, 1 H) 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 mmole) and tetrakistriphenylphosphinopalladium (8 mg, 0.0074 mmole) and the mixture was refluxed 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 brine, dried over sodium sulfate and filtered. The organic layer was concentrated under vacuum leaving the crude title compound as an orange oil, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (15 mg, 30%). HNR (300 Hz, D SO-d6) d 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 = 7.35 Hz, 2H), 7.75-7.87 (m , 3H), 8.44 (d, J = 6.62 Hz, 1H), 9.02 (d, J = 8.82 Hz, 1H), 10.10 (s, '1H) 11.12 (s, 1H), 14.41 (s, 1H); S (ESI +) m / z 477 (+ H) +.

Example 34 W-. { 4- [5-Hydro ».- 4-meftDll-2- (7-meft .. ^^ ffenóís lfainiSS] -ff © iniil.}. -ace¾ainnióda EjeoTrap. © 34A A mixture of 2-methyl-4-nitro-5-chloro phenol (1.5 g, 8.0 mmol), 4-acetamido thiophenol (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 10% aqueous sodium chloride solution, then dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was removed under vacuum leaving the title compound as a solid (2.5 g, 81%).

Ejem Do 34b A solution of the product of 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 solution (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 under vacuum 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 under vacuum to provide the title compound (17g, 91%).

Example 34c N- ^ - | [®-Mi «airoKa - ^ - m®1toO-2 - C7-innisttaO- | [l, ®] or ^ stirftBfrocElD (rD > ^ -BlsiinniDinio) - < T © mi i 0 s 0 ff a n 101 - < F e mi 5 II} - a c © í a mro i a The product of Example 1d (102 mg, 0.570 mmol) was reacted in ethanoi (2 mL) with the product of Example 34b (161 mg, 0.560 mmol) for 18 hours following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (50 mg, 21%). *? NMR (300 Hz, DMSO-d6) d 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 (br s, 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-trifluoromethyl-phenylamine (250 mg, 1.11 mmol) in DMF was reacted with N- (4-mercapto-phenyl) -acetamide (185 mg, 1.11 mmol) following the procedure of Example le during 16 hours to give the product (350 mg, 88%) which was reduced with SnCl 2 following the procedure 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA to yield the ditrifluoroacetic acid salt (10.5 mg, 10%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 0.98 (t, J = 735 Hz, 3 H), 1.81-1.92 (m, J = 7.35 Hz, 2 H), 2.07 (s, 3 H), 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 +) miz 497 (M + H) +, ESI-m / z 495 (M-H) -.

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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA to provide the trifluoroacetic acid salt (21.5 mg, 20%). 1H NR (300 MHz, D SO-d6) d 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); S (ESI +) m / z 469 (M + H-TFA) +, (ESI-) m / z 467 (-H-TFA) -.

EjeinnipD © 37 Esteír tter-lbiLiiitDÍiico di © D acid [2 - ([4-ac © 1ióla [nni5inio-ein) ólsylllfaimD [l¡) -5 m © ft -ff © iniHl- [7- (2-hiroirojij- © í) -n, 8] inaffiirir8 (ni-4- 3-cairbámDco The product of Example 24 (22 mg, 0.05 mmol) was reacted with di-tert-butyl dicarbonate (16 mg, 0.07 mmol) in 2 ml dry THF. Et3N (8.0 mg, 0.08 mmol) and a catalytic amount of?,? - 4-dimethylaminopyridine were added and stirred for 2 hours. It was poured into water and neutralized with 1M HCl. Extract with EtOAc, dry over Na2SO4 and filter and concentrate in vacuo to give the crude title compound, which is purified through silica gel column chromatography eluting with 1% MeOH / CH2Cl2 to provide the product as a free base solid (7.0 mg, 26%). 1 H NMR (300 MHz, DMSO-de) d ppm: 1.59 (s, 9 H) 2.03 (s, 3 H) 2.25 (s, 3 H) 2.96 (t, J = 6.62 Hz, 2 H) 3.81 (m, 2 H) 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) +, Ejerapraplo 38 N-. { 4- [2- (7-Bu il- [i), 8] tniaihti iridia fferaill} -acetaimi.da The product of Example 20 (100 mg, 0.226 mmol) was dissolved in HOAc (1 mL) and cooled to 0 ° C. To this was added magnesium bis (monoperoxyphthalate) hexahydrate (56 mg, 0.113 mmol) and the reaction mixture was allowed to warm to room temperature. The crude title compound was purified by HPLC with TFA to afford the product as a trifluoroacetic acid (34 mg, 32%). H NMR (500 MHz, DMSO-de) d ppm: 1.07 (t, J = 7.32 Hz, 3H), 1.91-1.98 (m, 4H), 2.11 (s, 3H), 2749 (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 (+ 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 To a solution of 1,2-difluoro-4-nitrobenzene (1.50 g, 9.3 mmol) in MeOH (150 mL) was added 1 5% aqueous NaSMe solution (4.44 mL, 10.3 mmol) dropwise at 5 °. C, and then the mixture was stirred at room temperature for 1 hour and evaporated. The solid obtained was dissolved in 150 ml of EtOAc, washed with H20 (twice) and brine, dried over MgSO4 and evaporated to give the 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-phen i lamina The product of Example 39a (1.57 g, 8.4 mmol) and Fe powder (1.41 g, 25.2 mmol) in a mixture of EtOH (7.5 ml) and HOAc (7.5 ml) was gradually heated to 80 ° C and it was heated at the same temperature for 1 hour. The reaction mixture was evaporated. The residue was partitioned between CHCl3 and 1.0% NaHCO3, and then filtered through celite. The organic layer was washed with H20, dried over MgSO4, and evaporated to give the 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 Ac20 (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 H20, acidified to a pH of 3 with 10% HCl, and then extracted with EtOAc. The organic layer was washed with H20 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 t-BuSNa (1.88 g), 15.1 mmoles) in anhydrous DMF (10 mL) was heated at 160 ° C for 4 hours under a flow of N2, and then cooled to room temperature. To the reaction mixture was added 1-chloro-4-methyl-2-nitrobenzene (2.36 ml, 17.6 mmol) at room temperature and then the mixture was heated at 80 ° C for 4 hours under a flow of N2. The mixture was diluted with H20 and then extracted with EtOAc. The extract was washed with H20 and brine, dried over gS0, and evaporated. The residue was purified through silica gel column chromatography eluting with 2: 1 EtOAc / hexane to give the title compound as yellow crystals (1.04 g, 65%).

Example 3Se The product from Example 39d was reduced with Fe and NH 4 Cl following the procedure of Example 237E to give the title compound.

Example 39f N-. { 3-F.yoro- - [4-m®tDÍ-2- (7-piropyll- [1, 8] nafftgrídon-4. Lamino) f® mi 50 s or 0 Ifa? P? or I] -If © 50 > -a c ® tta m i «fl a 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 following the procedure of Example 1g to give the title compound as a solid ( 120 mg, 54%). 1H NMR (300 Hz, DMSO-d6) d 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 = 7.3 Hz, 2H), 6.28 (d, J = 6.9 Hz, 1H), 7.12-7.35 (m, 5H), 7.55 (dd, J = 12.1, 2.2 Hz, 1 H), 7.82 ( d, J = 8.8 Hz, 1 H), 8.42 (d, J = 6.9 Hz, 1 H), 9.04 (d, J = 8.8 Hz, 1 H); MS (ES I +) m / z 461 (M + H) +, ESl-m / z 459 (M-H) - Example 40 N-. { 3,5-Difluoro-4- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamido Example 40a N- [3 > 5-Difluoro-4- (4-methyl-2-nitro-phenylsulfanyl) -phenyl] -acetamide The title compound was prepared using the procedure 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 procedures of Examples 39b, 39c and 39d to give the title compound.

Example 40b N- [4- (2-Amino-4-methyl-phenylsulfanyl) -3,5-difluoro-phenyl] -acetamide The product of Example 40a was reduced with Fe and N H4C I following the procedure of Example 237E to give 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 following the procedure of Example 1g to give the title compound as a salt ( 120 mg, 52%). 1 H NMR (300 MHz, DMSO-de) d 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 = 7.3 Hz, 2H), 6.28 (d, J = 6.9 Hz, 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); S (ESI +) m / z 461 (M + H) +, (ESI-) m / z 459 (M-H) -.

Example 41 (7-MetM- [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 following the procedure of Example 1c The product was purified through silica gel column chromatography eluting with CH2Cl2 to give the title compound as an orange solid (136 g, 30%).

Example 41b 5-Methyl-2-phenoxy-phenylamine The product of Example 41a (884 mg, 3.86 mmol) was treated with SnCl 2 (3.5 g, 19.0 mmol) for 24 hours following the procedure of 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 from Example 41b (65 mg, 0.36 mmol) was reacted with the product of Example 1d following the procedure of Example 1g to give the title compound which was titrated with ether to give the product as a hydrochloride salt (12 mg, 8.8 g. %). H NMR (300 MHz, D SO-de) d 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, 1 H) 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 (br s, 1H) 14.45 (brs, 1H); MS (ESI +) m / z 390 (M-CI) +; (ESI-) m / z 388 (M-HCl) -.

EjemmpHo 42 (5-CBoro-2-ffeiniojiD-fferBal) - (7-eííll- [1l a Ejtstnn ipDo 42a 4-Cloro-2-inig1-iro-1l-f®ít02iD-l3 > (S7iicisinio To a solution of DMF (50 ml) was added 1-bromo-2-nitro-4-chloro-benzene (5.0 g, 21.1 mmol), phenol (1.9 g, 21.1 mmol), and Na 2 CO 3 (2.3 g, 21.1 mmol) . The solution was heated to 85 ° C and stirred overnight. The reaction was poured into water and extracted with EtOAc. Washed with water and dried over Na 2 SO 4, filtered and concentrated in vacuo to give a yellow oil which was purified through silica gel column chromatography eluting with Hexanes.Acid ethyl acetate (90:10) to give the compound of the title (3.8 g, 74%).

Ej®inn > | p > D® 421b 5 - C 0 or r o - 2 - ff ® a or J? B - ff © my or ß a BTÍB D ETD a The product from Example 42a (13 g, 52.1 mmol) was reacted with SnCl 2 (49.3 g, 260 mmol) following the procedure of Example 1f to give the title compound as a white solid 9.0 g, 79%).

Example 42c (5-Chloro-2-phenoxy-H-phexyl) - (7-elt! H [1,8] iniafltirBdiini-4-5l) -amSna The product of Example 42b (100 mg, 0.46 mmol) was reacted with the product of Example 3f (88 mg, 0.46 mmol) following the procedure of Example 1g to give the title compound, which was titrated with 2: 1 ether / THF giving the product as a hydrochloride salt (134 mg, 70%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 1.34 (t, J = 7.35 Hz, 3 H) 3.02 (q J = 7.35 Hz, 2 H) 6.69 (d, J = 6.99 Hz, 1 H) 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 = 8.09 Hz, J = 7.72 Hz, 2H) 7.56 (dd, J = 2.94 Hz, J = 9.19 Hz, 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 (br s, 1H) 14.56 (br s, 1H); MS (ESI +) m / z 376 (M-CI) +; (ESI-) m / z 374 (M-HCl) -.

EXAMPLE 43 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 following the procedure of Example 1g to give the crude title compound as a solid, which was titrated with 4: 1 ether / THF giving the product as a hydrochloride salt (112 mg, 91%). 'H NMR (300 MHz, DMSO-de) d 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 = 7.73- Hz, J = 8.82 Hz, 2H) 7.57 (dd, J = 2.57 Hz, J = 8.82 Hz, 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 (br s, 1H) 14.40 (br s, 1H); MS (ESI +) m / z 416 (M-CI) +; (ESI-) m / z 414 (M-HCl) -.

Example 44 4- [4-Benzylamino-2- (7-propyl- [1,8] naphthyridin-4-ylammon) -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 to 100 ° C. 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 under vacuum to give the title compound as a red solid (1.45 g, 92%).

Example 44b 4- (4-B enzilami non-2-nitro-phenylsulfanyl) -phenol A solution of the product from 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 leaving a light yellow oil. The oil was applied to a column of silica gel and eluted with CH2Cl2 then 1% methanol in CH2Cl2. The fractions containing 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 NH CI following the procedure of Example 237E to give the title compound.

Example 4d | Bemi? OlamSno-2- (7-piropi! - [1l. SJiniaftiiridoini - ^ - ilamiinio) - f e p ii 1 s 1111F a? P? i 11 - 1F ®? p o I 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 following the procedure of Example 1g to give the crude title compound which was purified through HPLC with TFA to yield the trifluoroacetic acid salt (68 mg, 22%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 0.97 (t, J = 7.35 Hz, 3 H) 1.83 (sextet, 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 (br s, 1H) 14.21 (br s, 1H); MS (ESI +) m / z 493 (M + H-TFA) +.

Ejemrcpfl © 45 f ® p i 0 s? I to you i II] -ff and ini o 1 The product from Example 1d (57 mg, 0.319 mmol) was reacted with the product of Example 44c (102 mg, 0.319 mmol) for 72 hours following the procedure of Example 1g to give the crude title compound which was purified through HPLC with TFA affording the trifluoroacetic acid salt (169 mg, 91%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.74 (s, 3 H) 4.30 (s, 2 H) 6.15 (d, J = 6.99 Hz, 1 H) 6.52 (d, J = 8.46 Hz, 1 H) 6.56-7.39 (m, 11H) 7.75 (d, J = 8.46 Hz, 1H) 8.28 (d, J = 7.36 Hz, 1H) 9.50 (br s, 1H) 10.85 (br s, 1H) 14.25 (br s, 1H); MS (ESI +) m / z 465 (M + H-TFA) +; (ESI-) m / z 463 (M-H-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-methyl-phenylsulfanyl] -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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA to yield the trifluoroacetic acid salt (200 mg, 45%).

Example 46b N-. { 4- [4-ethyl-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) were 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%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.04 (s, 3 H), 2.33 (s, 3 H), 3.56-3.93 (m, 8 H), 6.07 (d, J = 6.99 Hz, 1 H), 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-tolylsulfan i I -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 following the procedure of Example le for 18 hours to give the crude title compound, which was purified through silica gel column chromatography eluting with 5% EtOAc / hexane to provide a solid (3.53 g, 78%).

Example 47h 5-Methyl-2-p-tolylsulfanyl-phen i lamina The product of Example 47a was reduced with SnCl 2 following the procedure of Example 1f to give 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 following the procedure of Example 1g to give the crude title compound which was purified through HPLC with TFA to yield the trifluoroacetic acid salt (347 mg, 46%). 1 H NMR (300 Hz, DMSO-de) d 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 (br. S., 1H) 14.39 (br. , 1 HOUR); 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 following the procedure of Example le for 18 hours to give the crude title compound, which was purified through silica gel column chromatography eluting with 5% EtOAc / hexane to provide a solid (7.50 g, 87%).

Example 48b 5-Methyl-2-m-tolylsulfanyl-phen i lamina The product of Example 48a was reduced with SnCl 2 following the procedure of Example 1f to give the title compound.

Example 48c (7- ethyl- [1,8] naphthridin-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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA to yield the trifluoroacetic acid salt (116 mg, 15%). 1 H NMR (300 MHz, DMSO-de) d ppm: 2.10 (s, 3 H) 2.38 (s, 3 H) 2.76 (s, 3 H) 6.27 (d, J = 7.35 Hz, 1 H) 7.00 (m, 3 H) 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 (br. s., 1, H) 14.45 (d. br. s., 1H); MS (ESI +) m / z 372 (M + H) +.

Example 49 [2- (4-Fluoro-phenylsulfanyl) -5-methyl-phenyl] - (7-methyl- [1,8] naphthyridyl) -amine Example 49a 1 - (4-Fluoro-phenylsulfanyl) -4-methyl-2-nitrobenzene 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 following the procedure of Example le for 18 hours to give the crude title compound which was purified at through column chromatography on silica gel eluting with 5% EtOAc / hexane to provide a solid (3.39 g, 74%).

Example 49b 2- (4-Fluoro-phenylsulfanyl) -5-methyl-phenylamine The product of Example 49a was reduced with SnCl 2 following the procedure of Example 1f to give the title compound.

Example 49c [2- (4-Fluoro-phenylsulfanyl) -5-methyl-phenyl] - (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 by following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA to yield the trifluoroacetic acid salt (224 mg, 49%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.37 (m, 3 H) 2.77 (m, 3 H) 6.29 (d, J = 6.99 Hz, 1 H) 7.10 (m, 2 H) 7.32 (m, 5 H) 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 (br. s., 1H) 14.43 (br. s., 1H); MS (ESI +) m / z 376 (M + H) +.

Example 50 [2- (4-Methoxy-phenylsulfanyl) -5-methyl-phenyl] - (7-methyl- [1,8] naphthyridin-4-l) -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-methoxy-benzene thiol (2.45 g, 175 mmol) for 18 hours following the procedure of Example 4b giving the product as a solid (3.76 g, 78%) .

Example 50b 2- (4-Methoxy-phenylsulfanyl) -5-methyl-phenylamine The product of Example 50a was reduced with SnCl 2 following the procedure of Example 1f to give the title compound.

Example 50c [2- (4-Methoxy-phenylsulfanyl) -5-methyl-phenyl] - (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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA to yield the trifluoroacetic acid salt (325 mg, 70%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.35 (s, 3 H) 2.77 (s, 3 H) 3.73 (s, 3 H) 6.26 (d, J = 6.99 Hz, 1 H) 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 (br.s, 1H) 14.32 (br.s, 1H); MS ESI + m / z 388 (M + H) +.

EXAMPLE SU [2- (3, 1-Diimeio¾S-ffe (! IHs l1FanDll) -5-meíií-1F® JTiill- (7-imieísl- [1, 8] nafftiiridin-4-ill) -ainn) ina Example 5a [2- (3,4-D5m © 1íonó-ffecT) eís lffair¾jl) -5-mett5l-ifeiniól amoima The product of Example 4a (11.25 g, 39.5 mmol) was reacted with 3,4-dimethoxy-benzenethiol (6.71 g, 39.5 mmol) for 18 hours following the procedure of Example 4b giving the product as a solid (7.75 g, 64%). %).

Example 511 b 2- (3, J-Dom © So ^ 5-phenyls llffanii!) - 5-methyl-phenylamide The product of Example 51a was reduced with SnCl 2 following the procedure of Example 1f to give the title compound.

Example SUc [2- (3,4-0ime1.OKD- { R®in) syD1Faini) -S-m®1. -1F®in) i.] - (7-m®1.D.- | [1l, 8] - mi aííó irscO i m 1) -am i n a 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 following the procedure of Example 1g to give the crude title compound which was purified through HPLC with TFA affording the trifluoroacetic acid salt (628 mg, 79%). H NMR (300 MHz, DMSO-de) d 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 following the procedure of Example 4b to give the product as a solid (7.88 g, 85%).

Example 52b 3- (2-Amino-4-methyl-phenylsulfanyl) phenol The product of Example 52a was reduced with SnCl 2 following the procedure of Example 1f to give the title compound.

Example 52c 3- [4- ethyl-2- (7-methyl-t1,8] naphthridin-4-ylamino) -phenylsulfanyl] -phenol The product of Example 1d (277 mg, 1.56 mmol) was reacted with the product from Example 52b (245 mg, 1.56 mmol) for 5 hours following the procedure of Example 1g to give the crude title compound, which was purified through of / PLC with TFA to provide the trifluoroacetic acid salt (399 mg, 52%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.38 (s, 3 H) 2.75 (s, 3 H) 6.30 (d, J = 6.99 Hz, 1 H) 6.53-6.58 (m, 2 H) 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); S (ESI +) m / z 374 (M + H) +.

Example 53 [3- (7-Methyl- [1,8] naphthyridin-4-ylamino) -4-phenylsulfanyl-phenyl] -methanol Example 53a Ethyl ester of 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 trifiuoromethanesulfonic anhydride (14.0 ml, 83.7 mmol) for 15 minutes following the procedure of Example 4a to give the title as an amber oil (22.26 g, 89%).

Example 53b Ethyl ester of 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 following the procedure of Example to give the title compound as a solid (13.2 g, 67%) .

Example 53c 3-Amino-4-phenylsulfanyl-benzoic acid ethyl ester The product of Example 53b was reacted with SnCl 2 following the procedure of 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 Id (2.06 g, 1.16 mmol) was reacted with the product of Example 53b (3.18 g, 1.16 mmol) for 5 hours following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA to yield the trifluoroacetic acid salt (3.61 g, 59%).

Example 53d [3- (7-Rfletyl- [1, 8] iniafíóirjdón-4-sSamino) -4- einiHsy! IainiH-1FefTit [l3-íTiie1taDiol The product of Example 53c (2.30 g, 5.54 mmol) in 60 mL of THF was reacted with LiAIH (420 mg, 11.0 mmol) for 18 hours followed by quenching with diluted HCl. The pH was adjusted to 10 with NH 4 OH. Extract with CH2Cl2, dry over gSO4, filter and concentrate in vacuo to give the crude title compound, which is purified by HPLC with TFA to yield the trifluoroacetic acid salt (325 mg, 70%). 1 H NMR (300 IV) Hz, DMSO-de) d ppm: 2.76 (s, 3 H) 3.99 (br. S, 1 H) 4.58 (s, 2 H) 6.31 (d, J = 7.35 Hz, 1 H) 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 (br s., 1H) 14.44 (br. s., 1H); MS (ESI +) m / z 374 (+ H) +.

Ejemropl © 54 [2- (-Uile? Ii-1? E [n) ysM0. { fa [niy] -5-metty-íf © ro ií J-am iima Example 54a H - (4-Eíoni-ff © niilsyllffainiD8) -4-fTnieíóI-2-iniüttiro - jeiniceinio 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. It was warmed to room temperature and Etl (0.232 mL, 2.87 mmol) was added slowly after stirring at room temperature for 4 days. The separated layers were quenched with water and dried dried over MgSO, filtered and concentrated in vacuo to give the product as a solid (510 mg, 92%). It was reduced with SnCl2 following the procedure of Example 1f to give the title compound.

Example 54b [2- (4-Ethoxy-phenylsulfanyl) -5-methyl-phenyl] - (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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA to provide the trifluoroacetic acid salt (241 mg, 30%). 1H NMR (300 MHz, DMSO-d ") d 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. It was warmed to room temperature and Etl (0.232 mL, 2.87 mmol) was added slowly after it was filtered at 50 ° C for 7 days. The separated layers were quenched with water and dried over MgSO4, filtered and concentrated under vacuum to give the product as a solid (700 mg, 100%). It was reduced with SnCl2 following the procedure of Example 1f to give the title compound.

Example 55b (7- ethyl- [1,8] naphthyridin-4-yl) 45-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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA to yield the trifluoroacetic acid salt (187 mg, 23%). 1 H NMR (300 MHz, D SO-d 6) d ppm: 0.97 (t, J = 7.35 Hz, 3 H) 1.62-1.79 (m, 2 H) 2.34 (s, 3 H) 2.76 (s, 3 H) 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-lsopropoxy-phenylsulfanyl) -5-methyl-phenyl] - (7-methyl- [1,8] naphthyridin-4-yl) -amine Example 56a 2- (4-lsopropoxy-phenylsulfanyl) -5-methyl-phenylamine The product of Example 4b (600 mg, 2.30 mmol) was reacted with NaH (0.83 g, 2.44 mmol) in 10 ml THF at 0 ° C for 2 hours. It was warmed to room temperature and i-Pr-I (0.574 mL, 5.74 mmol) was added slowly after it was filtered at 50 ° C for 10 days. The separated layers were quenched with water and dried over MgSO4, filtered and concentrated in vacuo to give the product as a solid (730 mg, 100%). It was reduced with SnCf2 following the procedure of Example 1f to give the title compound.

Example 56b [2- (4-lsopropoxy-phenylsulfanyl) -5-methyl-phenyl] - (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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA to provide the trifluoroacetic acid salt (185 mg, 23%). 1H NMR (300 MHz, DMSO-d6) d 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-n-t-benzamide A mixture of 4-bromoaniline (2.58 g, 14.99 mmol) in dry CH 2 Cl 2 (100 mL) was treated with 4-chloro-3-nitrobenzoyl chloride (3.60 g, 1 7.99 mmol) and α, β-diisopropyl-ethylamine (3.14 ml). , 7.99 mmoles), and the resulting mixture was stirred at room temperature for 1.7 hours. The solvent was concentrated under vacuum to give the title compound and the residue was taken up in ethyl acetate (100 ml) and washed with water and brine. The organic extract was dried over Na2SO4, filtered and concentrated under vacuum to give the title compound as a tan solid (5.122 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 (1.01 g, 3%). 1 14 mmol) at room temperature, then heated to 1000 ° under a nitrogen atmosphere for 3 hours. The reaction was cooled to room temperature and the solvent was concentrated under vacuum to give the title compound. The residue was taken in H20 (30 mL) and the pH was adjusted to 3 with 1 N aqueous HCl. The aqueous layer was then extracted with ethyl acetate, and the organic extracts were washed with brine (25 ml). The organic layer was dried over Na2S04 > it was filtered and concentrated under vacuum to give the title compound. The residue was titrated with methylene chloride and purified by flash chromatography on silica gel with gradient from 6% to 30% ethyl acetate / methylene chloride to give the title product as a dark yellow solid (517 mg , 1.16 mmole, 75%).

Example 57c 3-Amino-N- (4-bromo-phenyl) -4- (4-hydroxy-phenylsulfanyl) -benzamide The product of Example 57b was reduced with Fe and NH 4 Cl following the procedure of Example 237E to give 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA to yield the trifluoroacetic acid salt (30 mg, 20%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 0.99 (t, J = 7.35 Hz, 3 H) 1.69-1.96 (m, 2 H) 3.02 (t, J = 7.35 Hz, 2 H) 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 mmole) in 10 ml of CH2Cl2 with N, N-diisopropylethylamine (0.530 ml, 410 mmol) for 22 hours. It was washed with water and dried over Na 2 SO 4, filtered and concentrated under vacuum to give the crude title compound, which was purified by HPLC with TFA to yield the trifluoroacetic acid salt (35 mg, 40%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.75 (s, 3 H) 2.86 (s, 6 H) 6.65 (d, J = 6.99 Hz, 1 H) 6.76 (d, J = 9.19 Hz, 2 H) 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) +.

EjemnipDo SS > Esther 4- [4-mme1toD-2- (7-innieiol- [1l, 8] iniafíDirDdlSini-4-jiainnioinio) -1FenSuífairti3] - femiOico of acid eía? P? SILO and "IFó mucus The product of Example 5 (100 mg, 0.24 mmol) was reacted with ethanesulfonyl chloride (31.0 mg, 0.24 mmol) for 18 hours following the procedure of Example 58 to give the crude title compound, which was purified through HPLC with TFA affording the trifluoroacetic acid salt (20 mg, 14%). 1H NA / IR (300 MHz, DMSO-de) d 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 Eslíe ir feiniii.suBtfainiDlJ-iFein). lloco di ©, propairo-2-stullffóin acid) iic The product of Example 5 (80.0 mg, 0.195 mmol) was reacted with the propan-2-sulfonyl chloride (27.8 mg, 0.195 mmol) for 18 hours following the procedure of Example 58 to give the crude title compound, which was purified by HPLC with TFA to provide the trifluoroacetic acid salt (20 mg, 21%). 1H NR (300 MHz, DMSO-d6) d ppm: 8.90 (d, J = 8.46 Hz, 1H) 8.39 (d, J = 6.99 Hz, 1H) 7.76 (d, J = 8.82 Hz, 1 H) 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 = 699 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 the methanesulfonyl chloride (22.3 mg, 0.195 mmol) for 18 hours following the procedure of Example 58 to give the crude title compound, which was purified through HPLC with TFA to yield the trifluoroacetic acid salt (36 mg, 32%). 1 H NMR (300 MHz, DMSO-de) d 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 following the procedure of Example 58 to give the crude title compound, which was purified by HPLC. with TFA affording the trifluoroacetic acid salt (70 mg, 25%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 8.31 (d, 1 H) 7.73 (d, 1 H) 7.11 (d, 1 H) 6.85 (d, 1 H) 6.74 (s, 2 H) 6.64 (d, 2 H) 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: Phenyl-methanesulfonic acid 4- [4-methyl-2- (7-methyl- [1,8] -naphthyridin-4-ylamino) -phenylsulfanyl] -phenylenyl The product of Example 5 (120 mg, 0.294 mmol) was reacted with phenyl-methanesulfonyl chloride (55 mg, 0.294 mmol) for 22 hours following the procedure of Example 58 to give the crude title compound, which was purified HPLC with TFA to yield the trifluoroacetic acid salt (15 mg, 9%). 1 H NMR (300 MHz, DMSO-de) d 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 64 Ethyl ester of the acid. { 4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenoxy} -acetic The material of Example 5 (0.200g, 0.536 mmole) was suspended in acetone to which K2C03 was added. This was treated with bromoethylacetate (0.089 g, 0.536 mmol) at which time the reaction mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, the solid was filtered and concentrated under vacuum to give the crude title compound, which was purified by HPLC with TFA to give the product as a trifluoroacetic acid salt (24 mg, 10%). 1 H NMR (300 MHz, DMSO-de) d ppm: 1.22 (t, J = 6.99 Hz, 3 H), 2.34 (s, 3 H), 2.74 (s, 3 H), 4.20 (q, J = 6.99 Hz, 2 H) , 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 (M-H) -.

Example 65 Acid. { 4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] phenoxy} -acetic The product of Example 64 (0.246g 535mmol) was dissolved in 10 ml of 5% NaOH and 10 ml of EtOH and heated at 100 ° C for 2 hours and then stirred at room temperature for 10 hours. At that time all the solvent was removed under vacuum and the brown oil was redissolved in water, to which 2 ml of HCl was added and a yellow precipitate formed. The precipitate was collected through filtration and the solid was dried under vacuum overnight (150 mg, 64%) HNR (300 MHz, DMSO-d6) d 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 (-H) -.

Ejjeomipl) © ® (B 2,2-0.-tp? < e4.?-^- { 4? - [[4-? Pp) © (??? - 2-? 7-m © ¾5 .-! [1l. SIiniaiFftSirSc Dini - ^ - flOaainniatrDo) - < F e n 58 s i 1f a mi 5 II J - 1F e mi i II} - p go o p o o mi a m 5 d a The product of Example 83 (0.50 g, 0.134 mmol) was dissolved in DMF and treated with 2,2-dimethyl-propionyl chloride (0.016 g, 0.134 mmol) and stirred at room temperature for 1 hour. The DMF was removed under a stream of N2, and the crude residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (40.0 mg, 65%). 1 H NMR (300 MHz, DMSO-de) d 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, 1 H) 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. The DMF was removed under a stream of N2 > and the crude residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (41.0 mg, 65%). 1H NMR (300 MHz, DMSO-d6) d 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, 1 H); MS (ESI +) m / z 443 (M + H) +, (ESI-) m / z 441 (M-H) -.

Example 68 { 4- [4-ethyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} - cyclopropanecarboxylic acid amide The product of Example 83 (0.50 g, 0.134 mmol) was dissolved in DMF and treated with cyclopropanecarbonyl chloride (0.016 g, 0.134 mmol) and stirred at room temperature for 1 hour. The DMF was removed under a stream of N2, and the crude residue was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (25. mg, 40%). 1H NMR (300 MHz, DMSO-d6) d 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 (M-H) - Example 69 Benzyl ester of 2- acid. { 4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] phenylcarbamoyl) -pyrrolidin-1-carboxylic acid Carbobenzyloxy-proline (0.110 g, 0.443 mmol) was dissolved in THF to which was added N-methyl-morpholine (0.133 g, 0.443 mmol). Then, net isopropeny chloroformate (0.053 g, 0.443 mmol) was added and the reaction mixture was stirred at room temperature for 30 minutes. At this time the product of Example 83 (0.150 g, 0.402 mmol) was added as a solution in THF, stirred at room temperature for 1 hour. The reaction mixture was diluted with water and extracted with CH 2 Cl 2, dried over Na 2 SO 4) filtered and concentrated under vacuum to give the crude title compound, which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (118 mg, 48%). 1 H NMR (300 MHz. DMSO-de) d ppm: 1.82-1.98 (m, 3H), 2.22 (s, 2 1-1), 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- ethyl-2- (4-phenoxy-phenylsulfanyl) -phenyl amine The product of Example 4c (0.500 g, 1.91 mmol) was dissolved in CH2Cl2 together with phenyl boronic acid (0.701 g, 5.74 mmol), copper (II) acetate (0.659 g, 3.83 mmol), and triethylamine (0.387 g, 3.83 mmoles). It was stirred at room temperature for 48 hours, at which time 2 more equivalents of each reagent were added. It was stirred at room temperature for another 16 hours, at which time another 2 eq of each reagent was added. It was stirred at room temperature for another 16 hours. The reaction was diluted with water and extracted with ethyl acetate, dried over Na 2 SO 4, filtered and concentrated under vacuum to give the crude product, which was purified through silica gel column chromatography eluting with 20% EtOAc / hexane (0.100 g, 15%). The product was reduced with SnCl 2 following the procedure of Example 1f to give the title compound (90 mg, 98%).

Example 70b (7- ethyl- [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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid salt (64 mg, 50%). ? NMR (300 MHz, D SO-d6) d 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 (M-H) -.

Example 71 N- (3- [4-ethyl-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 (1.00g, 3.51 mmol) and 3-Amino-benzenethiol (658 mg, 5.26 mmol) were dissolved in DMF, to which was added 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. It was allowed to stir at room temperature for 1 hour, at which time, a solid was collected through filtration to give the title compound (690 mg, 61%). Example 71c N- [3- (2-Amino-4-methyl- phenylsulfanyl) -phenyl] -acetamide The product of Example 71b was reduced with SnCl2 following the procedure of Example 1f to provide the title compound (120mg, 20%).

Example 71d N-. { 3- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenyl-sulfanyl] -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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (45 mg, 18%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 1.97 (s, 3 H), 2.38 (s, 3 H), 2.74 (s, 3 H), 6.26 (d, J = 6.99 Hz, 1 H), 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 (M-H) -.

Example 72 { 2-. { 4- (1-amino-ethyl) -phenylsulfanyl] -5-methyl-phenyl} - (7-methyl- [1,8] naphthyridin-4-yl) -amine Example 72a Naphthalen-2-ylmethyl ester of thioacetymidic acid; salt of HBr 2-Bromomethyl-naphthalene (2.00 g, 9.05 mmol) and thioacetimide (680 mg, 9.05 mmol) were dissolved in CH 3 Cl and stirred at room temperature for 1 hour. The product was collected through filtration to provide the title compound (1500 g, 77%).

Example 72b. { 244- (1-L-ethyl-ethyl) -phenylsulfanyl) -5-methyl-phenyl} - (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 a trifluoroacetic acid salt (118 mg, 70%). 'H NMR (300 MHz, DMSO-de) d 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 (M-H) -.

Example 73 1-. { 4- [4-ethyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -ethantiona The product of Example 18 (265mg, 639mmol) and Lawesson's reagent (517mg, 1.28mmol) were dissolved in 3ml of toluene and heated at 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 yield the trifluoroacetic acid salt (14 mg, 5%). 1 H NMR (300 MHz, DMSO-d 5) d ppm: 2.33 (s, 3 H), 2.59 (s, 3 H), 2.63 (s, 3 H), 3.75 (s, 1 H), 6.17 (s, 1 H), 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 (M-H) - Example 74 N-. { 4- [4-Methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -2-phenyl-butyramide flask containing 3 equivalents of PS-DCC resin (polymer-bound '?,?,' - dicylcohexylcarbodiimide) was added 2-phenyl-butyric acid (27 mg, 0.16 mmol) dissolved in 3 ml of DMA, followed by HOBt (22 mg , 0.16 mmol), the product of Example 83 (50 mg, 0.134 mmol) and diethyl isopropylamine (52 mg, 0.402 mmol). The reaction was heated to 55 ° C overnight, filtered and transferred to a flask containing 3 equivalents of MP-Carbonate resin (macroporous carbonate). The reaction vessel and the PS-DCC resin were washed with MeOH and the combined filtrates were stirred on the MP-carbonate resin for 2 hours at room temperature. The MO-carbonate resin was removed by filtration and the reactions were concentrated to dryness. They were purified by HPLC with TFA to give the product as a trifluoroacetic acid (2 mg, 4%). 1 H NMR (500 MHz, DMSO-D 20) d 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 ?? -. { 4- [4-? ® 0-2- (7-? Pp) ß ?? - [1?, D1 ^ ff © mi S 0} - 4 - 1f © mi 5 II - Ib uid to my 5 di a The title compound was prepared using 4-phenyl butyric acid (27 mg, 0.16 mmol) as the acid following the procedure of Example 74. (1 mg, 2%). 1 H NMR (300 MHz, DMSO-d 6) d 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 the acid following the procedure of Example 74 (3 mg, 5%). 1 H NMR (300 MHz, DMSO-de) d ppm: 2.25 (s, 3 H), 2.36 (s, 3 H), 2.75 (s, 3 H), 4.70 (s, 2 H), 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-ethyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -2-p-tolyloxy-acetamide The title compound was prepared using p-tolyloxy-acetic acid (26 mg, 0.16 mmol) as the acid following the procedure of Example 74 (3 mg, 5%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.24 (s, 3 H), 2.36 (s, 3 H), 2.75 (s, 3 H), 4.64 (s, 2 H), 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 R-methoxy-phenyl-acetic acid (26 mg, 0.16 mmol) as the acid following the procedure of Example 74 (3 mg, 5%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.35 (s, 3 H), 2.73 (s, 3 H), 3.36 (s, 3 H), 4.82 (s, 1 H), 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 prepared using S-methoxy-phenyl-acetic acid (26 mg, 0.16 mmol) as the acid following the procedure of Example 74 (3 mg, 5%). 1H NMR (300 MHz, DMSO-de) d ppm: 2.35 (s, 3H), 2.73 (s, 3H), 3.36 (s, 3H), 4.82 (s, 1H), 6.36 (d, ¡= 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-ethyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenylcarbamoyl} - methyl) -amide of furan-3 carboxylic The title compound was prepared using [(furan-2-carbonyl) -amino] -acetic acid (27 mg, 0.16 mmol) as the acid following the procedure of Example 74 (1 mg, 2%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.36 (s, 3 H), 2.75 (s, 3 H), 4.02 (s, 2 H), 6.34 (d, J = 7.02 Hz, 1 H), 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-butyric acid (27 mg, 0.16 mmol) as the acid following the procedure of Example 74 (0.7 mg, 1%). 1 H NMR (300 MHz, DMSO-de) d 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 , 1 HOUR); 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 prepared using 1-acetyl-piperidine-4-carboxylic acid (27 mg, 0.16 mmol) as the acid following the procedure of Example 74 (0.7 mg, 1%). 1 H NMR (300 MHz, DMSO-de) d ppm: 1.77-1.84 (m, 2 H), 2.03 (s, 3 H), 2.36 (s, 4 H), 2.56-2.64 (m, 2 H), 2.75 (s, 3 H) ), 3.05-3.12 (m, 1 H), 3.83-3.91 (m, 1H), 4.37-4.43 (m, 1H), 6.30-6.36 (m, 1 H), 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-methyl-phenyl] - (7-methyl- [1,8] naphthyridin-4-yl) -amine The product of Example 18 (200 mg, 0.48 mmol) was suspended in 6N HCl (10 mL) and heated in air at 100 ° C for 1 hour. The solution was subsequently cooled in an ice bath and made basic with solid NaOH (2.64 gm). The crude product was isolated through extraction with dichloromethane and purified by HPLC with TFA to give the title compound as the trifluoroacetic acid salt (96.1 mg, 37%). 1 H NMR (300 MHz, DMSO-de) d 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. = 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 (ESL +) m / z 373.1 (M + H) +; (ESI-) m / z 371.1 (M-H) -.

EJemropí © 84 4- 4-G½le. { .aa-2- (7-inniGlt§ll-Iil, S | iniairtDiradg -4 - Damiinio) -feinióOsuiDf arBiO] - beinizainniida Example 84a Layer 4-¾4-innie1i -2-iniSiro-ff [niBSsi-] iFair¾ J-bein)? ODCoo 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 nitrogen. The reaction mixture was poured into water and acidified with glacial acetic acid. The solid product was collected through filtration, washed with water and dried under vacuum to give the title compound (0.877 g, 91%) sufficiently pure to be used as an isolate.

Example 84b 4-í4-Kjettil-2-6iiüíiro-ffeiniilsylíasiil) -beini? AmDtíla 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) followed by cooling in an ice bath and addition of isobutylchloroformate (0.148 mL, 1.14 mmoles). The resulting mixture was allowed to warm to room temperature with stirring for 30 minutes. Subsequent cooling was allowed in an ice bath followed by the addition of ammonia gas and heating to room temperature. The title compound was isolated through the addition of water and the solid collection through vacuum filtration was used without further purification (0.289 g, 96%).

Example 84c The product of Example 84c (0.289 g, 1.0 mmol) was reacted with stannous chloride (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 mmole) was reacted with the product of Example 84d (0.226 g, 0.875 mmole) for 24 hours following the procedure of Example 1 g to give the crude title compound, which was purified at HPLC with TFA to yield the product as the trifluoroacetic acid salt (0.185 g, 38%). ? NMR (300 MHz, DMSO-d6) d ppm: 2.37-2.46 (m, 3H) 2.74 (s, 3H) 6.36 (d, J = 6.99 Hz, 1H) 7.19 (d, 7 = 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 (M-H-).

Example 85 N-Methyl-4- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanylj-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 substituting N-methyl amine in methanol for 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) -phenylsulfanylj-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 mmoles) for 41 hours following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to give the product as the trifluoroacetic acid salt (0.078 g) g, 28%). 1 H NMR (300 Hz, DMSO-d 6) d ppm: 2.41 (s, 3 H) 2.70-2.82 (m, 6 H) 6.36 (d, J = 6.99 Hz, 1 H) 7.20 (d, J = 8.46 Hz, 2 H) 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 (M-H) -.

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-Methylene-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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as the trifluoroacetic acid salt (0.159gm, 38%). 1 H NMR (300 MHz, D SO-de) d ppm 2.39 (s, 3 H) 2.74 (s 3 H) 6.31 (d, J = 6.99 Hz, 1 H) 7.18-7.55 (m, 6 H) 7.61-7.79 (m, 3H) 7.90 (s, 1H) 837 (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 (-H) -.

Example 87 N -Methyl-3- [4-methyl-2- (7-methyl- [1,8] naphthyrin-4-i lam i) phenylsulfanyl] -benzamide Example 87a N-Methyl-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 by substituting N-methyl amine in methanol for ammonia to give the title compound (0.25 g, 96%).

Example 87b N-Methyl-3- (4-methyl-2-amino-phenylsulfan-yl) -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) -phenylsulfani-l-benzamide The product of Example 87b (0.208 g, 0.76 mmol) was reacted with the product of Example 1 d (0.1 36 g, 0.76 mmol) for 24 hours following the procedure of Example 1g to give the crude title compound, which was purified HPLC with TFA to give the product as the trifluoroacetic acid salt (0.204, 49%). 1 H NMR (300 MHz, DMSO-d 9) d ppm: 2.39 (s, 3 H) 2.65-2.81 (m, 6 H) 6.27 (d, J = 7.35 Hz, 1 H) 7.20-7.82 (m, 8 H) 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 4110 (M-H) -.

Example 88 Dimethyl-3- [4-methyl-2- (7-methyl- [1,8] naphthyridin-4-ylammon) -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 substituting N, N-dimethylamine in methanol for ammonia to give the title compound (0.26 g, 100%) Example 88b 3- (2-Amino-4-methyl phenylsulfanyl) N.N-dimethyl-benzamide The product of Example 88a was reacted as described in Example 84d to give the title compound (0.175g, 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 following the procedure of Example 1g to give the title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid salt (0.1552 g, 45%). 1 H NMR (300 Hz, DMSO-d ") d ppm: 2:40 (s, 3H) 2. 75 (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); S (ESI +) m / z 429.0 (M + H) +; (ESI-) m / z 427.0 (M-H) -.

Example 89 [2- (2-Fluoro-phenylsulfanyl) -5-methyl-phenyl] - (7-methyl- [1,8] naphthyridin-4-yl) -amine Example 89a 1- (2-Fluoro-phenylsulfanyl) -4-methyl-2-nitrobenzene 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 a solution of aqueous Na2COa (0.563 g, 5.3 mmol) dropwise at room temperature. The mixture was heated to reflux for 1 hour, and then evaporated. The residue was diluted with EtOAc, washed with H20, 5% KOH and brine, dried over MgSO4, filtered and concentrated under vacuum to give the title compound as a yellow crystal, which was purified by washing with water. -hexane cold to give the title product as a yellow crystal (1.15 g, 83%).

EXAMPLE 89b 2- (2-Fl oiro-feii¾iSs (L3JiFainii5) -5-fne1.D¡-1FefTi5íamina The product of Example 89a was reduced with Fe and NH 4 Cl following the procedure of Example 237E to give the title compound.

Example 8Sc [2- (2-Ffluoiro-ff © [ra5BsMlffaroiil) -5-! M © fty ^ j¡0) -amni.na 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (180 mg, 43%). 1 H NMR (300 MHz, DMSO-de) d ppm: 2.32 (s, 3 H), 2.62 (s, 3 H), 6.11 (br-s, 1 H), 6.95-7.45 (m, 811), 8.26 (br-s) , 1H), 8.55-8.70 (m, 1H), 9.08 (br-s, 1H); S (ESI +) m / z 376 (+ H) +, (ESI-) m / z 374 (M-H) -.

Example 90 [3- (7-Mephryl- [1, 8] naphthyridin-4-ylamino) -4- etr-0- 0 ffa mi-b-mi ® S 0] - ca bs mni ico Example 90a 3 -n 9ttiro-4- (iFe n i ??? o) be ??? S? n iftn 0 or A solution of sodium phlophenolate (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. It was cooled to room temperature and diluted with EtOAc. It was washed with water and the organic layer was dried over MgSO4. Filtered and concentrated in vacuo to give the title compound, which was purified through silica gel column chromatography eluting with 5% EtOAc / hexane to give a yellow solid (4.0 g, 19%).

EXAMPLE 9 © b 3-Amoirao-4- (feirii ¾óo) b © iniCBllcairbamaSo d® tteir-biLottilo A solution of the product of Example 90a (4.0 g, 15.6 mmol) and di-tert-butyl-dicarbonate (1.70 g, 7.79 mmol) was catalytically reduced using Ra-Ni in MeOH at 4,218 kg / cm 2 under an atmosphere of 1-12. . Removal of the catalyst and concentration under vacuum gave the title compound, which was purified through silica gel column chromatography eluting with 10% EtOAc / hexane to give a mixture of the 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 from Example I d (557 mg, 3.12 mmol) was reacted with the product of Example 90b (1032 mg, 3.12 mmol) for 18 hours following the procedure of Example 1g to give the crude title compound, which was purified at HPLC with TFA to give the product as a trifluoroacetic acid (310 mg, 17%). 'H NMR (300 MHz, D SO-de) d 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, 1 H) 11.05 (s, 1H) 14.43 (s, 1H); S (ESI +) m / z 473 (+ H) +.

Example 91 [2- (2,5-Dimethyl-furan-3-ylsulfanyl) -5-methyl-phenyl] - (7-methyl- [1,8] naphthyridin-4-yl) -amine Example 91A 2,5-Dimethyl-3- (4-methyl-2-n-phenyl-sulfanyl) -furan The title compound was prepared from 1-chloro-4-methyl-2-nitro-benzene (2.00 g, 11.7 mmol), 2,5-dimethyl-furan-3-thiol (1.50 g, 11.7 mmol), and K2C03 (3.233 g, 23.4 mmol) heated in DMF at 100 ° C for 4 hours. The reaction mixture was then cooled to room temperature and diluted with water and extracted with ethyl acetate. Dry over Na 2 SO 4, filter and concentrate in vacuo to give the title compound (3.5 g, 85%).

Example 91b 2- (2,5-Dimethyl-furan-3-ylsulfanyl) -5-methyl-phenylamine The product of Example 91a was reduced with SnCl 2 following the procedure of Example 1f to give the title compound.

Example 91c [2- (2,5-Dimethyl-furan-3-ylsulfanyl) -5-methyl-phenyl] - (7-methyl- [1,8] naphthyridin-4-yl) -amine The product of Example 1d ( 50 mg, 0.217 mmole) was reacted with the product of Example 91b (51 mg, 0.217 mmol) for 18 hours following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to provide the product as a trifluoroacetic acid (2.6 mg, 3.2%). 'H NMR (300 MHz, DMSO-de) d 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 ??, 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 + NaTFA) -.

Example 92 Estteir © íóOoco d®. Acid it. { ^ -. { 2-l < BiOKtC3¡Tbo im < siU-. { 7-meW- [1, ®] iraairi.iiir.doini-4-) -ainniiiiniol-4-raiei -1Feini s OtFamiiiOJ-lFeíTiojiii J-acéíóco The product of Example 5 (200 mg, 0.536 mmol) was suspended in acetone to which K2CO3 (81 mg, 0.589 mmol), and ethyl bromoacetate (89 mg, 0.536 mmol) were added. The reaction mixture was then heated to reflux for 4 hours, the reaction mixture was cooled to room temperature and the solvent was removed under vacuum. It was purified by HPLC with TFA to give the product as a trifluoroacetic acid (15 mg, 6%). 1 H NMR (300 MHz, DMSO-de) d 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); S (ESI +) m / z 546 (+ H-TFA) +.

Ejeinniplo 93 amiinia EXAMPLE 93A 2-CORO-1 - (4-C-Doiro-i-EIN) -4-! Tiiiiro-benzeneTio A solution of 1,2-dichloro-4-nitro-benzene (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 at 90 ° C 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 under vacuum to provide the title compound (13.5 g, 99%).

Example 33 B 3-CDoiro-4- (4-clloB-o-f © noní) -enieieamoinia 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 solution (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 with water and ethyl acetate. The aqueous layer was extracted through ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified with silica gel eluting with hexane to 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 Example 93B (254 mg, 1.0 mmol) and Example 1d (179 mg, 1. 0 mmol) in ethanol (10 ml) were brought to reflux 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%). 1H NMR (300 MHz, DMSO-D6) d 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, 1. H); (ESI-) m / z 394 (M-HK Example 94 [2- (4-Methoxy-phenylsulfanyl) -5-methyl-phenyl] - (7-trifluoromethyl- [1,8] naphthyridin-4-M) -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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA to yield the product as a trifluoroacetic acid (28 mg, 30%). * H NMR (300 MHz, DMSO-de) d 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 + HTFA) +; (ESI-) m / z 440 (M-H-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) under stirring and stirred at 5 ° C for 30 minutes. The deposited crystals were collected by filtration, washed with H20 and n-hexane, and dried at 40 ° C under vacuum to give the title compound as a pale brown crystal (4.85 g, 87%).

For example, they were pious SSIb 4 - CKI ® i i - 2 - mi i i r o - W - ff e ira ÓD - b e ira z a mro 5 é a The product of Example 95a (1.00 g, 5.5 mmol) and SOCI2 (4.03 mL, 55.0 mmol) were refluxed for 2 hours. The excess SOCI2 was removed under reduced pressure to give the corresponding acid chloride as a pale yellow oil. To a solution of the acid chloride obtained above in THF (15 mL) was added aniline (0.53 mL, 5.8 mmol) and Et3N (1.17 mL, 8.3 mmol) dropwise 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 H20, acidified to a pH of 3 with 10% HCl and then extracted with EtOAc. The extract was washed with 10% NaHC03, dried over gSO4 filtered and concentrated under vacuum to give the title compound as a pale brown crystal, which was purified through washing with n-hexane to give the desired product as a pale brown glass (0.80 g, 57%).

Ejjeinmpll © S) @e 2 - A mro o your o - < $ - m © ft ?? - M - ff ® ira i i - b e mi z a mn > The product of Example 95b was reduced with Fe and NH CI following the procedure of Example 237E to give the title compound.

For example 95dl - eKU-2-. { 7-meW-i, ®in8¡Uiñ'-Q-'ü3imino) M - ife my 51- toe miz a mi ú a 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 following the procedure of Example 1g to give the crude title compound, which was purified through of silica gel column chromatography eluting with 50: 1 CH2Cl2 / eOH to provide the title compound (210 mg, 68%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.40 (s, 3 H), 2.68 (s, 3 H), 6.62 (d, J = 6.9 Hz, 1 H), 6.98 (t, J = 7.3 Hz, 1 H) , 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, 11.1), 8.94 (d, J = 8.8 Hz, 1H); MS (ESI +) m / z 369 (SW + H), ESI-m / z367 (M-H).

EXAMPLE 96 M- [3- (7-Rae-y- [1.8 J a (Fioirid-N-4-ammono-4 - (? In in sy [fafTiól-fee 3- ac íamDdla Example 96a 3 - N í ir o - 4 - © ira SD si ff a mi 80 - pheno I a mni S mi a A mixture of 2-nitro-4-chloroaniline (1.0 g, 5.79 mmoles), thiophenol sodium ( 0.84 g, 6.4 mmol) in DMF (10 mL) was heated 2.5 hours at 1000 ° C. The mixture was cooled, diluted with ethyl acetate (100 ml) and the organic layer was washed with water, 20% aqueous potassium hydroxide solution and 10% aqueous sodium chloride solution, then dried over sodium sulfate. anhydrous sodium The drying agent was filtered and the solvent was concentrated under vacuum leaving 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 under vacuum leaving 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 A solution of the product of Example 96b was reduced with Fe NH 4 Cl following the procedure of Example 237E to give the title compound.

Example S6d) N- [3- (7-Meim- [1.8] iniaffi5ridiB-4-ii.amfno) -4-phenylsulfanyl-phenyl] -acettannioda 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (77 mg, 27%). 1 H NMR (300 MHz, DMSO-de) d 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 [Z - ^ - Mettoxy-ffeiro-Dsuflffaroyj S-me & ^ si J-ainraómia The product of Example 2g (275mg, 1.33mmol) was reacted with the product of Example 50b (326mg, 1.33mmol) for 18h following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (392 mg, 56%). 'H NMR (300 MHz, DMSO-de) d 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 (br. S., 1H) 14.37 (br. S., 1H); MS (ESI +) m / z 416 (M + H) +.

Example 98 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (305 mg, 45%). 1H NfWR (300 MHz, DMSO-de) d 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, 1 H) 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) +.

Ejeinnipfl © 99 The product of Example 6 (120 mg, 0.274 mmole) was reacted with isopropyl sulfonyl chloride (43 mg, 0.30 mmol), NN-diisopropylethylamine (43 mg, 0.33 mmol). , and catalytic DMAP in CH2CI2 for 18 hours to give the crude title compound, which was purified by HPLC with TFA to afford the product as trifluoroacetic acid (40 mg, 23%). 1 H NMR (300 MHz, DMSO-de) d 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 Ester 4- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) phenylsulfanyl] -phenyl methanesulfonic acid The product of Example 6 (100 mg, 0.228 mmol) was reacted with methanesulfonyl chloride (28 mg, 0.251 mmol), NN-diisopropylethylamine (88.4 mg, 0.684 mmol), and catalytic DMAP in CH2Cl2 for 18 hours to give the crude title, which was purified by HPLC with TFA to give the product as trifluoroacetic acid (20 mg, 15%). 1H NMR (300 MHz, DMSO-de) d 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 +) 480 m / z (M + H) +.

EXAMPLE 101 Ester 4- [4-methyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl 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 catalytic DMAP in dichloroethane for 18 h giving the compound of crude title, which was purified by HPLC with TFA to give the product as trifluoroacetic acid (30 mg, 22%). H NMR (300 MHz, DMSO-de) d 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, 2 11) 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 Ester 4- [2- (7-ethyl- [1,8] naphthyridin-4-ylamino) -4-methyl-phenylsulfanyl] -phenyl of propan-2-sulfonic acid The product of Example 4 (100 mg, 0.233 mmol) was reacted with isopropyl sulfonyl chloride (40 mg, 0.280 mmol), NN-diisopropylethylamine (90 mg, 0.70 mmol), and catalytic DMAP in dichloroethane for 18 hours to give the title compound. crude title, which was purified by HPLC with TFA to give the product as trifluoroacetic acid (12 mg, 12%). 1 H NMR (300 MHz, DMSO-de) d 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 Phenyl-methanesulfonic acid 4- [2- (7-ethyl- [1,8] naphthyridin-4-ylamino) -4-methyl phenylsulfanyl] -phenyl ester The product of Example 4 (98 mg, 0.228 mmol) was reacted with benzyl sulfonyl chloride (43 mg, 0.228 mmol), NN-diisopropylethylamine (88 mg, 0.686 mmol), and catalytic DMAP in dichloroethane for 18 h to give the compound of crude title, which was purified by HPLC with TFA to give the product as trifluoroacetic acid (35 mg, 23%). H NMR (300 MHz, DMSO-de) d 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-RfletN-2- (7-me1tH- [1,8] naphthyridm-phemethyl) -ac © liainniiida Example 104A 4-M © tt -2- (7-me4H- [1l, 83iniaffííródiiri-4-illainnBinio) -feiríoll The product of Example 1d (893 mg, 5 mmole) and 2-amino-4-methyl-phenol (616 mg, 5 mmole) in ethanol (20 mL) were refluxed for 4 hours. The mixture was cooled to room temperature and evaporated. The residue was titrated with hexane / ethyl acetate (3: 1) to give the title compound in a quantitative yield as the hydrochloride salt.

EjerapSo 104B Esther 4®rl oííljco acid (2-hódiroji! -S-inniei.i8-feiniií) - (7-mei.jll- [H, S] iraalFft5rDdíiro- < 3-51.}. -ca [rbá [nraico To a mixture of Example 104 A (1.51 g, 5 mmole) and di-tert-butyl dicarbonate (2.4 g, 11 mmole) in 20 ml anhydrous THF was added NaOH (40 ml, 1N, 40 mmole). The solution was stirred at room temperature for 40 hours and was 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 eluting with 2% methanol in dichloromethane to give the title compound (1.70 g, 93%).

EXAMPLE H04C M- (4- [4-M®2i-2- (7-meiS- [1,8] nafí6-! < .in-4-t! Amiíio) -feinioKimeíi5] - 1F emi II} - ace 4 a mni 5 ú a A solution 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 fetrabutylammonium iodide (0.001 g) in DF (1 mL) was stirred at room temperature for 16 hours. The mixture was poured into water and extracted through 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 eluting with 2% methanol in dichloromethane to 5% methanol in dichloromethane to give the title compound as a trifluoroacetic acid salt (11 mg, 21%). 1 H NMR (300 MHz, D SO-d 6) d ppm 2.00 (s, 3 H) 2.31 (s, 3 H) 2.74 (s, 3 H) 5.05 (s, 2 H) 6.36 (d, J = 6.99 Hz, 1 H) 7.12 ( d, J = 8.46 Hz, 2H) 7.25 (m, 3H) 7.40 (d, J = 8.46 Hz, 2H) · 7.73 (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 Ethyl ester of 2- acid. { 5- [2- (4-Acetylamino-phenylsulfanyl) -5-methyl-phenylamino] - [1,8] naphthyridin-2-yl} -propionic To a slurry of sodium borohydride (95%, 0.025 g, 1.0 mmol) in 5 ml anhydrous THF at 0 ° C under an atmosphere of N 2 was added 2-methyl-malonic acid diethyl ester (0.174 g, 1.0 mmol) drop a drop. The mixture was stirred for 30 minutes at room temperature, treated with the product of Example 24a (0.047 g, 1.0 mmol), microwaved at 120 ° C for 1 hour, cooled, partitioned between ethyl acetate and water and neutralized with 1M HCI. The aqueous layer was extracted through ethyl acetate and the combined organic layers were dried over Na 2 SO 4, filtered and concentrated under vacuum to give the crude title compound. The residue was purified by chromatography on silica eluting with 1% methanol in dichloromethane to give the title compound (0.031 g, 62%). 1H NMR (300 MHz, DMSO-D6) d 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-bromo nitrobenzene (0.875 g, 3.9 mmol), 4-acetamido thiophenol (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, emptied to ice and the resulting solid was collected through filtration and dried under vacuum leaving the title compound as a yellow solid (1.4 g, 100%).

Example 106b N- [4- (2-Amino-4-bromo-phenylsulfanyl) -phenyl} -acetamida 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 solution (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 under vacuum 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 under vacuum to provide the title compound (1.2 g, 92%).

Example ü © 6c N-. { 4- [4-Bromo-2- (7-metf l-C1,8] naffiirtdin ^ 1F e m > i 0.}. - a c e tt a mi i d a 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 following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (53mg, 19%). 1H MR MR (300 MHz, DMSO-de) d ppm: 2.05 (s, 3.-H) 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) +.

Ej®mn) | pDo OID)? < f or orí S 0 s and 1 ffa n 3 II] - IFe cu 50} - a c e 4 a m l a The title compound was prepared according to the procedure of Example 47 substituting hydrazine hydrate (0.050 g, 1.0 mmol) for morpholine. The crude product was purified through HTP using HPLC with TFA to give the title compound as the trifluoroacetic acid salt (0.0125 g, 19%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.04 (s, 3 H), 2.33 (s, 3 H), 6.13 (d, J = 7.35 Hz, 1 H, 7.06 (d, J = 8.09 Hz, 1 H) , 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 +) miz 431 (M + H) +; Example 108 N- (4-. {2- [7- (2-Dimethylamino-ethoxy) - [1,8] naphthyridin-4-ylamino] -4-methyl-phenylsulfanyl}. Phenyl) -acetamide The title compound was prepared according to the procedure of Example 27 by substituting N. N-dimethylethanolamine (0.044 g, 0.5 mmol) for diethyl malonate. The crude product was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (0.05 g, 70%). 1 H NMR (300 MHz, DMSO-de) d 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-Methoxy-ethylamino) - [1,8] naphthyridin-4-ylamino] -4-methyl-phenylsulfanyl}. Phenyl) -acetamide The title compound was prepared according to the procedure of Example 47 substituting 2-methoxyethylamine (75 mg, 1.0 mmol) for morpholine. The crude product was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (10 mg, 17%). 1H NMR (300 MHz, DMSO-d6) d 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-lsobutyl- [1,8] naphthyridin-4-yl) - [2- (4-methoxy-phenylsulfanyl) -5-methyl-phenyl-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 by following the procedure of Example 1g the crude title compound that was titrated with 3: 1. ether / THF affording the title compound as a hydrochloride salt (121 mg, 96%). '? NMR (300 MHz, DMSO-de) d 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 = 7.35 Hz, 2H ) 3.72 (s, 3H) 6.27 (d, J = 6.99 Hz, 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. d, J = 8.46 Hz, 1H) 8.41 (d, J = 6.99 Hz, 1H) 9.07 (d, J = 8.46 Hz, 1H) 11.09 (br s, 1H) 14.40 (br s, 1H); MS (ESI +) m / z 430 (M-CI) +; (ESI-) m / z 428 (-HCl) -.

Example 111 Ethyl ester of the acid. { 5- [2- (4-Amino-phenylsulfanyl) -5-methyl phenylamino] - [1,8] naphthyridin-2-yl} -cyano-acetic The product of Example 30 (19 mg, 0.037 mmol), 2 ml of ethanol and 1 M hydrochloric acid (1.5 ml) were combined and heated at 90 ° C for 3 hours, cooled and concentrated in vacuo to give the title compound. Title. The crude product was purified by HPLC with TFA to give the title compound as a trifluoroacetic acid salt (10. mg, 46%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 1.28 (t, J = 6.99 Hz, 3 H), 2.28 (s, 3 H), 4.25 (q, J = 7.11 Hz, 2 H), 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) +.

EjemnipDo 11112 M-. { 4- [2- (7-DsobySi! - [1l, 83na1FltkDdBini-4-yamono) -4-mein-fenys í? Ainióll] - íf¾üí} -aceydam 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (35 mg, 33%). 1 H NMR (300 MHz, DMSO-de) d 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 (-H-TFA) -.

Eg they were pious 1113 ff © mi S II s 0 ff a mi i II] - b e orí? a innt i d a The product of Example 85b (0.155 g, 0.57 mmol) was reacted with the product of Example 2g as a solution of 3.15IV1 in ethanol (0.18 ml, 0.57 mmol) for 24 hours following the procedure of Example 1 g to give the crude title, which was purified by HPLC with TFA to give the product as a trifluoroacetic acid salt (0.180 g, 56%). 1H NMR (300 MHz, DMSO-d6) d ppm: 0.97 (t, J = 7.35 Hz, 3H) 1.72- I.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- II. 09 (s, 1H); MS (ESI +) m / z 443.2 (+ H) +; (ESI-) m / z 441.2 (-H) -.

Ejeinra Do 114 M-raeíDS-3- [4-rai © ¾ -2- (7-pirop5S- [1 1G and in ó 0 s u I ff a n 1] -he n za m i? A The product of Example 87b (0.155 g, 0.57 mmol) was reacted with the product of Example 2g as a 3.15 solution in ethanol (0.18 ml, 0.57 mmol) for 24 hours following the procedure of Example 1g to give the crude title compound which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (0.042 g, 13%). 1H NMR (300 MHz, DMSO-de) d 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 (M-H) -.

EXAMPLE 115 (4- [4-t-yl-4-yl-2- (7-piropii- [1, 8] natftirid n-4-5! Amin) -tfemlsulffaniO] | - femyl.} - methaneO Example 115a The product of Example 84b (0.5 g, 1.73 mmol) was dissolved in THF (15 ml) and cooled in an ice bath. To the solution cooled under nitrogen diborane was added as a solution of 1.0WI 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 through extraction (ether / water) processing and dried with MgSO 4, filtered and concentrated under vacuum to give the crude title compound. Purification through flash chromatography on silica gel gave the alcohol as a bright yellow solid (0.392 g, 82%).

Example 111151b l < & -. { 2-fommo- -m < Bk'ü ~ $ < Bm'ü &Ml $ am'ü) einiDl] -inn) eíain) oO The product of Example 115a (0.389 g, 1.41 mmol) was reacted with stannous 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-Met.l-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -metanol The product of Example 2g as a 3.15M 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 hours following the procedure of Example 1 g to give the compound of crude title, which was purified by HPLC with TFA to give the product as a trifluoroacetic acid salt (0.0195 g, 14%). 1 H NMR (300 MHz, DMSO-de) d 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 (M-H) -.

Example 116 4- [4- (4-Bromo-benzyloxy) -2- (7-methyl-pyrido [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-bromomethyl-benzene using the conditions described in Example 237C to provide 4- (4-bromo-benzyloxy) -1-chloro-2 -nitro-benzene which was treated sequentially using the procedures of Examples 237D and 237E to provide the title product.

Example 11683 4-f4- (4-Biromo-be ^ cyonS) -2- (7-mey-poirodo [2,3-d] pkimB (C.oini-4-50 to mro 5 mi o) -ff ® ira YES yes no 0 to anger or BJ -ff © ira or D The product of Example 116A was reacted with the product of Example 237B using the procedure of Example 237F substituting the product of Example 116A for the product of Example 237E to provide the crude title compound, which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (19 mg, 17%). 1H NftAR (300 M z, DMSO-D6) d 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 (s, 1H) 7.73 (d, J = 8.46 Hz, 1H) 8.72 (s, 1H) 8.84 (d, J = 8.46 Hz, 1H) 9.69 (s, 1H) 11.08 (m, 1H); MS (ESI +) m / z 545, 547 (M + H) +.

Example 117 M-. { ^ - [[4l-iHáíílironi-2- (7-piropiSfi- | ['., 8]] ir, © ffaSró (tí] óoT) -41-iflam.6io) -ff © ira SOsisliFainií 0] - IFe ira D} -ac © tta mra 8 ú a 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 following the procedure of Example 1 g to give the crude title compound, which was purified by HPLC with TFA to give the product as a trifluoroacetic acid salt (15mg, 20%). 1H NMR (300 MHz, DMSO-d6) d ppm: 0.97 (t, J = 7.35 Hz, 3H) 1.72-1.92 (m, 2H) 2.01 (s, 3H) 2.98 (t, J = 7.35 Hz, 2H) 6.30 (d, J = 7.35 Hz, 1H) 6.89 (d, J = 2.57 Hz, 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) , 1 HOUR); MS (ESI +) m / z 445 (M + H) +.

Ejjeinntip.o 11118 [2- (2,5 - ??? pp? © 1.5.-1G ?? G8 ??) - 3 ^ [1, 8] iroafttür5t_orii-4-ol) -ami (nia 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (28 mg, 19%). 1 H NMR (300 MHz, DMSO-de) d 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 (br.S., 1H); MS (ESI +) m / z 418 (+ HTFA) +.

Example 119 N-. { 4- [4- (2-ethyl-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 from 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. hours. The next day, the reaction mixture was emptied on ice and the solid was collected through filtration to give the title compound (32 mg, 100%).

Example 119b N-. { 4- (4- (2-ethyl-benzyloxy) -2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide The product from 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 following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (23mg, 42%). 1H NMR (300 M z, DMSO-de) d 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 (1 + H) +.

Example 112 © N-. { ^ - ^ - (3-E! ÍII®üDB-lb®inicioD 3iD) -2- (7-piiro | sD- (1l ^^ intafftSir.cfliiini-'d-DlIainniDinitai]) - (f © n 51 s II an 5 II] - 1F e mi ii.}. - ace 4 a pp? ¡da EjeinrapOo H2 © a 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. hours. The next day, the reaction mixture was emptied on ice and the solid was collected through filtration to give the title compound (32 mg, 100%).

Ejemnip. © Ü2 © b W-. { 4- [4- (3-fM®4i0-b®mc.loK1) -2- (7-me «S0 - [^ fphenylsulffaroyljl-feni! ^ - acetami id The product of Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (100 mL) with the product of Example 120a (32 mg, 0.085 mmol) for 18 hours following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to provide the product as a trifluoroacetic acid salt (14 mg, 26%). 1H NMR (300 MHz, DMSO-d6) d 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, 1 H); MS (ESI +) m / z 549 (M + H) +.

Example 121 (5-Bromo-2-phenylsulfanyl-phenyl) - (7-methyl- [1 &g;; 8] naphthyridin-4-yl) -amine Example 121a S-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 of CH2Cl2 under an N2 atmosphere was treated with trifluoromethanesulfonic anhydride (8.5 mL, 50.5 mmol) at 0 ° C for 30 minutes. It was quenched through the addition of MeOH. It was washed sequentially with 10% citric acid, 0.5 m KOH and water. Dried over MgSO4, filtered and concentrated in vacuo to give the title compound which was purified through silica gel column chromatography eluting with CH2Cl2 to give an amber oil (15.2 g, 95%).

Example 121b (4-Bromo-2-nitrophenyl) (phenyl) sulfan 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 Na 2 CO 3 and heated overnight under reflux. It was cooled to room temperature and extinguished with water. It was extracted with EtOAc. Dried over MgSO4, filtered and concentrated in vacuo to give the title compound, which was purified through silica gel column chromatography eluting with 5% EtOAc / hexane to give a yellow oil (133 g, 99%). .

Example 121c 5-bromo-2- (phenylthio) benzenamine The product of Example 121b (2.0 g, 6.45 mmol) was reduced with SnCl 2 following the procedure of Example 1f to give 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (129 mg, 15%). H NMR (300 MHz, DMSO-de) d 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 K2C03 (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 agitation for 24 hours. It was cooled to room temperature and diluted with EtOAc. It was washed with water and the organic layer was dried over gS04. Filtered and concentrated in vacuo to give the title compound, which was purified through silica gel column chromatography eluting with 5% EtOAc / hexane to give an orange oil (1.89 g, 40%).

Example 122b 4 - (2 - a pp> d mi o - 4 - mni e tt 50 ff etr o n) 1F e my o í í The product from Example 122a (1.89 g, 7.71 mmol) was reduced with SnCl 2 following the procedure of 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (226 mg, 31%). HNR (300 Hz, DMSO-de) d 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, 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 (+ H-TFA) +.

EXAMPLE 1123 Acodlo éstteir ieir-lljyttiilliico foi-lZ-. { 7 -m® U-l ^, Q] maUwMiñ- -'ü3im'm € > } The product of Example 1d (556 mg, 3.12 mmol) was reacted with the product of Example 90c (1032 g, 3.12 mmol) for 18 h following the procedure of Example 1d (556 mg, 3.12 mmol). Procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid (228 mg, 31%). 1H NR (300 MHz, DMSO-d ") d 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, 21-1) 8.40 (d, J = 6.99 Hz, 2H) 8.90 (d, J = 8.82 Hz, 2H) 11.00 (s, 2H) 14.40 ( s, 2H); S (ESI +) m / z 829 (M + H-TFA) +.

Example Ü24 (5-Biroinn) 0-2-? EnoxD-fenDD) - (7-piropiiD- | [H .SlroatfttondDm - ^ - ilIJ-ainnHinia Example 124a 4-biromo-2 ira.tiro-11-hydroxybenzinium A solution of phenol (2.35 g, 25.0 mmoles) and 2C03 (9.4 g, 68.1 mmoles) in 40 ml of DF was heated at 100 ° C with 4-bromo-1-fluoro-2-nitrobenzene (5.0 g, 22.7 mmoles) with agitation for 24 hours. It was cooled to room temperature and diluted with EtOAc. It was washed with water and the organic layer was dried over MgSO4. Filtered and concentrated in vacuo to give the title compound, which was purified through silica gel column chromatography eluting with 15% EtOAc / hexane to give a yellow oil (6.6 g, 99%).

EXAMPLE Ü24to 5-B iromo-2 -f e moni benzesia mona The product of Example 124a (6.6 g, 22.5 mmol) was reduced with SnCl 2 following the procedure of Example 1f to give the title compound as a brown oil (5.9 g, 100%).

Example Ü24c N- (5 biroinmo-2-1? EiraoJiD? EsTii8) -7- | iropiBS-1l f®-inia1FllóródIóini-4-ainn) ói¡T) a The product of Example 2g (275mg, 1.33mmol) was reacted with the product of Example 124b (351mg, 1.33mmol) for 18 hours following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (470 mg, 65%). 'H NM (300 MHz, DMSO-de) d 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 12S (5-Biroimio-2-pheneOKS-f-ire) - (7-m í ii ¡[[1,, 8] naffiridin-4-yl) -aniine The product of Example 1d (278 mg, 1.56 mmol) was react with the product of Example 124b (412 mg, 1.56 mmoles) for 18 hours following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to give the product as a trifluoroacetic acid (206 mg , 25%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.73 (s, 3 H) 6.69 (d, J = 7.35 Hz, 2 H) 6.96 (d, J = 7.72 Hz, 2 H) 7.05-7.15 (m, 3 H) 7.24 -7.36 (m, 2H) 7.68 (dd, J = 8.82, 2.57 13z, 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-TFAJ +.

Example 126 4- [4-CDoiro-2- (7-inrc® O- [il. @] Irca? ^ Inri eiox or -eti 1) - toe raza ira. or I gave Example 126a 4- (4-Chloro-2-snitrofenoxi) bein) methyl zoalo 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 Na 2 CO 3 and heated overnight under reflux. It was cooled to room temperature and extinguished with water. It was extracted with EtOAc. Dry over WlgS04, filter and concentrate in vacuo to give the title compound, which is purified through silica gel column chromatography eluting with 10% EtOAc / hexane to give the title compound as a yellow solid (29.6 g, 92%).

Example 1126b Layer 4- (4-c8oiro-2-roDirotefeirox) benzoic © 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 under reflux for 1 hour. It was cooled to room temperature and acidified with aqueous HCl (1). The precipitate was filtered, washed with H20 and dried with air to give the title compound as a yellow solid (28.2 g, 100%).

Example 128c COoiruiro of 4- (4-chloro-2-nitrophenium K) ben? Oi The product of Example 126b (4.0 g, 13.6 mmol) in 40 ml of CH 2 Cl 2 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 under vacuum to give the title compound as a yellow oil (4.2 g, 100%).

Example 126d 4- (4-cllo [ro-2-iniiírofefTioJi5) -M- (2-metoKDetSÍ) berí? Aim) oda The compound of Example 126c (1.0 g, 3.2 mmol) in CH 2 Cl 2 was added to a mixture of 2-methoxyethamine (722 mg, 9.61 mmol) in CH 2 Cl 2. The mixture was stirred for 12 hours. The mixture was concentrated under vacuum to give the title compound, which was purified through silica gel column chromatography eluting with 50% EtOAc / hexane 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 following the procedure of 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 from Example 1d (111 mg, 0.62 mmol) was reacted with the product of Example 126e (200 mg, 0.62 mmol) for 18 hours following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (89.4 mg, 25%). 1 H NMR (300 MHz, DMSO-D 6) d ppm: 2.73 (s, 3 H) 3.25 (s, 3 H) 3.32-3.50 (m, 4 H) 6.72 (d, J = 6.99 Hz, 1 H) 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 hours, 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 propan-1-amine (568 mg, 9.61 mmol) for 12 hours following the procedure of Example 126d to give the 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 following the procedure of Example 1f to give 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (45.9 mg, 13%). 1 H NMR (300 MHz, DMSO-de) d 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-methoxime detanamine (391 mg, 6.41 mmol) for 12 hours following the procedure of Example 126d to give the title compound (1.03 g, 100%).

EXAMPLE 11281b 4- (2-amino-4-chloro-Feirrio-N-meioKi-tVi-meft Ibeinizainriiidla The product of Example 128a (1.0 g, 2.97 mmol) was reduced with SnCl2 following the procedure of Example 1f to give the title compound as a clear oil (911 mg, 100%).

Example 128c 4- (4-C uoro-2- (7-rhinethyiO-1, 8-nafflliirodin -4-5 lame n) phenoxy) -N-methoxy-N-m e 4? II b e ra z. to inm o di a The product from Example 1d (111 mg, 0.62 mmol) was reacted with the product of Example 128b (192 mg, 0.62 mmol) for 18 hours following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (50.9 mg, 15%). 1H NR (300 MHz, D SO-de) d 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 CH 2 Cl 2 was added to a mixture of diethylamine (469 mg, 6.41 mmol) in CH 2 Cl 2 - The mixture was stirred for 12 hours. The mixture was concentrated under vacuum to give the title compound, which was purified through silica gel column chromatography 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 following the procedure of Example 1f to give 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 following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifiuoroacetic acid (49.2 mg, %). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 1.01 (s, 6 H) 2.73 (s, 3 H) 3.35 (s, 1 H) 3.53-3.81 (m, 4 H) 6.70 (d, J = 7.35 Hz, 1 H) 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) +.

Execution H3fl > benzainniiidla The product of Example 2g (75mg, 0.36 mmol) was reacted with the product of Example 127b (111 mg, 0.36 mmol) for 18 hours following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifiuoroacetic acid (25.8 mg, 12%). 'H NMR (300 MHz, DMSO-de) d 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 (+ H-TFA) +.

EJemrapBo 1131 4- [4-CBo [ro-2-í7- | piropól- [1l, © l ^ afÍDirSdDini-4-DDainniD [nioJi-1Fein) 0¾51-KI-í2- irm e 4 o? S - e t or 1) - b e mi? a m i ú a The product from Example 2g (75mg, 0.36 mmol) was reacted with the product of Example 126e (116 mg, 0.36 mmol) for 18 hours following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (101.7 mg, 46%). 1 H NMR (300 MHz, D SO-de) d 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) +.

Ejjemrapl © H32 - [4-Cloir © -2- (7-p [r © py- [1l, S] (mafftt5nd5 [^^ M - pp) © 4 S II - b © m? A pp? 5 d¡ to The product of Example 2g (75mg, 0.36 mmol) was reacted with the product of Example 128b (111 mg, 0.36 mmol) for 18 hours following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (76.3 mg, 36%). 1 H NMR (300 MHz, D SO-de) d 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 CH 2 Cl 2 was added to a mixture of N-methylenatamine (379 mg, 6.41 mmol) in CH 2 Cl 2 - The mixture was stirred for 12 hours. The mixture was concentrated under vacuum to give the title compound, which was purified through silica gel column chromatography 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 following the procedure of Example 1f to give 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 (100mg, 0.61 mmol) was reacted with the product of Example 133b (185 mg, 0.61 mmol) for 18 hours following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (141 mg, 42%). 1H NR (300 MHz, DMSO-de) d 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-Biromo-beimcóllo3iD) -2- (7-innietol- [1, 8 | imaffíS redo? P? -4-i lame imo) - 1F e mi o II s and II ff tro ii] - ff eno I 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (129 mg, 61%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.76 (s, 3 H) 5.12 (s, 2 H) 6.26 (d, J = 6.99 Hz, 1 H) 6.65 (d, J = 8.45 HZ, 2 H) 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 (br s, 1H) 14.40 (br s, 1H); MS (ESI +) m / z 544.546 (M + H-TFA) +; (ESI-) m / z 542, 544 (-HTFA) -.

EXAMPLE 1135 ff e mi 5 II s no 0 IFa n § §] - ffe ira or I A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromo-3-bromomethyl-benzene using the conditions described in Example 237C to provide 4- (3-bromo-benzyloxy) -1-chloro-2. -nitrobenzene which was treated sequentially using the procedures of Examples 237D and 237E to provide 4- [2-amino-4- (3-bromo-benzyloxy) -phenylsulfanyl] -phenol. The product from Example 1 d (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 following the Procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid (118 mg, 56%). 1H NMR (300 MHz, DMSO-de) d 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 , 811) 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 (br s, 1H) 14.39 (br s, 1H); MS (ESI +) m / z 544. 546 (M + H-TFA) +; (ESI-) m / z 542, 544 (M-H-TFA) -.

EjemnipDo Ü36 4-l [4-i (3-Biroinnio-_jesTicSloiii) -2- (7-pirop5i- [1l, &Wtñúm - ^ - Usímino faith mi ó 1 si »í a mi ¡II J - e my or I 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 following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to give the product as a trifluoroacetic acid (86 mg, 41%). 1H NMR (300 MHz, DMSO-de) d 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 (br s, 1H) 14.43 (br s, 1H); MS (ESI +) m / z 572, 574 (M + H-TFA) +; (ESI-) m / z 570-572 (M-H-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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifiuoroacetic acid (95 mg, 49%). 1H NMR (300 MHz, DMSO-de) d 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 (br s, 1H) 14.49 (br s, 1H); (ESI +) m / z 529, 531 (M + H-TFA) +; (ESI-) m / z 528, 530 (M-H-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 following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to provide the product as a trifluoroacetic acid (87 mg, 45%). 1H NMR (300 MHz, DMSO-de) d 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 (br s, 1H) 14.53 (br s, 1H); S (ESI +) m / z 529, 531 (+ H-TFA) +; (ESI-) m / z 528, 530 (M-H-TFA) -.

Example H3S ffenillsiuillffan.lj-ffenol A solution of 4-chloro-3-nitro-phenol was reacted with 1-bromomethyl-3-fluoro-benzene using the conditions described in Example 237C to provide 1-chloro-4- (3-fluoro-benzyloxy) -2 -nitrobenzene which was treated sequentially using the procedures of Examples 237D and 237E to provide 4- [2-amino-4- (3-fluoro-benzyloxy) -phenylsulfanyl] -phenol. The product of Example id (53 mg, 0.30 mmole) was reacted with 4- [2-amino-4- (3-fluoro-benzyloxy) -phenylsulfanyl] -phenol (102 mg, 0.30 mmol) for 20 hours following the procedure of Example 1g to give the title compound crude, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid (60 mg, 33%). 1H MR (300 MHz, DMSO-d6) d ppm: 2.76 (s, 3H) 5.16 (s, 2H) 6.27 (d, J = 6.99 Hz, 1H) 6.64 (d, 5 = 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 = 6.98 Hz, 1H) 8.99 (d, J = 8.82 Hz, 1H) 9.78 (s, 1H) 11.02 (br s, 1H) 14.39 (br s, 1H); MS (ESI +) m / z, 484 (M + H-TFA) +; (ESI-) m / z, 482 (M-H-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-fluoro-benzene using the conditions described in Example 237C to provide 1-chloro-4- (4-fluoro-benzyloxy) -2 -nitrobenzene which was treated sequentially using the procedures of Examples 237D and 237E to provide 4-. { 2-amino-4- (4-fluoro-benzyloxy) -phenylsulfanyl] -phenol. The product from Example 1 d (53 mg, 0.30 mmol) was reacted with 4- [2-amino-4- (4-fluoro-benzyloxy) phenylsulfanylj-phenol (102 mg, 0.30 mmol) for 18 hours following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to give the product as a trifluoroacetic acid (115 mg, 64%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.76 (s, 3 H) 5.11 (s, 2 H) 6.26 (d, 5 = 6.99 Hz, 1 H) 6.65 (d, J = 8.46 Hz, 2 H) 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 (br s, 1H) 14.36 (br s, 1H); MS (ESI +) m / z, 484 (M + H-TFA) +; (ESI-) m / z, 482 (-H-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 the product of 4- [2-amino-4- (4-fluoro-benzyloxy) -phenylsulfanyl] -phenol (102 mg, 0.30 mmol) for 20 hours following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid (99 mg, 56%). 1H NMR (300 Hz, DMSO-de) d 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 (br s, 1H) 14.50 (br s, 1H); MS (ESI +) m / z.470 (M + H-TFA) +; (ESI-) m / z, 468 (M-H-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 mmoies) was reacted with 4- [2-amino-4- (3-fluoro-benzyloxy) -phenylsulfanyl] -phenol (102 mg, 0.30 mmoies) for 22 hours following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to give the product as a trifluoroacetic acid (75 mg, 43%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 5.16 (s, 2 H) 6.31 (d, J = 7.36 Hz, 1 H) 6.64 (d, J = 8.82 Hz, 2 H) 7.09-7.28 (m, 6 H) 7.29 (2, 1H) 7.44 (m, J = 6.61 Hz, 1H) 7.93 (dd, J = 4.41 Hz, 1H) 8.47 (d, J = 6.98 Hz, 1H) 9.14 (dd, J = 1.47 Hz, J = 8.46 Hz, 1H) 9.18 (dd, J = 1.47 Hz, J = 4.41 Hz, 1H) 9.79 (s, 1H) 11.16 (br s, 1H) 14.52 (br s, 1H); MS (ESI +) m / z, 470 (M + H-TFA) +; (ESI-) m / z, 468 (-H-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-bromomethyl benzene using the conditions described in Example 237C to provide 4- (4-chloro-benzyloxy) -1-chloro-2- nitrobenzene which was treated sequentially using the procedures of Examples 237D and 237E to provide the title compound.

EXAMPLE 143b 4- [4- (4-C-loro-be ncyloxy) -2- (7-propyl- [1, 8] naphthyridyl-4-i lamin o) -phenylsulfanyl] -phenol The product from Example 2g (85 mg, 0.41 mmol) was reacted with the product of Example 143a (146 mg, 0.41 mmol) for 26 hours following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (89 mg, 68%). 'HNR (300 MHz, DMSO-d6) d ppm: 0.98 (t J = 7.35 Hz, 3 H) 1.83 (sextet, 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 = 8.45 Hz, 4H) 7.48 (m, 4H) 7.83 (d, J = 8 A5 Hz, 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 (M-H-TFA) -.

Example 144 4- [4- (3-CI gold-be ncyloxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenol Example 144a 4- [2-Am ino-4- (3-chloro-benzyloxy) -phenylsulfanyl] -phenol A solution of 4-chloro-3-nitro-phenol was reacted with 1-chloro-3-bromomethyl benzene using the conditions described in Example 237C to provide 4- (3-chloro-benzyloxy) -1-chloro-2 -nitrobenzene which was treated sequentially using the procedures of Examples 237D and 237E to provide the title compound.

Example 144b 4- [2-Am ino-4- (3-chloro-benzyloxy) -phenylsulfanyl] -phenol The product of Example 2g (85 mg, 0.41 mmol) was reacted with the product of Example 1 44a (146 mg, 0.41 mmol) for 24 hours following the procedure of Example 1 g to give the crude title compound, which was purified through H PLC with TFA providing the product as a trifluoroacetic acid (85 mg, 65%). 1 H NMR (300 MHz, DMSO-d ") d ppm: 0.98 (t, J = 7.32 Hz, 3H) 1.85 (sextet, J = 7.35 Hz, 2H) 3.00 (dd, J = 7.72 Hz, 2H) 5.1 5 (s, 2H) 6.26 (d, J = 6.99 Hz, 1 H) 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 (br s, 1H) 14.39 (br s, 1H); MS (ESI +) n, / z, 528, 530 (M + H-TFA) +; (ESI-) m / z, 526, 528 (M-H-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 following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid (95 mg, 37%). 1 H NMR (300 MHz, DMSO-de) d ppm: 0.98 (t, J = 7.36 Hz, 3 H) 1.85 (sextet, 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 = 6.25 Hz, 1H) 7.83 (d, J = 8.83 Hz, 1H) 8.40 (d, J = 6.99 Hz, 1H) 9.03 (d, J = 8.83 Hz, 1H) 9.80 (s, 1H) 11.04 (br s, 1H) 14.45 (br s, 1H); MS (ESI +) m / z, 512 (M + H-TFA) +; (ESI-) m / z 510 (M-H-TFA) -.

Example 1146 - (3-CDoro-l einicilQxS) -2- ([[1,8] iniafíoiridlDini-4-iSainnióinio) -fenii! Ll1Fainyl3-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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (109 mg, 60%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.77 (s, 3 H) 5.16 (s, 2 H) 6.25 (d, J = 6.98 Hz, 1 H) 6.66 (d, J = 8.83 Hz, 2 H) 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 (br s, 1H) 14.38 (br s, 1H); MS (ESI +) m / z 500 (M + H-TFA) +; (ESI-) m / z 498 (M-H-TFA) -.

Example 1147 feuiiol 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (50 mg, 27%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 5.14 (s, 2 H) 6.31 (d, J = 7.36 Hz, 1 H) 6.64 (d, J = 8.82 Hz, 2 H) 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 = 6.98 Hz, 1H) 9.17 (m, J = 1.47 Hz, J = 5.88 Hz , 3H) 9.79 (s, 1H) 11.15 (br s, 1H) 14.54 (br s, 1H); MS (ESI +) m / z.486 (+ H-TFA) +; (ESI-) m / z, 484 (M-H-TFA) -.

Ejemropll © 148 IMImI-JlFainioIlJ-íIinioll 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (122 mg, 49%). 1 H NMR (300 MHz, DMSO-de) d ppm: 2.77 (s, 3 H) 5.16 (s, 2 H) 6.25 (d, J = 6.98 Hz, 1 H) 6.66 (d, J = 8.83 Hz, 2 H) 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 (br s, 1H) 14.38 (br s, 1H); MS (ESI +) m / z 500 (M + H-TFA) +; (ESI-) m / z 498 (M-H-TFA) -.Example H4S A solution of 4-chloro-3-nitro-phenol was reacted with bromomethyl-benzene using the conditions described in Example 237C to provide 4-benzyloxy-1-chloro-2-nitro-benzene which was treated sequentially using the procedures of Examples 237D and 237E to provide 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 following the procedure of Example 1g to give the crude title compound , which was purified by HPLC with TFA to provide the product as a trifluoroacetic acid (mg,%). 1 H NMR (300 MHz, DMSO-de) d ppm: 5.14 (s, 2 H), 6.31 (d, J = 6.99 Hz, 1 H), 6.61-6.69 (m, 2 H), 7.08-7.23 (m, 5 H), 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 (M-H-TFA) -.

Example europium 15§ 4- | [4 - ([< ^ -Cloiro-0s® inicDflojrD > -2- (7- (nni®í.al-S1l, S] | imalFltiiri ilS initi- DDaoini iinio] i- ff e mi i 0 if ff a mi i 0] - tf e mi o 0 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (mg,%). H NMR (300 MHz, DMSO-d6) d 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 (+ H-TFA) +; (ESI-) m / z 498 (-H-TFA) -.

EjeinnipOo 191 4- [4-Beiracy © ni¡-2- (7- [nroetty- [il, @] maffft.F fe ira oí 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 following the procedure of Example 1g to give the compound of the crude title, which was purified by HPLC with TFA to give the product as a trifluoroacetic acid (22 mg, 17%). 1 H NMR (300 MHz, DMSO-de) d ppm: 2.76 (s, 3 H), 5.13 (s, 2 H), 6.26 (d, J = 6.99 Hz, 1 H), 6.65 (d, J = 8.46 Hz, 2 H) , 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 (M-H-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 following the procedure of Example 1g to give the compound of crude title, which was purified by HPLC with TFA to give the product as a trifluoroacetic acid (2 mg, 2%). * H NMR (300 MHz, DMSO-d6) d 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 (M-H-TFA) -.

Example 153 N-. { 4- [4- (3-Ethoxy-benzyloxy) -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 from 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. 15 hours environment. The next day, the reaction mixture was emptied on ice and the solid was collected through filtration to give the title compound (33 mg, 100%).

Example 153b N-. { ^ [4- (3 - (&ethoxy-benz..oxy) -2- (7-propyl- [1,8] naphthyridin-4-ylamino) -ffemi or Os p Dffa mi S 0] -ffe my S B.} -a celia mra S u a 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 following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (14mg, 30%). 1H NR (300 MHz, DMSO-de) d 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. hours. The next day, the reaction mixture was emptied on ice and the solid was collected through 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 following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (15mg, 30%). 1H NMR (300 MHz, DMSO-d6) d 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-nitrobenzyl bromide (21 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DMF (1 mL) was stirred at room temperature. hours. The next day, the reaction mixture was emptied on ice and the solid was collected through 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 following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (13 mg, 29%). 1H NMR (300 MHz, DMSO-de) d 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 +) miz 580 (M + H) +.

Example 1S6 M-. { 4- [4- (4-Cimamo-fo © nc¡0oKi) -2- (7-piropi .- [il, 8] mafíiinc-iin-4-? Oa momio) - ffe ira D II su I ffa my 5 í] - 1F® mi i 0} - yes c ® 4 a m i ú a Example HSSa M-. { 4- | [2-.¾ oira0-4- (4-ci¡a! Rao-b © m ^ 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. hours. The next day, the reaction mixture was emptied on ice and the solid was collected through 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 following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (12 mg, 21%). 1H NMR (300 MHz, DMSO-d6) d ppm: 0.97 (t, J = 7.35 Hz, 3?) 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 (s, 1H); S (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} - A mixture of the product from Example 232B (56 mg, 0.17 mmol), 2-bromobenzyl bromide (26 μ ?, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 mL) was stirred at room temperature 15 hours. The next day, the reaction mixture was emptied on ice and the solid was collected through filtration to give the title compound (75 mg, 100%).

Example © H57fe > M-. { ^ -l ^ -. { 2-ET mo-ben¡cUo) -2-. { 7-p7op-l ^, & n ^ U7Íd "m - ^ - 3ímimiai.} ff © ira or 0 s EYE II ff a n i II] -ff e n o II.}. -a c e4a m 5 d a 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 following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (18 mg, 29%). 'H NMR (300 MHz, DMSO-de), d 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 (d, 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 613M + 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-Am ino-4- (4-bromo-benzyloxy) -phenylsulfanyl] -phenyl} - acetamide A mixture of the product from Example 232B (28 mg, 0.085 mmol), 4-bromobenzyl bromide (24 mg, 0.096 mmol) and potassium carbonate (13 mg, 0.09 mmol) in DM F (1 mL) was stirred at room temperature. Environment 1 5 hours. The next day, the reaction mixture was emptied on ice and the solid was collected through filtration to give the title compound (37 mg, 100%).

Example 158b N-. { 4- [4- (4-Bromo-benzyloxy) -2- (7-methyl- [1,8,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl} -acetamide The product of Example 1 d (1 8 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product of Example 1 58a (37 mg, 0.085 mmol) for 18 hours following the procedure of Example 1 g to give the compound of crude title, which was purified by HPLC with TFA to give the product as a trifluoroacetic acid salt (26 mg, 42%). 1 H NMR (300 MHz, DMSO-de) d 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) , 1 HOUR); MS (ESI +) m / z 615 (M + H) +.

Example 159 W- (4- [4-Cyclo-2- (7-m S5! - [¾ 98] miafySyrityl-4-ylaminium) -phiinylil-feriid.}.

Example 159a M- | 4- (4-Chloro-2-rl-5-yl-pheinioxy) -ffeinol] -aceiainni «da A mixture of 2-fluoro-5-chloro-nitro-benzene (0.5 g, 2.85 mmol), 4-acetamidophenol (0.45 g, 3.00 mmol) and cesium carbonate (0.98 g, 3.00 mmol) in DIVISO (5 ml) heated 6 hours at 90 ° C. The mixture was cooled, diluted with ethyl acetate (100 ml) and the organic layer was washed with water, 20% aqueous potassium hydroxide solution and 10% aqueous sodium chloride solution, then dried over sodium sulfate. anhydrous. The drying agent was filtered and the solvent was concentrated under vacuum leaving 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 NH 4 Cl following the procedure of Example 237E to give 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (25 mg, 17%). 'H NMR (300 Hz, DMSO-de) d 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 (+ H) +, (ESI-) m / z 417 (M-H) -.

Example USE [2- (3, ^ - Oiime1.DE-7einiilsuDirainiy) -S-met.i8-1FeiniD] - (7-pro | pil- [1, 8] - n atf í 5 ri din -4-í 1 -am ina The product of Example 2g (70 mg, 0.338 mmol) was reacted with the product of Example 4c substituting 3,4-dimethylbenzentiol for 4-mercaptophenol for 20 hours following the procedure of Example 1g to give the crude title compound which was titled with 4: 1 ether / THF affording the title compound as a hydrochloride salt (135 mg, 88%). 1 H NMR (300 Hz, DMSO-de) d ppm: 0.99 (t, J = 7.35 Hz, 3H) 1.82 (m, J = 7.35 HZ, 2H) 1.93 (s, 3H) 2.05 (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 (br s, 1H) 14.29 (br s, 1H); MS (ESI +) m / z 414 (M-CI) +; (ESI-) m / z 412 (M-HCl) -.

Ejjemrap.o ÜSD (T-Eftii.-ílI.ejiniatfttDir.dSro - ^ - t ^^ f © íijS.}. -amjna 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 to give following the procedure of Example 1g to give the crude title compound which was titrated with 3: 1 ether / THF to give the title compound (162 mg, 90%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 1.37 (t, J = 7.35 Hz, 3 H) 2.34 (s, 3 H) 3.05 (q, J = 7.35 Hz, 2 H) 3.72 (s, 3 H) 6.27 (d , J = 6.98 Hz, 1H) 6.85 (m, J = 8.82 Hz, J = 2.20 Hz, 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 (br s, 1H) 14.39 (br s, 1H); MS (ESI +) m / z 402 (M-CI) +; (ESI-) m / z 400 (M-HCI) -.

Example 162 4- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylammon) -phenoxy] -N-methyl-benzamide Example 162a 4- (4-Chloro-2-nitro-phenoxy) - -methyl-benzamide The product of Example 126c (225 mg, 0.72 mmoies) was reacted with methylamine (1.0 ml, 2.0 mmole) in THF (20 ml) at room temperature. The THF was removed under reduced pressure. The crude residue was purified by flash chromatography eluting with hexanes / 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 mmoies) was reacted with SnCl 2 as described in Example 1f to give the compound of title (100 mg, 55%).

Example ÜS2c 4- [4-Cioiro-2- (7-piropy- | [1!, 8Jiraa1F1 ..! Ri¡d¡ ^^ beirozanruide The product from Example 2g (64 mg, 0.31 mmol) was reacted with 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 with TFA to give the product as trifluoroacetic acid (25 mg, 31%). 1H NMR (300 MHz, DMSO-d8) d 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) +.

Exemplary 163 Oxiinnia of i-. { 4- [4-chloro-2- (7-piropií- [1,8] iriiafítir5tílSfTi-4-BlainniSinio) 1f e ira o? X ij -1f © mi or i} - and to anger or anger Example H @ 3a 1 - | 4- (2-Ameirao-4-c [© FO-ff © m0XD) -ffeiraDÍ] -eia! Reoinia The product of Example 164a (1.0 g, 3.4 mmole) was reacted with SnCl2 as was described in Example 1f to give the title compound (0.70 g, 78%).

Example 163b Oxima of 1 - [4- (2-amino-4-chloro-phenoxy) -phenyl] -ethanone To the product of Example 163a (150 mg, 0.57 mmol) in ethanol (15 mL) was added hydroxylamine hydrochloride (41.8 mg, 0.60 mmol), and disopropylethylamine (82 mg, 0.63 mmol). The reaction was heated at 60 ° C for 3 hours. The reaction 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 under vacuum to give the title compound (65 mg, 42%).

EXAMPLE 163c 1- (4- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} -ethanone oxime The product of Example 2g (45 mg, 0.217 mmol) was reacted with Example 163b (60.0 mg, 0.217 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 to give the product as trifluoroacetic acid (25 mg, 31%). 1 H NMR (500 MHz, DMSO-de) d 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); S (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 was poured into water. The aqueous phase was extracted with ethyl acetate (2x) and the combined phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum to give the crude title compound. The crude product was purified by flash chromatography eluting with (hexanes / ethyl acetate 70:30) to give the title compound (4.8 g, 77.8%).

Example 11 S 4 Ib H - [4- (4-Chloiro-2- oíiro-1 Feiniojíi) -feraill 3-ettaiinioI 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 was stirred for 1 hour and then the excess of sodium borohydride was destroyed by the dropwise addition of acetic acid. The reaction was poured into ice / water and extracted with ethyl acetate. The organic phase was washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum to give the title compound (0.634 g, 90%).

Ejjemropll © ü @ 4c ü - [4 -. { 2 - A m i m o -4-c 0 o PO -ff © DD OK i) -ff © on d 1] -® (ia mi oí The product of Example 164b (0.58 g, 1.9 mmol) was reduced with SnCl 2 as described in Example 1f to give the title compound (0.36 g, 70%).

Example Ü64d 1-. { 4-I4-C0oir © -2- (7-propy- [1l, 8IiraaffSSn ^ eftaeoD The product of Example 2g (125 mg, 0.60 mmol) was reacted with Example 164c (160 mg, 0.60 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 to give the product as trifluoroacetic acid (40 mg, 12%). H NMR (300 MHz, DMSO-d6) d 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 (-H) -.

Example ÜSS Estes * 4-. { 4-clloiro-2- (7-innieiDl- [1l, &Jms¡Wi7iúi - ^ 'Usímino) - ^ ®mo} femiííüco Ú < BÍ ptropaini-S-siuillfómiDCo acid Ejjeinropll © H (S5a 4-Cloiro-1I- (4-DTnie (loi: ó-iFeinioiió) -2-ini5 (liro-l © inic © DTio 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 K2C03 (14.5 g, 105 mmol) in DftflF (50 mL) . The mixture was heated at 80 ° C for 16 hours. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate and the combined phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum to give the crude title compound. The crude product was purified through silica gel chromatography eluting with (hexanes / ethyl acetate 90: 1 0) to give the title compound (8.0 g, 67%).

Example 165b 4- (4-Chloro-2-n-phenoxy) -phenol To Example 1 65a (0.98 g, 3.5 mmol) in CH 2 Cl 2 (20 mL) was added boron tribromide (0.95 g, 3.90 mmol). The reaction was stirred for 1 8 hours. Methanol was added to destroy excess boron tribromide. The reaction was poured into water and extracted with methylene chloride. The phases separated. The organic phase was washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum to give the crude title compound. The crude product was purified through silica gel chromatography eluting with (hexanes / ethyl acetate 90: 1 0) to give the title compound (0.57, 60%).

Example 165c 4- (2-Amino-4-chloro-phenoxy) -phenol The product of Example 1 65b (1.0 g, 3.7 mmol) was reacted with SnCl2 as described in Example 1 f to give the title compound (0.7 g, 78%).

Example ü (S5d 4- [4-Chloro-2- (7-inniettill- [1l, 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 give the title compound crude, which was purified by HPLC with TFA to give the product as trifluoroacetic acid (40 mg, 18%).

Example 1S5e feim 5 íico de. piropaini-Z-siLii acid. fornico The product of Example 165d (43 mg, 0.085 mmol) was reacted with isopropylsulfonyl chloride (14.5 mg, 0.102 mmol),?,? -diisopropylethylamine (33 mg, 0.255 mmol), and catalytic DWJAP in CH2Cl2 for 18 hours giving the compound of crude title, which was purified by HPLC with TFA to give the product as trifluoroacetic acid (16 mg, 31%). 1H NMR (300 Hz, DMSO-d6) d 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, ¡= 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 from Example 1d (100 mg, 0.562 mmol) was reacted with Example 162b (155.0 mg, 0.562 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 with TFA to give the product as trifluoroacetic acid (40 mg, 13%). H NMR (300 MHz, DMSO-d ") d 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 K2C03 (14.6 g, 0.10 mol) in DiViF (50 g). my) . The mixture was heated at 80 ° C for 1 5 hours. The reaction 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 with saturated (hexanes / ethyl acetate 4: 1) to give the product (9.0 g, 77.8%).

Axle pD © D (S7 lb To the product of Example 1 1 6a (0.5 g, 1.8 mmoles) in absolute ethanol (20 mL) was added BiCI3 (0.86 g, 27.3 mmol), and NaBH4 (0.55 g, 14.6 mmol) while cooling in a water bath. ice water. The mixture was stirred for 20 hours. The reaction was filtered through celite to remove the bismuth. The solution was concentrated under reduced pressure. The residue was treated with 5% HCl for 1 5 hours and then made basic 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 under vacuum to give the title compound as a solid (0.34 g, 77%).

EXAMPLE 1S7c 4- [4-Chloro-2- (7-meity- [i, 8] imaff1iSyridloini-4-i! Ainnioinium) -ie (niOKi) benzoinioiirillo The product of Example 1d (100 mg, 0.408 mmol) was reacted with 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 to give the product as trifluoroacetic acid (125 mg, 44%).

EXAMPLE 167 (9 [2- (4-Amoinyl-1-Dll-lfeinios-D) -S-c-phenyl-phenyl] - (7-iiinie < til- [1l, 8jina1Fí5ntíloini-4- 5D J-ammoima The product of Example 167c (88 mg, 0.175 mmol) was reacted with lithium aluminum hydride (13.3 mg, 0.351 mmol) in THF (50 mL) at 60 ° C for 15 hours to give the crude title compound, which it was purified by HPLC with TFA to give the product as trifluoroacetic acid (15 mg, 14%). 1H NMR (300 Hz, D SO-de) d 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); S (ESI +) m / z 391 (M + H) +.

Example 1168 3-. { 4-C0oiro-2- (7-piropií-f1, 8jnaffímd5ini-4-Dlam¡rao) -fferooj -.] - N, N- doinraeftDl-lbeirazainniü la Example 168a 3- (4-C! Gold-2-miiro-phenoxyn) -lbenzotcoo acid To a solution of DMF (50 ml) was added 1-bromo-2-nitro-4-chloro-benzene (10.0 g, 42.2 mmol), 3-hydroxy-benzoic acid (5.8 g, 42.0 mmol), and K2C03 (17.5 g, 0.13 mol). The solution was heated to 85 ° C and stirred overnight. The reaction was poured into distilled water and extracted with ethyl acetate. The combined organic layers were washed with distilled water, brine, and dried over Na 2 SO 4, filtered and concentrated under vacuum to give a crude oil. This oil was purified through silica gel column chromatography eluting with CH2Cl2 / MeOH (90:10) to give the title compound (7.4 gm, 60%).

EXAMPLE 168b CDoruiro of 3- (4-cloco-2-iniiíiro-FeinioKo) -lbein? Oilo The product of Example 168a (2.0 g, 6.8 mmol) was treated with oxalyl chloride (9.0 g, 13.6 mmol) and catalytic DMF at 60 ° C for 5 hours. Excess oxalyl chloride was removed under vacuum. The residue was expelled with benzene to give the desired product (2.2 g, 94%).

Ejemmpl © U68c 3 - (^ - CDoiro-2-n.t.iro-feinioKD) -N, N-d.m® &iD-beinizamDda To the product of Example 168b (2.0 g, 6.4 mmol) in THF (25 mL) was added dimethylamine (0.6 g, 13.3 mmol) and the reaction was stirred for 16 h. The reaction 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 under vacuum to give the title compound (1.9 g, 87%).

For example, US® di 3-í2-Amoin) o-4-cOoiro-1f © in) oii -W, W-dDmeiDÍ-b © rii? FflinniódIa The product of Example 168c (1.5 g, 4.6 mmol) was reacted with SnCl 2 as described in Example 1f to give the title compound (0.91 g, 68%).

Example 168e 3- [4-Clloiro-2- (7-piropH-E1l, 8] fTiaiFííirídjn-4- amifTio) -ffeinioji53-W, W- "3 i mni e 4 S 0 - Ib © mi z s¡ m i d a 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 the title compound crude, which was purified by HPLC with TFA. providing the product as trifluoroacetic acid (100 mg, 20.2%). 'H NMR (500 MHz, DMSO-D6) d 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 (+ H) +.

EJeinnipí © HS9 Esíef éíólóco acid 3- [4-cDoiro-2-l [7-piropQD- [il, 9!] InisifitDiriidl9ini-4- 5 D a im J? P? o) - 1f e ra o x 91 - b e ra z o 5 c o o Ejemrapll® HSSa Estteir eSíOoco di®, aka 3-. { 4-e! Qir © -2- [moftir © -i? © [m © KD} -to © [fi) z © oc ©© To the product of Example 168a (2.0 g, 6.8 mmol) in ethanol (50 ml) with cooling, HCl gas was bubbled for 10 hours. The excess ethanoi was removed under vacuum. The solid was taken in ethyl acetate. The organic layer was washed with saturated NaHCO 3, water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum to give the title compound (2.0 g, 91%).

Example ü & SIb 3- (2-amoimo-4-chloiro-phenyloxyD) -benzoic acid ethyl ester The product of Example 169a (1.5 g, 4.7 mmol) was reacted with SnCl 2 as described in Example 1f to give the title compound (1.0 g, 73%).

Ejoinrapio HSSc Ethyl ester of 3- [4-chloroiro-2- (7-pirop5i-I1l, 8] miaiFltiiroiil5mi-4- or 1 to pp? O n o) - i e si o x i 1 - b e n z o i c o The product from Example 2g (113 mg, 0.55 mmol) was reacted with Example 169b (160 mg, 0.55 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 with TFA to give the product as trifluoroacetic acid (200 mg, 63%). 1 H NMR (300 MHz, DMSO-de) d 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 (+ H) +.

Example ü 70 H -. { 3-H-Cloroiro-2- (7-piropiyl- [1l, 8] iniaffi.iiiriidiin-4-amDinio) -ffenojxD] -1Feiniiii} - eIarool Example (D7lD) a 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 K2C03 (11.7 g, 84.6 mmol) in DMF (50 mL) . The mixture was heated at 80 ° C for 16 hours. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate (2x) and the combined phases were washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum to give the title compound. The crude product was purified by flash chromatography eluting with (hexanes / ethyl acetate 70:30) to give the title compound (8.6 g, 70%).

EjemrapJ © H7 © to H - [3- (4-CIIoiro-2 (-iro 1F < ginioxo) -ff < BroiiD] | -®1.ain > o.

To the product of Example 170a (1.8 g, 6.2 mmol) in ethanol (50 mL) was added sodium borohydride (0.32 g, 8.64 mmol) in portions. The reaction was stirred at room temperature for 16 hours. The excess of sodium borohydride was destroyed through the addition of acetic acid. The reaction was poured into ice / water and extracted with ethyl acetate. The organic phase was washed with water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum to give the title compound. The crude residue was purified through silica gel chromatography eluting with (hexanes / ethyl acetate / methanol (75: 15: 5) to give the desired product (0.98 g, 54%).

Ejemnipll © D7 © c ü- [3- (2-¾inni5inio-4-cloiro Ifoimoir? J-ífeire i OJ -etta tra oO The product from Example 170b (0.98 g, 3.3 mmol) was reduced with SnCl 2 as described in Example 1f to give the title compound (0.61 g, 70%).

Example 170d 1 -. { 3- [4-CHoiro-2- (7-piropill- [1l, 8JiniatFltiiridiirí-4-ylaimino) -1Fe or »S] -1Feiniii} - eftarooQ The product of Example 2g (140 mg, 0.68 mmol) was reacted with Example 170c (178 mg, 0.68 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 with TFA to give the product as trifluoroacetic acid (110 mg, 30%). 1 H NMR (300 M z, DMSO-de) d ppm: 8.86 (d, J = 8.46 Hz, 1 H) 8.53 (d, J = 7.35 Hz, 1 H) 7.77 (d, J = 8.82 Hz, 1 H) 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) +.

Ejemnipllo 1711 EJempSo 1711a 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 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 under vacuum to give the title compound (1.66 g, 92%).

EjjemropO © 117111b 3- (2-Ainnióinio- < -cDoiro-f < siniox9) -b®Bi? AinniD «3s The product of Example 171a (0.56 g, 1.9 mmol) was reacted with SnCl 2 following the procedure described in Example 1f to give 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 the title compound crude, which was purified by HPLC with TFA to give the product as trifluoroacetic acid (110 mg, 30%). 'HNR (500 MHz, DMSO-de) d 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 1-. { 3- [4-Chloro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -phenyl} - ethanol 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 was stirred for 16 hours. The reaction 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 under vacuum to give the title compound (1.4 g, 85%).

Example H72b 3- (2-AmniDinio-4-cDoiro-einio? Ii) -W-e1tjS-bei¡Ti? Am¡dla The product of Example 172a (0.90 g, 2.8 mmol) was reacted with SnCl 2 as described in Example 1f to give the title compound (0.65 g, 81%).

Example 172c 3- [4-C [oiro-2- (7-pirop - [1,8Jna1f4kidifTi-4-illammo) -1? EiriOKÓ3-N-eí-beirD? Ainn) D (dla The product of Example 2g (128 mg, 0.62 mmol) was reacted with Example 172b (180 mg, 0.62 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 to give the product as trifluoroacetic acid (70 mg, 20%). HNR (500 M z, D SO-de) d 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 D73 beinizamide Example 1173a 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 was stirred for 16 hours. The reaction 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 under vacuum to give the title compound (0.8 g, 85%).

Ejection 173b 3- (2-Am8iroo-4-chloro-feffioxj) -W-phen !! - b © [ra2am5da The product of Example 173a (0.84 g, 2 3 mmol) was reacted with SnCl 2 as described in Example 1f to give the desired product (0.60 g, 77%).

EXAMPLE 173c 3- [4-Cyclo-2- (7-pyra-ill- | [1, S-3-amino-4-amino-4-Slainnylinium) -1-F-inyoate] -N-1-Phinephi was 2-mida The product of Example 2g (131 mg, 0.63 mmol) was reacted with Example 173b (214 mg, 0.63 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 to give the product as trifluoroacetic acid (125 mg, 31%). 1 H NMR (300 MHz, DMSO-de) d 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-C.oir®-2- (7-p ^ p.9- | 1. @! IroatfttDir. < ^ h or di irox 5 -ff e mi i 0) - toe iraza or di a Example 174a M- - (í®ir-B íDÍ-cílím © íy-syainiíloK5) -ìini i-3- (4-cDoro-2-in5íiro-íeiniOK - I eimzamódla To the product of Example 168b (1.3 g, 4.2 mmol) in THF (25 mL) was added 3- (tert-Butyl-dimethylsilanyloxy) -phenylamine (1.0 g, 4.2 mmol), and?,? -diisopropylethylamine (0.67 g). , 5.2 mmoies). The reaction was stirred for 16 hours. The reaction 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 under vacuum 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 mmole) in THF (25 mL) was added tetrabutylammonium fluoride (0.94 g, 3.6 mmole). The reaction was stirred for 16 hours. The reaction 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 under vacuum 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 mmoies) was reacted with SnCl 2 as described in Example 1f to give 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 Example 174c (247 mg, 0.70 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 to give the product as trifluoroacetic acid (123 mg, 27%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 10.02 (s, 1 H) 9.45 (s, 1 H) 8.81 (d, J = 8.82 Hz, 1 H) 8.53 (d, J = 7.35 Hz, 1 H) 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] naphthyridn-4-ylamino) -phenoxy] -N-propyl-benzamide Example 175a 3- (4-Chloro-2-nitro-phenoxy) -N-propyl-benzamide To 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 was stirred for 16 hours. The reaction was poured into water and extracted with ethyl acetate.

The organic layer was washed with 5% HCi, water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum 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 SnCl 2 as described in Example 1f to give the title compound (0.61 g, 76%).

Example 175c 3- [4-Chloro-2- (7-propyl- [1,8] naphthindin-4-mamino) -phenoxy] -N-propyl-benzamide The product from Example 2g (110 mg, 0.53 mmol) was reacted with Example 175b (162 mg, 0.53 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 to give the product as trifluoroacetic acid (50 mg, 16%). 1 H NMR (300 MHz, D SO-d 6) d 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); S (ESI +) m / z 475 (+ H) +.

Example 176 { 3-I4-COoiT0-2- (7-m®4.O- [1I, 8] in) affftDir.d ^ methanol Execute 1176a To a solution of DF (50 ml) was added 1-bromo-2-nitro-4-chloro-benzene (10.0 g, 42.2 mmol), 3-hydroxybenzaldehyde (5.2 g, 42.2 mmol), and K2C03 (11.5 g, 84.6 g. mmoles). The solution was heated to 85 ° C and stirred overnight. The reaction was poured into distilled water and extracted with ethyl acetate. The combined organic layers were washed with distilled water, brine, and dried over Na 2 SO 4, filtered and concentrated under vacuum to give the crude title compound. This solid was purified through silica gel column chromatography eluting with hexanes / ethyl acetate (4: 1) to give the title compound (4.4 gm, 41%).

Example H7Sb [3- (4-Cioiro-2- [roa4ro-ff <(raojn) -tfeiroS] 3-meinin) ol To the product of Example 176a (2.0 g 7.2 mmole) in ethanol (25 ml) was added borohydride. sodium (0.32 g, 8.6 mmol). The reaction was stirred for 4 hours. The excess of sodium borohydride was destroyed through the addition of acetic acid. The reaction 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 under vacuum to give the title compound (1.9 g, 94%).

EjtsmnipDo H7Sc [3- (2-Ainni5inio-4-c8oiro-1F © iiTiosó) - < Fein) 8] - [nn) ®linoinol The product of Example 176b (1.9 g, 6.8 mmol) was reacted with SnCl 2 as described in Example 1f to give the title compound (1.4 g, 83%).

Example 176d. { 3- [4-Chloro-2- (7-m s s - [1l, 8l (nia1fíjirSd5in-4- amóin) o) -fenoKi] -ffeiniüll} - The product of Example 1d (110 mg, 0.62 mmol) was reacted with Example 176c (153 mg, 0.62 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 to give the product as trifluoroacetic acid (50 mg, 16%). H NMR (300 MHz, DMSO-de) d 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 H -. { 3- [4-Cory-2- (7-innieiS- [il. SJfnaiiiridiin - ^ - ilamiinioJ-feinonoJ-lfeineO.}. - eftamioll The product from Example 1d (125 mg, 0.70 mmol) was reacted with Example 170c (184 mg, 0.70 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 to give the product as trifluoroacetic acid (59 mg, 16%). HNR (300 Hz, DMSO-de) d 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 H7S 3- [4-Chloro-2- (7-mettH- [il, 83l-yl-1-yl-4-yiam5no) -i © no ^! JN- (3- OI id? T? P ü -ff e ira i I) - be n? a DTTD one way The product of Example 1d (125 mg, 0.70 mmol) was reacted with Example 174c (237 mg, 0.70 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 to afford the product as trifluoroacetic acid (120 mg, 28%). 'H NMR (300 MHz, DMSO-de) d 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 (M-H) -.

Example 1179 [5-CDoiro-2- (sopmp -ff®in> oxii) -7®irM ^ a finí i na Example Ü79a 4 - ???? t? -1? - (4-03 ??? G? | ??? - ?? © ??)? ?) - 2-? P? D ?? G? -? 1? ©? T ?? ©? T ?? 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 K2C03 (14.0 g, 101 mmol) in DMF (70 ml) . The mixture was heated at 80 ° C for 16 hours. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate 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 through silica gel chromatography eluting with (hexanes / ethyl acetate 90:10) to give the title compound (13.5 g, 92%).

Example H7Sb The product of Example 179a (13.7 g, 46.8 mmol) was reacted with SnCl 2 as described in Example 1f to give the title compound (10.3 g, 84.4%).

Example 179 | S-C0oiro-2- (4-jisopiropii-feiniosg) -f®ini.9] - (7-innietill-1l, 8] ñafió iri din -4-50) - ammioiia The product from Example 1d (120 mg, 0.67 mmol) was reacted with Example 179b (175 mg, 0.67 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 to give the product as trifluoroacetic acid (60 mg, 17%). 1 H NMR (300 Hz, D SO-de) d 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) +.

Ejemnipll © USE. { 2- | 3- (1-Azic9o-®t.iO) -1PeiniOKgl-S-clo or-1F®iniDD} - (7- iropoll- [1, 8] naí1.iriritílóini- 4 - i II) -a mó my a Example ü @ © a 2- [3-n - ^? 8d < oi-ellóD) -lf © [nioiiD] -5-cloiro-fe [niDllamisTia To the product of Example 170c in toluene (25 mL) was added diphenylphosphoryl azide (1.72 g, 6.23 mmole), followed by 1,8-diazabicyclo [4.3.0] undec-7-ene (0.95 g, 6.2 mmole). The mixture was stirred at 25 ° C for 18 hours. The reaction 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 under vacuum to give the title compound. The crude product was purified on silica gel, eluting with hexanes / ethyl acetate / methanol (85: 17: 3) to give the title compound (700 mg, 50%).

Ejjemropll © US © Ib. { 2- [3- (1-A? .do-®4i.) - ffenoK¡] -5-e.oiro-ffe ^ The product of Example 2g (130 mg, 0.63 mmole) was reacted with Example 180a (181 mg, 0.63 mmole) 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 to give the product as trifluoroacetic acid (11 mg, 11%). 1H NR (500 MHz, DMSO-d6) d 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 1811 3- [4-F0uoiro-2- (7-piropyl- [1, 81-amino-iiirjc-in-4-ylamino) -1-Phynylene-N. W-d or mro e ft i 0 - Ib © ora z a mro 5 d a Example 181a Ethyl ester of 3- (4-1fiuoro-2-nitiro-tferooKj) -lberj? Oieo acid 2,5-difluoronitrobenzene (5.0 g, 31.4 mmol), ethyl 3-hydroxybenzoate (5.2 g, 31.4 mmol), and KZCO 3 (8.7 g, 62.8 mmol) were added to DMF (50 mL). The solution was heated to 85 ° C and stirred for 16 hours. The reaction cooled. The reaction 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 through silica gel column chromatography eluting with hexanes / ethyl acetate (90:10) to give the title compound (7.0 g, 73%).

Example 1811b Ac.dlo 3- (4-ffÍMO [ro-2-irosttro-1FerooJiB) -toeiro2o5eo The product of Example 181a (3.0 g, 9.8 mmol) was added to a THF / H20 solution (5: 1). Lithium hydroxide monohydrate (0.82 g, 19.5 mmol) was added in one portion. The solution was heated at 60 ° C for 2 hours. The reaction 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 NaHCO3, water, brine, and dried over sodium sulfate, filtered and concentrated in vacuo to give the title compound (2.65 g, 97%).

Example HSÜc sleep © of 3- (4-Fluor © -2-ira5tt [ro-1T © [rooi: o) - [beini20DBo The product of Example 181b (1.6 g, 5.6 mmol) was treated with oxalyl chloride (0.86 g, 6.7 mmol) and catalytic DMF at room temperature for 6 hours. Excess oxalyl chloride was removed under vacuum. The residue was expelled with benzene to give 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 was stirred at room temperature for 16 hours. The reaction 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 under vacuum 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 81 d (1.1 g, 3.4 mmol) was reduced with SnCl2 as described in Example 1f to give the title compound (0.88 g, 88%).

Example 181f 3- (4-Fluoro-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenoxy] -N, N-dimethyl-benzamide The product of Example 2g (110 mg, 0.53 mmol) was reacted with Example 181e (154 mg, 0.53 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 to give the product as trifluoroacetic acid (65 mg, 20%). 1H NR (300 MHz, D SO-d6) d 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) +.

EXECUTE 182. { 2- [4-í1l-Amí (rao- © íDl) -feiniOKiJ-5-clloiro-í © nül} - (7-innieftSÍ - ['í, S | roa-tFíñ e-ñ < ril 0 im - Example 182a 1 - [< ¾- (1 -Azi do-eíi l) -f © nosi] -4-cl o? T? -2-nittiro-to © im ceno To the product of Example 164b (0.30 g, 1.0 mmol) in toluene (20 mL) was added diphenylphosphoryl azide (036 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 was poured into water and extracted with ethyl acetate. The combined organic layers were washed with 5% HCl, NaCl sat. (1X), dried over sodium sulfate, filtered and concentrated under vacuum to give the crude title compound. The crude product was purified through silica gel chromatography, eluting with hexanes / ethyl acetate / methanol (85: 15: 5) to give the title compound (300 mg, 94%).

Example 1182b Eslíes * benzyl acid. { 1 - [4- (4-C! Oro-2-nóíro-tfemoxi) -feml] -eti !} -carfoamic 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). After the mixture was stirred for 30 minutes at room temperature, the reaction mixture was treated with benzyl chloroformate (0.85 g, 5.0 mmol) and stirred 18 hours. The reaction was poured into 0.1 M potassium phosphate regulator, pH = 7.0 and extracted with methylene chloride. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated under vacuum to give the crude title compound. The residue was treated with cold ethyl ether. The resulting white precipitate was collected to give the title compound (1.9 g, 74%).

Example 1182c E site go benzylic acid. { 1l- [< H2-ainniino-4-cDoiro-? OOTOXi) -i½nó.] Eíelj-cacbámico The product of Example 182b (1.0 g, 2.34 mmol) was reacted with SnCl 2 as described in Example 237E to give the title compound (0.75 g, 80%).

Example 182d. { 2- [4- (1-Amoinium-etSt) -phenoJii] -5-cyloiro-phenyl} - (7-meyil - ['i. EjnalFíiiridin- 4-SII) -a mummy The product of Example 1d (120 mg, 0.67 mmol) was reacted with 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 under vacuum. The crude compound was then treated with an excess of 48% HBr for 10 hours. The excess HBr was removed under vacuum and the crude residue was purified by HPLC with TFA to give the title compound as trifluoroacetic acid (15 mg, 17%). 1 H NMR (300 MHz, DMSO-de) d 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 (M-H) -.

Example 1S3 N- (4- 2- (7- [M © s - | 1l, 83yriaftikodSirs-4- a5oo) -4-1.iri1f! Oiom © it 1F ens no II 1F a mi 5 í] - © nii} - ac © 4 am or di a Example 183a N- [4- (2 Nitro-4-ftinffl <igorom® i-? Nilsulf ini!) Pheidj-acetamide The title compound was prepared from 1-chloro-2-nitro-4-trifluoromethyl- Benzene (250 mg, 1.10 mmol), N- (4-mercaptophenyl) -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 1183b The product of Example 183a (350 mg, 0.985 mmol), and Pt (IV) 02 (4 mg, 0.2 mmol) were placed in a 50 ml round bottom flask and dissolved in 1 ml EtOH and 1 ml THF . The reaction mixture placed under vacuum and filled with H2 using a balloon. The balloon was left overnight and the next day the reaction mixture was purged and refilled with N2, filtered and concentrated under vacuum to give the title compound (260 mg, 80%).

Example 183c N-. { 4- [2- (7-R9efll- [1,8] naftlricln-4-llafnino) -4-trifluoromefil é n S II s no 11? a n 5 II] - 1F © n i II} - a © © a ron d d a The product from Example 1d (50 mg, 0.280 mmol) was reacted with the product of Example 183b (91 mg, 0.280 mmol) for 18 hours following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (18 mg, 16%). 1 H NMR (300 Hz, D SO-d 6) d ppm: 2.07 (s, 3 H), 2.78 (s, 3 H), 6.43 (d, J = 6.99 Hz, 1 H), 7.09-7.15 (m, 1 H), 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 (M-H-TFA) -.

EXAMPLE 184 [S-l ^ ®tt -2- (IIKI- | 1,2,4] 1tiri? A? Og-3- sul1FaEii) -f®ini] - (7-pyro | poO- Example 184A -M © llH-2- (1lH- [1,2,4] llroa? OD-3- s llfainioO) -lF © iniDOainnióin) a The title compound was prepared from 1-chloro-4-methyl-2-nitro-benzene (3.00 g, 17.5 mmol), 1 H- [1, 2,4] triazole-3-thiol (1.94 g, 19.2 mmoles), and 2C03 (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. Dry over Na 2 SO 4, filter and concentrate in vacuo to give the title compound (1.1 g, 26%).

Example 11841b 5-Methyl-2- (1 Hl - [11,2,4] triazol-1 -3-ylsulfanyl) -phenyllamine The product of Example 184a was reduced with SnC12 following the procedure of Example 1f to give the title compound.

Example 184c [5-l ^ et.ill-2- (1IHI- [1l, 2,4-iri-azol-3-ylsiranyl) -feiriill] - (7-propyl- [H, 8] inia1fllii [rDdlüíTi-4- 5ll) -ainniS [nia 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (17 mg, 16%). 1H NR (300 Hz, D SO-de) d 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); S (ESI +) m / z 377 (+ H-TFA) +; (ESI-) m / z 375 (M-HTFA) -.

Example H 85 t2- (2-AmD O-íFeir.y suBfffflBTiÍBÍ-5-meíiD-feoTii.] - (7- | p (ropá J-E11, 8] inaffí.B'ó «ílór.-4- SO) -aura 5 na Example D85A 2- (4-KJeftól-2 imólliro-iF iniDlIs tfainiolJ-fesTiíliainnióinia The title compound was prepared from 1-chloro-4-methyl-2-nitro-benzene (3.00 g, 17.5 mmol), 2-amino-benzenethiol (2.41 g, 19.23 mmol), and 2 C03 (4.22 g, 30.6 g). mmoles) 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 W- [2- (4-raettBÍ-2-iniiiiliro-ifeirDysull? A [n)) -i? © ini 3- ce¾amDitila The material of Example 185a (0.990 3.80 mmol) was dissolved in CH2Cl2 to which was added acetyl chloride (0.328 g, 4.183 mmol). The reaction mixture was stirred at room temperature for 1 hour, at which time the title compound was collected through filtration (910 mg, 79%).

Example 185c N- [2- (2-Amino-4-methyl-phenylsulfanyl) -phenyl] -acetamide The product of Example 185b was reduced with SnCl 2 following the procedure of Example 1f to give 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 following the procedure of Example 1g to give the crude title compound which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (150 mg, 46%) Example 185e [2- (2-Amino-phenylsulfanyl) -5-methyl-phenyl] - (7-propyl- [1,8] naphthyridin-4-yl) -amine The product of Example 185d was dissolved in 50% HCl: H20 and heated at 100 ° C for 1 hour. The reaction mixture was then cooled to room temperature, made basic with 2N NaOH, and extracted with CH2Cl2. Dry over Na 2 SO 4, filter and concentrate in vacuo to give the crude title compound. It was purified by HPLC with TFA to give the product as a trifluoroacetic acid (87 mg, 64%). HNR (300 Hz, D SO-d6) d 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 HSS M-. { 3- [3-l¡ $ ett.ll-5- (7-piropy- | [1l, 8] in) affttó ^^ < F e mi i I) - a c © 4 a m o d a Example 3-AmDinio-l orDceiDOI.Dol cotoire 3-Amino-benzenethiol (2.00 g, 15.98 mmol) was treated according to the conditions described in 187a to provide the title compound (3.67 g, 100%).

EXAMPLE 1861b 3. (3 EIlelljl-S-iniDiriro-1F © ini¡ll ¡faini5i) -iinitiamine The title compound was prepared following the procedure of Example 187d using Example 187c (400 mg, 1.85 mmoles), and Example 186a (348 mg, 1.85 mmol) afforded the title compound (300 mg, 62%).

Example Ü8 (5c M- [3- (3-EM © 1. -5-n8 (.iro-ffeini s (U! S1Fainiy) - einióll-ac © iíamódla The title compound was prepared following the procedure of Example 185b using Example 186b (115 mg, 0.442 mmol) and acetyl chloride (52 mg, 0.663 mmol) to provide (130 mg, 97%).

EXAMPLE 186d M-I3- (3-Am Sinium-5-Roxy-1-Feinyl S-aryi) -fisfy-3-aceiafTTijda The title compound was obtained following the procedure of Example 183b using the product of Example 186c (130 mg, 0.430 mmol), and Pt02 (2 mg, 0.009 mmol) to provide (73 mg, 62%).

Example 186? M-. { 3- [3-raeí -5- (7-po-op -n ^ l afíBródi ^ - ^ - naminoí-feraílsiLJiilfanBBJ- lfeinijílJ-aceliainniDdla 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (14 mg, 10%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 0.96 (t, J = 7.35 Hz, 3 H), 1.75-1.89 (m, 2 H), 2.03 (s, 3 H), 2.36 (s, 3 H), 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) , 1 HOUR); MS (ESI +) m / z 443 (M + H-TFA) +; (ESI-) m / z 441 (-H-TFA) -.

Ejeinnipllo U S 7 W-. { 4- [3-B3e1.ii.-5- (7 piropiD-íü, 8] | na7l.liiridin-4-ilainniino) -1Fenyl8uI? Aiit91] | tFenó !} -One-axis-axis A-087a M- (4- [¡3 © ircap1.o-ifeiniyj ace1tainni.da cobire N- (4-mercapto-phenyl) -acetamide (1.00 g, 5.98 mmol) and Cu20 (385 mg, 27.0 mmol) were dissolved in EtOH and heated to reflux for 24 hours. At this time, the reaction mixture was cooled to room temperature and the title compound was collected through filtration (1374 g, 100%).

Example ÜS7fc > 2 - B ir o m o - 4 - m and í I - S - mi i t r o - ff e mi i a m a mi a 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 the course of 10 minutes. An orange solid formed, and after the end of the addition the reaction mixture was diluted with water and the title compound was collected through filtration (29 g, 96%).

Example 187c 11 -Bromo-3-meísí-S-miíio-jeniceno The title compound was prepared from Example 187b (10.0 g, 43.2 mmol) was dissolved in 60 mL of MeOH and 8 mL of H2SO4 (concentrated). This mixture was heated to 85 ° C, at which time NaN02 (7.466 g, 108.2 mmol) was added in portions so that the reaction mixture did not bubble anymore. After the addition was complete, the reaction mixture was allowed to stir at 85 ° C for another 30 minutes. The reaction mixture was then cooled to room temperature, diluted with water and extracted with CH2Cl2. Dry over Na 2 SO, filter and concentrate in vacuo to give the title compound (8.00 g, 85%).

EXAMPLE 187d W- [4- (3- [Meium-5-ni! 4-phenylsulfanyl) -1Feri 3-ace4aimi-a The title compound was prepared from Example 187c (400 mg, 1.85 mmol), Example 187a (425 mg, 1852 mmol), 10 mL of quinoline, and 2 mL of pyridine was heated at 170 ° C for 22 hours. At this time the reaction mixture was cooled to room temperature and quenched with 30% HCl and extracted with ether and dried over Na 2 SO 4, filtered and concentrated under vacuum to give the title compound. Purify by column chromatography on silica gel eluting with 30% ethyl acetate in hexanes (280 mg, 50%).

Example H87e W- [- (3-AmDir90-5-im © l.iS-1f © iniys [L5lfa) -f®ini i-ac © 1íamDd! A The title compound was obtained using the procedure of Example 183b using the product of Example 187d (280 mg, 0.926 mmol), and Pt02 (2 mg, 0.009 mmol) to provide the title compound (240 mg, 95%).

Example 187? W-. { - [3- ^ eíjl-5- (7-prop - [il, 8] a 1i! Pdiira-4-olamino) -f © n? S Jlfaf ^ il] - íeí ^? 5 !} -a? ceiamide 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (5 mg, 4%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 0.96 (t, J = 7.35 Hz, 3 H), 1.76-1.89 (m, 2 H), 2.05 (s, 3 H), 2.33 (s, 3 H), 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 (+ H-TFA) +; (ESI-) m / z 441 (M-H-TFA) -.

Example Ü88 [3- (4-A iinium-1? ®irM. (UiJffain) 5]) - ^^ or 0) -a m i roa The product of Example 187 (60 mg, 0.136 mmol) was treated according to the conditions of Example 185 to provide the title compound (10 mg, 18%). 1 H NMR (300 MHz, DMSO-de) d 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-BeBTiC! LOKB-íeini j |) - (7-p (TO (p. Í- [1, 8] ríafíiirid on-4-ü) -am ina Example 1189a 11 -BeirocS.oxi-S-iroDíiroI einiceiroo 3-Nitro-phenol (1.00 g, 7,189 mmol) was treated with benzyl bromide (1352 g, 7.91 mmol), and K2C03 (1242 g, 8,986 mmol) in DMF. The reaction mixture was heated at 100 ° C for 1 hour, at which time the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. It was dried over Na2SO4, filtered and concentrated under vacuum to give the title compound (1.6 g, 97%).

Example H89b 3 - B e ro c 51 o? i - e i i a m i n a The title compound was obtained following the procedure of Example 183b using the product of Example 189a (1600 g, 6.98 mmol), and Pt02 (15 mg, 0.070 mmol) providing (1.00 g, 72%).

Exercis) pio 189c (3-Besiiciíojiü-ff nil) - (7-piropn- | 1l, 8] miaiFíüiridóm-4-óll) -ainni5iíTia 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (27 mg, 50%). 1H R (300 Hz, DMSO-d6) d 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); S (ESI +) m / z 370 (+ H-TFA) +; (ESI-) m / z 368 (-H-TFA) -.

USA © © Example 1S0A ü - (4-Bir © inni © lb © inic5. © HÍ) -3-in) .1-iro-b®in) C © in) © 3-Nitro-phenol (1.00 g, 7,189 mmol) was treated with 4-bromo-benzyl bromide (1976 g, 7.90 mmol) following the procedure of 189a affording the title compound (2.1 g, 97%).

Example 1S0B 3- (4-Biromo-bePCiONone) -1Feinium! AmS a The title compound was prepared by reducing the product of Example 190a with SnCl 2 following the procedure of Example 1f.

Ejeomipi® Ü90c 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (80 mg, 60%). 1 H NMR (300 Hz, D SO-de) d ppm: 2.75 (s, 3 H), 5.16 (s, 2 H), 6.81 (d, J = 7.35 Hz, 1 H), 7.04-7.14 (m, 3 H); 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.; 17. (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 (M-H-TFA) -.

Example 1191 N-. { 4 - ([3-F. Lio ?? - 5- (7 -piro pit- [H, 8] n af &go ñ d. Ori - S - D mino) -? In ??] -7® nor S > - aceiainnodol Exemplify HSHa M- [4i-iI3-FD oiro-5-inii1tiroi-feinioitó J-1FeiniS0] -aceSainniDda To a solution of N- (4-hydroxyphenyl) acetamide (1.00 g, 6.5 mmol) in D SO (12 mL) was added a solution of 1M t-BuOK / THF (7.13 mL, 7.13 mmol) dropwise at room temperature and the mixture was stirred at room temperature for 30 minutes under a flow 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 under a flow of N2. The reaction mixture was cooled to room temperature, diluted with H20, and then extracted with EtOAc. The extract was washed with H20 and brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a pale brown solid, which was purified through washing with i-Pr20 to give the desired product as a slightly brown glass (1.73 g, 92%).

Ej@mi.pllo ÜSUto N- [4- (3-Amiinio-S- { F0 oiro -? @ Iniosi) -. { The product of Example 191a was reduced with Fe and NH 4 Cl following the procedure of Example 237E to give the title compound.

Example D91c N-. { 4- [3-FDuoiro-5- (7-piropDB- (1.8lroaftt.n ^ a c © ís inm i d 3 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 following the procedure of Example 1g to give the crude title compound, which was purified through of silica gel column chromatography eluting with 50: 1 CH2Cl2 / MeOH affording the title compound (210 mg, 68%). 1 H NMR (300 MHz, DMSO-de) d ppm: 2.40 (s, 3 H), 2.68 (s, 3 H), 6.62 (d, J = 6.9 Hz, 1 H), 6.98 (t, J = 7.3 Hz, 1 H) , 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 = 88 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); S (ESI +) m / z 369 (M + H) +, (ESI-) m / z 367 (M-H) -.

EjetnnipOo DS2 Exemplification DS2a Esíoir meftífl DCO dl @ D acid - (3-ffDiuioiro-5-inióíiro-f © iniono) -lb © [ni20DCO To a solution of 4-hydroxybenzoic acid methyl ester (3.00 g, 1 9.5 mmoles) in DIVISO ( 30 ml) t-BuOK (2.56 g, 21.5 mmol) was added at room temperature and the mixture was stirred at room temperature for 30 minutes under a flow of N2. 1,3-Difluoro-5-nitrobenzene (2.34 ml, 20.5 mmol) was added dropwise at room temperature. The mixture was heated at 90 ° C for 2 hours under a flow of N2. The reaction mixture was cooled to room temperature, diluted with H20, and then extracted with EtOAc. The extract was washed with H20 and brine, dried over MgSO4, filtered and concentrated in vacuo to give the title compound as a dark brown oil, which was crystallized with i-Pr20. The crystals were collected by filtration to give the desired product as a pale yellow crystal (1.92 g, 40%). The filtrate gave additional product (1.46 g, 30%) as a pale yellow crystal through silica gel column chromatography eluting with 4: 1 EtOAc / hexane.

Example 192b Layer 4- (3-fíco-5 iraittro-tFeinoxgl-lbe! Nizoico The product of Example 1 92a (3.30 g, 11.3 mmol) and 2N NaOH (11.1 mL, 22.7 mmol) in eOH (33 mL) was refluxed for 30 minutes, and then evaporated. The residue was dissolved in H20 and acidified to a pH of 2 with 10% HCl under stirring. The precipitate was collected by filtration, washed with H20, and dried under vacuum overnight to give the title compound as a slightly yellow crystal (3.03 g, 96%).

Ejeinropll © 1192c 4- -FDi.oiro-5-iniS1íro-feinio? Ió) -M, W-dom © í -b © ini? AmD (da The product of Example 192b (1.00 g, 3.6 mmol) and SOCI2 (3.97 mL, 54.1 mmol) was refluxed for 1 hour. The excess of SOCI2 was removed under reduced pressure to give the corresponding acid chloride as a pale brown oil. To a solution of 2N e2NH / THF was added a solution (18.0 ml, 36.1 mmoles) of acid chloride obtained in THF (10 ml) dropwise at 5 ° C for 15 minutes. The mixture was stirred at 5 ° C for 1 hour and then evaporated. The residue was treated with H20 and the resulting solid was collected through filtration. The solid was washed with H20 and dried under vacuum to give the title compound as a pale yellow crystal (1.09 g, 99%).

EXAMPLE 192d Estimating Mulfonic acid from 41- (3-ameinium-S-fDiuioiro-1F © inioj: i) -ben? ODCO The product from Example 192c was reduced with Fe and NH 4 Cl following the procedure of Example 237E to give the title compound.

Ejeinmpll® 1S2 © 4- [3-Fliuioiro-5- (7-imieil- [il, 8] inia. {Ftii iic9oini-4-ollainniiinio) -lfeinioxDl-N, N- damettol-beinizainniidla 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 following the procedure of Example 1g to give the crude title compound, which was purified through titration with EtOAc to provide the product (150 mg, 79%). 1 H NM (300 MHz, DMSO-de) d ppm: 2.77 (s, 3 H), 2.98 (br-s, 611), 6.97-7.08 (m, 2 H), 7.12 (d, J = 7.0 Hz, 1 H), 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, 11-1); MS (ESI +) m / z 417 (M + H) +, (ESI-) m / z 415 (M-H) -.

Example 1193 4-. { 3-C0oiro-5- (7-p> g > p5ll- | [H, ®Jñ8iHí \ rMim-i & ~ U8imm < D) -ti < BmQ] itl'ti < & n «yes Example 193a 1 -Cioiro-3, S-dSmieíiro-lbeiniceinio To a mixture of t-BuONO (5.41 ml, 41.0 mmol) and CuCI2 (4.41 g, 32.8 mmol) in CH3CN (100 ml) was added 3,5-dinitroaniline (5.00 g, 27.3 mmol) slowly at 58-60 ° C. . After the 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% NaHCO 3 and brine. The organic layer was dried over gSO4 filtered and concentrated in vacuo to give the title compound which was purified through silica gel column chromatography eluting with 10: 1 EtOAc / hexane to give the title product as a crystal pale yellow (4.60 g, 83%).

Ejemmpll © H 933 4 - (3 -C 0 or r © -5 - your i 4 iro -ffe my or »5) -ff ® BU O 0 The product of Example 193a (1.00 g, 5.0 mmol), hydroquinone (0.50 g, 4.5 mmol) and 2 CO 3 (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 H20 and then extracted with EtOAc. The extract was washed with H20 and brine, dried over EWgSO4, filtered and concentrated under vacuum to give the title compound. The residue was treated with i-Pr20 and the insoluble material was filtered. The filtrate was evaporated and purified through silica gel column chromatography eluting with 5: 2 EtOAc / hexane to give the title product as a pale yellow oil (0.51 g, 43%).

Example 193c 4- (3-Am8no-5-cBoiro-ff®noKii) -f®iniumI The product of Example 192c was reduced with Fe and NH CI following the procedure of Example 237E to give the title compound.

Example 193 (9 The product from Example 2g (100 mg, 0.48 mmol) was reacted with the product of Example 134c (140 mg, 0.48 mmol) for 17 hours following the procedure of Example 1g to give the crude title compound, which was purified through titration with EtOAc to provide the title compound (140 mg, 71%). 1 H NMR (300 MHz, DMSO-de) d ppm: 0.98 (t, J = 7.4 Hz, 3 H), 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, 214), 7.04 (d, J = 8.8 Hz, 2H), 7.28 (d, J = 1.8 Hz, III), 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 (+ H) +, (ESI-) m / z 404, 406 (M-H) -.

Example 194 M-. { H3-Clloiro-5- (7-pirop -f1,83 < n) afttin ^ Example 194a W- [4- (3-Cioro-5-inijíiro juvenile IFeirm] -a ceta ida The product of Example 193a (1.06 g, 5.2 mmoles), N- (4-hydroxyphenyl) acetamido (0.70 g, 4.5 mmoles) and K2CO3 (0.79 g, 5.7 mmol) in DMF (14 mL) was heated at 1110 ° C for 6 hours.The reaction mixture was cooled to room temperature, diluted with H20 and then extracted with EtOAc. The extract was washed with H20 and brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude title compound as a pale brown crystal, which was purified through washing with i-Pr20 to give the desired product as a pale brown glass (1.28 g, 92%).

Example 194b N- [4- (3-Amino-5-chloro-phenoxy) -phenyl] -acetamide The product of Example 1 92c was reduced with Fe and NH 4 Cl following the procedure of Example 237E to give 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 (1000 mg, 0.48 mmol) was reacted with the product of Example 1 94oc (1 30 mg, 0.48 mmol) for 22 hours following the procedure of Example 1 g to give the crude title compound, which it was purified by titration with EtOAc to give the product (11.0 mg, 51%). 1 H NMR (300 Hz, DMSO-d6) d ppm: 1.00 (t, J = 7.0 Hz, 3H), 1.87 (sextet, J = 7.0 Hz, 21), 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 (M-H) -.

Example 195 4- [3-Chloro-5- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxymethyl] -N-methyl-benzamide Example 195a 4- (3-Chloro-5-nitro-phenoxymethyl) -benzoic acid methyl ester 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 h. hours. The reaction mixture was cooled to room temperature and diluted with H20. The precipitate was collected through filtration and washed with H20 and i-Pr20 to give the title compound as a pale brown crystal (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-2 N NaOH (7.77 mL, 15.5 mmol) in MeOH (25 mL) was brought to reflux for 1 hour, and then evaporated. The residue was dissolved in H20 and acidified to a pH of 2 with 10% HCl under stirring. The precipitate was collected by filtration, washed with H20, and dried under vacuum overnight to give the title compound as a pale brown crystal (2.30g, 62%).

Example 195c 4- (3-Chloro-5-nitro-phenoxymethyl) -N-methyl-benzamide The product of Example 1 95b (0.70 g, 2.3 mmol) and SOCI2 (2.50 mL, 34.1 mmol) was refluxed for 1 hour. The excess of SOCI2 was removed under reduced pressure to give the corresponding acid chloride as a pale brown solid. To a solution of 2N MeNH2 / THF (1.1 mL, 22.8 mmol) was added a solution of the acid chloride obtained above in THF (7 mL) dropwise at 5 ° C. The mixture was stirred at 5 ° C for 1 hour and then evaporated. The residue was treated with H20, acidified to a pH of 2 with 1 0% HCl, and then the resulting solid was collected through filtration. The solid was washed with H20 and i-Pr20, and dried under vacuum to give the title compound as a pale brown crystal (0.69 g, 95%).

Example 195d 4- (3-Amino-5-chloro-phenoxymethyl) -N-methyl-benzamide The product of Example 1 95c was reduced with Fe and NH 4 Cl following the procedure of. Example 237E to give the title compound.

Example 195e 4-t3-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 following the procedure of Example 1g to give the crude title compound, which was purified through titration with EtOAc to provide the product (240 mg, 99%). 1 H NMR (300 Hz, DMSO-de) d ppm: 2.75 (s, 3 H), 2.79 (d, J = 4.4 Hz, 3 H), 5.26 (s, 2 H), 6.90 (d, J = 7.0 Hz, 1 H) , 7.14 (br-t, J = 1.9 Hz, 1H), 7.18 (br-t, J = 1.9 Hz, III), 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 (br-s, 1H), 8.50 (d, J = 7.0 Hz, 1H), 9.08 (d, J = 8.8 Hz, 1H), 11.08 (br-s, 1H); MS (ESI +) m / z 433, 435 (M + H) +, (ESI-) m / z 431, 433 (M-H) -.

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 1 93a (0.75 g, 3.7 mmol), 4-bromobenzyl alcohol (0.77 g, 4. 1 mmol) and K2C03 (0.64 g, 4.6 mmol) in DMF (1.5 mL) was heated to 11.0 g. ° C for 23 hours. The reaction mixture was cooled to room temperature, diluted with H20, acidified to a pH of 2 with 10% HCl, and then extracted with EtOAc. The extract was washed with H20 and brine, dried over MgSO4, filtered and concentrated under vacuum 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 being stirred at room temperature for 30 minutes, the mixture was filtered through celite. The filtrate was evaporated and the resulting solid was washed with i-Pr20 to give the title compound as a pale yellow crystal (0.70 g).

Example 196b 3- (4-Bromo-benzyloxy) -5-chloro-phenylamine The product of Example 1 96a was reduced with Fe and N H4CI following the procedure of Example 237E to give the title compound.

Example 1SSc [3-í -Btromo-beiniCíloKc) -5-clofO-1FefTiíl] - (7-pirop5S- [1l, 8jiraaíttsródlSini-4-iill) - a mummy 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 following the procedure of Example 1g to give the crude title compound, which was purified through titration with EtOAc to provide the title compound (1990 mg, 100%). 1 H NMR (300 Hz, DMSO-d 6) d ppm: 0.96 (t, J = 7.4 Hz, 3 H), 1.83 (sextet, J = 7.4 Hz, 2 H), 2.97 (t, J = 7.4 Hz, 2 H), 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 (M-H) -.

Example 1197 N-. { 4- [3-Chloro-5- (7-methyl- [1,8] naphthyridin-4-yl-amino-phenosylmethyl] - EXAMPLE 197a STATE OF 4-ACETTAINNI-SINO-INTRICATION OF ACETATE A solution of 4-hydroxymethylaniline (2.00 g, 15.9 mmol) in pyridine (20 mL) was added Ac20 (3.76 mL, 39.8 mmol) dropwise over 5 hours. minutes at room temperature and the mixture was allowed to stir for 1 hour and then evaporated. The residue was diluted with H20 (20 mL) and acidified to a pH of 3 with conc. HCl. at 5 ° C under agitation. The resulting crystal was collected through filtration, washed with a small amount of cold H20 and dried at room temperature under vacuum overnight to give the title compound as a pale brown glass (2.90 g, 88%).

EXAMPLE 197b N- (4-Midiroxom © ttil-tf © nSfl) -ac © üa! Nrcida The product of Example 197a (4.00 g, 9.3 mmoles) in THF (40 mL) was added a solution of aqueous LiOH (0.91 g, 21.2 mmol, dropwise at room temperature for 10 minutes, the mixture was left stirring at room temperature for 27 hours and then evaporated The aqueous residue was diluted with H20, the pH was adjusted to 4 with 10% HCl, and then extracted with EtOAc The extract was washed with brine, dried over gSO, it was filtered and concentrated under vacuum 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-n-Ithro-phenoxymethyl) -phenyl] -acetamide The product of Example 1 93a (1.00 g, 4.9 mmol), and the product of Example 197b (0.90 g, 5.4 mmol) and K2C03 (0.86 g, 6.2 mmol) in DMF (20 mL) were heated to 1000 °. C for 1 0 hours. The reaction mixture was cooled to room temperature, diluted with H20. The resulting solid was collected through filtration, washed with H20, and dried under vacuum to give a brown crystal, which was purified through silica gel column chromatography eluting with 5: 2 EtOAc / hexane to give the title compound as a dark orange crystal (0.47 g, 30%).

Example 197d N- [4- (3-Amino-5-chloro-phenoxymethyl) -fenM] -acetamide The product of Example 196c was reduced with Fe and NH 4 Cl following the procedure of Example 237E to give the title compound.

Example 197e N-. { 4- [3-Chloro-5- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenoxymethyl] -phenyl} -acetamide The product of Example 1 d (70 mg, 0.39 mmol) was reacted with the product of Example 197d (110 mg, 0.39 mmol) for 23 hours following the procedure of Example 1g to give the crude title compound, which was purified at titration with EtOAc to provide the title compound (140 mg, 82%). 1 H NMR (300 MHz, DMSO-de) d ppm: 2.05 (s, 3H), 2.75 (s, 3H), 5.11 (s, 2H), 6.90 (d, J = 7.0 Hz, 1H), 7.12 (br s, 1H), 7.17 (br-s, 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 (br-s, 1H); MS (ESI +) m / z 433, 435 (M + H) +, (ESI-) m / z 431, 433 (M-H) -.

Example 198 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 following the procedure of Example 1g to give the crude title compound which was titrated with 3: 1. ether / THF affording the title compound as a hydrochloride salt (159 mg, 93%). 1 H-NMR (300 MHz, DMSO-de) 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 (br s, 1H) 14.45 (brs, 1H); MS (ESI +) m / z 390 (M-CI) +; (ESI-) m / z 388 (M-HCl) -.

Example 199 2,2-Dimethyl-N-. { 3-. { 4-Methyl-2- (7-propyl- [1,8] naphthridin-4-ylamido) -phenylsulfanyl] -phenyl} -propionamide Example 199a 3- (4-Methyl-2-nitro-phenylsulfanyl) -pheni sheet The title compound was prepared from 3-amino-benzenethiol (5.034 g, 40.21 mmol), 1-chloro-4-methyl-2-nitro-benzene (4,600 g, 26.81 mmol) and K2C03 (6,484 g, 46.92 mmol) ) dissolved in DMF and heated at 100 ° C for 16 hours. At this time the reaction mixture was cooled to room temperature and diluted with water, extracted with ethyl acetate. Dry over Na 2 SO 4, filter and concentrate 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. This was stirred at room temperature for 2 hours, at which time the title compound was collected through filtration (8.78 g, 92%).

Ejemropllo ilSSc W- [3- (2-Amiinio- -meíól-1Ferü !! syllíaini¡!) - 1Feiniill3-aceilamSda The product of Example 199b was reduced with SnCl2 following the procedure of Example 14 to give the title compound.

Example H99d? -. { 3- [4 ·? ® ???? · 2- (7 - ?? G ????? -? .SlmafíiiricaSini - ^ - ilaminoJ-íenóísiilIlFaeTiDll] - 1F © mo II.}. - ac © 4a mra S day 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) combined in 10 mL of EtOH and heated at 80 ° C for 40 hours. . After cooling to room temperature the solvent was removed under vacuum to give the title compound (1.2 g, 74%).

EjeroapDo Ü9S) ® iH) -amine The title compound was prepared 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 at 100 ° C for 1 hour. At this time the reaction mixture was cooled to room temperature and made basic with 2N NaOH. This was then extracted with CH2Cl2, which was then dried over Na2SO4, filtered and concentrated under vacuum to give the title compound (720 mg, 66%).

Example 199? 2,2-DSmeí -W-. { 3- [4-mett -2- (7-piropH-E1l, 8] iriaf1téirBdiii¾- -llamDno) - ff in 5 D su II 1f a mi 50] If © mi S i) - p ir op ¡o im a mn > or d a The title compound was prepared using 2,2-dimethyl-propionic acid (26 mg, 0.16 mmol) as the acid in the procedure for Example 74 to provide the title compound (3 mg, 5%). 'H NMR (500 MHz, DMSO-D20) d 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) r 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 (+ TFA + H) +; (ESI-) m / z 483 · (M + TFA-H).

Example 200 { 3- | 4-M © ¾ -2- (7-piropíl- [1,8] naffíSir3dlin-4-amíno) -1F © mi sMÍ1fanó [l-ffeiraolj-amide deí ácido 2, S-dimeíS! -ifyiraini-3 -cairbonóllico The title compound was prepared using 2,5-dimethyl-furan-3-carboxylic acid (26 mg, 0.16 mmol) as the acid in the procedure for Example 74 to provide the title compound (3 mg, 5%). 1 H NMR (500 MHz, DMSO-D 20) d ppm: 0.93 (t, J = 7.32 Hz, 3 H), 1.70-1.77 (m, 2 H), 2.26 (s, 3 H), 2.39 (s, 3 H), 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} -thiophene-2-carboxylic acid amide The title compound was prepared using thiophen-2-carboxylic acid (26 mg, 0.16 mmol) as the acid in the procedure for Example 74 to provide the title compound (3 mg, 5%). 1 H NMR (500 MHz, 0MSO-D 2 O) d ppm: 0.90 (t, J = 7.32 Hz, 3 H), 1.67-1.75 (m, 2 H), 2.40 (s, 3 H), 2.76-2.82 (m, 2 H), 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 21012 S-Hod (roKi-M- (3- [4-meyOS-2-y7-p [ropBi- [1, 8] af affíSnd] ilí1-4-o] ami (I ^ o) - ff ©? Plísyllffa? Pl5ß] -fef ^ l ^!) - niicoío? Pla? Pp? Ddla The title compound was prepared using 6-hydroxy-nicotinic acid (26 mg, 0.16 mmol) as the acid in the procedure for Example 74 providing the title compound (3 mg, 5%). H NMR (500 MHz, DMSO-D20) d 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 (+ TFA-H).

Ejjeinnipll © 203 The title compound was prepared using 2-hydroxy-6-methyl-nicotinic acid (26 mg, 0.16 mmol) as the acid in the procedure for Example 74 to provide the title compound (3 mg, 5%). 1 H NMR (500 MHz, DMSO-D 20) 8 ppm: 0.89 (t, J = 7.48 Hz, 3 H), 1.64-1.71 (m, J = 7.48, 7.48, 7.48, 7.48 Hz, 2 H), 2.36 (s, 3 H) ), 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, 1 HOUR); MS (ESI +) m / z 536 (+ TFA + H) +.

Ejemnipilo 204. { 3- [4-M © 1iD [l-2- (7-p [ro | p - [il, ®lna liD [r5dSsTi-4- ainniiii) T) 0 Jl-. { F®m.0suO? Aini0I] -feini90} -ainniD .a c9 @ B piira acid? Sn-2-ca6-bo¾ílsco The title compound was prepared using pyrazine-2-carboxylic acid (26 mg, 0.16 mmol) as the acid in the procedure for Example 74 to provide the title compound (3 mg, 5%). HNR (500 Hz, 0 SO-D2O) d 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 (d, 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- 3- [4-meyi [-2- (7-pi-opBi- [il, 8] nafitit-in-''-i! Amono) - 1f®n syllfaini9ll] -fe ( ni cairbainnioiifi) -metill) -ami -a from ffiuiraini-2-eairboi-.Diic © acid The title compound was prepared using [(furan-2-carbonyl) -amino] -acetic acid (26 mg, 0.16 mmol) as the acid in the procedure for Example 74 to provide the title compound (3 mg, 5%) . 1H NMR (500 MHz, DMSO-DzO) d 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 (+ TFA + H) +.

Example 2 © S W-. { 3-. { 4-M © fiiI- - (7-piropy-iil, 83in) a1Ft, 5irD ^^ 1f e n i 0} - 4 - (t o o ff ® m - 2 - or J - Ib y t í ir a m i d a The title compound was prepared using 4-thiophen-2-yl-butyric acid (26 mg, 0.16 mmol) as the acid in the procedure for Example 74 to provide the title compound (3 mg, 5%). 1H NMR (500 MHz, DMSO-D20) d 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 (+ TFA + H) +.

Example 207 ff © e¾ l} -2- (3-1F © inioK! -ffenií) -aceíainniDí_a The title compound was prepared using (3-phenoxy phenyl) -acetic acid (26 mg, 0.16 mmol) as the acid in the procedure for Example 74 to provide the title compound (3 mg, 5%). H NMR (500 MHz, D SO-DzO) d 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 W-ADoi-3- [4-cioiro-2- (7-me (ii5- [1l, 8] inia1ftl5rSc! Lüirí-4-jíainiTijfi) o) -f © ini02io3- Ibeinizainnioda Example 20 @ a Esirir methotloco of 3-4 4-chloiro-2-ini5llro-FFe [n) OKDj) -l! -) © ini? O5co 1-bromo-4-chloro-2-nitro-benzene (7.00 g, 29.60 mmol) was dissolved in DMF to which was added K2CO3 (5.11 g, 37.01 mmol) and 3-hydroxy-benzoic acid methyl ester (4.95 g, 32.57 mmoles). The reaction mixture was then heated at 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 Na 2 SO 4, filtered and concentrated under vacuum to give the title compound. (7.2 g, 79%) Example 208b Ester metí. ico acid 3- (2-amSno-4-c8oro-iFenonS) -besTizoico The product of Example 208a (7.20 g, 23.40 mmol) was reduced with SnCl 2 (13,310 g, 70.20 mmol) following the procedure of Example 1f to give the title compound (6.2 g, 95%).

Example 208c 3- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-iiam-i-no) -phenoxy] -benzoic acid methyl ester The product of Example 1 d (1.75 mg, 0.979 mmol) and the product of Example 208b (272 mg, 0.979 mmol) were dissolved in 2 ml of EtOH abs. and heated at 80 ° C for 1 6 hours. At this time the reaction mixture was cooled and the solvent was removed yielding the title compound as a brown foam which was then taken without purification (41.0 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 (TH F: water). To this was added LiOH (51 mg, 2129 mmol) and the reaction mixture was heated at 60 ° C for 2 hours, then the reaction mixture was allowed to cool to room temperature and neutralized with HOAc. ethyl acetate, dried over Na 2 SO 4, filtered and concentrated in vacuo to give the title compound (180 mg, 42%).

Example 2 © 8e N-Aiyl-3- [4-chloro-2- (7-methyl- [1.SJnaftiiridin ^ -Uaminc-phenoxy] Ib ero 2 a mida The product of Example 208d (60 mg, 0.147 mmol) was dissolved in THF to which was added N-methyl-morpholine (49 mg, 0.162 mmol), and isopropenyl chloroformate (36 mg, 0.295 mmol). This was stirred at room temperature for 1 hour, at which time the allylamine (42 mg, 0.739 mmol) was added and the reaction mixture was stirred at room temperature for another 1 hour. The THF was then stirred under a stream of N2 and then the crude oil was purified by HPLC with TFA to afford the product as a trifluoroacetic acid. (8.0 mg, 9.5%). 1 H NMR (300 MHz, DMSO-de) d ppm: 1.92 (s, 3 H), 2.74 (s, 2 H), 3.86 (d, J = 5.15 Hz, 2 H), 5.04-5.16 (m, 2 H), 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 tributyl-phenyl-stannane (0.185) mi, 0.564 mmole) under nitrogen in toluene at 75 ° C in the presence of 2 mol% of tetrakis (triphenylphosphine) palladium (O). The volatiles were subsequently removed under reduced pressure to produce the crude product, which was purified by flash chromatography on silica gel to give the title compound (0.103 g, 88%).

Example 211b 6-Fen i l-pyridin-2-i lamina The substituted pyridine described in Example 211a (0.289 g, 1. 7 mmole) was reacted as described in Example 2c to give the title compound in quantitative yield.

Example 211 He 5 - C II or 7 o - 2 - ff e mi i I - [H, 8] n a f t i r i d 5 n a The product of Example 211b was reacted following the procedures from Examples 2d, 2e, 2f and 2g to give the title compound.

AxisD © 2HHdl í 5-C.oiro-2-ff © [rBO? I.-iF © ín) itDÍ-í T-ffeintDD-lf l, @ [TttaffíiirD (Eafl (JT) - '0 - DOJ-a (nniü (n) a 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as the trifluoroacetic acid salt (0.144 g, 57%). H NMR (300 MHz, DMSO-d6) d 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 (M-H) -.

EXAMPLE 212 2- (7-Methyl- [1,8] naphthyl-ridin-4-ylamido) -biphenyl-4-carboxylic acid methyl ester Example 21 2a 4-Bromo-3-nitro-benzoic acid methyl ester Commercially available 4-bromo-3-nitro-benzoic acid (1.1 g, 4.76 mmoles) was dissolved in methanol (5 ml) containing 5 drops of concentrated sulfuric acid. The mixture was heated in air at 90 ° C for 6 hours and more MeOH (7 ml) was added followed by concentrated sulfuric acid (0.6 ml). The heating was continued for another 24 hours. Extraction processing (ethyl acetate-water) was followed by drying over MgSO4, filtered and concentrated in vacuo to give the title compound in quantitative yield.

Example 21 2b 2-Nitro-biphenyl-4-carboxylic acid methyl ester The product of Example 212a (0.100 g, 0.384 mmoies) was combined with iodobenzene (0.375 ml, 3.35 mmole) and copper powder (0.1 88 g, 2.96 mmole) and the mixture was heated in a sealed tube to 21 8. ° C for 90 minutes. The reaction mixture was subsequently diluted with dichloromethane and filtered through celite. The crude product, obtained by concentration under vacuum, was purified by flash chromatography on silica gel (ethyl acetate-hexanes) to give the title compound (0.0847 g, 86%).

EJ europium 2112c The site of the 2-awiiiinio acid irraettíico of the acid irD o The product of Example 21 2b (0.0795 g, 0.309 mmol) was dissolved in ethanol (2 mL) and to this solution was added Pt (IV) oxide (5.2 mg). The reaction mixture was degassed under vacuum, then exposed to a hydrogen atmosphere for 3 hours at room temperature. The catalyst was removed by filtration through celite and the filtrate was concentrated under vacuum to give the title compound in quantitative yield.

Example 21 2 (9 Testing the acid 2- (7-ßtp? D d5 ?? - | 1, 8J nfflffíiir5diini-4-i llamoirío) - b 5 i? ® n i 0 - 4 - c a? B o x.5 i i c o The product of Example 1 d (0.0552 g, 0.309 mmol) was reacted with the product of Example 21 2c (0.070 g, 0.309 mmol) for 92 hours following the procedure of Example 1 g to give the crude title compound, which was purified by HPLC with AA. The resulting solid was titrated with 4N HCl in dioxane to generate the hydrochloride salt which was collected by vacuum filtration (0.0747 g, 55%). '? NMR (300 MHz, DMSO-d6) d 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-M) -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) was added CsC03 (0.305 g, 0.94 mmol) followed by phenyl boronic acid (0.062 g, 0.49 mmole) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo [3.3.3.] Undecane as a 0.1M solution in toluene (0.200 ml, 4 mol%). Nitrogen was bubbled through the resulting suspension for 3 minutes then palladium acetate (0.0043 g, 4 mol%) was added, the reaction vessel was sealed and immersed in an oil bath at 80 ° C and heated during 22 hours Subsequent filtration through celite and removal of volatiles under vacuum gave the crude product (0.105g, 100%), which was pure enough to be used as an isolate.

EjemropD © 213b leííi-l ilfeiniüJ-2-ilamSinia The product of Example 213a was reacted as described in Example 212c to give the title amine (0.088 g, 100%).

EJotnm pBo 2113c 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 hours following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid salt (0.122 g, 52%). 1H NÍWR (300 MHz, DMSO-d6) d 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, 8H) 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 (M-H) -.

Example 214 (^ -Meüil-l óieini-a-í-IT-piro-il.Sliniaffl.SirDdiini - ^ - Daj-amiinia Example 214a Jeíoni-4-meí -2-m! Íiro-bo1FeiniHo 1-Bromo-4-methyl-2-nitro-benzene (0.107 g, 0.49 mmoles) was reacted as described in Example 213a substituting 4-methoxyphenylboronic acid (0.074 g, 0.49 mmol) for boronic acid to give the biphenyl title in quantitative performance and enough purity to be used as an asylee in the next step.

Example 214b 4 ° -Rflettoxi -biferous i J-2-i lamo na The product of Example 214a was reacted as described in 212c to give the title amine (0.107 g, 100%).

Example 214c (4 * -IM®ttoxii-4-m © yil-lb.1f © iroy ^ 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 hours following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid salt (0.106 g, 45%). 1H NR (300 Hz, DMSO-de) d 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, 1 HOUR); MS (ESI +) m / z 356.0 (+ H) +; (ESI-) m / z 354.1 (-H) -.

Example 2 * 33 Exemplar 2115a M- (4'-Ríl © 1íií-2, -ii¾i1tiro-bjffeiiij! -4-D!) - aceiamide 1-Bromo-4-methyl-2-nitro-benzene (0.102 g, 0.49 mmol) was reacted as described in Example 213a substituting N- [4- (4,4,5,5-tetramethyl- [1, 3,2] dioxaborolan-2-yl) -phenyl] -acetamide (0.130 g, 0.49 mmol) for phenylboronic acid and heating for 18 hours at 100 ° C. The reaction mixture was filtered through celite and the volatiles were removed under vacuum and the crude product was purified by flash chromatography on silica gel eluting with EtOAc-hexanes to give the title biphenyl (0.051 mg, 38 %).

Example 215b? - (2 '- ??? 5 Sinio-4'-meíy-tejf © iAiiS-4-5ll) -ac © 4aíTniDda The product of Example 215a (0.062 g, 0.23 mmole) 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 mmole) was reacted with the product of Example 215b (0.062 g, 0.23 mmole) for 46 hours at 100 ° C following the procedure of Example 1 g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (0.073 g, 60%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 1.98 (s, 3 H) 2.42 (s, 3 H) 2.72 (s, 3 H) 6.28 (d, J = 6.99 Hz, 1 H) 7.27-7.56 (m, 7 H) 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); S (ESI +) m / z 383.1 (+ H) +, (ESI-) m / z 381.1 (M-H) -.

Example 216 N- [4, -Methyl-2, - (7-methyl- [1,8] naphthyridin-4-ylamino) -biphenyl-3-yl] -acetamide Example 216a N- (4, -ethyl-2'-nitro-biphenyl-3-yl) -acetamide. 1-Bromo-4-methyl-2-nitro-benzene (0.107 g, 0.49 mmol) was reacted as described in Example 215a substituting 3-acetamidophenylboronic acid (0.086 g, 0.49 mmol) for phenylboronic acid, dicyclohexylamine (4 mol%) for 2,8,9-trisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo [3.3. 3.] undecane and substituting dioxane for toluene to give the title biphenyl (0.0552 g, 42%).

Example 2HS.J M- (2'-Amíin) o-4'-me¾tí-b! F © inííí-3-Bt) -ac © íamidla 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 2116 acetamni iclla The product of Example 1g (0.046 g, 0.26 mmol) was reacted with the product of Example 216b (0.063 g, 0.26 mmol) for 47 hours at 100 ° C following the procedure of Example 1g to give the crude title compound, which it was purified by HPLC with TFA to give the product as a trifluoroacetic acid salt (0.085 g, 64%). 'H NM (300 M z, DMSO-de) d ppm: 1.93 (s, 3H) 2.43 (s, 3H) 2.71 (s, 3 H) 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 (M-H) -.

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-nitro-benzene (0.107 g, 0.49 mmol) was reacted as described in Example 216a by substituting 3-methoxyphenylboronic acid (0.074 g, 0.45 mmol) for 3-acetamidophenylboronic acid to give the biphenyl title (0.083 g, 76%).

Example 217b 3'-Methoxy-4-methyl-bifen i-2-plate 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-Ethoxy-4-methyl-biphenyl-2-yl) - (7-methyl- [1,8] naphthyridin-4-yl) -amine The product of Example id (0.065 g, 0.36 mmol) was made react with the product of Example 2171) (0.072 g, 0.34 mmol) for 96 hours at 100 ° C following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to give an acid salt trifluoroacetic (0.102 gm, 64%). 1 H NMR (300 MHz, DMSO-de) d ppm: 2.43 (s, 3 H) 2.72 (s, 3 H) 3.62 (s, 3 H) 6.29 (d, J = 7.35 Hz, 1 TI) 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 (+ H) +; (ESI-) m / z 354.0 (M-H) -.

EjjemmipDo 2118 (7-Piro | pj.- [1l, 8] iniaffMiri) d5ira ^ Example 2118a 2 - N 5 í go o - - i B * 5 ff I no or go or m 4 S I - Ib S < F e tro i I o Commercially available 1-bromo-2-nitro-4-trifluoromethyl-benzene (0.130 g, 0.48 mmole) was reacted with phenylboronic acid (0.072 g, 0.59 mmole) as described in Example 213a substituting dioxane for toluene, bis chloride. (friphenylphosphine) -palladium (II) for palladium acetate and omitting 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo [3.3.3.] undecane. The reaction was complete after 3 hours and the title biphenyl was recovered in a quantitative yield, sufficiently pure to be used as an isolate.

Example 218b 4-TntfBuorom © ii! -foiffefnSI-2-i lamina The product of Example 218a was reacted as described in Example 212c substituting 3: 1 THF / EtOH (4 mL) for ethanol to give the title amine in a quantitative yield.

EXAMPLE 218c The product of Example 2g as a 3.15 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 following the procedure of Example 1g. The consumption of the starting material required the periodic addition of the product of Example 2g (0.103 ml, 0.32 mmol) in all, and heating was continued at 100 ° C (70 hours). The crude title compound was purified by HPLC with TFA to give the product as a trifluoroacetic acid salt (0.0058 g, 5%). 1H NR (300 ivlHz, D SO-d6) d 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 (d, 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 (M-H) - EXAMPLE 219 (S-raeiol-boffeinic 0-2-5 D) - (7- (propSI- [il, 8] naf1tiiricnn-4-iI) -amine Example 219a 2 - B ir o m o - 4 - mra ® 45! - 1 - mi i 4 go o - b e on c e mi o To a flask containing 90% t-butyl nitrite (1.47 ml, 11.1 mmole) and copper (II) bromide (2.0 g, 8.95 mmole) in CH3CN (40 ml) at 70 ° C under nitrogen were added. added dropwise a commercially available solution of 5-methyl-2-nitro-phenylamine (1.1 g, 7.46 mmoles) in CH3CN (8 mL). After 20 minutes, the reaction was quenched by diluting to dilute HCl and the crude product was isolated through extraction with ether, drying with MgSO 4 and concentration under vacuum. Flash chromatography on silica gel gave the title compound (0.81 1 g, 50%).

Example 219b S-G9e-ethyl-2-ni1.iro-biphenyl The product of Example 219a (0.20 g, 0.93 mmoies) was reacted with phenylboronic acid (0. 135 g, 1.1 mmoles) for 19.5 hours at 80 ° C as described in Example 21 8a. The reaction mixture was cooled and filtered through celite, the filtrate was concentrated under vacuum to give the 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 MetH-bi-1-ene-2-. sheet The product of Example 219b (0.0885 g, 0.41 mmol) was reacted following the procedure described in Example 212c to give the title amine (0.0724 g, 96%).

Example 2SSd The product of Example 2g as a 4.1 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 following the procedure of Example 1g. The consumption of the starting material required a second addition of the product of Example 2g (0.03 ml, 0.12 mmol) and the heating continued at 100 ° C (19 hours). The crude title compound was purified by HPLC with TFA to give the product as a trifluoroacetic acid salt (0.060 g, 32%). 1H NA / IR (300 Hz, DMSO-de) d 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, 8H) 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-methyl-phenyl] - (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. 1H NMR (500 MHz, DMSO-de) d 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 (M-H) -.

Example 221 4- [4-Phenoxymethyl-2- (7-propyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanylj-phenol Example 221a (4-Bromo-3-nitro-phenyl) -methanol Commercially available 4-bromo-3-nitro-benzoic acid (5.95 g, 0.024 mole) was reacted as described in Example 1 15a to give the title in a raw quantitative yield pure enough to be used as an isolate.

Example 221 b 1 -Biromo-2-ini Bíiro-4-1Feii¾OK5meSiD-6jeiricerío The product of Example 221 a (0.5 g, 2.1.5 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 solution It cooled in an ice bath. To the cold solution was added dropwise diisopropylazodicarboxylafo (0.467 ml, 2.37 mmol). Stirring at 0 ° C was continued for 1 5 minutes, then the cold bath was removed and the reaction mixture was allowed to warm to room temperature and 90 minutes before it was quenched and processed by diluting to dilute HCl and extraction with ether. The combined extracts were dried MgSO4, filtered and concentrated in vacuo to give the crude title compound which was purified via flash chromatography on silica gel eluting with EtOAc hexanes to give the title compound (0.162 g, 25%).

EjemnipOo 221 c 4- (2-l ^ ifi (ro-4-1feinionem © 1-oD-iF © fi D! Sullfafió5) -í®ffiiol The product of Example 221 b (0.16 g, 0.52 mmoles) was made react with 90% 4-mercapto-phenol (0.073 g, 0.52 mmole) in DMF at 80 ° C under nitrogen in the presence of potassium carbonate (0.126 g, 0.91 mmol) The reaction was quenched after 18 hours by diluting to dilute HCl Extraction with ether The combined organic extracts were dried over MgSO4, 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-hexanes give the title compound (0.155 g, 84%).

Example 221 d 4- (2-Ainnióirao-4-fenoí: Dinrs © ¾SI-íF © in) óDs SiFain) iiS) l-f © [niol The product of Example 221c (0.154 g, 0.43 mmol) was reacted with stannous chloride (0.41 g, 2.17 mmol) as described in Example 1f to give the title compound (0.132 g, 100%).

Example 221 4- [4-F © ini © Jiiinraett5S-2- (7-piro iH ^, 8! Ii ^ ffeimi.saaBfaffBDOS - © ira or D p The product of Example 2g as a 4.1M 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 hours following the procedure of Example 1g. The consumption of the starting material required a second addition of the product of Example 2g (0.025 ml, 0.102 mmol) and the 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%). 1H NR (300 Hz, D SO-d6) d 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); S (ESI +) m / z 494.2 (M + H) +; (ESI-) m / z 492.2 (M-H) -.

EXAMPLE 222 4- [2- (7 - [^ ®y .- [1l, 8] in) a1Htiiirid.ro ^ phenol The product from 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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid salt (0.041 g, 34%). 1 H NMR (300 MHz, DMSO-de) d ppm: 2.77 (s, 3 H) 5.13 (s, 2 H) 6.31 (d, J = 6.99 Hz, 1 H) 6.79 (d, J = 8.46 Hz, 2 H) 6.88-7.12 (m, 4H) 7.20-7.36 (m, 4H) 7.467.56 (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 (M-H) - 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-nitrobenzene The product of Example 221a (0.5 g, 2.15 mmol) was reacted as described in Example 221b substituting 4-bromo-phenol (0.372 g, 2.15 mmol) for phenol to give the title compound as a white solid (0.238 g). , 29%).

Example 223b 4- [4- (4-Bromo-phenoxymethyl) -2-nitro-phenylsulfanylphenol 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-H ~ Biroinn) O-1F®irooK0innieft ..) - ^^ and im 5 I s your 0 ffa ñ i 10 -f e? P? or I The product of Example 1 d (0.03 g, 0.167 mmol) was reacted with the product of Example 223c (0.060 g, 0.15 mmol) for 17.5 hours following the procedure of Example 1g. The consumption of the starting material required a second addition of the product of Example 1d (0.016 g, 0.09 mmol) and heating was continued at 80 ° C (18 hours). The crude title compound was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (0.056 g, 55%). 1H NR (300 Hz, DMSO-de) d 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, .1 = 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-l [4- (4-B [romo-b © inicolloiiii.} -2- (7-pirop - ['íl, 811 iaffíí oo So? - 4-oOininni. i 0 its II ff a tro i I] - If e my o 0 The product of Example 2g as a solution 4.1 (Vi 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 hours following the procedure of Example 1g. The starting material required a second addition of the product from Example 2g (0.028 ml, 0.114 mmol) and heating was continued at 80 ° C (18 hours) The crude title compound was purified by HPLC with TFA to give the product as a salt of trifluoroacetic acid (0.044 g, 41%). 1 H NMR (300 MHz, DMSO-de) d 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 4l- (4- (3-Biroinnio-lb © iniclloaii) | - 2- (7-m © 1l5l-f1l, 8Jnaffttiir.düiro- 4-iHaimSin > o) - ff © m 5 D s HD 0 ff a mi o 01 -iF® mi o II Example 225a 1 -! Biromo-4- (3-l iromo-íiniooSm © ísl) -2-iniSíiro- (hieiniceirío The product of Example 221a (0.5 g, 2.15 mmol) was reacted as described in Example 221b by substituting 3-bromo-phenol (0.372 g, 2.15 mmol) for 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 225d 4- [4- (3-Bromo-phenoxymethyl) -2- (7-methyl- {1,8,8-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 following the procedure of Example 1g. The consumption of the starting material required a second addition of the product of Example 1d (0.019 g, 0.109 mmol) and the heating was continued at 80 ° C (18 hours). The crude title compound was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (0.041 g, 32%). 1 H NMR (300 Hz, DMSO-de) d ppm: 2.77 (s, 3 H) 5.15 (s, 2 H) 6.30 (d, J = 7.35 Hz, 1 H) 6.79 (d, J = 8.46 Hz, 2 H) 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.

Ejemnipdo 226 4 - [^ - (3-Bí-oinnio-lbeoTicólo? Ió) -2- (7- | piropiil-n, @] msini ém '- - ~ ü3imiwD) - The product of Example 2g as a 4.1 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 following the procedure of Example 1g. The consumption of the starting material required a second addition of the product of Example 2g (0.028 ml, 0.114 mmol) and the heating was continued at 80 ° C (18 hours). The crude title compound was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (0.038 g, 28%). 'H NMR (300 MHz, DMSO-d6) d 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 = 8.46Hz, 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, 1 HOUR); MS (ESI +) m / z 573.9 (M + H) +; (ESI-) m / z 572.3 (M-H) -.

Ahem pBo 227 (7-PuTeii -ff ^ ®] palfiikidñirí-4-) - [S-mei.y-2- (kodi -2-¡! FafTiol) -fferiol] - aomióinia Example 227a The title compound was prepared from the reaction of trifluoro-methanesulfonic acid 4-methyl-2-nitro-phenyl ester (3.50 g, 12.27 mmol) reacted with pyridine-2-thiol (2.046 g, 18.41 mmol), and 2C03 (2968 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 Na 2 SO 4, filtered and concentrated under vacuum to give the title compound (2.52 g, 78%).

EjemnipSo 227b 5-í¾ © ííl-2- (pBG-BdSn-2-¡yy8tf3mill) í en ti amina The product of Example 277a (2250 g, 10.23 mmol) was reduced with SnCl 2 (5,820 g, 30.70 mmol) 2 hrs. 80 ° C following the procedure of Example 1f to provide the title compound, which was purified through silica gel column chromatography eluting with 30% EtOAc / hexanes (1.52 g, 70%).

Example 227c (7-G9ethyl- [1f8] naphthlldn-4-yl) - [5-methyl-2- (pi-ridin-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 following the procedure of Example 1g to give the crude title compound, which was purified through HPLC with TFA affording the product as a trifluoroacetic acid (24 mg, 28%). 1H NMR (300 MHz, DW.SO-d6) d 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 (-H-TFA) -.

EXAMPLE 228 5-Chloro-2-fαiniOKÍi-1f © ini í- [1I.SJinia 1íóiródD [ni-5- -ainniDinia Example 228a 2 - T ir or mni ® 4 or II s i i a mi Si © í i n i II - st > 5 c or 4 i ira or n 511 r 50 o In a suitably sized pressure vessel, commercially available 2-chloro-nicotinonitrile (1.5 g, 10.8 mmol) was combined with triphenylphosphine (0.228 g, 8 mole%) and palladium (II) acetate (0.083 g, 3.5 mol%) in triethylamine (20 ml). Nitrogen was bubbled through the resulting suspension at room temperature for 5 minutes then trimethylsilylacetylene (8.5 ml, 60.1 mmol) was added, the vessel was sealed and immersed 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 via flash chromatography on silica gel eluting with EtOAc / hexanes 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% solution / weight (8.74 g, 40.4 mmol) in methanol (5 mL) for 2 hours at 80 ° C. The crude product was isolated by exotherm with ether, dried over gSO4, filtered and concentrated under vacuum to give the title compound (1.46 g, 94%) sufficiently pure to be used as an isolate.

Example 228c 2- (2,2-D5inraetoK5-eiüí) -fH! COttinafiniidla The product of Example 228b (1.46 g, 7.6 mmol) was dissolved in methanol (20 mL) to which sodium carbonate was added at room temperature as a solution. 3 N (35 ml) followed by hydrogen peroxide as a 15% solution (35 ml). The reaction was allowed to stir for 4.5 hours then was partitioned through the addition of ethyl acetate and solid sodium chloride. The aqueous phase was extracted several times with ethyl acetate and the combined organics were stirred with solid sodium bisulfite followed by drying over MgSO4, filtered and concentrated under vacuum to give the title compound (1.36 g, 85%) sufficiently pure to be used as an isolated Ejemraplo 22®dl [1,6] WaffttondiffD-S-o » The product of Example 228c (1.36 g, 6.47 mmol) was dissolved in benzene (35 ml) and pyridinium para-toluenesulfonate (0.20 g, 0.8 mmol) was added to this solution. The mixture was heated to reflux for 23 hours then concentrated under vacuum to give the title compound in quantitative yield sufficiently pure to be used as an isolate.

Ejj © implo 22 ©© S-C.ore-P.SJinialFft.ir.dliinia The product of Example 228d (0.250 g, 1.71 mmol) was combined with phosphorus oxychloride (4 mL) and heated under a nitrogen atmosphere at 80 ° C for 18.5 hours followed by vacuum distillation to remove the volatiles. The residue was made a slurry with ice and made basic (pH 7-8) with concentrated ammonium hydroxide. The title compound was collected by vacuum filtration, washed with water and dried under vacuum to give a gray solid (0.245 g, 87%) sufficiently pure to be used as an isolate.

Example 22 (5-C8oiro-2-1f © iniOK íf © irBÍI) - [1l.iS] iniaí1ljiródDini-5-SS-ainnióin) a 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 following the procedure of Example 1g to give the crude title compound, which it was purified by HPLC with TFA to give the product as a trifluoroacetic acid salt (0.046 g, 40%). 1HR (300MHz, D SO-d6) d 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 (M-H) -.

EjeoinipOo 2 9 W-. { 4-I4 - [^ eioD-2-í [1.SlfialfíSt-idon-S-aíamonoí-íeffíñDsySffanítl-iFeíii ^ - acislainnió ílaThe product of Example 228e (0.040 g, 0.24 mmol) was reacted with the product of Example 18b as a 1.5M solution in ethanol (0.162 mL, 0.24 mmol) for 17.5 hours at 100 ° C following the procedure of Example 1g. The consumption of the starting material required a second addition of the product of Example 228e (0.027 g, 0.16 mmol) and heating was continued at 100 ° C (24h) to give the crude title compound, which was purified by HPLC. with TFA affording the product as a trifluoroacetic acid salt (0.038 g, 27%). H NMR (300 MHz, DMSO-d6) d 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); S (ESI +) m / z 401.3 (M + H) +; (ESI-) m / z 399.0 (M-H) -.

Example 230 (S-Meftyl-Z-fonyl 8-sulfanyl-phenyl) - [il, 8] n &ftiridin-4-yl-aroiin 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 hours following the procedure of Example 1g. Consumption of the starting material required a second addition of the product of Example 16c (0.018 g, 0.113 mmol) and heating continued at 80 ° C (22 hours) to give the crude title compound, which was purified through HPLC with ammonium acetate affording the product as the free base, which was subsequently treated with trifluoroacetic acid to yield the corresponding trifluoroacetic acid salt (0.062 g, 43%). 1H NMR (300 MHz, DMSO-d ") d 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 (+ H) +; (ESI-) m / z 342.0 (M-H) -.

Example 231 N-. { 4- [4-Chloro-2- (7-methyl- [1,8] naphthyridin-4-ylamino) -phenylsulfanyl] -phenyl) -acetamide Example 231a N-. { 4- (5-Chloro-2-nitro-phenylsulfanyl) -phenyl} -acetamide A mixture of 2,4-dichloro-nitro-benzene (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 (3 ml) were added. 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 10% aqueous sodium chloride solution, then dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent was removed under vacuum. The residue was purified through silica gel column chromatography eluting with CH2Cl2 / methanol leaving the title compound as a yellow solid (0.25 g, 63%).

Example 231 1b W- (4- (5-chloro-2- [n) iiíiro1F © in) D] ttSo) 1Feini! D) ace1íainriiódla A solution of the product of Example 231 A (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). mi), and water solution (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 under vacuum 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 under vacuum to provide the title compound (0.20 g, 87%).

EjeimipBo 231 c N- (4- [5-Chloro-2- (7-mephyl- [1, 8] naphthyridine-4-Ham ff® p y.}. -a c ® 3a imó < dl si The product of Example 1 d (48 mg, 0.27 mmol) was reacted in ethanol (2 mL) with the product of Example 231 b (78 mg, 0.27 mmol) for 18 hours following the procedure of Example 1g to give the title compound crude, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt. (12 mg, 28%). 1 H NM (300 MHz, DMSO-d 6) d ppm: 2.06 (s, 3 H) 2.77 (s, 3 H), 6.39 (d, J = 7.35 Hz, 1 H), 6.96 (d, J = 1.84 Hz, 1 H), 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 (s, 1H), 11.01 (s, 1H), 14.48 (s, 1H); MS (DCI / NH3) m / z 435 (M + H) +.

Example 232 M-. { 4- | [4-C5aimom © fto? XD-2-J7-ffiii) ®1iSI- | 1! . © inia ltSir.dlSini - ^ - DlfflmDiJiioJi ff e mi 0 s 0 < F a mi or I] - tf e ira 5 II) - a c © ¾ a mni i ú a Example 232a W - [^ - (4-Hl8droni-2-irD5-yl-ylsilyuifethiol) -y-iryryl-acylamide 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 DF (20 mL) was heated 2.5 hours to 100 ° C. The mixture was cooled, emptied on ice and the resulting solid was collected through filtration and the title compound was dried under vacuum leaving a yellow solid (2.7 g, 100%).

Example 2321b M- [4- (2-Am5iio- -hidliroKi-feinioDsullffarí¡l) -feniD3-ace4aimi5 (-a 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) solution 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 under vacuum 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 under vacuum to provide the title compound (2.46 g, 77%).

Ejjemropl® 232c ^ - [4 - (-? P ???? p? O - - c i a int o? P ?? e Ito 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 for 15 hours. The next day, the reaction mixture was emptied on ice and the solid was collected through filtration to give the title compound (53 mg, 100%).

Example 232d N-. { 4- [4-Cyanomethoxy-2- (7-methyl- [1,8] naphthyridin-4-yl) amino) -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 following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (9 mg, 19%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 2.03 (s, 3 H) 2.76 (s, 3 H), 5.23 (s, 2 H), 6.32 (d, J = 6.99 Hz, 1 H), 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 (+ 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, mmol), benzyl bromide (21 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in D F (1 mL) was stirred at room temperature for 15 hours. The next day, the reaction mixture was emptied on ice and the solid was collected through filtration to give the title compound (62 mg, 100%).

Example 233b N-. { 4- [4-BeiniciDo} ii¡-2- (7-m®till- [1,8] iniaftiridiiri-4-yaitnino) - ff e one or D s 8 ff to a S 0] - ff e mi 3 D) - ac © 4 ami ú a 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 following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (24 mg, 47%). 1H NMR (300 Hz, D SO-d6) d ppm: 2.02 (s, 3H) 2.75 0.3H) 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, 8H) 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); S (ESI +) m / z 507 (M + H) +.

Ejenrapll © 234 l ^ -. { ^ - | [4-. { 2-I ^ I @ ^ B-aD5D (aiKs.} -2-C7-innt (&1íóB-f'0 t @] iroa? FtDiridDini-- - i0amÍin) ci $ - ff e ira 5 II sy II tf a im 51] - ® mi l.}. - acetamide EXAMPLE 234a -. {4- [2-Amainium-4- (2-m-alkyl-ali (loKi) -iFenHsiL-] fainH3-ieny} -aceiainniidla A mixture of the product from Example 232b (56 mg, 0.17 mmol), 2-methyl-3-bromo-propene (20 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 mL) was stirred at room temperature 15 hours. The next day, the reaction mixture was emptied on ice and the solid was collected through filtration to give the title compound (55 mg, 100%).

Example 234b © n S 0 s B IFa ira d 0 J - ff © tu i II} - a c © 4 a mra 5 d a 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 following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (12mg, 25%). 1 H NMR (300 Hz, DMSO-de) d ppm: 1.76 (s, 3 H) 2.02 (s, 3 H), 2.75 (s, 3 H), 4.52 (s, 2 H), 4.98 (s, 1 H), 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-Meiol- | 1l, 8] na < Pttoridiiin-4-ollamino) - ^ - piropo-tii-fenH3ull1Fainil] - ffemiill} -acetamide Ejemnip. © 235a M- [4-í2-Amoinium-4-ps'opoiiB-feiniysylffai¡¾DD) -ffeiniiill-acetlainniB (dla A mixture of the product of Example 232b (56 mg, 0.17 mmol), 2-methyl-3-bromo-propene (20 mg, 0.17 mmol) and potassium carbonate (26 mg, 0.19 mmol) in DMF (1 mL) was stirred at room temperature 15 hours. The next day, the reaction mixture was emptied on ice and the solid was collected through filtration to give the title compound (55 mg, 100%).

EjjeinropO © 235b feini} -ac © Sams the 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 following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (14 mg, 30%). 1 H NMR (300 MHz, DMSO-d 6) d ppm: 0.97 (t, J = 7.35 Hz, 3 H) 1.59-1.83 (m, 2 H) 2.02 (s, 3 H) 2.75 (s, 3 H) 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-yl-i-yl) -phenoxymethyl] -benzoic acid methyl ester EXAMPLE 236a 4- [4- (4-Acetylamino-phenylsulfanyl) -3-am i non-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. hours. The next day, the reaction mixture was emptied on ice and the solid was collected through 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 following the procedure of Example 1g to give the crude title compound, which was purified by HPLC with TFA to afford the product as a trifluoroacetic acid salt (22 mg, 37%). 1 H NMR (300 MHz, DMSO-de) d 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 = 7.35 Hz, 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 (1 + H) +.

Example 237 4- [H4-M®1tox.-lb®inicyo2ii) -2- (7-me1HI ^ or ímira i ira o) -ff ® mi 50 s < u 0 ffa mi 5 OJ -ff® ira or í Example 237a 2 - A mro n n - S - mro ® 4 or I - my c o t ü DD O ira í 4 r 51 o 2-Chloro-6-methyl-nicotinonitrile (25 g, 0.164 mol) and liquid ammonia (250 ml) were reacted in 500 ml of ethanol in a high-pressure vessel sealed at 130 ° C for 20 hours. The reaction mixture was concentrated under vacuum and the residue was washed with water (2 x 50 mL) then dried in a vacuum oven for 24 hours to give the title compound as a light yellow solid (18 g, 82%). . 1H NR (300 MHz, DMSO-de) d ppm: 2.30 (s, 3H), 6.52 (d, 7.7 Hz, 1H), 6.78 (s, 2H), 7:73 (d, J = 7.7 Hz, 1H ).

EXAMPLE 237b N '- (3-C iairo? -d-meit.0 -pii iród? ??? ^ A solution of the product of Example 237a (10 g, 75.19 mmol) and?,? - dimethylformamide dimethyl acetal (11 mL, 82.71 mmol) in toluene (100 mL) was heated to reflux for 6 hours. After cooling to room temperature, the solution was concentrated under vacuum to provide the title compound as a yellow solid (13.78 g, 98%). 1 H NMR (300 MHz, DMSO-de) d ppm: 2.41 (s, 3 H), 3.06 (s, 3 H), 3.14 (s, 3 H), 6.87 (d, J = 7.7 Hz, 1 H), 7.89 (d, J = 8.1 Hz, 1H), 8.59 (s, 1H).

Example 237c -C! Gold-4- (4-m © 1ioj: i beincsloj: í) -2-iniiís, o-to © iniceinio A solution of 4-chloro-3-nitro-phenol (0.5 g, 2.88 mmol), 1-chioromethyl-4-methoxy-benzene (0.496 g, 3.17 mmol), potassium carbonate (1.19 g, 8.64 mmol) and iodide tetrabutylammonium (0.005 g, 0.0135 mmol) in N, N-dimethylformamide (5 mL) was stirred at room temperature for 16 hours. Ice-water (10 ml) was then added to the solution and the resulting solid was collected through a pad and dried in a vacuum oven to provide the title compound (0.812 g, 96%).

Ej mnipío 237dl 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, N-dimethylformamide (5 mL) was heated to 100 ° C. 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 aqueous hydrochloric acid. The solution was then extracted with ethyl acetate (3 x 10 mL), the combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (1.06 g, 100%).

Ejjenniipllo 237® 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 meianol (18 ml), tefrahydrofuran (18 ml), and Water solution (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 under vacuum 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 under vacuum to provide the title compound (0.99 g, 100%).

Example 237f 4-. { 4- (4-Ethoxy-benzyloxy) -2- (7-methyl-pyrido [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 a preheated oil bath at 130 ° C for 20 minutes. The mixture was then cooled to room temperature, the acetic acid was removed under vacuum, and the resulting residue was titrated with methanol to provide the title compound as a tan solid (26.5 mg, 35%). 1 H NMR (300 MHz, D SO-d 6) d ppm: 9.92 (s, 1 H), 9.63 (s, 1 H), 8.70 (d, J = 8.09 Hz, 1 H), 8.55 (s, 1 H), 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 (M-H) -.

Biological Evaluation The representative compounds of the invention were analyzed according to the tests described below.

The following acronyms were used here: I C50 50% inhibitory concentration TC50 50% toxicity concentration ???? Essential Medium Modified with Dulbecco ™ RNA Ribonucleic Acid RT-PCR Reverse Transcriptase Polymerase Chain Reaction SEAP Secreted Alkaline Phosphatase The hepatitis C virus genome encodes a large polyprotein, which after processing produces the functional components needed to synthesize progeny RNA. Selectable cell lines that produce high and sustained levels of sub-genomic HCV RNA (replicons) have been derived from human hepatoma cells (Huh7) as described in I keda et al., J. VIROLOGY, 76 (6): 2997-3006 (2002), and Blight et al., SCIENCE, 290: 1972-1974 (2000). The mechanism of RNA replication in these cell lines is considered identical to the replication of full-length HCV RNA in infected hepatocytes. The compounds of this invention are inhibitors of HCV RNA replication in replicon assay systems described below.

Evaluation of HCW Inhibitors in MCW Replicon Representative compounds of the invention were evaluated for their inhibitory effect on the 1 a and 1 b replicons of the HCV genotype.

They were also evaluated through the MTT assay for cytotoxicity to host cells. The cell lines were maintained according to the methods described by Yi et al., VI ROLOGY, 304 (2): 1 97-21 0 (2002).

? Assay «Se RNA and SEAP Assay The purpose of these assays was to evaluate the efficiency of the compounds to inhibit the replication of replicons 1 a and 1 b of the HCV genotype in vitro. 1 a and / or 1 b replicon cells of the genotype were plated at 3-5 x 1 03 cells per well in a 96-well plate in a DMEM medium containing 5% fetal calf serum. 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 an identical manner except that no inhibitor was added to the medium. Plates were incubated in a C02 incubator at 37 ° C. On day 4, 1 00 μ? of lysis pH regulator (RTL) (Qiagen) to each cavity after the removal of the culture. The RNA was purified according to the manufacturer's recommendations (Qiagen RNAeasy) and eluted in 200 μ? OF WATER. The level of HCV RNA was quantified from portions (5 μ? Of 200 μ?) Of the purified RNA through the RT-PCR method in real time. The primers and probe were derived from a specific sequence in Region 5 * Untranslated (5'UTR). The RT-PCR reaction was performed at 48 ° C for 30 minutes, followed by 40 cycles set at 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 reduction percentage of HCV or SEAP RNA in the presence of the compound was calculated and the 50% inhibitory concentration (IC50) was calculated through a non-linear regression analysis using the Prism program (version 4.0, GraphPad software, San Diego , CA). When tested using the above method, the representative compounds of the present invention inhibited the replication of the inhibited HCV replicon with IC 50 values in the range of about 0.3 nM to about 100 μ ?.

B. Cytotoxicity Assay The purpose of this assay was to determine the toxicity of the compounds in viral host cells in vitro. The cytotoxicity of the compounds was measured using a cell proliferation / viability assay based on mitochondrial enzyme in replicon cells. Briefly, HCV replicon cells were plated at 3-5 x 10 3 pro cavity cells in a 96-well plate in a DME medium containing 5% FCS. 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 an identical manner except that no inhibitor was added to the medium. Plates were incubated in a C02 incubator at 37 ° C. On day 4, a solution for the supply of the tetrazole salt, MTT (4 mg / μl in PBS, Sigma # cat.M 21 28) was added to each cavity at 25 μ? per cavity. The plates were incubated for a further 4 hours, treated with 20% SDS plus 0.02 N HCI at 50 μ? per cavity to use the cells. After an overnight incubation, the optical density was measured by reading the plates at 570/650 nm wavelengths. The percentage of reduction of the formazan blue color formed in relation to the control was calculated and the 50% toxicity concentration (TC50) was calculated through a non-linear regression analysis using the Prism program (version 4.0, GraphPad software, San Diego, CA). When treated using the above method, the TC50 values of the representative compounds of the present invention were greater than the corresponding IC50 values of these compounds.

Pharmaceutical Compositions and Uses The present invention modalizes pharmaceutical compositions comprising the compounds of the invention. As a non-limiting example, a pharmaceutical composition of the present invention comprises one or more compounds of this invention, wherein each compound is independently selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b) ). Preferably, each compound is independently selected from Examples 1 -237.

The present invention also provides pharmaceutical compositions comprising pharmaceutically acceptable salts, solvates, or prodrugs of the compounds of this invention. The pharmaceutically acceptable salts can be zwitterions or derived from pharmaceutically acceptable inorganic or organic acids or bases. Preferably, a pharmaceutically acceptable salt of a compound of the invention retains the biological effectiveness of the free acid or base of the compound without undue toxicity, irritation, or allergic response, has a reasonable benefit / risk ratio, and is effective for its intended use and not biologically or otherwise undesirable. Non-limiting examples of pharmaceutically acceptable salts include, but are not limited to the following: acetate, adipafo, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanpropionate, dodecylsulfafo, ethanesulfonate, glucoheptanoate, glycerophosphate , hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, iodhydrate, 2-hydroxy-ethanesulfonate (isethionate), lactate, maleate, mephansulfonate, nicotinate, 2-naphthalenesulfone, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinafo, tartrate, thiocyanate, p-toluenesulfonate and undecanoate. Groups containing basic nitrogen can also be quaternized with agents such as lower alkyl halides (for example, methyl, ethyl, propyl or butyl chlorides, bromides or iodides), dialkyl sulfates (for example, dimethyl, diethyl, dibutyl or diamyl) sulfates), long-chain halides (for example decyl, lauryl, myristyl or stearyl chlorides, bromides or iodides), aralkyl halides (for example, benzyl or phenethyl bromides). Other salts that can be used in the present invention include salts with alkaline or alkaline earth metals, such as sodium, potassium, calcium or magnesium, or with organic bases. Examples of acids that can be used to 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 inorganic acids or suitable organic The present invention also modalizes pharmaceutical compositions comprising a compound of the invention (or a salt, solvate or prodrug thereof) and another therapeutic agent. In a non-limiting example, a pharmaceutical composition of the present invention includes 1, 2, 3 or more compounds of the invention (or salts, solvates or prodrugs thereof), and 1, 2, 3 or more therapeutic agents. By way of illustration and not limitation, these other therapeutic agents may be selected from antiviral agents (e.g., anti-HIV agents or other amph-HCV agents), immunomodulators, anti-cancer or chemotherapeutic agents, or anti-inflammatory agents. Specific examples of these other therapeutic agents include, but are not limited to, ribavirin; interferons (for example, IFN alpha 2a or 2b); protease inhibitors; immunosuppressants; antibodies (e.g., monoclonal or therapeutic chimeric antibodies); Antisense siRNA; HIV inhibitors; hepatitis B inhibitors (HBV); agents to test cirrhosis and inflammation in the liver; IFN Omega (Bio edicines Inc., Emeryville, CA); serine protease inhibitor BILN-2061 (Boehringer Ingelheim Pharma KG, Ingelheim, Germany); antiviral from Summetrel (endo Pharmaceuticals Holdings Inc., Chadds Ford, PA); Roferon A IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); Pegasys PEGylated IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); Pegays and PEGylated Ribavirin IFN-alpha 2a / ribavirin (F. Hoffmann-La Roche LTD, Basel, Switzerland); immunosuppressant of HCV IgG CelICept (F. Hoffmann-La Roche LTD, Basel, Switzerland); IFN-alpha lymphoblastoid Wellferon (GalxoSmithKIine foot, Uxbridge, UK); Albumin IFN-alpha 2b Albuferon-alpha (Human Genome Sciences Inc., Rockville, D); Levovirin ribaviridine (ICN Pharmaceuticals, Costa Mesa, CA); inhibitor of IDN-6556 caspase (Idun Pharmaceuticals Inc., San Diego, CA); IP-501 antifibrotic (Indevus Pharmaceuticals Inc., Lexington, MA); INF-Actimmune range (InterMune Inc., Brisbaen, CA); Infergen to IFN alfacon-1 (InterMune Inc., Brisbaen, CA); ISIS 14803 anfisenfide (ISIS Pharmaceuticals Inc., Carlsbad, CA / Elan Pharmacueticals Inc., New York, NY); inhibitor JTK-003 RdRp (Japan Tobacco Inc., Tokyo, Japan); Pegasys and Ceplene PEGylated IFN-alpha 2a / immune modulator (Maxim Pharmaceuticals Inc., San Diego, CA); Ceplene immune modulator (Maxim Pharmaceuticals Inc., San Diego, CA); immunosuppressant HCV IgG Civacir (Nabi Biopharmaceuticals Inc., Boca Raton, FL); Intron A and Zadaxin IFN-alpha 2b / alpha 1-thymosin (RegeneRx Biopharmaceuticals Inc., Bethesda, MD / SciClone Pharmaceuticals Inc., San Mateo, CA); inhibitor of Levovirin IMPDH (Ribapharm Inc., Costa Mesa, CA); inhibitor of Viramidine IMPDH (Ribapharm Inc., Costa Mesa, CA); Heptazyme 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 / PEGylated Ribavirin IFN-alpha 2b / ribavirin (Schering-Plow Corporation, Kenilworth, NJ); Zadazim immune modulator (SciClone Pharmacueticals 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 beta-fubulin inhibitor (Tularik Inc., South San Francisco, CA); inhibitor of VX-497 IMPDH (Vertex Pharmaceuticals Inc., Cambridge, MA); serine protease inhibitor VX-950 / LY-570310 (Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and Co., Inc., Indianapolis, IN); Natural IFN-alpha Omniferon (Viragen Inc., Plantatiom FL); monoclonal antibody XTL-002 (XTL Biopharmaceuticals); compound VX-950, Vért (hereinafter compound SCH503034, Schering-Plow Co.); Y (hereinafter composed GS91 37, Gilead Sciences, I nc., Foster City, CA). Any other desirable therapeutic agent (s) may also be included in a pharmaceutical composition of the present invention. In one embodiment, a pharmaceutical composition of the present invention comprises one or more compounds of the present invention (or salts, solvates or prodrugs thereof), and one or more other antiviral agents. In another embodiment, a pharmaceutical composition of the present invention comprises one or more compounds of the present invention (or salts, solvates or prodrugs thereof), and one or more other anti-HCV agents. In one example, each of the compounds of the present invention is independently selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or Examples 1 -237, and each of the other anti-HCV agents are independently selected from inhibitors of HCV RNA-dependent polymerase (eg, nucleoside or non-nucleoside polymerase inhibitors), HCV protease inhibitors, or HCV helicase inhibitors. In a further embodiment, a pharmaceutical composition of the present invention comprises one or more compounds of the present invention (or salts, solvates or prodrugs thereof), and two or more other anti-HCV inhibitors. Preferably, each compound of the present invention is independently selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or Examples 1-237. The other anti-HCV inhibitors can be selected from the same class of inhibitor (for example, all of these are selected from RNA polymerase inhibitors dependent on HCV RNA, or HCV protease inhibitors), or are selected from different classes of inhibitor (e.g., one or more are selected from an RNA polymerase inhibitor dependent on HCV RNA and the other or others are selected from HCV protease inhibitors). In still another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention (or salts, solvafos or prodrugs thereof), and at least one RNA polymerase inhibitor dependent on HCV RNA. Preferably, each compound of the present invention is independently selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or Examples 1-237. In another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention (or salts, solvates or prodrugs thereof), and at least one HCV protease inhibitor. Preferably, the compound of the present invention is independently selected from Formulas l (a), l (b), 11 (a) or l l (b), or Examples 1 -237. In yet another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention (or salts, solvates or prodrugs thereof), and at least one RNA polymerase inhibitor dependent on HCV RNA, and at least one HCV protease inhibitor. Preferably, the compound of the present invention is independently selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or Examples 1-237. In still another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention (or salts, solvates or prodrugs thereof), and two or more anti-HCV agents, each of which is independently selects HCV RNA-dependent RNA polymerase inhibitors or HCV protease inhibitors. Preferably, the compound of the present invention is independently selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or Examples 1-237. In another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention (or salts, solvates or prodrugs thereof), and three or more other anti-HCV agents, each of which is independently selects HCV RNA-dependent RNA polymerase inhibitors or HCV protease inhibitors. Preferably, the compound of the present invention is independently selected from Formulas l (a), l (b), l l (a) or l l (b), or Examples 1 -237.

Non-limiting examples of HCV RNA-dependent RNA polymerase inhibitors include those described in WO 01901 21 (A2), US 6348587B 1, WO 016031 5, WO 01 321 53, EP 1 162196A1, and WO 0204425. Non-limiting examples of HCV protease inhibitors include BILN-2061, VX-950, and SCH503034. In another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention (or salts, solvates or prodrugs thereof), and one or more other antiviral agents, such as anti-HBV or anti-HIV agents. -VI H. Non-limiting examples of anti-HBV agents include adefovir, lamivudine, and tenofovir. Non-limiting examples of anti-HIV drugs include ritonavir, lopinavir, nelfinavir, saquinavir, amprenavir, atazanavir, fipranavir, TMC-1 14, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-1 25, L-870812, S-1360, enfuvirtide, T-1249, and other inhibitors of HIV protease, reverse transcriptase, integrase or fusion. Other desirable antiviral agents may also be included in a pharmaceutical composition of the present invention, as appreciated by those skilled in the art. In one embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention selected from Formulas l (a), l (b), 11 (a) oll (b), or Examples 1 -237, or a salt, solvate or prodrug thereof, and at least one anti-HBV agent. In another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or Examples 1 -237 , or a salt, solvate or prodrug thereof, and at least one anti-HIV agent. In still another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention selected from Formulas l (a), l (b), 11 (a) or M (b), or Examples 1 - 237, or a salt, solvate or prodrug thereof, and at least one anti-hepatitis A, anti-hepatitis D, anti-hepatifis E or anti-hepatitis G agent. In still another embodiment, a pharmaceutical composition of the present invention comprises at least one compound of the present invention selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or Examples 1 - 237, or a salt, solvate or prodrug thereof, and at least one agent suitable for the treatment of liver inflammation. A pharmaceutical composition of the present invention typically includes a pharmaceutically acceptable carrier or excipient. Non-limiting examples of pharmaceutically acceptable carriers / excipients include sugars (e.g., lactose, glucose or sucrose), starches (e.g., corn starch or potato starch), cellulose or its derivatives (e.g., sodium carboxymethylcellulose, ethylcellulose or cellulose acetate), oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil or soybean oil), glycols (e.g., polyethylene glycol), pH regulating agents (eg, magnesium hydroxide or aluminum hydroxide), agar, alginic acid, tragacanth powder, malt, talc, cocoa butter, pyrogen-free water, isotonic saline, Ringer's solution, ethanol or solutions Phosphate pH regulators. Also, in a pharmaceutical composition of the present invention, as appreciated by those skilled in the art, lubricants, coloring agents, release agents, coating agents, sweeteners, flavoring or perfume-providing agents, or antioxidants may be included. A pharmaceutical composition of the present invention can be administered to a patient in need thereof through a variety of routes, such as oral, parenteral, sublingual, rectal, topically or through a spray for inhalation. Topical administration may involve the use of transdermal administration such as transdermal patches or iontophoresis devices. Parenteral administration includes, but not limited to, subcutaneous, intravenous, intramuscular or intrasternal injections, and infusion techniques. The pharmaceutical compositions of the present invention can be formulated based on their routes of administration using methods well known in the art. For example, a sterile injectable preparation can be prepared as a sterile injectable aqueous or oleaginous suspension, using suitable dispersing agents or humectants and suspending agents. Suppositories for rectal administration can be prepared by mixing drugs with a suitable non-irritating excipient such as cocoa butter or polyethylene glycols, which are solid at ordinary temperatures but liquid at rectal temperature and, therefore, will melt in the rectum and they will release the drugs. The solid dosage forms for oral administration can 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. The solid dosage forms may also comprise other substances in addition to inert diluents, such as lubricating agents. In the case of capsules, tablets and pills, the dosage forms can also comprise pH regulating agents. The tablets and pills can also be prepared with 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. The liquid dosage forms may also comprise wetting, emulsifying, suspending, sweetening, flavoring or perfume-providing agents. The pharmaceutical compositions of the present invention can also be admired in the form of liposomes, as described in the patent of E.U.A. No. 6, 703,403. The formulation of drugs that are applicable to the present invention is generally discussed in, for example, Hoover, John E., REMI NGTON'S PHARMACEUTICAL SCI ENCES (ack Publishing Co., Easton, PA: 1 975), and Lachman, L., eds. , PHARMACEUTICALS DOSAGE FORMS (Marcel Decker, New York, N.Y., 1 980). The present invention also modalizes methods for using the compounds of the present invention (or salts, solvates or prodrugs thereof) to inhibit the replication of HCV. In one embodiment, the methods comprise contacting the HCV virus with an effective amount of a compound of the present invention (or salts, solvates or prodrugs thereof), thereby inhibiting the replication of the HCV virus. In another embodiment, the methods comprise contacting cells infected with HCV virus with an effective amount of a compound of the present invention (or salts, solvates or prodrugs thereof), thereby inhibiting the replication of the HCV virus in the cells. In yet another embodiment, the methods comprise contacting the HCV virus or infected cells with an effective amount of two or more compounds of the present invention (or salts, solvates or prodrugs thereof), thereby inhibiting the replication of the HCV virus. As used herein, "inhibit" means to significantly reduce, or abolish, the activity that is being inhibited (e.g., viral replication). In many cases, the representative compounds of the present invention can reduce the replication of the HCV virus (eg, in the HCV replicon assays 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 HCV subtypes. Examples of HCV subtypes which are manageable for the present invention include, but are not limited to, HCV genotypes 1, 2, 3, 4, 5 and 6, including genotypes 1 a, 1 b, 2 a, 2 b, 2 c or 3c of HCV. In one embodiment, a compound or compounds of the present invention (or salts, solvates or prodrugs thereof) are used to inhibit the replication of HCV genotype 1a. In another embodiment, a compound or compounds of the present invention (or salts, solvates or prodrugs thereof) are used to inhibit the replication of HCV genotype 1b. In yet another embodiment, a compound or compounds of the present invention (or salts, solvates or prodrugs thereof) are used to inhibit the replication of both 1 a and 1 b HCV genotypes. The present invention also modalizes methods for using the compounds of the present invention (or salts, solvates or prodrugs thereof) to treat HCV infection. These methods typically comprise administering a therapeutically amount of a compound of the present invention (or a salt, solvate or prodrug thereof) to a patient with HCV, thereby reducing the viral level of HCV in the patient's blood or liver. As used herein, the term "treating" refers to reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition, or one or more symptoms of said disorder or condition to which said term applies. The term "treatment" refers to the act of treating. In one embodiment, the methods comprise administering an effective therapeutic amount of two or more compounds of the present invention (or salts, solvates or prodrugs thereof) to a patient with HCV, thereby reducing the viral level of HCV in the blood or liver. of the patient. Preferably, the compound (s) employed in these methods has Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or is selected from Examples 1 -237, or is a salt, solvate or drug of the same. In another aspect, the present invention modalizes methods for using a pharmaceutical composition of the present invention to treat an HCV infection. Any pharmaceutical composition described herein can be used for this purpose. These methods typically comprise administering an effective therapeutic amount of a pharmaceutical composition of the present invention to a patient with HCV, thereby reducing the viral level of HCV in the patient's blood or liver. When the pharmaceutical composition includes other therapeutic agents, it may also treat other diseases, disorders or conditions in the patient. In one embodiment, the pharmaceutical composition that is administered comprises at least one compound of the present invention selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or from Examples 1 - 237, or is a salt, solvate or drug thereof, and at least one other anti-HCV agent selected from inhibitors of RNA polymerase dependent on HCV RNA, inhibitors of HCV protease or inhibitors of HCV heiicase. In another embodiment, the pharmaceutical composition that is administered comprises at least one compound of the present invention selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or from Examples 1- 237, or is a salt, solvate or drug thereof, and at least other anti-HCV agents, each of which is independently selected from inhibitors of RNA polymerase dependent on HCV RNA, inhibitors of HCV protease or inhibitors. of HCV heiicase. In yet another embodiment, the pharmaceutical composition that is administered comprises at least one compound of the present invention selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or from Examples 1 -237, or is a salt, solvate or drug thereof, and 1, 2 or more inhibitors of RNA polymerase dependent on HCV RNA (for example those described in WO 0190121 (A2), US 6348587 B1, WO 0160315, WO 0132153, EP 1162196 A1 and WO 0204425). In still another embodiment, the pharmaceutical composition that is administered comprises at least one compound of the present invention selected from Formulas I (a), I (b), II (a) or II (b), or from Examples 1 -237, or is a salt, solvate or drug thereof, and 1, 2 or more inhibitors of HCV protease (e.g., BILN-2061, VX-950 and SCH503034). In yet another embodiment, the pharmaceutical composition that is administered comprises at least one compound of the present invention selected from Formulas I (a), I (b), 11 (a) or II (b), or from Examples 1 -237, or is a salt, solvate or drug thereof, and at least one anti-VI H agent, anti-HBV agents, anti-hepatitis A agents, anti-hepatitis D agent, anti-hepatitis E agents, or anti-HIV agents. hepatitis G In still another aspect, the present invention provides methods for using a compound (s) of the present invention and another therapeutic agent (s) to treat HCV infection. The methods comprise administering an effective therapeutic amount of a compound (s) of the present invention and another therapeutic agent (s) to a patient with HCV, thereby reducing the viral level of HCV in the blood or liver of the patient. Each compound of the present invention of the present invention (or a salt, solvate or prodrug thereof) and the therapeutic agent (s) can be combined in a single formulation and administered simultaneously to the patient. They can also be administered simultaneously but in different formulations. In addition, they can be administered sequentially. In one embodiment, the compound (s) of the present invention that is administered includes one or more compounds selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or from Examples 1 -237, or is a salt, solvate or drug thereof, and the other therapeutic agent (s) that is administered includes one or more agents selected from inhibitors of RNA polymerase dependent on HCV RNA, inhibitors of HCV protease or inhibitors of HCV helicase. In another embodiment, the compound (s) of the present invention that is administered includes one or more compounds selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or from Examples 1 -237, or is a salt, solvate or drug thereof, and the other therapeutic agent (s) that is administered includes two or more agents selected from inhibitors of RNA polymerase dependent on HCV RNA, inhibitors of HCV protease or inhibitors of HCV helicase. In yet another embodiment, the compound (s) of the present invention that is administered includes one or more compounds selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or the Examples 1-237, or is a salt, solvate or drug thereof, and the other therapeutic agent (s) that is administered includes one, two or more RNA polymerase inhibitors dependent on HCV RNA (eg, those described in WO). 0190121 (A2), US 6348587B1, WO 0160315, WO 0132153, EP1162196A1 and WO 0204425). In still another embodiment, the compound (s) of the present invention that is administered includes one or more compounds selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or the Examples 1-237, or is a salt, solvate or drug thereof, and the other therapeutic agent (s) that is administered includes one, two or more HCV protease inhibitors (e.g., BILN-2061, VX-950 and SCH503034 ). A compound of the present invention (or a salt, solvate or prodrug thereof) can also be co-administered with other desired drugs, such as anti-HIV agents, anti-HBV agents, anti-hepatitis A agents, anti-hepatitis agents. D, anti-hepatitis E agents, anti-hepatitis G agents, or other antiviral drugs. A compound of the present invention (or a salt, solvate or prodrug thereof) can be administered to a patient in a single dose or divided doses. A typical daily dose may vary, without limitation, from 0. 1 to 200 mg / kg of body weight, such as 0.25 to 1 00 mg / kg of body weight. The individual dose compositions may contain these amounts or sub-multiples thereof to form the daily dose. Preferably, each dose contains a sufficient amount of a compound of the present invention that is effective to reduce the viral load of HCV in the blood or liver of the patient. The amount of the active ingredient, or the active ingredients that are combined, to produce an individual dosage form may vary depending on the host treated and the particular mode of administration. It should be understood that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of administration. administration, excretion rate, drug combination, and the severity of the therapy that the particular disease experiences. In yet another aspect, the compounds of Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or their pharmaceutically acceptable salts, stereoisomers or faufomers, can be administered as a single pharmaceutical agent, or used in combination with one or more other agents to treat infections or symptoms associated with other RNA-containing viruses. The treatment or prevention of infection caused by RNA-containing viruses can be provided through a combination therapy comprising a therapeutically effective amount of a first anti-viral agent provided by one or more compounds, or salts thereof, of the Formulas 1 (a), 1 (b), 11 (a) or 11 (b), together with a therapeutically effective amount of a second agent provided by one or more compounds selected from the group consisting of another anti-viral agent; a host immune modulator; interferon derivative, such as interferon-alpha, pegylated interferon-alpha, interferon-beta, and interferon-gamma; a cytokine; a vaccine; a nucleoside analogue; inhibitors of key enzymes that result in HCV dysfunction, examples of such enzymes are HCV metalloprotease, HCV serine protease, inosine monophosphate dehydrogenase (I PDH), and HCV helicase; inhibitors of viral particle proteins such as HCV NS4B protein, and HCV NS5a protein; and agents that inhibit HCV function, such as HCV entry, HCV assembly, and HCV discharge. Also included are vaccines comprising HCV antigens or auxiliary antigen combinations directed against HCV. Also included are agents that interact with host cellular components to block viral protein synthesis by inhibiting the translation step initiated by the internal ribosome entry site (I RES) of HCV viral replication or to block the maturation of the viral particle and release with agents directed towards the virophorin family of membrane proteins such as, for example, HCV P7.

In one embodiment, the present invention is directed to a method of treating or preventing infection caused by a virus containing RNA comprising administering to a patient in need of such treatment, a therapeutically effective amount of a compound of Formula 1 (a ), 1 (b), 11 (a) or 11 (b), or a pharmaceutically acceptable salt thereof. In another embodiment, the present invention is directed to a method of treating or preventing infection caused by a virus containing RNA comprising co-administering to a patient in need of such treatment, one or more agents selected from the group consisting of a host immune modulator and a second antiviral agent, or a combination thereof, with a therapeutically effective amount of a compound of Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or a salt pharmaceutically acceptable thereof. In yet another embodiment, the present invention is directed to a method of treating or preventing infection caused by a virus containing RNA comprising co-administering to a patient in need of such treatment, one or more agents selected from the group consisting of interferon-alpha, pegylated interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an auxiliary, and a second antiviral agent, or a combination thereof, with an amount Therapeutically effective of a compound of Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or a pharmaceutically acceptable salt thereof. In still another embodiment, the present invention is directed to a method of treating or preventing infection caused by a virus containing RNA comprising co-administering to a patient in need of such treatment, one or more agents selected from the group consisting of a host immune modulator and a second amphiphilic agent that inhibits the replacement of HCV by inhibiting host cellular functions associated with viral replication, or a combination thereof, with a therapeutically effective amount of a compound of Formulas 1 (a), 1 (b) ), 11 (a) or 11 (b), or a pharmaceutically acceptable salt thereof. In yet another embodiment, the present invention is directed to a method of treating or preventing infection caused by a virus containing RNA comprising co-administering to a patient in need of such treatment, an agent or combination of agents treating or alleviate symptoms of HCV infection including cirrhosis and inflammation of the liver, with a therapeutically effective amount of a compound of Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or a pharmaceutically acceptable salt of the same. In another embodiment, the present invention is directed to a method of treating or preventing infection caused by a virus containing RNA comprising co-administering to a patient in need of such treatment, one or more agents treating patients with disease caused by hepatitis B infection (HBV), with a therapeutically effective amount of a compound of Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or a pharmaceutically acceptable salt thereof.

In still another embodiment, the present invention is directed to a method of treating or preventing infection caused by a virus containing RNA comprising co-administering to a patient in need of such treatment, one or more agents treating patients with disease caused by infection with human immunodeficiency virus (VI H), with a therapeutically effective amount of a compound of Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or a pharmaceutically acceptable salt of the same. The phrase "combination therapy" (or "co-therapy") is intended to encompass the administration of each agent in a sequential manner in a regimen that will provide beneficial effects of the drug combination, and is also intended to encompass the co-administration of these agents in a substantially simultaneous form, such as through oral ingestion or an individual capsule having a fixed ratio of these active agents or ingestion of multiple separate capsules for each agent. "Combination therapy" will also include simultaneous or sequential administration through oral routes, intravenous, intramuscular or other parenteral routes in the body, including direct absorption through mucous membrane tissues, such as those found in the passages of senos. Sequential administration also includes drug combinations, wherein the individual agents can be administered at different times and / or different routes but which act in combination to provide a beneficial effect, for example, through co-action of pharmacokinetic or pharmacodynamic effects. of each agent. The present invention also relates to the use of the compounds of the invention, or pharmaceutically acceptable salts, solvates or prodrugs thereof, for the manufacture of medicaments for the treatment of HCV or other viral infections. In one embodiment, the present invention relates to the use of compounds of the present invention selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b), or a salt, solvate or prodrug thereof. m isms, for the manufacture of a medicament for the treatment of 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 the two or more compounds independently is selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b). In yet another embodiment, the present invention modalizes 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 manufacture of a medicament for the treatment of HCV infection. Preferably, the compound (s) of the present invention is selected from Formula 1 (a), 1 (b), 11 (a) or 11 (b), and the additional therapeutic agent (s) may be selected, by way of illustration and not limitation, antiviral agents (for example, anti-VI H agents or other anti-HCV agents), immunomodulators, amph-cancer or chemotherapeutic agents, and anti-inflammatory agents. Specific examples of additional therapeutic agents include, but are not limited to, ribavirin; interferons (for example, IFN alpha 2a or 2b); protease inhibitors; immunosuppressants; antibodies (e.g., monoclonal or therapeutic chimeric antibodies); antisense or siRNA; HIV inhibitors; hepatitis B inhibitors (HBV); agents for the treatment of cirrhosis and inflammation of the liver; Omega IFN (BioMedicines Inc., Emeryville, CA); serine protease inhibitor BILN-2061 (Boehringer Ingelheim Pharma KG, Ingeiheim, Germany); antiviral from Summetrel (endo Pharmaceuticals Holdings Inc., Chadds Ford, PA); Roferon A IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); Pegasys PEGylated IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); Pegays and PEGylated Ribavirin IFN-alpha 2a / ribavirin (F. Hoffmann-La Roche LTD, Basel, Switzerland); immunosuppressant of HCV IgG CelICept (F. Hoffmann-La Roche LTD, Basel, Switzerland); IFN-alpha lymphoblastoid Wellferon (GalxoSmithKIine foot, Uxbridge, U); Albumin IFN-alpha 2b Albuferon-alpha (Human Genome Sciences Inc., Rockville, MD); Levovirin ribaviridine (ICN Pharmaceuticals, Costa Mesa, CA); inhibitor of IDN-6556 caspase (Idun Pharmaceuticals Inc., San Diego, CA); IP-501 antifibrotic (Indevus Pharmaceuticals Inc., Lexington, MA); INF-range Acfimmune (InterMune Inc., Brisbaen, CA); Infergen to IFN alfacon-1 (InterMune Inc., Brisbaen, CA); ISIS 14803 antisense (ISIS Pharmaceuticals Inc., Carlsbad, CA / Elan Pharmacueticals Inc., New York, NY); inhibitor JTK-003 RdRp (Japan Tobacco Inc., Tokyo, Japan); Pegasys and Ceplene PEGylated IFN-alpha 2a / immune modulator (Maxim Pharmaceuticals Inc., San Diego, CA); Ceplene immune modulator (Maxim Pharmaceuticals Inc., San Diego, CA); immunosuppressant HCV IgG Civacir (Nabi Biopharmaceuticals Inc., Boca Raton, FL); Intron A and Zadaxin IFN-alpha 2b / alpha 1-thymosin (RegeneRx Biopharmaceuticals Inc., Bethesda, MD / SciClone Pharmaceuticals Inc., San Mateo, CA); inhibitor of Levovirin IMPDH (Ribapharm Inc., Costa Mesa, CA); inhibitor of Viramidine IMPDH (Ribapharm Inc., Costa Mesa, CA); Heptazima ribozyme (Ríbozyme 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 / PEGylated Ribavirin IFN-alpha 2b / ribavirin (Schering-Plow Corporation, Kenilworth, NJ); Zadazim immune modulator (SciClone Pharmacueticals 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 beta-tubulin inhibitor (Tularik Inc., South San Francisco, CA); inhibitor of VX-497 IMPDH (Vertex Pharmaceuticals Inc., Cambridge, MA); serine protease inhibitor VX-950 / LY-570310 (Vertex Pharmaceuticals Inc., Cambridge, MA / Eli Lilly and Co., Inc., Indianapolis, IN); Natural IFN-alpha Omniferon (Viragen Inc., Plantatíom FL); monoclonal antibody XTL-002 (XTL Biopharmaceuticals); VX-950 compound (Vértex Pharmaceuticals Inc.); compound SCH503034 (Schering-Plow Co); and Compound GS91 37 (Gilead Sciences, I nc., Foster City, CA). In yet another embodiment, the present invention modalizes the use of at least one compound of the present invention (or a salt, solvate or prodrug thereof) and at least one additional anti-viral agent for the manufacture of a medicament for the viral infection treatment. Preferably, the compound (s) of the present invention is selected from Formulas I (a), I (b), 11 (a) or 11 (b), and the additional antiviral agent (s) can be selected, without limitation. , of anti-HCV or anti-VI H agents. In one example, the present invention modalizes the use of at least one compound of the present invention selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b) (or a salt, solvate or prodrug thereof), and at least one additional anti-HCV agent for the manufacture of a medicament for the treatment of HCV infection. Non-limiting examples of anti-HCV agents include inhibitors of RNA polymerase dependent on HCV RNA (e.g., nucleoside or non-nucleoside polymerase inhibitors) or inhibitors of HCV protease. In another example, the present invention modalizes the use of at least one compound of the present invention selected from Formulas 1 (a), 1 (b). 11 (a) or 11 (b) (or a salt, solvate or prodrug thereof), and at least two or more additional anti-HCV agents for the manufacture of a medicament for the treatment of HCV infection. Each of the additional anti-HCV agents can be independently selected from inhibitors of RNA polymerase dependent on HCV RNA or HCV protease inhibitors.

In still another embodiment, the present invention provides the use of at least one compound of the present invention selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b) (or a salt , solvate or prodrug thereof), and at least one anti-VI agent for the manufacture of a medicament for the treatment of infection by HCV or VI H. In still another embodiment, the present invention modalizes the use of at least one compound of the present invention selected from Formulas I 1 (a), 1 (b), 11 (a) or 11 (b) (or a salt, solvate or prodrug thereof), and at least one anti-hepatitis A, anti-hepatitis B, anti-hepatitis D, hepatitis E or anti-hepatitis G agent for the manufacture of a medicament for the treatment of viral hepatitis. In a further embodiment, the present invention modalizes the use of at least one compound of the present invention selected from Formulas 1 (a), 1 (b), 11 (a) or 11 (b) (or a salt, solvate or prodrug thereof), and at least one agent for treating inflammation of the liver, for the manufacture of a medicament for the treatment of hepatitis C. The foregoing description of the present invention provides the illustration and description, but is not intended to be exhaustive or limit the invention to what is just described. Modifications and variations are possible in view of the above teachings or can be acquired from the practice of the invention. In this way, it should be noted that the scope of the invention is defined by the claims and their equivalents.

Claims (9)

REB ¥ W W W W W W W W W W

1. - A compound, tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, wherein the compound has Formula l (a) or l (b), wherein: Z is -NR41-; A is a carbocyclyl or heterocyclyl, and is optionally substituted with one or more of R 8, wherein R18 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy , formyl, phosphate, azido, alkyl, alkenyl, alkynyl, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C ( 0) ORs, -LS-N (RSRS), -Ls-C (= NRS) RS, -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs |), - Ls-N (Rs) C (0) Rs, -Ls-C (= NRs) N (Rs Rs) | -Ls-N (Rs) C (= NRs) RS ", -Ls-N (Rs) C ( 0) N (Rs Rs). -Ls-N (Rs) S02Rs, -Ls-S02N (RsRs), -Ls- N (RS) S02N (RS Rs), R1 0, R1 7, R31, R33, R35 and R41 are independently selected at each occurrence from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, -Ls -O-Rs, -Ls-S-RS) - Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -Ls-N (RsRs), -Ls- C (= NRs) Rs -, -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls-N (Rs) C (0) Rs-, -Ls-C (= NRs) N (Rs Rs-), -Ls- N (RS) C (= NRS) RS-, -Ls -N (Rs) C (0) N (Rs Rs), -Ls-N (Rs) S02Rs-, -Ls-S02N (RsRs). -Ls-N (Rs) S02N (Rs Rs-). -LE-Q-LE- (carbocyclyl of C3-C1 e) and -LE-Q-LE- (heterocyclyl of M3-M1 8); X is selected from the group consisting of a bond, -Ls-0-, -Ls-S-, -Ls-C (O) -, -Ls-N (Rs) -, - Ls-N (Rs) C ( 0) -, -Ls-C (0) N (Rs) -, -Ls-N (Rs) C (0) 0-, -Ls-OC (0) N (Rs) -Ls-N (Rs) C (0) N (Rs) -, -Ls-C (= N RS) N (RS |) -, -LS-N (RS) C (= N RS) -, -Ls-S (0) -, - Ls-S02-, -Ls-C (0) 0-and-Ls-OC (O) -; R22 is carbocyclyl or heterocyclyl, and is optionally substituted with one or more of R26, wherein R26 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl , phosphate, azido, alkyl, alkenyl, alkynyl, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -Ls-N (RsRs), -Ls-C (= NRs) Rs. -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls-N (Rs) C (0) Rs, -Ls-C (= NRs) N (Rs) -Rs). -Ls-N (Rs) C (= NRs) Rs -, -Ls-N (Rs) C (0) N (Rs Rs), -LS-N = C (NRSRS) (NRSRS), -Ls-N ( Rs) S02RS ', -Ls-S02N (RSRS), -Ls-N (Rs) S02N (Rs Rs-). - LE-Q-LE- (carbocyclyl of C3 -Ci8) and -LE-Q-LE- (heterocyclyl of M3-M18); or R22 is alkyl, alkenyl or alkynyl, and is optionally substituted with one or more of R26; or R22 is hydrogen; And it is selected from the group consisting of a link, -O-, -C (O) -, -S (0) 2-, -S (O) -, -OS (0) 2-, - OS (O) -, -C (0) 0-, -OC (O) -, -OC (0) 0-, -C (0) N (R1 5) -, -N (R1 5) C (0), -C (0) N (R1 5) 0-, - N (R1 5) C (0) 0-, -C (0) N (R 1 5) N (R 1 5), -S-, -C (S) -, -C (S) 0-, -OC (S) - , -C (S) N (R15), -N (R1 5) -, -N (R5) C (S) -, -N (R1 5) S (0) -, -N (R1 5) S (0) 2-, -S (0) 2N (R15) -, S (0) N (R1 5), -C (S) N (R1 5) 0-, and -C (S) N (R1 S ) N (R1 5) -, wherein R1 and R1 are independently selected at each occurrence from the group consisting of hydrogen, alkyl, alkenyl and alkynyl; R50 is -L1-A1, wherein 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 is optionally substituted with one or more of R30, and R30 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl , -Ls-0-Rs, -Ls-S-Rs. -Ls-C (0) Rs, -Ls-OC (0) Rs. -Ls-C (0) ORs, -LS-N (RSRS). -Ls-C (= NRs) Rs -, -Ls-S (0) RS) -LS-S02RS, -Ls-C (0) N (RsRs |). -Ls-N (Rs) C (0) Rs-, -Ls-C (= NRs) N (Rs Rs), -Ls-N (RS.) C (= NRS) RS -, -Ls-N (RS ) C (0) N (RS'-Rs ·), -LS-N (RS) S02RS'-, -LS-S02N (RsRs), -LS-N (RS) S02N (RS'RS "), -LE -Q-LE - (carbocyclyl of C3-C1 8) and -LE-Q-LE- (heterocyclyl of M3-) 8), and wherein L1 is optionally substituted with one or more of R38, and R38 is independently selected in each occurrence of the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkoxy, thioalkoxy, alkylcarbonyl, alkoxycarbonyl, alkylcarbonyloxy, alkylamino, alkoxycarbonylamino, -Ls-O-Rs, -Ls-S-Rs , -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -Ls-N (RsRs), -Ls-C (= NRs) Rs-, -Ls- S (0) Rs. -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls-N (Rs) C (0) Rs, -Ls-C (= NRs) N (Rs Rs-), -Ls-N ( Rs) C (= NRs) Rs -. -Ls-N (Rs) C (0) N (Rs.Rs "), -Ls-N (Rs) S02Rs, -Ls-S02N (RsRs), -Ls-N (Rs) S02N (Rs Rs), carbocyclyl , heterocyclyl, carbocyclylalkyl, heterocyclylalkyl, -LE-Q-LE - (carbocyclyl of C3-C1 e) and - LE-Q-LE- (heterocyclyl of M3-Mi e); I s is independently selected at each occurrence of the group consisting of a bond, alkylene, alkenylene and alkynylene; Rs. Rs and Rs are independently selected at each occurrence 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; LE and LE are independently selected at each occurrence from the group consisting of a bond, alkylene, alkenylene, alkynylene, -alkylene-O-alkylene-, alkylene-S-alkylene, -alkylene-NC (0) -alkylene, and alkylene- C (0) N-alkylene; Q is independently selected at each occurrence from the group consisting of a bond, alkylene, alkenylene, alkynylene, _s-, -O-, -C (O) -, -N (Rs) -, -N (Rs) C (0 ), -C (0) N (RS) -. - N (Rs) C (0) 0-, -OC (0) iS! (Rs) -, -N (Rs) C (0) N (Rs) -. -C (= NRS) N (RS |) -, -N (RS) C (= N RS) -, -S (O) -, -SO2-. -0-S02-, -SO2-O-, -O-S (O), -S (0) -0-, -C (0) 0- and -OC (O); R 1 0 R 1 5 R1 5- R 1 7 R 1 8 R 2B R30 R31 R33 R 35 R38 and R41 e s t a n independently optionally substituted in each occurrence 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 each carbocyclyl portion of C3-C8 and heterocyclyl of M3-M1 8 in -LE-Q-LE - (C3-C1 carbocyclyl 8) and -LE-Q-LE - (heterocyclyl of M3-M1 8) is independently optionally substituted in each occurrence with at least one substituent selected from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, alkynyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl, alkycarbonyl, alkylcarbonylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy , alkylcarbonyloxyalkyl, alkylamino, alkylaminoalkyl, alkoxycarbonylamino, carbocyclyloxy, heterocyclyloxy, carbocycloalkoxy, heterocycloalkoxy, carbocycloalkoxycarbonyl, heterocycloalkoxycarbonyl, and alkoxycarbonylaminoalkyl.

2. The compound, tautomer, or salt according to claim 1, wherein: Z is -NR41-; A is a carbocyclyl or heterocyclyl, and is optionally substituted with one or more of R 1 8, wherein R 1 8 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C-C6 alkyl, C2-C6 alkenyl, C2-C alkynyl, -Ls-O-Rs, -Ls-S-Rs, -Ls-C (0) Rs , -Ls-OC (0) Rs, -Ls-C (0) ORs. -Ls-N (RsRs), -Ls-C (= NRs) Rs', -Ls-S (0) RS) -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls- N ( Rs) C (0) Rs., -Ls-C (= NRs) N (Rs Rs-). -Ls-N (Rs) C (= N Rs) Rs, -Ls-N (Rs) C (0) N (Rs Rs), -Ls-N (Rs) S02RS '. -Ls-S02N (RsRS -), and -Ls-N (Rs) S02N (Rs Rs); R1 0, R17, R31, R33, R35 and R41 are independently selected at each occurrence from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl of Ci-Ce, C2-Ce alkenyl, C2-Ce alkynyl, C3-Ce carbocyclyl, M3-Me heterocyclyl, -Ls-0-Rs, -Ls-S-Rs, - Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -Ls-N (RSRs), -Ls-C (= N RS) RS -, -Ls-S (0) Rs, - Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls-N (Rs) C (0) RS ', -Ls-C (= NRs) N (Rs Rs). -Ls- N (Rs) C (= NRs) Rs-, -Ls-N (Rs) C (0) N (Rs Rs), -Ls-N (Rs) S02Rs-, -Ls-S02N (RsRs). -Ls-N (Rs) S02N (Rs Rs). -LE-Q-LE- (carbocyclyl of C3-C1 8) and -LE-Q-LE- (heterocyclyl of M3-M18); X is selected from the group consisting of a bond, -Ls-0-, -Ls-S-, -Ls-C (0) -, -Ls-N (Rs) -, - Ls-N (Rs) C ( 0) -, -Ls-C (0) N (Rs) -, -Ls-N (Rs) C (0) 0-, -Ls-OC (0) N (Rs) -Ls-N (Rs) C (0) N (Rs) -. -Ls-C (= NRs) N (Rs) -, -Ls-N (Rs) C (= NRs) -, -Ls-S (0) -, -Ls-S02-, -Ls-C (0) 0-and-Ls-OC (O) -; R22 is carbocyclyl, heterocyclyl, carbocyclylalkyl of C-Ce or heterocyclylalkyl of Ci-Ce, and is optionally substituted with one or more of R28, wherein R26 is independently selected in each occurrence of the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C, -Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl > , -Ls-O-Rs. -Ls-S-Rs. -Ls-C (0) Rs, -Ls-OC (0) Rs, -Ls-C (0) ORs, -Ls-N (RSRs), -Ls-C (= NRs) Rs, -Ls-S ( 0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs |), -Ls-N (Rs) C (0) Rs, -Ls-C (= NRs) N (Rs Rs'). -LS-N (RS) C (= NRS) RS ", -Ls-N (Rs) C (0) N (Rs Rs '), -Ls-N = C (NRsRs) (NRsRs'). -Ls- N (Rs) S02RS ', -Ls-S02N (RSRs), -Ls-N (Rs) S02N (Rs Rs ·), - LE-Q-LE- (carbocyclyl of C3-Cie) and -LE-Q-LE - (? 3- ß heterocyclyl), or R22 is Ci-Ce alkyl, C2-Ce alkenyl, or C2-Ce alkynyl, and is optionally substituted with one or more of R2S, or R22 is hydrogen; is selected from the group consisting of a bond, -Ls-0-, -Ls-C (O) -, -Ls-S (0) 2-, -Ls-S (O) -, -Ls-OS (0 ) 2-, -Ls-OS (0) -, -Ls-C (0) 0, -Ls-OC (O) -, -Ls-OC (0) 0-, -Ls-C (0) N ( R15) -, -Ls-N (R15) C (0), -Ls-C (0) N (R15) 0-, -Ls-N (R15) C (0) 0-, -Ls-C (0 ) N (R15) N (R15 '), -Ls-S-, -Ls-C (S) -, -Ls-C (S) 0-, -Ls-OC (S) -, -LS-C ( S) N (R15), -LS-N (R15) -, -LS-N (R15) C (S) -, -Ls-N (R1) S (0) -, -Ls-N (R15) S (0) 2-, -Ls-S (0) 2N (R15) -, -Ls-S (0) N (R15), -Ls-C (S) N (R15) 0-, and -LS-C (S) N (R1S) N (R15 ') -, wherein R15 and R15 are independently selected at each occurrence from the group consisting of hydrogen, Ci-Ce alkyl, C2-Ce alkenyl, and C2-CB alkynyl; R50 is -L1-A1, wherein 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 is optionally substituted with one or more of R30, and R30 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, Ci-C3 alkyl , C2-Ce alkenyl, C2-Ce alkynyl, -Ls-0-Rs, -Ls-S-Rs, -Ls-C (0) RSl-Ls-OC (0) Rs, -Ls-C (0 ) ORs, -Ls-N (RSRS), -LS-C (= NRS) RS -. -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls- N (Rs) C (0) Rs, -LS-C (= NRS) N (RS) Rs), -Ls-N (Rs) C (= NRs) Rs, -Ls-N (RS) C (0) N (RS'-Rs). -LS-N (RS) S02RS'-, -LS-S02N (RsRs), -LS-N (RS) S02N (Rs RS "), -LE-Q-LE - (carbocyclyl of C3-Ci8) and -LE -Q-LE- (3-M-8 heterocyclyl), and wherein L1 is optionally substituted with one or more of R38, and R38 is independently selected at each occurrence from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, Ci-Ce alkoxy, C-C6 thioalkoxy, C, -CB alkylcarbonyl, C-C6 alkoxycarbonyl, Ci-Ce alkylcarbonyloxy, alkylamino Ci-C6, alkoxycarbonylamino of Ci-C6, -Ls-0-Rs. -Ls-S-Rs, -Ls-C (0) Rs, -Ls-OC (0) Rs. -Ls-C (0) ORs , -LS-N (RSRS |), -Ls-C (= N Rs) Rs, -Ls-S (0) Rs, -Ls-S02Rs, -Ls-C (0) N (RsRs), -Ls- N (Rs) C (0) Rs, -Ls-C (= N Rs) N (Rs Rs), -LS-N (RS) C (= NRS) RS |, -Ls-N (Rs) C (0 ) N (Rs Rs "), -Ls-N (Rs) S02Rs, -Ls-S02N (RsRs), -Ls-N (Rs) S02N (RS'Rs"). Carbocyclyl, heterocyclyl, carbocyclylalkyl of C-Ce, Ci-Ce heterocyclylalkyl, -LE-Q-LE - (C 3 -C 8 carbocyclyl) and -LE-Q-LE- (3-M 1 8 heterocyclyl); L-s is independently selected at each occurrence from the group consisting of a bond, Ci-Ce alkylene, C2-Ce alkenylene and C2-C6 alkynylene; Rs, Rs and Rs are independently selected at each occurrence from the group consisting of hydrogen, Ci-Ce alkyl, C2-C6 alkenyl, C2-Ce alkynyl, Ci-C6 alkoxy, Ci-Ce thioalkoxy, Ci -Ce-Ci-Ce alkyl, Ci-Ce-alkoxy of C i -Ce-Ci-C alkyl, thioalkoxy of d -d-Ci -6 alkyl, Ci-C alkylcarbonyl, d-alkylcarbonyl -C8-Ci-Ce alkyl, Ci-C-alkoxycarbonyl, Ci-C6 alkoxycarbonyl-Ci-C6 alkyl > C 1 -Ce alkylcarbonyloxy, C 1 -C 4 alkylcarbonyloxy, C 1 -Ce alkyl, Ci-Ce alkylamino, Ci-C 6 alkylamino, Ci-C 6 alkoxycarbonylamino and d-Ce alkoxycarbonylamino -alkyl LE and LE are independently selected in each occurrence of the group consisting of a bond, alkylene of d -Ce, alkenylene of C2-Ce and alkynylene of C2-Ce, -alkylene of C2-Ce-0-alkylene of Ci- Ce-, -C-C-S-alkylene alkylene of Ci-Ce-, -alkylene of d- Ce-NC (0) -alkyliene of C, -C6-, and alkylene of ddC (0) N-alkylene of d -Ce; Q is independently selected at each occurrence from the group consisting of a bond, alkylene of dd, alkenylene of C2-Ce, alkynylene of C2-Ce, -S-, -O-, -C (O) -, -N (RS ) -, -N (Rs) C (0), -C (0) N (Rs) -, -N (Rs) C (0) 0-, -OC (0) N (Rs) -, -N ( Rs) C (0) N (Rs) -, -C (= NRS) N (RS) -, -N (RS) C (= NRS) -, -S (O) -, -S02-, -0- S02-, -S02-0-, -OS (O), -S (0) -0-, -C (0) 0- and -OC (O); R1 0, R1 5, R1 5 ', R17, R18, R26, R30, R31, R33, R35, R38, and R41 are independently optionally substituted in each occurrence with at least one substituent selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, dd alkoxy. alkylamino of d-Ce, alkoxycarbonyl of d -d, and azido; and each carbocyclyl portion of C3-C8 and heterocyclyl of M3-M1 8 in -LE-Q-LE - (C3-Ci carbocyclyl e) and -LE-Q-LE - (heterocyclyl of W3-M 8) is independently optionally substituted in each occurrence with at least one substituent selected from the group consisting of of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, dd alkyl. C2-Ce alkenyl, C2-Ce alkynyl, Ci-Ce alkoxy, dd thioalkoxy, dd-alkyloxy of dd, d-Ce-alkoxy thioalkoxy of dd, d-d alkylcarbonyl, alkylcarbonyl d-d-alkyl of d -Ce, Ci-Ce alkoxycarbonyl. alkoxycarbonyl of dd-Ci-C-alkyl, C-C-alkylcarbonyloxy, d-d-alkyl-alkyl-C-Ce alkyl, Ci-Ce alkylamino, Ci-Ce alkylamino Ci-Ce alkyl, alkoxycarbonylazo -Ce, C3-C7 carbocyclyloxy, M3-M7 heterocyclyloxy, C3-C7 carbocycle-Ci-C alkoxy, M3-M7 heterocycle of C ^ Ce alloy, C3-C7 carbocycle-C6-C6 alkoxycarbonyl , heterocycle of M3-M7-alkoxycarbonyl of Ci-C6, and alkoxycarbonylamino of d -Ce-alkyl of C ^ -Ce.

3. The compound, tautomer, or salt according to one of claims 1 -2, wherein A is C5-C6 carbocyclyl or M5-Me heterocyclyl and is optionally substituted with one or more of R1 8.

4. - The compound, tautomer, or salt according to one of claims 1 -3, wherein Y is -Ls-0-, -Ls-S-, Ls-C (0) N (R1 5) -, or - LS-N (R1 5) C (0) -, R15 is hydrogen, Ci-Ce alkyl > C2-Ce alkenyl or C2-C6 alkynyl, and L is Ci-C6 alkylene optionally substituted with one or more of R38, wherein A1 is a C4-Ce carbocyclyl or heterocyclyl M4-Y1 / e and is optionally replaced with one or more of R30.

5. The compound, tautomer, or salt according to one of claims 1 -3, wherein Y is -Ls-0-, -Ls-S-, -Ls-C (0) N (R1 5) - or -Ls-N (R1 5) C (0) -, R15 is hydrogen, C, -Ce, C2-C6 alkenyl or C2-Ce alkynyl, and L1 is a bond, wherein A1 is a carbocyclyl of C4-C6 or heterocyclyl M4-M6 and is optionally substituted with one or more of R30.

6. The compound, tautomer, or salt according to one of claims 1 -3, wherein Y is -Ls-0-, -Ls-S-, -Ls-C (0) N (R15) - or -LS-N (R 5) C (0) -, R 1 5 is hydrogen, C 1 -C 6 alkenyl, C 2 -C 6 alkenyl, C 1 -C 6 alkynyl, and L 1 is a bond or alkyl of C, -C6 optionally substituted with one or more of R38, wherein A1 is a bicyclic ring (for example, a bicyclic fused ring or a bridged bicyclic ring), which has from 6 to 14 atoms in the ring and is optionally substituted with one or more of R30.

7. The compound, tautomer, or salt according to one of claims 1-6, wherein X is -O-, or -S-, and R22 is C5-Ce carbocyclyl or heterocyclyl M5-fVl6 and is optionally replaced with one or more of R26.

8. The compound, tautomer, or salt according to one of claims 1-6, wherein X is -S- or -O-, and R22 is , where R is hydroxy, amino, Ci-Ce alkylamino, Ci-C alkoxy, d-C6 alkoxycarbonylamino or C-C alkoxycarbonyloxy, and R22 is optionally substituted with one or more of R28.

9. A compound, tautomer of the compound, or a pharmaceutically acceptable salt of the compound or tautomer, wherein the compound has Formula 11 (a) or 1 (b), wherein: R2 and R3 are independently selected from the group consisting of hydrogen, alkyl, alkoxycarbonyl, and alkoxyalkylamidocarbonyl; R 4 is selected from the group consisting of hydrogen, alkoxycarbonyl, and alkoxycarbonylalkyl; R7 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- [alkylarylamido (arylsulfanyl) arylalkyl] -N - [(alkoxycarbonyl) alkyl] amino, alkoxyarylalkoxy , haloarylalkoxy, nitroarylalkoxy, cyanoarylalkoxy, aryloxyalkyl, haloaryloxyalkyl, cyanoalkoxy, arylalkoxy, alkylarylalkoxy, haloalkylarylaminocarbonyl, alkylaminoarylaminocarbonyl, arylalkoxy, alkylalkyloxy, and alkoxycarbonyl; R1 1 is selected from the group consisting of hydrogen, hydroxy, haloaryloxy, and alkyl; R1 2 is selected from the group consisting of hydrogen, arylsulfanyl, arylsulfinyl, aryloxy, mercapto, arylaminocarbonyl, aryl, alkoxyaryl, arylalkoxy, and alkylcarbonylaminoaryl; wherein 12 is optionally substituted with one or more substituents independently selected from R 1 6; R 6 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alkylheteroarylcarbonylamino, heteroarylcarbonylamino, hydroxyheteroarylcarbonylamino, hydroxyalkylheteroarylcarbonylamino, heteroarylcarbonylaminoalkylcarbonylamino, heteroarylalkylcarbonylamino, aryloxyarylalkylcarbonylamino, allylaminocarbonyl, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, hidroxiarilaminocarbonilo, alkoxyalkyl, alcoxíarilaminocarbonilo, azidoalkyl, alquilaminoarilsulfoniloxi, alkylsulfonyloxy, arylalkylsulfonyloxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, cycloalkylcarbonylamino, arilalcoxicarbonilheterociclocarbonilamino, aryloxy, iminoalkyl, alquiltiona, arylalkylcarbonylamino, alquilariloxialquilcarbonilamino, arilalcoxialquilcarbonilamino, heteroarilcarbonilaminoalquilcarbonil-amino, heíeroarilalquilcarbon i lamino, alquilcarbonilheterociclo-carbonylamino, am ino, am incarbonyl, alkylamonocarbonyl, hydroxyalkyl, aminoalkyl, alkoxyalkylaminocarbonyl, hydroxyiminoalkyl, heteroaryl substituted with alkyl and heteroaryl; R 3 is selected from the group consisting of hydrogen, halogen, alkyl, alkylcarbonylaminoarylsulfonyl, aminoarylsulfanyl, arylalkoxy, haloarylalkoxy, alkylcarbonylaminoaryloxy, alkylaminoaryloxy, hydroxyaryloxy, alkylaminocarbonylarylalkoxy and alkylcarbonylaminoarylalkoxy. 1. The compound, tautomer, or salt according to claim 9, wherein: R1 2 is selected from the group consisting of, n is an integer selected from the group consisting of zero and one; R 14 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alkylheteroarylcarbonylamino, het roa ri coal and lamino, hydroxyheteroaryl carbon and lamino, hydroxyalkylcarbonylamino, heteroarylcarbonylaminoalkylcarbonylamino, heteroarylalkylcarbonylamino , aryloxyarylalkylcarbonylamino, allylaminocarbonyl, alkoxycarbonyl, hydroxyalkyl, arylaminocarbonyl, hydroxyarylaminocarbonyl, alkoxyalkyl, alkoxyarylaminocarbonyl, and azidoalkyl; R16 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, hydroxy, aminocarbonyl, alkylaminocarbonyl, amino, alkylcarbonylamino, alkylheteroarylcarbonylamino, heteroarylcarbonylamino, hydroxyheteroarylcarbonylamino, hydroxyalkylheteroarylcarbonylamino, heteroarylcarbonylaminoalkylcarbonyl, heteroarylalkylcarbonylamino, aryloxycarbarylcarbonyl; lam ino, alilaminocarbonilo, alkoxycarbonyl, hydroxy, arylaminocarbonyl, hidroxiarilaminocarbonilo, alkoxyalkyl, alcoxiarilaminocarbonilo, azidoalkyl, alquilaminoarilsulfoniloxi, alkylsulfonyloxy, arylalkylsulfonyloxy, alkoxycarbonylalkoxy, hydroxycarbonylalkoxy, cycloalkylcarbonylamino to rilalcoxicarbonilheterociclocarbon Lamino, aryloxy, iminoalkyl, alquiltiona, arilalqu i Lamino Icarboni, alquilariloxialquilcarbonilamino to rylcocoxia Iquilcarbon i lam ino, heterocarbon Icarbon i laminoa Iquilcarbon i la mi no, heteroarylalkylcarbonylamino, alkylcarbon locarboni lamino, amino, aminocarbonyl, alkylamonocarbonyl, hydroxyalkyl, aminoalkyl, alkoxyalkylaminocarbonyl, hydroxyiminoalkyl, heteroaryl substituted with alkyl, and heteroaryl. The compound, tautomer, or salt according to claim 9, wherein R2 and R3 are independently selected from the group consisting of hydrogen, ethoxycarbonyl, 3-N-methoxy-N-methylaminocarbonyl and methyl; R 4 is selected from the group consisting of hydrogen, t-butoxycarbonyl, and ethoxycarbonylmethyl; R7 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- (t-butoxycarbonyl), cyano-1-ethyoxycarbonylmethyl, cyano-1-t-butoxycarbonylmethyl, cyanomethyl, morpholinyl, ethoxycarbonylethyl, hydrazino? ,? -dimethylaminoethoxy, methoxyethylamino, and cyano-1-ethoxy-carbonylmethyl; R9 is selected from the group consisting of hydrogen, methyl, methyl, phenyl, trifluoromethyl, phenylmethylamino, hydroxy, t-butoxy-carbonylaminomethyl, carbonylamino, mefylcarbonyl, amino, bromo, chloro, fluoro, methyl [1,8] naphthyridin-4- ilamino- (2-phenylsulfanylphen-5-flmetfl) amino- (Nt-butoxycarbonyl-N-methyl), methoxyphenylmethoxy, bromophenylmethoxy, nitrophenylmethoxy, cyanophenylmethoxy, trifluoromethyl, phenoxymethyl, bromophenoxymethyl, cyanomethoxy, phenylmethoxy, methylalkyloxy, propoxy, methylphenylmethoxy, methylphenylmethoxy , fluoro-3-methylphenylaminocarbonyl, trifluoromethylphenylaminocarbonyl, trifluoromethylphenylaminocarbonyl, N, N-dimethylamidophenylaminocarbonyl, fluorophenylmethoxy, and chlorophenylmethoxy; R1 1 is selected from the group consisting of hydrogen, hydroxy, chlorophenoxy and methyl; R1 2 is as described above with respect to Formulas 11 (a) and l l (b); R1 3 is selected from the group consisting of hydrogen, chlorine, methyl, methylcarbonylaminophenylsulfanyl, aminophenylsulfanyl, phenylmethoxy, bromophenylmethoxy, methylcarbonylaminophenoxy, N, N-dimethyiaminophenoxy, hydroxyphenoxy, and methylaminocarbonylphenoxy; R 14 is selected from the group consisting of hydrogen, fluoro, methyl, methoxy, hydroxy, aminocarbonyl, N-methylaminocarbonyl, N, N-dimethylaminocarbonyl, amino, t-butylcarbonylamino, 2,6-dimethylfuranyl) carbonylamino, thienylcarbonylamino, hydroxypyridinylcarbonylamino, (2) -hydroxy-6-methotlptridinyl) -carboni lamino, (3-pyrazinyl) carbonyl lamino, furanylcarbonylamino-methylcarbonylamino, (3-thienyl) propylcarbonylamino, (3-phenoxy) phenylmethylcarbonylamino, N-allylaminocarbonyl, ethoxycarbonyl, 1-hydroxyethyl, aminocarbonyl, ethylaminocarbonyl, phenylaminocarbonyl, hydroxyphenylaminocarbonyl, propylaminocarbonyl, hydroxymethyl, hydroxyethyl, azidoethyl, and N, Nd imet i I aminocarbonyl; R 1 S is selected from the group consisting of hydrogen, hydroxy, methylcarbonylamino, methyl, isopropyl, fluoro, methoxy, ethoxy, propoxy, isopropoxy, N, N-dimethylamido-naphth-1-ylsulfonyloxy, ethylsulfonyl, isopropylsulfonyloxy, methylsulfonyloxy, benzylsulfonyloxy , ethoxycarbonyl, methoxy, hydroxycarbonyl, methoxy, t-butylcarbonylamino, cyclopropylcarbonylamino, benzyloxycarbonylpyrrole id inilcarbonylamino, phenoxy, methylcarbonylamino, iminoethyl, thionoethyl, (S) -1- phenylpropylcarbonyl, methylphenylphenylcarbonyl, (R) - 1 - phenyl- 1 -metoximetilcarbo or lamino, (S) -1 -phenyl-1 -metoximetilcarbonilamino, furanilcarbonilaminometilcarbonilamino, tienilpropilcarbonilamino, metilcarbonilpiperidinilcarbonilamino, am ino, aminocarbonyl, N-methylaminocarbonyl, ethoxycarbonylmethoxy, isopropylsulfonyloxy, methylsulfonyloxy, ethylsulfonyloxy, fenilmefilsulfoniloxi, methylcarbonylamino, N-methylaminocarbonyl , hydroxymethyl, aminoethyl, methoxyethylaminocarbonyl, propylaminocarb onyl, N-methoxy-N-methylaminocarbonyl,? ,? -diethylaminocarbonyl, N- (2-methoxyethyl) aminocarbonyl, N-ethyl-N-methylaminocarbonyl, W-hydroxy-1-iminoethyl, hydroxyethyl, aminomethyl, N, N-dimethylaminocarbonyl, 2,6-dimethylfuranyl, 1 H- [ 1, 2,4] triazolyl, and pyridinyl. 2. A pharmaceutical composition comprising a compound, tautomer or salt according to claim 1. 3. The use of a compound, tautomer or salt according to claim 1 for the manufacture of a medicament for inhibiting replication of HCV virus. 14. The use of a compound, tautomer or salt according to one of claims 1-11 for the manufacture of a medicament for the treatment of HCV infection. 15. - A method for inhibiting replication of HCV virus, comprising contacting the HCV virus with an effective amount of a compound, tautomer or salt according to one of claims 1-11, thereby inhibiting the replication of said virus. 16. - A method for treating HCV infection, comprising administering an effective amount of a compound, tautomer or salt according to one of claims 1-11 to a patient with HCV, thereby reducing the viral level of HCV in the blood or the patient's liver. 17. - A method for making a compound according to one of claims 1-11, comprising the steps described in one of Schemes 1-6.